Enantioselective Additions of Stabilized Carbanions to Imines Generated from α-Amido Sulfones by Using Lipophilic Salts of Chiral Tris(1,2-diphenylethylenediamine) Cobalt(III) Trications as Hydrogen Bond Donor Catalysts

Article abstract of DOI:10.1055/s-0036-1590502

The enantiopure salt -[Co((S, S)-dpen) ₃ ] ³⁺ 2Cl ^- BAr _f ^- [BAr _f = B(3,5-C ₆ H ₃ (CF ₃) ₂) ₄ ] is an effective hydrogen bond donor catalyst (10 mol%, r.t., CH ₂ Cl ₂) for enantioselective additions of dialkyl malonates to Boc-derivatized aryl imines generated from sulfones [ArCH(SO ₂ Ph)NHBoc] in the presence of K ₂ CO ₃ (ten examples, 91-97% isolated yields, 87-99% ee). The diastereomeric salt Λ-[Co((S, S)-dpen) ₃ ] ³⁺ 2Cl ^- BAr _f20 ^- [BAr _f20 ^- = B(C ₆ F ₅) ₄ ^- ] is similarly applied to additions of nitroalkanes (four examples, 89-93% isolated yields, 79-91% ee). Precautions to exclude air or moisture are unnecessary.

Full text of DOI:10.1055/s-0036-1590502

SYNTHESIS
0
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9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–K
special topic
A
en
H. Joshi et al.
Special Topic
Synthesis
Enantioselective Additions of Stabilized Carbanions to Imines
Generated from α-Amido Sulfones By Using Lipophilic Salts of
Chiral Tris(1,2-diphenylethylenediamine) Cobalt(III) Trications as
Hydrogen Bond Donor Catalysts
Hemant Joshi
0
0
0
0
0-
0
0
2
7-
6
1
6
0-
2
4
1
H
PG
H
PG
Δ-[Co((S,S)-dpen)3]3+2Cl–BArf–
Ph
N
N
COOR
COOR
(10 mol%)
Subrata K. Ghosh
John A. Gladysz*
0
0
0
0
0-
0
0
2
1-
0
4
8
9-
1
0
8
Ph
H2N
Ph
COOR
COOR
+
NH2
Ar
S
Ar
H2
N
0
0
0
0
0-
0
0
2
7-
0
1
2
4-
8
7
2
90–98% yield, 79–99% ee
O
O
Ph
Ph
3+
Co
R = Me, Et
PG = Boc
Cbz
Department of Chemistry, Texas A&M University,
P.O. Box 30012, College Station, Texas 77842-3012,
USA
i Pr, Bn
H2N
Ph
N
versatile synthetic
building blocks
H2
NH2
gladysz@chem.tamu.edu
2Cl–BArf–
/
Ph
–
BArf20
–
Λ-[Co((S,S)-dpen)3]3+2Cl–BArf20
H
Boc
H
Boc
Published as part of the Special Topic Cobalt in
Organic Synthesis
N
N
(10 mol%)
Δ or Λ-[Co((S,S)-dpen)3]3+
Ph
NO2
2Cl–BArf–/BArf20
R′CH2NO2
R′ = H, Me
–
+
Ar
S
Ar
89–93% yield, 79–91% ee
high diastereoselectivity
O
O
R'
Received: 10.04.2017
Accepted after revision: 04.05.2017
Published online: 13.06.2017
tended shelf life. Then the imine is prepared using a base
such as K2CO3.6 However, imines frequently undergo facile
hydrolysis or are otherwise problematic to store.5 Accord-
ingly, there is an increasing trend toward utilization of the
precursors 1 in enantioselective syntheses.5,7 These proto-
cols employ (1) a common base to generate the imine as
well as the carbanion that adds to the imine, and (2) various
catalysts, most often ‘organocatalysts’,8 that act as hydrogen
bond donors toward one or both reactants (Scheme 1, mid-
dle and bottom).7
We have been engaged in developing novel types of chi-
ral metal-containing hydrogen bond donors for use in enan-
tioselective catalysis.9–16 This represents an overlooked type
of catalyst, as many researchers approach this subject from
the organocatalysis angle. All too frequently, this communi-
ty erects a ‘Maginot line’ when it comes to transition met-
als, rather than thinking opportunistically about all classes
of hydrogen bond donors. Only a few other investigators
have sought to develop metal-containing hydrogen bond
donor catalysts.17,18
Most, but not all of our efforts have involved substituted
tris(ethylenediamine) complexes of cobalt(III).9–12,14,15 This
focus was inspired by the pioneering work of Werner, who
first resolved the helically chiral enantiomers of the water-
soluble trication [Co(en)3]3+ – the configurations of which
are denoted ∆ and Λ – via easily separated diastereomeric
tartrate salts some 105 years ago.19 Despite the promising
beginning, this system has languished without applications
in synthesis, as the cobalt center is ‘substitution inert’ (low
spin d6 with high field ligands) and therefore not accessible
to organic substrates for activation via the usual modes of
transition-metal-mediated catalysis. Our contributions
were to (1) recognize that the coordinated NH groups are
strong hydrogen bond donors,9,12,15a,16b and (2) apply lipo-
DOI: 10.1055/s-0036-1590502; Art ID: ss-2017-c0236-st
Abstract The enantiopure salt ∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf– [BArf =
B(3,5-C6H3(CF3)2)4] is an effective hydrogen bond donor catalyst (10
mol%, r.t., CH2Cl2) for enantioselective additions of dialkyl malonates to
Boc-derivatized aryl imines generated from sulfones [ArCH(SO2Ph)NHBoc]
in the presence of K2CO3 (ten examples, 91–97% isolated yields, 87–
99% ee). The diastereomeric salt Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
–
[BArf20– = B(C6F5)4–] is similarly applied to additions of nitroalkanes (four
examples, 89–93% isolated yields, 79–91% ee). Precautions to exclude
air or moisture are unnecessary.
Key words Werner complexes, cobalt, 1,2-diamine ligands, chiral-at-
metal complexes, hydrogen bonding, enantioselective catalysis, chiral
benzylic amines, lipophilic anions
There have been a variety of approaches to catalytic
asymmetric syntheses of secondary benzylic amines of the
formula ArCH(R)NHX,1 which represent large families of
pharmacologically active compounds or precursors thereof.
Many of these have entailed nucleophilic additions to aryl
imines (ArCH=NX), which are often termed Mannich reac-
tions when malonate ester enolates are the nucleophiles, or
aza-Henry reactions when conjugate bases of nitroalkanes
are the nucleophiles. Electron-withdrawing nitrogen sub-
stituents (X) such as Boc [tert-butoxycarbonyl or O(C=O)t-Bu]
or Cbz [carboxybenzyl or O(C=O)CH2Ph] are often employed
to facilitate additions and/or directly generate protected
amines.1–4
Such Boc or Cbz derivatives are often synthesized as ex-
emplified in Scheme 1 (top). First, a three-component con-
densation of an aromatic aldehyde, tert-butyl carbamate,
and sodium phenyl sulfinate is carried out to give what is
usually termed an α-amido sulfone (1).5,6 These have an ex-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

B
H. Joshi et al.
Special Topic
Synthesis
O
Boc
R
H
S
Boc
R
N
O
N
K2CO3
HCO2H
H
Ph
PhSO2Na
O
NH2
MeOH
H2O
H
O
O
R
Boc
NH2
1
Boc
H
Boc
R
H
Boc
R
H
COOR'
COOR'
N
N
catalyst
N
or
or
R"CH2NO2
Ph
R"
NO2
COOR'
base
solvent
S
O
O
COOR'
R
5
2
4
3
1
Cl–
N
H
H
H
H
N
N
N
N
CF3
F3C
N
N
H
H
H
N
H
N
S
Me
Me
S
H
yield of 3,
CF3
CF3
S
NR2
83–96%, 52–97% ee
Cs2CO3 base
10 mol%, –15 to 20 °C, 43–120 h
reference 7b
yield of 3
yield of 5 (R = Me),
80–93%, 76–98% ee
K2CO3 base
15 mol%, 0 °C, 48 h
reference 7e
(R = linker to Fe3O4),
80–90%, 90–96% ee
K2CO3 base
yield of 5,
5 mol%, –15 °C, 48 h
reference 7c
MeO
68–98%, 88–98% ee
KOH base
S
5 mol%, –20 °C, 5 h
reference 7h
Br–
N
N
H
H
PPh2Bn
yield of 5
yield of 3
yield of 5
H
(X = N-benzotriazolyl),
(X = 3-C6H4OMe),
77–98%, 78–99% ee
K2CO3 base
(X = C6H5),
HO
N
55–94%, 83–99% ee
CsOH base
40–88%, 78–99% ee
CsOH base
10 mol%, –60 to –40 °C, 24 h
reference 7g
12 mol%, –50 °C, 44 h
reference 7d
5 mol%, –24 °C, 60 h
reference 7a
X
MeO
Cl–
N
Scheme 1 Syntheses of α-amido sulfones and prior art regarding enantioselective reactions involving stabilized carbanions catalyzed by chiral hydro-
gen bond donors
philic anions to render these trications soluble in nonpolar
organic solvents, thereby avoiding hydroxylic media that
could compete with substrates for the hydrogen bonding
sites.9–11,15a
CH2Cl2, MeCN, or toluene at room temperature or 0 °C.
These and all other reactions below were conducted in air
with ‘off the shelf’ solvents and reagents. Entries 1–5 (Table
1) pair the diastereomer Δ-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
with five different bases in CH2Cl2. Of these, K2CO3 (Table 1,
entry 5) gave the product 3aa with the highest enantiose-
lectivity (91% ee) and close to the highest isolated yield
Accordingly, in this paper we detail the successful appli-
cation of two previously reported ‘mixed salt’ catalysts, ∆-
[Co((S,S)-dpen)3]3+ 2Cl–BArf– and Λ-[Co((S,S)-dpen)3]3+ 2Cl–
– 15a,20
BArf20
,
to Mannich and aza-Henry reactions involving
the imine precursor 1 (Scheme 1, middle). As shown in Fig-
ure 1, dpen refers to 1,2-diphenylethylenediamine, both en-
antiomers of which are commercially available at very inex-
pensive prices for enantiopure ligands (ca. $408–$420/100
Ar
Ar
Ar
H2N
Ar
NH2
NH2
H2N
H2
N
H2
N
Ar
Ar
Ar
Ar
3+
3+
Co
Co
–
g).21 The abbreviations BArf– and BArf20 denote the well-
H2N
Ar
N
N
NH2
Ar
H2
H2
–
–
known lipophilic anions B(3,5-C6H3(CF3)2)4 and B(C6F5)4 .
These catalysts, one of which is commercially available,22
afford addition products 3 and 5 in yields and enantioselec-
tivities that compare favorably with the highest achieved to
date (Scheme 1, bottom).
NH2
H2N
2X–X′–
2X–X′–
Ar
Ar
Λ-[((S,S)-diamine)3Co]3+ 2X–X'–
Δ-[((S,S)-diamine)3Co]3+ 2X–X'–
Ar
NH2
Ar = C6H5, (S,S)-dpen
4-C6H4Bu, (S,S)-d4bpen
α-naphthyl, (S,S)-dαnen
As shown in Table 1, reactions of diethyl malonate (2a)
(1.2 equiv) and the imine precursor 1a (1.0 equiv) were car-
ried out in the presence of a base (1.5 equiv) and 10 mol% of
a catalyst derived from the trication [Co((S,S)-dpen)3]3+ in
Ar
NH2
X/X' = Cl/BArf, Cl/BArf20, BF4/BArf
Figure 1 Catalysts used in this study
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

C
H. Joshi et al.
Special Topic
Synthesis
(95%). When lower loadings of K2CO3 were employed, the
yield diminished, but higher loadings did not further help
(Table 1, entries 6 and 7). Both MeCN and toluene were also
evaluated as solvents (Table 1, entries 8 and 9). The former
gave nearly racemic product; the latter gave a slightly high-
er enantioselectivity (94% ee), but the rate was much slow-
er (28 vs 16 h).
As shown in Table 1, entry 10, the diastereomeric cata-
lyst with the opposite configuration at cobalt, Λ-[Co((S,S)-
dpen)3]3+ 2Cl–BArf–, afforded a lower enantioselectivity (65%
vs 91% ee). The dominant configuration of 3aa switched
from R to S, establishing the cobalt configuration as the
principal determinant of the product configuration, as usu-
ally observed with other reactions.10,11 Additional experi-
ments with this catalyst, salts of each diastereomer with al-
ternative counter anions, and analogues with other aryl
groups in place of the phenyl moieties of dpen, are present-
ed (entries 11–17). None of these offered any improvement,
although switching the tetraarylborate anion of the Δ dia-
stereomer from BArf– to BArf20– gave only a slight drop in ee
(87%).
Next entry 5 was repeated, but at 0 °C (entry 18). The
reaction was complete within 16 hours, and work-up gave
3aa in 93% yield with a moderately higher ee value (95%).
When the catalyst loading was reduced to 5.0 mol% (entry
19), the ee value dropped (89%), and the reaction slowed
somewhat. Accordingly, the conditions in entry 18 were se-
lected for the substrate scope studies summarized in
Scheme 2.
Table 1 Optimization of the Catalyst and Conditions for the Addition of Diethyl Malonate (2a) to the Imine Derived from α-Amido Sulfone 1a
Boc
H
S
Boc
H
N
catalyst (10 mol%)
base (1.5 equiv)
N
COOEt
COOEt
Ph
COOEt
COOEt
3aa
solvent, temp
O
O
2a
1a
Entrya
Catalyst
Solvent
Base
Temp
Yield (%)b (time)
ee (%)c (config)
1
2
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
toluene
CH2Cl2
Et3N
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0 °C
0 °C
95 (12 h)
98 (9 h)
12 (S)
41 (R)
79 (R)
10 (R)
91 (R)
90 (R)
90 (R)
1 (R)
Cs2CO3
Na2CO3
KOH
3
93 (18 h)
36 (22 h)
95 (16 h)
72 (12 h)
95 (12 h)
92 (18 h)
96 (28 h)
96 (12 h)
0 (72 h)
4
5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
6d
7e
8
9
94 (R)
65 (S)
–
10
11
12
13
14
15
16
17
18
19g
f
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
94 (18 h)
97 (10 h)
98 (12 h)
98 (8 h)
1 (S)
–
63 (S)
87 (R)
73 (R)
30 (R)
72 (S)
95 (R)
89 (R)
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
–
∆-[Co((S,S)-dpen)3]3+ 2BF4–BArf–
Δ-[Co((S,S)-dαnen)3]3+ 2Cl–BArf–
94 (12 h)
98 (12 h)
93 (16 h)
91 (24 h)
Λ-[Co((S,S)-d4bpen)3]3+ 2Cl–BArf–
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
a Reactions were carried out with 0.10 mmol of 1a and 0.12 mmol of 2a in 1.0 mL of solvent.
b Yield of isolated product.
c Enantioselectivities were determined by chiral HPLC analyses.
d 1.0 equiv of base.
e 2.0 equiv of base.
f 2 drops of H2O were added.
g 5.0 mol% catalyst; with 2.0 mol%: 82% yield (37 h) and 88% ee (R).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

D
H. Joshi et al.
Special Topic
Synthesis
equiv) in CH2Cl2. As with Table 1, K2CO3 (entry 5) gave the
product 5aa with the highest enantioselectivity (87% ee)
and isolated yield (96%). Lower or higher loadings of K2CO3
(entries 6 and 7), or MeCN or toluene solvents (entries 8
and 9), gave poorer results.
PG
R
H
PG
H
S
Δ-[Co((S,S)-dpen)3]3+ 2Cl−BArf−
N
N
COOR'
COOR'
(10 mol%)
COOR'
COOR'
Ph
+
K2CO3 (1.5 equiv)
CH2Cl2 (1 mL), 16 h, 0 °C
O
O
R
2a–d
1a–g
3
Several other catalysts were evaluated (entries 10–13).
The diastereomer with the opposite configuration at cobalt,
Δ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20–, gave 5aa in only 55% ee,
and with the dominant carbon configuration S as opposed
to R. The best catalyst in Table 1, Δ-[Co((S,S)-dpen)3]3+ 2Cl–
BArf–, gave a still lower ee value (41%, S). The opposite dias-
tereomer, Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf–, afforded a higher
ee value (79%, R). The analogous catalyst in which the di-
amine phenyl groups had been replaced by 4-(butyl)phenyl
groups (entry 13) gave poorer results (58% ee).
Finally, entry 5 was repeated, but at 0 °C (entry 14). The
reaction was complete within a reasonable time frame (18
h), and afforded a 94% yield of 5aa upon work-up. The ee
value was moderately higher (91% vs 87%). Accordingly,
these conditions were selected for the substrate scope stud-
ies summarized in Scheme 3. Although the enantioselectiv-
ities are quite good (79–91% ee), they lag behind those real-
ized in Scheme 2. When nitroethane (4b) was employed, a
second stereocenter was generated, and the diastereoselec-
tivity was quite high (95:5). Note that the configurations of
the benzylic stereocenters obtained using a Λ catalyst in
Scheme 3 are, in a relative sense, opposite of those obtained
using a Δ catalyst in Scheme 2.
1
R/PG = H/Boc, a; 4-Cl/Boc, b; 2-Cl/Boc, c; 4-NO2/Boc, d; 4-OMe/Boc, e;
2-Me/Boc, f; H/Cbz, g.
2 R' = Et, a; Me, b; i Pr, c; Bn, d
Boc
H
Boc
H
Boc
H
N
N
N
COOiPr
COOiPr
COOEt
COOEt
COOMe
COOMe
3aa
92%
95% ee (R)
3ab
91%
93% ee (R)
3ac
90%
94% ee (R)
Boc
H
Boc
H
Boc
H
N
N
N
COOMe
COOMe
COOEt
COOEt
COOBn
COOBn
Cl
Cl
3ad
3bb
3ba
90%
92%
95%
87% ee (R)
93% ee (R)
97% ee (R)
Boc
H
Boc
H
Boc
H
N
N
N
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
Cl
O2N
MeO
3da
93%
96% ee (R)
3ca
97%
3ea
91%
96% ee (R)
98% ee (R)
Cbz
H
Boc
H
N
N
COOEt
COOEt
Boc
H
COOEt
COOEt
Boc
H
S
−
Λ-[Co((S,S)-dpen)3]3+ 2Cl−BArf20
N
N
(10 mol%)
NO2
Ph
R''CH2NO2
+
Me
K2CO3 (1.5 equiv)
CH2Cl2 (1.0 mL), 18 h, 0 °C
O
O
R"
3fa
3ga
95%
90%
R
R
99% ee (R)
79% ee (R)
1a,c,e
R = H, a;
2-Cl, c; 4-OMe, e.
5
4a,b
R'' = H, a; Me, b.
Scheme 2 Substrate scope for additions of dialkyl malonates 2a–d to
the imines derived from α-amido sulfones 1a–g under the optimal con-
ditions from Table 1
Boc
H
Boc
H
Boc
H
Boc
H
N
N
N
N
NO2
NO2
Me
NO2
NO2
Scheme 2 shows that essentially identical results are ob-
tained with aliphatic esters of malonic acid (3aa, 3ab, 3ac).
The ee value dips to 87% for dibenzyl malonate (3ad). The
excellent results with 3bb, 3ba, 3ca, 3da, 3ea, and 3fa (91–
97% yields, 93–99% ee) show that both electron-withdraw-
ing and electron-donating groups on the phenyl ring are ac-
commodated, as well as ortho substituents. When the nitro-
gen functionality is switched from Boc to Cbz, the ee value
drops to 79%. While this is acceptable for some applica-
tions, the Cbz analogues may benefit from a separate opti-
mization protocol analogous to that in Table 1.
As summarized in Table 2, parallel efforts were made to
optimize the reaction of nitromethane (4a) (2.0 equiv) and
1a (1.0 equiv). In initial screens, a lead catalyst, Λ-[Co((S,S)-
dpen)3]3+ 2Cl–BArf20–, emerged from the diastereomer series
opposite of the lead catalyst in Table 1. As shown in entries
1–5 (Table 2), it was paired with five different bases (1.5
MeO
Cl
5aa
5ca
5ea
5ab
90%
79% ee (R)
90%
85% ee (R)
89% 95:5 syn/anti
83% ee (1R,2R)
93%
91% ee (R)
Scheme 3 Substrate scope for additions of nitroalkanes 4a,b to the
imines derived from α-amido sulfones 1a,c,e under the optimal condi-
tions from Table 2
Several ancillary experiments were conducted. First, we
wondered whether the cobalt(III) complexes might catalyze
conversions of 1a–f into the imines ArCH=NBoc. Thus,
chloro-substituted 1b (1.0 equiv), K2CO3 (1.5 equiv), CD2Cl2
(0.50 mL), and ∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf– (10 mol%)
were combined in an NMR tube in the absence of a
malonate ester or nitroalkane. A second NMR tube was sim-
ilarly charged, but without the cobalt(III) complex. Over the
course of 11 hours, the second tube showed the clean con-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

E
H. Joshi et al.
Special Topic
Synthesis
Table 2 Optimization of the Catalyst and Conditions for the Addition of Nitromethane (4a) to the Imine Derived from α-Amido Sulfone 1a
Boc
H
S
Boc
H
catalyst (10 mol%)
base (1.5 equiv)
N
N
Ph
MeNO2
NO2
solvent, temp
O
O
4a
5aa
1a
Entrya
Catalyst
Solvent
Base
Temp
Yield (%)b (time)
ee (%)c (config)
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et3N
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0 °C
92 (14 h)
98 (13 h)
93 (20 h)
27 (24 h)
96 (14 h)
67 (21 h)
96 (14 h)
94 (18 h)
95 (29 h)
95 (14 h)
95 (14 h)
94 (18 h)
97 (14 h)
94 (18 h)
11 (R)
13 (R)
64 (R)
3 (R)
–
–
–
–
–
–
–
–
–
1
2
Cs2CO3
Na2CO3
KOH
3
4
5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
87 (R)
76 (R)
77 (R)
14 (R)
65 (R)
79 (R)
55 (S)
41 (S)
58 (R)
91 (R)
6d
7e
8
9
10
11
12
13
14
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
–
Λ-[Co((S,S)-dbpen)3]3+ 2Cl–BArf–
Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20
–
a Reactions were carried out with 0.10 mmol of 1a and 0.20 mmol of 4a in 1.0 mL of solvent.
b Yield of isolated product.
c Enantioselectivities were determined by chiral HPLC analyses.
d 1.0 equiv of base.
e 2.0 equiv of base.
version of 1b into the previously described imine (4-
ClC6H4)CH=NBoc, consistent with literature reports (1.5 h,
68:32; 5.0 h, 33:67; 7.0 h, 24:76; 11 h, <1:>99).3c,6a Over the
same time frame, 1b was also consumed in the first tube,
but concurrent hydrolysis of the imine to 4-chlorobenzal-
dehyde was evident (1.5 h, 33:34:33 1b/imine/aldehyde;
5.0 h, 16:22:62; 7.0 h, 14:19:67; 11 h, <1:<1:>99).
These data suggest two conclusions. First, the faster
consumption of 1b in the presence of ∆-[Co((S,S)-dpen)3]3+
2Cl–BArf– (33% vs 68% remaining after 1.5 h) implies a cata-
lyzed pathway. Second, the cobalt complex (a monohy-
drate)20 appears to catalyze the hydrolysis of the imine (4-
ClC6H4)CH=NBoc. This is not in itself surprising given the
absence of any of the carbon nucleophiles in Schemes 1–3
and Tables 1 and 2. Accordingly, the conditions in Scheme 2
were applied to the isolated imine PhCH=NBoc3c and
malonate ester 2a. However, no addition product (3aa)
could be detected. Rather, the hydrolysis products benzal-
dehyde and BocNH2 formed in quantitative NMR yields. The
same result was obtained when Et3N was used in place of
K2CO3. A scenario that reconciles these disparate observa-
tions is proposed below.
The preceding data dramatically illustrate the efficacy
of the catalyst families in Figure 1 for enantioselective addi-
tions of stabilized carbanions to Boc derivatives of aryl
imines that are generated in situ from the shelf-stable α-
amido sulfone precursors 1. Curiously, however, opposite
cobalt/carbon diastereomers prove to be more effective for
the two types of addends studied, dialkyl malonates 2 (Ta-
ble 1 and Scheme 2) and nitroalkanes 4 (Table 2 and
Scheme 3). This dichotomy has been encountered with oth-
er transformations,10,11 and calls attention to how little is
presently known about the mechanisms and the basis for
enantioselection.
Many of the previously reported hydrogen bond donor
catalysts applied to these transformations are based upon
thioureas (Scheme 1, bottom). Since thioureas feature only
two NH donor groups, there is a more restricted range of
substrate binding possibilities. Accordingly, plausible tran-
sition-state models have been developed (usually with the
aid of computations) for a number of enantioselective reac-
tions catalyzed by chiral thioureas.23 In contrast, the cata-
lysts in Figure 1 feature twelve NH units. These are arrayed,
in accord with the idealized D3 symmetry, between two ‘C3
symmetric faces’ and three ‘C2 symmetric faces’, as shown
in Figure 2. Transition-state assemblies that simultaneously
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

F
H. Joshi et al.
Special Topic
Synthesis
access as many as 4–5 of these NH units are easily envi-
sioned,16b making for a daunting number of possible geom-
etries.
lectivities are greater with one set of counter anions for a
given reaction, but a different set of anions for another. We
note in passing that it would be possible for one C3 face to
be engaged in hydrogen bonding with substrates, while the
opposite C3 face maintains hydrogen bonding with a count-
er anion or anions.
Regardless of the mechanisms by which these cobalt(III)
catalysts function, one is usually able to achieve ee values of
>50% for a transformation known to be catalyzed by chiral
bond donors with a minimum of effort. In many cases, this
can be optimized to the 90% ee range by varying the cobalt
configuration, counter anions, solvent, and related parame-
ters, or by introducing additional catalyst functionality.12 In
a separate effort, Meggers has applied a bifunctional chiral
iridium(III) catalyst that can serve as both a hydrogen bond
donor and Brønsted base to aza-Henry reactions of isolated
aryl imines ArCH=NBoc.17c
It is always difficult to objectively compare the effec-
tiveness of different classes of enantioselective catalysts.
For example, the range of ee values (or average ee value) re-
ported might be skewed by the inclusion of a single prob-
lematic substrate in one study, but not another. With this
caveat, we note that 3ab, 3ad, and 3bb in Scheme 2 have
previously been similarly synthesized by others, but using
different hydrogen bond donor catalysts, generally of the
types depicted in Scheme 1. The best enantioselectivities
reported earlier are 94% (vs our 93%),7b 95% (vs 87%),7c and
92% (vs 93%),7b respectively. Alternatively, 3bb, 3ea, and 3ga
have previously been prepared from the isolated imines
ArCH=NBoc. The best results reported earlier are 90% (vs
our 93%),2d 93% (vs 96%),25 and 61% (vs 79%),26 respectively.
With regard to the nitroalkane additions in Scheme 3, our
enantioselectivities are somewhat lower than the best liter-
ature results (5aa, 99%7g vs our 91%; 5ca, 97%7c vs 79%; 5ea,
97%7h vs 85%; 5ab, 98%7g vs 83%).
Other types of comparisons are also relevant. For exam-
ple, our catalyst system operates on more practical times-
cales than most of the others depicted in Scheme 1 (bot-
tom). Naturally, longer timescales are often associated with
lower temperatures applied to maximize ee values. Second,
our catalyst loadings fall into the middle of the range, but
could probably be optimized lower (with a trade off in tem-
perature and time).
In summary, two principal conclusions derive from the
preceding data. First, the scope of enantioselective reac-
tions to which chiral hydrogen bond catalysts based upon
the cobalt(III) trication [Co((S,S)-dpen)3]3+ can be applied
has been significantly extended. Second, practical new
methodology for additions of conjugate bases derived from
dialkyl malonates and nitroalkanes to Boc derivatives of
aromatic imines – or their functional equivalents – has
been developed. There is no need to exclude air or water,
and one of the catalysts is commercially available. Addition-
al applications of these and related systems in enantioselec-
tive catalysis will be reported in the near future.
Figure 2 Hydrogen bonding sites of the trication [Co((S,S)-dpen)3]3+
(left, Λ diastereomer; right, Δ diastereomer). The representations are
taken from the crystal structures of the 3Cl– salts, which lack idealized
D3 symmetry. What would correspond to the C3 sites are shown at the
top (green NH) and the C2 sites at the bottom (yellow NH)
NMR experiments reported in connection with other
synthetic studies have established that dialkyl malonates
and β-nitrostyrene strongly interact with the C2 faces of the
catalyst Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf–.10 However, the two
C3 faces of this catalyst are strongly hydrogen bonded to the
two chloride counter anions, and there is good evidence
that conjugate additions of malonates to β-nitrostyrene re-
quire a chloride ion to dissociate from at least one C3 site
(presumably to allow substrate binding).10 It follows that
both the α-amido sulfone precursors 1 and any imine inter-
mediates ArCH=NBoc in Schemes 2 and 3 and Tables 1 and 2
should similarly hydrogen bond to these cobalt(III) systems,
either via the Boc C=O or sulfone S=O moieties.
Given that basic solutions of ∆-[Co((S,S)-dpen)3]3+ 2Cl–
BArf– appear to catalyze both the disappearance of precur-
sors 1 and the hydrolysis of imines ArCH=NBoc, we current-
ly favor mechanisms in which 1 undergoes net phenyl
sulfinic acid elimination and dialkyl malonate or nitroal-
kane addition without dissociating a free imine from the
second coordination sphere of cobalt. To our knowledge,
the possibility that the other hydrogen bond donor cata-
lysts in Scheme 1 (bottom) might initially act upon 1 has
not been previously considered. However, we presently lack
any further insight.24 The same goes as to why enantiose-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

G
H. Joshi et al.
Special Topic
Synthesis
Reactions, Scheme 3
Reactions were conducted under air. CDCl3 and CD2Cl2 were stored
over molecular sieves. HPLC solvents (hexanes, Fischer; isopropanol,
JT Baker, 2 × HPLC Grade) were degassed before use. Other solvents
and materials: CH2Cl2 (EMD, ACS grade), hexanes, EtOAc (2 × Macron,
ACS grade), toluene, MeCN (2 × BDH, ACS grade), diethyl malonate
(2a) (Alfa Aesar, 99%), dimethyl malonate (2b) (Alfa Aesar, 98%), diiso-
propyl malonate (2c) (TCI, 99%), dibenzyl malonate (2d) (TCI, 99%), ni-
tromethane (4a) (Sigma-Aldrich, 95+%), nitroethane (4b) (Alfa Aesar,
99%), Cs2CO3 (Alfa Aesar, 99%), K2CO3 (Fluka Analytical, 99%), Na2CO3
(Mallinckrodt Chemicals, ACS grade), KOH (Macron Fine Chemicals,
ACS grade), Et3N (Alfa Aesar, 98%), and silica gel (Silicycle SiliaFlash®
F60) were used as received. The educts N-(tert-butoxycarbonyl)-α-
(phenylsulfonyl)benzylamine (1a),6a N-(tert-butoxycarbonyl)-α-(phe-
nylsulfonyl)-4-chlorobenzylamine (1b),6a N-(tert-butoxycarbonyl)-α-
(phenylsulfonyl)-2-chlorobenzylamine (1c),6a N-(tert-butoxycarbon-
yl)-α-(phenylsulfonyl)-4-nitrobenzylamine (1d),6b N-(tert-butoxycar-
bonyl)-α-(phenylsulfonyl)-4-methoxybenzylamine (1e),6b N-(tert-bu-
toxycarbonyl)-α-(phenylsulfonyl)-2-methylbenzylamine (1f),27 and
benzyl phenyl(phenylsulfonyl)methylcarbamate (1g)6b and catalysts
(see Figure 1 for abbreviations) ∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–·H2O,
∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf20–·3H2O, Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf–
·2H2O, Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20–·3H2O, ∆-[Co((S,S)-dpen)3]3+
2BF4–BArf–·3H2O, Δ-[Co((S,S)-dαnen)3]3+ 2Cl–BArf–·4H2O, and Λ-
[Co((S,S)-d4bpen)3]3+ 2Cl–BArf–·H2O were prepared by literature pro-
cedures.15a Melting points were determined using an OptiMelt MPA
100 instrument. NMR spectra were recorded in CDCl3 or CD2Cl2 on a
Varian NMRS 500 MHz spectrometer at ambient probe temperature
and referenced (δ in ppm) to solvent signals (1H: residual CHCl3, 7.26
or CDHCl2, 5.32; 13C{1H}: CDCl3, 77.2). HPLC analyses were carried out
with a Shimadzu instrument package (pump/autosampler/detector
LC-20AD/SIL-20A/SPD-M20A). Microanalyses were conducted by At-
lantic Microlab.
A 5 mL vial was charged with 1a,c,e (0.10 mmol, 1.0 equiv), 4a,b (0.20
mmol, 2.0 equiv), Λ-[Co((S,S)-dpen)3]3+ 2Cl–BArf20–·3H2O (0.0150 g,
0.0010 mmol, 10 mol%), and CH2Cl2 (1.0 mL). The mixture was cooled
to 0 °C and K2CO3 (0.021 g, 0.15 mmol, 1.5 equiv) was added with stir-
ring. Work-ups identical to those for Table 2 gave the data in Scheme
3. The enantiomeric purities were assayed by chiral HPLC (see Figures
s12–s15 in the Supporting Information).29
2-(tert-Butoxycarbonylaminophenylmethyl)malonic Acid Diethyl
Ester (3aa)2a
This known compound was obtained as a white solid (0.0335 g, 0.092
mmol, 92%) per the procedure for Scheme 2.
1H NMR (500 MHz, CDCl3): δ = 7.29–7.18 (m, 5 H, C6H5), 6.17 (br s, 1
H, NH), 5.46 (br s, 1 H, NHCH), 4.22–3.99 (m, 4 H, OCH2, OC′H2), 3.86
[br s, 1 H, CHC(O)OCH2], 1.37 [s, 9 H, C(CH3)3], 1.21 (t, J = 7.3 Hz, 3 H,
CH2CH3), 1.08 (t, J = 7.0 Hz, 3 H, C′H2C′H3).
13C{1H} NMR (125 MHz, CDCl3): δ = 168.0 [s, C(O)OCH2], 166.7 [s,
C′(O)OC′H2], 154.7 [s, C(O)OC(CH3)3], 139.6, 128.4, 127.4, 126.1 (4 × s,
C6H5), 79.5 [s, C(CH3)3], 61.8, 61.4, 56.8, 53.3 [4 × s, NHCH,
CHC(O)OCH2, CH2CH3, C′H2C′H3], 28.2 [s, C(CH3)3], 13.9 (s, CH2CH3),
13.7 (s, C′H2C′H3).
HPLC (Figure s1): Chiralpak AD column (90:10 v/v hexane/isopropa-
nol, 0.8 mL/min, λ = 254 nm); tR = 15.4 min (minor), 17.6 min (ma-
jor).2a,28
2-(tert-Butoxycarbonylaminophenylmethyl)malonic Acid Dimeth-
yl Ester (3ab)2a
This known compound was obtained as a white solid (0.0306 g, 0.091
mmol, 91%) per the procedure for Scheme 2.
1H NMR (500 MHz, CDCl3): δ = 7.33–7.22 (m, 5 H, C6H5), 6.14 (br s, 1
H, NH), 5.48 (br s, 1 H, NHCH), 3.92 [br s, 1 H, CHC(O)OCH3], 3.73 (s, 3
H, OCH3), 3.62 (s, 3 H, OC′H3), 1.41 [s, 9 H, C(CH3)3].
13C{1H} NMR (125 MHz, CDCl3): δ = 168.2 [s, C(O)OCH3], 167.5 [s,
C′(O)OCH3], 154.9 [s, C(O)OC(CH3)3], 139.2, 128.5, 127.5, 126.1 (4 × s,
C6H5), 79.6 [s, C(CH3)3], 56.5, 53.3, 52.8, 52.4 [4 × s, NHCH,
CHC(O)OCH3, OCH3, OC′H3], 28.2 [s, C(CH3)3].
Reactions, Table 1
A 5 mL vial was charged with 1a (0.035 g, 0.10 mmol, 1.0 equiv), 2a
(0.019 g, 0.12 mmol, 1.2 equiv), catalyst (0.010 mmol, 10 mol%) and
CH2Cl2 (1.0 mL). Then the base (0.15 mmol, 1.5 equiv) was added with
stirring. The progress of the reaction was monitored by TLC. After the
specified time, the mixture was chromatographed on a silica gel col-
umn (1.9 × 14 cm, 9:1 v/v hexanes/EtOAc). The solvent was removed
from the product-containing fractions by rotary evaporation and oil
pump vacuum (1 h) at r.t. The enantiomeric purities were assayed by
chiral HPLC.28
HPLC (Figure s2): Chiralpak AD column (90:10 v/v hexane/isopropa-
nol, 1.0 mL/min, λ = 254 nm); tR = 15.9 min (minor), 20.5 min (ma-
jor).2a,28
2-(tert-Butoxycarbonylaminophenylmethyl)malonic Acid Diiso-
propyl Ester (3ac)2e
Reactions, Scheme 2
A 5 mL vial was charged with 1a–g (0.10 mmol, 1.0 equiv), 2a–d (0.12
mmol, 1.2 equiv), ∆-[Co((S,S)-dpen)3]3+ 2Cl–BArf–·H2O (0.0170 g, 0.010
mmol, 10 mol%), and CH2Cl2 (1.0 mL). The mixture was cooled to 0 °C
and K2CO3 (0.021 g, 0.15 mmol, 1.5 equiv) was added with stirring.
Work-ups identical to those for Table 1 gave the data in Scheme 2. The
enantiomeric purities were assayed by chiral HPLC (see Figures s1–
s11 in the Supporting Information).28
This known compound was obtained as a white solid (0.0354 g, 0.090
mmol, 90%) per the procedure for Scheme 2.
1H NMR (500 MHz, CDCl3): δ = 7.30–7.21 (m, 5 H, C6H5), 6.22 (br s, 1
H, NH), 5.47 (br s, 1 H, NHCH), 5.08–5.03 [m, 1 H, CH(CH3)2], 4.97–
4.92 [m, 1 H, C′H(C′H3)2], 3.82 [br s, 1 H, CHC(O)OCH(CH3)2], 1.40 [s, 9
H, C(CH3)3], 1.25, 1.23, 1.18, 1.03 [4 × d, J = 6.0/6.0/6.0/6.0 Hz, 3 H
each, CH(C′H3)(CH3)/C′H(C′H3)(CH3)].
13C{1H} NMR (125 MHz, CDCl3): δ = 167.7 [s, C(O)OCH(CH3)2], 166.5
[s, C′(O)OCH(CH3)2], 155.0 [s, C(O)OC(CH3)3], 139.6, 128.5, 127.4,
126.2 (4 × s, C6H5), 79.5 [s, OC(CH3)3], 69.6, 69.2, 57.1, 53.4, [4 × s,
NHCH, CHC(O)OCH(CH3)2, CH(CH3)2, C′H(C′H3)2], 28.3 [s, C(CH3)3],
21.6, 21.4, 21.4, 21.3 [4 × s, CH(C′H3)(CH3), C′H(C′H3)(CH3)].
Reactions, Table 2
A 5 mL vial was charged with 1a (0.035 g, 0.10 mmol, 1.0 equiv), 4a
(0.012 g, 0.20 mmol, 2.0 equiv), catalyst (0.0010 mmol, 10 mol%), and
CH2Cl2 (1.0 mL). Then the base (0.15 mmol, 1.5 equiv) was added with
stirring. Work-ups similar to those for Table 1 (silica gel column:
1.9 × 14 cm, 8:2 v/v hexanes/EtOAc) gave the data in Table 2. The en-
antiomeric purities were assayed by chiral HPLC.29
HPLC (Figure s3): Chiralpak AD column (95:5 v/v hexane/isopropanol,
0.8 mL/min, λ = 254 nm); tR = 18.1 min (major), 22.1 min (minor).28
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

H
H. Joshi et al.
Special Topic
Synthesis
2-(tert-Butoxycarbonylaminophenylmethyl)malonic Acid Diben-
1H NMR (500 MHz, CDCl3): δ = 7.36 (d, J = 8.5 Hz, 1 H, C6H4), 7.31 (d,
J = 7.5 Hz, 1 H, C6H4), 7.22–7.16 (m, 2 H, C6H4), 6.50 (br s, 1 H, NH),
5.77 (br s, 1 H, NHCH), 4.29–3.95 [m, 5 H, OCH2, OC′H2, CHC(O)OCH2],
1.38 [s, 9 H, C(CH3)3], 1.26 (t, J = 7.0 Hz, 3 H, CH2CH3), 1.08 (t, J = 7.0
Hz, 3 H, C′H2C′H3).
13C{1H} NMR (125 MHz, CDCl3): δ = 168.1 [s, C(O)OCH2], 167.0 [s,
C′(O)OC′H2], 154.7 [s, C(O)OC(CH3)3], 136.7, 132.3, 129.6, 128.9, 128.1,
126.8 (6 × s, C6H4), 79.6 [s, C(CH3)3], 61.9, 61.4, 53.9, 51.1 [4 × s, NHCH,
CHC(O)OCH2, CH2CH3, C′H2C′H3], 28.2 [s, C(CH3)3], 13.9 (s, CH2CH3),
13.7 (s, C′H2C′H3).
zyl Ester (3ad)2d
This known compound was obtained as a white solid (0.0441 g, 0.090
mmol, 90%) per the procedure for Scheme 2.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.22 (m, 13 H, C6H5, CH2C6H5,
C′H2C′6H5), 7.13–7.11 (m, 2 H, CH2C6H5), 6.23 (br s, 1 H, NH), 5.59 (br s,
1 H, NHCH), 5.16 (s, 2 H, CH2C6H5), 5.07 (s, 2 H, C′H2C′6H5), 4.04 [br s, 1
H, CHC(O)OCH2C6H5], 1.44 [s, 9 H, C(CH3)3].
13C{1H} NMR (125 MHz, CDCl3): δ = 167.7 [s, C(O)OCH2C6H5], 166.7 [s,
C′(O)OC′H2C′6H5], 154.9 [s, C(O)OC(CH3)3], 139.2, 134.9, 134.8, 128.6,
128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.5, 126.1 (12 × s, C6H5,
CH2C6H5, C′H2C′6H5), 79.7 [s, OC(CH3)3], 67.6, 67.2, 56.8, 53.3, [4 × s,
NHCH, CHC(O)OCH2C6H5, CH2C6H5, C′H2C′6H5], 28.1 [s, C(CH3)3].
Anal. Calcd for C19H26ClNO6 (399.87): C, 57.07; H, 6.55. Found: C,
56.94; H, 6.56.
HPLC (Figure s7): Chiralpak AD column (98:2 v/v hexane/isopropanol,
1.0 mL/min, λ = 254 nm); tR = 21.4 min (minor), 23.6 min (major).28
HPLC (Figure s4): Chiralpak OD-H column (95:5 v/v hexane/isopropa-
nol, 1.0 mL/min, λ = 254 nm); tR = 11.9 min (major), 14.4 min (mi-
nor).2d,28
2-[tert-Butoxycarbonylamino(4-nitrophenyl)methyl]malonicAcid
Diethyl Ester (3da)30
2-[tert-Butoxycarbonylamino(4-chlorophenyl)methyl]malonic
This known compound was obtained as a yellow solid (0.0382 g,
0.093 mmol, 93%) per the procedure for Scheme 2.
Acid Dimethyl Ester (3bb)2d
1H NMR (500 MHz, CDCl3): δ = 8.16 (d, J = 8.5 Hz, 2 H, C6H4), 7.50 (d,
J = 9.0 Hz, 2 H, C6H4), 6.28 (br s, 1 H, NH), 5.54 (br s, 1 H, NHCH), 4.25–
4.01 (m, 4 H, OCH2, OC′H2), 3.89 [br s, 1 H, CHC(O)OCH2], 1.39 [s, 9 H,
C(CH3)3], 1.25 (t, J = 7.0 Hz, 3 H, CH2CH3), 1.13 (t, J = 7.0 Hz, 3 H,
C′H2C′H3).
This known compound was obtained as a white solid (0.0343 g, 0.092
mmol, 92%) per the procedure for Scheme 2.
1H NMR (500 MHz, CDCl3): δ = 7.29–7.22 (m, 4 H, C6H4), 6.14 (br s, 1
H, NH), 5.44 (br s, 1 H, NHCH), 3.87 [br s, 1 H, CHC(O)OCH3], 3.74 (s, 3
H, OCH3), 3.64 (s, 3 H, OC′H3), 1.41 [s, 9 H, C(CH3)3].
13C{1H} NMR (125 MHz, CDCl3): δ = 167.6 [s, C(O)OCH2], 166.5 [s,
C′(O)OC′H2], 154.9 [s, C(O)OC(CH3)3], 147.3, 147.0, 127.4, 123.7 (4 × s,
C6H4), 80.2 [s, C(CH3)3], 62.2, 61.7, 56.2, 53.0 [4 × s, NHCH,
CHC(O)OCH2, CH2CH3, C′H2C′H3], 28.2 [s, C(CH3)3], 13.9 (s, CH2CH3),
13.8 (s, C′H2C′H3).
13C{1H} NMR (125 MHz, CDCl3): δ = 168.2 [s, C(O)OCH3], 167.3 [s,
C′(O)OCH3], 155.0 [s, C(O)OC(CH3)3], 137.9, 133.5, 128.7, 127.7 (4 × s,
C6H4), 80.0 [s, C(CH3)3], 56.4, 52.9, 52.6 [3 × s, NHCH, CHC(O)OCH3,
OCH3], 28.2 [s, C(CH3)3].
HPLC (Figure s5): Chiralpak OD-H column (95:5 v/v hexane/isopropa-
nol, 1.0 mL/min, λ = 254 nm); tR = 7.6 min (major), 9.3 min (minor).28
HPLC (Figure s8): Chiralpak AS-H column (95:5 v/v hexane/isopropa-
nol, 1.0 mL/min, λ = 254 nm); tR = 19.7 min (major), 25.1 min (mi-
nor).28
2-[tert-Butoxycarbonylamino(4-chlorophenyl)methyl]malonic
Acid Diethyl Ester (3ba)
2-[tert-Butoxycarbonylamino(4-methoxyphenyl)methyl]malonic
This new compound was obtained as a white solid (0.0381 g, 0.095
mmol, 95%) per the procedure for Scheme 2.
Acid Diethyl Ester (3ea)25
This known compound was obtained as a white solid (0.0361 g, 0.091
mmol, 91%) per the procedure for Scheme 2.
Mp 73–75 °C (open capillary).
1H NMR (500 MHz, CDCl3): δ = 7.28–7.22 (m, 4 H, C6H4), 6.19 (br s, 1
H, NH), 5.43 (br s, 1 H, NHCH), 4.23–4.02 (m, 4 H, OCH2, OC′H2), 3.82
[br s, 1 H, CHC(O)OCH2], 1.39 [s, 9 H, C(CH3)3], 1.24 (t, J = 7.0 Hz, 3 H,
CH2CH3), 1.13 (t, J = 7.3 Hz, 3 H, C′H2C′H3).
13C{1H} NMR (125 MHz, CDCl3): δ = 167.9 [s, C(O)OCH2], 166.9 [s,
C′(O)OC′H2], 154.9 [s, C(O)OC(CH3)3], 138.1, 133.3, 128.6, 127.6 (4 × s,
C6H4), 79.7 [s, C(CH3)3], 61.9, 61.6, 56.6, 52.8 [4 × s, NHCH,
CHC(O)OCH2, CH2CH3, C′H2C′H3], 28.2 [s, C(CH3)3], 13.9 (s, CH2CH3),
13.8 (s, C′H2C′H3).
1H NMR (500 MHz, CDCl3): δ = 7.20 (d, J = 9.0 Hz, 2 H, C6H4), 6.82 (d,
J = 8.5 Hz, 2 H, C6H4), 6.12 (br s, 1 H, NH), 5.42 (br s, 1 H, NHCH), 4.23–
4.02 (m, 4 H, OCH2, OC′H2), 3.83 [br s, 1 H, CHC(O)OCH2], 3.75 (s, 3 H,
OCH3), 1.39 [s, 9 H, C(CH3)3], 1.23 (t, J = 7.3 Hz, 3 H, CH2CH3), 1.14 (t,
J = 7.3 Hz, 3 H, C′H2C′H3).
13C{1H} NMR (125 MHz, CDCl3): δ = 168.0 [s, C(O)OCH2], 167.1 [s,
C′(O)OC′H2], 158.8 (s, C6H4), 154.9 [s, C(O)OC(CH3)3], 131.6, 127.3,
113.7 (3 × s, C6H4), 79.3 [s, C(CH3)3], 61.8, 61.4, 57.0, 55.1, 52.8 [5 × s,
NHCH, CHC(O)OCH2, OCH3, CH2CH3, C′H2C′H3], 28.2 [s, C(CH3)3], 13.9
(s, CH2CH3), 13.8 (s, C′H2C′H3).
Anal. Calcd for C19H26ClNO6 (399.87): C, 57.07; H, 6.55. Found: C,
57.11; H, 6.67.
HPLC (Figure s9): Chiralpak AD column (95:5 v/v hexane/isopropanol,
1.0 mL/min, λ = 254 nm); tR = 33.8 min (major), 41.3 min (minor).28
HPLC (Figure s6): Chiralpak OD-H column (99:1 v/v, hexane/isopro-
panol, 1.0 mL/min, λ = 254 nm); tR = 11.6 min (major), 17.3 min (mi-
nor).28
2-[tert-Butoxycarbonylamino(2-methylphenyl)methyl]malonic
Acid Diethyl Ester (3fa)31
2-[tert-Butoxycarbonylamino(2-chlorophenyl)methyl]malonic
Acid Diethyl Ester (3ca)
This known compound was obtained as a white solid (0.0361 g, 0.095
mmol, 95%) per the procedure for Scheme 2.
This new compound was obtained as a colorless oil (0.0389 g, 0.097
mmol, 97%) per the procedure for Scheme 2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

I
H. Joshi et al.
Special Topic
Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.25–7.24 (m, 1 H, C6H4), 7.15–7.11 (m,
3 H, C6H4), 6.26 (br s, 1 H, NH), 5.65 (br s, 1 H, NHCH), 4.22–4.01 (m, 4
H, OCH2, OC′H2), 3.73 [br s, 1 H, CHC(O)OCH2], 2.44 (s, 3 H, CH3), 1.37
[s, 9 H, C(CH3)3], 1.22 (t, J = 7.0 Hz, 3 H, CH2CH3), 1.12 (t, J = 7.0 Hz, 3 H,
C′H2C′H3).
13C{1H} NMR (125 MHz, CDCl3): δ = 167.9 [s, C(O)OCH2], 167.0 [s,
C′(O)OC′H2], 154.7 [s, C(O)OC(CH3)3], 137.8, 134.9, 130.5, 127.4, 126.0,
125.6 (6 × s, C6H4), 79.4 [s, C(CH3)3], 61.7, 61.4, 55.4, 50.2 [4 × s, NHCH,
CHC(O)OCH2, CH2CH3, C′H2C′H3], 28.1 [s, C(CH3)3], 18.9 (s, CH3), 13.8
(s, CH2CH3), 13.7 (s, C′H2C′H3).
tert-Butyl [1-(4-Methoxyphenyl)-2-nitroethyl]carbamate (5ea)6a
This known compound was obtained as a white solid (0.0268 g, 0.090
mmol, 90%) per the procedure for Scheme 3.
1H NMR (500 MHz, CDCl3): δ = 7.22 (d, J = 8.5 Hz, 2 H, C6H4), 6.89 (d,
J = 9.0 Hz, 2 H, C6H4), 5.32 (br s, 1 H, NH), 5.18 (br s, 1 H, NHCH), 4.83
(br s, 1 H, CH2NO2), 4.64–4.48 (m, 1 H, CH2NO2), 3.79 (s, 3 H, OCH3),
1.44 [s, 9 H, C(CH3)3].
13C{1H} NMR (125 MHz, CDCl3): δ = 159.7 [s, C(O)OC(CH3)3], 154.8,
128.7, 127.6, 114.5 (4 × s, C6H4), 80.5, 78.8 [2 × s, C(CH3)3, CH2NO2],
55.3 (s, OCH3), 52.3 (s, NHCH), 28.2 [s, C(CH3)3].
HPLC (Figure s10): Chiralpak AS-H column (95:5 v/v hexane/isopro-
panol, 1.0 mL/min, λ = 254 nm); tR = 5.8 min (major), 8.0 min (mi-
nor).28
HPLC (Figure s14): Chiralpak OD column (90:10 v/v hexane/isopropa-
nol, 1.0 mL/min, λ = 254 nm); tR = 26.6 min (major), 31.8 min (mi-
nor).3c,29
2-(Benzyloxycarbonylaminophenylmethyl)malonic Acid Diethyl
Ester (3ga)26
tert-Butyl (2-Nitro-1-phenylpropyl)carbamate (5ab)4b
This known compound was obtained as a white solid (0.0249 g, 0.089
mmol, 89%) and a 95:5 mixture of syn/anti diastereomers (deter-
mined by 1H NMR) per the procedure for Scheme 3.
1H NMR (500 MHz, CDCl3; syn): δ = 7.38–7.30 (m, 3 H, C6H5), 7.26–
7.24 (m, 2 H, C6H5), 5.59 (br s, 1 H, NHCH), 5.11 (br s, 1 H, CHNO2),
4.95 (br s, 1 H, NH), 1.55 (d, J = 6.0 Hz, 3 H, CHCH3), 1.42 [s, 9 H,
C(CH3)3].
13C{1H} NMR (125 MHz, CDCl3; syn): δ = 155.08 [s, C(O)OC(CH3)3],
137.4, 129.0, 128.4, 126.4 (4 × s, C6H5), 86.7 (s, CHNO2), 80.4 [s,
C(CH3)3], 57.0 (s, NHCH), 28.1 [s, C(CH3)3], 16.9 (s, CHCH3).
This known compound was obtained as a white solid (0.0360 g, 0.090
mmol, 90%) per the procedure for Scheme 2.
1H NMR (500 MHz, CDCl3): δ = 7.34–7.24 (m, 10 H, C6H5, CH2C6H5),
6.54 (br s, 1 H, NH), 5.57 (br s, 1 H, NHCH), 5.14–5.06 (m, 2 H,
OCH2C6H5), 4.18–4.03 (m, 4 H, OCH2, OC′H2), 3.93 [br s, 1 H,
CHC(O)OCH2], 1.20 (t, J = 7.3 Hz, 3 H, CH2CH3), 1.12 (t, J = 7.0 Hz, 3 H,
C′H2C′H3).
13C{1H} NMR (125 MHz, CDCl3): δ = 167.8 [s, C(O)OCH2], 166.8 [s,
C′(O)OC′H2], 155.6 [s, C(O)OCH2C6H5], 139.0, 136.3, 128.5, 128.3,
127.9, 127.6, 126.1 (7 × s, C6H5, CH2C6H5), 66.8, 61.9, 61.5, 56.7, 53.8
[5 × s, NHCH, CHC(O)OCH2, CH2C6H5, CH2CH3, C′H2C′H3], 13.8 (s,
CH2CH3), 13.7 (s, C′H2C′H3).
HPLC (Figure s15): Chiralpak AD-H column (90:10 v/v hexane/iso-
propanol, 1.0 mL/min, λ = 254 nm); tR = 13.0 min (synmajor), 15.6 min
(synminor).4b,29
HPLC (Figure s11): Chiralpak AS-H column (98:2 v/v hexane/isopro-
panol, 1.0 mL/min, λ = 254 nm); tR = 45.2 min (major), 63.7 min (mi-
nor).28
NMR Experiments
A
tert-Butyl (2-Nitro-1-phenylethyl)carbamate (5aa)6b
A 5 mm NMR tube was sequentially charged with 1b (0.038 g, 0.10
mmol, 1.0 equiv), K2CO3 (0.210 g, 0.15 mmol, 1.5 equiv), ∆-[Co((S,S)-
dpen)3]3+ 2Cl–BArf–·H2O (0.017 g, 0.010 mmol, 10 mol%), and CD2Cl2
(0.50 mL). The relative amounts of 1b, (4-ClC6H4)CH=NBoc, and 4-
chlorobenzaldehyde were calculated using the integrals of the
OC(CH3)3, CH=N, and CH=O signals, respectively. Data: see text.
This known compound was obtained as a white solid (0.0248 g, 0.093
mmol, 93%) per the procedure for Scheme 3.
1H NMR (500 MHz, CDCl3): δ = 7.42–7.30 (m, 5 H, C6H5), 5.38 (br s, 1
H, NH), 5.30 (br s, 1 H, NHCH), 4.86 (br s, 1 H, CH2NO2), 4.72–4.60 (m,
1 H, CH2NO2), 1.44 [s, 9 H, C(CH3)3].
13C{1H} NMR (125 MHz, CDCl3): δ = 154.9 [s, C(O)OC(CH3)3], 137.0,
129.2, 128.7, 126.4 (4 × s, C6H5), 80.7, 78.9 [2 × s, C(CH3)3, CH2NO2],
52.9 (s, NHCH), 28.3 [s, C(CH3)3].
B
A 5 mm NMR tube was sequentially charged with 1b (0.038 g, 0.10
mmol, 1.0 equiv), K2CO3 (0.210 g, 0.15 mmol, 1.5 equiv), and CD2Cl2
(0.50 mL). Data were collected as in A.
HPLC (Figure s12): Chiralpak AD column (98:2 v/v hexane/isopropa-
nol, 1.0 mL/min, λ = 254 nm); tR = 45.9 min (minor), 49.1 min (ma-
jor).3c,29
tert-Butyl [1-(2-Chlorophenyl)-2-nitroethyl]carbamate (5ca)3c
Funding Information
This known compound was obtained as a white solid (0.0271 g, 0.090
mmol, 90%) per the procedure for Scheme 3.
We thank the Welch Foundation (Grant A-1656) for support.
Weclh
F
o
u
n
d
oaitn
A(-1
6
5
6)
1H NMR (500 MHz, CDCl3): δ = 7.40–7.26 (m, 4 H, C6H4), 5.79 (br s, 1
H, NH), 5.74 (br s, 1 H, NHCH), 4.84 (br s, 1 H, CH2NO2), 4.79 (br s, 1 H,
CH2NO2), 1.42 [s, 9 H, C(CH3)3].
Acknowledgment
13C{1H} NMR (125 MHz, CDCl3): δ = 154.5 [s, C(O)OC(CH3)3], 134.1,
132.5, 130.4, 129.8, 128.0, 127.6 (6 × s, C6H4), 80.6, 77.4 [2 × s,
C(CH3)3, CH2NO2], 50.5 (s, NHCH), 28.2 [s, C(CH3)3].
We thank Mr. Sugam Kharel for help in purifying some starting mate-
rials.
HPLC (Figure s13): Chiralpak AD-H column (90:10 v/v hexane/isopro-
panol, 1.0 mL/min, λ = 254 nm); tR = 10.3 min (major), 14.4 min (mi-
nor).7g,29
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590502.
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u
p
p
o
nrtogI
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rmoaitn
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ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

J
H. Joshi et al.
Special Topic
Synthesis
References
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(21) These compounds are available from many vendors. The best
prices in effect as of the submission date of this manuscript are
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($420/100 g) and Aris Pharmaceuticals (http://www.arispharma.com)
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Special Topic
Synthesis
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(h) Yan, C.-X.; Yang, F.; Yang, X.; Zhou, D.-G.; Zhou, P.-P. J. Org.
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(27) Wang, D.; Cao, P.; Wang, B.; Jia, T.; Lou, Y.; Wang, M.; Liao, J. Org.
Lett. 2015, 17, 2420.
(28) The absolute configurations of 3aa, 3ab, and 3ad were assigned
by HPLC using conditions similar to those in the literature (see
references 2a and 2d). The dominant enantiomers of the other
products 3 were assumed to have analogous (relative) configu-
rations.
(29) The absolute configurations of 5aa, 5ca, 5ea, and 5ab were
assigned by HPLC using conditions similar to those in the litera-
ture (see references 3c, 4b, and 7g).
(24) Additional scenarios have been raised by the reviewers, such as
the direct displacement of the PhSO2 moiety in 1 by nucleop-
hiles. However, given that all substrates 1 are racemic, some
type of dual pathway mechanism would be required. We have
attempted to assay for a kinetic resolution in the consumption
of 1, but have been thwarted by experimental issues (data
suggest little or no differentiation).
(25) Yamaoka, Y.; Miyabe, H.; Yasui, Y.; Takemoto, Y. Synthesis 2007,
2571.
(30) Ananthanawat, C.; Banphavichit, V.; Vilaivan, T. Synth. Commun.
2006, 36, 1845.
(26) Puglisi, A.; Benaglia, M.; Annunziata, R.; Rossi, D. Tetrahedron:
Asymmetry 2008, 19, 2258.
(31) Kano, T.; Yurino, T.; Asakawa, D.; Maruoka, K. Angew. Chem. Int.
Ed. 2013, 52, 5532; Angew. Chem. 2013, 125, 5642.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K