New applications of dithiocarbamates in organic synthesis

Article abstract of DOI:10.1002/hc.20336

The application of dithiocarbamates in group transfer radical cyclization reactions is described. Carbamoyl diethyldithiocarbamates are synthesized in two high-yielding steps from secondary amines and act as sources of carbamoyl radicals through chemical

Full text of DOI:10.1002/hc.20336

Heteroatom Chemistry
Volume 18, Number 5, 2007
New Applications of Dithiocarbamates
in Organic Synthesis
Richard S. Grainger1 and Paolo Innocenti2
1School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
2Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
Received 10 November 2006
boxylic acids [2]. More recently, the radicophilicity
ABSTRACT: The application of dithiocarbamates
of the xanthate group has been exploited to great ef-
in group transfer radical cyclization reactions is
fect by Zard for the generation of a variety of radicals
described. Carbamoyl diethyldithiocarbamates are
that have found application in a number of versa-
synthesized in two high-yielding steps from sec-
tile and effective carbon–carbon bond-forming reac-
ondary amines and act as sources of carbamoyl
tions [3].
radicals through chemical or photochemical ini-
Our own interest in the field of radical chemistry
tiation. Group transfer radical cyclization reac-
arose from a need to employ a carbamoyl radical cy-
tions lead to dithiocarbamate-functionalized lac-
clization as a key step in a natural product synthesis.
ꢀ
C
tams.
2007 Wiley Periodicals, Inc. Heteroatom Chem
The intramolecular addition of a carbamoyl radical 1
to a carbon–carbon double bond leads to the forma-
tion of a lactam 3 after H-atom transfer to the alkyl
radical 2 (Fig. 1). This process represents an unusual
synthesis of amides through a C C bond-forming re-
action, which complements the more usual C(O) N
bond-forming reaction between an amine and an ac-
tivated carboxylic acid derivative.
Although a number of methods have been devel-
oped for the generation and cyclization of carbamoyl
radicals [4–8], in all but one case they rely on a hy-
drogen transfer step to continue the radical chain
process. This places a limit on the size and type of
ring system that can be formed, since the rate of in-
termolecular hydrogen atom transfer to the initial
carbamoyl radical to form 4 becomes comparable
to, or can exceed, the rate of intramolecular cycliza-
tion, especially for more difficult, and hence slower,
cyclizations. Indeed, highest yields are typically ob-
served for the formation of γ -lactams through a
5-exo trig cyclization reaction, an extremely rapid
reaction in free-radical chemistry, and extension to
the formation of larger ring systems is problematic.
However, four-membered ring formation can be ef-
fective in some cases, and the cobalt group transfer
18:568–571, 2007; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20336
INTRODUCTION
The high radicophilicity of the thiocarbonyl group
has resulted in a long association with synthetic free-
radical chemistry. Radicals typically add reversibly
at the sulfur of the thiocarbonyl group leading to
a new carbon-centered radical, which can in turn
undergo further free-radical processes. This reactiv-
ity forms the basis of a number of important func-
tional group transformations, including the Barton–
McCombie deoxygenation of alcohols [1], and the
use of Barton esters for the decarboxylation of car-
Correspondence to: Richard S. Grainger; e-mail: r.s.grainger@
bham.ac.uk.
Contract grant sponsor: King’s College London.
Contract grant sponsor: The University of Birmingham.
Contract grant sponsor: EPSRC.
Contract grant sponsor: AstraZeneca.
Contract grant sponsor: EPSRC Advanced Research Fellowship.
Contract grant number: 2005–2010.
2007 Wiley Periodicals, Inc.
c
ꢀ
568

New Applications of Dithiocarbamates in Organic Synthesis 569
O
S
O
R
R
O
O
R
R
O
N
5-exo trig
a X = O, n = 1
b X = N, n = 2
N
S
XEtn
N
N
R
R
N
S
S
N
5
1
2
XEtn
H-atom
abstraction
H-atom
abstraction
initiation
8
O
5
R
N
O
H
R
O
H
O
N
R
N
4
3
Et
2
1
O
O
Ph
R
R
N
S
S
N
O
O
O
N
O
Me
Ts
Bn
Bn
5
XEtn−1
N
SePh
N
N
O
9
R
O
N
R
TMS3SiH, AIBN
toluene, reflux
(46%) [4]
Bz2O2
benzene, reflux
(53%) [5]
h , MAP
toluene, 100°C
(84%) [6]
O
O
N
R
O
S
+
N
R
S
N
S
XEtn
O
1
Bn
N
S
XEtn
S
N
N
O
7
6
Co
O
N
FIGURE 2 Group transfer cyclization of carbamoyl radicals.
O
PhSH, ACCN
toluene, reflux
(63%) [7]
Bu
h
toluene, reflux
(64%) [8]
The competitive addition of carbamoyl radical 1
to the thiocarbonyl group of the starting xanthate 5a
represents a degenerate reaction process—the sym-
metrical radical 8a will simply fragment back to 1
and a molecule of 5a. The alternative fragmentation
of 8a (or indeed 6a) to a primary ethyl radical is
unlikely on energetic grounds. The degenerate reac-
tion pathway and the absence of a H-atom trans-
fer step means that carbamoyl radicals, such as 1,
generated from xanthate precursors 5a should have
sufficient lifetime to adopt conformations required
for less facile cyclizations (than the simple 5-exo trig
case).
FIGURE 1 Carbamoyl radical cyclization precursors (yields
in parentheses are for five-membered ring formation).
methodology of Pattenden and coworkers has found
notable application in a formal synthesis of the β-
lactam antibiotic thienamycin [8,9].
RESULTS AND DISCUSSION
The inherent limitations of free-radical chain pro-
cesses that rely on a H-atom abstraction step are
overcome to a great extent by the xanthate group
transfer chemistry developed by Zard [3]. The prin-
ciple is shown in Fig. 2, in the context of our own
interest in developing a method that is applicable to
the synthesis of more challenging ring systems than
a γ -lactam. A carbamoyl xanthate 5a should act as
a source of carbamoyl radical 1, which can cyclize
to form alkyl radical 2. Xanthate group transfer via
addition of 2 to the thiocarbonyl group of 5a and
subsequent fragmentation of 6a leads to the desired
product 7a along with carbamoyl radical 1 to con-
tinue the chain process.
Preparation of 5a was attempted from the reac-
tion of readily prepared carbamoyl chloride 10 with
a xanthate salt (Fig. 3). The major product of the
reaction was O-ethyl thiocarbamate 11. Formation
of 11 can be rationalized by attack of the xanthate
salt on the initially formed 5a at the thiocarbonyl
carbon, followed by further ionic processes that also
regenerate xanthate salt, resulting in further break-
down of 5a [10]. Despite intensive investigation of
the reaction conditions, we were unable to limit this
reaction and prepare a carbamoyl xanthate such as
5a in anything greater than 30% yield.
Reasoning that a carbamoyl dithiocarbamate 5b
should be less susceptible to nucleophilic attack
Heteroatom Chemistry DOI 10.1002/hc

570 Grainger and Innocenti
S
S
S
O
S
S
O
Bn
O
h
N
S
Et2N
Bn
Bn
O
S
OEt
S
(1)
(2)
N
N
S
S
S
OEt
OEt
N
S
cyclohexane
reflux
S
S
S
N
O
H
Bn
H
Et2N
Et2N
Et2N
70%
h
S
Bn
O
O
S
N
S
cyclohexane
reflux
Et2N
S
Bn
N
Bn
OEt
S
O
OEt
92%
S
OEt
Bn
5a
N
S
O
5 : 1
Et2N
S
Me
O
h
11
N
S
(3)
(4)
N Me
KS
OEt
cyclohexane
reflux
S
S
S
O
triphosgene
pyridine
78%
S
Bn
Bn
Et2N
SNa.3H2O
NH
N
Cl
Bn
h
N
acetone, rt
>90%
toluene
>90%
Bn
N
10
cyclohexane
reflux
Et2N
S
S
O
O
Et2N
S
52% (0.1 M)
58% (0.5 M)
O
S
O
S
cyclohexane
Bn
N
S
NEt2
Bn
NEt2
S
NEt2
N
reflux
Et2N
S
S
S
h , 96%
Bn
7b
S
+
5b
N
or lauroyl
peroxide, 80%
(5)
cyclohexane
S
O
O
N
N
O
reflux
Bn
Bn
Et2N
S
FIGURE
dithiocarbamates.
3 Preparation and cyclization of carbamoyl
h , 65%
8.4 : 1
5.6 : 1
lauroyl
peroxide, 58%
because of the increased electron density in the thio-
carbonyl group compared with a xanthate, we in-
vestigated the reaction of carbamoyl chloride 10
with commercially available diethyldithiocarbamate
sodium salt. In stark contrast to the xanthate case,
we were delighted to find this resulted in a clean
transformation to the carbamoyl dithiocarbamate
5b in high yield. Furthermore, carbamoyl dithiocar-
bamates were found to undergo group transfer rad-
ical cyclization reactions in an analogous manner
to that expected for the xanthate (Fig. 2). Initiation
of a radical chain process, using either a peroxide
or more conveniently by irradiation using a 500-W
halogen lamp, gave the functionalized γ -lactam 7b
in high yield (Fig. 3) [11].
lauroyl
Bn
S
peroxide
N
Et2N
(6)
(7)
S
chlorobenzene
reflux
S
O
N
Bn
O
Et2N
S
N
37%
O
Bn
S
O
N
H
Bn
Et2N
S
h
cyclohexane
reflux
S
S
56%
NEt2
1.7 : 1
FIGURE 4 Synthesis of four to eight membered ring lactams.
Dithiocarbamates,
along
with
other
donating effect of nitrogen versus oxygen [17]. This
will have an effect on the rate of addition of radicals
toward the thiocarbonyl group. Nucleophilic radi-
cals, such as simple alkyl radicals 2, are expected
to add more slowly to the thiocarbonyl group of a
dithiocarbamate, and as with any radical process,
a slow individual step can lead to unproductive
radical reactions and a termination of the radical
chain process. However, in the present case, the
rate is clearly sufficient to maintain a chain process,
when the two equilibria that lead to dithiocarbamate
thiocarbonyl-based functional groups, have been
extensively investigated as mediators in living
radical polymerizations by the reversible addition-
fragmentation chain transfer (RAFT) mechanism
[12]. However, despite the structural similarity of
dithiocarbamates to xanthates, examples of their
use in small-molecule free-radical reactions are rare
[13–16]. The thiocarbonyl of a dithiocarbamate is
expected to be more electron-rich than that in a
xanthate because of the more pronounced electron-
Heteroatom Chemistry DOI 10.1002/hc

New Applications of Dithiocarbamates in Organic Synthesis 571
group transfer are driven in the desired direction
(Fig. 2). The intermediate 6b in the group transfer
process will fragment to carbamoyl radical 1 and
lactam 7b, the major driving force being the relative
stability of 1 compared with the primary alkyl
radical 2.
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of carbamoyl radicals has proven to be a relatively
general approach to functionalized lactams of vari-
ous ring sizes (Fig. 4) [11]. After cyclization, dithio-
carbamate group transfer to secondary (Eqs. (2), (3),
(5), and (6)) and tertiary (Eq. (4)) radicals can also
be achieved; although in the latter case yields are
lower, presumably due to a slower addition step from
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of a bicyclic ring system through two consecutive
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transfer is also possible (Eq. (7)).
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been shown to be an efficient mediator of carbamoyl
radical cyclization reactions, complementing the
radical chemistry of xanthates. The procedure is ex-
perimentally simple, requiring neither high dilution
nor syringe pump techniques, and avoids the use of
toxic tin reagents characteristic of a large number of
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can be used for further functional group manipula-
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Heteroatom Chemistry DOI 10.1002/hc