Low-valent zirconocene-mediated cyclization of γ,δ-unsaturated oximes

Article abstract of DOI:10.1016/j.tetlet.2010.07.055

γ,δ-Unsaturated O-methyl oximes were cyclized to dihydropyrrole by the treatment of (1-butene)ZrCp₂ 3 prepared by Negishi's procedure (reaction with Cp₂ZrCl₂ and two equivalents of n-BuLi). In this cyclization, the geometr

Full text of DOI:10.1016/j.tetlet.2010.07.055

Tetrahedron Letters 51 (2010) 4890–4893
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Low-valent zirconocene-mediated cyclization of c,d-unsaturated oximes
a
b
a
Mitsuru Kitamura a, , Yuki Shintaku , Daisuke Kudo , Tatsuo Okauchi
*
a Department of Applied Chemistry, Kyushu Institute of Technology, 1-1 Sensui-cho, Tobata-ku, Kitakyushu-shi, Fukuoka 804-8550, Japan
b Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
c
,d-Unsaturated O-methyl oximes were cyclized to dihydropyrrole by the treatment of (1-butene)ZrCp2 3
Received 10 June 2010
Revised 9 July 2010
Accepted 12 July 2010
Available online 15 July 2010
prepared by Negishi’s procedure (reaction with Cp2ZrCl2 and two equivalents of n-BuLi). In this cycliza-
tion, the geometry of oximes was affected and syn-oximes were cyclized efficiently. However, it was
found that the anti-oxime is not suitable for the cyclization.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cyclization
Heterocycles
Oxime
Zirconium
Previously, we reported that N–O bonds of oxime derivatives
are cleaved by the oxidative addition to Pd(0) complexes to gener-
ate alkylideneaminopalladium(II) species.1,2 When olefinic O-pen-
tafluorobenzoyloximes are treated with a catalytic amount of
Pd(PPh3)4 in the presence of Et3N, Mizoroki–Heck-type cyclization
(amino-Heck reaction) proceeds via the amino-palladium interme-
diates, affording various aza-heterocycles.3,4 In Scheme 1, the syn-
thesis of pyrrole is shown as a typical example.3a,b In this reaction,
the selection of the pentafluorobenzoyloxy group as a leaving
group on the oxime nitrogen is important. When the leaving group
has higher leaving ability, such as sulfonate, Beckmann rearrange-
ment also proceeds in the reaction conditions. In the case of lower
leaving ability, the oxidative addition of the oxime to Pd(0) is dif-
ficult. This amino-Heck reaction is not affected by the geometry of
oximes, probably due to the linear-like structures of the alkylide-
OCOC6F5
OCOC6F5
L
Pd
N
L
10 mol% Pd(PPh3)4
Et3N
N
Ph
Ph
DMF
80 °C, 1 h
1a
I
CH3
N
Me3SiCl
HN
CH2Cl2
rt, 0.5 h
Ph
Ph
2
from syn-1a 85%
from anti-1a 82%
Scheme 1. Amino Heck-reaction of
1a.
c
,d-unsaturated O-pentafluorobenzoyl oxime
neaminometal species I.2,5 Both syn and anti
c,d-unsaturated ke-
tone oximes 1a cyclized to pyrrole 2 in good yields.6
In our continuation study on the metal-catalyzed cyclization of
,d-unsaturated ketone oximes, we were interested in the reaction
with low-valent zirconocene species, such as (1-butene)ZrCp2 3,
which is reported by Negishi et al. to be easily prepared by the
reaction of Cp2ZrCl2 with two equivalents of n-BuLi.7 If the olefin
lent titanocene occurred,2b alkylideneaminozirconium species 5b
thus formed may cyclize to 6 similar to a Pd(0)-catalyzed amino-
Heck reaction. Therefore, we examined the reaction of (1-bute-
ne)ZrCp2 3 with c,d-unsaturated ketone oximes. In this Letter, we
describe the outcome of this investigation.
c
exchange of (1-butene)ZrCp2 3 with anti-c,d-unsaturated ketone
In Table 1, the results of the reaction of syn-1-phenyl-4-penten-
1-one oxime 1 with (1-butene)ZrCp2 3 are listed.6 First we exam-
ined the effect of the substituents on the oxime nitrogen atom in
THF (runs 1–7). O-Pentafluorobenzoyl oxime 1a cyclized to cyclic
imine 7 in 43% yield accompanied with the formation of oxime
10, which was predominantly formed in the reaction of O-acetyl
oxime 1b (runs 1 and 2). Oxime 10 would be formed by the reac-
tion of zirconocene 3 and ester part in 1.9 Although the formation
oximes 4 occurred to give 5a, internal SN2-type substitution is ex-
pected to proceed to give a cyclized product since 5a has a nucle-
ophilic moiety which could place at the backside of the leaving
group (R2O in 5a) on the oxime sp2 nitrogen1b,8 (Scheme 2). If
the oxidative addition of oxime to zirconocene 3 similar to low-va-
* Corresponding author. Tel./fax: +81 93 884 3304.
E-mail address: kita@che.kyutech.ac.jp (M. Kitamura).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.055

M. Kitamura et al. / Tetrahedron Letters 51 (2010) 4890–4893
4891
employed, while O-methyl oxime 1d was cyclized to 7 in 53% yield
(run 4). However, from anti-oxime 1d, the yield of cyclic imine 7
was only 9% (run 5). O-Methoxymethyl (MOM) and O-benzyl
(Bn) oximes were ineffective for the cyclization (runs 6 and 7).
Next, we examined the solvent using O-methyl oxime 1d (runs
8–12). In Et2O and benzene, the reaction proceeded more rapidly
than in THF, and 7 was obtained in 47% and 49%, respectively (runs
8 and 9). In toluene, cyclic imines 7 and 8 having hydroxymethyl
group were formed as cyclized products in combined yields of
50% (run 10). Hexane and dichloromethane were not suitable for
the cyclization of oxime 1d (runs 11 and 12). When the reaction
of 1a in THF was quenched with D2O, deuterated cyclic imine[D]-
7 (D 78%) was obtained suggesting that alkyl zirconium species like
II were formed before quenching. Cyclic imine 7 was also obtained
by adding n-BuLi to the mixture of oxime 1d and Cp2ZrCl2 (runs 13
and 14), while 7 was not obtained only by treating with n-BuLi. In
addition, we should mention that the formation of many by-prod-
ucts such as 11 and 12 in small amounts was observed in all reac-
tions in Table 1, which is one of the reasons for the mid-level yield
of the cyclized product 7 even though the starting oxime 1 was
consumed.
To explore the scope and limitation of this cyclization reaction,
we examined various O-methyl oximes with particular focus on
the stereochemistry of the oximes (Table 2). For the oximes having
terminal alkenes, the efficiency of the cyclization of syn-isomers of
oximes was observed regardless of the aryl or alkylketone oximes
(runs 1–7). From anti-oxime 15, a trace amount of cyclic imine 19
was obtained and ketone 20 was obtained predominantly (run 7).
In contrast, the cyclization of oximes 16 having a di- or tri-substi-
tuted alkene did not proceed smoothly, though the oximes were
syn isomers (runs 11 and 12).
Cp
Zr
Cp
Cp
Cp
R2O
R1
Zr
R2O
N
N
and/or
Cp2Zr
Et
OR2
+
R1
5a
ZrCp2
Et
N
4
R1
3
5b
Cp
Cp
Zr OR2
H+
N
N
R1
R1
6
Scheme 2. Expected cyclization reaction of
butene)ZrCp2 3.
c,d-unsaturated oxime 4 with (1-
of oxime 10 was suppressed by using the bulky pivaloyl group (Piv)
as a substituent R, the yield of cyclized product 7 was 6% (run 3). In
the Pd(0)-catalyzed amino-Heck reaction, O-alkyl oxime cannot be
Table 1
Reaction of
c
,d-unsaturated oxime 1 with (1-butene)ZrCp2 3a
Cp
Cp
Cp
Cp
Zr
Zr
X
OR
syn-1
N
Et
N
3
II
Ph
rt
Ph
X = Cl and/or OR
In Figure 1, two plausible reaction mechanisms for the forma-
tion of cyclic imine 7 from 1d are depicted (paths A and B). Path
A is as follows: (1-butene)ZrCp2 3 reacted with the alkene part in
1d to form zirconium species 23, which reacted with the oxime
part via metathesis to give a cyclic compound. With syn-23 derived
from syn-oxime 1d, interaction occurred easily between the
methoxy group on the oxime nitrogen and the alkene–zirconium
complex because of their proximity, while anti-23 did not interact
R
OH
N
O
N
H2O
+
+
Ph
Ph
Ph
7: R = H
9
10
[D]-7: R = D
8: R = OH
OMe
OMe
N
N
Ph
Ph
2
Me
O
Cp
Zr Cp
11
12
Run
R
1
Solvent
Time
Yieldb (%)
N
7
9
10
1
Ph
1
2
3
C6F5CO
Ac
Piv
Me
Me
MOM
Bn
Me
Me
Me
1a
1b
1c
1d
1d
1e
1f
1d
1d
1d
1d
1d
1d
1d
THF
THF
THF
THF
THF
THF
THF
Et2O
Benzene
Toluene
Hexane
CH2Cl2
THF
1 d
1 d
1 d
6 h
5 h
2 d
2 d
3 h
2 h
2 h
1 d
1 d
3 h
3 h
43
5
0
25
6
36
24
32
10
10
10
25
0
22
88
6
0
0
0
0
0
0
0
0
0
0
15
7
9
—
—
18
6
10
—
syn-23
Cp
path A
0
6
Cp
OMe
4
53
9
Zr
N
MeO
Ph
5c
6
N
30
35
47
49
36f
21
0
Ph
7d
8
1d
anti-23
9e
10
11
12
13g
14g
H2O
7
+
II
Me
Me
Me
Me
25
64
—
Cp
Cp
Cp
OMe
Zr
N
Zr
Cp
37
48
4
3
Et
Et2O
0
—
3
Ph
a
Each reaction is carried out by treating Cp2ZrCl2 (0.5 mmol) with n-BuLi in
E-24
hexane (1.0 mmol) for 30 min at À78 °C in given solvent followed by addition of a
oxime (0.47 mmol) at À78 °C, warming the mixture to room temperature for 1 h,
and further stirring for given time.
path B
MeO
Cp
Zr
N
b
Cp
Isolated yield.
c
anti-O-Methyl oxime 1d was used for the reaction.
H2O
d
BnOH was obtained in 66% yield.
Compound 1d was added at 0 °C.
Compound 8 was obtained in 14% yield.
e
Ph
9
Z-24
f
g
To a solution of 1d and Cp2ZrCl2, n-BuLi was added at 0 °C, and the mixture was
warmed to room temperature.
Figure 1. Plausible reaction mechanisms for the formation of cyclic imine 7.

4892
M. Kitamura et al. / Tetrahedron Letters 51 (2010) 4890–4893
Table 2
Reaction of various c
,d-unsaturated O-methyl oxime with (1-butene)ZrCp2 3a
Cp
Cp
Zr
H2O
Et
3
product(s)
oxime
THF
–78 °C → rt
Run
Oxime (syn:anti)
Time (h)
Product(s) (%)
OMe
N
N
R
R
1
2
3
4
5
syn-13a: R = 4-MeOC6H4
13b: R = 2,4-(MeO)C6H3 (5:1)
13c: R = Ph(CH2)2 (1:1)
13d: R = (PhCH2)2CH (2:1)
syn-13e: R = PhCH2C(Me)2
14
20
5
16
24
17a
17b
17c
17d
17e
49
42
32
33
51
OMe
N
O
N
6
7
syn-14
2
17f 52%
18 11%
MeO
N
O
N
Ph
Ph
Ph
anti-15
18
19 Trace
20 95%
OMe
R
O
R
N
R
Ph
Ph
N
Ph
21a 6%
21b 2%
8b
9d
syn-16ac: R = H
syn-16b: R = Me
21
68
22a 20%
22b 11%
a
Each reaction is carried out by treating Cp2ZrCl2 (0.5 mmol) with n-BuLi in hexane (1.0 mmol) for 30 min at À78 °C in given solvent followed by addition of an oxime
(0.47 mmol) at À78 °C, warming the mixture to room temperature for 1 h, and then further stirring for given time.
b
Compound 16a was recovered in 43% yield.
The stereochemistry of olefin moiety was E/Z = 4:1.
Compound 16b was recovered in 74% yield.
c
d
easily. Path B is similar to the Pd(0)-mediated cyclization. That is
oxidative addition of the oxime part to low-valent zirconocene 3
and the successive addition of alkylideneamino zirconium species
24 to the internal olefin. Erker et al. have reported that geometric
isomerization of (E)- and (Z)-Cp2ZrCl(N@CHPh) could be effected
neither thermally nor photochemically.5a,b Although Erker et al.
also reported that linear-to-bent-to-linear isomerization of
Cp2ZrX(N@CR2) occurred rapidly in solution,5b the good yield of 7
from the syn-oxime may be attributed to the selective formation
of syn-24 which did not isomerize to anti-24, and the internal addi-
tion to the alkene. Ketone 9 would be formed by the hydrolysis of
24. The result that ketone was formed as a main by-product when
the yield of cyclic imine was low suggested that the formation of
alkylideneamino zirconium species like 24 prevents the cycliza-
tion. Therefore, we suppose that path A is the main pathway to
form cyclic imine 7.
References and notes
1. For reviews, see: (a) Kitamura, M.; Narasaka, K. Chem. Rec. 2002, 2, 268; (b)
Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005, 4505.
2. Oxidative addition of metal complex to oxime, see: (a) Ferreira, C. M. P.; Guedes
da Silva, M. F. C.; Kukushkin, V. Y.; Fraústo da Silva, J. J. R.; Pombeiro, A. J. L. J.
Chem. Soc., Dalton Trans. 1998, 325; (b) Tillack, A.; Arndt, P.; Spannenberg, A.;
Kempe, R.; Rosenthal, U. Z. Anorg. Allg. Chem. 1998, 624, 737.
3. For the synthesis of pyrroles, see: (a) Tsutsui, H.; Narasaka, K. Chem. Lett. 1999,
45; (b) Tsutsui, H.; Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2002, 75,
1451; (c) Zaman, S.; Kitamura, M.; Abell, A. D. Aust. J. Chem. 2007, 60, 624; For
the synthesis of pyridines, see: (d) Tsutsui, H.; Narasaka, K. Chem. Lett. 2001,
526; (e) Kitamura, M.; Kudo, D.; Narasaka, K. ARKIVOC 2006, iii, 148; For the
synthesis of spiro imines, see: (f) Kitamura, M.; Zaman, S.; Narasaka, K. Synlett
2001, 974; (g) Zaman, S.; Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003,
76, 1055; For the synthesis of aza-azulenes, see: (h) Kitamura, M.; Chiba, S.;
Saku, O.; Narasaka, K. Chem. Lett. 2002, 606; (i) Chiba, S.; Kitamura, M.; Saku, O.;
Narasaka, K. Bull. Chem. Soc. Jpn. 2004, 77, 785; For the synthesis of imidazoles,
see: Zaman, S.; Kitamura, M.; Abell, A. D. Org. Lett. 2005, 7, 609.
4. (a) Fürstner, A.; Radkowski, K.; Peters, H. Angew. Chem., Int. Ed. 2005, 44, 2777;
(b) Fürstner, A.; Radkowski, K.; Peters, H.; Seidel, G.; Wirtz, C.; Mynott, R.;
Lehmann, C. W. Chem. Eur. J. 2007, 13, 1929.
In conclusion, we found that c,d-unsaturated oximes cyclized to
dihydropyrrole by the treatment of low-valent zirconocene pre-
pared by Negishi’s procedure. In this reaction the geometry of oxime
is strongly affected, syn-oximes having terminal olefin cyclized effi-
ciently but anti-oxime was not suitable for the cyclization.
5. (a) Erker, G.; Frömberg, W.; Atwood, J. L.; Hunter, W. E. Angew. Chem., Int. Ed.
Engl. 1984, 23, 2400; (b) Erker, G.; Frömberg, W.; Krüger, C.; Raabe, E. J. Am.
Chem. Soc. 1988, 110, 2400; (c) Huang, J.-S.; Leung, S. K.-Y.; Cheng, K.-K.; Che, C.-
M. Chem. Eur. J. 2000, 6, 2971. and references cited here in.
6. In this manuscript, syn of c,d-unsaturated oxime means the alkoxy or acyloxy
group on the oxime nitrogen and an alkenyl moiety are on the same side of the
oxime carbon–nitrogen double bond and anti means that these groups are on
opposite sides.
Acknowledgment
OR
RO
N
N
This research was partially supported by a Grant-in-Aid for Sci-
entific Research from the Ministry of Education, Science, Sports and
Culture.
R
R
syn
anti

M. Kitamura et al. / Tetrahedron Letters 51 (2010) 4890–4893
4893
7. (a) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett. 1986, 27, 2829;
(b) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum, F. E.; Swanso, D.
R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336.
Chem. Lett. 1998, 607; (c) Yoshida, M.; Uchiyama, K.; Narasaka, K. Heterocycles
2000, 52, 681; (d) Tanaka, K.; Mori, Y.; Narasaka, K. Chem. Lett. 2004, 33, 26; (e)
Kitamura, M.; Yoshida, M.; Kikuchi, T.; Narasaka, K. Synthesis 2003, 2415.
9. See: Fujita, K.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2004,
126, 6776.
8. Intramolecular cyclization of oximes based on the SN2-type substitution on sp2
nitrogen, see: (a) Mori, S.; Uchiyama, K.; Hayashi, Y.; Narasaka, K.; Nakamura, E.
Chem. Lett. 1998, 111; (b) Uchiyama, K.; Yoshida, M.; Hayashi, Y.; Narasaka, K.