Enantioselective aza-Henry reactions of cyclic α-carbonyl ketimines under bifunctional catalysis

Article abstract of DOI:10.1039/c2cc34053d

The aza-Henry reaction of nitroalkanes with the C=N group of 2-aryl-3H-indol-3-ones catalyzed by thiourea-chincona derivatives takes place with good yield and high ee's. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc34053d

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COMMUNICATION
Enantioselective aza-Henry reactions of cyclic a-carbonyl ketimines
under bifunctional catalysisw
Alejandro Parra, Ricardo Alfaro, Leyre Marzo, Alberto Moreno-Carrasco,
´
´ ´
´
Jose Luis Garcıa Ruano and Jose Aleman*
Received 6th June 2012, Accepted 7th August 2012
DOI: 10.1039/c2cc34053d
Q
The aza-Henry reaction of nitroalkanes with the C N group of
2-aryl-3H-indol-3-ones catalyzed by thiourea-chincona derivatives
takes place with good yield and high ee’s.
The aza-Henry reaction1 represents one the most useful and
efficient methodologies for preparing chiral amines. Moreover,
the resulting nitroamines can be used as intermediates for the
synthesis of 1,2-diamines2 and other moieties present in important
pharmaceutical and biological products.3 Therefore, a number of
new approaches towards the catalytic asymmetric aza-Henry
reaction have been reported over the last decade. Excellent results
have been described in the seminal works of Shibasaki et al.4 and
Jørgensen et al.5 using aldimines as electrophiles,6 which were
further improved by other authors working with metal catalysts6a,b
and also with aldimines under bifunctional catalysis.6c–g However,
the reactions with the less reactive ketimines, which give access to
the more challenging t-alkyl amines,7 are much less satisfactory
and, to our knowledge, only two examples involving catalytic
asymmetric aza-Henry reactions of ketimines have been reported.
Feng et al. described the reactions of sulfonylketimines catalyzed
by chiral N,N0-dioxide-copper(I) complexes, with moderate to
excellent enantioselectivity, but rather low yields (eqn (a),
Scheme 1),8 whereas, more recently, Wang et al.9 reported the
first organocatalytic protocol for performing the addition of
nitroalkanes to highly reactive trifluoromethyl ketimines under
thiourea catalysis (eqn (b), Scheme 1). Unfortunately, this method
could not be extended beyond trifluoromethyl ketimines to other
less reactive derivatives. These precedents indicate that the cata-
lytic enantioselective aza-Henry reaction remains unsolved.
Indol-3-ones bearing a chiral quaternary center at the
2-position are important skeletons because they are present in
the structure of several natural products, such as pseudoindoxyl
alkaloids (Fig. 1), and in pharmaceutical agents.10 They have also
been used as intermediates in the synthesis of natural products
such as hinckdentine A11 (Fig. 1). Consequently, the search for
Scheme 1 Two different approaches for the aza-Henry reaction with
ketimines and the present work.
Fig. 1 Natural products with 2,2-disubstituted indolin-3-one moieties.
new protocols for the enantioselective synthesis of these indol-
3-ones is also important.12 At this point, we reasoned that the
addition of nitroalkanes to indolone derivatives (eqn (c),
Scheme 1) could be interesting as an example of aza-Henry
reactions of ketimines to provide 2,2-disubstituted indol-3-ones.
In this work we present the results obtained in the addition of
nitroalkanes to 2-aryl-3H-indol-3-ones under bifunctional cata-
lysis for obtaining enantiomerically enriched indolin-3-ones
bearing a chiral quaternary centre at the 2-position.
As the main problem observed in the use of ketimines as
electrophiles derives from the low reactivity of the CQN, we
chose the indolone derivatives shown in Scheme 1 as our
substrates because of the double activation conferred by the
carbonyl group on the CQN. These two groups are connected
and coplanar, thus maximizing their mutual electronic influ-
ences (I and M effects). On the other hand, bifunctional
catalysis was chosen to simultaneously govern the approach
of the reagent to the planar substrate. However, the pre-
sence of two electrophilic functional groups in the same ring
Departamento de Quı´mica Orga´nica (Mo´dulo 1),
´
Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco,
28049-Madrid, Spain. E-mail: jose.aleman@uam.es
w Electronic supplementary information (ESI) available: Experimental
procedure for synthesis of compounds 3 and X-ray data of compound
3g. CCDC 884937. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc34053d
c
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Table 1 Screening of various reaction conditionsa
gave poor conversion (entry 6). The best results were achieved
with catalyst 4e, derived from hydroquinine-thiourea (entry 5),
which provided complete conversion in 48 h at rt (er = 92 : 8).
Stereoselectivity was not improved by decreasing the reaction
temperature (entries 10 and 11) nor by increasing the solvent
concentration (entry 12). Finally, we studied the influence of
solvent (entries 13–20), obtaining the best results, full conver-
sion and 95 : 5 er with p-xylene (entry 15). Unfortunately, the
reaction with the pseudo-enantiomer catalyst 4f gave only poor
conversion (entry 21).
With these optimized conditions in hand, we then tested the
scope of this reaction (Table 2). When the reaction was scaled
up to 1.0 mmol, neither the yields nor the stereoselectivities
were significantly affected (compare entries 1 and 2). The study of
a variety of 2-aryl-3H-indol-3-ones revealed that this reaction was
similarly efficient for aryl residues containing electron-donating
and electron-withdrawing groups (entries 3–8). The 2-naphthyl
(1h) (entry 9) and the biphenyl derivatives (1i) were also tolerated,
though the latter group gave worse conversion (entry 10). A
Boc-protected indol (1j) is also compatible, providing 3j with
good yield and moderate enantioselectivity (entry 11).
Cat
Entry (10 mol%) Solvent
Conversion
T (1C) (%)
er
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
DABCO
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Toluene
p-Xylene
p-Xylene/DCMd
o-Xylene
C6F6
TBME
DCE
p-Xylene
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
0
60
>99
70
>99
>99
30
10
50
10
40
23 : 77
90 : 10
21 : 79
89 : 11
92 : 8
—
Next, we focused our attention on nitroderivatives different
to nitromethane (Scheme 2), yielding compounds with two
chiral centers. Reactivity of nitroethane was similar, affording
a 3:1 diastereomeric mixture 3k/3k0, presumably differing in the
configuration at the carbon joined to the nitrogen, with both
epimers exhibiting er values similar to that observed in the
examples shown in Table 2. As a control experiment, the major
24 : 76
87 : 13
25 : 75
91 : 9
90 : 10
89 : 11
77 : 23
92 : 8
95 : 5
90 : 10
92 : 8
67 : 33
82 : 18
92 : 8
—
6
7
9
10
11
12b
13
14
15
16c
17c
18c
19c
20c
21
4e
4e
4e
4e
4e
4e
4e
4e
4e
4e
4e
4f
ꢀ20
Rt
Rt
Rt
Rt
0
10
>99
10
>99
>99
20
Table 2 Scope of various 2-aryl-3H-indol-3-onesa
Rt
Rt
Rt
Rt
Rt
15
15
20
60
Entry
R
Product
Yield (%)
er
o5
1
Ph-1a
Ph-1a
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
90
85
93
93
95
93
81
81
95 : 5
93 : 7
91 : 9
92 : 8
85 : 15
91 : 9
93 : 7
98 : 2
92 : 8
92 : 8
a
All the reactions were performed on a 0.064 mmol scale in 0.24 mL
b
of the indicated solvent and 10 equiv. of nitromethane. A 1.0 M
2b
3
p-Me–C6H4-1b
p-Et–C6H4-1c
p-MeO–C6H4-1d
p-F–C6H4-1e
p-Cl–C6H4-1f
o-Br–C6H4-1g
2-Naphthyl-1h
p-C6H4-Ph-1i
c
d
concentration was used. 24 h reaction time. A 5 : 1 mixture was
used.
4
5
6
7
8
9
10
could generate chemoselectivity problems (CQN13 versus
CQO14 addition).
>99
37
The addition of nitromethane 2a to 2-phenyl-3H-indol-3-one
1a was used as a model reaction for optimization (Table 1). A
series of thioureas15 and squaramides16 (entries 1–9) were tested
at different temperatures (10–12) and solvents (13–20). The use
of the alkaloid thiourea 4a in CH2Cl2 at rt gave 3a as the only
product in 60% conversion after 48 h, indicating a completely
chemoselective reaction (attack on the CQO was not detected
in the reaction mixture). However, 3a was obtained in a rather
low enantiomeric ratio (23 : 77, entry 1, Table 1). Using 4b,
higher conversion (>99%) and better er (90 : 10) were
obtained (entry 2, Table 1). Thioureas 4c–d (entries 3 and 4,
Table 1) and Takemoto’s catalyst 6 (entry 8, Table 1) showed
lower enantiomeric ratios, and squaramides, 5 (entry 7, Table 1)
and 7 (entry 9, Table 1), decreased the conversion to 10% (no
catalytic activity). The monofunctional catalyst DABCO also
11
3j
52
80 : 20
a
All reactions were performed on a 0.2 mmol scale in 0.72 mL of dry
b
p-xylene using 10 equiv. of nitromethane. Reaction was carried out
on a 1.0 mmol scale.
Scheme 2 Reaction with nitroethane.
c
9760 Chem. Commun., 2012, 48, 9759–9761
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J. A. thanks the MICINN for a ‘‘Ramon y Cajal’’ contract.
R. A. and L. M. thank ‘‘CONACYT’’ for a postdoctoral
fellowship and ‘‘Ministerio de Educacion y Ciencia’’ for a
FPU fellowship, respectively.
Notes and references
1 For a recent review, see: E. Marques-Lopez, P. Merino, T. Tejero
and R. P. Herrera, Eur. J. Org. Chem., 2009, 2401.
2 For a review, see: D. Lucet, T. Le Gall and C. Mioskowski, Angew.
Chem., Int. Ed., 1998, 37, 2580.
3 N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH,
New York, 2001.
4 (a) K. Yamada, S. J. Harwood, H. Groger and M. Shibasaki,
Angew. Chem., Int. Ed., 1999, 38, 3504; (b) K. Yamada, G. Moll
and M. Shibasaki, Synlett, 2001, 980; (c) N. Tsuritani, K. Yamada,
N. Yoshikawa and M. Shibasaki, Chem. Lett., 2002, 276;
(d) S. Handa, V. Gnanadesikan, S. Matsunaga and M. Shibasaki,
J. Am. Chem. Soc., 2007, 129, 4900; (e) Z. Chen, H. Morimoto,
S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2008,
130, 2170.
Scheme 3 Stereochemical proposal.
5 (a) K. R. Knudsen, T. Risgaard, N. Nishiwaki, K. V. Gothelf and
K. A. Jørgensen, J. Am. Chem. Soc., 2001, 123, 5843;
(b) N. Nishiwaki, K. R. Knudsen, K. V. Gothelf and K. A.
Jørgensen, Angew. Chem., Int. Ed., 2001, 40, 2992; (c) K. R.
Knudsen and K. A. Jørgensen, Org. Biomol. Chem., 2005, 3, 1362.
6 (a) For selected examples, see: B. M. Trost and D. W. Lupton, Org.
Lett., 2007, 9, 2023(b) H. Zhou, D. Peng, B. Qin, Z. R. Hou,
X. H. Liu and X. M. Feng, J. Org. Chem., 2007, 72, 10302; (c) For
leading references in organocatalytic aza-Henry reaction with
aldimines, see: T. Okino, S. Nakamura, T. Furukawa and
Y. Takemoto, Org. Lett., 2004, 6, 625(d) B. M. Nugent,
R. A. Yoder and J. N. Johnston, J. Am. Chem. Soc., 2004,
126, 3128; (e) T. Yoon and E. N. Jacobsen, Angew. Chem.,
Int. Ed., 2005, 44, 466; (f) L. Bernardi, F. Fini, R. P. Herrera,
A. Ricci and V. Sgarzani, Tetrahedron, 2006, 375; (g) C. M. Bode,
A. Ting and S. E. Schaus, Tetrahedron, 2006, 11499.
diastereoisomer 3k was placed under the same reaction condi-
tions with catalyst 4e (10 mol%). A mixture of diastereoisomers
3k/3k0 (3 : 1) was obtained, indicating the easy epimerization of
the obtained product by the basic catalyst.
We were able to obtain proper crystals for X-ray analysis in
the case of compound 3g,w which allowed us to unequivocally
assign its absolute configuration as S (see ESIw). This assign-
ment was then used for the remainder of the compounds 3
depicted in Table 2. The stereochemical proposal is outlined in
Scheme 3. The carbonyl oxygen at the 2-aryl-3H-indol-3-one 1
can be doubly associated to the thiourea catalyst 4e through
hydrogen bonds. Simultaneously, the nitronate (generated by
deprotonation of nitromethane at the quinuclidine core) will
also be associated to the catalyst. Starting from this preorganized
superstructure, the nucleophilic attack can take place on the pro-S
(approach I) and the pro-R (approach II) faces of the associated
indoline 1, respectively, yielding isomers 3 and 30 (Scheme 3). The
stronger stereoelectronic interactions of the nitronate with the
indoline in approach II (nitronate is over the indolone system
which is not in approach I) would explain the observed enantio-
selectivity, with enantiomers 3 being predominant in reactions
with nitromethane. A similar situation is observed in reactions
with nitroethane, yielding a mixture of diastereoisomers (the
a-proton with respect to the NO2 group is easily epimerizable),
with both exhibiting similar er values to that observed in Table 2.
The Newman projection for approach I (bottom, Scheme 3)
suggests that its stability would not be strongly affected when
R is not hydrogen (as with R = Me and R0 = H, see Scheme 2),
thus maintaining a similar enantioselectivity to nitromethane.
However, the stability of I would be substantially decreased
when R0 is not hydrogen. In order to confirm this hypothesis, we
carried out the reaction of the indolone 1 with 2-nitropropane
(R = R0 = Me) (bottom, Scheme 3). Interestingly, the reaction
gave the expected product 3l, but the enantioselectivity was
strongly decreased (12% ee). The reversibility of this reaction
was proved by isolation of 3l and was placed with catalyst 4e
and nitromethane. Non incorporation of nitromethane or
alteration of product 3l was detected, indicating that reversi-
bility under these conditions cannot occur.
7 For
a review of chiral quaternary centers, see: Bella and
T. Gasperi, Synthesis, 2009, 1583 and references cited therein.
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Chem., Int. Ed., 2011, 50, 11773.
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E. Kobajashi, K. Gomi and H. Saito, Bioorg. Med. Chem. Lett.,
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11 (a) A. J. Blackman, T. W. Hambly, K. Picker, W. C. Taylor and
N. Thirasasana, Tetrahedron Lett., 1987, 28, 5561. For synthesis of
8-desbromohinckentine A, see: (b) Y. Liu and W. W. McWhorter
Jr, J. Am. Chem. Soc., 2003, 125, 4240 and references cited therein.
12 (a) For other approaches to the synthesis of quaternary centers of
indolone derivatives, for racemic versions, see: A. Wetzel and
F. Gagosz, Angew. Chem., Int. Ed., 2011, 50, 7354(b) J.-M. Adam
and T. Winkler, Helv. Chim. Acta, 1984, 67, 2186; (c) K.-Q. Ling,
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versions, see; (e) M. Rueping, S. Raja and A. Nunez, Adv. Synth.
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Synlett, 2011, 1727; (g) Q. Yin and S.-L. You, Chem. Sci., 2011,
3, 1344.
13 (a) C. Berti, L. Greci and L. Marchetti, J. Chem. Soc., Perkin
Trans. 2, 1979, 233; (b) G. Tommasi, P. Bruni, L. Greci,
P. Sgarabotto and L. Righi, J. Chem. Soc., Perkin Trans. 1,
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L. Marchetti, Gazz. Chim. Ital., 1975, 105, 993.
14 For a competitive reaction with Grignard reagents in the CQN
and CQO addition, see: Y. Liu and W. W. McWhorter, J. Org.
Chem., 2003, 68, 2618.
15 (a) M. S. Taylor and E. N. Jacobsen, Angew. Chem., Int. Ed., 2006,
45, 1520; (b) T. Akiyama, Chem. Rev., 2007, 107, 5744.
16 (a) J. Aleman, A. Parra, H. Jiang and K. A. Jørgensen, Chem.–Eur. J.,
2011, 17, 6890; (b) R. Ian Storer, C. Aciro and L. H. Jones, Chem. Soc.
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Financial support from Spanish Government (CTQ-2009-12168)
and CAM (CS2009/PPQ-1634) is gratefully acknowledged.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9759–9761 9761