Reactions of 3,4-dihydroisoquinolines and dihydrothieno[3,2-c]pyridines with benzyne

Article abstract of DOI:10.1016/j.mencom.2017.09.026

Cyanomethyl-substituted tetrahydroisoquinolines and tetrahydrothieno[3,2-c]pyridines were synthesized by multicomponent reaction of the dihydro analogues of aforesaid systems with benzyne and acetonitrile. The products obtained relate to alkaloids of isoq

Full text of DOI:10.1016/j.mencom.2017.09.026

Mendeleev
Communications
Mendeleev Commun., 2017, 27, 506–508
Reactions of 3,4-dihydroisoquinolines and
dihydrothieno[3,2-c]pyridines with benzyne
Natalia I. Guranova,a Alexey V. Varlamov,a Valentina V. Ilyushenkova,a Ekaterina A. Sokolova,a
Tatiana N. Borisova,a Alexander V. Aksenov,b Viktor N. Khrustaleva and Leonid G. Voskressensky*a
a Department of Organic Chemistry, RUDN University, 117198 Moscow, Russian Federation.
Fax: +7 495 955 0779; e-mail: lvoskressensky@sci.pfu.edu.ru
b North-Caucasus Federal University, 355009 Stavropol, Russian Federation
DOI: 10.1016/j.mencom.2017.09.026
TMS
OTf
R2
R2
R2
R2
R2
R2
MeO
MeO
Cyanomethyl-substituted tetrahydroisoquinolines and tetra-
hydrothieno[3,2-c]pyridines were synthesized by multicom-
ponent reaction of the dihydro analogues of aforesaid systems
with benzyne and acetonitrile. The products obtained relate
to alkaloids of isoquinoline family of 1,2,3,4-tetrahydro level.
+
N
N
N
CsF, MeCN
20–65 °C
Ph
Ph
R1 Ph
R1
R1
CN
R1 = H, Me, Ar
2 = H, Me
14 examples
(6–62%)
5 examples
(7–22%)
R
Isoquinolines and derivatives thereof represent a class of organic
compounds with wide range of biological activity,1,2 most of
them being used in medicine. Among isoquinoline alkaloids those
with dihydro- and especially tetrahydroisoquinoline core are
prevalent.3 Moreover, such compounds are often applied as building
blocks in organic synthesis. Most approaches to functionalized
tetrahydroisoquinolines are based on the trapping of iminium salts
with nucleophiles4,5 or organometallic compounds6–8 alongside
with oxidative C–H functionalization.9–11 In recent decades, the
chemistry of arynes received a widespread use due to their ability
to react with a variety of heterocycles and even with neutral
nucleophiles.12–17 The multicomponent reactions (MCR) with the
involvement of arynes are often employed for the functionalization
of heterocyclic compounds18–22 especially of (iso)quinolines and
pyridines as well as for the synthesis of complex structures.23–26
Herein we disclose an approach towards 1,1-disubstituted
tetrahydroisoquinolines and 4,4-disubstituted tetrahydrothieno-
[3,2-c]pyridines bearing cyanomethyl group at C-1 and C-4
position, respectively, based on MCR of dihydro analogues of
the aforesaid compounds with aryne and acetonitrile.
The starting 3,4-dihydroisoquinolines 1a–j and dihydrothieno-
[3,2-c]pyridines 1m,n were obtained by the Bischler–Napieralski
method (Scheme 1). Dihydroisoquinolines 1k,l were synthesized
by the Ritter-type reactions.27
We started our investigation with the model reaction between
1-methyl substituted dihydroisoquinoline 1a and benzyne in the
presence of CsF (Scheme 2, Table 1). It was found that the reaction
proceeded slowly at room temperature even with twofold excess
MeO
N
MeO
O
MeO
POCl3
(Het)Ar
SiMe3
OTf
+
Me
NH2
1a
N
F
R
Cl
MeO
MeCN
R
POCl3
S
1a R = H
1b R = Me
MeO
MeO
MeO
MeO
1c R = 2-thienyl
1d R = 2-furyl
1e R = Ph
1f R = 4-MeC6H4
1g R = 4-MeOC6H4
1h R = 4-O2NC6H4
1i R = 4-FC6H4
1j R = Bn
+
N
N
N
Ph
CN
Ph
R
Me
Me Ph
1m R = 4-MeOC6H4
1n R = Ph
2a
3a
Scheme 2
Table 1 Optimization of addition of benzyne to tetrahydroisoquinoline 1a
in MeCN.
Me
CHO
R2
R2
MeO
MeO
MeO
MeO
or
Me
O
Entry
Promoter
T/°C
Reaction time
Yield of 2a (%)
R1CN, H+
N
1
2
3
4
CsF
CsF
CsF
TBATb
20
65
125a
20
3 days
24 h
5 min
24 h
15
30
R1
1k R1 = Ph, R2 = Me
1l R1 = Me, R2 + R2 = (CH2)5
41 (+7% of 3a)
–
a Under MW irradiation. b Tetrabutylammonium difluoro(diphenyl)silicate.
Scheme 1
© 2017 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 506 –

Mendeleev Commun., 2017, 27, 506–508
of aryne: the target 1-cyanomethylated derivative 2a was isolated
in 15% yield while most of the starting dihydroisoquinoline was
recovered (see Table 1).
afforded a considerable amount of tar products, none of them
having been major. It is noteworthy that the presence of strong
electron-donating group in the C-1-positioned aryl substituent
favors formation of both the target compounds and side-products
(entry 7). In cases of thienopyridines 1m,n, the reaction
proceeded at moderate heating smoothly and faster as compared
to isoquinoline analogues.
We suppose that the reaction starts with addition of dihydro-
isoquinoline at the triple bond of aryne resulting in zwitter-ion A
(Scheme 4) which can further eliminate hydrogen atom from
acetonitrile giving intermediate B. The nucleophilic attack of
thus generated cyanomethyl anion at C-1 position of dihydro-
isoquinoline leads to 1-R-1-cyanomethyl derivatives. The forma-
tion of diphenyl substituted products 3b,e,f,g,i possibly occurs
through the intramolecular [2+2]-cycloaddition in the zwitter-
ion A28–30 to give intermediate C. Its subsequent reaction with the
second molecule of aryne and acetonitrile affords (as a hydrogen
source) products of double benzyne addition. The cyanomethyl
anion serves as cryptobase for cationic intermediate D.
Raising the temperature up to 65°C accelerates the reaction
leading to target compound 2a in 30% yield. The use of micro-
wave irradiation significantly reduces the reaction time and
increases the yield up to 41%. However, higher temperature
provoked the formation of compound 3a, a side product of
double aryne insertion, lacking cyanomethyl grouping. Despite
of substantial advantage of microwave irradiation, this procedure
didnotworkfor1-furylandsome1-arylsubstitutedisoquinolines.
Although the TBAT-promoted reaction occurred smoothly, the
target product could not be completely separated from this reagent
even after several purifications. Therefore, in our further investiga-
tion we used moderate heating unless indicated otherwise (Table 2).
Our attempts to involve other CH-acids such as propanedinitrile,
nitromethane, and nitroethane in this reaction were unsuccess-
full. Inseparable multicomponent mixtures and resins were mostly
obtained. None of compounds reacted with malononitrile even
after boiling in toluene for a week with tenfold excess of benzyne
precursor.
The structure of compound 2d was unambiguously confirmed
by X-ray analysis (Figure 1).† Its tetrahydropyrimidine ring adopts
a slightly distorted sofa conformation. The N(2) atom has a
As can be seen from Table 2, the better yields of products 2
(Scheme 3) were achieved when the reactant had no substituent
at the C-1 position of isoquinoline core (entry 2) or was deprived
of electron-withdrawing group in such an aromatic substituent
(compare entries 4–7 with 8). The reaction with 1h (entry 8)
R2
R2
R2
R2
R2
R2
+
MeCN,
20–65 °C
N
N
N
Ph
Ph
R1
R1
R1
Ph
R2
R2
R2
R2
CN
3
1
2
MeCN,
20–65 °C
N
N
[H–] – CH2CN
– CH2CN
Ph
R1
R1
CN
R2
R2
R2
R2
R2
R2
1a–n
2a–n
MeCN
– CH2CN
a R1 = R2 = H
N
N
N
R1
R2
Ph
Ph
b R1 = Me, R2 = H
MeO
MeO
R1
R1
R1
c R1 = 2-thienyl, R2 = H
d R1 = 2-furyl, R2 = H
e R1 = Ph, R2 = H
+
N
A
B
Ph
R1
Ph
R1 = 4-MeC6H4, R2 = H
D
f
g R1 = 4-MeOC6H4, R2 = H
3b,e,f,g,i
[H+] MeCN
h R1 = 4-O2NC6H4, R2 = H
i
R2
R2
R2
R2
R1 = 4-FC6H4, R2 = H
R1 = Bn, R2 = H
j
k R1 = Ph, R2 = Me
NH
N
l
R1 = Me, R2 + R2 = (CH2)5
R1
R1
m R1 = 4-MeOC6H4, R2 = H
n R1 = Ph, R2 = H
C
Scheme 3
Scheme 4
Table 2 Reaction of 3,4-dihydroisoquinolines and dihydrothieno[3,2-c]-
pyridines with benzyne.
†
Crystal data for 1: C34H24N2O6Zn (M = 621.92) monoclinic, space
group P21/c, at 293 K: a = 8.0301(9), b = 21.012(2) and c = 17.3295(17) Å,
b = 112.532(4)°, V = 2700.8(5) Å3, Z = 4, dcalc = 1.530 g cm–3, m(MoKa) =
= 0.963 mm–1, F(000) = 1280. Total of 13255 reflections were measured
and 4756 independent reflections (Rint = 0.0438) were used in a further
refinement, which converged to wR2 = 0.1123 and GOF = 0.948 for all
independent reflections [R1 = 0.0469 was calculated against F for 3458
observed reflections with I > 2s(I)]. The measurements were made on
a Bruker Apex Smart CCD diffractometer with graphite-monochromated
MoKa radiation (l = 0.71073 Å). The structure was solved by direct
methods, and the non-hydrogen atoms were located from the trial structure
and then refined anisotropically with SHELXTL using a full-matrix least-
squares procedure based on F2.16 The hydrogen atom positions were
fixed geometrically at calculated distances and allowed them to ride on
the parent atoms.
Entry
Conditions
Reactant 1 Product 2
By-product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
MW, 125°C, 5 min 1a
20°C, 24 h
2a (41%)
2b (58%)
2c (45%)
2d (49%)
2e (55%)
2f (50%)
2g (61%)
2h (6%)
2i (50%)
2j (35%)
2k (44%)
2l (38%)
2m (45%)
2n (62%)
3a (7%)
–
–
–
3e (13%)
3f (9%)
3g (22%)
–
3i (10%)
4 (10%)
–
–
–
–
1b
1c
1d
1e
1f
1g
1h
1i
65°C, 5 days
65°C, 6 days
65°C, 1 month
20°C, 2 days
65°C, 4 days
65°C, 1 month
65°C, 5 days
65°C, 2 days
20°C, 5 days
20°C, 5 days
65°C, 24 h
1j
1k
1l
1m
1n
CCDC 885118 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
65°C, 24 h
– 507 –

Mendeleev Commun., 2017, 27, 506–508
This work was supported by the Russian Foundation for Basic
C(21)
C(4)
C(3)
Research (grant no. 16-33-00640 mol_a) and the Ministry of
Education and Science of the Russian Federation (agreement
no. 02.a03.21.0008).
C(5)
N(1)
C(14)
C(15)
C(6)
C(4A)
C(16)
C(19)
C(17)
C(18)
O(2)
N(2)
C(1)
C(8A)
C(8)
C(20)
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2017.09.026.
C(7)
C(13)
O(1)
C(12)
C(9)
O(3)
C(10)
C(11)
C(22)
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[2,1-a]isoquinolinone 4.
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In summary, we developed an approach toward 1- and 4-func-
tionalized tetrahydroisoquinolines and tetrahydrothienopyridines,
respectively, based on MCR of dihydroisoquinolines or thieno-
pyridines with benzyne and acetonitrile used both as a solvent and
as a third component. These compounds are of interest from the
synthetic point of view due to the presence of cyano group that
can be readily modified for further transformations. Benzyl
substituted dihydroisoquinoline gave a product of aryne insertion
along with the expected 1-cyanomethyl substituted tetrahydro-
isoquinoline.
Received: 16th January 2017; Com. 17/5148
– 508 –