Synthesis of 2-arylbenzofuran-3-carbaldehydes: via an organocatalytic [3+2] annulation/oxidative aromatization reaction

Article abstract of DOI:10.1039/c8cc02474j

A novel organocatalytic [3+2] annulation/oxidative aromatization reaction of enals with 2-halophenols or β-naphthols is reported. This process enables chemo- and regioselective access to 2-arylbenzofuran-3-carbaldehydes without the use of transition metals or strong oxidants. Preliminary mechanistic studies reveal that an unprecedented, organocatalytic, direct α-arylation pathway is involved.

Full text of DOI:10.1039/c8cc02474j

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Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Synthesis
of
2-arylbenzofuran-3-carbaldehydes
via
an
organocatalytic [3+2] annulation/oxidative aromatization reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Huiwen Zhang, Chunmei Ma, Ziwei Zheng, Rengwei Sun, Xinhong Yu* and Jianhong Zhao*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel organocatalytic [3+2] annulation/oxidative aromatization arylation (cross-coupling) reactions have provided elegant
reaction of enals with 2-halophenols or β-naphthols is reported. approaches to achieve C−C bond formation.7 In 2007, Wang et
This process enables chemo- and regioselective access to 2- al. disclosed the first organocatalytic α-arylation of enals with
arylbenzofuran-3-carbaldehydes without the use of transition para-halophenols via
a
Michael-type Friedel−Craꢀs
metals or strong oxidants. Preliminary mechanistic studies reveal reaction/cyclopropanation/ring-opening cascade.8 We recently
that an unprecedented orgaocatalytic direct α-arylation pathway questioned whether this strategy could be extended to
is involved.
sterically hindered 2-halophenols, thereby giving the
corresponding α-arylation intermediates that might undergo
the chemoselective (C=C versus C=O) intramolecular
cyclization and aromatization to afford 2,3-disubstituted
benzofurans (Scheme 1b).
Benzofurans, particularly 2,3-disubstituted benzofurans, are
privileged scaffolds found in a wide range of natural products1
and pharmaceuticals.2 In contrast to classical two-step
synthetic routes, employing internal alkynes or alkenes as
substrates offers an ideal approach to construct such
skeletons, whereby the introduction of two pre-installed
functional groups onto benzofuran cores is achieved in a single
step. In this context, prominent strategies include: (i) base-
mediated nucleophilic addition followed by the intramolecular
Heck coupling of 2-halophenols with activated alkynes,3 (ii)
transition-metal-catalyzed oxidative annulation of phenols
with symmetrical alkynes,4 and (iii) Pd-catalyzed
decarboxylative cyclization of phenols and alkenylcarboxylic
acids.5 However, these methods generally yield poor site-
selectivity and still require the use of transition-metal catalysts
or strong oxidants. Therefore, the development of a selective
and transition-metal-free method for the synthesis of 2,3-
disubstituted benzofurans is highly desirable.
Previous work:
R3
R2
R2
R2
FG
(i)
a)
X
Transition-metal (TM)
Catalysis
R1
R2
R1
(ii)
O
OH
E
R2
FG = (i) R3; (ii) R2; (iii) Methyl
(iii)
X= H, Cl, Br, I
HOOC
This work:
CHO
α
via
R2
TM free α-Arylation
Cyclization/Aromatization
R1
b)
chemoselective
CHO
regioselective
OH
X
R1
OHC
Z or E
Organocatalysis
Air
R1
R2
R2
OH
O
X= Br, I
TM free
Air as a terminal oxidant
Organocatalytic direct -arylation
α
•
•
•
c)
Potential entry to natural products and pharmaceuticals
R3 = O(CH2)2NEt2
O
I
O
H
O
O
R3
OH
Over the past two decades, organocatalytic annulations of
arenes with α,β-unsaturated aldehydes have become powerful
tools for the construction of diverse heterocycles.6 However,
the use of aryl halides as substrates to undergo organocatalyitc
annulations with α,β-unsaturated aldehydes, in which the C−C
bond form at the challenging ipso-positions (C−X), is still very
limited. Recent advances in organocatalytic direct C−H
R2
3
I
HO
nBu
amiodarone
R6
O
R1
OMe
O
O
coumestans
salvinal
OMe
R6 = O(CH2)3NnBu2
O
Br
O
O
OH
R5
H
nBu
Br
O
N
R4
O
Et
benzbromarone
S
O
O
O
pterocarpenes
dronedarone
Scheme 1 Synthesis of 2,3-disubstituted benzofurans
At the outset, two key challenges arose in this proposition.
First, compared with para-halophenols, the initial Michael-
type Friedel−Craꢀs reacꢁon of ortho-halophenols leading to
ipso-substitution (C−X) is energeꢁcally unfavorable, owing to
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the difficulty of forming sterically more crowded halogen-
We first studied the reaction of 2-bromophenol (0.2 mmol)
substituted quaternary carbon centers. Six-membered lactol with trans-cinnamaldehyde (0.1 mmol) using diphenylprolinol
derivatives were often preferentially generated as the trimethylsilyl ether (Cat. , 20 mol ) as the catalyst, Na2CO3
undesired side-products by an ortho-selective (C−H) (0.5 mmol) as the additive and CHCl3 (2.0 mL) as the solvent at
I
%
o
Friedel−Craꢀs alkylaꢁon and hemiacetalizaꢁon sequence.9 60 C for 7 days. However, neither the desired molecule nor
Second, intramolecular
C−O cyclizaꢁon/aromaꢁzation the competitive reaction byproduct (often formed in the
reactions are generally performed under harsh oxidative presence of acid co-catalysts9,14) was observed under these
conditions (e.g., DDQ,10 m-CPBA,11 TBHP12), which may conditions. Considering 2-bromophenol was not nucleophilic
promote the overoxidation of aldehyde moieties to carboxylic enough to initiate the ipso-selective (C−Br) Michael-type
acids. We addressed these issues, and herein disclose the first Friedel-Crafts
reaction,
electron-rich
2-bromo-5-
chemo- and regioselective synthesis of 2,3-disubstituted methyoxyphenol was chosen as a Michael donor. Gratifyingly,
benzofurans via an organocatalytic [3+2] annulation/oxidative the demanding energy barrier was overcome by the increased
aromatization reaction. Key to the success of this chemistry is electron density to afford the desired product 3aa, albeit in
a novel α-arylation of enals with sterically encumbered 2- only 20% yield (Table 1, entry 1). Screening of additives
halophenols, which is, to the best of our knowledge, the first revealed K2CO3 to be optimal (entry 2). Although variation of
example of this kind. The transition-metal-free reaction solvents and catalysts did not enhance the efficiency (entries
proceeds under mild conditions and uses atmospheric oxygen 6-11, for more details see ESI†), further investigations revealed
as an oxidant. Moreover, this step-economical cascade gives that increasing the amount of 1a could improve the reaction
products bearing a formyl group at the C3 position, allowing yields (entries 12 and 13). Inspired by these results, slow
for further elaboration to various natural products1a,1c,1d and addition of 2a was employed. However, it didn’t lead to
pharmaceuticals2 (Scheme 1c), whereas it was typically desirable results (entries 14-16). Other potential leaving
introduced by the Vilsmeier-Haack reaction using large groups were also evaluated while giving lower yields (entry 17,
excesses of environmentally unfriendly POCl3 and DMF.13
for more details see ESI†).
Table 1 Optimization of reaction conditionsa
Table 2 [3+2] Annulations of enals with 2-bromophenolsa,b
Time
Yieldb
Entry
Catalyst Solvent Additive
(days)
(%)
20
1
I
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH3CN
THF
Na2CO3
K2CO3
Cs2CO3
NaOAc
DABCO
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
5
5
5
5
5
5
5
5
5
5
5
2
2
2
2
2
2
2
I
35
3
I
n.r.
30
4
I
5
I
25
6
I
16
7
I
trace
29
8
II
III
IV
V
I
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
9
25
10
11
12c
13d
14f
15g
16h
17d,i
<10
trace
51
85e
<10
23
I
aReactions conditions: a mixture of 1 (6.0 equiv.), 2 (0.1 mmol, 1.0 equiv.), K2CO3
(5.0 equiv.) and catalyst I (20 mol%) in CHCl3 (2.0 mL) was stirred at 60 oC.
bIsolated yields. cPerformed for 7 days. dPerformed on a 0.2 mmol scale.
I
I
I
17
I
38
With the optimized conditions in hand, the scope of enals
was further explored. Enals bearing substituents with different
electronic properties at the para or meta-position of the
phenyl ring were converted to the corresponding products in
moderate to excellent yields (Table 2, 3aa-3aj), while
introducing functional groups at the ortho-position of the
phenyl ring led to lower yields probably due to the steric
aReaction conditions: a mixture of 1a (2.0 equiv.), 2a (0.1 mmol, 1.0 equiv.),
additive (5.0 equiv.) and catalyst (20 mol%) in solvent (2.0 mL) was stirred at 60
oC. bDetermined by 1H NMR analysis using dibromomethane as an internal
standard. c4 equiv. of 1a. d6 equiv. of 1a. eisolated yield. fSlow addition of 2a over
i
7 h. gSlow addition of 2a over 14 h. hSlow addition of 2a over 21 h. 2-iodo-5-
methoxypheol was used instead of 1a. DABCO = 1,4-diazabicyclo[2.2.2]octane.
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hindrance (3ak-3an). Heteroaryl enals were also amenable to our delight, cis-cinnamaldehyde could also be applied to
this reaction and the target products were isolated in 83% and generate 5aa without a compromising yield, indicating the E/Z
78% yields, respectively (3ao and 3ap). However, aliphatic stereoisomeric of enals did not affect the reaction efficiency.
enals didn’t react to give the desired products.
Naphthols bearing alkoxyl group were applicable to the
A series of 2-bromophenols were also tested. Substrates reaction and gave the intended products 5ba-5ca in 71-73%
with strong electron-donating groups (e.g., methoxyl, yields. In contrast, substrates with electron-deficient
benzyloxy) were well-tolerated to produce the 3- substituents on the naphthyl ring afforded the products 5da-
formylbenzofurans in good yields (3ia and 3ba). On the other 5ga in relatively lower yield. The structure of 5ac was
hand, moderate electron-donating groups, such as methyl and unambiguously confirmed by X-ray crystallography (see ESI†).
tert-butyl, were also viable substrates (3ea 3fa and 3da). To highlight the practicability of this method, a gram-scale
,
Gratifyingly, incorporation of an amino group on the phenol reaction of 4a with 2a was performed. As illustrated in Scheme
moiety did not interfere with the reaction and afforded 3ca in 2a, the reaction was easily scalable and 5aa was isolated in
47% yield, while it proved ineffectual in the previously 50% yield even with pyrrolidine as the catalyst. Moreover,
reported oxidative annulation method.4c When 2,4- benzofurans bearing a formyl group at the C3 position could
dibrominated substituent 1h was employed in this reaction, serve as versatile building blocks for isoflavonoid-derived
target product 3ha was provided in 45% yield along with a natural products syntheses,15 as exemplified by the concise
para-cross-coupling product 3ha’ in 30% yield. Unfortunately, synthesis of pterocarpene derivative
meta-chloro and para-methoxyl substituted phenol derivatives derivative in moderate yields (Scheme 2b).
failed to give the target products (see ESI ), suggesting that
6 and coumestan
7
†
electron-donating groups at C5 position of phenols were
essential to increase the electron density for the electrophilic
aromatic substitution step.
Table 3 [3+2] Annulations of enals with β-naphtholsa,b
Scheme 2 Gram-scale reaction and further transformations
aReaction conditions: 0 oC, to a solution of 4 (1.2 equiv.) was added PHBP (1.2
equiv.), followed by addition of 2 (1.0 mmol, 1.0 equiv.), Cat. I (20 mol%) and
K2CO3 (5.0 equiv.), then the reaction was stirred at 60 oC for 48 h. bisolated yields.
cUsing pyrrolidine (20 mol%) as the catalyst. dcis-cinnamaldehyde was used.
ePerformed on a 2 mmol scale.
Scheme 3 Control experiments
Note that our previous study demonstrated the selective
bromination of β-naphthol in the presence of pyridine
hydrobromide perbromide (PHBP),8b we thus began to develop
a one-pot strategy for the preparation of 2,3-disubstituted
naphthofurans using simple β-naphthols as substrates. We
found that in situ generated 1-bromo-2-naphthols showed
higher reactivity than 2-bromophenols, as only a slight excess
of β-naphthols (1.2 equiv.) was required for this
transformation (Table 3). Various enals were transformed to
the desired products in moderate to good yields (5aa-5ap). To
To gain mechanistic insight into this reaction, several
control experiments were conducted. We succeeded in
isolating the putative intermediates 3aa’ and 5aa’ (Scheme
3).16 As expected, isolated intermediate 5aa’ could be
converted to 5aa in a quantitative yield under the standard
conditions. These evidences strongly support the proposed
pathway in Scheme 1b, and also represent the first example of
organocatalytic α-arylation of enals using sterically congested
2-bromophenols as coupling partners. Thus,
a plausible
mechanism is depicted in Scheme 4. The Michael-type
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2
3
R. J. Nevagi, S. N. Dighe and S. N. Dighe, Eur. J. Med. Chem.,
2015, 97, 561.
Friedel−Craꢀs reacꢁon of 1a with iminium ion
A selectively
occurs at the C2 position (C−Br) to generate the Michael
adduct which then undergoes an intramolecular
cyclopropanation17 to give
Deprotonation of with
subsequent ring-opening reaction affords the zwitterionic
species E 8a,17c
The α-arylation intermediate 3aa’ can be
obtained through hydrolysis of . Alternatively, participates
in intramolecular oxa-Michael addition followed by air
oxidation of enamine18 to produce
. Finally, product 3aa is
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B,
C
.
C
.
4
E
E
G
formed after hydrolysis and regenerates the amine catalyst for
the next catalytic cycle.
5
6
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Zweifel and K. A. Jørgensen, Angew. Chem. Int. Ed., 2011, 50,
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7
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Scheme 4 Proposed mechanism
8
9
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In summary, we have reported a transition-metal-free
method for the synthesis of 2-arylbenzofuran-3-carbaldehydes
based on an organocatalytic [3+2] annulation/oxidative
aromatization reaction of enals with 2-halophenols or β-
naphthols. The reaction proceeds under mild conditions and
uses air as the terminal oxidant. Mechanistic investigations
provide evidence for a novel organocatalytic direct α-arylation
event. Further mechanistic studies as well as other
applications of this method are in progress.
10 G. Cardillo, R. Cricchio and L. Merlini, Tetrahedron, 1971, 27
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We gratefully acknowledge financial support from the
National Natural Science Foundation of China (21476078).
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Chem., 2007, 119, 4844; (b) A. Goel, A. Kumar and A.
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Conflicts of interest
There are no conflicts to declare.
16 For details see ESI†.
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Table of Contents
A novel organocatalytic [3+2] annulation/oxidative aromatization reaction of enals with
2-halophenols is developed for the synthesis of 2-arylbenzofuran-3-carbaldehydes.