N,N′-ditosylhydrazine: A convenient reagent for facile synthesis of diazoacetates

Article abstract of DOI:10.1021/ol701432k

A novel entry to the synthesis of diazoacetates is disclosed. A variety of diazoacetates were synthesized from the corresponding bromoacetates by treatment with N,N′-ditosylhydrazine in moderate to high yields. Ease of operation with the stable crystalline reagent as well as a short reaction time offer a useful alternative to the conventional methods.

Full text of DOI:10.1021/ol701432k

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3195-3197
N,N′-Ditosylhydrazine: A Convenient
Reagent for Facile Synthesis of
Diazoacetates†
Tatsuya Toma, Jun Shimokawa, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received June 18, 2007
ABSTRACT
A novel entry to the synthesis of diazoacetates is disclosed. A variety of diazoacetates were synthesized from the corresponding bromoacetates
by treatment with N,N -ditosylhydrazine in moderate to high yields. Ease of operation with the stable crystalline reagent as well as a short
′
reaction time offer a useful alternative to the conventional methods.
Diazocarbonyl compounds are useful in organic synthesis
because of their unique and powerful reactivities.1 Over the
past several decades, the synthetic utility of diazocarbonyl
compounds has been greatly expanded by the advent of such
important reactions as cyclopropanations,2 C-H insertion
reactions,3 Wolff rearrangements,4 etc.5 This expansion in
use is due mainly to the development of the appropriate metal
reagents, which offer improved chemoselectivity and ste-
reoselectivity, and in certain cases, high enantioselectivity.
We describe herein a novel synthetic method for the
preparation of a variety of diazoacetates from the corre-
sponding bromoacetates by treatment with N,N′-ditosylhy-
drazine and DBU.
To date, diazoacetates have been prepared mainly by
diazotransfer reactions with sulfonyl azides under basic
conditions (Scheme 1).6 However, this strategy calls for an
† This paper is dedicated to the memory of Professor Yoshihiko Ito whose
untimely death on December 23, 2006, was a great loss to the chemical
community in the world.
(1) For reviews, see: (a) Ye, T.; McKervey, M. A. Chem. ReV. 1994,
94, 1091. (b) Padwa, A.; Austin, D. Angew. Chem., Int. Ed. Engl. 1994,
33, 1797. (c) Doyle, M. P. Chem. ReV. 1986, 86, 919. (d) Doyle, M. P.;
McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds from Cyclopropanes to Ylides; Wiley-Interscience:
New York, 1998.
Scheme 1
(2) For a review of cyclopropanation, see: Lebel, H.; Marcoux, J.-F.;
Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977.
(3) (a) Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2003,
125, 8112. (b) For a recent review of C-H activation using diazo
compounds, see: Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003,
103, 2861.
(4) (a) Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc. 2003,
125, 13624. (b) For a review, see: Kirmse, W. Eur. J. Org. Chem. 2002,
2193.
(5) (a) Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223. (b)
Padwa, A. Chem. Commun. 1998, 1417. (c) Padwa, A.; Austin, D. J.;
Hornbuckle, S. F.; Price, A. T. Tetrahedron Lett. 1992, 33, 6427. (d) Padwa,
A.; Austin, D. J.; Hornbuckle, S. F. J. Org. Chem. 1996, 61, 63. (e) Kitagaki,
S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda, C.; Watanabe, N.;
Hashimoto, S.-I.; J. Am. Chem. Soc. 1999, 121, 1417.
appropriate activation of the acetate group such as aceto-
acetates for lowering the pKa of the methylene proton.7 A
(6) Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733.
10.1021/ol701432k CCC: $37.00
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need for removing the activating group under basic condi-
tions after the introduction of the diazo group precludes its
application to base-sensitive substrates.
various attempts with other sulfonylhydrazines, N,N′-di-
tosylhydrazine proved to be the best reagent with regard to
ease of handling, stability, and ease of preparation.11,12 The
use of other bases such as Et3N, i-Pr2NEt, N-methylmor-
pholine, pyridine, and K2CO3 did not give better results.
To examine the scope and limitations of this method, we
next investigated the diazoacetylation of a range of alcohols.
As shown in Table 1, various diazoacetates were synthesized
from the corresponding alcohols via the bromoacetates in
moderate to good yields. In the case of menthol, the yield
House and co-workers reported an alternative procedure,
which employs p-toluenesulfonylhydrazone of glyoxylic acid
chloride (1).8 While a one-pot conversion of an alcohol to
the corresponding diazoacetate can be performed with this
procedure, it takes two steps to prepare the reagent from
glyoxylic acid. Thus, we initiated efforts to develop a novel
method for the synthesis of diazoacetates from the corre-
sponding alcohols.
Table 1. Two-Step Diazoacetylation of Alcohols
Scheme 2
As illustrated in Scheme 2, in view of the ease of
elimination of a sulfonyl group as a sulfinic acid, we
envisioned the possibility of employing disulfonylhydrazine
3 as a precursor to the diazo group. Namely, elimination of
two molecules of sulfinic acid from 4 would lead to the
formation of diazoacetate 5.
In our initial studies, we employed a tosyl group due to
the availability of inexpensive p-toluenesulfonyl hydrazide
and p-toluenesulfonyl chloride. Much to our delight, 3-phen-
ylpropyl 2-bromoacetate (6) underwent a facile conversion
to the corresponding diazoacetate (8) upon treatment with
N,N′-ditosylhydrazine (7)9 and DBU at 0 °C (88% yield,
Scheme 3).10
Scheme 3
In an effort to optimize this novel transformation, we next
investigated a series of disulfonylhydrazines and bases. After
(7) Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone,
W. P.; Bagheri, V; Pearson M. M. J. Am. Chem. Soc. 1993, 115, 958. (b)
Regitz, M.; Hocker, J; Liedhegener, A. Organic Synthesis; Wiley: New
York, 1973; Collect. Vol. V, p 179. (c) Doyle, M. P.; Austin, R. E.; Bailey,
A. S.; Dwyer, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.;
Liras, S.; Oalmann, C. J.; Pieters, R. J.; Protopopova, M. N.; Raab, C. E.;
Roos, G. H. P.; Zhou, Q.-L.; Martin, S. F. J. Am. Chem. Soc. 1995, 117,
5763.
(8) (a) House, H. O.; Blankley, C. J. J. Org. Chem. 1968, 33, 53. (b)
Blankley, C. J.; Sauter, F. J.; House, H. O. Organic Synthesis; Wiley: New
York, 1973; Collect. Vol. V, p 258. (c) Corey and Myers reported the
improved modification of this procedure: Corey, E. J.; Myers, A. G.
Tetrahedron Lett. 1984, 25, 3559.
a Yields for the two steps after purification by column chromatography
on neutral silica gel. b Yield was low due to the volatile nature of the
product.
(9) Jennings, K. F. J. Chem. Soc. 1957, 1172.
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Org. Lett., Vol. 9, No. 16, 2007

of the diazoacetate was lower and formation of more
byproducts were observed, presumably due to the steric
hindrance exerted by the nearby isopropyl group (entry 10).
In addition, this protocol could be successfully applied to
the formation of a diazoketone when the R-bromomethyl
ketone was used as a substrate (Scheme 4).
Scheme 4
In conclusion, we have developed a general method for
synthesizing diazoacetates from the corresponding bromo-
acetates by treatment with N,N′-ditosylhydrazine and DBU.
Because of the ease of handling of the stable crystalline
reagent and the ready accessibility of a variety of bromo-
acetates from the corresponding alcohols, this method is
likely to find widespread use in organic synthesis.
(10) From the TLC analysis of the reaction mixture, we found a small
amount of a byproduct (<5%) which was characterized as sulfone 9, formed
by the nucleophilic attack of p-toluenesulfinic acid to the bromoacetate.
Acknowledgment. We are grateful for the Grant-in-Aid
(15109001 and 18890048) from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
(11) Attempts to prepare bis(2-nitrobenzenesulfonyl)hydrazine were
unsuccessful due to their decreased stability in the presence of a weak base
such as pyridine.
(12) N,N′-Ditosylhydrazine can be recrystallized easily from MeOH. It
is stable at room temperature and melts at 209 °C with decomposition. No
appreciable decomposition occurred after storage for 6 months at room
temperature.
Supporting Information Available: Experimental details
and spectroscopic data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
OL701432K
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