Nickel-Catalyzed Asymmetric C-Alkylation of Nitroalkanes: Synthesis of Enantioenriched β-Nitroamides

Article abstract of DOI:10.1021/jacs.9b04175

A general catalytic method for asymmetric C-alkylation of nitroalkanes using nickel catalysis is described. This method enables the formation of highly enantioenriched β-nitroamides from readily available α-bromoamides using mild reaction conditions that are compatible with a wide range of functional groups. When combined with subsequent reactions, this method allows access to highly enantioenriched products with nitrogen-bearing fully substituted carbon centers.

Full text of DOI:10.1021/jacs.9b04175

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Communication
Nickel-Catalyzed Asymmetric C-Alkylation of
Nitroalkanes: Synthesis of Enantioenriched #-Nitroamides
Vijayarajan Devannah, Rajgopal Sharma, and Donald A. Watson
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 13 May 2019
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Journal of the American Chemical Society
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Nickel-Catalyzed Asymmetric C-Alkylation of Nitroalkanes:
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Synthesis of Enantioenriched -Nitroamides
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Vijayarajan Devannah, Rajgopal Sharma, Donald A. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716
Supporting Information Placeholder
suggested that the reactions are proceeding via a radical pathway
ABSTRACT: A general catalytic method for asymmetric C-alkylation
of nitroalkanes using nickel catalysis is described. This method enables
the formation of highly enantioenriched b-nitroamides from readily
available a-bromoamides using mild reaction conditions that are
compatible with a wide range of functional groups. When combined
with subsequent reactions, this method allows access to highly
enantioenriched products with nitrogen-bearing fully substituted
carbon centers.
involving an outer-sphere C–C bond-forming step that does not
directly involve the metal catalyst or ligand.3a, 3c, 3d Thus, prior data
strongly suggested that asymmetric nitroalkane alkylation would not be
possible using current catalytic methods, and the asymmetric alkylation
of nitroalkanes has remained an open challenge.
Table 1. Discovery of the Catalytic System.
O
10 mol % catalyst
2 mol % additive
O
NO2
Et
Me
Bn
Br
Bn
O2N
N
N
+
1.1 equiv NaOMe
Et2O, rt, 24 h
Ph Me
(1.0 equiv)
Ph Me
Nitroalkanes are broadly useful building blocks in organic synthesis.1
Not only can the nitro group be converted into a range of other
functional groups, but nitroalkanes also participate in a variety of C–C
bond-forming reactions, including Michael, Henry, nitro-Mannich, and
palladium-catalyzed allylation and arylation reactions. However,
despite this great synthetic versatility, for many years the simple C-
alkylation of nitroalkanes – a potentially important reaction for
converting simple nitroalkanes into more complex nitroalkanes –
remained challenging due to the dominance of O-alkylation, which
ultimately yields aldehydes instead of the desired nitroalkane
products.2
1
(1.2 equiv)
d.r
%eeb
syn
12
Yield
Entry
Catalyst
Additive
of 1a
syn/anti
50:50
92:08
78:22
82:18
84:16
85:15
1
2
3
4
5
6
Ni(COD)2/2
Ni(COD)2/3
Ni(COD)2/4
Ni(COD)2/5
Ni(COD)2/6
Ni(COD)2/7
-
30
27
18
80
80
82
97
-
72
-
78
-
79
-
-
82
Over the past several years, our group has begun to address this gap by
developing transition metal-catalyzed alkylation reactions of
nitroalkanes.3 By using a transition metal catalyst, we were able to
change from the inherent two-electron chemistry of nitroalkanes to
single-electron manifolds, thus changing the preference for C- vs. O-
alkylation. With these new protocols, alkylation with a variety of alkyl
halides, including aliphatic alkyl halides, is now possible.
88
7
8c
Et2Zn
79:21
90
a
1
b
Determined via H NMR against internal standard; Determined
using chiral HPLC analysis; c 0 °C.
R
Scheme 1: General Method for Asymmetric Nitroalkane Alkylation.
Me
N
Me
N
H
N
NHMe
NHMe
NHMe
NHMe
O
O
Prior Work: Non-Selective Nitroalkane Alkylation
R
R
cat.M/L
M = Cu, or Ni
NO2
NO2
N
H
R
Br
+
iPr
iPr
R
base
R1
R1
5: R = H
2
4
3
racemic only
R
6: R = CH3
7: R = CF3
8: NiCl2·7
This Work: Enantioselective Nitroalkane Alkylation
cat Ni/L*
cat Et2Zn
base
• asymmetric nitroalkane alkylation
using alkyl halides
• enabled by chiral nickel catalyst
• no epimerization of product
• high enantiomeric excess
O
O
NO2
R3
Recently, while exploring copper-catalyzed reactions, we observed
modest, ligand-dependent changes in diastereoselection in nitroalkane
alkylation.5 Those experiments suggested a role for the ligand in C–C
bond formation, prompting us to reevaluate an outer-sphere pathway
and opening the possibility of asymmetric induction. Herein we report
the nickel-catalyzed asymmetric alkylation of nitroalkanes using a-
bromoamides (Scheme 1),6 which is the first example of an asymmetric
nitroalkane alkylation using an alkyl halide electrophile. We show that
alkylation of nitroalkanes with racemic a-bromoamides leads to highly
enantioselective formation of a-substituted, b-nitroamides with good
levels of diastereocontrol.7 We demonstrate that these products can be
utilized to prepare asymmetric b-aminoamides with fully substituted b-
Br
R2N
R2N
NO2
R1
R = alkyl, aryl
R1
enantioselective
R3
Despite these advances in the ability to control the site-selectivity of
the alkylation reactions, control of stereoselectivity has remained
elusive. This is particularly noteworthy, because asymmetric variants of
many other C–C bond-forming reactions of nitroalkanes have been
described, and those reactions now constitute important ways to install
nitrogen-containing stereocenters.4 The seeming inability to render
nitroalkane alkylation asymmetric stems not only from that fact that
the previously identified optimal ligands are not easily rendered chiral,
but more significantly from the fact that all prior mechanistic data
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carbons with outstanding levels of enantioselectivity. Moreover, these
observations also cast new light onto transition metal-catalyzed
nitroalkane alkylations, and suggest a more complex mechanism than
previously understood.
Page 2 of 6
With optimized conditions in hand, we investigated the scope of the
nitroalkane (Scheme 2). A variety of primary nitroalkanes were
subjected to the reaction using ( )-N-benzyl-2-bromo-N-
phenylpropionamide as the alkylating reagent. High ee was observed
for 1-nitropropane (1), as well as with a b-branched nitroalkane (9). A
variety of functionalized nitroalkanes including those with alkene, aryl,
aryl ether, acetate, free alcohol, ester, unprotected and protected
ketone groups, were all alkylated with good to excellent ee (10–17). In
all the above cases, good to excellent levels of dr were also observed.
Nitromethane can also be alkylated albeit with low yield and ee (18).
Scheme 3. Scope of a-Bromoamides.
1
2
3
4
5
6
7
8
Scheme 2. Scope of Nitroalkanes.
Ar
10 mol % 8
2 mol % Et2Zn
O
O
NO2
R1
NH
NO2
Cl
Cl
Bn
Br
Bn
Ni
NH
N
N
1.1 equiv NaOMe
Et2O, 0 °C, 24 h
+
R1
Ph Me
Ph Me
8
Ar
Ar = 3,5-(CF3)2C6H3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ar
O
NO2
O
NO2
O
NO2
10 mol % 8
2 mol % Et2Zn
Bn
N
Me
Bn
N
Me
Bn
O
O
NO2
R4
NH
N
NO2
Cl
Cl
3
R1
Br
R1
Ni
NH
Ph Me
Ph Me Me
Ph Me
N
N
1.1 equiv NaOMe
Et2O, rt, 24 h
+
R4
R2 R3
R2 R3
1, 89%, (75:25)a
syn/anti 91/83% ee
9, 87%, (93:07)a
syn/anti 94/76% ee
10, 84%, (79:21)
syn/anti 91/79% ee
8
Ar
Ar = 3,5-(CF3)2C6H3
O
O
O
NO2
O
NO2
O
NO2
O
NO2
Bn
Bn
N
O
NO2
N
Bn
N
Bn
N
3
Bn
3
Ph Me
Ph Me
N
3
Me
Me
Me
Me
11, 83%, (88:12)b
syn/anti 87/68% ee
12, 80%, (87:13)
syn/anti 89/81% ee
Me
CF3
OMe
19, 79%, (82:18)a
syn/anti 90/82% ee
O
NO2
O
NO2
O
NO2
20,79%, (79:21)a
syn/anti 89/80% ee
21, 76%, (83:17)a
syn/anti 91/83% ee
Bn
OH
5
Bn
OAc
3
Bn
N
CO2Me
N
N
Ph Me
Ph Me
Ph Me
O
NO2
O
NO2
O
NO2
13, 71%, (72:28)
14, 68%, (72:28)
syn/anti 88/77% ee
15, 78%, (71:29)b
syn/anti 87/63% ee
X-ray (minor)
Bn
Me
Bn
Me
Me
N
N
N
syn/anti 91/76% ee
NO2
Me Me
Ph Bu
Ph Et
23, 89%, (54:46)a
syn/anti 83/77% ee
O
NO2
24, 88%, (95:05)
99% ee
X-ray (major)
O
O
NO2
22, 90%, (55:45)a
syn/anti 85/81% ee
Bn
Me
O
Bn
Me
Bn
N
N
N
O
Ph Me
Ph Me
O
Ph Me
O
NO2
O
NO2
O
NO2
Me
Ph
Me
MeO
Me
Me Me Me
27, 74%, (93:07)
syn/anti 90/44% eeb
N
N
Me Me Me
N
16, 71%, (67:33)
syn/anti 85/84% ee
17, 86%, (71:29)
syn/anti 89/75% ee
Me Me
18, 41%, 82% ee
O
25, 82%, (92:08)
syn 88% ee
26, 80%, (91:09)
syn/anti 90/43% ee
a 5 mol % 8, 1 mol % Et2Zn b 25 °C.
Our investigation began with reaction of commercially available
O
NO2
O
NO2
O
NO2
Me
Me
Ph
Me
N
N
N
Me Me
racemic N-benzyl-2-bromo-N-phenylpropionamide with 1-
Me
Me
O
nitropropane to make b-nitroamide 1 (Table 1). Using conditions
similar to our prior non-stereocontrolled nickel-catalyzed alkylation
reactions (10 mol% Ni(COD)2, slight excess of NaOMe),3d we began
to systematically investigate a variety of chiral ligands. Although many
classes of ligands provided either no enantioinduction or yield of
product, we were pleased to find that use of commercially available
bis(oxazoline) ligand 2 provided desired product 1 with a measurable
12% ee, albeit in 30% yield and no measurable diastereoselectivity
(entry 1). Eventually we found that the C2 symmetric chiral 1,2-
diamine 3 provided considerably higher levels of enantioselectivity
(72% ee) and good diastereoselectivity (92:8, favoring the syn-
isomer),8 but did not improve the yield of the reaction (entry 2). N,N’-
Dimethylcyclohexane-1,2-diamine (4) gave slightly lower dr and yield,
but provided better enantioselectivity (78% ee, entry 3). However,
increasing the size of the amino substituents provided much higher
yield, good diastereoselectivity, and retained enantioselectivity (entry
4). Although increasing the size of the aromatic groups with the use of
meta-methyl groups (ligand 6) did not provide substantially different
results (entry 5), placing electron-withdrawing CF3 groups at the same
position (ligand 7) provided a substantial increase in enantioselectivity
and higher diastereoselectivity (entry 6). Several rounds of additional
optimization led us to find that the optimal combination of
enantioselectivity, diastereoselectivity, and reactivity was achieved by
using the NiCl2 complex of this optimal ligand (complex 8), Et2Zn as
an in situ reductant, and 0 °C as the reaction temperature (entry 7).5
These conditions resulted in high enantioselectivity, good
diastereoselectivity, and outstanding yields.
30, 84%, (79:21)
syn/anti 84/54% ee
28, 86%, (88:12)
syn/anti 85/64% ee
NO2
29, 87%, (81:19)
syn/anti 82/49% ee
O
O
NO2
Et
O
Me NO2
MeO
Me
N
Me Me
MeO
N
N
Me
Me
Me
Me
Me
31, 74%, (92:08)
syn/anti 85/52% ee
32, 38%, 78% ee
33, 41%, 61% ee
a 0 °C b1.1 equiv KOtBu.
The scope with respect to the a-bromoamide is also broad (Scheme
3). Good dr and high ee were observed for amides possessing electron-
rich, electron-poor and sterically encumbered groups (19–21). a-
Bromoamides possessing a-alkyl substituents larger than methyl were
tolerated well, albeit with lower dr and ee (22, 23). Significantly,
several amide backbones, including indoline, morpholine, aryl-alkyl,
and Weinreb amides, were tolerated and all resulted in products with
high dr and ee. These reactions were most effective when the
nitroalkane starting material was b-branched (24–27), but substrates
without b-branching also proceeded smoothly (28–31). Amides
bearing tertiary bromides (32) and secondary nitroalkanes (33) could
also be utilized in the alkylation reaction. In both cases, lower yields
and ee were observed. However, these highly congested products
would be challenging to prepare by other methods.
As shown in Schemes 2 and 3, in most cases the asymmetric
nitroalkane alkylation exhibits good to excellent levels of
diastereoselectivity. In all cases, the major diastereomer was formed
with higher enantioselectivity, but good enantioselection was also
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Journal of the American Chemical Society
observed for the minor isomer. In many cases, the diastereomers can be
nature of the transformation. Consistent with our earlier non-
stereoselective nitroalkane alkylation reactions, these studies indicate a
mechanism involving radical intermediates. First, when the reaction
was run in the presence of 1 equiv TEMPO, a known radical
scavenger,15 no alkylation product 1 was formed (Scheme 5, top).
Second, cyclopropylcarbinyl rearrangement is observed with substrate
40, resulting exclusively in ring-opened product 41 (Scheme 5,
middle).16 Finally, the enantiopurity of the starting a-bromoamide
does not affect the stereoselectivity of the reaction; both enantiomers
of 42 lead to identical dr and ee of products, albeit with slightly
different yields. Additionally, when starting material was re-isolated
from reactions stopped at partial conversion, no erosion of ee of the
bromoamide was observed (Scheme 5, bottom).5 This result indicates
that activation of the C–Br is irreversible.
1
2
3
4
5
6
7
8
easily separated by standard flash column chromatography. In two
cases (15 and 24), we were able to determine the relative and absolute
stereochemistry of one of the diastereomers using X-ray
crystallography. In both cases, the (1R,2S)-syn-isomer proved to be the
1
major isomer using the R,R-catalyst.5 Diagnostic H NMR signals
supported this relative configuration for the other entries as well.9
Scheme 4. Downstream Functionalization of Alkylated Products.
CO2Me
O
NO2
O
O2N
DBU
Bn
Bn
+
N
N
3
3
CH CN, rt
3
CO2Me
9
Ph Me
Ph Me
34
10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Run 1 84%, (95:05), 91% ee
Run 2 83%, (95:05), 89% ee
Run 1 dr: 95:05, 91% ee
Run 2 dr: 79:21, 91/82% ee
Cl
CO2Me
O
H3N
Zn/HCl
0 °C to rt
Bn
Scheme 5. Mechanistic Probes.
N
3
A
Ph Me
5 mol % 8
1.0 mol % Et2Zn
O
O
NO2
Et
37, 94%, 88% ee
Me
Bn
Br
Bn
+
O2N
N
N
1.1 equiv NaOMe
Et2O, 0 °C, 24 h
Umemoto’s reagent
DBU
O2N
O
Zn/HCl
0 °C to rt
O
NO2
Et
CF3
Et
Ph Me
(1.0 equiv)
Ph Me
Bn
Bn
1
N
N
(1.2 equiv)
CH2Cl2, —20 °C
1 equiv TEMPO: 0% (NMR)
no TEMPO: 93% (NMR)
Ph Me
Ph Me
1, dr: 95:05
90% ee
35,67%, 95:05
88% ee
H2N
O
CF3
Et
B
Bn
O
NO2
Et
O
10 mol % 8
2.0 mol % Et2Zn
N
Bn
Bn
Br
N
Ph Me
Me
N
2
O2N
+
1.1 equiv NaOMe
Et2O, 0 °C, 24 h
38, 81%, 88% ee
Ph
Ph
cat. Pd2dba3·CHCl3
rac. BINAP
O
NO2
Et
O2N
O
41, 25%, 16% ee
(1.2 equiv)
40, (1.0 equiv)
Bn
Bn
+
N
N
Et
cat. DBU
DMSO, 50 °C
C
OCO2tBu
Ph Me
Ph Me
NO2
Me
10 mol %
2.0 mol % Et2Zn
8
O
NO2
1, dr: 95:05
90% ee
36,72%, 93:07
90% ee
10% recovered
(R)-42
>99% ee
+
+
1.1 equiv NaOMe
Et2O, rt
N
Et
O
1. Zn/HCl
0 °C to rt
TsHN
O
Me
Me
86% conversion
N
Bn
N
2. TsCl, cat. DMAP
Et3N, DCM, rt
Et
28, 84% (NMR)
syn/anti (81:19)
84% ee
Br
Ph Me
39, 81%, 96% ee
(R)-42
Although further studies will be required to fully elucidate the
mechanism, at present we favor the NiI/NiIII catalytic cycle shown in
Scheme 6.17 Initial reduction of the Ni(II) precatalyst by Et2Zn results
in formation of a Ni(0) complex. Comproportionation with excess
Ni(II) complex then results in a Ni(I) catalyst.18 This pathway would
explain the need for excess Ni(II) compared to Et2Zn. Simultaneously,
exothermic deprotonation of the acidic nitroalkane by the alkoxide
base results in an insoluble (or sparingly soluble) nitronate anion,
which undergoes anion exchange with the Ni(I) complex resulting in a
soluble Ni(I) nitronate. This electron-rich Ni(I) complex then reacts
with the alkyl bromide via a stepwise oxidative addition to form a
Ni(III) alkyl nitronate. Reductive elimination then provides the
observed product and regenerates the catalyst.5
The ability to prepare enantioenriched b-nitroamides using this
method has distinct advantages over other methods for construction of
amides bearing b-nitrogen atoms (such as the Mannich reaction).4h, 10
Specifically, unlike Mannich products, the acidity of the proton a to
the nitrogen atom allows b-nitroamides to be used in further synthetic
transformations.11 These transformations lead to highly substituted
products. For example, use of the alkylation products as nucleophiles in
C–C bond-forming reactions leads to b-nitroamides with fully
substituted b-carbons (Scheme 4). In these reactions, the stereocenter
a to the carbonyl controls facial selection, leading to highly
diastereoselective conjugate addition (top),11 trifluoromethylation
(middle),12 and Tsuji-Trost allylation (bottom) reactions,13 all without
erosion of ee. Consistent with our earlier studies,11-12 the syn-
diastereomer is observed in all cases, and the nitro groups of the
products are readily reduced to the corresponding amines (37–39).
Scheme 6. Possible Mechanistic Pathway.
Et2Zn
LnNiIIX2
LnNi0
LnNi0 + LnNiIIX2
Et
NO2
Significantly, isolation of a single diastereomer of the alkylation
product is not required for use in these downsteam reactions. As shown
at the top of Scheme 4, the conjugate addition reaction can be
conducted either with a single isolated diastereomer or with the
mixture of diastereomers obtained from the nickel-catalyzed reaction.
In both cases, identical diastereoselectivity and nearly identical
enantiopurity of product are obtained. These results indicate that the
diastereomers observed in the alkylation reaction are epimeric at the b-
center, and that the diastereomers converge upon deprotonation of the
nitroalkane in the subsequent reactions.14 From a practical standpoint,
this is highly advantageous when utilizing the alkylation products in
this way.
O
H
ONa
Et
N
O
NO2
Et
NaOMe
Bn
N
insoluble
LnNiI–X
Ph Me
phase
transfer
NaX
Et
NO2
LnNiI
O
O
Et
Et
NO2
LnNiI
R
LnNiIII
X
N
soluble
Me
R
Br
Me
Et
LnNiII
NO2
O
R
Bn
+
N
R =
Me
X
Several mechanistic experiments were carried out to probe the
Ph
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Page 4 of 6
C-Alkylation of Nitroalkane Anions by 1-Alkyl-2,4,6-triphenylpyridiniums:
In conclusion, the first Ni-catalyzed asymmetric C-alkylation of
nitroalkanes using an alkyl halide has been developed. This method
enables formation of highly enantioenriched b-nitroamide from readily
available a-bromoamides using mild reaction conditions that are
compatible with a wide range of functional groups. Significantly, due to
both the acidity of the b-proton and the ability of the a stereocenter to
control subsequent reactions, these products can be easily manipulated
to access a range of highly substituted b-aminoamides, providing
distinct advantages over competing technologies. This study also
demonstrates that the mechanism of transition metal-catalyzed
nitroalkane alkylation reactions are more complex than earlier believed,
and indicate that nickel-catalyzed nitroalkane alkylation occurs via
metal-mediated C–C bond formation. Current efforts are directed at
further expanding the scope of asymmetric nitroalkane alkylation
reactions and better defining the mechanisms by which they proceed.
A Nonchain Reaction with Radicaloid Characteristics. J. Am. Chem. Soc.
1983, 105, 90, doi:10.1021/ja00339a016; (h) Russell, G. A.; Khanna, R. K.
The Reaction of Carbanions with tert-Butyl Radicals. Tetrahedron 1985,
41, 4133, doi:10.1016/S0040-4020(01)97189-3; (i) Branchaud, P. B.; Yu,
G.-X. Cobaloxime-Mediated Radical Alkyl-Nitroalkylanion Cross
Coupling. Tetrahedron Lett. 1988, 29, 6545, doi:10.1016/S0040-
4039(00)82393-X
(3) (a) Gildner, P. G.; Gietter, A. A. S.; Cui, D.; Watson, D. A.
Benzylation of Nitroalkanes Using Copper-Catalyzed Thermal Redox
Catalysis: Toward the Facile C-Alkylation of Nitroalkanes. J. Am. Chem.
Soc. 2012, 134, 9942, doi:10.1021/ja304561c; (b) Gietter, A. A. S.;
Gildner, P. G.; Cinderella, A. P.; Watson, D. A. General Route for
Preparing β-Nitrocarbonyl Compounds Using Copper Thermal Redox
Catalysis. Org. Lett. 2014, 16, 3166, doi:10.1021/ol5014153; (c) Shimkin,
K. W.; Gildner, P. G.; Watson, D. A. Copper-Catalyzed Alkylation of
Nitroalkanes with α-Bromonitriles: Synthesis of β-Cyanonitroalkanes. Org.
Lett. 2016, 18, 988, doi:10.1021/acs.orglett.6b00093; (d) Rezazadeh, S.;
Devannah, V.; Watson, D. A. Nickel-Catalyzed C-Alkylation of
Nitroalkanes with Unactivated Alkyl Iodides. J. Am. Chem. Soc. 2017, 139,
8110, doi:10.1021/jacs.7b04312
(4) (a) Trost, B. M.; Surivet, J.-P. Diastereo- and Enantioselective
Allylation of Substituted Nitroalkanes. J. Am. Chem. Soc. 2000, 122, 6291,
doi:10.1021/ja001062s; (b) Ooi, T.; Takada, S.; Doda, K.; Maruoka, K.
Highly Diastereo- and Enantioselective Formal Conjugate Addition of
Nitroalkanes to Nitroalkenes by Chiral Ammonium Bifluoride Catalysis.
Angew. Chem., Int. Ed. 2006, 45, 7606, doi:10.1002/anie.200602787; (c)
Palomo, C.; Oiarbide, M.; Laso, A. Recent Advances in the Catalytic
Asymmetric Nitroaldol (Henry) Reaction. Eur. J. Org. Chem. 2007, 2007,
2561, doi:10.1002/ejoc.200700021; (d) Dobish, M. C.; Johnston, J. N.
Chiral Brønsted Base-Promoted Nitroalkane Alkylation: Enantioselective
Synthesis of sec-Alkyl-3-Substituted Indoles. Org. Lett. 2010, 12, 5744,
doi:10.1021/ol1025712; (e) Roca-Lopez, D.; Sadaba, D.; Delso, I.;
Herrera, R. P.; Tejero, T.; Merino, P. Asymmetric organocatalytic synthesis
of γ-nitrocarbonyl compounds through Michael and Domino reactions.
Tetrahedron: Asymmetry 2010, 21, 2561, doi:10.1016/j.tetasy.2010.11.001;
(f) Blay, G.; Hernández-Olmos, V.; Pedro, J. R. Development of New N,N-
Ligands for the Enantioselective Copper(II)-Catalyzed Henry Reaction.
Synlett 2011, 2011, 1195, doi:10.1055/s-0030-1260558; (g) Ohmatsu, K.;
Ito, M.; Kunieda, T.; Ooi, T. Ion-paired Chiral Ligands for Asymmetric
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental Procedures (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
dawatson@udel.edu
Funding Sources
The University of Delaware (UD), the University of Delaware
Research Foundation, the Research Corp. Cottrell Scholars Program,
and the NIH NIGMS (R01 GM102358) are gratefully acknowledged
for support. Data was acquired at UD on instruments obtained with the
assistance of NSF and NIH funding (NSF CHE0421224,
CHE0840401, CHE1229234, CHE1048367; NIH S10 OD016267-01,
S10 RR026962-01, P20GM104316, P30GM110758).
ACKNOWLEDGMENT
Palladium
Catalysis.
Nature
Chem.
2012,
4,
473,
doi:10.1038/nchem.1311; (h) Noble, A.; Anderson, J. C. Nitro-Mannich
Reaction. Chem. Rev. 2013, 113, 2887, doi:10.1021/cr300272t; (i) Qian,
H.; Yu, X.; Zhang, J.; Sun, J. Organocatalytic Enantioselective Synthesis of
2,3-Allenoates by Intermolecular Addition of Nitroalkanes to Activated
Enynes. J. Am. Chem. Soc. 2013, 135, 18020, doi:10.1021/ja409080v; (j)
Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B. Bifunctional Primary
Amine-Thioureas in Asymmetric Organocatalysis. Org. Biomol. Chem.
2013, 11, 7051, doi:10.1039/C3OB41403E; (k) Tsakos, M.; Kokotos, C.
G. Primary and Secondary Amine-(thio)ureas and Squaramides and Their
Applications in Asymmetric Organocatalysis. Tetrahedron 2013, 69,
10199, doi:10.1016/j.tet.2013.09.080; (l) Manna, M. S.; Mukherjee, S.
Organocatalytic Enantioselective Formal C(sp2)–H Alkylation. J. Am.
Chem. Soc. 2015, 137, 130, doi:10.1021/ja5117556; (m) Vara, B. A.;
Johnston, J. N. Enantioselective Synthesis of β-Fluoro Amines via β-Amino
α-Fluoro Nitroalkanes and a Traceless Activating Group Strategy. J. Am.
Chem. Soc. 2016, 138, 13794, doi:10.1021/jacs.6b07731; (n) Kawada, M.;
Nakashima, K.; Hirashima, S.-i.; Yoshida, A.; Koseki, Y.; Miura, T.
Asymmetric Conjugate Addition of Nitroalkanes to Enones Using a
Sulfonamide–Thiourea Organocatalyst. J. Org. Chem 2017, 82, 6986,
doi:10.1021/acs.joc.7b00835; (o) Li, Y.; Huang, Y.; Gui, Y.; Sun, J.; Li, J.;
Zha, Z.; Wang, Z. Copper-Catalyzed Enantioselective Henry Reaction of
β,γ-Unsaturated α-Ketoesters with Nitromethane in Water. Org. Lett.
2017, 19, 6416, doi:10.1021/acs.orglett.7b03299; (p) Lu, N.; Bai, F.; Fang,
Y.; Wei, Z.; Cao, J.; Liang, D.; Lin, Y.; Duan, H. Bifunctional Phase-
Transfer Catalysts Catalyzed Diastereo- and Enantioselective Aza-Henry
Reaction of β,γ-Unsaturated Nitroalkenes With Amidosulfones. Adv.
Synth. Catal. 2017, 359, 4111, doi:10.1002/adsc.201700787
Dr. Glenn Yap (UD) is acknowledged for assistant with X-ray
crystallography.
REFERENCES
(1) (a) Ono, N., The Nitro Group In Organic Synthesis. John Wiley And
Sons: New York, 2001; (b) Ballini, R.; Palmieri, A. Synthetic Procedures
for the Preparation of Nitroalkanes. Adv. Synth. Catal. 2018, 360, 2240,
doi:10.1002/adsc.201800163
(2) (a) Weisler, L.; Helmkamp, R. W. The Action of Some Benzyl
Halides on Salts of Phenylnitromethane and Phenylnitro-acetonitrile. J.
Am. Chem. Soc. 1945, 67, 1167, doi:10.1021/ja01223a040; (b) Hass, H. B.;
Bender, M. L. The Reaction of Benzyl Halides with the Sodium Salt of 2-
Nitropropane. A General Synthesis of Substituted Benzaldehydes. J. Am.
Chem. Soc. 1949, 71, 1767, doi:10.1021/ja01173a066; (c) Kornblum, N.
Substitution Reactions Which Proceed via Radical Anion Intermediates.
Angew. Chem., Int. Ed. Engl. 1975, 14, 734, doi:10.1002/anie.197507341;
(d) Seebach, D.; Henning, R.; Lehr, F.; Gonnermann, J. Carbon
Alkylations of α.α- and α.β-doubly Deprotonated Nitroalkanes.
Tetrahedron Lett. 1977, 18, 1161, doi:10.1016/S0040-4039(01)92859-X;
(e) Seebach, D.; Henning, R.; Lehr, F. Double Deprotonation of 3-
Nitropropene and 4-Nitro-1-butene: Derivatives of Their Dianions as
Novel Reagents for CC-Linkage. Angew. Chem., Int. Ed. Engl. 1978, 17,
458, doi:10.1002/anie.197804581; (f) Katritzky, A. R.; de Ville, G.; Patel,
R. C. Carbon-Alkylation of Simple Nitronate Anions. J. Chem. Soc., Chem.
Commun. 1979, 602, doi:10.1039/C3979000602A; (g) Katritzky, A. R.;
Kashmiri, M. A.; De Ville, G. Z.; Patel, R. C. Kinetics and Mechanism of the
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(5) See Supporting Information for further detail.
(6) For recent reviews of asymmetric reactions involving alkyl halides,
see: (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Enantioselective
and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling Reactions
of Organometallic Reagents To Construct C–C Bonds. Chem. Rev. 2015,
115, 9587, doi:10.1021/acs.chemrev.5b00162; (b) Choi, J.; Fu, G. C.
Transition Metal–Catalyzed Alkyl-Alkyl Bond Formation: Another
1
2
3
4
5
6
Dimension in Cross-Coupling Chemistry.
Science 2017, 356,
doi:10.1126/science.aaf7230; (c) Bhat, V.; Welin, E. R.; Guo, X.; Stoltz, B.
M. Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-
Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions,
and Dynamic Kinetic Asymmetric Transformations. Chem. Rev. 2017, 117,
4528, doi:10.1021/acs.chemrev.6b00731
(7) Wilson, J. E.; Casarez, A. D.; MacMillan, D. W. C. Enantioselective
Aldehyde α-Nitroalkylation via Oxidative Organocatalysis. J. Am. Chem.
Soc. 2009, 131, 11332, doi:10.1021/ja904504j
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(8) Lundin, P. M.; Fu, G. C. Asymmetric Suzuki Cross-Couplings of
Activated Secondary Alkyl Electrophiles: Arylations of Racemic α-
Chloroamides.
J. Am. Chem. Soc. 2010, 132, 11027,
doi:10.1021/ja105148g
(9) The absolute configuration of the other beta-nitroamide products
were assigned by analogy.
(10) Arend, M.; Westermann, B.; Risch, N. Modern Variants of the
Mannich Reaction.
Angew. Chem., Int. Ed. 1998, 37, 1044,
doi:10.1002/(SICI)1521-3773(19980504)37:8<1044::AID-
ANIE1044>3.0.CO;2-E
(11) Gietter-Burch, A. A. S.; Mitrut, R. E.; Watson, D. A. Highly
Diastereoselective Michael Reactions Using β-Nitrocarbonyl Nucleophiles.
Org. Lett. 2015, 17, 5468, doi:10.1021/acs.orglett.5b02832
(12) Gietter-Burch, A. A. S.; Devannah, V.; Watson, D. A.
Trifluoromethylation of Secondary Nitroalkanes. Org. Lett. 2017, 19,
2957, doi:10.1021/acs.orglett.7b01196
(13) Maki, K.; Kanai, M.; Shibasaki, M. Pd-Catalyzed Allylic Alkylation
of Secondary Nitroalkanes.
doi:10.1016/j.tet.2007.03.062
Tetrahedron 2007, 63, 4250,
(14) Interestingly, the use of weaker bases, such as DBU leads to
inconsistent stereoselection in the alkylation reaction due to epimerization
of both the alpha and beta stereocenters. We attribute the stability of the
product under the tert-butoxide conditions to be due to the solubility of the
base. DBU is soluble under the reaction condition; tert-butoxide
quantitively deprotonates the nitronate substrate, which then precipitates
from the reaction media. The fact that there is little to no free base in
solution during the reaction protects the product against epimerization. See
Supporting Information for more details.
(15) Bowry, V. W.; Ingold, K. U. Kinetics of Nitroxide Radical
Trapping. 2. Structural Effects. J. Am. Chem. Soc. 1992, 114, 4992,
doi:10.1021/ja00039a006
(16) Newcomb, M. Competition Methods and Scales for Alkyl Radical
Reaction Kinetics. Tetrahedron 1993, 49, 1151, doi:10.1016/S0040-
4020(01)85808-7
(17) (a) Hu, X. Nickel-Catalyzed Cross Coupling of Non-Activated
Alkyl Halides: A Mechanistic Perspective. Chemical Science 2011, 2, 1867,
doi:10.1039/C1SC00368B; (b) Schley, N. D.; Fu, G. C. Nickel-Catalyzed
Negishi Arylations of Propargylic Bromides: A Mechanistic Investigation.
J. Am. Chem. Soc. 2014, 136, 16588, doi:10.1021/ja508718m
(18) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.; Hall, R. E.;
Haley, A. D.; Brandon, R. J.; Konovalova, T.; Desrochers, P. J.; Pulay, P.;
Vicic, D. A. Ligand Redox Effects in the Synthesis, Electronic Structure,
and Reactivity of an Alkyl−Alkyl Cross-Coupling Catalyst. J. Am. Chem.
Soc. 2006, 128, 13175, doi:10.1021/ja063334i
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Enantioselective Nitroalkane Alkylation
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O
O
NO2
NO2
R4
cat. (L*)NiCl2/ Et2Zn
R1
Br
R1
+
N
N
R4
NaOMe
R2
R3
R2
R3
5
CF3
CF3
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CF3
F3C
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N
N
H
H
Ni
Cl
Cl
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(L*)NiCl2
26 examples, up to 99% ee and 95:05 d.r.
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