Enantioselective vinylogous aldol reaction of acylphosphonates with 3-alkylidene oxindoles

Article abstract of DOI:10.1039/d1ob00140j

A simple strategy for yielding chiral tertiary α-hydroxy phosphonates that integrates two highly biologically relevant scaffolds namely 3-alkylidene-2-oxindoles and phosphonates has been described. The hydrogen bonding ability of the bifunctional thiourea catalyst allows simultaneous dual activation of a vinylogous oxindole nucleophile and an acylphosphonate electrophile, affording hydroxyphosphonato-3-alkylidene-2-oxindoles as aldol adducts in high yields (up to 92%) with excellent stereocontrol (up to 99% ee).

Full text of DOI:10.1039/d1ob00140j

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DOI: 10.1039/D1OB00140J
ARTICLE
Enantioselective Vinylogous Aldol Reaction of Acyl Phosphonates
with 3-Alkylidene oxindoles
Manish K. Jaiswal, Sanjay Singh, and Ravi P. Singh*
Received 00th January 20xx,
Accepted 00th January 20xx
A simple strategy for yielding chiral tertiary α-hydroxyphosphonates that integrates two highly biologically relevant
scaffolds such as 3-alkylidene-2-oxindoles and phosphonates has been described. The hydrogen bonding ability of the
bifunctional thiourea catalyst allows simultaneous dual activation of vinylogous oxindole nucleophile and
acylphosphonates electrophile affording hydroxyphosphonato-3-alkylidene-2-oxindoles as aldol adduct in high yield (up
to 92%) and excellent stereocontrol (up to 99% ee).
DOI: 10.1039/x0xx00000x
Bio-active compounds
Introduction
OH
O
N
H
Hybrid molecules with two or more heterocycles or functional
groups have unique characteristics that enable them to display
dual mode of action against a variety of biological hosts.1 Thus,
designing such molecules from simple precursors have gained
tremendous momentum in recent years.2 Of particular, interest
is the chiral organophosphonates with high biological activities
and multifaceted applications in biology, medicine and
agrochemicals.3 A specific example would be the α-hydroxy
phosphonates that are known antioxidants,4a renin
inhibitors,4b,c herbicides, anti-human immunodeficiency virus
(HIV) drug4d,e and have also shown promise for treating
osteoporosis and other bone diseases.4f-h Apart from the
bioactivity they also represent useful precursors for further
transformations, resulting in many α-functionalized derivatives.
While many synthetic methods exist for yielding racemic α-
hydroxyphosphonates, the asymmetric synthesis is primarily
focused on secondary α-hydroxy phosphonates via enzymatic5
and metal-catalyzed reactions.6 The more challenging tertiary
α-hydroxy phosphonates still do not have any practical
synthetic routes. Previously, the tertiary α-hydroxy
phosphonates were synthesized via the addition of phosphites
to ketones,7 oxygenation of ketophosphonates8 and the
addition of carbon nucleophiles to α-ketophosphonates.9 It is
worth noting that the synthetically least explored tertiary α-
hydroxy phosphonates may have higher structural rigidity and
hence improved stability against protease enzymes, thus,
enhancing its bioactivity. Classically, the chiral α-hydroxy
phosphonates have been synthesized by proline catalyzed aldol
addition of acetone to acyl phosphonates.10 Additionally,
asymmetric transformations have also been explored in the
synthesis of tertiary α-hydroxyphosphonates.11 It is important
to note that while all these strategies yield secondary and the
tertiary organophosphonates with high yield and selectivity,
these reactions result into “terminal” derivatives that cannot be
OH
OH
O
N
P
N
H2N
N
O
OH
NH4
O
N
P
HN
HO
OH
O
N
N
Ph
OH
OH
O
OH
P
O
P
NHMe
HO
OH
O
K-4
Zoledronate
Anti-osteoporosis
Anti-hypertensive
Anti-viral
Route to chiral a-hydroxy phosphonates
Transition metal/ligands
OH
O
H
P
or chiral bases
OR
OR
OR
P
+
R1
R1
H
Pudovik Reaction
O
O
RO
OH
Chiral Lewis acid
or organocatalyst
O
Nu
R3
OR
OR
+
Nu
P
OR
R3
P
O
RO
O
Organocatalysed vinylogous
aldol reaction
Cu-catalysed Mukaiyama type
aldol reaction
O
R3
OH
O
R2
OR
R3
R'
X
OR
OH
OR
R3
P
P
OR
R1
OR
O
P
O
O
OR
O
X = O, NMe
CH3
This work
R3
OH
OEt
OEt
R2
R2
P
O
O
Chiral bifunctional
organocatalyst
OEt
R1
R1
O
+
O
R3
P
N
OEt
N
O
Boc
Boc
Figure 1. Representative bioactive compounds containing phosphonates and
catalytic enantioselective methodologies for chiral phosphate synthesis.
manipulated further due to lack of sufficient functional
synthetic handles for further group transformations.
Thus,
a method that directly provides functionalized
organophosphonates still remains a challenge. Towards this, an
alternative strategy incorporating phosphonate moieties in
various chiral functional molecules have been explored. An
example of this is the relatively straightforward method by
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Table 1. Catalyst screening and reaction optimization
Pudovik-type reaction where a chiral base or a metal catalyst
can directly form carbon-phosphorous (C-P) bond
View Article Online
DOI: 10.1039/D1OB00140J
a
stereoselectively.12 Later, the use of functionalized
phosphonates as electrophiles in the asymmetric catalytic
reaction was demonstrated as an efficient route to obtain
tertiary α-hydroxy phosphonates.13 While these strategies
resulted in tertiary α-hydroxy phosphonates derived from
functionalized precursors, it did not allow achieving molecular
diversity, again due to limited group transformations. This issue
of obtaining functional tertiary α-hydroxy phosphonates that
can be further manipulated can be addressed by simply
integration with synthetically vulnerable nucleophiles such as
the vinylogous nucleophiles. In fact, vinylogous nucleophiles
like the 3-alkylidene oxindole would also provide multiple
advantages as these themselves represent a privileged class of
scaffolds that are ubiquitously found in many biologically active
molecules and natural products.14 Examples representing this
strategy are limited in literature and some tertiary α-hydroxy
phosphonates through asymmetric vinylogous aldol reactions
have been elegantly demonstrated.15 This limitation is due to
the difficulties in obtaining selectivity with various heterocyclic
vinylogous nucleophiles. Herein, we report the exploration of
direct asymmetric vinylogous aldol reaction of 3-alkylidine-
oxindole to acylphosphonates catalyzed by a bifunctional
thiourea catalyst as illustrated in figure 1.
OH
Ph
OEt
OEt
Ph
Ph
P
CH3
O
O
Catalyst
OEt
OEt
O
+
O
Ph
P
N
N
O
Boc
Boc
3a
2a
1a
Ar = 3,5-(CF3)2C6H3
Ph
Ph
HN
S
S
S
N
Ar
N
X
HN
N
H
N
H
HN Ar
HN Ar
III, X =
II, X =
I
NMe2
N
IV
OMe
OMe
OMe
N
N
N
HN
HN
NH
N
N
O
N
HN
Ar
HN
Ar
S
S
NH
Ar
VII
VI
V
O
dr (E/Z)c
Yield (%)b
ee (%)d
Solvent
Entry
Catalyst
nd
1
2
nr
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
-
-
-
Et3N
nd
0
5
I
I
>19:1
>19:1
>19:1
>19:1
3
0
0
4e
10
72
20
I
5f
6
0
II
64
Results and discussion
III
>19:1
nd
7
Toluene
Toluene
15
60
-
IV
Investigations were initiated to examine the feasibility of the
vinylogous aldol reaction between 3 alkylidene-2-oxindole 1a
and acylphosphonates 2a. Initially, the reaction was conducted
in absence of catalyst at rt, but no reactivity was observed,
which clearly shows the non-spontaneous nature of the
reaction (Table 1, entry 1). To further testify our objective, a
racemic version of the reaction was carried at rt using Et3N as a
base promotor, which unfortunately again resulted in no
reaction (Table 1, entry 2). Interestingly, the same reaction,
when performed with the racemic thiourea catalyst I, the
desired aldol adduct 3a was obtained in only 5% yield with very
high diastereoselectivity (Table 1, entry 3). Further, the
introduction of basic K2HPO4 additive in the reaction medium
was found to influence the yield with no loss in
diastereoselectivity (Table 1, entry 4). Next, to enhance the
reactivity, the reaction was conducted at -20 C and
surprisingly, a significant increase in yield was observed (Table1,
entry 5). This observation indicates the importance of
temperature on the progress of the reaction. The chiral version
of this reaction was then investigated by using series of
bifunctional organocatalysts (III-VII). The reaction was first
performed using Takemoto catalyst II and K2HPO4 as a basic
additive in toluene at -20 °C, where desired product 3a was
formed in poor yield with moderate enantioselectivity (64%)
and excellent E/Z selectivity (Table 1, entry 6).
8
trace
V
>19:1
>19:1
9
Toluene
Toluene
50
48
98
VI
-98
10
VII
V
>19:1
>19:1
40
30
80
98
11
12
Toluene
DCM
V
V
CH3CN
THF
>19:1
>19:1
13
10
15
86
86
14
V
V
>19:1
>19:1
15g
82
80
98
98
Toluene
Toluene
16h
aUnless otherwise noted all the reactions were carried out with 1a (0.12
mmol), 2a (0.10 mmol) and catalyst (0.02 mmol) in toluene (1 mL) at rt for
b
c
1
d
96 h. Isolated yield. Determined by HNMR. Determined by chiral HPLC.
eK2HPO4 (0.12 mmol), K2HPO4 (0.12 mmol) at -20 C. g1a (0.2 mmol) and
f
o
K2HPO4 (0.2 mmol) at -20 oC. h1a (0.3 mmol) and K2HPO4 (0.3 mmol) at -20
oC.
For the improvement of reactivity and enantioselectivity,
several other bifunctional tertiary-amine catalysts were
screened such as trans- cyclohexane 1,2–diamine derived
thiourea III, trans-1,2–diphenylethylene diamine derived
thiourea IV and cinchona alkaloid derived thiourea (V and VI)
and quinidine squaramide VII. Performing the reaction with
catalyst III, yielded the adduct 3a in only 15% yield, although,
the reactivity was poor, moderate enantioselectivity (60%) and
excellent E/Z selectivity (>19:1) were noticed (Table 1, entry 7).
The trans-1,2–diphenylethylene diamine derived thiourea IV
was then examined, and afforded 3a in trace yield (Table 1,
2 | J. Name., 2012, 00, 1-3
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entry 8). To our delight, quinidine derived thiourea V turned out poor yield (35%) and excellent selectivities. On the other hand,
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to be the most effective candidate with respect to reactivity and long chain containing nButyl group failedDtOoIg: 1iv0e.10a3n9y/Dr1eOaBc0ti0v1i4t0yJ.
enantioselectivity, providing the adduct 3a in good yield of up To further explore the substrate scope of the reaction, various
to 50% and very high enantioselectivity (99%) while maintaining alkylidene-oxindole donors 1b-k were studied (Table 3). Based
excellent diastereoselectivity (Table 1, entry 9). Also, catalyst VI, on these observations it was evident that irrespective of the
a pseudoenantiomer of catalyst V when tested, delivered electronic and steric aspect of the structure, such as electron
similar results as catalyst V with opposite enantiomer of the releasing or withdrawing substituents present at different
product 3a (Table 1, entry 10).
Quinidine derived squaramide VII resulted the product 3a in
relatively low yield and enantioselectivity (Table 1, entry 11).
Table 2. Substrate scope of α-hydroxyphosphonato)-alkylidene-oxindoles
R3
OH
OEt
Ph
Ph
P
CH3
Subsequently, when the reaction was performed at rt,
corresponding 3a was obtained in reduced yield with similar E/Z
selectivity. Hence, catalyst V was considered for the optimized
catalytic condition for the reaction procedure. Further varying
solvents under optimal catalyst V although failed to improvise
the reactivity as well as enantioselectivity in case of CH3CN and
THF, while DCM provided equivalent enantioselectivity up to
99% ee with diminished reaction yield (Table 1, entries 12-14).
Finally, when the loading of the substrate 3-alkylidene-2-
oxindole 1a was increased from 1.2 equivalent to 2.0
equivalent, interestingly, there was a significant increase in the
yield without affecting enantioselectivity and E/Z selectivity
(Table 1, entry 15). Further increasing the loading of 1a did not
result any change in the yield and selectivity of the product
(Table 1, entry 16).
With the optimal reaction conditions established (Table 1, entry
15), the generality of the asymmetric vinylogous aldol reaction
was examined with respect to both the substrates, alkylidene-
oxindole 1 and acylphosphonates 2 as shown in Table 2 and 3.
A wide range of acylphosphonates 2 was reacted with
alkylideneoxindole 1 (Table 2) in the optimized reaction
conditions. The corresponding aldol products 3a-j were
obtained in moderate to good yields with single geometrical
OEt
O
O
Cat. V (20 mol%)
K2HPO4 (2 eqiv.)
OEt
OEt
O
P
O
R3
+
Toluene, -20 °C, 96 h
N
N
O
Boc
3a-h
Boc
1a
2a-h
Br
Cl
OH
P
OH
P
OH
P
OH
P
OEt
Ph
OEt
OEt
OEt
OEt
Ph
Ph
Ph
OEt
O
OEt
O
O
OEt
O
O
O
O
O
N
N
N
N
Boc
Boc
Boc
Boc
3a
3b
68% Yield
3c
70% Yield
3d
80% Yield
82% Yield
E/Z >19:1, ee 99%
E/Z >19:1, ee 99%
E/Z >19:1, ee 93%
E/Z >19:1, ee 99%
F
Br
MeO
OH
P
OEt
OEt
OH
OH
P
OH
P
Ph
OEt
OEt
OEt
OEt
OEt
OEt
O
Ph
P
Ph
Ph
O
O
O
O
N
O
O
O
Boc
N
N
N
Boc
Boc
Boc
3h
No reaction
3e
3f
55% Yield
E/Z >19:1, ee 99%
3g
70% Yield
E/Z >19:1, ee 99%
75% Yield
E/Z >19:1, ee 92%
OH
OH
OMe
OBu
Ph
Ph
P
P
OMe
OBu
O
O
O
O
N
N
Boc
Boc
3i
35 % Yield
E/Z >19:1, ee 99%
isomer
and
excellent
enantioselectivities.
The
3j
No reaction
acylphosphonates bearing electron-withdrawing group -Cl and
-Br at the para- position of the aryl group led to the marginal
loss in reactivity and provided corresponding aldol adducts (3b
and 3c) in good to high yield (68%-70%) with outstanding
enantioselectivities, respectively. In contrast, an electron-
donating group such as Me at the para-position of the aryl
group afforded corresponding aldol product 3d in 80% yield
with excellent selectivity of 99% ee. Similarly, OMe at the para-
position of the aryl group delivered 3e in high yield 75% with
92% ee. Interestingly, the acylphosphonates with halogen group
at meta-position of the aryl group (2f and 2g) yielded the
corresponding aldol products (3f and 3g) in 55% and 70% yield
respectively with the same selectivity (>19:1 dr and 99% ee).
Thus, it was concluded that while no significant influence of
either electronic nature or steric effect of the substituents on
the benzene ring of the acylphosphonates was observed on the
selectivity, a slight decrease in yields was noticed between the
halo and electron-donating groups. The scope of the reaction
with less reactive aliphatic acylphosphonates was also studied
but no progress in the reaction was observed. Moreover, when
-OEt group of acylphosphonate was replaced with -OMe and -
nButyl groups, it was noted that -OMe containing
acylphosphonates produced the corresponding adduct 3i in
aUnless otherwise noted, reactions were carried out with 1a (0.2 mmol), 2a (0.1
mmol), K2HPO4 (0.2 mmol) and catalyst (0.02 mmol) in the toluene (1 mL) at -20 oC
for 96 h. Yield of the isolated product. Determined by H NMR. Determined by
chiral HPLC.
b
c
1
d
positions on a benzo- as well as on benzene ring of alkylidene-
oxindole were well tolerated and corresponding adducts 3k-t
were obtained in good to excellent yields with equally high
enantioselectivities (19:1 dr and 99% ee). Moreover, vinylogous
donors bearing electron-withdrawing group on 5-position of
benzo-core of alkylidene-oxindole (1b and 1c) worked very well
to provide corresponding aldol adduct (3k and 3l) in 70% and
52% yield respectively with (slightly low in the case of 3j) high
stereocontrol (19:1 dr and 99% ee). In contrast, electron-
donating group 5-Me on benzo-core of alkylidene-oxindole
afforded the corresponding 3m in 78% yield with excellent
selectivity of 99% ee. The 5-OMe bearing benzo-core of
alkylidene-oxindole delivered 3m with both excellent yield
(92%) and selectivity (99% ee) respectively. Moreover, 6-Cl and
6-Br alkylidene-oxindoles gave the aldol products (3o and 3p) in
55% and 62% yield with equally high enantioselectivities.
Interestingly, both electron-withdrawing group (p-Cl and p-Br)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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OEt
OEt
and electron-donating group (p-Me) on the benzene ring
connected with the double bond of donors, proceeded very
smoothly and gave good to an excellent yield of the desired
product. Other substituted alkylidene-oxindole such as 1g and
1h afforded 3q and 3r respectively, in similar yields (63% and
65%) and enantioselectivities (19:1 dr, 99% ee) while 1j yielded
3s in high yield with excellent stereocontrol. On the other hand,
electron-donating substituents at the benzene ring connected
with the double bond of donors did not show any large
deviation in the yields of the product. Also, methyl substitution
in place of phenyl carbon-carbon double bond of alkylidene-
oxindole 1k gave 3t in good yield and very high
enantioselectivity (19:1 dr and 99% ee).
Ph
Ph
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HO
HO
OEt
OEt
P
P
(S)
(R) O
DOI: 10.1039/D1OB00140J
O
(E)
(E)
O
O
N
N
Br
Br
Boc
Boc
3p
62% Yield
3p'
62% Yield
E/Z >19:1, ee -98%
Catalyst V (QTU)
E/Z >19:1, ee -98%
Catalyst VI (QNTU)
CCDC No. 2024642
CCDC No.2024647
Figure 2. Single crystal X-ray of α-hydroxy phosphonate derivative 3o.
To explore the practicality of the developed methodology, the
optimized vinylogous aldol reaction was carried out at 0.5 mmol
scale using only 20 mol% of the catalyst V (Scheme 1). The
reaction proceeded smoothly in the optimized conditions and
the expected product 3a was isolated in 65% yield in the
stipulated time with the same level of diastereo and
enantioselectivity as observed for small scale experimentation.
Table 3. Substrate scope of α-hydroxyphosphonato)-alkylidene-oxindoles
OH
P
Ph
OEt
OEt
R2
OH
Ph
R2
CH3
O
O
O
OEt
Cat. V (20 mol%)
K2HPO4 (2 eqiv.)
Ph
Ph
OEt
OEt
P
Ph
P
R1
R1
CH3
O
O
+
OEt
O
O
Toluene, -20 °C, 96 h
Cat. V (20 mol%)
K2HPO4 (2 equiv)
O
N
N
OEt
OEt
Boc
3i-r
Boc
1b-k
O
P
Ph
+
Toluene, -20 °C, 96 h
2a
N
N
O
Boc
Boc
OH
P
OH
P
OH
P
OH
P
Ph
Ph
Ph
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
1a
(6 mmol)
2a
3a
65% Yield
>19:1 E/Z, 99% ee
(3 mmol)
OEt
O
O
O
O
F
Cl
MeO
O
O
O
O
N
N
N
N
Scheme 1. Scale up experiment of 3a.
Boc
Boc
3l
52% Yield
E/Z >19:1, ee 86%
Boc
Boc
3n
3k
3m
92% Yield
E/Z >19:1, ee 99%
70% Yield
E/Z >19:1, ee 99%
78% Yield
E/Z >19:1, ee 99%
The optimized (α-hydroxyphosphonato)-alkylidene-oxindoles
adduct 3a was further processed for Boc deprotection by
treating it with TFA which yielded 4 in excellent yield and
selectivity (Scheme 2).
Cl
Br
OH
OH
P
Ph
Ph
OH
P
OH
P
Ph
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
P
OEt
O
O
O
O
O
O
O
O
N
N
Cl
Br
N
N
Boc
Boc
OH
OH
Ph
Ph
Boc
Boc
OEt
OEt
3o
3p
OEt
OEt
3q
63% Yield
E/Z >19:1, ee 99%
3r
Ph
P
Ph
55% Yield
E/Z >19:1, ee 98%
P
62% Yield
E/Z >19:1, ee 98%
65% Yield
E/Z >19:1, ee 99%
O
O
TFA, DCM
0 °C-rt, 1 h
O
OH
Ph
O
OH
P
Ph
OEt
N
N
H
OEt
OEt
P
Boc
OEt
O
O
4
3a
O
99% yield
>19:1 E/Z, 99% ee
O
N
N
Boc
Boc
3t
3s
60% Yield
E/Z >19:1, ee 99%
Scheme 2. Conversion of α-hydroxyphosphonato)-alkylidene-oxindoles
product 3a.
70% Yield
E/Z >19:1, ee 99%
aUnless otherwise noted, reactions were carried out with 1a (0.2 mmol), 2a (0.1
1H NMR titration studies of the cat. V was conducted in toluene-
d8 and with an increasing amount of the keto-phosphonate. The
low-field shifts of the C9-H (Figure 3) thiourea protons clearly
indicated the H-bonding interaction with the α-
mmol), K2HPO4 (0.2 mmol) and catalyst (0.02 mmol) in the toluene (1 mL) at -20 oC
b
c
1
d
for 96 h. Yield of the isolated product. Determined by H NMR. Determined by
chiral HPLC.
We have confirmed the relative and absolute configuration of ketophosphonate. Our NMR studies also showed the down field
the vinylogous aldol adduct by X-ray crystal structure analysis of shift of ortho protons of the 3,5-bis (trifluoromethyl)phenyl
chiral α-hydroxy phosphonate derivative 3p (Figure 2). The catalyst moiety, strongly indicates the catalyst-substrate
relative configuration of the major stereoisomer of aldol adduct interaction (Figure 4). Furthurmore, a comparative evaluation
was established to be trans. Since cinchona catalysts do not shows the (-CH2)2, mutltiplet of 2a at δ = 3.94 - 4.07 ppm clearly
have their respective enantiomers thus limiting the accessibility shifts in presence of catalyst (see SI. Figure S2).
of both product enantiomers, the reaction was performed To further investigate the mechanism, the formation of 3a was
between 1f and 2a under the established reaction conditions monitored by 31P NMR spectroscopy. The starting reaction
using cat. VI, a pseudoenantiomer of cat.V. Interestingly, the mixture in toluene-d8 showed signal in the 31P NMR spectrum at
reaction resulted in 3p' with similar yield and enantioselectivity, δ = -1.22 ppm (ketophosphonate) and peak at δ = 6.68 ppm
which was further confirmed by single-crystal X-ray analysis
(Figure 1). This observation indicates the broad applicability of
our protocol.
4 | J. Name., 2012, 00, 1-3
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Page 5 of 6
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
N
CF3
Conclusions
View Article Online
H
S
O
C9
N
H
N
In summary, we have demonstrated anDOefI:fi1c0i.e10n3t9a/Ds1yOmBm00e1t4r0iJc
vinylogous aldol reaction of 3-alkylidene-2-oxindoles to
acylphosphonates catalyzed by bifunctional tertiary-amine
thiourea organocatalyst. The stereocenter and the alkene
geometries of the products were precisely controlled by the
F3
C
N
H
H
H
O
O
P
OEt
Ph
EtO
Ar-H
C9-H
Cat.: 0.8 eqv K.P
Cat.: 0.6 eqv K.P
Cat.: 0.4 eqv K.P
bifunctional amine-thiourea catalyst.
A broad range of
enantioenriched aldol adduct containing oxindole and
acylphosphonates moiety could be synthesized in good to
excellent yields with high E/Z (>19:1) and enantioselectivities
(up to 99%).
Cat.: 0.2 eqv K.P
Cat.: 0.0 eqv K.P
Author Contributions
We strongly encourage authors to include author contributions and
recommend using CRediT for standardised contribution
descriptions. Please refer to our general author guidelines for more
information about authorship.
9.8
9.6
9.4
9.2
9.0
8.8
8.6
8.4
8.2
8.0
7.8
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
5.8
5.6
5.4
5.2
5.0
4.8
4.6
4.4
4.2
f1 (ppm)
Figure 3. 1H NMR spectra of the Cat. V (0.02 mmol in toluene-d8) upon the
addition of increasing amounts of keto-phosphonate.
(diethylphosphite). As time progressed, the 31P NMR signals of
the starting material disappeared gradually and the reaction
was almost complete after 96 hours according to the 31P NMR
spectra (see SI. Figure S3).
Conflicts of interest
There are no conflicts to declare.
On the basis of above observations of X-ray analysis and NMR
studies, we proposed a plausible reaction mechanism (Scheme
4) for the vinylogous aldol reaction. Initially, the catalyst
interacts with acyl phosphonate 2a which is activated by
hydrogen bonding giving an intermediate A, subsequently other
reactant that is 3-alkylidene-2-oxindole is added to the reaction
mixture gets deprotonated by tertiary amine leading to the
formation s-cis dienolate through the Si-face to
Acknowledgements
We are grateful for the generous financial support from DST
India (EMR/2017/000319), CSIR [02(0254)/16/EMR-II], and
DAE(201804BRE02RP04978-BRNS). MKJ and SS grateful to the
CSIR and UGC, New Delhi, India for SRF. We thank DST-FIST for
the mass spectrometer facility.
N
Notes and references
CF3
OH
P
Ph
OEt
OEt
S
O
Ph
(R)
O
F3
C
N
F
N
H
1
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Chem. Res., 2008, 41, 69-77; b) K. V. S. Mani Chandrika and S.
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O
N
O
OEt
OEt
N
(cat. v)
P
Ph
Boc
O
2a
3a
N
N
CF3
CF3
S
O
2
S
O
(R)
(R)
F3
C
N
H
N
F3
C
N
N
H
H
N
H
H
N
O
O
O
O
OEt
OEt
O
Ph
P
Boc
P
CH3
O
OEt
Ph
Ph
N
EtO
Ph
N
A
B
Boc
1a
3
4
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Scheme 4. Plausible reaction mechanism.
acylphosphonate giving corresponding intermediate B. The desired
product 3a can be obtained from intermediate B by protonation
regeneration of the catalyst for the next cycle. It is worth to note that
the relative spatial arrangement of the two reacting partners, as
synchronized by the bifunctional catalyst, establishes the selective
attack to the Si face of the acylphosphonates.
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