Non-Bonding 1,4-Sulphur-Oxygen Interaction Governs the Reactivity of α-Ketothioesters in Triphenylphosphine-Catalyzed Cyclization with Acetylenedicarboxylates

Article abstract of DOI:10.1002/adsc.202001376

α-Ketothioesters undergo triphenylphosphine (PPh₃)-catalyzed cyclization with acetylenedicarboxylate esters smoothly, in contrast to α-ketooxoesters which require more drastic conditions with the limited substrate scope. The reaction works well

Full text of DOI:10.1002/adsc.202001376

Title: Non-Bonding 1,4-Sulphur‒Oxygen Interaction Governs the
Reactivity of α-Ketothioesters in Triphenylphosphine-Catalyzed
Cyclization with Acetylenedicarboxylates
Authors: Abhijit Bankura, Jayanta Saha, Rajib Maity, and INDRAJIT
DAS
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10.1002/adsc.202001376
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Non-Bonding 1,4-Sulphur‒Oxygen Interaction Governs the
Reactivity of α-Ketothioesters in Triphenylphosphine-Catalyzed
Cyclization with Acetylenedicarboxylates
Abhijit Bankura,a Jayanta Saha,a Rajib Maity,a and Indrajit Dasa,*
a
Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road,
Jadavpur, Kolkata 700 032, India; E-mail: indrajit@iicb.res.in
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
interaction is likely to account for the reactivity of the
Abstract. α-Ketothioesters undergo triphenylphosphine
ketone carbon of α-ketothioesters in their cyclization
(PPh3)-catalyzed cyclization with acetylenedicarboxylate
reaction with acetylenedicarboxylates.
esters smoothly, in contrast to α-ketooxoesters which
Nozaki and co-workers reported in 1996 a
require more drastic conditions with the limited substrate
triphenylphosphine (PPh3)-catalyzed cyclization of α-
scope. The reaction works well with a wide range of α-
ketooxoesters 1 with dimethyl acetylenedicarboxylate
ketothioesters, delivering highly functionalized α,β-
2a in toluene at 70 oC to afford the highly
unsaturated γ-butyrolactones in moderate to excellent
functionalized α,β-unsaturated γ-butyrolactones 3
yields. The higher reactivity of the thioester derivatives is
(Scheme 1).[5] They found that highly electron-
seemingly due to a favourable intramolecular non-
deficient α-ketooxoester 1a bearing a nitro group at
bonding electrostatic 1,4-interaction involving C‒S σ*
the 4-position of the α-aromatic ring produced the
orbital on the sulphur atom and the lone pair of electrons
desired product 3a in excellent yield. Quite
surprisingly, the corresponding electron-withdrawing
4-Cl-substituted derivative 1b was recovered
unchanged under the same reaction conditions,
whereas use of the phenyl-substituted derivative 1c
did lead to product 3c, but only in 11% yield. The
authors presumed that the presence of a strong
electron-withdrawing substituent
in the electron-donating oxygen atom. This is apparent
from the X-ray crystallographically determined
internuclear distance between the sulphur and ketone
(C=O) oxygen atoms (2.71-2.85 Å), which is
significantly less than the sum of their van der Waals
radii (3.25-3.30 Å). The substitution on the S atom is
oriented diametrically away from the ketone O atom to
maximize the interaction between them. The trend is also
seen in the 1,4-S···O contact between the S and furan O
atoms (2.70 Å) in the γ-butyrolactone products.
Keywords: Cyclization; α-Ketothioesters; Nucleophilic
addition; 1,4-S···O interaction; Zwitterion intermediate
Certain non-oxidized sulphur atoms in organic and
bioorganic molecules can participate in attractive non-
bonding 1,4-interactions with oxygen atoms, that are
proving to be useful in governing important properties
such as molecular conformation, and chemical as well
as biochemical activity.[1] This effect is based on the
σ-holes on sulphur atom that possess positive
electrostatic potential and are available for interaction
with lone pairs of electrons in the electron-donating
oxygen atom.[2] These strong intramolecular
electrostatic 1,4-S···O contacts ranging from 2.77-
3.16 Å can be clearly observed in the X-ray crystal
structures of many compounds, the distance being
substantially less than the sum of the van der Waals
radii (3.25-3.30 Å).[3] Computational studies have
elucidated the origins of these stabilizing contacts,
and this interaction has been widely demonstrated in
model systems.[4] We herein show that such
1
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10.1002/adsc.202001376
Advanced Synthesis & Catalysis
Scheme 1. PPh3-catalyzed cyclization of α-ketooxoesters 1 iso-propyl (2e) or tert-butyl (2f) groups were either
and α-ketothioesters 4 with acetylenedicarboxylate esters 2. stirred at -20 to 0 oC or heated at ambient temperature
(Table 1), possibly due to the poor nucleophilic
t
character of the alkoxide anions (iPrO− and BuO−).
(4-NO2-C6H4) is essential to facilitate the initial Moreover, the generated alkoxides are strong bases,
nucleophilic addition of a zwitterion intermediate to which may also lead to the undesired side reactions.
ketone carbon of 1.
Moreover,
During the course of our continuing investigation Table 1. Substrate scope for the synthesis of highly
on the reactivity of α-ketothioesters and its functionalized α,β-unsaturated γ-butyrolactones 5.[a]
unsaturated analogues with various nucleophiles,[6] we
observed that a similar zwitterion intermediate can be
efficiently trapped by 4 as a dipolarophile, even at
ambient temperature, and the reaction is compatible
with a diverse range of substrates (Scheme 1). The
sharply contrasting results concerning the difference
in reactivity of the ketone moiety between the α-
ketooxoesters 1 and α-ketothioesters 4 in the
formation of γ-butyrolactones have prompted us to
investigate the notable sulphur atom effects[7] of the
latter in detail. We herein report our findings on the
PPh3-catalyzed cyclization of α-ketothioesters with
acetylenedicarboxylate esters to yield the substituted
γ-butyrolactones[8] 5. It is nothworthy that although
substantial progress has been made with the reaction
of the zwitterion to various electron-deficient
carbonyl compounds,[5,9] similar cyclization has not
been reported with the corresponding α-
ketothioesters[10] due to the lack of methods available
to access them.
The requisite α-ketothioesters or its unsaturated
analogues 4 were readily prepared in pure form
following the previous reports.[6,11] When 4a was
treated with 2a in presence of 20 mol % of PPh3 in
o
dry toluene at ambient temperature (25-30 C), the
desired γ-butyrolactone 5a was isolated in 80% yield
within 45 min; the initial light yellow solution slowly
turned to an orange-coloured solution with the
progress of the reaction (Table 1). But increasing the
reaction temperature upto 70 oC proved
counterproductive. It should be noted that a similar
cyclization with the oxoester analogues needed
o
reaction at 70 C for 8-22 h (Scheme 1),[5] suggesting
that the ketone carbon of 4 is more reactive than 1. To
improve the yield of 5a further, different solvents
were tried. But tetrahydrofuran, 1,4-dioxane,
ethylacetate, methanol, or acetonitrile all proved
unsuccessful.
We next assessed the substrate scope of this
reaction with dialkyl (methyl, ethyl, n-propyl, and n-
butyl) acetylenedicarboxylates 2 (Table 1). It was
found that the α-ketothioesters containing electron-
donating, electron-neutral, or electron-withdrawing
substituents on the α-aromatic ring (4a–i) gave the
expected products 5a–i in moderate to excellent
yields. Substrates containing 2-naphthyl (4j) moiety
[a] Reaction conditions: α-Ketothioesters or β,γ-unsaturated
at the α-position also furnished the expected product
α-ketomethylthioesters 4 (0.05 g, 1 equiv), PPh3 (20 mol%),
(5j). Further investigation demonstrated that
and acetylenedicarboxylate esters 2 (1.2 equiv/mmol) in
methylthioesters (4k-o) containing substituted α-
dry toluene (2.0 mL) at room temperature (25-30 oC);
styryl moiety could also be converted to the
yields are of isolated products.
corresponding products in moderate to good yields
[b]
With trace amount of desired product, inseparable
(5k-o). But the expected products 5fd or 5ab were not
mixtures of minor unidentified spots were observed.
obtained when acetylenedicarboxylates bearing either
[c] NMR indicates the presence of noticeable impurities.
2
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10.1002/adsc.202001376
Advanced Synthesis & Catalysis
[d]
5l contains trace amount of impurity not resolved by
column chromatography.
[a] Reaction conditions: α-Ketothioesters 4 (0.05 g, 1 equiv),
PPh3 (20 mol%), and acetylenedicarboxylate esters 2 (1.2
equiv/mmol) in dry toluene (2.0 mL) at room temperature
replacing the ester group of acetylenedicarboxylates 2 (25-30 oC); yields are of isolated products.
[b]
with aromatic ring (such as for diphenylacetylene)
With trace amount of desired product, inseparable
was found to be completely inactive under the mixtures of minor unidentified spots were observed.
standard reaction conditions (not shown), ostensibly [c] NMR contains noticeable peaks for impurities.
owing to the lack of stability and subsequent
reactivity of the in situ generated zwitterion. Efforts 4 were found to be more reactive than oxoester
to address this limitation are presently ongoing in our analogous toward zwitterion addition and
laboratory. subsequent cyclization. This difference in behavior
Based on the experimental results, α-ketothioesters
1
We next sought to extend the scope of this reaction may be due to the presence of an attractive non-
by changing the substituents on the sulphur atom. As bonding electrostatic 1,4-interaction in 4 involving
indicated in Table 2, electron-donating (4p) or low-lying C‒S σ* orbital on the S atom and lone pairs
electron-withdrawing (4q-r) substituents in the of electrons in the ketone O atom, with the favourable
aromatic ring, or naphthyl substituents (4s) were well- contact influencing the electrophilicity of the ketone
tolerated and produced the expected products in carbon of α-ketothioesters. In the single-crystal X-ray
moderate to excellent yields (5p-5sa). Substrates structure of the α-ketothioester 4g, the syn preference
bearing aliphatic thiols such as benzyl (4t) or tert- of the ketone O and S atoms is noticeable with the
butyl (4u) groups were also found to react under these distance between these two atoms measured at 2.71 Å
conditions, delivering the products in good yields (5t- (Figure 1),[12] substaintially less than the sum of the
u).
van der Waals radii. This finding is indicative of a
favorable interaction between them. Such a stabilizing
interaction between two electron-donating oxygen
atoms is lacking in α-ketooxoesters 1. Further support
comes from the observation that the S-phenyl ring is
oriented diametrically away from the ketone O atom.
This arrangement would permit an optimal interaction
between these two atoms. The powerful electron-
withdrawing property associated with a thioester
C(O)SR1 moiety might also work for a productive
interaction and subsequent reactivity of the ketone
group in α-ketothioester. In related examples,
similarly short 1,4-S···O distance of 2.74 Å in 4q
(Figure 2)[12] and 4r (Figure 3),[12] syn direction for S
and ketone O atoms, and the orientation of the S-aryl
ring away from the ketone group had been observed.
Table 2. Substrate scope for the sulphur moiety.[a]
Figure 1. Single-crystal X-ray structure of 4g (CCDC
2041719), demonstrating the close contact between the
ketone O and S atoms (2.71 Å).
3
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10.1002/adsc.202001376
Advanced Synthesis & Catalysis
Figure 2. Single-crystal X-ray structure of 4q (CCDC
2041720), demonstrating the close contact between the
ketone O and S atoms (2.74 Å).
Figure 4. Single-crystal X-ray structure of 5f (CCDC
2041722), illustrating the close contact between the furan
O and S atoms (2.70 Å).
For α-ketooxoesters, the syn preference of the
ketone O and the pendent O atoms is also noticeable
in the single-crystal X-ray structure of 3-NO2-C6H4-
C(=O)-C(=O)-OMe with the distance between these
two oxygen atoms measured at 2.62 Å, which is
significantly less than the sum of the van der Waals
radii (3.04 Å).[17] Although the distance supports the
favorable interaction, however, it is reasonable to
assume that such a stabilizing interaction (like α-
ketothioesters) is lacking in α-ketooxoesters 1 and
also in the corresponding products 3 (Scheme 1), as
the electron-rich oxygen atoms may experience
electrostatic repulsion due to their electronegativity.[1]
The electrophilicity of the ketone carbon of 1 may be
dependent upon the substituents in the α-aromatic ring.
Thus, the presence of a strongly electron-withdrawing
nitro (NO2) group is essential to facilitate the initial
zwitterion addition to the ketone (C=O) carbon of 1.[5]
Based on earlier reports,[5,9] a plausible reaction
mechanism is proposed in Scheme 2. We presume
that in presence of acetylenedicarboxylate ester 2,
Figure 3. Single-crystal X-ray structure of 4r (CCDC
2041721), demonstrating the close contact between the
ketone O and S atoms (2.74 Å).
A perusal of the X-ray crystallographic literature
on α-ketothioesters also revealed the existence of
attractive non-bonded electrostatic 1,4-S···O contact
between the S and O atoms. The S···O distances of
2.80 Å, 2.85 Å, 2.75 Å, and 2.76 Å observed in single
crystal structures such as for Ph-CH=CH(E)-C(=O)-
C(=O)-SMe (4k),[11c,13-14] 4-CN-C6H4-CH=CH(E)-
C(=O)-C(=O)-SMe,[13] MeSO2-C6H4-C(=O)-C(=O)-
SCH2Ph,[14-15] and Ph-C(=O)-C(=O)-S-C6H4-p-Me
(4p)[16] respectively are significantly less than the sum
of the van der Waals radii of S and O atoms with the
substituents on the sulphur atom oriented away from
the ketone O atom.
Beside α-ketothioesters, the most striking
observation with the single crystal X-ray crystal
structure of the product γ-butyrolactone 5f was that
the S atom of the thioester moiety was proximal to the
O-1 atom of the furan ring with contact distance of
2.70 Å (Figure 4),[12] indicative of an attractive
electrostatic interaction between these atoms. This
might also play a contributing role in influencing the
stability of 5f and subsequent reactivity of the
substrates.
PPh3 would initially generate
a
zwitterionic
intermediate I, which can add to the highly reactive
ketone carbon (C=O) of α-ketothioester 4 to produce
the intermediate II. It is reasonable to expect that
strongly electrophilic carbonyl carbon accelerates the
nucleophilic addition of I due to the presence of an
attractive non-bonding electrostatic 1,4-S···O
interaction. Intermediate II undergoes cyclization
with concomitant elimination of the alkoxide anion to
generate the intermediate III bearing a phosphonium
cation at C-4, which may be replaced by the in situ
generated alkoxide anion to yield γ-butyrolactones 5,
and regenerate the catalyst PPh3 to continue the
catalytic cycle.[18]
4
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10.1002/adsc.202001376
Advanced Synthesis & Catalysis
Scheme 2. Proposed mechanism for the formation of 5
from 4.
To further demonstrate non-bonded 1,4-S···O
interaction-supported
reactivity
of
the
α-
[a] Reaction conditions: α-Ketothioesters 4 (0.05 g, 1 equiv),
dialkyl acetylenedicarboxylate 2 (1.2 equiv/mmol), and
aromatic or alkyl isocyanide 6 (1.2 equiv/mmol) in dry
MeCN (2.0 mL) at 80 oC; yields are of isolated products.
ketothioesters, we treated 4 with aromatic isocyanide
6 and dialkyl acetylenedicarboxylate 2 in acetonitrile
o
solvent at 80 C, and isolated the corresponding
highly substituted α,β-unsaturated γ-iminolactones
7a-d in moderate to excellent yields (Table 3).
Isocyanide containing an aliphatic group (cyclohexyl)
was transformed into the corresponding product 7e
under slightly modified conditions (THF instead of
[b]
THF as solvent instead of MeCN under ambient
temperature (25 – 30 oC).
The versatility of the developed procedure was
highlighted by scaling up the reaction to 0.5 g batch
of α-ketothioesters 4 under optimized reaction
conditions
MeCN)
at
room
temperature.
An
acetylenedicarboxylate ester bearing a tert-butyl
group also furnished the expected product 7f in
moderate yield. Based on earlier reports, the reaction
is believed to proceed via zwitterionic intermediate
from the reaction of dialkyl acetylenedicarboxylate 2
and isocyanide 6 followed by the addition to the
ketone carbon of 4 and subsequent cyclization to yield
7.[19]
Table 4. Scale-up batches.[a]
Table 3. Synthesis of highly functionalized α,β-unsaturated
γ-iminolactones 7 from 4.[a]
[a]
α-Ketothioesters 4a, 4g, or 4s (0.5 g, 1 equiv), PPh3 (20
mol%), and acetylenedicarboxylate esters 2a or 2b (1.2
equiv) in dry toluene (14.0 mL) at room temperature (25-30
oC); yields are of isolated products. For detailed procedure,
see the Supporting Information.
5
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10.1002/adsc.202001376
Advanced Synthesis & Catalysis
159.5, 147.8, 135.1, 134.7 (2 CH), 130.0, 129.6, 129.5 (2
CH), 126.4, 123.0, 119.4, 115.0, 113.3, 89.8, 60.0, 55.4,
52.6 ppm; IR (KBr): ṽmax = 1786, 1718, 1654, 1451, 1410,
1114, 1021 cm-1; HRMS (ESI): m/z calcd for C21H18O7SNa
[M + Na]+: 437.0671; found: 437.0664.
to isolate 5a, 5g, and 5sa without any significant
diminution in the yields (Table 4).
In conclusion, we have demonstrated the reaction
of α-ketothioesters with zwitterion intermediate
General Procedure for the Synthesis of 7. To a well-
stirred solution of α-ketothioesters 4 (0.05 g, 1 equiv) in
dry acetonitrile (2.0 mL) and 3Å MS under an argon
atmosphere, aromatic and aliphatic isocyanide R3NC (6,
1.2 equiv) was added. Dialkyl acetylenedicarboxylate 2
(1.2 equiv/mmol) was successively added drop-wise via
syringe. The resulting reaction mixture was heated under
reflux (80 oC) employing time as mentioned. After
completion of the reaction (TLC), saturated NH4Cl solution
was added, and the mixture was extracted with
dichloromethane (10 mL). The combined organic layers
were dried over anhydrous Na2SO4 and filtered, and the
filtrate was concentrated under reduced pressure to get a
residue. The crude residue was purified by silica gel
column chromatography [230−400; eluent: ethyl acetate/n-
hexane] to obtain 7.
generated
from
catalytic
PPh3
and
acetylenedicarboxylate esters to obtain highly
substituted γ-butyrolactones in moderate to excellent
yields. An α-ketothioester was found to be more
reactive than the analogous α-ketooxoester for this
transformation. This difference in behavior may be
due to the presence of an attractive non-bonding
electrostatic 1,4-interaction in α-ketothioester
involving low-lying C‒S σ* orbital on sulphur atom
and the lone pairs of electrons in ketone oxygen atom
(C=O). Such a stabilizing interaction is lacking in the
corresponding α-ketooxoesters, as electron-rich
oxygen atoms may not form particularly favorable
contact with each other due to their electronegativity.
The remarkably short 1,4-S···O distances observed in
the single-crystal X-ray structures of the α-
ketothioesters (2.71-2.85 Å) or its product γ-
butyrolactone (2.70 Å) support the favorable
interaction between the S and O atoms. Further
evidence for the existence of a productive S···O
interaction in α-ketothioesters is the observation that
Dimethyl (Z)-5-((4-methoxyphenyl)imino)-2-phenyl-2-
((phenylthio)carbonyl)-2,5-dihydrofuran-3,4-
dicarboxylate 7a: Prepared according to the general
procedure discussed above: time: 1 h; Rf = 0.3; eluent,
EtOAc/n-hexane (15%); colourless gum (0.096 g, 90%). 1H
NMR (300 MHz, CDCl3): δ = 7.62 (d, J = 9.0 Hz, 2 H),
7.40 - 7.51 (m, 10 H), 6.91 (d, J = 9.0 Hz, 2 H), 3.98 (s, 3
H), 3.82 (s, 3 H), 3.73 ppm (s, 3 H); 13C{1H} NMR (75
MHz, CDCl3): δ = 193.9, 161.5, 160.6, 158.1, 151.5, 143.7,
137.0, 136.1, 134.8 (2 CH), 133.8, 130.0, 129.7, 129.4 (2
CH), 128.6 (2 CH), 127.0 (2 CH), 126.6 (2 CH), 126.2,
113.9 (2 CH), 96.8, 55.4, 53.3, 52.9 ppm; IR (KBr): ṽmax
=
the substitution on the
S
atom is oriented
1739, 1684, 1504, 1442, 1353, 1287, 1241, 1042, 1003,
836, 746 cm-1; HRMS (ESI): m/z calcd for C28H24NO7S [M
+ H]+: 518.1273; found: 518.1271 and m/z calcd for
C28H23NO7SNa [M + Na]+: 540.1093; found: 540.1088.
diametrically away from the ketone O atom, which
also maximizes the non-bonded interaction between
them. To further demonstrate non-bonded 1,4-S···O
interaction-supported
reactivity
of
the
α-
ketothioesters, the synthesis of α,β-unsaturated γ-
iminolactones has been reported. Computational
studies concerning the relative reactivities of the O-
and S-analogues will be reported in due course.
Acknowledgements
Financial support for this work was provided by SERB-
EMR/2016/001720. A.B. thanks CSIR-India and J.S., and R.M.,
thank UGC-India for their fellowships. We are especially grateful
to Dr. Basudeb Achari, ex-scientist of CSIR-IICB for insightful
discussions. We are thankful to Mr. Diptendhu Bhattacharyya and
Mr. Soumik Laha, CIF-Division of CSIR-IICB, for recording the
mass spectra.
Experimental Section
General Procedure and Representative Examples
General Procedure for the Synthesis of 5. To a well-
stirred solution of α-ketothioesters or its unsaturated
analogues 4 (0.05 g, 1 equiv) in dry toluene (2.0 mL) under
an argon atmosphere at room temperature (25-30 oC),
triphenylphosphine (PPh3, 20 mol%) was added.
Acetylenedicarboxylate ester 2 (1.2 equiv/mmol) was then
added drop-wise via syringe. The resulting reaction mixture
was stirred at the same temperature employing time as
mentioned. After completion of the reaction (TLC),
saturated NH4Cl solution was added, and the mixture was
extracted with dichloromethane (10 mL). The combined
organic layers were dried over anhydrous Na2SO4 and
filtered, and the filtrate was concentrated under reduced
pressure to get a residue. The crude residue was purified by
silica gel column chromatography [230−400; eluent: ethyl
acetate/n-hexane] to obtain 5.
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10.1002/adsc.202001376
Advanced Synthesis & Catalysis
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contain
the
supplementary crystallographic data for this paper.
These data can be obtained free of charge via
www.ccdc.cam. ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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X-ray structures of Ph-CH=CH(E)-C(=O)-C(=O)-SMe
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C(=O)-C(=O)-SCH2Ph are 960814 and 1895971,
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7
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10.1002/adsc.202001376
Advanced Synthesis & Catalysis
[17] CCDC accession number for 3-NO2-C6H4-C(=O)-
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[18] One of the reviewers suggested another plausible
mechanism via the attack of PPh3 to the ketone centre
of α-ketothioesters to generate the corresponding
zwitterionic intermediate, which undergoes subsequent
cyclization with acetylenedicarboxylates 2 to yield γ-
butyrolactones 5. However, we believe that the
zwitterion is less stable than that of the generated from
acetylenedicarboxylates 2 and PPh3 (intermediate I,
Scheme 2), probably due to the lack of resonance
structures, steric effects at the tertiary centre, and also
from the HSAB principle (the ketone carbon being a
hard electrophile and the phosphorus as a soft
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8
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10.1002/adsc.202001376
Advanced Synthesis & Catalysis
COMMUNICATION
Non-Bonding 1,4-Sulphur‒Oxygen Interaction
Governs the Reactivity of α-Ketothioesters in
Triphenylphosphine-Catalyzed Cyclization with
Acetylenedicarboxylates
Adv. Synth. Catal. Year, Volume, Page – Page
Abhijit Bankura, Jayanta Saha, Rajib Maity, and
Indrajit Das*
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