Highly efficient CuBr-catalyzed cross-dehydrogenative coupling (CDC) between tetrahydroisoquinolines and activated methylene compounds

Article abstract of DOI:10.1002/ejoc.200500226

A novel and efficient C-C bond-formation method was developed: the cross-dehydrogenative coupling (CDC) reaction catalyzed by copper bromide in the presence of an oxidizing reagent, tBuOOH. The CDC reaction provides a simple and efficient catalytic method to construct β-amino diesters and β-dicyano amines by a combination of two different sp³ C-H bonds followed by C-C bond formation. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500226

SHORT COMMUNICATION
Highly Efficient CuBr-Catalyzed Cross-Dehydrogenative Coupling (CDC)
between Tetrahydroisoquinolines and Activated Methylene Compounds
[a]
[a]
Zhiping Li and Chao-Jun Li*
Keywords: Amine / Cross coupling / C–H activation / C–CN bond cleavage / Copper catalyst
3
A novel and efficient C–C bond-formation method was de-
veloped: the cross-dehydrogenative coupling (CDC) reaction
catalyzed by copper bromide in the presence of an oxidizing
reagent, tBuOOH. The CDC reaction provides a simple and
efficient catalytic method to construct β-amino diesters and
β-dicyano amines by a combination of two different sp C–H
bonds followed by C–C bond formation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Tetrahydroisoquinoline derivatives are important struc-
tural features of natural products and pharmaceuticals;
therefore, numerous studies on their synthesis have been de-
Pursuing efficient C–C bond formation reactions has
been of cntinuous interest in chemistry, because they pro-
vide key steps in building more complex molecules from
simple precursors. In this respect, transition metal catalyzed
cross-coupling reactions of various reactive functional
groups have shown to be powerful methods of constructing
[4]
veloped. We recently reported two new types of C–C bond
formations to generate tetrahydroisoquinoline derivatives
by CDC reactions: (i) sp3 C–H and sp C–H coupling
3
(
CuBr-catalyzed alkynylation of sp C–H bonds adjacent to
[3a,3b]
3
3
a nitrogen atom)
and (ii) sp C–H and sp C–H coup-
[
1]
C–C bonds.
ling (an efficient catalytic method to construct β-nitro
Cross-dehydrogenative coupling (CDC) reaction, namely,
the cross coupling of two different C–H bonds of pronu-
cleophiles and proelectrophiles, will avoid the preparation
of functional groups and thus make synthetic schemes
shorter and more efficient (Scheme 1).[ Therefore, the de-
velopment of CDC reactions is highly desirable for the next
generation of C–C bond formations. There has been excel-
lent, but very limited, progress in this area.[ However, from
a practical point of view, highly efficient CDC reactions
under mild reaction conditions are still greatly needed for
synthesis. To realize CDC reactions, it is a prerequisite to
activate the C–H bonds in both the pronuleophile and the
proelectrophile in situ and selectively, while avoiding homo-
coupling.
[2]
amines). Herein, we report a highly efficient CDC reac-
tion under mild reaction conditions to construct β-diester-
and β-dicyano-substituted tetrahydroisoquinoline deriva-
tives catalyzed by copper bromide in the presence of
2]
3
tBuOOH (TBHP) by a combined reaction of sp C–H
3
bonds in pronucleophiles and sp C–H bonds of proelectro-
philes followed by C–C bond formation (Scheme 2).
3]
3
Scheme 2. CDC reaction between different sp C–H bonds.
Scheme 1. Cross-dehydrogenative coupling (CDC) for the forma-
tion of C–C bonds.
Results and Discussion
We began our study by examining various reaction con-
ditions for the desired CDC reaction between tetrahydroiso-
01 Sherbrooke St. West, Montreal, Quebec H3A 2K6, Canada quinoline derivative 1a and dimethyl malonate (2a)
[
a] Department of Chemistry, McGill University
8
Fax: +1-514-398-3797
E-mail: cj.li@McGill.ca
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
(Table 1). Without any solvent, the reactions generated the
desired products 3a in good to excellent yields at room tem-
perature (Entries 1–3). The yield increased to 90% when 3
Eur. J. Org. Chem. 2005, 3173–3176
DOI: 10.1002/ejoc.200500226
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3173

Z. Li, C.-J. Li
equiv. of dimethyl malonate were used (Entry 3 vs. 1). In- Table 2. CDC reaction of tetrahydroisoquinolines 1 with malonates
SHORT COMMUNICATION
[a]
2.
crease of the temperature reduced the reaction time (Entry
). Various solvents were also tested for the reaction. In
4
polar solvents, the desired products were obtained with rea-
sonable to good yields (Entries 5–11). However, with hex-
ane as solvent, the product was obtained in less than 5%
yield (Entry 12). Although a higher isolated yield was ob-
tained when dimethyl malonate was in excess (Entries 2 and
3), we chose the conditions of the equimolar reaction of 1a
and 2a (Entry 1), which is more “atom-economical” as our
standard reaction conditions.
Table 1. Optimization of the reaction conditions.[a]
[
(
(
a] Tetrahydroisoquinoline (0.1 mmol), dimethyl malonate
0.1 mmol), and tBuOOH (0.02 mL, 5–6 m in decane). [b] Solvent
0.5 mL) was used, if needed. [c] Determined by NMR spec-
troscopy from recovered 1a. [d] Determined by NMR spectroscopy
by using an internal standard. [e] Standard conditions, except that
dimethyl malonate (0.2 mmol) was used. [f] Standard conditions,
except that dimethyl malonate (0.3 mmol) was used. [g] Standard
conditions, except that the reaction was carried out at 35 °C for
[
a] Tetrahydroisoquinoline (0.1 mmol), malonate (0.1 mmol), and
tBuOOH (0.02 mL, 5–6 m in decane). [b] Determined by NMR
spectroscopy from recovered 1. [c] Isolated yields. [d] CuBr
(
3
h.
0.005 mmol, 0.5 mol-%), tetrahydroisoquinoline (1.0 mmol), ma-
lonate (1.0 mmol), tBuOOH (0.2 mL, 5–6 m in decane), reaction
time 53 h. [e] Tetrahydroisoquinoline (0.1 mmol), malonate
Under the standard conditions, various β-amino diester
(
0.2 mmol), and tBuOOH (0.02 mL, 5–6 m in decane).
derivatives were generated by this new methodology. Repre-
sentative results obtained by the CDC reaction are summa-
rized in Table 2. The reaction of 2-phenyltetrahydroisoquin-
Next, we investigated the synthesis of β-dicyano-substi-
oline with various dialkyl malonates gave the desired prod- tuted tetrahydroisoquinoline derivatives by using malono-
ucts in excellent yields (Entries 1, 3–6). For substituted 2- nitrile as the pronucleophile under the standard reaction
phenyltetrahydroisoquinoline, the expected products were conditions. The results are listed in Table 3. The desired
also obtained with reasonable to good yields (Entries 7–10). product 5 was obtained in 29% isolated yield (Entry 1).
[
5]
To further improve the high efficiency of this new method- Surprisingly, α-cyano product 6 was also obtained as one
ology, the reaction was carried out on a 1 mmol scale with of the unexpected by-products. The yield of product 5 was
0.5 mol-% of CuBr as the catalyst. The progress of this increased to 46% along with 6% of 6 when 6 equiv. of ma-
reaction is clearly seen by the changes of the reaction mix- lononitrile were used (Entry 2). More interestingly, if 2
ture: the reaction starts with a clear solution, then changes equiv. of TBHP were used, product 5 was not observed by
to a red color solution gradually, and turns into a reddish NMR spectroscopy and only compound 6 was obtained as
solid after 53 h. The desired product 3a was obtained in the main product (Entry 3). This unexpected result is prob-
72% isolated yield (Entry 2).
ably due to a certain oxidative degradation of malononitrile
3174
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 3173–3176

Coupling between Tetrahydroisoquinolines and Activated Methylene Compounds
SHORT COMMUNICATION
to cleave the C–CN bond by CuII[6] and to give the corre- synthetic application of this reaction are under investiga-
sponding product 6.
tion.
Table 3. CDC reaction of tetrahydroisoquinoline with malononi-
[
a]
triles.
Experimental Section
Representative Procedure and Results: To a mixture of CuBr
(
(
0.7 mg, 0.005 mmol) and 2-phenyl-1,2,3,4-tetrahydroisoquinoline
209 mg, 1.0 mmol), dimethyl malonate (116 μL, 1.0 mmol) was
added. Then tert-butyl hydroperoxide (0.20 mL, 5–6 m in decane)
was added dropwise into the mixture under nitrogen at room tem-
perature. The resulting mixture was stirred at room temperature for
a certain time as mentioned in the tables. The resulting suspension
was diluted with dichloromethane. The solvent was removed by
rotary evaporation and purified by column chromatography on sil-
ica gel (eluting with hexane/ethyl acetate = 5:1), and the fraction
f
with an R = 0.5 was collected and concentrated to give the desired
product 3a in 72% isolated yield.
[a] Tetrahydroisoquinoline (0.1 mmol). [b] Determined by NMR
spectroscopy from recovered 1a. [c] Isolated yields based on tetra-
hydroisoquinoline.
Dimethyl 2-(2-Phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)malonate
(
3a): IR (neat liquid): ν˜ max = 3065, 3022, 2959, 2911, 2843, 1765,
1
1
754, 1740, 1596, 1577, 1504, 1476, 1450, 1436, 1386, 1344, 1307,
A tentative mechanism for the formation of the β-diester
–
1
1
273, 1232, 1199, 1162, 1136, 1111, 1019 cm .
, 25 °C): δ = 7.21–7.15 (m, 3 H), 7.13–7.05 (m, 3
H), 6.96 (d, J = 8.1 Hz, 2 H), 6.73 (dd, J = 6.9, 6.9 Hz, 1 H), 5.69
d, J = 9.3 Hz, 1 H), 3.94 (d, J = 9.3 Hz, 1 H), 3.72–3.56 (m, 2 H),
H NMR
derivatives is proposed in Scheme 3. Copper catalyzes the
[7]
(300 MHz, CDCl
3
formation of an imine-type intermediate (coordinated to
[
8]
3
the copper ion ) through H-abstraction of the sp C–H
group adjacent to the nitrogen atom. The copper catalyst
also activates the malonate.[ Subsequently, coupling of the
two intermediates results in the desired product and regen-
(
3
2
2
.63 (s, 3 H), 3.52 (s, 3 H), 3.05 (ddd, J = 16.2, 8.7, 6.3 Hz, 1 H),
9]
13
.85 (dt, J = 16.2, 5.1 Hz, 1 H) ppm. C NMR (75 MHz, CDCl
3
,
5 °C): δ = 168.00, 167.13, 148.55, 135.47, 134.58, 128.92, 128.79,
erates the copper catalyst. Alternatively, it is possible that 127.45, 126.86, 125.85, 118.45, 115.03, 59.05, 58.12, 52.48, 52.47,
tert-butyl peroxide products are involved as intermedi- 42.15, 26.06 ppm. MS (EI): m/z (%) = 339, 209, 208 (100), 193,
ates[
3b,10]
which are further converted into the correspond- 165, 128, 115, 104, 91, 77, 65, 51. HRMS: calcd. for C20H21NO
4
339.1471; found: 339.1475.
ing cross-coupling products with CuBr.
Acknowledgments
This work was supported by the Canada Research Chair (Tier I)
foundation (to C. J. L.), the CFI, NSERC, Merck Frosst and
McGill University.
[
[
[
1] F. Diederich, P. J. Stang, Eds. Metal-Catalyzed Cross-Coupling
Reactions, Wiley-VCH, New York, 1998.
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Z. Li, C.-J. Li, J. Am. Chem. Soc. 2005, 127, 6968–6969.
3
3
3] For representative references, see: A) sp C–H and sp C–H:
ref.[ B) sp C–H and sp C–H: a) Z. Li, C.-J. Li, Org. Lett.
2]
3
2
004, 6, 4997–4999; b) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2004,
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Nakae, J. Am. Chem. Soc. 2003, 125, 15312–15313; d) S. Mur-
Scheme 3. Tentative mechanism for the CDC reaction of amine
with malonate.
ata, K. Teramoto, M. Miura, M. Nomura, J. Chem. Res. Mini-
2
2
print 1993, 2827–2839; C) sp C–H and sp C–H: e) Y. Hatam-
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2
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2
3
hedron 1984, 40, 2699–2702; D) sp C–H and sp C–H: i) B.
DeBoef, S. J. Pastine, D. Sames, J. Am. Chem. Soc. 2004, 126,
In conclusion, a new type of tetrahydroquinoline deriva-
tives, β-diester and β-dicyano derivatives, were efficiently
synthesized by a CDC reaction between two different sp3
6
556–6557; E) sp C–H and sp C–H: j) K. C. Nicolaou, R. E.
Zipkin, N. A. Petasis, J. Am. Chem. Soc. 1982, 104, 5558–5560.
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1
3
04, 3341–3370; b) K. W. Bentley, Nat. Prod. Rep. 2004, 21,
95–424.
conditions. This novel methodology provides the simplest
way to construct such β-diester and β-dicyano derivatives.
We also report here an unexpected C–CN bond cleavage
under mild reaction conditions. The scope, mechanism, and
[
5] Oxidative synthesis of α-amino nitriles: a) M. North, Angew.
Chem. Int. Ed. 2004, 43, 4126–4128 and references cited
therein; b) ref.[
3c]
Eur. J. Org. Chem. 2005, 3173–3176
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3175

Z. Li, C.-J. Li
SHORT COMMUNICATION
[
II
6] C–CN bond cleaved by Cu : D. S. Marlin, M. M. Olmstead, [9] a) Y. Kanda, O. Onomura, T. Maki, Y. Matsumura, Chirality
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bayashi, S. Akutagawa, J. Am. Chem. Soc. 1990, 112, 7820–
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Chem. Soc. 1988, 110, 8256–8258.
[
3d]
[
7] Ref. Other oxidants are also known to oxidize tetrahydroiso-
quinolines to quinolinium intermediate, see: N. J. Leonard,
G. W. Leubner, J. Am. Chem. Soc. 1949, 71, 3408–3411.
[
8] a) N. Gommermann, C. Koradin, K. Polborn, P. Knochel, An-
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Received March 30, 2005
2797–2811.
Published Online: June 14, 2005
3176
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3173–3176