Ring contraction of N-chlorolactams, a novel rearrangement

Article abstract of DOI:10.1016/j.tetlet.2006.04.024

Upon photolysis in methylene chloride at -78 °C, different N-chlorolactams underwent a novel ring contraction to the corresponding carbamoyl chlorides, which were converted to the methyl carbamates. The rearrangement is 100% stereoselective, occurring with retention of configuration at the migrating carbon center. The yields of isolated carbamates ranged from 40% to 57%, the other product being the parent lactam, 18% to 38%.

Full text of DOI:10.1016/j.tetlet.2006.04.024

Tetrahedron Letters 47 (2006) 4285–4288
Ring contraction of N-chlorolactams, a novel rearrangement
Alexandre Drouin and Jean Lessard*
D e´ partement de Chimie, Universit e´ de Sherbrooke, 2500 Boul. Univsersit e´ , Sherbrooke, Qu e´ bec, Canada J1K 2X9
Received 21 February 2006; revised 31 March 2006; accepted 5 April 2006
Available online 4 May 2006
Abstract—Upon photolysis in methylene chloride at À78 °C, different N-chlorolactams underwent a novel ring contraction to the
corresponding carbamoyl chlorides, which were converted to the methyl carbamates. The rearrangement is 100% stereoselective,
occurring with retention of configuration at the migrating carbon center. The yields of isolated carbamates ranged from 40% to
5
7%, the other product being the parent lactam, 18% to 38%.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
Cl
O
Cl
O
O
N
Amidyl radicals have been extensively studied over the
past years. Back and Brunner and Phan and Shannon
photolyzed different N-chlorolactams derived from aza-
steroids to generate the corresponding N-acyl imines.
The formation of polymers upon photolysis of N-chloro-
O
N
254 nm
1
2
3
DCM -78 ºC
Cl
N
Table 1
4
2
+
X
+ O
Cl
4
5
1
lactams in benzene was also reported. Chow and Perry,
H
N
6
7,8
N
Kuehne and Horne, Lessard and collaborators, as
9
well as Surzur and collaborators showed that amidyl
3
5
radicals add to double bonds to generate a carbon–
nitrogen bond, both in intramolecular and intermole-
cular reactions. Other studies were carried out by Neale
Johnson and Green, Chow and collabora-
tors, Beckwith and collaborators.
demonstrated that amidyl radicals could also abstract
a nonactivated hydrogen atom in an intramolecular
reaction. In the course of our studies on the reactivity
of PN amidyl radicals in intramolecular additions to
Scheme 1. Photolysis of N-chlorolactam 1.
4
,10
11
et al.,
1
2
13,14
Those studies
has been observed only once by Edwards and collabora-
tors as a side reaction from the photolysis or thermo-
lysis of O-mesylated hydroxamic acids. In this letter, we
report the preliminary results on this new rearrangement
of N-chlorolactams, which is conceptually similar to
the Lossen, Curtius, Schmidt or Hofmann rearrange-
19
1
5,16
double bonds,
we had prepared the N-chlorolactam
the amidyl radical of which could add to the double
1
7
1
,
20
ments, except that it can be applied to cyclic systems.
1
8
bond only via the PN configuration. The cyclization
would have given rise to a tricyclic core via a 5-exo-trig
or 6-endo-trig cyclization (see 2 and 3, respectively, in
Scheme 1). However, upon photolysis, no cyclized prod-
uct was observed, nor any N-acyl imines. Instead,
N-chlorolactam 1 underwent a ring contraction to gen-
erate the carbamoyl chloride 4 (Scheme 1). To the best
of our knowledge, such ring contraction of a lactam
This ring contraction opens new possibilities for the syn-
thesis of N-heterocycles bearing one or two chiral
centers next to the nitrogen. Applications to the synthe-
sis of complex alkaloids are foreseen.
2. Results and discussion
The photolysis of N-chlorolactams 1, 6, 7, and 8 was
carried out in anhydrous dichloromethane (DCM) at
À78 °C in a Rayonnet reactor equipped with 254 nm
Keywords: N-Chlorolactams; Nitrogen-heterocycles; Photolysis;
Rearrangement; Ring contraction.
1
6
*
Corresponding author. Tel.: +1 819 821 7091; fax: +1 819 821
017; e-mail: Jean.Lessard@usherbrooke.ca
UV lamps. The results are reported in Table 1. The
rearrangement product, isolated as the carbamoyl
8
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.024

4286
A. Drouin, J. Lessard / Tetrahedron Letters 47 (2006) 4285–4288
Table 1. Results obtained from the photolysis of N-chlorolactams 1, 6,
Photolysis of N-chlorolactams 6, 7, and 8 gave the rear-
ranged methylcarbamates 9, 11, and 13, respectively,
together with the corresponding parent lactams 10, 12,
and 14 (Table 1, entries 3–5). Comparison of the results
obtained with N-chlorolactams 1 and 6 (entries 2 and 3)
indicates that the vinyl group of 1 had no influence on
the course of the reaction. When the photolysis of 1
was repeated on a larger scale, products resulting from
the addition of molecular chlorine (generated through
a
7, and 8
Entry
N-Chlorolactam
Rearranged
product (yield)
Parent lactam
(yield)
b
b
O
O
O
Cl
Cl
N
H
N
c
N
1
1
5 (48%)
2
3
the Goldfinger mechanism) to the double bond were
obtained in relatively important amounts. Indeed, the
dichloro derivative of carbamate 15 was isolated in
19% yield together with 25% of 15 (for a total of 44%
of rearranged products). In addition, the dichloro deriv-
ative of parent lactam 5 was isolated in 8% yield
together with 26% of 5 (34% of unrearranged lactams)
4
(40%)
O
O
MeO
O
Cl
N
N
H
N
c,d
2
g
1
e,f
5 (34%)
1
5 (44%)
(
Table 1, entry 2).
O
O
MeO
O
We also studied the photolysis of monocyclic N-chloro-
lactams 16 derived from d-valerolactam and, 17, 18, and
Cl
N
N
H
N
d
3
1
9 derived from e-caprolactam (Table 2). d-N-Chloro-3-
methylvalerolactam 16 gave the methyl carbamate 20
and the parent lactam 21 in a 45:55 ratio (entry 1; deter-
mined by GC–MS). On the other hand, unsubstituted
e-N-chlorocaprolactam 17 gave the methyl carbamate
6
f
10 (28%)
9
(53%)
O
O
O
Cl
N
N
OMe
H
N
d
4
2
2 and the parent lactam 23 in a 6:94 ratio (entry 2;
f
7
11 (48%)
12 (32%)
determined by GC–MS). In comparison with 17, e-N-
chloro-caprolactams 18 and 19 gave much better yields
of rearranged methyl carbamates 24 and 26 (entries 3
and 4). Indeed, 52% of methyl carbamate 24 and 33%
of parent lactam 25 were isolated from the photolysis
of 18, and 43% of methyl carbamate 26 and 38% of par-
Cl
N
H
N
d
N
5
OMe
O
3 (57%)
O
8
O
f
14 (18%)
1
a
b
c
In anhydrous DCM at 254 nm.
Yield of isolated product.
Table 2. Results obtained from the photolysis of N-chlorolactams 16,
The difference in yields between entries 1 and 2 is due to the variation
of the temperature during the photolysis (À78 to 0 °C in entry 1, and
À78 to À60 °C in entry 2).
1
7, 18, and 19
Entry N-Chlorolactam
Rearranged
product (yield)
Parent lactam
(yield)
d
e
The reaction mixture was poured into methanol containing 2 equiv of
triethylamine.
O
O
O
OMe
Methyl carbamate 15 isolated in 25% yield and its dichloro-derivative
in 19% yield.
Cl
H
N
N
N
1
f
The formation of small amounts (5–10%) of C-chlorinated products
was evidenced by GC–MS.
a
a
1
6
21 (55%)
2
0 (45%)
g
Parent lactam 5 isolated in 26% yield and its dichloro-derivative in 8%
yield.
MeO
O
O
O
H
Cl
N
N
N
2
3
4
chloride (Scheme 1 and Table 1) or the methylcarbamate
Table 1), and the parent lactam accounted for 75–88%
a
a
1
7
23 (94%)
2
2 (6%)
(
of the isolated products. N-Chlorolactam 1 gave 40% of
carbamoyl chloride 4 and 48% of parent lactam 5 after
chromatographic separation (Table 1, entry 1). As it
was more convenient to isolate the product of rearrange-
ment as the methyl carbamate, the crude reaction mix-
ture was treated with methanol and triethylamine to
convert the carbamoyl chloride to the methyl carbamate
MeO
O
O
O
H
Cl
N
N
N
b
b
rac-18
rac-25 (33%)
2
4 (52%)
O
MeO
O
O
H
(
Table 1, entries 2–5).
Cl
N
N
N
The parent lactams observed in all reactions were
formed by intermolecular hydrogen abstraction from
the solvent or from the substrate, either by the amidyl
b
b
rac-19
26 (43%)
rac-27 (38%)
2
1
22
a
radical (Bloomfield type mechanism) or by the chlo-
Ratios determined by GC–MS.
Yield of isolated products.
2
3
b
rine atom (Goldfinger type mechanism).

A. Drouin, J. Lessard / Tetrahedron Letters 47 (2006) 4285–4288
4287
ent lactam 27 were isolated from the photolysis of 19.
The difference in the observed ratio of rearranged prod-
uct to parent lactam in the photolysis of N-chlorolac-
tams 17 on one hand, and N-chlorolactam 16, 18, and
Table 3. Results obtained from thermal treatment of N-chlorolactam 7
Entry
Conditions
Products observed
1
2
3
4
7, DCM, AgBF
4
, reflux 16 h
7
7, TFA, AgBF
7, 200 °C, 1 h
4
, reflux 16 h
7
1
9 on the other hand, could be explained by the migra-
a
12 and decomposition
12 and decomposition
a
tory aptitude of the carbon, the migration of a second-
ary carbon being faster than that of a primary
7, Toluene, 200 °C, 1 h
a
Reaction carried out in a sealed tube.
2
4
carbon. Methyl carbamates 24 and 26 were isolated
as single diastereoisomers, as shown, revealing that the
rearrangement is 100% stereoselective and that migration
occurs with retention of configuration at the migrating
carbon (determined by NMR and GC). This result sug-
gests that the migration is a concerted process. It is note-
worthy that ring contraction from six- to five-membered
ring (entry 5 of Table 1 and entry 1 of Table 2) is as effi-
cient as ring contraction from a seven- to a six-membered
ring (entries 2–4 of Table 1 and entries 3 and 4 of Table 2).
O
O
O
H
N
O
R
R
R
R
N
R
R
n
n
n
n = 1 or 2
Scheme 3. Conversion of ketones and ring contraction of lactam to the
corresponding N-heterocycle.
Concerning the mechanistic aspect of the reaction, we
know from literature precedents that photolysis of N-
chlorolactams gives rise to homolytic cleavage of the
N–Cl bond. One possible mechanism for the rear-
rangement could thus involve radical species (Scheme
roborate was added. The mixture was refluxed for 16 h,
then treated with methanol. The sole compound recov-
ered was the starting N-chlorolactam 7. The same result
was obtained when using aluminum trichloride. A simi-
lar experiment was realized in trifluoroacetic acid with
silver tetrafluoroborate, and again, the only compound
recovered was 7.
1
6
2
, radical pathway). Homolytic cleavage of the N–Cl
bond would be followed by a 1,2-rearrangement of the
amidyl radical 28 to a more stable formyl radical 29,
and then, reaction of 29 with the parent N-chlorolactam
N-Chlorolactam 7 was also heated, in a sealed tube, to
200 °C for 1 h as a neat liquid and also in solution in tolu-
ene. After treatment with methanol, no trace of the
rearranged compound 11 was observed. The parent lac-
tam 12 was the main product of this reaction together
with various compounds arising from the decomposition
of N-chlorolactam 7.
6
to form the carbamoyl chloride 30 would regenerate
the amidyl radical 28. However, this mechanism is
difficult to reconcile with the observation that the rear-
rangement is 100% stereoselective. We therefore propose
a mechanism implying ionic species (Scheme 2, ionic path-
way). The first step would also be the homolytic clevage
of the N–Cl bond, followed by electron transfer from
1
9,25
the nitrogen atom to the chlorine atom
to generate
the acylnitrenium ion 31 and chloride ion. Concerted
and rapid [1,2]-migration of the carbon a to the
carbonyl onto nitrogen would give the corresponding
N-acylium ion 32. The close-by chloride ion (solvent
cage) would then react with 32 to generate the corre-
sponding carbamoyl chloride 30.
3. Conclusion
In conclusion we have discovered a novel ring contrac-
tion of N-chlorolactams, which opens new perspectives
for the synthesis of nitrogen heterocycles. It allows, in
principle, the conversion of a cyclic ketone to the corre-
sponding nitrogen heterocycle of the same ring size
(replacement of the carbonyl group by a nitrogen atom)
via a sequence initiated with a Beckmann ring enlarge-
ment followed by our novel ring contraction rearrange-
ment (Scheme 3). Further studies currently underway in
our laboratory are aimed at optimizing the ring contrac-
tion as well as determining its mechanism and scope.
Finally, a series of experiments were carried out to deter-
mine if the rearrangement could be induced thermally.
The results are shown in Table 3. First, N-chlorolactam
7
was dissolved in dichloromethane and silver tetrafluo-
Radical pathway
O
O
O
Cl
O
O
Cl
N
6
N
N
Acknowledgments
Cl
N
254 nm
N
We thank Dr. Claude Spino for fruitful discussion and
Dr. Daniel Fortin for the X-ray structure determination.
This work was supported by a research grant form the
Natural Sciences and Engineering Council of Canada
(NSERC).
6
28
29
30
Ionic pathway
O
O
O
O
+
Cl-
Cl
Cl-
N
Cl
+N
N
254 nm
N
Supplementary data
6
28
31
32
Scheme 2. Proposed mechanisms for the rearrangement with ring
contraction of N-chlorolactams.
Complete procedure and characterization of all
compounds can be found in the supplementary data.

4288
A. Drouin, J. Lessard / Tetrahedron Letters 47 (2006) 4285–4288
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
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1
4. Beckwith, A. L. J.; Goodrich, J. E. Aust. J. Chem. 1965,
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2
006.04.024.
1
1
N
: (a) Lessard,
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3
1
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2
3
4
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