Ru(II)-Catalyzed Synthesis of Substituted Furans and Their Conversion to Butenolides

Article abstract of DOI:10.1021/acs.orglett.8b02554

The synthesis of densely functionalized trisubstituted and tetrasubstituted furans via a novel Ru(II)-catalyzed intramolecular cyclization of vinyl diazoesters is reported. The synthetic utility of these furans is further demonstrated through a simple aci

Full text of DOI:10.1021/acs.orglett.8b02554

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ru(II)-Catalyzed Synthesis of Substituted Furans and Their
Conversion to Butenolides
Marie El Arba, Sara E. Dibrell, Frederick Meece, and Doug E. Frantz*
Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States
S
* Supporting Information
ABSTRACT: The synthesis of densely functionalized trisub-
stituted and tetrasubstituted furans via a novel Ru(II)-
catalyzed intramolecular cyclization of vinyl diazoesters is
reported. The synthetic utility of these furans is further
demonstrated through a simple acid-mediated reaction to
access highly substituted Δα,β-butenolides.
urans are perhaps the most versatile of all 5-membered
heterocycles. Their emergence in biologically active
as richly functionalized precursors to other valuable building
blocks through transition-metal-catalyzed carbenoid-type path-
ways (see Figure 1). In particular, we anticipated that the close
F
synthetic and naturally occurring compounds has piqued the
interest of synthetic chemists for more than a century.1
Furthermore, furans have recently found a place as potential
organic semiconductors with broad implications in optoelec-
tronic applications and related industries.2 Furans are also
considered one of the most readily available platform building
blocks derived from lignocellulosic biomass, solidifying their
future as renewable, nonpetroleum based feedstocks.3 Finally,
because of their relatively low resonance energy (16.2 kcal/
mol), furans have unique intrinsic reactivity profiles that
traverse across both classical arene chemistry and traditional
electron-rich olefin and diene pathways.4 From these
combined perspectives, the versatility of furans in organic
chemistry is hard to deny.
Figure 1. Divergent pathways of vinyl diazoesters toward pyrazoles or
furans.
Given the multitude of methods developed to synthesize
furans, one could argue that this is a mature area where only
incremental advances can be made.5,6 Yet, close inspection of
both classical and modern approaches to substituted furans
reveals several synthetic gaps. In particular, metal-catalyzed
routes toward densely functionalized furans from simple,
readily available starting materials remains an under-developed
tactic toward these heterocycles. One successful approach
pioneered by research groups led by Davies,7 Padwa,8 and
others is the metal-catalyzed [3 + 2] cycloadditions between
alkynes and α-diazocarbonyl compounds through the inter-
mediacy of a metal carbenoid species.9 Several metals beyond
the prototypical Rh2-based catalysts have demonstrated
competency in these types of reactions, including Cu,10
Co,11 Fe,12 and Ru.13 However, each approach possesses
inherent limitations with respect to broad substrate generality
and elevated reaction temperatures that solicits additional
complementary methods to synthesize substituted furans.
Several years ago, we reported our discovery and develop-
ment of an approach to substituted pyrazoles via an initial Pd-
catalyzed cross-coupling between (Z)-enol triflates and
diazoacetates, followed by a thermal 6π electrocyclic ring
closure.14 Given the ease of accessing the intermediate vinyl
diazoester intermediates, we envisioned that they could serve
proximity of the ester functional group derived from the (Z)-
enol triflate would participate in a facile ring closure through
insertion into the metal carbenoid, resulting in a novel
approach to substituted furans. Here, we wish to report our
success in this approach through a Ru(II)-catalyzed process
that provides trisubstituted and tetrasubstituted furans that are
rich in functional diversification.
Our initial unbiased efforts began with vinyl diazoester 1 to
identify a metal catalyst that could effect this transformation
through a catalytic decomposition via a presumed metal
carbenoid intermediate. We quickly found several Pd(II)- and
Ru(II)-based catalysts that provided trisubstituted furan 2 in
good yields (see Table 1). Of these, Ru[Cp(ACN)3]PF6
(Table 1, entry 12) at a loading of 5 mol % proved to be far
superior than all other catalysts we had screened up to this
point. In contrast, we were somewhat surprised that both
Rh(I)- and Ru(I)-derived catalysts were not productive toward
2 (Table 1, entries 8 and 9) and led to a complex mixture of
products.
Received: August 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02554
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the method lies in the ease of incorporating substituents into
the starting vinyl diazoesters that translates directly to the
diversity of the products. Thus, both trisubstituted and
tetrasubstituted furans are readily obtained in a regiospecific
manner dictated by the starting materials. Furthermore, the
unique substitution pattern attained (2-carboxylate-5-alkoxy)
that is predicated by the starting vinyl diazoesters is also
advantageous since furans of this type have shown distinctive
chemical reactivity and serve as potential topical sebum
inhibitors for the treatment of acne.15,16 Previous syntheses
of these furan analogues in the past have been less than ideal.17
Furans have served as excellent precursors toward the
synthesis of γ-butenolides through a multitude of trans-
formations.18 With this in mind, we were curious to examine
the conversion of our furan products to the corresponding γ-
butenolides using the 5-alkoxy substituent as a convenient
handle. In the presence of TFA (1.5 equiv), we have found that
5-ethoxy and 5-tert-butoxy furans are cleaved into the
corresponding substituted Δα,β-butenolides exclusively (see
Scheme 2). It is important to note that 5-ethoxy analogues
required noticeably longer reaction times than the 5-tert-
butoxy analogues.
Table 1. Catalyst Screening Efforts for the Conversion of
Vinyl Diazoester 1 to Furan 2
a
b
entry
catalyst
Pd(OAc)2
Pd(TFA)2
Pd(PPh3)2Cl2
Pd(ACN)4(BF4)2
Zn(OTf)2
2, yield (%)
1, recovery (%)
1
2
3
4
5
10
69
0
0
0
41
0
61
0
0
6
7
8
9
PdCl2
bipyPdCl2
39
0
0
29
79
17
13
0
66
0
0
Rh(PPh3)3Cl
Ru(PPh3)3Cl
Ru(PPh3)2CpCl
Ru[Cp*(ACN)3]PF6
Ru[Cp(ACN)3PF6
0
10
11
12
39
18
90
c
13
Ru[Cp(ACN)3PF6
78
a
b
c
Reaction time = 24 h. Isolated yields. Reaction was performed
using 2.5 mol % catalyst at 50 °C.
Scheme 2. Acid-Mediated Conversion of Selected 5-
Alkoxyfurans to Δα,β-Butenolides
With the optimal catalyst identified, we embarked on
exploring the scope of this method with a variety of vinyl
diazoesters. Our results on 20 successful examples are
summarized in Scheme 1. Given the relatively mild conditions
of the reaction, a broad range of functional groups can be
tolerated. This includes terminal olefins (as in 10), ketones 16,
reactive aryl halides 13, and silanes 7. A key salient feature of
ab
Scheme 1. Ru(II)-Catalyzed Conversion of Vinyl
a b
,
Diazoesters to Substituted Furans
a
Reactions were performed on a 1 mmol scale with reaction times of
b
24 h in all cases. Isolated yields reported as an average of two
experiments.
Finally, we have been able to telescope both methods into a
one-pot synthesis of Δα,β-butenolides (see Scheme 3).
Following the Ru(II)-catalyzed decomposition of the vinyl
diazoesters to the corresponding furans, TFA (1.5 equiv) can
be added directly to the reaction flask to obtain the Δα,β-
butenolides after silica gel flash chromatography. We believe
this uninterrupted approach to highly functionalized buteno-
lides will find general synthetic utility in both academic and
industrial settings.
In conclusion, we have identified a novel Ru(II)-catalyzed
conversion of vinyl diazoesters to trisubstituted and tetrasub-
stituted furans that proceeds under mild reaction conditions
with broad substrate scope. We also developed a simple acid-
mediated cleavage of both 5-ethoxy and 5-tert-butoxy furans to
the corresponding Δα,β-butenolides. Additional studies on
a
Reactions were performed on a 1 mmol scale with reaction times of
b
24 h in all cases. Isolated yields reported as an average of two
experiments. Reaction performed at 50 °C.
c
B
DOI: 10.1021/acs.orglett.8b02554
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) (a) Teixeira, I. F.; Lo, B. T. W.; Kostetskyy, P.; Ye, L.; Tang, C.
C.; Mpourmpakis, G.; Tsang, S. C. E. ACS Catal. 2018, 8, 1843−
1850. (b) Gupta, K.; Rai, R. K.; Dwivedi, A. D.; Singh, S. K.
ChemCatChem 2017, 9, 2760−2767. (c) Binder, J. B.; Raines, R. T. J.
Am. Chem. Soc. 2009, 131, 1979−1985.
Scheme 3. One-Pot Synthesis of Δα,β-Butenolides from 5-
Ethoxy and 5-tert-Butoxy Furans
(4) (a) Hao, H. − D.; Trauner, D. J. Am. Chem. Soc. 2017, 139,
4117−4122. (b) Reiser, O. Isr. J. Chem. 2016, 56, 531−539. (c) Parr,
B. T.; Green, S. A.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135,
4716−4718. (d) Palmer, L. I.; Read de Alaniz, J. Angew. Chem., Int.
Ed. 2011, 50, 7167−7170. (e) Martin, S. F.; Zinke, P. W. J. Org. Chem.
1991, 56, 6600−6606. (f) Lipshutz, B. H. Chem. Rev. 1986, 86, 795−
819.
(5) For recent reviews, see: (a) Gulevich, A. V.; Dudnik, A. S.;
Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084−3213.
(b) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850−852.
(6) For selected examples, see: (a) Wang, X.; Lerchen, A.; Daniliuc,
C. G.; Glorius, F. Angew. Chem., Int. Ed. 2018, 57, 1712−1716.
(b) Xu, C.; Wittmann, S.; Gemander, M.; Ruohonen, V.; Clark, S.
Org. Lett. 2017, 19, 3556−3559. (c) Wu, J.; Yoshikai, N. Angew.
Chem., Int. Ed. 2015, 54, 11107−11111. (d) Xia, Y.; Xia, Y.; Ge, R.;
Liu, Z.; Xiao, Q.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2014, 53,
3917−3921. (e) Shiroodi, R. Z.; Koleda, O.; Gevorgyan, V. J. Am.
Chem. Soc. 2014, 136, 13146−13149. (f) Sevov, C. S.; Hartwig, J. F. J.
Am. Chem. Soc. 2014, 136, 10625−10631. (g) Lian, Y.; Huber, T.;
Hesp, K. D.; Bergman, R. G.; Ellman, J. A. Angew. Chem., Int. Ed.
2013, 52, 629−633. (h) McInturff, E. L.; Nguyen, K. D.; Krische, M.
J. Angew. Chem., Int. Ed. 2014, 53, 3232−3235. (i) Butkevich, A. N.;
Meerpoel, L.; Stansfield, I.; Angibaud, P.; Corbu, A.; Cossy, J. Org.
Lett. 2013, 15, 3840−3843. (j) Kramer, S.; Skrydstrup, T. Angew.
Chem., Int. Ed. 2012, 51, 4681−4684. (k) Fournier, J.; Arseniyadis, S.;
Cossy, J. Angew. Chem., Int. Ed. 2012, 51, 7562−7566. (l) He, C.;
Guo, S.; Ke, J.; Hao, J.; Xu, H.; Chen, H.; Lei, A. J. Am. Chem. Soc.
2012, 134, 5766−5769. (m) Allegretti, P. A.; Ferreira, E. M. Org. Lett.
2011, 13, 5924−5927. (n) Jung, C. − K.; Wang, J. − C.; Krische, M.
J. J. Am. Chem. Soc. 2004, 126, 4118−4119.
further synthetic manipulations of the furans reported here are
ongoing in our laboratories.
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.8b02554.
(7) (a) Briones, J. F.; Davies, H. M. L. Tetrahedron 2011, 67, 4313−
4317. (b) Davies, H. M. L.; Romines, K. R. Tetrahedron 1988, 44,
3343−3348.
Experimental procedures and spectroscopic data for all
compounds are given (1H NMR, 13C NMR, and
HRMS), including images of all NMR spectra obtained
(PDF)
(8) (a) Padwa, A.; Straub, C. S. J. Org. Chem. 2003, 68, 227−239.
(b) Padwa, A.; Straub, C. S. Org. Lett. 2000, 2, 2093−2095.
(c) Padwa, A.; Kinder, F. R. J. Org. Chem. 1993, 58, 21−28.
(d) Kinder, F. R.; Padwa, A. Tetrahedron Lett. 1990, 31, 6835−6838.
(9) (a) Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, A. R.;
McKervey, M. A. Chem. Rev. 2015, 115, 9981−10080. (b) Doyle, M.
P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; Wiley−Interscience: New York,
1998.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: doug.frantz@utsa.edu.
ORCID
Doug E. Frantz: 0000-0002-4509-4579
Notes
(10) (a) Tan, W. W.; Yoshikai, N. J. Org. Chem. 2016, 81, 5566−
5573. (b) Hossain, M. L.; Ye, F.; Zhang, Y.; Wang, J. Tetrahedron
2014, 70, 6957−6982.
The authors declare no competing financial interest.
(11) Cui, X.; Xu, X.; Wojtas, L.; Kim, M. M.; Zhang, X. P. J. Am.
Chem. Soc. 2012, 134, 19981−19984.
ACKNOWLEDGMENTS
■
(12) Atiq-ur-Rehman; Schnatter, W. F. K.; Manolache, N. J. Am.
Chem. Soc. 1993, 115, 9848−9849.
We would like to thank the National Science Foundation
(Nos. CHE-1362953 and MRI-1625963) for supporting this
work. High-resolution mass spectrometry data were obtained
through support from the National Institute of Minority
Health and Health Disparities (No. G12MD007591) within
the NIH. D.E.F. would also like to thank the Max and Minnie
Tomerlin Voelcker Fund for providing unrestricted support.
(13) Xia, L.; Lee, Y. R. Eur. J. Org. Chem. 2014, 2014, 3430−3442.
(14) (a) Babinski, D. J.; Bao, X.; El Arba, M.; Chen, B.; Hrovat, D.
A.; Borden, W. T.; Frantz, D. E. J. Am. Chem. Soc. 2012, 134, 16139−
16142. (b) Babinski, D. J.; Aguilar, H. R.; Still, R.; Frantz, D. E. J. Org.
Chem. 2011, 76, 5915−5923.
(15) Mandel, J.; Dubois, N.; Neuburger, M.; Blanchard, N. Chem.
Commun. 2011, 47, 10284−10286.
(16) Bissonnette, R.; Poulin, Y.; Drew, J.; Hofland, H.; Tan, J. J. Am.
Acad. Dermatol. 2017, 76, 33−39.
REFERENCES
■
(1) For reviews, see: (a) Palframan, M. J.; Pattenden, G. Chem.
Commun. 2014, 50, 7223. (b) Sperry, J. B.; Wright, D. L. Curr. Opin.
Drug. Discov. Devel. 2005, 42, 7709−7717. (c) Pozharskii, A. F.;
Katritzky, A. R.; Soldatenkov, A. T. Heterocycles in Life and Society: An
Introduction to Heterocyclic Chemistry, Biochemistry and Applications,
2nd Edition; Wiley: Chichester, West Sussex, U.K., 2011.
(17) Manly, D. G.; Amstutz, E. D. J. Org. Chem. 1956, 21, 516−519.
́
(18) Mao, B.; Fan
117, 10502−10566.
̃
anas-Mastral, M.; Feringa, B. L. Chem. Rev. 2017,
(2) Tsuji, H.; Nakamura, E. Acc. Chem. Res. 2017, 50, 396−406.
C
DOI: 10.1021/acs.orglett.8b02554
Org. Lett. XXXX, XXX, XXX−XXX