Diazo-transfer reactions to 1,3-dicarbonyl compounds with tosyl azide

Article abstract of DOI:10.1055/s-0030-1260107

A practical protocol for the large-scale preparation of 2-diazo-1,3-dicarbonyl compounds is described by diazo-transfer reactions with tosyl azide followed by efficient chromatographic purifications on silica gel and/or alumina. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0030-1260107

PRACTICAL SYNTHETIC PROCEDURES
2549
Diazo-Transfer Reactions to 1,3-Dicarbonyl Compounds with Tosyl Azide
D
iazo-Transfer Reactio
a
ns with To
r
syl
A
zid
c
e
Presset, Damien Mailhol, Yoann Coquerel,* Jean Rodriguez*
Institut des Sciences Moléculaires de Marseille, iSm2-UMR CNRS 6263, Aix-Marseille Université,
Centre Saint-Jérôme, Service 531, 13397 Marseille Cedex 20, France
Fax +33(4)91289187; E-mail: yoann.coquerel@univ-cezanne.fr; E-mail: jean.rodriguez@univ-cezanne.fr
Received 18 May 2011
PSP
No205
Abstract: A practical protocol for the large-scale preparation of 2-diazo-1,3-dicarbonyl compounds is described by diazo-transfer reactions
with tosyl azide followed by efficient chromatographic purifications on silica gel and/or alumina.
Key words: diazo compounds, ketones, esters, Regitz reaction, chromatography
N2
1) TsN3, base
r.t., 1–13 h
O
O
O
O
no contamination
by TsNH2
2) SiO2 and/or Al2O3
chromatography
up to 94% (40 g scale)
Scheme 1 Practical, large-scale preparation of 2-diazo-1,3-dicarbonyl compounds
Sequential multiple bond-forming transformations when compared to other diazo-transfer reagents. More re-
(MBFTs), which include consecutive and domino multi- cently, imidazole-1-sulfonyl azide hydrochloride
component reactions (MCRs),1 allow the preparation of (HCl⋅Im-SO2N3) has advantageously been introduced as
diverse and sometimes impressively complex molecules an efficient reagent for diazo-transfer reactions to primary
in a single chemical operation. Some families of densely amines (when compared to the standard trifluoromethane-
functionalized small organic molecules are well suited for sulfonyl azide, TfN3),12 but its efficiency in diazo-transfer
use in these reactions. In connection with our program on reactions to activated methylene compounds is moderate.
the use of 1,3-dicarbonyl compounds in MBFTs,2 we have Even more recently, 2-azido-1,3-dimethylimidazolinium
recently introduced acylketenes obtained by microwave- chloride (ADMC) revealed as an effective diazo-transfer
assisted Wolff rearrangement3 of 2-diazo-1,3-diketones as reagent to activated methylene compounds.13a This new
particularly valuable substrates in domino MCRs.4
reagent is not sulfonyl azide-based, thus avoiding the pu-
rification problems associated with the formation of the
corresponding sulfonylamide co-product, but due to its
hygroscopic character the reagent must be prepared in situ
immediately before use. The corresponding 2-azido-1,3-
dimethylimidazolinium hexafluorophosphate (ADMP)
was also prepared, and found less hygroscopic and easier
to handle.13b
Diazo compounds are commonly used in organic
synthesis5 and new methods for their preparation are con-
stantly being developed.6 In the case of compounds bear-
ing an active methylene, the Regitz reaction7 using p-
toluenesulfonyl azide (TsN3) as the diazo-transfer reagent
remains the most efficient approach despite it being ham-
pered by potential hazard8 and purification problems to re-
move the p-tosylamide co-product. Several alternative In the past few years, we have repeatedly prepared in our
diazo-transfer reagents have been proposed to circumvent laboratory several 2-diazo-1,3-dicarbonyl compounds
these problems (Figure 1). For example, methanesulfonyl from the corresponding 1,3-dicarbonyl compounds
azide (MsN3)9 and p-acetamidobenzenesulfonyl azide (p- (Table 1). Representative diazo-transfer reagents were
ABSA)10 have been found efficient complementary re- tested, and it was found that TsN3 combined with efficient
agents but with similar purification issues. A polystyrene- chromatographic purification on silica gel and/or alumina
supported benzenesulfonyl azide (PS-SO2N3)11 has been gave the most satisfactory and reproducible results
proposed as a safer alternative to TsN3, which also solved (Scheme 1). The diazotation reactions of cyclohexan-1,3-
the purification problem by elimination of the polysty- diones 1a and 1b served as model reactions. In early trials
rene-supported benzenesulfonamide co-product by sim- with TsN3 as the diazo-transfer reagent under standard
ple filtration, but the cost of the reagent is prohibitive conditions (Table 1, entry 1), the corresponding diazo
compound 2a was always contaminated with p-tosyl-
amide (ca. 10–20%) following silica gel chromatography.
After optimization of the purification procedure, it was
found that iterative short chromatography on first silica
SYNTHESIS 2011, No. 16, pp 2549–2552
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260107; Art ID: Z52211SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

2550
M. Presset et al.
PRACTICAL SYNTHETIC PROCEDURES
O
S
O
S
O
N3
Me
N3
HN
O
S
N3
O
O
O
TsN3
MsN3
p-ABSA
N3
X
O
S
O
S
HCl⋅
N
N
N3
N3
Me
Me
N
N
O
O
HCl⋅Im-SO2N3
PS-SO2N3
ADMC (X = Cl)
ADMP (X = PF6)
Figure 1 Representative diazo-transfer reagents
gel (500 g) and then basic alumina (250 g) could solve this reaction with PS-SO2N3 afforded 2a in excellent yield and
problem and allow the isolation of pure 2a with 90% yield without purification problem, but the cost of PS-SO2Cl
on a 40-gram scale. For comparison purpose, the results of precluded its utilization on a 40-gram scale in our labora-
diazo-transfer reactions to 1a or 1b with p-ABSA, PS- tory, and HCl⋅Im-SO2N3 was found less efficient, while p-
SO2N3, HCl⋅Im-SO2N3, and ADMP are also given in ABSA14 and ADMP13b were reported to give lower yields
Table 1 (entries 2–4 and 6, respectively). In our hands, the of 2a and 2b, respectively. Similar conditions were ap-
Table 1 Diazo-Transfer Reactions
Entry
Substrate
Conditions
Product
Yield (%)
90
N2
O
O
O
O
1
TsN3 (1 equiv), K2CO3 (1.1 equiv), MeCN, r.t.
1a
1a
2a
2a
2
3
4
p-ABSA (0.81 equiv), KF (6 equiv), CH2Cl2, r.t.
PS-SO2N3 (1 equiv), Et3N (1.1 equiv), MeCN, r.t.
HCl⋅Im-SO2N3 (1.2 equiv), K2CO3 (5 equiv), MeCN, r.t.
76a
97
36
1a
1a
2a
2a
N2
O
O
O
O
5
TsN3 (1 equiv), K2CO3 (1.1 equiv), MeCN, r.t.
94
1b
1b
2b
2b
6
7
ADMP (1.2 equiv), Et3N (2 equiv), 0 °C, MeCN–THF (1:4)
TsN3 (1 equiv), Et3N (1.1 equiv), MeCN, r.t.
86b
86c
N2
O
O
O
O
1c
2c
O
O
O
O
8
9
TsN3 (1 equiv), K2CO3 (1.1 equiv), MeCN, r.t.
TsN3 (1 equiv), K2CO3 (1.1 equiv), MeCN, r.t.
83d
90e
N2
1d
2d
O
O
O
O
OMe
OMe
N2
1e
2e
a Ref. 14.
b Ref. 13b.
c Yield not reported in ref. 15 and citing papers.
d Yield 83% with ADMP in ref. 13b, and 70% with TsN3 in ref. 16.
e Yield 92% with p-ABSA in ref. 17.
Synthesis 2011, No. 16, 2549–2552 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Diazo-Transfer Reactions with Tosyl Azide
2-Diazodimedone (2b)
2551
plied to the representative 1,3-diketones 1c and 1d, and
the 1,3-keto ester 1e, which allowed the isolation of the
corresponding 2-diazo compounds 2c–e in good yields
following SiO2 and/or Al2O3 chromatography without de-
tectable contamination by p-tosylamide (by 1H NMR).
A 500 mL round-bottomed flask equipped with an adequate stirring
bar was charged with dimedone (1b; 36.4 g, 0.26 mol) and MeCN
(150 mL). Tosyl azide (51.2 g, 0.26 mol) and K2CO3 (39.5 g, 0.29
mol) were successively added and the mixture was stirred for 13 h
at r.t. The mixture was filtered through a pad of silica gel (rinsed out
with CH2Cl2) and concentrated under vacuum to give the crude
product. Purification of this material by flash chromatography (2 ×
500 g of SiO2 eluting with 2:8 EtOAc–PE) afforded 40.4 g (94%) of
2b as a white-greenish solid, which should be stored at ca. +4 °C;
mp 104–107 °C (amorphous) [Lit.18 mp 108 °C (i-PrOH)]; Rf = 0.58
(4:6 EtOAc–PE).
In conclusion, despite efforts to discover an ideal diazo-
transfer reagent, multigram-scale syntheses of 2-diazo-
1,3-dicarbonyl compounds are still very competitively
performed with tosyl azide, and the problem of p-tosyl-
amide contamination can be solved by short chromato-
graphic purifications on silica gel and/or alumina.
1H NMR (300 MHz, CDCl3): d = 2.34 (s, 4 H), 1.02 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 189.5 (2 C), 83.3 (C), 50.2 (2
CH2), 30.8 (C), 28.1 (2 CH3).
Caution! Azide reagents are potentially hazardous.8
Reactions were generally carried out under an argon atmosphere.
All reagents and solvents were used as received from commercial
sources. Anhyd solvents were obtained from an automated solvent
purification system. TLC analyses were performed on Merck
60F254 plates and visualized under UV (254 nm) or with p-anisal-
dehyde and H2SO4 in EtOH. Flash chromatography was performed
with Merck 40–63 mm silica gel, and/or Merck 63–200 mm basic
Al2O3 90, and/or Merck 63–200 mm neutral Al2O3 90. Petroleum
ether (PE) refers to the fraction with the boiling range 40–65 °C.
NMR data were recorded on a Bruker Avance 300 spectrometer in
CDCl3. Chemical shifts are given in ppm using as internal standards
the residual CHCl3 signal for 1H NMR (d = 7.26 ppm) and the deu-
terated solvent signal for 13C NMR (d = 77.0 ppm).
2-Diazocyclopentane-1,3-dione (2c)
A 100 mL round-bottomed flask, protected from sunlight with alu-
minum foil, equipped with an adequate stirring bar was charged
with cyclopentane-1,3-dione (1c; 1.47 g, 15 mmol) and MeCN (5
mL). Tosyl azide (2.96 g, 15 mmol) and Et3N (2.30 mL, 16.5 mmol)
were successively added and the mixture was stirred for 4 h at r.t.
The mixture was concentrated under vacuum to give the crude prod-
uct. Purification of this material by flash chromatography (250 g of
neutral Al2O3, eluent: 4:6 EtOAc–PE) afforded 1.59 g (86%) of 2c
as a yellowish solid, which should be protected from light and
stored at ca. –25 °C; mp 63–64 °C (amorphous) (Lit.15 mp 64–66
°C) Rf = 0.25 (4:6 EtOAc–PE).
1H NMR (300 MHz, CDCl3): d = 2.74 (s, 4 H).
13C NMR (75 MHz, CDCl3): d = 193.0 (2 C), 33.9 (2 CH) (C=N2
not detected).
Tosyl Azide (TsN3)
This procedure is a slight modification of Regitz’s procedure.7d In a
1 L Erlenmeyer flask equipped with an adequate magnetic stirring
bar, NaN3 (38.9 g, 0.60 mol) was dissolved in H2O (100 mL) and
then diluted with acetone (100 mL). In a 500 mL Erlenmeyer flask,
p-tosyl chloride (103.7 g, 0.54 mol) was dissolved in acetone (500
mL), and this solution was added to the former. The resulting mix-
ture was stirred at r.t. for 2 h, concentrated under vacuum, and trans-
ferred to a separatory funnel containing H2O (300 mL). The
biphasic solution was shaken vigorously, decanted, and the collect-
ed organic layer was dried (Na2SO4), filtered, and placed under high
vacuum to afford 96.0 g (89%) of TsN3 as a colorless oil, which
should be stored at ca. +4 °C.
2-Diazoacetylacetone (2d)
A 250 mL round-bottomed flask equipped with an adequate stirring
bar was charged with acetylacetone (1d, 10.0 mL, 97.4 mmol) and
MeCN (90 mL). Tosyl azide (19.2 g, 97.4 mmol) and K2CO3 (14.8
g, 107.1 mmol) were successively added and the mixture was stirred
for 1 h at r.t. The mixture was then filtered through a pad of Celite
(rinsed out with CH2Cl2) and concentrated under vacuum to give the
crude product. Purification of this material by flash chromatography
(first on 125 g of SiO2 eluting with 3:7 EtOAc–PE, and then on 250
g of basic Al2O3 eluting with 3:7 EtOAc–PE) afforded 10.2 g (83%)
of 2d as a yellow oil, which should be stored at ca. +4 °C; Rf = 0.24
(2:8 EtOAc–PE).
1H NMR (300 MHz, CDCl3): d = 7.79 (d, J = 8.3 Hz, 2 H), 7.37 (d,
J = 8.3 Hz, 2 H), 2.43 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 146.1 (C), 135.2 (C), 130.1 (2
1H NMR (300 MHz, CDCl3): d = 2.32 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 187.9 (2 C), 84.3 (C), 28.1 (2
CH3).
CH), 127.2 (2 CH), 21.4 (CH3).
2-Diazocyclohexane-1,3-dione (2a)
A 500 mL round-bottomed flask equipped with an adequate stirring
bar was charged with cyclohexane-1,3-dione (1a; 36.4 g, 0.32 mol)
and MeCN (150 mL). Tosyl azide (64.0 g, 0.32 mol) and K2CO3
(49.3 g, 0.36 mol) were successively added and the mixture was
stirred for 13 h at r.t. The mixture was then filtered through a pad of
silica gel (rinsed out with CH2Cl2) and concentrated under vacuum
to give the crude product. Purification of this material by flash chro-
matography (first on 500 g of SiO2 eluting with 2:8 EtOAc–PE, and
then on 250 g of basic Al2O3 eluting with 2:8 EtOAc–PE) afforded
40.4 g (90%) of 2a as a yellowish solid, which should be stored at
ca. –25 °C; mp 48–49 °C (amorphous) [Lit.14 mp 48–49 °C (Et2O)];
Rf = 0.37 (3:7 EtOAc–PE).
Methyl 2-Diazoacetylacetate (2e)
A 250 mL round-bottomed flask equipped with an adequate stirring
bar was charged with methyl acetoacetate (1e; 10.0 mL, 92.7 mmol)
and MeCN (90 mL). Tosyl azide (18.3 g, 92.8 mmol) and K2CO3
(14.1 g, 102.0 mmol) were successively added and the mixture was
stirred for 1 h at r.t. The mixture was then filtered through a pad of
Celite (rinsed out with CH2Cl2) and concentrated under vacuum to
give the crude product. Purification of this material by flash chro-
matography (first on 125 g of SiO2 eluting with 1:9 EtOAc–PE, and
then on 250 g of basic Al2O3 eluting with 2:8 EtOAc–PE) afforded
11.9 g (90%) of 2e as a yellow oil, which should be stored at ca. +4
°C; Rf = 0.52 (2:8 EtOAc–PE).
1H NMR (300 MHz, CDCl3): d = 2.50 (t, J = 6.4 Hz, 4 H), 2.03–
1.95 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 190.2 (2 C), 84.7 (C), 36.6 (2
CH2), 18.4 (CH2).
1H NMR (300 MHz, CDCl3): d = 3.73 (s, 3 H), 2.36 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 189.6 (C), 161.5 (C), 75.8 (C),
51.9 (CH3), 27.8 (CH3).
Synthesis 2011, No. 16, 2549–2552 © Thieme Stuttgart · New York

2552
M. Presset et al.
PRACTICAL SYNTHETIC PROCEDURES
(5) Reviews: (a) Zhang, Z.; Wang, J. Tetrahedron 2008, 64,
6577. (b) Doyle, M. P.; Ye, T.; McKervey, M. A. Modern
Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley: New York, 1998.
(6) Maas, G. Angew. Chem. Int. Ed. 2009, 48, 8186.
(7) (a) Regitz, M. Tetrahedron Lett. 1964, 1403. (b) Regitz, M.
Angew. Chem., Int. Ed. Engl. 1967, 6, 733. (c) Regitz, M.
Synthesis 1972, 351. (d) Regitz, M.; Hocker, J.;
Liedhegener, A. Org. Synth. Coll. Vol. 5; Wiley: New York,
1973, 183.
(8) Explosive decompositions of TsN3 have been reported at
temperatures above 120 °C in: Hazen, G. G.; Weinstock, L.
M.; Connell, R.; Bollinger, F. W. Synth. Commun. 1981, 11,
947.
(9) Taber, D. F.; Ruckle, R. E. Jr.; Hennessy, M. J. J. Org.
Chem. 1986, 51, 4077.
Acknowledgment
M.P. thanks the ENS Cachan for a fellowship award. Financial sup-
port from the Agence Nationale pour la Recherche (A.N.R. 07-
BLAN-0269), the French Research Ministry, Université Aix-
Marseille, and the CNRS is gratefully acknowledged.
References
(1) For efforts to clarify the terminologies of MBFTs, see:
(a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Eng.
1993, 32, 131. (b) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(c) Domino Reactions in Organic Synthesis; Tietze, L. F.;
Brasche, G.; Gericke, K. M., Eds.; Wiley-VCH: Weinheim,
2006. (d) Multicomponent Reactions; Zhu, J.; Bienaymé, H.,
Eds.; Wiley-VCH: Weinheim, 2005. (e) Coquerel, Y.;
Boddaert, T.; Presset, M.; Mailhol, D.; Rodriguez, J. In
Ideas in Chemistry and Molecular Sciences: Advances in
Synthetic Chemistry; Pignataro, B., Ed.; Wiley-VCH:
Weinheim, 2010, Chap. 9, 187.
(10) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D.
Synth. Commun. 1987, 17, 1709.
(11) Green, G. M.; Peet, N. P.; Metz, W. A. J. Org. Chem. 2001,
66, 2509.
(12) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797.
(13) (a) Kitamura, M.; Tashiro, N.; Okauchi, T. Synlett 2009,
2943. (b) Kitamura, M.; Tashiro, N.; Miyagawa, S.;
Okauchi, T. Synthesis 2011, 1037.
(2) Reviews: (a) Bonne, D.; Coquerel, Y.; Constantieux, T.;
Rodriguez, J. Tetrahedron: Asymmetry 2010, 21, 1085.
(b) Sanchez Duque, M. M.; Allais, C.; Isambert, N.;
Contantieux, T.; Rodriguez, J. In Topics in Heterocyclic
Chemistry, 23; Orru, R. V., Ed.; Springer-Verlag: Berlin,
2010, 227.
(14) Chiang, Y.; Kresge, A. J.; Nikolaev, V. A.; Popik, V. V.
J. Am. Chem. Soc. 1997, 119, 11183.
(15) Oda, M.; Kasai, M.; Kitahara, Y. Chem. Lett. 1977, 307.
(16) Popik, V. V.; Korneev, S. M.; Nikolaev, V. A.; Korobitsyna,
I. K. Synthesis 1991, 195.
(3) Kirmse, W. Eur. J. Org. Chem. 2002, 2193.
(4) (a) Presset, M.; Coquerel, Y.; Rodriguez, J. J. Org. Chem.
2009, 74, 415. (b) Presset, M.; Coquerel, Y.; Rodriguez, J.
Org. Lett. 2009, 11, 5706. (c) Presset, M.; Coquerel, Y.;
Rodriguez, J. Org. Lett. 2010, 12, 4212. (d) Boddaert, T.;
Coquerel, Y.; Rodriguez, J. Chem. Eur. J. 2011, 17, 2048.
(17) Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004,
60, 3967.
(18) Kokel, B.; Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1980,
19, 716.
Synthesis 2011, No. 16, 2549–2552 © Thieme Stuttgart · New York