Facile cyclization of amidyl radicals generated from N-acyltriazenes

Article abstract of DOI:10.1016/j.tetlet.2005.07.023

N-Acyltriazenes serve as a tin-free and initiator-free source for amidyl radicals. Thermal decomposition of N,N′-diaryl-N-(4-pentenoyl)triazenes in refluxing toluene led to the formation of monocyclic and tricyclic lactams in satisfactory yields via 5-exo amidyl radical cyclization.

Full text of DOI:10.1016/j.tetlet.2005.07.023

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5983–5985
Facile cyclization of amidyl radicals generated from
N-acyltriazenes
Hongjian Lu and Chaozhong Li*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 20 June 2005; revised 7 July 2005; accepted 8 July 2005
Available online 25 July 2005
Abstract—N-Acyltriazenes serve as a tin-free and initiator-free source for amidyl radicals. Thermal decomposition of N,N0-diaryl-N-
(4-pentenoyl)triazenes in refluxing toluene led to the formation of monocyclic and tricyclic lactams in satisfactory yields via 5-exo
amidyl radical cyclization.
Ó 2005 Elsevier Ltd. All rights reserved.
Amidyl radicals are highly reactive and electrophilic
radicals.1 This Umpolung reactivity offers a great poten-
tial in organic synthesis via intramolecular cyclization to
afford lactams or cyclic amines. However, amidyl radi-
cal-based synthetic methodologies have drawn much less
attention than they deserve.2 This is, in part, because
most of the amidyl radical precursors are either very
unstable or difficult to prepare. For example, precursors
such as N-halo amides3 and N-hydroxypyridine-2-thione
imidate esters4,5 are very unstable. Other precursors
such as N-(phenylthio)amides6 or N-(O-ethyl thio-
carbonylsulfanyl)amides2b suffer from the low yields of
preparation in many cases. Recently, Nicolaou et al. re-
ported the o-iodoxybenzoic acid (IBX)-initiated amidyl
radical cyclization with the direct use of amides as the
substrates.2a However, only the 5-exo cyclization reac-
tions of N-aryl-substituted amides could proceed under
the IBX-mediated conditions. It is therefore desirable
to develop novel methods to conduct amidyl radical
reactions. We report here, that N-acyltriazenes serve as
a convenient precursor for unsaturated amidyl radicals
under tin-free and initiator-free conditions.
matic solvents leads to a free radical arylation reaction,
as shown in Scheme 1.8 We envisioned that, if the R
group in 1 bears a C@C double bond, the amidyl radical
2a might undergo cyclization (to give the cyclized car-
bon-centered radical 5) rather than H-abstraction (to
give the amide 4). The cyclized radical 5 then might ab-
stract a hydrogen presumably from radical 3 to afford
the corresponding lactam 6a as the final product
(Scheme 2). This would provide a facile entry to the gen-
eration and cyclization of amidyl radicals under tin-free
and initiator-free conditions. However, to our surprise,
such a process was never examined in the literature.
Based on the above discussion, we carried out the fol-
lowing investigation.
Thus, N,N0-diphenyl-N-(4-pentenoyl)triazene 1a was
prepared from aniline, benzenediazonium fluoroborate
and 4-pentenoyl chloride in 85% yield according to the
literature method.9 Compound 1a turned out to be very
stable and no decomposition was observed in benzene at
COR
C H
COR
C H
N-Acyltriazenes have been known for a long time.7 They
can be easily prepared from the reaction of an amide
with an arenediazonium ion with NaH as the base,8 or
from the reaction of an amine with an arenediazonium
salt followed by the treatment with an acyl chloride
and triethylamine in a one-pot, two-stage manner.9
Thermal decomposition of N-acytriazenes (1) in aro-
C H
6 5
C H N
N
N
5
N
+
N
+
6
5
2
6
5
6
5
1
2
C H
+
C H
6
C H C H
5 6 6
6
6
6
3
COR
C H
COR
C H C H
+
C H C H
6 5 6 5
+
HN
N
6
5
6
6
C H
6
5
6
5
3
4
2
*
Corresponding author. Tel.: +86 21 5492 5160; fax: +86 21 6416
6128; e-mail: clig@mail.sioc.ac.cn
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.023

5984
H. Lu, C. Li / Tetrahedron Letters 46 (2005) 5983–5985
Table 1. Thermal decomposition of triazenes 1 at 110 °C
O
O
Entry
Substratea
Product (yield)b
N Ph
N
Ph
O
O
2a
N Ph
2
N
1
5
N
Ph
Ph
O
O
6a (78%)
1a
+
C6H5C6H5
+
C6H5C6H6
N Ph
N Ph
O
O
O
3
N Ph
2
N
2
3
N
Ph
5
6a
Ph
6b (67%)
1b
Scheme 2.
O
O
N Ph
2
N
N
N
Ph
+
refluxing temperature. Direct photolysis of 1a in benz-
ene at room temperature with the aid of a 125 W high-
pressure mercury lamp gave a complicated mixture in
which N-phenyl-4-pentenamide (4a) was isolated in
24% yield and the desired cyclized product c-lactam 6a
was obtained in 14% yield. However, to our delight,
when 1a was heated up in toluene at reflux (110 °C)
for 6 h, the expected cyclization product 6a was achieved
in 78% isolated yield (Eq. 1).
Ph
1c
6c (35%)
7c (29%)
O
O
O
N Ph
2
+
N
N
N
Ph
4
5
Ph
1d
7d (65%)
6d (20%)
O
O
O
O
1
N Ar
2
1
N
N
We then synthesized a number of N-acyltriazenes 1a–g
to explore the scope and limitation of the above method.
The results are summarized in Table 1.
N
Ar
+
1
Ar
OMe
6e (63%)
1e
7e (22%)
O
O
1
N Ar
2
1
N
+
N
Ar
N
O
O
6
7
1
Ar
N Ph
2
PhCH
N
3
OMe
7f (46%)
ð1Þ
N
Ph
6a
Ph
1f
6f (25%)
reflux, 6 h
78%
1a
O
O
O
2
N Ar
2
2
+
N
N
N
Ar
2
Ar
NO
2
As can be seen in Table 1, the 5-exo cyclization prod-
ucts 6a and b were obtained in high yields in the
thermal decomposition of triazenes 1a and b with a
mono-substituted terminal double bond (Table 1,
entries 1 and 2). With substrate 1c having an internal
double bond, the corresponding 5-exo cyclization prod-
uct 6c was isolated in 35% yield along with the forma-
1g
6g (22%)
7g (11%)
a Ar1: p-methoxyphenyl, Ar2: p-nitrophenyl.
b Isolated yield based on 1.
We next, tested the effect of N-aryl groups on the cycli-
zation. With N,N0-di(p-methoxyphenyl)-substituted sub-
strate 1e and f, both the expected monocyclization
products 6 and the tricyclic products 7 were achieved
in satisfactory overall yields (Table 1, entries 5 and 6).
On the other hand, the N,N0-di(p-nitrophenyl)-substi-
tuted triazene 1g gave the mixture of 6g and 7g in low
yield. The comparison between 1a and e showed that
the p-methoxy-substitution at the phenyl group encour-
ages the formation of the tricyclic products 7. However,
the reason remains unclear.
tion of tetracyclic compound 7c as
a
single
stereoisomer in 29% yield (Table 1, entry 3). Appar-
ently, product 7c resulted from the further addition
of the cyclized radical similar to 5 to the phenyl ring.
For triazene 1d with a dimethyl-substitution at the
C@C double bond, the 5-exo cyclization product 6d
was obtained in 20% yield while the tricyclic product
7d was achieved in 65% yield (Table 1, entry 4). These
results indicate that the formation of tricyclic products
such as 7d is encouraged by the terminal substitution at
the C@C double bond. This trend might be rational-
ized by the enhanced stability of the corresponding cyc-
lized radical 5 from a primary carbon radical (such as
in the case of 1a) to a tertiary carbon radical (in the
case of 1d), which allows the addition of 5 to the phe-
nyl ring to become a competitive process to the direct
H-abstraction of 5. It is worth mentioning that the for-
mation of tricyclic products 7 was not observed in the
IBX-mediated reactions of unsaturated N-arylamides.
The formation of tricyclic products 7 is certainly of great
interest in organic synthesis as this tricyclic skeleton is
widely embedded in a number of biologically active nat-
ural products such as mitomycins.10 In order to increase
the yield of 7, we carried out the thermal decomposition
of 1 at higher temperature. Indeed, when 1a was added
into chlorobenzene at reflux (ꢀ132 °C), the correspond-
ing tricyclic product 7a was obtained in 36% yield while

H. Lu, C. Li / Tetrahedron Letters 46 (2005) 5983–5985
5985
2. For recent examples, see: (a) Nicolaou, K. C.; Baran, P. S.;
Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.;
Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233; (b) Gagosz,
F.; Moutrille, C.; Zard, S. Z. Org. Lett. 2002, 4, 2707; (c)
Tang, Y.; Li, C. Org. Lett. 2004, 6, 3229; (d) Chen, Q.;
Shen, M.; Tang, Y.; Li, C. Org. Lett. 2005, 7, 1625.
3. (a) Barton, D. H. R.; Beckwith, A. L. J.; Goosen, A. J.
Chem. Soc. 1965, 181; (b) Neale, R. S. Synthesis 1971, 1.
4. Newcomb, M.; Esker, J. L. Tetrahedron Lett. 1991, 32,
1035.
no 6a could be isolated (Eq. 2). However, the thermoly-
sis of 1e in refluxing chlorobenzene gave 7e in only 19%
yield along with a significant amount of unidentified
byproducts. Nevertheless, the results in Eqs. 1 and 2
clearly indicate that, under certain experimental condi-
tions, the reaction of 1 could be pushed towards the for-
mation of tricyclic products 7, thus of more synthetic
value. This is now actively pursued in our laboratory.
5. (a) Esker, J. L.; Newcomb, M. Tetrahedron Lett. 1992, 33,
5913; (b) Boivin, J.; Callier-Dublanchet, A.-C.; Quiclet-
Sire, B.; Schiano, A.-M.; Zard, S. Z. Tetrahedron 1995, 51,
6517.
6. Esker, J. L.; Newcomb, M. Tetrahedron Lett. 1993, 34,
6877.
7. Campbell, T. W.; Day, B. F. Chem. Rev. 1951, 48, 299.
8. Curtin, D. Y.; Druliner, J. D. J. Org. Chem. 1967, 32,
1552.
O
O
N2Ph
PhCl
N
N
ð2Þ
Ph
reflux, 2 h
1a
7a (36%)
9. Klages, F.; Mesch, W. Chem. Ber. 1955, 88, 388.
10. (a) Webbs, J. S.; Cosulich, D. B.; Mowat, J. H.; Patrick, J.
B.; Broschard, R. W.; Meyer, W. E.; Williams, R. P.;
Wolf, C. F.; Fulmor, W.; Pidacks, C.; Lancaster, J. E. J.
Am. Chem. Soc. 1962, 84, 3185; (b) Webbs, J. S.; Cosulich,
D. B.; Mowat, J. H.; Patrick, J. B.; Broschard, R. W.;
Meyer, W. E.; Williams, R. P.; Wolf, C. F.; Fulmor, W.;
Pidacks, C.; Lancaster, J. E. J. Am. Chem. Soc. 1962, 84,
3187.
In summary, the above preliminary results clearly dem-
onstrate that the thermal decomposition of unsaturated
N-acyltriazenes provides a convenient entry to the gen-
eration and cyclization of amidyl radicals.11 Tandem
radical cyclization leading to the formation of tricyclic
lactams could also be achieved via this method, which
should be of important application in organic synthesis.
11. Typical procedure for the thermal decomposition of N-
acyltriazenes 1. The solution of triazene 1e (102 mg,
0.3 mmol) in toluene (10 mL) was refluxed for 6 h. The
resulting mixture was then concentrated under reduced
pressure and the residue was subjected to column chroma-
tography on silica gel with ethyl acetate–hexane (1:4, v/v)
as the eluent. The amide 6e (38.7 mg, 63% yield) was
isolated as a white solid, whose spectra were identical with
those reported in the literature (Koebel, R. F.; Needham,
L. L.; Blantom, C. D. J. Med. Chem. 1975, 18, 192).
Compound 7e (13.4 mg, 22% yield) was isolated as a white
Acknowledgements
This project was supported by the National Natural
Science Foundation of China (Nos. 20325207 and
20472109) and by the Shanghai Municipal Committee
of Science and Technology (No. 04QMH1418).
1
References and notes
solid. H NMR (300 MHz, CDCl3) d 1.92–2.05 (1H, m),
2.42–2.51 (1H, m), 2.58 (1H, dd, J = 8.1, 16.5 Hz), 2.78–
2.92 (2H, m), 3.14 (1H, dd, J = 8.4, 15.6 Hz), 3.78 (3H, s),
4.59–4.70 (1H, m), 6.73–6.76 (2H, m), 7.52 (1H, d,
J = 8.4 Hz); 13C NMR (CDCl3) d 29.2, 29.7, 36.2, 55.7,
63.4, 111.3, 112.1, 115.2, 133.0, 135.8, 156.9, 171.2; EIMS:
m/z (rel intensity) 203 (M+, 74), 188 (16), 148 (100), 117
(14), 104 (14), 89 (5), 77 (9), 63 (4), 55 (8); HRMS calcd for
C12H13NO2: 203.0946. Found: 203.0948.
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