Atom-economical access to highly substituted indenes and furan-2-ones via tandem reaction of diazo compounds and propargyl alcohols

Article abstract of DOI:10.1021/ol501942y

A facile synthesis of highly substituted as well as conjugated indene/furanone systems via a BF₃·OEt₂ catalyzed tandem reaction of α-diazo-esters/-amides and propargyl alcohols has been demonstrated under mild conditions. This method

Full text of DOI:10.1021/ol501942y

Letter
pubs.acs.org/OrgLett
Atom-Economical Access to Highly Substituted Indenes and Furan-2-
ones via Tandem Reaction of Diazo Compounds and Propargyl
Alcohols
Sengodagounder Muthusamy* and Manickasamy Sivaguru
School of Chemistry, Bharathidasan University, Tiruchirappalli, 620024, India
*
S Supporting Information
ABSTRACT: A facile synthesis of highly substituted as well as
conjugated indene/furanone systems via a BF ·OEt catalyzed
3
2
tandem reaction of α-diazo-esters/-amides and propargyl
alcohols has been demonstrated under mild conditions. This
method offers great potential for the synthesis of biologically
active indene and furanone derivatives and their related
polycyclic compounds.
1
2
ndenes and furanones are an important class of
compounds that display a wide range of biological
pharmaceutical research, many methods involving transition-
metal-catalyzed reactions for indenes and furanones have been
reported. Although the above-mentioned methods are quite
effective in synthesizing indenes and furanones, certain
drawbacks are unavoidable in the preparation of substituted
indenes and furanones, namely lengthy reaction sequences,
strong acid conditions, heavy or rare earth metals, toxicity, low
natural abundance, and expensiveness. These constitute severe
drawbacks for industrial applications. The reaction of α-
diazocarbonyl compounds with tertiary propargylic alcohols
in the presence of a rhodium(II) catalyst was known to
I
3
4
properties. Many natural products having these skeletons
Figure 1) have shown interesting properties in the field of
(
5
6
medicine and materials science. Indene core structure
containing metallocene complexes have been utilized in the
polymerization process as catalysts. Substituted indene and
furanone derivatives serve as an important class of compounds
that are used as building blocks. The literature methods for the
7
8
synthesis of indenes or furanones involve the cyclization of
substituted allylic alcohols, ring expansion of substituted
9
1
0
cyclopropenes, Lewis acid catalyzed Friedel−Crafts cycliza-
1
1
12
tion, transition metals, ruthenium-catalyzed carbonylative
16
furnish hydroxy allenes (Scheme 1a). In continuation of our
1
3
14
15
cyclization, enyne methatesis, and cross-coupling reac-
tions. Because of their importance in both chemical and
17
research interest on the chemistry of α-diazocarbonyl
compounds, we herein describe a novel tandem reaction that
can afford a variety of highly substituted indenes and furanones
Scheme 1. Reaction of Diazocarbonyl Compound and
Propargyl Alcohol: (a) Insertion−Rearrangement; (b)
Annulation
Received: July 4, 2014
Published: August 1, 2014
Figure 1. Selected examples of natural products.
©
2014 American Chemical Society
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Organic Letters
Letter
from α-diazo-esters/-amides and propargyl alcohols with 10
mol % of BF ·OEt at 0 °C.
On the other hand, a low product yield was observed when
the reaction was performed in 1,2-dichloroethane (DCE) or
hexane (Table 1, entries 2 and 3). The reaction was also
performed in tetrahydrofuran (THF) but did not yield the
desired product 3a (Table 1, entry 4). Similarly, a low yield of
the product was observed when the reaction was performed in
the presence of Yb(OTf) , Sc(OTf) , FeCl , or InCl as a
catalyst (Table 1, entries 5−8). Use of CuOTf or TfOH as a
catalyst also provided 3a in a very low yield (Table 1, entries 9
and 10). The reaction was found to result in a mixture of
3
2
18
The required α-diazo-esters/-amides 1 and propargyl
1
9
alcohols 2 were synthesized according to the literature
methods. Initial study on the feasibility of a dichloromethane
(DCM) solution containing an equimolar mixture of α-
diazoester 1a and propargyl alcohol 2a in the presence of 10
mol % of BF ·OEt at 0 °C for 10 min afforded highly
3
3
3
3
3
2
substituted indene 3a in 92% yield (Table 1, entry 1) in a
tandem manner.
products when AlCl was used as a catalyst (Table 1, entry 11).
3
Table 1. Optimization of Reaction Conditions
Further, experiments with a stoichiometric amount of BF ·OEt
3
2
did not improve the product yield compared to the catalytic
reaction conditions (Table 1, entry 12). Thus, the optimized
reaction conditions for the formation of 3a were found to be 10
mol % of BF ·OEt at 0 °C (Table 1, entry 1).
3
2
Encouraged by the above-mentioned result, we tested the
substrate scope for the transformation, and the results are
presented in Table 2. Reactions of α-diazoesters and propargyl
alcohols bearing either an electron-donating or -withdrawing
group on the arene gave the corresponding highly substituted
and conjugated indene in excellent yields (Table 2, entries 1−6,
8, 10, 12−16). Substrates bearing an aliphatic moiety attached
to the alkyne of propargylic alcohols smoothly furnished
indenes 3g and 3k in good yield (Table 2, entries 7 and 11).
The effect of the substituent at the para-position of phenyl
acetylene was not noticeable in yielding product 3h (Table 2,
entry 8). A propargylic alcohol bearing a terminal alkyne unit
was also examined under the above-mentioned conditions to
afford indene 3i in 79% yield (Table 2, entry 9). Employment
of unsymmetrical propargyl alcohols also yielded product 3n
(Table 2, entry 14) in 96% yield. In general, the electron-
donating/-withdrawing substituent on the starting substrates
afforded the highly substituted indene derivatives in a tandem
manner, and the results are presented in Table 2.
b
entry
Lewis acid
temp (°C) time (min)
solvent
yield (%)
1
2
3
4
5
6
7
8
9
BF ·OEt2
0
10
10
10
15
15
30
30
30
30
30
60
10
DCM
DCE
92
79
83
3
BF ·OEt2
0
3
BF ·OEt2
0
hexane
THF
3
c
BF ·OEt2
0
nd
3
Yb(OTf)3
Sc(OTf)3
FeCl3
30
0
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
64
71
68
66
25
38
0
InCl3
0
CuOTf
TfOH
30
0
10
11
12
c
AlCl3
0
nd
d
BF ·OEt2
3
0
84
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), solvent (5 mL).
Isolated yield. nd = no desired product. Stoichiometric amount of
BF ·OEt used.
b
c
d
3
2
a
Table 2. Synthesis of Highly Substituted Indenes 3
3
4
5
b
entry
R1/R2
R /R /R
2a (Ph/Ph/Ph)
product/yield (%)
1
2
3
4
5
6
7
8
9
1a (4-Br/Et)
3a/92
3b/89
3c/88
3d/90
3e/95
3f/97
3g/86
3h/90
3i/79
3j/94
3k/83
3l/90
3m/81
3n/96
3o/93
3p/91
1b (4-Br/propargyl)
1c (4-Cl/allyl)
2a
2a
1d (4-NO /n-butyl)
2b (Ph/p-tolyl/p-tolyl)
2
1e (4-H/Me)
2a
1f (4-CH /n-butyl)
2a
3
1g (2-CH /Et)
2c (cyclopropyl/Ph/Ph)
2d (4-MeC H /Ph/Ph)
3
1a
1a
1b
1c
1c
1d
1e
1f
6
4
2e (H/Ph/Ph)
2b
10
11
12
13
14
15
16
2f (n-C H /Ph/Ph)
4
9
2g (Ph/4-ClC H /4-ClC H )
6
4
6
4
2c
2h (Ph/4-OMeC H /Ph)
6
4
2g
2i (Ph/4-FC H /4-FC H )
1g
6
4
6
4
a
b
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), solvent (5 mL). Isolated yield refers to highly substituted indenes.
4
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Organic Letters
Letter
A proposed mechanism for the above tandem reaction is
shown in Scheme 2. The propargylic alcohol 2 was converted
ycarbonyl group on the N atom was also examined for this
transformation, but in vain.
to the allene carbocation intermediate 5 in the presence of BF ·
3
20
a
OEt via Meyer−Schuster rearrangement. Subsequently, the
2
Table 3. Synthesis of Functionalized Furanones 10a−j
carbocation 5 was trapped by nucleophilic attack of diazo
compound 1 to produce the key intermediate aryl allene
derived compound 6. Meanwhile, elimination of nitrogen gas
from 6 led to the vinylic cationic species 7, which may undergo
an electrocyclic ring closure of intermediate 7 (Nazarov
cyclization), affording the cationic species of indene 8, and
the subsequent elimination of a proton led to the desired
product 3.
b
entry
R1
R2/R3
product/yield (%)
1
2
3
4
5
6
7
8
9
9a (allyl)
2a
2a
2d
2e
2a
2f
10a/98
10b/94
10c/96
10d/88
10e/95
10f/83
10g/89
10h/98
10i/95
10j/90
9b (benzyl)
Scheme 2. Proposed Mechanism for Substituted Indenes 3
9b
9b
9c (Me)
9c
9c
2i
9d (Et)
9d
2b
2g
1
0
9d
2j (n-C H /C H )
7 15 6 5
a
Reaction conditions: 9a (0.5 mmol), 2a (0.5 mmol), solvent (5 mL).
Isolated yield refers to highly substituted furanones.
b
On the basis of the aforesaid experiments, a plausible
mechanism is outlined in Scheme 4. A Lewis acid generates
allene carbocation 5 in situ from propargyl alcohol, which was
trapped by the nucleophilic addition on the diazo substituted
carbon affording allene intermediate 11 (Scheme 4). The loss
Scheme 4. Proposed Mechanism for Furanones 10
After studying the generality of the mechanism for the one-
pot synthesis of highly substituted indene derivatives from
phenyl α-diazoesters and tertiary propargylic alcohols, we next
focused our attention on expanding the utility of this method
using a variety of cyclic α-diazoamides. With this view, a
solution containing an equimolar mixture of α-diazoamide 9a
and alcohol 2a in the presence of 10 mol % of BF ·OEt for 10
3
2
min in dry DCM furnished highly substituted furanone 10a in
8% yield (Scheme 3) instead of yielding an indene derivative
9
as described above.
Scheme 3. Synthesis of Highly Substituted Furanone 10a
of nitrogen on 11 may furnish cation 12, which may undergo an
electrocyclization process providing intermediate 13. Nucleo-
philic addition of the hydroxyl group to the carbocation 13
cleaves the C−N bond vs the C−O bond in the tricyclic moiety
14. The latter may undergo hydrogen abstraction affording
more stable substituted furanones 10. Interestingly, diazo esters
afforded indenes whereas diazoamides yielded furanones
involving the electrocyclization process.
Next, the scope of reactions was studied with a variety of
reactants, and the results are summarized in Table 3. A similar
reaction of α-diazoamides 9 and propargylic alcohols 2
furnished the corresponding furanones 10a−j in a tandem
manner. The alkynol bearing an electron-donating or
-
withdrawing group at the para-position of the aryl moiety
gave the product in excellent yields. Similarly, propargyl
alcohols having a hydrogen or an alkyl group on R afforded
2
In conclusion, a novel tandem reaction of α-diazocarbonyl
compounds and propargyl alcohols catalyzed by BF ·OEt is
furanone derivatives 10d,f,j in comparable yields (Table 3,
entries 4, 6, and 10). α-Diazoamide having a tert-butylox-
3
2
demonstrated to furnish highly substituted and conjugated
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Organic Letters
Letter
indene/furanone systems in excellent yields. Further studies on
the application of this process in organic synthesis toward
natural products are underway in our laboratory.
(6) (a) Yang, J.; Lakshmikantham, M. V.; Cava, M. P. J. Org. Chem.
2
000, 65, 6739. (b) Barbera, J.; Rakitin, O. A.; Rosand, M. B.; Torroba,
T. Angew. Chem., Int. Ed. 1998, 37, 296.
(7) (a) Izmer, V. V.; Lebedev, A. Y.; Nikulin, M. V.; Ryabov, A. N.;
Asachenko, A. F.; Lygin, A. V.; Sorokin, D. A.; Voskoboynikov, A. Z.
Organometallics 2006, 25, 1217. (b) Wang, B. Coord. Chem. Rev. 2006,
ASSOCIATED CONTENT
■
2
(
50, 242. (c) Alt, H. G.; Koppl, A. Chem. Rev. 2000, 100, 1205.
8) (a) Liu, C. R.; Wang, T.-T.; Qia, Q.-B.; Tian, S. K. Chem.
*
S
Supporting Information
Experimental procedures, characterization data, H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
Commun. 2012, 48, 10913. (b) Lattmann, E.; Billington, D. C.;
Langley, C. A. Drug Des. Discovery 1999, 16, 243. (c) Zhang, D.; Liu,
Z.; Yum, E. K.; Larock, R. C. J. Org. Chem. 2007, 72, 251.
(d) Lattmann, E.; Sattayasai, N.; Schwalbe, C. S.; Niamsanit, S.;
Billington, D. C.; Lattmann, P.; Langley, C. A.; Singh, H.; Dunn, S.
Curr. Drug Discovery Technol. 2006, 125.
(9) Recent example: Dattatraya, D. H.; Murhade, G. Chem. Commun.
AUTHOR INFORMATION
■
*
Corresponding Author
2
(
013, 49, 8051.
10) Recent example: Rosocha, G.; Batey, R. A. Tetrahedron 2013,
69, 8758.
11) Selected examples: (a) Yamazaki, S.; Yamamoto, Y.; Fukushima,
Y.; Takebayashi, M.; Ukai, T.; Miketa, Y. J. Org. Chem. 2010, 75, 5216.
b) Tejedor, D.; Santos-Exposito, A.; García-Tellado, F. Synlett 2006,
607. (c) Zhu, Y.; Yin, G.; Hong, D.; Lu, P.; Wang, Y. Org. Lett. 2011,
E-mail: muthu@bdu.ac.in.
Notes
(
The authors declare no competing financial interest.
(
́
ACKNOWLEDGMENTS
1
1
7
■
3, 1024. (d) Zhou, X.; Zhang, H.; Xie, X.; Li, Y. J. Org. Chem. 2008,
3, 3958.
M.S. thanks the Council of Scientific and Industrial Research,
New Delhi for a senior research fellowship. We thank the
Department of Science and Technology, New Delhi for
providing the 400 MHz NMR facility under the FIST program
and supporting this research.
(12) Selected examples: (a) Wencel-Delord, J.; Droge, T.; Liu, F.;
Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (b) Patureau, F.; Besset, T.;
Kuhl, N.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154. (c) Zhang, X.;
Teo, W.; Chan, P. Org. Lett. 2009, 11, 4990. (d) Wang, S.; Zhu, Y.;
Wang, Y.; Lu, P. Org. Lett. 2009, 11, 2615. (e) Yang, S.; Li, Z.; Jiang,
X.; He, C. Angew. Chem., Int. Ed. 2009, 48, 3999. (f) Alfonsi, M.;
Arcadi, A.; Chiarini, M.; Marinelli, F. J. Org. Chem. 2007, 72, 9510.
REFERENCES
■
(
1) For reviews: (a) Kuninobu, Y.; Nishina, Y.; Kawata, A.; Shouho,
(13) Yoneda, E.; Kaneko, T.; Zhang, S. W.; Onitsuka, K.; Tkahashi, S.
M.; Takai, K. Pure Appl. Chem. 2008, 80, 1149. (b) Enders, M.; Baker,
R. W. Curr. Org. Chem. 2006, 10, 937. (c) Huffman, J. W.; Padgett, L.
W. Curr. Med. Chem. 2005, 12, 1395. (d) Kawazoe, K.; Yamamoto, M.;
Takaishi, Y.; Honda, G.; Fujita, T.; Sezik, E.; Yesilada, E.
Phytochemistry 1999, 50, 493.
2) For reviews: (a) Ugurchieva, T. M.; Veselovsky, V. V. Russ. Chem.
Rev. 2009, 78, 337. (b) Dai, S.-J.; Tao, J.-Y.; Liu, K.; Jiang, Y.-T.; Shen,
L. Phytochemistry 2006, 67, 1326. (c) Langer, P. Synlett 2006, 3369.
d) Ma, S. Pure Appl. Chem. 2004, 76, 651. (e) Ma, S. Acc. Chem. Res.
003, 36, 701.
3) (a) Kutty, S. K.; Barraud, N.; Pham, A.; Iskander, G.; Rice, S. A.;
Black, D. S.; Kumar, N. J. Med. Chem. 2013, 56, 9517. (b) Majetich,
G.; Shimkus, J. M. J. Nat. Prod. 2010, 73, 284. (c) Renard, M.; Ghosez,
L. A. Tetrahedron 2001, 57, 2597. (d) Clegg, N. J.; Paruthiyil, S.;
Leitman, D. C.; Scanlan, T. S. J. Med. Chem. 2005, 48, 5989. (e) Korte,
A.; Legros, J.; Bolm, C. Synlett 2004, 2397. (f) Maguire, A. R.; Papot,
S.; Ford, A.; Touhey, S.; O’Connor, R.; Clynes, M. Synlett 2001, 41.
Org. Lett. 2000, 2, 441.
(
(
14) Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1, 277.
15) (a) Tsuji, J. Palladium Reagents and Catalysts; John Wiley &
Sons Ltd.: London, 2004. (b) Ye, J.; Ma, S. Acc. Chem. Res. 2014, 47,
89.
16) Li, Z.; Boyarskikh, V.; Hansen, J. H.; Autschbach, J.; G. Musaev,
D. G.; Davies, H. M. L. J. Am. Chem. Soc. 2012, 134, 15497.
17) (a) Muthusamy, S.; Sivaguru, M.; Suresh, E. Synthesis 2013, 45,
9
(
(
(
(
2
(
2
6
034. (b) Muthusamy, S.; Sivaguru, M. Tetrahedron Lett. 2013, 54,
810. (c) Muthusamy, S.; Karikalan, T. Tetrahedron 2012, 68, 1443.
(d) Muthusamy, S.; Gunanathan, C.; Babu, S. A.; Suresh, E.; Dastidar,
P. Chem. Commun. 2002, 824. (e) Muthusamy, S.; Gunanathan, C.
Synlett 2002, 1783. (f) Muthusamy, S.; Gunanathan, C. Synlett 2003,
1
(
599.
18) (a) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem.
Soc. 2000, 122, 3063. (b) Muthusamy, S.; Gunanathan, C.; Nethaji, M.
P. J. Org. Chem. 2004, 69, 5631.
(
1
g) Gao, H.; Katzenellenbogen, J. A.; Garg, R.; Hansch, C. Chem. Rev.
999, 99, 723. (h) Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.;
Murakami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T. J. Med. Chem.
996, 39, 3636. (i) Ortega, M. J.; Zubía, E.; Ocana, G. M.; Naranjo, S.;
Salva, J. Tetrahedron 2000, 56, 3963. (j) Makabe, H.; Hattori, Y.;
Tanaka, A.; Oritani, T. Org. Lett. 2002, 4, 1083.
4) (a) Adesanya, S. A.; Nia, R.; Martin, M. T.; Boukamcha, N.;
(
(
19) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027.
20) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429.
1
̃
́
(
Montagnac, A.; Païs, M. J. Nat. Prod. 1999, 62, 1694. (b) Huang, K.-S.;
Wang, Y.-H.; Li, R.-L.; Lin, M. Phytochemistry 2000, 54, 875. (c) Won,
T. H.; Jeon, J.; Kim, S.-H.; Lee, S.-H.; Rho, B. J.; Oh, D.-C.; Oh, K.-B.;
Shin, J. J. Nat. Prod. 2012, 75, 2055. (d) Sikorska, J.; Parker-Nance, S.;
Davies-Coleman, M. T.; Vining, O. B.; Sikora, A. E.; McPhail, K. L. J.
Nat. Prod. 2012, 75, 1824.
(
5) Few selected examples (a) Liedtke, A. J.; Crews, B. C.; Daniel, C.
M.; Blobaum, A. L.; Kingsley, P. J.; Ghebreselasie, K.; Marnett, L. J. J.
Med. Chem. 2012, 55, 2287. (b) Oda, T.; So, Y.; Sato, Y.; Shimizu, N.;
Handa, H.; Yasukochi, Y.; Kasahara, T. Mutat. Res. 2003, 534, 187.
(
c) Barbosa, L. C. A.; Rocha, M. E.; Teixeira, R. R.; Maltha, C. R. A.;
Forlani, G. J. Agric. Food Chem. 2007, 55, 8562. (d) Gleason, F. K.
Arch. Microbiol. 1984, 138, 273. (e) Bogeso, K. P.; Christensen, A. V.;
Hyttel, J.; Liljefors, T. J. Med. Chem. 1985, 28, 1817.
4
251
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