A simple and fast procedure for efficient synthesis of β- and γ-azidoarylketones

Article abstract of DOI:10.1016/j.tetlet.2003.10.033

A simple and efficient method for preparing β- and γ-azido substituted arylketones has been achieved by short microwave irradiation of the corresponding halo arylketones and sodium azide in DMSO.

Full text of DOI:10.1016/j.tetlet.2003.10.033

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9169–9171
A simple and fast procedure for efficient synthesis of b- and
g-azidoarylketones
Pradeep N. D. Singh, Sivaramakrishnan Muthukrishnan, Rajesh S. Murthy, Rodney F. Klima,
Sarah M. Mandel, Michael Hawk, Nina Yarbrough and Anna D. Gudmundsd o´ ttir*
Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, USA
Received 23 September 2003; revised 4 October 2003; accepted 6 October 2003
Abstract—A simple and efficient method for preparing b- and g-azido substituted arylketones has been achieved by short
microwave irradiation of the corresponding halo arylketones and sodium azide in DMSO.
©
2003 Elsevier Ltd. All rights reserved.
Recently, there has been a new focus on using azide
through 1,3 dipolar addition to alkenes in excellent
yields.
1
–3
17
functional groups in synthesis. For example, Rozen
et al. have demonstrated that alkyl azides can be safely
1
oxidized to nitroalkyl. Furthermore, alkyl azides
We set out to prepare b- and g-azidoarylketones 2 from
the corresponding halo compounds 1 and sodium azide
with the aid of flash heating by microwave irradiation
(see Scheme 4). Azides 2 are representative of different
substituted analogs.
undergo copper catalyzed cycloadditions in high yields
2
and selectivity. Azidoarylketones are also valuable in
organic synthesis and can be transformed to yield a
wide variety of organic molecules such as heterocyclic
3
,5
compounds. There are several methods available for
synthesizing azido carbonyl compounds, for example
the oxidative addition of azide anion to silyl enol
15
Azidoarylketones are thermally labile, and we are
using a conventional microwave oven that cannot be
fitted with a condenser to prevent overheating. There-
fore, we followed the procedure of Chan and co-work-
6
3–5,7
ether, the reaction of halo ketone
or nosyloxy
8
ketone via nucleophilic substitution with sodium azide.
These methods generally yield a-substituted azidocar-
bonyl compounds in good yields, however, the prepara-
tion of b- and g-azidocarbonyl compounds have long
19
ers, and ran the reaction in a water bath inside the
microwave. This ploy allowed us to safely make the
azidoarylketones up to a 10 gram scale. The water was
replaced whenever it boiled.
9–13
reaction times and low yields.
Microwave irradiation has become popular since it
requires shorter reaction times, and generally gives high
yields and enhanced selectivity compared to conven-
In a typical experiment, g-chlorobutyrophenone (180
mg, 1.00 mmol) dissolved in DMSO (5 mL) and
1
4
tional heating. We were curious whether microwave
irradiation can be used to accelerate the formation of
alkyl azides from the corresponding alkyl halogens and
sodium azides (see Scheme 1), especially since alkyl
azides are thermally labile and rearrange to form imines
1
5
upon thermal activation (see Scheme 2). We have
shown that vinyl alkyl azides rearrange upon
microwave irradiation to form 2H-azidirines (see
Scheme 1.
Scheme 2.
1
6
Scheme 3) and microwave irradiation has been used
17,18
to catalyze cycloaddition of azides.
Thus,
microwave irradiation of alkyl azides yields triazoles
*
0
Corresponding author. Tel.: +1-513-556-3380; fax: +1-513-556-9239;
e-mail: anna.gudmundsdottir@uc.edu
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.033

9
170
P. N. D. Singh et al. / Tetrahedron Letters 44 (2003) 9169–9171
silica column, eluting with 95:5 hexane:ethyl acetate to
obtain g-azidobutyrophenone in 95% yield.
This same reaction was also done in ethanol and with-
out solvent. In both instances the reaction proceeded
but the yields were lower. Thin layer chromatography
of the reaction mixtures, which had undergone pro-
longed microwave irradiation, indicated the formation
of additional products, presumably coming from the
thermal reactivity of the azidoarylketone.
Scheme 3.
Azides 2a, 2c, and 2f have been made previously and
1
were characterized by obtaining their IR and H NMR
2
0,21
spectra,
which were identical to those in the litera-
Azides 2b, 2d, 2e, 2f, 2g, 2h, 2i and 2j were
1
0,11
ture.
characterized by obtaining their IR, H and C NMR
1
13
20,21
spectra.
The isolated yields and the reaction times for preparing
b- and g-azidoarylketones 2 using sodium azide and
microwave irradiation are summarized in Table 1. In all
instances the azidoarylketones 2 are formed in high
yield after a reaction time of 12 min or less. There is
essentially no difference in the reaction rate for halo
ketone bearing an electron withdrawing or donating
substituent. The b- and g-azidoarylketones are stable
enough under this short microwave irradiation that
they do not undergo thermal rearrangements to form
imines. In all cases we noticed a remarkable accelera-
tion in reaction rates compared to conventional heat-
9–12
ing.
The yields in the microwave assisted reaction
are either as good or better than using conventional
heating. Further, the method requires no catalyst such
1
0
as sodium iodide as in the conventional method. The
high boiling point and the substantial dipole moment of
DMSO were exploited in these reactions for the
efficient absorption of the microwave irradiation.
Scheme 4.
aqueous sodium azide (100 mg, 1.50 mmol) was placed
in a test tube and the resulting solution stirred. The test
tube was stored in a glass beaker containing water and
irradiated with microwaves for 8 min. The reaction was
monitored by TLC and after the completion, water was
added to the reaction mixture and the resulting solution
extracted with diethyl ether. The solvent was removed
under vacuum and the resulting oil was purified on a
In conclusion, the present work describes an efficient
synthetic route to prepare b- and g-azidoarylketones
from easily available haloarylketones using sodium
azide under microwave irradiation. This method gener-
ates b- and g-azidoketones in a short reaction time, in
high yield and by a simple procedure with excellent
Table 1. Isolated yields of azidoarylketones from microwave irradiations and conventional heating of haloarylketones and
sodium azide
Halide
Azide
Reaction time (min)
Microwave yields (%)a
Reaction time (h)
Thermal yield (%)b
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
g
h
i
2a
2b
2c
2d
2e
2f
2g
2h
2i
8
10
10
8
12
6
6
7
6
12
95
88
90
90
86
87
91
90
89
85
14
14
93–999
9
93–99
1
0
77
5412
j
2j
a
Isolated yields of azidoarylketone from microwave irradiations of the corresponding haloarylketone and sodium azide.
Literature values for isolated yields of azidoarylketone obtained from conventional heating of the corresponding haloarylketone and sodium
azide.
b

P. N. D. Singh et al. / Tetrahedron Letters 44 (2003) 9169–9171
9171
purity. Experiments in progress show that this same
method can be used to prepare alkyl azides without any
ketones and azido formate esters and will be reported in
due course. Whereas the more reactive acyl azides cannot
be prepared in the same manner.
2000, 100, 1025; (g) Deshayes, S.; Liagre, M.; Loupy, A.;
Luche, J. L.; Petit, A. Tetrahedron 1999, 55, 10851; (h)
Varma, R. S. Green Chem. 1999, 1, 43; (i) Loupy, A.; Petit,
A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mather,
D. Synthesis 1998, 1213; (j) Caddick, S. Tetrahedron, 1995,
51, 10403.
1
1
5. Azides and Nitrenes. Reactivity and Utility; Scriven, E. F.
V., Ed.; Academic Press: New York, 1984.
6. Singh, N. D. P.; Carter, C. L.; Gudmundsdottir, A. D.
Tetrahedron Lett. 2003, 44, 6763.
Acknowledgements
We thank the National Science Foundation (CAREER
Award c0093622) for supporting this work. Financial
support from the Petroleum Research Foundation (ACS-
PRFc 35809-G4) is also gratefully acknowledged. N.Y.
thanks the ACS SEED program for financial support.
17. Katritzky, A. R.; Singh, S. K. J. Org. Chem. 2002, 67, 9077.
18. Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984.
19. Law, M. C.; Wong, L.-Y.; Chan, T. H. Green Chem. 2002,
4, 328.
2
0. The NMR and IR spectra of the g-azidoarylketones are as
1
follow. 2a: Yellowish dense liquid. H NMR (250 MHz,
References
CDCl ) l 2.03 (quin, 7 Hz, 2H), 3.07 (t, 7 Hz, 2H), 3.41
3
(
t, 7 Hz, 2H), 7.45 (t, 7 Hz, 2H), 7.5 (t, 7 Hz, 1H), 7.95
−
1
1
2
. Rozen, S.; Carmeli, M. J. Am. Chem. Soc. 2003, 125, 8118.
. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596; (b) Speers,
A. E.; Adam, G. C.; Cravatt, B. F. J. Am. Chem. Soc. 2003,
25, 4686; (c) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin,
V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc.
003, 125, 3192.
(d, 7 Hz, 2 H) ppm. IR (neat): 1687, 2098 cm . 2b: White
crystalline solid. Mp 41°C. H NMR (250 MHz, CDCl )
1
3
l 2.03 (quin. 7 Hz, 2H), 3.03 (t, 7 Hz, 2H), 3.41 (t, 7 Hz,
2H), 3.41 (s, 3H), 6.92 (d, 8.5 Hz, 2H), 7.93 (d, 8.5 Hz, 2H)
1
3
1
ppm. C NMR (60 MHz, CDCl ) l 23.2, 34.4, 50.6, 55.1,
3
−
1
113.5, 129.6, 163.3, 197.1 ppm. IR (KBr): 1677; 2099 cm .
2c: Yellowish dense liquid H NMR (250 MHz, CDCl ) l
1
2
3
3
. (a) Milligan, G. L.; Mossman, C. J.; Aube, J. J. Am. Chem.
Soc. 1995, 117, 10449; (b) Kim, S.; Joe, G. H.; Do, J. Y.
J. Am. Chem. Soc. 1994, 116, 5521; (c) Aube, J.; Milligan,
G. L. J. Am. Chem. Soc. 1991, 113, 8965.
2.03 (quin, 7 Hz, 2H), 3.05 (t, 7 Hz, 2H), 3.42 (t, 7 Hz, 2H),
7.60 (d, 8 Hz, 2H), 7.81 (d, 8 Hz, 2H) ppm. IR (neat): 1686,
−
1
1
2098 cm . 2d: Crystalline solid. Mp 66–67°C. H NMR
(250 MHz, CDCl ) l 2.03 (quin, 7 Hz, 2H), 3.04 (t, 7 Hz,
2H), 3.41 (t, 7 Hz, 2H), 7.03 (broad s, 1H), 6.91 (d, 8.4 Hz,
3
4. (a) Watanabe, S.; Nakazumi, H.; Kitao, T. J. Chem. Soc.
13
Perkin Trans.
1
1988, 1829; (b) Edwards, O. E.;
2H), 7.90 (d, 8.4 Hz, 2H) ppm. C NMR (60 MHz, CDCl )
3
Purushothaman, K. K. Can. J. Chem. 1964, 42, 712; (c)
Boyer, J. H.; Canter, F. C. Chem. Rev. 1954, 54, 1.
. (a) Scriven, E. F. V.; Trunbull, K. Chem. Rev. 1988, 88,
l 20.6, 23.9, 52.1, 71.6, 126.8, 128.1, 128.2, 128.3, 128.8,
130.4, 135.9, 139.7, 209.4, 23.8, 33.2, 35.1, 50.9, 114.4, 117.1,
−
1
5
132.3, 132.4, 161.4, 199.6 ppm. IR (KBr): 1660, 2100 cm .
1
2
98; (b) Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara,
2e: Colorless dense liquid. H NMR (250 MHz, CDCl ) l
3
S.; Eguchi, S. J. Org. Chem. 1989, 54, 431.
. (a) Magnus, P.; Barth, L. Tetrahedron Lett. 1992, 33, 2777;
1.34 (s, 9H), 2.03 (quin, 7 Hz, 2H); 3.06 (t, 7 Hz, 2H), 3.41
(t, 7 Hz, 2H); 7.46 (d, 8 Hz, 2H), 7.89 (d, 8 Hz, 2H) ppm.
6
13
(b) Trahanovsky, W. S.; Robbins, M. D. J. Am. Chem. Soc.
C NMR (60 MHz, CDCl
) l 23.2, 30.1, 31.9, 32.0, 32.1,
3
1
971, 93, 5256; (c) Sant, K. V.; South, M. S. Tetrahedron
32.9, 35.0, 50.8, 126.2, 126.7, 129.2, 134.0, 156.9, 198.5 ppm.
IR (neat): 1682, 2098 cm .
−
1
Lett. 1987, 28, 6019; (d) Patony, T.; Hoffman, R. V. J. Org.
Chem. 1995, 60, 2368.
. (a) Singh, P. N. D.; Mandel, S. M.; Zhu, Z.; Franz, R.; Ault,
21. The NMR and IR spectra of the b-azidoarylketones are as
1
7
follows 2f: Yellowish dense liquid. H NMR (250 MHz,
B. S.; Gudmundsd o´ ttir, A. D. J. Org. Chem. 2003, 68,
7
Eur. J. Org. Chem. 2002, 285; (c) Majo, V. J.; Perumal, P.
T. J. Org. Chem. 1998, 63, 7136.
CDCl
3
) l 3.15 (t, 7.5 Hz, 2H), 3.63 (t, 7.5 Hz, 2H), 7.37
´
951–7960; (b) Patonay, T.; Juh a´ sz-T o´ th, E.; B e´ nyei, A.
(t, 7.4 Hz, 2H), 7.47 (t, 7.0 Hz, 1H), 7.86 (d, 7.6 Hz, 2H)
−
1
ppm. IR (neat): 1684, 2105 cm . 2g: Yellowish dense liquid
1
H NMR (250 MHz, CDCl
) l 3.21 (t, 6.3 Hz, 2H); 3.74
3
8
9
. Patony, T.; Hoffman, R. V. J. Org. Chem. 1994, 59, 2902.
. De Kimpe, N.; Tehrani, K. A.; Stevens, C.; De Cooman,
P. Tetrahedron 1997, 53, 3693.
(t, 6.2 Hz, 2H), 7.63 (d, 8.4 Hz, 2H), 7.83 (d, 8.4 Hz, 2 H)
13
ppm. C NMR (60 MHz, CDCl
131.8, 134.8, 195.8 ppm. IR (Neat): 1686, 2105 cm . 2h
) l 37.3, 45.7, 128.5, 129.2,
3
−
1
1
1
1
1
0. Vaultier, M.; Lambert, P. H.; Carrie, R. Bull. Soc. Chim.
Brownish dense liquid. H NMR (250 MHz, CDCl
) l 3.42
3
Fr. 1986, 1, 83.
1. Wagner, P. J.; Scheve, B. J. J. Am. Chem. Soc. 1979, 101,
(t, 7.5 Hz, 2H), 3.88 (s, 3H), 3.92 (t, 7.5 Hz, 2H), 6.95 (d,
1
3
8 z, 2H), 7.95 (d, 8 Hz, 2H) ppm. C NMR (60 MHz,
CDCl ) l 36.9, 46.1, 55.2, 113.6, 129.3, 130.0, 163.5, 195.3
ppm. IR (neat): 1693, 2099 cm . 2i: Yellowish dense liquid.
3
78.
2. Eguchi, S.; Takeuchi, H.; Esaki, T. Nippon Kagaku Kaishi
987, 7, 1250.
3
−
1
1
1
H NMR (250 MHz, CDCl
) l 3.20 (t, 7.5 Hz, 2H), 3.74
3
1
1
3. Ma, Y. Heteroat. Chem. 2002, 13, 307.
4. For some recent reviews, see: (a) Pillai, U. R.; Sahle-
(t, 7.5 Hz, 2H), 7.63 (d, 8 Hz, 2H), 7.83 (d, 8 Hz, 2H) ppm.
1
3
C NMR (60 MHz, CDCl
) l 38.8, 41.4, 116.1 (d) 130.1,
3
−
1
Demessie, E.; Varma, R. S. J. Mat. Chem. 2002, 12, 3199;
165 (d), 195.1 ppm. IR (neat): 1686, 2105 cm . 2j: White
crystalline solid: 54–57°C. H NMR (250 MHz, CDCl
1
(b) Perreux, L.; Loupy, A. Tetrahedron, 2001, 57, 9199; (c)
) l
3
Varma, R. S. Pure Appl. Chem. 2001, 73, 193; (d) Lidstrom,
P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron, 2001,
1.13 (s, 3H), 1.25 (s, 3H), 5.24 (s, 1H), 7.34–7.46 (m, 10H)
1
3
ppm. C NMR (60 MHz, CDCl
126.8, 128.1, 128.2, 128.3, 128.8, 130.4, 135.9, 139.7, 209.4
) l 20.6, 23.9, 52.1, 71.6,
3
5
7, 9225; (e) Diaz-Ortiz, A.; de la Hoz, A.; Langa, F. Green
−
1
Chem. 2000, 2, 165; (f) Tanaka, K.; Toda, F. Chem. Rev.
ppm. IR (neat): 1677, 2103 cm .