Enantioselective Decarboxylative Cyanation Employing Cooperative Photoredox Catalysis and Copper Catalysis

Article abstract of DOI:10.1021/jacs.7b09802

The merger of photoredox catalysis with asymmetric copper catalysis have been realized to convert achiral carboxylic acids into enantiomerically enriched alkyl nitriles. Under mild reaction conditions, the reaction exhibits broad substrate scope, high yields and high enantioselectivities. Furthermore, the reaction can be scaled up to synthesize key chiral intermediates to bioactive compounds.

Full text of DOI:10.1021/jacs.7b09802

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Communication
Enantioselective Decarboxylative Cyanation Employing
Cooperative Photoredox Catalysis and Copper Catalysis
Dinghai Wang, Na Zhu, Pinhong Chen, Zhenyang Lin, and Guosheng Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09802 • Publication Date (Web): 17 Oct 2017
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Enantioselective Decarboxylative Cyanation Employing Cooperative
Photoredox Catalysis and Copper Catalysis
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Dinghai Wang,† Na Zhu,† Pinhong Chen,† Zhenyang Lin,*,‡ Guosheng Liu*,†
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, China, 200032
‡Department of Chemistry, the Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong,
China
Supporting Information Placeholder
ABSTRACT: The merger of photoredox catalysis with
asymmetric copper catalysis have been realized to convert achiral
carboxylic acids into enantiomerically enriched alkyl nitriles.
Under mild reaction condition, the reaction exhibits broad
substrate scope, high yields and high enantioselectivities.
Furthermore, the reaction can be scaled up to synthesize key
chiral intermediates to bioactive compounds.
Carboxylic acids are stable and readily available, which makes
decarboxylative coupling a useful reaction in organic synthesis.1
Among them, the thermodynamically favorable radical
2
decarboxylation reactions have received much attention.
Recently, a new strategy by merging transition metal (TM)
catalysis into the decarboxylation reaction has been applied to
cross-coupling reactions,3 in which carboxylic acids act as both
carbon nucleophiles and electrophiles by releasing CO2. However,
formation of highly reactive carbon-centered radical makes
asymmetric decarboxylative coupling extremely difficult.
In the last decades, asymmetric radical transformations (ARTs)
using TM catalysis have become a powerful method.4,5 Trapping
alkyl radical by reactive chiral TM species was generally invovled
as a key step in these reactions. With this strategy, asymmetric
decarboxylative arylation reactions by cooperative photocatalysis
and nickel catalysis were first disclosed by Fu and MacMillian.6
Scheme 1. Merging Photocatalysis into Asymmetric
Decarboxylation (PC = photocatalyst).
Notably, two key species, an alkyl radical produced by
photocatalysis via reductive quenching cycle and a chiral aryl-
Ni(II) species generated through oxidative addition (OA) were
formed in parallel (Scheme 1a). Subsequently, Reisman and
coworkers reported a Ni-catalyzed asymmetric decarboxylative
vinylation reaction without photoredox activation.7
Asymmetric decarboxylative cyanation represents one of most
efficient and straightforward strategy to convert achiral carboxylic
acids into enantiomer-enriched alkyl nitriles, which prompted us
to test the feasibility.11 Comparing to the previously used F+ and
+
CF3 reagent,8 unfortunately, the relatively inert N-O bond of
As part of our efforts to develop ARTs reactions, 8,9 we have
demonstrated that a benzylic radical generated via a radical replay
process can be trapped by a reactive chiral copper(II) cyanide
enantioselectively, delivering optically pure benzyl nitriles
efficiently.8 The key reactive L*CuII(CN)2 (L* = bisoxazoline,
Box) species was generated via a single electron oxidation of
L*CuI, using electrophilic F+ reagents or CF3+ reagents as oxidant
(cycle C in Scheme 1b).
NHP ester 1a failed to oxidize L*CuI, and the decarboxylation
reaction didn't occur.12 Thus, we believe that, how to initiate the
radical decarboxylation of the NHP ester and generate L*CuII
cyanide species is critical to the success of the designed reaction.
Herein, we communicate the catalytic asymmetric radical
decarboxylative cyanation by merging photoredox catalysis with
copper catalysis.
Recent studies on photocatalyzed decarboxylation of NHP
esters reveals that the excited photocatalyst (PC*) can transfer an
electron to NHP ester 1 and form PC+, and the formed anionic
Recently, N-hydroxy-phthalimide (NHP) esters 1 have been
extensively studied in radical decarboxylation reactions.1d,3a,10
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radical of NHP ester undergoes radical decarboxylation to
reaction in p-xylene gave the product in 11% yield with slightly
generate benzylic radical. 13 , 14 Inspired by these reports, we
hypothesized that, if the strongly oxidizing PC+ could be used to
oxidize L*CuICN to form L*CuIICN rapidly, 15 the L*CuIICN
species can further react with TMSCN, followed by combining
with the benzyl radical to give coupling product 2 (cycle B). With
chiral ligands, the asymmetric decarboxylative reaction could give
rise to enantiomer-enriched organic nitriles (Scheme 1b, left).16
The key step of the oxidation of L*Cu(I) by PC+ makes the
resulting oxidative quenching cycle (A) to distinguish the
mechanisms of our previous studies (Scheme 1b, right)8 and
nickel catalyzed photoredox reactions in the literature (Scheme
1a).6
better ee (88%, entry 6). Pleasingly, mixed solvent of DMF and p-
xylene provided the product in 83% yield with 87% ee (entry 7).
Furthermore, decreasing the catalysts loading is beneficial to give
better results. When Ir(ppy)3 was decreased to 0.5 mol% and
CuBr to 1 mol%, product 2a was obtained in 98% yield with 87%
ee (Table 1, entry 8). No reaction occurred in dark (Table 1, entry
9), and both the photocatalyst and the Cu catalyst were essential
to the asymmetric radical decarboxylative cyanation (Table 1,
entries 10-11).22
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Other imides in substrate were also examined. As shown in
Table 1 (bottom), the substrates 1ab and 1ac were also tested in
the reaction under the optimal reaction conditions, giving the
product 2a with the similar yields and same enantioselectivies. In
contrast, 1ad and 1ae having a higher LUMO are not suitable for
the reaction. These results indicated that conjugate imides (1a,
1ab and 1ac) could accommodate an incoming electron better
than unconjugated imides (1ad and 1ae) (for details, see SI).
With the optimized reaction condition in hand, the substrate
scope and functional group tolerance were further examined. As
shown in Table 2, various NHP esters derived from simple
carboxylic acids were compatible to the reaction condition to
provide the corresponding products 2a-2r in good yields (71-99%)
and excellent enantioselectivities (82-99% ee). In contrast,
substrates with bulky steric hindrance (2i, 2o, 2r) provided higher
enantioselectivities. A series of functional groups, such as halide,
ether and ester, were very well tolerated. Notably, aryl boronic
ester (Bpin) was also tolerated in the reaction to provide product
2k with excellent enantioselectivity (94% ee), which allows for
the further transformation. In addition, functional groups such as
alkene, alkyne and anthracenyl ring that incompatible in our
pervious C-H cyanation, could survive in the current reaction
condition to give desired products 2v, 2w and 2u in good yields
(92%, 66% and 90% respectively) with excellent ee values (93%
and 92% ee). Excitingly, NHP esters containing heterocycles
including thianaphthenyl and pyridyl were also suitable for the
decarboxylative cyanation to give products 2x and 2y in good
yields and ee. Finally, for the commercially available racemic
arylpropanoic acids commonly used as anti-inflammatory drugs,
such as ibuprofen (2a), ketoprofen (2z), flurbiprofen (3a),
loxoprofen (3b), pranoprofen (3c), carprofen (3d) and zaltoprofen
(3e), the related NHP esters were suitable to the asymmetric
cyanation to yield the corresponding enantiomer-enriched
benzylic nitriles in good to excellent yields (59-98%) with good
enantioselectivities (82-92% ee). Unfortunately, the NHP esters
derived from secondary aliphatic carboxylic acid, which involves
non-benzylic carbon radical, provided poor enantioselectivity.
To demonstrate the preparative utility of our method, the
enantioselective decarboxylative radical cyanation was conducted
on a 270 mmol scale with low catalyst loading (0.1 mol% Ir(ppy)3
and 0.26 mol% CuBr/L1), delivering the desired product 2d in 95%
yield with 88% ee, albeit in a prolonged time (Scheme 2a). In
addition, the chiral alkyl nitriles can be obtained from carboxylic
acids in one-pot: after condensation of carboxylic acid with NHP,
the unpurified NHP ester was subjected to our standard conditions,
providing the optically enriched nitriles 3a, 3b and 3e in goods
yields and good ee (Scheme 2b); compared to the reaction of the
pure NHP esters, there was no significant loss of the reaction
efficiency and enantioselectivity. Furthermore, the enantiomeric-
enriched alkyl nitriles could be easily hydrogenated to give the
We measured the reduction potential of 1a to be Ep0/-1 = -1.33
V vs SCE in MeCN.17 The commonly used photocatalyst Ir(ppy)3
(ppy = 2-phenyl pyridine) could be a sufficiently strong electron
donor to reduce NHP ester 1a directly from its excited state
{(E1/2red[IrIV/IrIII*]) = -1.73 V vs SCE in MeCN}.18 Meanwhile,
+
the oxidized photocatalyst Ir(ppy)3 exhibits a strong oxidative
power {E1/2red[IrIV/IrIII] = +0.77 V vs SCE in MeCN},18 which
could oxidize L*CuICN to generate L*CuIICN (L* = L1),
{E1/2red[CuII/CuI] = +0.36 V vs SCE in MeCN}.17 Thus, our initial
study focused on the reaction of 1a and TMSCN under irradiation
of 12 W blue LEDs, with Ir(ppy)3 (2 mol %) and CuBr (10
mol %)/L1 (12 mol %) in DMF at room temperature. To our
delight, the decarboxylative cyanation reaction proceeded
smoothly, yielding the desired product 2a in 87% yield with 84%
ee (Table 1, entry 1). Other photocatalysts with higher oxidation
potential, such as Ir(ppy)2(dtbbpy)PF6 {E1/2red[IrIV/IrIII] = +1.21 V
vs SCE in MeCN},19 Ir(dFCF3ppy)2(dtbbpy)PF6 {E1/2red [IrIV/IrIII]
= +1.69V vs SCE in MeCN}20 and Ru(bpy)3Cl2 {E1/2red[RuIII/RuII]
= +1.29 V vs SCE in MeCN}21 didn't affect the enantioselectivity
(84% ee), with slightly lower yields (entries 2-4). The organic
photocatalyst Eosin Y was not suitable for the decarboxylative
cyanation (entry 5). Further solvent screening showed that the
Table 1. Reaction Optimization.a
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Table 2. Substrate Scope.a
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Scheme 2. Synthetic applications.
substrate 1d, rather than (L1)Cu(I) catalyst, presumably
signifying an one-electron reduction event of the substrate to form
corresponding radical anion. Thus,
involving reductive quenching cycle is less likely in this reaction
(For more detailed discussions, see SI).
a photoredox catalysis
corresponding amines 4 and 5 in excellent yields without loss of
enantiomeric excess, which were regarded as a key intermediate
for the synthesis of chiral anti-depressant active molecule (R)-
phenibut and weight-lossing drug (R)-Lorcaserin (Scheme 2c).
To gain some insights into the plausible mechanism, some
control experiments were conducted. First, when TEMPO as a
radical scavenger was subjected to our model reaction, the
decarboxylative cyanation was inhibited completely, and the new
product 6 generated from the resultant benzylic radical trapped by
TEMPO was obtained in 37% yield (Scheme 3a). Second, the
reaction of radical clock substrate 7 under the standard conditions
still gave a major decarboxylative cyanation product 8 in 49%
yield with 75% ee, along with a ring-opening /cyanation product 9
in 12% yield (Scheme 3b). Third, when the reaction of the chiral
NHP ester 10 was performed by copper catalyst with (1R,2S)-L1
or copper catalyst with (1S,2R)-L1 respectively, the product 11
was obtained with opposite configurations (Scheme 3c). These
evidences strongly support a radical decarboxylative process of
our reaction. In addition, the results in entries 8-11 ( Table 1)
revealed that the decarboxylation of NHP ester indeed undergoes
via a photoredox catalysis process, and the sequential asymmetric
cyanation was catalyzed by copper (Scheme 1b). Finally Stern-
Volmer fluorescence quench experiments demonstrated that the
emission intensity of IrIII* is diminished in the presence of
Scheme 3. Mechanistic Investigation.
In summary, we have developed a novel enantioselective
decarboxylative radical cyanation reaction by merging
photocatalysis with copper catalysis, which provides
straightforward access to chiral alkyl nitriles with high yields and
enantioselectivity. The tolerance of broad functional groups
allows the method to be used in further synthetic application.
Mechanistically, both benzylic radicals and reactive chiral
copper(II) species are generated from photocatalysis cycle.
Further expansion of this new cooperative strategy by
photocatalysis and metal catalysis is under progress.
a
ASSOCIATED CONTENT
Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
S.; Dong, X.-Y.; Li, T.-T.; Jiang, N.-C.; Tan, B.; Liu, X.-Y. J. Am. Chem.
Soc. 2016, 138, 9357.
(6) Zuo, Z.; Cong, H.; Li, W.; Choi, J.; Fu, G. C.; MacMillian, D. W. C. J.
Am. Chem. Soc. 2016, 138, 1832.
(7) Suzuki, N.; Hofstra, J. L.; Poremba, K. E.; Reisman, S. E. Org. Lett.
2017, 19, 2150.
chzlin@ust.hk; gliu@mail.sioc.ac.cn
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Notes
The authors declare no competing financial interests.
(8) For the asymmetric cyanantion, see: (a) Zhang, W.; Wang, F.; McCann,
S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G. Science 2016, 353, 1014.
(b) Wang, F.; Wang, D.; Wan, X.; Wu, L.; Chen, P.; Liu, G. J. Am. Chem.
Soc. 2016, 138, 15547. (c) Wang, D.; Wang, F.; Chen, P.; Lin, Z.; Liu, G.
Angew. Chem. Int. Ed. 2017, 56, 2054.
(9) For the asymmetric arylation, see: (a) Wu, L.; Wang, F.; Wan, X.;
Wang, D.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2017, 139, 2904. (b) Wang,
D.; Wu, L.; Wang, F.; Wan, X.; Chen, P.; Lin, Z.; Liu, G. J. Am. Chem.
Soc. 2017, 139, 6811.
(10 ) For the pioneering studies on NHP esters, see: (a) Okada, K.;
Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1988, 110, 8736. (b) Okada, K.;
Okamoto, K.; Morita, N.; Okubo, K.; Oda, M. J. Am. Chem. Soc. 1991,
113, 9401. (c) Schnermann, M. J.; Overman, L. E. Angew. Chem. Int. Ed.
2012, 51, 9576. (d) Pratsch, G.; Lackner, G. L.; Overman, L. E. J. Org.
Chem. 2015, 80, 6025.
(11) The classic multi-steps process involves a chiral resolution, see: (a)
Miyagi, K.; Moriyama, K.; Togo, H. Eur. J. Org. Chem. 2013, 5886.
Recently, Waser reported a radical decarboxylative cyanation reaction via
photocatalysis, which involves a radical electrophilic cyanation, see: (b)
Le Vailant, F.; Wodrich, M. D.; Waser, J. Chem. Sci. 2017, 8, 1790.
ACKNOWLEDGMENT
We are grateful for financial support from the National Basic
Research Program of China (973-2015CB856600), the National
Nature Science Foundation of China (Nos. 21532009, 21421091,
and 21472217), the Science and Technology Commission of
Shanghai Municipality (Nos. 17XD1404500 and 17JC1401200),
the Strategic Priority Research Program (No. XDB20000000) and
the Key Research Program of Frontier Science (QYZDJSSW-
SLH055) of the Chinese Academy of Sciences. This research was
also supported by the Key Laboratory of Functional Molecular
Engineering of Guangdong Province (2016kfxx, South China
University of Technology).
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a
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form carbocation. But in the presence of L*Cu(I) catalyst, the oxidation of
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cyanation reaction with high ee.
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60
5
ACS Paragon Plus Environment