First examples of intramolecular addition of primary amidyl radicals to olefins

Article abstract of DOI:10.1139/v05-029

The first examples of intramolecular addition of primary amidyl radicals to olefins are described. Amidyl radicals were generated from N-(phenylthio)amides in refluxing benzene using a catalytic amount of 2,2′- azobis(isobutyronitrile) (5 mol%) and tributyltin hydride (sim;2.2 equiv.). The resulting yields of cyclic products ranged from 63% to 85%.

Full text of DOI:10.1139/v05-029

543
First examples of intramolecular addition of
primary amidyl radicals to olefins1
Philippe Gaudreault, Christian Drouin, and Jean Lessard
Abstract: The first examples of intramolecular addition of primary amidyl radicals to olefins are described. Amidyl
radicals were generated from N-(phenylthio)amides in refluxing benzene using a catalytic amount of 2,2′-azobis(iso-
butyronitrile) (5 mol%) and tributyltin hydride (~2.2 equiv.). The resulting yields of cyclic products ranged from 63%
to 85%.
Key words: radical cyclization, amidyl radicals, nitrogen heterocycles.
Résumé : Les premiers exemples de cyclisation radicalaire impliquant un radical amidyle primaire et une oléfine sont
décrits. Les radicaux amidyles sont obtenus à partir de N-(phénylthio)amides dans le benzène à reflux en présence
d’une quantité catalytique de 2,2′-azobis(isobutyronitrile) (5 mol%) et d’hydrure de tributylétain (~2.2 équiv.). Des ren-
dements en produits cyclisés variant de 63 % à 85 % sont obtenus.
Mots clés : cyclisation radicalaire, radicaux amidyles, hétérocycles azotés.
Gaudreault et al. 545
Introduction
easily prepared and that nitrogen heterocycles resulting from
their radical cyclization can be obtained in good to very
good yields.
Over the years, amidyl radicals have attracted continuous
interest with regard to their structure (1, 2), their reactivity
(3–5), and ways to generate them (3, 4). Clearly, it appears
that intramolecular addition of an amidyl radical on a pen-
dant olefin is a powerful synthetic tool for the formation of
nitrogen-containing heterocycles. Numerous examples of
cyclization involving secondary amidyl radicals can be
found in the literature (4). However, as far as we know, there
are no examples of a successful cyclization involving a pri-
mary amidyl radical (4k, 6), even if there are many examples
of successful intermolecular additions of primary amidyl
radicals to olefins (3). The main reason for the lack of data
on the cyclization of primary amidyl radicals is that
endeavours to prepare the usual radical precursors such as
N-haloamides (3, 4a, 4b), N-(pyridine-2-thione-oxycarbonyl)
amides (PTOC amides) (4c, 4f ), and N-(ethoxythiocarbonyl-
sulfanyl)amides (4h), have failed when applied to olefinic
primary amides (7).3 In the present paper, we report that N-
(phenylthio) derivatives of olefinic primary amides can be
The four olefinic primary amides 5–8 were selected as
models for radical cyclization of primary amidyl radicals.
They were prepared from the corresponding carboxylic acids
1–4 via the acid chlorides as shown in Scheme 1.4
Carboxylic acids 1, 2, and 4 are commercially available and
cyclohept-4-ene carboxylic acid 3 was synthesized in four
steps from cyclopentanone following a method developed by
Stork and Landesman (8).
Next, conversion of primary amides 5–8 into suitable amidyl
radical precursors was examined. We found that N-
(phenylthio)amides 9–12 could be easily prepared in good to
very good yields (60%–84%) following a protocol developed
by Esker and Newcomb (4d), but slightly modified, by react-
ing the anion of the amide with phenylsulfenyl chloride (9).4
N-(Phenylthio)amides 9–12 were the sole amidyl precursors
that could be obtained from olefinic primary amides 5–8.3
Having the primary amidyl radical precursors in hand,
intramolecular addition was next investigated. N-
Received 27 October 2004. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 24 May 2005.
This paper is dedicated to Howard Alper in recognition of his many achievements in chemistry.
P. Gaudreault, C. Drouin, and J. Lessard.2 Université de Sherbrooke, Département de chimie, 2500 Boul. Université, Sherbrooke,
QC J1K 2R1, Canada.
1This article is part of a Special Issue dedicated to Professor Howard Alper.
2Corresponding author (e-mail: Jean.Lessard@USherbrooke.ca).
3We tried to prepare N-(PTOC)amides (4c, 4f) and N-(ethoxythiocarbonylsulfanyl)amides (4h) of primary amides 5–7, but all
attempts were unsuccessful.
4Supplementary material: general procedures for the preparation of primary amides 5–8 and of N-(phenylthio)amides 9–12;
spectroscopic data of compounds synthesized. Supplementary data for this article are available on the Web site or may be
purchased from the Depository of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa,
ON K1A 0S2, Canada. DUD 3661. For more information on obtaining material refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/
unpub_e.shtml.
Can. J. Chem. 83: 543–545 (2005)
doi: 10.1139/V05-029
© 2005 NRC Canada

544
Can. J. Chem. Vol. 83, 2005
Scheme 1. Preparation of primary amides and N-(phenylthio) derivatives.
1) SOCl2 or (COCl)2
2) NH3 (g), THF
i) n-BuLi
ii) PhSCl
O
O
O
R
NHSPh
R
OH
R
NH2
THF
-78 °C r.t.
1, 2, 3, 4
9, 10, 11, 12
5, 6, 7, 8
1, 5, 9 : R =
2, 6, 10 : R =
3, 7, 11 : R =
4, 8, 12 : R =
Scheme 2. Radical chain mechanism.
Bu3Sn
Bu3SnH
.
NH2
NH
O
NH
SPh
O
O
.
Bu3SnSPh
Bu3Sn
parent amide
.
Bu3SnH
NH
NH
O
O
.
Bu3Sn
cyclic product
Table 1. Cyclization results.
(Phenylthio)amides 9–12 were heated in refluxing benzene
and a solution of 2,2′-azobis(isobutyronitrile) (AIBN)
(5 mol%) and tributyltin hydride (~2.2 equiv.) in benzene
was added. As shown in Table 1, all four models underwent
radical cyclization to afford the corresponding heterocyles
13–164 in good to very good yields (63%–85%). Interest-
ingly, the use of less than ~2.2 equiv. of tributyltin hydride
resulted in incomplete conversion of the starting olefinic N-
(phenylthio) amide.
Entry
Primary amide
N-(PhS)amidea
Cyclic productb,c
O
O
1
NH
9
84%
84%
NH2
5
13
As expected (10), 5-exo-trig cyclizations were favoured
over 6-endo-trig cyclizations for all concerned models (en-
tries 1, 2, and 4). Also, 6-exo-trig cyclization occurred in
good yield (71%) when this was the sole possibility (entry
3). The reactions also gave small amounts of the parent am-
ide (8%–16% yield) as a result of the reduction of the amidyl
radical by tributyltin hydride. The radical chain mechanism
involved is illustrated in Scheme 2.
To the best of our knowledge, this paper reports the first
examples of radical cyclizations involving a primary amidyl
radical and a pendant olefin. Olefinic N-(phenylthio)amides
were prepared in good yields (60%–84%) and used as pri-
mary amidyl radical precursors in a reaction with AIBN
in catalytic amount (5 mol%) and tributyltin hydride
(~2.2 equiv.), acting, respectively, as radical initiator and
chain carrier. Good to very good yields of cyclization were
obtained (63%–85%). Thus, it is no longer necessary to pre-
pare an N-protected precursor and then remove the protecting
group after cyclization (4k). Further studies are currently be-
ing conducted.
O
NH2
6
2
O
10 63%
85%
N
H
14
O
O
3
4
11 64%
12 60%
71%
NH2
N
H
7
15
H
63%
NH
NH2
O
O
8
16
aReaction conditions: (i) n-BuLi, (ii) PhSCl, THF, –78 °C → r.t.
bReaction conditions: AIBNcat–Bu3SnH (slow addition), benzene, reflux.
cYield of parent amide: 8%, 11%, 16%, and 16% in entries 1–4,
respectively.
© 2005 NRC Canada

Gaudreault et al.
545
Can. J. Chem. 56, 119 (1978); (d) H. Driguez, J.M. Paton, and
J. Lessard. Can. J. Chem. 55, 700 (1977).
General procedure for cyclization
To a refluxing solution of N-(phenylthio)amide (0.5 mmol)
in anhydrous and degassed benzene (20 mL) under a nitrogen
atmosphere, 2,2′-azobis(isobutyronitrile) (4 mg, 0.024 mmol)
and tributyltin hydride (0.28 mL, 1.0 mmol) dissolved in an-
hydrous and degassed benzene (10 mL) were added over 4 h.
If required, a small additional amount of AIBN–Bu3SnH in
benzene was added to complete the reaction. The solvent
was removed under reduced pressure and the residue was
purified by flash chromatography (acetone–toluene, 2:3)
monitored by GC to afford the desired lactam.
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Acknowledgements
Financial support from the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) is gratefully
acknowledged. We are thankful to Mr. Gaston Boulay for
the mass spectral and GC–MS analyses and Mr. Dave Lee
for preparing some compounds.
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© 2005 NRC Canada