Heck alkynylation (copper-free sonogashira coupling) of aryl and heteroaryl chlorides, using Pd complexes of t -Bu2(p -NMe2C 6H4)P: Understanding the structure-activity relationships and copper effects

Article abstract of DOI:10.1021/jo302195y

L₂Pd(0) and L₂Pd(II) complexes, where L= t-Bu ₂(p-NMe₂C₆H₄)P, have been identified as efficient catalyst systems for the Heck alkynylation of a variety of aryl bromides (17 examples) and aryl/heteroaryl chlorides (31 examples) with a range of aryl- and alkyl-acetylenes in excellent yields, under relatively low Pd loadings. The single-crystal X-ray structure determination of the presumably active catalytic species, L₂Pd(0), was carried out in this study to better understand the superior activity of the current catalyst system from a structure-activity relationship point of view. The P-Pd-P bond angle indicates that the complex is bent (174.7) in comparison to the perfectly linear (180.0) structure of the analogous Pd(t-Bu₃P)₂. Preliminary mechanistic studies on the negative copper effect and substrate effect of aryl acetylenes were conducted to better understand the cross-coupling pathway of Heck alkynylation.

Full text of DOI:10.1021/jo302195y

Article
pubs.acs.org/joc
Heck Alkynylation (Copper-Free Sonogashira Coupling) of Aryl and
Heteroaryl Chlorides, Using Pd Complexes of t‑Bu2(p‑NMe2C6H4)P:
Understanding the Structure−Activity Relationships and Copper
Effects
Xiaotao Pu, Hongbo Li, and Thomas J. Colacot*
Johnson Matthey Catalysis and Chiral Technologies, 2001 Nolte Drive, West Deptford, New Jersey 08066, United States
S
* Supporting Information
ABSTRACT: L2Pd(0) and L2Pd(II) complexes, where L= t-Bu2(p-NMe2C6H4)P, have been identified as efficient catalyst
systems for the Heck alkynylation of a variety of aryl bromides (17 examples) and aryl/heteroaryl chlorides (31 examples) with a
range of aryl- and alkyl-acetylenes in excellent yields, under relatively low Pd loadings. The single-crystal X-ray structure
determination of the presumably active catalytic species, L2Pd(0), was carried out in this study to better understand the superior
activity of the current catalyst system from a structure−activity relationship point of view. The P−Pd−P bond angle indicates that
the complex is bent (174.7°) in comparison to the perfectly linear (180.0°) structure of the analogous Pd(t-Bu3P)2. Preliminary
mechanistic studies on the negative copper effect and substrate effect of aryl acetylenes were conducted to better understand the
cross-coupling pathway of Heck alkynylation.
aryl iodides and aryl bromides. Removal of Cu from the
coupled product further complicates the workup and
purification, especially in the pharmaceutical processes.8
Various attempts have been made to either eliminate copper
salts or replace them with less-toxic transmetalating agents.9
Along with the development of copper-free reaction conditions,
investigations to couple challenging aryl chlorides or even less
reactive tosylates have emerged as a new trend during the past
decade.10
These improvements have mainly benefited from the
utilization of novel bulky electron-rich phosphine ligands
(Figure 1). For example, in 2003, Plenio and co-workers
were one of the earlier groups to demonstrate the coupling of
aryl chlorides with selected alkynes using Ad2P(n-Bu) ligand in
the presence of a catalyst precursor, Na2PdCl4, and CuI
cocatalyst.11 Although activated aryl chlorides (electron with-
drawing) gave very good yields (90−95%), electron neutral and
electron-donating chlorides gave lower yields (54−85%). For
INTRODUCTION
■
Sonogashira coupling has recently become the third most
popular organic transformation1 in the area of Pd-catalyzed C−
C bond-forming reactions.2 This was based on the number of
publications and patents reported,2a,b since the original
publications of the Pd-catalyzed coupling of acetylene with
aryl halides in 1975 by three independent groups: Sonogashira,3
Cassar,4 and Heck.5 While Cassar and Heck employed Cu-free
conditions at relatively higher temperatures using aryl bromide
substrates, Sonogashira developed a room temperature protocol
to couple aryl iodides in the presence of a CuI cocatalyst
(Scheme 1). The original Sonogashira procedure has been
subsequently modified from time to time to further expand its
scope from a practical point of view.1,6The industrial
application of Sonogashira protocol is demonstrated very
effectively for the production of a widely used antimyotic drug,
Terbinafin (Lamisil, Sandoz).7 However, the classical Sonoga-
shira reaction suffers many drawbacks, such as the use of
environmentally less friendly amine bases; copper cocatalysts,
which can accelerate the dimerization of the acetylene via
Glaser coupling. In addition, there are substrate limitations to
Received: November 2, 2012
© XXXX American Chemical Society
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Scheme 1. Original Conditions for Coupling of Aryl Iodides and Bromides with Phenyl and Butyl Acetylenes Using Ph3P-Based
Pd Catalysts
Figure 1. Ligands/catalysts used for Sonogashira coupling of aryl chlorides.
Figure 2. Examples of new generation precatalysts developed in-house for commercial applications, involving challenging cross coupling.
the latter systems, t-Bu3P gave slightly better yields (77−84%).
During the same year, the Buchwald group reported a Cu-free
Sonogashira coupling protocol for aryl chlorides using X-Phos
in conjunction with PdCl2(MeCN)2.12 As of today, this work
stands out as an important publication in this area. Three years
later, Hua et al. used a commercially available precatalyst,
(Cy3P)2PdCl2, to couple a few examples of relatively less
challenging aryl chlorides with alkyl-substituted alkynes at 150
°C in the absence of Cu.13 In 2009, Beller also reported a Cu-
free coupling of activated aryl chlorides (with the exception of
p-chloroanisole) with limited examples of heteroaryl chlorides
(3-chlorothiophene and 4-chlorobenzopyridine) using a
“Buchwald type” heteroaryl−aryl-based monophospine li-
gand.14 The Sonogashira coupling of aryl halides was also
conducted in water: in 2003, Plenio15 and Najera16
́
independently demonstrated the use of aryl halide coupling
in the presence of water by taking advantage of the water
solubility of the ligands. Recently, the Buchwald group17
coupled aryl chlorides by using sulfonated S-Phos, while
Lipshtuz18 carried out a room temperature coupling of aryl
bromides using phase-transfer surfactants (PTS) technology in
conjunction with X-Phos/PdCl2(MeCN)2. Buchwald et al. have
also explored Heck alkynylations with examples of aryl- and
heteroaryl chlorides under both batch and continuous flow
conditions.10l
B
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a
Table 1. Catalyst Screening for Heck Alkynylation of Aryl Bromides
b
entry
catalyst
code
% yield
d
1
2
3
4
5
6
7
8
PdCl2(t-Bu2(p-NMe2C6H4)P)/CuI
PdCl2(t-Bu2(p-NMe2C6H4)P)
PdCl2(t-Bu2PhP)2
PdCl2(dtbpf)
Pd-132
Pd-132
Pd-122
Pd-118
Pd-116
Pd-113
Pd-101
Pd-114
56
c
99 (95)
96
91
73
61
15
2
Pd(t-Bu3P)2
[Pd(t-Bu3P)Br]2
Pd(PPh3)4
PdCl2(PCy3)2
a
b
Conditions: 1.5 mmol of aryl bromide, 1.2 equiv of phenylacetylene, 2 equiv of Cs2CO3, 2.0 mL of CH3CN, 0.5 mol % of catalyst. GC yield.
c
d
Isolated yield in parentheses. 0.1 mol % CuI.
b
Table 2. Cu-Free Sonogashira Coupling of Aryl Bromides
a
b
Isolated yield. Conditions: 1.5 mmol of aryl bromide, 1.2 equiv of alkyne, 2 equiv of Cs2CO3, 2.0 mL of CH3CN, 0.5 mol % of catalyst.
Although the catalytic systems mentioned above are fairly
and conditions to expand the scope of this class of reaction by
addressing problematic substrates such as unactivated aryl
chlorides and heteroaromatic chlorides containing more than
one heteroatom. In addition, aromatic acetylenes are also
effective in covering a series of aryl chloride substrates, there is
still room for further development of this area. Clearly there is a
need to develop more reliable, robust, practical catalyst systems
C
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challenging coupling partners. Therefore, in this study, our
main intention is to expand the scope of Heck alkynylations to
various aryl and heteroaryl chlorides with challenging
acetylenes using commercially available precatalysts.
Using the optimal conditions from Table 1, a variety of aryl/
heteroaryl bromides (17 examples) with various acetylenes
were coupled (Table 2). Electron-deficient, electron-rich, and
sterically demanding (e.g., 2-bromoxylene) substrates were
coupled in excellent yields. An aryl bromide containing a
hydroxyl functional group was also successfully coupled (Table
2, entry 6). As heterocyclic moieties are important in the
pharmaceutical industry, we have also studied several coupling
reactions using heterocyclic bromides containing one or more
hetero atoms. Bromopyridines, pyrimidines, and thiophenes
were also coupled in excellent yield (Table 2, entries 10−17).
Heck Alkynylation of Aryl and Heteroaryl Chlorides.
Because aryl bromide coupling is somewhat well established,
the major effort of this study has been focused on challenging
aryl chlorides and heterocyclic chlorides containing more than
one heteroatom. As mentioned in the Introduction, very limited
systematic studies have been conducted on such systems.
It is well established that during the catalytic cycle, LnPd(0)
(n = 1 or 2) is the active catalytic species. Therefore, L2PdCl2
complexes, such as Pd-132, have to undergo reduction to form
the corresponding 14 electron species. Recently, we have
developed a novel process for the synthesis and commercializa-
tion of L2Pd(0) precatalysts and have done a preliminary
investigation on the use of Pd[p-MeNC6H4(t-Bu)2P]2 (Pd-
149) in the Cu-free Sonogashira coupling of aryl/heteroaryl
chlorides.19b The precursor to the LPd(0) catalyst, p-
Me2NC6H4(t-Bu)2P(η3-allyl)Cl Pd (Pd-158), was also included
in the study for comparison. Table 3 shows the screening
results of p-chloroanisole with decyne using three Pd complexes
of p-Me2NC6H4(t-Bu)2P.
In our ongoing efforts to discover/develop new and efficient
practical cross-coupling catalysts, in recent years, we have
implemented several catalytic systems for solving some of the
unmet challenges.19 Among those catalyst systems, preformed
palladium phosphine complexes that we have developed have
been effectively used for a wide variety of challenging cross-
coupling reactions (Figure 2). The benefits on the design and
the use of these preformed catalysts versus in situ systems were
reviewed recently.20 Of the various precatalysts that we
developed and commercialized, Pd-118 and Pd-132 stood
out to be the two best catalysts of choice based on their air
stability, versatility, and high catalytic activity.20 From the
preliminary work on Cu-free Sonogashira reactions, we have
realized that the Pd(0) version of Pd-132, named Pd-149, is a
very good catalyst for both aryl and heteroaryl chlorides under
Cu-free conditions.19b We have also synthesized a mono
coordinated Pd-phosphine complex, (η3-allyl)Pd(L)Cl, using
the common ligand, p-Me2NC6H4(t-Bu)2P used for making
both Pd-132 and Pd-149. Preliminary studies indicated that
(η3-allyl)Pd(L)Cl (Pd-158) is more superior than our well-
known catalyst, Pd-118, for the α-arylation of tetralone.19a
Therefore, we decided to focus our effort to study the
effectiveness of p-Me2NC6H4(t-Bu)2P-based L2Pd(II), L2Pd(0),
and LPd(II) catalysts for the Heck alkynation reaction (Cu-free
Sonogashira reaction) along with the other well-known
catalysts that we have commercialized as controls. This study
also provides some insight into the structure−activity relation-
ship with respect to substrates and catalysts as well as the roles
of Cu salts, bases, and solvents.
Table 3. Heck Alkynylation of p-Chloroanisole Using
L2Pd(0), L2Pd(II), and LPd(II) Precatalysts, Where L = p-
a
Me2NC6H4(t-Bu)2P
RESULTS AND DISCUSSION
■
Heck Alkynylation of Aryl Bromides. As Cu has several
drawbacks in the manufacture of pharmaceutical materials, we
tested air-stable [p-Me2NC6H4(t-Bu)2P]2PdCl2 (Pd-132) for
its effectiveness in the coupling of a relatively challenging model
substrate, p-bromoanisole, with phenyl acetylene, with and
without Cu (Table 1). As reported by Buchwald12 and Beller,14
we have also observed that Cu salts have a deleterious effect
(56% vs 99% GC yield). The choice of the solvent as well as the
base was also important for the success of the coupling. Both
DMF and CH3CN were optimal solvents in comparison to the
nonpolar or polar protic solvents. Numerous bases were
screened, and only Cs2CO3 and K3PO4 were proven to be
suitable. Addition of different metal salts, such as ZnCl2, to the
reaction was also investigated with no significant improvement
on conversion. Under optimal conditions, we tested five new
generation commercially available catalysts, along with the
classical catalyst Pd(PPh3)4 (see Table 1). Both [Ph(t-
Bu)2P]2PdCl2 (Pd-122)21 and (dtbpf)PdCl2 (Pd-118)22 were
good (90%); however, both gave slightly lower yield than that
of Pd-132.23 Bulky electron-rich tri-t-butylphosphine-based
L2Pd and LPd-based catalysts, (t-Bu3P)2Pd (Pd-116 (also
known as the Fu catalyst)24 and [t-Bu3P(μ-Br)Pd]2 (Pd-113
(Mingos/Hartwig Pd(I) dimer),25 gave only 73% and 61%
yields, respectively (entries 5 and 6). Unlike Hua’s observation,
under these milder conditions, (Cy3P)2PdCl2 (Pd-114) gave
only 2% yield (entry 8), while interestingly (PPh3)4Pd gave
15% yield (entry 7).
b
precatalyst
Pd code
% yield
95 (90)
c
Pd[p-Me2NC6H4(t-Bu)2P]2
Pd-149
Pd-132
Pd-158
PdCl2[p-Me2NC6H4(t-Bu)2P]2
PdCl[p-Me2NC6H4(t-Bu)2P](η3-allyl)
89
74
a
Conditions: 0.5 mol % catalyst, Cs2CO3, DMF solvent, 100 °C, 7 h.
b
c
GC yields. Isolated yield in parentheses.
Although the ligand was the same, three catalysts showed
different activities when an aliphatic acetylene, such as 1-
decyne, was coupled with p-chloroanisole. Pd-149 was the best
catalyst of choice with 95% GC yield (90% isolated). This is
because under these conditions, the preactivated catalysts is
more active than its corresponding air-stable Pd(II) complex.
Interestingly, monoligated palladium complex Pd-158 has given
only 74% yield, although it is supposed to generate a highly
active 12 electron-based LPd(0) catalytic species during
catalysis. The fact that Pd-158 (Table 3) was less active than
Pd-132 and Pd-149 suggests that L2Pd complexes may not be
either dissociating to LPd(0) or the 12 electron LPd(0) species
formed is thermodynamically less stable, at least in this class of
reactions under these conditions. Results from Table 1, entry 6
versus entry 5, are also in agreement with this observation.
However, when attempting to couple aromatic acetylenes,
both Pd-149 and Pd-132 afforded no desired product (Table
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4). Presumably, this is due to the fact that aromatic acetylenes
are susceptible to undergo dimerization or oligomerization to
Alkynes containing polar functional groups also gave the
desired products in good yield (Table 5, entries 17,18).
Because of the importance of heterocyclic compounds
containing alkyne moieties in the pharmaceutical industry, we
have made a special effort in developing routes for a few
examples (Table 5, entries 20−30) using the heteroaryl
chlorides. Although several groups have reported the cross-
coupling of heteroaryl chlorides, a very limited substrate scope
has been explored.10,26,27 In this study, several nitrogen-
containing five- or six-membered heterocycles have been
coupled in good to excellent yields. Noteworthy is that
heteroaryl chlorides such as dimethoxy- and methylthioether-
substituted pyrimidine gave very good yield of the desired
coupled products. On the basis of selected GC studies, it is
observed that in certain cases product decomposition in DMF
occurs much faster than that in CH3CN, especially when the
reaction is carried out at higher temperatures. Therefore, for
certain heteroaryl chlorides, CH3CN is the solvent of
preference.
Aryl-substituted propargylic alcohols are versatile building
blocks, as these structural motifs are present in several drugs on
the market.28 Although they can be synthesized by the 1,2
addition of terminal alkynes to carbonyls, the Sonogashira
reaction is a very practical and diversified way to construct
propargylic alcohols with different aryl substituents. Several
catalysts have been utilized for coupling aryl iodides and
bromides with propargylic alcohols in good yield.6,29 However,
the corresponding aryl chlorides in comparison to the bromides
are far more challenging to couple with terminal propargylic
alcohols, as these reactions tend to undergo unpredictable
rearrangements. Under the conditions (Table 5, methods A, B)
developed for simple alkynes, no desired coupling product was
isolated in satisfactory yields. To determine the optimal
reaction conditions for propargyl systems, further screening
was conducted with the use of a milder K3PO4 base. Coupled
product was obtained in 72% isolated yield in DMF (Table 5,
entry 31).
Having established a protocol for propargyl systems, we have
extended the method to ethynylestradiol systems (Scheme 2),
as these types of compounds are capable of binding to estrogen
receptors (ER) with high affinity. These derivatives have been
studied as diagnostic reagents for breast cancer treatments.30
We were able to functionalize the alkyne of the propagylic
moiety by selectively coupling with challenging aryl or
heteroaryl chlorides in the presence of unmasked polar
functional groups.
Understanding the Structure−Activity Relationships
(SAR) of L2Pd (L = p-Me2NC6H4(t-Bu2)P Catalysts. Because
L2Pd(0) is presumably the active catalytic species based on the
results from Table 3, we decided to compare the activity of Pd-
149 with the other new generation L2Pd(0) catalysts as well as
the classical Pd(0) catalyst, Pd(PPh3)4 (Table 6). While
Pd(PPh3)4 is the least active catalyst (Table 6, entry 6), the
other catalysts containing electron-rich/bulky ligands also
performed poorly (Table 6, entries 3−5). The catalyst that
showed the second best activity was Pd-148 (Table 6, entry 2).
This is somewhat understandable as the Me2N group at the
para position makes the catalyst more electron-rich for Pd-149
in comparison to Pd-148. It is surprising to note that the Pd(0)
catalyst Pd-116 gave only modest conversion under these
conditions (Table 6, entry 3). Although Pd-141 is sterically
bulkier than Pd-116 based on the cone angle data,31 it was one
of the least active catalysts for this model system.
Table 4. Results of Catalyst and Condition Optimization in
the Heck Alkynylation of p-Chloroanisole with
Phenylacetylene by Slow Addition of Acetylene
a
b
entry
catalyst
addition time
base
% yield
trace
1
2
3
4
5
6
7
8
9
Pd-132
Pd-132
Pd-149
Pd-149
Pd-132
Pd-149
Pd-132
Pd-149
Pd-132
<1 min
<1 min
<1 min
<1 min
1 h
Cs2CO3
K3PO4
trace
trace
trace
47%
Cs2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1 h
<5%
75%
3 h
3 h
<10%
c
5 h
>98% (90%)
a
b
Conditions: 1.0 mol % catalyst, base, DMF solvent, 100 °C. GC
c
yield. Isolated yield on a 1.0 mmol scale in parentheses.
form side products if the oxidative addition of aryl halide is
relatively more challenging. Inspired by Buchwald’s results on
the slow addition of aromatic acetylenes,12 pheylacetylene was
added slowly, thereby diluting its initial concentration.
Interestingly, Pd-132 gave 99% GC yield with 90% isolated
yield, when the aryl acetylene is added over a period of 6 h.
Monitoring the slow addition over a period of 1 and 3 h gave
47% and 75% GC conversion to product, respectively. The
Pd(0) complex Pd-149 did not give any satisfactory results.
This could be due to the poor stability of the catalyst under
these conditions. These results confirm that both Pd-132 and
Pd-149 complement each other, depending on the choice of
the coupling partners and the reaction conditions employed.
Having identified Pd-132 and Pd-149 as two good catalysts
with optimal conditions for the Cu-free Sonogashira reaction of
p-chloroanisole, we expanded the substrate scope to couple
several aryl and heteroaryl chlorides with excellent isolated
yields (Table 5). Both electron-rich and electron-deficient aryl
chlorides were coupled in excellent yield (91−96%) with
aliphatic acetylenes (Table 5, entries 1−3), using Pd-149 in
DMF with Cs2CO3 base. An elevated temperature is required
for difficult substrates, such as electron rich and sterically
hindered aryl chlorides (Table 5, entries 4,5). In such cases,
DMF is usually preferred over CH3CN as a solvent because of
its high boiling point. The slow addition of phenylacetylene
minimized the side reactions, which delivered a useful synthetic
procedure for the coupling of aryl acetylenes with both
electron-rich and -deficient aryl chlorides (Table 5, entries 9−
11). However, as mentioned earlier, Pd-132 complements Pd-
149. Substrates with unprotected free primary amines, alcohols,
and amides can be problematic for palladium-catalyzed
coupling reactions. However, these catalyst systems have very
good functional group tolerance. Meta-substituted chlorophe-
nol (Table 5, entry 13) and aniline (Table 5, entry 15) gave
higher yields than their respective para-analogues (Table 5,
entry 12), whereas the corresponding ortho-substituted
derivatives were inefficient. This poor reactivity might be due
to the strong coordination of the ortho-hetero atoms to the
palladium species, thereby slowing the rate of the reaction.
E
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b
Table 5. Pd-132- and Pd-149-Catalyzed Cu-Free Coupling of Aryl Chlorides with Terminal Alkynes
a
b
Isolated yield on a 1.0 mmol scale. Conditions: (A) 0.5−1.5 mol % Pd-132, Cs2CO3, DMF, 90−110 °C, 4−8 h. (B) 0.5−1.5 mol % Pd-149,
CH3CN, 90 °C, 4−8 h. (C) 0.5−1.5 mol % Pd-132, DMF, 90 °C, slow addition of arylacetylene during reaction, 5 h. (D) 1 mol % Pd-132, K3PO4,
DMF, 90 °C, 6 h.
These results have further prompted us to determine the X-
ray structure of Pd-149 (Figure 3), which reveals that it has
Pd−P bond lengths similar to those of the other L2Pd(0)
complexes reported in Table 7. However, it has the smallest P−
Pd−P angle (174.7°) (Table 7, entry 1), while Pd-116 and Pd-
141 have shown perfectly linear (180°) structures (Table 7,
entries 3,5). Interestingly, the second most active catalyst Pd-
148 (Table7, entry 2) also has a slightly bent structure
(176.8°). The X-ray structure of Pd-150 is not reported, but
the closest is [(Fc)(t-Bu)2]2Pd, which also has a P−Pd−P bond
angle of 180°. By analyzing the combined data from Tables 6
and 7, one can infer that the “bent” L2Pd(0) species tend to be
more active than the linear Pd complexes containing
monodentate ligands. This observation has been discussed in
Hartwig’s text book that “L2Pd(0) bent into a less stable
F
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Scheme 2. Coupling of Ethynylestradiol with Aryl and Heteroaryl Chlorides under Cu-Free Conditions
Table 6. Ligand Effect in L2Pd(0) Complexes for Copper-
Free Sonogashira Reaction
Table 7. Comparison of Bond Angle and Bond Length of
Pd[p-Me2NC6H4(t-Bu)2P] with Other L2Pd(0) Complexes
a
Pd
Pd−P bond
P−Pd−P
entry
1
complex
code
lengths
angle
Pd[p-Me2NC6H4(t-
Bu)2P]2
Pd-149 2.299(3);
174.7(0)
176.8(1)
180.0(0)
180.0(0)
180.0(0)
a
b
c
2.299(2)
b
% yield
2
3
4
5
Pd[Ph(t-Bu)2P]2
(t-Bu3P)2Pd
Pd-148 2.282(4);
2.273(4)
entry
catalyst
1 h
7 h
Pd-116 2.285(3);
1
2
3
4
5
6
Pd[p-Me2NC6H4(t-Bu)2P]2 (Pd-149)
Pd[Ph(t-Bu)2P]2 (Pd-148)
Pd(t-Bu3P)2 (Pd-116)
75
30
15
5
95
69
48
20
<5
2.285(3)
[(Fc)(t-Bu)2]2Pd
N/A
2.276(4);
2.276(4)
d
e
[(o-Tol)3P]2Pd
Pd-141 2.276(1);
Pd(QPhos)2 (Pd-150)
2.276(1)
Pd[(o-Tol)3P]2 (Pd-141)
Pd(Ph3P)4 (Pd-101)
<5
<5
a
b
c
d
e
See ref 34. See ref 35. See ref 36. See ref 37. See ref 38.
<5
a
b
Conditions: 1 mol % catalyst, Cs2CO3, DMF solvent, 100 °C. GC
More Insight into the Copper Effect. There is a belief
that commercially available palladium salts such as palladium
dichloride or palladium acetate may contain a very small
amount of copper that would accelerate the conventional
Sonogashira reaction even without the addition of copper.39,1d
If that is the case, addition of Cu should enhance the coupling.
However, on the contrary, we observed a significant negative
Cu effect for both Pd-132 and Pd-149 catalyst systems (Table
8).
yield.
In the presence of 2 mol % copper iodide, both bromo- and
chloro-anisole were inhibited to couple with acetylene using
both Pd-132 and Pd-149 catalysts (Table 8, entries 2,4,6).
When KI was used as an additive, no negative effect was
observed in the coupling of bromoanisole to the product in
high yield, ruling out iodide as an inhibitor40(Tables 8 and 9).
At the same time, other copper salts also inhibited the reaction
(Table 8, entries 7,8,10). The concentration of copper in the
reaction is also identified to be important (Table 9). It should
be noted that the acetylene was almost completely consumed
by Pd-149 with the formation of conjugated addition product
of acetylene, whereas almost no conversion of acetylene was
observed when Pd-132 was used. The reaction listed in Table 8
was also studied by varying the amount of Cu (Table 9). This
observation is similar to what Buchwald and Beller observed for
various biaryl ligands.12,14 Recently, Schoenebeck et al.
discovered that Cu(I)X (X = Br, I) species can readily oxidize
electron-rich (t-Bu3P)2Pd(0) (Pd-116) to a dinuclear Pd(I)
complex, [(t-Bu3P)BrPd]2 (Pd-113), with the formation of a
Cu-cubane, (Cu(t-Bu3P)X)4.41 They also found that Pd-113
polymerizes acetylene, rather than promoting the cross
Figure 3. Single-crystal X-ray structure of Pd-149. Hydrogen atoms
are omitted for clarity. The thermal ellipsoids correspond to 50%
probability.
conformation than the linear L2Pd(0) fragment, the frontier
orbitals are more available for coordination and addition.”32
From these preliminary data, we believe that the electronic
and steric properties of the catalysts as well as the P−Pd−P
bond angles have an important impact on the Heck
alkynylation reaction.33 However, more detailed studies are
required to fully understand the catalyst activation and
reactivity.
G
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are no other regio- and stereoisomers of conjugated enynes
detected or isolated from the reaction. Trost’s group has done a
tremendous amount of work on palladium-catalyzed alkyne
dimerization reactions.42 In many cases, they observed a head-
to-tail addition of terminal alkynes in the presence of TDMPP
(TDMPP = P[(2,6-OMe)2C6H3]3) ligand in conjunction with
Pd(OAc)2. Gevorgyan et al. later observed the formation of an
enyne product with opposite regioselectivity, using TDMPP
with a different palladium source (allylpalladium chloride
dimer) and base.43 Several head-to-head aryl E-enynes were
prepared under these conditions, whereas ortho-substituted aryl
acetylenes gave the product (E-enyne) in low to no yield. An
agostic interaction between the palladium and ortho protons of
the aromatic ring in the substrate is proposed to be responsible
for facilitating the conjugate addition, following anti-Markovni-
kov selectivity. The above work inspired us to envision that if
the side reaction in the coupling of aryl acetylenes with aryl
chlorides is also caused by a similar agostic interaction, the
undesired dimerization should be inhibited by ortho-
substitutions on the aryl acetylene ring.
Table 10 shows the control experiments done on the Cu-free
Sonogashira coupling of p-chlorotoluene with unsubstituted
and ortho-disubstituted arylacetylenes: (a) phenyl acetylene
and (b) 2,4,6-trimethylphenyl acetylene. The desired coupling
product was isolated in 72% yield (>85% GC conversion of aryl
chloride) within 4 h, when 2,6-dimethylphenyl acetylene was
used, while the unsubstituted phenyl acetylene gave only 12%
yield of the coupled product with nonselective formation of the
enyne dimer.
Table 8. Cu Effect in Sonogashira Reaction in the Presence
of Pd-132 and Pd-149
a
b
entry
R
catalyst
additive
temp (°C)
% yield
1
2
Br
Br
Cl
Cl
Cl
Cl
Br
Br
Br
Cl
Pd-132
Pd-132
Pd-132
Pd-132
Pd-149
Pd-149
Pd-132
Pd-132
Pd-132
Pd-132
none
CuI
90
90
>95%
<10%
90%
3
none
CuI
110
110
95
c
4
<10% (<10%)
5
none
CuI
94%
c
6
95
<5% (95%)
7
CuBr
CuCl
KI
90
5%
3%
8
90
9
90
95%
<5%
10
CuBr, KI
90
a
Conditions: 0.5 mol % catalyst, 2 mol % additive, DMF solvent, 100
b
c
°C. GC yield. GC conversion of acetylene in parentheses.
Table 9. Concentration Effect of Cu in Pd-132-Catalyzed
a
Reaction of Chloroanisole with 1-Decyne
% CuI
% yield
0.1
0.5
2
85
59
10
<5
5
To better understand the enyne formation reaction, a
deuterium labeling study has been conducted, which revealed
that both olefin protons are from the acetylene substrate
(Scheme 4). When the oxidation step is challenging, acetylene
coordination takes preference, which leads to the formation of
the enyne. That is why we see coupled product with aryl
bromides and activated aryl chlorides, where oxidative addition
takes preference over acetylene coordination.
a
Conditions: 1.5 mol % Pd-132, DMF, 100 °C, 6 h.
coupling of aryl halides in the Sonogashira reaction. From these
findings, we can infer that Cu salts can act as an oxidizing agent
with electron-rich L2Pd(0) species (Pd-149) in the coupling
catalytic cycle, but also can inhibit the formation of the active
Pd(0) species from Pd(II) precatalyst (Pd-132).
Why Is Aryl Chloride Coupling with Aryl Acetylene
Difficult? Understanding the Mechanism. On the basis of
the literature reports12 and from our in-house study, slow
addition of aryl acetylenes (Table 4) is required to achieve high
yields of the desired coupled product when unactivated aryl
chlorides are used. Typically, one pot addition leads to very low
yield of the coupled product at the expense of the acetylene
being consumed. However, there are no reported studies on the
fate of acetylenes in these cases. Therefore, we report the
results of some preliminary mechanistic investigations to
understand this anomaly under copper-free conditions.
On the basis of the above experimental studies, a reported
mechanism of Cu-free Sonogashira reaction by Soheili and co-
workers from Merck, and a recent computational study by
9d,44
́
Garcia-Melchor et al.,
we propose the following plausible
mechanisms for aryl acetylene participated Heck alkynylation of
aryl chlorides and the corresponding side reaction (Scheme 5).
The desired catalytic cycle starts with the oxidative addition of
an aryl chloride to the active Pd(0) species. This is followed by
the acetylene coordination and the subsequent deprotonation
in the presence of a base. Once the acetylene is rearranged from
π to δ bonding, the product is reductively eliminated. On the
other hand, with challenging aryl chloride substrates, oxidative
addition becomes the turnover-limiting step; acetylene
coordination takes preference over aryl halide addition to the
LnPd(0) to form a palladium hydride intermediate. This species
further interacts with another molecule of phenylacetylene to
undergo a carbopalladation (insertion) rearrangement, which is
A major side product isolated under the one-pot addition
conditions was identified to be the conjugated head-to-head
addition product, E-enyne (Scheme 3, 11) when Pd-132 was
used as a catalyst. Under elevated temperature, this styrene
analogue could be more reactive than the phenyl acetylene,
leading toward undesired polymerization. Interestingly, there
Scheme 3. Challenges Associated with the Coupling of Unactivated Aryl Chloride with Phenyl Acetylene
H
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a
Table 10. Ortho-Disubstitution Effect of Aryl Acetylene in the Heck Alkynylation
b
b
entry
R
C:D (GC ratio)
yield of C (%)
yield of D (%)
16
c
1
2
H
1:1
12 (32)
c
Me
>99:1
72 (85)
a
b
c
Conditions: Aryl halide (1.6 mmol), alkyne (2.0 mmol), Cs2CO3 (2.4 mmol), toluene (2.0 mL) using 1 mol % Pd-149. Isolated yield. GC
conversion of A.
Scheme 4. Deuterium Labeled Acetylene Giving the E-Enyne
via Head-to-Tail Addition
CONCLUSION
■
We have identified that the p-Me2NC6H4P(t-Bu)2 ligand and its
palladium(0) and (II) complexes as active catalysts or
precatalysts for the Heck alkynylation of aryl chlorides without
the assistance of copper salts. By slightly varying the reaction
conditions, a wide variety of aryl bromides, aryl chlordes, and
heteroaryl chlorides have been coupled with both aryl and
aliphatic acetylenes in good to excellent yields. Noteworthy is
that unstable terminal propargylic alcohols can also be coupled
with unactivated aryl chlorides in good yields. Because both Pd-
132 (air-stable) and Pd-149 (air-sensitive)45 are commercially
available in multikilogram quantities, these are promising
catalysts for large-scale coupling processes. Our structure−
activity relationship (SAR) study suggests that the smaller P−
Pd−P bond angle of Pd-149 in comparison to the other similar
L2Pd(0) might be an important factor in deciding the activity of
the catalyst. We also support Buchwald’s observation that Cu is
detrimental with the new generation bulky electron-rich Pd-
phosphine-based catalytic systems. For coupling aryl acetylenes
containing no ortho substitution, slow addition is required to
prevent the formation of enyne byproducts, while ortho-
substituted aryl acetylenes selectively form the desired coupling
products without significant process variations. A catalytic cycle
for Heck alkynylations and byproduct formation is proposed. A
detailed study on mechanism is underway.
regioselectively controlled by the agostic interaction of the
ortho protons. Reductive elimination provided the enyne
byproduct with regeneration of the LnPd(0) catalyst.
Therefore, a one-pot addition of acetylene could be possible
for coupling of most aryl acetylenes with activated aryl bromide
substrates. Coupling is also possible for challenging aryl
chlorides with ortho-substituted aryl acetylenes under one-pot
addition conditions. However, in many cases, the slow addition
of ortho-unsubstituted aryl acetylenes is necessary for coupling
unactivated aryl chlorides to control the concentration of the
acetylene, thereby preventing the self-conjugated addition
reaction catalyzed by the palladium catalyst. So to speak, it is
necessary to tweak the reaction conditions by understanding
the nature of the catalyst and substrates.
Scheme 5. Proposed Mechanism for the Byproduct Formation during the Cu-Free Sonogashira Coupling Reaction (Heck
Alkynylation) Using LnPd(0) Where n = 1 or 2
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(Table 2, Entry 13) 3-Pyridine Phenyl Acetylene.54 The general
procedure afforded the title compound (250 mg) in 93% isolated yield
(yellowish solid).
EXPERIMENTAL SECTION
■
General Experimental Details. Unless otherwise stated, all
reactions were carried out under nitrogen atmosphere in 20 mL 12-
space Radley carousels with magnetic stirring. Anhydrous DMF and
CH3CN used in the study were purchased from commercial sources.
(Table 2, Entry 14) 2-Thiophene Phenyl Acetylene.13 The general
procedure afforded the title compound (248 mg) in 90% isolated yield
(yellowish solid).
(Table 2, Entry 15) 3-Thiophene Phenyl Acetylene.55 The general
procedure afforded the title compound (254 mg) in 92% isolated yield
(yellowish solid).
Cs2CO3 and K3PO4 were grounded into fine powder before use. All
reactions were monitored by GC or silica gel TLC plates. H and 13
C
1
NMR spectra were recorded on a 400 MHz spectrometer. Proton and
carbon-13 chemical shifts were reported relative to CDCl3 peaks as
internal standards (1H, δ = 7.27, 13C, δ = 77.26 ppm), while 31P{1H}
NMR spectra were externally referenced to 85% H3PO4. MS were
obtained on a high-resolution GC/MS. Compounds were purified with
Teledyne isco combiflash Rf or silica gel flash column with ethyl
acetate and hexane as eluent. Elemental analyses were performed by an
outside lab.
(Table 2, Entry 16) 3,5-Pyrimidine Phenyl Acetylene.56 The
general procedure afforded the title compound (250 mg) in 93%
isolated yield (yellowish solid).
(Table 2, Entry 17) 2,6-Pyrimidine Phenyl Acetylene.56 The
general procedure afforded the title compound (250 mg) in 93%
isolated yield (yellowish solid).
Procedure for Copper-Free Sonogashira Reaction (Method
A and Method B). A Radley tube was charged with 2 equiv of
Cs2CO3(2 mmol, 648 mg), 0.5−1.5 mol % palladium catalysts,
followed by aryl chloride (1 mmol), 1.5 mL of DMF (method A), or
1.5 mL of CH3CN (method B) under an atmosphere of nitrogen.
Using a syringe, 1.2 equiv of the respective actylene was injected into
the tube via septum. The reaction was heated to 90−105 °C under
stirring for 4−7 h. All reactions were monitored by GC or TLC plates.
Products were purified by Combiflash auto chromatographic system
using a mixture of hexanes and ethyl acetate as the eluent.
Procedure for Copper-Free Sonogashira Reaction of
Arylacetylenes (Method C). A Radley tube was charged with 2
equiv of Cs2CO3 (2 mmol, 648 mg), 0.5−1.5 mol % palladium catalyst,
and aryl chloride (1 mmol), followed by the addition of 1.5 mL of
DMF under an atmosphere of nitrogen. The reaction mixture was
heated to 90−105 °C and with stirring, followed by the addition of 1.2
equiv of actylenes via a syringe pump over a period of 3−5 h. After the
addition of acetylene, the reaction was further stirred for an additional
hour. All reactions were monitored by either GC or TLC plates.
Products were purified by a Combiflash auto chromatographic system
using a mixture of hexanes and ethyl acetate as the eluent.
Procedure for Copper-Free Sonogashira Reaction (Method
D). A Radley tube was charged with 2 equiv of K3PO4 (2 mmol, 425
mg), 0.5−1.5 mol % palladium catalyst, and aryl chlorides (1 mmol).
1.5 mL of DMF under a nitrogen atmosphere was injected, followed
by the addition of 1.5 equiv of propargyl alcohol. The reaction was
heated to 95 °C with stirring and kept for 7 h. All reactions were
monitored by either GC or TLC plates. Products were purified on a
Combiflash auto chromatographic system using a mixture of hexanes
and ethyl acetate as the eluent.
(Table 5, Entry 1) 1-(Dec-1-ynyl)-4-methoxybenzene. The general
procedure method A in Table 5 with 0.5 mol % catalyst afforded the
title compound (220 mg) in 90% isolated yield. 1H NMR (CDCl3): δ
(ppm) 7.32 (d, J = 6.8 Hz, 2H), 6.81 (d, J = 7.5 Hz, 2H), 3.78 (s, 3H),
2.38 (t, J = 6.8 Hz, 2H), 1.59 (m, 2H), 1.21−1.41 (m, 10H), 0.89 (t, J
= 6.8 Hz, 3H). 13C NMR (CDCl3): δ (ppm) 159.0, 132.8, 116.4,
113.8, 88.8, 80.3, 55.2, 32.0, 29.2, 29.2, 29.0, 28.9, 22.7, 19.4, 14.1.
Anal. Calcd for C17H24O: C, 83.55; H, 9.90. Found: C, 83.28; H,
10.04.
(Table 5, Entry 2) 2-(Dec-1-ynyl)benzonitrile. The general
procedure method A in Table 5 with 0.5 mol % catalyst afforded
the title compound (230 mg) in 96% isolated yield (yellowish solid).
1H NMR (CDCl3): δ (ppm) 7.60 (d, J = 7.2 Hz, 1H), 7.50 (m, 2H),
General Procedure for Copper-Free Sonogashira Coupling
of Aryl Bromide with Alkyne. An oven-dried Schlenk tube was
charged with Cs2CO3 (3 mmol) and Pd catalyst (7.5 μmol, 0.5 mol %)
and sealed under nitrogen. It was then degassed three times (vacuum
and nitrogen), followed by the stepwise injection of aryl bromide (1.5
mmol), alkyne (1.8 mmol), and anhydrous acetonitrile (2 mL) under
N2 atmosphere. The resulting pale yellow suspension was stirred at the
desired temperature for the indicated period of time. The reaction
mixture was allowed to cool to room temperature, followed by the
addition of water (10 mL) to dissolve the inorganic salts. It was later
extracted with diethyl ether (3 × 4 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered, and concentrated to purify
by flash chromatography using silica gel catridge with 10% ether/
hexane solvent combination to isolate the desired product. The known
compounds were characterized by comparing their NMR data with
those reported. The other ones were fully characterized by NMR,
elemental, and GC/MS. The NMR spectra of the isolated products are
provided in the Supporting Information.
(Table 2, Entry 1) Diphenyl Acetylene.46 The general procedure
afforded the title compound (248 mg) in 93% isolated yield (yellowish
solid).
(Table 2, Entry 2) 1-Phenyl-1-octyne.13 The general procedure
afforded the title compound (251 mg) in 90% isolated yield (yellowish
solid).
(Table 2, Entry 3) 1-Cyclohexene Phenyl Acetylene.47 The general
procedure afforded the title compound (237 mg) in 87% isolated yield
(yellowish solid).
(Table 2, Entry 4) 4-Methoxyphenyl Phenyl Acetylene.29 The
general procedure afforded the title compound (268 mg) in 86%
isolated yield (yellowish solid).
(Table 2, Entry 5) 4-(Phenyl-1-ynyl)benzonitrile.48 The general
procedure afforded the title compound (277 mg) in 91% isolated yield
(yellowish solid).
(Table 2, Entry 6) 3-Hydroxylphenyl Phenyl Acetylene.49 The
general procedure afforded the title compound (250 mg) in 86%
isolated yield (yellowish solid).
(Table 2, Entry 7) 4-Acetylphenyl Phenyl Acetylene.50 The general
procedure afforded the title compound (293 mg) in 88% isolated yield
(yellowish solid).
(Table 2, Entry 8) 2,6-Dimethylphenyl Phenyl Acetylene.11 The
general procedure afforded the title compound (284 mg) in 92%
isolated yield (yellowish solid).
(Table 2, Entry 9) 4-tert-Butylphenyl Phenyl Acetylene.51 The
general procedure afforded the title compound (325 mg) in 93%
isolated yield (yellowish solid).
7.33 (m, 1H), 2.48 (t, J = 7.2 Hz, 2H), 1.68 (m, 2H), 1.50 (m, 2H),
1.32 (m, 8H), 0.89 (t, J = 6.4, 3H). 13C NMR (CDCl3): δ (ppm)
132.3, 132.5, 132.2, 128.1, 127.5, 117.7, 115.4, 98.0, 77.2, 31.8, 29.2,
29.1, 28.9, 28.4, 22.7, 19.6, 14.1. Anal. Calcd for C17H21N: C, 85.33; H,
8.84. Found: C, 84.92; H, 9.31.
(Table 5, Entry 3) 1-Octyl (4-Acetonphenone) Acetylene. The
general procedure method A in Table 5 with 0.5 mol % catalyst
afforded the title compound (233 mg) in 91% isolated yield. 1H NMR
(CDCl3): δ (ppm) 7.83 (dd, J = 2.0, 6.8 Hz, 2H), 7.42 (dd, J = 1.6, 6.4
Hz, 2H), 2.54 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 1.57 (m, 2H), 1.42 (m,
2H), 1.26−1.28 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (CDCl3):
δ (ppm) 197.1, 135.6, 131.5, 129.1, 128.1, 94.3, 80.0, 31.8, 29.1, 29.01,
(Table 2, Entry 10) 2-Pyridine Phenyl Acetylene.13 The general
procedure afforded the title compound (240 mg) in 89% isolated yield
(yellowish solid).
(Table 2, Entry 11) 1-(2-Pyridine)-1-octyne.52 The general
procedure afforded the title compound (241 mg) in 86% isolated
yield (yellowish solid).
(Table 2, Entry 12) 1-Cyclohexene (2-Pyridine) Acetylene.53 The
general procedure afforded the title compound (250 mg) in 91%
isolated yield (yellowish solid).
J
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28.9, 28.5, 26.4, 22.56, 19.5, 14.0. Anal. Calcd for C18H24O: C, 84.32;
H, 9.44. Found: C, 84.20; H, 9.69.
(ppm) 7.29 (d, J = 6.4 Hz, 2H), 6.75 (d, J = 6.0 Hz, 2H), 5.16 (s, 1H),
2.38 (m, 2H), 1.60 (m, 2H), 1.46 (m, 2H), 1.32 (m, 8H), 0.89 (t, J =
6.0 Hz, 3H). 13C NMR (CDCl3): δ (ppm) 155.0, 133.1, 116.5, 115.3,
88.9, 80.2, 31.9, 29.2, 29.14, 29.0, 28.9, 22.7, 19.4, 14.1. Anal. Calcd for
C16H22O: C, 83.43; H, 9.63. Found: C, 83.08; H, 9.74.
(Table 5, Entry 13) 3-(Dec-1-ynyl)phenol. The general procedure
method A in Table 5 with 1.5 mol % catalyst afforded the title
compound (172 mg) in 75% isolated yield (yellowish solid). 1H NMR
(CDCl3): δ (ppm) 7.15 (t, J = 8.0 Hz, 1H), 6.97 (dd, J = 7.6, 1.2 Hz,
2H), 6.88 (dd, J = 1.2 Hz, 1H), 6.75 (dt, J = 8.0, 1.6 Hz, 1H), 5.55 (s,
1H), 2.38 (t, J = 7.2 Hz, 2H), 1.56−1.64 (m, 2H), 1.46 (m, 2H), 1.31
(m, 8H), 0.90 (t, J = 6.8 Hz, 3H). 13C NMR (CDCl3): δ (ppm) 155.2,
129.5, 125.4, 124.4, 118.4, 115.0, 90.8, 80.3, 31.9, 29.2, 29.2, 20.0, 28.8,
22.7, 19.4, 14.1. Anal. Calcd for C16H22O: C, 83.43; H, 9.63. Found: C,
83.25; H, 9.37.
(Table 5, Entry 14) 4-((Triisopropylsilyl)ethynyl)benzonitrile. The
general procedure method A in Table 5 with 0.5 mol % catalyst
afforded the title compound (229 mg) in 81% isolated yield. 1H NMR
(CDCl3): δ (ppm) 7.58 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H),
1.11 (s, 18H), 1.09 (m, 3H). 13C NMR (CDCl3): δ (ppm) 132.5,
131.9, 128.3, 118.4, 111.6, 105.1, 96.4, 18.6, 18.5, 11.23. MS (EI) m/z:
283 (M+ − 43).
(Table 5, Entry 15) 3-(Dec-1-ynyl)aniline. The general procedure
method A in Table 5 with 1.5 mol % catalyst afforded the title
compound (180 mg) in 79% isolated yield (yellowish solid). 1H NMR
(CDCl3): δ (ppm) 7.06 (t, J = 8 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H),
6.73 (s, 1H), 6.60 (d, J = 8 Hz, 1H), 3.62 (s, 2H), 2.39 (t, J = 7.2 Hz,
2H), 1.62 (m, 2H), 1.45 (m, 2H), 1.28−1.33 (m, 8H), 0.92 (t, J = 6.8,
3H). 13C NMR (CDCl3): δ (ppm) 146.2, 129.1, 124.9, 122.0, 118.1,
114.6, 89.9, 80.7, 31.9, 29.2, 29.2, 29.0, 28.8, 22.7, 19.4, 14.1. Anal.
Calcd for C16H23N: C, 83.79; H, 10.11. Found: C, 83.67; H, 10.17.
(Table 5, Entry 16) 4-(Dec-1-ynyl)benzamide. The general
procedure method A in Table 5 with 1.5 mol % catalyst afforded
the title compound (224 mg) in 87% isolated yield (yellowish solid).
1H NMR (CDCl3): δ (ppm) 7.70 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4
Hz, 2H), 6.41 (s, 2H), 2.38 (t, J = 7.2 Hz, 2H), 1.57 (m, 2H), 1.40 (m,
2H), 1.22−1.28 (m, 8H), 0.86 (t, J = 6.0 Hz, 3H). 13C NMR (CDCl3):
δ (ppm) 169.3, 131.7, 128.9, 128.1, 127.3, 93.6, 80.0, 31.8, 29.2, 29.1,
28.9, 28.6, 22.6, 19.5, 14.1. Anal. Calcd for C17H23NO: C, 79.33; H,
9.01. Found: C, 78.96; H, 8.85.
(Table 5, Entry 4) 2-(Dec-1-ynyl)-1,3,5-trimethylbenzene. The
general procedure method A in Table 5 with 0.5 mol % catalyst
afforded the title compound (215 mg) in 84% isolated yield (yellowish
1
solid). H NMR (CDCl3): δ (ppm) 6.88 (s, 2H), 2.54 (t, J = 6.8 Hz,
2H), 2.44 (s, 6H), 2.31 (s, 3H), 1.69 (m, 2H), 1.55 (m, 2H), 1.21−
1.37 (m, 8H), 0.95 (t, J = 6.7 Hz, 3H). 13C NMR (CDCl3): δ (ppm)
139.8, 136.5, 127.4, 120.9, 98.0, 78.2, 31.9, 29.3, 29.1, 28.9, 22.66, 21.2,
21.0, 19.7, 14.1. Anal. Calcd for C19H28: C, 88.99; H, 11.01. Found: C,
88.96; H, 10.99.
(Table 5, Entry 5) 2-(Dec-1-ynyl)-4-fluoro-1-methoxybenzene.
The general procedure method A in Table 5 with 1 mol % catalyst
afforded the title compound (236 mg) in 90% isolated yield. 1H NMR
(CDCl3): δ (ppm) 7.06 (dd, J = 3.2 8.8 Hz, 1H), 6.89 (td, J = 3.2, 8.4
Hz, 1H), 6.74 (dd, J = 4.4, 8.8 Hz, 1H), 3.82 (s, 3H), 2.44 (t, J = 6.8
Hz, 2H), 1.61 (m, 2H), 1.44 (m, 2H), 1.29 (m, 8H), 0.88 (t, J = 6.8
Hz, 3H). 13C NMR (CDCl3): δ (ppm) 157.6, 156.2, 156. 2, 155.2,
119.9, 119.7, 115.1, 114.9, 114.5, 114.4, 111.53, 111.4, 95.7, 75.8, 75.7,
56.3, 31.8, 29.1, 29.1, 28.8, 28.6, 22.6, 19.6, 14.1. Anal. Calcd for
C17H23FO: C, 77.82; H, 8.84; Found: C, 77.90; H, 9.22.
(Table 5, Entry 6) 2-(Cyclohexenylethynyl)benzonitrile. The
general procedure method A in Table 5 with 1 mol % catalyst
afforded the title compound (201 mg) in 97% isolated yield. 1H NMR
(CDCl3): δ (ppm) 7.58 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 4.4 Hz, 2H),
7.31 (m, 1H), 6.33 (m, 1H), 2.33 (m, 2H), 2.63 (m, 2H), 1.65−1.68
(m, 2H), 1.58−1.64 (m, 2H). 13C NMR (CDCl3): δ (ppm) 137.7,
132.5, 132.2, 131.9, 127.9, 127.6, 120.2, 117.6, 115.1, 98.1, 83.2, 28.8,
25.9, 22.2, 21.4. MS(EI) m/z: 207 (M+).
(Table 5, Entry 7) 4-(Cyclohexenylethynyl)benzonitrile. The
general procedure method A in Table 5 with 1 mol % catalyst
afforded the title compound (195 mg) in 94% isolated yield (yellowish
solid). 1H NMR (CDCl3): δ (ppm) 7.54 (d, J = 8.0 Hz, 2H), 7.44 (d, J
= 8.0 Hz, 2H), 6.25 (m, 1H), 2.13−2.21 (m, 4H), 1.59−1.68 (m, 4H).
13C NMR (CDCl3): δ (ppm) 137.2, 132.0, 131.9, 129.0, 120.3, 118.6,
110.9, 95.9, 85.4, 29.1, 25.9, 22.2, 21.4. MS (EI) m/z: 207 (M+).
(Table 5, Entry 8) 9-(Cyclohexenylethynyl)anthracene. The
general procedure method A in Table 5 with 1 mol % catalyst
afforded the title compound (237 mg) in 84% isolated yield (yellowish
solid). 1H NMR (CDCl3): δ (ppm) 8.58 (d, J = 8.4 Hz, 2H), 8.40 (s,
1H), 8.01 (d, J = 8.4 Hz, 2H), 7.58 (t, J = 6.4 Hz, 2H), 7.52 (t, J = 6.8
Hz, 2H), 6.50 (s, 1H), 2.52 (m, 2H), 2.29 (m, 2H), 1.84 (m, 2H), 1.76
(m, 2H). 13C NMR (CDCl3): δ (ppm) 135.4, 132.4, 131.2, 128.6,
127.0, 126. 9, 126.3, 125.6, 121.3, 118.0, 103.1, 83.8, 29.6, 26.0, 22.5,
21.6. Anal. Calcd for C22H18: C, 93.57; H, 6.43. Found: C, 93.35; H,
6.26.
(Table 5, Entry 9) 2-(Phenylethynyl)benzonitrile. The general
procedure method C in Table 5 with 1 mol % catalyst afforded the title
compound (187 mg) in 92% isolated yield (yellowish solid). 1H NMR
(CDCl3): δ (ppm) 7.59 (m, 1H), 7.56 (m, 3H), 7.52 (m, 1H), 7.36
(m, 4H). 13C NMR (CDCl3): δ (ppm) 132.7, 132.4, 132.1, 132.0,
129.2, 128.5, 128.2, 127.3, 122.1, 117.5, 115.4, 96.0, 85.6. MS(EI) m/z:
203 (M+).
(Table 5, Entry 10) 4-(Phenylethynyl)benzonitrile. The general
procedure method C in Table 5 with 1 mol % catalyst afforded the title
compound (177 mg) in 87% isolated yield (yellowish solid). 1H NMR
(CDCl3): δ (ppm) 7.61 (d, J = 5.6 Hz, 2H), 7.59 (d, J = 6.4 Hz, 2H),
7.54 (dd, J = 2.4, 6.4 Hz, 2H), 7.36 (m, 3H). 13C NMR (CDCl3): δ
(ppm) 132.0, 132.0, 131.7, 129.0, 128.4, 128.2, 122.19, 118.4, 111.5,
93.7, 87.6. MS(EI) m/z: 203 (M+).
(Table 5, Entry 11) 1-Methoxy-4-(phenylethynyl)benzene. The
general procedure method C in Table 5 with 1 mol % catalyst afforded
the title compound (187 mg) in 91% isolated yield (yellowish solid).
1H NMR (CDCl3): δ (ppm) 7.50 (d, J = 6.0 Hz, 2H), 7.47 (d, J = 6.8
Hz, 2H), 7.33 (m, 3H), 6.85 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). 13C
NMR (CDCl3): δ (ppm) 159.6, 133.0, 131.4, 128.2, 127.9, 123.6,
115.4, 114.0, 89.3, 88.0, 55.2. MS(EI) m/z: 208 (M+).
(Table 5, Entry 17) 5-(Pyridin-2-yl)pent-4-yn-1-ol. The general
procedure method B in Table 5 with 1 mol % catalyst afforded the title
1
compound (129 mg) in 80% isolated yield. H NMR (CDCl3): δ
(ppm) 8.24 (d, J = 1.6 Hz, 1H), 7.52 (td, J = 8.0, 1.2 Hz, 1H), 7.27
(dd, J = 8.0, 1.2 Hz, 1H), 7.09 (td, J = 8.0, 1.2 Hz, 1H), 4.0 (s, 1H),
3.73 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 8.8 Hz, 2H), 1.82 (q, J = 6.4 Hz,
2H). 13C NMR (CDCl3): δ (ppm) 149.5, 143.6, 136.2, 126.9, 122.4,
90.8, 80.4, 60.9, 31.2, 15.9. Anal. Calcd for C10H11NO: C, 74.51; H,
6.88. Found: C, 74.43; H, 6.92.
(Table 5, Entry 18) 2-((3-Aminophenyl)ethynyl)benzonitrile. The
general procedure method C in Table 5 with 1 mol % catalyst afforded
the title compound (157 mg) in 72% isolated yield. 1H NMR
(CDCl3): δ (ppm) 7.65 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8 Hz, 1H),
7.56 (m, 1H), 7.39 (m, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.02 (m, 1H),
6.72 (m, 1H), 6.70 (d, J = 8.0 Hz, 1H), 3.78 (s, 2H). 13C NMR
(CDCl3): δ (ppm) 146.6, 132.6, 132.4, 132.1, 129.4, 128.2, 127.4,
122.7, 122.2, 118.1, 117.7, 116.3, 115.2, 96.5, 85.1. Anal. Calcd for
C15H10N2: C, 82.55; H, 4.62. Found: C, 82.29; H, 4.73.
(Table 5, Entry 19) 4-(5-Chloropent-1-ynyl)benzonitrile. The
general procedure method A in Table 5 with 1 mol % catalyst
afforded the title compound (183 mg) in 90% isolated yield. 1H NMR
(CDCl3): δ (ppm) 7.55 (d, J = 6.8 Hz, 2H), 7.45 (d, J = 6.8 Hz, 2H),
3.69 (t, J = 6.4 Hz, 2H), 2.60 (t, J = 6.8 Hz, 2H), 2.05 (q, J = 6.4 Hz,
2H). 13C NMR (CDCl3): δ (ppm) 132.2, 131.95, 128.6, 118.5, 111.1,
93.25, 80.3, 43.6, 31.1, 17.0. MS (EI) m/z: 203 (M+).
(Table 5, Entry 20) 4-(Cyclohexenylethynyl)-2-(methylthio)-
pyrimidine. The general procedure method B in Table 5 with 1 mol
% catalyst afforded the title compound (238 mg) in 91% isolated yield.
1H NMR (CDCl3): δ (ppm) 8.42 (d, J = 5.21 Hz, 1H), 6.96 (d, J = 5.2
(Table 5, Entry 12) 4-(Dec-1-ynyl)phenol. The general procedure
method A in Table 5 with 1.5 mol % catalyst afforded the title
1
compound (145 mg) in 67% isolated yield. H NMR (CDCl3): δ
Hz, 1H), 6.41 (m, 1H), 2.56 (s, 3H), 2.23 (m, 2H), 2.17 (m, 2H),
K
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The Journal of Organic Chemistry
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1.61−1.69 (m, 4H). 13C NMR (CDCl3): δ (ppm) 173.0, 156.7, 151.4,
139.69, 119.7, 118.3, 96.1, 84.7, 28.6, 26.0, 22.1, 21.3, 14.1. Anal. Calcd
for C13H14N2S: C, 67.79; H, 6.13. Found: C, 67.53; H, 6.26.
(Table 5, Entry 21) 5-(Dec-1-ynyl)-1,3-dimethyl-1H-pyrazole. The
general procedure method B in Table 5 with 1 mol % catalyst afforded
the title compound (181 mg) in 78% isolated yield. 1H NMR
(CDCl3): δ (ppm) 6.08 (m, 1H), 3.82 (s, 3H), 2.44 (t, J = 7.2 Hz,
2H), 2.23 (s, 3H), 1.62 (m, 2H), 1.45 (m, 2H), 1.31 (m, 8H), 0.89 (t,
J = 6.8 Hz, 3H). 13C NMR (CDCl3): δ (ppm) 150.2, 129.4, 111.4,
100.5, 72.3, 39.5, 34.7, 32.0, 31.9, 31.7, 31.3, 25.5, 22.3, 16.9, 16.2.
Anal. Calcd for C15H24N2: C, 77.53; H, 10.41. Found: C, 77.31; H,
10.56.
NMR (CDCl3): δ (ppm) 143.5, 143.2, 142.7, 138.3, 136.5, 132.6,
131.2, 129.8, 128.8, 122.38, 119.5, 100.4, 76.3, 31.8, 29.7, 29.1, 29.0,
28.8, 27.9, 22.6, 19.7, 14.0. Anal. Calcd for C19H21F3N2: C, 68.25; H,
6.33. Found: C, 68.71; H, 6.42.
(Table 5, Entry 29) 5-(Dec-1-ynyl)-1,3-dimethyl-1H-pyrazole-4-
carbaldehyde. The general procedure method B in Table 5 with 1
mol % catalyst afforded the title compound (223 mg) in 86% isolated
yield. 1H NMR (CDCl3): δ (ppm) 9.89 (s, 1H), 3.82 (s, 3H), 2.51 (t, J
= 7.2 Hz, 2H), 2.42 (s, 3H), 1.62 (q, J = 8.0 Hz, 2H), 1.44 (m, 2H),
1.26−1.31 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (CDCl3): δ
(ppm) 184.5, 144.5, 132.5, 121.7, 103.6, 66.9, 36.8, 31.8, 29.1, 28.8,
28.9, 28.2, 22.6, 19.6, 14.0, 13.3. Anal. Calcd for C16H24N2O: C, 73.81;
H, 9.29. Found: C, 74.02; H, 9.37.
(Table 5, Entry 22) 3-(Cyclohexenylethynyl)-6-methoxypyrida-
zine. The general procedure method B in Table 5 with 1 mol %
catalyst afforded the title compound (193 mg) in 90% isolated yield
(Table 5, Entry 30) 2-(Dec-1-ynyl)thiophene. The general
procedure method B in Table 5 with 1 mol % catalyst afforded the
1
1
(yellowish solid). H NMR (CDCl3): δ (ppm) 7.33 (d, J = 8.8 Hz,
title compound (183 mg) in 83% isolated yield (yellowish solid). H
1H), 6.84 (d, J = 9.2 Hz, 1H), 6.29 (m, 1H), 4.09 (s, 3H), 2.21 (m,
2H), 2.11 (m, 2H), 1.56−1.64 (m, 4H). 13C NMR (CDCl3): δ (ppm)
163.2, 144.2, 137.6, 132.2, 120.0, 116.4, 94.1, 83.3, 54.9, 28.7, 25.8,
22.2, 21.4. Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59. Found: C,
72.82; H, 6.48.
(Table 5, Entry 23) 2-(Dec-1-ynyl)pyrimidine. The general
procedure method B in Table 5 with 1.5 mol % catalyst afforded
the title compound (183 mg) in 85% isolated yield (yellowish solid).
1H NMR (CDCl3): δ (ppm) 8.64 (d, J = 4.8 Hz, 2H), 7.15 (t, J = 4.8
Hz, 1H), 2.43 (t, J = 7.2 Hz, 2H), 1.61 (m, 2H), 1.41 (m, 2H), 1.22−
1.25 (m, 8H), 0.83 (t, J = 5.8 Hz, 3H). 13C NMR (CDCl3): δ (ppm)
157.1, 153.4, 119.3, 90.8, 80.0, 31.8, 29.1, 29.0, 29.0, 28.0, 22.6, 19.2,
14.0. Anal. Calcd for C14H20N2: C, 77.73; H, 9.32. Found: C, 77.56; H,
9.34.
(Table 5, Entry 24) Methyl 6-(Dec-1-ynyl)nicotinate. The general
procedure method B in Table 5 with 0.5 mol % catalyst afforded the
title compound (259 mg) in 95% isolated yield. 1H NMR (CDCl3): δ
(ppm) 9.12 (t, J = 1.2 Hz, 1H), 8.18 (dd, J = 8.0, 1.5 Hz, 1H), 7.41
(dd, J = 8.0, 0.8 Hz, 1H), 3.92 (s, 3H), 2.45 (t, J = 7.2 Hz, 2H), 1.63
(m, 2H), 1.44 (m, 2H), 1.28 (m, 8H), 0.87 (t, J = 6.4 Hz, 3H). 13C
NMR (CDCl3): δ (ppm) 165.5, 151.0, 147.7, 137.0, 126.2, 124.2, 81.0,
94.0, 52.4, 31.8, 29.1, 29.1, 29.0, 28.2, 22.6, 19.5, 14.1. Anal. Calcd for
C17H23NO2: C, 74.69; H, 8.48. Found: C, 74.53; H, 8.37.
NMR (CDCl3): δ (ppm) 7.17 (dd, J = 5.2, 1.2 Hz, 1H), 7.12 (d, J =
3.2 Hz, 1H), 6.93 (dd, J = 5.2, 3.2 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H),
1.63 (m, 2H), 1.45 (m, 2H), 1.32 (m, 8H), 0.89 (t, J = 6.8 Hz, 3H).
13C NMR (CDCl3): δ (ppm) 130.8, 126.7, 125.8, 124.3, 94.6, 73.7,
31.8, 29.2, 29.1, 29.0, 28.6, 22.7, 19.7, 14.1. Anal. Calcd for C14H20S: C,
76.30; H, 9.15. Found: C, 76.32; H, 9.07.
(Table 5, Entry 31) 4-(3-Hydroxy-3-methylnon-1-ynyl)-
benzonitrile. The general procedure method D in Table 5 with 1
mol % catalyst afforded the title compound (183 mg) in 72% isolated
1
yield (yellowish solid). H NMR (CDCl3): δ (ppm) 7.56 (d, J = 8.0
Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 2.29 (s, 1H), 1.72 (m, 2H), 1.51 (s,
3H), 1.46 (m, 2H), 1.23−1.34 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H). 13C
NMR (CDCl3): δ (ppm) 132.2, 131.9, 127.9, 118.4, 111.6, 97.7, 81.7,
68.7, 43.6, 31.7, 29.6, 29.4, 24.7, 22.6, 14.0. Anal. Calcd for C17H21NO:
C, 79.96; H, 8.29. Found: C, 80.31; H, 7.96.
Compound 7. Using the general procedure described as method D
in Table 5, 2 mol % catalyst loading afforded the title compound in
1
59% isolated yield (250 mg) as a yellowish white solid. H NMR
(CDCl3): δ (ppm) 7.58 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H),
7.13 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 8.4, 2.4 Hz, 1H), 6.57 (d, J = 2.8
Hz, 1H), 5.9 (s, 1H), 2.78 (m, 2H), 2.50 (m, 1H), 2.30−2.45 (m, 2H),
2.1−2.2 (m, 2H), 1.82−1.88 (m, 4H), 1.70 (m, 1H), 1.26−1.49 (m,
3H), 0.93 (s, 3H). 13C NMR (CDCl3): δ (ppm) 153.8, 138.17, 132.2,
132.0, 132.0, 128.0, 126.4, 118. 5, 115.4, 113.0, 111.4, 97.6, 84.6, 80.5,
50.1, 47.8, 43.7, 39.6, 39.1, 33.1, 29.6, 27.5, 26.3, 23.2, 12.9. Anal.
Calcd for C27H27NO2: C, 81.58; H, 6.85. Found: C, 81.49; H, 7.01.
Compound 8. Using the general procedure described as method D
in Table 5, 2 mol % catalyst loading afforded the title compound in
(Table 5, Entry 25) 2-(Cyclohexenylethynyl)-4,6-dimethoxypyr-
imidine. The general procedure method B in Table 5 with 1 mol %
catalyst afforded the title compound (227 mg) in 91% isolated yield
1
(yellowish solid). H NMR (CDCl3): δ (ppm) 6.32 (m, 1H), 5.86 (s,
1H), 3.86 (s, 6H), 2.17 (m, 2H), 2.06 (m, 2H), 1.52−1.58 (m, 4H).
13C NMR (CDCl3): δ (ppm) 171.0, 151.5, 138.8, 119. 7, 89.6, 88.6,
1
62% (250 mg) isolated yield as a yellowish white solid. H NMR
86.0, 54.1, 28.6, 25.9, 22.1, 21.3. Anal. Calcd for C14H16N2O2: C,
68.83; H, 6.60. Found: C, 68.82; H, 6.77.
(CDCl3): δ (ppm) 8.64 (s, 1H), 7.45 (d, J = 9.2 Hz, 1H), 6.93 (d, J =
8.8 Hz, 2H), 6.69 (dd, J = 8.0, 2.0 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H),
4.10 (s, 3H), 3.40 (s, 1H), 2.67 (m, 2H), 2.43 (m, 1H), 2.09 (m, 2H),
1.89 (m, 1H), 1.66−1.76 (m, 5H), 1.22−1.34 (m, 4H), 0.89 (s, 3H).
13C NMR (CDCl3): δ (ppm) 163.8, 154.6, 143.0, 137.6, 132.9, 131.52,
126.3, 117.5, 115.4, 112.9, 97.5, 81.6, 80.4, 55.2, 49.8, 47.82, 42.9, 39.3,
38.9, 33.1, 29.7, 27.16, 26.3, 22.8, 12.9. Anal. Calcd for C25H28N2O3:
C, 74.23; H, 6.98. Found: C, 73.89; H, 7.04.
(Table 5, Entry 26) 2-(Cyclohexenylethynyl)pyrimidine. The
general procedure method B in Table 5 with 1 mol % catalyst
afforded the title compound (227 mg) in 91% isolated yield (yellowish
solid). 1H NMR (CDCl3): δ (ppm) 8.56 (m, 2H), 7.06 (m, 1H), 6.30
(m, 1H), 2.02 (m, 2H), 2.12 (m, 2H), 1.48−1.53 (m, 4H). 13C NMR
(CDCl3): δ (ppm) 157.1, 153.5, 139.4, 119.5, 119.2, 90.2, 85.8, 29.0,
25.9, 22.0, 21.2. Anal. Calcd for C12H12N2: C, 78.23; H, 6.57. Found:
C, 78.04; H, 6.32.
(Table 5, Entry 27) 5-(Dec-1-ynyl)-1,3-dimethyl-4-nitro-1H-pyr-
azole. The general procedure method B in Table 5 with 1 mol %
catalyst afforded the title compound (213 mg) in 79% isolated yield
(yellowish solid). 1H NMR (CDCl3): δ (ppm) 3.85 (s, 3H), 2.55 (t, J
= 7.2 Hz, 2H), 2.48 (s, 3H), 1.66 (m, 2H), 1.48 (m, 2H), 1.26−1.30
(m, 8H), 0.85 (t, J = 6.8 Hz, 3H). 13C NMR (CDCl3): δ (ppm) 145.3,
133.3, 126.2, 106.2, 67.2, 37.6, 31.7, 29.1, 29.0, 28. 8, 28.0, 22.6, 19.9,
14.0, 13.8. Anal. Calcd for C15H23N3O2: C, 64.95; H, 8.36. Found: C,
6.49; H, 8.33.
Compound 11, (E)-But-1-en-3-yne-1,4-diyldibenzene.57 1H NMR
(CDCl3): δ (ppm) 7.46−7.48 (m, 2H), 7.40−7.43 (m, 2H), 7.28−7.36
(m, 6H), 7.04 (d, J = 16 Hz, 1H), 6.38 (d, J = 16 Hz, 1H). MS (EI) m/
z: 204 (M+).
Compound 12, 1,3,5-Trimethyl-2-(p-tolylethynyl)benzene.33
Using the general procedure described as method A in Table 5, 1
mol % catalyst loading afforded the title compound in 72% isolated
1
yield ((250 mg) as a yellowish white solid. H NMR (CDCl3): δ
(ppm) 7.50 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 6.95 (s, 2H),
2.55 (s, 6H), 2.43 (s, 3H), 2.36 (s, 3H). MS (EI) m/z: 234 (M+).
(Table 5, Entry 28) 2-(Dec-1-ynyl)-3-(trifluoromethyl)quinoxaline.
The general procedure method B in Table 5 with 0.5 mol % catalyst
afforded the title compound (290 mg) in 87% isolated yield (yellowish
solid). 1H NMR (CDCl3): δ (ppm) 8.18 (d, J = 8.0 Hz, 1H), 8.13 (d, J
= 8.0 Hz, 1H), 7.81−7.91 (m, 2H), 2.57 (t, J = 7.2 Hz, 2H), 1.71 (m,
2H), 1.52 (m, 2H), 1.25−1.33 (m, 8H) 0.89 (t, J = 6.8 Hz, 3H). 13C
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C NMR spectra of all of the compounds
synthesized in this work, along with the X-ray crystal data in cif
L
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Article
2005, 70, 391. (q) Liang, Y.; Xie, Y. X.; Li, J. H. J. Org. Chem. 2006, 71,
379.
format of Pd-149. This material is available free of charge via
the Internet at http://pubs.acs.org.
(10) Sonogashira coupling of aryl chlorides: (a) Choudary, B. M.;
Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J. Am. Chem.
Soc. 2002, 124, 14127. (b) Hierso, J.; Fihri, A.; Amardeil, R.; Meunier,
P. Org. Lett. 2004, 6, 3473. (c) Feuerstein, M.; Doucet, H.; Santelli, M.
Tetrahedron Lett. 2004, 45, 8443. (d) Yi, C.; Hua, R.; Zeng, H.; Huang,
Q. Adv. Synth. Catal. 2007, 349, 1738. (e) Fleckenstein, C. A.; Plenio,
H. Organometallics 2007, 26, 2758. (f) Hill, L. L.; Smith, J. M.; Brown,
W. S.; Moore, L. R.; Guevara, P.; Pair, E. S.; Porter, J.; Chou, J.;
Wolterman, C. J.; Craciun, R.; Dixon, D. A.; Shaughnessy, K. H.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: colactj@jmusa.com.
Notes
The authors declare the following competing financial interest:
The catalysts used in this study are commercially available from
Johnson Matthey.
́ ́
Tetrahedron 2008, 64, 6920. (g) Komaromi, A.; Novak, Z. Chem.
Commun. 2008, 4968. (h) Huang, H.; Liu, H.; Jiang, H.; Chen, K. J.
Org. Chem. 2008, 73, 6037. (i) Torborg, C.; Huang, J.; Schulz, T.;
ACKNOWLEDGMENTS
■
Schaffner, B.; Zapf, A.; Spannenberg, A.; Borner, A.; Beller, M. Chem.-
̈
̈
We thank Dr. Glenn Yap at the University of Delaware, for
carrying out the X-ray structure analysis. We also thank Fred
Hancock, Technical Director (JMCCT), and Gerard Compag-
noni, General Manager (JMCCT), for supporting this work. In
addition, we acknowledge William Carole for his help in
formatting the figures and tables during the manuscript
preparation.
Eur. J. 2009, 1329. (j) Jin, M.; Lee, D. Angew. Chem., Int. Ed. 2010, 49,
1119. (k) Lee, D.; Kwon, Y.; Jin, M. Adv. Synth. Catal. 2011, 353,
3090. (l) Shu, W.; Buchwald, S. L. Chem. Sci. 2011, 2, 2321.
(11) Kollhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed.
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