Single-isomer iodochlorination of alkynes and chlorination of alkenes using tetrabutylammonium iodide and dichloroethane

Article abstract of DOI:10.1021/jo062188w

(Chemical Equation Presented) The efficient formation of single-isomer, differentially halogenated alkenes and alkanes is described. These structures were generated by treatment of the appropriate alkyne or alkene with tetrabutylammonium iodide in refluxing dichloroethane. This process is highly selective as evidenced by control experiments using ICl. Treatment of the same alkenes and alkynes directly with iodine monochloride resulted in complex, inseparable mixtures of regio- and stereoisomers. Mechanistic studies indicated that the Bu₄NI reaction most likely proceeded through the slow generation of ICl. Complexation of ICl with Bu₄NI is also a key controlling element that leads to perfect regio-, chemo-, and stereoselectivity in these processes.

Full text of DOI:10.1021/jo062188w

Single-Isomer Iodochlorination of Alkynes and Chlorination of
Alkenes Using Tetrabutylammonium Iodide and Dichloroethane
Michael L. Ho, Alison B. Flynn, and William W. Ogilvie*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
wogilVie@science.uottawa.ca
ReceiVed October 20, 2006
The efficient formation of single-isomer, differentially halogenated alkenes and alkanes is described.
These structures were generated by treatment of the appropriate alkyne or alkene with tetrabutylammonium
iodide in refluxing dichloroethane. This process is highly selective as evidenced by control experiments
using ICl. Treatment of the same alkenes and alkynes directly with iodine monochloride resulted in
complex, inseparable mixtures of regio- and stereoisomers. Mechanistic studies indicated that the Bu4NI
reaction most likely proceeded through the slow generation of ICl. Complexation of ICl with Bu4NI is
also a key controlling element that leads to perfect regio-, chemo-, and stereoselectivity in these processes.
Introduction
of alkenes4 and aromatic compounds,5 and many of these involve
generation of ICl in situ. For example, halogenation of alkenes
can be done using iodine and copper(II) chloride, but the method
tends to give mixtures of iodochlorinated regioisomers and
dichlorinated products.4a,b Thallium(I) azide has been employed
as an additive in combination with iodine and gives predomi-
nantly anti addition products.4c As in the case of other methods,
control of the regioselectivity and stereoselectivity are significant
issues associated with this technique.
Halogenation reactions feature prominently in the toolbox of
the organic chemist. Bromination and chlorination are straight-
forward processes. Iodination is frequently more difficult
because the reaction proceeds very slowly and is often reversible
under standard conditions.1 Because of these reactivity chal-
lenges, additives are typically required to promote iodination
of alkenes and alkynes. Halogenation using iodine monochloride
is more facile because a permanent dipole exists in the reagent
that greatly facilitates electrophilic attack.2 Unfortunately, this
process usually produces regio- and stereoisomers that are
difficult to separate and purify. Use of iodine monochloride for
iodination of aromatic compounds frequently gives mixtures of
mono-, di-, and tri-iodinated arene products.3 To overcome these
selectivity and reactivity difficulties, a variety of conditions have
been developed for the more efficient and selective iodination
(4) (a) Raju, B. R.; Kumar, E. K. P.; Saikia, A. K. Tetrahedron Lett.
2005, 47, 1997. (b) Bortolini, O.; Bottai, M.; Chiappe, C.; Conte, V.;
Pieraccini, D. Green Chem. 2002, 4, 621. (c) Baird, W. C., Jr.; Surridge, J.
H.; Buza, M. J. Org. Chem. 1971, 36, 2088. (d) Baird, W. C., Jr.; Surridge,
J. H.; Buza, M. J. Org. Chem. 1971, 36, 3324. (e) Cambie, R. C.; Hayward,
R. C.; Rutledge, P. S.; Smith-Palmer, T.; Woodgate, P. D. J. Chem. Soc.,
Perkin Trans. 1 1976, 840. (f) Cambie, R. C.; Hayward, R. C.; Lindsay, B.
G.; Phan, A. I. T.; Rutledge, P. S. Woodgate, P. D. J. Chem. Soc., Perkin
Trans.1 1976, 1961.
(5) (a) Mohan, K. V. V. K.; Narender, N.; Kulkarni, S. J. Tetrahedron
Lett. 2004, 45, 8015. (b) Yang, S. G.; Kim, Y. H. Tetrahedron Lett. 1999,
40, 6051. (c) Baird, W. C., Jr.; Surridge, J. H. J. Org. Chem. 1970, 35,
3436. (d) Merkushev, E. B. Synthesis 1980, 486. (e) Garden, S. J.; Torres,
J. C.; de SouzaMelo, S. C.; Lima, A. S.; Pinto, A. C.; Lima, E. L. S.
Tetrahedron Lett. 2001, 42, 2089. (f) Kosynkin, D. V.; Tour, J. M. Org.
Lett. 2001, 3, 991. (g) Cambie, R. C.; Rutledge, P. S.; Smith-Palmer, T.;
Woodgate, P. D. J. Chem. Soc., Perkin Trans. 1 1976, 1161.
(1) (a) Mohanakrishnan, A. K.; Prakash, C.; Ramesh, N. Tetrahedron
2006, 62, 3242 and references therein. (b) Sumrell, G.; Wyman, B. M.;
Howell, R. G.; Harvey. M. C. Can. J. Chem. 1964, 42, 2710. (c) Zanger,
M.; Rabinowitz, J. Org. Chem. 1975, 40, 248.
(2) McCleland, C. W. Synthetic Reagents; Pizey, J. S., Ed.; Ellis Horwood
Limited: Chichester, 1983; Vol. 5, pp 85-164.
(3) Hubig, S. M.; Jung, W.; Kochi, J. K. J. Org. Chem. 1994, 59, 6233.
10.1021/jo062188w CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/11/2007
J. Org. Chem. 2007, 72, 977-983
977

Ho et al.
SCHEME 1
SCHEME 2. Plausible Mechanisms for the Iodochlorination
of 4 with Bu4NI and DCE
Iodination of silyl enol ethers has been accomplished using
a combination of NaI and FeCl3.1a Aromatic compounds have
been iodinated with moderate selectivity for the para position
using combinations of ammonium iodide and oxone,5a tetrabu-
tylammonium peroxydisulfate and iodine,5b iodine and copper-
(II) chloride,5c and hypervalent iodine.5d Iodination of aromatic
heterocycles has been reported using aqueous potassium
dichloroiodate.5e Anilines have been iodinated with high para
selectivity using benzyltriethylammonium dichloroiodate and
sodium bicarbonate.5f Iodination of phenols is selective for the
ortho position when thallium acetate is used in combination with
iodine.5g
Iodochlorination of alkynes also remains problematic. Ad-
dition of ICl to alkynes provides the desired iodochlorinated
alkenes; unfortunately mixtures of regio- and stereoisomers are
normally observed.6 This is somewhat inefficient because the
products can be extremely difficult to separate and purify.
Because of their use in the production of asymmetrically
substituted olefins,7,8 methods to prepare single-isomer iodo-
chlorinated products are highly desirable. In this paper we
describe a simple method that leads to complete regio- and
stereocontrol during additions to alkynes. Chemoselectivity is
also realized by suppressing the normal reactivity of ICl toward
electrophilic aromatic substitution. Reactions with olefins
produce exclusively the dichlorinated products in an extremely
clean and selective process. Mechanistic studies of the Bu4NI
method and applications to various substrates are also described.
of iodide to the â position of the R,â-unsaturated ester 4. The
resulting allenoate 5 would then react with dichloroethane,
thereby generating ethene and producing stereoisomeric R-chloro-
â-iodo-R,â-unsaturated esters 6 and 7. The second possible
mechanism involves initial attack of the iodide onto dichloro-
ethane, generating iodine monochloride and ethene. Alkyne 4
could then react with the electrophilic iodine to generate cyclic
iodonium 8.6 This intermediate would undergo backside attack
by the chloride at the more electropositive â-position to generate
the E-â-chloro-R-iodo-R,â-unsaturated ester 9. The first mech-
anism was ruled out by establishing the identity of the isomer
produced. Carbon and DEPT NMR analysis of the product
showed a chemical shift of 129.4 ppm for the CH carbon,
consistent with chlorine substitution at the â position of an R,â-
unsaturated ester. A strong upfield chemical shift of 84.3 ppm
was observed for the quaternary olefinic carbon, consistent with
iodine substitution at that position.8 The configuration of the
alkene products was determined using NMR methods.9 These
results confirmed that the only product produced was olefin 9,
proving the conjugate addition mechanism to be inoperative and
clearly supporting the electrophilic addition mechanism.8
Results and Discussion
As part of a study directed toward generation of single-isomer
tetrasubstituted olefins, we recently disclosed an efficient method
for generation of single-isomer iodochlorinated alkenes by
exposure of the appropriate alkynes to tetrabutylammonium
iodide in refluxing dichloroethane (DCE) (Scheme 1, eq 1).8
This method was highly efficient in converting 2-alkynyl esters
such as 1 into the corresponding E-â-chloro-R-iodo-R,â-
unsaturated ester compounds 2, giving the products as single
isomers. Use of ICl directly generated the same regioisomers
but produced an equimolar mixture of E and Z stereoisomers 2
and 3, respectively (eq 2).
The electrophilic addition mechanism was tested by parallel
experiments performed using ICl. Exposure of 4 to ICl in DCE
gave a mixture of alkenes 6, 7, 9, and 10 (Scheme 3).10 This
reaction using ICl was completely nonselective as the products
were formed as a mixture of regioisomers and mixtures of E
SCHEME 3
Two plausible mechanisms can be proposed for the combina-
tion of tetrabutylammonium iodide with an alkynyl ester such
as 4 and DCE (Scheme 2). The first involves conjugate addition
(6) (a) Bellina, F.; Colzi, F.; Mannina, L.; Rossi, R.; Viel, S. J. Org.
Chem. 2003, 68, 10175. (b) Tendil, J.; Verney, M.; Vessiere, R. Tetrahedron
1974, 30, 579. (c) Uemura, S.; Okazaki, H.; Onoe, A.; Okano, M. J. Chem.
Soc., Perkin Trans. 1 1977, 676. (d) Voorhees, V.; Skinner, G. S. J. Am.
Chem. Soc. 1925, 47, 1124. (e) Francis, A. W. J. Am. Chem. Soc. 1925,
47, 1124.
(7) (a) Organ, M. G.; Ghasemi, H.; Valente, C. Tetrahedron 2004, 60,
9453. (b) Rathore, R.; Deselnicu, M. I.; Burns, C. L. J. Am. Chem. Soc.
2002, 124, 14832.
(8) Lemay, A. B.; Vulic, K. S.; Ogilvie, W. W. J. Org. Chem. 2006, 71,
3615.
978 J. Org. Chem., Vol. 72, No. 3, 2007

Single-Isomer Iodochlorination of Alkynes
TABLE 1. Conversion of Alkynes to Single-Isomer Products with Bu4NI in DCE, and Comparison to Analogous Reaction with ICl Alone
a Isolated yield. b Combined isolated yield. c These products were successfully generated on >5 g scale. d Mass spectrum shows the presence of diiodinated
compounds.
and Z isomers 6, 7, 9, and 10. In contrast, exposure of alkyne
4 to Bu4NI in refluxing DCE gave E-alkene 9 as the only
product.
products were present. The Bu4NI/DCE reaction was very
successful if the substituent was a functionalized alkyl chain
(entry 3) or a branched alkyl group (entry 4) as a single isomer
was obtained in each case (17 entry 3, 20 entry 4). Inseparable
mixtures were obtained upon exposure of the same substrates
(16, 19) to ICl. The Bu4NI/DCE reaction of an alkyne bearing
a phenyl substituent (entry 5) followed the same trend, producing
a single isomer (23) in good yield. This same substrate 22, when
treated with ICl alone, afforded an inseparable mixture of
products.
The clear superiority of the Bu4NI/DCE method led us to
examine the process with other substrates. To our delight, use
of Bu4NI in refluxing DCE with a variety of alkynes gave single
isomers in every reaction. In contrast, control reactions employ-
ing direct use of ICl gave mixtures in almost every case. This
completely regio- and stereoselective Bu4NI/DCE reaction
tolerates a variety of substituents on the alkyne terminus,
including a hydrogen (Table 1, entry 1) and a simple alkyl group
(entry 2). In contrast, treatment of these substrates (4, 11) with
ICl gave mixtures of at least three chloroiodinated products as
mixtures of regio- and stereoisomers. Mass spectral analysis of
these mixtures also indicated that small amounts of diiodinated
The Bu4NI/DCE reaction could be extended to other carbonyl
derivatives, such as alkynyl amides (entry 6), with perfect
control of selectivity. Exposure of unconjugated alkyne 27 to
Bu4NI in DCE gave a single-isomer product in excellent yield
(entry 7). A single isomer was obtained from use of ICl in only
this case in which symmetry in the substrate most likely
controlled the outcome of the process. Functionalized alkyne
29 was cleanly converted to E-isomer 30 using Bu4NI in DCE,
whereas this same compound gave a mixture of E and Z
products, 30 and 31, when ICl was used. The reliability,
selectivity, and effectiveness of the Bu4NI/DCE reactions were
remarkable, and this method enabled efficient generation of
single-isomer chloroiodinated alkenes, a class of compounds
whose utility has until now been limited by preparative
challenges.7,8
(9) The E-esters were briefly photolyzed to generate the correspond-
ing Z-isomers, and then the esters were reduced with DIBAL, giving the
corresponding alcohols. Consistent with the structural assignments shown,
nOe enhancements were observed between the methyl and methylene of
the Z-isomer whereas these interactions were lacking in the E-isomer. See
ref 8 for details.
Use of Bu4NI in refluxing DCE with related alkene substrates
such as 32 did not give the anticipated iodochlorinated products.
Instead, single-isomer dichlorinated products such as 33 were
cleanly obtained (Table 2, entry 1).11 Once again, this was in
stark contrast to the results obtained by use of ICl with the same
(10) Diiodinated products were also detected by mass spectroscopy.
J. Org. Chem, Vol. 72, No. 3, 2007 979

Ho et al.
TABLE 2. Conversion of Alkenes to Single Isomer Dichlorinated Products Using Bu4NI in DCE, and Comparison to Reaction of the Same
Alkenes with ICl That Gave Mixtures of Halogenated Products
a All reactions performed with 0.98 equiv of ICl. b Isolated yield. c Combined isolated yield. d NR ) no reaction. e Reaction performed in DCE at reflux.
f Reaction time was 4 days.
SCHEME 4
substrate, a procedure that gave a mixture of dichlorinated (33)
and iodochlorinated (34) compounds. While many reactions
have been reported in which iodine monochloride has been
found to give chlorinated products, these materials are typically
only minor components in the reaction mixture.2 Clean produc-
tion of dichlorinated products using the Bu4NI/DCE method was
a surprising and useful result.
The remarkable selectivity of halogenations using Bu4NI in
refluxing DCE was further investigated using a variety of
alkenes as substrates. An alkene bearing a substituted alkyl chain
(35, entry 2) gave single-isomer dichlorinated product 36 using
Bu4NI/DCE. In contrast, treatment of the same alkene with ICl
gave an inseparable mixture of dichlorinated and iodochlorinated
products. Thus, reaction of ICl with compound 35 gave a
mixture of 36 and 37. An alkene tethered to an unprotected
phenol (entry 3) cleanly reacted with Bu4NI/DCE to give
compound 39 exclusively and in high yield. Reaction of the
same substrate with ICl gave a mixture of products (39, 40) as
patterns and for chlorination of monosubstituted alkenes,
aromatic rings were completely unreactive. Anisole did not react
upon exposure to Bu4NI in DCE even after several days at
reflux. However, anisole reacted readily upon exposure to ICl
at room temperature, giving a mixture of multiple addition
products. N,N-Dimethylaniline was completely unreactive upon
exposure to Bu4NI in refluxing DCE but rapidly gave a mixture
of multiple addition products in the related ICl reaction. Even
the electron-rich 1,3-dimethoxybenzene was unreactive in the
presence of Bu4NI/DCE and again readily gave a mixture of
products in the presence of ICl. This property of the Bu4NI/
DCE system allowed for selective reaction at alkenyl or alkynyl
with other examples. Internal trans alkene 41 (entry 4) reacted
very well under the Bu4NI/DCE conditions to give a single-
1
isomer 42 as evidenced by both H and 13C NMR spectra. In
contrast, treatment of alkene 41 with ICl gave the iodochlori-
nated compound 43. A 2,2-disubstituted alkene proved to be
completely unreactive toward Bu4NI/DCE (entry 5). A low yield
was also observed in the corresponding ICl reaction of 44 under
forcing conditions in which a mixture of products 45 and 46
functional groups in the presence of electron-rich aromatic
was obtained. An electron-deficient alkene (entry 6) reacted
systems while leaving the aromatic moieties untouched. Thus,
sluggishly under refluxing conditions with Bu4NI in DCE but
allyloxybenzene 32 was cleanly converted to dichloride 33 with
nevertheless produced a single product 48. Treatment of the
Bu4NI/DCE, leaving the aromatic group undisturbed (Table 2,
entry 1). This is in contrast to treatment of the same substrate
(32) with ICl which gave inseparable mixtures of products
bearing mono-, di-, and trisubstitution (50-52) of the aromatic
ring even if only a slight excess of ICl was employed (Scheme
same Michael acceptor with ICl produced a mixture of products
48 and 49 in moderate yield.
While the Bu4NI/DCE system was highly selective for
iodochlorination of alkynes with a wide variety of substitution
4). Many conditions have been developed for halogenation of
aromatic compounds, but the current Bu4NI method is remark-
able for the chemoselectivity demonstrated toward the electro-
(11) A control reaction performed by refluxing allyloxybenzene in DCE
gave no reaction. This illustrated that the tetrabutylammonium iodide was
an essential component of this process.
980 J. Org. Chem., Vol. 72, No. 3, 2007

Single-Isomer Iodochlorination of Alkynes
TABLE 3. Reaction of 53 with ICl in the Presence of Varying
Amounts of Bu4NI
philic addition to alkenes and alkynes rather than electrophilic
aromatic substitution.
Mechanistic Considerations. The notable selectivity of the
Bu4NI/DCE method warranted an investigation of the mecha-
nism. As noted above, the regioselectivity in the reaction with
alkynyl substrates such as 1, producing products such as 2,
suggested that ICl was involved in the process. As this
intermediate was presumably formed by reaction between Bu4-
NI and DCE, it was reasonable to assume that similar reactivity
could be realized with other electropositive chloride sources.
entry
equiv Bu4NI
solvent
temp. (°C)
yield (%)
1
2
3
4
5
6
7
0
DCE
DCE
DCE
DCE
DCE
DCE
benzene
22
22
22
22
22
83
80
90
56
14
3
trace
trace
trace
0.25
0.5
1.05
3.0
3.0
3.0
Treatment of alkyne 11 with Bu4NI and N-chlorosuccinimide
(NCS) in refluxing CH2Cl2 gave product 12 exclusively in 85%
yield. This supported the supposition that ICl was being formed
slowly in situ by the reaction between Bu4NI and electrophilic
chloride sources such as DCE or NCS. However, this in situ
generation of ICl could not by itself explain the remarkable
selectivity observed when using Bu4NI. If the effect was due
to slow generation of ICl, then presumably the selectivity of
the Bu4NI/DCE was simply the result of a low concentration
of ICl. This was examined by adding ICl via syringe-pump to
a solution of alkyne 11 in CH2Cl2 over 24 h. The reaction
resulted in excellent conversion to products 12, 13, 14, and 15,
but virtually no selectivity was observed, thus ruling out this
possible concentration effect.
SCHEME 5
Another possible explanation for the Bu4NI selectivity could
be a buffering effect. In other words, the ICl reactions may have
given poor selectivity because of an acid-catalyzed isomerization
of the alkenes. To test this hypothesis, compound 11 was
exposed, in separate reactions, to ICl in the presence of an excess
of the bases imidazole and lutidine. Despite this precaution, these
reactions again gave mixtures of isomeric products 12 to 15 as
before. If Bu4NI was reacting with DCE to generate ICl, it was
possible that the Bu4NCl generated as a byproduct was somehow
modulating the reactivity of the ICl. To test this hypothesis,
alkyne 11 was treated with ICl in the presence of excess Bu4-
NCl. Once again the outcome of the reaction was indistinguish-
able from the results obtained using ICl alone.
regardless of the solvent used (entries 5-7). These results
strongly suggested that complexation between ICl and Bu4NI
was responsible for the reactivity control observed when Bu4-
NI was used in DCE.
Control reactions performed with alkyne 11 further confirmed
that a complex was involved in the stereocontrol of the
reaction.12 Adding increasing amounts of Bu4NI to a reaction
mixture containing alkyne 11 and ICl suppressed the reactivity
of ICl. Decreases in yield were strongly dependent on the
amount of Bu4NI present. The reaction was completely sup-
pressed when alkyne 11 was treated with 3.0 equiv of Bu4NI at
room temperature in DCE in the presence of ICl. In contrast to
the reaction with anisole, reactivity returned when the reaction
was heated to reflux, giving a 30% conversion to single-isomer
product 12. This indicated that Bu4NI exerted strong stereo-
control over the reaction, presumably through complexation with
the ICl present.
Formation of dichlorinated products from reaction of Bu4NI
with alkenes in DCE could also be accounted for by formation
of a Bu4NI-ICl complex, which presumably was modulating
the reactivity of ICl. Disproportionation and radical mechanisms
are the typical means by which the chlorination of alkenes is
thought to occur in the presence of ICl.2 In the case of Bu4NI/
DCE, the radical mechanism was ruled out by adding the radical
inhibitor 3,5-di-tert-butyl-4-hydroxytoluene (BHT) to a reaction
of alkene 32 and Bu4NI in DCE (Scheme 5).13 The results of
this reaction were comparable to those obtained without BHT
as dichloride 33 was obtained in 84% yield. Similarly, use of
BHT had no effect on the reaction of alkene 32 with ICl, as a
Two significant observations led us to suspect that a Bu4-
NI-ICl complex was forming and that this complex was
responsible for the remarkable selectivity achieved with Bu4-
NI. The first was the low reactivity of the Bu4NI/DCE system
toward electrophilic aromatic substitution when all other reac-
tions clearly showed that ICl was implicated in the transforma-
tions. Given the high reactivity of ICl toward electrophilic
aromatic substitution with electron-rich substrates such as
anisole, an attenuating factor must have been operative if ICl
was being slowly generated to account for the lowered reactivity
when Bu4NI was used. The second observation was the fact
that slow introduction of ICl into a solution of alkene 32 did
not result in a selective reaction. Control reactions were
performed using anisole to investigate the role of complexation.
Exposure of anisole (53) to 0.98 equiv of ICl in DCE gave
p-iodoanisole 54 in 90% yield after 1 h at room temperature
(Table 3, entry 1). Adding small amounts of Bu4NI to the
mixture suppressed the reactivity of ICl, resulting in yield
decreases that were dependent on the amount of ICl present.
Thus, addition of 0.25 equiv of Bu4NI gave a drop in yield from
90% to 54% (entry 2). Recovery of 54 was reduced to 14%
when 0.5 equiv of Bu4NI was present (entry 3), and the reaction
was effectively suppressed when 1 equiv of Bu4NI was
introduced (entry 4). Increasing the temperature of the reaction
did not restore the reactivity of ICl when Bu4NI was present,
(12) Full reaction details are described in the Supporting Information.
(13) BHT (20 mol %) was added to a mixture of alkene 32 (1 equiv)
and Bu4NI (3 equiv) in DCE. The solution was heated at reflux until
consumption of starting material was complete as indicated by TLC.
J. Org. Chem, Vol. 72, No. 3, 2007 981

Ho et al.
SCHEME 6. Investigation of a Complexation Effect of
Bu4NI with ICl
Mechanistic experiments using NCS indicated that ICl was
being slowly generated in the Bu4NI/DCE system and that this
species could explain the observed regioselectivity. A series of
experiments in which Bu4NI was found to attenuate the
reactivity of ICl toward electrophilic aromatic substitution
indicated that a complex between Bu4NI and ICl was responsible
for the modulation of reactivity in these processes. This was
confirmed for the alkyne series by experiments using alkynyl
ester 11 and alkene 32, which indicated that the Bu4NI-ICl
complex was responsible for the extreme selectivity in this
process. This complex also appeared to moderate the reactivity
of the ICl during additions to alkenes such that dichlorinated
products were obtained rather than the expected chloroiodinated
derivatives. This reagent combination will undoubtedly be
frequently utilized to access these single-isomer substrates
cleanly and in preparatively useful quantities.
Experimental Section
General Procedure for the Halogenation of Alkenes and
Alkynes Using Bu4NI.15 (E)-Methyl 3-Chloro-2-iodoacrylate (9).8
A solution of methyl-2-propiolate 4 (250 mg, 2.98 mmol, 1.0 equiv)
and tetrabutylammonium iodide (3.25 g, 8.95 mmol, 3.0 equiv) in
dichloroethane (25 mL) was heated at reflux for 18 h. The reaction
mixture was cooled, diluted with Et2O, and washed with NaHSO3
(20 wt % solution), saturated NaHCO3, and brine. The organic phase
was then dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. The pure product was obtained by flash chromatography
eluting with hexanes and then 5% EtOAc in hexanes to give the
title product as a colorless oil (528 mg, 72%). 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.
mixture of products 33 and 34 was obtained. As this radical
scavenger did not inhibit the reactions, the process was most
likely proceeding via the disproportionation of complexed ICl
rather than by the intermediacy of free radicals.
A series of reactions was performed to confirm whether the
chlorination reaction resulted from a disproportionation of ICl.
Thus, ICl was added to reaction mixtures of alkene 32 containing
increasing amounts of Bu4NI (Scheme 6). Utilization of 3 equiv
of Bu4NI and 1 equiv of ICl in DCE at room temperature gave
only traces of isomers 33 and 34. The same reagents, in the
same relative proportions, gave dichlorinated compound 33 as
the exclusive product when the reaction was heated to reflux.
Exposure of an equimolar mixture of dichlorinated ether 33 and
chloroiodinated ether 34 to Bu4NI in refluxing dichloroethane
gave essentially quantitative recovery of dichlorinated ether 33.
No chloroiodinated compound 34 was recovered; however,
alkene 32 was now present in the mixture. This suggested that
the chloroiodinated compound 34 underwent an elimination to
give alkene 32 which could then be dichlorinated. Formation
of 33 was consistent with a disproportionation mechanism.
Support for this was obtained by refluxing dichlorinated ether
33 with Bu4NI in DCE. After 3 days at reflux, dichloride 33
was recovered in quantitative yield, showing that 33 was stable
under the reaction conditions.14
(E)-Ethyl 4-(tert-Butyldimethylsilyloxy)-3-chloro-2-iodobut-
2-enoate (17). Prepared from ethyl 4-(tert-butyldimethylsilyloxy)-
but-2-ynoate (100 mg, 0.41 mmol) using a procedure similar to
that described above for compound 9 that provided the title
1
compound as a colorless oil (152 mg, 92%). H NMR (400 MHz,
CDCl3) δ 4.53 (s, 2H), 4.31 (q, J ) 7.2 Hz, 2H), 1.34 (t, J ) 7.2
Hz, 3H), 0.93 (s, 9H), 0.13 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 164.6 (C), 137.1 (C), 80.1 (C), 68.6 (CH2), 62.6 (CH2), 25.8
(CH3), 18.3 (C), 13.9 (CH3); IR (neat) 2956, 1733, 1472 cm-1
;
HRMS calcd for C8H13ClIO3Si (M+ - t-Bu) 346.9367, found
346.9352; calcd for C11H19ClIO3Si (M+ - CH3) 388.9837, found
388.9830.
N-Methoxy-N-Methylnon-2-ynamide (25). To a solution of
1-hexyne (2.6 mL, 17.7 mmol, 1.0 equiv) in hexanes (150 mL) at
-78 °C was added a solution of butyllithium (2.26 M in THF,
8.63 mL, 19.5 mmol, 1.1 equiv). After 1 h a solution of N-methoxy-
N-methylcarbamoyl chloride16 (2.40 g, 19.4 mmol, 1.1 equiv) in
THF (20 mL) was slowly added via canula. The reaction was stirred
for 1 h at -78 °C and then allowed to warm to room temperature
for 1 h. The reaction was quenched by the dropwise addition of
10% HCl and diluted with ether. The organic layer was washed
sequentially with a saturated solution of sodium bicarbonate and
brine and then dried over anhydrous MgSO4, filtered, and concen-
trated. The pure product was obtained by chromatography eluting
with 5% EtOAc in hexanes and then 20% EtOAc in hexanes to
give the title product as a pale yellow oil (3.02 g, 77%). 1H NMR
(400 MHz, CDCl3) δ 3.40 (s, 3H), 2.94 (s, 3H), 2.03 (t, J ) 6.4
Hz, 2H), 1.36-1.14 (m, 8H), 0.93 (t, J ) 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 73.0 (CH3), 61.8 (CH3), 31.1 (CH2), 30.8
Conclusion
Exposure of a wide variety of alkynes to Bu4NI in refluxing
DCE gave single-isomer E-â-chloro-R-iodo-R,â-unsaturated
ester products in every instance. This method is far superior to
the direct use of ICl, which gave mixtures of stereoisomers.
Treatment of alkenes with Bu4NI in refluxing DCE cleanly gave
single-isomer dichloroalkane products, representing a useful and
convenient method for formation of such materials. The same
alkenes, when treated with ICl, gave inseparable mixtures of
dichlorinated and regioisomeric chloroiodinated alkanes. Most
notable was the selectivity for reactions at the alkynyl and
alkenyl functions rather than electrophilic aromatic substitutions.
(15) Detailed descriptions of the preparation of compounds 9, 12, 20,
and 23 are found in ref 8.
(16) Smith, A. B., III; Beiger, J. J.; Davulcu, A. H.; Cox, J. M. Org.
Synth. 2005, 82, 147.
(14) Exposure of an E:Z mixture of â-chloro-R-iodo-R,â-unsaturated
esters 12 and 13 (2.8:1) to Bu4NI in refluxing DCE for 18 h returned the
material in an unaltered ratio (95 %, 12:13, 2.8:1).
982 J. Org. Chem., Vol. 72, No. 3, 2007

Single-Isomer Iodochlorination of Alkynes
(CH2), 28.4 (CH2), 27.6 (CH2), 22.4 (CH2), 18.8 (CH2), 13.6 (CH3);
IR (neat) 2237, 1644 cm-1; HRMS calcd for C11H19NO2 (M+)
197.1416, found 197.1405.
8.0, 1.6 Hz, 2H), 4.38-4.35 (m, 2H), 4.13-4.10 (m, 1H), 3.79
(dd, J ) 11.0, 5.0 Hz, 1H), 3.66 (dd, J ) 11.4, 7.8 Hz, 1H), 2.22-
1.84 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 166.4 (C), 132.9
(CH), 130.0 (C), 129.5 (CH), 128.3 (CH), 63.9 (CH2), 60.4 (CH),
47.9 (CH2), 31.7 (CH2), 25.2 (CH2); IR (neat) 2956, 2849, 1718,
1451 cm-1; MS (EI) 260 (M+); HRMS calcd for C12H14ClO2 (M+
- Cl) 225.0682, found 225.0700.
(E)-3-Chloro-2-iodo-N-methoxy-N-methylnon-2-enamide (26).
Prepared from N-methoxy-N-methylnon-2-ynamide (3.02 g, 15.3
mmol) using a procedure similar to that described above for
compound 9 that provided the title compound as a colorless oil
(5.05 g, 92%). 1H NMR (400 MHz, C6D6) δ 3.22 (s, 3H), 2.82 (s,
3H), 2.46 (br s, 2H), 1.48-1.45 (m, 2H), 1.19-1.14 (m, 6H), 0.84
(t, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, C6D6) δ 166.3 (C), 135.1
(C), 82.7 (C), 60.8 (CH3), 40.4 (CH2), 32.4 (CH3), 31.8 (CH2), 28.3
(CH2), 27.1 (CH2), 22.8 (CH2), 14.1 (CH3); IR (neat) 2954, 2930,
2858, 1654, 1459 cm-1; HRMS calcd for C11H10ClIO2 (M+)
359.0149, found 359.0201.
2-(2,3-Dichloropropyl)phenol (39). Prepared from 2-allylphe-
nol20 (100 mg, 0.74 mmol) using a procedure similar to that
described above for compound 9 that provided the title compound
1
as a colorless oil (135 mg, 89%). H NMR (400 MHz, CDCl3) δ
7.23-7.16 (m, 2H), 6.94 (dd, J ) 7.4, 7.4 Hz, 1H), 6.79 (d, J )
8.0 Hz, 1H), 5.42 (br s, 1H), 4.53-4.66 (m, 1H), 3.78 (dd, J )
11.7, 5.5 Hz, 1H), 3.76 (dd, J) 11.7, 5.36 Hz, 1H), 3.35 (dd, J )
14.0, 6.0 Hz, 1H), 3.09 (dd, J ) 14.0, 7.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 153.6 (C), 131.8 (CH), 128.6 (CH), 123.1 (C),
120.9 (CH), 115.5 (CH), 60.3 (CH), 48.4 (CH2), 36.5 (CH2); IR
(neat) 3540, 2951, 1609, 1502 cm-1; MS (EI) 204 (M+); HRMS
calcd for C9H10Cl2O (M+) 204.0109, found 204.0121.
(E)-5-Chloro-6-iododec-5-ene (28). Prepared from 5-decyne
(0.13 mL, 0.76 mmol) using a procedure similar to that described
above for compound 9 that provided the title compound as a
1
colorless oil (210 mg, 92%). H NMR (400 MHz, acetone-d6) δ
2.68 (t, J ) 7.2 Hz, 4H), 1.60-1.48 (m, 4H), 1.39-1.32 (m, 4H),
0.94 (t, J ) 7.2 Hz, 3H), 0.93 (t, J ) 7.2 Hz, 3H); 13C NMR (100
MHz, acetone-d6) δ 133.0 (C), 100.6 (C), 44.3 (CH2), 43.2 (CH2),
32.2 (CH2), 30.9 (CH2), 23.3 (CH2), 23.0 (CH2), 15.2 (CH3), IR
(neat) 2957, 2860, 1623, 1464 cm-1; MS (EI) 300 (M+); HRMS
calcd for C10H18ClI (M+) 300.0142, found 300.0132.
Butyl 2,3-dichloropropanoate21 (48). Prepared from n-butyl
acrylate (50 mg, 0.39 mmol) using a procedure similar to that
described above for compound 9 that provided the title compound
1
as a colorless oil (15.5 mg, 20%). H NMR (400 MHz, CDCl3) δ
4.42 (dd, J ) 8.7, 5.2 Hz, 1H), 4.24 (t, J ) 6.8 Hz, 2H), 3.96 (dd,
J ) 11.1, 8.7 Hz, 1H), 3.80 (dd, J ) 11.1, 5.2 Hz, 1H), 1.71-1.64
(m, 2H), 1.44-1.39 (m, 2H), 0.95 (t, J ) 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 167.1 (C), 66.5 (CH2), 55.1 (CH), 43.9 (CH2),
(E)-(2-Chloro-3-iodobut-2-ene-1,4-diyl)bis(oxy)bis(methyl-
ene)dibenzene (30). Prepared from 1,4-bis(benzyloxy)but-2-yne17
(50 mg, 0.19 mmol) using a procedure similar to that described
above for compound 9 that provided the title compound as a
30.4 (CH2), 18.9 (CH2), 13.6 (CH3); IR (neat) 2936, 1750 cm-1
.
1
General Procedure for the Halogenation of Alkenes and
Alkynes Using ICl. Reaction of Methyl-2-propiolate with ICl.
To a solution of methyl-2-propiolate 4 (50 mg, 0.60 mmol, 1.0
equiv) in dichloroethane (25 mL) was added iodine monochloride
(1.0 M solution in DCM, 0.60 mL, 0.60 mmol, 1 equiv), and the
resulting mixture was stirred for 2 h. The reaction was diluted with
Et2O and washed sequentially with NaHSO3 (20 wt % solution),
saturated NaHCO3, and brine. The organic phase was then dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. The
pure product was obtained by flash chromatography eluting with
hexanes and then 5% EtOAc in hexanes to give an inseparable
mixture of compounds 9, 10, 6, and 7 as a pale yellow oil (100
mg, 68%).
colorless oil (75 mg, 93%). H NMR (400 MHz, acetone-d6) δ
7.42-7.29 (m, 10 H), 4.57 (s, 2H), 4.55 (s, 2H), 4.51 (s, 2H), 4.44
(s, 2H); 13C NMR (100 MHz, acetone-d6) δ 139.9 (C), 139.8 (C),
132.7 (C), 130.03 (CH), 130.01 (CH), 129.63 (CH), 129.56 (CH),
129.41 (CH), 129.38 (CH), 102.6 (C), 77.9 (CH2), 74.8 (CH2), 73.5
(CH2), 73.2 (CH2); IR (nujol) 2957, 1640, 1458 cm-1; MS (EI)
428 (M+); HRMS calcd for C18H18ClIO2 (M+) 428.0040, found
428.0043.
(2,3-Dichloropropoxy)benzene (33).18 Prepared from allyloxy-
benzene (100 mg, 0.75 mmol) using a procedure similar to that
described above for compound 9 that provided the title compound
1
as a colorless oil (151 mg, 99%). H NMR (400 MHz, CDCl3) δ
7.34-7.31 (m, 2H), 7.05-6.94 (m, 3H), 4.41-4.35 (m, 1H), 4.30
(dd, J ) 6.4, 1.2 Hz, 2H), 4.02-3.89 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 157.9 (C), 129.6 (CH), 121.6 (CH), 114.7 (CH),
68.1 (CH2), 57.3 (CH), 45.0 (CH2); IR (neat) 2959, 2933, 1599,
1496 cm-1; MS (EI) 204 (M+); HRMS calcd for C9H10Cl2O (M+)
204.0109, found 204.0105.
Acknowledgment. We thank the Natural Science and
Engineering Research Council of Canada (NSERC), Canada
Foundation for Innovation, Ontario Innovation Trust, and
University of Ottawa for generous funding. M.L.H. thanks the
Natural Science and Engineering Research Council of Canada
for an undergraduate research award.
4,5-Dichloropentyl benzoate (36). Prepared from pent-4-enyl
benzoate19 (100 mg, 0.53 mmol) using a procedure similar to that
described above for compound 9 that provided the title compound
Supporting Information Available: 1H NMR spectra for
compounds 9, 12, 17, 19, 20, 23, 25, 26, 29, 30, 33, 35, 36, 39, 48,
and 54; summary of ICl control reactions. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
as a colorless oil (118 mg, 99%). H NMR (400 MHz, CDCl3) δ
8.05 (dd, J ) 6.4, 1.2 Hz, 2H), 7.55-7.54 (m, 1H), 7.44 (dd, J )
JO062188W
(17) Hecht, S.; Frechet, J. M. J. J. Am. Chem. Soc. 1999, 121, 4084.
(18) Alternative preparation from epoxides: (a) Iranpoor, N.; Firouzabadi,
H.; Azadi, R.; Ebrahimzadeh, F. Can. J. Chem. 2006, 84, 69. (b) Firouzabadi,
H.; Shiriny, F. Tetrahedron 1996, 52, 14929. (c) Iranpoor, N.; Firouzabadi,
H.; Aghapour, G.; Nahid, A. Bull. Chem. Soc. Jpn. 2004, 77, 1885.
(19) Kabalka, G. W.; Gooch, E. E., III. J. Org. Chem. 1980, 45, 3578.
(20) Van, T. N.; Debenedetti, S.; De Kimpe, N. Tetrahedron Lett. 2003,
44, 4199.
(21) Horna, A.; Taborsky, J.; Churacek, J.; Dufka, O. J. Chromatogr.
1985, 348, 141.
J. Org. Chem, Vol. 72, No. 3, 2007 983