γ-Amino Butyric Acid (GABA) Synthesis Enabled by Copper-Catalyzed Carboamination of Alkenes

Article abstract of DOI:10.1021/acs.orglett.7b01969

γ-Amino butyric acid (GABA) is the chief inhibitory neurotransmitter in the mammalian central nervous system. Many GABA derivatives are used clinically to prevent or treat neurodegenerative diseases. Copper-catalyzed carboamination of alkenes offers an efficient method to fashion the core structure of GABA derivatives from alkenes. In this reaction, acetonitrile serves as the source of the carbon and nitrogen functionalities used to difunctionalize alkenes. Experimental and density functional theory (DFT) studies were carried out to investigate the mechanism of the reaction, and a copper-catalyzed radical-polar crossover mechanism is proposed.

Full text of DOI:10.1021/acs.orglett.7b01969

Letter
pubs.acs.org/OrgLett
γ‑Amino Butyric Acid (GABA) Synthesis Enabled by Copper-Catalyzed
Carboamination of Alkenes
Nengbo Zhu,§,† Ting Wang,§,‡ Liang Ge,† Yajun Li,† Xinhao Zhang,*,‡ and Hongli Bao*,†
†Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, University of Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou,
Fujian 350002, People’s Republic of China
‡Lab of Computational Chemistry and Drug Design, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate
School, Shenzhen 518055, People’s Republic of China
S
* Supporting Information
ABSTRACT: γ-Amino butyric acid (GABA) is the chief inhibitory
neurotransmitter in the mammalian central nervous system. Many GABA
derivatives are used clinically to prevent or treat neurodegenerative diseases.
Copper-catalyzed carboamination of alkenes offers an efficient method to
fashion the core structure of GABA derivatives from alkenes. In this
reaction, acetonitrile serves as the source of the carbon and nitrogen
functionalities used to difunctionalize alkenes. Experimental and density
functional theory (DFT) studies were carried out to investigate the mechanism of the reaction, and a copper-catalyzed radical-
polar crossover mechanism is proposed.
lkenes are readily available, and intermolecular carboami-
Anation of alkenes is a very effective strategy to construct
C−C bonds and C−N bonds simultaneously.1−4 Carboamina-
tion products of olefins include amines, amino acids, and other
core structures present in natural products and pharmaceuti-
cally important chemicals. Despite the great synthetic potential
of this strategy, the successful carboamination of olefins mainly
focused on the reaction with intramolecular carbon sources,1
nitrogen sources,2 or both carbon and nitrogen sources.3 The
carboamination of olefins with both intermolecular carbon and
nitrogen sources4 is still difficult and has rarely been explored.
γ-Amino butyric acid (GABA) is a significant inhibitory
neurotransmitter in the mammalian central nervous system.5
Many GABA derivatives capable of crossing the blood−brain
barrier are used clinically to prevent or treat neurodegenerative
diseases.6 A convenient synthesis of structurally diverse
compounds containing the GABA moiety could facilitate the
drug development process. Substituted pyrrolidines and
pyrrolidinone derivatives are extremely common core structures
of biologically active molecules and ligands.7 Despite the
numerous methods developed for the synthesis of substituted
pyrrolidine and pyrrolidinones, synthesis of these structures,
especially 2,3-trans-disubstuted pyrrolidines and pyrrolidinones
from alkenes, has been reported infrequently.8
alkylation reactions via a radical pathway,11 and here, we report
our continuing efforts to achieve the carboamination of alkenes
with nitriles as both carbon and nitrogen functionalities to
afford GABA analogues, substituted pyrrolidines and pyrrolidi-
nones (Figure 1).
Figure 1. Carboamination of alkenes to GABA derivatives.
We began this study by seeking an appropriate radical
precursor, which is reactive enough to abstract a hydrogen atom
from the nitrile to initiate the radical relay process. The radical
precursor should not be too reactive, or it could add to the
alkene and produce undesired compounds. Radical precursors
(1a−1g) were screened using the model reaction depicted in
Scheme 1, but unfortunately, none of these reactions yielded
the desired product (4a). In the case of the phenyl radical
Nitriles are inexpensive chemicals, widely used as solvents in
organic reactions. Recently, they have been used elegantly by
Zhu et al.9 and other groups10 in the functionalization of
alkenes. Very recently, Li et al. developed an efficient 1,2-
carboamination of alkenes with alkyl nitriles as carbon
functionality.4k It would be interesting if nitriles could serve
as the source of carbon and nitrogen functionalities in the
difunctionalization of alkenes. We have developed a series of
Received: June 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01969
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Optimization of the amounts of solvent and acid showed that
the most effective conditions afforded the product in 88% yield.
No desired product was observed in the absence of copper
catalyst, and acid screening revealed that HPF6 was necessary
for the reaction, while other acids failed to improve the reaction
further (see details in Table S1).
Scheme 1. Initial Studies for Carboamination of Styrene
With the optimal conditions in hand, the generality of this
strategy with respect to different alkene substrates was
examined (Table 2). Reactions of terminal vinylarenes afforded
a b
,
Table 2. Copper-Catalyzed Carboamination of Alkenes
precursor (1c, BPO) and alkyl radical precursor (1g, LPO), 3a
and 5 were isolated in 43% and 13% yield, respectively.
A computational DFT study was performed to evaluate the
competitive radical additions and seek a possible mechanism
leading to the desired product (4a). The overall potential
energy surface and the critical competitive steps are depicted in
Figures S2 and S3. The difference in the calculated activation
free energy (ΔG‡) between A-TS2 and B-TS2 is 3.4 kcal/mol.
According to the Boltzmann distribution, the addition of the
phenyl radical to styrene is about 300 times faster than
hydrogen abstraction from acetonitrile which generates a ·
CH2CN radical. This free energy difference suggests that it may
be possible to control the outcome of the competitive pathways
by regulating concentrations of CH3CN and styrene.12
As suggested by these DFT calculations, we reoptimized the
reaction conditions and used a larger volume of CH3CN (Table
1). When the quantity of CH3CN was increased from 2 to 8
a
Table 1. Reaction Condition Optimizations
a
Reaction conditions: alkene (0.5 mmol), BPO (1.5 equiv), and
CH3CN (30 mL). BPO was added in three portions at intervals of 2 h.
solvent/
mL
BPO
yield
b
entry
metal/mol %
acid (equiv) (equiv)
(%)
b
c
Yields of isolated products. 1 equiv of H2SO4 was added as an
1
Cu(CH3CN)4PF6/5
Cu(CH3CN)4PF6/5
Cu(CH3CN)4PF6/5
Fe(OTf)3/10
Pd(OAc)2/10
NiBr2/10
2
8
HPF6 (0.4)
HPF6 (0.4)
HPF6 (0.4)
HPF6 (0.4)
HPF6 (0.4)
HPF6 (0.4)
HPF6 (0.4)
HPF6 (0.4)
HPF6 (0.4)
HPF6 (0.4)
HPF6 (0.6)
HPF6 (0.6)
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
0
d
e
additive. H2O (2.0 equiv), HPF6 (0.2 equiv). The yield of scale-up
reaction: alkene (3 mmol) and CH3CN (130 mL).
2
40
3
20
20
20
20
20
20
20
30
30
30
68
4
ND
ND
ND
ND
73
the corresponding product (4b−4r) in 44−84% yields.
Styrenes with various substituents, such as Bu, Me, halogens,
5
t
6
OAc, and COOH, were tolerated in this reaction. Reaction of
the enyne delivered the target product 4s in 52% yield.
Remarkably, when 1,2-disubstituted olefins were served as the
suitable substrates in this reaction (6a−6g), the diaster-
eoisomer ratios range from 4:1 to 10:1 in the presence of
conc. H2SO4 as an additive.13 For the cyclic olefins, the yields
were moderate although the dr values were low. Reactions of
unconjugated olefins afforded the corresponding products
(7k−7m) in 36−48% yields, along with Heck-type byproducts.
Unfortunately, only a trace amount of the desired product was
detected with 4-isopropenyltoluene as the reaction substrate.4l
Next, mechanistic studies were conducted in an effort to
understand the details of the competitive pathways. Radical
trapping and isotope labeling experiments shown in Scheme 2
were carried out to probe the fate of the phenyl and α-
cyanoalkyl radicals. Upon addition of TEMPO [(2,2,6,6-
tetramethylpiperidin-1-yl)oxyl] to the reaction, compounds 9
and 10 were detected by GC-MS (see Supporting Information
(SI)), implying the existence of both α-cyanoalkyl and benzylic
radicals. When CD3CN was used as the solvent, deuterated
7
CoCl2/10
d
d
d
8
Cu(CH3CN)4PF6/5
CuI/5
9
79
10
11
CuI/5
85
d
CuI/5
1.5
88
e
d
c
12
CuI/5
1.5
88 (84)
a
Reactions were conducted with styrene (0.5 mmol), BPO and
b
CH3CN, H2O (2 equiv), 70 °C for 18 h. Yield of product detected by
c
d
GC. Yield of isolated product in parentheses. BPO was added in
e
three portions at intervals of 2 h. Without adding H2O.
mL, the desired product 4a was obtained in 40% yield.
Encouraged by this result, we further increased the amount of
CH3CN to 20 mL and found that 4a could be isolated from this
reaction in 68% yield. Other catalysts such as Fe(OTf)3,
Pd(OAc)2, NiBr2, and CoCl2 were examined under these
conditions, but no desired product was formed. When BPO was
added into the reaction solution in three portions, the yield was
improved to 73%. Further screening of copper catalysts showed
that CuI was the optimum catalyst, delivering a yield of 79%.
B
DOI: 10.1021/acs.orglett.7b01969
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oxidized by Cu(II) to a carbocation which undergoes a Ritter
reaction in the presence of acid, delivering the desired
product.16 These steps are supported by our DFT calculations
(Figure S3) and mechanistic experiments (Scheme 2). The
oxidation of Cu(I) to Cu(III) by BPO is an alternative pathway.4b
To explore the synthetic potential of this method, trans-
formations of various products were carried out as shown in
Scheme 4. The product 4l was readily transformed to 19, an
Scheme 2. Experimental Mechanistic Studies
Scheme 4. Synthetic Applications of Carboamination
a
Reactions
a
Reagents and conditions: (i) Cs2CO3, CH3CN, rt, 16 h; (ii) Na, n-
BuOH, 120 °C, 2 h; (iii) EtOH, Conc. HCl, 80 °C, 8 h; (iv) EtOH,
Conc. HCl, H2SO4 (30%), 100 °C, 10 h. See details in SI.
benzene was formed, indicating that the phenyl radical was
indeed able to abstract an H(D) atom from acetonitrile. Next,
intermolecular competition between CD3CN and CH3CN was
carried out. The product ((13 + 4a)/(11 + 14)) ratio of the
reaction in a 1:1 mixed solvent is approximately 7:1, implying
that the formation of the α-cyanoalkyl radical is irreversible.14
Similar yields for the couples 13/4a, 11/14, and 15/3a suggest
that no isotope effect could be found in the Ritter reaction step.
According to DFT calculations, butyronitrile and isobutyroni-
trile are expected to be more susceptible to H-abstraction to
form radicals (Figure S4). These two nitriles were examined
under similar reaction conditions, and it was found that with a
smaller volume of nitrile, products 16 and 17 were obtained in
63% and 47% yield, respectively.
A radical-polar crossover mechanism for the reaction is
proposed in Scheme 3.15 The Cu(I) complex transfers an
electron to BPO to form the Cu(II) compound and a phenyl
acyloxy radical. Subsequent decarboxylation affords a phenyl
radical. This phenyl radical further abstracts hydrogen from
acetonitrile and generates an α-cyanoalkyl radical which reacts
with styrene to form the benzylic radical. The benzylic radical is
analogue of a bioactive molecule.17 Next, products 7c and 4a
were converted to the 2,3-trans-disubstituted pyrrolidine 20 and
2-substituted pyrrolidine 21. This type of reaction is
unprecedented. Furthermore, the protected γ-amino acid (22)
was synthesized from 4f in 52% yield. Significantly, the
carboamination products can be converted to analogues of
racetam family drug molecules.18 As an example of this type of
transformation, compound 23 was synthesized from 7c.
In summary, we have developed a copper-catalyzed
carboamination reaction of alkenes which offers an efficient
pathway to construct the core structure of GABA derivatives
from alkenes. Nitriles serve as the source of carbon and
nitrogen functionalities and difunctionalize the alkenes.
Experimental studies and DFT calculations were carried out
to probe the mechanism, and a copper-catalyzed radical-polar
crossover mechanism is proposed. Analogues of drug molecules
and other useful compounds were synthesized from the
carboamination products and exemplify the potential value of
this method.
Scheme 3. Proposed Catalytic Cycle
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.7b01969.
Experimental details, data, and spectra (PDF)
Crystallographic data (CIF, CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hlbao@fjirsm.ac.cn.
*E-mail: zhangxh@pkusz.edu.cn.
ORCID
Xinhao Zhang: 0000-0002-8210-2531
C
DOI: 10.1021/acs.orglett.7b01969
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Hongli Bao: 0000-0003-1030-5089
Author Contributions
§N.Z. and T.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NSFC (Grant Nos. 21402200, 21502191, 21672213,
21232001), Strategic Priority Research Program of the Chinese
Academy of Sciences (Grant No. XDB20000000), The 100
Talents Program, and “The 1000 Youth Talents Program” for
financial support. We also thank Professor Daqiang Yuan and
Yinghua Yu from our institute for X-ray structural analysis.
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