Intramolecular cyclization of ene-imine using dibutylzirconocene

Article abstract of DOI:10.1021/jo049662n

The reaction of ene-imine with Cp₂ZrBu₂ was carried out. When a crude imine, which was prepared from ene-aldehyde and primary amine in the presence of MgSO₄, was treated with Cp₂ZrBu ₂ at room tempera

Full text of DOI:10.1021/jo049662n

In tr a m olecu la r Cycliza tion of En e-Im in e Usin g
Dibu tylzir con ocen e
Muneyoshi Makabe, Yoshihiro Sato, and Miwako Mori*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, J apan
mori@pharm.hokudai.ac.jp
Received February 28, 2004
The reaction of ene-imine with Cp2ZrBu2 was carried out. When a crude imine, which was prepared
from ene-aldehyde and primary amine in the presence of MgSO4, was treated with Cp2ZrBu2 at
room temperature overnight, cyclopentane derivative having trans-substituents was obtained in
high yield along with a small amount of cyclopentane derivative having cis-substituents. Presum-
ably, cis-zirconacycle is a thermodynamic product. Reactions using various ene-imines were carried
t
out. In the case of ene-imine prepared from ene-aldehyde and BuNH2, only cyclopentane having
cis-substituents was produced. In this reaction, chiral amine was used, and diastereoselective
cyclization of ene-imine was carried out. As a result, cyclopentane derivative having cis-substituents
was obtained in an optically active form after hydrogenolysis of the cyclized compound.
In tr od u ction
Since Negishi and Takahashi reported the generation
of Cp2ZrBu2 from Cp2ZrCl2 and BuLi,1 many reactions
using this reagent have been developed.2 The reaction of
an alkyne and an alkene with Cp2ZrBu2 produces zir-
conacyclopropene or zirconacyclopropane, which can fur-
ther react with various multiple bonds to form zircona-
cyclopentenes or zirconacyclopentanes. Intramolecular
coupling reaction of diyne,3 diene,4 and enyne5 using Cp2-
ZrBu2 is very effective for the formation of cyclic com-
pounds. The coupling reaction of multiple bonds contain-
ing nitrogen is very interesting because azazirconacycle
is formed as an intermediate, and various heterocycles
and nitrogen-containing cyclized compounds have been
synthesized. As multiple bonds, nitrile,6 isocyanate,7 and
hydrazone8 can be reacted with Cp2ZrBu2, forming vari-
ous cyclic compounds. Livinghouse reported the coupling
reaction of ene- or yne-hydrazone and obtained cyclopen-
tane derivatives having cis-substituents (eq 1).8
However, little is known about the reaction of ene-
or yne-imine using Cp2ZrBu2. Here we report the coup-
ling reaction of ene-imime generated from ene-aldehyde
and the reactivity of the formed azazirconacycle (Scheme
1).
SCHEME 1. Syn th esis of Im in ozir con a cycle
(1) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett.
1986, 27, 2829.
(2) (a) Negishi, E. Acc. Chem. Res. 1987, 20, 65. (b) Negishi, E.;
Takahashi. T. Synthesis 1988, 1. (c) Nugent, W. A.; Taber, D. F. J .
Am. Chem. Soc. 1989, 111, 6435. (d) Negishi, E.; Holmes, S. J .; Tour,
J . M.; Miller, J . A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi. T.
J . Am. Chem. Soc. 1989, 111, 3336.
(3) (a) Nugent, W. A.; Thorn, D. L.; Harlow, R. L. J . Am. Chem. Soc.
1987, 109, 2788. (b) Fagan, P. J .; Nugent, W. A. J . Am. Chem. Soc.
1988, 110, 2310.
(4) (a) Rousset, C. J .; Swanson, D. R.; Lamaty, F.; Negishi, E.
Tetrahedron Lett. 1989, 30, 5105. (b) Nugent, W. A.; Taber. D. F. J .
Am. Chem. Soc. 1989, 111, 6435. (c) Akita, M.; Yasuda, H.; Yamamoto,
H.; Nakamura, A. Polyhedron 1991, 10, 1. (d) Mori, M.; Uesaka, N.;
Shibasaki, M. J . Org. Chem. 1992, 57, 3519. (e) Maye, J . P.; Negishi,
E. Tetrahedron Lett. 1993, 34, 3359. (f) Mori, M.; Saitoh, F.; Uesaka,
N.; Okamura, K.; Date, T. J . Org. Chem. 1994, 59, 4993. (g) Uesaka,
N.; Saitoh, F.; Mori, M.; Shibasaki, M.; Okamura, K.; Date, T. J . Org.
Chem. 1994, 59, 5633. (h) Mori, M.; Uesaka, N.; Saitoh, F.; Shibasaki,
M. J . Org. Chem. 1994, 59, 5643. (i) Mori, M.; Imai, A. E.; Uesaka, N.
Heterocycles 1995, 40, 551. (j) Saitoh, F.; Mori, M.; Okamura, K.; Date,
T. Tetrahedron 1995, 51, 4439. (k) Negishi, E.; Maye, J . P.; Choueiry,
D. Tetrahedron 1995, 51, 4447. (l) Taber, D. F.; Louey, J . P. Tetrahe-
dron 1995, 51, 4495. (m) Mori, M.; Kuroda, S.; Zhang C.-S.; Sato, Y.
J . Org. Chem. 1997, 62, 3263.
(5) (a) Negishi, E.; Swanson, D. R.; Cederbaum, F. E.; Takahashi,
T. Tetrahedron Lett. 1987, 28, 917. (b) Takahashi, T.; Swanson, D. R.;
Negishi, E. Chem. Lett. 1987, 623. (c) RajanBabu, T. V.; Nugent, W.
A.; Taber. D. F.; Fagan, P. J . J . Am. Chem. Soc. 1988, 110, 7128. (d)
Lund, E. C.; Livinghouse, T. J . Org. Chem. 1989, 54, 4487. (e) Mori,
M.; Uesaka, N.; Shibasaki, M. J . Chem. Soc., Chem. Commun. 1990,
1222. (f) Wender, P. A.; McDonald, F. E. Tetrahedron Lett. 1990, 31,
3691. (g) Wender, P. A.; McDonald, F. E. J . Am. Chem. Soc. 1990, 112,
4956. (h) Agnel, G.; Negishi, E. J . Am. Chem. Soc. 1991, 113, 7424. (i)
Agnel, G.; Owczarkzyk, Z.; Negishi, E. Tetrahedron Lett. 1992, 33,
1543. (j) Pagenkopf, B. L.; Lund, E. C.; Livinghouse, T. Tetrahedron
1995, 51, 4421. (k) Negishi, E.; Ma, S.; Sugihara, T.; Noda, Y. J . Org.
Chem. 1997, 62, 1922.
(6) (a) Mori, M.; Uesaka, N.; Shibasaki, M. J . Chem. Soc., Chem.
Commun. 1989, 776. (b) Takahashi, T.; Kageyama, M.; Denisov, V.;
Hara, R.; Negishi, E. Tetrahedron Lett. 1993, 34, 687. (c) Hara, R.; Xi,
Z.; Kotora, M.; Xi, C.; Takahashi, T. Chem. Lett. 1996, 1003. (d)
Takahashi, T.; Xi, C.; Xi, Z.; Kageyama, M.; Fischer, R.; Nakajima,
K.; Negishi, E. J . Org. Chem. 1998, 63, 6802.
(7) Takahashi, T.; Tsai, F. Y.; Li, Y.; Nakajima, K. Organometallics
2001, 20, 595.
(8) J ensen, M.; Livinghouse, T. J . Am. Chem. Soc. 1989, 111, 4495.
10.1021/jo049662n CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/17/2004
6238
J . Org. Chem. 2004, 69, 6238-6243

Cyclization of Ene-Imine Using Dibutylzirconocene
SCHEME 2. Rea ction of En e-Im in e w ith Dibu tylzir con ocen e
SCHEME 3. P ossible Rea ction Cou r se for
F or m a tion of cis-2a a n d tr a n s-2a
TABLE 1. Rea ction of Va r iou s En e-Im in es w ith
Cp 2Zr Bu 2
F IGURE 1.
Resu lts a n d Discu ssion
Rea ction of En e-Im in e w ith Cp 2Zr Bu 2. A THF
solution of ene-aldehyde 3a and benzylamine was stirred
at room temperature overnight in the presence of MgSO4,
and then undissolved material was filtered off. The
filtrate was concentrated under reduced pressure to give
yield (%)
ratio of
run
R1
time (h) total trans-2 cis-2 trans-2:cis-2
1
ene-imine 1a , whose structure was confirmed by the H
1
2
3
4
5
Me 1b
12
12
15
16
3
87
84
71
78
89
77
72
60
61
0
10
12
11
17
89
7.3:1
6.0:1
5.7:1
3.5:1
0:1
NMR spectrum. To a solution of Cp2ZrCl2 (1.3 equiv) in
THF (0.1 M) was added BuLi (1.6 M solution in hexane,
2.6 equiv) at -78 °C, and the solution was stirred at the
same temperature for 1 h. To this solution was added
the crude imine 1a in THF, and the solution was stirred
at room temperature for 12 h. After hydrolysis of the
reaction mixture, cyclopentane derivatives trans-2a and
cis-2a were obtained in 72% and 12% yields, respectively
(Scheme 2). The stereochemistry of each of these products
was determined by NOE experiments. It is clear that
cyclopentane derivative trans-2a having trans-substitu-
ents is the major product. The reaction mixture was
treated with D2O to give trans-2a -D and cis-2a -D in high
yields (D-contents: 99% and 77%, respectively, Figure
1). When the reaction mixture was refluxed for 18 h, the
yield of trans-2a slightly decreased to 63% and that of
cis-2a increased to 19% yield. These results indicated that
azazirconacyclopentanes trans-5a and cis-5a were formed
as intermediates and that cis-5a is a thermodynamically
stable azazirconacyclopentane.
Bn
nPr 1c
iPr
1d
tBu 1e
1a
Next, to examine the influence of the substituents on
the nitrogen of imine in this cyclization, various amines
such as methylamine, n-propylamine, isopropylamine,
and tert-butylamine were used and each imine was
synthesized from the corresponding amine and ene-
aldehyde 3a . The cyclization reactions were carried out
at room temperature in a similar manner, and the results
were shown in Table 1. The ratio of trans-2 to cis-2 is
slightly decreased in the case of imines having the larger
substituenes (Table 1, runs 1-4). Even in the case of
isopropylamine, trans-azazirconacycle 5e was formed
predominantly (run 4). However, surprisingly, when
imine having a tert-butyl group on the nitrogen was
reacted with Cp2ZrBu2, the reaction rate was accelerated,
and after 3 h only cis-2e was produced in 89% yield (run
5). The stereochemistries of the substituents were deter-
mined by NOE experiments. Presumably, cis-2e should
be formed predominantly by steric hindrance between the
alkene parts and the methyl group on the tert-butyl group
of iminozirconacyclopropane 4e as shown in Figure 2.
The possible reaction course is shown in Scheme 3. At
first, the imine part of 1a reacts with Cp2ZrBu2 to give
azazirconacyclopropane 4a . Insertion of the alkene parts
into carbon-zirconium bonds of 4a gives two azazircona-
cyclopentanes, trans-5a and cis-5a , which were hydro-
lyzed to give trans-2a and cis-2a .
J . Org. Chem, Vol. 69, No. 19, 2004 6239

Makabe et al.
SCHEME 5. Dia ster eoselective
Zir on iu m -Ca ta lyzed Cycliza tion
F IGURE 2.
SCHEME 4. Rea ction of Zir con a cycle w ith
Va r iou s Rea gen ts
TABLE 2. Zir con iu m -Med ia ted Dia ster eoselective
Cycliza tion
run
trans-8f
trans-8f ′
cis-8f
cis-8f ′
1
2
3
rt, 13 h
rt, 47
reflux, 18 h
39
32
10
22
22
7
17
20
53
17
6a and cis-6a were obtained in 28% and 12% yields,
respectively.
Next, carbon-carbon bond formation using azazircona-
cyclopentane was investigated. When CuCl and allyl
chloride10 were added to a THF solution of azazircona-
cyclopentane cis-5e, which was prepared from 1e and
Cp2ZrBu2, and the solution was stirred at room temper-
ature for 24 h, allylated compound 7e was obtained in
57% yield.
It was expected that if a chiral amine is used for
formation of imine,11 diastereoselective cyclization will
occur in the reaction of ene-imine with Cp2ZrBu2 (Scheme
5). When a THF solution of ene-imine 1f, which was
prepared from 3a and (R)-phenethylamine 9a , was
stirred in the presence of Cp2ZrBu2 at room temperature
for 18 h, cyclized compounds trans-8f, trans-8f ′, and cis-
8f were obtained in 39%, 22%, and 17% yields, respec-
tively, after hydrolysis. The stereochemistry of each of
these products was determined by NOE, and the ratio of
trans-8f to cis-8f was determined to be 3:1. A longer
reaction time did not affect the yield of each product (run
2). When the reaction mixture was refluxed for 18 h, the
ratio of trans-8 to cis-8 changed to 1:4 and cis-8f was
obtained as the major product in 53% yield along with
cis-8f ′ in 17% yield (Table 2, run 1). The results are
interesting because when the reaction of 1a with Cp2-
ZrBu2 was carried out in THF upon heating, trans-2a was
obtained as the major product (Scheme 2). However, the
major product was a cis-form when the THF solution of
5f was refluxed for 18 h.
It has been reported that zirconium-mediated cycliza-
tion of ene-hydrazone using Cp2ZrBu2 gave a cyclized
compound having cis-substituents,8 which means that cis-
azazirconacycle was formed as an intermediate (eq 1).
In this case, the steric effect between the alkene part and
the hydazone part of ene-hydrazone should form cis-
azazirconacyclopentene.
Rea ctivities of Aza zir con a cycles. The remarkable
feature of zirconium-mediated cyclization is that various
reagents could be reacted with intermediary zirconacycle
to give cyclic compounds having functionalized substit-
uents by a one-pot reaction (Scheme 4). When the
atmosphere of the vessel used for formation of azazir-
conacyclopentane 5a , prepared from 1a and Cp2ZrBu2,
was changed from argon to oxygen and the solution was
stirred at room temperature overnight, only small amounts
of alcohols trans-6a and cis-6a were obtained (2% and
7% yields, respectively). Thus, the transmetalation of
azazirconacyclopentane into a nickel complex was carried
out.9 To a THF solution of azazirconacyclopentanes 5a
was added NiCl2(PPh3)2 (1.2 equiv), and the solution was
stirred at room temperature for 12 h under an oxygen
atmosphere. After the usual workup, the desired trans-
(10) (a) Takahashi, T.; Kotora, M.; Suzuki, N. Organometallics 1994,
13, 4183. (b) Kasai, K.; Kotora, M.; Suzuki, N.; Takahashi, T. J . Chem.
Soc., Chem. Commun. 1995, 109. (c) Honda, T.; Mori, M. Organome-
tallics 1996, 15, 5664.
(11) Intermolecular coupling raction of chiral imine and aldehyde
using Cp2ZrBu2: Ito, H.; Tagutchi, T.; Hanzawa, Y. Tetrahedron Lett.
1992, 33, 4469.
(9) Takahashi, T.; Tsai, F. Y.; Li, Y.; Nakajima, K.; Kotora, M. J .
Am. Chem. Soc. 2000, 122, 4994.
6240 J . Org. Chem., Vol. 69, No. 19, 2004

Cyclization of Ene-Imine Using Dibutylzirconocene
TABLE 3. Dia ster eoselective Zir con iu m -Med ia ted
Cycliza tion
SCHEME 6. Attem p t of Hyd ogen olysis of Am in e 8
Presumably, formation of cis-zirconacycle would be
accelerated by the large substituent like the tert-butyl
group on the nitrogen.
To examine the effect of various chiral imines with Cp2-
ZrBu2, their ratios were determined by HPLC. Hydro-
genolysis of N-benzyl and O-benzyl groups was carried
out using Pd(OH)2 on charcoal.12 Although the starting
material 8 disappeared on TLC, the desired amine-
alcohol could not be isolated (Scheme 6). Various at-
tempts were made, but the results were fruitless.
Thus, the starting material was changed from 3a to
3b, and the various chiral amines 9 were used for this
reaction. The reactions were carried out at room tem-
perature or upon heating in THF for 18 h. The yields of
the diastereomers were determined as follows. A mixture
of diastereomers 11 was hydrogenated using Pd(OH)2 on
charcoal followed by benzoylation to give trans-12, trans-
12′, cis-12, and cis-12′. The trans- and cis-isomers were
separated by column chromatography on silica gel. The
ee’s of trans-12 and cis-12 were determined by HPLC
(trans-12, DAICEL CHIRAPAK AD, hexane/iPrOH ) 95/
5; cis-12. DAICEL CHIRAPAK AS, hexane/iPrOH ) 9/1),
and the yield of each diastereomer could be calculated
from the results of HPLC. The results are shown in Table
2. When the reaction was carried out at room tempera-
ture, the larger substituents on the nitrogen decreased
the yields of the trans-cyclopentane derivative, but the
major product was trans-12 in each case (Table 3, runs
1, 3, 5, and 7). The reaction was carried out upon heating
in THF to give cis-12, but a relatively amount of cis-12′
was formed in each case (runs 2, 4 and 8). In the case of
amine 9d ,13 the yields of trans-12, trans-12′, cis-12, and
cis-12′ were almost same when the reaction was carried
out at room temperature and upon heating (runs 5 and
6).
yield (%)a of
temp
ratio of
run
(°C) total trans-12 trans-12′ cis-12 cis-12′ trans:cis
1
2
3
4
5
6
7
8
9
9b rt
9b reflux
9c rt
9c reflux
9d rt
9d reflux
9e rt
100
94
100
95
99
87
98
84
75
44
7
20
6
17
7
14
16
15
4
28
56
35
59
30
28
38
59
52
63
8
25
7
18
8
8
5
13
13
9
1.8:1
1:6.1
1.4:1
1:4.3
1.4:1
1.4:1
1.3:1
1:6.1
1:6.5
1:2.8
41
11
39
35
40
8
9e reflux
9e refluxb
7
3
10 9e
98
16
10
a
All reactions were carried out using 1.3 equiv of Cp2ZrCl2 in
b
THF for 18 h. Reaction time: 65 h.
F IGURE 3.
Presumably, the methoxy group of the substituent
coordinates to the zirconium metal as shown in Figure
3, and each zirconacyclopentane could not isomerize even
upon heating. The best results of the ratio of cis- to trans-
substituents and the yield of cis-12 were obtained when
amine 9e14 was used and the reaction was carried out
upon heating (run 8). Thus, the reaction of 9e with Cp2-
ZrBu2 was further examined. A THF solution of zircona-
cycle 10e was refluxed for 65 h, but the yield was not
improved (run 9). When the reaction was carried out at
40 °C for 18 h, cis-12 was obtained in 63% yield (run 10).
The absolute configuration of cis-13 was determined
using Kusumi’s method (Scheme 7).15 Amine cis-11 was
hydrogenated, and the resultant cis-13 was treated with
(S)- and (R)-MTPA chlorides in the presence of pyridine
to give cis-(S)-14 and cis-(R)-14, respectively. From the
differences between δ values of 1H NMR spectra, the
absolute configuration of the major isomer cis-11 was
determined to be (1R,2S). In a similar manner, the minor
isomer of trans-11 was also determined to be (1S,2S).
The possible reaction course is shown in Scheme 8.
When the imine part of ene-imine 15e reacts with Cp2Zr
to form azazirconacyclopropanes, there are two pathways,
path a and path b. Then insertion of the alkene part into
the carbon-zirconium bond of azazirconacyclopropane
16e produces azazirconacyclopentanes trans-10e and cis-
10e. In a similar process, trans-10e′ and cis-10e′ should
be formed. In these pathways, diastereoselection would
occur at the first stage, when the imine part reacts with
Cp2Zr to give azazirconacyclopropane. Presumably, the
most stable conformation of 15e should be 15e-I, not 15e-
(12) Bernotas, R. C.; Cube, R. V. Synth. Commun. 1990, 20, 1209.
(13) Meyers, A. I.; Poindexter, G. S.; Brich, Z. J . Org. Chem. 1978,
43, 892.
(14) Miller, S. A.; Chamberlin, A. R. J . Org. Chem. 1989, 54, 2502.
(15) Kusumi, T.; Fukushima, T.; Ohtani, I.; Kakisawa, H. Tetrahe-
dron Lett. 1991, 25, 2942.
J . Org. Chem, Vol. 69, No. 19, 2004 6241

Makabe et al.
SCHEME 7. Deter m in a tion of Absolu te
Con figu r a tion
F IGURE 4.
group or the silyloxyethyl group in 15e-III. (Figure 4).
Thus, Cp2Zr would attack from the backside of this plane
(path a in Scheme 8, the proton side of 15e-I in Figure
4). In the early stage of this reaction at room tempera-
ture, trans-zirconacycle trans-10e is formed from 16e as
a kinetic product. However, when the THF solution of
the reaction mixture was refluxed for 18 h, cis-11e was
formed as a thermodynamic product. The reason for
II or 15e-III, because of the electronic repulsion between
the phenyl group and the lone pair of nitrogen in 15e-II
or the steric interaction between Cp2Zr and the phenyl
SCHEME 8. P ossible Rea ction Cou r se
6242 J . Org. Chem., Vol. 69, No. 19, 2004

Cyclization of Ene-Imine Using Dibutylzirconocene
(s, 4 H), 4.49 (s, 2 H), 5.00-5.02 (m, 1 H), 5.04 (s, 1 H), 5.74-
5.84 (m, 1 H), 7.83 (dt, J ) 1.6, 5.6 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ 37.7, 39.9, 42.4, 65.3, 73.0, 73.2, 118.1, 126.7,
127.3 (x 2), 127.9 (x 4), 128.2 (x 4), 128.3 (x 2), 128.3 (x 2),
133.8 (× 2), 138.5, 164.3; LRMS (EI) m/z 428 (M+ + H), 386,
350, 336, 306, 133, 91; HRMS (EI) calcd for C29H33NO2 (M+)
427.2511, found 427.2520.
Gen er a l P r oced u r e for Zir con iu m -Med ia ted Cycliza -
tion of En e-Im in e. To a solution of Cp2ZrCl2 (1.3 equiv) in
THF (0.1 M) was added BuLi (1.6 M solution in hexane, 2.6
equiv) at -78 °C, and the solution was stirred at the same
temperature for 1 h. To this solution was added at -78 °C
ene-imine 1 (1 equiv), which was prepared from 3a and PhCH2-
NH2 (1 equiv) in benzene in the presence of MgSO4 at room
temperature, and the solution was stirred at room temperature
for the appropriate hours. Saturated NH4Cl solution was
added, and the solution was stirred at room temperature for
2 h. The aqueous layer was made basic by K2CO3, and
extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and concentrated. The residue was
purified by flash column chromatography on silica gel to give
the cyclized product.
formation of cis-11e as a major product upon heating is
presumably the steric effect of the substituent on the
nitrogen. When the reaction mixture was further refluxed
for a long time, the yield of cis-11e decreased but that of
cis-11e′ was not changed (Table 3, run 9). Presumably,
zirconacycles trans-10e and cis-10e were not stable under
these reaction conditions. It is not clear whether cis-11e
was gradually changed to cis-11e′ or cis-11 was decom-
posed under these reaction conditions.
Con clu sion
Little is known about zirconium-mediated cyclization
of ene-imine. The reaction of ene-imine 1a with Cp2ZrBu2
at room temperature gave cyclopentane derivatives trans-
2a and cis-2a , the major product being a compound
having trans-substituents. It was interesting that the
cyclization is affected by the bulkiness of the substituents
on nitrogen. Cyclization of ene-imine 1e having a tert-
butyl group on nitrogen gave only cis-2e. The intermedi-
ary azazirconacyclopentane is very useful in synthetic
organic chemistry. Using transmetalation from azazir-
conacycle to other metals, various functionalized cyclo-
pentylamine derivatives should be formed. Since this
reaction was affected by the substituents on nitrogen,
diastereoselective cyclization occurred and cis-fused aza-
zirconacycle was formed as a major product upon heating.
Thus, optically active cyclopentylamine derivative cis-13
was obtained in good yield. Zirconium-catalyzed asym-
metric cyclization has already been developed, and this
reaction had been carried out using a catalytic amount
of EBTHIZr(BINOL) in the presence of an excess amount
of Grignard reagent.16 However, Grignard reagent cannot
be used for the reaction of ene-imine cyclization. Thus,
zirconium-mediated diastereoselective cyclization should
be a useful tool for the synthesis of a chiral cyclized
product.
Ben zyl-(4,4-bisben zyloxym eth yl-2-m eth ylcyclop en tyl)-
a m in e (tr a n s-2a , cis-2a ). trans-2a : IR (neat) ν 2919, 2856,
1
1095 cm-1; H NMR (400 MHz, CDCl3) δ 0.97 (d, J ) 6.4 Hz,
3 H), 1.10 (dd, J ) 10.6, 12.4 Hz, 1 H), 1.27 (dd, J ) 9.6, 13.2
Hz, 1 H), 1.40 (bs, 1 H), 1.71-1.78 (m, 1 H), 1.81 (dd, J ) 7.2,
13.2 Hz, 1 H), 2.04 (dd, J ) 7.2, 13.2 Hz, 1 H), 2.58 (dd, J )
9.2, 9.6 Hz, 1 H), 3.33 (s, 2 H), 3.38 (dd, J ) 8.8, 12.2 Hz, 2 H),
3.67 (d, J ) 13.2 Hz, 1 H), 3.83 (d, J ) 12.8 Hz, 1 H), 4.51 (s,
4 H), 7.22-7.34 (m, 15 H); 13C NMR (100 MHz, CDCl3) δ 17.9,
39.7, 39.8, 44.5, 52.7, 64.9, 73.1, 73.2, 75.2, 75.4, 126.7, 127.2
(x 2), 127.3 (x 4), 127.9 (x 2), 128.2 (x 4), 127.3 (x 2), 138.6 (x
2), 140.8; LRMS (FAB) m/z 430 (M+ + H), 338, 91; HRMS
(FAB) calcd for C29H36NO2 (M+ + H) 430.2746, found 430.2726.
cis-2a : IR (neat) ν 2922, 2856, 1095 cm-1; 1H NMR (400 MHz,
CDCl3) δ 0.93 (d, J ) 7.2 Hz, 3 H), 1.39 (dd, J ) 7.6, 13.6 Hz,
1 H), 1.58 (dd, J ) 6.0, 13.2 Hz, 1 H), 1.64-1.71 (m, 2 H),
2.10-2.20 (m, 1 H), 3.04 (dd, J ) 6.0 Hz, 12 Hz, 1 H), 3.33 (s,
2 H), 3.45 (s, 2 H), 3.63 (d, J ) 13.2 Hz, 1 H), 3.75 (d, J ) 13.2
Hz, 1 H), 4.51 (d, J ) 2.0 Hz, 4 H), 7.22-7.34 (m, 15 H); 13C
NMR (100 MHz, CDCl3) δ 14.6, 36.5, 37.4, 38.6, 45.7, 52.2,
61.1, 73.1, 73.2, 75.2, 75.7, 126.6, 127.2 (x 2), 127.3 (x 4), 127.4
(x 2), 128.0 (x 4), 128.2 (x 2), 138.8 (x 2), 141.0; LRMS (FAB)
m/z 430 (M+ + H), 338, 91; HRMS (FAB) calcd for C29H36NO2
(M+ + H) 430.2746, found 430.2765.
Exp er im en ta l Section
Gen er a l P r oced u r e for Syn th esis of Im in es (1a -e)
fr om Ald eh yd es (3a ) a n d Am in es. A solution of ene-
aldehyde 3a (1 equiv) and amine (1 equiv) in benzene (0.1 M)
was stirred in the presence of MgSO4 (10 equiv) at room
temperature overnight. The solution was filtered, and the
filtrate was concentrated. The residue used without further
purification.
Note Ad d ed a fter ASAP P ostin g. There was an
error in the cyclic intermediate in the Table of Contents
graphic in the version posted ASAP August 17, 2004; the
corrected version was posted September 1, 2004.
Ben zyl-(3,3-bisben zyloxym eth yl-h ex-5-en ylid en e)a m -
in e (1a ). IR (neat) ν 3063, 3028, 2857, 1662, 1495, 1453, 1364,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for compounds 1a -f, trans-2b-d ,
cis-2b-e, trans- and cis-6a , 7e, cis-8f and -8f ′, trans-8f and
-8f ′, trans- and cis-12, trans-(R)-14, 18-23, 3a , and 3b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
1099 cm-1; H NMR (400 MHz, CDCl3) δ 2.21 (d, J ) 7.6 Hz,
2 H), 2.39 (d, J ) 5.6 Hz, 2 H), 3.39 (d, J ) 2.8 Hz, 4 H), 4.45
(16) (a) Yamaura, Y.; Hyakutake, M.; Mori, M. J . Am. Chem. Soc.
1997, 119, 7615. (b) Yamaura, Y.; Mori, M. Tetrahedron Lett. 1999,
40, 3221.
J O049662N
J . Org. Chem, Vol. 69, No. 19, 2004 6243