Secondary amine-catalyzed [3 + 3] benzannulation to access polysubstituted benzenes through iminium activation

Article abstract of DOI:10.1080/00397911.2017.1402351

An organocatalytic [3 + 3] benzannulation to access polysubstituted benzenes from readily available α,β-unsaturated aldehydes and 1,3-bis(phenylsulfonyl)propene or 4-sulfonylcrotonates is described. The key reaction step is considered to be the iminium ac

Full text of DOI:10.1080/00397911.2017.1402351

Synthetic Communications
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Secondary amine-catalyzed [3ꢀ+ꢀ3] benzannulation
to access polysubstituted benzenes through
iminium activation
Lin Jiang, Hang Li, Jiang-Feng Zhou, Ming-Wei Yuan, Hong-Li Li, Yong-Ming
Chuan & Ming-Long Yuan
To cite this article: Lin Jiang, Hang Li, Jiang-Feng Zhou, Ming-Wei Yuan, Hong-Li Li, Yong-
Ming Chuan & Ming-Long Yuan (2018): Secondary amine-catalyzed [3ꢀ+ꢀ3] benzannulation to
access polysubstituted benzenes through iminium activation, Synthetic Communications, DOI:
10.1080/00397911.2017.1402351
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https://doi.org/10.1080/00397911.2017.1402351
Secondary amine-catalyzed [3 + 3] benzannulation to access
polysubstituted benzenes through iminium activation
Lin Jianga,b, Hang Lia,b, Jiang-Feng Zhoua, Ming-Wei Yuanb, Hong-Li Lia,b,
Yong-Ming Chuana, and Ming-Long Yuana,b
aSchool of Chemistry and Environment, Yunnan Minzu University, Kunming, Yunnan, China;
bEngineering Research Center of Biopolymer Functional Materials of Yunnan, Yunnan Minzu University,
Kunming, Yunnan, China
ABSTRACT
ARTICLE HISTORY
Received 31 August 2017
An organocatalytic [3 þ 3] benzannulation to access polysubstituted
benzenes from readily available α,β-unsaturated aldehydes and 1,3-bis
(phenylsulfonyl)propene or 4-sulfonylcrotonates is described. The key
reaction step is considered to be the iminium activation of enals by a
secondary aminocatalyst. This organocatalytic protocol avoids the
traditional strategy which is always with the aid of a transition-metal
or a stoichiometric amount of strong base, and allows the synthesis of
trisubstituted benzenes in high to excellent yields (74–96%).
KEYWORDS
[3 þ 3] Benzannulation;
aminocatalysis; biaryl
sulfones; iminium activation;
polysubstituted benzenes
GRAPHICAL ABSTRACT
Introduction
Polysubstituted benzenes are highly valued for their diverse applications in organic synthesis
and in material science.[1] Besides, they are also important structural units of a number of
natural products or pharmacologically active molecules.[2] Regio- and chemoselective con-
struction of polysubstituted benzene derivatives has been a challenging task in organic syn-
thesis. The traditional synthetic routes feature the introduction of a desired substituent into
a specific position of preexisting arene ring. Accordingly, the predominant strategies include
the classic aromatic nucleophilic or electrophilic substitution,[3] catalytic coupling reaction[4]
and metalation functionalization.[5] However, these methods often encounter difficulties in
synthesizing certain substituted benzenes where the desired regioselectivity and the steric or
orienting effect of the substituents already in place on arene precusors are mutually repulsive.
Alternatively, benzannulation reactions, especially those under transition-metal-free con-
ditions, offer a straightforward and environmentally-friendly way to transform various acyclic
building blocks into substituted aromatic skeletons.[6] Based on the number of reaction
CONTACT Lin Jiang
jianglin_1981@163.com; Ming-Long Yuan
yml@vip.163.com
School of Chemistry and
Environment, Yunnan Minzu University, Kunming 650500, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2017 Taylor & Francis

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L. JIANG ET AL.
components and the number of carbon atoms involved into the benzene ring of final product,
a variety of benzannulation reactions, with diverse substrate forms, catalytic modes and reac-
tion mechanisms have been reported during the past few decades.[7–9] These reactions in turn
demonstrate the importance of benzannulation reaction, which serves as a powerful tool and a
superior complement toward synthesizing polysubstituted benzene compounds.
α,β-Unsaturated aldehydes or ketones have been successfully applied in the transition-
metal-free benzannulation strategies. For instance, in 2012, Zhao and Liu developed an
efficient method to synthesize polysubstituted benzenes from glutaconates through [3 þ 3]
aerobic oxidative benzannulation (Scheme 1a).[8a] In 2015, Menon and co-workers
reported the regioselective synthesis of highly substituted sulfonylarenes using
4-sulfonylcrotonates
or
1,3-bis(phenylsulfonyl)propene
as
1,3-bisnucleophiles
[Scheme 1b, Eq. (1)].[8b] Later on, the same research group described an approach to
produce substituted phenols from γ-phosphonyl crotonates [Scheme 1b, Eq. (2)].[8c] Very
recently, Zhang and Ye[9a] discovered the N-heterocyclic carbene catalyzed [4 þ 2]
benzannulation to give 1,3,5-trisubstituted benzenes from α-bromoenals and α-cyano-β-
methylenones (Scheme 1c). All of these listed reactions were triggered by the deprotona-
tion of nucleophilic reaction components by strong bases (i.e., NaOH,[8a] 1,8-diazabicyclo
[5.4.0]undec-7-ene,[8b] tBuOK[8c] and Cs2CO3 [9a]). Although enals have emerged as one
of the most reliable substrates in aminocatalysis,[10] to the best of our knowledge, the
secondary amine-catalyzed benzannulation of enals has not yet been reported. Aryl
Scheme 1. (a) Strong base-catalyzed [3 þ 3] benzannulation; (b) stoichiometric amount of
strong bases-directed [3 þ 3] benzannulation through deprotonative reaction pathway;
(c) NHC-catalyzed [4 þ 2] benzannulation; (d) this work: secondary amine-catalyzed [3 þ 3] benzannulation
through iminium activation. Note: NHC, N-heterocyclic carbine.

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3
sulfones not only represent ubiquitous structural motifs in biologically active natural
products, pharmaceuticals and synthetic intermediates,[11] but they are also used in optical
and functional materials.[12] Herein, we reported the first secondary amine-catalyzed
[3 þ 3] benzannulation of enals and allylic sulfone-containing 1,3-bisnucleophiles through
iminium activation strategy, allowing the synthesis of a variety of biaryl sulfone derivatives
under extremely mild conditions (without transition-metal or strong base and open to air)
in a single step (Scheme 1d).
Results and discussion
Initially, trans-cinnamaldehyde 1a (0.15 mmol) and 1,3-bis(phenylsulfonyl)propene 2a
(0.1 mmol) were used as model substrates to optimize the reaction conditions. As
illustrated in Table 1, in open air, the expected [3 þ 3] benzannulation could smoothly
proceed to produce 1,3-bissulfonyl benzene derivative 3a in 69% yield within 6 h under
the catalysis of piperidine 4a (20 mol%) in chloroform (1 mL) at ambient temperature
Table 1. Optimization of reaction conditionsa.
Entry
Catalyst
Solvent
T (°C)
t (h)
Yield (%)b
1
2
4a
4b
4c
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCE
CH3CN
Toluene
PhCF3
THF
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
25
25
25
25
25
25
25
25
25
25
40
0
25
25
25
25
25
6
6
69
83
25
30
NRc
76
70
74
55
73
80
75
83
71
82
78
82
3
18
18
18
6
4
4d
4e
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
5
6
7
6
8
6
9
6
10
11
12
13d
14e
15f
16g
17h
6
4
24
6
10
6
10
8
aReaction conditions: unless otherwise noted, reactions were conducted with cinnamaldehyde 1a (0.15 mmol), 1,3-bis
(phenylsulfonyl)propene 2a (0.1 mmol) and catalyst (20 mol%) in solvent (1 mL) at indicated reaction temperature in open
air.
bYield of isolated product.
cNR ¼ no reaction.
d30 mol% of catalyst.
e10 mol% of catalyst.
f50 mg of 4 Å MS.
gIn 2 mL of solvent.
hReaction run at 0.5 mmol scale of 2a.

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L. JIANG ET AL.
(Table 1, entry 1).[13] We were pleased to find that higher yield could be obtained when
pyrrolidine 4b was used under the same conditions (83%, Table 1, entry 2). In comparison,
other nucleophilic amines including morpholine 4c, 4-dimethylaminopyridine 4d and
pyridine 4e were less or no effective (Table 1, entries 3–5). To test the solvent effect, all
of the DCE, acetonitrile, toluene, benzotrifluoride and THF provided lower product yields
(55–76%, Table 1, entries 6–10), thus the initially used chloroform seemed to be the best
choice. Examination of reaction temperature revealed that both the higher and lower
temperature rendered the loss of product yield (80 and 75%, Table 1, entries 11 and 12).
No improvement in yield was observed when the catalyst loading was increased to 30 mol%
(83%, Table 1, entry 13). Moreover, a decrease in the amount of the catalyst made product
yield even worse (71%, Table 1, entry 14). Likewise, no better result was observed when 4 Å
molecular sieves (4 Å MS) were added as a water scavenger (82%, Table 1, entry 15).
Diluting the starting concentration of 2a to 0.05 M also showed no positive influence on
product yield (78%, Table 1, entry 16). Therefore, the optimal reaction parameters were
determined as the following: cinnamaldehyde 1a (0.15 mmol) and 1,3-bis(phenylsulfonyl)
propene 2a (0.1 mmol) were stirred in chloroform (1 mL) at 25 °C with pyrrolidine 4b
(20 mol%) as catalyst in open air (Table 1, entry 2). Furthermore, conducting the reaction
on up to 0.5 mmol scale of 2a under the optimized reaction conditions resulted in no
obvious change in yield (82%, Table 1, entry 17).
Having identified the optimal reaction conditions, we next explored the scope and
limitation of this [3 þ 3] benzannulation reaction of α,β-unsaturated aldehydes 1 and
various allylic sulfone-containing 1,3-bisnucleophiles 2 under the catalysis of pyrrolidine.
The results are summarized in Scheme 2. In general, the variants of substituents on
substrate 1 or 2 can tolerate reaction conditions well and polysubstituted benzenes 3a–o
were afforded in high to excellent yields (74–96%) within 6 h. Using 1,3-bis(phenylsulfo-
nyl)propene 2a as the reacting partner, an extensive range of α,β-unsaturated aldehydes
1 could be transformed into 1,3-bissulfonylarene 3a–m. Among them, α,β-unsaturated
aldehydes 1 with halogen or electron-withdrawing substituents in the meta- or
para-positions of aromatic rings (3c–g) provided higher yields, whereas enal armed with
an ortho-substituent (3b) resulted in lower yield. The position of electron-donating substi-
tuents on the aryl rings seemed to have no obvious effect on the efficiency of the reactions
(3h–j). β-Aryl ring of enal can also accommodate bulky 1-naphthyl group, giving product
3k in 83% yield. Similarly, other heteroaryl groups such as 2-furyl and 2-thienyl were
compatible with favorable reactivity (3l and 3m). It was worth mentioning that
4-sulfonylcrotonates 2b and 2c were also suitable substrates, regioselectively furnishing
3-sulfonyl benzoates 3n and 3o under the present reaction conditions. However,
compared to analogous product 3a, the yields were diminished. Unfortunately, when
trans-crotonaldehyde was applied to the system, only complex mixture was detected. It
was probably due to the dienamine activation that might coexist compared to the aromatic
enals.
After the reaction scope was investigated, we turned our attention to the reaction
mechanism. Based on the above results and literature precedent,[8b] a plausible mechanism
of the secondary amine-catalyzed regioselective [3 þ 3] benzannulation of enals and allylic
sulfone-containing 1,3-bisnucleophiles is proposed in Scheme 3. The benzannulation is
firstly triggered by activation of cinnamaldehyde 1a by pyrrolidine 4b, and the so-formed
iminium ion 5 would suffer a Michael addition with 4-sulfonyl crotonate 2b. Although the

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Scheme 2. Evaluation of substrate scope. Reaction conditions: reactions were performed with 1
(0.15 mmol), 2 (0.1 mmol) and pyrrolidine 4b (20 mol%) in chloroform (1 mL) at 25 °C in open air for
a
6 h; yield of isolated product. Single isomer. The regioisomeric structure was confirmed by comparison
of its NMR data with that reported in Joshi et al.[8b]
potential reaction site of 2b may be at either C1 or C3, it seems like that the bulky complex
5 and the phenylsulfonyl group of 2b just allow the less hindered C3 site to participate in
the reaction. Subsequently, the enamine intermediate 6 could tautomerize to its iminium
=
form 7, which undergoes 1,3-H-shift and migration of C C bond to afford the zwitterionic
intermediate 8. So, the intramolecular nucleophilic addition could occur to generate
Scheme 3. A plausible mechanism of the pyrrolidine-catalyzed [3 þ 3] benzannulation.

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L. JIANG ET AL.
cyclization intermediate 9 by elimination of catalyst. Finally, an aerobic oxidative
aromatization of 9 gives rise to the corresponding product 3n.
Conclusion
In summary, we have developed a straightforward [3 þ 3] benzannulation reaction of α,
β-unsaturated aldehydes and 1,3-bis(phenylsulfonyl)propene or 4-sulfonylcrotonates in
an organocatalytic manner to afford multisubstituted benzenes in high to excellent yields.
The benzannulation is triggered by iminium activation of enals by pyrrolidine and
proceeds through cascade regioselective Michael addition/intramolecular imino aldol/
oxidative aromatization. Compared with previously reported methods, the key reaction
step is considered to be the iminium activation of enals by a secondary aminocatalyst.
Besides, this protocol avoids the addition of transition-metal or stoichiometric amount
of strong base and can be handled easily with good substrate diversity, thus offering a
greener and milder alternative to access the polysubstituted benzenes. Further studies for
the transformations of the functionalities of products and new applications of this strategy
are currently underway.
Experimental
1H NMR spectra were recorded at 400 MHz and 13C NMR spectra were recorded at
100 MHz (Avance 400, Bruker, Faellanden, Switzerland). Chemical shift δ are given in
ppm on a scale downfield from TMS, and the coupling constant J are in Hz. ESI HRMS
was recorded on a Waters SYNAPT G2 (Milford, MA, USA). Melting points were uncor-
rected. Reactions were monitored by TLC, which was performed on precoated aluminum
sheets of silica gel (G254). Flash column chromatography was performed using silica gel
(200–300 mesh) and eluting with ethyl acetate and petroleum ether. In experiments requir-
ing dry solvents, CHCl3 was distilled from P2O5. DCE, CH3CN and toluene were distilled
from CaH2. PhCF3 was stored over 4 Å molecular sieves. THF was dried over sodium
metal. All other chemicals were used without purification as commercially available unless
otherwise noted. α,β-Unsaturated aldehydes were prepared from commercially available
aromatic aldehydes by successive Witting reaction with ethyl (triphenylphosphoranyli-
dene)acetate, reduction using diisobutyl aluminium hydride and oxidation using MnO2.[14]
1,3-Bis(phenylsulfonyl)propene and 4-sulfonylcrotonates were prepared as reported.[8b]
General procedure for pyrrolidine-catalyzed benzannulation reaction
To a mixture of α,β-unsaturated aldehyde 1 (0.15 mmol), 1,3-bisnucleophile 2 (0.1 mmol)
and pyrrolidine 4b (1.7 µL, 0.02 mmol) was added chloroform (1 mL). After stirring at
25 °C for 6 h, the reaction mixture was directly purified by flash column chromatography
on silica gel using petroleum/ethyl acetate as eluent to afford the product 3.
2,4-Bis(phenylsulfonyl)-1,10-biphenyl (3a)
1
Yield: 40.0 mg (92%); white solid; mp 159–161 °C. H NMR (400 MHz, CDCl3): δ ¼ 8.97
(d, J ¼ 4.0 Hz, 1H), 8.16 (dd, J ¼ 8.0, 4.0 Hz, 1H), 8.06–8.04 (m, 2H), 7.68–7.64 (m, 1H),
7.61–7.57 (m, 2H), 7.44–7.38 (m, 1H), 7.35–7.31 (m, 2H), 7.22–7.17 (m, 6H), 6.90 (d,
J ¼ 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ ¼ 147.1, 141.9, 141.7, 140.8, 139.8,

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136.6, 134.1, 134.0, 133.2, 131.6, 129.8, 129.7, 128.7, 128.6, 128.2, 128.1, 128.1, 127.7. ESI
HRMS: m/z calcd for [C24H18O4S2þNa]þ: 457.0544; found 457.0546.
Funding
We are grateful to the National Natural Science Foundation of China (21302163) for financial
support.
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