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Home , Annulation, Buchner ring expansion, Carbenoid, Copper, Diazo, Insertion reaction

Literature Seminar (D2 Part) 2011/04/06 (Wed) Noriaki Takasu (D2)

Diazo-mediated ~Recent Developments of Variety Bond Formation Methods~

Cyclopropanation C-H Insertion [4+3] Cyclization

R1 R2

N2 R1 LnM 2 LnM R [3+2] Cyclization Metal Carbenoid

Ylide Formation Coupling N-H, O-H Insertion

Recently, many metal catalyzed C-H activation reactions have been reported, but many reactions have not become reaction using wide range (selectivity, functional tolerance). The metal-carbenoid intermediates are capable of undergoing a range of unconventional reactions, and due to their high energy, they are ideal for initiating cascade sequences leading to the rapid generation of structural complexity. These species are using for many type C-H activated reactions, C-C or C-heteroatom bond formations, and skeletal constructions. In this seminar, I talk about many -carbenoid reactions from various metal.

Contents 1. Carbenoid (P.1-2) 2. Carbenoid Induced Reaction (P.3-10) 3. Carbenoid Induced Reaction (P.11-12) 4. Carbenoid Induced Reaction (P.13-14) 5. Other Metal Carbenoid Induced Reaction (P.15-16) 6. Summary & Perspective (P.17) 1. Carbenoid 1-1. Carbene is a containing a neutral with a 2 valences R NN R R and 2 unshared electrons. C are classified as either singlets or triprets depending upon their NHC R' electronic structure. Most carbenes are very short lived, although persistent carbenes are ref.) Nojiri's Lit known (example of stable carbene: N-Heterocyclic carbene; NHC). (M1 Part) p p R R Singlet Triplet R' R' • unshared electron pair ( orbital) and empty p orbital • 2 electron was shared with p orbital and orbital • resembles carbocation and carboanion united on same • resembles biradical carbon, so have nucleophilicity and electrophilicity • Typical angle (calculated) : 130~150° (reactivity depends on substituted groups). • many R and R' groups can stabilize singlet carbene (more than triplet carbene). • Typical angle (calculated) : 100~110° One of the typical carbene formation : decomposition

Diazo compounds readily decompose thermally or photochemically N or h or Metal CO2R N CO2R driving force : formation of N2 bond and generation of N2 gas -N H Generated carbene is high reactivity. H 2 In the case of using to generated carbene C-H Insertion Metal-Carbenoid species is generated 1,2-migration of alkyl Cyclopropanylation and other reaction... 1-2. Metal-Carbenoid Carbenoid is a vague term used for a molecule in which all are tetravalent but still has properties resembling those of a carbene, typically the carbene-like carbon has multiple bonds with a metal. Carbene is stabilized by Metal. Carbenoid has unique reactivity that carbene has not, keeping the reactivity of free carbene. Carbenoid is structurally related to singlet carbenes and posses similarly reactivity.

R can be formed by reacting salts of transition . e.g. Cu, Rh, Pd, etc... many metals can be formed. MLn These are formed by metal with carbenoid precursor, typically diazo compound. R'

Kind of Diazo Compound (Carbenoid Precursor) Carbenoid can be controled carbene reactivity through substituent (acceptors and donors). Not enough electrophilicity causes less reactivity, and too much electrophilicity causes side-reaction, so control of electrophilicity is important. Metal-carbenoid reaction requires appropriate level of electrophilic ability at the carbenoid carbon center.

Acceptor Acceptor/Acceptor Acceptor/Donor •Acceptor/Acceptor and Acceptor/Donor types stabilize O O O O diazo compound (so more active catalyst needed for decomposition). H Y X X Y X • Donor substituent stabilized carbenoid through resonance.

N2 N2 N2 • Almost metal-carbenoids have electrophilicity. X = R, OR, NR2 X, Y = R, OR, NR2 X = R, OR, NR2 • Carbenoids formed from Acceptor/Acceptor compounds Y = vinyl, Aryl has high electrophilicity. too much electrophilicity causes side-reaction, so control of electrophilicity is important.

Electron Feature of This Type Metal-Carbenoid R lone pair on carbon to M : strong C-M bond M C d electrons to p orbital on carbon : weak~moderate bond, stabilize carbene a little R' but still maintain its enough electrophilicity

desired metal : bind to the carbene through strong -acceptor interactions and weak (appropriate) back donation interaction. 1/17 Observation of Carbenoid Cu-Carbenoid P. Hofmann et al., ACIE, 2001, 40, 1288. TMS TMS CO Me CO Me tBu N 2 tBu N 2 2 P Cu + N P Cu tBu 2 tBu N Ph N Ph 5 TMS TMS Cu-Carbenoid In toliene-d8 or -d6 at rt, 15-25% Cu-complex was detected. atropisomer Caractarization from 1H NMR (Figure 2), 13C NMR (229.9 ppm of 5 + (C=N2), 177.9 ppm (C=O), MS (FAB; 531.2, [M ]). (At -33 C, this comoplex was maintained for several hours without significant evolution of .)

Rh2-Carbenoid J. P. Snyder et al., JACS, 2001, 123, 11318. tBu

O tBu N O O Rh (OCOtBu) + Rh O 2 4 toluene O Rh Me X-ray structure N O N rt t O MeN Bu O tBu

1-3. Early Example of Metal-Carbenoid Reaction Insertion P. Yate, JACS, 1952, 74, 5376. :NuH O Cu O O -N2 N2 H H R R Nu = RO, RS, R2N R (complex with Cu) Nu Cyclopropanyration Cl A. F. Noels et al., Tetrahedron, 1983, 39, 2169. Cl Metal Metal; Cl Rh (OAc) : 54% 2 4 In this paper, other example, Cl N HC CO R Cu(OTf) : 42% 2 2 2 reactivity is [Rh] > [Cu] > [Pd] Pd(OAc)2 : 12% CO2R Dimerization (Homometathesis)

Ph Ph Ph O O Cu + N OO 2 toluene Ph Ph Ph 86% R. Noyori et al., TL, 1966, 1, 59.

general metal of metal-carbenoid reaction : Rh, Cu, Pd ; most useful metal is Rhodium.

Dirhodium carboxylate (Rh2L4) H. Reimlinger et al., TL, 1973, 24, 2233. Catalyst diazo/Catalyst R Yield First example of Rhodium carbenoid generation from diazo decomposition. Rh2(OAc)4 600 Et 88 catalyst i R OH + N CO Et RO CO Et Rh2(OAc)4 600 Pr 83 2 2 2 t 25 C Rh2(OAc)4 600 Bu 82 Reactivity using Rh2(OAc)4 (Rh(II)) was higher than Rh(I), Rh(III). Rh2(OAc)4 600 H 80 Rh2(OAc)4 600 Ac 93 RhCl3•3H2O 125 Et 64 t RhCl3•3H2O 125 Bu 58 RhCl(PPh3)3 125 Et 49

2/17 2. Rhodium Carbenoid Induced Reaction 2-1. C-H Insertion ref.) Yamaguchi's Lit (M1 Part) Trend in Selectivity In simple case, Reactivity is determined with both electric effect and steric effect. D. F. Taver et al., JACS, 1986, 108, 7686. O O O R1 CO Et Rh (OAc) 1 2 3 2 2 4 CO Et CO Et R = Me, R = Me, R = Me (3 vs 2 ) 23 : 1 R3 2 R1 2 2 1 1 2 3 t R N2 R R = Me, R = H, R = Bu (2 vs 2 bulky) 34 : 1 R2 R2 R3 steric effect R3 tertially > secondary > primary (electric effect; electron in the C-H bond)

G. Stork et al., TL, 1988, 29, 2283. O O COCHN2 Rh (OAc) COCHN2 Rh2(OAc)4 2 4 CO Me CO2Et 2 CH2Cl2 (0.01 M) CO Me CH2Cl2 (0.01 M) CO2Et 2 rt rt 81% 0% : 33% O COCHN2 Rh2(OAc)4 O COCHN2 Rh2(OAc)4 CH2Cl2 (0.01 M) CO2Me rt CO2Me CH2Cl2 (0.01 M) CO2Me 64% rt CO2Me 0% • electron-withdrawing groups inhibit adjacent C-H bond dimer : 31%

Mechanism M. P. Doyle et al., JACS, 1993, 115, 958. D. F. Taber et al., JACS, 1996, 118, 547.

C-Rh-Rh is 180 from calculation. They didn't perfom DFT calculation, but they expected from alined (L) effect of C-H insertion. This mechanism was expected from experiments results, low EWG : general selectivity and ZINDO calculation was performed to intermediate. high EWG : selectivity is decreased (attack low steric barrier)

These mechanisms were plausible and widely accepted, but additional analysis of mechanism was performed for further development of the C-H activation chemistry.

Proposed mechanism from DFT calculation E. Nakamura et al., JACS, 2002, 124, 7181.

DFT using B3LYP on Rh2(O2CR)4 C-H activation/C-C bond formation reaction. calclated for [Rh2(O2CH)4 - CH2N2 - metane or propane] and [Rh2(O2CH)4 -N2CHCO2Et - metane or propane] 2 -Donation • carboxylate groups serves as anchors of the Rh • electron-withdrawing group (E) enhances the electrophilicity of the carbene carbon center • Rh1 has positive charge which increases the electrophilicity Rh2 Rh1 Rh Carbenoid of carbon center Formation • electron donation from Rh2 to Rh1 assist the C-C bond formation and catalyst regeneration. • If chiral ligand was used, it also serves as the site to harness chirarity. C-H Activation Activated energy is decreased, so C-H Insertion is enhanced. C-H Insertion compared to Cu-carbenoid and Ru-carbenoid, energy of C-H insertion to carbenoid is lower (-methane). Dissociation H of NH Rh-Catalyst Cl O H H N Ru Cu (HCO2)4Rh2 CH2 C-C Bond H H Cl O Formation NH H 27.6 kcal/mol > 15.6 kcal/mol > 5.7 kcal/mol 3/17 Stereo-/Chemo-Selective Reaction Review; H. M. L. Davies et al., Chem. Rev., 2003, 103, 2861. H. M. L. Davies, ACIE, 2006, 45, 6422. Intramolecular reaction H. M. L. Davies et al., Nature, 2008, 451, 417. H. M. L. Davies et al., Chem. Soc. Rev., 2009, 38, 3061. M. P. Doyle et al., JACS, 1996, 118, 8837. M. P. Doyle et al., JOC, 2005, 70, 5291. 1.0 mol%

I II Rh2(OAc)4 10 7 Rh2(4S-MPPIM)4 53 19 Rh2(5S-MEPY)4 62 23 Rh2(4S-MEOX)4 87 trace

Rh2(4S-MPPIM)4 Rh2(5S-MEPY)4 Rh2(4S-MEOX)4

In this type reaction, it was thought that Rh-carbenoid reacts with equatrial C-H, because access to axial C-H is prevented by crowding of the .

Proposed mechanism; sterically hindered

Rh2(4S-MPPIM)4 1

react with additional chiral attachment, so ee was increased. Me of iPr • 12, 16 : direction of additional chiral attachment is mismatched. • diastereoselectivity; H H Me O H L* Rh 4 2 O conformation should be locked as all the substituents are placed at equatrial position • Equilibrium depends on the ligand (catalyst) (whether the substituent is at axial or equatrial). insertion to • Small ligand to low diastereoselectivity. equatrial C-H (L=OAc, 40:60 ; JACS, 1994, 116, 4507.) • Rh-carbenoid reacts with equatrial C-H, so in appropriate ligand, reaction is cis selectivity.

• Model for aymmetric induction with Doyle's catalysts; ester H

O N CO2Me Rh Rh

Rh2(5S-MEPY)4 O (4R) Doyle's catalyst N2 O

R

In the cases of other type , they are expected by similarly catalysit model.

4/17 • lactam formation S. Hashimoto et al., Synlett, 1994, 12, 1031. H. M. L. Davies et al., Chem. Rev., 2003, 103, 2861.

t Ar= BuC6H4 Rh2(S-TBSP)4

2 • In the case of R2 is alkyl group, -lactam is obtained, but in R is Aryl groups, -lactam is obtained. Electron density of nitrogen atom is important. When N has electron-enough, C-H insertion at adjacent to N is enhanced (in insertion mechanism, C-H insertion process is activated by push of unshared-electron pair). When N has electron-withdraing group (Ar, carbonyl), -lactam cyclization is inactivated, and -lactam is obtained. • This is acceptor/acceptor type, reactivity is so high. So enantioselectiviry is low, but R1 = Ar, selectivity is increased. Benzyl position is slightly lower reactivity than saturated aliphatic C-H because of electron-withdrawing nature of Ph group, so reactivity is controlled, and enantioselectivity is increased. • Model for aymmetric induction in -lactam formation with Hashimoto's catalyst. phthalimide O H O Rh N Bn O 4 O Rh

Rh2(S-PTPA)4 Hashimoto's catalyst

Intermolecular reaction H. M. L. Davies et al., JACS, 2000, 122, 3063. H. M. L. Davies et al., JACS, 1999, 121, 6509. • Simple reaction system and chemoselectivity H. M. L. Davies et al., JACS, 1997, 119, 9075.

O Rh

N O Rh SO2Ar 4 Ar = p-C12H25C6H4

Rh2(S-DOSP)4

Mannich type products.

Newmann model of intermolecularreaciton (Rh2(S-DOSP)4).

a 3 mol% of catalyst was used. At 80 C, 85%, 67%ee.

• enantioselective reaction • electron-donating groups on Ar decrease reactivity, H. M. L. Davies et al., JOC, 2009, 74, 6555. probably because of the lower electrophilicity. • adjacent to heteroatom, reactivity is increased. diastereoselectivity is depended on size of substituents. 5/17 Relative rates of reaction various substrates. OL, 2001, 3, 3587. JACS, 2001, 123, 2070. Boc N H

1 0.66 0.078 2700

O Ph 24000 1700 28000 cyclopropane reaction rate is so defferent with respect to substrates (functional groups), so selective reaction is possible. C-H activationat C-H activationat adjacent to N adjacent to O

Intermolecular metal-carbenoid C-H insertion can replace with classical C-C bond formation, in high .

JOC, 2005, 70, 10737. C-H activation as a surrogate of classic reactions of .

C-H Insertion/Cope Rearrangement H. M. L. Davies et al., JACS, 2004, 126, 10862.

previous work Ph Rh (S-DOSP) R 2 4 Ph R (0.5 mol%) 1 N Ar 6 + N2 R 2 Rh2(S-DOSP)4 R 2,2-dimethylbutane + X Ar CO Et 0 C CO2Et 7 X 2 H H CO2Me CO2Me 1 normal C-C bond formation morerate yield R = H, X = CH2 : 95%, >98%de, 99.5%ee high ee R = 6-OMe, X = CH : 77%, >98%de, 99.3%ee moderate dr 2 R = 7-OMe, X = CH2 : 90%, >98%de, 98.9%ee H. M. L. Davies et al., OL, 2001, 3, 3587. R = H, X = O : 75%, >98%de, 95.1%ee Ph Et high ee and de other mechanism??

• first step: C-C bond formation of benzyl position (olefin side) (3) high stereoselective reaction by Rh2(S-DOSP)4 C-H activation/Cope rearrangement • second step: cope rearrangement

consecutive 2 steps reaction, apparent direct C-H activation • using diazo 4, second retro cope rearrangement is unfavored, so high temperature is required. Et Ph, because of cunjugated with Ph after rearrantement, Proposed mechanism so retro cope rearrangement undergo low temperature. • Aromatization

• surrogate of Michael addtion OTBS O OTBS Ph Ph Rh2(S-DOSP)4 1.1 eq 1 DMB, 0 C H H CO2Me CO2Me 78%, >98%de, 95.2%ee

6/17 2-2. diastereoselective cyclopropanation Ph CO2Me Rh2(OAc)4 (1 mol%) Ph + R N2 94%, E/Z = >20:1 CO Me 2 Ph

H. M. L. Davies et al., TL, 1989, 30, 5057. model of diastereoselectivity •R1 is saturated alkyl group (not shown, TL paper) : enantio/diastereoselective cyclopropanation diastereoselectivity is decreased. Ph CO2Me Rh2(S-DOSP)4 intermediate is not stabilized?? (1 mol%) R + R (but when bulky ligand is used, it is improved (JACS paper).) N2 penetane, -78 C 2 CO Me •R is donor group (Ar, allyl) diastereoselectivity is increase. 2 Ph (R2 = acceptor(e.g. ester) : selectivity is decreased, R % ee yield (%) acceptor/acceptor type carbenoid is too much reactivity) C6H5 98 68 p-ClC6H4 97 70 • using chiral Rh catalyst, high ee was obtained. p-MeOC6H4 90 41 EtO 93 65 H. M. L. Davies et al., JACS, 1996, 118, 6897.

Enantioselective Cyclopropanation of Allenes H. M. T. M. Gregg et al., OL, 2009, 11, 4434.

CO2Me Rh (S-DOSP) CO2Me 2 4 Rh2(S-DOSP)4 + N2 + N2

Br Br 2 2

positive charge

• In toluene solvent, trace procuct is obtained. Maybe cyclopropanation of aromatic rings and - methyl C-H insertion is proceeded, so it is suggested that cyclopropanation of allene is slowly. • Reaction is proceeded at only indicated no substituted olefin. • Aryl allene and aliphatic allene are succeeded moderate~good yield and ee. • Disubstituted allenes are decreased reactivity because of sterically barrier (see TS). • In TS, there is positive carbon on the central carbon of the allene, so stabilized substituents give high reactivity (e.g. silyl).

TS from DFT calc.

Buchner ring expansion A. R. Maguire et al., Chem. Comm., 1996, 2595.

R R O R Rh2(OAc)4 Ph O CH2Cl2, heat N2 O in NMR, rapidly equilibrating mixture R = H, Et, Pr, iPr, nBu, tBu, allyl major (>97%) : trans allyl : 49% (byproduct : cyclopropanation of allyl olefin, other alkyl substrate : 59-79%

• Benzen ring is reacted with metal-carbenoid species. • In this case, R groups stericallyblock, diastereoselectivity is appearred.

steric effect of cyclization

7/17 Enantioselective Cyclopropenation of H. M. L. Davies et al., JACS, 2010, 132, 17211. H. M. L. Davies et al., OL, 2004, 6, 1233. Allyldiazoester R N2 Rh2(S-DOSP)4 (1 mol%) CO2Me Ar CO Me 2 hexane, rt R Ar R = alkyl, aryl, allyl : 48-74%, 84-92%ee Ar = EWG, heteroaromatic : moderate yield and high ee EDG : low yield and moderate ee lower reacivity of p-methoxyphenyl carbenoid. allylic : not obtained (can't isolate)

unstable

Predictive model with Rh2(S-DOSP)4 from result and DFT calculation

unstable, tentatively assigned on the basis of NOE Formation of

• At low temperature, cyclopropen is generally obtained in high enantioselectivity. • When Ar has EDG, cyclopentadiene is generated. • At reflux, cyclopropene is not observed, cyclopentadiene is obtained. • Disubstituted are no reaction sterically barrier (in TS)

Mechanistic hypothesis of cyclopentadiene [4+3] Cyclization : Tandem Cyclopropanatin/Cope Rearrangement (for diene) With simple diene With heteroaromatic H. M. L. Davies et al., JACS, 2009, 131, 8329. H. M. L. Davies et al., JACS, 2007, 129, 10312.

toluene

Proposed mechanism of stereoselective [4+3]

[3.3] cyclopropanation CO2Me Rh2(S-PTAD)4 (1 mol%) bicyclo + N2 substrate product OTBS DMB, 50 C

product; Boc Boc Boc N N N CO2Me CO2Me CO2Me OTBS OTBS OTBS MeO2C 69%, 96%ee 72%, 98%ee 71%, 89%ee Boc Ph p-tol N N N CO Me CO2Me 2 1) CO2Me CO2Me O OTBS OTBS (3.0 eq) OTBS OTBS TBSO OMe 64%, 97%ee 68%, 94%ee Rh2(S-PTAD)4 (1 mol%) 76%, 91%ee N2 toluene, -10 C 2) reflux, 4 h 67%, 90%ee

less substituted olefin is preferentially proceeded first cyclopropanation 8/17 2-4. Other C-C Bond Formaiton 2-methylindole [3+2] Annulation of H. M. L. Davies et al., JACS, 2010, 132, 440.

2- substituted or

3-substituted indole

exo endo In simple N-methylindole, 2 isomers are obtained. initial reaction at C2 or C3 position of indole?? reactivity of substituted indols • 2-methylindole : endo compound is obtained. • 3-methylindole : exo compound is obtained. • Reactivity is stability of 2 or 3-position? So author's said, this reaction is step-by-step reaction, stable 3 carbocation is generated in transition state, maybe not concerted reaction. Proposed mechanism;

3-methylindole

Ylide Formation H. M. L. Davies et al., JACS, 2009, 131, 1101. Carbenoid can generate ylide with appropriate carbonyls or imines. R4 H R3 H 1 1 1 2 N 5 H R reaction rate of intermolecular reaction; H R R CO2R R epoxide O aziridine epoxidation of benzaldehyde > R3 N CHO R4 R3 O CO R2 N 2 cyclopropanation of styrene 2 2 R5 O-Ylide N-Ylide M. P. Doyle et al., OL, 2001, 3, 933. Three-Component Cycloaddition

proposed model of reaction.

• Rh2Piv4 is most suitable.

• Rh2(OAc)4, yield is decreased. • regioselective reaction • endo selective reaction

9/17 2-5. Heteroatom-H Insertion Si-H Insertion N-H Insertion H. M. L. Davies et al., TL, 1998, 38, 1741. F. A. Davis et al., OL, 2004, 6, 4523.

Me2PhSiH Boc Rh (OAc) O R R NH O O 2 2 Rh2(S-DOSP)4 (4 mol%) N2 Me2PhSi P(OMe)2 pentane, -78 C R CH Cl , 35 C R P(OMe)2 CO2Me CO2Me 2 2 N N2 Boc O Me Ph R = Ph : 68% (cis/trans = 81:19) Ph CH=CH2 : 65% (cis/trans = 92:8) Me2PhSi Me2PhSi Me2PhSi Me : 88% (cis/trans = 96:4) CO2Me n CO2Me CO2Me Bu : 79% (cis/trans = 95:5) 50%, 85%ee 64%, 95%ee 76%, 91%ee tBu : 84% (cis/trans = 99:1) Ph

Me PhSi O-H Insertion Me2PhSi 2 Me2PhSi CO Me Y. Landais et al., JOC, 1997, 62, 1630. CO2Me 2 CO2Me 68%, 77%ee 63%, 85%ee 77%, 92%ee 2 R N2 OR Rh2(OAc)4 1 3 R CO2R ROH CO2Et

R = H, Me, Et, Ph; R1 = Ar, vinyl, alkyl; R2 = H, Me; R3 = Me or Et. 40-77%.

2-6. Total Synthesis using Rhodium Carbenoid T. Fukuyama et al., JACS, 2008, 130, 16854.

(0.3 mol%)

Combined chiral auxiliary and stereoselective intramolecular C-H insertion. chiral ligand (S-DOSP) provided an excellent result. T. Fukuyama et al., OL, 2011, 13, 1089.

Rh ( -DOSP) R R 2 R 4 R (0.2 mol%) , CO2H R* = Ph N N2 CH2Cl2 CO H R*O2C R*O2C N 2 HO O R = H, 88%, >95%de H OMe, 63% >95%de R = H : Phenylkainic R = OMe : Methoxyphenylkainic Acid stereoselective intermolecular C-H insertion.

R. Sarpong et al., ACIS, 2009, 48, 2398. When racemic SM was employed, 41 and 44 (diastereomer) was mainly obtained (depend of chiral ligand).

Although they have inverse absolute configuration at reactive site, using Rh2(R-DOSP)4, [4+3] cyclization was proceeded in 'same' stereochemistry so diastereomers are obtained.

'pallarel kinetic resolution' diastereoselective intermolecular [4+3] to diterpenes.

10/17 3. Copper Carbenoid Induced Reaction Copper carbenoid is shown the similar reaction for Rhodium carbeoid reaction. But to manipulate reagents and condtions, higher reactivity and selectivity can be afforded. Copper carbenoid can be proceeded main metal-carbenoid reaction, C-H insertion and cyclopropanation, and total synthesis was performed by copper carbenoid induced reaction. ex) Y. Qin et al., JACS, 2007, 129, 13794. O O O O Br O Br O Br PBu3 CuOTf THF aq. N 2 88% 83% N N3 N N N N 3 H Me Me Me 1.6:1.0 dr ( )-communesin F

Reactivity of many C-H insertion or cyclopropanation using Copper carbenoid is lower or same for Rhodium carbenoid. But heteroatom(N, O, Si, S)-H is significantly improvement of ee compared for Rhodium carbenoid.

N-H Insertion Q.-L. Zhou et al., JACS, 2007, 129, 5834. - derivative (N-Ar) synthesis.

Ph

Ph

(Sa,S,S)-1a

F3C CF3

F3C CF3

B

F3C CF3

F3C CF3 BASF-

• Counter anion effect is so high, the smaller and slightly coordinating OTf is inferior to the PF6 in the enantiocontrol. • with the larger and non-coordination BARF-, reactivity and enantioselectivity is significantly increased. • steric-hindrance diazoacetate (Entry 17), secondary (Entry 18), (Entry 19) enantioselectivity is so low. O-H Insertion Q.-L. Zhou et al., JACS, 2010, 132, 16374. OH 5 mol% CuOTf•1/2toluene 6 mol % (Sa,S,S)-1b OH 6 mol% NaBASF N2 * CO2R CH2Cl2, 25 C CO2R

t (Sa,S,S)-1b : R = Bu i (Sa,S,S)-1b : R = Pr

high yield and high selective reaction for pyran rings and furan rings. In seven-menbered ring, reactivity is so decreased, but using ligand 1c, good yield and selectivity is obtained.

11/17 ○Calculated Study for O-H Insertion into Water, Cu vs. Rh Z.-X. Yu et al., JACS, 2009, 131, 17783.

Ph CO2Me ML * Ph CO2Me + O n H H N2 HO H

Cu(I) Rh(II)

• TS-O : 2 H2O and metal-coordinated TS before product TS-F : only 2 H2O cordinated TS before product • In DFT calculation; Cu : TS-3-O is more favor than TS-3-F (Figure 1) Rh : TS-7-O is more unfavor than TS-7-F (Figure 2) • Scheme 4 , FY : metal is not coordinated at protonation step MY : metal is coordinated at protonation step G(FY-MY) ( G'solTS-(FY-MY))> 0 Ligand affects protonation step determining ee.

in Rh2L4, G(FY-MY)< 0, so ligand effect is decreased. in CuLn, G(FY-MY)> 0, so ligand effect is significantly obtained. in O-H insertion Cu prefers to Rh.

S-H Insertion Q.-L. Zhou et al., Chem. Comm., 2009, 5362.

Ph

Ph

(Sa,S,S)-4a

moderate~good yield was obtained, but enantioselectivity was moderate.

other heteroatom-H insertion; Si-H : high yield and high enantioselectivity for the similar ligand ; Q.-L. Zhou et al., ACIE, 2008, 47, 8496. 12/17 4. Palladium Carbenoid Induced Reaction Review : Y. Zhang et al., EurJOC, 2011, 1015. Palladium carbenoid shows different behavior for other metal carbenoid. L. Wang et al., TL, 2008, 6781. Early report D. F. Taber et al., JOC, 1986, 51, 3382. O O O CO Me Pd(PhCN)2Cl2 2 (1.5 mol%) CO2Me CO Me + N2 PhCN, reflux, 5 h 2

34% 14%

O O

CO2Me CO2Me PdL PdLn n

palladocyclobutane ?? in reactive olefin, even Rh2(OAc)4 was not reacted. Mechanism is different from other metal carbenoid. Authors believed to proceed through a palladocyclobutane In after report, enantioselective reaction was failed. whitch partitions to the enone or the cyclopropane. S. E. Denmark et al., JOC, 1997, 62, 3375. Pd-Carbenoid can perform other type reaction ?? Insertion of Palladium Carbenoid D. L. V. Vranken et al., TL, 1999, 40, 1617. D. L. V. Vranken et al., Tetrahedron, 2001, 57, 5219. Pd2dba3CHCl3 (2.5 mol%) Br SiMe AsPh3 3 (15 mol%) Oxidative addition + -Hydride elimination Insertion to olefin N2 DIPEA, DCE Elimination of TMS and regeneration of Pd(0) MeO reflux MeO Proposed mechanism; Pd(0) reacts with diazo compounds to rapidly form a Pd-carbenoid, and Pd(II) can be formed in situ from Pd(0).

Nucleophilic Addition Cross-Coupling with Diazoacetate

D. L. V. Vranken et al., OL, 2007, 9, 2047. X = TMSCH2N2 J. Wang et al., JACS, 2007, 129, 8708. D. L. V. Vranken et al., ACIE, 2009, 48, 3677. X = CO2Et

Pd2dba3CHCl3 (2.5 mol%) 1 2 R1 PPh3 R R X (15 mol%) HNR2 + IH+ X R2 R2N N THF, heat R3 R3 2 O

N N N N Me Bn Bn Bn Bn TMS TMS TMS TMS 27% 80% 91% 55% O O

N N N Bn Bn CO2Et CO2EtNC CO2Et 94% 55% 91% Proposed mechanism This substituent is , this reaction is occurred. attack from low steric barrier position. In other groups, coupling of In X=CO2Et, carbenoid with Aryl product is stable . conjugated ester. (I show next.) maybe this route is plausible.

Tsuji-Trost Migratry insertion

13/17 Cross Coupling with Aryl Group J. Wang et al., JACS, 2010, 49, 1139. CO Insertion J. Wang et al., JACS, 2008, 130, 1566. PhB(OH)2

Using CuCl (10 mol%) & O2, reaction was proceeded. Et3SiH is hydrogen source, -hydrogen exchange (From ; shown below.) process promotes reaction. J. Wang et al., Chem. Comm., 2010, 46, 1724. Coupling of tosylhydrazone

Pd2dba (1 mol%) Xphos (2 mol%) Ar NNTs t 3 Ar X LiO Bu (2.2 eq) 3 R + 1 R R1 (X = Cl, Br) dioxane R 2 R2 R OMe p-tol Ph CN Ph Ph 90 C, 10 h 70 C, 4 h 68% 98% 90 C, 4 h 98% p-tol S tBu N 90 C, 16 h 90 C, 17 h 100 C, 16 h 99% 50% 90% (Pd:2 mol%, L:4 mol%)

in situ, diazo intermediate is generated from tosylhydrazone with , and next carbenoid generation, migratory -elimination. 14/17 5. Recent Other Metal Carbenoid Induced Reaction

Iridium Carbenoid Cyclopropanation ; ACIE, 2007, 46, 3889. JACS, 2008, 130, 10327. Recently, -salen complexes are employed for metal-carbenoid ACIE, 2009, 48, 3121. reactions, by Katsuki's group. C-H Insertion ; JACS, 2009, 131, 14218. Si-H Insertion ; JACS, 2010, 132, 4510. Cyclopropenation ; JACS, 2011, 133, 170. ACIE, 2007, 46, 3889 ; Cyclopropanation

Ph Ph

L = p-MeC6H4

• at -78 C, in THF, high yields and high stereoselectivity. • cis selective reaction.

JACS, 2010, 132, 4510 ; Si-H Insertion

• in aryldiazozcetate, nomal salen complex (R=C6H5) gives high yiled and enantioselectivity

• in alkyldiazozcetate, salen complex 4 (R=p-TBDPSC6H4) gives high yiled and enantioselectivity. (the complexes having a higher molecular recognition ability would serve as an efficient catalyst for this reaction.)

15/17 Carbenoid There are a few examples. X. P. Zhang et al., ACIE, 2008, 47, 8460. CO2Et [Co(P1)] (1 mol%) CO2R R' + N2 R NO hexane, rt, 24 h NO 2 N 2 (1.2 eq) 2

• [h] 5 mol% catalyst. • enantioselective cyclopropanation of acceptor/acceptor type (Hydrogen bond of N-H of amide vs NO2 and ester of diazosubstrate, reactive face is determined.)

Iron Carbenoid Carbenoid is so cheap metal, but reaction example is not enough... Y. Tang et al., JACS, 2010, 12, 604. Y. Tang et al., JACS, 2009, 131, 4192.

sterically barrier is critically affected. Entry 10, 13, 14.

Cl

tandem carbenoid reaction/ Wittig. N Cl N good E/Z selectivity for Wittig Cl Fe Cl N N reaction. Cyclo propanation Fe(TCP)Cl

Cl

CO2Me Ph3P CO2Me Bu3P CO2Me + (PCT)Fe CO Me 2 CO Me CO Me 2 2 PPh3

Aldehyde CO Me R 2

CO2Me Other example of iron carbenoid, asymmmeric cyclopropanation Ruthenium is the similar reactivity for Rhodium, many high efficient using porphyrin complex, moderate yield (up to 67%), good examples of Ruthenium are reported, but enantioselective reaction diastereoselectivity (up to 96:4) and moderate enantioselectivity is a few report. (See Review ; Enantioselective Ruthenium- (up to 80%ee), further improvements are required... porphyrin-carbenoid ; C.-M. Che et al., Synlett, 2010, 2681.) G. Simonneaux et al., TL, 2009, 50, 5149. 16/17 6. Sammury & Perspective Metal-carbenoid-mediated-reactions are so useful reactions for several type bond formation and skeletal construction. C-H Insertion, cyclopropanation, ylide formation, and others.... These reaction was used for several total syntheses.

N2 MLn MLn Various Bond Formations further transformations Natural Products R1 R2 R1 R2 stereoselective

Futher Improvement • Main metal of carbenoid reaction is Rhodium, that is so expensive. We would like to use other cheap and available metal ; Cu, Fe, Co, Ni, Mn, .... Recently, several cheap metals is used for metal-carbenoid reaction (further improvements were required).

• Usually, many type diazo compounds are thermally and photochemically unstable, and diazo precursor is unstable, explosive, and toxic.

ex) Most available diazo preparation method ; Regitz diazo transfer O O S O O N Ar O O O O NHAc O O O O N 1 2 N R R R1 R2 R1 R2 1 2 1 2 H N R R R R N3 TsN or p-ASBA N N N H :Base 3 N p-ASBA Ar N N

Carbenoid generation method not using diazo precursor ??

available substrate and useful addtitive, easy conditons... e.g.) substrate (dihalogen, monohalogen, active methylene (benzylic, allylic, -position of carbonyl), directing group, , or alkane), additive (base, oxidant), ligand effect of metal (steric, other several character), and the other addtivie and conditions...

If these reactions will be achieved, metal-carbenoid reactions is sure to become more general and conventional reaction.

17/17