Lewis Acid Catalyzed Tandem Polycyclization of Internal Alkynols and Vinyl Azides

Article abstract of DOI:10.1021/acs.orglett.5b02556

A novel Lewis acid catalyzed tandem cyclization reaction of internal alkynols and vinyl azides has been achieved to afford a series of products containing a pyran-based indeno[1,2-c]isochromene scaffold in moderate to high yields. This tandem polycyclization protocol provides a straightforward entry to construct the complex polycyclic skeleton through cycloisomerization, formal [4 + 2] cycloaddition, and an elimination process.

Full text of DOI:10.1021/acs.orglett.5b02556

Letter
pubs.acs.org/OrgLett
Lewis Acid Catalyzed Tandem Polycyclization of Internal Alkynols
and Vinyl Azides
Hai Xiao Siyang,† Xiao Yue Ji,† Xu Rui Wu, Xin Yan Wu, and Pei Nian Liu*
Shanghai Key Laboratory of Functional Materials Chemistry, Key Lab for Advanced Materials and Institute of Fine Chemicals, East
China University of Science and Technology, Meilong Road 130, Shanghai 200237, China
S
* Supporting Information
ABSTRACT: A novel Lewis acid catalyzed tandem cyclization reaction of internal alkynols and vinyl azides has been achieved to
afford a series of products containing a pyran-based indeno[1,2-c]isochromene scaffold in moderate to high yields. This tandem
polycyclization protocol provides a straightforward entry to construct the complex polycyclic skeleton through
cycloisomerization, formal [4 + 2] cycloaddition, and an elimination process.
etrahydropyran rings are prevalent in a wide array of
Tbiologically and pharmacologically relevant natural
products. Of particular interest are the octahydrocyclopenta-
[b]pyran structural units, which are present in a number of
biologically active molecules.1 For example, the triterpenoid
alisol F (I)1a,b was isolated from the rhizomes of Alisma
orientalis. Triterpene-based γ-secretase modulators (II),1c
isolated from Actaea racemose, may be even more pharmaco-
logically useful because of their superior metabolic stability.1d
Elaeocarpucin C (III)1e was isolated from the fruits and stem
bark of Elaeocarpus chinensis samples collected in Vietnam.
Haplosamate A (IV) was isolated from the Indonesian sponge
Dasychalina sp., and its desulfohaplosamate shows selective
affinity for cannabinoid receptors1f (Figure 1). Furthermore,
Figure 1. Natural products containing octahydrocyclopenta[b]pyran
motif.
the compounds containing octahydrocyclopenta[b]pyran struc-
tural units have been used extensively as key intermediates.2
In recent years, alkynol-based tandem reactions have become
increasingly important in chemical synthesis. These reactions
involve the concatenation of several steps to form several new
bonds to connect simple building blocks in a single operation.3
As a result, these tandem reactions have been used to
synthesize highly valuable nitrogen- and oxygen-containing
heterocycles, as well as complex polycyclic structural units.4
Vinyl azides have worked well in tremendous synthetic
procedures,5 and in particular they have attracted much
attention as versatile synthons for developing novel synthetic
methods. These methods include the synthesis of indoles,6
pyrazoles,7 pyridines,8 pyrroles,9 and imidazoles.10 Vinyl azides
have also been used in metal-catalyzed systems involving
rhodium,11 rhodium−copper,12 or manganese13 to construct
diverse heterocyclic compounds. Moreover, vinyl azides have
been used to generate N-unsubstituted imines in situ,12 and
these imines are pivotal intermediates in organic synthesis.14
In the present study, we aimed to incorporate vinyl azides
into alkynol-based tandem reactions as part of our ongoing
interests in exploring synthetically useful alkynol-based systems
for heterocyclic structure construction.15 Here we report a
novel Lewis acid catalyzed intermolecular tandem cyclization
reaction that uses readily available internal alkynol and vinyl
azide to generate a octahydrocyclopenta[b]pyran related
polycyclic indeno[1,2-c]isochromene skeleton in a single
operation.
Received: September 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Our study of Lewis acid mediated polycyclization began by
evaluating the model reaction of internal alkynol 1a and vinyl
azide 2a (Table 1). Initially, treating 1a and 2a with 30 mol %
promote the desired transformation. Decreasing the catalyst
loading to 20 mol % reduced the yield of 3a to 18% (entry 2).
The solvents CH3CN, THF, DCE, DMF, and dioxane proved
ineffective, giving 3a in lower yield (entries 2−7). Gradually
changing the ratio of 1a:2a to 1:2 increased the yield of 3a to
29% (entry 8).
Table 1. Optimization of Reaction Conditions for the
a
Reaction between 1a and 2a
Next we examined the influence of several additives on the
reaction. Screening various additives such as acetic acid
(AcOH), trifluoroacetic acid (TFA), and water did not fulfill
the expectations of increasing yield (entries 9−12), but carrying
out the reaction in the presence of 2 equiv of hexafluoro-
isopropanol (HFIP) at a lower reaction temperature (rt)
increased the yield of 3a dramatically to 50% (entry 13). Using
3 equiv of HFIP slightly increased the yield to 54% (entry 14),
whereas using 2,2,2-trifluoroethanol (TFE) gave 3a in only 48%
yield (entry 15). Surprisingly, using a mixed additive of TFE (3
equiv) and HFIP (3 equiv) enhanced the reaction, giving 3a in
higher yield (entry 16). As the catalyst was changed to
Bi(OTf)3 and Fe(OTf)3 from Cu(OTf)3, lower yields were
observed (entries 17 and 18). Interestingly, when In(OTf)3 was
used as the catalyst and the mole ratio of 1a and 2a was
increased to 1:3, the best 72% yield of 3a was obtained with a
shorter reaction time (entry 21).
After identifying a selective catalyst and suitable reaction
conditions, we evaluated the substrate scope of this
polycyclization protocol. As shown in Table 2, we examined
the ability of various substituted alkynols 1 to react with vinyl
azide 2a using optimized reaction conditions [1a:2a = 1:3, 30
mol % In(OTf)3, mixture of HFIP (3 equiv)/TFE (3 equiv) as
additive, 2 mL of toluene, rt]. A substrate carrying a methoxyl
group at position R1 reacted smoothly, leading to the formation
of 3b in excellent 91% yield. The internal alkynols 1 with Me
and F groups at the R1 positions were both effective, affording
the corresponding polycyclic indeno[1,2-c]isochromenes 3c
and 3d in respective yields of 71% and 75%. However, placing
the electron-withdrawing CF3 group at position R1 hampered
the reaction a little, generating 3e in 50% yield. The reaction
also proceeded with 1 bearing an electron-donating methyl
group at the R2 position, although it produced 3f in only 41%
yield. Internal alkynol with fluorine at the same positions gave
the corresponding product 3g in 53% yield. Several other
substrates that we tested, such as alkynols with alkyl
substitution (R3) and alkynols attached to cyclohexene instead
of Ph, failed to give the desired products. Heteroaryl thiophene
alkynol and chained alkoxy alkynols also worked well to
produce 3h and 3i in respective isolated yields of 71% and 56%.
To explore the full scope of the reaction, we examined the
ability of vinyl azides to react with internal alkynols 1. Methyl-
substituted vinyl azides were a good partner for an internal
alkynol with a MeO substitution at the R1 position, leading to
3j in 70% yield. Steric hindrance in the substrates also worked
well, delivering 3k in 65% yield. Vinyl azide with an electron-
donating group Me group at the meta-position also worked
well, affording the corresponding 3l in 56% yield. Similarly,
vinyl azide with a methoxyl substitution at the meta position
reacted with internal alkynol 1a to produce 3m in 55% yield. In
contrast, naphthalene-based vinyl azide generated 3n in 95%
yield. The reaction also tolerated naphthalene-substituted vinyl
azide, though 3o was obtained in only 63% yield. Moreover, the
reaction was applied to the natural product derivatization: an
alkynol derived from cholesterol reacted with vinyl azide 2a in
the presence of In(OTf)3, affording the desired product 3p in
66% yield.
temp
additive
3a
b
b
c
entry
1
catalyst
(°C) t (h)
(equiv)
solvent
(%)
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Bi(OTf)2
Fe(OTf)3
In(OTf)3
Cu(OTf)2
In(OTf)3
60
60
60
60
60
60
60
60
60
60
60
60
rt
8
−
−
−
−
−
−
−
−
toluene
toluene
CH3CN
THF
21
18
d
2
8
3
4
5
6
7
8
<5%
<5%
<5%
0
8
8
DCE
8
DMF
8
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
e
8
e
12
12
12
12
12
20
20
20
40
40
14
40
40
24
29
20
17
8
9
AcOH/2
e
10
TFA/2
e
11
H2O/2
e
12
HFIP/2
29
50
54
48
65
29
43
50
66
72
e
13
HFIP/2
e
14
rt
HFIP/3
e
15
rt
TFE/3
e
e
e
e
,
,
,
,
f
f
f
f
16
17
18
19
rt
TFE-HFIP/3
TFE-HFIP/3
TFE-HFIP/3
TFE-HFIP/3
TFE-HFIP/3
TFE-HFIP/3
rt
rt
rt
f g
20 ,
f g
21 ,
rt
rt
a
Reactions were performed in sealed tubes containing 1a (0.3 mmol),
2a (0.36 mmol), catalyst (0.09 mmol), and solvent (2 mL) under Ar,
b
c
unless noted otherwise. Equivalents based on 1a. Isolated yield.
d
e
Cu(OTf)2 (0.06 mmol) was used. 1a (0.3 mmol) and 2a (0.6
mmol) were used. TFE (0.45 mmol) and HFIP (0.45 mmol) were
used. 1a (0.3 mmol) and 2a (0.9 mmol) were used.
f
g
Cu(OTf)2 at 60 °C in toluene for 8 h gave the polycyclic
product indeno[1,2-c]isochromene 3a in 21% isolated yield
(entry 1). The structure of 3a was confirmed by single-crystal
X-ray diffraction analysis (Figure 2). Next we optimized the
reaction conditions for formation of 3a. Other copper species
such as CuBr, Cu(acac)2, and [Cu(CH3CN)4]PF6 failed to
Figure 2. Crystal structure of compound 3a.
B
DOI: 10.1021/acs.orglett.5b02556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
perform the reaction of 1a with N-substituted imine 4a instead
of vinyl azide 2a (Scheme 1). As expected, the product 3a
Table 2. Tandem Reactions of Various Internal Alkynols 1
and Vinyl Azide 2a in the Presence of In(OTf)3
a b
,
Scheme 1. Reaction of 1a and N-Substituted Analogues
formed in 25% isolated yield, verifying that the imine from vinyl
azide may be the intermediate of this reaction. Moreover, the
acetophenone 5a was isolated from the above reactions but the
reaction of 1a with 5a did not proceed, suggesting that the vinyl
azide may convert to the imine and then transform to the
acetophenone after hydration.
Based on our experimental findings and the literature,16,17 we
propose a tentative mechanism for the In(OTf)3-catalyzed
tandem polycyclization reaction of internal alkynol and vinyl
azide to generate polycyclic indeno[1,2-c]isochromene
(Scheme 2). The triple bond of 1a coordinates with In(OTf)3,
Scheme 2. Proposed Mechanism for In(OTf)3-Catalyzed
Tandem Polycyclization of Internal Alkynol and Vinyl Azide
increasing the electrophilicity of the alkyne. Then the hydroxyl
group adds to the electron-deficient alkyne, producing
vinylindium species B. Intermediate B is trapped by a N-
unsubstituted imine produced in situ from 2a,14,18 which leads
to intermediate C.19 The following carbocyclization gives
intermediate D to finish a formal [3 + 2] cycloaddition from B.
Subsequent acid-promoted cleavage of the carbon−metal bond
and elimination lead to the desired polycyclic 3a and regenerate
the catalytic species.
In summary, we have described a novel tandem polycycliza-
tion reaction that provides a straightforward route to polycyclic
products containing a pyran-based indeno[1,2-c]isochromene
scaffold, starting from readily available internal alkynols and
vinyl azides. This tandem cyclization protocol, which requires
only In(OTf)3 as a promoter, provides a novel approach for
constructing complex polycyclic units in a single operation, and
it may expand the usefulness of transition-metal-catalyzed
heterocycle synthesis. Further studies to expand the scope of
a
Reactions were conducted under Ar at rt for 24 h using 1 (0.3 mmol),
2a (0.9 mmol), In(OTf)3 (0.09 mmol), TFE (0.45 mmol), and HFIP
b
(0.45 mmol) in 2 mL of toluene, unless otherwise noted. Isolated
yields are shown.
The substrates with 3,4,5-trimethoxyphenyl, 5-methyl-
thiophen-2-yl, 4-(1H-pyrrol-1-yl)phenyl, and furanyl at the R3
position were tested in the reactions with 2-(1-azidovinyl)-
naphthalene to give the products 3q−3t in moderate isolated
yields. Moreover, the vinyl azides containing heteroatoms
reacted smoothly with 1a to give the products 3u, 3v in 52%
and 57% yield, respectively.
In past work related to the reaction of vinyl azides, N-
unsubstituted imines were proposed as an intermediate,
although such species have not been isolated or detected in
most cases.13,15 Due to the fact that the N-substituted imines
are much more stable than the N-unsubstituted analogues, we
C
DOI: 10.1021/acs.orglett.5b02556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) O'Brien, A. G.; Lev
2011, 47, 2688.
(7) Zou, H.; Zhu, H.; Shao, J.; Wu, J.; Chen, W.; Giulianotti, M. A.;
́
esque, F.; Seeberger, P. H. Chem. Commun.
alkynol-based polycyclization are under investigation in our
laboratory.
Yu, Y. Tetrahedron 2011, 67, 4887.
(8) Wang, Y.-F.; Toh, K. K.; Ng, E. P. J.; Chiba, S. J. Am. Chem. Soc.
2011, 133, 6411.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02556.
(9) Ng, E. P. J.; Wang, Y.-F.; Hui, B. W.-Q.; Lapointe, G.; Chiba, S.
Tetrahedron 2011, 67, 7728.
(10) Hu, B.; Wang, Z.; Ai, N.; Zheng, J.; Liu, X.-H.; Shan, S.; Wang,
Z. Org. Lett. 2011, 13, 6362.
(11) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T.
G. J. Am. Chem. Soc. 2007, 129, 7500.
Experimental procedures and compound characterization
data (PDF)
Crystallographic data for 3a (CIF)
(12) Wang, Y. F.; Toh, K. K.; Lee, J. Y.; Chiba, S. Angew. Chem., Int.
Ed. 2011, 50, 5927.
(13) Chiba, S. Synlett 2012, 2012, 21.
AUTHOR INFORMATION
Corresponding Author
■
(14) (a) Chen, G.-M.; Brown, H. C. J. Am. Chem. Soc. 2000, 122,
4217. (b) Itsuno, S.; Watanabe, K.; Matsumoto, T.; Kuroda, S.; Yokoi,
A.; El-Shehawy, A. J. Chem. Soc., Perkin Trans. 1 1999, 2011.
(15) (a) Siyang, H. X.; Wu, X. R.; Ji, X. Y.; Wu, X. Y.; Liu, P. N.
Chem. Commun. 2014, 50, 8514. (b) Siyang, H. X.; Wu, X. R.; Liu, H.
L.; Wu, X. Y.; Liu, P. N. J. Org. Chem. 2014, 79, 1505. (c) Li, D. Y.; Shi,
K. J.; Mao, X. F.; Chen, G. R.; Liu, P. N. J. Org. Chem. 2014, 79, 4602.
(d) Li, D. Y.; Shang, X. S.; Chen, G. R.; Liu, P. N. Org. Lett. 2013, 15,
3848. (e) Li, D. Y.; Mao, X. F.; Chen, H. J.; Chen, G. R.; Liu, P. N.
Org. Lett. 2014, 16, 3476. (f) Li, D. Y.; Chen, H. J.; Liu, P. N. Org. Lett.
2014, 16, 6176. (g) Li, X. G.; Sun, M.; Liu, K.; Jin, Q.; Liu, P. N. Chem.
Commun. 2015, 51, 2380.
*E-mail: liupn@ecust.edu.cn.
Author Contributions
†H.X.S. and X.Y.J. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC/China (Project Nos.
21421004, 21172069, 21372072, and 21190033), NCET
(NCET-13-0798), the Basic Research Program of the Shanghai
Committee of Sci. & Tech. (Project No. 13M1400802), the
Program for Eastern Scholar Distinguished Professor, and the
Fundamental Research Funds for the Central Universities.
́ ́ ̌
(16) (a) Vegh, D.; Zalupsky, P.; Kovac, J. Synth. Commun. 1990, 20,
1113. (b) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64,
7687. (c) Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7,
5409. (d) Barluenga, J.; Dieg
́ ́
uez, A.; Fernandez, A.; Rodríguez, F.;
Fananas, F. J. Angew. Chem., Int. Ed. 2006, 45, 2091.
́
̃
(17) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org. Lett.
2006, 8, 2803.
REFERENCES
■
(18) (a) Boyd, D. R.; Hamilton, R.; Thompson, N. T.; Stubbs, M. E.
Tetrahedron Lett. 1979, 20, 3201. (b) Bogdamovic,
Angew. Chem., Int. Ed. Engl. 1967, 6, 803.
(19) Zhang, J.; Ugrinov, A.; Zhao, P. Angew. Chem., Int. Ed. 2013, 52,
(1) (a) Li, Q.; Qu, H. Fitoterapia 2012, 83, 1046. (b) Hu, X. Y.; Guo,
Y. Q.; Gao, W. Y.; Chen, H. X.; Zhang, T. J. Chin. Chem. Lett. 2008,
19, 438. (c) Findeis, M. A.; Schroeder, F.; McKee, T. D.; Yager, D.;
Fraering, P. C.; Creaser, S. P.; Austin, W. F.; Clardy, J.; Wang, R.;
Selkoe, D.; Eckman, C. B. ACS Chem. Neurosci. 2012, 3, 941.
(d) Hubbs, J. L.; Fuller, N. O.; Austin, W. F.; Shen, R.; Creaser, S. P.;
McKee, T. D.; Loureiro, R. M. B.; Tate, B.; Xia, W.; Ives, J.; Bronk, B.
S. J. Med. Chem. 2012, 55, 9270. (e) Pan, L.; Yong, Y.; Deng, Y.;
Lantvit, D. D.; Ninh, T. N.; Chai, H.; de Blanco, E. J. C.; Soejarto, D.
D.; Swanson, S. M.; Kinghorn, A. D. J. Nat. Prod. 2012, 75, 444.
(f) Chianese, G.; Fattorusso, E.; Taglialatela-Scafati, O.; Bavestrello,
G.; Calcinai, B.; Dien, H. A.; Ligresti, A.; Di Marzo, V. Steroids 2011,
76, 998.
́ ́
B.; Velic, D.-I. M.
6681 and the references therein.
(2) (a) Liu, G.; Romo, D. Angew. Chem., Int. Ed. 2011, 50, 7537.
(b) Marmsater, F. P.; Murphy, G. K.; West, F. G. J. Am. Chem. Soc.
̈
2003, 125, 14724. (c) Wu, J.; Becerril, J.; Lian, Y.; Davies, H. M. L.;
Porco, J. A., Jr.; Panek, J. S. Angew. Chem., Int. Ed. 2011, 50, 5938.
(3) For selected reviews, see: (a) Inoue, M. Chem. Rev. 2005, 105,
4379. (b) Randic, M. Chem. Rev. 2003, 103, 3449. (c) Nakata, T.
Chem. Rev. 2005, 105, 4314. (d) Malacria, M. Chem. Rev. 1996, 96,
́
289. For selected examples, see: (e) Koh, J. H.; Gagne, M. R. Angew.
Chem., Int. Ed. 2004, 43, 3459. (f) Knowles, R. R.; Lin, S.; Jacobsen, E.
N. J. Am. Chem. Soc. 2010, 132, 5030. (g) Surendra, K.; Corey, E. J. J.
Am. Chem. Soc. 2012, 134, 11992. (h) Schafroth, M. A.; Sarlah, D.;
Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2012, 134, 20276.
(i) Surendra, K.; Rajendar, G.; Corey, E. J. J. Am. Chem. Soc. 2014, 136,
642. (j) Pronin, S. V.; Shenvi, R. A. Nat. Chem. 2012, 4, 915.
(k) Riveira, M. J.; Mischne, M. P. Chem. - Eur. J. 2012, 18, 2382.
(4) Zeng, X. Chem. Rev. 2013, 113, 6864. (b) Alcaide, B.; Almendros,
P.; Alonso, J. M. Molecules 2011, 16, 7815. (c) Alcaide, B.; Almendros,
P.; Alonso, J. M. Org. Biomol. Chem. 2011, 9, 4405. (d) Alcaide, B.;
Almendros, P. Acc. Chem. Res. 2014, 47, 939.
(5) (a) Jung, N.; Brase, S. Angew. Chem., Int. Ed. 2012, 51, 12169.
̈
(b) Palacios, F.; de Retana, A. M. O.; de Marigorta, E. M.; de los
Santos, J. M. Eur. J. Org. Chem. 2001, 2001, 2401.
D
DOI: 10.1021/acs.orglett.5b02556
Org. Lett. XXXX, XXX, XXX−XXX