Oxygenative and Dehydrogenative [3 + 3] Benzannulation Reactions of α,β-Unsaturated Aldehydes and γ-Phosphonyl Crotonates Mediated by Air: Regioselective Synthesis of 4-Hydroxybiaryl-2-carboxylates

Article abstract of DOI:10.1021/acs.orglett.6b00016

Regioselective synthesis of 4-hydroxybiphenyl-2-carboxylates via the base-mediated oxygenative [3 + 3] benzannulation reaction of α,β-unsaturated aldehydes and γ-phosphonyl crotonates is reported. A hydroxyl group is installed in the final product on the originally phosphorus-bound carbon via a novel oxygenative and dehydrogenative transformation. The reaction proceeds rapidly in an open flask, uses atmospheric oxygen as an oxidant, and affords good yields of substituted biaryl phenols. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.6b00016

Letter
pubs.acs.org/OrgLett
Oxygenative and Dehydrogenative [3 + 3] Benzannulation Reactions
of α,β-Unsaturated Aldehydes and γ‑Phosphonyl Crotonates
Mediated by Air: Regioselective Synthesis of 4‑Hydroxybiaryl-2-
carboxylates
Prabhakar Ramchandra Joshi,† Jagadeesh Babu Nanubolu,‡ and Rajeev S. Menon*,†
†Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
‡Centre for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
S
* Supporting Information
ABSTRACT: Regioselective synthesis of 4-hydroxybiphenyl-2-carbox-
ylates via the base-mediated oxygenative [3 + 3] benzannulation reaction
of α,β-unsaturated aldehydes and γ-phosphonyl crotonates is reported. A
hydroxyl group is installed in the final product on the originally
phosphorus-bound carbon via a novel oxygenative and dehydrogenative
transformation. The reaction proceeds rapidly in an open flask, uses
atmospheric oxygen as an oxidant, and affords good yields of substituted biaryl phenols.
A careful survey of benzannulation chemistry reveals that the
aerial oxidation of cyclohexadiene intermediates to arenes is a
frequently encountered mechanistic event. Two such oxidative
benzannulation reactions pertinent to the present work are
depicted in Scheme 1.
he biaryl motif is a recurring substructure of a number of
Tnatural products, bioactive molecules, chiral catalysts, and
functional materials.1 Development of methods for biaryl
synthesis has, therefore, been an important and fertile area of
investigation.2 Transition-metal-mediated reactions such as
Suzuki−Miyaura, Negishi, and Stille couplings are among the
most commonly used methods of biaryl construction.3 Directed
arylation via metal-catalyzed C−H activation has recently
emerged as a powerful method of biaryl synthesis.4 Both of
these approaches, however, rely on the availability of arene
building blocks armed with functional or directing groups. Such
functionalized arenes are, in turn, mostly prepared from
feedstock chemicals by electrophilic and (less frequently)
nucleophilic aromatic substitution reactions.5 Regioselectivity
of aromatic substitution reactions is controlled by the electronic
nature of the arene and the directing effects of existing
substituents. The construction of polysubstituted arenes via
aromatic substitution becomes challenging when such directing
effects do not favor the desired regiochemistry. Benzannulation
reactions, the denovo assembly of arenes from acyclic precursors,
constitute an alternative and superior approach for the
regioselective synthesis of polysubstituted aromatic rings.6 A
vast majority of benzannulation reactions involve two
components, and they are classified on the basis of the number
of carbon atoms that each of them contributes.7 The
benzannulation approach is characterized by beneficial attributes
such as the availability of a variety of acyclic precursors, different
modes of annulations, and scope for catalysis. Recent reports by
Lee and others on the synthesis of highly substituted phenols and
benzene derivatives from acyclic precursors illustrate the
synthetic potential of benzannulation reactions.8 The elegant
work of Li on the construction of various terpenoid natural
products also showcases the utility of benzannulation reactions.9
In 2012, Liu and Zhao reported an oxidative [3 + 3]
benzannulation reaction of dimethyl glutaconate 1 and α,β-
unsaturated carbonyl compounds 2 to afford highly substituted
arenes 3 (Scheme 1a).10 Our recent investigations on the
cyclocondensation reactions of unsaturated sulfones led to the
discovery of an oxidative [3 + 3] benzannulation reaction for the
regioselective synthesis of substituted sulfonylarenes 4 (Scheme
1b).11 These benzannulations presumably proceed via base-
mediated cyclocondensation of a 1,3-bisnucleophile with a 1,3-
biselectrophile to generate a cyclohexadiene intermediate 5.
Subsequent aerial oxidation (dehydrogenation) of the latter
affords the substituted arene (Scheme 1c). The success of this
reaction provided an impetus to explore this area in detail. In this
context, the utility of the γ-phosphonyl crotonate 6 as a 1,3-
bisnucleophile was examined. Our efforts along this direction
culminated in the serendipitous discovery of a novel oxidative
benzannulation reaction for the synthesis of substituted biaryl
phenols 7 (Scheme 1d).
Interestingly, the overall process may be termed a dehydrogen-
ative and oxygenative [3 + 3+O] benzannulation wherein the
phosphonate unit of 6 is replaced by a hydroxyl group in the final
product 7. The details of our preliminary investigation that led to
the development of this novel transformation are presented in
the following sections.
The study was initiated by screening various bases for the
reaction of cinnamaldehyde 8 and the phosphonate 6a12 in an
Received: January 4, 2016
© XXXX American Chemical Society
A
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Letter
(entries 1−4). It was observed that only sodium hydride in THF
promoted the Wadsworth−Emmons reaction to afford 35% of
the triene ester 913 (entry 5). On the other hand, the reactions
mediated by potassium tert-butoxide (entries 7−10) furnished an
unexpected product that was assigned the structure 7a based on
its spectroscopic data (see the SI for details). The best yield for
7a was obtained when 8 was reacted with 2 molar equiv each of
the phosphonate 6a and base in acetonitrile in an open flask
(entry 7). Interestingly, the substituted cyclohexadiene 10 was
obtained in 62% yield when the reaction was run at carefully
deoxygenated conditions (entry 11). The yield of the
benzannulation reaction was practically unchanged when the
reaction was carried out under a balloon filled with oxygen.
The unexpected formation of a phenol derivative prompted us
to explore the scope of this reaction. A variety of α,β-unsaturated
aldehydes were prepared, and they were treated with the
phosphonates 6a,b under the optimized reaction conditions. The
results are summarized in Scheme 2.
Scheme 1. (a) [3 + 3] Benzannulation of Glutaconates; (b) [3
+ 3] Benzannulation of Sulfonyl Crotonates; (c) Common
Mechanistic Framework for These Benzannulations; (d)
Present Work
a,b
Scheme 2. Scope of the Oxidative Benzannulation Reaction
open flask at room temperature (Table 1). Although the
likelihood of a facile Wadsworth−Emmons reaction was obvious,
our recent experience11 with a similar combination of ambident
reactants (Scheme 1b) warranted an exploration. The use of
potassium carbonate, DBU, and cesium carbonate led to the
consumption of 6a; however, no stable product could be isolated
Table 1. Optimization of Reaction Conditions for the Base-
a
Mediated Union of Cinnamaldehyde 8 and Phosphonate 6a
b
entry
base (equiv)
solvent
time (h)
product (yield, %)
1
2
3
4
5
6
7
8
9
K2CO3 (3)
K2CO3 (2)
DBU (2)
CH3CN
DMF
2
2
DMF
1
Cs2CO3 (2)
NaH (2)
CH3CN
THF
2
2
9 (35)
KOtBu (2)
KOtBu (2)
KOtBu (3)
KOtBu (1)
KOtBu (2)
KOtBu (2)
KOtBu (2)
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
2
a
Reaction conditions: 6a,b (1 mmol), enal (0.5 mmol), KOtBu (1
b
0.5
0.5
0.5
0.5
0.5
0.5
7a (67)
7a (60)
7a (52)
7a (44)
10 (62)
7a (66)
mmol), acetonitrile (4 mL), 25 °C, air, 0.5 h. Yields of products
isolated after column chromatography. Expected product for the
reaction of 6a and (E)-oct-2-enal.
c
c
10
d
11
An array of 2-carboxy-4-hydroxy biaryls 7a−r was obtained
from readily available starting materials. The β-aryl rings of enals
can accommodate electron-releasing as well as electron-with-
drawing substituents without compromising the efficiency of the
oxidative benzannulation reaction. A cyano group on the enal−
aryl ring is tolerated under the reaction conditions as illustrated
e
12
a
Reaction conditions: 6a (0.50 mmol), 8 (0.25 mmol), base, CH3CN
(2 mL). Isolated yield after chromatography. Reaction at 0 °C.
Reaction under deoxygenated conditions. Reaction under an oxygen
balloon.
b
c
d
e
B
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Letter
by the formation of phenol 7i. Heterobiaryls 7p−r endowed with
2-furyl and 2-thienyl rings are produced from β-heteroaryl enals.
It is noteworthy that palladium-mediated coupling reactions of
the bromine-carrying biaryls 7c,d,h could potentially lead to the
formation of valuable p- and m-terphenyls. Attempted reactions
of β-alkyl enals and α,β-unsaturated ketones, however, failed to
deliver the benzannulation products. Although both the starting
materials were consumed, no identifiable products could be
isolated in these cases.
Scheme 4. Synthetic Transformations of Representative
Phenol 7a
Interestingly, treatment of 4-nitrocinnamaldehyde and 6a
under benzannulation conditions did not afford the phenol
product. Instead, the substituted cyclohexadiene 12 was obtained
in 63% yield (Scheme 3a). It may be recalled that analogous
Scheme 3. (a) 4-Nitrocinnamaldehyde Affords the
Cyclohexadiene 12 under Benzannulation Conditions. (b)
Compounds 10 and 12 Are Not Converted to the
Corresponding Phenols under Benzannulation Conditions
Scheme 5. Mechanistic Hypothesis for the Oxidative
Benzannulation
cyclohexadiene 10 was obtained from cinnamaldehyde during
optimization studies when oxygen was excluded from the
reaction mixture (Table 1, entry 11). Moreover, the formation
of similar cyclohexadienes in the reaction of tetrazolylacroleins
and methyl (2E)-4-(triphenylphosphoranylidene)but-2-enoate
has been reported.14 Isolated samples of cyclohexadienes 10 and
12 were largely unchanged even after 24 h when they were
subjected to the conditions of benzannulation under air (Scheme
3b). Evidently, the cyclohexadienes 10 and 12 are not
intermediates in the formation of the phenol products.
Presumably, the cyclohexadienes are generated as a result of a
parallel reaction pathway.
It is clear from the aforementioned results that a convenient
protocol for the synthesis of substituted phenols has been
developed. Such methods are extremely important as phenols are
versatile building blocks for industrial chemicals, pharmaceut-
icals, and polymers.15 The synthetic malleability of the biaryl
phenols generated in the present study is evident in the
transformations depicted in Scheme 4a. The triflate 13 derived
from the phenol 7a was employed in a Suzuki−Miyaura coupling
to obtain the p-terphenyl derivative 14 in 75% yield. Additionally,
base-mediated acylation of the representative phenol 7a with p-
nitrobenzoyl chloride afforded a crystalline derivative 15
(Scheme 4b). Single-crystal X-ray analysis of the latter confirmed
the structural assignment and the regiochemical outcome of the
benzannulation reaction.16
of the phosphonate anion A to the enal to afford an acylic
intermediate B. The preferential addition at the less hindered end
of the allylic anion A sets the regiochemistry of the overall
transformation. Deprotonation of B and subsequent intra-
molecular nucleophilic attack of the resultant carbanion C on
the aldehyde would produce β-hydroxyphosphonate D. Such β-
hydroxyphosphonates are generally stable and isolable in the
absence of an electron-withdrawing group at the β-position.17
Here, D presumably generates the stabilized carbanion E via
proton shift (path a), and the latter interacts with atmospheric
oxygen to furnish the peroxide F. Incidentally, the reaction of
stabilized carbanions with oxygen is well-known and has been
employed in targeted synthesis, most notably by Stork in the
synthesis of quinine.18 Peroxide F may undergo internal proton
transfer to form the alkoxide G, which then attacks the adjacent
Although the mechanistic underpinnings of the oxidative
benzannulation reaction are not clear at this stage, a plausible
rationalization may be advanced as follows (Scheme 5). The
initial carbon−carbon bond-forming event is a Michael addition
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00016.
■
S
Detailed experimental procedures and characterization
data for all compounds (PDF)
X-ray data for 15 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rajeevmenon@iict.res.in, srajeevmenon@gmail.com.
Notes
(10) Diallo, A.; Zhao, Y.-L.; Wang, H.; Li, S.-S.; Ren, C.-Q.; Liu, Q. Org.
Lett. 2012, 14, 5776.
(11) Joshi, P. R.; Undeela, S.; Reddy, D. D.; Singarapu, K. K.; Menon,
R. S. Org. Lett. 2015, 17, 1449.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(12) Baeckstrom, P.; Jacobsson, U.; Norin, T.; Unelius, C. R.
Tetrahedron 1988, 44, 2541.
(13) Mascitti, V.; Corey, E. J. Tetrahedron Lett. 2006, 47, 5879.
̈
■
The Science and Engineering Research Board, Department of
Science and Technology (SERB, DST), India, is acknowledged
for the award of a Ramanujan fellowship (SR/S2/RJN-05-2011)
and a Start-up Research Grant (SR/FT/CS-141/2011) for
R.S.M. Financial support in part from the XIIth five year plan
project “Affordable Cancer Therapeutics (ACT, CSC 0301)”
and Research Fellowship for P.R.J. from the Council of Scientific
and Industrial Research (CSIR), India, is also acknowledged.
(14) Nagy, I.; Hajos
2007, 63, 4730.
́ ́
, G.; Riedl, Z.; Egyed, O.; Papai, I. Tetrahedron
(15) Rappoport, Z. The Chemistry of Phenols; Wiley-VCH: Weinheim,
2003.
(16) CCDC 1431949 (15) contains the supplementary crystallo-
graphic data for this compound.
(17) Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5654.
(18) Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J. M.; Tata,
J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239.
(19) Reichwein, J. F.; Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125,
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