A new and efficient route toward the preparation of diazo ketones using cyanuric chloride and diazomethane

Article abstract of DOI:10.1016/S0040-4039(00)01791-3

A new method for the preparation of diazo ketones has been developed. 2,4,6-Trichloro-1,3,5-triazine (cyanuric chloride) has been found to be an excellent coupling reagent allowing for the efficient transfer of diazomethane to a carboxylic acid. Preparation of diazo ketones using carboxylic acids and triazine reagents is considerably more convenient than classical diazo transfer protocols because water does not have to be stringently removed and the entire procedure can be carried out in one-pot. Electron deficient and neutral aryl carboxylic acids were found to give better results than electron rich or aliphatic carboxylic acids. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01791-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9943–9947
A new and efficient route toward the preparation of diazo
ketones using cyanuric chloride and diazomethane
David C. Forbes,* Elvis J. Barrett, Derrick L. Lewis and Mary C. Smith
Department of Chemistry, University of South Alabama, Mobile, AL 36688-0002, USA
Received 9 October 2000; accepted 12 October 2000
Abstract
A new method for the preparation of diazo ketones has been developed. 2,4,6-Trichloro-1,3,5-triazine
(cyanuric chloride) has been found to be an excellent coupling reagent allowing for the efficient transfer
of diazomethane to a carboxylic acid. Preparation of diazo ketones using carboxylic acids and triazine
reagents is considerably more convenient than classical diazo transfer protocols because water does not
have to be stringently removed and the entire procedure can be carried out in one-pot. Electron deficient
and neutral aryl carboxylic acids were found to give better results than electron rich or aliphatic
carboxylic acids. © 2000 Elsevier Science Ltd. All rights reserved.
Since the first recorded synthesis of an a-diazocarbonyl compound by Curtius in 1883,1 the
diazo moiety has become a key component in a number of synthetic transformations.2
Diazocarbonyl compounds are extremely versatile and have been prominent in many catalytic
carbonꢀcarbon bond forming reactions. Most notable would be those involving cyclopropana-
tion, cyclopropenation, aromatic cycloaddition and ylide-type transformations.2b,3 The prepara-
tion of a-diazocarbonyl compounds can be accomplished by two main routes, derivatization of
existing diazoalkanes and diazo transfer processes using a sulfonyl azide (Fig. 1).2
derivatization
O
N2
O
N2
diazotization
H
H
Figure 1. Strategic methods for a-diazocarbonyl preparation
* Corresponding author. Fax: 334 460-7359; e-mail: dforbes@jaguar1.usouthal.edu
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01791-3

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Excluding cyclic derivatives, the most logical retrosynthetic disconnection of a-diazocarbonyl
compounds involves simple acylation of diazoalkane derivatives. Indeed the most popular
protocol involves the use of an acid chloride and diazomethane in excess. This route is
sometimes complicated by the presence of other functional groups in the molecule and thus
diazotization of the carboxylic acid via a mixed carbonic anhydride or an activated a-methylene
group flanked by an additional carbonyl derivative has also been used.2 As alternative synthetic
schemes are either circuitous or mandate the exclusion of water and typically involve two or
more steps using reagents of moderate to high cost, we began an investigation designed to find
a more convenient synthesis of these key compounds.
2,4,6-Trichloro-1,3,5-triazine (cyanuric chloride) has been reported as an efficient reagent in a
number of coupling processes involving the preparation of amides, esters and anhydrides.4 This
cost-effective reagent is amenable to large-scale processes with the only by-product being
insoluble hydroxytriazine. We have found, for the first time, that this reagent can be used in
conjunction with diazomethane for the preparation of diazo ketones in one-pot without the
exclusion of water. The need to either use or prepare moisture sensitive and perhaps expensive
compounds is completely circumvented with this new synthetic method.
Our investigation into the use of cyanuric chloride began when we found that classical acid
chloride and diazomethane protocols were unsuitable for the synthesis of a number of function-
alized diazo ketones. Although the yields were modest, we were delighted to observe the
feasibility of diazo ketone preparation using cyanuric chloride as promoter (Scheme 1). Using
sub-stoichiometric quantities of cyanuric chloride in the presence of carboxylic acid 1 and base
as a slurry in acetonitrile, diazocarbonyl compounds (3) are formed upon addition of ethereal
diazomethane.
O
Cl
O
N
R
O
O
O
CH2N2
Et2O
CH3CN
base
N
N
O
N
N
O
+
N2
R
R
OH
Cl
N
Cl
R
O
3
1
R = alkyl or aryl
R
2
Scheme 1.
We quickly realized that an evaluation of the reaction conditions employed was necessary.
Reaction conditions were optimized in terms of base, solvent, temperature, addition rate and
stoichiometry. Although tertiary amines were suitable bases in previous triazine-promoted
studies, the formation of a protonated tertiary amine would be problematic when working with
either diazo ketones or diazomethane.2,5,6 Using potassium carbonate (pKa=10.33)7 as the base
in the synthesis of diazoacetophenone (R=Ph, Scheme 1) improved the yield by 14% compared
to the same reaction with diisopropylethylamine (approx. pKa=10.5–11.0).8 The selection of
potassium carbonate is ideal because it: (1) insures a basic reaction medium; (2) can react with
the diazonium ion (pKa:−2)9 derived from diazoketone 3; and (3) forms innocuous by-products
of water and carbon dioxide in the presence of two equivalents of acid.
As was found in the amidation studies, the dipolar aprotic solvent acetonitrile was found to
be the best solvent.4 When issues of insolubility of the carboxylic acid were encountered, THF

9945
was used as co-solvent which resulted in no changes in overall yield (vide infra). Using water as
co-solvent with either benzoic acid or sodium benzoate, we were able to isolate diazoacetophe-
none in 35 and 29% yields, respectively. This illustrates a significant advantage with this
procedure. These examples provide a unique opportunity in the area of diazo ketone prepara-
tion where carboxylic acid derivatives that require the use of either an aqueous medium or are
extremely hydrophilic can be used without difficulty.
The reaction temperature prior to the addition of ethereal diazomethane also played an
important role. Using benzoic acid as the starting carboxylic acid, an optimal reaction
temperature of 0°C was observed. Listed below are the results obtained when changing the
reaction temperature prior to addition of diazomethane as a function of the percent isolated
yield of diazoacetophenone: 23% at 40°C, 48% at 25°C, 58% at 0°C and 18% at −10°C. The
mass balances for all the reactions surveyed were excellent (92–97%). In conjunction with diazo
ketone formation was isolation of the corresponding methyl ester. Interestingly, no change in the
ratio of diazo ketone to methyl ester was observed when performing the reactions under
anhydrous conditions. Formation of methyl ester could be attributed to either incomplete
addition of the carboxylic acid onto the triazine promoter due to solubility problems or
adventitious formation of an anhydride which is known to occur with triazine derivatives.10
Efforts to provide some insight into the identity of the intermediates responsible for this
coupling process via NMR were inconclusive; however, there does exist experimental evidence
supporting the formation of peracylated triazine intermediate 2 and not the corresponding acid
chloride (Scheme 1).4,10
We also observed, using benzoic acid, a moderate change in the isolated yield of diazo ketone
when an inverse addition of carboxylic acid and cyanuric chloride was performed, 46% yield
(inverse) versus 58% yield (standard). When the rate of addition (mL/min) of the carboxylic acid
solution increased, a drop in overall diazo ketone production was observed, 1 min addition (50%
yield) versus a 60 min addition (58% yield). Thus a slow addition of the carboxylic acid as a
solution in either THF or CH3CN was found to be superior to other modes of addition. No
improvements were observed when the addition was performed over more than 1 h.
The temperature and addition rate studies reveal a delicate balance between both processes of
diazo ketone and methyl ester formation. Optimal reaction conditions involved a slow addition
of the carboxylic acid as a solution in THF over 1 h to a rapidly stirring slurry consisting of
cyanuric chloride and potassium carbonate in CH3CN at 0°C. The use of a minimum of 2.0
equivalents of potassium carbonate and 2.7 equivalents of diazomethane resulted in higher
yields. This insured a basic medium which has been shown to give the best results in
diazotization protocols of carboxylic acid derivatives.6 With optimized conditions in hand, we
examined the scope and limitations of this new diazo ketone synthesis (Table 1).11
Table 1 reveals some interesting trends. First, aryl carboxylic acids (entries 1–5) were superior
to aliphatic carboxylic acids (entry 7). Numerous attempts using a variety of reaction conditions
with other aliphatic acids, e.g. hexanoic acid (entry 8), consistently resulted in very low yields of
the desired diazo ketone. Aryl derivatives such as picolinic (entry 4) and 2-naphthoic acid (entry
5) afforded the desired diazo ketone in good yield. Second, the efficiency of diazo ketone
formation was observed to be sensitive to changes in the electronic properties of the carboxylic
acid. Electron deficient (entries 1 and 2) or neutral (entry 3) aryl carboxylic acids were
significantly better candidates than their electron rich adducts. 4-Methoxybenzoic acid (entry 9)
afforded the desired diazocarbonyl compound in less than 10% yield. Here again, the methyl
ester was the main product isolated (82% yield). Interestingly, when 3,5-dinitrobenzoic acid was

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Table 1
Triazine-promoted diazo ketone preparation
Cl
O
O
O
CH3CN/THF
CH2N2
Et2O
0 oC - rt
+
+
N
N
N2
K2CO3
0 oC
R
OCH3
R
OH
R
Cl
N
Cl
1a-j
3a-j
4a-j
carboxylic acid
O
3:4b
entry
6
carboxylic acid
O
3:4b
3, %a
entry
1
3, %a
a,
OH
f,
OH
29
50
55:45
35:65
O2N
O
O
N
g,
h,
b,
c,
61:39
60:40
29
15
39:61
18:82
2
3
56
58
7
8
OH
OH
O
O
Cl
O
O
OH
H3C
OH
O
O
OH
OH
O
i,
d,
e,
4
66
67:33
14:86
9
<10
N
H3CO
O2N
O
OH
OH
j,
5
63
77:23
10
2:98
NO2
Isolated yields of chromatographically homogeneous spectroscopically pure products are reported. b Ratios were determined
using NMR analysis of the crude products.
a
used (entry 10), only a trace of the desired diazo ketone was isolated which indicates that
strongly electron deficient carboxylic acids are also not appropriate substrates. The third and
final observation involved sterics. Carboxylic acid derivatives without a-methylenes or deriva-
tives which are sterically robust, e.g. 2,2-dimethylpropanoic acid, resulted in no diazo ketone
formation.
In summary, a simple protocol has been developed that permits the transformation of aryl
carboxylic acid derivatives into diazocarbonyl compounds in good yield using cyanuric chloride
as promoter and diazomethane. This procedure can be carried out in water and is affected in
one-pot, which is a significant advantage over current methods. Efforts to understand the subtle
electronic and steric effects as well as the use of other carbon-based nucleophiles with this
technology are underway and will be reported in due course.

9947
Acknowledgements
We are grateful to the donors of the Petroleum Research Fund, administered by the American
Chemical Society, the Department of Chemistry and Research Council at the University of
South Alabama for support of this research.
References
1. (a) Curtius, T. Bericht 1883, 16, 2230. (b) Curtius, T. J. Prakt. Chem. 1888, 38, 396.
2. (a) Regitz, M.; Maas, G. Diazo Compounds, Properties and Synthesis; Academic Press: Orlando, 1986. (b) Doyle,
M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides; Wiley: New York, 1998.
3. Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911.
4. (a) Rayle, H. L.; Fellmeth, L. Org. Proc. Res. Dev. 1999, 3, 172 and references cited therein. (b) Kaminski, Z.
J.; Paneth, P.; Rudzinski, J. J. Org. Chem. 1998, 63, 4248.
5. Staudinger, H.; Gaule, A. Ber. Dtsch. Chem. Ges. 1916, 49, 1897.
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Oxford, 1982.
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9. For diazomethane: McGarrity, J. F.; Smyth, T. J. Am. Chem. Soc. 1980, 102, 7303. For diazonium derivatives:
McGarrity, J. F. The Chemistry of Diazonium and Diazo Groups; Patai, S., Ed.; Wiley: New York, 1978; Part 1,
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11. Typical procedure for the preparation of diazo ketones 3a–j: To a 125 mL Erlenmeyer flask containing a large
magnetic stir bar was added, in the following order, potassium carbonate (2.0 equiv.), anhydrous CH3CN (20
mL) and cyanuric chloride (0.4 equiv.). The flask was cooled externally with an ice bath (0°C) and after
approximately 5 min a solution of anhydrous THF (20 mL) containing the carboxylic acid (1.0 equiv.) was added
via syringe pump over a period of 1 h. The reaction mixture was kept at 0°C for a period of 2 h at which time
the contents of the reaction mixture slowly turned into a milky-white slurry. The reaction mixture was allowed
to stir for an additional 45 min at which time CH2N2 (2.7 equiv.) as a 0°C diethyl ether solution (50 mL) was
added in three equal portions. The ice bath containing the reaction mixture was packed with ice and allowed to
slowly warm to room temperature as it stirred overnight (approx. 12 h). The crude reaction mixture was
transferred to a larger flask (approx. 250 mL) and diluted with diethyl ether (total volume approx. 200 mL). The
yellow solution was filtered and concentrated in vacuo. The viscous oil was then immediately purified via silica
gel chromatography [hexane/EtOAc, 8/1, 30×60 mm SiO2, 10 mL fractions] to afford analytically pure diazo
ketone.
.
.