Nonmetal catalyzed insertion reactions of diazocarbonyls to acid derivatives in fluorinated alcohols

Article abstract of DOI:10.1021/ol102923h

The insertion reaction of diazocarbonyls to acids could be performed smoothly in fluorinated alcohols in the absence of metal catalyst. This new procedure allowed the chemoselective preparation of various functionalized compounds such as acyloxyesters, depsipeptides, and sulfonate, phosphonate, or boronate derivatives.

Full text of DOI:10.1021/ol102923h

ORGANIC
LETTERS
2011
Vol. 13, No. 4
692–695
Nonmetal Catalyzed Insertion Reactions
of Diazocarbonyls to Acid Derivatives
in Fluorinated Alcohols
ꢀ
Lidia Dumitrescu, Kaouther Azzouzi-Zriba, Daniele Bonnet-Delpon, and
Benoit Crousse*
ꢁ
Laboratoire BioCIS-CNRS, Faculte de Pharmacie, Univ. Paris-Sud,
rue J. B. Clement, F-92296 Chatenay-Malabry, France
ꢁ
^
benoit.crousse@u-psud.fr
Received December 2, 2010
ABSTRACT
The insertion reaction of diazocarbonyls to acids could be performed smoothly in fluorinated alcohols in the absence of metal catalyst. This new
procedure allowed the chemoselective preparation of various functionalized compounds such as acyloxyesters, depsipeptides, and sulfonate,
phosphonate, or boronate derivatives.
R-Acyloxy carbonyls are found as structural units in
many natural products and are also useful synthetic build-
ing blocks. Among them depsipeptides are interesting
classes of biopolymers (Figure 1). They show various
biological activities with antibacterial, antiviral, anti-
fungal, and anti-inflammatory properties,1 and some of
them are also efficient in cancer treatment.2 R-Acyloxy
ester motifs are obtained by several methods, generally by
treatment of acids with R-hydroxy,3 R-halogeno car-
bonyls4 or via the Passerini reaction.5 Another alternative
method whichislessdeveloped is the reaction of carboxylic
acids with diazocarbonyl compounds. However, the latter
are poorly reactive and harsh conditions are required:
a large excess of carboxylic acid used as solvent, high
temperature, and long reaction times.6,7 A few examples
of insertion into carboxylic acids under metal catalysis are
(4) (a) Wang, H.-W.; Liu, Z.-C.; Chen, C.-H.; Lim, T.-S.; Fann, W.;
Chao, C.-G.; Yu, J. Y.; Lee, S.-L.; Chen, C.-H.; Huang, S.-L.; Luh, T.-Y.
Chem.;Eur. J. 2009, 15, 5719. (b) White, J. D.; Jeffrey, S. C. Tetrahedron
2009, 65, 6642. (c) Drager, G.; Kiss, C.; Kunz, U.; Kirschning, A. Org.
Biomol. Chem. 2007, 5, 3657.
(5) (a) Berlozecki, S.; Szymanski, W.; Ostaszewski, R. Tetrahedron
2008, 64, 9780 and references cited therein. (b) Gulevich, A. V.; Shpilevaya,
I. V.; Nenajdenko, V. G. Eur. J. Org. Chem. 2009, 3801.
(6) (a) Smith, A. B., III; Dieter, R. K. Tetrahedron 1981, 37, 2407. (b)
Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091. (c) Miller, D. J.;
Moody, C. J. Tetrahedron 1995, 51, 10811.
(7) (a) Regitz, M.; Maas, G.; Diazo Compounds-Properties and
Synthesis; Academic Press: Orlando, 1986. (b) Maas, G. Angew. Chem.,
Int. Ed. 2009, 48, 8186 and references cited herein.
(1) (a) Hamada, Y.; Shioiri, T. Chem. Rev. 2005, 105, 4441. (b)
Sarabia, F.; Chammaa, S.; Sanchez Ruiz, A.; Martin Ortiz, L.; Lopez
Herrera, F. J. Curr. Med. Chem. 2004, 11, 1309. (c) Ballard, C. E.; Yu,
H.; Wang, B. Curr. Med. Chem. 2002, 9, 471. (d) Bartlett, P. A.; Otake,
A. J. Org. Chem. 1995, 60, 3107. (e) Li, W.; Gan, J.; Ma, D. Org. Lett.
2009, 11, 5694. (f) Barratt, B. J. W.; Easton, C. J.; Henry, D. J.; Li,
I. H. W.; Radom, L.; Simpson, J. S. J. Am. Chem. Soc. 2004, 126, 13306.
(2) Hamel, E.; Covell, D. G. Curr. Med. Chem. Anti-Cancer Agents
2002, 2, 19.
(3) (a) Nahrwold, M.; Bogner, T.; Eisler, S.; Verma, S.; Sewald, N.
Org. Lett. 2010, 12, 1064. (b) Franz, N.; Menin, L.; Klok, H.-A. Eur. J.
Org. Chem. 2009, 5390. (c) Xiao, Z.-Y.; Hou, J.-L.; Jiang, X.-K.; Li,
Z.-T.; Ma, Z. Tetrahedron 2009, 65, 10182. (d) Allais, F.; Martinet, S.;
Ducrot, P.-H. Synthesis 2009, 3571.
€
r
10.1021/ol102923h
Published on Web 01/19/2011
2011 American Chemical Society

We thus could investigate the reactivity of the system
fluorinated alcohol/diazoacetate with carboxylic acids.
When 1 equiv of BnCO2H 2a was added to the diazoace-
tate in HFIP or TFE, a reaction occurred to afford, after 4
and 10 h respectively, a single product 3a which corre-
sponds to the acid insertion on the diazo (Scheme 2). The
reaction is completely chemoselective. After distillation of
the solvent and purification, the product 3a was obtained
in good yield (80% (HFIP), 77% (TFE)). Interestingly,
when the reaction was performed in other solvents (diethyl
ether, dichloromethane, ethanol), no reaction occurred at
room temperature, and some traces of product appeared at
reflux after one day in ethanol. This revealed the unique
role of fluoro alcohols in the promotion of the reaction.
Figure 1. R-Acyloxy carbonyl motifs.
reported.8 However reactions required protection/
deprotection steps.
We report here a straightforward method which speci-
fically introduces acids on diazocarbonyl compounds by
using fluoroalkyl alcohols as solvents.
The specific physicochemical properties of fluorinated
alcohols as solvents (hexafluoro-2-propanol, HFIP; tri-
fluoroethanol, TFE) allowed us to facilitate many classical
reactions and to improve yields under mild conditions.9
Their high ability to donate a hydrogen bond and their
strong ionizing power allow for avoiding Lewis acid or
metal catalysis.9 Furthermore these fluoro alcohols facil-
itate reactions involving poor nucleophiles.10 For example
in HFIPassolvent, carboxylic acids can act asnucleophiles
for oxirane ring-opening reactions.11
Scheme 2. Insertion Reaction of 1 with Acid 2a
The reaction could be generalized to a wide range of
carboxylic acids (Table 1). Alkyl and aryl acids led to the
corresponding acetoxy esters (Table 1, entries 1-2). Func-
tionalized acids having hydroxyl groups and double bonds
reacted easily to afford the acetoxy acetate (Table 1, entries
3-7). This clearly demonstrates that the insertion of diazo
intoalcohol and a double bond is nota competitiveprocess
under these mild conditions. Another advantage of these
conditions is the compatibility with sensitive protective
groups. The insertion reaction with 1 and amino acids
protected with a Boc or an acyl group on the nitrogen
resulted in the formation of protected products 3i-3k in
very good yields (entries 9-11). The reaction with function-
alized amino acids was again chemoselective with no
insertion of the hydroxyl or the thiol observed (entries
12-13). Furthermore conditions are smooth avoiding any
epimerization of the amino acids. It is worth noting that
the reaction is as efficient in TFE as in HFIP albeit with a
longer reaction time in some cases. Consequently this
procedure allowed the easy and efficient access to depsi-
peptides under particularly mild conditions.
Scheme 1. Stability of the Ethyl Diazoacetate 1
First the reactivity and the stability of the ethyl dia-
zoacetate (EDA) 1 was evaluated in fluorinated alcohols
(TFE and HFIP). As a matter of fact, diazocompounds are
known to easily dimerize. Moreover, TFE and HFIP could
also behave as reagents and undergo insertion. Compound
1 was solubilized either in HFIP or in TFE. Whatever the
conditions, at room temperature or at reflux, no decom-
position, no dimerization, and no Wolff rearrangement
occurred (Scheme 1).6,7 In addition, fluorinated alcohols
were unreactive toward the diazocompound and no inser-
tion occurred even after one day. The diazo compound was
completely recovered.
In order to study the scope of the reaction, we investi-
gated the reaction with the disubstituted diazocarbonyl
derivative 412 (Table 1, entries 14-16). With all acids, the
reaction efficiently afforded corresponding acyloxyesters
in excellent yields. With amino acids, corresponding pro-
ducts were obtained in very good yields as a 1/1 mixture of
diastereomers.
(8) (a) Bertelen, S.; Nielsen, M.; Bachmann, S.; Jorgensen, K. A.
Synthesis 2005, 2234. (b) Vorob’eva, D. V.; Titanyuk, I. D.; Beletskaya,
I. P.; Osipov, S. N. Mendeleev Commun. 2005, 15, 222. (c) Shinada, T.;
Kawakami, T.; Sakai, H.; Takada, I.; Ohfune, Y. Tetrahedron Lett.
1998, 39, 3757.
In the polar OH insertion reactions, three mechanisms
are generally postulated (Scheme 3):6c,13 (a) a protonation
ꢁ
ꢁ
(9) (a) Begue, J. P.; Crousse, B.; Bonnet-Delpon, D. Synlett 2004, 18.
€
(b) Shuklov, I. A.; Dubrovina, N. V.; Borner, A. Synthesis 2007, 2925.
(10) (a) Das, U.; Crousse, B.; Kesavan, V.; Bonnet-Delpon, D.;
(12) Yu, W. Y.; Tsoi, Y. T; Zhou, Z. Y.; Chan, A. S. C. Org. Lett.
2009, 11, 469.
(13) For mechanism with diazomethane and TMSCH2N2 and car-
ꢁ
ꢁ
Begue, J. P. J. Org. Chem. 2000, 65, 6749. (b) De, K.; Legros, J.; Crousse,
B.; Bonnet-Delpon, D. J. Org. Chem. 2009, 74, 6260.
€
boxylic acids: Kuhnel, E.; Laffan, D. D. P.; Lloyd-Jones, G. C.;
ꢁ
(11) Iskra, J.; Bonnet-Delpon, D.; Begue, J. P. Eur. J. Org. Chem.
2002, 3402.
ꢁ
Martinez del Campo, T.; Shepperson, I. R.; Slaughter, J. L. Angew.
chem. 2007, 119, 7205.
Org. Lett., Vol. 13, No. 4, 2011
693

Table 1. Carboxylic Acids Insertions of Diazoacetates 1, 4a
Scheme 3. Mechanism Postulated
Table 2. Acid Reaction Insertion of Diazo Compounds 1, 4
a 1.2 equiv of 1 or 4. b 3.3 equiv of 1 or 4. c 2.2 equiv of 1 or 4.
the diazo, followed by the displacement of nitrogen by
a carboxylate.
These excellent results prompted us to extend the
reaction to noncarboxylic acids. Indeed there are
few reports of the insertion of sulfonic14 and phos-
phonic15 acids, and to our knowledge, no example
is reported with boronic acids. These various acidic
compounds could then be involved in the system
HFIP/diazo compound leading to sulfonate, phos-
phate, and boronate derivatives, respectively, in good
yields (Table 2).
a 2.2 equiv of 1.
of the diazo compound to give a diazonium ion which then
loses nitrogen; (b) a nucleophilic attack on the electrophilic
carbene to give an ylide, followed by hydrogen transfer;
and (c) a concerted insertion.
(14) For sulfonic acids: (a) Vedejs, E.; Engler, D. A.; Mullins, M. J. J.
Org. Chem. 1977, 42, 3109. (b) Collins, J. C.; Dilworth, B. M.; Garvey,
N. T.; Kennedy, M.; McKervey, M. A.; O’Sullivan, M. B. J. Chem. Soc.,
Chem. Commun. 1990, 362. (c) Ogawa, K.; Terada, T.; Muranaka, Y.;
Hamakawa, T.; Ohta, S.; Okamoto, M.; Fujii, S. Chem. Pharm. Bull.
Tokyo 1987, 35, 3276. (d) Hua, D. H.; Peacock, N. J.; Meyera, C. Y. J.
Org. Chem. 1980, 45, 1717. (e) Charlton, J. L.; Lai, H. K.; Lypka, G. N.
Can. J. Chem. 1980, 58, 458.
Since diazocompounds are stable in fluorinated
alcohols, pathways involving a previous departure
of nitrogen are unlikely. Consequently it is reasonable
to assume that the mechanism via the pathway a is more
acceptable. The fluorous alcohol through its excellent
hydrogen bond donor ability and its high ionizing
power would be expected to reinforce the acidity of
the carboxylic acid, thus favoring the protonation of
(15) For phosphonic acids: Bischofberger, N.; Waldmann, H.; Saito,
T.; Simon, E. S.; Lees, W.; Bednarski, M. D.; Whitesides, G. M. J. Org.
Chem. 1988, 53, 3457.
694
Org. Lett., Vol. 13, No. 4, 2011

In summary, we have described a practical procedure
for the free-catalyzed acid derivative insertion with ethyl
diazo acetate and methyl diazo phenylacetate. Due to the
high stability of diazoester compounds in fluorinated
alcohols (HFIP and TFE), the reaction is possible under
mild conditions to afford a wide range of R-acetoesters
and depsipeptides. Furthermore the insertion reaction
with noncarboxylic acids such as sulfonic, phosphonic,
and boronic acids led to new interesting sulfonate, phos-
phate, and boronate derivatives. The process was completely
chemoselective and required no specific treatment.
Acknowledgment. Central Glass Co. Ltd. is gratefully
acknowledged for kindly providing HFIP. Authors would
like to thank Pr. V. Gouverneur for fruitful discussions.
We thank the European Union (EU) within the EST
network BIOMEDCHEM (MEST-CT-2005-020580) for
a Ph.D. grant (to L.D.) and for financial support. Region
Ile-de-France is also acknowledged for support.
Supporting Information Available. Procedures and
compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 4, 2011
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