Divergent selectivity in Mgl2-mediated ring expansions of methylenecyclopropyl amides and imides

Article abstract of DOI:10.1021/ja011110o

We report a novel approach to prepare five- and six-membered heterocyclic compounds via a ring expansion of monoactivated methylenecyclopropanes (MCPs) with aldimines and aldehydes in the presence of MgI₂. Monoactivated MCPs behave as homo-Mich

Full text of DOI:10.1021/ja011110o

Published on Web 05/10/2002
Divergent Selectivity in MgI2-Mediated Ring Expansions of
Methylenecyclopropyl Amides and Imides
Mark Lautens* and Wooseok Han
Contribution from the DaVenport Research Laboratories, Department of Chemistry,
UniVersity of Toronto, Toronto, Ontario, Canada M5S 3H6
Received May 2, 2001
Abstract: We report a novel approach to prepare five- and six-membered heterocyclic compounds via a
ring expansion of monoactivated methylenecyclopropanes (MCPs) with aldimines and aldehydes in the
presence of MgI2. Monoactivated MCPs behave as homo-Michael acceptors to afford bifunctional vinylogous
enolates in the presence of MgI2. The carbonyl moiety of the monoactivated MCP dramatically influences
the reaction site in the dienolate with aryl aldimines and aldehydes as well as the size of the ring. Excellent
divergent selectivity to five- vs. six-membered heterocycles is observed: R-alkylation/5-exo-tet cyclization
(Z ) NPh2) vs. γ-alkylation/6-exo-trig cyclization (Z ) 2-oxazolidone). Analogously, the reaction of the
MCP imide with alkyl aldimines demonstrates the same selectivity by varing the size of electrophile or the
reaction temperature. In addition, we observe the first example of the formation of the γ-alkylation adduct
in the reaction of a vinylogous imide enolate with a carbonyl compound.
Scheme 1
Introduction
Ring expansion reactions1 of highly strained rings such as
cyclopropanes constitute an efficient method for the construction
of cyclic compounds. One useful approach to ring expansion
involves the ring opening of a monoactivated or doubly-activated
cyclopropane, which can act as a homo-Michael acceptor,2
where the enolate or enol intermediate generated in situ acts as
a nucleophile in a cyclization. Recently, Carreira and co-workers
reported the ring expansion reaction of spiro[cyclopropane-1,3′-
oxindole] with aldimines in the presence of catalytic MgI2 which
nicely illustrates this concept.3 One example of a cyclopropan-
ecarboxamide was disclosed as shown in Scheme 1.
intermediates9 leading to ring opening or expansion. For
instance, we studied a palladium-catalyzed hydrostannation of
MCPs where ring opening was observed.10
A few reactions of MCPs activated by an electron withdraw-
ing group have been reported. Nakamura and co-workers
reported the thermal [3+2] cycloaddition reactions of highly
activated methylenecyclopropanone derivatives with aldehydes
and imines.11 A thermally generated dipolar TMM (trimethyl-
enemethane) was used as a reactive intermediate. The TiCl4-
mediated [3+2] cylcoaddition reactions of MCP ketones with
allyltrimethylsilane were reported by Monti and co-workers12
where the ketone, activated by TiCl4, produced a zwitterionic
reactive intermediate. Recently, Liu and co-workers described
that the key step of the inactivation of crotonase is the ring
opening of (methylene-cyclopropyl)formyl-CoA as homo-
Michael acceptor.13
In contrast, the most widely investigated reactions of meth-
ylenecyclopropanes (MCPs) are [3+2] cycloaddition processes.4
We have examined the stereoselectivity in transition metal
catalyzed intramolecular [3+2] cycloadditions of MCPs with
alkynes and alkenes for the synthesis of five-membered car-
bocycles.5 In addition, the double bond of MCPs has been used
as a dienophile6 in cycloaddition reactions and as an acceptor
for reactive species such as radicals,7 cations,8 and metal
* Corresponding author. E-mail: mlautens@chem.utoronto.ca.
(1) For recent reviews, see: (a) Kantorowsk, E. J.; Kurth, M. J. Tetrahedron
2000, 56, 4317. (b) Kim, S.; Yoon, J.-Y. Synthesis 2000, 1622. (c) Hoberg,
J. O. Tetrahedron 1998, 54, 12631.
(7) For a recent publication, see: Boffey, R.; Whittingham, W. G.; Kilburn, J.
D. J. Chem. Soc., Perkin Trans. 1 2001, 487.
(2) (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.;
Hudlicky, T. Chem. ReV. 1989, 89, 165. (b) Danishefsky, S. Acc. Chem.
Res. 1979, 12, 66.
(3) (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M.
Angew. Chem., Int. Ed. 1999, 38, 3186. (b) Fischer, C.; Meyers, C.; Carreira,
E. M. HelV. Chim. Acta 2000, 83, 1175.
(4) For reviews, see: (a) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996,
96, 49. (b) Binger, P.; Bu¨ch, M. Top. Curr. Chem. 1987, 135, 77. (c) Trost,
B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1.
(5) (a) Lautens, M.; Ren, Y.; Delanghe, P. H. M. J. Am. Chem. Soc. 1994,
116, 8821. (b) Lautens, M.; Ren, Y. J. Am. Chem. Soc. 1996, 118, 9597.
(c) Lautens, M.; Ren, Y. J. Am. Chem. Soc. 1996, 118, 10668.
(6) Goti, A.; Cordero, F. M.; Brandi, A. Top. Curr. Chem. 1996, 178, 1.
(8) For recent publications, see: (a) Miura, K.; Takasumi, M.; Hondo, T.; Saito,
H.; Hosomi, A. Tetrahedron Lett. 1997, 38, 4587. (b) Peron, G. L. N.;
Kitteringham, J.; Kilburn, J. D. Tetrahedron Lett. 1999, 40, 3045.
(9) Nishihara, Y.; Yoda, C.; Osakada, K. Organometallics 2001, 20, 2124 and
references therein.
(10) Lautens, M.; Meyer, C.; Lorenz, A. J. Am. Chem. Soc. 1996, 118, 10676.
(11) (a) Yamago, S.; Nakamura, M.; Wang, X. Q.; Yanagawa, M.; Tokumitsu,
S.; Nakamura, E. J. Org. Chem. 1998, 63, 1694 and references therein.
For the palladium-catalyzed [3+2] cycloaddition of alkylidenecyclopropanes
with aldehydes and imines, see: (b) Nakamura, I.; Oh, B. H.; Saito, S.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2001, 40, 1298. (c) Oh, B. H.;
Nakamura, I.; Saito, S.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 6203.
(12) Monti, H.; Rizzotto, D.; Le´andri, G. Tetrahedron 1998, 54, 6725.
9
6312
J. AM. CHEM. SOC. 2002, 124, 6312-6316
10.1021/ja011110o CCC: $22.00 © 2002 American Chemical Society

MgI2-Mediated Ring Expansions of MCP Amides and Imides
A R T I C L E S
Scheme 2
Table 1. Reactions between MCP Amide 1a and Aryl Aldimines
Scheme 3
entry
3
X
Y
time (h)
6
yield (%)b
d.r. (trans:cis)
1
2
a
b
c
d
e
e
f
g
h
i
NTsc 4-CF3
10
6
10
6
6
15
6
10
10
10
a
b
c
d
e
e
f
g
h
i
65
1.6:1
2.2:1
NTs
NTs
NTs
NBsc
NBs
NTs
NTs
NTs
NTs
4-NO2
4-Br
4-OMe
H
H
2-Br
2-CF3
2,4-dichloro
2,4-dimethyl
57d
85d,e
78
3
2.3:1
4
5.3:1
5
81
4.1:1
6
76f
71
3.8:1
7
>20:1g
>20:1g
>20:1g
>20:1g
8
81d,e
78e
82e
9
10
Inspired by the work of Carreira and Liu, we envisioned that
monoactivated MCPs would be a homo-Michael acceptor. Thus,
the ring opening of 1 could afford a Vinylogous enolate
intermediate 2 having both nucleophilic and electrophilic centers
(Scheme 2). Enolate 2 could then undergo reaction with
electrophiles such as aldehydes or aldimines at the R- or γ-site
followed by a cyclization reaction, leading to two different
regioisomeric five-membered heterocycles (Scheme 3). During
the course of investigating the reaction of several monoactivated
MCPs 1, unexpected divergent selectivty to five- vs. six-
membered heterocyclic compounds was observed depending on
the nature of Z, the size of the electrophile, and the reaction
temperature.
a Reactions were carried out in refluxing THF (0.05 M) with a
stoichiometric amount of MgI2 unless mentioned. b Isolated yield. c Ts )
4-toluenesulfonyl, Bs ) benzenesulfonyl. d The relative stereochemistry for
the major diastereomer was proven to be trans by X-ray crystallography.
e The reactions were carried out with 30 mol % MgI2. f The reaction was
carried out with 10 mol % MgI2 in 0.2 M THF. g Only one diastereomer
1
was observed in the crude H NMR.
an inseparable mixture of diastereomeric methylenetetrahydro-
furans, which could not be identified. In the case of 2-bro-
mobenzaldehyde, the minor diastereomer was contaminated with
Scheme 4
We now report the development of a novel tandem cyclization
via a bifunctional vinylogous enolate intermediate generated in
situ from a monoactivated MCP in the presence of MgI2.
an unknown byproduct, but the major diastereomer 4 (i.e.
structure 6e where X ) O, see Supplementary Material) was
isolated in 41% yield.
We attempted the ring opening reaction of 1d with MgI2 in
the absence of electrophiles (Scheme 4). In refuxing THF, the
dienolate intermediate 2d was smoothly produced and then
Results and Discussion
Reaction of MCP Amides. Our studies began with the
reactions of several monoactivated MCP esters14 1a and amides
1b, 1c, and 1d with aryl aldimines in the presence of stoichio-
metric MgI2. Initial attempts to react 1a-c with 3e in refluxing
THF did not succeed. Ester 1a did not react with MgI2 whereas
amides 1b and 1c gave complex mixtures even in the reactions
with aryl aldehydes. In contrast the diphenyl amide 1d reacted
with 3e to yield the methylenepyrrolidine 6e in good yield as a
mixture of diastereomers (Table 1). The formation of 6e
indicates a highly regioselective R-alkylation of the dienolate
intermediate 2d takes place. Reactions of the aldimines having
a para-substituent yielded two diastereomers in good yields and
modest to good stereoselectivities (entries 1, 2, and 4).
Significantly, in the case of aldimines bearing an ortho-
substitutent (entries 7-10) only the trans diastereomers were
obtained. Furthermore, it was found that the use of stoichio-
metric MgI2 is not required since the reactions could also be
carried out with 10-30 mol % of MgI2 without any loss in
yield (entries 3, 6, and 8-10). When 10 mol % MgI2 was used,
an increase in the reaction concentration to 0.2 M was required
to ensure complete reaction (entry 6).
Table 2. Reactions between MCP Imide 1e and Aryl Aldimines
and Aldehydes
yield
c
entry
3
X
Y
method
7
Nuc
N3
I
N3
Ts
OAc
N3
SPh
OAc
Ts
(%)d
1
2
3
4
5
6
7
8
9
c
c
j
g
i
k
l
m
n
o
NTs
NTs
NTs
NTs
NTs
O
O
O
O
O
4-Br
4-Br
H
2-CF3
2,4-dimethyl
H
2-Br
4-NO2
3,4-OCH2O
2,4-dichloro
A
B
A
B
A
A
A
B
A
B
c
c′
j
g
i
k
l
m
n
o
78e
60f
81
75
72
88
67
71
65
74
10
N3
We also examined the reaction with aryl aldehydes under
the same conditions. Reaction of 1d with benzaldehyde gave
a Reactions were carried out using a stoichiometric amount of MgI2 in
THF (0.05 M). b The crude product was used for the next step without
purification. c Method A: 0 °C to room temperature for 3 h. Method B:
reflux for 1 h. d Isolated yield in two steps. e The structure of the product
was identified by X-ray crystallography. f Compound 7c′ was isolated using
silica flash chromatography and fully characterized by spectroscopic
analysis, but it was not stable.
(13) (a) Li D.; Guo, Z.; Liu, H.-w. J. Am. Chem. Soc. 1996, 118, 275. (b) Li,
D.; Agnihotri, G.; Dakoji, S.; Oh, E.; Lantz, M.; Liu, H.-w. J. Am. Chem.
Soc. 1999, 121, 9034.
(14) For a recent review of the synthesis of MCP derivatives, see: Brandi, A.;
Goti, A. Chem. ReV. 1998, 98, 589.
9
J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002 6313

A R T I C L E S
Lautens and Han
Scheme 5
Scheme 6
trapped with NaN3 resulting in the isolation of the γ′-azido-
â,γ-unsaturated amide 5 in 66% yield.
Reaction of MCP Imide. We reasoned that a more strongly
activated MCP 1 could undergo the facile ring opening reaction
under much milder conditions. MCP imide 1e bearing a
2-oxazolidone reacted under the same conditions with aldimines
3 very quickly (entries 2 and 4, Table 2) and these reactions
were rapid even at 0 °C (entries 1, 3, and 5). However, to our
surprise, in contrast to the results with the diphenyl amide 1d,
the products obtained were exclusively six-membered hetero-
cycles 7 bearing an allyl iodide and lacking the oxazolidone
group. The reaction required a stoichiometric amount of MgI2
in order to go to completion. The products 7 were isolated after
functional group transformation because the iodo-substituted
products were not stable to silica flash chromatography. In
addition, reactions with aryl aldehydes furnished 5,6-dihydro-
pyranones 7 in good yields in two steps (entries 6-10, Table
2).
the R-alkylation adduct.16 To the best of our knowledge, this is
the first example of the γ-alkylation of a Vinylogous imide
enolate.
At this time we cannot completely exclude a concerted [4+2]
hetero-Diels-Alder reaction pathway17 to 7 (Scheme 6). Thus,
the intermediate 2e could react with an aldimine leading to a
cycloadduct 14, which would generate a six-membered hetero-
cycle 7 via expulsion of the Z group.
To expand the scope of the reaction, we investigated the
reaction with alkyl aldimines18 (Table 3). Whereas 7 was the
only product in the reactions with aryl aldimines (Table 2), the
reaction of 1e with alkyl aldimine 8p furnished the methyl-
enepyrrolidine 6p as a major product (entry 1, Table 3) even in
the presence of only 30 mol % MgI2 (entry 2). Reaction with a
more hindered imine such as 8q led to a mixture of 6q and 7q
in a ratio of ∼1:1 with a concomitant formation of 9q19 (entry
4). Reaction with the most hindered imine 8r did not give any
ring expanded products (entry 6). Significantly, in refluxing
THF, 8q and even 8p furnished only six-membered pyridinones
7p and 7q in moderate yields (entries 3 and 5) while 8r failed
completely (entry 6). It appears these reactions are governed
by the size of alkyl aldimines 8 and the reaction temperature.
The monoactivated MCPs 1 can potentially undergo the
tandem cyclization leading to four possible cycloadducts: 6, 7,
12, and 13 (Scheme 5). The reaction of the amide 1d furnished
only the five-membered heterocycles 6 via R-alkylation followed
by 5-exo-tet cyclization pathway a, whereas the reaction of the
imide 1e proceeded via γ-alkylation followed by 6-exo-trig
cyclization pathway d resulting in the exclusive formation of
six-membered heterocycles 7. Clearly, the substituent Z has a
dramatic influence on the site of the alkylation and the eventual
size of the ring formed. The facility of the tandem cyclizations
can be attributed to the presence of a good leaving group: the
allyl iodide in 10 or the oxazolidone15 in 11. We note that
intermediate 11 having two potentially good leaving groups
prefers 6-exo-trig cyclization (pathway d) to 5-exo-tet cyclization
(pathway c).
(16) For a general review for vinylogous aldol reaction, see: (a) Casiraghi, G.;
Zanardi, F.; Appendino, G. Chem. ReV. 2000, 100, 1929. For examples of
vinylogous imide enolates, see: (b) Evans, D. A.; Sjogren, E. B.; Bartroli,
J.; Dow, R. L. Tetrahedron Lett. 1986, 27, 4957. (c) Black, W. C.; Giroux,
A.; Greidanus, G. Tetrahedron Lett. 1996, 37, 4471.
(17) For a discussion of a stepwise vs. a cycloaddition mechanism, see a recent
review of the vinylogous Mannich reaction: Bur, S. K.; Martin, S. F.
Tetrahedron 2001, 57, 322
More significantly, it is known that the reaction of vinylogous
imide enolates with carbonyl compounds generally affords only
(18) Reactions of 1d and 1e with aliphatic aldehydes do not afford any products.
In the case of 1d, no reaction with alkyl aldimines occurred. In the presence
of MgI2, these electrophiles bearing an acidic proton appear not to be stable
in refluxing THF.
(15) For example, it was easily removed from acyloxazolidinone in the presence
of methoxymagnesium halide. See: Evans, D. A.; Morrissey, M. M.;
Dorow, R. L. J. Am. Chem. Soc. 1985, 107, 4346.
(19) These products were not observed in the reactions in Table 2.
9
6314 J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002

MgI2-Mediated Ring Expansions of MCP Amides and Imides
A R T I C L E S
Table 3. Reactions between MCP Imide 1e and Alkyl Aldimines
obtained on a VG70-250S (double focusing) mass spectrometer at 70
eV. Melting points were measured with a Fisher-Johns melting point
apparatus.
Tosyl aryl aldimines and alkyl aldimines were prepared in moderate
to good yields according to the known methods.20 2-Methylenecyclo-
propanecarboxylic acid ethyl ester (MCP ester, 1a) and 2-methylenecy-
clopropanecarboxylic acid (MCP acid, 1z) were prepared from 2-bro-
mopropene.21 MCP amides 1b-d and MCP imide 1e were prepared
from 1z.
yield (%)d
c
entry
8
R
method
6 (trans:cis)
7
9
1
2
3
4
5
6
p
n-propyl
n-propyl
n-propyl
cyclohexyl
cyclohexyl
t-butyl
A
B
C
A
72 (6.2:1)
66 (4.5:1)
0
11
8
e
e
e
Representative Procedure for the Synthesis of Methylenepyrro-
lidines from MCP Amide (1d) and Aryl Aldimines. To a solution of
MCP amide 1d (77.4 mg, 0.31 mmol) and aldimine 3d (95.4 mg, 0.33
mmol) in THF (6 mL, 0.05 M) was added MgI2 (86.2 mg, 0.31 mmol)
rapidly under a positive nitrogen pressure. The reaction mixture was
gently refluxed at 80 °C (oil bath temperature) for 6 h. The reaction
mixture was then cooled to room temperature and quenched with a
small portion of saturated aqueous Na2SO3 solution. The mixture was
extracted with EtOAc (2 × 100 mL) and the combined organic phases
were washed with H2O (200 mL), brine (200 mL), dried over MgSO4,
filtered, and concentrated. Two diastereomers of 6d (129 mg, 78%)
were isolated by flash chromatography on silica gel (ethyl acetate:
hexanes 1:5 f 1:3), which furnished the trans diastereomer (108 mg)
as a white solid and the cis diastereomer as a colorless oil (21 mg).
trans-2-(4-Methoxyphenyl)-4-methylene-1-(4-toluenesulfonyl)pyr-
rolidine-3-carboxylic acid diphenylamide (6d): white solid, mp 225-
227 °C (ethyl acetate), Rf ) 0.21 (silica gel, EtOAc:hexanes 1:3); IR
(CHCl3) νmax (cm-1) 3060, 2918, 2847, 1674, 1610, 1594, 1510, 1490,
1449, 1345, 1291, 1246, 1159, 1094, 1072, 1027, 843, 808, 752, 698;
1H NMR (300 MHz, CDCl3) δ 7.61-7.56 (m, 2H), 7.32-7.05 (m,
10H), 7.09-6.96 (m, 2H), 6.89-6.83 (m, 2H), 6.74-6.61 (bs, 2H),
5.04 (dm, 1H, J ) 2.19 Hz), 4.99 (dm, 1H, J ) 2.19 Hz), 4.62 (d, 1H,
J ) 7.95 Hz), 4.25 (dm, 1H, J ) 13.96 Hz), 4.00 (ddd, 1H, J ) 13.96,
2.19, 2.19 Hz), 3.85 (s, 3H), 3.72 (m, 1H), 2.41 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 170.0, 159.6, 144.0, 142.6, 132.8, 131.8, 129.8, 129.1,
128.5, 128.5, 128.4, 126.6, 126.3, 114.0, 108.5, 68.0, 58.1, 55.6, 54.6,
21.8; HRMS calcd for C32H30N2O4S (M)+ 538.1926, found 538.1914.
cis-2-(4-Methoxyphenyl)-4-methylene-1-(4-toluenesulfonyl)pyr-
rolidine-3-carboxylic acid diphenylamide (6d): colorless oil, Rf )
0.42 (silica gel, EtOAc:hexanes 1:3); IR (CHCl3) νmax (cm-1) 3305,
3061, 2924, 2832, 1650, 1611, 1592, 1512, 1489, 1447, 1386, 1337,
1321, 1269, 1249, 1154, 1090, 1032, 963, 906, 811, 761, 731, 700,
p
p
q
qg
r
23
34f
40
0
31 (>20:1)
30f
42
0
C
0
0
A or C
a Reactions were carried out with a stoichiometric amount of MgI2 in
THF (0.05 M). b The crude product was used for the next step without
purification. c Method A: 0 °C to room temperature for 3 h. Method B:
30 mol % of MgI2, room temperature for 7 h. Method C: reflux for 10
min. d Isolated yield in two steps. e Not determined. f The structure of the
product was identified by X-ray crystallography. g Two equivalents of 8q
were used.
By controlling these two factors, it is possible to obtain two
different heterocycles from the reactions of 1e with alkyl
aldimines 8.
Conclusion
In conclusion, we have discovered a novel methodology to
prepare five- and six-membered heterocyclic compounds via a
tandem cyclization of monoactivated MCPs with aldimines or
aldehydes in the presence of MgI2. A key step is the in situ
generation of an ambiphilic vinylogous enolate intermediate
through the ring opening of a monoactivated MCP. In the
reaction of monoactivated MCPs 1 with aryl aldimines and
aldehydes, excellent divergent selectivity (five-membered vs.
six-membered heterocycle) was achieved by changing the Z
group in the carbonyl moiety of 1. When the imide 1e reacted
with alkyl aldimines, depending on the size of the electrophile
or the reaction temperature, the same divergent selectivity was
observed. In both cases, the selectivity was attributed to the
regioselective reaction of the dienolate 2 with electrophiles via
R-alkylation/5-exo-tet cyclization or γ-alkylation/6-exo-trig cy-
clization. We also observed the first example of a vinylogous
imide enolate 2e, reacting at the γ-carbon with carbonyl
compounds.
1
662; H NMR (300 MHz, CDCl3) δ 7.48-7.42 (m, 2H), 7.34-7.13
(m, 6H), 7.06-6.92 (m, 6H), 6.77-6.71 (m, 2H), 6.66-6.52 (bs, 2H),
5.56 (s, 1H), 5.44 (d, 1H, J ) 1.7 Hz), 4.78 (dd, 1H, J ) 9.19, 3.70
Hz), 4.12 (d, 1H, J ) 10.42 Hz), 3.94 (d, 1H, J ) 3.57 Hz), 3.88 (d,
1H, J ) 10.56 Hz), 3.80 (s, 3H), 2.31 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 171.6, 159.2, 142.6, 141.8, 141.5, 140.8, 138.8, 131.2, 130.1,
129.2, 129.2, 128.7, 128.2, 128.1, 127.1, 127.0, 126.6, 118.8, 113.7,
56.6, 55.6, 52.5, 21.6, 8.8; HRMS calcd for C32H30N2O4S (M)+
538.1926, found 538.1929.
Experimental Section
General Procedures. All reactions were carried out in flame-dried
glassware sealed with rubber septa under a positive pressure of dry
nitrogen. Tetrahydrofuran (THF) was distilled from sodium benzophe-
none ketyl. All commercial materials were purchased from Sigma-
Aldrich Co. and were used without further purification. Anhydrous
magnesium iodide (MgI2, g99%) was purchased from Fluka and stored
in a glovebox under inert atmosphere. Weighing and transfer outside
the glovebox were performed as quickly as possible to minimize air
exposure. All reactions were monitored by analytical thin-layer
chromatography (TLC), which was visualized by ultraviolet light (254
nm) and treatment with acidic p-anisaldehyde or ceric ammonium nitrate
stain followed by gentle heating. Purification of products was ac-
complished by flash chromatography using silica gel 60 (230-400
mesh) purchased from Silicycle Inc.
Representative Procedure for the Synthesis of Dihydropyridi-
nones and Dihydropyranones from MCP Imide (1e) and Aryl
Aldimines and Aldehydes. To a solution of MCP imide 1e (42 mg,
0.25 mmol) and aldimine 3c (91 mg, 0.27 mmol) in THF (5 mL, 0.05
M) was added MgI2 (75.1 mg, 0.27 mmol) rapidly at 0 °C under a
positive nitrogen pressure. The reaction mixture was allowed to warm
to room temperature for 3 h. The reaction mixture was then quenched
with small portion of saturated aqueous Na2SO3 solution. The mixture
was extracted with EtOAc (2 × 100 mL) and the combined organic
phases were washed with H2O (200 mL) and brine (200 mL), dried
over MgSO4, filtered, and concentrated. The resulting product was used
directly in the next step. The crude product was dissolved in acetone
(3 mL) followed by the addition of sodium azide (81 mg, 1.25 mmol).
All 1H and 13C NMR spectra were recorded on Varian XL 400 and
Varian Mercury 300 spectrometers. IR spectra were obtained on a
Nicolet DX FT-IR spectrometer. High-resolution mass spectra were
(20) (a) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561. (b) Chemla,
F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75.
(21) Lai, M.; Liu, L.; Liu, H.-w. J. Am. Chem. Soc. 1991, 113, 7388.
9
J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002 6315

A R T I C L E S
Lautens and Han
The reaction mixture was stirred at room temperature for 16 h. The
mixture was extracted with EtOAc (2 × 50 mL), washed with brine
(100 mL), dried over MgSO4, filtered, and concentrated. Flash
chromatography on silica gel (ethyl acetate:hexanes 1:5 f 1:3)
furnished the product 7c (81 mg, 78%) as a colorless oil.
88% as a colorless oil. Rf ) 0.43 (silica gel, EtOAc:hexanes 1:3); IR
(CHCl3) νmax (cm-1) 3064, 3036, 2917, 2098, 1717, 1496, 1454, 1423,
1377, 1346, 1265, 1244, 1132, 1066, 1017, 849, 758, 695; H NMR
(300 MHz, CDCl3) δ 7.45-7.33 (m, 5H), 6.15 (dm, 1H, J ) 1.8 Hz),
5.45 (dd, 1H, J ) 11.7, 4.2 Hz), 4.06 (s, 2H), 2.69 (ddt, 1H, J ) 17.7,
11.4, 1.2 Hz), 2.55 (dd, 1H, J ) 17.7, 4.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 164.0, 152.9, 138.2, 129.0, 128.9, 126.2, 117.7, 78.9, 54.3,
33.4; HRMS calcd for C12H11N3O2 (M)+ 229.0851, found 229.0853.
1
4-Azidomethyl-6-(4-bromophenyl)-1-(4-toluenesulfonyl)-5,6-dihy-
dro-1H-pyridin-2-one (7c): Rf ) 0.15 (silica gel, EtOAc:hexanes 1:5);
IR (CHCl3) νmax (cm-1) 3064, 2978, 2106, 1775,1686, 1647, 1597, 1488,
1350, 1290, 1227, 1166, 1117, 1085, 1007, 958, 908, 848, 813, 703,
679; 1H NMR (300 MHz, CDCl3) δ 7.67 (d, 2H, J ) 8.1 Hz), 7.39 (d,
2H, J ) 8.4 Hz), 7.21 (d, 2H, J ) 8.1 Hz), 6.97 (d, 2H, J ) 8.4 Hz),
5.96 (m, 2H), 3.85 (d, 1H, J ) 15.9 Hz), 3.71 (d, 1H, J ) 16.2 Hz),
3.19 (ddt, 1H, J ) 17.4, 6.9, 1.2 Hz), 2.54 (dd, 1H, J ) 17.7, 1.2 Hz),
2.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 148.9, 145.3, 138.3,
135.5, 132.0, 129.5, 129.2, 128.2, 122.4, 121.3, 56.9, 54.2, 34.6, 21.8;
HRMS calcd for C19H17BrN4O3S (M)+ 461.0283, found 461.0266.
4-Azidomethyl-6-phenyl-5,6-dihydro-pyran-2-one (7k). 7k was
prepared as above using benzaldehyde 3k instead of aldimine 3c in
Acknowledgment. We thank BioChem Pharma Inc., NSERC
(Canada), and the University of Toronto for funding this
research. W.H. thanks Dr. Gregory Hughes for helpful discus-
sion and the University of Toronto for financial support.
Supporting Information Available: Details of all experi-
mental procedures and analytical data (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA011110O
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6316 J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002