One-pot construction of aza-or oxa-bridged benzocycloheptanes from readily available 2,3-allenyl malonates or 2,3-allenols and o-iodobenzaldehyde or imine

Article abstract of DOI:10.1021/ol102811x

A Pd(OAc)₂-catalyzed reaction of 2,3-alkadienyl malonates or 2,3-allenols with o-iodobenzaldehyde or its N-tosyl imine occurred smoothly in MeCN at 80 °C to form the oxa-or aza-bridged benzocycloheptane derivatives with important biological pot

Full text of DOI:10.1021/ol102811x

ORGANIC
LETTERS
2011
Vol. 13, No. 3
466-469
One-Pot Construction of Aza- or
Oxa-Bridged Benzocycloheptanes from
Readily Available 2,3-Allenyl Malonates
or 2,3-Allenols and o-Iodobenzaldehyde
or Imine
Qiankun Li, Xinpeng Jiang, Chunling Fu, and Shengming Ma*
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang UniVersity, Hangzhou 310027, Zhejiang, People’s Republic of China
masm@mail.sioc.ac.cn
Received November 19, 2010
ABSTRACT
A Pd(OAc)2-catalyzed reaction of 2,3-alkadienyl malonates or 2,3-allenols with o-iodobenzaldehyde or its N-tosyl imine occurred smoothly in
MeCN at 80 °C to form the oxa- or aza-bridged benzocycloheptane derivatives with important biological potential. With the optically active
2,3-allenols, the absolute configurations of all the three chiral centers have been conveniently established.
Aza- or oxa-bridged benzocycloheptane compounds A are
core structures in a class of compounds with interesting
pharmacological activities for type II diabetes (A1 and A2)1
and ALK- or c-Met-mediated diseases (A3 and A4)2 (Figure
1). Very limited methods have been developed for the
synthesis of these type of products;3 thus, new methodologies
for the efficient synthesis of this type of skeleton are highly
desirable.
On the other hand, Pd-catalyzed cyclization of allenes has
been extensively developed as an efficient methodology for the
synthesis of simple cyclic products via the intermediacy of
Figure 1. Pharmaceutically active aza-bridged benzocycloheptanes.
(1) Ammenn, J.; Paal, M.; Ruehter, G.; Schotten, T.; Stenzel, W. PCT
Int. Appl. WO 2000078724, 2000.
π-allylic palladium species (Scheme 1) by Cazes, Cheng, Grigg,
Ibuka, Larock, Negishi, Walkup, us, etc.4 Thus, we envisioned
that the A-type compounds may be efficiently constructed via
the intramolecular allylic substitution of π-allylic palladium
(2) Ahmed, G.; Bohnstedt, A.; Breslin, H. J.; Burke, J.; Curry, M. A.;
Diebold, J. L.; Dorsey, B.; Dugan, B. J.; Feng, D.; Gingrich, D. E.; Guo,
T.; Ho, K.-K.; Learn, K. S.; Lisko, J. G.; Liu, R.-Q.; Mesaros, E. F.;
Milkiewicz, K.; Ott, G. R.; Parrish, J.; Theroff, J. P.; Thieu, T. V.; Tripathy,
R.; Underiner, T. L.; Wagner, J. C.; Weinberg, L.; Wells, G. J.; You, M.;
Zificsak, C. A. PCT Int. Appl. WO 2008051547, 2008.
(4) For related reviews, see: (a) Zimmer, R.; Dinesh, C. U.; Nandanan,
E.; Khan, F. A. Chem. ReV. 2000, 100, 3067. (b) Yamamoto, Y.;
Radhakrishnan, U. Chem. Soc. ReV. 1999, 28, 199. (c) Bates, R. W.;
Satcharoen, V. Chem. Soc. ReV. 2002, 31, 12. (d) Ma, S. Chem. ReV. 2005,
105, 2829.
(3) (a) Curphey, M.; Lennon, M.; Murphy, E.; Proctor, G. R. J. Chem.
Soc., Perkin Trans. 1 1979, 2013. (b) Grunewald, G. L.; Sall, D. J.; Monn,
J. A. J. Med. Chem. 1988, 31, 433. (c) Nicolas, T. E.; Franck, R. W. J.
Org. Chem. 1995, 60, 6904.
10.1021/ol102811x  2011 American Chemical Society
Published on Web 12/23/2010

In this paper, we wish to report our recent achievement in
the realization of such a multistep one-pot transformation
with the convenient establishment of the absolute configura-
tions of all the three chiral centers by using the optically
active alcohols, showing the beauty and efficiency of allene
chemistry.
Scheme 1
. Concept for the One-Step Construction of
Oxa-Bridged Benzocycloheptanes
We started this project by using dimethyl 2,3-butadienyl
malonate 1a and o-iodobenzaldehyde N-tosyl imine 2 to develop
the reaction conditions with K2CO3 as the base (Table 1).
Table 1. Pd-Catalyzed Cyclization of Dimethyl 2,3-Butadienyl
Malonate 1a and o-Iodobenzaldehyde N-Tosyl Imine 2:
Optimization of Reaction Conditionsa
yield of
entry catalyst/ligand/additive
solvent
time(h)
3a (%)b
1
2
3
4
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/TFP
dioxane
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10.5
17.5
5.5
3
0
17
38
49
30
62
80
80
5
Pd(dba)2/TFP
47
6c
7c
8d
Pd(OAc)2/TFP/4 Å MS
Pd(OAc)2/4 Å MS
Pd(OAc)2/4 Å MS
Pd(OAc)2/4 Å MS
Pd(OAc)2/4 Å MS
7.5
3.5
3.5
3.5
3.5
9d e
80
,
10d e f
80(77g)
,
,
a [1a] ) 0.033 mmol/mL. b NMR yield determined by using CH2Br2 as
the internal standard. c 4 Å MS (61.3 mg/mL) was added. d 4 Å MS (12.2
mg/mL) was added. e [1a] ) 0.067 mmol/mL. f 1.5 equiv of 2 were used.
g Isolated yield.
intermediate B, in which the nucleophilic Y anion may be
generated from the intramolecular 1,2-addition of the X anion
to the CdY moiety of intermediate syn-C; the π-allylic
palladium moiety in syn-C may be easily generated from the
intermolecular carbopalladation of allenes (Scheme 1).5 If these
sequential transformations are feasible, it may provide one of
the most straightforward pathways for the synthesis of the
A-type of relatively complicated skeletons with biological
potential. With this notion in mind, although there is a report
on a three-component cyclization of 2-(2′,3′-dienyl)malonates,
organic halides, and imines forming simple cis-pyrrolidine
derivatives,6 we realized that the challenge here would be the
expected ring strain in the target skeleton, which requires the
sequential smooth match of the reactivities of all the in situ
generated intermediates or leading to the easy formation of
three- or five-membered products D or E;7,8 the regioselectivity
of Pd-catalyzed allylation (forming bridged product G by
attacking at the less-sterically hindered carbon terminal of
B); and the diastereoselectivity and the final construction of
the absolute configurations of the chiral centers in target A.
However, with Pd(OAc)2-PPh3 as the catalyst, the reaction in
dioxane failed to afford the expected product 3a (entry 1);
interestingly, it was observed that the solvent effect is obvious:
the reaction in toluene and MeCN yielded 3a in 17% and 38%,
respectively (entries 2 and 3); with TFP (TFP ) tri-(2-
furyl)phosphine) as the ligand instead of PPh3, the yield in
MeCN was improved to 49% (entry 4); furthermore, we
reasoned that the trace amount of water may be critical to the
reaction since all the anionic intermediates are sensitive to water;
thus, 4 Å MS was added to remove moisture, and the yield
was improved to 62% (entry 6); to our surprise, with the
addition of 4 Å MS, TFP is not required and the yield was
further improved to 80% (Compare entry 6 with entry 7); the
concentration of the starting materials has no effect on the yield
(5) For a seminal report on a Pd-promoted insertion reaction of allenes
forming π-allylic palladium species, see: Schultz, R. G. Tetrahedron Lett.
1964, 5, 301. For a recent review on carbopalladation of allenes, see: Bai,
T.; Ma, S.; Jia, G. Coord. Chem. ReV. 2009, 253, 423.
(8) (a) Ahmar, M.; Cazes, B.; Gore, J. Tetrahedron Lett. 1985, 26, 3795.
(b) Ahmar, M.; Cazes, B.; Gore, J. Tetrahedron 1987, 43, 3453. (c) Besson,
L.; Bazin, J.; Gore, J.; Cazes, B. Tetrahedron Lett. 1994, 35, 2881. (d)
Gamez, P.; Ariente, C.; Gore, J.; Cazes, B. Tetrahedron 1998, 54, 14835.
(e) Ma, S.; Zhao, S. Org. Lett. 2000, 2, 2495. (f) Ma, S.; Jiao, N.; Zhao, S.;
Hou, H. J. Org. Chem. 2002, 67, 2837.
(6) Ma, S.; Jiao, N. Angew. Chem., Int. Ed. 2002, 41, 4737.
(7) Ma, S.; Zhao, S. J. Am. Chem. Soc. 1999, 121, 7943
Org. Lett., Vol. 13, No. 3, 2011
.
467

of 3a, and 1.5 equiv of 2 are sufficient. The structure of 3a
was confirmed by an X-ray single crystal diffraction study
(Figure 2).9
addition of 4 Å MS was not required here. However, the
reaction with TFP afforded the product 6a in a much higher
yield (70% vs 56%). In addition, it should also be noted that 1
equiv of the aldehyde is sufficient with an even higher yield
(Table 3, entry 1). Under these optimized reaction conditions,
Table 3. Pd(OAc)2-TFP-Catalyzed Cyclization of 2,3-Allenols
and o-Iodobenzaldehydea
4
Figure 2. ORTEP representation of 3a.
isolated yield
entry
R1
R2
H (4a)
time(h)
of 6 (%)
1
2
H
H
H
H
H
Ph
4.5
10.5
52.8
11
75 (6a)
73 (6b)
87 (6c)
68 (6d)
66 (6e)
92 (6f)
90 (6g)
88 (6h)
90 (6i)
77 (6j)
n-C7H15 (4b)
Ph (4c)
Bn (4d)
allyl (4e)
H (4f)
With this set of optimized reaction conditions, a different
R1 group may be introduced to the allylic position of the
CdC bond in 3 in 91-95% yields (entries 2-5, Table 2).
3
4
5
19
6
2.5
13.5
21
7
2-BrC6H4
2-MeOC6H4
n-C6H13
H (4g)
8
H (4h)
9
H (4i)
6
6.5
10
4-ClC6H4
H (4j)
Table 2. Pd(OAc)2-Catalyzed Synthesis of Aza-Bridged
Benzo[a,d]cycloheptenes 3a
a [4] ) 0.1 mmol/mL.
the scope was then studied. Different R1 and R2 may be
introduced to the allylic and homoallylic positions of the CdC
bond in 6 (Table 3). Gratifyingly, only one diastereomer was
observed to form even with the R1 substituent as determined
1
1
by H NMR analysis of the crude reaction mixture before
entry
R1
time(h)
isolated yield of 3 (%)
chromatographic separation on silica gel (entries 6-10). The
relative configurations in these products 6f-j were determined
by the X-ray single crystal diffraction study of 6f (Figure 3).10
Again, it should be noted that the three- or five-membered D-
or E-type products and bridged products G were not formed.
1
2
3
4
5
H (1a)
Ph (1b)
Bn (1c)
n-C4H9 (1d)
Allyl (1e)
3.5
7
6.2
4
77 (3a)
94 (3b)
95 (3c)
94 (3d)
91 (3e)
3
a [1] ) 0.067 mmol/mL.
In all the cases, only the bridged product 3 was formed as
1
judged by H NMR analysis of the crude product before
chromatographic purification on silica gel; the three- or five-
membered D- or E-type products and bridged products G
were not formed.
With these results in hand we started to expand the scope of
the reaction by using 2,3-allenols and o-iodobenzaldehyde as
the starting materials. A control experiment showed that the
(9) Crystal data for compound 3a: C23H23NO6S, MW ) 441.48, Triclinic,
space group P-1, final R indices [I > 2σ(I)], R1 ) 0.0578, wR2 ) 0.1489;
R indices (all data), R1 ) 0.0593, wR2 ) 0.1517; a ) 10.2477(5) Å, b )
10.6579(5) Å, c ) 11.7877(6) Å, R ) 97.6360(10)°, ꢀ ) 99.7840(10)°, γ
) 117.3550(10)°, V ) 1093.62(9) Å3, T ) 173(2) K, Z ) 2, reflections
collected/unique 12886/3836 (Rint ) 0.1482), number of observations
[> 2σ(I)] 3635, parameters: 288. Supplementary crystallographic data have
been deposited at the Cambridge Crystallographic Data Centre, CCDC
779702.
Figure 3. ORTEP representation of 6f.
Optically active 2,3-allenols are readily available from
optically active propargylic alcohol.11 With these optically active
alcohols 4f, 4g, 4i, and 4j as the starting materials, the absolute
468
Org. Lett., Vol. 13, No. 3, 2011

configurations of the other two chiral centers in optically active
products 6f, 6g, 6i, and 6j have been efficiently established with
excellent de in >97% ee (Table 4). The absolute configurations
Table 4. Pd(OAc)2-TFP-Catalyzed Cyclization of Optically
Active 2,3-Allenols with o-Iodobenzaldehydea
Figure 4. ORTEP representation of (1R,9R,10R)-6j.
that the terminal position attack would form a seven-membered
ring instead of the current much more favored five-membered
ring in 6 (Scheme 2).
4
Scheme 2
isolated yield
ee of
entry
R
time (h)
of 6 (%)
6 (%)
1
2
3
4
5
Ph ((S)-4f)
2.5
2
13.5
6.5
3.5
92 ((1R,9R,10R)-6f)
91 ((1S,9S,10S)-6f)
98.0
97.9
Ph ((R)-4f)
2-BrC6H4 ((S)-4g)
n-C6H13 ((R)-4i)
4-ClC6H4 ((S)-4j)
91 ((1R,9R,10R)-6g) 99.8
90 ((1S,9R,10R)-6i)
84 ((1R,9R,10R)-6j)
99.8
99.8
a [4] ) 0.1 mmol/mL.
in these products were determined by an X-ray single crystal
diffraction study of (1R,9R,10R)-6j (Figure 4).12 Obviously, no
reracemization occurred here.
The diastereoselectivity may be explained as follows: Car-
bopalladation of allenols in the presence of K2CO3 would favor
the formation of π-allylic palladium intermediate syn-8 due to
the steric interaction of Pd and the substituent containing the
hydroxyl group in anti-8. Intramolecular 1,2-addition of the
alkoxyl anion to the aldehyde functionality would form 9 or
10. However, the subsequent intramolecular allylation of 10
forming 6′ would be largely disfavored due to the steric
interaction of the endo-H with the formed oxa-bridge and the
R group with the exocyclic methylene group. Thus, diastere-
oisomer 6 was formed exclusively via the intermediacy of 9.
The regioselectivity of allylation has been controlled by the fact
In conclusion, we have developed an efficient and high-
yielding synthesis of aza or oxa-bridged benzocycloheptanes
from readily available 2,3-allenyl malonates or 2,3-allenols and
o-iodobenzaldehyde or N-tosyl imine. This one-pot reaction is
clean and highly diastereoselective. With optically active 2,3-
allenols, smooth double stereoinductions led to the formation
of highly optically active oxa-bridged benzocycloheptanes. Due
to the efficiency of the one-pot process, potential of the products,
easy availability of these starting materials, and the excellent
diastereoselectivity, this chemistry will be of high interest for
organic and medicinal chemists. Further studies including the
scope and application are being conducted in our laboratory.
(10) Crystal data for compound 6f: C68H56O8, MW ) 1001.13, mono-
clinic, space group P2(1)/c, final R indices [I > 2σ(I)], R1 ) 0.0496, wR2
) 0.0934; R indices (all data), R1 ) 0.1132, wR2 ) 0.1131; a ) 10.6114(6)
Å, b ) 10.5287 (6) Å, c ) 46.396(3) Å, R ) 90°, ꢀ ) 98.255(2)°, γ )
90°, V ) 5129.8(5) Å3, T ) 173(2) K, Z ) 4, reflections collected/unique
68695/12248 (Rint ) 0.0818), number of observations [> 2σ(I)] 6982,
parameters: 717. Supplementary crystallographic data have been deposited
at the Cambridge Crystallographic Data Centre, CCDC 779703.
(11) (a) Xu, D.; Li, Z.; Ma, S. Tetrahedron Lett. 2003, 44, 6343. (b)
Kuang, J.; Ma, S. J. Org. Chem. 2009, 74, 1763. (c) Ma, S.; Hou, H.; Zhao,
S.; Wang, G. Synthesis 2002, 1643.
Acknowledgment. Financial support from the Major State
Basic Research & Development Program (2011CB808700) and
National Natural Science Foundation of China (20732005) are
greatly appreciated. We thank Mr. Bo Chen in this group for
reproducing the preparation of 3d in Table 2, 6e in Table 3,
and (1R, 9R, 10R)-6g in Table 4. Shengming Ma is a Qiu Shi
Adjunct Professor at Zhejiang University.
(12) Crystal data for compound (1R,9R,10R)-6j: C2.27H1.73Cl0.13O0.27, MW
) 37.96, monoclinic, space group P2(1), final R indices [I > 2σ(I)], R1 )
0.0234, wR2 ) 0.0632; R indices (all data), R1 ) 0.0239, wR2 ) 0.0637; a
) 8.1646(3) Å, b ) 5.2885(2) Å, c ) 16.1885(6) Å, R ) 90°, ꢀ )
99.2100(10)°, γ ) 90°, V ) 689.98(4) Å3, T ) 173(2) K, Z ) 15, reflections
collected/unique 7972/2408 (Rint ) 0.0164), number of observations [> 2σ(I)]
2362, parameters: 189. Supplementary crystallographic data have been deposited
at the Cambridge Crystallographic Data Centre, CCDC 779701.
Supporting Information Available: General procedure
and spectroscopic data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
OL102811X
Org. Lett., Vol. 13, No. 3, 2011
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