One-pot transformation of trichloroacetamide into readily deprotectable carbamates

Article abstract of DOI:10.1021/ol061123c

A trichloroacetamide group was converted to an isocyanate, which was in situ captured by a variety of alcohols in the presence of CuCl and n-BuN ₄Cl to afford the corresponding carbamates. The scope and limitation of this transformation are als

Full text of DOI:10.1021/ol061123c

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3263-3265
One-Pot Transformation of
Trichloroacetamide into Readily
Deprotectable Carbamates
Toshio Nishikawa,*,†,‡ Daisuke Urabe,† Miho Tomita,† Takashi Tsujimoto,‡
Tomoko Iwabuchi,† and Minoru Isobe*,†
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya
UniVersity, Chikusa, Nagoya 464-8601, Japan, and PRESTO, Japan Science and
Technology Agency (JST), Honcho 4-1-8, Kawaguchi, Saitama, 332-0012, Japan
nisikawa@agr.nagoya-u.ac.jp
Received May 8, 2006
ABSTRACT
A trichloroacetamide group was converted to an isocyanate, which was in situ captured by a variety of alcohols in the presence of CuCl and
n-BuN4Cl to afford the corresponding carbamates. The scope and limitation of this transformation are also described.
The rearrangement of allylic trichloroacetimidates into
trichloroacetamides (Overman rearrangement) has been
widely used for the synthesis of a variety of nitrogen-
containing compounds.1,2 Recent development of a catalytic
version of the asymmetric Overman rearrangement has
increased the importance.3 The resulting trichloroacetamides
have been deprotected under hydrolytic conditions with 4-6
N HCl or 6 N NaOH in hot ethanol and reductive conditions
with NaBH44 or DIBAL-H.5 However, in the early stages of
our synthetic studies on tetrodotoxin analogues, deprotection
of trichloroacetamide from our advanced intermediates was
extremely difficult under the precedent conditions because
of various sensitive functional groups in the substrates.6
Therefore, conventional procedures for guanidinylation of
amines could not be employed. To overcome the above
problem, we developed a new synthetic route of guanidines
from trichloroacetamides not through the unprotected amines;7
thus, trichloroacetamides were heated with benzylamine in
the presence of Na2CO3 to give benzylureas (Scheme 1),
Scheme 1
† Nagoya University.
‡ Japan Science and Technology Agency.
(1) Reviews on the Overman rearrangement: (a) Overman, L. E. Acc.
Chem. Res. 1980, 13, 218-224. (b) Ritter, K. In Houben-Weyl. Stereo-
selectiVe Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann,
E., Eds.; Thieme: Stuttgart, 1996; E 21, Vol. 9, pp 5677-5699. (c) Sato,
H.; Oishi, T.; Chida, N. J. Synth. Org. Chem. Jpn. 2004, 62, 693-704. (d)
Overman, L. E.; Carpentaer, N. E. Org. React. 2005, 66, 1-107.
(2) For improved conditions for facile Overman rearrangement, see:
Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem. 1998, 63,
188-192.
which were eventually transformed into dibenzylguanidinium
compounds. In fact, the method was successfully employed
in the total synthesis of 5,11-dideoxytetrodotoxin6 and 11-
deoxytetrodotoxin.8 We supposed that the benzylurea was
formed by addition of benzylamine to an isocyanate gener-
(3) (a) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125,
12412-12413. (b) Kirch, S. F.; Overman, L. E.; Watson, M. P. J. Org.
Chem. 2004, 69, 8101-8104.
(4) Weygand, F.; Frauendorfer, E. Chem. Ber. 1970, 103, 2437-2449.
(5) Oishi, T.; Ando, K.; Inomoya, K.; Sato, H.; Iida, M.; Chida, N. Org.
Lett. 2002, 4, 151-154.
10.1021/ol061123c CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/20/2006

ated from the trichloroacetamide under the conditions,9
although the intermediate had not been detected. We
anticipated that in situ trapping of the unstable isocyanate
with alcohol (ROH) instead of amine would afford the
corresponding carbamate.10 This report discloses realization
of the protective group transformation of trichloroacetamide
into several carbamates under mild conditions.
Table 1. Transformation of Trichloroacetamide to Carbamates
According to the synthesis of benzylurea, a key intermedi-
ate 111 for tetrodotoxin synthesis in this laboratory was heated
with benzyl alcohol (5 equiv) in the presence of Na2CO3 (2
equiv) under a reflux temperature of dry DMF12 to give
benzyl carbamate 2a in excellent yield (eq 1). Unfortunately,
the procedure was found not to be general for some other
alcohols such as trichloroethanol, tert-butyl alcohol, and
9-fluorenylmethanol (vide infra). Therefore, a more general
procedure was required for the transformation.
additive (equiv)
products
yield urea
CuCl n-Bu4NCl carbamate (%) 4 (%)
entry
ROH
1
2
3
4
5
6
7
8
BnOH
BnOH
BnOH
CCl3CH2OH
CH2dHCH2OH
t-BuOH
TMS-CH2CH2OH
9-fluorenyl-
methanol
2
2
0
2
2
2
2
2
2
0
2
2
2
2
2
2
2a Cbz
2a Cbz
2a Cbz
2b Troc
2c Alloc
2d Boc
2e Teoc
2f Fmoc
83
47
0
70
69
38
69
73
0
0
55a
0
0
22
0
0
a Dimethylurea was obtained as a byproduct in 28% yield.
same reaction in the absence of n-Bu4NCl gave a lower yield
of the product 2a (entry 2), while the reaction in the absence
of CuCl did not give the desired product, but gave urea 4 as
a major product (entry 3), indicating the importance of both
the additives (CuCl and n-Bu4NCl) in the addition of alcohol
to the isocyanate.
The above one-pot, two-step procedure allowed the
synthesis of a variety of carbamates as shown in Table 1;
addition of trichloroethanol, allyl alcohol, 2-(trimethylsilyl)-
ethanol and 9-fluorenylmethanol under the optimized condi-
tions gave the corresponding carbamates such as Troc-,
Alloc-, Teoc-, and Fmoc-protected amine (2b, 2c, 2e, and
2f) in good yields (entries 4, 5, 7, and 8). The reaction with
tert-butyl alcohol gave 38% of the desired Boc-protected
product 2d along with urea 4 in 22% yield, presumably due
to steric reasons (entry 6). It is worthwhile to note that the
procedure for eq 1 could not be applied to the synthesis of
2b, 2d, and 2f.
The generation of isocyanate 3 was confirmed by IR
spectra (2272 cm-1) of the crude product obtained from
heating trichlroroacetamide 1 with Na2CO3 (2.0 equiv) in
the absence of the alcohol. We then explored an alternative
condition that allowed addition of various alcohols to the
isocyanate generated from compound 1 in one pot. Consider-
able experimentation enabled us to find a satisfactory
condition, giving the carbamate 2a in a comparable yield
(Table 1). Thus, trichloroacetamide 1 was heated with
Na2CO3 (2.0 equiv) in DMF at the reflux temperature to give
isocyanate 3,13 which was directly treated at room temper-
ature with a large excess of benzyl alcohol (10 equiv)14 in
the presence of n-Bu4NCl (2.0 equiv) and CuCl (2.0 equiv)15
to furnish benzyl carbamate 2a in 83% yield (entry 1). The
(6) (a) Nishikawa, T.; Asai, M.; Ohyabu, N.; Yamamoto, N.; Isobe, M.
Angew. Chem., Int. Ed. 1999, 38, 3081-3084. (b) Asai, M.; Nishikawa,
T.; Ohyabu, N.; Yamamoto, N.; Isobe, M. Tetrahedron 2001, 57, 4543-
4558.
With the suitable conditions for the protective group
transformation in hand, we next examined some substrate
generality (Table 2).16 Trichloroacetamide 5 prepared from
the Overman rearrangement of geraniol underwent the above
transformation with benzyl alcohol to give the corresponding
benzyl carbamate 10 in 82% yield. The same transformation
of 6 and 7 in which trichloroacetamides were connected to
secondary carbons gave the corresponding benzyl carbamates
11 and 12 in 79% and 43% yield, respectively, along with
the corresponding symmetric urea in about 20% yield (entries
2 and 3). In the case of diacetone-D-glucose-derived substrate
8, the desired benzyl carbamate 13 was obtained in 77% yield
without the corresponding symmetric urea. When a similar
(7) (a) Yamamoto, N.; Isobe, M. Chem Lett. 1994, 2299-2302. (b)
Nishikawa, T.; Ohyabu, N.; Yamamoto, N.; Isobe, N. Tetrahedron 1999,
55, 4325-4340.
(8) Nishikawa, T.; Asai, M.; Isobe, M. J. Am. Chem. Soc. 2002, 124,
7847-7852.
(9) Atanassova, I. A.; Petrov, J. S.; Mollov, N. M. Synthesis 1987, 734-
736.
(10) In our recent report for a new deprotection of trichloroacetamide
with Cs2CO3 at 100 °C in DMF, we proposed that an isocyante produced
under the conditions would immediately react with the carbonate to give
the corresponding amine. See: Urabe, D.; Sugino, K.; Nishikawa, T.; Isobe,
M. Tetrahedron Lett. 2004, 45, 9405-9407.
(11) For synthesis of the key intermediate, see: Nishikawa, T.; Asai,
M.; Ohyabu, N.; Yamamoto, N.; Fukuda, Y.; Isobe, M. Tetrahedron 2001,
57, 3875-3883.
(12) Dry DMF was purchased as dehydrated DMF from Kanto Chemical
Co., Inc.
(13) In this specific case, the isocyanate 3 was detected on a silica gel
TLC plate.
(14) Excess of benzyl alcohol was indispensable to prevent the formation
of urea 4a as the byproduct.
(15) Duggan, M. E.; Imagire, J. S. Synthesis 1989, 131-132.
(16) (a) For preparation of 5, 6, and 7, see ref 2. (b) For preparation of
8, see: Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005,
433-436. (c) For preparation of 9, see the Supporting Information.
3264
Org. Lett., Vol. 8, No. 15, 2006

Scheme 2
Table 2. Protective Group Transformation of
Trichloroacetamides to Benzyl Carbamates
expected, the reaction of unprotected alcohol 20 gave cyclic
carbamate 21 in high yield. These results indicate that acetals
and silyl ethers are compatible with the conditions, while
neighboring alcohols and esters should be avoided in the
transformation.
In summary, we have developed a novel protective group
transformation of trichloroacetamide into a variety of car-
bamates via an isocyanate in one pot. Since the milder
deprotection procedures for the resulting carbamates have
been established,19 the present studies should increase the
utility of trichloroacetamide and, therefore, the importance
of the Overman rearrangement for the synthesis of nitrogen-
containing compounds having a variety of functional groups.
Acknowledgment. We thank Professor Y. Ichikawa
(Kochi University, Japan) for valuable discussions on the
chemistry of isocyanate. Financial support provided by
PRESTO of the Japan Science and Technology Agency
(JST), a Grant-in-Aid Scientific Research, Specially Pro-
moted Research (16002007) and the 21st century COE grant
from MEXT, and the Fujisawa Foundation is gratefully
acknowledged. We thank JSPS for a scholarship to D.U.
Elemental analyses were performed by Mr. S. Kitamura in
this departement, whom we thank.
a The reaction was carried out by heating 6 with Na2CO3 in the presence
of n-BuN4Cl followed by addition of benzyl alcohol at rt.
substrate 9 with a silyl ether derived from 8 was subjected
to the same reaction conditions, Cbz-protected amine 14 was
obtained in about 80% yield.
In sharp contrast, the corresponding pivaloate 15 exhibited
different reactivity (Scheme 2); when 15 was exposed to the
same reaction sequence, unprotected amine 17 was exclu-
sively obtained.17 In the reaction of the benzoate 16, amine
18 and urea 19 were obtained in 52% and 44% yields,
respectively. These amines might be formed through neigh-
boring group participation of the ester groups.18 Thus, the
proximate hydroxyl group of trichloroacetamide should be
protected not as an ester but as a silyl ether such as 9. As
Supporting Information Available: Preparation of sub-
strates 9, 15, 16, and 20, experimental procedure for eq 1,
typical experimental procedure exemplified for 1 to 2a, and
spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL061123C
(17) The pivaloyl and benzoyl groups did not migrate to the amino group.
The structures of these esters were confirmed by HMBC spectra.
(18) In the reaction of 15 and 16, amines 17 and 18 and urea 19 were
detected on silica gel TLC before addition of benzyl alcohol, CuCl, and
n-Bu4NCl.
(19) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; pp 503-550.
(b) Kocienski, P. J. Protecting Groups, 3rd ed.; Georg Thieme Verlag:
Stuttgart, 2000; pp 502-542.
Org. Lett., Vol. 8, No. 15, 2006
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