A new convenient method for the generation of alkoxy radicals from N-alkoxydithiocarbamates

Article abstract of DOI:10.1055/s-2001-13384

N-Alkoxydithiocarbamates 2, which can be conveniently prepared from alkyl halides or alcohols using N-methylhydroxydithiocarbamate 1, are very useful precursors of alkoxy radicais.

Full text of DOI:10.1055/s-2001-13384

688
LETTER
A New Convenient Method for the Generation of Alkoxy Radicals from
N-Alkoxydithiocarbamates
Sunggak Kim,a* Chae Jo Lim,a Sang-Eun Song,b Han-Young Kang b*
a Center for Molecular Design and Synthesis and Department of Chemistry, School of Molecular Science, Korea Advanced Institute of Sci-
ence and Technology, Taejon 305-701, Korea
b Department of Chemistry, Chungbuk National University, Cheongju 361-763, Korea
Fax +82-42-869-8370; E-mail: skim@mail.kaist.ac.kr
Received 23 February 2001
S
Abstract: N-Alkoxydithiocarbamates 2, which can be conveniently
prepared from alkyl halides or alcohols using N-methylhydroxy-
dithiocarbamate 1, are very useful precursors of alkoxy radicals.
Et3N
HO
Me
+
CS2
+
Me-I
HO NHMe HCl
N
S
CH2Cl2
Me
1
Key words: radicals, alcohols, alkyl halides, alkoxy radicals, thio-
hydroxamates
Equation 1
Thiocarbonyl-containing compounds such as xanthates
and thiohydroxamic acid esters have enjoyed their role as
radical precursors in radical chemistry.1 Since thiohy-
droxamic acid esters were introduced in radical chemistry
by Barton, they have attracted a great deal of attention
among synthetic chemists as useful radical precursors of
alkyl,2 aminyl,3 and alkoxycarbonyloxy radicals.4 Howev-
er, the generation of alkoxy radicals via N-alkoxypyri-
dine-2-thiones5 was hampered due to the difficulty of their
preparations because alkylations occurred at sulfur rather
than at oxygen to give pyridyl sulfides as a major prod-
uct.6 Thus, several improved procedures have been report-
ed, but the chemical yields were not very high.7 Further
studies on the generation of alkoxy radicals using similar
types of thiohydroxamic esters have not been actively in-
vestigated.8
S
1, NaH
1
O
Me
R-OH
R-X
R
N
S
DEAD, PPh3
DMF
Me
2
A, B, or C
A: n-Bu3SnH/AIBN
B: PhSH/V-40
RO
ROH
C: PhSH/hv at 300 nm
3
Equation 2
could be used for the preparation of N-alkoxydithiocar-
bamates 2 without further purification.12 Decomposition
of 1 occurred upon heating at above 100 °C but it could be
distilled at ~60 °C in vacuo. The preparation of 2 could be
conveniently carried out by routine operations using alkyl
halides or alcohols as substrates. First, treatment of sodi-
um salt of 1 with alkyl bromides in DMF at room temper-
ature for 0.5 h gave 2 in high yields, being stable on silica
gel and on heating.13 Second, 2 were conveniently pre-
pared by treatment of alcohols with 1, diethyl azodicar-
boxylate, and triphenylphosphine in tetrahydrofuran
using the Mitsunobu method.14 Both methods were equal-
ly effective and provided 2 in high yields.
In connection with our recent interest in tin-free radical
reactions,9 we wanted to generate alkoxy radicals under
tin-free conditions. Since the generation of alkoxy radi-
cals generally involves the cleavage of weak N-O and S-
O bonds,10,11 we investigated the feasibility of utilizing a
similar type of N-alkoxypyridine-2-thiones to generate
alkoxy radicals in a reliable manner. Since radical precur-
sors are needed to be stable for safe handling and better
chemical yields, we turned our attention to N-alkoxy-
dithiocarbamates 2. N-Alkoxydithiocarbamates 2 have
several advantages over N-alkoxypyridine-2-thiones.
First, it is expected that alkylation should occur at oxygen
rather than at sulfur. Thus, 2 are readily accessible and
should be more stable and less reactive than N-alkoxypy-
ridine-2-thiones due to facile aromatization of the latter
upon fragmentation. Furthermore, as compared to N-
alkoxyphthalimides,10d the generation of alkoxy radicals
from 2 would be feasible under tin-free conditions.
To generate alkoxy radicals from 2, we examined several
different conditions. First, a standard radical condition us-
ing n-Bu3SnH/AIBN was employed. Radical reaction of 2
(R = PhO(CH2)4) with n-Bu3SnH/AIBN in refluxing ben-
zene for 3 h afforded 4-phenoxy-1-butanol in 95% yield.
Second, the generation of alkoxy radicals was carried out
under tin-free conditions using PhSH as a radical mediator
in the presence of AIBN in refluxing benzene. However,
the reaction was very slow. Reaction of 2 with PhSH
(2 equiv) and AIBN in refluxing benzene for 24 h gave al-
cohol 3 in 55% yield along with the unreacted starting ma-
terial 2 (43%). When the reaction was carried out in
N-Methylhydroxydithiocarbamate 1 was readily prepared
in an essentially quantitative yield by treatment of N-me-
thylhydroxylamine hydrochloride with carbon disulfide,
methyl iodide, and triethylamine in dichloromethane and
Synlett 2001, No. 5, 688–690 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Method for the Generation of Alkoxy Radicals from N-Alkoxy-dithiocarbamates
689
Table Preparation of N-Alkoxy Dithiocarbamates and Generation of Alkoxy Radicals
Conditiona
R-Y (Y = O-NMe(C=S)SMe)
R-X
R-OH
1
2
3
(yield)
A (95%)
B (92%)
C (78%)
X
Y
OH
OH
X=Br (90%)
PhO
Ph
PhO
Ph
PhO
Ph
B (94%)
C (62%)
X
Y
X=OH (84%)
X=Br (86%)
A (88%)
Ph
X
Ph
Y
Ph
OH
A (73%)
B (83%)
C (66%)
X=Br (78%)
X=OH (75%)
Ph
Ph
X
X
Ph
Ph
Y
Y
Ph
Ph
OH
OH
X=Br (74%)
X=OH (72%)
A (64%)
B (61%)
X=Br (64%)
X=OH (68%)
A (55%)
B (52%)
Br
Br
Br
X
Y
OH
O
O
O
X=Br (81%)
A (73%)
Ph
Ph
O
Ph
O
Ph
O
X
OH
Y
X
Y
X=Br (65%)
X=OH (62%)
A (86%)b
Ph
O
Ph
a A = n-Bu3SnH/AIBN in benzene at 80 °C for 3 h, B = PhSH/V-40 in chlorobenzene at 110 °C
for 12 h, C = PhSH in benzene at 300 nm for 8 h.b A 1:1 mixture of stereoisomers.
chlorobenzene using V-40 as an initiator15 at 110 °C for
12 h, the desired alcohol 3 was obtained in 92% yield. Fi-
nally, it is also possible to generate alkoxy radicals under
photochemically initiated conditions. When a benzene so-
lution of 2 and PhSH (2 equiv) was irradiated under visi-
ble light using a 300W tungsten lamp for 5 h, the reaction
did not occur. Gratifyingly, when the solution was irradi-
ated at 300 nm for 8 h, the reaction occurred smoothly and
the alcohol was isolated in 78% yield. Thus, remaining re-
actions were carried out with the following three different
procedures (Table).
S
O
Me
V-40
O
PhO
N
S
PhO
chlorobenzene
110 °C
Me
4
Me
N
[1,5-H]
OH
PhO
S
SMe
OH
PhO
5
OH
+
PhO
PhO
O
The Table summarizes some experimental results for the
preparation of N-alkoxydithiocarbamates 2 and the gener-
ation of alkoxy radicals from 2. Under the condition A, the
reactions were complete within 3 h and the yields were
consistently high. The radical cyclization of the generated
alkoxy radical onto the double bond occurred smoothly.
When the reaction was subjected to the condition B, 2 pro-
vided very high yields of the desired alcohols 3 under tin-
free conditions. It is noteworthy that the use of t-butylm-
ercaptan is not required because 2 are thermally and hy-
drolytically stable and inert toward PhSH under thermal
conditions.16 Similarly, the generation of alkoxy radicals
6 (78%)
7 (18%)
Equation 3
in 18% yield. Evidently, 1,5-hydrogen transfer was fol-
lowed by the addition of the alkyl radical onto the thiocar-
bonyl group of 4 to provide 5 and subsequent
acetalization.18 Further studies on the remote functional-
izations via 1,5-hydrogen transfer from carbon to oxygen
under tin-free conditions are under way.
via photochemical initiation proceeded smoothly, yield- In conclusion, we have developed a new reliable method
ing the desired alcohols in good yields. In general, condi- for the generation of alkoxy radicals from N-alkoxydithio-
tion B gave better yields than condition C.
carbamates. The present method has several advantages
over previously known methods in terms of easy avail-
ability and stability of N-alkoxydithiocarbamates, and the
generation of alkoxy radicals under tin-free condi-
tions.10,11
We briefly studied 1,5-hydrogen transfer from carbon to
oxygen.17 Reaction of 4 with V-40 (0.1 equiv) as an initi-
ator in refluxing chlorobenzene for 12 h resulted in acetal
6 in 78% yield along with the direct reduction product 7
Synlett 2001, No. 5, 688–690 ISSN 0936-5214 © Thieme Stuttgart · New York

690
S. Kim et al.
LETTER
product was pure enough for the preparation of 2 without
Acknowledgement
further purification. The crude product could be purified by
distillation in vacuo (bp 64-65 °C/0.02 mm Hg) to give 1 in
60% yield. 1H NMR (300 MHz, CDCl3): 2.64 (s, 3H), 3.59
(s, 3H), 10.31 (br s, 1H); 13C NMR (75 MHz, CDCl3): 19.3,
38.6, 182.6; IR(NaCl): 3103, 2919, 1420, 1376, 1216, 1099,
1011, 962, 892, 864 cm-1.
This work was financially supported by the Center for Molecular
Design and Synthesis (CMDS) and BK21 project.
References and Notes
(13) To a solution of N-methylhydroxydithiocarbamate 1 (164 mg,
1.2 mmol) and sodium hydride (56 mg, 1.4 mmol) in DMF (3
mL) was added 4-phenoxybutyl bromide (328 mg, 1.4 mmol)
at 0 °C. After being stirred for 30 min at room temperature, the
reaction mixture was diluted with water and extracted with
diethyl ether. The organic layer was dried over anhydrous
MgSO4, filtered and concentrated. The product was purified
by passing through a column of silica gel using n-hexane and
ethyl acetate (10:1) as an eluant to give N-alkoxydithio-
carbamate (308 mg, 90%). 1H NMR (400 MHz, CDCl3):
1.88-1.96 (m, 4H), 2.51 (s, 3H), 3.70 (s, 3H), 4.00 (t, J = 5.7
Hz, 2H), 4.05 (t, J = 6.1 Hz, 2H), 6.87-6.95 (m, 3H), 7.25-7.29
(m, 2H); 13C NMR (100 MHz, CDCl3): 18.2, 24.7, 25.8,
40.4, 67.0, 73.3, 114.3, 120.6, 129.4, 158.7, 196.9; IR(NaCl):
3451, 2947, 1652, 1599, 1496, 1470, 1243, 1096, 1018, 754,
691 cm-1; HRMS (EI/70eV) calcd for C13H19NO2S2:
285.0857, found 285.0865.
(14) To a solution of N-methylhydroxydithiocarbamate 1 (164 mg,
1.2 mmol), 4-phenyl-1-butanol (220 L, 1.4 mmol) and
triphenylphosphine (344 mg, 1.3 mmol) in THF (1 mL) was
slowly added diethyl azodicarboxylate (210 L, 1.3 mmol) at
room temperature. After being stirred for 2 h at room
temperature, the reaction mixture was diluted with water and
extracted with diethyl ether. The organic layer was dried over
anhydrous MgSO4, filtered and concentrated. The product was
purified by passing through a column of silica gel using n-
hexane and ethyl acetate (10:1) as an eluant to give
N-alkoxydithiocarbamate (272 mg, 84%). 1H NMR (400
MHz, CDCl3): 1.72-1.81 (m, 4H), 2.52 (s, 3H), 2.67 (t,
J = 7.1 Hz, 2H), 3.68 (s, 3H), 3.98 (t, J = 6.2 Hz, 2H), 7.17-
7.20 (m, 3H), 7.26-7.30 (m, 2H); 13C NMR (100 MHz,
CDCl3): 18.2, 27.3, 27.6, 35.5, 40.3, 73.4, 125.8, 128.30,
128.33, 141.7, 196.9; IR(NaCl): 3458, 2941, 1652, 1495,
1453, 1361, 1259, 1190, 1097, 1019, 959, 749, 699 cm-1;
HRMS (EI/70eV) calcd for C13H19NOS2: 269.0908, found
269.0907.
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(12) Typical procedure for the preparation of N-methylhydroxy-
dithiocarbamate 1: To a solution of N-methylhydroxylamine
hydrochloride (830 mg, 10 mmol), carbon disulfide (660 L,
11 mmol) and methyl iodide (680 L, 11 mmol) in
dichloromethane (20 mL) was added triethylamine (1.55 mL,
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dried over anhydrous MgSO4, filtered and concentrated. The
product was purified by passing through a short column of
silica gel using n-hexane and ethyl acetate (2:1) as an eluant to
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Article Identifier:
1437-2096,E;2001,0,05,0688,0690,ftx,en;Y05201ST.pdf
Synlett 2001, No. 5, 688–690 ISSN 0936-5214 © Thieme Stuttgart · New York