Synthesis of diverse indene derivatives from 1-diazonaphthalen-2(1 H)-ones via thermal cascade reactions

Article abstract of DOI:10.1021/ol4019908

A sequential Wolff rearrangement of 1-diazonaphthalen-2(1H)-ones followed by trapping of the ketene intermediate with primary and aromatic amines or alcohols and phenols in the presence of various aldehydes generates 1H-indene-3-carboxamides or 1H-indene-3-carboxylates. This constitutes an unprecedented three-component coupling reaction that allows for the synthesis of functionalized indene derivatives under catalyst-free thermal conditions.

Full text of DOI:10.1021/ol4019908

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Diverse Indene Derivatives
from 1‑Diazonaphthalen-2(1H)‑ones via
Thermal Cascade Reactions
Krishna Bahadur Somai Magar and Yong Rok Lee*
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749,
Republic of Korea
yrlee@yu.ac.kr
Received May 28, 2013
ABSTRACT
A sequential Wolff rearrangement of 1-diazonaphthalen-2(1H)-ones followed by trapping of the ketene intermediate with primary and aromatic amines or
alcohols and phenols in the presence of various aldehydes generates 1H-indene-3-carboxamides or 1H-indene-3-carboxylates. This constitutes an
unprecedented three-component coupling reaction that allows for the synthesis of functionalized indene derivatives under catalyst-free thermal conditions.
The indene framework is an important structural motif
contained in many natural products and pharmaceuticals
(Figure 1).1 These indene-based molecules have shown a
wide range of biological activities such as antineoplastic,2
antimicrobial,3 anti-inflammatory,4 aromatase inhibitory,5
and cytotoxic activities;6 thus some of them are currently
under evaluation for their potential as drug leads.7 In
addition, indene derivatives are widely used as building
blocks for the synthesis of functional materials8 and
metallocene complexes for olefin polymerization.9
(1) (a) Lautens, M.; Marquardt, T. J. Org. Chem. 2004, 69, 4607. (b)
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Figure 1. Selected examples of natural products and pharma-
ceuticals bearing the indene skeleton.
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Because of their importance and usefulness, various
synthetic approaches have been developed to construct
indene derivatives based on intra-10ꢀ14 and intermolecular
cyclization reactions.15ꢀ21 Representative intramolecular
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r
10.1021/ol4019908
XXXX American Chemical Society

approaches include the ring expansion of suitably substi-
tuted cyclopropenes,10 Lewis acid-catalyzed FriedelꢀCrafts
cyclization,11 the Brønsted acid-catalyzed cyclization of alkyl
aryl-1,3-dienes,12 the transition metal-catalyzed cyclization of
alkynes,13 and the gold-catalyzed cycloisomerization of ben-
zene-1,2-dialkynes.14
A variety of effective intermolecular approaches were
also reported for indene synthesis, which include [3þ2]
annulation of aromatic aldimines and acetylenes,15 copper-
catalyzed arylative cyclization of arylalkynes and aromatic
sulfonyl chlorides,16 palladium-catalyzed carboiodination
of aryl iodide and internal alkynes,17 FeCl3-catalyzed
cyclization of N-benzylic sulfonamides and disubsti-
tuted alkynes,18 Lewis acid-catalyzed cascade reac-
tion between aziridines and propargyl alcohols,19 the
FeCl3-catalyzed cyclization of arylallenes to N-alkyl
sulfonamides,20 and palladium-catalyzed carboannulation
of diethyl 2-(2-(1-alkynyl)phenyl)malonate and or-
ganic halides.21
thermal Wolff rearrangement of cyclic 2-diazo-1,3-
dicarbonyls.26 As the result of our continued interest in this
area, herein we describe catalyst-free thermal cascade reac-
tions where the Wolff rearrangement of 1-diazonaphthalen-
2(1H)-one induces the formation of structurally diverse
indene derivatives. Although a photochemical Wolff rear-
rangement of 1-diazonaphthalen-2(1H)-one to give a ketene
intermediate has been reported,27 this is the first example of a
one-pot synthesis of complex 1H-indene-3-carboxamide and
1H-indene-3-carboxylate derivatives under relatively mild
conditions without catalysts.
Diazo compounds 1aꢀ1d were prepared from 2-naphthols
and 2-azido-1,3-dimethylimidazolinium chloride following
the Kitamura protocol (Scheme 1).28
Scheme 1. Preparation of Diazo Compounds 1aꢀ1d
Despite their own merits, many existing methods suffer
from shortcomings including low tolerance of functional-
ity, long reaction times, the necessity of expensive transi-
tion metal catalysts, and harsh reaction conditions. There-
fore, more environmentally benign and efficient arsenals are
still needed improving on these shortcomings, which prompt
us to develop new approaches relying on the characteristic
reactivity of diazo compounds. The decomposition of diazo-
carbonyl compounds is one of the significant reaction in
organic synthesis.22 Among these, Wolff rearrangement is a
useful method for the formation of reactive ketene
intermediates.23 This method has a lot of applications in
DNA cleavage, β-peptides, drug delivery, and photoaffinity
labeling.24
Our investigation commenced with the optimization of
reaction conditions for the thermal decomposition of 1a in
the presence of n-butylamine and benzaldehyde in various
solvents and temperatures (Table 1). Treatment of 1a
(1.0 mmol) with n-butylamine (1.1 mmol) and benzaldehyde
(1.1 mmol) in fluorobenzene at 85 °C for 18 h provided 2a
in 30% yield (entry 1), whereas that in chlorobenzene at
110 °C for 8 h afforded 2a in 63% yield (entry 2). Reaction
in toluene at 70 °C for 18 h remained starting material 1a
(entry 3), but at 110 °C, 2a was obtained in 80% yield after
6 h (entry 4). Reaction in m-xylene under reflux for 4 h did
not provide 2a but only intractable material (entry 5).
Although in 1,4-dioxane, 2a was produced in 52% yield
(entry 6), in more polar solvents such as acetonitrile and
DMF, 2a was not obtained at all (entries 7 and 8). The
identity of 2a was confirmed by spectroscopic analysis; the
1H NMR of 2a shows two vinylic protons at δ = 7.54 and
7.22 ppm as the two signals for the indene and benzylidene
moiety, respectively. The E-stereochemistry of 2a was de-
duced from the X-ray crystallographic analysis of structur-
ally related compound 2k (see Supporting Information).
Next, rhodium(II)-catalyzed and microwave-assisted
reactions were attempted. Reaction of 1a with n-buty-
lamine and benzaldehyde in the presence of 2 mol % of
Rh2(OAc)4 in toluene at room temperature for 48 h
provided 2a (5%) and 2-naphthol (23%), and unreacted
starting material was recorved (35%). MW irradiation of
1a with n-butylamine and benzaldehyde in DMF at 400 W
and 50 °C for 10 min afforded 2a in 64% yield.
In this context, we became interested in the decomposi-
tion of cyclic diazodicarbonyl compounds as a powerful
means of synthesizing heterocycles and novel compounds;25
for example, we prepared cyclic β-enaminoamides via the
(14) (a) Ye, L.; Wang, Y.; Aue, D. H.; Zhang, L. J. Am. Chem. Soc.
€
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2012, 134, 31. (b) Hashmi, A. S. K.; Braun, I.; Nosel, P.; Schadlich, J.;
Wieteck, M.; Rudolph, M.; Rominger, F. Angew. Chem., Int. Ed. 2012,
51, 4456.
(15) (a) Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc.
2005, 127, 13498. (b) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai,
K. J. Am. Chem. Soc. 2006, 128, 202.
(16) Zeng, X.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011, 133,
17638.
(17) Jia, X.; Petrone, D. A.; Lautens, M. Angew. Chem., Int. Ed. 2012,
51, 9870.
(18) Liu, C.-R.; Yang, F.-L.; Jin, Y.-Z.; Ma, X.-T.; Cheng, D.-J.; Li,
N.; Tian, S.-K. Org. Lett. 2010, 12, 3832.
(19) Wang, S.; Zhu, Y.; Wang, Y.; Lu, P. Org. Lett. 2009, 11, 2615.
(20) Liu, C.-R.; Wang, T.-T.; Qi, Q.-B.; Tian, S.-K. Chem. Commun.
2012, 48, 10913.
(21) Guan, Z.-H.; Ren, Z.-H.; Zhao, L.-B.; Liang, Y.-M. Org.
Biomol. Chem. 2008, 6, 1040.
(22) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley: New York,
NY, 1998. (b) Maas, G. Angew. Chem., Int. Ed. 2009, 48, 8186.
(23) (a) Tidwell, T. T. Angew. Chem., Int. Ed. 2005, 44, 5778. (b) Cui,
G.; Thiel, W. Angew. Chem., Int. Ed. 2013, 52, 433. (c) Rudolf, P.;
Buback, J.; Aulbach, J.; Nuernberger, P.; Brixner, T. J. Am. Chem. Soc.
2010, 132, 15213.
(26) Neupane, P.; Li, X.; Jung, J. H.; Lee, Y. R.; Kim, S. H.
Tetrahedron 2012, 68, 2496.
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1994, 116, 954. (b) Hacker, N. P.; Kasai, P. H. J. Am. Chem. Soc. 1993,
115, 5410.
(24) Kirmse, W. Eur. J. Org. Chem. 2002, 2193.
(25) (a) Lee, Y. R.; Hwang, J. C. Eur. J. Org. Chem. 2005, 1568. (b)
Lee, Y. R.; Suk, J. Y. Chem. Commun. 1998, 2621.
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2010, 2503.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of the Thermal Decomposition of 1a in
the Presence of n-Butylamine and Benzaldehyde
Scheme 2. Formation of Indene Derivatives 2bꢀ2t and 3aꢀ3p
by Thermal Decomposition of 1aꢀ1d with Primary Amines and
Aromatic/Heteroaromatic/Aliphatic Aldehydesa,b
entry
solvent
temperature (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
fluorobenzene
chlorobenzene
toluene
85
110
70
18
8
30
63
0
18
6
toluene
110
140
100
80
80
0
m-xylene
4
1,4-dioxane
acetonitrile
DMF
15
24
8
52
0
110
0
With the optimized conditions in hand, we further ex-
plored the generality of this thermal multicomponent reac-
tion employing different primary amines and aldehydes
(Scheme 2). Reactions of 1a in refluxing toluene for 6 h in
the presence of n-butylamine together with 4-methyl-,
4-methoxy-, 4-formyl-, 3-methoxy-, and 2-chlorobenzalde-
hyde afforded the expected products 2bꢀ2f in the range of
64ꢀ78% yield. Also, the cascade reactions of diazo com-
pound 1bꢀ1d bearing electron-donating or -withdrawing
groups on the aromatic ring were also successful. Reaction
of 1b and 1c bearing electron-donating groups provided the
desired products 2g (91%) and 2h (88%), and that of 1d
bearing an electron-withdrawing group afforded 2i in 73%
yield. The combinations of diazo compounds 1a and 1b with
benzyl amine and benzaldehyde or 4-methoxybenzaldehyde
afforded 2j (77%), 2k (78%), and 2l (85%), respectively.
With tryptamine together with benzaldehyde and its deriva-
tives containing a substituent at the 4-position products
2mꢀ2q were obtained in a slightly lower range of yields
(48ꢀ70%). The combinations of 1- and 2-napthaldehyde and
butyl-, benzyl-, and tryptamine provided the corresponding
products 2rꢀ2t in 71%, 78%, and 63% yield, respectively.
Next, we explored the multicomponent reaction of diazo
compounds 1aꢀ1d with primary amines and various hetero-
aromatic aldehydes such as furfural, 3-furancarboxaldehyde,
2-thiophenecarboxaldehyde, N-methyl-2-pyrrolecarboxalde-
hyde, and 2,20-bithiophene-5-carboxaldehyde under the op-
timized conditions. These reactions with heteroaromatic
aldehydes generally afforded slightly increased yields of the
expected products 3aꢀ3p in the range of 45ꢀ94%.
a Conditions: toluene, 110 °C, 6 h (1:amine:aldehyde = 1:1.1:1.1).
b Reactions with aliphatic aldehydes failed in generating the desired
products.
To further demonstrate the versatility of this multi-
component reaction, we examined reactions with aromatic
amines and aromatic/heterocyclic aldehydes (Scheme 3).
The thermal decoposition of 1aꢀ1d with aniline or sub-
stituted anilines and aromatic aldehydes in refluxing tol-
uene for 6 h afforded the corresponding products 4aꢀ4n
in 44ꢀ88% yield.
Having seen the general applicability of the multicom-
ponent reaction by employing amines as the nucleophilic
component, we were intrigued by the possibility of using
oxygen-based nucleophiles, which will lead to the forma-
tion of 1H-indene-3-carboxylate derivatives. We were
gratified to observe that the reactions of 1a, 1b, and 1d
with aliphatic alcohols or phenol derivatives together with
aromatic/heteroaromatic aldehydes provided the expected
products (Scheme 4). Reactions of 1a with benzaldehyde in
combination with 1-propanol, benzyl, and phenethyl alco-
hol provided desired products 5aꢀ5c in 56%, 55%, and
65% yield, respectively. Treatment of 1d with 1-propanol
and benzaldehyde provided 5d in 56% yield, whereas that
of 1b with phenethyl alcohol and benzaldehyde afforded5e
in 63% yield. With phenol and its derivatives, reactions
were also successful. In general, the yields of the isolated
1H-indene-3-carboxylate derivatives 5fꢀ5o are some-
what lower (in the range of 39ꢀ57%) than those of the
corresponding carboxamides (in the range of 45ꢀ94%).
We also tried the reaction with aliphatic aldehydes, but
we did not observe any desired indene products with these
aldehydes and amines being incorporated. For example,
reaction of 1c with benzylamine and 3-methylbutanal in
refluxing toluene for 6 h gave complex mixtures. However,
reactions of 1a with n-butylamine and 3-methyl-2-butenal
or trans-cinnamaldehyde in refluxing toluene for 6 h
provided unexpected cycloadducts 3q and 3r in 66% and
61% yield, respectively.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Formation of Indene Derivatives 4aꢀ4n by Thermal
Decomposition of 1aꢀ1d with Aniline and Substituted Anilines
and Aromatic/Heteroaromatic Aldehydesa
Scheme 4. Formation of Indene Derivatives 5aꢀ5o by Thermal
Decomposition of 1a, 1b, and 1d with Aliphatic Alcohols or
Phenol Derivatives and Aromatic/Heteroaromatic Aldehydesa
a Conditions: toluene, 110 °C, 6 h (1:amine:aldehyde = 1:1.1:1.1).
The formation of 5k was identified by 1H NMR analysis,
in which a proton peak of OH appeared downfield at δ
12.46 ppm due to the presence of intramolecular hydrogen
bonding to a carbonyl group. These reduced yields com-
pared to those of the other series are most likely the con-
sequence of the lower nucleophilicity of aliphatic alcohols
and phenol derivatives that undergo the initial addition to
the ketene intermediate.
a Conditions: toluene, 110 °C, 6 h (1:alcohol:aldehyde = 1:1.1:1.1).
Scheme 5. Proposed Mechanism for the Formation of 2
The formation of observed products 2 is assummed to be
initiated by the thermal decomposition of 1-diazonaphtha-
len-2(1H)-one (1a) to the corresponding ketene intermedi-
ate, benzofulven-8-one(6), via the initial N2 loss27 followed
by a Wolff rearrangenent (Scheme 5). The Wolff rearrange-
ment induced by photolysis of 1-diazonaphthalen-2(1H)-
one (1a) to generate ketene 6 and its subsequent reaction
with water to form indene-3-carboxylic acid was previously
reported by Wirz and Kasai.27 Once formed, ketene 6 would
undergo nucleophilic addition by either amines or alcohols
in the presence of aldehydes. In the case of amine nucleo-
philes, zwitterionic ylide 7 would interact with an incoming
aldehyde through hydrogen bonding to facilitate the car-
bonyl addition, leading to the formation of intermediate 8.
As evidence for intermediate 7, a stable keteneꢀamine or
keteneꢀpyridine ylide intermediate has been reported.29
Finally, a thermodynamically driven stereospecific anti-
elimination of water from 8 would lead to observed
product 2. The high selectivity for 2 might simply be a
consequence of isomerization of the products formed
through nonstereospecific processes driven by the steric
interaction between the indene and phenyl moieties.
In summary, we developed a novel one-pot cascade
approach to the synthesis of 1H-indene-3-carboxamides
and 1H-indene-3-carboxylate derivatives from the thermal
decomposition of 1-diazonaphthalen-2(1H)-ones. Aliphatic
or aromatic primary amines and aliphatic alcohols or
phenol derivatives are used as the nucleophilic compo-
nent together with various aromatic and heteroaromatic
aldehydes. This catalyst-free multicomponent coupling
reaction allows for the synthesis of various functionalized
indene derivatives, which should find various applications
in the synthesis of natural products and pharmaceuticals.
Further expansion of the reaction scope using other nu-
cleophilic components in the presence of amine and Lewis
acid catalysts is in progress.
Acknowledgment. This research was supported by the
Ministry of Education, Science and Technology
(2012M3A7B4049675) through the Nano Material Tech-
nology Development Program of the Korean National
Research Foundation (NRF).
Supporting Information Available. Experimental pro-
cedures and characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(29) (a) Ortica, F.; Pohlers, G.; Scaiano, J. C.; Cameron, J. F.;
Zampini, A. Org. Lett. 2000, 2, 1357. (b) Qiao, G. G.; Andraos, J.;
Wentrup, C. J. Am. Chem. Soc. 1996, 118, 5634.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX