Dimethylthiocarbamate (DMTC): An Alcohol Protecting Group

Article abstract of DOI:10.1021/ol0354573

(Equation Presented) Dimethylthiocarbamates (DMTCs), prepared from the corresponding alcohols using commercial dimethylthiocarbamoyl chloride, are spectrally simple, achiral, and nonpolar. DMTCs are moderately to highly stable to a wide range of reagents and conditions including metal hydrides, hydroboration, ylides, NaOH, HCl, organolithiums, Grignards, DDQ, PCC, Swern, n-Bu₄NF, CrCl₂, heat, and Lewis acids. They are readily removed by NalO₄ or H₂O₂ in the presence of other common alcohol protecting groups.

Full text of DOI:10.1021/ol0354573

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4755-4757
Dimethylthiocarbamate (DMTC): An
Alcohol Protecting Group
,†
D. K. Barma,† A. Bandyopadhyay,† Jorge H. Capdevila,‡ and J. R. Falck*
Departments of Biochemistry and Pharmacology, UniVersity of Texas Southwestern
Medical Center, Dallas, Texas 75390-9038, and Departments of Medicine and
Biochemistry, Vanderbilt UniVersity School of Medicine, NashVille, Tennessee 37232
j.falck@utsouthwestern.edu
Received August 1, 2003
ABSTRACT
Dimethylthiocarbamates (DMTCs), prepared from the corresponding alcohols using commercial dimethylthiocarbamoyl chloride, are spectrally
simple, achiral, and nonpolar. DMTCs are moderately to highly stable to a wide range of reagents and conditions including metal hydrides,
hydroboration, ylides, NaOH, HCl, organolithiums, Grignards, DDQ, PCC, Swern, n-Bu4NF, CrCl2, heat, and Lewis acids. They are readily
removed by NaIO or H O in the presence of other common alcohol protecting groups.
4
2 2
The introduction and removal of protecting groups (PGs)
are among the most common transformations during the
synthesis of polyfunctional molecules.1 There is, conse-
quently, continuing demand for more varied, robust, eco-
nomical, and/or chemically differentiable PGs.2 As part of
our ongoing program in this area,3 we had occasion to
evaluate thionocarbamates4 as potential PGs.5 Herein, we
propose N,N-dimethylthiocarbamate (DMTC) as a versatile
alcohol PG and highlight some of its more germane
qualifications.
Primary alcohols are smoothly derivatized in excellent
yields using stoichiometric N,N-dimethylthiocarbamoyl chlo-
ride6 and NaH in THF at room temperature.7
† UT Southwestern.
‡ Vanderbilt University School of Medicine.
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999.
(2) Recent examples: (a) Almog, J.; Zehavy, Y.; Cohen, S. Tetrahedron
Lett. 2003, 44, 3285-3288. (b) Kessler, M.; Glatthar, R.; Giese, B.; Bochet,
C. G. Org. Lett. 2003, 5, 1179-1181. (c) Ellervik, U. Tetrahedron Lett.
2003, 44, 2279-2281. (d) Miura, T.; Inazu, T. Tetrahedron Lett. 2003, 44,
1819-1821. (e) Dinkel, C.; Wichmann, O.; Schultz, C. Tetrahedron Lett.
2003, 44, 1153-1155. (f) Csavas, M.; Borbas, A.; Janossy, L.; Liptak, A.
Tetrahedron Lett. 2003, 44, 631-635.
(3) For other studies of protecting groups from our laboratories, see: (a)
Falck, J. R.; Barma, D. K.; Venkataraman, S. K.; Baati, R.; Mioskowski,
C. Tetrahedron Lett. 2002, 43, 963-966. (b) Falck, J. R.; Barma, D. K.;
Baati, R.; Mioskowski, C. Angew. Chem., Int. Ed. 2001, 40, 1281-1283.
(c) Baati, R.; Valleix, A.; Mioskowski, C.; Barma, D. K.; Falck, J. R. Org.
Lett. 2000, 2, 485-487. (d) Cho, H.-S.; Yu, J.; Falck, J. R. J. Am. Chem.
Soc. 1994, 116, 8354-8355. (e) Bolitt, V.; Mioskowski, C.; Shin, D. S.;
Falck, J. R. Tetrahedron Lett. 1988, 29, 4583-4586.
These conditions are compatible with a variety of func-
tionality, e.g., acetate 1, silyl ethers 2 and 3, benzyloxy 4,
(4) Review of thiocarbamate syntheses: Walter, W.; Bode, K. D. Angew.
Chem., Int. Ed. Engl. 1967, 6, 281-293.
(5) The ability of thionocarbamates to stabilize organocopper reagents
has been exploited for the cross-coupling of R,â-dialkoxy- and R-alkoxy-
â-aminostannanes: Mohapatra, S.; Bandyopadhyay, A.; Barma, D. K.;
Capdevila, J. H.; Falck, J. R. Org. Lett. 2003, 5, 4759-4762.
(6) Commercial N,N-dimethylthiocarbamoyl chloride can vary in quality.
Impure samples were refined by molecular (Kugelrohr) distillation, bp 65
°C at 0.2 mmHg, to give a white solid (mp 41 °C) that could be stored
indefinitely at room temperature under an argon atmosphere.
10.1021/ol0354573 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/19/2003

p-methoxybenzyloxy 5, MOM ether 6, MEM ether 7, and
tetrahydropyranyloxy 8. Likewise, cyclic secondary 9, acyclic
secondary 10, allylic 11, benzylic 12, and propargyl 13
alcohols, as well as Vic-diols 14, are efficiently converted
to DMTCs.8
Scheme 1. DMTC Reagent Compatibilitya
For alkali-intolerant compounds, the alcohol is thiocar-
bamoylated via sequential treatment with 1,1′-thiocarbonyl-
diimidazole followed by a THF solution of dimethylamine,
e.g., 15 f 16 (eq 1).7
The DMTC group is endowed with many features that
make it an attractive protective group, inter alia, low polarity,
no chiral centers, distinctive spectral signature,8 thermal
stability,9 and low reactivity. As demonstrated in the ac-
companying reactions (Scheme 1), DMTCs are compatible
under typical conditions with PCC (route a), Swern oxidation
(route b), chromium reagents10 (routes c and l), Grignards
(route d), alkyllithiums (route k), ylides (routes e and i), metal
hydrides (routes f-h), and hydroboration (route j).
a Reagents and conditions: (a) PCC, CH2Cl2, 23 °C, 3 h. (b)
DMSO, (COCl)2, CH2Cl2, -78 °C, 1 h; Et3N, -78 to 0 °C, 1 h.
(c) Cl3CCO2Me, CrCl2, THF, 23 °C, 0.5 h. (d) EtMgBr, Et2O, 0
°C, 0.5 h. (e) EtO2CC(PPh3)CH3, CH2Cl2, 23 °C, 12 h. (f) DIBAL-
H, CH2Cl2, -78 °C, 0.5 h. (g) LiAlH4, Et2O, 0 °C, 0.5 h. (h) NaBH4,
MeOH, 0 °C, 0.5 h. (i) n-BuLi, Ph3P+CH3Br-, Et2O, -78 °C, 0.5
h; aldehyde, -78 to -20 °C, 1 h. (j) H3B‚Me2S, THF, 0 °C, 3 h;
H2O2, NaOH, 23 °C, 1 h. (k) n-BuLi, THF, -78 °C, 0.5 h. (l)
PhCHdCHCH2CCl3, CrCl2, THF, 23 °C, 12 h.
Results from the selective deprotection of several repre-
sentative alcohol PGs in the presence of a DMTC moiety
are summarized in Table 1. Parental alcohols are readily
regenerated from tert-butyldimethylsilyl (entry 1) and tert-
butyldiphenylsilyl (entry 2) ethers using fluoride, p-meth-
oxybenzyl ether (entry 3) via DDQ, MOM (entry 4) and THP
ethers (entry 5) by mild acid, MEM ether (entry 6) with the
Lewis acid TiCl4, and acetate (entry 7) upon exposure to
base. As anticipated, catalytic hydrogenation of a benzyl ether
in the presence of a DMTC failed; cleavage via in situ
generated trimethylsilyl iodide, on the other hand, was
successful, albeit in modest yield (entry 8).
(7) Dimethylthiocarbamoylation. Method A. A solution of alcohol (5.0
mmol) in dry THF (5 mL) was added to a stirring, 0 °C suspension of NaH
(5.1 mmol) in dry THF (20 mL) under an argon atmosphere. After 30 min,
NaI (0.1 mmol) and N,N-dimethylthiocarbamoyl chloride (6.0 mmol, 1.2
equiv) were added successively, and the resulting mixture was stirred at
room temperature for 10 h. The reaction mixture was quenched with
saturated aqueous NH4Cl and extracted with ether (3 × 10 mL). The
combined ethereal extracts were washed with water and brine and dried
over Na2SO4. Removal of all volatiles in vacuo and chromatographic
purification of the residue on SiO2 furnished the DMTC protected alcohol.
Method B. 1,1′-Thiocarbonyldiimidazole (1.1 mmol) was added to a stirring
solution of alcohol (1 mmol) in dry CH2Cl2 (5 mL) containing DMAP (0.1
mmol) under an argon atmosphere. After 2-10 h, the reaction mixture was
filtered through a small pad of silica gel, and the filter cake was washed
with EtOAc (5 mL). The combined filtrate was concentrated under reduced
pressure, and the residue was dissolved in a 2 M THF solution of
dimethylamine (4 mL). After 2-4 h, all volatiles were removed in vacuo,
and the residue was chromatographed over silica gel affording thiocarbam-
oylated alcohol.
Table 1. Cleavage of Alcohol Protective Groups in the
Presence of DMTC
(8) Spectral data for 6: 1H NMR (CDCl3, 300 MHz) δ 1.32-1.44 (m,
6H), 1.54-1.63 (m, 2H), 1.67-1.77 (m, 2H), 3.08 (s, 3H), 3.35 (s, 6H),
3.51 (t, 2H, J ) 6.3 Hz), 4.42 (t, 2H, J ) 6.3 Hz), 4.61 (s, 2H); 13C NMR
(CDCl3, 75 MHz) δ 26.06, 26.26, 28.84, 29.20, 29.79, 37.78, 42.71, 55.18,
67.84, 71.74, 96.49, 188.46; IR (neat) 2933, 1520, 1393, 1293, 1193, 1146,
1110, 1043 cm-1. Spectral data for 9: 1H NMR (CDCl3, 300 MHz) δ 0.81
(d, 3H, J ) 7.5 Hz), 0.86-0.93 (m, 7H), 1.01-1.17 (m, 1H), 1.43-1.59
(m, 2H), 1.63-1.73 (m, 2H), 1.81-1.94 (m, 1H), 2.17-2.26 (m, 1H), 3.07
(s, 3H), 3.35 (s, 3H), 5.24 (dt, 1H, J ) 4.5, 10.8 Hz); 13C NMR (CDCl3,
75 MHz) δ 17.10, 20.99, 22.25, 23.75, 26.65, 31.41, 34.52, 37.72, 41.06,
time yield
entry
PG
reagent
solvent/temp (°C) (h)
(%)
1
2
3
4
5
6
7
8
TBDMS n-Bu4NF
TBDMS n-Bu4NF
THF/23
THF/23
2
4
1
10
3
0.5
92
98
96
95
94
92
98
75
PMB
MOM
THP
MEM
Ac
DDQ
CH2Cl2/23
MeOH/50
MeOH/23
CH2Cl2/0
MeOH/0
CH2Cl2/23
42.70, 47.66, 81.64, 187.86; IR (neat) 2953, 1520, 1390, 1293, 1196 cm-1
.
Spectral data for 12: 1H NMR (CDCl3, 400 MHz) δ 3.15 (s, 3H), 3.41 (s,
3H), 5.55 (s, 2H), 7.33-7.47 (m, 5H), 7.56-7.61 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 38.20, 43.16, 72.93, 127.31, 127.37, 127.53, 127.71,
128.80, 129.03, 129.09, 129.65, 135.46, 140.92, 141.36, 188.25. Spectral
data for 14: 1H NMR (CDCl3, 300 MHz) δ 0.84 (t, 3H, J ) 7.2 Hz), 1.19-
1.41 (m, 12H), 1.58-1.77 (m, 2H), 3.08 (s, 6H), 3.32 (s, 3H), 3.33 (s, 3H),
4.50-4.61 (m, 2H), 5.70-5.86 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ
14.21, 22.74, 25.23, 29.28, 29.46, 29.60, 31.08, 31.92, 37.87, 38.06, 42.87,
72.19, 78.88, 187.82, 187.95.
HCl (1 M)
PTSA (5 mol %)
TiCl4
K2CO3
Me3SiCl/Nal
1
10
Bn
(9) The Neuman-Kwart rearrangement (O f S migration) normally
becomes significant only at temperatures of g220 °C, e.g.: Relles, H. M.;
Pizzolato, G. J. Org. Chem. 1968, 33, 2249-2253.
(10) (a) Barma, D. K.; Kundu, A.; Zhang, H.; Mioskowski, C.; Falck, J.
R. J. Am. Chem. Soc. 2003, 125, 3218-3219. (b) Barma, D. K.; Baati, R.;
Valleix, A.; Mioskowski, C.; Falck, J. R. Org. Lett. 2001, 3, 4237-4238.
Importantly, the orthogonal removal of the DMTC group
(Table 2) is readily effected with NaIO4 in MeOH/H2O at
45 °C for 2 h followed by brief exposure to dilute base to
hydrolyze variable but usually minor amounts of formate
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Org. Lett., Vol. 5, No. 25, 2003

Scheme 2. Proposed Deprotection Mechanism
Table 2. NalO4 Cleavage of N,N-Dimethylthiocarbamates
(DMTCs)a
entry
PG
yield (%)
1
2
3
4
5
6
7
8
TBDMS
TBDPS
PMB
MOM
THP
MEM
Ac
Bn
95
92
95
93
93
92
94
94
subsequent extrusion of SO2, affording immonium 18. Simple
hydrolysis leads to formate 19 and finally to the parent
alcohol.
Alternatively, DMTCs are severed, albeit slowly, in
excellent yield by basic hydrogen peroxide at room temper-
ature. This protocol has proven useful for Vic-diols (eq 2)
and other systems not compatible with periodate.
a See ref 11 for general procedure.
ester 19 (Scheme 2).11 Although the details of the overall
transformation are obscure, it is known12 that thionocarbam-
ates undergo S-oxidation. We speculate that the resultant
sulfenic acid 17 is further oxidized by excess NaIO4 with
In summary, DMTC is a robust, spectrally simple, sym-
metrical, and nonpolar alcohol protective group. It is readily
introduced using inexpensive reagents and is orthogonally
differentiated from most other alcohol PGs.
(11) DMTC Cleavage. Method A. NaIO4 (4.0 mmol) was added to a
stirring, room-temperature solution of DMTC (1.0 mmol) in MeOH/H2O
(10 mL, 20:1). The resulting solution was heated to 45 °C for 2 h and
cooled to room temperature, and Na2CO3 (6.0 mmol) was added. Following
another 2 h, the reaction mixture was extracted with ether (3 × 6 mL), and
the combined ethereal extracts were washed with water and brine and dried
over Na2SO4. Concentration under reduced pressure and chromatographic
purification of the residue over silica gel afforded pure alcohol. Method
B. The DMTC-protected alcohol (1.0 mmol) was stirred at 50 °C with 30%
H2O2 (1 mL) in THF or CH3CN (2 mL). After 4 h, an aqueous solution of
NaOH (2 M, 1 mL) was added, and the stirring was continued at the same
temperatrure overnight. The reaction mixture was cooled to room temper-
ature and extracted with Et2O (3 × 5 mL), and the combined ethereal
extracts were washed with water (until the aqueous layer was negative to
starch/iodine paper) and brine and dried over Na2SO4. Concentration under
reduced pressure and purification of the residue over silica gel afforded
pure alcohol (85-90%).
Acknowledgment. Financial support provided by the
Robert A. Welch Foundation and NIH (GM31278, DK38226,
GM37922).
Supporting Information Available: Physical and spec-
troscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) Walter, W.; Wohlers, K. Ann. Chem. 1971, 752, 115-135.
OL0354573
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