Palladium(0)-catalyzed synthesis of medium-sized heterocycles by using bromoallenes as an allyl dication equivalent

Article abstract of DOI:10.1021/ja048693x

We have developed a highly regio- and stereoselective synthesis of medium-sized heterocycles containing one or two heteroatoms via cyclization of bromoallenes bearing an oxygen, nitrogen, or carbon nucleophilic functionality in the presence of a palladium

Full text of DOI:10.1021/ja048693x

Published on Web 06/26/2004
Palladium(0)-Catalyzed Synthesis of Medium-Sized
Heterocycles by Using Bromoallenes as an Allyl Dication
Equivalent
Hiroaki Ohno,* Hisao Hamaguchi, Miyo Ohata, Shohei Kosaka, and
Tetsuaki Tanaka*
Contribution from the Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Received March 8, 2004; E-mail: t-tanaka@phs.osaka-u.ac.jp
Abstract: We have developed a highly regio- and stereoselective synthesis of medium-sized heterocycles
containing one or two heteroatoms via cyclization of bromoallenes bearing an oxygen, nitrogen, or carbon
nucleophilic functionality in the presence of a palladium(0) catalyst and alcohol. In this reaction, bromoallenes
act as an allyl dication equivalent, and the intramolecular nucleophilic attack takes place exclusively at the
central carbon atom of the allene moiety. Interestingly, bromoallenes having a carbon nucleophile with a
five-atom tether afford eight-membered rings with trans-configuration, while those having an oxygen or a
nitrogen nucleophile give the corresponding cis-rings selectively. This is the first example that demonstrates
the synthesis of medium-sized rings via cyclization of bromoallenes, and this reaction provides a very
useful method for a catalytic synthesis of seven- and eight-membered heterocycles without using high
dilution conditions.
Introduction
Currently, reactions of bromoallenes have attracted much
interest due to their interesting chemical properties associated
Medium-sized heterocycles are an extremely important class
of compounds, the structural units of which are commonly found
within the framework of a variety of natural products.1 In
particular, seven- and eight-membered heterocycles are con-
stituents of a number of compounds with interesting pharma-
cological properties.2,3 The abundance of medium rings bearing
oxygen or nitrogen atom(s) in medicinally interesting com-
pounds continues to ensure that they are important synthetic
targets for organic chemists. Synthetic routes to medium-ring
heterocycles involving direct ring closure are often slow and
hampered by unfavorable enthalpies (the strain in many medium
rings) and entropies (probability of the chain ends meeting) of
the reaction. Today, the most powerful methodology for the
synthesis of medium-sized rings is the ring-closing metathesis
(RCM),4,5 that sometimes requires high dilution conditions for
successful conversion and often involves generation of byprod-
ucts such as ethylene.
with the cumulated double bonds and a bromine atom. However,
all the reactions of bromoallenes reported to date are intermo-
lecular reactions such as organocopper-mediated substitutions,6
palladium-catalyzed cross-coupling reactions,7 and formation of
allenylmetal reagents.8 Recently, we reported a highly stereo-
selective synthetic method of 2,3-cis-2-ethynylaziridines via the
(4) For a recent review, see: (a) Maier, M. E. Angew. Chem., Int. Ed. 2000,
39, 2073-2077. For selected examples, see: (b) Fu, G. C.; Grubbs, R. H.
J. Am. Chem. Soc. 1992, 114, 7324-7325. (c) Miller, S. J.; Kim, S.-H.;
Chen, Z.-R.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 2108-2109. (d)
Visser, M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda, A. H.
J. Am. Chem. Soc. 1996, 118, 4291-4298. (e) Paquette, L. A.; Leit, S. M.
J. Am. Chem. Soc. 1999, 121, 8126-8127. (f) Cook, G. R.; Shanker, P. S.;
Peterson, S. L. Org. Lett. 1999, 1, 615-617. (g) Mori, M.; Kitamura, T.;
Sakakibara, N.; Sato, Y. Org. Lett. 2000, 2, 543-545. (h) Fu¨rstner, A.;
Guth, O.; Du¨ffels, A.; Seidel, G.; Liebl, M.; Gabor, B.; Mynott, R. Chem.
Eur. J. 2001, 7, 4811-4820. (i) Dolman, S. J.; Sattely, E. S.; Hoveyda, A.
H.; Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991-6997.
(5) For other recent synthesis of medium-ring heterocycles, see: (a) Evans, P.
A.; Holmes, A. B.; Russel, K. Tetrahedron: Asymmetry 1990, 1, 593-
596. (b) Kitano, T.; Shirai, N.; Motoi, M.; Sato, Y. J. Chem. Soc., Perkin
Trans. 1 1992, 2851-2854. (c) Crombie, L.; Haigh, D.; Jones, R. C. F.;
Mat-Zin, A. R. J. Chem. Soc., Perkin Trans. 1 1993, 2047-2054. (d)
Coates, W. J.; Dhanak, D. Heterocycles 1993, 36, 1631-1639. (e) Wright,
D. L.; Weekly, R. M.; Groff, R.; McMills, M. C. Tetrahedron Lett. 1996,
37, 2165-2168. (f) Bergmann, D. J.; Campi, E. M.; Jackson, W. R.; Patti,
A. F.; Saylik, D. Tetrahedron Lett. 1999, 40, 5597-5600. (g) Ouyang, X.;
Kiselyov, A. S. Tetrahedron 1999, 55, 8295-8302. (h) Zhang, J.; Jacobson,
A.; Rusche, J. R.; Herlihy, W. J. Org. Chem. 1999, 64, 1074-1076. (i)
Monovich, L. G.; Hue´rou. Y. L.; Ro¨nn. M.; Molander, G. A. J. Am. Chem.
Soc. 2000, 122, 52-57. (j) Ra¨cker, R.; Do¨ring, K.; Reiser, O. J. Org. Chem.
2000, 65, 6932-6939. (k) Meyers, A. I.; Downing, S. V.; Weiser, M. J. J.
Org. Chem. 2001, 66, 1413-1419. (l) Donohoe, T. J.; Raoof, A.; Linney,
I. D.; Helliwell, M. Org. Lett. 2001, 3, 861-864. (m) Iradier, F.; Arraya´s,
R. G.; Carretero, J. C. Org. Lett. 2001, 3, 2957-2960. (n) Tempest, P.;
Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C. Tetrahedron Lett. 2001, 42,
4963-4968. (o) Kan, T.; Kobayashi, H.; Fukuyama, T. Synlett 2002, 697-
699. (p) Ma, D.; Tang, G.; Kozikowski, A. P. Org. Lett. 2002, 4, 2377-
2380. See also ref 3c.
(1) For a recent review, see: Evans, P. A.; Holmes, A. B. Tetrahedron 1991,
47, 9131-9166.
(2) For selected examples for seven-membered heterocycles, see: (a) Duong,
T.; Prager, R. H.; Tippett, J. M.; Ward, A. D.; Kerr, D. I. Aus. J. Chem.
1976, 29, 2667-2682. (b) Boros, C.; Hamilton, S. M.; Katz, B.; Kulan-
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(3) For selected examples for eight-membered heterocycles, see: (a) Basil,
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9
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J. AM. CHEM. SOC. 2004, 126, 8744-8754
10.1021/ja048693x CCC: $27.50 © 2004 American Chemical Society

Medium-Sized Rings by Cyclization of Bromoallenes
A R T I C L E S
Scheme 1. Aziridination of Bromoallene 1 in the Presence of a
Palladium Catalyst
Scheme 2. Formation of Medium Rings via
Palladium(0)-Catalyzed Cyclization of Bromoallenes
Scheme 3. Synthesis of Bromoallenes Bearing an Oxygen
Nucleophilea
Figure 1. Bromoallenes as allyl dication equivalents.
intramolecular amination of bromoallenes.9 In the course of our
examination of this aziridination reaction, we found that the
reaction of bromoallene 1 with Pd(PPh3)4 and NaOMe in MeOH
provided 2,3-cis-2-(1-methoxy)vinylaziridine 3 stereoselectively
(Scheme 1). This result strongly suggests the formation of η3-
allylpalladium complex 2 bearing a methoxy group on the
central carbon. Namely, bromoallene 4 can act as allyl dication
equivalent 5 when treated with palladium(0) in an alcoholic
solvent (Figure 1). Although similar types of reaction are often
observed in propargylic carbonates with a palladium catalyst
and soft nucleophiles such as active methylene, aryl alcohols
or amide,10 the reaction of allenic substrates and the synthesis
of eight-membered rings are unprecedented.11
Utilizing this chemistry, we expected that various heterocyclic
medium rings could be formed via intramolecular attack of an
appropriate functionality such as an oxygen, a nitrogen, or active
methylene nucleophile (Scheme 2). If the intermolecular nu-
cleophilic attack at the central carbon atom of the allene moiety
predominates over the intramolecular reaction (path A), cyclized
products 8 and/or 9 would be obtained. On the other hand, if
a Reagents and conditions: (a) HO(CH2)2OTBS, DEAD, PPh3, THF, rt;
(b) TBAF, THF, 0 °C; (c) 1% HCl/EtOH, rt; (d) HO(CH2)3OTBS, DEAD,
PPh3, THF, rt. Abbreviations: TBS ) tert-butyldimethylsilyl; DEAD )
diethyl azodicarboxylate; TBAF ) tetrabutylammonium fluoride.
the intramolecular nucleophilic attack takes place predominantly,
cyclization at the central carbon atom of the allenic moiety
would proceed to give 11 and/or 12. In this contribution, we
detail a highly regioselective synthetic method for medium-sized
heterocycles 11 containing one or two heteroatoms by the pal-
ladium(0)-catalyzed cyclization of bromoallenes.12 In all cases
examined, the cyclization takes place at the central carbon
regioselectively via path B to give a variety of medium-sized
heterocycles.
(6) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3059-3062. (b)
Caporusso, A. M.; Polizzi, C.; Lardicci, L. Tetrahedron Lett. 1987, 28,
6073-6076. (c) D’Aniello, F.; Mann, A.; Taddei, M. J. Org. Chem. 1996,
61, 4870-4871. (d) D’Aniello, F.; Mann, A.; Schoenfelder, A.; Taddei,
M. Tetrahedron 1997, 53, 1447-1456. (e) Bernard, N.; Chemla, F.;
Normant, J. F. Tetrahedron Lett. 1999, 40, 1649-1652. (f) Chemla, F.;
Bernard, N.; Normant, J. Eur. J. Org. Chem. 1999, 2067-2078. (g)
Caporusso, A. M.; Filippi, S.; Barontini, F.; Salvadori, P. Tetrahedron Lett.
2000, 41, 1227-1230. (h) Conde, J. J.; Mendelson, W. Tetrahedron Lett.
2000, 41, 811-814.
Results and Discussion
(7) (a) Ma¨rkl, G.; Attenberger, P.; Kellner, J. Tetrahedron Lett. 1988, 29, 3651-
3654. (b) Gillmann, T.; Hu¨lsen, T.; Massa, W.; Wocadlo, S. Synlett 1995,
1257-1259. (c) Saalfrank, R. W.; Haubner, M.; Deutscher, C.; Bauer, W.;
Clark, T. J. Org. Chem. 1999, 64, 6166-6168. (d) Saalfrank, R. W.;
Haubner, M.; Deutscher, C.; Bauer, W. Eur. J. Org. Chem. 1999, 2367-
2372.
(8) (a) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1997, 62, 8976-8977.
(b) Ma, S.; Yu, S.; Yin, S. J. Org. Chem. 2003, 68, 8996-9002.
(9) (a) Ohno, H.; Hamaguchi, H.; Tanaka, T. Org. Lett. 2001, 3, 2269-2271.
(b) Ohno, H.; Ando, K.; Hamaguchi, H.; Takeoka, Y.; Tanaka, T. J. Am.
Chem. Soc. 2002, 124, 15255-15266.
(10) (a) Tsuji, J.; Watanabe, H.; Minami, I.; Shimizu, I. J. Am. Chem. Soc. 1985,
107, 2196-2198. For an excellent review, see: (b) Tsuji, J.; Mandai, T.
Angew. Chem., Int. Ed. 1995, 34, 2589-2612. For recent examples: (c)
Monteiro, N.; Arnold, A.; Balme, G. Synlett 1998, 1111-1113. (d) Yoshida,
M.; Ihara, M. Angew. Chem., Int. Ed. 2001, 40, 616-619. (e) Labrosse,
J.-R.; Lhoste, P.; Sinou, D. J. Org. Chem. 2001, 66, 6634-6642. (f)
Kozawa, Y.; Mori, M. Tetrahedron Lett. 2001, 42, 4869-4873. (g) Kozawa,
Y.; Mori, M. Tetrahedron Lett. 2002, 43, 1499-1502. (h) Yoshida, M.;
Ihara, M. J. Am. Chem. Soc. 2003, 125, 4874-4881. (i) Kozawa, Y.; Mori,
M. J. Org. Chem. 2003, 68, 8068-8074. (j) Yoshida, M.; Fujita, M.; Ihara,
M. Org. Lett. 2003, 5, 3325-3327.
(11) For other synthesis of medium-ring heterocycles from allenes, see: (a)
Shaw, R. W.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1 1994, 3549-
3555. (b) Okawara, T.; Ehara, S.; Takenaka, A.; Hiwatashi, T.; Furukawa,
M. Heterocycles 1995, 41, 1709-1714. (c) Grigg, R.; Sansano, J. M.
Tetrahedron 1996, 52, 13441-13454. (d) Trost, B. M.; Michellys, P.-Y.;
Gerusz, V. J. Angew. Chem., Int. Ed. 1997, 36, 1750-1753. (e) Larock,
R. C.; Tu, C.; Pace, P. J. Org. Chem. 1998, 63, 6859-6866.
Synthesis of Bromoallenes Bearing an Oxygen or a
Nitrogen Nucleophilic Functionality. To investigate the syn-
thesis of medium-ring heterocycles via cyclization of bromoal-
lenes using a palladium catalyst as described in Scheme 2, the
bromoallenes 15 and 17 bearing an oxygen nucleophilic
functionality were prepared from bromoallenes 1313 as shown
in Scheme 3. Diastereomerically pure (S,aS)-bromoallenes 13
were used to see the effect of the axial chirality on the
cyclization reaction. Thus, the treatment of 13 with HO(CH2)2-
OTBS or HO(CH2)3OTBS under the Mitsunobu conditions gave
14 and 16 bearing the TBS group. The silyl group was then
removed by TBAF or 1% HCl/EtOH to afford the desired (S,aS)-
bromoallenes 15 and 17 having a hydroxyalkyl group.
(12) For preliminary communications, 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.
(13) The bromoallenes 13b-d were synthesized according to the reported
procedure.9 For synthesis of the bromoallene 13a, see the Supporting
Information.
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A R T I C L E S
Ohno et al.
Scheme 4. Synthesis of Bromoallenes Bearing a Nitrogen
Table 1. Synthesis of Seven-Membered Nitrogen Heterocycles via
Cyclization of Bromoallenes Bearing an Oxygen Nucleophilic
Functionalitya
Nucleophilea
a Reagents and conditions: (a) TsNHBoc or MsNHBoc, DEAD, PPh3,
THF, rt; (b) 3 N HCl, EtOAc, 60 °C.
The bromoallene 20 bearing a nitrogen nucleophilic func-
tionality was also prepared from 15b, as shown in Scheme 4.
The Mitsunobu reaction of 15b with TsNHBoc14 gave the N-Boc
derivative 18, the Boc group of which was removed with 3 N
HCl to afford the desired bromoallene 20. Similarly, 17b and
15d were converted into (S,aS)-bromoallenes 21 and 23,
respectively, through the reaction with MsNHBoc.14
Synthesis of Medium-Sized Nitrogen Heterocycles via
Cyclization of Bromoallenes. According to the working
hypothesis as depicted in Scheme 2, we next investigated the
synthesis of medium-sized nitrogen heterocycles via cyclization
of bromoallenes using a palladium catalyst. First, the bromoal-
lene 15a lacking a C-4 substituent was treated with NaOMe
(1.5 equiv) in MeOH in the presence of Pd(PPh3)4 (10 mol %)
to afford the seven-membered ring 24a (61%) and its regioi-
somer 25a (28%, Table 1, entry 1). When the bromoallene 15b
was employed, the seven-membered ring 24b15 (73%) and a
small amount of its regioisomer 25b were obtained (9%, entry
2). In contrast, bromoallenes 15c-e16 with a bulkier substituent
at C-4 gave the seven-membered rings 24c-e as the only
isolable isomers (entries 3-5). These results clearly demon-
strated that the regioselectivity of the second nucleophilic attack
was controlled by the steric size of the substituent at C-4 of the
bromoallenes. Next, the same reactions were conducted with
bromoallenes 17a-e bearing a five-atom tether between the
allenic and hydroxyl groups (Table 2). In contrast to the seven-
membered ring formation, reaction of bromoallenes 17a-e16
gave the eight-membered rings 26a-e as the sole isolable
isomers,17 irrespective of the C-4 substituent of the bromoal-
lenes. Unfortunately, the bromoallene 17c with a bulkier
substituent at C-4 gave the eight-membered ring 26c in low
yield (14%) under the identical reaction conditions. However,
the reactivity of 17c was slightly improved by using fresh
NaOMe prepared in situ from NaH and MeOH (entry 3). On
a Reactions were carried out at 25 °C in MeOH with diastereomerically
pure bromoallenes, Pd(PPh3)4 (5-10 mol %), and NaOMe (1.5 equiv).
b Isolated yields.
the other hand, in the case of bromoallene 17e which has a
bulkier substituent at C-5, the reaction proceeded smoothly to
give eight-membered ring 26e in 73% yield (entry 5).
Next, we investigated the synthesis of seven- and eight-
membered nitrogen heterocycles via cyclization of bromoallenes
bearing a nitrogen functionality (Table 3). Under the identical
reaction conditions, bromoallenes 20 and 23 gave the seven-
membered rings 27a and 27b, respectively as a single isomer
(entries 1 and 2). Furthermore, bromoallene 21 gave the eight-
membered ring 27c as a single isomer (entry 3). From the results
shown in Tables 1-3, we found that the intramolecular
nucleophilic attack takes place at the central position of the
(14) N-Boc sulfonamides, a useful nitrogen nucleophile in the Mitsunobu
reaction, can be readily prepared by the reaction of sulfonamides with di-
(tert-butyl) dicarbonate catalyzed by 4-(dimethylamino)pyridine: Neustadt,
B. R. Tetrahedron Lett. 1994, 35, 379-380.
(15) Structure of 24b was confirmed by NOE analysis. Irradiation of the signal
of 6-H in 1,4-oxazepine 24b led to NOE enhancement of the signal of 5-H
and 1′-H (12.3% for 5-H and 7.2% for 1′-H).
(17) The cis-configuration of the eight-membered ring 26 was determined by
NOE analysis. For example, in the case of 1,5-oxazocine 26b, NOE was
observed between [6-H and 7-H (9.6%)] and [7-H and 1′-H (5.2%)].
(16) For synthesis of bromoallenes 15e and 17e, see the Supporting Information.
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Medium-Sized Rings by Cyclization of Bromoallenes
A R T I C L E S
Table 2. Synthesis of Eight-Membered Nitrogen Heterocycles via
Cyclization of Bromoallenes Bearing an Oxygen Nucleophilic
Functionalitya
Scheme 5. Reaction of (S,aR)-Bromoallenes
a Reagents and conditions: (a) Pd(PPh3)4 (5 mol %), NaOMe (1.5 equiv),
MeOH, rt, 2 h; (b) Pd(PPh3)4 (15 mol %), NaOMe (1.5 equiv), MeOH, rt,
12 h.
Scheme 6. Cyclization with Other Alcohols as the Second
Nucleophile
(67%) and 25b (10%) that is comparable to the result of (S,aS)-
bromoallene 15b (Table 1, entry 2). Similarly, (S,aR)-29 was
also cyclized into 1,4-diazepine derivative 27a under identical
reaction conditions in 50% yield (compare with Table 3, entry
1). From these results, both the (S,aS)- and (S,aR)-bromoallenes
equally undergo the present transformation to give the same
products, which means that a diastereomeric mixture of bro-
moallenes can be directly employed for preparative use.
Other alcohols could be analogously used instead of MeOH
for the present cyclization reaction (Scheme 6). For example,
bromoallene 15d was treated with a preformed mixture of NaH
(1.5 equiv) and EtOH-THF (1:1) in the presence of Pd(PPh3)4
(10 mol %) to afford the seven-membered ring 30 having an
ethoxy group (60%). Similarly, the reaction of bromoallene 15b
with BnOH gave benzyloxy derivatives 31 (81%) and 32 (6%).19
Next, we synthesized the bromoallene 36 with SES (2-
trimethylsilylethanesulfonyl) group20 as a nitrogen protecting
group, and investigated the cyclization reaction and deprotection
(Scheme 7). Compound 33 was readily prepared from L-
phenylalanine following the literature.9 The treatment of 33 with
MsCl and Et3N gave the corresponding mesylate, and the crude
mesylate was then allowed to react with CuBr‚SMe2/LiBr21 to
afford the (S,aS)-bromoallene 34. Removal of the Boc group
a Reactions were carried out at 25 °C in MeOH with diastereomerically
pure bromoallenes, Pd(PPh3)4 (5-15 mol %), and NaOMe (1.5 equiv).
b The reaction was conducted with NaH (1.5 equiv) and MeOH/THF (1:1)
at 25 °C. c The reaction was conducted at 50 °C. d Isolated yields.
Table 3. Synthesis of Medium-Sized Nitrogen Heterocycles via
Cyclization of Bromoallenes Bearing a Nitrogen Nucleophilic
Functionalitya
a Reactions were carried out at 25 °C in MeOH with diastereomerically
pure bromoallenes, Pd(PPh3)4 (10 mol %), and NaOMe (1.5 equiv) unless
otherwise stated. b The reaction was conducted under reflux. c Isolated
yields.
(18) The (S,aR)-bromoallenes 28 and 29 were synthesized by the identical
procedure shown in Scheme 4 from known allenes.9 For details, see the
Supporting Information.
(19) Structure of 32 was confirmed by NOE analysis as shown below.
allenic moiety (path B in Scheme 2) and, in most cases, the
regioselectivity of the attack of methoxide is extremely high.
We next investigated the effect of axial chirality with (S,aR)-
bromoallenes 28 and 2918 on the formation of medium-sized
nitrogen heterocycles, as shown in Scheme 5. Thus, reaction
of (S,aR)-bromoallene 28 gave 1,4-oxazepine derivatives 24b
(20) Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron Lett. 1986, 27,
2099-2102.
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A R T I C L E S
Ohno et al.
Scheme 7. Synthesis and Deprotection of N-SES-1,4-Oxazepine
Scheme 8. Synthesis of Bromoallenes 40 and 44a
37a
a Reagents and conditions: (a) MsCl, Et3N, THF, -60 °C; (b) CuBr‚DMS,
LiBr, THF, rt; (c) 3 N HCl, EtOAc, 50 °C; (d) SESCl, Et3N, DMF, 0 °C;
(e) DEAD, PPh3, HO(CH2)2OTBS, THF; (f) 1% HCl/EtOH.
a Reagents and conditions: (a) 39, PPh3, DEAD, THF, rt; (b) 1% HCl/
EtOH, 75 °C; (c) TBSCl, imidazole, DMF, rt; (d) 43, PPh3, DEAD, THF,
rt; (e) 1% HCl/EtOH, rt.
gave the corresponding amine, which was then treated with
SESCl to afford the SES amide 35. The treatment of 35 with
HO(CH2)2OTBS under the Mitsunobu conditions gave the
corresponding bromoallene, the silyl ether of which was then
cleaved with 1% HCl/EtOH to afford 36 bearing an oxygen
nucleophilic functionality. As we expected, the palladium(0)-
catalyzed cyclization of the bromoallene 36 gave the seven-
membered ring 37 as a single isomer. The SES group of 37
was readily removed by treatment with CsF in DMF20 at 95 °C
to give 38 in 73% yield. From these observations, the described
transformation is also useful for the synthesis of 1,4-oxazepine
bearing a free amino group, by using the SES group as an easily
removable protecting group.
Table 4. Synthesis of Benzo-1,5-oxazocines 45 and 46a
We investigated the synthesis of benzo-annulated medium-
sized heterocycles, which are the basic structures of pharma-
cologically important compounds,22 by cyclization of bromoal-
lenes. The requisite bromoallenes 40 and 44 were synthesized
by a similar procedure as described in Scheme 3. The treatment
of 13b with 2-(tert-butyldimethylsiloxy)benzyl alcohol 3923
under the Mitsunobu conditions followed by cleavage of the
silyl ether by 1% HCl/EtOH afforded 40 having a phenolic
hydroxyl group as the nucleophilic functionality (Scheme 8).
The bromoallene 44 was also synthesized by the Mitsunobu
reaction of an aniline derivative 42, which was prepared from
4125 by protection of the primary hydroxyl group with the TBS
group, with the known bromoallenol 43.24
The palladium(0)-catalyzed cyclization of bromoallene 40 in
MeOH gave benzo[b]-1,5-oxazocine 45 in low yield (15%;
Table 4, entry 1). The yield was slightly improved by use of
fresh NaOMe prepared from NaH and MeOH (33%; entry 2);
however, a considerable amount of the starting material was
recovered (24%). In contrast, when the reaction was conducted
in a mixed solvent of MeOH/THF (1:1), the cyclized product
a Reactions were carried out at 25 °C with Pd(PPh3)4 (10 mol %) and a
base (1.5 equiv). b Isolated yields. c 24% of 40 was recovered.
45 was obtained in a better yield (57%; entry 3). Similarly, the
reaction of the bromoallene 44 gave benzo[c]-1,5-oxazocine 46
under the same reaction conditions in high yield (82%; entry
4).
Synthesis of Azocine, Azepine, Oxocine, and Oxepine
Derivatives. From these results, we found that bromoallenes
can act as allyl dication equivalents that are extremely useful
for the synthesis of medium-sized nitrogen heterocycles bearing
two heteroatoms. Next, we investigated a novel synthesis of
seven- and eight-membered rings possessing one heteroatom,
such as hexahydroazocines, tetrahydroazepines, tetrahydrooxo-
cines, and tetrahydrooxepines. The requisite bromoallene 49
which bears an oxygen nucleophilic functionality was readily
synthesized from monosilylated diol 4726 as shown in Scheme
9. Swern oxidation of 47, ethynylation of the resulting aldehyde,
and removal of the TMS group afforded a propargyl alcohol
48, which was converted into the bromoallene 49 by treatment
of the corresponding mesylate with CuBr‚SMe2/LiBr21 followed
by desilylation. Furthermore, 49 was converted into the corre-
sponding azacycle precursor 50, which bears an amide group
as a nucleophilic functionality, by Mitsunobu condensa-
(21) (a) Montury, M.; Gore´, J. Synth. Commun. 1980, 10, 873-879. (b) Elsevier,
C. J.; Meijer, J.; Tadema, G.; Stehouwer, P. M.; Bos, H. J. T.; Vermeer, P.
J. Org. Chem. 1982, 47, 2194-2196.
(22) See for example: (a) Kricka, L. J.; Ledwith, A. Chem. ReV. 1974, 74, 101-
123. (b) Kaiser, C.; Ali, F. E.; Bondinell, W. E.; Brenner, M.; Holden, K.
G.; Ku, T. W.; Oh, H.-J.; Ross, S. T.; Yim, N. C. F.; Zirkle, C. L.; Hahn,
R. A.; Sarau, H. M.; Setler, P. E.; Wardell, J. R., Jr. J. Med. Chem. 1980,
23, 975-976. (c) Flynn, G. A.; Giroux, E. L.; Dage, R. C. J. Am. Chem.
Soc. 1987, 109, 7914-7915. See also refs 2c and 3d.
(23) Prakash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett. 1994, 35, 7565-7568.
(24) Landor, P. D.; Landor, S. R.; Leighton, P. J. Chem. Soc., Perkin Trans. 1
1975, 1628-1632.
(25) Consonni, R.; Croce, P. D.; Ferraccioli, R.; Rosa, C. L. J. Chem. Soc.,
Perkin Trans. 1 1996, 1809-1814.
(26) Krafft, M.; Schmidt, P. Synth. Commun. 2002, 32, 2723-2732.
9
8748 J. AM. CHEM. SOC. VOL. 126, NO. 28, 2004

Medium-Sized Rings by Cyclization of Bromoallenes
A R T I C L E S
Scheme 9. Synthesis of Bromoallenes 49 and 50a
Scheme 10. Reaction of Bromoallene 63 Having an Unsubstituted
Carbon Tether
mixture of NaH, BnOH, and THF in the presence of Pd(PPh3)4
gave the tetrahydrooxepine derivative 55 in 72% yield by the
first intramolecular nucleophilic addition to form an η3-allyl
palladium intermediate followed by the second nucleophilic
attack by benzyloxide (entry 1). Similarly, the bromoallene 52
having a protected diol moiety was converted into 56 (entry 2).
In contrast, exposure of 49 to the identical cyclization conditions
afforded eight-membered heterocyclic diene 58 as a major
product (entry 3), which was formed by â-hydride elimination
of the η3-allylpalladium(II) intermediate of the type 10 (Scheme
2). This is presumably due to the relatively highly acidic nature
of the â-hydride at the benzylic position.27 Medium-sized
nitrogen heterocycles were also synthesized starting from the
bromoallenes 53, 54, and 50 bearing a protected amino group
(entries 4-6). Interestingly, when the amino allene 50 was used
(entry 6), a methoxylated benzo[d]azocine derivative 61 was
obtained as a major product (60% yield) along with a small
amount of â-elimination product 62 (5% yield, compare with
entry 3).
a Reagents and conditions: (a) (COCl)2, DMSO, then (i-Pr)2NEt; (b)
TMS-acetylene, n-BuLi; (c) NaOMe, MeOH; (d) MsCl, Et3N; (e)
CuBr‚SMe2, LiBr; (f) 1% HCl/EtOH; (g) MsNHBoc, PPh3, DEAD; (h) 3
N HCl, EtOAc.
Table 5. Palladium-Catalyzed Formation Medium Rings Including
One Heteroatoma
It should be clearly noted that, in contrast to the seven- and
eight-membered ring formations possessing two heteroatoms
(Table 1, entry 1 and Table 2, entry 1), bromoallene 6324 having
an unsubstituted carbon tether afforded six-membered ring 6428
in 65% yield (Scheme 10) as a result of the first intermolecular
nucleophilic attack by benzyloxide to form an η3-allylpalladium
intermediate of the type 7 described in Scheme 2, followed by
the intramolecular nucleophilic reaction. From these results, it
is apparent that the substituents or a heteroatom on the tether
assists the formation of the intermediate of the type 10 described
in Scheme 2.29
Reaction of Bromoallenes Having a Carbon Nucleophile.
We next investigated the cyclization reaction of bromoallenes
which have an active methylene as a nucleophile. Primary
alcohols 17b and 17d were converted to the corresponding
iodides, which were treated with NaH and dimethyl malonate
to afford the requisite bromoallenes 66 and 68, respectively, as
shown in Scheme 11.
In contrast to the reaction of the bromoallenes having an
oxygen or nitrogen nucleophile affording cis-rings exclusively,
the bromoallenes 66 and 68 having an active methylene
nucleophile gave eight-membered rings 67 and 69 with trans-
configuration (56% and 31%, respectively).30 These allenes are
found to be less reactive than those having an oxygen or nitrogen
nucleophile, presumably due to the steric hindrance. The
observed trans-selectivity will be discussed later (Scheme
13).
a All reactions were carried out using Pd(PPh3)4 (5 mol %) and NaH
(1.5 equiv). b Isolated yields.
(27) Exposure of the minor product 57 to the cyclization conditions led to
complete recovery of 57.
(28) Structure of 64 was confirmed by NOE analysis as shown below.
tion followed by deprotection with dilute HCl. Other requisite
bromoallenes 51, 52, 53, and 54 (Table 5) were also prepared
by a similar procedure (see the Supporting Information).
We next investigated the cyclization reaction using the
prepared bromoallenes. The results are summarized in Table 5.
As we expected, treatment of the bromoallene 51 with a stirred
9
J. AM. CHEM. SOC. VOL. 126, NO. 28, 2004 8749

A R T I C L E S
Ohno et al.
Scheme 11. Synthesis and Cyclization Reaction of Bromoallenes
reported by Mori: the reaction with a palladium catalyst in the
presence of a bidentate ligand gave carbacepham derivatives
which can be formed by the central attack of the lactam nitrogen
onto an η3-propargylpalladium complex, while the reaction in
the presence of a monodentate ligand yielded carbapenams by
a nucleophilic attack on the terminal carbon of an η1-allenylpal-
ladium complex.10f,g,i In contrast, our bromoallene cyclization
proceeds in the presence of a monodentate ligand to afford
medium rings by the reaction of nucleophiles onto the central
carbon of the propargyl palladium complex.35 Kurosawa,
Ogoshi, and co-workers recently reported that a polar solvent
shifts the equilibrium between η1-allenyl- and η3-propargylpal-
ladium complexes toward the latter31c which is a reactive
intermediate for the central attack.36 Although the exact reason
for the observed central attack in the presence of a monodentate
ligand and an alcohol is unclear, the polar alcoholic solvent
might promote the central attack by shifting the equilibrium
toward the η3-propargylpalladium complex 72. An alcoholic
solvent will also promote the reaction by protonation of the
palladacyclobutene intermediate 73.
Having a Carbon Nucleophilea
a Reagents and conditions: (a) (i-Pr)2NEt, PPh3, I2, CH2Cl2, rt; (b) NaH,
CH2(CO2Me)2, DMF, rt; (c) Pd(PPh3)4 (20 mol %), NaOMe (1.5 equiv),
MeOH, 50 °C, 3 h; (d) Pd(PPh3)4 (10 mol %), NaH (1.5 equiv), MeOH-
THF (1:1), 50 °C, 4 h.
Scheme 12. Possible Reaction Course
As described above, bromoallenes 77 having an oxygen or
nitrogen nucleophile afforded the eight-membered rings 79 with
cis-configuration (Scheme 13), while bromoallene 66 (Scheme
11) having an active methylene nucleophile gave the corre-
sponding trans-ring selectively. In the reaction of 77, the
methoxide will attack the less hindered terminal carbon of the
syn-η3-allylpalladium complex 78 to afford cis-79. On the other
hand, the syn-η3-allylpalladium complex 80, which can be
formed from 66, will be less stable because of the steric
repulsion between the axial proton and one ester group.
Accordingly, the methoxide would attack the anti-η3-allylpal-
Mechanism of the Cyclization. A possible reaction course
is shown in Scheme 12. Oxidative addition of bromoallene 70
to Pd(0) gives η1-allenylpalladium complex 71, which is in a
state of equilibrium with η3-propargylpalladium complex 72.31
The first intramolecular nucleophilic addition occurs to the
central carbon of η3-propargylpalladium complex 72 to produce
a palladacyclobutene 73.32 This is followed by protonation by
MeOH to generate η3-allylpalladium complex 74. In many cases,
the methoxide attacks the terminal carbon to give 75 because
of the steric repulsion with the R substituent. When the R
substituent is effectively smaller (R ) H or Me), a considerable
amount of the adduct 76 is obtained by the attack of methoxide
to the internal carbon of η3-allylpalladium complex 74 from
the backside of the palladium atom.33,34
(32) In the reaction of propargylic carbonates, it is proposed that the first
nucleophilic addition onto the η3-propargylpalladium produces a metalla-
cyclobutene, protonation of which generates the η3-allylpalladium com-
plex: Casey, C. P.; Nash, J. R.; Yi, C. S.; Selmeczy, A. D.; Chung, S.;
Powell, D. R.; Hayashi, R. K. J. Am. Chem. Soc. 1998, 120, 722-733.
See also, ref 10j.
(33) As an alternative mechanism, the protonation of 71 by MeOH would lead
to a terminal allene such as 92 and Pd(II), which activates the allene
π-system and allows the first nucleophilic attack.34 The second nucleophilic
reaction of the resulting η3-allylpalladium intermediate by the methoxide
might lead to 59 and Pd(0). However, the cyclization reaction of the amino
allene 92 with PdBr2 gave the 2-vinylpiperidine 93 in 51% yield along
with a trace amount of 59 (ca. 1% yield). From this result, the alternative
mechanism through the terminal allene 92 cannot be the major reaction
pathway.
Recently, a related palladium-catalyzed cyclization of prop-
argyl carbonates bearing a nucleophilic â-lactam moiety was
(29) Although formation of benzo-annulated eight-membered ring proceeded
in good yields (Table 5, entries 3 and 6), reaction of bromoallene 90 under
the same reaction conditions afforded dimethoxylated product 91. Therefore,
it is apparent that a substitution which effectively assists the cyclization is
essential for the eight-membered ring formation containing one hetero-
atom.
(34) A palladium(II) catalyst induces nucleophilic reaction onto allenes, see:
(a) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29, 4257-
4260. (b) Kimura, M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem.
1992, 57, 6377-6379. Hiemstra reported that the cyclization of allenic
lactams takes place at the central carbon atom of allene: (c) Karstens, W.
F. J.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 1997, 38, 6275-
6278. (d) Karstens, W. F. J.; Stol, M.; Rutjes, F. P. J. T.; Hiemstra, H.
Synlett 1998, 1126-1128. 2-Vinylpiperidines were synthesized from amino
allenes in the presence of a catalytic amount of a palladium complex under
weakly acidic conditions: (e) Meguro, M.; Yamamoto, Y. Tetrahedron
Lett. 1998, 39, 5421-5424.
(30) The trans-configuration of 67 was determined by NOE analysis as shown
below.
(35) It should be clearly noted that propargylic substrates are not suitable for
the palladium-catalyzed medium-ring cyclization. For example, while the
bromoallene 15d yielded 1,4-oxazepine 24d in 73% yield (Table 1), the
corresponding propargylic carbonate was converted to the diol by solvolysis
under identical reaction conditions. Similarly, the corresponding propargyl
bromide to 17b was found to be relatively unstable under the cyclization
conditions, and only a small amount of the desired cyclized product 26b
was obtained (12% yield) by treatment with NaOMe in MeOH in the
presence of Pd(PPh3)4.12a
(31) (a) Ogoshi, S.; Tsutsumi, K.; Nishiguchi, S.; Kurosawa, H. J. Organomet.
Chem. 1995, 493, C19-C21. (b) Tsutsumi, K.; Ogoshi, S.; Nishiguchi, S.;
Kurosawa, H. J. Am. Chem. Soc. 1998, 120, 1938-1939. (c) Tsutsumi,
K.; Kawase, T.; Kakiuchi, K.; Ogoshi, S.; Okada, Y.; Kurosawa, H. Bull.
Chem. Soc. Jpn. 1999, 72, 2687-2692. (d) Ogoshi, S.; Kurosawa, H. J.
Synth. Org. Chem. Jpn. 2003, 61, 14-23.
(36) Baize, M. W.; Blosser, P. W.; Plantevin, V.; Schimpff, D. G.; Gallucci, J.
C.; Wojcicki, A. Organometallics 1996, 15, 164-173. See also, refs 31c
and 32.
9
8750 J. AM. CHEM. SOC. VOL. 126, NO. 28, 2004

Medium-Sized Rings by Cyclization of Bromoallenes
A R T I C L E S
Scheme 13. Possible Reaction Course
carbon nucleophile, the eight-membered rings with trans-
configuration were obtained. On the other hand, the reaction of
the bromoallenes having an oxygen or nitrogen nucleophile
afforded the corresponding cis-rings exclusively. This synthetic
method would provide a wide variety of heterocycles including
those having an enamine or enol moiety without using high
dilution conditions.
Experimental Section
General Methods. Melting points are uncorrected. 1H NMR spectra
were recorded in CDCl3. Chemical shifts are reported in parts per
million downfield from internal Me4Si (s ) singlet, d ) doublet, dd )
double doublet, ddd ) doublet of double doublet, t ) triplet, q )
quartet, m ) multiplet). Optical rotations were measured in CHCl3.
For flash chromatography, silica gel 60 H (silica gel for thin-layer
chromatography, Merck) or silica gel 60 (finer than 230 mesh, Merck)
was employed.
The known compounds 1,9 13b-d,9 33,9 39,23 41,25 43,24 47,26 and
6324 were synthesized according to the literature.
Scheme 14. Cyclization of Bromoallene 83 Bearing Two Oxygen
(4S,aS)-1-Bromo-4-[N,N-(2-tert-butyldimethylsilyloxyethyl)(4-me-
thylphenylsulfonyl)amino]penta-1,2-diene (14b). To a stirred solution
of PPh3 (551 mg, 2.1 mmol) in THF (1.5 mL) under nitrogen were
added a solution of the bromoallene 13b (190 mg, 0.60 mmol) in THF
(1.5 mL), a solution of HO(CH2)2OTBS (317 mg, 1.8 mmol) in THF
(1.0 mL), and diethyl azodicarboxylate (914 mg, 2.1 mmol; 40%
solution in toluene) at 0 °C, and the mixture was stirred for 2 h at
room temperature. Concentration under reduced pressure gave an oily
residue, which was purified by flash chromatography over silica gel
with n-hexane-ethyl acetate (10:1) to give 14b (250 mg, 88% yield,
>98% de) as a colorless oil: [R]26D -48.3 (c 1.00, CHCl3); IR (KBr)
Functionalities
1
cm-1 1957 (CdCdC), 1342 (NSO2); H NMR (500 MHz, CDCl3) δ
0.08 (s, 6H, SiMe2), 0.90 (s, 9H, CMe3), 1.21 (d, J ) 7.0 Hz, 3H,
CMe), 2.43 (s, 3H, PhMe), 3.13 (ddd, J ) 15.0, 8.0, 6.5 Hz, 1H, CHH),
3.24 (ddd, J ) 15.0, 8.0, 5.5 Hz, 1H, CHH), 3.76 (ddd, J ) 10.0, 8.0,
6.5 Hz, 1H, CHH), 3.85 (ddd, J ) 10.0, 8.0, 5.5 Hz, 1H, CHH), 4.63-
4.69 (m, 1H, 4-H), 5.12 (dd, J ) 5.5, 5.0 Hz, 1H, 3-H), 6.05 (dd, J )
5.5, 2.5 Hz, 1H, 1-H), 7.29-7.31 (m, 2H, Ph), 7.72-7.74 (m, 2H, Ph);
13C NMR (75 MHz, CDCl3) δ -5.3 (2C), 18.1, 18.3, 21.5, 25.9 (3C),
45.7, 51.4, 63.0, 74.8, 101.3, 127.2 (2C), 129.8 (2C), 137.4, 143.5,
202.4; MS (FAB) m/z (%) 476 (MH+, 81Br, 27), 474 (MH+, 79Br, 28),
73 (100); HRMS (FAB) calcd for C20H33BrNO3SSi (MH+, 79Br),
474.1134; found, 474.1128.
ladium complex 82 to give the eight-membered ring 67 with
trans-configuration.
Finally, we investigated the reaction of bromoallene 8337
bearing two oxygen functionalities, which has two reaction
pathways (Scheme 14). If the hydroxyl group A (OHA) attacks
η3-propargylpalladium(II) bromide 84 (path A), 86 and/or 87
will be produced via the intermediate 85. In contrast, reaction
of OHB in η3-propargylpalladium 84 (path B) leads to the seven-
membered ring 89. Interestingly, exposure of 83 to the pal-
ladium-catalyzed cyclization conditions gave 86 (31% yield),
8738 (11%), and 89 (45%). Although the seven-membered ring
89 has two heteroatoms, this result clearly shows that the
bromoallenes cyclize into seven-membered heterocycles as
easily as five-membered rings.
(4S,aS)-1-Bromo-4-[N,N-(2-hydroxyethyl)(4-methylphenylsulfo-
nyl)amino]penta-1,2-diene (15b). To a stirred solution of the bro-
moallene 14b (230 mg, 0.485 mmol) in THF (1.5 mL) under nitrogen
was added tetrabutylammonium fluoride (1.0 M solution in THF; 0.63
mL, 0.632 mmol) at 0 °C, and the mixture was stirred for 3 h at this
temperature. The mixture was made acidic with 4% HCl, and the whole
was extracted with Et2O. The extract was washed with water and brine
and dried over MgSO4. The filtrate was concentrated under reduced
pressure to give an oily residue, which was purified by column
chromatography over silica gel with n-hexane-ethyl acetate (2:1) to
give 15b (160 mg, 92% yield, >99% de) as a colorless oil: [R]21
D
-45.2 (c 1.00, CHCl3); IR (KBr) cm-1 3552 (OH), 1957 (CdCdC),
1335 (NSO2); 1H NMR (300 MHz, CDCl3) δ 1.20 (d, J ) 6.6 Hz, 3H,
CMe), 2.44 (s, 3H, PhMe), 2.51 (dd, J ) 6.0, 5.7 Hz, 1H, OH), 3.18-
3.33 (m, 2H, CH2), 3.79-3.84 (m, 2H, CH2), 4.70-4.79 (m, 1H, 4-H),
5.14 (dd, J ) 5.7, 5.1 Hz, 1H, 3-H), 6.08 (dd, J ) 5.7, 2.7 Hz, 1H,
Conclusions
In conclusion, we have developed a novel synthesis of
medium-sized heterocycles containing one or two heteroatoms
via cyclization of bromoallenes bearing an oxygen, nitrogen or
carbon nucleophile in the presence of a palladium(0) catalyst
and alcohol. In many cases, this reaction proceeds in high regio-
and stereoselectivity, and affords desired medium rings in good
to high yields. In the reaction of the bromoallenes having a
(38) The stereochemistry of the bicyclic product 87 was confirmed by NOE
experiment and COSY analysis.
(37) For synthesis of the bromoallene 83 bearing two oxygen nucleophiles, see
the Supporting Information.
9
J. AM. CHEM. SOC. VOL. 126, NO. 28, 2004 8751

A R T I C L E S
Ohno et al.
1-H), 7.31-7.34 (m, 2H, Ph), 7.73-7.75 (m, 2H, Ph); 13C NMR (75
MHz, CDCl3) δ 17.7, 21.5, 45.8, 51.6, 62.7, 75.2, 100.9, 127.2 (2C),
129.9 (2C), 136.7, 143.9, 202.5; MS (FAB) m/z (%) 362 (MH+, 81Br,
29), 360 (MH+, 79Br, 30), 136 (100); HRMS (FAB) calcd for C14H19-
BrNO3S (MH+, 79Br), 360.0269; found, 360.0261.
(4S,aS)-1-Bromo-4-{N,N-(4-methylphenylsulfonyl)[2-[N-(4-
methylphenylsulfonyl)amino]ethyl]amino}penta-1,2-diene (20). To
a stirred solution of the bromoallene 18 (153 mg, 0.25 mmol) in EtOAc
(3 mL) was added 3 N HCl (2 mL) at room temperature. After stirring
for 3 h at 60 °C, the mixture was made basic with 28% NH4OH. The
whole was extracted with EtOAc. The extract was washed with water
and brine and dried over MgSO4. The filtrate was concentrated under
reduced pressure to give an oily residue, which was purified by column
chromatography over silica gel with n-hexane-ethyl acetate (2:1) to
(4S,aS)-1-Bromo-4-[N,N-(3-tert-butyldimethylsilyloxypropyl)(4-
methylphenylsulfonyl)amino]penta-1,2-diene (16b). By a procedure
similar to that described for the preparation of the bromoallene 15b
from 14b, the bromoallene 13b (474.3 mg, 1.5 mmol) was converted
give 20 (118 mg, 92% yield) as a colorless oil; [R]25 -22.6 (c 1.00,
into 16b (674 mg, 92% yield, >98% de) as a colorless oil: [R]24
D
D
CHCl3); IR (KBr) cm-1 3286 (NHSO2), 1957 (CdCdC), 1331 (NSO2);
1H NMR (300 MHz, CDCl3) δ 1.09 (d, J ) 6.9 Hz, 3H, CMe), 2.435
(s, 3H, PhMe), 2.441 (s, 3H, PhMe), 3.16-3.23 (m, 4H, 2 × CH2),
4.61-4.70 (m, 1H, 4-H), 4.95 (dd, J ) 5.4, 5.1 Hz, 1H, 3-H), 5.17 (br
s, 1H, NH), 6.05 (dd, J ) 5.4, 2.7 Hz, 1H, 1-H), 7.29-7.35 (m, 4H,
Ph), 7.65-7.68 (m, 2H, Ph), 7.78-7.80 (m, 2H, Ph); 13C NMR (75
MHz, CDCl3) δ 17.5, 21.5 (2C), 43.1, 43.8, 51.5, 75.3, 100.5, 127.18
(2C), 127.19 (2C), 129.7 (2C), 130.0 (2C), 136.3, 136.7, 143.4, 144.0,
202.4; MS (FAB) m/z (%) 515 (MH+, 81Br, 24), 513 (MH+, 79Br, 19),
369 (100); HRMS (FAB) calcd for C21H26BrN2O4S2 (MH+, 79Br):
513.0517; found: 513.0535.
-31.3 (c 0.945, CHCl3); IR (KBr) cm-1 1957 (CdCdC), 1342 (NSO2);
1H NMR (300 MHz, CDCl3) δ 0.05 (s, 6H, SiMe2), 0.89 (s, 9H, CMe3),
1.22 (d, J ) 6.6 Hz, 3H, CMe), 1.78-2.01 (m, 2H, CH2), 2.43 (s, 3H,
PhMe), 3.16-3.22 (m, 2H, CH2), 3.58-3.70 (m, 2H, CH2), 4.68-4.77
(m, 1H, 4-H), 5.16 (dd, J ) 5.4, 5.4 Hz, 1H, 3-H), 6.04 (dd, J ) 5.4,
2.7 Hz, 1H, 1-H), 7.28-7.31 (m, 2H, Ph), 7.69-7.72 (m, 2H, Ph); 13
C
NMR (75 MHz, CDCl3) δ -5.4 (2C), 17.8, 18.2, 21.5, 25.9 (3C), 34.5,
41.5, 51.4, 60.6, 74.8, 101.6, 127.1 (2C), 129.7 (2C), 137.5, 143.3,
202.2; MS (FAB) m/z (%) 490 (MH+, 81Br, 24), 488 (MH+, 79Br, 23),
73 (100); HRMS (FAB) calcd for C21H35BrNO3SSi (MH+, 79Br),
488.1290; found, 488.1277.
General Procedure for the Synthesis of Medium-Sized Hetero-
cycles via Cyclization of Bromoallenes. Synthesis of (5S)-7-Meth-
oxymethyl-5-methyl-4-(4-methylphenylsulfonyl)-2H,3H,4H,5H-1,4-
oxazepine (24b) and (5S,6R)-6-Methoxy-5-methyl-7-methylene-4-
(4-methylphenylsulfonyl)-1,4-oxazepine (25b) (Table 1, Entry 2).
To a stirred mixture of NaOMe (12.2 mg, 0.225 mmol) and Pd(PPh3)4
(8.7 mg, 0.0075 mmol) in MeOH (1 mL) under nitrogen was added
dropwise a solution of the bromoallene 15b (54 mg, 0.15 mmol) in
MeOH (1 mL) at room temperature, and the mixture was stirred for 3
h at this temperature. Concentration under reduced pressure gave an
oily residue, which was purified by column chromatography over silica
gel with n-hexane-ethyl acetate (3:1) to give, in order of elution, 25b
(4.4 mg, 9.4% yield) and 24b (34.1 mg, 73% yield). Compound 24b:
colorless oil; [R]25D +24.7 (c 1.00, CHCl3); IR (KBr) cm-1 1674 (Cd
(4S,aS)-1-Bromo-4-[N,N-(3-hydroxypropyl)(4-methylphenylsul-
fonyl)amino]penta-1,2-diene (17b). The bromoallene 16b (537 mg,
1.1 mmol) was dissolved in a 1% HCl solution in ethanol (6 mL), which
was prepared from concentrated HCl and EtOH, and the mixture was
stirred for 25 min at room temperature. Water was added to the mixture,
and the whole was extracted with EtOAc. The extract was washed with
brine and dried over MgSO4. The filtrate was concentrated under
reduced pressure to give an oily residue, which was purified by column
chromatography over silica gel with n-hexane-ethyl acetate (2:1) to
give 17b (386 mg, 94% yield, de ) >99%) as a colorless oil: [R]24
D
-20.7 (c 0.77, CHCl3); IR (KBr) cm-1 3531 (OH), 1957 (CdCdC),
1336 (NSO2); 1H NMR (500 MHz, CDCl3) δ 1.20 (d, J ) 6.5 Hz, 3H,
CMe), 1.83-1.92 (m, 2H, CH2), 2.19 (dd, J ) 6.5, 4.5 Hz, 1H, OH),
2.44 (s, 3H, PhMe), 3.29-3.31 (m, 2H, CH2), 3.75-3.78 (m, 2H, CH2),
4.68-4.74 (m, 1H, 4-H), 5.18 (dd, J ) 5.5, 4.5 Hz, 1H, 3-H), 6.08
(dd, J ) 5.5, 2.0 Hz, 1H, 1-H), 7.31-7.32 (m, 2H, Ph), 7.70-7.72 (m,
2H, Ph); 13C NMR (75 MHz, CDCl3) δ 17.6, 21.5, 33.8, 40.5, 51.1,
59.2, 75.2, 101.5, 127.0 (2C), 129.9 (2C), 137.2, 143.6, 202.2; MS
(FAB) m/z (%) 376 (MH+, 81Br, 16), 374 (MH+, 79Br, 16), 69 (100);
HRMS (FAB) calcd for C15H21BrNO3S (MH+, 79Br), 374.0426; found,
374.0424.
1
C-O), 1331 (NSO2); H NMR (500 MHz, CDCl3) δ 1.28 (d, J ) 7.0
Hz, 3H, CMe), 2.41 (s, 3H, PhMe), 3.24 (s, 3H, OMe), 3.48 (ddd, J )
14.5, 6.0, 2.5 Hz, 1H, CHH), 3.56 (d, J ) 12.5 Hz, 1H, MeOCHH),
3.60 (d, J ) 12.5 Hz, 1H, MeOCHH), 3.91 (ddd, J ) 12.5, 6.0, 3.0
Hz, 1H, CHH), 4.04 (ddd, J ) 14.5, 7.0, 3.0 Hz, 1H, CHH), 4.14 (ddd,
J ) 12.5, 7.0, 2.5 Hz, 1H, CHH), 4.68 (qd, J ) 7.0, 6.5 Hz, 1H, 5-H),
4.86 (d, J ) 6.5 Hz, 1H, 6-H), 7.26-7.27 (m, 2H, Ph), 7.68-7.70 (m,
2H, Ph); 13C NMR (75 MHz, CDCl3) δ 20.3, 21.4, 45.0, 50.2, 58.0,
71.0, 73.0, 108.0, 127.1 (2C), 129.5 (2C), 137.7, 143.1, 154.5; MS
(FAB) m/z (%) 312 (MH+, 71), 296 (100); HRMS (FAB) calcd for
C15H22NO4S (MH+), 312.1270; found, 312.1274. Compound 25b:
colorless oil: [R]28D +46.8 (c 0.49, CHCl3); IR (KBr) cm-1 1635 (Cd
C), 1346 (NSO2); 1H NMR (500 MHz, CDCl3) δ 1.22 (d, J ) 6.5 Hz,
3H, CMe), 2.43 (s, 3H, PhMe), 3.18 (ddd, J ) 13.0, 5.0, 3.5 Hz, 1H,
CHH), 3.46 (ddd, J ) 13.0, 8.5, 3.0 Hz, 1H, CHH), 3.53 (s, 3H, OMe),
3.67 (ddd, J ) 11.5, 5.0, 3.0 Hz, 1H, CHH), 3.83-3.88 (m, 2H, 5-H
and 6-H), 3.90 (ddd, J ) 11.5, 8.5, 3.5 Hz, 1H, CHH), 4.22 (d, J )
2.5 Hz, 1H, CdCHH), 4.40 (d, J ) 2.5 Hz, 1H, CdCHH), 7.30-7.32
(m, 2H, Ph), 7.67-7.69 (m, 2H, Ph); 13C NMR (75 MHz, CDCl3) δ
15.6, 21.5, 42.5, 50.9, 55.0, 62.8, 79.1, 85.4, 127.4 (2C), 129.7 (2C),
136.4, 143.4, 158.6; MS (FAB) m/z (%) 312 (MH+, 24), 136 (100);
HRMS (FAB) calcd for C15H22NO4S (MH+), 312.1270; found, 312.1286.
(4S,aS)-1-Bromo-4-{N,N-[2-N,N-(tert-butoxycarbonyl)[(4-meth-
ylphenylsulfonyl)amino]ethyl](4-methylphenylsulfonyl)amino}penta-
1,2-diene (18). To a stirred mixture of PPh3 (85.2 mg, 0.325 mmol)
and TsNHBoc (88.2 mg, 0.325 mmol) in THF (1 mL) under nitrogen
were added a solution of the bromoallene 15b (90 mg, 0.25 mmol) in
THF (1 mL) and diethyl azodicarboxylate (142 mg, 0.325 mmol; 40%
solution in toluene) at 0 °C, and the mixture was stirred for 1 h at
room temperature. Concentration under reduced pressure gave an oily
residue, which was purified by flash chromatography over silica gel
with n-hexane-ethyl acetate (5:1) to give 18 (130 mg, 85% yield) as
colorless crystals: mp 142 °C (n-hexane-ethyl acetate); [R]27D -68.4
(c 1.00, CHCl3); IR (KBr) cm-1 1957 (CdCdC), 1728 (CdO), 1358
(NSO2); 1H NMR (300 MHz, CDCl3) δ 1.34 (d, J ) 6.9 Hz, 3H, CMe),
1.40 (s, 9H, CMe3), 2.44 (s, 6H, 2 × PhMe), 3.25 (ddd, J ) 15.3,
10.8, 4.8 Hz, 1H, CHH), 3.45 (ddd, J ) 15.3, 10.8, 5.4 Hz, 1H, CHH),
3.94 (ddd, J ) 14.1, 10.8, 4.8 Hz, 1H, CHH), 4.20 (ddd, J ) 14.1,
10.8, 5.4 Hz, 1H, CHH), 4.72-4.81 (m, 1H, 4-H), 5.06 (dd, J ) 5.7,
5.7 Hz, 1H, 3-H), 6.05 (dd, J ) 5.7, 2.7 Hz, 1H, 1-H), 7.29-7.34 (m,
4H, Ph), 7.77-7.83 (m, 4H, Ph); 13C NMR (75 MHz, CDCl3) δ 18.3,
21.5, 21.6, 27.9 (3C), 43.0, 47.6, 52.1, 74.8, 84.6, 100.6, 127.4 (2C),
128.0 (2C), 129.3 (2C), 129.9 (2C), 136.7, 136.9, 143.7, 144.3, 150.7,
202.5; MS (FAB) m/z (%) 615 (MH+, 81Br, 4.5), 613 (MH+, 79Br, 4.8),
369 (100); HRMS (FAB) calcd for C26H34BrN2O6S2 (MH+, 79Br),
613.1042; found, 613.1023.
(5S)-5-Benzyl-7-ethoxymethyl-4-(4-methylphenylsulfonyl)-2H,
3H,4H,5H-1,4-oxazepine (30). To NaH (6 mg, 0.15 mmol) was added
EtOH (0.5 mL) at 0 °C under nitrogen, and the solution was stirred for
15 min at room temperature. To the stirred mixture were added Pd-
(PPh3)4 (11.6 mg, 0.01 mmol) and a solution of the bromoallene 15d
(43.6 mg, 0.10 mmol) in THF (0.5 mL) at room temperature. After
stirring for 1.5 h at this temperature, the mixture was poured into ice-
water (1 mL) saturated with NH4Cl. The whole was extracted with
Et2O, and the extract was washed with water and brine and dried over
9
8752 J. AM. CHEM. SOC. VOL. 126, NO. 28, 2004

Medium-Sized Rings by Cyclization of Bromoallenes
A R T I C L E S
MgSO4. The filtrate was concentrated under reduced pressure to give
an oily residue, which was purified by flash chromatography over silica
gel with n-hexane-ethyl acetate (7:2) to give 30 (24 mg, 60% yield)
as a colorless oil: [R]28D +51.3 (c 0.82, CHCl3); IR (KBr) cm-1 1684
(CdC-O), 1331 (NSO2); 1H NMR (500 MHz, CDCl3) δ 1.14 (t, J )
7.0 Hz, 3H, CMe), 2.38 (s, 3H, PhMe), 2.95 (dd, J ) 13.0, 7.0 Hz,
1H, PhCHH), 2.98 (dd, J ) 13.0, 8.0 Hz, 1H, PhCHH), 3.35 (q, J )
7.0 Hz, 2H, OCH2Me), 3.53 (ddd, J ) 15.5, 7.0, 3.0 Hz, 1H, CHH),
3.61 (d, J ) 13.5 Hz, 1H, EtOCHH), 3.69 (d, J ) 13.5 Hz, 1H,
EtOCHH), 3.92 (ddd, J ) 13.0, 7.0, 3.0 Hz, 1H, CHH), 3.97 (ddd, J
) 15.5, 8.5, 3.0 Hz, 1H, CHH), 4.19 (ddd, J ) 13.0, 8.5, 3.0 Hz, 1H,
CHH), 4.77-4.83 (m, 1H, 5-H), 4.83 (d, J ) 6.5 Hz, 1H, 6-H), 7.13-
7.28 (m, 7H, Ph), 7.49-7.51 (m, 2H, Ph); 13C NMR (75 MHz, CDCl3)
δ 15.1, 21.5, 40.8, 45.7, 56.0, 65.6, 70.9, 71.1, 106.7, 126.6, 127.2
(2C), 128.5 (2C), 129.2 (2C), 129.4 (2C), 137.4, 137.6, 143.0, 155.6;
MS (FAB) m/z (%) 402 (MH+, 24), 310 (100); HRMS (FAB) calcd
for C22H28NO4S (MH+), 402.1739; found, 402.1748.
4.30-4.39 (m, 2H, 4-H and NH), 5.51 (dd, J ) 5.5, 5.5 Hz, 1H, 3-H),
6.12 (dd, J ) 5.5, 2.5 Hz, 1H, 1-H), 7.22-7.34 (m, 5H, Ph); 13C NMR
(75 MHz, CDCl3) δ -2.0 (3C), 10.2, 42.4, 50.2, 53.1, 75.7, 102.3,
127.2, 128.7 (2C), 129.7 (2C), 136.2, 200.9. Anal. Calcd for C16H24-
BrNO2SSi: C, 47.75; H, 6.01; N, 3.48. Found: C, 47.53; H, 5.87; N,
3.39.
(5S,aS)-1-Bromo-4-{N,N-(2-hydroxyethyl)[2-(trimethylsilyl)ethane-
sulfonyl]amino}-5-phenylpenta-1,2-diene (36). By a procedure similar
to that described for the preparation of the bromoallene 17b from 13b,
the bromoallene 35 (205 mg, 0.50 mmol) was converted into 36 (130
mg, 58% yield) as colorless crystals: mp 63-65 °C; [R]28 +42.3 (c
D
1.00, CHCl3); IR (KBr) cm-1 3527 (OH), 1957 (CdCdC), 1325
1
(NSO2); H NMR (300 MHz, CDCl3) δ -0.04 (s, 9H, SiMe3), 0.82-
0.88 (m, 2H, TMSCH2), 2.09 (br s, 1H, OH), 2.31-2.42 (m, 1H,
SO2CHH), 2.51-2.61 (m, 1H, SO2CHH), 2.99 (dd, J ) 14.1, 8.4 Hz,
1H, 5-CHH), 3.06 (dd, J ) 14.1, 6.9 Hz, 1H, 5-CHH), 3.35-3.53 (m,
2H, CH2), 3.75-3.87 (m, 2H, CH2), 4.77-4.85 (m, 1H, 4-H), 5.55
(dd, J ) 5.7, 5.7 Hz, 1H, 3-H), 6.17 (dd, J ) 5.7, 2.4 Hz, 1H, 1-H),
7.22-7.35 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3) δ -2.0 (3C),
10.0, 38.5, 46.6, 48.9, 57.9, 62.3, 75.5, 100.7, 127.2, 128.8 (2C), 129.2
(2C), 137.4, 202.1. Anal. Calcd for C18H28BrNO3SSi: C, 48.42; H,
6.32; N, 3.14. Found: C, 48.59; H, 6.27; N, 3.09.
(4S,aS)-1-Bromo-4-[N-(tert-butoxycarbonyl)amino]-5-phenylpenta-
1,2-diene (34). To a stirred mixture of the propargylic alcohol 33 (1.24
g, 4.5 mmol) and Et3N (3.1 mL, 22.5 mmol) in THF (10 mL) was
added MsCl (0.69 mL, 9.0 mmol) at -78 °C, and the mixture was
stirred for 0.5 h with warming to -60 °C. The mixture was made acidic
with 4% HCl at -60 °C, and the whole was extracted with Et2O. The
extract was washed with water, saturated NaHCO3, water, and brine
and was dried over MgSO4. Concentration of the filtrate under reduced
pressure followed by rapid filtration through a short pad of SiO2 with
Et2O gave a crude mesylate, which was used without further purifica-
tion. A mixture of CuBr‚DMS (1.8 g, 9.0 mmol) and LiBr (782 mg,
9.0 mmol) were dissolved in THF (6 mL) at room temperature under
nitrogen. After stirring for 2 min, a solution of the above crude mesylate
in THF (10 mL) was added to this reagent at room temperature. The
mixture was stirred for 6 h at this temperature and quenched with
saturated NH4Cl (5 mL) and 28% NH4OH (5 mL). The whole was
extracted with Et2O. The extract was washed with water and brine and
dried over MgSO4. The filtrate was concentrated under reduced pressure
to give an oily residue, which was purified by column chromatography
over silica gel with n-hexane-ethyl acetate (7:1) to give 34 (1.05 g,
69% yield). Recrystallization from n-hexane-ethanol gave essentially
pure 34 as colorless needles: mp 73 °C; [R]26D +140 (c 1.00, CHCl3);
IR (KBr) cm-1 3348 (NHCO2), 1959 (CdCdC), 1693 (CdO); 1H NMR
(300 MHz, CDCl3, 333 K) δ 1.42 (s, 9H, CMe3), 2.83-2.96 (m, 2H,
5-CH2), 4.47-4.59 (m, 2H, NH and 4-H), 5.42 (dd, J ) 5.4, 5.4 Hz,
1H, 3-H), 6.04 (dd, J ) 5.4, 2.1 Hz, 1H, 1-H), 7.17-7.31 (m, 5H, Ph);
13C NMR (75 MHz, CDCl3, 333 K) δ 28.4 (3C), 41.2, 50.0, 74.9, 79.9,
102.3, 126.8, 128.5 (2C), 129.5 (2C), 136.9, 154.9, 201.1. Anal. Calcd
for C16H20BrNO2: C, 56.82; H, 5.96; N, 4.14. Found: C, 56.81; H,
5.95; N, 4.09.
(5S)-5-Benzyl-7-methoxymethyl-4-[2-(trimethylsilyl)ethanesulfo-
nyl]-2H,3H,4H,5H-1,4-oxazepine (37). By a procedure identical to
that described for the preparation of the 1,4-oxazepines 24b and 25b
from 15b, the bromoallene 36 (49 mg, 0.11 mmol) was converted into
37 (34 mg, 78% yield) as a colorless oil: [R]28D +3.17 (c 1.02, CHCl3);
1
IR (KBr) cm-1 1674 (CdC-O), 1327 (NSO2); H NMR (300 MHz,
CDCl3) δ -0.06 (s, 9H, SiMe3), 0.71-0.88 (m, 2H, TMSCH2), 2.28-
2.38 (m, 1H, SO2CHH), 2.41-2.52 (m, 1H, SO2CHH), 2.98 (dd, J )
13.8, 6.9 Hz, 1H, BnCHH), 3.06 (dd, J ) 13.8, 8.7 Hz, 1H, BnCHH),
3.34 (s, 3H, OMe), 3.57 (ddd, J ) 15.3, 6.9, 2.4 Hz, 1H, CHH), 3.75
(d, J ) 12.6 Hz, 1H, MeOCHH), 3.80 (d, J ) 12.6 Hz, 1H, MeOCHH),
3.94 (ddd, J ) 15.3, 6.0, 3.0 Hz, 1H, CHH), 4.05 (ddd, J ) 12.6, 6.9,
3.0 Hz, 1H, CHH), 4.30 (ddd, J ) 12.6, 6.0, 2.4 Hz, 1H, CHH), 4.61-
4.69 (m, 1H, 5-H), 5.05 (d, J ) 6.9 Hz, 1H, 6-H), 7.21-7.31 (m, 5H,
Ph); 13C NMR (75 MHz, CDCl3) δ -2.1 (3C), 10.0, 40.5, 45.9, 48.9,
56.7, 58.2, 72.3, 73.3, 108.6, 127.0, 128.6 (2C), 129.2 (2C), 137.9,
155.5; MS (FAB) m/z (%) 398 (MH+, 6), 73 (100); HRMS (FAB) calcd
for C19H32NO4SSi (MH+), 398.1821; found, 398.1838.
(5S)-5-Benzyl-7-methoxymethyl-2H,3H,4H,5H-1,4-oxazepine (38).
To a stirred solution of CsF (159 mg, 10.5 mmol) in DMF (1 mL) was
added 1,4-oxazepine 37 (83 mg, 0.21 mmol) in DMF (1 mL) at room
temperature. After stirring for 12 h at 95 °C, MeOH (3 mL) was added,
and the mixture was concentrated under reduced pressure. The residue
was diluted with Et2O (5 mL), filtered, and evaporated. The crude amine
was purified by column chromatography over silica gel with n-hexane-
ethanol-chloroform (5:1:1) to give 38 (36 mg, 73% yield) as a colorless
(4S,aS)-1-Bromo-4-{N-[2-(trimethylsilyl)ethanesulfonyl]amino}-
5-phenylpenta-1,2-diene (35). To a stirred solution of the bromoallene
34 (778 mg, 2.3 mmol) in EtOAc (6 mL) was added 3 N HCl (6 mL)
at room temperature. After stirring for 1 h at 50 °C, the mixture was
made basic with 28% NH4OH. The whole was extracted with EtOAc.
The extract was washed with water and brine and dried over MgSO4.
The filtrate was concentrated under reduced pressure to give an oily
residue. To a stirred solution of the residue in DMF (4 mL) was added
Et3N (1.6 mL, 11.5 mmol) and SESCl (831 mg, 4.14 mmol) at 0 °C.
The mixture was stirred for 1 h at this temperature and poured into
water and extracted with Et2O. The extract was washed with water
and brine and dried over MgSO4. Concentration of the filtrate under
reduced pressure followed by flash column chromatography over silica
gel with n-hexane-ethyl acetate (6:1) gave 35 (780 mg, 84% yield) as
oil: [R]27 +19.6 (c 1.00, CHCl3); IR (KBr) cm-1 3323 (NH), 1672
D
(CdC-O); 1H NMR (300 MHz, CDCl3) δ 1.92 (br s, 1H, NH), 2.77-
2.86 (m, 2H, PhCH2), 2.90 (ddd, J ) 13.8, 7.8, 1.8 Hz, 1H, CHH),
3.17 (ddd, J ) 13.8, 6.0, 2.4 Hz, 1H, CHH), 3.34 (s, 3H, OMe), 3.66-
3.86 (m, 4H, 5-H, MeOCH2 and CHH), 4.24 (ddd, J ) 12.3, 6.0, 1.8
Hz, 1H, CHH), 4.94 (d, J ) 3.0 Hz, 1H, 6-H), 7.21-7.34 (m, 5H, Ph);
13C NMR (75 MHz, CDCl3) δ 43.2, 50.1, 56.9, 58.1, 73.6, 73.7, 111.6,
126.5, 128.5 (2C), 129.2 (2C), 138.7, 155.0; MS (FAB) m/z (%) 234
(MH+, 85), 142 (100); HRMS (FAB) calcd for C14H20NO2 (MH+),
234.1494; found, 234.1499.
1-{2-[2-(tert-Butyldimethylsiloxy)ethyl]phenyl}but-3-yn-2-ol (48).
To a stirred solution of oxalyl chloride (2.93 mL, 33.6 mmol) in CH2-
Cl2 (30 mL) at -78 °C under nitrogen was added dropwise a solution
of DMSO (7.96 mL, 112 mmol) in CH2Cl2 (10 mL). After 45 min, a
solution of the alcohol 47 (6.28 g, 22.4 mmol) in CH2Cl2 (20 mL) was
added to the above reagent at -78 °C, and the mixture was stirred for
1 h at this temperature. Diisopropylethylamine (27.0 mL, 157 mmol)
was added to the above solution at -78 °C, and the mixture was stirred
colorless needles: mp 80 °C (n-hexane-Et2O); [R]27 +105 (c 1.00,
D
CHCl3); IR (KBr) cm-1 3265 (NHSO2), 1959 (CdCdC), 1325
(NHSO2); 1H NMR (500 MHz, CDCl3) δ -0.02 (s, 9H, SiMe3), 0.80-
0.91 (m, 2H, TMSCH2), 2.66-2.70 (m, 2H, SO2CH2), 2.91 (dd, J )
13.0, 6.5 Hz, 1H, 5-CHH), 3.00 (dd, J ) 13.0, 6.0 Hz, 1H, 5-CHH),
9
J. AM. CHEM. SOC. VOL. 126, NO. 28, 2004 8753

A R T I C L E S
Ohno et al.
for 30 min with warming to 0 °C. The mixture was made acidic with
4% HCl, and the whole was extracted with Et2O. The extract was
washed successively with water, saturated NaHCO3, and brine and was
dried over MgSO4. The filtrate was concentrated under reduced pressure
to give a crude aldehyde as an oil. To a stirred solution of trimethyl-
silylacetylene (3.96 mL, 28.0 mmol) in dry THF (10 mL) under nitrogen
was added n-BuLi (1.56 M solution in n-hexane; 17.2 mL, 26.9 mmol)
at 0 °C, and the mixture was stirred for 20 min at this temperature. A
solution of the crude aldehyde in dry THF (15 mL) was added to the
above stirred reagent at -78 °C, and the mixture was stirred for 1 h
with warming to -60 °C, followed by quenching with saturated NH4-
Cl. The mixture was made acidic with 4% HCl, and the whole was
extracted with Et2O. The extract was washed successively with water,
saturated NaHCO3, and brine and was dried over MgSO4. The filtrate
was concentrated under reduced pressure to give the TMS derivative
as an oil. To a stirred solution of this oil in MeOH (20 mL) was added
dropwise NaOMe (242 mg, 4.5 mmol) in MeOH (4.5 mL) at 0 °C,
and the mixture was stirred for 2 h at room temperature. The mixture
was concentrated under reduced pressure, and the residue was filtered
through a short pad of SiO2 with n-hexane-ethyl acetate (5:2) and
concentrated. The residue was purified by column chromatography over
silica gel with n-hexane-ethyl acetate (4:1) to give 48 (4.43 g, 65%
yield) as a colorless oil: IR (KBr) cm-1 3298 (OH), 2116 (CtC); 1H
NMR (300 MHz, CDCl3) δ -0.02 (s, 6H, SiMe2), 0.85 (s, 9H, CMe3),
2.44 (d, J ) 5.7 Hz, 1H, OH), 2.49 (d, J ) 1.8 Hz, 1H, 4-H), 2.94 (t,
J ) 6.9 Hz, 2H, 1′-CH2), 3.10-3.13 (m, 2H, 1-CH2), 3.84 (t, J ) 6.9
Hz, 2H, 2′-CH2), 4.56-4.63 (m, 1H, 2-H), 7.13-7.27 (m, 4H, Ph);
13C NMR (75 MHz, CDCl3) δ -5.48 (2C), 18.4, 25.9 (3C), 35.8, 40.6,
62.9, 64.3, 73.6, 84.3, 126.3, 127.0, 130.1, 130.8, 135.0, 137.9; MS
(FAB) m/z (%) 305 (MH+, 29), 155 (100); HRMS (FAB) calcd for
C18H29O2Si (MH+), 305.1937; found, 305.1931.
General Procedure for the Synthesis of Bromoallenes Bearing
an Active Methylene Nucleophile. Synthesis of (4S,aS)-1-Bromo-
4-{N,N-[4,4-bis(methoxycarbonyl)butyl](4-methylphenylsulfonyl)-
amino}penta-1,2-diene (66). To a stirred mixture of PPh3 (157 mg,
0.60 mmol), the bromoallene 15b (150 mg, 0.40 mmol), and diisopro-
pylethylamine (0.104 mL, 0.60 mmol) in CH2Cl2 (4 mL) under nitrogen
was added I2 (152 mg, 0.60 mmol) at room temperature, and the mixture
was stirred for 6 h at this temperature. Concentration under reduced
pressure gave an oily residue, which was purified by column chroma-
tography over silica gel with n-hexane-ethyl acetate (5:1) to give the
corresponding iodide (184 mg, 95% yield) as colorless needles. To a
stirred suspension of NaH (18 mg, 0.45 mmol) in DMF (1 mL) under
nitrogen was added dimethyl malonate (0.057 mL, 0.50 mmol) at 0
°C, and the mixture was stirred for 20 min at room temperature. To
the stirred mixture was added a solution of the above iodide (121 mg,
0.25 mmol) in DMF (2 mL) at 0 °C, and the mixture was stirred for
2.5 h at room temperature. The mixture was poured into ice-water (1
mL) saturated with NH4Cl, and the whole was extracted with Et2O.
The extract was washed with water and brine and was dried over
MgSO4. Concentration under reduced pressure gave an oily residue,
which was purified by column chromatography over silica gel with
n-hexane-ethyl acetate (3:1) to give 66 (110 mg, 90% yield; 86% yield
for two steps) as a colorless oil: [R]27
-34.5 (c 1.05, CHCl3); IR
D
(KBr) cm-1 1957 (CdCdC), 1751 (CdO), 1736 (CdO), 1340 (NSO2);
1H NMR (300 MHz, CDCl3) δ 1.17 (d, J ) 6.9 Hz, 3H, CMe), 1.61-
1.83 (m, 2H, CH2), 1.89-1.97 (m, 2H, CH2), 2.43 (s, 3H, PhMe), 3.07-
3.13 (m, 2H, CH2), 3.40 [dd, J ) 7.5, 7.5 Hz, 1H, CH(CO2Me)2], 3.75
(s, 6H, 2 × OMe), 4.63-4.73 (m, 1H, 4-H), 5.16 (dd, J ) 5.4, 5.4 Hz,
1H, 3-H), 6.07 (dd, J ) 5.4, 2.4 Hz, 1H, 1-H), 7.29-7.32 (m, 2H, Ph),
7.68-7.71 (m, 2H, Ph); 13C NMR (75 MHz, CDCl3) δ 17.5, 21.5, 26.1,
29.0, 43.4, 51.10, 51.14, 52.5 (2C), 75.1, 101.3, 127.1 (2C), 129.8 (2C),
137.4, 143.5, 169.5 (2C), 202.3; MS (FAB) m/z (%) 490 (MH+, 81Br,
54), 488 (MH+, 79Br, 54), 344 (100); HRMS (FAB) calcd for C20H27-
BrNO6S (MH+, 79Br), 488.0742; found, 488.0747.
(8S,6Z)-5,5-Bis(methoxycarbonyl)-6-methoxymethyl-8-methyl-1-
(4-methylphenylsulfonyl)-1H,3H,4H,8H-tetrahydroazocine (67). By
a procedure identical to that described for the preparation of the 1,4-
oxazepines 24b and 25b from 15b, the bromoallene 66 (48.8 mg, 0.10
mmol) was converted into 67 (24.5 mg, 56% yield) as colorless
needles: mp 150-153 °C (n-hexane-ethyl acetate); [R]27 +7.88 (c
D
0.90, CHCl3); IR (KBr) cm-1 1747 (CdO), 1716 (CdO), 1335 (NSO2);
1H NMR (500 MHz, CDCl3) δ 1.27-1.34 (m, 1H, 3-CHH), 1.41 (d, J
) 7.0 Hz, 3H, CMe), 1.88-1.95 (m, 1H, 3-CHH), 2.32-2.37 (m, 1H,
4-CHH), 2.42 (s, 3H, PhMe), 2.55-2.59 (m, 1H, 4-CHH), 2.93-2.97
(m, 1H, 2-CHH), 3.23 (s, 3H, OMe), 3.65-3.75 (m, 1H, 2-CHH), 3.67
(s, 3H, OMe), 3.72 (s, 3H, OMe), 3.92 (d, J ) 11.5 Hz, 1H, MeOCHH),
4.29 (d, J ) 11.5 Hz, 1H, MeOCHH), 4.93 (qd, J ) 7.0, 5.0 Hz, 1H,
8-H), 5.53 (d, J ) 5.0 Hz, 1H, 7-H), 7.27-7.29 (m, 2H, Ph), 7.70-
7.72 (m, 2H, Ph); 13C NMR (75 MHz, CDCl3) δ 17.7, 21.4, 28.2, 41.0,
43.7, 52.6, 52.9, 56.6, 58.5, 65.7, 67.6, 126.9 (2C), 129.6 (2C), 135.8,
138.0, 139.0, 143.0, 169.4, 169.9; MS (FAB) m/z (%) 440 (MH+, 32.0),
136 (100); HRMS (FAB) calcd for C21H30NO7S (MH+), 440.1743;
found, 440.1735.
Acknowledgment. We thank Dr. S. Ogoshi, Osaka Univer-
sity, for useful information regarding the mechanism of the
reaction. This work was supported by a Grant-in-Aid for
Encouragement of Young Scientists from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
H.H. is grateful to Research Fellowships of the Japan Society
for the Promotion of Science (JSPS) for Young Scientists.
Supporting Information Available: Synthetic procedures and
characterization for 3, 13a, 15a, 15c-e, 17a, 17c-e, 21, 23,
24a, 24c-e, 25a, 26a-e, 27a-c, 28, 29, 31, 32, 40, 42, 44-
46, 49-62, 64, 65, 68, 69, 83, 86, 87, 89-92, and 93; 1H NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA048693X
9
8754 J. AM. CHEM. SOC. VOL. 126, NO. 28, 2004