Copper-Catalyzed Asymmetric Hydroamination of Styrenes with pivZPhos as Ligand

Article abstract of DOI:10.1055/s-0040-1707346

A copper-catalyzed hydroamination of styrenes using ^pivZPhos as ligand is reported. Enantioselectivities up to 94% are achieved under optimized conditions with aryl and heteroaryl styrenes. A variety of electrophilic O -benzoylhydroxylamines are well tolerated.

Full text of DOI:10.1055/s-0040-1707346

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–E
special topic
A
en
C. Chen et al.
Special Topic
Synthesis
Copper-Catalyzed Asymmetric Hydroamination of Styrenes with
pivZPhos as Ligand
Chengsheng Chen
Piv
N
Ling Wu
Cu(OAc)2 (10 mol%)
R1 R2
N
P
pivZPhos (10 mol%)
R1 R2
N
tBu
Yuwen Wang
Linglin Wu*
tBu
R
+
Ar
P
R
Ph2MeSi-H
LiOtBu, THF
OBz
Ar
Yongda Zhang*
N
Piv
pivZPhos
14 examples
up to 89% yield
up to 94% ee
Department of Chemical Development, Boehringer I
ngelheim Pharmaceuticals, Inc., 900 Ridgebury Road/
P.O. Box 368, Ridgefield, CT 06877-0368, USA
yongda.zhang@boehringer-ingelheim.com
linglin.wu@boehringer-ingelheim.com
Published as part of the Special Topic Synthesis in Industry
Received: 15.05.2020
Accepted after revision: 19.06.2020
Published online: 06.08.2020
riety of different alkenes.5 Recently a breakthrough was
achieved by the Buchwald group where unactivated inter-
nal olefins containing two minimally differentiated aliphat-
ic substituents were effectively functionalized with excel-
lent enantioselectivities via a mild and general copper-
catalyzed hydroamination.6
DOI: 10.1055/s-0040-1707346; Art ID: ss-2020-c0264-st
Abstract A copper-catalyzed hydroamination of styrenes using pivZPhos
as ligand is reported. Enantioselectivities up to 94% are achieved under
optimized conditions with aryl and heteroaryl styrenes. A variety of
electrophilic O-benzoylhydroxylamines are well tolerated.
In the past decade, our group has developed a series of
P-chiral bis- and monophosphorus ligands based on 2,3-di-
hydrobenzo[d][1,3]oxaphosphole motif.7 This type of li-
gands have shown high reactivities and exceptional selec-
tivities in numerous asymmetric transformations including
recent examples of asymmetric hydrogenation,8 asymmet-
ric hydroformylation,9 asymmetric Suzuki–Miyaura cou-
pling,10 asymmetric addition of arylboroxines to ketones,11
and asymmetric dearomatization,12 etc. As part of our ongo-
ing research program, we have reported the synthesis of
new modular dihydrobenzoazaphosphole ligands by re-
placing the oxygen in 2,3-dihydrobenzo[d][1,3]oxaphos-
phole motif with a nitrogen.13 This modification improves
the tunability of electronic and steric properties of ligands
by adjustment of the nitrogen substituting groups. Indeed,
the pivZPhos shows superior reactivity and enantioselectivi-
ty to its O-counterpart in the copper-catalyzed asymmetric
hydrogenation of 2-substituted ketones14 and aminobora-
tion of alkenes.15 Considering that pivZPhos gives excellent
enantioselectivities in the aminoboration of alkenes, we
were interested in the application of pivZPhos to hydromina-
tion of alkenes. Here we report the copper-catalyzed asym-
metric hydroamination of alkenes with good reactivities
and enantioselectivities using pivZPhos as a ligand.
Key words hydroamination, asymmetric catalysis, copper catalysis,
styrene, phosphine ligand
Efficient syntheses of chiral amines with synthetically
useful enantiopurity are highly desirable due to the pres-
ence of chiral amines in numerous pharmaceutically active
compounds and agrochemicals. Asymmetric hydroamina-
tion, which proceeds through addition of N–H bond of a
suitable amine (primary or secondary) across an alkene
double bond, represents the most straightforward and
atom-economic approach to construct the target enantio-
enriched chiral amine. In the past decade, a great progress
has been achieved in the field of asymmetric hydroamina-
tion employing late transition metal catalysis.1 Nonetheless,
some limitations and challenges remain with this ‘tradi-
tional’ hydroamination. For example, high selectivities and
reactivities could only be realized in the intramolecular hy-
droamination. Moreover, addition of amine to unactivated
internal alkenes remains a challenge for synthetic chemists.
In 2013, a different and ‘umpolung’ approach to hydroami-
nation was reported by Buchwald2 and Miura3 groups inde-
pendently in the presence of chiral phosphine/copper cata-
lyst with hydrosilane and O-benzoylhydroxylamine as the
sources for hydrogen and nitrogen, respectively. High enan-
tioselectivities were observed in the sequential hydrocu-
pration and electrophilic amination of a series of styrenes
and -substituted styrenes.4 Later on, these and other
groups extended this hydroamination methodology to a va-
We initiated our studies by adapting Miura’s conditions
with 10 mol% of CuCl and ligand, PMHS (polymethylhydro-
siloxane) as hydride source and LiOtBu as base in THF (Table
1, entry 1).3 Although the yield in the reaction between sty-
rene (1a) and O-benzoyldibenzylhydroxylamine (2a) was
low (22%) the initial trial gave promising enantioselectivity
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
C. Chen et al.
Special Topic
Synthesis
Table 1 Reaction Condition Optimization for the Asymmetric Hy-
droamination of Styrene (1a) with O-Benzoyldibenzylhydroxylamine
(2a)a
Based on the optimization studies, we set out to evalu-
ate the alkene scope with O-benzoyldibenzylhydroxyl-
amine (Scheme 1). 2-Vinylnaphthalene (1b) delivered the
product 3b in 75% yield and 78% ee. Sterically hindered sty-
renes such as 1c were well tolerated and the product was
isolated in moderate yield and good ee (3c). When the sty-
rene bearing an electron-withdrawing group at the ortho-
position was used, the selectivity decreased to moderate
level (62% ee) in 72% yield (3d). Reactions of substrates with
electron-donating (3e) or electron-withdrawing (3f) groups
at para-position proceeded smoothly delivering the amines
in high yields and enantioselectivities. Vinyl-substituted
heteroarenes are challenging substrates and very limited
examples were reported by the Buchwald group using 1,2-
benzisoxazole as electrophilic amine source.17 We found
that nitrogen-containing substrates proved to be poor start-
ing materials for the hydroamination and only low to mod-
erate reactivities and enantioselectivities were observed
(3i, 3j). To our delight, our catalytic system was able to ac-
commodate oxygen- and sulfur-bearing substrates includ-
ing 5-vinylbenzofuran(3g) and 5-vinylbenzo[b]thiophene
(3h). For trans--methylstyrene, chiral amine 3k was pre-
pared in moderate yield and with excellent enantioselectiv-
Bn
Bn
Cu source (10 mol%)
pivZPhos (10 mol%)
N
Bn
Bn
N
+
silane (4.0 equiv)
LiOtBu (3.0 equiv)
THF, 20 °C, 16 h
OBz
1a
2a
3a
(1.0 equiv)
(3.0 equiv)
Entry
Cu source
Silane
Yield (%)
ee
1
2b
3
4
5
6
7
8
9
CuCl
PMHS
22
15
<10
47
<5
74
16
54
48
78
32
42
76
45
84
80
–
CuCl
PMHS
CuCl
DMMS
CuCl
Ph3SiH
86
–
CuCl
PhSiH3
CuCl
Ph2MeSiH
Ph2MeSiH
Ph2MeSiH
Ph2MeSiH
Ph2MeSiH
Ph2MeSiH
Ph2MeSiH
Ph2MeSiH
Ph2MeSiH
86
56
52
80
86
74
82
82
52
CuOAc
CuOTf
CuCl2
10
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
11c
12d
13e
14f
Bn
Bn
Cu(OAc)2 (10 mol%)
pivZPhos (10 mol%)
N
R1
R1
Bn
Bn
+
N
Ar
a Absolute configuration was determined by comparing specific rotation
Ph2MeSi-H (4.0 equiv)
LiOtBu (3.0 equiv)
THF, 20 °C, 16 h
OBz
with literature.2
b Ligand: O-BABIPhos.
c Base: NaOtBu.
1
2a
3
(1.0 equiv)
(3.0 equiv)
d Solvent: toluene.
e Catalyst: 5 mol%.
f 10 mol% of PPh3 was added.
Bn Bn
Bn
Bn
Bn
Bn
N
N
N
3a
78% yield, 86% ee
3b
75% yield, 78% ee
3c
60% yield, 84% ee
(84% ee) for the product 3a. Switching the ligand to its oxy-
gen analogue O-BABIPhos led to lower yield and ee (entry
2). The hydride source had a profound effect on the reactiv-
ity and enantioselectivity. While DMMS (dimethoxymeth-
ylsilane) and PhSiH3 gave little product, Ph3SiH delivered
the product 3a in moderate yield and high enantiomeric ex-
cess (entries 3–5). The optimal silane turned out to be
Ph2MeSiH, which gave the product 3a in 74% yield and 86%
ee (entry 6). An additional screen of copper source revealed
that Cu(OAc)2 (entry 10) gave higher yield and enantiomer-
ic excess than those of CuCl (entry 6), CuOAc (entry 7),
CuOTf (entry 8), or CuCl2(entry 9). Changing other reaction
parameters such as base (NaOtBu, entry 11) or solvent (tol-
uene, entry 12) proved to be detrimental to both reactivity
and enantioselectivity. Reduction of the catalyst loading re-
sulted in lower yield and enantiomeric excess of the prod-
uct 3a (entry 13). Lipshutz16 and Buchwald4a groups found
that addition of secondary ligand PPh3 is beneficial to the
reactivity of the reaction. However, in our catalytic system,
introduction of a secondary ligand such as PPh3 led to lower
reactivity and enantioselectivity (entry 14)
Bn
Bn
Bn
Bn
Bn
Bn
N
N
N
Cl
O
F
3d
72% yield, 62% ee
3e
70% yield, 90% ee
3f
78% yield, 83% ee
Bn
Bn
Bn
Bn
Bn Bn
N
N
N
O
S
N
3g
89% yield, 88% ee
3h
85% yield, 91% ee
3i
42% yield, 57% ee
Bn
Bn
Bn
Bn
N
N
N
3j
3k
60% yield, 92% ee
1l
32% yield, 49% ee
<5% yield
Scheme 1 Substrate scope of alkenes for the hydroamination
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E

C
C. Chen et al.
Special Topic
Synthesis
ity (92% ee). As expected, cis-isomer 1l showed little activi-
ty, which is consistent with our previous observations in
the aminoboration.15
Our catalytic system was also applicable to cyclic amine
coupling partners (Scheme 2). The cyclic amine products
containing piperidine (4b), morpholine (4c), and azepane
(4d) were prepared in moderate yields (33–59%) and with
good to excellent enantioselectivities (84–94% ee).
with 86% ee. Enantiomeric excess was determined by SFC with a Lux
Cellulose-3 column (CO2/MeOH, 3 mL/min, 220 nm); tR = 2.32, 3.09
min; []D20 –47.0 (c 1.30, CHCl3).
1H NMR spectrum was identical with that reported.3
(S)-N,N-Dibenzyl-1-(naphthalen-2-yl)ethan-1-amine (3b)
Prepared according to the general procedure from 2-vinylnaphtha-
lene (62 mg, 0.40 mmol) and O-benzoyl-N,N-dibenzylhydroxylamine
(380 mg, 1.20 mmol). The product was isolated as a colorless oil (106
mg, 75%) with 78% ee. Enantiomeric excess was determined by SFC
with a Lux Cellulose-3 column (CO2/IPA, 3 mL/min, 220 nm); tR = 5.18,
6.55 min.
R1 R2
Cu(OAc)2 (10 mol%)
pivZPhos (10 mol%)
N
R1 R2
N
+
Ph2MeSi-H (4.0 equiv)
LiOtBu (3.0 equiv)
THF, 20 °C, 16h
OBz
1H NMR spectrum was identical with that reported.2
1a
2b–d
4b–d
(1.0 equiv)
(3.0 equiv)
(S)-N,N-Dibenzyl-1-(o-tolyl)ethan-1-amine (3c)
Prepared according to the general procedure from 2-methylstyrene
(47 mg, 0.40 mmol) and O-benzoyl-N,N-dibenzylhydroxylamine (380
mg, 1.20 mmol). The product was isolated as a colorless oil (76 mg,
60%) with 84% ee. Enantiomeric excess was determined by SFC with a
Lux Cellulose-3 column (CO2/IPA, 3 mL/min, 220 nm); tR = 2.37, 2.97
min.
O
Piv
N
N
N
N
tBu
P
tBu
P
N
4b
4c
4d
1H NMR spectrum was identical with that reported.2
Piv
pivZPhos
33% yield
94% ee
59% yield
84% ee
42% yield
84% ee
(S)-N,N-Dibenzyl-1-(2-chlorophenyl)ethan-1-amine (3d)
Scheme 2 Substrate scope of cyclic O-benzoylhydroxylamine for the
Prepared according to the general procedure from 2-chlorostyrene
(55 mg, 0.40 mmol) and O-benzoyl-N,N-dibenzylhydroxylamine (380
mg, 1.20 mmol). The product was isolated as a colorless oil (97 mg,
72%) with 62% ee. Enantiomeric excess was determined by SFC with a
Lux Cellulose-3 column (CO2/IPA, 3 mL/min, 220 nm); tR = 2.96, 3.51
min.
hydroamination
In summary, we have demonstrated the application of
pivZPhos as a versatile ligand in copper-catalyzed asymmet-
ric hydroamination of styrenes, delivering the resulting chi-
ral amines with up to 89% yields and 94% enantioselectivi-
ties. Styrenes with a variety of substitution groups and het-
erocyclic styrenes are suitable substrates. A series of
electrophilic O-benzoylhydroxylamines are well tolerated.
Further studies on application of the same catalytic system
to other asymmetric transformations are currently under-
way.
1H NMR spectrum was identical with that reported.2
(S)-N,N-Dibenzyl-1-(4-methoxyphenyl)ethan-1-amine (3e)
Prepared according to the general procedure from 4-methoxystyrene
(54 mg, 0.40 mmol) and O-benzoyl-N,N-dibenzylhydroxylamine (380
mg, 1.20 mmol). The product was isolated as a colorless oil (93 mg,
70%) with 90% ee. Enantiomeric excess was determined by SFC with a
Lux Cellulose-3 column (CO2/IPA, 3 mL/min, 220 nm); tR = 4.27, 5.18
min.
1H NMR spectrum is identical to the one reported in literature.2
(S)-N,N-Dibenzyl-1-(4-fluorophenyl)ethan-1-amine (3f)
Copper-Catalyzed Hydroamination of Styrenes; General Procedure
Prepared according to the general procedure from 4-fluorostyrene
(49 mg, 0.40 mmol) and O-benzoyl-N,N-dibenzylhydroxylamine (380
mg, 1.20 mmol). The product was isolated as a colorless oil (100 mg,
78%) with 83% ee. Enantiomeric excess was determined by SFC with a
Lux Cellulose-3 column (CO2/MeOH, 3 mL/min, 220 nm); tR = 2.18,
3.63 min.
To a sealed tube was added Cu(OAc)2 (7 mg, 10 mol%), pivZPhos
(22 mg, 10 mol%), LiOtBu (96 mg, 3.0 equiv), and anhyd THF (2.0 mL).
The tube was evacuated and refilled with argon and stirred for 15
min. A solution of the respective styrene (0.40 mmol, 1 equiv) and O-
benzoylhydroxlyamine (1.20 mmol, 3.0 equiv) in anhyd THF (2.0 mL)
was added to the tube followed by the addition of silane Ph2MeSiH
(317 mg, 1.60 mmol, 4 equiv). The reaction mixture was stirred at
20 °C for 16 h before being quenched with H2O (20 mL). The mixture
was extracted with EtOAc (2 × 20 mL) and dried (anhyd Na2SO4). After
filtration and concentration, the product was purified by silica gel
column chromatography.
1H NMR spectrum is identical to the one reported in literature.2
(S)-1-(Benzofuran-5-yl)-N,N-dibenzylethan-1-amine (3g)
Prepared according to the general procedure from 5-vinylbenzofuran
(58 mg, 0.40 mmol) and O-benzoyl-N,N-dibenzylhydroxylamine (380
mg, 1.20 mmol). The product was isolated as a colorless oil (122 mg,
89%) with 88% ee. Enantiomeric excess was determined by SFC with a
Lux Cellulose-3 column (CO2/MeOH, 3 mL/min, 220 nm); tR = 4.11,
5.62 min; []D20 –90.4 (c 0.20, MeOH).
(S)-N,N-Dibenzyl-1-phenylethan-1-amine (3a)
Prepared according to the general procedure from styrene (42 mg,
0.40 mmol) and O-benzoyl-N,N-dibenzylhydroxylamine (380 mg,
1.20 mmol). The product was isolated as a colorless oil (94 mg, 78%)
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–E

D
C. Chen et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3):  = 7.60 (d, J = 2.2 Hz, 1 H), 7.57–7.56 (m, 1
H), 4.47 (d, J = 8.6 Hz, 1 H), 7.40–7.35 (m, 5 H), 7.32–7.28 (m, 4 H),
7.22–7.28 (m, 2 H), 6.76 (dd, J = 2.2, 0.9 Hz, 1 H), 4.02 (q, J = 6.8 Hz, 1
H), 3.62 (d, J = 13.8 Hz, 2 H), 3.48 (d, J = 13.8 Hz, 2 H), 1.48 (d, J = 6.9
Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 157.8, 147.1, 139.6, 137.1, 134.7,
129.0, 128.1, 126.9, 120.8, 54.2, 29.7, 22.2, 13.2.
HRMS (ESI+): m/z calcd for C22H25N2 [M + H]+: 317.2012; found:
317.2013.
13C NMR (101 MHz, CDCl3):  = 154.0, 145.0, 140.5, 137.4, 128.7,
128.2, 126.7, 125.0, 120.0, 110.7, 106.7, 56.2, 53.6, 14.3.
HRMS (ESI+): m/z calcd for C24H24NO [M + H]+: 342.1852; found:
342.1853.
(S)-N,N-Dibenzyl-1-phenylpropan-1-amine (3k)
Prepared according to the general procedure from trans--methylsty-
rene (47 mg, 0.40 mmol) and O-benzoyl-N,N-dibenzylhydroxylamine
(380 mg, 1.20 mmol). The product was isolated as a colorless oil (78
mg, 60%) with 92% ee. Enantiomeric excess was determined by SFC
with a Lux Cellulose-4 column (CO2/MeOH, 3 mL/min, 220 nm);
tR = 1.81, 2.41 min.
(S)-1-(Benzo[b]thiophen-5-yl)-N,N-dibenzylethan-1-amine (3h)
Prepared according to the general procedure from 5-vinylben-
zo[b]thiophene (64 mg, 0.40 mmol) and O-benzoyl-N,N-dibenzylhy-
droxylamine (380 mg, 1.20 mmol). After column chromatography,
impurity could be washed off by acid/base extraction. The product
was isolated as a colorless oil (122 mg, 85%) with 91% ee. Enantiomer-
ic excess was determined by SFC with a Lux Cellulose-3 column
(CO2/MeOH, 3 mL/min, 220 nm); tR = 5.50, 8.19 min; []D20 –69.4
(c 1.30, MeOH).
1H NMR (400 MHz, CDCl3):  = 8.88 (d, J = 4.2, 1.7 Hz, 1 H), 8.14 (d,
J = 8.0 Hz, 1 H), 8.09 (d, J = 8.8 Hz, 1 H), 7.88 (dd, J = 8.8, J = 1.9 Hz, 1
H), 7.72 (s, 1 H), 7.40–7.37 (m, 5 H), 7.33–7.29 (m, 4 H), 7.24–7.20 (m,
2 H), 4.1 (q, J = 6.8 Hz, 1 H), 3.58 (d, J = 3.5 Hz, 4 H), 1.54 (d, J = 6.8 Hz,
3 H).
1H NMR spectrum was identical with that reported.2
(S)-1-(1-Phenylethyl)piperidine (4b)
Prepared according to the general procedure from styrene (42 mg,
0.40 mmol) and piperidin-1-yl benzoate (246 mg, 1.20 mmol). The
product was isolated as a colorless oil (25 mg, 33%) with 94% ee. Enan-
tiomeric excess was determined by chiral GC with a Supelco beta-
DEX325 column (30 m × 0.25 mm × 0.25 m), He 1.0 mL/min, 100 °C;
tR = 23.05, 23.32 min.
1H NMR spectrum was identical with that reported.3
(S)-4-(1-Phenylethyl)morpholine (4c)
13C NMR (101 MHz, CDCl3):  = 150.0, 147.7, 141.8, 140.1, 136.0,
130.9, 129.0, 128.7, 128.3, 126.9, 125.6, 121.0, 55.9, 53.6, 12.5.
HRMS (ESI+): m/z calcd for C24H24NS [M + H]+: 358.1624; found:
358.1623.
Prepared according to the general procedure from styrene (42 mg,
0.40 mmol) and morpholino benzoate (248 mg, 1.20 mmol). The
product was isolated as a colorless oil (45 mg, 59%) with 84% ee. Enan-
tiomeric excess was determined by chiral GC with a Supelco beta-
DEX325 column (30 m × 0.25 mm × 0.25 m), He 1.0 mL/min, 120 °C;
tR = 32.20, 32.72 min.
(S)-N,N-Dibenzyl-1-(quinolin-6-yl)ethan-1-amine (3i)
1H NMR spectrum was identical with that reported.3
Prepared according to the general procedure from 6-vinylquinoline
(62 mg, 0.40 mmol) and O-benzoyl-N,N-dibenzylhydroxylamine (380
mg, 1.20 mmol). The product was isolated as a colorless oil (59 mg,
42%) with 57% ee. Enantiomeric excess was determined by SFC with a
Lux Cellulose-4 column (CO2/MeOH, 3 mL/min, 220 nm); tR = 4.69,
5.44 min; []D20 +8.0 (c 0.30, MeOH).
1H NMR (400 MHz, CDCl3):  = 8.88 (dd, J = 4.2, 1.8 Hz, 1 H), 8.15–8.12
(m, 1 H), 8.09 (d, J = 9.2 Hz, 1 H), 7.88 (dd, J = 8.8, 2.0 Hz, 1 H), 7.72 (br,
1 H), 7.39–7.29 (m, 9 H), 7.24–7.20 (m, 2 H), 4.10 (q, J = 6.9 Hz, 1 H),
3.58 (q, J = 3.60 Hz, 4 H), 1.54 (d, J = 6.8 Hz, 3 H).
(S)-1-(1-Phenylethyl)azepane (4d)
Prepared according to the general procedure from styrene (42 mg,
0.40 mmol) and azepan-1-yl benzoate (263 mg, 1.20 mmol). The
product was isolated as a colorless oil (34 mg, 42%) with 84% ee. Enan-
tiomeric excess was determined by chiral GC with a Supelco beta-
DEX325 column (30 m × 0.25 mm × 0.25 m), He 1.0 mL/min, 100 °C;
tR = 31.85, 32.37 min.
1H NMR spectrum was identical with that reported.3
13C NMR (101 MHz, CDCl3):  = 149.0, 146.7, 140.8, 139.1, 135.0,
129.9, 128.0, 127.7, 127.2, 126.8, 125.9, 124.5, 120.0 54.8, 52.6, 28.7.
HRMS (ESI+): m/z calcd for C25H25N2 [M + H]+: 353.2012; found:
353.2013.
Funding Information
We thank Boehringer Ingelheim Pharmaceuticals for financial sup-
port.()
(S)-N,N-Dibenzyl-1-(2-methylpyridin-3-yl)ethan-1-amine (3j)
Prepared according to the general procedure A from 2-methyl-3-vin-
ylpyridine (48 mg, 0.40 mmol) and O-benzoyl-N,N-dibenzylhydroxyl-
amine (380 mg, 1.20 mmol). The product was isolated as a colorless
oil (41 mg, 32%) with 49% ee. Enantiomeric excess was determined by
SFC with a Lux Cellulose-4 column (CO2/MeOH, 3 mL/min, 220 nm);
tR = 2.29, 2.82 min; []D20 +103.3 (c 0.50, MeOH).
Acknowledgment
We thank Scott Pennino and Lifen Wu of Boehringer Ingelheim Phar-
maceuticals for HRMS analysis.
1H NMR (400 MHz, CDCl3):  = 8.35 (dd, J = 4.8, 1.6 Hz, 1 H), 7.73 (dd,
J = 7.8, 1.5 Hz, 1 H), 7.29–7.21 (m, 10 H), 7.09 (dd, J = 7.8, 4.8 Hz, 1 H),
4.09 (q, J = 6.8 Hz, 1 H), 3.58 (q, J = 13.8 Hz, 4 H), 2.35 (s, 3 H), 1.40 (d,
J = 6.8 Hz, 3 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707346.
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E
C. Chen et al.
Special Topic
Synthesis
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