Organocatalyzed Enantioselective Allylation of Isatins by Using a Chiral Amino Alcohol Derived Squaramide as Catalyst

Article abstract of DOI:10.1002/ejoc.201500155

A series of new squaramide-based organocatalysts were synthesized from commercially available 3,4-dimethoxycyclobut-3-ene-1,2-dione in two steps. A 2.5 mol-% loading of the organocatalyst successfully catalyzed the asymmetric allylation of isatins with al

Full text of DOI:10.1002/ejoc.201500155

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500155
Organocatalyzed Enantioselective Allylation of Isatins by Using a Chiral
Amino Alcohol Derived Squaramide as Catalyst[‡]
Debashis Ghosh,[a,b] Naveen Gupta,[a,b] Sayed H. R. Abdi,*[a,b] Sekhar Nandi,[a,b]
Noor-ul H. Khan,[a,b] Rukhsana I. Kureshy,[a,b] and Hari C. Bajaj[a,b]
Keywords: Organocatalysis / Enantioselectivity / Allylation / Isatins / Squaramides
A series of new squaramide-based organocatalysts were syn-
thesized from commercially available 3,4-dimethoxycyclo-
but-3-ene-1,2-dione in two steps. A 2.5 mol-% loading of the
organocatalyst successfully catalyzed the asymmetric allyl-
ation of isatins with allyltributyltin to give the corresponding
3-allyl-3-hydroxyoxindoles in high yields and enantio-
selectivities (up to 98% ee).
time a chiral squaramide as organocatalyst for the enantio-
selective allylation of isatins [Equation (2)].
Introduction
Optically active oxindole derivatives, which have found
widespread uses in natural product, agricultural and
pharmaceutical chemistry,[1] are important building blocks
for various biologically active compounds.[2] In addition,
the alkene functionality in 3-allyl-3-hydroxyoxindole can be
utilized to synthesize desired organic molecules.[3,4] In the
last few years, various metal-based efficient catalytic
systems were reported[5] [Equation (1)] for enantioselective
allylation of isatins; however, an organocatalyst version had
remained unexplored for this type of substrates, although
very recently an organocatalytic asymmetric allylation of
isatins has been reported by Hoveyda et al.[6] In our quest
to develop a new and efficient metal-free catalytic system
for the asymmetric allylation reaction of isatins with allyltin
or allylsilane compounds, we are now reporting for the first
(2)
Prior works on organocatalysts for different organic
transformations had revealed that the presence of key
features such as the ability to act as hydrogen-bond donor
or the presence of one or more chiral centres with critical
and desired electronic environments are necessary to affect
high reaction rate and stereoinduction. Organic molecules
having a squaramide[7] or thiourea[8] skeleton have these de-
sired features; therefore, for the present study we have syn-
thesized a series of thiourea- (Scheme 1) as well as squar-
amide-based (Scheme 2) organocatalysts (Figure 1) and
(1)
[‡] CSIR-CSMCRI registration number 008/2015
[a] Discipline of Inorganic Materials and Catalysis, CSIR – Central
Salt and Marine Chemicals Research Institute
(CSIR-CSMCRI)
G. B. Marg, Bhavnagar 364021, Gujarat, India
E-mail: shrabdi@csmcri.org
http://chiralgroups.webs.com/
[b] Academy of Scientific and Innovative Research, CSIR – Central
Salt and Marine Chemicals Research Institute
(CSIR-CSMCRI),
G. B. Marg, Bhavnagar 364021, Gujarat, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500155.
Scheme 1. Synthesis of thiourea-based organocatalysts 1–2.
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S. H. R. Abdi et al.
SHORT COMMUNICATION
Scheme 2. (a) Synthesis of squaramide-based organocatalyst 9. Other organocatalysts 3, 4, 6–11 were synthesized according to the same
procedure. (b) Synthesis of C2-symmetric organocatalyst 5.
Figure 1. Various organocatalysts used in the present study.
tested their efficacies for asymmetric allylation of isatins enantioselectivity (ee) was observed. As a result we synthe-
with allyltributyltin in dichloromethane (DCM) as solvent sized chiral squaramide 3 (containing the l-tert-leucinol
at room temperature (r.t.).
moiety) and 4 [containing the (1S,2R)-2-amino-1,2-diphen-
ylethanol moiety] to use them as catalysts for this reaction.
This met with some degree of success (Entries 3–4), par-
ticularly in the case of catalyst 4 (Entry 4; 80% yield, 35%
Results and Discussion
Our present investigation started with the synthesis of ee). Although the product ees were low, we visualized an
chiral thiourea 1 and bis(thiourea) 2 from l-tert-leucinol improvement in the results by varying the steric and elec-
and (1R,2R)-1,2-diaminocyclohexane, respectively, and we tronic features in the squaramide-based catalyst. Notice-
used them as catalysts for the enantioselective allylation re- ably, on replacing the 3,5-bis(trifluoromethyl)aniline moiety
action of N-benzylisatin with allyltributyltin in DCM at of catalyst 4 by the (1S,2R)-2-amino-1,2-diphenylethanol
room temperature Although allylation product was ob- moiety of C2-symmetric catalyst 5, both product yield
tained with moderate yield (Table 1, Entries 1–2), no (50%) and ee (20%) decreased significantly (Entry 5).
2
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Allylation of Isatins
Table 1. Screening of the catalysts.[a]
thatDCM was the most suitable solvent among the those
studied (Table 3, Entry 5). The temperature ranged from
–40 °C to room temperature (Table 2, Entries 6–9); it was
revealed that –20 °C is the best temperature as a product ee
(90%) with a 85% yield was obtained within 24 h (Entry 8).
Table 2. Optimization of solvents and reaction temperature.[a]
Entry
Catalyst
Time
[h]
Yield[b]
[%]
ee[c]
[%]
1
2
3
4
5
6
7
8
9
1
2
24
24
24
14
24
24
24
24
12
12
36
25
50
45
80
50
70
60
30
87
82
25
0
0
3
20 (S)[d]
35 (R)[d]
15 (R)[d]
18 (R)[d]
0
4
5
Entry
Solvent
Temp.
[°C]
Time
[h]
Yield[b]
[%]
ee[c]
[%]
6
7
8
12 (R)[d]
65 (R)[d]
50 (S)[d]
10 (S)[d]
1
2
3
4
5
6
7
8
9
toluene
THF
CHCl3
DCE
DCM
DCM
DCM
DCM
DCM
r.t.
r.t.
r.t.
r.t.
r.t.
0
–10
–20
–40
36
36
36
24
12
24
24
24
36
35
50
62
65
87
85
85
85
60
25
33
52
49
65
70
80
90
89
9
10
11
10
11
[a] All the reactions were carried out by using substrate 1a
(0.5 mmol), allyltributyltin (0.6 mmol), and catalyst (2.5 mol-%) in
DCM at room temp. [b] Isolated yields after column chromatog-
raphy. [c] ee determined by chiral HPLC using a Daicel Chiralcel
OD-H column. [d] Absolute configurations were assigned by com-
paring both retention time and optical rotation with reported reli-
able data.
[a] Reaction conditions as per Table 1. [b] Isolated yields after col-
umn chromatography. [c] ee determined by chiral HPLC using a
Daicel Chiralcel OD-H column.
Therefore, for subsequent changes in the catalyst we kept
the 3,5-bis(trifluoromethyl)aniline moiety intact and re-
placed the amino alcohol part of the organocatalyst 4 by
(1R,2S)-1-amino-2-indanol, (R)-2-amino-1-phenylethanol
and (R)-α-methylbenzylamine to obtain organocatalysts 6,
7 and 8, respectively, with variable steric features; but even
these could not match the performance of catalyst 4
(Entries 4, 6–8). To our pleasant surprise, sterically more
demanding organocatalysts 9 and 10 derived from (R)-2-
amino-3-methyl-1,1-diphenylbutanol and (S)-2-amino-
1,1,2-triphenylethanol, respectively, showed a dramatic im-
provement in the product enantioselectivity (Entries 9–10).
It is also worth noticing that the organocatalyst 9 (Entry 9;
87% yield, 65% ee) gave a higher ee in the product with
opposite configuration as compared to the organocatalyst
10. We also synthesized the quinine-based squaramide cata-
lyst 11, but it gave the allylation product with significantly
lower yield (25%) and ee (10%) (Entry 11). When compar-
ing the catalytic efficacy of the organocatalysts 3–11, it can
be concluded that the presence of a chiral centre near the
amine moiety and a high steric crowding around the
alcohol carbon atom of the amino alcohol side of the cata-
Table 3. Optimization of catalyst loading and allylating agents.[a]
Entry Catalyst loading
Allylating agent 2Ј Time Yield[b] ee[c]
(x [mol-%])
[h]
[%]
[%]
1
2
3
4
5
6
7
1
2.5
5
2.5
2.5
2.5
2.5
allyltributyltin
allyltributyltin
allyltributyltin
36
24
24
48
48
48
48
75
85
85
70
60
30
90
90
90
35
15
25
tetraallyltin
pinacol allylboronate
allyltrimethylsilane
allyltrichlorosilane
n.d.[d] n.d.[d]
[a] All the reactions were carried out by using substrate 1a
(0.5 mmol), allyltributyltin (0.6 mmol), and catalyst (1–5 mol-%) in
DCM at –20 °C. [b] Isolated yields after column chromatography.
[c] ee determined by chiral HPLC using a Daicel Chiralcel OD-H
column. [d] Not determined.
Further, the catalyst loading of 2.5 mol-%, which was
lyst possibly help in increasing the stereoinduction in the used in the preceding experiments, was found to be optimal
product. (Table 3, Entry 2) as it was observed that by decreasing the
Having identified catalyst 9 as the best among many, the catalyst loading (1 mol-%) the product yield (75%) dropped
optimization of other reaction conditions such as tempera- significantly (Entry 1). On the other hand, there was no
ture and solvents were investigated for the model reaction added advantage by increasing the catalyst loading (5 mol-
as these parameters are known to influence the yield and %) (Entry 3). To know the effect of allylating agents we have
enantioselectivity of the products. First, we screened used various other allylating agents e.g. allyltrimethylsilane,
various solvents frequently used for this type of reaction by allyltrichlorosilane, pinacol allylboronate and tetraallyltin,
using allyltributyltin as an allylating agent and keeping but the results showed that allyltributytin was the most suit-
other parameters constant (Table 2, Entries 1–5); we found able one (Entries 2, 4–7).
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SHORT COMMUNICATION
Table 4. Substrate scope.[a]
[a] Conditions: Isatins 1a–13a (0.5 mmol), allyltributyltin 2Јa (0.6 mmol), chiral organocatalyst (0.0125 mmol) in DCM, reaction tempera-
ture –20 °C, reaction time 24 h. [b] Isolated yields after column chromatography. [c] ee determined by chiral HPLC using a Daicel
Chiralcel OD-H/IA column. [d] Not determined.
With the optimal reaction conditions (Table 3, Entry 2), amide-based catalyst.[7] Secondly, by comparing the cata-
the scope of the organocatalyst 9 was extended to the asym- lytic activity of the catalysts 7, 8 and 9 (Table 1, Entries 7,
metric allylation reaction of various substituted isatins 8 and 9) we can say that the presence of an –OH group in
(Table 4). The results showed that the present catalytic the active catalyst is necessary to achieve good yields of the
system is highly efficient for most of the N-protected isatins, allylation product. Thus, the –OH group in active catalyst
whereas it fails for unprotected isatin. For most of the N- 9 probably helps in activating the allyltributyltin reagent as
protected isatins, product yields were very good (75–95%) given in the proposed transition-state model. Thus, a prefer-
and ees were good to excellent (62–98%), irrespective of the ential Re-face attack of the allyltributyltin nucleophile on
position of the substituents, although for electron-donating
substituents (e.g. 5-methyl) the product yield and ee were
comparatively lower than those obtained with electron-
withdrawing substituents (e.g. 5-nitro, 5-fluoro).
Based on the results obtained from the catalyst variation
study, we propose a possible transition state for this reac-
tion (Scheme 3). Firstly, by comparing the catalytic activity
of the catalysts 4 and 5 (Table 1, Entries 4, 5) we can say
that the 3,5-bis(trifluoromethyl)aniline moiety in the active
catalyst 9 is essential to obtain good yields as well as ees of
the allylation product. This happens probably due to the
substrate activation by two –NH protons of the squar- Scheme 3. Proposed transition state.
4
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Allylation of Isatins
Scheme 4. Allylation of N-protected isatins derived from nitro olefins.
the isatins results in the observed major (R) enantiomer
(Scheme 3).
Acknowledgments
We have also tested the efficacy of the organocatalyst 9
for nitro olefin derived isatins. However, instead of ob-
taining allylation products, we detected structurally interest-
ing 1-substituted 3-allylideneindolin-2-one compounds; but
at this point of time we do not know if these compounds
have any practical use (Scheme 4).
The authors are thankful to the Council of Scientific and Industrial
Research (CSIR) and the CSIR-Indus Magic Project (CSC0123)
for financial support. D. G. is thankful to the Academy of Scientific
and Innovative Research (AcSIR) for a Ph.D. enrollment. Analyti-
cal Discipline and Centralized Instrumental Facility is gratefully
acknowledged for providing instrumental facilities.
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Conclusions
We have developed a series of new squaramide-based
organocatalysts among which catalyst 9 showed very good
catalytic efficiency in the asymmetric allylation reaction of
various isatins with allyltributyltin as allyl source. A
2.5 mol-% loading of the organocatalyst is sufficient to give
the corresponding 3-allyl-3-hydroxyoxindoles in high yields
with enantioselectivities of up to 98% ee. An attempt for
the allylation of N-protected isatins derived from nitro
olefins was also made, which gave substituted allylidene-
indolin-2-ones instead of the expected allylated products.
Further work in this direction is currently in progress in our
laboratory to further expand the scope of the organocata-
lyst thus developed.
Experimental Section
General Procedure for the Catalytic Asymmetric Allylation of Isatins
with Allyltributyltin by Using 9 as Organocatalyst: In an oven-dried
5 mL glass flask were placed catalyst 9 (7 mg, 0.0125 mmol) and
isatin (0.5 mmol), and DCM (2 mL) was added. The reaction mix-
ture was then cooled to –20 °C. Allyltributyltin (1.2 equiv. with re-
spect to isatin) was added dropwise. The resulting mixture was
stirred at this temperature until the reaction was complete as indi-
cated by TLC. The reaction was quenched with distilled H2O and
the mixture extracted with EtOAc. The combined organic layers
were washed with H2O, saturated aqueous NaCl solution, dried
with anhydrous Na2SO4 and concentrated under vacuum. The
products were purified by flash chromatography on silica gel. Prod-
ucts were identified by NMR spectroscopic data corresponding to
those published.
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1
and substrates, HPLC profile of the products and copies of the H
and 13C NMR spectra of all new catalysts and products.
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SHORT COMMUNICATION
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Received: January 31, 2015
Published Online: ᭿
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Allylation of Isatins
Squaramide Catalysis
D. Ghosh, N. Gupta, S. H. R. Abdi,*
S. Nandi, N. H. Khan, R. I. Kureshy,
H. C. Bajaj ........................................ 1–7
Organocatalyzed Enantioselective Allyl-
ation of Isatins by Using a Chiral Amino
Alcohol Derived Squaramide as Catalyst
Keywords: Organocatalysis / Enantioselec-
tivity / Allylation / Isatins / Squaramides
A new series of squaramide-based organo-
catalysts were developed and successfully
applied for the asymmetric allylation reac-
tion of isatins with allyltributltin. The pre-
sent catalytic system was highly efficient for
the allylation of N-protected isatins giving
very good yields (75–95%) and excellent
enantioselectivities (62–98%) of the allyl-
ation products.
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