Ortho substituents direct regioselective addition of tributyltin hydride to unsymmetrical diaryl (or heteroaryl) alkynes: An efficient route to stannylated stilbene derivatives

Article abstract of DOI:10.1002/1521-3773(20020503)41:9<1578::AID-ANIE1578>3.0.CO;2-C

An unprecedented ortho-directing effect (ODE) in diaryl alkynes 1 (R=electron-withdrawing or electron-donating group) promotes regioselective addition of tributyltin hydride to the triple bond and afforded efficiently stannylated unsymmetrical 1,2-diaryl olefins 2. The precise contributions of steric, electronic, and coordinative factors, which control this regioselectivity are highlighted. The results are rationalized in terms of electronic polarization across the alkyne bond, induced by the ortho substituent whatever its electronic nature.

Full text of DOI:10.1002/1521-3773(20020503)41:9<1578::AID-ANIE1578>3.0.CO;2-C

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Table 1. Palladium-catalyzed hydrostannylation of unsymmetrical diaryl alkynes 1.
Ortho Substituents Direct
Regioselective Addition of
Tributyltin Hydride to
Unsymmetrical Diaryl
(or Heteroaryl) Alkynes: An
Efficient Route to Stannylated
Stilbene Derivatives**
Entry
R
Isolated yield [%]
2
3
√
¬
Mouad Alami,* Frederic Liron,
Marina Gervais, Jean-FranÁois Peyrat,
and Jean-Daniel Brion
[a]
1
2
3
4
5
6
7
a: p-NO2
7
5
b: p-CHO
c: p-CO2Et
d: p-CH2OH
e: o-CHO
f: o-CO2Et
g: o-CH2OH
98[b]
81[b]
86[b]
[a]
It is well known that the palladium-cata-
lyzed hydrostannylation of internal alkynes
proceeds in a stereoselective manner (cis
addition) to yield vinyl stannanes.[1] Regio-
chemical control of this reaction, neverthe-
less, remains a challenge, especially in the case
of unsymmetrical disubstituted alkynes. In
95
81
95
[a]
[a]
[a] Stereoisomers 3 were not detected by 1H NMR spectra in the crude reaction mixture. [b] Isolated
yields of inseparable mixture of regioisomers. The ratios 2b:3b 85:15, 2c:3c 75:25 and 2d:3d 50:50
were determined by H NMR spectra in the crude reaction mixture.
1
this respect, to our knowledge, hydrostannylation of alkynes
with two different aromatic (or heteroaromatic) rings is not
known.[2] Herein, we describe the first highly regioselective
Pd-catalyzed addition of tributyltin hydride to alkynes 1,
which is controlled by the ortho substituent at the aromatic
ring, regardless of the electronic nature of this substituent.
This reaction readily allows an efficient synthesis of stanny-
lated, unsymmetrical 1,2-diaryl olefins 2, which can be further
transformed to variously substituted stilbenoid olefins. The
latter are an interesting class of compounds, not only be-
cause of their occurrence as natural and biologically active
substances,[3] but also for their interesting physical proper-
ties.[4]
Recently, we reported the effect of ortho substituents on
the regioselectivity in the hydrostannylation of aryl-substi-
tuted alkynes.[5] It then occurred to us that this unprecedented
ortho-directing effect (ODE) could be extended to control the
regiochemistry of the reaction of unsymmetrical diaryl (or
heteroaryl) alkynes 1. Initially, we examined the hydrostan-
nylation of diaryl alkynes bearing a para p-electron-with-
drawing group, which induces strong polarization of the
carbon carbon triple bond. Thus, reaction of 1a with Bu3SnH
in the presence of 1% [PdCl2(PPh3)2] in THF gave 2a in 75%
yield as a single isomer, through an exclusive syn addition
(entry 1, Table 1). This regioselectivity is expected as the
palladium-catalyzed hydrostannylation of electron-deficient
alkynes formally proceeds by conjugate addition of the
hydride.[1c] In contrast to 1a, hydrostannylation of diaryl
alkyne derivatives 1b and 1c, which have a formyl or an
ethoxycarbonyl group (less powerful p-electron-withdrawing
groups than the NO2 moiety) in the para-position of the
phenyl group, was less regioselective and gave a regioisomeric
mixture with a preference for 2b c over 3b c (entries 2 and
3). In the case of alkyne 1d, which contains a para s-electron-
donating group (R ˆ p-CH2OH, entry 4), the tributyltin
hydride does not discriminate in its addition between the
two carbon atoms of the triple bond, because the electronic
effects of substituent groups through the aromatic ring appear
to be minimal, and the reaction provided an inseparable 1:1
mixture of vinyl stannanes 2d and 3d. However, when the
reaction was carried out with alkynes 1e g[6] with an ortho
substituent, regardless of the electronic nature of the sub-
stituent (p-electron-withdrawing group: entries 5 and 6, or s-
electron-donating group: entry 7) a total selectivity was
obtained in favor of the a isomers 2e g (Bu3Sn group being
a relative to the ortho-substituted aryl moiety, selectivity
a:b ˆ 100:0, entries 5, 6, and 7). Stereoisomers 3e g were not
1
detected by H NMR analysis in the crude reaction mixture.
From alkynes 1e and 1 f, a reasonable explanation of the
remarkable level of regioselectivity lies in the electronic
effects of ortho p-electron-withdrawing groups together with
a possible intramolecular chelation between the palladium
center and the heteroatom. However, the result obtained
from alkyne 1g with an ortho s-electron-donating group
strongly indicates that this a selectivity could not be con-
trolled by the electronic effects of substituents.
Hydrostannylation of various unsymmetrical ortho-substi-
tuted diaryl alkynes, as well as of alkynes bearing a pyridyl
moiety, was examined (Table 2). Total regioselectivity toward
the formation of the a isomers 2 was obtained from diaryl (or
heteroaryl) alkynes 1h l (entries 1 to 5, Table 2) bearing an
ortho benzylic substituent with a heteroatom or an ortho ha-
lide substituent, except in the case of 1m where small amounts
of b isomer 3m were formed (R ˆ o-OMe, a:b 90:10, en-
try 6).[10] It is worth noting that the presence of an ortho
benzylic substituent with a heteroatom or an ortho halide
substituent on the aryl ring is not crucial to obtain regiose-
lective addition of Bu3SnH. Thus, hydrostannylation of 1o,
which bears an ortho methyl substituent, resulted mainly in
[*] Dr. M. Alami, F. Liron, M. Gervais, Dr. J.-F. Peyrat,
Prof. Dr. J.-D. Brion
BioCIS
¬
Laboratoire de Chimie Therapeutique CNRS UPRES-A 8076
¬
¬
Universite Paris XI, Faculte de Pharmacie
¬
√
rue J.B. Clement, 92296 Chatenay Malabry Cedex (France)
Fax : (‡33)1-4683-5828
E-mail: mouad.alami@cep.u-psud.fr
[**] ADIR (Servier Group) is gratefully acknowledged for a doctoral
fellowship to M.G. We also thank the CNRS for support of this
research and M. Ourevitch for the NMR analysis.
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1433-7851/02/4109-1578 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 9

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Table 2. Synthesis of various stannylated stilbene derivatives and related
compounds.[a]
the formation of the a adduct 2o (a:b 93:7, entry 8),
although no stabilizing effect can occur between the Pd
atom and the methyl substituent. On the other hand, the
reaction with the corresponding alkyne with a methyl group
in the para position gives almost a 1:1 mixture of the two
regioisomeric adducts. More interestingly, the presence of
bulky substituents in the diaryl alkyne derivatives (1n: R ˆ
OBn, entry 7or 1p: R ˆ iPr, entry 9) does not affect the
hydrostannylation reaction and gives a adducts 2n and 2p
selectively, in good yields (76 81%), without any b adduct.
Finally, the addition of Bu3SnH also proved to be regiose-
lective with alkyne 1q, in which the aromatic substituent on
the triple bond is a 1-naphthyl group (entry 10).
The regiochemical outcome for the selective formation of
a adducts was established as follows. First, we showed that
both sequences hydrostannylation reduction (Path AB,
Scheme 1) and reduction hydrostannylation (Path BA,
Scheme 1) of 1e and 1i, which have an ortho electron-
withdrawing group, afforded the same a regioisomer 2g and
2h, respectively. Further evidence for the regioselectivity of
compound 2g was obtained by its conversion into 4-benzy-
lidene-2-benzopyran-3-one 5 by an intramolecular lactoni-
zation of the ester 4, which was readily obtained from 2g,
according to Scheme 1.
Entry
Diaryl alkyne[b]
1
Vinyl stannane[c]
2
Yield[d]
[%]
1
81
2
3
90
91
4
60
5
85
The results obtained in the case of ortho-substituted diaryl
alkynes 1 show that the preferential attack of the tin atom
occurs mainly and sometimes exclusively at the Ca atom,
regardless of the electronic nature of the ortho substituent
(compare hydrostannylation of 1e and f with 1g; Table 1 and
1h with 1i; Table 2). This ODE can not be explained by only
chelation between the palladium atom and the group
containing the heteroatom, because ortho alkyl derivatives
exhibit very high selectivity (entries 8 and 9, Table 2).
Moreover, our results also suggest that the reaction is not
governed by steric effects, as an increase in the size of the
ortho substituent resulted in an exclusive a selectivity
(compare hydrostannylation of 1m with 1n entries 6 and 7,
Table 2, and 1o with 1p entries 8 and 9, Table 2). There may
be others factors in the reaction which account for the
observed regiochemistry. We found that ortho substituents
induced dramatic variations in the 13C NMR chemical shifts
of the triple bond.[11] Table 3 summarizes the difference
(DdCb-Ca) values found for the considered ortho- and para-
substituted diaryl alkynes 1. Thus, ortho-substituted alkynes
6
94[e]
7
81
8
91[e]
9
76
10
67
[a] All the reported compounds exhibited spectral data in agreement with
assigned structures. The regiochemistry of entries 4 and 8 was established by
comparison of compounds 2k and 2o with samples obtained by the following
sequence: 1) reaction of 2g with CBr4, PPh3 in
CH2Cl2 followed by amination[7] (Et2NH, K2CO3,
KI, MeCN) of the corresponding bromide afforded
2k. 2) Reduction of this bromide with NaBH4 in
DMSO[8] led to 2o. Regiochemical assignment of
entry 3 was made as follows: 2j showed the same
1H NMR spectra with sample obtained by condensa-
tion of 2e with EtMgBr. On the basis of these results,
the regiochemistry shown was assumed for the
products of entries 5 7, 9, and 10. [b] Diarylalkynes
1 were prepared according to ref. [9]. [c] All the
compounds reported herein exhibited J values for the
Sn H coupling ranging from 60 70 Hz which are
typical for cis configurations. [d] Yields are given for
pure isolated products. [e] Isolated yields of insepa-
rable mixture of regioisomers. Regioselectivity:
2m:3m 90:10, 2o:3o 93:7, as determined by
1H NMR spectra of the crude reaction mixture.
Scheme 1. Synthesis of tricycle 5. Reagents and conditions: a) Bu3SnH (1.1 equiv),
[PdCl2(PPh3)2] (1%), THF, 208C, 30 min (2e: 95%, 2i: 90%, 2g: 95%, 2h: 81%); b) NaBH4,
MeOH, À208C (1g: 7 4%,1h: 7 0%,2g: 67 %,2 h: 7 8%); c)tBuMe2SiCl (1.2 equiv), imidazole,
DMF, 208C, 80%; d) 1) nBuLi (1.1 equiv), THF, À408C, 0.5 h; 2) (EtO)2CO, THF,
À788C !208C, 1 h, 57%; e) nBu4NF (1.2 equiv), THF, 08 !208C, 60%.
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13
ꢀ
Table 3. Comparative chemical shifts ( C NMR) of C C in ortho- and para-substituted diaryl alkynes 1.
Experimental Section
Entry
Ratio[a] 2a:2b
13C shifts[b] (Æ0.05 ppm)
DdCb-Ca
2g: Tributyltin hydride (11 mmol, 2.95 mL)
was added dropwise at room temperature to a
solution of [PdCl2(PPh3)2] (0.1 mmol, 71 mg)
and alkyne 1g (10 mmol, 2.08 g) in THF
(15 mL). The dark brown reaction mixture
was stirred for an additional 15 min and then
concentrated in vacuo. Purification by flash
chromatography on silica gel (petroleum
ether:AcOEt 80:20 gave 4.74 g (95%) of
pure 2g. 1H NMR (270 MHz, CDCl3): d ˆ
7.31 (d, 1H, J ˆ 7.6 Hz), 7.19 to 6.84 (m,
8H), 6.63 (s, 1H, JH-Sn ˆ 65 Hz), 1.47to
1.11 (m, 13H), 0.96 to 0.71 (m, 15H);
dCa
dCb
1
2
3
4
5
6
7
8
9
1s: R ˆ p-Me
50:50
93:788.6
(40:60)[c]
90:10
50:50
100:0
75:25
100:0
85:15
100:0
89.6
88.7
À 0.9
À 1.3
À 0.3
1o: R ˆ o-Me
93.6
5.0
7
1r: R ˆ p-OMe
1m: R ˆ o-OMe
1d: R ˆ p-CH2OH
1g: R ˆ o-CH2OH
1c: R ˆ p-CO2Et
1f: R ˆ o-CO2Et
1b: R ˆ p-CHO
1e: R ˆ o-CHO
89.4
88.1
85.793.4
89.789.4
86.794.0
88.6
88.2
88.5
.7
.3
7
92.2
94.1
93.3
96.3
3.6
5.9
4.8
10
84.9
11.4
1
13C NMR (67.5 MHz, CDCl ): d ˆ 148.7,
[a] Ratios were determined by H NMR spectra of the crude reaction mixture. [b] Shifts are relative to
external CDCl3. The assignment of the 13C NMR chemical shifts of the triple bond was established by
HMBC and HSQC NMR spectroscopy. [c] Interchangeable ratio.
3
143.6, 138.9, 137.1, 134.9, 128.6, 128.2, 127.9,
127.8, 127.1, 126.0, 125.6, 63.2, 28.2, 27.3, 13.6,
10.2.
Received: December 10, 2001 [Z18354]
1e and 1 f, in comparison to the para derivatives (1b and 1c),
[1] For a recent review on metal-catalyzed hydrostannylations, see:
showed that the presence of an ortho p-electron-withdrawing
group induces strong electronic polarization of the carbon
carbon triple bond, which makes the Cb atom more electron
positive and the Ca atom more electron negative (i.e. the
signal arising from the Cb atom is 3.0 ppm upfield and the
signal from the Ca atom is 3.6 ppm downfield when 1b and 1e
are compared). More interestingly, for alkynes 1g, 1m, and 1o
in comparison with the para derivatives (1d, 1r, and 1s), the
presence of an ortho s-electron-donating group induced an
inversion of the polarization of the carbon carbon triple
bond (the Ca atom becomes more electron rich than the Cb
atom). This is illustrated by the change of sign of
DdCb-Ca values in ortho-substituted alkynes, which becomes
positive rather than negative in the para derivatives. In
Table 3, the presence of a methyl substituent in the ortho po-
sition increases the difference in the 13C NMR chemical shift
of the signals arising from the DdCb-Ca atom from À0.9 ppm
(for the DdC atom of the para-substituted aryl alkyne 1s) to
5.0 ppm (1o; entries 1 and 2, Table 3). A similar situation was
noted when comparing various ortho- and para-substituted
diaryl alkynes 1 (Table 3). We believe that this electronic
polarization may be responsible for the remarkable regiose-
lectivity observed, and therefore the hydride (H-PdSnBu3)
preferentially adds to the more electron-deficient terminus of
the alkyne. To our knowledge, this reflection of the electronic
effect of ortho substituents across the triple bond in the
13C NMR spectra has never been reported.
In summary, we have demonstrated, for the first time, that a
wide variety of unsymmetrical diaryl alkynes can undergo
regioselective hydrostannylation when the diaryl alkyne is
ortho substituted, regardless of the electronic nature of the
substituent. Additionally, we showed for the first time that this
ortho substituent induced dramatic electronic polarization of
the carbon carbon triple bond of the diaryl alkyne, which
was presumably responsible for the a regioselectivity ob-
served. The synthetic methodology described not only pro-
vides an easy access to stannylated-stilbene derivatives that
are not easily prepared by other routes, but also will open up
significant possibilities for performing various regioselective
hydro- and carbo-metallation reactions of unsymmetrical
diaryl (or heteroaryl) alkynes.
a) N. D. Smith, J. Mancuso, M. Lautens, Chem. Rev. 2000, 100, 3257
¬
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¬
29, 619 622; c) H. X. Zhang, F. Guibe, G. Balavoine, J. Org. Chem.
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[2] The hydrostannylation of diphenylacetylene has been reported see:
a) J. C. Cochran, B. S. Bronk, K. M. Terrence, H. K. Phillips, Tetrahe-
dron Lett. 1990, 31, 6621 6624; b) N. Asao, J. X. Liu, T. Sudoh, Y.
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Gevorgyan, J. X. Liu, Y. Yamamoto, J. Chem. Soc. Chem. Commun.
1998, 37 38; For the stannylcupration of diphenylacetylene, see:
d) A. Barbero, P. Cyadrado, I. Fleming, A. M. Gonzalez, F. J. Pulido, J.
Chem. Soc. Chem. Commun. 1992, 351 353; e) C. H. Cummins, E. J.
Gordon, Tetrahedron Lett. 1994, 35, 8133 8136.
[3] a) K. S. Huang, M. Lin, L. N. Yu, M. Kong, Tetrahedron 2000, 56,
1321 1329; b) M. Medarde, A. Ramos, E. Caballero, R. P. L.
de Clairac, J. L. Lopez, D. G. Gravalos, A. S. Feliciano, Eur. J. Med.
Chem. 1998, 33, 71 77; c) C. H. Cummins, Synth. Commun. 1995, 25,
4071 4079, and references therein; d) K. Ohsumi, R. Nakagawa, R.
Fuduka, T. Hatanaka, Y. Morinaga, Y. Nihei, K. Ohishi, Y. Suga, Y.
¬
Akiyama, T. Tsuji, J. Med. Chem. 1998, 41, 3022 3032; e) J. C. Dore, J.
Gilbert, E. Bignon, A. C. de Paulet, T. Ojasoo, M. Pons, J. P. Raynaud,
J. F. Miquel, J. Med. Chem. 1992, 35, 573 583.
[4] a) H. Meier, M. Lehmann, Angew. Chem. 1998, 110, 666 669; Angew.
Chem. Int. Ed. 1998, 37, 643 645; b) W. R. Young, A. Aviram, R. J.
Cox, J. Am. Chem. Soc. 1972, 94, 3976 3981.
[5] F. Liron, P. Le Garrec, M. Alami, Synlett 1999, 246 248.
[6] Under radical conditions (azobisisobutyronitrile, 808C), hydrostan-
nylation of 1g gave a mixture of all four regio- and stereoisomers in
52% yield.
[7] R. A. T. M. Van Benthem, J. J. Mitchels, H. Hiemstra, W. N. Speck-
amp, Synlett 1994, 368 370.
[8] H. Lee, R. G. Harvey, J. Org. Chem. 1986, 51, 3502 3507.
[9] M. Alami, F. Ferri, G. Linstrumelle, Tetrahedron Lett. 1993, 34, 6403
6406.
[10] Performing the hydrostannylation of diaryl alkyne 1r (see Table 3)
with a methoxy group in the para position of the phenyl group
produced a 40:60 mixture of geometric isomers.
[11] The 13C NMR chemical shifts are proportional to the electron density
of carbon, see: D. J. Sardella, J. Am. Chem. Soc. 1973, 95, 3809 3811.
1580
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4109-1580 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 9