Dehydrative condensation of carbonyls with non-acidic methylenes enabled by light: Synthesis of benzofurans

Article abstract of DOI:10.1039/c6cc07626b

Condensation of carbonyls with non-acidic methylenes such as those adjacent to heteroatoms and allylic types to generate CC bonds is challenging but highly desirable. Inventing novel methods that can accomplish such condensations can enrich synthetic chemists' toolbox. Herein, we report a simple, clean, and high yielding protocol promoted by light to achieve condensation of non-acidic methylenes with carbonyls. As examples to demonstrate the power of this methodology, one class of ubiquitous and highly important heterocycles, i.e. benzofurans, were synthesized with broad functional group compatibility. Furthermore, intermolecular condensations were also briefly investigated.

Full text of DOI:10.1039/c6cc07626b

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Dehydrative condensation of carbonyls with non-acidic
methylenes enabled by light: synthesis of benzofurans
Received 00th January 20xx,
Accepted 00th January 20xx
Wenbo Liua, Ning Chena, Xiaobo Yanga, Lu Lia, and Chao-Jun Li*a
DOI: 10.1039/x0xx00000x
Condensation of carbonyls with non-acidic methylenes such as those adjacent to heteroatoms and allylic
types to generate C=C bonds is challenging but highly desirable. Inventing novel methods that can
accomplish these condensations can enrich synthetic chemists’ toolbox. Herein, we report a simple, clean,
and high yielding protocol promoted by light to achieve the non-acidic methylenes’ condensation with
carbonyls. As examples to demonstrate the power of this methodology, one type of ubiquitous and highly
important heterocycles, i.e. benzofurans, were synthesized with broad functional group compatibility.
www.rsc.org/
Furthermore,
intermolecular
condensations
were
also
briefly
investigated.
has been extensively investigated in the past 80 years.34
Inspired
Introduction
Dehydrative condensation of carbonyls is one type of
fundamental reaction to generate C=C bonds in organic
synthesis.1 However, all known condensations such as the
aldol and Knoevenagel reactions require acidic protons (pKa <
25) to enable the deprotonation by strong bases (for example,
lithium diisopropylamide (LDA)) (Scheme 1a). With regards to
non-acidic methylenes such as those near heteroatoms (for
example, O and N) and allylic ones, unfortunately, they are
challenging substrates to condense with carbonyls (Scheme
1b).2 In view of the prevalence of these non-acidic methylenes
in organic compounds (for example, in ethers and olefins),
developing condensations that encompass these substrates
will greatly upgrade current knowledge and enlarge the
condensation scope tremendously.
(a) Classical dehydrative condensation:
R
H
FG1
R1
R3
R2
O
H
3 FG1
base
+
H2O
+
R1
R2
FG1 = electron withdrawing groups
acidic proton, pKa < 25
(b) Challenging dehydrative condensation:
FG2
R1
R3
R2
R3
O
?
H
FG2
+
H2O
+
R1
R2
H
FG2 = heteroatoms or C=C bonds
non-acidic proton, pKa > 45
Scheme 1: (a) Classical dehydrative condensation. (b) Challenging dehydrative
condensation that involves non-acidic methylenes and carbonyls.
In the past decade, photochemistry, particularly those
involving photo-redox catalysts,3-5 has witnessed renaissance
in organic synthesis because of its greenness.6, 7 Despite the
powerfulness of photo-redox catalysts, they are not without
limitations such as the concern with expensive metals and
ligands as well as catalysts’ deactivation.8 On the other hand,
photochemistry triggered by ultra-violet light obviates these
drawbacks and has found wide applications as well.9-18 Clearly,
chemistry that solely depends on the innate properties of
reactants (if allowed) without relying on additives is superior
and greener. Pioneered by Norrish,19 Yang,20 Breslow,21-24
Wagner,25-28 and others,29-33 photochemistry of carbonyl group
by these preceding work, herein, we described reactions that
fully exploit the ketones’ innate photochemistry to achieve the
condensation between non-acidic methylenes with carbonyls,
providing a novel method for C=C bond formations. We
hypothesized that under UV irradiation, the ground state of
ketone group (in C1 of Scheme 2a) would be excited to the (n,
π
*) state, which showcases diradical property (C2). Due to the
high electronegativity of oxygen, the oxygen radical will
abstract one hydrogen from its carbon intramolecularly via
[1, 6] hydrogen transfer, generating another carbon radical
C3). Subsequently, two carbon radicals in C3 would combine
α
(
to form C-C bond, producing intermediate C4. Under suitable
conditions, for example, with aromaticity energy as the driving
force, C4 would further dehydrate to produce the
condensation compound (C5). Via this pathway, the overall
transformation would be a condensation from C1 to C5 to
form C=C bond and water. Following this working model,
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herein, we report the synthesis of an important type of the reaction could proceed at room temperature in presence
heterocycles i.e. benzofuran as outlined in Scheme 2b.35
of acid, effects of Brønsted and Lewis acids were explored. The
Benzofuran is a ubiquitous heterocycle in natural products, results showed that, at room temperature, the added acid was
drug candidates, and organic materials.36 Moreover, they are not beneficial to the reaction yields (entries 4 and 5). The
also principal precursors to produce valuable chiral atmosphere impact on this reaction was also explored and O2
dihydrobenzofurans.37 Therefore, extensive research has been was found to be deleterious to this reaction (entries 6 and 7).
investigated to synthesize them. Traditional approaches A longer reaction time (6h) slightly decreased the reaction
employ Lewis acids or bases as the catalysts.38 Besides, yield (entry 8), implying that benzofuran decomposed slowly
numerous transition metal catalysed procedures have also under the reaction conditions. Additionally, we also examined
been developed, among which Pd and Cu are typical.39, 40 To the concentration effect, and either too concentrated or too
our knowledge, there is no such a method to synthesize diluted would decrease the yield (entries 9 and 10). Finally, the
benzofuran only in one step without acid/base/metals. control experiment showed that no reaction was observed in
Although we are aware of a few examples41, 42 in the literature absence of UV (entry 11). Therefore, the optimal reaction
to synthesize benzofuran by using light as well, they are only conditions were at 60 oC, 0.05 M in PhCF3 under argon
restricted to some specific substrates such as allylic (benzylic atmosphere without any other additive for 2.5 h.
or propargylic) ethers. More importantly, all the reported
Table 1: Optimization of the model reaction
protocol required a second step to achieve the dehydration by
using either Lewis acids or Brønsted acids. In strikingly contrast
to previous methods, we wish to report herein the dehydrative
condensation of regular non-activated ortho-alkoxyphenone
with broad functional group tolerance in just one step without
any acid work-up to synthesize benzofurans, enabled by light in
absence of any catalyst.
Entry
Variations from “Standard
Conditions”
Yield [%]a
1
2
50 oC instead of 60 oC (2.5 h)
65
82
94
0
50 oC instead of 60 oC (6 h)
80 oC instead of 60 oC (2.5 h)
with 0.1 equiv HCl at r.t
with 0.1 equiv TiCl4 at r.t
air instead of argon
3
4
5
0
6
70
<5
91
71
70
0
7
O2 instead of argon
8
6 h instead of 2.5 h
9
0.2 M instead of 0.05 M
0.02 M instead of 0.05 M
NO hv
Scheme 2: (a) Intramolecular condensation of carbonyls with non-acidic methylenes.
10
11
(b) Direct condensation to synthesize benzofurans.
a: Determined through 1HNMR analysis by using 1,3,5-trimethoxybenzene as the
internal standard.
Results and discussion
To begin the investigation, 2-butyloxybenzophenone was
readily synthesized from commercially available and cheap 2-
hydroxylbenzophenone and 1-bromobutane in excellent yield.
We first examined the solvent effect of this reaction and found
that PhCF3 was the best solvent (see SI), which produced the
desired product in 93% isolated yield with complete
conversion of the starting material. Then, temperature effect
With the optimized conditions obtained, the substrates’ scope
was investigated subsequently. The functional group
compatibility at 2’ position was explored first. Various alkyl
groups (2a, 2b, 2c, 2d) could deliver the desired condensation
products with high yields. Not only primary alkyl substituents,
secondary alkyl substituent could also be tolerated (2e).
Besides the non-activated alkyl substituents, benzylic
substituent was also compatible (2f), which suggests that the
[1,6] hydrogen transfer is much more favourable relative to
other positions even in presence of activated benzylic
hydrogens. With a hydrogen instead of alkyl substituent at 2’
o
was investigated. With temperature lower than 60 C, a lower
yield was obtained even with a prolonged reaction time
(entries 1 and 2). A higher temperature (80 oC) did not
enhance the reaction yield (entry 3). It is known that acid
catalyst could promote alcohol’s dehydration. To test whether
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g) was used in 15 mL PhCF3 and additional acidic work-up was applied for this gram
scale reaction. b: 24 h instead of 2.5 h.
position, the product could still be isolated in good yield (83%,
2g). Other common functional groups were also studied.
Gratifyingly, most organic functional groups such as alkene
With the success of the intramolecular reactions, we then
turned our attention to the intermolecular condensation
between benzophenone and the substrates with methylenes
adjacent to the heteroatoms and allylic types. The
intermolecular reaction is much more challenging because the
separated radicals would homo-dimerize to form by-products
apart from the desired cross-dimerized product. Despite the
challenge, we were still able to obtain the products with
reasonable yields when the reactions were conducted under
neat conditions. Under UV irradiation followed by the
dehydration, benzophenone can condense with THF and p-
dioxane with modest yields (40% and 46% respectively).
Besides the ethers, olefins including cyclic and acyclic types
can also condense with benzophenone in presence of UV in
good yields. These results indicate the synthetic potentials to
couple carbonyls with sp3 non-acidic methylenes
intermolecularly under photochemical conditions. Although
metal-catalyzed C-H activation of these substrates has been
widely recorded in the literature,43, 44 nonetheless, we believe
that these metal-free ultra-violet light-enabled activations of
sp3 C-H bonds would complement and enrich the current
knowledge, for example allowing the novel dehydrative
condensation with ketones in the present report although
further improvements are necessary for them to be widely
synthetically useful.
(
2h), alkyne (2i), -Cl (2j, 2k), -Br (2l), -I (2m), -OH (2n, 2o),
esters (2q, 2r), -CN (2s), -COOH (2t), and -amide (2u) were all
compatible with the standard reaction conditions, to give the
desired products in good to excellent yields. Moreover, TBS (t-
butyldimethylsilyl), as a frequently used protecting group in
organic synthesis, could also be tolerated (2p). This broad
functional group compatibility demonstrated significant
potentials of this method in complex multi-step synthesis.
Moreover, benzofuran product could be obtained with
substituent attached on the benzene ring (2v). Finally, when
the phenyl ring at the 3 position was replaced by a methyl
group, the benzofuran could also be generated albeit with a
slower reaction rate and a decreased yield (2w), possibly due
to
a lower photon absorption ability of acetophenone
chromophore compared to benzophenone. When R2 is an
aromatic group, unfortunately, the desired benzofuran
product cannot be obtained probably due to the further light-
promoted 6π electrocyclization reaction. To further examine
the synthetic utility of this protocol, a gram scale reaction was
conducted and the desired benzofuran was isolated in good
yield (75%, 2a).
Scheme 4: Examples of intermolecular condensation reactions of non-acidic hydrogens
with carbonyl group. Reaction conditions: 1): benzophenone (50 mg, 0.27 mmol), ether
or alkene (2 mL), argon, 60 oC, 12 h; 2): TFA (0.5 equiv) and TFAA (0.5 equiv), 3h. a: the
reaction yield was determined by using 1HNMR analysis by using 1,3,5-
trimethoxybenzene as the internal standard; b: the ratio was determined by using
GC/MS.
Conclusions
In conclusion, we have achieved the dehydrative condensation
between non-acidic methylenes with carbonyls to synthesize
C=C bonds in benzofurans by using a very simple and clean
method promoted by light with high yields and broad
functional group compatibility. Besides the intramolecular
Scheme 3: Scope of the benzofurans. All the reactions were conducted at 0.1 mmol
scale in 2 mL PhCF3 at 60 oC for 2.5 h unless otherwise specified and all the yields are
referred to average isolated yields of two runs. a: o-butoxybenzophenone (3 mmol, 0.7
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