Single-isomer tetrasubstituted olefins from regioselective and stereospecific palladium-catalyzed coupling of β-chloro-α-iodo- α,β-unsaturated esters

Article abstract of DOI:10.1021/jo060144h

The efficient regioselective and stereospecific synthesis of tetrasubstituted olefins using a mild and convenient method is disclosed. 2-Alkynyl esters are selectively converted to E-β-chloro-α-iodo- α,β-unsaturated esters by exposure to Bu₄-NI

Full text of DOI:10.1021/jo060144h

bonds.7 This has mandated the development of indirect methods
to prepare these moieties, including the carbometalation of
alkynes followed by organometallic coupling (eq 1)8 and the
functionalization of existing alkene templates (eq 2).9
Single-Isomer Tetrasubstituted Olefins from
Regioselective and Stereospecific
Palladium-Catalyzed Coupling of
â-Chloro-r-iodo-r,â-unsaturated Esters
Alison B. Lemay, Katarina S. Vulic, and
William W. Ogilvie*
Department of Chemistry, UniVersity of Ottawa,
10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
wogilVie@science.uottawa.ca
ReceiVed January 23, 2006
Regioselectivity is often problematic in the first method, an
issue often overcome by the use of directing groups. The use
of alkene templates ameliorates the regiochemical difficulty;
however, the preparation of the olefin template often becomes
challenging. Many processes of both types give mixtures of
regio- and stereoisomers.6 There are few techniques that
construct acyclic tetrasubstituted olefins,6,10 and preparations of
alkenes bearing four distinct carbon substituents are rare.6,11
In this paper, we describe a mild and convenient method of
forming acyclic, single isomer tetrasubstituted alkenes bearing
four different carbon substituents. E-â-Chloro-R-iodo-R,â-un-
saturated esters are generated from 2-alkynyl esters by exposure
to Bu4NI in refluxing dichloroethane. This process occurs with
complete selectivity and sets the foundation for the remaining
steps in the method. Sequential organometallic coupling of the
â-chloro-R-iodo-R,â-unsaturated esters with a variety of partners
occurs with complete regioselectivity and stereospecificity,
The efficient regioselective and stereospecific synthesis of
tetrasubstituted olefins using a mild and convenient method
is disclosed. 2-Alkynyl esters are selectively converted to
E-â-chloro-R-iodo-R,â-unsaturated esters by exposure to Bu4-
NI in refluxing dichloroethane. These products are produced
cleanly, regio- and stereoselectively, and in high yields.
Single-isomer tetrasubstituted olefins bearing four different
carbon substituents are then synthesized by sequential
palladium-catalyzed coupling reactions. Selectivity results
from reactivity differences in the intermediate substrates.
Tetrasubstituted olefins are key structural elements of natural
products and pharmaceuticals such as Nileprost1 and Tamox-
ifen.2 These moieties also serve as substrates for asymmetric
transformations that generate contiguous, asymmetric, quater-
nary centers such as osmylations,3 epoxidations,4 and conjugate
additions.5 To ensure high stereocontrol in synthesis, and
enantioselectivity in the latter processes, it is imperative that
methods be available to prepare tetrasubstituted olefins with tight
control of regio- and stereochemistry.
The efficient regio- and stereoselective synthesis of tetrasub-
stituted olefins is particularly challenging.6 Steric encumbrance
about the olefin and frequent lack of directing substituents
contribute significantly to this problem. Classic double-bond-
forming methods such as the Wittig and Horner-Wadsworth-
Emmons reactions encounter serious issues of generality and
stereoselectivity when used to form tetrasubstituted double
(7) (a) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. (b)
Healy, M. P.; Parsons, A. F.; Rawlinson, J. G. T. Org. Lett. 2005, 7, 1597.
(c) Boutagy, J.; Thomas, R. Chem. ReV. 1974, 74, 87.
(8) (a) Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57, 5899. (b) Zhou,
C.; Larock, R. C. Org. Lett. 2005, 7, 259. (c) Zhang, X.; Larock, R. C.
Org. Lett. 2003, 5, 2993. (d) Zhou, C.; Emrich, D. E.; Larock, R. C. Org.
Lett. 2003, 5, 1579 and references therein. (e) Zhou, C.; Larock, R. C. J.
Org. Chem. 2005, 70, 3765 and references therein. (f) Thadani, A. N.;
Rawal, V. H. Org. Lett. 2002, 4, 4317. (g) Takahashi, T.; Xi, C.; Ura, Y.;
Nakajima, K. J. Am. Chem. Soc. 2000, 122, 3228. (h) Piers, E.; Skerlj, R.
T. J. Org. Chem. 1987, 52, 4421. (i) Piers, E.; Morton, H. E. J. Org. Chem.
1980, 45, 4263. (j) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997,
119, 9065. (k) Suginome, M.; Yamamoto, A.; Murakami, M. J. Am. Chem.
Soc. 2003, 125, 6358. (l) Tsuda, T.; Kiyoi, T.; Saegusa, T. J. Org. Chem.
1990, 55, 2554 and references therein.
(9) Functionalization of existing alkene templates (selected examples):
(a) Itami, K.; Mineno, M.; Muraoka, N.; Yoshida, J. J. Am. Chem. Soc.
2004, 126, 11778. (b) Shimizu, M.; Nakamaki, C.; Shimono, K.; Schelper,
M.; Kurahashi, T.; Hiyama, T. J. Am. Chem. Soc. 2005, 127, 12506. (c)
Rathore, R.; Deselnicu, M. I.; Burns, C. L. J. Am. Chem. Soc. 2002, 124,
14832. (d) Bellina, F.; Anselmi, C.; Martina, F.; Rossi, R. Eur. J. Org.
Chem. 2003, 2290. (e) Bauer, A.; Miller, M. W.; Vice, S. F.; McCombie,
S. W. Synlett 2001, 2, 254. (f) Shao, L.-X.; Shi, M. J. Org. Chem. 2005,
70, 8635. (g) Angell, R.; Parsons, P. J.; Naylor, A. Synlett 1993, 189.
(10) Selected preparations of tetrasubstituted olefins using identical
vicinal olefinic halogens: (a) Rossi, R.; Bellina, F.; Carpita, A.; Mazzarella,
F. Tetrahedron 1996, 52, 4095. (b) Boldi, A. M.; Anthony, J.; Knobler, C.
B.; Diederich, F. Angew. Chem., Int. Ed. Engl. 1992, 31, 1240. (c) Fitzgerald,
J.; Taylor, W.; Owen, H. Synthesis 1991, 686. (d) He´naff, N.; Whiting, A.
J. Chem. Soc., Perkin Trans. 1 2000, 395.
(1) Takahashi, A.; Kirio, Y.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J.
Am. Chem. Soc. 1989, 111, 643.
(2) (a) Mohammed, A.-H. Synthesis 1987, 816. (b) Itami, K.; Kamei,
T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670. (c) Tessier, P. E.;
Penwell, A. J.; Souza, F. E. S.; Fallis, A. G. Org. Lett. 2003, 5, 2989.
(3) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.Chem. ReV.
1994, 94, 2483. (b) Dobler, C.; Mehltretter, G. M.; Sundermeier, U.; Beller,
M. J. Am. Chem. Soc. 2000, 122, 10289.
(4) Katsuki, T.; Martin, V. Org. React. 1996, 48, 1.
(5) (a) Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; p 224. (b) Hayashi, T.; Yamasaki, K.
Chem. ReV. 2003, 103, 2829.
(6) Selected methods: (a) Yang, F.-Y.; Shanmugasundaram, M.; Chuang,
S.-Y.; Ku, P.-J.; Wu, M. Y.; Cheng, C.-H. J. Am. Chem. Soc. 2003, 125,
12576. (b) Shimizu, M.; Nakamaki, C.; Shimono, K.; Schelper, M.;
Kurahashi, T.; Hiyama, T. J. Am. Chem. Soc. 2005, 127, 12506. (c) Zhu,
N.; Hall, D. G. J. Org. Chem. 2003, 68, 6066. (d) Pospisil, J.; Pospisil, T.;
Marko, I. E. Org. Lett. 2005, 7, 2373. (e) Gerard, J.; Hevesi, L. Tetrahedron
2004, 60, 367.
(11) Selected preparations of alkenes bearing four different carbon
substituents: (a) Rossi, R.; Bellina, F.; Bechini, C.; Mannina, L.; Vergamini,
P. Tetrahedron 1998, 54, 135. (b) Myers, A. G.; Alauddin, M. M.; Fuhry,
M. A. M.; Dragovich, P. S.; Finney, N. S.; Harringlton, P. M. Tetrahedron
Lett. 1989, 30, 6997.
10.1021/jo060144h CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/28/2006
J. Org. Chem. 2006, 71, 3615-3618
3615

TABLE 1. Formation of â-Chloro-r-iodo-r,â-unsaturated Esters
SCHEME 1. Confirmation of Olefin Template
Stereochemistry
entry
R1
product
yield (%)
1
2
3
4
5
H
CH3
cyclohexyl
TBSOCH2CH2
Ph
1
2
3
4
5
89
91
62
67
76
delivering the desired tetrasubstituted olefins as single isomers.
This method is simple, reliable, does not require specialized
equipment or substrates, and is amenable to large scale.
The required â-chloro-R-iodo-R,â-unsaturated esters were
readily prepared as single isomers by treatment of the corre-
sponding 2-alkynyl esters with Bu4NI in refluxing dichloroeth-
ane (DCE) (Table 1). The products of the Bu4NI process were
easily obtained as pure, single isomers by simple filtration
through silica gel.12 This reaction was compatible with a variety
of functionalities, including unsubstituted (entry 1), simple alkyl
(entry 2), branched alkyl (entry 3), silyl ethers (entry 4), and
aryl alkynyl esters (entry 5). Previously, it was reported that
2-alkynyl esters could be converted to â-chloro-R-iodo-R,â-
unsaturated esters by treatment with ICl.13,14 We found that this
procedure gave side products, mixtures of E/Z isomers, required
an extractive workup, and consistently gave lower yields.
Exposure to Bu4NI in DCE was superior to the ICl process,
giving cleaner, higher yielding reactions from simpler workups.
Although related â-chloro-R-iodo products have been de-
scribed in the literature, the stereochemistry of these products
has never been unequivocally established.13 The regiochemistry
of the products in Table 1 was verified by 13C NMR analysis
in which the R-carbons exhibited strong upfield shifts consistent
with iodine substitution.15 The configuration of the alkene pro-
ducts was determined using NMR methods. In a representative
example, E-ester 2 was briefly photolyzed to generate the cor-
responding Z-isomer 6 (Scheme 1).16 The esters were imme-
diately reduced with DIBAL, giving the corresponding alcohols
7 and 8. Consistent with the structural assignments shown, NOE
enhancements were observed between the methyl and methylene
of compound 8, whereas these interactions were lacking in iso-
mer 7. This procedure was repeated for all products described
in Table 1, and in all cases, the stereochemistry shown was
confirmed.
2 as substrate, evaluating a variety of catalysts, solvents, and
bases. A screen of palladium catalysts identified Pd(PPh3)2Cl2,
Pd(PPh3)4, and Pd(dppf)Cl2 as effective catalysts for the reaction,
while Pd(OAc)2 and Pd2(dba)3 gave lower yields. For reasons
of convenience, Pd(PPh3)2Cl2 was selected for further investiga-
tion. Bases were examined using the same test system that show-
ed Hu¨nig’s base (DIPEA) to be superior to NEt3, 1,4-diazabicyclo-
[2.2.2]octane (DABCO), K2CO3, and Cs2CO3. A solvent screen
revealed 1,4-dioxane (0.1 M) to be the optimal solvent.20,21
Complete conversion and good yields were achieved in all
cases examined within 2 h for a wide range of acetylenes (Table
2). The reaction was scalable22 and tolerated a variety of sub-
stituent functionalities, including aryl (entries 1 and 2), silyl
(entry 3), and alkyl groups (entry 4), as well as tethered silyl
ethers of varying chain lengths (entries 5 and 6). Other sub-
stituents at R1 were well-tolerated, and trisubstituted alkenes
were prepared employing a bulky cyclohexyl group (entry 7)
and a functionalized alkyl chain (entry 8). These reactions all
1
gave single-isomer products as evidenced by GC-MS and H
and 13C NMR analysis.
Notably, coupling was observed exclusively at the R-position.
This result is in stark contrast to those reported for related sub-
strates incorporating the same halogen at both the R and â po-
sitions.9,10 In those substrates, the â-position was far more ac-
tivated toward oxidative addition than was the R-position giving
selective coupling at the â-position23 (see also eq 2). In our
substrates, the enhanced reactivity of the iodide over the chloride
overrode the inherent reactivity of the system.17 To our know-
ledge, this is the first time that selective coupling has been
observed at the R-position of R,â-dihalo-R,â-unsaturated esters.
We then faced the challenge of forming all-carbon tetrasub-
stituted olefins from our trisubstituted precursors (Table 3). We
were delighted with the speed and high conversion of the coup-
lings as the formation of these congested centers is often quite
The â-chloro-R-iodo-R,â-unsaturated esters were subjected
to sequential cross-coupling reactions to generate tetrasubstituted
olefins. We initially investigated the selective Sonogashira coup-
ling reaction of â-chloro-R-iodo-R,â-unsaturated esters.17,18,19
Our initial experiments produced significant amounts of doubly
coupled products. To identify conditions that would produce
mono-coupling, optimization studies were done using dihalide
(17) General references: (a) Tsuji, J. Palladium Reagents and Catalysts;
John Wiley & Sons: Ltd: Chichester, West Sussex, England, 2004; and
references therein. (b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc.
2000, 122, 4020 and references therein.
(18) Use of different vicinal olefinic halogens in cross-coupling reac-
tions: Organ, M. G.; Ghasemi, H. Valente, C. Tetrahedron 2004, 60, 9453
and references therein.
(19) (a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46 and
references therein. (b) Kollhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem.,
Int. Ed. 2003, 42, 1056 and references therein.
(20) Solvents screened included CH2Cl2, CH3CN, DMF, 1,4-dioxane,
THF, and DMSO.
(21) Glaser-type products were prominent unless the reaction was
carefully degassed prior to addition of the acetylenic component. Siemsen,
P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632.
(22) Multigram (3 g) scale reactions were performed successfully giving
yields consistent with those shown.
(12) On a large scale, washing with saturated NaHSO3 immediately after
the reaction facilitated subsequent purification by flash chromatography.
(13) Bellina, F.; Colzi, R.; Mannina, L.; Rossi, R.; Viel, S. J. Org. Chem.
2003, 68, 10175.
(14) For reactions of ICl with other types of alkynes, see: (a) Tendil, J.;
Verney, M.; Vessiere, R. Tetrahedron 1974, 30, 579. (b) Heasley, V. L.;
Buczala, D. M.; Chappell, A. E.; Hill, D. J.; Whisenand, J. M.; Shellhamer,
D. F. J. Org. Chem. 2002, 67, 2183.
(15) This was confirmed by DEPT analysis of ester 1 and by subsequent
NOE analysis of tetrasubstituted olefins 17-25.
(16) O’Connor, J. M.; Friese, S. J.; Rodgers, B. L. J. Am. Chem. Soc.
2005, 127, 16342.
3616 J. Org. Chem., Vol. 71, No. 9, 2006

TABLE 2. Preparation of Trisubstituted Alkenes from
TABLE 3. Preparation of Tetrasubstituted Alkenes from
â-Chloro-r,â-unsaturated Esters
â-Chloro-r-iodo-r,â-unsaturated Estersa
a Reaction conditions: 2 (1 equiv), alkyne (3 equiv), Pd(PPh3)2Cl2 (10
mol %), CuI (15 mol %), DIPEA (3 equiv), dioxane (0.1 M), rt, 2 h.
b Isolated yield. c 0 °C. d 3 (1 equiv). e 4 (1 equiv).
difficult. Employing the optimized coupling conditions for the
Sonogashira reaction, we successfully coupled phenyl acetylene
to two different trisubstituted olefins (entries 1 and 2).
Seeking structural variety in the coupling partners, we next
explored the Suzuki-Miyaura coupling reaction.24 Tetrasub-
stituted olefins were obtained in good yields by coupling aryl-
and alkenylboronic acids with our trisubstituted vinylic chlorides
(Table 3). The reactions proved to be scalable25 and tolerated
aryl groups bearing electron-donating and electron-withdrawing
substituents (entries 3-5). The use of styrenyl (entry 6) and
alkenylboronic acids (entry 7) were also effective, smoothly
a Isolated yield. b Reaction conditions: acetylene (6 equiv), Pd(PPh3)2Cl2
(10 mol %), CuI (15 mol %), DIPEA (3 equiv), dioxane (0.1 M), rt, 18 h.
c Reaction conditions: R2B(OH)2 (2 equiv), Pd2(dba)3 (5 mol %), P(t-
Bu)3‚HBF4 (20 mol %), Cs2CO3 (2 equiv), dioxane (0.1 M), rt, 2 h.
d Reaction conditions: R3B(OH)2 (2 equiv), Pd2(dba)3 (5 mol %), S-Phos
(20 mol %), K3PO4 (2 equiv), THF (0.1 M), rt, 2 h.
(23) R, â-Dibromo-R, â-unsaturated esters such as i underwent Negishi
coupling to give products of type ii in 18-61% yield. One of these products
ii (R ) C5H11) was transformed by further Negishi coupling to iii (Ar )
Ph-4-OMe) in 13% yield as an 88:12 mixture of E/Z isomers. Direct coupling
of i (R ) C5H11) with excess zinc reagent (ZnClPh-4-OMe) gave only ii
and iii (1:1 ratio of E/Z isomers, no yield reported). In all cases, no trace
of the R-coupled product was reported. Reference 10a.
giving rise to conjugated dienynes. The use of other R1 groups
was equally successful, and tetrasubstituted alkenes were pre-
pared bearing a cyclohexyl group (entry 8) and a functionalized
alkyl chain (entry 9). In all cases, single isomers were obtained
from the process thus overcoming the most difficult hurdle in
(24) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Miura, M. Angew. Chem., Int.
Ed. 2004, 43, 2201.
(25) Reactions up to 500 mg scale were performed giving yields
consistent with those shown.
J. Org. Chem, Vol. 71, No. 9, 2006 3617

SCHEME 2. Confirmation of Tetrasubstituted Olefin
Configuration
of methyl propiolate (250 mg, 2.98 mmol, 1 equiv) and tetrabu-
tylammonium iodide (3.25 g, 8.95 mmol, 3 equiv) in dichloroethane
(25 mL) was heated at reflux for 18 h. The pure product was ob-
tained by column chromatography on silica gel eluting with hexanes
and then 5% EtOAc in hexanes to give the title compound as a
colorless oil (652 mg, 89%): 1H NMR (300 MHz, CDCl3) δ 7.00
(s, 1H), 3.79 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6 (C),
129.4 (CH), 84.3 (C), 53.2 (CH3); IR (neat) 1728, 1567 cm-1; MS
(EI) 246 (M+); HRMS calcd for C4H4ClIO2 (M+) 245.8945, found
245.8926.
General Procedure for the Sonogashira Coupling of (E)-â-
Chloro-r-iodo-r,â-unsaturated Esters (Table 2, Compounds
9-16). (Z)-Ethyl 3-Chloro-2-(2-phenylethynyl)but-2-enoate (9).
A flask was charged with Pd(PPh3)2Cl2 (13 mg, 0.018 mmol, 0.10
equiv) and copper iodide (5.1 mg, 0.027 mmol, 0.15 equiv). To
this were added dichloromethane (2 mL) and diisopropylethylamine
(0.13 mL, 0.72 mmol, 4 equiv) via syringe. (E)-Ethyl 3-chloro-2-
iodobut-2-enoate (2) (50 mg, 0.18 mmol, 1 equiv) was then intro-
duced, and the resulting yellow solution was carefully sparged with
nitrogen for 10 min. Phenylacetylene (0.06 mL, 0.55 mmol, 3 equiv)
was then added via syringe, and the resulting black solution was
stirred for 2 h. The mixture was partitioned between water and
EtOAc and the organic layer collected and then dried over
anhydrous MgSO4, filtered, and concentrated. The product was
purified by column chromatography on silica gel eluting with
hexanes then 5% EtOAc in hexanes to afford the title product (35
mg, 78%) as a clear, tan oil: 1H NMR (300 MHz, CDCl3) δ 7.48-
7.46 (m, 2H), 7.35-7.34 (m, 3H), 4.33 (q, J ) 7.0 Hz, 2H), 2.52
(s, 3H), 1.37 (t, J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
163.5 (C), 146.6 (C), 131.4 (CH), 128.8 (CH), 128.3 (CH), 122.5
(C), 115.3 (C), 96.8 (C), 83.0 (C), 61.7 (CH2), 26.2 (CH3), 14.0
(CH3); IR (neat) 2201, 1734, 1612 cm-1; MS (EI) 248 (M+); HRMS
calcd for C14H13ClO2 (M+) 248.0604, found 248.0617.
General Procedure for the Suzuki Coupling of â-Chloro-r-
alkynyl-r,â-unsaturated Esters (Table 3, Compounds 19-25).
(Z)-Ethyl 3-Phenyl-2-(2-(trimethylsilyl)ethynyl)but-2-enoate (19).
A flame-dried round-bottom flask was charged with a solution of
(Z)-ethyl 3-chloro-2-(2-(trimethylsilyl)ethynyl)but-2-enoate (11) (50
mg, 0.20 mmol, 1 equiv) in 1,4-dioxane (2 mL), and the solution
was sparged for 10 min with N2. Pd2(dba)3 (9.2 mg, 0.010 mmol,
0.05 equiv), phenylboronic acid (49 mg, 0.40 mmol, 2 equiv), and
tri-tert-butylphosphine tetrafluoroborate (11.6 mg, 0.040 mmol, 0.20
equiv) were then added. The solution was sparged for an additional
5 min with N2 before the addition of Cs2CO3 (130 mg, 0.40 mmol,
2 equiv). The resulting black solution was stirred for 2 h after which
water was added. The mixture was extracted with EtOAc, and the
organic layer was dried over anhydrous MgSO4, filtered, and
concentrated. The product was purified by column chromatography
on silica gel, eluting with hexanes then 5% EtOAc in hexanes
affording the product as a pale yellow oil (44 mg, 77%): 1H NMR
(300 MHz, CDCl3) δ 7.36-7.30 (m, 3H), 7.29-7.16 (m, 2H), 3.98
(q, J ) 7.2 Hz, 2H), 2.39 (s, 3H), 0.98 (t, J ) 7.2 Hz, 3H), 0.26
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 165.7 (C), 156.4 (C), 141.3
(C), 128.1 (CH), 128.0 (CH), 126.5 (CH), 115.0 (C), 101.5 (C),
100.5 (C), 61.0 (CH2), 24.5 (CH3), 13.6 (CH3), -0.1 (CH3); IR
(neat) 2146, 1728, 1592 cm-1; MS (EI) 286 (M+); HRMS calcd
for C17H22O2Si (M+) 286.1389, found 286.1366.
the formation of tetrasubstituted olefins.26 The regio- and ster-
eochemistry of the final products was confirmed as before using
NMR methods (Scheme 2). In a typical example, a sample of
19 was isomerized by brief photolysis and the E/Z isomers 19
and 26 were then reduced with DIBAL to give alcohols 27 and
28.27 NOE enhancements were observed between the methyl
and methylene of alcohol 28, indicating a cis relationship
between these substituents. Alcohol 27, corresponding to the
initial product 19, did not give enhancements between these
substituents. Instead, NOE interactions were clearly noted
between the Ph and CH2 moieties. The network of NOE
interactions observed for both isomers was consistent with the
assignments shown and correlated exactly with the earlier
structural assignments (Scheme 1). Other compounds in Table
3 were treated in a similar manner and gave consistent results.
This corroborated the regiochemical assignments for compounds
1-5.
We have illustrated a new, high-yielding method for the regio-
and stereocontrolled formation of tetrasubstituted olefins bearing
four different carbon substituents. Treatment of 2-alkynyl esters
with Bu4NI in DCE gave the corresponding E-â-chloro-R-iodo-
R,â-unsaturated esters cleanly and selectively. These materials
then served as olefin templates from which tetrasubstituted
olefins were obtained by sequential cross-coupling reactions.
By carefully optimizing the conditions, complete selectivity
could be achieved in the first coupling. The subsequent coupling
reactions all occurred under mild conditions and gave the desired
olefins in good yields. In all cases investigated, the product
olefins were cleanly obtained as single isomers. This method
is simple, reliable, and scalable. The stereochemistry of the
products was unequivocally determined by NMR analysis.
Current efforts in our laboratory are being devoted to the
expansion of the scope of this methodology, as well as to the
application of these valuable substrates to further asymmetric
transformations. Results will be reported in due course.
Experimental Section
Acknowledgment. We thank the Natural Science and Engi-
neering Research Council of Canada (NSERC), Canada Foun-
dation for Innovation, Ontario Innovation Trust, and the Uni-
versity of Ottawa for generous funding. K.S.V. thanks the Uni-
versity of Ottawa for an undergraduate student research award.
General Procedure for the Conversion of 2-Alkynyl Esters
into (E)-â-Chloro-r-iodo-r,â-unsaturated Esters (Table 1, Com-
pounds 1-5). (E)-Methyl 3-Chloro-2-iodoacrylate (1). A solution
(26) Every tetrasubstituted olefin prepared in this study was shown by
1H, 13C, and GC-MS analysis to be a single isomer. After a few weeks at
room temperature, partial E/Z isomerization occurred, observable by 1H,
13C, and GC-MS. This was prevented by storing the products frozen in
benzene.
(27) A pure sample of 19 was separately reduced in order to verify the
identity of the corresponding alcohol isomer 27.
Supporting Information Available: Experimental procedures,
1
product characterization data, and H and 13C NMR spectra for
compounds 1-28. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO060144H
3618 J. Org. Chem., Vol. 71, No. 9, 2006