Copper-Catalyzed Cyanomethylation of Substituted Tetrahydroisoquinolines with Acetonitrile

Article abstract of DOI:10.1002/adsc.201600050

A novel method for the synthesis of cyanomethylated tetrahydroisoquinolines has been developed with mild reaction conditions, good yields and a broad substrate scope. Acetonitrile, a common solvent, is for the first time used as a pronucleophile for this type of two sp³C?H bonds cross-dehydrogenative coupling (CDC) reaction. A new oxidative system (CuCl₂/TEMPO/Cs₂CO₃) has been established by our group, in which the mild TEMPO reagent was found to be a highly efficient oxidant. (Figure presented.).

Full text of DOI:10.1002/adsc.201600050

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DOI: 10.1002/adsc.201600050
Copper-Catalyzed Cyanomethylation of Substituted
Tetrahydroisoquinolines with Acetonitrile
Wei Zhang,a,b Shiping Yang,b and Zengming Shena,*
a
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240,
Peopleꢀs Republic of China
Fax : (+86)-21-5474-8325; e-mail: shenzengming@sjtu.edu.cn
The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional
b
Materials, Shanghai Normal University, Shanghai 200234, Peopleꢀs Republic of China
Received: January 14, 2016; Revised: April 25, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600050.
3
À
Abstract: A novel method for the synthesis of cya-
nomethylated tetrahydroisoquinolines has been de-
veloped with mild reaction conditions, good yields
serve as sp C H coupling partners. It is noteworthy
that these active nucleophiles have an acidic proton
which exhibits low pKa values {pKa (CH3NO2)=
17.2,[17a] pKa [CH2(COOCH3)2]=15.9[17b] in DMSO}
and
a
broad substrate scope. Acetonitrile,
a common solvent, is for the first time used as a pro-
nucleophile for this type of two sp C H bonds
cross-dehydrogenative coupling (CDC) reaction. A
new oxidative system (CuCl2/TEMPO/Cs2CO3) has
been established by our group, in which the mild
TEMPO reagent was found to be a highly efficient
oxidant.
[Scheme 1, (a)]. In sharp contrast, there are very lim-
3
3
ited examples[18] for using unactivated sp C H bonds
À
À
as the pronucleophile to couple with THIQ due to
3
À
the unactivated sp C H bonds possessing high pKa
values.
Cyanomethylation is a pretty useful reaction in or-
ganic synthesis due to the importance of the cyano
group in medicinal and synthetic organic chemis-
try.[19,20a] An ideal approach is to employ acetonitrile,
the simplest alkyl nitrile, directly by activating the sp3
3
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Keywords: acetonitrile; cyanomethylation; sp C H
bond activation; TEMPO; tetrahydroisoquinolines
À
C H bond. In fact, however, acetonitrile is generally
viewed as an inert chemical reagent and used as a sol-
Tetrahydroisoquinolines (THIQs) are among the most
common skeletons in natural compounds with various
biological activities.[1] Therefore, the development of
new methods for functionalizing THIQs is of tremen-
dous significance in organic chemistry. During the
past decade, oxidative cross-dehydrogenative coupling
(CDC) has received considerable attention for attain-
ing C-1 substituted THIQs.[2] This methodology pro-
À
vides an efficient way to form a C C bond directly
through activating two C H bonds and coupling the
À
fragments without special leaving groups. Since the
pioneering works reported by Murahashi[3a] and Li,[3b]
substantial reaction systems have emerged and a large
number of pronucleophile species (NuH)[4–16] have
been discovered to react with iminium intermediates
which are believed to be generated from the oxida-
tion of tertiary amines. Concerning the coupling of
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two sp C H bonds, the oxidative CDC reactions of
3
À
THIQs with different types of C(sp ) H bonds
remain a big challenge. In most cases, highly active
nucleophiles such as nitromethane[6] and malonate[8] Scheme 1. CDC reactions by activating two sp C H bonds.
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Table 1. Optimization of the reaction conditions.[a]
vent frequently. Due to its high pKa value [pKa
(CH3CN)=31.3[17a] in DMSO], it is relatively difficult
to be used as a pronucleophile. And the related re-
ports are still rare and limited.[20] To the best of our
knowledge, there are no examples of CDC reactions
between THIQs and acetonitrile. Thus, we become in-
terested to meet this challenge. Herein we report
a Cu-catalyzed C(sp ) C(sp ) bond formation be-
tween substituted THIQs and acetonitrile, for the first
time, in the presence of TEMPO as an oxidant and
Cs2CO3 as a base, which is a new system for the cross-
dehydrogenative coupling (CDC) reaction [Scheme 1,
(b)].
3
3
À
Initially, we selected N-phenyl-1,2,3,4-tertrahydro-
ACHTUNGTRENNUNGisoquinoline (1a) as a model substrate to optimize the
conditions. In considering acetonitrileꢀs high pKa
value, we systematically surveyed reaction parameters
by screening bases, oxidants, and copper salts under
a nitrogen atmosphere. To our delight, when substrate
1a was subjected to the initial conditions with CuCl
(20 mol%), KO-t-Bu (1.0 equiv.), and TBHP
(1.5 equiv.) in CH3CN (2 mL) solvent at 1208C, it af-
forded the desired cyanomethylated product 2a in
11% yield. However, a side reaction occurred along
with our designed pathway. An oxidative by-product
3a was predominantly formed in 62% yield (Table 1,
entry 1). In order to suppress the formation of 3a,
a variety of bases were first tested (Table 1, entries 2–
5). When using Cs2CO3 as a base, a promising result
was obtained, providing 2a in 34% yield and a trace
amount of 3a (Table 1, entry 5). It was suggested that
the oxygen atom in the molecule of 3a comes from
TBHP. In this context, we examined other oxidants,
which are not peroxides, to avoid the generation of
side product 3a. Various oxidants, such as benzoqui-
none (BQ), 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ), ceric ammonium nitrate (CAN),
K2S2O8, and 2,2,6,6-tetramethylpiperidine 1-oxyl free
radical (TEMPO), were tested. TEMPO proved to be
particularly effective to give 2a in 62% yield without
forming 3a (Table 1, entry 10). Further optimization
showed that this reaction was significantly improved
with CuCl2 as a catalyst to give the desired product 2a ality of this catalytic two sp C H bonds coupling
in 87% yield and no trace amount of 3a was observed with acetonitrile as a pronucleophile under the CuCl2/
(Table 1, entry 11). Additionally, CuBr, Cu(OAc)2, TEMPO/Cs2CO3 system (Table 2). Gratifyingly, a vari-
and Cu(OTf)2 also gave the acceptable yields ety of N-substituted tetrahydroisoquinolines (THIQs)
(Table 1, entries 12–14). When decreasing the temper- reacted well with CH3CN under the standard condi-
ature to 1008C, or reducing the amount of copper salt tions to afford the desired products in good yields
or Cs2CO3 or TEMPO, the reactions gave slightly in- (Table 2). When THIQ is substituted with a naphthyl
ferior yields (Table 1, entries 15–18). Notably, the re- group (1b) at the nitrogen atom, or phenyl groups
action yield was dramatically decreased in the ab- with alkyl substituents such as Me (1c, 1d), i-Pr (1e),
sence of copper salt or TEMPO, implying that this re- or t-Bu (1f), the corresponding oxidative coupling
action might proceed through a radical pathway products were obtained in 67–85% yields (2b–2f).
(Table 1, entries 19 and 21). However, no reaction Substrate 1g with 3-methoxyphenyl on nitrogen gave
[a]
Conditions: 1a (0.1425 mmol, 30 mg), CH3CN (2 mL).
Isolated yield; n.d.=not detected.
1008C.
CuCl2 (10 mol%).
Cs2CO3 (50 mol%).
TEMPO (1.0 equiv.).
[b]
[c]
[d]
[e]
[f]
Next, we attempted to explore the scope and gener-
3
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occurs without Cs2CO3, indicating that Cs2CO3 is es- the target product in 79% yield (2g). To our surprise,
3
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sential for the two sp C H bonds coupling reaction when tetrahydroisoquinoline (THIQ) was installed
(Table 1, entry 20).
with 4-methoxyphenyl on the nitrogen, it resulted in
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Table 2. Scope of substituted THIQs.[a]
[a]
Conditions: 1 (0.25 mmol), CH3CN (3.5 mL), CuCl2 (20 mol%), TEMPO (1.5 equiv.), Cs2CO3 (1.0 equiv.), isolated yields.
1a (0.1425 mmol), CH3CN (2 mL).
Complex mixture.
[b]
[c]
a low yield (2h, 42%). When the more electron-rich tremely strong electron-withdrawing group (NO2) and
compound 1j was used as the substrate, the reaction led to complicated mixture under the standard condi-
gave a complex mixture. The possible reason was con- tions. In the case of N-methyltetrahydroisoquinoline
sidered to be that the electron-rich phenyl group on (1s), we did not find the corresponding cyanomethy-
the nitrogen is prone to form an imine cation inter- lated product.
mediate, but it results in a decrease of the electrophil-
We then performed reactions with isobutyronitrile
ic property of the imine cation. On the other hand, and n-pentanenitrile under the optimal conditions.
weak electron-withdrawing groups on the phenyl ring Unexpectedly, we obtained the amide products 4 and
such as F, Cl, and Br could give the corresponding 5 rather than the corresponding cyanoalkylated com-
products (2k–2n) with good yields (72–85%). Never- pounds (see Scheme 2). We inferred that the nitrile
theless, once strong electron-withdrawing groups such was first transformed to an amide followed by cou-
as OCF3 (1o) and CF3 (1p) were attached on the pling with an imine cation intermediate.[14a]
phenyl ring, the desired products were obtained with
Actually, the removal of the N-aryl substituent is
inferior yields (55% for 2o, 37% for 2p). The sub- significant for expanding the full value of this
strate with an electron-poor pyridyl group also gave method. According to the reported method,[12b] the
an inferior yield (47% for 2q). We speculate that the aryl group (p-methoxyphenyl) of 2h could be readily
strong electron-withdrawing groups on the nitrogen removed with CAN to generate the secondary amine
are unfavorable to form an imine cation intermediate 6 (see the Supporting Information) which is the inter-
due to the decrease of electron density on the nitro- mediate for the synthesis of various nitrogen-contain-
gen with a strongly electron-poor aryl ring (for details, ing substances of both natural and synthetic origin[21]
please see the Supporting Information). This specula- (87% yield, Scheme 3).
tion was proved by substrate 1r which has an ex-
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Scheme 4. Asymmetric cyanomethylation.
Scheme 2. The reaction of other alkyl nitriles.
pose a plausible reaction pathway as shown in
Scheme 5: 1a was transformed to 7a by single electron
transfer (SET) followed by TEMPO abstracting a hy-
drogen of 7a to yield the iminium cation 8a and
TEMPOH which was determined by GC (see the
Supporting Information). Due to the coordination
ability of nitriles to copper metal, we speculate that
Scheme 3. The removal of 2hꢀs aryl group.
Interestingly, a stereocenter was established at the acetonitrile was activated by the Cu salt and depro-
C-1 position after cyanomethylation.[5a,d,7a,h,9b,11a,14c] tonated by Cs2CO3 to generate the nucleophile 9
Therefore, we attempted to explore the catalytic which couples with the intermediate 8a to generate
3
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asymmetric 1-cyanomethlation of THIQs by adding the desired product 2a. Accordingly, the sp C H acti-
a chiral ligand into the system (Scheme 4). By varying vation of acetonitrile is probably promoted by both
the chiral ligands, we found that the use of ligand L1 copper species and base.[20g]
produced a moderate yield (46%) and low enantiose-
In conclusion, we have developed a novel method
lectivity (4% ee). Pleasingly, slightly increased enan- for the synthesis of cyanomethylated tetrahydroiso-
tioselectivity was obtained (11% ee) when using chiral quinolines. Acetonitrile, a common solvent, was first
3
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ligand L2. Given the fact that the reaction could pro- used as a pronucleophile for this type of two sp C H
ceed without copper salt (see Table 1, entry 19), it bonds CDC reaction. During this investigation, an ef-
may be hard to realize high enantioselectivity at the ficient system (CuCl2/TEMPO/Cs2CO3) has been es-
current stage. However, this promising result means tablished by our group. The mild TEMPO reagent
that the catalytic asymmetric 1-cyanomethylation of was found to be a highly efficient oxidant. This reac-
THIQs is plausible.
tion has mild reaction conditions, good yields and
On the basis of previous mechanistic studies[2,22] a broad substrate scope for the coupling of tetrahy-
and our investigation on this reaction by GC, we pro- droisoquinolines with acetonitrile.
Scheme 5. Plausible reaction mechanism.
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[5] For selected recent examples of alkynes as nucleo-
Experimental Section
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General Procedure for CDC of THIQs and Alkyl
Nitriles
Corresponding
2-substituted
tetrahydroisoquinoline
(0.25 mmol), CuCl2 (7 mg, 20 mol%), Cs2CO3 (82 mg,
1 equiv.), alkyl nitrile (3.5 mL), and TEMPO (58.5 mg,
1.5 equiv.) were added into a Schlenk tube which was evacu-
ated and back filled with nitrogen at room temperature.
Then the reaction tube was sealed. The tube was heated up
to 1208C for 20 h. After cooling to room temperature, the
solid material was removed by filtration and washed with
30 mL of ethyl acetate. The combined organic layers were
evaporated, and the resulting crude product was purified by
column chromatography on silica gel to give the products.
All products (2a–2i, 2k–2q, 4, and 5) were unknown com-
pounds. When we performed the reaction with isobutyroni-
trile and n-pentanenitrile, the amount of the substrate used
was 0.2 mmol and 2 mL isobutyronitrile or n-pentanenitrile
were added.
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This work was supported by NSFC (21272001), Shanghai
Education Committee (13ZZ014) and Shanghai Jiao Tong
University. We are grateful to the Instrumental Analysis
Center of SJTU for compound analysis.
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Copper-Catalyzed Cyanomethylation of Substituted
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