Amino acid-catalyzed asymmetric α-amination of carbonyls

Article abstract of DOI:10.1016/j.tetlet.2005.12.028

Electrophilic amination of ketones and aldehydes in the presence of dibenzylazodicarboxylate in dichloromethane, using L-azetidine carboxylic acid as a catalyst, is described. Yields and ee are discussed in comparison with the corresponding L-proline-cata

Full text of DOI:10.1016/j.tetlet.2005.12.028

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1117–1119
Amino acid-catalyzed asymmetric a-amination of carbonyls
Christine Thomassigny, Damien Prim and Christine Greck*
Universite´ de Versailles St-Quentin-en-Yvelines, SIRCOB-UMR CNRS 8086, 45 Av. des Etats Unis, 78035 Versailles Cedex, France
Received 24 October 2005; revised 5 December 2005; accepted 6 December 2005
Available online 27 December 2005
Abstract—Electrophilic amination of ketones and aldehydes in the presence of dibenzylazodicarboxylate in dichloromethane, using
L-azetidine carboxylic acid as a catalyst, is described. Yields and ee are discussed in comparison with the corresponding L-proline-
catalyzed reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
Electrophilic amination of sp3 hybridized carbon atoms
is one of the most attractive reaction to generate C–N
bonds in organic synthesis. The methods for a-amina-
tion of carbonyl compounds using the ÔNHþ2 Õ synthon
have been recently reviewed.1,2 In particular, it has been
shown that asymmetric electrophilic amination is possi-
ble in the presence of chiral promoters, leading to the
expected aminated products with high stereoselectivities.
The a-amination of carbonyls in the presence of a
chiral catalyst was introduced by Evans et al. in 1997,3
who added a magnesium-bis(sulfonamide) complex to
the reaction mixture for the enantioselective amination
of N-acyloxazolidinones. Later, combinations based on
copper(II)4 and silver5 catalysts with azodicarboxylate
reagents were explored. In particular, the former are
more efficient for the formation of a-hydrazino carbonyl
compounds and b-amino-a-keto esters from the corre-
sponding enolsilanes or b-ketoesters, respectively.
The direct amination of aldehydes using azodicarboxyl-
ates as the nitrogen source, and L-proline (1a) as the
catalyst has been described in 2002 concomitantly by
List9 and Jorgensen.10 This reaction was the first one
which required a relatively low amount of an inexpen-
sive and non-toxic catalyst available in both enantio-
meric forms. Later, the reaction was extended to
ketones, and produced the a-hydrazino adducts in good
yields and enantioselectivities.
The observed enantioselectivity was explained with a
proline–enamine involving transition state, in which
the approach of the azodicarboxylate is directed by an
interaction between the incoming nitrogen atom and
the proton of the carboxylic acid.10,11 Duthaler12 has
proposed a chair conformation that could explain the
mechanism for L-proline-catalyzed reactions—including
amination reactions—of ketones or aldehydes with elec-
trophiles. In this model, interactions between the azodi-
carboxylate moiety, the acidic proton of the carboxylic
acid, and the nitrogen atom of the enamine intermediate
may account for the regio- and stereoselectivities
observed. Thus, changing the nature and the size of
the catalytic heterocycle may induce a modification
of the conformation of the transition state and thereby
the stereochemical outcome. In particular, we have
tested the effect of the corresponding four-membered
ring heterocycle, namely L-azetidine carboxylic acid
(1b), for electrophilic a-amination of carbonyl
compounds. The general transition state model may still
be applicable (Fig. 1), the more constrained ring should
only induce modified conformational angles. We
described in this letter the synthesis of several a-hydraz-
inoketones by electrophilic amination in the presence of
1b as a catalyst.
Pihko et al.6 showed the importance of cinchonine and
cinchonidine alkaloids in the a-amination of b-ketoest-
ers and b-ketolactones. Later, Jorgensen et al.7 reported
the first quinidine-derived catalyst allowing the amina-
tion of substituted a-cyanoacetates and b-dicarbonyl
compounds, with very high enantioselectivities. Very
recently, it has been shown8 that 60-OH modified cinchona
alkaloids derived from either quinine and quinidine pro-
vide easy access to both enantiomers, respectively, in the
formation of a quaternary center by electrophilic amina-
tion of a-cyanoacetates.
Keywords: Amination; Organocatalysis; Enantioselectivity; L-Azet-
idine carboxylic acid; Azodicarboxylates.
*
Corresponding author. Tel.: +33 139 25 44 74; fax: +33 139 25 44
52; e-mail: greck@chimie.uvsq.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.028

1118
C. Thomassigny et al. / Tetrahedron Letters 47 (2006) 1117–1119
tially the same whether organocatalyst 1a or 1b was
CO2R2
used: 56% and 60%, respectively (entries 1 and 3). But
we noticed a remarkable increase in the enantiomeric
excess, gaining a 29% increase in ee when the smaller
N-heterocycle was used. Importantly, after 8 h of reac-
tion time an isolated yield of 50% can be achieved with
the same ee (entry 2). Cooling the reaction mixture to
0 °C did not influence the enantioselectivity: ee = 88%
and afforded 2b in a low yield: 25% (entry 4). A higher
reaction temperature as 40 °C induced an important
decrease of the enantiomeric excess 6%.
N
R1
R2O2C
N
N
H
R
O
O
Figure 1.
The Jorgensen et al.11 experimental procedures have
been followed using 20 mol % catalyst in dichlorometh-
ane. All reactions were stirred until yellow color of the
azodicarboxylates had faded.
Several complementary assays have been performed,
confirming the catalyst efficiency not only with other
ketones, but also with aldehydes (Scheme 2 and Table
2). We have aminated butanone, propanal, and heptanal
first with the racemic proline, leading to the racemic
mixture for HPLC analysis, then with 1a and 1b, in
the presence of DBAD.14
First, we compared the ee obtained from the symmetric
cyclohexanone in the presence of DEAD (Scheme 1).
Jorgensen et al.11 obtained the expected hydrazines 2a
(R = Et) in 79% ee in dichloromethane, and the yield
was not reported. We first repeated this experiment
and obtained 2a with a comparable ee, and an isolated
yield of 46%. The same conditions (20% catalyst, room
temperature, DEAD) in the presence of L-azetidine
carboxylic acid led to the a-hydrazino ketone after
24 h with a yield of 73% and an increased ee: 85%.
Electrophilic amination of butanone 3 by DEAD in the
presence of L-proline has been described by Jorgensen
et al.11 leading to an inseparable mixture of the expected
3-hydrazino ketone and its 1-hydrazino regioisomer
(91% and 9% yield, respectively). In our case, the elec-
trophilic amination of butanone 3 using DBAD give
a-hydrazinoketone 6 as a sole product. The experiments
were run at room temperature in dichloromethane in
the presence of 20 mol % catalyst, 6 was obtained with
yields of 49% and 54% and enantiomeric excesses of
94% and 90% using, respectively, 1a and 1b as organo-
catalyst (entries 1 and 2). Aldehydes such as propanal
(entries 3 and 4) and heptanal (entries 5 and 6) also
react with DBAD in the presence of the a-amino acids.
Reaction times are shorter with L-proline, but after
decoloration the yields are comparable. In the presence
of L-azetidine carboxylic acid, the enantiomeric excesses
were in both cases ranging from 72% to 74%.
Encouraged by this result, we have decided to test the
reaction with DBAD (Table 1), which has the advantage
of being easily detected by UV for HPLC analyses.
Moreover, it is known that a-hydrazinoketones derived
from DBAD can be easily hydrogenolized in a one-step
process in the presence of hydrated platinium oxide to
obtain the corresponding amino ketone.13 The reaction
with cyclohexanone, and later with other substrates,
was first performed with DL-proline leading to the race-
mic amination product. Purification over silica gel
allowed its use as a reference for HPLC analyses.14 After
24 h of stirring the symmetric ketone with DBAD in
dichloromethane, the isolated yield of 2b15 was essen-
O
O
CO2R
N
DEAD or DBAD,
DCM
O
NHCO2R
O
20 % of 1a or 1b
1
DCM
DBAD,
R
1
R
R
2a R = Et
2b R = Bn
R
20 % of 1a or 1b
CbzN NHCbz
1
1
6 R = R = Me
3 R = R = Me
CO2H
CO2H
1
1
N
N
7 R =H; R = Me
8 R = H; R = nC H
4 R =H; R = Me
5 R = H; R = nC H
H
H
1
1
1a
1b
5
13
5
13
Scheme 1.
Scheme 2.
Table 1. Enantioselective a-amination of cyclohexanone by DBAD catalyzed by L-proline 1a or L-azetidine carboxylic acid 1b
Entry
Reagent
Catalyst
Time (h)
Temperature (°C)
Product
Yieldb (%)
eec (%)
1
2
3
4
DBAD
DBAD
DBAD
DBAD
1a
1b
1b
1b
24a
8a
24
48a
25
25
25
0
2b
2b
2b
2b
56
50
60
25
61
90
90
88
Conditions: Reactions mixtures were stirred in DCM. The time indicates the disappearance of the yellow color.
a Decoloration was not complete.
b Isolated yield after column chromatography.
c Ee determined after workup by chiral HPLC.

C. Thomassigny et al. / Tetrahedron Letters 47 (2006) 1117–1119
1119
Table 2. Enantioselective a-amination of ketones and aldehydes by
DBAD catalyzed by L-proline 1a or L-azetidine carboxylic acid 1b
6. Pihko, P. M.; Pohjakallio, A. Synlett 2004, 12, 2115–
2118.
7. Saaby, S.; Bella, M.; Jorgensen, K. A. J. Am. Chem. Soc.
2004, 126, 8120–8121.
Entry Substrate Catalyst Time Product Yield ee
(h)
(%)
(%)
8. Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167–169.
9. List, B. J. Am. Chem. Soc. 2002, 124, 5656–5657.
10. Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang,
W.; Jorgensen, K. A. Angew. Chem. 2002, 114, 1868–1871;
Angew. Chem., Int. Ed. 2002, 41, 1790–1793.
11. Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig,
A.; Jorgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254–
6255.
1
2
3
4
5
6
3
3
4
4
5
5
1a
1b
1a
1b
1a
1b
114a
114a
3.5
22
1.25
15
6
6
7
7
8
8
49
54
62
60
62
69
94
90
54
74
91
72
Conditions: Reactions mixtures were stirred at rt in DCM.
a Decoloration was not complete.
12. Duthaler, R. O. Angew. Chem. 2003, 115, 1005–1008;
Angew. Chem., Int. Ed. 2003, 42, 975–978.
13. Poupardin, O.; Greck, C.; Genet, J.-P. Synlett 1998, 1279–
1281.
14. The enantiomeric excess (ee) of the products were deter-
mined by HPLC using a JACSO PU2089plus apparatus and
a column Chiralcel OD. Eluant: heptane/i-PrOH: 93/7; flow
In summary, we have shown that L-azetidine carboxylic
acid can be used as a catalyst for the asymmetric electro-
philic amination of aldehydes and ketones by DBAD.
Generally, if the yields are comparable to those obtained
by using L-proline, the enantiomeric excesses are
increased for substrates such as cyclohexanone and
propanal.
0.9 ml/min; k 260 nm. Compound 2b (T 45 °C): sminor
=
=
18.52 min and smajor = 24.91 min; 6 (T 30 °C): sminor
21.45 min and
smajor = 25.01 min; for
7
(T 45 °C):
sminor = 16.02 min and smajor = 17.19 min; for 8 (T 45
°C): sminor = 30.14 min and smajor = 38.38 min.
15. Compound 2b was purified by flash chromatography
(Et2O/pentane, 2/1): yield 60%; mp 103 °C; as reported
before,11 the enantioselectivity of the a-aminated product
is only reduced by a few percent by purification using silica
References and notes
1. Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org.
Chem. 2004, 7, 1377–1385.
2. Erdik, E. Tetrahedron 2004, 60, 8747–8782.
3. Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119,
6452–6453.
4. (a) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595–
598; (b) Juhl, K.; Jorgensen, K. A. J. Am. Chem. Soc.
2002, 124, 2420–2421.
5. Yamashita, Y.; Ishitani, H.; Kobayashi, S. Can. J. Chem.
2000, 78, 666–672.
25
column chromatography: ½aꢀD ꢁ24.1 (c 0.1, DCM, 81%
ee); 1H NMR (CDCl3, 200 MHz) d 7.32 (m, 10H, Ar), 6.88
(s, 1H, NH), 5.10 (m, 5H, CH2Ph and H-2), 2.47–1.65
(m, 8H, H-3, H-4, H-5, and H-6); 13C NMR (CDCl3,
60 MHz) d 207.54 (C-1), 156.09 (CO), 135.63–127.52 (Ar),
68.21, 67.56 (CH2Ph), 65.73 (C-2), 41.28 (C-6), 30.64,
26.88, 26.66, 24.22 (C-2, C-3, C-4, and C-5); Anal. Calcd
for C22H24N2O5 (396.17): C, 66.65; H, 6.10; N, 7.07.
Found C, 66.39; H, 5.88; N, 7.19.