Indium-mediated double Barbier reaction of γ-cyanoesters derived from Baylis-Hillman adduct

Article abstract of DOI:10.1016/j.tetlet.2009.01.149

We developed an efficient synthetic method of diallylated δ-valerolactam and γ-butyrolactam derivatives via an indium-mediated successive double Barbier type allylations starting from the Baylis-Hillman adducts.

Full text of DOI:10.1016/j.tetlet.2009.01.149

Tetrahedron Letters 50 (2009) 1696–1698
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium-mediated double Barbier reaction of
from Baylis–Hillman adduct
c-cyanoesters derived
*
Sung Hwan Kim, Hyun Seung Lee, Ko Hoon Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed an efficient synthetic method of diallylated d-valerolactam and c-butyrolactam derivatives
via an indium-mediated successive double Barbier type allylations starting from the Baylis–Hillman
adducts.
Received 18 December 2008
Revised 15 January 2009
Accepted 19 January 2009
Available online 5 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indium
Barbier reaction
Lactam
Baylis–Hillman adducts
Allylindium reagents have been used extensively for the intro-
duction of allyl group in a Barbier type manner.1–3 Although allyl-
indium reagents can be added to many reactive functional groups
including aldehyde, ketone, and activated imine with acyl or tosyl
group,1,2 the reaction with nitrile has not been reported except for
the recent Yamamoto’s paper.3 According to the results, introduc-
tion of allylindium can be carried out with only nitrile compounds
compounds 2a–c in the presence of K2CO3.5 With these com-
pounds, we examined the Barbier reaction with in situ generated
allylindium reagent from allyl bromide and indium powder in
THF. Mono-allylated compounds 4a–d were isolated in low yields
(12–16%). Instead diallylated d-valerolactam derivatives 5a–d
were obtained as the major products (52–61%).6,7 The results are
summarized in Table 1.
having both an
a
-hydrogen atom and an
a
-EWG group
Diallylated compound 5 must be formed by double Barbier
reaction via the cyclic N-acylimine intermediate (II), a tautomer
of minor product 4. As reported, N-acylimine is more reactive than
nitrile toward allylindium species,1,2 thus the second allylation oc-
curs to a larger extent to give 5 as the major product. Trials for the
synthesis of mono-allylated compound as the major product failed.
(Scheme 1).3
Recently Baylis–Hillman adducts have been used for the syn-
thesis of various cyclic compounds.4,5 Among them, many of the
interesting cyclic compounds were synthesized from the suitably
modified Baylis–Hillman adducts with active methylene com-
pounds like ethyl cyanoacetate, dimethyl malonate, and ethyl ace-
toacetate.5 Based on the Yamamoto’s results,3 we reasoned that we
could prepare the allylated pyridine derivative (III) by the double
bond isomerization of compound 4a, which could be prepared
from the Baylis–Hillman acetate 1a as in Scheme 2.5a However,
we obtained diallyl compound 5a as the major product presumably
via the second introduction of allyl group to the reactive cyclic
N-acylimine intermediate (II), the tautomer of 4a. This type of con-
secutive double allylation reaction has not been reported to the
best of our knowledge.
As next entries, we examined the synthesis of diallylated c-butyro-
lactam derivatives via the double-Barbier reaction with 6a and 6b
(Scheme 3).6 The starting materials were synthesized from Baylis–
Hillman acetates 1c and 1e with KCN in good yields.5d The follow-
ing In-mediated allylation reaction provided diallylated com-
pounds 7a and 7b in reasonable yields. In these cases we did not
observe the formation of appreciable amounts of mono-allylated
compounds. The reaction of 6a with crotyl bromide under the same
conditions was very sluggish, unfortunately. Dicrotyl c-butyrolac-
tam 7c was obtained in low yield (10%) after 30 h and we recov-
Encouraged by the results, we examined the generality of this
successive In-mediated Barbier type allylation with c-cyanoesters
3a–d. The starting materials 3 were prepared by the reaction of
Baylis–Hillman acetates (1a–c)/bromide (1d) and active methylene
In2I3
3
R
R
C
N
EWG
THF
EWG
NH2
* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.149

S. H. Kim et al. / Tetrahedron Letters 50 (2009) 1696–1698
1697
CN
COOMe
allyl bromide
In, THF
COOMe
COOMe
NH2
OAc
Ph
Ph
Ph
2a
COOMe
Ph
CN
K2CO3 / CH3CN
COOMe
COOMe
1a
3a
(I)
O
O
N
O
- MeOH
Ph
NH
Ph
NH
COOMe
COOMe
COOMe
4a
5a
(II)
OH
Ph
N
(III)
COOMe
Scheme 2.
Table 1
Synthesis of diallylated lactam 5a–d
Entry Substrate
1
Conditions
NCCH2COOMe (2a), K2CO3 (1.5 equiv), CH3CN, rt, 2 h
Compound 3 (%)
Productsa (%)
OAc
COOEt
O
O
Ph
COOEt
Ph
Ph
NH
Ph
NH
CN
COOMe
1a
3a (68)
4a (16)
5a (58)
COOMe
COOMe
OAc
COOEt
O
O
2
NCCH2Ph (2b), K2CO3 (1.5 equiv), CH3CN, rt, 3 h
p-ClPh
COOEt
p-ClPh
p-ClPh
NH
p-ClPh
NH
CN
Ph
1b
3b (61)
4b (13)
5b (54)
Ph
Ph
OAc
COOMe
O
O
3
4
NCCH2SO2Ph (2c), K2CO3 (1.5 equiv), CH3CN, rt, 2 h
Ph
COOMe
Ph
Ph
NH
Ph
NH
CN
SO2Ph
1c
3c (75)
4c (12)
5c (52)
SO2Ph
SO2Ph
2a, K2CO3 (1.5 equiv), CH3CN, rt, 2 h
COOEt
Br
COOEt
O
O
C5H11
C5H11
C5H11
4d (15)
NH
C5H11
NH
CN
1d
COOMe
3d (77)
5d (61)
COOMe
COOMe
a
Conditions: compound 3 (1.0 equiv), allyl bromide (4.0 equiv), In (2.0 equiv), THF, reflux, 30 min.
ered 6a (61%). The compound 8 showed no reaction under the
ated successive double Barbier type allylations. Further synthetic
applications of this interesting double allylation concept are under
study.
same conditions as expected due to the lack of
a-hydrogen atom
around nitrile group (Scheme 4).3
As one of the synthetic applications of diallylated d-valerolac-
tam derivatives, we examined the RCM (ring-closing metathesis)
reaction of compound 5a with 2nd generation Grubbs catalyst
(3 mol %) in toluene (50 °C, 10 h) and obtained the corresponding
spiro-cyclopentene compound 9 in 84% yield (Scheme 5).8
In summary, we disclosed an efficient synthesis of diallylated d-
valerolactam and c-butyrolactam derivatives via an indium-medi-
Acknowledgments
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, KRF-2008-
313-C00487). Spectroscopic data were obtained from the Korea Ba-
sic Science Institute, Gwangju branch.

1698
S. H. Kim et al. / Tetrahedron Letters 50 (2009) 1696–1698
O
allyl bromide
Ph
NH
COOMe
CN
KCN, H2O
rt, 20 h
In, THF
Ph
Ph
1c
6a (68%)
7a (67%)
allyl bromide
In, THF
OAc
KCN, H2O
rt, 12 h
Ph
CN
CN
Ph
N
CN
6b (88%)
H2N
1e
7b (49%)
Scheme 3.
O
crotyl bromide (4.0 equiv)
In (2.0 equiv), THF, reflux, 30 h
Ph
NH
+
6a (61%)
6a
7c (10%)
COOEt
allyl bromide
K2CO3, CH3CN
allyl bromide
In, THF
Ph
CN
no reaction
3a
COOMe
8 (87%)
Scheme 4.
2007, 9, 3631–3634; (f) Lee, K. Y.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007, 48,
2007–2011.
7. Typical procedure for the synthesis of compounds 3a, 4a and 5a: A mixture of
compound 1a (248 mg, 1.0 mmol), methyl cyanoacetate (297 mg, 3.0 mmol),
and K2CO3 (207 mg, 1.5 mmol) in CH3CN (3 mL) was stirred at room
temperature for 2 h. After the usual aqueous workup and column
chromatographic purification process (hexanes/EtOAc, 8:1), we obtained
compound 3a (195 mg, 68%) as colorless oil. A stirred mixture of compound
3a (144 mg, 0.5 mmol), allyl bromide (242 mg, 2.0 mmol), and indium
(114 mg, 1.0 mmol) in THF (1.5 mL) was heated to reflux for 30 min. After
the usual aqueous workup and column chromatographic purification process
(hexanes/CH2Cl2/EtOAc, 16:2:1), we obtained compound 4a (23 mg, 16%) and
compound 5a (93 mg, 58%). Other compounds were synthesized similarly and
the spectroscopic data of 3a, 4a, 5a, and 7a are as follows:Compound 3a: 68%;
O
N Mes
Cl
Ph
NH
Grubbs catalyst (3 mol%)
toluene, 50 ºC, 10 h
Mes
N
Ru
5a
Cl
Ph
COOMe
PCy3
9 (84%)
Scheme 5.
References and notes
colorless oil; IR (film) 2958, 2251, 1751, 1703, 1259 cmÀ1 1H NMR (CDCl3,
;
300 MHz) d 1.37 (t, J = 7.2 Hz, 3H), 3.16–3.19 (m, 2H), 3.75 (s, 3H), 4.12 (dd, J =
8.7 and 7.5 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 7.34–7.45 (m, 5H), 7.98 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 14.2, 27.6, 36.1, 53.4, 61.4, 115.9, 126.8, 128.7, 128.9,
129.0, 134.4, 144.1, 166.0, 168.8.Compound 4a: 16%; yellow solid, mp 128–
1. For the general review on indium-mediated reactions, see: (a) Auge, J.; Lubin-
Germain, N.; Uziel, J. Synthesis 2007, 1739–1764; (b) Li, C.-J.; Chan, T.-H.
Tetrahedron 1999, 55, 11149–11176; (c) Pae, A. N.; Cho, Y. S. Curr. Org. Chem.
2002, 6, 715–737.
129 °C; IR (KBr) 3211, 1709, 1642, 1229 cmÀ1 1H NMR (CDCl3, 300 MHz) d
;
2. For the indium-mediated Barbier type allylation of imine, acylimine,
sulfonimine and related compounds, see: (a) Vilaivan, T.; Winotapan, C.;
Banphavichit, V.; Shinada, T.; Ohfune, Y. J. Org. Chem. 2005, 70, 3464–3471;
(b) Schneider, U.; Chen, I.-H.; Kobayashi, S. Org. Lett. 2008, 10, 737–740; (c)
Kumar, H. M. S.; Anjaneyulu, S.; Reddy, E. J.; Yadav, J. S. Tetrahedron Lett. 2000,
41, 9311–9314; (d) Piao, X.; Jung, J.-K.; Kang, H.-Y. Bull. Korean Chem. Soc. 2007,
28, 139–142; (e) Ritson, D. J.; Cox, R. J.; Berge, J. Org. Biomol. Chem. 2004, 2,
1921–1933; (f) Lu, W.; Chan, T. H. J. Org. Chem. 2000, 65, 8589–8594.
3. (a) Fujiwara, N.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 4729–4732; (b)
Fujiwara, N.; Yamamoto, Y. J. Org. Chem. 1999, 64, 4095–4101.
4. For the general review on Baylis–Hillman chemistry, see: (a) Basavaiah, D.; Rao,
A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891; (b) Kim, J. N.; Lee, K. Y.
Curr. Org. Chem. 2002, 6, 627–645; (c) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull.
Korean Chem. Soc. 2005, 26, 1481–1490; (d) Singh, V.; Batra, S. Tetrahedron 2008,
64, 4511–4574. and further references cited therein.
3.56–3.59 (m, 2H), 3.75 (s, 3H), 3.79–3.80 (m, 2H), 5.18–5.34 (m, 2H), 5.78–
5.91 (m, 1H), 7.30–7.50 (m, 5H), 7.82 (t, J = 2.7 Hz, 1H), 7.86 (s, 1H); 13C NMR
(CDCl3, 75 MHz) d 28.2, 36.0, 51.5, 101.9, 119.4, 125.4, 128.6, 129.0, 130.4,
132.6, 135.0, 138.1, 144.6, 165.3, 167.0; ESIMS m/z 284 (M++1). Anal. Calcd for
C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 72.43; H, 6.35; N,
4.88.Compound 5a: 58%; pale yellow solid, mp 113–114 °C; IR (KBr) 3178,
1734, 1668, 1614, 1396 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.33–2.57 (m, 4H),
;
2.90–2.97 (m, 1H), 3.09–3.12 (m, 2H), 3.70 (s, 3H), 5.16–5.25 (m, 4H), 5.76–
5.92 (m, 2H), 6.20 (s, 1H), 7.29–7.42 (m, 5H), 7.85 (s, 1H); 13C NMR (CDCl3,
75 MHz) d 25.7, 41.1, 42.6, 45.1, 51.9, 57.5, 120.7 (2C), 126.1, 128.4, 128.5,
129.9, 131.6, 131.6, 135.3, 137.3, 165.8, 172.0; ESIMS m/z 326 (M++1). Anal.
Calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 73.75; H, 7.34; N,
4.45.Compound 7a: 67%; pale yellow solid, mp 115–116 °C; IR (KBr) 3201,
1693, 1651 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.27–2.44 (m, 4H), 2.93 (d, J =
;
1.8 Hz, 2H), 5.13–5.20 (m, 4H), 5.72–5.86 (m, 2H), 6.23 (s, 1H), 7.31–7.48 (m,
6H); 13C NMR (CDCl3, 75 MHz) d 37.3, 44.8, 58.6, 120.1, 128.7, 128.7, 129.6,
130.4, 131.0, 132.0, 135.6, 170.9; ESIMS m/z 254 (M++1). Anal. Calcd for
C17H19NO: C, 80.60; H, 7.56; N, 5.53. Found: C, 80.53; H, 7.76; N, 5.72.
5. For the synthesis of starting materials and similar pyridine derivatives from
Baylis–Hillman adducts, see: (a) Kim, S. H.; Kim, K. H.; Kim, H. S.; Kim, J. N.
Tetrahedron Lett. 2008, 49, 1948–1951; (b) Zhong, W.; Lin, F.; Chen, R.; Su, W.
Synthesis 2008, 2561–2568; (c) Im, Y. J.; Kim, J. M.; Kim, J. N. Bull. Korean Chem.
Soc. 2002, 23, 1361–1362; (d) Hong, W. P.; Lim, H. N.; Park, H. W.; Lee, K-J. Bull.
Korean Chem. Soc. 2005, 26, 655–657.
8. Compound 9: 84%; pale yellow solid, mp 132–133 °C; IR (film) 3171, 1733,
1668, 1613, 1394 cmÀ1 1H NMR (CDCl3, 300 MHz) d 2.44–2.49 (m, 2H), 2.82–
;
6. For the synthesis of similar lactam derivatives and their synthetic applications,
see: (a) Pohmakotr, M.; Yotapan, N.; Tuchinda, P.; Kuhakarn, C.; Reutrakul, V. J.
Org. Chem. 2007, 72, 5016–5019; (b) Yang, T.; Campbell, L.; Dixon, D. J. J. Am.
Chem. Soc. 2007, 129, 12070–12071; (c) Doan, H. D.; Gore, J.; Vatele, J.-M.
Tetrahedron Lett. 1999, 40, 6765–6768; (d) Zhou, C.-Y.; Che, C.-M. J. Am. Chem.
Soc. 2007, 129, 5828–5829; (e) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett.
3.13 (m, 5H), 3.66 (s, 3H), 5.66–5.71 (m, 2H), 6.30 (s, 1H), 7.30–7.44 (m, 5H),
7.86 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 27.0, 43.0, 46.5, 47.0, 52.1, 63.3, 126.2,
127.4, 128.4, 128.5, 128.7, 129.9, 135.4, 137.3, 165.3, 172.1; ESIMS m/z 298
(M++1). For similar spiro-pyridone synthesis, see: Kersten, L.; Taylor, R. H.;
Felpin, F.-X. Tetrahedron Lett. 2009, 50, 506–508.