Efficient and General Aerobic Oxidative Cross-Coupling of THIQs with Organozinc Reagents Catalyzed by CuCl2: Proof of a Radical Intermediate

Article abstract of DOI:10.1021/acs.orglett.5b01845

A general new method for the highly concise synthesis of C-1-alkylated tetrahydroisoquinolines (THIQ) is reported. The CuCl₂-catalyzed procedure is based on a coupling of nonfunctionalized THIQs with organozinc reagents under aerobic conditions. It proceeds in high yields and is broadly applicable to a wide range of substrates. It relies on a regioselective sp³ C-H bond activation allowing for an sp³-sp³ bond union under mild reaction conditions in a rapid and effective manner. Mechanistically it involves an iminium ion intermediate that is formed via an organic radical involving a single-electron-transfer process. For the first time for this type of reaction a radical intermediate has been proven by EPR spectroscopy.

Full text of DOI:10.1021/acs.orglett.5b01845

Letter
pubs.acs.org/OrgLett
Efficient and General Aerobic Oxidative Cross-Coupling of THIQs
with Organozinc Reagents Catalyzed by CuCl2: Proof of a Radical
Intermediate
Tongtong Wang,†,§ Michael Schrempp,†,§ Andreas Berndhauser,‡,∥ Olav Schiemann,‡ and Dirk Menche*,†
̈
†Kekule-
́
Intitute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany
‡Institute of Physical and Theoretical Chemistry, University of Bonn, Wegelerstrasse 12, D-53115 Bonn, Germany
S
* Supporting Information
ABSTRACT: A general new method for the highly concise
synthesis of C-1-alkylated tetrahydroisoquinolines (THIQ) is
reported. The CuCl2-catalyzed procedure is based on a
coupling of nonfunctionalized THIQs with organozinc
reagents under aerobic conditions. It proceeds in high yields
and is broadly applicable to a wide range of substrates. It relies on a regioselective sp3 C−H bond activation allowing for an sp3−
sp3 bond union under mild reaction conditions in a rapid and effective manner. Mechanistically it involves an iminium ion
intermediate that is formed via an organic radical involving a single-electron-transfer process. For the first time for this type of
reaction a radical intermediate has been proven by EPR spectroscopy.
C−C bond formation via C−H bond activation is one of the
most challenging reactions in organic synthesis and has attracted
great interest.1 It not only breaks limitations of the traditional
cross-coupling reaction but also enables direct access to C−C
bonds quickly and effectively. However, this kind of reaction
usually requires harsh conditions such as higher temperature,
pressure, and acidic and oxidative conditions2 and poses
additional challenges of regioselectivity.3 Within this context,
the selective functionalization of reactive sp3 C−H bonds
adjacent to a nitrogen atom hold a special place as they may be
effectively activated under oxidative conditions and the resulting
iminium ion intermediates may react with various nucleophiles.
Various metals such as copper,4 ruthenium,5 iron,6 rhodium,7
vanadium,8 and platinum9 have been developed for the activation
of such positions, and several of these metal-catalyzed methods
have been applied for activation of N-benzylic positions and used
for C-1 derivatizations of tetrahydroisoquinolines
(THIQs).4b−l,5a,b,d−f,8,9 Alternatively, metal-free variants using
DDQ,10 hypervalent iodine,11 or DEAD12 were reported to
oxidize THIQ structures.
Figure 1. Proposed sp3-CH-activation cross-coupling strategy of THIQs
with organometallic reagents.
type of oxidative THIQ functionalization to organozinc
reagents5dand is characterized by an extremely broad substrate
scope that compares favorably to all existing methods.4−12
To test our notion for a modular approach to C-1-substituted
tetrahydroisoquinolines by means of a copper-catalyzed coupling
with various organozinc reagents, we evaluated the reaction of
substrate 3 with diethylzinc under various reaction conditions, as
shown in Table 1. Starting with CuCl2 as catalyst, the reaction
was carried out under various conditions with different solvents
(entries 1−7). Best results were obtained in acetonitrile (0.1 M)
with CuCl2 (10 mol %) and O2 as oxidant. After 4 h at room
temperature, the desired ethyl derivative 4 was obtained in high
yields (92%, entry 7). Only poor degrees of conversions were
obtained with other solvents like THF, acetone, toluene, DMF,
dichloromethane (DCM), and MeOH (entries 1−6), demon-
strating a pronounced effect of the solvent on the outcome of the
reaction. Among the oxidants evaluated (entries 7−10), oxygen
(1 atm) was found to be optimal. Lower degrees of conversion
were obtained with TBHP (entry 8), MnO2 (entry 9), and
tBuOOtBu (entry 10). Also other copper metals like CuCl,
CuBr2, CuBr, CuI, Cu(OTf)2, and anhydrous Cu2SO4 (entries
Inspired by analogue studies in our group13 and a hit in a
screening program14 in combination with certain limitations of
existing methods in particular with respect to modularity and
substrate scope, we desired a very general method for the
synthesis of various C-1-substituted tetrahydroisoquinolines
(THIQ) that would be based on a direct C−H activation.15
Herein, we report the design, development, and scope of a
broadly applicable aerobic oxidative cross-coupling of THIQs (2,
Figure 1) with organozinc reagents catalyzed by CuCl2 to access
diversely substituted derivatives 1 in an effective and broadly
applicable manner. Furthermore, we report for the first time the
detection and structural information on a radical intermediate in
these oxidative amine activations by EPR spectroscopy. The
reported procedure presents the first general extension of this
Received: June 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01845
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a d
−
Table 1. Development and Optimization of Reaction
Conditions
Scheme 1. Reaction Scope with Diethylzinc Reagent
a
b
c
entry
catalyst
CuCl2
oxidant
O2
solvent
conversion (%)
1
2
3
4
5
6
7
8
THF
10
20
<5
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl
O2
acetone
toluene
DMF
O2
d
O2
35
O2
DCM
<5
10
O2
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
d
O2
92
e
d
TBHP
64
f
9
MnO2
30
35
7
f
10
tBuOOtBu
O2
a
11
12
13
14
15
16
17
18
19
Reaction was performed with 5 (0.20 mmol), Et2Zn (3.0 equiv),
CuBr2
CuBr
O2
28
15
8
CuCl2 (10 mol %), and O2 (1 atm) in CH3CN (0.1 M) for 4 h under
b
60 °C to room temperature. All solvents were dried by molecular
O2
c
d
sieves. Isolated yield. Reaction temperature: rt.
CuI
O2
d
Cu(OTf)2
Cu2SO4
FeCl3
O2
55
this method. Importanly, the groups of Stephensen5f and
Tomioka16 have reported on closely related C-1-alkylated
THIQs with 2-methoxy-bearing and 4-methoxy-bearing aryl
substituents that these aryl substitutents may be removed in high
yields with CAN in the presence of stoichiometric amounts of
O2
9
13
10
0
O2
RuCl3·xH2O
V5O2
O2
O2
a
Reaction was performed with 3 (0.20 mmol), Et2Zn (3.0 equiv),
5f
[Fe(bpy)3]3+ (o-methoxy group) or without a catalyst (p-
[catalyst] (10 mol %), and the indicated oxidant in the given solvent
b
methoxy group).20 Indeed, the PMP group of 6b could be readily
removed with CAN.17 This opens the valuable option of
accessing the free secondary amines if a suitable protective group
strategy is implemented.
(0.1 M) for 4 h under the room temperature. All solvents were dried
c
by molecular sieves. Conversion was determined by 1H NMR.
d
e
f
Isolated yield. TBHP solution (5.0−6.0 M) in decane. Reaction
temperature, 60 °C, and time, 14 h.
As shown in Scheme 2, the reaction could also be readily
expanded to other dialkylzinc reagents demonstrating the
generality of this process. All dialkylzinc reagents may be readily
prepared in situ by a method involving borane−diethylzinc
11−16) and other metallic oxidants like FeCl3, RuCl3, and V5O2
(entries 17−19) resulted in all cases in lower degrees of
conversion.
Having established optimal conditions for the coupling of 3
with Et2Zn, we evaluated the generality of this C−H alkylation
sequence. As shown in Scheme 1, the coupling of THIQs with
various nitrogen bearing aryl substituents (5) was studied. It
became apparent that variations of the electronic nature of these
substituents had a strong effect on the conversion of the reaction.
Therefore, after careful consideration, higher temperatures were
employed to promote the reaction. After 1 h of oxidation at 60
°C, the reaction was cooled to room temperature, and
subsequently, diethylzinc was added (Scheme 1). Substrates
with strong electron-donating groups like a methoxy group (6b),
with weak electron-donating groups like a methyl group (6c,e)
all gave high yields. In addition, useful yields were obtained for
substrates with halogen atoms such as Cl (6d). In contrast, no
reaction with substrates that lack an N-aryl substituent or bear an
alternative substitutent (e.g., a BOC group) was observed (not
shown), demonstrating again that the N-aryl substituent is very
important for reactivity, in full agreement with previous
work.4−12
Scheme 2. Reaction Scope with Different Dialkylzinc
ab
,
Reagents
Importantly, aryl substituents with an o- or a p-methoxy group
(i.e., compounds 6c and 6e) serve as suitable surrogates for the
phenyl group, giving the products in similar yields as compared
to the phenyl-protected amines. This is important, as removal of
the N-aryl substituent may be required. While an N-aryl
substituent was initially desired within this study,14 removal of
this substituent may be important to to expand the full value of
a
Reaction was performed with 3 (0.20 mmol), Et2Zn (4.0 equiv),
CuCl2 (10 mol %), and O2 (1 atm) in CH3CN (0.1 M, dried by
molecular sieves) for 4 h at room temperature. Isolated yield.
b
B
DOI: 10.1021/acs.orglett.5b01845
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Organic Letters
Letter
exchange18,19 and includes reagents with valuable functionalities
like an iodide (7b), an ester (7c), or a cyanide (7d). In all cases,
good yields were obtained in the C−C coupling. However, steric
hindrance at the α (see 7f) or the β position (see 7e) may result
in a slight decrease of the reaction yield under the same
conditions.
Scheme 4. Proposed Mechanism of the Cu-Catalyzed Aerobic
Oxidative Cross-Coupling of THIQs with Organozinc
Reagents
We then turned our attention to organozinc bromide reagents.
The respective allylzinc, propargylzinc, and benzylzinc bromide
derivatives were prepared by insertion from the corresponding
bromide using activated zinc.20 As shown in Scheme 3, good
Scheme 3. Reaction Scope Different Alkylzinc Bromide
a b
,
Reagents
addition reactions of phenyltetrahydroisoquinolines with various
nucleophiles,4i,j as well as calculations by the group of Zhang,
Wiest, and Wu21 and an additional mechanistic proposal.22 This
electrophilic intermediate should then react with the nucleophilic
zinc reagent. Presumably, the copper catalyst has a direct
influence on this coupling as alternative methods for oxidative
generation of the iminium ion intermediate in the absence of a
copper catalyst did not result in similar degrees of CC bond
formation (see Table 1). Two main pathways have been
postulated for generation of this iminium ion intermediate in
these types of copper-catalyzed oxidative addition reactions.
These involve either a single-electron-transfer process or a
process in which O2 is directly involved.4a,i,j,21 In order to shine
some light on this aspect of the coupling reaction we measured an
EPR spectrum of THIQ and CuCl2 in dry acetonitrile. We were
able to detect a radical with a g value of 2.014 and a peak to peak
line width of approximately 66 G. This is consistent with an
organic radical that supports a reaction mechanism that involves
a radical intermediate, presumably of type 9. This should be
formed by a single electron transfer (SET). The g value of 2.014
is much larger than the g value of the free electron (2.0023),
which indicates that the radical is predominantly centered at the
nitrogen, since carbon-centered radicals usually exhibit a g value
near the value for a free electron.23 Therefore, the radical
intermediate is most likely not a benzylic radical. In principle, this
may also be possibly due to the low pKa associated with the α C−
H bond of radical cations, particularly benzylic ones. Another
SET and deprotonation should then give iminium ion 10.
In conclusion, we have developed a new and broadly applicable
alkylation of THIQ derivatives by an aerobic cross-coupling with
diorganozinc reagents or organozinc bromide reagents under
CuCl2 catalyst in good yields. THIQ derivatives were oxidized to
an intermediate iminium ion, which subsequently underwent a
cross-coupling of organocuprate reagents. Furthermore, we have
shown that this reaction proceeds via a nitrogen-centered radical
that is produced by a single-electron-transfer reaction. This
method could introduce a broad range of alkyl groups, allyl
groups, propargyl groups, and benzyl groups efficiently. In
addition, ortho- and para-susbstituted N-phenyl substrates react
with similar efficiency, which opens the valuable option to also
access the secondary amines. It is expected that this reaction will
find useful applications in synthetic chemistry and pharmaceutics
due to the attractive skeleton of the products and the broad
applicability and generality of the process. The present studies
are directed toward shedding further light on the mechanism of
this reaction, to expand this type of cross-coupling also to other
a
Reaction was performed with 3 (0.20 mmol), Et2Zn (4.0 equiv),
CuCl2 (10 mol %), and O2 (1 atm) in CH3CN (0.1 M, dried by
molecular sieves) for 4 h at room temperature. Isolated yield.
b
yields were obtained with terminal allyl bromide reagents (viz.
8a, 8b). In addition, all propargylzinc bromides studied gave rise
to the desired products (8c, 8d, and 8e) with highest yields being
obtained for simple propargylzinc bromide (8c, 80%). Due to
partial alkyne to allene rearrangements, the other two
propargylzinc bromide derivatives (8d and 8e) gave slightly
lower yields (60%, 65%). Benzyl bromide reagents were likewise
added with useful yields (8f−l). A tendency of benzyl bromides
with strong a electron-donating group such as methoxy (8h)
toward dimerization during zinc insertion was observed,
resulting in decreased yields for these substrates (8h: 70%).
Benzyl bromide derivatives with weak electron-donating group
or electron-withdrawing groups such as methyl, fluoride, or
trifluoromethoxy groups or trifluoromethyl and cyanide groups
reacted smoothly (8f,g,i−l: 75−85%).
As shown in Scheme 4, this reaction is expected to proceed via
an iminium ion intermediate of type 10, in agreement with
mechanistic studies of Klussmann on copper-catalyzed oxidative
C
DOI: 10.1021/acs.orglett.5b01845
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Organic Letters
Letter
Klussmann, M. J. Am. Chem. Soc. 2012, 134, 5317−5325. (k) Zheng,
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radical-mediated processes, and to apply it in directed SAR
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01845.
́ ́
Soc. 2008, 130, 11005−11012. (d) Condie, A. G.; Gonzalez-Gomez, J.
Experimental details, spectral data, and copies of NMR
spectra for all new compounds (PDF)
C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464−1465.
(e) Barham, J. P.; John, M. P.; Murphy, J. A. Beilstein J. Org. Chem. 2014,
10, 2981−2988. (f) Bergonzini, G.; Schindler, C. S.; Wallentin, C.-J.;
Jacobsen, E. N.; Stephenson, C. R. J. Chem. Sci. 2014, 5, 112−116.
(6) For iron catalysis: (a) Bi, H.-P.; Chen, W.-W.; Liang, Y.-M.; Li, C.-J.
Org. Lett. 2009, 11, 3246−3249. (b) Volla, M. R.; Vogel, P. Org. Lett.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dirk.menche@uni-bonn.de.
(7) For rhodium catalysis, see: Catino, A. J.; Nichols, J. M.; Nettles, B.
J.; Doyle, M. P. J. Am. Chem. Soc. 2006, 128, 5648−5649.
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M. Chem. Commun. 2009, 3169−3171.
Author Contributions
§T.W. performed the synthetic work. M.S. performed the PMP
deprotection.
(9) For platinum catalysis, see: Shu, X.-Z.; Yang, Y.-F.; Xia, X.-F.; Ji, K.-
G.; Liu, X.-Y.; Liang, Y.-M. Org. Biomol. Chem. 2010, 8, 4077−4079.
(10) Muramatsu, W.; Nakano, K.; Li, C.-J. Org. Lett. 2013, 15, 3650−
3653.
Author Contributions
∥A.B. performed the EPR measurements.
Notes
(11) Muramatsu, W.; Nakano, K.; Li, C.-L. Org. Biomol. Chem. 2014,
12, 2189−2192.
The authors declare no competing financial interest.
(12) Singh, K. N.; Kessar, S. V.; Singh, P.; Singh, P.; Kaur, M.; Batra, A.
Synthesis 2014, 46, 2644−2650.
ACKNOWLEDGMENTS
■
Generous financial support by the Deutsche Forschungsgemein-
schaft (SFB 813) and the Chinese Scholarship Council (stipend
to T.W.) is gratefully acknowledged.
(13) Essig, S.; Bretzke, S.; Muller, R.; Menche, D. J. Am. Chem. Soc.
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(14) Compound 8l showed potent inhibitory effects against the P2X3
receptor.
(15) For previous reports on organometallic nucleophilic additions to
THIQs, which are, however, not as general and broadly applicable as the
work described herein, see refs 4g, 5e, 10, 11, and 12.
(16) Taniyama, D.; Hasegawa, M.; Tomioka, K. Tetrahedron:
Asymmetry 1999, 10, 221−223.
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