Synthesis of highly substituted 1,3-dienes, 1,3,5-trienes, and 3,6-disubstituted cyclohexenes by the palladium-catalyzed coupling of organic halides, internal alkynes or 1,3-cyclohexadienes, and organoboranes

Article abstract of DOI:10.1016/j.tet.2010.03.119

A number of highly substituted 1,3-dienes and 1,3,5-trienes have been stereoselectively prepared in moderate to good yields by the coupling of vinylic iodides, internal alkynes, and organoboranes in the presence of a palladium catalyst. Optimal reaction conditions for different organoboron substrates have been developed. The analogous three-component coupling of aryl halides, 1,3-cyclohexadiene, and boronic acids provides a synthetically useful route to 3,6-disubstituted cyclohexenes. These methods are very efficient and provide an expeditious way to synthesize the indicated alkenes, dienes, and trienes, whose preparation would normally require multi-step synthesis.

Full text of DOI:10.1016/j.tet.2010.03.119

Tetrahedron 66 (2010) 4265–4277
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of highly substituted 1,3-dienes, 1,3,5-trienes, and 3,6-disubstituted
cyclohexenes by the palladium-catalyzed coupling of organic halides, internal
alkynes or 1,3-cyclohexadienes, and organoboranes
*
Xiaoxia Zhang, Richard C. Larock
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of highly substituted 1,3-dienes and 1,3,5-trienes have been stereoselectively prepared in
moderate to good yields by the coupling of vinylic iodides, internal alkynes, and organoboranes in the
presence of a palladium catalyst. Optimal reaction conditions for different organoboron substrates have
been developed. The analogous three-component coupling of aryl halides, 1,3-cyclohexadiene, and bo-
ronic acids provides a synthetically useful route to 3,6-disubstituted cyclohexenes. These methods are
very efficient and provide an expeditious way to synthesize the indicated alkenes, dienes, and trienes,
whose preparation would normally require multi-step synthesis.
Received 17 January 2010
Received in revised form 31 March 2010
Accepted 31 March 2010
Available online 3 April 2010
Published by Elsevier Ltd.
1. Introduction
Rawal et al. have reported the synthesis of skipped dienes by the
palladium-catalyzed allylation of alkynes and a subsequent Suzuki
1,3-Dienes and 1,3,5-trienes are important products or in-
termediates in organic chemistry.1 They are of great interest for
their photochemical, electrochemical, and biological properties.2
While there are numerous previous methods to prepare simple
dienes and trienes, the regio- and stereoselective construction of
highly-substituted dienes and trienes, and especially those bearing
tetrasubstituted double bonds, remains one of the biggest chal-
lenges in organic synthesis.3 Therefore, a strategic and diverse ap-
proach to such olefins is highly desirable.
cross-coupling reaction (Eq. 1).6
The propensity of unsaturated compounds, such as alkenes,
allenes, 1,3-dienes, and alkynes, to undergo insertion into carbon–
metal bonds makes these substrates some of the most useful for
transition metal-catalyzed organic transformations.4 Organo-
boronic acids and borates are widely used in the palladium-
catalyzed Suzuki coupling with organic halides, providing an
extremely useful route for carbon–carbon bond formation.5 Thus,
the palladium-catalyzed sequential ternary coupling of organic
halides, unsaturated compounds, and organoboronic acids is
expected to be a highly efficient process employing multiple re-
action steps in a single pot. The practical advantage of the Suzuki
reaction compared with other coupling reactions lies in the fact
that boronic acids are readily prepared, non-toxic and thermally,
air, and moisture stable, as well as being compatible with diverse
functional groups.
Grigg et al. have synthesized polycyclic compounds bearing
a substituted 1,3-diene moiety through the intramolecular tandem
reaction of an aromatic halide with an internal alkyne, followed by
cross-coupling with an external arylborate (Eq. 2).7 We have
previously reported8 a highly efficient, stereo- and regioselective
synthesis of tetrasubstituted olefins by the palladium-catalyzed
cross-coupling of aryl halides, internal alkynes, and arylboronic
acids (Eq. 3). Herein, we report full details of our investigation of
* Corresponding author. E-mail address: larock@iastate.edu (R.C. Larock).
0040-4020/$ – see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.03.119

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X. Zhang, R.C. Larock / Tetrahedron 66 (2010) 4265–4277
a one-pot, intermolecular palladium-catalyzed coupling of vinylic
halides, internal alkynes, and aryl or vinylic boron organometallics,
which offers an efficient, direct route for the construction of
a number of highly substituted 1,3-dienes or 1,3,5-trienes in
a chemo-, regio-, and stereoselective manner from simple, readily
available starting materials.9
(entry 3). However, the use of KF as the base improved the yield
(entry 4). The weak basicity and poor nucleophilicity of the fluoride
ion could make this base particularly useful in the case of base-
sensitive substrates. Adding triphenylphosphine or tri-2-
furylphosphine as ligands slowed down the reaction and lowered
the yield (entries 5 and 6). Using a Pd(0) catalyst, Pd2(dba)3, pro-
vided a yield similar to that of PdCl2 (entry 7). Contrary to our
previous observations that much better regioselectivities for the
coupling of aryl iodides, internal alkynes, and boronic acids could
be achieved at room temperature,8 a higher reaction temperature
here not only shortened the reaction time, it gave a better yield
than the room temperature reaction, although the effect of the
reaction temperature on the regioselectivity of the reaction is
minimal (compare entries 4 and 9). We, therefore, chose 100 ꢀC as
the optimal reaction temperature. The presence of water greatly
facilitates the desired reaction (entries 10 and 11), perhaps because
water is needed to dissolve the KF base, and Fꢁ or OHꢁ ion most
likely combines with the arylboronic acid to form an ‘ate complex’,
which is crucial in Suzuki cross-coupling reactions.5,10 With in-
sufficient water, substantial amounts of fulvenes are formed by the
double insertion of alkynes, followed by ring closure, without the
involvement of the boronic acid.11 However, too much water fa-
cilitates the direct Suzuki reaction of the vinylic iodide and the
arylboronic acid and is detrimental to the yield of the desired three-
component coupling product (entry 12). We thus settled on the
following ‘optimal’ conditions A, employing 1 equiv of vinylic ha-
lide, 2 equiv of internal alkyne, 2 equiv of arylboronic acid, 5 mol %
of PdCl2, 2 equiv of KF, and 5:1 DMF/H2O as the solvent at 100 ꢀC in
the presence of air (the conditions of entry 5 in Table 1).
2. Results and discussion
2.1. Optimization
Our initial work was aimed at developing a set of reaction
conditions that would work well for a variety of substrates. The
reaction of vinylic iodide 1, 1-phenylpropyne, and phenylboronic
acid was chosen as the model system for optimization of this
process (Eq. 4), and the results are summarized in Table 1. The
Table 1
Optimization of the reaction of vinylic iodide 1,1-phenylpropyne, and phenylboronic
acid (Eq. 4)a
Entry Base (equiv) Pd catalyst
Temp (ꢀC) DMF/H2O % yield
of 2b
1
2
3
4
5
K2CO3 (1)
K2CO3 (1)
K3PO4 (1)
KF (2)
PdCl2(PhCN)2
PdCl2
PdCl2
PdCl2
PdCl2(PPh3)2
100
100
100
100
100
5:1
5:1
5:1
5:1
5:1
45
46
38
This ‘optimal’ procedure has thus been employed on a variety of
representative substrates, which were carefully selected in order to
establish the generality of the process and its applicability to
commonly encountered synthetic problems. While the yields from
this model system are not particularly high, subsequent research
established that our ‘optimal’ procedure actually works quite well
when a number of different vinylic halides, alkynes, and boronic
acids are employed (Table 2).
51c
25
KF (2)
6
KF (2)
100
5:1
16
7
8
9
10
11
12
KF (2)
KF (2)
KF (2)
KF (2)
KF (2)
KF (2)
Pd2(dba)3
PdCl2
PdCl2
PdCl2
PdCl2
100
80
5:1
5:1
5:1
7:1
100:0
5:2
45
40
29
37
32
23
rtd
100
100
100
2.2. Scope of the vinylic halide
PdCl2
a
All reactions were run using 0.25 mmol of iodide 1, 0.5 mmol of alkyne, and
0.5 mmol of phenylboronic acid, employing 5 mol % of the Pd catalyst, plus 10 mol %
of a phosphine in 10 mL of DMF/H2O for 2 h unless otherwise specified.
The scope and limitations of this reaction for the synthesis of
a wide variety of 1,3-dienes is indicated in Table 2. Moderate yields
of the desired 1,3-dienes were obtained from the reaction of b-
b
Two regioisomers were observed in all cases.
The two regioisomers were obtained in a 40:60 (2a:2b) ratio.
The reaction was incomplete after 24 h, and the two regioisomers were
c
monosubstituted trans-vinylic iodides (entries 1–3, Table 2) with
diphenylacetylene and phenylboronic acid. In all of these reactions,
we were also able to isolate 20–30% of the product from direct
coupling of the vinylic iodides and phenylboronic acid, together
with small amounts of tetraphenylethene, which is apparently
formed by the reaction of phenylboronic acid and diphenylacety-
lene.12 In all cases, geometrically pure dienes were obtained when
using (E)-alkenes as determined by GC–MS and 1H and 13C NMR
d
obtained in a 37:63 (2a:2b) ratio.
spectroscopy. When an 86:14 mixture of Z- and E-b-iodostyrene
was employed, a 2.5:1 mixture of the corresponding E- and Z-ste-
reoisomeric 1,3-dienes was obtained, indicating substantial loss of
stereochemistry during this particular coupling process. The ther-
modynamically more stable and configurationally inverted E-iso-
mer 3 was generated as the major isomer (entry 4). The desired
original set of reaction conditions used included 5 mol %
PdCl2(PhCN)2, 1 equiv of K2CO3, and 5:1 DMF/H2O as the solvent at
100 ꢀC in the presence of air, conditions which were developed8 for
our previous three-component coupling reaction of aryl halides,
internal alkynes, and arylboronic acids (entry 1, Table 1). Here, we
have chosen the vinylic iodide as the limiting reagent simply be-
cause it is generally less readily available and usually must be
prepared in the lab, while many alkynes and boronic acids are
commercially available.
reaction proceeded very efficiently when the
b,b-disubstituted
vinylic iodide and 1-iodo-4-phenylcyclohexene (11) were
9
employed (entries 5 and 6). However, the reaction of 3-iodo-5,5-
dimethylcyclohex-2-enone (13) and diphenylacetylene afforded
a product in which the vinylic halide and arylboronic acid had
undergone direct cross-coupling without insertion of the alkyne
(entry 7). None of the desired 1,3-diene was observed. Obviously, an
Using PdCl2 as a catalyst gave a yield comparable to that of
PdCl2(PhCN)2 (Table 1, compare entries 1 and 2). Using PdCl2 as the
palladium source and K3PO4 as a base resulted in a lower yield
electron-withdrawing group on the
b-position of the vinylic halide
greatly facilitates direct nucleophilic transmetalation of the boronic

Table 2
Palladium-catalyzed three-component coupling of vinylic (aryl) halides, internal alkynes or 1,3-cyclohexadiene, and organoboranes
Entry
Halide
Alkyne or 1,3-cyclohexadiene
Organoborane
Cond.,a time (h)
Product(s)
% yieldb
1
PhB(OH)2
A, 2
45
62
2
A, 2
3
A, 2
54
7
4
5
6
A, 2
A, 2
A, 2
42d
87
78
7
A, 2
90
(continued on next page)

Table 2 (continued)
Entry
Halide
Alkyne or 1,3-cyclohexadiene
Organoborane
Cond.,a time (h)
Product(s)
% yieldb
8
A, 2
41
9
A, 2
24e
10
A, 2
31
11
12
13
A, 2
30
A, 16
5
p-MeOC6H4B(OH)2
A, 2
93
14
o-MeC6H4B(OH)2
A, 2
82

m-O2NC6H4B(OH)2
A, 2
56
15
16
17
m-H2NC6H4B(OH)2
A, 2
86
60
p-MeO2CC6H4B(OH)2
A, 2
18
A, 2
63
19
A, 2
68
20
21
22
p-ClC6H4B(OH)2
A, 2
A, 2
A, 2
37
31, 57f
32
(continued on next page)

Table 2 (continued)
Entry
Halide
Alkyne or 1,3-cyclohexadiene
Organoborane
NaBPh4
Cond.,a time (h)
Product(s)
% yieldb
23
24
B, 12
71
80
B, 12
25
KBF3Ph
A, 12
31g
26
27
PhB(OH)2
A, 2
A, 2
68
85
28
A, 2
63
29
A, 2
51h (60:40)

30
A, 2
90h (59:41)
31
A, 2
71h,i (56:44)
32
A, 2
62h (88:12)
33
PhB(OH)2
A, 2
60h,j (85:15)
34
PhB(OH)2
A, 2
35h (95:5)
35
A, 2
62h (86:14)
(continued on next page)

Table 2 (continued)
Entry
Halide
Alkyne or 1,3-cyclohexadiene
Organoborane
Cond.,a time (h)
Product(s)
% yieldb
36
A, 2
60h (83:17)
37
A, 2
93h, i (70:30)
38
A, 4
85h, i (68:32)
39
A, 2
71h (63:37)
40
A, 2
62h (68:32)
48a + 48b
41
A, 2
82h (71:29)
9

42
PhI
C, 4
58
43
C, 4
51
44
45
46
47
48
49
50
51
p-MeC6H4I
p-H2NC6H4I
p-HOC6H4I
p-MeOC6H4I
p-MeCOC6H4I
o-MeC6H4I
p-H2NC6H4I
p-H2NC6H4I
PhB(OH)2
D, 24
D, 24
D, 24
D, 24
D, 24
D, 24
D, 24
D, 24
50
51
52
53
54
55
56
57
59k
89
70
58
0
19
72
53
o-MeC6H4B(OH)2
p-ClC6H4B(OH)2
52
PhB(OH)2
D, 24
88
a
See the text for conditions A–D.
b
c
d
e
f
Isolated yield.
This compound was prepared and utilized as an 86:14 mixture of Z/E isomers.
The product was obtained as a 2.5:1 mixture of E- and Z-stereoisomers.
A 59% yield of 4,4-dimethyl-2-phenylcyclohex-2-en-1-ol was obtained.
6 equiv of KF were employed.
Only a trace amount of 7 was obtained without KF as the base.
The products are inseparable.
g
h
i
The regioisomers are tentatively assigned according to the general rule for the insertion of alkynes in organopalladium reactions.
The reaction was run employing a ratio of iodide/alkyne/boronic acid¼2:1:2.
j
k
The yield was determined by 1H and 13C NMR spectral analysis.

4274
X. Zhang, R.C. Larock / Tetrahedron 66 (2010) 4265–4277
acid by the organopalladium(II) intermediate, rather than alkyne
insertion, resulting in the monoene product (see the later
Mechanistic discussion). On the other hand, the hydroxy-
containing vinylic halide 15 reacts with diphenylacetylene under
our standard reaction conditions to give the desired dienol 16 in
a 41% yield, which should be easily oxidized to the corresponding
ketone (entry 8). Placing the halide nearer the alcohol functionality
resulted in a still lower 24% yield of the desired diene 18, alongside
a 59% yield of the direct Suzuki product 4,4-dimethyl-2-phenyl-
cyclohex-2-en-1-ol (entry 9). The presence of a vicinal OH group is
apparently detrimental to carbopalladiation of the alkyne. The re-
action of methyl trans-2-iodoacrylate generated a 31% yield of
methyl cinnamate without any of the desired diene being detected.
It appears that this iodide is unstable under our reaction conditions.
A vinylic triflate has been cross-coupled using this process, al-
though a much lower yield was observed than that obtained using
the analogous iodide (compare entries 5 and 11). Unfortunately, the
analogous vinylic bromide proved to be essentially inert in this
process (entry 12). Only a 5% yield of the expected diene was
formed after 16 h reaction and most of the vinylic bromide
remained unreacted.
NaBPh4, the desired diene was obtained under non-aqueous and
non-basic conditions. The ‘optimal’ reaction conditions B for this
process utilize 2 equiv of the vinylic halide, 1 equiv of the internal
alkyne, 2 equiv of borate, 5 mol % of Pd(OAc)2, and 1 equiv of LiCl in
DMF at 100 ꢀC in the presence of air.14 Under these conditions, vi-
nylic halide 1 reacts with diphenylacetylene and NaBPh4 to afford
the desired product 3 in a 71% yield (entry 23). Transmetallation of
a thiophene group from sodium tetra(2-thiophenyl)borate was
even more facile, producing 34 in an 80% yield (entry 24). The re-
action of postassium phenytrifluoroborate also provides the de-
sired 1,3-diene 7, but in a lower yield (compare entry 3 and 25). It is
noteworthy that the base KF is still necessary in this latter reaction,
since only a trace amount of the product is obtained without it.
2.4. Scope of the internal alkyne
Under our ‘optimal’ conditions, a wide variety of internal al-
kynes have been successfully employed in all cases studied so far.
The reactions proceed in a very stereoselective manner. When
symmetrical alkynes, such as diphenylacetylene or 4-octyne, are
employed, only one pure stereoisomer is generated and the vinylic
group and the aryl group from the arylboronic acid have been
unambiguously determined by NOSEY experiments (see the
Supporting data) to exist in a cis-configuration. Diaryl and more
electron-rich dialkyl acetylenes have provided the desired 1,3-di-
enes in excellent yields (entries 26–28), as opposed to the gener-
ation of substantial amounts of multi-alkyne insertion products in
the analogous coupling of aryl iodides and 4-octyne.8
2.3. Scope of the boronic acid
A wide variety of dienes can be synthesized in excellent yields
from the reaction of vinylic iodide 9, diphenylacetylene, and vari-
ous functionally-substituted arylboronic acids. For example, the
electron-rich arylboronic acid p-methoxyphenylboronic acid (entry
13) and the relatively hindered o-tolylboronic acid (entry 14) gave
excellent yields of dienes. However, the yield dropped considerably
Two isomers have generally been obtained with moderate to
excellent regioselectivity when unsymmetrical alkynes are
employed. The regiochemistry is primarily controlled by steric ef-
fects in all examples so far examined. The initial vinylic palladium
intermediate usually adds the Pd moiety to the more hindered end
of the triple bond, where the longer carbon–palladium bond is
presumably more favorable energetically than the shorter carbon–
carbon bond, that is, formed. Thus, the vinylic group generated
from the vinylic halide generally adds to the less hindered end of
the alkyne, while the aryl group from the arylboronic acid adds to
the other end of the alkyne. Obviously, the greater the difference in
the size of the two groups attached to the end of the alkyne, the
better the regioselectivity is expected to be. Only modest selectivity
was observed for 1-phenylpropyne, no matter what vinylic halide
was employed (entries 29–31). The regioselectivity was improved
greatly when using 1,4-diphenylbutadiyne (entry 32). Quite good
regioselectivities were obtained for 1-phenyl-3,3-dimethyl-1-
butyne (entry 33) and 4,4-dimethyl-2-butyne (entry 34). The rel-
atively low yield from 4,4-dimethyl-2-butyne may in part be due to
the fact that 4,4-dimethyl-2-butyne is relatively volatile (bp 80 ꢀC)
under our standard reaction conditions (100 ꢀC). These results are
consistent with our and others’ previous work13,15 on the regio-
chemistry of palladium-catalyzed additions to alkynes.
when
a relatively electron-poor boronic acid, like 3-nitro-
phenylboronic acid, was employed (entry 15). The generation of
substantial amounts of the direct cross-coupling product 3-nitro-
benzylidenecyclohexane accounts for the decrease in the yield.
Similar electronic effects have been observed in the reactions of
vinylic iodide 26 and 3-aminophenylboronic acid (entry 16) and 4-
methoxycarbonylphenylboronic acid (entry 17). While the former
boronic acid gave an 86% yield of the desired product, the yield
dropped to 60% for the latter boronic acid. We were pleased to find
that important heterocyclic moieties, such as furyl and pyridyl
groups, can be successfully incorporated into dienes using our
procedure and the corresponding boronic acids (entries 18 and 19).
Using E-1-iodo-1-octene and 4-chlorophenylboronic acid, instead
of phenylboronic acid, resulted in the yield dropping from 62% to
37% (compare entry 2 with entry 20).
The nature of the boronic acid was expanded to alkenyl variants
to generate 1,3,5-trienes. When vinylic iodide 26 was allowed to
react with 2-butyne-1,4-diol and styrylboronic acid under the
standard reaction conditions, triene 33 was generated in a 31%
yield. The yield could be further improved to 57% when 6 equiv of
KF were employed, but further increasing the equivalents of KF to
10 lowered the yield to 48% (entry 21). The synthesis of trienes
utilizing
b
-iodostyrene has consistently given lower yields than
Electronic effects also play an important role in the regio-
chemistry. The aryl group from the arylboronic acid prefers to add
to the more electron-poor end of the alkyne, assuming steric effects
are comparable. Therefore, surprisingly high 86:14 regioselectivity
is observed when 1-(4-nitrophenyl)-1-hexyne is used as the alkyne
(compare entry 35 with entry 29). In the absence of the nitro group,
we get only a 60:40 ratio of regioisomeric dienes in a 44% yield.
Substitution of the phenyl group with an electron-poor pyrimidine
group has a similar effect (compare entries 36 and 29). When the
steric and electronic effects work in opposition to each other, rel-
atively poor regioselectivity is expected and indeed observed, as
seen in examples involving a ketone- or ester-containing internal
alkyne (entries 39–41). In these cases, steric effects apparently
overrule electronic effects (presumably the phenyl group is more
other more substituted vinylic iodides (entry 22).
Unfortunately, extensive optimization efforts devoted toward
incorporating alkyl, allyl, and cyclopropyl groups from the corre-
sponding boronic acids or esters have proven fruitless when
employing vinylic iodide 1 and diphenylacetylene. Under condi-
tions A, all of the above boronic acids afforded products of vinyl-
palladium addition to the alkyne, followed by hydrogen
substitution of the Pd moiety. It is unclear where the hydrogen is
coming from in these reactions. We hypothesize that it might be
coming from formate possibly produced by the hydrolysis of the
DMF in the presence of base.13
Other organometallics can also be employed in these cross-
coupling reactions. For example, when PhB(OH)2 was replaced by

X. Zhang, R.C. Larock / Tetrahedron 66 (2010) 4265–4277
4275
sterically hindered than the ketone or ester groups, and the ketone
and ester groups are more electron-poor than the phenyl group).
This process is tolerant of considerable functionality. Thus, ke-
tone, ester, nitro, and alcohol (entries 37 and 38) groups are readily
accommodated, providing the desired tetrasubstituted olefins in
good to excellent yields.
reduction of any of the organopalladium intermediates, and (4)
dimerization of either the vinylic groups from the vinylic halide or
the aryl groups from the arylboronic acid. All are well known
organopalladium reactions,17 whose presence is likely to depend on
steric and electronic effects, as well as the reagents available and
the specific reaction conditions.
The cross-coupling reactions of vinylic halides with terminal al-
kynes (either phenylacetylene or 1-heptyne) do not give clean prod-
ucts. The desired product; the product generated by carbopalladation
of the alkyne by the vinylic halide, followed by cross-coupling of the
vinylic palladium intermediate with the terminal alkyne in a Sonoga-
shira-type reaction; along with side products formed by direct cou-
pling of the vinylic halide and either the boronic acid or the terminal
alkyne were all generated, making the reactions fairly messy.
It seemed obvious that the regiochemistry of the 1,3-dienes
should be readily reversed if one were to start with an aryl iodide
and cross-couple with a vinylic boronic acid. Thus, PhI, diphenyla-
cetylene, and styrylboronic acid were allowed to react under con-
ditions A. Unfortunately, only around a 5% yield of the desired
product 3 was obtained and trans-1,2-diphenylethene was the
primary product. We later found that reasonable yields of 3 and 5
can be obtained by employing 5 mol % of PdCl2(PhCN)2, 1 equiv of
the aryl halide (0.25 mmol), 2 equiv of alkyne, 2 equiv of the vinylic
boronic acid, 1 equiv of n-Bu4NCl (TBAC), 50 equiv of H2O, and 8 mL
of DMF as the solvent at 100 ꢀC in the presence of air for 12 h
(Conditions C) (entries 42 and 43). Without TBAC, the yield of the
reaction discussed in entry 42 dropped to 40%. H2O (50 equiv)
appears to be optimal, at least for this reaction.
2.6. Cross-coupling of 1,3-cyclohexadiene
A synthetically interesting question is whether one can achieve
the analogous coupling of aryl or vinylic halides with 1,3-dienes,
followed by quenching of the resulting
termediate with a boronic acid (Eq. 5). Our success in the reactions
of alkynes prompted us to investigate this intriguing reaction.
p-allylpalladium in-
A brief optimization study indicated that a reaction involving
1 equiv of p-tolyl iodide, 4 equiv of 1,3-cyclohexadiene, 2 equiv of
phenylboronic acid, 5 mol % of PdCl2(PhCN)2, 2 equiv of KF, and 5:1
DMF/H2O as the solvent at 100 ꢀC in the presence of air (Conditions
D) provided the desired alkene in a 59% yield (Table 2, entry 44).
The yield dropped to 50% when 2 equiv of K2CO3, instead of KF,
were used as the base. The reaction became sluggish when water
was not employed as a co-solvent. Based on known palladium
chemistry, both 3,6-diarylcyclohexene and 3,4-diarylcyclohexene
are possible products.17a However, only one isomer was detected in
our study through GC–MS and 1H and 13C NMR experiments. The
major product is believed to be the thermodynamically more stable
cis-3,6-diarylcyclohexene as indicated by 1H and 13C NMR spectral
analysis. An interesting feature of this chemistry is that reactions
employing electron-rich aryl iodides, such as 4-iodoaniline (entry
45), 4-iodophenol (entry 46) or 4-iodoanisole (entry 47) give the
best yields and more importantly, free NH2 and OH groups, which
are known to be reactive nucleophiles in intramolecular reactions
2.5. Mechanism
We propose the following mechanism for this three-component
coupling reaction (Scheme 1): (1) reduction of Pd(II) to the actual
catalyst Pd(0),16 (2) oxidative addition of the vinylic iodide to Pd(0)
to produce a vinylic palladium intermediate A, (3) vinylpalladium
coordination to the alkyne and subsequent cis insertion to form
a new vinylpalladium intermediate B, (4) transmetalation with an
‘ate’ complex of the organoborane to form intermediate C, and, (5)
reductive elimination of the product with regeneration of the Pd(0)
catalyst. All steps are well precedented in organopalladium chem-
istry.17 While the majority of the reactions reported here are quite
clean, in reactions affording much lower yields of dienes, side
products consistent with this mechanism are observed. The po-
tential side reactions are (1) immediate cross-coupling of in-
termediate A with the boronic acid to give simple Suzuki products,
(2) multiple alkyne insertion to produce polyene products, (3)
involving
p
-allylpalladium intermediates,18 remain untouched
under our reaction conditions (entries 45 and 46). The higher yields
obtained with these substrates presumably arise because the
electron-releasing groups decrease the electrophilicity of the aryl-
palladium intermediate and thus suppress direct coupling with the
boronic acid. In fact, when 4-iodoacetophenone was allowed to
react with 1,3-cyclohexadiene and phenylboronic acid, none of the
desired alkene product was observed (entry 48). Instead, 4-ace-
tylbiphenyl was formed primarily. Unfortunately, the presence of
Scheme 1.

4276
X. Zhang, R.C. Larock / Tetrahedron 66 (2010) 4265–4277
a group in the ortho-position of the aryl iodide appears to be
a problem also, since the yield dropped significantly when o-tolyl
iodide was employed as the aryl iodide (entry 49). On the other
hand, the presence of a methyl group ortho to the boronic acid only
slightly lowered the yield (entry 50). The yield also dropped when
4-chlorophenylboronic acid was employed (entry 51). We were
pleased to find that a vinylic iodide 26 can be successfully employed
in this process to generate a 1,4-skipped diene (entry 52). Un-
fortunately, other dienes, such as 1,3-cycloheptadiene and 2-
methyl-1,3-butadiene failed to generate synthetically useful yields
of the desired products. Direct cross-coupling of the aryl halide and
arylboronic acid was the dominant process in the former reaction,
while in the later case, the major product was the Heck product
been successful, providing a stereoselective method to prepare cis-
3,6-disubstituted cyclohexenes.
4. Experimental section
4.1. General
The 1H and 13C NMR spectra were recorded at 300 and 75.5 MHz
or400 and100 MHz, respectively. Allmelting points are uncorrected.
High resolution mass spectra were recorded on a double focusing
magnetic sector mass spectrometer using EI at 70 eV. All reagents
were used directlyas obtained commerciallyunless otherwise noted.
(E)-
cyclohexene, bis[4-(ethoxycarbonyl)phenyl]acetylene, 3-iodocyclo-
hex-2-en-1-ol, 3-iodo-5,5-dimethylcyclohex-2-enone, and
b-Iodostyrene, iodomethylenecyclohexane, 1-iodo-4-phenyl-
produced by
b-hydride elimination of the p-allylpalladium in-
termediate as determined by GC–MS.
We believe that a mechanism similar to that of Scheme 1 is
involved here (Scheme 2). The key steps are: (1) reduction of Pd(II)
to the actual catalyst Pd(0),16 (2) oxidative addition of the aryl io-
dide to Pd(0) to produce an arylpalladium intermediate, (3) aryl-
palladium coordination to the 1,3-diene and subsequent cis
compounds 3, 10, 12, 14, 16, 23–25, 32, 34–37, and 43 have been
previously reported.9 (E)-1-Iodooct-1-ene,19 (E)-2-cyclohexylvinyl
iodide,19 (Z)- -iodostyrene,20 2-iodo-4,4-dimethyl-2-cyclohexen-1-
b
ol,21 cyclohexylidenemethyl triflate,22 and (bromomethylene)cyclo-
hexane23 were prepared according to previous literature procedures.
Conditions A: To a solution of vinylic halide (0.25 mmol), internal
alkyne (0.50 mmol), and PdCl2 (0.0125 mmol) in 5 mL of DMF was
added 5 ml of a 2:1 DMF/H2O solution of KF (0.50 mmol) and the
boronic acid (0.50 mmol). The resulting mixture was stirred at room
temperature for 3 min in the presence of air, then sealed and heated
to 100 ꢀC with stirring for the specified time. Conditions B: A mixture
of DMF (1.0 mL), Pd(OAc)2 (2.8 mg, 0.0125 mmol), LiCl (10.5 mg,
0.25 mmol), vinylic halide (0.50 mmol), internal alkyne (0.25 mmol),
andtetraarylborate (0.50 mmol) was stirred in a reactionvialat room
temperature for 3 min in the presence of air and then the vial was
capped and heated to 100 ꢀC with stirring for the specified time.
Conditions C: To a solution of vinylic halide (0.25 mmol), internal
alkyne(0.50 mmol), water (12.50 mmol), n-Bu4NCl (0.25 mmol), and
PdCl2(PhCN)2 (0.0125 mmol) in 8 mL of DMF was added KF
(0.50 mmol) andtheboronic acid(0.50 mmol). Theresultingmixture
was stirred at room temperature for 3 min in the presence of air, then
sealed and heated to 100 ꢀC with stirring for the specified time.
Conditions D: To a solution of aryl halide (0.25 mmol), 1,3-cyclo-
hexadiene (1.00 mmol) and PdCl2(PhCN)2 (0.0125 mmol) in 10 mL of
DMF/H2O (5:1) was added KF (0.50 mmol) and the boronic acid
(0.50 mmol). The resulting mixture was stirred at room temperature
for3 min in the presence of air, then sealed and heated to 100 ꢀC with
stirring for the specified time. All reactions were monitored by TLC to
establish completion. The reaction mixture was then cooled to room
temperature, diluted with diethyl ether (30 mL) and washed with
brine (30 mL). The aqueous layer was reextracted with diethyl ether
(2ꢂ30 mL). The organic layers were combined, dried (MgSO4), fil-
tered, and the solvent removed under reduced pressure. The residue
was purified by column chromatography on a silica gel column. The
following 1,3-dienes, 1,3,5-trienes, and cyclohexenes have been
prepared using these general procedures.
insertion to form a
metalation with an ‘ate’ complex of the organoborane to form
a new -allylpalladium intermediate, and (5) reductive elimination
p-allylpalladium intermediate, (4) trans-
p
of the product with regeneration of the Pd(0) catalyst. All of these
steps are well precedented in the organopalladium literature,17
although it is a bit surprising that reductive elimination of the
olefin product is so regioselective. Presumably steric effects
strongly favor the less hindered 1,4-addition product.
Scheme 2.
3. Conclusions
In summary, the palladium-catalyzed three-component cou-
pling of vinylic halides, internal alkynes, and boron organometallics
has been successfully achieved. The reaction is quite efficient, since
it allows the selective construction of two carbon–carbon bonds in
a single reaction from three simple starting materials. The reaction
is insensitive to air and water. A wide range of vinylic halides,
organoboron compounds, and internal alkynes with various func-
tional groups can be employed in this process. The reaction involves
cis-addition to the internal alkyne. The vinylic group from the vi-
nylic iodide favors the less hindered or more electron-rich end of
the alkyne, while the aryl group from the arylboronic acid adds to
the other end of the alkyne. The generality of this process, com-
bined with the good regio- and stereoselectivity, make this one-pot,
two carbon–carbon bond forming process an attractive synthetic
route to 1,3-dienes and 1,3,5-trienes bearing a tetrasubstituted
carbon–carbon double bond. Finally, the analogous coupling of aryl
or vinylic halides with 1,3-cyclohexadiene, followed by trapping of
4.1.1. (E)-1,1,2-Triphenyl-1,3-decadiene (5). The reaction mixture
was chromatographed using hexanes to afford 57 mg (62%) of the
indicated compound as a light yellow oil: 1H NMR (CDCl3,
300 MHz)
d 0.88–0.93 (m, 3H), 1.24–1.32 (m, 8H), 2.02–2.08 (m,
2H), 5.39–5.49 (m, 1H), 6.43–6.48 (d, J¼15.6 Hz, 1H), 6.88–6.91 (m,
2H), 7.01–7.05 (m, 3H), 7.14–7.21 (m, 5H), 7.29–7.38 (m, 5H), 6.55–
6.57 (m, 2H), 6.70–6.72 (d, J¼7.6 Hz, 1H), 6.95–6.98 (m, 2H), 7.04–
7.45 (m, 14H); 13C NMR (CDCl3, 100 MHz)
d 14.2, 22.7, 28.9, 29.3,
31.8, 33.2, 125.9, 126.4, 127.0, 127.3, 127.7, 127.9, 131.1, 131.1, 131.5,
132.2, 136.2, 139.0, 139.8, 141.1, 142.8, 143.2; IR (CH2Cl2) 2935 cmꢁ1
HRMS m/z 366.2352 (calcd C28H30, 366.2348).
4.1.2. cis-3-(4-Aminophenyl)-6-phenylcyclohexene (51). The re-
the
p-allylpalladium intermediate with an arylboronic acid has also
action mixture was chromatographed using 4:1 hexanes/EtOAc to

X. Zhang, R.C. Larock / Tetrahedron 66 (2010) 4265–4277
4277
Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York,
NY, 1998; Chapter 2; (d) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2001, 40, 4544.
afford 55.4 mg (89%) of the indicated compound as an orange oil:
1H NMR (CDCl3, 300 MHz)
1.65–1.71 (m, 2H), 1.87–1.96 (m, 2H),
3.26 (br s, 1H), 3.37–3.49 (m, 2H), 5.93 (s, 2H), 6.64–6.69 (m, 2H),
7.08–7.12 (m, 2H), 7.19–7.31 (m, 5H); 13C NMR (CDCl3)
29.5, 29.8,
40.5, 41.5, 115.5, 126.3, 128.2, 128.6, 129.0, 131.0, 131.9, 136.3, 144.7,
146.4; IR (CH2Cl2) 3372, 2934, 2860, 1624 cmꢁ1; HRMS m/z
249.1523 (calcd C18H19N, 249.1518).
d
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Acknowledgements
10. For a reference indicating similar roles for Fꢁ and OHꢁ in promoting boron ‘ate’
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We gratefully acknowledge the donors of the Petroleum Re-
search Fund, administered by the American Chemical Society for
partial support of this research and Kawaken Fine Chemicals Co.,
Ltd., and Johnson Matthey, Inc. for donations of Pd(OAc)2.
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Supplementary data
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