Mechanistic studies on a Cu-catalyzed aerobic oxidative coupling reaction with N-phenyl tetrahydroisoquinoline: Structure of intermediates and the role of methanol as a solvent

Article abstract of DOI:10.1021/ja201610c

The mechanism of an aerobic copper-catalyzed oxidative coupling reaction with N-phenyl tetrahydroisoquinoline was investigated. The oxidized species formed from the reaction of the amine with the copper catalyst were analyzed by NMR-spectroscopy. An iminium dichlorocuprate was found to be the reactive intermediate and could be structurally characterized by X-ray crystallography. The effect of methanol to effectively stabilize the iminium ion was investigated and shown to be beneficial in an oxidative allylation reaction.

Full text of DOI:10.1021/ja201610c

COMMUNICATION
pubs.acs.org/JACS
Mechanistic Studies on a Cu-Catalyzed Aerobic Oxidative Coupling
Reaction with N-Phenyl Tetrahydroisoquinoline: Structure of
Intermediates and the Role of Methanol As a Solvent
Esther Boess, Devarajulu Sureshkumar,† Abhishek Sud,‡ Cornelia Wirtz, Christophe Farꢀes, and
Martin Klussmann*
Max-Planck-Institut f€ur Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 M€ulheim an der Ruhr, Germany
S Supporting Information
b
Scheme 1. Common Mechanistic Suggestion for Cu-Cata-
ABSTRACT: The mechanism of an aerobic copper-catalyzed
oxidative coupling reaction with N-phenyl tetrahydroisoquino-
line was investigated. The oxidized species formed from the
reaction of the amine with the copper catalyst were analyzed by
NMR-spectroscopy. An iminium dichlorocuprate was found to
be the reactive intermediate and could be structurally char-
acterized by X-ray crystallography. The effect of methanol to
effectively stabilize the iminium ion was investigated and
shown to be beneficial in an oxidative allylation reaction.
lyzed Oxidative Coupling Reactions with Amines
Scheme 2. Standard Reaction for the Present Study
he functionalization of carbonÀhydrogen bonds is a long-
T
standing goal in organic synthesis. Oxidative coupling reac-
tions can form new CÀC bonds starting from two CÀH bonds
and an oxidant.1 The prospect of using environmentally benign
and cheap oxidants like oxygen or hydrogen peroxide under
catalytic conditions with water as the only waste product makes
these reactions particularly attractive. In recent years, several
methods for the oxidative coupling of amines with various
nucleophiles2 using simple copper salts as catalysts have been
developed,3 but other metals like Ru,4 Fe,5 Rh,6 and V7 or metal-
free variants8 have been used as well. In general, mechanistic
studies of oxidative coupling reactions are rare and the lack of a
detailed understanding makes further developments difficult.
Here, we present mechanistic and synthetic studies on aerobic
copper-catalyzed coupling reactions between an amine and silyl
nucleophiles which elucidate the structure of the reactive inter-
mediate as well as the stabilizing effect of methanol.
Scheme 3. Products of the Reaction between Amine 1 and
CuCl2
exemplary in scope for other copper-catalyzed oxidative coupling
reactions with amines. The optimized conditions had been
established as 10 mol % of CuCl2 2H2O as the catalyst, acetone
3
Commonly, metal-catalyzed oxidative coupling reactions with
tertiary amines are proposed to proceed via catalystÀiminium
ion species1c,4a which subsequently react with a nucleophile to
form the final product (Scheme 1). Support for this mechanistic
proposal comes from a few studies involving the characterization
of potential intermediates like methanol and tert-butyl peroxide
adducts3e,h,4d,4f,6 or model compounds like preformed iminium
bromides.3e,j Iminium π-complexes with copper have not yet
been structurally characterized but are known for other metals
also used in oxidative coupling reactions.9 Recently, an iminium
ion formed in a metal-free oxidative coupling reaction has been
characterized by X-ray crystallography.8f
or methanol as the solvent, and elemental oxygen as the oxidant
(Scheme 2).3l
To gain information on potential intermediates, we reacted
amine 1 with 50 mol % CuCl2 2H2O in methanol under oxygen
3
and investigated the resulting products (Scheme 3).
After 1 h, full conversion of 1 was achieved and a green
precipitate had formed. After filtration, the solution was directly
analyzed by NMR spectroscopy. Two major compounds were
found, an iminium ion 4 and a methanol adduct 5 in a ratio of ca.
40:60. Performing the reaction in acetone resulted in a similar
amount of 4 and hemiaminal 6 as the major products. To facilitate
For the present mechanistic study, we chose the coupling of
N-phenyl tetrahydroisoquinoline 1 and the silyl enol ether 2 as a
test reaction which was recently developed in our lab and is
Received: March 2, 2011
Published: May 11, 2011
r
2011 American Chemical Society
8106
dx.doi.org/10.1021/ja201610c J. Am. Chem. Soc. 2011, 133, 8106–8109
|

Journal of the American Chemical Society
COMMUNICATION
Figure 1. X-ray structure of iminium salt 4a.
full characterization of the compounds, methanol was exchanged
by DMSO-d6 after filtration in further experiments. Under these
conditions, nearly equal amounts of 4, 5, and 6 were observed.
Repeating the reaction with different ratios of amine and CuCl2
did not significantly alter the outcome of the reaction except for
the formation of 3À4% of isoquinolinium salt 7 at higher ratios of
amine (see Supporting Information).
Figure 2. X-ray structure of iminium salt 4b.
Scheme 4. Reactivity Studies of the Amine-Derived Species
The precipitate was shown to be a copper(II) chloride
hydroxide by powder X-ray diffraction. Compound 4 could be
isolated in 26% yield by crystallization and was analyzed by X-ray
crystallography, revealing the counterion as dichlorocuprate
(4a). The distance between the iminium carbon C15 and copper
was found to be 4.15 Å and that between C15 and Cl2 3.34 Å,
indicating a purely ionic interaction (Figure 1).
Compound 5 had been observed before in related coupling
reactions run in methanol.3h,4c,6 The existence of dynamic
equilibria between the individual species 4, 5, 6, and 7 was
investigated by NMR Exchange Spectroscopy (2D EXSY).10 The
presence of exchange cross-peaks between corresponding pro-
tons revealed that both the methanol adduct 5 and the hemi-
aminal 6 were in chemical exchange with the iminium salt 4a.
No other exchange cross-peaks were observed from the isoqui-
nolinium salt (7) or between 5 and 6, indicating very slow or
absence of chemical exchange.
Repeating the experiment of Scheme 3 with CuBr, the most
common copper catalyst in related reactions,3aÀk resulted in the
same species 4À6 as indicated by NMR, only with a lower
amount of the iminium ion 4. X-ray crystallography revealed it to
be an ionic compound like 4a, with (Cu2Br4)2À as a counterion
(4b, Figure 2).
good agreement with the rate of the reaction under study.
Moreover, 4a and 4b are easily prepared and isolated and should
thus find applications in future mechanistic studies.
Methanol adduct 5 was synthesized independently by reacting
amine 1 with methanol under reaction conditions in the absence
of enolate 2. Full conversion was achieved only after 60 to 72 h,
giving 5 in good yield. For the coupling of 5 with 2, the presence
of CuCl2 as a catalyst was needed. Subjecting 5 to reaction
conditions in the presence of 2 gave the product 3 in 68% isolated
yield after 18 h (Scheme 4d).
To gain further understanding of the potential role of 4aÀ6,
we studied their reactivity. Adding enolate 2 to the mixture of
compounds from the experiment shown in Scheme 3 in acetone
resulted in the formation of product 3 in 94% conversion or 87%
isolated yield after 2 h (Scheme 4a). Reacting pure 4a with the
enolate gave 85% isolated yield of 3 after 1 h and quantitative
yield after 2 h (Scheme 4b). In comparison, the iminium bromide
4c11 was significantly less reactive in the same transformation,
giving very low yields after 1 h and even after 4 h (Scheme 4c).
The bromide in 4c apparently forms a contact ion pair with the
iminium that reduces its reactivity while the dichlorocuprate
anion is only weakly coordinating. This is further supported by
the difference in chemical shifts of the iminium methine proton
in acetone-d6: it appears at ca. 9.8 ppm for 4a and at 10.1 ppm for
4c, which is possibly due to a deshielding effect of the bromide by
hydrogen bonding.12 4c had been used as a model compound for
the proposed iminium ion reaction intermediate of oxidative
coupling reactions before.3e,j Our results show that its reactivity is
far too low to be a suitable model while the reactivity of 4a is in
These results indicate several details of the reaction under
study: The discovery of a Cu(I) counterion in 4a and of a
CuCl(OH) precipitate suggests that the main oxidation states of
copper in the catalytic cycle are (I) and (II). The oxidation of 1 to
the iminium ion 4a requires two electrons to be transferred, thus
2 equiv of CuCl2 would be reduced to Cu(I). One remains as a
counterion to the iminium ion while another is reoxidized by
oxygen to CuCl(OH), which precipitates. Under catalytic reac-
tion conditions, Cu species are probably kept in solution by
complexation due to a larger excess of amine.
The observed species 4aÀ6 derived from amine 1 can all be
converted to the product 3 under reaction conditions, i.e. in the
presence of a copper salt and enolate 2. The methanol adduct 5
can be discounted as a true reactive intermediate in the catalytic
cycle, as its separate formation and reaction to the product under
reaction conditions proceed slower than the oxidative coupling
reaction of Scheme 2 itself. Furthermore, it can only be formed in
methanol and not in reactions conducted in other solvents.
Hemiaminal 6 is unlikely as a true intermediate since an SN2-type
8107
dx.doi.org/10.1021/ja201610c |J. Am. Chem. Soc. 2011, 133, 8106–8109

Journal of the American Chemical Society
COMMUNICATION
Scheme 5. Suggested Catalytic Cycle
Scheme 6. Oxidative Allylation in Methanol
reaction with the enolate 2 appears much less facile than an
SN1-type reaction via the stabilized iminium ion 4.
Both the formation of iminium salt 4a and its reaction to the
product (Scheme 3 and Scheme 4b) proceed at a rate comparable
to that of the oxidative coupling reaction of Scheme 2 itself.
Accordingly, 4a appears to be the reactive species in the catalytic
cycle which is in off-cycle equilibrium with 5 and 6 in the presence
of methanol and water, respectively. The structures of 4a and 4b
confirm the general nature of the commonly proposed reactive
intermediate, a Cu-iminium species, but reveal that copper is in the
oxidation state (I) and bound ionically, not covalently. We thus
believe that iminium cuprates like 4a constitute the general
structure of the reactive intermediates in aerobic copper-catalyzed
oxidative coupling reactions with tertiary amines and possibly in
reactions using other oxidants as well.
Based on the above results, a tentative catalytic cycle can be
proposed. Oxidation of amine 1 leads to the reactive iminium
cuprate species 4a which can react with methanol or water in an
off-cycle equilibrium, the former catalyzed by copper acting as a
Lewis acid. Reaction of 4a with silyl enol ether 2 forms the
desired product 3 in an irreversible step. The active CuII catalyst
is then regenerated by reoxidation with oxygen (Scheme 5).
These findings also indicate why methanol is frequently found
to be a solvent of choice for oxidative coupling reactions with
amines.3g,h,l,4a,4b,5bÀ5e,6,7,8e Hemiaminal methyl ethers like 5 can
obviously act as a stable reservoir for the reactive iminium ion
intermediate. This could improve the yield and diminish un-
desired decomposition reactions of the iminium ion if nucleo-
phile addition is significantly slower than oxidative iminium
formation. This case has actually been reported for a photoredox
reaction.4e A similar role is discussed for tert-butylperoxide
adducts formed by the use of tert-butylhydroperoxide.3h,4d,4f,6
The synthesis of methyl hemiaminal ethers and subsequent
employment in metal-catalyzed reactions has also been used as
a two-step strategy to generate iminium ions.13
As an application of these mechanistic findings and to further
investigate the role of methanol as a solvent, we have developed an
aerobic oxidative allylation of amines.5h,14 Allyl silanes are less
nucleophilic than silyl enolates;15 accordingly, methanol should
exerta stronger positive influence onthe product yield if the model
discussed above is correct. Reacting amine 1 with 2-methylallylsi-
lane 8 did indeed give the desired product 9, taking considerably
longer than the reaction with 2. With the less nucleophilic
allyltrimethylsilane,15 no reaction was observed. The allylation
reaction with 8 proved to be general and several allylated
N-aryl tetrahydroisoquinolines (10À14) and one allylated N,N-
dimethyl aniline (15) could be synthesized. Of the solvents
screened, methanol gave the best results followed by acetone
(Scheme 6).
Figure 3. Reaction progress and formation of major intermediates of
the oxidative allylation of 1 with 8, monitored by 1H NMR spectroscopy.
Reaction conditions as given in Scheme 6.
To gain further information on the potential intermediates of
this reaction as proposed in Scheme 5, we compared the oxi-
dative coupling reactions of Schemes 2 and 6 in methanol-d4 and
acetone-d6 by NMR spectroscopy. The coupling of 1 with 2
proceeded faster in acetone than in methanol, without inter-
mediates 4, 5, or 6 being clearly visible in samples taken during
the reaction. In contrast, in the allylation with 8 all intermediates
were visible by 1H NMR spectroscopy (4 and 5 in methanol-d4
and 4 and 6 in acetone-d6) and the reaction proceeded faster in
methanol than in acetone (Figure 3). At the beginning of the
reaction in methanol, amine 1 is consumed quickly while the final
coupling product 9is formed at a much slower rate. 5is formed as an
intermediate product with nearly 50% yield at the beginning of the
reaction and is then fully consumed over 24 h. The amount of
iminium salt 4 is relatively constant throughout most of the reaction
at 4À8% and nearly vanishes at the end. The reaction is relatively
clean with an estimated product yield of 91% and the sum of
identifiable species accounting for over 90% of the signals in the
NMR after 24 h. In acetone, amine 1 is consumed at a considerably
slower rate, its conversion reaching ca. 80% after 24 h. 9 is formed as
the major product, giving an estimated yield of 60% after 24 h. The
amount of 4 is again relatively constant throughout most of the
reaction at 5À8% and nearly vanished at the end. Hemiaminal 6 was
initially formed with ca. 4% but was consumed after 5 h. The
reaction appeared less clean with the sum of identifiable species
accounting for only 80% of the signals in the NMR after 24 h.
These results support a mechanism as depicted in Scheme 5.
With less nucleophilic substrates like 8, methanol can effectively
8108
dx.doi.org/10.1021/ja201610c |J. Am. Chem. Soc. 2011, 133, 8106–8109

Journal of the American Chemical Society
COMMUNICATION
compete in the reaction with 4a, forming larger amounts of 5 in
an off-cycle equilibrium and liberating the catalyst. Over time, 5
acts as a reservoir to 4a and is finally converted to the product. In
acetone, 5 cannot be formed and thus the conversion of amine 1
is much slower as the catalyst is only liberated upon reaction with
a nucleophile. The reservoir effect in methanol could also be
responsible for the higher purity observed as compared to the
reaction in acetone: without the off-cycle equilibrium, unwanted
side reactions of 4a could compete with nucleophile addition if
the latter step is slow. In the case of good nucleophiles like 2, the
formation of iminium salt 4a is slower than nucleophile addition.
Accordingly, conversion of 4a to 3 isfast and intermediates 5 and 6
are not observable. Using methanol or acetone as solvent does not
have a significant effect on the product yield. The slower reaction
rate in methanol could be due to more subtle solvent effects, e.g.
different stabilization energies of the reactants. Solubility of the
Li, C.-J. Top. Curr. Chem. 2010, 292, 281. (d) Liu, C.; Zhang, H.; Shi, W.;
Lei, A. Chem. Rev. 2011, 111, 1780. (e) Yeung, C. S.; Dong, V. M. Chem.
Rev. 2011, 111, 1215.
(2) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069.
(3) (a) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006,
103, 8928. (b) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (c) Li,
Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173. (d) Li, Z.; Li, C.-J. J. Am. Chem.
Soc. 2005, 127, 3672. (e) Li, Z.; MacLeod, P. D.; Li, C.-J. Tetrahedron:
Asymmetry 2006, 17, 590. (f) Baslꢁe, O.; Li, C.-J. Green Chem. 2007,
9, 1047. (g) Baslꢁe, O.; Li, C.-J. Chem. Commun. 2009, 4124. (h) Shen, Y.;
Tan, Z.; Chen, D.; Feng, X.; Li, M.; Guo, C.-C.; Zhu, C. Tetrahedron
2009, 65, 158. (i) Yang, F.; Li, J.; Xie, J.; Huang, Z.-Z. Org. Lett. 2010,
12, 5214. (j) Baslꢁe, O.; Borduas, N.; Dubois, P.; Chapuzet, J. M.; Chan,
T.-H.; Lessard, J.; Li, C.-J. Chem.—Eur. J. 2010, 16, 8162. (k) Huang, L.;
Niu, T.; Wu, J.; Zhang, Y. J. Org. Chem. 2011, 76, 1759. (l) Sureshkumar,
D.; Sud, A.; Klussmann, M. Synlett 2009, 1558.
(4) (a) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. J. Am.
Chem. Soc. 2003, 125, 15312. (b) Murahashi, S.-I.; Nakae, T.; Terai, H.;
Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005. (c) Condie, A. G.;
Gonzꢁalez-Gꢁomez, J. C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2010,
132, 1464. (d) Wang, M.-Z.; Zhou, C.-Y.; Wong, M.-K.; Che, C.-M.
Chem.—Eur. J. 2010, 16, 5723. (e) Rueping, M.; Vila, C.; Koenigs, R. M.;
Poscharny, K.; Fabry, D. C. Chem. Commun. 2011, 2360. (f) Murahashi,
S.-I.; Naota, T.; Yonemura, K. J. Am. Chem. Soc. 1988, 110, 8256.
(5) (a) Murata, S.; Miura, M.; Nomura, M. J. Chem. Soc., Chem.
Commun. 1989, 116. (b) Han, W.; Ofial, A. R. Chem. Commun.
2009, 5024. (c) Han, W.; Ofial, A. R. Chem. Commun. 2009, 6023.
(d) Han, W.; Mayer, P.; Ofial, A. R. Adv. Synth. Catal. 2010, 352, 1667.
(e) Singhal, S.; Jain, S. L.; Sain, B. Adv. Synth. Catal. 2010, 352, 1338.
(f) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.; Schn€urch, M.
Chem. Commun. 2010, 8836. (g) Richter, H.; Manche~no, O. G. Eur.
J. Org. Chem. 2010, 4460. (h) Kumaraswamy, G.; Murthy, A. N.;
Pitchaiah, A. J. Org. Chem. 2010, 75, 3916.
catalyst cannot explain the different performances, as CuCl2 2H2O
3
dissolves well in both methanol and acetone.
In summary, we have investigated the mechanism of the aerobic
copper-catalyzed oxidative coupling reaction of N-phenyl-tetrahy-
droisoquinoline 1 with silyl enolate 2. Studies of the products formed
by reaction of the amine with the copper catalyst indicated iminium
dichlorocuprate 4a as the reactive intermediate in the catalytic cycle.
X-ray crystallography showed an ionic bond between the iminium
cation and cuprate in 4a. The beneficial role of methanol in oxidative
coupling reactions with amines could be explained by an off-cycle
equilibrium forming hemiaminal ethers, which act as a reservoir for
the more reactive iminium ions. This stabilizing effect could be
demonstrated to be effective in reactions with less nucleophilic
coupling partners like allyl silanes. We hope that this study will help
in the development of new and improved oxidative coupling
methods and in the mechanistic investigation of related reactions.
(6) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am.
Chem. Soc. 2006, 128, 5648.
(7) (a) Singhal, S.; Jain, S. L.; Sain, B. Chem. Commun. 2009, 2371.
(b) Sud, A.; Sureshkumar, D.; Klussmann, M. Chem. Commun.
2009, 3169.
’ ASSOCIATED CONTENT
(8) (a) Chiba, T.; Takata, Y. J. Org. Chem. 1977, 42, 2973.
(b) Santamaria, J.; Herlem, D.; Khuong-Huu, F. Tetrahedron 1977,
33, 2389. (c) Magnus, P.; Lacour, J.; Weber, W. J. Am. Chem. Soc. 1993,
115, 9347. (d) Sundberg, R. J.; Thꢁeret, M.-H.; Wright, L. Org. Prep. Proc.
S
Supporting Information. General experimental proce-
b
dures, spectroscopic and analytical data for new compounds, and
crystallographic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
ꢁ
Int. 1994, 26, 386. (e) Pintꢁer, A.; Sud, A.; Sureshkumar, D.; Klussmann,
M. Angew. Chem. 2010, 122, 5124. (f) Tsang, A. S.-K.; Jensen, P.; Hook,
J. M.; Hashmi, A. S. K.; Todd, M. H. Pure Appl. Chem. 2011, 83, 655.
(9) (a) Fukui, S.; Suzuki, N.; Wada, T.; Tanaka, K.; Nagao, H.
Organometallics 2010, 29, 1534. (b) Liu, G.; Beetstra, D. J.; Meetsma, A.;
Hessen, B. Organometallics 2004, 23, 3914. (c) Lu, C. C.; Peters, J. C.
J. Am. Chem. Soc. 2004, 126, 15818. (d) Siebenlist, R.; Fr€uhauf, H.-W.;
Vrieze, K.; Kooijman, H.; Smeets, W. J. J.; Spek, A. L. Organometallics
2000, 19, 3016.
(10) Jeener, J.; Meier, B. H.; Bachmann, P.; Ernst, R. R. J. Chem. Phys.
1979, 71, 4546.
(11) Bulman Page, P. C.; Buckley, B. R.; Appleby, L. F.; Alsters, P. A.
Synthesis 2005, 3405.
’ AUTHOR INFORMATION
Corresponding Author
klusi@mpi-muelheim.mpg.de
Present Addresses
†Institute of Microbial Chemistry, Shibasaki Laboratory, 3-14-23,
Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan.
‡University of Pittsburgh, Department of Chemistry, 219 Parkman
Avenue, Pittsburgh, PA 15260, USA.
(12) Mayr, H.; Ofial, A. R.; W€urthwein, E.-U.; Aust, N. C. J. Am.
Chem. Soc. 1997, 119, 12727.
’ ACKNOWLEDGMENT
(13) (a) Shono, T.; Matsumura, Y.; Inoue, K.; Ohmizu, H.; Kashimura,
S. J. Am. Chem. Soc. 1982, 104, 5753. (b) Murahashi, S.; Naota, T.;
Miyaguchi, N.; Nakato, T. Tetrahedron Lett. 1992, 33, 6991. (c) Matsumura,
Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000, 56, 7411.
(14) (a) Pandey, G.;Rani, K. S.;Lakshmaiah, G. Tetrahedron Lett. 1992,
33, 5107. (b) Kirira, P. G.; Kuriyama, M.; Onomura, O. Chem.—Eur.
J. 2010, 16, 3970.
Support from the MPI f€ur Kohlenforschung and Prof. Benjamin
List is gratefully acknowledged. We thank Dominique Bock,
J€org Rust, and Prof. Christian W. Lehmann for the X-ray crystal-
lography. D.S. thanks the Alexander von Humboldt Foundation
for a Research Fellowship.
(15) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003,
36, 66.
’ REFERENCES
(1) (a) Klussmann, M.; Sureshkumar, D. Synthesis 2011, 353.
(b) Scheuermann, C. J. Chem.—Asian J. 2010, 5, 436. (c) Yoo, W.-J.;
8109
dx.doi.org/10.1021/ja201610c |J. Am. Chem. Soc. 2011, 133, 8106–8109