A facile direct anti-selective catalytic asymmetric Mannich reaction of aldehydes with preformed N-Boc and N-Cbz imines

Article abstract of DOI:10.1039/c0cc05249c

Anti-selective Mannich reactions of N-Boc and N-Cbz protected imines with unmodified aldehydes proceeded smoothly under the catalysis of a secondary amine-thiourea catalyst, which led to high yields (70%-95%) and excellent enantioselectivity (up to 964 dr

Full text of DOI:10.1039/c0cc05249c

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COMMUNICATION
A facile direct anti-selective catalytic asymmetric Mannich reaction of
aldehydes with preformed N-Boc and N-Cbz iminesw
Yong-Ming Chuan,ab Gui-Hua Chen,ab Jiu-Zhi Gao,a Hui Zhanga and Yun-Gui Peng*a
Received 29th November 2010, Accepted 12th January 2011
DOI: 10.1039/c0cc05249c
Anti-selective Mannich reactions of N-Boc and N-Cbz protected
imines with unmodified aldehydes proceeded smoothly under the
catalysis of a secondary amine–thiourea catalyst, which led to high
yields (70%–95%) and excellent enantioselectivity (up to 96 : 4 dr
and >99% ee) under conventional organic synthetic operations.
by other groups.4f–h However, the work was mainly focused on
syn-fashion reactions, progress in the anti-Mannich reactions
of N-Boc or N-Cbz protected imines is very limited. To the best
of our knowledge, only two groups have reported in this area.
Maruoka’s group have identified an axially chiral bifunctional
amino sulfonamide as an effective catalyst for the direct
anti-Mannich reaction of aldehyde to N-Boc imine. However,
the reaction required controlled addition of the N-Boc imine
with the assistance of a syringe pump to prevent from deactiva-
tion of the catalyst by higher concentration of the N-Boc
imine;5a,b Melchiorre’s group have found that diaryl prolinol
silyl ether was also effective for the catalysis of anti-Mannich
reaction of aldehydes with in situ generated N-Boc and N-Cbz
imines. But, the reactivity is rather sensitive to the steric
hindrance of the aldehyde. When only slightly more-encumbered
isovaleraldehyde was used as the nucleophile substrate, reaction
time up to 65 h was needed. Thus the sensitivity to steric
hindrance has lowered the synthetic utility of this catalytic
system.5c,d Therefore, from the synthetic standpoint of practical
application of anti-selective Mannich reactions of N-Boc and
N-Cbz imines, development of highly effective catalytic systems,
in particular, those that are compatible with diverse substrates,
and that are free from deactivation of catalysts is still in demand.
Interested in developing efficiently and broadly useful chiral
organocatalysts for asymmetric synthesis, we have designed
and synthesized a pool of catalysts 1a–2c based on the
pyrrolidine scaffold. Those catalysts bear various H-bond
donor groups at the 4-position to activate electrophiles and
a cooperative stereocontrol silyl ether group at the a-position
of the pyrrolidine nitrogen atom (Scheme 1). The catalysts
1a–1c, 2a and 2b have been shown excellent performance in
the anti-selective Mannich reaction of aldehydes and ketones
to N-PMP iminoglyoxylates3j and the asymmetric Michael
Tremendous efforts have been devoted to the development of
new and effective methodologies of direct diastereo- and
enantioselective organocatalytic Mannich reactions in the last
decade.1 So far, great success has been achieved for both syn-2
and anti-3selective variants of direct Mannich reactions of
ketones and aldehydes with preformed (or made in situ)
N-PMP-protected a-imino esters. Good results have also been
obtained for the syn-selective4 and a limited number of reports
were documented for anti-selective variants5 of Mannich
reactions when aldimines (preformed or made in situ) were
used as electrophile substrates.
Protective groups on the amine of the amino carbonyl
compounds are crucial to the further synthetic utility of the
Mannich products. Although p-methoxyphenyl group is the
most commonly used protective group in the aldimine forma-
tion, the removal of such a protective group in the resulting
Mannich products often requires drastic oxidative conditions,
and thus have limited the synthetic potential and the scope of
the direct asymmetric catalytic Mannich reaction. Benzyloxy-
carbonyl (Cbz-) and tert-butoxycarbonyl (Boc-) have often
been used as an orthogonal N-protecting group in organic
synthesis due to the property of easy removability under mild
conditions. Accordingly, the use of N-Boc or N-Cbz protected
imine as an electrophile in the direct Mannich reaction has
spurred particular interest. Enders et al. has first introduced
N-Boc imine into the syn-Mannich reaction4a,b and an impor-
tant advance was achieved by List et al. who used preformed
aromatic N-Boc imines in proline-catalyzed Mannich reactions
of aldehydes.4c–e Such a reaction protocol was also established
a School of Chemistry and Chemical Engineering, Southwest
University, Chongqing, 400715, P.R. China.
E-mail: pyg@swu.edu.cn; Fax: +86 23-6825-3157
b Chengdu Institute of Organic Chemistry, Chinese Academy of
Sciences (CAS), Chengdu, 610041, P.R. China
w Electronic supplementary information (ESI) available: Catalysts
synthesis, spectroscopic data, enantioselectivities measurement, and
absolute configuration determinations for 5c. See DOI: 10.1039/
c0cc05249c
Scheme 1 Designed and synthesized pyrrolidine-based catalysts.
c
3260 Chem. Commun., 2011, 47, 3260–3262
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addition reactions of ketones and aldehydes to nitroolefins.6
Inspired by these results, we further evaluated our organo-
catalyst pool in the direct Mannich reactions of unmodified
aldehydes to N-Boc and N-Cbz imines. Herein we report the
results.
thiourea group at the 4-position was replaced by sulfonamides
(2a–2c), high reactivities were observed, but both the diastereo-
selectivities and enantioselectivities decreased (Table 1,
entries 7–9). All of the results indicated that the catalytic
performance of 1c was the best.
The reaction of isovaleraldehyde 3a with anisaldehyde
N-Boc imine 4a was selected as the model to evaluate the
efficiency of the catalysts 1a–2c. As shown in Table 1, the
reaction proceeded smoothly, giving moderate to excellent
yields and diastereoselectivities. However, all the reactions
gave excellent enantioselectivities (Table 1, entries 1–9). Both
H-bond donating ability of the group at the 4-position and the
steric hindrance of the a-substituent of the pyrrolidine have
great influence on the reactivities and diastereoselectivities.
The H-bond donating ability is closely related to acidity of
the thiourea or sulfonamide group, and is governed by the
electronic nature of the R1 and R3 substituents. Comparison
of the results obtained from the thiourea catalysis of 1a–1c,
which contains the same a-substituent (–CH2OTBDPS), we
can see that the catalytic performance of 1c is superior to that
of 1a and 1b (Table 1, entries 1–3). This maybe ascribed to the
two strong electron-withdrawing-CF3 groups on the phenyl
ring in 1c, which led to stronger acidity and thus H-bond
donating ability than that of 1a and 1b. In 1a, the electron-
donating –OMe group has made the resulting catalyst the
weakest H-bond donating ability among 1a to 1c, thus gave
the poorest results. When the a-substituent was changed from
–CH2OTBDPS into –CH2OTES (1d), –CH2OTBS (1e) and
–CH2OTPS (1f), the reactivities and diastereoselectivities
decreased to different extents, however, enantioselectivities
remained almost unchanged (Table 1, entries 4–6). When the
Among the examined solvents (Table 1, entries 3, 10–17),
CH2Cl2 and CHCl3 exhibit slightly better reactivity and
diastereoselectivity, giving 96% yield and 92 : 8 dr, and 94%
yield and 92 : 8 dr, respectively. In both cases, >99% ee was
achieved (Table 1, entries 3 and 10). When catalyst load was
5 mol% and the reaction temperature was 0 1C, the diastereo-
selectivity in CHCl3 is slightly better than that in CH2Cl2.
Thus CHCl3 was the preferred solvent. The reaction went
smoothly with the catalyst load of equal to or higher than
5 mol% (Table 1, entries 10 and 17). When the catalyst load
was lower than 5 mol%, a decrease in diastereoselectivity was
observed such as in the case of 1c (Table 1, entry 18), in which
85 : 15 dr was obtained with 3 mol% catalyst.
The scope of the anti-selective Mannich reaction was
investigated (Table 2). N-Boc and N-Cbz imines gave the
Table 2 Generality and scope of the anti-selective Mannich reactiona
Yieldb drc
Entry Product
t/h (%)
anti : syn eec (%)
i
5a: R4 = Pr, R5 = H;
1
5.5 94
95 : 5
>99
PG = Boc, R6 = 4-CH3OC6H4
5b: R4 = Pr, R5 = H;
i
2
6
93
90 : 10 >99
90 : 10 >99
PG = Boc, R6 = 4-CH3C6H4
5c: R4 = Pr, R5 = H;
i
3
23 91
24 92
28 84
Table 1 Screening the catalysts and optimizing the reaction conditionsa
PG = Boc, R6 = Ph
5d: R4 = Pr, R5 = H;
i
4
90 : 10
95 : 5
92 : 8
91 : 9
91 : 9
98
98
PG = Boc, R6 = 4-FC6H4
5e: R4 = Pr, R5 = H;
i
5
PG = Boc, R6 = 4-ClC6H4
5f: R4 = Pr, R5 = H;
i
6
7
81
>99
>99
>99
PG = Boc, R6 = 2-naphthyl
5g: R4 = Pr, R5 = H;
i
7
8.5 89
Entry Cat. Solvent t/h Yieldb (%) drc anti : syn eec (%)
PG = Boc, R6 = 2-furyl
5h: R4 = Me, R5 = H;
8d
9d
2
3
5
88
94
84
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
2a
2b
2c
1c
1c
1c
1c
1c
1c
1c
1c
1c
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
8
6
8
8
8
71
85
96
40
85
95
73 : 27
84 : 16
92 : 8
56 : 44
80 : 20
88 : 12
82 : 18
89 : 11
83 : 17
92 : 8
90 : 10
84 : 16
90 : 10
83 : 17
84 : 16
93 : 7
>97/10
>98/26
>99
>99/76
98
PG = Boc, R6 = 4-CH3OC6H4
5i: R4 = Et, R5 = H;
PG = Boc, R6 = 4-CH3OC6H4
90 : 10 >99
89 : 11 >99
10d 5j: R4 = Bu, R5 = H;
PG = Boc, R6 = 4-CH3OC6H4
5k: R4 = R5 = Me;
99
96
96
98
>99
>99
99
>99
>99
99
11
12
13
14
15
16
17
24 70
10 86
10.5 84
22 88
24 90
24 82
24 95
—
92
>99
>99
>99
>99
>99
>99
CH2Cl2 4.5 81
PG = Boc, R6 = 4-CH3OC6H4
5l: R4 = Pr, R5 = H;
i
CH2Cl2
CH2Cl2
CHCl3
DCE
1
8
7
8
8
8
8
8
84
80
94
88
96
95
87
96
95 : 5
93 : 7
95 : 5
94 : 6
96 : 4
95 : 5
9
PG = Cbz, R6 = 4-CH3OC6H4
5m: R4 = Pr, R5 = H;
i
10
11
12
13
14
15
16d
17d
18e
PG = Cbz, R6 = 4-CH3C6H4
5n: R4 = Pr, R5 = H;
i
CCl4
Toluene
THF
TBME
CH2Cl2 5.5 96
CHCl3
CHCl3
PG = Cbz, R6 = Ph
5o: R4 = Pr, R5 = H;
i
PG = Cbz, R6 = 4-ClC6H4
5p: R4 = Pr, R5 = H;
i
>99
>99
>99/24
5.5 94
93
95 : 5
85 : 15
PG = Cbz, R6 = 4-BrC6H4
5q: R4 = Pr, R5 = H;
PG = COOEt, R6 = Ph
i
7
a
Reaction conditions: 3a (0.2 mmol, 1 equiv.), 4a (1 mmol, 5 eqiuv.),
b
a
Reaction conditions: 3 (0.2 mmol, 1 equiv.), 4 (1 mmol, 5 eqiuv.), 1c
b
10 mol% catalyst (0.02 mmol) in 1 mL DCM at 10 1C. Isolated
yield. Determined by chiral HPLC. With 1c (0.01 mmol, 5 mol%)
c
d
(0.01 mmol, 5 mol%) in 1 mL CHCl3 at 0 1C. Isolated yield.
c
d
e
Detemined by chiral HPLC. Reaction proceeded at À20 1C.
at 0 1C. With 1c (0.006 mmol, 3 mol%) at 0 1C.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3260–3262 3261

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Scheme 2 Proposed transition state model of 1c-catalyzed anti-
Mannich reaction.
anti-Mannich products with high yields (81–95%), good
diastereoselectivity (90 : 10–96 : 4 dr), and excellent enantio-
selectivity (98%–>99% ee) at 0 1C under conventional
organic synthetic operations (Table 2, entries 1–7, 12–16).
Linear aldehydes gave high yields and excellent ee (Table 2,
entries 8–10). Even hindered 3-methylbutanal reacted
smoothly to afford aminoaldehyde 5k with good enantio-
selectivity (Table 2, entry 11). Interestingly, N-CO2Et imine
also gave excellent results (95% yield, 95 : 5 dr, and >99% ee)
(Table 2, entry 17). Regrettably, 1c could not catalyze the reac-
tion between isovaleraldehyde and cyclohexanecarboxaldehyde
N-Cbz imine, or that between acetone and anisaldehyde
N-Boc imine.
The absolute configuration of N-Boc-protected 5c was
determined to be (1S, 2R) by comparison of the HPLC
retention times with the data reported in the literature.5a,b
To account for the stereochemical outcome, a transition state
model is proposed and shown in Scheme 2. The bulky group
(–CH2OTBDPS) should effectively shield the re-face of an
enamine double bond, and make the si-face available for
attack to give the observed major enantiomer. Both thiourea
protons in the catalyst are believed to bind to the imine
nitrogen through hydrogen bonding interactions and may
serve to activate the imine substrate effectively.
In conclusion, we have identified an efficient catalytic system
for the direct anti-Mannich reaction of unmodified aldehydes
with preformed N-Boc and N-Cbz imines. Only 5 mol%
catalyst loading was enough to give the corresponding products
in excellent yields (up to 95%), diastereoselectivities (up to
96 : 4 dr) and enantioselectivities (up to >99% ee). Further
applications of the present catalysts in other asymmetric trans-
formations are ongoing in our laboratory.
This work was supported by the Natural Science Foun-
dation of China (NSFC 20872120) and the Municipal Science
Foundation of Chongqing City (CSTC, 2009BB5110).
Notes and references
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c
3262 Chem. Commun., 2011, 47, 3260–3262
This journal is The Royal Society of Chemistry 2011