A practical titanium-catalyzed synthesis of bicyclic cyclopentenones and allylic amines

Article abstract of DOI:10.1021/jo951763l

A practical titanium-catalyzed synthesis of bicyclic cyclopentenones and allylic amines is described. The process converts enyne substrates to iminocyclopentenes using 10 mol % of the air- and moisture-stable precatalyst Cp₂TiCl₂ in the presence of n-BuLi and triethylsilyl cyanide. The resulting iminocyclopentenes can be hydrolyzed to cyclopentenones in good yields or reduced to allylic silylamines with Red-Al or DIBALH. Treatment of the crude silylamines with acetyl chloride allows isolation of allylic amides in excellent yields.

Full text of DOI:10.1021/jo951763l

J . Org. Chem. 1996, 61, 2713-2718
2713
A P r a ctica l Tita n iu m -Ca ta lyzed Syn th esis of Bicyclic
Cyclop en ten on es a n d Allylic Am in es
Frederick A. Hicks,† Scott C. Berk,‡ and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received September 26, 1995X
A practical titanium-catalyzed synthesis of bicyclic cyclopentenones and allylic amines is described.
The process converts enyne substrates to iminocyclopentenes using 10 mol % of the air- and
moisture-stable precatalyst Cp2TiCl2 in the presence of n-BuLi and triethylsilyl cyanide. The
resulting iminocyclopentenes can be hydrolyzed to cyclopentenones in good yields or reduced to
allylic silylamines with Red-Al or DIBALH. Treatment of the crude silylamines with acetyl chloride
allows isolation of allylic amides in excellent yields.
Sch em e 1
In recent years, group IV metallocene-mediated reduc-
tive cyclizations of enynes,1 diynes,2 and dienes3 have
become an important methodology in organic synthesis
(Scheme 1). The metallacycles formed (1) can be hydro-
lyzed, carbonylated, iminylated,4 halogenated, and con-
verted into a wide range of main group heterocycles5 and
highly substituted benzene derivatives.6 These trans-
formations have as a limitation their requirement for a
stoichiometric quantity of metal.
Sch em e 2
On the basis of the observation4 that the product of
the reaction of tert-butyl isocyanide with titanacycle 2 is
converted to iminocyclopentene 4 with loss of “titanocene”
(Scheme 2), the catalytic cycle in Scheme 3 was proposed.
Initial efforts with tert-butyl isocyanide failed due to
catalyst deactivation in the presence of excess isocyanide.
This problem was overcome7 by keeping the concentration
of isocyanide low in solution with trialkylsilyl cyanides
(R′ ) Et3Si, t-Bu(Me)2Si),8 which exist in equilibria with
minor amounts of the isocyanides (99:1 for trimethylsilyl
cyanide). Scheme 4 outlines the course of the catalytic
procedure.9
Sch em e 3
Although this process, as the first early transition
metal catalyzed cyclopentenone synthesis, represents an
advance in methodology, there are a number of areas
where improvements can be made. A major problem is
† National Science Foundation Predoctoral Fellow 1994-97.
‡ Current address: Merck & Co., Inc., P.O. Box 2000, Rahway, NJ
07065.
X Abstract published in Advance ACS Abstracts, February 15, 1996.
(1) (a) For an extensive review, see: Negishi, E.-i. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 5, pp 1163-1184. (b) Urabe, H.; Hata, T.; Sato, F.
Tetrahedron Lett. 1995, 36, 4261.
(2) Nugent, W. A.; Calabrese, J . C. J . Am. Chem. Soc. 1984, 106,
6422.
(3) (a) Nugent, W. A.; Taber, D. F. J . Am. Chem. Soc. 1989, 111,
6435. (b) Negishi, E.-i.; Swanson, D. R.; Lamaty, F.; Rousset, C. J .
Tetrahedron Lett. 1989, 30, 5105.
Sch em e 4
(4) Buchwald, S. L.; Grossman, R. B. J . Org. Chem. 1992, 57, 5803.
(5) Fagan, P. J .; Nugent, W. A.; Calabrese, J . C. J . Am. Chem. Soc.
1994, 116, 1880.
(6) Takahashi, T.; Kotora, M.; Xi, Z. J . Chem. Soc., Chem. Commun.
1995, 361.
(7) (a) Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J . Am. Chem.
Soc. 1993, 115, 4912. (b) Berk, S. C.; Grossman, R. B.; Buchwald, S.
L. J . Am. Chem. Soc. 1994, 116, 8593.
(8) Rasmussen, J . K.; Heilmann, S. M.; Krepski, L. R. In Advances
in Silicon Chemistry; Larson, G. L., Ed.; J AI Press: Greenwich, CT,
1991; pp 65-187.
(9) For other examples of catalytic reactions involving group IV
metallacycles, see: (a) Kabaloui, N. M.; Buchwald, S. L. J . Am. Chem.
Soc. 1995, 117, 6785. (b) Crowe, W. E.; Rachita, M. J . J . Am. Chem.
Soc. 1995, 117, 6787. (c) Knight, K. S.; Waymouth, R. M. Tetrahedron
Lett. 1992, 33, 7735. (d) Knight, K. S.; Waymouth, R. M. Organome-
tallics 1994, 13, 4542.
that the precatalyst Cp2Ti(PMe3)210 is extremely air- and
moisture-sensitive and must be handled and stored in a
(10) Rausch, M. D.; Alt, H. G.; Kool, L. B.; Herberhold, M.; Thewalt,
U.; Wolf, B. Angew. Chem., Int. Ed. Engl. 1985, 24, 394.
0022-3263/96/1961-2713$12.00/0 © 1996 American Chemical Society

2714 J . Org. Chem., Vol. 61, No. 8, 1996
Hicks et al.
Ta ble 1. Com p a r ison of Cyclop en ten on e F or m a tion
Sch em e 5
fr om P r eca ta lysts Cp 2Ti(P Me3)2 a n d Cp 2TiCl2
Sch em e 6
glovebox under argon. In addition, it would be advanta-
geous to develop a catalyst system that did not require
PMe3 due to concerns about its stench and toxicity. A
method to generate the catalytically active species in situ
from Cp2TiCl2, which is air- and moisture-stable and
inexpensive, would greatly increase the practicality of
this methodology. The yields of cyclopentenones 8 (43-
80%),7 while comparable to related syntheses,11 are
disappointing considering that iminocyclopentene forma-
tion is quantitative (1H NMR). This led to the search
for alternative transformations that could give products
in higher yields and exploit the silylimine functionality.
Titanacyclopentenes 5 are intermediates in the cata-
lytic cycle depicted in Scheme 2. We have previously
shown4 that these metallacycles can be prepared from
enynes by treatment with a mixture of Cp2TiCl2 and 2
equiv of EtMgBr or n-BuLi (Scheme 5). We decided,
therefore, to see if the combination Cp2TiCl2/2 n-BuLi
could serve as a catalyst in lieu of Cp2Ti(PMe3)2.
Our initial attempts, employing THF as solvent, were
unsuccessful. Although metallacycle formation was nearly
quantitative (1H NMR), the catalyst was rapidly decom-
posed under the reaction conditions. Attempts to run the
reaction in the noncoordinating solvent toluene were
hampered by the extremely low solubility of Cp2TiCl2.
We found, however, that by using n-BuLi with finely
ground Cp2TiCl2 in toluene (Scheme 6), the titanacycle
5 (X ) O, R ) Ph) was produced in 92% yield (1H NMR)
and was catalytically active at 10 mol %, the same level
as with Cp2Ti(PMe3)2.
to the fact that the silyl group is easily removed from
the products formed. Thus, silylimines serve as synthetic
equivalents to unsubstituted imines. Hart initiated work
in this area13 by studying reductions of silylimines with
LiAlH4, addition reactions with alkyllithium and Grig-
nard reagents, and condensations with ester enolates to
form â-lactams.14 The reactions of silylimines have since
been expanded to include the synthesis of aziridines,15
1,2-amino alcohols,16 and R-amino phosphonic acids.17
Due to the importance of allylic amines18 both as syn-
thetic intermediates19 and as biologically active com-
pounds themselves,20 we chose to explore hydride reduc-
tions of the silylimines produced by our methodology.21
After a range of reducing agents were surveyed, Red-
Al (sodium bis(2-methoxyethoxy)aluminum hydride) and
DIBALH were found to give high yields of the corre-
sponding silylamines 8 (Scheme 7). In the one reported
example of silylimine reduction we are aware of, the
amine which was isolated had been desilylated.13 Since
silyl groups can be utilized to protect amines, the
development of reaction protocols which retain them is
significant.22 Although the crude silylamines could be
utilized for further transformations, their isolation proved
(13) Hart, D. J .; Kanai, K.-i.; Thomas, D. G.; Yang, T.-K. J . Org.
Chem. 1983, 48, 289.
(14) Hart D. J .; Ha, D.-C. Chem. Rev. 1989, 89, 1447.
(15) Cainelli, G.; Panunzio, M.; Giacomini, D. Tetrahedron Lett.
1991, 32, 121.
(16) Cainelli, G.; Mezzina, E.; Panunzio, M. Tetrahedron Lett. 1990,
31, 3481.
(17) Bongini, A.; Camerini, R.; Hofman, S.; Panunzio, M. Tetrahe-
dron Lett. 1994, 35, 8045.
(18) For a review on the synthesis of allylic amines, see: Chaabouni,
R.; Cheikh, R. D.; Laurent, A.; Mison, P.; Nafti, A. Synthesis 1983,
685. For a related synthesis of allylic amines with stoichiometric
zirconium, see: Whitby, R. J .; Probert, G. D.; Coote, S. J . Tetrahedron
Lett 1995, 36, 4113.
(19) For recent examples see: (a) Burgess, K.; Ohlmeyer. M. J . J .
Org. Chem. 1991, 56, 1027. (b) J ung, M.; Rhee, H. J . Org. Chem. 1994,
59, 4719. (c) Brunker, H.-G.; Adam, W. J . Am. Chem. Soc. 1995, 117,
3976.
To compare the two catalysts, a number of cyclopen-
tenones were synthesized using the new system (Table
1). The yields indicate the processes employing Cp2TiCl2
and Cp2Ti(PMe3)2 are equally effective. In addition, we
found that a bicyclic enyne (Table 1, entry 5), using the
new catalyst system, produces the tricyclic cyclopenten-
one in good yields.12
After developing the new in situ method of catalyst
generation, we decided to explore other reactions of the
silylimine intermediates. The chemistry of silylimines
has developed rapidly in the past decade due in large part
(20) (a) Stutz, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 320. (b)
Delaris, G.; Dunogues, J .; Gadras, A. Tetrahedron 1988, 44, 4293 and
references therein.
(21) For a review on hydride reductions of CdN, see: Hutchins, R.
O.; Hutchins, M. K. In Comprehensive Organic Chemistry; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, pp 25-78.
(22) Overman, L. E.; Okazaki, M. E.; Mishra, P. Tetrahedron Lett.
1986, 27, 4391.
(11) (a) Schore, N. E. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 1037-
1064. (b) J eony, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K. J . Am. Chem.
Soc. 1994, 116, 3159. (c) Tamao, K.; Kobayashi, K.; Ito, Y. J . Am. Chem.
Soc. 1988, 110, 1286. (d) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1941.
(e) Pearson, A. J .; Dubbert, R. A. Organometallics 1994, 13, 1656.
(12) See ref 11c for a related iminocyclopentene.

Synthesis of Bicyclic Cyclopentenones
J . Org. Chem., Vol. 61, No. 8, 1996 2715
Sch em e 7
The substrate with an allylic TIPS (triisopropylsilyl)
ether (Table 2, entry 7) was reduced by Red-Al, but
reaction occurred only slowly at elevated temperatures
to give a mixture of three diastereomers.25 With sub-
strates containing propargylic TIPS ethers (Table 2,
entries 8 and 9), reaction with Red-Al gave only low yields
of products. However, DIBALH cleanly reduces the
silylimines from entries 8 and 9 to give products in high
yields with varying levels of diastereocontrol.
Acetylation of the reduction products with TIPS pro-
tecting groups required the addition of 4 equiv of NEt3
to prevent decomposition. A substrate with an allylic
benzyl ether (Table 1, entry 4) was cleanly reduced with
Red-Al, but it decomposed upon attempted acetylation,
even in the presence of NEt3. Presumably, reaction of
the benzyl group leads to decomposition, since the
substrate with an allylic TIPS ether (Table 2, entry 8)
was acetylated without problem. For all substrates,
reduction and acetylation of the silylimines produces
allylic amides in higher yields than hydrolysis to the
corresponding cyclopentenones.
Ta ble 2. Con ver sion of En yn es to Bicyclic Allylic
Am id es
In conclusion, we have developed a practical, PMe3-
free catalytic system for synthesizing bicyclic iminocy-
clopentenes from the air- and moisture-stable precatalyst
Cp2TiCl2. The yields of cyclopentenones from hydrolysis
are the same as previously reported for the air- and
moisture-sensitive precatalyst Cp2Ti(PMe3)2. In addition,
we have developed a reduction to give allylic amides in
yields which are consistently higher than hydrolysis to
the cyclopentenones. Future work will include the
development both of intermolecular and asymmetric
versions of these and related cyclizations.
Exp er im en ta l Section
All reactions involving organometallic reagents were con-
ducted under an atmosphere of purified argon using standard
Schlenk techniques. All organic reactions were performed
under an atmosphere of argon or nitrogen. Nuclear magnetic
resonance (NMR) spectra were accumulated at 300 MHz.
Toluene and tetrahydrofuran were dried and deoxygenated by
continuous refluxing over sodium/benzophenone ketyl followed
by distillation. Methylene chloride was dried by continuous
refluxing over CaH2 followed by distillation. Diethyl ether was
used with no preparative drying. All enynes used for cycliza-
tion reactions, unless stated otherwise, were prepared as in
Berk et al.7 trans-1-(allyloxy)-2-(phenylethynyl)cyclohexane
(Table 1, entry 5, and Table 2, entry 6) was prepared by ring
opening of cyclohexene oxide with (phenylethynyl)lithium and
26
BF3‚OEt2 followed by protection of the alcohol with allyl
bromide.27 Et3SiCN was prepared by the procedure of Becu.28
All other reagents were either prepared according to published
procedures or were available from commercial sources and
used without further purification. For all products, the
stereochemistry at the ring carbon R to the acetamido group
was assigned on the basis of the characteristic 1H NMR shifts.
For the endo acetamido groups, the amide NH peak occurs at
around 7 ppm in CDCl3. For the exo acetamido groups, the
amide NH peak occurs at around 5.1 ppm in CDCl3. NOE data
difficult. Attempts to desilylate and isolate the free
amines led to deamination and to complex mixtures of
cyclopentadiene and allylic alcohol derivatives. For this
reason, the silylamines were converted to amides 9 for
their isolation.23
For most substrates (Table 2, entries 1-6), Red-Al
reduction was completely diastereoselective. Reduction
with DIBALH (substrate from Table 2, entry 1), however,
produced a mixture of two diastereomers (3:2), with the
same predominant product as from Red-Al reduction.24
(24) The origins of the diastereoselectivites are unclear at the
present time as the reduction of imines has received little mechanistic
investigation.
(25) The cyclization reaction itself results in two diastereomers at
the TIPS ether carbon (Table 2, entries 7-9). For diastereoselectivities
of entries 8 and 9, see ref 7b (also contains discussion on origins of
selectivities). NMR experiments have shown the selectivity for entry
7 to be 2.2:1 in favor of the exo TIPS ether.
(26) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(27) Bartlett, A. J .; Laird, T.; Ollis, W. D. J . Chem. Soc., Perkin
Trans. 1 1975, 1315.
(28) Becu, C.; Anteunis, M. J . O. Bull. Soc. Chem. Belg. 1987, 96,
115.
(23) Ojima, I.; Kogure, T.; Nagai, Y. Tetrahedron Lett. 1973, 2475.

2716 J . Org. Chem., Vol. 61, No. 8, 1996
Hicks et al.
for one set of diastereomers from DIBALH reduction of an
iminocyclopentene (Table 2, entry 5) were utilized to establish
the relative stereochemistry. All other stereocenters on
products were assigned by X-ray or NOE studies. Yields refer
to isolated yields of compounds estimated to be >95% pure
(unless otherwise noted) as determined by 1H NMR and either
capillary GC (known compounds) or combustion analysis (new
compounds). Elemental analyses were performed by E + R
Microanalytical Laboratory, Corona, NY.
Hz, 1 H), 3.18 (t, J ) 11.0 Hz, 1 H), 3.0 (m, 2 H), 2.50 (dd, J
) 7.0, 18.6 Hz, 1 H), 2.31 (m, 1 H), 1.90 (m, 2 H), 1.62 (m, 1
H), 1.40 (m, 3 H), 1.06 (m, 2 H), 0.77 (m, 1 H). 13C NMR (75
MHz, CDCl3): δ 206.6, 174.2, 138.7, 133.1, 129.9, 127.7, 127.6,
81.9, 73.6, 48.7, 41.0, 36.2, 33.2, 28.1, 25.6, 24.2. IR (KBr,
cm-1): 2920, 2858, 1692, 1643, 1443, 1108, 1092, 1003, 707.
Anal. Calcd for C18H20O2: C, 80.56; H, 7.51. Found: C, 80.66;
H, 7.72. The relative stereochemistry for the product was
determined by X-ray crystallographic analysis.
Gen er a l P r oced u r e for th e Con ver sion of En yn es to
Im in ocyclop en ten es. A flame-dried Schlenk flask was at-
tached to a Schlenk line and allowed to cool. Cp2TiCl2 (0.1
mmol, 26 mg) ground with a mortar and pestal and toluene
(2-3 mL) were added to the flask, which was cooled to -78
°C. n-BuLi (80 µL of 2.5 M in hexanes) was added dropwise,
with care to ensure that none of it touched the sides of the
flask. After 1 h at -78 °C, the enyne (1.0 mmol) was added.
The reaction mixture was stirred for another 1 h at -78 °C
and was allowed to warm to rt over 1 h. After 3-5 h at rt,
Et3SiCN (1.15 mmol) was added. The flask was then heated
overnight in an oil bath at 45-55 °C.
Con ver sion of Im in ocyclop en t en es t o Allylic Silyl-
a m in es. Gen er a l P r oced u r e A. The reaction was cooled
to rt, and Red-Al (6 mmol equiv of “H”, 840 µL) was added.
After 1 h at rt, the reaction was quenched into 50 mL each of
5% NaOH and ether, and the aqueous layer was extracted with
2 × 50 mL of ether. The combined organic extracts were
washed with brine and dried over MgSO4, and the crude
product mixture was concentrated to 15 mL.
3-Aceta m id o-2-p h en ylbicyclo[3.3.0]oct-1-en e (Ta ble 2,
En tr y 1). 1-Phenyl-6-hepten-1-yne (170 mg, 1.0 mmol) was
converted to the iminocyclopentene by the general procedure.
The reduction was accomplished with procedure A. The crude
amide was purified by filtering and washing several times with
cold pentane to yield 195 mg (83%) of a white solid. Mp: 141-
143 °C. 1H NMR (300 MHz, CDCl3): δ 7.36 (t, J ) 7.5 Hz, 3
H), 7.24 (d, J ) 7.5 Hz, 2 H), 7.02 (s, 1 H), 3.46 (m, 1 H), 3.15
(dd, J ) 9.6, 16.8 Hz, 1 H), 3.00 (m, 1 H), 2.72 (m, 1 H), 1.94
(s, 3 H), 1.78 (m, 1 H), 1.50 (m, 4 H), 1.33 (m, 1 H). 13C NMR
(75 MHz, CDCl3): δ 167.9, 136.4, 132.8, 128.9, 127.9, 126.8,
125.0, 50.6, 41.2, 38.2, 35.4, 31.5, 25.4, 24.1. IR (KBr, cm-1):
3282, 2945, 2858, 1664, 1517, 1492, 1356, 1267, 764, 693.
Anal. Calcd for C16H19NO: C, 79.63; H, 7.94. Found: C, 79.75;
H, 8.15. If reduction was accomplished with procedure B, two
diastereomers (3:2) were obtained. The two crude amides were
separated and purified by flash chromatography (ethyl acetate:
hexane ) 1:1). The minor diastereomer was isolated as 70
mg (30%) of a white solid. Mp: 147-149 °C. 1H NMR (300
MHz, CDCl3): δ 7.30 (m, 3 H), 7.15 (m, 2 H), 5.80 (m, 1 H),
5.37 (m, 1 H), 3.20 (m, 3 H), 2.37 (m, 1 H), 2.13 (m, 1 H), 1.95
(m, 2 H), 1.86 (s, 3 H), 1.15 (m, 2 H). 13C NMR (75 MHz,
CDCl3): δ 169.2, 153.6, 135.8, 128.4, 128.3, 126.6, 126.1, 60.9,
50.8, 40.0, 32.3, 28.7, 25.5, 23.4. IR (KBr, cm-1): 3307, 2956,
2859, 1644, 1538, 1497, 1443, 1372, 1303, 1152, 768, 693.
Anal. Calcd for C16H19NO: C, 79.63; H, 7.94. Found: C, 79.50;
H, 8.12.
Gen er a l P r oced u r e B. The reaction was cooled to rt, and
DIBALH (4 mL of 1 M in THF) was added. After the reaction
was heated to 50 °C overnight, it was quenched into 50 mL
each of 5% NaOH and ether. The aqueous layer was extracted
with 2 × 50 mL of ether, and the combined organic extracts
were washed with brine and dried over MgSO4. The crude
product mixture was concentrated to 15 mL.
Gen er a l P r oced u r e for th e Con ver sion of Silyla m in es
to Am id es. Acetyl chloride (2 mmol, 143 µL) was added to
the crude silylamine. After 1 h at rt, the reaction was
quenched with 50 mL each of 5% NaOH and ether. The
aqueous layer was extracted with 2 × 50 mL of ether, and the
combined organic extracts were washed with brine, dried over
MgSO4, filtered, and concentrated to produce the crude
product.
3-((Tr iisop r op ylsilyl)oxy)-1-u n d ecen -6-yn e (Ta ble 2,
En tr y 8). Undec-1-en-6-yn-3-ol7 (30 mmol) was protected by
the procedure of Corey.29 The product was purified by flash
chromatography (hexane) to yield 2.8 g (30%) of a pale yellow
liquid. 1H NMR (300MHz, CDCl3): δ 5.76 (m, 1 H), 5.14 (m,
1 H), 5.03 (m, 1 H), 4.32 (quart, J ) 3.0 Hz, 1 H), 2.15 (m, 4
H), 1.74 (m, 1 H), 1.64 (m, 1 H), 1.40 (m, 4 H), 1.04 (m, 21 H),
0.88 (t, J ) 7.0 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ 141.1,
114.4, 80.4, 79.7, 73.0, 37.4, 31.2, 21.9, 18.4, 18.1, 14.3, 13.6,
12.4. IR (neat, cm-1): 2943, 2866, 1464, 1382, 1093, 1067, 991,
922, 837, 681. Anal. Calcd for C20H38OSi: C, 74.46; H, 11.87.
Found: C, 74.64; H, 12.03.
Tr icyclic Cyclop en ten on e (Ta ble 1, En tr y 5). The
silylimine from trans-1-(allyloxy)-2-(phenylethynyl)cyclohex-
ane (240 mg, 1.0 mmol) was obtained using a modification of
the general procedure with 0.15 mmol of Cp2TiCl2, 0.30 mmol
of n-BuLi, and 5 mL of toluene. The toluene was removed from
the Schlenk flask in vacuo, and the crude silylimine was
cannula transferred with 30 mL of THF to a 250 mL Schlenk
flask under argon. Three mL of saturated aqueous CuSO4 was
added dropwise followed by vigorous stirring of the mixture
for 4 h at rt. The reaction mixture was extracted with 50 mL
each of 0.5 N HCl and ether, and the aqueous layer was
reextracted with 2 × 50 mL ether. The combined organic
layers were washed with 0.5 N NaOH and brine and dried
over MgSO4 to afford the crude product. Purification by flash
chromatography (ether:hexane ) 4:1) afforded 180 mg (67%)
of an off-white solid. Mp: 118-120 °C. 1H NMR (300 MHz,
CDCl3): δ 7.24 (m, 3 H), 7.01 (m, 2 H), 4.27 (dd, J ) 6.2, 10.2
3-Ace t a m id o-2-p h e n yl-7-oxa b icyclo[3.3.0]oct -1-e n e
(Ta ble 2, En tr y 2). 3-(Allyloxy)-1-phenyl-1-propyne (170 mg,
1.0 mmol) was converted to the iminocyclopentene by the
general procedure. The reduction was accomplished with
procedure A. The crude amide was purified by filtration and
washing several times with cold pentane to yield 215 mg (89%)
of a white solid. Mp: 120-122 °C. 1H NMR (300 MHz,
CDCl3): δ 7.37 (t, J ) 7.2 Hz, 3 H), 7.22 (d, J ) 7.2 Hz, 2 H),
7.10 (s, 1 H), 3.87 (t, J ) 8.1 Hz, 1 H), 3.64 (m, 3 H), 3.52 (m,
1 H), 3.18 (m, 2 H), 2.94 (m, 1 H), 1.94 (s, 3 H). 13C NMR (75
MHz, CDCl3): δ 168.1, 135.6, 133.6, 129.1, 127.7, 127.1, 122.6,
75.7, 72.1, 51.8, 39.2, 39.0, 24.0. IR (KBr, cm-1): 3292, 2963,
2833, 1665, 1515, 1490, 1366, 1268, 1088, 1044, 766, 693.
Anal. Calcd for C15H17NO2: C, 74.04; H, 7.04. Found: C,
73.99; H, 7.05.
3-Aceta m id o-2-m eth yl-7-p h en yl-7-a za bicyclo[3.3.0]oct-
1-en e (Ta ble 2, En tr y 3). N-(2-Butynyl)-N-allylaniline (247
mg, 1.0 mmol) was converted to the iminocyclopentene by the
general procedure. The reduction was accomplished with
procedure A. The product was purified by flash chromatog-
raphy (ethyl acetate:hexane ) 7:3) to afford 156 mg (61%) of
a light orange solid. Mp: 174-176 °C. 1H NMR (300 MHz,
CDCl3): δ 7.20 (t, J ) 8.1 Hz, 2 H), 6.67 (t, J ) 7.5 Hz, 1 H),
6.59 (d, J ) 7.8 Hz, 2 H), 6.55 (s, 1 H), 3.46 (t, J ) 9.0 Hz, 1
H), 3.28 (m, 3 H), 3.15 (m, 1 H), 3.00 (m, 2 H), 2.70 (d, J )
16.0 Hz, 1 H), 2.03 (s, 3 H), 1.60 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ 168.3, 148.4, 130.9, 129.1, 122.4, 116.5, 112.9, 55.7,
51.2, 50.8, 39.2, 37.9, 23.8, 11.8. IR (KBr, cm-1): 3321, 2940,
1661, 1600, 1505, 1476, 1369, 1338, 1274, 1187, 746, 690.
Anal. Calcd for C16H20N2O: C, 74.96; H, 7.76. Found: C,
74.79; H, 7.75.
3-Aceta m id o-5-m eth yl-2-p h en yl-7-oxa bicyclo[3.3.0]oct-
1-en e (Ta ble 2, En tr y 4). 3-((2-Methyl-2-propenyl)oxy)-1-
phenyl-1-propyne (372 mg, 2.0 mmol) was converted to the
iminocyclopentene by the general procedure with the modifica-
tion of 0.20 mmol of Cp2TiCl2, 0.40 mmol of n-BuLi, and 6 mL
of toluene. The reduction was accomplished with procedure
A. The product was purified by flash chromatography (ethyl
acetate:hexane ) 3:2) to give 370 mg (75%) of a white solid.
Mp: 127-129 °C. 1H NMR (300 MHz, CDCl3): δ 7.37 (t, J )
(29) Corey, E. J .; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett
1981, 22, 3455.

Synthesis of Bicyclic Cyclopentenones
J . Org. Chem., Vol. 61, No. 8, 1996 2717
7.3 Hz, 3 H), 7.21 (d, J ) 7.0 Hz, 2 H), 7.11 (s, 1 H) 3.82 (dd,
J ) 7.2, 8.7 Hz, 1 H), 3.72 (d, J ) 8.4 Hz, 1 H), 3.51 (d, J ) 8.7
Hz, 2 H), 3.33 (d, J ) 17.7 Hz, 1 H), 3.14 (m, 1 H), 2.93 (d, J
) 17.7 Hz, 1 H), 1.96 (s, 3 H), 1.30 (s, 3 H). 13C NMR (75
MHz, CDCl3): δ 167.6, 135.1, 132.1, 128.5, 127.2, 126.6, 121.9,
80.5, 72.0, 58.2, 46.6, 45.6, 24.8, 23.5. IR (KBr, cm-1): 3233,
2959, 2846, 1662, 1638, 1520, 1496, 1352, 1274, 1062, 922, 768,
695. Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44. Found:
C, 74.65; H, 7.44. To determine the relative stereochemistry
at the ring carbon R to the acetamido group, the iminocyclo-
pentene was also reduced by procedure B to yield a mixture
of two diastereomers (3:2). The major diastereomer was the
same one obtained exclusively with procedure A. A nuclear
Overhauser enhancement study was undertaken to determine
the relative configuration of each diastereomer. Irradiation
of the C-5 methyl group at δ 1.4 (C6D6) of the major diaste-
reomer gave no enhancement of the amide NH at δ 6.85, while
the same experiment produced a 2% enhancement in the minor
diastereomer. The stereochemistry for the two diastereomers
was therefore assigned as shown:
oxy)-1-undecen-6-yne (324mg, 1.0 mmol) was converted to the
iminocyclopentene by the general procedure with the modifica-
tion of 0.15 mmol of Cp2TiCl2, 0.30 mmol of n-BuLi, and 5 mL
of toluene. The reduction was accomplished by procedure A
with the modification of heating the reaction overnight at 50
°C. To prevent product decomposition, the acetylation was
carried out by the general procedure with the addition of 4
equiv of NEt3. The product was purified by flash chromatog-
raphy (ether:hexane ) 3:2) to afford 236 mg (63%) of a mixture
of three diastereomers (1:1:3.5) as a light yellow oil. A second
chromatography allowed the first diastereomer to be isolated
as a light yellow solid, but the other two diastereomers could
not be separated. First diastereomer. Mp: 88-90 °C. 1H
NMR (300 MHz, CDCl3): δ 5.23 (m, 2 H), 4.14 (t, J ) 3.2 Hz,
1 H), 2.66 (m, 1 H), 2.25 (m, 2 H), 2.03 (m, 4 H), 1.95 (s, 3 H),
1.42 (m, 3 H), 1.28 (m, 3 H), 1.03 (m, 21 H), 0.85 (t, J ) 7.2
Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ 169.0, 146.0, 131.2,
71.1, 61.1, 54.8, 38.3, 30.2, 25.9, 23.6, 22.6, 20.9, 18.2, 18.1,
13.9, 12.4. IR (KBr, cm-1): 3252, 3068, 2956, 2865, 1639, 1557,
1463, 1376, 1297, 1152, 1063, 1012, 882, 803, 682. Anal.
Calcd for C23H43NO2Si: C, 70.17; H, 11.01. Found: C, 70.32;
H, 10.99. To determine the relative stereochemistry of the
OTIPS group for the major diastereomeric product from Table
2, entry 7, an NOE study was undertaken. Irradiation of the
C-5 proton at δ 3.83 (C6D6) of the major diastereomer gave no
enhancement of the C-6 proton at δ 2.70, while the same
experiment produced an 8.5% enhancement in the first minor
diastereomer. The stereochemistry for the two diastereomers
was therefore assigned as shown:
Ta ble 2, En tr y 5. trans-1-(Allyloxy)-2-(phenylethynyl)-
cyclohexane (240 mg, 1.0 mmol) was converted to the iminocy-
clopentene by the general procedure with the modification of
0.15 mmol of Cp2TiCl2, 0.30 mmol of n- BuLi, and 5 mL of
toluene. The reduction was effected by procedure A with the
modification that the reaction was heated for 2 h at 50 °C.
The product was purified by flash chromatography (ether:
hexane ) 9:1) to give 224 mg (72%) of a pale orange solid. The
product exists as approximately a 3:2 mixture of amide
rotamers by NMR. Although the product is unstable at room
temperature for extended periods, it can be stored in the
freezer with little decomposition. Mp: 50-53 °C. It proved
difficult to assign 1H peaks to the individual rotamers, so a
3-Aceta m id o-2-bu tyl-8-((tr iisop r op ylsilyl)oxy)bicyclo-
[3.3.0]oct-1-en e (Ta ble 2, En tr y 8). 5-((Triisopropylsilyl)-
oxy)-1-undecen-6-yne (324 mg, 1.0 mmol) was converted to the
iminocyclopentene by the general procedure with the modifica-
tion of 0.15 mmol of Cp2TiCl2, 0.30 mmol of n-BuLi, and 5 mL
of toluene. The reduction was accomplished with procedure
B, and acetylation was carried out by the general procedure
with the addition of 4 equiv of NEt3. The product was purified
by flash chromatography (ether:hexane ) 3:2) to afford 300
mg (80%) of a 4:1 mixture of diastereomers as a light yellow
oil. A pure sample of the major diastereomer was obtained
by a second chromatography. Major diastereomer: 1H NMR
(300 MHz, CDCl3) δ 5.52 (quart, J ) 9 Hz, 1 H), 4.8 (s, 1 H),
4.56 (d, J ) 9 Hz, 1 H), 2.87 (m, 1 H), 2.43 (m, 1 H), 2.22 (m,
1 H), 1.97 (m, 4 H), 1.75 (m, 1 H), 1.57 (s, 3 H), 1.40 (m, 4 H),
1.14 (m, 21 H), 0.95 (t, J ) 7.0 Hz, 3 H), 0.75 (m, 1 H). 13C
NMR (75 MHz, CDCl3): δ 189.0, 148.8, 133.9, 68.2, 60.0, 44.4,
41.9, 38.8, 30.5, 29.8, 28.4, 23.4, 23.1, 18.1, 13.8, 12.5. IR (neat,
cm-1): 3275, 2956, 2865, 1650, 1556, 1464, 1373, 1296, 1052,
883, 681. Anal. Calcd for C23H43NO2Si: C, 70.17; H, 11.01.
Found: C, 70.29; H, 11.10. The stereochemistry of the TIPS
ether was assigned on the basis of NOE studies on the
corresponding cyclopentenone.7
3-Aceta m id o-2-bu tyl-9-((tr iisop r op ylsilyl)oxy)bicyclo-
[3.4.0]n on -1-en e (Ta ble 2, En tr y 9). 6-((Triisopropylsilyl)-
oxy)-1-dodecen-7-yne (336 mg, 1.0 mmol) was converted to the
iminocyclopentene by the general procedure with the modifica-
tion of 0.15 mmol of Cp2TiCl2, 0.30 mmol n-BuLi, and 5 mL of
toluene. In addition, the reaction time at rt was increased to
overnight. The reduction was affected by procedure B, while
acetylation was carried out by the general procedure with the
addition of 4 equiv of NEt3. The product was purified by flash
chromatography (ether:hexane ) 7:3) to give 253 mg (65%) of
a mixture of four diastereomers (16:16:2:1) as a yellow oil. The
1
list of peaks without assignments or integrations is given. H
NMR (300 MHz, CDCl3): δ 7.39-7.26 (m), 7.12 (d), 6.64 (s),
6.18 (s), 5.92 (s), 4.00 (dd), 3.81 (m), 3.50 (t), 3.28 (m), 3.13
(m), 2.89 (m), 2.77 (m), 2.68 (m), 1.94 (m), 1.85 (s), 1.81 (s),
1.71-0.87 (m), 0.35 (m). 13C NMR (75 MHz, CDCl3): δ 168.4,
167.6, 141.7, 138.7, 137.7, 136.4, 129.2, 128.9, 128.5, 127.5,
127.2, 122.9, 112.8, 77.5, 77.1, 70.8, 68.0, 50.6, 48.3, 47.5, 44.0,
43.0, 42.5, 36.2, 34.6, 33.0, 32.6, 30.6, 26.6, 26.2, 24.9, 24.6,
24.2, 24.0. Ir (neat, cm-1): 3288, 2932, 2857, 1682, 1514, 1450,
1367, 1260, 1100, 1012, 867, 751, 700. The relative stereo-
chemistry of the tricyclic ring system was assigned based upon
analogy to the related tricyclic ketone (Table 1, entry 5).
3-Aceta m id o-8-m eth yl-2-p h en yl-7-oxa bicyclo[3.3.0]oct-
1-en e (Ta ble 2, En tr y 6). 3-(Allyloxy)-1-phenyl-1-butyne (186
mg, 1 mmol) was converted to the iminocyclopentene by the
general procedure. The reduction was accomplished with
procedure A. The product was purified by flash chromatog-
raphy (ethyl acetate:hexane ) 4:1) to give 210 mg (82%) of a
95:5 mixture of diastereomers as a white solid. Recrystalli-
zation from ether yields 185 mg (73%) of a single diastereomer
as a white solid. Mp: 118-120 °C. 1H NMR (300 MHz,
CDCL3): δ 7.40 (t, J ) 7.2 Hz, 3 H), 7.25 (m, 2 H), 7.05 (s, 1
H), 4.18 (t, J ) 7.8 Hz, 1 H), 3.60 (quin, J ) 5.5 Hz, 1 H), 3.43
(t, J ) 8.4 Hz, 1 H), 3.26 (m, 1 H), 3.06 (m, 3 H), 1.96 (s, 3 H),
1.11 (d, J ) 6.6 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ 187.9,
135.4, 132.8, 129.2, 127.8, 127.3, 122.4, 80.3, 74.2, 58.6, 39.9,
38.9, 24.2, 21.0. IR (KBr, cm-1): 3296, 2966, 2849, 1665, 1516,
1493, 1355, 1254, 1056, 758, 696. Anal. Calcd for C16H19
NO2: C, 74.68; H, 7.44. Found: C, 74.51; H, 7.51.
-
3-Aceta m id o-2-bu tyl-6-((tr iisop r op ylsilyl)oxy)bicyclo-
[3.3.0]oct-1-en e (Ta ble 2, En tr y 7). 3-((Triisopropylsilyl)-

2718 J . Org. Chem., Vol. 61, No. 8, 1996
Hicks et al.
first diastereomer was isolated by a second chromatography
as a light yellow solid. First diastereomer. Mp: 74-76 °C.
1H NMR (300 MHz, CDCl3): δ 5.20 (d, J ) 9 Hz, 1 H), 4.92
(m, 1 H), 4.62 (t, J ) 2.8 Hz, 1 H), 2.8 (m, 1 H), 2.05 (m, 1 H),
1.9 (s, 3 H), 1.82 (m, 6H), 1.77 (m, 1 H), 1.39 (m, 1 H), 1.20
(m, 4 H), 0.99 (m, 21 H), 0.83 (m, 4 H). 13C NMR (75 MHz,
CDCl3): δ 189.2, 144.6, 132.3, 64.8, 55.8, 40.4, 37.9, 36.3, 35.7,
30.0, 24.9, 23.5, 22.4, 19.9, 18.1, 13.8, 12.3. IR (neat, cm-1):
3273, 2932, 2864, 1644, 1556, 1463, 1372, 1078, 1031, 883, 785,
680. Anal. Calcd for C24H45NO2Si: C, 70.70; H, 11.13.
Found: C, 70.98; H, 11.12. The stereochemistry of the TIPS
ether was assigned on the basis of NOE studies on the
corresponding cyclopentenone.7
Ack n ow led gm en t. We thank the National Institute
of Health for support of this research. S.L.B. acknowl-
edges additional support as an Alfred P. Sloan Fellow
and a Camille & Henry Dreyfus Teacher-Scholar.
F.A.H. thanks the National Science Foundation for a
predoctoral fellowship. We acknowledge Ms. Natasha
Kablaoui for assisting with the NOE studies.
J O951763L