Radical-mediated reduction of the dithiocarbamate group under tin-free conditions

Article abstract of DOI:10.1039/c2ob25434d

Reductive desulfurisation of dithiocarbamates is conveniently achieved using H₃PO₂-Et₃N-ACCN in refluxing dioxane. Fused and spirocyclic β-lactams, prepared through 4-exo trig carbamoyl radical cyclisation-dithiocarbamate group transfer reactions, are reduced without fragmentation of the strained 4-membered ring. Diethyl tetraacetyl-d-glucopyranosyl dithiocarbamate is selectively reduced with or without acyloxy group migration depending on reaction conditions and choice of reductant. Deuterium incorporation from D₃PO₂-Et ₃N is observed for a system involving a nucleophilic radical intermediate, but not in the case of the electrophilic radical obtained through acyloxy group migration on a glucose derivative.

Full text of DOI:10.1039/c2ob25434d

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PAPER
Radical-mediated reduction of the dithiocarbamate group under tin-free
conditions†
Claire McMaster,a Robert N. Breamb and Richard S. Grainger*a
Received 28th February 2012, Accepted 23rd April 2012
DOI: 10.1039/c2ob25434d
Reductive desulfurisation of dithiocarbamates is conveniently achieved using H3PO2–Et3N–ACCN in
refluxing dioxane. Fused and spirocyclic β-lactams, prepared through 4-exo trig carbamoyl radical
cyclisation–dithiocarbamate group transfer reactions, are reduced without fragmentation of the strained
4-membered ring. Diethyl tetraacetyl-D-glucopyranosyl dithiocarbamate is selectively reduced with or
without acyloxy group migration depending on reaction conditions and choice of reductant. Deuterium
incorporation from D3PO2–Et3N is observed for a system involving a nucleophilic radical intermediate,
but not in the case of the electrophilic radical obtained through acyloxy group migration on a glucose
derivative.
protocol for the reduction of the dithiocarbamate group under
tin-free radical conditions, allowing access to lactams formally
Introduction
Recent reports from our laboratory have shown carbamoyl
dithiocarbamates to be practical sources of carbamoyl radicals,
which undergo cyclisation reactions onto alkenes to form
lactams of varying ring sizes (Scheme 1).1,2 The dithiocarbamate
group is critical to maintaining the radical chain process, and
allows access to a wider variety of structures than can be pre-
pared through chain processes based on hydrogen-atom transfer.
The dithiocarbamate group also represents a useful handle for
further synthetic manipulations through its incorporation in the
product through formal group transfer.3 We have previously
developed conditions for both a photomediated dithiocarbamate–
oxygen exchange reaction,4 and for the elimination of
dithiocarbamates to alkenes,5 and applied these methodologies
in natural product synthesis.4,5a In this paper we now report a
the result of carbamoyl radical cyclisations based on hydrogen
atom transfer, and also its application in the reduction of anome-
ric dithiocarbamates and xanthates.
Reagents previously employed for the desulfurisation of
dithiocarbamates include lithium in ethylamine, RANEY®
Nickel, and LiAlH4–CuCl2.6,7 The presence of a radicophilic
thiocarbonyl in a dithiocarbamate group suggests a potentially
milder and more functional-group compatible radical-mediated
reduction should be possible, analogous to the classical Barton–
McCombie deoxygenation8 of xanthates (Scheme 2, eqn (1)).
Indeed, reduction of α-cyanodithiocarbamates under classical tin
hydride conditions was reported by Endo (Scheme 2, eqn (2)).9
In comparison with the Barton–McCombie deoxygenation, the
byproduct of this reaction contains a carbon–sulfur rather than a
carbon–oxygen double bond, although the presence of the nitrile
in this system will provide an additional driving force for frag-
mentation of the intermediate radical to a stabilized α-cyano
radical. Keen to avoid the use of toxic tin reagents,10 we were
attracted to the work of Zard11 and Boivin,12 who have reported
methods for the reductive removal of the xanthate group
(Scheme 2, eqn (3)). Their work also demonstrates that fragmen-
tation to form CvO is not a prerequisite for an efficient radical
chain process, even in the absence of an additional radical stabi-
lizing group on R.
Scheme 1 Carbamoyl radical cyclisation with dithiocarbamate group
transfer and proposed desulfurisation.
aSchool of Chemistry, University of Birmingham, Edgbaston,
Birmingham B15 2TT, UK. E-mail: r.s.grainger@bham.ac.uk;
Fax: +44 (0) 121 4144403; Tel: +44 (0) 121 4144465
Results and discussion
Dithiocarbamate reduction using H3PO2–Et3N–ACCN
bGlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
†Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR of all new compounds. See DOI: 10.1039/c2ob25434d
Our studies started with the previously reported dithiocarbamate
1, readily accessible through a 5-exo trig carbamoyl radical
4752 | Org. Biomol. Chem., 2012, 10, 4752–4758
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Scheme 2 Radical-mediated reduction of xanthates and dithio-
carbamates.
cyclisation–dithiocarbamate group transfer reaction.1 Gratify-
ingly, treatment of 1 with commercially available hypophosphor-
ous acid (H3PO2, 50 wt% in H2O, 5 equiv.) and triethylamine
(5.5 equiv.) in refluxing dioxane,12,13 initiated with substoichio-
metric
1,1′-azobis(cyclohexanecarbonitrile)
(ACCN,
or
VAZO-88), gave clean conversion to the γ-lactam 2 in good
yield (77%).14 After a simple aqueous work-up no products
arising from the dithiocarbamate group were observed in the
crude reaction mixture, consistent with formation of a water
soluble byproduct, [Et3NH]+[HPO2SC(S)NEt2]−. In contrast,
attempted radical-mediated reduction of 1 with dilauroyl per-
oxide in isopropanol11 or with diethylphosphite12a gave complex
reaction mixtures.
Scheme 3 Reduction of dithiocarbamates using Et3N–H3PO2–ACCN.
Application of the H3PO2–Et3N–ACCN conditions to other
dithiocarbamates showed it to be a generally high yielding
process (Scheme 3). Reduction of the cholesterol-derived dithio-
carbamate 315 occurs in excellent yield without addition of a
phosphorus-centred radical to the double bond, a potential com-
peting reaction.16 The diastereomeric dithiocarbamates 5 and 65a
are reduced to 7 in comparable yield, albeit with different reac-
tion times. Dithiocarbamate 91 is reduced without opening of the
4-membered β-lactam ring, either through a radical or hydrolytic
process.
cyclohexane to dioxane is necessary: it was neither possible to
cleanly cyclise 8 to 9 in dioxane (59% and 34% yields by hν or
ACCN initiation respectively), nor reduce 9 with H3PO2–Et3N–
ACCN in cyclohexane rather than dioxane as solvent. Similarly
treatment of 8 with H3PO2–Et3N–ACCN in dioxane gave only
approximately 5% of 10 as part of a complex reaction mixture.
Spirocyclic β-lactam synthesis
The two steps required to transform 8 to 10 can be con-
veniently combined without purification of the intermediate
dithiocarbamate 9. At the end of the photomediated cyclisation,
the solvent is simply removed and the crude reaction mixture dis-
solved in dioxane and submitted to the reduction conditions. In
this manner, a 68% overall yield of 10 was achieved, comparable
to the 65% expected from the individual transformations, but
requiring only one purification. A switch of solvents from
Radicals adjacent to 4-membered ring systems are prone to ring-
opening, driven by release of ring strain.17 However, as has been
previously noted,18,19 this reaction pathway has not been
observed for radicals adjacent to the β-lactam ring such as 11,
which is an intermediate both in the 4-exo trig carbamoyl radical
cyclisation of 8 and the reduction of 9. It therefore appeared
feasible that a 4-exo trig carbamoyl radical cyclisation could be
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used to prepare spirocyclic β-lactams, a class of compound
shown to display a range of interesting biological activities and
transformations.20 In order to investigate this novel approach, the
known amine 12, prepared in one step by reductive amination
of commercially available 1-cyclohexene-1-carboxaldehyde with
para-methoxyaniline,21 was converted to the carbamoyl radical
precursor 13 under our previously reported conditions
(Scheme 4).1 Irradiation of 13 with a 500 W halogen lamp gave
a spirocyclic dithiocarbamate 14 as a single diastereomer, the
stereochemistry of which was determined by nOe analysis,
which showed the proton adjacent to sulfur to be on the same
side of the cyclohexyl ring as the methylene group of the
β-lactam. Reduction of 14 successfully gave the spirocyclic
β-lactam 15, in reduced yield compared to reduction of 9.
Unfortunately it was not possible to isolate any other compounds
from the reaction mixture in sufficient purity to permit identifi-
cation of alternative reaction pathways.
Reduction of anomeric dithiocarbamates and xanthates
The reduction of anomeric sugar derivatives bearing acetyloxy
or related groups at C-2 is of long-standing interest both mechan-
istically and in selective carbohydrate synthesis. Anomeric
radicals such as 18 can undergo hydrogen abstraction to give 20,
or rearrange, through acyloxy group migration,22 to 19 prior to
reduction to give the 2-deoxysugar 21 (Scheme 5). Application
of our standard conditions to the known dithiocarbamate 1623
and xanthate 1724 gave approximately 1 : 1 mixtures of 20 and
21 in comparable yields and reaction times (Table 1, entries 1
and 5).
The ratio of 20 : 21 can be controlled through concentration
effects. Increased dilution gave solely the rearranged product 21,
the rate of intermolecular H-abstraction being slower at the lower
concentration, allowing the intramolecular rearrangement to
compete effectively (Table 1, entry 2). Conversely, at higher con-
centration, the radical 18 undergoes H-abstraction more rapidly,
giving a higher proportion of 20 compared to 21 in the isolated
mixture (entry 3). At still higher concentrations the reaction
becomes impractical due to solubility issues, but partial success
was achieved through doubling the concentration of Et3N and
H3PO2, which led solely to the non-rearranged reduction product
20, albeit in lower isolated yield (entry 4).
Zard has previously demonstrated that anomeric xanthate 17 is
reduced cleanly to 21 using lauroyl peroxide as radical initiator
and cyclohexane as solvent and hydrogen source.25 The inter-
mediate radical 19 is sufficiently electrophilic to abstract a hydro-
gen from cyclohexane, the process benefiting from charge
transfer in the transition state leading to 21 and the nucleophilic
cyclohexyl radical. The initial radical 18, in contrast, is nucleo-
philic, and H-abstraction is therefore unfavourable. We have
compared the reduction of xanthate 17 with dithiocarbamate 16
under the Zard conditions, and found the latter also to be an
effective substrate, giving 21 in comparable yield and a slightly
reduced reaction time (Table 1, entries 6 and 7).
Scheme 4 Spirocyclic β-lactam synthesis.
Deuterium incorporation
Oshima has reported the use of D3PO2 as a source of deuterium
in radical-mediated reduction of alkyl and aryl iodides.26 We
have found that certain dithiocarbamates can also be reduced
Scheme 5 Reduction of anomeric dithiocarbamates and xanthates.
Table 1 Reduction of anomeric dithiocarbamate 16 and xanthate 17
Entry
Substrate
Reagents (equivalents), solvent (substrate concentration)
Time/h
Ratioa 20 : 21
Isolated yield (%)
1
2
3
4
5
6
7
16
16
16
16
17
16
17
H3PO2 (5), Et3N (5.5), ACCN (0.3), dioxane (0.1 M)
H3PO2 (5), Et3N (5.5), ACCN (0.3), dioxane (0.01 M)
H3PO2 (5), Et3N (5.5), ACCN (0.3), dioxane (0.5 M)
H3PO2 (10), Et3N (11), ACCN (0.3), dioxane (0.5 M)
H3PO2 (5), Et3N (5.5), ACCN (0.3), dioxane (0.1 M)
Dilauroyl peroxide (0.4), cyclohexane (0.1), reflux
Dilauroyl peroxide (0.4), cyclohexane (0.1), reflux
18
18
18
18
18
4
1 : 1
0 : 1
3 : 1
1 : 0
1 : 1
0 : 1
0 : 1
85
86
71
44
79
88
86b
6
a Determined by integration in 1H NMR of crude reaction mixture. b Literature yield 65% (ref. 25a).
4754 | Org. Biomol. Chem., 2012, 10, 4752–4758
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intermediate radical 19, which is electrophilic in nature due to
the flanking electron-withdrawing acetate groups (Scheme 7). Of
the possible traps for 19, only hydrogen abstraction from
dioxane (or excess triethylamine, not shown) offers a polarity-
matched reaction pathway, resulting in the nucleophilic α-oxo
radical 23. Deuterium abstraction from the phosphonium salt is
now disfavoured due to both the increased strength of the P–D
bond compared to the P–H bond in Et3N–H3PO2, and also
because of the electrophilic nature of the resulting phosphorus-
centred radical 24. In contrast, polar effects favour deuterium
abstraction in the case of the nucleophilic alkyl radical 11
derived from 9, giving rise to the observed high level of deuter-
ium incorporation.
Conclusions
In conclusion, we have shown that the combination of H3PO2–
Et3N–ACCN in refluxing dioxane represents an efficient, tin-free
methodology for the reductive removal of the dithiocarbamate
group, the overall process also benefiting from formation of a
water-soluble byproduct. In combination with the advantages of
the dithiocarbamate group transfer reaction in terms of substrate
scope, this methodology expands the range of lactams that can
be prepared through carbamoyl radical cyclisation reactions.
Scheme 6 Deuterium incorporation studies.
Experimental
Unless otherwise stated, all reactions were run under argon
atmosphere using degassed solvents, and commercially available
reagents were used as supplied. 1H NMR are referenced to
residual CHCl3 at 7.26 ppm, and 13C to CDCl3 at 77.16 ppm.
General procedure for reduction of dithiocarbamates using
H3PO2–Et3N–ACCN
A
solution of dithiocarbamate (1 equiv.), triethylamine
(5.5 equiv.) and hypophosphorous acid (50 wt% in water,
5.0 equiv.) in dioxane (0.08 M dithiocarbamate in dioxane) was
heated to reflux for 20 min under an argon atmosphere. ACCN
(0.15 equiv.) was added to the solution, and the resultant reaction
mixture was heated to reflux. An additional portion of ACCN
(0.15 equiv.) was added if required, typically after 4 h of reflux.
Upon completion (by t.l.c. analysis) the reaction mixture was
cooled to room temperature. EtOAc and H2O were added, and
the aqueous layer extracted a further two times with EtOAc
(approximately equal volumes of H2O and EtOAc as dioxane
were used). The combined organic phases were washed with
brine, dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by column
chromatography.
Scheme 7 Polar effects in H/D-atom abstraction.
with good levels of deuterium incorporation using commercially
available D3PO2 in D2O (Scheme 6). Consistent with the obser-
vations of Oshima, better yields and higher levels of deuterium
incorporation were obtained using potassium peroxodisulfate as
radical initiator, compared with ACCN (for 10-d, 32% yield and
82% deuterium incorporation vs. 63% yield, 91% deuterium
incorporation using K2S2O8).
Deuterium incorporation was not observed when these con-
ditions were applied to the glucosyldithiocarbamate 16 nor to the
glucosylbromide 22 under conditions previously determined to
result in complete acyloxy group migration prior to reduction
(vide supra). The lack of deuterium incorporation points to a sig-
nificant role of polar effects27 in the reactions of the common
1-Benzyl-3-methylpyrrolidin-2-one (2). According to the
general procedure, a solution of dithiocarbamate 11 (0.25 g,
0.74 mmol) in dioxane (9.3 mL) was treated with Et3N
(0.56 mL, 4.07 mmol) and aq. H3PO2 (0.38 mL, 3.72 mmol),
then ACCN (0.027 g, 0.11 mmol). After 4 h at reflux, a further
portion of ACCN (0.027 g, 0.11 mmol) was added, and heating
continued for a further 14 h. Work-up followed by column
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Starting from carbamoyldithiocarbamate 8. A solution of carba-
moyl dithiocarbamate 81 (0.5 g, 1.38 mmol) in cyclohexane
(14 mL) was degassed and irradiated with a 500 W halogen
lamp that generated enough heat to bring the solvent to reflux.
After 5 h the solvent was removed under reduced pressure. The
crude material was dissolved in dioxane (17 mL) and treated
with triethylamine (1.05 mL, 7.59 mmol) and aq. H3PO2
(0.71 mL, 6.9 mmol). After 20 min at reflux ACCN (0.05 g,
0.2 mmol) was added. After a further 4 h at reflux, another
portion of ACCN (0.05 g, 0.2 mmol) was added, and heating
continued for a further 14 h. The work up was completed accord-
ing to the general procedure. The crude product was purified by
column chromatography (1 : 2 hexane–EtOAc) to afford the title
compound as a yellow oil (0.201 g, 68%).
chromatography (1 : 1 hexane–EtOAc) afforded the title com-
pound as a yellow oil (0.108 g, 77%), whose analytical data
were consistent with that reported in the literature.28
Cholest-5-ene (4). According to the general procedure, a sol-
ution of dithiocarbamate 315 (0.4 g, 0.84 mmol) in dioxane
(10 mL) was treated with Et3N (0.64 mL, 4.62 mmol) and aq.
H3PO2 (0.44 mL, 4.2 mmol), then ACCN (0.03 g, 0.12 mmol).
The reaction was complete after 5 h. Work-up followed by
column chromatography (60–80 petroleum ether) afforded the
title compound as a white solid (0.30 g, 97%), whose analytical
data were consistent with that reported in the literature.29
( )-(1R*,6R*)-7-Methyl-8-oxo-7-azabicyclo[4.2.2]decane (7)
Starting from dithiocarbamate 5. According to the general pro-
cedure, a solution of dithiocarbamate 55a (0.05 g, 0.16 mmol) in
dioxane (2 mL) was treated with Et3N (0.12 mL, 0.88 mmol),
aq. H3PO2 (0.08 mL, 0.80 mmol), and ACCN (0.006 g,
0.024 mmol). After 2 h at reflux, a further portion of ACCN
(0.027 g, 0.11 mmol) was added, and heating continued for a
further 2.5 h. Work-up followed by column chromatography
(EtOAc followed by 9 : 1 CH2Cl2–MeOH) afforded the title
compound as a white solid (0.022 g, 83%). m.p. 82–84 °C; νmax
(neat)/cm−1: 2925, 1634 (CvO), 1451, 1369; δH (300 MHz;
CDCl3); 1.37–1.84 (8H, m, 4 × CH2), 1.98–2.25 (4H, m, 2 ×
CH2), 2.75–2.84 (1H, m, CH), 2.96 (3H, s, NCH3), 3.62–3.71
(1H, m, CH); δC (100 MHz; CDCl3) 23.6 (CH2), 23.9 (CH2),
24.9 (CH2), 25.2 (CH2), 29.9 (CH2), 34.1 (CH3), 34.8 (CH2),
35.9 (CH2), 39.6 (CH), 57.0 (CH), 175.5 (CvO); m/z (EI) 167.1
([M]+, 71%), 139.1 (26%), 124.1 (36%), 96.1 (100%); HRMS
(EI) calculated for C10H17NO [M]+ 167.1310, found 167.1318.
Starting from dithiocarbamate 6. According to the general pro-
cedure, a solution of dithiocarbamate 65a (0.05 g, 0.16 mmol) in
dioxane (2 mL) was treated with Et3N (0.12 mL, 0.88 mmol)
and aq. H3PO2 (0.08 mL, 0.80 mmol), then ACCN (0.006 g,
0.024 mmol). The reaction was complete after 2.5 h. Work-up
followed by column chromatography (EtOAc followed by 9 : 1
CH2Cl2–MeOH) afforded the title compound as a white solid
(0.023 g, 87%).
Diethylthiocarbamic acid-[4-methoxyphenyl(cyclohex-2-enyl)-
carbamic acid]-thioanhydride (13). A solution of triphosgene
(0.50 g, 1.70 mmol) in toluene (43 mL) was treated with pyri-
dine (0.45 mL, 5.50 mmol), and subsequently with a solution of
(4-methoxyphenyl)cyclohex-1-enylmethylamine (12)21 (1.0 g,
4.6 mmol) in toluene (7 mL). The reaction was stirred at room
temperature for 18 h, quenched with saturated Na2CO3 (30 mL)
and extracted with Et2O (3 × 25 mL). The combined extracts
were washed with water (25 mL) and brine (25 mL), dried
(MgSO4), filtered and evaporated under reduced pressure to give
the carbamoyl chloride (1.24 g, 97%) as a yellow oil, of suffi-
cient purity to be used directly in the next step without any
further purification. δH (300 MHz; CDCl3); 1.51–1.70 (4H, m,
2 × CH2), 1.91–2.08 (4H, m, 2 × CH2), 3.83 (3H, s, ArOCH3),
4.19 (2H, s, CH2N), 5.41–5.43 (1H, m, CHvC), 6.89–6.97 (2H,
m, 2 × ArH), 7.17–7.23 (2H, m, 2 × ArH).
Sodium diethyldithiocarbamate trihydrate (7.09 g, 31.4 mmol)
was added to a solution of carbamoyl chloride (2.2 g,
7.87 mmol) in acetone (79 mL) at room temperature. The sol-
ution was stirred at room temperature for 18 h, quenched with
water (50 mL) and extracted with Et2O (3 × 50 mL). The com-
bined organic extracts were washed with brine (70 mL), dried
(MgSO4), filtered and evaporated under reduced pressure. Purifi-
cation by column chromatography (4 : 1 petroleum ether–
EtOAc) gave the title compound as a yellow oil (2.05 g, 67%).
νmax neat cm−1: 2929, 1669 (CvO), 1508, 1418, 1237, 1194; δH
(300 MHz; CDCl3) (mixture of rotamers) 1.28–1.39 (6H, t, J =
7.1 Hz, 2 × CH3), 1.48–1.68 (4H, m, 2 × CH2), 1.89–2.07 (4H,
m, 2 × CH2), 3.72–3.89 (2H, m, NCH2CH3), 3.84 (3H, s,
ArOCH3), 3.99–4.10 (2H, m, NCH2CH3), 4.19 (2H, s, CH2NH),
5.37–5.41 (1H, m, CHvC), 6.88–6.98 (2H, m, 2 × ArH),
7.12–7.20 (2H, m, 2 × ArH); δC (100 MHz; CDCl3) (mixture of
rotamers) 11.2 (CH3), 13.6 (CH3), 22.3 (CH2), 22.8 (CH2), 25.3
(CH2), 26.6 (CH2), 27.0 (CH2), 48.8 (CH2), 50.4 (CH2), 55.6
(CH3), 58.0 (CH2), 113.6 (CH), 114.6 (CH), 125.0 (CH), 127.0
(CH), 128.3 (CH), 132.5 (C), 134.5 (C), 137.9 (C), 157.1
(CvO), 185.6 (CvS); m/z (EI) 393 ([M]+ 22%), 331 (100%),
244 (33%), 218 (25%); HRMS (EI) calculated for
C20H29N2O2S2 [M]+ 393.1670, found 393.1652.
( )-(1S*,6R*)-7-Benzyl-7-azabicyclo[4.2.0]octan-8-one (10)
Starting from dithiocarbamate 9. According to the general pro-
cedure, a solution of dithiocarbamate 91 (0.15 g, 0.4 mmol) in
dioxane (5 mL) was treated with Et3N (0.31 mL, 2.2 mmol) and
aq. H3PO2 (0.21 mL, 2.0 mmol), then ACCN (0.015 g,
0.06 mmol). After 4 h at reflux, a further portion of ACCN
(0.015 g, 0.06 mmol) was added, and heating continued for a
further 14 h. Work-up followed by column chromatography
(1 : 2 hexane–EtOAc) afforded the title compound as a yellow
oil (0.068 g, 79%). νmax (neat)/cm−1: 2935 (br), 1734 (CvO),
1400; δH (300 MHz; CDCl3) 1.26–1.91 (8H, m, 4 × CH2), 3.20
(1H, q, J = 5.3 Hz CHCO), 3.65 (1H q, J = 4.0 Hz, NCH), 4.10
(1H, d, J = 15.0 Hz, NCH2Ph), 4.60 (1H, d, J = 15.0 Hz,
NCH2Ph), 7.26–7.37 (5H, m, Ph); δC (100 MHz; CDCl3) 16.8
(CH2), 18.9 (CH2), 19.7 (CH2), 22.9 (CH2), 44.4 (CH2), 47.0
(CH), 50.1 (CH), 127.6 (CH), 128.4 (2 × CH), 128.8 (2 × CH),
136.2 (C), 170.9 (CvO); m/z (EI) 215.1 ([M]+, 75%), 134.1
(28%), 124.1 (36%), 91.1 (100%), 82.1 (62%), 67.1 (63%);
HRMS (EI) calculated for C14H17NO [M]+ 215.1310, found
215.1318.
( )-(4R*,5S*)-2-(4-Methoxyphenyl)-1-oxo-2-azaspiro[3.5]nonan-
5-yl diethylcarbamodithioate (14). A solution of carbamoyl
dithiocarbamate 13 (0.32 g, 0.83 mmol) in cyclohexane
(8.3 mL) was degassed for 15 min and irradiated with a 500 W
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halogen lamp that generated enough heat to bring the solvent to
reflux. After 8 h the solvent was removed under reduced pressure
and the crude product purified by column chromatography (3 : 1
petroleum ether–EtOAc) to give the title compound as a white
solid (0.19 g, 60%). m.p. 147–148 °C; νmax (neat)/cm−1: 2929,
1671 (CvO), 1509, 1415, 1243; δH (300 MHz; CDCl3); 1.27
(6H, t, J = 7.1 Hz, 2 × CH3), 1.48–2.11 (7H, m, CH2),
2.36–2.48 (1H, m, CH2), 3.31 (1H, d, J = 5.8 Hz, NCH2C), 3.64
(1H, d, J = 5.8 Hz, NCH2C), 3.70–3.77 (2H, m, NCH2CH3),
3.80 (3H, s, ArOCH3) 3.98–4.05 (2H, m, NCH2CH3), 4.76–4.80
(1H, m, SCH), 6.88 (2H, d, J = 12.6 Hz, ArH), 7.31 (2H, d, J =
12.0 Hz, ArH); δC (100 MHz; CDCl3) 11.7 (CH3), 12.6 (CH3),
22.7 (CH2), 23.5 (CH2), 30.8 (CH2), 31.9 (CH2), 46.9 (CH2),
49.8 (CH2), 50.5 (CH2), 53.0 (CH), 55.6 (CH3), 58.7 (C), 114.1
(CH), 114.4 (CH), 117.6 (2 × CH), 132.2 (C), 156.0 (C), 167.7
(CvO), 193.7 (CvS); m/z (ESI) 415 ([M + Na]+, 100%);
HRMS (EI) calculated for C21H28N2O2S2Na [M]+ 415.1490,
found 415.1490.
(0.29 g, 85%), whose analytical data were consistent with that
reported in the literature.31
(b) Using dilauroyl peroxide/cyclohexane,25a Table 1 entry 9. A
solution of dithiocarbamate 1623 (0.48 g, 1.00 mmol) in cyclo-
hexane (10 mL) was heated to reflux under argon for 15 min.
Dilauroyl peroxide (0.08 g, 0.2 mmol) was added, and reflux
continued for 1 h, after which time a further portion of dilauroyl
peroxide (0.08 g, 0.2 mmol) was added. After 4 h at reflux, the
solvent was removed under reduced pressure. Purification by
column chromatography (hexane–EtOAc 9 : 1) gave the title
compound as a white solid (0.30 g, 88%), whose analytical data
were consistent with that reported in the literature.31
( )-(1S*,6R*)-2-Deuterio-7-benzyl-7-azabicyclo[4.2.0]octan-8-
one (10-d, 91% D). Dithiocarbamate 91 (0.05 g, 0.14 mmol) was
dissolved in dioxane (2 mL) and treated with triethylamine
(0.1 mL, 0.8 mmol) and D3PO2 (50 wt% in D2O, 0.07 mL,
0.69 mmol). After 20 min at reflux K2S2O8 (0.006 g,
0.02 mmol) was added. After a further 4 h at reflux, another
portion of K2S2O8 (0.006 g, 0.02 mmol) was added, and heating
continued for a further 14 h. The reaction mixture was cooled to
room temperature, EtOAc (2 mL) and H2O (2 mL) were added,
and the aqueous layer extracted a further two times with EtOAc
(2 × 2 mL). The combined organic phases were combined,
washed with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was purified by
column chromatography (1 : 2 hexane–EtOAc) to afford the title
compound as a clear oil (63%, 0.019 g). νmax (neat)/cm−1: 2935
(br), 1734 (CvO), 1400; δH (300 MHz; CDCl3) 1.15–2.18 (8H,
m, 4 × CH2), 3.15–3.23 (1H, m, CHCO), 3.65 (1H q, J = 4.0
Hz, NCH), 4.10 (1H, d, J = 15.2 Hz, NCH2), 4.60 (1H, d, J =
15.2 Hz, NCH2), 7.26–7.37 (5H, m, ArH); δC (100 MHz;
CDCl3) 16.8 (CH2), 18.8 (CH2), 19.3 (CHD, t, J = 19.4 Hz),
19.5, 22.8 (CH2), 44.4 (NCH2), 46.9 (CH), 50.1 (CH), 127.6
(ArCH), 128.3 (2 × ArCH), 128.7 (2 × ArCH), 136.2 (ArC),
170.9 (CvO); m/z (EI) 216.1 ([M]+, 71%), 125.1 (7%), 91.1
(100%), 82.1 (95%); HRMS (EI) calculated for C14H16NOD
[M]+ 216.1373, found 216.1376. 91% D by MS analysis.
2-(4-Methoxyphenyl)-2-azaspiro[3.5]nonan-1-one
(15).
According to the general procedure, a solution of dithiocarba-
mate 14 (0.29 g, 0.74 mmol) in dioxane (9.25 mL) was treated
with Et3N (0.56 mL, 4.07 mmol) and aq. H3PO2 (0.38 mL,
3.70 mmol), then ACCN (0.027 g, 0.11 mmol). The reaction
was complete after 6 h. Work-up followed by column chromato-
graphy (3 : 1 petroleum ether–EtOAc) afforded the title com-
pound as a white solid (0.069 g, 39%). m.p. 119–122 °C; νmax
(neat)/cm−1
: 2928, 1733 (CvO), 1511, 1392, 1243; δH
(300 MHz; CDCl3) 1.28–1.44 (2H, m, CH2), 1.56–1.71 (2H, m,
CH2), 1.73–1.97 (6H, m, 3 × CH2), 3.40 (2H, s, NCH2), 3.81
(3H, s, ArOCH3), 6.89 (2H, d, J = 12.6 Hz, ArH), 7.31 (2H, d,
J = 12.0 Hz, ArH); δC (100 MHz; CDCl3) 23.5 (2 × CH2), 25.3
(CH2), 31.2 (2 × CH2), 51.9 (NCH2), 55.4 (C), 55.6 (OCH3),
114.5 (2 × ArCH), 117.5 (2 × ArCH), 132.7 (ArC–N), 156.0
(ArC–O), 170.6 (CvO); m/z (EI) 245 ([M+] 52%), 149 (100%),
135 (22%); HRMS (EI) calculated for C15H19NO2 [M+]
245.1416, found 245.1417.
1,5-Anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol (20)
From dithiocarbamate 16, Table 1, entry 4. According to the
general procedure, dithiocarbamate 1623 (0.25 g, 0.52 mmol)
was treated with aq. H3PO2 (0.54 mL, 5.20 mmol), Et3N
(0.79 mL, 5.72 mmol) and ACCN (0.019 g, 0.08 mmol) in
dioxane (1 mL). After 4 h at reflux, a further portion of ACCN
(0.019 g, 0.08 mmol) was added, and heating continued for a
further 14 h. Work-up followed by column chromatography
(9 : 1 hexane–EtOAc) gave the title compound as a white solid
(0.037 g, 44%), whose analytical data were consistent with that
reported in the literature.30
Acknowledgements
We thank GlaxoSmithKline, University of Birmingham and
EPSRC for funding. The NMR spectrometers used in this
research were obtained through Birmingham Science City: Inno-
vative Uses for Advanced Materials in the Modern World (West
Midlands Centre for Advanced Materials Project 2), with
support from Advantage West Midlands (AWM) and part funded
by the European Regional Development Fund (ERDF). We
thank Dr Neil Spencer for help with NMR spectroscopy, and
Nick May and Peter Ashton (University of Birmingham) for
assistance with mass spectrometry.
1,3,4,6-Tetra-O-acetyl-2-deoxy-α-D-arabino-hexopyranose (21)
(a) Using H3PO2–Et3N–ACCN, Table 1 entry 2. According to
the general procedure, dithiocarbamate 1623 (0.50 g, 1.04 mmol)
was treated with aq. H3PO2 (0.54 mL, 5.20 mmol), Et3N
(0.79 mL, 5.72 mmol) and ACCN (0.038 g, 0.16 mmol) in
dioxane (104 mL). After 4 h at reflux, a further portion of
ACCN (0.038 g, 0.16 mmol) was added, and heating continued
for a further 14 h. Work-up followed by column chromatography
(9 : 1 hexane–EtOAc) gave the title compound as a white solid
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