Generation of iminyl copper species from α-azido carbonyl compounds and their catalytic C-C bond cleavage under an oxygen atmosphere

Article abstract of DOI:10.1021/ol100522z

Figure presented A copper-catalyzed reaction of α-azidocarbonyl compounds under an oxygen atmosphere is reported where nitriles are formed via C-C bond cleavage of a transient iminyl copper intermediate. The transformation is carried out by a sequence of denitrogenative formation of iminyl copper species from α-azidocarbonyl compounds and their C-C bond cleavage, where molecular oxygen (1 atm) is a prerequisite to achieve the catalytic process and one of the oxygen atoms of O₂ was found to be incorporated into the β-carbon fragment as a carboxylic acid.

Full text of DOI:10.1021/ol100522z

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2052-2055
Generation of Iminyl Copper Species
from r-Azido Carbonyl Compounds and
Their Catalytic C-C Bond Cleavage
under an Oxygen Atmosphere
Shunsuke Chiba,* Line Zhang, Gim Yean Ang, and Benjamin Wei-Qiang Hui
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received March 3, 2010
ABSTRACT
A copper-catalyzed reaction of r-azidocarbonyl compounds under an oxygen atmosphere is reported where nitriles are formed via C-C bond
cleavage of a transient iminyl copper intermediate. The transformation is carried out by a sequence of denitrogenative formation of iminyl
copper species from r-azidocarbonyl compounds and their C-C bond cleavage, where molecular oxygen (1 atm) is a prerequisite to achieve
the catalytic process and one of the oxygen atoms of O2 was found to be incorporated into the ꢀ-carbon fragment as a carboxylic acid.
Transition-metal-catalyzed C-C bond cleavage has attracted
attention as a versatile tool in organic synthesis, and various
modes of catalytic processes have been reported to activate inert
C-C bonds.1 Among them, ꢀ-carbon elimination of iminyl
metal species ([M]-NdCR-Cꢀ f Nt CR + Cꢀ-[M]) has
recently been disclosed, where release of ring strain or
formation of a relatively stable Cꢀ-[M] bond by cleavage
of the CR-Cꢀ bond contributes significantly to the driving
force of such reactions, although the examples are particularly
rare.2,3 Herein, we report a copper-catalyzed reaction of
R-azido carbonyl compounds under an oxygen atmosphere,
providing nitriles4 via C-C bond cleavage of a transient
iminyl copper intermediate (Scheme 1). The present trans-
formation is carried out by a sequence of denitrogenative
formation of iminyl copper species from R-azido carbonyl
compounds and their C-C bond cleavage, where molecular
oxygen is a prerequisite to achieve the catalytic process and
(1) For recent reviews, see: (a) Satoh, T.; Miura, M. Top. Organomet.
Chem. 2005, 14, 1. (b) Jun, C.-H. Chem. Soc. ReV. 2004, 33, 610. (c)
Rybtchinski, B.; Milstein, D. Angew. Chem., Int. Ed. 1999, 38, 870. (d)
Murakami, M.; Ito, Y. In ActiVation of UnreactiVe Bonds and Organic
Synthesis; Murai, S., Ed.; Springer: New York, 1999; pp 97-129.
(2) (a) Zhao, P.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 11618.
(b) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2000, 122, 12049.
(3) For generation of iminyl metal species and their application, see:
(a) Chiba, S.; Xu, Y.-J.; Wang, Y.-F. J. Am. Chem. Soc. 2009, 131, 12886.
(b) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131, 12570. (c)
Gerfaund, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 572.
(d) Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918. (e) Wang,
Y.-F.; Toh, K. K.; Chiba, S.; Narasaka, K. Org. Lett. 2008, 10, 5019. (f)
Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. (g)
Ichikawa, J.; Nadano, R.; Ito, N. Chem. Commun. 2006, 4423. (h) Narasaka,
K.; Kitamura, M. Eur. J. Org. Chem. 2005, 4505.
(4) For recent selected reports on synthesis of nitriles: (a) Zhou, W.;
Zhang, L.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 7094. (b) Oishi, T.;
Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2009, 48, 6286. (c)
Kangani, C. O.; Day, B. W.; Kelley, D. E. Tetrahedron Lett. 2008, 49,
914. (d) Yamaguchi, K.; Fujiwara, H.; Ogasawara, Y.; Kotani, M.; Mizuno,
N. Angew. Chem., Int. Ed. 2007, 46, 3922. (e) Kuo, C.-W.; Zhu, J.-L.; Wu,
J.-D.; Chu, C.-M.; Yao, C.-F.; Shia, K.-S. Chem. Commun. 2007, 301. (f)
Iida, S.; Togo, H. Tetrahedron 2007, 63, 8274. (g) Schareina, T.; Zapf, A.;
Beller, M. Chem. Commun. 2004, 1388. (h) Zanon, J.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 2890. (i) Ishihara, K.; Furuya,
Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2002, 41, 2983. (j) Choi, E.;
Lee, C.; Na, Y.; Chang, S. Org. Lett. 2002, 4, 2369. (k) Herna´ndez, R.;
Le´on, E. I.; Moreno, P.; Sua´rez, E. J. Org. Chem. 1997, 62, 8974.
10.1021/ol100522z  2010 American Chemical Society
Published on Web 03/25/2010

3a apparently occurred by elimination of an ethoxycarbonyl
group6,7 presumably via ꢀ-carbon elimination of an iminyl
copper intermediate B.
Further optimization of this nitrile formation was inves-
tigated by using ethyl 2-azido-2-(naphthalen-2-yl)acetate (1b)
(Table 1). Treatment of 1b with Cu(OAc)2 (1 equiv) and
Scheme 1. Copper-Catalyzed Nitrile Formation from R-Azido
Carbonyl Compounds under an Oxygen Atmosphere
Table 1. Optimization of Reaction Conditions
one of the oxygen atoms of O2 was found to be incorporated
into the ꢀ-carbon fragment as a carboxylic acid.
We have recently reported the synthesis of isoquinoline
derivatives from R-azido carbonyl compounds possessing a
2-alkenylaryl moiety at the R-position. The reaction proceeded
via 6π-electrocyclization of N-H imine intermediates A, which
are formed by treatment of azide such as 1a with K2CO3 in the
presence of EtOH as a proton source (Scheme 2).5
yielda (%)
copper salts
(equiv)
atmosphere
(1 atm)
entry
time (h)
3b
4
1b
2b
3b,c
4
5
6
7
8
9
10
11
12
13
14
Cu(OAc)2 (1.0)
Cu(OAc)2 (0.2)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.1)
Cu(OTf)2 (0.2)
Cu(acac)2 (0.2)
CuCl2 (0.2)
Ar
Ar
Ar
Air
O2
Air
O2
O2
O2
O2
O2
O2
O2
O2
24
24
11
4
78
11
71
89
94
70
90
83
45
32
38
83
52
43
3
12
6
0
0
2
0
0
6
32
41
0
26
41
4
25
7.5
24
29
25
32
5
Scheme 2. Isoquinoline Formation from R-Azido Carbonyl
Compounds Possessing a 2-Alkenylaryl Moiety at the R-Position
CuTC (0.2)
CuI (0.2)
CuCl (0.2)
25
24
a Isolated yield. b Degassed DMF was used. c PhI(OAc)2 (1 equiv) was
used as an additive. TC: thiophene-2 -carboxylate.
K2CO3 (1 equiv) in DMF at 60 °C directly delivered
2-naphthonitrile (3b) in 78% yield along with 3% yield of
R-keto ester 4, which should be formed by hydrolysis of the
corresponding iminyl copper or N-H imine intermediate
(Table 1, entry 1). In this case, coordination of Cu(OAc)2 to
the internal nitrogen of the azido moiety might induce
denitrogenative formation of iminyl copper (see Scheme 1).8
A catalytic amount of Cu(OAc)2 under an Ar atmosphere
could not complete the reaction (entry 2). It was found that
the reaction of 1 equiv of Cu(OAc)2 in the presence of
PhI(OAc)2 provided nitrile 3b in shorter reaction time (entry
3). Moreover, the reaction was dramatically accelerated in
the presence of molecular oxygen with excellent yields of
3b (entries 4 and 5). Under an oxygen atmosphere (1 atm),
nitrile 3b was obtained in 90% yield by using 20 mol % of
Cu(OAc)2 (entry 7), while lower catalytic loading (10 mol
%) needed longer time (entry 8). Cu(II) salts bearing the
The current study focused on generation of iminyl metal
species by trapping this N-H imine A with transition metals2a
and exploring their chemical reactivity. During the course
of this study, it was found that treatment of generated N-H
imine A with 1 equiv of Cu(OAc)2 at 60 °C under an Ar
atmosphere afforded unexpected aryl nitrile 3a in 32% yield
instead of isoquinoline 2 (Scheme 3). The formation of nitrile
Scheme 3. Unexpected Nitrile Formation Mediated by Cu(OAc)2
(5) Hui, B. W.-Q.; Chiba, S. Org. Lett. 2009, 11, 729
.
(6) For radical fragmentation of R-aminocarbonyliminyl radicals, see:
Bencivenni, G.; Lanza, T.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo,
P.; Zanardi, G. J. Org. Chem. 2008, 73, 4721
.
(7) For examples of C-C bond cleavage with elimination of a carbonyl
moiety, see: (a) Ram, R. N.; Singh, L. Tetrahedron Lett. 1995, 36, 5401.
(b) Jin, S.-J.; Arora, P. K.; Sayre, L. M. J. Org. Chem. 1990, 55, 3011
(8) For a report on the coordination of the internal nitrogen of azido
moiety with a Cu(II) complex, see: Barz, M.; Herdweck, E.; Thiel, W. R.
Angew. Chem., Int. Ed. 1998, 37, 2262.
.
Org. Lett., Vol. 12, No. 9, 2010
2053

other counteranions were not effective for this reaction
(entries 9-11). Cu(I) species also exhibited catalytic activity
(entries 12-14) in which copper(I) thiophene-2-carboxylate
(CuTC) provided good yield (entry 12). Other metal salts
like Pd(II), Mn(III), Co(II), and Fe(III) were not viable
catalysts for this transformation (see the Supporting Informa-
tion for more detailed studies).
molecular oxygen, substrates 6, 8, and 10 were employed
(Schemes 4-6).
Scheme 4. Reaction of 2,4,4-Trimethyl-1-pentyl Ester 6
With the optimized catalytic conditions in hand, we next
examined the generality of this catalytic method for the
synthesis of substituted nitriles using R-azido esters 1 (Table
2). The process could provide decarboxylated one-carbon
Table 2. Synthesis of Nitriles
Scheme 5. Reactions of R-Keto Azides 8
a Reactions were carried out using 0.3-0.55 mmol of 1. b Isolated yields
are recorded in parentheses. c 1 equiv of Cu(OAc)2 was used, and
phenanthridine 5 was obtained in 20% yield. In the case of 40 mol % of
Cu(OAc)2, 3e and 5 were obtained in 55 and 41% yields, respectively. d The
reactions were run using the corresponding bromide (for 3k) or mesylates
(for 3l, 3m, 3n) by treatment with NaN3 followed by Cu(OAc)2 and K2CO3
under O2 (1 atm). e 40 mol % of Cu(OAc)2 was used at 80 °C. f A methyl
ester was used as a starting material. g 1 equiv of NaOEt was used as a
base.
Scheme 6. Reactions of R-Keto Azides 10
shorter nitriles from the corresponding carboxylic acid
derivatives. For synthesis of aryl nitriles, the reaction allowed
installing both electron-donating (3b-h) and -withdrawing
groups (3i-n). When R is a 2-biphenyl group, nitrile 3e was
formed in 55% yield along with 41% yield of phenanthridine
5 using 40 mol % of Cu(OAc)2, while a stoichiometric use
of Cu(OAc)2 improved the yield of nitrile 3e to 74% (with
20% yield of 5).9 Halogen atoms like Br and F were
successfully incorporated with keeping the carbon-halogen
bond intact (3i-l). Alkyl nitriles were also accessed utilizing
NaOEt as a base. In particular, formation of tertiary nitriles
proceeded with good yields (3o, 3p), while secondary and
primary nitriles were obtained in moderate yields (3q, 3r).
To probe the reaction mechanism of this catalytic cycle,
especially for elucidation of co-products derived from the
carbonyl fragment after C-C bond cleavage and the role of
The reaction of 2,4,4-trimethyl-1-pentyl ester 6 afforded
nitrile 3b and 2,4,4-trimethyl-1-pentanol (7) in 81% and 72%
yields, respectively (Scheme 4).
Interestingly, treatment of R-keto azide 8 instead of
R-azido esters provided nitrile 3f and the corresponding
benzoic acid 9 in good yields (Scheme 5a). Utilization of
18O2 revealed that one of the oxygen atoms from O2 is
incorporated into the benzoic acids (see the Supporting
Information).10 A reaction of azide 8 with 1 equiv of
Cu(OAc)2 under an Ar atmosphere also delivered nitriles 3f
and benzoic acid 9 (Scheme 5-b). In this case, acid 9 might
(9) For proposed mechanisms on the formation of phenanthridine 5, see
the Supporting Information.
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Org. Lett., Vol. 12, No. 9, 2010

be formed via air oxidation of the resulting acylcopper
species (see ref 14) during the workup process.
moiety to induce C-C bond cleavage to deliver nitrile 3
and acylperoxy copper IV. Protonation of acylperoxy copper
IV provides carboxylic acid V with regeneration of Cu(II)
salts, while we are not certain as to the mechanism of this
oxidation process.14 When ester substrates are utilized, further
decarboxylation of V occurs to afford the alcohols.
R-Keto azide 10 also provided nitrile 3f and acid 11
(Scheme 6a). The reaction of 10 in the presence of styrene
(12) (1 equiv) under the present catalytic conditions gave 3f
(76%) and 11 (54%) along with styrene oxide (13) in 9%
yield (analyzed by GC), which suggested that acylperoxy
copper species might be involved in the catalytic cycle
(Scheme 6b).11,12
Based on these results, we propose a mechanistic pos-
sibility of this Cu(OAc)2-catalyzed reaction under an O2
atmosphere as shown in Scheme 7. Denitrogenative forma-
Continuous studies on the scope, mechanistic evaluation,
and synthetic applications of the present C-C bond cleavage
as well as further exploitation of new chemical reactivity of
iminyl metals are in progress.
Acknowledgment. This work was supported by funding
from Nanyang Technological University and Singapore
Ministry of Education.
Scheme 7. A Proposed Catalytic Cycle
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100522Z
(12) It was confirmed that the reaction of styrene (12) under the present
catalytic conditions without azide 10 did not form styrene oxide (13) at all.
(13) For generation of iminyl lithium species from R-azido carbonyl
compounds, see: Manis, P. A.; Rathke, M. W. J. Org. Chem. 1980, 45,
4952. For iminyl titanium(IV) species, see: Ciez, D. Org. Lett. 2009, 11,
4282.
(14) The stoichiometric reactions under an Ar atmosphere (Table 1, entry
1 and Scheme 5b) indicated that iminyl copper(II) II could form nitrile 3
and acylcopper VI by ꢀ-carbon elimination (path A). Based on these results,
it was speculated as another mechanistic possibility (path B) that peroxy-
copper III undergoes ꢀ-fission to lead formation of nitrile 3 and acylcopper
VII, which isomerizes to acylperoxy copper IV.
tion of iminyl copper intermediate II13 from 1 followed by
oxidation of II with O2 affords peroxycopper(III) species
III, which subsequently adds to the intramolecular carbonyl
(10) For copper-mediated incorporation of the oxygen atom into
carboxylic acid derivatives from O2, see: (a) Kim, S.; Lee, J. I. J. Chem.
Soc., Chem. Commun. 1981, 1231. (b) van Koten, G.; Noltes, J. G. J. Chem.
Soc., Chem. Commun. 1972, 59
.
(11) For the chemical reactivity of acylperoxy metals, see: Cornell, C. N.;
Sigman, M. S. In ActiVation of Small Molecules; Tolman, W. B., Ed.; Wiely:
Weinheim, 2006; pp 159-186 and references therein.
Org. Lett., Vol. 12, No. 9, 2010
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