Synthesis of dibenzocyclohepta[1,2-a]naphthalene derivatives from phenylacetaldehyde and alkynyl benzyl alcoholsviasequential electrophilic addition and double Friedel-Crafts reactions

Article abstract of DOI:10.1039/d1ob00057h

A simple methodology has been developed for the synthesis of substituted 9H-dibenzo[3,4:6,7]-cyclohepta[1,2-a]naphthalenes from phenylacetaldehydes andortho-alkynyl benzyl alcohols in the presence of a Lewis acid in moderate to good yields within a short reaction time. Interestingly, the reaction proceeds through a highly regioselective electrophilic addition followed by double Friedel-Crafts reaction to form uncommon dibenzo-fused seven-membered carbocycles.

Full text of DOI:10.1039/d1ob00057h

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Synthesis of dibenzocyclohepta[1,2-a]naphthalene
derivatives from phenylacetaldehyde and alkynyl
benzyl alcohols via sequential electrophilic
addition and double Friedel–Crafts reactions†
Cite this: Org. Biomol. Chem., 2021,
9, 2430
1
Received 12th January 2021,
Accepted 24th February 2021
DOI: 10.1039/d1ob00057h
Archana K. Sahu, Ramanjaneyulu Unnava, Bipin K. Behera and Anil K. Saikia
*
rsc.li/obc
A simple methodology has been developed for the synthesis of fused cycloheptatrienes from 1-benzyl-2-ethynylbenzenes
substituted 9H-dibenzo[3,4:6,7]-cyclohepta[1,2-a]naphthalenes having a terminal and butyl substituted alkyne moiety cata-
1
5
from phenylacetaldehydes and ortho-alkynyl benzyl alcohols in lysed by a gold complex (Scheme 1b). Herein, we have devel-
the presence of a Lewis acid in moderate to good yields within a oped a methodology for the synthesis of substituted 9H-
short reaction time. Interestingly, the reaction proceeds through a dibenzo[3,4:6,7]-cyclohepta[1,2-a]naphthalene via sequential
highly regioselective electrophilic addition followed by double electrophilic addition and double Friedel–Crafts cyclization
Friedel–Crafts reaction to form uncommon dibenzo-fused seven- reactions between arylacetaldehydes and alkynyl benzyl alco-
membered carbocycles.
hols in good yields (Scheme 1c).
In continuation of our interest in the synthesis of hetero-
cyclic compounds using alkynes as nucleophiles, we envi-
Carbocyclic compounds are found in many natural products
and biologically active molecules. These include carbocycles
16
1
sioned that alkyne 1a would add to phenyl acetaldehyde (2a)
under Lewis acidic conditions to generate vinyl carbocation A,
which after double Friedel–Crafts reaction would give com-
pound 3a or 4a (Scheme 2). Considering (2-(phenylethynyl)
phenyl)methanol (1a) and phenyl acetaldehyde (2a) as model
having a seven-membered ring, for example, ingenol is used
2
for the topical treatment of actinic keratosis, frondosins
3
inhibit the binding of interleukin-8 (IL-8) and guanacastepene
4
has antibiotic activity. Dibenzocycloheptane is an important
5
structural motif found in many biologically active molecules.
For instance, allocolchicine is active against many cancer cell
6
7
lines, tenuifolin shows antiproliferative activity against the
8
tumor cell line DU145, and subavenoside E, dibenzocyclohep-
8
9
tadiene sihydroisosubamol, and subamol show inhibitory
activity against α-glucosidase type IV. Similarly, substituted
naphthalenes are present in many biologically important com-
1
0
11
pounds and optical and electronic materials and constitute
1
2
the backbone of many chiral ligands. Although the synthesis
of dibenzo-fused six-membered carbocycles is easy, the syn-
thesis of dibenzo-fused seven- to nine-membered carbocycles
is challenging due to their instability. There are a few reports
on the synthesis of dibenzo-fused seven- to nine-membered
5
e,13
carbocycles.
The main drawback is their lengthy synthesis.
The Otani group has demonstrated a methodology for the syn-
thesis of seven- to nine-membered carbocycles via Brønsted
acid-promoted intramolecular Friedel–Crafts-type alkenylation
1
4
(
Scheme 1a). Very recently, Alcarazo synthesized dibenzo-
Department of Chemistry, Indian Institute of Technology, Guwahati, Guwahati
7
†
1
81039, Assam, India. E-mail: asaikia@iitg.ac.in
Electronic supplementary information (ESI) available. CCDC 1873106 and
873107. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1ob00057h
Scheme 1 Synthesis of dibenzocycloheptane.
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increased to 70%. A higher loading of the Lewis acid of 1.5
equivalents did not improve the yield (entry 8, Table 1). Other
Lewis acids such as InCl , FeCl , In(OTf) , Sc(OTf) , Cu(OTf)
3 3 3 3 2
and TMSOTf did not afford higher yields (entries 9–15,
Table 1). Similarly, the Brønsted acids trifluoromethane-
sulfonic acid (TfOH) and p-toluenesulfonic acid (PTSA) (entries
16 and 17, Table 1) were found to be inefficient reagents for
this transformation. Thus, 1 equivalent of BF ·OEt in toluene
3
2
at 100 °C was found to be the optimum condition for the reac-
tion. With these optimum reaction conditions in hand, the
scope of the reaction was investigated with a variety of sub-
strates as shown in Table 2. It is observed in Table 2 that the
success of the reaction depends on the substituents in the
alkyne side chain. Substrates having an electron-donating
group on the aromatic ring (entries 3–6, 8–11, Table 2) gave
Scheme 2 Proposed reaction pathway.
substrates, the reaction was performed with (BF ·OEt ) (0.5
3
2
equiv.) in dichloromethane (DCM) at room temperature. To
our delight, compound 3a was obtained in 34% yield without
the formation of 4a. Encouraged by the result, the reaction was
performed under different conditions as shown in Table 1.
The reaction was performed in dichloroethane (DCE), aceto-
nitrile and toluene at room temperature (entries 2–4, Table 1).
Reactions in DCE and toluene gave 33% and 41% yields,
respectively, whereas in acetonitrile no product was noticed. At
a higher temperature such as 60 and 100 °C (entries 5 and 6,
Table 1), the yield increased to 44 and 48%, respectively. After
observing the effect of the temperature on the yield, the quan-
tity of the reagent was increased from 0.5 equivalent to 1.0
equivalent (entry 7, Table 1) and it was observed that the yield
9
H-dibenzo[3,4:6,7]-cyclohepta[1,2-a]naphthalene in moderate
yields. On the other hand, a moderately electron-withdrawing
group such as chlorine on the aromatic group gave a very low
yield (entry 12, Table 2), which is due to the destabilization of
the carbocation A (Scheme 3). Similarly, a strong electron-with-
drawing group such as carboxylate on the aromatic ring (entry
7, Table 2) failed to give any product due to the strong de-
stabilizing effect of the carboxylate group. On the other hand,
phenylacetaldehyde gave good yields (entries 1 and 3, Table 2)
compared to 2-phenyl propanaldehyde (entries 2, 4, 9–11,
Table 2). meta-Substituted alkyne alcohol 1f and benzo[d][1,3]
dioxole substituted alkyne alcohol 1g gave two regioisomeric
products. It was also observed that substitution on the aro-
matic ring of alkyne alcohol (entries 13 and 14, Table 2)
afforded the desired product with high yields, which is attribu-
ted to the enhancement of nucleophilicity of alkyne 1i. 2,2-
Diphenyl acetaldehyde, on the other hand, gave moderate
yields (entries 15 and 16, Table 2). Similarly, naphthyl substi-
tuted alkyne alcohol 1j with phenylacetaldehyde 2a produced
two products 3q and 4q in 35% and 45% yields, respectively.
However, 2-phenylpropanal 2b produced an inseparable
mixture of 3u and 4u with a ratio of 2 : 3 with 84% overall
yield. To our dismay, the secondary alcohol 1n with 2b resulted
in a complex mixture. Interestingly, naphthyl substituted
alkynes (entries 17 and 21, Table 2) gave high yields which
might be due to the more stabilization of carbocation A
a
Table 1 Optimization of the reaction conditions
b
Reagent
(equiv.)
Temp.
(°C)
Time
(h)
Yield
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
9
BF
BF
BF
BF
BF
BF
BF
BF
3
3
3
3
3
3
3
3
·OEt
·OEt
·OEt
·OEt
·OEt
·OEt
·OEt
·OEt
2
2
2
2
2
2
2
2
(0.5)
(0.5)
(0.5)
(0.5)
(0.5)
(0.5)
(1.0)
(1.5)
DCM
DCE
rt
rt
rt
rt
1.5
2.0
4.0
1.5
1.5
0.5
0.5
0.5
2.0
2.0
1.0
2.0
2.0
2.5
2.0
2.5
3.0
34
33
c
3
CH CN
—
(
Scheme 3). Secondary benzylic alcohol 1k gave a diastereo-
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
41
44
48
70
69
47
46
65
31
17
21
29
28
8
meric mixture of 3r and 4r with a ratio of 4 : 1 in 40% overall
yield. The formation of the minor product 4r can be explained
on the basis of steric congestion between methyl and two
nearby hydrogens of two phenyl rings, which are aligned in
the same plane. The same is true for the formation of 3s and
60
100
100
100
100
100
100
100
100
100
100
100
100
InCl
FeCl
FeCl
In(OTf)
Cu(OTf)
Sc(OTf)
TMSOTf (1.2)
TfOH (1.2)
PTSA (1.2)
3
(0.1)
(0.1)
(0.1)
10
11
12
13
14
15
16
17
3
3
4s as a diastereomeric mixture with a ratio of 2 : 1. In this case,
3
(0.1)
(1.2)
(0.2)
the methylene group is less crowded as compared to the
methyl group and therefore, the ratio increases from 4 : 1 to
2
3
2
: 1. The phenyl substituted secondary alcohol 1m provided
only a single diastereomer 3t in 55% yield. This is because the
sterically hindered phenyl group prefers the opposite side of
the two adjacent aryl groups to reduce the steric repulsion.
The structure of all compounds was determined with the help
a
b
Reaction conditions: 1a (1.0 equiv.), 2a (1.1 equiv.). Yield refers to
1
13
the isolated yield. The compounds were characterised by H, C NMR,
c
IR and mass spectrometry. No reaction; the starting material was
1
13
recovered.
of H and C NMR and mass spectrometry. Finally, it was con-
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Table 2 (Contd.)
Table 2 Synthesis
of
9H-dibenzo[3,4:6,7]-cyclohepta[1,2-a]
naphthalene
a
Entry Alcohol 1
Aldehyde 2 Product 3
Yield (%)
a
Entry Alcohol 1
Aldehyde 2 Product 3
Yield (%)
1
70
10
30
2
3
4
50
60
40
11
25
1
5
12
15
5
6
48
50
1
1
3
4
85
78
b
7
8
0
15
40
48
2
9
16
48
35
17
9
48
4
5
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Table 2 (Contd.)
a
Entry Alcohol 1
Aldehyde 2 Product 3
Yield (%)
18
40
19
85
Scheme 3 Plausible reaction mechanism.
2
2
0
1
55
84
Fig. 1 X-ray crystallographic and energy-optimized structure of 3a at
the [DFT-B3LYP/6-311++G(d,p)] level of theory.
cules 3 and 4, these compounds might have two enantiomeric
forms (Fig. 2). To ascertain this, compounds 3a, 3f, 3q and 4q
were subjected to HPLC analysis and it was observed that they
are a mixture of equal amounts (1 : 1 ratio) of enantiomers. It
may be noted that these chiral molecules are important chiral
ligands in asymmetric synthesis and possess chiroptical
c
2
2
—
0
a
Yield refers to the isolated yield. The compounds were characterized
by IR, NMR and mass spectrometry. No reaction. The starting
b
18b,19
c
properties.
material was recovered in 95% yield. Complex mixture.
The mechanism is proposed on the basis of our findings
2
0
and the previous report (Scheme 3). Under Lewis acidic con-
firmed by X-ray crystallographic analysis of 3a and 3c and DFT ditions aldehyde 2 is activated for nucleophilic attack by
1
7
calculation of compound 3a (Fig. 1). Both X-ray crystallogra- alkyne 1 to give intermediate A, which after Friedel–Crafts reac-
phy and DFT (DFT-B3LYP/6-31+G(d,p)) optimized structures of tion generates intermediate B (Scheme 3). The intermediate B
3
a show a bend structure for 3a, which is due to the repulsion after aromatization and subsequent Friedel–Crafts reaction
among three aromatic rings attached to the cycloheptane ring. gives the final compounds 3 and 4. In most of the cases, the
Compound 4q is similar to a chiral biaryl compound where reaction provided compound 3 with a seven-membered ring in
naphthalene and benzo[b]fluorene rings are in a different the system. On the other hand, the starting material with the
plane and have restricted rotation about a single bond, which naphthalene derivative 1j in the alkyne side chain gave both
1
8
is termed atropisomerism. Due to the dissymmetry in mole- seven-membered 3q and five-membered 4q systems with 4q in
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In conclusion, we have developed a methodology for the
synthesis of unsymmetrical 9H-dibenzo[3,4:6,7]-cyclohepta[1,2-
a]naphthalene via sequential electrophilic addition of alde-
hyde to alkynes and double Friedel–Crafts cyclization reaction
in moderate to good yields in a short time span. The reaction
is highly regioselective and produces equal amounts of enan-
tiomers. The reaction provides a new type of dibenzocyclohep-
tane with an additional naphthalene ring in the molecule. The
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Conflicts of interest
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