Palladium(0)-catalyzed stereoselective cyclization of allenenes: Divergent synthesis of pyrrolidines and 3-azabicyclo[3.1.0]hexanes from single allenenes

Article abstract of DOI:10.1021/jo049663f

Two novel palladium(0)-catalyzed cyclizations of allenenes are described. Treatment of allenenes such as N-(1-alkyl-2,3-butadienyl)-N-allylsulfonamide with an aryl halide and K₂CO₃ in the presence of a catalytic amount of Pd(PPh

Full text of DOI:10.1021/jo049663f

SCHEME 1
P a lla d iu m (0)-Ca ta lyzed Ster eoselective
Cycliza tion of Allen en es: Diver gen t
Syn th esis of P yr r olid in es a n d
3-Aza bicyclo[3.1.0]h exa n es fr om Sin gle
Allen en es
Hiroaki Ohno,* Yusuke Takeoka, Yoichi Kadoh,
Kumiko Miyamura, and Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka
University, 1-6 Yamadaoka, Suita, Osaka 565-0871, J apan
t-tanaka@phs.osaka-u.ac.jp
Received February 28, 2004
SCHEME 2
Abstr a ct: Two novel palladium(0)-catalyzed cyclizations of
allenenes are described. Treatment of allenenes such as
N-(1-alkyl-2,3-butadienyl)-N-allylsulfonamide with an aryl
halide and K2CO3 in the presence of a catalytic amount of
Pd(PPh3)4 in dioxane affords 2,3-cis-pyrrolidines in a ste-
reoselective manner. In sharp contrast, cyclization of the
same allenenes using catalytic Pd2(dba)3‚CHCl3 in the
presence of allyl methyl carbonate in CH3CN leads to
stereoselective formation of a 3-azabicyclo[3.1.0]hexane
framework in moderate yields.
of the resulting allylstannanes.5 Palladium(II)-catalyzed
oxidative cyclization of allene-substituted alkenes and
palladium(0)-catalyzed cyclization of allenes bearing an
allyl ester moiety were reported by Ba¨ckvall.6 Although
some cyclizations of allenes with an additional multiple
bond such as Pauson-Khand-type reactions7 and cy-
cloadditions8 were reported, palladium(0)-catalyzed cy-
clization as shown in Scheme 1 is unknown as far as we
are aware. In the course of this study, we found an
unusual intramolecular cyclopropanation of the allenic
moiety with a double bond catalyzed by palladium(0). In
this paper, we describe full details of our study which
enables an efficient synthesis of both 2,3-cis-pyrroli-
dines 10 and 3-azabicyclo[3.1.0]hexanes 11 by the pal-
ladium(0)-catalyzed cyclization of the same allenenes 9
(Scheme 2).9
Allenes are an important class of compounds with
unique reactivities due to the existence of two orthogonal
π-bonds. In particular, in recent years transition-metal-
catalyzed cyclizations are becoming one attractive ap-
proach for the construction of heterocycles.1 Allenes of
the type 1, which bears a nucleophilic moiety such as a
nitrogen or oxygen-containing functional group, undergo
a variety of palladium(0)-catalyzed cyclizations to form
cyclic products 3 or 4 (Scheme 1).2,3 In sharp contrast,
palladium(0)-catalyzed reactions of allenes that contain
an additional multiple bond have scarcely been studied
until recently, despite their potential versatility in
organic synthesis. We expected that cyclization of alle-
nenes 5 would provide a useful approach to carbo- and
heterocycles such as 8.
Recently, Kang and co-workers reported that bisallenes
form five-membered rings on treatment with silylstan-
nane and palladium(0).4 Independently, RajanBabu and
co-workers observed stannylsilylation of allenynes under
similar reaction conditions followed by carbocyclization
With a view to synthesizing nitrogen heterocycles, we
prepared allenenes 17 through the diethylzinc-mediated
reductive synthesis of amino allenes catalyzed by pal-
ladium(0),10 starting from (S)-amino acid-derived amino
alcohols 12. A typical synthetic procedure is shown in
Scheme 3. Brominated R,â-enoates 13a -c were readily
(1) For recent reviews, see: (a) Zimmer, R.; Dinesh, C. U.; Nan-
danan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067-3125. (b) Hashmi,
A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590-3593.
(2) For pioneering works, see: (a) Larock, R. C.; Berrios-Pen˜a, N.
G.; Fried, C. A. J . Org. Chem. 1991, 56, 2615-2617. (b) Davies, I. W.;
Scopes, D. I. C.; Gallagher, T. Synlett 1993, 85. For a recent review,
see: (c) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12-
21.
(5) Shin, S.; RajanBabu, T. V. J . Am. Chem. Soc. 2001, 123, 8416-
8417.
(6) (a) Lo¨fstedt, J .; Franze´n, J .; Ba¨ckvall, J .-E. J . Org. Chem. 2001,
66, 8015-8025. (b) Franze´n, J .; Lo¨fstedt, J .; Dorange, I.; Ba¨ckvall, J .-
E. J . Am. Chem. Soc. 2002, 124, 11246-11247. (c) Franze´n, J .;
Ba¨ckvall, J .-E. J . Am. Chem. Soc. 2003, 125, 6056-6057.
(7) (a) Brummond, K. M.; Wan, H.; Kent, J . L. J . Org. Chem. 1998,
63, 6535-6545. (b) Mukai, C.; Nomura, I.; Yamanishi, K.; Hanaoka,
M. Org. Lett. 2002, 4, 1755-1758.
(8) (a) Wender, P. A.; J enkins, T. E.; Suzuki, S. J . Am. Chem. Soc.
1995, 117, 1843-1844. (b) Makino, T.; Itoh, K. J . Org. Chem. 2004,
69, 395-405 and references therein.
(9) For preliminary communications, see: (a) Ohno, H.; Miyamura,
K.; Takeoka, Y.; Tanaka, T. Angew. Chem., Int. Ed. 2003, 42, 2647-
2650. (b) Ohno, H.; Takeoka, Y.; Miyamura, K.; Kadoh, Y.; Tanaka, T.
Org. Lett. 2003, 5, 4763-4766.
(3) For some recent examples, see: (a) Ohno, H.; Toda, A.; Miwa,
Y.; Taga, T.; Osawa, E.; Yamaoka, Y.; Fujii, N.; Ibuka, T. J . Org. Chem.
1999, 64, 2992-2993. (b) Ma, S.; Zhao, S. J . Am. Chem. Soc. 1999,
121, 7943-7944. (c) Kang, S. K.; Kim, K.-J . Org. Lett. 2001, 3, 511-
514. (d) Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka,
T.; Takemoto, Y.; Ibuka, T. J . Org. Chem. 2001, 66, 4904-4914. (e)
Ohno, H. Yakugaku Zasshi 2001, 121, 733-741. (f) Hiroi, K.; Hirat-
suka, Y.; Watanabe, K.; Abe, I.; Kato, F.; Hiroi, M. Tetrahedron:
Asymmetry 2002, 13, 1351-1353.
(4) Kang, S.-K.; Baik, T.-G.; Kulak, A. N.; Ha, Y.-H.; Lim, Y.; Park,
J . J . Am. Chem. Soc. 2000, 122, 11529-11530.
10.1021/jo049663f CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/28/2004
J . Org. Chem. 2004, 69, 4541-4544
4541

SCHEME 3 a
SCHEME 5 a
a
Reagents: (a) TMS-acetylene, EtMgBr, CuCl; (b) TBAF; (c)
(HCHO)n, (i-Pr)2NH, CuBr; (d) NaH, allyl bromide; (e) LiAlH4; (f)
TsOH, 2,2-dimethoxypropane, MS 4A. TBAF ) tetrabutylammo-
nium fluoride.
preparation of 23 by way of Et2Zn-mediated reductive
allene synthesis was not possible because of a difficulty
in preparation of the substrate: Wittig olefination of the
corresponding aldehyde led to recovery of the starting
material. Furthermore, reaction of the propargyl alcohol
22 with o-nitrobenzenesulfonylhydrazine (NBSH) under
Mitsunobu conditions (Myers’ method)12 only gave an
unidentified byproduct.
a
Reagents: (a) DIBAL-H; (b) MsCl, Et3N; (c) Et2Zn, cat.
Pd(PPh3)4; (d) NaH, allyl bromide. Mts ) 2,4,6-trimethylphenyl-
sulfonyl.
SCHEME 4 a
To investigate the effect of the protected amino group
on the cyclization, we prepared allenenes 28 and 30,
which are carbocycle precursors, through the Crabbe´
reaction13 (Scheme 5). Copper-catalyzed 1,4-addition of
trimethylsilylacetylide to dibenzyl (isopropylidene)ma-
lonate 24 afforded 25 in 93% yield. Deprotection of the
trimethylsilyl group followed by the Crabbe´ reaction13 of
the resulting terminal acetylene 26 gave allene 27
although in low yield. The allene 27 was then treated
with NaH and allyl bromide in DMF to give 28, the ester
groups of which were reduced with LiAlH4 and protected
to afford acetonide 30 (Scheme 5).
In an initial experiment, we investigated the pal-
ladium(0)-catalyzed cyclization of the allenene 17d and
found that the carbocyclization of allenenes and subse-
quent â-hydride elimination proceeds efficiently upon
treatment with iodobenzene (7 equiv) and K2CO3 (7
equiv) in the presence of a catalytic amount of Pd(PPh3)4
(Table 1). Reaction of 17d in refluxing dioxane provided
the 2,3-cis-pyrrolidine 31a in 85% yield as the sole
isolable product (Table 1, entry 1). Decreased loading of
iodobenzene (2 equiv) and K2CO3 (2 equiv) lowered the
yield to 60% (entry 2). Although the reaction in CH3CN
gave 61% yield of 31a , other polar solvents such as
DMSO and DMF were less effective (entries 4 and 5).
From these results, dioxane was found to be the solvent
of choice for the pyrrolidine formation from allenenes.
Whereas the use of 4-iodoanisole (entry 6) and 4-iodo-
toluene (entry 7) as the aryl halide gave comparable
a
Reagents: (a) TsCl, Et3N; (b) TBSCl, imidazole; (c) NaH, allyl
bromide; (d) TBAF; (e) (COCl)2, DMSO, then (i-Pr)2NEt; (f) TMS-
acetylene, n-BuLi; (g) NaOMe, MeOH; (h) MsCl, Et3N; (i) LiAlH4,
AlCl3.
prepared from amino alcohols 12 (see the Supporting
Information). Reduction of 13 with DIBAL-H afforded
allylic alcohols 14a -c, which were then treated with
MsCl and Et3N. Reaction of the resulting mesylates
15a -c with Et2Zn and a catalytic amount of Pd(PPh3)4
in THF10 gave allenes 16a -c in high yields. Other known
amino allenes 16d and 16e were also prepared in a
similar manner according to the literature.10 Allylation
of the protected amino group of 16 gave the requisite
allenenes 17a -e in high yields. Similarly, N-Boc deriva-
tive 19 was readily synthesized from N-Boc-(S)-valinol
(see the Supporting Information).
Allenene 23 bearing a geminal dimethyl group was
synthesized from 2-amino-2-methyl-1-propanol 20 as
shown in Scheme 4. Tosylation followed by allylation of
the amino group by the standard procedure afforded 21,
which was converted into the corresponding propargyl
alcohol 22. Hydride reduction of the corresponding me-
sylate with LiAlH4 and AlCl311 afforded allenene 23 with
a geminal dimethyl group. It should be noted that
(11) (a) Claesson, A.; Olsson, L.-I. J . Am. Chem. Soc. 1979, 101,
7302-7311. See also, (b) Borden, W. T.; Corey, E. J . Tetrahedron Lett.
1969, 10, 313-316.
(10) (a) Ohno, H.; Toda, A.; Oishi, S.; Tanaka, T.; Takemoto, Y.; Fujii,
N.; Ibuka, T. Tetrahedron Lett. 2000, 41, 5131-5134. (b) Ohno, H.;
Miyamura, K.; Tanaka, T.; Oishi, S.; Toda, A.; Takemoto, Y.; Fujii,
N.; Ibuka, T. J . Org. Chem. 2002, 67, 1359-1367.
(12) Myers, A. G.; Zheng, B. J . Am. Chem. Soc. 1996, 118, 4492-
4493.
(13) Searles, S.; Li, Y.; Nassim, B.; Lopes, M.-T. R.; Tran, P. T.;
Crabbe´, P. J . Chem. Soc., Perkin Trans. 1 1984, 747-751.
4542 J . Org. Chem., Vol. 69, No. 13, 2004

TABLE 1. Op tim iza tion of Rea ction Con d ition s for
TABLE 2. Ster eoselective F or m a tion of Va r iou s
Ster eoselective Syn th esis of 2,3-cis-P yr r olid in es 31a a
2,3-cis-P yr r olid in esa
product
T (°C) time (h) (yield, %)b
entry solvent
ArI (equiv)
dioxane PhI (7)
dioxane PhI (2)
CH3CN PhI (7)
1
2
3
reflux
reflux
reflux
100
5
4.5
5
31a (85)
31a (60)
31a (61)
31a (28)
32 (3)
4c
DMSO
PhI (7)
3.5
5
DMF
PhI (7)
100
4
31a (50)
32 (6)
6
7
8
9
dioxane 4-MeOPhI (2)
dioxane 4-MePhI (2)
dioxane 4-NO2PhI (2)
reflux
reflux
reflux
3
8
11
31b (60)
31c (56)
31d (36)
31e (25)
dioxane 1-naphthyl-I (2) reflux
8
a
All reactions were carried out in the presence of Pd(PPh3)4
b
(10 mol %), PhI (2 or 7 equiv), and K2CO3 (1 equiv to ArI). Yields
of isolated products. The 2,3-trans isomers of 31 were not observed
(2,3-cis/trans ) >98:2). c Other unidentified products were also
isolated.
results to iodobenzene, only 36% of the pyrrolidine 31d
was obtained when the reaction was carried out with the
electron-poor 1-iodo-4-nitrobenzene (entry 8). Reaction
with sterically congested 1-iodonaphthalene gave pyrro-
lidine 31e in only 25% yield (entry 9), presumably due
to the lower reactivity of the iodide.14
Next, reaction of various amino allene-derived alle-
nenes was investigated. The results are summarized in
Table 2. While the allenene 17a bearing an isobutyl
group required prolonged reaction time for the complete
consumption of the starting materials (24-30 h, entries
1 and 2), the allenene 17b with a sec-butyl group yielded
the pyrrolidines 34 in shorter reaction time (4-6.5 h,
entries 3 and 4) similar to 17d (Table 1). Therefore, the
substituent R to the allene was found to be extremely
important for the efficiency of the cyclization.15 Similarly,
the allenene 17c with a bulky tert-butyl group (entry 5)
was more reactive than 17e having a smaller benzyl
group (entry 6). We speculate that the bulky R substitu-
ent stabilizes the conformation required for the carbocy-
clization. The allenene 19, the amino group of which is
protected by a Boc group, afforded N-Boc-pyrrolidine
derivative 37 although in relatively low yield (41%, entry
7). As we expected, a geminal dimethyl group of 23 assists
the cyclization to 38 (entry 8); however, this reaction
requires 20 h for the complete conversion. Thus, efficacy
of cyclization depends on a subtle balance between the
bulkiness of the substituent and the reactivity. Internal
allene 39, which was prepared by allylation of the known
amino allene16 (see the Supporting Information), was also
cyclized into the five-membered ring 40 in 59% yield. In
this case, 10% of the starting allenene 39 was re-
covered. The observed (Z)-geometry of the double bond
a
All reactions were carried out in the presence of Pd(PPh3)4
(10 mol %), PhI (2 equiv), and K2CO3 (2 equiv) unless otherwise
stated. Yields of isolated products. c Increased amounts of ArI
b
(4 equiv) and K2CO3 (4 equiv) were used.
of 40 will be a consequence of thermodynamic preference
for the syn-π-allylpalladium(II) intermediate over other
isomers.1a,3d
As shown in Scheme 6, the cis-selective carbocycliza-
tion of allenenes 28 and 30 to form methylidene cyclo-
pentanes 41 and 42 was also possible; however, yields of
41 and 42 were lower (40% and 27%, respectively). It has
been proven that a nitrogen atom substituted by an
(16) (a) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Fujii, N.; Ibuka, T.
Tetrahedron Lett. 1999, 40, 349-352. (b) Ohno, H.; Toda, A.; Fujii,
N.; Takemoto, Y.; Tanaka, T.; Ibuka, T. Tetrahedron 2000, 56, 2811-
2820. For preparation of 2-ethynylaziridines, see: (c) Ohno, H.; Toda,
A.; Fujii, N.; Ibuka, T. Tetrahedron: Asymmetry 1998, 9, 3929-3933.
(d) Ohno, H.; Toda, A.; Takemoto, Y.; Fujii, N.; Ibuka, T. J . Chem.
Soc., Perkin Trans. 1 1999, 2949-2962.
(14) Similarly, the reaction of 17d with sterically congested 2-iodo-
toluene gave a mixture of unidentified products, and the desired
arylated pyrrolidine was not isolated.
(15) The reaction of the unsubstituted allenene led to a complex
mixture of unidentified products.
J . Org. Chem, Vol. 69, No. 13, 2004 4543

TABLE 3. Ster eoselective F or m a tion of
3-Aza bicyclo[3.1.0]h exa n esa
SCHEME 6
entry allenene
R1
R2
R3 time (h) product (yield, %)b
1
2
3
4
5
6
7
8
9
17a
17b
17c
17d
17e
23
49a
49b
49c
i-Bu Mts
s-Bu Mts
t-Bu Mts
i-Pr Mts
H
H
H
H
H
H
24
7
24
5
50a (35)
50b (57)
50c (16)c
50d (64)
50e (18)
51 (24)d
52a (36)
52b (39)
52c (59)
Bn
Mts
6
Me2 Ts
60
24
24
7
SCHEME 7
i-Bu Mts Me
s-Bu Mts Me
i-Pr Mts Me
a
All reactions were carried out with Pd2(dba)3‚CHCl3 (10 mol
b
%) and allyl carbonate (6 equiv) in CH3CN. Yields of isolated
products. c Isomerized internal alkyne was obtained (40%). The
d
starting allenene 23 was recovered (29%).
2) and the valine derivatives 17d (entry 4) and 49c (entry
9) which bear a branched alkyl group on the R-posi-
tion, afforded 3-azabicyclo[3.1.0]hexanes in better yields
(57-64%). However, sterically too congested allenenes
17c (entry 3) and 23 (entry 6) were less reactive. These
results clearly show that the presence of an appropriate
substituent at the R-position to the allenic moiety is
extremely important for the successful conversion. Two
possible reaction mechanisms for the palladium(0)-cat-
alyzed cyclopropanation of allenenes were already pro-
posed in the preliminary communication.9b,19
In conclusion, we have developed two different pal-
ladium(0)-catalyzed cyclizations leading to substituted
pyrrolidines and 3-azabicyclo[3.1.0]hexanes using the
same allenenes. These results clearly demonstrate that
allenenes are extremely useful substrates for palladium-
catalyzed cyclization to heterocycles. Furthermore, the
latter reaction is a first example of palladium-catalyzed
cyclopropanation of allenes with a double bond, which
shows a novel reactivity of allenes.
arylsulfonyl group (Table 1, entry 2) stabilizes the
required conformation for the allenene cyclization more
effectively than carbamate (Table 2, entry 7) or a carbon
atom having a geminal substituent (Scheme 6).
In all cases examined, 2,3-trans-pyrrolidine could not
be isolated from the reaction mixture. The observed 2,3-
cis selectivity in the pyrrolidine formation can be ratio-
nalized as shown in Scheme 7. If the intermediate 43
underwent carbocyclization via the conformation 44, the
2,3-trans-pyrrolidine 45 would be formed. However, an
unfavorable steric interaction between pseudoaxial pro-
tons and the phenyl group in 44 does exist to destabilize
this conformer. Thus, the ring-formation would proceed
preferentially from the more abundant conformers 46
and/or 47, and â-hydride elimination of the resulting
alkylpalladium(II) yields the cis-pyrrolidine 48 as a single
isomer.
During the course of this study, we unexpectedly found
that 3-azabicyclo[3.1.0]hexanes can be stereoselectively
constructed from allenenes by simply changing the reac-
tion conditions. As shown in Table 3, treatment of alle-
nene 17a with allyl carbonate (6 equiv)17 in the presence
of a catalytic amount of Pd2(dba)3‚CHCl3 in CH3CN at
80 °C afforded 3-azabicyclo[3.1.0]hexane 50a in 35% yield
(entry 1). Although the formation of small rings including
cyclopropanes18 by intramolecular nucleophilic attack
onto the allenic moiety is well documented,3 direct syn-
thesis of bicyclic cyclopropanes by the reaction of allenes
with an additional multiple bond is unprecedented.
Similarly, the allenene 17e having a benzyl group gave
relatively low yields of the bicyclic cyclopropane 50e
(entry 5). In contrast, the isoleucine derivative 17b (entry
Ack n ow led gm en t. This work was supported by
Grant-in-Aid for Encouragement of Young Scientists
from the Ministry of Education, Culture, Sports, Science
and Technology of J apan.
Su p p or tin g In for m a tion Ava ila ble: Synthetic procedure
and characterization for all products, NOE experiment for the
determination of relative configurations, as well as 1H NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O049663F
(17) Decreased loading of the allyl carbonate (2 equiv) lowered the
yields. It is presumably due to the side reaction of allylpalladium(II)
intermediate with another molecule of the allyl carbonate.
(18) Ma, S.; J iao, N.; Zhao, S.; Hou, J . J . Org. Chem. 2002, 67, 2837-
2847.
(19) The reason the present reaction conditions promote the cyclo-
propanation reaction instead of the Oppolzer cyclization leading to 10
(Scheme 2) is not understood. Assuming that the methoxide which is
generated by the reaction of allyl carbonate with palladium(0) might
assist the present cyclopropanation, we investigated reaction of the
allenene 17d with iodobenzene or phenyl triflate and catalytic Pd2-
(dba)3‚CHCl3 in CH3CN in the presence of NaOMe. However, un-
changed starting allenene 17d was recovered in both cases. The
reaction in AcOH using the Oppolzer’s conditions afforded unidentified
products and no cyclopropane was obtained.
4544 J . Org. Chem., Vol. 69, No. 13, 2004