Solid-phase, multicomponent reactions of methyleneaziridines: Synthesis of 1,3-disubstituted propanones

Article abstract of DOI:10.1021/ol051953a

(Chemical Equation Presented) Polymer-supported methyleneaziridines undergo ring opening by Grignard reagents under copper catalysis to yield metalloenamines which are alkylated in situ to yield ketimines. Filtration and washing of these Merrifield resin-bound intermediates prior to hydrolysis provides the corresponding 1,3-disubstituted propanones in a high state of purity without recourse to column chromatography.

Full text of DOI:10.1021/ol051953a

ORGANIC
LETTERS
2005
Vol. 7, No. 22
4987-4990
Solid-Phase, Multicomponent Reactions
of Methyleneaziridines: Synthesis of
1,3-Disubstituted Propanones
Jean-Franc¸
ois Margathe,† Michael Shipman,*,† and Stephen C. Smith‡
Department of Chemistry, UniVersity of Warwick, Gibbet Hill Road, CoVentry CV4
7AL, U.K., and Syngenta, Jealott’s Hill International Research Centre, Bracknell,
Berkshire RG42 6EY, U.K.
m.shipman@warwick.ac.uk
Received August 12, 2005
ABSTRACT
Polymer-supported methyleneaziridines undergo ring opening by Grignard reagents under copper catalysis to yield metalloenamines which
are alkylated in situ to yield ketimines. Filtration and washing of these Merrifield resin-bound intermediates prior to hydrolysis provides the
corresponding 1,3-disubstituted propanones in a high state of purity without recourse to column chromatography.
Organic molecules are traditionally made by executing a
sequence of chemical reactions, which forge the union of
two components in each step. In this way, the complexity
of a target molecule is built up by a linear sequence of
transformations. An increasingly popular and intrinsically
more efficient approach to chemical synthesis centers around
the use of multicomponent and related processes which bring
together three or more components in an orchestrated way
in a single reaction vessel.1,2
mediate ketimine, amines5 and N-heterocycles6 were pro-
duced using the same general approach.
The methyleneaziridine-based MCR has a number of
attributes which make it quite attractive: (i) two new
intermolecular C-C bonds are produced; (ii) the initially
formed ketimines are extremely versatile synthetic intermedi-
Scheme 1. Ketone Synthesis Using Aziridine MCR
Recently, we reported a new and quite general multicom-
ponent reaction (MCR) based upon the highly strained
methyleneaziridine ring system.3-6 Using Grignard reagents
as the nucleophilic component and a range of different
electrophiles, a variety of 1,3-disubstituted propanones could
be produced in one-pot using the chemistry depicted in
Scheme 1.4 By reducing rather than hydrolyzing the inter-
† University of Warwick.
‡ Syngenta, Jealott’s Hill.
(1) For reviews, see: (a) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt,
P. Chem.sEur. J. 2000, 6, 3321. (b) Do¨mling, A.; Ugi, I. Angew. Chem.,
Int. Ed. 2000, 39, 3169. (c) Weber, L. Drug DiscoVery Today 2002, 7,
143. (d) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471. (e) Hulme, C.;
Nixey, T. Curr. Opin. Drug DiscoVery DeV. 2003, 6, 921. (f) Ramon, D.
J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (g) Syamala, M. Org.
Prep. Proc. Int. 2005, 37, 103.
10.1021/ol051953a CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/27/2005

ates; (iii) it is operationally simple with the methyleneazi-
ridine starting materials accessible in 2-3 chemical steps
and many Grignard reagents and electrophiles commercially
available; (iv) asymmetric variants of this MCR have been
demonstrated using chiral, nonracemic methyleneaziridines.5,6
However, limitations do exist with this method. For example,
we have witnessed competitive coupling of the Grignard
reagent with the electrophile producing R2-E under the
reaction conditions.4b While this byproduct can usually be
removed by chromatography, this is inconvenient and makes
the chemistry rather unsuitable for the synthesis of compound
libraries using high-throughput techniques. By attachment
of the methyleneaziridine to a solid support via the nitrogen
atom (i.e., R1 ) polymer support, Scheme 1), it was
anticipated that this limitation could be overcome. After ring
opening and alkylation, filtration and washing of the resin-
bound ketimine prior to hydrolysis would remove excess
reagents and solution byproducts (e.g., R2-E), negating the
need for chromatographic purification. The feasibility of
performing this chemistry on solid-phase was supported by
the work of Wipf and Henninger, who have demonstrated
that alkenyl-aziridines attached to Wang resin undergo SN2′
opening using alkylcyanocuprates.7
Scheme 2. Preparation of 2-Methyleneaziridine 1
led to mixtures of 1 and its O-silylated counterpart, indicating
that cyclization precedes deprotection. Unfortunately, direct
ring closure of 3 (NaNH2 (3.5 equiv), NH3, -33 °C, 30 min)
produced 1 and HO(CH2)3NHCH2CtCH as an inseparable
12:88 mixture.
Aziridine 2 was made in two steps as depicted in Scheme
3. Ring opening of 1,1-dibromo-2,2-dimethylcyclopropane
A number of strategies can be imagined for the attachment
of methyleneaziridines to polymer supports via the aziridine
nitrogen atom. For simplicity, we focused on using an ether
linkage because of the known tolerance of this functional
group to the organometallic reagents required for the MCR.
Thus, initial studies centered on the preparation of two
hydroxyl-functionalized methyleneaziridines 1 and 2 suitable
for attachment to halogenated polymers by means of the
Williamson ether synthesis. The synthesis of methyleneazi-
ridine 1 was achieved in three steps in 66% overall yield
(Scheme 2). Alkylation of 2,3-dibromopropene with 3-ami-
nopropanol yielded amino alcohol 3, which was further
protected as its tert-butyldiphenylsilyl ether. Ring closure
of silyl ether 4 with sodium amide in liquid ammonia8 yielded
methyleneaziridine 1, in which concomitant deprotection of
the silyl ether was achieved. The use of shorter reaction times
Scheme 3. Synthesis of 2-Isopropylidineaziridine 2
5 with 3-aminopropanol yielded 3-(2-bromo-3-methylbut-
2-enylamino)propan-1-ol,9 which in this instance was suc-
cessfully cyclized to 2 without recourse to O-protection.
Etherification of methyleneaziridines 1 and 2 with Mer-
rifield resin (4.15 mmol/g) provided excellent yields of the
resin-bound derivatives 6 and 7, respectively (Scheme 4).10
(2) For recent illustrative examples, see: (a) Janvier, P.; Bois-Choussy,
M.; Bienayme, H.; Zhu, J. P. Angew. Chem., Int. Ed. 2003, 42, 811. (b)
Lo, M. M. C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.; Schreiber,
S. L. J. Am. Chem. Soc. 2004, 126, 16077. (c) Toure, B. B.; Hall, D. G.
Angew. Chem., Int. Ed. 2004, 43, 2001. (d) Knapton, D. J.; Meyer, T. Y.
J. Org. Chem. 2005, 70, 785. (e) Wender, P. A.; Gamber, G. G.; Hubbard,
R. D.; Pham, S. M.; Zhang, L. J. Am. Chem. Soc. 2005, 127, 2836. (f)
Tejedor, D.; Santos-Exposito, A.; Gonzalez-Cruz, D.; Marrero-Tellado, J.
J.; Garcia-Tellado, F. J. Org. Chem. 2005, 70, 1042. (g) Dietrich, S. A.;
Banfi, L.; Basso, A.; Damonte, G.; Guanti, G.; Riva, R. Org. Biomol. Chem.
2005, 3, 97. (h) Nicolaou, K. C.; Tang, W.; Dagneau, P.; Faraoni, R. Angew.
Chem., Int. Ed. 2005, 44, 3874.
Scheme 4. Assembly of Resin-Bound Methyleneaziridines
(3) Since this process involves the reaction of two reagents together to
form an intermediate that is captured by the subsequent addition of a further
reagent, it is more precisely defined as a sequential component reaction;
see ref 1f.
(4) (a) Hayes, J. F.; Shipman, M.; Twin, H. Chem. Commun. 2000, 1791.
(b) Hayes, J. F.; Shipman, M.; Twin, H. J. Org. Chem. 2002, 67, 935.
(5) Hayes, J. F.; Shipman, M.; Slawin, A. M. Z.; Twin, H. Heterocycles
2002, 58, 243.
The supported methyleneaziridines were characterized by IR
spectroscopy, 13C gel-phase NMR spectroscopy (see Sup-
porting Information),11 and the resin loadings (2.85-3.12
(6) Hayes, J. F.; Shipman, M.; Twin, H. Chem. Commun. 2001, 1784.
(7) Wipf, P.; Henninger, T. C. J. Org. Chem. 1997, 62, 1586.
(8) (a) Pollard, C. B.; Parcell, R. F. J. Am. Chem. Soc. 1951, 73, 2925.
For the correct structural assignments, see: (b) Ettlinger, M. G.; Kennedy,
F. Chem. Ind. 1956, 166. (c) Bottini, A. T.; Roberts, J. D. J. Am. Chem.
Soc. 1957, 79, 1462.
(9) (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.; Jakob, R.; Peters, K.; Peters, E.-M.; von Schnering, H.
G. Chem. Ber. 1984, 117, 840.
(10) Nam, N.-H.; Sardari, S.; Parang, K. J. Comb. Chem. 2003, 5, 479
and references therein.
4988
Org. Lett., Vol. 7, No. 22, 2005

Scheme 5. Solid-Phase Ketone Synthesis
mmol/g) and percentage conversions calculated using com-
bustion analysis data.
spectroscopy and GC analysis (see Table 1 and Supporting
Information). This assessment was verified by HPLC analysis
conducted on selected examples. A range of Grignard
reagents and electrophiles could be employed, and moderate
to good yields (39-81%) were obtained in all cases. The
scope and limitations of this reaction are broadly similar to
the solution-phase reaction.4 However, two differences are
apparent. First, using supported aziridine 7, a small amount
of isomerization of the gem-dimethyl substituent was ob-
served in one case (Table 1, entry 14). Specifically, ketone
21 was produced contaminated with a small amount (14%)
of the isomeric ketone, 4,4-dimethyl-1-phenyloctan-3-one as
a result of isomerization during the ring opening/alkylation
sequence. This type of rearrangement has not previously been
witnessed in solution using isopropylidineaziridines of this
type. Second, we note that aldehydes, such as PhCHO, do
not perform well as the electrophilic component in the
supported process, but do give satisfactory results in solu-
tion.4
With supported methyleneaziridines 6 and 7 in hand, we
turned our attention to the solid-phase MCR. Under opti-
mized conditions, 6 was converted into 1-phenyloctan-3-one
(8) in 72% yield (Scheme 5 and Table 1, entry 1). This yield
is comparable to that obtained in solution using 1-(1-
phenylethyl)-2-methyleneaziridine.4b The optimized condi-
tions differed from the solution phase reaction in several
respects. Not unexpectedly, higher quantities of the reagents
(RMgCl, CuI, and electrophile) were required to effect good
conversions. With respect to the electrophile, better results
were obtained using benzyl bromide in place of benzyl
chloride. Furthermore, milder conditions (pH 4.5 buffer, CH2-
Cl2 (1:1 v/v)12) for the imine hydrolysis were needed to obtain
the ketone product free of impurities derived from the
polymer. Gratifyingly, for the solid-phase MCR, the purifica-
tion protocol was greatly simplified. Upon completion of the
imine hydrolysis, the organic phase was simply collected by
passage through an Argonaut Isolute phase separation
cartridge then passed directly through a plug of silica to
ensure removal of remaining inorganic byproducts prior to
evaporation to dryness. To establish the scope of the solid-
phase MCR, a series of ketones 8-22 were made using this
optimized protocol (Table 1). The ketones produced were
To conclude, we have developed methodology for the
synthesis of Merrifield resin-bound methyleneaziridines.
These supported materials can be used to produce a range
of 1,3-disubstituted propanones by way of a three-component
reaction which creates two new intermolecular carbon-
carbon bonds. This solid-supported MCR3 is expected to be
more useful for chemical library generation using automated
1
formed in a high state of purity as judged by H NMR
Table 1. Synthesis of 1,3-Disubstituted Propanones 8-22 Using Solid-Supported Methyleneaziridines 6 and 7
entry
aziridine
Grignard (R1MgX)
electrophile (R2X)
ketonea
% yieldb
GC purityc
>94%
>97% (>96%)
>96%
>96%
>99% (>99%)
>99%
>98%
>97%
>98%
>98%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
6
6
6
6
6
6
6
6
6
6
6
6
6
7
7
n-C4H9MgCl
n-C4H9MgCl
n-C4H9MgCl
n-C4H9MgCl
c-HexMgCl
c-HexMgCl
c-HexMgCl
c-HexMgCl
c-HexMgCl
PhCH2Br
8
9
72
56
81
59
58
70
61
64
53
70
64
64
40
74
39
(2-naphthyl)CH2Br
4-MeOC6H4CH2Cl
Cyclohexene oxide
THPOCH2CH2CH2Br
PhCH2Br
CH2dCHCH2CH2Br
CH2dCHCH2Br
CH3C≡CCH2Br
4-BrC6H4CH2Br
PhCH2Br
10
11d
12
13
14
15
16
17
18
19
20
21e
22
EtMgCl
(CH3)2CHCH2MgCl
CH3)2CHCH2MgCl
PhCH2MgCl
n-C4H9MgCl
(CH3)2CHCH2MgCl
>91%
(2-naphthyl)CH2Br
PhCH2Br
PhCH2Br
>95% (>94%)
>92% (>94%)
>99%
CH2dCHCH2CH2Br
>99%
a All of the ketones have been fully characterized (see Supporting Information). b Yields are based on resin loadings for 6 and 7 determined by combustion
analysis. c Additional values reported in parentheses obtained by HPLC analysis. d Additional washings with methanol prior to imine hydrolysis. e This
material was contaminated with 4,4-dimethyl-1-phenyloctan-3-one (ca. 14%).
Org. Lett., Vol. 7, No. 22, 2005
4989

techniques than its solution-phase counterpart. Efforts to
develop other MCRs of supported methyleneaziridines are
continuing in our laboratories.
Acknowledgment. We are indebted to Syngenta and the
University of Warwick for financial support.
1
Supporting Information Available: H NMR spectra and
experimental procedures for the preparation of 1-4 and
6-22; 13C gel-phase NMR spectra and preparative methods
for 6 and 7. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) The NMR measurements were conducted as described by Vidal-
Ferran, A.; Bampos, N.; Moyano, A.; Pericas, M. A.; Riera A.; Sanders, J.
K. M. J. Org. Chem. 1998, 63, 6309. The benzyl ether of 1 was prepared
(NaH, BnCl, cat. Bu4NI, DMF, 74%) and used for comparison purposes in
the 13C gel-phase NMR analysis (see Supporting Information).
(12) Worster, P. M.; McArthur, C. R.; Leznoff, C. C. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 221.
OL051953A
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Org. Lett., Vol. 7, No. 22, 2005