Chiral Bicyclic Bridgehead Phosphoramidite (Briphos) Ligands for Asymmetric Rhodium-Catalyzed 1,2- and 1,4-Addition

Article abstract of DOI:10.1021/acs.joc.6b00033

A complementary solution for Rh-catalyzed enantioselective 1,2- and 1,4-arylation with two structurally related chiral ligands is reported. A chiral bicyclic bridgehead phosphoramidite (briphos) ligand derived from 1-aminoindane was efficient for the 1,2-arylation of N-sulfonyl imines, while that derived from 1,2,3,4-tetrahydro-1-naphthylamine was efficient for 1,4-arylation of α,β-unsaturated cyclic ketones. For α,β-unsaturated N-tosyl ketimines, the briphos derived from 1-aminoindane was found to selectively provide γ, γ-diaryl N-tosyl enamines with high yields and stereoselectivities.

Full text of DOI:10.1021/acs.joc.6b00033

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Article
Chiral Bicyclic Bridgehead Phosphoramidite (Briphos) Ligands
for Asymmetric Rhodium-Catalyzed 1,2- and 1,4-Addition
Ansoo Lee, and Hyunwoo Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00033 • Publication Date (Web): 14 Apr 2016
Downloaded from http://pubs.acs.org on April 16, 2016
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Chiral Bicyclic Bridgehead Phosphoramidite (Briphos) Ligands for
Asymmetric Rhodium-Catalyzed 1,2- and 1,4-Addition
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Ansoo Lee and Hyunwoo Kim*
Department of Chemistry, KAIST, Daejeon 34141, Korea
ABSTRACT: A complementary solution for Rhꢀcatalyzed enantioselective 1,2ꢀ and 1,4ꢀ
arylation with two structurally related chiral ligands is reported. A chiral bicyclic bridgehead
phosphoramidite (briphos) ligand derived from 1ꢀaminoindane was efficient for the 1,2ꢀarylation
of Nꢀsulfonyl imines while that derived from 1,2,3,4ꢀtetrahydroꢀ1ꢀnaphthylamine was efficient
for 1,4ꢀarylation of α,βꢀunsaturated cyclic ketones. For α,βꢀunsaturated Nꢀtosyl ketimines, the
briphos derived from 1ꢀaminoindane was found to selectively provide γ,γꢀdiaryl Nꢀtosyl
enamines with high yields and stereoselectivities.
INTRODUCTION
The catalytic activity of lowꢀvalent transition metals such as Co(I), Ni(0), Rh(I), Pd(0), and Ir(I)
is known to be promoted by strong πꢀacceptor ligands when the reductive elimination is rateꢀ
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determining in the catalytic cycle.1,2 The reported πꢀacceptor phosphorus ligands include
phosphoramidites3, phosphites4, or electronꢀdeficient aryl phosphines5. For chiral ligand design,
several diolꢀbased chiral platforms such as 1,1'ꢀbiꢀ2ꢀnaphthol, 2,2'ꢀbiphenol, and TADDOL have
been used for making efficient chiral phosphoramidite or phosphite ligands.6 However, due to
their synthetic difficulty and limited availability, chiral πꢀacceptor phosphorus ligands are not
widely used as compared with privileged chiral phosphorus ligands. Thus, it is desirable to
develop a scalable and tunable chiral πꢀacceptor phosphorus ligand to investigate asymmetric
lowꢀvalent transitionꢀmetal catalysis. We recently developed bicyclic bridgehead
phosphoramidite (briphos) ligands as a new class of πꢀacceptor ligands.7 The geometrical
constraints in briphos enhanced the πꢀacceptor ability, which resulted in significant ligand
acceleration effects in Rhꢀcatalyzed conjugate addition reactions. The simple synthetic procedure
for briphos ligands allowed facile tuning of the ligand structure7b as well as chiral ligand design7a
by using commercially available chiral primary amines. Here we report that two structurally
related chiral briphos ligands L1 and L2 can efficiently promote Rhꢀcatalyzed asymmetric 1,2ꢀ
and 1,4ꢀaddition of aryl boronic acids, respectively.
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Various ligand platforms including phosphorous8, diene9, sulfoxide10, and NHC11, as
well as its hybrid structure12 have been creatively used to develop efficient chiral ligands for
asymmetric Rhꢀcatalyzed 1,2ꢀ or 1,4ꢀaddition of aryl boronic acid derivatives to carbonyls,
imines, and alkenes.13 As a new type of chiral ligand, we have reported chiral briphos ligand L1
derived from 1ꢀaminoindane which is highly efficient and selective for 1,4ꢀaddition of aryl
boronic acids to α,βꢀunsaturated N,Nꢀdimethylꢀsulfamoyl imino esters.7a Chiral briphos L1 is a
unique type of chiral ligand having only one chiral carbon center, given that many efficient chiral
ligands largely rely on the privileged axially chiral structures or chelating effects to achieve highꢀ
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Table 1. Rh-Catalyzed Asymmetric Arylation with Various Chiral Ligandsa
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entry
1
yield of 2a (%)b
ee of 2a (%)c
yield of 4a (%)b
ee of 4a (%)c
L
30
ꢀ30
94 (R)
ꢀ89
n.d.
n.d.
n.d.
87
95 (S)
ꢀ40
n.d.
n.d.
n.d.
n.d.
96
L1
98
10
<5
n.r.
n.r.
n.r.
24
84f
ꢀ
2
L2 86
3
10
L3
L4
L5
L6
L7
L1
L2
L7
4
trace
trace
trace
13
5
6
7
8d,e
9d,e
10d,e
ꢀ
ꢀ
90
60
92
ꢀ
57
83
89f
85
aConditions: (1) 1a (0.4 mmol), PhB(OH)2 (1.2 mmol), and [Rh(acac)(C2H4)2] (1 mol % Rh) were stirred in toluene
°
(1.0 mL) and H2O (0.1 mL) at 25 C for 3 h. (2) 3a (0.2 mmol), PhB(OH)2 (0.4 mmol), and [Rh(acac)(C2H4)2] (3
mol % Rh) were stirred in toluene (1.0 mL) at 25 °C for 3 h. bYield of isolated product. cDetermined by chiralꢀphase
d
e
f
HPLC analysis. KOH (1.0 M in H2O, 0.1 mL) was added. [Rh(C2H4)2Cl]2 was used. Decomposition of 3a to 4ꢀ
chlorobenzaldehyde was observed.
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stereoselectivity. Moreover, the favorable ligand effect by briphos ligands allowed the reaction
with aryl boronic acids to proceed under neutral conditions at ambient temperature. In order to
further investigate Rhꢀcatalyzed asymmetric arylation reactions with chiral briphos ligands, we
here selected cyclohexenone (1a) and a N,Nꢀdimethyl sulfamoyl imine (3a) as substrates for 1,4ꢀ
and 1,2ꢀaddition, respectively.
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RESULTS AND DISCUSSION
We investigated the asymmetric 1,4ꢀ and 1,2ꢀaddition reactions with Rh(acac)(C2H4)2 (1ꢀ
3 mol %), chiral ligands (1.1ꢀ7.5 mol%) and phenylboronic acid (2ꢀ3 equiv) at 25 oC. The results
are summarized in Table 1. Chiral briphos L1 from 1ꢀaminoindane was selective for 1,2ꢀaddition
of 3a (95% ee), but less selective for 1,4ꢀaddition to 1a (30% ee) (Table 1, entry 1). On the other
hand, chiral briphos L2 from 1,2,3,4ꢀtetrahydroꢀ1ꢀnaphthylamine was selective for 1,4ꢀaddition
of 1a (94% ee), but less selective for 1,2ꢀaddition to 3a (40% ee) (Table 1, entry 2). A subtle
structural difference between 5 and 6ꢀmembered ring in chiral briphos ligands is found to be
crucial to control stereoselectivities of Rhꢀcatalyzed 1,2ꢀ and 1,4ꢀadditions of aryl boronic acids.
Other chiral briphos ligands prepared from acyclic chiral amines showed low to moderate
enantioselectivity ranging from 16ꢀ81% ee (Supporting Information).14 Thus, we found that
chiral briphos L1 and L2 with fused bicyclic chiral amines are efficient chiral ligand structures
and they can be a complementary solution for Rhꢀcatalyzed enantioselective 1,2ꢀ or 1,4ꢀaddition
of boronic acids.
The reactivity and selectivity of chiral briphos was compared with known efficient chiral
ligands L3ꢀL7. Under the same reaction conditions, chiral phosphorus ligands including
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monophos (L3),6,8b BINAP (L4),8c,e difluorphos (L5),5a,e and pꢀphos (L6)15 showed poor
reactivity (< 10%) although monophos (L3) showed high enantioselectivity of 89% (Table 1,
entries 3ꢀ6). A chiral diene ligand L716 was found to be selective for both 1,2ꢀ and 1,4ꢀaddtion to
give 96 and 87% ee but gave products with only 24 and 13% yields, respectively (Table 1, entry
7). It has been demonstrated that base additives enhance Rhꢀcatalyzed additions of aryl boronic
acids.8c Indeed, in case of chiral diene L7, an addition of KOH increased the product yield with
compatible stereoselectivity (Table 1, entry 10). However, the reactions with chiral briphos L1
and L2 were retarded by the addition of KOH (Table 1, entries 8 and 9). Thus, compared with
existing chiral ligands, chiral briphos ligands will be useful for the Rhꢀcatalyzed boronic acid
addition under mild and neutral reaction conditions.
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Scheme 1. Substrate Scope of Rh/briphos-catalyzed asymmetric 1,4-addition and 1,2-
addition reactions.
aConditions for 2: 1 (0.4 mmol), ArB(OH)2 (1.2 mmol), [Rh(acac)(C2H4)2] (2 mol %), and (S)ꢀL2 (5 mol %) were
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°
b
stirred in toluene (1.0 mL) and H2O (0.1 mL) at 25 C Conditions for 4: 3 (0.2 mmol), ArB(OH)2 (0.4 mmol),
[Rh(acac)(C2H4)2] (3 mol %), and (R)ꢀL1 (7.5 mol %) were stirred in toluene (1.0 mL) at 25 °C for 3 h. c1 mol % Rh
was used. dReaction conducted at 50 °C. eReaction conducted for 10 h. fYield of isolated product. gee was determined
by chiralꢀphase HPLC analysis.
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Table 2. Ligand Screening for Rh-catalyzed Asymmetric 1,4-Addition of α,β-Unsaturated
N-tosyl Ketiminea
entry Rh catalyst
ligand
L1
yield (%)b
90
ee (%)c
94
1
Rh(acac)(C2H4)2
2
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
19
ꢀ97
n.d.
n.d.
n.d.
n.d.
47
L2
3
trace
n.r.
L3
4
L4
5
n.r.
L5
6
n.r.
L6
7
25
L7
8d
9d
88
94
L1
27
44
L7
aConditions: 5a (0.2 mmol), 4ꢀMeOC6H4B(OH)2 (0.6 mmol), and [Rh] (5 mol %) were stirred in toluene (1.0 mL) at
°
b
c
d
25 C for 30 h. Yield of isolated product. Determined by chiralꢀphase HPLC analysis. KOH (1.0 M in H2O, 0.1
mL) was added.
With two chiral briphos L1 and L2, we then explored the reaction scope of the Rhꢀcatalyzed
1,4ꢀ and 1,2ꢀadditions of aryl boronic acids. First, chiral briphos L2 was used for 1,4ꢀaddition of
aryl boronic acids to α,βꢀunsaturated ketones (Scheme 1, left). When phenylboronic acid was
used with Rh/L2, 2ꢀcyclohexenone provided the product 2a with high yield (86%) and
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stereoselectivity (94% ee), but 2ꢀcyclopentenone and 2ꢀcycloheptenone provided the products 2b
and 2c with somewhat reduced stereoselectivity of 77% and 83% ee, respectively. Aryl boronic
o
acids substituted with electronꢀdonating Me and OMe groups proceeded at 25 C, while those
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o
substituted with electronꢀwithdrawing F and CF3 groups required elevated temperature of 50 C
due to reduced reactivity. The results showed that high enantioselectivity of 88ꢀ91% was
observed for metaꢀ or paraꢀsubstituted aryl boronic acids while reduced enantioselectivity was
found for orthoꢀsubstituted ones such as 2ꢀmethylphenyl boronic acid (73% ee) and 1ꢀnaphthyl
boronic acid (85% ee). An acyclic enone, 3ꢀheptenꢀ2ꢀone, provided the product 2m with
moderate yield (69%) and low enantioselectivity (42% ee), whereas a heteroaromatic boronic
acid, 2ꢀthienyl boronic acid, yielded no product.
Second, chiral briphos L1 was used for the Rhꢀcatalyzed 1,2ꢀaddition of aryl boronic acids to
N,Nꢀdimethyl sulfamoyl imines (Scheme 1, right). Aryl imines with a substituent such as Cl, F,
CF3, Br, Me, and OMe at the para position reacted with phenylboronic acid to provide the
products 4a-f with high yields (80ꢀ98%) and good enantioselectivity (87ꢀ95% ee). In addition,
the reactions with aryl imines prepared from mꢀ or oꢀchlorobenzaldehyde or 2ꢀ
thiophenecarboxaldehyde as well as those with pꢀmethoxyphenyl, pꢀtolyl or mꢀtolyl boronic
acids gave the desired products 4g-l with moderate to good yield (65ꢀ97%) and high
enantioselectivity (89ꢀ96% ee). However, oꢀtolyl and 2ꢀthienyl boronic acids provided no
product.
In the Rhꢀcatalyzed arylations with aryl boronic acids, chiral briphos L1 was selective
for 1,2ꢀaddition of N,Nꢀdimethyl sulfamoyl imines and chiral briphos L2 was selective for 1,4ꢀ
addition of α,βꢀunsaturated ketones. We then expanded the reaction to α,βꢀunsaturated Nꢀtosyl
ketimines (5) in which both 1,2ꢀ and 1,4ꢀ reactions may take place. The arylation reactions were
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performed with [Rh] (5 mol %) and 4ꢀmethoxyphenyl boronic acid (3 equiv) at 25 C for 30 h
with chiral ligands L1ꢀL7 (5.5ꢀ12.5 mol%) (Table 2). Indeed, both chiral briphos L1 and L2
were selectively promoted the 1,4ꢀaddition reaction to provide γ,γꢀdiaryl Nꢀtosyl enamine 6a
with good enantioselectivities (94 and 97% ee). However, chiral briphos L1 showed high yield
(90%) while chiral briphos L2 showed low yield (19%) (Table 2, entries 1 and 2). Other chiral
phosphorus ligands L3ꢀL6 were inactive (Table 2, entries 3ꢀ6). In addition, chiral diene ligand
L7 provided the product with low yield (25%) and poor selectivity (47% ee) (Table 2, entry 7).
Addition of KOH was not affected to the yield and stereoselectivity (Table 2, entries 8 and 9). In
consideration of reactivity and selectivity, chiral briphos L1 was found to be the most suitable for
Rhꢀcatalyzed 1,4ꢀaddition of α,βꢀunsaturated Nꢀtosyl ketimines.
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Scheme 2. Substrate Scope of Rh/L1-catalyzed asymmetric 1,4-addition of α,β-Unsaturated
Ketimines.
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aConditions: 5 (0.2 mmol), ArB(OH)2 (0.6 mmol), and [Rh(acac)(C2H4)2] (5 mol %), and (R)ꢀL1 (12.5 mol %) were
°
b
c
stirred in toluene (2.0 mL) at 25 C. KOH (100 mol %, 1.0 M in aq) was added. The absolute configuration was
d
determined by comparison of the specific optical rotation with literature17 after acid hydrolysis of 6b. Yield of
isolated product. eee was determined by chiralꢀphase HPLC analysis.
The reaction scope of Rhꢀcatalyzed 1,4ꢀaddition of arylboronic acids to α,βꢀunsaturated
Nꢀtosyl ketimines 5 was investigated with chiral briphos L1 (Scheme 2). Aryl boronic acids
substituted with tBu, Me or OMe at the meta or para positions provided the products 6aꢀe with
good yields (80ꢀ95%) and enantioselectivities (91ꢀ96%) at ambient temperature. In addition, aryl
boronic acids substituted with electronꢀwithdrawing groups F, Cl or Br required the addition of
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KOH additive to proceed the reaction to give products 6gꢀj with moderate yields (35ꢀ80%) but
good enantioselectivity (91ꢀ93%). However, oꢀtolyl and 2ꢀthienyl boronic acids provided no
product. Several substituted α,βꢀunsaturated Nꢀtosyl ketimines with Me, Cl or F groups were
reacted with 4ꢀmethoxyphenyl or phenylboronic acid to provide the corresponding enamines 6kꢀ
6q with good yields (70ꢀ96%) and stereoselectivities (91ꢀ97% ee), although 4ꢀNO2ꢀsubstituted
Nꢀtosyl ketimine gave the product 6r with low yield (51%) and moderate stereoselectivity (84 %
ee).
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CONCLUSION
In summary, chiral bicyclic bridgehead phosphoramidite (briphos) ligands derived from
fused bicyclic amines were successfully applied for Rhꢀcatalyzed enantioselective 1,2ꢀ and 1,4ꢀ
addition of aryl boronic acids under neutral conditions at 25 – 50 oC. Chiral briphos L1 prepared
from 1ꢀaminoindane was used for 1,2ꢀaddition of N,Nꢀdimethyl sulfamoyl imines to provide
products 4 with 79ꢀ98 % yields and 87ꢀ96% enantioselectivities. Chiral briphos L2 prepared
from 1,2,3,4ꢀtetrahydroꢀ1ꢀnaphthylamine was used for 1,4ꢀaddition of α,βꢀunsaturated cyclic
ketones 1 to provide products 2 with 77ꢀ98 % yields and 73ꢀ94% enantioselectivities. Thus, two
chiral briphos L1 and L2 based on bicyclic fused chiral amines can be used as a complementary
solution for Rhꢀcatalyzed 1,2ꢀ and 1,4ꢀaddition of aryl boronic acids. In addition, chiral briphos
L1 was found to be selective for 1,4ꢀaddition of α,βꢀunsaturated Nꢀtosyl ketimines to provide
products 6 with 35ꢀ99 % yields and 84ꢀ97% enantioselectivities.
EXPERIMENTAL SECTION
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General Information. Commercially available compounds were used without further
6
7
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1
13
purification or drying. The H NMR (400 MHz), and C NMR (100 MHz) were recorded for
characterization of compounds. Mass spectra were obtained using a TOFꢀQ highꢀresolution mass
spectrometer (ESI). HPLC analysis was performed on UV detection monitored at 210, 230 or
254 nm, using Chiralpak ADꢀH, ODꢀH, OBꢀH, OJꢀH, IA, IB, IC, and ID column (250×4.5 mm
ID). Substrates (318 and 519) and chiral briphos (L1 and L2)7a were prepared according to the
reported procedures.
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General procedure for the Rh(I)-catalyzed 1,4-addition of arylboronic acids to α,βꢀ
unsaturated ketones
A 25 mL flask was flushed with nitrogen and charged with (S)ꢀL2 (7.5 mg, 0.02 mmol),
Rh(acac)(C2H4)2 (2.1 mg, 0.008 mmol) and 1 mL of degassed toluene. The mixture was stirred
for 10 min at ambient temperature. The reaction mixture was mixed with 0.1 mL of degassed
water, arylboronic acid (1.2 mmol), and α,βꢀunsaturated ketone (0.4 mmol). After stirred at 25 oC
or 50 oC for 1
̶ 5 h, the reaction mixture was passed through a pad of silica gel with ethyl acetate
and the filtrate was concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (EtOAc/hexane=1:5 to 1:20) to afford the corresponding product 2.
(R)ꢀ3ꢀPhenylcyclohexanone (2a).8b Colorless oil. (60.2 mg, 86% yield, 94% ee) H NMR (400
1
MHz, CDCl3): δ ppm 7.35 – 7.32 (m, 2H), 7.26 – 7.22 (m, 3H), 3.11 – 2.90 (m, 1H), 2.63 – 2.34
13
(m, 4H), 2.19 – 2.07 (m, 2H), 1.91 – 1.73 (m, 2H). C NMR (100 MHz, CDCl3): δ ppm 211.2,
144.5, 128.8, 126.8, 126.7, 49.1, 44.9, 41.3, 32.9, 25.7. HPLC chromatograms (Daicel Chiralpak
ADꢀH, Hexanes/iꢀPrOH = 99/1, flow rate = 1.0 mL/min): 8.7 min (minor), 10.4 min (major).
(R)ꢀ3ꢀPhenylcyclopentanone (2b).8b Colorless oil. (61.6 mg, 96% yield, 77% ee) H NMR (400
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MHz, CDCl3): δ ppm 7.43 – 7.32 (m, 2H), 7.30 – 7.22 (m, 3H), 3.53 – 3.37 (m, 1H), 2.68 (dd, J
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= 17.8, 8.2 Hz, 1H), 2.56 – 2.25 (m, 4H), 2.09 – 1.93 (m, 1H). C NMR (100 MHz, CDCl3): δ
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ppm 218.5, 143.2, 128.8, 126.9, 45.9, 42.4, 39.0, 31.3. HPLC chromatograms (Daicel Chiralpak
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OBꢀH, Hexanes/iꢀPrOH = 99/1, flow rate = 0.6 mL/min): 34.5 min (minor), 35.8 min (major).
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(R)ꢀ3ꢀPhenylcycloheptanone (2c).8b Colorless oil. (68.0 mg, 90% yield, 83% ee) H NMR (400
MHz, CDCl3): δ ppm 7.30 (t, J = 7.4 Hz, 2H), 7.24 – 7.14 (m, 3H), 2.93 (m, 2H), 2.70 – 2.51 (m,
13
3H), 2.15 – 1.95 (m, 3H), 1.82 – 1.65 (m, 2H), 1.50 (m, 1H). C NMR (100 MHz, CDCl3): δ
ppm 213.5, 147.0, 128.7, 126.5, 126.4, 51.4, 44.0, 42.8, 39.3, 29.3, 24.3. HPLC chromatograms
(Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 99/1, flow rate = 1.0 mL/min): 9.5 min (minor),
10.6 min (major).
(R)ꢀ3ꢀ(oꢀTolyl)cyclohexanone (2d).8b Colorless oil. (73.0 mg, 97% yield, 73% ee) 1H NMR (400
MHz, CDCl3): δ ppm 7.28 – 7.20 (m, 2H), 7.21 – 7.10 (m, 2H), 3.31 – 3.16 (m, 1H), 2.59 – 2.38
13
(m, 4H), 2.33 (s, 3H), 2.25 – 2.12 (m, 1H), 2.08 – 1.98 (m, 1H), 1.92 – 1.73 (m, 2H). C NMR
(100 MHz, CDCl3): δ ppm 211.3, 142.4, 135.2, 130.8, 126.6, 126.5, 125.2, 48.5, 41.4, 40.4, 32.2,
25.9, 19.4. HPLC chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 99/1, flow rate =
1.0 mL/min): 7.8 min (minor), 9.8 min (major).
(R)ꢀ3ꢀ(mꢀTolyl)cyclohexanone (2e).8b Colorless oil. (73.6 mg, 98% yield, 92% ee) 1H NMR (400
MHz, CDCl3): δ ppm 7.22 (t, J = 7.4 Hz, 1H), 7.08 – 6.99 (m, 3H), 3.06 – 2.89 (m, 1H), 2.63 –
13
2.36 (m, 4H), 2.35 (s, 3H), 2.20 – 2.11 (m, 1H), 2.11 – 2.04 (m, 1H), 1.91 – 1.70 (m, 2H). C
NMR (100 MHz, CDCl3): δ ppm 211.3, 144.5, 138.4, 128.7, 127.6, 127.5, 123.7, 49.1, 44.9, 41.4,
33.0, 25.7, 21.6. HPLC chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 99/1, flow
rate = 1.0 mL/min): 7.5 min (minor), 8.1 min (major).
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(R)ꢀ3ꢀ(pꢀTolyl)cyclohexanone (2f).8b Colorless oil. (64.5 mg, 86% yield, 93% ee) H NMR (400
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MHz, CDCl3): δ ppm 7.19 – 7.08 (m, 4H), 3.04 – 2.93 (m, 1H), 2.63 – 2.36 (m, 4H), 2.34 (s, 3H),
13
2.20 – 2.04 (m, 2H), 1.90 – 1.71 (m, 2H). C NMR (100 MHz, CDCl3): δ ppm 211.3, 141.5,
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136.4, 129.4, 126.5, 49.2, 44.5, 41.3, 33.0, 25.7, 21.1. HPLC chromatograms (Daicel Chiralpak
ADꢀH, Hexanes/iꢀPrOH = 99/1, flow rate = 1.0 mL/min): 7.5 min (minor), 8.3 min (major).
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(R)ꢀ3ꢀ(4ꢀMethoxyphenyl)cyclohexanone (2g).8b Colorless oil. (78.4 mg, 96% yield, 88% ee) H
NMR (400 MHz, CDCl3): δ ppm 7.14 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H),
13
3.02 – 2.90 (m, 1H), 2.63 – 2.32 (m, 4H), 2.19 – 2.02 (m, 2H), 1.88 – 1.70 (m, 2H). C NMR
(100 MHz, CDCl3): δ ppm 211.3, 158.4, 136.7, 127.6, 114.2, 55.4, 49.4, 44.1, 41.3, 33.2, 25.6.
HPLC chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 99/1, flow rate = 1.0
mL/min): 13.1 min (minor), 13.7 min (major).
(R)ꢀ3ꢀ(3,5ꢀDimethylphenyl)cyclohexanone (2h).10b Colorless oil. (73.5 mg, 91% yield, 90% ee)
1H NMR (400 MHz, CDCl3): δ ppm 6.88 (s, 1H), 6.84 (s, 2H), 3.00 – 2.87 (m, 1H), 2.61 – 2.34
13
(m, 4H), 2.31 (s, 6H), 2.19 – 2.11 (m, 1H), 2.11 – 2.02 (m, 1H), 1.91 – 1.71 (m, 2H). C NMR
(100 MHz, CDCl3): δ ppm 211.4, 144.5, 138.3, 128.5, 124.5, 49.2, 44.9, 41.4, 33.0, 25.8, 21.5.
HPLC chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 99/1, flow rate = 1.0
mL/min): 6.6 min (minor), 7.2 min (major).
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(R)ꢀ3ꢀ(4ꢀFluorophenyl)cyclohexanone (2i).8b Colorless oil. (64.2 mg, 83% yield, 88% ee) H
NMR (400 MHz, CDCl3): δ ppm 7.22 – 7.14 (m, 2H), 7.05 – 6.96 (m, 2H), 3.06 – 2.93 (m, 1H),
13
2.62 – 2.31 (m, 4H), 2.19 – 2.11 (m, 1H), 2.11 – 2.02 (m, 1H), 1.89 – 1.70 (m, 2H). C NMR
(100 MHz, CDCl3): δ ppm 210.9, 161.7 (d, J = 244.9 Hz), 140.2 (d, J = 3.0 Hz), 128.1 (d, J = 7.9
Hz), 115.6 (d, J = 21.2 Hz), 49.2, 44.1, 41.3, 33.0, 25.5. HPLC chromatograms (Daicel Chiralpak
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ADꢀH, Hexanes/iꢀPrOH = 99/1, flow rate = 1.0 mL/min): 10.0 min (minor), 13.0 min (major).
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(R)ꢀ3ꢀ(4ꢀTrifluoromethylphenyl)cyclohexanone (2j).10c Colorless oil. (74.6 mg, 77% yield, 90%
ee) 1H NMR (400 MHz, CDCl3): δ ppm 7.58 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 3.14 –
3.02 (m, 1H), 2.64 – 2.34 (m, 4H), 2.22 – 2.13 (m, 1H), 2.13 – 2.06 (m, 1H), 1.94 – 1.73 (m, 2H).
13C NMR (100 MHz, CDCl3): δ ppm 210.4, 148.3, 129.2 (q, J = 32.4 Hz), 125.8 (q, J = 3.8 Hz),
124.3 (q, J = 271.8 Hz), 48.6, 44.6, 41.2, 32.6, 25.5. HPLC chromatograms (Daicel Chiralpak
OJꢀH, Hexanes/iꢀPrOH = 99/1, flow rate = 1.0 mL/min): 13.9 min (minor), 17.5 min (major).
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(R)ꢀ3ꢀ(1ꢀNaphthyl)cyclohexanone (2k).10b White solid. (87.9 mg, 98% yield, 85% ee) H NMR
(400 MHz, CDCl3): δ ppm 8.04 (d, J = 8.8 Hz, 1H), 7.92 – 7.85 (m, 1H), 7.76 (d, J = 8.1 Hz, 1H),
7.57 – 7.38 (m, 4H), 3.93 – 3.79 (m, 1H), 2.83 – 2.41 (m, 4H), 2.30 – 2.15 (m, 2H), 2.08 – 1.85
13
(m, 2H). C NMR (100 MHz, CDCl3): δ ppm 211.4, 140.2, 134.1, 131.0, 129.2, 127.4, 126.4,
125.8, 125.7, 122.8, 122.6, 48.7, 41.6, 39.5, 32.4, 25.7. HPLC chromatograms (Daicel Chiralpak
ADꢀH, Hexanes/iꢀPrOH = 98/2, flow rate = 1.0 mL/min): 9.9 min (minor), 10.4 min (major).
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(R)ꢀ3ꢀ(2ꢀNaphthyl)cyclohexanone (2l).10b White solid. (74.6 mg, 83% yield, 91% ee) H NMR
(400 MHz, CDCl3): δ ppm 7.89 – 7.77 (m, 3H), 7.69 – 7.62 (m, 1H), 7.53 – 7.42 (m, 2H), 7.37
(dd, J = 8.6, 1.7 Hz, 1H), 3.26 – 3.13 (m, 1H), 2.75 – 2.59 (m, 2H), 2.55 – 2.37 (m, 2H), 2.24 –
13
2.12 (m, 2H), 2.04 – 1.76 (m, 2H). C NMR (100 MHz, CDCl3): δ ppm 211.1, 141.9, 133.7,
132.5, 128.5, 127.8, 127.7, 126.3, 125.8, 125.4, 124.9, 49.0, 44.9, 41.4, 32.8, 25.7. HPLC
chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 90/10, flow rate = 1.0 mL/min): 6.4
min (minor), 6.8 min (major).
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(S)ꢀ4ꢀPhenylheptanꢀ2ꢀone (2m).10b Colorless oil. (52.6 mg, 69% yield, 42% ee) H NMR (400
MHz, CDCl3): δ ppm 7.33 – 7.25 (m, 2H), 7.23 – 7.13 (m, 3H), 3.19 – 3.07 (m, 1H), 2.79 – 2.64
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(m, 2H), 2.01 (s, 3H), 1.67 – 1.48 (m, 2H), 1.28 – 1.05 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H). C
NMR (100 MHz, CDCl3): δ ppm 208.1, 144.7, 128.5, 127.6, 126.4, 51.0, 41.2, 38.8, 30.7, 20.6,
14.1. HPLC chromatograms (Daicel Chiralpak IA, Hexanes/iꢀPrOH = 99/1, flow rate = 0.5
mL/min): 10.2 min (major), 10.7 min (minor).
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General procedure for the Rh(I)-catalyzed 1,2-addition of arylboronic acids to N,N-
dimethylsulfamoyl aldimines
A 25 mL flask was flushed with nitrogen and charged with (R)ꢀL1 (5.4 mg, 0.015 mmol),
Rh(acac)(C2H4)2 (1.55 mg, 0.006 mmol) and 1 mL of degassed toluene. The mixture was stirred
for 10 min at ambient temperature. The reaction mixture was mixed with arylboronic acid (0.4
o
mmol) and aldimine (0.2 mmol). After stirred at 25 C for 3 h, the reaction mixture was passed
through a pad of silica gel with ethyl acetate and the filtrate was concentrated under vacuum. The
residue was purified by flash chromatography on silica gel (EtOAc/hexane=1:4 to 1:10) to afford
the corresponding product 4.
N'ꢀ[(S)ꢀ(4ꢀchlorophenyl)phenylmethyl]ꢀN,Nꢀdimethylsulfamide (4a).18 White solid. (63.6 mg, 98%
yield, 95% ee) 1H NMR (400 MHz, CDCl3): δ ppm 7.42 – 7.27 (m, 9H), 5.60 (d, J = 6.8 Hz, 1H),
4.87 (d, J = 6.7 Hz, 1H), 2.58 (s, 6H). 13C NMR (100 MHz, CDCl3): δ ppm 141.0, 140.0, 133.8,
129.1, 129.0, 128.9, 128.2, 127.5, 61.2, 37.8. HPLC chromatograms (Daicel Chiralpak ODꢀH,
Hexanes/iꢀPrOH = 90/10, flow rate = 0.8 mL/min): 10.4 min (major), 13.2 min (minor).
N'ꢀ[(S)ꢀ(4ꢀfluorophenyl)phenylmethyl]ꢀN,Nꢀdimethylsulfamide (4b).18 White solid. (55.8 mg, 90%
1
yield, 94% ee) H NMR (400 MHz, CDCl3): δ ppm 7.39 – 7.33 (m, 2H), 7.33 – 7.27 (m, 5H),
13
7.07 – 6.99 (m, 2H), 5.61 (d, J = 6.7 Hz, 1H), 4.87 (d, J = 6.8 Hz, 1H), 2.58 (s, 6H). C NMR
(100 MHz, CDCl3): δ ppm 162.4 (d, J = 246.8 Hz), 141.3, 137.4 (d, J = 3.2 Hz), 129.3 (d, J = 8.1
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Hz), 129.0, 128.1, 127.5, 115.7 (d, J = 21.5 Hz), 61.1, 37.8. 19F NMR (376 MHz, CDCl3): δ ppm
ꢀ114.4. HPLC chromatograms (Daicel Chiralpak ODꢀH, Hexanes/iꢀPrOH = 90/10, flow rate =
0.8 mL/min): 10.2 min (major), 12.0 min (minor).
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N'ꢀ[(S)ꢀ(4ꢀtrifluoromethylphenyl)phenylmethyl]ꢀN,Nꢀdimethylsulfamide (4c).18 White solid.
(64.5 mg, 90% yield, 94% ee) 1H NMR (400 MHz, CDCl3): δ ppm 7.61 (d, J = 8.2 Hz, 2H), 7.47
(d, J = 8.1 Hz, 2H), 7.39 – 7.27 (m, 5H), 5.67 (d, J = 7.0 Hz, 1H), 5.05 (d, J = 7.0 Hz, 1H), 2.59
(s, 6H). 13C NMR (100 MHz, CDCl3): δ ppm 145.5, 140.7, 130.1 (q, J = 32.5 Hz), 129.2, 128.4,
127.9, 127.5, 125.8 (q, J = 3.8 Hz), 61.4, 37.8. 19F NMR (376 MHz, CDCl3): δ ppm ꢀ62.6. HPLC
chromatograms (Daicel Chiralpak ODꢀH, Hexanes/iꢀPrOH = 90/10, flow rate = 0.8 mL/min): 8.9
min (major), 12.9 min (minor).
N'ꢀ[(S)ꢀ(4ꢀbromophenyl)phenylmethyl]ꢀN,Nꢀdimethylsulfamide (4d). Off white solid. (62.5 mg,
85% yield, 87% ee) 1H NMR (400 MHz, CDCl3): δ ppm 7.48 (d, J = 8.2 Hz, 2H), 7.39 – 7.27 (m,
5H), 7.21 (d, J = 8.6 Hz, 2H), 5.58 (d, J = 6.9 Hz, 1H), 4.78 (d, J = 7.2 Hz, 1H), 2.59 (s, 6H). 13C
NMR (100 MHz, CDCl3): δ ppm 141.0, 140.6, 132.0, 129.3, 129.1, 128.3, 127.5, 122.0, 61.2,
37.8. HRMS (ESI) calculated for C15H17BrN2O2S [M+Na]+: 391.0092, Found: 391.0090. HPLC
chromatograms (Daicel Chiralpak ODꢀH, Hexanes/iꢀPrOH = 90/10, flow rate = 0.8 mL/min):
10.5 min (major), 13.6 min (minor).
N'ꢀ[(S)ꢀ(pꢀtolyl)phenylmethyl]ꢀN,Nꢀdimethylsulfamide (4e).18 White solid. (48.9 mg, 80% yield,
95% ee for 4e and 58.1 mg, 95% yield, ꢀ91% ee for 4k) 1H NMR (400 MHz, CDCl3): δ ppm 7.37
– 7.26 (m, 5H), 7.20 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 5.59 (d, J = 6.6 Hz, 1H), 4.81
(d, J = 6.8 Hz, 1H), 2.57 (s, 6H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 141.7, 138.6,
137.7, 129.6, 128.8, 127.8, 127.5, 127.4, 61.5, 37.8, 21.2. HPLC chromatograms (Daicel
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N'ꢀ[(S)ꢀ(4ꢀmethoxyphenyl)phenylmethyl]ꢀN,Nꢀdimethylsulfamide (4f).18 White solid. (54.9 mg,
86% yield, 93% ee for 4f and 62.0 mg, 97% yield, ꢀ89% ee for 4j) 1H NMR (400 MHz, CDCl3):
δ ppm 7.39 – 7.27 (m, 5H), 7.23 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.58 (d, J = 6.6 Hz,
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1H), 4.89 (d, J = 6.7 Hz, 1H), 3.79 (s, 3H), 2.56 (s, 6H). C NMR (100 MHz, CDCl3): δ ppm
159.2, 141.8, 133.7, 128.8, 128.8, 127.8, 127.5, 114.2, 61.2, 55.4, 37.7. HPLC chromatograms
(Daicel Chiralpak ODꢀH, Hexanes/iꢀPrOH = 90/10, flow rate = 0.8 mL/min): 15.2 min (major),
18.8 min (minor).
N'ꢀ[(S)ꢀ(3ꢀchlorophenyl)phenylmethyl]ꢀN,Nꢀdimethylsulfamide (4g). White solid. (51.5 mg, 79%
yield, 96% ee) 1H NMR (400 MHz, CDCl3): δ ppm 7.39 – 7.20 (m, 9H), 5.59 (d, J = 6.6 Hz, 1H),
13
4.87 (d, J = 6.8 Hz, 1H), 2.59 (s, 6H) C NMR (100 MHz, CDCl3): δ ppm 143.5, 140.8, 134.8,
130.2, 129.1, 128.3, 128.1, 127.7, 127.5, 125.7, 61.3, 37.8. HRMS (ESI) calculated for
C15H17ClN2O2S [M+Na]+: 347.0597, Found: 347.0609. HPLC chromatograms (Daicel Chiralpak
IC, Hexanes/iꢀPrOH = 90/10, flow rate = 0.8 mL/min): 22.3 min (major), 23.6 min (minor).
N'ꢀ[(S)ꢀ(2ꢀchlorophenyl)phenylmethyl]ꢀN,Nꢀdimethylsulfamide (4h). White solid. (60.2 mg, 93%
yield, 89% ee) 1H NMR (400 MHz, CDCl3): δ ppm 7.56 (d, J = 8.2 Hz, 1H), 7.45 – 7.27 (m, 8H),
13
6.02 (d, J = 7.5 Hz, 1H), 4.94 (d, J = 7.8 Hz, 1H), 2.64 (s, 6H). C NMR (100 MHz, CDCl3): δ
ppm 140.1, 138.9, 133.1, 130.3, 129.2, 128.9, 128.0, 127.5, 127.3, 58.7, 37.8. HRMS (ESI)
calculated for C15H17ClN2O2S [M+Na]+: 347.0597, Found: 347.0604. HPLC chromatograms
(Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 80/20, flow rate = 0.5 mL/min): 13.4 min (major),
16.6 min (minor).
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N'ꢀ[(S)ꢀ(2ꢀthienyl)phenylmethyl]ꢀN,Nꢀdimethylsulfamide (4i).18 White solid. (56.1 mg, 95%
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yield, 92% ee) H NMR (400 MHz, CDCl3): δ ppm 7.42 – 7.30 (m, 5H), 7.27 – 7.24 (m, 1H),
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6.94 (dd, J = 5.1, 3.6 Hz, 1H), 6.91 – 6.86 (m, 1H), 5.83 (d, J = 6.9 Hz, 1H), 4.90 (d, J = 6.9 Hz,
1H), 2.61 (s, 6H). 13C NMR (100 MHz, CDCl3): δ ppm 145.6, 141.3, 128.9, 128.4, 127.3, 127.1,
126.2, 125.8, 58.0, 37.8. HPLC chromatograms (Daicel Chiralpak OJꢀH, Hexanes/iꢀPrOH =
80/20, flow rate = 1.0 mL/min): 18.5 min (minor), 27.3 min (major).
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N'ꢀ[(R)ꢀ(mꢀtolyl)phenylmethyl]ꢀN,Nꢀdimethylsulfamide (4l). White solid. (39.6 mg, 65% yield,
94% ee) 1H NMR (400 MHz, CDCl3): δ ppm 7.38 – 7.30 (m, 4H), 7.30 – 7.25 (m, 1H), 7.23 (t, J
= 7.6 Hz, 1H), 7.15 – 7.06 (m, 3H), 5.58 (d, J = 6.5 Hz, 1H), 4.82 (d, J = 6.8 Hz, 1H), 2.57 (s,
6H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 141.6, 141.5, 138.6, 128.8, 128.8, 128.7,
128.2, 127.9, 127.5, 124.5, 61.8, 37.7, 21.6. HRMS (ESI) calculated for C16H20N2O2S [M+Na]+:
327.1143, Found: 327.1132. HPLC chromatograms (Daicel Chiralpak IC, Hexanes/iꢀPrOH =
80/20, flow rate = 1.0 mL/min): 13.1 min (minor), 13.8 min (major).
General procedure for the Rh(I)-catalyzed 1,4-addition of arylboronic acids to α,β-
unsaturated N-tosyl ketimines.
A 25 mL flask was flushed with nitrogen and charged with (R)ꢀL2 (9.0 mg, 0.025 mmol),
Rh(acac)(C2H4)2 (2.6 mg, 0.01 mmol) and 2.0 mL of degassed toluene. The mixture was stirred
for 10 min at ambient temperature. The reaction mixture was mixed with arylboronic acid (0.6
o
mmol) and α,βꢀunsaturated Nꢀtosyl ketimine (0.2 mmol). After stirred at 25 C, the reaction
mixture was passed through a pad of silica gel with ethyl acetate and the filtrate was
concentrated under vacuum. The residue was purified by flash chromatography on silica gel
(Et2O/hexane=1:1 to 1:5) to afford the corresponding product 6.
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(6a).7b White solid (84.2 mg, 90% yield, 94% ee) H NMR (400 MHz, CDCl3): δ ppm 7.60 (d, J
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= 8.3 Hz, 2H), 7.45 (dd, J = 7.5, 2.1 Hz, 2H), 7.31 – 7.19 (m, 8H), 6.94 – 6.76 (m, 6H), 6.06 (s,
1H), 5.90 (dd, J = 8.8, 0.7 Hz, 2H), 4.33 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 2.43 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ ppm 158.5, 144.0, 143.4, 137.3, 137.0, 135.4, 134.9, 129.8, 129.1, 128.9,
128.7, 128.2, 128.0, 127.7, 127.6, 127.5, 126.9, 114.3, 55.4, 48.1, 21.7. HRMS (ESI) calculated
for C29H27NO3S [M+Na]+: 492.1609, Found: 492.1631. HPLC chromatograms (Daicel Chiralpak
ADꢀH, Hexanes/iꢀPrOH = 80/20, flow rate = 1.0 mL/min): 12.1 min (major), 13.3 min (minor).
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(Z)ꢀNꢀ[(3S)ꢀ3ꢀ(3ꢀmethoxyphenyl)ꢀ1,3ꢀdiphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide
(6b). White solid (79.4 mg, 85% yield, 91% ee) 1H NMR (400 MHz, CDCl3): δ ppm 7.60 (d, J =
8.3 Hz, 2H), 7.46 – 7.44 (m, 2H), 7.32 – 7.27 (m, 3H), 7.26 – 7.15 (m, 6H), 6.94 (d, J = 7.0 Hz,
1H), 6.74 (dd, J = 8.8, 2.2 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 6.49 (s, 1H), 6.03 (s, 1H), 5.92 (d, J
= 9.6 Hz, 1H), 4.33 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ ppm 160.0, 144.5, 144.0, 142.8, 137.3, 137.0, 135.6, 129.9, 129.8, 128.9, 128.7, 128.2, 128.1,
127.6, 127.4, 127.3, 127.0, 120.5, 114.4, 111.8, 55.3, 48.9, 21.7. HRMS (ESI) calculated for
C29H27NO3S [M+Na]+: 492.1609, Found: 492.1639. HPLC chromatograms (Daicel Chiralpak IB,
Hexanes/iꢀPrOH = 95/5, flow rate = 1.0 mL/min): 13.9 min (major), 14.8 min (minor).
(Z)ꢀNꢀ[(3S)ꢀ3ꢀ(4ꢀmethylphenyl)ꢀ1,3ꢀdiphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide (6c).
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White solid (89.8 mg, 99% yield, 93% ee) H NMR (400 MHz, CDCl3): δ ppm 7.61 (d, J = 8.2
Hz, 2H), 7.48 – 7.45 (m, 2H), 7.32 – 7.17 (m, 8H), 7.06 (d, J = 7.9 Hz, 2H), 6.92 (d, J = 6.9 Hz,
2H), 6.83 (d, J = 8.0 Hz, 2H), 6.03 (s, 1H), 5.92 (d, J = 8.8 Hz, 1H), 4.31 (d, J = 8.8 Hz, 1H),
2.43 (s, 3H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 144.0, 143.2, 139.9, 137.4, 136.9,
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136.6, 135.4, 129.7, 129.6, 128.8, 128.7, 128.2, 128.0, 128.0, 127.7, 127.6, 127.4, 126.8, 48.5,
21.7, 21.1. HRMS (ESI) calculated for C29H27NO2S [M+Na]+: 476.1660, Found: 476.1671.
HPLC chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 80/20, flow rate = 1.0
mL/min): 8.7 min (minor), 10.3 min (major).
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(Z)ꢀNꢀ[(3S)ꢀ3ꢀ(3ꢀmethylphenyl)ꢀ1,3ꢀdiphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide (6d).
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White solid (72.7 mg, 80% yield, 91% ee) H NMR (400 MHz, CDCl3): δ ppm 7.61 (d, J = 8.3
Hz, 2H), 7.48 – 7.45 (m, 2H), 7.32 – 7.18 (m, 8H), 7.14 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 7.5 Hz,
1H) 6.93 (d, J = 7.0 Hz, 1H), 6.75 – 6.74 (m, 2H), 6.02 (s, 1H), 5.92 (d, J = 8.7 Hz, 1H), 4.30 (d,
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J = 8.7 Hz, 1H), 2.43 (s, 3H), 2.29 (s, 3H). C NMR (100 MHz, CDCl3): δ ppm 144.0, 143.1,
142.9, 138.6, 137.4, 137.0, 135.5, 129.8, 128.9, 128.9, 128.8, 128.7, 128.2, 128.1, 127.8, 127.6,
127.6, 127.4, 126.9, 125.2, 48.9, 21.7, 21.6. HRMS (ESI) calculated for C29H27NO2S [M+Na]+:
476.1660, Found: 476.1677. HPLC chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH =
90/10, flow rate = 1.0 mL/min): 12.8 min (major), 14.1 min (minor).
(Z)ꢀNꢀ[(3S)ꢀ3ꢀ(4ꢀ(tertꢀbutyl)phenyl)ꢀ1,3ꢀdiphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide
(6e). White solid. (93.7 mg, 95% yield, 96% ee) 1H NMR (400 MHz, CDCl3): δ ppm 7.64 – 7.59
(m, 2H), 7.49 – 7.45 (m, 2H), 7.32 – 7.18 (m, 11H), 6.96 – 6.91 (m, 2H), 6.89 – 6.84 (m, 2H),
6.06 (s, 1H), 5.94 (dd, J = 8.7, 0.8 Hz, 1H), 4.31 (d, J = 8.8 Hz, 1H), 2.44 (s, 3H), 1.30 (s, 9H).
13C NMR (100 MHz, CDCl3) δ 149.8, 144.0, 143.2, 139.8, 137.4, 137.0, 135.4, 129.8, 128.9,
128.7, 128.2, 128.1, 127.7, 127.7, 127.6, 127.5, 126.9, 125.8, 48.5, 34.5, 31.5, 21.7. HRMS (ESI)
calculated for C32H33NO2S [M+Na]+: 518.2130, Found: 518.2175. HPLC chromatograms (Daicel
Chiralpak ADꢀH, Hexanes/iꢀPrOH = 80/20, flow rate = 1.0 mL/min): 6.6 min (minor), 7.4 min
(major).
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(Z)ꢀNꢀ[(3S)ꢀ3ꢀ(2ꢀnaphthyl)ꢀ1,3ꢀdiphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide
(6f).
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White solid (73.3 mg, 75% yield, 94% ee) H NMR (400 MHz, CDCl3): δ ppm 7.77 – 7.68 (m,
3H), 7.58 (d, J = 8.2 Hz, 2H), 7.46 – 7.40 (m, 4H), 7.38 (s, 1H), 7.29 – 7.16 (m, 8H), 7.03 (dd, J
= 8.5, 1.7 Hz, 1H), 6.96 (d, J = 7.2 Hz, 2H), 6.17 (s, 1H), 5.99 (d, J = 9.0 Hz, 1H), 4.58 (d, J =
9.0 Hz, 1H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 144.0, 142.9, 140.3, 137.3, 136.9,
135.7, 133.5, 132.4, 129.7, 128.9, 128.8, 128.7, 128.2, 127.9, 127.8, 127.6, 127.5, 127.2, 127.0,
126.6, 126.4, 126.3, 126.0, 49.0, 21.6. HRMS (ESI) calculated for C32H27NO2S [M+Na]+:
512.1660, Found: 512.1697. HPLC chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH =
90/10, flow rate = 1.0 mL/min): 21.5 min (minor), 26.3 min (major).
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(Z)ꢀNꢀ[(3S)ꢀ3ꢀ(4ꢀfluorophenyl)ꢀ1,3ꢀdiphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide (6g).
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White solid (30.7 mg, 35% yield, 93% ee for 6g and 80.3 mg, 91% yield, ꢀ94% ee for 6k) H
NMR (400 MHz, CDCl3): δ ppm 7.58 (d, J = 8.3 Hz, 2H), 7.42 (dd, J = 7.7, 1.8 Hz, 2H), 7.32 –
7.20 (m, 8H), 6.96 – 6.89 (m, 6H), 6.07 (s, 1H), 5.90 (d, J = 9.2 Hz, 1H), 4.48 (d, J = 9.2 Hz, 1H),
2.41 (s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 161.7 (d, J = 245.6 Hz), 144.0, 142.8, 138.8 (d,
J = 3.3 Hz), 137.2, 136.9, 135.5, 129.7, 129.6 (d, J = 7.9 Hz), 129.0, 128.8, 128.2, 128.1, 127.6,
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127.4, 127.3, 127.0, 115.6 (d, J = 21.3 Hz), 48.0, 21.7. F NMR (376 MHz, CDCl3): δ ppm ꢀ
115.9. HRMS (ESI) calculated for C28H24FNO2S [M+Na]+: 480.1409, Found: 480.1428. HPLC
chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 95/5, flow rate = 1.0 mL/min): 30.6
min (minor), 33.6 min (major).
(Z)ꢀNꢀ[(3S)ꢀ3ꢀ(4ꢀchlorophenyl)ꢀ1,3ꢀdiphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide (6h).
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White solid (73.4 mg, 77% yield, 91% ee for 6h and 90.9 mg, 96% yield, ꢀ91% ee for 6p) H
NMR (400 MHz, CDCl3): δ ppm 7.57 (d, J = 8.1 Hz, 2H), 7.42 – 7.38z (m, 2H), 7.28 – 7.16 (m,
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10H), 6.95 (d, J = 7.2 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.03 (s, 1H), 5.88 (d, J = 9.2 Hz, 1H),
4.47 (d, J = 9.2 Hz, 1H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 144.0, 142.5, 141.6,
137.2, 136.9, 135.6, 132.7, 129.7, 129.5, 129.0, 128.9, 128.8, 128.2, 128.1, 127.6, 127.4, 127.1,
127.0, 48.1, 21.7. HRMS (ESI) calculated for C28H24ClNO2S [M+Na]+: 496.1114, Found:
496.1135. HPLC chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 90/10, flow rate =
1.0 mL/min): 15.8 min (minor), 20.4 min (major).
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(Z)ꢀNꢀ[(3S)ꢀ3ꢀ(3ꢀchlorophenyl)ꢀ1,3ꢀdiphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide (6i).
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White solid. (45.7 mg, 48% yield, 95% ee) H NMR (400 MHz, CDCl3): δ ppm 7.63 – 7.57 (m,
2H), 7.47 – 7.42 (m, 2H), 7.32 – 7.26 (m, 5H), 7.26 – 7.21 (m, 3H), 7.19 – 7.15 (m, 2H), 6.97 (m,
2H), 6.83 (m, 2H), 6.06 (s, 1H), 5.89 (d, J = 9.1 Hz, 1H), 4.41 (d, J = 9.1 Hz, 1H), 2.43 (s, 3H).
13C NMR (100 MHz, CDCl3): δ ppm 145.2, 144.2, 142.1, 137.1, 136.9, 135.9, 134.6, 130.1,
129.8, 129.1, 128.9, 128.3, 128.3, 128.1, 127.6, 127.4, 127.3, 127.1, 126.6, 126.2, 48.6, 21.7.
HRMS (ESI) calculated for C28H24ClNO2S [M+Na]+: 496.1114, Found: 496.1139. HPLC
chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 95/5, flow rate = 1.0 mL/min): 25.7
min (major), 27.4 min (minor).
(Z)ꢀNꢀ[(3S)ꢀ3ꢀ(4ꢀbromophenyl)ꢀ1,3ꢀdiphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide (6j).
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White solid. (83.3 mg, 80% yield, 91% ee) H NMR (400 MHz, CDCl3): δ ppm 7.57 (d, J = 8.3
Hz, 2H), 7.44 – 7.39 (m, 2H), 7.38 – 7.34 (m, 2H), 7.31 – 7.18 (m, 8H), 6.98 – 6.92 (m, 2H),
6.82 (d, J = 8.4 Hz, 2H), 6.11 (s, 1H), 5.88 (d, J = 9.6 Hz, 1H), 4.48 (d, J = 9.1 Hz, 1H), 2.41 (s,
3H). 13C NMR (100 MHz, CDCl3): δ ppm 144.1, 142.4, 142.2, 137.1, 136.9, 135.7, 131.9, 129.9,
129.7, 129.0, 128.9, 128.2, 128.1, 127.6, 127.4, 127.2, 126.9, 120.8, 48.3, 21.7. HRMS (ESI)
calculated for C28H24BrNO2S [M+Na]+: 540.0609, Found: 540.0622. HPLC chromatograms
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(Z)ꢀNꢀ[(3R)ꢀ3ꢀphenylꢀ1,3ꢀbis(4ꢀfluorophenyl)ꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide (6l).
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White solid (80.9 mg, 85% yield, 93% ee) H NMR (400 MHz, CDCl3): δ ppm 7.58 – 7.56 (m,
2H), 7.42 – 7.38 (m, 2H), 7.29 – 7.19 (m, 5H), 6.99 – 6.87 (m, 8H), 6.07 (s, 1H), 5.81 (d, J = 9.1
Hz, 1H), 4.42 (d, J = 9.1 Hz, 1H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 163.7 (d, J
= 143.7 Hz), 161.2 (d, J = 141.3 Hz), 144.2, 142.7, 138.7 (d, J = 3.3 Hz), 136.8, 134.6, 133.3 (d,
J = 3.2 Hz), 129.8, 129.6 (d, J = 7.9 Hz), 129.4 (d, J = 8.2 Hz), 129.0, 128.1, 127.4, 127.1, 126.8,
115.7 (d, J = 21.3 Hz), 115.2 (d, J = 21.7 Hz), 48.0, 21.7. 19F NMR (376 MHz, CDCl3): δ ppm ꢀ
112.8, ꢀ115.8. HRMS (ESI) calculated for C28H23F2NO2S [M+Na]+: 498.1315, Found: 498.1333.
HPLC chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 95/5, flow rate = 1.0
mL/min): 29.0 min (major), 31.6 min (minor).
(Z)ꢀNꢀ[(3R)ꢀ3ꢀ(4ꢀfluorophenyl)ꢀ3ꢀphenylꢀ1ꢀ(pꢀtolyl)ꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀ
methylbenzenesulfonamide (6m). White solid (75.3 mg, 80% yield, 93% ee) 1H NMR (400 MHz,
CDCl3): δ ppm 7.59 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.28 – 7.19 (m, 5H), 7.09 (d, J
= 7.9 Hz, 2H), 6.95 – 6.86 (m, 6H), 6.00 (s, 1H), 5.84 (d, J = 9.7 Hz, 1H), 4.40 (d, J = 9.2 Hz,
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1H), 2.42 (s, 3H), 2.35 (s, 3H). C NMR (100 MHz, CDCl3): δ ppm 161.7 (d, J = 245.5 Hz),
143.9, 142.9, 138.9 (d, J = 3.2 Hz), 138.8, 136.9, 135.4, 134.4, 129.7, 129.6 (d, J = 8.0 Hz),
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128.9, 128.1, 127.5, 127.4, 127.0, 126.3, 115.6 (d, J = 21.3 Hz), 47.9, 21.6, 21.4. F NMR (376
MHz, CDCl3): δ ppm ꢀ116.0. HRMS (ESI) calculated for C29H26FNO2S [M+Na]+: 494.1566,
Found: 494.1577. HPLC chromatograms (Daicel Chiralpak IB, Hexanes/iꢀPrOH = 95/5, flow
rate = 1.0 mL/min): 13.4 min (major), 14.5 min (minor).
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methylbenzenesulfonamide (6n). White solid. (68.0 mg, 70% yield, 92% ee) 1H NMR (400 MHz,
CDCl3): δ ppm 7.60 (d, J = 8.3 Hz, 2H), 7.43 (dd, J = 8.8, 5.4 Hz, 2H), 7.28 – 7.17 (m, 5H), 7.00
– 6.77 (m, 8H), 6.14 (s, 1H), 5.83 (d, J = 8.8 Hz, 1H), 4.32 (d, J = 8.8 Hz, 1H), 3.78 (s, 3H), 2.43
(s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 163.1 (d, J = 248.0 Hz), 158.6, 144.1, 143.3, 136.9,
134.8, 134.4, 133.4 (d, J = 3.1 Hz), 129.8, 129.4 (d, J = 8.2 Hz), 129.1, 128.9, 128.0, 127.4,
127.3, 126.9, 115.1 (d, J = 21.7 Hz), 114.3, 55.4, 48.0, 21.7. 19F NMR (376 MHz, CDCl3): δ ppm
ꢀ113.1. HRMS (ESI) calculated for C29H26FNO3S [M+Na]+: 510.1515, Found: 510.1541. HPLC
chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 90/10, flow rate = 1.0 mL/min):
20.2 min (minor), 21.7 min (major).
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(Z)ꢀNꢀ[(3R)ꢀ3ꢀ(4ꢀfluorophenyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀ
methylbenzenesulfonamide (6o). White solid. (80.2 mg, 82% yield, 97% ee) 1H NMR (400 MHz,
CDCl3): δ ppm 7.59 (d, J = 8.3 Hz, 2H), 7.45 – 7.40 (m, 2H), 7.32 – 7.26 (m, 3H), 7.24 – 7.18
(m, 2H), 6.96 – 6.84 (m, 6H), 6.82 – 6.77 (m, 2H), 6.15 (s, 1H), 5.87 (dd, J = 9.0, 0.7 Hz, 1H),
4.44 (d, J = 9.0 Hz, 1H), 3.78 (s, 3H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ ppm 161.7 (d,
J = 245.4 Hz), 158.6, 144.0, 139.2 (d, J = 3.2 Hz), 137.2, 137.0, 135.3, 134.7, 129.7, 129.5 (d, J
= 7.9 Hz), 129.1, 128.7, 128.2, 127.6, 127.6, 127.4, 115.6 (d, J = 21.3 Hz), 114.4, 55.4, 47.2,
19
21.7. F NMR (376 MHz, CDCl3): δ ppm ꢀ116.1. HRMS (ESI) calculated for C29H26FNO3S
[M+Na]+: 510.1515, Found: 510.1527. HPLC chromatograms (Daicel Chiralpak ID, Hexanes/iꢀ
PrOH = 80/20, flow rate = 1.0 mL/min): 20.3 min (major), 22.6 min (minor).
(Z)ꢀNꢀ[(3R)ꢀ3ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀ
methylbenzenesulfonamide (6q). White solid. (87.9 mg, 87% yield, 93% ee) 1H NMR (400 MHz,
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CDCl3): δ ppm 7.58 (d, J = 8.3 Hz, 2H), 7.42 (dd, J = 7.8, 1.7 Hz, 2H), 7.31 – 7.26 (m, 3H), 7.23
– 7.18 (m, 4H), 6.87 (t, J = 9.2 Hz, 4H), 6.82 – 6.77 (m, 2H), 6.12 (s, 1H), 5.85 (d, J = 9.1 Hz,
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1H), 4.43 (d, J = 9.0 Hz, 1H), 3.78 (s, 3H), 2.41 (s, 3H). C NMR (100 MHz, CDCl3): δ ppm
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158.7, 144.0, 142.0, 137.1, 136.9, 135.5, 134.4, 132.6, 129.7, 129.4, 129.1, 128.9, 128.8, 128.2,
127.6, 127.4, 127.3, 114.4, 55.4, 47.4, 21.7. HRMS (ESI) calculated for C29H26ClNO3S [M+Na]+:
526.1220, Found: 526.1263. HPLC chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH =
90/10, flow rate = 1.0 mL/min): 22.2 min (major), 27.0 min (minor).
(Z)ꢀNꢀ[(3R)ꢀ3ꢀ(4ꢀnitrophenyl)ꢀ1,3ꢀdiphenylꢀ1ꢀpropenꢀ1ꢀyl]ꢀ4ꢀmethylbenzenesulfonamide (6r).
Pale yellow solid. (49.2 mg, 51% yield, 84% ee) 1H NMR (400 MHz, CDCl3): δ ppm 8.08 (d, J =
8.8 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.41 – 7.34 (m, 2H), 7.32 – 7.23 (m, 6H), 7.16 (dd, J = 8.7,
2.2 Hz, 4H), 7.04 – 6.97 (m, 2H), 6.41 (s, 1H), 5.93 (d, J = 9.6 Hz, 1H), 4.86 (d, J = 9.6 Hz, 1H),
13
2.39 (s, 3H). C NMR (100 MHz, CDCl3): δ ppm 150.9, 146.8, 144.1, 141.6, 136.9, 136.9,
136.1, 129.7, 129.2, 129.1, 129.0, 128.3, 128.2, 127.5, 127.5, 127.4, 126.1, 123.9, 48.6, 21.6.
HRMS (ESI) calculated for C28H24N2O4S [M+Na]+: 507.1354, Found: 507.1377. HPLC
chromatograms (Daicel Chiralpak ADꢀH, Hexanes/iꢀPrOH = 80/20, flow rate = 1.0 mL/min):
15.7 min (major), 17.5 min (minor).
Procedure for acid hydrolysis of 6b
A 5 mL reaction vial was charged with (S)ꢀ6b (47.0 mg, 0.1 mmol), THF (0.8 mL) and conc.
o
HCl (0.2 mL). The resulting solution was stirred at 100 C for 1 h. After cooling to ambient
temperature, saturated NaHCO3 solution (5 mL) was poured into the flask and the mixture was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by
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chromatography on silica gel (diethyl ether/hexane=1:5) to give (S)ꢀ3ꢀ(3ꢀmethoxyphenyl)ꢀ1,3ꢀ
diphenylpropanꢀ1ꢀone17 as white solid (27.6 mg, 87% yield).
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1H NMR (400 MHz, CDCl3): δ ppm 7.99 – 7.88 (m, 2H), 7.58 – 7.50 (m, 1H), 7.44 (t, J = 7.6 Hz,
2H), 7.30 – 7.24 (m, 4H), 7.22 – 7.12 (m, 2H), 6.91 – 6.78 (m, 2H), 6.72 (dd, J = 8.0, 2.2 Hz,
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1H), 4.80 (t, J = 7.2 Hz, 1H), 3.78 – 3.68 (m, 5H). C NMR (100 MHz, CDCl3): δ ppm 198.1,
159.8, 145.9, 144.1, 137.2, 133.2, 129.7, 128.7, 128.7, 128.2, 127.9, 126.5, 120.4, 114.2, 111.5,
55.3, 46.1, 44.8. [α]D25 = +7.7 (c 1.00, CHCl3) for 91% ee.
ASSOCIATE CONTENT
Supporting Information
The supporting information is available free of charge on the ACS Publication website at DOI:
1
13
Additional chiral briphos ligands experimental data, copies of H and C NMR spectra, and
HPLC chromatograms (PDF)
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: hwkim@kaist.edu
Notes
The authors declare no competing financial interest
ACKNOWLEDGEMENTS
The authors are grateful for the financial support provided by the Institute for Basic Science
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