Zirconium-mediated intramolecular cyclization of yne-imine

Article abstract of DOI:10.1055/s-2004-822398

Successful zirconium-mediated intramolecular cyclization of yne-imine was achieved. When a crude imine, which was prepared from yne-aldehyde and primary amine in the presence of MgSO₄, was treated with Cp ₂ZrBu₂ at room temperature for several hours, a cyclopentane derivative was obtained in high yield. The intermediary azazirconacycle was treated with D₃O⁺, I₂ or t-BuNC to give the desired deuterated, iodinated or formylated product, respectively, at the vinyl position in good yield. Transmetalation of zirconacycle to CuCl was carried out and then allyl chloride was added to give an allylated compound in good yield. Selective bond fission of a zirconium-nitrogen bond of the azazirconacycle was achieved by treatment of the azazirconacycle with acyl halide to give an N-acylated vinylzirconium compound.

Full text of DOI:10.1055/s-2004-822398

PAPER
1369
Zirconium-Mediated Intramolecular Cyclization of Yne-Imine
Z
irconium-MediatedIn
u
tramolecula
n
Cyclization
e
of
Y
ne-Im
y
ine oshi Makabe, Yoshihiro Sato, Miwako Mori*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
E-mail: mori@pharm.hokudai.ac.jp
Received 2 May 2004
Dedicated to Professor Mukaiyama on the occasion of his 77th birthday.
equivalent), which was prepared from yne-aldehyde (1
equivalent) and benzylamine (1 equivalent) in the pres-
ence of MgSO4, and the solution was stirred at room tem-
perature for 1.5 hours, cyclopentane derivative 4a was
Abstract: Successful zirconium-mediated intramolecular cycliza-
tion of yne-imine was achieved. When a crude imine, which was
prepared from yne-aldehyde and primary amine in the presence of
MgSO4, was treated with Cp2ZrBu2 at room temperature for several
hours, a cyclopentane derivative was obtained in high yield. The in- obtained in 91% yield after hydrolysis. The stereochemis-
termediary azazirconacycle was treated with D3O+, I2 or t-BuNC to
give the desired deuterated, iodinated or formylated product, re-
spectively, at the vinyl position in good yield. Transmetalation of
carried out under similar conditions, and 10% DCl solu-
zirconacycle to CuCl was carried out and then allyl chloride was
added to give an allylated compound in good yield. Selective bond
try of 4a was determined by an NOE experiment, and an
E-olefin was formed stereoselectively. The reaction was
tion was added to the reaction mixture to give deuterated
compound 4a-D in 82% yield (D-content, 95%). When
the reaction of yne-imine 3a with Cp2ZrBu2 was carried
out in a similar manner and then iodine was added, iodi-
nated compound 5a was obtained in 64% yield
(Scheme 2). These results indicated that the reaction pro-
ceeded in a high stereoselectivity.
fission of a zirconium-nitrogen bond of the azazirconacycle was
achieved by treatment of the azazirconacycle with acyl halide to
give an N-acylated vinylzirconium compound.
Key words: yne-imines, cyclization, zirconium
The possible reaction course is shown in Scheme 3. Pre-
sumably, an imine part of yne-imine 3a at first reacts with
Cp2ZrBu2 to give azazirconacyclopropane 6a. Then inser-
tion of the alkyne part of 6a into a zirconium-carbon bond
of azazirconacyclopropane gives azazirconacyclopentene
7a. Deuterolysis of azazirconacyclopentene 7a affords
deuterated compound 4a-D in a highly stereoselective
manner.
Since Negishi and Takahashi reported the generation of
Cp2ZrBu2 from Cp2ZrCl2 and BuLi,1 many reactions us-
ing this reagent have been developed.2 Intramolecular
coupling reaction of diyne,3 diene4 and enyne5 using
Cp2ZrBu2 is very effective for the formation of cyclic
compounds. The coupling reaction of multiple bonds con-
taining nitrogen is very attractive because an azazircona-
cycle is formed as an intermediate, and various
heterocycles or nitrogen-containing cyclized compounds
have been synthesized. As multiple bonds, nitrile,6 isocy-
anate,7 and hydrazone8 can be reacted with Cp2ZrBu2, and
various cyclic compounds have been formed. Living-
house reported the coupling reaction of ene- or yne-hydra-
zone with Cp2ZrBu2 and obtained cyclopentane
derivatives having cis substituents.8 However, little is
known about the reaction of ene- or yne-imines using
Cp2ZrBu2. Here we report the coupling reaction of yne-
imines generated from yne-aldehydes and the reactivity of
the formed azazirconacyclopentenes (Scheme 1).
Various yne-imines 3 were synthesized from yne-alde-
hydes, and reactions of yne-imines 3 with Cp2ZrBu2 were
carried out. When yne-imine 3b, which was prepared
from yne-aldehyde 1b and benzylamine in the presence of
MgSO4, was reacted with Cp2ZrBu2, cyclopentane deriv-
ative 4b was obtained in 88% yield after hydrolysis. In a
similar treatment of yne-imine 3c with Cp2ZrBu2, cyclo-
pentane derivatives 4c and 4c¢ were obtained in 23% and
68% yields, respectively. Compound 4c¢ should be ob-
tained during hydrolysis of azazirconacyclopentene 7c.
Presumably, coordination of oxygen of the silyloxy group
in 7c to zirconium metal accelerates the desilylation of
azazirconacyclopentene 7c (Scheme 4).
The remarkable feature of zirconium-mediated cycliza-
tion is that various reagents could be reacted with interme-
diary zirconacycle to give cyclic compounds having
functionalized substituents by a one-pot reaction
(Scheme 5). Thus, t-BuNC was added to a solution of aza-
zirconacyclopentene 7a (prepared from 3a). In this case, a
carbon-carbon bond formation occurs on the vinylic car-
bon to give 8 in 37% yield. Presumably, insertion of
isonitrile into the carbon-zirconium bond of azazir-
conacyclopentene 7a gives azazirconacyclohexene 9, the
imine nitrogen of which coordinates to the zirconium met-
al.9 The nitrogen carrying the benzyl group attacks the
imine carbon to give azazirconacyclopropane 10, which is
Scheme 1 Formation of azacirconacyclopentene
When to a THF solution of Cp2ZrBu2, prepared from
Cp2ZrCl2 (1.3 equivalents) and BuLi (2.6 equivalents),
was added at –78 °C a THF solution of yne-imine (1
SYNTHESIS 2004, No. 9, pp 1369–1374
x
x
.
x
x
.2
0
0
4
Advanced online publication: 08.06.2004
DOI: 10.1055/s-2004-822398; Art ID: C03804SS
© Georg Thieme Verlag Stuttgart · New York

1370
M. Makabe et al.
PAPER
Scheme 2 Reaction of yne-imine with Cp2ZrBu2
Scheme 3 Possible reaction course
in a state of equilibrium with imine-zirconium complex
11. Hydrolysis of 11 affords 8 via 12.
Next, a carbon-carbon bond-forming reaction to azazir-
conacyclopentene using transmetalation was carried out.
When to the solution of azazirconacyclopentene 7a,
which was prepared from yne-imine 3a and Cp2ZrBu2,
were added CuCl and then allyl chloride, allylated com-
pound 13 was obtained in 47% yield (Scheme 5). In this
case, desilylation of vinylsilane occurred though the rea-
son for this is not clear.
Subsequently, selective nitrogen-zirconium bond fission
was investigated. If azazirconacyclopentene 7a is treated
with acyl halide, acylation of nitrogen should occur10 and
the nitrogen-zirconium bond should be cleaved
(Scheme 6). Thus, when to a THF solution of azazircona-
cyclopentene 7a was added acetyl chloride at –78 °C and
the solution was stirred at the same temperature for one
hour, N-acetylated cyclized compound 15a was obtained
in 91% yield after hydrolysis. In a similar manner, when
methylchloroformate was added to the solution of 7a, the
desired compound 15b was obtained in 76% yield. These
results indicated that vinylzirconium chloride 14 should
be formed as an intermediate. This means that various re-
agents can be introduced at the vinylic position. Thus,
when to a THF solution of azazirconacyclopentene 7a was
added acetyl chloride and the solution was stirred at
Scheme 4 Reaction of various yne-imines with Cp2ZrBu2
Synthesis 2004, No. 9, 1369–1374 © Thieme Stuttgart · New York

PAPER
Zirconium-Mediated Intramolecular Cyclization of Yne-Imine
1371
Scheme 6 Selective nitrogen-zirconium bond cleavage of zircona-
cycle
Synthesis of Imines 2 from Aldehydes 1 and Benzyl Amine;
General Procedure
A solution of yne-aldehyde 1 (1 equiv) and benzyl amine (1 equiv)
in benzene (0.1 M) was stirred in the presence of MgSO4 (10 equiv)
at r.t. overnight. Undissolved materials were filtered off, and the fil-
trate was concentrated. The residue was used without further purifi-
cation.
Scheme
reagents
5
Reaction of azacirconacyclopentene with various
Zirconium-Mediated Cyclization of Yne-Imine; General Proce-
dure
–78 °C and then iodine was added, N-acetyl-iodinated
compound 16 was obtained in 58% yield. The results in-
dicated that selective nitrogen-zirconium bond fission oc-
curs and that the two functional groups could be
introduced on the nitrogen and the vinylic positions of
azazirconacyclopentene in a one-pot reaction. Further
studies are in progress.
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 solu-
tion was stirred at the same temperature for 1 h. To this solution was
added yne-imine 3 (1 equiv) at –78 °C and the solution was stirred
at r.t. for the appropriate hours. Saturated NH4Cl solution was add-
ed, and the solution was stirred at r.t. for 2 h. The aqueous layer was
made basic using 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 desired cyclized product.
All manipulations were performed under an argon atmosphere un-
less otherwise stated. Solvents were distilled under an argon atmo-
sphere from Na-ketyl (THF, Et2O, toluene, and benzene), CaH2
(CH2Cl2), or Na (EtOH, MeOH). All other solvents and reagents
were purified when necessary using standard procedures. Column
chromatography was performed on silica gel 60 (Merck, 70–230
mesh), and flash chromatography was performed on silica gel 60
3,3-Bis[(benzyloxy)methyl]-6-(trimethylsilyl)hex-5-ynal (1a)
IR (neat): 3030, 2956, 2859, 1719, 1249, 1097 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.13 (s, 9 H), 2.50 (s, 2 H), 2.51
(s, 2 H), 3.40 (dd, J = 9.2, 12.0 Hz, 4 H), 4.20 (s, 4 H), 7.05–7.18
(m, 10 H), 9.68 (t, J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 0.1 (CH3), 24.7 (CH2), 42.5 (C),
47.0 (CH2), 72.3 (CH2 × 2), 73.4 (CH2 × 2), 87.1 (C), 102.9 (C),
127.4 (CH), 127.5 (CH), 128.3 (CH), 138.0 (C), 201.3 (C).
LRMS (FAB): m/z 409 [M+ + H], 393, 317, 301, 287, 92, 73.
HRMS (FAB): m/z [M+ + H] calcd for C25H33O3Si: 409.2199;
1
(Merck, 230–400 mesh) using the indicated solvent. H and 13C
NMR spectra were recorded on JEOL EX-270 [270 MHz (1H), 67.5
MHz (13C)], JEOL EX-400 [400 MHz (1H), 100 MHz (13C)], or
JEOL AL-400 [400 MHz (1H), 100 MHz (13C)] instruments in
CDCl3 with Me4Si as an internal standard. IR spectra were recorded
on a Perkin Elmer FTIR 1605 spectrometer. Mass spectra were
measured on JEOL DX303, JEOL JMS-700TZ, and JEOL JMS-
FABmate mass spectrometers.
found: 409.2210.
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N-(E)-{(3,3-Bis[(benzyloxy)methyl]-6-(trimethylsilyl)hex-5-yn-
1-ylidene}-1-phenylmethanamine (3a)
silica gel (hexane–EtOAc, 15:1) to give 5a as a colorless oil (100.7
mg, 64%).
IR (neat): 3029, 2956, 2859, 2360, 2172, 1663, 1452, 1364, 1249,
IR (neat): 3027, 2951, 2854, 1496, 1453, 1249, 1098 cm–1.
1098, 1028 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.23 (s, 9 H), 1.85 (dd, J = 5.2,
13.6 Hz, 1 H), 1.93 (dd, J = 7.2, 13.6 Hz, 1 H), 2.12 (br s, 1 H), 2.37
(d, J = 16.0 Hz, 1 H), 2.60 (d, J = 16.0 Hz, 1 H), 3.21 (d, J = 8.8 Hz,
1 H), 3.31 (d, J = 8.8 Hz, 1 H), 3.52 (d, J = 8.4 Hz, 1 H), 2.58 (d,
J = 8.4 Hz, 1 H), 3.65 (dd, J = 12.0, 19.0 Hz, 2 H), 3.66–3.68 (m, 1
H), 4.46 (dd, J = 12.0, 18.8 Hz, 2 H), 4.52 (dd, J = 12.4, 17.2 Hz, 2
H), 7.21–7.33 (m, 15 H).
13C NMR (100 MHz, CDCl3): d = 1.0 (CH3), 37.0 (CH2), 40.2
(CH2), 48.0 (CH2), 51.2 (CH2), 69.0 (CH), 73.0 (CH2), 73.2
(CH2 × 2), 74.1 (CH2), 104.0 (C), 126.8 (CH), 127.3 (CH × 4),
128.2 (CH × 3), 128.5 (CH), 138.5 (C), 138.6 (C), 140.1 (C), 162.5
(C).
1H NMR (400 MHz, CDCl3): d = 0.11 (s, 9 H), 2.45 (s, 2 H), 2.50
(d, J = 5.2 Hz, 2 H), 3.47 (s, 4 H), 4.46 (s, 4 H), 4.49 (s, 2 H), 7.20–
7.36 (m, 15 H), 7.86 (t, J = 5.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 0.4 (CH3), 24.7 (CH2), 39.8
(CH2), 42.5 (C), 65.2 (CH2), 72.6 (CH2 × 2), 73.3 (CH2 × 2), 87.1
(C), 103.6 (C), 126.6 (CH2), 127.2 (CH2 × 2), 127.2 (CH2 × 2),
127.7 (CH2), 128.0 (CH2 × 2), 128.2 (CH2), 138.2 (C × 2), 139.1
(C), 163.7 (CH).
LRMS (EI): m/z 497 [M+], 482, 406, 376, 91.
HRMS (EI): m/z [M+] calcd for C32H39NO2Si: 497.2750; found:
497.2731.
LRMS (EI): m/z 625 [M+], 610 [M+ – Me], 534 [M+ – Bn], 498 [M+
(E)-N-Benzyl-4,4-bis[(benzyloxy)methyl]-2-[(trimethylsilyl)-
methylene]cyclopentanamine (4a)
– I], 91 [Bn].
HRMS (EI): m/z [M+] calcd for C32H40INO2Si: 625.1873; found:
625.1872.
Crude product 4a, which was prepared from 3a (124.4 mg, 0.25
mmol), Cp2ZrCl2 (95 mg, 0.325 mmol), and BuLi (1.49 M, 0.43
mL, 0.65 mmol) was purified by column chromatography on silica
gel (hexane–EtOAc, 10:1) to give 4a as a colorless oil (114.2 mg,
91%).
3,3-Bis[(benzyloxy)methyl]hept-5-ynal (1b)
IR (neat): 3030, 2918, 2858, 1717, 1454, 1364, 1096 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.74 (t, J = 2.4 Hz, 3 H), 2.40 (dd,
J = 2.4, 5.2 Hz, 2 H), 2.49 (d, J = 2.8 Hz, 2 H), 3.47–3.53 (m, 4 H),
4.47 (s, 4 H), 7.23–7.34 (m, 10 H), 9.80 (t, J = 2.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 3.7 (CH3), 23.8 (CH2), 42.8 (C),
47.1 (CH2), 72.4 (CH2 × 2), 73.3 (CH2 × 2), 74.8 (C), 78.5 (C),
127.2 (CH × 2), 127.3 (CH × 2), 128.1 (CH × 2), 137.9 (C × 2),
201.3 (CH).
IR (neat): 3028, 2951, 2853, 1453, 1249, 1099, 838, 734 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.09 (s, 9 H), 1.35 (dd, J = 8.8,
12.8 Hz, 1 H), 1.52 (br s, 1 H), 2.08 (dd, J = 7.6, 13.2 Hz, 1 H), 2.32
(dd, J = 1.6, 16.6 Hz, 1 H), 2.40 (td, J = 1.6, 16.8 Hz, 1 H), 3.33 (s,
2 H), 3.42 (s, 2 H), 3.48 (t, J = 8.0 Hz, 1 H), 3.71 (d, J = 12.8 Hz, 1
H), 3.80 (d, J = 12.8 Hz, 1 H), 4.48 (dd, J = 12.4, 16.0 Hz, 2 H), 4.51
(s, 2 H), 5.46 (q, J = 1.6 Hz, 1 H), 7.20–7.34 (m, 15 H).
LRMS (EI): m/z 350 [M+], 306 [M+ – CH2CHO – H], 259 [M+ –
13C NMR (100 MHz, CDCl3): d = –0.17 (CH3), 37.5 (CH2), 38.4
(CH2), 45.1 (C), 51.8 (CH2), 62.4 (CH), 73.2 (CH2 × 2), 73.3
(CH2 × 2), 119.5 (CH), 126.7 (CH2), 127.3 (CH2 × 2), 127.4 (CH2),
128.0 (CH2), 128.2 (CH2 × 2), 138.6 (C × 2), 140.5 (C), 161.6 (C).
Bn], 229 [M+ – CH2OBn], 107 [OBn], 91 [Bn].
HRMS (EI): m/z [M+] calcd for C23H26O3: 350.1882; found:
350.1885.
LRMS (EI): m/z 499 [M+], 426 [M+ – TMS], 408 [M+ – Bn], 378
(2E)-N-Benzyl-4,4-bis[(benzyloxy)methyl]-2-ethylidenecyclo-
pentanamine (4b)
[M+ – CH2OBn], 106 [BnNH], 91 [Bn], 73 [TMS].
HRMS (EI): m/z [M+] calcd for C32H41NO2Si: 499.2906; found:
IR (neat): 3061, 3028, 2854, 1453, 1363, 1098 cm–1.
499.2920.
1H NMR (400 MHz, CDCl3): d = 1.41 (dd, J = 7.2, 13.0 Hz, 1 H),
1.59 (dd, J = 1.6, 6.8 Hz, 3 H), 1.64 (br s, 1 H), 2.06 (dd, J = 7.2,
13.2 Hz, 1 H), 2.26 (dd, J = 16.8, 18.4 Hz, 2 H), 3.32 (dd, J = 8.8,
12.4 Hz, 2 H), 3.46–3.51 (m, 1 H), 3.48 (dd, J = 8.8, 10.4 Hz, 2 H),
3.71 (d, J = 13.2 Hz, 1 H), 3.79 (d, J = 13.2 Hz, 1 H), 4.49 (s, 2 H),
4.52 (s, 2 H), 5.40–5.43 (m, 1 H), 7.21–7.33 (m, 15 H).
13C NMR (100 MHz, CDCl3): d = 14.5 (CH3), 34.2 (CH2), 39.2
(CH2), 45.5 (C), 51.5 (CH2), 60.7 (CH), 73.1 (CH2), 73.2 (CH2),
73.7 (CH2), 75.0 (CH2), 117.1 (C), 126.7 (CH), 127.2 (CH × 2),
127.3 (CH), 127.4 (CH), 128.0 (CH), 128.2 (CH × 3), 138.6 (C),
138.7 (C), 140.4 (C), 143.7 (C).
(E)-N-Benzyl-4,4-bis[(benzyloxy)methyl]-2-[(trimethylsilyl)-
methylene]cyclopentanamine-d1 (4a-D)
IR (neat): 3028, 2951, 2853, 1453, 1249, 1099, 838, 734 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.09 (s, 9 H), 1.35 (dd, J = 8.0,
13.2 Hz, 1 H), 1.68 (br s, 1 H), 2.08 (dd, J = 8.0, 13.0 Hz, 1 H), 2.32
(d, J = 16.8 Hz, 1 H), 2.30 (td, J = 1.6, 16.8 Hz, 1 H), 3.33 (s, 2 H),
3.42 (s, 2 H), 3.48 (t, J = 8.4 Hz, 1 H), 3.72 (d, J = 8.4 Hz, 1 H), 3.81
(d, J = 13.2 Hz, 1 H), 4.49 (dd, J = 12.4, 15.8 Hz, 2 H), 4.50 (s, 2
H), 7.20–7.34 (m, 15 H).
LRMS (EI): m/z 500 [M+], 427 [M+ – TMS], 409 [M+ – Bn], 393
LRMS (EI): m/z 441 [M+], 413 [M+ – C2H4], 350 [M+ – Bn], 320
[M+ – OBn], 379 [M+ – CH2OBn], 106 [BnNH], 91 [Bn], 73 [TMS].
[M+ – CH2OBn], 91 [Bn].
HRMS (EI): m/z [M+] calcd for C32H40DNO2Si: 500.2968; found:
500.2967.
HRMS (EI): m/z [M+] calcd for C30H35NO2: 441.2668; found:
441.2658.
(2Z)-N-Benzyl-4,4-bis[(benzyloxy)methyl]-2-[iodo(trimethylsi-
lyl)methylene]cyclopentanamine (5a)
3,3-Bis[(benzyloxy)methyl]-7-{[t-butyl(dimethyl)silyl]oxy}-
hept-5-ynal (1c)
To a solution of azazirconacyclopentene 7a, which was prepared
from 3a (124.4 mg, 0.25 mmol), Cp2ZrCl2 (95 mg, 0.325 mmol),
and BuLi (1.49 M, 0.43 mL, 0.65 mmol) in THF (2 mL) was added
I2 (76 mg, 0.3 mmol) in THF (0.5 mL) at –78 °C. The solution was
stirred at r.t. for 2 h. To this solution was added a 20% solution of
Na2S2O3 and the aqueous layer was extracted with EtOAc. The or-
ganic layer was washed with brine, dried over Na2SO4 and concen-
trated. The residue was purified by column chromatography on
IR (neat): 3035, 2928, 2857, 1718, 1454, 1364, 1255, 1079 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.10 (s, 6 H), 0.90 (s, 9 H), 2.50
(s, 2 H), 2.51 (s, 2 H), 3.48–3.54 (m, 4 H), 4.26 (br s, 2 H), 4.47 (s,
4 H), 7.26–7.34 (m, 10 H), 9.79 (t, J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = -5.1 (CH3), 18.25 (C), 23.5 (CH2),
25.7 (CH3), 42.4 (C), 46.8 (CH2), 51.7 (CH2), 72.1 (CH2 × 2), 73.1
Synthesis 2004, No. 9, 1369–1374 © Thieme Stuttgart · New York

PAPER
Zirconium-Mediated Intramolecular Cyclization of Yne-Imine
1373
(CH2 × 2), 80.7 (C), 81.4 (C), 127.0 (CH × 2), 127.1 (CH × 4),
127.8 (CH × 4), 137.6 (C × 2), 200.7 (CH).
LRMS (EI): m/z 480 [M+], 423 [M+ – t-Bu], 348 [M+ – OTBDMS –
H], 331 [M+ – t-Bu – Bn – H], 315 [M+ – t-Bu – OBn – H], 301 [M+
– t-Bu – CH2OBn –H], 91 [Bn].
HRMS (EI): m/z [M+ – t-Bu] calcd for C25H31O4Si: 423.1992;
found: 423.1998.
1H NMR (400 MHz, CDCl3): d = 0.10 (s, 9 H), 1.29 (s, 9 H), 1.52
(dd, J = 8.4, 14.8 Hz, 1 H), 1.68 (br s, 1 H), 1.89 (dd, J = 2.4, 14.8
Hz, 1 H), 2.35 (d, J = 17.2, 1 H), 2.44 (d, J = 17.2 Hz, 1 H), 3.07
(dd, J = 2.4, 8.8 Hz, 1 H), 3.41 (dd, J = 6.8, 9.2 Hz, 2 H), 3.45 (dd,
J = 5.6, 9.6 Hz, 2 H), 3.53 (d, J = 13.2 Hz, 1 H), 3.61 (d, J = 13.2
Hz, 1 H), 4.40 (s, 2 H), 4.43 (s, 2 H), 7.10 (br s, 1 H), 7.20–7.32 (m,
15 H).
13C NMR (100 MHz, CDCl3): d = 0.3 (CH3), 24.7 (CH2), 28.7
(CH3), 37.7 (CH2), 41.9 (C), 50.2 (C), 53.0 (CH2), 60.1 (CH), 72.3
(CH2), 72.7 (CH2), 73.4 (CH2), 73.5 (CH2), 87.3 (C), 104.0 (C),
127.0 (CH), 127.4 (CH × 2), 127.5 (CH × 2), 128.1 (CH), 128.2
(CH × 2), 128.4 (CH), 138.2 (C), 138.3 (C), 139.8 (C), 174.1 (C).
LRMS (EI): m/z 598 [M+], 625 [M+ – Me], 498 [M+ – CONHt-Bu],
106 [BnNH], 91 [Bn].
(2E)-N-Benzyl-4,4-[(benzyloxy)methyl]-2-(2-{[t-butyl(dimeth-
yl)silyl]oxy}ethylidene)cyclopentanamine (4c) and (2E)-2-{2-
(Benzylamino)-4,4-bis[(benzyloxy)methyl]cyclopentyl-
idene}ethanol (4c¢)
4c
IR (neat): 3029, 2952, 2927, 2855, 1454, 1096, 835 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.06 (s, 6 H), 0.89 (s, 9 H), 1.40
(dd, J = 7.6, 13.2 Hz, 1 H), 1.75 (br s, 1 H), 2.06 (dd, J = 7.2, 13.2
Hz, 1 H), 2.26 (br t, J = 20.4 Hz, 2 H), 3.31 (t, J = 9.6 Hz, 2 H), 3.45
(dd, J = 8.8, 12.0 Hz, 2 H), 3.56 (t, J = 7.2 Hz, 1 H), 3.73 (d,
J = 13.2 Hz, 1 H), 3.81 (d, J = 13.2 Hz, 1 H), 4.15 (d, J = 4.8 Hz, 2
H), 4.44–4.51 (m, 4 H), 5.53 (br s, 1 H), 7.23–7.33 (m, 15 H).
HRMS (EI): m/z [M+] calcd for C37H50N2O3Si: 598.3591; found:
598.3591.
(2Z)-N-Benzyl-4,4-bis[(benzyloxy)methyl]-2-but-3-en-1-
ylidenecyclopentanamine (13)
To a solution of azazirconacyclopentene 7a, which was prepared
from 3a (50 mg, 0.1 mmol), Cp2ZrCl2 (38 mg, 0.13 mmol), and
BuLi (2.6 M, 0.10 mL, 0.26 mmol) in THF (0.9 mL) were added
CuCl (19.8 mg, 0.2 mmol) and allyl chloride (16 mL, 0.2 mmol).
The solution was stirred at r.t. for 24 h. To this solution was added
an aq solution of NH4Cl and the aqueous layer was extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel (hexane–EtOAc, 10:1) to give 13 as a
colorless oil (22.0 mg, 47%).
13C NMR (100 MHz, CDCl3): d = –-5.0 (CH3), 18.5 (C), 26.1
(CH3), 45.4 (C), 51.4 (CH2), 60.3 (CH2), 60.6 (CH), 73.2 (CH2),
73.2 (CH2), 73.6 (CH2), 74.8 (CH2), 121.7 (CH), 126.8 (CH2),
127.3 (CH), 127.4 (CH × 3), 128.0 (CH), 128.2 (CH × 2), 128.3
(CH), 138.4 (C × 2), 140.1 (C), 146.4 (C).
LRMS (EI): m/z 571 [M+], 556 [M+ – Me], 480 [M+ – Bn], 450 [M+
– CH2OBn], 426 [M+ – OCH2TBDMS], 91 [Bn].
HRMS (EI): calcd [M+] for C36H49NO3Si: 571.3482; found:
571.3468.
IR (neat): 3042, 2924, 2856, 1635, 1454, 1382 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.58 (br s, 1 H), 1.67 (dd, J = 3.2,
13.8 Hz, 1 H), 1.88 (dd, J = 7.0, 13.8 Hz, 1 H), 2.19 (d, J = 15.2 Hz,
1 H), 2.47 (d, J = 15.2 Hz, 1 H), 2.74 (br s, 2 H), 3.54 (dd, J = 8.4,
15.2 Hz, 2 H), 3.61–3.73 (m, 5 H), 4.48 (s, 2 H), 4.52 (s, 2 H), 4.92–
4.99 (m, 2 H), 5.31 (dd, J = 6.4, 6.8 Hz, 1 H), 5.73–5.81 (m, 1 H),
7.25–7.29 (m, 15 H).
13C NMR (100 MHz, CDCl3): d = 33.1 (CH2), 39.1 (CH2), 39.2 (C),
46.2 (CH2), 51.4 (CH), 56.8 (CH2), 73.1 (CH2), 73.3 (CH2), 73.4
(CH2), 74.8 (CH2), 114.4 (CH2), 121.6 (C), 126.6 (CH), 127.1
(CH × 2), 127.2 (CH × 2), 128.0 (CH × 2), 128.1 (CH × 2), 137.1
(C), 138.6 (C), 140.4 (C), 144.3 (C).
4c¢
IR (neat): 3299, 3028, 2854, 1453, 1097, 740 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.41 (dd, J = 7.6, 12.8 Hz, 1 H),
1.60 (br s, 2 H), 2.08 (dd, J = 7.2, 13.0 Hz, 1 H), 2.27 (d, J = 6.8 Hz,
1 H), 2.34 (d, J = 6.8 Hz, 1 H), 3.31 (s, 2 H), 3.45 (dd, J = 10.0, 10.8
Hz, 2 H), 3.56 (t, J = 7.2 Hz, 1 H), 3.73 (d, J = 12.8 Hz, 1 H), 3.81
(d, J = 12.8 Hz, 1 H), 4.11 (d, J = 6.4 Hz, 2 H), 4.49 (d, J = 11.2 Hz,
4 H), 5.61 (br s, 1 H), 7.23–7.33 (m, 15 H).
13C NMR (100 MHz, CDCl3): d = 34.1 (CH2), 38.6 (CH2), 45.4 (C),
51.4 (CH2), 60.3 (CH2), 60.6 (CH), 73.2 (CH2), 73.2 (CH2), 73.6
(CH2), 74.8 (CH2), 121.7 (CH), 126.8 (CH), 127.3 (CH), 127.4
(CH × 3), 128.0 (CH), 128.2 (CH × 2), 128.3 (CH), 138.4 (C × 2),
140.1 (C), 146.4 (C).
LRMS (EI): m/z 467 [M+], 426 [M+ – C3H5], 376 [M+ – Bn], 269
[M+ – OBn –Bn], 91 [Bn].
HRMS (EI): m/z [M+] calcd for C32H37NO2: 467.2824; found:
467.2824.
LRMS (EI): m/z 457 [M+], 426 [M+ – CH2OH], 480 [M+ – Bn], 336
[M+ – Bn], 318 [M+ – CH2OH – Bn – H], 108 [BnOH], 91 [Bn].
HRMS (EI): m/z [M+ – CH2OH] calcd for C29H32NO2: 426.2433;
found: 426.2442.
N-Benzyl-N-{(2E)-4,4-bis[(benzyloxy)methyl]-2-[(trimethylsi-
lyl)methylene]cyclopentyl}acetamide (15a)
To a solution of azazirconacyclopentene 7a, which was prepared
from 3a (50 mg, 0.1 mmol), Cp2ZrCl2 (38 mg, 0.13 mmol), and
BuLi (2.6 M, 0.10 mL, 0.26 mmol) in THF (0.9 mL), was added
AcCl (10 ml, 0.14 mL) at –78 °C and the solution was stirred at the
same temperature for 1 h and then at r.t. for 1 h. To this solution was
added a sat. solution of NH4Cl and the solution was stirred at r.t. for
several hours. The aqueous layer was made basic using a NaHCO3
solution and extracted with EtOAc. The organic layer was washed
with brine, dried over Na2SO4 and concentrated. The residue was
purified by column chromatography on silica gel (hexane–EtOAc,
10:1) to give 15a as a colorless oil (49.3 mg, 91%).
(2E)-2-{2-(Benzylamino)-4,4-bis[(benzyloxy)methyl]cyclopen-
tylidene}-N-(t-butyl)-2-(trimethylsilyl)acetamide (8)
To a solution of azazirconacyclopentene 7a, which was prepared
from 3a (50 mg, 0.1 mmol), Cp2ZrCl2 (38 mg, 0.13 mmol) and BuLi
(2.6 M, 0.10 mL, 0.26 mmol) in THF (0.9 mL) was added t-BuNC
(34 mL, 0.25 mmol) and the solution was stirred at r.t. for 1 h and
then at 40 °C for 1 h. To the solution was added a 20% solution of
HCl and the solution was stirred at r.t. overnight. The aqueous layer
was made basic using K2CO3 and extracted with EtOAc. The organ-
ic layer was washed with brine, dried over Na2SO4 and concentrat-
ed. The residue was purified by column chromatography on silica
gel (hexane–EtOAc, 10:1) to give 8 as a colorless oil (21.1 mg,
35%).
IR (neat): 3027, 2951, 2855, 1652, 1098 cm–1.
1H NMR [400 MHz, (CD3)2SO, 150 °C]: d = 0.07 (s, 9 H), 1.62 (br
t, J = 12.2 Hz, 1 H), 1.84 (dd, J = 8.3, 12.7 Hz, 1 H), 2.01 (s, 3 H),
2.37 (br s, 2 H), 3.34 (s, 2 H), 3.38 (s, 2 H), 4.17 (d, J = 16.6 Hz, 1
IR (neat): 3328, 2923, 2854, 1677, 1511, 1453, 1364, 1249, 1097,
843 cm–1.
Synthesis 2004, No. 9, 1369–1374 © Thieme Stuttgart · New York

1374
M. Makabe et al.
PAPER
H), 4.43 (s, 2 H), 4.48 (s, 2 H), 4.61 (d, J = 16.6 Hz, 1 H), 5.11 (br
s, 1 H), 5.21 (br d, J = 2.4 Hz, 1 H), 7.19–7.30 (m, 15 H).
LRMS (EI): m/z 541 [M+], 526 [M+ – Me], 450 [M+ – Bn], 91 [Bn],
(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, 11, 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. Tetrahedron 1995,
51, 4495. (m) Mori, M.; Kuroda, S.; Zhang, C.-S.; Sato, Y.
J. Org. Chem. 1997, 62, 3263.
73 [TMS].
HRMS (EI): m/z [M+] calcd for C34H43NO3Si: 541.3012; found:
541.3022.
(E)-Methyl Benzyl{[2E)-4,4-bis[(benzyloxy)methyl]-2-[(tri-
methylsilyl)methylene]cyclopentyl}carbamate (15b)
IR (neat): 3030, 2953, 2857, 1699, 1453, 1246, 1100 cm–1.
1H NMR [400 MHz, (CD3)2SO, 100 °C]: d = 0.04 (br s, 9 H), 1.61
(dd, J = 11.2, 12.7 Hz, 1 H), 1.77 (dd, J = 8.3, 12.7 Hz, 1 H), 2.29
(d, J = 17.1 Hz, 1 H), 2.36 (td, J = 2.0, 17.1 Hz, 1 H), 3.32 (d,
J = 2.4 Hz, 4 H), 3.60 (s, 3 H), 4.18 (d, J = 16.1 Hz, 1 H), 4.42 (s, 2
H), 4.46 (s, 2 H), 4.46 (d, J = 16.1 Hz, 1 H), 4.89 (br t, J = 10.2 Hz,
1 H), 5.16 (br d, J = 2.02 Hz, 1 H), 7.19–7.32 (m, 15 H).
LRMS (EI): m/z 557 [M+], 542 [M+ – Me], 466 [M+ – Bn], 436 [M+
– CH2OBn], 91 [Bn], 73 [TMS].
HRMS (EI): m/z [M+] calcd for C34H43NO4Si: 557.2961; found:
557.2979.
(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.
N-Benzyl-N-{(2Z)-4,4-bis[(benzyloxy)methyl]-2-[iodo(tri-
methylsilyl)methylene]cyclopentyl}acetamide (16)
IR (neat): 3030, 2953, 2857, 1699, 1453, 1246, 1100 cm–1.
1H NMR [400 MHz, (CD3)2SO, 150 °C]: d = 0.21 (s, 9 H), 1.69 (dd,
J = 8.8, 13.7 Hz, 1 H), 1.97 (m, 1 H), 2.11 (s, 3 H), 2.37 (br d,
J = 15.6 Hz, 1 H), 2.60 (br d, J = 15.6 Hz, 1 H), 3.24 (dd, J = 9.3,
13.2 Hz, 2 H), 3.29 (dd, J = 9.3, 16.1 Hz, 2 H), 3.36 (d, J = 16.4 Hz,
1 H), 4.41 (s, 2 H), 4.43 (s, 2 H), 4.57 (d, J = 16.1 Hz, 1 H), 4.64 (br
t, J = 9.3 Hz, 1 H), 7.25–7.36 (m, 15 H).
LRMS (EI): m/z 667 [M+], 552 [M+ – Me], 576 [M+ – Bn], 540 [M+
– I], 91 [Bn], 73 [TMS].
HRMS (EI) m/z [M+] calcd for C34H42INO3Si: 667.1979; found:
667.1976.
(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) Jensen, M.; Livinghouse, T. J. Am. Chem. Soc. 1989, 11,
4495.
(9) (a) Davis, J. M.; Whitby, R. J. Tetrahedron Lett. 1992, 33,
5655. (b) Davis, J. M.; Whitby, R.; Jaxa-Chamiec, A.
Tetrahedron Lett. 1994, 35, 1445. (c) Davis, J. M.; Whitby,
R.; Jaxa-Chamiec, A. Synlett 1994, 110. (d) Provert, G. D.;
Whitby, R. J. Tetrahedron Lett. 1995, 36, 4113.
(10) In azatitanacyclobutene a similar result was obtained:
McGrane, P. L.; Jensen, M.; Livinghouse, T. J. Am. Chem.
Soc. 1992, 114, 5469.
References
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E.; Takahashi, T. Synthesis 1988, 1. (c) Nugent, W. A.;
Taber, D. F. J. Am. Chem. Soc. 1989, 11, 6435. (d) Negishi,
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Synthesis 2004, No. 9, 1369–1374 © Thieme Stuttgart · New York