Asymmetric Copper-Catalyzed Intermolecular Aminoarylation of Styrenes: Efficient Access to Optical 2,2-Diarylethylamines

Article abstract of DOI:10.1021/jacs.7b02455

We have developed a copper-catalyzed enantioselective intermolecular aminoarylation of alkenes using a novel N-fluoro-N-alkylsulfonamide as the amine reagent, which could react with the Cu(I) catalyst to release a related amino radical. After addition to styrene, the generated benzylic radical could couple with a chiral L?Cu^IIAr complex to achieve enantioselective arylation. Various optical 2,2-diarylethylamines were efficiently synthesized from simple styrenes with high enantioselectivity, and these products can serve as valuable synthons toward bioactive molecules' synthesis.

Full text of DOI:10.1021/jacs.7b02455

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Communication
Asymmetric Copper-Catalyzed Intermolecular Aminoarylation
of Styrenes: Efficient Access to Optical 2,2-diarylethylamines
Dinghai Wang, Lianqian Wu, Fei Wang, Xiaolong Wan, Pinhong Chen, Zhenyang Lin, and Guosheng Liu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 04 May 2017
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Asymmetric Copper-Catalyzed Intermolecular Aminoarylation
of Styrenes: Efficient Access to Optical 2,2-diarylethylamines
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‡
Dinghai Wang,† Lianqian Wu,† Fei Wang,† Xiaolong Wan,§ Pinhong Chen,† Zhenyang Lin*, and
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
§Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, China, 200032
Supporting Information Placeholder
asymmetric radical transformation (ATR),8, 9 , 10 our group have
revealed that enantioselective arylation of benzylic radicals can be
achieved by copper catalyst in the case of enantioselective
trifluoromethylarylation of styrenes.11 Inspired by these studies,
ABSTRACT: We have developed
a
copperꢀcatalyzed
enantioselective intermolecular aminoarylation of alkenes using a
novel NꢀfluoroꢀNꢀalkylsulfonamide as the amine reagent, which
could react with the Cu(I) catalyst to release a related amino
radical. After adding to styrene, the generated benzylic radical
could couple with a chiral L*CuIIAr complex to achieve
enantioselective arylation. Varieties of optical 2,2ꢀdiarylꢀ
ethylamines were efficiently synthesized from simple styrenes
with high enantioselectivity, and these products can serve as
valuable synthons toward bioactive molecules synthesis.
we hypothesized that if βꢀamino benzylic radicals, generated from
amino radicals addition to styrenes,12 could be enantioselectively
coupled with L*CuIIꢀAr species, then asymmetric aminoarylation
of styrenes should be expected to deliver enantiopure 2,2ꢀ
diarylethylamines efficiently (Scheme 1a). Herein, we reported
this study, in which novel NꢀfluoroꢀNꢀalkylsulfonamides (NFAS)
were employed as the key amination reagents.
The optically pure 2,2ꢀdiarylethylamine scaffold serves as a
pharmacologically important motif in dopamine receptor agonists,
existing extensively in bioactive molecules and pharmaceuticals.1
Thus, enantioselective construction of such a skeleton is highly
demanded. However, only limited methods have been reported for
its efficient synthesis, such as arylation of enantiopure 2ꢀ
2
arylaziridines,
enantioselective arylation of βꢀnitroalkenes
3
followed by reduction, and asymmetric hydrogenation of
enamines. Compared with the aboveꢀmentioned reactions,
4
enantioselective intermolecular aminoarylation reaction represents
one of the most efficient approaches to chiral 2,2ꢀ
diarylethylamines from simple styrenes. In recent years,
transitionꢀmetal catalyzed enantioselective aminoarylation
reactions of alkenes have received considerable attention.
However, these reactions are limited to the intramolecular
version, 5 owing to the high entropic cost for intermolecular
aminometallation of alkenes.6 So far, to the best of our knowledge,
an intermolecular version of enantioselective aminoarylation
reaction has not been reported.
Scheme 1. Asymmetric Radical Transformation (ART) for the
Synthesis of Chiral 2,2ꢀdiarylethylamines.
As we already know, addition of active amino radical species to
styrenes often exhibits low energy barrier to generate benzylic
radicals, and sequential functionalization of the benzylic radicals
results in a variety of amination products.7 However, due to the
high reactivity of radical species, its enantioselective control is
extremely challenging. Recently, Fu and coꢀworkers disclosed
that a benzylic radical can react with an (L*)NiꢀAr complex with
high enantioselectivity.8 In connection with our interest in the
To test above hypothesis, the initial studies were focused on the
reaction of 1a with NFSI and PhB(OH)2 with an achiral
(phen)Cu(I) catalyst. As shown in Scheme 1b, we were delighted
to find that the reaction indeed gave the desired product 2a albeit
in low yield (19%). When the chiral ligand L1, one of the best
ligands found in our previous asymmetric trifluoromethylꢀ
arylation,11 was employed, the reaction provided 2a in a higher
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yield (35%) with a very promising ee of 84%. However, the
On the basis of the above analysis, a series of NꢀF reagents
styrene substrate 1a was completely consumed in these two
reactions. Unfortunately, further optimizing the reaction condition
did not improve the reaction yield. Our previous studies showed
that the transmetallation reaction of arylboronic acid with Cu(II)
intermediate is slow,13 while a highly electrophilic amino radical
(e.g., A in Figure 1) generated from NFSI can react extremely fast
with styrenes to generate benzylic radicals.9c Thus, we speculated
that, the slowly formed ArCu(II) species derived from the
transmetallation was unable to trap excess amount of the benzylic
radical, resulting in heavy side reactions.14 With this speculation,
we believed that lowering down the electrophility of amino
radical may help to slow the radical addition
NFASBꢀNFASH were synthesized and employed in the
asymmetric aminoarylation reaction. As shown in Table 1, due to
the larger steric hindrance, both NFASB and NFASC showed poor
reactivities and failed to provide the desired aminoarylation
products, but resulted in a side product of 1,2ꢀdiphenylation of 1a
(entries 1ꢀ2).15 In contrast, the radical D was indeed proved to be
efficient, and the reaction with NFSAD provided the desired
product 3aD in 77% yield with 85% ee (entry 3). Further modified
NꢀF reagents NFSAEꢀNFSAG were tested, and less electronic
effect on the aryl ring was observed in the reaction yield and ee
(entry 4ꢀ6). Compared to NFASD, NFASH with a smaller methyl
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group on the nitrogen exhibited
a
slightly higher
enantioselectivity (87% ee) to give 3aH in 65% yield (entry 7). In
consideration of methylamine as a popular motif in bioactive
compounds and natural products, NFASH was chosen as the
amino source for further optimizing reaction condition.16 First,
decreasing the reaction temperature was beneficial to enhance the
enantioselective excess (92% ee at 0 oC, 93% ee at ꢀ10 oC).
However, the reaction conversion was significantly decreased to
o
give a marked low yield (48% at 0 C in entry 8, and 28% at ꢀ10
oC in entry 9), even in a prolonged time. Excitingly, addition of an
Table 2. Substrate Scope of Alkenesa,b
Figure 1. DFT calculated energy barriers for the radical addition
processes with different electrophilic amino radicals.
process down, which possibly match the slow transmetallation
step. In order to test this possibility, a series of amino radicals (B-
H) were surveyed by DFT calculations (Figure 1) (see SI for
computational details. Note: the quality of the DFT calculations
can only give a qualitative picture). Compared with the radical A
which shows barrierless addition, the amino radicals B-H exhibit
higher energy barriers toward radical addition to styrenes, which
should lead to a relatively slow addition step. Among them, the
sterically bulky radicals B and C (21.8 and 20.4 kcal/mol
respectively) showed appreciably higher barriers than the
electronꢀpoor radical G (14.5 kcal/mol) or the less steric bulky
radical H (14.6 kcal/mol).
Table 1. Amine Reagents Screening and Condition Optimizationa
Cu(CH3CN)4PF6 (5 mol %)
Ph R1
O
S
O
L1
(10 mol %)
R1
PhB(OH)2 (2.0 equiv.)
N
Ar
N
S
+
O2
CH2Cl2/DMA (4:1)
r.t., Ar, 18 h
F
R2
3a
NFAS
NFAS (R1, R2)
1a
Yieldb (ee)c
Entry
Conversion
3a
NFASB
NFASC
NFASD (Et, H)
NFASE
NFASF
NFASG
NFASH
NFASH
NFASH
NFASH
NFASH
NFASH
(tBu, H)
(iPr, H)
3aB
1
42%
53%
94%
95%
96%
98%
100%
80%
55%
92%
100%
100%
60%
: 0
3aC:
2
trace
3aD
3aE
3
: 77% (85%)
: 65% (83%)
4
(Et, Me)
5
3aF: 54% (84%)
(Et, OMe)
3aG
6
: 73% (81%)
(Et, CF3)
3aH
7
8d
: 65% (87%)
(Me, H)
3aH
: 48% (92%)
3aH: 28% (93%)
(Me, H)
9e,f
10e,f,g
11e,g,h
12i
13j
(Me, H)
3aH
3aH
3aH
3aH
: 77% (92%)
: 81% (93%)
: trace
(Me, H)
(Me, H)
extraneous base LiOtBu was beneficial to accelerate the
transmetallation step, resulted in an obvious enhancement of the
reaction yield from 28% to 77% without eroding the
entantioselectivity (entry 10). Finally, the yield could be further
improved with a longer reaction time (81% yield, entry 11).
Notably, the mixture solvent of CH2Cl2/DMA was vital. The
reactions in pure CH2Cl2 or DMA alone only gave a trace amount
of the desired product 3aH (entries 12ꢀ13).
(Me, H)
NFASH
: trace
(Me, H)
a All reactions were run in 0.2 mmol scale in 2 mL solvent. b Yields were determined
by crude 1H NMR with CH2Br2 as internal standard. c Enantiomeric excess (ee)
values were determined by HPLC on a chiral stationary phase. d at 0 oC. e at -10 oC.
g
h
i
f 4 d. with LiOtBu ( 0.5 equiv) as additive. 5 d. Reaction of entry 12 in pure
CH2Cl2 (2 mL). j Reaction of entry 13 in pure DMA (2 mL).
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With the optimized reaction condition in hand, we firstly
Then, the substrate scope of aryl boronic acids was investigated.
As illustrated in Table 3, again, both electronꢀrich and electronꢀ
poor paraꢀaryl boronic acids could react with 1ꢀvinyl naphthalene
to give the target products 4aꢀ4e with excellent enantioꢀ
selectivities. The reactions of orthoꢀsubstituted aryl boronic acids
also proceeded to yield products 4fꢀ4g in excellent enantioꢀ
selectivities (94ꢀ95% ee). Moreover, for the reactions of 2ꢀvinyl
naphthalenes and vinyl benezenes, a variety of aryl boronic acids
were effective to yield products 4hꢀ4n in good enantioselectivities
(83ꢀ89% ee). Excitingly, thiophenyl and benzothiophenyl boronic
acids also showed good reactivities to deliver the target products
4oꢀ4q in excellent enantioselectivities (90% ee). In contrast, 2ꢀ
benzofuryl boronic acid was also active, but with only moderate
enantioselectivity (59% ee).
examined the substrate scope and functional group tolerance of
the reaction. As shown in Table 2, for both electronꢀpoor and
electronꢀrich αꢀvinylnaphthalenes, the reactions provided the
corresponding products 3a-3d in good yields (around 80% except
3d in 47%) with high enantioselectivity (90ꢀ93% ee). Meanwhile,
βꢀvinylꢀnaphthalenes were also proven to be suitable substrates,
furnishing the products 3eꢀ3g in good yields and ee’s (88ꢀ90%). A
variety of vinyl benzenes were next surveyed. The paraꢀ
substituted styrenes bearing both electronꢀpoor and electronꢀrich
arenes were effective for the reaction to give products 3hꢀ3o in
good yields (65ꢀ78%) with good to excellent enantioselectivities
(83ꢀ92% ee). In addition, metaꢀ and orthoꢀsubstituted styrenes
also exhibited good reactivities to give the desired products 3pꢀ3s
in moderate to good yields with 85%ꢀ90% ee. Beyond these,
styrenes with diꢀ and triꢀsubstitutents on the aryl ring were also
compatible to give products 3tꢀ3w with similar yields and ee’s.
Notably, when the reaction of 1v was scaled up to 5 mmol, the
desired product 3v was obtained with the same enantioselectivity
(92% ee) in a satisfactory yield (62% yield, 1.54 g). Moreover,
styrenes bearing heterocycles were suitable to give products 3xꢀ3y
with 84% ee and 88% ee, respectively. Finally, a more complex
substrate with an estrone moiety could be employed to generate
product 3z in 47% yield with a 93:7 diastereomeric ratio.
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Further synthesis of bioactive compounds was conducted by
utilizing this current method. Reaction of 3,4ꢀdimethoxystyrene
provided the desired product in 48% yield with 86% ee, and the
sequential desulfonylation under Mg/MeOH condition gave the
related methylamine 5 in 80% yield with a retained ee, which was
reported as an antidepressant agent.17 Meanwhile, compound 5
can be converted to bioactive SCH 12679 on the basis of a
18
previous report (Scheme 2a).
Moreover, compound 3l
underwent a sequential Suzuki coupling and desulfonylation to
provide optically enriched antiꢀcancer agent 6 efficiently (Scheme
2b).19 Finally, enantiopure tetrahydroisoquinoline as a privileged
skeleton often existed in bioactive molecules and
pharmaceuticals.20 After removal of sulfonyl protecting group, 3w
was converted to the chiral methylamine 7, which could conduct
condensation with formaldehyde to generate chiral tetrahydroꢀ
isoquinoline derivates 8 in 51% overall yield with 94% ee
(Scheme 2c).
Table 3. Scope of Aryl Boronic Acids.a,b
Cu(CH3CN)4PF6 (5 mol%)
Ar Me
L1 (10 mol%)
NFASH (2.0 equiv.)
N
R
SO2Ph
+ ArB(OH)2
R
LiOtBu (0.5 equiv.)
DCM/DMA (4:1), -10 oC, Ar
1
4 yield (ee)
R
R
Me
N
(a)
4a (R = OMe), 43% (91%)
4b (R = Et), 59% (91%)
4c (R = F), 65% (92%)
4d (R = Cl), 70% (94%)c
4e (R = Br), 56% (92%)c
Ph
Ph
Me
SO2Ph
1) standard cond.
48%, 86% ee
MeO
MeO
MeO
MeO
MeO
MeO
NHMe
Ref.
NSO Ph
2
N
Me
4f (R = Me), 49% (95%)
4g (R = F), 62% (94%)
2) Mg/MeOH
sonic., 80%
5
SCH 12679
O
O
Ph
antidepressant activity
dopamine D2 receptors
BnO
(b)
Ph
Ph Me
NSO2Ph
Me
Me
(1) cat. Pd(PPh3)4
NaHCO3
NHMe
Me
N
NSO2Ph
BPin
NSO2Ph
+
HN
SO2Ph
(2) Mg/MeOH
Sonication
35% for two steps
88% ee
Br
N
HN
Br
AcO
3l 88% ee
N
6
4j 72% (87%)
4i 57% (84%)
4h 49% (87%)
anti-cancer activity
F
Me
Me
(c)
F
Ph Me
NSO2Ph
Ph Me
Ph
MeO
MeO
MeO
MeO
NH
MeO
Me
Me
SO2Ph
Mg/MeOH
Sonication
N
NSO2Ph
CH2O/HCO2H
MeO
N
MeO
MeO
N
Me
Me
SO2Ph
OMe
OMe
OMe
AcO
Br
8
Br
3w 88% ee
7
51% overall yield, 94% ee
4k 46% (89%)
4l 63% (88%)
4m 51% (83%)
Me
S
Scheme 2. Synthetic Applications.
S
Me
Me
Me
N
In order to provide supporting evidence for the proposed radical
process, a novel NꢀF reagent NFASI bearing an alkene moiety
was treated under the standard aminoarylation reaction condition.
As shown in eq 1, the reaction failed to yield the aminoarylation
product 9a. Instead, the related alkylarylation product 9b was
obtained in 34% yield with 1:1 diastereomer ratio (88% ee and
84% ee respectively), companied with the Heckꢀtype product 9c.
In addition, the side products 9d and 9e were also obtained in
15% and 21% yields, respectively. Meanwhile, the equal amount
of diastereoisomers were obtained in the reactions of Eꢀ1kꢀ2ꢀd1
and Zꢀ1kꢀ2ꢀd1 (see SI). Moreover, the reaction could be inhibited
with addition of TEMPO. All these observations suggested that
the reaction is more likely to involve a radical process.
NSO2Ph
NSO2Ph
SO2Ph
F
F
Cl
4p 63% (90%)
4n 69% (87%)
4o 52% (90%)
S
O
Me
SO2Ph
NSO2Ph
N
Me
F
Cl
4q 72% (90%)
4r 58% (59%)
aAll reactions were run in 0.2 mmol scale in 2 mL solvent for 5-7 d. bIsolated yield, and the
enantiom-eric excess (ee) values were determined by HPLC on a chiral stationary phase.
c Catalyst loading: Cu(CH3CN)4PF6 (10 mol%)/L1 (20 mol%).
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(5) For some enantioselective examples, see: (a) Mai, D. N.; Wolfe, J. P.
J. Am. Chem. Soc. 2010, 132, 12157. (b) Zeng, W.; Chemler, S. R. J. Am.
Chem. Soc. 2007, 129, 12948. (c) Miao, L.; Haque, I.; Manzoni, M.
R.; Tham, W. S.; Chemler, S. R. Org. Lett. 2010, 12, 4739ꢀ4741. For
some nonꢀenantioselective examples, see: (d) Du, W.; Gu, Q.; Li, Z.;
Yang, D. J. Am. Chem. Soc. 2015, 137, 1130. (e) Rosewall, C. F.; Sibbald,
P. A.; Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 9488.
(6) For some reviews, see: (a) Müller, T. E.; Beller, M. Chem. Rev. 1998,
98, 675. (b) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem. Int.
Ed. 2004, 43, 3368. (c) Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400.
(7) For some reviews, see: (a) Studer, A.; Curran, D. P. Angew. Chem. Int.
Ed. 2016, 55, 58. (b) Xiong, T.; Zhang, Q. Chem. Soc. Rev. 2016, 45, 3069.
(8) For the reaction with achiral benzylic electrophiles, see: (a) Do, H.;
Chandrashekar, E. R. R.; Fu, G. C. J. Am. Chem. Soc. 2013, 135, 16288.
For the selected reaction with achiral alkyl electrophiles, see: (b) Binder, J.
T.; Cordier, C. J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 17003. (c) Choi,
J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 9102. (d) Wilsily, A.;
Tramutola, F.; Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134,
5794. (e) Oelke, A. J.; Sun, J.; Fu, G. C. J. Am. Chem. Soc. 2012, 134,
2966. (f) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482. (g)
Mao, J.; Liu, F.; Wang, M.; Wu, L.; Zheng, B.; Liu, S.; Zhong, J.; Bian,
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Science 2016, 351, 681.
( 9 ) 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.
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Q.; Glorius, F. Angew. Chem. Int. Ed. 2017, 56, 49. For oxygenation, see:
(b) Zhu, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52, 12655. (c)
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10.1021/acscentsci.6b00368. For amination, see: (e) Lin, J.ꢀS.; Dong, X.ꢀ
Y.; Li, T.ꢀT.; Jiang, N.ꢀC.; Tan, B.; Liu, X.ꢀY. J. Am. Chem. Soc. 2016,
138, 9357.
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In summary, we have developed an enantioselective aminoꢀ
arylation of styrenes using the Box/Cu(I) catalyst. A novel Nꢀ
fluoroꢀNꢀmethylsulfonamide was explored as an essential amino
source to generate amino radical, which exhibited good reactivity
toward benzylic radical formation to match the turnoverꢀlimiting
transmetallation step, resulted in the successful chemoꢀ and
enantioselective reactions. This method provided an efficient
approach to synthesize various enantiomerically enriched 2,2ꢀ
diarylehthanylamine derivatives. These products could be easily
converted to a series of valuable chiral bioactive molecules.
ASSOCIATED CONTENT
Supporting Information
Synthetic procedures, characterization, Computational study data,
and additional data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
chzlin@ust.hk; gliu@mail.sioc.ac.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful for financial support from the National Basic
Research Program of China (973ꢀ2015CB856600), the National
Nature Science Foundation of China (Nos. 21532009, 21421091,
and 21472219), and the Strategic Priority Research Program of
the Chinese Academy of Sciences (No. XDB20000000). This
research was also partially supported by CAS Interdisciplinary
Innovation Team.
(11) Wu, L.; Wang, F.; Wan, X.; Wang, D.; Chen, P.; Liu, G. J. Am. Chem.
Soc. 2017, 139, 2904.
(12) For more examples involving amino radical addition to alkenes, see:
(a) Zhang, H.; Pu, W.; Xiong, T.; Li, Y.; Zhou, X.; Sun, K.; Liu, Q.;
Zhang, Q. Angew. Chem. Int. Ed. 2013, 52, 2529. (b) Zhang, B.; Studer, A.
Org. Lett. 2014, 16, 1790. (c) Zhang, H.; Song, Y.; Zhao, J.; Zhang, J.;
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T.; Wang, Z.; Xu, G.; Wang, X.; Zhang, Q. Angew. Chem. Int. Ed. 2015,
54, 12649.
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(15) The reaction provided the diphenylation product in 28% (for NFASB)
and 24% yield (for NFASc), respectively. For more discussion, see the
Supporting Information.
(16) In addition to the highly reactive NFASH, NFSAD was also proven to
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