Tandem Diels-Alder/cross-coupling reactions of generated in situ organoindium reagents in a one-pot process

Article abstract of DOI:10.1021/ol902530k

[Chemical equation presented] Tandem Diels-Alder/ cross-coupling reactions with organoindium reagents generated in situ from 1-bromo-2,3-butadiene and indium were developed in a one-pot process. [4 + 2] Cycloaddition reactions using organoindium reagents and subsequent Pd-catalyzed cross-coupling reactions provided the rapid synthesis of six-membered carbocycles starting from 1-bromo-2,3-butadiene.

Full text of DOI:10.1021/ol902530k

ORGANIC
LETTERS
2010
Vol. 12, No. 3
424-427
Tandem Diels-Alder/Cross-Coupling
Reactions of Generated in Situ
Organoindium Reagents in a One-Pot
Process
Juntae Mo,† Sung Hong Kim,‡ and Phil Ho Lee*,†
Department of Chemistry, 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 November 2, 2009
ABSTRACT
Tandem Diels-Alder/ cross-coupling reactions with organoindium reagents generated in situ from 1-bromo-2,3-butadiene and indium were
developed in a one-pot process. [4 + 2] Cycloaddition reactions using organoindium reagents and subsequent Pd-catalyzed cross-coupling
reactions provided the rapid synthesis of six-membered carbocycles starting from 1-bromo-2,3-butadiene.
Because main group element substituted 1,3-dienes and their
synthons play an important role as building blocks in organic
synthesis, development of efficient synthetic methods for
their preparation has been required. Although a number of
1-main group element substituted 1,3-dienes were reported,1
2-main group element substituted 1,3-dienes are rather
difficult to prepare and, therefore, rarely reported. In
particular, of these compounds, 2-(1,3-butadienyl)magnesium
chloride has been known to be a tricky species mainly due
to the poor regioselectivity involved during the course of
the reactions.2 While synthesis of 2-phenylseleno- and
2-trialkylstannyl-1,3-butadiene was reported by Bates et al.,3
1,3-butadienyl-2-yllithium was indirectly prepared from the
2-stannyl precursor.4 Preparation of 2-trialkylsilyl-1,3-buta-
diene and 2-silyl-substituted 1,3-cyclohexadienes was also
reported.5 Eisch and Hoberg reported previously about
aluminum-substituted 1,3-dienes.6 In addition, 1,3-dienyl-
2-zirconium compounds were prepared from the reaction of
2-trimethylsilyloxy-1,3-dienes with zirconocene.7 Recently,
Welker et al. reported the preparation of 2-trialkylsiloxy-
substituted and 2-KBF3-substituted 1,3-dienes from the
treatment of 2-chloro-1,3-butadiene with Mg followed by
trimethyl boronate and tri(ethoxysilyl) chloride, respectively.8
(3) Bates, G. S.; Fryzuk, M. D.; Stone, C. Can. J. Chem. 1987, 65, 2612.
(4) Wada, E.; Kanemasa, S.; Fujiwara, I.; Tsuge, O. Bull. Chem. Soc.
Jpn. 1985, 58, 1942.
† Kangwon National University.
(5) (a) Batt, D. G.; Ganem, B. Tetrahedron Lett. 1978, 3323. (b) Daniels,
R. G.; Paquette, L. A. Organometallics 1982, 1, 1449. (c) Ikeda, Z.; Oshima,
K.; Matsubara, S. Org. Lett. 2005, 7, 4859.
‡ Korea Basic Science Institute.
(1) (a) Sadykh-Zade, S. I.; Petrov, A. D. Dokl. Akad. Nauk SSSR 1957,
112, 662. (b) Carter, M. J.; Fleming, I.; Percival, A. J. Chem. Soc., Perkin
Trans. 1 1981, 2415. (c) Fleming, I.; Percival, A. Chem. Commun. 1976,
681. (d) Vaultier, M.; Truchet, F.; Carboni, B.; Hoffmann, R. W.; Denne,
I. Tetrahedron Lett. 1987, 28, 4169. (e) Luh, T. Y.; Wong, K. T. Synthesis
1993, 349. (f) Stadnichuk, M. D.; Voropaeva, T. I. Russ. Chem. ReV. 1995,
64, 25. (g) Garnier, L.; Plunian, B.; Mortier, J.; Vaultier, M. Tetrahedron
Lett. 1996, 37, 6699.
(6) (a) Eisch, J. J; Kaska, W. C. J. Am. Chem. Soc. 1966, 88, 2976. (b)
Hoberg, H.; Krausegoing, R. J. Organomet. Chem. 1977, 127, C29.
(7) Granchegui, B.; Bertus, P.; Szymoniak, J. Synlett 2001, 123.
(8) (a) De, S.; Welker, M. E. Org. Lett. 2005, 7, 2481. (b) Pidaparthi,
R. R.; Welker, M. E.; Day, C. S.; Wright, M. W. Org. Lett. 2007, 9, 1623.
(c) De, S.; Day, C.; Welker, M. E. Tetrahedron 2007, 63, 10939. (d) Wang,
L.; Day, C. S.; Wright, M. W.; Welker, M. E. Beilstein J. Org. Chem 2009,
5, 45.
(2) Nunomoto, S.; Yamashita, Y. J. Org. Chem. 1979, 44, 4788.
10.1021/ol902530k  2010 American Chemical Society
Published on Web 01/11/2010

However, synthons for 2-main group element substituted 1,3-
dienes such as homoallenyl silane,9 stannane,10 and bor-
onate11 are inconvenient to prepare. Because so much is now
known about the Diels-Alder reaction,12 we were convinced
that when we developed an efficient synthon for 2-main
group element substituted 1,3-dienes, this would prove useful
for the synthesis of six-membered carbocycles bearing a vinyl
metal moiety. Recently, we discovered that organoindium
reagents generated in situ from the reaction of indium with
1-bromo-2,3-butadiene or 1,3-dibromo-2-butyne acted as
efficient synthons for 1,3-dienyl-2-yl species in Pd-catalyzed
cross-coupling reactions13 and addition reactions to imines
and aldehydes.14 During the course of our research program
aimed at finding new indium-mediated organic reactions,15
we envisioned the possibility of extending the tandem
reaction by using an easily accessible homoallenyl indium.
Herein, we report tandem Diels-Alder/cross-coupling reac-
tions with organoindium reagents generated in situ from
1-bromo-2,3-butadiene and indium in a one-pot process,
producing cyclohexene derivatives via formation of 1-cy-
clohexenyl-1-indium (Scheme 1).
First, we examined whether organoindium reagents gener-
ated in situ from 1-bromo-2,3-butadiene and indium could
work as an efficient partner suitable for a Diels-Alder
reaction with dienophiles (Table 1). When N-methylmale-
imide 2b (0.5 mmol) was treated with organoindium reagent,
generated in situ from 1-bromo-2,3-butadiene 1 (0.75
mmol) and indium (0.5 mmol) in DMF, at 80 °C for 2 h,
tetrahydroisoindole-1,3-dione 5b was obtained in 82%
yield (entry 2). This result implies that the organoindium
reagent acted efficiently as 1,3-butadienyl-2-ylindium.
Quenching of the reaction mixture with D2O after the
initial Diels-Alder reaction gave rise to the corresponding
deuterated adduct 4 in 82% yield with 50% d-incorpora-
tion, indicating that 1-cyclohexenyl-1-indium 3 was indeed
Scheme 1. Tandem Diels-Alder Reaction/Cross-Coupling
Reaction
Table 2. Optimization of Tandem Diels-Alder/Cross-Coupling
Reactiona
Table 1. Diels-Alder Reaction of Organoindium with Dienophilea
yieldb (%)
time
entry
ligand
16 PPh3
8 Xantphos
8 DPEphos
8 DPPF
16 P(2-furyl)3
16 (biphenyl)Pcy2
16 P(C6F5)3
16 P(p-MeO-C6H4)3 LiI
16 P(p-CF3-C6H4)3
additive solvent (h) 5b
7a
26c 48c
13 43
1
2
3
4
5
6
7
8
9
10
11
12
13
LiI
LiI
LiI
LiI
LiI
LiI
LiI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
2
3
3
2
2
2
2
3
2
2
2
2
3
2
2
2
6
5
33
47
11 69 (64)c
13 31
5
66 (60)c
26
52c
16 P(p-CF3-C6H4)3
16 P(p-CF3-C6H4)3
16 P(p-CF3-C6H4)3
16 P(p-CF3-C6H4)3
LiI
70c
LiId
LiI
5
65 28
LiI
LiI
LiCl
CH3CN
DMF
DMF
7
8
56 (54)c
14e 16 P(p-CF3-C6H4)3
15e 16 P(p-CF3-C6H4)3
16e 16 P(p-CF3-C6H4)3
92 (89)c
93c
LiBr DMF
84c
a 2 mol % of Pd2dba3CHCl3, 1 (1.5 equiv), 6a (1 equiv), In (1 equiv),
2b (1.5 equiv), and additive (1 equiv) were used. Stereochemistry of 7a is
cis. b GC yield based on C14H30 as an internal standard. c Isolated yield.
d LiI (2 equiv) was used. e 1 (2.3 equiv) was used.
a 1 (0.75 mmol), In (0.5 mmol), and 2 (0.5 mmol) in DMF (0.25 M)
was used. b 2 equiv of 2 was used. c Cis. d 2.
Org. Lett., Vol. 12, No. 3, 2010
425

formed. Next, we applied these conditions to a variety of
dienophiles. N-Phenylmaleimide afforded the correspond-
ing adduct (5c) in 76% yield under the optimum reaction
conditions (entry 3). DMAD reacted with the organoin-
dium reagent in DMF at 80 °C for 3 h, producing 1,2-
bis(methoxycarbonyl)-1,4-cyclohexadiene 5a in 83% yield
(entry 1). We were particularly pleased to obtain cyclo-
hexene adducts in 83% and 84% yields, respectively, from
the reaction with maleic anhydride and ethyl acrylate
(entries 4 and 5).
Table 3. Tandem Diels-Alder/Cross-Coupling Reaction in a One-Pot Processa
a Reaction were carried out with 1 (1.1 mmol), In (0.75 mmol), and 6 (0.5 mmol) in DMF (0.25 M). b Cis. c Diastereomeric ratio. d 2 (3 equiv) was used.
e Reactions were carried out with 1 (1.5 mmol), In (1.0 mmol), In (1.0 mmol), 2 (1.0 mmol), and 6 (0.5 mmol). f Trans. g Ratio of meta- and para-isomers.
426
Org. Lett., Vol. 12, No. 3, 2010

Next, detection of cyclohexenylindium as an intermediate
led us to investigate tandem Diels-Alder/ cross-coupling
reactions using 1-bromo-2,3-butadiene and indium in a one-
pot process. These results are summarized in Table 2. After
N-methylmaleimide 2b reacted with organoindium reagents
in DMF, the reaction mixture was treated with ethyl
4-iodobenzoate in the presence of a variety of Pd catalysts
to provoke tandem Diels-Alder/cross-coupling reactions. Of
the catalytic systems examined, the best results were obtained
with 2 mol % of Pd2dba3CHCl3 and 16 mol % of (p-CF3-
C6H4)3P in the presence of 1 equiv of LiCl in DMF at 100
°C for 2 h under a nitrogen atmosphere, affording 7a
selectively in 93% yield (entry 15). When Ph3P, Xantphos,
or (biphenyl)PCy2 was used, the cross-coupling reactions did
not completely proceed (entries 1, 2, and 6). The use of (p-
MeO-C6H4)3P provided tandem reaction product in only 26%
yield (entry 8). THF gave the desired product 7a in 28%
yield together with Diels-Alder adduct 5b in 65% yield
(entry 12). Of the additives examined, LiCl (1 equiv) gave
the best results.
To demonstrate the efficiency and scope of the present
method, we applied this catalytic system to a variety of
dienophiles and electrophilic coupling partners in the tandem
Diels-Alder/cross-coupling reactions. These results are
summarized in Table 3. Although ethyl 4-chlorobenzoate did
not react with cyclohexenylindium derived from N-methyl-
maleimide, 1-bromo-2,3-butadiene, and indium under the
optimum reaction conditions (entry1), the corresponding
bromide and triflate produced the desired tandem reaction
products 7a in 76% and 72% yields, respectively (entries 2
and 4). Exposure of cyclohexenylindium to vinyl bromide
and vinyl triflate afforded 7b and 7c in 81% and 88% (dr )
1:1.3) yields, respectively (entries 5 and 6). The present
method worked equally well with diverse aryl iodides such
as 4-iodo-n-butylbenzene and 2-iodothiophene (entries 7 and
8). Cyclohexenylindium generated in situ from N-phenyl-
maleimide reacted efficiently with 2-iodobenzaldehyde and
3-iodoaniline, producing tandem Diels-Alder/cross-coupling
products (7f and 7g) possessing a 2-formylphenyl and a
3-aminophenyl group in 79% and 73% yields (entries 9 and
10). Vinylindium generated in situ from dimethyl fumarate
coupled with 2-iodoanisole, affording tandem reaction
products (7h) in 60% yield (entry 11). 3-Iodopyridine turned
out to be compatible with the present reaction conditions,
producing adduct 7i in 78% yield (entry 12). Treatment of
cyclohexenylindium generated in situ from DMAD and
maleic anhydride with 4-iodo-n-butylbenzene and ethyl
4-iodobenzoate provided 7j and 7k in 68% and 53% yields,
respectively, in a one-pot process (entries 13 and 14). We
were pleased to obtain the functionalized cyclohexene 7l in
86% yield from the reaction of ethyl acrylate with ethyl
4-iodobenzoate (entry 15).
In summary, we have developed an efficient new tandem
procedure of Diels-Alder/cross-coupling reactions with
organoindium reagents generated in situ from 1-bromo-2,3-
butadiene and indium in a one-pot process. [4 + 2]
Cycloaddition reactions of organoindium reagents with
various dienophiles and subsequent Pd-catalyzed cross-
coupling reactions provided the rapid synthesis of six-
membered carbocycles starting from aryl bromides and
iodides, vinyl bromides and triflates, 1-bromo-2,3-butadiene,
and dienophiles.
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Acknowledgment. This work is dedicated to Professor
Bong Young Chung on the occasion of his honorable
retirement from Korea University. This work was supported
by the NRF through the NRL Program (No. M10600000203-
06J0000-20310), by the KRF Grant funded by the Korean
government (KRF-2008-314-C00213) by the NRF grant
funded by the Korea government (MEST) (2009-0087013),
and by Korea Sanhak Foundation. This work was supported
by the second phase of the BK 21 Program in 2009. The
NMR data were obtained from the central instrumental
facility in Kangwon National University. We thank Professor
S. Chang of KAIST and Professor M. E. Welker of Wake
Forest University for proofreading this manuscript.
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Supporting Information Available: Experimental pro-
cedure and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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