Asymmetric α-amination of aldehydes and ketones catalyzed by tert-butoxy-l-proline

Article abstract of DOI:10.2174/157017809788681293

Asymmetric electrophilic α-amination of aldehydes and ketones is described using trans-3-tert-butoxy-Lproline and trans-4-tert-butoxy-L-proline as efficient catalysts. Good yields and high enantioselectivities are obtained working at 0°C or at room temper

Full text of DOI:10.2174/157017809788681293

Letters in Organic Chemistry, 2009, 6, 377-380
377
Asymmetric ꢀ-Amination of Aldehydes and Ketones Catalyzed by
tert-Butoxy-L-Proline
Ramzi Ait-Youcef, Delphine Kalch, Xavier Moreau, Christine Thomassigny and Christine Greck*
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles-St-Quentin-en Yvelines, 45 Avenue des
Etats-Unis, 78035 Versailles cedex, France
Received February 20, 2009: Revised May 18, 2009: Accepted June 03, 2009
Abstract: Asymmetric electrophilic ꢀ-amination of aldehydes and ketones is described using trans-3-tert-butoxy-L-
proline and trans-4-tert-butoxy-L-proline as efficient catalysts. Good yields and high enantioselectivities are obtained
working at 0°C or at room temperature with a catalyst loading of only 5 mol%.
Keywords: Electrophilic amination, organocatalysis, tert-butoxyproline, azodicarboxylate, ꢀ-hydrazinoalcohol.
INTRODUCTION
Proline is one of the most popular catalyst for this kind of
transformation. However, its poor solubility in organic
solvents remained a limitation in regard with the loading of
catalyst required (10 to 50 mol%). One of the great tasks in
organocatalysis is to conceive new highly reactive catalysts
which afford high level of enantioselectivity. We report
herein the use of 3- and 4-tert-butoxyproline as efficient
catalysts for ꢀ-amination of carbonyl compounds.
The stereocontrol of C-N bond formation is of great
interest in organic synthesis due to the large presence of
amino group functionalities in biologically active molecules.
Several stereoselective methods have been described in the
literature involving nucleophilic or electrophilic nitrogen
reagents [1]. The last few years have seen the great
emergence of organocatalysis as new metal-free asymmetric
reaction [2]. Various known reactions have been developed
using this process [3] and notably ꢀ-functionalization of
carbonyl compounds [4]. Jorgensen [5] and List [6] both
reported the first examples of electrophilic amination of
aldehydes using proline and dialkyl azodicarboxylate. We [7]
and others [8] have shown that this reaction could be
RESULTS AND DISCUSSION
Organocatalysis, by using small and readily available
molecules as catalysts, constitue a great application to the
concept of green chemistry. In this context, development of
OH
O
1- 2-methylpropene, TsOH
CH2Cl2, -78°C to rt, 3d.
O
O
N
H
2- NaOH 1M, 4 h, then HCl 1M, 0°C
N
H
OH
OH
1
69% 2 steps
HO
O
1- 2-methylpropene, TsOH
CH2Cl2, -78°C to rt, 3d.
O
O
N
H
N
H
2- NaOH 1M, 4 h, then HCl 1M, 0°C
OH
OH
73% 2 steps
2
Scheme 1.
extended to functionalized aldehydes or ketones using
different organocatalysts.
new organocatalysts requires straightforward synthesis
without the use of protecting groups and purification steps.
Starting from natural 3- and 4-hydroxyproline, trans-3-tert-
butoxy-L-proline 1 [9] and trans-4-tert-butoxy-L-proline 2
[10] were obtained in 2 steps respectively in 69 and 73%
yield (Scheme 1).
*Address correspondence to this author at the Institut Lavoisier de
Versailles, UMR CNRS 8180, Université de Versailles-St-Quentin-en
Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles cedex, France; Tel:
+33-139254474; Fax: +33-139254452; E-mail: greck@chimie.uvsq.fr
The reaction of 6,6-dimethoxyhexanal with dibenzyl
azodicarboxylate was chosen as a model reaction to test the
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378 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
Ait-Youcef et al.
NHCbz
1. Catalyst
DBAD, CH2Cl2
CbzN
OMe
OMe
OMe
O
HO
OMe
2. NaBH4, EtOH
0°C, 15 min
3
Scheme 2.
efficiency of catalysts 1 and 2 in the electrophilic amination
reaction (Scheme 2). The corresponding hydrazino aldehyde
was reduced in situ using NaBH4 in EtOH [11] and the
enantiomeric excess of 3 was determined on the crude
hydrazino alcohol [12]. The results are summarized in Table
1.
using this catalyst afforded the enantiomer of 3 with
comparable yield and enantioselectivity.
Then, we studied electrophilic amination of different
aliphatic aldehydes in presence of the catalysts 1 and 2
(Table 2).
The reactions involving trans-3-tert-butoxy-L-proline 1
afforded the expected aminated products in good yields and
moderate to good enantioselectivities, up to 87% ee (entries
1, 3 and 5).
In the presence of 10 mol% L-proline at 0°C, the ꢀ-
aminated alcohol was obtained in 76% yield and 94% ee
(entry 1). When the reactions were carried out in the
presence of the catalysts 1 and 2, higher reactivities were
observed (entries 2 and 3) : the reaction time decreased
dramatically and enantioselectivities were slightly elevated.
This result prompted us to lower the loading of catalyst.
When the reaction was conducted using 5 mol% of 1 at room
temperature, the enantiomeric excess dropped to 71% and
the expected product 3 was obtained in 67% yield (entry 4).
At 0°C, the kinetic of the reaction was slower. 22 hours were
necessary to perform the amination step but the chemical
yield and the enantioselectivity were higher compared to
those obtained at room temperature: 80% yield and 82% ee
(entry 5).
When the reaction was catalyzed by trans-4-tert-butoxy-
L-proline 2, the level of enantiocontrol was good to
excellent. The amination of propionaldehyde provided
compound 4 in 68% yield and 93% ee [15] (entry 2). The
hydrazino alcohol 5 derived from heptanal was synthesized
in 75% yield and 95% ee [16] (entry 4). Finally, the best
result was obtained with 5,5-dimethoxypentanal and
compound 6 was isolated in 69% yield and 97% ee [17]
(entry 6).
The reaction was further applied to more challenging
substrates (Table 3). The efficiency of catalysts 1 and 2 was
tested using cyclic and acyclic ketones. L-Proline [8a] as
well as 4-siloxy-L-proline [8f] are known to catalyze ꢀ-
amination of ketones. Trans-3- and trans-4-tert-butoxy-L-
proline proved to be very efficient using only 5 mol% of
catalyst loading at room temperature.
The electrophilic amination of 6,6-dimethoxyhexanal
performed at room temperature in presence of 2 5 mol%,
afforded 3 in 78% yield and 88% ee (entry 6). Lowering
temperature to 0°C increased the efficiency of the catalyst
providing 3 in 84% yield and 94% ee (entry 7). This result
validated our attempt to find a highly reactive catalyst for the
electrophilic amination reaction.
The electrophilic amination of butanone with DBAD led
to the 3-hydrazinobutanone 7 as a sole product (entries 1 and
2). The formation of the 1-hydrazino regioisomer was
precedently reported when DEAD was used as electrophilic
aminating reagent [8a]. These results could be compare with
what was obtained using L-proline 20 mol% as catalyst and
DBAD as reagent [7a]. We observed similar e.e. and
increased chemical yields probably due to the best
solubilities of the catalysts 1 and 2 in the reaction mixture.
Compound 7 was obtained in 65% yield and 90% ee [18]
The antipode of 1, trans-3-tert-butoxy-D-proline, was
also tested as catalyst. We previously reported the synthesis
of trans-3-hydroxy-D-proline by
a classical way of
enantioselective catalytic hydrogenation of functionalized ꢁ-
ketoester and diastereoselective electrophilic amination of
the resulting ꢁ-hydroxyester [13]. Trans-3-hydroxy-D-
proline was protected in two steps as precedently to give the
enantiomer of 1 [14]. ꢀ-Amination of 6,6-dimethoxyhexanal
Table 1. ꢀ-Amination Reaction of 6,6-Dimethoxyhexanal with DBAD Catalyzed by trans-3-tert-butoxy-L-proline 1 and trans-4-
tert-butoxy-L-proline 2a
Entry
Catalyst
Temp.
Time
Yield (%)
Ee (%)
1
2
3
4
5
6
7
L-Prol (10 mol%)
1 (10 mol%)
2 (10 mol%)
1 (5 mol%)
0°C
0°C
0°C
r.t.
16h
4h30
3h30
55 min
22h
76%
74%
71%
67%
80%
78%
84%
94%
94%
96%
71%
82%
88%
94%
1 (5 mol%)
0°C
r.t.
2 (5 mol%)
3h30
22h
2 (5 mol%)
0°C
aReactions were conducted with DBAD (1.0 equiv), and carbonyl compound (1.5 equiv) in CH2Cl2.

Asymmetric ꢀ-Amination of Aldehydes
Letters in Organic Chemistry, 2009, Vol. 6, No. 5
379
Table 2. ꢀ-Amination Reaction of Various Aldehydes with DBAD Catalyzed trans-3-tert-butoxy-L-proline 1 and trans-4-tert-
butoxy-L-proline 2 (5 mol%)a
Aldehyde
Product
Entry
Catalyst
Time
Yield (%)
Ee (%)
1
2
1
2
1h50
74%
68%
80%
93%
HO
O
1h15b
CbzN
NHCbz
4
3
4
1
2
2h20
3h10
72%
75%
87%c
95%c
( )4
O
HO
4
CbzN
NHCbz
5
5
6
OMe
OMe
1
2
14h
14h
68%
69%
83%
97%
( )2
O
HO
(OMe)2
3
CbzN
NHCbz
6
aUnless otherwise shown, reactions were conducted with catalyst 1 or 2 (5 mol%), DBAD (1.0 equiv), and carbonyl compound (1.5 equiv) in CH2Cl2 at 0°C.
breaction was conducted at room temperature.
cDetermined before reduction step on the ꢀ-aminoaldehyde.
Table 3. ꢀ-Amination Reaction of ꢀ, ꢀ-Disubstituted Aldehydes or Ketones with DBAD Catalyzed by trans-3-tert-butoxy-L-proline
(1) and trans-4-tert-butoxy-L-proline (2)a
Starting mat.
Product
NHCbz
Entry
Catalyst
Time
Yield (%)
Ee (%)
1
2
1
2
40h
40h
63%
65%
84%
90%
O
O
NCbz
7
3
4
1
2
40h
40h
71%
72%
86%
90%
O
O
NHCbz
NCbz
8
5
6
1
2
4h
76%
61%
45%
77%
Ph
Ph
HO
O
14h
CbzN
9
NHCbz
aUnless otherwise shown, reactions were conducted with catalyst 1 or 2 (5 mol%, for entries 1 to 4 and 30 mol% for entries 5 and 6), DBAD (1.0 equiv), and carbonyl compound (1.5
equiv) in CH2Cl2 at r.t.
using 2 as catalyst (entry 2). The electrophilic amination of
cyclohexanone with DBAD in the presence of 1 and 2 5
mol% as catalysts gave similar or even better results
compared to those obtained respectively with with 4-
silyloxy-L-proline 10 mol% [8f] or L-proline 20 mol% [7a].
The aminated product 8 was isolated in 72% yield and 90%
ee [19] using 2 as catalyst (entry 4).
CONCLUSION
In summary, trans-3-tert-butoxy-L-proline 1 and trans-4-
tert-butoxy-L-proline 2 proved to be efficient catalysts for
the electrophilic ꢀ-amination of carbonyl compounds. The
loading of catalyst was lowered to 5 mol%. Various
aldehydes were aminated at 0°C affording the hydrazino
derivatives in good yields and high level of
enantioselectivities.
ꢀ-Amination reaction of ꢀ,ꢀ-disubstituted aldehydes was
previously reported using 50 mol% of proline [8b,d,g] or 30
mol% of silyloxyproline [8f]. While the amination of 2-
phenylpropanal in the presence of the catalyst 1 gave low
enantioselectivity (entry 5), the use of trans-4-tert-butoxy-L-
proline 2 (30 mol%) afforded a similar result compared to
the one reported in the literature : 61% yield and 77% ee [20]
(entry 6).
ACKNOWLEDGEMENTS
We thank the Ministère de la Recherche for a grant to
D.K. and the ANR CP2D for financial support.

380 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
Ait-Youcef et al.
combined organic layers were then washed once with water, dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was suspended in 1 M NaOH (30 mL) and stirred until
the reaction mixture became homogeneous, that is, for about 4h.
The reaction mixture was then cooled to 0 °C and acidified with
HCl (1M) (30 mL). The mixture was stirred at 0 °C for 30 min then
concentrated in vacuo. The product was isolated after elution on
Dowex 50WX8-200 ion exchange column (NH4OH, 1N) to yield
compound 2 as a white solid (0.520 g, 73 % over two steps); mp
REFERENCES
[1]
(a) Erdik, M.; Ay, M. Chem. Rev., 1989, 89, 1947. (b) Greck, C.;
Genêt, J.P. Synlett, 1997, 741. (c) Genêt, J.P.; Greck, C.; Lavergne,
D. Modern Amination Methods, Wiley-VCH: Weinheim, 2000; pp.
65-102. (d) Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J.,
2000, 6, 1281.(e) Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J.
Org. Chem., 2004, 1377.
[2]
[3]
List, B. Chem. Rev., 2007, 107, 5413.
For an overview of organocatalysis see Special Issue: Chem Rev.,
2007, 107.
22
204-206°C; [ꢀ]D = + 34.6 (c 1; MeOH); IR ꢁ3484, 3119, 2977,
1593, 1465, 1393, 1362, 1195, 1109, 1022, 898 cm-1; 1H NMR (300
MHz, MeOD) ꢂ 4.61 (m; 1H); 4.30 (t, J = 8.7 Hz, 1H); 3,59 (dd, J
= 5.0, 2.1 Hz, 1H); 3,26 (dd, J = 5.0, 2.1 Hz, 1H); 2.31 (m; 2H);
[4]
[5]
(a) Marigo, M.; Jørgensen, K. A. Chem. Commun., 2006, 2001. (b)
Guillena, G.; Ramón, D.J. Tetrahedron: Asymmetry, 2006, 17,
1465.
Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jorgensen, K. A. Angew. Chem., Int. Ed. Engl., 2002, 41, 1790.
List, B. J. Am. Chem. Soc., 2002, 124, 5656.
(a) Thomassigny, C.; Prim, D.; Greck, C. Tetrahedron Lett., 2006,
47, 1117. (b) Kalch, D.; De Rycke, N.; Moreau, X.; Greck, C.
Tetrahedron Lett., 2009, 50, 492.
1.26 (s; 9H); 13C NMR (75 MHz, MeOD) ꢂ 174.0, 76.1, 69.9, 59.9,
52.1, 36.9, 27.1; Anal. calcd for C9H17NO3:C, 57.73; H, 9.15; N,
7.48. Found: C, 57.46; H, 8.98; N, 7.63.
[6]
[7]
[11]
General procedure for the amination step: Dibenzylazo-
dicarboxylate (1 mmol) and catalyst (5 mol% or 10 mol%) in
dichloromethane (3 mL) were treated with an aldehyde (1.5 mmol)
at 0°C or room temperature. The reaction mixture was stirred until
the yellow color of the azodicarboxylate had disappeared. The
mixture was treated with ethanol (3 mL) and NaBH4 (1.05 mmol)
and was stirred for 15 min. at 0°C. The reaction was worked up
with aqueous ammonium chloride solution and ethyl acetate. The
organic layers were dried over MgSO4, filtered, and concentrated.
Purification by flash chromatography on silica gel (EtOAc/CH2Cl2
1/2) afforded the alcohols.
Compound 3: the enantiomeric excess was determinated by HPLC
analysis of the crude product using Chiralpack AD-H; Eluant:
heptane/propan-2-ol: 90/10 + 0,2% TFA; flow 0.5 ml/min; ꢃ 260
nm; T 25°C; ꢄminor = 52.07 min, ꢄmajor = 55.31 min.
(a) Poupardin, O.; Greck, C.; Genêt, J.P. Synlett, 1998, 1279. See
[8]
(a) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig, A.;
Jorgensen, K. A. J. Am. Chem. Soc., 2002, 124, 6254. (b) Vogt, H.;
Vanderheiden, S.; Bräse, S. Chem. Commun., 2003, 2448. (c)
Janey, J. M. Angew. Chem., Int. Ed. Engl., 2005, 44, 4292. (d)
Baumann, T.; Vogt, H.; Bräse S. Eur. J. Org. Chem., 2007, 266. (e)
Liu, T.; Cui, H.; Zhang, Y.; Jiang, K.; Du, W.; He, Z.; Chen, Y.
Org. Lett., 2007, 9, 3671. (f) Hayashi, Y.; Arakate, S.; Imai, Y.;
Hibino, K.; Chen, Q.Y.;Yamaguchi, J.; Uchimaru, T. Chem. Asian
J., 2008, 3, 225. (g) Baumann, T.; Bächle, M.; Hartmann, C.;
Bräse, S. Eur. J. Org. Chem., 2008, 2207.
[12]
[13]
[9]
Trans-3-tert-butoxy-L-proline 1: 2-Methyl-propene (4 mL) was
condensed into a pear-shaped flask at -78 °C and then added to a
suspension of trans-3-hydroxy-L-proline (0.130 g, 0.99 mmol) and
p-toluenesulfonic acid hydrate (0.736 g, 3.86 mmol) in
dichloromethane (5 mL) at -78 °C. The reaction was stirred for 3
days, allowing the mixture to come to room temperature. The
reaction mixture was then cooled to 0 °C, vented carefully, and
then poured into a separatory funnel and washed twice with a
saturated aqueous solution of NaHCO3. The combined aqueous
layers were extracted once with dichloromethane, and the
combined organic layers were then washed once with water, dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was suspended in 1 M NaOH (6.5 mL) and stirred until
the reaction mixture became homogeneous, that is, for about 4h.
The reaction mixture was then cooled to 0 °C and acidified with
HCl (1M) (6.5mL). The mixture was stirred at 0 °C for 30 min then
concentrated in vacuo. The product was isolated after elution on
Dowex 50WX8-200 ion exchange column (NH4OH, 1N) to yield
compound 1 as a white solid (0.128 g, 69 % over two steps); mp
also: (b) Greck, C.; Bischoff, L.; Genêt, J.P. Tetrahedron:
Asymmetry, 1995, 6, 1989. (c) Greck, C.; Ferreira, F.; Genêt, J.P.
Tetrahedron Lett., 1996, 37, 2031. (d) Poupardin, O.; Greck, C.;
Genêt, J.P. Tetrahedron Lett., 2000, 41, 8795.
[14]
[15]
Trans-3-tert-butoxy-D-proline: [ꢀ]D22 = - 12.3 (c 1; MeOH).
Compound 4: the enantiomeric excess was determinated by HPLC
analysis of the crude product using Chiralpack AD-H; Eluant:
heptane/propan-2-ol: 90/10 + 0,2% TFA; flow 0.5 ml/min; ꢃ 260
nm; T 25°C; ꢄminor = 41.68 min, ꢄmajor = 37.90 min.
[16]
[17]
[18]
[19]
[20]
Compound 5: the enantiomeric excess was determined before
reduction step on the ꢀ-aminoaldehyde by HPLC analysis using
Chiralpack OD-H; Eluant: heptane/propan-2-ol: 93/7; flow 0.9
ml/min; ꢃ 260 nm; T 25°C; ꢄminor = 33.23 min, ꢄmajor = 42.30 min.
Compound 6: the enantiomeric excess was determinated by HPLC
analysis of the crude product using Chiralpack AD-H; Eluant:
heptane/propan-2-ol: 90/10 + 0,2% TFA; flow 0.5 ml/min; ꢃ 260
22
200-202°C; [ꢀ]D = + 12.4 (c 1; MeOH); IR ꢁ 3441, 3098, 2976,
1586, 1452, 1386, 1363, 1195, 1094, 1015, 872 cm-1; 1H NMR (300
nm; T 25°C; ꢄminor = 58.67 min, ꢄmajor = 53.28 min.
Compound 7: the enantiomeric excess was determinated by HPLC
analysis of the crude product using Chiralpack OD-H; Eluant:
MHz, MeOD) ꢂ 4.49 (m; 1H); 3,85 (d, J = 2.3 Hz, 1H); 3.36 (m;
2H); 1.93 (m; 2H); 1.17 (s; 9H); 13C NMR (75 MHz, MeOD) ꢂ
171.8, 76.5, 74.5, 68.3, 44.4, 31.8, 27.3; Anal. calcd for C9H17NO3:
C, 57.73; H, 9.15; N, 7.48. Found: C, 57.54; H, 8.94; N, 6.91.
Trans-4-tert-butoxy-L-proline 2: 2-Methyl-propene (8 mL) was
condensed into a pear-shaped flask at -78 °C and then added to a
suspension of trans-4-hydroxy-L-proline (0.500 g, 3.81 mmol) and
p-toluenesulfonic acid hydrate (2.81 g, 14.81 mmol) in
dichloromethane (20 mL) at -78 °C. The reaction was stirred for 3
days, allowing the mixture to come to room temperature. The
reaction mixture was then cooled to 0 °C, vented carefully, and
then poured into a separatory funnel and washed twice with a
saturated aqueous solution of NaHCO3. The combined aqueous
layers were extracted once with dichloromethane, and the
heptane/propan-2-ol: 93/7; flow 0.9 ml/min; ꢃ 260 nm; T 25°C;
ꢄminor = 64.75 min, ꢄmajor = 50.03 min
Compound 8: the enantiomeric excess was determinated by HPLC
analysis of the crude product using Chiralpack OD-H; Eluant:
heptane/propan-2-ol: 93/7; flow 0.9 ml/min; ꢃ 260 nm; T 25°C;
[10]
ꢄ
minor = 35.72 min, ꢄmajor = 48.37 min
Compound 9: the enantiomeric excess was determinated by HPLC
analysis of the crude product using Chiralpack AD-H; Eluant:
heptane/propan-2-ol: 90/10 + 0,2% TFA; flow 0.5 ml/min; ꢃ 260
nm; T 25°C; ꢄminor = 85.11 min, ꢄmajor = 80.11 min.