A highly regio- and stereoselective formation of bicyclo[4.2.0]oct-5-ene derivatives through thermal intramolecular [2 + 2] cycloaddition of allenes

Article abstract of DOI:10.1021/jo0700528

(Chemical Equation Presented) Thermal [2 + 2] cycloaddition of allenes with an additional multiple bond is described. By simply heating the allenenes or allenynes having a three-atom tether in an appropriate solvent such as dioxane or DMF, the distal doub

Full text of DOI:10.1021/jo0700528

A Highly Regio- and Stereoselective Formation of
Bicyclo[4.2.0]oct-5-ene Derivatives through Thermal
Intramolecular [2 + 2] Cycloaddition of Allenes
Hiroaki Ohno,*,‡ Tsuyoshi Mizutani,† Yoichi Kadoh,† Akimasa Aso,† Kumiko Miyamura,†
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 January 9, 2007
Thermal [2 + 2] cycloaddition of allenes with an additional multiple bond is described. By simply heating
the allenenes or allenynes having a three-atom tether in an appropriate solvent such as dioxane or DMF,
the distal double bond of the allenic moiety regioselectively participates in the cycloaddition to form
bicyclo[4.2.0]oct-5-ene derivatives in good to excellent yields. In all the reactions of allenenes, the olefin
geometry was completely transferred to the cycloadducts. While the reaction of terminal allenes afforded
bicyclic cyclobutane derivatives as a single isomer, the cycloaddition of some internal allenes with axial
chirality yielded a diastereomeric mixture of cycloadducts. These results are in good accordance with
the stepwise mechanism through a biradical intermediate with a coplanar allyl radical.
Introduction
research efforts have been focused on the development of
cycloaddition of allenes. Intermolecular [2 + 2] cycloaddition
reaction of allenes is well documented and constitutes an
efficient method for accessing strained cyclobutane rings with
one extra carbon-carbon double bond for further elaboration.4,5
Meanwhile, the intramolecular [2 + 2] version of this cycload-
dition is an extremely attractive approach to bicyclic derivatives
The design and discovery of reactions with high atom
economy that proceed, ideally, in the absence of any reagents
or catalysts, without forming any waste are critical to extending
the practical reach of organic synthesis.1 Particularly, atom-
economical reactions involving formation of two or more
carbon-carbon bonds with a great increase in complexity of
the molecule are attractive to achieve this goal. Thermal
cycloaddition between carbon-carbon multiple bonds is one
powerful approach to construct various cyclic molecules with
extremely high atom economy.
During the past decades, allene chemistry has been revealed
as an established member of the weaponry utilized in modern
synthetic chemistry. On account of the current interest in the
reactions of allenes with an additional multiple bond including
transition metal-catalyzed carbocyclizations,2,3 considerable
(2) (a) Shin, S.; RajanBabu, T. V. J. Am. Chem. Soc. 2001, 123, 8416-
8417. (b) Oh, C. H.; Jung, S. H.; Rhim, C. Y. Tetrahedron Lett. 2001, 42,
8669-8671. (c) Franze´n, J.; Lo¨fstedt, J.; Dorange, I.; Ba¨ckvall, J.-E. J.
Am. Chem. Soc. 2002, 124, 11246-11247. (d) Franze´n, J.; Ba¨ckvall, J.-E.
J. Am. Chem. Soc. 2003, 125, 6056-6057. (e) Oh, C. H.; Jung, S. H.; Park,
D. I.; Choi, J. H. Tetrahedron Lett. 2004, 45, 2499-2502.
(3) (a) Ohno, H.; Takeoka, Y.; Miyamura, K.; Kadoh, Y.; Tanaka, T.
Org. Lett. 2003, 5, 4763-4766. (b) Ohno, H.; Takeoka, Y.; Kadoh, Y.;
Miyamura, K.; Tanaka, T. J. Org. Chem. 2004, 69, 4541-4544.
(4) For excellent reviews, see: (a) Pasto, D. J. Tetrahedron 1984, 40,
2805-2827. (b) Murakami, M.; Matsuda, T. In Modern Allene Chemistry;
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2, pp 727-815.
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Tanaka, S.; Okajima, T.; Tamaru, Y. Chem. Eur. J. 2003, 9, 2419-2439.
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J. H.; Hiemstra, H. Eur. J. Org. Chem. 2006, 127-137.
* Author to whom correspondence should be addressed. Tel: 81-6-6879-
8210. Fax: 81-6-6879-8214.
† Osaka University.
‡ Kyoto University.
(1) (a) Trost, B. M. Acc. Chem. Res. 2002, 35, 695-705. See also, (b)
Trost, B. M. Science 1991, 254, 1471-1477.
10.1021/jo0700528 CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/10/2007
4378
J. Org. Chem. 2007, 72, 4378-4389

Bicyclo[4.2.0]oct-5-ene DeriVatiVes
SCHEME 1. Intramolecular [2 + 2] Cycloaddition of
Allenenes
SCHEME 2. Palladium(0)-Catalyzed Tandem Cyclization of
Allenenes
fused with a strained cyclobutane ring (Scheme 1).6 However,
intramolecular cycloaddition, including the reaction of bisal-
lenes,7,8 always encounters regioselectivity problems: formation
of proximal and distal adducts.9 In 1965, Skattebøl and Solomon
observed unselective formation of a distal adduct of the type 3
as well as a proximal adduct in the vapor-phase thermal
cycloaddition of octa-1,2,7-triene at 410 °C.10 Recently, highly
regioselective preparations of distal adducts under thermal
conditions were reported; however, these reactions were limited
to a special class of allenes as substrates, such as allene
carboxylates,11 allenyl sulfones,12 difluoroallenes,13 â-lactam-
SCHEME 3. Formation of Distal Adduct 11a
14
or aryl-tethered allenes,15 or diyne-diallenes.16
As a part of our ongoing program aimed at development of
novel useful methodologies for construction of nitrogen-
containing heterocycles from allenic compounds,3,17,18 we
recently reported a palladium-catalyzed tandem cyclization of
a Abbreviation: Mts ) 2,4,6-trimethylphenylsulfonyl.
(6) For recent examples, see: (a) Shepard, M. S.; Carreira, E. M.; J.
Am. Chem. Soc. 1997, 119, 2597-2605. (b) Tsuno, T.; Sugiyama, K. Bull.
Chem. Soc. Jpn. 1999, 72, 519-531.
allenenes 4 in the presence of an aryl halide and potassium
carbonate to yield tricyclic products 7, through insertion of
arylpalladium halide to allene, carbopalladation onto the double
bond, and aromatic C-H functionalization (Scheme 2).19 In the
course of this study, we observed regioselective formation of
distal adducts 11 in the reaction mixture of the palladium-
catalyzed cyclization of allenene 8 with 5-bromopyrimidine 9
possessing relatively low reactivity (Scheme 3). On the basis
of this result, we found that this cycloaddition proceeds by
simply heating the allenenes in an appropriate solvent in the
absence of any catalyst.20 Quite recently, microwave-assisted21
or palladium-catalyzed [2 + 2] cycloaddition of allenynes22
providing distal adducts regioselectively have appeared; how-
ever, our cycloaddition is the sole example of exclusive
conversion of unactivated simple allenes to distal adducts under
thermal conditions. In this contribution, we present full details
(7) (a) Murakami, M.; Ashida, S.; Matsuda,T. J. Am. Chem. Soc. 2004,
126, 10838-10839. (b) Jiang, X.; Cheng, X.; Ma, S. Angew. Chem., Int.
Ed. 2006, 45, 8009-8013. For transition metal-catalyzed [2 + 2] cycload-
dition, see: (c) Kang, S.-K.; Baik, T.-G.; Kulak, A. N.; Ha, Y.-H.; Lim,
Y.; Park, J. J. Am. Chem. Soc. 2000, 122, 11529-11530.
(8) An interesting [2 + 2] cycloaddition of in situ-generated bis-
(phosphinylallene)s furnishing naphtho[b]cyclobutenes has recently ap-
peared, see: Kitagaki, S.; Okumura, Y.; Mukai, C. Tetrahedron Lett. 2006,
47, 1849-1852.
(9) The compounds having the bicyclo[4.2.0]octane skeleton constitute
an important class of molecules in synthetic and natural product chemistry.
For example, see: (a) Piers, E.; Lu, Y.-F. J. Org. Chem. 1989, 54, 2267-
2268. (b) Suginome, H.; Takeda, T.; Itoh, M.; Nakayama, Y.; Kobayashi,
K. J. Chem. Soc. Perkin Trans. 1 1995, 49-61. (c) Crimmins, M. T.; Huang,
S.; Guise-Zawacki, L. E. Tetrahedron Lett. 1996, 37, 6519-6522. (d) Naik,
J. T.; Mantle, P. G.; Sheppard, R. N.; Waight, E. S. J. Chem. Soc. Perkin
Trans. 1 1995, 1121-1125. (e) Carotenuto, A.; Conte, M. R.; Fattorusso,
E.; Lanzotti, V.; Magno, S. Tetrahedron 1995, 51, 10751-10758. (f) Kurata,
K.; Taniguchi, K.; Agatsuma, Y.; Suzuki, M. Phytochemistry 1998, 47, 363-
369. (g) Kashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.; Yamagishi, T.; Fujioka,
T.; Mihashi, K.; Mizuki, K.; Cosentino, L. M.; Fowke, K.; Morris-Natschke,
S. L.; Lee, K.-H. Tetrahedron 2001, 57, 1559-1563.
(16) Recently, in their study of molybdenum-mediated allenic Pauson-
Khand reaction, Cook and co-workers observed the formation of distal
adducts in 30-40% yield, by heating of conformationally restricted diyne-
allenes in toluene at 100 °C in the absence of any catalyst. As far as we are
aware, this is the first example of thermal [2 + 2] cycloaddition between
unactivated allenes and alkynes, see: (a) Cao, H.; Flippen-Anderson, J.;
Cook, J. M. J. Am. Chem. Soc. 2003, 125, 3230-3231. (b) Cao, H.; Van
Ornum, S. G.; Deschamps, J.; Flippen-Anderson, J.; Laib, F.; Cook, J. M.
J. Am. Chem. Soc. 2005, 127, 933-943.
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Y.; Fujii, N.; Ibuka, T. J. Org. Chem. 1999, 64, 2992-2993. (b) Ohno, H.;
Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.; Takemoto, Y.; Ibuka,
T. J. Org. Chem. 2001, 66, 4904-4914. (c) Ohno, H.; Hamaguchi, H.;
Ohata, M.; Tanaka, T. Angew. Chem., Int. Ed. 2003, 42, 1749-1753. (d)
Ohno, H.; Hamaguchi, H.; Ohata, M.; Kosaka, S.; Tanaka, T. J. Am. Chem.
Soc. 2004, 126, 8744-8754. (e) Hamaguchi, H.; Kosaka, S.; Ohno, H.;
Tanaka, T. Angew. Chem., Int. Ed. 2005, 44, 1513-1517. (f) Ohno, H.;
Kadoh, Y.; Fujii, N.; Tanaka, T. Org. Lett. 2006, 8, 947-950.
(18) For recent reviews, see: (a) Ohno, H. Yakugaku Zasshi 2001, 121,
733-741. (b) Ohno, H. Chem. Pharm. Bull. 2005, 53, 1211-1226. (c) Ohno,
H. Yakugaku Zasshi 2005, 125, 899-925.
(10) Skattebøl, L.; Solomon, S. J. Am. Chem. Soc. 1965, 87, 4506-
4511.
(11) (a) Yoshida, M.; Hiromatsu, M.; Kanematsu, K. J. Chem. Soc. Chem.
Commun. 1986, 1168-1170. (b) Yoshida, M.; Hiromatsu, M.; Kanematsu,
K. Heterocycles 1986, 24, 881-884. (c) Yoshida, M.; Hidaka, Y.; Nawata,
Y.; Rudzin˜ski, J. M.; O˜ sawa, E.; Kanematsu, K. J. Am. Chem. Soc. 1988,
110, 1232-1238. (d) Gillmann, T.; Hu¨lsen, T.; Massa, W.; Wocadlo, S.
Synlett 1995, 1257-1259. For a related reaction of cumulenes, see: (e)
Garcia, J. G.; Ramos, B.; Pratt, L. M.; Rodr´ıguez, A. Tetrahedron Lett.
1995, 36, 7391-7394.
(12) (a) Kanematsu, K.; Sugimoto, N.; Kawaoka, M.; Yeo, S.; Shiro,
M. Tetrahedron Lett. 1991, 32, 1351-1354. (b) Padwa, A.; Filipkowski,
M. A.; Meske, M.; Watterson, S. H.; Ni, Z. J. Am. Chem. Soc. 1993, 115,
3776-3777. (c) Padwa, A.; Meske, M.; Murphree, S. S.; Watterson, S. H.;
Ni, Z. J. Am. Chem. Soc. 1995, 117, 7071-7080. (d) Padwa, A.; Lipka,
H.; Watterson, S. H.; Murphree, S. S. J. Org. Chem. 2003, 68, 6238-
6250. See also, (e) Inagaki, F.; Mukai, C. Org. Lett. 2006, 8, 1217-1220.
(13) Shen, Q.; Hammond, G. B. J. Am. Chem. Soc. 2002, 124, 6534-
6535.
(14) (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Org. Lett. 2003, 5,
3795-3798. (b) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Redondo, M.
C.; Torres, M. R. Chem. Eur. J. 2006, 12, 1539-1546.
(15) Ikemoto, C.; Kawano, T.; Ueda, I. Tetrahedron Lett. 1998, 39,
5053-5056.
(19) (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.
J. Org. Chem, Vol. 72, No. 12, 2007 4379

Ohno et al.
SCHEME 5. Preparation of Allenenes 18, 20, and 22a
SCHEME 4. Preparation of Allenenes 8 and 13a-c
of our investigation into the thermal intramolecular [2 + 2]
cycloaddition of allenenes and allenynes. The stereochemical
outcome of axially chiral allenenes as well as mechanistic
considerations of this transformation are also described.
Results and Discussion
Preparation of Allenenes. Known allenene 8 was synthesized
according to our reported procedure through cinnamylation of
protected amino allene 12,19b which, in turn, was readily
obtained through diethylzinc-mediated allene synthesis catalyzed
by palladium(0) (Scheme 4).23 Other L-valine-derivatives 13a-c
having a substituted phenyl group were similarly prepared by
the reaction of 12 with a substituted (E)-cinnamyl bromide under
basic conditions. The trimethylphenylsulfonyl (Mts) group was
used as a nitrogen protecting group because it can withstand a
wide range of chemical manipulations and yet be removed by
the use of Yajima’s protocol.24 In addition, many Mts amides
forming good crystals can be easily handled.
a Reagents: (a) NaH, (E)-cinnamyl bromide, DMF; (b) SO3‚py, Et3N,
DMSO; (c) Ph3PdC(Br)CO2Me, CHCl3; (d) DIBAL-H, CH2Cl2; (e) MsCl,
Et3N, THF; (f) cat. Pd(PPh3)4, Et2Zn, THF; (g) (HCHO)n, CuBr, i-Pr2NH,
dioxane.
SCHEME 6. Preparation of Allenene 29a
R-Unsubstituted allene 18 was prepared as shown in Scheme
5. Alkylation of protected 2-aminoethanol 14, oxidation with
SO3‚pyridine, and Wittig olefination with brominated ylide25
afforded R-bromo-R,â-unsaturated ester 16. Reduction of 16
with DIBAL-H and mesylation of the resulting alcohol 17
followed by treatment with diethylzinc in the presence of
palladium(0)23 furnished the desired allenene 18 in good yield.
Allenene 20 tethered by an oxygen atom was prepared by
copper(I)-mediated one-carbon elongation of terminal alkyne
19 with paraformaldehyde in the presence of i-Pr2NH (Crabbe´
conditions).26 Treatment of known allene 2127 with NaH and
(E)-cinnamyl bromide gave dimethyl malonate-derived allenene
22 in 91% yield.
a Reagents: (a) MtsCl, Et3N, DMF; (b) (E)-cinnamyl bromide, NaH,
DMF; (c) LiAlH4, THF; (d) SO3‚py, Et3N, DMSO; (e) Ph3PdC(Br)CO2Me,
CHCl3; (f) DIBAL-H, CH2Cl2; (g) MsCl, Et3N, THF; (h) cat. Pd(PPh3)4,
Et2Zn, THF.
For preparation of alanine-derived substrate 29, N-cinnamy-
lated methyl alaninate derivative 25 was employed (Scheme
6):28 by a sequence of reactions including Wittig olefination
and reductive allene formation, the ester 25 was converted to
allenene 29.
We encountered difficulty in preparation of R,R-dimethylated
allene derivative 34: thus, the desired brominated enoate 31
was not obtained by Wittig olefination of aldehyde derived from
N-protected 2-amino-2-metylpropan-1-ol 30 with brominated
phosphorus ylide, presumably due to steric hindrance of the
neighboring quaternary carbon center (Scheme 7). However,
the reaction with in situ-generated brominated phosphonate,
(EtO)2P(O)CH(Br)CO2Et, afforded 31 in synthetically accept-
able yield (49%). The usual transformation through reduction,
allene formation, and alkylation yielded 34 having a quaternary
carbon center.
(20) A portion of this study on the reaction of terminal allenes was already
reported in a preliminary communication: Ohno, H.; Mizutani, T.; Kadoh,
Y.; Miyamura, K.; Tanaka, T. Angew. Chem., Int. Ed. 2005, 44, 5113-
5115.
(21) (a) Brummond, K. M.; Chen, D. Org. Lett. 2005, 7, 3473-3475.
(b) Oh, C. H.; Gupta, A. K.; Park, D. I.; Kim, N. Chem. Commun. 2005,
5670-5672.
(22) Oh, C. H.; Park, D. I.; Jung, S. H.; Reddy, V. R.; Gupta, A. K.;
Kim, Y. M. Synlett 2005, 2092-2094.
(23) (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.
(24) Fujii, N.; Otaka, A.; Ikemura, O.; Akaji, K.; Funakoshi, S.; Hayashi,
Y.; Kuroda, Y.; Yajima, H. J. Chem. Soc., Chem. Commun. 1987, 274-
275.
(25) (a) Denney, D. B.; Ross, S. T. J. Org. Chem. 1962, 27, 998-1000.
For a recent synthesis of stabilized halo-ylides, see: (b) Kayser, M. M.;
Zhu, J.; Hooper, D. L. Can. J. Chem. 1997, 75, 1315-1321.
(26) Searles, S.; Li, Y.; Nassim, B.; Lopes, M.-T. R.; Tran, P. T.; Crabbe´,
P. J. Chem. Soc., Perkin Trans. 1 1984, 747-751.
(28) For a reason that is unclear, preparation of 23-derived aldehyde
having an NH group by oxidation of the corresponding alcohol was not
reproductive.
(27) Ma, S.; Jiao, N.; Zhao, S.; Hou, H. J. Org. Chem. 2002, 67, 2837-
2847.
4380 J. Org. Chem., Vol. 72, No. 12, 2007

Bicyclo[4.2.0]oct-5-ene DeriVatiVes
SCHEME 7. Preparation of Allenene 34a
SCHEME 10. Preparation of Allenenes 46, 49, 51, and 53a
a Reagents: (a) SO3‚py, Et3N, DMSO; (b) (EtO)2P(O)CH2CO2Et, NaH,
Br2, THF; (c) DIBAL-H, CH2Cl2; (d) MsCl, Et3N, THF; (e) cat. Pd(PPh3)4,
Et2Zn, THF; (f) NaH, (E)-cinnamyl bromide, DMF.
SCHEME 8. Preparation of Allenenes 36 and 37a
a Reagents: (a) BrCH2CH2OTHP, K2CO3, DMF; (b) 4 N HCl, MeOH;
(c) SO3‚py, Et3N, DMSO; (d) Ph3PdC(R)CO2Me, THF; (e) Ph3PdCHCN,
THF.
a Reagents: (a) NaH, (E)-cinnamyl bromide, DMF; (b) SO3‚py, Et3N,
DMSO; (c) trimethylsilylacetylene, n-BuLi, THF; (d) MeONa, MeOH; (e)
prop-1-ynylmagnesium bromide, THF; (f) MsCl, Et3N, THF; (g) MeMgBr,
CuBr, THF.
SCHEME 9. Preparation of Allenene 40 and 44a
Finally, we synthesized allenenes having various substituent-
(s) on the allenic moiety as shown in Scheme 10. Cinnamylation
of known protected amino allene 4517b gave 46 having a methyl
group on the proximal allenic carbon. Alkynylation of 30-
derived aldehyde, mesylation of the resulting propargylic
alcohols 47a and 47b, and methylcopper-mediated SN2′ sub-
stitution gave internal allenes 48a and 48b, which were readily
transformed to the corresponding allenenes 49a and 49b.
Similarly, known protected amino allene 5031 was converted to
51. In order to examine the stereochemical course of the [2 +
2] cycloaddition of allenes with axial chirality, diastereomeri-
cally pure allenenes, (S,aS)-53a and (S,aR)-53b, were prepared
from known allenes 52a and 52b, respectively, which were
stereospecifically obtained by organocopper-mediated ring-
opening reaction of chiral ethynylaziridines.31
Preparation of Allenynes. Next, we prepared various al-
lenynes as shown in Scheme 11. Alkylation of 12 with NaH
and 3-phenylpropargyl halide gave allenynes 54a and 54b in
good yields (87-94%). Similarly, N-tosyl derivative 57a was
prepared starting from known N-Boc amino allene 55.3b
Synthesis of allenynes 57b and 57c with a substituent on the
phenyl group by direct alkylation of 56 was inefficient, because
of the relatively low stability of 3-phenylpropargyl bromides
having a substituent on the phenyl group.32 However, stepwise
a Reagents: (a) 3-bromopropyne, NaH, DMF; (b) (HCHO)n, CuBr,
i-Pr2NH, dioxane; (c) TFA, CH2Cl2; (d) (E)-cinnamoyl chloride, NaH, DMF.
Next, various allenenes bearing substituents on the double
bond other than the phenyl group were synthesized. Alkylation
of the protected amino allene 12 with BrCH2CH2OTHP and
treatment with HCl gave allenol 35 in 87% yield (Scheme 8).
Oxidation with SO3‚pyridine and subsequent Wittig reaction
gave (E)-enoate 36a and R-methylated derivative 36b. In
contrast, unselective formation of (E)- and (Z)-nitriles 37 was
observed in the reaction with cyanated phosphonium ylide.
Cinnamide-derived allenes 40 and 44 were readily synthesized
as shown in Scheme 9. Propargylation of N-methyl cinnamide
3829 followed by Crabbe´ reaction of the resulting amide 39
yielded 40. Similarly, a sequence of reactions through Crabbe´
reaction of 41,30 removal of the Boc group with TFA, and
acylation with cinnamoyl chloride afforded 44 in good yield.
(30) (a) Oppolzer, W.; Stammen, B. Tetrahedron 1997, 53, 3577-3586.
(b) Lee, S. I.; Park, S. Y.; Park, J. H.; Jung, I. G.; Choi, S. Y.; Chung, Y.
K. J. Org. Chem. 2006, 71, 91-96.
(31) (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.
(29) Lewis, F. D.; Reddy, G. D.; Schneider, S.; Gahr, M. J. Am. Chem.
Soc. 1991, 113, 3498-3506.
J. Org. Chem, Vol. 72, No. 12, 2007 4381

Ohno et al.
SCHEME 12. Preparation of Allenynes 60 and 66a
SCHEME 11. Preparation of Allenynes 54 and 57a
a Reagents: (a) 3-phenylpropargyl bromide, NaH, DMF; (b) 3-(4-
methylphenyl)propargyl iodide, NaH, DMF; (c) TFA, CH2Cl2; (d) TsCl,
Et3N, CH2Cl2; (e) propargyl bromide, NaH, DMF; (f) 4-RPhI, PdCl2(PPh3)2,
CuI, i-Pr2NH, THF.
reaction including propargylation of 56 and Sonogashira cross-
coupling of 58 with 1-iodo-4-methoxybenzene or methyl
4-iodobenzoate afforded 57b and 57c, respectively.
a Reagents: (a) 3-phenylpropargyl bromide, NaH, DMF; (b) LiAlH4,
THF; (c) SO3‚py, Et3N, DMSO; (d) Ph3PdC(Br)CO2Me, CHCl3; (e)
DIBAL-H, CH2Cl2; (f) MsCl, Et3N, THF; (g) cat. Pd(PPh3)4, Et2Zn, THF;
(h) 3-phenylpropargyl alcohol, PPh3, DIAD, THF.
L-Phenylalanine- and isoleucine-derived allenynes 60a and
60b, and R-unsubstituted allene derivative 66, were similarly
obtained as shown in Scheme 12. In a similar manner to the
preparation of alanine-derived allenene 29 (Scheme 6), allenyne
60c was synthesized through N-(3-phenylpropargyl)alaninate
derivative 61. R-Unsubstituted allenene 66 was prepared by
condensation of known protected amino allene 6523 with
3-phenylpropargyl alcohol.
TABLE 1. Effect of Additive and a Palladium Catalysta
[2 + 2] Cycloaddition of Allenenes. On the basis of the
result shown in Scheme 3 in which the [2 + 2] cycloadduct 11
was obtained in 43% yield under the palladium-catalyzed
cyclization conditions using aryl halide and potassium carbonate,
we began our investigations by screening a variety of conditions
to find the optimal procedure for the cycloaddition to occur.
The results in Table 1 showed that addition of aryl halide,
palladium catalyst, or potassium carbonate is not essential for
this transformation: these reagents, especially the palladium
catalyst, did decrease the yield of 11a rather than promote the
cycloaddition (entries 1-3). Thermal cycloaddition in dioxane
in the absence of any reagent or catalyst proceeded quite well
to give the desired bicyclic cyclobutane 11a in 89% yield (entry
4). It should be noted that addition of galvinoxyl to the reaction
of (E)-8 did not affect the cycloaddition.33 This is the first
example of exclusive conversion of unactivated simple allenes
to distal adducts under thermal conditions without using
microwave irradiation.21,34
entry
PhI
Pd(PPh3)4
K2CO3
time (h)b
yield (%)
1
2
3
4
2 equiv
none
none
10 mol %
10 mol %
none
2 equiv
2 equiv
2 equiv
none
7.5
18
60
65
8
19
87
89
none
none
a Addition of galvinoxyl did not affect the cycloaddition. b The required
time for complete consumption of all the starting material on TLC.
TABLE 2. Effect of Solvent and Reaction Temperature
entry substrate solvent
temp
time (h) product yield (%)
1
2
3
4
5
6
7
8
(E)
(E)
(E)
(E)
(E)
(E)
(E)
(Z)
dioxane reflux
xylenes reflux
xylenes 110 °C
65
3
40
3
65
2
11a
11a
11a
11a
11a
11a
11a
67
89
81
32
96
86
84
79
63
Next, the thermal [2 + 2] cycloaddition of allenene 8 under
various reaction conditions was examined (Table 2). As well
as dioxane (entry 1), solvents with high boiling points such as
xylenes (entry 2), DMF (entries 4 and 5), NMP (entry 6), and
DMF
DMF
NMP
DMI
150 °C
110 °C
150 °C
150 °C
2
(32) Mitsunobu condensation with the corresponding alcohols required
higher reaction temperature, which makes control of the selective alkylation
(without causing [2 + 2] cycloaddition) difficult.
dioxane reflux
65
(33) However, these result does not conflict with the biradical mechanism
depicted in Schemes 14 and 15, because intramolecular coupling or
biradicals such as 94 and 101 to the corresponding cyclobutanes would be
extremely fast.
DMI (entry 7) can be similarly used for this transformation.
Among them, dioxane and DMF were the solvents of choice
leading to 3-azabicyclo[4.2.0]oct-5-ene derivative 11a in 89%
4382 J. Org. Chem., Vol. 72, No. 12, 2007

Bicyclo[4.2.0]oct-5-ene DeriVatiVes
TABLE 3. [2 + 2] Cycloaddition of Various Allenenes
SCHEME 13. Synthesis and NOE Analysis of Saturated
Derivatives 68 and 69
and 96% yields, respectively, as the sole isolable isomer (entries
1 and 4). As we expected, the reaction of (Z)-8 exclusively
furnished cycloadduct 67 with the opposite configuration to 11a
at the 8-position. These stereochemical outcomes with complete
selectivity are in good accordance with the observation using
allenyl sulfones.12b-d
The structure and configuration of the cycloadducts 11a and
67 were confirmed by COSY and NOESY analyses of the
corresponding saturated derivatives 68 and 69. Results of the
NOE experiment are summarized in Scheme 13.35 We observed
NOE between 4-H and the methylene proton at C-5 in 68, which
was assigned as HB. NOE between HA and another methylene
proton allowed assignment of HE. Finally, NOE between HE
and 8-H revealed that the phenyl group at C-8 directs the
opposite side to the isopropyl group at C-4. On the other hand,
NOE was observed between the methyne proton of the isopropyl
group and one of the methylene protons at C-2, which was
assigned as HC. We confirmed the configuration at the 1-position
by NOE between HD and 1-H. Similarly, NOE experiment of
69 was consistent with the relative configuration shown in
Scheme 13. Furthermore, the structure determination of 68 and
69 was unequivocally made by HMQC analysis.
Next, we investigated the thermal [2 + 2] cycloaddition of
allenes having a cinnamyl group (Table 3). Although we already
confirmed that the reaction in dioxane under reflux was rather
slow (Table 2), we first performed the cycloaddition of allenenes
8 and 13a-c in dioxane for a careful examination of the
substituent effect on the aryl group. While the reaction of 13a
having a methoxy group was slow (60 h) to give 11b in 44%
yield, this cycloaddition was strongly promoted by the presence
of an electron-withdrawing group such as a nitro or cyano group
to afford 11c (entry 3) and 11d (entry 4) in 10-20 h. As can
be expected, the reaction of 8 and 13a-c in DMF at 150 °C
completed in 1-3 h to afford the desired products 11a-d in
good yields (71-96%, entries 5-8). More important than the
effect of the electron-donating and -withdrawing aryl group is
the R-substituent of the allene: the reaction of R-unsubstituted
allene derivative 18 required prolonged reaction time (19 h)
even at the refluxed temperature in DMF (entry 9). Similarly,
allenenes 20 and 22 tethered by an oxygen or a carbon atom,
respectively, required 30 h to complete the reaction giving
3-oxabicyclo[4.2.0]oct-5-ene derivative 71 and its carbocycle
analogue 72 both in a stereospecific manner (entries 10 and
11). It should be clearly noted that alanine-derived allenene 29
having an R-methyl group cyclized into 73 as a diastereomixture
(ca. 5:2; entries 12 and 13). As expected, R,R-disubstituted
derivative 34 showed extremely high reactivity to give 74
bearing a quaternary carbon center in 91% yield within 1 h
(entry 14).
Next, intramolecular [2 + 2] cycloaddition of allenes with
various types of double bond was examined. The results are
summarized in Table 4. The reaction of allenene 75 with a
geminal dimethyl group on the olefinic carbon atom was a good
substrate for this transformation, although the reaction was
relatively slow (entry 1). In contrast, N-allylated amino allene
derivative 77 was completely inert under the cycloaddition
conditions, leading to recovery of unchanged starting material
(entry 2). These results are comparable to Padwa’s observation,12c
in which a tertiary radical intermediate promotes the [2 + 2]
cycloaddition of sulfonyl allenes (45 min) better than the
cyclization via a primary radical intermediate (22 h). In this
case, a sulfonyl group on the allenic carbon did stabilize the
allyl radical intermediate for cycloaddition to occur.
(34) Formation of the same framework (3-azabicyclo[4.2.0]oct-5-ene)
via intermolecular [2 + 2] cycloaddition of in situ-generated cyclic amino
allenes with styrene was reported: Christl, M.; Braun, M.; Wolz, E.; Wagner,
W. Chem. Ber. 1994, 127, 1137-1142.
(35) In order to determine the relative configuration between C-4 and
C-1 (or C-4 and C-8), transformation of 11a and 67 to the corresponding
saturated analogues 68 and 69 was desirable. We could unambiguously
confirm the relative configuration of 68 and 69 by NOEs including that of
the introduced hydrogens at C-5 and C-6. For more details, see the
Supporting Information
Allene 36a having an R,â-unsaturated ester group showed
sufficient reactivity to give the cycloadduct 79 in 73-76% yield
(entries 3 and 4). Similarly, the reaction of R-methylated enoate
J. Org. Chem, Vol. 72, No. 12, 2007 4383

Ohno et al.
TABLE 4. [2 + 2] Cycloaddition of Allenes with Various Double
Bonds
TABLE 5. [2 + 2] Cycloaddition of Allenenes Having
Substituent(s) on the Allenic Carbona
a All reactions were carried out at 150 °C in DMF.
derivative 36b gave bicyclic ester 80 with a chiral quaternary
carbon (entries 5 and 6). As well as the reaction of the allenes
(E)- and (Z)-8 having a cinnamyl group on the nitrogen atom
(Table 2), the cycloaddition of (E)- and (Z)-R,â-unsaturated
nitriles (E)-37 and (Z)-37 proceeded stereospecifically to afford
isomeric bicyclic nitriles, 81 and 82 (entries 7 and 8). Compared
to allenenes 36 and 37 having an electron-withdrawing group
on the terminal olefinic carbon, cinnamide-derived allenes 40
and 44 gave relatively low yields of the cycloadducts 83 and
84 after prolonged reaction times (entries 9 and 10). Although
the exact reason is unclear, this marked difference of reactivities
can be attributed to the electronic character of the olefinic
moiety, in addition to the effect of an R-substituent. Since the
phenyl-stabilized radical generated on the olefinic moiety (Vide
infra) would have a similar reactivity to other related substrates
having a cinnamyl group (Table 3), the cinnamide derivatives
40 and 44 would have low reactivity on the first cyclization.
This hypothesis is partially supported by the fact that radical
reaction of cinnamide derivatives generally proceeds at the
â-position to give the radical intermediates stabilized by the
carbonyl group.36 Additionally, we could not rule out the first
cyclization at the â-position of the cinnamide forming an eight-
membered ring biradical intermediate, followed by the second
cyclization.12c,14b
Finally, [2 + 2] cycloaddition of allenenes bearing substit-
uent(s) on the allenic moiety was investigated (Table 5).
Monosubstitution at the proximal allenic carbon (entry 1) and
distal carbon (entry 2) has proven to be tolerated and the
expected products 85 and 86 were obtained in high yields (90-
94%). On the other hand, decreased reactivity toward the
cycloaddition was observed with allenenes 49b and 51 bearing
a geminal dimethyl group at the terminal position, leading to
cycloadducts 87 (63%) and 88 (46%; 3:1 mixture of diastere-
omers) in longer reaction time at 150 °C (entries 3 and 4). Quite
interestingly, the reaction of internal (S,aS)-allene 53a showed
lower reactivity to produce bicyclic cyclobutane 89 as the major
product in 65% yield (entry 5), in which the chirality of the
allenic moiety is not preserved. In this case, the corresponding
(36) (a) Ru¨ck, K.; Kunz, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 694-
696. (b) Sibi, M. P.; Jasperse, C. P.; Ji, J. J. Am. Chem. Soc. 1995, 117,
10779-10780. (c) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T.
Tetrahedron 2004, 60, 4227-4235. (d) Hein, J. E.; Zimmerman, J.; Sibi,
M. P.; Hultin, P. G. Org. Lett. 2005, 7, 2755-2758.
4384 J. Org. Chem., Vol. 72, No. 12, 2007

Bicyclo[4.2.0]oct-5-ene DeriVatiVes
SCHEME 15. Stereoselectivity on the Reaction of Internal
Allenes 53
FIGURE 1. Determination of relative configuration of the adducts 89
and 90 by NOE analyses.
SCHEME 14. Stereoselective Formation of 96 as the Single
Isomer
diastereomer 90 was also isolated in 23% yield. In sharp
contrast, the reaction of the (S,aR)-isomer 53b completed in 3
h to give 89 having the same configuration as the starting
allenes. Thus, cycloadduct 89 was obtained as the favored
product in both cases. These stereochemical outcomes strongly
support the formation of biradical intermediates having a
coplanar allyl radical moiety (Vide infra). Assignment of the
relative configuration of these adducts was readily made by NOE
analysis shown in Figure 1.
Mechanism and Stereoselectivity of the Cycloaddition.
Although the [2 + 2] thermal reactions of allenes are usually
assumed to proceed via two steps including the participation of
a biradical intermediate,37,10,12,14b a π2a + π2s concerted process
via antarafacial-suprafacial orbital interaction cannot be ruled
out.38 While the concerted process would result in a stereospe-
cific cyclization, a stepwise reaction can also give cycloaddition
products stereoselectively preserving the olefin geometry when
the second cyclization process is more rapid than the bond
rotation.12b-d Because the known cycloaddition reaction of
allenenes proceeds in a stereospecific manner in many cases, it
has not been unequivocally established from the aspect of
product distribution of the cycloaddition whether the reactions
are concerted or stepwise.12 In contrast, our present study,
including a novel finding on the stereospecificity of the alkene
geometry and stereomutation of the allenic axial chirality,
strongly supports the biradical mechanism.
be destabilized by unfavorable steric interaction between
methylene protons of the terminal allenic carbon and the R′
group at the olefin terminal. Accordingly, the first cyclization
preferentially occurred through 92 to give a biradical intermedi-
ate 94. Since the geometry of the olefin is completely preserved
to yield the cycloadduct 96 without formation of 97 in all cases
examined, the second cyclization would involve a rapid ring-
closure before the bond rotation can occur. The fact that
diastereomer 98 derived from relatively unstable conformer 93
was not detected from terminal allenes suggests that the energy
difference between the two conformers 92 and 93 is significant
in the case of terminal allenes.
Stereoselectivity of the cycloaddition of internal allenes 53a
including partial stereomutation (Table 5, entry 5) can be
rationalized as follows (Scheme 15): the first cyclization of
the more abundant conformer 99 would give biradical inter-
mediate 101, in which the allyl radical moiety will have a
coplanar structure by rotation of the terminal allenic bond.39
At this stage, the butyl group directs the same side as the vinyl
proton, avoiding the steric crowding, and information of the
allenic axial chirality will be completely lost. The second
cyclization would proceed through the conformation 103 to
minimize the unfavorable steric interaction between the butyl
and phenyl groups, giving rise to cyclobutane 89 as the major
First, stereoselective formation of the cycloadducts 96 from
terminal allenes 91 is shown in Scheme 14. Among the two
conformations 92 and 93 of the first cyclization, the latter would
(37) (a) Dolbier, W. R., Jr. Acc. Chem. Res. 1991, 24, 63-69. (b) Dai,
S.-H.; Dolbier, W. R., Jr. J. Am. Chem. Soc. 1972, 94, 3946-3952. (c)
Froese, R. D.; Lange, G. L.; Goddard, J. D. J. Org. Chem. 1996, 61, 952-
961. (d) Schmittel, M.; Maywald, M.; Strittmatter, M. Synlett 1997, 165-
166. (e) Yang, Y.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2003, 68,
8545-8549.
(39) (a) Roth, W. R.; Ruf, G.; Ford, P. W. Chem. Ber. 1974, 107, 48-
52. (b) Dolbier, W. R., Jr.; Wicks, G. E. J. Am. Chem. Soc. 1985, 107,
3626-3631. For a review, see: (c) Hartung, J.; Kopf, T. In Modern Allene
Chemistry; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim,
2004; Vol. 2, pp 701-726.
(38) Woodward, R. B.; Hoffmann, R. The ConserVation of Orbital
Symmetry; Academic Press: New York, 1970.
J. Org. Chem, Vol. 72, No. 12, 2007 4385

Ohno et al.
TABLE 6. [2 + 2] Cycloaddition of Allenynesa
using N-tosylated analogues 57a-c (entries 3-5). In all cases,
the desired cycloadducts 107a-c were obtained in 61-70%
yield in 2-3 h. These results show that the effect of aryl
substituents on the reactivity is not dramatic. Likewise as in
the reaction of allenenes, the R-substituent of the allene has
proven to be significantly important (entries 6-9): the reaction
of allenynes 60a and 60c bearing a smaller substituent (benzyl
and methyl group, respectively) at the R-position required longer
reaction time (8 and 54 h, respectively). It should be clearly
noted that the cycloaddition of R-unsubstituted allene derivative
66 required several days for completion of the reaction.
The relatively high reactivity of allenynes over allenenes is
consistent with the observation of Pasto et al. on intermolecular
[2 + 2] cycloaddition of allenes with a multiple bond.40 They
claimed that the difference of the reactivity comes from the
relative changes in the heats of formation on going from the
reactants to the intermediate biradicals and on to the products,
because heat of formation of acetylene is considerably higher
compared to that of ethene.
Conclusion
In conclusion, we have developed thermal [2 + 2] cycload-
dition of allenenes or allenynes leading to bicyclo[4.2.0]octane
derivatives in good to excellent yields. Interestingly, the reaction
of terminal allenes afforded bicyclic cyclobutane derivatives in
a highly stereoselective manner, while the cycloaddition of some
internal allenes yielded a diastereomeric mixture of cycload-
ducts. Furthermore, the olefin geometry was completely trans-
ferred to the cycloadducts in all cases. These stereochemical
outcomes can be rationalized by considering the formation of
biradical intermediates with the allyl radical moiety having a
coplanar structure. This study first demonstrated that the distal
double bond of unactivated simple allenes can regioselectively
undergo intramolecular [2 + 2] cycloaddition with an ap-
propriately substituted multiple bond. This simple and environ-
mentally benign process would extend the potential application
of fused bicyclic cyclobutane derivatives in synthetic and
medicinal chemistry.
a All reactions were carried out in dioxane under reflux.
product. In contrast to the terminal allenes 91, the presence of
a butyl group of (S,aS)-internal allene 53a would partially
destabilize the favorable conformer 99 of the first cyclization.
Accordingly, both the prolonged reaction time required for the
reaction of 53a (15 h) and formation of the minor cycloadduct
90 through a relatively unfavorable conformer 100 are under-
standable. The lower reactivity of allenene 51 having a dimethyl
group on the terminal allenic carbon as well as formation of
cycloadduct 88 as a diastereomixture from this allenene (Table
5, entry 4) can be explained by the same reason. On the other
hand, the (S,aR)-substrate 53b exclusively gave cycloadduct 89
as the single isomer within 3 h (Table 5, entry 6). This result
can be attributed to the predominance of the conformer 105
(Scheme 15) on the first cyclization, in which the butyl group
directs the opposite side of the reacting alkene and would not
destabilize this conformer.
[2 + 2] Cycloaddition of Allenynes. Finally, the thermal
cycloaddition of allenynes was investigated (Table 6). In contrast
to the cycloaddition of allenenes 8 which required 65 h in
refluxed dioxane (Table 3, entry 1), the reaction of allenyne
54a completed within 2 h under the identical reaction conditions
to give cyclobutene derivative 106a in 92% yield (entry 1).
Similarly, cycloaddition of 54b bearing a methyl substituent
on the benzene ring afforded the corresponding cyclobutene
derivative 106b (entry 2). Next, the effect of electron-donating
and -withdrawing substituents on the aryl group was investigated
Experimental Section
N-(2-Hydroxyethyl)-2,4,6-trimethyl-N-[(E)-3-phenylprop-2-
enyl]phenylsulfonamide (15). To a mixture of 14 (3.00 g, 12.3
mmol) and K2CO3 (3.41 g, 24.7 mmol) in DMF (15 mL) was added
(E)-cinnamyl bromide (2.92 g, 14.8 mmol), and the mixture was
stirred at room temperature for 15 h. The mixture was partitioned
between EtOAc and water. The organic layer was separated, washed
with water and brine, dried over MgSO4, and evaporated in Vacuo.
The residue was chromatographed on silica gel eluting with
n-hexane-EtOAc (20:1 to 1:1) to give 15 (2.82 g, 64%): colorless
1
oil; IR (KBr) cm-1 3521 (OH), 1313 (SO2N), 1149 (SO2N); H
NMR (300 MHz, CDCl3) δ 2.10 (br, 1H, OH), 2.29 (s, 3H, CMe),
2.64 (s, 6H, 2 × CMe), 3.40 (t, J ) 5.6 Hz, 2H, 1-CH2), 3.72 (dt,
J ) 5.6, 5.0 Hz, 2H, 2-CH2), 4.00 (d, J ) 6.9 Hz, 2H, 1′-CH2),
6.00 (dt, J ) 16.2, 6.9 Hz, 1H, 2′-H), 6.46 (d, J ) 16.2 Hz, 1H,
3′-H), 6.96 (s, 2H, Ar), 7.23-7.30 (m, 5H, Ar); 13C NMR (75.5
MHz, CDCl3) δ 20.9, 22.9 (2C), 48.0, 49.3, 60.2, 123.8, 126.4 (2C),
128.0, 128.5 (2C), 132.1 (2C), 132.6, 134.3, 136.0, 140.2 (2C),
142.8; MS (FAB) m/z (%) 360 (MH+, 30), 117 (100); HRMS (FAB)
calcd for C20H26NO3S (MH+) 360.1633; found 360.1628.
(40) Pasto, D. J.; Kong, W. J. Org. Chem. 1989, 54, 3215-3216.
4386 J. Org. Chem., Vol. 72, No. 12, 2007

Bicyclo[4.2.0]oct-5-ene DeriVatiVes
General Procedure for Oxidation and Wittig Olefination of
Alcohols: Synthesis of N-[(Z)-3-Bromo-3-methoxycarbonylprop-
2-enyl]-2,4,6-trimethyl-N-[(E)-3-phenylprop-2-enyl]phenylsul-
fonamide (16). To a solution of 15 (2.30 g, 6.40 mmol) and Et3N
(4.46 mL, 32.0 mmol) in DMSO (12 mL) was added SO3‚Py (2.04
g, 12.8 mmol), and the mixture was stirred at room temperature
for 1 h. The mixture was partitioned between EtOAc and water.
The organic layer was separated, washed with 1 N HCl, water,
saturated NaHCO3, and brine, dried over MgSO4, and evaporated
in Vacuo to give aldehyde as a yellow oil. To a solution of the
aldehyde in CHCl3 (50 mL) was added Ph3P)C(Br)CO2Me (3.16
g, 7.65 mmol), and the mixture was stirred at room temperature
for 15 h. After evaporation of solvent, the residue was chromato-
graphed on silica gel eluting with n-hexane-EtOAc (20:1 to 5:1)
to give 16 (1.47 g, 47%): pale yellow oil; IR (KBr) cm-1 1732
(s, 6H, 2 × CMe), 3.83 (dt, J ) 7.4, 2.4 Hz, 2H, 1-CH2), 3.97 (d,
J ) 6.6 Hz, 2H, 1′-CH2), 4.73 (dt, J ) 6.6, 2.4 Hz, 2H, 4-CH2),
5.05 (tt, J ) 7.4, 6.6 Hz, 1H, 2-H), 6.00 (dt, J ) 15.9, 6.6 Hz, 1H,
2′-H), 6.45 (d, J ) 15.9 Hz, 1H, 3′-H), 6.94 (s, 2H, Ar), 7.22-
7.31 (m, 5H, Ar); 13C NMR (75.5 MHz, CDCl3) δ 20.9, 22.8 (2C),
44.4, 47.7, 76.0, 85.7, 123.6, 126.4 (2C), 127.8, 128.5 (2C), 131.9
(2C), 133.0, 134.4, 136.2, 140.2 (2C), 142.5, 209.7; MS (FAB)
m/z (%) 368 (MH+, 24), 117 (100); HRMS (FAB) calcd for C22H26-
NO2S (MH+) 368.1684; found 368.1681.
General Procedure for Allene Formation by Crabbe´ Reac-
tion: Synthesis of 4-[(E)-3-Phenylprop-2-enyloxy]buta-1,2-diene
(20). To a mixture of paraformaldehyde (102 mg, 3.40 mmol) and
CuBr (97.5 mg, 0.679 mmol) in dioxane (5 mL) were added 19
(234 mg, 1.36 mmol) and i-Pr2NH (275 mg, 2.72 mmol), and the
mixture was heated under reflux for 8 h. The mixture was cooled
to room temperature and diluted with EtOAc. The insolubles were
filtered off, and the filtrate was evaporated in Vacuo. The residue
was chromatographed on silica gel eluting with n-hexane-EtOAc
(20:1 to 10:1) to give 20 (198 mg, 78%): colorless oil; IR (KBr)
cm-1 1955 (CdCdC), 1080 (COC); 1H NMR (300 MHz, CDCl3)
δ 4.07 (dt, J ) 7.1, 2.4 Hz, 2H, 1-CH2), 4.17 (d, J ) 6.1 Hz, 2H,
1′-CH2), 4.80 (dt, J ) 6.6, 2.4 Hz, 2H, 4-CH2), 5.28 (tt, J ) 7.1,
6.6 Hz, 1H, 2-H), 6.29 (dt, J ) 16.1, 6.1 Hz, 1H, 2′-H), 6.61 (d, J
) 16.1 Hz, 1H, 3′-H), 7.20-7.41 (m, 5H, Ar); 13C NMR (75.5
MHz, CDCl3) δ 67.8, 70.4, 75.7, 87.7, 125.8, 126.4 (2C), 127.6,
128.5 (2C), 132.6, 136.6, 209.3; MS (FAB) m/z (%) 193 (MLi+,
38), 160 (100); HRMS (FAB) calcd for C13H14LiO (MLi+)
193.1205; found 193.1207.
1
(CO2Me), 1321 (SO2N), 1263 (CO2Me), 1153 (SO2N); H NMR
(300 MHz, CDCl3) δ 2.30 (s, 3H, CMe), 2.64 (s, 6H, 2 × CMe),
3.77 (s, 3H, OMe), 3.92 (d, J ) 6.2 Hz, 2H, 1′-CH2), 4.08 (d, J )
6.2 Hz, 2H, 1-CH2), 6.00 (dt, J ) 16.2, 6.2 Hz, 1H, 2′-H), 6.47 (d,
J ) 16.2 Hz, 1H, 3′-H), 6.97 (s, 2H, Ar), 7.23-7.33 (m, 6H, 2-H
and Ar); 13C NMR (75.5 MHz, CDCl3) δ 20.9, 22.8 (2C), 47.1,
49.4, 53.4, 117.4, 123.0, 126.5 (2C), 128.0, 128.5 (2C), 132.1 (2C),
132.2, 135.2, 136.0, 140.3 (2C), 141.3, 143.0, 162.0; MS (FAB)
m/z (%) 494 (MH+, 81Br, 15), 492 (MH+, 79Br, 19), 117 (100);
HRMS (FAB) calcd for C23H27BrNO4S (MH+, 79Br) 492.0844;
found 492.0816.
General Procedure for Reduction of R,â-Unsaturated Esters
with DIBAL-H: Synthesis of N-[(Z)-3-Bromo-4-hydroxybut-2-
enyl]-2,4,6-trimethyl-N-[(E)-3-phenylprop-2-enyl]phenylsulfona-
mide (17). To a solution of 16 (1.25 g, 2.54 mmol) in CH2Cl2 (15
mL) was added 0.94 M DIBAL-H in n-hexane (9.5 mL, 8.93 mmol)
under dry ice-acetone cooling, and the mixture was stirred at 0
°C for 1 h. HCl (4 N) was added, and the aqueous solution was
diluted with water and extracted with EtOAc. The organic layer
was separated, washed with water, saturated NaHCO3 and brine,
dried over MgSO4, and evaporated in Vacuo. The residue was
chromatographed on silica gel eluting with n-hexane-EtOAc (10:1
to 3:1). The crude product was recrystalized with n-hexane-Et2O
(1:1) to give 17 (997 mg, 85%): colorless crystals; mp 86-88 °C
(n-hexane-Et2O); IR (KBr) cm-1 3504 (OH), 1313 (SO2N), 1151
General Procedure for Cinnamylation: Synthesis of Dimethyl
2-Buta-2,3-dienyl-2-[(E)-3-phenylprop-2-enyl]malonate (22). To
a suspension of 60% NaH (23.5 mg, 0.586 mmol) in DMF (2 mL)
was added 21 (72.0 mg, 0.391 mmol) under ice-water cooling,
and the mixture was stirred at 0 °C for 0.5 h. (E)-Cinnamyl bromide
(84.7 mg, 0.430 mmol) was added under ice-water cooling, and
the mixture was stirred at 0 °C for 2 h. The mixture was partitioned
between EtOAc and water. The organic layer was separated, washed
with water and brine, dried over MgSO4, and evaporated in Vacuo.
The residue was chromatographed on silica gel eluting with
n-hexane-EtOAc (20:1 to 10:1) to give 22 (107 mg, 91%):
colorless oil; IR (KBr) cm-1 1955 (CdCdC), 1736 (CO2Me), 1275
1
1
(SO2N); H NMR (300 MHz, CDCl3) δ 2.29 (s, 3H, CMe), 2.41
(CO2Me); H NMR (300 MHz, CDCl3) δ 2.66 (dt, J ) 8.1, 2.4
(br, 1H, OH), 2.62 (s, 6H, 2 × CMe), 3.89 (d, J ) 6.9 Hz, 2H,
1′-CH2), 3.99 (d, J ) 6.2 Hz, 2H, 1-CH2), 4.18 (s, 2H, 4-CH2),
5.98 (dt, J ) 16.2, 6.9 Hz, 1H, 2′-H), 6.13 (t, J ) 6.2 Hz, 1H,
2-H), 6.48 (d, J ) 16.2 Hz, 1H, 3′-H), 6.95 (s, 2H, Ar), 7.22-7.31
(m, 5H, Ar); 13C NMR (75.5 MHz, CDCl3) δ 20.9, 22.8 (2C), 46.3,
48.7, 67.7, 123.4, 124.6, 126.5 (2C), 127.9, 128.5 (2C), 129.5, 132.0
(2C), 132.6, 134.7, 136.2, 140.3 (2C), 142.8. Anal. Calcd for C22H26-
BrNO3S: C, 56.90; H, 5.64; N, 3.02. Found: C, 56.90; H, 5.59;
N, 2.97.
Hz, 2H, 1-CH2), 2.84 (d, J ) 7.6 Hz, 2H, 1′-CH2), 3.73 (s, 6H, 2
× OMe), 4.69 (dt, J ) 6.6, 2.4 Hz, 2H, 4-CH2), 4.99 (tt, J ) 8.1,
6.6 Hz, 1H, 2-H), 6.03 (dt, J ) 15.6, 7.6 Hz, 1H, 2′-H), 6.44 (d, J
) 15.6 Hz, 1H, 3′-H), 7.18-7.34 (m, 5H, Ar); 13C NMR (75.5
MHz, CDCl3) δ 32.1, 36.2, 52.4 (2C), 58.1, 74.7, 84.1, 123.7, 126.2
(2C), 127.4, 128.5 (2C), 134.2, 137.0, 171.0 (2C), 210.1; MS (FAB)
m/z (%) 301 (MH+, 41), 117 (100); HRMS (FAB) calcd for
C18H21O4 (MH+) 301.1440; found 301.1450.
General Procedure for Preparation of Ethanol Amine De-
rivatives: Synthesis of N-(2-Hydroxyethyl)-N-[(1S)-1-isopropy-
lbuta-2,3-dienyl]-2,4,6-trimethylphenylsulfonamide (35). To a
mixture of 12 (500 mg, 1.70 mmol) and K2CO3 (824 mg, 5.96
mmol) in DMF (5 mL) was added BrCH2CH2OTHP (891 mg, 4.26
mmol) and the mixture was stirred at 80 °C for 20 h. The mixture
was partitioned between EtOAc and water. The organic layer was
separated, washed with water and brine, dried over MgSO4, and
evaporated in Vacuo. To the residue in MeOH (5 mL) was added
4 N HCl (0.5 mL), and the mixture was stirred at room temperature
for 1 h. The solution was diluted with water and extracted with
EtOAc. The organic layer was separated, washed with water,
saturated NaHCO3 and brine, dried over MgSO4, and evaporated
in Vacuo. The residue was chromatographed on silica gel eluting
with n-hexane-EtOAc (50:1 to 1:1) to give 35 (500 mg, 87%):
colorless oil; [R]26D -84.7 (c 1.035, CHCl3); IR (KBr) cm-1 3527
(OH), 1955 (CdCdC), 1321 (SO2N), 1151 (SO2N); 1H NMR (300
MHz, CDCl3) δ 0.86 (d, J ) 6.8 Hz, 3H, CMe), 0.88 (d, J ) 6.3
Hz, 3H, CMe), 1.80-1.88 (m, 1H, CHMe2), 2.30 (s, 3H, CMe),
2.39 (br, 1H, OH), 2.63 (s, 6H, 2 × CMe), 3.38 (t, J ) 6.6 Hz,
General Procedure for Reductive Allenylation of Brominated
Allylic Alcohols: Synthesis of N-(Buta-2,3-dienyl)-2,4,6-trim-
ethyl-N-[(E)-3-phenylprop-2-enyl]phenylsulfonamide (18). To a
solution of 17 (500 mg, 1.08 mmol) and Et3N (0.30 mL, 2.15 mmol)
in THF (10 mL) was added MsCl (185 mg, 1.61 mmol) under dry
ice-acetone cooling and the mixture was stirred at 0 °C for 1 h.
The mixture was partitioned between EtOAc and water. The organic
layer was separated, washed with 1 N HCl, water, saturated
NaHCO3 and brine, dried over MgSO4, and evaporated in Vacuo.
To a solution of the mesylate and Pd(PPh3)4 (37.3 mg, 0.032 mmol)
in THF (10 mL) was added 1 M Et2Zn in n-hexane (2.16 mL, 2.16
mmol) and the mixture was stirred at room temperature for 1 h.
After adding saturated NH4Cl, the mixture was diluted with water
and extracted with EtOAc. The organic layer was separated, washed
with water and brine, dried over MgSO4, and evaporated in Vacuo.
The residue was chromatographed on silica gel eluting with
n-hexane-EtOAc (50:1 to 10:1) to give 18 (270 mg, 68%): pale
yellow oil; IR (KBr) cm-1 1954 (CdCdC), 1317 (SO2N), 1153
1
(SO2N); H NMR (300 MHz, CDCl3) δ 2.29 (s, 3H, CMe), 2.63
J. Org. Chem, Vol. 72, No. 12, 2007 4387

Ohno et al.
2H, 1′-CH2), 3.61 (ddt, J ) 8.1, 8.1, 2.0 Hz, 1H, 1-H), 3.64-3.82
(m, 2H, 2′-CH2), 4.68 (dd, J ) 6.8, 2.0 Hz, 2H, 4-CH2), 5.16 (dt,
J ) 8.1, 6.8 Hz, 1H, 2-H), 6.95 (s, 2H, Ar); 13C NMR (75.5 MHz,
CDCl3) δ 20.0, 20.7, 20.9, 23.4 (2C), 30.7, 46.0, 61.9, 63.2, 76.2,
88.3, 132.1 (2C), 133.0, 140.1 (2C), 142.5, 209.1; MS (FAB) m/z
(%) 338 (MH+, 14), 244 (100); HRMS (FAB) calcd for C18H28-
NO3S (MH+) 338.1790; found 338.1793.
General Procedure for Sonogashira Cross-Coupling: Syn-
thesis of N-[(1S)-1-Isopropylbuta-2,3-dienyl]-N-[3-(4-methox-
yphenyl)prop-2-ynyl]-4-methylphenylsulfonamide (57b). To a
suspension of 4-iodoanisole (425 mg, 1.82 mmol), Pd(PPh3)2Cl2
(12.7 mg, 0.0185 mmol), CuI (1.40 mg, 0.00726 mmol), and i-Pr2-
NH (0.0509 mL, 0.363 mmol) in THF (2 mL) was added 58 (110
mg, 0.363 mmol) in THF (1 mL) under ice-water cooling, and
the mixture was stirred at 0 °C for 6 h. Pd(PPh3)2Cl2 (12.7 mg,
0.0185 mmol) and CuI (3.5 mg, 0.0185 mmol) were added, and
the mixture was stirred at room temperature for 1 h. The insolubles
were filtered off and the filtrate was evaporated in Vacuo. The
residue was chromatographed on silica gel eluting with n-hexane-
EtOAc (15:1) to give 57b (36.5 mg, 25%): yellow oil; [R]26D -11.5
(c 0.560, CHCl3); IR (KBr) cm-1 2251 (CtC), 1955 (CdCdC),
1329 (SO2N), 1147 (SO2N), 1200 (ArOMe); 1H NMR (300 MHz,
CDCl3) δ 0.97 (d, J ) 6.6 Hz, 3H, CMe), 1.05 (d, J ) 6.6 Hz, 3H,
CMe), 1.96-2.05 (m, 1H, CHMe2), 2.36 (s, 3H, CMe), 3.80 (s,
3H, OMe), 4.07 (dddd, J ) 8.3, 6.8, 1.7, 1.7 Hz, 1H, 1-H), 4.16
(d, J ) 18.6 Hz, 1H, 1′-CHH), 4.31 (d, J ) 18.6 Hz, 1H, 1′-CHH),
4.56 (ddd, J ) 11.0, 6.6, 1.7 Hz, 1H, 4-CHH), 4.67 (ddd, J )
11.0, 6.6, 1.7 Hz, 1H, 4-CHH), 5.07 (ddd, J ) 6.8, 6.6, 6.6 Hz,
1H, 2-H), 6.80 (d, J ) 6.6 Hz, 2H, Ar), 7.15 (d, J ) 6.6 Hz, 2H,
Ar), 7.20 (d, J ) 6.6 Hz, 2H, Ar), 7.80 (d, J ) 6.6 Hz, 2H, Ar);
13C NMR (75.5 MHz, CDCl3) δ 20.1, 20.4, 21.5, 30.8, 33.8, 55.3,
64.1, 76.1, 83.5, 84.2, 88.2, 113.8 (2C), 114.8, 127.8 (2C), 129.2
(2C), 132.8 (2C), 137.9, 143.0, 159.5, 209.0; MS (FAB) m/z (%)
410 (MH+, 23), 73 (100); HRMS (FAB) calcd for C24H28NO3S
(MH+) 410.1790; found 410.1803.
General Procedure for Oxidation and Alkynylation of Alco-
hols: Synthesis of N-(2-Hydroxy-1,1-dimethylbut-3-ynyl)-4-
methylphenylsulfonamide (47a). To a stirred mixture of 30 (2.50
g, 10.3 mmol) and Et3N (7.16 mL, 51.4 mmol) in DMSO (20 mL)
was added SO3‚Py (3.27 g, 20.5 mmol) under water cooling, and
the mixture was stirred at room temperature for 1 h. The mixture
was partitioned between EtOAc and water. The organic layer was
separated, washed with 1 N HCl, water, saturated NaHCO3, and
brine, dried over MgSO4, and evaporated in Vacuo to give aldehyde
as a yellow oil. To a solution of trimethylsilylacetylene (1.83 mL,
13.0 mmol) in THF (15 mL) was added 1.5 M n-BuLi in n-hexane
(16.0 mL, 24.0 mmol) under dry ice-acetone cooling, and the
mixture was stirred at -78 °C for 0.5 h. The aldehyde (2.41 g,
9.99 mmol) in THF (5 mL) was added, and the mixture was stirred
at -78 °C for 1 h. The mixture was partitioned between EtOAc
and saturated NH4Cl. The organic layer was separated, washed with
brine, dried over MgSO4, and evaporated in Vacuo. To the residue
in MeOH (30 mL) was added MeONa (54.0 mg, 0.999 mmol),
and the mixture was stirred at room temperature for 15 h. After
evaporation of solvent, the residue was partitioned between EtOAc
and water. The organic layer was separated, washed with brine,
dried over MgSO4, and evaporated in Vacuo. The residue was
chromatographed on silica gel eluting with n-hexane-EtOAc (20:1
to 1:1). The crude product was recrystalized with n-hexane-EtOAc
(2:1) to give 47a (2.03 g, 72%): colorless crystals; mp 127-128
°C (n-hexane-EtOAc); IR (KBr) cm-1 3487 (OH), 3296 (CtCH),
General Procedure for Mitsunobu Condensation: Synthesis
of N-(Buta-2,3-dienyl)-4-methyl-N-(3-phenylprop-2-ynyl)phe-
nylsulfonamide (66). To a solution of 65 (130 mg, 0.582 mmol),
HOCH2CtCPh (0.22 mL, 1.75 mmol), PPh3 (458 mg, 1.75 mmol)
in THF (3 mL) was added DIAD (0.34 mL, 1.75 mmol) under ice-
water cooling, and the mixture was stirred at 0 °C for 7 h. After
evaporation of solvent, the residue was chromatographed on silica
gel eluting with n-hexane-EtOAc (10:1) to give 66 (176 mg,
89%): colorless crystals; mp 64-65 °C (n-hexane-Et2O); IR (KBr)
cm-1 2243 (CtC), 1955 (CdCdC), 1348 (SO2N), 1163 (SO2N);
1H NMR (500 MHz, CDCl3) δ 2.33 (s, 3H, CMe), 3.93 (dt, J )
6.7, 2.4 Hz, 2H, 1-CH2), 4.37 (s, 2H, 1′-CH2), 4.80 (dt, J ) 7.3,
2.4 Hz, 2H, 4-CH2), 5.11 (tt, J ) 7.3, 6.7 Hz, 1H, 2-H), 7.09 (d, J
) 8.5 Hz, 2H, Ar), 7.22-7.29 (m, 5H, Ar), 7.77 (d, J ) 8.5 Hz,
2H, Ar); 13C NMR (75.5 MHz, CDCl3) δ 21.4, 36.8, 45.9, 76.4,
81.6, 85.6 (2C), 122.2, 127.7 (2C), 128.1 (2C), 128.3, 129.5 (2C),
131.5 (2C), 136.0, 143.5, 209.9. Anal. Calcd for C20H19NO2S: C,
71.19; H, 5.68; N, 4.15. Found: C, 71.01; H, 5.73; N, 4.14.
General Procedure for [2 + 2] Cycloaddition of Allenenes:
Synthesis of (1R,4S,8S)-3-Aza-4-isopropyl-8-phenyl-3-(2,4,6-
trimethylphenylsulfonyl)bicyclo[4.2.0]oct-5-ene (11a). A solution
of (E)-8 (30.0 mg, 0.073 mmol) in DMF (1 mL) was stirred at 150
°C for 3 h. The mixture was partitioned between EtOAc and water.
The organic layer was separated, washed with water and brine, dried
over MgSO4, and evaporated in Vacuo. The residue was chromato-
graphed on silica gel eluting with n-hexane-EtOAc (50:1 to 20:1)
1
3271 (SO2NH), 2117 (CtCH), 1319 (SO2N), 1157 (SO2N); H
NMR (300 MHz, CDCl3) δ 1.25 (s, 3H, CMe), 1.26 (s, 3H, CMe),
2.43 (s, 3H, CMe), 2.51 (d, J ) 2.2 Hz, 1H, 4-CH), 2.77 (br, 1H,
OH), 4.28 (m, 1H, 2-H), 5.07 (br, 1H, NH), 7.30 (d, J ) 8.2 Hz,
2H, Ar), 7.80 (d, J ) 8.2 Hz, 2H, Ar); 13C NMR (75.5 MHz, CDCl3)
δ 21.5, 22.6, 23.5, 59.7, 69.4, 75.3, 81.4, 127.1 (2C), 129.6 (2C),
139.6, 143.4. Anal. Calcd for C13H17NO3S: C, 58.40; H, 6.41; N,
5.24. Found: C, 58.22; H, 6.33; N, 5.22.
General Procedure for Allenylation of Propargyl Alcohols:
Synthesis of N-(1,1-Dimethylpenta-2,3-dienyl)-4-methylphenyl-
sulfonamide (48a). To a solution of 47a (887 mg, 3.32 mmol),
Et3N (671 mg, 6.64 mmol) in THF (10 mL) was added MsCl (570
mg, 4.98 mmol) under ice-water cooling, and the mixture was
stirred at 0 °C for 1 h. The mixture was partitioned between EtOAc
and water. The organic layer was separated, washed with brine,
dried over MgSO4, and evaporated in Vacuo to give the corre-
sponding mesylate as a yellow oil. To a solution of 1 M MeMgBr
in THF (15 mL, 15 mmol) in THF (10 mL) was added CuBr (1.89
g, 13.2 mmol) under dry ice-acetone cooling, and the mixture was
stirred at -20 °C for 0.5 h. The mesylate in THF (5 mL) was added
under dry ice-acetone cooling, and the mixture was stirred at -78
°C for 0.5 h and at 0 °C for 0.5 h. The mixture was partitioned
between EtOAc and saturated NH4Cl. The organic layer was
separated, washed with saturated NH4Cl and brine, dried over
MgSO4, and evaporated in Vacuo. The residue was chromatographed
on silica gel eluting with n-hexane-EtOAc (50:1 to 5:1) to give
48a (581 mg, 66%): colorless oil; IR (KBr) cm-1 3271 (SO2NH),
1963 (CdCdC), 1321 (SO2N), 1144 (SO2N); 1H NMR (300 MHz,
CDCl3) δ 1.31 (s, 6H, 2 × CMe), 1.64 (dd, J ) 7.0, 3.1 Hz, 3H,
5-CH3), 2.42 (s, 3H, CMe), 4.69 (br, 1H, NH), 5.09 (dq, J ) 6.4,
3.1 Hz, 1H, 2-H), 5.23 (dq, J ) 7.0, 6.4 Hz, 1H, 4-H), 7.27 (d, J
) 8.2 Hz, 2H, Ar), 7.76 (d, J ) 8.2 Hz, 2H, Ar); 13C NMR (75.5
MHz, CDCl3) δ 14.0, 21.4, 28.6, 28.8, 55.5, 89.6, 98.6, 127.1 (2C),
129.3 (2C), 140.2, 142.7, 202.0; MS (FAB) m/z (%) 266 (MH+,
39), 95 (100); HRMS (FAB) calcd for C14H20NO2S (MH+)
266.1215 found 266.1221.
to give 11a (28.7 mg, 96%): colorless oil; [R]26 +110 (c 1.025,
D
CHCl3); IR (KBr) cm-1 1319 (SO2N), 1146 (SO2N); 1H NMR (300
MHz, CDCl3) δ 0.78 (d, J ) 6.9 Hz, 3H, CMe), 0.89 (d, J ) 6.9
Hz, 3H, CMe), 1.74-1.82 (m, 1H, CHMe2), 2.28 (s, 3H, CMe),
2.60 (s, 6H, 2 × CMe), 2.82 (dd, J ) 13.1, 10.8 Hz, 1H, 2-CHH),
2.96-3.11 (m, 4H, 1-H, 7-CH2 and 8-H), 3.96-4.04 (m, 2H,
2-CHH and 4-H), 5.49 (d, J ) 1.9 Hz, 1H, 5-H), 6.93 (s, 2H, Ar),
7.12 (d, J ) 6.9 Hz, 2H, Ar), 7.17-7.31 (m, 3H, Ar); 13C NMR
(75.5 MHz, CDCl3) δ 18.8, 19.8, 20.9, 22.8 (2C), 34.0, 39.8, 43.9,
44.7, 46.9, 58.8, 111.9, 126.4 (3C), 128.4 (2C), 131.9 (2C), 134.0,
138.3, 140.0 (2C), 142.2, 143.0; MS (FAB) m/z (%) 410 (MH+,
56), 366 (100); HRMS (FAB) calcd for C25H32NO2S (MH+)
410.2154; found 410.2156.
(1R,4S,8R)-3-Aza-4-isopropyl-8-phenyl-3-(2,4,6-trimethyl-
phenylsulfonyl)bicyclo[4.2.0]oct-5-ene (67). A solution of (Z)-8
4388 J. Org. Chem., Vol. 72, No. 12, 2007

Bicyclo[4.2.0]oct-5-ene DeriVatiVes
(50.0 mg, 0.122 mmol) in dioxane (2 mL) was heated under reflux
for 65 h. After evaporation of solvent, the residue was chromato-
graphed on silica gel eluting with n-hexane-EtOAc (30:1) to give
MHz, CDCl3) δ 13.9, 18.8, 19.8, 20.9, 22.8 (3C), 29.8, 32.9, 34.1,
44.5, 44.8, 50.7, 53.9, 58.5, 110.1, 126.4, 126.8 (2C), 128.4 (2C),
131.9 (2C), 133.9, 140.0 (2C), 142.1, 142.7, 144.3; MS (FAB) m/z
(%) 466 (MH+, 74), 422 (100); HRMS (FAB) calcd C29H40NO2S
(MH+) 466.2780; found 466.2794.
67 (31.5 mg, 63%): colorless oil; [R]24 +42.9 (c 1.00, CHCl3);
D
1
IR (KBr) cm-1 1317 (SO2N), 1146 (SO2N); H NMR (300 MHz,
Compound 90: colorless oil; [R]22 +3.78 (c 0.570, CHCl3);
CDCl3) δ 0.66 (d, J ) 7.1 Hz, 3H, CMe), 0.76 (d, J ) 6.8 Hz, 3H,
CMe), 1.57-1.64 (m, 1H, CHMe2), 2.10 (dd, J ) 13.2, 10.3 Hz,
1H, 2-CHH), 2.29 (s, 3H, CMe), 2.54 (s, 6H, 2 × CMe), 2.89 (d,
J ) 14.4 Hz, 1H, 7-CHH), 3.23-3.40 (m, 3H, 1-H, 7-CHH and
8-H), 3.72 (ddd, J ) 13.2, 9.3, 2.7 Hz, 1H, 2-CHH), 3.90 (m, 1H,
4-H), 5.54 (d, J ) 1.7 Hz, 1H, 5-H), 6.91 (s, 2H, Ar), 7.17-7.31
(m, 5H, Ar); 13C NMR (75.5 MHz, CDCl3) δ 18.8, 19.7, 20.9, 22.8
(2C), 33.9, 36.2, 40.1, 40.4, 43.1, 58.6, 112.8, 126.6, 127.3 (2C),
128.3 (2C), 131.8 (2C), 134.0, 139.6, 140.0 (2C), 140.7, 142.1;
MS (FAB) m/z (%) 410 (MH+, 54), 366 (100); HRMS (FAB) calcd
for C25H32NO2S (MH+) 410.2154; found 410.2162.
General Procedure Hydrogenation of Cycloadducts: Syn-
thesis of (1S,4R,6R,8S)-3-Aza-4-isopropyl-8-phenyl-3-(2,4,6-
trimethylphenylsulfonyl)bicyclo[4.2.0]octane (68). A mixture of
11a (119 mg, 0.291 mmol) and 10% Pd/C (12 mg) in MeOH (3
mL) was stirred under 1 atm H2 at room temperature for 2 h. The
catalyst was filtered off, and the filtrate was evaporated in Vacuo.
The residue was chromatographed on silica gel eluting with
n-hexane-EtOAc (50:1 to 20:1) to give 68 (90.0 mg, 75%):
colorless oil; [R]25D +82.2 (c 1.105, CHCl3); IR (KBr) cm-1 1317
(SO2N), 1149 (SO2N); 1H NMR (300 MHz, CDCl3) δ 0.70 (d, J )
7.1 Hz, 3H, CMe), 0.86 (d, J ) 6.8 Hz, 3H, CMe), 1.60-1.69 (m,
2H, CHMe2 and 5-CHH), 1.90 (ddd, J ) 13.4, 5.6, 5.6 Hz, 1H,
5-CHH), 2.07-2.14 (m, 1H, 7-CHH), 2.28 (s, 3H, CMe), 2.31-
2.39 (m, 2H, 6-H and 7-CHH), 2.62 (s, 6H, 2 × CMe), 2.88-3.00
(m, 1H, 1-H), 3.00 (dd, J ) 13.4, 10.5 Hz, 1H, 2-CHH), 3.28-
3.38 (m, 1H, 8-H), 3.67 (ddd, J ) 5.9, 5.6, 5.4 Hz, 1H, 4-H), 3.95
(dd, J ) 13.4, 7.1 Hz, 1H, 2-CHH), 6.91 (s, 2H, Ar), 7.13-7.20
(m, 3H, Ar), 7.22-7.30 (m, 2H, Ar); 13C NMR (75.5 MHz, CDCl3)
δ 16.0, 19.1, 20.9, 22.9 (2C), 24.3, 26.2, 31.8, 32.6, 39.5, 43.5,
45.6, 58.0, 125.9, 126.3 (2C), 128.3 (2C), 131.8 (2C), 133.9, 139.9
(2C), 142.1, 144.6; MS (FAB) m/z (%) 412 (MH+, 70), 368 (100);
HRMS (FAB) calcd for C25H34NO2S (MH+) 412.2310; found
412.2300.
D
1
IR (KBr) cm-1 1321 (SO2N), 1151 (SO2N); H NMR (300 MHz,
CDCl3) δ 0.83 (d, J ) 6.8 Hz, 3H, CMe), 0.85 (d, J ) 6.8 Hz, 3H,
CMe), 0.86 (t, J ) 6.8 Hz, 3H, (CH2)3CH3), 1.10-1.28 (m, 4H,
(CH2)2CH3), 1.40-1.51 (m, 1H, (CHH)C3H7), 1.60-1.70 (m, 1H,
(CHH)C3H7), 1.86-1.94 (m, 1H, CHMe2), 2.24 (dd, J ) 8.5, 8.3
Hz, 1H, 8-H), 2.31 (s, 3H, CMe), 2.63 (s, 6H, 2 × CMe), 2.78-
2.84 (m, 1H, 1-H), 3.04-3.10 (m, 1H, 7-H), 3.33 (dd, J ) 13.4,
3.2 Hz, 1H, 2-CHH), 3.43 (dd, J ) 13.4, 7.3 Hz, 1H, 2-CHH),
3.89 (dd, J ) 8.3, 6.6 Hz, 1H, 4-H), 5.89 (dt, J ) 6.6, 2.4 Hz, 1H,
5-H), 6.95 (s, 2H, Ar), 7.08 (d, J ) 6.8 Hz, 2H, Ar), 7.19-7.31
(m, 3H, Ar); 13C NMR (75.5 MHz, CDCl3) δ 13.9, 18.8, 20.2, 20.9,
22.7, 23.2 (2C), 29.8, 32.4, 32.5, 42.4, 46.0, 50.4, 52.8, 58.9, 115.7,
126.5, 126.8 (2C), 128.4 (2C), 131.9 (2C), 134.1, 139.8 (2C), 142.0,
142.4, 143.3; MS (FAB) m/z (%) 466 (MH+, 67), 422 (100);
HRMS (FAB) calcd for C29H40NO2S (MH+) 466.2780; found
466.2787.
General Procedure for [2 + 2] Cycloaddition of Allenynes:
Synthesis of (4S)-3-Aza-4-isopropyl-8-phenyl-3-(2,4,6-trimethyl-
phenylsulfonyl)bicyclo[4.2.0]octa-1(8),5-diene (106a). By a pro-
cedure identical with that described for the synthesis of 67, 54a
(50.5 mg, 0.124 mmol) was converted into 106a (46.6 mg, 92%):
yellow oil; [R]25 -74.3 (c 0.655, CHCl3); IR (KBr) cm-1 1323
D
(SO2N), 1159 (SO2N); 1H NMR (500 MHz, CDCl3) δ 0.88 (d, J )
6.7 Hz, 3H, CMe), 0.95 (d, J ) 6.7 Hz, 3H, CMe), 1.98-2.05 (m,
1H, CHMe2), 2.25 (s, 3H, CMe), 2.59 (s, 6H, 2 × CMe), 3.25 (dd,
J ) 13.4, 3.7 Hz, 1H, 7-CHH), 3.29 (ddd, J ) 13.4, 3.7, 3.7 Hz,
1H, 7-CHH), 3.98 (dd, J ) 7.9, 4.9 Hz, 1H, 4-H), 4.14 (ddd, J )
17.7, 3.7, 3.7 Hz, 1H, 2-CHH), 4.66 (d, J ) 17.7 Hz, 1H, 2-CHH),
5.44 (d, J ) 4.9 Hz, 1H, 5-H), 6.88 (s, 2H, Ar), 7.18-7.35 (m,
5H, Ar); 13C NMR (75.5 MHz, CDCl3) δ 19.1, 20.4, 20.9, 23.1
(2C), 34.5, 35.9, 39.8, 59.6, 109.0, 126.2 (2C), 127.8, 128.6 (2C),
131.9 (2C), 133.4, 134.2 (2C), 136.2, 138.7, 139.9 (2C), 142.0;
MS (FAB) m/z (%) 408 (MH+, 12), 119 (100); HRMS (FAB) calcd
for C25H30NO2S (MH+) 408.1997; found 408.1972.
(1R,4S,7S,8S)-3-Aza-7-butyl-4-isopropyl-8-phenyl-3-(2,4,6-
trimethylphenylsulfonyl)bicyclo[4.2.0]oct-5-ene (89) and Its
(1S,4S,7R,8R)-Isomer (90). By a procedure identical with that
described for the synthesis of 11a, 53a (50.0 mg, 0.107 mmol) was
converted into 89 (32.5 mg, 65%) and 90 (11.5 mg, 23%).
Acknowledgment. We thank Dr. S. Aoki, Graduate School
of Pharmaceutical Sciences, Osaka University, for NMR
analyses. 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
and Mitsubishi Chemical Corporation Fund, which are gratefully
acknowledged.
Compound 89: colorless oil; [R]25 +61.3 (c 1.04, CHCl3); IR
D
(KBr) cm-1 1321 (SO2N), 1151 (SO2N); 1H NMR (300 MHz,
CDCl3) δ 0.80 (d, J ) 6.8 Hz, 3H, CMe), 0.83 (t, J ) 6.8 Hz, 3H,
(CH2)3CH3), 0.89 (d, J ) 6.8 Hz, 3H, CMe), 1.23-1.29 (m, 4H,
(CH2)2CH3), 1.54-1.60 (m, 1H, (CHH)C3H7), 1.68-1.75 (m, 1H,
(CHH)C3H7), 1.75-1.84 (m, 1H, CHMe2), 2.29 (s, 3H, CMe), 2.55
(dd, J ) 8.1, 8.1 Hz, 1H, 8-H), 2.59 (s, 6H, 2 × CMe), 2.77 (dd,
J ) 12.7, 10.0 Hz, 1H, 2-CHH), 2.82-2.88 (m, 1H, 1-H), 3.15-
3.27 (m, 1H, 7-H), 3.93 (dd, J ) 12.7, 5.9 Hz, 1H, 2-CHH), 3.99-
4.03 (m, 1H, 4-H), 5.48 (d, J ) 2.2 Hz, 1H, 5-H), 6.92 (s, 2H, Ar),
7.09-7.22 (m, 3H, Ar), 7.25-7.31 (m, 2H, Ar); 13C NMR (75.5
Supporting Information Available: Synthetic procedure, char-
acterization, and 1H NMR for all new compounds. This material is
available free of charge via Internet at http://pubs.acs.org.
JO0700528
J. Org. Chem, Vol. 72, No. 12, 2007 4389