Strained enamines as versatile intermediates for stereocontrolled construction of nitrogen heterocycles

Article abstract of DOI:10.1021/jo0607921

This contribution assesses the synthetic utility of molecules that impose conformational constrains onto aziridine-derived enamines. Synthetically versatile [3.1.0] and [4.1.0] bicyclic enamines have been prepared by intramolecular oxidative cycloamination of aziridine-containing olefins. This process is initiated by N-bromosuccinimide followed by base-mediated elimination of HBr to afford highly strained exo-bicyclic enamines. In addition, intramolecular aziridine addition to aldehyde functionality was found to afford the [3.1.0] and [4.1.0] bicyclic hemiaminals. These routes highlight possibilities for chemoselective oxidative transformations of aziridine-containing precursors without nitrogen protection/deprotection steps. The resulting products provide straightforward synthetic entries into a wide range of pyrrolidine- and piperidine-containing heterocycles that are positioned toward subsequent transformations via aziridine ring opening.

Full text of DOI:10.1021/jo0607921

Strained Enamines as Versatile Intermediates for Stereocontrolled
Construction of Nitrogen Heterocycles
Gang Chen, Mikio Sasaki, Xinghan Li, and Andrei K. Yudin*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
ayudin@chem.utoronto.ca
ReceiVed April 13, 2006
This contribution assesses the synthetic utility of molecules that impose conformational constrains onto
aziridine-derived enamines. Synthetically versatile [3.1.0] and [4.1.0] bicyclic enamines have been prepared
by intramolecular oxidative cycloamination of aziridine-containing olefins. This process is initiated by
N-bromosuccinimide followed by base-mediated elimination of HBr to afford highly strained exo-bicyclic
enamines. In addition, intramolecular aziridine addition to aldehyde functionality was found to afford
the [3.1.0] and [4.1.0] bicyclic hemiaminals. These routes highlight possibilities for chemoselective
oxidative transformations of aziridine-containing precursors without nitrogen protection/deprotection steps.
The resulting products provide straightforward synthetic entries into a wide range of pyrrolidine- and
piperidine-containing heterocycles that are positioned toward subsequent transformations via aziridine
ring opening.
Introduction
D1 receptor antagonist, methylated aziridinium salt was used
as the key intermediate, which was later reacted with Grignard
reagents.6 Despite these advances, aziridines are still underuti-
lized in complex molecule synthesis.7 If functionalization of
an aziridine-containing building block is required during syn-
thesis, nitrogen protection/deprotection sequences typically
present challenges due to susceptibility of aziridines to premature
ring opening.
Our interest in synthetic applications of functionalized aziri-
dines8 has led us to evaluate the utility of aziridine-containing
strained enamines in the synthesis of larger nitrogen-containing
heterocycles. We became interested in examining the extent of
interaction between aziridine nitrogen and enamine double bond
and pursued applications of aziridine enamines as synthetic
The aziridine ring is recognized as a valuable building block
for construction of nitrogen-containing molecules.1 For example,
aziridinecarboxylates have been used as intermediates in the
synthesis of amino acids.2 Cycloadditions of N-protected aziri-
dines with Pd-trimethylenemethane complexes afford protected
piperidines.3 Under Lewis acid activation, p-toluenesulfonyl-
containing aziridines undergo cyclization with π-nucleophiles
to afford six-membered heterocycles.4 2-Methyleneaziridine
phenylselenide derivatives undergo radical cyclizations to
produce functionalized piperidines or bicyclic octahydroindoliz-
ines.5 In the large-scale synthesis of Sch 39166, a dopamine
* Corresponding author. Phone: 416-946-5042. Fax: 416-946-7676.
(1) Yudin, A. K., Ed. Aziridines and Epoxides in Organic Synthesis; John
Wiley & Sons: New York, 2006.
(2) For review, see: Lee, W. K.; Ha, H. Aldrichimica Acta. 2003, 36
(2), 57-63.
(3) Hedley, S. J.; Morgan, W. J.; Prenzel, A. H. G. P.; Price, D. A.;
Harrity, J. P. A. Synlett. 2001, 1596-1598.
(4) Bergmeier, S. C.; Katz, S. J.; Huang, J.; McPherson, H.; Donoghue,
P. J.; Reed, D. D. Tetrahedron Lett. 2004, 45, 5011-5014.
(5) (a) Prevost, N.; Shipman, M. Org. Lett. 2001, 3, 2386-2385. (b)
Prevost, N.; Shipman, M. Tetrahedron 2002, 58, 7165-7175.
(6) Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas, J.
L.; Tormos, W.; Vater, E. J. Org. Proc. Res. DeV. 1998, 2, 175-185.
(7) For use of aziridines in complex molecule synthesis, see: Tanner,
D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-619.
(8) (a) Siu, T.; Yudin, A. K. J. Am. Chem. Soc. 2002, 124, 530-531.
(b) Caiazzo, A.; Dalili, S.; Yudin, A. K. Org. Lett. 2002, 4, 2597-2560.
(c) Sasaki, M.; Dalili, S.; Yudin, A. K. J. Org. Chem. 2003, 68, 2045-
2407. (d) Watson, I. D. G.; Yudin, A. K. Curr. Opin. Drug DiscoVery.
DeV. 2002, 5, 906-917.
10.1021/jo0607921 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/11/2006
J. Org. Chem. 2006, 71, 6067-6073
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Chen et al.
SCHEME 1
intermediates. Enamines are among the most widely used
building blocks in synthesis. A conventional enamine acts as a
nucleophile in a chemical transformation by enlisting its nitrogen
lone pair toward nucleophilic attack. However, the aziridine
enamine has no such option due to a high kinetic barrier, leading
to the strained iminium species.9 During our initial foray into
this area we utilized transition-metal catalysis in order to prepare
and evaluate the unconstrained aziridine enamines.
In the area of constrained systems, our studies took advantage
of the oxidative stability of unprotected aziridines (Scheme 1).
In a preliminary communication, we described the oxidative
cycloamination of olefins with trans-aziridines through a two-
step addition-elimination protocol initiated by N-bromosuc-
cinimide. The azabicyclic compounds were synthesized and
subsequently converted into substituted pyrrolidine derivatives.10
In the present paper, we describe substantial expansion of this
method to a broad range of substrates including piperidine pre-
cursors, control of relative stereochemistry by using cis-aziri-
dines, and the possibility of cyclization through intramolecular
aziridine addition to aldehydes produced without protecting
group manipulations at nitrogen. The scope of aziridine ring-
opening reactions is explored through the synthesis of substituted
piperidines and pyrrolidines.
FIGURE 1. The aziridine-containing olefins.
(1c,d). From the key intermediate 1a, derivatives 1f and 1g were
synthesized through functionalization of the terminal olefin by
the Heck reaction15 or by the cross-metathesis.16 In the case of
metathesis, protection of the NH aziridine was found to be
mandatory, whereas the Heck coupling took place on the parent
NH system using Pd(OAc)2/P(o-tolyl)3 catalyst. Thereby, the
aziridine-containing olefins having structural variations in terms
of linker length, substituents on the olefin moiety, and cis/trans
isomerism were prepared in a few straightforward steps.
The aziridines 1a-g were converted into the corresponding
1-azabicyclo[3.1.0]hexane or 1-azabicyclo[4.1.0]heptane deriva-
tives 2a-g upon treatment with N-bromosuccinimide (Table
1). The reactions were carried out in DME/water17 or in
dichloromethane at different temperatures depending on sub-
strates. The TLC analysis indicated complete conversion of the
NH aziridine to the corresponding N-Br species 2k (Figure 2)
within the first 2 min of the reaction.18 The bromoamine sub-
sequently attacked the double bond of the molecule to give the
cycloamination product. The DME/water solvent mixture en-
abled fast conversion of the starting materials within 2 h. How-
ever, when this condition was applied to compounds 1b-d, the
bromonium intermediate was preferentially attacked by the
solvent water molecule. Instead of the cyclized product, the
bromohydrins 2j (Figure 2) were isolated. After screening a
series of solvents, the reaction was found to proceed without
the bromohydrin formation in dichloromethane. The new con-
dition B afforded higher yields of the bicycles. For the sub-
strates with trans-aziridine and two methylene linkers, the
Results and Discussion
At the outset, we considered the aziridine-containing building
blocks in which the NH aziridine unit is separated from the
olefin by several methylene linkers (Figure 1). If successful,
the cyclization of these molecules would deliver piperidine and
pyrrolidine derivatives equipped with an aziridine ring. The
pyrrolidine and piperidine rings are incorporated into the
structures of a wide range of natural products and pharmaceu-
ticals, which makes them an important class of targets for
stereoselective synthesis. For example, diverse alkaloids that
contain these rings are widely encountered in ants’ venoms and
amphibian skin.11,12 If the relative stereochemistry of the initial
cyclization products can be controlled, the cycloamination
methodology will be a valuable addition to established methods
such as stereoselective [3 + 2] cycloadditions and asymmetric
aza Diels-Alder reactions.13 This methodology would offer
additional advantages in terms of making diverse pyrrolidine
and piperidine derivatives.
The model molecules were prepared from commercially
available starting materials. The aziridine functionality was
installed by a 1,4-addition of methyl hydroxylamine to R,â-
unsaturated ketones followed by a base-promoted elimination
of methanol.14 In the elimination step, trans-aziridine was
formed exclusively at room temperature (1a,b). Upon heating
the reaction mixture, the cis-aziridine was isolated in 10% yield
(13) For reviews, see: (a) Mitchinson, A.; Nadin, A. J. Chem. Soc.,
Perkin Trans. 2000, 1 (17), 2862-2892 and references therein. (b) Pichon,
M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7 (4), 927-946 and
references therein. (c) Higasio, Y.; Shoji, T. Applied Catal. A: Gen. 2001,
221 (1-2), 197-207. For the synthesis of [5.3] bicyclic aziridines, see:
(d) Coleman, R. S.; Kong, J.-S.; Richardson, T. E. J. Am. Chem. Soc. 1999,
121, 9088-9095. (e) Mulzer, J.; Becker, R.; Brunner, E. J. Am. Chem.
Soc. 1989, 111, 7500-7504. (f) Guillemin, J. C.; Denis, J. M. Angew. Chem.
1982, 94, 715-723. (g) Chaabouni, R.; Laurent, A.; Marquet, B. Tetrahe-
dron 1980, 36, 877-885.
(9) For an account of recent contributions from our laboratory, see:
Watson, D. G.; Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194-206.
(10) Sasaki, M.; Yudin A. K. J. Am. Chem. Soc. 2003, 125, 14242-
14243.
(14) Sasaki, M, Yudin, A. K. Synlett 2004, 13, 2443-2444.
(15) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
Press: London, 1985.
(16) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34 (1), 18-29.
(17) Tamaru, Y.; Kawamura, S.; Bando, T.; Tanaka, K.; Hojo, M.;
Yoshida, Z. J. Org. Chem. 1988, 53, 5491-5501.
(18) We were able to isolate and characterize the N-Cl containing
intermediate from 1a to 2a.
(11) (a) Dewick, P. M. In Medicinal Natural Products; J. Wiley &
Sons: Chichester, 1997; Chapter 6. (b) O’Hagan, D. Nat. Prod. Rep. 2000,
17 (5), 435-446.
(12) Daly, J. W. J. Nat. Prod. 1998, 61, 162-185.
6068 J. Org. Chem., Vol. 71, No. 16, 2006

Strained Enamine Intermediates for Heterocycles
TABLE 1. Intramolecular Cycloamination of Olefins
a Condition A: DME/water ) 4:1, NBS (1.2 eq), 0 °C, 2 h. Condition B: dichloromethane (anhydrous), NBS (1.1 equiv), rt, 30 min, then 40 °C, 24 h.
b The diastereomeric ratios indicated in brackets were determined by NMR analysis (NOE, HMBC, and COSY). c The reaction was carried out at room
temperature and was completed in 4 h. Condition A affords a combined yield of 76% with dr of 41:59. d The reaction was carried out at room temperature
and was completed in 18 h. e Starting material was recovered along with a trace amount of product.
higher temperature (Table 1, entry 2).19 Meanwhile, the cis-aziri-
dine 1c (Table 1, entry 3) was found to react slower than the
trans isomer 1a, but with significantly better diastereoselectivity
due to more effective differentiation between the possible
transition states in the case of 1c (TS4 vs TS3 in Figure 3)
compared to 1a (TS2 vs TS1 in Figure 3). In the case of 1d, a
cis-aziridine containing three methylene linkers, the initial N-Br
intermediate was formed without any difficulty; however, only
a trace amount of desired product was found by crude LC/MS
(Table 1, entry 4). The aziridines with an aryl-substituted double
bond (Table 1, entry 6) preferentially gave the six-membered
ring products with bromine addition at the more substituted
position. This change of regioselectivity is due to positive charge
FIGURE 2. Bromoaziridine intermediate 2k and bromohydrin 2j.
process was faster than for the cis isomers (Table 1, entry 1
and entries 5-7). For the substrates 1b-d containing cis-aziri-
dine moieties or three methylene linkers (Table 1, entry 1-4),
the cyclization was relatively slow. For example, the aziridine
1a was converted to bicycle 2a within 4 h at room temperature
(Table 1, entry 1). In the case of 1b, which contains three meth-
ylene linkers, the reaction was much longer and required a
(19) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476-482.
J. Org. Chem, Vol. 71, No. 16, 2006 6069

Chen et al.
SCHEME 2
surprisingly stable. A single crystal of 3a was obtained. The
X-ray data shows that the bond length between C(6A) and C(7A)
is 1.32 Å, typical of an olefin system. The perpendicular
orientation of the nitrogen electron pair in relation to the double
bond is evident from crystallographic analysis.10 This interesting
and uncommon structural motif is present in the azinomycin
family of antitumor agents.20 The stereoelectronic effect of
aziridine nitrogen causes the enamine to be less nucleophilic
and, therefore, more stable in handling compared to similar
systems derived from conventional secondary amines. The
compound 3b is not as stable as 3a and rearranges to the more
thermodynamically stable endocyclic enamine 3d on silica gel
(Scheme 2). The aziridine ring in 3 is highly active toward
nucleophilic ring opening, which releases the strain of the
azabicyclic ring.
FIGURE 3. Proposed transition states leading to 2a and 2c.
TABLE 2. Elimination of HBr to the Strained Bicyclic Enamines
The molecules 1a and 1b can be further converted into
aldehydes 1h and 1i by selective oxidation of the terminal olefin.
This direct two-step oxidative cleavage gave the aldehyde in
quantitative yield (Scheme 3). This chemistry owes its efficiency
to the oxidative stability of the aziridine nitrogen, which
contrasts with the relative susceptibility of other secondary
amines to oxidative conditions that typically necessitates
protecting steps. The products underwent intramolecular cy-
clization in situ to afford diastereomeric hemiaminals 1h and
1i. The N-acetylaziridinyl aldehydes 1k and 1l were obtained
by treating the products with acetic anhydride.21
The compound 1h was obtained as a mixture of two
diasteromers, whereas its homologue 1i contained only 5%
1
of the cyclized product based on H NMR. When 1h was
treated with trimethylsilyl chloride in the presence of triethy-
lamine, the azabicyclic hemiaminal 2h was isolated with good
diastereoselectivity (Scheme 4). It is instructive to note that the
cyclization can be readily controlled by the use of base (cf.
formation of 1k and 1l). No products arising from iminium ion
1j were observed due to the high energy barrier required to form
the thermodynamically disfavored aziridinium ion (Scheme 4).
Therefore, further elaboration at the hemiaminal position on the
molecule was not pursued.
The conversion of 1h into the endo-cyclic enamine 3f under
basic condition was found to be problematic, due to the
substantial increase in strain in the target enamine. Additionally,
several attempts to direct the aziridine ring opening of 1h, 1i,
or 2h under acidic conditions were not successful. The compet-
ing reaction at the hemiaminal functionality gave back the linear
aziridine-containing aldehydes, which underwent polymeriza-
tion. The desired cyclic imine products are extremely labile and
tend to decompose during the purification process. In an
unanticipated development, the aziridine ring was cleanly
transformed into cyclic imine under basic hydrazinolysis condi-
tions. Thus, compound 1h serves as a precursor to pyrrolidine
derivatives (Table 3, entry 15).
stabilization at the benzylic position, which affords a polarized
bromonium intermediate.
From the diastereomeric bicyclic compounds 2, the desired
strained bicyclic enamines 3 were readily obtained in good to
excellent yields by simple dehydrobromination with potassium
hydroxide. The reactions proceeded smoothly at room temper-
ature in THF/methanol solution (Table 2). The products were
purified by column chromatography and were found to be
(19) Nagaoka, K.; Matsumoto, M.; Ono, J.; Yokoi, K.; Ishizeki, S.;
Nakashima, T. J. Antibiot. 1986, 39, 1527-1529.
(20) The NMR analysis was complicated due to fast equilibrium between
the hemiaminal diastereomers.
6070 J. Org. Chem., Vol. 71, No. 16, 2006

Strained Enamine Intermediates for Heterocycles
SCHEME 3
TABLE 3. Ring-Opening Reactions of Bicyclic Aziridines
SCHEME 4
The ring-opening reactions of 3a-e were found to proceed
well with different nucleophiles and to afford high yields and
excellent diastereoselectivities in most cases. The reactions are
regioselective and preferentially give the corresponding pyrro-
lidine or piperidine precursors by the ring opening at the
R-position (Table 3). The resulting enamines are in situ
tautomerized into cyclic imines. When 3a-c and 3e were treated
with trimethylsilyl azide (Table 3, entries 1, 9, 12, and 13),
pyrrolidine- or piperidine-derived azides were obtained. We
were gratified to observe stereospecific transformation of the
diastereomers 3a and 3c into the corresponding syn or anti
products. The aziridine 3a gave quantitative yield of the syn
product with no epimerization, whereas 3c afforded the anti
product along with a trace amount of the epimer, which was
separated by column chromatography. The control of the relative
stereochemistry of the azido substituent by using cis- or trans-
aziridine precursor has potential application in the synthesis of
the core structure of ficellomycin.22
Furthermore, reductive ring opening of aziridine 3a and 3b
by hydrogen on Pd/C gives pyrrolidine or piperidine derivatives
in excellent yields (Table 3, entries 2 and 10). Carboxylic acid,
alcohol, and water can serve as sources of oxygen nucleophiles
to afford the corresponding ester-, ether-, or alcohol-derived
pyrrolidine or piperidine derivatives in good yields (Table 3,
entries 3, 4, 5, and 11). All of the reactions were carried out
under acidic conditions. The aziridine ring opening was also
triggered upon basic hydrazinolysis (Table 3, entries 8, 14, and
15).23 Thus, upon treatment with hydrazine, cyclic allylamines
were prepared in moderate to good yields. If the product is
further reduced with DIBAL-H, the cis-pyrrolidine is obtained
in good yields (Table 3, entry 15). The bicycles can also react
with sulfur and halogen nucleophiles to afford sulfides and halo
derivatives, though in these instances epimerization of the
R-stereocenter afforded the mixture of diastereomers.
a The product epimerizes to afford a mixture of two diastereomers (dr
) 70:30 by 1H NMR). b The product epimerizes to afford a mixture of two
1
diastereomers (dr ) 75:25 by H NMR).
(21) (a) Argoudelis, A. D.; Reusser, F.; Whaley, H. A. J. Antibiot. 1976,
29 (10), 1001-1006. (b) Kuo, M.-S.; Yurek D. A.; Mizsak, S. A. J. Antibiot.
1989, 42 (3), 357-360.
In summary, we have shown that the versatile chemistry of
strained bicyclic enamines enables straightforward construction
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Chen et al.
δ 8.02-8.05 (m, 2H), 7.57-7.59 (m, 1H), 7.47-7.51 (m, 2H),
3.46-3.62 (m, 3H), 3.35 (d, J ) 2.4 Hz, 1H), 2.69-2.71 (m, 1H),
2.07-2.15 (m, 1H), 1.66-1.78 (m, 2H), 1.45-1.57 (m, 1H), 1.20-
1.30 (m, 1H). NMR (CDCl3, 100 MHz) δ 196.6, 137.2, 133.8,
128.8, 128.5, 55.8, 41.5, 40.5, 37.2, 23.3, 20.3, 18.9; HR-MS (ESI)
m/z calcd for C14H17NOBr (M + H+) 294.0488, found 294.0498.
General Procedure for Dehydrobromination. To a mixture
of 2a (mixture of diastereomers), THF (200 mL), and methanol (2
mL) was added crushed potassium hydroxide (1.4 g, 25 mmol) at
room temperature and the mixture stirred for 4 h. Upon completion
(as judged by TLC), dichloromethane (500 mL) and water (300
mL) were added, the layers were then separated, and the water layer
was extracted with dichloromethane (150 mL). The combined
organic layers were washed with water (200 mL) followed by drying
over sodium sulfate, and the solvent was removed in vacuo, to give
1.70 g of (5R*,6S*)-(2-methylene-1-azabicyclo[3.1.0]hex-6-yl)-
phenylmethanone (3a, quant. yield). Further purification was
achieved on a silica gel column (hexane/ethyl acetate ) 6/4).
(5R*,6S*)-(2-Methylene-1-azabicyclo[3.1.0]hex-6-yl)phenylmeth-
anone (3a): 1H NMR (CDCl3, 400 MHz) δ 8.02-8.05 (m, 2H),
7.61-7.65 (m, 1H), 7.50-7.54 (m, 2H), 5.31 (d, J ) 1.6 Hz, 1H),
4.74 (d, J ) 1.6 Hz, 1H), 3.22-3.25 (m, 2H), 2.24-2.60 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ 196.2, 158.6, 136.8, 133.3, 128.7,
128.4, 101.9, 50.6, 45.4, 26.2, 25.3; HR-MS (EI) m/z calcd for
C13H13NO 199.0997, found 199.0998.
General Procedure of Aziridine Opening with Azidotrimeth-
ylsilane. (2S*,2′S*)-2-Azido-2-(5′-methyl-3′,4′-dihydro-2H-pyr-
rol-2′-yl)-1-phenylethanone (Table 3, entry 1). To a mixture of
3a (380 mg, 1.9 mmol), dichloromethane (10 mL), and water (343
mg, 19 mmol) was added azidotrimethylsilane (440 mg, 3.8 mmol)
at room temperature and the mixture stirred overnight. Upon
completion (as judged by TLC), the solvent and other volatiles were
removed in vacuo to give 460 mg of (2S*,2′S*)-2-azido-2-(5′-
methyl-3′,4′-dihydro-2H-pyrrol-2′-yl)-1-phenylethanone (quant.
yield): 1H NMR (CDCl3, 300 MHz) δ 8.04-8.07 (m, 2H), 7.65-
7.71 (m, 1H), 7.53-7.59 (m, 2H), 5.44 (d, J ) 3.6 Hz, 1H), 4.63-
4.68 (m, 1H), 2.67-2.79 (m, 1H), 2.49-2.61 (m, 1H), 2.13 (d, J
) 1.5 Hz, 3H), 1.81-2.02 (m, 2H); 13C NMR (CDCl3, 100 MHz)
δ 194.8, 178.1, 134.9, 134.0, 129.0, 128.8, 73.8, 67.5, 39.6, 23.2,
19.7; HR-MS (ESI) m/z calcd for C13H15N4O (M + H+) 243.1240,
found 243.1246.
General Procedure of Hydrogenation of Aziridine. 2-(5′-
Methyl-3′,4′-dihydro-2H-pyrrol-2′-yl)-1-phenylethanone. (Table
3, entry 2). A mixture of 3a (20 mg, 0.1 mmol), 10% palladium
on carbon (2 mg), and methanol (1 mL) was stirred under hydrogen
(1 atm) at room temperature for 1 h. The solid was removed by
filtration and the solvent was removed from the filtrate in vacuo,
to give 20 mg of 2-(5′-methyl-3′,4′-dihydro-2H-pyrrol-2′-yl)-1-
phenylethanone (quant. yield): 1H NMR (CDCl3, 300 MHz) δ
7.99-8.02 (m, 2H), 7.56-7.61 (m, 1H), 7.46-7.51 (m, 2H), 4.53-
4.58 (m, 1H), 3.64 (dd, J ) 16.8 Hz, 4.5 Hz, 1H), 2.98 (dd, J )
16.8 Hz, 9.0 Hz, 1H), 2.53-2.61 (m, 2H), 2.26-2.37 (m, 1H),2.07
(d, J ) 1.5 Hz, 3H), 1.47-1.60 (m, 1H); 13C NMR (CDCl3, 75
MHz) δ 198.6, 175.1, 137.1, 133.1, 128.6, 128.2, 68.8, 45.5, 39.1,
29.6, 19.8.
General Procedure of Aziridine Opening with Water.
(2S*,2′S*)-2-Hydroxy-2-(5′-methyl-3′,4′-dihydro-2H-pyrrol-2′-
yl)-1-phenylethanone (Table 3, entry 4). To the mixture of 3a
(100 mg, 0.5 mmol) in dichloromethane (5 mL) was added
trifloroacetice acid (56 µL, 0.5 mmol). The reaction was stirred at
room temperature for 5 min. Sodium bicarbonate aqueous solution
(5 mL) was added. The mixture was extracted with dichloromethane
and washed with brine. The combine organic layer was dried and
concentrated. The residue was purified by silica gel column (EtOAc)
to afford (2S*,2′S*)-2-hydroxy-2-(5-methyl-3,4-dihydro-2H-pyrrol-
2-yl)-1-phenylethanone as a yellow oil (102 mg, 94%): 1H NMR
(CDCl3, 400 MHz) δ 8.01 (d, J ) 7.2 Hz, 2H), 7.60 (t, J ) 7.2
Hz, 1H), 7.48 (t, J ) 8.0 Hz, 2H), 5.59 (b, 1H), 4.42 (b, 1H), 3.81
(b, 1H), 2.52-2.62 (m, 1H), 2.31-2.42 (m, 1H), 2.05 (d, J ) 1.2
of a variety of heterocyclic products with high levels of
stereocontrol. The unprotected aziridines undergo cyclization
through addition-elimination to afford [n.1.0] strained azabi-
cyclic enamines or through addition to aldehyde to afford the
[n.1.0] hemiaminal compounds. In the presence of nucleophiles,
the strained bicyclic enamines undergo regio- and diastereose-
lective ring openings. The strain-release step affords various
cyclic imines that are not readily available using conventional
protocols. The stereospecificity of these transformations is
noteworthy. If the imine functionalities are further reduced in
the subsequent step, substituted piperidine or pyrrolidine deriva-
tives can be synthesized. Applications of this methodology in
target-oriented synthesis are in progress.
Experimental Section
General Procedure for Intramolecular Cycloamination.
Method A. To a mixture of 1a (2.5 g, 12.4 mmol), dimethoxyethane
(100 mL), and water (25 mL) was added N-bromosuccinimide (2.65
g, 14.9 mmol) at 0 °C. The mixture was stirred for 2 h in an ice
bath. After completion (as judged by TLC), 10% aqueous Na2SO3
(50 mL) and diethyl ether (100 mL) were added. The layers were
separated, and the water layer was extracted with diethyl ether (50
mL). The combined organic layers were dried over sodium sul-
fate, and the solvent was removed in vacuo. It is essential to
maintain the bath at lower than room temperature during solvent
evaporation. The residue was purified on a silica gel column
(hexane/ethyl acetate ) 6/4) to afford (2R*,5R*,6S*)-(2-bromo-
methyl-1-azabicyclo[3.1.0]hex-6-yl)phenylmethanone (1.08 g) and
(2S*,5R*,6S*)-(2-bromomethyl-1-azabicyclo[3.1.0]hex-6-yl)phenyl-
methanone (1.56 g) (2a, combined yield 76%; diastereomeric ratio
41:59). (2R*,5R*,6S*)-2a: 1H NMR (CDCl3, 400 MHz) δ 8.00-
8.02 (m, 2H), 7.61-7.64 (m, 1H),7.50-7.53 (m, 2H), 3.68-3.73
(m, 2H), 3.25-3.30 (m, 1H), 3.03 (d, J ) 2.5 Hz, 1H), 2.97 (dd,
J ) 4.5 Hz, 2.5 Hz, 1H), 2.19-2.35 (m, 2H), 2.01-2.06 (m, 1H),
1.78-1.85 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 195.9, 136.9,
133.3, 128.7, 128.2, 66.3, 49.9, 41.5, 35.7, 25.2, 24.4. (2S*,5R*,6S*)-
2a: 1H NMR (CDCl3, 400 MHz) δ 7.99-8.02 (m, 2H), 7.57-
7.61 (m, 1H), 7.46-7.50 (m, 2H), 3.68-3.75 (m, 2H), 3.48-3.52
(m, 1H), 3.27 (d, J ) 2.5 Hz, 1H), 2.93 (dd, J ) 4.5 Hz, 2.5 Hz,
1H), 2.35 (dd, J ) 14.0, 8.0, 1H), 2.12-2.19 (m, 1H), 1.95-2.01
(m, 1H), 1.37-1.44 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 195.0,
137.0, 133.3, 128.7, 128.2, 65.0, 49.1, 35.9, 33.1, 27.0, 25.1.
Method B. To a mixture of 1b (0.500 g, 2.33 mmol) and
dichloromethane (50 mL) was added N-bromosuccinimide (0.456
g, 2.56 mmol) at room temperature. The mixture was stirred for
30 min. After starting material was converted to the N-Br species
(judged by TLC, Rf ) 0.8 in ethyl acetate/hexanes ) 2/8) the
mixture was heated at 40 °C for 24 h. Toward the end of the
reaction, all of the N-Br species was consumed and precipitate
was formed. The reaction was filtrated to remove the insol-
uble material. The filtrate was concentrated and the residue was
purified on a silica gel column to afford (2R*,5R*,6S*)-(2-
bromomethyl-1-azabicyclo[4.1.0]hept-7-yl)phenylmethanone (470
mg) and (2S*,5R*,6S*)-(2-bromomethyl-1-azabicyclo[4.1.0]hept-
7-yl)phenylmethanone (132 mg) (2b, combined yield 88%; dia-
stereomeric ratio 78:22). (2R*,5R*,6S*)-2b: 1H NMR (CDCl3, 400
MHz) δ 8.00-8.03 (m, 2H), 7.56-7.61 (m, 1H), 7.48-7.51 (m,
2H), 3.64 (dd, J ) 10 Hz, J ) 6.4 Hz, 1H), 3.40 (dd, J ) 10 Hz,
J ) 7.6 Hz, 1H), 3.18 (d, J ) 3.2 Hz, 1H), 2.83-2.88 (m, 1H),
2.62-2.65 (m, 1H), 1.97-2.12 (m, 3H), 1.72-1.78 (m, 1H), 1.35-
1.39 (m, 1H), 1.16-1.22 (m, 1H). NMR (CDCl3, 100 MHz) δ
196.9, 137.1, 133.4, 128.8, 128.5, 61.8, 47.4, 42.4, 38.4, 26.7, 21.8,
17.6; HR-MS (ESI) m/z calcd for C14H17NOBr (M + H+) 294.0488,
found 294.0495. (2S*,5R*,6S*)-2b:1H NMR (CDCl3, 400 MHz)
(22) Chen, G.; Sasaki, M.; Yudin, A. K. Tetrahedron Lett. 2006, 47,
255-259.
6072 J. Org. Chem., Vol. 71, No. 16, 2006

Strained Enamine Intermediates for Heterocycles
Hz, 3H), 1.42-1.70 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ200.4,
176.7, 134.1, 133.6, 128.9, 128.7, 75.3, 75.2, 40.0, 20.9, 19.6;
HR-MS (ESI) m/z calcd for C13H16NO2 (M + H+) 218.1176, found
218.1186.
11.4 Hz, 1H), 5.59 (dd, J ) 11.4 Hz, 9.6 Hz, 1H), 4.92-5.01 (m,
1H), 2.46-2.70 (m, 2H), 2.17-2.28 (m, 1H), 2.11 (d, J ) 1.8 Hz,
3H), 1.62-1.75 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 175.5,
137.1, 134.4,129.9, 129.0, 128.1, 126.9, 69.9, 39.4, 30.9, 19.9; HR-
MS (EI) m/z calcd for C13H15N 185.1205, found 185.1202.
General Procedure for Hydrazine Reduction. 5-Methyl-2-
styryl-3,4-dihydro-2H-pyrrole (Table 3, entry 8). A mixture of
3a, (100 mg, 0.5 mmol), hydrazine monohydrate (250 mg, 5.0
mmol), potassium hydroxide (84 mg, 1.5 mmol), and ethylene
glycol (2 mL) was stirred at 100 °C for 30 min. Upon completion
as judged by TLC, dichloromethane (10 mL) and water (10 mL)
were added, and the aqueous layer was extracted with dichlo-
romethane (5 mL). The combined organic layers were washed with
water (10 mL) followed by drying over sodium sulfate, and the
solvent was removed in vacuo. The residue was purified on a silica
gel column (dichloromethane/methanol ) 9/1) to give 5-methyl-
2-styryl-3,4-dihydro-2H-pyrrole (60 mg, 65%): 1H NMR (CDCl3,
300 MHz) δ 7.34-7.45 (m, 4H), 7.24-7.30 (m, 1H), 6.59 (d, J )
Acknowledgment. We thank NSERC, Canada Foundation
for Innovation, ORDCF, Amgen, and University of Toronto for
financial support. Sumitomo Chemical Co, Ltd. is gratefully
acknowledged for a fellowship (M.S.).
Supporting Information Available: Experimental procedures
and spectra data for 1a-l, 2c-h, 3b-e and products in Table 3.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0607921
J. Org. Chem, Vol. 71, No. 16, 2006 6073