Organocatalytic asymmetric Michael/hemiketalization/acyl transfer reaction of 1,3-propanediones with (: E)-2-(2-nitrovinyl)phenols

Article abstract of DOI:10.1039/c8ob01771a

An organocatalytic asymmetric cascade Michael/hemiketalization/acyl transfer reaction between (E)-2-(2-nitrovinyl)phenols and 1,3-propanediones is disclosed. A cinchona alkaloid derived bifunctional thiourea catalyst was found to be the most effective for this reaction and provided the desired products in moderate to good yields with good to high enantioselectivities.

Full text of DOI:10.1039/c8ob01771a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. C. Pan and N.
Bania, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB01771A.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 5
View Article Online
DOI: 10.1039/C8OB01771A
Journal Name
COMMUNICATION
Received 00th January 20xx,
Accepted 00th January 20xx
Organocatalytic
Asymmetric
Michael/Hemiketalization/Acyl
DOI: 10.1039/x0xx00000x
Transfer Reaction of 1,3-Propanediones with (E)-2-(2-
www.rsc.org/
nitrovinyl)phenols
Nimisha Bania and Subhas Chandra Pan*
An organocatalytic asymmetric cascade Michael/ hemiketalization organocatalytic asymmetric versions of such processes have
/acyl transfer reaction between (E)-2-(2-nitrovinyl)phenols and been studied extensively in recent years by a large number of
1,3-propanediones is disclosed. Cinchona alkaloid derived synthetic organic chemistry groups.1 Also, Michael addition
bifunctional thiourea catalyst was found to be the most effective reaction-triggered cascade reactions have drawn significant
for this reaction and provided the desired products in moderate attention because of the ultimate formation of different
to good yields with good to high enantioselectivities.
structural frameworks having multiple stereocentres.2 Thus
the development of new organocatalytic asymmetric Michael
based cascade reactions is an important arena of research.
In this regard, (E)-2-(2-nitrovinyl)phenols have been broadly
utilized as bidentate substrate and a range of asymmetric
organocatalytic one-pot double Michael or Michael-cyclization
reactions has been developed with the induction of
neighboring ortho hydroxyl group.3 The conjugate addition of
1,3-dicarbonyl compounds to these substrates could
potentially lead to different types of products. For example, in
The Michael reaction of carbon-centered nucleophiles to nitro
olefins represents one of the direct and fascinating routes to
nitroalkanes, which are important synthetic intermediates in
organic chemistry as diverse transformations of the nitro
group into other functional groups could be possible. The
2012
Enders
disclosed
domino
Michael–
hemiacetalization/lactonization and dehydration sequences
for the generation of tricyclic chroman scaffolds by employing
cyclic β-ketoesters and cyclic 1,3-diketones (Scheme 1).3b In
the same year Ramachary and co-workers reported a related
Michael–lactonization
reaction
between
(E)-2-(2-
nitrovinyl)phenols and cyclic β-ketoesters (Scheme 1).3c In
2013, Tang and co-workers developed an organocatalytic
Michael-acyl transfer reaction between 2,4-dioxo-4-
arylbutanoates and (E)-2-(2-nitrovinyl)phenols (Scheme 1).3g
However, acyclic 1,3-diketones have not been investigated in
the asymmetric reaction with (E)-2-(2-nitrovinyl)phenols
though an achiral method was developed by Wang and co-
workers.4 Realizing the potential of γ-nitrocarbonyl
compounds, we envisaged in developing an asymmetric
Michael/hemiacetalization/retro-aldol reaction5 between
linear 1,3-diketones and (E)-2-(2-nitrovinyl)phenols (Scheme
1).
Scheme 1 Organocatalytic asymmetric reaction between 1,3-dicarbonyl
compounds and (E)-2-(2-nitrovinyl)phenols.
Initially, the reaction between (E)-2-(2-nitrovinyl)phenol (1a) and
1,3-diphenyl-1,3-propane-1,3-dione (2a) was examined with
6
)
cinchona alkaloid derived bifunctional thiourea catalysts (I-III
in dichloromethane solvent at room temperature (Table 1,
entry 1). To our delight, the reaction progressed well in 3 days
with quinidine derived thiourea I to deliver the Michael-acyl
transfer product 3a in 70% yield, however the
enantioselectivity was moderate (47% ee, Table 1, entry 1).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 5
View Article Online
DOI: 10.1039/C8OB01771A
COMMUNICATION
Journal Name
The enantioselectivity did not improve with cinchonine derived
thiourea catalyst II (entry 2). Then cinhonidine derived catalyst
III was employed in the reaction and gratifyingly a big jump to
92% ee was observed (entry 3). Bifunctional squaramide
number of substituents can be incorporated in the ortho-,
meta- and para-position of the aryl group and good results
were achieved (entries 2-9). At first, different meta-substituted
di-aryl propanediones 2b-e were screened and the products
catalysts
IV
-
V
were
also
screened
but
lower
3b-e were isolated in good yields with high enantioselectivities
(entries 2-5). For example, 3-methoxy substituted
diarylpropanedione 2b reacted smoothly to provide product
3b in 75% yield with 95% ee (entry 2). Inspired by this result,
other 3-alkoxy propanediones 2c and 2d were employed and
high enantioselectivities were detected for the products 3c
and 3d respectively (entries 3-4). 3-Bromo substituted
propanedione 2e also participated in the reaction delivering
the product 3e in 78% yield with 95% ee (entry 5). Then
different para-substituted
enantioselectivities were detected (entries 4-5). Then we
turned our attention on the solvent optimization and this
proved to be rewarding. For example, the enantiomeric excess
got enhanced to 94% ee in toluene and similar conversion was
observed (entry 6). Xylene as a solvent also afforded similar
enantioselectivity (entry 7). Finally the best solvent was found
to be mesitylene which provided the product in 73% yield with
96% ee (entry 8).
Table 1 Catalyst screening and optimization of reaction conditions
Table 2 Scope of 1,3-propanediones
entrya
Ar
Time (d)
3
yieldb
eec
1
2
Ph
3
3
3
3
3
3
4
3
3
3a
3b
3c
3d
3e
3f
73
75
68
66
78
77
65
73
76
96
95
94
90
95
81
74
77
86
3-OMeC6H4
3-OEtC6H4
3-OnPrC6H4
3-BrC6H4
3
4
5
6
4-MeC6H4
4-OMeC6H4
4-FC6H4
7d
3g
3h
3i
8
entrya
catalyst
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
yieldb
70
eec
(-) 47
(-) 47
92
9
4-BrC6H4
1
2
3
4
5
I
aUnless otherwise mentioned, reactions were carried out with 0.1 mmol of 1a
and 0.11 mmol of 2 with 10 mol% catalyst III in mesitylene at room temperature.
bIsolated yield after silica gel column chromatography. cDetermined by HPLC.
dReaction was run at 0 oC.
II
67
III
IV
V
71
70
64
propane diones 2f-2i were prepared and engaged in the
69
82
reaction (entries 6-9). Propanedione 2f having tolyl groups
afforded the corresponding product 3f in 77% yield with 81%
ee (entry 6). The enantiomeric excess for product 3g having
anisyl substituents was less at room temperature, thus the
6
7
8
III
III
III
toluene
xylene
73
72
73
94
95
96
reaction was studied at
0
oC to obtain acceptable
mesitylene
enantioselectivity (entry 7). Further lowering of the reaction
temperature could not improve the enantioselectivity. 4-Halo
substitutions were also tolerated in the reaction and the
aReactions were carried out with 0.05 mmol of 1a with 0.055 mmol of 2a in 0.2
mL solvent using 10 mol% catalyst at room temperature. bIsolated yield after
silica gel column chromatography. cDetermined by chiral HPLC.
products 3h-3i were obtained in similar yields. Though the
enantiomeric excess for product 3h was moderate (entry 8),
product 3i was isolated in high enantioselectivity (entry 9).
These halo substituted products could be further elaborated
via cross-coupling reactions.
.
____________________________________________________
After the identification of suitable conditions, the scope and
generality of the reaction was investigated. Initially a range of
Then the scope of (E)-2-(2-nitrovinyl)phenol was studied and
here also good results were achieved with different
1,3-propanediones
2 having different aryl groups were tested
and the results are shown in Table 2. Gratifyingly quite a
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 5
View Article Online
DOI: 10.1039/C8OB01771A
Journal Name
COMMUNICATION
substitutions (Table 3). Initially different 4-substituted
nitrovinylphenols were employed in the reaction and
acceptable yields were detected. Though 4-methyl substitution
lowered the enantioselectivity a little, high
Scheme 2 Employment of unsymmetrical 1,3-diketones 2j and 2k
The scope of the reaction was then further extended by
incorporating unsymmetrical 1,3-diketones in the reaction. Thus
initially 4-phenyl,1,4-butanedione 2j was prepared and reacted with
(E)-2-(2-nitrovinyl)phenols 1a and 1e (Scheme 2). Pleasingly the
reactions progressed smoothly to deliver major O-acetyl containing
products 3p and 3q in good yields. The enantioselectivity of 3p was
moderate at room temperature and thus the reaction was
performed at 0 oC to improve the ee (79%). Another unsymmetrical
diketone 2k having methoxy substituent was also prepared and
engaged in the reaction. This resulted in the formation of 3r in 70%
ee.
Table 3 Scope of (E)-2-(2-nitrovinyl)phenols
entrya
R
1
Time (d)
3
yieldb
eec
To strengthen our methodology few derivatizations were
performed on 3a (Scheme 3). At first, the ester moiety of 3a was
hydrolyzed with sodium hydroxide to provide phenol 4 in 40% yield
and enantioselectivity was almost retained. Then methoxy
1
2
4-Me
4-OMe
4-Cl
1b
1c
1d
1e
1f
3
3
3
3
4
3
3j
3k
3l
75
75
78
72
70
73
83
86
81
81
92
97
3
4
4-Br
3m
3n
3o
protection with iodomethane delivered
5 with retention in
5d
5-OMe
6-Me
enantioselectivity. (Scheme 3). Based on the HPLC chromatogram of
5 as reported by Kwiatkowski and co-workers,7 the absolute
configuration of product 3a was assigned to be (S).
6
1g
aUnless otherwise mentioned, reactions were carried out with 0.1 mmol of 1 and
0.11 mmol of 2a with 10 mol% catalyst III in mesitylene at room temperature.
bIsolated yield after silica gel column chromatography. cDetermined by HPLC.
dReaction was run at -20 oC.
____________________________________________________
enantioselectivity was obtained for product 3k having 4-
methoxy substitution (entries 1-2). 4-chloro and 4-bromo gave
similar enantioselectivities (entry 3-4). The reaction was also
found to be smooth with 5-methoxy substituted nitrophenol 1f
however less enantioselectivity was obtained at room
temperature.
Gratifyingly lowering the temperature to -20 oC
could improve the enantioselectivity to 92% ee (entry 5).
Finally, 6-substitutions were also tolerated in the reaction and
6-methyl substituted nitrovinylphenol 1g emerged as the best
substrate for the reaction providing product 3o in 73% yield
with 96% ee (entry 6).
Scheme 3 Synthetic transformations of 3a
.
A plausible mechanism8 has been shown in Scheme 4 to explain the
stereochemistry of the product. It is believed that the nitro
functionality of (E)-2-(2-nitrovinyl)phenol 1a will co-ordinate with
the thiourea motif of the catalyst III. Since the Re face of the
nitroolefin is blocked by the catalyst, the addition of enol 2a' occurs
only from the Si face to provide intermediate A. Intramolecular
hemiketalization then generates B. Finally retro-aldol reaction of B
delivers product 3a.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 5
View Article Online
DOI: 10.1039/C8OB01771A
COMMUNICATION
Journal Name
356, 1753; (j) L.-Y. Cui, Y.-H. Wang, S.-R. Chen, Y.-M. Wang,
Z.-H. Zhou, RSC Adv., 2015, , 88133; (k) Y. Wang, J. Pan, R.
5
Jiang, Y. Wang, Z. Zhou, Adv. Synth. Catal., 2016, 358, 195; (l)
M. Frias, R. Mas-Ballesté, S. Arias, C. Alvarado, J. Alemán, J.
Am. Chem. Soc., 2017, 139, 672; (m) Y.-Y. Hseih, A. Raja, B.-C.
Hong, P. Kotame, W.-C. Chang, G.-H. Lee, J. Org. Chem.,
2017, 82, 12840; (n) W.-L. Huang, A. Raja, B.-C. Hong, G.-H.
Lee, Org. Lett., 2017, 19, 3494; (o) S. Wang, J. He, Z. An,
Chem. Commun., 2017, 53, 8882; (p) J. M. Andrés, J. Losada,
A. Maestro, P. Rodríguez-Ferrer, R. Pedrosa, J. Org. Chem.;
2017, 82, 8444; (q) T. C. Nugent, H. A. E. D. Hussein, S.
Ahmed, F. T. Najafian, I. Hussain, T. Georgiev, M. K.
Aljoumhawy, Adv. Synth. Catal., 2017, 359, 2824; (r) S. Ruan,
X. Lin, L. Xie, L. Lin, X. Feng, X. Liu, Org. Chem. Front., 2018, 5,
32.
4
5
W. Zhang, Y. Wang, C. Bai, J. Wen, N. Wang, Chin. J. Chem.,
2015, 33, 401.
For related organocatalytic asymmetric acyl transfer reactions,
see: Ref 3g and (a) Y. Gao, Q. Ren, W.-Y. Siau and J. Wang,
Chem. Commun., 2011, 47, 5819; (b) R.-J. Lu, J.-Y. Yan, J.-J.
Wang, Q.-S. Du, S.-Z. Nie and M. Yan, J. Org. Chem., 2011, 76,
6230; (c) P. Li, S. H. Chan, A. S. C. Chan and F. Y. Kwong, Org.
Biomol. Chem., 2011, 9, 7997; (d) R. Maity, C. Gharui, A. K. Sil
and S. C. Pan, Org. Lett., 2017, 19, 662. (e) R. Maity and S. C.
Pan, Org. Biomol. Chem., 2018, 16, 1598; (f) K. Mondal and S. C.
Pan, J. Org. Chem., 2018, 83, 5301.
Scheme 4 Proposed mechanism.
In summary, this report has shown the development of an
efficient Michael-hemiketalization-acyl transfer reaction
between 1,3-propanediones and (E)-2-(2-nitrovinyl)phenols.
The products having nitro, keto and ester functionalities were
obtained in moderate to good yields with good to high
enantioselectivities. Also selective acetyl transfer was
observed from unsymmetrical 1,3-diketones. Given the high
importance of chiral nitroalkanes in synthetic organic
chemistry our method might be useful to prepare these
compounds in a convenient way.
6
7
For a review on bifunctional cinchona alkaloid-based urea and
thiourea organocatalysts, see: S. J. Connon, Chem. Commun.,
2008, 2499.
A. Cholewiak, K. Adamczyk, M. Kopyt, A. Kasztelan, P.
Kwiatkowski, Org. Biomol. Chem., 2018, 16, 4365.
8. For a review on thiourea activation by H-bonding, see: Y.
Takemoto, Org. Biomol. Chem. 2005, 3, 4299.
Acknowledgements
We thank the Central Instruments Facility, Indian Institute of
Technology Guwahati for the instrumental help.
Notes and references
1
For reviews, see: (a) A. M. Berner, L. Tedeschi, D. Enders, Eur.
J. Org. Chem., 2002, 1877; (b) S. B. Tsogoeva, Eur. J. Org.
Chem., 2007, 1701.
2
For selected reviews on organocatalytic cascade or domino
reactions, see: (a) H. Pellesie Organocatalysis in Domino
Processes, In Domino Reactions; L. F. Tietze, Ed.; Wiley-VCH:
Weinheim, 2014, pp 325-405. (b) C. M. R. Volla, I. Atodiresi
and M. Rueping, Chem. Rev., 2014, 114, 2390; (c) H.
Pellesier, Adv. Synth. Catal., 2012, 354, 237; (d) A. Moyano
and R. Rios, Chem. Rev., 2011, 111, 4703.
For selected recent examples, see: (a) D. Enders, X. Yang, C.
3
Wang, G. Raabe, J. Runsik, Chem. Asian. J., 2011, 6, 2255; (b)
D. Enders, G. Urbanietz, R. Hahn, G. Raabe, Synthesis 2012,
44, 773; (c) D. B. Ramachary, R. Madhavachary, M. S. Prasad,
Org. Biomol. Chem., 2012, 10, 5825; (d) D. B. Ramachary, R.
Sakthidevi, K. S. Shruthi, Chem. Eur. J., 2012, 18, 8008; (e) C.
Wang, X. Yang, G. Raabe, D. Enders, Adv. Synth. Catal., 2012,
354, 2629; (f) A. Ray Choudhury, S. Mukherjee, Org. Biomol.
Chem.; 2012, 10, 7313; (g) Y. Liu, Y. Wang, H. Song, Z. Zhou,
C. Tang, Adv. Synth. Catal., 2013, 355, 2544; (h) D. B.
Ramachary, P. S. Reddy, M. S. Prasad, Eur. J. Org. Chem.,
2014, 3076; (i) A.-B. Xia, C. Wu, T. Wang, Y.-P. Zhang, X.-H.
Du, A.-G. Zhong, D.-Q. Xu, Z.-Y. Xu, Adv. Synth. Catal., 2014,
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01771A
An organocatalytic asymmetric cascade Michael/hemiketalization /acyl transfer reaction between (E)-2-
(2-nitrovinyl)phenols and 1,3-propanediones is disclosed to generate products having keto, ester and
nitro functionalities.