Chemo-, regio- and stereoselective addition of triorganoindium reagents to acetates of Baylis-Hillman adducts: a new strategy for the synthesis of (E)- and (Z)-trisubstituted alkenes

Article abstract of DOI:10.1016/j.tetlet.2007.03.154

The addition of several trialkyl or triarylindium reagents to the acetates of Baylis-Hillman adducts proceeds readily under the catalysis of copper and palladium derivatives. The reactions of trialkylindiums are catalyzed efficiently by CuI whereas additi

Full text of DOI:10.1016/j.tetlet.2007.03.154

Tetrahedron Letters 48 (2007) 3847–3850
Chemo-, regio- and stereoselective addition of triorganoindium
reagents to acetates of Baylis–Hillman adducts: a new strategy
for the synthesis of (E)- and (Z)-trisubstituted alkenes
Brindaban C. Ranu,* Kalicharan Chattopadhyay and Ranjan Jana
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 6 February 2007; revised 17 March 2007; accepted 28 March 2007
Available online 3 April 2007
Abstract—The addition of several trialkyl or triarylindium reagents to the acetates of Baylis–Hillman adducts proceeds readily
under the catalysis of copper and palladium derivatives. The reactions of trialkylindiums are catalyzed efficiently by CuI whereas
additions of triarylindiums produce better results with Pd(PPh3)4. The reactions with 3-acetoxy-2-methylenealkanoates provide
(E)-alkenes, whereas similar reactions with 3-acetoxy-2-methylenealkanenitriles lead to (Z)-alkenes. All the reactions are highly
regio- and stereoselective and high yielding.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The Baylis–Hillman reaction1 is a unique carbon–car-
bon bond forming reaction producing synthetically use-
ful multifunctional molecules having wide applications.2
Several reports3 have described the stereoselective
synthesis of trisubstituted alkenes using acetates of Bay-
lis–Hillman adducts. Some of these reported procedures
involve Grignard reagents,3a potassium organotrifluo-
roborates catalyzed by Pd(OAc)2,3b [Rh(Cod)Cl]2,3c
organosilanes in the presence of Pd2(dba)3,3d alkyl
halides in the presence of Zn/aqueous NH4Cl solution3e
and Friedel–Crafts reaction with benzene catalyzed by
concd H2SO4.3f However, these procedures have limita-
tions with regard to addition of either only alkyl3e or
aryl moieties,3b–f long reaction times3c,e and complexity
of the reagents.3b,c The increasing interest in organoin-
dium reagents because of their environmentally benign
characteristics and their synthetic utility for carbon–car-
bon bond formation has led to the development of sev-
eral new indium reagents.4 Triorganoindium has high
potential and has been found to be capable of participat-
ing in various reactions.5 As a part of our continued
activities in the area of indium-mediated reactions,6 we
report here a very efficient and convenient synthesis of
trisubstituted alkenes by the addition of trialkyl- or tri-
arylindium derivatives to the acetates of Baylis–Hillman
adducts catalyzed by CuI and Pd(PPh3)4 (Scheme 1).
The addition of triorganoindiums to allyl derivatives is
usually carried out using Pd-catalysts.5 Thus, in our ini-
tial attempts, the reaction of tributylindium with 2-
(acetoxy-phenyl-methyl)-acrylic acid methyl ester was
investigated with different Pd-catalysts such as
Pd(PPh3)4, Pd2(dba)3/PPh3 and Pd(OAc)2/PPh3. How-
ever, all these catalysts failed to transfer the alkyl group
to the olefinic moiety and a rearranged product (B)
(Table 1) was formed by nucleophilic hydride attack fol-
lowed by elimination of OAc. This may be explained by
the fact that b-H elimination is faster in an n-Bu moiety
than C–C bond formation under Pd-catalysis. However,
when the reaction was tried with Ph3In, product A was
formed rapidly by phenyl transfer under identical condi-
tions. In the search for a suitable catalyst for alkyl trans-
fer, we investigated Cu-catalysts following a report by
1
R
CuI
CO2Me
R= alkyl
OAc
R
R3In
CO2Me
1
R
THF, reflux
1
R
Pd(PPh3)4
CO2Me
Keywords: Triorganoindium; Baylis–Hillman adduct; Trisubstituted
alkene; Copper(I) iodide; Tetrakistriphenylphosphine palladium.
R= aryl, vinyl
1
R
aryl, alkyl.
R
=
*
Corresponding author. Tel.: +91 33 2473 4971; fax: 91 33 2473
2805; e-mail: ocbcr@iacs.res.in
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.154

3848
B. C. Ranu et al. / Tetrahedron Letters 48 (2007) 3847–3850
Table 1. Study of the effect of catalyst on the reaction of triorgano-
Table 2. Addition of trialkylindiums to acetates of Baylis–Hillman
indiums with 2-(acetoxy-phenyl-methyl)-acrylic acid methyl ester
adducts catalyzed by CuI
O
1
O
OAc
OAc
R
Ph
Ph
), R In
CuI (15 mol%
R In, Catalyst
3
THF, reflux
3
CO2Me
CO2Me
CO2Me
1
+
OMe
R
OMe
THF, reflux
Ph
R
H
R
Entry R1
R
Time (h) Yielda (%) Reference
A
B
Entry Catalyst
R
Yielda (%) Ratio of A:B
1
2
3
4
5
6
7
Ph
Ph
n-Bu 6.0
Me 5.0
n-Bu 6.5
n-Bu 5.5
n-Bu 5.0
82
60
78
75
80
75
85
3a
11
3e
1
Pd2(dba)3, PPh3
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Ph
50
45
72
82
75
20
10
—
—
—
70
—
—
0:100
0:100
0:100
100:0
100:0
100:0
100:0
—
—
—
100:0
—
—
p-MeO–C6H4
p-O2N–C6H4
p-Cl–C6H4
p-MeCO–C6H4 n-Bu 6.0
n-C3H7 n-Bu 5.5
2
3
4
Pd(OAc)2, PPh3
Pd(PPh3)4
CuI
5
6
7
CuBrÆSMe2
Cu(OTf)2
CuI
a Yields refer to those of pure isolated products fully characterized by
spectroscopic data.
8
CuI, BF3Æetherate Ph
9
Cu(OTf)2
CuCN
Pd(PPh3)4
CuI
Ph
Ph
Ph
Ph
Ph
10
11
12
13
The experimental procedure is very simple.7 Several
diversely substituted 3-acetoxy-2-methylenealkanoates
(acetates of Baylis–Hillman adducts)8 underwent very
easy reactions with trimethyl and tri-n-butylindiums9
in the presence of CuI to produce the corresponding
(E)-2-substituted alken-2-enoates. The results are sum-
marized in Table 2. The presence of electron donating
and electron withdrawing groups on the aromatic ring
of the adduct (entries 3 and 4, Table 2) did not make
any difference with regard to reactivity and yields of
products. The addition of trialkylindiums was also
highly chemoselective as the keto-carbonyl present in
the substrate in entry 6, Table 2 and entry 4, Table 3
remained intact even when excess trialkylindium was
Pd(PPh3)4
a Yields refer to those of pure isolated products characterized by IR,
1H and 13C NMR spectroscopic data.
Sarandeses5b in which Cu(OTf)2 was successfully used
for the cross coupling of trialkyl- and triarylindiums to
cinnamyl bromide although it did not work for cinn-
amyl acetate. We also found that Cu(OTf)2 was not very
efficient in tributylindium addition to a Baylis–Hillman
acetate, however, CuI produced very encouraging
results. Thus, it was decided to carry out the reactions
of trialkylindiums under CuI catalysis and those of tri-
arylindiums with Pd(PPh3)4.
Table 3. Addition of triarylindiums to acetates of Baylis–Hillman adducts catalyzed by Pd(PPh3)4
R1
Z = CO Me
2
OAc
CO2Me
Z
R3In, Pd(PPh3)4
THF, reflux
R
1
R
R1
Z = CN
CN
R
Entry
1
R1
Ph
Z
R
Time (h)
Yielda (%)
Ratio of E:Z isomers
Reference
3b
CO2Me
CO2Me
3.5
4.0
75
95:5
2
3
Ph
70
72
100:0
80:20
12
3d
p-Cl–C6H4
CO2Me
CO2Me
CN
3.0
4.0
3.5
3.2
3.5
4
5
6
7
p-MeCO–C6H4
70
72
75
70
90:10
0:100
0:100
5:95
p-Me–C6H4
Ph
CN
3b
13
Ph
CN
a Yields refer to those of pure isolated products fully characterized by spectroscopic data.

B. C. Ranu et al. / Tetrahedron Letters 48 (2007) 3847–3850
3849
used. It should be mentioned that no existing procedures
References and notes
have addressed the compatibility of carbonyl groups
present in the molecule.3
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2,155,113, 1972; Chem. Abstr. 1972, 77, 34174q.
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Rev. 2003, 103, 811–891, and references cited therein; (b)
Drewes, S. E.; Roos, G. H. P. Tetrahedron 1998, 44, 4653–
4670.
A number of triaryl- and trivinylindiums were subjected
to additions with several acetates of Baylis–Hillman ad-
ducts under the catalysis of Pd(PPh3)4 using this proce-
dure to provide the corresponding products. The results
are reported in Table 3. In accordance with the results
obtained by other groups,3 the acetates of Baylis–Hill-
man carboalkoxy adducts produced mainly (E)-alkenes
(entries 1–4, Table 3) whereas Baylis–Hillman nitrile
adducts led to (Z)-isomers (entries 5–7, Table 3)
exclusively, or stereoselectively. The stereochemistry of
the products was established by comparing NMR
parameters for the olefinic and methylene protons with
literature values.3 It was observed that small amounts
(2–5%) of the corresponding homocoupled prod-
ucts from triarylindiums were also formed in these
reactions.
3. (a) Basavaiah, D.; Sarma, P. K. S.; Bhavani, A. K. D.
Chem. Commun. 1994, 1091–1092; (b) Kabalka, G. W.;
Venkataiah, B.; Dong, G. Org. Lett. 2003, 5, 3803–3805;
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2006, 348, 317–322; (d) Kabalka, G. W.; Dong, G.;
Venkataiah, B.; Chen, C. J. Org. Chem. 2005, 70, 9207–
9210; (e) Das, B.; Banerjee, J.; Mahender, G.; Majhi, A.
Org. Lett. 2004, 6, 3349–3352; (f) Basavaiah, D.; Krish-
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Tetrahedron 1996, 52, 5643–5668; (c) Li, C.-J.; Chan, T. H.
Tetrahedron 1999, 55, 11149–11176; (d) Chauhan, K. K.;
Frost, C. G. J. Chem. Soc., Perkin Trans. 1 2000, 3015–
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(f) Ghosh, R. Indian J. Chem. 2001, 40B, 550–557; (g)
Podelech, J.; Maier, T. C. Synthesis 2003, 633–655; (h)
Nair, V.; Ros, S.; Jayan, C. N.; Pillai, B. S. Tetrahedron
2004, 68, 1959–1982.
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J. P.; Sarandeses, L. A. J. Am. Chem. Soc. 2001, 123,
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6. (a) Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000,
65, 6270–6272; (b) Ranu, B. C.; Hajra, A.; Jana, U.
Tetrahedron Lett. 2000, 41, 531–533; (c) Ranu, B. C.;
Samanta, S.; Hajra, A. Synlett 2002, 987–989; (d) Ranu, B.
C.; Das, A.; Samanta, S. Synlett 2002, 727–730; (e) Ranu,
B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58, 2529–
2532; (f) Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U.
Tetrahedron 2003, 59, 813–819; (g) Ranu, B. C.; Samanta,
S. J. Org. Chem. 2003, 68, 7130–7132; (h) Ranu, B. C.;
Das, A.; Hajra, A. Synthesis 2003, 1012–1014; (i) Ranu, B.
C.; Samanta, S. Tetrahedron 2003, 59, 7901–7906; (j)
Ranu, B. C.; Mandal, T.; Samanta, S. Org. Lett. 2003, 5,
1439–1441; (k) Ranu, B. C.; Mandal, T. J. Org. Chem.
2004, 69, 5793–5795; (l) Ranu, B. C.; Mandal, T. Synlett
2004, 1239–1242; (m) Ranu, B. C.; Das, A. Tetrahedron
Lett. 2004, 45, 6875–6877; (n) Ranu, B. C.; Jana, R.;
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In general, the reactions were high yielding. THF was
found to be the most suitable solvent and the reactions
were carried out under reflux. As is evident from the re-
sults, aryl transfer from the triarylindiums proceeded
smoothly under Pd-catalysis, whereas alkyl transfer oc-
curred via CuI catalysis. Although Pd-catalysis is well
documented,3,5 Cu-catalysis in alkyl additions to Bay-
lis–Hillman acetates is less explored. It may be assumed
that the trialkylindium undergoes transmetallation with
CuI and subsequently the organocuprate forms a p-
complex with the Baylis–Hillman acetate adduct in
which the cuprate fragment is bound anti to the acetate
moiety. Reductive elimination of alkylcopper through a
r-copper(III) species with retention of configuration
gives rise to the SN20 product.10 It is worth mentioning
that Cu(OTf)2-catalyzed coupling of triorganylindiums
to cinnamyl bromide provided both SN2 and SN20 prod-
ucts and that Cu(OTf)2 did not initiate addition to cinn-
amyl acetate. Significantly, this CuI-catalyzed reaction
led only to SN20 products.
In conclusion, we have developed a general and efficient
method for the addition of triorganoindiums to Baylis–
Hillman acetate adducts to provide (E)- and (Z)-trisub-
stituted alkenes stereoselectively. Substrates bearing car-
boalkoxy moieties produced (E)-alkenes, whereas those
having a nitrile group gave (Z)-alkenes. This protocol
is applicable to both alkyl and aryl transfer under CuI
and Pd(PPh3)4 catalysis, respectively. The use of trior-
ganoindiums in this addition reaction made this proce-
dure chemoselective being inert to carbonyl groups,
which is not likely to be achieved with Grignard
reagents.
Acknowledgements
We are pleased to acknowledge financial support from
the CSIR [Grant No. 01(1936)/04/EMR-1], New Delhi,
for this project. K.C. and R.J. also thank the CSIR for
their fellowships.
7. Representative procedure for the addition of tributylindium
to 2-[acetoxy-(4-acetylphenyl)-methyl]-acrylic acid methyl
ester (Table 2, entry 6). A solution of 2-[acetoxy-(4-
acetylphenyl)-methyl]-acrylic acid methyl ester (276 mg,

3850
B. C. Ranu et al. / Tetrahedron Letters 48 (2007) 3847–3850
1 mmol) and tributylindium (1.2 mmol) in THF (3 mL)
75 MHz) d 13.9, 22.2, 27.4, 28.7, 31.8, 51.9, 128.6 (2C),
130.3 (2C), 134.1, 134.2, 134.3, 137.2, 168.6. Anal. Calcd
for C15H19ClO2: C, 67.54; H, 7.18. Found: C, 67.49; H,
7.17.
was heated under reflux for 6 h (TLC) in the presence of
CuI (28 mg, 15 mol %). The reaction mixture was then
quenched with a few drops of H2O and extracted with
Et2O (3 · 6 mL). The extract was washed with aqueous
HCl (0.5 N), brine, water and dried over Na2SO4. Evap-
oration of the solvent gave a crude product, which was
purified by column chromatography over silica gel (hex-
ane–ethyl acetate 98:2) to furnish 3-(4-acetylphenyl)-2-
pentylacrylic acid methyl ester (205 mg, 75%) as a yellow
2-Pentyl-hex-2-enoic acid methyl ester (entry 7, Table 2):
Yellow oil; IR (neat) 2956, 2871, 1716, 1458 cmꢀ1 1H
;
NMR (CDCl3, 300 MHz) d 0.84–0.97 (m, 6H), 1.24–1.73
(m, 8H), 2.13 (q, J = 7.3 Hz, 2H), 2.26 (t, J = 6.9 Hz, 2H),
3.7 (s, 3H), 6.7 (t, J = 15.0 Hz, 1H); 13C NMR (CDCl3,
75 MHz) d 14.2, 14.3, 22.4, 22.8, 27.1, 29.3, 30.9, 32.1,
51.9, 132.9, 142.9, 168.9. Anal. Calcd for C12H22O2: C,
72.68; H, 11.18. Found: C, 72.36; H, 11.05.
semi-solid; IR (neat): 2954, 2929, 2860, 1714, 1686 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 0.86–0.89 (m, 3H), 1.29–
1.30 (m, 4H), 1.49–1.54 (m, 2H), 2.45–2.50 (m, 2H), 2.60
(s, 3H), 3.81 (s, 3H), 7.41 (d, J = 8.07 Hz, 2H), 7.62 (s,
1H), 7.96 (d, J = 8.07 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 14.0, 22.4, 26.7, 27.7, 29.0, 31.9, 52.1, 128.5
(2C), 128.6, 129.3 (2C), 135.8, 136.5, 140.7, 168.6, 197.5.
Anal. Calcd for C17H27O3: C, 74.42; H, 8.08. Found: C,
74.39; H, 8.01.
3-(4-Acetyl-phenyl)-2-benzyl
(entry 4, Table 3): Yellow semi-solid; IR (neat)
2952, 2929, 1715, 1682, 1602 cmꢀ1 1H NMR (CDCl3,
acrylic
methyl
ester
;
300 MHz) d 2.57 (s, 3H), 3.75 (s, 3H), 3.93 (s, 2H), 7.15–
7.31 (m, 6H), 7.43–7.45 (m, 2H), 7.91–7.94 (m, 2H); 13C
NMR (CDCl3, 75 MHz) d 26.7, 33.3, 52.4, 126.4, 127.9
(2C), 128.6 (2C), 128.7 (2C), 129.1, 129.4 (2C), 130.1,
132.8, 139.0, 140.0, 168.3, 197.5. Anal. Calcd for
C19H18O3: C, 77.53; H, 6.16. Found: C, 77.28; H,
6.07.
This procedure was followed for the reactions of all the
substrates listed in Tables 2 and 3. The products (entries
1–3, Table 2) and entries (1, 2, 3, 6 and 7, Table 3) were
identified by comparison of their spectroscopic data (IR,
1H NMR and 13C NMR) with those reported (see
references in Tables 2 and 3). New compounds (entries
4–7, Table 2) and entries (4 and 5, Table 3) were
characterized from their spectroscopic data and elemental
analysis. These data are presented below:
3-(4-Nitrophenyl)-2-pentyl-acrylic acid methyl ester (entry
4, Table 2): Yellow semi-solid; IR (neat) 2954, 2929, 1517,
1597, 1346 cmꢀ1; 1H NMR (CDCl3, 300 MHz) d 0.85–0.90
(m, 3H), 1.25–1.32 (m, 4H), 1.49–1.59 (m, 2H), 2.44–2.49
(m, 2H), 3.84 (s, 3H), 7.47 (d, J = 8.8 Hz, 2H), 7.64 (s,
1H), 8.25 (d, J = 8.8 Hz, 2H); 13C NMR (CDCl3,
75 MHz)d 14.3, 22.7, 28.0, 29.2, 32.1, 51.8, 124.1 (2C),
130.1 (2C), 136.4, 137.5, 142.9, 147.8, 168.5. Anal. Calcd
for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C,
64.91; H, 7.01; N, 5.15.
(Z)-2-(4-Methyl-benzyl)-3-p-tolyl-acrylonitrile (entry 5,
Table 3): Yellow semi-solid; IR (neat) 3024, 2860, 2208,
1610 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 2.33 (s, 3H),
;
2.35 (s, 3H), 3.63 (s, 2H), 6.90 (s, 1H), 7.14–7.23 (m, 6H),
7.61 (d, J = 8 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d
21.2, 21.5, 41.8, 109.8, 118.5, 128.8 (2C), 128.9 (2C), 129.6
(2C), 129.7 (2C), 131.0, 133.8, 137.0, 140.5,143.9. Anal.
Calcd for C18H17N: C, 87.41; H, 6.93; N, 5.66. Found: C,
87.11; H, 7.01; N, 5.52.
8. (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed.
Engl. 1983, 22, 795–796; (b) Basavaiah, D.; Gowriswari,
V. V. L. Synth. Commun. 1987, 17, 587–591.
9. Perez, I.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 1999,
1, 1267–1269.
10. Krause, N.; Gerold, A. Angew. Chem., Int. Ed. 1997, 36,
186–204, and references cited therein.
3-(4-Chloro-phenyl)-2-pentyl-acrylic acid methyl ester
(entry 5, Table 2): Yellow semi-solid; IR (neat) 3026,
11. Murakami, M.; Ishida, N.; Miura, T. Chem. Commun.
2006, 643–645.
12. Datta, A.; Ila, H.; Junjappa, H. Tetrahedron 1987, 43,
5367–5374.
13. Thibornet, J.; Knochel, P. Tetrahedron Lett. 2000, 41,
3319–3322.
3001, 1714, 1404 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d
0.85–0.90 (m, 3H), 1.30–1.33 (m, 4H), 1.46–1.54 (m, 2H),
2.44–2.49 (m, 2H), 3.80 (s, 3H), 7.26 (d, J = 8.3 Hz, 2H),
7.35 (d, J = 8.3 Hz, 2H), 7.57 (s, 1H); 13C NMR (CDCl3,