3.06 Furans and Their Benzo Derivatives: Reactivity
H. N. C. Wong The Chinese University of Hong Kong, Hong Kong, People’s Republic of China K.-S. Yeung Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA Z. Yang Peking University, Beijing, People’s Republic of China ª 2008 Elsevier Ltd. All rights reserved.
3.06.1 Introduction 2 3.06.2 Reactivity of Fully Conjugated Rings 2 3.06.2.1 Reactivities of Furans 2 3.06.2.1.1 Reactions with electrophiles 2 3.06.2.1.2 Reactions with nucleophiles 11 3.06.2.1.3 Reactions with oxidants 12 3.06.2.1.4 Reactions with reductants 16 3.06.2.1.5 Reactions as nuclear anion equivalents 17 3.06.2.1.6 Reactions catalyzed by metals and metallic derivatives 18 3.06.2.1.7 Reactions involving free radicals 22 3.06.2.1.8 Cycloaddition reactions 23 3.06.2.1.9 Photochemical reactions 31 3.06.2.2 Reactivity of Fully Conjugated Benzo[b]furans 33 3.06.2.2.1 Reactions with electrophiles 33 3.06.2.2.2 Reactions with oxidants 37 3.06.2.2.3 Reactions with reductants 38 3.06.2.2.4 Reactions as nuclear anion equivalents 38 3.06.2.2.5 Reactions catalyzed by metals and metallic derivatives 40 3.06.2.2.6 Reaction involving free radicals 43 3.06.2.2.7 Cycloaddition reactions 44 3.06.2.2.8 Photochemical reactions 46 3.06.2.3 Reactivity of Fully Conjugated Benzo[c]furans 48 3.06.2.3.1 Cycloaddition reactions 49 3.06.2.3.2 Miscellaneous reactions 56 3.06.3 Reactivity of Nonconjugated Rings 56 3.06.3.1 Reactivity of Dihydrofurans and Tetrahydrofurans 56 3.06.3.1.1 Reactions of 2,3-dihydrofurans and 2,5-dihydrofurans 56 3.06.3.1.2 Reactions of tetrahydrofurans 62 3.06.3.2 Reactivity of Dihydrobenzo[b]furans 66 3.06.3.3 Reactivity of Dihydrobenzo[c]furans 67 3.06.4 Reactivity of Substituents Attached to Ring Carbons 72 3.06.4.1 Alkyl and Substituted Alkyl Substituents 72 3.06.4.2 Carboxylic Acids and Their Reactions 74 3.06.4.3 Acyl Substituents and Their Reactions 74 3.06.4.4 Heteroatom-Linked Substituents and Their Reactions 75 3.06.5 Further Developments 77 References 79
1 2 Furans and Their Benzo Derivatives: Reactivity
3.06.1 Introduction
The chemistry of furans, their benzologs, and their derivatives was covered in CHEC(1984) <1984CHEC(3)599> and in CHEC-II(1996) <1996CHEC-II(2)297>. This chapter is intended to update the previous work concentrating on major new reactions published in 1996–2006. Attention is placed on the more interesting reactivities of these compounds, instead of executing an exhaustive literature search of all relevant articles that were recorded in 1996– 2006. A number of books
3.06.2 Reactivity of Fully Conjugated Rings 3.06.2.1 Reactivities of Furans 3.06.2.1.1 Reactions with electrophiles 3.06.2.1.1(i) Protonation Interesting intra- and intermolecular transformations involving oxonium ions formed by protonation of furan rings were shown to lead to elaborated ring systems. As shown in Scheme 1, interception of a transient cation by the pendant hydroxyl group led to the ketone intermediate 1, which further cyclized to provide the tetracyclic isochro- mene product <2005TL8439>.
OH MeO MeO MeO O O
O HCl O EtOH O O O reflux 70% 1
Scheme 1
As exemplified in Scheme 2, a one-pot C-5-benzylation/eliminative cyclization of N-tosylfurfurylamine with electron-rich benzyl alcohols in strong acids under refluxing conditions provided indole derivatives in modest yield <2005TL8443>. Presumably, the indole ring was formed via trapping of the cation 2, generated by the loss of the furan N-tosyl group in the benzylated intermediate, by the aniline nitrogen.
MeO NHTs MeO NHTs H3PO4 + OH AcOH MeO O MeO O NHTs reflux + 46% 2 Ts MeO N O MeO
Scheme 2 Furans and Their Benzo Derivatives: Reactivity 3
3.06.2.1.1(ii) Alkylation As illustrated in Equation (1), a Lewis acid-promoted intramolecular conjugate addition of a furan to a dienone was used to generate the seven-membered ring of the fused tricyclic framework of sesquiterpene echinofuran <2003T1877>.
The use of Et2AlCl provided the best result, minimizing undesired polymerization of the furan substrate 3.
O O
Et2AlCl ð1Þ O PhMe O 0 °C, 10 h 3 65%
An intramolecular Friedel–Crafts alkylation of a furan was employed to construct the unusual bicyclo[6.1.0]nonane skeleton of the crenulide diterpenoids. As shown in Equation (2), the formation of the eight-membered ring under the Lewis-acidic conditions proceeded in high yield and without resorting to high dilution <2003JOC9487>.
O O HO2CH H Me2AlOTf R R ð2Þ H ClCH CH Cl O 2 2 O 85 °C, 24 h R = H, 86% R = Me, 83%
Asymmetric carboselenenylation of furans was achieved by using the C2-symmetric selenenyl triflate 4, as shown in Equation (3). The reaction was only effective for styrene derivatives <2005AGE3588>.
O OMe
Ph ++SeOTf Ph OMe ð3Þ O 4 Å MS (10 equiv) OMe Se CH2Cl2 MeO 4 −78 °C, 2 h 73%
dr = 91:9
Kinetic investigations of the electrophilic substitution of 2-(trialkylsilyl)furans <2001OL1629> and 2-(tri-n-butyl- stannyl)furan <2001OL1633> with benzhydryl cations suggested that 2-organometallic groups activate the 5-position to a much greater extent than the 2-position. Therefore, the apparent electrophilic ipso-substitution was the net result of electrophilic substitution at the 5-position followed by protodemetallation.
3.06.2.1.1(iii) Reactions with aldehydes and ketones
Electron-rich furans were found to condense with aryl aldehydes under mild AuCl3-catalyzed conditions, forming triheteroarylmethanes as exemplified in Equation (4) <2005OL5857>. This reaction was applied to the synthesis of dendritic structures.
CHO
AuCl3 (1 mol%) O O + ð4Þ O N MeCN H rt HN 77% 4 Furans and Their Benzo Derivatives: Reactivity
1-(3-Furanyl)ethanol derivatives participated in acid-catalyzed oxa-Pictet–Spengler reaction with aldehydes to give cis-5,7-disubstituted 4,5-dihydro-7H-furano[2,3-c]pyrans under kinetic control, as illustrated in Equation (5) <2002S1541>.
p-TsOH (1 mol%) O O OH MgSO4 O + O H ð5Þ MeCN rt, 2 h 76%
The syn-selective vinylogous Mukaiyama aldol addition of 2-trimethylsilyloxyfuran to aldehydes, and the corre- sponding anti-selective addition to aldimines as well as their synthetic applications were extensively reviewed <1999SL1333, 2000CSR109, 2000CRV1929>. The aldol addition of 2-trimethylsilyloxyfuran to achiral aldehydes in the presence of a catalytic amount of BINOL–titanium complex was discovered to undergo asymmetric auto- induction by the -hydroxy- -butenolide products formed, leading to higher yields and better enantioselectivity
(BINOL ¼ 1,19-bi-2-naphthol) <2000AGE1799>. This reaction, when catalyzed by the C2-symmetric chromium(sa- len) complex 5, produced an enantiomeric excess (ee) of up to 97% for the major syn-isomer in the presence of isopropanol (salen ¼ N,N9-bis(salicylaldehydo) ethylenediamine) <2003CL974>. A typical example of this process is shown in Equation (6). However, these catalytic systems for the enantioselective addition to aldehydes have not been shown to be generally applicable, and the syn/anti-diastereoselectivity would require further improvement. The less well studied 3-trimethylsilyloxyfurans were also shown to react with aldehydes at the 2-position in an aldol addition manner under Lewis-acidic conditions. High syn-diastereoselectivity was obtained with bulky aldehydes as shown in Equation (7) <2005OL387>.
– SbF6 NN+ Cr OO Ph Ph
ð6Þ
5
(2.5 mol%) O i Pr OH HO + O + HO Me SiOH Ph O O 3 O CH2Cl2 O ° Ph 0 C, 24 h syn: 93% ee Ph anti 86% syn:anti = 85:15
O OSiMe3 O BF3·Et2O OH + CH (CH ) H 3 2 5 O ð7Þ CH3(CH2)5 O CH2Cl2 −78 °C
99% syn:anti = >95:5
Furfurylamine derivatives could be prepared, via an in situ-generated aldimine intermediate, by treatment of an
aldehyde and N-sulfinyl-p-toluenesulfonamide with furan in the presence of ZnCl2 <2003T4939>. As shown in Equation (8), enantioselective addition of 2-methoxyfuran to aldimines was achieved using the chiral C2-symmetric phosphoric acid 6 as an organocatalyst <2004JA11804>. This reaction uniformly provided 94% ee irrespective of the substitution pattern on the aldimine phenyl ring. Furans and Their Benzo Derivatives: Reactivity 5
Ar
O O P O OH
Ar ð8Þ 6 Boc NHBoc N (Ar = 3, 5-dimesitylphenyl) MeOO (2 mol%) MeO O + H ClCH2CH2Cl −35 °C, 24 h 97% ee 96% The Lewis acid-catalyzed addition of 2-trimethylsilyloxyfuran to N-gulosylnitrones was shown to be diasteroese- lective <2002OL1111, 1997T11721>. In particular, the reaction with the D-glyceraldehyde-derived gulosylnitrone 7, shown in Equation (9), provided tetrahydrofuro[2,3-d]isoxazol-5(2H)one 8 as the predominant product, which was converted into a ribofuranosylglycine precursor to polyocin C <2002OL1111>.
O O O O H H O O H O O H H O OSiMe H H N 3 O N O + O Me3SiOTf (10 mol%) O O H – + ð9Þ O CH2Cl2 OO −78 °C OO 72% 78 dr > 97:3 Structural characterizations of reaction intermediates and products of the addition of 2-trimethylsilyloxyfuran to naphthoquinones <1998TA1257> and benzoquinones <1999TA4357> to form furanofuranones indicated that the reaction proceeded via Michael addition, rather than Diels–Alder cycloaddition, in which the type of intermediate 9 shown in Scheme 3 was observed by proton nuclear magnetic resonance (NMR) spectroscopy.
MeO MeO O HO S S O O + H Me SiO CHCl3 O 3 O O –20 °C, 3 h O OH 90% MeO dr = 90:10 9 HO S O H O O H O
Scheme 3
A syn-selective, organocatalytic, enantioselective vinylogous Mukaiyama–Michael addition of 2-trimethylsilyloxy- furan to , -unsaturated aldehydes to produce -butenolides was achieved by using a chiral amine catalyst 6 Furans and Their Benzo Derivatives: Reactivity
<2003JA1192>. The methodology was adopted to prepare the key intermediate 11 using the catalyst 10 in a formal total synthesis of campactin <2006OL597>, as depicted in Scheme 4. This type of reaction was extended to incorporate a chlorination reaction of the enamine intermediate in the reaction cycle as shown in Equation (10). Furans also function as effective nucleophiles in such catalytic organocascade reactions <2005JA15051>.
Me O N Ph N H O 10 H O CHO + Me3Si Me3Si Me3SiO O H2O–CHCl3 –40 °C OH CHO HO 95% H 11 syn:anti = >30:1 82% ee
Scheme 4
Bn Me O N N
N O O Me H Me3SiO O Cl O Cl Cl (10 mol%) ð10Þ H + Cl O EtOAc Cl Cl O −55 °C Me H Cl 71% dr > 24:1 >99% ee
3.06.2.1.1(iv) Reactions with diazonium salts and diazo compounds The copper(I)-catalyzed asymmetric cyclopropanation of methyl furan-2-carboxylate with ethyl diazoacetate was achieved by the use of the bisoxazoline ligand 12 to provide the exo-isomer of 2-oxa[3.0.1]bicyclohexene 13, as shown in Scheme 5 <2003CEJ260>. The product was transformed into 1,2,3-trisubstituted cyclopropane by ozonolysis
O O N N 12 But But
(2.5 mol%)
Cu(OTf) (2 mol%) 2 H O3 EtO C PhNHNH (2 mol%) 2 2 EtO C DMS + 2 CO2Me N2 O CH2Cl2 CO Me CH2Cl2 H O 2 0 °C –78 °C 13 94% 91% ee recrystallization CHO 53%, >99% ee EtO2C OCOCO2Et 2 steps
O O CHO
Scheme 5 Furans and Their Benzo Derivatives: Reactivity 7
<2000EJO2955>, and then elaborated to -butyrolactones by a two-step sequence comprising of allylsilane addition and retro-aldol lactonization <2003CEJ260>. This methodology was applied to the asymmetric synthesis of para- conic acids <2003CEJ260>, (–)-roccellaric acid <2001OL1315>, the fused cyclic ring systems of xanthanolides, guaianolides, and eudesmanolides <2003OL941>, and the cis-fused 5-oxofuro[2,3-b]furan core of spongiane diterpe- noids <2005OL5353>.
Rh2(OAc)4-catalyzed intermolecular addition of ethyl diazoacetate to 2-methylfuran proceeded on the 4,5-double bond of the furan ring, leading to ethyl 6-oxo-2,4-heptadienoate, with a 19:1 regioselectivity. The corresponding reaction with 3-methylfuran gave a low 2:1 regioselectivity, although still favoring the unsubstituted side. Consistently, reaction with 2,4-dimethylfuran predominantly occurred at the 4-methyl side of the furan nucleus, as shown in Equation (11) <1999TL5171>. These results are in accord with a mechanism involving nucleophilic attack on the carbenoid carbon by the more nucleophilic furan C-2-position. The reactions of other 2-methyl analogs of furan also exhibited similar regioselectivity <1999TL5439>. These types of reactions were also performed on 2-methoxy- and 2-trimethylsilyloxyfurans using aryl diazoketones to give 6-aryl-6-oxo-(2Z,4E)-hexadienoates and
6-aryl-6-oxo-(2Z,4E)-hexadienoic acids, respectively, using Rh2(OAc)4 as catalyst <2001T7303>, as well as with diazoarylacetates using pentacarbonyl( 2-cis-cyclooctene)chromium(0) as a catalyst <2004JOM2662>.
O Rh2(OAc)4 + OEt O + O ð11Þ O CH2Cl2 CO Et H CO Et N2 2 2 rt, 10 h >80% Trace
1-Diazo-3-(3-furanyl)-2-propanone underwent intramolecular metal carbenoid addition and, subsequently, the typical rearrangement to provide a 1,6-dicarbonyl product. However, as shown in Scheme 6, the cyclopropane intermediate 15 formed during the reaction of the isomeric 1-diazo-3-(2-furanyl)-2-propanone 14 underwent a Wolff-type rearrangement to give 2-(2-methylfuranyl)acetic acid as the major product in the presence of water <1998JOC9828>. When the tether was constrained by the introduction of a fused ring, the usual rearrangement occurred and was exploited for the synthesis of [6,6], [6,5], and even [6,4]-fused ring systems, as exemplified in Scheme 7 <2005HCA330>.
CO2H
O N • 2 O 60% Rh2(OAc)4 O + O CH Cl O 2 2 O O O H O 2 O 14 rt, 1 h 15 O 15%
Scheme 6
O N2 O O Rh2(OAc)4 I2 O CH2Cl2 CH2Cl2 15 min rt, 1 h O CHO 83%, 2 steps
Scheme 7
Intramolecular addition of more elaborated diazoacetates and diazoketones to a pendant furan moiety are more complex <1997TL5623>. 2-Substituted substrates uniformly provided the 2,4-diene-1,6-dicarbonyl products. Products of 3-substituted substrates depended on the structure of the diazocarbonyl and the rhodium catalyst used. For example, 8 Furans and Their Benzo Derivatives: Reactivity
in contrast to the reaction of diazomalonate 16 (Scheme 8), reaction of the diazoacetoacetate 17 produced the fused tricycle 19, presumably as a result of [3þ2] annulation of the intermediate 18. This type of transformation was exploited in the construction of the [6,7]-fused ring system of guanacastepenes, as shown in Equation (12) <2003OL4113>. Furans tethered with diazocarbonyl moieties to the 2-position were also used for generating macrocyclic rings <1999OL1327>. Regioselectivity with respect to addition to furan 2,3-double bond was dependent on the metal catalyst, as well as the inherent selectivity differences between diazoacetates and diazoketones used.
O O O R = OEt O 62% Rh (O CC H ) EtO2C H N2 2 2 9 19 4 O R CH2Cl2 + O O O O O O
16: R = OEt R = Me 17: R = Me 78% O O O O 18 19
Scheme 8
O Me Me EtO2C Rh2(OAc)4 O N ð12Þ 2 t CH2Cl2 t OSiBu Ph2 OSiBu Ph2 rt EtO O 50% O H O
Ruthenium and platinum carbenoids, derived from tertiary propargyl carboxylates, also reacted with furans in a similar manner, leading to triene systems (as represented in Scheme 9) <2006OL1741>. The initially formed mixture of (2Z,4E)and(2Z,4Z)isomers20 and 21, respectively, could be isomerized completely to a single (2E,4E)isomer.
OAc [RuCl2(CO)2]2 (2.5 mol%) OAc + OMe O ClCH2CH2Cl [Ru] 50 °C, 18 h 86%
OAc CO2Me OAc OAc + CO2Me CO2Me 2043:58 21
Scheme 9
The feasibility of intramolecular type II annulations between furans and vinylcarbenoids to give highly strained molecular frameworks that contained anti-Bredt alkenes is depicted in Equation (13) <1997TL1737>.
O O Rh2(O2CC9H19)4
N2 O ð13Þ O hexanes t 83% Me2Bu SiO O t Me2Bu SiO O Furans and Their Benzo Derivatives: Reactivity 9
3.06.2.1.1(v) Reactions with other electrophiles An intramolecular Mannich-type cyclization of the functionalized furan 22, shown in Equation (14), to the cyclic iminium cation that was generated from the aminal was the key step in the construction of the strained ABCD ring system during the total synthesis of nakadomarin A. The fused tetracyclic advanced intermediate 23 was obtained as a single isomer <2003JA7484>. As illustrated in Equation (15), when the furan was tethered at the 2-position, a novel spirocyclization occurred, giving the spiro-2,5-dihydrofuran derivative 24 as the sole diastereoisomer. This spirocy- clization proceeded irrespective of the length of the carbon linker <2006OL27>.
OAc
H H O i, p-TsOH CH2Cl2 O OAc OAc BsN BsN ð14Þ ii, 1 N HCl NBoc THF NBoc 87% OTHP OH 22 23
OTBDMS TBDMSO O O OH HOAc OH BsN ð15Þ BsN PhMe NBoc NBoc rt, 72 h 80% 24
An interesting example concerning hydrolytic cleavage of furan rings that occurred following the addition to N-acyliminium ions to give dicarbonyl compounds is shown in Scheme 10. This reaction presumably occurred via the oxonium ion intermediates 25 that were generated from a 1,5-proton shift of the initially formed oxonium ions <1998JOC6914>.
O O O HCO H N N O 2 n N n n O C6H12 O + OH rt, 30 min O
25 n = 1 (75%) n = 2 (64%)
Scheme 10
The synthetic utility of vinylogous Mannich additions of 2-silyloxyfurans to cyclic iminum ions <2001T3221> that provided threo-products predominantly was demonstrated by the assembly of the complete carbon framework during the total synthesis of the plant alkaloid, crommine, as shown in Scheme 11 <1996JA3299, 1999JA6990>. Vinylogous Mukaiyama–Michael additions of 2-trimethylsilyloxyfuran to 3-alkenoyl-2-oxazolidinones to provide -butenolides were shown to be anti-selective. The reaction could be rendered enantioselective in the presence of a
C2-symmetric copper–bisoxazoline complex <1997T17015, 1997SL568> or a 1,19-binaphthyl-2,29-diamine-nickel(II) complex as catalyst, as depicted in Equation (16) <2004CC1414>. 10 Furans and Their Benzo Derivatives: Reactivity
Br Boc Br Boc i i H Pr 3SiO O MeO N 5% Pr SiOTf O CO2Me 3 O N + CO 2Me CH2Cl2 0 °C 32% i Pr 3SiO O
POCl H 3 H H H O N O N O CO H O O 2 DMF O 31%
H2 10% Pd/C H H H O N O O 10% HCl–EtOH O 85%
Crommine
Scheme 11
Ni(ClO4)2•6H2O (10 mol%) BINIM-2QN (10 mol%) O O O O (CF3)2CHOH molecular seives N O + N O Me SiO O 3 O CHCl3 ° −25 C, 87 h O anti:syn = 99:1 82% 93% ee ð16Þ
N N
N N
BINIM-2QN
As shown in Equation (17), 2-trimethylsilyloxyfuran also participated in a triphenylphosphine-catalyzed substitu- tion reaction with Morita–Baylis–Hillman acetates to provide interesting -butenolides regio- and diastereoselec- tively <2004AGE6689>. However, the reaction mechanism (vinylogous Michael vs. Diels–Alder) has not been distinguished.
O
O OAc O PPh3 (20 mol%) O + R H H ð17Þ Me SiO 3 O THF R 25 °C R = Me, 80% R = OMe, 86% dr > 95:5 Furans and Their Benzo Derivatives: Reactivity 11
2-Trimethylsilyloxyfuran reacted stereoselectively with chiral tungsten carbene complexes in a Mukaiyama– Michael addition fashion to provide anti-products, as shown in Equation (18) <2005AGE6583>. The metal carbene in the butenolide product serves as a useful functional group for further transformations.
MeO W(CO) W(CO)5 O 5 O + OMe Me SiO 3 O PhMe O ð18Þ O O −60 °C O 92% anti:syn = 11:1 face selectivity = 38:1
Reaction of 2,5-disubstituted and 2,3,5-trisubstituted furans with the cyclic trithiazyl trichloride 26, which was in thermal equilibrium with the monomeric thiazyl chloride, in boiling solvents resulted in the regiospecific formation of isothiazoles, as shown in Scheme 12 <1997CC367, 1997J(P1)1617, 1997J(P1)2247>. Electrophilic thiazylation that occurred at the more nucleophilic C-3 position of the furan ring was favored as the mechanism. This reaction could also be performed using a premixed mixture of ethyl carbamate, thionyl chloride, and pyridine. Furans having electron-withdrawing groups directly at the 2-position are poor substrates <2001J(P1)1304, 1999S757>. 4-Chloro- and 3-chloromethylisothiazole side products were obtained with substituted 2-methylfurans <1997J(P1)2247>.
NO2
NO MeO 2 R = H
THF N Cl reflux, 30 min S S 85% O N N R O + OMe S S Cl N Cl 26 O2N R = Br Br
THF N OMe reflux, 1 h S 3 N S Cl 64% O
Scheme 12
Aminomethylation of furans that directly delivered primary furfurylamine products was realized using N-silyl-N,O- acetal 27 under Lewis acid-catalyzed conditions, as illustrated in Equation (19). However, furans are less nucleophilic toward 27 than pyrroles <2003JOC483>.
Hf(OTf)4 (20 mol%) NHSiMe3 TMSCl + NH2 O ð19Þ O Me3SiO CCl3 CH2Cl2 CCl 27 rt, 6 h 3 89%
3.06.2.1.2 Reactions with nucleophiles The addition of Grignard reagents to 2-nitrofuran provided trans-2,3-disubstituted 2,3-dihydrofurans as the predo- minant isomers <2003TL3167>. 2- and 3-(Phenylsulfinyl)furans underwent Pummerer-type reaction-initiated regioselective nucleophilic additions, as shown in Equation (20) and Scheme 13, respectively <2004OL3793>. 12 Furans and Their Benzo Derivatives: Reactivity
The sulfinyl group in the products enables further substitution of the furan ring, for example, via sulfoxide–lithium exchange (as illustrated in Scheme 13).
O H O O O (CF3CO)2O SOPh + ð20Þ O MeCN 0 °C, 30 min SPh O 54%
SOPh SPh (CF CO) O n 3 2 + SnBu 3 MeCN O O 0 °C, 30 min 73%
i, MCPBA ii, PhLi (2 equiv) PhMe CO2Me –78 °C, 10 min
iii, ClCO2Me O –78 °C to rt 71%
Scheme 13
The chiral Fischer-type chromium carbene complex of furan 28, shown in Scheme 14, participated in nucleophilic 1,4-addition with organolithium reagents followed by alkylation in a regioselective and diastereoselective manner, creating a quaternary C-3 stereocenter in the 2,3-trisubstituted 2,3-dihydrofuran products after oxidative decom- plexation and reductive cleavage of the chiral auxiliary <2003CEJ5725>.
i, PhLi
Et2O O HO O –80 °C 3 steps (OC)5Cr (OC)4Cr ii, MeOTf 90% Ph –80 °C to rt O Ph 78% ee O 78% O 28 dr = 84:16
Scheme 14
3.06.2.1.3 Reactions with oxidants Useful new procedures for the oxidation of furans were reported. Mono-, di-, and trisubstituted furans were oxidized
to (Z)-enediones by methyltrioxorhenium/urea hydrogen peroxide <1998TL5651>. Mo(CO)6-catalyzed oxidation of 2,5-dialkyl furans by cumyl hydroperoxide provided (E)-enediones selectively. In the presence of Na2CO3, the corresponding (Z)-isomers were obtained <2003TL835>. Sodium chlorite in acidic aqueous medium was found to be an efficient oxidation system for the conversion of symmetrical 3,4-disubstituted furans to -hydroxybutenolides <2005JOC3318>, and 2-substituted and 2,5-disubstituted furans to , -unsaturated 1,4-dicarbonyl compounds <2005SL1468>. As shown in Scheme 15, a regioselective oxidation of 3-substituted furans (except 3-carboxylate) to -substituted -butenolides was achieved by using N-bromosuccinimide (NBS), followed by elimination of the more acidic C-2 proton of the 2,5-diethoxy intermediate under acidic hydrolytic conditions <2005SL1575>. Furans and Their Benzo Derivatives: Reactivity 13
HO NBS HO HO NaHCO3 HCl
2 EtOH−CHCl3 EtO OEt H2O−acetone O O O O rt rt 75%
Scheme 15
The useful synthetic utilities of photosensitized oxidation of furans were demonstrated. A notable example was the oxidation of the trisubstituted furan 29 shown in Scheme 16 to the (Z)- -keto- , -unsaturated ester intermediate 30, a crucial step for the construction of the ABC ring system of the complex heptacyclic marine alkaloid norzoanthamine <2004SCI495>.
ν i, O2, h Rose Bengal AcO AcO CH Cl 2 2 O 0 °C, 12 h CO2Me O t SiBu Me2 ii, MeI n Bu 4NF THF 29O rt, 1 h 30 O 97%, 2 steps
AcO H 3 steps O
H H CO2Me
O
Scheme 16
Another novel example as generalized in Scheme 17 is the photooxidation of the furan moiety in the presence of two trisubstituted alkenes in the side chain during the total synthesis of litseaverticillols <2005CEJ5899, 2003AGE5465, 2004OL2039>.
O O ν O2, h R i R MB Me2S Pr 2NEt R H O MeOH MeO O CHCl3 CHCl3 ° HOOH O 0 C 25 °C ° OH R 25 C, 5–6 h 0.5–1 min 5–8 h 51–55%, 2 steps 97%
MB = methylene blue R =
Scheme 17
Photosensitized oxidation of a bis(2-trimethylsilylfuran) followed by spirocyclization of the intermediate bis( -hydroxybutenolide) was employed to construct the tricyclic bis(spiroketal) core of prunolides. As shown in 14 Furans and Their Benzo Derivatives: Reactivity
Equation (21), both the (Z)- and (E)-isomers of 31 provided the same 2:1 mixture of the trans- and cis-products <2005OL2357>.
Me Si SiMe3 ν 3 i, O , h 2 O O Rose Bengal O O O OO MeOH 2 min
ii, silica gel ð21Þ 80%
MeO OMe MeO OMe 31
The oxidation of 2,5-disubstituted furans by NBS <2005OL27> and singlet oxygen <2006OL1945> was adopted for the synthesis of [5,5,5]- and [6,5,6]-bis(spiroketals). An interesting example is depicted in Scheme 18.
ν i, O2, h methylene blue 5 min O OH O O CH2Cl2 p-TsOH O O O ii, DMS 80% HO 1:1 mixture OH HO
Scheme 18
The aza-Achmatowicz oxidative ring expansion of furans and its synthetic application were reviewed <1998SL105>. An interesting example of performing the Achmatowicz oxidation of furfuryl alcohol and its aza variant simultaneously on the bisfuran-containing 1,3-amino alcohol 32 in the synthesis of aza-C-linked disaccharides is depicted in Scheme 19 <2005CC1646>.
i, NBS O O NaOAc
THF–H2O OO NTs O ii, (MeO)3CH Tol NH OH BF3•Et2O S OMe OMe CH2Cl2 O 32 34% OAc OAc AcO OAc
NTs O AcO OAc
AcO OMe OAc
Scheme 19
Annulation of furans via electrochemical oxidation at the anode has become an important process for the synthesis of complex polycycles, and was covered in a review <2000T9527>. Furans tethered at the 3-position to electron-rich alkenes, enol ethers, or vinyl sulfides were converted to [6,5] and [7,5]-fused ring systems <1996JOC1578, 2002OL3763, 2004JOC3726, 2005JA8034>, as illustrated in Scheme 20. Analysis of crude reaction mixtures and side Furans and Their Benzo Derivatives: Reactivity 15 products indicated that the furan moiety tethered to alkenes was oxidized to radical cation (initiator), while when tethered to methyl enol ether, it served as terminator to capture the enol ether radical cation <1996JOC1578>.Studies using cyclic voltammetry and probe molecules also suggested that in reaction involving furans tethered to silyl enol ether, the silyl enol ether was preferentially oxidized according to its lower oxidation potential to give a radical cation (e.g., 33) <2004JOC3726>. In contrast to the six-membered ring formation (Scheme 20), annulations to form seven- membered rings were influenced by the gem-dialkyl effect, as evidenced by Equation (22) <2005JA8034>.
carbon anode R LiClO4 R R 2,6-lutidine + H MeCN–PriOH –1 Me3SiO 2 F mol Me3SiO O H O O O rt 33 OPri R 1 N HCl
rt O H O
R = H, 70% R = Me, 78%
Scheme 20
carbon anode
R LiClO4 R 2,6-lutidine
MeCN−PriOH –1 H ð22Þ Me SiO 2 F mol O 3 O O rt acidic workup
R = H, 0%
R = Me, 61% The anodic cyclization reaction of furans was applied as a key step to construct the [5-6-7]-fused tricyclic core of cyathins <1999OL1535>, and the [5-6-5]-fused tricyclic core of alliacol A using the acyclic silyl enol ether tethered furan 34 during its total synthesis (Scheme 21) <2004JA9106, 2003JA36>.
RVC anode carbon cathode t Me2Bu SiO O 2,6-lutidine H 0.4 M LiClO4
t MeOH–CH2Cl2 (1:4) t Me2Bu SiO –1 Me2Bu SiO O 15–20 mA, 2.2 F mol O rt 34 MeO O O H TsOH
rt O OH 88% HO O O Alliacol A
Scheme 21 16 Furans and Their Benzo Derivatives: Reactivity
Another example is the assembly of the complex [6-7-5]-fused tricyclic core 35 of guanacastepenes, obtained as a single diastereoisomer, as shown in Scheme 22 <2005OL3425>. The efficiency of this reaction is consistent with the gem-dialkyl effect that is required for the seven-membered ring formation in this type of electron-transfer reaction.
RVC anode (0.2 mA) t 2,6-lutidine Ph ButSiO Ph2Bu SiO 2 0.06 M LiClO4 H O 20% MeOH–CH2Cl2 MeO O –1 H 2.44 F mol t Me Bu SiO t rt, 17 h t 2 OSiBu Me2 O OSiBu Me2 70%
t Ph2Bu SiO HCl
H O, THF 2 O rt H 85% t O OSiBu Me2 35
Scheme 22
When furans were tethered at the 2-position to silyl enol ethers, an electrochemical spiroannulation occurred at the 2-position, as exemplified in Equation (23) <2006CC194>. This reaction pathway is a manifestation of the higher nucleophilicity of the furan C-2 position, resulting in the isolation of the kinetic products.
carbon anode
LiClO4 2,6-lutidine + i O O H ð23Þ O MeOH−Pr OH O H O Me SiO 3 OPri OPri 69% 23%
3.06.2.1.4 Reactions with reductants The reduction of furans was reviewed in an article concerning the reduction of aromatic heterocycles <1996TA317>. Birch reduction of 2-silyl-3-furoic acids provided 2-silyl-2,3-dihydrofuran-3-carboxylic acids as mixtures of cis- and trans-isomers <1996TL9119>. Stereoselective reduction of chiral 2-furoic amides to form dihydrofuran derivatives was accomplished under Birch-type reductive alkylation conditions. Methyl <1998TL3071, 2000J(P1)3724> and trimethylsilyl <2001TL5841, 2002J(P1)1748> substituents at the 3-position of the furan moiety are essential for achieving high diastereoselectivity in the alkylation step as illustrated in Equation (24), presumably by controlling the enolate geometry. This methodology was applied as a key step in the synthesis of (þ)-nemorensic acid <2000CC465, 2002J(P1)1369>, (–)-cis- and (–)-trans-crobarbatic acids <1999TA1315>, eight- and nine-membered cyclic ethers <2001OL861>, dihydropyranones <2002OL3059>, and 2,5-dihydrofuran 36 for a formal total synthesis of ( )-secosyrin 1, as illustrated in Scheme 23 <2004OL465>.
OMe OMe R Na, NH3 R then MeI N N O THF O O −78 °C O ð24Þ OMe OMe
R = H (45%, dr = 41:59) R = Me (98%, dr = 30:1)
R = SiMe3 (94%, dr = 97:3) Furans and Their Benzo Derivatives: Reactivity 17
OMe OMe SiMe3 SiMe 3 Na, NH3 O p-MeOC6H4CH2Br N 2 steps N O OH O 68% O 42% O dr > 20 : 1 OMe 90% ee OMe MeO MeO 36
HO OCO(CH2)4CH3
O O O (–)-Secosyrin 1
Scheme 23
Hydrogenation of dimethyl 2-phenylfuran-3,4-dicarboxylates using Pd/C at 100 C provided tetrahydrofuran (THF) products without undesired reduction of the phenyl ring. A 2:1 mixture of 2,3-cis-3,4-cis- and 2,3-cis-3,4- trans-diastereoisomers was obtained from 2-alkoxyphenyl substrates <2000S2069>. Hydrogenation of furfuryl alco- hol derivatives to tetrahydrofuranylcarbinols using Raney nickel provided much higher erythro-(anti-)selectivity than using Pd/C or rhodium on alumina. Moreover, as illustrated in Equation (25), the erythro-selectivity in the formation of 37 and 38 was decreased by increasing the polarity of the alcohol solvent used, presumably by influencing the substrate conformation through the disruption of the intramolecular hydrogen bonding between the hydroxyl and the furan oxygen atom <1996S349>.
H2 (80 b) Raney nickel OH OH + OH i ð25Þ O Pr OH, 37:38 = 81:19 O O C12H25 EtOH, 37:38 = 69:31 C12H25 C12H25 37 38 MeOH, 37:38 = 53:47
3.06.2.1.5 Reactions as nuclear anion equivalents Applications of furanyl anion equivalents in stereoselective manner have been increased. An example of asymmetric conjugate addition of a furanyllithium to 1-nitrocyclohexene induced by a chiral amino alcohol derivative is shown in Equation (26). The 2-trityloxymethyl group was essential for obtaining the selectivity in the product, which was used as an entry to prepare arene-fused piperidine analogs <2004JA1954>.
Ph Ph
Me2N O Li MeO NO2 + ð26Þ PhMe O NO2 −78 to −95 °C OTr OTr O 99% cis:trans = 89:11 91% ee
3-Furanylmagnesium bromide reacted with chiral N-[p-tolylsulfinyl]-bornane-10,2-sultam to provide 3-furanylsulf- oxide with 99% ee <1997TL2825>, and with chiral N-tert-butanesulfinimines (e.g., 39) to provide diarylmethyl- amines diastereoselectively <2002TA303>. The diastereoselectivity observed for the reaction indicated in Equation (27) is consistent with a six-membered magnesium chelate transition state. Di(2-furanyl)zinc added to a chiral glycal epoxide in the presence of trifluoracetic acid (TFA) to provide -C-furanylglycoside selectively. Addition using 2-furanylzinc chloride also provided the product with similar efficiency <2003SL870>. 18 Furans and Their Benzo Derivatives: Reactivity
MgBr H i, PhMe ° −45 C, 4 h O + O N ii, 4 N HCl ð27Þ O S MeOH NH3Cl 25 °C, 30 min dr = 97:3 39 76%
Furanyltitanium reagents were shown to add readily to aliphatic aldehydes in the absence of any promoter, providing more desirable yields and stereoselectivity than furanyllithium, magnesium, and zinc reagents. They were employed as key steps in the total syntheses of (þ)-dysidiolide <1998JOC228> and (þ)-ricciocarpins A and B <2004OL1749>, as depicted in Scheme 24.
O H i i, Et O H (Pr )3Ti 2 CO2Me −78 °C O + i ii, dilute HCl O OSi(Pr )3 H rt, 12 h H CHO O 78% O Ricciocarpin B
Scheme 24
The furanylcerium that was generated from lithiation/transmetallation of furan 40 as shown in Equation (28) was a highly nucleophilic species that added readily to the sterically hindered ketopyrrole to provide the penultimate intermediate during the total synthesis of roseophilin <1998JA2817>.
MeO BunLi
O CeCl3 + MeO N THF OH SEM ð28Þ Cl SiPri N N 3 −50 °C O O SEM then −78 °C to rt 40 62% Cl i N SiPr 3
The lithiation of 3-(N-tert-butoxycarbonylamino)furan occurred regioselectively at the 2-position as a result of the apparent ortho-directing effect of the NHBoc group, providing 2-substituted-3-aminofurans after subsequent reac- tions with electrophiles, as represented in Scheme 25 <2006SL789>. In contrast, the lithiation of 2-(N-tert- butoxycarbonylamino)furan took place exclusively at the 5-position instead of the 3-position <2003T5831>.
t NHBoc Bu Li NHBoc NHBoc TMEDA O + THF THF CO Et O O Li Cl OEt O 2 –90 to –70 °C −70 °C to rt 1–2 h overnight 97%
Scheme 25
3.06.2.1.6 Reactions catalyzed by metals and metallic derivatives The electrophilic propargylation at the C-2-position of furans with propargylic alcohols can be effected by using 5 mol% of the cationic methanethiolate diruthenium complex 41 as a catalyst (Equation 29). Substrates are limited to 1-phenyl-substituted secondary propargylic alcohols <2003AGE1495>. Furans and Their Benzo Derivatives: Reactivity 19
Cp* Cp* Ru Ru MeS SMe Cl Cl Ph 41 Ph Ph ð29Þ O (5 mol%) + Ph ClCH2CH2Cl O OH 60 °C, 1 h 88% As shown in Equation (30), furan reacted with ethyl acetylenecarboxylate under gold-catalyzed conditions to form the hydroarylation product that contained a (Z)-alkene selectively <2003EJO3485>.
Ph3PAuCl (1 mol%) CO2Et AgSbF6 (1 mol%) + CO Et 2 ð30Þ O MeNO2 O 40 °C, 3 h 82% Palladium catalysts were able to catalyze the allylation of furans with alkylidenecyclopropanes, presumably via an allylpalladium intermediate, to furnish 2-allylated products, as illustrated in Equation (31) <2000JA2661>.
Pd(PPh3)4 (5 mol%) n n Bu POBu 3 (10 mol%) + Bun CO2Et ð31Þ Bun CO Et no solvent O O 2 n 120 °C Bu 77% The diorganozinc 42 and the high-order zincates, 43 and 44, of 2-furaldehyde diethyl acetal, as shown in Equation (32), participated in a Negishi-type cross-coupling reaction with 2-chloropyridines and bromobenzenes as effectively as the corresponding furanylzinc chloride. These reagents transfer all the organic groups during the reaction <2002OL375>. The synthetic utility of furanylzinc species is further illustrated by the elaborated coupling employed in the total synthesis of bipinnatin J, as shown in Equation (33) <2006OL543>.
OEt OEt OEt O O O Zn ZnLi ZnLi2 EtO EtO EtO 4 2 3 42 43 44
OEt O N Cl O Cl O ZnLi N i, Pd(dppf)Cl2 EtO + H ð32Þ 3 Cl ii, 5 N HCl 43 85%
O ClZn O O Pd(dppf)Cl O O 2 + O I THF OMOM ð33Þ 0 °C, 2 h OMOM O 100% O O
O 20 Furans and Their Benzo Derivatives: Reactivity
The cross-coupling of sodium 2-furanylsilanolate with aryl iodides and aryl bromides as catalyzed by palladium species 45 was developed, as illustrated in Equation (34). Coupling with aryl iodides could be performed at room
temperature, using Pd2(dba)3?CHCl3 as the catalyst <2006OL793>.
O Br Cl i, NaH t t (Bu )3PPd PdP(Bu )3 PhMe + ð34Þ O Si ii, 45 (2.5 mol%) OH PhMe CO Et 45 2 50 °C, 3 h CO2Et 60% A method of forming 2-furanylsilane in a regioselective manner involved iridium catalyzed silylation using
(t-BuF2Si)2 in the presence of 2-tert-butyl-1,10-phenanthroline as a ligand. As shown in Equation (35), 3-methylfuran provided the 5-silylated product 46 as the predominant regioisomer <2005CC5065>.
NN But (3 mol%) ð35Þ Ir[(OMe)COD]2 (1.5 mol%) + + (ButF Si) ButF Si t 2 2 2 OOSiF2Bu O octane 46 47 120 °C, 32 h 88:12 99% Unsymmetrical 2,5-disubstituted alkynylfurans could be prepared from 2,5-bis(butyltelluro)furan by sequential palladium-catalyzed cross-couplings. As represented in Scheme 26, the use of THF, a less effective solvent than MeOH for the symmetrical bis-coupling to alkynes, enabled the first monocoupling to occur <2003TL1387>.
PdCl2 Et3N n n Bu Te Bu Te TeBun + O O THF OH ° 25 C, 6 h OH Ph 82% PdCl2 Et3N
MeOH Ph O 25 °C, 5 h OH 65%
Scheme 26
A direct Heck-type coupling of 2-furaldehyde with various electron-rich and electron-deficient aryl iodides and bromides to provide 5-aryl-2-furaldehydes regioselectively was also developed <2001OL1677>. An interesting example is shown in Equation (36).
PdCl2 (5 mol%) (c-C6H5)3P (10 mol%) KOAc O O n OHC CHO OHC Br CHO Bu 4NBr O O ð36Þ + DMF 110 °C, 10 h 64% Furans and Their Benzo Derivatives: Reactivity 21
Regioselective palladium-catalyzed arylation of ethyl 3-furoate at either the 2- or the 5-position can be achieved by the judicious choice of solvent and palladium catalyst, as shown in Scheme 27. However, efficient arylation requires the use of aryl bromides substituted with electron-withdrawing groups (e.g., NO2) <2003OL301>. This method was applied to the synthesis of furo[3,2-c]quinolinone from 1-bromo-2-nitrobenzene.
EtO C Br 2 EtO2C Pd/C EtO2C Pd(PPh3)4 KOAc KOAc + O O NMP PhMe O O2N 110 °C 110 °C 42% 73% O2N NO2
Scheme 27
As shown in Equation (37), 4,5-dibromo-2-furaldehyde and methyl 4,5-dibromo-2-furoate underwent regioselective cross-coupling reaction at the 5-position with alkynes under Sonogashira-type conditions, presumably due to the activation of the 5-position by the electron-withdrawing groups at the 2-position toward oxidative palladium insertion <1998TL1729, 1999EJO2045>.
Br PdCl (PPh ) (5 mol%) Br 2 3 2 CuI (10 mol%) + R HO O ð37Þ Br R Et3N (solvent) O HO rt, 48–96 h R = CHO, 71% R = CO2Me, 97%
Palladium-catalyzed Stille cross-coupling of furanylstannanes to an allyl bromide was also regioselective. An example, as employed in the total synthesis of 6 -hydroxyeuryopsin, is depicted in Equation (38) <2004CC44>. This type of reaction could also be performed by using a catalytic amount of CuCl, rather than a palladium catalyst <1999SL1942>.
Pd2(dba)3 (20 mol%) O t SiBu Me2 Br AsPh3 (80 mol%) + Bun Sn t THF ð38Þ 3 O SiBu Me2 i rt, 48 h OSi(Pr ) OSi(Pri) 3 3 85%
Analogous to 3,4-bis(trialkylsilyl)furans <1996PAC335, 1997LA459, 1998T1955, 1999CSR209>, the use of 2,4- bis(trialkylsilyl)furans, in which the silyl groups served as blocking groups and ipso-directing groups, for the regioselective synthesis of substituted furans was also developed. An application to the preparation of differentially functionalized furans as useful intermediates is shown in Scheme 28 <1997T3497>.
i, BunLi THF I2 Me3Si Me3Si Me3Si 0.5 h AgO2CCF3
SiMe ii, BnBr BnTHF Bn I O 3 O SiMe3 O THF –78 °C, 2 h 0.5 h 74% 82%
Scheme 28 22 Furans and Their Benzo Derivatives: Reactivity
2-Furanylcuprate 48 was discovered to undergo 1,2-metallate rearrangement, leading to ring opening to provide , -unsaturated ketone 49, as shown in Scheme 29 <2003JOC4008>.
i, ButLi Bun CuBun Li Bun n THF 2 2 Bu −78 °C CuLi2 H2O O O O O n 68% ii, Bu 2CuLi Bun Bun Et2O−Me2S Bun Bun ° −78 to 0 C 48 49
Scheme 29
Furan was demonstrated to function as a 1,3-propene dipole when it was dihapto-coordinated to a rhenium p-base, which enhanced the nucleophilicity of the uncoordinated C-3-position. As represented in Scheme 30, the 2,5- dimethylfuran complex 50 (Tp ¼ hydridotris(pyrazolyl)borate; MeIm ¼ 1-methylimidazole) reacted with Michael acceptors to form substituted cyclopentenes <2003JA14980, 2005OM2903>.
O O MeIm O CO MeIm CO BF •Et O H O 3 2 [Re] 2 2 + [Re] Tp O CH Cl Tp 2 2 –40 °C O O 50 72%
Scheme 30
Fischer-type chromium carbene complexes of furans underwent Do¨tz benzannulation with alkynes to provide trisubstituted benzo[b]furan derivatives. An example used in the synthesis of isodityrosine is depicted in Equation (39) <2005JOC7422>. The efficiency of the reaction could be improved by ultrasound sonication <1999OL1721>.
I I CO2Me O O + NHCOCF3 ð39Þ 60 °C O O CO2Me Cr(CO)5 then air 68% NHCOCF3 OH
3.06.2.1.7 Reactions involving free radicals Furans trapped aryl radicals, generated from the oxidation of arylboronic acids <2003JOC578> and from arylhydra-
zines <2002T8055> by Mn(OAc)3, to give 2-arylfuran derivatives. A perfluoroalkyl radical, produced by using sodium dithionite, initiated dimerization of furan derivatives via addition to the furan 2-position <2002TL443>. The ethoxycarbonylmethyl radical, generated from xanthate 51 by dilauroyl peroxide, added to the 5-position of 2-acetylfuran, giving the addition product as shown in Equation (40) <2003CC2316>.
O S OEt dilauroyl peroxide O EtO + 40 ClCH2CH2Cl EtO ð Þ S O O 51 O reflux O 65% Furans and Their Benzo Derivatives: Reactivity 23
An intramolecular cascade reaction initiated by the addition of an alkenyl radical to a furan was used to synthesize an indene <1998SL1215>. As illustrated in Scheme 31, radical fragmentation in the spiro-dihydrofuran radical 52 provided the intermediate triene 53, which underwent Cope-type rearrangement to form the product. A related reaction with 1-bromocyclohexene that led to unsaturated ketone product was also developed <2003EJO1729>.
OTHP THPO H C O 11 5 Bun SnH O 3 H C O THPO AIBN 11 5 I H11C5 PhMe • reflux, 21 h 51% SPh SPh 53 52
O OTHP
H11C5
Scheme 31
Similar methodology was employed to the synthesis of more complex polycyclic ring system, as shown in Scheme 32 <1997TL9069>. The initial alkenyl radical 54, formed by an intramolecular radical 13-endo-dig macro- cyclization, initiated a radical cascade reaction by first reacting at the -position of the furan ring.
n Bu 3SnH O AIBN O O 40% I O
O O 54
Scheme 32
3.06.2.1.8 Cycloaddition reactions 3.06.2.1.8(i) Diels–Alder reactions The inter- and intramolecular Diels–Alder reactions of furans, and their applications to the synthesis of natural products as well as synthetic materials, were reviewed <1997T14179>. HfCl4 promoted the endo-selective inter- molecular Diels–Alder cycloadditions of furans with , -unsaturated esters <2002AGE4079>. The cycloaddition between furan and methacrylate was also achieved under these conditions, providing, however the exo-isomer as the major cycloadduct. A catalytic enantioselective Diels–Alder reaction between furan and acryloyl oxazolidinone to provide the endo-adduct in 97% ee was achieved by using the cationic bis(4-tert-butyloxazoline)copper(II) complex 55, as shown in Equation (41) <1997TL57>.
O O 2+ N N Cu t O But Bu
O O 2SbF6 O 55 (5 mol%) ð41Þ O + N O –78 °C, 42 h O N O 97% endo:exo = 80:20 Recrystallization 97% ee 67% 100% ee 24 Furans and Their Benzo Derivatives: Reactivity
The presence of a halogen substituent at the 5-position of 2-furanyl amides markedly enhanced the rate of intramolecular Diels–Alder reaction. For example, 5-bromofuran 56 shown in Equation (42) provided the oxatricyclic adduct after heating for 90 min. In contrast, the 5-unsubstituted furan 57 required 1 week for the cycloaddition to be completed <2003OL3337>. The enhanced reaction rate and yield, as determined by CBS-QB3 calculations, were attributed to the decreased activation energy as well as a greater stabilization of the cycloadduct imparted by the halogen substitution. The computational results also suggested that substitution at the 2-position has a greater effect than that at the 3-position, and that a 2-methoxy group is as beneficial as a halogen <2006AGE1442>.
O X O O X O NBn PhMe NBn ð42Þ 110 °C 90 min, 100% 56: X = Br 57: X = H 1 week, 90%
An intramolecular Diels–Alder reaction of a furan with a strained and sterically hindered bicyclopropylidene that proceeded under high pressure to provide the acid-labile cycloadduct is shown in Equation (43) <1996T12185>.An apparent increase in the reaction rate was observed with the 5-methoxyfuran 58 compared to the 5-unsubstituted analog 59.
R
R 10 kb O O 58: THF, 85 °C, 20 h, >95% ð43Þ ° 59: C5H12, 90 C, 43 h, 32% 58: R = OMe 59: R = H
Structural elements can also be incorporated into the furan starting materials so that intramolecular cycloadditions proceed at or below ambient temperature even with an unactivated dienophile, such as the example illustrated in Scheme 33 <2002OL473, 2002JOC3412>. Based on B3LYP/6-31G* calculations, the amidofuran substrate 60 was shown to be populated in a reactive conformation that was imparted by the amide carbonyl of the tether.
Me Me Me N SMe SMe SMe N O N O O rt,12 h O O H O 60
Scheme 33
A complexation-induced intramolecular Diels–Alder cycloaddition of furan is depicted in Scheme 34. Upon
exposure to silica gel, the alkyne–Co2(CO)6 complex 61 was transformed to the cycloadduct that contained a seven-membered ring <2000OL871>. This facile process was supposed to be arisen from the bending of the linear triple bond to a structure with a 140 angle between the two carbon substituents in the cobalt complex 61.
O O O i, silica gel ° Co2(CO)8 0 C O O PhMe ii, H O Co2(CO)6 2 Pd/C 61 EtOAc Co2(CO)6 0 °C 62%
Scheme 34 Furans and Their Benzo Derivatives: Reactivity 25
Introduction of hydrogen-bonding recognition elements into furans and dienophiles could also facilitate disfavored Diels–Alder reactions. For example, the pair of hydrogen bonds formed between the phenylfuran 62 and maleimide 63 shown in Equation (44) enhanced the rate of the cycloaddition, as well as stabilized the ground state of the exo- product 64 <1999OL1087>.
O O N N N N H H H H O O O O O ð44Þ O CDCl3 H O 50 °C, 15 h N N 62 O H O O 63 64
An interesting and rare example of inverse electron demand transannular Diels–Alder reaction of the furanophane 65 was employed for the synthesis of the chatancin core as depicted in Equation (45) <2003JOC6847>. The diastereoselectivity of this reaction was controlled by the macrocyclic conformation of 65 in the protic reaction medium.
O O ð45Þ OH H2O−DMSO (1:2)
CO2Me 115 °C, 72 h OH CO2Me 67% 65
3.06.2.1.8(ii) Other cycloadditions The inter- and intramolecular [4þ3] cycloaddition between furans and oxyallyl cations to generate seven-membered rings were reviewed
<2003OL4117>. Similar calculations of a TiCl4-catalyzed intramolecular [4þ3] cycloaddition between furan and allyl p-toluenesulfone-derived oxyallyl cation also suggested a stepwise mechanism <2001OL3663>.
Me3SiO O O OSiMe3 O OSiMe3 Al O O + Al + O
Scheme 35
The phenylalanine-derived chiral amine catalyst 10 was used to promote the asymmetric [4þ3] cycloaddition between 2,5-dialkylfurans and trialkylsilyloxypentadienals to generate seven-membered carbocycles with endo-selec- tivity and 81–90% ee, as represented in Equation (46) <2003JA2058>. However, the absolute configurations of the cycloadducts have not been determined. 26 Furans and Their Benzo Derivatives: Reactivity
Me O N Ph N H O O OSiMe3 ð46Þ 10 (20 mol%) CHO O + CHO CH2Cl2 −78 °C, 96 h 89% ee 64%
A[4þ3] cycloaddition between 2,5-bis((tert-butyldimethylsilyloxy)methyl)furan and the oxyallyl cation generated from 1,1,3-trichloroacetone was a pivotal step for the construction of phorbol B ring during a formal total synthesis of (þ)- phorbol <2001JA5590>. This type of furan–oxyallyl cation cycloaddition was used as a unifying strategy for the synthesis of tropoloisoquinoline alkaloids <2001JA3243>, and a key step in the total synthesis of colchicine, as shown in Equation (47) <1998JOC2804, 2000T10175>. Regioselective coupling of the complex furan 66 with the -alkoxy-substituted oxyallyl cation generated from the silyl enol ether 67 provided the desired endo-adduct as a single diastereoisomer. Interestingly, the reaction of the N-acetyl analog of 66 gave the undesired regio- and diastereoselectivity.
MeO MeO NHBoc OSiMe3 NHBoc Me3SiOTf MeO + ð47Þ MeO EtNO MeO O O MeO OMe 2 O OMe −60 °C 66 67 45% OMe
The intermolecular [4þ3] cycloaddition between furan and the nitrogen-stabilized oxyallyl cation generated from
N-(1,3-dibromoacetonyl)phthalimide 68 by LiClO4/Et3N, as represented in Equation (48), was predicted by frontier molecular orbital (FMO) calculations at the PM3 level to be a stepwise process <1996JOC1478>. The diastereose- lective inter- and intramolecular [4þ3] cycloadditions of a furan with a nitrogen-stabilized chiral oxyallyl cation, generated by epoxidation of a chiral oxazolidinone-substituted allenamide using dimethyl dioxirane, to form complex polycyclic structures were developed <2001JA7174, 2003JA12694>. This reaction was further extended to the use of a furan tethered to either the -or -position of the allene, as demonstrated in Equation (49) <2004AGE615>. The
catalytic enantioselective variant of this type of cycloaddition was also achieved by using a C2-symmetric copper- (salen) complex, providing ee up to 99% <2005JA50>.
O O O LiClO4 Br NPhth Br NPhth PhthN Et3N + O + O ð48Þ MeO O Br Br MeCN MeO MeO rt 68 57% 94:6 O O O O OSiEt O 3 N H H H O N dimethyl dioxirane ð49Þ Ph • Ph O CH2Cl2 ° H −78 C, 5−15 min dr = 93:7 Et3SiO 65%
The [4þ3] cycloaddition between furan and amino-stabilized allyl cations has not been as actively studied. An intramolecular cycloaddition between a furan and a 2-aminoallyl cation, generated from methyleneaziridine under
Lewis acid-promoted conditions, is shown in Equation (50) <2004AGE6517>. An AgBF4-promoted asymmetric intermolecular [4þ3] cycloaddition of 2-aminoallyl cations, derived from chiral -chloroimines, with furan to give cycloadducts of up to 60% ee was also reported <1997TL3353>. Furans and Their Benzo Derivatives: Reactivity 27
i, BF3•Et2O (150 mol%) O Bn CH2Cl2 H
N −30 °C, 1 h; rt, 16 h O O ð50Þ ii, aq. H2SO4 (10%) MeOH
rt, 16 h
70%
In contrast to the extensively developed type-I intramolecular [4þ3] cycloadditions as illustrated above, type-II intramolecular [4þ3] cycloadditions with cation moieties tethered to the 3-position of furans have not been shown to be versatile transformations. As shown in Equation (51), an attempt on the cycloaddition of furan 69 only resulted in a low yield of the fused tricycle product that resembled the BC ring of ingenol <2003JOC7899>.
Cl Et3N (2.2 equiv) O Cl (CF3)2CHOH Cl O rt, 7 d ð51Þ O O 14% 69
The intramolecular [5þ2] cycloaddition of oxidopyrylium ions, obtained from the Achmatowicz oxidative ring expansion of furfuryl alcohols, with alkenes was employed as a key strategy for the construction of the [6,7]-fused BC ring system of the daphnane diterpene phorbol <1997JA7897> and resiniferatoxin (Scheme 36) <1997JA12976> during their total synthesis, as well as for the assembly of the cyathin diterpene skeleton <1999T3553>. A version of this type of cycloaddition using a chiral sulfinyl auxiliary on the alkene component is shown in Scheme 37 <2002OL3683>.
i, MCPBA THF t 0 °C OSiBu Me2 ii, Ac2O t OSiBu Me2 t DMAP OSiBu Me2 O C5H5N 96% + O O OH O H iii, DBU OBn OBn MeCN O 80 °C OBn OAc OAc OAc 84%
Scheme 36
O CO Et CO2Et HO 2 i, NBS CO Et 2 CO Et CO2Et O 2 THF–H2O CO2Et 0 °C O DBU O H O + ii, Ac2O + PhMe H S p-Tol OAc • S p-Tol 0 °C, 1 h + • • • S – – • • O O – 81% O p-Tol
dr = 100 : 0
Scheme 37 28 Furans and Their Benzo Derivatives: Reactivity
As shown in Equation (52), the intramolecular [6þ4] cycloaddition between a furan and a tropone was successfully achieved for the first time during the construction of the highly functionalized ABC ring of ingenol <2005SL2501>.
O H O ð52Þ O O t t SiBu Ph2 C6H6 SiBu Ph2 reflux MOMO MOMO OSiButMe t 60% 2 OSiBu Me2
Methyl 2-methyl-5-vinyl-3-furoate participated in intermolecular extraannular [4þ2] cycloadditions in which the 5- vinyl group and the furan 2,3-p bond acts as the 4p-component with dienophiles to form tetrahydrobenzo[b]furans. However, the reaction was very sluggish under either thermal or high-pressure conditions <2002EJO3589>. Extraannular [4þ2] cycloadditions of 3-vinylfurans were also slow, except for reactions with phenylsulfinylated dienophiles, which occurred at room temperature with shorter reaction times. An application to the regioselective synthesis of substituted benzo[b]furan is illustrated in Scheme 38 <1996JOC1487>. A 5-trialkylsilyl substituent could enhance tendency of 2- and 3- vinylfurans toward the extraannular [4þ2] cycloadditions <1997H(45)1795>.
Me ButSiO OH t O 2 Me2Bu SiO i, PhMe PhS CO Me 2 reflux, 2 h + PhMe O ii, 10% Pd/C O SOPh O rt, 5 h H Ph2O CO2Me CO Me 67% 160 °C, 2 70%
Scheme 38
In contrast, the [8þ2] cycloaddition of 2-butadienylfurans, that participated as 8p-components, with dimethyl acetylenedicarboxylate (DMAD) was facile, giving oxygen-bridged 10-membered [8þ2] cycloadducts, as illustrated in Equation (53) <2005OL1665>.
CO2Me
+ O 1,4-dioxane ð53Þ O 80 °C, 10 h R CO2Me R = H, 84% MeO2C CO2Me R R = Me, 77% R = OMe, 79%
Gold(III) catalyzed the cycloisomerization of furans tethered via carbon, oxygen, and nitrogen linkages to a terminal
alkyne to produce phenols, as depicted in Scheme 39 <2000JA11553>. This reaction was also catalyzed by PtCl2 <2001AGE4754>. Based on density functional theory (DFT) calculations and on the trapping of reaction inter- mediates, the mechanism was proposed to involve a cyclopropyl platinacarbene complex <2003JA5757> that led to
AuCl3 (2 mol%) O NTs NTs NTs MeCN 20 °C O OH 97% 70
Scheme 39 Furans and Their Benzo Derivatives: Reactivity 29 an arene oxide intermediate (e.g., 70), which was observed experimentally for the first time under the gold-catalyzed conditions <2005AGE2798>. New gold(III)–pyridine-2-carboxylate complexes that provided higher reaction conver- sions than AuCl3 were developed <2004AGE6545>. This methodology was adapted to the synthesis of interesting spiroannulated dihydrobenzo[c]furans containing pentofuranosides, hexofuranosides, and hexopyranosides, as repre- sented in Equation (54) <2006TL3307>.
O OMe O OMe O O O O AuCl3 (3 mol%) Ph Ph O O ð54Þ BnO BnO O MeCN OH rt,10 min 78%
The furan 2,3-double bond was found to participate in regio- and stereoselective cyclization with masked o-benzoquinones <1998JA13254, 1999CC713>. An example of a diastereoselective cyclization involving (R)-furfuryl alcohol in which the -hydroxyl group controlled the facial selectivity to produce the ortho,endo-adduct is shown in Equation (55) <2003OL1637>.DFT<2002JOC959> and experimental <2003JOC7193> studies suggested a step- wise mechanism with the nucleophilic attack of furan to the conjugated dienone as the rate-determining step for this reaction. The 4,5-double bond of 2-methoxyfuran underwent inverse electron demand cycloaddition with pentacarbo- nylbenzopyranylidenetungsten(0) complexes in THF at room temperature. As illustrated in Scheme 40, subsequent elimination of W(CO)6 and rearrangement of the adduct provided intermediate 71, which was converted to naphthalene and benzonorcaradiene derivatives in the presence of TsOH and triethylamine, respectively <2002CL124>.
OH
HO MeO O O CO2Me MeO + 55 MeOH MeO C OMe ð Þ O 2 40 °C, 1 h OMe OMe MeO 60% O 99% de
Ph Ph –W(CO) O 6 + O THF OMe W(CO) O OMe 5 rt 71 Ph TsOH
CO Me 2 h 2 87% Ph
Et3N H
0.5 h 86% H CO2Me
Scheme 40
As depicted in Scheme 41, an intramolecular cycloaddition of the furan 2,3-double bond of a furan tethered to a cyano-substituted benzocyclobutene via an intermediate quinone dimethide was used for the synthesis of the tetracyclic core of halenaquinol and halenaquinone <2001SL1123, 2002T6097>. The reaction proceeded via an endo-transition state to produce the cycloadduct 72 exclusively. A related chemistry is shown in Equation (56), in 30 Furans and Their Benzo Derivatives: Reactivity
which the furan 2,3-double bond of the furanylbenzocyclobutene participated in an efficient 6p-disrotatory electro- cyclization with the intermediate quinone dimethide to form the fused tetracyclic ring system of the furanosteroid, viridin <2004AGE1998>. Additional examples of furan-substituted bicyclo[3.2.0]heptenones that participated in oxy-Cope transannular rearrangement involving furan 2,3-double bond were reported <1996JOC7976>, demonstrat- ing a feasible approach for the synthesis of poly [5,5]-fused ring systems.
O O O CN O CN O O MeO 1,2-dichlorobenzene MeO reflux, 2 h O 75%
NC H O
O MeO H 72
Scheme 41
t OSiBu Me2 OSiButMe i 2 i, Pr 2NEt xylenes
140 °C, 3.5 h ð56Þ OSiEt3 ii, DDQ rt, 15 min OSiEt O 3 83% O
Me3Si SiMe3
2,3-Dimethylene-2,3-dihydrofuran 73 was generated from 3-(acetoxymethyl)-2-(tributylstannylmethyl)furan by
using BF3?Et2O and captured by dienophiles to form adducts in a regioselective manner <1996CC2251>. The reaction with methyl acrylate is illustrated in Scheme 42.
OAc CO2Me BF3•Et2O ° O 0 C O dr = 91:9 O SnBun CO2Me 3 73 92%
Scheme 42
Intermolecular [3þ2] 1,3-dipolar cycloaddition of a D-glyceraldehyde-derived nitrile oxide to the 4,5-double bond of 2-methylfuran gave a 60:40 diastereomeric ratio of the two furoisozaxoline isomers. This chemistry was employed in the synthesis of L-furanomycin <2005EJO3450>. As depicted in Scheme 43, an intramolecular cycloaddition of a furan with a carbonyl ylide dipole proceeded under rhodium-catalyzed microwave-promoted conditions to provide the cycloadduct in a modest yield <2004OL3241>. Furans and Their Benzo Derivatives: Reactivity 31
O O O
N N N Rh ((CH ) CHCO ) 2 3 2 2 4 + O O O Et EtC6H6 Et O N2 O – O microwave O O EtO HC O 90 °C 2 CO Et CO2Et 2 35%
Scheme 43
3.06.2.1.9 Photochemical reactions The regio- and stereoselectivities of the Paterno–Bu` ¨ chi [2þ2] photocycloaddition of furans with carbonyl compounds are determined by the conformational stability of the triplet diradical intermediates <2004JA2838>. As illustrated in a study with 2-silyloxyfurans shown in Equation (57) <2000JOC3426>, reaction with ketones provided higher substituted products regioselectively (e.g., 74,R¼ Me), while those with aldehydes were nonselective. As usual, exo-oxetanes were produced predominantly in both examples. exo/endo-Selectivity was, however, influenced by the substituents of the carbonyl compounds. For example, the exo-selectivity was completely reversed by electronegative substituents (e.g., OMe and CO2R), providing endo-isomers as the predominant products <1998JOC3847>.
R R Ph Ph R Ph hν (>290 nm) + O + O OSiButMe O MeCN t ð57Þ O 2 O t O OSiBu Me2 0 °C OSiBu Me2
R = Me: 74:75 = 93:7 74 75 R = H: 74:75 = 60:40
A remarkable example of [2þ2] photocycloaddition of furans with alkenes, as shown in Equation (58), is the pivotal intramolecular cyclization employed in the total synthesis of ginkgolide B <2000JA8453>. The stereochemical outcome of this triplet transformation was predominately influenced by the relative 1,3-stereochemistry of the substrate 76.
O Et CO O EtO2C 2 O O hν (>350 nm)
C6H14 ð58Þ
OSiEt3 100% OSiEt3 76
Furan underwent photocyclization reactions with 2-alkoxy-3-cyanopyridines <1999J(P1)171> and 2-alkoxynico- tinic acid esters <2002TL6103>, forming cage-like adducts, as shown in Scheme 44, that presumably resulted from a singlet [4þ4] cycloaddition followed by a triplet [2þ2] cycloaddition. Reaction of 2-cyanofuran, however, provided the [4þ4] product as the major isomer <2004TL4437>.
O O MeO C 2 hν (>290 nm) + N N benzene MeO N O 73% OMeMeO2C OMe MeO O
Scheme 44 32 Furans and Their Benzo Derivatives: Reactivity
Photocyclization of N-alkylfuran-2-carboxyanilides conducted in inclusion crystals with optically active tartaric acid-derived hosts led to the formation of tricyclic trans-dihydrofuran compounds with up to 99% ee <1996JOC6490, 1999JOC2096>. 2-(p-Alkoxystyryl)furans underwent photocyclization to give 5-(3-oxo-(1E)-butenyl)benzo[b]furans as the predominant isomers in undehydrated dichloromethane as shown in Equation (59). The intermediate alkyl enol ether could be obtained by performing the reaction in anhydrous benzene <1999OL1039>.
O
hν (350 nm) ð59Þ O CH2Cl2 O OEt 96%
Unlike 2- and 3-furanylcarbenes <1997LA897>, 2- and 3-furanylchlorocarbenes could be characterized in a nitrogen matrix at low temperature. The syn-2-furanylchlorocarbene 77 was more photoreactive than its anti-isomer and rearranged to a mixture of conformers of 5-chloropent-2-en-4-yn-1-al (Scheme 45). It could also be trapped in solution by alkenes at room temperature <1998JA233>. The syn- and anti- isomers of 3-furanylchlorocarbene 78 and 79, respectively, could be photochemically interconverted. Both isomers rearranged to an isomeric mixture of methylenecyclopropenes 80 and 81 upon irradiation (Scheme 46) <1999OL1091>. The effect on the ring-opening rearrangement by the substituent on the carbene moiety was further investigated by ab initio calculations, which were found to be consistent with experimental results <1999JOC9170>. Substituents with a lone pair of electrons increased the energy barrier due to greater stabilization on the carbene reactant than on the transition state, suggesting that carbenes with this kind of substituents could be isolated experimentally. The predicted tendency
of rearrangement is in the order: SiH3 > H > CHTCH2 > CH3 > Br > Cl > F > NH2 > OH. Substituents on the furan ring also affected the outcome of the photo-rearrangement. For example, photolysis of 2-diazomethyl-5- trimethylsilylfuran and 2-diazomethyl-5-trimethylstannylfuran at >420 nm provided the (Z)-isomer of 1-(trimethyl- silyl)pent-2-en-4-ynone and 1-(trimethylstannyl)pent-2-en-4-ynone, respectively (Equation 60). However, both were very stable and did not isomerize to the (E)-isomers on prolonged irradiation <2001EJO269>.
Cl
hν (404 nm) hν (>400 nm) hν (<400 nm) H Cl • O O N2 O • N N 10 K Cl Cl H 77 O
Scheme 45
Cl O H •
•• Cl • ν h (366 nm) hν (313 nm) H O + O hν (578 nm) O Cl Cl 78 79 80 81
Scheme 46
hν (435 nm) N2 Me3X Me3X O Ar O ð60Þ H 30 K X = Si X = Sn Furans and Their Benzo Derivatives: Reactivity 33
3.06.2.2 Reactivity of Fully Conjugated Benzo[b]furans
According to the frontier orbital theory, the frontier electron populations of the parent benzo[b]furan 82 are represented as illustrated
–0.38 0.47 –0.01 0.54 –0.38 O –0.23 82
3.06.2.2.1 Reactions with electrophiles 3.06.2.2.1(i) Acylation Two types of 3-benzoylbenzo[b]furans were regioselectively prepared from their corresponding starting materials 2-methylbenzo[b]furan and 2-benzylbenzo[b]furan through a Friedel–Crafts reaction pathway, as shown in Scheme 47 <2002JME623>.
MeO MeO
p-MeOC6H4COCl p-MeOC6H4COCl SnCl4 SnCl4 R O O CS2 O CH2CI2 rt 63% Me 85% R = Me O O R = Bn
Scheme 47
Regioselective formylation was also achieved by treatment of a 3-phenylbenzo[b]furan with N,N-dimethylforma- mide and phosphoryl chloride (Vilsmeier reagent) at 0–25 C to give 2-carbaldehyde derivative in 90% yield (Equation 61). In addition, a variety of interesting 2-acylbenzo[b]furan derivatives were described in the same article <2002T5125>.
Ph Ph POCl3 MeO MeO DMF CHO ð61Þ O 0–25 °C O 90% OMe OMe
With 2-substituted benzo[b]furans, the regioselective electrophilic aromatic substitutions of formyl and nitro groups to C-3 of 5-alkyl-7-methoxy-2-phenylbenzo[b]furans were achieved (Equation 62). Further synthetic trans- formations of the resulting formyl group into methyl, hydroxymethyl, 1-hydroxyethyl, and cyano groups were also reported <1992JOC7248>.
i, Zn(CN)2, HCl CHO ° MeO C MeO2C Et2O, 0 C 2 OH OH ð62Þ O ii, H2O, EtOH O 50 °C OMe OMe OMe OMe 62% 34 Furans and Their Benzo Derivatives: Reactivity
2-Lithiated benzo[b]furan was found to be a useful reagent in reactions with amides to give the corresponding 2-acylbenzo[b]furan product (Equation 63). The acylation yield was not reported <2002TL6937>.
O O Me2N n-BuLi OEt + O ð63Þ O THF–hexane O O – 78 °C OEt 82 A key synthetic step to an unnatural nucleotide bearing benzo[b]furan by the reaction of 2-lithiated benzo[b]furan with lactone 83 is illustrated in Equation (64) <2003JA6134>.
OH i, BuLi, THF, then 83 O H O ii, BF3•Et2O, Et3SiH OH + i O O ð64Þ O Pr 2Si iii, TBAF, THF O O H 82 83
3.06.2.2.1(ii) Halogenation Since halogen-substituted benzo[b]furans play an important role in the transition metal-catalyzed coupling of benzo[b]furans with other substrates, synthetic methods to regioselectively synthesize substituted benzo[b]furan halides have become very critical routes. Several syntheses of benzo[b]furan based aryl halides are described here. When benzo[b]furan derived polycyclic phenol 84 was allowed to react with bromine, tribromide 85 was formed in high yield (Equation 65) <1999JME3199>. 3-Bromo-2-methyl-benzo[b]furan 87 couldalsobemadebyreactionofN-bromo- succinimide (NBS) with 2-methyl benzo[b]furan 86 at room temperature, as illustrated in Equation (66) <2005JOC10323>.
HO HO Br
Br
ð65Þ Br2
O HOAc O Br rt 8483% 85
Br NBS Me Me ð66Þ O THF O rt 86 87 85%
Another interesting bromination strategy was developed to obtain 3,5-dibromobenzo[b]furan and 2,3,5-tribromo- benzo[b]furan by sequential treatment of the corresponding benzo[b]furans with bromine followed by the base- mediated elimination of HBr (Scheme 48) <2003S925>.
i, Br2 Br Br i, Br2 Br Br Br Br Br CH2Cl2 KOH CH2Cl2 Br Br ii, NaHSO ii, NaHSO O 3 O EtOH O 3 O H2O H2O 23% 95%
Scheme 48 Furans and Their Benzo Derivatives: Reactivity 35
In a total synthesis of XH14 reported recently, the key intermediate 3-bromobenzo[b]furan was made by bromine- promoted cyclization of an o-methoxy phenylacetylene, as depicted in Equation (67) <2002JOC6772>.
OBn O O OMe Br O O Br2 ð67Þ OBn CHCl OMe 3 O 92% OMe OMe OMe
As depicted in Equation (68), anodic fluorination of ethyl 3-benzo[b]furanyl acetate was applied to the synthesis of a 2,3-difluoro-2,3-dihydrobenzo[b]furan derivative. A 2-fluoro-3-hydroxyl derivative was also obtained as a minor product <2003SL1631>.
COOEt F COOEt HO COOEt
Et4NF•4HF F + F ð68Þ O MeCN–H2O O O –1 1.8 V, 4 F mol 40%
The C-2 trimethylsilyl-derived pyridino[b]furan was treated with the combined reagent NIS/KF to give 2-iodopyrido[b]furan, a key intermediate for the synthesis of sesquiterpenoid furanoeudesmanes (NIS ¼ N-iodosuc- cinimide) (Equation 69) <2003T325>.
OH OH NIS KF SiMe3 I ð69Þ N N O THF O 51% Cl Cl
3.06.2.2.1(iii) Reactions with aldehydes and ketones Due to the electronic richness of the C-3 of benzo[b]furan 82, the Yb-catalyzed electrophilic substitution of benzo[b]furan 82 with glyoxalate led to a 3- -hydroxybenzo[b]furan ester in a regioselective manner, as depicted in Equation (70) <2000JOC4732>.
HO CO Et Yb(OTf)3 2 (5 mol%) + EtO2CCHO ð70Þ O CH2Cl2 O 82 rt, 24 h 76%
The C-2 proton of benzo[b]furan 82 underwent regioselective metallation by treatment with n-butyllithium to form 2-lithiated benzo[b]furan, which directly reacted with electrophiles, such as 1,4-cyclohexadienone to form 4-(ben- zo[b]furan-2-yl)-4-hydroxy-2,5-cyclohexadien-1-one in high yield, as shown in Equation (71) <2005TL7511>.
n-BuLi THF HO –78 °C O ð71Þ O O O O 82 96% 36 Furans and Their Benzo Derivatives: Reactivity
Another application of 2-lithiated benzo[b]furan to generate a structurally interesting benzo[b]furan derivative was realized by reaction of 2-lithiated benzo[b]furan with 4,4-dimethoxy-4H-naphthalen-1-one, followed by hydrolysis, as shown in Equation (72) <2003JME532>.
i, n-BuLi O THF–hexane –78 °C + O ð72Þ ii, HOAc O O HO MeO OMe H2O 82 82%
A benzo[b]furan derived acetylenic alcohol was also prepared by reaction of 2-lithiated benzo[b]furan with a cyclopentanone (Equation 73) <2004SL2579>.
n-BuLi + Et O–hexane ð73Þ O O 2 O HO –78 °C 82 53%
3.06.2.2.1(iv) Reactions with diazonium salts and diazo compounds Benzo[b]furan-based diazobutenoates were used as a substrate to make a cyclopropane in 89% yield via a rhodium- catalyzed intramolecular process, as can be seen in Equation (74). Cyclopropane 88 was the key intermediate for the total synthesis of diazonamide A <2000OL3521>.
O N2 O O O Me Rh2(cap)4 Me ð74Þ OMe OMe O CH2Cl2 O 89% 88
The rhodium-catalyzed intermolecular cyclopropanation of diazobutenoates with benzo[b]furan 82 resulted in the formation of a benzo[b]furan-derived cyclopropane in a diastereo- and enantioselective manner, as depicted in Equation (75) <1998JOC6586>.
Ph H
Rh2(S-DOSP)4 + MeO2CPh CO2Me ð75Þ O pentane O N 2 57% 96% ee 82
3.06.2.2.1(v) Reactions with other electrophiles Direct nitration of benzo[b]furan 82 is another important reaction to provide benzo[b]furan derivatives. Because of its electronic richness, benzo[b]furan 82 can undergo regioselective nitration to give 2-nitrobenzo[b]furan in 62% yield by using sodium nitrate and ceric ammonium nitrate under ultrasonic conditions (Equation 76) <1996OM499>.
NaNO3 (NH4)2Ce(NO3)6 NO2 ð76Þ O HOAc–CHCl3 O 62% 82 Furans and Their Benzo Derivatives: Reactivity 37
As illustrated in Equation (77), the regioselective nitration of 2-(trimethylstannyl)benzo[b]furan was also applied to the synthesis of 2-nitrobenzo[b]furan. The reaction proceeded by an initial treatment of benzo[b]furan 82 with n-BuLi/
Me3SnCl, and was then followed by reaction with tetranitromethane (TNM) or dinitrogen tetroxide <2003EJO1711>.
i, n-BuLi
Et2O–hexane then Me3SnCl ð77Þ NO2 O ii, C(NO2)4 O
DMSO 82
3.06.2.2.2 Reactions with oxidants In contrast to furan, because of its large resonance energy, the benzene ring of benzo[b]furan 82 is dominant to such an extent that [4þ2] cycloadditions of the furan ring are not possible. On the other hand, photochemical [2þ2] cycloaddition occurs readily on the C-2/C-3 double bond. For example, photooxygenation of 2,3-dimethylbenzo[b]furan at 78 C produced dioxetane 89, which isomerized at room temperature to give 2-acetoxyacetophenone (as shown in Scheme 49) <1995ACR289>.
O Me Me O2 O hν O Me Me sensitizer O O Me O 89 O Me
Scheme 49
3-Alkylbenzo[b]furans were oxidized by chloroperoxidase from Caldariomyces fumago to their trans-2,3-diols as major products, and these were all fully characterized because of their stability (Equation 78) <2001T8581>.
chloroperoxidase
CH2CO2Me H2O2, NaCl CH2CO2Me HO CH2CO2Me HO CH2CO2Me pH 2.75 ð78Þ Cl + OH + OH O acetone O O O 16% 23% 24%
The ruthenium(II) porphyrin-catalyzed amidation of benzo[b]furan 82 was reported for the first time to make 2-N- nosylamide in 50% yield under mild conditions, as can be seen in Equation (79) <2004OL2405>.
[RuII(TTP)(CO)] SO NH 2 2 PhI=NTs + NHSO2 NO2 ð79Þ O CH Cl O O2N 2 2 50% 82 The structurally interesting bis(benzo[4,5]-furo)[2,3-e:39,29-g][1,2,3,4]tetrathiocine was obtained by an oxidative coupling reaction of 2-lithiated benzo[b]furan with elemental sulfur (Equation 80) <2002JOC6220>.
i, n-BuL S S THF S S
–78 °C O O ð80Þ O ii, S8 –78 °C to rt 82 6.5 h
35% 38 Furans and Their Benzo Derivatives: Reactivity
3.06.2.2.3 Reactions with reductants At 0 C, the reduction of benzo[b]furan 82 with lithium in the presence of a catalytic amount of 4,49-di-tert- butylbiphenyl (DTBB, 5 mol%) in THF was observed to give 2-vinylphenol in high yield, as illustrated in Equation (81) <2002T4907>.
Li DTBB (cat.) 81 THF ð Þ OOH 0 °C 82 93%
Another regioselectively reductive ring-opening of benzo[b]furan 82 was also utilized to afford the active vinyl- lithium species in the presence of a catalytic amount of DTBB (5 mol%) in THF at 0 C, and the formed vinyllithium
was able to further react with electrophiles (such as t-BuCHO, PhCHO, Ph(CH2)2CHO, Me2CO, n-PrCOMe, PhCOMe, (CH2)4CO) at –78 C to give their corresponding (Z)-products. Further reaction of the diols led to substituted 2H-chromenes under acid-catalyzed cyclization, as depicted in Scheme 50 <2001EJO2809>.
Li OH DTBB PhCOMe H3PO4
THF PhPhMe Ph O Me O 56% OH reflux Me 82 85%
Scheme 50
3-Substituted-2-phenylbenzo[b]furans were able to undergo a palladium-catalyzed hydrogenation reaction to give their corresponding 2,3-dihydrobenzo[b]furans, but the yields are quite low (Scheme 51) <2002T4261>.
H Me R H CO Me H2 H2 2 Pd Pd Ph Ph Ph O H MeOH O MeOH O H 48% 11%
R = Me R = CO2Me
Scheme 51
The surfactant-stabilized aqueous colloidal rhodium(0) was used to hydrogenate unsubstituted nitrogen-, oxygen-, or sulfur-derived heterocycles (such as benzo[b]furan 82) in quantitative yield, as can be seen in Equation (82) <2004ICA3099>.
NaBH4 RhCl3 H (40 b) 2 ð82Þ ° O 20 C, 2.5 h O 82 100%
3.06.2.2.4 Reactions as nuclear anion equivalents 2-Metallated benzo[b]furans play a very important role as nucleophiles in the quest for structurally diverse 2-substituted benzo[b]furans. For example, benzo[b]furan-2-sulfonamide 90 was synthesized by sequential reactions
of a benzo[b]furan with n-BuLi/SO2, N-chlorosuccinimide (NCS), and NH4OH (Scheme 52) <1990JME749>. Furans and Their Benzo Derivatives: Reactivity 39
i, n-BuLi THF-hexanes MeO MeOO MeO O –78 °C i, NCS S OH S NH2 O ii, SO2 O ii, NH4OH O 98% 34% 90
Scheme 52
As shown in Equation (83), 2-iodobenzo[b]furan was also prepared by reaction of benzo[b]furan 82 with tert- butyllithium in ether at –78 C, followed by reaction with iodine <2002JOC7048>.
i, t-BuLi
Et2O–hexane ° –78 C ð83Þ I O ii, I2 O 82 95%
An efficient approach for asymmetric syntheses of benzo[b]furan-1-alkylamines was developed by reaction of 2-lithiated benzo[b]furan with aldehyde–SAMP-derived hydrazones (SAMP ¼ (S)-( )-1-amino-2-methoxymethyl- pyrollidine; Equation 84). In this way, an efficient synthesis of hydrazine 91 was achieved <2004TA747>.
NH2 N n-BuLi HN N + OMe + EtCHO s s ð84Þ O Et2O O Et –78 °C OMe 82 85% 91
A phenylacetylene-substituted benzo[b]furan was prepared by reaction of 2-lithiated benzo[b]furan with 1-(phe- nylethynyl)-1H-1,2,3-benzotriazole (Equation 85) <2002JOC7526>.
N N n-BuLi + N Ph ð85Þ O THF–hexane O –78 °C 82 Ph 67%
The synthesis of a novel compound 1,2-bis(2-methylbenzo[b]furan-3-yl)-perfluorocyclopentene 92 was realized by reaction of octafluorocyclopentene with 3-lithiated 2-methylbenzo[b]furan, which was generated by the treatment of 2-methyl-3-bromobenzo[b]furan with n-BuLi at 78 C in THF, as can be seen in Equation (86) <2005JOC10323>.
O Br F F F F n-BuLi Me Me + F F O THF ð86Þ F F F F –78 °C O F 46% F F F Me 92 An initial formation of a sodium salt of benzo[b]furan 82 with sodium sand in the presence of 1-chlorooctane gave the 2-sodium salt of benzo[b]furan, which with CO2 gave the carboxylic acid 93 (Equation 87) <2002AGE340>. 40 Furans and Their Benzo Derivatives: Reactivity
i, Na 1-chlorooctane PhMe 87 COOH ð Þ O ii, CO2 O 82 85% 93
As can be seen in Equation (88), the 2-sodium salt of benzo[b]furan could also be formed by treatment of benzo[b]furan 82 with sodium dithionite in the presence of fluoroalkyl chlorides in dimethyl sulfoxide (DMSO), leading to the corresponding fluoroalkylated products in moderate yields <2001JFC107>.
Na2(S2O4) Cl(CH2)7CF3 (CH2)7CF3 ð88Þ O DMSO O 82 65%
3.06.2.2.5 Reactions catalyzed by metals and metallic derivatives In the total synthesis of naturally occurring frondosin B, the palladium-catalyzed coupling reaction of C-3 stannylated benzo[b]furan 94 with the vinyl triflate 95 was employed as a key step to build up the framework of the final target, as depicted in Equation (89) <2001JA1878>.
Pd2(dba)3 SnBu3 OTf MeO LiCl, NMO MeO ð89Þ + THF O O 50 °C 94 95 23%
A palladium-catalyzed cyclization was applied to establish the skeleton of the benzo[b]furan derived tetracyclic ring in frondosin B (Equation 90) <2004T9675>.
O
Pd(OAc)2 TfO Ph3P Et3N ð90Þ (CH2)3 MeCN MeO O MeO O O reflux 54%
The regioselective coupling reaction of 2,3-dibromobenzo[b]furan with several terminal acetylenes was achieved using a palladium-catalyzed Sonogashira reaction, as exemplified in Equation (91) <2003S925>.
PdCl2(PPh3)2 Br CuI Br Et3N ð91Þ Br + But But O THF O 84%
Other regioselective C–C bond formation reactions were also reported by using palladium-catalyzed coupling of 2,3,5-tribromobenzo[b]furan 96 as a substrate. Thus, the palladium-catalyzed coupling between tribromide 96 and arylzinc 97 gave a dibromide 98, which underwent sequential Kumada coupling with a Grignard reagent and a Furans and Their Benzo Derivatives: Reactivity 41
Negishi coupling with methyl zinc chloride to regioselectively afford a trisubstituted benzo[b]furan 99, as illustrated in Scheme 53 <2002TL9125>.
OMe
Br ClZn OMe Br OMe Br Br 97 Br OMe O PdCl2(PPh3)2 O 96 98
i, NiCl2(dppe) MeCH=CHMgBr THF rt Me OMe 87% OMe ii, PdCl2(dppf) O MeZnCl THF 99 reflux 85%
Scheme 53
The palladium-catalyzed Suzuki–Miyaura reaction of 3,5-dibromo-2-pyrone 100 with benzo[b]furan-2-boronic acid 101 was applied to the synthesis of 3-(benzo[b]furan-2-yl)-5-bromo-pyrone 102 in 50% yield (Equation 92) <2004SL2197>.
Pd(PPH3)4 O O O K2CO3 O B(OH) + 2 ð92Þ Br Br O PhMe O ° 100 101100 C, 4 h 102 Br 50%
The C–H coupling of benzo[b]furan 82 with bis(pinacolato)diboron 103 was carried out in octane with
[IrCl(COD)]2-(4,49-di-tert-butyl-2,29-bipyridine) as a catalyst (3 mol%), leading to the formation of the 2-borylated product 104, as can be seen in Equation (93) <2002TL5649>.
[IrCl(COD)]2 O O dtbpy O + B B B ð93Þ O O O octane O O 80 °C 82 10391% 104
A highly regioselective borylation of arenes and heteroarenes (such as benzo[b]furan 82) was achieved by the iridium-catalyzed C–H activation reaction, as shown in Equation (94) <2003CC2924>.
[Ir(OMe)(COD)]2 O dtbpy O + HB B ð94Þ O O hexane O O 25 °C,1 h 82 104 90% 42 Furans and Their Benzo Derivatives: Reactivity
An additional method to prepare 2-aryl benzo[b]furan was realized by the palladium-catalyzed C–H activation of benzo[b]furan with aryldiazonium trifluoroacetate (Equation 95) <1999EJO1357>.
N + 2 Pd(OAc)2 + Me CF CO – EtOH ð95Þ O Me 3 2 O 43% 82
The palladium-catalyzed hydrofuranylation of alkylidenecyclopropane 105 with unfunctionalized benzo[b]furan was utilized in the synthesis of a 2-allylbenzo[b]furan derivative 106, as illustrated in Equation (96) <2000JA2661>.
n Bu Pd(OAc)2 + O n O Bun EtOH CH(Bu )2 ð96Þ 43% 82 105 106
As depicted in Equation (97), oxidative cross-coupling of -aryl- , -difluoroenol silyl ether with unfunctionalized
benzo[b]furan 82 in the presence of Cu(OTf)2 in wet acetonitrile proceeded smoothly to give benzo[b]furan difluoromethyl aryl ketone in 50% yield <2004OL2733>.
CF2 OMe F F Cu(CF3SO3)2 OSiMe3 + ð97Þ MeCN O MeO O O 0 °C, 3 h 82 50%
3-Chloromercurio-benzo[b]furans 107 were key intermediates for the syntheses of natural product XH14 and its analogs. The synthesis proceeded by the palladium-catalyzed carbonylation reaction as a pivotal step. The
3-chloromercurio-benzo[b]furan 107 was also reduced to form its hydride derivative by NaBH4 reduction, as illustrated in Scheme 54 <2002JOC6772>.
PdCl2 HgCl OMe MgO–LiCl CO2Me OMe CO R OBn R OBn O MeOH O 69% 107
NaBH4 KOH 85%
CHO H OMe OMe HO R OBn OH O O XH 14
Scheme 54
A C2-symmetric benzo[b]furan-containing heterocycle 108 was constructed by the palladium-catalyzed coupling reaction between the lactam-derived vinyl phosphates and benzo[b]furan-2-boronic acid 101 (Equation 98) <2005TL3703>. Furans and Their Benzo Derivatives: Reactivity 43
Boc OP(O)(OPh)2 PdCl2(PPh3)2 Na OC O N 2 3 O ð98Þ N Boc + B(OH)2 O THF-EtOH reflux OP(O)(OPh)2 101 108 25% As can be seen in Equation (99), a platinum-catalyzed intramolecular cyclization was also utilized in the formation of benzo[b]furan-based tricycles. A platinum carbene was proposed as an intermediate in this reaction <2003JA5757>.
i, NaH CO2Me CO Me 2 DMF CO2Me CH2Br + MeO2C C CH2 C CH ð99Þ H O ii, PtCl2 O acetone reflux
Triflates of 3-benzo[b]furans were prepared, and evaluated in the palladium-catalyzed Stille, Heck, Suzuki, and Sonogashira coupling reactions. As can be seen in Scheme 55, results demonstrated that benzo[b]furan-3-triflate 109 was a good coupling partner in the metal-catalyzed reactions, and good to excellent results were obtained <2002SL501>.
Pd(OAc) 2 CN dppp PdCl2(PPh3)2 OMe OMe OMe Et N CO2Me Et3N OTf 3 CO CH2=CHCN
MeOH THF O O O reflux 109
Scheme 55
3.06.2.2.6 Reaction involving free radicals A regioselective addition of N,N-dichlorobenzenesulfonamide (dichloramine-B) 110 to benzo[b]furan 82 was achieved to make a pyrrolidine-derived tricyclic compound 111 at room temperature in good yield. Triethylborane was selected as a radical initiator in this reaction (Equation 100) <2003JOC3248>.
Cl Cl
Et3B ð100Þ = = Ph-SO NCl N Ph + CH2 CHCH CH2 + 2 2 S O PhMe O OO 25 °C 82 110 80% 111 Under similar conditions, a radical-initiated [3þ2] cycloaddition of N-centered radical with benzo[b]furan 82 was examined. A benzo[b]furan-derived pyrrolidine 112 was obtained in good yield with again Et3B as a radical initiator (as depicted in Equation 101) <2001OL2709>.
CH Cl 2 Me OO H S Et B N 3 N + S ð101Þ C H H O Me Cl 6 6 O O O rt, 3 h 82 112 83% 44 Furans and Their Benzo Derivatives: Reactivity
3.06.2.2.7 Cycloaddition reactions Benzo[b]furan 82 is a very important building block in materials science and drug discovery. Because it is electro- nically rich at C-2 and C-3, many important synthetic transformations occur at these two positions. For example, o-benzoquinones oxidatively generated from the corresponding substituted 2-methoxyphenols reacted with ben- zo[b]furan 82 to form polycyclic molecules, as depicted in Scheme 56 <1999JA13254>.
MeO OMe CO Me O H 2 CO2Me CO Me O PhI(OAc)2 2 82
MeOH reflux O O H HO 64% OMe MeO OMe
Scheme 56
A domino process for the construction of a tetracyclic ring was achieved by the gold-catalyzed formation of an isobenzopyrylium derived from a phenylacetylene-based benzaldehyde. This was followed by reaction with electron- rich benzo[b]furan as a dienophile in a Diels–Alder reaction with inverse electron demand (Equation 102) <2003AGE4399>.
O Ph Ph
AuCl3 ð102Þ + O MeCN O OH CHO ° 82 80 C 61%
The reaction of benzodifuran 113 with 3,6-dimethoxycarbonyl-1,2,4,5-tetrazine 114 proved to be an efficient way to make pyridazino–psoralen-based aromatic polycycles such as 115 through a reaction sequence illustrated in Scheme 57 <2005T4805>.
CHO CO2Me CHO CHO OO –N OO O OH N N 2 CO Me CO2Me + 2 NN dioxane N N reflux, 2 h CO2Me N N MeO C MeO C 113 114 2 H 2 CHO O O O
65% N 115 N
CO2Me
Scheme 57
3-Vinylbenzo[b]furans, 3-vinylfuropyridines, and 3-vinylindoles were employed as conjugated dienes in the Diels– Alder reaction with ethyl acrylate, affording tricyclic adducts in fair to good yields, as shown in Equation (103) <2002OL2791>. Furans and Their Benzo Derivatives: Reactivity 45
OEt OEt
CO2Et CO2Et ð103Þ O PhMe O 110 °C, 72 h (endo:exo = 37:63) 59%
The enol form of dihydrofuro[2,3-h]coumarin-9-one 116 was also employed as a dienophile in the Diels–Alder reaction with 3,6-bis(trifluoromethyl)1,2,4,5-tetrazine 117 to afford the desired tetracyclic product 118 in 54% yield (Equation 104) <2002S43>.
N N
F3C CF3 NN117
dioxane O O O O O ð104Þ O reflux 54% F C O 3 CF3 N N 116 118
As can be seen in Scheme 58, a new synthesis of -lactams was also achieved by reaction of benzo[b]furan-derived vinyl sulfilimines with dichloroketene, a reaction which proceeded through a [3,3] sigmatropic rearrangement <2005OL839>.
Cl O Cl Cl Cl H O – – NTs [3,3] +NTs + N S SEt Ts Cl2C=C=O O O SEt O Et
Scheme 58
As illustrated in Equation (105), 6-(diethylamino)benzo[b]furan-2-carbaldehyde 119 reacted with 49-bromo-29- hydroxyacetophenone 120 in dry dimethyl formamide (DMF) in the presence of an excess of sodium methoxide to afford a heterodimer of benzo[b]furan and flavone <2004TL8391>.
O NaOMe HO Br H2O2 CHO + O Br ð105Þ O DMF–H2O–EtOH O Et N Et2N 2 21% OH O 119 120
A regioselective lithiation was achieved by treatment of 3-substituted benzo[b]furan 121 with n-BuLi at 0 Cin THF, and the 2-lithiated benzo[b]furan so generated was allowed to couple with quinone monoketal followed by a regioselective cyclization to give kushecarpin A’s analog 122 (Scheme 59) <2005TL7511>. Under microwave conditions, 5-nitro-substituted furfuryl amide 123 underwent an unusual isomerization– cyclization reaction pathway to give 1,4-dihydro-2H-benzo[4,5]-furo[2,3-c]pyridine-3-one 124 (Equation 106) <2003OL3337>. 46 Furans and Their Benzo Derivatives: Reactivity
i, n-BuLi OEt OH CH2O OMe THF Me OMe 0 °C + O ii, HOAc O O O HO 80% 121 O NaH O THF O HO 25 °C 122
Scheme 59
But O N NMP MW (300 W) N O MeO O But O 15 min ð106Þ O MeO 36% O
NO2 O2N 123 124
The palladium-catalyzed carbonylative annulation of 3-(2-iodophenyl)-benzo[b]furan 125 provided benzo[b]- indeno[1,2-d]furan-6-one 126 in 81% yield, as can be seen in Equation (107) <2002JOC5616>.
Pd(PCy3)2 (5 mol%) CsPiv I CO (1 atm) ð107Þ O O DMF O 125110 °C, 7 h 126 81%
2-Benzo[b]furyl-4-chloromethyl-1,3-oxazole 127, an important intermediate for the synthesis of potent and highly selective D3 receptor ligands, was realized by a direct condensation of benzo[b]furan-2-carbamide and 1,3-dichloro- propan-2-one (Equation 108) <2003JME3822>.
CH Cl ClCH2C(O)CH2Cl N 2 CONH 2 ð108Þ O 130 °C, 1 h O O 54% 127
3.06.2.2.8 Photochemical reactions As shown in Equation (109), irradiation of a benzene solution containing 3-cyano-2-ethoxypyridine (0.02 M) and benzo[b]furan 82 (0.5 M) resulted in the formation of two tetracyclic stereoisomeric adducts <2000CC1201>. Furans and Their Benzo Derivatives: Reactivity 47
EtO EtO N N Me H Me H Me EtO N hν + + ð109Þ C H O NC 6 6 O H CN O H CN 82 27% 34%
The diastereoselective Paterno–Bu` ¨ chi reaction of benzoin 128 with benzo[b]furan 82 was utilized to stereoselec- tively construct a [6-5-4] tricyclic heterocycle 129 (Equation 110). The observed diastereoselective excess was also explained <2004TL3877>.
O Ph hν O H + O O O n-hexane O Et Me 2-propanol H O Et ð110Þ 82 128 20% Ph O Me 129 58% de
The photoinduced Paterno–Bu` ¨ chi reaction of 1-acetylisatin 130 with benzo[b]furan 82 was employed to make a structurally interesting spiro-type molecule 131 in good yield, as depicted in Equation (111) <2002J(P1)345>.
Ac H O N hν + O N ð111Þ O C6H6 O H O Ac O 76% 82 130 131
As shown in Equation (112), the photolytic reaction of benzoxazole-2-thione 132 with unsubstituted benzo[b]furan 82 was utilized to make 2-benzofuryl-benzoxazole 133, but the yield is relatively low <2003HCA3255>.
Ac N N hν + S ð112Þ O O C6H6 O O 82 13235% 133
A novel tandem photolysis was observed for the synthetic conversion of 2,3-diphenylbenzo[b]furan to benzo[b]- phenanthro[9,10-d]furan 134. This process might involve sequential photochemical cyclization and aerial oxidation (Scheme 60) <2003TL3151>.
H H hν [O]
O MeCN O O EtOH 134
Scheme 60 48 Furans and Their Benzo Derivatives: Reactivity
3.06.2.3 Reactivity of Fully Conjugated Benzo[c]furans
A review article summarizing various aspects of the chemistry of benzo[c]furans (isobenzofurans) bridging the gap between these theoretically interesting but usually fugitive molecules and natural products was published
7 1 6 O2 5 3 O 4 135 82
Although many research articles state that 135 and its derivatives are rather reactive and as a result are difficult to be isolated at room temperature unless electron-withdrawing or bulky groups are substituted at the C-1 or C-3 position, there are reports concerning the isolation of stable derivatives of 135. For example, as shown in Equation (113), attempts to purify 136 by flash chromatography led to the formation of 1-(diethylamino)-3-phenylbenzo[c]- furan hydrochloride 137 in a yield as high as 81% <1997JME2936>.
Ph flash Ph Cl chromatography O NEt2 ð113Þ
• O NEt2 HCl 136 137 Other intriguing observations were the identification of relatively stable 1-t-butyldimethylsilyl-4-methylbenzo[c]furan <1996JA10766>, and the preparation of the stable benzo[c]furan derivative 138 starting from dimethyl 3,4-furandicarboxylate and N-methyl succinimide via a base-promoted condensation reaction, as can be seen in Equation (114) <1996S1180>.
i, NaH (2.2 equiv) OH O THF, MeOH (cat.) O CO2Me reflux O + NMe O NMe ð114Þ ii, H+ CO2Me O 73% OH O 138 A novel crystalline benzo[c]furan 139 was also reported by Warrener, in which the 1,3-positions are linked with an alicyclophane <2001CC1550>.
O CF3
O OF3C O N O N O
139 Furans and Their Benzo Derivatives: Reactivity 49
In addition to being a very reactive Diels–Alder diene, 1,3,4,5,6,7-hexaphenylbenzo[c]furan was reported to be highly fluorescent in toluene solution, as well as in its solid state. This benzo[c]furan may therefore be used as electron transport material in an organic light-emitting diode <2002SM247>.
3.06.2.3.1 Cycloaddition reactions Although being itself rather elusive, freshly generated 135 has been used time and again in trapping reactions. For example, its Diels–Alder cycloaddition with dienophiles such as quinone <1999AJC1123> and DMAD <2002SL1868, 2002OL3355> led to the formation of cycloaddition adducts. Benzo[c]furan 135 was also used to trap dienophiles 140 <2000J(P1)195>, 141 <2001SC1167>, 142 <2003CEJ2068>, and 143 <2003OL2639>.
O O O O
O 140 141 142 143
Several reviews summarized the use of benzo[c]furan derivatives in trapping reactions <1996BCJ1149, 1997SL145, 1998CC1417>. The most popular benzo[c]furan derivative used in trapping reactions must be the 1,3-diphenyl derivative 144, which is commercially available and is a crystalline compound.
Ph
O
Ph 144
There is a plethora of reactive and/or unstable dienophiles 145 <1996TL7251, 2001J(P1)1929>, 146 <1998TL6529>, 147 <1996JOC3392, 1998T9175>, 148 <1996TL8605>, 149 <1997SL44>, 150 <1996J(P2)1233>, 151 <1996TL4907>, 152 <1996JOC6462>, 153 <1996T3409>, 154 <1996T10955>, 155 <1996JCCS297>, 156 <1996JOC764>, 157 <1997JOC3355>, 158 <1998JOM1>, 159 <2004JOC7220>, 160 <2000TL6611>, 161 <1997BCJ1935>, 162 <1997TL4125>, 163 <2001JOC3806>, 164, 165 <1996H(43)527, 1998BCJ711>, 166 <1997JOC1642>, 167 <1996CC1519>, 168 <1997JOM41>, and 169 <1998JCD755> that were successfully trapped by 144.
Cl Cl Cl F O F Cl Cl Fe Cl F SO Ph Cl 2 Cl Cl 145 146 147 148 149 150 151
Me
Cl Fe Br Br CO2Me Cl 152 153 154 155 156 157 158 50 Furans and Their Benzo Derivatives: Reactivity
CO2Me
(CH2)6
159 160 161 162 163
O O O O O OC CO N N CO Et O 2 O 164 165 166 167 168 169
Diels–Alder cycloaddition of 144 and its derivatives with singlet oxygen, leading eventually to the formation of 1,2- dibenzoylbenzenes, has been employed to determine the presence of singlet oxygen <1996NJC571, 1996JPH49, 1997JPPA273, 1997JA5286, 1997OM4386>. An [8pþ8p] cycloaddition was observed for 144 and o-thiobenzoquinonemethide 170, as shown in Scheme 61 <1996JHC1727>.
Ph
O Ph S S S 144 Ph O PhMe reflux, 5 h 170 84% Ph
Scheme 61
Substituted benzo[c]furans played a very important role in the quest for natural as well as non-natural molecules. The schemes depicted here are examples showing the use of substituted benzo[c]furans in the synthesis of complex molecules. A short synthesis of ( )-halenaquinone 173 was reported <2001JOC3639>, in which the pivotal step was the Diels–Alder cycloaddition of 4,7-dimethoxybenzo[c]furan 171 to 172, as illustrated in Scheme 62. In a similar manner, the total synthesis of ( )-xestoquinone, ( )-9-methoxyxestoquinone, ( )-10-methoxyxestoquinone <2001T309>, and the naphtho[2,3-h]quinoline portion of dynemicin A <1997JA5591> was also achieved.
SPh SPh O OMe OMe O H H H H
O + O O PhMe O O OMe reflux, 21 h OMe O O O O OMe 94% OMe 171 172 173
Scheme 62 Furans and Their Benzo Derivatives: Reactivity 51
Diels–Alder cycloaddition between 1,4,7-tris(trimethylsilyloxy)benzo[c]furan 174 and the dienophile 175 was also the key step in the total synthesis of (þ)-dynemicin A 176 reported by Myers <1997JA6072>, as can be seen in Scheme 63.
Me Me H H CO SiPri CO SiPri 2 3 RO 2 3 RO OR N H N O H O OMe OMe O + O HHTHF –20 to 55 °C H RO O O 5 min RO RO 174 175 75%
R = Me3Si Me H CO2H OH O HN MnO2 O 3HF•NEt3 OMe THF H 23 °C, 9 min OH O OH 53% 176
Scheme 63
Kelly reported a short synthesis of the CDEF fragment of lactonamycin 178 in eight steps. As can be seen in Scheme 64, the Diels–Alder reaction between the tricyclic 177 and 2,3-dimethylbenzoquinone was used for construction of the tetracyclic skeleton <2002OL1527>.
O Me Me Me N N RO O OR Me RO RO Me O O O –60 °C RO RO Me 177 O
t R = SiMe2Bu
Me N OH O Me TFA O
HO Me 178 O
Scheme 64
Two novel mono- and bisoxadisilole-fused benzo[c]furans were prepared and isolated. They were shown to undergo facile Diels–Alder cycloaddition reactions with dienophiles such as the oxadisilole-fused benzyne, as illustrated in Equations (115) and (116), to form acene precursors <2006JOC3512>. 52 Furans and Their Benzo Derivatives: Reactivity
Si O Si Si Si Si ð115Þ O O O O O Si CHCl3 Si Si 85%
Si O Si O O Si Si Si Si Si ð116Þ O O O CHCl3 Si Si Si 45% O Si O Si
Many benzo[c]furan derivatives have been prepared and their intermolecular Diels–Alder cycloaddition reactions led to many intriguing structures. These benzo[c]furans are: 179 <1996JA9426, 1996TA1577>, 180–184 <1996AJC1263, 1997T3975>, 185–187 <1997LA663>, 188 <2000TL5957, 2002T9413>, 189 <2000OL923, 2001JOC3797>, 190 <2000IJB738>, 191 <2000OL1267>, 192 <1996TL6089>, 193 <1996TL6797>, 194 <1996TL5963>, 195 <1996JOC3706>, 196 <1996JOC6166>, 197, 198 <1996JOC3706>, 199–201 <1997JOC2786, 1997S1353>, 202 <1997SL47>, 203 <2004OM4121>, 204 <1996JA741, 1997AGE1531>, 205 <1998EJO99>, 206 <1996S77>, 207 <2001TL789>, and 208 <1996TL8845, 2003JOC8373, 2003JA2974>.
O Me Br O O O O O O O Me Br 179 180 181 182 183 184
C H OC H 6 13 6 13 Ph Br Me Si H C O Br 3 13 6 O O O O O Br Me3Si H13C6O Br C H 6 13 OC6H13 185 186 187 188 189
OMe Bu MeO Ph OSiMe OSiMe3 3 Me Me O O O O MeO Ph MeO CN SiMe3 190 191 192 193
PO(OR)2 SEt SEt SEt
O O O O
Me (CH2)nCH=CH2 Ph 194 195 196 197 R = Me, Et, n-Pr, i-Pr n = 3, 4 Furans and Their Benzo Derivatives: Reactivity 53
SEt SEt SEt SEt
O O O O
NEt N N E 2 (CH2)nCH=CH2 (CH2)2CH=CHSO2Tol Me Me
O 199 200 201 O n = 2, 3 198
O R Me O Ph Ph O O O Ph O O Re(CO)2Cp O R Ph Ph Ph
202 203 204 t R = H, -p-C6H4Bu R
(CH2)4 O C H H 12 25 O
O O O O O
H O C12H25 (CH2)4 205 206 207 208
Intramolecular Diels–Alder reactions involving in situ generation of benzo[c]furan species have also been a viable method in the construction of polycyclic molecules. As can be seen in Scheme 65, a nitrogen-containing heterocycle 210 was obtained via a sequence of Pummerer reaction and Diels–Alder cycloaddition, starting from the enesulfoxide 209, presumably via a benzo[c]furan intermediate <1997JOC2786>. A new entry into the erythrinane skeleton was achieved by employing a similar strategy, as illustrated in Scheme 66 <1996JOC4888, 1998JOC1144>.
SEt O OAc SOEt p-TsOH O O Ac2O xylene + Me N Me N Me N 81% Me N
O O O O 209 210
Scheme 65
The Hamaguchi–Ibata methodology was employed in the conversion of dizaoketone 211 to benzo[h]quinoline 212 <1999J(P1)59>, as depicted in Scheme 67, again via a benzo[c]furan. Benzo[c]phenanthridines can be obtained in a similar way <1998TL9785>. 54 Furans and Their Benzo Derivatives: Reactivity
SEt SOEt TFAA O CO2Me O Et3N CO2Me MeO N MeO N O O O MeO MeO SEt CO2Me p-TsOH O CO Me 2 MeO 66% N O MeO N MeO O MeO
Scheme 66
O O O O O O MeN MeN MeN
Cu(hfa)2 O H O O H N PhMe H MeO 2 MeO MeO reflux,12 h CO2Me CO2Me 52% CO2Me 211 O O MeN
H MeO
HO CO2Me 212
Scheme 67
A more structurally intriguing furanophane 216 was obtained by Herndon, who utilized an [8þ2] cycloaddition of dienylbenzo[c]furan 215 and DMAD (Scheme 68). The dienylbenzo[c]furan, in turn, was generated from a reaction between alkynylbenzophenone 213 and an alkenyl chromium carbene 214 <2003JA12720>.
OMe OMe Bu Bu Bu
Cr(CO)5 DMAD H O + MeO O O dioxane CO Me 85 °C, 1 h 2 Ph Ph Ph 76% CO2Me
213 214 215 216
Scheme 68 Furans and Their Benzo Derivatives: Reactivity 55
A similar one-pot synthesis as can be seen in Scheme 69 led to the formation of isoquinolines after spontaneous deoxygenation <2003OL4261>.
Me2N NMe2 H Bu H Bu Bu (CO) Cr 5 H
Me2N + O H PhMe H N CHO NC N H 100 °C 59%
Scheme 69
The syntheses of several nonbenzenoid and heterocyclic benzo[c]furans were reported in 1996–2005. These heterocycles undergo similar cycloaddition reactions as their benzenoid analogs. These molecules are: 217 <1996JOC6166>, 218 <1996H(43)1165>, 219 <1998H(48)853, 1998JOC7680>, 220 <1999TL397>, 221 <2003JOC6919>, 222 <2003AJC811>, 223 <1997HCA2520, 2005HCA1250>, 224 and 225 <2003OBC2383>.
SEt Me OR1 OMe R2 1 N R O N O Me O O N S O S 2 1 3 Ph CO2R CO2Me R R 217 218 219 220 1 R1 = R2 = R3 = H R = Me, Ph, -(CH2)3C CH, -(CH2)3C CCO2Me 2 R1 = H; R2 = R3 = Me R = Me, -CH2C CH 1 2 i 3 R = H; R = NPr 2; R = H 1 2 3 R = R = H; R = NEt2 1 2 3 R = H; R = CO2Me; R = NEt2 1 2 3 R = Cl; R = CO2Me; R = NEt2
SPh Cl N O OHC O O N N O Cl Cl N
N O R
221 222 223 224 225 R = H R = Me R = OMe
An appropriate example to show the reactivity of a nonbenzenoid benzo[c]furan is the realization of a fused carbazole 228 from maleic anhydride and benzo[c]furan 227, which was generated from sulfoxide 226 through a Pummerer reaction as shown in Scheme 70 <1996JOC6166>. 56 Furans and Their Benzo Derivatives: Reactivity
O O EtS O EtS O SOEt O O Ac2O O CHO N p-TsOH N N 78% PhSO2 PhSO2 PhSO2 226 227 228
Scheme 70
3.06.2.3.2 Miscellaneous reactions 1,3-Dithienylbenzo[c]furan 229 was converted to benzo[c]selenophene 230 on interaction with Woollins reagent at room temperature, as can be seen in Equation (117) <2005TL7201>.
S S Woollins reagent (0.25 equiv) O Se 117 CH2Cl2 ð Þ 67% S S
229 230
3.06.3 Reactivity of Nonconjugated Rings 3.06.3.1 Reactivity of Dihydrofurans and Tetrahydrofurans 3.06.3.1.1 Reactions of 2,3-dihydrofurans and 2,5-dihydrofurans As depicted in Equation (118), the regioselective addition of an active methylene compound to 2,3-dihydrofuran was
promoted by catalytic amounts of AuCl3–AgOTf, providing a 2-substituted THF as the product <2005OL673>.
OO OO AuCl3−AgOTf Ph Ph + Ph Ph ð118Þ CH Cl O 2 2 O rt 58%
Palladium-catalyzed regioselective hydroamination of 2,3-dihydrofuran under ligand-free and neutral conditions was found to be general with secondary alkyl amines, as exemplified in Equation (119) <2001T5445>.
K2Pd(SCN)4 + HN O N ° O ð119Þ O 20 C, 12 h O 91%
Palladium-catalyzed enantioselective Heck reaction of 2,3-dihydrofuran to provide 2-substituted-2,5-dihydrofurans was achieved by using the chiral phosphinooxazoline ligand 231, as shown in Equation (120) <1996AGE200>. Analogous chiral phosphinooxazoline ligands 232 <2001OL161>, 233 <2003CEJ3073>, 234 <2004SL106>, as well as phosphite-oxazoline 235 <2005OL5597> were also effective for this reaction. This Heck coupling, in contrast to that using 2,2-bis(diphenyl-phosphanyl)-1,1-binaphthyl (BINAP) to obtain 2-substituted-2,3-dihydrofuran isomers, was reviewed <1997S1338, 2004S1879>. As indicated in Equation (121), a transient intermediate 236 that was probably formed by a double dyotropic rearrangement of the initial Pd arylation adduct for the BINAP–palladium- catalyzed reaction was characterized spectroscopically at low temperature <2001HCA3043, 1997AGE984>. Furans and Their Benzo Derivatives: Reactivity 57
Pd(dba)2(3 mol%) 231 (6 mol%) O TfO i Pr NEt2 + N C H O ð120Þ O 6 6 Ph2P ° 30 C, 72 h 231 92% >99% ee
O O O Ph Ph O N O O
S O P O N Me SiOO SiMe Ph P PPh 3 3 2 N 2 Fe N
P(3,5-(CF3)2C6H3)2 PPh2
232 233 234 235
Ph PPh 2 O + Pd –OTf Ph O ð121Þ O PPh2
236 As represented in Equation (122), a rhodium-catalyzed hydroformylation of 2,3- and 2,5-dihydrofuran using furanoside-derived chiral diphosphite ligands, for example, 237, provided 3-formyltetrahydrofuran as the major product with ee up to 75% <2005CC1221>.
OPL* But But CO/H2 Rh(acac)(CO) O 2 O OPL* 237 O O L* = O ð122Þ 45 °C, 24 h O O 98% conversion CHO 74% ee But But 237
Platinum-catalyzed cyclization of a 2,3-dihydrofuran to the tethered alkyne provided the fused tricyclic compound 238, as shown in Scheme 71. Acid-promoted benzannulation of 238 then produced the dihydrobenzofuran, presumably via a retro-hetero-Diels–Alder opening of the dihydropyran ring <2004OL3191>.
H
PtCl2 (5 mol%) p-TsOH O O PhMe PhMe O O O Ph 50 °C, 24 h 70–110 °C Ph Ph 58% 2–30 min 238 95%
Scheme 71 58 Furans and Their Benzo Derivatives: Reactivity
Enantioselective [3þ2] cycloaddition between 2,3-dihydrofuran and 1,4-benzoquinones was performed using the oxazaborolidinium catalyst. As shown in Equation (123), reaction of unsymmetrical 1,4-benzoquinones gave a mixture
of two regioisomers. This methodology was applied to a concise total synthesis of aflatoxin B2 <2005JA11958>.A Do¨tz benzannulation involving a dihydrofuran containing chromium carbene complex and an alkyne was also
employed to form the aflatoxin B2 skeleton regioselectively <2006TL2299>. As depicted in Equation (124), annulated product 239 was the only regioisomer obtained. Ph H Ph
+ N B – H Tf2N OH OH O MeO ð123Þ MeO (20 mol%) H H + + MeO CH2Cl2−MeCN (1:1) O O O −78 °C, 2 h (1.5 equiv) O H O O −78 to 23 °C, 5 h H 65% 32% 92% ee 90% ee
t OSiBu Me2 t (CO)5Cr OSiBu Me2 HO OMe H OEt + H OEt ð124Þ O THF OMe 80 °C, 2 h O O H 31% O H 239 An example of enantioselective 1,3-dipolar cycloaddition of ethyl diazopyruvate to 2,3-dihydrofuran, catalyzed by a chiral ruthenium-PyBox complex, to provide a tetrahydrofurofuran was reported (Equation 125). However, the adduct 240 was only obtained in 74% ee, and its absolute configuration not determined <2004SL2573, 2005HCA1010>.As shown in Equation (126), 2,3-dihydrofuran also participated in 1,3-dipolar cycloaddition with dipoles derived from
aziridines under Sc(OTf)3-catalyzed conditions, forming cis-fused furopyrrolidines <2001TL9089>.
O N O N N Pri Pri PyBox O ð125Þ O RuCl2(p-cymene) OO EtO C + EtO2C 2 PhMe N 2 0 °C 240 68% 74% ee
H Sc(OTf)3 (3 mol%) + ð126Þ N O CH2Cl2 N O Ts Ts 0 °C, 1.5 h H 72% dr = 50:50 Furans and Their Benzo Derivatives: Reactivity 59
2,3-Dihydrofuran participated in Pauson–Khand reaction with alkyne–dicobalt complexes, giving furocyclopente- nones regioselectively <2001JOM104>. An example of employing this reaction as a starting point for a total synthesis of terpestacin is shown in Equation (127) <2003JA11514>.
SiMe O 3 H O NMO O + Co (CO) SiMe 2 6 3 ð127Þ CH2Cl2 51% H dr > 95:5
An interesting example of triple electrophilic aromatic substitution between a dihydrofuran derivative and phloroglu- cinol was exploited for the total synthesis of the C3-symmetric xyloketal A, as shown in Equation (128) <2006OL1427>.
O
OH BF •Et O O HO 3 2 H H MgSO4 + Et O O HO OH 2 O O O ð128Þ −78 °C,20 min 79% O H Xyloketal A
dr = 80:20
Two equivalents of 2,3-dihydrofuran, that served as two different reaction components, were coupled to anilines to form cis-fused furotetrahydroquinolines by using catalytic amounts of Dy(OTf)3 <2001TL7935> and InCl3 in water <2002JOC3969>, as illustrated in Scheme 72. Similar reactions making use of Sc(OTf)3 in 1-butyl-3-methylimida- zolium hexafluorophosphate were also reported <2002S2537>. The isolation of a furo[2,3-b]oxepin side product 242
<2001TL7935>, which was the major product obtained in the InCl3-catalyzed coupling between 2,3-dihydrofuran and 2-methylindoles <2003TL2221>, suggested a stepwise pathway involving an oxonium intermediate 241 for the second reaction. InCl3 in water catalyzed the hydration of dihydrofuran to the corresponding lactol, which was the first reactive species in the reactions described above and also in an indium-promoted allylation with various allylic bromides to provide allylated 1,4-diols <2004SL829>.
O InCl3 (cat.) Cl Cl O H2O + 45 °C, 10 h OH NH N 2 77% H cis:trans = 74:26
Dy(OTf)3 (5 mol%) MeCN 4 °C, 48 h 81% cis:trans = 76:24
+ O O H Cl Cl O H H 10% OH N N H H 241 242
Scheme 72 60 Furans and Their Benzo Derivatives: Reactivity
Dihydrofuran was used as a ketone equivalent in a Fischer-type indole synthesis with an aryl hydrazine under strongly acidic conditions to give a tryptophol. As shown in Equation (129), 5-methyl-2,3-dihydrofuran gave rise to 2-methyltryptophol regioselectively <2004OL79>.
OH
O 4% H2SO4 + ð129Þ NH2 MeCONMe N 2 N H 100 °C H 80%
Coupling of 2,3-dihydrofuran with alkene–zirconocene <2004AGE3932> or aryne–zirconocene <2005SL2513> complexes and subsequent addition of an electrophile provided cis-disubstituted homoallylic alcohols, as illustrated in Equation (130). An insertion/ -elimination pathway that involved the formation of an oxazirconacyclooctene inter- mediate was proposed for the reaction mechanism.
I Et i, THF O –78 to 25 °C OH + Cp2Zr Et ð130Þ ii, I2 –20 to 25 °C, 1 h 75%
The dyotropic rearrangement of lithiodihydrofuran-derived dihydrofuranyl cuprate followed by electrophilic addition was further extended to the stereoselective preparation of differentially functionalized 1,1-disubstituted alkenes, as illustrated in Scheme 73 <2003SL955, 2003S2530>. This method was applied to the elaborated dihydrofuran 243 for the synthesis of the C-10–C-15 segment of tylosin II <1996SL1125, 1996T6613>, as depicted in Equation (131), as well as to the synthesis of the C(12)–C(15) segment of apoptolidin <2005T401>.
i, (Me3Si)2CuCNLi2 HO HO THF−Et2O (1:1) –5 °C, 1.5 h I2
Li n O ii, Bu 3SnCl CH2Cl2 n –40 to 20 °C, 5 h SiMe 0 °C Bu 3Sn 3 I SiMe3 87% 91%
Scheme 73
i, ButLi THF
–60 to −5 °C, 1 h SiMe ii, (Me3SiCHCH)2CuCNLi2 3 HO THF−Et O (1:1) 2 ð131Þ –10 to −5 °C, 2 h
O iii, MeI HO –60 to 20 °C, 4 h 243 76% OH
As shown in Equation (132), dihydrofurans having a 3-acetyl group underwent benzannulation via photoinduced cleavage of the dihydrofuran ring to give naphthalene products <2001TL3351>. Helicene-type compounds and benzo[kl]xanthenes were also produced by this method <2005TL7303>. Furans and Their Benzo Derivatives: Reactivity 61
O Cl Cl hν O 2 M HCl ð132Þ MeCN O argon 23 °C, 3 h Cl 96% Cl
The diastereoselective and enantioselective [2þ2] cycloaddition of a 7-oxanorbornene with a chiral alkynyl acyl sultam was effected by using a ruthenium catalyst to provide the exo-cycloadduct as shown in Equation (133) <2004AGE610>.
Xc O O O O MeO MeO CpRuCl(COD) Xc MeO + MeO THF Ph Ph 25 °C, 168 h dr = 97:3 73% 95% ee ð133Þ
Xc = N
S O O
As demonstrated in Equation (134), a tandem ring opening/cross metathesis of endo-2-tosyl-7-oxanorbornene with vinyl ether or vinyl acetate as catalyzed by Grubbs’ second generation catalyst 244 afforded a 2,5-disubstituted THF as a single regioisomer. The same regioselectivity was obtained from the reaction of the 2-exo-isomer. 2-Carboxylate and benzoxymethyl groups could also exert a similar directing effect on this reaction as the tosyl group <2004OL1625, 2005OL131>. However, opposite regioselectivity (viz. the formation of 245 and 246) was observed with an acetate substituent (Equation 135) <1999JOC9739, 2000TL9777>. These reactions were reviewed <2003EJO611>.
N N OEt Mes Mes O Ts 244 (6 mol%) Cl EtO Ru Cl Ph ð134Þ CHCl3 O PCy3 Ts 55 °C, 4 h 94% 244
E : Z = 55 : 45 Grubbs’ catalyst
i, 244 (5 mol%)
CH2Cl2 rt, 2 h O AcO 75% + OAc R1 R2 ð135Þ ii, H2 (50 Psi) O OAc 10% Pd/C 1 2 245: R = Et; R = (CH2)3OAc MeOH 1 2 246: R = (CH2)3OAc; R = Et 245:246 = 81:19 75% 62 Furans and Their Benzo Derivatives: Reactivity
The tandem ring-opening/ring-closing metathesis of 7-oxanorbornene derivatives as catalyzed by Grubbs’ catalyst 244 was applied to synthesize a key bicyclic cyclopentenone intermediate in a total synthesis of trans-kumausyne <2005OL3493>, bicyclic seven- and eight-membered sulfonamides <2006TL189>, a seven-membered ring in a spirotricyclic -lactam <2005HCA1387>, and the 9-oxabicyclo[4.2.1]nona-2,4-diene of mycoepoxydiene <2004JOC8789>. Equation (136) depicts an interesting example of this type of reaction in which the formation of new six-, seven-, and eight-membered rings in the polycyclic product was achieved in a single step, although a stoichiometric amount of the catalyst was used <2004OL3821>.
O O O O 244 (1 equiv) ° TsN ð136Þ O TsN BocN 25 C to reflux, 24 h BocN O 10% O O
(0.5 mM in CH2Cl2)
The synthetic applications of 8-oxabicyclo[3.2.1]oct-6-en-3-ones as polyoxygenated building blocks were reviewed <2004AGE1934>. The reactivity of 8-oxabicyclo[3.2.1]octane toward the inter- and intramolecular ring-opening/ ring-closing metathesis could be modulated by substitution on the ring <2001OL4275, 2002AGE4560>. For example, the intramolecular formation of a spiro-seven-membered ring, as shown in Equation (137), was more effective in the substrate 247 that has an endo-hydroxyl group than in substrate 248 which has a keto group.
2 1 R2 R1 R R 244 O CH Cl 2 2 O ð137Þ
1 t 2 247: R = OSBu Me2; R = H (80%) 1 2 248: R = R = O (<15%)
3.06.3.1.2 Reactions of tetrahydrofurans It was found that the THF -radical was readily generated from THF by dimethylzinc and air. The THF -radical added to aldimines at room temperature to form threo THF-substituted benzylamine derivatives as major isomers <2002OL3509>. It was less reactive toward aldehydes, although reaction with aldehydes was made possible at 50 C to give -hydroxylated -substituted THFs, which were isolated as the keto-lactones in modest yields after Jones oxidation (Scheme 74). The initially generated THF -radical probably reacted with molecular oxygen to generate an -peroxygenated THF -radical as the key intermediate <2004TL795>. Generation of a THF oxonium ion by the oxidation of the initially formed THF -radical was proposed to account for the 4-tetrahydrofuranyl-4-aminobu- tanols obtained in the reaction of two THF molecules with anilines at room temperature under the dimethylzinc/air conditions, as indicated in Equation (138) <2005T379>.
CrO Me2Zn (12 equiv) OH OH 3 O O O air H2SO4 + O Ph O Ph O Ph H THF acetone ° 50 °C, 2 d 0 C,15 min 54%
Scheme 74
NH2 Me2Zn (12 equiv) air Cl O + O ð138Þ rt, 20 h OH N 87% Cl H Furans and Their Benzo Derivatives: Reactivity 63
Triethylborane together with air <1999CC1745> or tert-butylhydroperoxide <2003JOC625> also generated the THF -radical from THF at room temperature, and promoted its addition to aldehydes to provide the threo-adducts as the major isomers. This method was applied to the synthesis of the cytotoxin muricatacin <2003JOC7548>.As demonstrated in Equation (139), chemoselective addition of THF -radical to an aldimine or an aldehyde could therefore be achieved in a three-component reaction system, depending on the radical initiator used <2003OL1797>.
O O air O H2N + + O + Ph H rt Ph N OMe H Ph OH ð139Þ OMe
Me2Zn (12 equiv), 21 h 74% 0% Et3B (12 equiv), 16 h 10% 75%
Addition of the THF -radical, generated by using triethylborane or benzoyl peroxide, to styrylsulfimides produced 2-styryltetrahydrofurans <1996TL909>. As exemplified in Equation (140), THF was coupled to a variety of aryl- and alkyl-substituted terminal alkynes under microwave irradiation to provide a mixture of cis- and trans-2- vinyltetrahydrofurans <2004TL7581>. It was proposed that the THF -radical was the reactive species that was generated by oxygen under the microwave conditions.
alkyne/THF (1:200) microwave 300 W + OH ð140Þ OH ° O 200 C, 40 min O 56% cis:trans = 31:69
Tetrahydrofuranyl ethers, which served as hydroxyl protecting groups, were prepared from the reaction between
THF and alcohols via the THF -radical by using CrCl2/CCl4 <2000OL485>, or BrCCl3/2,4,6-collidine <2000TL6249>,or1-tert-butylperoxy-1,2-benziodoxol-3(1H)-one/CCl4 <2004TL3557>. THF ethers can also be formed by the reaction of alcohols with THF using (diacetoxyiodo)benzene under microwave irradiation <2004SL2291>. The sole example of a reaction with a hindered tertiary alcohol <2000OL485> under these newly developed conditions is shown in Equation (141).
CrCl2 CCl O OH 4 O ð141Þ + O 47% solvent
The hydroxylation at the C-2 position of THF to form lactol by iodosylbenzene in the presence of an Mn(III)–salen complex was reported <1997SL836>. Selective oxidation of the C-3 methylene carbon of the tetrahydrofuran moiety over the C-7 methylene carbon of the bicyclic ketal of buergerinin F to form its lactone analog, buergerinin G, was performed by using ruthenium tetroxide (Equation 142) <2003JOC4117>. An unusual oxidation of hexahydroben- zofuran-3a-ol using a catalytic amount of in situ-generated RuO4 provided nine-membered keto-lactones as shown in Equation (143). The usual regioselectivity in RuO4-promoted oxidation of ethers was reversed in this example, with the tertiary C-7a proton oxidized selectively over the secondary C-2 proton <2003OL1337>.
RuCl3 O NaIO4 3 O NaHCO3 O O O ð142Þ O H2O−CCl4−MeCN (1:1:1) O 7 rt, 22 h Buergerinin F Buergerinin G 77% 64 Furans and Their Benzo Derivatives: Reactivity
OH RuCl3 (2.4 mol%) O NaIO4 (4.1 equiv) 2 H O−CCl −MeCN (3:2:2) ð143Þ 7a O 2 4 O rt, 75 min O 81%
Similar regioselective hydroxylation of the C-16 tertiary -carbon of the tetrahydrofuran moiety in cephalostatin-
related steroids could also be achieved with retention of configuration by in situ-generated dioxoperoxy CrO4 (from a mixture of CrO3 and n-Bu4NIO4). Notably, alkenes and iodides were unaffected under these conditions <2004OL1437>. A remarkable example, as shown in Equation (144), is the preferential oxidation by this Cr(VI) oxidant at C-16 of the bis-THF containing substrate 249 to provide 250 as the major product.
CrO3 (3 equiv) n Bu 4NIO4 (3 equiv) O O AcO AcO O O Cr ð144Þ O O O 16 O OH MeCN−CH2Cl2 (3:1) AcO −40 °C, 10 min AcO 249 250 62%
Bicyclo[3.n.0]oxonium ions derived from THFs could produce either ring expansion, ring-switched, or non-rear- ranged products in the presence of protic nucleophiles <1996J(P1)413>. Tetrahydrofurfuryl monochlorates under-
went a Zn(OAc)2-induced regio- and stereoselective 1,2-rearrangement/ring expansion via bicyclo[3.1.0]oxonium ions to provide tetrahydropyrans <1999TL2145>. Extension of this methodology to a novel stereoselective and stereo- specific 1,4-rearrangement/ring expansion of 251 via bicyclo[3.3.0]oxonium ions 252 to form oxocanes 253 and 254 is depicted in Scheme 75 <2002OL675>. Related methodology in which the THF oxygen atom trapped a dico- balthexacarbonyl-stabilized cation to generate the bicyclo[3.3.0]oxonium and bicyclo[3.4.0]oxonium ions for the formation of oxocane and oxonane (Scheme 76) respectively was also developed <2000T2203>. Ring expansion
of 2-(iodomethyl)tetrahydrofurans by p-iodotoluene difluoride/Et3N–HF to give 3-fluorotetrahydropyrans also involved bicyclo[3.1.0]oxonium intermediates (Scheme 77) <2003TL4117>.
OH
i, ClSO2CH2Cl O 2,6-lutidine 253 CH Cl 2 2 H + H2O 0 °C O OH ii, 1:1 THF−H O O O OH 2 + rt, 22 h 254 82% +
251 253:254:251 = 85:8:7 252 O OH 251
Scheme 75 Furans and Their Benzo Derivatives: Reactivity 65
SiMe3 SiMe SiMe MsCl 3 3 + Et3N
O CH2Cl2 O O + OH rt
Co2(CO)6 Co2(CO)6 Co2(CO)6
Ph Ph Ph
CAN
O MeOH rt O 52% Co2(CO)6
Ph Ph
Scheme 76
p-Tol-IF2 Et N–5HF + Ph O Ph O 3 O Ph H I CH Cl 2 2 F rt 66%
Scheme 77
As shown in Scheme 78, the transient bicyclo[3.3.0]oxonium ylide 255 that was generated from a THF-substituted diazoketone was first protonated by acetic acid to the corresponding bicyclo[3.3.0]oxonium ion, which then provided the ring expansion product <1996CC1077>. In the presence of the weakly acidic MeOH, the ylide underwent a concerted [3þ2] cycloreversion to a ketene intermediate to form the ring cleavage product <2004JOC1331>.
OAc
HOAc O >90% O Rh2(OAc)4 O O N2 O O CH Cl O O 2 2 – MeOH rt + OMe 255 84%
Scheme 78
Transient oxonium ions could be generated from 2-tetrahydrofuranylsilanes <1996TL9119> and 2-tetrahydrofur- anylstannanes <2006TL3607> by oxidation with cerium ammonium nitrate. Intramolecular capture of the cations by the hydroxyl group provided furo[2,3-b]pyrans, as depicted in Equation (145).
O O
MeO2C CAN (2 equiv) MeO2C OH ð145Þ MeCN n ° O O SnBu 3 20 C O 54% H 66 Furans and Their Benzo Derivatives: Reactivity
As illustrated in Equation (146), the C-2 hydrogen of 2-substituted THFs was found to undergo 1,5-hydride migration to pendant electron-deficient alkenes <2005JA12180> and aldehydes <2005OL5429> under Lewis acid- promoted conditions, providing spiro-carbocycles and spiro-ketals, respectively, after subsequent cyclization. Such a transformation occurred with 2-tetrahydrofuranylstannane 256 and in the absence of the Thorpe–Ingold effect, as shown in Equation (147) <2006TL3607>.
CO2Et CO2Et Sc(OTf) (5 mol%) 3 CO2Et O CO2Et O ð146Þ CH2Cl2 MeO C 2 CO Me rt, <1 h 2 MeO CCOMe 2 2 96%
Ph Ph MeO C 2 CHO MeO2C BF3•Et2O ð147Þ n CH Cl O SnBu 3 2 2 O O 20 °C n 256 SnBu 3 32%
Regioselective acylative cleavage of 2-methyltetrahydrofuran to 4-halopentanoates could be achieved by using bismuth(III) halides as catalyst <2005T4447>. This methodology was applied to the synthesis of a tetralin, as shown in Equation (148).
AcCl
BiCl3 ð148Þ O 87% AcO
As illustrated in Equation (149), 2-alkyne-substituted THFs could be ring-opened via intramolecular transfer
hydrogenation using TpRuPPh3(MeCN)2PF6 (Tp ¼ tris(1-pyrazolyl)borate) as a catalyst to provide dienyl ketones <2004JOC4692>.
H H O TpRuPPh (MeCN) PF (10 mol%) Ph O 3 2 6 Ph ClCH2CH2Cl ð149Þ 80 °C, 12 h 93%
3.06.3.2 Reactivity of Dihydrobenzo[b]furans
The chemistry of 2,3-dihydrobenzo[b]furan 257 discussed herein is focused on the furan part, rather than on the phenyl part, where its chemistry is similar to that of benzenoid molecules. For the chemistry based on the furan part,
the frequent reports are related to the C–O bond cleavage. For example, by using an electron-rich ligand-based PCy3/ Ni(acac)2 as a catalyst, 2,3-dihydrobenzo[b]furan 257 was employed to couple aryl group to afford biaryl compounds, as can be seen in Equation (150) <2004AGE2428>.
NiCl2PCy3 p-TolMgBr OH ð150Þ O i-Pr2O ° 257 60 C, 15 h 62%
As shown in Equation (151), in the presence of a catalytic amount of BF3, 2,3-dihydrobenzo[b]furan 257 was converted to its corresponding phenol iodide by treatment with SiCl4/LiI <2004TL3729>. o-2-Bromoethylphenol Furans and Their Benzo Derivatives: Reactivity 67 was also obtained by reaction of 2,3-dihydrobenzo[b]furan 257 using the high nucleophilicity of bromide ion in an ionic liquid, 1-n-butyl-3-methyl-imidazolium bromide ([bmim][Br], although the yield is low at 40% <2004JOC3340>.
SiCl4 LiI I BF3 ð151Þ MeCN O OH 70 °C, 45 min 257 90%
The DTBB-catalyzed lithiation of 2,3-dihydrobenzo[b]furan 257 in THF at 20 C led to a suspension, which, after filtration of the excess of lithium, gave a solution of the corresponding functionalized organolithium compound. This intermediate was treated with zinc bromide (1:1 molar ratio), and then the generated organozinc reagent was successfully coupled with aryl bromide by the palladium-catalyzed Negishi reaction to yield the expected coupling product (Equation 152) <2002EJO1989, 2001TL5721>. The reaction of the organolithium compound derived from 2,3-dihydrobenzo[b]furan 257 with a variety of electrophiles was also reported <2002T4907, 1998TL7759>.
i–iv Ar
O OH ð152Þ 257 ° ° i, Li, DTBB, THF, 20 C; ii, ZnBr2, THF, 20 C; iii, ArBr, Pd(PPh3)4, ° THF, 70 C; iv, HCl–H2O
2,3-Dihydrobenzo[b]furan was reported to be reductively cleaved by treatment with hydrosilanes in the presence of catalytic amounts of B(C6F5)3 in high yield, as depicted in Equation (153) <2000JOC6179>.
HSiEt3 OH B(C6F5)3
CH Cl ð153Þ O 2 2 rt, 20 h 257 99%
3.06.3.3 Reactivity of Dihydrobenzo[c]furans
The thermal reactions of dihydrobenzo[c]furan 258 were studied behind reflected shock waves in a single pulse shock tube over the temperature range 1050–1300 K to lead to products from a unimolecular cleavage of 258 <2001PCA3148>. Intriguingly, carbon monoxide and toluene were among the products of the highest concentration, while benzo[c]furan, benzene, ethylbenzene, styrene, ethylene, methane, and acetylene were the other products. Trace amounts of allene and propyne were also detected.
O
258
As depicted in Scheme 79, reductive ring opening of 258 using a small excess of Li and a substoichiometric amount of DTBB led to the organolithium species 259, which was quenched by the electrophile (–)-menthone to give diol 260 in 76% yield <2004S1115>. In a similar manner, lithiation reactions catalyzed by linear and cross-linked arene-based polymers generated the same organolithium species 259 that reacted with electrophiles such as 3-pentanone, cyclohexanone, tert-pentanal, benzaldehyde, and acetophenone to give diols of diversified structures <2004RJOC795>. 68 Furans and Their Benzo Derivatives: Reactivity
Li Li O
DTBB (3%) i, –78 to –20 °C O OLi OH THF ii, H2O 0 °C, 6 h –20 °C OH 258 259 76% 260
Scheme 79
Exhaustive cleavage of the carbon–silicon bond followed by treatment with an acid converted the complex benzo[c]furan 261 to phenol 262, as illustrated in Equation (154) <2003JA12994>. Villeneuve and Tam were able to interrupt this phenol formation by choosing Cp*Ru(COD)Cl as the catalyst. Thus, the reaction of 1,4-epoxy-1,4- dihydronaphthalene 263 with a ruthenium catalyst in 1,2-dichloroethane at 60 C afforded the 1,2-naphthalene oxide 264 (Equation 155) <2006JA3514>.
OBn OBn OBn OBn O SiMe2 MeO OH i, n-Bu4NF Cl Cl O DMF O O H H OBn ii, TFA OBn ð154Þ H CH Cl H MeO 2 2 MeO O 0 °C to rt O 72% OMe OMe MeO OMe MeO OMe 261 262
O O Cp*Ru(COD)Cl (5 mol%)
ClCH2CH2Cl ð155Þ CO2Et CO2Et 60 °C, 2 h 26382% 264
Another way in which 1,4-epoxy-1,4-dihydronaphthalenes can react is via the deoxygenation reaction to form naphthalenes. For example, as shown in Equation (156), when 265 was allowed to react with 10 equiv of a commercially available Grignard reagent in refluxing THF, naphthalene 266 was obtained <1997TL4761>.
Me Me PhMgBr O ð156Þ THF 265reflux, 2 h 266 75%
Ring opening of 1,4-epoxy-1,4-dihydronaphthalenes in general follows an exo-SN29 or SN29-like mechanism, leading to cis-alcohols. A review summarizing these conversions appeared in 1996 <1996S669>. An example depict- ing this transformation is shown in Equation (157) <2004OL3581>. Cheng also made use of nickel-catalyzed reactions to open 1,4-epoxy-1,4-dihydronaphthalenes by alkynyl <2002OL1679> and alkenyl groups <2004JOC8407>. Butyllithium was also used to open 1,4,5,8-diepoxy-1,4,5,8-tetrahydroanthracenes to give similar ring-opening products <1998H(47)977>. Most interestingly, an efficient ring closure of 2-iodophenoxyallene 267 catalyzed by palladium(0), followed by ring opening of 1,4-epoxy-1,4-dihydronaphthalene 268, led to the formation of 2-benzofuran-3-ylmethyl-1,2-dihydro-1-naphthalenol 269 in very good yield (Equation 158) <2006OL621>. Furans and Their Benzo Derivatives: Reactivity 69
O O
OMe Me OMe OH Me I O Pd(OAc)2 (5 mol%) ð157Þ PPh (11 mol%) OMe 3 OMe PMP (0.5 equiv)
Zn (10 equiv) DMF 95%
O
OH PdCl2(PPh3)2 • O Zn ð158Þ + O I THF 80 °C, 16 h 267 26885% 269
Enantioselective ring opening of 1,4-epoxy-1,4-dihydronaphthalene remains a very active research area because the use of chiral catalysts to control the absolute stereochemistry of products could lead to optically active building blocks that can be employed in the quest for complex bioactive molecules. Lautens reported in 1997 that the oxygen bridge of 268 can be reductively opened, utilizing Ni(COD)2 as a catalyst and (R)-BINAP as a ligand to give alcohol 270 in good chemical and optical yields as depicted in Equation (159) <1997JOC5246, 1998T1107>.
Ni(COD)2 (14 mol%) (R)-BINAP (21 mol%) O THF ð159Þ 2 h HO 88% 268 270 98% ee
Nickel- or palladium-catalyzed asymmetric reductive ring opening of 268 and its derivatives with organic acids and zinc powder under mild conditions also led to the formation of alcohols such as 270, as shown in Equation (160) <2003OL1621>.
Pd(binap)Cl2 (5 mol%) Zn O (CH3CH2CH2)2CHCO2H ð160Þ PhMe HO 268 2 h 270 89% 90% ee
It is also known that the formation of trans-alcohols through a rhodium-catalyzed ring opening of 1,4-epoxy-1,4- dihydronaphthalenes by amines can be achieved <2003CCL697>. This transformation is believed to involve the formation of a new carbon–nitrogen bond via an intermolecular highly regioselective allylic displacement of the bridgehead oxygen with a piperazine derivative. Another example for the formation of the trans-1,2-diol derivative 271 was reported by Lautens and co-workers <2000OL1677, 2001T5067, 2001JOM259, 2002JOC8043, 2004PNAS5455>, who treated 268 with a rhodium catalyst in the presence of phenols or carboxylates as nucleo- t philes, and (R)-(S)-PPF-PBu 2 and other chiral ferrocenes as ligands. Good yields and high enantioselectivities were obtained, as can be seen in the example shown in Equation (161). Copper-catalyzed enantioselective ring opening of 70 Furans and Their Benzo Derivatives: Reactivity
268 and its derivatives by dialkylzinc or Grignard reagents to form trans-alcohols was also reported by Feringa <2002OL2703> and Zhou <2005JOC3734>, making use of phosphoramidite catalysts 272 and 273, respectively. Salzer <2005JOM1166> also reported the optimized synthesis of a trans-alcohol in 59% yield and 97.5% ee using a rhodium-catalyzed reaction in the presence of the ‘Daniphos’-ligand 274. The formation of trans-alcohols can be explained by a rhodium-catalyzed mechanism, as outlined in Scheme 80 <2004PNAS5455>.
t PBu 2 [Rh(COD)Cl]2 (0.5 mol%) t Br (R)-(S)-PPF-PBu 2 (1 mol%) PPh2 O Fe p-Br-C6H4OH O ð161Þ THF HO 80 °C t 268 271 (R)-(S)-PPF-PBu 2 94% 98% ee
Ph N Ph P Ph O O O PN O Ph P PBut Ph 2 2 (CO)3Cr H Me
272 273 274
Cl L2*Rh RhL2* Cl O
OR Solvent OH L2*Rh Cl
L2* ⊕ Cl H Rh Cl O O RhL2*
– OR Cl RhL * – O 2 RO
ROH
Scheme 80
Rhodium-catalyzed nucleophilic ring opening of 1,4-epoxy-dihydronaphthalenes to form amino-alcohols was reported by Lautens <2002JOC8043>. An enantioselective rhodium-catalyzed version of this approach was recorded <2003JA14884> in which 268 was converted to an amino-alcohol 275, as illustrated in Equation (162). Biaryl and binaphthyl monodentate and bidentate catalysts have also been shown by Pregosin to provide similar results <2004OM2295>. Furans and Their Benzo Derivatives: Reactivity 71
[Rh(COD)Cl]2 (0.5 mol%) t PPF-PBu 2 (1.5 mol%) Me OH N AgOTf (1.5 mol%) N n-Bu4NI (2 mol%) O ð162Þ N-methylpiperazine 268 THF 275 80 °C 99% ee 96%
Sulfur nucleophiles are also able to afford 2-sulfanyl-1,2-dihydronaphthalen-1-ols such as 276 via rhodium catalyzed asymmetric ring-opening reactions, as shown in Equation (163) <2004JOC2194>.
[Rh(COD)Cl]2 (2.5 mol%) t (R)-(S)-PPF-PBu 2 (6 mol%) OH AgOTf (7 mol%) S NH4I (1.5 equiv) O 2,6-Me2C6H3SH ð163Þ galvinoxy (5 mol%) 268 THF 276 reflux 98% ee 79%
Palladium-catalyzed enantioselective alkylative ring opening of 277 and analogous molecules, on the other hand, was reported to lead to cis-alcohols such as 278 in good yields and high enantioselectivities. An example is shown in Equation (164) <2000JA1804, 2004JA1437>. Mechanistic studies <2001JA6834> and effects of halide ligands and protic additives <2001JA7170> have all been studied. The mechanism of the palladium-catalyzed ring opening of 1,4-epoxy-1,4-dihydronaphthalene 268 with dialkylzinc to form cis-alcohols was proposed to go through a carbopalla- dation pathway, as depicted in Scheme 81 <2001JA6834>.
Pd(MeCN)2Cl2 (5 mol%) OH Et2Zn O (R)-Tol-BINAP O O ð164Þ O CH2Cl2 O 277 91% 278 92% ee
O
+ R2Zn 268 O ⊕ – R2Zn X carbopalladation PdL2 R2ZnX Cl2PdL2 L2Pd R R X = R or Cl X R Zn L Pd ⊕ 2 2 O – R PdL2 R2ZnX R R R R Zn 2 OPdL2X OZnR
Scheme 81 72 Furans and Their Benzo Derivatives: Reactivity
Carretero and co-workers reported a similar palladium-catalyzed approach with the use of a ferrocene ligand 279 but the products are of opposite absolute structures <2002CC2512>. The same group also reported that in the presence of a Grignard reagent, the copper-catalyzed ring opening reaction of 268 and its derivatives afforded trans-alcohols as major products. Scheme 82 shows a plausible mechanism. As can be seen, the results are consistent with a copper-catalyzed
endo SN29 attack of the organocuprate generated from a copper salt and a Grignard reagent, providing a trans-alcohol after a reductive elimination of the organocopper species and subsequent hydrolysis <2006S1205>.
SBut
PCy2 Fe
279
OMgX OMgX O CuR R R2Cu 2
2MgX2 268
Scheme 82
Lautens reported various limitations in rhodium-catalyzed cis-alcohol formation. As can be seen in Equation (165), the yield of 280 is only 16%, albeit with 96% ee <2003OL3695>. On the other hand, an identical reaction utilizing
Pd(dppp)Cl2 as a catalyst gave 280 in 82% yield but only with 71% ee (dppp ¼ 1,3-bis(diphenylphosphino)propane) <2003OL3695>.
B(OH)2 OH O O O [Rh(COD)Cl] (2.5 mol%) 2 165 t ð Þ (R)-(S)-PPF-PBu 2 (5 mol%) 268 280 Cs2CO3 (0.5 equiv) THF 96% ee 16%
3.06.4 Reactivity of Substituents Attached to Ring Carbons 3.06.4.1 Alkyl and Substituted Alkyl Substituents
Treatment of tri-2-furylmethane with n-BuLi resulted in the unanticipated formation of 1,1-bisfuryl-1-[5-(tri-2- furylmethyl)]furylmethane, as shown in Equation (166). Presumably, a tri-2-furylmethane anion was generated in preference to a 2-furyl anion. The same product could also be obtained using ButOK as the base <2004OL3513>.
BunLi TMEDA THF O O O –78 °C, 30 min 40% O ð166Þ O O or ButOK O THF O O rt, 30 min 50% Furans and Their Benzo Derivatives: Reactivity 73
Deprotonation of allyl furfuryl ethers by t-BuLi occurred at the -position, as shown in Equation (167), whereas deprotonation of the corresponding propargyl furfuryl ethers occurred at the 9-position (Equation 168). The resultant anions then underwent a [2,3]-Wittig rearrangement preferentially over a [1,2]-Wittig rearrangement, giving homoallylic alcohols and a propargyl alcohol, respectively <1999CC2263>.
ButLi O O α THF O ð167Þ −78 to −20 °C OH
58% syn:anti = 90:10
HO ButLi ð168Þ O THF O α′ −78 to −20 °C O 43%
The double bond of the side chain in the benzo[b]furan as shown in Equation (169) was oxidized to an epoxide employing m-chloroperbenzoic acid (MCPBA), while the other double bonds in the molecule remained intact <2006OBC1604>.
O O O O O MCPBA O
CH2Cl2 ð169Þ O O rt O 86%
As can be seen in Equation (170), the dienophilic reactivity of the double bond in 1,4-epoxy-1,4-dihydronaphtha- lenes can further be illustrated by its reaction with bisepoxide 281, leading to the formation of the structurally intriguing 282 and 283 in 34% and 44% yield, respectively <2001T571>.
O O E O O E sealed tube + O CF3 CH2Cl2 CF3 140 °C, 5 h E = CO Me 281 2 ð170Þ OOOOE O O O E O O + CF 3 E CF3 E CF3 CF3 O 282 283
A new phosphine-functionalized N-heterocyclic carbene ligand as shown in Equation (171) for palladium-catalyzed hydroarylation reaction on 268 led to the formation of an aryl substituted compound 284 <2006SL1193>.
NN+ – O Cl O Ph2P Ph ð171Þ
t PhI, Pd(OAc)2, KOBu , Et3N 268DMSO, 120 °C 284 69% 74 Furans and Their Benzo Derivatives: Reactivity
3.06.4.2 Carboxylic Acids and Their Reactions
The ester moiety of methyl 2-methoxy-4-furoates underwent the usual addition reaction with Grignard reagents to provide tertiary alcohols, as exemplified in Equation (172). However, displacement of the 2-methoxy group of the corresponding 3-furoate isomers occurred under the same reaction conditions, presumably via a six-membered organomagnesium chelate, to give 2-substituted-3-furoates as the major products (Equation 173) <2003TL5781>.
Et OH
MeO2C Et EtMgBr ð172Þ OMe Ph Ph O Et2O O OMe rt 90%
HO Et CO Me CO2Me 2 Et EtMgBr + ð173Þ OMe Et Ph Et2O Ph O Et O Ph O rt 70% 16%
Copper-mediated decarboxylation was observed to convert benzo[b]furan-2-carboxylic acid into its corresponding benzo[b]furan, albeit in low yield (Equation 174) <2002EJO1937>.
Me Me Me Me HO Cu HO COOH ð174Þ quinoline O N O O N O 2 25% 2
3.06.4.3 Acyl Substituents and Their Reactions
Furfural-derived 2-furylhydrazone underwent alkylated ring opening with phenyl Grignard reagents to produce dienal products, as shown in Equation (175). However, only reductive alkylation occurred with alkyl Grignard reagents (Equation 176) <2000TL2667>. Different elimination pathways of dinitrogen in the reaction intermediates, that is, [3,3]-sigmatropic rearrangement versus radical fragmentation, were probably responsible for the different products obtained.
MgBr O
NNHTs H + ð175Þ THF O MeO rt OMe 70%
NNHTs + MgBr O THF O ð176Þ rt 80%
2-Formyl and 2-acetylfuran underwent an unusual reaction with ethyl azodicarboxylate to form adducts 285 and 286, respectively, as depicted in Equation (177) <1997T9313, 1999J(P1)73>. Computational studies of the reaction suggested an initial Diels–Alder reaction between the furan and azodicarboxylate, followed by rearrangement of the cycloadducts. A similar transformation was observed for the reaction between furfurals and 1,4-phthalazinedione in
the presence of Pb(OAc)4, as shown in Equation (178) <2002OL773>. Furans and Their Benzo Derivatives: Reactivity 75
O CO2Et O R R N sealed tube CO2Et + N O N R = H, CH Cl , 100 °C, 1 d N ð177Þ O 2 2 ° CO Et CO2Et R = Me, CHCl3, 70 C, 9 d 2 285 (40%) 286 (35%)
O R O Pb(OAc) HN 4 N + CHO HN CH Cl N R O 2 2 ð178Þ rt, 30 min O HO2C O R = H, 64%
R = Me, 46%
Biologically interesting benzo[b]furyl quinoxalines were prepared by sequential oxidation and condensation (Scheme 83) <2004T6063>.
H2N Me Me
O Me SeO2 H2N N Me Ac O dioxane O CHO 56% O N
Scheme 83
Chou and co-workers discovered that flash vacuum pyrolysis (FVP) at 550 C and ca. 10 2 Torr converted 7-oxa-1- naphthonorbornenyl)methyl benzoate 287 to isonaphthofuran 288, which led to a mixture of 289, 290, and 291 in 48%, 9%, and 28% yield, respectively, as illustrated in Scheme 84 <1998TL7381>. The same treatment of (1-benzo[c]furanyl)methyl benzoate led to a similar result <1997T17115>.
3.06.4.4 Heteroatom-Linked Substituents and Their Reactions
As shown in Equation (179), a tandem Claisen rearrangement–lactonization involving the C-3 side chain of furan 292 was employed for a concise synthesis of hyperolactone C <2003JNP1039>. Although the product yield was low, the reaction created two contiguous quaternary carbon centers in one step.
O O OH
Ph CO2Me sealed tube Ph ð179Þ O O O PhMe 292 O 130 °C, 15 h 25% Hyperolactone C
Benzo[b]furan-based azide was also reported to undergo a 1,3-dipolar cycloaddition with norbornadiene as dipolar- ophile to give a triazole after extrusion of cyclopentadiene (Equation 180) <2001T7729>. 76 Furans and Their Benzo Derivatives: Reactivity
Ph O O O O O Ph FVP O O –CH2=CH2 O 288 O Ph 287 ring contraction O •• O 289 [2+2] O ring –PhCO2H expansion O H • •• Ph O • O O C–H [1,5]H insertion
OHC O 290 291
Scheme 84
N N3 NN norbornadiene ð180Þ O C6H6 O reflux, 15 h 72%
Cycloaddition of the less-electrophilic azirine 293 and 1,3-diphenylbenzo[c]furan was carried out in the presence of
ZnCl2, as shown in Scheme 85, which led to the formation of an adduct 294. Thermolysis of 294 in toluene was shown to give another adduct 295 <2005H(65)1329>.
Ph Ph OH H O Ph ZnCl 4 Å MS H N 2 N + O O CO2Et EtO C Me 1.5 d NH PhMe 2 Ph Ph Ph reflux, 16 h Me Me 293 55% CO2Et 294 295
Scheme 85 Furans and Their Benzo Derivatives: Reactivity 77
3.06.5 Further Developments
Reactions of furans, dihydrofurans, tetrahydrofurans and benzo[c]furans have been reviewed <2007PHC187>. Derivatives of new furan skeletons were synthesized from bicyclic azo compounds and nitriles in the presence of
SbCl5 or AlCl3. An example of which is shown in Scheme 86 <2007S33>.
Scheme 86
Cinchonidine-derived quaternary ammonium phenoxides (e.g., 296) have been shown to catalyze vinylogous aldol- type reaction between benzaldehyde and 4-methyl-2-(trimethylsilyloxy)furan, leading to the formation of a 5-substituted butenolide in good yield and good ee% as can be seen in Equation (181) <2007CL8>.
ð181Þ
Singlet oxygen reaction with a furan provided a spiroketal that reacted further under acidic condition to give eventually a bis-spiroketal as shown in Scheme 87 <2007OBC772>. 78 Furans and Their Benzo Derivatives: Reactivity
Scheme 87
An enantiopure Fischer carbene complexes was able to react with 2-methoxyfuran in an intriguing manner that led to the formation of trisubstituted cyclopropane molecules in excellent diastereoselectivities. The relevant mechanism for the formation of a cyclopropane is depicted in Scheme 88 <2007CEJ1326>.
Scheme 88
As illustrated in Equation (182), a seven-membered lactam was formed by utilizing a ring closure reaction under Heck coupling conditions <2007OBC655>.
ð182Þ
The lithiation of the phthalan shown in Scheme 89 with an excess of lithium in the presence of a catalytic amount of 4,49-di-tert-butylbiphenyl (DTBB) afforded a dianionic species, which on treatment with tert-pentanal provided a diol <2007TL3379>.
Scheme 89 Furans and Their Benzo Derivatives: Reactivity 79
Upon reaction of the benzobisoxadisilole shown in Equation (183) with 1.5 equivalents of BF3?OMe2 for 25 hours at room temperature, 50% yield of the dehydration product was obtained together with the recovery of 31% unreacted starting material <2007TL2421>.
ð183Þ
Reissig showed that when a variety of 3-alkoxy-2,5-dihydrofurans were subjected to manganese(III)-catalyzed allylic oxidation, -alkoxylbutenolides were obtained as can be seen in Equation (184). The total synthesis of ( )- annularin H was achieved employing this procedure as a pivotal step <2007SL1294>.
ð184Þ
Reissig also oxidatively cleaved the aforementioned 3-alkoxy-2,5-dihydrofurans to lead to the formation of , - unsaturated -ketoaldehydes, as can be seen in Equation (185) <2007AGE1634>.
ð185Þ
Immobilized box-Cu complexes were shown to efficiently catalyze the insertion of carbenes into the C–H bond of tetrahydrofuran with enantioselectivity of up to 88%ee. The use of immobilized catalysts allows their recovery and reuse. As can be seen in Equation (186), the major syn-isomer was shown to be of 2R, S absolute configuration by comparing its sign of optical rotation with that of an authentic sample <2007OL731>.
ð186Þ
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Biographical Sketch
Henry N. C. Wong was born in Hong Kong, and he studied at the Chinese University of Hong Kong, where he obtained a B.Sc. in 1973. He obtained his Ph.D. from University College London in 1976 under the mentorship of Professor Franz Sondheimer. After spending 1976–78 at Harvard University under the direction of Professor Robert B. Woodward, he returned to University College London as a Ramsay Memorial Fellow. Subsequently, he did research at Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences in 1980–82, and finally returned to The Chinese University of Hong Kong in 1983, where he is now professor of chemistry and head of New Asia College. His scientific interests include syntheses and studies of non-natural molecules and natural products.
Kap-Sun Yeung was born in Fujian, China, and he studied at the Chinese University of Hong Kong, where he conducted undergraduate research with Professor Henry N. C. Wong and received his B.Sc. in 1990. He then spent a year as a research assistant with Professor Chi-Ming Che at the University of Hong Kong. In 1991, he was awarded a Croucher Scholarship to study at the University of Cambridge, where he was involved in the total synthesis of swinholide A and scytophycin C under the guidance of Professor Ian Paterson. After obtaining his Ph.D. in 1994, he carried out postdoctoral research in Professor Chi-Huey Wong’s group at the Scripps Research Institute, California. In 1996, he joined the Bristol-Myers Squibb drug discovery chemistry group in Connecticut. His research interests include all aspects of synthetic organic chemistry, pharma- ceutically important heterocycles, and drug design. 90 Furans and Their Benzo Derivatives: Reactivity
Zhen Yang was born in Liaoning, China, and got his B.Sc. in 1978 and M.Sc. in 1986 at the Shenyang College of Pharmacy. He spent three years as a graduate student at the Chinese University of Hong Kong, where he conducted his research under the guidance of Professor Henry N. C. Wong and received his Ph.D. in 1992. He carried out postdoctoral research with Professor K. C. Nicolaou at the Scripps Research Institute from 1992 to 1995, and was an assistant in Professor Nicolaou’s domain from 1995 to 1998, where he was involved in the total syntheses of taxol, epothilone A, and brevetoxin A. He then moved to the Institute of Chemistry and Cell Biology, Harvard University, in 1998 as an institute fellow to conduct his independent research in the field of chemical genetics. In 1998, he joined the College of Chemistry and Molecular Engineering, Peking University, as a Changjiang Professor, and founded VivoQuest Inc. His research interests include total synthesis of natural product, organometallic chemistry, chemical biology, and drug discovery.