Stereocontrolled formation of epoxy peroxide functionality appended to a lactam ring

Article abstract of DOI:10.1021/jo001313f

The action of tert-butyl hydroperoxide and tin(IV) chloride upon allylic alcohols containing a lactam ring leads mainly to epoxy alkyl peroxides with high diastereoselection. Both the stereochemistry and the products formed are in marked contrast to the r

Full text of DOI:10.1021/jo001313f

J . Org. Chem. 2001, 66, 4771-4775
4771
Ster eocon tr olled F or m a tion of Ep oxy P er oxid e
F u n ction a lityAp p en d ed to a La cta m Rin g
Charles M. Marson,*,†,‡ Afzal Khan,† and Rod A. Porter§
Department of Chemistry, Queen Mary and Westfield College, University of London,
London E1 4NS, U.K., and GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park,
Third Avenue, Harlow, CM19 5AW, U.K.
c.m.marson@ucl.ac.uk
Received August 31, 2000 (Revised Manuscript Received April 26, 2001)
The action of tert-butyl hydroperoxide and tin(IV) chloride upon allylic alcohols containing a lactam
ring leads mainly to epoxy alkyl peroxides with high diastereoselection. Both the stereochemistry
and the products formed are in marked contrast to the reactions of the analogous carbocyclic allylic
alcohols with tert-butyl hydroperoxide-VO(acac)2.
Sch em e 1
The epoxidation of allylic alcohols has achieved out-
standing importance, mainly because of their ease of
enantioselective formation1 and the variety of useful
transformations that the resulting 2,3-epoxy alcohols can
undergo.2 Recently we employed diastereoselective ep-
oxidations as part of new methodology for the stereocon-
trolled construction of polyoxygenated bicyclic systems
(Scheme 1, eqs. i and ii).3 We have also shown that such
epoxidations take a markedly different course when the
carbocyclic backbone is replaced by a lactam system
(Scheme 1, eqs. iii),4 the results of which are described
in detail in this paper. Although it is unlikely that these
epoxidations can readily be made enantioselective, the
convenience of the procedure and the good diastereose-
lectivities are of benefit. Generally, our studies show that
an allylic hydroxyl group, when adjacent to the nitrogen
atom of an amidic linkage, is replaced by an alkyl peroxy
group, usually with concomitant epoxidation of an exo-
cyclic double bond, giving epoxy alkyl peroxides 6 as the
major products. Considering that stereocontrol is also
quite high, such processes could find use in the prepara-
tion of alkyl peroxide analogues to the many dialkyl
peroxides of importance in nature (e.g. prostaglandin
endoperoxides).5 Endoperoxides possess potent physi-
ological activity, and together with thromboxane A2 and
prostacyclin have been implicated in the control of
platelet aggregation.6 Additionally, the biological activity
of dialkyl peroxides, formed in lipids by the action of
reactive oxygen species on unsaturated lipid membranes,
is of continuing interest.7
The diastereoselective epoxidations (eqs. i and ii)
shown in Scheme 1 are prerequisite to Lewis acid
mediated cyclizations that furnish polyfunctionalized
fused carbocycles.3 The π-face selectivity exhibited by 1
and 3 is notable and in both cases the syn epoxy alcohols
2 and 4 result (in this context, we have found it useful
to define the configuration by orienting the carbon
framework as prior to a cyclization as in Scheme 1, and
then to apply the terms syn and anti). With cyclizations3
resulting in nitrogen heterocycles in mind, an investiga-
tion of the epoxidation of lactam analogues such as 5 was
undertaken. Whereas 1 and 3 can be epoxidized using
either m-CPBA in CHCl3, or by tert-butyl hydroperoxide
(TBHP) (1.5 eq., catalytic VO(acac)2, benzene, 18 h
reflux), neither of those methods was successful for 5;
instead attempted epoxidation led to fragmentation to
the N-substituted cyclic imide, whose formation evidently
reflects the increase in electron density of the quaternary
center owing to the nitrogen atom.
† University of London.
‡ Current address: Department of Chemistry, University College
London, Christopher Ingold Laboratories, 20 Gordon Street, London
WC1H 0AJ , U.K.
§ GlaxoSmithKline Pharmaceuticals.
(1) J ohnson, R. A.; Sharpless, K. B. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991; vol. 7, pp 389-436. Morgans, D. J .; Sharpless, K. B. J . Am. Chem.
Soc. 1981, 103, 462.
(2) J ohnson, W. S. Bioorg. Chem., 1976, 5, 51. Sutherland, J . K.
Chem. Soc. Rev. 1980, 9, 265. Rickborn, B. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991; vol. 3, p 733.
(3) Marson, C. M.; McGregor, J .; Khan, A.; Grinter, T. J . J . Org.
Chem. 1998, 63, 7833.
(4) Hursthouse, M. B.; Khan, A.; Marson, C. M.; Porter, R. Tetra-
hedron Lett. 1995, 36, 5979.
(5) Hamberg, M.; Samuelsson, B. Proc. Natl. Acad. Sci. 1973, 70,
899.
(6) Hamberg, M.; Svensson, J .; Samuelsson, B. Proc. Natl. Acad. Sci.
1975, 72, 2994.
10.1021/jo001313f CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/09/2001

4772 J . Org. Chem., Vol. 66, No. 14, 2001
Marson et al.
Ta ble 1. Rea ction of Allylic Alcoh ols w ith TBHP a n d
Sn Cl4
concentrations of SnCl4, the diperoxide 8b is formed,
perhaps via consecutive addition of peroxide to the
1-azabutadienium cation (9) (Scheme 4). The catalytic
effect of SnCl4 on the formation of the allylic peroxides
was also shown by treatment of 5a and TBHP (2.2 eq.)
in dichloromethane with 8 mol % of SnCl4; the corre-
sponding allylic peroxide 7a was formed in 59%, whereas
5a was recovered quantitatively when SnCl4 was omitted
(Scheme 2).
The good diastereoselection in the products of eq. iii
1
was established by H NMR spectroscopy. Thus, for the
epoxy peroxides 6c the methine hydrogen atom of the
epoxide unit resonated at δ 3.32 (dd, J ) 4.5 and 2.8 Hz)
for the anti-diastereoisomer and at δ 3.37 (dd, J ) 4.1
and 3.0 Hz) for the syn-diastereoisomer. For epoxy
peroxides 6a the methine hydrogen atom of the epoxide
unit resonated at δ 3.11 (dd, J ) 4.0 and 2.5 Hz) for the
anti-diastereoisomer and at δ 3.18 (dd, J ) 3.8 and 2.5
1
Hz) for the syn-diastereoisomer. The H NMR spectrum
of the reaction mixture for entry 3 (Table 1) indicated a
9:1 ratio of diastereoisomers that were subsequently
shown to be anti-6c and syn-6c respectively. The major
diastereoisomer anti-6c crystallized from ethyl acetate
- 40-60 °C petroleum ether as cubes, mp 98-99 °C. Its
relative configuration was confirmed by an X-ray deter-
mination on a single crystal. (For crystallographic data
of 6a see: Coles, S. J .; Hibbs, D. E.; Hursthouse, M. B.
Acta Cryst. 2001, E57, 066-067). The TBHP-SnCl4
system is of particular significance, since reaction of
m-CPBA (1.5 eq.) and SnCl4 (2.0 eq.) with 5c (CH2Cl2, 0
°C, 0.5 h) gave N-propargylsuccinimide (85%).
Ta ble 2. Rea ction of 7a w ith TBHP a n d Sn Cl4
The above results are markedly different from epoxi-
dations of the carbocyclic analogues in the presence of
TBHP-VO(acac)2, and suggest substantially different
mechanisms. Tin(IV) alkyl peroxides are known to dis-
place trifluoromethanesulfonates to give dialkyl perox-
ides,9 and cyclic peroxides can be prepared from bis-
(trifluoromethanesulfonates) and bis(tri-n-butyltin)per-
oxide.9 This well-established use of tin(IV) in the context
of peroxides as nucleophiles is consistent with the
catalytic formation of the R-peroxy lactams, which in turn
strongly suggests an acyliminium intermediate, presum-
ably 9 (Scheme 4), that could be subject to both R- and
â-addition of nucleophiles (here peroxide). The addition
of hydroperoxide to an acyliminium species rapidly
results in an allyl peroxide,10 and we consider that the
peroxy amides 7 are formed by the analogous R-addition
to 9. A likely route to the diperoxides 8 proceeds via
conjugate addition to the acyliminium species 9 followed
by R-addition of a second molecule of peroxide (Scheme
4). The mechanism of formation of the epoxy peroxides 6
has not been established. While hydroxyl-directed (or
peroxy-directed) epoxidations (of 5) involving coordination
to tin cannot currently be excluded, a plausible alterna-
tive route proceeds via intramolecular cyclization of
enamide 12 giving 13, followed by R-addition of per-
oxide.10
SnCl4 peroxide 7b diperoxide 8b epoxy peroxide 6b
entry (mol %)
(%)
(%)
(%)
1
2
3
4
5
6
0.33
10
25
50
100
220
33
13
-
-
-
13
25
28
20
-
-
-
10
32
67
38
-
-
Products of the reaction of a variety of the amidic allylic
alcohols 5 with TBHP in the presence of 2.5 mol eq. of
SnCl4 are given in Table 1. Good yields of the epoxy alkyl
peroxides 6 were obtained for a variety of N-substituents,
and for γ- and δ-lactam rings. This is notable since
tertiary alcohols have been converted into the corre-
sponding tert-butyl peroxides by reaction with trichloro-
acetonitrile followed by TBHP and BF3.OEt2, but in low
yields.8 The homoallylic alcohol 10 (entry 5) did not
undergo epoxidation. However, it was converted into the
peroxide 11, suggesting that an allylic peroxide may be
the means by which epoxy alkyl peroxides 6 are formed.
Treatment of the allylic peroxide 7a with TBHP in the
presence of only 2.5 mol eq. of SnCl4 indeed afforded
peroxy epoxide 6a , though in considerably lower yield
(35%) than the one-pot reaction (Table 1, entry 1). A
similar pattern was observed when 5b was treated with
tert-butyl hydroperoxide in dichloromethane and a widely
varying stoichiometry of SnCl4 (Table 2 and Scheme 3).
The initial product was the R-peroxy amide 7b, and the
epoxy peroxide 6b was the final product. At intermediate
The diastereoselective peroxidation with concomitant
epoxidation processes herein described are a new means
(9) Salomon, M. F.; Salomon, R. G. J . Am. Chem. Soc. 1979, 101,
4290.
(10) Murahashi, S.-I.; Naota, T.; Kuwabara, T.; Saito, T.; Kumoba-
yashi, H.; Akutagawa, S. J . Am. Chem. Soc. 1990, 112, 7820. We are
grateful to a referee for suggesting the analogy with the intramolecular
attack of an enolate on a peroxide, formed by conjugate addition of
peroxide anion to an electrophilic alkene.
(7) Matsugo, S.; Saito, I. In Organic Peroxides; Wiley: New York,
Ando, W., Ed.; 1992; pp 157-194.
(8) Bourgeois, M. J .; Montaudon, E.; Millard, B. Tetrahedron 1993,
49, 2477.

Epoxy Peroxide Functionality on a Lactam Ring
J . Org. Chem., Vol. 66, No. 14, 2001 4773
Sch em e 2
Sch em e 3
prepared and handled according to the safety procedures
previously described.14
Sch em e 4
N-Meth ylglu ta r im id e. A mixture of glutarimide (1.00 g,
8.84 mmol), methyl iodide (1.51 g, 10.6 mmol), and anhydrous
potassium carbonate (1.47 g, 10.6 mmol) was heated at reflux
in anhydrous acetone (20 mL) for 16 h. After cooling, more
methyl iodide (1.60 g, 4.42 mmol) and potassium carbonate
(0.61 g, 4.42 mmol) were added, and the mixture was again
heated at reflux for a further 7.5 h. After cooling to 0 °C, the
mixture was filtered and the acetone evaporated to give an
orange oil which was subjected to Kugelrohr distillation to give
N-methylglutarimide as prisms (1.10 g, 98%); bp 115 °C/0.25
1
mmHg, mp 30-31 °C, lit.15 mp 30 °C; H NMR (D2O) δ 3.12
(3H, s), 2.75 (4H, t, J ) 6.5 Hz), 2.00 (2H, quint., J ) 6.5 Hz);
of difunctionalization that could find use in the synthesis
of polyoxygenated natural products. Unsymmetrical di-
alkyl peroxides can be prepared, but often in modest
yields, by other methods.8,9,11 The ability to cleave
peroxides reductively would provide access to the corre-
sponding alcohols. In the context of methods of epoxida-
tion, these peroxidations mediated by tin(IV) are note-
worthy, as is the “direct” replacement of an hydroxy
group by peroxyalkyl, related cases requiring activation
of the hydroxyl group, e.g., as the trichloroacetimidate.8
13C NMR (D2O) δ 176.7 (s), 32.0 (q), 26.2 (q), 16.3 (t).
N-P r op a r gylsu ccin im id e. A mixture of succinimide (2.0
g, 20.2 mmol), propargyl bromide (3.17 g, 22.2 mmol, 80% w/w
in toluene) and anhydrous potassium carbonate (3.35 g, 24.2
mmol) was heated at reflux in anhydrous acetone (30 mL) for
6 h. A fine, milky precipitate of potassium bromide formed.
After cooling to 20 °C the mixture was filtered and the acetone
evaporated to give an orange oil which was subjected to
Kugelrohr distillation to give N-propargylsuccinimide as a
clear oil (2.70 g, 97%), bp 163 °C/1.0 mmHg, lit.16 bp 120 °C/
0.03 mmHg; 1H NMR (CDCl3): δ 4.20 (2H, d, J ) 4.7 Hz), 2.70
(4H, s), 2.16 (1H, t, J ) 4.7 Hz); 13C NMR (CDCl3): δ 175.9
(s), 76.7 (s), 71.3 (d), 28.2 (t), 27.6 (t).
Exp er im en ta l Section
5-Hyd r oxy-1-p r op -2-yn yl-5-vin yl-2-p yr r olid in on e (5c).
To N-propargylsuccinimide (2.32 g, 16.9 mmol) in THF (140
mL), cooled to -78 °C, was added vinylmagnesium bromide
(22.0 mL, 22.0 mmol, 1 M solution in THF) dropwise, and when
the addition was complete the mixture was then stirred at 20
°C for 1.5 h. It was then poured onto saturated ammonium
chloride (100 mL), the layers were separated, and the aqueous
layer was extracted with diethyl ether (2 × 30 mL). The
combined organic extracts were dried (MgSO4) and evaporated
to give an orange oil which was purified by column chroma-
tography (55:45 ethyl acetate:40-60 °C petroleum ether) to
give 5c (1.71 g, 62%) as prisms, mp 71-72 °C (ethyl acetate/
petroleum ether); IR νmax (KBr disk) 3280, 1675 cm-1; 1H NMR
(CDCl3) δ 5.90 (1H, dd, J ) 17.0, 10.0 Hz), 5.56 (1H, dd, J )
17.0, 1.0 Hz), 5.35 (1H, dd, J ) 10.0, 1.0 Hz), 4.08 (1H, dd, J
) 17.5 Hz, J ) 2.5 Hz), 3.81 (1H, dd, J ) 17.5 Hz, J ) 2.5
Gen er a l. Melting points were determined on a microscope
1
hot-stage apparatus. H and 13C NMR spectra were obtained
at 250 and 68.8 MHz, respectively. Thin-layer chromatography
was performed on Merck 0.2 mm aluminum-backed silica gel
60 F254 plates and visualized using an alkaline KMnO4 spray
or by ultraviolet light. Flash column chromatography was
performed using Merck 0.040 to 0.063 mm, 230 to 400 mesh
silica gel. Petroleum ether (40-60 °C fraction) and ethyl
acetate were distilled before use; tetrahydrofuran was distilled
from sodium and benzophenone; dichloromethane was distilled
from calcium hydride. Evaporation refers to the removal of
solvent under reduced pressure.
5-Hydroxy-1-methyl-5-vinyl-2-pyrrolidinone 5a 12 and 1-
benzyl-5-hydroxy-5-vinyl-2-pyrrolidinone 5b13 were prepared
according to literature procedures. Anhydrous TBHP was
(11) Foglia, T. A.; Silbert, L. S. Synthesis 1992, 1587.
(12) Drage, J . S.; Earle, R. A.; Vollhardt, K. P. C. J . Heterocycl.
Chem. 1982, 19, 701.
(13) Khan, A.; Marson, C. M.; Porter R. A. Synth. Commun. 2001,
0000.
(14) Hanson, R. M.; Sharpless, K. B. J . Org. Chem. 1986, 51, 1922.
(15) Hall, H. K., J r.; Brandt, M. K.; Mason, R. M. J . Am. Chem.
Soc. 1958, 80, 6420.
(16) Schoemaker, H. E.; Boer-Terpstra, Tj.; Dijkink, J .; Speckamp,
W. N. Tetrahedron 1980, 36, 143.

4774 J . Org. Chem., Vol. 66, No. 14, 2001
Marson et al.
Hz), 2.70-2.05 (5H, m); 13C NMR (CDCl3) δ 174.8 (s), 138.4
(d), 117.4 (t), 98.1 (s), 79.7 (s), 71.2 (d), 34.3 (t), 28.9 (t), 28.0
(t); m/z (EI): 165 (M+, 32%), 147 (16%), 138 (34%), 119 (27%),
111 (38%), 83 (37%), 55 (100%); HRMS, M+ found 165.0794,
C9H11NO2 requires 165.0790; and 4-oxoh ex-5-en oic a cid
p r op -2-yn yla m id e, (0.73 g, 26%), as prisms, mp 66-67 °C
(ethyl acetate/petroleum ether); IR ν max (KBr disk) 3300, 3230,
mixture was then stirred at -78 °C for 1.25 h and poured onto
ice (20 mL), and the layers were separated. The aqueous layer
was extracted with dichloromethane (3 × 5 mL), and the
combined organic extracts were dried (MgSO4) and evaporated.
The residue was purified by column chromatography (23:77
ethyl acetate: 40-60 °C petroleum ether) to give 6b (9 anti:
1 syn) as a colorless oil (133 mg, 67%); IR νmax (KBr disk) 3394,
1704 cm-1; 1H NMR (CDCl3; anti-6b) δ 7.40-7.15 (5H, m), 4.91
(1H, d, J ) 15.5 Hz), 4.19 (1H, d, J ) 15.5 Hz), 2.89 (1H, dd,
J ) 4.5, 2.8 Hz), 2.80-2.50 (1H, m), 2.45-2.15 (4H, m), 1.90-
1
1650 cm-1; H NMR (CDCl3) δ 6.30 (1H, d, J ) 9.8 Hz), 6.28
(1H, d, J ) 2.0 Hz), 5.84 (1H, dd, J ) 9.8, 2.0 Hz), 3.98 (2H,
dd, J ) 5.5, 2.5 Hz), 2.95 (2H, t, J ) 6.5 Hz), 2.47 (2H, t, J )
6.5 Hz), 2.19 (1H, t, J ) 2.5 Hz); 13C NMR (CDCl3) δ 199.6 (s),
171.8 (s), 136.2 (d), 128.9 (t), 79.7 (s), 71.5 (d), 34.6 (t), 29.6
(t), 29.2 (t); m/z (EI): 165 (M+, 12%), 137 (14%), 111 (43%), 83
(34%), 55 (100%). HRMS, calcd for C9H11NO2 165.0790, found
165.0792.
1
1.70 (1H, m), 1.22 (9H, s); H NMR (CDCl3; syn-6b) δ 7.40-
7.15 (5H, m), 4.88 (1H, d, J ) 15.3 Hz), 4.24 (1H, d, J ) 15.3
Hz), δ 2.73 (1H, dd, J ) 5.0, 2.5 Hz), 2.70-2.50 (1H, m), 2.45-
2.10 (4H, m), 2.92-2.13 (1H, m), 1.20 (9H, s); 13C NMR (CDCl3)
δ 176.3 (s), 138.6 (s), 128.4 (d), 128.1 (d), 127.2 (d), 96.9 (s),
80.4 (s), 53.1 (d), 43.2 (t), 49.8 (t), 29.7 (t), 26.5 (q), 24.7 (t);
m/z (FAB): 306 (MH+, 89%), 216 (100%), 190 (84%). HRMS,
calcd for C17H24NO4 306.1705, found 306.1720.
1-Meth yl-6-h yd r oxy-6-vin yl-2-p ip er id in on e (5d ). To N-
methylglutarimide (0.3 g, 2.36 mmol) in THF (20 mL), cooled
to -78 °C, was added vinylmagnesium bromide (3.1 mL, 3.1
mmol, 1 M solution in THF) dropwise. When the addition was
complete, the mixture was stirred at 20 °C for 16 h. Since TLC
indicated the presence of starting material, additional vinyl-
magnesium bromide (1.2 mL, 1.2 mmol) was then added and
the mixture stirred for an additional 50 min. It was then
poured onto saturated ammonium chloride (10 mL), the layers
were separated, and the aqueous layer was extracted with
ether (2 × 8 mL). The combined organic extracts were dried
5-(ter t-Bu t ylp er oxy)-1-p r op -2-yn yl-5-oxir a n yl-2-p yr -
r olid in on e (6c). To a solution of 5c (0.15 g, 0.91 mmol) in
dichloromethane (30 mL), cooled to -78 °C, was added tin-
(IV) chloride (0.31 mL, 2.66 mmol) dropwise to give a cloudy
solution. To this was added tert-butyl hydroperoxide (0.42 mL,
2.29 mmol, 5.46 M solution in dichloromethane) and the
mixture stirred at -78 °C for 1.5 h then poured onto ice (30
mL). The layers were separated, the aqueous layer was
extracted with dichloromethane (3 × 10 mL), and the combined
organic extracts were washed with brine (20 mL) and then
dried (MgSO4). Evaporation gave an oil which was purified
by column chromatography (15:85 ethyl acetate: 40-60 °C
petroleum ether) to give a mixture of two diastereoisomers (9
anti: 1 syn) of 6c (172 mg, 80%) as an oily solid. To this
mixture was added hot petroleum (40-60 °C), followed by ethyl
acetate added dropwise until a homogeneous mixture was
obtained. On standing, the solution deposited anti-6c as cubes,
mp 98-99 °C (the X-ray crystallographic sample); IR νmax (thin
film) 3240, 2588, 1707, cm-1; 1H NMR (CDCl3; anti-6c) δ 4.36
(1H, dd, J ) 18.0, 2.0 Hz), 3.82 (1H, dd, J ) 18.0, 2.0 Hz),
3.32 (1H, dd, J ) 4.5, 2.8 Hz), 2.78 (1H, t, J ) 5.0 Hz), 2.69
(1H, dd, J ) 5.0, 2.8 Hz), 2.60-2.16 (4H, m), 2.15 (1H, t, J )
2.0 Hz), 1.18 (9H, s); 1H NMR (CDCl3; syn-6c) δ 4.33 (1H, dd,
J ) 18.0, 2.0 Hz), 3.82 (1H, m), 3.38 (1H, dd, J ) 4.6, 3.0 Hz),
2.86 (1H, t, J ) 5.0 Hz), 2.69 (1H, m), 2.60-1.75 (5H, m), 1.18
(9H, s); 13C NMR (CDCl3) δ 175.2 (s), 96.4 (s), 80.6 (s), 79.5
(s), 75.5 (d), 52.8 (d), 43.6 (t), 29.4 (t), 28.5 (t), 26.4 (q), 24.6
(t). Anal. Calcd for C 61.63, H 7.58, N 5.53. Found C 61.68, H
7.45, N 5.28%.
1
(MgSO4) and evaporated to give an orange oil whose H NMR
showed a 3:7 mixture of 5d : 5-oxo-h ep t-6-en oic a cid m e-
th yla m id e (0.18 g, 49%). This mixture was treated directly
with TBHP-SnCl4, since attempted purification of the mixture
by column chromatography (80:20 ethyl acetate: 40-60 °C
petroleum ether) resulted solely in 5-oxohept-6-enoic acid
methylamide as an oil; IR ν
(thin film) 3305, 1650 cm-1
;
max
1H NMR (CDCl3) δ 6.34 (NH, bs), 6.31-6.07 (2H, m), 5.75 (1H,
dd, J ) 10.0, 2.0 Hz), 2.67 (3H, d, J ) 4.8 Hz), 2.57 (2H, t, J
) 7.5 Hz), 2.30 (2H, t, J ) 7.5 Hz), 1.83 (2H, quint., J ) 7.5
Hz); 13C NMR (CDCl3) δ 200.6 (s), 173.3 (s), 136.3 (d), 128.5
(t), 38.4 (t), 35.1 (t), 26.1 (q), 19.8 (t); m/z (EI): 156 (MH+, 79%),
138 (10%), 125 (100%), 97 (20%), 58 (11%). HRMS, calcd for
C8H13NO2 155.0948, found 155.0957.
5-(ter t-Bu t ylp er oxy)-1-m et h yl-5-oxir a n yl-2-p yr r olid i-
n on e (6a ). To a solution of 5a (0.2 g, 1.42 mmol) in dichlo-
romethane (30 mL), cooled to -78 °C, was added tin(IV)
chloride (0.36 mL, 3.12 mmol) dropwise followed by tert-butyl
hydroperoxide (0.57 mL, 3.12 mmol, 5.46 M solution in
dichloromethane). The mixture was then stirred at -78 °C for
2 h and poured onto ice (30 mL), and the layers were
separated. The aqueous layer was extracted with diethyl ether
(3 × 10 mL), and the combined organic extracts were washed
with brine (20 mL), dried (MgSO4), and evaporated. This gave
6a (9 anti: 1 syn) as a colorless oil (0.22 g, 69%) which required
5-(ter t-Bu t ylp er oxy)-1-m et h yl-5-oxir a n yl-2-p ip er id i-
n on e (6d ). To the 3:7 mixture (360 mg) described above
(equivalent to 108 mg, 0.70 mmol of pure 5d ) in dichlo-
romethane (26 mL), cooled to -78 °C, was added tin(IV)
chloride (0.45 mL, 3.86 mmol) dropwise to give a cloudy
solution. To this was added tert-butyl hydroperoxide (0.78 mL,
4.25 mmol), the mixture was stirred at -78 °C for 2 h and
then poured onto ice (20 mL), and the layers were separated.
The aqueous layer was extracted with diethyl ether (3 × 5 mL),
and the combined organic extracts were washed with brine
(15 mL) and then dried (MgSO4). Evaporation gave an oil
which was purified by column chromatography (20:80 ethyl
acetate: 40-60 °C petroleum ether) to give two diastereoiso-
mers (7 anti: 1 syn) of 6d as a colorless oil (109 mg, 64%); IR
no further purification; IR ν
(thin film) 3475, 1702 cm-1
;
max
1H NMR (CDCl3; anti-6a ) δ 3.11 (1H, dd, J ) 4.0, 2.5 Hz), 2.86
(3H, s), 2.81 (1H, dd, J ) 5.0, 4.0 Hz), 2.73 (1H, dd, J ) 5.0,
2.5 Hz), 2.60-2.40 (1H, m), 2.40-2.10 (2H, m), 2.05-1.80 (1H,
m), 1.20 (9H, m); 1H NMR (CDCl3; syn-6a ) δ 3.18 (1H, dd, J )
4.0, 2.4 Hz), 2.86 (3H, s), 2.81 (1H, m), 2.65-2.40 (2H, m),
2.35-2.05 (2H, m), 2.00-1.70 (1H, m), 1.19 (9H, s); 13C NMR
(CDCl3) δ 176.3 (s), 96.4 (s), 80.3 (s), 53.1 (d), 42.7 (t), 29.8 (t),
26.4 (q), 25.8 (q), 25.0 (t); m/z (CI): 230 (M - H+, 100%), 172
(21%), 158 (15%), 140 (77%), 128 (16%), 114 (52%), 57 (51%).
HRMS, calcd for C11H20NO4 230.1392, found 230.1398.
1
νmax (thin film) 3476, 1659 cm-1; H NMR (CDCl3; anti-6d ) δ
3.20 (1H, dd, J ) 4.0, 2.9 Hz), 2.94 (3H, s), 2.70 (1H, dd, J )
5.0, 4.0 Hz), 2.54 (1H, dd, J ) 5.0, 2.9 Hz), 2.50-1.50 (6H, m),
1.18 (9H, m); 1H NMR (CDCl3; syn-6d ) δ 3.11 (1H, dd, J )
4.1, 2.9 Hz), 2.92 (3H, s), 2.78 (1H, dd, J ) 5.2, 4.1 Hz), 2.60
(1H, dd, J ) 5.2, 2.9 Hz), 2.90-2.50 (6H, m), 1.20 (9H, m); 13
C
NMR (CDCl3) δ 171.7 (s), 91.2 (s), 80.2 (s), 54.9 (d), 32.0 (t),
28.7 (q), 28.0 (t), 26.5 (t), 16.9 (t); m/z (EI): 209 (21%), 170
(16%), 154 (100%), 126 (22%), 55 (10%).
1-Ben zyl-5-(ter t-b u t ylp er oxy)-5-oxir a n yl-2-p yr r olid i-
n on e (6b). A solution of 5b (0.2 g, 0.92 mmol) in dichlo-
romethane (20 mL) was cooled to -78 °C and treated dropwise
with tin(IV) chloride (0.11 mL, 0.92 mmol) to give a cloudy
solution to which was added tert-butyl hydroperoxide (0.35 mL,
2.12 mmol, 6.08 M solution in dichloromethane) dropwise. The
5-(t er t -Bu t ylp e r oxy)-1-m e t h yl-5-vin yl-2-p yr r olid i-
n on e (7a ) a n d 5-(ter t-Bu tylp er oxy)-5-(2-ter t-bu tylp er -
oxyeth yl)-1-m eth yl-2-p yr r olid in on e (8a ). A solution of 5a
(0.15 g, 1.06 mmol) in dichloromethane (24 mL) was cooled to

Epoxy Peroxide Functionality on a Lactam Ring
J . Org. Chem., Vol. 66, No. 14, 2001 4775
-78 °C and treated dropwise with tin(IV) chloride (22.8 mg,
0.088 mmol) followed by tert-butyl hydroperoxide (0.43 mL,
2.33 mmol, 5.46 M solution in dichloromethane) and the
stirring continued at -78 °C for 2.5 h. The mixture was then
poured onto ice (15 g), the layers were separated, and the
aqueous layer was extracted with dichloromethane (3 × 10
mL). The combined organic extracts were dried (MgSO4) and
evaporated, and the residue was purified by column chroma-
tography (30:70 ethyl acetate: 40-60 °C petroleum ether) to
give 7a as a colorless oil (52 mg, 23%); IR νmax (thin film) 1707
cm-1; 1H NMR (CDCl3) δ 5.68 (1H, dd, J ) 18.0, 11.0 Hz), 5.24
(1H, dd, J ) 18.0, 1.0 Hz), 5.23 (1H, dd, J ) 11.0, 1.0 Hz),
2.69 (3H, s), 2.60-1.90 (4H, m), 1.16 (9H, s); 13C NMR (CDCl3)
δ 176.4 (s), 135.7 (d), 117.7 (t), 97.8 (s), 79.9 (s), 30.6 (t), 30.2
(t), 26.5 (s), 26.3 (s); m/z (EI): 214 (MH+, 97%), 172 (15%),
158 (42%), 142 (88%), 124 (100%), 114 (39%), 73 (27%), 57
(41%); HRMS, calcd for C11H20NO3 214.1443, found 214.1442;
and 8a as a colorless oil (125 mg, 41%); IR νmax (thin film):
5-Allyl-5-h yd r oxy-1-p r op -2-yn yl-2-p yr r olid in on e (10)
a n d 5-Allylid en e-1-p r op -2-yn yl-2-p yr r olid in on e. P r ep a -
r a tion of Allylzin c Br om id e. Zinc powder was washed three
times with dilute hydrochloric acid and then filtered under
vacuum before washing initially with water and then with
acetone. The zinc was then flame-dried under nitrogen in the
reaction flask. To this activated zinc (1.91 g, 29.2 mmol),
covered by THF, was added neat allyl bromide (3.53 g, 29.2
mmol; CAUTION: TOXIC) dropwise to initiate the reaction.
Once the reaction had been initiated, the remaining solution
of allyl bromide in THF (30 mL; CAUTION: TOXIC) was
added dropwise, maintaining gentle reflux. When the addition
was complete the mixture was heated at reflux for a further
0.5 h and then allowed to cool to 20 °C to give a solution of
allylzinc bromide.
To N-propargylsuccinimide (1.00 g, 7.29 mmol), cooled in
an ice-salt bath, was added dropwise a solution of allylzinc
bromide (30 mL, 29.2 mmol, 0.97 M solution in THF) prepared
as described above. The mixture was then stirred at 20 °C for
75 min and poured onto saturated ammonium chloride (15
mL), and the layers were separated. The aqueous layer was
extracted with diethyl ether (2 × 10 mL), dried (MgSO4), and
evaporated to give the crude title compound as a reddish-
brown oil (1.85 g). Attempted purification of the crude 10 by
column chromatography (50:50 ethyl acetate: 40-60 °C
petroleum ether) induced dehydration to give 5-a llylid en e-
1-p r op -2-yn yl-2-p yr r olid in on e as a colorless oil (0.59 g,
50%); IR νmax (thin film) 1655 cm-1;1H NMR (CDCl3) δ 6.34
(1H, ddd, J ) 20.0, 17.0, 12.0 Hz), 5.62 (1H, dt, J ) 12.0, 2.5
Hz), 5.01 (1H, dd, J ) 17.0, 1.0 Hz), 4.95 (1H, d, J ) 12.0 Hz),
4.24 (2H, d, J ) 3.0 Hz), 2.80 (2H, m), 2.53 (2H, m), 2.18 (1H,
t, J ) 3.0 Hz); 13C NMR (CDCl3) δ 174.8 (s), 141.0 (s), 131.3
(d), 113.8 (t), 103.8 (d), 77.0 (s), 71.8 (d), 29.3 (t), 28.5 (t), 21.5
(t); m/z (EI): 162 (MH+, 85%), 138 (100%), 106 (27%), 95 (27%),
84 (78%), 56 (66%); HRMS calcd for C10H12NO 162.0919, found
162.0910.
5-Allyl-5-(ter t-bu tylp er oxy)-1-p r op -2-yn yl-2-p yr r olid i-
n on e (11). To a solution 10 (0.30 g, 1.67 mmol, crude) in
dichloromethane (30 mL), cooled to -78 °C, was added tin-
(IV) chloride (0.59 mL, 5.01 mmol) dropwise to give a cloudy
solution. To this was added tert-butyl hydroperoxide (0.77 mL,
4.18 mmol, 5.46M solution in dichloromethane) and the
mixture stirred at -78 °C for 1.5 h, then poured onto ice (30
mL). The layers were separated and the aqueous layer
extracted with dichloromethane (3 × 10 mL) and the combined
organic extracts dried (MgSO4). Evaporation gave an oil which
was purified by column chromatography (10:90 ethyl acetate:
40-60 °C petroleum ether) to give 11 as a colorless oil (168
mg, 40%); IR νmax (thin film) 3286, 1694 cm-1; 1H NMR (CDCl3)
δ 5.77 (1H, m), 5.15 (2H, m), 4.30 (1H, dd, J ) 18.0, 1.6 Hz),
3.73 (1H, dd, J ) 18.0, 1.6 Hz), 2.70-1.95 (7H, m), 1.15 (9H,
s); 13C NMR (CDCl3) δ 175.9 (s), 131.4 (d), 119.7 (t), 98.2 (s),
79.9 (s), 70.6 (d), 40.1 (t), 29.9 (t), 27.8 (t), 27.5 (t), 26.5 (q);
m/z (EI): 252 (MH+, 12%), 220 (20%), 204 (39%), 162 (100%).
HRMS calcd for C14H22NO3 252.1600, found 252.1610.
1
1707 cm-1; H NMR (CDCl3) δ 3.69 (2H, dt, J ) 7.0, 2.0 Hz),
2.71 (3H, s), 2.60-1.79 (6H, m), 1.17 (9H, s), 1.13 (9H, s); 13
C
NMR (CDCl3) δ 176.3 (s), 97.5 (s), 80.3 (s), 79.7 (s), 69.9 (t),
32.9 (t), 30.2 (t), 28.1 (t), 26.5 (q), 26.3 (q), 24.8 (q); m/z (EI):
304 (MH+, 76%), 214 (100%), 158 (69%), 140 (43%), 124 (28%),
111(54%), 73 (24%), 57 (40%). HRMS calcd for C15H30NO5
304.2124, found 304.2140.
Rea ction of 5-(ter t-Bu tylp er oxy)-1-m eth yl-5-vin yl-2-
p yr r olid in on e (7a ) w ith Tin (IV) Ch lor id e. A solution of
7a (251 mg, 1.18 mmol) in dichloromethane (30 mL) was cooled
to -78 °C and treated dropwise with tin(IV) chloride (0.28 mL,
2.36 mmol) followed by tert-butyl hydroperoxide (0.48 mL, 2.60
mmol, 5.46 M solution in dichloromethane). The mixture was
then stirred at -78 °C for 2 h and poured onto ice (20 g), and
the layers were separated. The aqueous layer was extracted
with dichloromethane (3 × 5 mL), and the combined organic
extracts were dried (MgSO4) and evaporated. The residue was
then purified by column chromatography (36:64 ethyl ac-
etate: 40-60 °C petroleum ether) to give 6a as a colorless oil
(70 mg, 35%); with spectral data identical with those given
above.
1-Ben zyl-5-(ter t-b u t ylp er oxy)-5-(2-ter t-b u t ylp er oxy-
et h yl)p yr r olid in -2-on e (8b ) a n d 1-Ben zyl-5-(ter t-b u t yl-
p er oxy)-5-vin yl-2-p yr r olid in on e (7b). A solution of 5b (0.3
g, 1.38 mmol) in dichloromethane (20 mL) was cooled to -78
°C and treated dropwise with tin(IV) chloride (118 mg, 0.45
mmol) followed by tert-butyl hydroperoxide (0.52 mL, 3.18
mmol, 6.08 M solution in dichloromethane). The reaction
mixture was then stirred at -78 °C for 2 h and poured onto
ice (15 g), and the layers were separated. The aqueous phase
was extracted with dichloromethane (3 × 10 mL), and the
combined organic extracts were dried (MgSO4) and evaporated
to give an oil which was purified by column chromatography
(14:86 ethyl acetate: 40-60 °C petroleum ether) to give 8b as
1
a colorless oil (69 mg, 13%); IR νmax (thin film) 1707 cm-1; H
NMR (CDCl3) δ 7.35-7.10 (5H, m), 4.79 (1H, d, J ) 15.5 Hz),
4.12 (1H, d, J ) 15.5 Hz), 3.87 (2H, t, J ) 13.5 Hz), 2.70-1.70
(6H, m), 1.20 (9H, s), 1.15 (9H, s); 13C NMR (CDCl3) δ 177.0
(s), 138.6 (s), 128.4 (d), 127.7 (d), 127.0 (d), 98.2 (d), 80.1 (s),
79.9 (s), 69.8 (t), 42.8 (t), 34.7 (t), 30.2 (t), 28.7 (t), 26.5 (q),
26.3 (q); m/z (FAB): 380 (MH+, 100%), 290 (90%), 234 (14%),
216 (16%), 190 (65%); HRMS calcd for C21H34NO5 380.2437,
Ack n ow led gm en t. This work was supported by the
Engineering and Physical Sciences Research Council
and SmithKline Beecham as a CASE studentship (to
A.K.). We are also grateful for use of the EPSRC
National Crystallography Service and for use of the
ULIRS for mass spectrometry.
1
found 380.2450; and 7b as a colorless oil (136 mg, 33%); H
NMR (CDCl3) δ 7.40-7.20 (5H, m), 5.62 (1H, dd, J ) 17.5 Hz,
J ) 11.0 Hz), 5.35 (1H, dd, J ) 17.5, 1.5 Hz), 5.16 (1H, dd, J
) 11.0, 1.5 Hz), 4.63 (1H, d, J ) 15.5 Hz), 4.16 (1H, d, J )
15.5 Hz), 2.55-2.35 (2H, m), 2.20-2.00 (2H, m), 1.15 (9H, s);
13C NMR (CDCl3) δ 177.0 (s), 138.5 (s), 136.2 (d), 128.6 (d),
127.9 (d), 127.3 (d), 117.7 (d), 97.6 (s), 80.0 (s), 43.4 (t), 32.0
(t), 30.7 (t), 26.6 (q); m/z (FAB): 290 (MH+, 100%), 234 (18%),
216 (31%), 190 (67%). HRMS calcd for C17H24NO3 290.1756,
found 290.1770.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of methyl glutarimide, propargyl succinimide,
5c, byproduct of 5c, byproduct of 5d , 6a -d , 7a , 8a , 8b,
byproduct of 10, and 11; ORTEP of anti-6c. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O001313F