Organocatalytic Enantioselective Synthesis of Chiral Diarylmethylamines from Racemic Alcohols

Article abstract of DOI:10.1002/cjoc.201800135

An organocatalytic approach for direct conversion of racemic diarylmethanols to valuable chiral diarylmethylamines is described. Different from the previously reported elegant “borrowing hydrogen” approach, the present process employs a distinct complementary formal S_N1 strategy. This approach enjoys excellent enantioselectivity, mild conditions, broad scope, and easy product derivatization. Mechanistically, control experiments also provided important insights into some notable features, such as substrate kinetic resolution and reversibility as well as the critical role of the ortho- hydroxy group in the substrate.

Full text of DOI:10.1002/cjoc.201800135

Organocatalytic Enantioselective Synthesis of Chiral Diarylmethylamines
from Racemic Alcohols
Min Chen, +a Yaodong Han,+a Dengke Ma,+a Yong Wanga, Zengwei Laia and Jianwei Sun *a
ABSTRACT An organocatalytic approach for direct conversion of racemic diarylmethanols to valuable chiral diarylmethylamines is described. Different
from the previously reported elegant “borrowing hydrogen” approach, the present process employs a distinct complementary formal SN1 strategy. This
approach enjoys excellent enantioselectivity, mild conditions, broad scope, and easy product derivatization. Mechanistically, control experiments also
provided important insights into some notable features, such as substrate kinetic resolution and reversibility as well as the critical role of the
ortho-hydroxy group in the substrate
KEYWORDS amination, asymmetric catalysis, nucleophilic substitution, chirality, organocatalysis
biased bis(alkyl) groups (i.e., R1 and/or R2 = alkyl), unfortunately,
Introduction
their capability for the synthesis of chiral diarylmethylamines
(both R1 and R2 = aryl) has not been demonstrated so far. This
Chiral diarylmethylamines are important structural motifs
widely present in natural products, pharmaceuticals, and other
limitation might be due to the challenging steric differentiation of
bioactive molecules of strong relevance to human health (Figure
the two aryl groups in the enantiodetermining imine
1).[1] Moreover, they also serve as key chiral backbones of some
hydrogenation step.
useful ligands in organic synthesis, such as Ming-Phos developed
by Zhang and co-workers.[2] Owning to their ubiquitous versatility,
Scheme 1 Catalytic Asymmetric Synthesis of Chiral Amines from Racemic
substantial efforts from the synthetic community have been
devoted to the efficient assembly of enantioenriched
diarylmethylamines in the past two decades.[3] Consequently, a
wide variety of catalytic asymmetric approaches have been
developed, including kinetic resolution, desymmetrization, aryl
addition to imines, and asymmetric hydrogenation, etc.[3] Notably,
metal catalysis has been dominant in these reactions. Here we
Alcohols.
describe
a
new organocatalytic approach for highly
enantioselective synthesis of chiral diarylmethylamines from
racemic diarylmethanols.
In the above contexts, it is thus highly desirable to develop a
complementary protocol for the analogous direct conversion of
racemic diarylmethanols to enantioenriched diarylmethylamines.
We hypothesized a completely different approach to address the
above limitation. Instead of using “borrowing hydrogen” strategy,
we envisioned a formal SN1 strategy, namely, the reaction will
proceed via initial formation of a carbocation, which can be
stabilized by the two aryl groups. Furthermore, rather than
employing metal or enzymatic catalysis, an organocatalytic
approach is employed.
Figure 1 Useful chiral diarylmethylamine derivatives.
Recently, direct asymmetric amination of readily accessible
racemic secondary alcohols has been demonstrated to be a highly
attractive approach for expedient synthesis of chiral amines
(Scheme 1a).[4] Pioneered by Zhao, Dong & Guan, Beller, Zhou,
and Turner, etc., these elegant processes via “borrowing
hydrogen” strategy proceed very efficiently through an
intrinsically well-organized one-pot multistep sequence
comprising dehydrogenation to ketone and imine formation
followed by asymmetric imine hydrogenation. While such
state-of-the-art protocols proved successful for highly
enantioenriched methinylamines with alkyl/aryl or sterically
Results and Discussion
In order to differentiate the two aryl groups with subtle steric
difference in the C‒N bond formation step, here we hypothesized
that introduction of a removable hydrogen bonding anchor (e.g.,
hydroxy group) would be helpful, particularly when hydrogen
a The Hong Kong University of Science and Technology (HKUST) Shenzhen
Research Institute, Shenzhen, China; Department of Chemistry, HKUST, Clear
Water Bay, Kowloon, Hong Kong SAR, China
+ These authors contributed equally to this work.
E-mail: sunjw@ust.hk
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800135
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bonding catalysis is employed (Table 1). With this in mind, we
started to test our hypothesis with racemic 1a as the model
noting that in some cases the free hydroxy group in the product
was protected immediately before work-up to minimize erosion of
substrate and p-toluenesulfonamide (TsNH2) 2a as the nucleophile. the product optical purity and also simplify purification, as the
Chiral phosphoric acids were employed as potential catalyst.[5]
Initially, range of BINOL-derived phosphoric acids were
nucleophile has similar polarity with the product. The mild
conditions can tolerate various functional groups. This process is
not limited to arenesulfonamide nucleophiles. Other easily
deprotectable nitrogen-based nucleophiles, such as BocNH2 and
CbzNH2, exhibit equally excellent performance. Secondary amide
BocNH(OBn) is also suitable. These results indicate that our
process allows straightforward access to other chiral
diarylmethylamine analogues by simple modification of the
substituents on the nitrogen atom.
a
evaluated. Unfortunately, the well-known TRIP catalyst A1
showed no reactivity (Table 1, entry 1), presumably due to the too
bulky substituents in the 3,3’-positions. Gratifyingly, variation to
other substituents in the BINOL-based catalysts did afford the
desired diarylmethylamine 3a, albeit with moderate efficiency and
enantioselectivity (entries 2-4). Among these catalysts, the one
with 1-naphthyl substituent was most promising in terms of
enantioselectivity. Evaluation of other catalysts indicated that the
Scheme 2 Reaction Scope.[a]
[H8]-BINOL-derived
enantioselectivity (64% ee, entry 5).[6] However, the other
analogue bearing spirocyclic backbone proved inferior.
analogue
B
could
improve
the
OH OH
OP NHR
(R)-B (10 mol%)
C
a
*
Ar
+
RNH2
Ar
Furthermore, 1,2-dichloroethane was found to be the best solvent
(entry 7). The reaction did not show reactivity in diethyl ether,
presumably due to its competing binding with the acidic catalyst,
leading to catalyst deactivation. Subsequent substantial efforts by
tuning other reaction parameters, such as using molecular sieves
and decreasing reaction temperature and concentration,
successfully optimized the reaction and achieved good efficiency
and excellent enantioselectivity (entry 13).
DCE, 5Å MS,
10 oC, 24 h
R'
R'
1
-
2
(
3 (P = H)
AcCl, Et3N
b
3'
(P = Ac)
OAc NHTs
PMP
OH NHTs
OAc NHTs
PMP
OAc NHTs
PMP
Me
MeO
PMP
3bc
Me
75%, 85% ee
3a'
3c'
84%, 96% ee
3d'
Table 1 Condition Optimization[a]
59%, 90% ee
98%, 99% ee
OAc NHTs
OAc NHTs
OAc NHTs
OAc NHTs
PMP
Me
Me
PMP
OBn
O
F
O
R
3i'
3h'd
3g'
81%, >99% ee
75%, 86% ee
63%, 97% ee
3e' (R = OMe)
50%, 85% ee
3f' (R = Br)
O
O
74%, 78% ee
Boc OBn
OH
S
N
OH NHBoc
PMP
OH HN
Me
Me
Me
tBu
PMP
PMP
3jc
3kc
3lc
91%, 89% ee
80%, 98% ee
87%, 95% ee
OAc NHCbz
OAc NHCbz
PMP
OH NHCbz
PMP
Me
MeO
Me
OBn
3mc
3n'
3o'
60%, 95% ee
88%, >99% ee
91%, >99% ee
[a] The yield provided is isolated yield. [b] In some cases, the phenol
product was protected immediately to minimize erosion of the optical
purity during work-up/purification and simplify purification (3 and 2 have
similar Rf values). Reaction conditions: 1 (0.2 mmol), 2 (0.21 mmol), (R)-B
(12.2 mg, 10 mol%), DCE (8 mL), ‒10 °C, 24 h. [c] Catalyst loading: 15
mol%. [d] Run with 5 equiv. of TsNH2
We have proposed a possible mechanism (Scheme 3). In the
presence of the acid catalyst, the diarylmethanol undergoes
protonation followed by C‒O bond cleavage to form carbocation
IM-1, which is paired with the chiral phosphate anion. The two
aryl groups can stabilize this carbocation, thereby decreasing the
reaction barrier. Moreover, the interaction of the counter anion
with the hydroxy group in the ortho-position provides additional
stabilization. This stabilization can also be viewed in its resonance
form IM-2, which is indeed an activated ortho-quinone methide.
Subsequent addition by the nitrogen nucleophile forms the C‒N
bond with concomitant stereocontrol. Therefore, the second step
is also asymmetric addition of nitrogen nucleophiles to
ortho-quinone methides, a topic that still remains challenging.[7,8]
Asymmetric induction by the chiral anion (in IM-1) or hydrogen
bonding (in IM-2) is critically important. Overall, this whole
[a] Reaction scale: 1a (0.05 mmol), 2a (0.055 mmol), solvent (1 mL). [b]
Yield was determined by 1H NMR of the crude reaction mixture using
CH2Br2 as internal standard. Ee value was determined by HPLC with a chiral
column. [c] Run with 0.025 M of 1a. [d] Run with 5Å MS (20 mg). [e] Run
at ‒10 °C. PMP = para-methoxyphenyl.
We next examined the reaction scope (Scheme 2). From
readily prepared racemic diarylmethanols, this organocatalytic
protocol is applicable to the synthesis of a wide range of chiral
diarylmethylamines with excellent enantioselectivity. Different
substituents,
including
electron-donating
and
electron-withdrawing groups, at different positions of the two aryl
moieties did not dramatically influence the good result. It is worth
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process resembles a formal SN1 process, which is also a challenge
in asymmetric catalysis.
We carried out some derivatizations to demonstrate the
product utility. In particular, it would be ideal if the free
ortho-hydroxy anchor can be easily removed or converted,
although diarylmethylamines containing such a hydroxy group are
already useful structures themselves (e.g., Betti base).[9]
Gratifyingly, triflation of the phenol motif in the product can work
efficiently in a one-pot operation immediately after the standard
protocol, furnishing aryl triflate 4 in good yield (Scheme 4).
Subsequent reduction led to successful removal of the triflate
moiety to form 5 in good yield. The triflate can also undergo
cross-coupling to form biaryl 6. Finally, palladium-catalyzed
phosphonylation gave phosphine oxide 7, which is poised for
further reduction to form a chiral P,N ligand, a highly analogous
structure to Ming-Phos (shown in Scheme 1).[2] Furthermore, the
Cbz group in proudct 3n′ can be easily deprotected to form free
amine 8′, which easily underwent intramolecular acyl shift to give
amide 8. Notably, in all these reactions, the enantiomeric excess
remained excellent.
Scheme 3 Proposed Mechanism.
To help understand the mechanism, we carried out a series of
control experiments. We carefully monitored the reaction of
racemic 1b under the standard conditions. At partial conversions,
product 3b was generated with constantly high enantiomeric
excess (ee). In contrast, the ee value of 1b (originally racemic)
changed over time during the progress of the reaction, indicating
substrate kinetic resolution (Eq 1). Next, enantiopure substrate 1b
was prepared and subjected to the standard conditions to further
probe the reversibility of the first step. As shown in Eqs 2-3, both
(+)-1b and (‒)-1b led to product (‒)-3b with the same absolute
configuration, indicating that it is not the substrate, but the
catalyst configuration that determines the product
stereochemistry. This is consistent with the proposed mechanism
involving loss of substrate stereochemical information in the
carbocation intermediate. Furthermore, in these two experiments,
the substrate ee values gradually decreased (see SI for more
details), suggesting that the first step is reversible. Indeed, in the
absence of a nucleophile, gradual racemization of 1b was also
observed upon treatment with the catalyst, but without obvious
conversion to any intermediate or byproduct (Eq 4). Based on
these observations, a qualitative reaction coordinate diagram is
proposed (Scheme 3), showing that the first step is an equilibrium
thermodynamically favoring substrate, and the second step is
rate-limiting. Finally, for comparison, substrate 1a′ bearing an
ortho-methoxy group (instead of OH) was subjected to the
standard reaction protocol. Unfortunately, essentially no desired
C‒N bond formation product was observed (Eq 5). This
observation further confirmed that the initial design to take
advantage of this free hydroxy group for hydrogen bonding is
crucial for effective enantiocontrol and attainable reaction barrier.
Scheme 4 Product Transformations.
1b
+
2a
Mg, Pd/C
NH4Cl
H
NHTs
PMP
1) std. cond.
5
Me
Me
79% yield
98% ee
2) Et3N, Tf2O
MeOH, r.t., 4 h
OTf NHTs
PMP
PhB(OH)2, K3PO4
Pd(PPh3)4
Ph NHTs
PMP
Me
6
63% yield
95% ee
1,4-dioxane
100 oC, 24 h
4 (98% ee)
81% over 2 steps
O
dppp,
Pd2(dba)3
O
PPh2 NHTs
PMP
Ph2PH
7
Me
78% yield
98% ee
iPr2NEt, toluene
105 oC, 48 h
Pd/C
2 (1 atm)
NHAc
PMP
OH
OAc NH2
MeO
H
3n'
(95% ee)
MeO
PMP
MeOH
RT, 4 h
8
(95% ee)
8'
63% overall yield
Conclusions
In summary, we have developed the first organocatalytic
approach for direct conversion of racemic diarylmethanols to
valuable chiral diarylmethylamines. It represents an excellent
complement to the elegant metal-catalyzed “borrowing hydrogen”
approach for chiral amine synthesis, with regard to both
mechanism and scope. By proper design of the substrate as well
as careful optimization of the catalytic system, the intermolecular
C‒N bond formation process provides expedient access to a range
of chiral diarylmethylamines with excellent efficiency and
enantioselectivity. The mild conditions tolerate a diverse set of
functional groups. Mechanistically, a series of control experiments
provided important insights into some key features of the distinct
formal SN1 pathway, such as substrate kinetic resolution and
reversible first step. The presence of the ortho-hydroxy group in
the substrate is critically important for achieving both high
chemical efficiency and excellent asymmetric induction via
hydrogen
bonding.
Finally,
the
enantioenriched
diarylmethylamines products are important precursors to other
useful chiral molecules.
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calculated for C22H23NO4SK [M+K]+: 436.0985, found: 436.0975.
(S)-2-Methoxy-6-((4-methoxyphenyl)(4-methylphenylsulfona
mido)methyl) phenyl acetate (3c’) was prepared (purified by
column chromatography, eluent: Et2O/hexanes = 1:1) as a pale
Experimental
General information All air moisture sensitive reactions
were conducted in oven-dried glassware under nitrogen
atmosphere using dry solvents. Flash column chromatography
was performed over silica gel (230-400 mesh) purchased from
Qindao Puke Co., China. Anhydrous diethyl ether,
dichloromethane, toluene, and tetrahydrofuran were purified by
25
yellow oil (69.5 mg, 84% yield, 96% ee). [ꢀ]D = −8.1 (c = 1.0,
CHCl3). HPLC analysis of the product: Daicel CHIRALPAK® AD-H
column; 50% i-PrOH in hexanes; 1.0 mL/min; retention times:
1
7.94 min (minor), 16.45 min (major). H NMR (400 MHz, CDCl3) δ
Innovative®
solvent
purification
system.
Chloroform,
7.54 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.02 – 6.96 (m, 3H),
6.81 (d, J = 0.8 Hz, 1H), 6.72 – 6.68 (m, 3H), 5.67 (d, J = 87.0 Hz,
1H), 5.64 – 5.62 (m, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 2.34 (s, 3H),
2.08 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.9, 159.0, 151.5,
143.0, 137.5, 134.0, 131.6, 129.3 (2C), 128.3, 127.2, 126.4, 120.2,
113.8, 111.7, 56.3, 56.0, 55.3, 21.5, 20.4. IR (neat, cm-1) 3277,
2973, 2937, 1768, 1610, 1512, 1161. HRMS (CI+) calculated for
tetrachloromethane, methanol, 1,4-dioxane, and dichloroethane
(DCE) were purchased from Sigma-Aldrich® and used as received.
1H and 13C NMR were collected on a Bruker AV 400 MHz NMR
spectrometer using residue solvent peaks as an internal standard
(1H NMR: CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm; 13C NMR:
CDCl3 at 77.2 ppm, DMSO-d6 at 39.5 ppm).
24H25NO6S [M+]: 455.1403, found: 455.1396.
General procedure for the catalytic asymmetric synthesis of
diarylmethylamines 3
C
(S)-2-((4-Methoxyphenyl)(4-methylphenylsulfonamido)meth
At ‒10°C, to a 20-mL vial charged with a mixture of the
alcohol 1 (0.2 mmol), the amine 2 (0.21 mmol), 5Å molecular
sieves (80 mg), and DCE (8 mL). Next, a solution of the catalyst
(R)-B (12.2 mg, 10 mol%) in DCE (0.2 mL) was added. The reaction
mixture was stirred at ‒10°C for 24 h. Upon completion, the
reaction mixture was warmed to room temperature and
concentrated. The crude product was purified by silica gel column
chromatography to afford the desired product 3.
yl)-4-methyl phenyl acetate (3d’) was prepared (purified by
column chromatography, eluent: Et2O/hexanes = 2:3 to 1:1) as a
25
white solid (66.0 mg, 75% yield, 85% ee). [ꢀ]D = ‒7.7 (c = 1.0,
CHCl3). HPLC analysis of the product: Daicel CHIRALPAK® AD-H
column; 30% i-PrOH in hexanes; 1.0 mL/min; retention times:
1
8.87 min (major), 10.35 min (minor). H NMR (400 MHz, CDCl3) δ
7.53 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.02 – 6.97 (m, 3H),
6.86 – 6.81 (m, 2H), 6.70 (d, J = 8.4 Hz, 2H), 5.71 – 5.67 (m, 1H),
5.63 (d, J = 8.4 Hz, 1H), 3.72 (s, 3H), 2.34 (s, 3H), 2.13 (s, 3H). 2.00
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.0, 159.0, 145.8, 143.0,
137.6, 135.5, 131.8, 131.6, 129.6, 129.3, 129.1, 128.2, 127.2,
123.0, 113.9, 56.7, 55.3, 21.5, 20.8 (2C).IR (neat, cm-1) 3276, 2956,
2925, 1763, 1511, 1192, 1158. HRMS (CI+) calculated for
General procedure for the catalytic asymmetric synthesis of
diarylmethylamines 3′
At ‒10 °C, to a 20-mL vial charged with a mixture of the
alcohol 1 (0.2 mmol), the amine 2 (0.21 mmol), 5Å molecular
sieves (80 mg), and DCE (8 mL). Next, a solution of the catalyst
(R)-B (12.2 mg, 10 mol%) in DCE (0.2 mL) was added. The reaction
mixture was stirred at ‒10 °C for 24 h. After that, DCM (8 mL) was
added to the vial, and the reaction mixture was cooled to ‒78 °C.
Then, triethylamine (1.0 mmol, 150 μL) and acetyl chloride (0.8
mmol, 80 μL) were added sequentially. The mixture was stirred at
the same temperature for 2 h. Upon completion, the reaction
mixture was warmed to room temperature and concentrated. The
crude product was purified by silica gel column chromatography
to afford the desired product 3′.
C
24H24NO5S [M–H]+: 438.1375, found: 438.1374.
(S)-4-Methoxy-2-((4-methoxyphenyl)(4-methylphenylsulfona
mido)methyl) phenyl acetate (3e’) was prepared (purified by
column chromatography, eluent: Et2O/hexanes = 1:1) as a yellow
25
oil (45.6 mg, 50% yield, 85% ee). [ꢀ]D = +7.7 (c = 1.0, CHCl3).
HPLC analysis of the product: Daicel CHIRALPAK® AD-H column; 50%
i-PrOH in hexanes; 1.0 mL/min; retention times: 12.45 min
(minor), 33.18 min (major). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J
= 8.4 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.89
(d, J = 8.8 Hz, 1H), 6.73 – 6.70 (m, 3H), 6.57 (d, J = 3.2 Hz, 1H), 5.61
(d, J = 8.0 Hz, 1H), 5.42 (d, J = 8.0 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 3H),
2.35 (s, 3H), 2.00 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.3, 159.2,
157.2, 143.3, 141.5, 137.6, 133.1, 131.5, 129.5, 128.3, 127.3,
124.2, 114.3, 114.0, 113.7, 56.8, 55.6, 55.4, 21.6, 20.8. IR (neat,
cm-1) 3276, 2935, 1763, 1511, 1180, 1159, 1035. HRMS (CI+)
calculated for C24H25NO6S [M+]: 455.1403, found: 455.1391.
(S)-2-((4-Methoxyphenyl)(4-methylphenylsulfonamido)meth
yl)phenyl acetate (3a’) was prepared (purified by column
chromatography, eluent: Et2O/hexanes = 2:3 to 1:1) as a white
25
solid (50.5 mg, 59% yield, 90% ee). [ꢀ]D = −5.8 (c = 1.0, CHCl3).
HPLC analysis of the product: Daicel CHIRALPAK® AD-H column; 30%
i-PrOH in hexanes; 1.0 mL/min; retention times: 12.05 min
(minor), 19.12 min (major). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J
= 8.0 Hz, 2H), 7.25 – 7.21 (m, 1H), 7.12 – 7.10 (m, 3H), 7.05 (d, J =
1.2 Hz, 1H), 7.03 – 6.97 (m, 3H), 6.71 (d, J = 8.8 Hz, 2H), 5.68 (d, J =
8.0 Hz, 1H), 5.26 (d, J = 8.0 Hz, 1H), 3.74 (s, 3H), 2.36 (s, 3H), 2.03
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.9, 159.2, 148.2, 143.3,
137.6, 132.4, 131.7, 129.5, 129.2, 128.8, 128.4, 127.3, 126.0,
123.5, 114.0, 56.7, 55.4, 21.7, 20.9. IR (neat, cm-1) 3276, 2957,
2923, 1713, 1511, 1377, 1159. HRMS (CI+) calculated for
(S)-4-Bromo-2-((4-methoxyphenyl)(4-methylphenylsulfonami
do)methyl) phenyl acetate (3f’) was prepared (purified by column
chromatography, eluent: Et2O/hexanes = 2:3 to 1:1) as a pale
25
yellow oil (74.2 mg, 74% yield, 78% ee). [ꢀ]D = +1.12 (c = 1.0,
CHCl3). HPLC analysis of the product: Daicel CHIRALPAK® AD-H
column; 30% i-PrOH in hexanes; 1.0 mL/min; retention times:
11.83 min (minor), 15.14 min (major). 1H NMR (400 MHz, CDCl3) δ
7.55 (d, J = 8.4 Hz, 2H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.16 – 7.12
(m, 3H), 6.99 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.8 Hz, 1H), 6.73 (d, J =
8.8 Hz, 2H), 5.79 (d, J = 8.4 Hz, 1H), 5.66 (d, J = 8.0 Hz, 1H), 3.74 (s,
3H), 2.39 (s, 3H), 2.02 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.5,
159.2, 147.0, 143.5, 137.2, 134.1, 131.8, 131.4, 130.9, 129.5,
128.2, 127.1, 125.1, 119.0, 114.1, 56.4, 55.3, 21.6, 20.7. IR (neat,
cm-1) 3278, 2975, 1768, 1512, 1162. HRMS (CI+) calculated for
C
23H22NO5S [M–H]+: 424.1219, found: 424.1222.
(S)-N-((2-Hydroxy-3-methylphenyl)(4-methoxyphenyl)meth
yl)-4-methyl benzenesulfonamide (3b) was prepared (purified by
column chromatography, eluent: Et2O/hexanes = 2:3 to 1:1) as a
25
pale yellow solid (77.9 mg, 98% yield, 99% ee). [ꢀ]D = ‒10.0 (c =
1.0, CHCl3). HPLC analysis of the product: Daicel CHIRALPAK® AD-H
column; 15% i-PrOH in hexanes; 1.0 mL/min; retention times:
16.00 min (minor), 16.87 min (major). 1H NMR (400 MHz, CDCl3) δ
7.53 (d, J = 8.3 Hz, 2H), 7.07 (dd, J = 8.5, 2.3 Hz, 4H), 6.97 (d, J =
6.6 Hz, 1H), 6.78 – 6.72 (m, 3H), 6.68 (t, J = 7.5 Hz, 1H), 5.63 (d, J =
8.2 Hz, 1H), 5.44 (d, J = 8.2 Hz, 1H), 5.36 (s, 1H), 3.75 (s, 3H), 2.33
(s, 3H), 2.11 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.9, 151.5,
143.1, 136.8, 131.7, 130.4, 129.1, 128.2, 127.3, 127.1, 125.7,
124.5, 120.4, 113.8, 58.7, 55.3, 21.4, 15.6. IR (neat, cm-1) 3431,
3289, 2926, 1603, 1441, 1250, 1150, 1028.HRMS (MALDI)
C
23H22BrNO5S [M+]: 503.0402, found: 503.0411.
(S)-5-Fluoro-2-((4-methoxyphenyl)((4-methylphenyl)sulfona
mido)methyl) phenyl acetate (3g’) was prepared (purified by
column chromatography, eluent: Et2O/hexanes = 2:3 to 1:1) as a
25
white solid (86.5 mg, 75% yield, 86% ee). [ꢀ]D = ‒9.4 (c = 1.0,
CHCl3). HPLC analysis of the product: Daicel CHIRALPAK® AD-H
column; 30% i-PrOH in hexanes; 1.0 mL/min; retention times:
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11.59 min (minor), 15.75 min (major). 1H NMR (400 MHz, CDCl3) δ
7.52 (d, J = 8.0 Hz, 2H), 7.09 (t, J = 9.2 Hz, 3H), 6.95 (d, J = 8.4 Hz,
2H), 6.80 – 6.71 (m, 2H), 6.70 (d, J = 8.4 Hz, 2H), 5.71 – 5.63 (m,
2H), 3.72 (s, 3H), 2.35 (s, 3H), 2.04 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 168.3, 161.9 (JC-F = 248.4 Hz), 159.0, 148.6 (d, JC-F = 10.9
Hz), 143.2, 137.4, 131.3, 129.9 (d, JC-F = 9.4 Hz), 129.3, 128.3 (d,
JC-F = 3.6 Hz), 128.1, 127.1, 113.90, 112.7 (d, JC-F = 21.2 Hz), 111.1
(d, JC-F = 24.7 Hz), 56.0, 55.2, 21.4, 20.7. 19F NMR (376Hz, CDCl3) δ
‒112.1. IR (neat, cm-1) 2931, 1752, 1602, 1502, 1204, 1150, 1015,
3.80 (s, 3H), 2.26 (s, 3H), 1.44 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
158.1, 156.0, 152.1, 131.9, 129.6, 127.9, 127.3, 125.7, 125.1,
119.3, 113.2, 80.1, 54.7 (2C), 27.7, 15.6. IR (neat, cm-1) 3423, 3180,
2928, 1660, 1501, 1243, 1156, 1033, 768. HRMS (CI+) calculated
for C20H25NO4 [M+]: 343.1784, found: 343.1777.
tert-Butyl(S)-(benzyloxy)((2-hydroxy-3-methylphenyl)(4-met
hoxyphenyl) methyl)carbamate (3l) was prepared (purified by
column chromatography, eluent: Et2O/hexanes = 1:5) as a pale
25
yellow oil (81.8 mg, 91% yield, 89% ee). [ꢀ]D = ‒6.8 (c = 1.0,
665. HRMS (MALDI) calculated for
466.1100, found: 466.1058.
C
23H22FNO4SNa [M+Na+]:
CHCl3). HPLC analysis of the product: Daicel CHIRALPAK® AD-H
column; 5% i-PrOH in hexanes; 1.0 mL/min; retention times:
13.29 min (major), 13.97 min (minor). 1H NMR (400 MHz, CDCl3) δ
7.32 (d, J = 8.7 Hz, 2H), 7.29 – 7.21 (m, 3H), 7.11 (d, J = 7.5 Hz, 1H),
7.06 (dd, J = 7.3, 2.1 Hz, 2H), 7.01 (d, J = 7.5 Hz, 1H), 6.91 – 6.84
(m, 2H), 6.79 (t, J = 7.6 Hz, 1H), 6.42 (s, 1H), 6.29 (s, 1H), 4.50 (d, J
= 11.8 Hz, 2H), 3.80 (s, 3H), 2.24 (s, 3H), 1.45 (s, 9H). 13C NMR (101
MHz, CDCl3) δ 159.1, 156.9, 152.6, 134.7, 130.7, 129.8, 129.6,
129.1, 128.7, 128.5, 128.3, 125.4, 124.4, 119.9, 113.9, 82.4, 78.6,
64.1, 55.3, 28.2, 16.2. IR (neat, cm-1) 3404, 2973, 1682, 1510,
1247, 1163, 749. HRMS (CI+) calculated for C27H31NO5 [M+]:
499.2202, found: 499.2214.
(S)-2-(Benzo[d][1,3]dioxol-5-yl(4-methylphenylsulfonamido)
methyl)-6-methylphenyl acetate (3h’) was prepared (purified by
column chromatography, eluent: Et2O/hexanes = 2:3 to 1:1) as an
25
orange solid (50.7 mg, 63% yield, 97% ee). [ꢀ]D = ‒14.3 (c = 1.0,
CHCl3). HPLC analysis of the product: Daicel CHIRALPAK® AD-H
column; 50% i-PrOH in hexanes; 1.0 mL/min; retention times:
1
9.70 min (minor), 21.18 min (major). H NMR (400 MHz, CDCl3) δ
7.52 (d, J = 8.4 Hz, 2H), 7.11 – 7.07 (m, 3H), 6.97 – 6.91 (m, 2H),
6.60 – 6.54 (m, 3H), 5.86 (d, J = 7.2 Hz, 2H), 5.60 (d, J = 7.6 Hz, 1H),
5.50 (d, J = 7.6 Hz, 1H), 2.35 (s, 3H), 2.15 (s, 3H), 2.05 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 168.5, 147.8, 147.1, 143.2, 137.5, 133.4,
132.6, 131.5, 130.8, 129.3, 127.3 (2C), 126.6, 126.1, 120.8, 108.1
Benzyl(S)-((2-hydroxy-3-methylphenyl)(4-methoxyphenyl)me
thyl) carbamate (3m) was prepared (purified by column
(2C), 101.2, 56.9, 21.6, 20.6, 16.5. IR (neat, cm-1) 3274, 2957, 2920, chromatography, eluent: Et2O/hexanes = 1:2) as a yellow oil (68.7
1762, 1488, 1162. HRMS (CI+) calculated for C24H23NO6S [M+]:
453.1246, found: 453.1268
mg, 91% yield, >99% ee). [ꢀ]D = ‒31.7 (c = 1.0, CHCl3). HPLC
analysis of the product: Daicel CHIRALPAK® IC column; 10% i-PrOH
in hexanes; 1.0 mL/min; retention times: 14.48 min (major), 18.63
min (minor). 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.29 (m, 5H), 7.19
(d, J = 8.5 Hz, 2H), 7.07 (dd, J = 7.4, 0.7 Hz, 1H), 6.90 (d, J = 7.4 Hz,
1H), 6.88 – 6.82 (m, 2H), 6.82 – 6.76 (m, 1H), 6.57 (br s, 1H), 6.18
(d, J = 8.9 Hz, 1H), 5.85 (d, J = 9.1 Hz, 1H), 5.13 (dd, J = 28.2, 12.2
Hz, 2H), 3.79 (s, 3H), 2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
158.2, 156.2, 156.2, 151.7, 135.4, 131.9, 129.7, 128.0, 127.62,
127.58, 127.5, 127.3, 126.0, 119.7, 113.3, 66.8 (2C), 54.6, 15.4. IR
(neat, cm-1) 3332, 3026, 2949, 1964, 1505, 1237, 1032, 747. HRMS
(CI+) calculated for C23H23NO4 [M+]: 377.1627, found: 377.1627.
(S)-2-((((Benzyloxy)carbonyl)amino)(4-methoxyphenyl)methy
l)-6-methoxy phenyl acetate (3n’) was prepared (purified by
25
(S)-2-((4-(Benzyloxy)phenyl)((4-methylphenyl)sulfonamido)m
ethyl)-6-methylphenyl acetate (3i’) was prepared (purified by
column chromatography, eluent: Et2O/hexanes = 1:2) as a pale
25
yellow solid (83.5 mg, 81% yield, >99% ee). [ꢀ]D = ‒8.8 (c = 1.0,
CHCl3). HPLC analysis of the product: Daicel CHIRALPAK® AD-H
column; 50% i-PrOH in hexanes; 1.0 mL/min; retention times:
15.06 min (minor), 33.25 min (major). 1H NMR (400 MHz, CDCl3) δ
7.53 (d, J = 8.2 Hz, 2H), 7.43 – 7.37 (m, 4H), 7.35 - 7.30 (m, 1H),
7.13 – 7.06 (m, 3H), 7.00 (d, J = 8.6 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H),
6.92 (d, J = 7.5 Hz, 1H), 6.83 – 6.75 (m, 2H), 5.66 (d, J = 7.7 Hz, 1H),
5.34 (s, 1H), 4.99 (s, 2H), 2.36 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H). 13
C
NMR (101 MHz, CDCl3) δ 168.2, 158.2, 146.9, 143.0, 137.5, 136.8,
132.6, 131.7, 131.5, 130.6, 129.2, 128.6, 128.4, 128.0, 127.5,
127.1, 126.8, 126.7, 125.9, 114.7, 70.0, 21.5, 20.4, 16.4. IR (neat,
cm-1) 3033, 2924, 1757, 1507, 1210, 1157, 1012, 665. HRMS
(MALDI) calculated for C30H29NO5SK [M+K+]: 554.1404, found:
554.1437.
(S)-4-(tert-Butyl)-N-((2-hydroxy-3-methylphenyl)(4-methoxyp
henyl)methyl) benzenesulfonamide (3j) was (purified by column
chromatography, eluent: Et2O/hexanes = 1:2) as a white solid
(69.5 mg, 80% yield, 98% ee). [ꢀ]D25 = ‒20.9 (c = 1.0, CHCl3). HPLC
analysis of the product: Daicel CHIRALPAK® AD-H column; 15%
i-PrOH in hexanes; 1.0 mL/min; retention times: 10.64 min
(minor), 11.49 min (major). 1H NMR (400 MHz, CDCl3) δ 7.56 –
7.50 (m, 2H), 7.26 – 7.20 (m, 2H), 7.10 – 7.04 (m, 2H), 6.92 (d, J =
7.3 Hz, 1H), 6.76 – 6.68 (m, 3H), 6.63 (t, J = 7.5 Hz, 1H), 5.64 (s,
2H), 5.49 (s, 1H), 3.74 (s, 3H), 2.10 (s, 3H), 1.27 (s, 9H). 13C NMR
column chromatography, eluent: hexanes/EtOAc
= 4:1 to
DCM/EtOAc = 20:1) as a pale yellow oil (52.3 mg, 60% yield, 95%
25
ee). [ꢀ]D = ‒12.3 (c = 1.0, CHCl3). HPLC analysis of the product:
Daicel CHIRALPAK® AD-H column; 15% i-PrOH in hexanes; 1.0
mL/min; retention times: 36.21 min (minor), 38.32 min (major).
1H NMR (400 MHz, CDCl3) δ 7.41 – 7.27 (m, 5H), 7.19 – 7.11 (m,
3H), 6.91 (dd, J = 8.3, 1.1 Hz, 1H), 6.83 (d, J = 8.7 Hz, 3H), 6.11 (d, J
= 8.2 Hz, 1H), 5.43 (d, J = 7.2 Hz, 1H), 5.11 (s, 2H), 3.80 (s, 3H),
3.77 (s, 3H), 2.09 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.1, 158.9,
155.5, 151.7, 137.9, 136.4, 135.3, 132.5, 128.5, 128.2 (2C), 128.0,
126.7, 119.8, 113.9, 111.8, 67.0, 56.1, 55.3, 53.6, 20.3. IR (neat,
cm-1) 2944, 1764, 1707, 1508, 1169, 1029, 732. HRMS (CI+)
calculated for C25H25NO6 [M+]:435.1682, found: 435.1662.
(S)-2-((((Benzyloxy)carbonyl)amino)(4-(benzyloxy)phenyl)me
thyl)-6-methylphenyl acetate (3o’) was prepared (purified by
(101 MHz, CDCl3) δ 158.2, 155.4, 150.9, 135.9, 130.9, 129.8, 127.6, column chromatography, eluent: Et2O/hexanes = 1:2) as a white
25
126.7, 126.3, 124.8 (2C), 123.7, 119.7, 113.1, 58.1, 54.6, 34.3,
solid (87.2 mg, 88% yield, >99% ee). [ꢀ]D = ‒2.1 (c = 1.0, CHCl3).
HPLC analysis of the product: Daicel CHIRALPAK® AD-H column; 50%
i-PrOH in hexanes; 1.0 mL/min; retention times: 17.41 min
(major), 20.03 min (minor). 1H NMR (400 MHz, CDCl3) δ 7.45 –
7.40 (m, 3H), 7.39 – 7.29 (m, 7H), 7.19 (d, J = 7.6 Hz, 1H), 7.14 (d, J
= 8.3 Hz, 3H), 7.04 (d, J = 6.9 Hz, 1H), 6.92 (d, J = 8.6 Hz, 2H), 6.10
(d, J = 7.8 Hz, 1H), 5.34 (s, 1H), 5.12 (s, 2H), 5.04 (s, 2H), 2.14 (s,
3H), 2.09 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.4, 158.1, 155.5,
147.5, 136.9, 136.4, 134.0, 132.9, 131.6, 130.7, 128.62, 128.55,
128.3, 128.2, 128.1, 128.0, 127.5, 126.2, 114.9, 114.6, 70.0, 67.0,
53.7, 20.3, 16.5. IR (neat, cm-1) 3032, 2940, 1708, 1505, 1211,
30.4, 15.0. IR (neat, cm-1) 3290, 2962, 1600, 1506, 1154, 1024,
648. HRMS (MALDI) calculated for
462.1715, found: 462.1709.
C
25H29NO4SNa [M+Na]+:
tert-Butyl(S)-((2-hydroxy-3-methylphenyl)(4-methoxyphenyl)
methyl)carbamate (3k) was prepared (purified by column
chromatography, eluent: hexanes/EtOAc = 8:1 to 4:1) as an
25
orange solid (59.8 mg, 87% yield, 95% ee). [ꢀ]D = ‒44.5 (c = 1.0,
CHCl3). HPLC analysis of the product: Daicel CHIRALPAK® AD-H
column; 10% i-PrOH in hexanes; 1.0 mL/min; retention times:
1
10.00 min (major), 11.12 min (minor) H NMR (400 MHz, CDCl3) δ
7.19 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 6.8 Hz, 1H), 6.91 – 6.84 (m, 2H),
6.79 – 6.70 (m, 2H), 6.11 (d, J = 9.2 Hz, 1H), 5.42 (d, J = 8.7 Hz, 1H),
1162, 735. HRMS (MALDI) calculated for
495.2046, found: 495.1954.
C
31H29NO5 [M+]:
This article is protected by copyright. All rights reserved.

(S)-2-((4-Methoxyphenyl)(4-methylphenylsulfonamido)meth
yl)-6-methyl phenyl trifluoromethanesulfonate (4). At ‒10 °C, to a
flask charged with a mixture of the alcohol 1b (244.4 mg, 1.0
mmol), TsNH2 (1.2 mmol, 205 mg), 5Å molecular sieves (500 mg),
and DCE (20 mL). Next, a solution of the catalyst (R)-B (30.5 mg,
10 mol%) in DCE (0.5 mL) was added slowly. The reaction mixture
was stirred at ‒10 °C for 24 h. After that, anhydrous DCM (20 mL)
was added to the flask, and the reaction mixture was cooled to
‒78 °C. Then triethylamine (6.0 mmol, 604 mg) and
trifluoromethanesulfonic anhydride (4.0 mmol, 672 uL) were
added sequentially. The mixture was stirred at the same
temperature for 2 h before it was filtered through a pad of celite,
which was washed with DCM (40 mL). The filtrate was
concentrated under reduced pressure to give the crude product,
7.50 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 15.5 Hz, 2H), 7.32 – 7.27 (m,
1H), 7.22 (t, J = 7.6 Hz, 1H), 7.12 – 7.08 (m, 6H), 6.60 (m, 3H), 6.54
(d, J = 7.6 Hz, 1H), 5.25 (d, J = 5.6 Hz, 1H), 4.81 (d, J = 6.0 Hz, 1H),
3.72 (s, 3H), 2.40 (s, 3H), 1.94 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
159.0, 143.3, 140.7, 139.2, 138.8, 136.8, 133.3, 129.9, 129.5,
129.2, 129.0, 128.7, 128.2, 127.6, 127.5, 127.2, 124.7, 113.9, 58.3,
55.4, 21.7, 21.0. IR (neat, cm-1) 3277, 2957, 2924, 1511, 1159.
HRMS (EI+) calculated for C28H27NO3S [M+]: 457.1712, found:
457.1710.
(S)-N-((2-(Diphenylphosphoryl)-3-methylphenyl)(4-methoxyp
henyl)methyl) -4-methylbenzenesulfonamide (7). Under N2, a
4-mL vial was charged with trifluoromethanesulfonate 4 (140 mg,
0.264 mmol), diphenylphosphine oxide (106 mg, 0.528 mmol),
redistilled N,N-diisopropylethylamine (100 ꢂ L, 0.60 mmol),
1,3-bis(diphenylphosphino)propane (12 mg, 10 mol%), Pd2(dba)3
(11 mg, 5.0 mol%) and degassed toluene (1.5 mL). The vial was
sealed and stirred at 105 oC for 48 h. Upon completion, the
mixture was cooled to room temperature, and directly subject to
silica gel column chromatography (eluent: Et2O/hexanes = 3:1 to
1:1) to afford pure 7 as a white solid (120 mg, 78% yield, 98% ee).
[ꢀ]D25 = −48.3 (ꢁ = 1.0, CHCl3). HPLC analysis of the product: Daicel
CHIRALPAK® IC column; 40% i-PrOH in hexanes; 1.0 mL/min;
retention times: 40.47 min (minor), 44.28 min (major). 1H NMR
(400 MHz, CDCl3) δ 7.74 - 7.54 (m, 3H), 7.50 - 7.36 (m, 3H), 7.34 -
7.24 (m, 6H), 7.23 - 7.11 (m, 4H), 7.11 - 7.04 (m, 1H), 6.79 (d, J =
8.8 Hz, 2H), 6.48 (s, 1H), 6.35 (d, J = 8.8 Hz, 2H), 3.58 (s, 3H), 2.35
(s, 3H), 1.70 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.0, 149.4 (d, J
= 7.3 Hz), 142.7 (d, J = 10.9 Hz), 142.4, 133.2, 132.0 (d, J = 2.5 Hz),
131.9 (d, J = 11.1 Hz), 131.7 (d, J = 10.1 Hz), 131.4, 131.4 (d, J = 5.6
Hz), 131.1 (d, J = 10.3 Hz), 129.2, 128.5 (d, J = 12.2 Hz), 128.4,
128.2 (d, J = 12.4 Hz), 127.2, 127.1 (d, J = 96.4 Hz), 112.8, 55.0,
25.4, 25.3, 21.5. 31P NMR (162 MHz, CDCl3) δ 33.3. IR (neat, cm-1)
3270, 2973, 1511, 1438, 1115. HRMS (CI+) calculated for
which was purified by silica gel column chromatography to afford
25
triflate 4 as white foam (426 mg, 81% yield, 98% ee). [ꢀ]D
=
−4.70 (ꢁ = 1.0, CHCl3). HPLC analysis of the product: Daicel
CHIRALPAK® AD-H column; 30% i-PrOH in hexanes; 1.0 mL/min;
retention times: 5.72 min (minor), 8.58 min (major). 1H NMR (400
MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 6.8 Hz, 1H), 7.22
– 7.14 (m, 4H), 6.90 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 5.92
(d, J = 7.2 Hz, 1H), 5.50 (d, J = 7.2 Hz, 1H), 3.72 (s, 3H), 2.39 (s, 3H),
2.27 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.4 (2C), 144.4, 143.6,
137.0, 135.1, 132.2, 131.9, 131.5, 129.6, 128.8, 128.7, 127.53,
127.45, 114.1, 55.4, 55.2, 21.7, 17.2. 19F NMR (376 MHz, CDCl3) δ
−73.2. IR (neat, cm-1) 3268, 2975, 1512, 1334, 1160, 1139, 881.
HRMS (CI+) calculated for C23H22F3NO6S2 [M+]: 529.0841, found:
529.0839.
(S)-N-((4-Methoxyphenyl)(m-tolyl)methyl)-4-methylbenzene
sulfonamide (5). At room temperature, a 10-mL flask was charged
with trifluoromethane sulfonate
4 (53.0 mg, 0.1 mmol),
magnesium turnings (24 mg, 1 mmol), palladium on carbon (26.5
mg, 50 wt%), ammonium chloride (53.5 mg, 1.0 mmol) and
methanol (2 mL). The mixture was stirred under nitrogen at room
temperature for 4 h. Then it was filtered through a pad of silica
gel. The silica gel was washed with EtOAc (3×20 mL). The filtrate
was concentrated, and the crude product was purified by silica gel
C
34H32NO4PS [M+]: 581.1790, found: 581.1780.
(S)-N-((2-hydroxy-3-methoxyphenyl)(4-methoxyphenyl)meth
yl)acetamide (8). Under H2 atmosphere (H2 balloon, 1 atm), to an
oven-dried Schlenk tube were added Pd/C (10 wt%, 13 mg), 3n’
(56.9 mg, 0.13 mmol) and MeOH (3 mL). The reaction mixture was
stirred at room temperature for 4 h, and it was filtered through a
short pad of celite (eluent: DCM/MeOH = 1:1). After evaporation,
the crude product was purified by preparative thin layer
chromatography on silica gel (eluent: DCM/MeOH = 20:1) to
afford pure product 8 as a white solid (24.8 mg, 63% yield, 95%
column chromatography (eluent: Et2O/hexanes = 1:3) to afford
25
pure 5 as a white solid (30.1 mg, 79% yield, 98% ee). [ꢀ]D
=
−12.0 (ꢁ = 1.0, CHCl3). HPLC analysis of the product: Daicel
CHIRALPAK® AD-H column; 30% i-PrOH in hexanes; 1.0 mL/min;
retention times: 8.36 min (minor), 9.09 min (major). 1H NMR (400
MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 2H), 7.14 – 7.03 (m, 3H), 7.01 –
6.97 (m, 3H), 6.90 – 6.86 (m, 2H), 6.74 – 6.71 (m, 2H), 5.49 (d, J =
7.2 Hz, 1H), 5.28 (d, J = 7.2 Hz, 1H), 3.74 (s, 3H), 2.38 (s, 3H), 2.02
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.1, 143.2, 140.8, 138.3,
137.7, 133.1, 129.4, 128.8, 128.6, 128.3, 128.1, 127.4, 124.5,
114.0, 61.0, 55.4, 21.6, 21.5. IR (neat, cm-1) 3277, 2957, 2925,
1512, 1159. HRMS (CI+) calculated for C22H23NO3S [M+]: 381.1399,
found: 381.1393.
25
ee). [ꢀ]D = +1.6 (c = 0.5, CHCl3). HPLC analysis of the product:
Daicel CHIRALPAK® AD-H column; 15% i-PrOH in hexanes; 1.0
mL/min; retention times: 22.43 min (major), 27.66 min (minor).
1H NMR (400 MHz, acetone-d6) δ 7.76 (s, 1H), 7.75 (s, 1H), 7.27 -
7.19 (m, 2H), 6.96 - 6.88 (m, 2H), 6.88 - 6.77 (m, 3H), 6.53 (d, J =
8.8 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 2.00 (s, 3H). 13H NMR (100
MHz, acetone-d6) δ 169.8, 160.2, 149.1, 145.4, 136.4, 130.6, 129.8,
121.6, 120.7, 115.0, 111.7, 57.1, 56.2, 52.6, 23.8. IR (neat, cm-1)
3332, 2960, 2927, 1725, 1685, 1260. HRMS (CI+) calculated for
(S)-N-((4-Methoxyphenyl)(6-methyl-[1,1'-biphenyl]-2-yl)met
hyl)-4-methyl benzenesulfonamide (6). Under N2, a 4-mL vial was
charged with trifluoromethanesulfonate 4 (53.0 mg, 0.1 mmol),
phenylboronic acid (13.4 mg, 0.11 mmol), potassium phosphate
(31.8 mg, 0.15 mmol), Pd(PPh3)4 (2.9 mg, 2.5 mol%) and degassed
1,4-dioxane (0.5 mL). The vial was sealed and stirred at 100 oC for
24 h. Upon completion, the mixture was cooled to room
temperature, diluted with Et2O (1.0 mL) and water (1.0 mL). The
layers were separated. The aqueous layer was extracted by Et2O
(3×1.0 mL). The combined organic layers were washed with water
(10 mL) and brine (5 mL), then dried over anhydrous Na2SO4, and
concentrated. The crude product was purified by silica gel column
chromatography (eluent: Et2O/hexanes = 2:3) to afford pure 6 as
a white solid (29.0 mg, 63% yield, 95% ee). [ꢀ]D25 = −15.6 (ꢁ = 1.0,
CHCl3). HPLC analysis of the product: Daicel CHIRALPAK® OD-H
column; 15% i-PrOH in hexanes; 1.0 mL/min; retention times:
C
17H19NO4 [M+]: 301.1314, found: 301.1320.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
This
work
was
supported
by
Shenzhen
STIC
(JCYJ20160229205441091) and Hong Kong RGC (16304115,
16311616, and 16302617). We thank Mr. Yuk Fai Wong for
preliminary studies.
1
8.94 min (minor), 11.76 min (major). H NMR (400 MHz, CDCl3) δ
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Rueping, M. Chem. Rev. 2014, 114, 9047; (f) James, T.; van
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Entry for the Table of Contents
Page No.
Organocatalytic
Enantioselective
Synthesis of Chiral Diarylmethylamines
from Racemic Alcohols
An organocatalytic approach for direct conversion of racemic diarylmethanols to valuable chiral
diarylmethylamines is described. Different from the previously reported elegant “borrowing
hydrogen” approach, the present process employs a distinct formal SN1 strategy, thereby leading
to complementary features on reaction scope and catalytic system. This new approach enjoys
excellent enantioselectivity, mild conditions, broad scope, and easy derivatization of products.
Mechanistically, control experiments also provided important insights into some notable features,
such as substrate kinetic resolution and reversibility as well as the critical role of the ortho-hydroxy
group in the substrate.
Min Chen,+ Yaodong Han,+ Dengke Ma,+
Yong Wang, Zengwei Lai and Jianwei Sun*
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