Fluorous dimethylthiocarbamate (FDMTC) protecting groups for alcohols

Article abstract of DOI:10.1016/j.tetlet.2006.05.142

N,N-Bis(perfluoroalkyl)thiocarbamoyl chlorides (^FDMTC-Cls) were synthesized as reagent for the protection of alcohols. Using the crystalline ^FDMTC-Cls, the ^FDMTC groups were introduced into the alcohol molecules in excellent yields in the presence of sodium hydride in THF at room temperature. The products were separated from the excess alcohols by solid-phase extraction with a fluorous reverse-phase silica gel column (Fluorous Solid Phase Extraction; FSPE). The ^FDMTC groups were readily removed by oxidation with m-chloroperbenzoic acid (m-CPBA) and subsequent hydrolysis with KHCO₃.

Full text of DOI:10.1016/j.tetlet.2006.05.142

Tetrahedron Letters 47 (2006) 6309–6314
Fluorous dimethylthiocarbamate (FDMTC) protecting groups
for alcohols
Masaru Kojima, Yutaka Nakamura, Takuma Ishikawa and Seiji Takeuchi*
Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Niigata 956-8603, Japan
Received 29 March 2006; revised 18 May 2006; accepted 19 May 2006
Available online 18 July 2006
Abstract—N,N-Bis(perfluoroalkyl)thiocarbamoyl chlorides (FDMTC-Cls) were synthesized as reagent for the protection of alco-
hols. Using the crystalline FDMTC-Cls, the FDMTC groups were introduced into the alcohol molecules in excellent yields in the
presence of sodium hydride in THF at room temperature. The products were separated from the excess alcohols by solid-phase
extraction with a fluorous reverse-phase silica gel column (Fluorous Solid Phase Extraction; FSPE). The FDMTC groups were read-
ily removed by oxidation with m-chloroperbenzoic acid (m-CPBA) and subsequent hydrolysis with KHCO3.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Fluorous compounds that bear one, two, or three perflu-
oroalkylchains are easily separated from organic com-
pounds by liquid–liquid extraction using a fluorous
solvent or solid-phase extraction with a fluorous re-
verse-phase silica gel column.1 In order to apply the tech-
nologies to total, parallel and combinatorial synthesis of
complex molecules, various fluorous protecting groups
such as Cbz,2 Boc,3 t-Bu,4 Bn,5 THP,6 Msc,7 acyl-type,8
silyl-type,9 alkoxyethyl ether,10 and Troc11 have been syn-
thesized so far, and some of them are commercially avail-
able. Utilizing these protecting groups, natural products
including oligosaccharides, oligonucleotides and peptides
have successfully been synthesized.2b,8,12 Recently, we
have also reported an expeditious synthesis of bistrat-
amide H using a new ‘highly’ fluorous amino protecting
group, tris(perfluorodecyl)silylethoxycarbonyl (FTeoc)
group.13 The synthetic intermediates were easily isolated
by liquid–liquid extraction with FC-72.14 Optimization
of the reaction conditions was carried out as usual by
monitoring the reactions with TLC. In addition, the
FTeoc group was demonstrated to be recyclable.
proposed an N,N-dimethylthiocarbamate (DMTC)
group as a useful protecting group for alcohols.16 The
DMTC group is moderately to highly stable under a
wide range of reaction conditions, including metal hy-
drides, hydroboration, ylides, base, acid, organolithi-
ums, Grignards, DDQ, PCC, Swern, n-Bu4NF, CrCl2,
heat, and Lewis acids. The protecting group is selectively
removed with NaIO4 or H2O2 without damaging other
common protecting groups. Accordingly, we synthe-
sized fluorous DMTC-Cl and used it for the protection
of various alcohols. Fluorous protecting reagents,
bis(perfluoroalkyl)thiocarbamoyl
chlorides
(6a–d;
FDMTC-Cl), were prepared by the route shown in
Scheme 1. Four kinds of FDMTC groups in which the
length of the perfluoroalkyl chain differed were synthe-
sized in order to apply them for a fluorous mixture syn-
thesis as well.17 In these compounds, a three-carbon
spacer between nitrogen and perfluorinated alkyl groups
was also introduced instead of a two-carbon spacer to
effectively insulate the strong electron-withdrawing
effect of the perfluorinated alkyl parts.
Protection of a functional group with protecting groups
is inevitable to synthesize a complicated molecule,15 so
finding a more convenient and efficient protecting group
is still a challenging target. Recently, Falck’s group has
3-(Perfluoroalkyl)propyl iodides 3a–d18 were synthesized
according to a modified Fish’s method19 from the corre-
sponding CnF2n+1I (n = 4, 6, 8, 10) via three-step reac-
tions. The iodides 3a–d were reacted with benzylamine
in the presence of potassium carbonate to give the cor-
responding tertiary amines 4a–d.20 Compounds 4a–d
were hydrogenated with 10% Pd–C in EtOAc to give
secondary amines 5a–d. To avoid forming tetra-
alkylthiourea, compounds 5a–d (1.0 equiv) were reacted
Keywords: Dimethylthiocarbamate; Protecting group; Fluorous;
Fluorous solid-phase extraction (FSPE).
*
Corresponding author. Tel.: +81 250 25 5165; fax: +81 250 25
5021; e-mail: takeuchi@niigata-pharm.ac.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.142

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M. Kojima et al. / Tetrahedron Letters 47 (2006) 6309–6314
Ph3P, I2, Imidazole
LiAlH4 / THF
CH2Cl2
OH, AIBN
75 oC
BnNH2, K2CO3
CnF2n+1
1a-d
OH
CnF2n+1
OH
CnF2n+1
I
CnF2n+1
I
0 oC then reflux
CH3CN, 80 o
C
I
H
0
oC then rt
n = 4, 6, 8, 10
2a (C4F9); y. 70%
2b (C6F13); y. 89%
2c (C8F17); y. 76%
2d (C10F21); y. 51%
3a; quant.
3b; y. 75%
3c; y. 76%
3d; y. 43%
S
10% Pd-C, H2
CSCl2
CnF2n+1
N
2
Cl
•
+
CnF2n+1
CnF2n+1
2NH HCl
NH
2
CnF2n+1
NBn
2
EtOAc, rt
FDMTC-Cls
Et2O or THF
-20 o
C
4a; quant.
5a; y. 99%
5b; y. 87%
5c; y. 92%
6a; y. 45%
6b; y. 47%
6c; y. 46%
7a; y. 40%
7b; y. 41%
7c; y. 50%
4b; y. 76%
4c; quant.
4d; y. 93%
5d; y. 57%
6d; y. 18%
7d; y. 50%
Scheme 1. Preparation of FDMTC-Cls.
with thiophosgene (0.5 equiv) in Et2O or THF.21 After
the reaction, the precipitated amine hydrochlorides 7a–
d were filtered off and the filtrates were concentrated.
After recrystallization of the crude products from chlo-
nol (2.0 equiv) was reacted with FDMTC-Cls 6a–d
(1.0 equiv) under similar reaction conditions and
the results are summarized in Scheme 3. The reac-
tions proceeded smoothly to give the corresponding
FDMTC-protected compounds 9a–d in excellent yields
(89%-quantitative). 1H NMR spectra of 8a and 9a,
which were isolated by FSPE, are shown in Figure 1.
As seen from the spectra, the FDMTC-protected
compounds were almost pure.23
F
roform and petroleum ether, DMTC-Cls 6a–d22 were
obtained in 45% (6a), 47% (6b), 46% (6c) and 18% (6d)
yields as colorless solids. However, since compounds
4d and 5d were insoluble in organic solvents, the yields
of products 5d and 6d were decreased.
F
F
We next examined the introduction of DMTC groups
Since DMTC groups were successfully introduced into
into primary alcohol (1-dodecanol), secondary alcohol
(1-phenyl-2-propanol) and sugar derivatives using
FDMTC-Cls 6a–d.
the simple alcohols, we also examined the protection of
hydroxyl groups in various sugar derivatives in order to
demonstrate the versatility of FDMTC groups. The
results are summarized in Table 1. As seen from the
table, the FDMTC-protected compounds (10b, 10c,
11c, 12b, 12c, and 13c) were obtained in high yields from
the MeOH fraction by FSPE. The unreacted starting
alcohols were also recovered from 80% MeOH aq frac-
tion by FSPE.
1-Dodecanol (1.5 equiv) was reacted with FDMTC-Cl
6a (1.0 equiv) and NaH in THF at room temperature.
After 12 h, the reaction was quenched with saturated
NH4Cl aq and then the reaction mixture was extracted
with Et2O. The Et2O layer was washed, dried, and con-
centrated. The residue including FDMTC-protected
product 8a and excess 1-dodecanol was loaded onto a
fluorous reverse-phase silica gel (FluoroFlashꢁ) column
and then the column was eluted successively with 80%
MeOH aq and MeOH. The MeOH fraction was concen-
trated to give FDMTC-protected compound 8a in quan-
titative yield (Scheme 2). Similarly, 1-dodecanol was
To find the optimal reaction conditions for FDMTC
group cleavage, we initially examined deprotection of
a non-fluorous DMTC group in the model compound
14 under Falck’s conditions (NaIO4 or H2O2)16 and
Mukaiyama’s conditions (m-CPBA).24 As shown in
Table 2, ester 15 was obtained as a by-product under
Falck’s conditions (entries 1 and 2). On the other hand,
deprotection of the DMTC group with m-CPBA gave
1-dodecanol in good yield (entry 3).
F
reacted with DMTC-Cls 6b–d. After separation of the
crude products by FSPE, FDMTC-protected com-
pounds 8b–d were obtained in quantitative (8b), 93%
(8c), 95% (8d) yields (Scheme 2). Next, 1-pheny-2-propa-
S
S
CnF2n+1
2N
Cl
CnF2n+1
2N
Cl
80 % MeOH aq.
OH
80 % MeOH aq.
6a-d (1.0 equiv)
6a-d (1.0 equiv)
OH
11
OH
FSPE
NaH / THF
FSPE
NaH / THF
OH
OFDMTC
11
0 oC then rt
0
oC then rt
OFDMTC
11
(2.0 equiv)
(1.5 equiv)
MeOH or Et2O25
MeOH or Et2O25
8a (C4F9); quant.
8b (C6F13); quant.
8c (C8F17); y. 93%
8d (C10F21); y. 95%
9a (C4F9); quant.
S
S
9b (C6F13); quant.
9c (C8F17); y. 89%
9d (C10F21); quant.
FDMTC =
FDMTC =
N
CnF2n+1
N
CnF2n+1
2
2
Scheme 2. Introduction of FDMTC groups into 1-dodecanol with
6a–d.
Scheme 3. Introduction of FDMTC groups into 1-phenyl-2-propanol
with 6a–d.

M. Kojima et al. / Tetrahedron Letters 47 (2006) 6309–6314
6311
Figure 1. 1H NMR spectra of compounds 8a and 9a (250 MHz, CDCl3).
Table 1. Introduction of FDMTC groups into sugar derivativesa
Entry
Product
Yield (%)
Recovered yield (%) of starting alcohol
O
O
OFDMTC
O
1
10b C6F13; 92
10c C8F17; 93
C6F13; 88
C8F17; quant.
O
O
O
O
FDMTCO
O
2
3
11c C8F17; 97
C8F17; quant.
OBn
Ph
FDMTCO
O
O
O
12b C6F13; 99
12c C8F17; quant.
C6F13; 98
C8F17; quant.
BnO
OMe
O
Ph
O
O
MOMO
FDMTCO
OMe
N
4
13c C8F17; quant.
C8F17; quant.
S
FDMTC =
CnF2n+1
2
a Sugar derivatives (2.0 equiv) and FDMTC-Cls (6b or 6c; 1.0 equiv) were used for the reaction.
F
Finally, we tried to deprotect the DMTC group under
the optimal reaction conditions (entry 3 in Table 2). The
results are summarized in Table 3. FDMTC-protected
compounds were reacted with m-CPBA (5.0 equiv) in
CH2Cl2 at À78 ꢂC. After 1 h, the reaction was quenched
with saturated NaHCO3 aq and then the reaction

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M. Kojima et al. / Tetrahedron Letters 47 (2006) 6309–6314
Table 2. Deprotection of DMTC group with various peroxides
1) Peroxide
2) Base
S
O
Me
Me
Me
Me
11 O
14
N
11 OH
+
11O
N
Solvent
Reaction temp. (oC)
15
13C NMR 156.8 ppm (C=O)
IR 1710 cm-1 (C=O)
Entry
Peroxide
Base
Solvent
Reaction temperature (ꢂC)
Yield (%)
1-Dodecanol
15
1
2
3
NaIO4
H2O2
m-CPBA
Na2CO3
2 N NaOH aq
KHCO3
MeOH/H2O
THF
CH2Cl2
45
50
À78
81
14
85
7
48
15
Table 3. Deprotection of FDMTC groups with m-CPBA
O
80 % MeOH aq.
Solid KHCO3
R
OH
R
O
m-CPBA
H
(5.0 equiv)
FSPE
Formyl compound
Alcohol
OFDMTC
R
CH2Cl2
- 78 oC, 1 h
Substrate
HO
N
CnF2n+1
2
MeOH
or
Et2O, EtOAc25
S
16a-d (n = 4, 6, 8, 10)
FDMTC =
N
CnF2n+1
2
Entry
Substrate
Alcohol
Yield (%)
1
2
3
4
8a
8b
8c
8d
82
quant.
92
11 OH
77
5
6
7
8
9a
9b
9c
9d
86
90
85
88
OH
O
O
OH
O
9
10
10b
10c
75
85
O
O
O
O
HO
O
11
11c
78
OBn
O
Ph
Ph
O
O
12
13
12b
12c
91
86
HO
BnO
OMe
O
O
O
14
13c
75
MOMO
HO
OMe
mixture was extracted with Et2O. The Et2O layer was
washed with 1 N NaOH aq and then with brine, dried,
and concentrated. The residue including the intermedi-
ate formyl compound was loaded onto a FluoroFlashꢁ
column and then the column was eluted successively
with 80% MeOH aq and MeOH, Et2O or EtOAc.25
The 80% MeOH aq layer was treated with solid KHCO3
to give the corresponding alcohols in good yields. The
reaction conditions for the FDMTC group cleavage
are compatible with several protecting groups such as
Bn, MOM, isopropylidene, and benzylidene (entries 9–
14). On the other hand, fluorous hydroxylamines 16a–
d were obtained from the MeOH, Et2O or EtOAc layer
as a main product. Currently, we are examining reduc-

M. Kojima et al. / Tetrahedron Letters 47 (2006) 6309–6314
6313
13. Nakamura, Y.; Okumura, K.; Kojima, M.; Takeuchi, S.
Tetrahedron Lett. 2006, 47, 239–243.
14. FC-72 is a commercially available fluorocarbon solvent
(3 M). It consists of isomers of C6F14, mostly
perfluorohexane.
tive cleavage of the N–O bond in order to convert the
hydroxylamines 16a–d to the corresponding secondary
amines 5a–d.
In conclusion, we have developed fluorous dimeth-
ylthiocarbamate (FDMTC) groups as a new fluorous
protecting group for alcohols. The FDMTC groups were
easily introduced into the simple alcohols and carbohy-
drates in high yields, and selectively cleaved with m-
CPBA. The isolation of the FDMTC-protected products
by FSPE was very easy and quick. The fluorous com-
pounds were also purified by normal silica gel column
chromatography, if necessary. Optimization of the reac-
tions was carried out as usual by monitoring the reac-
tions with TLC. Considering these attributes, the
FDMTC groups may find valuable and versatile use in
synthetic organic chemistry.
15. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons: New
York, 1999.
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from Fluorous Technologies, Inc.
19. Vincent, J. M.; Rabion, A.; Yachandra, V. K.; Fish, R. H.
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1
22. Compound 6a: H NMR (250 MHz, CDCl3): d 3.97 (2H,
References and notes
t, J = 7.2 Hz, NCH2), 3.85 (2H, t, NCH2), 2.16 (8H, m,
CH2CH2C4F9 · 2); 13C NMR (63 MHz, CDCl3): d 175.23
(C@S), 54.39 (NCH2 · 2), 28.10, 27.93 (each t,
J = 22.6 Hz, CH2C4F9 · 2) 19.18, 17.20 (CH2CH2C4F9 ·
2); IR (KBr, disk) m (cmÀ1): 2949, 1508, 1465, 1425, 1379,
1358, 1299, 1236, 1150, 1132, 1105, 1013, 990, 878, 853,
733, 719, 592. Compound 6b: 1H NMR (250 MHz,
CDCl3): d 3.97 (2H, t, J = 6.8 Hz, NCH2), 3.85 (2H, t,
NCH2), 2.16 (8H, m, CH2CH2C6F13 · 2); 13C NMR (63
MHz, CDCl3): d 175.24 (C@S), 54.41 (NCH2 · 2), 28.20,
28.03 (each t, J = 22.6 Hz, CH2C6F13 · 2) 19.23, 17.24
(CH2CH2C6F13 · 2); IR (KBr, disk) m (cmÀ1): 1507, 1421,
1368, 1299, 1246, 1209, 1144, 1123, 1103, 1082, 1034, 984,
846, 792, 746, 700, 655. Compound 6c: 1H NMR
(250 MHz, C6D6/C6F6 (1:1)): d 3.45 (2H, t, J = 6.7 Hz,
NCH2), 3.19 (2H, t, NCH2), 1.79 (8H, m, CH2CH2-
C8F17 · 2); 13C NMR (63 MHz, C6D6/C6F6 (1:1)): d
175.03 (C@S), 54.58, 54.40 (NCH2 · 2), 28.60, 28.40 (each
t, J = 22.6 Hz, CH2C8F17 · 2) 19.30, 17.45 (CH2CH2-
C8F17 · 2); IR (KBr, disk) m (cmÀ1): 2981, 1506, 1463,
1442, 1420, 1372, 1335, 1297, 1247, 1204, 1151, 1117, 1038,
978, 959, 705, 661. Compound 6d: 1H NMR (250 MHz,
C6D6/C6F6 (2:3)): d 3.40 (2H, t, J = 6.4 Hz, NCH2), 3.12
(2H, t, NCH2), 1.79 (8H, m, CH2CH2C10F21 · 2); 13C
NMR (63 MHz, C6D6/C6F6 (2:3)): d 174.96 (C@S), 54.49,
54.32 (NCH2 · 2), 28.51, 28.35 (each t, J = 22.1 Hz,
CH2C10F21 · 2) 19.25, 17.43 (CH2CH2C10F21 · 2); IR
(KBr, disk) m (cmÀ1): 1506, 1463, 1420, 1374, 1344, 1298,
1214, 1152, 1113, 1084, 1038, 984, 885, 664, 647, 557.
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1
23. Compound 8a: H NMR (250 MHz, CDCl3): d 4.45 (2H,
t, J = 6.7 Hz, H-1), 3.86, 3.53 (4H, each t, J = 7.4 Hz,
NCH2 · 2), 2.06 (8H, m, CH2CH2C4F9 · 2), 1.72 (2H, m,
H-2), 1.26 (18H, s, H-3, 4, 5, 6, 7, 8, 9, 10, 11), 0.88 (3H, t,
J = 6.8 Hz, H-12); 13C NMR (63 MHz, CDCl3): d 188.97
(C@S), 72.09 (C-1), 51.90, 47.86 (NCH2 · 2), 31.89, 29.70,
29.60, 29.56, 29.49, 29.33, 29.27, 28.63, 26.08, 22.66, 14.01
(C-2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12), 28.55, 28.19 (each t,
J = 22.1 Hz, CH2C4F9 · 2) 19.17, 18.04 (CH2CH2-
C4F9 · 2); IR (NaCl, neat) m (cmÀ1): 2928, 2857, 1464,
1356, 1235, 1167, 1134, 1071, 930, 880, 736, 720.
Compound 9a: 1H NMR (250 MHz, CDCl3): d 7.35–
7.18 (5H, m, aromatic protons), 5.79 (1H, ddq, J = 6.0,
6.3, 7.0 Hz, OCH), 3.83, 3.43 (4H, each m, NCH2 · 2),
3.09 (2H, dd, J = 6.3, 13.6 Hz, PhCH2), 2.87 (2H, dd,
J = 7.0, 13.6 Hz, PhCH2), 1.98 (8H, m, CH2CH2-
C4F9 · 2), 1.31 (3H, d, J = 6.3 Hz, CH3); 13C NMR
(63 MHz, CDCl3): d 187.97 (C@S), 137.12, 129.34, 128.36,
126.59 (aromatic carbon), 78.59 (OCH), 51.71, 47.61

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M. Kojima et al. / Tetrahedron Letters 47 (2006) 6309–6314
(NCH2 · 2), 41.90 (PhCH2), 28.14 (t, J = 22.5 Hz,
25. Usually 80% MeOH aq is used to elute organic compounds
and then MeOH is used to elute light fluorous compounds
from the column. In the case of highly fluorinated
compounds, the column is eluted first with 80% MeOH
aq to get organic compounds and then Et2O or EtOAc is
used to elute the highly fluorinated compounds.
CH2C4F9 · 2) 19.04, 18.04 (CH2CH2C4F9 · 2), 18.94
(CH3); IR (NaCl, neat) m (cmÀ1): 2924, 2835, 1496, 1456,
1357, 1235, 1133, 1012, 880, 746, 719, 701.
24. Mukaiyama, T.; Hirano, N.; Nishida, M.; Uchiro, H.
Chem. Lett. 1996, 99–100.