Enantioselective Decarboxylative α-Alkynylation of β-Ketocarbonyls via a Catalytic α-Imino Radical Intermediate

Article abstract of DOI:10.1021/acs.orglett.7b02386

A distinctive aminocatalysis via α-imino radical is reported on the basis of SET oxidation of a secondary enamine. The combination of chiral primary amine catalysis and visible-light photoredox catalysis enables the enantioselective decarboxylative coupling of propiolic acid and β-ketocarbonyls to afford alkynylation adducts with high enantioselectivity. Mechanism studies indicate the reaction proceeds via an α-imino radical addition.

Full text of DOI:10.1021/acs.orglett.7b02386

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Letter
pubs.acs.org/OrgLett
Enantioselective Decarboxylative α‑Alkynylation of β‑Ketocarbonyls
via a Catalytic α‑Imino Radical Intermediate
Dehong Wang,†,‡ Long Zhang,†,‡,§ and Sanzhong Luo*,†,‡,§
†Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190,
China
‡University of Chinese Academy of Sciences, Beijing 100490, China
§Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A distinctive aminocatalysis via α-imino radical is
reported on the basis of SET oxidation of a secondary enamine. The
combination of chiral primary amine catalysis and visible-light
photoredox catalysis enables the enantioselective decarboxylative
coupling of propiolic acid and β-ketocarbonyls to afford alkynylation
adducts with high enantioselectivity. Mechanism studies indicate the
reaction proceeds via an α-imino radical addition.
eyond its nucleophilic feature,1 enamine is also rich in
Scheme 1. Enantioselective Aminocatalysis via α-Imino
Radical
B
redox properties and can be readily oxidized toa radical
cation upon single-electron transfer.2 The resulting radical
cation could couple with nucleophiles, setting the basis for
SOMO catalysis in the context of modern enamine chemistry as
pioneered by MacMillan and co-workers.3 Most of the SOMO
catalyses are based on tertiary enamines derived from chiral
secondary amine catalysts. On the other hand, SOMO-type
catalysis with a secondary enamine, derived from the equally
prevalent chiral primary amine catalysts,4 have surprisingly
remained underdeveloped. Unlike tertiary enamine, secondary
enamine may easily lose an N−H proton after SET oxidation to
form an α-imino radical (Scheme 1) as it is known that SET
could dramatically activate the N−H bond (e.g., aniline pKa
5
6
+•
30.6, vs C6H5NH2 pKa 6.5 ). A neutral α-imino radical, in a
close resemblance to its α-carbonyl counterpart, is less
electrophilic compared with the parent radical cation, which
would contribute to broadening the scope of SOMO catalysis.
We have tried to substantiate α-imino radical catalysis on the
basis of enamine catalysis of β-ketocarbonyls by chiral primary
amines.4a The oxidation potential of enamine ester (Scheme 1,
II) was determined to be 1.13 V versus Ag/AgCl in CH3CN,7
and selective SET with the in situ generated enamine ester is
plausible with most chemical or photo-redox processes. DFT
calculation gave a pKa (N−H) of 5.87 for the radical cation II,8
indicating a facile proton transfer favoring the generation of α-
imino radical III. Efforts were then devoted to search for a
feasible and chemoselective oxidative system. In this context, a
photoredox catalytic system involving Ru(bpy)3Cl2 and hyper-
valent iodine reagent (BI-OH), initially utilized by Chen,9 was
identified as the optimal oxidative reagent. The joint force of
our chiral primary amine with the photoredox system enabled
radical α-addition to propiolic acids via imino radical species,
leading to an unprecedented decarboxylative α-alkynylation and
alkylation reaction. Although enantioselective α-alkynylation of
β-ketocarbonyls has been reported previously,10 the substrates
were limited to cyclic β-ketocarbonyls with bulky ester groups.
Our initial investigation was performed with acetoacetate 2a
and propiolic acids 3a employing the hypervalent iodine
photoredox system under blue LED irradiation. Gratifyingly, in
the catalysis with our chiral primary amine catalyst 1/TfOH,
Received: August 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02386
Org. Lett. XXXX, XXX, XXX−XXX

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Organic Letters
Letter
the desired α-alkynylation product 4aa was obtained in 54%
yield and 95% ee under the standard conditions, along with the
formation of α-alkylation product 5aa in 22% yield and 80% ee
(Table 1, entry 1). In control experiments, 4aa could not be
Scheme 2. Scope of the Asymmetric α-Alkynylation of β-
Ketocarbonyls and Propiolic Acids
a,d
a
Table 1. Screening and Optimization
b
c
variation from standard
conditions
yield (4aa/5aa)
ee (4aa/5aa)
entry
(%)
(%)
1
none
54/22
0
95/80
2
no Ru(bpy)3Cl2·6H2O
no BI−OH
no aminocatalyst
no TfOH
3
0
4
dimer of 2a
12/4
20/15
trace
5
rac/8
6
Ir(ppy)3
91/63
7
Ir(ppy)2(dtbbpy)(PF6)
Eosin Y
8
trace
9
PhI(OCOCF3)
PhI(OAc)2
BI-OAc
trace
10
11
12
13
mess
dimer of 2a
trace
BI-OMe
dark
0
a
Reactions were performed at room temperature in 0.5 mL of CH2Cl2
with 2a (0.10 mmol), 3a (0.15 mmol), hypervalent iodine reagent
(0.15 mmol), 1 (20 mol %), and photocatalysts (1 mol %) under Ar
with 0.5 W blue LED irradiation for 48 h, unless otherwise noted.
b
c
Isolated yield. Determined by HPLC analysis.
converted into 5aa under the reaction conditions, indicating
two coexisting C−C bond formation pathways. Among
different photocatalysts (entries 6−8) and hyervalent iodine
reagents (entries 9−12) examined, Ru(bpy)3Cl2·6H2O and
hydroxybenziodoxole (BI-OH) were identified to give the
optimal results in terms of both yield and enantioselectivity. In
the absence of Ru(bpy)3Cl2·6H2O, hydroxybenziodoxole (BI-
OH), or light, neither 4aa nor 5aa was observed (entries 2, 3,
and 13). No desired product was obtained in the absence of
primary aminocatalyst 1/TfOH (entry 4), and the reaction was
rather poor yielding and virtually racemic if no TfOH was
added (entry 5). These results highlight the critical role of the
primary amine−TfOH catalyst. Efforts to suppress the
formation of alkylation product have been in vain, and two
C−C bond formations coexisted with the alkynylation process
generally favored (see the Supporting Information for details).
With the optimized conditions in hand, we first investigated
the scope of β-ketocarbonyl compounds (Scheme 2).
Acetoacetates with different ester moieties including those
with sterically bulky tert-butyl ester, benzyl, and allyl ester
groups afforded the desired alkynylation adducts in moderate
yields with excellent enantioselectivities (4aa−ha), along with
the corresponding minor alkylation products with good
enantioselectivities (5aa−ca, 5ea−fa). Interestingly, when R′
= tBu, allyl, and cinnamyl, the reaction afforded mainly
alkynylation products with only trace amounts of alkylation
products detected (5da, 5ga, 5ha). Larger α-substituents on
acetoacetates (e.g., R2 = Et) led to reduced yields, but
enantioselectivities were not affected (4ia, 5ia). Cyclic β-
a
All of the reactions were performed at room temperature in 0.5 mL of
CH2Cl2 with 2 (0.10 mmol), 3a (0.15 mmol), BI-OH (0.15 mmol), 1
(20 mol %), and Ru(bpy)3Cl2·6H2O (1 mol %) under Ar with 0.5 W
blue LED irradiation for 48 h, unless otherwise noted. Yields shown
are of isolated products; ee was determined by HPLC (slight peak
b
overlapping was noted for compound 4ma and 4ah). Reaction time:
60 h. Trace product; ee values not determined. The ee value was
determined after one-step transformation into 5ea.
c
d
ketoesters were also tolerated to give the desired products 4ja/
5ja and 4ka/5ka with high enantioselectivities. Notably, acyclic
1,3-diketones are workable substrates with excellent enantiose-
lectivities under the current conditions (4la−na), and only
alkynylation products were isolated with trace alkylation
adducts observed.
We then set out to explore the scope of propiolic acids under
the standard conditions. It was observed that a variety of
phenylpropiolic acids bearing either electron-donating or
electron-withdrawing groups at the meta or para position of
the arene moiety reacted to produce the alkynylation products
in moderate yield and excellent enantioselectivities (4ab−ah).
At the same time, the corresponding alkylation products were
obtained in low yields and moderate to good enantioselectiv-
ities (5ab−ah). Markedly, 3-(6-methoxynaphthalen-2-yl)prop-
2-ynoic acid (3k) underwent this transformation with 2a
leading to 4ak and 5ak in moderate yields and good
B
DOI: 10.1021/acs.orglett.7b02386
Org. Lett. XXXX, XXX, XXX−XXX

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Organic Letters
Letter
enantioselectivities. Unfortunately, alkylpropiolic acids did not
work in the reactions.
precursor of BI radical, which participates in the oxidative
quenching of photoexcited *Ru(II) species. The determined
reduction potential of 9 (Ered1/2 = 0.20 V vs Ag/AgCl) indicates
that both 9 and its homolytic cleavage product BI radical can
serve as the oxidant for SET process. Our control experiment
with preformed 9 also led to the formation 4ab and 5ab in
comparable yields and enantioselectivities, thus suggesting the
complex 9 might be a key intermediate (Scheme 4, B).
To probe the utility of our method in preparative synthesis, a
gram-scale reaction of β-ketoesters 2a was performed,
delivering the product 4aa and 5aa with similar yield and
enantioselectivity (Scheme 3). It is noted that stronger power
blue LEDs are required to allow the reaction to proceed
efficiently due to the heterogeneity of the reaction system.
On the basis of the mechanistic investigations above, a
plausible mechanism for this photoreaction is proposed
(Scheme 5). Photoexcited [Ru(bpy)3]2+* was oxidatively
Scheme 3. Gram-Scale Reaction
Scheme 5. Proposed Catalytic Cycle
Alkyl radical was known to undergo α-addition to α,β-
unsaturated carboxylic acids, leading to decarboxylative
processes.9b,11 For the current enamine-based process, the
exclusive formation of α-addition product, instead of the typical
nucleophilic β-addition with enamine, is reminiscent of a radical
process. Radical-quenching experiments were then conducted,
and the reactions were completely inhibited in the presence of
TEMPO or butylated hydroxytoluene (BHT) (Scheme 4, A).
Scheme 4. Control Experiments
quenched by benziodoxole radical (BI·) to [Ru(bpy)3]3+,
which oxidizes enamine intermediate 8 to radical cation 10.
This SET process can be reasoned by considering the
experimentally determined oxidative potential of 8 (Eox
=
1/2
Ru(III)/(II)
1.13 V vs Ag/AgCl, E1/2
= 1.40 V vs Ag/AgCl). α-
Imino radical 11, formed by a facile N−H proton loss process
from 10, undergoes α-addition to 9, leading to the alkynylation
product 4ab along with the loss of CO2 and the regeneration of
benziodoxole radical. An alternative radical−radical cross-
coupling between phenylacetylene radical and 11 can be
discounted by the facts that (1) radical−radical cross-coupling
is kinetically disfavored and (2) enamine facial selection with a
neutral acetylene radical would be notoriously challenging to
control. The absolute configuration of the alkynylation product
was determined to be R by comparison with the known
compound.12 On the basis of our previous studies, an H-
bonding transition state involving H-bonding between
protonated N−H and propiolate carbonyl was proposed to
account for the observed R selectivity (Scheme 5). As products
5ab are not derived from 4ab, a competing side cycle involved
an unavoidable hydration of phenyl propiolic acid with BI-OH,
which generates intermediate 14, was proposed. The
interception of 11 by 14 led to the formation of 5ab (see the
SI for a complete cycle).
HRMS analysis of the quenched reaction mixture clearly
indicated radical-trapped adducts 6 and 7 from TEMPO and
BHT, respectively. This observation provided direct support to
the radical mechanism. Stoichiometric experiment with
preformed enamine 8 led to the desired adducts with
consistently high enantioselectivity under otherwise identical
conditions, verifying the enamine catalytic nature (Scheme 4,
B).
To elucidate a photoredox process, a series of Stern−Volmer
fluorescence quenching studies were performed with Ru-
(bpy)3Cl2. Surprisingly, none of the added species showed a
significant quenching effect; only with the preformed propiolate
hypervalent iodine 9 was obvious fluorescence quenching
observed (see the SI for details). According to recent studies on
the Ru/BI-OH photoredox system,9 propiolate 9, readily
formed in situ under the reaction conditions, may serve as a
We have attempted to apply the proposed mechanism to
other radical acceptor candidates. Preliminary studies have
revealed that alkenyl carboxylic acids such as cinnamic acid 16
C
DOI: 10.1021/acs.orglett.7b02386
Org. Lett. XXXX, XXX, XXX−XXX

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Organic Letters
Letter
(3) (a) Comito, R. J.; Finelli, F. G.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2013, 135, 9358−9361. (b) Jui, N. T.; Garber, J. A.; Finelli, F. G.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 11400−11403.
(c) Pham, P. V.; Ashton, K.; MacMillan, D. W. C. Chem. Sci. 2011, 2,
1470−1473. (d) Mastracchio, A.; Warkentin, A. A.; Walji, A. M.;
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20648−
20651. (e) Devery, J. J.; Conrad, J. C.; MacMillan, D. W. C.; Flowers,
R. A. Angew. Chem., Int. Ed. 2010, 49, 6106−6110. (f) Jui, N. T.; Lee,
E. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10015−
10017. (g) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012−10014.
(h) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk, K. N.;
MacMillan, D. W.C. J. Am. Chem. Soc. 2010, 132, 6001−6005.
(i) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
5027−5029. (j) Wilson, J. E.; Casarez, A. D.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2009, 131, 11332−11334. (k) Conrad, J. C.; Kong, J.;
Laforteza, B. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,
11640−11641. (l) Amatore, M.; Beeson, T. D.; Brown, S. P.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48, 5121−5124.
(m) Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2008, 130, 16494−16495. (n) Kim, H.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2008, 130, 398−399. (o) Jang, H. Y.; Hong, J.
B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004−7005.
(p) Beeson, T. D.; Mastracchio, A.; Hong, J. B.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582−585.
(4) (a) Zhang, L.; Fu, N.; Luo, S. Acc. Chem. Res. 2015, 48, 986−997.
(b) Duan, J.; Li, P. Catal. Sci. Technol. 2014, 4, 311−320.
(c) Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 9748−9770.
(d) Xu, L. W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 14, 1807−1821.
(5) (a) For an internet bond-energy database, seehttp://ibond.chem.
tsinghua.edu.cn, accessed August 17, 2017. (b) Bordwell, F. G.; Cheng,
J. P. J. Am. Chem. Soc. 1989, 111, 1792−1795.
(6) (a) Tsai, A. I.; Chuang, C. P. Tetrahedron 2006, 62, 2235−2239.
(b) Chuang, C. P.; Wu, Y. L. Tetrahedron Lett. 2001, 42, 1717−1719.
(c) Cossy, J.; Bouzide, A.; Leblanc, C. J. Org. Chem. 2000, 65, 7257−
7265. (d) Cossy, J.; Bouzide, A. Tetrahedron 1999, 55, 6483−6496.
(7) For details, see the Supporting Information.
also work to give the decarboxylative adduct 17, albeit with
moderate yield and enantioselectivity (eq1).
In conclusion, we have developed an unprecedented
enantioselective direct α-alkynylation of β-ketocarbonyls via
visible-light-induced oxidative decarboxylation coupling. The
reactions enable the creation of all-carbon stereocenters with
excellent enantioselectivities under mild conditions. Mechanism
studies formulate a distinctive aminocatalytic mode via an α-
imino radical intermediate that facilitates α-radical addition
process. Further explorations on α-imino radical chemistry are
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02386.
1
Experimental procedures, characterization data, and H
NMR and 13C NMR spectra and HPLC traces (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: luosz@iccas.ac.cn.
ORCID
(8) A model enamine ester derived from isopropylamine was used for
DFT calculations.
Sanzhong Luo: 0000-0001-8714-4047
Notes
(9) (a) Huang, H.; Zhang, G.; Chen, Y. Angew. Chem., Int. Ed. 2015,
54, 7872−7876. (b) Huang, H.; Jia, K.; Chen, Y. Angew. Chem., Int. Ed.
2015, 54, 1881−1884.
The authors declare no competing financial interest.
(10) (a) Wu, X.; Shirakawa, S.; Maruoka, K. Org. Biomol. Chem. 2014,
ACKNOWLEDGMENTS
■
12, 5388−5392. (b) Fernan
R.; Waser, J. Adv. Synth. Catal. 2013, 355, 1631−1639. (c) Fernan
Gonzalez, D.; Brand, J. P.; Waser, J. Chem. - Eur. J. 2010, 16, 9457−
9461. (d) Poulsen, T. B.; Bernardi, L.; Aleman, J.; Overgaard, J.;
́
dez Gonzal
́
ez, D.; Brand, J. P.; Mondiere,
We thank the Natural Science Foundation of China (21390400,
21521002, 21572232, and 21672217) and the Chinese
Academy of Science (QYZDJ-SSW-SLH023) for financial
support. S.L. is supported by the National Program of Top-
notch Young Professionals. We thank Han Li and Prof.
Mingtian Zhang from Tsinghua University for assistance with
the fluorescence quenching studies.
́
dez
́
́
Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 441−449.
(11) (a) Gao, C.; Li, J.; Yu, J.; Yang, H.; Fu, H. Chem. Commun.
2016, 52, 7292−7294. (b) Mai, W. P.; Song, G.; Sun, G. C.; Yang, L.
R.; Yuan, J. W.; Xiao, Y. M.; Qu, L. B. RSC Adv. 2013, 3, 19264−
19267.
(12) Zhu, Y.; Zhang, L.; Luo, S. J. Am. Chem. Soc. 2014, 136, 14642−
14645.
REFERENCES
■
(1) For recent reviews on asymmetric aminocatalysis, see:
(a) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178−
2189. (b) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew.
Chem., Int. Ed. 2008, 47, 6138−6171. (c) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471−5569. (d) Erkkila,
̈
A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416−5470.
(2) (a) Schoeller, W. W.; Niemann, J.; Rademacher, P. J. Chem. Soc.,
Perkin Trans. 2 1988, 369−373. (b) Renaud, P.; Schubert, S. Angew.
Chem., Int. Ed. Engl. 1990, 29, 433−434. (c) Shono, T.; Matsumura, Y.;
Hamaguchi, H.; Imanishi, T.; Yoshida, K. Bull. Chem. Soc. Jpn. 1978,
51, 2179−2180. (d) Chiba, T.; Okimoto, M.; Nagai, H.; Takata, Y. J.
Org. Chem. 1979, 44, 3519−3523. (e) Audebert, P.; Bekolo, H.; Cossy,
J.; Bouzide, A. J. Electroanaly. Chem. 1995, 389, 215−218. (f) Eilenberg,
W.; Schafer, H. J. Tetrahedron Lett. 1984, 25, 5023−5026.
̈
(g) Narasaka, K.; Okauchi, T.; Tanaka, K.; Murakami, M. Chem.
Lett. 1992, 21, 2099−2102.
D
DOI: 10.1021/acs.orglett.7b02386
Org. Lett. XXXX, XXX, XXX−XXX