Design and Synthesis of Chiral Diene Ligands for RhI-Catalyzed Enantioselective Arylation of N-DPP-protected Aldimines: Synthesis of the Antifungal Agent Bifonazole

Article abstract of DOI:10.1002/chem.201702509

Herein we describe the design and synthesis of a novel family of bifunctional, chiral bicyclo[2.2.1]heptadiene ligands bearing aryl and secondary amido groups, and demonstrate their usefulness in the Rh^I-catalyzed enantioselective addition reaction of arylboronic acids to N-diphenylphosphinyl (N-DPP)-protected aldimines. Unlike the analogous Rh^I-catalysts comprising diene ligands substituted with aryl and carboxylic ester groups, or only with aryl groups, the addition reaction proceeded with high stereoselectivity. The protocol tolerated a range of N-DPP-aldimines and arylboronic acids, producing the desired optically active N-DPP-protected amines with yields between 31–99 % and with ee values up to 91–99 %. The synthetic utility of the method was demonstrated by the conversion of N-DPP-protected amine 3 ae into the antifungal agent, bifonazole (13).

Full text of DOI:10.1002/chem.201702509

A Journal of
Accepted Article
Title: Design and Synthesis of Chiral Diene Ligands for Rh(I)-Catalyzed
Enantioselective Arylation of N-DPP-protected Aldimines:
Synthesis of the Antifungal Agent Bifonazole
Authors: Jin-Fong Syu, Huang-Ying Lin, Yu-Yi Cheng, Yao-Chu Tsai,
Yi-Ching Ting, Damodar Janmanchi, Ting-Shen Kuo, Ping-Yu
Wu, Julian P Henschke, and Hsyueh-Liang Wu
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201702509
Link to VoR: http://dx.doi.org/10.1002/chem.201702509
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10.1002/chem.201702509
Chemistry - A European Journal
FULL PAPER
Design and Synthesis of Chiral Diene Ligands for Rh(I)-Catalyzed
Enantioselective Arylation of N-DPP-protected Aldimines:
Synthesis of the Antifungal Agent Bifonazole
Jin-Fong Syu,[a] Huang-Ying Lin,[a] Yu-Yi Cheng,[a] Yao-Chu Tsai,[a] Yi-Ching Ting,[a] Ting-Shen Kuo,[a]
Damodar Janmanchi,[a] Ping-Yu Wu,[b] Julian P. Henschke[c] and Hsyueh-Liang Wu*[a]
Dedication ((optional))
Abstract: Herein we describe the design and synthesis of a novel
family of bifunctional, chiral bicyclo[2.2.1]heptadiene ligands bearing
aryl and secondary amido groups, and demonstrate their usefulness
in the Rh(I)-catalyzed enantioselective addition reaction of
arylboronic acids to N-diphenylphosphinyl- (N-DPP-) protected
aldimines. Unlike the analogous Rh(I)-catalysts comprising diene
ligands substituted with aryl and carboxylic ester groups, or with aryl
groups only, the addition reaction proceeded with high
stereoselectivity. The protocol tolerated a range of N-DPP-aldimines
and arylboronic acids offering the desired optically active N-DPP-
protected amines in 31–>99% yields and 91–>99% ee. The synthetic
utility of the method was demonstrated by the conversion of N-DPP-
protected amine 3ae into the antifungal agent, bifonazole (13).
transformation was subsequently explored using a variety of
chiral ligands and protected aldimines.[5] While N-
sulfonylaldimines are popular substrates, the arylation of N-
phosphinylaldimines has also been reported.[5a,h,j,q,r] In fact, we
ourselves have previously reported the efficient, enantioselective
and rapid Rh(I)-catalyzed addition reaction of arylboronic acids
to N-tosyl- and N-nosyl- (4-NO2-C6H4SO2) aldimines employing
chiral, 2,5-diaryl-substituted bicyclo[2.2.1]heptadiene ligands
under mild conditions;[6] the reaction could be performed at as
low as room temperature in the presence of only 1 mol% of the
Rh-catalyst in the industrially acceptable solvent MeOH.[6f]
Although we were able to apply the method to the concise
preparation
of
a
homochiral
1-phenyl
substituted
tetrahydroisoquinoline, removal of the N-tosyl protecting group
was troublesome. With this in mind we were prompted to extend
our catalyst system to the preparation of enantio-enriched
diarylmethylamines harboring more readily cleavable N-
protecting groups. Herein, we report the rational design of novel
family of secondary amido-substituted chiral diene ligands and
Introduction
Due to their use as intermediates and building blocks in the
preparation of pharmaceutically active compounds,[1] the need to
access optically pure diarylmethylamines has prompted
significant synthetic efforts towards their enantioselective
synthesis.[2] Among the reported methods, the asymmetric
arylation of imines employing aryl-organoboron reagents as pre-
nucleophiles offers high functional group tolerance and mild
reaction conditions, and benefits from the wide availability and
high stability of organoboron reagents.[3] In the pioneering
studies of Tomioka[4a] and Hayashi,[4b] Rh(I)-catalysts comprising
demonstrate
their
usefulness
in
the
Rh(I)-catalyzed
enantioselective arylation of N-DPP- (N-diphenylphosphinyl-)
aldimines with arylboronic acids.
Results and Discussion
Studies were initiated using previously[6f] optimized reaction
conditions for the Rh(I)-catalyzed enantioselective arylation of N-
sulfonylaldimines with chiral diene ligands L1 (Table 1). In the
presence of 3.0 mol% of the chiral Rh(I)-catalyst generated in
situ from [RhCl(C2H4)2]2 and chiral diene L1a, arylation of N-
DPP-imine 1a with p-tolylboronic acid (2a) in MeOH with Et3N at
30 °C resulted in the isolation of diarylmethylamine 3aa in a
disappointing 27% yield with 70% ee (entry 1); the yield of 3aa
was increased to 51% when the reaction temperature was
increased to 60 °C (entry 2). Using dioxane as solvent and KOH
(20 mol%) as an additive, 3aa was produced in a moderately
improved 67% yield and 85% ee (entry 3). Unfortunately, when
other members (L1b–L1e) of our diene ligand family bearing
various 2,5-substituents were tested (entries 4–7), the reaction
proceeded with less catalytic efficiency (28–57% yields) and
stereoselectivity (34–83% ees). Frustrated with the only
moderate catalytic activity and selectivity when employing
ligands L1 in current study, and given the important synthetic
utility of homochiral N-diphenylphosphinyl diarylmethylamines,
we sought to redesign our novel chiral diene ligand family for the
transformation.
chiral
amidomonophosphane
ligands
and
chiral
bicyclo[2.2.2]octadiene ligands were used in the efficient and
enantioselective arylation of N-sulfonylaldimines, offering
optically active N-sulfonyl protected diarylmethylamines. The
catalytic activity and enantioselectivity in this type of
[a]
J.-F. Syu, H.-Y. Lin, Y.-Y. Cheng, Y.-C. Tsai, Y.-C. Ting, T.-S. Kuo,
Prof. Dr. H.-L. Wu
Department of Chemistry, National Taiwan Normal University
No. 88, Section 4, Tingzhou Road, Taipei City 11677, Taiwan (ROC)
E-mail: hlw@ntnu.edu.tw
[b]
[c]
Dr. Ping-Yu Wu
Oleader Technologies Co., Ltd.
1F., No. 8, Aly. 29, Ln. 335, Chenggong Rd., Hukou Township,
Hsinchu County 30345, Taiwan (ROC)
Dr. Julian P. Henschke
ScinoPharm Taiwan,
No. 1, Nan-Ke Eighth Road, Tainan Science-Based Industrial Park
Shan-Hua, Tainan County 74144, Taiwan (ROC)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
1
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(a)
Table 1. Asymmetric addition of p-tolylboronic acid (2a) to N-DPP-aldimine 1a:
ligand (L1) effect.[a]
Rh(acac)(C2H4)2]2 (6.0 mol%)
P(O)Ph2
H
P(O)Ph2
Ar2
L2a (6.6 mol%)
N
HN
Ar1
Ar2B(OH)2
+
P(O)Ph2
dioxane/PrOH (5/1), MS 4Å
80 °C, 12 h
Ar1
[RhCl(C2H4)2]2 (3.0 mol% of Rh)
HN
Ph
(HO)2B
P(O)Ph2
H
L1 (3.3 mol%)
N
+
up to 96% yield
and 99% ee
solvent, additive, temp., 5 h
Ph
N
P(o-tolyl)2
1a (1.0 equiv)
2a (1.5 equiv)
3aa
O
L1a: Ar = 4-NO2-C6H4
L1b: Ar = C6H5
L1c: Ar = 4-Biphenyl
L1d: Ar = 1-Naphthyl
L1e: Ar = 2-Naphthyl
L2a
NHBoc
Ar
Ar
Yield
Temp (°C)
ee
(b)
Entry
L1
Solvent
Additive
[RhCl(C2H4)2]2 (2.5 mol%)
(%)[b]
(%)[c]
N
Ar
N
L2b (6.0 mol%)
Ar
X
Ar
X
ArB(OH)2
+
R
R
1
2
3
4
5
6
7
L1a
L1a
L1a
L1b
L1c
L1d
L1e
MeOH
MeOH
Et3N
30
60
60
60
60
60
60
27
51
67
47
57
28
55
70
KOH (2.5 equiv),80 °C (µW)
dioxane/H2O (9/1)
up to 95% yield
and 99% ee
Et3N
75
iPr
O
iPr
dioxane
dioxane
dioxane
dioxane
dioxane
aq. KOH
aq. KOH
aq. KOH
aq. KOH
aq. KOH
85
N
H
83
Me
iPr
L2b
(c)
77
PI/CB Rh/Ag (0.25 mol%)
O
O
Ar
L2c (0.05 mol%)
ArB(OH)2
+
34
R1
R2
R1
R2
toluene/H2O (1/2), 100 °C, 16 h
up to 97% yield
and >99.5% ee
80
O
N
H
[a] Solutions of 1a (0.15 mmol), 2a (0.225 mmol), [RhCl(C2H4)2]2 (1.5 mol%,
3.0 mol% of Rh), L1 (3.3 mol%) and Et3N (0.9 mmol), or aq. KOH (3.1 M, 9.75
μL, 30 μmol, 20 mol% based on 1a), in MeOH or dioxane were stirred at 30 °C
or 60 °C for 5 h. [b] Isolated yield. [c] Determined by chiral HPLC analysis.
Me
L2c
(d)
PI/CB Rh/Ag (0.5 mol%)
Ts
H
Ts
L2c (0.1 mol%)
N
HN
Ar2B(OH)2
+
In Tomioka’s studies of the arylation of aldimines, high
selectivities were obtained by utilizing proline-derived
monophosphine ligands harboring D- or L-N-Boc-valine moieties
connected by amide bonds (Scheme 1a).[4a,5j,q,r] Very recently,
chiral diene-containing amide functional groups have been
shown to be effective ligands. For example, Lam and coworkers
have reported the asymmetric arylation of alkenylazaarenes in
the presence of a Rh(I) catalyst comprising chiral diene ligand
L2b having a secondary amide functional group (Scheme 1b).[7a]
Kobayashi showed that the chiral diene analogue L2c displayed
high catalytic activity and selectivity, when utilized in conjunction
with a heterogeneous chiral Rh(I)-nanoparticle system, in both
the asymmetric arylation of α,β-unsaturated carbonyl
compounds (Scheme 1c)[7b] and of N-tosyl imines (Scheme
1d).[7c] Interestingly, Nishimura and coworker demonstrated that
that amido diene ligand L2d is useful in the Ir(I)-catalyzed
asymmetric [3+2] annulation of α-oxo iminocarboxamides
(Scheme 1e).[7d]
Inspired by these examples, and disappointed by the results
described above for the arylation of N-DPP-imine 1a, our family
of diaryl-substituted diene ligands L1 was redesigned by
replacing one aryl group with a secondary amido group. While
coordination of the Rh(I) metal to the diene moiety of the newly
devised ligands L4 was still expected to occur, activation of the
phosphinylaldimine by hydrogen bonding of the neighboring
acidic secondary amide proton to the phosphine oxide unit was
predicted to enhance both the efficiency and the
enantioselectivity of the arylation reaction, relative to that when
using ligands L1.
toluene/H2O (8/1), 100 °C, 16 h
Ar1
Ar1
Ar2
up to 96% yield
and 99% ee
(e)
O
[{Ir(OH)(L2d)}2]
(5 mol% Ir)
O
Ph
R2
Ph
TsN
+
TsHN
OH
toluene
R1
60 °C, 24 h
O
R2
R1
F
F
up to 96% yield
and 99% ee
F
F
Me
L2d
NHtBu
O
Scheme
1.
(a)
Enantioselective
arylation
of
N-DPP-aldimines.
(b) Enantioselective arylation of alkenylazaarenes. (c) Enantioselective
arylation of α,β-unsaturated carbonyl compounds. (d) Enantioselective
arylation of N-tosylimines. (e) Enantioselective annulation of α-
oxocarboxamides.
Synthesis of ligands L4
The preparation of ligand family L4 commenced with
diketone 4[6a] (Scheme 2). Formation of monotriflate 5 was
observed as the major regioisomer (13:1) in 83% yield when
diketone 4 was treated with KHMDS and Comins’ reagent[8] at
−78 °C; the sterically encumbered nature around the quaternary
2
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Pd(PPh3)4 (10 mol%)
ArB(OH)2, Na2CO3(aq)
KHMDS (1.1 equiv)
Comins' reagent (1.1 equiv)
KHMDS (1.1 equiv)
Comins' reagent (1.1 equiv)
O
OTf
Ar
Ar
THF, –78 °C
toluene / EtOH, reflux
THF, –78 °C, 83%
O
O
O
TfO
4
5
6a : Ar = C6H5 (99%)
6b : Ar = 1-Naphthyl (96%)
6c : Ar = 4-CF3-C6H4 (86%)
7a : Ar = C6H5 (86%)
7b : Ar = 1-Naphthyl (90%)
7c : Ar = 4-CF3-C6H4 (35%)
Pd(OAc)2 (10 mol%)
PPh3 (10 mol%), CO (1 atm)
DCC, DMAP, R2R3NH
CH2Cl2, 0 °C to rt
Ph
LiOH, THF / H2O, 50 °C
>99%
R2
Ar
Ar
DMF, NEt3, MeOH, 0 °C to rt
MeO2C
N
R3
HO2C
O
L4aa : R2 = n-propyl, R3 = H (69%)
9
8a : Ar = C6H5 (98%)
8b : Ar = 1-Naphthyl (75%)
8c : Ar = 4-CF3-C6H4 (69%)
DCC, DMAP, R1OH
CH2Cl2, 0 °C to rt
L4ab : R2 = (S)-1-phenylethyl, R3 = H (26%)
L4ac : R2 = (R)-1-phenylethyl, R3 = H (59%)
L4ad : R2 = benzyl, R3 = H (80%)
DCC, DMAP, BnNH2
CH2Cl2, 0 °C to rt
L4ae : R2 = 1-naphthylmethyl, R3 = H (62%)
L4af : R2 = 2-naphthylmethyl, R3 = H (46%)
L4ag : R2 = 4-biphenylmethyl, R3 = H (71%)
L4ah : R2 = R3 = ethyl (71%)
Ph
R1O
Ar
H
O
N
Ph
L3aa : R1 = 1-Naphthyl (68%)
L3ab : R1 = 2-Naphthyl (68%)
L4ai : R2 = benzyl, R3 = Me (57%)
O
L4bd : Ar = 1-Naphthyl (62%)
L4cd : Ar = 4-CF3-C6H4 (32%)
Scheme 2. Synthesis of novel ester- and amino-substituted chiral diene ligands.
mol% of the Rh(I) complex formed from amide-containing ligand
L4aa provided N-DPP-protected amine 3aa in 66% yield and
97% ee (entry 3). Reactions catalyzed by ligands L4ab and
L4ac gave 3aa in 48% yield with 96% ee and 81% yield with
98% ee, respectively, showing that L4ac imparted comparably
higher catalytic reactivity as a result of matching stereochemistry
(R)-phenylethylamine with the ligand backbone (entries 4 and 5).
While the reaction performed with the Rh(I) catalyst derived from
benzylamido-substituted ligand L4ad afforded 3aa in 96% yield
and 98% ee (entry 6) within the 6 h test period, the chemical
stereogenic center at C1 presumably prohibits deprotonation at
C6. Suzuki-Miyaura coupling of triflate 5 with phenylboronic acid
proceeded smoothly to furnish the corresponding styrene 6a in
99%. Subsequent triflation of the keto group of 6a using the
established reaction conditions afforded triflate 7a in high yield
(86%). The ensuing Pd(0)-catalyzed carbonylation[9] of 7a in the
presence of MeOH provided methyl ester 8a in a pleasing 98%
yield, which was then hydrolyzed under basic conditions to
provide carboxylic acid 9a in quantitative yield. In addition to the
desired amides, the intermediacy of carboxylic acid 9a allowed
access to other carbonyl derivatives. Thus DCC- (N,N’-
dicyclohexylcarbodiimide) mediated esterification or amidation of
9a yielded nonsymmetrically substituted chiral diene ligands
comprising a phenyl group, and ester (L3a) or amide groups
(L4a).[10] The structure of chiral diene L4ac was unambiguously
confirmed by X-ray crystallographic analysis.
yields
diminished
(17–63%)
upon
employing
naphthylmethylamido-substituted ligands L4ae–L4ag though
high levels of selectivity remained (96–97% ee) (entries 7–9). In
cases where low yields were witnessed, simply increasing the
reaction time led to significantly improved yields (e.g., entries 4,
7 and 11). Carrying out the reaction in the presence of
diethylamido-substituted ligand L4ah and N-benzyl-N-methyl-
substituted ligand L4ai, which both possess tertiary amide
groups, gave 3aa in only 36% and 35% yield, respectively, with
a low degree of stereoselectivity (9% ee, entry 10; 30% ee, entry
11). By reference to the other ligands in the series, including the
esters L3aa and L3ab, this result suggests that high asymmetric
induction requires the presence of a free NH group, as present
in secondary amides L4aa–L4ag. To explore the distal aryl
substituent effect of ligand family L4, L4bd and L4cd comprising
1-naphthyl and 4-CF3-phenyl groups at the C2-position were
prepared using the synthetic route described in Scheme 2; these
were selected based on the parent benzylamido-substituted
ligand L4ad showing the best combination of yield and ee in the
prior ligand screening (Table 2, entry 6). Under the reaction
conditions of entry 6, application of ligands L4bd and L4cd saw
the production of 3aa in 20% and 79% yield with 95% ee and
97% ee, respectively (entries 12 and 13).
Figure 1. Crystal structure of L4ac
With the new ligands in hand, the asymmetric addition reaction
of p-tolylboronic acid (2a) and aldimine 1a was tested (Table 2).
Whereas no reaction was observed within the 6 h test period
when employing Rh(I) complexes comprising ester-containing
chiral diene ligands L3aa and L3ab in dioxane in the presence
of KOH (entries 1 and 2), the same reaction in the presence of 3
3
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xylene, offering 3aa in low 24% and 37% yields with 91% and
96% ee, respectively (entries 1 and 2), the same reaction in
alcohol solvents gave 3aa in yields of 47–>99% and 89–96% ee
(entries 3–5). In DMF, 3aa was isolated in 52% and in 97% ee
after 6 h (entry 6). While using dioxane as solvent, replacing
KOH(aq) with Et3N provided an inferior outcome, giving rise to
3aa in 5% yield (entry 7). Reducing the loading of the catalyst
from 3.0 mol% to 1.5 mol% and 1.0 mol% in the presence of
KOH(aq) provided 3aa in 81% and 69% yields both with 94% ee,
albeit at the expense of reaction time (entries 8 and 9).
Table 2. Asymmetric addition of p-tolylboronic acid (2a) to N-DPP-aldimine 1a:
ligand effect (I).
P(O)Ph2
[RhCl(C2H4)2]2 (3.0 mol% of Rh)
HN
Ph
(HO)2B
P(O)Ph2
L3 or L4 (3.3 mol%)
N
+
dioxane, KOH(aq), 60 °C, 6 h
Ph
H
1a (1.0 equiv)
2a (1.5 equiv)
3aa
Entry[a]
L
Yield[b]
N.R.[d]
N.R.[d]
66
ee[c]
1
2
L3aa
L3ab
L4aa
L4ab
L4ac
L4ad
L4ae
L4af
L4ag
L4ah
L4ai
N.D.[e]
N.D.[e]
97
Table 3. Optimization of reaction conditions.
P(O)Ph2
[RhCl(C2H4)2]2 (x mol% of Rh)
HN
Ph
(HO)2B
3
P(O)Ph2
H
L4ad (1.1x mol%)
N
+
solvent, additive
60 °C, 6 h
4
48 (85)[f]
81
96
Ph
1a (1.0 equiv)
2a (1.5 equiv)
3aa
5
98
Entry[a]
x
Solvent
toluene
xylene
MeOH
EtOH
Additive
KOH
KOH
KOH
KOH
KOH
KOH
Et3N
Yield (%)[b]
ee (%)[c]
91
6
96
98
1
2
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.5
1.0
24
37
47
88
>99
52
5
7
17 (51)[f]
74
96
96
8
96
3
92
9
63
97
4
89
10
11
12
13
36
9
5
iPrOH
96
35
30
6
DMF
97
L4bd
L4cd
20 (46)[f]
79
95
7
dioxane
dioxane
dioxane
94
97
8[d]
9[e]
KOH
KOH
81
69
94
[a] Solutions of 1a (0.15 mmol), 2a (0.225 mmol), [RhCl(C2H4)2]2 (1.5 mol%,
3.0 mol% of Rh), L3 or L4 (3.3 mol%) and aq. KOH (3.1 M, 9.75 μL, 30 μmol)
in dioxane (0.8 mL) were stirred at 60 °C for 6 h. [b] Isolated yield. [c]
Determined by chiral HPLC. [d] No reaction. [e] Not determined. [f] Isolated
yield after 12 h.
94
[a] Solutions of 1a (0.15 mmol), 2a (0.225 mmol), [RhCl(C2H4)2]2, L4ad, and
aq. KOH (3.1 M, 9.75 μL, 30 μmol), or Et3N (0.9 mmol), in solvents were stirred
at 60 °C for 6 h. [b] Isolated yield. [c] Determined by chiral HPLC. [d] The
reaction was conducted for 10 h. [e] The reaction was conducted for 24 h.
The absolute configuration of 3aa was determined to be R
by comparing the optical rotation of 3aa ([α]ꢁꢀꢂ +10.0 (c 1.0,
CHCl3; 98% ee)) with the reported value for (S)-3aa (([α]ꢁꢀꢃ–11.0
(c 1.04, CHCl3; 98% ee)).[5j] Coordination of aldimine 1a with the
Si-face to the rhodium center and concurrent hydrogen bonding
between the N-H and P=O groups explains the observed
stereochemical outcome (Figure 2).
The reaction scope was investigated next employing
variously substituted arylboronic acids (Table 4) using the
reaction conditions established for the enantioselective addition
of p-tolylboronic acid (2a) to N-DPP-imine 1a. Reaction of alkyl-
or phenyl-substituted arylboronic acids with 1a furnished the
corresponding addition adducts in 59%–>99% yields and in
94%–>99% ee (entries 1–5). Arylboronic acids harboring
electron-donating (entries 6–9) or electron-withdrawing groups
(entries 12–18), or naphthylboronic acids (entries 10 and 11)
gave the corresponding addition products in 31%–>99% yields
and in 91%–99% ee. Poignantly, the steric hindrance of 1-
naphthylboronic acid (2j) (entry 10) and 2-substituted arylboronic
acids 2c, 2h and 2i (entries 3, 8 and 9), or the electronically
deficient nature of nitro-substituted arylboronic acids 2q and 2r
(entries 17 and 18), resulted in diminished chemical yields.
Bn
H
O
N
H
N
N
Rh
O
Tolyl
O
Tolyl
H
P
P
Ph
Ph
Ph
Ph
Figure 2. The proposed transition structure for the stereochemical outcome of
the 1,2-addition reaction of 1a and 2a catalyzed by Rh(I)/L4ad.
Examination of the solvent, additive, and the loading of the
Rh(I)-catalyst was studied next using ligand L4ad (Table 3).
While the chemical yield was negatively impacted in toluene and
4
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The reaction scope was expanded further by varying the
pendant aromatic group of the N-DPP-aldimines 1. Reaction of
3-methylbenzaldehyde-derived N-DPP-imine 1b with various
Table 4. Asymmetric addition of various arylboronic acids 2 to aldimines 1.
[RhCl(C2H4)2]2 (3 mol% of Rh)
P(O)Ph2
P(O)Ph2
L4ad (3.3 mol%)
N
HN
Ar1
Ar2B(OH)2
+
dioxane, KOH
60 °C, time
Ar1
H
Ar2
arylboronic
acids
furnished
the
corresponding
N-
1 (1.0 equiv)
2 (1.5 equiv)
3
diphenylphosphinyl-protected diarylmethylamines 3ab–3bo in
78%–97% yields and 94%–98% ee (entries 19–23). Good
chemical yields (55–77%) and enantioselectivity (92–96% ee)
were also obtained when reacting electrophiles 1c–1f, derived
from 4-fluoro- and 3,4-dimethoxy-benzaldehyde, 2-furaldehyde
and 2-thiophenecarboxaldehyde, with boronic acids 2c and 2s
(entries 24–27).
Conversion of phosphinyl-protected diarylmethylamine 3ae
into bifonazole (13; Mycospor®) was investigated next to
demonstrate the synthetic usefulness of the asymmetric addition
reaction described above (Scheme 3). Bifonazole (13),
comprising an imidazole ring appended to a diarylmethylamine
framework, is a broad-spectrum antifungal drug used for the
treatment of fungal infections of the skin that has also been
shown to harbor in vitro antibacterial activity against certain
Gram-positive bacteria.[11a]
t
Yield
(%)[b]
ee
Entry[a]
Ar1
Ar2
(h)
(%)[c]
1
2
3
4
5
6
7
8
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
4-Me-C6H4 (2a)
3-Me-C6H4 (2b)
2-Me-C6H4 (2c)
4-tBu-C6H4 (2d)
4-Ph-C6H4 (2e)
4-MeO-C6H4 (2f)
3-MeO-C6H4 (2g)
2-MeO-C6H4 (2h)
6
96 (3aa)
98 (3ab)
59 (3ac)
93 (3ad)
99 (3ae)
>99 (3af)
95 (3ag)
43 (3ah)
98
97
>99
94
95
91
99
97
6
16
7
7
16
6
18
The synthesis of 13 began with the efficient removal of the
N-diphenylphosphinyl protecting group of 3ae by treatment with
HCl in dioxane/MeOH at room temperature, providing primary
amine 11 in 96% yield. Alkylation of 11 with bromoacetaldehyde
diethyl acetal under basic conditions supplied secondary amine
12 in 77% yield. Treatment of 12 with butylformate under
refluxing temperature followed by amination and ring-closure in
the presence of ammonium acetate/acetic acid furnished the
target, bifonazole (13), in 55% yield over two steps; notably,
degradation of the enantio excess derived from the starting
material 3ae was not witnessed.
2,4-(MeO)2C6H3
9
C6H5 (1a)
7
67 (3ai)
96
(2i)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
C6H5 (1a)
C6H5 (1a)
1-Naphthyl (2j)
2-Naphthyl (2k)
4-CF3-C6H4 (2l)
3-CF3-C6H4 (2m)
4-F-C6H4 (2n)
7
51 (3aj)
>99 (3ak)
80 (3al)
93
94
98
96
92
96
97
93
95
95
95
98
96
94
96
7
C6H5 (1a)
15
15
11
16
10
16
17
10
10
19
19
19
17
C6H5 (1a)
75 (3am)
83 (3an)
90 (3ao)
61 (3ap)
35 (3aq)
31 (3ar)
97 (3ab)
86 (3be)
85 (3bf)
78 (3bg)
82 (3bo)
55 (3ca)
C6H5 (1a)
C6H5 (1a)
4-Cl-C6H4 (2o)
3-Cl-C6H4 (2p)
4-NO2-C6H4 (2q)
3-NO2-C6H4 (2r)
C6H5 (2s)
O
OEt
NH2
PPh2
C6H5 (1a)
Br
HCl in dioxane
HN
Ph
OEt
Ph
MeOH, rt, overnight
K2CO3, DMF
C6H5 (1a)
refulx, overnight
Ph
11 (96% yield)
Ph
3ae (95% ee)
C6H5 (1a)
3-Me-C6H4 (1b)
3-Me-C6H4 (1b)
3-Me-C6H4 (1b)
3-Me-C6H4 (1b)
3-Me-C6H4 (1b)
4-F-C6H4 (1c)
4-Ph-C6H4 (2e)
4-MeO-C6H4 (2f)
3-MeO-C6H4 (2g)
4-Cl-C6H4 (2o)
4-Me-C6H4 (2a)
EtO
HN
OEt
N
O
1)
N
, reflux overnight
H
BuO
2) AcONH4, AcOH, reflux, 3 h
Ph
Ph
Ph
Ph
12 (77% yield)
13 (55% yield after
2 steps, 95% ee)
Scheme 3. Synthesis of bifonazole (13) from 3ae.
3,4-(MeO)2C6H3
25
C6H5 (2s)
23
73 (3ds)
94
(1d)
26
27
2-furyl (1e)
C6H5 (2s)
C6H5 (2s)
8
77 (3es)
77 (3fs)
95
92
Finally, comparison of ligand L4ad to previously reported chiral
diene ligands that have shown good catalytic activity and
enantioselectivity in the arylation of N-tosyl protected aldimines
was investigated (Table 5). While 3aa was obtained in 96% yield
with 98% ee (Table 4, entry 1) from the addition of 4-tolylboronic
acid (2a) to aldimine 1a using ligand L4ad, under the same
conditions and reaction time Rh(I)-catalysts derived from chiral
diene ligands L5 and L6 provided less satisfactory results: 70%
2-thienyl (1f)
12
[a] 1a (0.15 mmol), 2a (0.225 mmol), [RhCl(C2H4)2]2 (1.5 mol%), L4ad (3.3
mol%), and aq. KOH (3.1 M, 9.75 μL, 30 μmol) in dioxane were stirred at 60 °C
for 6 h. [b] Isolated yield. [c] Determined by chiral HPLC. [d] The reaction was
conducted for 10 h. [e] The reaction was conducted for 24 h.
5
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10.1002/chem.201702509
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yield with 92% ee (Table 5, entry 1) and 75% yield with 96% ee
(entry 2), respectively. Moreover, no reaction was observed
when ligand L7 was tested. Given the poor results seen with
ester-containing ligands L3aa and L3ab (Table 2, entries 1 and
2), and the improved catalytic reactivity and selectivity of amide-
containing ligand L4ad, as compared to ligands L5, L6 and L7 in
Table 5 for example, we believe that the bicyclo[2.2.1] skeleton
and secondary amide of these diene ligands play a pivotal role
in achieving high yields and ees in the arylation of N-
diphenylphosphinyl protected aldimines. The asymmetric
addition reaction of 4-tolylboronic acid (2a) to N-Ts aldimine 14
proceeded, in the presence of the same catalytic system, in a
highly enantioselective fashion, affording the corresponding
adduct 15 in 88% yield with 97% ee (entry 5).
optical purities. To demonstrate the synthetic utility of the
method, synthesis of the antifungal agent bifonazole (13) was
conducted. Further investigations employing chiral amide-
containing diene ligands L4 for a variety of other asymmetric
transformations are currently being carrying out in our laboratory.
Experimental Section
General
All commercial chemicals and solvents were reagent grade and were
distilled before use. All reactions were carried out under an atmosphere
of argon or nitrogen gas. Reactions were monitored by TLC using Merck
60 F 254 silica gel plates; zones were detected visually under ultraviolet
irradiation (254 nm) or by spraying with KMnO4 solution followed by
heating with a heat gun or on a hot plate. Column chromatography was
conducted over silica gel. NMR spectra were recorded at room
temperature in deuterated solvents on Bruker spectrometers. Chemical
shifts δ were recorded in parts per million (ppm) and were reported
relative to the deuterated solvent signal for 13C NMR spectroscopy, the
residual 1H-solvent signal for 1H NMR spectroscopy and the signal of
H3PO4 for 31P NMR spectroscopy. First order spin multiplicities are
abbreviated as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet
of doublets), dq (doublet of quartet), quin (quintet) and sex (sextet);
mutiplets are abbreviated as (m). High-resolution mass spectra were
obtained using FAB, EI and ESI ionization methods. Optical rotations
were measured on a Jasco P-2000 polarimeter. Enantiomeric excess
was determined by HPLC analysis on a Chiralcel OD-H, Chiralpak AD-H,
or IB columns (Daicel Chemical Industries, Ltd). Substrates 1 were
Table 5. Asymmetric addition of p-tolylboronic acid (2a) to N-DPP-aldimine 1a:
ligand effect (II).
R
[RhCl(C2H4)2]2 (3.0 mol% of Rh)
HN
(HO)2B
R
H
L (3.3 mol%)
N
+
Ph
dioxane, KOH(aq)
60 °C, 6 h
Ph
1a R = P(O)Ph2
14 R = Ts
2a
3aa R = P(O)Ph2
15 R = Ts
Ph
H
O
Ph
R
Ph
H
Ph
L5
L6a: R = O-2-Naphthyl
L6b: R = NHCH2C6H5
L7
Entry[a]
imine
1a
L
L5
Yield[b]
70 (3aa)
75 (3aa)
63 (3aa)
N.R.[d]
ee[c]
prepared according to the literature.[5a] Boronic acids
2 that were
1
2
92
96
commercially available were used as supplied and/or were prepared
using methods reported in the literature.[12] Chiral diene ligands L1 were
prepared according to the reported procedure.[6a]
1a
L6a
L6b
L7
3
1a
92
Synthesis of 5: to a solution of compound 4 (2.0 g, 12.0 mmol) and
Comins’ reagent (4.7 g, 12.0 mmol) in THF (90 mL) was added KHMDS
(0.7 M, 10.4 mL, 7.3 mmol) dropwise at −78 °C under Ar atmosphere.
After being stirred for an additional hour, sat. NaHCO3 (aq) (100 mL) was
added. The aqueous layer was separated and extracted with ethyl
acetate (100 mL ×3). The combined organic layer was subsequently
washed with 5% NaOH (aq), water, brine, and dried over anhydrous
Na2SO4, filtered, and evaporated to give the crude product, which was
purified by column chromatography over silica gel (hexanes–EtOAc=
40:1) to give compound 5 (2.98 g, 83%).
4
1a
N.D.[e]
97
5[f]
14
L4ad
88 (15)ꢀ
[a] Solutions of 1a (0.15 mmol), 2a (0.225 mmol), [RhCl(C2H4)2]2 (1.5 mol%),
L4ad (3.3 mol%) and aq. KOH (3.1 M, 9.75 μL, 30 μmol) in solvents were
stirred at 60 °C for 6 h. [b] Isolated yield. [c] Determined by chiral HPLC. [d] No
reaction, even when the reaction was extended to 12 h. [e] Not determined.
[f] The reaction was conducted for 8 h.
(1S,4S)-1,7,7-trimethyl-5-oxobicyclo[2.2.1]hept-2-en-2-yl
trifluoromethanesulfonate (5)
Conclusion
[ꢄ]ꢆꢅꢇ +84.1 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.02 (s, 3H),
1.12 (s, 3H), 1.13 (s, 3H), 2.10 (d, J = 17.0 Hz, 1H), 2.15 (d, J = 17.0 Hz,
1H), 2.79 (d, J = 4.0 Hz, 1H), 5.71 (d, J = 4.0 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 8.9, 17.5, 19.6, 40.4, 53.8, 60.8, 64.2, 111.1, 118.4 (q, J
In conclusion, a novel family of chiral diene ligands L4 bearing
variously substituted amido groups has been developed. When
harboring a secondary amido group, these ligands are superior,
in terms of yield and stereoselectivity, to their non-amide
containing analogues L1a–L1e and L3 in the asymmetric
addition reaction of an array of arylboronic acids 2 to variously
substituted N- diphenylphosphinyl-protected aldimines 1.
Screening of these new ligands along with other experimental
parameters revealed that the reaction proceeded most efficiently
and selectivity in the presence of the catalyst formed from 3
mol% of Rh(I) and ligand L4ad in dioxane at 60 °C, furnishing N-
diphenylphosphinyl protected diarylmethylamines 3 with high
= 318.9 Hz), 160.7, 210.8; FTIR (KBr, neat) ν̃ 1754, 1623, 1428, 1248,
1217, 1140, 1077, 1027, 898, 857, 606 cm−1; HRMS (EI) m/z calcd for
C11H13O4F3S+ [M]+ 298.0487, found 298.0481.
Synthesis of compound 6: to a solution of compound 5 (1.0 g, 3.4
mmol), Pd(PPh3)4 (0.19 g, 0.17 mmol) and phenylboronic acid (0.82 g,
mmol) in toluene (11 mL) was added EtOH (3.6 mL) and sat. Na2CO3 (aq)
(5.5 mL) at rt under Ar atmosphere, and it was heated to reflux for 90
min., before sat. NH4Cl(aq) was added. The aqueous layer was separated
and extracted with ethyl acetate (36 mL ×3). The combined organic layer
6
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10.1002/chem.201702509
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was washed with brine and dried over anhydrous Na2SO4, filtered, and
evaporated to give the crude product, which was purified by column
chromatography over silica gel (hexanes–EtOAc= 9:1) to furnish
compound 6a (0.75 g, 99%).
9a (0.52 g, crude) which was used in the next step without further
purification.
(1S,4S)-4,7,7-trimethyl-5-phenylbicyclo[2.2.1]hepta-2,5-diene-2-
carboxylic acid (9a)
[ꢄ]ꢆꢅꢉ +69.0 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.11 (s, 3H),
1.16 (s, 3H), 1.25 (s, 3H), 3.53 (dd, J = 3.2, 0.8 Hz, 1H), 6.71 (d, J = 3.2
Hz, 1H), 7.16–7.21 (m, 2H), 7.22–7.28 (m, 1H), 7.29–7.37 (m, 2H), 7.63
(d, J = 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 10.5, 21.2, 21.4, 59.3,
67.3, 85.2, 126.2, 127.1, 128.2, 137.0, 138.4, 147.5, 156.5, 161.6, 169.7;
(1S,4S)-4,7,7-trimethyl-5-phenylbicyclo[2.2.1]hept-5-en-2-one (6a)
1
[ꢄ]ꢆꢅꢈ +376.6 (c 1.00, CHCl3); H NMR (400 MHz, CDCl3): δ 1.06 (s, 3H),
1.10 (s, 3H), 1.20 (s, 3H), 2.11 (d, J = 16.8 Hz, 1H), 2.18 (d, J = 16.8 Hz,
1H), 2.81 (d, J = 3.6 Hz, 1H), 5.93 (d, J = 3.6 Hz, 1H), 7.22–7.44 (m, 5H);
13C NMR (100 MHz, CDCl3): δ 11.9, 17.9, 19.6, 42.3, 54.9, 60.8, 67.2,
123.7, 126.3, 127.7, 128.3, 136.6, 157.3, 213.6; FTIR (KBr, neat) ν̃ 1740,
FTIR (KBr, neat) ν̃ 3754, 2985, 1676, 1596, 1444, 1391, 1315, 1216,
1594, 1482, 1432, 1388, 1177, 1026, 739, 694 cm−1; HRMS (EI) m/z
calcd for C16H18O+ [M]+ 226.1358, found 226.1357.
−
1099, 1041, 844, 754, 698 cm−1; HRMS (ESI) m/z calcd for C17H17O2
[M−H]− 253.1229, found 253.1223.
Synthesis of compound 7: to a solution of compound 6a (0.7 g, 3.1
mmol) in anhydrous THF (32 mL) was added KHMDS (0.7 M, 13.0 mL,
9.1 mmol) dropwise at −78 °C under Ar atmosphere. Comins’ reagent
(2.2 g, 6.2 mmol) in THF (14 mL) was added 10 min. later. After being
stirred for an additional hour, sat. NaHCO3 (aq) (35 mL) was added. The
aqueous layer was separated and extracted with ethyl acetate (35 mL
×3). The combined organic layer was subsequently washed with 5%
NaOH(aq), water, brine, and dried over anhydrous Na2SO4, filtered, and
evaporated to give the crude product, which was purified by column
chromatography over silica gel (hexanes–EtOAc= 40:1) to get compound
7a (0.95 g, 86%).
Synthesis of chiral diene ligands L3 and L4: to a dichloromethane
solution of acid 9 (1 mmol), alcohol or amine (1.1 mmol) and 4-
dimethylaminopyridine (0.2 mmol) were added. The solution was cooled
to 0 °C while dicyclohexylcarbodiimide (1.2 mmol) was added. After a
further 5 min. at 0 °C, the ice bath was removed and the reaction mixture
was stirred for 12 h at rt. The reaction mixture was filtered through a pad
of Celite. The filterate was dried over anhydrous Na2SO4, filtered and
evaporated to give the crude product, which was purified by silica gel
column chromatography to get L3 and L4.
Naphthalen-1-yl (1S,4S)-4,7,7-trimethyl-5-phenylbicyclo[2.2.1]hepta-
2,5-diene-2-carboxylate (L3aa)
Isolated in 68% yield. [ꢄ]ꢅꢆꢊ +293.82 (c 0.2, CH2Cl2); 1H NMR (400 MHz,
CDCl3): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.35 (s, 3H), 3.76 (d, J = 3.2 Hz, 1H),
6.85 (d, J = 3.2 Hz, 1H), 7.27–7.35 (m, 4H), 7.35–7.43 (m, 2H) 7.44–7.54
(m, 3H), 7.75 (d, J = 8.4 Hz, 1H), 7.83–7.91 (m, 3H); 13C NMR (100 MHz,
CDCl3): δ 10.7, 21.3, 21.7, 59.7, 67.4, 85.4, 118.2, 121.3, 125.5, 125.8,
126.3, 126.4, 127.1, 127.2, 128.0, 128.3, 134.7, 137.0, 138.5, 146.7,
(1S,4S)-4,7,7-trimethyl-5-phenylbicyclo[2.2.1]hepta-2,5-dien-2-yl
trifluoromethanesulfonate (7a)
[ꢄ]ꢆꢅꢉ +114 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 3H),
1.24 (s, 3H), 1.32 (s, 3H), 3.12 (dd, J = 3.2, 1.6 Hz, 1H), 6.13 (d, J = 1.6
Hz, 1H), 6.72 (d, J = 3.2 Hz, 1H), 7.19–7.25 (m, 2H), 7.27–7.33 (m, 1H),
7.34–7.43 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 11.1, 21.1, 21.3, 60.8,
64.4, 83.8, 118.5 (q, J = 319.2 Hz), 126.3, 127.3, 127.5, 128.3, 135.6,
147.6, 151.7, 156.8, 161.2, 163.6; FTIR (KBr, neat) ν̃ 1722, 1585, 1509,
1463, 1364, 1301, 1238, 1210, 1160, 1012, 803, 749, 698 cm−1; HRMS
136.8, 158.9, 166.6; FTIR (KBr, neat) ν̃ 2965, 1628, 1422, 1248, 1213,
1170, 1141, 1055, 838, 751, 608 cm−1; HRMS (EI) m/z calcd for
C17H17O3F3S+ [M]+ 358.0850, found 358.0849.
(ESI) cacld for C27H25O2+ [M + H]+ 381.1855, found 381.1857.
(1S,4S)-4,7,7-trimethyl-5-phenyl-N-propylbicyclo[2.2.1]hepta-2,5-
diene-2-carboxamide (L4aa)
Synthesis of compound 8: to a solution of compound 7a (0.8 g, 2.2
mmol), Pd(OAc)2 (50 mg, 0.22 mmol), PPh3 (59 mg, 0.22 mmol), Et3N
Isolated in 69% yield. [ꢄ]ꢅꢆꢉ +23.3 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3): δ 0.93 (t, J = 7.6 Hz, 3H), 1.11 (s, 3H), 1.14 (s, 3H), 1.23 (s, 3H),
1.55 (sex, J = 7.6 Hz, 2H), 3.28 (q, J = 7.6 Hz, 2H), 3.46 (d, J = 2.8 Hz,
1H), 5.71 (br, 1H), 6.68 (d, J = 3.4 Hz, 1H), 7.05 (d, J = 0.8 Hz, 1H),
7.17–7.23 (m, 2H), 7.23–7.28 (m, 1H), 7.28–7.36 (m, 2H); 13C NMR (100
MHz, CDCl3): δ 10.8, 11.4, 21.3, 21.5, 23.0, 41.2, 59.8, 66.5, 84.4, 126.2,
127.0, 128.2, 137.3, 137.8, 150.3, 151.6, 157.3, 165.3; FTIR (KBr, neat)
(0.48 mL) and MeOH (17 mL) in DMF (16 mL) at 0 °C was passed CO(g)
.
After saturation with CO(g), the reaction mixture was stirred for overnight
at rt. The mixture was then extracted with ethyl acetate (20 mL ×3), and
the combined organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and evaporated to give the crude product, which was
purified by column chromatography over silica gel (hexanes–EtOAc= 6:1)
to furnish compound 8a (0.59 g, 98%).
ν̃ 3366, 2930, 1704, 1649, 1521, 1449, 1375, 1345, 1226, 1077, 893,
760, 700 cm−1; HRMS (EI) m/z calcd for C20H25ON+ [M]+ 295.1936, found
(1S,4S)-methyl 4,7,7-trimethyl-5-phenylbicyclo[2.2.1]hepta-2,5-diene-
2-carboxylate (8a)
295.1937.
[ꢄ]ꢆꢅꢉ +136 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.12 (s, 3H),
1.17 (s, 3H), 1.25 (s, 3H), 3.56 (d, J = 3.2 Hz, 1H), 3.75 (s, 3H), 6.71 (d, J
= 3.2 Hz, 1H), 7.16–7.22 (m, 2H), 7.22–7.28 (m, 1H), 7.28–7.38 (m, 2H),
7.48 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 10.5, 21.1, 21.4, 51.2, 59.4,
66.8, 84.6, 126.1, 126.9, 128.1, 137.0, 138.2, 148.0, 156.7, 158.4, 165.6;
General procedures for rhodium-catalyzed 1,2-addition reactions:
Under a N2 atmosphere, to a mixture of [RhCl(C2H4)2]2 (0.88 mg, 2.25
μmol, 3.0 mol% of Rh), chiral ligand L4ad (1.7 mg, 5.0 μmol, 3.3 mol%),
aldimine 1 (0.15 mmol, 1.0 equiv) and arylboronic acid 2 (0.225 mmol,
1.5 equiv) was added dioxane (0.8 mL) and aqueous KOH (3.1 M, 9.75
μL, 30 μmol, 20 mol%). The resulting mixture was heated at 60 °C. After
TLC indicated complete consumption of arylboronic acid, the product
mixture was concentrated in vacuo and the residue was purified by
column chromatography over silica gel (hexanes–acetone= 5:1) to afford
the desired products 3aa as white solid (57.2 mg, 96% yield).
FTIR (KBr, neat) ν̃ 1727, 1468, 1366, 1254, 1144, 1029, 842, 762, 699
cm−1; HRMS (EI) m/z calcd for C18H20O2+ [M]+ 268.1463, found 268.1456.
Synthesis of compound 9: to a solution of compound 8a (0.49 g, 1.8
mmol) in THF–H2O (2:1, 35 mL) was added LiOH•H2O (0.46 g, 11.0
mmol) and the mixture was stirred at 50 °C for 12 h. The mixture was
neutralized with 2 N HCl, and the aqueous layer was separated,
extracted with chloroform (50 mL ×2). The combined organic layer was
dried over anhydrous Na2SO4, filtered, and evaporated to give the acid
(R)-P,P-diphenyl-N-phenyl(p-tolyl)methyl)phosphinic amide (3aa)[5j]
The ee was determined on a Chiralcel OD-H column with hexane–2-
propanol= 9:1, flow= 1 mL/min., wavelength= 210 nm. Retention times:
7
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10.1002/chem.201702509
Chemistry - A European Journal
FULL PAPER
11.68 min. (minor), 13.39 min. (major). 98% ee; [ꢄ]ꢆꢅꢋ +10.0 (c 1.00,
CHCl3); M.p. 179.0–179.2 °C; 1H NMR (500 MHz, CDCl3): δ 2.32 (3H, s),
3.65 (dd, J = 10.1, 6.7 Hz, 1H), 5.42 (dd, J = 10.9, 10.8 Hz, 1H), 7.10 (d,
J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.19–7.25 (m, 1H), 7.25–7.31
(m, 4H), 7.32–7.40 (m, 4H), 7.42–7.49 (m, 2H), 7.79–7.88 (m, 4H); 13C
NMR (125 MHz, CDCl3): δ 21.0, 58.3, 127.0, 127.45, 127.48, 128.27,
128.28, 128.4, 129.1, 131.8 (d, J = 2.5 Hz), 132.2 (d, J = 10.0 Hz),
132.36 (d, J = 128.8 Hz), 132.38 (d, J = 128.8 Hz), 136.8, 140.4 (d, J =
5.0 Hz), 143.5 (d, J = 5.0 Hz); 31P NMR (202 MHz, CDCl3): δ 23.4.FTIR
(R)-1-(biphenyl-4-yl(phenyl)methyl)-1H-imidazole (13)
55% yield after 2 steps, 95% ee. The ee was determined on a Chiralcel
AD-H column with hexane/2-propanol= 9:1, flow= 1 mL/min, wavelength=
210 nm. Retention times: 13.33 min (minor), 17.04 min (major). [ꢄ]ꢅꢌꢊ
+3.67 (c 1.00, CHCl3). M.p. 167.2–167.6 °C. 1H NMR (500 MHz): δ 6.56
(s, 1H), 6.90 (s, 1H), 7.09–7.21 (m, 5H), 7.32–7.51 (m, 7H), 7.54–7.62 (m,
4H). 13C NMR (125 MHz): δ 64.8, 119.4, 127.1, 127.55, 127.63, 128.1,
128.4, 128.5, 128.86, 128.92, 129.4, 137.4, 138.1, 139.1, 140.2, 141.3.
FTIR (KBr neat) ν̃ 3442, 2924, 2096, 2639, 1489, 1076, 730, 699, 661
(KBr, neat) ν
̃
3171, 3056, 2922, 1595, 1440, 1189, 725, 751, 697, 539
cm−1. HRMS (FAB): m/z Calcd for C22H18N2Na+ [M + Na]+ 333.1368,
found 3333.1377.
cm−1; HRMS (FAB): m/z Calcd for C26H25NOP+ [M + H]+ 398.1674, found
397.1684.
Synthesis of Bifonazole (13): to a 5 mL round bottom were added 3ae
(50 mg, 0.18 mmol), MeOH (0.7 mL) and HCl (0.42 mL, 7.2 M solution in
dioxane, 3.02 mmol) at room temperature. After being stirred at r.t. for
14 h, brine (5 mL) was added to the mixture. The mixture was extracted
with Et2O (10 mL ×4). After separation, the organic layer was washed
with sat. NaHCO3 (aq), brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo and the residue was purified by column
chromatography over silica gel (hexanes–EtOAc= 4:1 afford amine 11
(27 mg, 96%)
Acknowledgements ((optional))
Financial support from Ministry of Science and Technology of
Republic of China (102-2113-M-003-006-MY2 & 104-2628-M-
003-001-MY3) is gratefully acknowledged.
Keywords: rhodium catalysis • 1,2-addition reaction •
arylboronic acids • phosphinylaldimines • bifonazole
(R)-(4-Biphenylyl)phenylmethylamine (11)
[ꢄ]ꢆꢅꢌ +12.6 (c 1.00, CHCl3). M.p. 74–75 °C. 1H NMR (400 MHz, CD3OD):
δ 5.20 (s, 1H), 7.21–7.27 (m, 1H), 7.29–7.37 (m, 3H), 7.38–7.47 (m, 6H),
7.56–7.64 (m, 4H). 13C NMR (100 MHz, CD3OD): δ 61.3, 128.8, 128.87,
128.89, 129.1, 129.4, 130.4, 130.7, 142.0, 143.0, 146.4, 147.2. FTIR
[1]
a) C. M. Spencer, D. Foulds, D. H. Peters, Drugs 1993, 46, 1055–1080;
b) M. J. Bishop, R. W. McNutt, Bioorg. Med. Chem. Lett. 1995, 5,
1311–1314; c) S. Sakurai, N. Ogawa, T. Suzuki, K. Kato, T. Ohashi, S.
Yasuda, H. Kato, Y. Ito, Chem. Pharm. Bull. 1996, 44, 765–777; d) S. N.
Calderon, K. C. Rice, R. B. Rothman, F. Porreca, J. L. Flippen-
Anderson, H. Kayakiri, H. Xu, K. Becketts, L. E. Smith, E. J. Bilsky, P.
Davis, R. Horvath, J. Med. Chem. 1997, 40, 695–704; e) J. L. Devalia,
C. De Vos, F. Hanotte, E. Baltes, Allergy 2001, 56, 50–57; f) D. Ameen,
T. J. Snape, Med. Chem. Comm. 2013, 4, 893–907.
(KBr, neat) ν̃ 3292, 3029, 2927, 2848, 1621, 1478, 1272, 842, 757, 696
cm−1. HRMS (TOF MS ES+): m/z Calcd for C19H15 [M - NH2]+ 243.1168,
found 243.1242.
+
To amine 11 (24 mg, 0.09 mmol), bromoacetaldehyde diethyl acetal
(27.8 µL, 0.19 mmol), anhydrous K2CO3 (63.9 mg, 0.46 mmol), and
CH3CN (4 mL) were added. After being stirred at 120 °C for 2 days, the
reaction mixture was cooled to r.t., concentrated in vacuo and the residue
was purified by column chromatography over silica gel (Et2O–hexanes=
1:3) to afford the desired products 12 as a yellow oil (27 mg, 77%).
[2]
a) F. Schmidt, R. T. Stemmler, J. Rudolph, C. Bolm, Chem. Soc. Rev.
2006, 35, 454–470; b) S. Kobayashi, Y. Mori, J. S. Fossey, M. M. Salter,
Chem. Rev. 2011, 111, 2626–2704.
[3]
[4]
a) C. S. Marques, A. J. Burke, Chem. Cat. Chem. 2011, 3, 635–645; b)
P. Tien, H.-Q. Dong, G.-Q. Lin, ACS Catal. 2012, 2, 95–119.
a) M. Kuriyama, T. Soeta, X. Hao, Q. Chen, K. Tomioka, J. Am. Chem.
Soc. 2004, 126, 8128–8129; b) N. Tokunaga, Y. Otomaru, K. Okamoto,
K. Ueyama, R. Shintani, T. Hayashi, J. Am. Chem. Soc. 2004, 126,
13584–13585.
(R)-N-([1,1'-biphenyl]-4-yl(phenyl)methyl)-2,2-diethoxyethan-1-amine
(12)
[ꢄ]ꢆꢅꢌ −12.6 (c 1.10, CHCl3).1H NMR (400 MHz, CDCl3): δ 1.20 (t, J = 7.0
Hz, 6H), 2.74 (d, J = 5.6 Hz, 2H), 3.53 (dq, J = 9.2, 7.2 Hz, 2H), 3.68 (dq,
J = 9.2, 7.2 Hz, 2H), 4.67 (t, J = 5.6 Hz, 1H), 4.88 (s, 1H), 7.19–7.25 (m,
1H), 7.27–7.35 (m, 3H), 7.38–7.49 (m, 6H), 7.49–7.57 (m, 4H). 13C NMR
(100 MHz, CDCl3): δ 15.4, 50.4, 62.2, 67.0, 102.2, 127.0, 127.05, 127.09,
127.2, 127.3, 127.7, 128.5, 128.7, 139.9, 140.9, 143.1, 144.0. FTIR (KBr,
[5]
a) D. J. Weix, Y. Shi, J. A. Ellman, J. Am. Chem. Soc. 2005, 127,
1092–1093; b) Y. Otomaru, N. Tokunaga, R. Shintani, T. Hayashi, Org.
Lett. 2005, 7, 307–310; c) H.-F. Duan, Y.-X. Jia, L.-X. Wang, Q.-L.
Zhou, Org. Lett. 2006, 8, 2567–2569; d) R. B. C. Jagt, P. Y. Toullec, D.
Geerdink, J. G. de Vries, B. L. Feringa, A. D. J. Minnaard, Angew.
Chem. 2006, 118, 2855–2857; Angew. Chem., Int. Ed. 2006, 45, 2789–
2791; e) C. Marelli, C. Monti, C. Gennari, U. Piarulli, Synlett 2007,
2213–2216; f) H. Nakagawa, J. C. Rech, R. W. Sindelar, J. A. Ellman,
Org. Lett. 2007, 9, 5155–5157; g) Z.-Q. Wang, C.-G. Feng, M.-H. Xu,
G.-Q. Lin, J. Am. Chem. Soc. 2007, 129, 5336–5337; h) M. Trincado, J.
A. Ellman, Angew. Chem. 2008, 120, 5705–5708; Angew. Chem., Int.
Ed. 2008, 47, 5623–5626; i) J. A. Bishop, S. Lou, S. E. Schaus, Angew.
Chem. 2009, 121, 4401–4404; Angew. Chem., Int. Ed. 2009, 48, 4337–
4340; j) X. Hao, M. Kuriyama, Q. Chen, Y. Yamamoto, K.-I. Yamada, K.
Tomioka, Org. Lett. 2009, 11, 4470–4473; k) K. Kurihara, Y. Yamamoto,
N. Miyaura, Adv. Synth. Catal. 2009, 351, 260–270; l) K. Okamoto, T.
Hayashi, V. H. Rawal, Chem. Commun. 2009, 4815–4817; m) Z. Cao,
H. Du, Org. Lett. 2010, 12, 2602–2605; n) C. Shao, H.-J. Yu, N.-Y. Wu,
C.-G. Feng, G.-Q. Lin, Org. Lett. 2010, 12, 3820–3823; o) H.-Y. Yang,
M.-H. Xu, Chem. Commun. 2010, 46, 9223–9225; p) Z. Cui, H.-J. Yu,
R.-F. Yang, W.-Y. Gao, C.-G. Feng, G.-Q. Lin, J. Am. Chem. Soc. 2011,
133, 12394–12397; q) X. Hao, Q. Chen, M. Kuriyama, K.-I. Yamada, Y.
neat) ν
̃
3020, 2971, 2921, 1671, 1604, 1482, 1445, 1124, 1064, 822cm−1
.
+
HRMS (FAB): m/z Calcd for C25H30NO2 [M + H]+ 376.2277, found
376.2278.
To amine 12 (34 mg, 0.09 mmol) was added butyl formate (5 mL) and the
mixture was refluxed for overnight. After cooling down to r.t., the mixture
was concentrated in vacuo and the residue was passed through a short
path of silica gel (Et2O–hexanes= 1:3) to remove unreacted butyl formate.
The resulting product were added AcONH4 (45 mg, 0.58 mmol) and
glacial acetic acid (1.4 mL). The mixture was refluxed for 3 h, cooled
down to r.t., and concentrated in vacuo. To the residue, a saturated
solution of Na2CO3 (0.32 mL) was added. The aqueous layer was
extracted with EtOAc (3 mL ×3). The combined organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The crude was purified by column
chromatography over silica gel (EtOAc) to provide 13 (17 mg, 0.05 mmol).
8
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Yamamoto, K. Tomioka, Catal. Sci. Technol. 2011, 1, 62–64; r) X. Hao,
Q. Chen, K.-I. Yamada, Y. Yamamoto, K. Tomioka, Tetrahedron 2011,
67, 6469–6473; s) T. Korenaga, A. Ko, K. Uotani, Y. Tanaka, T. Sakai,
Angew. Chem. 2011, 123, 10891–10895; Angew. Chem., Int. Ed. 2011,
50, 10703–10707; t) R. Shintani, R. Narui, Y. Tsutsumi, S.; Hayashi, T.
Hayashi, Chem. Commun. 2011, 47, 6123–6125; u) Y.-J. Chen, Z. Cui,
C.-G. Feng, G.-Q. Lin, Adv. Synth. Catal. 2015, 357, 2815–2820; v) N.
Sieffert, J. Boisson, S. Py, Chem. Eur. J. 2015, 21, 9753–9768; w) T.
Yasukawa, T. Kuremoto, H. Miyamura, S. Kobayashi, Org. Lett. 2016,
18, 2716–2718.
Henschke, H.-L. Wu, Asian J. Org. Chem. 2016, 5, 481–485; j) J.-F.
Syu, Y.-T. Wang, K.-C. Liu, P.-Y. Wu, J. P. Henschke, H.-L. Wu, J. Org.
Chem. 2016, 81, 10832–10844; k) J.-H. Fang, J.-H. Jian, H.-C. Chang,
T.-S. Kuo, W.-Z. Lee, P.-Y. Wu, H.-L. Wu, Chem. Eur. J. 2017, 23,
1830–1838.
[7]
a) Roy, I. D.; Burns, A. R.; Pattison, G.; Michel, B.; Parker, A. J.; Lam,
H. W. Chem. Commun., 2014, 50, 2865–2868; b) Yasukawa, T.; Suzuki,
A.; Miyamura, H.; Nishino, K.; Kobayashi, S. J. Am. Chem. Soc. 2015,
137, 6616–6623; c) Yasukawa, T.; Kuremoto, T.; Miyamura, H.;
Kobayashi, S. Org. Lett. 2016, 18, 2716–2718; d) Hatano, M.;
Nishimura, T. Angew. Chem. 2015, 127, 11099–11102; Angew. Chem.,
Int. Ed. 2015, 54, 10949–10952.
[6]
a) W.-T. Wei, J.-Y. Yeh, T.-S. Kuo, H.-L. Wu, Chem. Eur. J. 2011, 17,
11405–11409; b) C.-C. Liu, D. Janmanchi, C.-C. Chen, H.-L. Wu, Eur. J.
Org. Chem. 2012, 2503–2507; c) Y.-C. Chung, D. Janmanchi, H.-L. Wu,
Org. Lett. 2012, 14, 2766–2769; d) K.-C. Huang, B. Gopula, T.-S. Kuo,
C.-W. Chiang, P.-Y. Wu, J. P. Henschke, H.-L. Wu, Org. Lett. 2013, 15,
5730–5733; e) B. Gopula, C.-W. Chiang, W.-Z. Lee, T.-S. Kuo, P.-Y.
Wu, J. P. Henschke, H.-L. Wu, Org. Lett. 2014, 16, 632–635; f) C.-C.
Chen, B. Gopula, J.-F. Syu, J.-H. Pan, T.-S. Kuo, P.-Y. Wu, J. P.
Henschke, H.-L. Wu, J. Org. Chem. 2014, 79, 8077–8085; g) B. Gopula,
Y.-F. Tsai, T.-S. Kuo, P.-Y. Wu, J. P. Henschke, H.-L. Wu, Org. Lett.
2015, 17, 1142–1145; h) B. Gopula, S.-H. Yang, T.-S. Kuo, J.-C. Hsieh,
P.-Y. Wu, J. P. Henschke, H.-L. Wu, Chem. Eur. J. 2015, 21, 11050–
11055; i) J.-H. Fang, C.-A. Chang, B. Gopula, T.-S. Kuo, P.-Y. Wu, J. P.
[8]
[9]
Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299–6302.
Barnard, C. F. J. Organometallics, 2008, 27, 5402–5422.
[10] Neises, B.; Steglich, W. Angew. Chem. 1978, 90, 556–557; Angew.
Chem. Int. Ed. 1978, 17, 522–524.
[11] a) Lackner, T. E.; Clissold, S. P. Drugs 1989, 38, 204–225; b) Botta, M.;
Corelli, F.; Gasparrini, F.; Messina, F.; Mugnaini, C. J. Org. Chem.
2000, 65, 4736–4739; c) Castagnolo, D.; Giorgi, G.; Spinosa, R.; Corelli,
F.; Botta, M. Eur. J. Org. Chem. 2007, 3676–3686.
[12] A. S. Paraskar, A. Sudalai, Tetrahedron 2006, 62, 4907–4916.
9
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[RhCl(C2H4)2]2 (3.0 mol% of Rh)
P(O)Ph2
H
P(O)Ph2
Ar2
Ph
L4ad (3.3 mol%)
N
HN
Ar1
Ar2B(OH)2
+
BnHN
Page No. – Page No.
KOH (20 mol%), 60 °C
dioxane / H2O
Ar1
O
L4ad
Title
27 examples
up to >99% yields
up to >99% ee
The design, synthesis and testing of a novel set of chiral diene ligands bearing
amido groups for the highly enantioselective 1,2-arylation reactions of N-
diphenylphosphinyl-protected aldimines is described. In the presence of 3 mol% of
the chiral Rh(I)/L4ad catalyst at 60 °C in dioxane, the corresponding addition
products were isolated in yields of 31–>99% in 91–>99% ee.
10
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