Cyanuric chloride: an efficient reagent for the Lossen rearrangement

Article abstract of DOI:10.1016/j.tetlet.2009.09.115

An efficient method for the Lossen rearrangement that uses 2,4,6-trichloro-1,3,5-triazine (TCT) as a promoter is reported. This procedure allowed the preparation of various carbamates, thiocarbamates, and ureas in good yields directly from the correspondi

Full text of DOI:10.1016/j.tetlet.2009.09.115

Tetrahedron Letters 50 (2009) 6800–6802
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cyanuric chloride: an efficient reagent for the Lossen rearrangement
*
Florian Hamon, Gildas Prié, Frédéric Lecornué, Sébastien Papot
Université de Poitiers, UMR-CNRS 6514, Synthèse et Réactivité des Substances Naturelles, 40, Av. du Recteur Pineau, F-86022 Poitiers, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2009
Revised 16 September 2009
Accepted 18 September 2009
Available online 24 September 2009
An efficient method for the Lossen rearrangement that uses 2,4,6-trichloro-1,3,5-triazine (TCT) as a pro-
moter is reported. This procedure allowed the preparation of various carbamates, thiocarbamates, and
ureas in good yields directly from the corresponding hydroxamic acids.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Lossen rearrangement
Cyanuric chloride
Hydroxamic acids
Isocyanates
2,4,6-Trichloro-1,3,5-triazine (cyanuric chloride, TCT)
1
Our initial efforts focused upon the preparation of the phenyl-
carbamic acid ethyl ester 3a directly from the commercially avail-
able benzohydroxamic acid 2a. Best results were obtained when 2a
reacted with 0.4 equiv of TCT 1 in the presence of an excess of
N-methylmorpholine (NMM, 2 equiv) in dichloroethane (DCE) at
(Scheme 1) is a very inexpensive commercially available reagent
making its use extremely attractive in organic synthesis.1 This
compound was widely employed as a starting point for the prepa-
ration of 2,4,6-mono, di- or tri-substituted triazine derivatives.
Recently, there has been a growth of interest in the use of cyanuric
chloride in a wide range of functional group transformations. For
instance, it has been shown that TCT can promote efficiently
carboxylic acid activation,2 Swern oxidation,3 Friedel–Crafts acyla-
tion,4 Beckman rearrangement,5 or glycosyl chlorination.6 Interest-
ingly, in most of these cases the use of TCT presented advantages
compared to other classical methods in terms of cost, yield, and
mildness. Thus, in the light of these results, the discovery of new
applications for TCT in organic synthesis is of interest.
The Lossen rearrangement is a useful chemical reaction in
which O-activated hydroxamic acids can be converted into the
corresponding isocyanates.7 However, although the Lossen trans-
formation has been known for more than one century,8 it has
received only little attention as a general synthetic method mainly
due to complicated experimental procedure and formation of
by-products.9,10
Cl
N
N
1
Cl
N
Cl
O
O
1) 1, NMM, DCE, 0 °C.
3: X = O
4: X = S
5: X = NH
R1
R2
OH
R1
N
2) R2XH, 0 °C to reflux.
N
X
H
H
2
Scheme 1. Lossen rearrangement promoted by TCT.
O
In this Letter, we report a new simple and efficient method for
the Lossen rearrangement employing TCT as a promoter (Scheme 1).
NH
O
Thus, we demonstrated that hydroxamic acids
2 can be
N
N
H
O-activated with a sub-stoichiometric quantity of 1 and then trans-
formed into the expected isocyanates which were subsequently
trapped in situ by various nucleophiles (R2XH) in the course of a
one-pot procedure (Table 1).
N
O
N
O
O
HN
O
6
* Corresponding author. Tel.: +33 549453862; fax: +33 549453501.
E-mail address: sebastien.papot@univ-poitiers.fr (S. Papot).
Scheme 2. Proposed tri-substituted triazine intermediate.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.115

F. Hamon et al. / Tetrahedron Letters 50 (2009) 6800–6802
6801
Table 1
Synthesis of carbamates, thiocarbamates and ureas from hydroxamic acids using TCT as a promoter
O
O
O
O
NHOH
NHOH
( )6
NHOH
O
NHOH
N
H
2a
2b
2c
2d (SAHA)
Entry
1
R1CONHOH
R2XH
R1NHCOXR2
Yield (%)
H
N
O
O
O
O
2a
87
84
81
77
OH
O
O
O
O
3a
H
N
2
3
4
2a
2a
2a
OH
3b
H
N
OH
3c
H
N
OH
SH
3d
H
N
S
5
6
2a
2a
73
99
O
O
4a
H
N
H
N
NH2
5a
H
N
H
N
NH2
7
8
2a
2a
2a
2b
2b
2c
2c
90
87
88
80
77
76
67
O
O
5b
H
H
N
NH2
N
5c
H
N
H
N
NH2
9
O
5d
H
N
H
N
NH2
10
11
12
13
O
O
5e
H
N
H
N
NH2
5f
O
O
NH2
N
H
N
H
5g
H
N
SH
S
4b
O
H
N
H
NH2
N
14
2d
73
( )6
N
H
O
5h

6802
F. Hamon et al. / Tetrahedron Letters 50 (2009) 6800–6802
O
1) 1, NMM, DCE, 0 °C.
NHOH
N
O
H
2) (-)-menthol, 0 °C to reflux.
O
2e
3e
Scheme 3. Stereospecific Lossen rearrangement.
0 °C. After 90 min under such conditions TLC analysis indicated to-
tal consumption of the starting hydroxamic acid together with the
clean formation of one less polar product. Since 1 has been intro-
duced in only sub-stoichiometric amounts, the structure of this
intermediate could be attributed to the tri-substituted triazine 6
(Scheme 2). Similar tri-substituted intermediates have been postu-
lated by some authors in the course of carboxylic acid’s activation
by TCT.2a,b However, it is worth mentioning here that the di-substi-
tuted triazine intermediate could also be formed in the reaction
media. Two equivalents of EtOH were then added at 0 °C and the
reaction mixture was refluxed overnight to afford carbamate 3a
in 87% yield (entry 1).
order to avoid the problems of phosgene-based approaches for
the preparation of isocyanates. Thus, it seems that this methodol-
ogy could be used as a valuable alternative to other known proce-
dures for the Lossen transformation.
General procedure: To a solution of hydroxamic acid (1 mmol) in
dichloroethane (3 mL) at 0 °C under nitrogen atmosphere, N-meth-
ylmorpholine (2 mmol) then TCT (0.4 mmol) were added and the
mixture was stirred during 90 min at 0 °C. The amine, alcohol, or
thiol (2 mmol) was then added and the reaction mixture was stir-
red during 15 h at 84 °C. The crude mixture was acidified with HCl
(0.1 N) and the solution was extracted with CH2Cl2 (twice) and
EtOAc. The organic layers were then combined, dried with MgSO4,
and concentrated under vacuum. The crude material was purified
by flash chromatography on silica gel (230–400 mesh) using petro-
leum ether and ethyl acetate as eluent.
It is worth mentioning here that other attempts with higher
quantities of TCT gave lower yields. Moreover, the addition of EtOH
at the beginning of the reaction or before the total consumption of
2a resulted in a complex mixture.
At this stage, we decided to pursue our investigations with other
nucleophiles including alcohols, thiols, and amines (Table 1). In the
course of these experiments, we obtained the corresponding carba-
mates 3b–d (entries 2–4), thiocarbamate 4a (entry 5), and ureas
5a–d (entries 6–9), respectively, in good to excellent yields (73–
99%) after purification by flash column chromatography.
References and notes
1. For a recent review see: Blotny, G. Tetrahedron 2006, 62, 9507–9522.
2. (a) Forbes, D. C.; Barret, E. J.; Lewis, D. L.; Smith, M. C. Tetrahedron Lett. 2000, 41,
9943–9947; (b) Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2002, 43,
3413–3414; (c) De Luca, L.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001, 66,
7907–7909; (d) Giacomelli, G.; Porcheddu, A.; Salaries, M. Org. Lett. 2003, 5,
2715–2717.
We examined next the Lossen rearrangement under the same
reaction conditions with the two commercially available hydroxa-
mic acids 2b and 2c as well as with the well known HDAC inhibitor
SAHA 2d.11 In all cases, the reaction provided the expected product
4 or 5 resulting from the trapping in situ of the corresponding iso-
cyanate by the nucleophile indicated in Table 1 (entries 10–14).
Interestingly, since our reaction conditions appeared to be compat-
ible with the presence of SAHA, this procedure may open a new
door for the synthesis of new analogues of this bioactive compound.
Finally, we investigated the stereo-chemical aspects of this
reaction. Indeed, previous studies showed that the Lossen rear-
rangement proceeds in a stereospecific manner with retention of
configuration of the migrating group.12 For this purpose, we first
prepared the novel hydroxamic acid 2e from the corresponding
chiral methyl ester in the presence of hydroxylamine (Scheme
3).13 When 2e was placed under the reaction conditions described
above, carbamate 3e was produced as a single diastereoisomer
without any detectable racemization of the stereogenic center at
the benzylic position hence demonstrating the stereospecificity
of this reaction.14 In this case, 3e was isolated in 40% yield after
purification by flash column chromatography.
3. De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2001, 66, 7907–7909.
4. Kangani, C. O.; Day, B. W. Org. Lett. 2008, 10, 2645–2648.
5. (a) De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 6272–
6274; (b) Furuya, Y.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2005,
127, 11240–11241; (c) Betti, C.; Landini, D.; Maia, A.; Pasi, M. Synlett 2008,
908–910.
6. Chang, C.-W.; Chang, S.-S.; Chao, C.-S.; Mong, K.-K. T. Tetrahedron Lett. 2009, 50,
4536–4540.
7. For a review see: Bauer, L.; Exner, O. Angew. Chem., Int. Ed. Engl. 1974, 13,
376–384.
8. Lossen, W. Liebigs Ann. Chem. 1872, 161, 347.
9. Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett. 2002, 41,
5291–5293.
10. Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E. M.; Feldman, P. L. J. Org.
Chem. 1998, 63, 10040–10044.
11. Krug, L. M.; Curley, T.; Schwartz, L.; Richardson, S.; Marks, P.; Chiao, J.; Kelly, W.
K. Clin. Lung Cancer 2006, 7, 257–261.
12. Bauer, L.; Miarka, S. V. J. Org. Chem. 1959, 24, 1293–1296.
13. Ho, C. Y.; Strobel, E.; Ralbovsky, J.; Galemmo, R. A. J. Org. Chem. 2005, 70,
4873–4875.
14. Composition of the crude product was analyzed by HPLC. Pure samples of
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (R)-1-phenylethylcarbamate 3e
and (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (S)-1-phenylethylcarbamate
were
prepared
by
coupling
either
(R)-(+)-
or
(S)-(À)-alpha-
methylbenzylamine with (À)-(1R)-menthylchloroformate according to
literature procedure and used as references.15 Analytical HPLC was carried
out using
Analyses were performed on
(SunFireTM, C18, 5
CH3CN/H2O 7/3 (+0.1% HCOOH). Retention times is for 3e and (1R,2S,5R)-2-
isopropyl-5-methylcyclohexyl (S)-1-phenylethylcarbamate were 6.18 and
5.83 min, respectively.
a
Waters 2695 System with UV variable wavelength detector.
In summary, we developed a simple and efficient method for
the Lossen rearrangement that uses the 2,4,6-trichloro-1,3,5-tri-
azine as a promoter. This procedure appeared to be general and
appropriate to the one-pot synthesis of a wide range of carba-
mates, thiocarbamates, and ureas directly from the corresponding
hydroxamic acids. Additionally, this procedure could be useful in
a
reverse phase column chromatography
lm, 1 Â 150 mm) using a mobile phase (0.5 mL/min) of
15. Serradeil-Albalat, M.; Roussel, C.; Vanthuyne, N.; Vallejos, J.-C.; Wilhelm, D.
Tetrahedron: Asymmetry 2008, 19, 2682–2692.