Preparation of polyfunctional acyl azides

Article abstract of DOI:10.1021/jo070162e

(Chemical Equation Presented) A general synthesis of acyl azides from the corresponding N-acyl benzotriazoles is described. The procedure affords acyl azides in good yields and avoids the use of acid activators and NO⁺ equivalents typically emp

Full text of DOI:10.1021/jo070162e

Preparation of Polyfunctional Acyl Azides
SCHEME 1. Survey of Literature Syntheses of Acyl Azides
,
§
§,‡
Alan R. Katritzky,* Khalid Widyan, and
Kostyantyn Kirichenko§
Center of Heterocyclic Compounds, Department of Chemistry,
UniVersity of Florida, GainesVille, Florida 32611-7200, and
Department of Chemistry, Tafila Technical UniVersity,
Tafila, Jordan
katritzky@chem.ufl.edu
ReceiVed January 26, 2007
or store, and they are highly sensitive to moisture and re-
quire care in handling. Mixed anhydrides need to be gener-
ated from a carboxylic acid and alkyl chloroformate. We located
only a single successful preparation of a Fmoc-protected amino
acid azide from the corresponding acid chloride or mixed
A general synthesis of acyl azides from the corresponding
N-acyl benzotriazoles is described. The procedure affords
7
anhydride. Attempts to prepare acyl azides from the corre-
acyl azides in good yields and avoids the use of acid
activators and NO+ equivalents typically employed to
sponding (Z)-R,â-unsaturated acids via the mixed anhydride
with ethyl chloroformate followed by reaction with so-
dium azide led to isomerization to (E)-R,â-unsaturated acyl
synthesize these compounds from acid chlorides and hy-
drazides, respectively.
1
2,13
azides.
Direct conversion of carboxylic acids to acyl azides is
achieved (iii) using diphenylphosphoryl azide (DPPA) in the
Acyl azides (1) have found widespread use as highly reactive
reagents in organic chemistry: in cycloadditions, they are used
for the preparation of amides by N-acylation and by thermal
Curtius rearrangement to isocyanates, which in turn undergo
easy conversion into urethanes, ureas, and other derivatives.
Acyl azides are commonly prepared (Scheme 1) by reactions
6
,12,13,17-23
presence of base (Scheme 1);
the use of DPPA also
reduces ZfE-isomerization in R,â-unsaturated azides.12 Other
suggested protocols for direct conversion of carboxylic acids
to acyl azides use (iv) “acid activators” such as SOCl /DMF
1
,2
24-27
2
2
8
or cyanuric chloride/N-methylmorpholine. (v) Triphosgene/
2
9
triethylamine also converts various aryl and alkyl carboxylic
acids into the corresponding acyl azides (Scheme 1), but this
method is not applicable to N-Boc-amino acids because of the
3
-7
(14) Bolm, C.; Dinter, C. L.; Schiffers, I.; Defr e` re, L. Synlett 2001, 1875.
of sodium azide with (i) acid chlorides
or (ii) mixed
(15) Kuramochi, K.; Osada, Y.; Kitahara, T. Tetrahedron 2003, 59, 9447.
(16) Binder, D.; Habison, G.; Noe, C. R. Synthesis 1977, 255.
(17) Shioiri, T.; Ninomiya, K.; Yamada, S.-i. J. Am. Chem. Soc. 1972,
anhydrides.8
-16
Acid chlorides are not always easy to access
§
University of Florida.
94, 6203.
(18) Pavia, M. R.; Lobbestael, S. J.; Taylor, C. P.; Hershenson, F. M.;
Miskell, D. L. J. Med. Chem. 1990, 33, 854.
(19) Shao, H.; Colucci, M.; Tong, S.; Zhang, H.; Castelhano, A. L.
Tetrahedron Lett. 1998, 39, 7235.
(20) Wu, Y.; Esser, L.; De Brabander, J. K. Angew. Chem., Int. Ed. 2000,
39, 4308.
(21) Bhattacharjee, A.; Seguil, O. R.; De Brabander, J. K. Tetrahedron
Lett. 2001, 42, 1217.
(22) Kedrowski, B. L. J. Org. Chem. 2003, 68, 5403.
(23) Holt, J.; Andreassen, T.; Bakke, J. M.; Fiksdahl, A. J. Heterocycl.
Chem. 2005, 259.
(24) Arrieta, A.; Aizpurua, J. M.; Palomo, C. Tetrahedron Lett. 1984,
25, 3365.
‡
Tafila Technical University.
1) Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 297 and
references therein.
2) Br a¨ se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
Int. Ed. 2005, 44, 5188.
(
(
(
(
(
(
3) van Reijendam, J. W.; Baardman, F. Synthesis 1973, 413.
4) Erhardt, P. W. J. Org. Chem. 1979, 44, 883.
5) Pfister, J. R.; Wymann, W. E. Synthesis 1983, 38.
6) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T. J. Org. Chem.
999, 64, 3595.
7) Babu, V. V. S.; Ananda, K.; Vasanthakumar, G.-R. J. Chem. Soc.,
Perkin Trans. 1 2000, 4328.
1
(
(
8) Weinstock, J. J. Org. Chem. 1961, 26, 3511.
(
9) Overman, L. E.; Taylor, G. F.; Petty, C. B; Jessup, P. J. J. Org. Chem.
(25) New, J. S.; Christopher, W. L.; Yevich, J. P.; Butler, R.; Schlemmer,
R. F., Jr.; VanderMaelen, C. P.; Cipollina, J. A. J. Med. Chem. 1989, 32,
1147.
(26) Chambers, J.; Reese, C. B. Tetrahedron Lett. 1975, 32, 2783.
(27) Padwa, A.; Crawford, K. R.; Rashatasakhon, P.; Rose, M. J. Org.
Chem. 2003, 68, 2609.
1
978, 43, 2164.
10) Chorev, M.; MacDonald, S. A.; Goodman, M. J. Org. Chem. 1984,
9, 821.
11) Kobayashi, S.; Kamiyama, K.; Iimori, T.; Ohno, M. Tetrahedron
Lett. 1984, 25, 2557.
(
4
(
(
(
12) Kuramochi, K.; Watanabe, H.; Kitahara, T. Synlett 2000, 397.
13) Stefanuti, I.; Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2000,
(28) Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2002, 43, 3413.
(29) Gumaste, V. K.; Bhawal, B. M.; Deshmukh, A. R. A. S. Tetrahedron
Lett. 2002, 43, 1345.
4
1, 3735.
10.1021/jo070162e CCC: $37.00 © 2007 American Chemical Society
5
802
J. Org. Chem. 2007, 72, 5802-5804
Published on Web 06/19/2007

SCHEME 2. Synthesis of Acyl Azides
TABLE 1. The Preparation of Acyl Azides 1
Literature
ref
1
R
yield %a
method
yield %
b
a
b
c
C6H5
4-CH3C6H4
2-thienyl
82 (80)
82 (81)
80 (79)
75 (71)
iv
v
ii
28
29
16
27
34
33
49
28
39
23
18
28
29
25
32
-
86
83
73
84
b
b
b
d
2-furanyl
iv
vii
vii
iv
iv
vii
iii
iv
iv
v
iv
vii
-
-
-
formation of oxazolidin-2,5-diones (Leuchs’ anhydrides).30 (vi)
Dess-Martin periodinane (DMP) and sodium azide have given
direct conversion of aldehydes to acyl azides, but the reaction
has to be conducted below 0 °C to suppress thermal rearrange-
c
22
75
34
c
e
f
g
2-indolyl
2-pyridyl
3-pyridyl
78 (76)
80 (73)
78 (72)
c
b
73
c
58
31
ment to isocyanate. (vii) Acyl azides can also be prepared
b
h
i
4-pyridyl
82 (73)
72 (71)
80
75
84
72
from acylhydrazines3
2-39
with NO equivalents, but this requires
+
b
b
availability of the hydrazide (Scheme 1).
PhCHdCH
b
Although methods (i)-(vii) are available for the preparation
of acyl azides, the majority involve acid chlorides as intermedi-
ates, which are difficult to achieve for many amino- or hydroxy-
substituted, unsaturated, heteroaromatic acids or those with other
sensitive functionalities. Thus a new and convenient method
for the preparation of acyl azides would be advantageous.
Recently, we described the synthesis of a wide range of
N-acylbenzotriazoles 3 as stable alternatives to acid chlo-
b
j
k
l
m
n
2-furanyl-CHdCH
3-hydroxy-2-naphthyl
L-Cbz-Phe
DL-Cbz-Phe
L-Tryp
81 (76)
81 (77)
85 (81)
88 (82)
83 (77)
83
c
81
-
-
-
-
-
a
Overall yield from acid is in parentheses. b Overall yield from acid.
c
Yield from hydrazide.
4
0,41
of L-1l with DL-1m, which showed two peaks for DL-1m and
one single peak for L-1l, which demonstrated chiral preservation
in the synthesis of R-amino acyl azides.
In conclusion, this approach affords a variety of acyl azides
a-n in overall good yields that are comparable to the literature
rides,
which have been used as acylation agents for the
42-44
45
preparation of amides,
Weinreb amides, cinnamoyl hy-
drazides, N-acylsulfonamides,47 and substituted 2-azinyl-1-
46
ethanones.48 Herein, we report their application to the prepa-
1
ration of acyl azides.
for the simple aromatic acid azides (1a, 1b) but improved for
compounds 1c,e-g under mild conditions. The procedure avoids
the following: (1) the use of cyanuric chloride, triphosgene,
and diphenylphosphoryl azide (DPPA) as reagents; (2) the use
N-Acylbenzotriazoles 3 are accessible in excellent yields from
benzotriazole, thionyl chloride, and the appropriate carboxylic
acid 2 according to established procedures.4
0,41
Treatment of 3
with sodium azide (1.5 equiv) in acetonitrile at room temperature
for 16 h afforded acyl azides in 72-83% yield (Scheme 2 and
Table 1). Reaction of sodium azide with chiral N-(Cbz-
aminoacyl)benzotriazoles provides the corresponding azides
without racemization as demonstrated by the L-form and DL-
form of phenylalanine. The chirality control in the synthesis
was confirmed by comparison of chiral HPLC chromatograms
+
of hydrazides and NO equivalents in multistep reactions for
1
d,e,s,k; (3) isomerization of R,â-unsaturated derivatives; (4)
racemization of the chiral center when amino acid derivatives
were used; and (5) Curtius rearrangements.
Experimental Section
Typical Procedure for Preparation of Acyl Azides 1a-n:
Sodium azide (1.5 mmol, 97 mg) was added to a solution of
appropriate N-acylbenzotriazoles (1 mmol) in acetonitrile
(
(
(
30) Wilder, R.; Mobashery, S. J. Org. Chem. 1992, 57, 2755.
31) Bose, D. S; Reddy, A. V. N. Tetrahedron Lett. 2003, 3543.
32) Wolf, G.; Friedman, O. M.; Dickinson, S. J.; Seligman, A. M. J.
(10 mL). One drop of water was added, and the mixture was stir-
Am. Chem. Soc. 1950, 72, 390.
33) Rinderknecht, H.; Koechlin, H.; Niemann, C. J. Org. Chem. 1953,
8, 971.
34) Yale, H. L.; Losee, K.; Martins, J.; Holsing, M.; Perry, F. M.;
Bernstein, J. J. Am. Chem. Soc. 1953, 75, 1933.
(
red at room temperature for 16 h. The solvent was evaporated, and
the residue was dissolved in diethyl ether and washed with
dilute aqueous sodium carbonate and water. The organic layer was
1
(
4
dried over MgSO and filtered. The solvent was evaporated under
(
(
(
35) Saxena, S.; Haksar, C. N. Curr. Sci. 1979, 48, 63.
36) Nettekoven, M. Synlett 2001, 1917.
37) Tarabara, I. N.; Yarovoi, M. Y.; Kas’yan, L. I. Russ. J. Org. Chem.
reduced pressure, and the residue was purified by column chro-
matography using hexane/diethyl ether (2:1) to give the acyl
azides 1a-n.
2
003, 39, 1676.
38) Macor, J. E.; Mullen, G.; Verhoest, P.; Sampognaro, A.; Shepardson,
B.; Mack, R. A. J. Org. Chem. 2004, 69, 6493.
(
N-Benzyloxycarbonyl-L-phenylalanine Azide (1l): yield 85%;
23
white microcrystals (Et
2
O/hexane); mp 148-149 °C; [R]
D
)
(39) Papeo, G.; Posteri, H.; Vianello, P.; Varasi, M. Synthesis 2004, 2886.
(40) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003, 2795.
(41) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005, 1656.
(42) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65,
1
-
2.90° (c 1.39, DMF); H NMR (300 MHz, DMSO-d
6
) δ 2.79-
2
.87 (m, 1H), 3.04-3.10 (m, 1H), 4.15-4.22 (m, 1H), 5.00 (s,
13
2H), 7.19-7.36 (m, 10H), 7.66 (d, J ) 8.5 Hz, 1H); C NMR (75
MHz, DMSO-d ) δ 36.5, 55.6, 65.3, 126.4, 127.5, 127.8, 128.2,
28.3, 129.1, 137.0, 128.0, 156.0, 173.4. Anal. Calcd for
: C, 62.96; H, 4.98; N, 17.28. Found: C, 63.28; H,
8
7
210.
6
(43) Katritzky, A. R.; Yang, B.; Semenzin, D. J. Org. Chem. 1997, 62,
1
26.
17 16 4 3
C H N O
(
44) Katritzky, A. R.; Wang, M.; Yang, H.; Zhang, S.; Akhmedov, N.
G. ARKIVOC 2002, Viii, 134.
45) Katritzky, A. R.; Yang, H.; Zhang, S.; Wang, M. ARKIVOC 2002,
xi, 39.
5.16; N, 16.88.
N-Benzyloxycarbonyl-DL-phenylalanine Azide (1m): yield
(
1
88%; white microcrystals (Et
(300 MHz, DMSO-d
2
O/hexane); mp 130-132 °C; H NMR
(
46) Katritzky, A. R.; Wang, M.; Zhang, S. ARKIVOC 2001, ix, 19.
) δ 2.79-2.86 (m, 1H), 3.04-3.10 (m, 1H),
.15-4.22 (m, 1H), 5.00 (s, 2H), 7.19-7.36 (m, 10H), 7.67 (d, J
8.5 Hz, 1H); C NMR (75 MHz, DMSO-d ) δ 36.5, 55.6, 65.3,
6
26.4, 127.6, 127.8, 128.2, 128.3, 129.1, 137.0, 138.0, 156.0, 173.4.
: C, 62.96; H, 4.98; N, 17.28. Found:
C, 63.24; H, 5.17; N, 16.89.
6
(47) Katritzky, A. R.; Hoffmann, S.; Suzuki, K. ARKIVOC 2004, xii,
4
)
1
1
4.
(
13
48) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Akhmedova, R. G.
ARKIVOC 2005, Vi, 329.
49) Saikachi, H.; Kitagawa, T.; Nasu, A.; Sasaki, H. Chem. Pharm. Bull.
981, 29, 237.
(
16 4 3
Anal. Calcd for C17H N O
1
J. Org. Chem, Vol. 72, No. 15, 2007 5803

N-Benzyloxycarbonyl-L-tryptophane Azide (1n): yield 83%;
white microcrystals (Et
O/hexane); mp 166-168 °C; [R]23
17 5 3
for C19H N O : C, 62.80; H, 4.72; N, 19.27. Found: C, 63.12;
H, 5.04; N, 19.52.
2
1
D
)
-
8.76° (c 1.39, DMF); H NMR (300 MHz, DMSO-d
.06 (m, 1H), 3.18-3.24 (m, 1H), 4.23-4.30 (m, 1H), 4.99 (q, J
12.7 Hz, 2H), 7.00 (t, J ) 7.2 Hz, 1H), 7.07-7.11 (m, 1H),
.19 (s, 1H), 7.31-7.38 (m, 6H), 7.56 (d, J ) 7.7 Hz, 1H), 7.63
d, J ) 8.1 Hz, 1H), 10.88 (s, 1H); 13C NMR (75 MHz, DMSO-
6
) δ 2.79-
3
)
7
(
d
Supporting Information Available: Experimental procedures,
spectroscopic data, and melting points for compounds 1a-k, and
1
13
copies of the H and C NMR spectra of compounds 11-n. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
6
) δ 27.0, 55.0, 65.4, 110.2, 111.5, 118.2, 118.5, 121.0, 123.9,
127.2, 127.7, 127.8, 128.4, 136.2, 137.1, 156.1, 173.9. Anal. Calcd
JO070162E
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804 J. Org. Chem., Vol. 72, No. 15, 2007