Copper-catalyzed stereoselective hydroarylation of 3-aryl-2-propynenitriles with arylboronic acids

Article abstract of DOI:10.1002/adsc.200900067

The selective synthesis of 3,3-diarylacrylonitriles has been achieved by copper-catalyzed hydroarylation of 3-aryl-2-propynenitriles with arylboronic acids. The starting cyanoalkynes were efficiently prepared from the appropriate aromatic aldehydes and di

Full text of DOI:10.1002/adsc.200900067

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DOI: 10.1002/adsc.200900067
Copper-Catalyzed Stereoselective Hydroarylation of 3-Aryl-2-
propynenitriles with Arylboronic Acids
Yoshihiko Yamamoto,a,b,* Tsuyoshi Asatani,a and Naohiro Kiraia
a
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
Ookayama, Meguro-ku, Tokyo 152-8552, Japan
Fax : (+81)-3-5734-3339; e-mail: omyy@apc.titech.ac.jp
Current address: Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Chikusa-ku,
b
Nagoya 464-8603, Japan
E-mail: yamamoto@apchem.nagoya-u.ac.jp
Received: February 1, 2009; Revised: April 15, 2009; Published online: June 2, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900067.
Abstract: The selective synthesis of 3,3-diarylacrylo-
nitriles has been achieved by copper-catalyzed hy-
droarylation of 3-aryl-2-propynenitriles with aryl-
boronic acids. The starting cyanoalkynes were effi-
ciently prepared from the appropriate aromatic al-
dehydes and diethyl cyanomethylphosphonate in
two steps. The hydroarylation of the obtained cya-
noalkyne substrates proceeded in methanol at am-
bient temperature to produce 3,3-diarylacryloni-
triles in good to high yields with excellent syn selec-
tivity. The present method was successfully applied
to the regiospecific synthesis of both stereoisomers
of CC-5079, which was recently reported as a
potent anticancer drug.
tivities of relevant 3,3-diarylacrylonitriles depend
highly on their olefin geometry.[4] The results of these
reports suggest that it is very important to develop a
stereospecific method to obtain 3,3-diarylacryloni-
triles to carry out further bioactivity screening of this
class of compounds. In this communication, we pres-
ent the results of our study on Cu-catalyzed stereose-
lective hydroarylation of 3-aryl-2-propynenitriles
using arylboronic acids.
The stereoselective synthesis of acrylonitriles pos-
sessing different aryl rings on the 3 position has been
accomplished by the following different processes:
the Heck reaction of 3-arylacrylonitriles with aryl io-
dides,[5] the Suzuki–Miyaura coupling of 3-aryl-3-
chloroacrylonitriles with arylboronic acids,[1d] and the
Stille coupling of 3-aryl-3-(tributylstannyl)acryloni-
triles with aryl iodides.[4] However, these precedents
require expensive palladium catalysts, ligands, and/or
additives. Therefore, it is beneficial to develop a new
method involving an inexpensive non-precious metal
catalyst. We have previously reported that the syn-hy-
Keywords: alkynes; arylation; boron; copper; ni-
triles
3,3-Diarylacrylonitriles are potential building blocks droarylation of propiolates with arylboronic acids pro-
for the synthesis of 3,3-diarylpropylamines,[1] which ceeds at ambient temperature without any additives
are important structural motifs widely found in syn- in the presence of a catalytic amount of inexpensive
thetic drugs.[2] In addition, the biological activity of copper salts in methanol.[6] If our Cu-catalyzed hydro-
highly oxygenated 3,3-diarylacrylonitriles has gained arylation is applicable to 3-aryl-2-propynenitriles, the
renewed interest since the recent discovery of CC- desired 3,3-diarylacrylonitriles can be obtained in a
5079.[3] CC-5079, which is an acrylonitrile possessing material-economic way. Although the related conju-
3,4- and 3,5-dimethoxyphenyl rings on the 3 position, gate addition of cuprates to cyanoalkynes has been
was reported to inhibit the growth of cancer cells by reported,[7] only symmetrical 3,3-diphenylacrylonitrile
interrupting the microtubule assembly process. CC- has been synthesized using this method.[7b] In addi-
5079 also inhibits the production of tumor necrosis tion, our method has a significant advantage over
factor-a, whose excessive production is assumed to precedents in that it introduces aromatic rings bearing
cause the pathogenesis of cancers with inhibiting reactive functional groups, which can be used for fur-
apoptosis. Although a mixture of stereoisomers of ther transformations.
CC-5079 was tested for biological activity in the previ-
Our investigations commenced with the develop-
ous study, it was later reported that the biological ac- ment of a new method for the preparation of cyanoal-
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Yoshihiko Yamamoto et al.
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kyne substrates 1a–c from readily available arylalde-
hydes (Scheme 1). The literature precedents require
the toxic cyanide nucleophile CuCN[8] or cyano elec-
Scheme 2. Cu-Catalyzed hydroarylation of 1a with 3a.
Scheme 1. Synthesis of 3-aryl-2-propynenitriles 1a–c.
trophiles such as BrCN[9] or PhOCN.[10] Therefore, we
used diethyl cyanomethylphosphonate as a less toxic
nitrile precursor. According to a previous report,[11] p-
methoxy-, 3,4-dimethoxy-, and 3,5-dimethoxy-substi-
tuted benzaldehydes were treated with an iodinated
Horner–Emmons reagent in situ prepared from cya-
nomethylphosphonate in THF to yield 2-iodoacryloni-
triles 2a–c in 82%, 76%, and 72% yields, respectively.
Then, 2a was dehydroiodinated using 2 equivalents of
lithium hexamethyldisilazide (LHMDS) in THF at
À508C to obtain the desired alkyne 1a in 87% yield.
The use of LHMDS is quite essential to obtain a high
Scheme 3. Cu-Catalyzed hydroarylation of 2-heptynenitrile
with 3a.
yield of 1a; the use of other bases such as sodium and The reaction of 2-heptynenitrile with phenylboronic
potassium hexamethyldisilazides, LDA, t-BuOK, or acid was carried out to obtain syn-5 in 83% yield as a
DBU results in low yields or no reaction. Similarly, single stereoisomer. The syn selectivity was again con-
1
dehydroiodination of 2b and 2c with LHMDS at firmed by comparison of its H NMR data with those
À508C (À608C for 2c) furnished 1b and 1c in 92% reported previously.[7b] From these observations, we
and 91% yields, respectively. Under optimized condi- concluded that the Cu-catalyzed hydroarylation of
tions, an aliphatic cyanoalkyne was not obtained from cyanoalkynes also proceeds with excellent syn selec-
the corresponding iodoacrylonitrile precursor 2d.
tivity, as previously observed for alkynoates.[6]
We then examined the Cu-catalyzed reaction of 1a
In order to examine the influence of the substitu-
with arylboronic acid 3a. Under our previously opti- ents on arylboronic acids, boron reagents 3b–k
mized conditions, 1a reacted with phenylboronic acid (Figure 1) were used for the reaction with 1a
(3a, 3 equiv.) in the presence of 5 mol% CuOAc for (Table 1). Although higher catalyst loadings were re-
4 h to yield crude 4aa with >98% syn selectivity quired for the reaction of sterically demanding o- and
(1H NMR). Purification of the obtained compound by m-isomers, tolylboronic acids 3b–d afforded the de-
silica gel column chromatography afforded 4aa in sired products 4ab–ad uneventfully in high yields with
83% yield as an exclusive syn isomer (Scheme 2). Di- excellent syn selectivity (entries 1–3). It should be
agnostic resonances of the vinyl and methoxy protons noted that our protocol well tolerates various func-
of 4aa appeared as singlets at d=5.61 and 3.87 ppm, tional groups such as halides, electron-withdrawing
respectively, which were in good agreement with ester, nitro, and electron-donating methoxy groups
those reported for the expected Z isomer as shown in (entries 4–9). In cases of arylboronic acids 3g, i, j, the
parentheses.[5b] On the other hand, the corresponding chromatographic purification was hampered due to
resonances of E isomer were reported to appear at the formation of several aromatic by-products from
1
lower and higher fields, respectively (d=5.67 and these reagents, although the H NMR analysis of the
3.84 ppm).[5b]
crude mixture showed that hydroarylation products
The Cu-catalyzed hydroarylation also effectively were formed in high yields. Therefore, 4ai was sepa-
proceeded with an aliphatic cyanoalkyne (Scheme 3). rated with preparative TLC in 76% yield (entry 8).
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Because a decrease in stereoselectivity was observed
for electron-rich 4ag and 4aj after PTLC, these prod-
ucts were purified by recrystallization (entries 6 and
9). In addition to these phenylboronic acid deriva-
tives, 2-naphthylboronic acid 3k produced the corre-
sponding adduct 4ak in 94% yield (entry 10).
Iodide 4ag is of particular importance among the
obtained products, because it is otherwise difficult to
be synthesized using other methods and can be used
for further transformations. In order to demonstrate
its synthetic potential, the Ullmann coupling of 4ag
with indole was examined as shown in Scheme 4. The
isolated 4ag was subjected to Ullmann coupling with
slightly excess amounts of indole according to the
Figure 1. Arylboronic acids used in this study.
Table 1. Hydroarylation of 1a with 3b–k.[a]
Entry
3
Cu [mol%]
Time [h]
12
4
Yield [%][b,c]
1
3b
10
4ab
80
2
3
3c
8
5
12
12
4ac
4ad
81
85
3d
4
5
3e
5
8
10
4ae
91
3f
8
4af
96
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Yoshihiko Yamamoto et al.
Yield [%][b,c]
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Table 1. (Continued)
Entry
3
Cu [mol%]
Time [h]
4
6
3g
8
8
4ag
68 (93)[d]
7
8
9
3h
8
8
5
4
8
4
4ah
4ai
4aj
87
3i
76 (96)[d]
3j
72 (82)[d]
10
3k
5
24
4ak
94
[a]
All reactions were carried out in MeOH (0.5M) at 288C under argon.
[b]
[c]
[d]
Isolated yields.
Stereoselectivity of >99% was inferred from 1H NMR and GC-MS analyses of isolated products.
Yields in parentheses were estimated by 1H NMR analysis of crude samples.
procedures reported by Buchwald and co-workers.[12] carried out (Scheme 5). In the original report,[3b] CC-
In the presence of 5 mol% CuI, 20 mol% N,N’-dime- 5079 was obtained as an E/Z mixture via the Horner–
thylethylenediamine (DMEDA), and K3PO4, 4ag and Emmons reaction of 3,4,3’,5’-tetramethoxybenzophe-
indole were refluxed in toluene for 24 h to obtain 6 in none with diethyl cyanomethylphophonate. In turn,
86% yield. No erosion of olefin stereochemistry was the starting benzophenone was prepared from 3,5-di-
observed for the isolated 6.
methoxybenzonitrile and 4-bromoveratrole in a low
After the successful selective formation of highly yield of 26%. Our method involves the highly syn-se-
oxygenated 3,3-diarylacrylonitrile 4aj, which is the lective Cu-catalyzed hydroarylation of readily avail-
substitutional isomer of CC-5079, the stereospecific able 3-aryl-2-propynenitriles and arylboronic acids,
synthesis of the two stereoisomers of CC-5079 was thereby enabling practical and stereospecific access to
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Copper-Catalyzed Stereoselective Hydroarylation of 3-Aryl-2-propynenitriles
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Scheme 4. Cu-Catalyzed Ullmann coupling of 4ag with
indole.
the desired target molecules. In fact, the reaction of
1b and 3l was carried out under optimal conditions to
obtain 4bl in 84% yield as an exclusive stereoisomer.
Similarly, the opposite stereoisomer 4cm was synthe-
sized in 71% yield by coupling 1c with 3m.
We finally synthesized several known derivatives
Scheme 5. Stereospecific synthesis of CC-5079.
relevant to CC-5079. In the previous studies, the 3,4-
dimethoxyphenyl moiety was found to play a role in
biological activities of this class of compounds.[3,4] summarized in Table 2. In the presence of 5 or
Therefore, the coupling of 1b with several commer- 8 mol% CuOAc as a catalyst, 1b was allowed to react
cially available arylboronic acids were carried out as with arylboronic acids 3d, k, n–p in MeOH at 288C
Table 2. Coupling of 1b with 3d, k, n–p.[a]
Entry
3
Cu [mol%]
Time [h]
4
Yield [%][b,c]
1
3d
5
12
4bd
84
2
3
3k
3n
5
8
24
4bk
4bn
89
6
90
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Yoshihiko Yamamoto et al.
Yield [%][b,c]
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Table 2. (Continued)
Entry
3
Cu [mol%]
Time [h]
4
4
3o
8
8
4bo
97
92
5
3p
5
10
4bp
[a]
All reactions were carried out in MeOH (0.5M) at 288C under argon.
[b]
[c]
Isolated yields.
Stereoselectivity of >99% was inferred from 1H NMR and GC-MS analyses of isolated products.
(Tokyo Instituted of Technology) for use of mass spectrome-
ters.
for 6–24 h to deliver the corresponding hydroarylation
products in 84–97% yields. The perfect syn stereose-
lectivity was again observed for each case. These re-
sults successfully demonstrate the feasibility of the
copper-catalyzed hydroarylation toward the stereose-
lective synthesis of pharmaceutically important 3,3-di-
arylacrylonitriles.
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Experimental Section
Representative Procedures for Cu-Catalyzed
Hydroarylation
To a solution of 3-(p-methoxyphenyl)-2-propynenitrile (1a)
(78.58 mg, 0.50 mmol) and phenylboronic acid (3a)
(182.88 mg, 1.50 mmol) in methanol (1.0 mL) was added
CuOAc (3.08 mg, 0.025 mmol). The reaction mixture was
degassed at À788C, and then stirred at 288C under an argon
atmosphere for 4 h. After filtration through a pad of Celiteꢁ
to remove insoluble materials, the filtrate was concentrated
under vacuum. The residue was purified by silica gel flash
column chromatography (hexane-AcOEt 50:1) to give 4aa
as a colorless oil; yield: 97.5 mg (83%).
Acknowledgements
This research was partially supported by the Ministry of Edu-
cation, Science, Sports and Culture, Grant-in-Aid for Scientif-
ic Research (B) (20350045), Scientific Research on Priority
Area “Chemistry on Concerto Catalysis” (20037018). We
thank Prof. K. Tomooka (Kyushu University) for use of an
NMR spectrometer and Profs. H. Suzuki and T. Ikariya
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