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Haloselectivity of Heterocycles Will Gutekunst

Haloselectivity of Heterocycles Will Gutekunst

Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst

Background SN(ANRORC) Addition of Nuclophile, Ring Opening, Ring Closure Polysubstituted heterocycles represent some of the most important compounds in the realm of pharmaceutical and material sciences. New and more efficient ways to selectively produce these Br Br molecules are of great importance and one approach is though the use of polyhalo heterocycles. Br NaNH2 N N Consider: Ar N 3 Ar2 NH3(l), 90% NH2 3 Halogenations H NH2 H N CO2Me Ar H 3 Suzuki Couplings 1 N CO2Me - Br H Ar 3 Ar2 1 Triple Halogenation NH2 NH CO Me N N 2 Ar1 H 1 Triple Suzuki Coupling N CO2Me N NH H NH2 Ar H 3 Ar2 1 Triple C-H activation? CO Me N 2 Ar1 H N CO2Me Cross Coupling H Virtually all types of cross coupling have been utilized in regioselective cross coupling reactions: Nucleophilic Substitution Kumada, Negishi, Sonogashira, Stille, Suzuki, Hiyama, etc.

SNAr or SN(AE) In all of these examples, the oxidative addition of the metal to the heterocycle is the selectivity determining steps and is frequently considered to be irreversible. This addition highly resembles a nucleophilic substitution and it frequently follows similar regioselectivities in traditional S Ar reactions. Nu N The regioselectivity of cross coupling reaction in polyhalo heterocycles do not always follow the BDE's Nu of the corresponding C-X bonds. N X N X N Nu 2nd 2nd Meisenheimer Complex 1st Br Br 88.9 83.2 S (EA) Br 88.9 N 87.3 Br O O via: st OMe 1 Br NaNH , t-BuONa 2 N N pyrrolidine + Merlic and Houk have determined that the oxidative addition in palladium catalyzed cross coupling N N THF, 40ºC N reactions is determined by the distortion energy of the C-X bond (related to BDE) and the interaction of N the LUMO of the heterocycle to the HOMO of the Pd species. Tetrahedron 1982, 38, 427

SET Mechanism can also be operative (SRN1)

OK HetX + Nu HetX + Nu

N N O HetX Het + X N Cl h!, NH3(l) N Het + Nu HetNu 88% JOC 1981, 46, 294 HetNu + HetX HetNu + HetX JACS, 2007, 129, 12664; JACS, 2009, 131, 6632 Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst

Predicting Reactivity can also be selectively monoarylated at C-2 under C-H activation conditions. The Handy Method Handy and coworkers disclosed an experimental method in 2006 for predicting the regiochemical Ph I+BF - outcome of multiply halogenated heterocycles using 1H-NMR of the dehalogenated substrate. The 2 4 5% IMesPd(OAc)2 proton that displays the largest chemical shift implies it is attached to the most electron deficient Ph N N carbon atom and, therefore, the preferred site of cross coupling. While this method is not foolproof Me rt, AcOH, 67% Me (it does not take into account sterics, directing groups, or interactions noted by Merlic), it is a good start for predicting regioselectivities of cross coupling reactions. JACS 2006, 128, 4972 Chem. Comm. 2006, 299 Pyrroles 2nd 7.00 7.55 6.45 - Like , SNAr is very difficult without strong EWG's nd - Due to the electron rich nature, SNAr reactions do not readily take place last 2 7.08 6.22 without strong EWGs. - Cross coupling occurs first at C-2, with C-4 to C-7 reacting 7.27 before electron rich C-3. A C-2 vs C-4/7 has not been reported. - Cross coupling reactions occur fastest at the 2/5 positions, in accord with 7.40 N 6.68 st chemical shift prediction. H 1st N 1 H - Monocoupling in 2,5 dihalo substrates is difficult, but 3,4 dihalo (Acetone) (CDCl3) substrates can be easily controlled on steric grounds. - B(OH) S 2 Br Br O O Br S H Cl 2.5 eq EtSH H Cl N 10% Pd(PPh ) N TBS 3 4 TBS TEA, DMSO Na2CO3, Tol/H2O H H reflux, 8 hrs Cl N 86% EtS N 78% Me Me O O Orthogonally, the 3-position could be selectively exchanged with t-BuLi. Tetrahedron 2005, 61, 5831 Br Br Br t-BuLi, MeI Br Br Br Br Cl B(OH) 2 -78º C, THF Br N N N TBS 81% TBS 6% Pd(PPh ) Me Br N Br 3 4 Me K3PO4, Tol/H2O Chem. Pharm. Bull. 1996, 44,1831 90ºC, 12 hrs Cl 71% Tet. Lett. 2009, 49, 1698 The C-H activation conditions for pyrrole are also successful on indole and tolerates aryl bromides MeO MeO OMOM MeO MeO OMe Br + - Br MeO B(OH)2 MeO B(OH)2 Ph2I BF4 TfO OTf MeO 5% IMesPd(OAc)2 2% Pd(PPh3)4 8% Pd(PPh3)4 OMOM Ph MeO C CO Me N 60º C, AcOH, 74% N 2 N 2 aq. Na CO , THF aq. Na CO , THF H H 2 3 2 3 MeO2C CO2Me R reflux, 4 hrs reflux, 20 hrs N 78% 58% R

Tet. Lett. 2003, 44, 4443 Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst

Furan Much like the dibromo indole, after the first Negishi coupling, the lithium halogen exchange at C-3 is favored. - Not as resistant as pyrrole, but SNAr reactions still do not readily take place 2nd 6.24 without strong EWGs. Br OMe t-BuLi, MeI OMe - Cross coupling reactions occur fastest at the 2/5 positions, in accord with Br -78ºC, THF Br 7.29 st chemical shift prediction. OMe OMe O 1 54% - Halogenated have general stability problems, making cross couplings O O (CDCl3) sometimes troublesome. Synthesis 2003, 6, 925

Br SnMe Br Bu3Sn 4 5% [PdCl (Po-Tol ) ] 2 3 2 - A better substrate for SNAr than and two orders of magnitude more nd reactive than , but not many examples of haloselective reactions. MeO2C Br MeO2C 6.99 2 O 4% Pd(PPH3)4 O DMA, 90ºC, 70% - Cross coupling reactions occur fastest at the 2/5 positions and the 3/4 DMA, 90ºC, 79% 7.18 much slower. Selectivity on 2,5 dihalothiophenes is scarcely obtained st S 1 though some success has been seen with Sonogashira reaction and cases with substrate bias. 2 steps (CDCl3)

64% MeO2C O O Br Br NBnMe BnNHCH rosefuran 3 Synlett 1998, 11, 1185 O O + O Br BnMeN Br S 46% S S H H H Furfural can be selectively arylated in the 5- position directly. 4:1 Synlett 2000, 4, 459 OMe PhBr O O

O 10% Pd(OH)2, K2CO3 O Ph Br Br H DMA, 130ºC, 75% H S ZnCl Two more Br Br Br cross-couplings S JOC 2005, 70, 7578 S 2.5% [PdCl2(dppf)] S S 54% S Et2O 63% S Eur. JOC 2008, 5, 801

nd 2 BnZnBr p-TolMgCl 7.23 7.63 - Like indole, SNAr is uncommon on benzofuran Br Br Pd(PPh ) NiCl2(dppp) 6.76 - Cross coupling also mimics indole first at C-2, with C-4 to C-7 reacting 3 4 Br last 7.30 before electron rich C-3. Seems to follow Handy rules, though selectivity 52 - 57% quant 7.78 among C-4 through C-7 is unknown. S 7.51 O S st S (acetone) 1 Tet. Lett. 1980, 21, 4017

ClZn OMe Again, Lithium Halogen Exchange shows a different regioselection Br OMe Br OMe Br Br MgBr MeZnCl nBuLi, Et2O OMe -78ºC; H2O Br 5% [PdCl2(PPh ) ] O Br Br O 3 2 10% [NiCl2(dppe)] 10% [PdCl2(dppf)] S Br THF, rt, 75% THF, rt, 86% THF, reflux, 93% 79% S , pg 693 Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst

Benzothiophene Attempts to displace the second chloride leads to mixtures with ring opened products. nd 2 - SNAr occurs readily on , but they have some strange 7.70 7.5 7.26 7.72 7.56 8.45 7.22 reactions with nucleophiles. last - Cross coupling also mimics indole: first at C-2, with C-4 to C-7 reacting Cl MeS 7.24 N before C-3. S 1) 2 eq Na2S S MeS SMe 7.58 7.33 + 7.79 S N 7.85 9.11 1st NC NC N 2) MeI NC CN (CCl ) (CCl ) 4 4 Cl SMe JOC 1964, 29, 660

Br Br shows similar reactivity, with a bromide being displaces before an iodide. NH NH Br N N S 106ºC S 200ºC S Me Me 73% Br EtO2C S N N 1.2 eq Na2S, DMF, 100ºC; N JOC 1973, 88,1365 N Ethyl bromoacetate, rt EtO C MeO EtO2C 2 I 80% I MeO B(OH) B(OH)2 2 Syn. Comm. 2008, 38, 674 Br MeO OMe Ph Br 3% Pd(PPh ) 5% Pd(PPh ) S S 3 4 3 4 Br Na2CO3, EtOH/DME Ba(OH)2, H2O/DME Ph 95% 71% S Ph Ph N S Br 4% PdCl2(PPh3)2 N Synthesis 2002, 2, 213 Br CuI, TEA/MeCN, rt Br 56% Br The remaining two bromides were unreactive in further Sonogashira couplings, even at higher temps 1,2-Azoles st 1 MeO Ph Me 8.39 O 8.72 S 7.45 N I Ph N N rd S N 3 7.26 6.28 8.54 S 6.20 8.14 2nd N 2% PdCl2(PPh3)2 4% PdCl2(PPh3)2 7.31 I CuI, TEA/MeCN, rt CuI, TEA/MeCN, 50ºC N Br 45% (also 45% deiodo) 42% (CS ) Isothiazole (CCl4) MeO N-methyl pyrazole (CDCl3) 2 Br

- Selective SNAr reactions are only known with EWGs on the 4-position, but strongly favors substitution Russ. Chem. Bull. 1998, 47, 537 at the 5-position over the 3. This can be rationalized by both innate electronics (seen by NMR) and conjugation to the EWG. Tribromopyrazoles also lithiate at the most reactive C-5 - Cross coupling also follows Handy rules: first at C-5, then at C-2 and lastly C-3.

Br N n-BuLi, -78ºC; Bu3Sn N Cl EtO N Bu3SnCl N S EtOH (xs) S Br N N 77% Br NC 94% NC Br Br Cl Cl Tetrahedron 2007, 63, 56 Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst

1,3-Azoles Workers at Merck recently disclosed specific ligands to override and reinforce substrate bias in 2nd the 1,3-azoles in a screen of ~200 achiral phosphines. st Me 1 7.41 S P 6.86 N 7.69 O 7.95 8.88 10% 7.39 7.09 N N 7.98 N 7.01 N N 2.5% Pd(OAc) N 3rd O 2 O O 2.5% Xantphos 5% Pd(OAc)2 I I Ph (CCl4) (CDCl3) N-methyl (CDCl3) N N I N Ph K3PO4, PhB(OH)2 I K3PO4, PhB(OH)2 THF, 64% THF, 55% - SNAr reactions occur readily at C-2, though not very well at C-4/5 without assistance, and trends are not general among the series. Similar or better results were obtained for , but selective C-4/C-5 over C-2 Suzuki - Cross coupling also does not follow the Handy rules, with usual order of cross coupling being 2>5>4, couplings of dihalo thiophenes was not observed in any cases. No C-4 vs C-5 studies were Also note that the relative order chemical shifts switches in oxazole. undertaken.

JOC 2010, 75, 1733 OMe KCN, DMSO NaH, PhSH PhS Br N Br N THF N 18-crown-6 B(OH) Br CN CN 2 N O N N rt, 75% O N N PhB(OH)2 O2N 80ºC, 85% 2 2 Br N Br N 10% Pd(PPh3)4, Na2CO3 10% Pd(PPh3)4, Na2CO3 Br Ph N N Br PhH/MeOH/H2O PhH/MeOH/H2O MOM 94% 71% MOM OMe O2N N MeOH/NaOMe O2N N Br Br Chem. Pharm. Bull. 1996, 44, 1831 Br N reflux, 40% MeO N Regioselective Mg-Halogen exchange was observed of this dibromothiophene. J. Het. Chem 2000, 37, 119

EtO2C N N I EtO2C N Br Br Br S i-PrMgCl, THF Me2N N S -78ºC, 66% EtO2C N N SH EtO2C N Heterocycles 2007, 72, 293 Br S S n-BuLi, THF Br Br S 33% 1,3 azoles selectively C-H arylate at C-5 or C-2 Heterocycles 2007, 72, 293 PhBr Ph S S 10% Pd(OH) , K CO O N 2 2 3 DMA, 130ºC, 82% N X N X X JOC 2005, 70, 7578 OH H Br HN S S Br S I Br O O K CO , DMF O PdCl (PPh ) N 2 3 2 3 2 N MeO I N N N 125-180ºC µw CuI, TEA, THF N MeO 51-84% 80ºC, 53-89% OMe N N 5% Pd(OAc) Ph Bioorg. Med. Chem. Lett. 2006, 16, 6078 N 5% Pd(OAc)2 Ph 2 Ph CuI, DMF, 140ºC AsPh3, DMF, CsF MeO 76% 140ºC, 46% JOC 2005, 70, 3997, Eur. JOC 2006, 1379 Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst

Some Relative Rates of Azines (Joule and Mills 4th Edition) O PhB(OH)2 O O - BnNH For EtO at 20ºC NHR 5% PXPd2 2 Cl Cl NHR NHR 140ºC, 93% Cl Cl N Cl K2CO3, THF N reflux, 61% Cl N Ph BnHN N Ph N N R = CH2CH2OPh N Cl N N Cl N N Cl Cl 1 1.7x102 7.3x103 5.3x104 5.4x104 5.8x104 1.3x108 OL 2003, 5, 3131

X X X Cl Cl Ph X N NH2 N N NH2 > > > > > > 5% PdCl2(PPH3)2 N N CuI, TEA, 80ºC N N X N N N X N N X N N Cl 90% Ph

Pyridine JMC 2000, 43, 4288 - readily undergo S Ar, usually faster at C-4 than C-2/6, but highly soft nucleophiles nd N 7.55 2 dependent on nucleophile and conditions. C-3/5 react much slower. Br 7.16 3rd - Cross coupling reactions occur fastest at the 2/6 positions followed by C-4 F F hard nuclephiles and C-3/5 much slower, much in accord with the Handy predictions. Mono Tetrahedron 2005, 61, 2245 8.52 N 1st substitution can usually be acheived with 2,6-dihalo and 3,5-dihalo Br N Br (C6D6) pyridines. cross coupling

In, 4% Pd(PPh ) OH 3 4 Br LiI, DMF, 100ºC OH OR Cl Cl OAr Cl NaH, THF + + N Br Br , then N NaH, DMSO 61% N OAr N Cl N Cl N OR Br 65%, one pot 130ºC, 85% N Cl 1:6 1:3 ACIEE 2002, 41,3901

OH NH Cl OH O O 1) o-tolMgCl MeN 2) DDQ O O NHtBu NHtBu 98% NHtBu N Cl KOt-Bu, CuI, py KOt-Bu, DMA 100ºC, 97% THF, 120ºC, 84% N O Cl N 120ºC, 61% Cl N N N MeN OPRD 2008, 12, 411 JOC 2006, 71, 2000

O O O PhB(OH)2 Usefully, Li-Halogen exchange is slow at 2/6 positions due to lone pair repulsion 5% Pd(PPh ) OMe 3 4 OMe OMe + Br n-BuLi, -100ºC; D Cl N Cl K2CO3, THF Ph N Cl Cl N Ph reflux D SO , 85% 5:1 N Br 2 4 N Br Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst

Quinoline/ Isoquinoline /

nd st 7.52 7.73 8.05 2 7.70 7.5 1 9.17 N 7.46 7.31 7.56 8.45

8.82 N N 8.6 7.65 7.58 nd N N N st st 2 8.05 1 7.85 9.11 1 Pyrazine (C D ) Isoquinoline (CCl ) Pyridazine (C6D6) 6 6 (CCl4) 4

- SNAr reactions of quinoline mimic largely, with C-4>C-2 generally preferred, but usually - SNAr reactions occur readily at all of the positions. All sites are degenerate on pyrazine, and the dependent on reaction conditions. Isoquinoline reacts fastest at C-1 followed by C-3 in SNAr. 4-position is most activated for nucleophilic attack, despite NMR chemical shift. - Cross coupling reactions in quinoline strongly favor the 2 position followed by 4. Regioselection - Selective cross coupling reactions have not been well studied on pyridazine, but modest selectivity between the other positions has not been well investigated. Preference of 1 vs 3 is well established can be obtained from 3,6-dichloro compounds. in , but other positions not as well.

Cl HO HO N Cl MeO2C Cl Cl N MeO2C MeO2C N NH N Cl N ZnBr ZnBr N N N DMA, Na2CO3 Cl 74% Pd(PPh ) THF Cl LiCl, DMF, rt N Cl 3 4 N Cl 83% 60ºC, 80% Bioorg. Med. Chem. 2009, 17, 621 CO2Me

SnBu JOC 1999, 64, 453 aq. Me2NH S 3 EtOH, reflux S I I Me2N I Me2N N N 99% N N 5% PdCl2(PPh3)2 N N Cl Cl 80ºC, DMF MeOH, NaOMe 77% N N JOC 1995, 60, 748 60% Cl OMe SnBu3 OEt OEt SnBu O Cl 3 Cl Cl Cl N N 5% PdCl2(PPh3)2 N N OEt 80ºC, DMF 54% 4% [Pd(dba)2]PPh3 Chem. Eur. J. 2002, 8, 3448 Cl N Tol reflux Cl N 80% B(OH)2 Tetrahedron 2001, 57, 2507 Br N OMe

N Br N OMe Br N N Cl B(OH)2 TBS NTBS N SnBu3 N N N Br 10% Pd(PPh3)4 3% Pd(PPh3)4 4% Pd(PPh3)4 Na2CO3, MeOH/PhH Cl CsF, DME DMF, 100ºC 52% 87% 61% Br Tetrahedron 2001, 57, 2507 JOC 2002, 67, 9392 Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst

Pyrimidine Benzannelated st st rd st 1 1 3 8.78 1 - readily undergo SNAr at the 2 and 4/6 positions. 4/6 being 7.77 8.01 8.18 nd 8.13 9.60 7.93 9.91 7.36 N generally more reactive, but is very sensitive to reaction conditions. The 3- 7.86 2 8.11 N 7.93 8.00 8.84 N 2nd position is greatly deactivated relative to the others. 9.29 N 2nd 9.26 N - Cross coupling reactions occur fastest at the 4/6 positions followed by C-2 N N 7.67 9.35 7.95 N N N and C-5 much slower, in direct contrast to the Handy predictions. 8.44 8.06 (C6D6) (CDCl3) (acetone) (CDCl3) (CDCl3)

- SNAr reactions occur readily at all of the heterocyclic positions. Behavior seems to be similar to the counterparts, ie C-4 more reactive than C-2 in , C-4>C-3 in cinnoline. Cl 4.2 eq N HN NH N - Cross coupling reactions have not been well studied on these systems, but the few examples mimic N N H N N the corresponding diazines well. THF, -10 C to rt 86% Cl N Cl 92% Cl N N N N N HN SMe HN NH2 OPRD 2006, 10, 921 N N MeCN, 130ºC N SMe 84% N SMe Cl OH TMS Cl MeOH OMe n-BuLi, THF NaOMe N N N JMC 1993, 36, 2196 TMS rt, 90% N O -68ºC,-rt, 90% N Cl N Cl

OTHP Chem. Soc. Perkin 2 1989, 1499; J. Het. Chem. 1994, 31, 989 Cl N Cl N

N Cl 7.5% Pd(OAc)2, PPh3 CuI, MeCN, TEA N Cl PhB(OH) PhB(OH) OTHP 2 Ph 2 Ph PhB(OH)2 60ºC, 56% Cl 5% Pd(PPh3)4 5% Pd(PPh3)4 5% Pd(Pt-Bu3)2 N Cl Cl N N J. Chem. Soc. Perkin 1 2001, 978 K CO , Tol/DMF K CO , Tol/DMF K CO , Tol/DMF N Cl 2 3 2 3 2 3 Bu µw, 185ºC N Cl µw, 185ºC N Ph µw, 185ºC 10 min, 58% 10 min, 65% 10 min, 70% Cl Bu Tet. Lett. 2006, 47, 4415 Br Br N N 2% PdCl2(PPH3)2 CuI, TEA, rt Lithium reagents can directly add into C-4/6, which can be oxidized back to easily N Cl N Cl 67% Li Acta Chem. Scand. 1996, 50, 914 O Me N Me2N 2 O Li SH S N O N N N Cl Et2O, -40ºC; EtOH, NaOEt Et2O, -40ºC; then DDQ, 92% 70ºC, 81% then DDQ, 72%% N Cl N S

Me2N S JMC 2008, 51, 2734 Me2N Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst

Purine Misc Examples st 1 - can participate in S Ar reactions at all carbon centers. For 9-H F 8.83 N NH2 N purines, the order of reactivity is 6>8>2. For substitution at 9, reactivity N 3rd 8.5 changes to 8>6>2. Cl - Cross coupling reactions usually occur fastest at the 6 position, though NH2 8.72 N N 2nd KCN, DMSO HN F H C-8 becomes competitive in some cases. C-2 is slowest. N N F F (D2O) DCM, Et Ni-Pr º N N Cl N Cl 2 DCM, Et2Ni-Pr 120 C, 89% 86% 91% N N CN Ph Ph Ph Ph H H2N Ph JMC 2010, 53, 52 Cl 1) K2CO3, MeOH, 100% HN HN 2) PdCl2(dppf)DCM N Ph N N N N CO, THF N SMe NHBn N TEA, MeCN I N RHN N Sug 95% I N N N N N BnNH2 N Sug Sug N N O N NH2 N UK-371,104 MeS N 50ºC, 95% MeS N OPRD 2008, 12, 575

S JMC 2009, 52, 655 Cl SnBu S 3 N N N N OEt Cl SNAr, Sonogashira OEt R Cl Cl Stille and Suzuki 5% PdCl (PPh ) N N 2 3 2 N N N N N N THP DCE, 75ºC THP 63% Single regioisomer N Cl (no yields reported) N Cl Acta Chem. Scand. 1999, 53, 366 Tet. Lett. 2006, 47, 8917

C-8 can be directly functionalized to give highly flexible syntheses of trisubstituted purines S B(OH) S 2 N Cl PhB(OH)2 N 5% Pd(PPh ) 5% Pd(PPh ) Cl I 3 4 3 4 MeMgCl PhB(OH)2 N N 5% Pd(PPh ) N N N Fe(acac)3 3 4 5% Pd(OAc)2 K CO , Tol Na2CO3, Tol/EtOH N N N 2 3 Cl 100ºC, 84% 100ºC, 98% Ph 72% Cl N N K2CO3, Tol CuI, Cs2CO3 Bn Ph N N 100ºC DMF, 160ºC Bn OL 2007, 9, 4673 79% (two steps) OL 2006, 8, 5389

F O OH OH OH Br Ar Cl Cl F MeMgCl O N OH OH N 30% Fe(acac)3 N O N N N Br O Cl O Ar N N N N NMP/THF N NaHMDS N LiHMDS THP N 37% THP N THF, -10ºC Br THF, -40ºC Br 78% 60% Synlett 2004, 6, 889 HO OPRD 2006, 10, 512 Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst

Conclusions

Selective reactions of polyhaloheterocycles has proven to be a very powerful method for synthesis of functionalized heterocycles. Frequently cross-coupling and SNAr are complementary methods, with C-H functionalization rapidly growing. While the prediction of regioselectivity is difficult to rationalize at times, common trends are seen in certain heterocyclic motifs and can be extrapolated to more complex situations, though, screening seems to still be needed for many cases. Future directions are in the ligand controlled cross coupling and further development of C-H activation reactions.

Key References

Cross coupling reviews: Tetrahedron 2005, 61, 2245 Chem. Soc. Rev. 2007, 36, 1036 Synthesis 2009, 9, 1405

Computational Analysis of Polyhalo Heterocycles JACS, 2007, 129, 12664 JACS, 2009, 131, 6632

Handy Predictions Chem. Comm. 2006, 299

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