Remarkable reaction rate and excellent enantioselective direct α-amination of aldehydes with azodicarboxylates catalyzed by pyrrolidinylcamphor-derived organocatalysts

Article abstract of DOI:10.1002/ejoc.200901151

Remarkable reaction rate and excellent enantioselective direct α-amination of unmodified aldehydes with various azodicarboxylates was catalyzed by pyrrolidinylcamphor organocatalyst 2a (5 mol-%) to provide the desired aminated products with excellent chemical yields and high to excellent levels of enantioselectivity (up to >99%ee) at 0 °C in CH ₂Cl₂.

Full text of DOI:10.1002/ejoc.200901151

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901151
Remarkable Reaction Rate and Excellent Enantioselective Direct α-Amination
of Aldehydes with Azodicarboxylates Catalyzed by
Pyrrolidinylcamphor-Derived Organocatalysts
Pang-Min Liu,[a] Chihliang Chang,[a] Raju Jannapu Reddy,[a] Ying-Fang Ting,[a]
Hsuan-Hao Kuan,[a] and Kwunmin Chen*[a]
Keywords: Amination / Asymmetric catalysis / Organocatalysis / Nitrogen heterocycles
Remarkable reaction rate and excellent enantioselective di-
rect α-amination of unmodified aldehydes with various azo-
dicarboxylates was catalyzed by pyrrolidinylcamphor organo-
catalyst 2a (5 mol-%) to provide the desired aminated prod-
ucts with excellent chemical yields and high to excellent
levels of enantioselectivity (up to Ͼ99%ee) at 0 °C in
CH2Cl2.
products in high chemical yields and excellent enantio-
selectivities. In addition, the amination of α,α-disubstituted
aldehydes with azodicarboxylate catalyzed by a variety of
organocatalysts have been reported.[8e,8g,8h,8m,8n] However,
the reactions generally require high catalyst loading
(50 mol-%) under thermal or microwave-assisted conditions
and resulted in moderate to good chemical yields and en-
antioselectivities.[8m,8n] Despite the excellent results
achieved by several research groups, the development of an
efficient method for the direct organocatalytic α-amination
of aldehydes to azodicarboxylates with low catalyst load-
ings and shorter reaction time remains a challenging task
in asymmetric synthesis.
Although many practical organocatalysts have been de-
veloped, only relatively few are effective with low catalyst
loadings (5 mol-%).[9] We have recently designed and syn-
thesized a series of novel pyrrolidinylcamphor-based organ-
ocatalysts for asymmetric organocatalysis.[10] In our con-
tinuous efforts toward developing new organocatalysts, we
envision that the assembly of a well-defined structural cam-
phor scaffold with a pyrrolidinyl motif linked with appro-
priate functionalities, such as, sulfides (1a–f), sulfones (2a
and 2b), sulfonamides (3a and 3b), and amide (4), would
act as efficient bifunctional organocatalysts in asymmetric
synthesis (Scheme 1). We wish to report here an excellent
enantioselective direct α-amination of aldehydes with vari-
ous azodicarboxylates catalyzed by pyrrolidinylcamphor bi-
functional organocatalysts. The desired α-aminated
alcohols were obtained with high chemical yields and excel-
lent enantioselectivities at 0 °C in 5–10 min with only
5 mol-% of organocatalyst 2a.
Introduction
The formation of carbon–nitrogen bonds has received
considerable attention in recent years, as nitrogen-contain-
ing molecules are potentially important building blocks.[1]
Diastereoselective electrophilic amination of metal enolates
with azodicarboxylates as the nitrogen source has been de-
veloped for the synthesis of α-hydrazino acids and α-amino
acids with high levels of diastereoselectivity.[2] The metal-
mediated catalytic enantioselective α-amination of 1,3-di-
carbonyls,[3] keto esters,[4] and metal enolates/enolsilanes[5]
with azodicarboxylates has recently been realized. In con-
trast, the efficient organocatalytic α-amination of α-substi-
tuted α-cyanoacetates, 1,3-dicarbonyls, or β-keto esters with
azodicarboxylates has been documented, which leads to the
synthesis of α-aminated products.[6] Asymmetric organocat-
alysis has recently attracted much attention due to the fact
that organocatalysts are typically nontoxic, highly efficient,
environmentally friendly, and stable under both aerobic and
aqueous reaction conditions.[7] Recently, methods have been
developed for the direct organocatalytic α-amination of un-
modified aldehydes/ketones with azodicarboxylates.[8]
Since the ingenious work of List[8a] and Jørgensen,[8b] -
proline-catalyzed α-amination of aldehydes with azodicar-
boxylates has been shown to produce the corresponding
[a] Department of Chemistry,
National Taiwan Normal University,
Taipei, Taiwan 116, ROC
Fax: +886-2-29324249
E-mail: kchen@ntnu.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901151.
42
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 42–46

Enantioselective Direct α-Amination of Aldehydes
Scheme 1. Chemical structures of pyrrolidinylcamphor catalysts 1–4.
propionaldehyde (7a) was chosen as a model substrate and
dibenzyl azodicarboxylate (8a) was used as the nitrogen
source. The reaction was carried out with catalytic quanti-
ties of organocatalysts 1–4 in toluene at ambient tempera-
ture (Table 1). Treatment of 7a with 8a in the presence of
1a (5 mol-%) followed by NaBH4 reduction afforded corre-
sponding primary alcohol 9a in 96% chemical yield and
Results and Discussion
The synthesis of organocatalysts 1–4 began with known
N-Boc protected -proline analogues 5a–d and camphor de-
rivatives 6a–c (Scheme 1). Organocatalysts 1a–c were ob-
tained by the reaction of N-Boc O-tosylated prolinol deriva-
tives 5a–c with 1-mercaptomethyl-7,7-dimethylbicyclo-
[2.2.1]heptan-2-one (6a) in the presence of NaH, followed
by Boc deprotection with trifluoroacetic acid (TFA). The
NaBH4 reduction of N-Boc 1a–c provided the correspond-
ing exo-alcohol (C2-camphor numbering) as a single dia-
stereomer, which was treated with TFA in CH2Cl2 to gener-
ate desired organocatalysts 1d–f without any incident. De-
sired sulfone-linked organocatalyst 2a was obtained by the
oxidation of N-Boc 1c with Oxone under basic conditions.
The removal of the Boc group was performed after the re-
duction step to afford the corresponding exo-alcohol organo-
catalyst 2b as a single diastereomer.
In contrast, sulfonamide organocatalysts 3a and 3b were
prepared by conventional coupling between Boc-protected
(S)-2-aminomethylpyrrolidine (5d) and camphorsulfonyl
chloride [in situ prepared from camphorsulfonic acid (6b)
with SOCl2], followed by TFA treatment to produce 3a. Or-
ganocatalyst 3b was obtained as a single diastereomer after
NaBH4 reduction of Boc-protected 3a, followed by the de-
protection of the Boc group. A similar synthetic route was
used to prepare 4: Boc-protected (S)-2-aminomethylpyrrol-
idine (5d) was treated with ketopinic acid (6c) under stan-
dard coupling conditions.[10c]
Table 1. Direct α-amination of 7a with 8a in toluene at ambient
temperature by organocatalysts 1–4.[a]
Entry
Catalyst
Time [min]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
2a
2b
3a
3b
4
5
5
20
5
5
5
20
30
90
30
5
96
83
88
88
91
68
90
92
89
78
80
–16[d]
–52[d]
31
2
–39[d]
74
92
90
93
94
9
10
11
84
[a] In all cases dibenzyl azodicarboxylate (8a; 0.5 mmol) was added
to a mixture of propionaldehyde (7a; 2.0 mmol) and the appropri-
ate catalyst (5 mol-%). [b] Isolated yield. [c] Determined by chiral
HPLC analysis. The newly generated stereogenic center of the
major product had the (R) configuration. [d] Opposite enantiomer
With pyrrolidinylcamphor compounds 1–4 in hand, we
explored the catalytic properties of these organocatalysts in
the direct α-amination of unmodified aldehydes. Initially, was obtained as the major product.
Eur. J. Org. Chem. 2010, 42–46
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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43

P.-M. Liu, C. Chang, R. J. Reddy, Y.-F. Ting, H.-H. Kuan, K. Chen
SHORT COMMUNICATION
only 16%ee (Table 1, Entry 1). The newly generated ficantly decreased when 0.5 mol-% of organocatalyst 2a
stereogenic center of the major product was determined to was used under the same reaction conditions (Table 2,
have the S configuration. A slight improvement in the Entry 8).
enantioselectivity was obtained when 4-hydroxypyrrolidinyl
To assess the general utility of this asymmetric α-amin-
catalyst 1b was used (Table 1, Entry 2). Interestingly, the ation reaction, we examined the reaction of a variety of
enantioselectivity was reversed when 4-hydroxy-protected alkyl-substituted aldehydes 7a–f with azodicarboxylates 8a–
silyl ether (OTBDPS) organocatalyst 1c was used (31%ee; c under optimal reaction conditions (Table 3). Reactions
Table 1, Entry 3). Unsatisfactory results were achieved were performed in CH2Cl2 at 0 °C in the presence of 2a
when the reaction was performed with organocatalysts 1d– (5 mol-%) followed by reduction with NaBH4 at 0 °C. High
f (Table 1, Entries 4–6). To our delight, catalysts 2a and 2b chemical yields (80–95%) and excellent enantioselectivities
bearing a sulfone linkage provide the desired α-aminated (95 to Ͼ99%ee) were obtained when linear alkyl substrates
products in high chemical yields and enantioselectivities (92 7a–d were used (Table 3, Entries 1–4). The reaction with
and 90%ee, respectively; Table 1, Entries 7 and 8). Further, isobutyraldehyde (7e) and 3-phenylpropionaldehyde (7f)
sulfonamides 3a and 3b and amide 4 organocatalysts also also resulted in satisfactory yields (97 and 93%, respec-
afforded high chemical yields and enantioselectivities tively) and enantioselectivities (97 and 94%ee, respectively;
(Table 1, Entries 9–11). It is worth noting that the α-aminat- Table 3, Entries 5 and 6). Diethyl and diisopropyl azodicarb-
ing reaction required 4.0 equivalents of the aldehyde in the oxylates (8b and 8c) were also successfully employed in the
presence of 5 mol-% of the catalyst in a short period of α-amination process with 7f under optimal reaction condi-
reaction time.
tions. Aminated alcohols 9g and 9h were also obtained in
Regarding the reactivity and enantioselectivity, organo- high chemical yields (95 and 97%, respectively) and
catalyst 2a was chosen for further optimization α-amin- enantioselectivities (92 and 94%ee, respectively; Table 3,
ation studies (Table 2). Changing the solvent to CH2Cl2 af- Entries 7 and 8).
forded comparable chemical yields and selectivities as those
Table 3. Generality of the direct α-amination of various unmodified
aldehydes 7a–f with amine sources 8a–c by catalyst 2a.[a]
detected in toluene. However, the catalysis rate was much
faster; only 5 min was needed to complete the α-amination
process (Table 2, Entry 1). The reactivity and stereoselecti-
vity failed to improve when the reaction was carried out in
THF and MeOH (Table 2, Entries 2 and 3). The chemical
yields and enantioselectivities were not significantly im-
proved when water and brine were used as the reaction me-
dia (Table 2, Entries 4 and 5). Up to 96%ee was attained
when the reaction was carried out in CH2Cl2 at 0 °C, and
negligible reaction time was sacrificed (Table 2, Entry 6).
Surprisingly, the same level of enantioselectivity was re-
tained when the reaction proceeded with only 2 mol-% of
organocatalyst 2a (Table 2, Entry 7). The reactivity signi-
Entry
R1
R2
Time [min] Product,
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Me (7a)
Et (7b)
Pr (7c)
Bu (7d)
iPr (7e)
Bn (7f)
Bn (7f)
Bn (7f)
Bn (8a)
Bn (8a)
Bn (8a)
Bn (8a)
Bn (8a)
Bn (8a)
Et (8b)
iPr (8c)
10
10
10
5
5
10
5
9a, 90
9b, 95
9c, 80
9d, 91
9e, 97
9f, 93
9g, 95
9h, 97
96
Ͼ99
95
97
97
94
92
94
Table 2. Effect of solvent and temperature in the direct α-amination
of 7a with 8a in the presence of 2a.[a]
5
[a] In all cases, azodicarboxylates 8a–c were added to a mixture
of aldehydes 7a–f and catalyst 2a (5 mol-%) in CH2Cl2 at 0 °C.
[b] Isolated yield. [c] Determined by chiral HPLC analysis.
The utility of this approach is illustrated in the reaction
of propionaldehyde (7a) with dibenzyl azodicarboxylate
(8a). The reaction can be easily scaled up to gram quantities
(2.0 g) by using organocatalyst 2a (0.5 mol-%) to give 9a
after NaBH4 reduction, with a 90% isolated yield and high
level of enantioselectivity (92%ee). As shown in Scheme 2,
aminated alcohol 9a was treated with TsCl in the presence
of pyridine, followed by sodium azide treatment and subse-
quent “click” chemistry[11] under copper-catalyzed cycload-
dition to afford enantiomerically enriched triazole deriva-
tive 11. The stereochemistry of the triazole derivative was
retained during the reaction process. Triazole derivatives are
important building blocks in medicinal chemistry and find
various applications in both material science and pharma-
ceutical research.[12]
Entry
Solvent
Time [min]
Yield [%][b]
ee [%][c]
1
2
3
4
CH2Cl2
THF
MeOH
brine
5
90
84
86
86
79
90
84
90
92
88
86
87
87
96
95
95
10
20
30
90
10
20
60
5
H2O
6[d]
7[e]
8[f]
CH2Cl2
CH2Cl2
CH2Cl2
[a] Unless otherwise specified, in all cases 8a (0.5 mmol) was added
to a mixture of 7a (2.0 mmol) and 2a. [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis; major product has the (R) configu-
ration. [d] The reaction was carried out at 0 °C. [e] Reaction was
carried out at 0 °C with 2.5 mol-% of 2a. [f] Catalyst 2a (0.5 mol-
%) was added to the reaction mixture at 0 °C.
44
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Eur. J. Org. Chem. 2010, 42–46

Enantioselective Direct α-Amination of Aldehydes
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Conclusions
In conclusion, we have demonstrated a practical method
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with different azodicarboxylates catalyzed by structurally
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(5 mol-%) in CH2Cl2 at 0 °C. These data compare favorably
[6]
to the best results reported previously, and this method rep-
resents an alternative, efficient α-amination of unmodified
aldehydes. More studies are underway.
Experimental Section
General Procedure for the Asymmetric α-Amination: To a stirred
solution of catalyst 2a (0.025 mmol) and aldehyde 7a–f (2.0 mmol)
in CH2Cl2 (0.5 mL) cooled to 0 °C was added azodicarboxylate 8a–
c (0.5 mmol) at the same temperature. The reaction mixture was
stirred at 0 °C for the time indicated in Tables 2 and 3. After the
azodicarboxylate was consumed as indicated by TLC analysis (the
decolorization of azodicarboxylate was also observed), the reaction
was treated with sodium borohydride (0.5 mmol, 20 mg) in meth-
anol (0.5 mL). After 5 min, the reaction was quenched with aque-
ous NH4Cl (1 mL) and brine. The mixture was extracted with ethyl
acetate (2ϫ20 mL) and dried with anhydrous MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
column chromatography on silica gel (ethyl acetate/hexanes, 1:8 to
1:4) to afford pure α-aminated products 9a–h.
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Acknowledgments
We thank the National Science Council of the Republic of China
(NSC 96-2113-M-003-005-MY3) for financial support of this work.
We are grateful to the Academic Paper Editing Clinic at NTNU
and the National Center for High-Performance Computing for pro-
viding us with computer time and facilities.
Eur. J. Org. Chem. 2010, 42–46
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45

P.-M. Liu, C. Chang, R. J. Reddy, Y.-F. Ting, H.-H. Kuan, K. Chen
SHORT COMMUNICATION
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Received: October 13, 2009
Published Online: November 5, 2009
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Eur. J. Org. Chem. 2010, 42–46