General route for preparing β-nitrocarbonyl compounds using copper thermal redox catalysis

Article abstract of DOI:10.1021/ol5014153

Using a simple copper catalyst, the alkylation of nitroalkanes with α-bromocarbonyls is now possible. This method provides a general, functional group tolerant route to β-nitrocarbonyl compounds, including nitro amides, esters, ketones, and aldehydes. The

Full text of DOI:10.1021/ol5014153

Letter
pubs.acs.org/OrgLett
General Route for Preparing β‑Nitrocarbonyl Compounds Using
Copper Thermal Redox Catalysis
Amber A. S. Gietter, Peter G. Gildner, Andrew P. Cinderella, and Donald A. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: Using a simple copper catalyst, the alkylation of
nitroalkanes with α-bromocarbonyls is now possible. This method
provides a general, functional group tolerant route to β-nitrocarbonyl
compounds, including nitro amides, esters, ketones, and aldehydes.
The highly sterically dense, functional group rich products from
these reactions can be readily elaborated into a range of complex
nitrogen-containing molecules, including highly substituted β-amino acids.
itroalkanes are extraordinarily useful intermediates in
extremely elegant and efficient, it is limited to preparation of β-
Norganic synthesis. These compounds participate in a wide nitroaldehydes and cannot access highly substituted products.11
1
While a few additional sundry methods exist,12 to date, no
general method has been reported for the preparation of β-
nitrocarbonyls that is general for a wide variety of carbonyl
range of carbon−carbon bond-forming reactions (including
Henry reactions,2 conjugate additions,2 allylations,3 and
arylations4), serve as starting materials for the installation of
groups with varying substitution and proceeds under syntheti-
cally tractable conditions.
numerous functional groups (including alkylamines, ketones,
hydroxyl amines, alkanes),2 and serve as radical precursors
(Scheme 1).5
One potential entry to β-nitrocarbonyls involves the alkylation
of a nitronate anion by a readily available α-bromocarbonyl
compound. However, this reaction has been shown to lead to a
complex mixture of products, presumably due to the strong
preference for nitronate anions to undergo alkylation at oxygen
in reactions involving alkyl halide electrophiles.10,13,14
Scheme 1. Synthesis of Nitrocarbonyl Compounds
We recently reported a simple and inexpensive copper catalyst,
prepared in situ from copper bromide and an easily synthesized
1,3-diketimine (nacnac) ligand, that successfully catalyzes the C-
alkylation of nitroalkanes using benzyl bromides.15,16 We believe
this reaction proceeds via a benzyl-stabilized radical,16 which
suggests that other alkyl bromides bearing radical-stabilizing
groups might be viable coupling partners for the reaction.
We now show that nitroalkanes can be alkylated with α-
bromocarbonyls using this copper-catalyzed strategy. This new
protocol provides direct access to a wide range of β-nitrocarbonyl
compounds, including nitro esters, amides, ketones, and
aldehydes with excellent functional group compatibility.
Importantly, this method also demonstrates remarkable steric
tolerance, and allows the synthesis of β-nitrocarbonyls
containing fully substituted vicinal carbons at both the α and β
positions. This method can be used to access a range of
downstream products, including complex, sterically encumbered
β-amino acids.
Among nitroalkanes, nitrocarbonyl compounds are a partic-
ularly interesting class, as the two functional groups have widely
orthogonal reactivity, making them highly versatile intermediates
in complex molecule synthesis.1 α-Nitrocarbonyls can be easily
prepared by acylation of a nitronate anion6 or by nitration of a
carbonyl.7 Similarly, γ-nitrocarbonyls can be prepared by
conjugate addition of a nitronate anion to an α,β-unsaturated
carbonyl,8 or by the addition of an enolate to a nitroalkene.9 In
contrast, however, the synthesis of β-nitrocarbonyls is consid-
erably more challenging. In 1970, Kornblum demonstrated that
tertiary α-nitrocarbonyls can undergo coupling with nitronate
anions to prepare β-nitroesters and ketones;10 however, these
reactions, which likely proceed via radical intermediates, have not
been widely adopted, possibly due to the required starting
materials and/or need for light-promoted reaction conditions
with many substrates. More recently, MacMillan reported the
enantioselective α-nitroalkylation of aldehydes using silylnitro-
nates and organo-SOMO catalysis. While this latter method is
We began by studying the reaction of ethyl 2-bromovalerate
with 1-nitropropane to make β-nitroester 1 (Table 1). Starting
with the optimized conditions for alkylation of nitroalkanes using
benzyl bromides (20 mol % of CuBr, 20 mol % of diketimine 2,
Received: May 17, 2014
Published: May 28, 2014
© 2014 American Chemical Society
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Table 1. Optimization of Reaction Conditions
Scheme 2. Scope with Respect to α-Bromocarbonyl
Compound
b
b
entry
base
solvent
yield of 1 (%)
dr
58:42
n/a
1
2
3
4
5
6
7
8
9
NaOEt
benzene
benzene
benzene
toluene
hexanes
Et2O
75
c
NaOEt
0
NaOSiMe3
NaOSiMe3
NaOSiMe3
NaOSiMe3
NaOSiMe3
NaOSiMe3
NaOSiMe3
92 (89)
69
59:41
61:39
62:38
62:38
56:44
62:38
∼50:50
94 (90)
68
dioxane
77
d
CH2Cl2
96 (94)
4
DMF
a
b
1.2 equiv of 1-nitropropane. Yield and diastereomeric ratio (dr)
determined by NMR using 1,3,5-trimethoxybenzene or mesitylene as
an internal standard; parenthetical yields are isolated yields of pure
c
d
material. No copper, no ligand. 40 °C.
NaOEt, benzene, 60 °C), we were pleased to observe a 75% yield
of desired product 1 (entry 1). The nitroester was observed as a
58:42 mixture of diastereoisomers, which was later shown to
favor the erythro-isomer, as shown (see below). In the absence of
catalyst, none of the desired product was observed (entry 2).
When NaOSiMe3 was used as the base, 1 was observed in 92%
yield (89% isolated yield) with a similar diastereomeric ratio as
above (entry 3). Further studies revealed that the reaction was
tolerant of a range of solvents (entries 4−8). Whereas nonpolar
solvents generally provided the highest yields, moderate to good
yields were observed in all but the most polar solvents
investigated (entry 9). Particularly effective solvents include
benzene, hexanes, and methylene chloride, all of which provide
excellent yield in the model reaction. In subsequent studies,
benzene proved to be the most general solvent and was therefore
used most often. In many cases, however, hexanes could also be
employed. For the sake of comparison, yields in both solvents are
reported in some of the studied examples described below. In a
few cases, often those involving more polar substrates, other
solvents such as dioxane, cyclohexane, or methylene chloride
provided superior yields. These cases are denoted in the tables.
The optimized reaction conditions are highly general for the
preparation of β-nitrocarbonyl compounds. As shown in Scheme
2 (top), a broad range of α-bromoesters bearing diverse
substitution and functional groups participate in the reaction.
Branching and aromatic substitution at the α-position (3 and 4)
do not adversely affect the yield of the reaction. Both primary and
tertiary α-bromoesters are also effective substrates. With primary
substrates (5 and 9), we have found that increased catalyst
loading is required to achieve good yields. We assume this relates
to the difficulty in forming a primary radical intermediate.
However, given the cost of the catalyst, we do not believe this to
be a serious impediment.
a
Conditions: 1 equiv of α-bromocarbonyl, 1.2−1.4 equiv of nitro-
alkane, 20 mol % of CuBr, 20 mol % of 2, and 1.1−1.3 equiv of
NaOSiMe3; see the Supporting Information for exact conditions.
Diastereomeric ratio determined from NMR of crude product using
b
c
mesitylene as internal standard. 50 mol % of CuBr and 2. 48 h.
In contrast, tertiary α-bromo esters react very smoothly with
standard catalyst loadings to provide highly substituted β-nitro
esters (6 and 7). A variety of esters can also be used (11, 12, and
14). Finally, β-nitrolactones can also be prepared using this route
(13).
α-Bromo amides also serve as alkylating reagents in this
transformation (Scheme 2, middle). N,N-Dialkylamides bearing
a secondary α-bromide react in excellent yield under the
optimized reaction conditions (21). As with the ester substrates,
primary bromide substrates can also be used, but the yield is
slightly attenuated and higher catalyst loading is required (22).
With tertiary amides bearing a tertiary halogen, the facility of the
reaction depends greatly on the nature of the nitrogen
substituents.
With amides bearing two alkyl groups, a low yield of the
desired product (23) was observed, even when forcing
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conditions were employed. We attribute this to the extreme steric
encumbrance imparted by the s-trans amide substituent in the
putative radical intermediate.17 This hypothesis is supported by
the fact that formation of pyrrolidine-derived product 24, in
which the s-trans substituent is constrained, is formed in much
higher yield under the standard conditions. α-Bromoamides
bearing other nitrogen substituents can also be used in the
reaction. This includes protic primary (25) and secondary
amides (26). Weinreb amide substrates are also very good
substrates in the reaction; products derived from both secondary
(27) and tertiary bromides (28) can be obtained in high yield.
The versatility of the Weinreb amide products will allow a broad
range of downstream synthetic manipulations.18
Finally, with respect to the scope of the α-bromocarbonyl
substrate, both α-bromo ketones and aldehydes can be used
(Scheme 2, bottom). Ketones both with (31) and without (32)
enolizable protons at the adjacent α-center performed equally
well. As with previous examples, reduced substitution at the
bromide center of the starting material decreased the yield of the
product (33). With aldehydes, the degree of substitution at the
halogen center proved highly critical. Only tertiary α-
bromoaldehydes provided useful yields in the reaction (34). In
this way, the current reaction is highly complementary to the
transformation reported by MacMillan described above.11
The reaction is also highly robust with respect to the
nitroalkane coupling partner (Scheme 3). Longer aliphatic
nitroalkanes (35), as well as those with β-branching (36), are
well tolerated. The alkylation of nitromethane proceeded
without incident (41). Most strikingly, secondary nitroalkanes
could also be alkylated using this protocol. This includes the use
of secondary (43 and 44) as well as tertiary (45−51) α-
bromocarbonyls. In the latter case, both simple secondary
nitroalkanes, such as 2-nitropropane and nitrocyclohexane, as
well as more complex nitroalkanes participated in the reaction
with equal facility (49 and 51). The products from these
reactions lead to fully substituted vicinal carbons bearing a
nitrogen center, which are highly challenging to prepare by other
means.19 There does, however, appear to be a steric limit in these
reactions (see 47 and 50); very highly encumbered products are
formed in only limited yield.
Finally, more complex nitroalkanes bearing additional func-
tional groups were also well tolerated in the reaction (37−40 and
49−51). These examples, as well as the additional examples in
Scheme 2, demonstrate the broad functional group compatibility
observed with this transformation. In total, compatible functional
groups include aromatic chlorides (30), bromides (11 and 12),
and iodides (14), trifluoromethyl arenes (29), alkenes (15),
internal alkynes (16), silyl ethers (17), esters (37), and amides
(38) located away from the reaction center, acyl-protected
alcohols (39), and secondary Boc-protected amines (40). In
addition, a variety of heterocyclic substrates are tolerated in the
reaction, including lactones (mentioned above, 13), furans (18),
thiophenes (19), and pyridines (20). Finally, it is notable that the
preparation of 18 was accomplished on multigram scale,
demonstrating the scalability of these reactions, even on more
complex substrates.
Only modest levels of diastereoselectivity were observed in
cases where stereoisomers were possible. In most cases, however,
the stereoisomers were readily separated by simple chromatog-
raphy, and in several cases we were able to characterize one of the
isomers via X-ray crystallography (see Scheme 2). Correlation of
Scheme 3. Scope with Respect to Nitroalkane
1
these structures to their H NMR spectra revealed that the
erythro isomer consistently displayed downfield shifts at the
hydrogen atom α to the nitro group compared to the threo
isomer.20 Based upon this analysis, we were able to determine
that the erythro isomer was the predominant product in all but
two cases (the exceptions were for aromatic product 4 and
lactone 13).21
The products from the alkylation reaction are highly useful
intermediates for further synthetic manipulations. For example,
the products can be elaborated by C−C bond-forming reactions.
This includes traditional reactions, such as their use as
nucleophiles in conjugate addition reactions (e.g., Scheme 4,
top)22 or our previously reported copper-catalyzed benzylation
reaction (e.g., Scheme 4, bottom).15 Notably, both of these
reactions form congested, nitrogen-bearing, fully substituted
carbons. The ability to functionalize further α to the nitro group
highlights the importance of this transformation compared to
Scheme 4. Subsequent C−C Bond-Forming Reactions of
Alkylation Products
a
Conditions: 1 equiv α-bromocarbonyl, 1.2−1.6 equiv nitroalkane, 20
mol % CuBr, 20 mol % 2, and 1.1−1.7 equiv NaOSiMe3, see
Supporting Information for exact conditions. 48 h. 50 mol % CuBr
and 2. 30 mol % CuBr and 2, 48 h. 40 mol % CuBr and 2.
b
c
d
e
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other protocols for preparing β-azacarbonyl compounds, such as
the β-aminocarbonyls that result from Mannich reactions.19
Moreover, β-nitrocarbonyls are excellent precursors for β-
amino acids and their derivatives.23 For example, Zn/AcOH
provides a high-yielding, mild reagent for the selective reduction
of the nitro group to the corresponding amine (Scheme 5, top).
Alternatively, Pd/C-catalyzed hydrogenolysis of benzyl ester
derivatives leads cleanly to the unprotected β-amino acids in very
high yield (Scheme 5, bottom).
REFERENCES
■
(1) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979, 33, 1.
(2) Ono, N. The Nitro Group In Organic Synthesis; John Wiley & Sons:
New York, 2001.
(3) (a) Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Tetrahedron 1982,
38, 1321. (b) Maki, K.; Kanai, M.; Shibasaki, M. Tetrahedron 2007, 63,
4250. (c) Trost, B. M.; Surivet, J.-P. Angew. Chem., Int. Ed. 2000, 39,
3122. (d) Tsuji, J.; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.;
Shimizu, I. J. Org. Chem. 1987, 52, 2988. (e) Wade, P. A.; Morrow, S. D.;
Hardinger, S. A. J. Org. Chem. 1982, 47, 365.
(4) Vogl, E. M.; Buchwald, S. L. J. Org. Chem. 2001, 67, 106.
(5) (a) Kornblum, N.; Carlson, S. C.; Smith, R. G. J. Am. Chem. Soc.
1979, 101, 647. (b) Ono, N.; Miyake, H.; Kaji, A. Chem. Lett. 1985, 14,
635. (c) Tormo, J.; Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 5296.
(6) (a) Bachman, G. B.; Hokama, T. J. Am. Chem. Soc. 1959, 81, 4882.
(b) Baker, D. C.; Putt, S. R. Synthesis 1978, 1978, 478. (c) Crumbie, R.
L.; Nimitz, J. S.; Mosher, H. S. J. Org. Chem. 1982, 47, 4040.
(d) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Gromova, A. V.; Witek, R.;
Steel, P. J. J. Org. Chem. 2005, 70, 9211. (e) Ono, N.; Fujii, M.; Kaji, A.
Synthesis 1987, 1987, 532. (f) Nakamura, K.; Kitayama, T.; Inoue, Y.;
Ohno, A. Tetrahedron 1990, 46, 7471.
Scheme 5. Reduction of Alkylation Products
(7) (a) Fischer, R. H.; Weitz, H. M. Synthesis 1980, 1980, 261.
(b) Kornblum, N.; Chalmers, M. E.; Daniels, R. J. Am. Chem. Soc. 1955,
77, 6654. (c) Laikhter, A. L.; Kislyi, V. P.; Semenov, V. V. Mendeleev
Commun. 1993, 3, 20.
(8) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem.
Rev. 2005, 105, 933.
(9) Roca-Lopez, D.; Sadaba, D.; Delso, I.; Herrera, R. P.; Tejero, T.;
Merino, P. Tetrahedron: Asymmetry 2010, 21, 2561.
(10) Kornblum, N.; Boyd, S. D.; Stuchal, F. W. J. Am. Chem. Soc. 1970,
92, 5783.
(11) Wilson, J. E.; Casarez, A. D.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2009, 131, 11332.
(12) (a) Miyakoshi, T.; Saito, S.; Kumanotani, J. Chem. Lett. 1981, 10,
1677. (b) Russell, G. A.; Ros, F. J. Am. Chem. Soc. 1982, 104, 7349.
(c) Kunetsky, R. A.; Dilman, A. D.; Tsvaygboym, K. P.; Ioffe, S. L.;
Strelenko, Y. A.; Tartakovsky, V. A. Synthesis 2003, 2003, 1339.
(13) (a) Kornblum, N.; Boyd, S. D. J. Am. Chem. Soc. 1970, 92, 5784.
(b) Hass, H. B.; Bender, M. L. J. Am. Chem. Soc. 1949, 71, 1767.
(14) For an isolated case involving a specific substrate class, see:
Easton, C. J.; Roselt, P. D.; Tiekink, E. R. T. Tetrahedron 1995, 51, 7809.
(15) Gildner, P. G.; Gietter, A. A. S.; Cui, D.; Watson, D. A. J. Am.
Chem. Soc. 2012, 134, 9942.
It is particularly notable that this latter reaction works
efficiently to prepare a range of highly substituted β-amino
acids, including those bearing additional functional groups.
In summary, using copper-catalyzed thermal redox catalysis,
we have developed a general and high-yielding route for the
preparation of β-nitrocarbonyl compounds from readily available
α-bromocarbonyls. The method is applicable to the synthesis of
nitro esters, amides, ketones, and aldehydes, and the mild
reaction conditions are compatible with a vast range of functional
groups. The versatile products from the reaction offer a range of
options for additional synthetic manipulations, including ready
access to highly substituted β-amino acids and their derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
(16) For conceptually related Heck-type reactions, see: (a) Liu, C.;
Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A. Angew. Chem., Int.
Ed. 2012, 51, 3638. (b) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita,
T. J. Am. Chem. Soc. 2013, 135, 16372.
S
Experimental procedures; crystallographic and spectral data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(17) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(18) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 3707.
(19) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471. (c) Tramontini, M.; Angiolini, L. Mannich
Bases, Chemistry and Uses; CRC Press Inc.: Boca Raton, FL, 1994.
(20) See the Supporting Information for further details regarding this
analysis.
(21) With the possible exceptions of 4 and 13, we believe this product
mixture to be kinetic in origin. See the Supporting Information.
(22) Interestingly, this reaction is highly diastereoselective. A 63:37
mixture of diastereomers of starting material affords a single
diastereomer of product (NMR). The relative stereochemistry was
determined by X-ray crystallography, after reduction to the amine. See
the Supporting Information.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dawatson@udel.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Mr. Di Cui (University of Delaware) is acknowledged for
preliminary experiments in this area. Dr. Glenn Yap (University
of Delaware) is thanked for crystallography. The University of
Delaware, the University of Delaware Research Foundation, the
Research Corporation (Cottrell Scholars Program), and the
NIGMS (R01GM102358) are gratefully acknowledged for
support. Data was acquired at UD on instruments obtained
with the assistance of NSF and NIH funding (NSF
CHE0421224, CHE1229234, CHE0840401, and
CHE1048367; NIH P20 GM103541 and S10 RR02692).
(23) (a) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290. (b) Juaristi, E.;
Soloshonok, V. A Enantioselective Synthesis of β-Amino Acids, 2nd ed.;
John Wiley & Sons, Inc.: Hoboken, NJ, 2005;. (c) Weiner, B.;
Szymanski, W.; Janssen, D. B.; Minnaard, A. J.; Feringa, B. L. Chem. Soc.
Rev. 2010, 39, 1656.
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