Mechanistic studies on the Heck-Mizoroki cross-coupling reaction of a hindered vinylboronate ester as a key approach to developing a highly stereoselective synthesis of a C1-C7 Z,Z,E,-triene synthon for viridenomycin

Article abstract of DOI:10.1021/jo0626010

Mechanistic studies of the Heck-Mizoroki reaction of a vinylboronate ester with electronically different (four-substituted) aryl iodides shows that electron donors accelerate the cross-coupling, demonstrating that the oxidative addition step is not rate d

Full text of DOI:10.1021/jo0626010

Mechanistic Studies on the Heck-Mizoroki Cross-Coupling
Reaction of a Hindered Vinylboronate Ester as a Key Approach to
Developing a Highly Stereoselective Synthesis of a C1-C7
Z,Z,E-Triene Synthon for Viridenomycin
Andrei S. Batsanov, Jonathan P. Knowles, and Andrew Whiting*
UniVersity of Durham, Department of Chemistry,
Sciences Laboratories South Road DH1 3LE, Durham, United Kingdom
andy.whiting@durham.ac.uk
ReceiVed December 18, 2006
Mechanistic studies of the Heck-Mizoroki reaction of a vinylboronate ester with electronically different
(four-substituted) aryl iodides shows that electron donors accelerate the cross-coupling, demonstrating
that the oxidative addition step is not rate determining and that there is development of some degree of
positive charge in the rate determining step. These results were used as a basis to allow the development
of reaction conditions for the Heck-Mizoroki coupling of a hindered vinylboronate ester with electron
deficient methyl cis-2-iodoacrylate. The resulting dienylboronate ester was converted through a series of
highly stereoselective iodo-deboronations and Heck-Mizoroki reactions into a trienyl iodide precursor
for further application in the total synthesis of viridenomycin.
TABLE 1. σ and k Values for each Aryl Iodide Reacted as in Eq 2
Using Ph3P and (4-MeOPh)3P
Introduction
The Heck-Mizoroki (HM) coupling of hindered vinylbor-
onate esters with aryl1 and alkenyl iodides2 is of considerable
synthetic utility, especially in the latter case for the stereo-
controlled synthesis of polyenes3 due to its ability to act as a
vinyl dianion equivalent by combination with a highly stereo-
selective iodo-deboronation process.4 Viridenomycin 15 has yet
k
obs for PPh3
kobs for P (p-MeOPh)3
entry aryl iodide 7 (10-5 mmol dm-3 s-1
)
(10-5 mmol dm-3 s-1
)
δ
1
2
3
4
5
6
a
b
c
d
e
f
160
130
120
120
80
390
300
220
a
a
55
0.268
0.170
0
0.062
0.227
0.788
28
* Corresponding author. Tel: +44 191 334 2081. Fax: +44 191 384 4737.
(1) (a) Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett. 1993,
34, 3599-3602. (b) Stewart, S. K.; Whiting, A. J. Organomet. Chem. 1994,
482, 293-300. (c) Lightfoot, A. P.; Maw, G.; Thirsk, C.; Twiddle, S.;
Whiting, A. Tetrahedron Lett. 2003, 44, 7645-7648.
a These reactions showed significant curvature in their conversion vs
time plots very early in the reactions preventing the initial rates being
obtained.
to succumb to total synthesis,6 and as part of a program
concerned with its synthesis using this type of methodology,7
the retrosynthetic analysis (Scheme 1) suggested the need for a
trienyl iodide of type 3 to construct the C7-C8 bond in
viridenomycin 1. The triene 3 could in turn be accessed from
the corresponding boronate 4 via a series of HM couplings2
with a vinylboronate ester of type 6, followed by stereoselective
iodo-deboronations.4 However, initial investigations into the
(2) Stewart, S. K.; Whiting, A. Tetrahedron Lett. 1995, 36, 3925-
3928.
(3) (a) He´naff, N.; Whiting, A. Org. Lett. 1999, 1, 1137-1139. (b)
He´naff, N.; Whiting, A. Tetrahedron 2000, 56, 5193-5204. (c) Lightfoot,
A. P.; Twiddle, S. J. R.; Whiting, A. Org. Biomol. Chem. 2005, 3, 3167-
3172.
(4) (a) Stewart, S. K.; Whiting, A. Tetrahedron Lett. 1995, 36, 3929-
3932. (b) Lightfoot, A. P.; Twiddle, S. J. R.; Whiting, A. Tetrahedron Lett.
2004, 45, 8557-8861. (c) Batsanov, A.; Howard, J. A. K.; Lightfoot, A.
P.; Twiddle, S. J. R.; Whiting, A. Eur. J. Org. Chem. 2005, 1876-1883.
10.1021/jo0626010 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/03/2007
J. Org. Chem. 2007, 72, 2525-2532
2525

Batsanov et al.
SCHEME 1. Retrosynthetic Scheme for the Synthesis of the Northern Tetraene Section of Viridenomycin
coupling of a hindered vinylboronate ester with methyl cis-
iodoacrylate led to a series of unexpected amine-acrylate
Michael addition products or the formation of the Suzuki-
Miyaura (SM) product.8
In this paper, we present mechanistic investigations into the
factors that affect the HM coupling of a hindered boronate ester
with aryl and alkenyl iodides and the application of this
information in solving the problem controlling HM versus SM
coupling of such systems to allow the selective synthesis of
products of type 7 and, hence, systems of type 3.
boronate moiety in alkyl-substituted boronates. Hence, to obtain
a better understanding of the effects influencing the process
outlined in eq 1, and to try and solve the problem of the syn-
thesis of dienylboronate 11, mechanistic studies were required.
However, these experiments would be easier to carryout on a
series of readily available, and directly comparable, aryl iodides
in place of the acrylate 10.
Results and Discussion
Our starting point was an investigation into the coupling of
methylpentanediol boronate ester 9 (a vinylboronate ester with
superior shelf stability and ease of preparation as compared to
other hindered vinylboronate esters1c) with iodoacrylate 10,8
which despite carrying out screening of a range of conditions
(solvents, phosphines, amines, etc.), failed to provide the HM
product 11. To solve this problem, involving a reactive electron
deficient alkenyl iodide and a seemingly rather unreactive vinyl
system, it was realized that an improved understanding of the
mechanism operating in this attempted HM reaction was
required. While vinylboronate esters, such as 9, may at first
appear to be electronically similar to acrylates, we note that (a)
boron is electropositive and thus is a σ-donor and (b) B-O
π-bonding drastically reduces the π-acceptor properties of the
Hammett Studies on the Reaction of Boronate Ester 9 with
Four-Substituted Aryl Iodides. An often reproduced repre-
sentation of the HM mechanism9 is shown in Scheme 2. This
process has been investigated by several groups10 and portrays
the HM reaction as a process that is accelerated by electron-
withdrawing substituents on the aryl halide, yet not necessarily
having the oxidative addition as rate determining. However,
recently, Dupont et al.11 have shown that electron-withdrawing
substituents on the aryl group (Scheme 2, R ) aryl) increase
the rate of reaction, as demonstrated by a clear positive Hammett
correlation,11 which suggests that oxidative addition of R-X
to the Pd(0) complex 12 providing palladium(II) complex 13 is
(5) (a) Nakagawa, M.; Toda, Y.; Furihata, K.; Hayakawa, Y.; Seto, H.
J. Antibiot. 1992, 45, 1133-1138. (b) Nakagawa, M.; Furihata, K.;
Hayakawa, Y.; Seto, H. Tetrahedron Lett. 1991, 32, 659-662. (c) Hasegawa,
T.; Kamiya, T.; Henmi, T.; Iwasaki, H.; Yamatodani, S. J. Antibiot. 1975,
28, 167-175.
SCHEME 2. General Mechanistic Scheme for the HM
Cross-Coupling Reaction
(6) (a) Pattenden, G.; Blake, A. J.; Constandinos, L. Tetrahedron Lett.
2005, 46, 1913-1915. (b) Mulholland, N. P.; Pattenden, G. Tetrahedron
Lett. 2005, 46, 937-939. (c) Kruger, A. W.; Meyers, A. I. Tetrahedron
Lett. 2001, 42, 4301-4304. (d) Waterson, A. G.; Kruger, A. W.; Meyers,
A. I. Tetrahedron Lett. 2001, 42, 4305-4308. (e) Ishihara, J.; Hagihara,
K.; Chiba, H.; Ito, K.; Yanagisawa, Y.; Totani, K.; Tadano, K.-I.
Tetrahedron Lett. 2000, 41, 1771-1774. (f) Arrington, M. P; Meyers, A.
I. Chem. Commun. 1999, 1371-1372. (g) Trost, B. M; Jiang, C. Org. Lett.
2003, 5, 1563-1565.
(7) Maw, G. N.; Thirsk, C. T.; Toujas, J.-L.; Vaultier, M.; Whiting, A.
Synlett 2004, 1883-1886.
(8) Maw, G.; Thirsk, C.; Whiting, A. Tetrahedron Lett. 2001, 42, 8387-
8390.
2526 J. Org. Chem., Vol. 72, No. 7, 2007

Mechanistic Studies on Heck-Mizoroki Reaction
CHART 1. Hammett Plot Resulting from the Reaction
Shown in Eq 2 with Ph3P
CHART 2. Hammett Plot Resulting from the Reaction
Shown in Eq 2 with (4-MeOPh)3P
some degree of a positive charge in the rate determining step.
In an attempt to stabilize any forming positive charge while
also reducing the aryl-aryl exchange, the study was repeated
using tris(4-methoxyphenyl)phosphine instead of triphenylphos-
phine. This was initially found to give no reaction with 18f;
however, reducing the amount of phosphine from 15 to 10 mol
% was found to give an active catalyst. Instead of reducing the
aryl-aryl exchange as hoped (with triphenylphosphine, the
exchange was only seen when the aryl group of the iodide was
more electron rich than that of the phosphine), the exchange
was now seen to some extent in all reactions. Combination of
the product concentrations was again employed, and this resulted
in the Hammett plot shown in Chart 2.
rate determining. Clearly, to exercise control over processes such
as the coupling outlined in eq 1, one needs to understand both
the nature of the rate determining step and the nature of the
probable type of palladium complex involved that determines
which mechanism predominates and, hence, which product may
be obtained. To this end, a Hammett study of the reaction of
boronate ester 9 with a range of four-substituted aryl iodides
was undertaken, as outlined in eq 2.
The similar, negative Hammett parameters seen for the two
reactions suggests that the same rate determining step is involved
in both cases. It also appears, from the case using 15 mol %
tris(4-methoxyphenyl)phosphine, that an excess of an electron
rich phosphine can saturate palladium and render it unreactive.
This also implies that the active palladium catalyst contains at
most two phosphine ligands, which is entirely consistent with
the results of a recent theoretical study that suggested that the
active catalytic species in such reactions contained only one
phosphine ligand.13
Since studies of reactions involving only the oxidative
addition step of aryl halides to palladium has been shown to
give a positive Hammett parameter,10f,14 it therefore shows that
in the present case, oxidative addition is not rate determining.
This is not unexpected, as other studies15 have also suggested
that oxidative addition is not rate limiting for related HM
reactions involving aryl iodides. A recent study also showed
that the rate determining step in the oxidative addition of
iodobenzene to Pd(dba)L2 complexes is the dissociation of dba,16
proving how facile the oxidative addition can be. Interestingly,
a Hammett parameter of -1.6 has been reported to the HM
couplings of allylic alcohols with aryl iodides, although the rate
determining step in this case is unclear.17 It is also interesting
to note that the Hammett parameters obtained when the olefin
component is electronically varied in the HM reaction of
Our standard HM conditions (1.2 equiv of tributylamine, 5
mol % Pd(OAc)2, 15 mol % PPh3) were investigated, and the
reactions were followed by GC-MS. Unfortunately, in the cases
of 18a and 18b, considerable aryl-aryl exchange between the
aryl halide and the phosphine12 complicated the kinetics, leading
to the formation of both the expected product and the unsub-
stituted styrylboronate 19c. However, combination of the two
product concentrations to give a total product concentration
allowed the direct comparison of all six reactions. Using initial
rates, the Hammett plot shown in Chart 1 was generated, and
the negative correlation indicated that there was formation of
(9) (a) Knowles, J. P.; Whiting, A. Org. Biomol. Chem. 2007, 5, 31-
44. (b) Bra¨se, S.; de Meijere, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998;
Ch. 3.
(10) (a) Amatore, C.; Pflu¨ger, F. Organometallics 1990, 9, 2276-2282.
(b) Jutand, A.; Mosleh, A. Organometallics 1995, 14, 1810-1817. (c)
Cianfriglia, P.; Narducci, V.; Sterzo, C. L.; Viola, E.; Bocelli, G.;
Kodenkandath, T. A. Organometallics 1996, 15, 5220-5230. (d) Amatore,
C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314-321. (e) Bo¨hm, V. P. W.;
Herrmann, W. A. Chem.sEur. J. 2001, 7, 4191-4197. (f) Portnoy, M.;
Milstein, D. Organometallics 1993, 12, 1665-1673. (g) Amatore, C.; Carre,
E.; Jutand, A.; M’Barki, M. A.; Meyer, G. Organometallics 1995, 14, 5605-
5614.
(13) Ahlquist, M.; Fristrup, P.; Tanner, D.; Norrby, P.-O. Organometallics
2006, 25, 2066-2073.
(14) (a) Fauvarque, J.-F.; Pflu¨ger, F.; Troupel, M. J. Organomet. Chem.
1981, 208, 419-427. (b) Amatore, C.; Pflu¨ger, F. Organometallics 1999,
9, 2276-2282.
(15) (a) Ohff, M.; Ohff, A.; van der Boom, M. E.; Milstein, D. J. Am.
Chem. Soc. 1997, 119, 11687-11688. (b) Consorti, C. S.; Ebeling, G.;
Flores, F. R.; Rominger, F.; Dupont, J. AdV. Synth. Catal. 2004, 346, 617-
624.
(16) Mace, Y.; Kapdi, A. R.; Fairlamb, I. J. S.; Jutand, A. Organome-
tallics 2006, 25, 1795-1800.
(17) Benhaddou, R.; Czernecki, S.; Ville, G.; Zegar, A. Organometallics
1988, 7, 2435-2439.
(11) Consorti, C. S.; Flores, F. R.; Dupont, J. J. Am. Chem. Soc. 2005,
127, 12054.
(12) (a) Goodson, F. E.; Wallow, T. I.; Novak, B. M. J. Am. Chem. Soc.
1997, 119, 12441-12453. (b) Kong, K. C.; Cheng, C. H. J. Am. Chem.
Soc. 1991, 113, 6313-6315. (c) Kwong, F. Y.; Lai, C. W.; Tian, Y.; Chan,
K. S. Tetrahedron Lett. 2000, 41, 10285-10289. (d) Hodgson, P. B.;
Salingue, F. H. Tetrahedron Lett. 2004, 45, 685-687. (e) Herrmann, W.
A.; Brobmer, C.; O¨ fele, K.; Beller, M.; Fisher, H. J. Mol. Catal. 1995,
103, 133-146.
J. Org. Chem, Vol. 72, No. 7, 2007 2527

Batsanov et al.
iodobenzene with four-substituted styrenes18 matches closely
with the results reported here. This related study also
suggested18 that the electrophilic attack of palladium on the
double bond gave rise to the negative Hammett parameter,
although only in the case of R-substitution. In the case of
â-substitution, the forming positive charge at the non-benzylic
position was not stabilized by an electron-donating aryl sub-
stituent. In the present case, the observed products are due only
to â-substitution of the boronate 9 (see Scheme 3, path B, via
intermediate 25), and because the electronically varied group
is on the iodide, it is able to stabilize a developing positive
charge at the forming benzylic position. Hence, it appears that
the rate determining step in the HM coupling of vinylboronate
9 with aryl iodides is the electrophilic attack of palladium
on the olefin double bond of vinylboronate 6 after an initial
rapid oxidative addition, via 21 to give 25. Our current view of
the HM process involving the vinylboronate ester system
with an aryl iodide is outlined in Scheme 3, which also
explains the origin of the competing aryl crossover reaction.12
It should be noted that an equivalent reactive entity to the
iodo-palladium(II) complex 25 may also be the corresponding
acetate complex resulting from iodide-acetate exchange on
complex 21.10g
possessed insufficient basicity to effectively regenerate the
palladium(0) catalyst led to the investigation of Proton Sponge
as the base [as in eq 1, HM conditions: 5% Pd(OAc)2, 10%
P(p-MeOPh)3, Proton Sponge, MeCN, 70 °C] since this
aniline-type base was also ineffective in the Michael addition
to acrylate 10. This improved the level of conversion to the
dienylboronate 11, but again, the product remained impossible
to isolate from the crude reaction mixture. Reduction of the
reaction temperature from 70 to 50 °C due to concerns over
product stability led to the isolation of dienylboronate 11, but
only in 1.6% yield, whereas use of N,N-diethylaniline under
the same conditions proved unsuccessful. Although the SM
reaction of boronate 9 with iodide 10 was not competing under
these conditions,8 the addition of silver(I) acetate to the reaction
was investigated to try and improve the HM selectivity in these
reactions.2,3 This led to a dramatic increase in the overall
conversion, with dienylboronate 11 being isolated in 16%
yield; however, the major product was identified as dienyldiester
26 (eq 3).
SCHEME 3. Postulated Mechanism Scheme for the HM
versus Aryl Crossover Reaction
Nickel catalyzed reductive dimerization of iodide 10 has
previously been reported;20 however, this involved the use of
stoichiometric zinc reductant and the isomeric purity of the
product was poor, which is characteristic of nickel catalyzed
homocouplings.21 In this case, only silver(I) is present as a
potential reductant; however, since the reaction mixture turned
purple (presumably due to the generation of elemental iodine),
the reaction with silver(I) is either slow or does not contribute
to the formation of the observed product 26. It may be that
vinylboronate 9 is responsible for the reduction of any palla-
dium(II) iodide complex that could result from any oxidative
addition of iodine to palladium(0).22 The isomeric purity of the
isolated diene 26 was notably high (13:1, E,Z/Z,Z; no E,E
detectable), and this stereochemistry suggests that the product
is formed in a Michael addition-elimination process, as shown
in Scheme 4, with reductive elimination of elemental iodine
occurring from the palladium species eliminated from 28 leading
to regeneration of the active catalyst.
Although slow addition of iodide 10 to the reaction shown
in eq 3 proved to be successful in increasing the ratio of dienes
11 to 26, the reactions failed to reach completion, and the highest
yield of dienylboronate 11 achieved using this method was still
only 5%. Increasing the steric bulk around the palladium seemed
to be another possibility for reducing the competing Michael
addition process; hence, tri(o-tolyl)phosphine was investigated
due to both its steric bulk and its increased basicity relative to
triphenylphosphine. This proved highly successful in preventing
Synthetic Approaches to the Viridenomycin Triene Syn-
thon 3. With this piece of mechanistic knowledge in hand,
attention was turned to the seemingly intractable HM coupling
of vinylboronate ester 9 with iodoacrylate 10. Since in this case,
the forming positive charge would not be at a benzyl but on an
allyl position, which would be additionally destabilized
by the strong electron-withdrawing ester function (presumably
explaining the previous lack of reactivity), it appeared that a
polar solvent would be necessary to stabilize the transition
state. Since use of standard amine bases was not possible
due to reaction with the acrylate8 and inorganic bases appeared
to force the SM reaction,8,19 N,N-diethylaniline was used as
base [as in eq 1, HM conditions: 5% Pd(OAc)2, 10% P(p-
MeOPh)3, N,N-diethylaniline, MeCN, 70 °C] since this had
been shown to be unreactive in the Michael addition to acrylate
10.8 Although this gave rise to a detectable level of dienylbo-
ronate 11 (GC-MS), the conversion was insufficient to
allow isolation. In addition, concerns that N,N-diethylaniline
(20) Kotora, M.; Matsumara, H.; Takahashi, T. Chem. Lett. 2000, 236-
237.
(21) (a) Takagi, K.; Mimura, H.; Inokawa, S. Bull. Chem. Soc. Jpn. 1984,
57, 3517-3522. (b) Sasaki, K.; Nakao, K.; Kobayashi, Y.; Sakai, M.;
Uchino, N.; Sakakibara, Y.; Takagi, K. Bull. Chem. Soc. Jpn. 1993, 66,
2446-2448. (c) Cannes, C.; Labbe, E.; Durandetti, M.; Nedelec, J. Y. J.
Electroanal. Chem. 1996, 412, 85-93.
(22) Gray, L. R.; Gulliver, D. J.; Levason, W.; Webster, M. Inorg. Chem.
1983, 22, 2362-2366.
(18) Fristrup, P.; Le Quement, S.; Tanner, D.; Norrby, P.-O. Organo-
metallics 2004, 23, 6160-6165.
(19) Lightfoot, A. P.; Twiddle, S. J. R.; Whiting, A. Synlett 2005, 529-
530.
2528 J. Org. Chem., Vol. 72, No. 7, 2007

Mechanistic Studies on Heck-Mizoroki Reaction
SCHEME 4. Proposed Mechanistic Explanation for the
Origin of Diene 26
silver(I) salt is recognized to promote a cationic reaction
pathway,25 this result is perhaps not surprising since the
generation of methyl propiolate results from facile deprotonation
of a cationic organo-palladium species [presumably not dis-
similar to the palladium(II) complex 27 (Scheme 4)].
In an effort to reduce the elimination of HI in the reaction
involving tri(o-tolyl)phosphine, as in eq 4, Conditions A, Proton
Sponge was removed, and the reaction was run using stoichio-
metric silver(I) acetate as sole base (eq 4, Conditions C). This
not only significantly increased the pH of the reaction but also
produced the desired dienylboronate 11 in quantitative yield.
The successful Conditions C (eq 4) also work well with the
corresponding E-iodoacrylate,26 as in eq 5, producing the all-
trans-dienylboronate 31 in essentially quantitative yield. It is
interesting to note that silver(I) is ideal for both cis- and trans-
iodoalkenes in this case (eqs 4 and 5), which contrasts with
earlier findings that suggested that thallium(I) and silver(I) salts
were best applied to cis- and trans-iodoalkenes, respectively;
however, the current conditions are vastly improved in terms
of efficiency and selectivity.2
the formation of the unwanted diene 26; however, a new
unwanted byproduct was observed. Purification gave dienyl-
boronate 11 in 15% yield and the new species 29 in 21% yield
(eq 4, Conditions A). Given the virtually identical Tolman
electronic parameters23 of tris(4-methoxyphenyl)phosphine and
tri(o-tolyl)phosphine (2066.1 and 2066.6 cm-1, respectively) this
seems to be an entirely steric effect, the bulk around palladium
preventing the organometallic intermediate from behaving as a
nucleophile in the case of tri(o-tolyl)phosphine.
Thus, with dienylboronate 11 in hand, the iododeboronation
reaction was investigated with inversion of the stereochemistry
at the boronate double bond4 being necessary for the formation
of dienyl iodide 32 (Scheme 5).
This reaction proved successful, with the light and seemingly
heat sensitive dienyl iodide 32 being isolated in 49% yield
initially. Samples of dienyl iodide 32 in chloroform were
completely degraded after several days of standing; however,
larger scale reactions led to an improved 69% yield by using
chilled solvent in the chromatographic purification (Scheme 5)
and a 94:6 isomeric purity [minor isomer appears to be the
(2E,4Z,6E) isomer]. The sensitivity of dienyl iodide 32 meant
that it was used immediately in the HM coupling with
vinylboronate 9, and since the potential for Michael addition
was still present, the amine-free HM conditions (vide supra)
were again utilized. This gave trienylboronate 33 in 81% yield
as a major stereoisomer (i.e., 90:10 isomeric purity), with the
minor isomer appearing to be the (2E,4Z,6E) isomer carried
over from dienyliodide 32. This was then exposed to the
iododeboronation reaction, this time with retention of the
alkenylboronate geometry, which gratifyingly provided trienyl
The formation of enyne 29 is assumed to arise from
elimination of HI from palladium(II) complex 27 (Scheme 4)
to give methyl propiolate, which then undergoes Sonogashira
coupling24 with acrylate 10, which may well require silver(I)
to be present to promote this reaction. It is noteworthy that
elimination of HI from acrylate 10 appears to occur only when
tri(o-tolyl)phosphine is used as the palladium ligand. In addition,
the reaction of acrylate 10 with Proton Sponge shows no
detectable methyl propiolate generation even over several weeks.
It also seems that the presence of vinylboronate 9 is essential
for this reaction to occur, possibly acting as a reactant to remove
HI from the reaction; in the absence of the boronate 9, yields
of the enyne 29 are low.
(25) (a) Moritani, I.; Fujiwara, Y.; Danno, S. J. Organomet. Chem. 1971,
27, 279-282. (b) Stang, P. J.; Kowalski, M. H.; Schiavelli, M. D.; Longford,
D. J. Am. Chem. Soc. 1989, 111, 3347-3356. (c) Stang, P. J.; Kowalski,
M. H. J. Am. Chem. Soc. 1989, 111, 3356-3362. (d) Hinkle, R. J.; Stang,
P. J.; Kowalski, M. H. J. Org. Chem. 1990, 55, 5033-5036. (e) Ozawa,
F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 1417-1419. (f)
Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem.
1992, 57, 1481-1486. (g) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R.
J. Org. Chem. 1992, 57, 3558-3563. (h) Portnoy, M.; Ben-David, Y.;
Milstein, D.; Organometallics 1994, 13, 3465-3479.
Use of 1,3-bis(diphenylphosphino)propane (eq 4, Conditions
B) was also investigated as a palladium ligand. This gave a
mixture of unreacted acrylate 10, together with enyne 29, the
desired dienylboronate 11 being virtually undetectable. Since
the combination of bidentate phosphine, alkenyl iodide, and
(23) Tolman, C. A. Chem. ReV. 1977, 77, 313-348.
(24) (a) Although it is known that Sonogashira reactions involving
alkynes bearing electron-withdrawing groups can be problematic (see ref
23b), we have found that the coupling of methyl propiolate and 10 can be
performed in reasonable yield (see Experimental Section). (b) Negishi, E.;
Anastasia, L. Chem. ReV. 2003, 1979-2018.
(26) Methyl E-iodoacrylate is prepared from the corresponding Z-
iodoacrylic acid by an HI-mediated isomerization-methylation sequence
(see Experimental Section), which needs to be carried out under carefully
controlled conditions, otherwise 3,3-diiodopropionic acid is produced (see
single-crystal X-ray structure, Figure 1, ESI).
J. Org. Chem, Vol. 72, No. 7, 2007 2529

Batsanov et al.
SCHEME 5. Conversion of Dienylboronate 11 to Trienyl
Iodide 34
heated to 110 °C. After 24 h, the reaction mixture was cooled,
diluted with Et2O (80 mL), and passed through Celite before
washing with 10% HCl (40 mL), water (40 mL), and saturated
aqueous sodium chloride (40 mL). Drying (MgSO4) and solvent
removal provided the crude product as a yellow oil that was purified
by silica gel chromatography (hexane/Et2O, 96:4 as eluent) to afford
styrylboronate 19e (376 mg, 87%) as a clear oil. νmax/cm-1 (film):
1623 (m), 1490 (m), 1391 (vs), 1303 (vs), 1270 (vs), 1206 (vs),
1160 (vs), 1090 (vs); UV (CHCl3, nm): 216 (ꢀ 7990), 232 (ꢀ 6380),
272 (ꢀ 15700); δH (400 MHz, CDCl3) 1.31 (d, J ) 6.0 Hz, 3H),
1.34 (s, 6H), 1.56 (t, J ) 6.0 Hz, 1H), 1.83 (dd, J ) 13.8 and 3.2
Hz, 1H), 4.22-4.32 (m, 1H), 6.07 (d, J ) 18.0 Hz, 1H) 7.20-
7.30 (m, 3H), 7.40 (d, J ) 8.4 Hz, 2H); δC (101 MHz, CDCl3)
23.3, 28.3, 31.4, 46.1, 65.1, 71.1, 128.3, 128.8, 134.1, 136.6, 145.2;
δB (128 MHz, CDCl3) 26.8; m/z (EI+) 264.1084 (M+, C14H18BO2-
Cl+ 264.1083), 266, 251, 249, 164 (100%).
4,4,6-Trimethyl-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3,2-dioxa-
borinane 19d. To a dried Schlenk tube under a positive pressure
of argon was added Pd(OAc)2 (19 mg, 0.085 mmol), tri(2-furyl)-
phosphine (58 mg, 0.25 mmol), 4-iodo-fluorobenzene (0.184 cm3,
1.6 mmol), nBu3N (0.46 mL, 1.9 mmol), and vinylboronate27 9 (300
mg, 1.95 mmol). Syringe addition of toluene (20 mL) was followed
by degassing using the freeze-pump-thaw method (3×), and the
stirred mixture was heated to 110 °C. After 24 h, the reaction
mixture was cooled, diluted with Et2O (80 mL), and passed through
Celite before washing with 10% HCl (40 mL), water (40 mL), and
saturated aqueous sodium chloride (40 mL). Drying (MgSO4) and
solvent removal provided the crude product as a red-brown oil
that was purified by silica gel chromatography (hexane/Et2O, 96:4
as eluent) to afford 19d (210 mg, 53%) as a pale yellow oil. IR
(film, cm-1): 1625 (m), 1599 (m), 1505 (m), 1389 (vs), 1304 (vs),
(C-B) 1269 (vs), 1205 (vs), 1156 (vs), 1093 (m). UV (CHCl3,
nm): 203 (ꢀ 6000), 228 (ꢀ 6030), 264 (ꢀ 8810); δH (400 MHz,
CDCl3) 1.31 (d, J 6.0, 3H), 1.34 (s, 6H), 1.57 (t, J 6.0, 1H), 1.83
(dd, J 13.8 and 3.2, 1H), 4.22-4.32 (m, 1H), 6.07 (dd, J 18.2 and
0.8, 1H) 6.96-7.15 (m, 2H), 7.25 (d, J 18.4, 1H), 7.41-7.44 (m,
2H). δC (101 MHz, CDCl3) 23.3, 28.3, 31.4, 46.1, 65.0, 71.1, 115.6
(d, JC-F 22), 128.7 (d, JC-F 7.9), 134.3 (d, JC-F 3.4), 145.3, 161.7,
164.2; δF (376 MHz, CDCl3) -113.9 (m); δB (128 MHz, CDCl3)
26.4 (br); m/z (EI+) 248.1378 (M+, C14H18BO2F+ 248.1378), 233,
148 (100%).
Methyl 3-Z-Iodoacrylate28 10. A stirred solution of methyl
propiolate (5.3 mL, 59.6 mmol) and sodium iodide (14.4 g, 96
mmol) in acetic acid (22 mL) under argon was heated to 115 °C.
After 1 h, the hot mixture was poured onto water (100 mL),
extracted with Et2O (3 × 100 mL), washed with saturated aq
NaHCO3 (4 × 50 mL), saturated aq sodium metabisulphate (50
mL), and brine (50 mL), dried (MgSO4), and evaporated to give
10 as a yellow oil (12.49 g, 99%). All spectral and analytical
properties were as reported.28
(2Z,4E)-Hexa-2,4-dienoic Acid Dimethyl Ester 26. To a dried
Schlenk tube under a positive pressure of argon was added AgOAc
(140 mg, 0.84 mmol), Pd(OAc)2 (9 mg, 0.040 mmol), tris(4-
methoxyphenyl)phosphine (27.5 mg, 0.078 mmol), and dry MeCN
(5 mL). The mixture was degassed using the freeze-pump-thaw
method (1×), and Proton Sponge (200 mg, 0.93 mmol), vinylbo-
ronate27 9 (0.16 mL, 0.95 mmol), and 10 (0.090 mL, 0.80 mmol)
were added. The mixture was degassed using the freeze-pump-
thaw method (2×) and heated to 50 °C. After 21 h, the mixture
was cooled, diluted with Et2O (60 mL), passed through Celite,
washed with 5% HCl (20 mL) and brine (20 mL), dried (MgSO4),
concentrated, and purified by silica gel chromatography (EtOAc/
petroleum ether, 1:9 as eluent) to give 11 (28 mg, 16%) as a clear
iodide 34 in 90% yield with high stereochemical purity (90:10
isomeric purity [minor isomer again appears to be the (2E,4Z,6E)
isomer]).
Conclusion
Although it is difficult to be sure of the latter parts of the
HM reaction mechanism involving aryl iodides and a hindered
vinylboronate ester, it is clear that the rate determining step is
not oxidative addition. Indeed, there is a need for a more detailed
kinetic study to determine actual reaction orders and hence
reveal the mechanism operating in such systems. However, with
knowledge that oxidative addition is not rate determining at
hand, it is possible to make suitable choices about catalyst,
ligand, and reaction conditions, which provide the required
control in subsequent coupling reactions involving systems that
formerly did not produce any of the desired HM products.
Hence, it becomes possible to use iodoacrylates for HM
reactions to develop an approach toward carboxylate-substituted
polyenes, such as that required for an attempted synthesis of
viridenomycin 1. Thus, this approach can be usefully employed
for the synthesis of building block 34, which is required for
the northern tetraene section of viridenomycin 1. This has been
achieved in a promising overall 50% yield from methyl
propiolate. In the process, new conditions for the selective HM
coupling of vinyl iodides with vinylboronates have been
developed. These conditions are not only of potential use for
the further application of vinylboronates as vinyl dianion
equivalents in synthesis but have also provided further insight
into the HM coupling of seemingly low reactivity vinylboronate
esters.
Experimental Section
Synthesis of 4,4,6-Trimethyl-2-[(E)-2-(4-chlorophenyl)ethe-
nyl]-1,3,2-dioxaborinane 19e. To a dried Schlenk tube under a
positive pressure of argon was added Pd(OAc)2 (19 mg, 0.085
mmol), PPh3 (63 mg, 0.24 mmol), 4-iodo-chlorobenzene (390 mg,
1.64 mmol), and AgOAc (308 mg, 1.85 mmol). Syringe addition
(27) Woods, W. G.; Strong, P. L. J. Organomet. Chem. 1967, 7, 371-
376.
(28) Piers, E.; Wong, T.; Coish, P. D.; Rogers, C. Can. J. Chem. 1994,
72, 1816-1819.
n
of toluene (20 mL), Bu3N (0.46 mL, 1.9 mmol), and vinylbor-
onate26 9 (300 mg, 1.95 mmol) was followed by degassing using
the freeze-pump-thaw method (3×), and the stirred mixture was
2530 J. Org. Chem., Vol. 72, No. 7, 2007

Mechanistic Studies on Heck-Mizoroki Reaction
oil and 26 (45 mg, 66%) as a white solid. Mp 72.4-73.2 °C (lit.29
72-73 °C). All spectral properties were identical to those reported
in the literature.29
as a pale yellow oil in >99:1 isomeric purity; νmax/cm-1 (film) 2980
(weak, various C-H), 1720 (s, CdO), 1590 (s, CdC), 1390 (s),
1300 (vs), 1270 (s), 1200 (vs), 1160 (vs), 1020 (s); δH (400 MHz,
CDCl3) 1.28 (3H, d, J 6), 1.30 (3H, s), 1.31 (3H, s), 1.48-1.55
(m, 1H), 1.78-1.82 (1H, m), 3.74 (3H, s), 4.19-4.28 (1H, m),
5.71 (1H, d, J 11), 5.83 (1H, d, J 17.5), 6.59 (1H, dt, J 11, 1), 8.04
(1H, ddd, J 17.5, 11, 1); δC (101 MHz, CDCl3) 23.2 (CHMe), 28.3,
31.3, 46.1, 51.4, 65.1, 71.2, 118.8, 125.9, 141.4, 146.5, 166.6; δB
(128 MHz, CDCl3) 26.0; m/z (CI+) 256 (M + NH4+, 100%), 239,
Z-Hex-2-en-4-ynedioic Acid Dimethyl Ester 29. Conditions
A. To a dried Schlenk tube under a positive pressure of argon was
added silver(I) acetate (140 mg, 0.84 mmol), Pd(OAc)2 (9 mg, 0.040
mmol), tri(o-tolyl)phosphine (24.5 mg, 0.081 mmol), and dry MeCN
(5 mL). The mixture was degassed using the freeze-pump-thaw
method (2×), and Proton Sponge (198 mg, 0.92 mmol), vinylbo-
ronate27 9 (0.160 mL, 0.95 mmol), and 10 (0.090 mL, 0.80 mmol)
were added. The mixture was degassed using the freeze-pump-
thaw method (3×), and the stirred mixture was heated to 50 °C.
After 26 h, the mixture was cooled, diluted with Et2O (60 mL),
passed through Celite, washed with 5% HCl (20 mL), water (20
mL) and brine (20 mL), dried (MgSO4), and evaporated to give a
brown oil. Purification by silica gel chromatography (gradient
elution, EtOAc/petroleum ether, 5:95 to 20:80 as eluent) gave 11
(28 mg, 15%) as a pale yellow oil and 29 (14 mg, 21%) as a pale
yellow oil; 29: νmax/cm-1 (film) 2950 (w), 2160 (w), 1710 (vs),
1434 (m), 1260 (s), 1220 (s), 1180 (s), 1070 (m); δH (CDCl3, 400
MHz) 3.80 (3H, s), 3.83 (3H, s), 6.21 (1H, d, J 11.6), 6.35 (1H, d,
J 11.6); δC (CDCl3, 101 MHz) 52.1, 53.1, 81.6, 89.9, 119.9, 133.4,
+
162, 136; HRMS (ES+) 256.1717 (C12H23NBO4+, M + NH4
256.1715).
Z-Iodoacrylic Acid.28,30 A stirred mixture of acetic acid (22 mL),
propiolic acid (3.7 mL, 60 mmol), and sodium iodide (14.3 g, 95
mmol) was heated to 115 °C under Ar. After 90 h, the hot mixture
was poured onto water (150 mL), extracted with Et2O (100 mL),
separated, and re-extracted with Et2O (2 × 50 mL), and the
combined organic phase was washed with saturated aqueous
Na2S2O3 (75 mL) and brine (75 mL) and dried (MgSO4). Evapora-
tion gave Z-iodoacrylic acid28,30 as a pale yellow solid (9.76 g, 82%).
Mp 64-66 °C (lit.28 62-64 °C). All spectral properties were
identical to those reported in the literature.28
3,3-Diiodopropanoic Acid.31 Z-Iodoacrylic acid (4.00 g, 20.2
mmol) was dissolved in 57% aqueous HI (5.3 mL, 40 mmol), and
the stirred mixture was heated to 90 °C under argon. After 24 h,
the mixture was cooled, diluted with 5% HCl (50 mL) and Et2O
(50 mL), separated, and re-extracted with Et2O (4 × 25 mL), and
the combined organic phases were washed with saturated aq
Na2S2O3 (10 mL) and brine (10 mL) and dried (MgSO4), and
evaporation gave the crude product as an orange solid. Recrystal-
lization from DCM/hexane gave a white crystalline solid (3.87 g).
Further purification by repeated crystallization from DCM/hexane
(4×) gave 3,3-diiodopropanoic acid (0.879 g, 18%) as a white
crystalline solid. Mp 85.0-86.1 °C (lit.31 87 °C) δH (500 MHz,
CDCl3) 3.80 (2H, d, J 7) and 5.24 (1H, t, J 7); δC (126 MHz,
CDCl3) -45.8, 53.0, 175.2; νmax/cm-1 (neat) 3000 (broad, acid
O-H), 1690 (vs), 1430 (s), 1320, 1250 (s), 1140; m/z (EI+)
+
153.9, 164.3; m/z (EI+) 168.0417 (M+, C8H8O4 168.0417) and
153 (100%, M - Me+).
Conditions B. To a dried Schlenk tube under a positive pressure
of argon was added silver(I) acetate (280 mg, 1.68 mmol), Pd-
(OAc)2 (18 mg, 0.080 mmol), 1,3-bis(diphenylphosphino)propane
(33 mg, 0.081 mmol), and dry MeCN (10 mL). The mixture was
degassed using the freeze-pump-thaw method (2×), and Proton
Sponge (400 mg, 0.92 mmol), vinylboronate27 9 (0.080 mL, 0.48
mmol), and 10 (0.180 mL, 1.60 mmol) were added. The mixture
was degassed using the freeze-pump-thaw method (2×), and the
stirred mixture was heated to 50 °C. After 26 h, the mixture was
cooled, diluted with Et2O (80 mL), passed through Celite, washed
with 5% HCl (40 mL), water (40 mL), and brine (40 mL), dried
(MgSO4), and evaporated to give a brown oil. Purification by silica
gel chromatography (gradient elution, EtOAc/petroleum ether, 10:
90 to 100:0) yielded 29 (39 mg, 28%) as a pale yellow oil.
Sonogashira Method. To a dried Schlenk tube under a positive
pressure of argon was added K2CO3 (290 mg, 2.1 mmol), Pd(OAc)2
(16 mg, 0.071 mmol), triphenylphosphine (38 mg, 0.055 mmol),
copper(I) iodide (28 mg, 0.15 mmol), and dry DMF (10 mL). The
mixture was degassed using the freeze-pump-thaw method (2×),
methylpropiolate (0.17 mL, 1.9 mmol) and 10 (348 mg, 1.6 mmol)
were added, followed by a further degassing (3×) and heating to
50 °C. After 5 h, the mixture was cooled, diluted with Et2O (80
mL), passed through Celite, and washed with 5% HCl (20 mL),
water (40 mL), and brine (40 mL), dried (MgSO4), and evaporated
to give the crude product as a brown oil. Purification by silica gel
chromatography (EtOAc/petroleum ether, 1:9 to 1:4 as eluent) gave
29 (85 mg, 32%) as a pale yellow oil. All spectroscopic and
analytical properties were identical to those reported previously.
(2Z,4E)-5-(4,4,6-Trimethyl-[1,3,2-dioxaborinan-2-yl])-penta-
2,4-dienoic Acid Methyl Ester 11. To a dried Schlenk tube under
a positive pressure of argon was added silver(I) acetate (150 mg,
0.90 mmol), Pd(OAc)2 (9 mg, 0.040 mmol), tri(o-tolyl)phosphine
(25 mg, 0.082 mmol), and dry MeCN (5 mL). The mixture degassed
using the freeze-pump-thaw method (2×), and vinylboronate27
9 (0.16 mL, 0.95 mmol) and 10 (175 mg, 0.83 mmol) were added,
and then the mixture was degassed using the freeze-pump-thaw
method (2×) and heated to 50 °C with vigorous stirring. After 23
h, the mixture was cooled, diluted with Et2O (70 mL), passed
through Celtite, washed with 5% HCl (10 mL), water (20 mL),
and brine (20 mL), dried (MgSO4), and evaporated to give crude
product as a yellow oil. Purification by silica gel chromatography
(EtOAc/petroleum ether, 1:9 as eluent) gave 11 (197 mg, 100%)
325.8291 (M+, C3H4I2O2 325.8295), 199, 127 (100%), 71.
+
C3H2I2O2 C, 11.06; H, 1.24; found C, 10.89; H, 1.22%.
The structure was characterized by a single-crystal X-ray
diffraction study, using a Siemens SMART 1K CCD area detector,
graphite-monochromated Mo KR radiation (λh ) 0.71073 Å) and
SHELXTL 6.14 programs.33 Crystal data: C3H4I2O2, M ) 325.86,
T ) 130 K, monoclinic, space group P21/c (No. 14), a ) 12.724-
(2) Å, b ) 6.5787(9) Å, c ) 8.808(1) Å, R ) 102.61(1)°, U )
719.5(2) Å,3 Z ) 4, Dc ) 3.008 g cm-3, µ ) 8.65 mm-1, 8140
reflections with 2θ e58°, absorption correction by numerical
integration (transmission max. 0.6394, min. 0.3387, Rint ) 8.0%
before and 2.6% after correction), final R(F) ) 1.8% on 1739 data
with I g 2σ (I), wR(F2) ) 4.5% on all 1898 unique data.
Crystallographic file in CIF format is available as Supporting
Information.
E-Iodoacrylic Acid.32 Z-Iodoacrylic acid (3.10 g, 15.7 mmol)
was added to a solution of 57% aqueous HI (0.300 mL, 2.3 mmol)
in benzene (8 mL), and the stirred mixture was heated to 80 °C
under argon. After 18 h, the mixture was cooled, diluted with Et2O
(40 mL) and water (1.5 mL), and re-extracted with Et2O (20 mL),
and the combined organic phase was washed with dilute aqueous
Na2S2O3 (10 mL) and dried (MgSO4), and the solvent evaporated
to give the crude product, which was washed with hexane (100
mL) to give E-iodoacrylic acid30 (2.76 g, 89%) as a white crystalline
solid: Mp. 142-144 °C (lit.32 140-141 °C). All spectral properties
were identical to those reported in the literature.32
(30) Jung, M. E.; Hagenah, J. A.; Long-Mei, Z. Tetrahedron Lett. 1983,
24, 3973-3974.
(31) (a) Masuda, E.; Nishida, K. J. Pharm. Soc. Jpn. 1934, 54, 1091-
1100. (b) Ibid, Chem. Abstr. 1935, 29, 3305.
(32) Takeuchi, R.; Tanabe, K.; Tanaka, S. J. Org. Chem. 2000, 65, 1558-
1561.
(29) Martin, M.-E.; Planchenault, D.; Huetl, F. Tetrahedron 1995, 51,
4985-4990.
(33) SHELXTL 6.14; Bruker AXS: Madison, WI, 2003.
J. Org. Chem, Vol. 72, No. 7, 2007 2531

Batsanov et al.
Methyl E-Iodoacrylate 30. E-Iodoacrylic acid (671 mg, 3.39
mmol) was dissolved in MeOH (8 mL), H2SO4 (0.205 mL, 3.69
mmol) was added, and the stirred mixture was heated to 85 °C
under argon. After 4.25 h, the mixture was cooled, evaporated, and
redissolved in a mixture of Et2O and chloroform (150 mL, 4:1,
respectively). Washing with water (40 mL), 5% aq sodium
metabisulphite (40 mL), saturated aq NaHCO3 (40 mL) and brine
(40 mL), drying (MgSO4), and evaporation gave 30 (532 mg, 74%)
as a pale yellow solid; Mp 41-44 °C; δH (500 MHz, CDCl3) 3.75
(3H, s), 6.88 (1H, d, J 15), 7.89 (1H, d, J 15); δC (126 MHz, CDCl3)
52.1, 99.8, 136.3, 164.8; νmax/cm-1 (neat) 2900 (w), 1721 (vs), 1589
(s), 1434 (s), 1350 (s), 1262 (s), 1216 (s); m/z (EI+) 211.9327 (M+,
(2Z,4Z,6E)-7-(4,4,6-Trimethyl-[1,3,2-dioxaborinan-2-yl)-hepta-
2,4,6-trienoic Acid Methyl Ester 33. To a dried Schlenk tube under
a positive pressure of argon was added silver(I) acetate (190 mg,
1.14 mmol), Pd(OAc)2 (11.5 mg, 0.051 mmol), tri(o-tolyl)phosphine
(31 mg, 0.10 mmol), and a solution of 33 (250 mg, 1.05 mmol) in
dry MeCN (6 mL). The mixture was degassed using the freeze-
pump-thaw method (2×), 9 (0.20 mL, 1.2 mmol) was added, and
the mixture was further degassed (2×) and heated to 50 °C with
vigorous stirring. After 21 h, the mixture was cooled, diluted with
Et2O (80 mL), washed with 5% HCl (20 mL), water (40 mL), and
brine (40 mL), dried (MgSO4), and evaporated to give the crude
product as an orange oil. Purification by silica gel chromatography
(EtOAc/petroleum ether, 1:9 as eluent) gave 33 (225 mg, 81%) as
a viscous pale yellow oil in 90:10 isomeric purity [minor isomer
appears be to the (2E,4Z,6E) isomer]; νmax/cm-1 (film) 2970 (w),
1720 (s), 1610 (s), 1440 (m), 1390 (m), 1290 (s), 1160 (vs), 1020
(m); δH (400 MHz, CDCl3) 1.28 (3H, d, J 6), 1.30 (3H, s), 1.31
(3H, s), 1.48-1.55 (m, 1H), 1.80 (1H, dd, J 11.2, 3.2, CHH), 3.73
(3H, s), 4.20-4.28 (1H, m), 5.66-5.78 (2H, m), 6.39 (1H, t, J
10), 7.19-7.25 (1H, m), 7.32 (1H, m), 7.44 (1H, dd, J 17, 11); δC
(101 MHz, CDCl3) 23.3, 28.3, 31.4, 46.2, 51.3, 65.1, 71.2 (CMe2),
118.1, 126.0, 138.9, 139.3, 139.7, 166.9; δB (128 MHz, CDCl3) 26
(brs); m/z (EI+) 264 (M+), 164, 106 (100%), 83; HRMS (ES+)
287.1428 (M + Na+, C14H21BO4Na+ 287.1425).
(2Z,4Z,6E)-7-Iodo-hepta-2,4,6-trienoic Acid Methyl Ester 34.
A solution of 33 (233 mg, 0.87 mmol) in dry THF (5 mL) was
cooled to -78 °C under argon in the absence of light. NaOMe
(2.1 mL of a 0.5 M solution in MeOH, 1.05 mmol) was added
dropwise, the mixture was stirred for 30 min, and iodine monochlo-
ride (0.90 mL of a 1.0 M solution in DCM, 0.90 mmol) was added
dropwise. The mixture was stirred for 1 h, warmed to room
temperature, diluted with Et2O (60 mL), and washed with 5% aq
sodium metabisulphite (30 mL), water (30 mL), and brine (30 mL).
Drying (MgSO4) and evaporation gave the crude product as a yellow
oil that was immediately purified by silica gel chromatography
(EtOAc/petroleum ether, 5:95 as eluent, cooled to 0 °C) to give 34
(209 mg, 90%) as a pale yellow oil in 90:10 isomeric purity [minor
isomer appears to be the (2E,4Z,6E) isomer]; νmax/cm-1 (film) 3050
(w, C-H), 2950 (w), 1710 (vs), 1610 (s), 1540 (s), 1440 (m), 1290
(w), 1230 (m), 1200 (vs), 1160 (vs), 1020 (w); δH (500 MHz,
CDCl3) 3.74 (3H, s), 5.81 (1H, d, J 11.5), 6.24 (1H, t, J 11.5),
6.68 (1H, d, J 14), 7.02 (1H, t, J 11.5), 7.30 (1H, t, J 11.5), 7.58
(1H, dd, J 14, 11.5); δC (126 MHz, CDCl3) 51.5, 85.8, 119.1, 124.3,
135.8, 137.9, 139.9, 166.9; m/z (CI+) 264.9721 (C8H10IO2+, MH+
264.9720), 252, 239, 156, 139.
+
C4H5IO2 211.9329), 181, 153, 127, 85 (100%).
(2E,4E)-5-(4,4,6-Trimethyl-[1,3,2-dioxaborinan-2-yl])-penta-
2,4-dienoic Acid Methyl Ester 31. To a dried Schlenk tube under
a positive pressure of argon was added silver(I) acetate (430 mg,
2.58 mmol), Pd(OAc)2 (26 mg, 0.12 mmol), tri(o-tolyl)phosphine
(70 mg, 0.23 mmol), and a solution of methyl E-iodoacrylate 30
(500 mg, 2.36 mmol) in dry MeCN (14.5 mL). The mixture was
degassed using the freeze-pump-thaw method (2×), vinylbor-
onate27 9 (0.46 mL, 2.76 mmol) was added, and the mixture was
degassed using the freeze-pump-thaw method (1×) and heated
to 50 °C with vigorous stirring. After 22 h, the mixture was cooled,
diluted with Et2O (80 mL), passed through Celite, and washed with
5% HCl (20 mL), water (40 mL), and brine (40 mL). Drying
(MgSO4) and evaporation gave the crude product as a yellow oil.
Purification by silica gel chromatography (EtOAc/petroleum ether,
1:9 as eluent) gave product 31 (560 mg, 100%) as a pale yellow
oil in >99:1 isomeric purity; νmax/cm-1 (film) 2980 (w, C-H), 1710
(s, CdO), 1600 (s, CdC), 1425 (w), 1395 (s), 1305 (s), 1245 (vs),
1155 (vs), 1120 (s), 1010 (s); δH (500 MHz, CDCl3) 1.28 (3H, d,
J 6), 1.30 (3H, s), 1.31 (3H, s), 1.48-1.55 (m, 1H, CHH), 1.78-
1.82 (1H, m), 3.74 (3H, s), 4.19-4.28 (1H, m), 5.91 (1H, d, J 17.5),
5.96 (1H, d, J 15), 6.96 (1H, dd, J 17.5, 11), 7.27 (1H, dd, J 15,
11); δC (126 MHz, CDCl3) 23.2, 28.2, 31.3, 46.0, 51.8, 65.1, 71.3,
122.8, 143.5, 146.2, 167.6; δB (128 MHz, CDCl3) 26; m/z (CI+)
256 (M + NH4+, 100%), 239, 162, 136; HRMS (ES+) 256.1717
+
(C12H23NBO4+, M + NH4 256.1715).
(2Z,4Z)-5-Iodo-penta-2,4-dienoic Acid Methyl Ester 32. A
solution of 11 (385 mg, 1.46 mmol) in dry DCM (10 mL) was
degassed using the freeze-pump-thaw method (3×) and cooled
to -78 °C under argon. Iodine monochloride (1.9 mL of a 1.0 M
solution in DCM, 1.9 mmol) was added dropwise, the mixture
stirred for 4 h, NaOMe (3.8 mL of a 0.5 M solution in MeOH, 1.9
mmol) was added dropwise, and the mixture was allowed to warm
to room temperature. After 30 min, the mixture was diluted with
Et2O (80 mL), washed with 5% aq sodium metabisulphite (40 mL),
water (40 mL), and brine (40 mL), dried (MgSO4), and evaporated
to give the crude product as a yellow oil. Purification by silica gel
chromatography (EtOAc/petroleum ether, 5:95 as eluent, cooled
to 0 °C) gave 32 (267 mg, 69%) as a yellow oil in 94:6 isomeric
purity [minor isomer appears to be the (2E,4Z) isomer]; νmax/cm-1
(film) 3030 (w, C-H), 2950 (w), 1710 (vs), 1620 (s), 1430 (m),
1400 (m), 1280 (m), 1200 (vs), 1160 (vs), 1050 (m); δH (CDCl3,
500 MHz) 3.75 (3H, s), 5.91 (1H, dt, J 11 and 1), 6.74 (1H, ddd,
J 11, 8, 1), 6.86 (1H, dt, J 8, 1), 8.02 (1H, ddd, J 11, 8, 1); δC
(CDCl3, 126 MHz) 51.5, 94.0, 121.2, 134.6, 143.0, 166.2; m/z (EI+)
238 (M+), 207, 179, 127, 111; HRMS (ES+) 260.9385 (C6H7O2-
INa+, M + Na+ 260.9383).
Acknowledgment. We thank the EPSRC for a DTA stu-
dentship (J.P.K.), Prof. T. B. Marder, and Drs. M. Crampton,
C. Grosjean, and S. J. R. Twiddle (all Durham University) for
helpful discussions and the EPSRC National Mass Spectrometry
Service at Swansea and the NMR service at Durham.
Supporting Information Available: General experimental
1
methods, all kinetic data and analyses, H and 13C NMR spectra
for compounds 19e, 19d, 29, 11, 30, 31, 32, 33, and 34, 19F NMR
spectrum for 19d, and crystallographic data for 3,3-diiodopropanoic
acid. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0626010
2532 J. Org. Chem., Vol. 72, No. 7, 2007