Rapid synthesis of 1,3,4,4-tetrasubstituted β-lactams from methyleneaziridines using a four-component reaction

Article abstract of DOI:10.1021/jo801664g

(Chemical Equation Presented) 2-Methyleneaziridines can be transformed into a variety of 1,3,4,4-tetrasubstituted β-lactams in moderate to good yields (46-63%) via a one-pot process that brings together four components with the formation of three new intermolecular carbon-carbon bonds.

Full text of DOI:10.1021/jo801664g

ꢀ-Lactams are an important class of heterocycles that are
renowned for their potent antibiotic activity.4,5 They also serve
as useful building blocks for the synthesis of other classes of
compounds.6 Taken together, these factors have encouraged
researchers to search for MCR methods for the efficient
synthesis of libraries of ꢀ-lactams, and some notable successes
have been achieved.7
Rapid Synthesis of 1,3,4,4-Tetrasubstituted
ꢀ-Lactams from Methyleneaziridines Using a
Four-Component Reaction‡
Claire C. A. Cariou, Guy J. Clarkson, and
Michael Shipman*
Over the past few years, a powerful new MCR based upon
the highly strained 2-methyleneaziridine ring system has been
developed in our laboratory.8 The reaction involves ring opening
of methyleneaziridine 1 at C-3 using a Grignard reagent under
Cu(I) catalysis and capture of the resultant metalloenamine with
a carbon-based electrophile (R2X). By combining this approach
to ketimines with a Staudinger [2π + 2π] cycloaddition,9,10 we
reasoned that it might be possible to develop a flexible approach
to 1,3,4,4-tetrasubstituted ꢀ-lactams (Scheme 1). Several features
of this sequence are especially noteworthy. This four-component
reaction (4-CR) creates three new intermolecular C-C bonds
via a “one-pot” process and generates four points of chemical
diversity. Moreover, since it creates one quaternary center11 and
one tertiary center, the products are expected to have consider-
able synthetic value.12 In this paper, we report the successful
development of this MCR approach to 1,3,4,4-tetrasubstituted
ꢀ-lactams and outline its scope and limitations.
Department of Chemistry, UniVersity of Warwick,
Gibbet Hill Road, CoVentry, CV4 7AL, U.K.
m.shipman@warwick.ac.uk
ReceiVed July 27, 2008
Three methyleneaziridines, namely 1a-c, were prepared and
used in this study. 1-(4-Methoxybenzyl)-2-methyleneaziridine
2-Methyleneaziridines can be transformed into a variety of
1,3,4,4-tetrasubstituted ꢀ-lactams in moderate to good yields
(46-63%) via a “one-pot” process that brings together four
components with the formation of three new intermolecular
carbon-carbon bonds.
(4) The Organic Chemistry of ꢀ-Lactams; Georg, G. I., Ed.; VCH: New York,
1993.
(5) For reviews concerning the synthesis of ꢀ-lactams, see: (a) Singh, G. S.
Tetrahedron 2003, 59, 7631–7649. (b) France, S.; Weatherwax, A.; Taggi, A. E.;
Lectka, T. Acc. Chem. Res. 2004, 37, 594–600.
(6) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. ReV. 2007, 107, 4437–
4492.
(7) (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810–819. (b) Pitlik,
J.; Townsend, C. A. Bioorg. Med. Chem. Lett. 1997, 7, 3129–3134. (c) Gedey,
S.; Van der Eycken, J.; Fueloep, F. Org. Lett. 2002, 4, 1967–1969. (d) Gedey,
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2003, 40, 951–956. (e) Gedey, S.; Van der Eycken, J.; Fueloep, F. Lett. Org.
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Sillanpaeae, R.; Fueloep, F. Tetrahedron Lett. 2006, 47, 9113–9116.
(8) (a) Hayes, J. F.; Shipman, M.; Twin, H. Chem. Commun. 2000, 1791–
1792. (b) Hayes, J. F.; Shipman, M.; Twin, H. Chem. Commun. 2001, 1784–
1785. (c) Hayes, J. F.; Shipman, M.; Twin, H. J. Org. Chem. 2002, 67, 935–
942. (d) Hayes, J. F.; Shipman, M.; Slawin, A. M. Z.; Twin, H. Heterocycles
2002, 58, 243–250. (e) Margathe, J. F.; Shipman, M.; Smith, S. C. Org. Lett.
2005, 7, 4987–4990. (f) Shiers, J. J.; Clarkson, G. J.; Shipman, M.; Hayes, J. F.
Chem. Commun. 2006, 649–651. (g) Montagne, C.; Shiers, J. J.; Shipman, M.
Tetrahedron Lett. 2006, 47, 9207–9209.
Multicomponent reactions (MCRs) are one-pot processes that
bring together three or more starting materials to form a product
that contains most if not all elements of the reactants.1,2 They
represent a fundamentally more efficient approach to chemical
synthesis than traditional bimolecular reactions. Important
examples include the Ugi, Passerini, Strecker, and Biginelli
reactions. MCRs have emerged as powerful tools for drug
discovery because of their ability to produce small druglike
molecules with several degrees of structural diversity via single
transformations.3
(9) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51–123.
‡ This paper is dedicated to the memory of Professor A. I. Meyers.
(1) For a monograph, see: (a) Multicomponent Reactions; Zhu, J.; Bienayme´,
H., Eds.; Wiley-VCH: Weinheim, Germany, 2005.
(2) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169–3210.
(b) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471–1499. (c) Ramon, D. J.;
Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634. (d) Syamala, M. Org.
Prep. Proced. Int. 2005, 37, 103–171. (e) Do¨mling, A. Chem. ReV. 2006, 106,
17–89. (f) D’Souza, D. M.; Mueller, T. J. J. Chem. Soc. ReV. 2007, 36, 1095–
1108. (g) Eckert, H. Heterocycles 2007, 73, 149–158.
(3) (a) Ugi, I.; Heck, S. Comb. Chem. High Throughput Screen 2001, 4,
1–34. (b) Weber, L. Drug DiscoV. Today 2002, 7, 143–147. (c) Hulme, C.; Gore,
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DiscoVery DeV. 2005, 8, 776–788. (e) Mironov, M. A. QSAR Comb. Sci. 2006,
25, 423–431.
(10) For recent applications, see: (a) France, S.; Shah, M. H.; Weatherwax,
A.; Wack, H.; Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206–1215.
(b) Lee, E. C.; Hodous, B. L.; Bergin, E.; Shih, C.; Fu, G. C. J. Am. Chem. Soc.
2005, 127, 11586–11587. (c) Jiao, L.; Liang, Y.; Xu, J. J. Am. Chem. Soc. 2006,
128, 6060–6069. (d) Van Brabandt, W.; Vanwalleghem, M.; D’hooghe, M.; De
Kimpe, N. J. Org. Chem. 2006, 71, 7083–7086. (e) Sierra, M. A.; Pellico, D.;
Gomez-Gallego, M.; Mancheno, M. J.; Torres, R. J. Org. Chem. 2006, 71, 8787–
8793. (f) Shaikh, A. L.; Kale, A. S.; Shaikh, Md. A.; Puranik, V. G.; Deshmukh,
A. R. A. S. Tetrahedron 2007, 63, 3380–3388. (g) Allen, A. D.; Godoy, J.; Fu,
N.; Nagy, M.; Spadaro, S.; Tidwell, T. T.; Vukovic, S. J. Am. Chem. Soc. 2008,
130, 2386–2387.
(11) For reviews on this topic, see: (a) Denissova, I.; Barriault, L. Tetrahedron
2003, 59, 10105–10146. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363–5367.
9762 J. Org. Chem. 2008, 73, 9762–9764
10.1021/jo801664g CCC: $40.75 2008 American Chemical Society
Published on Web 09/23/2008

TABLE 1. 4-Component ꢀ-Lactam Synthesis
entry aziridine R1 R2X R3 lactam yielda (%)
SCHEME 1. MCR Approach to ꢀ-Lactams
1
2
3
4
5
6
7
8
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
Bn BnBr
Bn
Bn
Bn
Me
2a
2b
2c
2d
2e
2f
2g
2h
2i
50
62
60
55
49
58
46
59
63b
49
54
55b
47
Et
Et
Et
BnCl
BnCl
BnCl
Bn CH2dCHCH2Br Bn
Bn PMBCl
Bn
Bn
Bn
Bn
Et
Et
Et
Et
MeI
BnCl
9
THPO(CH2)3Br
CH3Ct CCH2Br Bn
10
11
12
13
2j
2k
2l
Bu BnBr
Bu MeI
iPr BnCl
Bn
Bn
Bn
2m
SCHEME 2. Synthesis of 2-Methyleneaziridine 1a
a Isolated yield after aqueous workup and column chromatography.
Unless otherwise noted, all compounds (except 2a) were isolated as ca.
1:1 mixture of diastereomers as judged by 1H NMR spectroscopy.
Detailed experimental procedures and full characterization data are
provided in the Supporting Information. b Combined yield of separated
diastereomers.
SCHEME 3. ꢀ-Lactam Synthesis by “One-Pot” 4-CR
electrophile, methyleneaziridine, and ketene components (Table
1). These studies reveal that this MCR tolerates changes in all
four components, and that many common functional groups can
be incorporated into the ꢀ-lactam products. The only significant
byproduct observed was R1COCH2OR3 derived from direct
addition of the organometallic reagent to the ketene. By adding
AcOH to destroy excess Grignard reagent prior to addition of
the ketene, the yields of the ꢀ-lactam were improved in many
cases by minimizing the formation of this byproduct. Lower
yields were also noted if the RCOCl was added to a mixture of
the ketimine and Et3N rather than by preforming the ketene. In
relation to changes in the Grignard and electrophile component,
the scope of this reaction broadly parallels that found for the
ketone MCR.8c Although the yields are quite modest (46-63%),
the efficiency with respect to each individual C-C bond forming
step is very good (77-86%/C-C bond). Little control over
diasteroselectivity is observed with near equal quantities of the
cis and trans diastereomers being produced.17 This lack of
stereocontrol is presumably because both R-carbons of the
ketimine are structurally similar, resulting in little stereodiffer-
entiation with respect to the approaching ketene. Despite this
limitation, this method provides an efficient way to make a
diverse range of racemic ꢀ-lactams.
(1a) was made in 87% yield from 2,3-dibromopropene and
4-methoxybenzylamine using a sodium amide induced ring
closure (Scheme 2).13 Aziridine 1a was selected as N-depro-
tection of the PMB group in the resultant ꢀ-lactam was
anticipated to be straightforward (vide infra).14 1-Benzyl-2-
methyleneaziridine (1b) and 1-cyclohexyl-2-methyleneaziridine
(1c) were made in a similar manner according to published
methods.15
With methyleneaziridines 1a-c in hand, conditions for
effecting the MCR were developed. After some optimization,
it was established that treatment of 1a in THF with BnMgCl
(3.0 equiv) and CuI (20 mol %) induced ring opening of the
aziridine at C-3 to generate the metalloenamine, which was
alkylated with BnBr (1.5 equiv). Subsequent addition of glacial
acetic acid (2 equiv) and then (benzyloxy)ketene (generated from
BnOCH2COCl, Et3N, -78 °C16) in CH2Cl2 yielded ꢀ-lactam
2a in 50% yield after silica gel column chromatography (Scheme
3 and Table 1, entry 1). The structural changes arising from
this “one-pot” sequence were verified by X-ray diffraction on
a single crystal of 2a grown from CH2Cl2/pentane (see Sup-
porting Information). To test the scope of this 4-CR, ꢀ-lactams
2a-m were synthesized by variation of the Grignard reagent,
To demonstrate the utility of the derived 1,3,4,4-tetrasubsti-
tuted ꢀ-lactams, diastereomerically pure trans-2l18 was depro-
tected using cerium ammonium nitrate14 by cleavage of the
p-methoxybenzyl group to give trans-3 in 59% yield (Scheme
4). Alternatively, the ꢀ-lactam ring of trans-2l can be ring-
opened with methanol and trimethylsilyl chloride to provide
diastereomerically pure ꢀ-amino ester 4 (Scheme 4).
To conclude, a versatile 4-CR has been developed for the
rapid synthesis of 1,3,4,4-tetrasubstituted ꢀ-lactams from me-
thyleneaziridines by the sequential formation of three C-C
bonds through a sequence that involves aziridine opening,
C-alkylation and Staudinger [2π + 2π] cycloaddition. Work to
(12) For elegant approaches to 1,3,4,4-tetrasubstituted ꢀ-lactams and leading
references, see: (a) He, M.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 418–419.
(b) Pe´rez-Faginas, P.; O’Reilly, F.; O’Byrne, A.; Garc´ıa-Aparicio, C.; Mart´ın-
Mart´ınez, M.; Pe´rez de Vega, M. J.; Garc´ıa-Lo´pez, M. T.; Gonzlez-Mun˜iz, R.
Org. Lett. 2007, 9, 1593–1596. (c) Bianchi, L.; Dell’Erba, C.; Maccagno, M.;
Mugnoli, A.; Novi, M.; Petrillo, G.; Sancassan, F.; Tavani, C. Tetrahedron 2003,
59, 10195–10201.
(13) Shiers, J. J.; Shipman, M.; Hayes, J. F.; Slawin, A. M. Z. J. Am. Chem.
Soc. 2004, 126, 6868–6869, and references cited therein.
(14) Maruyama, H.; Shiozaki, M.; Oida, S.; Hiraoka, T. Tetrahedron Lett.
1985, 26, 4521–4522.
(15) (a) Ennis, D. S.; Ince, J.; Rahman, S.; Shipman, M. J. Chem. Soc., Perkin
Trans. 1 2000, 2047–2053. (b) Shipman, M. Synlett 2006, 3205–3217.
(16) Palomo, C.; Aizpurua, J. M.; Garcia, J. M.; Galarza, R.; Legido, M.;
Urchegui, R.; Roman, P.; Luque, A.; Server-Carrio, J.; Linden, A. J. Org. Chem.
1997, 62, 2070–2079.
(17) Here, cis and trans are used to indicate the relative position of the
“largest” carbon substituent at C-4 relative to the C-3 ether (OR3).
(18) NOE difference measurements conducted on trans-3 allowed its
configuration to be established. Strong NOEs were observed between CHOBn
and-CH2(CH2)3CH3 indicating a syn relationship between these substituents.
Furthermore, CAN deprotection of cis-2l (details not shown) gave cis-3, which
produced analogous NOEs between the CHOBn and-CH2CH3 hydrogens. The
stereochemistries of cis- and trans-2l and (2S*,3S*)-4 were derived by extrapola-
tion of these findings.
J. Org. Chem. Vol. 73, No. 24, 2008 9763

SCHEME 4. Further Manipulations of ꢀ-Lactams
6.88 (2H, d, J ) 8.5 Hz), 4.94 (1H, d, J ) 11.8 Hz), 4.66 (1H, d,
J ) 11.8 Hz), 4.43 (1H, s), 4.34 (1H, d, J ) 15.6 Hz), 4.30 (1H,
d, J ) 15.6 Hz), 3.79 (3H, s), 2.66 (1H, dt, J ) 12.8, 5.0 Hz),
2.58-2.44 (2H, m), 2.39-2.32 (1H, dt, J ) 12.6, 5.0 Hz),
2.10-1.89 (3H, m), 1.77-1.65 (1H, m); 13C NMR (100 MHz,
CDCl3) 167.7 (C), 159.4 (C), 142.1 (C), 140.9 (C), 137.4 (C), 129.8
(CH), 129.1 (C), 128.6 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH),
128.2 (CH), 128.1 (CH), 128.0 (CH), 126.3 (CH), 125.9 (CH), 114.3
(CH), 85.7 (CH), 73.2 (CH2), 67.7 (C), 55.4 (CH3), 43.1 (CH2),
37.6 (CH2), 35.6 (CH2), 30.8 (CH2), 30.6 (CH2); MS (ES+) m/z )
506 ([M + H]+, 100); HRMS (ES+) m/z calcd for C34H35NNaO3
(M + Na)+ 528.2515, found 528.2509.
3-Benzyloxy-1-cyclohexyl-4-phenylethyl-4-propylazetidin-2-
one (2c). ꢀ-Lactam 2c was prepared from CuI (28 mg, 0.15 mmol)
in THF (2 mL), ethylmagnesium chloride (2.0 M in THF, 1.20 mL,
2.40 mmol), methyleneaziridine 1c (109 mg, 0.79 mmol) in THF
(1 mL), benzyl chloride (190 µL, 1.65 mmol), acetic acid (90 µL,
1.57 mmol), benzyloxyacetyl chloride (180 µL, 1.14 mmol), and
triethylamine (490 µL, 3.52 mmol) in CH2Cl2 (2.5 mL) according
to the general procedure. Workup followed by column chromatog-
raphy (petroleum ether/ethyl acetate, 8:1, Rf ) 0.21) afforded 2c
(191 mg, 60%) as a pale yellow oil as ca. 1:1 mixture of
diastereomers as judged by 1H NMR spectroscopy: IR (film) 2927,
2856, 1736, 1601, 1493, 1453 cm-1; 1H NMR (400 MHz, CDCl3)
7.46-7.03 (10H, m), 4.90 (0.5H, d, J ) 11.8 Hz), 4.84 (0.5H, d,
J ) 11.8 Hz), 4.67 (0.5H, d, J ) 11.8 Hz), 4.62 (0.5H, d, J ) 11.8
Hz), 4.24 (0.5H, s), 4.20 (0.5H, s), 3.07-2.87 (1H, m), 2.84-2.65
(1H, m), 2.64-2.54 (0.5H, m), 2.52-2.39 (0.5H, m), 2.20-1.09
(16H, m), 1.06-0.85 (3H, m); 13C NMR (100 MHz, CDCl3)
166.9 (C), 166.8 (C), 142.3 (C), 141.3 (C), 137.7 (C), 137.6 (C),
128.7 (CH), 128.49 (CH), 128.45 (CH), 128.42 (CH), 128.3 (CH),
128.2 (CH), 127.89 (CH), 127.86 (CH), 127.8 (CH), 126.3 (CH),
126.0 (CH), 85.6 (CH), 85.4 (CH), 73.0 (CH2), 72.9 (CH2), 67.35
(C), 67.31 (C), 53.4 (CH), 53.3 (CH), 38.5 (CH2), 38.1 (CH2),
36.0 (CH2), 35.7 (CH2), 32.1 (CH2), 31.9 (CH2), 31.73 (CH2), 31.68
(CH2), 31.0 (CH2), 25.93 (CH2), 25.87 (CH2), 25.21 (CH2), 25.17
(CH2), 17.9 (CH2), 17.8 (CH2), 15.0 (CH3), 14.6 (CH3); MS (ES+)
m/z ) 406 ([M + H]+, 100); HRMS (ES+) m/z calcd for C27H35
NNaO2 (M + Na)+ 428.2565, found 428.2560.
generate other important classes of compounds using methyl-
eneaziridine MCRs continues in our laboratory.
Experimental Section
Synthesis of ꢀ-Lactams: General Procedure. Copper(I) iodide
(ca. 20 mol %) in a round-bottomed flask was heated under vacuum
and then purged with nitrogen (three cycles performed). Dry THF
was added and the mixture cooled to -30 °C, whereupon the
Grignard reagent (2.5-3.0 molar equiv) was added. After 10 min,
methyleneaziridine 1 in THF was added, and the reaction mixture
stirred at room temperature for 3 h. After the reaction mixture was
cooled to 0 °C, the electrophile (1.5-2.0 molar equiv) was added
dropwise, and the mixture heated at 40 °C for 3 h. After the reaction
mixture was cooled to 0 °C, acetic acid (2 molar equiv) was added
dropwise and the mixture stirred at room temperature for 30 min.
In a separate round-bottomed flask, triethylamine (4.4 molar equiv)
was added to a solution of the acid chloride (1.4 molar equiv) in
CH2Cl2 at -78 °C. After 5 min, this mixture was added via cannula
to the first reaction mixture at -78 °C. The resulting mixture was
stirred overnight, during which time the temperature was allowed
to rise to room temperature. The mixture was diluted with Et2O
(20 mL) and washed with water (5 mL), 0.1 M HCl (5 mL), and
a saturated aqueous solution of NaHCO3 (5 mL). The organic phase
was dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the ꢀ-lactam was achieved by column chromatography.
3-Benzyloxy-1-(4-methoxybenzyl)-4,4-diphenylethylazetidin-
2-one (2a). ꢀ-Lactam 2a was prepared from CuI (22 mg, 0.12
mmol) in THF (2 mL), benzylmagnesium chloride (2.0 M in THF,
860 µL, 1.72 mmol), methyleneaziridine 1a (100 mg, 0.57 mmol)
in THF (1 mL), benzyl bromide (102 µL, 0.86 mmol), acetic acid
(65 µL, 1.14 mmol), benzyloxyacetyl chloride (120 µL, 0.76 mmol),
and triethylamine (350 µL, 2.51 mmol) in CH2Cl2 (2.5 mL)
according to the general procedure. Workup followed by column
chromatography (petroleum ether:ethyl acetate, 5:1, Rf ) 0.22)
afforded 2a (145 mg, 50%) as a white solid: mp 88-90 °C; IR
Acknowledgment. This work was supported by the Engi-
neering and Physical Sciences Research Council (EP/D035384/
1). We acknowledge EPSRC for the provision of mass spec-
trometers (EP/C007999/1), and the EPSRC X-ray Crystal-
lographic Service for recording the crystallographic data.
Supporting Information Available: Characterization data
and 1H and 13C NMR spectra for compounds 1a, 2a-m, 3, and
4, experimental procedures for their preparation, and X-ray data
for 2a. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
(film) 2951, 2931, 2856, 1744, 1608, 1509, 1453 cm-1; H NMR
(400 MHz, CDCl3) 7.45-7.10 (13H, m), 6.95 (4H, d, J ) 7.5 Hz),
JO801664G
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