α-Alkylation of tertiary amines by C(sp3)–C(sp3) cross-coupling under redox neutral photocatalysis

Article abstract of DOI:10.1016/j.tetlet.2016.08.073

Direct α-alkylation of N-phenyl-tetrahydroisoquinoline with alkyl selenides of desired alkyl chain length and functionality is reported by photoredox catalysis. Construction of hexahydro pyrrolo- and pyrido-isoquinoline scaffolds along with indolines and tetrahydroquinolines is also described by intramolecular C(sp³)–C(sp³) cross-couplings.

Full text of DOI:10.1016/j.tetlet.2016.08.073

Accepted Manuscript
α-Alkylation of Tertiary Amines by C(sp3) - C(sp3) Cross-Coupling under Re-
dox Neutral Photocatalysis
Ganesh Pandey, Sandip Kumar Tiwari, Bhawana Singh
PII:
S0040-4039(16)31100-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.073
TETL 48044
Reference:
Tetrahedron Letters
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Accepted Date:
10 August 2016
22 August 2016
Please cite this article as: Pandey, G., Tiwari, S.K., Singh, B., α-Alkylation of Tertiary Amines by C(sp3) - C(sp3)
Cross-Coupling under Redox Neutral Photocatalysis, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.08.073
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α-Alkylation of Tertiary Amines by C(sp3) -
C(sp3) Cross-Coupling under Redox Neutral
Photocatalysis
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Ganesh Pandey*, Sandip Kumar Tiwari, Bhawana Singh

1
Tetrahedron Letters
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α-Alkylation of Tertiary Amines by C(sp3) - C(sp3) Cross-Coupling under Redox
Neutral Photocatalysis
Ganesh Pandey*, Sandip Kumar Tiwari, Bhawana Singh
Molecular Synthesis Laboratory, Centre of Bio-Medical Research (CBMR), Sanjay Gandhi Postgraduate Institute of Medical Science Campus Raebareli Road Lucknow-
226014 (India)
ARTICLE INFO
ABSTRACT
Article history:
Received
Direct α-alkylation of N-phenyl-tetrahydroisoquinoline with alkyl selenides of desired
alkyl chain length and functionality is reported by photoredox catalysis. Construction of
hexahydro pyrrolo- and pyrido-isoquinoline scaffolds along with indolines and
tetrahydroquinolines is also described by intramolecular C(sp3)-C(sp3) cross-couplings.
Received in revised form
Accepted
Available online
Keywords:
Photo chemistry
C-H alkylation
2009 Elsevier Ltd. All rights reserved.
Visible light
C(sp)3 - C(sp)3 C–H coupling
Tertiary amine
Usually, these reactions are achieved by the electrophilic
substitution of the dipole-stabilized carbanion3, however, this
1. Introduction
Developing new methodology for C-C bond forming reaction
involving C(sp3) C–H bond adjacent to nitrogen atom (α-
aminoalkylation) represents an important and useful reaction1 for
synthesizing various pharmaceutically important and biologically
active molecules 2.
strategy is limited with only activated alkyl halides (R-X, R= Me,
allyl and benzyl etc.). Oxidative cross-dehydrogenating coupling
(CDC) reactions, another popular approach4, mediated by metal
catalyst [(Ru5, Cu6, Fe7, V8, Rh9, Au10 and Pt 11)], photoredox
12
reactions and organic oxidant13-14 (stoichiometric) is limited to
pronucleophiles such as nitroalkanes, enol silyl ethers etc.
Ackermann15 has reported alkylation of pyrrolidine at its α-
position with alkenes [(C(sp3-C(sp2) coupling], however, this
strategy requires costly [Ru(II)] catalyst and pyridyl directed
group.
Previous work
a)
Alkylation through dipole stabilized carbanion:
metalation
R-X
N
N
O
N
Boc
Recently, we16 and others17 have reported α-aminoalkylation
reaction by photoredox α-C-H functionalisation of t-amines to an
α-aminoradical intermediate and its addition to olefins, but this
reaction works with only activated olefins. To the best of our
knowledge, there is no direct method of α-alkylation of tertiary
amines18 with desired carbon chain length and functionality.
Therefore, we hypothesised a strategy as shown in Fig.1 for α-
alkylation of N-aryl tetrahydroisoquinolines (1).
Boc
Li
O
R
R = Me, allyl, benzyl
X = I, Br
b)
Oxidative CDC reaction:
oxidative CDC
C-nucleophile
N+
N
N
R
R
R
Nu
c)
Photoredox catalysed reaction:
EWG
photoredox reaction
N
N
N
Ph
The feasibility of the proposed photoredox cycle was
established by estimating Gibbs free energy change for electron
transfer processes (- Ge = -31.01 kcal/M-1 and -28.88 kcal/M-1)
Ph
Ph
d)
EWG
This work
between excited DMA*(λmax = 410 nm) to alkyl phenyselenides
photoredox catalysis
Ph-Se-alkyl
+·
+
respectively19. Subsequent steps of
N
N
as well as 1 to DMA
R/Ar
R/Ar
mesolytic cleavage of A to produce an alkyl radical20 and α-
deprotonation from B to form α-amino radical (C)16 was obvious
from our earlier work. It was expected that cross-coupling of
alkyl
∗ Corresponding author. E-mail: gp.pandey@cbmr.res.in

2
Tetrahedron
these radicals would affect α-aminoalkylation reaction owing to
Table 1: Alkylation of N-phenyltetrahydroisoquinoline by
alkyl selenides
well established persistent radical effect 21
.
h , DMA, CH CN
ν
3
+
PhSeR
2
N
N
under argon atm.
Ph
Ph
R
1
3
2 (eq.)
R
Entry Time
Producta
Yieldb
40%
50%
70%
52%
59%
73%
68%
74%
55%
1.0
1.5
2
n-C4H9
n-C4H9
n-C4H9
n-C2H5
n-C3H7
n-C10H21
C2H5OH
CH2Ph
CH3(CH)
C2H5
1
2
3
4
5
6
7
8
10 h
10 h
8 h
8 h
8 h
8 h
8 h
8 h
8 h
3a
3a
3a
3b
3c
3d
3e
3f
2
2
2
2
2
3g
2
9
a: characterised by NMR and mass spectrometry.
b: isolated by column chromatography.
the intramolecular cyclization of N-alkyl selenide substituted
1,2,3,4-tetrahydroisoquinolines to prepare corresponding
4
hexahydro pyrrolo- and pyrido-isoquinoline scaffolds (5). These
heterocyclic scaffolds are known to possess wide range of
biological and pharmacological activities. For example,
hexahydropyrrolo [2.1-a] isoquinoline (5a) is known to be a 2-
adrenoreceptor antagonist27 and its 5-phenyl derivatives exhibit
antidepressant-like activity28. Similarly, benzo[a]quinolizidine
structural motifs (5d) have been found in numerous alkaloids that
have shown potent biological activity29. In fact, most of the
approaches for the construction of these structural frameworks
have relied on C-N bond formation as an approach for the ring
closing reaction30 which suffers from the requirement of a
number of steps, harsh reaction conditions and tedious work-up.
Therefore, we envisioned the extension of this strategy for the
synthesis of these heterocyclic scaffolds.
Figure 1. Proposed α-alkylation of tetrahydroisoquinoline
with alkyl selenide.
With these premises, we carried out first a reaction by
irradiating a mixture of 1 (N-phenyltetrahydroisoquinoline,
0.098g, 0.47 mmol), butylphenylselenide (2a, 0.2g, 0.94 mmol)
and a catalytic amount of DMA (0.034g, 0.140 mmol) in
acetonitrile in the presence of argon atmosphere utilizing visible-
light (410 nm), obtained by using a combination of Pyrex and a
CuSO4:NH3 solution filter22 from a 450-W Hanovia medium
pressure mercury lamp23. Progress of the reaction was monitored
by following the disappearance of 1 by HPLC (C18 reverse
phase, ACN: H2O/75:25). It was pleasing to note that other than
unreacted 1, DMA and diphenyldisenide, there was only a single
product peak observed on the chromatogram. There was no
significant loss in DMA concentration during or after the
reaction. After 8 h of photoirradiation, the solvent was removed
and the product was purified by column chromatography to
obtain 3a in 40% yield along with diphenyl diselenide24. The
maximum yield of 3a was optimised to 70 % when 2a was used
2.0 equivalents25. A control reaction without DMA and light did
not produce any product.
Thus, we proposed the synthesis of these compounds using a
general strategy as shown in Scheme 1
This reaction may be rationalised by considering transient
alkyl as well as persistent α-aminoalkyl radical C being
generated at equal rates and initial build-up in the concentration
of persistent radical C, due to self-termination of transient alky
radical, allows radical-radical cross-coupling due to persistent
radical effect.21 Mcmillan et al.26 has also reported similar
coupling recently for the synthesis of β-aminoethers.
Diphenydiselenide may be formed directly either by direct
dimerization of PhSe- (Path a) or via PhSeH (Path b) due to
presence of small impurity of oxygen20.
Scheme 1. C(sp3)-C(sp3) intramolecular cyclization.
Usual photoredox reaction of 4 in CH3CN in the presence of
DMA under identical reaction conditions, as described above,
gave corresponding cyclised products (5) in good yield. Crispine
Generality of the reaction was also established by irradiating 1
in the presence of a wide variety of 2 under optimized reaction
condition and results are shown in Table 1. The yields mentioned
in the Table is the isolated yield.
A
(5b)31,
a
naturally occurring alkaloid possessing
hexahydropyrroloisoquinoline structural framework which
displays high biological activity against SKOV3, KB and HeLa
human cancer cell lines is also synthesized utilizing this approach
to highlight the efficacy of the methodology (65%).
After successful demonstration of α-C-H alkylation of 1 with
alkyl groups of varying chain length and functionality by visible
light photoredox catalysis, we decided to explore this reaction for

3
However, when this strategy is applied to synthesize
tetrahydro-indolo[2,1-a] isoquinoline skeleton related to
cryptaustoline alkaloid (7)32 by the photoredox reaction of 6, the
reaction unfortunately failed and gave corresponding deselylated
product (Scheme 2).
tetrahydroquinolines. A general and metal free method is
limited17d to synthesize substituted heterocycles of type 9 or 10.
Easily synthesizable precursor 8 was subjected to usual
photoredox reaction which produced corresponding cyclised
products 9 or 10 in 58-78% yield. Regioselectivity of this
reaction was also evaluated by studying the reaction of
differently substituted aniline derivatives. For example, reaction
of N-methyl N’-ethyl substituted precursor
8 underwent
exclusively methyl activation giving rise to products like 9c,
whereas, N, N’-diethyl substituted 8 did not cyclise. In case of N-
methyl-N-benzyl derivatives, the activation occurred at benzylic
position producing compounds such as 9b, 9d, 9e, 10b, 10d and
10e. This observed regioselectivity is in tune with the
observations made by us12b and others41 earlier where α-
deprotonation to generate α-aminoradical is dependent on the
kinetic acidity of α-C-H subject to stereoelectronic factor. It is
important to highlight that this strategy provides an opportunity
to prepare 2-phenyl substituted indolines (9b, 9d and 9e) and
tetrahydroquinolines (10b, 10d and 10e) directly which otherwise
would require multiple steps.
Scheme 2. C(sp3)-C(sp3) intramolecular cyclization.
After accomplishing these transformations successfully, we
set out to explore further application of this reaction to synthesize
indolines and 1,2,3,4-tetrahydroisoquinolines by intramolecular
C(sp3)-C(sp3) coupling of 6 as shown in Scheme 3.
Conclusion
In summary, we have developed a new strategy of visible light
initiated photoredox reaction for α-alkylation of N-
phenyltetrahydroisoquinoline with alkyl selenides of any chain
length and functionality. The strategy is extended to carry out
intramolecular C(sp3)-C(sp3) coupling reaction to synthesize the
pyrolo-, pyrido-, and indolo tetrahydroquinoline frameworks.
Indolines, tetrahydroquinolines and their 2-phenyl derivatives
have also been synthesised directly utilizing this protocol.
Acknowledgments
The authors declare no competing financial interest. We
thank DST, New Delhi for financial support (J.C. Bose
Fellowship to G.P.) and B.S. and S.K.T thanks DST, New Delhi
for award of research fellowship.
Supplementary Data
Scheme 3. Examples of indolines and tetrahydroquinolines.
Supplementary data (experimental details and procedures,
compound characterization data, copies of 1H, 13C spectra for
The indolines 9 are found in numerous biologically active
alkaloids33 and pharmaceuticals34. Highly efficient indoline-based
organic dyes for dye-sensitized solar cells have also been
developed35. Similarly, tetrahydroquinoline derivatives 10 are
also found to exihibit interesting biological activity. For example,
new compounds) related to this article can be found at
http://dx.doi.org/10.1016/j.tetlet.xxxxxxx
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6
Tetrahedron
α-Alkylation of Tertiary Amines by C(sp3) -
Leave this area blank for abstract info.
C(sp3) Cross-Coupling under Redox Neutral
Photocatalysis
Ganesh Pandey*, Sandip Kumar Tiwari, Bhawana Singh

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1) This is also the first report of visible –light
photoredox catalysed C(sp)3 - C(sp)3 cross-
coupling reaction for C-C bond formation
reaction.
2) This manuscript also described the
construction of hexahydro pyrrolo- and
pyrido-isoquinoline
intramolecular C(sp)3 - C(sp)3 coupling.
3) The synthesis of Crispine A (5b) and
benzo[a]quinolizidine (5d) is also
described by this methodology.
scaffolds
by
4) The indolines and tetrahydroquinolines is
also described by intramolecular C(sp3)-
C(sp3) cross-couplings.
5)