Oxidative transformation of azides to aryl nitriles using DIB/TBHP: Scope and mechanistic insights

Article abstract of DOI:10.1016/j.tetlet.2012.06.131

Bis(tert-butylperoxy)iodobenzene, generated in situ by the reaction between diacetoxyl iodobenzene (DIB) and tert-butyl hydroperoxide (TBHP), was used in the oxidative transformation of primary azides to nitriles, and secondary azides to ketones.

Full text of DOI:10.1016/j.tetlet.2012.06.131

Tetrahedron Letters 53 (2012) 4766–4769
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative transformation of azides to aryl nitriles using DIB/TBHP: scope
and mechanistic insights
a
a,b
b
a,
⇑
Yi Zhao , Xinying Chew , Gulice Y. C. Leung , Ying-Yeung Yeung
a
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
A STAR—Institute of Chemical & Engineering Science, 11 Biopolis Way, Helios, #03-08, Singapore 138667, Singapore
b
⁄
a r t i c l e i n f o
a b s t r a c t
Article history:
Bis(tert-butylperoxy)iodobenzene, generated in situ by the reaction between diacetoxyl iodobenzene
Received 25 May 2012
Revised 13 June 2012
Accepted 27 June 2012
Available online 4 July 2012
(
DIB) and tert-butyl hydroperoxide (TBHP), was used in the oxidative transformation of primary azides
to nitriles, and secondary azides to ketones.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Oxidation
Hypervalent iodine
Nitrile
Selectivity
Mechanism
Nitriles are important and useful organic building blocks.1 In
is preferential with organic azides due to their potentially explo-
sive nature.
2
particular, aryl nitriles are essential elements of natural products,
3
4
5
pharmaceuticals, agricultural chemicals, materials, and dyes. To
date, a number of methods have been developed for their synthesis
An initial experiment was performed using 1-(azidomethyl)-4-
methoxybenzene (8a) together with DIB/TBHP in MeCN at 0 °C.
To our delight, a 52% isolated yield of the desired 4-methoxybenzo-
nitrile (9a) was obtained when using a 2:4 ratio of DIB/TBHP (Table
1, entry 1). Bearing this preliminary result in mind, the ratio of DIB/
TBHP was varied systematically and it was found that the reaction
occurred very smoothly when the ratio was 3:4, resulting in the
formation of 4-methoxybenzonitrile (9a) in 83% yield (Table 1, en-
tries 2–5).
6
including substitution of alkyl halides with inorganic cyanides,
replacement of the aryl diazo-compound (Sandmeyer reaction),
dehydration of amides or oximes, and oxidation of azides. Among
7
8
these methods, transforming azides into nitriles has attracted
much attention. Efforts have involved the use of metallic re-
9
a
9b,9c
9d
9e
agents/catalysts including Pd,
Cu(II),
Cu(I),
Fe,
and
9
f
x 2 3
Ru(OH) /Al O .
In contrast, sporadic studies have been reported
1
0
on non-metallic-based methods.
Having identified the appropriate ratio of DIB and TBHP, other
solvents were screened and it was found that acetonitrile remained
superior (Table 1, entries 2 and 6–9). Using these optimized condi-
Recently, we developed a novel protocol using diacetoxyl iodo-
benzene (DIB) (1)/tert-butyl hydroperoxide (TBHP) (2) toward
11
13
allylic oxidation (Scheme 1, Eq. 2), and for the oxidation of unac-
tions, other substrates were examined. In general, the reactions
3
tivated and remote methylene sp C–Hs to ketones (Scheme 1, Eq.
proceeded smoothly with excellent selectivity and good yields,
resulting in the formation of the corresponding nitriles (Table 2).
Benzylic azides bearing electron-donating groups underwent effi-
cient oxidation to provide the corresponding benzonitriles in high
yields (Table 2, entries 3 and 4). Electron-deficient benzylic azides
are known to be less active toward such oxidative transformations.
Nevertheless, the DIB/TBHP protocol promoted the reactions in
good yields (Table 2, entries 5 and 6). Double oxidation of diazide
8h also worked well to offer dinitrile 9h (Table 2, entry 7). Notably,
sensitive functional groups survived under the reaction conditions.
For instance, cinnamyl azide 8i underwent facile oxidation to
afford the corresponding cinnamonitrile 9i in 76% yield (Table 2,
entry 8). Moreover, azide 8j was oxidized smoothly to yield the
1
2
3
). Based on the observations in these studies, bis(tert-butylper-
oxy)iodobenzene (3), which was generated in situ by the reaction
between DIB (1) and TBHP (2), would provide a reactive but con-
Å
trollable tBuOO species for methylene proton abstraction and oxi-
dation in specific solvents (Scheme 1, Eq. 1). Herein, we report an
efficient, mildly acidic, and non-metallic-based oxidative transfor-
mation of azides into aryl nitriles using the DIB/TBHP protocol. The
same protocol can also be used to convert secondary azides into
ketones (Scheme 1, Eq. 4). The reaction proceeded at 0 °C which
⇑
Corresponding author. Tel.: +65 65167760; fax: +65 67791691.
E-mail address: chmyyy@nus.edu.sg (Y.-Y. Yeung).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.131

Y. Zhao et al. / Tetrahedron Letters 53 (2012) 4766–4769
4767
PhI(OAc)2
+
tBuOOH
PhI(OOtBu)2
(1)
Table 2
Oxidation of azides 8
1
2
3
DIB, TBHP
MeCN, 0 °C
Previous studies
R
N3
R
C
N
O
8
9
H
H
R1
H
R1
R2
H
PhI(OOtBu)2
ester solvent
(
2)
R4
R2
R4
R3
R3
Entrya
1
Substrate
Product
Time (h), yield (%)b
4
5
CN
N3
O
O
X
6, 71
6, 70
H
H
8
b
9b
H
PhI(OOtBu)2
O
R
X
n
H
R
n
(3)
(4)
CN
N3
8c
N3
H
2
3
m
m
9c
CN
6
H
7
This study
6, 72
6, 73
8
d
9d
tBu
tBu
CN
N3
R1
N3
O
H
PhI(OOtBu)2
R
C N
R
R1
4
MeO
8e
MeO
9e
R
OMe
(
for R1 = H)
(for R1 = Alkyl, Ar)
OMe
8
CN
9
10
N3
5
6
10, 72
10, 78
Br
8f
9f
Scheme 1. Comparison of previous studies and the present work.
Br
CN
N3
8g
O2N
N3
9g
Table 1
Optimization of the DIB/TBHP azide oxidation
O2N
CN
N3
7
8
9
12, 69
10, 76
6, 73
8
h
9h
NC
CN
N3
DIB, TBHP
CN
solvent, 6 h, 0 °C
N3
8i
N3
8j
MeO
MeO
8a
9a
9i
CN
BnO
9j
BnO
Entrya
Yield (%)b
OMe
OMe
Solvent
DIB (equiv)
TBHP (equiv)
CN
1
2
3
4
5
6
7
8
9
MeCN
MeCN
MeCN
MeCN
MeCN
EtOAc
THF
2
3
4
3
3
3
3
3
3
4
4
4
3
5
4
4
4
4
52
83
65
61
70
59
35
51
68
1
1
0
N3
12, 50
12, 61
9k
Br 8k
Br
1c
N3
N
N
CN
8
l
9l
toluene
CH Cl
a
Reactions were carried out with substrate (1.0 mmol), DIB (3.0 mmol), and
TBPH (4.0 mmol) in MeCN (1.0 mL) at 0 °C.
2
2
a
b
Reactions were carried out with substrate (0.5 mmol) in solvent (0.5 mL) at 0 °C.
Isolated yield.
Isolated yield.
Reaction was conducted at 40 °C.
b
c
and 9). A possible explanation is that the solvent may not partici-
pate in the iodine reagent interaction as was observed in the DIB/
desired nitrile without affecting the benzyl group (Table 2, entry
1
1
9
). The sterically bulky 2,6-disubstituted substrate 8k provided
TBHP allylic oxidation study.
a moderate yield of the expected nitrile 9k (Table 2, entry 10).
For the oxidation of 3-(azidomethyl)pyridine 8l, an increase in
the temperature was required to achieve a reasonable reaction rate
Based on the DIB/TBHP allylic oxidation reaction mechanism,11
the benzylic proton in 8 can be abstracted by a peroxy radical fol-
lowed by benzylic/tert-butylperoxy radical coupling to give peroxy
species 12 (Scheme 3). However, no peroxy 12 associated products
(Table 2, entry 11).
This reaction could also be conducted in a one-pot fashion. For
(
e.g., 13) were observed which imply that a dissociated tert-butyl-
example, benzyl bromide (8b) reacted firstly with sodium azide in
MeCN. After consumption of benzyl bromide (8b), the DIB/TBHP
reagent was added to the same pot to yield the desired nitrile 9b
peroxy radical may not be dominant in the mechanism of this type
of reaction.
(Scheme 2).
We attempted to understand the mechanism from several as-
1
1,12
pects. Unlike the allylic oxidation in our previous report,
this
CN
azide oxidation is relatively less solvent dependent (Table 1). A Le-
1. NaN3, MeCN, 60 °C
Br
wis basic solvent was essential for obtaining high yields in the DIB/
2. DIB, TBHP, MeCN, 0 °C
66%
TBHP allylic oxidation.11 In contrast, less polar solvents such as tol-
8
b
9b
uene led to yields comparable to those obtained using ethyl acetate
and dichloromethane in the present study (Table 1, entries 8 vs 6
Scheme 2. Synthesis of nitrile 9a in a one-pot fashion.

4
768
Y. Zhao et al. / Tetrahedron Letters 53 (2012) 4766–4769
R
H
R
R
OOtBu
N3
O
intermediate 15 (R = alkyl, Ar) during the work-up (Scheme 3); fur-
tBuOO
tBuOO
ther oxidation of such an imine to a nitrile was impossible due to
the absence of a methine proton. A careful study on the oxidation
of azide 8o using limited reagents and a shorter reaction time al-
lowed us to obtain an appreciable amount of aldehyde 17 (Scheme
Ar
R
N3
Ar
N3
Ar
Ar
Ar
N3
8
11
12
13
R = H
PhI(OOtBu)2
OOtBu
4, Eq. 2), a product that was potentially generated through the
H
R
decomposition of imine intermediate 15 (R = H) (Scheme 3).
The radical nature of this reaction was indicated by conducting
a radical scavenger experiment, in which the reaction was shut
down upon the addition of BHT. A competitive experiment on
the oxidation of azides 8b and 8p was performed (Scheme 5).
The result showed that the oxidation occurred more readily on
8p. This selectivity may be ascribed to a radical deprotonation pro-
cess which occurs preferentially on a secondary carbon. We
acknowledge that the mechanism remains unclear and requires
further investigation.
OOtBu
I
OOtBu
-N2
I
C
N
Ar
N
Ar
N
Ph
-tBuOOH
Ph
15
9
N2
R = H
1
4
H2O R = Alkyl, Ar
R
R
H2O
Ar
NH
Ar
O
1
6
10
In summary, a mild and efficient azide oxidation using inexpen-
sive and commercially available DIB/TBHP has been developed.
Further investigation on the mechanistic profile is in progress.
Scheme 3. Proposed mechanism for the azide oxidation.
N3
O
Acknowledgments
87%
8
m
10m
We thank the National University of Singapore for financial sup-
port (Grant No. 143-000-509-112) and for a scholarship to Y. Zhao
DIB, TBHP
MeCN
(1)
N3
O
(
NUS Research Scholarship).
76%
References and notes
8n
10n
1.
(a) Friedrich, K.; Wallenfels, K. In The Chemistry of the Cyano Group; Rappoport,
Z., Ed.; Wiley: New York, 1970. Patai Series; (b) Arseniyadis, S.; Kyler, K. S.;
Watt, D. S. In Organic Reactions; Dauben, W. G., Ed.; Wiley: New York, 1984;
Vol. 31, pp 1–374; (c) Fatiadi, A. J. In Preparation and Synthetic Applications of
Cyano Compounds; Patai, S., Rappaport, Z., Eds.; Wiley: New York, 1983; (d)
Larock, R. C. Comprehensive Organic Transformations; VCH: New York, 1989; (e)
Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances:
Synthesis Patents, Applications, 4th ed.; Georg Thieme: Stuttgart, 2001; (f) Smith,
M. B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 6th ed.; Wiley, Hoboken: New Jersey, 2007.
MeO
AcO
CN
9
1
o
7
58%
25%
MeO
AcO
N3
DIB, TBHP
MeCN
+
(2)
MeO
AcO
8o
O
2. Fleming, F. Nat. Prod. Rep. 1999, 16, 597.
3.
(a) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359; (b) Jones, L. H.;
Summerhill, N. W.; Swain, N. A.; Mills, J. E. Med. Chem. Commun. 2010, 1, 309;
Scheme 4. Oxidation of azides to carbonyl compounds.
(
c) Njar, V. C. O.; Brodie, A. M. H. Drugs 1999, 58, 233; (d) Murdoch, D.; Keam, S.
J. Drugs 2005, 65, 2379.
4
.
(a) Okada, A.; Watanabe, K.; Umeda, K.; Miyakado, M. Agric. Biol. Chem. 1991,
55, 2765; (b) Chiang, W. C. K.; Pusateri, D. J.; Leitz, R. E. A. J. Agric. Food Chem.
1998, 1018, 46.
N3
CN
(
0.1 mmol)
0.1 mmol)
1
0%
5. (a) Tang, J.; Hua, J.; Wu, W.; Li, J.; Jin, Z.; Long, Y.; Tian, H. Energy Environ. Sci.
2
2
010, 3, 1736; (b) Lee, W.; Cho, N.; Kwon, J.; Ko, J.; Hong, J.-I. Chem. Asian J.
012, 7, 343; (c) Chang, Y. J.; Chow, T. J. J. Mater. Chem. 2011, 21, 9523.
8b
9b
MeCN, 0 °C, 2 h
+
+
6. For classical Kolbe nitrile synthesis, see: (a) Kim, D. W.; Song, C. E.; Chi, D. Y. J.
Org. Chem. 2003, 68, 4281–4285; (b) Friedrich, K.; Wallenfels, K. In The
Chemistry of the Cyano Group; Rappoport, Z., Ed.; Wiley: New York, 1970; (c)
Fatiadi, A. J. In Preparation and Synthetic Applications of Cyano Compounds; Patai,
S., Rappaport, S. Z., Eds.; Wiley: New York, 1983; For recent reviews and
examples, see: (d) Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837; (e) Cristau,
H.-J.; Ouali, A.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2005, 11, 2483; (f)
Grossman, O.; Gelman, D. Org. Lett. 2006, 8, 1189; (g) Schareina, T.; Zapf, A.;
Maegerlein, W.; Müeller, N.; Beller, M. Chem. Eur. J. 2007, 13, 6249; (h) Chen, G.;
Weng, J.; Zheng, Z.; Zhu, X.; Cai, Y.; Cai, J.; Wan, Y. Eur. J. Org. Chem. 2008, 3524;
(i) Ren, Y.; Wang, W.; Zhao, S.; Tian, X.; Wang, J.; Yin, W.; Cheng, L. Tetrahedron
Lett. 2009, 50, 4595; (j) Ushkov, A. V.; Grushin, V. V. J. Am. Chem. Soc. 2011, 133,
10999; (k) Zhang, G.; Ren, X.; Chen, J.; Hu, M.; Cheng, J. Org. Lett. 2011, 13, 5004;
N3
DIB (0.1 mmol)
TBHP (0.3 mmol)
O
(
42%
8p
10p
Scheme 5. Competitive experiment between 8b and 8p.
The above-mentioned phenomena led us to speculate that the
hypervalent iodine species may coordinate to the azide and may
react through a metal-like transition state.
9c,9f,14
A proposed mech-
(
l) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev. 2011, 40, 5049; (m)
anistic pathway is shown in Scheme 3. The azide may be involved
in a weak interaction with the reactive species, bis(tert-butylper-
oxy)iodobenzene (3) to yield complex 14. Subsequent benzylic
proton abstraction accompanied by elimination of dinitrogen can
give imine intermediate 15. Finally, benzylic methine proton
abstraction followed by the collapse of complex 15 (R = H) affords
the aryl nitrile product 9.
We have also examined the oxidation of secondary azides 8m
and 8n. Under the standard conditions, ketones 10m and 10n were
obtained as the sole products (Scheme 4, Eq. 1). These
products might be produced through the hydrolysis of the imine
Yu, H.; Richey, R. N.; Miller, W. D.; Xu, J.; May, S. A. J. Org. Lett. 2010, 76, 665; (n)
Zhang, D.; Sun, H.; Zhang, L.; Zhou, Y.; Li, C.; Jiang, H.; Chen, K.; Liu, H. Chem.
Commun. 2012, 48, 2909.
For Reviews, see: (a) Hodgson, H. H. Chem. Rev. 1947, 40, 251; (b) Galli, C. Chem.
Rev. 1988, 88, 765; (c) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 1047, 94.
7.
8. (a) Yang, S. H.; Chang, S. Org. Lett. 2001, 3, 4209; (b) Ishihara, K.; Furuya, Y.;
Yamamoto, H. Angew. Chem., Int. Ed. 2002, 41, 2983; (c) Choi, E.; Lee, C.; Na, Y.;
Chang, S. Org. Lett. 2002, 4, 2369; (d) Yan, P.; Batamack, P.; Prakash, G. K. S.;
Olah, G. A. Catal. Lett. 2005, 101, 141; (e) Yamaguchi, K.; Fujiwara, H.;
Ogasawara, Y.; Kotani, M.; Mizuno, N. Angew. Chem., Int. Ed. 2007, 46, 3922; (f)
Singh, M. K.; Lakshman, M. K. J. Org. Chem. 2009, 74, 3079; (g) Zhou, S.; Junge,
K.; Addis, D.; Das, S.; Beller, M. Org. Lett. 2009, 11, 2461; (h) Zhou, S.; Addis, D.;
Das, S.; Junge, K.; Beller, M. Chem. Commun. 2009, 4883; (i) Sueoka, S.;
Mitsudome, T.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Chem. Commun. 2010, 46,

Y. Zhao et al. / Tetrahedron Letters 53 (2012) 4766–4769
4769
8
243; (j) Enthaler, S. Chem. Eur. J. 2011, 17, 9316; (k) Enthaler, S.; Weidauer, M.
13. Representative procedure: To a solution of 1-(azidomethyl)-4-methoxybenzene
(8a) (81 mg, 0.5 mmol) in MeCN (0.5 mL) was added PhI(OAc) (1) (483.1 mg,
1.5 mmol) at 0 °C. The resultant suspension was stirred vigorously while a
Catal. Lett. 2011, 1079, 141; (l) Denton, R. M.; An, J.; Lindovska, P.; Lewis, W.
Tetrahedron 2012, 68, 2899.
9
.
(a) Hayashi, H.; Ohno, A.; Oka, S. Bull. Chem. Soc. Jpn. 1976, 49, 506; (b) Zhou,
W.; Zhang, L.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 7094; (c) Chiba, S.; Zhang,
L.; Ang, G. Y.; Hui, B. W.-Q. Org. Lett. 2010, 12, 2052; (d) Lamani, M.; Prabhu, K.
R. Angew. Chem., Int. Ed. 2010, 49, 6622; (e) Zhou, W.; Xu, J.; Zhang, L.; Jiao, N.
Org. Lett. 2010, 12, 2888; (f) He, J.; Yamaguchi, K.; Mizuno, N. J. Org. Chem. 2011,
solution of tBuOOH (2) (5.0–6.0 M in decane, 360 lL, 2.0 mmol) was added
dropwise over 1 h. After the addition, the reaction mixture was stirred for 11 h
followed by chromatography on silica gel with n-hexanes/EtOAc (10:1) to yield
4-methoxybenzonitrile (9a) as a yellow oil (55.3 mg, 83%).
14. (a) Ochiai, M. Coord. Chem. Rev. 2006, 250, 2771; (b) Ochiai, M.; Miyamoto, K.;
Shiro, M.; Ozawa, T.; Yamaguchi, K. J. Am. Chem. Soc. 2003, 125, 13006; (c)
Ochiai, M.; Suefuji, T.; Miyamoto, K.; Tada, N.; Goto, S.; Shiro, M.; Sakamoto, S.;
Yamaguchi, K. J. Am. Chem. Soc. 2002, 125, 769; (d) Ochiai, M.; Kaneaki, T.; Tada,
N.; Miyamoto, K.; Chuman, H.; Shiro, M.; Hayashi, S.; Nakanishi, W. J. Am. Chem.
Soc. 2007, 129, 12938; (e) Ochiai, M.; Okada, T.; Tada, N.; Yoshimura, A.;
Miyamoto, K.; Shiro, M. J. Am. Chem. Soc. 2009, 131, 8392; (f) Kita, Y.; Morimoto,
K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am. Chem. Soc. 2009, 131, 1668.
76, 4606.
1
0. (a) Sasson, R.; Rozen, S. Org. Lett. 2005, 7, 2177; During the preparation of this
manuscript, a method which involved the use of KI as the catalyst appeared in
the literature, see: (b) Lamani, M.; Devadig, P.; Prabhu, K. R. Org. Biomol. Chem.
2
012, 10, 2753.
1
1. Zhao, Y.; Yeung, Y.-Y. Org. Lett. 2010, 12, 2128.
1
2. Zhao, Y.; Yim, W.-L.; Tan, C. K.; Yeung, Y.-Y. Org. Lett. 2011, 13, 4308.