Yb(OTf)3-catalyzed [4+2] cycloaddition of allenyltrimethylsilylthioketenes with arylaldimines

Article abstract of DOI:10.1055/s-2007-970748

Yb(OTf)₃-catalyzed [4+2] cycloaddition of an in situ generated allenyltrimethylsilylthioketene with arylaldimines afforded unsaturated δ-thiolactams, one of which was converted into a known 4-azafluorenone, a synthetic precursor of onychine, in

Full text of DOI:10.1055/s-2007-970748

LETTER
615
Yb(OTf)3-Catalyzed [4+2] Cycloaddition of Allenyltrimethylsilylthioketenes
with Arylaldimines
Y
b(O
T
f)3-Cath
a
lyzed [4+2]
i
Cycloa
g
ddition of
A
e
llenyltrime
n
thylsilylthiok
o
e
tenes bu Aoyagi,* Satoru Ohata, Kazuaki Shimada, Yuji Takikawa
Department of Chemical Engineering, Faculty of Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 0208551, Japan
Fax +81(19)6216324; E-mail: aoyagi@iwate-u.ac.jp
Received 6 December 2006
Table 1 Effect of Lewis Acids on Aza-Diels–Alder Reaction of 1a
Abstract: Yb(OTf)3-catalyzed [4+2] cycloaddition of an in situ
and 3a
generated allenyltrimethylsilylthioketene with arylaldimines af-
forded unsaturated d-thiolactams, one of which was converted into
a known 4-azafluorenone, a synthetic precursor of onychine, in
Bn
N
S
3a
Me3Si
Me
Bn
Ph
three steps.
Ph
(0.67 equiv)
N
Me3Si
Me
S
Key words: allenyltrimethylsilylthioketene, arylaldimine, [4+2]
cycloaddition, Yb(OTf)3, onychine
Lewis acid
CHCl3, reflux, 12 h
1a
4a
Entry
Lewis acid
None
Amount (mol%)
Yield (%)a
The [4+2] cycloaddition of Danishefsky’s diene and relat-
ed dienes with imines,1 including catalytic asymmetric
cycloaddition,2 has been widely studied in the light of its
synthetic utilities for the short access route to alkaloids of
biological relevance. Recently, aza-Diels–Alder reactions
of trialkylvinylketenes with N-trimethylsilyl imines were
reported.3 However, only the N-trimethylsilyl imines
without a-hydrogen were applicable.
1
2
0
10
10
10
10
20
20
20
10
20
30
5
0
BF3·OEt2
TiCl4
3
0
4
ZnCl2
7
5
Cu2Cl2
12
33
15
21
57
65
67
In the course of study on generation and trapping of
allenylchalcogenoketenes,4 we established a simple and
efficient preparation of unsaturated d-thiolactams through
[4+2] cycloaddition of allenyltrimethylsilylthioketenes 2
and imines 3.5 In this case, N-alkyl aliphatic aldimines
were applicable, whereas employment of arylaldimine
gave a poor result and we were urged to overcome the
limitation for versatility and utility of our methodology.
The [4+2] cycloaddition of Danishefsky’s diene with
imines is known to be activated by Lewis acids1,2 and em-
ployment of Lewis acids seemed to be a promising way to
improve the efficiency of our reaction. In this letter, we
wish to report the [4+2] cycloaddition of allenyltrimethyl-
silylthioketenes 2 and arylaldimines 3 catalyzed by
Yb(OTf)3 (Scheme 1), and the formal total synthesis of an
4-azafluorenone alkaloid, onychine (5) is also described.
6
Zn(OTf)2
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
7
8
9
10
11
a Isolated yield based on imine.
Danishefsky’s diene with imines, were ineffective in the
present reaction (Table 1).
Similar reactions employing allenylthioketenes 2a–c with
imines 3a–g in the presence of Yb(OTf)3 (20 mol%) were
examined and the results are summarized in Table 2.
Sulfide 1b, which underwent [3,3]-sigmatropic rearrange-
ment to generate 2b at ca. 80 °C,4e also afforded the cy-
cloadduct 4h in 62% yield under refluxing 1,2-
dichloroethane condition. Cycloadducts 4e and 4f having
a 2-bromophenyl group, which would serve as precursors
for intramolecular Heck reaction leading to 4-azafluo-
renes, were also furnished in 60% and 65% yields, respec-
tively. When N-trimethylsilylimine 3g was reacted with
2a, the desilylated product 4g was afforded in 37% yield.
The reaction of allenyltrimethylsilylthioketene 2c, gener-
ated in situ in THF at 0 °C by [3,3]-sigmatropic rearrange-
ment of unisolable sulfide 1c, with imine 3a and 3e in the
At the outset, we examined the [4+2] cycloaddition of al-
lenyltrimethylsilylthioketene 2a, thermally generated
from 1a, with N-benzylbenzylidenimine (3a) in the pres-
ence of Lewis acids. While the reaction in the absence of
Lewis acid afforded only 5% of cycloadduct 4a, a loading
of Yb(OTf)3 (20 mol%) dramatically changed the yield of
4a up to 65%. However, other metal triflates were not as
effective as Yb(OTf)3 under identical condition and other
Lewis acids, such as BF3·OEt2, TiCl4, ZnCl2, and Cu2Cl2,
which are commonly used for [4+2] cycloaddition of
SYNLETT 2007, No. 4, pp 0615–0618
0
1.
0
3.
2
0
0
7
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-970748; Art ID: U14606ST
© Georg Thieme Verlag Stuttgart · New York

616
S. Aoyagi et al.
LETTER
R2
N
S
S
Me3Si
R1
R2
Ar
Me3Si
R1
•
•
3
Me3Si
S
Ar
N
R1
[3,3]
Yb(OTf)3
[4+2]
2
1
4
Scheme 1 Aza-Diels–Alder reaction of allenyltrimethylsilylthioketenes 2 with imine 3 in the presence of Yb(OTf)3
absence of Lewis acid afforded cycloadducts 4i and 4j in Initially, we envisaged that the 4-azafluorenone skeleton
3% and 0% yields, respectively.5 Addition of 20 mol% of of onychine (5) could be established by intramolecular
Yb(OTf)3, which withstanded the Lewis basic THF Heck reaction of d-thiolactam 4f8 having an exo-methyl-
media,1d to the similar reactions also improved the yields ene and a 2-bromophenyl group. However, all efforts to
of 4i and 4j up to 35% and 47%, respectively.
obtain 4-azafluorene-3-thione by intramolecular Heck re-
action of 4f were unsuccessful presumably due to poison-
ing of the catalyst by thiolactam 4f. To avoid this problem,
the obtained d-thiolactams 4 were transformed into the
corresponding d-lactams 6. Treatment of 4i and 4j with
MCPBA (3 equiv) in CHCl3 at 0 °C for 30 minutes afford-
ed 6i and 6j in 52% and 48% yields, respectively,5,9
whereas similar oxidation of 4f, having a methyl group at
1-position, with MCPBA afforded trace amount of the
desilylated product of desired 6f.
To demonstrate the synthetic utility of the aza-Diels–
Alder reaction of allenyltrimethylsilylthioketene 2 and
arylaldimine 3 in the presence of Yb(OTf)3, we next
undertook the formal total synthesis of onycine (5).
Onychine is a 4-azafluorenone alkaloid, which was isolat-
ed from the Brazilian Annonacae species in 1976 and has
been shown to have anticandidal activity,6 and several
synthetic studies to confirm the structure have been re-
ported.7 However, to date a procedure for the construction
of the pyridine ring of onychine (5) using hetero-[4+2]
cycloaddition as a key step was not known.
Alternative oxidation of 4f using N-tosyl-3-phenlylox-
aziridine (1.2 equiv) in place of MCPBA successfully
afforded 6f in 68% yield (Scheme 2).10,11 With lactam 6f
Table 2 Yb(OTf)3-Catalyzed Aza-Diels–Alder Reaction of in situ Generated Allenyltrimethylsilylthioketenes 2 with Arylaldimines 3a
S
R2
Yb(OTf)3
(20 mol%)
Me3Si
R1
R2
Ar
N
N
Me3Si
R1
S
+
Ar
3
1
4
Entry
Sulfide
1a
R1
Imine
3a
Ar
Ph
4-ClC6H4
R2
Solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Temp (°C) Time (h) Product
Yield (%)b
65 (5)c
53
1
2
Me
Me
Me
Me
Me
Me
Me
Ph
Bn
Bn
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
12
12
12
12
12
12
14
14
14
14
4a
4b
4c
4d
4e
4f
1a
3b
3c
3
1a
4-MeOC6H4 Bn
57
4
1a
3d
3e
4-NCC6H4
2-BrC6H4
2-BrC6H4
2-BrC6H4
Ph
Bn
Bn
66
5
1a
60
6
1a
3f
PMB
Me3Si
Bn
65
7
1a
3g
4gd
4h
4i
37
8
1b
3a
ClCH2CH2Cl Reflux
62 (7)c
35 (3)c
47 (0)c
9
1ce
1ce
H
3a
Ph
Bn
THF
THF
0–r.t.
0–r.t.
10
H
3e
2-BrC6H4
PMB
4j
a Sulfide (1.5 equiv) and Yb(OTf)3 (0.2 equiv) were used (relative to amount of imine).
b Isolated yield based on used imine.
c The values in the parentheses are the yields of 4 in the absence of Yb(OTf)3.
d Desilylated product 4g (R2 = H) was afforded.
e Sulfide 1c was prepared in situ according to the reported procedure and used for the [4+2] cycloaddition without further concentration or
purification.
Synlett 2007, No. 4, 615–618 © Thieme Stuttgart · New York

LETTER
Yb(OTf)3-Catalyzed [4+2] Cycloaddition of Allenyltrimethylsilylthioketenes
617
X
O
O
Pd(OAc)2 (5 mol%),
(o-Tol)3P (10 mol%)
Me3Si
Me
PMB
PMB
N
Me3Si
Me
PMB
N
ref. 7g
TsOH (3.5 equiv)
CHCl3, refux, 12 h
N
N
Me
Et3N (5.0 equiv),
DMF, 90 °C, 12 h
Me
O
Br
O
7f (58%)
8f (88%)
onychine (5)
4f (X = S)
6f (X = O)
N
Ph
Ts
(1.2 equiv)
0 °C to r.t., 30 min
67%
Scheme 2 Formal total synthesis of onychine (5)
(3) Bennett, B.; Okamoto, I.; Danheiser, L. Org. Lett. 1999, 1,
641.
in our hand, we next undertook the intramolecular Heck
reaction of 6f leading to 4-azafluorenone. A DMF solu-
tion of d-lactam 6f, Pd(OAc)2 (10 mol%), (o-Tol)3P (20
mol%) and Et3N (5 equiv) was heated at 90 °C for 12
hours under a N2 atmosphere. Removal of the solvent
followed by column chromatographic separation afforded
4-azafluoren-3-one 7f in 58% yield (Scheme 2).12 Inter-
estingly, 7f was readily oxidized to give the correspond-
ing 4-azafluoren-3,9-dione 9f in aerobic storage and 7f
was immediately subjected to desilylation. Treatment of
7f with TsOH·H2O (3.5 equiv) under refluxing CHCl3
condition furnished desilylated 4-azafluoren-3-one 8f in
88% yield.13 It is noteworthy that desilylation of 7f using
TABF in THF or K2CO3 in MeOH resulted in the recovery
of 7f. The spectral aspects of 8f were identical to that of
the key intermediate of onychine synthesis reported by
Padwa.7g
(4) (a) Shimada, K.; Akimoto, S.; Itoh, H.; Nakamura, H.;
Takikawa, Y. Chem. Lett. 1994, 1743. (b) Shimada, K.;
Akimoto, S.; Takikawa, Y.; Kabuto, C. Chem. Lett. 1994,
2286. (c) Koketsu, M.; Kanoh, M.; Itoh, E.; Ishihara, H. J.
Org. Chem. 2001, 66, 4099. (d) Koketsu, M.; Kanoh, M.;
Yamamura, Y.; Ishihara, H. Tetrahedron Lett. 2005, 46,
1479. (e) Aoyagi, S.; Sugimura, K.; Kanno, N.; Watanabe,
D.; Shimada, K.; Takikawa, Y. Chem. Lett. 2006, 992.
(5) Aoyagi, S.; Hakoishi, M.; Suzuki, M.; Nakanoya, Y.;
Shimada, K.; Takikawa, Y. Tetrahedron Lett. 2006, 47,
7763.
(6) (a) de Almeida, M. E. I.; Braz, F. R.; von Bulow, M. V.;
Gottleib, O. R.; Maia, J. G. S. Phytochemistry 1976, 15,
1186. (b) Goulart, M. O. F.; Santana, A. E. G.; de Oliveira,
A. B.; de Oliveira, G. G.; Maia, J. G. S. Phytochemistry
1986, 25, 1691. (c) Arango, G. J.; Cortes, D.; Cassels, B. K.;
Cave, A.; Merienne, C. Phytochemistry 1987, 26, 2093.
(d) Tadic, D.; Cassels, B. K.; Cave, A.; Goulart, M. P. F.; de
Oliveira, A. B. Phytochemistry 1987, 26, 1551. (e) Tadic,
D.; Cassels, B. K.; Cave, A. Heterocycles 1988, 27, 407.
(7) (a) Koyama, J.; Sugita, T.; Suzuta, Y.; Irie, H. Heterocycles
1979, 12, 1017. (b) Zhang, J.; El-Shabrawy, O.; El-
Shabrawy, M. A.; Schiff, P. L. Jr.; Slatkin, D. J. J. Nat. Prod.
1987, 50, 800. (c) Alves, T.; de Oliveira, A. B.; Snieckus, V.
Tetrahedron Lett. 1988, 29, 2135. (d) Koyama, J.; Okatani,
T.; Tagahara, K. Heterocycles 1989, 29, 1648. (e) Bracher,
F. Synlett 1991, 95. (f) Nitta, M.; Ohnuma, M.; Iino, Y. J.
Chem. Soc., Perkin Trans. 1 1991, 1115. (g) Padwa, A.;
Heidelbaugh, T. M.; Kuethe, J. T. J. Org. Chem. 2000, 65,
2368.
(8) A CHCl3 (30 mL) solution of 1a (900 mg, 4.95 mmol), N-(p-
methoxybenzyl)-2-bromobenzylidenamine (3f; 100 mg,
3.29 mmol) and Yb(OTf)3 (408 mg, 0.66 mmol) was heated
to reflux for 14 h. The resulting reaction mixture was
subjected to column chromatography on silica gel (hexane–
EtOAc, 10:1). 4f: yield: 1040 mg (65%); yellow plates; mp
138.8–139.2 °C. MS: m/z (%) = 485 (6) [M+], 470 (47)
[M+ – Me], 412 (16) [M+ – TMS], 121 (100) [PMB]. IR
(KBr): 2943, 1514, 1514, 1475, 1253, 1244, 875, 844 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.45 (s, 9 H), 1.93 (s, 3 H),
3.78 (s, 3 H), 3.99 (d, J = 14.5 Hz, 1 H), 5.34 (s, 1 H), 5.61
(s, 1 H), 5.67 (s, 1 H), 8.08 (d, J = 14.5 Hz, 1 H), 6.81 (d,
J = 8.6 Hz, 2 H), 7.10–7.15 (m, 1 H), 7.21–7.25 (m, 2 H),
7.28 (d, J = 8.6 Hz, 2 H), 7.52 (d, J = 7.9 Hz, 1 H). 13C NMR
(100 MHz, CDCl3): d = 3.2 (q), 19.0 (q), 54.0 (t), 55.2 (q),
62.6 (d), 113.9 (d), 117.5 (dd), 123.1 (s), 127.5 (d), 127.8 (d),
128.1 (s), 129.5 (d), 129.7 (d), 133.6 (d), 136.6 (s), 141.4 (s),
141.9 (s), 142.7 (s), 159.1 (s), 195.6 (s). Anal. Calcd for
C24H28BrNOSSi: C, 59.25; H, 5.80; N, 2.88. Found: C,
59.14; H, 5.89; N, 2.90.
In conclusion, Yb(OTf)3-catalyzed [4+2] cycloaddition of
allenyltrimethylsilylthioketenes 2 with arylaldimines 3
proceeded smoothly to afford d-thiolactams 4. d-Lactam
6f, derived from d-thiolactam 4f, successfully underwent
intramolecular Heck reaction to give 4-azafluoren-3-one
7f and the following protodesilylation furnished 8f, a key
intermediate of onychine synthesis. Synthetic potentiality
of the Lewis acid catalyzed aza-Diels–Alder reaction
protocol, using allenyltrimethylsilylthioketenes 2, as a
convenient access route to azafluorenone alkaloids has
been demonstrated. Total synthesis of the related aza-
fluorenone alkaloids in this protocol are currently in
progress in our laboratory.
References and Notes
(1) (a) Barluenga, J.; Mateos, C.; Aznar, F.; Valdés, C. J. Org.
Chem. 2004, 69, 7114. (b) Mancheño, O. G.; Arrayás, R. G.;
Carretero, J. C. J. Am. Chem. Soc. 2004, 126, 456.
(c) Barluenga, J.; Mateos, C.; Aznar, F.; Valdés, C. Org.
Lett. 2002, 4, 1971. (d) Furman, B.; Dziedzic, M.
Tetrahedron Lett. 2003, 44, 6629.
(2) (a) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57,
3264. (b) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520.
(c) Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis
1995, 1195. (d) Kobayashi, S.; Komiyama, S.; Ishitani, H.
Angew. Chem. Int. Ed. 1998, 37, 979. (e) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069.
Synlett 2007, No. 4, 615–618 © Thieme Stuttgart · New York

618
S. Aoyagi et al.
LETTER
(9) Kochhar, K. S.; Cottrell, D. A.; Pinnick, H. W. Tetrahedron
Lett. 1983, 24, 1323.
(10) (a) Davis, F. A.; Jenkins, R. Jr.; Yochlovich, S. G.
Tetrahedron Lett. 1978, 5171. (b) Davis, F. A.; Awad, S. B.;
Jenkins, R. H. Jr.; Billmers, R. L.; Jenkins, L. A. J. Org.
Chem. 1983, 48, 3071.
EtOAc, 7:1). 7f: yield: 144 mg (58%); pale yellow plates;
mp 142.7–144.0 °C. MS: m/z (%) = 389 (42) [M+], 374 (23)
[M+ – Me], 121 (100) [PMB]. IR (KBr): 2951, 1619, 1579,
1247, 850 cm–1. 1H NMR (400 MHz, CDCl3): d = 0.39 (s, 9
H), 2.40 (s, 3 H), 3.62 (s, 2 H), 3.73 (s, 3 H), 5.66 (br s, 2 H),
6.80 (d, J = 8.2 Hz, 2 H), 7.09 (d, J = 8.2 Hz, 2 H), 7.21 (t,
J = 7.6 Hz, 1 H), 7.28 (t, J = 7.4 Hz, 1 H), 7.51 (d, J = 7.4
Hz, 1 H), 7.58 (d, J = 7.9 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): d = 1.7 (q), 19.7 (q), 34.4 (t), 46.6 (t), 55.1 (q), 114.1
(d), 122.4 (s), 122.5 (d), 124.5 (d), 125.1 (d), 126.95 (d),
127.01 (d), 127.4 (d), 128.4 (s), 136.4 (s), 144.0 (s), 146.1
(s), 153.6 (s), 158.5 (s), 166.4 (s). Anal. Calcd for
(11) To a CHCl3 (30 mL) solution of 4f (500 mg, 1.03 mmol) was
added N-tosyl-3-phenyloxaziridine (340 mg, 1.23 mmol)
portionwise at 0 °C and then the solution was stirred at r.t.
for 30 min. The reaction was quenched with an excess
amount of aq Na2SO3 solution and the organic layer was
separated and dried over anhyd Na2SO4. After evaporation
of the solvent, the residue was subjected to column
chromatography on silica gel (hexane–EtOAc = 7:1). 6f:
yield: 325 mg (67%); colorless oil. MS: m/z (%) = 469 (19)
[M+], 454 (19) [M+ – Me], 121 (100) [PMB]. IR (neat): 2951,
1625, 1512, 1247, 1036, 845 cm–1. 1H NMR (400 MHz,
CDCl3): d = 0.39 (s, 9 H), 1.99 (s, 3 H), 3.47 (d, J = 14.6 Hz,
1 H), 3.78 (s, 3 H), 5.22 (d, J = 14.6 Hz, 1 H), 5.28 (s, 1 H),
5.55 (s, 1 H), 5.59 (s, 1 H), 6.81 (d, J = 6.6 Hz, 2 H), 7.10–
7.20 (m, 1 H), 7.22 (d, J = 6.6 Hz, 2 H), 7.24–7.29 (m, 2 m),
7.53–7.55 (m, 1 H). 13C NMR (100 MHz, CDCl3): d = 2.0
(q), 18.6 (q), 47.0(dd), 55.1 (q), 61.1 (d), 113.6 (d), 115.7
(dd), 122.8 (s), 127.6 (d), 127.8 (d), 129.3 (s), 129.8 (d),
133.3 (d), 134.0 (s), 139.3 (s), 142.9 (s), 150.4 (s), 158.8 (s),
166.6 (s). Anal. Calcd for C24H28BrNO2Si: C, 61.27; H, 6.00;
N, 2.98. Found: C, 61.09; H, 6.07; N, 2.97.
C24H27NO2Si: C, 74.00; H, 6.99; N, 3.60. Found: C, 73.83;
H, 7.15; N, 3.65.
(13) A CHCl3 (30 mL) solution of 7f (120 mg, 31 mmol) and p-
toluenesulfonic acid monohydrate (205 mg, 108 mmol) was
heated to reflux for 5 h. The reaction was quenched with an
excess amount of aq NaHCO3 solution and the organic layer
was separated and dried over anhyd Na2SO4. After
evaporation of the solvent, the residue was subjected to
column chromatography on silica gel (hexane–EtOAc =
7:1). 8f: yield: 86 mg (88%); pale yellow solid; mp 162.2–
163.8 °C (lit.7g 164–165 °C). MS: m/z (%) = 317 (10) [M+],
121 (100) [PMB]. IR (KBr): 2956, 1651, 1526, 1516, 1252,
1174, 1032, 842 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.32
(s, 3 H), 3.62 (s, 2 H), 3.73 (s, 3 H), 5.71 (br s, 2 H), 6.48 (s,
1 H), 6.82 (d, J = 8.6 Hz, 2 H), 7.12 (d, J = 8.6 Hz, 2 H),
7.25–7.35 (m, 2 H), 7.54 (d, J = 7.1 Hz, 1 H), 7.62 (d, J = 7.6
Hz, 1 H). 13C NMR (100 MHz, CDCl3): d = 19.0 (q), 33.6 (t),
46.8 (t), 55.2 (q), 114.2 (d), 116.6 (d), 121.9 (s), 122.5 (d),
125.2 (d), 127.07 (d), 127.13 (d), 127.4 (d), 128.2 (s), 136.3
(s), 144.4 (s), 145.6 (s), 147.5 (s), 158.6 (s), 163.7 (s).
(12) A DMF solution (10 mL) of 6f (300 mg, 64 mmol), tri(o-
tolyl)phosphine (19 mg, 6 mmol), Pd(OAc)2 (7 mg, 3 mmol)
and Et3N (323 mg, 320 mmol) was stirred at 90 °C for 12 h
under a N2 atmosphere. After removal of DMF by
distillation under reduced pressure, the residue was
subjected to column chromatography on silica gel (hexane–
Synlett 2007, No. 4, 615–618 © Thieme Stuttgart · New York