Facile synthesis of biarylmethanes and tetrasubstituted arenes: Via a base-mediated [3 + 3] benzannulation reaction of Morita-Baylis-Hillman adducts and unsaturated sulfones

Article abstract of DOI:10.1039/c9ob00214f

A facile DBU-mediated [3 + 3] benzannulation reaction of 1,3-bis-sulfonyl propenes and Morita-Baylis-Hillman (MBH) bromides is described. The benzannulation reaction afforded bis-sulfonyl biarylmethanes/arenes with complete regioselectivity. The products

Full text of DOI:10.1039/c9ob00214f

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: D. Yadav, S. K.
Sharma and R. Menon, Org. Biomol. Chem., 2019, DOI: 10.1039/C9OB00214F.
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
Page 1 of 4
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB00214F
ARTICLE
Facile synthesis of biarylmethanes and tetrasubstituted arenes via
base-mediated [3+3] benzannulation reaction of Morita-Baylis-
Hillman adducts and unsaturated sulfones
Received 00th January 20xx,
Accepted 00th January 20xx
Deepak Yadav,a,b Sunil K. Sharmab and Rajeev S. Menona*
DOI: 10.1039/x0xx00000x
A facile DBU-mediated [3+3] benzannulation reaction of 1,3-bis-sulfonyl propenes and Morita-Baylis-Hillman (MBH)
bromides is described. The benzannulation reaction afforded bis-sulfonyl biarylmethanes/arenes with complete
regioselectivity. The products may be converted readily into corresponding benzophenones via site-selective benzylic
oxidation.
of benzannulation strategy in synthesis. Benzannulation
reactions are generally classified based on the number of
carbons contributed by each building block, such as [5+1],
[4+2], [3+3], [2+2+2] etc. More pertinent to the work
presented here are [3+3] benzannulation reactions.6 Elegant
applications of benzannulation reactions in the total synthesis
of a number of structurally intriguing, arene-containing natural
products demonstrate the power of this approach.7
Introduction
Phenyl derivatives constitute important building blocks in
organic synthesis due to their abundance and the ease of
carrying out aromatic electrophilic substitution reactions.
Regiochemical outcome of the substitution reactions is
determined by the directing influences of groups present on
the aryl ring.1 This very virtue may, however, prevent the
formation of a desired regioisomer when the construction of
poly-substituted arenes is attempted. Deactivating effects of
electron withdrawing groups and steric crowding also pose
serious challenges to this approach. Availability of methods
such as transition-metal mediated cross-coupling reactions2
and directed metallation reactions3 helps to overcome these
issues significantly. These reactions, however, employ arenes
pre-functionalised with groups which engage in coupling
reactions or anchor the metal catalyst at the desired position.
Such pre-functionalised arenes are mostly assembled via
standard aromatic substitution reactions which occasionally
bring the above-mentioned roadblocks back, especially when a
non-trivial, poly-substituted arene building block is required.
Benzannulation reactions, an unconventional approach,
wherein acyclic precursors are combined to afford substituted
arenes, addresses some of the above-mentioned concerns.
The acyclic building blocks can be of various types or sizes;
their assembly may be catalysed/mediated by acid, base, light
or metal complexes and the arene may result from the
combination of two, three or more building blocks. Important
and well-known transformations such as the Dötz reaction4
and Danheiser benzannulation5 amply demonstrate the power
Arylsulfones are important synthetic targets owing to their
well-described biological activities as well as synthetic utility.8
In addition, some arylsulfones also exhibit
excellent
coordinating properties.9 Common methods for the
construction of arylsulfones include oxidation of aryl sulfides,10
sulfonylation of arenes11 and coupling of sulfinates with aryl
halides.12 These protocols invariably require arene building
blocks and the challenges associated with their availability and
functionalisation (vide supra) often necessitate lengthy routes
and cumbersome procedures. We and others have attempted
to address these challenges by developing new benzannulation
methods for the convenient synthesis of arylsulfone
derivatives.13
a) Previous work (ref. 13)
PhO 2
S
SO 2Ph
PhO 2
S
SO 2R
PhO 2
S
SO 2R
DBU
[3+3]
1
aerial
oxidation
R
R
O
R
2
b) This work
R1O2
SO 2R1
S
R1O2
S
SO 2R1
R1O2
S
SO 2R1
3
Base
R3
R3
[3+3]
R3
isomerisation
O
Br
R2
R2
5
R2
a. Department of Chemistry, Central University of Haryana, Mahendergarh, Haryana
123029, India. E-mail: rajeevmenon@cuh.ac.in
4
b. Department of Chemistry, University of Delhi, Delhi 110007, India.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [Experimental procedures,
characterisation data and scanned NMR spectra of new compounds]. See
DOI: 10.1039/x0xx00000x
Scheme 1: a) [3+3] benzannulation reactions of enals/enones; b) The present work
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
ARTICLE
Journal Name
Me
O
SO2R1
This
mild,
base-mediated,
aerial-oxidative,
[3+3]
View Article Online
SO R1
DOI: 10.1039/C9OB00214F
2
DBU, DMF
25 oC, 1h
benzannulation method afforded substituted arylsulfones
from two simple 3-carbon building blocks, viz., the bis-
nucleophile 1 and the bis-electrophile 2 (Scheme 1a). The
innate simplicity of this approach along with the richly
functionalised nature of the arene products prompted us to
explore this method further. We surmised that union of
symmetric, sulfone-bearing, bis-nucleophile
multifunctional electrophilic partner, such as 4, could
potentially afford tetra-substituted bis-sulfonylarenes
(Scheme 1b). The easy generation of the substrate 4 via the
versatile Morita-Baylis-Hillman (MBH) reaction14 was indeed a
key driving factor behind the design of this route. In addition,
it was intriguing to examine the reactivity of the MBH bromide
4 which incorporated three reactive electrophilic centers in a
benzannulation reaction.
Br
SO2R1
SO2R1
5aa
4a
3a, R1 = p-tolyl
Scheme 3: DBU-mediated benzannulation reaction of 4a and 3a
3
and
a
The facile formation of a tetrasubstituted phenyl ring from two
simple acyclic precursors prompted us to investigate the scope
and generality of the benzannulation reaction. To this end, a
variety of MBH-bromides were prepared in the same manner
as described in Scheme 2. They were treated with 1,3-bis-
arylsulfonylpropenes 3a and 3b under the conditions for
benzannulation reaction. The results are summarised in table
1.
5
All of the MBH adducts 4a-4n employed in the study reacted
smoothly to afford the corresponding bis-sulfonylarenes. MBH-
adducts derived from substituted benzaldehydes afforded
biarylmethane products 5aa-5na endowed with nitro,
trifluoromethyl, thiomethyl, bromo and chloro groups.
Heterocyclic residues such as thiophene and furan may also be
incorporated in the final products (5ka, 5kb, 5la and 5lb) by
employing the corresponding heteroaryl MBH-adducts.
Electron donating aryl units such as p-methoxyphenyl ring is
also tolerated in the benzannulation reaction (5oa). It is
noteworthy that the benzannulation is not limited to aryl MBH
adducts. Alky group bearing substrates reacted uneventfully to
generate the corresponding tetrasubstituted arenes 5ma and
5na in very good yields. To test the scalability of the
benzannulation method, a representative reaction was carried
out using 1g of the MBH bromide 4j (R2 = 3-bromophenyl).
Pleasingly, the desired product 5ja was obtained in 71% yield.
Results and Discussion
The required MBH adduct 4a was prepared from benzaldehyde
and methyl vinyl ketone in two steps as reported earlier
(Scheme 2a).14a The nucleophilic reaction partners, 1,3-bis-
toluenesulfonylpropene
phenylsulfonylprpopene 3b were prepared from the
corresponding bromides 6a, 6b as depicted in Scheme 2b.15
3a
and
1,3-bis-
O
O
i) DABCO
Dioxane-water
Ph
(a)
(b)
Ph CHO
ii) HBr, H2SO4
Br
4a
R1O2S
SO2R1
R1O2S
6a, R1 = p-tolyl
R1SO2Na
Br
MeOH
3a, R1 = p-tolyl
3b, R1 = Ph
25 oC, 12 h
6b, R1 = Ph
Scheme 2: Preparation of substrates for benzannulation reactions
Following the synthesis of the precursors 3a and 4a, their
union in a benzannulation reaction was attempted. In a pilot
reaction, 3a and 4a were subjected to the conditions of our
previously reported benzannulation protocol.13a Pleasingly, a
facile reaction was observed and a crystalline product was
obtained after work-up and column chromatography. The
diphenylmethane structure 5aa was assigned to the product
on the basis of spectroscopic analysis. In the 1H NMR spectrum
of the product, a singlet at  3.99 corresponding to two
protons indicated the presence of the benzylic methylene
group. Another singlet at  2.35 (3H) was assigned to the
methyl group on the newly formed arene. The presence of
signals at  39.7 and  16.3 in the 13C NMR spectrum
confirmed the presence of these methylene and methyl groups
respectively. The two aromatic protons on the newly formed
aryl ring resonated as mutually coupled doublets (J = 2.0 Hz) at
 8.63 and  7.87. Other spectroscopic data were also in
complete agreement with the assigned structure.
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
Page 3 of 4
Organic & Biomolecular Chemistry
Journal Name
ARTICLE
Table 1: Substrate scope of the benzannulation reactiona
A simplified mechanistic rationalisation for the formation of
biaryl methane derivatives in the benzannulation reaction is
View Article Online
DOI: 10.1039/C9OB00214F
R1O2S
Me
O
SO2R1
advanced as depicted in Scheme 5. The reaction is initiated by
the displacement of the primary allylic bromide in 4a by the
stabilised carbanion 7 generated from 3b and DBU. This is
presumably because the bromine containing carbon is the
least hindered electrophilic site in 4a. Further deprotonation
and intramolecular Julia-type cyclisation affords the
cyclohexenol derivative 8 (Intramolecular Michael addition of
the stabilized carbanion to the enone moiety is presumably
less favoured due to higher steric demands). The carbinol 8
then undergoes dehydration to produce the cyclohexadiene
derivative 9. The final product 5ab is then formed via the
aromaticity-driven isomerisation of 9.
R2
DBU, DMF
R2
+
25 oC, 1h
R1O2S
Br
SO2R1
3a,
3b,
R
1 = p-tolyl
4a-o
5aa-oa
R
1 = phenyl
Me
Me
Me
SO2R1
SO2R1
SO2R1
F3C
Cl
SO2R1
SO2R1
SO2R1
, R1 = p-tolyl, 66%
, R1 = phenyl, 69%
, R1 = p-tolyl, 71%
, R1 = phenyl, 74%
, R1 = p-tolyl, 74%
, R1 = phenyl, 75%
5ca
5ba
5aa
5ab
5cb
5bb
Me
Me
NO2
Me
SO2R1
SO2R1
SO2R1
PhO2S
PhO2S
SO2Ph
SO2Ph
PhO2S
7
DBU
MeS
O2N
SO2R1
SO2R1
SO2R1
O
Br
DBUH
O
, R1 = p-tolyl, 78%
PhO2S
Ph
5da
, R1 = p-tolyl, 56%
5fa
, R1 = p-tolyl, 58%
5ea
5ha
5ka
Ph
3b
4a
Me
NO2
Me
Br
Me
SO2R1
SO2Ph
PhO2S
SO2R1
SO2Ph
SO2R1
PhO2S
DBUH
DBU
DBU
iPr
O
SO2R1
SO2R1
O
Cl
SO2R1
Cl
Ph
Ph
, R1 = p-tolyl, 75%
, R1 = p-tolyl, 62%
5ia
, R1 = p-tolyl, 67%
5ga
PhO2S
SO2Ph
-H2O
PhO2S
SO2Ph
isomerise
SO2Ph
PhO2S
Me
Me
Me
SO2R1
SO2R1
SO2R1
OH
S
O
Ph
Ph
Ph
SO2R1
SO2R1
Br
SO2R1
5ab
8
9
, R1 = p-tolyl, 72%
, R1 = phenyl, 74%
, R1 = p-tolyl, 73%
, R1 = p-tolyl, 69%
, R1 = phenyl, 71%
5ja
5la
5kb
(71% at 1g scale)
5lb
Scheme 5: Plausible mechanism of the benzannulation reaction
, R1 = phenyl, 76%
5jb
Me
Me
The biarylmethane derivatives are amenable to further
synthetic modifications. For example, tert-butyl hydroperoxide
(TBHP) and FeCl3-mediated benzylic oxidation17 of two
representative biarymethanes 5ab, 5bb afforded the
corresponding benzophenone derivatives 10a, 10b in excellent
yields (Scheme 6). It may be noted that the benzylic oxidation
proceeded exclusively at the methylene group and the methyl
group was unaffected.
Me
SO2R1
SO2R1
SO2R1
nBu
MeO
SO2R1
SO2R1
SO2R1
, R1 = p-tolyl, 82%
, R1 = p-tolyl, 73%
, R1 = p-tolyl, 72%
5oa
5na
5ma
aReaction conditions: 4 (0.3mmol), 3 (0.33mmol), DBU (0.45mmol), DMF (5ml),
1h, 25 °C.
Me
O
Me
The benzannulation reaction was also successfully carried out
using the MBH bromide 4p derived from ethyl vinyl ketone and
SO2Ph
SO2Ph
FeCl3, aq TBHP
Pyridine, 80 °C
3-chlorobenzaldehyde.
The
reaction
of
1,3-bis-
R3
R3
toluenesulfonylpropene 3a and 4p under the optimised
conditions afforded the ethyl group-bearing arene product 5pa
SO2Ph
SO2Ph
R3 = H, 5ab
R3 = Cl, 5bb
R3 = H, 10a, 92%
R3 = Cl, 10b, 93%
in 63% yield (Scheme 4).16
Me
SO2R1
O
Scheme 6: Benzophenone synthesis via site-selective oxidation of biarylmethanes
SO2R1
Me
DBU, DMF
25 oC, 1h
Br
SO2R1
Conclusions
SO2R1
Cl
Cl
5pa
4p
3a, R1 = p-tolyl
63%
In conclusion, a [3+3] benzannulation reaction of 1,3-bis-
sulfonyl propene derivatives and MBH-bromides has been
developed. A series of highly substituted bis-sulfonyl arene
derivative were synthesised in good yields. The
Scheme 4: Benzannulation reaction of MBH bromide derived from ethyl
vinyl ketone
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 4
ARTICLE
Journal Name
8
For biological activity of arylsulfones, see: (a) C. J. Dinsmore,
T. M. Williams, T. J. O’Neill, D. Liu, E. DROanI:d1s0,.1J0.3VC9ie/.wCC9AuOrtlibBcl0ee0rOs2no1li4nnFe,
R. B. Lobell, K. S. Koblan, N. E. Kohl and J. B. Gibbs, Bioorg.
Med. Chem. Lett., 1999, 9, 3301; (b) M. Pal, V. R.
Veeramaneni, M. Nagabelli, S. R. Kalleda, P. Misra, S. R.
Casturib and K. R. Yeleswarapu, Bioorg. Med. Chem. Lett.,
2003, 13, 1639; For reviews on synthetic applications of
sulfones, see: (c) V. G. Nenajdenko, A. L. Krasovskiy and E. S.
Balenkova, Tetrahedron, 2007, 63, 12481; (d) M. Nielsen, C.
B. Jacobsen, N. Holub, M. W. Paixao and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2010, 49, 2668.
benzannulation reactions are mediated by a common base
(DBU), proceed rapidly at room temperature and generate
significant levels of molecular complexity. The biaryl
derivatives thus obtained are readily converted into
corresponding benzophenone derivatives by site-selective
benzylic oxidation. It is presumable that the method may find
applications in the targeted synthesis of sulfonyl arenes and
benzophenones.
9
M. L. Ezzi, R. Lenk, D. Madec, J. –M. Sotiropoulos, S. Mallet-
Ladeira and A. Castel, Angew. Chem., Int. Ed., 2015, 54, 805.
Conflicts of interest
There are no conflicts to declare.
10 R. S. Ward and R. L. Diaper, Sulfur Rep., 2001, 22, 251.
11 C. G. Frost, J. P.Hartley and A. J. Whittle, Synlett, 2001, 830.
12 W. Zhu and D. Ma, J. Org. Chem., 2005, 70, 2696.
13 (a) P. R. Joshi, S. Undeela, D. D. Reddy, K. K. Singarapu and R.
S. Menon, Org. Lett., 2015, 17, 1449; (b) X.-Z. Tang, L. Tong,
H.-J. Liang, J. Liang, Y. Zou, X. J. Zhang, M. Yan and A. S. C.
Chan, Org. Biomol. Chem., 2018, 16, 3560; (c) L. Jiang, H. Li,
J.-F. Zhou, M.-W. Yuan, H.-L. Li, Y.-M. Chuan and M.-L. Yuan,
Synth. Commun., 2018, 48, 336.
14 (a) R. Buchholtz and H. M. R. Hoffmann, Helv. Chim. Acta.,
1991, 74, 1213; (b) D. Basavaiah, R. S. Hyma, K. Padmaja and
M. Krishnamacharyulu, Tetrahedron, 1999, 55, 6971.
Acknowledgements
DY acknowledges the award of a Junior Research Fellowship
from Council of Scientific and Industrial Research (CSIR), India.
RSM acknowledges the Science and Engineering Research
Board, Department of Science and Technology (SERB-DST),
India, for the award of an Early Career Award Grant
(ECR/2016/001401).
15 E. T. Gallagher and D. H. Grayson, Org. Biomol. Chem. 2003,
1, 1374. (b) (b) A. Padwa, Y. Gareau, B. Harrison, N. Brian
and H. Bryan, J. Org. Chem., 1991, 56, 2713.
16 Attempts to prepare the MBH bromide via bromination of
the MBH adduct derived from phenyl vinyl ketone failed and
hence its benzannulation reaction could not be tested.
17 M. Nakanishi and C. Bolm, Adv. Synth. Catal., 2007, 349, 861.
Notes and references
1
(a) V. Snieckus, Beilstein J. Org. Chem., 2011, 7, 1215 and
references cited therein. (b) J. F. Bunnett, Acc. Chem. Res.,
1978, 11, 413.
(a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457; (b)
J. K. Stille, Angew. Chem., Int. Ed., 1986, 25, 508; (c) M. M.
Heravi, Z. Kheilkordi, V. Zadsirjan, M. Heydari and M. Malmir,
J. Organomet. Chem., 2018, 861, 17.
2
3
(a) V. Snieckus, Chem. Rev., 1990, 90, 879; (b) N. Kuhl, M. N.
Hopkinson, J. Wencel-Delord and F. Glorius, Angew. Chem.,
Int. Ed., 2012, 51, 10236; (c) T. W. Lyons and M. S. Sanford,
Chem. Rev., 2010, 110, 1147.
4
5
(a) K. H. Dötz, Angew. Chem. Int. Ed. Engl., 1975, 14, 644; (b)
M. L. Waters and W. D. Wulff, Org. React., 2008, 70, 121.
(a) R. L. Danheiser and S. K. Gee, J. Org. Chem., 1984, 49,
1672; (b) R. L. Danheiser, R. G. Brisbois, J. J. Kowalczyk, R. F.
Miller, J. Am. Chem. Soc., 1990, 112, 3093.
6
For selected reviews, see: (a) A. R. Katritzky, J. Lie and L. Xie,
Tetrahedron, 1999, 55, 8263; (b) J. Feng and B. Liu,
Tetrahedron Lett., 2015, 56, 1474; (c) T. N. Poudel, R. J. I.
Tamargo, H. Cai and Y. R. Lee, Asian J. Org. Chem., 2018, 7,
985. For selected examples, see: (d) A. Diallo, Y. -L. Zhao, H.
Wang, S. -S. Li, C. -Q. Ren and Q. Liu, Org. Lett. 2012, 14,
5776; (e) L. Li, Y. -L. Zhao, H. Wang, Y. -J. Li, X. Xu and Q. Liu,
Chem. Commun., 2014, 50, 6458; (f) T. N. Poudel and Y. R.
Lee, Chem. Sci., 2015, 12, 7028; (g) E. Gopi and I. N. N.
Namboothiri, J. Org. Chem., 2014, 79, 7468; (h) L. Satham
and I. N. N. Namboothiri, J. Org. Chem., 2018, 83, 9471; (i)
W. Tong, Q.-Y. Li, Y.-L. Xu, H.-S. Wang, Y.-Y. Chen,Y.-M. Pan,
Adv. Synth. Catal., 2017, 359, 4025; (j) Z.-C. Shu, J.-B. Zhu, S.
Liao, X.-L. Sun and Y. Tang, Tetrahedron, 2005, 61, 11449; (k)
P. Xie, Y. Huang and R. Chen, Chem. Eur. J., 2012, 18, 7362.
(a) H. Li, Q. Chen, Z. Lu and A. Li, J. Am. Chem. Soc., 2016,
138, 48, 15558; (b) P. Yang, M. Yao, J. Li, Y. Li and A. Li,
Angew. Chem. Int. Ed., 2016, 55, 6964; (c) X. Y. Mak, L. A.
Crombie and R. L. Danheiser, J. Org. Chem., 2011, 76, 1852;
(d) A. Minatti and K. H. Dötz, J. Org. Chem., 2005, 70, 3045;
(e) P. Finkbeiner, K. Murai, M. Röpke and R. Sarpong, J. Am.
Chem. Soc., 2017, 139, 11349; (f) W. Chen, R. Guo, Z. Yang
and J. Gong, J. Org. Chem., 2018, 83, 15524.
7
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins