Chemoselective organocatalytic aerobic oxidation of primary amines to secondary imines

Article abstract of DOI:10.1021/ol301095j

Biomimetic aerobic oxidation of primary benzylic amines has been achieved by using a quinone catalyst. Excellent selectivity is observed for primary, unbranched benzylic amines relative to secondary/tertiary amines, branched benzylic amines, and aliphatic amines. The exquisite selectivity for benzylic amines enables oxidative self-sorting within dynamic mixtures of amines and imines to afford high yields of cross-coupled imine products.

Full text of DOI:10.1021/ol301095j

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Chemoselective Organocatalytic Aerobic
Oxidation of Primary Amines
to Secondary Imines
Alison E. Wendlandt and Shannon S. Stahl*
University of WisconsinÀMadison, 1101 University Avenue, Madison, Wisconsin 53706,
United States
stahl@chem.wisc.edu
Received April 24, 2012
ABSTRACT
Biomimetic aerobic oxidation of primary benzylic amines has been achieved by using a quinone catalyst. Excellent selectivity is observed for
primary, unbranched benzylic amines relative to secondary/tertiary amines, branched benzylic amines, and aliphatic amines. The exquisite
selectivity for benzylic amines enables oxidative self-sorting within dynamic mixtures of amines and imines to afford high yields of cross-coupled
imine products.
Imines are valuable synthetic intermediates,1 and a
range of methods for the preparation of secondary imines
from primary or secondary amines is known.2 Typical
strategies employ transition-metal catalysts with a stoi-
chiometric oxidant, and these include methods capable of
using molecular oxygen as the terminal oxidant.2aÀc,eÀh In
biology, copper amine oxidases mediate aerobic oxidation
of primary amines to aldehydes using ortho-quinone co-
factors, such as topaquinone (TPQ) and lysine tyrosylqui-
none (LTQ).3 Biochemical studies suggest that copper is
required for biosynthesis of the quinone cofactors, but it is
not involved in amine oxidation. Indeed, model quinones
have been shown to mediate amine oxidase activity ex vivo
in the absence of metals, using simple amine substrates.4
The synthetic scope of such reactions has received little
attention; however, and in connection with our broader
interest in aerobic oxidation catalysis,5 we sought to explore
this class of reactions. In the present study, we report a
highly chemoselective method for aerobic oxidative homo-
and heterocoupling of benzylic amines to secondary imines
using the TPQ analog, 4-tert-butyl-2-hydroxybenzoquinone
(4) For selected examples, see: (a) Eckert, T. S.; Bruice, T. C. J. Am.
Chem. Soc. 1983, 105, 4431–4441. (b) Itoh, S.; Mure, M.; Ogino, M.;
Ohshiro, Y. J. Org. Chem. 1991, 56, 6857–6865. (c) Ohshiro, Y.; Itoh, S.
Bioorg. Chem. 1991, 19, 169–189. (d) Lee, Y.; Sayre, L. M. J. Am. Chem.
Soc. 1995, 117, 3096–3105. (e) Mure, M.; Klinman, J. P. J. Am. Chem.
Soc. 1995, 117, 8698–8706. (f) Mure, M.; Klinman, J. P. J. Am. Chem.
Soc. 1995, 117, 8707–8718. (g) Itoh, S.; Takada, N.; Haranou, S.; Ando,
T.; Komatsu, M.; Ohshiro, Y.; Fukuzumi, S. J. Org. Chem. 1996, 61,
8967–8974. (h) Itoh, S.; Takada, N.; Ando, T.; Haranou, S.; Huang, X.;
Uenoyama, Y.; Ohshiro, Y.; Komatsu, M.; Fukuzumi, S. J. Org. Chem.
1997, 62, 5898–5907. (i) Ling, K.-Q.; Kim, J.; Sayre, L. M. J. Am. Chem.
Soc. 2001, 123, 9606–9611. (j) Mure, M.; Wang, S. X.; Klinman, J. P.
J. Am. Chem. Soc. 2003, 125, 6113–6125. (k) Murakami, Y.; Yoshimoto,
N.; Fujieda, N.; Ohkubo, K.; Hasegawa, T.; Kano, K.; Fukuzumi, S.;
Itoh, S. J. Org. Chem. 2007, 72, 3369–3380.
(1) For a recent review highlighting the versatility of imine electro-
philes, see: Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem.
Rev. 2011, 111, 2626–2704.
(2) For several recent examples, see: (a) Lang, X.; Ji, H.; Chen, C.;
Ma, W.; Zhao, J. Angew. Chem., Int. Ed. 2011, 50, 3934–3937.
(b) Murahashi, S.-I.; Okano, Y.; Sato, H.; Nakae, T.; Komiya, N.
Synlett 2007, 1675–1678. (c) Zhu, B.; Angelici, R. J. Chem. Commun.
2007, 2157–2159. (d) Choi, H.; Doyle, M. P. Chem. Commun. 2007, 745–
747. (e) Wang, J.-R.; Fu, Y.; Zhang, B.-B.; Cui, X.; Liu, L.; Guo, Q.-X.
ꢀ
Tetrahedron Lett. 2006, 47, 8293–8297. (f) Samec, J. S. M.; Ell, A. H.;
€
Backvall, J.-E. Chem.;Eur. J. 2005, 11, 2327–2334. (g) Maeda, Y.;
Nishimura, T.; Uemura, S. Bull. Chem. Soc. Jpn. 2003, 76, 2399–2403.
(h) Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2003, 42, 1480–
1483. (i) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am.
Chem. Soc. 2004, 126, 5192–5201.
(3) For reviews, see: (a) Mure, M. Acc. Chem. Res. 2004, 37, 131–139.
(b) Mure, M.; Mills, S. A.; Klinman, J. P. Biochemistry 2002, 41, 9269–
9278.
(5) (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400–3420.
(b) Stahl, S. S. Science 2005, 309, 1824–1826. (c) Wendlandt, A. E.; Suess,
A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062–11087.
(d) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. DOI: 10.1021/ar2002045.
r
10.1021/ol301095j
XXXX American Chemical Society

(TBHBQ), as the catalyst.6 Like the amine oxidases noted
above, the reactions proceed effectively in the absence of Cu
or another redox-active cocatalyst.
Table 1. Quinone-Catalyzed Aerobic Oxidation of Primary
Benzylic Aminesa
Important precedents to our work include the use of
quinones as stoichiometric reagents7 and catalysts8 in the
oxidation of primary amines to aldehydes and ketones and
as electrocatalysts for the oxidation of primary amines to
secondary imines9 and amines.10 And, during preparation
of this manuscript, Largeron et al. reported a study very
similar to the one presented here using an iminoquinone
catalyst in combination with a copper cocatalyst, which
facilitates aerobic reoxidation of the quinone.11
Building upon the work of Mure and Klinman,4e,f we
evaluated the oxidation of benzylamine 1a to N-benzyli-
denebenzylamine 1b with TBHBQ. Efficient oxidation
takes place with 1.5 mol % TBHBQ in a number of sol-
vents, including 1,4-dioxane, THF, DMF, and MeCN
(76%, 76%, 76%, and 87% yields, respectively) at room
temperature under 1 atm of O2. The reactions can be
carried out with ambient air as the oxidant, but the
reactions are slower. For example, 26% of unreacted 1a
was observed after 24 h.
Under the optimized conditions, a range of ortho-, meta-,
and para-substituted benzylamines undergo oxidation
to their secondary imine dimers under these conditions
(Table 1). Electon-rich amines, such as p-methoxybenzyl-
amine (93%, entry 3) and piperonylamine (91%, entry 12),
and some electron-deficient amines, such as p-chloro-
benzylamine (90%, entry 4) and p-fluorobenzylamine
(91%, entry 5), are readily converted to the secondary
imines in high yields. More electron-deficient benzyl-
amines, such as p-trifluoromethylbenzylamine (78%, entry
6) and m-chlorobenzylamine (72%, entry 7), oxidize more
slowly and require 48 h for complete conversion. The
observation that electron-withdrawing substituents react
more slowly is evident from an initial-rate study of sub-
strates 1aÀ3a, 5a, and 6a, from which a substantial nega-
tive Hammett correlation was determined (F = À1.3; see
Supporting Information).
a Conditions: amine substrate (1.0 mmol), TBHBQ (0.015 mmol, 1.5
mol %), O2 balloon, MeCN (3.5 mL), rt, 20 h. b Yield determined by 1H
NMR spectroscopy versus internal standard. c Reaction time was 48 h.
d Carried out in the presence of 1.0 equiv of Et3N.
The free amino group of p-aminobenzylamine does not
inhibit dimerization; however, the yield is slightly lower
than some of the other derivatives (76%, entry 2). As noted
above, halogen substituents, including m-iodobenzyl-
amine, are well tolerated(entries 4, 5, 7, and 8, respectively).
Sterically bulky groups, such as 1-naphthyl (81%, entry 11),
and ortho substitution on the aromatic ring (entries 9, 10)
cause only a slight diminution in yield. The heterocycle
furfurylamine (80%, entry 13) undergoes oxidative dimer-
ization, but 2- and 4-(aminomethyl)pyridines are not
efficient substrates (not shown). The hydrochloride salt
of benzylamine does not react, but good reactivity can be
recovered upon addition of a Brønsted base, such as Et3N
(entry 14).
(6) For previous reports by Mure and Klinman describing the use of
TBHBQ in enzyme model studies, see refs 4e, 4f.
(7) (a) Corey, E. J.; Achiwa, K. J. Am. Chem. Soc. 1969, 91, 1429–
1432. (b) Klein, R. F. X.; Bargas, L. M.; Horak, V.; Navarro, M.
Tetrahedron Lett. 1988, 29, 851–852.
(8) For an example involving CÀH bond oxidation, see: (a) Ohshiro,
Y.; Itoh, S.; Kurokawa, K.; Kato, J.; Hirao, T.; Agawa, T. Tetrahedon
Lett. 1983, 24, 3465–3468. For examples involving CÀC bond activa-
tion, see: (b) Itoh, S.; Kato, N.; Ohshiro, Y.; Agawa, T. Tetrahedron
Lett. 1984, 25, 4753–4756. (c) Mure, M.; Suzuki, A.; Itoh, S.; Ohshiro, Y.
J. Chem. Soc., Chem. Commun. 1990, 1608–1611.
(9) Largeron, M.; Chiaroni, A.; Fleury, M.-B. Chem.;Eur. J. 2008,
14, 996–1003.
(10) Largeron, M.; Fleury, M.-B. Org. Lett. 2009, 11, 883–886.
(11) Largeron, M.; Fleury, M.-B. Angew. Chem., Int. Ed. 2012,
10.1002/anie201200587.
Secondary amines, such as N-phenylbenzylamine and
indoline (Table 1, entries 15, 16), and tertiary amines, such
as Et3N and N,N-dimethybenzylamine (not shown), are
not oxidized under the reaction conditions. This selectivity
for primary amines is readily explained by the reaction
mechanism (Scheme 1), which has been elucidated in pre-
vious biochemical model studies.3 Condensation of the
primary amine 1a with TBHBQ leads to the iminoquinone
B
Org. Lett., Vol. XX, No. XX, XXXX

intermediate14. Tautomerization of this species to form15
results in the net two-electron oxidation of the amine.
Addition of a second equivalent of amine 1a to imine 15
generates an aminal that can react further to liberate the
product 1b and reduced aminohydroquinone 17. Aerobic
oxidation of 17 generates iminoquinone 18, which can
undergo transimination with substrate 1a to liberate
NH3 and close the catalytic cycle.
fragment. These observations highlight a potential advan-
tage of the organocatalytic oxidation method described
here, as transition-metal catalysts are unlikely to demon-
strate comparable chemoselectivity. The sterically hin-
dered tritylamine serves as an effective coupling partner
(78%, entry 7), with the product crystallizing out of the
reaction mixture. Aniline affords N-benzylidene aniline in
good yield after 48 h (76%, entry 8), provided a second
5 mol % portion of the catalyst is added after 24 h.
Scheme 1. Proposed Mechanism of Quinone-Catalyzed Aerobic
Oxidation of Primary Amines
Table 2. Quinone-Catalyzed Aerobic Cross-Coupling of Pri-
mary Aminesa
Aliphatic primary amines are not oxidized by TBHBQ
under these reaction conditions, probably because this
quinone is not sufficiently oxidizing to promote the reac-
tion. The sec-primary amine R-methylbenzylamine is also
not oxidized under these mild reaction conditions. In this
case, the lack of reactivity must be a steric effect because
the R-CÀH bond should be weaker than that of the parent
benzylamine. Reactivity is observed under more forcing
conditions, using 10 mol % TBHBQ. With 1.0 equiv of
sodium formate as a Brønsted base in DMF, a 69% yield
of the imine dimer is obtained after 48 h (eq 1).
a Conditions: benzylamine (1.0 mmol), amine (1.5À3.0 mmol),
TBHBQ (0.05 mmol), O2 balloon, MeCN (3.5 mL), rt, 20À48 h. b Yield
determined by 1H NMR spectroscopy versus internal standard. c After
24 h an additional aliquot of TBHBQ (5.0 mol %) was added, and the
reaction was run for a total of 48 h. e Isolated yield.
The exquisite selectivity for primary benzylic amines
suggested that selective heterocoupling could be achieved
by combining a benzylic amine with a less readily oxidized
amine. Upon increasing the catalyst loading to 5 mol %,
cross-coupled products were formed in very good yields,
often with excellent selectivities (Table 2). The coupling of
benzylamine and R-methylbenzylamine is facile (89%,
entry 1), forming N-benzylidene-R-methylbenzylamine 19
as the exclusive product. Linear and branched aliphatic
amines, such as cyclohexylamine (91%, entry 2), hexyl-
amine (83%, entry 5), and 2-ethylhexylamine (85%, entry
6), are also good substrates for cross-product formation,
though in the latter cases small amounts of N-benzyli-
denebenzylamine are also observed.
In order to explore the origin of the excellent cross-
product selectivity, two heterocoupling reactions were
1
monitored by H NMR spectroscopy (Figure 1). In the
reaction of benzylamine with 2.0 equiv of R-methylbenzyl-
amine (Figure 1A), the time course reveals the parallel
formation of homo- and heterocoupled products 1b and 19
at early stages of the reaction. As the reaction progresses,
the homocoupled product 1b is progressively consumed,
and the reaction converges to exclusive formation of 19 at
the end of the reaction. A different profile is evident in
the reaction of benzylamine and 2.0 equiv of aniline
(Figure 1B). In this case, the time course reveals that the
homocoupled dimer 1b is formed exclusively and accumu-
lates in good yield at early stages of the reaction (t< 300 min).
This observation is consistent with the tolerance of an
aromatic amine in the oxidative homocoupling reactions
Primary amines that contain a tertiary amine (92%,
entry 4) or primary alcohol (80%, entry 4) undergo
effective heterocoupling with benzylamine, with no back-
ground oxidation of the tertiary amine or primary alcohol
Org. Lett., Vol. XX, No. XX, XXXX
C

noted above (cf. Table 1, entry 2). At longer reaction times, the
homodimer 1b is slowly converted into the cross-product 26.
of benzylamine toward oxidation by TBHBQ (see above),
however, causes the equilibrium mixture to be driven
toward formation of the heterocoupled product 19.
Similar considerations rationalize the reactivity ob-
served with benzylamine and aniline in Figure 1B. Exclu-
sive formation of homodimer 1b early in the reaction is
readily explained by the higher reactivity of benzylamine
relative to aniline with imine-hydroquinone intermediate 15.
Formation of N-benzylidene aniline 26 at longer reaction
times is relatively sluggish. Formation of 26 via condensa-
tion of aniline with 1b is thermodynamically unfavorable
(Keq , 1; eq 3). Nevertheless, its formation can be driven by
continuous oxidation of the benzylamine generated, albeit
in small quantities, from this exchange reaction.
Figure 1. A 1H NMR time course of the TBHBQ-catalyzed
oxidation of (A) benzylamine and methylbenzylamine and (B)
benzylamine and aniline. Reaction conditions: benzylamine
(0.28 M), R-methylbenzlamine or aniline (0.57 M), TBHBQ
(0.014 M), trimethoxybenzene (internal standard, 0.078 M),
MeCN-d3, O2 balloon, rt.
The ability of a dynamic equilibrium mixture of species
to converge toward a single product by consumption of
one of the species has been termed “self-sorting.”12 With
the pair of substrates shown in Figure 1A, oxidatively
promoted self-sorting overcomes the slight thermody-
namic preference of 1b over 19, enabling exclusive forma-
tion of 19. With the substrate pair in Figure 1B, the
kinetically preferred product may be obtained in good
yield at short reaction times, or oxidative self-sorting can
be exploited to obtain the otherwise strongly disfavored
product. This oxidative strategy to achieve imine self-
sorting is complementary to other approaches being pur-
sued in the field of dynamic covalent chemistry13À15 (e.g.,
through the use of templates) to promote selective product
formation within an equilibrating mixture.
In summary, we have identified a highly chemoselective
method for the aerobic oxidative coupling of primary
benzylic amines to afford secondary imines, and dynamic
self-sorting of the imine products enables selective forma-
tion of heterocoupled imines. The mild reaction condi-
tions, the functional group compatibility, the use of O2 as
the oxidant, and the low catalyst loadings compare favor-
ably with previously reported metal-catalyzed methods.
The cross-coupling results depicted in Figure 1 can be
rationalized by three considerations: (1) the relative nucleo-
philicity of the two amines with the catalytic intermediate
15, (2) equilibrium exchange of the amine substrates with
the secondary imine products, and (3) the relative reactivity
of the amine substrates toward oxidation.
The parallel formation of 1b and 19 in Figure 1A
suggests that benzylamine and R-methylbenzylamine can
react with catalytic intermediate 15 to afford the homo-
and heterocoupled dimers, respectively. Control experi-
ments show that 1b and 19 equilibrate readily under the
reaction conditions in the presence of the amine substrates
(eq 2), and the equilbrium constant (Keq ≈ 0.7) shows a
slight preference for 1b. The substantially higher reactivity
(12) Belowich, M. E.; Stoddart, J. F. Chem. Soc. Rev. 2012, 41, 2003–
2024.
(13) For reviews, see: (a) Corbett, P. T.; Leclaire, J.; Vial, L.; West,
K. R.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S. Chem. Rev. 2006, 106,
3652–3711. (b) Lehn, J.-M. Chem. Soc. Rev. 2007, 36, 151–160.
(c) Ludlow, R. F.; Otto, S. Chem. Soc. Rev. 2008, 37, 101–108.
(14) For selected recent applications of dynamic covalent chemistry,
pertaining to the exchange of CdN bonds, see: (a) Dirksen, A.; Dirksen,
S.; Hackeng, T. M.; Dawson, P. E. J. Am. Chem. Soc. 2006, 128, 15602–
15603. (b) Dirksen, A.; Hackeng, T. M.; Dawson, P. E. Angew. Chem.,
Int. Ed. 2006, 45, 7581–7584. (c) Hartley, C. S.; Moore, J. S. J. Am.
Chem. Soc. 2007, 129, 11682–11683.
Acknowledgment. We thank the U.S. Department of
Energy (DE-FG02-05ER15690) for financial support of
this work. Analytical instrumentation was partially funded
by the NSF (CHE-9208463, CHE-0342998, CHE-9629688,
CHE-9974839).
(15) For representative fundamental studies of equilibrium-
controlled exchange of other covalent bonds, such as esters, alkenes, and
amides, see: (a) Stanton, M. G.; Allen, C. B.; Kissling, R. M.; Lincoln,
ꢀ
A. L.; Gagne, M. R. J. Am. Chem. Soc. 1998, 120, 5981–5989.
ꢀ
(b) Kissling, R. M.; Gagne, M. R. Org. Lett. 2000, 2, 4209–4212. (c) Nyce,
G. W.; Lamboy, J. A.; Connor, E. F.; Waymouth, R. M.; Hedrick, J. L.
Org. Lett. 2002, 4, 3587–3590. (d) Eldred, S. E.; Stone, D. A.; Gellman,
S. H.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 3422–3423. (e) Singh, R.;
Kissling, R. M.; Letellier, M.-A.; Nolan, S. P. J. Org. Chem. 2004, 69,
209–212. (f) Cantrill, S. J.; Grubbs, R. H.; Lanari, D.; Leung, K. C.-F.;
Nelson, A.; Poulin-Kerstien, K. G.; Smidt, S. P.; Stoddart, J. F.; Tirrell,
D. A. Org. Lett. 2005, 7, 4213–4216. (g) Stephenson, N. A.; Zhu, J.;
Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 10003–10008.
Supporting Information Available. Experimental pro-
1
cedures, product characterization data, and H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX