Selective indium-mediated 1,2,4-pentatrien-3-ylation of carbonyl compounds for the efficient synthesis of vinyl allenols

Article abstract of DOI:10.1021/ol802073q

(Chemical Equation Presented) A highly selective synthetic method of functionalized vinyl allenols was developed from the reactions of various carbonyl compounds with organoindium reagent in situ generated from indium and 1-bromopent-4-en-2-yne derivatives. Treatment of vinyl allenols with gold catalyst, dienophile, or indium trihalide produced the functionalized dihydrofuran, cyclohexene, or 2-halo-1,3-diene derivatives in good to excellent yields.

Full text of DOI:10.1021/ol802073q

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5067-5070
Selective Indium-Mediated
1,2,4-Pentatrien-3-ylation of Carbonyl
Compounds for the Efficient Synthesis
of Vinyl Allenols
Jisu Park,† Sung Hong Kim,‡ and Phil Ho Lee*,†
National Research Laboratory for Catalytic Organic Reaction, Department of
Chemistry, and Institute for Molecular Science and Fusion Technology, Kangwon
National UniVersity, Chuncheon 200-701, Republic of Korea, and Analysis Research
DiVision, Daegu Center, Korea Basic Science Institute, Daegu 702-701,
Republic of Korea
phlee@kangwon.ac.kr
Received September 4, 2008
ABSTRACT
A highly selective synthetic method of functionalized vinyl allenols was developed from the reactions of various carbonyl compounds with
organoindium reagent in situ generated from indium and 1-bromopent-4-en-2-yne derivatives. Treatment of vinyl allenols with gold catalyst,
dienophile, or indium trihalide produced the functionalized dihydrofuran, cyclohexene, or 2-halo-1,3-diene derivatives in good to excellent
yields.
In view of the usefulness of functionalized dienes in
organic synthesis, a number of reagents have been developed
for the 1,3-butadien-2-ylation of carbonyl compounds.1
However, the synthetic method of functionalized 1,3-dienes
possessing extended double bonds such as vinyl allene and
bis(allene) is still rare in organic reactions. Because so much
is now known about the Diels-Alder reaction,2 we were
convinced that when we developed an efficient synthetic
route to vinyl allenes and bis(allenes), this reaction would
prove useful for the synthesis of six-membered carbocycles
† Kangwon National University.
(2) (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, U.K., 1990. (b) Oppolzer, W. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: Oxford, U.K., 1991; Vol. 5, p 315. (c) Weinreb, S. M. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A.,
Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 5, p 401. (d) Kappe, C. O.;
Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53, 14179. (e) Fallis, A. G.
Acc. Chem. Res. 1999, 32, 464. (f) Buonora, P.; Olsen, J.-C.; Oh, T.
Tetrahedron 2001, 57, 6099. (g) Marsault, E.; Toro’, A.; Nowak, P.;
Deslongchamps, P. Tetrahedron 2001, 57, 4243. (h) Nicolaou, K. C.; Snyder,
S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002,
41, 1668.
‡ Korea Basic Science Institute.
(1) (a) Nunomoto, S.; Yamashita, Y. J. Org. Chem. 1979, 44, 4788. (b)
Wada, E.; Kanemasa, S.; Fujiwara, I.; Tsuge, O. Bull. Chem. Soc. Jpn.
1985, 58, 1942. (c) Zheng, B.; Srebnik, M. J. Org. Chem. 1995, 60, 486.
(d) Soundararajan, R.; Li, G.; Brown, H. C. J. Org. Chem. 1996, 61, 100.
(e) Hatakeyama, S.; Yoshida, M.; Esumi, T.; Iwabuchi, Y.; Irie, H.;
Kawamoto, T.; Yamada, H.; Nishizawa, M. Tetrahedron Lett. 1997, 38,
7887. (f) Nishiyama, T.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Hatakeyama, S.
Tetrahedron Lett. 1998, 39, 43. (g) Luo, M.; Iwabuchi, Y.; Hatakeyama,
S. Chem. Commun. 1999, 267. (h) Yu, C.-M.; Lee, S.-J.; Jeon, M. J. Chem.
Soc., Perkin Trans. 1 1999, 3557.
10.1021/ol802073q CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society

bearing exo-methylene groups. Moreover, recent progress of
transition metal-catalyzed multicomponent reactions and
cyclizations using vinyl allenes,3 vinyl allenols, and bis-
(allenes)4 led us to the development of convenient and
selective synthetic methods to these compounds. In the
pursuit of an ongoing program of indium-mediated organic
reactions,5 we reported the efficient synthetic method of vinyl
allenes through Pd-catalyzed cross-coupling reactions using
allenylindium reagent.3f Recently, we required a diverse
range of vinyl allenols in connection with Diels-Alder
reactions,6 Pd-catalyzed multicomponent reactions,3g and Au-
catalyzed cyclizations.7 The addition of organozinc and
organomagnesium reagents obtained from the corresponding
bromide to carbonyl compounds suffers from poor regiose-
lectivity.8 Organochromium reagents, though effective in
reacting with carbonyl compounds to afford vinyl allenols,
were derived from toxic CrCln (n ) 2 and 3) and have not
shown good functional group tolerance due to the use of
LAH.9 LDA-mediated selective addition reaction requires
vinylidenecyclopropanes, which are difficult to prepare.10 As
part of our continuing efforts to expand the synthetic utility
of vinyl allenes,3f,g vinyl allenols, and bis(allenes),11 we now
report highly selective 1,2,4-pentatrien-3-ylation reactions
from the reaction of carbonyl compounds with organoindium
reagents in situ generated from indium and 1-bromopent-4-
en-2-yne derivatives, producing vinyl allenols in good to
excellent yields (Scheme 1).
Table 1. Reaction Optimization of 1,2,4-Pentatrien-3-ylationa
yieldb (%)
entry Met additive (equiv) solvent time (h) 3g
4
5
1
2
3
In
In
In
In
In
In
In
In
In
Mg
Zn
DMF
DMF
DMF
THF
THF
THF
THF
THF
H2O
1
3
1
1
1
2
3
2
4
1
2
74
57
69
8
1
3
6
12
5
LiCl (3)
LiI (3)
4
27 29 12
73 16
5c
6
LiI (3)
LiI (3)
LiI (1)
LiI (1)
79
51
88
52
42
45
7
3
7
8
11
42
40
7d
8
9
10
Et2O
THF
11e
LiI (1.5)
a 1g was added to organoindium reagent derived from metal (1 equiv)
and 2 (1 equiv) under Grignard-type conditions unless otherwise noted.
b Ratios were determined by 1H NMR analysis after isolation. c In (2 equiv)
and 2 (2 equiv) were used. d Barbier-type conditions. e Zn (1.5 equiv) and
2 (1.5 equiv) were used.
of 1g with organoindium reagent in DMF at 25 °C gave 3g
(74%), 4 (8%), and 5 (6%) (entry 1). The model reaction
afforded the vinyl allenol 3g in 57% and 69% yields in the
presence of additives (3 equiv) such as LiCl and LiI,
respectively (entries 2 and 3). Although 3g was produced in
27% yield in THF without additive (entry 4), the vinyl allenol
3g was obtained in 79% yield in the presence of LiI (3 equiv)
in THF (entry 6). We attempted the present reaction under
the Barbier-type conditions, producing 3g in 51% yield (entry
7). Of the reaction conditions examined, the best results were
obtained with 1g (1 equiv), 2 (1 equiv), and indium (1 equiv)
in the presence of LiI (1 equiv) in THF at 25 °C for 2 h
under a nitrogen atmosphere, affording selectively 3g in 88%
yield and 5 in 8% yield (entry 8). 1-Iodopent-4-en-2-yne was
detected in part in 1H NMR after treatment of 2 with LiI in
THF-d8, indicating that iodide anion substituted bromide in
2 and then the corresponding iodide smoothly reacted with
indium to produce organoindium reagent. The high selectivity
of the present reaction using organoindium reagents was
compared to Grignard and organozinc reagents. Subjecting
1g to 2 and Mg in Et2O gave 3g (42%) and 5 (42%) (entry
10). Similar results were obtained in the case of Zn (1.5
equiv) in the presence of LiI in THF, indicating that
organoindium reagent was superior to other organometallic
Scheme 1
.
Selective 1,2,4-Pentatrien-3-ylation to Carbonyl
Compound
Our initial study focused on the reactions of benzaldehyde
(1g) with organoindium reagent in situ generated from
1-bromopent-4-en-2-yne (2)12 and indium (Table 1). Reaction
(3) (a) Murakami, M.; Ithami, K.; Ito; Yoshihiko, Angew. Chem., Int.
Ed. 1995, 34, 2691. (b) Murakami, M.; Ithami, K.; Ito; Yoshihiko, J. Am.
Chem. Soc. 1996, 118, 11672. (c) Murakami, M.; Ithami, K.; Ito; Yoshihiko,
Angew. Chem., Int. Ed. 1998, 37, 3418. (d) Murakami, M.; Itami, K.; Ito,
Y. Synlett 1999, 951. (e) Murakami, M.; Thami, K.; Ito, Y. Organometallics
1999, 18, 1326. (f) Lee, P. H.; Lee, K. Angew. Chem., Int. Ed. 2005, 44,
3253. (g) Lee, P. H.; Lee, K.; Kang, Y. J. Am. Chem. Soc. 2006, 128, 1139.
(4) (a) Eaton, B. E.; Rollman, B.; Kaduk, J. A. J. Am. Chem. Soc. 1992,
114, 6245. (b) Sigman, M. S.; Kerr, C. E.; Eaton, B. E. J. Am. Chem. Soc.
1993, 115, 7545. (c) Sigman, M. S.; Eaton, B. E. Organometallics 1996,
15, 2829. (d) Sigman, M. S.; Eaton, B. E. J. Am. Chem. Soc. 1996, 118,
11783.
(5) (a) Lee, P. H.; Sung, S.-Y.; Lee, K. Org. Lett. 2001, 3, 3201. (b)
Lee, K.; Seomoon, D.; Lee, P. H. Angew. Chem., Int. Ed. 2002, 41, 3901.
(c) Seomoon, D.; Lee, K.; Kim, H.; Lee, P. H. Chem. Eur. J. 2007, 13,
5197.
(8) Khrimyan, A. P.; Makaryan, G. M.; Badanyan, S. O. Zh. Org. Khim.
1988, 24, 94.
(6) (a) Regas, D.; Afonso, M. M.; Rodriguez, M. L.; Palenzuela, J. A.
J. Org. Chem. 2003, 68, 7845. (b) Regas, D.; Ruiz, J. M.; Afonso, M. M.;
Galindo, A.; Palenzuela, J. A. Tetrahedron Lett. 2003, 44, 8471. (c) Regas,
D.; Afonso, M. M.; Palenzuela, J. A. Synthesis 2004, 757. (d) Regas, D.;
Ruiz, J. M.; Afonso, M. M.; Palenzuela, J. A. J. Org. Chem. 2006, 71,
9153. (e) Lee, K.; Lee, P. H. Bull. Korean Chem. Soc. 2008, 29, 487.
(7) Kim, S.; Lee, P. H. AdV. Synth. Catal. 2008, 350, 547.
(9) (a) Delbecq, F.; Baudouy, R.; Gore, J. NouV. J. Chim. 1973, 3, 321.
(b) Doutheau, A.; Gore, J.; Diab, T. Tetrahedron 1985, 41, 329.
(10) Lu, J.-M.; Shi, M. Org. Lett. 2008, 10, 1943.
(11) Yu, H.; Lee, P. H. J. Org. Chem. 2008, 73, 5183.
(12) (a) Clardy, J.; Forsyth, C. J. J. Am. Chem. Soc. 1990, 112, 3497.
(b) Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M. J. Org. Chem. 2007,
72, 3868.
5068
Org. Lett., Vol. 10, No. 21, 2008

reagents (entry11). Formation of 4 could be explained by
1,2,4-pentatrien-3-ylation to the carbonyl group of 1g fol-
lowed by additional 1,2,4-pentatrien-3-ylation to the terminal
double bond of the allenyl group (Scheme 2). On the basis
Table 2. Reactions of Carbonyl Compounds with Indium and
1-Bromopent-4-en-2-ynea
Scheme 2. Plausible Mechanism for Formation of
1-Phenyl-2,5-divinyl-2,5,6-heptatrien-1-ol
entry
R
R1
time (h)
yield (%)b
3a 61 (1)c
1
2
3
4
5
6
7
8
H
H
1a
1b
1c
1d
2
2
2
2
2
2
2
1
1
2
2
2
2
2
1
1
1
1
2
1
4
n-Bu
C6H11
EtO2C
EtO2C
EtO2C
Ph
H
H
H
3b 81
3c 91 (3)c
3d 82 (8)c
3e 70
CH3 1e
Ph 1f
3f 71 (3)c
3g 88 (8)c
3h 77 (7)c (3)d
3i 75 (8)c (5)d
3j 49 (2)c (34)e
3k 82 (4)c (4)d
3l 84 (8)c (2)d
3m 83 (5)c
3n 80 (6)c
3o 82 (6)c
3p 88
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
4-Me-C6H4
2-Me-C6H4
2,4,6-Me3-C6H2
4-MeO-C6H4
3-MeO-C6H4
3,4-(OCH2O)-C6H3
3-HO-C6H4
4-Ac-C6H4
4-MeO2C-C6H4
3-Br-C6H4
2-I-C6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
of the result that the yield of 4 was increased by 29% without
an additive (entry 4), exposure of 1g to organoindium reagent
in situ generated from 2 (2 equiv) and indium (2 equiv) in
THF without LiI resulted in the selective formation of 4 in
73% yield (entry 5).
3q 86 (4)c
3r 89 (7)c
3s 90 (2)c
3t 93 (2)c
3u 45 (20)e
To demonstrate the efficiency and scope of the present
method, we applied this reaction system to a variety of
carbonyl compounds to obtain vinyl allenols (Table 2). Under
the optimized conditions, formaldehyde gave the vinyl allenol
3a in moderate yield (61%) mainly due to volatility (entry
1). Treatment of 1-butanal and cyclohexanecarbaldehyde with
indium and 2 in the presence of LiI selectively produced 3b
and 3c in 81% and 91% yields, respectively (entries 2 and
3). Ethyl glyoxalate reacted with the organoindium reagent
to give 3d in 82% yield (entry 4). Reactions of ethyl pyruvate
and ethyl benzoylformate with the indium reagent gave the
vinyl allenols (3e and 3f) in 70% and 71% yields, respec-
tively (entries 5 and 6). In the case of various aromatic
aldehydes, electronic variation on the aromatic substituents,
such as methyl, methoxy, hydroxyl, acetyl, methoxycarbonyl,
bromide, and iodide groups, did not diminish the efficiency
and selectivity of indium-mediated 1,2,4-pentatrien-3-ylation
(entries 8-18). Organoindium reagent in situ generated from
indium and 2 in the presence of LiI smoothly added to
methyl-, methoxy-, and 3,4-(methylenedioxy)benzaldehyde
to produce the desired products in good yields (75-84%
yields) (entries 8, 9, and 11-13). 2,4,6-Trimethylbenzalde-
hyde reacted with organoindium reagent to provide 3j in 49%
yield for 2 h (entry 10). It is noteworthy that protection of
a hydroxyl group on the substrates is not necessary as
demonstrated by the reaction of 3-hydroxybenzaldehyde
(entry 14). Addition of the organoindium reagent to 4-acetyl-
benzaldehyde led to the selective formation of 3o in 82%
yield (entry 15). Methyl 4-formylbenzoate reacted with
organoindium reagent to result in the exclusive formation
of 3p in 88% yield (entry 16). Indium reagent was treated
with 3-bromo- and 2-iodobenzaldehyde to afford 3q and 3r
selectively in good yields (entries 17 and 18). 2-Furfural and
3-pyridinecarboxaldehyde turned out to be compatible with
2-furyl
3-pyridyl
Ph
CH3 1u
a Reactions were carried out with indium (1 equiv), 2 (1 equiv), and
LiI (1 equiv) in THF at 25 °C. b Isolated yields. c Propargylation products.
d Compounds similar to 4 produced from sequential allenylation to aldehyde
followed by to allene. e Recovery yields of carbonyl compound.
the employed reaction conditions (entries 19 and 20).
Exposure of acetophenone to organoindium reagent provided
3u in 45% yield (entry 21).
With these results in hand, we applied the present method
to enynyl bromide possessing alkyl substituents. We were
pleased to obtain selectively vinyl allenol 11 in 90% yield
from the reaction of 1g with organoindium reagents in situ
generated from 10 and indium (eq 1).13 Treatment of 1g with
12 and indium selectively produced the vinyl allenol 13 in
75% yield (eq 2).14
Next, we examined further functionalization of vinyl
allenols (Scheme 3). Treatment of 3p with 5 mol % of AuCl3
in CH2Cl2 produced dihydrofuran 14 in 95% yield. The
Diels-Alder reaction of vinyl allenol 3p with N-methylma-
Org. Lett., Vol. 10, No. 21, 2008
5069

tives in THF at 25 °C selectively produced vinyl allenols in
good to excellent yields, indicating that 1-bromopent-4-en-
2-yne acted as synthon of 3-anion of 1,2,4-pentatriene. The
present reaction has shown good functional group tolerance.
Treatment of vinyl allenols with gold catalyst, dienophile,
or indium trihalide cleanly provided the functionalized
dihydrofuran, cyclohexene, or 2-halo-1,3-diene derivatives,
respectively.
Scheme 3. Functionalization of Vinyl Allenols
Acknowledgment. Dedicated to Professor Kwan Soo Kim
on the occasion of his 60th birthday. This work was
supported by the Korea Science and Engineering Foundation
(KOSEF) through the National Research Laboratory Program
funded by the Ministry of Science and Technology (No.
M10600000203-06J0000-20310) and KOSEF (R01-2006-
000-11283-0). The NMR data were obtained from the central
instrumental facility in Kangwon National University. We
thank Professor S. Chang of KAIST for proofreading this
manuscript.
Supporting Information Available: Experimental pro-
cedure and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
leimide afforded adduct 15 (dr ) 1:1.3) in 86% yield. Vinyl
allenols 3g and 3p reacted with indium trihalide to give
2-halo-3-vinyl-1,3-butadiene derivatives (16-18) in good
yields.
In summary, we have demonstrated that the reaction of
carbonyl compounds with organoindium reagents in situ
generated from indium and 1-bromopent-4-en-2-yne deriva-
OL802073Q
(13) Laird, T.; Ollis, D. W.; Ian, O. J. Chem. Soc., Perkin Trans. 1
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Org. Lett., Vol. 10, No. 21, 2008