Indium-mediated alkynylation of Baylis-Hillman acetates: a novel route to 1,4-enynes

Article abstract of DOI:10.1016/j.tetlet.2008.08.019

Baylis-Hillman acetates undergo smooth alkynylation with aryl-susbstituted iodoalkynes in the presence of indium metal in refluxing dichloromethane to furnish 1,4-enynes in high yields with (E)-stereoselectivity. In the absence of Lewis acid, the reaction follows both S_N2 and S_N2′ pathways affording 1:1 mixtures of 1,4-enynes. Upon addition of 10 mol % of InBr₃, the reaction proceeds preferably in the S_N2′ manner. In the case of adducts derived from acrylonitrile, the corresponding products are obtained in fairly good yields and with (Z)-stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2008.08.019

Tetrahedron Letters 49 (2008) 6090–6094
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium-mediated alkynylation of Baylis–Hillman acetates:
a novel route to 1,4-enynes
*
Jhillu S. Yadav , Basi V. Subba Reddy, Nagendra Nath Yadav, Ashutosh Pratap Singh,
Madavi Choudhary, Ajit C. Kunwar
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Baylis–Hillman acetates undergo smooth alkynylation with aryl-susbstituted iodoalkynes in the presence
of indium metal in refluxing dichloromethane to furnish 1,4-enynes in high yields with (E)-stereoselec-
tivity. In the absence of Lewis acid, the reaction follows both SN2 and SN20 pathways affording 1:1 mix-
tures of 1,4-enynes. Upon addition of 10 mol % of InBr3, the reaction proceeds preferably in the SN20
manner. In the case of adducts derived from acrylonitrile, the corresponding products are obtained in
fairly good yields and with (Z)-stereoselectivity.
Received 19 June 2008
Revised 25 July 2008
Accepted 3 August 2008
Available online 8 August 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Indium reagents
SN20 substitution
Allylic acetates
1,4-Enynes
Baylis–Hillman adducts and their acetates are well known car-
bon electrophiles capable of reacting with various nucleophiles.
Their ability to undergo SN20 allylic substitution reactions contri-
butes largely to their synthetic value.1 The ready availability and
versatility of Morita–Baylis–Hillman adducts makes them valuable
synthetic intermediates for the synthesis of a variety of hetero-
cycles such as quinolines, pyrimidones, isoxazolines, pyrazolones,
pyrrolidines, indolizines, azetidinones, diazacyclophanes and
chromanones as well as biologically active natural products inclu-
ates.3–7 However, there have been no reports on the allylic substi-
tution of Baylis–Hillman acetates with alkynylindium reagents to
produce 1,4-enynes.
Indium has emerged as a very useful metal in organic synthesis
as it possesses certain unique properties. Indium metal is
unaffected by air or oxygen at ambient temperatures and can be
handled safely without any apparent toxicity. In addition, indium
exhibits low heterophilicity in organic reactions, and thus oxygen-
and nitrogen-containing functional groups are usually well
tolerated by organoindium reagents.8 Moreover, indium-assisted
reactions display low nucleophilicity thus permitting chemoselec-
tive transformations of groups of similar reactivity.9
ding
a-alkylidene-b-lactams, a-methylene-c-butyrolactones and
mikanecic acids, frontalin, trimethoprim, sarkomycin, ilmofosine
nuciferol and many others.1,2 Consequently, various nucleophiles
such as allylzinc reagents, metal hydrides, halides, azides, cyanides,
alcohols, amines, arenes, indoles and active methylene compounds
have been used to prepare a wide range of synthetic intermedi-
In this Letter, we report a versatile approach for the preparation
of 1,4-enynes by means of allylic nucleophilic substitution of
Baylis–Hillman acetates with iodophenyl acetylenes using the
Ph
OAc
CO2Me
CO2Me
Indium/InBr3
CH2Cl2, reflux
CO2Me
Ph
I
+
+
Ph
1
2
(E
)-isomer
4a
3a
Scheme 1. Preparation of 3a/4a.
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J. S. Yadav).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.019

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 6090–6094
6091
Table 1
Indium/InBr3-promoted alkynylation of Baylis–Hillman acetates with iodophenylacetylenes
Entry
Acetate 1
Iodoalkyne 2
Producta
3
Time (h)
7.0
Yieldb (%)
Ratio (3:4)c
I
CO2Me
OAc
CO2Me
a
85
80:20
I
CO2Me
OAc
CO2Me
O2N
b
6.0
8.0
7.5
91
92
83
90:10
90:10
80:20
O2N
I
CO2Me
OAc
CO2Me
Cl
c
Cl
I
CO2Me
OAc
CO2Me
MeO
d
MeO
I
CO2Me
OAc
OAc
OAc
CO2Me
Cl
e
10.0
86
91
93
75:25
65:35
70:30
Cl
I
CO2Me
Cl
CO2Me
f
5.0
Cl
I
CO2Et
Me
CO2Et
g
4.5
Me
I
I
CO2Et
OAc
OAc
CO2Et
Me
h
8.5
7.5
87
96
80.20
Me
CO2Me
CO2Me
Cl
i
95:5
Cl
Cl
Cl
(continued on next page)

6092
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 6090–6094
Table 1 (continued)
Entry
Acetate 1
Iodoalkyne 2
Producta
3
Time (h)
5.0
Yieldb (%)
90
Ratio (3:4)c
I
OAc
Co2Me
CO2Me
j
80.20
F
F
I
I
CO2Me
OAc
CO2Me
MeO
k
8.0
87
72
85:15
65:35
MeO
OAc
CN
l
10.0
CN
I
I
I
OAc
CN
m
12.0
70
82
70
60:40
90:10
60:40
CN
Me
Me
OAc
CN
n
9.0
CN
F
F
OAc
CN
o
13.0
CN
Cl
Cl
a
The products were characterized by NMR, IR and mass spectrometry.
Yield refers to pure products after chromatography.
Ratio of products 3 and 4 was determined from the NMR spectra of the crude products.
b
c
In/InBr3 reagent system. Thus, treatment of the Baylis–Hillman
acetate derived from benzaldehyde and methyl acrylate, methyl
3-acetoxy-2-methylene-3-phenylpropanoate (1) with 2 equiv of
iodophenylacetylene (2) and 2 equiv of indium metal in the pres-
ence of 10 mol % InBr3 in refluxing dichloromethane gave the cor-
responding enyne product in 85% yield as a mixture of 3a and 4a in
an 8:2 ratio favouring 3a (Scheme 1).
1H NMR spectrum.10 The structure of 3f was established by
two-dimensional nuclear Overhauser effect spectroscopy (NOESY,
Fig. 1).
H
O
H
The products 3a and 4a could be separated easily by column
chromatography. In the absence of InBr3, 3a and 4a were obtained
in a 1:1 ratio. The ratio was determined by 1H NMR spectroscopy of
the crude product. Thus, the addition of 10 mol % of InBr3 is crucial
to achieve the desired product 3a predominantly. Other indium(III)
halides such as InCl3 and InI3 can also be used for this conversion.
Similarly, various aryl-substituted Baylis–Hillman acetates reacted
smoothly with iodophenylacetylene to provide (E)-methyl 2-benz-
ylidene-5-phenylpent-4-ynoate derivatives in good to excellent
yields and with complete (E)-selectivity (entries b, c and i, Table
1). The (E)-stereochemistry of the product 3a was assigned on
the basis of the chemical shift value of the olefinic proton in the
o
m
OMe
H2C
H
o
Cl
m
o'
m'
o'
m'
H
Me
Me
Me
Figure 1. Characteristic nOe’s of 3f.

J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 6090–6094
6093
Ph
Ph
OAc
CN
CN
In/InBr3
Ph
I
+
+
CH2Cl2, reflux
CN
3l (Z
)-isomer
4l
Scheme 2. Preparation of 3l/4l.
0
The nOe correlations, CH–Hortho and t-butyl-Hmeta , were suffi-
cient for assigning the aromatic resonances. The cis orientation of
the two aromatic substituents across the double bond was inferred
from a strong nOe cross peak between CH2 and Hortho. Additional
support for the proposed structure came from a weak nOe correla-
tion between CH2 and CH, being trans to each other. This result
provided incentive for an extensive study. Interestingly, various
aryl-substituted iodophenylacetylenes also participated in this
reaction (entries d, e, f and g, Table 1). However, reaction of the
Baylis–Hillman acetates derived from acrylonitrile, that is, 3-acet-
oxy-2-methylene-3-phenylpropionitrile, with iodophenylacety-
lene gave the product as a mixture of 3l and 4l favouring 3l
(Scheme 2).
try. Furthermore, the reactions were carried out with Baylis–Hill-
man adducts (hydroxy compounds) instead of acetates. Even
though the reactions succeeded with hydroxy compounds, low
conversions (20–45%) were obtained even after long reaction
times. The best results were obtained with Baylis–Hillman ace-
tates. As solvent, dichloromethane gave the best results. In the ab-
sence of indium metal, no nucleophilic substitution occurred even
after long reaction times (9–12 h) under reflux conditions. The
scope of this method was investigated with respect to various
allylic acetates, and the results are presented in Table 1.11 The
observation of (E)-selectivity with esters and (Z)-selectivity with
nitriles is consistent with earlier reports.12 The reversal of stereo-
chemistry may be attributed to the chelated structure, in the case
of ester leading to (E)-product and to non-chelated structure, in the
case of nitriles leading to (Z)-product (Scheme 3).
In conclusion, we have described a novel method for the prep-
aration of 1,4-enynes from Baylis–Hillman acetates and iodophen-
ylacetylenes via SN20 type allylic substitution. The method has
several advantages such as operational simplicity, mild reaction
conditions, clean reaction profiles and simple experimental and
work-up procedures which makes it a useful and attractive process
for the preparation of 1,4-enynes.
In the case of 3-acetoxy-2-methylene-3-aryl propionitriles, the
products were obtained with (Z)-stereoselectivity. The (Z)-stereo-
chemistry of the products was assigned on the basis of the chem-
ical shift value of the olefinic proton in the 1H NMR spectrum.10
The structure of 3m was established by nOe experiments
(Fig. 2).
The resonance assignments of the aromatic groups were facili-
tated by the nOes between Me–Hmeta and CH–Hortho. The presence
of a strong nOe correlation between the CH and CH2 protons
implies that they are cis to each other. In this geometry, unlike
3f, the CH2 and the Hortho distance is large and no nOe cross peak
is observed between CH2 and Hortho. The reactions were clean and
highly stereoselective affording the products in good yields. The
products were characterized by 1H NMR, IR and mass spectrome-
Acknowledgement
N.N.Y. and A.P.S. thank CSIR, New Delhi, for the award of
fellowships.
References and notes
1. Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811.
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Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653.
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Kim, J. M.; Kim, J. N. Tetrahedron 2003, 59, 385; (c) Im, Y. J.; Lee, K. Y.; Kim, T. H.;
Kim, J. N. Tetrahedron Lett. 2002, 43, 4675.
4. (a) Kim, J. N.; Kim, J. M.; Lee, K. Y. Synlett 2003, 821; (b) Kim, J. N.; Kim, H. S.;
Gong, J. H.; Chung, Y. M. Tetrahedron Lett. 2001, 42, 8341.
5. (a) Drewes, S. E.; Emslie, N. D. J. Chem. Soc., Perkin Trans. 1 1982, 2079; (b)
Hoffmann, H. M. R.; Rabe, J. Helv. Chim. Acta 1984, 67, 413; (c) Hoffmann, H. M.
R.; Rabe, J. J. Org. Chem. 1985, 50, 3849.
H
H
H2
C
o
m
o'
m'
p'
CN
o
Me
m
o'
H
m'
Figure 2. Characteristic nOe’s of 3m.
In(III)
O
O
Nu
O
Ac
Ar
SN2
OAc O
InBr3
O
Ar
OR
Nu
3a
Ar
OR
Ar
OR
+
OR
4a
SN2'
(-)
Nu
+
O
-
In(III)
Nu
Nu
OAc
InBr3
O
CN
CN
Ar
Ar
+
Ar
CN
CN
3l
Ar
4l
SN2'
SN2
(-)
Nu
Scheme 3. A plausible reaction mechanism.

6094
J. S. Yadav et al. / Tetrahedron Letters 49 (2008) 6090–6094
6. (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94; (b)
Buchholz, R.; Hoffmann, H. M. R. Helv. Chim. Acta 1991, 74, 1213; (c) Ameer, F.;
Drewes, S. E.; Hoole, R. F. A.; Kaye, P. T.; Pitchford, A. T. J. Chem. Soc., Perkin
Trans. 1 1985, 2713.
7. (a) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V.; Prabhakar, A.;
Jagadesh, B. Tetrahedron Lett. 2005, 46, 639; (b) Srihari, P.; Singh, A. P.; Basak, A.
K.; Yadav, J. S. Tetrahedron Lett. 2007, 48, 5999.
527 cmꢁ1 1H NMR (300 MHz, CDCl3): d 8.32 (d, J = 8.3 Hz, 2H), 7.78 (s, 1H),
;
7.74 (d, J = 8.3 Hz, 2H), 7.40–7.26 (m, 5H), 3.91 (s, 3H), 3.55 (s, 2H); 13C NMR
(75 MHz, CDCl3): d 166.8, 141.3, 137.9, 134.3, 131.6, 130.3, 129.0, 128.0, 126.0,
123.7, 123.2, 85.8, 81.8, 52.6, 18.7; LCMS: m/z: 322 (M+H+), 279, 258, 161, 133,
102; HRMS calcd for C19H15NO4Na: 344.0898, Found: 344.0912. Compound 3f:
Viscous liquid, IR (KBr):
m
2957, 2924, 2853, 1717, 1633, 1491, 1462, 1436,
1274, 1213, 1088, 834, 762, 562 cmꢁ1
;
1H NMR (500 MHz, CDCl3): d 7.73 (s, 1H,
8. (a) Phil, H. L. Bull. Korean Chem. Soc. 2007, 28, 17; (b) Podlech, J.; Maier, T. C.
Synthesis 2003, 633.
CH), 7.53 (d, J = 8.6 Hz, 2H, ortho), 7.40 (d, J = 8.6 Hz, 2H, meta), 7.33 (d,
J = 8.5 Hz, 2H, ortho0), 7.30 (d, J = 8.5 Hz, 2H, meta0), 3.87 (s, 3H, CO2Me), 3.56 (s,
2H, CH2), 1.30 (s, 9H, 3 ꢀ Me). 13C NMR (75 MHz, CDCl3): d 167.5, 151.1, 139.2,
135.0, 133.4, 131.3, 131.0, 128.8, 128.5, 125.1, 120.4, 85.8, 81.3, 52.3, 34.6,
31.1, 18.7; LCMS: m/z: 367 (M+H+). HRMS calcd for C23H23O2ClNa: 389.1284,
9. (a) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347; (b) Yadav, J. S.; Reddy, B. V. S.;
Reddy, K. S.; Reddy, K. B. Tetrahedron Lett. 2002, 43, 1549; (c) Yadav, J. S.;
Bandyopadhyay, A.; Reddy, B. V. S. Tetrahedron Lett. 2001, 42, 6385; (d) Yadav, J.
S.; Anjaneyulu, S.; Moinuddin Ahmed, Md.; Subba Reddy, B. V. Tetrahedron Lett.
2001, 42, 2557; (e) Yadav, J. S.; Bandyopadhyay, A.; Reddy, B. V. S. Synlett 2001,
1608; (f) Yadav, J. S.; Reddy, B. V. S.; Vishnumurthy, P.; Biswas, S. K. Tetrahedron
Lett. 2007, 48, 6641.
10. (a) Mandal, S. K.; Paira, M.; Roy, S. C. J. Org. Chem. 2008, 73, 3823; (b) Basavaiah,
D.; Sarma, P. K. S.; Bhavani, A. K. D. J. Chem. Soc., Chem. Commun. 1994, 1091.
11. General procedure: To a stirred suspension of indium metal (2.0 mmol) in
dichloromethane was added a solution of Baylis–Hillman acetate (1 mmol),
iodophenylacetylene (2.0 mmol) and InBr3 (10 mol %) in dichloromethane at
room temperature. The resulting mixture was stirred at room temperature for
2 h and then at reflux for 6–12 h. After complete conversion as indicated by
TLC, the reaction mixture was quenched with water (10 mL) and extracted
with dichloromethane (2 ꢀ 15 mL). The combined extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo. The resulting product was
purified by column chromatography on silica gel (Merck, 100–200 mesh, ethyl
acetate-hexane, 1:50) to afford pure product. Spectroscopic data for selected
Found: 389.1298. Compound 3j: Viscous liquid, IR (KBr):
m
2923, 2853, 1715,
1638, 1508, 1438, 1270, 1225, 1160, 1083, 836, 756, 692, 523 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d 7.73 (s, 1H), 7.58 (dd, J = 5.2, 8.3 Hz, 2H), 7.41–7.23 (m,
5H), 7.12 (t, J = 8.3 Hz, 2H), 3.87 (s, 3H), 3.56 (s, 2H); 13C NMR (75 MHz, CDCl3):
d 167.5, 164.6, 161.3, 139.5, 131.7, 131.6, 128.1, 127.8, 123.6, 115.8, 115.6,
86.7, 81.1, 52.3, 22.6, 18.6; LCMS: m/z: 317 (M+Na), 295, 232; HRMS calcd for
C
19H15FO2Na: 317.0953, Found: 317.0938. Compound 3m: Viscous liquid; IR
(KBr): 3028, 2923, 2854, 2210, 1726, 1604, 1510, 1490, 1446, 1416, 1378,
1261, 1183, 1067, 1027, 912, 813, 757, 693, 528 cmꢁ1 1H NMR (500 MHz,
m
;
CDCl3): d 7.67 (d, J = 8.2Hz, 2H, ortho), 7.47 (m, 2H, ortho0), 7.40 (m, 3H, meta0,
para0), 7.31 (t, J = 1.7 Hz, 1H, CH), 7.23 (d, J = 8.2 Hz, 2H, meta), 3.56 (d,
J = 1.7 Hz, 2H, CH2), 2.39 (s, 3H, Me); 13C NMR (75 MHz, CDCl3): d 144.2, 140.7,
131.7, 130.5, 129.5, 128.7, 128.5, 128.3, 122.7, 118.4, 104.9, 85.6, 83.0, 26.2,
21.4; LCMS: m/z: 258 (M+H+), 221, 102; HRMS calcd for C19H15NNa: 280.1102,
Found: 280.1104.
12. (a) Gowrisankar, S.; Lee, K. Y.; Lee, C. G.; Kim, J. N. Tetrahedron Lett. 2004, 45,
6141; (b) Ranu, B. C.; Chattopadhyay, K.; Jana, R. Tetrahedron Lett. 2007, 48,
3847.
products: Compound 3b: Yellow viscous liquid IR (KBr):
m 2925, 2853, 1717,
1597, 1519, 1490, 1439, 1345, 1297, 1268, 1219, 1087, 917, 853, 756, 693,