Copper-catalyzed aerobic spirocyclization of biaryl-N-H-imines via 1,4-aminooxygenation of benzene rings

Article abstract of DOI:10.1021/ol301583y

A synthetic method of azaspirocyclohexadienones has been developed through copper-catalyzed aerobic spirocyclization of biaryl-N-H-imines prepared by the reaction of biarylcarbonitriles and Grignard reagents.

Full text of DOI:10.1021/ol301583y

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3550–3553
Copper-Catalyzed Aerobic
Spirocyclization of Biaryl-N-H-imines via
1,4-Aminooxygenation of Benzene Rings
Ya Lin Tnay, Cheng Chen, Yi Yuan Chua, Line Zhang, and Shunsuke Chiba*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received June 8, 2012
ABSTRACT
A synthetic method of azaspirocyclohexadienones has been developed through copper-catalyzed aerobic spirocyclization of biaryl-N-H-imines
prepared by the reaction of biarylcarbonitriles and Grignard reagents.
The spirocyclic structures are prevalent in various kinds
of biologically active natural products.1 While the typical
method to construct the spirocyclic cores involves oxida-
tive spirocyclization of phenol derivatives, commonly with
a stoichiometric amount of hypervalent iodine reagents
that could deliver spirocyclohexadienones (Scheme 1a),2,3
it would be beneficial to develop conceptually novel,
practical, and environmentally benign processes for spiro-
cyclization from readilyavailablebuildingblocks. Wehave
recently been interested in copper-mediated oxidative
functionalization of CꢀC unsaturated bonds under aero-
bic reaction conditions.4ꢀ6 During the course of these
studies, we disclosed a copper-catalyzed aerobic synthesis
of diazaspirocyclohexadienones from R-azido-N-aryla-
mides, which was carried out by a sequence of denitro-
genative formation of iminyl copper species from R-azido-
N-arylamides and their 1,4-amino-cupration with an
intramolecular benzene ring on the amido nitrogen followed
by consecutive formation of CdO bonds (1,4-aminooxy-
genation of the benzene ring) (Scheme 1b).4d Inspired by
this unprecedented Cu-catalyzed aerobic spirocyclization,
we have further strived to explore more opportunities to
construct spirocycles with other types of substrates.
(1) For selected reviews, see: (a) Cai, Y.-S.; Guo, Y.-W.; Krohn, K.
Nat. Prod. Rep. 2010, 27, 1840. (b) Gravel, E.; Poupon, E. Nat. Prod.
Rep. 2010, 27, 32. (c) Jin, Z. Nat. Prod. Rep. 2005, 22, 111. (d) Antunes,
E. M.; Copp, B. R.; Davies-Coleman, M. T.; Samaai, T. Nat. Prod. Rep.
2005, 22, 62. (e) Chawla, A. S.; Jackson, A. H. Nat. Prod. Rep. 1989, 6,
55.
We have recently utilized readily available carbonitriles
as a precursor of N-H imines by reaction with Grignard
ꢀ
(2) For reviews, see: (a) Pouysegu, L.; Deffieux, D.; Quideau, S.
Tetrahedron 2010, 66, 2235. (b) Dohi, T.; Kita, Y. Chem. Commun. 2009,
ꢀ
2073. (c) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 467.
(d) Ciufolini, M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.;
Chai, D. Synthesis 2007, 3759. (e) Rodrıguez, S.; Wipf, P. Synthesis 2004,
2767. (e) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004,
104, 1383.
(3) Kusama, H.; Yamashita, Y.; Uchiyama, K.; Narasaka, K. Bull.
Chem. Soc. Jpn. 1997, 70, 965.
(4) (a) Wang, Y.-F.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134,
3679. (b) Toh, K. K.; Wang, Y.-F.; Ng, E. P. J.; Chiba, S. J. Am. Chem.
Soc. 2011, 133, 13942. (c) Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett.
2010, 12, 3682. (d) Chiba, S.; Zhang, L.; Lee, J.-Y. J. Am. Chem. Soc.
2010, 132, 7266.
(5) For recent reviews on the copper-catalyzed aerobic oxidative
transformation, see: (a) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc.
Rev. 2012, 41, 3464. (b) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc.
Rev. 2012, 41, 3381. (c) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S.
Angew. Chem., Int. Ed. 2011, 50, 11062.
(6) For recent selected reports on copper-catalyzed aerobic oxidative
transformation, see: (a) Zhang, C.; Xu, Z.; Zhang, L.; Jiao, N. Angew.
Chem., Int. Ed. 2011, 50, 11088. (b) Wang, H.; Wang, Y.; Liang, D.; Liu,
L.; Zhang, J.; Zhu, Q. Angew. Chem., Int. Ed. 2011, 50, 5678. (c) Wang,
J.; Wang, J.; Zhu, Y.; Lu, P.; Wang, Y. Chem. Commun. 2011, 3275.
(d) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl,
S. S. J. Am. Chem. Soc. 2010, 132, 12068. (e) Zhang, C.; Jiao, N. J. Am.
Chem. Soc. 2010, 132, 28. (f) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009,
74, 4272. (g) Yang, L.; Lu, Z.; Stahl, S. S. Chem. Commun. 2009, 6460.
(h) Hewgley, J. B.; Stahl, S. S.; Kozlowski, M. C. J. Am. Chem. Soc. 2008,
130, 12232. (i) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008,
47, 1932. (j) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 6790.
(7) (a) Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett. 2011, 13, 1622.
(b) Sanjaya, S.; Chiba, S. Tetrahedron 2011, 67, 590.
r
10.1021/ol301583y
Published on Web 06/15/2012
2012 American Chemical Society

Cu(OAc)2 (20 mol %) were subsequently added, and the
reaction mixture was stirred at 80 °C under an O2 atmo-
sphere (1 atm) for 20 h, affording the 1,4-aminooxygena-
tion product, azaspirocyclohexadienone (()-3aa9 in
34% yield as the sole product (entry 1). The addition
of nitrogen ligands such as 1,10-phenanthroline (phen), 1,
4-diazabicyclo[2.2.2]octane (DABCO), and 2,20-bipyridine
(bpy) improved the yield of 3aa to 52ꢀ61% (entries 2ꢀ4).
With 1,10-phenanthroline as a ligand, not only Cu(OAc)2
but also CuBr2 and CuBr•SMe2 showed similar catalytic
activity (entries 5 and 6). Interestingly, the reaction with
Cu(OAc)2 and 1,10-phenanthroline (20 mol %) proceeded
even at rt (entry 7), and further addition of H2O (10 equiv)
dramatically improved the yield of 3aa to 81% (entry 8).
Utilization of 18O2 showed that one of the oxygen atoms
from O2 was incorporated into a resulting carbonyl group
of the azaspirodienone (see Supporting Information for
more details). Furthermore, reduction of the oxygen par-
tial pressure using air (0.21 atm of O2) accelerated the
reaction (entry 9). Reduction of the catalyst loading to
10 mol % did not affect the chemical yield (entry 10),
while 5 mol % of the catalysts render the process
sluggish (entry 11). The structure of copper(II) acetate
is binuclear with four carboxylate bridges.10 We be-
came keen to know the effect of a bimetallic structure of
Cu species for the present spirocyclization. By using the
modified Du Bois’s procedure,11 we succeeded in pre-
paring CuII2(esp)2•2H2O,12 which is supposed to have a
more rigid and stable bimetallic structure with the
dicarboxylic acid ligands. Interestingly, the reaction
with 5 mol % of CuII2(esp)2•2H2O proceeded smoothly
without the aid of any additive such as 1,10-phen and
H2O, affording 3aa in 70% yield under air (72% yield
under an O2 atmosphere) (entry 12). It is noted that the
reaction under an Ar atmosphere (even with a stoichio-
metric amount of Cu(OAc)2-phen) did not proceed at
all (entry 13).
Scheme 1
reagents followed by proper protonation.7 For example,
we found that the biaryl-N-H imines generated from
biaryl-2-carbonitriles possess an intriguing chemical reac-
tivity toward Cu-catalyzed aerobic CꢀN bond forma-
tion on an intramolecular aryl CꢀH bond (aromatic
CꢀH amination), affording phenanthridine derivatives
(Scheme 1c).4c In the context of our continuous interests
in the chemical reactivity of biaryl N-H imines under Cu-
catalyzed aerobic conditions, we were attracted by the
ortho-substituent effects which can maintain the helical
sense of the biaryl motifs through hindered rotation about
the biaryl axis. It was expected that the putative iminyl
copper species could interact with the π-face of the benzene
ring rather than with aromatic CꢀH bonds in such
a nonplanar structure, leading to azaspirocyclohexadie-
nones via intramolecular 1,4-aminooxygenation. Herein,
we wish to report the Cu-catalyzed aerobic spirocycliza-
tion of biaryl N-H imine intermediates generated from
biaryl-2-carbonitriles and Grignard reagents (Scheme 1d).
With this hypothesis, our investigation commenced
with the reactions of 3-methyl-2-(1-naphthyl)benzonitrile
(()-(1a) and p-tolylmagnesium bromide (2a) (Table 1).
The reaction of Grignard reagent 2a to benzonitrile 1a
occurred smoothly in Et2O at 80 °C (in sealed tube). After
protonation with MeOH,8 DMF (diluted to 0.1 M) and
Withthe optimized reactionconditionsin hand (Table 1,
entry 10), we next investigated the scope of Grignard
reagents 2 for the synthesis of azaspirocyclohexadienones
3 from carbonitrile 1a (Table 2). Aryl Grignard reagents
bearing both electron-donating (entries 1ꢀ3) and -with-
drawing groups (entry 4) as well as a CꢀCl bond (entries 5
and 6) could be utilized to give the corresponding spir-
odienones 3 in good yields. Sterically bulky substituents
such as 1-naphthyl and mesityl groups could also be
installed as R1 (entries 7 and 8). The reaction of alkylk-
etimine generated from primary alkyl Grignard reagent 2j
proceeded smoothly, while that of secondary 2k was
sluggish (entries 9 and 10).
(9) The structure of 3aa was secured by X-ray crystallographic
analysis (CCDC-874162); see Supporting Information.
(10) (a) Rao, V. M.; Sathyanarayana, D. N.; Manohar, H. J. Chem.
Soc., Dalton Trans. 1983, 2167. (b) van Niekerk, J. N.; Schoening,
F. R. L. Nature 1953, 171, 36.
(11) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem.
Soc. 2004, 126, 15378.
(8) Protonation with MeOH could prevent the partial hydrolysis of
N-H imines to the corresponding ketone; see: Pickard, P. L.; Tolbert,
T. L. J. Org. Chem. 1961, 26, 4886.
(12) The structure of CuII2(esp)2•2H2O was secured by X-ray crystal-
lographic analysis (CCDC-874165); see Supporting Information for
more details.
Org. Lett., Vol. 14, No. 13, 2012
3551

Table 1. Optimization of Reaction Conditionsa
Cu salts
(mol %)
additive-1
(mol %)
additive-2
(equiv)
temp
time
(h)
yield
(%)b
entry
atmosphere
(°C)
1
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
CuBr2 (20)
ꢀ
ꢀ
O2
80
80
80
80
80
80
rt
20
3
34
2
1,10-phen (20)
DABCO (20)
bpy (20)
ꢀ
O2
61
3
ꢀ
O2
3
59
4
ꢀ
O2
5
52
5
1,10-phen (20)
1,10-phen (20)
1,10-phen (20)
1,10-phen (20)
1,10-phen (20)
1,10-phen (10)
1,10-phen (5)
ꢀ
ꢀ
O2
5
50
6
CuBr•SMe2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (10)
Cu(OAc)2 (5)
ꢀ
O2
4
61
7
ꢀ
O2
3
55
8
H2O (10)
H2O (10)
H2O (10)
H2O (10)
ꢀ
O2 (18O2)
air
rt
3
81 (82)c
82
9
rt
2
10
11
12
13
air
rt
3
80
air
rt
17
6
76
Cu2(esp)2•2H2O (5)
Cu(OAc)2 (100)
air
rt
70 (72)d
0
1,10-phen (100)
H2O (10)
Ar
rt
48
a All reactions were conducted using 0.5 mmol of carbonitrile 1a (racemic) with 1.3 equiv of Grignard reagents 2a in Et2O (0.5 mL) at 80 °C (sealed
tube) for 2 h followed by addition of MeOH (60 μL), DMF (5 mL), Cu catalysts, and additives. b Isolated yields. c Isolated yield when the reaction was
conducted under an 18O2 atmosphere. d Isolated yield when the reaction was conducted under an O2 atmosphere. 1,10-phen = 1,10-phenanthroline;
DABCO = 1,4-diazabicyclo[2.2.2]octane; bpy = 2,20-bipyridine; esp = R,R,R0,R0-tetramethyl-1,3-benzenedipropionate.
Next by varying the substituents on biaryl carboni-
triles 1, we further explored the substrate scope using
p-tolyl Grignard reagent 2a (Chart 1). In general, as
Table 2. Scope of Grignard Reagentsa,b
the configurational (rotational) stability of the biaryl
motifs become more rigid by installing more than two
substituents in R2 and R3, the present oxygenative
spirocyclization proceeded smoothly, affording the
corresponding azaspirodienones 3 in good yields (for
3caꢀ3ja, 3pa except for 3ha and 3oa). The reactions
of the substrates bearing only one substituent in either
entry
R1-MgBr 2
time (h)
yield (%)b
R2 or R3, however, became sluggish, giving azaspir-
odienones 3 in moderate yields (for 3ba, 3kaꢀ3na).
The reactions of [1,10-binaphthalene]-2-carbonitrile
(1q) and 2-(anthracen-9-yl)benzonitrile (1r) as well
as 2-(dibenzofuran-4-yl)benzonitrile (1s) proceeded
smoothly to give 3qa, 3ra, and 3sa, respectively, in
good yields. It is worth noting that the present oxyge-
nation (the CdO bond formation) was observed ex-
clusively at the para-position of the resulting aminated
carbon (1,4-aminooxygenation).
1
2b: 4-MeO-C6H4-MgBr
2c: 2-MeO-C6H4-MgBr
2d: 4-PhO-C6H4-MgBr
2e: 4-CF3-C6H4-MgBr
2f: 4-Cl-C6H4-MgBr
2g: 3-Cl-C6H4-MgBr
2h: 1-naphthyl-MgBr
2i: 2,4,6-(Me)3-C6H2-MgBr
2j: n-C8H17-MgBr
20
20
72
19
48
5
3ab: 80
3ac: 72
3ad: 76
3ae: 80
3af: 70
3ag: 70
3ah: 85
3ai: 65
3aj: 70
3ak: 29
2
3
4
5
6
7
4
8
3.5
3
9c
10c
2k: i-C3H7-MgBr
3
a All reactions were conducted using 0.5 mmol of carbonitrile 1a
(racemic) with 1.3 equiv of Grignard reagents 2 in Et2O (0.5 mL) at 80 °C
(sealed tube) for 2 h followed by addition of MeOH (60 μL), DMF
(5 mL), Cu(OAc)2ꢀ1,10-phenanthroline (10 mol %), H2O (10 equiv),
and stirring at rt under an air atmosphere. b Isolated yields. c The reac-
tions with Grignard reagents 2j and 2k were stirred for 24 h.
(13) For reviews on synthesis of axially chiral biaryl compounds, see:
(a) Shibata, Y.; Tanaka, K. Synthesis 2012, 44, 323. (b) Bringmann, G.;
Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111, 563.
(c) Tanaka, K. Chem.;Asian J. 2009, 4, 508. (d) Bringmann, G.; Price
Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M.
Angew. Chem., Int. Ed. 2005, 44, 5384. (e) Bringmann, G.; Breuning, M.;
Tasler, S. Synthesis 1999, 525.
(14) For reports on transmission of the biaryl axial chirality to the
central chirality in the other processes, see: (a) Yasui, Y.; Suzuki, K.;
Matsumoto, T. Synlett 2004, 619. (b) Ohmori, K.; Kitamura, M.;
Suzuki, K. Angew. Chem., Int. Ed. 1999, 38, 1226.
Having developed the Cu-catalyzed aerobic spirocycli-
zation of biaryl N-H-imine derivatives, we were interested
in the possibility of transmitting the axial chirality of the
3552
Org. Lett., Vol. 14, No. 13, 2012

Chart 1. Scope of Biaryl Carbonitriles 1a,b
Scheme 2. Transmission of Axial Chirality to Central One
phthalene]-2-carbaldehyde,15,16 the aerobic spirocycliza-
tion with p-tolylmagnesium bromide (2a) provided
azaspiridienone (þ)-3qa as an enantiomerically
pure form (>99% ee), which suggested that the
present process is most likely free from racemization
(Scheme 2).17,18
In summary, we have developed a method for Cu-
catalyzed aerobic spirocyclization of biaryl N-H imines
which could be prepared concisely from readily avail-
able biaryl-2-carbonitriles and Grignard reagents. Mo-
lecular oxygen (O2) is a prerequisite for achieving the
present catalytic spirocyclization, where one of the
oxygen atoms of O2 is regioselectively incorporated
into the benzene ring with dearomatization through
1,4-aminooxygenation. Further investigation of the
scope, detailed mechanism, and synthetic applications
of the present strategy to other spirocycles as well as
development of the intermolecular processes for the
benzene oxygenation is currently underway.
a Unless otherwise noted, reactions were conducted using 0.5 mmol
of carbonitrile 1 (racemic) with 1.3 equiv of Grignard reagents 2a in
Et2O (0.5 mL) at 80 °C (sealed tube) for 2 h followed by addition
of MeOH (60 μL), DMF (5 mL), Cu(OAc)2ꢀ1,10-phenanthroline
(10 mol %), H2O (10 equiv), and stirring at rt under an Air
atmosphere. b Isolated yields were recorded and are shown. c The reac-
tion was conducted without the addition of H2O. d The reaction was
carried out at 60 °C.
Acknowledgment. This work was supported by funding
from Nanyang Technological University and the Singa-
pore Ministry of Education (Academic Research Fund
Tier 2: MOE2010-T2-1-009). We thank Dr. Yongxin Li
and Dr. Rakesh Ganguly (Division of Chemistry and
Biological Chemistry, School of Physical and Mathema-
tical Sciences, Nanyang Technological University) for
assistance in X-ray crystallographic analysis.
biaryl-2-carbonitriles 113 to the spiro central chirality of 3
inthe present process.14 Starting from opticallyactive[1,10-
binaphthalene]-2-carbonitrile (þ)-(1q) (>99% ee) pre-
pared from known enantiomerically pure (R)-[1,10-bina-
(15) Shindo, M.; Koga, K.; Tomioka, K. J. Am. Chem. Soc. 1992,
114, 8732.
(16) Based on the transformation utilized to prepare (þ)-1q from
enantiomerically pure (R)-[1,10-binaphthalene]-2-carbaldehyde, the ab-
solute configuration of (þ)-1q is estimated to be (R). See Supporting
Information for more details.
(17) The structures of both 1q and 3qa were determined by X-ray
crystallographic analysis (CCDC-875163 and CCDC-874164, respectively);
see Supporting Information.
(18) Based on the proposed mechanism of the present spirocycliza-
tion (see ref 4d), the absolute configuration of (þ)-3qa is estimated to
be (R).
Supporting Information Available. Experimental pro-
cedures, characterization of new compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3553