Multicomponent reactions involving 2-methyleneaziridines: Rapid synthesis of 1,3-disubstituted propanones

Article abstract of DOI:10.1021/jo016164v

Ring opening of 1-alkyl-2-methyleneaziridines 1 or 2 is accomplished with organocopper reagents (R₂CuLi or RMgX/CuI) in the presence of boron trifluoride diethyl etherate giving 1-substituted propan-2-ones 3-9 in 42-88% yield. Ring opening with RMgC1/CuI in the absence of the Lewis acid allows further alkylation of the metalloenamine (metalated imine) intermediate in a regiocontrolled manner. The sequential formation of two new intermolecular carbon-carbon bonds in this reaction provides a rapid entry into a variety of 1,3-disubstituted propan-2-ones, including 11 and 14-23. The scope and mechanism of this multicomponent reaction (MCR) has been assessed. It is established that this MCR tolerates alkyl, aryl, and benzyiic Grignard reagents and a wide range of electrophiles, including alkyl iodides, bromides, and tosylates, as well as epoxides and aldehydes. In addition, gem-dimethyl substitution on the exocyclic double bond of the 2-methyleneaziridine is tolerated. This MCR has been applied to the one-pot synthesis of (Z)-6-heneicosen11-one, 25, an important sex attractant of the Tussock moth. Using 3-deuterio-1-(1-phenylethyl)2-methyleneaziridine, 26, we determined that this MCR occurs predominantly by direct ring opening at the sp³-hybridized aziridine carbon atom (C-3).

Full text of DOI:10.1021/jo016164v

J . Org. Chem. 2002, 67, 935-942
935
Mu lticom p on en t Rea ction s In volvin g 2-Meth ylen ea zir id in es:
Ra p id Syn th esis of 1,3-Disu bstitu ted P r op a n on es
J erome F. Hayes,† Michael Shipman,*,‡ and Heather Twin‡
GlaxoSmithKline, Old Powder Mills, Tonbridge, Kent, TN11 9AN, U.K., and School of Chemistry,
University of Exeter, Stocker Road, Exeter, Devon, EX4 4QD, U.K.
m.shipman@exeter.ac.uk
Received October 1, 2001
Ring opening of 1-alkyl-2-methyleneaziridines 1 or 2 is accomplished with organocopper reagents
(R2CuLi or RMgX/CuI) in the presence of boron trifluoride diethyl etherate giving 1-substituted
propan-2-ones 3-9 in 42-88% yield. Ring opening with RMgCl/CuI in the absence of the Lewis
acid allows further alkylation of the metalloenamine (metalated imine) intermediate in a
regiocontrolled manner. The sequential formation of two new intermolecular carbon-carbon bonds
in this reaction provides a rapid entry into a variety of 1,3-disubstituted propan-2-ones, including
11 and 14-23. The scope and mechanism of this multicomponent reaction (MCR) has been assessed.
It is established that this MCR tolerates alkyl, aryl, and benzylic Grignard reagents and a wide
range of electrophiles, including alkyl iodides, bromides, and tosylates, as well as epoxides and
aldehydes. In addition, gem-dimethyl substitution on the exocyclic double bond of the 2-methyl-
eneaziridine is tolerated. This MCR has been applied to the one-pot synthesis of (Z)-6-heneicosen-
11-one, 25, an important sex attractant of the Tussock moth. Using 3-deuterio-1-(1-phenylethyl)-
2-methyleneaziridine, 26, we determined that this MCR occurs predominantly by direct ring opening
at the sp3-hybridized aziridine carbon atom (C-3).
Sch em e 1
In tr od u ction
Multicomponent reactions (MCRs) are emerging as
important tools for the efficient synthesis of a wide
variety of organic molecules.1 Such reactions offer a
number of practical, environmental, and economic ad-
vantages over more traditional approaches to the con-
struction of complex molecular architectures. While
numerous MCRs have been devised, relatively few pro-
cesses that result in the formation of two or more
intermolecular carbon-carbon bonds are known. As part
of a program centered on the development of new
synthetic methods based on the highly strained yet
readily accessible 2-methyleneaziridine ring system,2 we
wondered whether these heterocycles could be used to
develop a novel and potentially general MCR leading to
the construction of two new carbon-carbon bonds. The
idea was to open a 2-methyleneaziridine with a nucleo-
phile to produce a transient metalloenamine (metalated
imine) that might be further C-alkylated with an elec-
trophile to yield a 1,3-disubstituted propanone after
imine hydrolysis (Scheme 1). This method is attractive
as considerable variation in this MCR can be imagined.
Most obviously, the structure of the nucleophile and the
electrophile could be changed to make a wide range of
1,3-disubstituted propanones. Furthermore, 2-methyl-
eneaziridines bearing substitutents at C-33 or on the
exocyclic double bond are known;4 thus, further substit-
uents could conceivably be incorporated at C-1 or C-3 of
the ketone products by opening more highly substituted
derivatives. Additionally, by reduction of the intermedi-
ate imine, access to the corresponding amines might be
possible, further increasing the utility of this MCR.5
If two carbon-carbon bonds are to be produced in the
MCR depicted in Scheme 1, an organometallic reagent
must be employed as the nucleophilic component. Since
2-methyleneaziridines bearing electron-withdrawing
groups (EWGs) on the nitrogen are not readily acces-
sible,6 this necessitates ring opening of an essentially
unactivated aziridine (R * EWG). Few examples of
organometallic ring-opening reactions of unactivated
† GlaxoSmithKline.
‡ University of Exeter. Phone: +44 1392 263469. Fax: +44 1392
263434.
(1) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J .
2000, 6, 3321. Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. Engl. 2000,
39, 3169. Ikeda, S.-I. Acc. Chem. Res. 2000, 33, 511 and references
therein.
(2) (a) Ince, J .; Ross, T. M.; Shipman, M.; Slawin, A. M. Z.; Ennis,
D. S. Tetrahedron 1996, 52, 7037. (b) Ince, J .; Ross, T. M.; Shipman
M.; Ennis, D. S. Tetrahedron: Asymmetry 1996, 7, 3397. (c) Ince, J .;
Shipman M.; Ennis, D. S. Tetrahedron Lett. 1997, 38, 5887. (d)
Shipman, M.; Ross, T. M.; Slawin, A. M. Z. Tetrahedron Lett. 1999,
40, 6091. (e) Ennis, D. S.; Ince, J .; Rahman, S.; Shipman, M. J . Chem.
Soc., Perkin Trans. 1 2000, 2047. (f) Pre´vost, N.; Shipman, M. Org.
Lett. 2001, 3, 2383.
(3) (a) Quast, H.; Weise Ve´lez, C. A. Angew. Chem., Int. Ed. Engl.
1974, 13, 342. (b) Quast, H.; Weise Ve´lez, C. A. Angew. Chem., Int.
Ed. Engl. 1978, 17, 213.
(4) (a) Quast, H.; Risler, W. Angew. Chem., Int. Ed. Engl. 1973, 12,
414. (b) Wijnberg, J . B. P. A.; Wiering, P. G.; Steinberg, H. Synthesis
1981, 901. (c) Quast, H.; J akob, R.; Peters, K.; Peters, E.-M.; von
Schnering, H. G. Chem. Ber. 1984, 117, 840. (d) Akasaka, T.; Nomura
Y.; Ando, W. J . Org. Chem. 1988, 53, 1670.
(5) We have recently developed a short asymmetric synthesis of (S)-
coniine on the basis of this idea, Hayes, J . F.; Shipman, M.; Twin, H.
Chem. Commun. 2001, 1784.
(6) Bingham, E. M.; Gilbert, J . C. J . Org. Chem. 1975, 40, 224.
10.1021/jo016164v CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/11/2002

936 J . Org. Chem., Vol. 67, No. 3, 2002
Hayes et al.
Ta ble 1. Cop p er -Ca ta lyzed Rin g Op en in g of
2-Meth ylen ea zir id in es in th e P r esen ce of Bor on
Tr iflu or id e Dieth yl Eth er a te
aziridines are known,7 although we anticipated that the
increased ring strain energy of 2-methyleneaziridine
compared to aziridine (12-13 kcal/mol; HF/6-31G*)8
might work to our advantage. A few ring-opening reac-
tions of 2-methyleneaziridines have been reported pre-
viously.9-11,2c,e,3a Of most relevance, Quast has proposed
that the decomposition of 3-lithio-1-tert-butyl-2-methyl-
eneaziridine involves nucleophilic ring opening of 1-tert-
butyl-2-methyleneaziridine by this organolithium species
with concurrent carbon-carbon bond formation.3a In light
of these observations, we felt that opening of a 2-meth-
yleneaziridine with a suitable organometallic reagent
should be feasible, allowing for the realization of the MCR
depicted in Scheme 1. In this article, we describe in detail
our observations concerning the ring-opening reactions
of 2-methyleneaziridines with organocopper reagents and
the use of this MCR strategy to make a wide variety of
1,3-disubstituted propanones.12
entry
aziridine
method
R1
product (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
2
A
B
B
B
B
B
B
B
B
-(CH2)3CH3
-(CH2)3CH3
-(CH2)7CH3
-Ph
3 (42{73a})
3 (56{90a})
4 (82)
5 (65)
6 (70)
7 (49)
8 (60)
9 (88)
4 (85)
-CH2Ph
-cyclohexyl
-C6H4OMe
-(CH2)6CHdCH2
-(CH2)7CH3
a
GC yield determined using nonane as the internal standard.
Sch em e 2a
Resu lts a n d Discu ssion
The most convenient and efficient method for the
synthesis of 2-methyleneaziridines involves ring closure
of the corresponding N-(2-bromoallyl)alkylamines with
sodium amide in liquid ammonia.9,13,14 1-(1-Phenylethyl)-
2-methyleneaziridine 12a and 1-cyclohexyl-2-methylene-
aziridine 22e used extensively in this study were made
in good yields by this method. As the first step toward
realizing the proposed MCR, we examined conditions for
effecting simple opening of the 2-methyleneaziridine ring
with simultaneous carbon-carbon bond formation. Since
Ganem has shown that N-alkylated aziridines can be ring
opened with Gilman-type cuprates in the presence of BF3‚
Et2O,15 we anticipated that these conditions might effect
ring opening of 2-methyleneaziridines. Treatment of
methyleneaziridine (()-1 with dibutyl copper lithium (1.5
equiv) and BF3‚Et2O (1.5 equiv) in THF (-78 f -10 °C)
and subsequent hydrolysis furnished heptan-2-one 3 in
42% isolated yield after bulb-to-bulb distillation (Table
1, entry 1). In fact, this transformation can be ac-
complished more conveniently, and in higher yield, using
butylmagnesium chloride in the presence of BF3‚Et2O and
a catalytic amount of copper(I) iodide (5 mol %) in THF
(-30 f 0 °C) over 1 h (Table 1, entry 2). The modest
isolated yields of heptan-2-one 3 obtained in these two
reactions are largely due to its volatility, as the chemical
conversion is good as judged by GC analysis. Further
studies using the RMgX/BF3‚Et2O/CuI method (Method
B) established that it is quite general, and a variety of
methyl ketones 3-9 can be made in moderate to good
yields (Table 1). Similar yields were obtained using
a
Reagents and conditions: (a) BuMgCl, CuI (5 mol %), BF3‚Et2O,
THF, -30 f 0 °C, 1 h; (b) PhCH2Cl, room temperature, 20 h; (c)
aq HCl, room temperature, 2 h.
N-cyclohexyl-2-methyleneaziridine 2 (entry 3 cf entry 9).
The use of other N-substituents has not been examined
at this point in time. Notably, in the absence of either
the BF3‚Et2O or the CuI, ring opening does not occur to
any great extent at -30 °C. If just the CuI is omitted,
and the reaction mixture is warmed to 0 °C over 1 h, then
ring opening is observed, albeit in much lower yield. For
example, in experiments performed in parallel, undecan-
2-one 4 was formed in 67% isolated yield with added CuI
(5 mol %) and in just 17% yield with no added CuI.
Encouraged by our initial results, we set about trying
to realize the MCR depicted in Scheme 1. However,
attempts to alkylate the presumed metalloenamine in-
termediate produced by ring opening of methyleneaziri-
dine 1 with RMgX/BF3‚Et2O/CuI were completely unsuc-
cessful. Introduction of an electrophile such as benzyl
chloride into the vessel prior to aqueous (aq) hydrolysis
did not result in the formation of the expected 1-phenyl-
octan-3-one 11. Similar experiments performed using
more reactive electrophiles (e.g., MeI or PhCH2Br) or
employing additives such as DMPU also failed to promote
the alkylation step. To account for this lack of reactivity,
we suggest that the stable boron “ate” complex 10 is
formed (Scheme 2).
(7) (a) Penkett, C. S.; Simpson, I. D. Tetrahedron Lett. 2001, 42,
1179. (b) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In Compre-
hensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Elsevier: Oxford, 1996; Vol. 1, p 1 and references therein.
(8) Bachrach, S. M. J . Phys. Chem. 1993, 97, 4996.
(9) Bottini, A. T.; Roberts, J . D. J . Am. Chem. Soc. 1957, 79, 1462.
(10) Crandall, J . K.; Crawley, L. C.; Komin, J . B. J . Org. Chem. 1975,
40, 2045.
(11) J ongejan, E.; Steinberg, H.; De Boer, T. J . Recl. Trav. Chim.
Pays-Bas 1979, 98, 66.
(12) For a preliminary account of part of this work, see: Hayes, J .
F.; Shipman, M.; Twin, H. Chem. Commun. 2000, 1791.
(13) Pollard, C. B.; Parcell, R. F. J . Am. Chem. Soc. 1951, 73, 2925.
Ettlinger, M. G.; Kennedy, F. Chem. Ind. 1956, 166.
To substantiate this proposal, we sought to ascertain
if a metalloenamine generated by the traditional method
of imine deprotonation16 would also be deactivated by the
presence of BF3‚Et2O. Treatment of heptan-2-one tert-
butylimine 1217 with EtMgBr and then benzyl chloride
yielded an inseparable mixture of ketones 11 and 13 in
an unoptimized 51% yield after acidic hydrolysis. 1H
NMR and GC analysis indicated that 13 was predomi-
nant (11:13 ) 2:3) (Scheme 3). Significantly, when BF3‚
(14) For alternative approaches to 2-methyleneaziridines, see: De
Kimpe, N.; De Smaele, D.; Sakonyi, Z. J . Org. Chem. 1997, 62, 2448.
Tehrani, K. A.; De Kimpe, N. Tetrahedron Lett. 2000, 41, 1975.
(15) Eis, M. J .; Ganem, B. Tetrahedron Lett. 1985, 26, 1153.
(16) For reviews, see: Hickmott, P. W. Tetrahedron 1982, 38, 3363.
Whitesell, J . K.; Whitesell, M. A. Synthesis 1983, 517.
(17) Hosomi, A.; Araki, Y.; Sakurai, H. J . Am. Chem. Soc. 1982, 104,
2081.

Multicomponent Reactions of 2-Methyleneaziridines
J . Org. Chem., Vol. 67, No. 3, 2002 937
Sch em e 3a
Ta ble 2. Th r ee-Com p on en t Cou p lin g Rea ction s of
2-Meth ylen ea zir id in e 1 Usin g RX a s th e Electr op h ile (X )
h a logen or OTs)
a
R1
2RX
product (%)
Reagents and conditions: (a) EtMgBr, THF, reflux, 18 h; (b)
entry
PhCH2Cl, reflux, 20 h; (c) aq HCl, reflux, 2 h; (d) BF3‚Et2O (1.5
equiv), 15 min.
1
2
3
4
5
6
7
8
9
n-C4H9
n-C8H17
n-C8H17
PhCH2
PhCH2
n-C4H9
n-C4H9
c-hex
PhCH2Cl
11 (70)
14 (80)
15 (67)
16 (80)
17 (66)
18 (58)
18 (65)
19 (57)
20 (52)
21 (74)
H2CdCHCH2Br
H2CdCHCH2CH2OTs
4-MeC6H4CH2Cl
PhCH2Cl
TBDMSOCH2CH2CH2Br
TBDMSOCH2CH2CH2I
PhCH2Cl
Et2O (1.5 equiv) was added to the reaction prior to
addition of benzyl chloride, 11 and 13 could not be
observed by either 1H NMR or GC-MS analysis. Thus,
we conclude that BF3‚Et2O efficiently suppresses the
reactivity of metalloenamines, a finding consistent with
our earlier failed attempts to achieve a MCR (Scheme
2).
Ph
Et
H2CdCHCH2Br
ClCH2CH2CH2I
10
Sch em e 4a
On the basis of these initial findings, we concluded that
it would be necessary to effect opening of 2-methylene-
aziridines with organometallic reagents in the absence
of an added Lewis acid. After further experimentation,
we determined that the ring opening could be effectively
achieved using just the Grignard reagent in the presence
of CuI (20 mol %) by warming the mixture to room
temperature and stirring for an extended period (24 h)
prior to introduction of the electrophile. Using these
conditions, treatment of methyleneaziridine 1 with
BuMgCl and then PhCH2Cl yielded alkylated ketone 11
in 70% isolated yield after imine hydrolysis and silica
gel chromatography (Table 2, entry 1). Significantly, the
formation of 11 occurs in a highly regiocontrolled fashion,
and no trace of 3-benzyl-heptan-2-one 13 could be de-
tected in the crude reaction mixture by GC analysis. This
finding reveals one important advantage of our MCR over
the traditional approach to metalloenamines by way of
imine deprotonation. In this latter method, even by
careful choice of the reaction conditions, it is not always
possible to achieve complete regiocontrol in the deproto-
nation of unsymmetrical imines.18,19 At this juncture, it
is worth noting that other copper(I) salts, namely, CuBr,
CuBr‚SMe2, CuCN, and CuI/Cu (1:3), can be used to effect
ring opening of 1 in the presence of BuMgCl. However,
none of these catalysts are as effective as CuI.
If the MCR proceeds through a genuine metallo-
enamine intermediate, one would expect a wide variety
of electrophiles (e.g., alkyl halides, epoxides, aldehydes,
and nitriles) to be effective as traps.16 Indeed, a variety
of R-X reagents (X ) Cl, Br, I, or OTs) have been used
successfully (Table 2). Using 3-chloro-1-iodopropane (en-
try 10), we observed only displacement of the more
reactive iodide leading to the chloroketone product, 21.
Furthermore, a variety of Grignard reagents can be
employed. Moderate to good yields of products were
obtained in all cases, and the method provides a flexible
and concise approach to a variety of 1,3-disubstituted
propanones, namely, 14-21.
a
Reagents and conditions: (a) BuMgCl, CuI, THF, room tem-
perature, 24 h; (b) cyclohexene oxide, -78 °C f room temperature,
18 h; (c) aq AcOH, hexane, 2 h, room temperature; (d) PhCHO, 40
°C, 2 h.
followed by quenching with cyclohexene oxide yielded
γ-hydroxyketone 22 in 71% yield as a single diastereomer
after imine hydrolysis (Scheme 4). We presume that trans
opening of the epoxide occurs, leading to 22, although
we have not unambiguously confirmed this stereochem-
ical assignment. Using benzaldehyde as the electrophile,
we obtained â-hydroxyketone 23 in 53% yield. As this
reaction generates a new asymmetric center, we wanted
to establish if any useful levels of asymmetric induction
could be obtained using an enantiopure 2-methylenea-
ziridine. In fact, â-hydroxyketone 23 produced from (S)-
12a displayed only modest enantiomeric enrichment (21%
ee), as determined using chiral HPLC analysis (see
Experimental Section). This low level of asymmetric
induction is consistent with studies by Sugasawa and
Toyoda,20 who obtained 3-hydroxy-3-(4-nitrophenyl)-1-
phenyl-propan-1-one in 19% ee using a similar “aldol-
type” condensation of a metalloenamine controlled by an
(S)-1-phenylethyl group on nitrogen. Thus, we conclude
that useful levels of asymmetric induction at a remote
stereocenter are not possible. However, we have observed
excellent levels of stereocontrol (90% de) in related MCRs
when the newly formed asymmetric center is much closer
to the chiral nitrogen substituent.5
In a simple application of this MCR, we have devised
a very short synthesis of (Z)-6-heneicosen-11-one, an
important sex pheromone of the Tussock moth.21 Treat-
ment of (()-1 with nonylmagnesium chloride and copper-
(I) iodide in THF at room temperature and then tosylate
2422 (made in 88% yield from commercially available (Z)-
Other types of electrophiles can be used in this MCR
beyond simple alkyl halides. Opening of 1 with BuMgCl
(18) For discussion of the factors influencing regioselectivity in the
deprotonation of imines, see: (a) Meyers, A. I.; Williams, D. R.;
Erickson, G. W.; White, S.; Druelinger, M. J . Am. Chem. Soc. 1981,
103, 3081. (b) Hosomi, A.; Araki, Y.; Sakurai, H. J . Am. Chem. Soc.
1982, 104, 2081. (c) Smith, J . K.; Bergbreiter, D. E.; Newcomb, M. J .
Am. Chem. Soc. 1983, 105, 4396 and references therein.
(20) Sugasawa, T.; Toyoda, T. Tetrahedron Lett. 1979, 1423.
(21) Smith, R. G.; Daterman, G. E.; Daves, G. D., J r. Science 1975,
188, 63.
(22) Corey, E. J .; Arai, Y.; Mioskowski, C. J . Am. Chem. Soc. 1979,
101, 6748. Cohen, N.; Banner, B. L.; Lopresti, R. J .; Wong, F.;
Rosenberger, M.; Liu, Y.-Y.; Thom, E.; Liebman, A. A. J . Am. Chem.
Soc. 1983, 105, 3661.
(19) For another regiospecific route to metalloenamines, see: Wend-
er, P. A.; Eissenstat, M. A. J . Am. Chem. Soc. 1978, 100, 292.

938 J . Org. Chem., Vol. 67, No. 3, 2002
Hayes et al.
Sch em e 5
Sch em e 7
Sch em e 8a
Sch em e 6
a
Reagents and conditions: (a) H2NCHMePh, 1,2-dichloroben-
zene, 150 °C; (b) NaNH2, NH3; (c) CuI, EtMgCl, THF, 24 h, room
temperature; (d) BnBr, 40 °C, 18 h; (e) aq HCl, 40 °C, 2 h.
and 28 in an 85:15 ratio. This conclusion was made on
the basis of the following pieces of spectroscopic data. The
presence of deuterium in the ketone product mixture was
3-nonen-1-ol) gave 25 in 62% yield (Scheme 5). (Z)-6-
heneicosen-11-one 25 produced by this MCR displayed
physical and spectroscopic data in very good agreement
with published values (see Experimental Section).23 In
this example, MPLC was required to facilitate separation
of 25 from (Z)-octadec-6-ene, produced as a result of direct
coupling of CH3(CH2)8MgCl with 24, and from octade-
cane, presumably a byproduct of Grignard formation.
Direct reaction of the Grignard with the electrophile is a
problem in these MCRs, although in most instances, this
contaminant can conveniently be removed using simple
flash chromatography. This side reaction arises because
the MCRs are performed using excess Grignard reagent
(2.5-3.0 molar equiv). To date, attempts to reduce the
amount of Grignard to suppress this competing process
have simply resulted in lower yields of the ketone product
being isolated.
Work to investigate the mechanism of the aziridine
ring-opening reaction has been undertaken. In principle,
the intermediate metalloenamine produced in these
MCRs could be generated by direct opening of the
aziridine ring at the sp3-hybridized carbon (Scheme 6,
path a), or alternatively, by attack at the exocyclic alkene
carbon by means of a “conjugate-type” process (Scheme
6, path b). In the context of 2-methyleneaziridine opening
by alkyl chloroformates, we have previously established
that ring opening occurs exclusively by direct opening
(i.e., path a).2c,e However, in the metalloenamine chem-
istry described herein, where copper(I) salts are present,
we felt that conjugate-type opening could not be dis-
counted.
+
readily established by mass spectrometry {M + NH4
)
223 (100%)}. In the 13C NMR spectrum, the carbon at
43.0 ppm moved slightly upfield to 42.7 ppm and was
observed as a triplet as a result of coupling to deuterium
(J ) 19.2 Hz). H-1H and H-13C correlation spectros-
1
1
copy using nondeuterated ketone 11 enabled this carbon
1
to be unambiguously assigned as C-4. Analysis of the H
NMR also indicated that the majority of the deuterium
was located at C-4. The methylene signal at 2.41-2.32
ppm (H-4) integrated to just 1.15H, whereas that at
2.77-2.68 ppm (H-2) integrated to 1.85H. Consistent
2
with this observation, the H NMR revealed two broad
singlets centered at 2.69 and 2.34 ppm in a 15:85 ratio.
From this experiment, it is clear that ring opening of
methyleneaziridine 1 by Grignard reagents in the pres-
ence of CuI occurs predominantly by direct attack at C-3
of the aziridine ring (Scheme 6, path a). The formation
of 28 might indicate that the conjugate-type process
(Scheme 6, path b) is occurring as a minor reaction
pathway in these copper-catalyzed MCRs, although other
mechanistic explanations for the formation of this prod-
uct cannot be fully discounted.24
To further substantiate these mechanistic findings, we
decided to examine if a methyleneaziridine bearing a
gem-dimethyl group on the exocyclic double bond would
participate in this MCR. (()-Isopropylideneaziridine 30
was easily made in two steps from 1,1-dibromo-2,2-
dimethylcyclopropane 2925 and (()-1-phenylethylamine
along similar lines to other known isopropylidineaziri-
dines (Scheme 8).4a-c Treatment of 30 with EtMgCl and
benzyl bromide gave ketone 31 in an unoptimized 50%
yield after acidic hydrolysis. The formation of 31 is
completely consistent with our mechanistic findings (vide
supra). In this instance, none of the corresponding
product derived from Grignard attack on the exocyclic
double bond (Scheme 6, path b) was observed. This
example establishes, for the first time, that highly
substituted metalloenamines can be generated using this
methodology.
To help elucidate the mechanism of opening, we
prepared C-3 deuterated methyleneaziridine 26 according
to the published method by lithiation of 1 using sec-
butyllithium followed by quenching with CD3OD.2e Deu-
terium incorporation was confirmed by mass spectrom-
etry {MH+ ) 161 (100%)}, and by reduction in the
integral for the aziridine hydrogens. Both diastereomers
of 26 were produced in a 3:1 ratio as judged by integra-
tion of the remaining aziridine signals at 2.11 ppm
(0.75H) and 2.01 ppm (0.25H). Subjection of 26 to the
standard MCR protocol using BuMgCl and PhCH2Cl
yielded an inseparable mixture of deuterated ketones 27
(24) In unpublished findings, we have established that 2-aminoallyl
cations can be generated from 2-methyleneaziridines in the presence
of Lewis acids. Thus, the formation of 28 might be explained by the
formation of a 2-amino-1-deuterio-allyl cation from 26 under the MCR
conditions. This cation would be expected to undergo attack by BuMgCl
with equal propensity at C-1 and C-3, ultimately leading to the
formation of quantities of both 27 and 28.
(23) For previous syntheses of (Z)-6-heneicosen-11-one, see: (a)
Smith, R. G.; Daves, G. D., J r.; Daterman, G. E. J . Org. Chem. 1975,
40, 1593. (b) Mori, K.; Uchida, M.; Matsui, M. Tetrahedron 1977, 33,
385. (c) Konda, K.; Murahashi, S.-I. Tetrahedron Lett. 1979, 1237. (d)
Wang, K. K.; Chu, K.-H. J . Org. Chem. 1984, 49, 5175. (e) Ballini, R.
J . Chem. Soc., Perkin Trans. 1 1991, 1419. (f) Stowell, J . C.; Polito, M.
A. J . Org. Chem. 1992, 57, 4560. (g) White, J .; Whiteley, C. G. Synthesis
1993, 1141 and references therein.
(25) Skattebol, L. Acta Chem. Scand. 1963, 17, 1683 and references
therein.

Multicomponent Reactions of 2-Methyleneaziridines
J . Org. Chem., Vol. 67, No. 3, 2002 939
petroleum ether) afforded 4 (105 mg, 85%) as a colorless liquid
(data as described above).
Con clu sion
1-P h en yl-p r op a n -2-on e, 5. To CuI (12 mg, 0.063 mmol),
PhMgCl (2.0 M in THF, 1.89 mL, 3.78 mmol), and BF3‚Et2O
(0.24 mL, 1.89 mmol) in THF (2 mL) was added 1 (200 mg,
1.26 mmol) in THF (1 mL) according to General Method 1.
Workup followed by column chromatography (2.5% EtOAc in
petroleum ether) afforded 5 (110 mg, 65%) as a yellow oil: IR
(film) 3023, 1721, 1450 cm-1; 1H NMR (300 MHz, CDCl3) 7.42-
7.20 (5H, m), 3.73 (2H, s), 2.18 (3H, s); 13C NMR (75 MHz,
CDCl3) 206.5, 134.3, 129.4, 128.8, 127.1, 51.0, 29.3; MS (CI)
m/z 152 (M + NH4+); HRMS calcd for C9H14NO 152.1075, found
152.1075.
In summary, we have devised a new regiocontrolled
approach to metalloenamines via carbon-carbon bond
formation that complements the original route to these
carbanions introduced by Stork26 and by Wittig.27 Quench-
ing of these intermediates with a variety of electrophiles
provides a very direct entry into 1,3-disubstituted ke-
tones. We believe this new type of MCR will find further
applications in organic synthesis, and studies in this area
are ongoing in our laboratories.
4-P h en yl-bu ta n -2-on e, 6. To CuI (6 mg, 0.032 mmol),
PhCH2MgCl (2.0 M in THF, 0.94 mL, 1.88 mmol), and BF3‚
Et2O (0.12 mL, 0.95 mmol) in THF (2 mL) was added 1 (100
mg, 0.63 mmol) in THF (1 mL) according to General Method
1. Workup followed by column chromatography (2.5% EtOAc
in petroleum ether) afforded 6 (65 mg, 70%) as a yellow oil:
Exp er im en ta l Section
Gen er a l. All experiments were performed under an inert
atmosphere in oven-dried glassware. Copper(I) iodide was
purified prior to use.28 Tetrahydrofuran (THF) was distilled
from sodium/benzophenone immediately prior to use. All other
solvents and reagents were purified by standard protocols.
Petroleum ether refers to that boiling in the range of 40-60
°C. Chromatography was performed on Fisher Matrex 60 silica
gel. Other general details have been reported previously.2e
Rin g Op en in g of 2-Meth ylen ea zir id in e (1 or 2) w ith
RMgX/Cu I in th e P r esen ce of Bor on Tr iflu or id e Dieth yl
Eth er a te (Gen er a l Meth od 1). Copper(I) iodide (5 mol %)
in a round-bottomed flask was heated under vacuum and then
purged with nitrogen (three cycles were performed). Freshly
distilled THF (2-4 mL) was added and the mixture cooled to
-30 °C whereupon the Grignard reagent (3.0 molar equiv) was
added. After stirring for 10 min, boron trifluoride diethyl
etherate (1.5 molar equiv) was added dropwise. Methylene-
aziridine 12a or 22e in THF (1-2 mL) was added and the
mixture allowed to warm slowly to 0 °C over a 1 h period.
Aqueous NH4Cl (4 mL) was added and the mixture allowed to
warm to room temperature and stirred for 1 h. The aqueous
phase was extracted with diethyl ether (3 × 5 mL), and the
combined organic fractions were washed with 0.1 M aq HCl
(3 × 15 mL) and brine (3 × 15 mL) and dried (MgSO4).
Removal of the solvent and purification gave the title com-
pounds.
Hep ta n -2-on e, 3. To CuI (18 mg, 0.095 mmol), BuMgCl (2.0
M in THF, 2.83 mL, 5.66 mmol), and BF3‚Et2O (0.36 mL, 2.84
mmol) in THF (4 mL) was added 1 (300 mg, 1.88 mmol) in
THF (2 mL) according to General Method 1. Workup followed
by bulb-to-bulb distillation (50 °C/water pump) afforded 3 (120
mg, 56%) as a colorless liquid: 1H NMR (300 MHz, CDCl3)
2.41 (2H, t, J ) 7.6 Hz), 2.13 (3H, s), 1.63-1.52 (2H, m), 1.38-
1.20 (4H, m), 0.89 (3H, t, J ) 6.8 Hz). This and other data
were identical with those of a commercial sample of heptan-
2-one.
Un d eca n -2-on e, 4 fr om 1. To CuI (6 mg, 0.032 mmol),
octylMgCl (2.0 M in THF, 0.95 mL, 1.90 mmol), and BF3‚Et2O
(0.12 mL, 0.95 mmol) in THF (2 mL) was added 1 (100 mg,
0.63 mmol) in THF (1 mL) according to General Method 1.
Workup followed by bulb-to-bulb distillation (100 °C/water
pump) afforded 4 (88 mg, 82%) as a colorless liquid: IR (film)
2925, 1718 cm-1; 1H NMR (300 MHz, CDCl3) 2.41 (2H, t, J )
7.8 Hz), 2.12 (3H, s), 1.58-1.48 (2H, m), 1.32-1.15 (12H, m),
0.87 (3H, t, J ) 6.6 Hz); 13C NMR (75 MHz, CDCl3) 209.5, 43.8,
31.9, 29.9, 29.7, 29.4, 29.3, 29.2, 23.9, 22.7, 14.1; MS (CI) m/z
188 (M + NH4+); HRMS calcd for C11H26NO 188.2014, found
188.2016.
1
IR (film) 3023, 1713, 1600 cm-1; H NMR (300 MHz, CDCl3)
7.35-7.10 (5H, m), 2.95-2.89 (2H, m), 2.82-2.75 (2H, m), 2.16
(3H, s); 13C NMR (75 MHz, CDCl3) 207.9, 140.9, 128.4, 128.2,
126.0, 45.1, 30.0, 29.6; MS (CI) m/z 166 (M + NH4+); HRMS
calcd for C10H12ONa 171.0786, found 171.0784.
1-Cycloh exyl-p r op a n -2-on e, 7. To CuI (12 mg, 0.063
mmol), cyclohexylMgCl (2.0 M in Et2O, 1.89 mL, 3.78 mmol),
and BF3‚Et2O (0.24 mL, 1.89 mmol) in THF (2 mL) was added
1 (200 mg, 1.26 mmol) in THF (1 mL) according to General
Method 1. Workup followed by column chromatography (2.5%
EtOAc in petroleum ether) afforded 7 (87 mg, 49%) as a yellow
oil: IR (film) 2926, 1713, 1353 cm-1 1H NMR (300 MHz,
;
CDCl3) 2.30 (2H, d, J ) 6.9 Hz), 2.14 (3H, s), 1.90-1.78 (1H,
m) 1.74-1.60 (5H, m), 1.36-1.05 (3H, m), 1.02-0.85 (2H, m);
13C NMR (75 MHz, CDCl3) 209.2, 51.6, 33.9, 33.2, 30.6, 26.2,
26.1; MS (CI) m/z 158 (M + NH4+); HRMS calcd for C9H20NO
158.1545, found 158.1546.
1-(4-Meth oxyp h en yl)-p r op a n -2-on e, 8. To CuI (12 mg,
0.063 mmol), anisylMgBr (0.5 M in THF, 7.56 mL, 3.78 mmol),
and BF3‚Et2O (0.24 mL, 1.89 mmol) in THF (2 mL) was added
1 (200 mg, 1.26 mmol) in THF (1 mL) according to General
Method 1. Workup followed by column chromatography (2.5-
10% EtOAc in petroleum ether) afforded 8 (124 mg, 60%) as a
yellow oil: IR (film) 1706, 1511 cm-1 1H NMR (300 MHz,
;
CDCl3) 7.14 (2H, d, J ) 8.5 Hz), 6.89 (2H, d, J ) 8.5 Hz), 3.82
(3H, s), 3.66 (2H, s), 2.16 (3H, s); 13C NMR (75 MHz, CDCl3)
207.0, 158.7, 130.4, 126.3, 114.2, 55.3, 50.1, 29.2; MS (CI) m/z
182 (M + NH4+); HRMS calcd for C10H12NaO2 187.0735, found
187.0736.
Un d ec-10-en -2-on e, 9. To CuI (6 mg, 0.030 mmol), 7-oc-
tenylMgBr (0.44 M, 4.0 mL, 1.76 mmol) (made by refluxing
8-bromo-1-octene (1.0 g, 5.23 mmol) and magnesium turnings
(0.13 g, 5.35 mmol) in THF (12 mL) for 1 h), and BF3‚Et2O
(0.11 mL, 0.87 mmol) in THF (2 mL) was added 1 (95 mg, 0.60
mmol) in THF (1 mL) according to General Method 1. Workup
followed by column chromatography (2.5% EtOAc in petroleum
ether) afforded 9 (89 mg, 88%) as a colorless oil: IR (film) 2921,
1
1713, 1637 cm-1; H NMR (300 MHz, CDCl3) 5.89-5.76 (1H,
m), 5.04-4.93 (2H, m), 2.43 (2H, t, J ) 7.4 Hz), 2.15 (3H, s),
2.09-2.01 (2H, m), 1.62-1.52 (2H, m), 1.45-1.23 (8H, m); 13
C
NMR (75 MHz, CDCl3) 209.5, 139.1, 114.2, 43.8, 33.8, 29.9,
29.2, 29.1, 28.94, 28.85, 23.8; MS (CI) m/z 186 (M + NH4+);
HRMS calcd for C11H20NaO 191.1412, found 191.1412.
Rin g Op en in g of 1 w ith Bu 2Cu Li in th e P r esen ce of
Bor on Tr iflu or id e Dieth yl Eth er a te. CuI (180 mg, 0.95
mmol) in a round-bottomed flask was heated under vacuum
and then purged with nitrogen (three cycles were performed).
Freshly distilled THF (2 mL) was added and the mixture cooled
to -40 °C. Butyllithium (2.5 M in hexanes, 0.75 mL, 1.88
mmol) was added dropwise and the mixture stirred for 10 min.
After the mixture was cooled to -78 °C, boron trifluoride
diethyl etherate (0.12 mL, 0.95 mmol) was added dropwise.
Methyleneaziridine 1 (100 mg, 0.63 mmol) in THF (1 mL) was
added and the mixture stirred at -78 °C for 1 h. Saturated
NH4Cl solution (2 mL) was added and the solution allowed to
warm to room temperature over 1 h. The layers were sepa-
Un d eca n -2-on e, 4 fr om 2. To CuI (7 mg, 0.037 mmol),
octylMgCl (2.0 M in THF, 1.09 mL, 2.18 mmol), and BF3‚Et2O
(0.14 mL, 1.10 mmol) in THF (2 mL) was added 2 (100 mg,
0.73 mmol) in THF (1 mL) according to General Method 1.
Workup followed by column chromatography (2.5% EtOAc in
(26) Stork, G.; Dowd, S. R. J . Am. Chem. Soc. 1963, 85, 2178.
(27) Wittig, G.; Frommeld, H. D.; Suchanek, P. Angew. Chem., Int.
Ed. Engl. 1963, 2, 683.
(28) Linstrumelle, G.; Krieger, J . K.; Whitesides, G. M. Org. Synth.
1976, 55, 103 and references therein.

940 J . Org. Chem., Vol. 67, No. 3, 2002
Hayes et al.
rated, and the aqueous phase was extracted with diethyl ether
(3 × 5 mL). The combined organic extracts were washed with
0.1 M HCl (3 × 15 mL) and water (3 × 15 mL) and then dried
(MgSO4). Careful removal of the solvent under reduced pres-
sure on a rotary evaporator using an ice/water bath, followed
by bulb-to-bulb distillation (50 °C/ca. 20 mmHg), gave 3 (30
mg, 42%) as a colorless liquid.
ane) gave 14 (211 mg, 80%) as a yellow oil: IR (film) 1710,
1597 cm-1 1H NMR (400 MHz, CDCl3) 5.86-5.75 (1H, m),
;
5.05-4.96 (2H, m), 2.50 (2H, t, J ) 8.0 Hz), 2.39 (2H, t, J )
8.0), 2.35-2.29 (2H, m), 1.58-1.50 (4H, m), 1.31-1.20 (10H,
m), 0.88 (3H, t, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) 211.5
(s), 138.2 (d), 116.1 (t), 43.9 (t), 42.7 (t), 32.8 (t), 30.4 (t), 30.3
(t), 30.2 (t), 28.7 (t), 24.8 (t), 23.6 (t), 15.0 (q); two carbons
Alk yla tion of Im in e 12 in th e Absen ce a n d in th e
P r esen ce of Bor on Tr iflu or id e Dieth yl Eth er a te. To a
three-necked flask equipped with a reflux condenser was added
EtMgBr (1.0 M in THF, 4.73 mL, 4.73 mmol). Imine 1217 (800
mg, 4.73 mmol) in THF (1 mL) was added dropwise and the
reaction mixture refluxed overnight. After the mixture was
cooled to room temperature, benzyl chloride (0.54 mL, 4.69
mmol) was added dropwise, and the reaction mixture was
refluxed for 20 h. The mixture was allowed to cool; 10% HCl
(3 mL) was added and the mixture refluxed for 2 h. The layers
were separated, and the organic phase was washed with 5%
HCl (5 mL) and brine (4 × 10 mL) and dried (MgSO4); the
solvent was removed under reduced pressure. Kugelrohr
distillation (150 °C/0.5 mmHg) afforded a 3:2 mixture of 13
and 11 (495 mg, 51%), which were inseparable by column
coincident; MS (EI) m/z 210 (M+) 155; HRMS calcd for C14H26
O
210.1984, found 210.1982. Anal. Calcd for C14H26O: C, 79.94;
H, 12.46%. Found C, 79.67; H, 12.51%.
P en ta d ec-1-en -6-on e, 15. OctylMgCl (2.0 M in THF, 1.89
mL, 3.78 mmol), 1 (200 mg, 1.26 mmol), and 3-butenyl
p-toluenesulfonate29 (610 mg, 2.52 mmol) were reacted accord-
ing to General Method 2. Workup B followed by chromatog-
raphy (2.5% EtOAc in hexane) gave 15 (190 mg, 67%) as a
yellow oil: IR (film) 2915, 1710, 1645 cm-1; 1H NMR (400 MHz,
CDCl3) 5.80-5.73 (1H, m), 5.04-4.95 (2H, m), 2.40 (2H, t, J
) 8.0 Hz), 2.38 (2H, t, J ) 8.0 Hz), 2.08-2.02 (2H, m), 1.67
(2H, pentet, J ) 7.2 Hz), 1.60-1.50 (2H, m), 1.35-1.20 (12H,
m), 0.88 (3H, t, J ) 6.4 Hz); 13C NMR (100 MHz, CDCl3) 211.7
(s), 138.4 (d), 115.5 (t), 43.3 (t), 42.3 (t), 33.5 (t), 32.3 (t), 29.83
(t), 29.81 (t), 29.7 (t), 24.3 (t), 23.2 (t), 23.1 (t), 14.5 (q) two
carbons coincident; MS (EI) m/z 224 (M+) 155 (M+ - C5H9);
HRMS calcd for C15H28O 224.2140, found 224.2138. Anal.
Calcd. for C15H28O: C, 80.29; H, 12.58%. Found C, 80.18; H,
12.34%.
1-P h en yl-5-p-tolyl-p en ta n -3-on e, 16. PhCH2MgCl (2.0 M
in THF, 1.89 mL, 3.78 mmol), 1 (200 mg, 1.26 mmol), and
4-methylbenzyl chloride (334 µL, 2.52 mmol) were reacted
according to General Method 2. Workup A followed by chro-
matography (2.5% EtOAc in hexane) gave 16 (254 mg, 80%)
as a yellow oil: IR (film) 1700 cm-1; 1H NMR (400 MHz, CDCl3)
7.28-7.02 (9H, m), 2.90-2.82 (4H, m), 2.71-2.66 (4H, m), 2.30
(3H, s); 13C NMR (100 MHz, CDCl3) 209.6 (s), 141.5 (s), 138.3
(s), 136.0 (s), 129.6 (d), 128.9 (d), 128.7 (d), 128.6 (d), 126.5
(d), 45.1 (t), 44.9 (t), 30.1 (t), 29.7 (t), 21.4 (q); MS (EI) m/z 252
(M+), 105; HRMS calcd for C18H20O 252.1514, found 252.1503.
Anal. Calcd for C18H20O: C, 85.67; H, 7.99%. Found C, 85.60;
H, 7.96%.
1
chromatography. H NMR (300 MHz, CDCl3) 7.30-7.17 (5H,
m), 2.92-2.65 (3.4H, m), 2.37 (0.8H, t, J ) 7.6 Hz), 2.05 (1.8H,
s), 1.70-1.40 (2H, m), 1.35-1.15 (4H, m), 0.92 and 0.88 (3H,
overlapping t, J ) 6.8 Hz). GC-MS 13 (7.3 min) 204 (M+), 189
(M+ - Me); 11 (8.1 min) 204 (M+), 148 (M+ - C4H8). Addition
of BF3‚Et2O (1.5 molar equiv) at room temperature with
stirring for 15 min prior to addition of the benzyl chloride
suppresses the formation of 11 and 13.
P r oced u r e for MCR (Gen er a l Meth od 2). Copper(I)
iodide (48 mg, 0.252 mmol) in a round-bottomed flask was
heated under vacuum and then purged with nitrogen (three
cycles were performed). Freshly distilled THF (4 mL) was
added and the mixture cooled to -30 °C whereupon the
Grignard reagent (2.5-3.0 molar equiv) was added. After the
mixture was stirred for 10 min, 1 (1.0 molar equiv) in THF (2
mL) was added. The mixture was allowed to warm to room
temperature and stirred for 24 h. The flask was then cooled
to 0 °C and the electrophile (1.1-2.0 molar equiv) added
dropwise. A reflux condenser was fitted and the reaction
mixture heated at 40 °C for 2 h, allowed to cool to room
temperature, and stirred overnight. Workup using either
method A or B (see below) followed by purification gave the
title compounds. Workup A: 10% aq HCl (2-3 mL) was added
and the mixture heated to 50 °C for 2 h. After the mixture
was cooled to room temperature, solid NaCl was added, and
the mixture was extracted with diethyl ether, washed with
0.5 M aq HCl (2 × 15 mL), aq NH4Cl (2 × 20 mL), aq NaHCO3
(2 × 20 mL), and brine (2 × 20 mL). The organic layer was
dried (MgSO4) and the solvent removed under reduced pres-
sure. Workup B: 1 M acetic acid (2-3 mL) was added with
hexane (2-3 mL), and the reaction was stirred at room
temperature for 2 h. The mixture was extracted with diethyl
ether and washed with aq NH4Cl (2 × 20 mL), aq NaHCO3 (2
× 20 mL), and brine (2 × 20 mL). The organic layer was dried
(MgSO4) and the solvent removed under reduced pressure.
1-P h en yloct a n -3-on e, 11. BuMgCl (2.0 M in THF, 0.94
mL, 1.88 mmol), 1 (100 mg, 0.63 mmol), and benzyl chloride
(79 µL, 0.69 mmol) were reacted according to General Method
2 on half of the normal scale. Consequently, the THF volumes
were halved, as was the amount of copper(I) iodide (24 mg,
0.126 mmol) used. Workup A followed by chromatography
(2.5% EtOAc in hexane) gave 11 (90 mg, 70%) as a yellow oil:
1,5-Dip h en yl-p en ta n -3-on e, 17. PhCH2MgCl (2.0 M in
THF, 1.89 mL, 3.78 mmol), 1 (200 mg, 1.26 mmol), and benzyl
chloride (218 µL, 1.89 mmol) were reacted according to General
Method 2. Workup A followed by chromatography (2.5% EtOAc
in hexane) gave 17 (197 mg, 66%) as a yellow oil: IR (film)
2928, 1710, 1464 cm-1; 1H NMR (400 MHz, CDCl3) 7.28-7.14
(10H, m), 2.88 (4H, t, J ) 7.6 Hz), 2.70 (4H, t, J ) 7.6 Hz); 13
C
NMR (100 MHz, CDCl3) 209.5 (s), 141.4 (s), 128.9 (d), 128.7
(d), 126.5 (d), 44.9 (t), 30.1 (t); MS (EI) m/z 238 (M+) 133, 105,
91; HRMS calcd for C17H18O 238.1358, found 238.1357.
1-(ter t-Bu t yld im et h ylsilyloxy)-d eca n -5-on e 18 Usin g
1-(ter t-Bu tyld im eth ylsilyloxy)-3-br om op r op a n e. BuMgCl
(2.0 M in THF, 1.89 mL, 3.78 mmol), 1 (200 mg, 1.26 mmol),
and 1-(tert-butyldimethylsilyloxy)-3-bromopropane (584 µL,
2.52 mmol) were reacted according to General Method 2.
Workup A followed by chromatography (2.5% EtOAc in hex-
ane) gave 18 (211 mg, 58%) as a yellow oil: IR (film) 2922,
1710, 1099, 839 cm-1; 1H NMR (400 MHz, CDCl3) 3.56 (2H, t,
J ) 6.0 Hz), 2.36 (4H, 2 overlapping t), 1.62-1.42 (6H, m),
1.32-1.18 (4H, m), 0.86 (12H, overlapping t and s), 0.00 (6H,
s); 13C NMR (100 MHz, CDCl3) 211.8 (s), 63.2 (t), 43.1 (t), 42.9
(t), 32.7 (t), 31.8 (t), 26.3 (q), 24.0 (t), 22.9 (t), 20.7 (t), 18.7 (s),
t
14.3 (q), -4.9 (q); MS (EI) m/z 229 (M+ - Bu); HRMS calcd
for C12H25O2Si 229.1623, found 229.1592. Anal. Calcd for
C
16H34O2Si: C, 67.07; H, 11.96%. Found C, 67.13; H, 11.80%.
1
IR (film) 2931, 1713 cm-1; H NMR (300 MHz, CDCl3) 7.32-
1-(ter t-Bu t yld im et h ylsilyloxy)-d eca n -5-on e 18 Usin g
7.19 (5H, m), 2.95-2.90 (2H, m), 2.78-2.73 (2H, m), 2.40 (2H,
t, J ) 7.4 Hz), 1.64-1.53 (2H, m), 1.39-1.20 (4H, m), 0.90 (3H,
t, J ) 6.9 Hz); 13C NMR (75 MHz, CDCl3) 210.5 (s), 141.2 (s),
128.5 (d), 128.3 (d), 126.1 (d), 44.3 (t), 43.0 (t), 31.4 (t), 29.8
(t), 23.5 (t), 22.5 (t), 13.9 (q); MS (EI) m/z 222 (M + NH4+);
HRMS calcd for C14H24NO 222.1858, found 222.1856.
1-(ter t-Bu tyldim eth ylsilyloxy)-3-iodopr opan e. BuMgCl (2.0
M in THF, 1.89 mL, 3.78 mmol), 1 (200 mg, 1.26 mmol), and
1-(tert-butyldimethylsilyloxy)-3-iodopropane30 (757 mg, 2.52
mmol) were reacted according to General Method 2. Workup
A followed by chromatography (2.5% EtOAc in hexane) gave
18 (237 mg, 65%) as a yellow oil (data as described above).
Tetr a d ec-1-en -5-on e, 14. OctylMgCl (2.0 M in THF, 1.89
mL, 3.78 mmol), 1 (200 mg, 1.26 mmol), and allyl bromide (218
µL, 2.52 mmol) were reacted according to General Method 2.
Workup B followed by chromatography (2.5% EtOAc in hex-
(29) Heck, R. F. J . Am. Chem. Soc. 1963, 85, 3116.
(30) Tanner, D.; Hagberg, L. Tetrahedron 1998, 54, 7907.

Multicomponent Reactions of 2-Methyleneaziridines
J . Org. Chem., Vol. 67, No. 3, 2002 941
1-Cycloh exyl-4-p h en yl-bu ta n -2-on e, 19. Cyclohexylmag-
nesium chloride (2.0 M in THF, 1.89 mL, 3.78 mmol), 1 (200
mg, 1.26 mmol), and benzyl chloride (290 µL, 2.52 mmol) were
reacted according to General Method 2. Workup B followed
by chromatography (2.5% EtOAc in hexane) gave 19 (164 mg,
57%) as a yellow oil: IR (neat) 2919, 1716, 1445 cm-1; 1H NMR
(400 MHz, CDCl3) 7.30-7.17 (5H, m), 2.89 (2H, t, J ) 7.6 Hz),
2.71 (2H, t, J ) 7.6 Hz), 2.26 (2H, d, J ) 6.9 Hz), 1.90-1.73
(1H, m), 1.70-1.55 (5H, m), 1.28-1.17 (2H, m), 1.16-1.05 (1H,
m), 0.95-0.80 (2H, m); 13C NMR (100 MHz, CDCl3) 210.0 (s),
141.2 (s), 128.5 (d), 128.3 (d), 126.0 (d), 50.8 (t), 44.9 (t), 33.9
(d), 33.2 (t), 29.7 (t), 26.2 (t), 26.1 (t); MS (CI) m/z 231 (MH+),
148; HRMS calcd for C16H23O 231.1749, found 231.1743.
1-P h en yl-h ex-5-en -2-on e, 20. PhMgCl (2.0 M in THF, 1.89
mL, 3.78 mmol), 1 (200 mg, 1.26 mmol), and allyl bromide (218
µL, 2.52 mmol) were reacted according to General Method 2.
Workup B followed by chromatography (2.5% EtOAc in
petroleum ether) gave 20 (114 mg, 52%) as a pale yellow oil:
(Z)-6-Hen eicosen -11-on e, 25.21,23 Nonylmagnesium chlo-
ride in THF (1.0 M, 3.78 mL, 3.78 mmol), prepared by refluxing
1-chlorononane (1.87 mL, 10.0 mmol) and magnesium turnings
(255 mg, 10.5 mmol) in THF (10 mL) for 2 h, 1 (200 mg, 1.26
mmol), and 3-cis-nonen-1-yl-p-toluenesulfonate 24 (746 mg,
2.52 mmol) were reacted according to General Method 2.
Workup B followed by medium-pressure liquid chromatogra-
phy (MPLC) on a Merck LiChroprep Si60 column (2% EtOAc
in petroleum ether) gave 25 (242 mg, 62%) as a colorless oil:
25
nD 1.4560 (lit. 1.454123b); IR (neat) 2919, 1716, 1460 cm-1
;
1H NMR (400 MHz, CDCl3) 5.41-5.37 (1H, m), 5.34-5.28 (1H,
m), 2.41-2.36 (4H, m), 2.06-1.97 (4H, m), 1.67-1.61 (2H, m),
1.61-1.54 (2H, m), 1.36-1.21 (20H, m), 0.91-0.86 (6H, m);
13C NMR (100 MHz, CDCl3) 211.3 (s), 131.0 (d), 128.7 (d), 42.8
(t), 42.1 (t), 31.9 (t), 31.5 (t), 29.5 (t), 29.45 (t), 29.39 (t), 29.36
(t), 29.27 (t), 27.2 (t), 26.6 (t), 23.9 (t), 23.8 (t), 22.6 (t), 22.5
(t), 14.04 (q), 14.00 (q) two carbons coincident; MS (CI) m/z
326 (M + NH4+), 309 (MH+); HRMS calcd for C21H44NO
326.3423, found 326.3419. Anal. Calcd for C21H40O: C, 81.75;
H, 13.07%. Found C, 81.79; H, 13.41%.
IR (film) 3032, 2919, 1716, 1644, 1496 cm-1 1H NMR (400
;
MHz, CDCl3) 7.35-7.20 (5H, m), 5.80-5.72 (1H, m), 5.02-
4.94 (2H, m), 3.70 (2H, s), 2.58 (2H, t, J ) 7.4 Hz), 2.34-2.25
(2H, m); 13C NMR (100 MHz, CDCl3) 207.6 (s), 137.0 (d), 134.2
(s), 129.4 (d), 128.7 (d), 127.0 (d), 115.3 (t), 50.2 (t), 41.0 (t),
27.7 (t); MS (CI) m/z 192 (M + NH4+) 175 (MH+); HRMS calcd
for C12H18NO 192.1388, found 192.1386.
3-cis-Non en -1-yl-p-tolu en esu lfon a te, 24.22 To a stirred
solution of cis-3-nonen-1-ol (2.9 mL, 17.2 mmol) in anhydrous
pyridine (50 mL) at 0 °C was added p-toluenesulfonyl chloride
(6.62 g, 34.7 mmol). The reaction was stirred at 0 °C for 90
min and then allowed to stand at 0 °C for 23 h. The mixture
was poured into cold HCl (1.4 mL, 1.5 M). After extraction
with diethyl ether, the organic layer was dried (MgSO4) and
the solvent removed in vacuo. Column chromatography (20%
EtOAc in petroleum ether) gave 24 (4.50 g, 88%) as a colorless
1-Ch lor o-oct a n -5-on e, 21. EtMgCl (2.0 M in THF, 1.58
mL, 3.16 mmol), 1 (200 mg, 1.26 mmol), and 1-chloro-3-iodo-
propane (203 µL, 1.89 mmol) were reacted according to General
Method 2. Workup B followed by chromatography (2.5% EtOAc
in petroleum ether) gave 21 (151 mg, 74%) as a yellow oil: IR
1
liquid: IR (film) 2925, 1598, 1178 cm-1; H NMR (400 MHz,
1
(film) 2960, 1701 cm-1; H NMR (400 MHz, CDCl3) 3.53 (2H,
CDCl3) 7.79 (2H, d, J ) 8.3 Hz), 7.34 (2H, d, J ) 8.3 Hz), 5.52-
5.44 (1H, m), 5.25-5.18 (1H, m), 3.99 (2H, t, J ) 7.0 Hz), 2.44
(3H, s), 2.44-2.36 (2H, m), 1.97-1.92 (2H, m), 1.31-1.18 (6H,
m), 0.87 (3H, t, J ) 6.9 Hz); 13C NMR (100 MHz, CDCl3) 144.7
(s), 134.0 (d), 133.1 (s), 129.8 (d), 127.9 (d), 122.6 (d), 69.8 (t),
31.4 (t), 29.1 (t), 27.2 (t), 27.1 (t), 22.5 (t), 21.6 (q), 14.0 (q);
MS (CI) m/z 314 (M + NH4+); HRMS calcd for C16H28NO3S
314.1790, found 314.1791.
t, J ) 6.3 Hz), 2.43 (2H, t, J ) 6.9 Hz), 2.38 (2H, t, J ) 7.3
Hz), 1.82-1.68 (4H, m), 1.63-1.55 (2H, m), 0.91 (3H, t, J )
7.4 Hz); 13C NMR (100 MHz, CDCl3) 210.6 (s), 44.73 (t), 44.70
(t), 41.7 (t), 32.0 (t), 21.0 (t), 17.3 (t), 13.8 (q); MS (CI), m/z
182 and 180 (M + NH4+); HRMS calcd for C8H19NO35Cl
180.1155, found 180.1157.
(1′S*,2′R*)-1-(2-Hyd r oxycycloh exyl)-h ep ta n -2-on e, 22.
BuMgCl (2.0 M in THF, 1.58 mL, 3.16 mmol), 1 (200 mg, 1.26
mmol), and cyclohexene oxide (254 µL, 2.51 mmol) were
reacted according to General Method 2 with minor modifica-
tions. The electrophile was added at -78 °C and the mixture
warmed to room temperature and stirred for 18 h prior to
workup. Workup B followed by chromatography (10% ethyl
acetate in petroleum ether) gave 22 (190 mg, 71%) as a pale
yellow oil: IR (film) 3416, 2925, 1706 cm-1; 1H NMR (400 MHz,
CDCl3) 3.17-3.05 (1H, m), 2.74 (1H, dd, J ) 16.6, 6.3 Hz),
2.50-2.35 (2H, m), 2.28 (1H, dd, J ) 16.6, 5.8 Hz), 2.07 (1H,
bs), 2.04-1.95 (1H, m), 1.85-1.65 (3H, m), 1.63-1.54 (3H, m),
1.35-1.15 (7H, m), 1.05-0.95 (1H, m), 0.88 (3H, t, J ) 7.0
Hz); 13C NMR (100 MHz, CDCl3) 212.8 (s), 75.4 (d), 47.5 (t),
43.5 (t), 41.4 (d), 36.1 (t), 32.0 (t), 31.4 (t), 25.5 (t), 24.9 (t),
23.5 (t), 22.5 (t), 13.9 (q); MS (CI) m/z 230 (M + NH4+), 213
(MH+), 195 (MH+ - H2O); HRMS calcd for C13H25O2 213.1854,
found 213.1854. Anal. Calcd for C13H24O2: C, 73.54; H, 11.39%.
Found C, 73.29; H, 11.73%.
Rin g Op en in g of Deu ter a ted Meth ylen ea zir id in e 26.
BuMgCl (2.0 M in THF, 0.94 mL, 1.88 mmol), 262e (100 mg,
0.62 mmol), and benzyl chloride (109 µL, 0.95 mmol) were
reacted according to General Method 2 on half of the normal
scale. Consequently, the THF volumes were halved, as was
the amount of copper(I) iodide (24 mg, 0.126 mmol). Workup
B followed by chromatography (2.5% EtOAc in petroleum
ether) gave 27 and 28 (75 mg, 59%) in a 85:15 ratio as
determined by NMR spectroscopy: IR (film) 2925, 1711 cm-1
;
1H NMR (300 MHz, CDCl3) 7.30-7.12 (5H, m), 2.92-2.87 (2H,
m), 2.77-2.68 (1.85H, m), 2.41-2.32 (1.15H, m), 1.58-1.52
(2H, m), 1.31-1.15 (4H, m), 0.88 (3H, t, J ) 6.9 Hz); 2H NMR
(61 MHz, CCl4) 2.69 (0.15D, br s), 2.34 (0.85D, br s); 13C NMR
(75 MHz, CDCl3) 42.7 (t, J ) 19.2 Hz, C-4), otherwise identical
to that of 11; MS (CI) m/z 223 (M + NH4+), 206 (MH+); HRMS
calcd for C14H20DO 206.1655, found 206.1655.
(()-N -(2-Br om o-3-m e t h yl-2-b u t e n yl)-1-p h e n yle t h yl-
a m in e, 32. To 1,1-dibromo-2,2-dimethyl-cyclopropane 2925
(2.00 g, 8.77 mmol) in 1,2-dichlorobenzene (15 mL) was added
(()-1-phenylethylamine (2.5 mL, 19.39 mmol), and the mixture
was heated for 72 h at 150 °C. After the mixture was cooled,
petroleum ether (20 mL) was added and the mixture filtered
and washed with additional petroleum ether (20 mL). The
solvent was removed by rotary evaporation followed by Kugel-
rohr distillation (60 °C/15 mmHg). Column chromatography
(5% EtOAc in petroleum ether) using silica pretreated with
triethylamine gave 32 (1.35 g, 57%) as a yellow oil: IR (film)
3334, 2960, 1445 cm-1; 1H NMR (400 MHz, CDCl3) 7.36-7.22
(5H, m), 3.75 (1H, q, J ) 6.6 Hz), 3.43 (1H, d, J ) 14.4 Hz),
3.34 (1H, d, J ) 14.4 Hz), 1.91 (1H, bs, NH), 1.88 (3H, s), 1.55
(3H, s), 1.35 (3H, d, J ) 6.6 Hz); 13C NMR (100 MHz, CDCl3)
145.1 (s), 133.4 (s), 128.4 (d), 127.0 (d), 126.9 (d), 121.7 (s),
55.8 (d), 51.1 (t), 25.5 (q), 24.8 (q), 20.5 (q); MS (EI) m/z 269
and 267 (M+), 254 and 252 (M+ - Me); HRMS calcd for
1-Hyd r oxy-1-p h en yl-octa n -3-on e, 23. BuMgCl (2.0 M in
THF, 1.58 mL, 3.16 mmol), 1 (200 mg, 1.26 mmol), and
benzaldehyde (192 µL, 1.89 mmol) were reacted according to
General Method 2. Workup B followed by chromatography
(10% EtOAc in petroleum ether) gave 23 (147 mg, 53%) as a
yellow oil: IR (film) 3633-3300, 2928, 2867, 1703, 1450 cm-1
;
1H NMR (400 MHz, CDCl3) 7.37-7.26 (5H, m), 5.15 (1H, dd,
J ) 8.8, 3.6 Hz), 3.42 (1H, bs), 2.85 (1H, dd, J ) 17.2, 8.8 Hz),
2.78 (1H, dd, J ) 17.2, 3.6 Hz), 2.42 (2H, t, J ) 7.4 Hz), 1.62-
1.54 (2H, m), 1.33-1.20 (4H, m), 0.89 (3H, t, J ) 7.0 Hz); 13
C
NMR (100 MHz, CDCl3) 211.8 (s), 142.8 (s), 128.5 (d), 127.6
(d), 125.6 (d), 70.0 (d), 51.0 (t), 43.7 (t), 31.3 (t), 23.2 (t), 22.4
(t), 13.9 (q); MS (EI) m/z 220 (M+) 149 (M+ - C5H11); HRMS
calcd for C14H20O2 220.1463, found 220.1464. Anal. Calcd for
C
14H20O2: C, 76.33; H, 9.15%. Found C, 76.10; H, 9.33%. The
enantiomers of 23 can be resolved by HPLC on a Diacel OD
column (1% IPA in hexanes; 0.7 mL/min; λ ) 220 nm): 23.2
and 24.6 min. Using (S)-12a in this procedure gave 23 in 21%
ee {23.2 min (major) and 24.6 min (minor)}.
C
13H18N79Br 267.0623, found 267.0620.
(()-2-Isop r op ylid en e-1-(1-p h en yleth yl)-a zir id in e, 30.
To a three-necked flask fitted with a dry ice condenser and

942 J . Org. Chem., Vol. 67, No. 3, 2002
Hayes et al.
gas inlet was added sodium amide (7.89 g, 202 mmol, 30 equiv),
and the system was purged with calcium chloride dried
ammonia. Ammonia (ca. 75 mL) was condensed into the flask,
and then 32 (1.80 g, 6.74 mmol) was added dropwise. After 30
min, diethyl ether (10 mL) was added, followed by water (10
mL) dropwise (CAUTION). After the ammonia had evaporated,
water (10 mL) and diethyl ether (10 mL) were added and the
mixture was stirred for 5 min. The organic phase was
separated and the aqueous phase extracted with diethyl ether
(3 × 10 mL). The organic extracts were washed successively
with 10% NaOH solution (2 × 10 mL), 0.1 M acetic acid (10
mL), sodium hydrogen carbonate (10 mL), water (10 mL), and
finally brine (10 mL). The organic extracts were dried (MgSO4),
and the solvent was removed under reduced pressure. Kugel-
rohr distillation (100 °C/1 mmHg) gave 30 (1.11 g, 88%) as a
was added, and the solution was heated at 40 °C for 2 h. Upon
cooling, the mixture was extracted with diethyl ether (20 mL)
and the combined organic extracts were washed successively
with aq NH4Cl (2 × 20 mL), aq NaHCO3 (2 × 20 mL), and
brine (2 × 20 mL). The organic layer was dried (MgSO4) and
the solvent removed under reduced pressure. Column chro-
matography on silica (2.5% EtOAc in petroleum ether) gave
31 (110 mg, 50%) as a pale yellow oil: IR (film) 3017, 2960,
1696 cm-1 1H NMR (300 MHz, CDCl3) 7.30-7.20 (3H, m),
;
7.10-7.07 (2H, m), 2.81 (2H, s), 2.38 (2H, t, J ) 7.2 Hz), 1.58
(2H, sextet, J ) 7.2 Hz), 1.12 (6H, s), 0.89 (3H, t, J ) 7.4 Hz);
13C NMR (75 MHz, CDCl3) 215.6 (s), 138.0 (s), 130.3 (d), 128.0
(d), 126.3 (d), 48.3 (s), 45.4 (t), 39.9 (t), 24.3 (q), 17.1 (t), 13.8
(q); MS (FI) m/z 204 (M+); HRMS calcd for C14H20O 204.1514,
found 204.1516.
clear, colorless oil: IR (film) 3027, 2966, 2925, 1793, 1450 cm-1
;
1H NMR (400 MHz, d6-DMSO at 80 °C) 7.36-7.20 (5H, m),
3.00 (1H, q, J ) 6.6 Hz), 2.00 (1H, s), 1.91 (1H, s), 1.67 (3H,
s), 1.38 (3H, d, J ) 6.6 Hz), 1.36 (3H, br s);13C NMR (100 MHz,
d6-DMSO at 80 °C) 145.3 (s), 128.6 (d), 127.3 (d), 125.2 (s),
102.1 (s), 67.5 (d), 29.5 (t), 23.6 (q), 21.0 (q), 19.4 (q) two
carbons coincident; MS (FI) m/z 187 (M+); HRMS calcd for
Ack n ow led gm en t. We thank EPSRC and Glaxo-
SmithKline for their generous financial support of this
work. We are indebted to J ulie Ince and David Ennis
for their assistance at the early stages of this project.
We thank the EPSRC National Mass Spectrometry
Centre for performing some of the mass spectral mea-
surements and the EPSRC Chemical Database Service
at Daresbury.31
C
13H17N 187.1361, found 187.1366.
2,2-Dim eth yl-1-p h en yl-h exa n -3-on e, 31. Copper(I) iodide
(41 mg, 0.215 mmol) was heated under vacuum in a round-
bottomed flask then purged with nitrogen (three cycles were
performed). Freshly distilled THF (4 mL) was added and the
mixture cooled to -30 °C whereupon EtMgCl in THF (2.0 M,
1.34 mL, 2.68 mmol) was added. After the mixture was stirred
for 10 min, 30 (200 mg, 1.07 mmol) in THF (2 mL) was added.
The mixture was allowed to warm to room temperature and
stirred for 24 h. The flask was then cooled to 0 °C and benzyl
bromide (255 µL, 2.14 mmol) added dropwise. A reflux
condenser was fitted and the reaction mixture heated at 40
°C for 18 h. After the mixture was cooled, 2 M aq HCl (3 mL)
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 4-9, 11, 14-25, and 30-32 and 1H
2
and H NMR spectra for 27/28. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O016164V
(31) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J . Chem. Inf.
Comput. Sci. 1996, 36, 746.