Enantioselective Synthesis of Atropisomeric Biaryls by Pd-Catalyzed Asymmetric Buchwald–Hartwig Amination

Article abstract of DOI:10.1002/anie.202108747

N?C Biaryl atropisomers are prevalent in natural products and bioactive drug molecules. However, the enantioselective synthesis of such molecules has not developed significantly. Particularly, the enantioselective synthesis of N?C biaryl atropisomers by stereoselective metal-catalyzed aryl amination remains unprecedented. Herein, a Pd-catalyzed cross-coupling strategy is presented for the synthesis of N?C axially chiral biaryl molecules. A broad spectrum of N?C axially chiral compounds was obtained with excellent enantioselectivities (up to 99 % ee) and good yields (up to 98 %). The practicality of this reaction was validated in the synthesis of useful biological molecules.

Full text of DOI:10.1002/anie.202108747

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International Edition: doi.org/10.1002/anie.202108747
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Biaryl Atropisomers
Hot Paper
Enantioselective Synthesis of Atropisomeric Biaryls by Pd-Catalyzed
Asymmetric Buchwald–Hartwig Amination
Peng Zhang, Xiao-Mei Wang, Qi Xu, Chang-Qiu Guo, Peng Wang, Chuan-Jun Lu,* and Ren-
Rong Liu*
À
Abstract: N C Biaryl atropisomers are prevalent in natural
products and bioactive drug molecules. However, the enantio-
selective synthesis of such molecules has not developed
À
significantly. Particularly, the enantioselective synthesis of N
C biaryl atropisomers by stereoselective metal-catalyzed aryl
amination remains unprecedented. Herein, a Pd-catalyzed
À
cross-coupling strategy is presented for the synthesis of N C
À
axially chiral biaryl molecules. A broad spectrum of N C
axially chiral compounds was obtained with excellent enantio-
selectivities (up to 99% ee) and good yields (up to 98%). The
practicality of this reaction was validated in the synthesis of
useful biological molecules.
A
tropisomerism arises from the hindered free rotation of
a molecule about an axis and exists widely in natural products,
biologically active molecules, and chiral ligands.[1] The most
À
representative examples are the axially chiral C C biaryl
compounds, which have been extensively investigated in
recent years.[2] However, compared with the well-developed
À
construction of chiral C C biaryl skeletons, the enantiose-
À
lective construction of N C axially chiral molecules, espe-
À
cially N C biaryl skeletons, is mostly unexplored and is
a remarkably challenging task.[3] There are only a limited
number of strategies for the atroposelective construction of
À
N C biaryl atropisomers, and these mainly comprise diaste-
reoselective SNAr reactions,[4] CPA-catalyzed enantioselec-
tive addition and cyclization,[5] asymmetric C H bond func-
À
Scheme 1. Representative N C biaryl molecules and asymmetric
À
tionalization of heteroarenes,[6] and metal-catalyzed annula-
À
cross-coupling reactions for the construction of N C atropisomers.
tion of alkynes.[7] Considering the prevalence of N C biaryl
À
atropisomers in natural products[8] and their remarkable
applications in drug design[9] and synthesis of chiral derivatiz-
ing agents[10] (Scheme 1), methods for accessing the general
catalyzed asymmetric N-arylation of anilides, where the
presence of an ortho t-butyl group in aniline was necessary
to obtain high ee values (Scheme 1Ba).[11] Recently, Gu et al.
reported an elegant Cu-catalyzed enantioselective intramo-
lecular Ullmann-type amination reaction of anilides for the
À
enantioselective forms of biaryl N C atropisomers are in high
demand.
Although the atroposelective construction of N C axially
synthesis of N C atropisomers (Scheme 1Bb).[12] Very
recently, Wencel-Delord and co-workers reported the first
case of a more challenging intermolecular atroposelective
Ullmann-type N C coupling reaction by utilizing C(sp )-
hypervalent iodine reagents as carbon substrates and sub-
stituted indolines as nitrogen substrates (Scheme 1Bc).[13]
Despite these contributions, the enantioselective synthesis
of N C biaryl atropisomers by metal-catalyzed aryl amina-
tion remains an unexplored field; however, the optically
active biaryl products formed are highly valuable. We herein
À
À
chiral molecules by transition-metal-catalyzed N-arylation is
one of the most attractive routes, it remains largely unex-
plored. Kitagawa, Taguchi, and co-workers pioneered the
2
À
À
construction of N C non-biaryl atropisomers by the Pd-
[*] P. Zhang, X.-M. Wang, Q. Xu, C.-Q. Guo, P. Wang, Dr. C.-J. Lu,
Prof. Dr. R.-R. Liu
À
College of Chemistry and Chemical Engineering
Qingdao University
Ningxia Road 308#, Qingdao 266071 (China)
E-mail: renrongliu@qdu.edu.cn
À
describe the Pd-catalyzed intramolecular N C cross-coupling
reactions of amidines[14] for the highly enantioselective syn-
chuanjunlu@qdu.edu.cn
À
thesis of biaryl atropisomers to obtain N C axially chiral
Supporting information and the ORCID identification number for
one of the authors of this article can be found under:
https://doi.org/10.1002/anie.202108747.
biaryl atropisomers by Buchwald–Hartwig amination (Sche-
me 1C).[15–17] It is worth noting that amidines are challenging
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À
substrates for transition-metal-catalyzed N C cross-coupling
in good yields with moderate to good ee values (entries 6–10),
except ligand L7, which resulted in the yield decreasing
sharply (entry 11). Moreover, monophosphine L8 was also
effective, giving 4a in 70% yield and 63% ee (entry 12).
Furthermore, the catalyst loading could be lowered to
2.5 mol% to allow completion of the reaction with only
a slight decrease in the yield and ee value (entry 13).
reactions not only because they coordinate strongly to the
transition metal and cause catalyst deactivation but also
because they undergo tautomerization and E/Z isomerization
(6 possible isomers).[18] These issues make enantioselective
control more complex and challenging.
We began optimizing the reaction conditions using
amidine 3a, which was easily prepared by a two-step reaction,
as the model substrate (Table 1). Condensation of 2-bromoa-
niline (1a) with TFA in CCl4 in the presence of triphenyl-
phosphine afforded a trifluoroacetimidoyl chloride. Subse-
quent addition/elimination with substituted aniline 2a pro-
duced amidine 3a in a good yield. The reaction of 3a in the
presence of Pd(OAc)2 (5 mol%), (S)-BINAP L1 (7.5 mol%),
and K2CO3 (1.2 equiv) in toluene at 608C afforded the desired
product 4a in 82% yield and 75% ee (entry 1). Slightly lower
enantioselectivity was obtained when the Br substituent in the
substrate was replaced by I (entry 2). To our delight, when
KOH was used instead of K2CO3, 4a was formed in 93% yield
and 89% ee (entry 3). Further screening revealed that the
best result was obtained when Cs2CO3 was used, with 4a
obtained in 98% yield and 92% ee (entry 4). A comparable ee
was obtained when NaOH was used as the base, although the
yield was slightly lower (entry 5). Next, the effect of different
ligands was tested. Most of the biphosphine ligands resulted
With the optimal conditions in hand, we next examined
the substrate scope of the amidine (Scheme 2). A wide range
of amidines were suitable, affording the desired biaryl
atropisomers in good to excellent yields and enantioselectiv-
ities. First, the effect of substituents at the C1-position of the
amidine moiety was examined. Slightly lower enantioselec-
tivity was obtained when CF3 was replaced by CF2Cl (4b) or
C2F5 (4c) on the substrate. However, when alkyl- and aryl-
substituted amidines were used under identical reaction
conditions, the enantioselectivities were reduced significantly
(4d, 4e), thus demonstrating the unique fluorine effect of the
CF3-bearing substrate. The racemization barriers (DG°) of 4a
and 4d were measured to be 34.3 and 31.5 kcalmolÀ1,
respectively (see the Supporting Information for details),
which may indicate that partial thermal racemization of the
product can be excluded as the reason for the decrease in the
ee value with 4d. To investigate the effect of substituent R on
the phenyl ring of the 2-bromophenyl moiety, we carried out
the reaction of 3 with a series of amidines with meta and/or
para substituents on the 2-bromophenyl moiety. The sub-
stituents included Me (4 f, 4n), t-Bu (4k), MeO (4r), halogen
(4g-4i, 4p, 4q), CF3 (4j, 4o), OCF3 (4l, 4s), CN (4m), and
CO2Me (4t). The reactions smoothly furnished the coupling
products with good to excellent yields (63–98%) and
enantioselectivities (86–93%). The absolute configuration
of 4r (> 99% ee after recrystallization) was determined by X-
ray crystallographic analysis.[19] In general, the ee values for
substrates bearing electron-withdrawing substituents were
higher than those for substrates bearing electron-donating
substituents (4 f vs. 4j and 4o vs. 4r). Furthermore, ortho-F-2-
bromophenylamidine also underwent transformation to form
biaryl atropisomer 4u in good yield and enantioselectivity. As
expected, disubstituted substrates underwent the title reac-
tion to give 4v–4x with excellent ee values. The effect of
substituents (R1) on the aniline moiety was also examined.
The ortho-alkyl group in the aniline moiety could be a simple
methyl or ethyl group, although the yields slightly decreased
when the MeO group was not introduced at the 4-position (4y
and 4z). Additional groups adjacent to the 2-methyl group
affected neither the yield nor the enantioselectivity, with
methyl (4ae, 4ag) or methoxy groups (4aa, 4af) at different
positions affording the products in 90–92% ee. In addition,
a substrate with a free hydroxy group was compatible in this
reaction, with 4ah obtained in 93% yield and 86% ee. The
ortho groups in the aniline structure can be efficiently
extended to a naphthyl (4ab) or (tetrahydro)naphthyl (4ad)
scaffold to achieve good enantioselectivity. Furthermore, this
reaction is also compatible with halogen-containing sub-
strates and gives the corresponding product 4ai containing
a sensitive free NH2 group in high yield and 89% ee.
Moreover, the reaction is also compatible with quinoline
and indole heterocyclic substrates. However, when indole
Table 1: Optimization of the reaction conditions.[a]
Entry
Ligand
Base
X
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L1
K2CO3
K2CO3
KOH
Br
I
82
84
93
98
92
90
85
82
80
78
10
70
80
75
68
89
92
92
89
88
84
70
62
–
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cs2CO3
NaOH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13[d]
63
90
[a] Reaction conditions: 1 (0.1 mmol), Pd(OAc)2 (5.0 mol%), ligand
(7.5 mol%), and base (1.2 equiv) in solvent (1.0 mL) at 608C for 18 h.
[b] Yield of isolated product. [c] Determined by chiral HPLC. [d] Pd(OAc)2
(2.5 mol%), ligand (3.75 mol%), reaction time: 36 h.
2
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Scheme 3. Generality of the Pd-catalyzed double asymmetric amina-
tion reaction. [a] Reaction conditions: 5 (0.2 mmol), Pd(OAc)2
(10.0 mol%), L1 (15.0 mol%), and Cs2CO3 (2.4 equiv) in toluene
(2.0 mL) at 608C for 18 h. [b] NaOH (2.4 equiv) was used as the base
instead of Cs2CO3.
sequently, 2,4-diamidine 5a was prepared and subjected to the
standard reaction conditions. Gratifyingly, this double atro-
poselective amination reaction proceeded to give the desired
1,4-benzimidazole 6a in excellent diastereoselectivity and
enantioselectivity. To demonstrate the generality of this
transformation, other 2,4-diamidines with various substitu-
ents on the phenyl ring of the 2-bromophenyl moiety were
tested. All the desired products (6b–6g) were generated in
good yields with ee values higher than 95%. Gratifyingly,
besides the methyl group, 1,5-naphthyldiamidine reacted
well, generating the corresponding 1,5-benzimidazole product
6h in 85% yield and 97% ee.
The title reaction was applied in a relatively straightfor-
ward synthesis of an anti-diabetes type 2 drug candidate
(shown in Scheme 1), starting from commercially available 2-
bromoaniline derivative 1t (Scheme 4 [Eq. (1)]). To imple-
ment this, 1t underwent a condensation reaction with TFA in
CCl4 in the presence of triphenylphosphine to yield trifluor-
oacetimidoyl chloride 7, which underwent an addition/elim-
ination of substituted aniline 8 to yield amidine 9. Amidine 9
was subsequently subjected to the Pd-catalyzed intramolec-
Scheme 2. Generality of the Pd-catalyzed asymmetric amination reac-
tion. Reaction conditions: [a] 3 (0.2 mmol), Pd(OAc)2 (5.0 mol%), L1
(7.5 mol%), and Cs2CO3 (1.2 equiv) in toluene (2.0 mL) at 608C for
18 h. [b] NaOH (1.2 equiv) was used as the base instead of Cs2CO3.
[c] Reaction time: 72 h. [d] Reaction was performed at 508C.
À
substrate 3aj was used, the target product 4aj was obtained
with very low enantioselectivity, presumably because of
reduced steric hindrance.
Inspired by the above results, we further used the
developed strategy to extend the construction to structural
motifs possessing two chiral N-aryl axes (Scheme 3). Con-
ular C N bond formation to afford the desired product 10 in
90% yield and 94% ee. Hydrolysis of the ester group afforded
drug candidate 11. Moreover, the present method can also be
used for synthesizing a potential D1 agonist analogue
(Scheme 4 [Eq. (2)]).[20] For example, phenol 4ah successfully
À
underwent the Pd-catalyzed C O cross-coupling reaction
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Scheme 6. Plausible catalytic cycle.
Scheme 4. Synthetic transformations.
group in the aniline moiety of C’ experiences strong steric
repulsion from the equatorial phenyl group on the phospho-
rus atom. Consequently, attack from the less sterically
hindered site would be favored. Finally, reductive elimination
of C affords 4a and regenerates the Pd0 catalyst.
with halopyridine to give the products in good yield under
mild conditions. Importantly, the ee value was unaffected by
this transformation.
À
A gram-scale reaction of 3a was conducted, with N C
In conclusion, we have developed a procedure for the Pd-
catalyzed enantioselective amination of amidines to synthe-
atropisomer 4a obtained in 95% yield and 90% ee, thus
showing the reliability of the developed procedure (Scheme 5
[Eq. (1)]). Moreover, to demonstrate the tautomerization of
amidines in the reaction, we synthesized substrate 13 from
2,2,2-trifluoro-N-(4-methoxy-2-methylphenyl)acetimidoyl
chloride and 2-bromoaniline. Under the optimal conditions,
13 afforded the desired product 4a in 85% yield and 88% ee
(Scheme 5 [Eq. (2)]), thus confirming the tautomerization of
amidines in this reaction.
À
size N C biaryl atropisomers. Awide range of benzimidazoles
À
with N C axial chirality can be conveniently constructed with
excellent enantioselectivity. Moreover, highly enantioen-
riched 1,4- and 1,5-dibenzimidazole possessing two chiral
À
N C axes could be accessed using this procedure. The gram-
scale synthesis and the versatile transformations of the
products may have broad applications in the synthesis of
À
valuable pharmaceuticals containing N C biaryl atropisomer
skeletons.
Finally, a plausible catalytic cycle and a stereoinduction
model were proposed (Scheme 6). Initially, amidine 3a can
undergo oxidative addition with the Pd0 catalyst to give PdII
complex A. Deprotonation generates amidine-Pd complex B
or B’ via tautomerization, which further gives C or C’ by
substitution of the bromide ligand with amidine. The ortho
Acknowledgements
We are grateful for the generous support from the Taishan
Scholar Youth Expert Program in Shandong Province
(tsqn201909096) and the start-up fund from Qingdao Uni-
versity.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: amidines · amination · asymmetric catalysis ·
atropisomerism · palladium
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4
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Manuscript received: July 1, 2021
Revised manuscript received: August 2, 2021
Accepted manuscript online: August 9, 2021
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Biaryl Atropisomers
P. Zhang, X.-M. Wang, Q. Xu, C.-Q. Guo,
P. Wang, C.-J. Lu,*
R.-R. Liu*
&&&& — &&&&
Enantioselective Synthesis of
Atropisomeric Biaryls by Pd-Catalyzed
Asymmetric Buchwald–Hartwig
Amination
À
A Pd-catalyzed enantioselective amina-
tion of amidines has been developed for
tives containing N C axial chirality can be
conveniently constructed in excellent
yields and enantioselectivities by intra-
molecular amination.
À
the synthesis of N C biaryl atropisomers.
A wide range of benzimidazole deriva-
6
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
These are not the final page numbers!