Synthesis of naphthalene derivatives from ortho -alkynylacetophenone derivatives via tandem in situ incorporation of acetal and intramolecular heteroalkyne metathesis/annulation

Article abstract of DOI:10.1021/ol5003835

An interesting domino reaction for the synthesis of substituted naphthyl ketones has been developed using readily accessible starting materials. This domino reaction proceeds via in situ incorporation of an acetal followed by intramolecular heteroalkyne metathesis/annulation in an ortho- alkynylacetophenone derivative. A deuterium incorporation experiment has been carried out to understand the mechanism.

Full text of DOI:10.1021/ol5003835

Letter
pubs.acs.org/OrgLett
Synthesis of Naphthalene Derivatives from ortho-
Alkynylacetophenone Derivatives via Tandem in Situ Incorporation
of Acetal and Intramolecular Heteroalkyne Metathesis/Annulation
Seetharaman Manojveer and Rengarajan Balamurugan*
School of Chemistry, University of Hyderabad, Gachibowli, Hyderabad, India 500046
S
* Supporting Information
ABSTRACT: An interesting domino reaction for the synthesis of substituted
naphthyl ketones has been developed using readily accessible starting materials.
This domino reaction proceeds via in situ incorporation of an acetal followed by
intramolecular heteroalkyne metathesis/annulation in an ortho-alkynylaceto-
phenone derivative. A deuterium incorporation experiment has been carried out
to understand the mechanism.
he naphthalene core is an important structural motif
present in many natural products and bioactive
in situ formed acetal incorporates an acetal moiety at the α-
carbon which undergoes [2 + 2] heteroalkyne metathesis or
annulation with an alkyne under the influence of an acid to
form the naphthalene core. Hence the additional carbon atom
present in the naphthalene core is from the trimethyl
orthoformate.
Incorporation of an acetal at the α-carbon of ketones is
known to occur in the presence of trialkyl orthoformate and
Lewis/Brønsted acids. Mukaiyama and co-workers reported the
formation of a β-ketoacetal from silyl enol ether and trimethyl
orthoformate in the presence of TiCl4.10 Formation of β-
ketoacetals from aliphatic and aromatic ketones was achieved
by Mock and Tsou in the presence of N,N-diisopropylethyl-
amine, triethyl orthoformate, and boron trifluoride etherate.11
Using perchloric acid, Dusza et al. developed the alkylation of
steriod ketones using trialkyl orthoformate.12 Ghatak and co-
workers have utilized such an in situ formed β-ketoacetal in the
synthesis of polycyclic compounds.13 Apart from these reports,
the potential of such a facile in situ acetal incorporation has not
been utilized in organic synthesis.
T
compounds.1 In addition, it has numerous applications in
material science.2 Hence development of new methods for the
efficient synthesis of substituted naphthalenes has always been
attractive. Different strategies have been reported for the
construction of a naphthalene framework.3 Very recently, Lee
and co-workers have reported regioselective synthesis of
naphthalenes by employing Pt-catalyzed selective 6-endo
hydroarylation of aryl enynes.4 Wu and co-workers have
developed a new method for the construction of substituted
naphthalenes via novel rearrangement of benzo[c]oxepine.5
In contrast to transition metal mediated processes, use of a
Brønsted acid for the construction of a naphthalene core is very
limited.6 Brønsted acid catalysts have their own advantage over
transition metal catalysts in the pharmaceutical industries since
complete removal of the metal based impurities is a significant
task.7 It is known that the carbonyl compounds (aldehyde/
ketone) form acetal in the presence of a Lewis/Brønsted acid
and trialkyl orthoformate. During our research endeavor in
utilizing an in situ formed acetal,8,9 we have found that alkyl
ketones can directly be alkylated using diaryl methanols, allyl
and propargyl alcohols via in situ acetal formation using
trimethyl orthoformate and triflic acid.9 Along these lines, we
observed that the reaction of o-alkynylacetophenone derivatives
with trimethyl orthoformate and catalytic triflic acid generated
naphthyl ketones efficiently (Scheme 1). It is expected that the
In recent years there has been quite an interest in the alkyne-
carbonyl metathesis reaction.14,15 Different molecular skeletons
have been synthesized, utilizing it as the key reaction. The
alkyne-carbonyl metathesis has mainly been accomplished by
Lewis acid catalysts.14 Only a few reports exist where such a
reaction is carried out using a Brønsted acid.15 Saa
́
and co-
workers have used the Brønsted acid HBF4 or TFA to carry out
the intramolecular metathesis of an alkyne with either an
acetal15a or aldehyde15b functionalities. In the former case they
have advantageously utilized the intermediate to undergo
subsequent Nazarov cyclization under the reaction condition-
s.15a Yamamoto and co-workers have established that acetal/
hemiacetal formed in the TfOH catalyzed reaction of an alkynal
in MeOH undergoes the [2 + 2] heteroalkyne metathesis
efficiently with an alkyne.15c Zhu et al. have used acetals in a
Scheme 1. Incorporation of Acetal and Alkyne-Carbonyl
Metathesis/Annulation of ortho-Alkynylacetophenone
Derivatives 1
Received: February 6, 2014
Published: March 5, 2014
© 2014 American Chemical Society
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Letter
similar metathesis reaction with an alkyne, however using a
Lewis acid, to form a Nazarov intermediate for the construction
of indanones.14b The reaction using an acetal might be more
facile because it proceeds through an oxonium ion
intermediate. In the reaction presented in this manuscript we
have effectively trapped intramolecularly the in situ incorpo-
rated acetal with an alkyne to make naphthyl ketone derivatives.
Using substrate 1a, optimization of the reaction conditions
was established. This substrate was prepared by Sonogashira
coupling of commercially available 2′-iodo acetophenone and
phenylacetylene. The results are summarized in Table 1.
solvent, as the yield of 2a was 89% when the reaction was
carried out in it (Table 1, entry 14). When the amount of
catalyst was reduced to 5 and 10 mol %, the yield of 2a dropped
to 25% and 80% respectively (Table 1, entries 15 and 16).
Gratifyingly, the yield of 2a improved to 90% when the loading
of TfOH was increased to 20 mol % (Table 1, entry 17).
Reduction in the amount of trimethyl orthoformate to 1.0 equiv
was found to decrease the yield of 2a to 40% (Table 1, entry
18). Subsequently, the scope of the transformation was
examined with substrates having a different substitution pattern.
The reaction conditions given in Table 1, entry 17, i.e., 20 mol
% of TfOH and 2.0 equiv of trimethyl orthoformate in
nitromethane solvent at room temperature, were used in these
reactions. The results are shown in Figure 1. It is important to
mention that there is no significant influence of electronic
Table 1. Optimization of Incorporation of Acetal and
Alkyne-Carbonyl Metathesis/Annulation Using Compound
1a
a
entry
solvent
catalyst
TfOH
cat. (mol %) time (h) yield (%)
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
50
50
50
50
5
0.5
24
84
2
conc. HCl
TFA
NR
NR
NR
−
3
24
4
PTSA
24
5
AuCl3/AgSbF6
AgOTf
Cu(OTf)2
TfOH
24
6
5
24
−
7
5
24
NR
8
50
50
50
50
50
50
50
5
0.5
0.5
0.5
0.5
24
76
9
hexane
TfOH
34
10
11
12
13
14
15
16
17
18
toluene
dioxane
CH3CN
MeOH
CH3NO2
CH3NO2
CH3NO2
CH3NO2
TfOH
65
TfOH
52
TfOH
NR
NR
89
TfOH
24
TfOH
0.5
0.5
0.5
0.5
0.5
TfOH
25
TfOH
10
20
20
80
TfOH
90
b
CH3NO2
TfOH
40
a
b
Isolated yield. 1.0 equiv of trimethyl orthoformate was used. NR: no
reaction.
Initially 1a was treated with 2.0 equiv of trimethyl orthoformate
and 50 mol % of trifluoromethanesulfonic acid (TfOH) in
dichloromethane at room temperature. Interestingly, the
product 2a was obtained in 84% yield in 30 min (Table 1,
entry 1). The reaction did not work with other Brønsted acids
such as conc. HCl, TFA, and PTSA (Table 1, entries 2−4) even
after 24 h. Then, the reaction was attempted with Lewis acids
and found to be ineffective, as they resulted in either a complex
mixture or no reaction (Table 1, entries 5−7). Since TfOH
alone worked in effecting the reaction, further optimization was
carried out using TfOH only by changing other parameters
such as solvent and catalyst loading. In dichloroethane, the
yield of 2a decreased to 76% (Table 1, entry 8). In nonpolar
solvents such as hexane and toluene the yields obtained were
34% and 65% respectively (Table 1, entries 9 and 10). When
the reaction was performed in dioxane the yield of 2a obtained
was 52% (Table 1, entry 11). There were no reactions in
acetonitrile and methanol even after 24 h (Table 1, entries 12
and 13). To our delight, nitromethane was found to be the best
Figure 1. Scope of naphthyl ketone derivatives synthesis.
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effects on the outcome of this transformation. Good yields of 1-
methoxy-4-naphthyl ketone derivatives 2 were obtained with
both electron-releasing groups (such as −OMe and Me) and
-accepting group (such as −Cl). The reaction required 60 min
for completion when either R2 or R3 is an alkyl group.
Otherwise the reactions are fast and completed within 30 min.
Moderate yields of 2d and 2e were obtained when R3 is an alkyl
group such as n-hexyl and n-butyl. Interestingly, heterocyclic
thiophene tolerated the reaction conditions and the corre-
sponding naphthyl ketone derivative 2m was obtained in 72%
yield. The structure of compound 2c was further confirmed by
single crystal X-ray analysis.16 Unfortunately the reaction was
not clean with a terminal alkyne (R3 = H). This may be due to
the absence of groups to stabilize the vinyl carbocation
intermediate which will form during the reaction. When R2 is
a phenyl group the reaction was not clean as it resulted in a
complex mixture. A similar reaction with trimethyl orthoacetate
gave a complex mixture of products. Since the starting ortho-
alkynylacetophenones 1 were prepared by a Sonogashira
coupling reaction, the possible role of trace metal compound
impurities (Pd and Cu compounds) as cocatalysts in the
present transformation was evaluated by carrying out two
control experiments. In the first experiment, the reaction of 1a
was carried out in the presence of 2 mol % each of Pd(PPh3)4
and CuI along with 20 mol % of TfOH and 2 equiv of trimethyl
orthoformate. There was no appreciable acceleration in the
reaction rate, as 30 min were required for completion to result
in 2a in 88% yield. The above reaction without TfOH did not
result in any product even after 24 h. With these experiments,
the possibility of the transition metal impurities cocatalyzing
the present reaction of 1 could be ruled out.
+ 2] cycloaddition and cylcoreversion between an alkyne and
oxonium ion through oxetene intermediate E in the presence
TfOH. The pathway involving annulation could not be
excluded (Path II). This is initiated by the electrophilic attack
of an oxocarbenium ion on the alkyne. The formed vinylic
carbocation is trapped by methanol formed during the reaction
to give intermediate F. Subsequent elimination of methanol
from F assisted by an acid would afford naphthalene derivative
2.
In order to confirm the proposed mechanism, fully
deuterated trimethyl orthoformate (DC(OCD3)3) was pre-
pared as per reported procedure.17 The reaction of 1a was
carried out with DC(OCD3)3 under standard conditions
(Scheme 3). Incorporation of −OCD3 and D in the
Scheme 3. Deuterium Incorporation Study
1
naphthalene 2a-d4 was inferred from the H NMR spectra.
The disappearances of a singlet at 4.07 ppm corresponding to
OCH3 protons and doublet at 7.60 ppm and appearance of a
singlet at 6.80 ppm corresponding to aromatic protons were
1
observed in the H NMR. Further, the reaction of 1b was
monitored by 1H NMR to check whether the proposed
intermediates are formed in the reaction. Among the proposed
intermediates, the formation of ketal A from 1 could only be
A schematic representation of plausible mechanistic pathways
is shown in Scheme 2. In the presence of TfOH and trimethyl
1
seen while recording H NMR. This might be due to a fast
domino reaction.
In summary, we have developed a new method to construct a
naphthalene core through incorporation of an acetal followed
by intramolecular heteroalkyne metathesis/annulation involv-
ing orthoformate and triflic acid. This is a simple and an
efficient approach for the synthesis of naphthalene derivatives
from readily available starting materials and reagents.
Scheme 2. Plausible Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, 1H/13C spectroscopic data of all new
compounds, and ORTEP of compound 2c. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rbsc@uohyd.ernet.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was supported by the Department of Science and
Technology (DST) India. S.M. is grateful to Council of
Scientific and Industrial Research (CSIR), India for a
fellowship.
orthoformate, ketal A is formed from 1 which will be in
equilibrium with α-methoxy styrene derivative B. The
intermediate B attacks trimethyl orthoformate to give
intermediate C which will be in equilibrium with the oxonium
ion D. There are two possible pathways (Paths I and II) to
construct the naphthalene skeleton 2 from D. As shown in path
I, naphthalene derivative 2 will be formed via intramolecular [2
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