Visible-light photoredox catalysis: Aza-Henry reactions via C-H functionalization

Article abstract of DOI:10.1021/ja909145y

(Chemical Equation Presented) We report the application of visible-light photoredox catalysis for the formation of C-C bonds between tertiary N-arylamines and nitroalkanes via an oxidative aza-Henry reaction. In the presence of 1 mol % Ir(ppy)₂

Full text of DOI:10.1021/ja909145y

Published on Web 01/13/2010
Visible-Light Photoredox Catalysis: Aza-Henry Reactions via C-H
Functionalization
Allison G. Condie, Jose´ C. Gonza´lez-Go´mez, and Corey R. J. Stephenson*
Department of Chemistry, Boston UniVersity, Boston, Massachusetts 02215
Received October 27, 2009; E-mail: crjsteph@bu.edu
The catalytic oxidation of sp3 C-H bonds adjacent to nitrogen
Table 1. Oxidative Iminium Ion Generation and Trapping
provides reactive imines or iminium ions and is a powerful method
for amine functionalization.1 Preliminary mechanistic investigations
during our recent studies of photoredox catalysis for reductive
dehalogenation reactions2 suggested that iminium ions were likely
byproducts in the reaction using tertiary amines as reductants (Scheme
1).3,4 In light of the mechanism presented in Scheme 1, we anticipated
that with an appropriately chosen oxidant (R4-X functions as an
oxidant in this reaction), the generated iminium ion could be trapped
by a variety of nucleophiles under photoredox conditions. Indeed,
radical cation intermediates generated under electrochemical,5a
metal-5b or electron-transfer-mediated5c,d oxidation conditions have
been shown to undergo decomposition to give the corresponding
imines.5e In this communication, we describe the realization of the
generation of iminium ions under photoredox conditions in the context
of an oxidative aza-Henry reaction.6
conversionb
(yieldc)
entry
conditionsa
1
3 (2 mol %), (EtO2C)2CHBr
(5, 1.5 equiv) DMF, 2 h; X ) OCH3
3 (1 mol %), 5 (1.5 equiv),
100 (73)d
2
3
100
CH3OH, 2 h; X ) OCH3
3 (1 mol %), no additiWe,
100
CH3OH, 16 h; X ) OCH3
4
5
3 (1 mol %), CH3NO2, 20 h; X ) CH2NO2
3 (1 mol %), CH3NO2, 20 h;
100 (81)
76
X ) CH2NO2; reaction was degassed
4 (1 mol %), CH3NO2, 10 h; X ) CH2NO2
4 (1 mol %), no light, CH3NO2,
48 h; X ) CH2NO2
6
7
100 (92)
0
8
no catalyst, CH3NO2, 180 h; X ) CH2NO2
83
Scheme 1. Iminium Ion Generation Using Photoredox Catalysis
a With the exception of entry 5, the reactions were not rigorously
b
degassed. Calculated on the basis of crude H NMR analysis. c Isolated
yield after purification by chromatography on SiO2. d Purified on SiO2
using CH3OH as a cosolvent.
1
A variety of N-aryltetrahydroisoquinolines were subjected to the
optimized conditions [4 (1 mol %), RCH2NO2, r.t.] and uniformly
afforded the desired coupling products in excellent yields (90-96%;
Table 2, entries 1-8). Both nitromethane (entries 1, 3, and 5-9) and
nitroethane (entries 2 and 4) provided the desired products. The reaction
was generally insensitive to electronic effects on the aromatic rings
(entries 3-8). Although the process was markedly slower, C-H
oxidation of a nonbenzylic amine cleanly afforded the desired coupling
product in moderate yield (40% conversion after 72 h; entry 9). These
results compare favorably with the known oxidative aza-Henry reaction
reported by Li and co-workers using Cu(I) and tBuOOH.6b,c Although
the Cu-mediated process is faster, the Ir-mediated process reported
herein provides the desired products in higher yields, with the notable
exception of the unactivated amine in entry 9.
Both light and catalyst are required for efficient conversion to the aza-
Henry products (Table 1, entries 7 and 8). In addition, the exclusion of
oxygen from the reaction results in a lower rate (Table 1, entry 5). Since
nitrobenzene is a known oxidative quencher of Ru(bpy)32+*,13 we could
not immediately rule out possible mechanisms involving this pathway.
Accordingly, we conducted a series of fluorescence quenching experiments
in which the fluorescence emission of a solution of 4 in CH3NO2 was
found to be decreased by 1 in a concentration-dependent fashion,
implicating the amine as a reductive quencher of the excited-state iridium
complex.14 On the basis of this information, we propose the following
mechanism for the C-H oxidation/aza-Henry reaction under photoredox
catalysis (Scheme 2). Radical cation 7 is formed by reductive quenching
of the excited state of 4 by 6, forming the powerful reducing agent Ir2+
[Ir(III)/Ir(II) -1.51 V vs SCE]. Catalyst turnover may be accomplished
by the reduction of nitromethane to its radical anion and/or adventitious
Our initial studies focused on tetrahydroisoquinoline 1, a substrate
that is known to undergo oxidative C-H functionalization by Ru(III),7
Cu(I),8 and, as shown more recently, V(IV)9 or I(III).10 Using
conditions closely related to those we used for reductive dehalogena-
tion, we subjected 1 to oxidation using diethyl bromomalonate (5) as
the stoichiometric oxidant.2 After 2 h, 1 was converted into a more
polar compound upon treatment with 2 mol % Ru(bpy)3Cl2 in N,N-
dimethylformamide (DMF) in the presence of 5 (Table 1, entry 1),
providing methoxyaminal 2 (X ) OMe) in 73% yield. Use of CH3OH
as the solvent for the reaction also resulted in the complete conversion
of 1 to the methoxyaminal (entry 2). We were surprised to find that
the latter compound was formed even in the absence of 5; however,
the reaction was significantly slower (entry 3). From this surprising
result, a change of solvent to nitromethane provided the oxidative
Henry reaction product in 81% isolated yield after 20 h (entry 4).
Degassing the reaction slowed the reaction (76% conversion after 20 h;
entry 5), indicating that adventitious oxygen in the reaction may play
a role in the mechanism but is not explicitly required. The use of a
more reactive iridium catalyst,11 Ir(ppy)2(dtbbpy)PF6, 4,4d,12 signifi-
cantly accelerated the reaction, and complete conversion was observed
after 10 h (92% isolated yield; entry 6). Importantly, no conversion
was observed when the reaction was conducted in the dark (entry 7),
while a very slow background reaction (83% conversion after ∼7.5
days) was observed in the absence of catalyst (entry 8).
9
1464 J. AM. CHEM. SOC. 2010, 132, 1464–1465
10.1021/ja909145y  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Oxidative Aza-Henry Reaction
of nitro compounds other than those conveniently used as the solvent
also cleanly provide the desired product using DMF as solvent.
In summary, we have reported an operationally simple method for
the oxidative coupling of nitroalkanes with tertiary N-arylamines using
visible-light photoredox catalysis. Importantly, the reaction proceeds
in high chemical yield using only 1 mol % Ir(III) catalyst and visible
light without the need for an external oxidant. Further studies expanding
upon the scope of this transformation as well as further mechanistic
investigations are currently underway.
Acknowledgment. Boston University and the Department of
Chemistry are gratefully acknowledged for financial support.
Acknowledgment is made to the donors of the American Chemical
Society Petroleum Research Fund (48479-G1) for partial support
of this research. NMR (CHE-0619339) and MS (CHE-0443618)
facilities at BU are supported by the NSF. The authors thank
Professor John Porco (Boston University) and Professor Peter Wipf
(University of Pittsburgh) for critical comments on this manuscript.
Supporting Information Available: Experimental procedures and
1H and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Murahashi, S.-I.; Zhang,
D. Chem. Soc. ReV. 2008, 37, 1490.
(2) Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem.
Soc. 2009, 131, 8756.
2+
(3) For reviews of the photochemistry and photophysics of Ru(bpy)3 and
related complexes, see: (a) Kalyanasundaram, K. Coord. Chem. ReV. 1982,
46, 159. (b) Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser,
P.; von Zelewsky, A. Coord. Chem. ReV. 1988, 84, 85.
a Isolated yield after purification on SiO2. b Conditions: 4 (1.0 mol
%), visible light, CH3NO2, rt. c dr ) 2:1. d dr ) 2.3:1. e Conversion )
(4) (a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77. (b) Ischay,
M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2008, 130,
12886. (c) Koike, T.; Akita, M. Chem. Lett. 2009, 38, 166. (d) Nagib, D. A.;
Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875. (e)
Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2009, 131, 14604. (f) Tucker, J. W.;
Narayanam, J. M. R.; Krabbe, S. W.; Stephenson, C. R. J. Org. Lett. 2010, 12,
368.
40% as determined by crude H NMR analysis. f See ref 15.
1
Scheme 2. Plausible Mechanism
(5) (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981, 103,
1172. (b) Murahashi, S.-I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443.
(c) Kalyanasundaram, K.; Kiwi, J.; Gra¨tzel, M. HelV. Chim. Acta 1978,
61, 2720. (d) DeLaive, P. J.; Sullivan, B. P.; Meyer, T. J.; Whitten, D. G.
J. Am. Chem. Soc. 1979, 101, 4007. (e) Nelson, S. F.; Ippoliti, T. J. J. Am.
Chem. Soc. 1986, 108, 4879.
(6) (a) Arraya´s, R. G.; Carretero, J. C. Chem. Soc. ReV. 2009, 38, 1940. (b)
Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (c) Basle, O.; Li, C.-J.
Green Chem. 2007, 9, 1047.
(7) (a) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem. Soc.
2008, 130, 11005. (b) Murahashi, S.-I.; Komiya, N.; Terai, H. Angew.
Chem., Int. Ed. 2005, 44, 6931. (c) Murahashi, S.-I.; Komiya, N.; Terai,
H.; Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312.
oxygen.16 This radical anion may abstract a hydrogen atom from the
trialkylammonium radical cation to form the desired iminium ion, 8.2
Addition of 9 to the iminium forms the observed product.
The product of nitromethane reduction is presumably nitrosomethane
(or the oxime tautomer), neither of which were we able to observe in our
reactions. We reasoned that the use of a less volatile nitro compound could
provide evidence in favor of our proposed mechanism. Treatment of 11
with PhCH2NO2 (5 equiv) in DMF in the presence of Ir(dtbbpy)(ppy)2PF6
(1 mol %) and visible light resulted in full conversion to the desired
oxidative coupling product 12 (5:1 dr) (eq 1):17
(8) (a) Basle, O.; Li, C.-J. Chem. Commun. 2009, 4124. (b) Li, Z.; Bohle, S.;
Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 9828.
(9) Sud, A.; Sureshkumar, D.; Klussmann, M. Chem. Commun. 2009, 3169.
(10) Shu, X.-Z.; Xia, X.-F.; Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.; Liang, Y.-M. J.
Org. Chem. 2009, 74, 7464.
(11) For a review of photoactive iridium complexes, see: Flamigni, L.; Barbieri,
A.; Sabatini, C.; Ventura, B.; Barigelletti, F. Top. Curr. Chem. 2007, 281, 143.
(12) For the preparation of Ir(ppy)2(dtbbpy)PF6, see: Slinker, J. D.; Gorodetsky,
A. A.; Lowry, M. S.; Wang, J.; Parker, S.; Rohl, R.; Bernhard, S.; Malliaras,
G. G. J. Am. Chem. Soc. 2004, 126, 2763.
(13) Bock, C. R.; Connor, J. A.; Gutierrez, A. R.; Meyer, T. J.; Whitten, D. G.;
Sullivan, B. P.; Nagle, J. K. J. Am. Chem. Soc. 1979, 101, 4815.
(14) See the Supporting Information for details.
(15) N-Aryltetrahydroisoquinolines were prepared via Buchwald-Hartwig
coupling (see: Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002,
4, 581). For an alternative approach to N-arylation, see: Barker, T. J.; Jarvo,
E. R. J. Am. Chem. Soc. 2009, 131, 15598.
(16) An insightful reviewer suggested that this reaction may be mediated by singlet
O2 sensitization by 4 (see: Demas, J. N.; Harris, E. W.; McBride, R. P. J. Am.
Chem. Soc. 1977, 99, 3547). Initial mechanistic investigations provided the
following data for the known singlet O2-mediated oxidation of dibenzylamine
to the corresponding imine (see: Jiang, G.; Chen, J.; Huang, J.-S.; Che, C.-M.
Org. Lett. 2009, 11, 4568): Using 4 under an oxygen atmosphere, we
observed only 12% conversion of dibenzylamine to its imine after 12 h
(cf. TPP, O2, 10-14 h). In contrast, we found that TPP is capable of
mediating the oxidative aza-Henry reaction of 1, but the reaction required
72 h for complete conversion compared with only 10 h under our conditions
using 4. See the Supporting Information for further details.
1
We did not observe the presence of 13 by H NMR analysis of the
crude reaction mixture, indicating that catalyst turnover may proceed
via reaction with oxygen. However, rigorous degassing of the reaction
in eq 1 also resulted in clean formation of 12, albeit with an attenuated
rate, suggesting that the nitroalkane may also play a role in catalyst
turnover. Importantly, these experiments demonstrate that the reaction
(17) Full conversion of 11 to 12 was observed by crude 1H NMR analysis, but
12 was not stable under purification by chromatography.
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