Diazo preparation via dehydrogenation of hydrazones with "activated" DMSO

Article abstract of DOI:10.1021/ol070515w

We report that "activated" dimethyl sulfoxide efficiently dehydrogenates hydrazones to the respective diazo species at -78°C. Under optimized conditions, triethylamine hydrochloride is removed quantitatively by vacuum filtration to provide solutions of diazo compounds. Stable diazo species can be isolated in high yield, or alternatively, the direct treatment of these solutions with carboxylic acids provides esters.

Full text of DOI:10.1021/ol070515w

ORGANIC
LETTERS
2
007
Vol. 9, No. 9
789-1792
Diazo Preparation via Dehydrogenation
of Hydrazones with “Activated” DMSO
1
Muhammad I. Javed and Matthias Brewer*
The UniVersity of Vermont, Department of Chemistry, 82 UniVersity Place,
Burlington, Vermont 05405
matthias.brewer@uVm.edu
Received February 28, 2007
ABSTRACT
We report that “activated” dimethyl sulfoxide efficiently dehydrogenates hydrazones to the respective diazo species at −78 °C. Under optimized
conditions, triethylamine hydrochloride is removed quantitatively by vacuum filtration to provide solutions of diazo compounds. Stable diazo
species can be isolated in high yield, or alternatively, the direct treatment of these solutions with carboxylic acids provides esters.
Diazo compounds have a rich history in organic synthesis
manipulations of the diazo solution. Herein, we wish to report
conditions for the preparation of diazo compounds via
dehydrogenation of hydrazones with “activated” DMSO.
In this operationally simple and mild method, solutions of
diazo compounds are easily isolated by simply filtering the
reaction mixture.
1
as carbene and carbenoid precursors, as components of 1,3-
2
10
dipolar cycloadditions, and as reagents for carbonyl ho-
3
4
mologation and acid esterification. In a small number of
cases, diazo compounds have been isolated from natural
5
sources. The preparation of diazo compounds is often
achieved by the dehydrogenation of hydrazones with stoi-
chiometric quantities of toxic heavy-metal salts (i.e., mer-
While conducting research on the conversion of N-
unsubstituted hydrazones to alkyl chlorides by treatment with
chlorodimethylsulfonium chloride, we noted that when
4,6-9
11
cury(II) oxide, lead(IV) acetate).
Not only are these
reagents hazardous and environmentally unfriendly, but the
isolation and purification of the resulting diazo product can
also be problematic and can involve potentially hazardous
benzophenone hydrazone was the substrate a short-lived and
localized red coloration would occasionally appear. We
reasoned that this red coloration might be due to the transient
formation of diphenyldiazomethane in the reaction mixture
and sought to develop this into a useful method for diazo
preparation. Our initial studies focused on preparing the
isolable and relatively stable diphenyldiazomethane (2,
Scheme 1) from commercially available benzophenone
hydrazone (1).
(
1) (a) Bethell, D.; Parker, V. D. Acc. Chem. Res. 1988, 21, 400-407.
b) Doyle, M. Acc. Chem. Res. 1986, 19, 348-356. (c) Padwa, A. J.
Organomet. Chem. 2001, 617, 3-16.
2) Mass, G. In Heterocyclic Compounds: 1,3-Dipolar Cycloaddition;
Padwa, A., Pearson, W. H., Eds.; John Wiley and Sons, Inc.: New York,
002; Vol. 59, pp 541-621.
3) (a) Gutsche, C. D. Org. React. 1954, 8, 364-429. (b) Maruoka, K.;
Concepcion, A. B.; Yamamoto, H. J. Org. Chem. 1994, 59, 4725-4726.
4) Regitz, M.; Mass, G. Diazo Compounds Properties and Synthesis;
Academic Press, Inc.: Orlando, 1986.
5) Laufer, R. S.; Dmitrienko, G. I. J. Am. Chem. Soc. 2002, 124, 1854-
855.
6) Heydt, H. In Science of Synthesis Houben-Weyl Methods of Molecular
(
(
2
(
When a solution of benzophenone hydrazone in CH
containing 2.1 equiv of triethylamine was added to a -78 °C
solution of chlorodimethylsulfonium chloride in CH Cl , the
2 2
Cl
(
(
2
2
1
(
color of the reaction immediately changed to dark red. IR
spectroscopy of this clear red solution showed the charac-
teristic diazo stretch. In an attempt to utilize the diazo
compound directly in an esterification reaction, excess
Transformations: Heteroatom Analogues of Aldehydes and Ketones, 5th
ed.; Padwa, A., Ed.; Thieme: Stuttgart, 2004; Vol. 27, pp 843-935.
(
7) Holton, T. L.; Shechter, H. J. Org. Chem. 1995, 60, 4725-4729.
(8) For recent nonheavy-metal-mediated hydrazone dehydrogenation
methods, see: (a) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004,
1
26, 12222-12223. (b) McGuiness, M.; Shechter, H. Tetrahedron Lett.
2
002, 43, 8425-8427.
(10) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480-2482.
(11) Brewer, M. Tetrahedron Lett. 2006, 47, 7731-7733.
(9) For a summary of other oxidants that effect this conversion but find
less use, see ref 7.
1
0.1021/ol070515w CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/05/2007

Scheme 1
Table 1. Yield of Diazo Compounds as Determined by Gas
Evolution Measurements
benzoic acid was added and the solution was warmed to room
temperature. The resulting product mixture contained diphe-
nylmethyl benzoate (3) and chlorodiphenylmethane (4) in a
5:1 ratio as determined by NMR. The reactions of diphenyl-
diazomethane with triethylamine hydrochloride and benzoic
acid were clearly competitive. We reasoned that alkyl
chloride formation might be suppressed by changing the
solvent to one in which triethylamine hydrochloride is
insoluble. This was ultimately realized by using THF as the
reaction solvent.12 Dropwise addition of a mixture of
benzophenone hydrazone and triethylamine in THF to a
solution of preformed chlorodimethylsulfonium chloride in
THF at -78 °C provided a red solution containing copious
amounts of white precipitate. Filtration of the cold solution
provided a clear red solution of diphenyldiazomethane and
1
3
a quantitative yield of solid triethylamine hydrochloride.
Addition of benzoic acid to the red solution and warming to
room temperature provided diphenylmethyl benzoate (3) in
8
3
8% yield after purification by chromatography; less than
% of chlorodiphenylmethane (4) was observed.
The yield of diazo compounds is difficult to establish due
As seen from the results in Table 1, gas evolution studies
show uniformly good yields for the formation of R-aryl diazo
18
compounds. Benzophenone hydrazone provided diphenyl-
diazomethane in 99% yield, whereas acetophenone hydra-
zone, benzaldehyde hydrazone, and 9-anthraldehyde hydra-
zone returned their respective diazo products in 97%, 87%,
and 88% yield. As observed in all previous methods of diazo
preparation, the yields of nonstabilized secondary and
primary R-alkyl diazo compounds were significantly lower.
For example, pivaldehyde hydrazone provided tert-butyl-
diazomethane in 51% yield. The yield of diazocyclohexane,
as determined by gas evolution experiments, was highly
variable with results ranging from 5% to 42% yield. We
attribute this variability to the instability of diazocyclohexane,
which we suspect decomposes during filtration.
to their high reactivity. Yields are most commonly estimated
either by conversion of the diazo compound to an isolable
ester on treatment with a carboxylic acid or by measuring
2
the volume of N gas evolved upon treatment of the diazo
solution with acid.1
4,15
Due to competitive side reactions
(azine formation, elimination reactions, etc.), neither of these
procedures is ideal, and the actual yield of the diazo
compound has been estimated to be as much as 20% higher
1
6
than the observed yield determined by these methods. In
our studies, we determined the yield of the diazo product
by both gas evolution17 (Table 1) and esterification (Table
2) methods.
(
12) The activation of DMSO with oxalyl chloride in THF was initially
Alternatively, stable diazo compounds were easily isolated
from the reaction mixture. For example, dehydrogenation of
benzil monohydrazone (5, Scheme 2) followed by a simple
extractive workup provided 2-diazo-1,2-diphenylethanone19
problematic. When DMSO was added to a precooled solution of oxalyl
chloride in THF, the DMSO solidified and only slowly dissolved and
reacted. This was circumvented by changing the order of addition: oxalyl
chloride was added to a cold solution of DMSO in THF.
(13) Caution: Diazo compounds are known to be explosive, and ground
(6) in 97% isolated yield. In the case of diphenyldiaz-
glass is thought to catalyze the explosive decomposition of diazomethane.
Although we had no explosions while working with these compounds,
suitable safety precautions were taken and all manipulations were conducted
behind safety blast shields.
(17) The apparatus and procedure we used to measure nitrogen gas
evolution was based on that described by: (i) Holton, T. C. The Synthesis
of Diazo Compounds by Low-Temperature Oxidation of Hydrazones with
Lead Tetraacetate. Ph.D. Thesis, The Ohio State University, 1971, 98-
102. (ii) McGuiness, M. J. Synthesis of Diazo Compounds with Azidotris-
(diethylamino)phosphodium Bromide. Ph.D. Thesis, The Ohio State
University, 1991, 242-245. (iii) Holton, T. C.; Shechter, H. J. Org. Chem.
1995, 60, 4725.
(
14) Smith, P. A. S. DeriVatiVes of Hydrazine and Other Hydronitrogens
HaVing N-N Bonds; The Benjamin/Cummings Publishing Co.: Reading,
MA, 1983.
(
15) Cheronis, N. D.; Ma, T. S. Organic Functional Group Analysis;
Interscience Publishers: New York, 1964.
16) Andrews, S. D.; Day, A. C.; Raymond, P.; Whiting, M. C. Organic
Syntheses; Coll. Vol. 6, p 392 (1988); Vol. 50, p 50 (1970).
(
(18) Pross, A.; Sternhell, S. Aust. J. Chem. 1970, 23, 989-1003.
1790
Org. Lett., Vol. 9, No. 9, 2007

Table 2. Isolated Yield of Esters Derived from Diazo
Scheme 3
Intermediates
2
1
4
-(benzyloxy)butyl benzoate (12). Ester 12 is likely derived
22
by solvent participation as shown in Scheme 3. Initial
protonation of phenyldiazomethane by benzoic acid would
provide the corresponding diazonium that could lose nitrogen
to provide benzylic cation 9. Reaction of THF with the
benzylic cation would provide oxonium ion 10, which in
turn would be attacked by the benzoate anion to provide ester
1
2. Solvent participation was also noted to a lesser extent in
the reaction of 1-phenyldiazoethane with benzoic acid. In
this case, 1-phenylethyl benzoate and 4-(1-phenylethoxy)-
butyl benzoate were isolated in a 16:1 ratio. On the basis of
these results, it appears that the degree of solvent participation
reflects the stability of the cation intermediate.
To circumvent the problem of solvent participation, we
sought an alternative reaction medium. The primary difficulty
in establishing a good solvent for diazo preparation lay in
balancing the solubility of chlorodimethylsulfonium chloride
to that of triethylamine hydrochloride. Ultimately, a 9:1
mixture of diethyl ether and dichloromethane provided the
right solvent characteristics, and no solvent participation was
noted in any of the esterification reactions shown in Table
omethane, simply removing the triethylamine hydrochloride
salt by filtration and removing the solvents in vacuo provided
diphenyldiazomethane20 in 99% yield as a viscous red oil
that solidified on cooling. Proton NMR of this material
showed only trace contaminants that were readily removed
by crystallization from pentane.
2
. Due to the high vapor pressures of diethyl ether and
dichloromethane, this solvent system did not provide repro-
ducible results in gas evolution measurements; all gas
evolution measurements were conducted using THF as
solvent.
Scheme 2
Subjecting benzylic hydrazones to the two-step process
of diazo formation and subsequent esterification with excess
benzoic acid provided good yields of benzoate esters. For
example, benzophenone hydrazone provided diphenylmethyl
Table 2 shows the yields of benzoate esters obtained for
the two-step sequence of diazo formation and subsequent
reaction with excess benzoic acid. Interestingly, treating the
THF solution of phenyldiazomethane (8, Scheme 3) with
benzoic acid returned a mixture of the expected benzyl
benzoate (11) in 40% yield and an additional 20% yield of
2
3
benzoate in 88% yield, whereas benzaldehyde hydrazone
(
21) Suzuki, T.; Ohashi, K.; Oriyama, T. Synthesis 1999, 1561-1563.
13
The C NMR data for this compound are identical to those described in
the literature. The H NMR data are also identical except for the chemical
1
shift of one set of protons that appears to have been reported in error. We
observed the methylene protons on the carbon bearing the ester as a triplet
at 4.38 ppm. We believe the reported shift of 4.85 ppm is in error as it is
presented out of numerical order in the original publication.
(22) Song, F. H.; Darbeau, R. W.; White, E. H. J. Org. Chem. 2000, 65,
1825-1829.
(
19) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem.
Soc. 2004, 126, 5192-5201.
20) Smith, L. I.; Howard, K. L. Organic Syntheses; Coll. Vol. 3, p 351
1955); Vol. 24, p 53 (1944).
(
(23) Strazzolini, P.; Giumanini, A. G.; Verardo, G. Tetrahedron 1994,
50, 217-254.
(
Org. Lett., Vol. 9, No. 9, 2007
1791

and 9-anthraldehyde hydrazone provided benzyl benzoate24
and 9-anthracenylmethyl benzoate in 75% and 90% yield,
respectively. Acetophenone hydrazone provided a mixture
of 1-phenylethyl benzoate24 and styrene in 61% and 13%
yield. Unstabilized alkyl diazo compounds are typically not
synthetically useful in esterification reactions due to their
high acid lability and propensity to undergo elimination or
Acknowledgment. We thank John Greaves (University
of California, Irvine) for obtaining mass spectral data on
9-anthracenylmethyl benzoate. Financial support from the
University of Vermont is gratefully acknowledged. Support
from the Vermont Experimental Program to Stimulate
Competitive Research (grant no. EPS0236976) is gratefully
acknowledged. Amgen is gratefully acknowledged for fi-
nancial support of this research in the form of an Amgen
new faculty award. The project described was supported by
the Vermont Genetics Network through Grant No. P20
RR16462 from the INBRE Program of the National Center
for Research Resources (NCRR), a component of the
National Institutes of Health (NIH). Its contents are solely
the responsibility of the authors and do not necessarily
represent the official views of the NCRR or NIH.
4
rearrangement reactions. Not surprisingly, our attempts to
isolate esters derived from unstabilized alkyl diazo com-
pounds returned little to no product. Cyclohexanone hydra-
2
5
zone provided only 4% yield of cyclohexyl benzoate,
whereas pivaldehyde hydrazone failed to yield any neopentyl
benzoate.
The dehydrogenation of hydrazones with activated DMSO
in the presence of at least two equivalents of triethylamine
offers a new method for the synthesis of diazo compounds.
Significantly, this method avoids the use of the toxic heavy-
metal salts used in previous diazo preparations. A simple
filtration provided R-aryl diazo compounds in high yields
as determined by gas evolution measurements and esterifi-
cation reactions.
Supporting Information Available: Complete experi-
mental details for the preparation of diazo compounds, the
formation of esters from diazo compounds, and the method
used to determine yield based on gas evolution and spec-
troscopic data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
(
24) Chen, C. T.; Munot, Y. S. J. Org. Chem. 2005, 70, 8625-8627.
25) Werner, T.; Barrett, A. G. M. J. Org. Chem. 2006, 71, 4302-4304.
OL070515W
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Org. Lett., Vol. 9, No. 9, 2007