Dithiocarbamate group transfer cyclization reactions of carbamoyl radicals under "tin-free" conditions

Article abstract of DOI:10.1002/anie.200453600

Oxygen or nitrogen? Radical chemists overwhelmingly choose to work with xanthates rather than dithiocarbamates, yet the latter offer a distinct advantage in the case of a new method for generating carbamoyl radicals. Functionalized lactams of various ring

Full text of DOI:10.1002/anie.200453600

Angewandte
Chemie
considered that xanthate chemistry would offer a potential
solution. The principle is outlined in Scheme 1: radical
cyclization of carbamoyl radical 2 should lead to the alkyl
radical 3, which after addition to the carbon–sulfur double
Radical Reactions
Dithiocarbamate Group Transfer Cyclization
Reactions of Carbamoyl Radicals under “Tin-
Free” Conditions**
Richard S. Grainger* and Paolo Innocenti
Scheme 1. Group transfer radical cyclization of carbamoyl radicals.
The use of radical reactions in modern organic synthesis is
now well-established.[1] Despite the many well-documented
advantages of free-radical chain reactions in organic chemis-
try, the majority of examples still rely on the use of tributyltin
hydride in stoichiometric amounts, and a major area of
current research is the development of processes which seek
to either alleviate the problems associated with toxic tin
residues, or remove the need for tin completely.[2] Among
these methods, the group transfer chemistry of xanthates,
extensively developed by Zard and co-workers, is one of the
most powerful.[3] Xanthate precursors to acyl,[4] alkoxycar-
bonyl,[5] and a variety of other carbon-centered[6] and nitro-
gen-centered[7] radicals have been reported, and found
numerous applications in synthesis.[5,8] However, group trans-
fer of xanthates from carbamoyl radical precursors has not
been described. Herein we describe the difficulties associated
with using xanthates as carbamoyl radical precursors, and
report a solution based on replacing the classical xanthate
with a dithiocarbamate group.
bond of a carbamoyl xanthate 1a and fragmentation of the
resulting carbon-centered radical gives the desired lactam 4a
along with the initial radical 2, which can continue the chain
process. An alternative reaction pathway available to carba-
moyl radical 2 is addition to the radical precursor 1 to give the
intermediate radical 5. However, this process is fast and
reversible as 5 will fragment backto 1 and 2.[10] The
continuous regeneration of carbamoyl radical 2 by this
degenerate pathway means it should be capable of under-
going cyclizations which would not otherwise compete
favorably with premature reduction of 2 under conditions
used for tin hydride (or other hydrogen atom abstrac-
tion).[9d,g–l]
A survey of the literature showed that carbamoyl
xanthates have been proposed as intermediates in the
reaction between readily prepared carbamoyl chlorides and
xanthate salts, which ultimately affords the corresponding S-
substituted thiocarbamates upon loss of carbon oxysulfide.[11]
Aware of this behavior, we investigated the possibility that the
reaction could be stopped at the carbamoyl xanthate stage by
choosing appropriate conditions. However, despite extensive
variations of temperature, solvent, xanthate salt (R = ethyl,
neopentyl), leaving group,[12] and stoichiometry we were
unable to isolate the desired carbamoyl xanthate 1a in
anything other than small amounts (< 10% yield). All the
conditions tried invariably gave a complex mixture of
compounds (e.g. compounds 1a, 6–9 in the reaction shown
in Scheme 2);[13] formation of S-substituted thiocarbamates
was not observed in our experiments. Incorporation of an
electron-withdrawing group (phenylsulfonyl) on the nitrogen
atom in place of the benzyl group also failed to alleviate this
problem.[9g,14] Frustratingly, the desired cyclization of 1a to
the expected pyrrolidinone 4a is readily achieved in 67%
yield simply upon irradiation of a refluxing toluene solution of
1a using a halogen or tungsten lamp, but the overall process
remains untenable in the absence of an efficient method for
the preparation of 1a.
Carbamoyl radicals, or aminoacyl radicals, offer a useful
means to introduce an amide functional group into an organic
molecule through a nonclassical disconnection. A number of
elegant methods for the generation of carbamoyl radicals are
known.[9] Faced with a problematic carbamoyl radical cycli-
zation in the course of a recent synthetic endeavor, we
[*] Dr. R. S. Grainger, P. Innocenti
Department of Chemistry
King’s College London
Strand
London WC2R2LS (UK)
Fax: (+44)20-7848-2810
E-mail: richard.grainger@kcl.ac.uk
[**] We thank King’s College London for funding this work, and
AstraZeneca and Pfizer for additional financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200453600
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Table 1: Carbamoyl radical cyclization reactions through dithiocarbamate group transfer.[a]
In a search for a “xanthate-
Lactam product(s)[b]
Method
Yield [%]
like” radical precursor, our atten-
tion turned to the corresponding
Entry
Radical precursor
N,N-dialkyl
dithiocarbamates.
Apart from aromatic amines, such
compounds were described in a
patent as unstable to heat.[15] In
fact, the desired dithiocarbamate
1b can be prepared in high yield
(> 95%) from the corresponding
carbamoyl chloride 6 by treatment
1
A
70
2
3
A
92
with
commercially
available
sodium diethyldithiocarbamate tri-
hydrate, without any of the prob-
lems known from the correspond-
ing xanthates (Scheme 2). More
importantly, N,N-dialkyldithiocar-
bamates substitute for xanthates
in group transfer radical cyclization
reactions of carbamoyl radicals.
Two methods can be used to ini-
tiate the radical process. The first
simply involves irradiation with
visible light using a 500-W halogen
lamp. The second uses commer-
cially available dilauroyl peroxide
(DLP) as an initiator, added por-
tionwise. The desired cyclization of
1b to 4b can be achieved in up to
96% yield (Table 1, entry 3).
A
B
96
80
4
5
A
78 (15:16 1:5)
A
B
65 (18:19 8.4:1)
58 (18:19 5.6:1)
The results of the cyclization of
a selection of dithiocarbamates to
the corresponding cyclic amides
are shown in Table 1.[16] A range
of ring sizes can be achieved with
this chemistry. As has been previ-
ously demonstrated by others,[9d,e,i–l]
carbamoyl radicals efficiently
6
C
37
[a] Reaction conditions: A: hn, cyclohexane, reflux; B: DLP, cyclohexane, reflux; C: DLP, chlorobenzene,
reflux. [b] Details on the synthesis of the lactams along with analytical data are given in the Supporting
Information.
cyclize to form four-membered rings (Table 1, entries 1 and
2). In the case of b lactam 13, a single diastereomeric adduct is
formed, the configuration of which has been proven by X-ray
crystallography. The stereochemical outcome is consistent
with group transfer to the intermediate cyclohexyl radical
occurring on the less hindered convex face of the [4.2.0]bicy-
clic ring system. Five-membered rings are also formed with
complete regioselectivity and in good to excellent yields
through the 5-exo-trig radical cyclization mode (Table 1,
entries 3 and 4). The orientation of the resulting dithiocarba-
mate group in the spirobycyclic g lactams 15 and 16 relative to
the heterocycle has been tentatively assigned on the basis of
NOESY experiments.[17]
Six-membered rings are also readily obtained using this
chemistry, with a small amount of the seven-membered ring
lactam 19 formed in addition to the expected product 18
(Table 1, entry 5). Lactam 19 presumably arises through a 7-
endo-trig pathway, although ring expansion of the alkyl
radical arising from the 6-exo-trig pathway through 3-exo-
trig cyclization onto the amide carbonyl group followed by
cyclopropyloxy radical fragmentation prior to group transfer
cannot be excluded.[9d]
We are not aware of any reports of the cyclization of
carbamoyl radicals being used to form ring sizes larger than
Scheme 2. Reaction of carbamoyl chlorides with xanthate and dithio-
carbamate salts. Np=neopentyl.
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reduced pressure and the crude was purified by column chromatog-
raphy.
Representative procedure for the DLP-induced cyclization
six. The formation of an eight-membered ring using this
chemistry is therefore notable (Table 1, entry 6). Although
the yield is only moderate, there are relatively few reports of
direct formation of an eight-membered ring in the radical
chemistry literature.[18] The use of a higher-boiling solvent was
found to be beneficial in this case.
The replacement of a xanthate with an N,N-dialkyl
dithiocarbamate in the above process is notable and has
little precedent in the literature: workon controlled radical
polymerization has shown that dithiocarbamates only
undergo radical group transfer reactions if an electron-
withdrawing group is placed on the nitrogen atom.[19,20] In
the present case, even though the carbon–sulfur double bond
in N,N-dialkyl dithiocarbamate 1b is more electron rich than
in xanthate 1a, efficient group transfer to the nucleophilic
alkyl radical 3 is still observed.
In conclusion, N,N-diethyldithiocarbamates are ideal
substitutes for xanthates in a new method for generating
carbamoyl radicals undergoing efficient group transfer to
both primary and secondary alkyl radicals after cyclization.
The overall process is simple to carry out, requires no special
precautions, and has a number of advantages over existing
radical methodologies: the lackof toxic tin hydrides, the mild
and safe method for initiating the radical chain process, the
functionalization of the final radical which can lead to further
useful chemical transformations,[21] and the nonreliance on
slow (syringe pump) addition and high-dilution techniques.
We are currently extending this workto include other radical
acceptors, asymmetric variants, and applications in target-
directed synthesis.
(method B): Carbamoyl dithiocarbamate (0.4 mmol) was dissolved
in cyclohexane (4 mL) and oxygen was removed from the resulting
solution using a nitrogen stream for ca. 15 min. The solvent was
heated to reflux and DLP (0.04 mmol) was added to the boiling
solution. The reaction progress was monitored by TLC and fresh
portions of initiator were added every 1.5–2 h. After the reaction was
complete (2–10 h) the solvent was removed under reduced pressure
and the crude was purified by column chromatography.
Received: December 22, 2003
Revised: May 7, 2004 [Z53600]
Keywords: cyclization · group transfer · lactams ·
.
radical reactions · synthetic methods
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Experimental Section
Representative procedure for the preparation of carbamoyl dieth-
yldithiocarbamates from secondary amines:
Pyridine (10.1 mmol) was added dropwise to a solution of
triphosgene (2.9 mmol) in toluene (70 mL); the resulting suspension
was treated with a solution of the secondary amine (7.8 mmol) in
toluene (10 mL). The reaction was stirred overnight at room temper-
ature, quenched with saturated aqueous NaHCO3, and extracted with
Et2O. The organic layer was washed with 0.3m HCl, water and brine,
and dried over MgSO4. The solvent was removed under reduced
pressure to give the crude carbamoyl chloride which was used directly
in the next step.
A solution of the crude carbamoyl chloride (ca. 6.6 mmol) in
acetone (45 mL) was treated with sodium diethyldithiocarbamate
trihydrate (26.2 mmol). The reaction was stirred overnight at room
temperature, quenched with saturated aqueous NaHCO3, and
extracted with Et2O. The organic layer was washed with water and
brine, and dried over MgSO4. The solvent was removed under
reduced pressure to give the crude carbamoyl diethyldithiocarba-
mate, which in most cases was sufficiently pure to be used directly in
the cyclization reactions.
Representative procedure for the photomediated cyclization
(method A): Carbamoyl dithiocarbamate (0.8 mmol) was dissolved
in cyclohexane (8 mL) and oxygen was removed from the resulting
solution using a nitrogen stream for ca. 15 min. The solution was
irradiated with a 500-W halogen or tungsten lamp that generated
sufficient heat to bring the solvent to reflux. The reaction progress
was monitored by thin-layer chromatography (TLC). After the
reaction was complete (1–8 h) the solvent was removed under
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radicals to thiocarbonyl groups are regarded as fast compared to
other competitive processes; see for example refs. [3,5]. For
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[13] The formation of products analogous to 8 and 9 has been
observed by Zard in his preparation of acyl radical precursors. In
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chloride) together with the correct order of addition was
sufficient to ensure good yields of the radical precursor. See
ref. [3].
[14] The incorporation of a Cbz group in place of the benzyl group
could not be achieved. Keckhas reported an example of a
carbamoyl xanthate where the nitrogen atom is part of an
oxazolidinone ring; see ref. [9h].
[15] I. Williams (DuPont de Nemours), US 2171420, 1939.
[16] All dithiocarbamate radical precursors were prepared in > 80%
yield from the corresponding secondary amine in a two-step
procedure (see Experimental Section), with the exception of 14
which was prepared from the corresponding tertiary dimethyl-
amine.
[17] The coupling constants for the proton on the carbon atom
adjacent to the sulfur atom in both 15 and 16 are consistent with
an equatorial arrangement of the dithiocarbamate group on the
cyclohexane ring. This proton shows a NOE interaction to one of
the pyrrolidinone ring hydrogen atoms in the case of 15, whereas
no NOE interaction is observed to either of these hydrogen
atoms in the case of 16.
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