Primary amine catalyzed electrophilic amination of α,α- disubstituted aldehydes

Article abstract of DOI:10.1016/j.tetlet.2011.06.063

Organocatalytic α-amination of α,α-disubstituted aldehydes promoted by 9-amino-(9-deoxy)-epi-quinine is described. α-Hydrazino aldehydes bearing a quaternary stereogenic center are obtained in good to excellent yields and enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2011.06.063

Tetrahedron Letters 52 (2011) 4430–4432
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Primary amine catalyzed electrophilic amination of
a,a-disubstituted aldehydes
⇑
⇑
Alaric Desmarchelier, Hasret Yalgin, Vincent Coeffard, Xavier Moreau , Christine Greck
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles-Saint-Quentin-en-Yvelines, 45, Avenue des Etats-Unis, 78035 Versailles Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Organocatalytic
nine is described.
to excellent yields and enantioselectivities.
a
-amination of
a,a-disubstituted aldehydes promoted by 9-amino-(9-deoxy)-epi-qui-
Received 12 May 2011
Revised 14 June 2011
Accepted 15 June 2011
Available online 23 June 2011
a
-Hydrazino aldehydes bearing a quaternary stereogenic center are obtained in good
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Organocatalysis
Primary amine
Branched aldehydes
Quaternary stereocenter
Over the last decade, organocatalytic
a
-amination of aldehydes
(5 mol %) and TFA (15 mol %) in chloroform was first investigated
(entry 1) since this catalyst system was successfully applied for
such a transformation by our group.8 While the reactivity was
excellent (full conversion within 3 h at rt and 94% of isolated yield),
the enantioselectivity was disappointing (68% ee). When the reac-
tion was run in CH2Cl2 or toluene (entries 2 and 3) the reactivity
remained good but the selectivity was lower (respectively 58%
and 50% ee). If more polar or protic polar solvents such as MeCN
or iPrOH (entries 4 and 5) were used for this reaction, both reactiv-
ity and selectivity dropped (after 3 h, the conversion was not com-
plete and the selectivity was poor). As the stereoselectivity was not
improved by lowering the temperature to 0 °C (entry 6), we then
screened various primary amine catalysts derived from cinchona
alkaloids. Moving from 9-amino-(9-deoxy)-epi-cinchonidine I to
9-amino-(9-deoxy)-epi-quinine II greatly enhanced the ee (entry
7). The expected product was obtained in 95% yield and 90% ee.
Pseudo-enantiomers of these catalysts were not effective for this
transformation (entries 8 and 9). 9-Amino-(9-deoxy)-epi-cincho-
nine III almost led to a racemic sample and 9-amino-(9-deoxy)-
epi-quinidine IV delivered the product as the opposite enantiomer
in 95% yield and only 55% ee. Finally the influence of the amount of
acid co-catalyst was also investigated. Slow conversion and poor
selectivity were observed when the reaction was carried out with-
out TFA (entry 10) while using 7.5 mol % TFA required longer reac-
tion time and the product was obtained in 84% yield and 92% ee
(entry 11).
and ketones has emerged as one of the most powerful methods for
stereoselective CAN bond formation.1 While electrophilic amina-
tion of simple aliphatic carbonyl compounds is well documented
in the literature,2 the use of
a,a-disubstituted aldehydes to form
quaternary stereocenter-containing products bearing a nitrogen
atom still remains scarce. In 2003, Bräse and co-workers reported
the first example of this transformation using proline as a catalyst.3
In 2005, Barbas and co-workers applied this strategy to the synthe-
sis of three biologically active products namely, BIRT-377,4 AIDA
and APICA.5 More recently, Wang et al. have shown that the same
reaction could be efficiently promoted by chiral secondary amine
derived from proline.6 Primary amine catalysts were also found
to be effective for this transformation. Melchiorre and co-workers
developed a cascade reaction involving an electrophilic amination
catalyzed by a primary amine derived from hydroquinine.7 Finally,
our group has recently described an organocatalytic sequence
combining Michael addition/
ed cinchonine derivative.8 In this letter, we would like to report our
results about the enantioselective amination of -disubstituted
a-amination promoted by an aminat-
a,a
aldehydes catalyzed by primary amines derived from cinchona
alkaloids.
Electrophilic amination of commercially available 2-phenylpro-
pionaldehyde with diisopropyl azodicarboxylate (0.83 equiv) was
examined as the reaction model and the results are summarized
in Table 1. Combination of 9-amino-(9-deoxy)-epi-cinchonidine I
With the optimized conditions in hands9 (1 equiv DIAD,
1.2 equiv aldehyde, 5 mol % catalyst II, 15 mol % TFA in CHCl3 at
rt), we then turned our attention to the influence of the electro-
philic nitrogen source and the reaction was conducted with differ-
ent azodicarboxylates (Table 2). As expected, less hindered
⇑
Corresponding authors. Tel.: +33 (0) 1 39 25 44 05; fax: +33 (0) 1 39 25 44 52
(X.M.).
E-mail addresses: moreau@chimie.uvsq.fr, xavier.moreau@chimie.uvsq.fr (X.
Moreau), greck@chimie.uvsq.fr (C. Greck).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.063

A. Desmarchelier et al. / Tetrahedron Letters 52 (2011) 4430–4432
4431
Table 1
Catalyst and solvent screening
R*NH2
(5 mol%)
CO2iPr
Ph
N
iPrO2C
N
+
O
NHCO2iPr
O
N
CO2iPr
TFA (15 mol%)
Solvent (0.5M)
r.t., 3h
Ph
OMe
N
OMe
NH2
NH2
NH2
NH2
N
N
N
N
H
N
N
H
H
H
N
II
III
IV
I
Entry
Catalyst
Solvent
Yielda (%)
eeb (%)
1
2
3
4
I
I
I
I
I
I
II
III
IV
II
II
CHCl3
CH2Cl2
Toluene
CH3CN
iPrOH
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
94
82
94
36
56
91
95
86
95
59
84
68 (S)
58 (S)
50 (S)
28 (S)
40 (S)
60 (S)
90 (S)
4 (R)
5
6c
7
8
9
55 (R)
19 (R)
92 (S)
10d
11e
a
b
c
Isolated yield after column chromatography.
Ee was determined by chiral phase HPLC analysis (AS-H column, 10% iPrOH/heptane, 0.8 mL/min, 30 °C).
Reaction run at 0 °C during 24 h.
Reaction run without TFA during 56 h.
Reaction run with 7.5 mol % TFA during 8 h.
d
e
Table 3
Aldehyde screening
Table 2
Azodicarboxylate screening
OMe
OMe
N
NH2
NH2
N
N
H
N
H
CO2R
N
Boc
N
(5 mol%)
Ph
(5 mol%)
R2
RO2C
N
Boc
N
O
NHCO2R
+
+
O
O
NHBoc
N
CO2R
O
N
Boc
TFA (15 mol%)
CHCl3 (0.5M)
r.t., 3h
R1
Ph
TFA (15 mol%)
CHCl3 (0.5M)
r.t.
R2 R1
Entry
Azodicarboxylate
Yielda (%)
eeb (%)
90
\
Entry
R1
R2
Product
Yieldb (%)a
ee (%)
N
iPrO2C
EtO2C
BnO2C
1
2
3
4
5
6
Ph
Ph
Me
Et
Me
Me
Me
Me
1
2
3
4
5
6
96
82
87
95
83
72
95c
94c
88d
99d
94e
36c
1
2
3
4
95
88
72
96
N
CO2i Pr
CO2Et
N
p-MeOC6H4
o-MeOC6H4
o-NO2C6H4
Bn
84
N
N
82
N
CO2Bn
N
tBuO2C
95
N
CO2tBu
a
b
c
Isolated yield after column chromatography.
Ee was determined by chiral phase HPLC analysis.
AD-H column, 10% iPrOH/heptane, 0.8 mL/min, 30 °C.
OD-H column, 2% iPrOH/heptane, 0.9 mL/min, 30 °C.
AS-H column, 5% iPrOH/heptane, 0.9 mL/min, 30 °C.
a
Isolated yield after column chromatography.
Ee was determined by chiral phase HPLC analysis.
b
d
e
azodicarboxylates such as diethyl or dibenzyl (DEAD or DBAD)
afforded the aminated product with slightly lower selectivity. In
contrast, more hindered di-tert-butylazodicarboxylate (DtBAD)
were well tolerated and provided good to excellent results in terms
of reactivities and selectivities (entries 3–5). However, if the phe-
nyl group was replaced by a benzyl group, the product was ob-
tained in 72% yield but the enantioselectivity dropped to 36% ee
(entry 6).
afforded the expected
a-aminoaldehyde with excellent yield
(96%) and selectivity (95% ee).
Various branched aldehydes were tested for this reaction and
the results are listed in Table 3. Switching from 2-phenylpropion-
aldehyde to 2-phenylbutyraldehyde afforded the expected
a
-
Finally, this methodology was applied to the synthesis of a qua-
hydrazino aldehyde in 82% yield and 94% ee (entry 2). Lower yield
and enantioselectivity due to the increasing steric demand were
not observed as reported previously.3b Electron-rich and elec-
tron-deficient aryl groups substituted in ortho- or para-position
ternary
was oxidized under smooth conditions and esterified to provide
the -hydrazino methyl ester 7 in 67% yield over two steps. Boc
protecting groups were removed under acidic conditions and the
a a-hydrazino aldehyde 2
-aminoester (Scheme 1).10 The
a

4432
A. Desmarchelier et al. / Tetrahedron Letters 52 (2011) 4430–4432
Thomassigny, C.; Greck, C. Lett. Org. Chem. 2009, 6, 377–380; (d) Ait-Youcef, R.;
O
O
O
Boc
N
Boc
N
Sbargoud, K.; Moreau, X.; Greck, C. Synlett 2009, 3007–3010; (e) Ait-Youcef, R.;
Moreau, X.; Greck, C. J. Org. Chem. 2009, 75, 5312–5315; (f) Liu, P.-M.; Chang, C.;
Reddy, R.-J.; Ting, Y.-F.; Kuan, H.-H.; Chen, K. Eur. J. Org. Chem. 2010, 5705–
5713.
a
b
NH2
Ph
MeO
H
NHBoc
MeO
NHBoc
Ph
Ph
8
2
7
3. (a) Vogt, H.; Vanderheiden, S.; Bräse, S. Chem. Commun. 2003, 2448–2449; (b)
Baumann, T.; Vogt, H.; Bräse, S. Eur. J. Org. Chem. 2007, 266–282; (c) Baumann,
T.; Bächle, M.; Hartmann, C.; Bräse, S. Eur. J. Org. Chem. 2008, 2207–2212;
During the preparation of this manuscript, two publications have appeared: (d)
Liu, C.; Zhu, Q.; Huang, K.-W.; Lu, Y. Org. Lett. 2011, 12, 2638–2641; (e) Fu, J.-Y.;
Yang, Q.-C.; Wang, Q.-L.; Ming, J.-N.; Wang, F.-Y.; Xu, X.-Y.; Wang, L.-X. J. Org.
Chem. 2011, 76, 4661–4664.
Scheme 1. Reagents and conditions: (a) (i) KH2PO4, NaClO2, H2O2, MeOH/MeCN/
H2O (1/1/1), 0 °C to rt, 2 h; (ii) TMSCHN2, MeOH, rt, 0.5 h, 67% (over two steps); (b)
(i) TFA, DCM, 0 °C to rt, 3 h; (ii) H2, Ni-Raney, MeOH, rt, 48 h, 76% (over two steps).
4. Chowdari, N. S.; Barbas, C. F., III Org. Lett. 2005, 7, 867–870.
5. Suri, J. T.; Steiner, D. D.; Barbas, C. F., III Org. Lett. 2005, 7, 3885–3888.
6. Fu, J.-Y.; Xu, X.-Y.; Li, Y.-C.; Huang, Q.-C.; Wang, L.-X. Org. Biomol. Chem. 2010, 8,
4524–4526.
7. Galzerano, P.; Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew.
Chem., Int. Ed. 2009, 48, 7892–7894.
hydrazine bond was hydrogenated in the presence of Ni-Raney to
afford (S)-ethyl phenylglycine methyl ester 811 in 76% yield over
two steps.
In summary, we have developed an organocatalytic
tion of -disubstituted aldehydes promoted by 9-amino-(9-
deoxy)-epi-quinine. -Hydrazino aldehydes bearing a tetrasubsti-
a-amina-
a,a
8. Desmarchelier, A.; Marrot, J.; Moreau, X.; Greck, C. Org. Biomol. Chem. 2011, 9,
994–997.
a
9. General procedure for the organocatalytic
a-amination: aldehyde (0.6 mmol),
tuted stereocenter were obtained in good to excellent yields and
enantioselectivities. This methodology was successfully applied
to the synthesis of a quaternary a-aminoester.
azodicarboxylate (0.5 mmol), primary amine catalyst (5 mol %), TFA (15 mol %)
in CHCl3 (1 mL) were stirred at room temperature until the completion of the
reaction (monitored by TLC). Solvent was removed in vacuo and the residue
was purified by flash chromatography (pentane/Et2O) to yield the desired
product.
Acknowledgment
The reaction has been scaled up 10-fold for the synthesis of (S)-ethyl
phenylglycine methyl ester 8 without changes in the procedure.
10. For recent general reviews dealing with syntheses of a,a-dialkyl-a-aminoacids,
The authors thank the Ministère de la Recherche for a Grant to
A.D.
see: (a) Soloshonok, V. A.; Sorochinsky, A. E. Synthesis 2010, 2319–2344; (b)
Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2007, 18, 569–
623; (c) Vogt, H.; Bräse, S. Org. Biomol. Chem. 2007, 5, 406–430.
11. Garbarino, J. A.; Sierra, J.; Tapia, R. J. Chem. Soc., Perkin Trans. 1 1973, 1866–
1869
References and notes
Compound 8: ½a 2D5
ꢀ
+13,0 (c 1; CH2Cl2); 1H NMR (300 MHz, CDCl3) d: 7.48–7.53
(m, 2H), 7.25–7.38 (m, 3H), 3.72 (s, 3H), 2.15-2.27 (m, 3H), 1.99–2.11 (m, 1H),
1. (a) Vilaivan, T.; Bhanthumnavin, W. Molecules 2010, 15, 917–958; (b) Greck, C.;
Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem. 2004, 1377–1385.
2. For seminal reports, see: (a) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang,
W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790–1793; (b) List, B. J. Am.
Chem. Soc. 2002, 124, 5656–5657; (c) Ait-Youcef, R.; Kalch, D.; Moreau, X.;
0.90 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d: 176.2, 143.0, 128.5, 127.5,
125.6, 64.3, 52.6, 32.8, 8.5; IR
HRMS. Anal. calcd for C11H16NO2 [M+H+]: 194.1181. Found: 194.1184.
t
(cmꢁ1): 3385, 3317, 2952, 1731, 1447, 1228;