Asymmetric Synthesis of Axially Chiral 2-Aminobiaryls by Rhodium-Catalyzed Benzannulation of 1-Arylalkynes with 2-(Cyanomethyl)phenylboronates

Article abstract of DOI:10.1002/anie.201806324

Asymmetric benzannulation of 1-arylalkynes, where the aryl group is an ortho-substituted aromatic group, with 2-(cyanomethyl)phenylboronate was catalyzed by a rhodium complex coordinated with a chiral diene ligand to give high yields of axially chiral 2-aminobiaryls with greater than 90 % ee.

Full text of DOI:10.1002/anie.201806324

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Accepted Article
Title: Asymmetric Synthesis of Axially Chiral 2-Aminobiaryls by
Rhodium-Catalyzed Benzannulation of 1-Arylalkynes with 2-
(Cyanomethyl)phenylboronates
Authors: Fei Xue and Tamio Hayashi
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Angewandte Chemie International Edition
10.1002/anie.201806324
COMMUNICATION
Asymmetric Synthesis of Axially Chiral 2-Aminobiaryls by
Rhodium-Catalyzed Benzannulation of 1-Arylalkynes with 2-
(
Cyanomethyl)phenylboronates
Fei Xue and Tamio Hayashi*
Abstract: Asymmetric benzannulation of 1-arylalkynes, where the
aryl group is ortho-substituted aromatic group, with 2-(cyano-
(
a) Catalytic asymmetric synthesis of axially chiral biaryls
R1
X
methyl)phenylboronate was catalyzed by
a rhodium complex
R3
R4
R1
R
2 +
type 1
type 2
R1
R3
R2
R4
[2+2+2]
+
coordinated with a chiral diene ligand to give high yields of axially
chiral 2-aminobiaryls with >90% ee.
4 R2
m
type 3 R3
R
R1
(
This work)
There have recently been considerable interests in catalytic
asymmetric synthesis of axially chiral biaryls because of their
high utility in various research areas including synthetic organic
R1
R3
R1
R4
R1
R3
R1
R3
+
m
H
R4
or
R4 or
R3
R4
Y
Y = CN, COOMe
[
1]
(type 2a)
(type 2b)
(type 2c)
chemistry. The asymmetric reactions producing axially chiral
biaryls are classified into three types dependent on which bonds
are formed (Scheme 1a). The most extensively studied is the
asymmetric coupling between two aryl groups, where the axial
chirality is generated at formation of the carbon-carbon bond
between two aryl groups of the biaryl skeleton (type 1). Typical
(b) Pd-catalyzed annulation of alkynes with 2(cyanomethyl)phenylboronate producing
-aminonaphthalenes (by Tsukamoto)
2
R1
R2
Pd(OCOCF3)(dppe)
5.0 mol%)
R2
R1
Bpin
CN
R1
(
+
+
R2
MeOH, 65 °C, 16 h
NH2
NH2
[
2]
examples are Ni- or Pd-catalyzed cross-coupling reactions.
Scheme 1. Catalytic asymmetric synthesis of axially chiral biaryls.
The second type is asymmetric substitution on achiral (or
pseudo-achiral) biaryls, where desymmetrization makes the
biaryls axially chiral (type 2). Desymmetrization by an
enantioposition-selective reaction of symmetrically substituted
We have examined rhodium catalysts coordinated with chiral
bisphosphines and chiral dienes, which have been shown to be
active catalysts for the asymmetric reactions where their
catalytic cycle involves addition of aryl-rhodium intermediates to
[
3]
biaryls
(type 2a), asymmetric ring-opening of cyclic
[
4]
compounds (type 2b), and C-H functionalization of ortho-
unsubstituted biaryls, which stops the rotation around biaryl
[8]
alkynes, for the reaction of 1-(1-naphthyl)-1-propyne (1a) with
[
5]
axis (type 2c), are the examples. The last type is the reaction
where the axial chirality is generated at the formation of one of
the two aromatic rings (type 3). A most successful example is
asymmetric synthesis at the benzene ring formation by [2+2+2]
[7]
2
-(cyanomethyl)phenylboronate 2. The benzannulation was
found to proceed smoothly at 22 °C in most cases with chiral
diene ligands to give high yields of axially chiral 1,2’-binaphthyl
3
a together with 1,1’-binaphthyl 4a as a minor product. The
[
6]
cycloaddition of alkynes. Here we wish to report a new type of
catalytic asymmetric synthesis of axially chiral biaryls, which is
classified as type 3 and is realized by benzannulation of 1-
arylalkynes with ortho-functionalized phenylboronates catalyzed
by a chiral diene/Rh complex.
enantioselectivity was strongly dependent on the chiral ligands
[9]
[10]
used. Of the reported chiral diene ligands we examined, L5*
which bears amide of tert-butylamine showed the highest
enantioselectivity of 93% ee (entry in Table 1). The
enantioselectivity was lower with those diene ligands containing
6
Recently Tsukamoto reported that palladium complex
[11]
[12]
ester groups L1* and L2* (entries 2 and 3) and the amide-
Pd(OCOCF
3
)(dppe) catalyzes the reaction of internal alkynes
[13]
diene ligands substituted with less bulky amino groups L3*
with 2-(cyanomethyl)phenylboronate to give 3,4-disubstituted 2-
[14]
[10b]
and L4* (entries 4 and 5). With diene ligand L6*,
which is
[
7]
aminonaphthalenes (Scheme 1b). This report inspired us to
apply this annulation reaction to asymmetric synthesis of axially
chiral biaryls. For the asymmetric synthesis of high utility to be
realized, the following requirements are to be fulfilled: 1) The
reaction must proceed in a high yield for the alkyne substrates
substituted with a bulky aromatic group, which is large enough to
prevent the biaryl product from racemization. 2) The
regioselectivity at the addition to unsymmetrically substituted
alkynes must be high. 3) Most importantly, the reaction must
proceed with high enantioselectivity.
an N-methylated version of L5*, the reaction was slow resulting
in a low yield of the annulation product (entry 7). Based on the
results above that the amide of tert-butylamine L5* is more
enantioselective than others for the present reaction, the diene
ligand was modified for the higher enantioselectivity. Thus, the
tert-butyl in L5* was replaced by larger tert-alkyl groups, i.e., 1-
adamantyl (L7*), 3-methyl-3-pentyl (L8*), and 3-ethyl-3-heptyl
(
L9*). This modification was successful to increase the
enantioselectivity to 94%, 95%, and 97% ee with L7*, L8*, and
L9*, respectively (entries 8–10). The chiral bisphosphine ligands
are not the ligands of choice for the present asymmetric reaction,
because the enantioselectivity was generally low (53–65% ee)
and the formation of uncyclized product 5a was observed as a
[*]
Dr. F. Xue, Prof. Dr. T. Hayashi
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
side product (entries 11–13). The use of 40 mol% of K
base in dioxane/H O (10/1) is the optimized reaction condition.
The yield was lower with a smaller amount (5 mol%) of K PO
entry 14). The reaction with KOH as a base or those in
THF/H O and toluene/H O did not give better results than that
3 4
PO as a
2
21 Nanyang Link, Singapore 637371 (Singapore)
3
4
E-mail: hayashi@ntu.edu.sg
(
Supporting information for this article is given via a link at the end of
the document.
2
2
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Angewandte Chemie International Edition
10.1002/anie.201806324
COMMUNICATION
Table 2. Rhodium-catalyzed asymmetric benzannulation of alkynes 1 with 2-
under the optimized condition (entries 15–17). Palladium
[
a]
(
cyanomethyl)phenylborate 2.
complex Pd(OCOCF
3 2
) (dppe) efficiently catalyzed the reaction
of 1a with 2 giving a high yield of 3a in MeOH at 65 °C under the
R1
[RhCl(coe)2]2 (5.0 mol% Rh)
L9* (5.5 mol%)
K3PO4 (40 mol%)
NH2
R1
[
7]
conditions reported by Tsukamoto (entry 18), but the reaction
was very sluggish with chiral bisphosphine ligands in place of
dppe and the enantioselectivity was not high (entries 18–20) .
+
R1
R2
NH2
+
R2
dioxane/H2O (20/1), 22 °C, 16 h
R2
Bpin CN
O
1
2
3
4
N
H
Me
L9*
Table 1. Catalytic asymmetric benzannulation of 1-(1-naphthyl)propyne (1a)
[
a]
with 2-(cyanomethyl)phenylborate 2.
Me
NH2 Me
NH2 Me
MeO
NH2 Me
NH2 Me
CF3
NH2 Me
NC
NH2
Cl
NH
Me
2
Me
[
RhCl(coe)
L* (5.5 mol%)
PO (40 mol%)
dioxane/H O (20/1)
2 °C, 16 h
2 2
] (5.0 mol% Rh)
3a: 87% yield
3c: 95% yield
83% ee (R)
3c/4c = 95/5
3d: 95% yield
94% ee (R)
3d/4d = 98/2
3e: 78% yield
94% ee (R)
3e/4e = 87/13
3f: 84% yield
94% ee (R)
3f/4f = 97/3
+
+
+
CN
F
K
3
4
Me
NH
2
Me
9
7% ee (R)
3
a/4a = 90/10
3b: 85% yield
95% ee (R)
b/4b = 88/12
Bpin CN
2
2
3
1
a
2
3a
4a
5a
O
O
L1*: OR = O(2-naphthyl)
2 6 3
L2*: OR = O(2,6-(iPr) C H )
PPh
PPh2
2
O
O
PAr2
PAr
NH2 Me
O2N
NH2
NH2
NH2 Me
Me
NH2
OR
Me
Me
Me
Me
Me
Me
Me
L3*: NRR' = NHCH Ph
L4*: NRR' = NHPh
Ph
R,R)-Ph-bod
2
2
Me2N
Ph
L5*: NRR' = NHCMe
L6*: NRR' = NMeCMe
L7*: NRR' = NH(1-adamantyl)
3
(
O
O
3
(R)-binap
(R)-segphos: Ar = Ph
(R)-DTBMsegphos:
Ar = 3,5-(tBu)
3
g: 84% yield
3h: 94% yield
95% ee (R)
3i: 73% yield
95% ee (R)
3i/4i = 72/28
NRR'
L8*: NRR' = NHCEt
L9*: NRR' = NHCEt
2
2
Me
Bu
94% ee (R)
3
CN
3j: 85% yield
NO2
2
-4-MeOC
6
H
2
3k: 88% yield
96% ee (R)
3k/4k = 91/9
g/4g = 84/16
3h/4h = 97/3
9
5% ee (R)
3
j/4j = 90/10
[
c]
[d]
Entry Ligand L* on Rh and variations from Yield % ee Ratio
Yield
(%)
[
b]
[d]
standard conditions (shown above) (%)
of 3a
of
Cl
NH2
HO
MeO
NH2
of 3a
3a:4a of 5a
Et
NH2
Bu
NH2
NH2
Cl
Cl
Cl
Cl
Cl
1
2
3
4
5
6
(R,R)-Ph-bod
53
63
73
72
84
91
65 (R) 95:5
65 (R) 91:9
85 (R) 80:20
65 (R) 95:5
60 (R) 94:6
93 (R) 90:10
5
0
0
0
0
0
L1*
L2*
L3*
L4*
L5*
3l: 86% yield
4% ee (R)
l/4l = 89/11
3m: 86% yield
92% ee (R)
3m/4m = 88/12
3n: 81% yield
95% ee (R)
3n/4n = 86/14
3o: 72% yield
92% ee (R)
3o/4o = 76/24
3p: 71% yield
94% ee (R)
3p/4p = 88/12
9
3
NH2
Me
Me
NH2
Me
Bpin CN
6
Me
iPr
NH2
Me
+
iPr
Cl
7
8
9
L6*
L7*
L8*
21
92
90
60 (R) 95:5
94 (R) 94:6
95 (R) 89:11
0
0
0
3q: 62% yield
4q: 33% yield
97% ee (R)
3r: 92% yield
90% ee (R)
3r/4r = 96/4
7
2% ee (R)
3
q/4q = 64/36
[a] Reaction conditions: alkyne 1 (0.15 mmol), 2 (0.30 mmol), K PO (0.060
3
4
mmol, 40 mol%), [{RhCl(coe)
mmol), dioxane (0.50 mL), and H
2
}
2
] (0.0038 mmol, 5.0 mol% of Rh), L9* (0.0083
O (0.025 mL) at 22 °C for 16 h. The yields
1
0
1
L9*
87
81
97 (R) 89:11
53 (R) 90:10
0
5
2
1
1
1
1
1
1
1
1
(R)-binap
are Isolated yields. The ratios of 3/4 were determined by H NMR of the
crude reaction mixture. The % ee’s were determined by HPLC on chiral
stationary phase columns. Absolute configuration was determined by X-ray
crystal analysis of some of the products (see ref 15). [b] The reaction with
borate 6.
2
3
4
5
6
7
(R)-segphos
88
75
48
84
83
82
85
5
57 (R) 95:5
65 (R) 95:5
9
17
0
(R)-DTBMsegphos
L10*, K
3
PO
4
(5 mol%)
96
96
84
95
—
89:11
87:13
85:15
86:14
88:12
L10*, KOH (40 mol%)
0
The condition using chiral diene ligand L9* optimized for the
reaction of alkyne 1a (entry 11 in Table 1) was applied to several
other 1-arylalkynes 1 where the aryl groups are ortho-substituted
phenyl groups. The results are summarized in Table 2. High
enantioselectivity ranging between 94% and 96% ee was
observed in the reactions of 1-arylpropynes 1d-1i producing the
L10*, THF/H
2
O (10/1)
O (10/1)
0
L10*, toluene/H
2
0
[
[
[
e]
1
8
9
0
Pd(OCOCF
Pd(OCOCF
Pd(OCOCF
3
)
2
(dppe)
0
e]
e]
1
2
3
)
2
((R)-binap)
25 (S) 65:35
63 (R) 67:33
0
[f]
chiral biaryls substituted with 2-Cl 3d, 2-CF
3
3e, 2-CN 3f, 2-
3
)
2
((R)-segphos)
4
0
NMe 3g, 2-NO 3h, and 2-Me 3i. One exception is the reaction
2
2
[
4
a] Reaction conditions: 1a (0.15 mmol), 2 (0.30 mmol), K
0 mol%), [{RhCl(coe) ] (0.0038 mmol, 5.0 mol% of Rh), L* (0.0083 mmol),
dioxane (0.50 mL), and H O (0.025 mL) at 22 °C for 16 h. [b] Isolated yield. [c]
3
PO
4
(0.060 mmol,
of 2-MeO-substituted alkyne, which gave the corresponding
biaryl 3c with 83% ee. The regioselectivity in giving 2-naphthyl
products 3 over 1-naphthyl isomers 4 is generally high except for
the synthesis of 2-Me-substituted biaryl 3i where 3i/4i is 72/28.
This regioselectivity was improved by introducing electron-
2 2
}
2
The % ee was determined by HPLC on a chiral stationary phase column. [d]
The ratio of 3a:4a and the yield of 5a were determined by H NMR of the
1
crude reaction mixture. [e] In MeOH (0.50 mL) at 65 °C (ref 7). [f] In situ
3 2
generation from Pd(OCOCF ) and (R)-segphos.
withdrawing groups into the para-position of the 2-MeC
Thus, the alkynes bearing 4-CN-2-MeC and 4-NO -2-MeC
gave the corresponding biaryls 3j and 3k with the ratio of 3/4
6 4
H group.
6
H
3
2
6 3
H
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Angewandte Chemie International Edition
10.1002/anie.201806324
COMMUNICATION
being 90/10 and 91/9, respectively. The scope of the alkyl group
proceeds through β-methoxy elimination from intermediate D in
the catalytic cycle, which is consistent with the high yielding
reaction in aprotic solvent.
1
R in the alkyne 1 is broad. In addition to Me, longer alkyl groups
(
Et and Bu) and those containing functional groups such as OH,
OMe, and Cl, gave the corresponding biaryls 3l-3p with not
Me
[
(
RhCl(coe)2]2
5.0 mol% Rh)
lower than 92% ee. The minor 1-naphthyl isomer 4q, which was
i
+
L9* (5.5 mol%)
OMe
[Rh]
formed together with 3q in the reaction of 2-PrC
6
H
4
-substituted
Me
Cl
OH
Me
Cl
(3)
Cl
K3PO4 (40 mol%)
Bpin COOMe 16 h
O
alkyne, was found to have 97% ee, while the regioselectivity was
not high (64/36). The biaryl 3r, which is substituted with two
methyls and one amino on the 2-naphthyl moiety, was also
synthesized using boronate 6.
1
c
9
10
D
dioxane/H2O, 22 °C: 27% yield, 90% ee
2
dioxane/H O, 80 °C: 75% yield, 88% ee
dioxane, 80 °C:
90% yield, 88% ee
The reaction of 1,4-dialkynylnaphthalene 7a with borate 2
gave 73% yield of ternaphthalene 8a with >99% ee (eq 1). This
The axially chiral 2-aminobiaryls 3 obtained here may be
high
% ee is as expected because unfavored isomer is
applied to the asymmetric reactions where 2-amino-1,1’-
binaphthyl is used as a chiral catalyst or its precursor without
consumed as its meso isomer in this type of double asymmetric
[
16]
reaction system. Similarly, ternaphthalene 8b of >99% ee was
obtained from 1,5-isomer 7b under the same conditions (eq 2).
[18]
modifications. Two examples of transformation of (R)-3 into
2
,2’-diaminobiaryls, which are an important class of chiral
[
19]
auxiliaries,
are shown in Scheme 3. Oxidative homocoupling
[
20]
of (R)-3a with mCPBA
gave 2,2’-diamino-1,1’-binaphthyls 11
Me
Me
and 12, both of which have a unique quaternaphthyl backbone
with three axes of axial chirality (Scheme 3a). Reduction of nitro
group of (R)-3h (95% ee) gave another type of 2,2’-
diaminobiaryl (R)-14 (Scheme 3b). Protection of amino group in
Me
NH2
Me
NH2
2
(4 equiv)
2 (4 equiv)
(
1)
(2)
Same as
in Table 2
Same as
in Table 2
Me
NH2
H2N
Me
3
h forming amide 13 before palladium-catalyzed hydrogenation
Me
Me
is necessary because free diamine undergoes slow racemization
during the hydrogenation. The 2-aminobiaryl (R)-3a (97% ee)
was converted into 2-phosphinobiaryl (R)-16 by way of iodide
7
a
8a: 73% yield
7b
8b: 71% yield
>99% ee (R,R)
meso-8b: 16% yield
>
99% ee (R,R)
meso-8a: 15% yield
[
21]
1
5
without loss of enantiomeric purity (Scheme 3c). The
The absolute configuration (R) for the biaryl 3a obtained with
L9* ligand may well be rationalized by steric repulsions between
the bulky amido group on the ligand and benzo moiety of 1-
naphthyl group on alkyne 1a. The alkenyl-Rh intermediate B,
which is generated by addition of aryl-Rh A to alkyne 1a, adopts
the conformation shown in B to avoid the steric repulsions at
intramolecular attack to cyano group leading to imino-Rh
axially chiral phosphine (R)-16 was made enantiomerically pure
by recrystallization (90% recovery) and used as a ligand for
[22]
palladium-catalyzed asymmetric hydrosilylation of styrene
to
[23]
demonstrate its high efficiency as chiral ligand.
(a)
intermediate C, hydrolysis of which results in 3a with
R
H2N
Me
H2N
Me
a)
Me
NH2
+
configuration. All the biaryls 3 obtained with L9* ligand are
assumed to have the same absolute configuration (R).
Me
NH2
Me
NH2
(R,S,R)-12
(
R)-3a (97% ee)
(R,R,R)-11
Me
Me
(b)
(c)
1
a
H2O
C
(
R)-3a
[
Rh]
N
N
O
+
b), c)
NH2
d), e)
Me
[Rh] CN
N
[Rh]
Me
O N
NH2
Me
H N
NHCOCF3
Me
Y
[
Rh] OH
H
2
2
R
A
B
C
(
R)-3h (95% ee)
(R)-14 (95% ee)
by way of (R)-13
(R)-3a (97% ee)
Y = I: (R)-15 (97% ee)
Y = PPh2: (R)-16 (97% ee)
Scheme 2. Proposed stereochemical pathway to produce (R)-3a with the
chiral diene ligand L9*.
a) mCPBA, CF3COOH, (R,R,R)-11 (21%), (R,S,R)-12 (13%). b) (CF3CO)2O, CF3COOH, (R)-13 (81%).
t
c) H2, Pd/C, (R)-14 (93%). d) i) HCl, ii) NaNO2, iii) KI, (R)-15 (59%). e) i) Bu Li, ii) ClPPh2, (R)-16 (83%).
The asymmetric benzannulation is also successful with 2-
Scheme 3. Transformation of axially chiral biarylamines 3.
(
carbomethoxymethyl)phenylboronate 9, which produces axially
chiral biaryl bearing hydroxyl group at 2 position instead of
[
17]
amino group (eq 3). The reaction of boronate 9 was slower Acknowledgements
than that of the cyanomethyl analog 2, and the reaction of 9 with
alkyne 1c under the conditions used for 2 (dioxane/H
2 °C, 16 h) gave only a low yield (27%) of the benzannulation
product 10. Heating the reaction to 80 °C improved the yield of
0 to 75%, although the % ee was slightly decreased from 90%
2
O (10/1),
This work was supported by funding from Nanyang Techno-
logical University and the Singapore Ministry of Education (AcRF
MOE 2016-T1-001-247 and 2017-T2-1-064).
2
1
to 88%. The yield was higher under an aprotic condition (in
Keywords: axially chiral biaryl • asymmetric benzannulation •
dioxane) to give 90% yield of 10 with 88% ee. The reaction
chiral diene ligand • rhodium catalyst
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Angewandte Chemie International Edition
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COMMUNICATION
[
1]
For reviews on catalytic asymmetric synthesis of axially chiral biaryls: a)
P. Loxq, E. Manoury, R. Poli, E. Deydier, A. Labande, Coord. Chem.
Rev. 2016, 308, 131; b) B. Zilate, A. Castrogiovanni, C. Sparr, ACS
Catal. 2018, 8, 2981; c) D. Zhang, Q. Wang, Coord. Chem. Rev. 2015,
Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2007, 129, 6996. A pertinent
review: f) K. Tanaka, Chem. Asian J. 2009, 4, 508.
[7]
[8]
H. Tsukamoto, T. Ikeda, T. Doi, J. Org. Chem. 2016, 81, 1733.
a) R. Shintani, K. Okamoto, Y. Otomaru, K. Ueyama, T. Hayashi, J. Am.
Chem. Soc. 2005, 127, 54; b) R. Shintani, K. Okamoto, T. Hayashi,
Chem. Lett. 2005, 34, 1294; c) R. Shintani, A. Tsurusaki, K. Okamoto,
T. Hayashi, Angew. Chem. Int. Ed. 2005, 44, 3909; Angew. Chem.
2005, 117, 3977; d) T. Miura, T. Sasaki, H. Nakazawa, M. Murakami, J.
Am. Chem. Soc. 2005, 127, 1390; e) R. Shintani, S. Isobe, M. Takeda,
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23] See Supporting Information.
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Angewandte Chemie International Edition
10.1002/anie.201806324
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Fei Xue and Tamio Hayashi*
Page No. – Page No.
Asymmetric Synthesis of Axially
Chiral 2-Aminobiaryls by Rhodium-
Catalyzed Benzannulation of 1-
Arylalkynes with 2-
((Insert TOC Graphic here))
(
Cyanomethyl)phenylboronates
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Fei Xue and Tamio Hayashi*
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Asymmetric Synthesis of Axially
Chiral 2-Aminobiaryls by Rhodium-
Catalyzed Benzannulation of 1-
Arylalkynes with 2-
Asymmetric benzannulation of 1-arylalkynes, where the aryl group is ortho-
substituted aromatic group, with 2-(cyanomethyl)phenylboronate was catalyzed by
a rhodium complex coordinated with a chiral diene ligand to give high yields of
axially chiral 2-aminobiaryls with >90% ee.
(
Cyanomethyl)phenylboronates
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