Electrophilic α-amination reaction of β-ketoesters using N -hydroxycarbamates: Merging aerobic oxidation and lewis acid catalysis

Article abstract of DOI:10.1021/ja310784f

The copper-catalyzed α-amination of carbonyl compounds using nitrosoformate intermediates as the electrophilic source of nitrogen is reported. The reaction merges aerobic oxidation and Lewis acid catalysis. The scope of the reaction is broad in terms of both the N-substituted hydroxylamines and the β-ketoesters. The new methodology harnesses the power of nitrosoformate intermediates and demonstrates their potential as a viable electrophilic source of nitrogen in α-functionalization reactions.

Full text of DOI:10.1021/ja310784f

Communication
pubs.acs.org/JACS
Electrophilic α‑Amination Reaction of β‑Ketoesters Using
N‑Hydroxycarbamates: Merging Aerobic Oxidation and Lewis Acid
Catalysis
David Sandoval, Charles P. Frazier, Alejandro Bugarin, and Javier Read de Alaniz*
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
S
* Supporting Information
ABSTRACT: The copper-catalyzed α-amination of car-
bonyl compounds using nitrosoformate intermediates as
the electrophilic source of nitrogen is reported. The
reaction merges aerobic oxidation and Lewis acid catalysis.
The scope of the reaction is broad in terms of both the N-
substituted hydroxylamines and the β-ketoesters. The new
methodology harnesses the power of nitrosoformate
intermediates and demonstrates their potential as a viable
electrophilic source of nitrogen in α-functionalization
reactions.
he efficient and direct synthetic construction of α-amino
carbonyl compounds using an electrophilic source of
T
nitrogen has been a long-standing challenge in organic
synthesis.1 Recently, nitrosobenzene and its analogues have
been recognized as an attractive electrophile for α-heteroatom
functionalization reactions of carbonyl compounds.2 Nitro-
soarenes can serve as both an electrophilic source of nitrogen or
oxygen depending on the reaction conditions.3 The amino-
oxylation reaction to afford α-oxygenated carbonyl compounds
has been extensively developed and now represents a versatile
method to gain access to the α-oxycarbonyl synthon (Figure
1a).4 In contrast, while the N-selective nitroso aldol reaction
has made considerable progress,3d−f,5 the products of the
hydroxyamination reaction are synthetically limited because it is
often difficult to cleave the N-aryl bond to allow for subsequent
nitrogen-bond forming transformations (Figure 1b).5f,6 Notably
absent from nitroso aldol methods are examples with
nitrosocarbonyl intermediates, which can easily be modified
and would represent a desirable alternative to arylnitroso
compounds in electrophilic amination. In this communication,
we present the development of the first N-selective nitroso
aldol reaction utilizing nitrosoformate esters, generated in situ,
as the electrophilic source of nitrogen (Figure 1c).7 This new
process is highly N-selective, uses an operationally convenient
procedure, air, as the sole oxidant, and provides direct entry
into α-amino carbonyl derivatives with functional groups that
are easy to manipulate.
Figure 1. α-Functionalization of carbonyl compounds.
studies and the limitations associated with the N-selective
arylnitroso aldol reaction, we were encouraged to investigate if
the transient electrophilic nitrosoformate intermediate could be
trapped with an enolate equivalent.
With this in mind, we set out to merge aerobic oxidation with
Lewis acid catalysis. The use of synergistic catalysis is a
powerful approach to reaction design and has emerged as a
highly attractive strategy for developing new and valuable
transformations.10 As shown in Figure 1c, we envisioned that
the concurrent activation of latent nucleophilic (β-ketoester)
and electrophilic (nitrosoformate) partners could be achieved.
The union of these catalytic processes would result in a direct
α-amination reaction of β-ketoesters. The central challenge was
to identify conditions that would allow for the compatible
formation of the electrophile and nucelophile in situ, would
facilitate subsequent C−N bond formation, and would avoid
Recently, we reported the formation of nitroso compounds
using a copper-catalyzed aerobic oxidation of N-substituted
hydroxylamines.8 In these reactions, the highly reactive and
transient nitroso intermediates are generated catalytically under
mild reaction conditions, which appears to help avoid
previously reported problems associated with their in situ
formation and subsequent chemistry.9 On the basis of these
Received: November 1, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja310784f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
decomposition of the highly reactive nitrosoformate ester
intermediate. In this regard, we felt copper complexes held
tremendous promise and would be an excellent choice to
initiate our investigations. In addition to our studies on Cu(I)-
catalyzed nitroso formation, Shea and Whiting have developed
a Cu(II)-catalyzed aerobic oxidation of N-hydroxycarbamates
to nitrosoformates.11 Moreover, copper(II) complexes have
proven effective as a means of enolate generation in metal-
catalyzed functionization of β-ketoesters.12
Table 2. Substrate Scope Studies for the Nitrosoformate α-
Amination Reaction
a,b
The reaction of ethyl β-keto ester 1 with carbobenzyloxy
(Cbz)-protected hydroxylamine 2 was chosen as a test reaction
(Table 1). Our initial studies revealed that the proposed α-
Table 1. Copper-Catalyzed Nitrosoformate α-Amination
Reaction
time
(h)
yield
a
N/O
b
entry CuCl/Cu(OTf)2 additive
solvent
(%)
ratio
c
1
2
3
4
5
6
7
8
10/10 mol %
10/10 mol %
10/10 mol %
10/10 mol %
10/10 mol %
10/0 mol %
0/10 mol %
5/5 mol %
pyr
pyr
−
−
−
−
−
−
THF
56
9
86
91
94
90
80
94
74
97
3:1
c
MeOH
MeOH
EtOH
11:1
14:1
4:1
12
24
53
24
192
iPrOH
MeOH
MeOH
MeOH
2:1
a
All reactions were performed with reagent-grade MeOH, using 1.2
9:1
b
equiv of 4 and 1 equiv of 5. Yields are reported as isolated yields of
d
14:1
the N-regioisomer.
24
b
14:1
1
a
Isolated yield of the N- and O-product mixture. Determined by H
NMR spectroscopy of the crude reaction mixture. Reaction
conducted with 1.25 mol % of pyridine. The reaction with 5 mol
7−9). X-ray crystal structure analysis of 9 was used to establish
that the reaction had taken place on nitrogen.14 In addition,
steric and electronic modifications to the N-substituent on the
hydroxylamine were also well tolerated. N-Hydroxycarbamates
bearing protecting groups that could be orthogonally
deprotected, Cbz, Boc, Fmoc, Troc, and Nppoc, all participated
in greater than 79% yield (10−13). In all cases, the O-selective
adduct was observed in minor amounts and could be separated
by column chromatography.15
c
d
% catalyst was prohibitively long.
amination with nitrosoformate could be accomplished by the
addition of copper(II) trifluoromethanesulfonate (Cu(OTf)2)
to our original optimized conditions (entries 1), albeit in a
modest 3:1 N/O-selectivity.13 To our gratification, promising
levels of N/O-selectivity were obtained by changing the solvent
from THF to MeOH (entry 2). A further increase in N-
selectivity (11:1 to 14:1) resulted when pyridine was removed
from the reaction (entry 3). We found that other polar protic
solvents, such as ethanol and isopropanol, negatively affected
the N-selectivity (entries 4 and 5). In the absence of either
Cu(OTf)2 or CuCl, we observe a slight decrease in the N/O-
selectivity or efficiency, respectively (entries 6 and 7). The
conditions that provided the optimal balance between efficiency
and selectivity was 5 mol % CuCl and 5 mol % Cu(OTf)2
(entry 8). It is conceivable that two separate catalysts
simultaneously activate the nucelophile and electrophile;
however, other possibilities cannot be ruled out at this time.
Importantly, the optimized protocol is practical and operation-
ally simple. It involves simultaneous addition and mixing of all
reagents, at room temperature, open to air, with reagent grade
solvent and inexpensive and readily available metal catalysts.
With optimized reaction conditions in hand (5 mol % CuCl
and Cu(OTf)2, MeOH, air, rt), we investigated the scope of the
α-amination reaction by initially varying the ester group on the
β-ketoesters and the N-substituent on the hydroxylamine
(Table 2). There appears to be no substantial steric restrictions
of the ester moiety. Methyl, ethyl, allyl and t-butyl derivatives
all proceed in high yield, with comparable reaction rates (3 and
Encouraged by these results, we further explored the scope of
the transformation with a series of substituted β-keto esters. β-
Keto esters with alkyl, benzyl, or aryl substituents at R1 all
afforded excellent yields of the desired hydroxyamination
product (Table 3). Notably, a more sterically bulky α-branched
substrate underwent smooth conversion to give 21 in 91%
yield. Next, the electronic nature of aryl substitutents at R1 was
investigated and found to have minimal effect on the reaction
outcome. Both electron rich and electron deficient aryl groups
were found to be compatible (22−26). Importantly, initial
studies suggest that there is some leeway in the steric bulk of
the α-substituent (27−32). For example, α-substitution (R2)
with methyl, ethyl and benzyl groups all proceeded in excellent
yield. The methodology can also be used for cyclic β-ketoesters
(29 and 30) but the O-regioisomer became more competitive
in such cases, affording O-selective products in 25% and 40%,
respectively. In general, the rate of the reaction slowed and
higher ratios of the O-selective adduct were observed as the
steric bulk of the α-substitution increased (29−31). Unsub-
stituted carbonyl compound (32, R2 = H) can be activated
toward electrophilic substitution. Interestingly, in this case we
observed N−O bond heterolysis and presumably the formation
of an α-imino β-ketoester that is trapped by methanol to afford
32.16
B
dx.doi.org/10.1021/ja310784f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 3. β-Keto Ester Substrate Scope Studies for α-
Amination Reaction
Scheme 1. Synthetic Utility of α-Amination Adducts
a
a
(a) Pd/C (5 mol %), MeOH, H2 (73%); (b) TFA, CH2Cl2 (95%);
(c) Zn, 2N HCl, reflux, (79% yield); (d) (1) Zn, 2N HCl, reflux
(79%), (2) Pd/C (5 mol %), H2 (90%) ; (e) (i) NaBH4, MeOH, (ii)
SiO2 (71%).
sodium borohydride. The reduction was highly diastereose-
lective and the relative stereochemistry was established by X-ray
crystal structure analysis of a corresponding O-acylated
derivative.18 As illustrated in Scheme 1, the hydroxylamine
(35), the carbamate (36), the free amine (37), and the N-
oxazolidinone (38) were all obtained in a straightforward
manner using conditions that should be amenable to a more
complex setting and would be difficult to access using current
methodology.
In conclusion, we have developed the first α-amination of
carbonyls using nitrosoformate intermediates generated in situ
from readily available N-hydroxycarbamates. The new method-
ology harnesses the power of nitrosocarbonyl chemistry and
demonstrates their potential as a new viable electrophilic source
of nitrogen in α-functionalization reactions. The reactions are
operationally simple to perform, take advantage of dual catalysis
and the products are easy to modify. Further investigations are
underway to render this process asymmetric.
a
All reactions were performed with reagent-grade MeOH, using 1.2
b
equiv of 17 and 1 equiv of 2. Reaction was conducted with 20 mol %
c
of each copper catalyst. Unsubstituted β-keto ester (R2 = H) was used
as the starting material for this reaction.
To demonstrate the synthetic utility of this method, the
reaction was performed on gram-scale (Scheme 1). The catalyst
loading could be lowered to 1 mol % with no significant loss in
overall yield, although the reaction required 10 days for
completion. Although a number of synthetic transformations
could be envisioned for the α-amination products, we focused
on a series of functional group manipulations that highlight the
utility of using a nitrosoformate intermediate as the electro-
philic source of nitrogen. For example, hydrogenation of the
Cbz-group with 5 mol % Pd/C or an acid catalyzed
deprotection of Boc-group leads to α-hydroxylamine product
(35). It is worth noting that the expected N−O bond cleavage
under the reducing conditions was not observed. In addition,
this compound was surprisingly stable to column chromatog-
raphy; presumably these effects are due to steric hindrance.
Alternatively, the N−O bond can be cleaved using Zn and 2N
HCl to afford 36 in excellent yield. Most notably, the free
amine can be obtained by a hydrogenation of 37.17 Given the
difficulty in isolating 37 and its tendency to undergo self-
condensation, we were unable to isolate the α-amination
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
javier@chem.ucsb.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by UCSB. Additional support was
kindly provided by Eli Lilly, the Hellman Family Foundation
and Bridge to the Doctorate Fellowship Program (D.S.).
1
product directly from 12. The H NMR of the crude material
from the deprotection of 12 showed the desired product 37,
but isolation resulted in substantial amounts of decomposition
and poor mass recovery. Lastly, N-oxazolidinone 38 can be
obtained directly by a reduction of the β-keto functionality with
REFERENCES
■
(1) For some recent reviews, see: (a) Greck, C.; Genet, J. P. Synlett
1997, 741. (b) Dembech, P.; Seconi, G.; Ricci, A. Chem.Eur. J. 2000,
C
dx.doi.org/10.1021/ja310784f | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
6, 1281. (c) Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org.
Chem. 2004, 1377.
(2) For some recent reviews, see: (a) Janey, J. M. Angew. Chem., Int.
Ed. 2005, 44, 4292. (b) Smith, A. M. R.; Hii, K. K. Chem. Rev. 2011,
111, 1637.
(13) Use of conditions developed for the ene reaction (5 mol %
CuCl, 1.25 mol % pyr and THF) resulted in an N/O ratio of 1:1 and
significant amount of decomposition of the nitrosoformate inter-
mediate. Other Cu(II) Lewis acids were screened but Cu(OTf)2
proved optimal.
(14) See Supporting Information for details.
(3) (a) Cheong, P. H.-Y.; Houk, K. N. J. Am. Chem. Soc. 2004, 126,
13912. (b) Akakura, M.; Kawasaki, M.; Yamamoto, H. Eur. J. Org.
Chem. 2008, 4245. (c) Nelson, D. J.; Kumar, R.; Shagufta. Eur. J. Org.
Chem. 2012, 6013. For select examples of N and O-selective nitroso
aldol reactions, see: (d) Momiyama, N.; Yamamoto, H. J. Am. Chem.
Soc. 2003, 125, 6038. (e) Momiyama, N.; Yamamoto, H. J. Am. Chem.
Soc. 2004, 126, 5360. (f) Momiyama, N.; Yamamoto, H. J. Am. Chem.
Soc. 2005, 127, 1080.
(4) (a) Momiyama, N.; Yamamoto, H. Angew. Chem., Int. Ed. 2002,
41, 2986. (b) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M.
Tetrahedron Lett. 2003, 44, 8293. (c) Brown, S. P.; Brochu, M. P.; Sinz,
C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808.
(d) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247. (e) Momiyama,
N.; Torii, H.; Saito, S.; Yamamoto, H. Proc. Natl. Acad. Sci. U.S.A.
(15) The aminooxylation product could be easily removed by column
chromatography. The O- and N-selective adducts have ΔRf of ∼0.3 in
1:2 EtOAc/hexane. Flash column chromatography was performed
using normal phase silica gel (60 Å, 230−240 mesh, Guduran).
(16) For the synthesis of similar compounds, see: (a) Walker, T. K. J.
Chem. Soc., Trans. 1924, 125, 1622. (b) Nohira, H..; Sato, K.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1963, 36, 870. (c) Bhan, A.;
Hosmane, R. S. Tetrahedron Lett. 1994, 35, 6831. (d) Wnuk, S. F.;
Lewandowska, E.; Valdez, C. A.; Kinastowski, S. Tetrahedron 2000, 56,
7667.
(17) For isolation of α,α-disubstituted α-amino acid derivative, see:
Mashiko, T.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
14990.
(18) See Supporting Information for details.
́ ́
2004, 101, 5374. (f) Bøgevig, A.; Sunden, H.; Cordova, A. Angew.
Chem., Int. Ed. 2004, 43, 1109. (g) Hayashi, Y.; Yamaguchi, J.; Sumiya,
T.; Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112. (h) Kawasaki, M.;
Li, P.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 3795. (i) Lu, M.;
Zhu, D.; Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G. J. Am. Chem. Soc.
2009, 131, 4562. (j) Yanagisawa, A.; Takeshita, S.; Izumi, Y.; Yoshida,
K. J. Am. Chem. Soc. 2010, 132, 5328.
(5) (a) Momiyama, N.; Yamamoto, H. Org. Lett. 2002, 4, 3579.
(b) Kano, T.; Ueda, M.; Takai, J.; Maruoka, K. J. Am. Chem. Soc. 2006,
128, 6046. (c) Guo, H.-M.; Cheng, L.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-
Q.; Jiang, Y.-Z. Chem. Commun. 2006, 429. (d) Palomo, C.; Vera, S.;
́
Velilla, I.; Mielgo, A.; Gomez-Bengoa, E. Angew. Chem., Int. Ed. 2007,
46, 8054. (e) Lopez-Cantarero, J. s.; Cid, M. B.; Poulsen, T. B.; Bella,
M.; Ruano, J. L. G.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 7062.
(f) Shen, K.; Liu, X.; Wang, G.; Lin, L.; Feng, X. Angew. Chem., Int. Ed.
2011, 50, 4684. (g) Yanagisawa, A.; Fujinami, T.; Oyokawa, Y.; Sugita,
T.; Yoshida, K. Org. Lett. 2012, 14, 2434.
(6) Strategies to access α-amino carbonyl compounds have relied
extensively on azodicarboxylate derivatives as the electrophilic source
of nitrogen. For select examples, see: (a) Marigo, M.; Juhl, K.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1367. (b) Ma, S.;
Jiao, N.; Zheng, Z.; Ma, Z.; Lu, Z.; Ye, L.; Deng, Y.; Chen, G. Org. Lett.
2004, 6, 2193. (c) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc.
2006, 128, 16044. (d) Huber, D. P.; Stanek, K.; Togni, A. Tetrahedron:
Asymmetry 2006, 17, 658. (e) Nandakumar, M. V.; Ghosh, S.;
Schneider, C. Eur. J. Org. Chem. 2009, 6393. (f) Ghosh, S.;
Nandakumar, M. V.; Krautscheid, H.; Schneider, C. Tetrahedron Lett.
2010, 51, 1860.
(7) Baidya, M.; Griffin, K. A.; Yamamoto, H. J. Am. Chem. Soc. 2012,
DOI: 10.1021/ja309311z.
(8) (a) Frazier, C. P.; Engelking, J. R.; Read de Alaniz, J. J. Am. Chem.
Soc. 2011, 133, 10430. (b) Frazier, C. P.; Bugarin, A.; Engelking, J. R.;
Read de Alaniz, J. Org. Lett. 2012, 14, 3620.
(9) For some recent reviews on nitroso chemistry, see: (a) Adam, W.;
Krebs, O. Chem. Rev. 2003, 103, 4131. (b) Iwasa, S.; Fakhruddin, A.;
Nishiyama, H. Mini-Rev. Org. Chem. 2005, 2, 157. (c) Yamamoto, Y.;
Yamamoto, H. Eur. J. Org. Chem. 2006, 2031. (d) Bodnar, B. S.; Miller,
M. J. Angew. Chem., Int. Ed. 2011, 50, 5630.
(10) For some recent reviews, see: (a) Allen, A. E.; MacMillan, D. W.
C. Chem. Sci. 2012, 3, 633. (b) Haak, R. M.; Wezenberg, S. J.; Kleij, A.
W. Chem. Commun. 2010, 46, 2713. (c) Stegbauer, L.; Sladojevich, F.;
Dixon, D. J. Chem. Sci. 2012, 3, 942.
(11) Chaiyaveij, D.; Cleary, L.; Batsanov, A. S.; Marder, T. B.; Shea,
K. J.; Whiting, A. Org. Lett. 2011, 13, 3442.
(12) (a) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269.
(b) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J. J.
Am. Chem. Soc. 2009, 131, 9140. (c) Basle, O.; Li, C.-J. Green Chem.
2007, 9, 1047. (d) Zhang, G.; Zhang, Y.; Wang, R. Angew. Chem., Int.
Ed. 2011, 50, 10429.
D
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