N-heterocyclic carbene-catalyzed homoenolate additions with N-Aryl ketimines as electrophiles: Efficient synthesis of spirocyclic γ-lactam oxindoles

Article abstract of DOI:10.1002/chem.201201375

In pole position: A simple and efficient approach to spirocyclic γ-lactam oxindoles by the N-heterocyclic carbene catalyzed addition of homoenloate equivalents to N-aryl isatinimines has been developed (see scheme). The use of N-aryl isatinimines as electrophiles in the NHC-catalyzed umpolung reaction of α,β-unsaturated aldehydes is demonstrated for the first time. Copyright

Full text of DOI:10.1002/chem.201201375

COMMUNICATION
DOI: 10.1002/chem.201201375
N-Heterocyclic Carbene-Catalyzed Homoenolate Additions with N-Aryl
Ketimines as Electrophiles: Efficient Synthesis of Spirocyclic g-Lactam
Oxindoles
Bo Zhang,[a] Peng Feng,[a] Li-Hui Sun,[c] Yuxin Cui,[a] Song Ye,*[c] and Ning Jiao*[a, b]
The indole unit is a ubiquitous
skeleton in pharmaceuticals and
bioactive natural products.[1]
Among these, spirocyclic oxin-
dole frameworks are present in
a large number of bioactive,
Scheme 1. Retrosynthetic analysis of spirocyclic g-lactam oxindoles.
naturally occurring alkaloids
and medicinally relevant com-
pounds (Figure 1).[2,3] Consequently, numerous synthetic
methods to construct these fascinating architectures have
been established.[2,3] Alternatively, the spirocyclic g-lactam
oxindoles could be simply constructed by the N-heterocyclic
carbene catalyzed conjugate umpolung reaction of a,b-unsa-
turated aldehydes with isatinimines as electrophiles
(Scheme 1).
Over the past few years, there has been significant growth
in the field of N-heterocyclic carbene (NHC) catalysis due
to the unique umpolung ability of these compounds, which
provides unconventional access to various target mole-
cules.[4] The classic NHC-catalyzed a1–d1 umpolung reactions
of aldehydes,[5] such as the benzoin condensation and the
Stetter reaction, are generally thought to proceed via nucle-
ophilic Breslow intermediates, which are generated by the
addition of NHCs to aldehydes.[6,7] In recent years, umpo-
lung reactions involving the use of enals have been reported
independently by the groups of Glorius[8] and Bode.[9] Since
then, a number of electrophiles for the synthesis of g-butyro-
lactones have been found to be suitable acceptors for the
homoenolate species, including aldehydes and ketones.[10,11]
In contrast, the use of imines as electrophiles for the synthe-
sis of g-butyrolactams is limited and challenging; this is pos-
sibly due to decomposition of the imine and the potential
reaction between NHC catalysts and imines leading to
stable adducts that inhibit this catalytic reaction.[12] More re-
cently, Bodeꢀs and Scheidtꢀs groups have made significant
progress towards the NHC-catalyzed addition of enals to
imine electrophiles. However, the imine electrophiles are
still limited to aromatic aldehyde-derived N-sulfonyl
imines,[12] azomethine imines,[13] and N-phenyl nitrones.[14] N-
Alkyl and N-aryl imines are unreactive, leading to lactone
dimers of the starting enals. By using a Brønsted acid as the
cooperative catalyst, Rovis and co-workers demonstrated
the umpolung reaction of enals to N-aryl aldimine electro-
philes.[15] Thus new types of electrophiles are highly desira-
ble and would further widen the versatility of the reaction.
Herein, we describe the first application of N-aryl ketimines
as the electrophiles in NHC-catalyzed homoenolate addi-
tions, which provides a simple and efficient approach to spi-
rocyclic g-lactam oxindoles (Scheme 2).
Figure 1. Examples of synthetic, bioactive compounds containing spirocy-
clic oxindole frameworks. AChE=acetylcholinesterase inhibitor.
[a] B. Zhang, P. Feng, Dr. Y. Cui, Dr. N. Jiao
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences, Peking University
Xue Yuan Rd. 38, Beijing 100191 (P.R. China)
Fax : (+86)10-82805297
E-mail: jiaoning@bjmu.edu.cn
Homepage: http://sklnbd.bjmu.edu.cn/nj
[b] Dr. N. Jiao
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences
Shanghai 200032 (P.R. China)
[c] L.-H. Sun, Dr. S. Ye
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing, 100190 (P.R. China)
Fax : (+86)10-62554449
Considering our interest in the construction and modifica-
tion of the indole structure,[16] we investigated the possibility
for the direct synthesis of a spirocyclic oxindole by the
E-mail: songye@iccas.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201375.
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g-amino acid ester 4aa to a 1m
solution of aqueous HCl in
methanol, the target product
3aa was generated, and its
structure was confirmed by
single-crystal X-ray analysis
(Figure 2). Notably, these two
reaction steps can be performed
in a one-pot process starting
with the enal, making the trans-
Scheme 2. Imines as the electrophiles for homoenolate addition.
formation more convenient.
NHC-catalyzed conjugate umpolung strategy (Scheme 1).
We envisioned that N-aryl isatinimines, which have a differ-
ent reaction activity to ordinary
Encouraged by this result, the reaction conditions for
a one-pot process were optimized (Table 1). The NHCs
N-aryl ketimines,[17] could be
electrophiles for homoenolate
addition. Initially, the reaction
of N-aryl isatinimine 1a with
trans-cinnamaldehyde (2a) in
the presence of imidazolium
salt
A and 1,8-diazabicyclo-
ACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU) in
THF was investigated [Eq. (1),
Bn=benzyl]. Unfortunately, the desired product 3aa was
not detected, and only starting materials were recovered.
We hypothesized that this outcome is a result of the steric
were first screened, and in the presence of imidazolium salt
A (10 mol%) and DBU (20 mol%) the desired product 3aa
was obtained in 80% yield without diastereoselectivity
(Table 1, entry 1). NHC catalysts B–H performed less effec-
tively (Table 1, entries 2–8). Different solvents then were
tested. The results showed that toluene and chlorobenzene
promoted diastereoselectivity (1:4 and 1:8, respectively) but
with low yields (Table 1, en-
À
hindrance of the Ph NH group of the intermediate imidazo-
lium species III (see the mechanism described later), which
can not undergo further intramolecular acylation to gener-
ate the desired spirocyclic g-lactam oxindole product, 3aa.
tries 11 and 12; see also
Table S2, entries 7–8 in the Sup-
porting Information). Subse-
quently, various organic and in-
organic bases were surveyed in
toluene. K2CO3 gave promising
results based on the yield and
diastereoselectivity
(Table 1,
entry 15; see also Table S3,
entry 5 in the Supporting Infor-
mation). After further optimi-
Considering that the use of an appropriate, nucleophilic
co-catalyst for a relay catalysis, such as those employed in
acylation reactions described concurrently by the groups of
Rovis[18] and Bode,[19] may provide a possible route for the
amide bond formation, we next screened various nucleophil-
ic co-catalysts. To our delight, the desired spirocyclic g-
lactam oxindole 3aa was obtained in 12–13% yields by
using imidazole or benzimidazole as the co-catalyst (see the
Supporting Information; Table S1, entries 2 and 3). Other
additives, such as 1-hydroxy-7-azabenzotriazole (HOAt), 1-
hydroxybenzotriazole (HOBt), or 4-dimethylaminopyridine
(DMAP), were ineffective in this reaction (see Table S1, en-
tries 5–7). Interestingly, g-amino acid ester 4aa was obtained
in 83% yield when MeOH (100 mL) was added to the above
reaction [Eq. (2)]. After subsequent exposure of the isolated
zation, including the examination of mixed solvents and the
concentration of the reaction, the best results were obtained
when the reaction was conducted in 4 mL dioxane/toluene
Figure 2. The X-ray crystal structure of 3aa.
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Synthesis of Spirocyclic g-Lactam Oxindoles
COMMUNICATION
Table 1. Optimization of reaction conditions for the NHC-catalyzed,
We then examined the scope of the reaction to-
wards a,b-unsaturated aldehydes (Table 2). Elec-
tron-rich and electron-deficient cinnamaldehydes
performed well in this transformation, leading to
the desired spirocyclic g-lactam oxindoles 3aa–
3ag in good yields (82–88%; Table 2). Moreover,
thiophene- and naphthalene-derived enals under-
went this transformation smoothly to generate the
desired products in moderate yields (3ah: 53%,
and 3ai: 71%, respectively). It is worth noting
that alkenyl- and alkyl-substituted enals were also smoothly
converted into the corresponding products (see examples
3aj and 3ak, Table 2). Furthermore, when acrolein was em-
ployed as the substrate, spirocyclic g-lactam oxindole 3al
was obtained in 35% yield (Table 2).
one-pot synthesis of spirocyclic g-lactam oxindoles.[a]
When the reaction was carried out on a preparative scale
(3.0 mmol), there was no change in yield or diastereoselec-
tivity (81%, d.r. 1:4; see the Supporting Information). For
the further application of these products, the spirocyclic g-
lactam oxindoles, such as 3aa’’, were easily reduced by 9-
Entry Catalyst Solvent
Base
Yield [%][b] d.r.[c]
1
2
A
B
THF
THF
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Et3N
80
25
32
trace
27
1:1
1:1
2:1
–
3
C
THF
borabicycloACTHNUGRTNEUNG[3.3.1]nonane (9-BBN) to afford the correspond-
4
5
D
E
THF
THF
ing spirocyclic oxindole 5 in 54% yield [Eq. (3)].[20] This spi-
rocyclic oxindole scaffold is present in many synthetic com-
pounds exhibiting important biological activities.[3d–i]
1:1
1:1
1:1
1:1
1:2
1:2
1:4
1:8
1:5
1:5
1:4
1:4
1:4[d]
1:3
6
F
THF
16
6
10
20
67
54
19
20
15
64
54
78
7
8
9
G
H
A
A
A
A
A
A
A
A
A
A
THF
THF
CH2Cl2
dioxane
toluene
C6H5Cl
toluene
toluene
toluene
toluene
10
11
12
13
14
15
16
17
18
iPr2NEt
K2CO3
Cs2CO3
dioxane/toluene (1:1) K2CO3
dioxane/C6H5Cl (1:1) K2CO3
70
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst
(0.02 mmol), base (0.04 mmol), and MeOH (100 mL) were dissolved in
the solvent (4.0 mL) and stirred under Ar at RT for 24 h. Then MeOH
(2.0 mL) and 1m HCl (2.0 mL) were added and the reaction was stirred
at 658C for an additional 24 h. [b] Isolated yields. [c] The d.r. was deter-
mined by 1HNMR analysis of the crude products (d.r. 3aa’/3aa’’).
[d] Structure was determined by X-ray crystal-structure analysis.
An enantioselective variant of this methodology would be
useful, but highlights the established challenges of asymmet-
ric addition to N-aryl ketimines. A range of chiral NHC cat-
alysts were investigated for the asymmetric reaction
(Table 3, see also the Supporting Information). The results
show that I2 is an effective catalyst for this asymmetric
transformation, giving 3aa in 80% yield with 1:6 d.r. (3aa’/
3aa’’), and 3aa’’ with an enantiomeric ratio of 87:13 (e.r.;
Table 3, entry 2). Moreover, the opposite enantioselectivity
(e.r.) could be induced by catalyst J1 (e.r. 14:86, Table 3,
entry 6). Significantly, the e.r. values were improved to 99:1
and 2.5:97.5, respectively, by fast recrystallization with ace-
tone–hexane. Importantly, the use of catalyst K dramatically
improved the diastereoselectivity (Table 3, entries 8 and 9).
A plausible mechanism for this reaction is illustrated in
Scheme 3.[9–11] An NHC is generated by the deprotonation
of an imidazolium salt in the presence of K2CO3. Addition
of the NHC to a,b-unsaturated aldehydes 2 affords the Bre-
slow intermediates I after addition and rearrangement,
which serve as homoenolate equivalents. The homoenolate
intermediates I attack the electrophilic N-aryl isatinimines
1 to produce the intermediates II. Tautomerization of the in-
termediates II generate the intermediates III. Subsequently,
(1:1; Table 1, entry 17; see also Table S4, entry 11, and
Table S5, entry 4 in the Supporting Information).
With the optimized conditions in hand, the scope of this
reaction with regard to N-aryl isatinimines was then investi-
gated (Table 2). The N-aryl isatinimines derived from ani-
lines and containing an electron-rich or electron-deficient
group proceeded efficiently and afforded the products 3aa–
3ha in excellent yields (73–91%) and with good diastereose-
lectivity (Table 2). Moreover, electron-withdrawing and
electron-donating substituents at the 5 or 7 positions of the
benzene ring of N-aryl isatinimines provided good yields
(3ia–3la; Table 2). Different protecting groups on the nitro-
gen of the oxindole backbone were also examined. Various
protecting groups, such as benzyl, methyl, diphenyl methyl-
ene, allyl, para-methoxybenzyl, and methoxymethyl groups,
were tolerated, affording the products with good to excel-
lent yields (3ma–3qa, 69–88%; Table 2).
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N. Jiao, S. Ye et al.
Table 2. The reaction scope of the NHC-catalyzed, one-pot synthesis of spirocyclic g-lactam oxindoles.[a–c]
[a] Reaction conditions: see Table 1, entry 17. [b] Isolated yields. [c] The d.r. was determined by 1HNMR analysis of the crude products (d.r. 3’/3’’).
[d] DBU was used as the base, and the reaction was stirred for 24 h in the first step. [e] Compound 2 (0.6 mmol), catalyst A (20 mol%) and K2CO3
(40 mol%) were employed, and the reaction was stirred for 24 h in the first step. PMB=para-methoxybenzyl.
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Synthesis of Spirocyclic g-Lactam Oxindoles
COMMUNICATION
Table 3. Enantioselective studies of this methodology.[a]
the g-amino acid esters 4 are produced by proto-
nation and attack of MeOH[11l,12b] with the refor-
mation of the NHC to complete the catalytic
cycle. Finally, the target products 3 can be ob-
tained by acid hydrolysis of the g-amino acid
esters 4.
In summary, we have demonstrated that N-aryl
isatinimines can be used as stable and useful elec-
trophiles in the NHC-catalyzed addition of enals
to imines, and have developed an efficient one-pot
protocol for the synthesis of spirocyclic g-lactam
oxindoles 3 (which are ubiquitous structural units
in a number of biologically active compounds) by
a synthetically challenging addition of homoenloate equiva-
lents to N-aryl isatinimines and subsequent acid hydrolysis.
The possibility of a catalytic enantioselective process is also
shown. Further studies on the scope, asymmetric catalysis,
and synthetic applications of this reaction are ongoing in
our laboratory
Entry
Catalyst
T [oC]
Yield [%][b]
d.r.[c]
e.r. (3aa’’)[d]
1
2
3
4
5
6
7
I1
I2
I3
I4
I5
J1
J2
K
RT
RT
RT
0
RT
0
RT
0
0
NR
80
trace
56
trace
77
82
1:6
87:13 (99:1)[g]
1:5
86:14
1:8
1:3
1:15
1:19
14:86 (2.5:97.5)[g]
48.5:51.5
35:65
Acknowledgements
8[e]
9[f]
88
38
Financial support from the National Basic Research Program of China
(the 973 Program; Grant No. 2009CB825300), the National Science Foun-
dation of China (No. 21172006), and Peking University are greatly appre-
ciated. We thank Yuepeng Yan and Peng Feng in this group for repro-
ducing the results of 3ga, 3ma, 3aj, and 3al.
K
35.5:64.5
[a] Reaction conditions: see Table 1, entry 17. [b] Isolated yields. [c] The
ratio was determined by 1HNMR analysis of the crude products (d.r.
3aa’/3aa’’). [d] The e.r. value was determined by chiral HPLC analysis.
[e] THF was used as the solvent. [f] 4 ꢂ MS were added (200 mg).
[g] The e.r. values in parentheses were measured after fast recrystalliza-
tion with acetone–hexane (see the Supporting Information). TBS=tert-
butyldimethylsilyl, Mes=mesitylene.
Keywords: carbenes · lactams · organocatalysis · spiro
compounds · umpolung
Scheme 3. Proposed mechanism for the transformation. Mes=mesitylene.
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N. Jiao, S. Ye et al.
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[20] C. J. Collins, M. Lanz, B. Singaram, Tetrahedron Lett. 1999, 40, 3673.
[7] For recent examples of NHC-catalyzed a1–d1 umpolung reactions of
aldehydes, see: a) L. Baragwanath, C. A. Rose, K. Zeitler, S. J.
Connon, J. Org. Chem. 2009, 74, 9214; b) N. Kuhl, F. Glorius, Chem.
Commun. 2011, 47, 573; c) C. A. Rose, S. Gundala, C.-L. Fagan, J. F.
Franz, S. J. Connon, K. Zeitler, Chem. Sci. 2012, 3, 735; d) E.
Sꢄnchez-Larios, K. Thai, F. Bilodeau, M. Gravel, Org. Lett. 2011, 13,
4942; e) J. M. Um, D. A. DiRocco, E. L. Noey, T. Rovis, K. N. Houk,
J. Am. Chem. Soc. 2011, 133, 11249; f) D. A. DiRocco, T. Rovis, J.
Am. Chem. Soc. 2011, 133, 10402.
[8] C. Burstein, F. Glorius, Angew. Chem. 2004, 116, 6331; Angew.
Chem. Int. Ed. 2004, 43, 6205.
[9] S. S. Sohn, E. L. Rosen, J. W. Bode, J. Am. Chem. Soc. 2004, 126,
14370.
[10] For examples, see: a) S. S. Sohn, E. L. Rosen, J. W. Bode, J. Am.
Chem. Soc. 2004, 126, 14370; b) K. Hirano, I. Piel, F. Glorius, Adv.
Synth. Catal. 2008, 350, 984; c) C. Burstein, F. Glorius, Angew.
Received: April 22, 2012
Published online: && &&, 0000
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www.chemeurj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!

Synthesis of Spirocyclic g-Lactam Oxindoles
COMMUNICATION
Heterocyclic Carbenes
B. Zhang, P. Feng, L.-H. Sun, Y. Cui,
S. Ye,* N. Jiao* ............... &&&& — &&&&
N-Heterocyclic Carbene-Catalyzed
Homoenolate Additions with N-Aryl
Ketimines as Electrophiles: Efficient
Synthesis of Spirocyclic g-Lactam
Oxindoles
In pole position: A simple and effi-
cient approach to spirocyclic g-lactam
oxindoles by the N-heterocyclic car-
bene catalyzed addition of homoen-
loate equivalents to N-aryl isatinimines
has been developed (see scheme). The
use of N-aryl isatinimines as electro-
philes in the NHC-catalyzed umpolung
reaction of a,b-unsaturated aldehydes
is demonstrated for the first time.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!