A chemoselective aerobic oxidation of benzylic azides catalyzed by molybdenum xanthate in an aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2008.05.047

A mild molybdenum-catalyzed, aerobic, chemoselective oxidation of benzylic azides to the corresponding aldehydes in an aqueous medium that tolerates a variety of functional groups including alcohols, esters, ketones, halides and olefins is described.

Full text of DOI:10.1016/j.tetlet.2008.05.047

Tetrahedron Letters 49 (2008) 4526–4530
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A chemoselective aerobic oxidation of benzylic azides catalyzed by
molybdenum xanthate in an aqueous medium
*
Mahagundappa Maddani, Kandikere Ramaiah Prabhu
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild molybdenum-catalyzed, aerobic, chemoselective oxidation of benzylic azides to the corresponding
aldehydes in an aqueous medium that tolerates a variety of functional groups including alcohols, esters,
ketones, halides and olefins is described.
Received 27 February 2008
Revised 29 April 2008
Accepted 8 May 2008
Available online 13 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Benzyl azides
Molybdenum
Redox reactions
Aerobic oxidations
Chemoselectivity
Green chemistry
Table 1
Transition metal-catalyzed oxidations in water using molecular
oxygen as the reoxidant are of importance in both academia and
industry.1–4 Furthermore, the use of molybdenum catalysts for oxi-
dation is a well-explored area.5 Research in this direction, apart
from aiding the understanding of the role of molybdenum and its
derivatives in oxo-transfer reactions, has produced numerous
methods which are useful in organic synthesis.5–8 In this context,
herein we present an efficient chemoselective aerobic oxidation
of benzylic azides to the corresponding aldehydes catalyzed by
molybdenum complex 19 using molecular oxygen as the reoxidant.
For optimization of the reaction conditions, we chose p-
methoxybenzyl azide (2) as a model substrate and treated it with
various Mo(VI) reagents. As shown in Table 1, the reaction of azide
2 with ammonium molybdate and sodium molybdate, either in
toluene or in water, did not produce any significant amount of
product even after prolonged reaction times (Table 1, entries
1–4). However, the reaction of azide 2 with a stoichiometric
amount of dioxobis(N,N-diethyldithiocarbamato)molybdenum 1
(MoO2[S2CNEt2]2) in toluene under refluxing conditions furnished
the corresponding aldehyde 2a in excellent yield (87%, 8 h, entry
5, Table 1). Surprisingly, the reaction of 2 with 1 in water resulted
an 85% yield of the aldehyde 2a under reflux (10 h, entry 6, Table
Reaction of p-methoxybenzyl azide with different Mo-reagents
CHO
Solvent
N
3
2
2a
O
O
Reflux
Entry
Reagenta
Solvent
Timeb (h)
Yieldc
1
2
3
4
5
6
7
8
9
(NH4)6MoO7O24Á4H2O
(NH4)6MoO7O24Á4H2O
Na2MoO4Á2H2O
Na2MoO4Á2H2O
MoO2(Et2NCS2)2
MoO2(Et2NCS2)2
MoO2(acac)2
MoO2(acac)2
MoO2(acac)2
—
H2O
Toluene
H2O
Toluene
Toluene
H2O
20
20
20
20
8
10
20
20
20
20
20
No reaction
No reaction
No reaction
No reaction
87%
85%
H2O
No reaction
No reaction
No reaction
No reaction
No reaction
Toluene
DMSO
Toluene
H2O
10
11
—
a
Stoichiometric amount.
Heated at 100 °C.
Isolated yields.
b
c
7–9). Also, control experiments in the absence of 1 under refluxing
conditions for >48 h did not produce any aldehyde, and the starting
material was recovered unchanged (Table 1, entries 10 and 11).
Oxidants such as H2O2 and NMO did not produce any significant
result under refluxing conditions either in toluene or in water
(Table 2, entries 1–4). However, reaction of azide 2 with a catalytic
amount 1 and DMSO in toluene produced aldehyde 2a (36 h, yield
40%, entry 5, Table 2). Similar reaction of 2 with a catalytic amount
10
1). Reaction of azide 2 with MoO2(acac)2 in water, DMSO or tol-
uene (in stoichiometric amount) under reflux was not effective and
the starting material was recovered unchanged (Table 1, entries
* Corresponding author. Tel.: +91 80 2293 2887; fax: +91 80 2360 0529.
E-mail address: prabhu@orgchem.iisc.ernet.in (K. R. Prabhu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.047

M. Maddani, K. R. Prabhu / Tetrahedron Letters 49 (2008) 4526–4530
4527
Table 2
of 1 and DMSO in water produced 2a in good yield (90%) after 3 h
(Table 2, entry 6). Use of a catalytic amount of 1 in the presence of
m-CPBA in water turned out to be a good reaction medium produc-
ing 2a in 80% yield (5 h, entry 7, Table 2). However, the yield was
poor on similar reaction in toluene (10%, 36 h, entry 8, Table 2).
The reaction of 2 with 1 in the presence of molecular oxygen
(1 atm) in toluene resulted in the formation of 2a in good yield
(8 h, reflux, 86%, entry 9, Table 2). A similar reaction in water pro-
duced 2a in 83% yield (Table 2, entry 10). Accordingly, we contin-
ued our study using molecular oxygen as the reoxidant.11
Under the optimized reaction conditions, 10 mol % of 1 in tolu-
ene/water, O2 atmosphere, 100 °C, a wide range of benzylic azides
were smoothly converted to the corresponding aldehydes in excel-
lent yields (Table 3). p-Methoxybenzyl azide (2) produced the cor-
responding aldehyde 2a in excellent yield both in water and in
toluene (Table 3, entry 1). Benzyl azide (3) produced benzaldehyde
(3a) in almost quantitative yield in toluene and in good yield in
water (99% and 78%, respectively, entry 2, Table 3). Similarly,
Optimization of the reaction conditions
N3
CHO
MoO2(S2CNEt2)2 (cat), 1
Oxygen Source, Reflux
O
2
2a
O
Entry
Oxygen source
Solvent
Timea (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
H2O2
H2O2
NMO
NMO
DMSO
DMSO
m-CPBA
m-CPBA
O2
Toluene
H2O
Toluene
H2O
Toluene
H2O
36
36
36
36
36
3
No reaction
No reaction
No reaction
No reaction
40
90
80
10
86
83
H2O
5
Toluene
Toluene
H2O
36
8
10
10
O2
a
Heated at 100 °C.
Isolated yields.
b
Table 3
Catalytic oxidation of benzylic azides
CHO
N3
Toluene, N2
R
R
MoO2(S2CNEt2)2
+
1
Reflux
Entry
Substrate
Timea,b (h)
Product
Yieldc,d
83 (86)
CHO
N3
1
2
10 (8)
2a
O
O
CHO
N3
2
3
4
8 (10)
3a
4a
99 (78)
78 (61)
CHO
N3
3
4
5
6
7
16 (14)
Cl
Cl
CHO
N3
5
6
7
8
10 (3)
20 (3)
5a
6a
7a
8a
82 (95)
80 (81)
74 (82)
92 (90)
CHO
OMe
N3
OMe
MeO
MeO
MeO
MeO
CHO
N3
10 (8)
CHO
N3
15 (12)
N3
CHO
8
9
9
10 (12)
16 (17)
9a
88 (80)
86 (88)
OH
OH
10
10a
N3
CHO
CHO
O
O
O
O
CHO
N3
10
11
11
12
12 (7)
12 (6)
11a
12a
92 (92)
50 (48)
N3
O
O

4528
M. Maddani, K. R. Prabhu / Tetrahedron Letters 49 (2008) 4526–4530
Table 3 (continued)
Entry
Substrate
Timea,b (h)
Product
Yieldc,d
45 (40)
CHO
N3
12
13
14
13
14
15
18 (8)
20 (8)
13a
14a
15a
COOCH3
COOCH3
O2N
O2N
CHO
N3
19 (24)
5 (10)
36 (36)
N3
O
a
Heated at 100 °C.
Time in parentheses indicates the reaction in toluene.
Isolated yields.
Value in parentheses indicates the yield in toluene.
b
c
d
p-chlorobenzyl azide 4, p-methylbenzyl azide 5 and o-methoxy-
benzyl azide 6 afforded the corresponding aldehydes 4a, 5a and
6a in excellent yields (Table 3, entries 4–6). 3,4-Dimethoxybenzyl
azide (7) produced the corresponding aldehyde 7a in good yields
both in toluene and in aqueous medium (Table 3, entry 7). 2-(Azi-
domethyl)naphthalene (8) and 10-(azidomethyl)anthracene (9)
gave the corresponding aldehydes 8a and 9a in very good yields
both in water and in toluene (Table 3, entries 7 and 8). The
oxidation of azides was chemoselective and tolerates a variety of
functional groups as exemplified in entries 9–12 (Table 3). Func-
tional groups such as alcohols and olefins were unaffected (Table
3, entries 9 and 10). In the reaction of p-acetylbenzyl azide (12)
with 1, the ketone group remained inert to provide p-acetylbenz-
aldehyde 12a in moderate yield. Similarly, reaction of methyl
2-(azidomethyl)benzoate (13), with 1 provided aldehyde 13a in
moderate yield and the ester group was unaffected. However,
m-nitrobenzyl azide (14) and a-methylbenzyl azide (15) produced
the expected products in low yields. Reaction of aliphatic azides
with 1 did not produce any products even after prolonged
reactions.
OH
O
CHO
+
OH
2b
O
O
N3
2b
(quantitative,
recovered)
2a (85%)
O
CHO
+
Cl
2a
O
O
2c
Cl
2a (86%)
(quantitative,
recovered)
O
2c
The chemoselectivity of the above oxidation was demonstrated
further by performing additional experiments as presented in
Scheme 1. Chemoselective oxidation.
Ph
N
N
N
-N2
O
S
S
S
Et2N
Ph
Mo
O
NEt2
S
H
N
N
N
Ph
I
O
N
O
VI
S
S
S
S
S
S
Et2N
Et2N
Mo
O
Mo
O
NEt2
NEt2
S
S
II
1
IV
S
S
S
O2
Et2N
Mo
NEt2
S
H
Ph
O
III
PhCHO
+
N
HO
Scheme 2. Proposed catalytic cycle.

M. Maddani, K. R. Prabhu / Tetrahedron Letters 49 (2008) 4526–4530
4529
OH
CHO
1, Reflux, O , toluene, 40 h
2
N
OMe
MeO
No reaction
2d
2a
CHO
OH
OH
N
N
N
3
1, Reflux, O , toluene, 20 h
2
+
+
2d (50%)
recovered)
MeO
MeO
MeO
MeO
2d
2d
2
2a, 131%
OH
CHO
+
OH
CHO
N
N
N
1, Reflux, O , toluene, 20 h
3
2
+
+
2d (50%)
recovered)
MeO
MeO
MeO
8
8a (88%)
2a (45%)
Scheme 3. Reaction of various azides and oxime 2d with 1.
Scheme 1. The alcohol 2b and p-methoxybenzyl chloride remained
unaffected under these reaction conditions. Clearly, this method
provides an opportunity to synthesize aldehydes from azides in
the presence of alcohols, chlorides, olefins, esters and ketones.
Also, this strategy produces only the corresponding aldehyde,
without any over-oxidation.
Acknowledgements
We are thankful to Professor S. Chandrasekaran for encourage-
ment and laboratory facilities. We are grateful to IISc. for the finan-
cial support.
Interestingly, the reaction of azide 2 and reagent 1 (10 mol %) in
H2O (or toluene) in the absence of molecular oxygen (reflux, 40 h)
produced the corresponding aldehyde 2a in 10% yield, 90% of the
starting material was recovered (by 1H NMR).12 This experiment
indicates that molecular oxygen is essential for the reaction. This
observation contrasts that observed in the reaction of xanthine
with xanthine oxidase where the oxygen is transferred from
water.13
A tentative mechanism based on the available information in
the literature is presented in Scheme 2.5 Reagent 1 reacts with ben-
zyl azide to form complex I, which in turn could lose nitrogen to
generate complex II.14 Further, the complex II could lose a proton
to furnish III, along with the oxime. The oxime thus generated
could be converted to the corresponding aldehyde under the reac-
tion conditions. Furthermore, the complex III could react with
molecular oxygen to produce the reagent 1 and the cycle contin-
ues. The catalytic cycle persists until at the end of the reaction
the cycle terminates in producing a molybdenum complex, which
can no longer catalyze the oxygen transfer reaction.15
To substantiate the proposed intermediacy of an oxime, we
performed a few control experiments (Scheme 3). Surprisingly,
the reaction of p-methoxybenzaldoxime (2d) and 1 under an
oxygen atmosphere (toluene or water as the solvent) at reflux
(40 h) did not furnish the expected aldehyde; however, the starting
material was recovered unchanged. Similar reaction of p-meth-
oxybenzaldoxime (2d) and p-methoxybenzyl azide (2) with 1
under the standard reaction conditions produced the aldehyde 2a
in 131% yield, indicating that the oxime is also converted to
aldehyde 2a under the reaction conditions employed for the
oxidation. The reaction of p-methoxybenzaldoxime (2d) and 2-
(azidomethyl)naphthalene (8) in toluene with 1 under an oxygen
atmosphere produced 2-naphthaldehyde (8a, 88% yield) and
p-methoxybenzaldehyde (2a, 45%). Presumably, the species
formed from azides may be essential for the conversion of oximes
to aldehydes.
In conclusion, we have reported a useful, chemoselective aero-
bic oxidation of benzylic azides to the corresponding aldehydes.16
Interestingly, over-oxidation to the acid was not observed.
Preliminary studies indicate that the oxygen is transferred from
molecular oxygen and not from the solvent. This aerobic reaction
may be helpful in understanding the role of molybdenum in
molybdo-enzyme-catalyzed oxidations in Nature.
Supplementary data
The analytical data, spectral data, and 1H and 13C NMR spectra
of compounds 2–13 and 2a–13a are available. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.05.047.
References and notes
1. (a) Li, C.; Zheng, P.; Li, J.; Zhang, H.; Cui, Y.; Shao, Q.; Ji, X.; Zhang, J.; Zhao, P.; Xu,
Y. Angew. Chem., Int. Ed. 2003, 42, 5063; (b) Velusamy, S.; Ahamed, M.;
Punniyamurthy, T. Org. Lett. 2004, 6, 4821; (c) Gupta, M.; Paul, S.; Gupta, R.;
Loupy, A. Tetrahedron Lett. 2005, 46, 4957 and references cited therein.
2. For reactions in water see: (a) Ribe, S.; Wipf, P. Chem. Commun. 2001, 299–300;
(b) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103; (c) Narayan, S.; Muldon, J.;
Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005,
44, 3275; (d) Dioumaev, V. K.; Bullock, R. M. Nature 2003, 424, 530.
3. (a) ten Brink, G. J.; Arends, I. W. C. E.; Sheldon, R. A. Science 2000, 287, 1636; (b)
Dudas, J.; Parkinson, C. J.; Cukan, V.; Chokwe, T. B. Org. Process Res. Dev. 2005, 9,
976 and references cited therein; (c) Chauhan, S. M. S.; Kumar, A.; Srinivas, K. A.
Chem. Commun. 2003, 2348; (d) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun.
2003, 1977; (e) Tang, J.; Zhu, J.; Shen, Z.; Zhang, Y. Tetrahedron Lett. 2007, 48,
1919; (f) Holm, R. H. Chem. Rev. 1987, 87, 1401; (g) Chen, G. J.-J.; McDonald, J.
W.; Newton, W. E. Inorg. Chem. 1976, 15, 2612; (h) Harlan, E. W.; Berg, J. M.;
Holm, R. H. J. Am. Chem. Soc. 1986, 108, 6992; (i) Barral, R.; Board, C.; de Roch, I.
S.; Sajus, L. Tetrahedron Lett. 1972, 13, 1963.
4. (a) Markó, I. E.; Giles, P. R.; Tsukazaki, M.; Brown, S. M.; Urch, C. J. Science 1996,
274, 2044; (b) Wang, J.; Yan, L.; Qian, G.; Wang, X. Tetrahedron Lett. 2006, 47,
7171; (c) Markó, I. E.; Gautier, A.; Dumeunier, R.; Doda, K.; Philippart, F.;
Brown, S. M.; Urch, C. J. Angew. Chem., Int. Ed. 2004, 43, 1588.
5. (a) Arnaiz, F. J.; Aguado, R.; De Ilarduya, J. M. M. Polyhedron 1994, 13, 3257 and
references cited therein; (b) Jeyakumar, K.; Chand, D. K. Tetrahedron Lett. 2006,
47, 4573; (c) Neumann, R.; Khenkin, A. M. Chem. Commun. 2006, 2529.
6. (a) Kühn, F. E.; Santos, A. M.; Abrantes, M. Chem. Rev. 2006, 106, 2455; (b)
Schrock, R. R. J. Mol. Catal. A: Chem. 2004, 213, 21; (c) Lehtonen, A.; Sillanpää, R.
Polyhedron 2005, 24, 257–265; (d) Arzoumanian, H. Coordin. Chem. Rev. 1998,
178–180, 191; (e) Wang, G.; Chen, G.; Luck, R. L.; Wang, Z.; Mu, Z.; Evans, D. G.;
Duan, X. Inorg. Chim. Acta 2004, 357, 3223.
7. (a) Enemark, J. H.; Cooney, J. J. A.; Wang, J. J.; Holm, R. H. Chem. Rev. 2004, 104,
1175; (b) Wilson, G. L.; Greenwood, R. J.; Pilbrow, J. R.; Spence, J. T.; Wedd, A. G.
J. Am. Chem. Soc. 1991, 113, 6803; (c) Morris, R. H.; Ressner, J. M.; Sawyer, J. F.;
Shiralian, M. J. Am. Chem. Soc. 1984, 106, 3683; (d) Sugimoto, H.; Siren, K.;
Tsukube, H.; Tanaka, K. Eur. J. Inorg. Chem. 2003, 2633 and references cited
therein.
8. Maddani, M.; Prabhu, K. R. Tetrahedron Lett. 2007, 48, 7151.
9. (a) Moore, F. W.; Larson, M. L. Inorg. Chem. 1967, 6, 998; (b) Newton, W. E.;
Corbin, J. L.; Bravard, D. C.; Searles, J. E.; McDonald, J. W. Inorg. Chem. 1974, 13,
1100.
10. Barlan, A. U.; Basak, A.; Yamamoto, H. Angew. Chem., Int. Ed. 2006, 45, 5849.
11. (a) Mallat, T.; Baiker, A. Chem. Rev. 2004, 104, 3037 and references cited
therein; (b) Lorber, C. Y.; Smidt, S. P.; Osborn, J. A. Eur. J. Inorg. Chem. 2000, 655;

4530
M. Maddani, K. R. Prabhu / Tetrahedron Letters 49 (2008) 4526–4530
(c) Fujibayashi, S.; Nakayama, K.; Hamamoto, M.; Sakaguchi, S.; Nishiyama, Y.;
equivalent of azide 2 under similar aerobic reaction conditions. However, even
after prolonged reaction time, the starting material was recovered
unchanged. This indicates that the reaction cycle proposed in Scheme 2,
terminates in producing a molybdenum complex, which does not facilitate the
oxo-transfer reaction.
Ishii, Y. J. Mol. Catal. A: Chem. 1996, 110, 105; (d) Bortolini, O.; Campestrini, V.;
Di Furia, F.; Modena, G. J. Org. Chem. 1987, 52, 5467; (e) Trost, B. M.; Masuyama,
Y. Tetrahedron Lett. 1984, 25, 173; (f) Jacobson, S. E.; Muccigrosso, D. A.; Mares,
F. J. Org. Chem. 1979, 44, 921.
a
12. It was confirmed by an independent experiment that a stoichiometric amount
16. Typical experimental procedures: Method A: A well-stirred solution of
of reagent
1
was essential to convert p-methoxybenzyl azide
2
to the
benzylic azide (1 mmol) and 1 (10 mol %) in water (3 mL) under an oxygen
atmosphere was refluxed until completion of the reaction (monitored by TLC).
The reaction mixture was cooled, extracted with dichloromethane,
concentrated and purified by silica gel column chromatography (hexane–
EtOAc, 9:1) to furnish the corresponding aldehyde. Method B: A well-stirred
solution of benzylic azide (1 mmol) and 1 (10 mol %) in toluene (3 mL) under
an oxygen atmosphere was refluxed until completion of the reaction
(monitored by TLC). The reaction mixture was concentrated and purified by
silica gel column chromatography (hexane–EtOAc, 9:1) to furnish the
corresponding aldehyde.
corresponding aldehyde 2a under a nitrogen atmosphere (or in the absence
of oxygen). Therefore, the reaction of azide 2 with 10 mol % of 1 under a
nitrogen atmosphere converts only 10% of the azide to the corresponding
aldehyde 2a, which is consistent with our observations.
13. Hille, R.; Sprecher, H. J. Biol. Chem. 1987, 262, 10914.
14. Liebeskind, L. S.; Sharpless, K. B.; Wilson, R. D.; Ibers, J. A. J. Am. Chem. Soc. 1978,
100, 7061.
15. After isolating the product aldehyde 2a in the reaction of p-methoxybenzyl
azide (2) with 1, the aqueous solution was reacted again with another