Pd-catalyzed tandem sp2-sp3 coupling reactions of chiral stannolanes: An efficient preparation of optically active tetrahydrobenz[f]isoindoles

Article abstract of DOI:10.1021/ol4003948

A novel double Migita-Kosugi-Stille coupling reaction with dihydrostannolanes, which are readily available from a radical cascade reaction, was achieved with dihalobenzenes in the presence of a palladium catalyst. Use of unsymmetrical 1-bromo-2-iodobenzene derivatives accomplished the double coupling reaction which gave tetrahydrobenz[f]isoindoles in a regioselective manner.

Full text of DOI:10.1021/ol4003948

ORGANIC
LETTERS
Pd-Catalyzed Tandem sp2Àsp3 Coupling
Reactions of Chiral Stannolanes: An
Efficient Preparation of Optically Active
Tetrahydrobenz[f]isoindoles
2013
Vol. 15, No. 6
1402–1405
Akio Kamimura,*,† Masahiro So,† Shingo Ishikawa,† and Hidemitsu Uno‡
Department of Applied Molecular Bioscience, Yamaguchi University, Ube, 755-8611,
Japan, and Department of Chemistry, Graduate School of Science and Engineering,
Ehime University, Matsuyama, 790-8577, Japan
ak10@yamaguchi-u.ac.jp
Received February 9, 2013
ABSTRACT
A novel double MigitaÀKosugiÀStille coupling reaction with dihydrostannolanes, which are readily available from a radical cascade reaction, was
achieved with dihalobenzenes in the presence of a palladium catalyst. Use of unsymmetrical 1-bromo-2-iodobenzene derivatives accomplished
the double coupling reaction which gave tetrahydrobenz[f]isoindoles in a regioselective manner.
The MigitaÀKosugiÀStille coupling reaction1 is one of
the most useful reactions in organic chemistry,2 and it is
frequently used in natural product synthesis and advanced
materials science.3 The reaction employs oraganotin com-
pounds as a coupling partner, with tributyltin-substituted
aromatic or vinylic compounds being those most com-
monly used. Although the reaction provides an efficient
coupling method, the coupling reactions are generally
limited to the tin compounds that have an sp2-carbonÀtin
(Csp2ÀSn) bond. On the other hand, an sp3-carbonÀtin
(Csp3ÀSn) bond is rarely used as the coupling partner
which was limited to methyl, allyl, and benzyl groups
and R-oxy- or R-amino-substituted tin compounds.4 For
example, Falck utilized R-acyloxytributylstannane in the
coupling reaction.4a,c,d,fÀh Chirality at the R-carbon of an
alkyl tin compound is maintained after the coupling.
Vedejs and Jensen succeeded in introducing an amino-
methyl group by the coupling reaction.4b,e Simple alkyl
† Yamaguchi University.
‡ Ehime University.
(1) Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett.
1977, 301. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636.
(2) Review: Mitchell, T. N. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH Verlag
GmbH & Co.: Weinheim, 2004; Vol. 1, Chapter 3.
(3) (a) Masters, K.-S.; Flynn, B. L. Org. Biomol. Chem. 2010, 8, 1290.
(b) Tang, B.; Bray, C. D.; Pattenden, G.; Rogers, J. Tetrahedron 2010,
66, 2492. (c) Candy, M.; Audran, G.; Bienayme, H.; Bressy, C.; Pons,
J.-M. J. Org. Chem. 2010, 75, 1354. (d) Amans, D.; Bareille, L.; Bellosta,
V.; Cossy, J. J. Org. Chem. 2009, 74, 7665.
(4) (a) Bhatt, R. K.; Shin, D. S.; Falck, J. R.; Mioskowski, C.
Tetrahedron Lett. 1992, 33, 4885. (b) Vedejs, E.; Haight, A. R.; Moss,
W. O. J. Am. Chem. Soc. 1992, 114, 6556. (c) Belosludtsev, Y. Y.; Bhatt,
R. K.; Falck, J. R. Tetrahedron Lett. 1995, 36, 5881. (d) Falck, J. R.; Bhatt,
R. K.; Reddy, K. M.; Ye, J. Synlett 1997, 481. (e) Linderman, R. J.; Graves,
D. M.; Kwochka, W. R.; Ghannam, A. F.; Anklekar, T. V. J. Am. Chem.
Soc. 1990, 112, 7438. (f) Ye, J.; Bhatt, R. K.; Falck, J. R. J. Am. Chem. Soc.
1994, 116, 1. (g) Jensen, M. S.; Yang, C.; Hsiao, Y.; Rivera, N.; Wells,
K. M.; Chung, J. Y. L.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett.
2000, 2, 1081. (h) Jarosz, S. Tetrahedron Lett. 1996, 37, 3063. (i) Kells,
K. W.; Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666. (j) Goli, M.; He,
A.; Falck, J. R. Org. Lett. 2011, 13, 344. (k) Labadie, J. W.; Stille, J. K.
J. Am. Chem. Soc. 1983, 105, 6129. (l) Milstein, D.; Stille, J. K. J. Am. Chem.
Soc. 1979, 101, 4992. (m) Fouquet, E.; Pereyre, M.; Rodriguez, Al. L.
J. Org. Chem. 1997, 62, 5242.
(5) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38, 2411.
(b) Barros, M. T.; Maycock, C. D.; Madureira, M. I.; Ventura, M. R.
Chem. Commun. 2001, 1662. (c) Scott, W. J.; Stille, J. K. J. Am. Chem.
Soc. 1986, 108, 3033. (d) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 6343. (e) Furukawa, A.; Arita, T.; Fukuzaki, T.;
Mori, M.; Honda, T.; Satoh, S.; Matsui, Y.; Wakabayashi, K.; Hayashi,
S.; Nakamura, K.; Araki, K.; Kuroha, M.; Tanaka, J.; Wakimoto, S.;
Suzuki, O.; Ohsumi, J. Eur. J. Med. Chem. 2012, 54, 522. (f) Modha,
S. G.; Trivedi, J. C.; Mehta, V. P.; Ermolat’ev, D. S.; Va der Eycken,
E. V. J. Org. Chem. 2011, 76, 846.
r
10.1021/ol4003948
Published on Web 03/05/2013
2013 American Chemical Society

groups without an activating group in the alkyltin com-
pound are usually very inert in this chemical transforma-
tion except for methyl, allyl, and benzyl groups, although
this type of transfer is often desired in organic synthesis.5
Recently we developed a simple preparation of optically
active dihydrostannolanes via radical cyclization6 of chiral
aza-MoritaÀBaylisÀHillman adducts.7 The transforma-
tion passes through a radical SH2 process at the tin atom.8
The obtained stannolanes contain Csp3Àtin and Csp2Àtin
bonds in a single molecule and are potentially good candi-
dates for the double coupling reaction under Pd-catalyzed
conditions and could provide an efficient and novel synthe-
sis of tetrahydrobenz[f]isoindoles (Scheme 1).9
2a, but the yield was only 18% (entry 1). Use of 100 mol %
of Pd(t-Bu3P)2 and 5 equiv of CsF improved the yield of 2a
to 41% (entry 2). The structure of 2a was unambiguously
determined by X-ray crystallographic analysis.12 To im-
prove the yield of the coupling products, we modified the
ester group. Conversion of the ester to hydroxymethyl
derivatives 3a was achieved by simple DIBAL-H reduc-
tion of 1a. Compound 3a (X = CH2OH) was examined
in the double coupling reaction with 1,2-dibromobenzene
(Y = Br). The reaction performed under ambient tem-
perature conditions did not progress, and starting materi-
als were recovered.
Table 1. Optimization for Double Coupling Reaction of 1a, 3a,
and 5a
Scheme 1. Double MigitaÀKosugiÀStille Coupling Strategy for
the Preparation of Tetrahydrobenz[f]Isoindoles
Tetrahydrobenz[f]isoindoles are of interest for their
biological activities such as analgesic, antidepressant, anti-
hypertensive, antiasthmatic, or antiallergic activities.10
The preparation of this heterocyclic system has previously
been achieved by intramolecular DielsÀAlder reactions
with styrene,11 but the stereoselectivity was not really high.
In this paper we report a novel double coupling reaction
using a nonactivated Csp3ÀSn bond to give optically active
tetrahydrobenz[f]isoindoles. Two different aryl groups were
also introduced using inter- and intramolecular double
coupling conditions. A regioselective coupling reaction was
also achieved using 1-bromo-2-iodobenzene derivatives.
We first examined the reaction of bicyclic dihydrostan-
nolane ester 1a (X = CO2t-Bu) with 1,2-dibromobenzene
(Y = Br). The results are summarized in Table 1. We
successfully obtained the desired double coupling product
Pd
additives
(equiv)
yield
(%)a
entry
1
(mol %)
subst
Y
prod
Pd(t-Bu3P)2 1a
(10)
Br CsF (5)
2a
18
41
48
24
26
0b
37
55
76
66
66
0
2
Pd(t-Bu3P)2 1a
(100)
Br CsF (5)
2a
4a
4a
4a
4a
4a
3
Pd(OAc)2
(10)c
3a
3a
3a
Br DABCO (3)
Br DABCO (3)
Br DABCO (3)
4
Pd(OAc)2
(10)d
5
Pd(OAc)2
(10)e
6
Pd(t-Bu3P)2 3a
Br
À
(10)
7
Pd(t-Bu3P)2 3a
Br K2CO3 (3)
(10)
8
Pd(t-Bu3P)2 3a
Br iPr2NEt (3) 4a
(10)
9
Pd(t-Bu3P)2 3a
Br DABCO (3)
Br DABCO (3)
Br DABCO (3)
4a
4a
4a
4a
6a
(6) Kamimura, A.; Ishikawa, S.; Noguchi, F.; Moriyama, T.; So, M.;
Murafuji, T.; Uno, H. Chem. Commun. 2012, 48, 6592.
(7) (a) Kamimura, A.; Okawa, H.; Morisaki, Y.; Ishikawa, S.; Uno,
H. J. Org. Chem. 2007, 72, 3569. (b) Ishikawa, S.; Noguchi, F.;
Kamimura, A. J. Org. Chem. 2010, 75, 3578.
(8) (a) Ryu, I.; Kurihara, A.; Muraoka, H.; Tsunoi, S.; Kambe, N.;
Sonoda, N. J. Org. Chem. 1994, 59, 7570. See also: (b) Kulicke, K. J.;
Chatgilialoglu, C.; Kopping, B.; Giese, B. Helv. Chim. Acta 1992, 75,
935. Kopping, B.; Chatgilialoglu, C.; Zehnder, M.; Giese, B. J. Org.
Chem. 1992, 57, 3994. (c) Miura, K.; Oshima, K.; Utimoto, K. Chem.
Lett. 1992, 2477. (d) Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1995, 117,
7283. (e) Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 6375.
(9) Nagao, I.; Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2009,
48, 7573.
(10)
10
11
12
13
Pd(t-Bu3P)2 3a
(5)
Pd(t-Bu3P)2 3a
(2)
Pd(t-Bu3P)2 3a
(10)
Cl
DABCO (3)
Pd(t-Bu3P)2 5a
(10)
Br DABCO (3)
48
a Isolated yield. b Complex mixture. c Xphos (32 mol %) was added.
d PPh3 (29 mol %) was added. e BINAP (16 mol %) was added.
(10) (a) Middlemiss, D. Ger. Pat. 2259498; Chem. Abstr. 1973, 79,
66171u. (b) Achini, R.; Oppolzer, W. Ger. Pat. 2348593; Chem. Abstr.
1974, 81, 13386c. (c) Achini, A.; Oppolzer, W.; Pfenninger, E. Swiss Pat.
611886, 1979; Chem. Abstr. 1979, 91, 140720p. (d) Achini, A.; Oppolzer,
W.; Pfenninger, E. Swiss Pat. 611884, 1979; Chem. Abstr. 1980, 92,
41756u. (e) Debernardis, J. F.; Meyer, M. D.; Sippy, K. B. U.S. Pat. WO
9006927, 1990; Chem. Abstr. 1991, 114, 815704. (f) Bowman, R. M.;
Gschwend, H. W. U.S. Pat. 4014899, 1977; Chem. Abstr. 1977, 87,
53077h.
The desired double coupling adduct 4a was isolated in
48% yield when the reaction was carried out in the pre-
sence of Pd(OAc)2 with Xphos and DABCO (entry 3).
(12) Crystallographic data for the structures 2 and 7a have been
deposited as CCDC 845992 and CCDC 915372, respectively.
ꢀ
(11) Pedrosa, R.; Andres, C.; Nieto, J. J. Org. Chem. 2002, 67, 782.
Org. Lett., Vol. 15, No. 6, 2013
1403

Use of other ligands such as PPh3 and BINAP also
progressed the reaction, but the yield of 4a remained at a
low level (entries 4 and 5). The absence of base in the
reaction mixture a gave complex mixture (entry 6). DAB-
CO afforded the best results for the reaction catalyzed by
Pd(t-Bu3P)2 (entries 7À9). A catalyst loading could be
reduced to 2 mol % with a slight loss of yield (entries
9À11). Use of dichlorobenzene failed to form double
coupling adducts although the starting material was com-
pletely consumed (entry 12). Thus, we concluded that use
of 10 mol % Pd(t-Bu3P)2 and 3 equiv of DABCO provided
the optimal conditions for the double coupling reaction.
Methyl ether 5a also afforded the corresponding double
coupling products 6a, but the yield remained at a moderate
level (entry 13). The existence of an OH group in 3a
probably activated the alkyl group transfer to progress
the double coupling reaction.13
products 4 were isolated in good yields. For example,
treatment of 3a with 1,2-dibromo-4,5-dimethoxybenzene
smoothly produced 4b in 73% yield as a single diastereo-
mer. During the coupling reaction no scrambling of stereo-
chemistry was observed and enantiomeric excesses of the
starting materials were maintained in the products.
To explore the possibility of introducing two different
aryl groups via the double coupling reaction, we examined
compound 3f, which we hoped would serve as a good
candidate for a tandem coupling reaction (Scheme 2).
Treatment of 3f under similar conditions, in the absence
of halobenzene (ArX), gave 7a in 76% yield. The structure
of 7a was determined by X-ray crystallographic analysis.12
To oursurprise, an exo-methylene unit was introducedand
an intramolecular coupling reaction occurred only at the
sp3-carbon site. We assume that the hydrogen source in 7a
might come from the OH in 3f or water in wet dioxane.
Compound 3f underwent partial double coupling when
treated with bromobenzene; the double coupling product
7b was formed along with 7a in a 61% total yield. The ratio
of 7a:7b was 41:59. To improve the selectivity of the
reaction in favor of 7b we examined iodobenzene instead.
The reaction, in the presence of iodobenzene, under the
same conditions, predominantly gave 7b in 63% yield. The
ratio between 7a and 7b now reached 9:91. Thus we achieved
the introduction of two different aryl groups using inter- and
intramolecular coupling reactions.
The aforementioned reaction conditions were applied to
various compounds of general structure 3, which were
prepared by the reduction of 1 with DIBAL-H. The results
are summarized in Table 2.
Table 2. Double Coupling Reaction for 3
Scheme 2. Introduction of Two Different Aryl Groups Using
Inter- and Intramolecular Coupling Reactions
entry
substrate
Ar
R
4; yield (%)a
1
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3c
3d
3d
3d
3d
3e
3e
3e
3e
Ph
Ph
Ph
MeO
F
4b; 73
4c; 78
4d; 64
4e; 71
4f; 64
4g; 70
4h; 75
4i; 73
4j; 56
4k; 67
4l; 76
4m; 73
4n; 59
4o; 70
4p; 70
4q; 66
4r; 65
4s; 73
4t; 74
2
3
Me
H
4
p-MeOC6H4-
p-MeOC6H4-
p-MeOC6H4-
p-MeOC6H4-
p-FC6H4-
p-FC6H4-
p-FC6H4-
p-FC6H4-
o-Tol
5
MeO
F
6
7
Me
H
8
9
MeO
F
10
11
12
13
14
15
16
17
18
19
Me
H
o-Tol
MeO
F
We next examined the regioselective double coupling reac-
tion with 1-bromo-2-iodobenzene derivatives (Scheme 3).
For example, 1-bromo-4-fluoro-2-iodobenzene underwent
regioselective coupling under the standard conditions using
CsF, and couplingproduct8wasisolated in52%yield. The
regioisomeric ratio of 8:9 was 91:9. Although TLC analyses
indicated that other products were formed in the reaction,
we could not isolate them because of their high polarity.
On the other hand, 2-bromo-4-fluoro-1-iodobenzene gave
its regioisomer 9 in 49% yield; compounds 8 and 9 were
formed in 4:96 ratio. Both coupling reactions progressed in
a highly regioselective manner. The structure of these
compounds was unambiguously determined by NOE ob-
servation. Thus, H8 was unambiguously assigned from the
o-Tol
o-Tol
Me
H
m-Tol
m-Tol
MeO
F
m-Tol
m-Tol
Me
a Isolated yields.
The double coupling reaction with 1,2-bromoarenes
took place smoothly, and the desired double coupling
(13) An intramolecular activation in 2-(2-hydroxyprop-2-yl)phenyl-
substituted alkylsilanes is reported; see: Nakao, Y.; Takeda, M.;
Matsumoto, T.; Hiyama, T. Angew. Chem., Int. Ed. 2010, 49, 444.
1404
Org. Lett., Vol. 15, No. 6, 2013

that the double coupling reaction happened in a sequen-
tial manner. Thus, the iodine-attached carbon was selec-
tively substituted by the Csp2Àtin bond and the bromine-
attached carbon was selectively substituted by the Csp3
carbon. Addition of CsF was necessary to progress the
reaction smoothly for iodobenzene derivatives.14 Hence the
double coupling reaction was readily controlled by the use
of substituted 1-bromo-2-iodobenzene derivatives.
Scheme 3. Regioselective Double Coupling Reaction Using
1,2-Bromoiodobenzenes
In conclusion we have successfully developed a new
Csp3ÀSn unit for the coupling partner of an intramolecular
MigitaÀKosugiÀStille coupling reaction and effectively
prepared tetrahydrobenz[f]isoindoles in one step from an
optically active stannolane, which was readily produced by
a radical cascade reaction. Use of 1-bromo-2-iodobenzene
achieved regioselective coupling reactions. The present
methodology will provide a useful synthetic method and
good information to progress nonactivated Csp3ÀSn com-
pounds for the palladium-catalyzed coupling partner.
Acknowledgment. We are grateful to Dr. Tsuyoshi Arai
and Dr. Yousuke Oota, UBE Scientific Analysis Labora-
tory Inc. for NMR analyses of several compounds.
coupling constant between H8 and F. For example, H8 in
1
compound 8 appeared at 6.66 ppm with a large J19 FÀ H
coupling constant of 9.2 Hz, while H8 in compound 9 was
1
observed at 6.90 ppm with a moderate level of J 19FÀ H
Supporting Information Available. Experimental pro-
cedures, compound characterization data, and CIF files.
This material is available free of charge via Internet at
http://pubs.acs.org.
coupling of 5.7 Hz. Signal enhancements for H9 were
observed at 8% for 8 and 13% for 8 when H8 in 8 and 9
were irradiated, respectively. These results clearly suggested
(14) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Angew. Chem., Int. Ed.
2004, 43, 1132; see also ref 9.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
1405