Copper-catalyzed amination of ketene silyl acetals with hydroxylamines: Electrophilic amination approach to α-amino acids

Article abstract of DOI:10.1002/anie.201206755

Role reversal: The title reaction has been developed to deliver α-amino acids under very mild reaction conditions (see scheme; dpppen=1,5-bis(diphenylphosphino)pentane). The catalysis provides a new C-N bond-forming approach for the synthesis of α-amino a

Full text of DOI:10.1002/anie.201206755

Angewandte
Chemie
DOI: 10.1002/anie.201206755
Synthetic Methods
Copper-Catalyzed Amination of Ketene Silyl Acetals with
Hydroxylamines: Electrophilic Amination Approach to a-Amino
Acids**
Naoki Matsuda, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
a-Amino acid derivatives are a fundamental and important
structural motif in many biologically active compounds and
pharmaceutical targets, especially peptide drugs. In particular,
significant attention has recently been focused on unnatural
a-amino acids because when used to replace natural a-amino
acids in the original drug structure, the potential for the
discovery of new functions as well as improved activity
increases.[1] Multicomponent couplings such as the Strecker,
Ugi, and Petasis reactions rank as one of the most powerful
approaches to the target structure.[2] As a useful alternative,
the decoration of N-protected glycine esters with organic
halides under phase-transfer[3] or palladium catalysis[4] con-
ditions has also been widely developed. These protocols
acetals with hydroxylamines is described.[12] The copper
catalysis allows various a-amino acid esters to be formed
under very mild reaction conditions from starting materials
which are at the carboxylic acid oxidation level.[13]
Our study commenced with O-benzoyl-N,N-dibenzyl-
hydroxylamine (1a; 0.30 mmol) and the ketene silyl acetal
2a (0.25 mmol) as the model substrate (Table 1). In an early
Table 1: Optimization studies for copper-catalyzed amination of ketene
silyl acetals 2a and 2b with O-benzoyl-N,N-dibenzylhydroxylamine
(1a).[a]
À
À
generally rely on C C bond formation. In contrast, the C N
formation at the position a to the carbonyl group can provide
a complementary and potentially more efficient access to the
above amino acids. A traditional halogenation a to carbonyls
and subsequent nucleophilic substitution with amines is
practical, but often suffers from lower efficiency and forcing
conditions in the case of sterically hindered substrates,
particularly, for the combination of acetates, substituted
with secondary alkyl groups, and acyclic secondary amines.[5]
To overcome these limitations, an electrophilic amination
Entry
2
Cu/ligand
Additive
3
Yield [%][b]
1
2
3
4
5
6
7
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2a
CuCl/phen
CuCl/bpy
CuCl/dppbz
CuCl/dppe
CuCl/dppp
CuCl/dppb
CuCl/dpppen
CuCl/dpppen
CuCl/dpppen
[Cu(OAc)2]/dpppen
[Cu(OAc)2]/dpppen
[Cu(OAc)2]/dpppen
[Cu(OAc)2]/dpppen
[Cu(OAc)2]/dpppen
none
none
none
none
none
none
none
none
none
NaHCO3
Na2CO3
KOAc
LiF
3aa: 26
3aa: 0
3aa: 27
3aa: 31
3aa: 15
3aa: 0
3aa: 36
3aa: (56)
3ab: 0
3ab: (92)
3ab: (78)
3ab: (77)
3ab: 73
3aa: (67)
=
with azodicarboxylate esters (RO2CN NCO2R) has been
explored, and versatile metal-catalyzed[6] and organocata-
8[c]
9[c]
10[c]
11[c]
12[c]
13[c]
14[c]
lytic[7] processes have now become available. However, the
À
resultant N N bond in the aminated product should undergo
cleavage under relatively harsh reductive conditions, which is
often problematic. Although another protocol involving the
aziridination of enols with phenyl iodinane (TsN = IPh) or
chloramine T[8] is reported, most of them are restricted to the
aldehyde and ketone oxidation levels. Thus, there still remains
KOAc
[a] Reaction conditions: Cu (0.025 mmol), ligand (0.025 mmol), additive
(0.50 mmol), 1a (0.30 mmol), 2 (0.25 mmol), DMF (1.5 mL), N2, RT, 2–
4 h. [b] Yield estimated by GC methods. Yield of isolated product given
within parentheses. [c] With 1a (0.25 mmol) and 2 (0.50 mmol).
Bz=benzoyl, Bn=benzyl, dppb=1,4-bis(diphenylphosphino)butane,
dppbz=1,2-bis(diphenylphosphanyl)benzene, dppe=1,2-bis(diphenyl-
phosphanyl)ethane, dppp=1,3-bis(diphenylphosphanyl)propane.
À
a demand for further developments in C N bond formation
directed toward unnatural a-amino acid analogues. Herein,
we introduce O-acylated hydroxylamine[9–11] as an effective
electrophilic amination reagent for the synthesis of a-amino
acid derivatives: a copper-catalyzed amination of ketene silyl
[*] N. Matsuda, Dr. K. Hirano, Prof. Dr. T. Satoh, Prof. Dr. M. Miura
Department of Applied Chemistry, Faculty of Engineering
Osaka University
experiment,
a
CuCl/phen (phen = 1,10-phenanthroline)
system in N,N’-dimethylformamide (DMF) afforded the
corresponding glycine ester 3aa even at room temperature,
albeit in only 26% yield (GC; entry 1). With the preliminary
result in hand, other ancillary ligands were tested. While 2,2’-
bibyridine (bpy) was ineffective (entry 2), some bidentate
phosphines improved the reaction efficiency (entries 3–7),
with 1,5-bis(diphenylphosphino)pentane (dpppen) proving to
Suita, Osaka 565-0871 (Japan)
E-mail: k_hirano@chem.eng.osaka-u.ac.jp
miura@chem.eng.osaka-u.ac.jp
[**] This work was partly supported by Grants-in-Aid from the MEXTand
JSPS (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206755.
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be optimal (entry 7). Investigations into the reaction stoichi-
ometry identified that a 1:2 ratio of 1a and 2a increased the
yield, and 3aa was isolated in 56% yield (entry 8). However,
we immediately found that the above catalyst was not
applicable to the reaction with the methyl-substituted
ketene silyl acetal 2b for the synthesis of the alanine
derivative 3ab (entry 9). Thus, additional optimization studies
were carried out. We were pleased to find that several
combinations of basic additives and the [Cu(OAc)2]/dpppen
catalyst afforded the desired 3ab in a good yield. In particular,
NaHCO3, Na2CO3, KOAc, and LiF showed high activity
(entry 10–13). The best additive is dependent upon the
electronic and steric nature of the hydroxylamine and
ketene silyl acetal employed (see below). For example, the
highest yield of 3ab was obtained with NaHCO3 (entry 10),
whereas KOAc was the most effective for the synthesis of 3aa
(entry 14).[14]
Table 2: (Continued)
Entry
8[d]
2
Additive
3
Yield [%][b]
51
2i: R=Br
3ai: R=Br
(E/Z=20:1)
9
2j (E/Z=3.5:1)
Na2CO 3aj
75
10
11
12
2k (E/Z=8.1:1)
LiF
3ak
37
89
42
Various ketene silyl acetals 2 underwent amination with
1a to form the corresponding a-amino esters 3 (Table 2). The
allyl-substituted 2c and benzyl-substituted 2d coupled with
2l
Na2CO3 3al
Table 2: Copper-catalyzed amination of various ketene silyl acetals 2 with
O-benzoyl-N,N-dibenzylhydroxylamine (1a).[a]
2m
KOAc
3am
[a] Reaction conditions: [Cu(OAc)2] (0.025 mmol), dpppen
(0.025 mmol), additive (0.50 mmol), 1a (0.25 mmol), 2 (0.50 mmol),
DMF (1.5 mL), N2, RT, 2–4 h. [b] Yield of the isolated product. [c] With
0.30 mmol of 2e and KOAc. [d] With 0.75 mmol of 2i and LiF.
Entry
2
Additive
3
Yield [%][b]
1a smoothly in the presence of Na2CO3 to provide the
allylglycine and phenylalanine esters 3ac (85%) and 3ad
(79%), respectively (entries 1 and 2). Notably, the substrate
2e that bears the bulky isopropyl group also could be
aminated with the assistance of KOAc, and the valine
derivative 3ae was obtained in high yield (entry 3). Aromatic
substituents at the vinylic position were also tolerated to
deliver the phenylglycine esters 3af–aj effectively (entries 4–
8). In these cases, LiF acted as a promising promoter. The
amination occurred smoothly irrespective of the E/Z geom-
etry of the starting ketene silyl acetals (entry 4 versus 5). It is
worth noting that the aryl–Br bond was compatible under the
reaction conditions (entry 8). Additionally, the tryptophan
derivative 3aj and its truncated analogue 3ak were readily
accessible (entries 9 and 10). The cyclic ketene silyl acetal 2l
also could be employed for the electrophilic amination
without any difficulties (entry 11). The sterically demanding
dimethyl-substituted 2m was transformed into 3am with an
acceptable yield (entry 12). In sharp contrast, the present
copper catalyst was insufficient for the amination of 2-
trimethylsilyloxyfuran and silyl enolates derived from
ketones, such as propiophenone (data not shown). While
the reaction with ketene silyl acetals as the limiting reagent
was unsuccessful, we succeeded by decreasing the amount of
the reagent to 1.2 equivalents, albeit with a moderate yield of
the aminated product (entry 3).
1
2c (E/Z=5:1)
Na2CO3 3ac
85
2
3
2d (E/Z=5.5:1)
2e (E/Z>20:1)
Na2CO3 3ad
79
KOAc
3ae
90 (42)[c]
4
5
2 f (E/Z=3.3:1)
2 f (E/Z=1:16)
LiF
LiF
3af
3af
75
74
6
7
2g: R=Me
(E/Z=3.8:1)
2h: R=F
LiF
3ag: R=Me
3ah: R=F
81
77
We next performed the amination with a variety of
hydroxylamines (1; Scheme 1). In addition to 1a, acyclic
(E/Z=2.7:1)
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Scheme 1. Copper-catalyzed electrophilic amination of the ketene silyl
acetals 2 with various hydroxylamines (1) using the reaction conditions
detailed in Table 2. [a] Used 1.2 equiv of 2 and KOAc. The additive is
given in parentheses. Boc=tert-butoxycarbonyl.
the precedented nitrogen- and carbon-centered radical (or
their copper-coordinated form) pathways.[17] Although the
exact reaction mechanism remains to be elucidated, one
possibility involves 1) a base-accelerated transmetalation of
the copper acetate complexe with the ketene silyl acetal, thus
generating a copper enolate species which exists as an
equilibrium mixture of the O- and C-bound forms,[18] and
2) subsequent electrophilic amination with the hydroxyl-
amine.[19] At present, we speculate that bases can provide an
additional anionic ligand to the copper center in the catalytic
cycle. Thus, the best base is highly dependent upon the
electronic and steric nature of the ketene silyl acetal as well as
hydroxylamine. Another possibility can be the direct attack of
the ketene silyl acetal on the nitrogen center of the hydroxyl-
amine, which is activated through coordination to [Cu(OAc)2]
given its Lewis acidic nature. However, the result of the
reaction with 2o containing the cyclopropyl substituent
contrasts with the above Lewis acid promoted pathway
[Eq. (4)]: the reaction occurred with concomitant cyclopropyl
ring opening to afford the d-amino-a,b-unsaturated ester 3ao
as the sole product.[20] Given that a Lewis acid mediated
reaction of ketene silyl acetals of the type 2o furnished the
coupling product with the cyclopropyl group left intact,[21] the
phenomenon is suggestive of in situ formation of a cyclo-
propylmethyl copper species which is a C-bonded copper
enolate. A relevant reaction mode of cyclopropylmethyl
boron reagents is also reported.[22] However, we cannot
exclude an alternative that includes 1) oxidative addition of
amines containing N,N-diethyl, N,N-diallyl, and N-benzyl-N-
methyl substituents participated in the reaction (3bd, 3ce,
and 3de). The resultant allyl and benzyl moieties can be
a useful synthetic handle for further manipulations after the
selective deprotection.[15] Monocyclic piperizine, morpholine,
N-Boc piperazine, and bicyclic tetrahydroisoquinoline also
could be introduced to the a position of esters effectively
(3ee, 3 fe, 3ge, and 3he). Moreover, the hindered 2,2,6,6-
tetramethylpiperizine and decahydroquinoline reacted with
the ketene silyl acetal 2a to furnish the corresponding bulky
amino esters 3ia and 3ja in a satisfying yield. Notably, the
secondary amine was also available for use (3kd).
To investigate whether radical intermediates are involved
in the catalytic reaction, the following experiments were
performed. The reaction with the N-4-pentenylhydroxyl-
amine 1l produced the usual aminated product 3le exclu-
sively, and no pyrrolidine-containing product from a 5-exo
radical cyclization was detected [Eq. (1); Bz = benzoyl].[16] In
contrast, the ketene silyl acetal 2n also afforded the simple
aminated product 3an, thus leaving the pendant olefinic
moiety untouched [Eq. (2)]. The addition of the radical
scavenger 2,2,6,6,-tetramethylpiperidine 1-oxyl (TEMPO)
had little influence on the outcome of the reaction [Eq. (3)
versus Table 2, entry 3]. These results are inconsistent with
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.
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Communications
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[10a–d,23]
À
3) productive C N formation by reductive elimination.
Efforts to clarify the details of the mechanism are ongoing.
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the asymmetric synthesis of a-amino acids. While preliminary
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the result shows the potential of the copper catalysis directed
toward a new electrophilic amination approach to optically
active unnatural a-amino acids. Development of catalytic
asymmetric variants as well as additional optimization studies
on the chiral auxiliary are currently underway.
In conclusion, we have developed a copper-catalyzed
amination of ketene silyl acetals with O-benzoylhydroxyl-
amines directed toward synthesis of unnatural a-amino acids.
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À
The catalysis provides a complementary C N bond-forming
approach to a-amino acids starting from substrates at the
carboxylic acid oxidation level. Moreover, the reaction
system is a successful example of the introduction of mild
carbon nucleophiles in the electrophilic amination reaction
with the hydroxylamine.
Received: August 21, 2012
Published online: October 15, 2012
Keywords: amination · amino acids · copper ·
.
synthetic methods · umpolung
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À
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[12] A stoichiometric reaction of copper enolates generated in situ
À
with TsO N(Li)Boc is known: a) J. P. Genet, S. Mallart, C.
[20] A relevant ring-opening mode of cyclopropylmethyl metal
intermediates was proposed: a) M. Suginome, T. Matsuda, Y.
Ito, J. Am. Chem. Soc. 2000, 122, 11015; b) T. Ohmura, H.
Taniguchi, Y. Kondo, M. Suginome, J. Am. Chem. Soc. 2007, 129,
3518; c) L. Zhou, F. Ye, Y. Zhang, J. Wang, Org. Lett. 2012, 14,
922.
Greck, E. Piveteau, Tetrahedron Lett. 1991, 32, 2359; b) N.
Zheng, J. D. Armstrong III, J. C. MacWilliams, R. P. Volante,
Tetrahedron Lett. 1997, 38, 2817. A tBuOK-mediated electro-
philic amination of active methylene compounds with a special
diarylphosphinylhydroxylamine,
(4-MeOC6H4)2(O)PO-NH2,
was also reported: c) J. A. Smulik, E. Vedejs, Org. Lett. 2003,
5, 4187.
[21] T. N. Wheeler, J. Org. Chem. 1984, 49, 706.
[22] W. Pei, I. J. Krauss, J. Am. Chem. Soc. 2011, 133, 18514.
[23] See the Supporting Information for preliminary investigation
with an isolated CuI enolate complex.
[24] Unsuccessful ligands included Chiraphos, Norphos, DIOP,
BDPP, and DIPAMP.
[13] Very recently, Loh and co-workers reported an a amination of
aldehydes with amines with the aid of tBuOOH or in situ
generated hypoiodites: a) J.-S. Tian, T.-P. Loh, Chem. Commun.
2011, 47, 5458; b) J.-S. Tian, K. W. J. Ng, J.-R. Wong, T.-P. Loh,
Angew. Chem. 2012, 124, 9239; Angew. Chem. Int. Ed. 2012, 51,
9105.
Angew. Chem. Int. Ed. 2012, 51, 11827 –11831
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