Potassium carbonate-promoted stereospecific 5-endo-trig cyclization of unactivated allenes in the absence of any transition metals

Article abstract of DOI:10.1021/ol053094w

Formation of 3-pyrrolines from simple unactivated allenes bearing a protected amino group under basic conditions is described. Treatment of α-amino allenes with potassium carbonate in DMF under reflux in the absence of any transition-metal catalysts gave

Full text of DOI:10.1021/ol053094w

ORGANIC
LETTERS
2
006
Vol. 8, No. 5
47-950
Potassium Carbonate-Promoted
Stereospecific 5-Endo-Trig Cyclization of
Unactivated Allenes in the Absence of
Any Transition Metals
9
Hiroaki Ohno,*,† Yoichi Kadoh, Nobutaka Fujii, and Tetsuaki Tanaka*
‡
†
,‡
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamadaoka,
Suita, Osaka 565-0871, Japan, and Graduate School of Pharmaceutical Sciences,
Kyoto UniVersity, Sakyo-ku, Kyoto 606-8501, Japan
hohno@pharm.kyoto-u.ac.jp; t-tanaka@phs.osaka-u.ac.jp
Received December 21, 2005
ABSTRACT
Formation of 3-pyrrolines from simple unactivated allenes bearing a protected amino group under basic conditions is described. Treatment
of -amino allenes with potassium carbonate in DMF under reflux in the absence of any transition-metal catalysts gave the corresponding
-pyrrolines in good to excellent yields, by 5-endo-trig mode cycloisomerization. The reaction of internal allenes with an axial chirality afforded
r
3
the corresponding 3-pyrrolines in a stereoselective manner.
Chiral 3-pyrrolines including 3,4-dehydroproline are known
as useful synthetic intermediates for modified proline
Scheme 1. Cycloisomerization of Allenes through
5-Endo-Trig Mode by Activation of Allenic Double Bond
1
a
analogues, conformationally restricted amino acid ana-
2
3
logues, antibiotic anisomycin, and other related com-
4
pounds. Cycloisomerization of allenes through a 5-endo-
trig mode is a powerful strategy for the construction of
5
6
3
-pyrrolines and other heterocycles such as dihydrofurans
7
and butenolides. As shown in Scheme 1, this type of reaction
†
Kyoto University.
Osaka University.
‡
(1) (a) Baldwin, J. E.; Field, R. A.; Lawrence, C. C.; Lee, V.; Robinson,
J. K.; Schofield, C. J. Tetrahedron Lett. 1994, 35, 4649-4652. (b) Robinson,
J. K.; Lee, V.; Claridge, T. D. W.; Baldwin, J. E.; Schofield, C. J.
Tetrahedron 1998, 54, 981-996. (c) Ishii, K.; Ohno, H.; Takemoto, Y.;
Ibuka, T. Synlett 1999, 228-230. (d) Ishii, K.; Ohno, H.; Takemoto, Y.;
Osawa, E.; Yamaoka, Y.; Fujii, N.; Ibuka, T. J. Chem. Soc., Perkin Trans.
a
FG ) functional group.
1
1999, 2155-2163.
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866. (b) Chung, J. Y. L.; Wasicak, J. T.; Arnold, W. A.; May, C. S.;
generally proceeds through activation of the allenic moiety
of 1 by coordination of transition metals such as Ag(I),
(
5-7
1
8
9
10
Nadzan, A. M.; Holladay, M. W. J. Org. Chem. 1990, 55, 270-275. (c)
Holladay, M. W.; Lin, C. W.; May, C. S.; Garvey, D. S.; Witte, D. G.;
Miller, T. R.; Wolfram, C. A. W.; Nadzan, A. M. J. Med. Chem. 1991, 34,
Pd(II), Cu(I), or Rh(I), and subsequent attack by nitrogen
or oxygen nucleophile onto the thus-activated allenic carbon
11
of 2 leads to cyclized products 4 stereoselectively. A recent
contribution toward this area by Krause and Hashmi revealed
that Au salts strongly catalyze the 5-endo-trig cycloisomer-
ization of allenes 1 having a nitrogen or oxygen functional-
4
55-457.
(3) Jegham, S.; Das, B. C. Tetrahedron Lett. 1988, 29, 4419-4422.
4) (a) Burley, I.; Hewson, A. T. Tetrahedron Lett. 1994, 35, 7099-
(
7
102. (b) Horikawa, M.; Shirahama, H. Synlett 1996, 95-96. (c) Sibi, M.
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1
0.1021/ol053094w CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/07/2006

ity.12,13 In contrast, only limited examples of the endo-mode
cycloisomerization under basic conditions in the absence of
any transition metals are reported to date, which used
preactivated allenes 1 (R or R′ ) functional group) such as
of amino allenes without using any transition-metal catalysts.
Herein, we describe K CO -mediated stereospecific cyclo-
isomerization of R-amino allenes, which is the first example
of base-induced 5-endo-trig mode cycloisomerization of
simple unactivated allenes in the absence of any activating
reagents toward the allenic π-bond.
2
3
methoxy allenes,1 fluorinated allenes, or allenyl sulfones
4,15
16
17
and related compounds, leading to functionalized cyclized
products 5 or 6.
We prepared R-amino allene 7 according to our reported
As a part of our ongoing program directed toward
economical and environmentally friendly cyclization of
allenic compounds,18-20 we investigated cycloisomerization
procedure through the diethylzinc-mediated reductive syn-
21
thesis of amino allenes catalyzed by palladium(0), starting
from L-valine. The choice of Mts as a protecting group was
2
2
based primarily on its ease of deprotection. First, cyclo-
isomerization of 7 under various basic conditions (NaH/
DMF, t-BuOK/DMF, or n-BuLi/THF, etc.) was investigated,
(5) (a) Claesson, A.; Sahlberg, C.; Luthman, K. Acta Chem. Scand. 1979,
B33, 309-310. (b) Lathbury, D.; Gallagher, T. J. Chem. Soc., Chem.
Commun. 1986, 114-115. (c) Kinsman, R.; Lathbury, D.; Vernon, P.;
Gallapher, T. J. Chem. Soc., Chem. Commun. 1987, 243-244. (d) Prasad,
J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29, 4253-4256. (e) Fox,
D. N. A.; Lathbury, D.; Mahon, M. F.; Molloy, K. C.; Gallagher, T. J.
Chem. Soc., Chem. Commun. 1989, 1073-1075. (f) Ohno, H.; Toda, A.;
Miwa, Y.; Taga, T.; Osawa, E.; Yamaoka, Y.; Fujii, N.; Ibuka, T. J. Org.
Chem. 1999, 64, 2992-2993. (g) Dieter, R. K.; Yu, H. Org. Lett. 2001, 3,
2 3
and we found that treatment of 7 with K CO in a polar
solvent in high temperature afforded the desired cyclo-
isomerized product 8 (Table 1). Among the solvents inves-
3
855-3858.
(
6) (a) Olsson, L.-I.; Claesson, A. Synthesis 1979, 743-745. (b) Fujisawa,
Table 1. Optimization of Reaction Conditions
T.; Maehata, E.; Kohama, H.; Sato, T. Chem. Lett. 1985, 1457-1458. (c)
Nikam, S. S.; Chu, K.-H.; Wang, K. K. J. Org. Chem. 1986, 51, 745-747.
(
d) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1990, 55, 2995-2996. (e)
VanBrunt, M. P.; Standaert, R. F. Org. Lett. 2000, 2, 705-708. (f) Lepage,
O.; Kattnig, E.; F u¨ rstner, A. J. Am. Chem. Soc. 2004, 126, 15970-15971.
(7) (a) Gill, G. B.; Idris, M. S. H. Tetrahedron Lett. 1985, 26, 4811-
4814. (b) Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997,
6
2, 367-371. (c) Yoneda, E.; Kaneko, T.; Zhang, S.-W.; Onitsuka, K.;
Takahashi, S. Org. Lett. 2000, 2, 441-443.
reaction
(
8) Hashmi, A. S. K.; Ruppert, T. L.; Kn o¨ fel, T.; Bats, J. W. J. Org.
Chem. 1997, 62, 7295-7304.
9) (a) Ma, S.; Yu, Z.; Wu, S. Tetrahedron 2001, 57, 1585-1588. (b)
Kel′in, A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95-98.
10) Marshall, J. A.; Robinson, E. D. J. Org. Chem. 1990, 55, 3450-
451.
11) For a related cycloisomerizations, see: (a) Arseniyadis, S.; Sartoretti,
a
entry K2CO3 (equiv) solvent T (°C) time (h) yield (%)
(
1
2
3
4
5
6
1.0
1.0
1.0
1.0
0.5
0.1
DMSO 180
3
1
3
6
24
120
61
75
80
84
71
47
DMI
180
(
NMP
DMF
DMF
DMF
180
3
reflux
reflux
reflux
(
J. Tetrahedron Lett. 1985, 26, 729-732. (b) Grimaldi, J.; Cormons, A.
Tetrahedron Lett. 1986, 27, 5089-5090. (c) Meguro, M.; Yamamoto, Y.
Tetrahedron Lett. 1998, 39, 5421-5424. (d) Arredondo, V. M.; Tian, S.;
McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1999, 121, 3633-3639.
a Isolated yields. Mts ) 2,4,6-trimethylphenylsulfonyl.
(e) Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012-10020.
(12) (a) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285-2288. (b) Hoffman-R o¨ der, A.; Krause, N.
tigated (Table 1, entries 1-4), DMF has proven to be the
solvent of choice for the desired transformation, leading to
Org. Lett. 2001, 3, 2537-2538. (c) Morita, N.; Krause, N. Org. Lett. 2004,
6
, 4121-4123. (d) Lee, P. H.; Kim, H.; Lee, K.; Kim, M.; Noh, K.; Kim,
H.; Seomoon, D. Angew. Chem., Int. Ed. 2005, 44, 1840-1843.
13) For HCl gas-mediated cyclization, see: Krause, N.; Laux, M.;
Hoffmann-R o¨ der, A. Tetrahedron Lett. 2000, 41, 9613-9616.
14) (a) Gange, D.; Magnus, P. J. Am. Chem. Soc. 1978, 100, 7746-
747. (b) Hormuth, S.; Reissig, H.-U. J. Org. Chem. 1994, 59, 67-73. (c)
3
-pyrroline 8 in 84% yield (Table 1, entry 4). A catalytic
amount of K CO did promote the cycloisomerization (Table
, entries 5 and 6) but required prolonged reaction time: the
cyclization with 0.1 equiv of K CO for 120 h yielded 8
(
2
3
(
1
7
Breuil-Desvergnes, V.; Compain, P.; Vat e` le, J.-M.; Gor e´ , J. Tetrahedron
Lett. 1999, 40, 5009-5012. (d) Amombo, M. O.; Hausherr, A.; Reissig,
H.-U. Synlett 1999, 1871-1874. (e) Breuil-Desvergnes, V.; Gor e´ , J.
Tetrahedron 2001, 57, 1939-1950. (f) Fl o¨ gel, O.; Amombo, M. G. O.;
Reissig, H.-U.; Zahn, G.; Br u¨ dgam, I.; Hartl, H. Chem. Eur. J. 2003, 9,
2
3
(47%) with the recovered starting material (7%). Structure
of 8 was unambiguously confirmed by comparison with the
2
3
authentic sample.
Next, K CO -promoted cyclization of other terminal
1
405-1415.
2
3
(
15) A methoxy group on the allenic carbon promotes single electron
allenes 9-12 was investigated (Table 2). The reaction of
transfer from the dimsylate anion to give radical anion intermediate; see:
Magnus, P.; Albaugh-Robertson, P. J. Chem. Soc., Chem. Commun. 1984,
8
6
3
04-806.
(20) For our recent contribution on tandem reaction of bromoallenes,
see: (a) Ohno, H.; Hamaguchi, H.; Ohata, M.; Tanaka, T. Angew. Chem.,
Int. Ed. 2003, 42, 1749-1753. (b) Ohno, H.; Hamaguchi, H.; Ohata, M.;
Kosaka, S.; Tanaka, T. Heterocycles 2003, 61, 65-68. (c) Ohno, H.;
Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T. J. Am. Chem. Soc. 2004,
126, 8744-8754. (d) Hamaguchi, H.; Kosaka, S.; Ohno, H.; Tanaka, T.
Angew. Chem., Int. Ed. 2005, 44, 1513-1517. (e) Ohno, H. Chem. Pharm.
Bull. 2005, 53, 1211-1226. (f) Ohno, H. Yakugaku Zasshi 2005, 125, 899-
925.
(21) (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.
(
16) (a) Wang, Z.; Hammond, G. B. J. Org. Chem. 2000, 65, 6547-
552. (b) Lan, Y.; Hammond, G. B. Org. Lett. 2002, 4, 2437-2439.
(17) (a) Mukai, C.; Yamashita, H.; Hanaoka, M. Org. Lett. 2001, 3,
385-3387. (b) Mukai, C.; Ohta, M.; Yamashita, H.; Kitagaki, S. J. Org.
Chem. 2004, 69, 6867-6873. See also: (c) Pravia, K.; White, R.; Fodda,
R.; Maynard, D. F. J. Org. Chem. 1996, 61, 6031-6032.
(18) For our recent contribution on [2 + 2] cycloisomerization of
allenenes or allenynes without using any reagents or catalysts, see: Ohno,
H.; Mizutani, T.; Kadoh, Y.; Miyamura, K.; Tanaka, T. Angew. Chem.,
Int. Ed. 2005, 44, 5113-5115.
(19) For our recent contribution on tandem cyclization of allenenes and
related compounds, see: (a) Ohno, H.; Miyamura, K.; Takeoka, Y.; Tanaka,
T. Angew. Chem., Int. Ed. 2003, 42, 2647-2650. (b) Ohno, H.; Miyamura,
K.; Mizutani, T.; Kadoh, Y.; Takeoka, Y.; Hamaguchi, H.; Tanaka, T. Chem.
Eur. J. 2005, 11, 3728-3741. (c) Ohno, H.; Yamamoto, M.; Iuchi, M.;
Tanaka, T. Angew. Chem., Int. Ed. 2005, 44, 5103-5106.
(22) Unfortunately, treatment of N-Boc derivatives under the K2CO3-
mediated cyclization conditions gave a mixture of unidentified products.
(23) Cyclized products 8, 14, and the enantiomers of 21 and 22 were
previously prepared by our group, see refs 1c,d and 5f.
948
Org. Lett., Vol. 8, No. 5, 2006

Table 2.
Allenesa
K
2
CO
3
-Promoted Cycloisomerization of Terminal
2 3
Table 3. K CO -Promoted Cycloisomerization of Internal
Allenesa
a
All reactions were carried out in the presence of K2CO3 (1 equiv) in
a
All reactions were carried out in the presence of K2CO3 (1 equiv) in
DMF under reflux. b Isolated yields.
b
DMF under reflux. Isolated yields.
2
having C -symmetry, were obtained after prolonged reaction
amino allene 9 or 10 having an isobutyl group or a sec-
butyl group, respectively, at the R-position of the allenic
moiety with K CO in DMF under reflux yielded the desired
2 3
cyclized products 13 and 14 in 61% and 60% yields,
respectively (Table 2, entries 1 and 2). Interestingly, both
the allenes 11 with a bulky tert-butyl group and 12 without
the R-substituent gave 3-pyrrolines 15 and 16 in slightly
improved yields (77-78%). The required reaction time for
this transformation is highly dependent on the R-substituent
25
time (102-312 h) but in good yields. The relative config-
uration of the cyclized products 21 and 22 was determined
2
3
by comparison with the authentic samples.
It should be clearly noted that the internal allene 19 bearing
an isopropyl group on the allenic carbon was completely inert
toward the well-established silver(I)-mediated cyclization
(Scheme 2). This result can be attributed to the steric
(
1-120 h). Among the terminal allenes 7 and 9-12, the
R-unsubstituted amino allenes 12 showed the highest reactiv-
ity toward the K CO -mediated cycloisomerization: the
Scheme 2
2
3
reaction was completed within 1 h under the standard reaction
conditions.
Then, the cycloisomerization of diastereomerically pure
internal allenes bearing an R-amino group was investigated.
The requisite chiral internal allenes 17-20 were easily
prepared by organocopper-mediated stereospecific ring-
opening reaction of 2-ethynylaziridines derived from L- or
D-amino acids.24 The results of the cycloisomerization
reaction are summarized in Table 3. We were pleased to find
that the reaction of all the internal allenes yielded 2,5-
disubstituted 3-pyrrolines in a stereospecific manner and in
good yields (75-87%). The reaction of (R,aS)- and (S,aR)-
allenes 17 and 19, respectively, completed within 24 h to
give the 2,5-cis-3-pyrrolines 21 and 23. In contrast, the
reactivity of (R,aR)- and (S,aS)-allenes 18 and 20 was
relatively low: the 2,5-trans-3-pyrrolines 22 and 24, the latter
crowding of the allenic moiety that inhibits access or
coordination of silver to the allenic double bond. In contrast,
K
2
CO
gested meso-2,5-disubstituted 3-pyrroline 23 in 87% yield
Table 3, entry 3), presumably because these conditions
3
-induced reaction of 19 afforded the sterically con-
(
activate the nitrogen atom of the amino allene 19.
In conclusion, we have first demonstrated that cyclo-
isomerization of unactivated allenes having a sulfonamide
group can be promoted under simple basic conditions using
(25) The lower reactivity of 18 and 20 will be an influence of the Mts
group: the aryl group of Mts will direct the opposite side to the isopropyl
group at the R position, which may cause an unfavorable steric interaction
to the alkyl group on the allenyl carbon on cyclization. However, the exact
reason for their lower reactivity is unclear.
(
24) (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.
Org. Lett., Vol. 8, No. 5, 2006
949

K
2
CO
and applicable to the synthesis of a wide variety of
-pyrrolines including highly congested ones. The scope and
3
in DMF. The present transformation is economical
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan and Mitsubishi Chemical Corporation Fund,
which are gratefully acknowledged.
3
limitation of the reaction, as well as further transformation
to complex nitrogen heterocycles, are currently under
investigation.
Supporting Information Available: Representative ex-
perimental procedure, as well as H NMR spectra for the
novel cyclized products. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
Acknowledgment. This work was supported by a Grant-
in-Aid for Encouragement of Young Scientists from the
OL053094W
950
Org. Lett., Vol. 8, No. 5, 2006