Thermal elimination of diethyldithiocarbamates and application in the synthesis of (±)-ferrugine

Article abstract of DOI:10.1021/jo801652x

(Chemical Equation Presented) Dithiocarbamate-substituted lactams, prepared through group-transfer cyclization reactions of carbamoyl radicals, undergo a Chugaev-like thermal elimination of the dithiocarbamate group in refluxing diphenyl ether to form α,β

Full text of DOI:10.1021/jo801652x

SCHEME 1. Dithiocarbamate Group Transfer Carbamoyl
Radical Cyclization and Proposed Elimination
Thermal Elimination of Diethyldithiocarbamates
and Application in the Synthesis of (()-Ferrugine
Shamim Ahmed,† Luke A. Baker,† Richard S. Grainger,*,†
Paolo Innocenti,‡ and Camilo E. Quevedo‡
School of Chemistry, UniVersity of Birmingham, Edgbaston,
Birmingham B15 2TT, U.K., and Department of Chemistry,
King’s College London, Strand, London WC2R 2LS, U.K.
SCHEME 2. Elimination of Dithiocarbamates under Basic
and Thermal Conditions
r.s.grainger@bham.ac.uk
ReceiVed July 25, 2008
Dithiocarbamate-substituted lactams, prepared through group-
transfer cyclization reactions of carbamoyl radicals, undergo
a Chugaev-like thermal elimination of the dithiocarbamate
group in refluxing diphenyl ether to form R,ꢀ- and/or ꢀ,γ-
unsaturated amides, depending on the structure of the starting
material. This reaction sequence was used to prepare an
unsaturated [3.2.2] bridged bicyclic amide, which was
convertedinaone-potproceduretothe8-azabicyclo[3.2.1]octane
ring system of the tropane alkaloid ferrugine by treatment
with phenyllithium followed by aqueous sodium hydroxide.
both R,ꢀ- and ꢀ,γ-unsaturated amides, depending on the
structure of the lactam.
A limited number of reports have described the elimination
of the dithiocarbamate group to give alkenes. Hayashi reported
that S-methylation of the nucleophilic thiocarbonyl group in
pyrrolidine dithiocarbamates, followed by base-mediated elimi-
nation of the resulting sulfonium salt, gave good to excellent
yields of conjugated alkenes (Scheme 2, eq 1; R, R′ ) aryl,
alkenyl).4
The thermal elimination of dithiocarbamates was first inves-
tigated by Chande.5 Heating S-ethyl N-disubstituted dithiocar-
bamates in the solid state (250-285 °C) gave rise to ethylene,
carbon disulfide, and a secondary amine, consistent with a
Chugaev-like pyrolytic elimination via an Ei mechanism fol-
lowed by further decomposition of the dithiocarbamic acid thus
formed (Scheme 2, eq 2). When one or both of the N-
substituents was ethyl, additional products were observed
resulting from competitive elimination of ethylene from the ethyl
group on nitrogen as well as sulfur. Thermal dithiocarbamate
elimination has been applied to the synthesis of highly conjugated
polymers by heating polymeric benzylic diethyldithiocarbamates
either as thin films or in solution (1,2-dichlorobenzene 175 °C).6
Thermal elimination from 1,2-bis(dithiocarbamato)-1,2-dialkoxy-
alkanes to form 1-dithiocarbamato-1,2-dialkoxyalkenes would
Nonreductive, atom- or group-transfer radical addition reac-
tions offer the advantage of greater product functionalization
compared with processes based on hydrogen atom abstraction
(e.g., from Bu3SnH).1 We have recently reported a new method
for the generation and cyclization of carbamoyl radicals from
diethyldithiocarbamate precursors (Scheme 1).2 Group transfer
of the dithiocarbamate is key to maintaining the radical chain
process, and also offers a useful functionality within the product
for further manipulation. In order to extend the synthetic utility
of this methodology, we have investigated further transforma-
tions of the dithiocarbamate group. In the course of a synthesis
of the alkaloid aphanorphine, we have described a novel
photomediated dithiocarbamate-TEMPO exchange reaction that
formally achieves the transformation of a carbon-sulfur bond
into a carbon-oxygen bond.3 In this note, we report our studies
into the elimination of the diethyldithiocarbamate group to form
(4) (a) Hayashi, T.; Sakurai, A.; Osihi, T. Chem. Lett. 1977, 1483. (b)
Hayashi, T.; Hori, I.; Oishi, T. J. Am. Chem. Soc. 1983, 105, 2909. (c) Hayashi,
T.; Yanagida, M.; Matsuda, Y.; Oishi, T. Tetrahedron Lett. 1983, 24, 2665. (d)
Hayashi, T.; Oishi, T. Chem. Lett. 1985, 413. (e) Hayashi, T.; Sasaoka, K.; Oishi,
T. J. Chem. Soc., Chem. Commun. 1990, 1362.
† University of Birmingham.
‡ King’s College London.
(5) Chande, M. S. J. Indian Chem. Soc. 1979, 56, 386.
(1) (a) Byers, J. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: New York, 2001; Vol. 1, pp 72-89. (b) Zard, S. Z. Radicals
Reactions in Organic Synthesis; Oxford University Press: New York, 2003;
Chapter 6.
(2) Grainger, R. S.; Innocenti, P. Angew. Chem., Int. Ed. 2004, 43, 3445.
(3) Grainger, R. S.; Welsh, E. J. Angew. Chem., Int. Ed. 2007, 46, 5377.
(6) (a) Padmanaban, G.; Nagesh, K.; Ramakrishnan, S. J. Polym. Sci. Part
A: Polym. Chem. 2003, 41, 3929. (b) Henckens, A.; Colladet, K.; Fourier, S.;
Cleij, T. J.; Lutsen, L.; Gelan, J.; Vanderzande, D. Macromolecules 2005, 38,
19. (c) Henckens, A.; Duyssens, I.; Lutsen, L.; Vanderzande, D.; Cleij, T. J.
Polymer 2006, 47, 123. (d) Palmaerts, A.; van Haren, M.; Lutsen, L.; Cleij,
T. J.; Vanderzande, D. Macromolecules 2006, 39, 2438.
8116 J. Org. Chem. 2008, 73, 8116–8119
10.1021/jo801652x CCC: $40.75 2008 American Chemical Society
Published on Web 09/12/2008

TABLE 1. Thermal Elimination of Diethyldithiocarbamatesa
appear to be relatively facile in solution (DMSO or toluene,
110 °C)7a,c-e and has also been reported to occur in the solid
state (190 °C, 0.2 Torr).7b Whether this variant occurs via a
concerted elimination or a stepwise process has not been
determined. Recently, 5,6-dihydropyridin-2(1H)-one was pre-
pared by heating 2-oxopiperidin-3-yl dimethyldithiocarbamate
to 260 °C at 1 Torr.8
We initiated our investigations by attempting a base-mediated
elimination of readily prepared diethyldithiocarbamate 2.2
Treatment of 2 with DBU in chloroform or toluene, conditions
used for the ꢀ-elimination of xanthates to form enoates at room
temperature,9 failed to provide any of the expected alkene 3,
even after refluxing for extended periods. In order to increase
the nucleofugacity of the dithiocarbamate group, we next applied
the Hayashi S-methylation-elimination conditions, in either
DMPU or DMF as solvent. However, even after prolonged
reaction times and heating, only traces of alkene 3 were observed
in the 1H NMR spectrum of the crude reaction mixture. Hayashi
noted that the nature of the N-alkyl moiety in the dithiocar-
bamate group is important for a successful reaction. N,N-
Dimethyl- and N,N-diisopropyldithiocarbamates did not give
good yields, whereas 1-pyrrolidinecarbodithioates gave fair to
excellent yields.
We therefore turned our attention to thermal elimination. A
survey of common laboratory solvents of increasing boiling
point (chlorobenzene, 1,3-dichlorobenzene, DMSO) demon-
strated that dithiocarbamate 2 was thermally stable to high
temperatures, with only a trace amount of alkene 3 being
observed after 10 h of reflux in 1,2,4-trichlorobenzene (bp 214
°C). However, in refluxing diphenyl ether (bp 259 °C), a smooth,
high-yielding transformation to alkene 3 occurred over the
course of a few hours. The alkene was easily purified by
subjecting the reaction mixture to direct column chromatogra-
phy. The nonpolar diphenyl ether is rapidly eluted, followed
by alkene 3 upon increasing solvent polarity.
To probe the generality of this method, a range of diethyl
dithiocarbamates, prepared through group transfer cyclization
of carbamoyl radicals,2,10 was subjected to thermal elimination
in refluxing diphenyl ether. The results are presented in Table
1.
Despite the high temperatures involved, the products of the
reaction proved to be thermally robust, and the reaction was
successful in all but one case evaluated (entry 4). In this latter
case, the simple ꢀ-lactam 9 containing an exocyclic methylene
group did not survive the reaction conditions (if formed);
however, ꢀ-lactam 11 was produced in good yield (entry 5).
Formation of a conjugated alkene is not a prerequisite for a
successful outcome of the reaction, and both exocyclic (entries
1-3) and endocyclic (entries 5-10) alkenes can be formed.
Two regiochemical outcomes are possible in the thermal
a Conditions: Ph2O, 0.05-0.1 M, reflux. b Isolated yield after column
(7) (a) Suzuki, T.; Yamochi, H.; Srdanov, G.; Hinkelmann, K.; Wudl, F.
J. Am. Chem. Soc. 1989, 111, 3108. (b) Hartke, K.; Lindenblatt, T. Synthesis
1990, 281. (c) Papavassiliou, G. C.; Kakoussis, V. C.; Lagouvardos, D. J.;
Mousdis, G. A. Mol. Cryst. Liq. Cryst. 1990, 181, 171. (d) Misaki, Y.; Nishikawa,
H.; Nomura, K.; Yamabe, T.; Yamochi, H.; Saito, G.; Sato, T.; Shiro, M. J. Chem.
Soc., Chem. Commun. 1992, 1410. (e) Iyoda, M.; Kuwatani, Y.; Ogura, E.; Hara,
K.; Suzuki, H.; Takano, T.; Takeda, K.; Takano, J.-i.; Ugawa, K.; Yoshida, M.;
Matsuyama, H.; Nishikawa, H.; Ikemoto, I.; Kato, T.; Yoneyama, N.; Nishijo,
J.-i.; Miyazaki, A.; Enoki, T. Heterocycles 2001, 54, 833.
(8) Simo´n, L.; Mun˜iz, F. M.; Sa´ez, S.; Raposo, C.; Sanz, F.; Mora´n, J. R.
HelV. Chim. Acta 2005, 88, 1682.
(9) Forbes, J. E.; Saicic, R. N.; Zard, S. Z. Tetrahedron 1999, 55, 3791.
(10) Dithiocarbamates 2, 4, 8, 10, 12, 15, and 16 have been previously
reported.2 The preparation of 6, 18, 19 and 20 is described in Supporting
Information.
chromatography.
elimination of dithiocarbamates 6, 10, and 12. Conjugated
tetrasubstituted alkene 7 is the exclusive product from elimina-
tion of 6 (entry 3), and high regioselectivity is also observed in
the formation of ꢀ,γ-unsaturated alkene 11 from ꢀ-lactam 10
(entry 5). In this case, elimination to form the R,ꢀ-unsaturated
amide is presumably disfavored due to developing strain. In
the case of 8-ring lactam 12, a mixture of double bond isomers
13 and 14 is obtained (entry 6). Independently resubjecting both
13 and 14 to refluxing diphenyl ether for 4 h did not result in
J. Org. Chem. Vol. 73, No. 20, 2008 8117

SCHEME 3
SCHEME 4. Total Synthesis of Ferrugine
any interconversion. Similar yields of spirocyclic alkene 17 are
obtained starting from the two diastereomeric diethyldithiocar-
bamates 15 and 16 (entries 7 and 8). Similarly, dithiocarbamates
19 and 20, formed from a regioselective 6-exo-trig radical
cyclization followed by a moderately diastereoselective dithio-
carbamate group transfer (Scheme 3), are eliminated in similar
yields in a stereoconvergent synthesis of alkene 21 (entries 9
and 10).11,12
Based on the Chugaev-like Ei mechanism proposed by
Chande, formation of diethylaminodithiocarbamic acid would
be one of the expected byproducts from the thermal elimination
of the diethyldithiocarbamates used in this study. At high
temperature diethylaminodithiocarbamic acid would break down
to diethylamine and CS2, whose volatility would result in both
byproducts being lost from solution under the reaction condi-
tions. The absence of any products derived from conjugate
addition of diethylamine to R,ꢀ-unsaturated enamides 3, 5, 7,
or 13 is perhaps notable in this regard. In contrast to the work
of Chande, we did not observe products arising from competitive
elimination into the ethyl group of the amine.
Application of this methodology in a synthesis of ferrugine,
a tropane alkaloid isolated from Darlingia ferruginea J. F.
Bailey,13 is shown in Scheme 4. Treatment of the known
carboxylic acid 2214 with DPPA gave the corresponding acyl
azide, which after Curtius rearrangement and trapping of the
resulting isocyanate with ethanol gave the carbamate 23.
Reduction of 23 using LiAlH4 gave the somewhat volatile
methylamine 24, which was treated first with triphosgene and
pyridine to give a carbamoyl chloride and then with sodium
diethyldithiocarbamate to give the radical cyclization precursor
25. Initiation of the radical chain process by irradiation of a
solution of 25 in cyclohexane with a 500 W halogen lamp gave
rise to a mixture of diastereomeric diethyldithiocarbamates 26
and 27 through a formal 6-exo-trig cyclization. The stereo-
chemistry of the major diastereomer 26 was confirmed by X-ray
crystallography.12 Both stereoisomers converged to a single
alkene 28 upon thermal elimination of the dithiocarbamate
group.15
stereochemistry in 29 was confirmed by X-ray crystallography
of the corresponding perchlorate salt.12 Similarly, reaction of
28 with MeLi gave the tropane alkaloid derivative as a 6:1
mixture of diastereomers from which the major isomer 30 could
be isolated in 76% yield. This one-pot, multistep transformation
is envisaged to occur through nucleophilic attack to give 31,
which upon workup liberates the aminoketone 32, presumably
in equilibrium with the corresponding hemiaminal (we did not
observe the formation of any tertiary alcohol resulting from over
addition to an intermediate ketone despite the use of excess
organolithium). Under the influence of base, the double bond
in 32 enters into conjugation with the ketone to give 33, which
undergoes intramolecular conjugate addition to give the tropane
alkaloid skeleton. The resulting stereocenter was found to be
under thermodynamic control, with 30 epimerizing to the same
6:1 mixture upon treatment with aqueous NaOH.
In conclusion, unsaturated lactams are produced in good yield
through the thermal elimination of a diethyldithiocarbamate
group in refluxing diphenyl ether. This operationally simple
reaction benefits from the volatile nature of the side products,
which renders workup and purification straightforward. This
methodology extends the synthetic utility of the carbamoyl
radical cyclization-dithiocarbamate group transfer reaction, as
demonstrated in the synthesis of the tropane alkaloid ferrugine.
Treatment of 6-azabicyclo[3.2.2]non-2-ene 28 with phenyl-
lithium for 1 h at 0 °C, followed by quenching with dilute
sodium hydroxide solution and stirring the resulting biphasic
mixture at room temperature for 6 h, gave directly the tropane
alkaloid ferrugine 29 in 66% isolated yield. The relative
(11) The regio-and stereoselectivity of the cyclization of 18 was determined
by X-ray analysis of alkene 21 and dithiocarbamate 20, respectively.
(12) File in cif format is available in Supporting Information. CCDC 682056
and CCDC 695282-695284 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/dat_arequest/cif.
(13) (a) Bick, I. R. C.; Gillard, J. W.; Woodruff, M. Chem. Ind. (London)
1975, 794. (b) Bick, I. R. C.; Gillard, J. W.; Leow, H.-M. Aust. J. Chem. 1979,
32, 2537.
(14) Marquardt, D. J.; Newcomb, M. Synth. Commun. 1988, 18, 1193.
(15) Alkene 28 can also be prepared directly from 25 through tandem radical
cyclization-thermal elimination, although in lower overall yield compared to
the two-step process. Irradiation of 25 in refluxing diphenyl ether gave 28 in
37% isolated yield.
Experimental Section
Representative Procedure for the Thermal Elimination of Dieth-
yldithiocarbamates.
1-Benzyl-3-methylene-pyrrolidin-2-one 3. A solution of dithio-
carbamate 22 (820 mg, 2.44 mmol) in diphenyl ether (24 mL) was
heated at reflux for a period of 2 h, under 1 atm of argon. The
reaction mixture was purified by column chromatography (2:1-1:1
petroleum ether/diethyl ether), yielding the exocyclic alkene 3 (394
8118 J. Org. Chem. Vol. 73, No. 20, 2008

mg, 86%) as a yellow oil. Analytical data agree with that reported
in the literature.16 max (neat)/cm-1 3031, 2239, 1684, 1655, 1448;
Dr. Richard A. Stephenson (EPSRC National Crystallography
Service, University of Southampton, UK) for X-ray crystal
structure determination. We thank the EPSRC (EP/C543130/
1), University of Birmingham, and King’s College London for
financial support. R.S.G. is an EPSRC Advanced Research
Fellow 2005-2010.
ν
δH (360 MHz; CDCl3) 2.71-2.77 (2H, m), 3.25 (2H, t, J ) 6.7),
4.56 (2H, s), 5.36-5.37 (1H, m), 6.02-6.06 (1H, m), 7.25-7.37
(5H, m); δC (90 MHz; CDCl3) 23.9 (CH2), 42.4 (CH2), 47.2 (CH2),
115.6 (CH2), 127.6 (CH), 128.2 (CH), 128.6 (CH), 136.2 (C), 139.5
(C), 167.8 (C); m/z (EI) 187 (M+•; 100), 158 (12), 130 (7), 110
(11), 104 (8), 96 (24), 91 (72), 83 (14), 77 (6); HRMS (EI) calcd
for C12H13N1O1Na 210.0890, found 210.0885.
Supporting Information Available: Experimental proce-
dures, analytic data and copies of 1H and 13C NMR for all new
compounds, and X-ray crystal data of 20, 21, 26 and perchlorate
salt of 29 as cif files. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Dr. Benson Kariuki (University
of Wales, Cardiff, U.K.), Dr. Andrew J. P. White (Imperial
College London, U.K.), and Professor M. B. Hursthouse and
(16) Crisp, G. T.; Meyer, A. G. Tetrahedron 1995, 51, 5585.
JO801652X
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