In(III)/PhCO2H binary acid catalyzed tandem [2 + 2] cycloaddition and nazarov reaction between alkynes and acetals

Article abstract of DOI:10.1021/ol4020464

A facile tandem [2 + 2] cycloaddition and Nazarov reaction has been developed. The combination of In(OTf)₃ and benzoic acid was found to synergistically promote the coupling of alkynes and acetals to form 2,3-disubstituted indanones in excellent yield and diastereoselectivity.

Full text of DOI:10.1021/ol4020464

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
In(III)/PhCO2H Binary Acid Catalyzed
Tandem [2 þ 2] Cycloaddition and
Nazarov Reaction between Alkynes and
Acetals
Lihui Zhu, Zhi-Guo Xi, Jian Lv, and Sanzhong Luo*
Beijing National Laboratory for Molecule Sciences (BNLMS), CAS Key Laboratory
for Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, People’s Republic of China
luosz@iccas.ac.cn
Received July 19, 2013
ABSTRACT
A facile tandem [2 þ 2] cycloaddition and Nazarov reaction has been developed. The combination of In(OTf)3 and benzoic acid was found to
synergistically promote the coupling of alkynes and acetals to form 2,3-disubstituted indanones in excellent yield and diastereoselectivity.
The Nazarov reaction of aryl vinyl ketones is one of the
moststraightforwardstrategiestobuildindanone-contain-
ing structures with promising biological profiles that
widely occur in natural products.1ꢀ3 Accordingly, new
catalysts or catalytic strategies for the cyclization of aryl
vinyl ketones have been actively pursued to address the
associated challenges such as insufficient reactivity, limited
scope, and the lack of enantioselective control.4,5
(4) For the Nazarov reaction of aryl vinyl ketones, see: (a) He, W.;
Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125, 14278. (b) Janka,
M.; He, W.; Frontier, A. J.; Eisenberg, R. J. Am. Chem. Soc. 2004, 126,
6864. (c) Malona, J. A.; Colbourne, J. M.; Frontier, A. J. Org. Lett. 2006,
8, 5661. (d) Kerr, D. J.; Hamel, E.; Jung, M. K.; Flynn, B. L. Bioorg.
Med. Chem. 2007, 15, 3290. (e) He, W.; Herrick, I. R.; Atesin, T. A.;
Caruana, P. A.; Kellenberger, C. A.; Frontier, A. J. J. Am. Chem. Soc.
2008, 130, 1003. (f) Marcus, A. P; Lee, A. S.; Davis, R. L.; Tantillo, D. J.;
Sarpong, R. Angew. Chem., Int. Ed. 2008, 47, 6379. (g) Vaidya, T.;
Atesin, A. C.; Herrick, I. R.; Frontier, A. J.; Eisenberg, R. Angew.
Chem., Int. Ed. 2010, 49, 3363. (h) Zhong, C.; Zhu, J.; Chang, J.; Sun, X.
Tetrahedron Lett. 2011, 52, 2815. (i) Wu, Y.-K.; Niu, T.; West, F. G.
Chem. Commun. 2012, 48, 9186.
(5) For tandem Nazarov reactions, see: (a) Sartori, G.; Bigi, F.;
Maggi, R.; Bernardi, G. L. Tetrahedron Lett. 1993, 34, 7339. (b)
Bhattacharya, A.; Segmuller, B.; Ybarra, A. Synth. Commun. 1996, 26,
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Frontier, A. J.; Eisenberg, R. J. Am. Chem. Soc. 2006, 128, 5312. (f)
Lebœuf, D.; Wright, C. M.; Frontier, A. J. Chem. Eur. J. 2013, 19, 4835.
(6) Vieregge, H.; Schmidt, H. M.; Renema, J.; Bos, H. J. T.; Arens,
J. F. Recl. Trav. Chim. Pays-Bas 1969, 88, 465.
(1) For reviews of the Nazarov reaction, see: (a) Vaidya, T.; Eisenberg,
R.; Frontier, A. J. ChemCatChem 2011, 3, 1531. (b) Shimada, N.; Stewart,
C.; Tius, M. A. Tetrahedron 2011, 67, 5851. (c) Grant, T. N.; Rieder, C. J.;
West, F. G. Chem. Commun. 2009, 5676. (d) Nakanishi, W.; West, F. G.
Curr. Opin. Drug Disc. 2009, 12, 732. (e) Tius, M. A. Eur. J. Org. Chem.
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Pellissier, H. Tetrahedron 2005, 61, 6479. (h) Tius, M. A. Acc. Chem. Res.
2003, 36, 284. (i) Spencer, W. T., III; Vaidya, T.; Frontier, A. J. Eur. J.
Org. Chem. 2013, 3621.
(2) For the indanone structure in natural products, see: (a) Kawazoe,
K.; Yamamoto, M.; Takaishi, Y.; Honda, G.; Fujita, T.; Sezik, E.;
Yesilada, E. Phytochemistry 1999, 50, 493. (b) Hanson, J. R. Nat. Prod.
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Johnson, W. S.; DeJongh, H. A. P.; Coverdale, C. E.; Scott, J. W.;
Burckhardt, U. J. Am. Chem. Soc. 1967, 89, 4523. (b) Banerjee, M.;
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r
10.1021/ol4020464
XXXX American Chemical Society

Yne-carbonyl metathesis is an atom-economic process
for the synthesis of enones.6,7 With judiciously designed
substrates, this reaction has been utilized to deliver versa-
tile structural skeletons such as cyclic enones,8 amides,9
oxetenes,10 and lactones11 in tandem transformations in-
itialized by the [2 þ 2] oxetene formation. Recently, the
combination of yne-carbonyl metathesis and Nazarov
cyclization have been reported, providing facile access
to the Nazarov adducts with readily available starting
materials.12 Unfortunately, those processes still suffer
from the use of overstoichiometric amounts of acid cata-
lysts, harsh conditions, or limited scope. Herein, we pres-
ent a new variant of tandem [2 þ 2] and Nazarov cycliza-
tion involving aryl alkynes and acetals (Scheme 1). The
reactions, which are enabled by the simple binary acid
In(OTf)3/benzoic acid,13,14 exhibit unprecedentedly broad
scope for the synthesis of 1-indanones under rather mild
conditions.
ketones have seriously limited the substrate scope, which
prompted us to seek a more convenient protocol. In this
regard, a [2 þ 2] coupling between methyl piperonylpro-
pionate (1a) and benzaldehyde (2a0) was attempted in the
presence of the previously identified optimal catalyst In-
(OTf)3/diphenylphosphoric acid (DPP). Unfortunately,
the reaction afforded only minor desired product along
with various major byproducts such as the hydration
product 3a and enone 3b (Scheme 2). Extensive optimiza-
tion by changing the Lewis acid, Brønsted acid, or solvent
did notlead toany improvements. Inall cases, hydrationof
the arylpropiolates were generally formed as the major
products, indicating that [2 þ 2] cycloaddition is not
favored under these conditions. At this point, we sought
to employ oxonium ions,16 more electrophilic species
generated in situ from acetals, for the coupling. An in-
tramolecular version of enyne-acetals coupling7f,g has
recently been reported to furnish Nazarov-type adducts.8c
To the best of our knowledge, intermolecular coupling of
alkynes and acetals in the context of Nazarov chemistry
has not been reported.
Scheme 1. [2 þ 2] and Nazarov Cyclization between Aryl
Alkynes and Acetals
Scheme 2. Tandem [2 þ 2] Cycloaddition using Aldehyde
To our delight, the desired Nazarov product was ob-
tained in a decent 46% yield when benzaldehyde dimethy-
lacetal (2a) was employed in the presence of In(OTf)3/DPP
(Table 1, entry 1). The reaction can be readily improved
by screening different Lewis acids, Brønsted acids, and
their combinations. In(OTf)3/benzoic acid was found to be
the optimal binary acid catalyst to furnish the desired
Nazarov product in quantitative yield (Table 1, entry 2).
Other screened binary acids gave inferior results (Table 1,
entries 3ꢀ9). In control reactions, the use of only a Lewis
acid or a Brønsted acid showed virtually no activity, high-
lighting the synergistic feature of the combinations of two
acids (Table 1, entries 10 and 11). The ratio of the two acids
has also been examined, and a 1/2 In(OTf)3/benzoic acid
ratio was found todeliver the best result(Table 1, entry 2 vs
entries 12 and 13).
Previously, we reported a binary acid strategy for the
Nazarov reaction of aryl vinyl ketones.15 However, the
nontrivial synthetic efforts to access the required vinyl
(8) (a) Jin, T.; Yamamoto, Y. Org. Lett. 2008, 10, 3137. (b) Jin, T.;
Yang, F.; Liu, C.; Yamamoto, Y. Chem. Commun. 2009, 3533. (c)
ꢀ
ꢀ
Escalante, L.; Gonzalez-Rodrıguez, C.; Varela, J. A.; Saa, C. Angew.
ꢀ
Chem., Int. Ed. 2012, 51, 12316. (d) Gonzalez-Rodrıguez, C.; Escalante,
L.; Varela, J. A.; Castedo, L.; Saa, C. Org. Lett. 2009, 11, 1531.
ꢀ
(9) (a) Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas, C. J.;
Xiong, H.; Mulder, J. A. Org. Lett. 1999, 1, 1237. (b) Kurtz, K. C. M.;
Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231. (c) You, L.; Al-Rashid,
Z. F.; Figueroa, R.; Ghosh, S. K.; Li, G.; Lu, T.; Hsung, R. P. Synlett
2007, 1656.
(10) (a) Middleton, W. J. J. Org. Chem. 1965, 30, 1307. (b) Aikawa,
K.; Hioki, Y.; Shimizu, N.; Mikami, K. J. Am. Chem. Soc. 2011, 133,
20092.
(11) Zhao, W.; Li, Z.; Sun, J. J. Am. Chem. Soc. 2013, 135, 4680.
(12) Saito, A.; Umakoshi, M.; Yagyu, N.; Hanzawa, Y. Org. Lett.
2008, 10, 1783.
After identifying In(OTf)3/benzoic acid as the optimal
catalyst, we turned our attention to explore the sub-
strate scope (Figure 1). The reactions are quite broad
with respect to internal alkynes. As usually observed in
Nazarov chemistry, electron-rich aryl moieties on aryl
(13) For a review, see: Lv, J.; Luo, S. Chem. Commun. 2013, 847–858.
(14) For examples, see: (a) Lv, J.; Li, X.; Zhang, L.; Luo, S.; Cheng,
J.-P. Org. Lett. 2010, 12, 1096. (b) Lv, J.; Zhang, L.; Zhou, Y.; Nie, Z.;
Luo, S.; Cheng, J.-P. Angew. Chem., Int. Ed. 2011, 50, 6610. (c) Lv, J.;
Zhang, L.; Hu, S.; Cheng, J.-P.; Luo, S. Chem. Eur. J. 2012, 18, 799. (d)
Chen, L.; Zhang, L.; Lv, J.; Cheng, J.-P.; Luo, S. Chem. Eur. J. 2012, 18,
8891. (e) Zhang, L.; Chen, L.; Lv, J.; Cheng, J.-P.; Luo, S. Chem. Asian J.
2012, 7, 2569. (f) Lv, J.; Zhong, X.; Cheng, J.-P.; Luo, S. Acta Chim. Sin.
2012, 70, 1518.
(16) For the electrophilicity of carbonꢀheteroatom bonds, see:
Appel, R.; Chelli, S.; Tokuyasu, T.; Troshin, K.; Mayr, H. J. Am. Chem.
Soc. 2013, 135, 6579.
(15) Xi, Z.-G.; Zhu, L.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2013, 78,
606.
B
Org. Lett., Vol. XX, No. XX, XXXX

cycloaddition step in this tandem [2 þ 2]-Nazarov se-
quence, since it is known that electron-deficient aldehydes
are favored in the yne-carbonyl metathesis.17,18
Table 1. Screening of Catalyst and Reaction Conditions for the
Tandem [2 þ 2] Cycloaddition and Nazarov Reactiona
Scheme 3. Proposed Mechanism
entry
Lewis acid
Brønsted acid
time (h)
yield (%)b
1
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
Bi(OTf)3
Ni(OTf)2
Cu(OTf)2
Sc(OTf)3
none
DPPc
24
24
46
99
30
<5
92
71
<5
<5
89
<5
10
72
89
2
PhCOOH
TFA
3
24
4
AcOH
24
5
TfOH
24
6
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
none
24
7
24
8
24
9
24
10
11
12d
13e
>72
>72
48
In(OTf)3
In(OTf)3
In(OTf)3
PhCOOH
PhCOOH
36
a The general reaction was conducted with 1a (0.1 mmol) and 2a (0.11
mol) in CH2Cl2 (0.5 mL) at 40 °C. b Isolated yield. c DPP = diphenyl-
phosphoric acid. d In(OTf)3 (5 mol %). e PhCOOH (10 mol %).
On the basis of the experimental results as well as the
known mechanistic features of [2 þ 2] cycloaddition18 and
the Nazarov reaction,19 a plausible mechanism is proposed
(Scheme 3). In this scheme, the highly active oxetene
cationic intermediate A, generated from the coupling of
alkyne with hemiacetal cation, would undergo sponta-
neous isomerization to form the 4π-Nazarov intermediate
B/C, followed by facile cyclization and proton transfer to
afford the Nazarov adduct. The collapse of intermediate
B/C to vinyl ketone, the typical yne-carbonyl metathesis
product, has not been observed under the present condi-
tions, suggesting that this pathway, if it exists, is slower
than the desired cyclization step. The observation of fast-
reacting electron-deficient acetals is also consistent with
this scenario, since the preformed vinyl ketones derived
from the same acetals are rather sluggish substrates in
Nazarovchemistry. Inaddition, wehavebeen able to detect
enol methyl ether D from the reaction mixture by ESI-MS,
adding further support to the proposed mechanism.
In conclusion, we have developed a novel type of tandem
[2 þ 2] cycloaddition and Nazarov reaction using cheap
and readily available starting materials as well as an
environmentally benign catalyst. Simply combining In-
(OTf)3 and benzoic acid as a dual catalyst provides ex-
cellent performance in widespread substrates with the
best activity so far for this type of substrate in Naz-
arov chemistry. Further synthetic applications and the
alkynes (e.g., methoxylbenzenes) are generally preferred to
facilitate the electrophilic cyclization. In our studies, an
unsubstituted phenyl ring can also participate in the [2 þ
2]-Nazarov tandem sequence (e.g., 3ba, 3ca and 3cb). On
the other hand, the other terminal position of aryl alkynes
can tolerate a number of different substituents including
carboxylic esters, as well as alkyl and aromatic groups. In
particular, 1,2-diphenylethynes reacts regioselectively to
form the desired 1-indanones as single isomers (Figure 1,
3ea-3ef, 3fa and 3ga), with the cyclization occurring dom-
inantly onto the electron-rich phenyl ring. 1,2-Dipheny-
lethynes bearing two electron-rich aromatic rings gave
rather complicated reaction mixtures, indicating that an
electronic bias is intrinsically preferred for smooth and
clean reactions.
As to the acetals, both aromatic and aliphatic aldehydes
(e.g., 3dhꢀ3dj) can be accommodated. It is noted that the
reactions worked with aromatic aldehydes bearing either
an electron-withdrawing or electron-rich group (e.g., 3dg),
with the former reacting much more quickly. In the latter
case, increasing the loading of benzoic acid to 50 mol %
was necessary to achieve a higher production. This ob-
servation stands in contrast to the typical Nazarov cycliza-
tion of preformed aryl vinyl ketones, wherein an electron-
rich phenyl ring on the vinyl moiety is preferred.15 Taken
together, the preference of electron-deficient aromatic
aldehydes is consistent with a rate-limiting [2 þ 2]
(19) For mechanistic studies of the Nazarov reaction, see: (a)
Motoyoshiya, J.; Yazaki, T.; Hayashi, S. J. Org. Chem. 1991, 56, 735.
ꢀ
(b) Polo, V.; Andres, J. J. Chem. Theory Comput. 2007, 3, 816. (c) Shi,
(17) For the stability of acetals, see: Jensen, B.; Counsell, R. Can. J.
Chem. 1973, 51, 3820.
(18) For mechanistic studies of [2 þ 2] cycloaddition, see: (a) Oblin,
M.; Parrain, J.-L.; Rajzmann, M.; Pons, J.-M. Chem. Commun. 1998,
1619. (b) Shindo, M.; Sato, Y.; Shishido, K. J. Org. Chem. 2000, 65,
5443.
F.-Q.; Li, X.; Xia, Y.; Zhang, L.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129,
15503. (d) Cavalli, A.; Masetti, M.; Recanatini, M.; Prandi, C.; Guarna,
A.; Occhiato, E. G. Chem. Eur. J. 2006, 12, 2836. (e) Lebœuf, D.; Huang,
J.; Gandon, V.; Frontier, A. J. Angew. Chem., Int. Ed. 2011, 50, 10981. (f)
Lebœuf, D.; Gandon, V.; Ciesielski, J.; Frontier, A. J. J. Am. Chem. Soc.
2012, 134, 6296.
Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 1. Scope of the tandem [2 þ 2] cycloaddition and Nazarov reaction between alkynes and acetals: (a) the reaction was carried out
with 1a (0.1 mmol) and 2a (0.11 mmol) in CH2Cl2 (0.5 mL) at 40 °C; (b) isolated yields are given; (c) 50 mol % benzoic acid was used.
development of asymmetric versions are underway and
will be reported in due course.
Supporting Information Available. Text and figures
1
giving experiment procedures and H and 13C NMR
spectral data for compounds 1d, lf, and 3. This material
is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. The project was supported by Min-
istry of Science and Technology (2012CB821600), the
Natural Science Foundation of China (NSFC 21202170
and 21025208), and the Chinese Academy of Sciences.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX