A Cascade Approach to Naphthalene Derivatives from o-Alkynylbenzaldehydes and Enolizable Ketones via in-situ-Formed Acetals

Article abstract of DOI:10.1002/ejoc.201500497

Using the in-situ-formed acetal strategy, a facile approach has been developed to synthesize naphthalene derivatives from o-alkynylbenzaldehydes and enolizable ketones. In situ acetal formation assists the condensation between o-alkynylbenzaldehydes and enolizable ketones to give chalcone derivatives under Bronsted acidic conditions. In situ acetal formation facilitates the reaction by increasing the electrophilicity of the carbonyl carbon of the o-alkynylaldehyde through oxonium ion formation, and also by enhancing the nucleophilicity of the α carbon of the ketone through the formation of an enol ether. The formed chalcones undergo trans to cis isomerization to effect alkyne-carbonyl metathesis to give naphthalene derivatives.

Full text of DOI:10.1002/ejoc.201500497

FULL PAPER
DOI: 10.1002/ejoc.201500497
A Cascade Approach to Naphthalene Derivatives from o-Alkynylbenzaldehydes
and Enolizable Ketones via in-situ-Formed Acetals
Seetharaman Manojveer[a] and Rengarajan Balamurugan*[a]
Keywords: Fused-ring systems / Cyclization / Aldol reactions / Acetals
Using the in-situ-formed acetal strategy, a facile approach
has been developed to synthesize naphthalene derivatives
from o-alkynylbenzaldehydes and enolizable ketones. In situ
acetal formation assists the condensation between o-alkynyl-
ity of the carbonyl carbon of the o-alkynylaldehyde through
oxonium ion formation, and also by enhancing the nucleo-
philicity of the α carbon of the ketone through the formation
of an enol ether. The formed chalcones undergo trans to cis
benzaldehydes and enolizable ketones to give chalcone de- isomerization to effect alkyne–carbonyl metathesis to give
rivatives under Brønsted acidic conditions. In situ acetal for- naphthalene derivatives.
mation facilitates the reaction by increasing the electrophilic-
Introduction
In our efforts to develop organic transformations using
o-Alkynylbenzaldehydes are versatile building blocks for
in-situ-formed acetals,[6] we found that alkyl ketones gener-
the synthesis of different polyaromatic and heterocyclic de-
ate enol ethers via in-situ-formed acetals under Lewis/
rivatives.[1,2] Substituted naphthalenes are one such class of
Brønsted acidic conditions in the presence of trimethyl or-
derivatives. They are useful compounds with applications in
thoformate. It was demonstrated that the formed enol ether
the fields of medicine[3] and materials.[4] Different ap-
could be alkylated directly with various alcohols using
proaches have been reported for the synthesis of substituted
either triflic acid (TfOH)[6d] or AgSbF6.[6e] Recently, we re-
naphthalenes.[5] Yamamoto and coworkers reported an
ported an acetal-assisted intermolecular alkyne–carbonyl
AuCl3-catalysed formal [4+2] benzannulation between o-
metathesis and intramolecular annulation between o-alk-
alkynylbenzaldehydes and alkynes for the synthesis of
ynylbenzaldehydes and alkynes in the presence of trimethyl
naphthyl ketones.[2a] Later, the same group developed an
orthoformate and catalytic Brønsted acid for the synthesis
unprecedented [4+2] benzannulation between enynal units
1 and carbonyl compounds 2 for the construction of
of substituted benzo[a]fluorene derivatives.[6c] The forma-
tion of the acetal intermediate in situ is crucial for the suc-
cess of this reaction. Along these lines, we anticipated that
the formation of an enol ether from a ketone, and forma-
tion of an acetal from o-alkynylbenzaldehyde, would facili-
tate the reaction between them. We have now discovered a
method for the smooth formation of naphthyl ketones from
o-alkynylbenzaldehydes and ketones at room temperature
via in-situ-formed acetals (Scheme 1, equation ii).
naphthalene derivatives using gold and copper salts as cata-
lysts.[2c] In that report, a pyrylium ion A was proposed as
the key intermediate, which undergoes an inverse-electron-
demand-type hetero-Diels–Alder reaction with the enol
form B of the ketone to give naphthyl ketone 3 as the major
product (Scheme 1, equation i). It was anticipated that trace
amounts of water might play an important role in the estab-
lishment of the keto–enol tautomerization of the ketone.
In striking contrast to Yamamoto’s report,[2c] this trans-
Recently, Srinivasan and coworkers reported a method for
formation is expected to take place through condensation
between in-situ-formed acetal D and enol ether E derived
from cyclohexanone to give chalcone F, followed by alkyne–
carbonyl metathesis/annulation to give naphthyl ketone de-
rivative 3 in one pot. This transformation does not take
place without trimethyl orthoformate. Thus, in situ acetal
the synthesis of naphthyl ketones by using In-
(OTf)3 as the catalyst for the same [4+2] benzannulation
under heating conditions.[2l] Both the catalysts [AuBr3 and
In(OTf)3] required heating conditions to effect the naphth-
alene formation.
formation assists the formation of the chalcone by increas-
[a] School of Chemistry, University of Hyderabad,
ing the electrophilicity of the carbonyl carbon of the o-alk-
ynylaldehyde through oxonium ion formation. Also, the nu-
cleophilicity of the α carbon of the ketone is enhanced
through formation of an enol ether.
Hyderabad 500046, India
E-mail: rbsc@uohyd.ernet.in
http://chemistry.uohyd.ernet.in/~rb/index.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500497.
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A Cascade Approach to Naphthalene Derivatives
Scheme 1. Reaction of o-alkynylbenzaldehydes with enolizable ketones under Lewis/Brønsted acidic conditions (BA = Brønsted acid).
Table 1. Optimization study for cyclic ketone.
Results and Discussion
The reaction conditions for formation of naphthyl
ketones were evaluated using o-alkynylbenzaldehyde 1a and
cyclohexanone (2a), and the results are summarized in
Table 1.
Based on our previous experience with the synthesis of
benzo[a]fluorene derivatives,[6c] we investigated the reaction
between 2-(phenylethynyl)benzaldehyde (1a) and cyclohex-
anone (2a) in the presence of trimethyl orthoformate
(2.0 equiv.) and TfOH (20 mol-%) in dichloromethane at
room temperature. The reaction was complete after 30 min,
and the naphthalene product, phenyl(1,2,3,4-tetrahydro-
anthracen-9-yl)methanone (3a), was isolated in 72% yield
(Table 1, entry 1). The yield of 3a increased to 90% when
the reaction was run in acetonitrile (Table 1, entry 2). Then,
the reaction was tried with other Brønsted acid and Lewis
acid catalysts using acetonitrile as the solvent. However,
there was no reaction with TFA (trifluoroacetic acid), pTSA
(p-toluenesulfonic acid), or HSbF6·6H2O, even after 24 h at
room temperature (Table 1, entries 3–5). With the Lewis
acid catalysts Cu(OTf)2 and AuBr3, the reactions were not
clean, and they resulted in complex mixtures of products
Entry Solvent
Catalyst
Cat.
[mol-%]
Time
[h]
Yield
[%][a]
1
2
3
4
5
6
7
8
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
TfOH
TfOH
HSbF6·6H2O
pTSA
TFA
Cu(OTf)2
AuBr3
20
20
20
20
20
5
0.5
0.5
24.0
24.0
24.0
6.0
5.5
24.0
1.0
72
90
n.r.
n.r.
n.r.
–
–
–
64
51
5
CH3CN[b] TfOH
20
10
20
9
10
CH3CN
TfOH
CH3CN[c] TfOH
24
[a] Isolated yield; n.r.: no reaction; LA = Lewis acid. [b] Without
trimethyl orthoformate. [c] 1.0 equiv. of trimethyl orthoformate was
used.
(Table 1, entries 6 and 7). In the absence of trimethyl ortho- isolated (Table 1, entry 8). Then, we decreased the catalyst
formate, the starting material (i.e., 1a) slowly started to de- loading to 10 mol-%, and we found that the yield of 3a
grade, and not even a small amount of the product was decreased to 64% (Table 1, entry 9). Hence, the appropriate
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conditions for naphthalene formation are: TfOH (20 mol- 83% yield. Various alkyl-substituted cyclohexanones (2b–
%), trimethyl orthoformate (2.0 equiv.), and acetonitrile as 2d) were examined, and the corresponding naphthyl ketone
solvent at room temp. (Table 1, entry 2).
derivatives (3j–3l) were obtained in good yields. With cyclo-
Using the optimized reaction conditions, the substrate pentanone (2e) and cyclooctanone (2f), the corresponding
scope was examined with cyclic ketones, and the results are naphthyl ketones (i.e., 3m and 3n) were obtained in 34 and
presented in Figure 1. Saturated ring-fused naphthyl ketone 52% yields, respectively. The change from sp2 to sp3 hybrid-
derivatives with different substituents, including methyl, ization in the reaction of the enol ether of cyclopentanone
methoxy, acetal, fluoro, chloro, and hydroxy groups, were (five-membered ring) may be expected to be unfavourable
prepared from cyclic ketones in moderate to good yields. due to an increase in I-strain. Thus, the reaction of 1a with
The TBDMS (tert-butyldimethylsilyl) group did not toler- cyclopentanone under the present reaction conditions is ex-
ate the reaction conditions, and deprotected naphthalene pected to give a low yield of naphthalene derivative 3m.[7]
derivative 3h was obtained in good yield. The same product Gratifyingly, this transformation could be used on cyclo-
was obtained in better yield from the corresponding hexene alkynylaldehyde 1k to synthesize product 3o in 87%
hydroxy-substituted o-alkynylbenzaldehyde (i.e., 1h). To our yield. In addition, alkynylaldehyde 1l, prepared from α-tet-
delight, thiophene tolerated the reaction conditions, and the ralone, could be used to synthesize polycyclic product 3p in
corresponding naphthyl ketone (i.e., 3i) was obtained in 62% yield. The applicability of the method was checked by
Figure 1. Scope of the reaction with cyclic ketones.
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A Cascade Approach to Naphthalene Derivatives
carrying out the reaction of 1a with cyclohexanone on a
3.0 mmol scale. The corresponding naphthalene derivative
(i.e., 3a) was obtained in 84% yield under the optimized
reaction conditions. Unfortunately, the transformation is
not suitable when R1 is an alkyl substituent.
Next, the reaction was attempted using acyclic ketones.
However, the optimized reaction conditions for cyclic
ketones were not suitable for the acyclic ketone 3-penta-
none (2g), and it gave a complex mixture of products
(Table 2, entry 1). Therefore, our attention turned to finding
suitable reaction conditions for naphthalene formation
from acyclic ketones, and the results are shown in Table 2.
The TfOH loading was increased to 1.0 equiv., which re-
sulted in 52% of naphthalene product 3q, along with con-
densation product 4 in 28% yield after 24 h (Table 2, en-
try 2). To our delight, the yield of 3q dramatically increased
to 82% when the reaction was carried out using 3.0 equiv.
of trimethyl orthoformate and 1.0 equiv. of TfOH for
30 min (Table 2, entry 3). In a control reaction, the reaction
of 1a and 2g was carried out with 1.0 equiv. of TfOH and
2.0 equiv. of trimethyl orthoformate in acetonitrile solvent
at room temp. This reaction resulted in two spots in TLC;
one corresponded to naphthalene product 3q, and the other
Scheme 2. Control experiment.
(more polar) spot corresponded to chalcone 4. This reac- ethers have to be used in reactions with acetals.[9] The syn-
tion did not go to completion, even after 24 h. Upon ad- thetic scope of our finding is under evaluation. Using gold-
dition of 1.0 equiv. of trimethyl orthoformate to the reac- catalysed alkyne–carbonyl metathesis,[10] product 5 could be
tion mixture, we found that the polar spot corresponding converted into naphthalene 3q in excellent yield (Scheme 3).
to chalcone 4 completely disappeared within 15 min to give However, the same catalytic system was inefficient for the
a single spot on TLC corresponding to naphthalene deriva- direct synthesis of naphthalene 3q from 1a and 2g, as it
tive 3q. Compound 3q was isolated in 78% yield by column resulted in a lower yield of 3q. In this experiment, aldehyde
chromatography (Scheme 2). Hence, in situ acetal formation 1a and ketone 2g underwent Claisen–Schmidt reaction first
not only helps the smooth Claisen–Schmidt condensation, to give product 5, which then gave naphthalene product 3q
but also here assists the trans to cis isomerization[8] of chalc- by alkyne–carbonyl metathesis/annulation. We realized this
one 4 to promote alkyne–carbonyl metathesis/annulation from the TLC analysis while monitoring the progress of the
for the construction of naphthalene derivatives.
reaction. These results suggest that the formation of the
The use of Lewis acid catalysts such as Cu(OTf)2 and naphthalene skeleton might not take place by a [4+2]
In(OTf)3 gave the product (i.e., 5) in 98 and 80% yields, benzannulation pathway in the presence of trimethyl ortho-
respectively (Table 2, entries 4 and 5). It has to be men- formate. Thus, in-situ-formed acetals react by a different
tioned that such a direct aldol reaction of a ketone has not mechanism for the construction of naphthalenes from o-
been reported before. Ketones in the form of silyl enol alkynylbenzaldehydes and enolizable ketones.
Table 2. Optimization study for acyclic ketone.
Entry
Solvent
Catalyst
Cat.
[equiv.]
Time
[h]
Yield [%][a]
3q
4
5
1
2
3
4
5
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
TfOH
0.2
1.0
1.0
0.05
0.05
0.05
24.0
24.0
0.5
3.0
5.0
–
52
82
–
–
61
–
28
–
–
–
–
–
–
98
80
–
TfOH
TfOH[b]
Cu(OTf)2
In(OTf)3
AuCl3/AgSbF6
24.0
–
[a] Isolated yield. [b] 3.0 equiv. of trimethyl orthoformate was used.
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was formed through deprotection of the acetal in the pres-
ence of the acid catalyst, and it slowly decomposed over
time. In addition, the reaction of substrate 1a with 1-meth-
oxycyclohex-1-ene (II in Scheme 5) in the presence of TfOH
(20 mol-%) was checked. But this reaction resulted in a
complex mixture of products as vinyl ether II was depro-
tected to give cyclohexanone soon after the addition of
acid. This is consistent with observations made during the
optimization (Table 1, entry 8). Hence we believe that the
presence of trimethyl orthoformate maintains the concen-
tration of acetals required for the reaction to take place.
Scheme 3. Gold-catalysed heteroalkyne metathesis.
Using a stoichiometric amount of TfOH and 3 equiv. of
trimethyl orthoformate, the substrate scope was studied
with acyclic ketones (Figure 2). Using acyclic ketone 2-but-
anone (2h), only one of the possible naphthalene derivatives
(3r–3u) was obtained with various o-alkynylbenzaldehydes.
However, both of the possible naphthyl ketone derivatives
(3v and 3w) were obtained in a 1:0.28 ratio starting from a
TBDMS-protected o-alkynylbenzaldehyde derivative. In
this reaction, the TBDMS group was deprotected, and the
corresponding hydroxy-substituted naphthyl ketones were
obtained in 89% yield. Interestingly, naphthyl ketone deriv-
ative 3x with an ester substituent could be prepared from
ethyl acetoacetate and 1a in 68% yield. It is noteworthy
Scheme 4. Reaction of acetal 6 with cyclohexanone.
Based on our results, a mechanism for the formation of
that 20 mol-% of TfOH was sufficient for the synthesis of naphthyl ketone 3 can be proposed, as shown in Scheme 5.
naphthalene derivative 3x. Initially, condensation might take place between enol ether
To further confirm the involvement of the acetal in this II, derived from the ketone, and oxonium ion IV, which
reaction, a control reaction was carried out using acetal 6 could form from o-alkynylbenzaldehyde 1. Intermediates II
prepared from 1a. Upon reaction of 6 with cyclohexanone and IV are both expected to form in the presence of tri-
in the presence of TfOH (20 mol-%) in CH3CN, 31% of methyl orthoformate and TfOH. This condensation will re-
naphthyl ketone derivative 3a was isolated (Scheme 4). TLC sult in the formation of chalcone-type intermediate VI via
analysis of the progress of the reaction revealed that alde- intermediate V. The fact that products 4 and 5 are formed
hyde 1a was formed along with the product. The aldehyde supports this pathway. Intermediate VI can, in principle, be
Figure 2. Scope of the reaction with acyclic ketones.
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A Cascade Approach to Naphthalene Derivatives
Scheme 5. Plausible mechanism.
transformed into product 3 by one of two ways. In path 1, reported for the construction of naphthalenes from o-alk-
intermediate VI establishes an equilibrium with its cis iso- ynylbenzaldehydes and enolizable ketones under gold catal-
mer VII through protonation. Annulation, followed by at- ysis. In addition, the trans/cis isomerization that is neces-
tack of the methanol generated during the formation of II sary for heteroalkyne metathesis/annulation is also facili-
and IV, would result in intermediate VIII. Upon proton- tated by the reactions conditions.
ation, this intermediate would lose a molecule of methanol
and water to give naphthyl ketone derivative 3. On the other
Experimental Section
hand, another mechanism given in path 2 is also possible.
In the presence of trimethyl orthoformate and TfOH, the
oxonium intermediate X derived from chalcone VI can form
by trans-to-cis isomerization. This will undergo intramolec-
ular [2+2] cycloaddition to give oxetene intermediate XI.[10]
It is known that oxonium ions facilitate such [2+2] carb-
onyl–alkyne cycloadditions.[9,10b,10c,10f] Upon cyclorever-
sion, intermediate XI will generate naphthyl ketone deriva-
tive 3. However, path 1 is more realistic because of the
strain associated with intermediate XI in path 2.
General Information: Chemicals and solvents were obtained from
commercial suppliers. Starting materials were prepared by follow-
ing known literature procedures. Trimethyl orthoformate and
acetonitrile were obtained from Merck. Triflic acid was purchased
from Sigma–Aldrich. THF was dried with sodium, and freshly dis-
tilled before use. 1H and 13C NMR spectra were recorded with a
400 MHz spectrometer in solution in CDCl3, with tetramethylsil-
ane as internal standard. IR spectra were recorded with an FTIR-
5300 spectrometer. High-resolution mass spectra (HRMS) were re-
corded using the ESI-Q-TOF technique. Melting points were deter-
mined with a visual melting range apparatus. TLC was carried out
using silica gel plates 60 F254, and compounds were visualized with
UV light and/or by treatment with Seebach solution [phosphomol-
ybdic acid (2.5 g), Ce(SO4)2 (1 g), H2SO4 (conc.; 6 mL), H2O
(94 mL)], followed by heating. Column chromatography was car-
ried out on silica gel (100–200 mesh) using mixtures of ethyl acetate
and hexanes as eluent. All the o-alkynylbenzaldehydes were pre-
pared by following the standard Sonogashira coupling reaction
procedure, and data of the prepared o-alkynylbenzaldehydes
matches reported literature data.[2]
Conclusions
We have developed a domino reaction for the synthesis
of naphthyl ketone derivatives from o-alkynylbenzaldehydes
and ketones in the presence of trimethyl orthoformate and
TfOH. Interestingly, this transformation occurs at room
temperature. This cascade reaction involves a condensation
between o-alkynylbenzaldehydes and enolizable ketones,
followed by annulation/alkyne–carbonyl metathesis. In situ
acetal formation assists the formation of chalcone by in-
creasing the electrophilicity of carbonyl carbon of the o-
alkynylbenzaldehyde through oxonium ion formation, and
also by enhancing the nucleophilicity of the α carbon of the
ketone through formation of an enol ether. This reaction is
General Procedure for the Synthesis of Naphthalene Derivatives 3:
Triflic acid (20 mol-%) was added to a solution of compound 1
(1.0 equiv.), ketone 2 (1.2 equiv.), and trimethyl orthoformate
(2.0 equiv.) in acetonitrile (5 mL/mmol) at room temperature. The
resulting mixture was stirred at room temperature under a nitrogen
atmosphere. The reaction was monitored by TLC. After the reac-
expected to proceed by a different mechanism from that tion was complete, the solvent was evaporated under reduced pres-
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Acknowledgments
The authors thank the Department of Science and Technology
(DST), New Delhi for financial support. S. M. is grateful to the
Council of Scientific and Industrial Research (CSIR), New Delhi
for a fellowship.
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