Enantioselective cross dehydrogenative coupling reaction catalyzed by Rose Bengal incorporated-Cu(I)-dimeric chiral complexes

Article abstract of DOI:10.1016/j.catcom.2017.05.026

A novel dimeric chiral Cu(I) amino alcohol based in-situ generated catalyst in combination with Rose Bengal as a photo-redox catalyst were used for the first time for asymmetric cross dehydrogenative coupling of N-aryl tetrahydroisoquinoline with terminal

Full text of DOI:10.1016/j.catcom.2017.05.026

Accepted Manuscript
Enantioselective cross dehydrogenative coupling reaction
catalyzed by Rose Bengal incorporated-Cu(I)-dimeric chiral
complexes
Gaurav Kumar, Shailesh Verma, Amamudin Ansari, Noor-ul H.
Khan, Rukhsana I. Kureshy
PII:
DOI:
Reference:
S1566-7367(17)30227-3
doi: 10.1016/j.catcom.2017.05.026
CATCOM 5062
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
7 April 2017
26 May 2017
27 May 2017
Please cite this article as: Gaurav Kumar, Shailesh Verma, Amamudin Ansari, Noor-ul H.
Khan, Rukhsana I. Kureshy , Enantioselective cross dehydrogenative coupling reaction
catalyzed by Rose Bengal incorporated-Cu(I)-dimeric chiral complexes. The address for
the corresponding author was captured as affiliation for all authors. Please check if
appropriate. Catcom(2017), doi: 10.1016/j.catcom.2017.05.026
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ACCEPTED MANUSCRIPT
Enantioselective Cross Dehydrogenative Coupling reaction catalyzed by
Rose Bengal incorporated-Cu(I)-Dimeric chiral complexes.
Gaurav Kumara,b, Shailesh Vermaa,b, Amamudin Ansaria,b, Noor-ul H. Khana,b,*, and
Rukhsana I. Kureshya,b
a Inorganic Materials and Catalysis Division, Central Salt and Marine Chemicals Research Institute
(CSMCRI), Bhavnagar- 364 002, Gujarat, India. Fax: +91-0278-2566970; E-mail: nhkhan@csmcri.org
bAcademy of Scientific and Innovative Research (AcSIR), Central Salt and Marine Chemicals Research Institute
(CSMCRI), Council of Scientific & Industrial Research (CSIR), G. B. Marg, Bhavnagar- 364 002, Gujarat,
India.

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Abstract:
A novel dimeric chiral Cu(I) amino alcohol based in-situ generated catalyst in combination with Rose
Bengal as a photo-redox catalyst were used for the first time for asymmetric cross dehydrogenative
coupling of N-aryl tetrahydroisoquinoline with terminal alkynes enroute for propargylic amines
synthesis using molecular oxygen as a terminal oxidant. This methodology provides an atom
economical and green way to access diversified optically active alkynylation product selectively at
C1-position of N-aryl tetrahydroisoquinoline under moderate conditions with high enantioselectivity
(up to 99%) and excellent yield (up to 90%).
Keywords: Cross Dehydrogenative Coupling • Tetrahydroisoquinoline • Schiff bases • photo
redox • Visible light • Alkynylation

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Introduction:
C-1 substituted tetrahydroisoquinoline derivatives have shown diverse biological
activities and are pharmaceutically important motifs such as ligand receptors,(1) enzyme
inhibitors,(2) anticancer,(3) antitubulin(4) and therapeutic agents.(5) Derivatisation of
tetrahydroisoquinoline at the C-1 position has provided potential bioactive compounds(6) like
methopoline, desoxyline and homolaudanosine(7) (Scheme 2). In this direction C-C bond
formation via cross-dehydrogenative coupling (CDC) reaction is one of the most atom
efficient processes to yield the desired products,(8-16) although other synthetic processes are
known in the literature.(17) Enantioselective CDC reaction on tetrahydroisoquinoline is
important but scantly reported.(18-24) These reports have utilized copper complexes of chiral
ligands selected from Pybox, BINAP, QUINAP as catalysts to give the desired products. This
pathway is alternative over A3 coupling for the synthesis of propargylic amines(25) (Scheme
1). In recent years several amino alcohol derived Schiff base complexes were efficiently used
for various organic transformation by our group(26) and also by others.(27) In order to check the
scope of chiral ligands, we utilized chiral amino alcohol-derived Schiff bases (L1-L5) in Cu(I)
catalyzed CDC of N-aryl tetrahydroisoquinolines with terminal alkynes.
Scheme1: Approach for Optically active C-1 substituted THIQ.

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On the other hand, the photo-redox pathway using visible light is well explored by the groups
of Macmillan, Stephenson, Yoon(28-29) and others.(30-31) For the substitution of N-aryl-
tetrahydroisoquinoline at C-1 position with a variety of nucleophiles, various metals (Ir, Ru)
and organic dyes have been used as a catalyst. Li et al.(22) for the first time combined
[Ir(ppy)2(dtbbpy)]PF6 complex with CuBr/QUINAP for enantioselective C-1 substitution of
N-aryl tetrahydroisoquinoline. These metal-based photocatalysts are expensive and at the
same time may leave toxic metal residue in the products. Various research groups have used
organic dyes as a photoredox catalyst in the past. For example Rueping et al. reported organic
dye catalysed C1 substitution of THIQ.(32) Konig et al. reported Eosin Y for various organic
transformations.(33)
Scheme 2. Important molecules contain chiral tetrahydroisoquinoline.
Here we are reporting low cost and eco-friendly organic dyes as a photo redox catalyst like
Rose Bengal (RB), Rhodamine B (RhB) and Fluorescein (F) in combination with in situ
formed Cu(I)-chiral complexes to produce optically active 1-alkynyl tetrahydroisoquinoline
derivatives with excellent enantiomeric excess (ee up to 99 %) and moderate to good yield.
Pharmaceutically important moieties can be synthesized by using this protocol.
Results and Discussion
In our quest to explore low cost and eco-friendly organic dye, chiral ligands (L1-L5 ) derived
by the reaction of readily available aminoalcohols selected from (1S,2R)-(+)-2-Amino-1,2-

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diphenylethanol L1, (S)-(-)-phenylalaninol L2, (S)-(+)-valinol L3, (S)-(+)-tert-leucinol L4,
and (1R,2S)-(+)-cis-1-amino-2-indanol L5 with 4-tert-butyl-2,6-diformylphenol were
synthesized. Initially we screened the in situ generated complexes derived from L1-L5 (6
mol%) with CuBr (5 mol%) as catalyst in combination with Rose Bengal (5 mol%) as
represntavive photoredox catalyst for cross-dehydrogenative coupling of (1a) with alkyne
(2a) (Table 1, entry 1-5) by irradiation of visible fluorescent green light (10 W) with
molecular oxygen as a mild oxidant. Data in Table 1 revealed that ligand L4 gave better
results in terms of enantioselectivity (60%) with moderate yield (65%) (Table 1, entry 4). In
order to improve the enantioselectivity and yield of the product attempts were made by
varying the metal source viz., CuI, CuCl, Cu(OTf) and Cu(OTf)2 with ligand L4 (Table 1,

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Scheme 3. Synthesis of Chiral Schiff bases.
entries 6-9). It was delighted to see that Cu(OTf) gave a good yield (80%) and moderate
enantioselectivity (75%) of the product (Table1, entry 9). Encouraged by the preliminary
results with the identified catalyst Cu(I)OTf-L4 and to ascertain an effective combination of
photoredox catalyst other organic dyes namely, Rhodamine-B and Fluorescein (5 mol%)
were used for cross-dehydrogenative coupling of (1a) with alkyne (2a) in THF (Table 1,
entries 10,11). Among the three dyes used Rose Bengal gave better results (Table 1, entry 9)
than other dyes where the conversion was low. This observation is inconsonance to the earlier
reports.30 Next attempts were made to vary the loading of Rose Bengal (RB) as photo redox
catalyst in the range (2.5 & 10 mol%) (Table 1, entries 12,13) where best results in term of
yield and enantioselectivity were obtained with 5 mol% loading (Table 1, entry 9). On
conducting the blank reaction in absence of visible light no conversion was observed which
infers that visible light is essential source for the reaction (Table 1, entry 14).
Table1. Optimization of the Ligand, Metal Source and Photocatalyst for
Enantioselective CDC reaction[a].
Entry
1(d)
2(d)
3(d)
4(d)
5(d)
6(d)
7(d)
Ligand
L1
Metal
CuBr
CuBr
CuBr
CuBr
CuBr
Cu(OTf)2
CuI
Yield[b][%]
ee[c][%]
35
50
60
55
65
45
45
35
L2
L3
L4
L5
L4
L4
39
40
60
45
21
50

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8(d)
9(d)
L4
L4
L4
L4
L4
L4
L4
CuCl
30
80
45
39
65
35
-
49
75
30
21
60
49
-
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
10(e)
11(f)
12(d1)
13(d2)
14(g)
[a]Reaction conditions: 1a (0.1mmol), 2a(0.2mmol,2.0equiv), metal (0.005mmol, 5 mol%)and L (0.006 mmol, 6 mol%), THF (1.0 ml),
Visible light 10 W CFL green light, 36 h, [b] yieldbasedon NMR usinginternal Standard, rt = room temperature(30 oC), MolecularOxygen
(O2) (1atm), [c] determinedby HPLC analysis onDaicel Chiralcel OD-H Column; [d] 5mol % Rose Bengal [d1] & [d2] 10 mol % & 2.5 mol %
Rose Bengal [e] & [f] Rhodamine-B & Fluorescein. (g) Without using Visible light source.
It is well known in literature that metal ligand ratio play an important role in cases
where the active catalyst is generated in situ. Therefore we conducted the catalytic reaction
with metal to ligand ratio 1:0.6, 1:1.2 and 1:1.8 using RB (5 mol%) for cross-
dehydrogenative coupling of (1a) with alkyne (2a) in THF (Table 2, entries 1-3). It is evident
from data that better results in term of product yield and ee is achieved in M:L (1:1.2) and
found to be optimum.
Having established the M:L ratio, we next studied other reaction parameters (i.e., catalyst
loading, effect of solvent and temperature) to maximize the yield and ee of the product using
(1a) as a representative substrate with alkyne (2a) in the presence of Cu(I)OTf-L4 as
catalyst and RB as photoredox catalyst. At first we altered the catalyst loading by keeping
other reaction parameters constant. On decreasing the catalyst loading to 2.5 mol% caused
decrease in both activity and enantioselectivity (Table 2, entry 4) however, on increasing the
catalyst loading from 5 mol% to 7.5 mol% and 10 mol% (Table 2, entries 5, 6) there was no
observable change in the product yield but there is loss in enantioselectivity. Hence 5 mol%
catalyst loading is found to be optimum.
Table 2. Optimization of the reaction parameters[a]

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Entry
Solvent
Catalyst
Temp[oC]
Metal/ L4 Yield[b][%] Ee[c][%]
Loading
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
CHCl3
CH2Cl2
CH3CN
C6H6
THF
5
5
5
2.5
7.5
10
5
5
5
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
1:0.6
1:1.2
1:1.8
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
78
80
80
45
80
82
20
45
54
40
81
80
50
75
65
40
65
70
18
65
21
32
99
92
9
10
11(d)
12(d)
5
5
5
THF
-10
[a]Reaction conditions: 1a (0.1mmol), 2a(0.2mmol, 2.0 equiv), (CuOTf)2tol.complex (0.005 mmol, 5 mol%) and L4 (0.006 mmol, 6
mol%), THF (1.0 ml), 5 mol% Rose Bengal, Visible light 10W CFL light, 36 h, [b] yield based on NMR using Internal Standard; [c]
determined by HPLC analysis on Daicel Chiralcel OD-H Column, (d) reaction time 48 h.
Next, we screened solvents like CHCl3, DCM, CH3CN, toluene and polar aprotic THF (Table
2, entries 7-10). Among these solvents screened, THF was found to be suitable for this study
in terms of enantioselectivity and yield of the desired product (ee 75%, yield 80%) (Table 2,
entry 3). Temperature also play crucial role for enantioselective CDC reaction so we varied
o
temperature from RT to 0 C. It was delighted to us that there was an improvement in the ee
99% of the CDC product with slight increase in the yield however, the reaction took little
o
longer time 48 h (Table 2, entry 11). Further decrease in temperature to -10 C has no effect
on yield but there was a drop in ee of the product and reaction became very slow (Table 2,
entry 12). The above optimized reaction condition (Table 2, entry 11) was further used to
carry
out
enantioselective
Cross-dehydrogenative
coupling
for
rest of the
tetrahydroisoquinolines
viz., 2-phenyl-1,2,3,4-tetrahydroisoquinoline, 2-(4-Chlorophenyl)-

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1,2,3,4-tetrahydroisoquinoline,
methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline,
with aliphatic and aromatic alkynes viz., phenyl acetylene, 4-Ethynyltoluene, 1-ethynyl-4-
fluorobenzene, 1-ethynyl-4-bromobenzene, 3-chloro-1-ethynylbenzene,
ethynyltrimethylsilane, 1-decyne, cyclopropylacetylene (Table 3).
2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline,
2-(2-
2-p-tolyl-1,2,3,4-tetrahydroisoquinoline,
Table 3. Cu(I)-Schiff base photocatalysed enantioselective CDC reaction of N-phenyl-
tetrahydroisoquinoline with terminal alkynes

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The data in Table 3 showed that non-substituted aromatic alkynes gave 99% ee with 81%
yield (Table 3, entry 3a), while para substituted electron donating as well as a withdrawing
group has a marginal effect on yield and ee of the product (Table 3, entry 3b-3d). Substitution
at meta-position played a negative role in ee and yield of the product which may be due to
steric effect at meta position (Table 3, entry 3e). Corresponding changing the substitution on
isoquinoline moiety has not shown any trend but good yield and high enantioinduction in the
desired products was obtained (Table 3, entry 3f-3j). While varying the alkynes from
aromatic to aliphatic with different groups such as trimethylsilyl, 1-decyne and cyclo propyl
(Table 3, entry 3j, 3k, 3l) afforded satisfactory yields and excellent ee.
Scheme 4. Plausible Reaction Mechanism of Enantioselective CDC reaction of N-Phenyl-
1,2,3,4-tetrahydroisoquinoline with terminal alkynes.
Based on experimental results a plausible mechanism is proposed (Scheme 3).
The asymmetric induction mechanism is proposed on the similar lines as reported by Tan et
al.30 In the catalytic cycle the Rose Bengal (RB) goes to the excited state RB*(34) under the
visible light irradiation and abstract one electron from THIQ (1a). Molecular oxygen
completes the photo-redox cycle by oxidizing the RB radical anion to its ground state RB.
Oxygen radical eventually abstracts the hydrogen from a C1 position of THIQ (1a) to form

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prochiral iminium ion (1c). The in situ generated Cu(I)OTf -L4 activates terminal alkyne to
form chiral acetylide species(35) which helps in the formation of optically active product (3a).
Conclusions
In conclusion, we have developed an atom economical and green way to access diversified
optically
active
alkynylation
product
selectively
at
C1-position
of N-aryl
tetrahydroisoquinoline under moderate conditions with high enantioselectivity (up to 99%)
and excellent yield (up to 90%) using dimeric Cu(I) amino alcohol Schiff base complex in
combination with Rose Bengal dye as a photoredox catalyst.
Experimental Section
General:
ESI)
All the tertiary amines were synthesized according to the reported procedure(see
and
terminal alkynes were used as received. All the solvents were dried by standard procedures,
1
distilled and stored under nitrogen. H NMR spectra were obtained with a Bruker F113V
spectrometer (200 MHz) and are referenced internally with TMS. Enantiomeric excesses (ee)
of the products were determined by UHPLC by (Shimadzu CBM-20A) using Daicel
Chiralpak OD-H, OD chiral columns with 2-IPA/hexane as eluent. Optical rotations were
measured with a Digipol 781 Automatic Polarimeter Rudolph Instruments. Synthesis of chiral
dimeric salen ligands L1-L5 was carried out by our reported procedure.r
Typical experimental procedure for the enantioselective CDC of N-aryl-
tetrahydroisoquinoline with terminal alkynes by using in situ Cu(I)OTf-L4 catalyst:
In a reaction vial, Cu(I)OTf (5 mol%), with ligand (L4) (6 mol%) were dissolved in THF and
the reaction was stirred for 1 h at RT under inert conditions (Argon Atmosphere). It was then
o
cooled to 0 C and 2-phenyl-tetrahydroisoquinoline (0.1 mmol) was added followed by
subsequently addition of RB (5 mol%) and phenylacetylene (0.2 mmol) under the irradiation
of visible light with molecular oxygen (1 atm). The reaction was checked on TLC, eluting
with hexane/dichloromethane/diethyl ether (100:60:1). When the reaction was completed, the
excess solvent was evaporated by using rotary evaporator and the product was purified by

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chromatography on silica gel (eluting with hexane/dichloromethane/diethyl ether, 100:60:1).
1H NMR spectroscopy was used for characterization of the final product.
Acknowledgements:
CSMCRI Communication no. 021, Authors thanks to CSIR for JRF, CSIR & INDUS
MAGIC PROJECT for financial Support. Gaurav Kumar is thankful to Academy of
Scientific and Industrial Research for Ph.D enrolment & Centralized Instrumental facility
Discipline for instrumentation facilities.
Appendix A. Supplementary data
All the Characterization data of cross dehydrogenative coupling products like 1H
NMR, 13C NMR, HPLC profile were provided in this section.
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Graphical abstract
13 examples
yield up to 99% ,
Rose Bengal
ee up to 90%

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Research Highlights
 First asymmetric CDC reaction using Rose Bengal with Cu(I) chiral
complexes.
 This protocol used for the synthesis of optically active propargylic
amines.
 Excellent catalytic activity in terms of enantioselectivity and product
yields.
 Synthesis of chiral Schiff base ligands using different amino alcohols.