Photooxygenation of azidoalkyl furans: Catalyst-free triazole and new endoperoxide rearrangement

Article abstract of DOI:10.1021/ol402163u

Photooxygenation of azidoalkyl furans has revealed both a novel triazole formation method and a unique endoperoxide rearrangement. The key step of this method is a 3 + 2 cycloaddion of the azide to the endoperoxide intermediate. The reduction of the peroxide bond and two subsequent C-C bond cleavages provide a triazole having a newly formed carboxylic acid functionality. The reactions are clean and efficient with yields ranging from 60% to 90%.

Full text of DOI:10.1021/ol402163u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Photooxygenation of Azidoalkyl Furans:
Catalyst-Free Triazole and New
Endoperoxide Rearrangement
Elif Akin Kazancioglu, Mustafa Zahrittin Kazancioglu, Meryem Fistikci, Hasan Secen,
and Ramazan Altundas*
Department of Chemistry, Ataturk University, 25240 Erzurum, Turkey
ramazanaltundas@atauni.edu.tr
Received July 30, 2013
ABSTRACT
Photooxygenation of azidoalkyl furans has revealed both a novel triazole formation method and a unique endoperoxide rearrangement. The key
step of this method is a 3 þ 2 cycloaddion of the azide to the endoperoxide intermediate. The reduction of the peroxide bond and two subsequent
CꢀC bond cleavages provide a triazole having a newly formed carboxylic acid functionality. The reactions are clean and efficient with yields
ranging from 60% to 90%.
Furan core units are widely distributed in natural
products and biologically important compounds.1 Furan
subunits also appear as building blocks in the synthesis of
natural products possessing biological activities.2 Furan
can be transformed either chemically3 or by photooxy-
genation of singlet oxygen into R,β-unsaturated-1,4-dione
moieties. Photochemical oxidation by singlet oxygen is
mostly preferred since singlet oxygen has been known to
be a nontoxic, higher yielding, and more functional group
tolerant oxidant.4 Due to their electron-rich nature, furans
can function as dienes and undergo a 4 þ 2 cycloaddition
reaction with singlet oxygen to produce tricyclic com-
pounds called endoperoxides. Endoperoxides are ther-
mally unstable and rearrange to R,β-unsaturated-1,4-
dicarbonyl compounds depending on the peroxide bond
cleavageconditions5 and the substituent on the furan.6 The
photooxidation of hydroxyalkylfuran derivatives has been
studied frequently for two reasons: (1) to explore the effect
of the hydroxyl group on the endoperoxide rearrange-
ment mechanism, depending on its position on the alkyl
chain and reaction conditions5b,7 and (2) to synthesize
stereoselectively natural and unnatural compounds having
multistereocenters with the help of an already existing
stereocenter where the hydroxyl group can be readily
installed.4b,8 The oxidation of 1-aminoalkyl furan has also
been of great interest in the syntheses of highly diversified
(1) (a) Stoye, A.; Quandt, G.; Brunnhofer, B.; Kapatsina, E.; Baron,
J.; Fischer, A.; Weymann, M.; Kunz, H. Angew. Chem., Int. Ed. 2009, 48,
2228. (b) Saquib, M.; Husain, I.; Kumar, B.; Shaw, A. K. Chem.;Eur. J.
2009, 15, 6041. (c) Kanokmedhakul, S.; Kanokmedhakul, K.;
Kantikeaw, I.; Phonkerd, N. J. Nat. Prod. 2006, 69, 68. (d) Tuchinda,
P.; Pohmakotr, M.; Reutrakul, V.; Thanyachareon, W.; Sophasan, S.;
Yoosook, C.; Santisuk, T.; Pezzuto, J. M. Planta Med. 2001, 67, 572.
(e) El Sayed, K. A.; Mayer, A. M. S.; Kelly, M.; Hamann, M. T. J. Org.
Chem. 1999, 64, 9258.
(2) (a) Canoa, P.; Gandara, Z.; Perez, M.; Gago, R.; Gomez, G.; Fall,
Y. Synthesis 2011, 431. (b) Procko, K. J.; Li, H.; Martin, S. F. Org. Lett.
2010, 12, 5632. (c) O’Keefe, B. M.; Mans, D. M.; Kaelin, D. E.; Martin,
S. F. J. Am. Chem. Soc. 2010, 132, 15528. (d) Kelly, A. R.; Kerrigan,
M. H.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 4097. (e) Garcia, I.;
Gomez, G.; Teijeira, M.; Teran, C.; Fall, Y. Tetrahedron Lett. 2006, 47,
1333. (f) Padwa, A.; Lynch, S. M.; Mejia-Oneto, J. M.; Zhang, H. J.
J. Org. Chem. 2005, 70, 2206. (g) Gomez, G.; Rivera, H.; Garcia, I.;
Estevez, L.; Fall, Y. Tetrahedron Lett. 2005, 46, 5819. (h) Demeke, D.;
Forsyth, C. J. Org. Lett. 2003, 5, 991. (i) Ballini, R.; Bosica, G. J. Nat.
Prod. 1998, 61, 673.
(5) (a) Balci, M. Chem. Rev. 1981, 81, 91. (b) Gollnick, K.; Griesbeck,
A. Tetrahedron 1985, 41, 2057. (c) Altundas, R.; Balci, M. Tetrahedron
1993, 49, 6521. (d) Greatrex, B. W.; Jenkins, N. F.; Taylor, D. K.;
Tiekink, E. R. T. J. Org. Chem. 2003, 68, 5205. (e) Jin, H. X.; Liu, H. H.;
Zhang, Q.; Wu, Y. K. J. Org. Chem. 2005, 70, 4240. (f) Onitsuka, S.;
Nishino, H.; Kurosawa, K. Tetrahedron 2001, 57, 6003.
(3) (a) Clive, D. L. J.; Minaruzzaman; Ou, L. J. Org. Chem. 2005, 70,
3318. (b) Massa, A.; Acocella, M. R.; De Rosa, M.; Soriente, A.; Villano,
R.; Scettri, A. Tetrahedron Lett. 2003, 44, 835.
(4) (a) Cermola, F.; Iesce, M. R. Tetrahedron 2006, 62, 10694. (b)
Montagnon, T.; Noutsias, D.; Alexopoulou, I.; Tofi, M.; Vassilikogiannakis,
G. Org. Biomol. Chem. 2011, 9, 2031.
(6) (a) Graziano, M. L.; Iesce, M. R.; Carli, B.; Scarpati, R. Synthesis
1983, 125. (b) Iesce, M. R.; Cermola, F.; Piazza, A.; Scarpati, R.;
Graziano, M. L. Synthesis 1995, 439. (c) Young, R. H.; Martin, R. L.;
Chinh, N.; Mallon, C.; Kayser, R. H. Can. J. Chem. 1972, 50, 932.
(7) Iesce, M. R.; Cermola, F.; De Lorenzo, F.; Orabona, I.; Graziano,
M. L. J. Org. Chem. 2001, 66, 4732.
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10.1021/ol402163u
XXXX American Chemical Society

structures exhibiting a wide range of pharmaceutical
activities.9 In addition to the hydroxyl and amine function-
ality, the azide is also a very common functional group and
serves as both an encoded amine10 and triazole precursor.
Triazoles have become targets in the fields of medicinal
chemistry11 and synthetic organic chemistry12 after the
revolutionary discovery of a new triazole synthesis.13 The
toxicity of the residual copper catalyst in biological studies
makes the metal-free triazole protocols more attractive in
drug discovery programs.14 Despite all of these beneficial
features of azides, thechemicalorphotooxidationofazides
bearingalkyl furansisexceedinglyrare.15 The only account
noted thus far was photooxidation of 2-(3-azidoalkyl)
furan carried out in order to establish the substituted
piperidine ring system.
Scheme 1. Photooxygenation of 1-Azido- and 2-Azidoalkylfurans
Here, we report herein the discovery of both a new
triazole formation method and endoperoxide rearrange-
ment pathway with two concomitant CꢀC bond cleavages
in the photooxydation of azidoalkyl furans. These trans-
formations were discovered during our research program,
which is primarily focused on the furan-based synthesis of
diverse structural motifs. Syntheses of azidoalkyl furans
were successively achieved by employing and tuning ap-
propriate bond formation and functional group trans-
formation methodologies. First, we studied the photo-
oxygenation of 2-(1-azidopentyl)furan (1) at ꢀ78 °C
(Scheme 1). A solution of 1 and a catalytic amount of
TPP (meso-tetraphenylporphyrin) were dissolved in DCM,
cooled toꢀ78°C, and then irradiated with a 500 W halogen
lamp while oxygen was bubbled into the solution. Upon
completion of the reaction (as monitored by TLC), excess
Me2S was added into the reaction mixture and then the
resulting mixture was allowed to warm to rt to completely
cleave the unstable peroxide bond. After the removal of
(8) (a) Tofi, M.; Koltsida, K.; Vassilikogiannakis, G. Org. Lett. 2009,
11, 313. (b) Pavlakos, E.; Georgiou, T.; Tofi, M.; Montagnon, T.;
Vassilikogiannakis, G. Org. Lett. 2009, 11, 4556. (c) Montagnon, T.;
Tofi, M.; Vassilikogiannakis, G. Acc. Chem. Res. 2008, 41, 1001. (d)
Zhu, L. Z.; Talukdar, A.; Zhang, G. S.; Kedenburg, J. P.; Wang, P. G.
Synlett 2005, 1547. (e) Teijeira, M.; Suarez, P. L.; Gomez, G.; Teran, C.;
Fall, Y. Tetrahedron Lett. 2005, 46, 5889. (f) Burke, M. D.; Berger,
E. M.; Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 14095. (g) Harris,
J. M.; Keranen, M. D.; Nguyen, H.; Young, V. G.; O’Doherty, G. A.
Carbohydr. Res. 2000, 328, 17. (h) Abrams, J. N.; Babu, R. S.; Guo, H.;
Le, D.; Le, J.; Osbourn, J. M.; O’Doherty, G. A. J. Org. Chem. 2008, 73,
1935.
(9) (a) Leverett, C. A.; Cassidy, M. P.; Padwa, A. J. Org. Chem. 2006,
71, 8591. (b) Cassidy, M. P.; Padwa, A. Org. Lett. 2004, 6, 4029.
(c) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401.
(10) Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
Int. Ed. 2005, 44, 5188.
1
solvent, H NMR showed that the starting material (1)
had been consumed and converted to the E/Z mixtures of
aldehyde 3 which was found to be unstable at 0 °C. The
crude product was sufficiently clean for structural assess-
1
ment by H and 13C NMR. Interestingly, photooxygena-
(11) (a) Weide, T.; Saldanha, S. A.; Minond, D.; Spicer, T. P.;
Fotsing, J. R.; Spaargaren, M.; Frere, J. M.; Bebrone, C.; Sharpless,
K. B.; Hodder, P. S.; Fokin, V. V. ACS Med. Chem. Lett. 2010, 1, 150.
(b) Kee, J. M.; Villani, B.; Carpenter, L. R.; Muir, T. W. J. Am. Chem.
Soc. 2010, 132, 14327. (c) Diaz, L.; Bujons, J.; Casas, J.; Llebaria, A.;
Delgado, A. J. Med. Chem. 2010, 53, 5248. (d) Minond, D.; Saldanha,
S. A.; Subramaniam, P.; Spaargaren, M.; Spicer, T.; Fotsing, J. R.;
Weide, T.; Fokin, V. V.; Sharpless, K. B.; Galleni, M.; Bebrone, C.;
Lassaux, P.; Hodder, P. Bioorg. Med. Chem. 2009, 17, 5027. (e) Hirose,
T.; Sunazuka, T.; Sugawara, A.; Endo, A.; Iguchi, K.; Yamamoto, T.;
Ui, H.; Shiomi, K.; Watanabe, T.; Sharpless, K. B.; Omura, S.
J. Antibiot. 2009, 62, 277. (f) Whiting, M.; Tripp, J. C.; Lin, Y. C.;
Lindstrom, W.; Olson, A. J.; Elder, J. H.; Sharpless, K. B.; Fokin, V. V.
J. Med. Chem. 2006, 49, 7697.
(12) (a) Kwok, S. W.; Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.;
Fokin, V. V. Org. Lett. 2010, 12, 4217. (b) Kalisiak, J.; Sharpless, K. B.;
Fokin, V. V. Org. Lett. 2008, 10, 3171. (c) Boren, B. C.; Narayan, S.;
Rasmussen, L. K.; Zhang, L.; Zhao, H. T.; Lin, Z. Y.; Jia, G. C.; Fokin,
V. V. J. Am. Chem. Soc. 2008, 130, 8923. (d) Yoo, E. J.; Ahlquist, M.;
Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless, K. B.; Chang, S. Angew.
Chem., Int. Ed. 2007, 46, 1730.
tion of the methylfuran analogue of 1 did not show any sign
of the product or starting material. Next, the photo-
oxygenation of 4, with an azide at C-2 of the alkyl chain,
was explored under the developed conditions (Scheme 1).
1
The crude H NMR showed only trace amounts of the
oxidation product 5. Unfortunately, we were unable to
fully characterize 5 due to its instability at rt. The RB
(Rose bengal)-sensitized oxygenations of 1 and 4 in MeOH
were also performed. Sadly, these experiments did not
provide 3 and 5 or any MeO group incorporated product
which is generally observed under these conditions.15 After
these disappointing observations, we turned our attention
to 3-azidoalkyl furan. First, 6 was exposed to the TPP-
1
sensitized oxygenation (Scheme 2). H and 13C NMR
from the isolated product showed new distinctive signals
that appeared at 11.09 (br s), 7.72 (s), 7.65 (s) ppm and
174.5 ppm. Surprisingly, the characteristic aldehyde and
R,β-unsaturated system signals of the expected oxidation
product were not seen in 1H and 13C NMR. In addition, the
expected total carbon signals were one carbon less than
the number of carbons in the starting material. From these
data, it was obvious that we had encountered a new
structural motif in furan oxidation. After this intriguing
(13) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596.
(14) (a) Niu, T. F.; Gu, L.; Yi, W. B.; Cai, C. ACS Comb. Sci. 2012,
14, 309. (b) Bernardin, A.; Cazet, A.; Guyon, L.; Delannoy, P.; Vinet, F.;
Bonnaffe, D.; Texier, I. Bioconjugate Chem. 2010, 21, 583. (c) Jewett,
J. C.; Bertozzi, C. R. Chem. Soc. Rev. 2010, 39, 1272. (d) Neef, A. B.;
Schultz, C. Angew. Chem., Int. Ed. 2009, 48, 1498. (e) van Dijk, M.;
Rijkers, D. T. S.; Liskamp, R. M. J.; van Nostrum, C. F.; Hennink,
W. E. Bioconjugate Chem 2009, 20, 2001.
(15) Garcia, I.; Perez, M.; Gandara, Z.; Gomez, G.; Fall, Y. Tetra-
hedron Lett. 2008, 49, 3609.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Photooxygenation Result of Azidoalkylfuransa
Scheme 2. Photooxygenation of 3-Azidoalkylfurans
result, the oxidation of 8, the 5-Me derivative of 6, was
1
carried out at 0 °C (Scheme 2). The H NMR from the
crude material was completely identical to the oxidation
product of 6. In addition, both IR spectra from the oxida-
tion reaction of 6 and 8 did not show an azide signal at
2200 cmꢀ1. From further spectral studies, the structures of
the products obtained from the oxidation of both 6 and 8
were elucidated as triazole 7. The effect of temperature on
the yield and product distribution was examined by repeat-
ing the reactions at ꢀ78 °C and rt. These studies showed
that temperature has almostno effecton the reaction yields.
Moreover, no workup and chromatography are needed
after the reaction; the simple tritutation of crude materials
provided clean triazole 7. Photooxygenation of 6 was also
repeated in the RB-sensitized oxygenation conditions.
However we did not observe 7 or any meaningful product
similar to a tetracyclic material containing triazoline unit
along with MeO group based on the crude 1H NMR as seen
in a similar subsrate by Fall and co-workers.15 After this
study, we preferred the TPP-sensitized oxidation in DCM
for the rest of our substrates. These remarkable discoveries
motivated us to explore further examples by interchanging
the azide functionality throughout the alkyl chain and
introducing additional substituents either to the carbon
where the azide resides or to the other carbons of the alkyl
chain. In order to test the impact of the steric effect around
azide, an n-butyl group was installed to the C-3 center
(Table 1, entry 1). Photooxygenation of 9 was carried out
under the optimized conditions, and triazole 10 was ob-
tained as the sole product in 87% yield (Table 1, entry 1).
Provoked by this observation, 11 was prepared by placing
the hydroxymethyl group to C-2 by leaving the azide at C-3.
To our delight 11 also provided triazole 12 (Table 1, entry 2).
Contrary to common observations, the hydroxyl group did
not interfere with the endoperoxide even though it was in
close proximity. Substrate 13 carrying a benzyl group at C-2
furthermore furnished triazole 14 in 90% yield (Table 1,
entry 3) without being affected by steric hindrance. Fasci-
natingly, the photooxygenation of 15 also provided only
triazole 16 in 80% yield under the established reaction
conditions (Table 1, entry 4). Upon enlightening results
from the above examples, we turned our attention to study
the photooxygenation of the trisubstituted furan. For this
purpose, 5-(3-azidopropyl)-2,3-dimethylfuran (17) was pre-
pared and then exposed to the photooxygenation (Table 1,
a Reaction conditions: Cat. TPP, O2, 500 W halogen lamp, 25 min to
2 h, 0 °C. b Isolated yields. c The reaction was carried out at ꢀ78 °C for
2 h and then stirred at ꢀ55 °C for 2 d; then Me2S was added, and the
reaction was stirred at ꢀ55 °C for 2 d.
scope of this new reaction, the azide was first moved to C-4.
Oxidation of 19 gave triazole 20 (Table 1, entry 6). Next, the
steric crowding around the azide at C-4 was also increased
by the introduction of a benzyl ether to C-3. Gratifyingly,
the oxidation of 21 also furnished triazole 22 in a moderate
yield (Table 1, entry 7). However, 23, with a C-5-azido, did
not furnish trace triazole when exposed to the oxidation,
and 24 was the sole product (Table 1, entry 8). This could be
attributed to the short lifespan of endoperoxides at 0 °C
at which the peroxide bond can be cleaved thermally
and rearranged to 1,4-diketone 24. To overcome this
obstacle, the new experiment was performed at ꢀ78 °C.
1
entry 5). The crude H NMR showed solely triazole 18
in 89% yield. The methyl group at the double bond of
endoperoxide showed no restriction in the endoperoxide
rearrangement en route to triazole 18. To determine the
Org. Lett., Vol. XX, No. XX, XXXX
C

Upon consumption of the starting material as judged by
TLC, the reaction was kept at ꢀ55 °C for 2 days to allow
more time for the azide to convene with the endoperoxide.
Disappointingly, not even a small amount of triazole was
observed, and only the R,β-unsaturated-1,4-diketone 24 was
again obtained. This experiment demonstrated that C-4 is
the maximum chain length for the azide. After all of these
instructive results, we proposed a plausible reaction me-
chanism for the triazole formation, using A as an example,
which is illustrated in Scheme 3. The photooxidation of
azidoalkyl furans first furnishes endoperoxide B. This is
followed up by azide interacting with the double bond of
endoperoxide B to undergo a 3 þ 2 cycloaddition. Upon
treatment with Me2S, the OꢀO bond of C is reduced, and D
rearranges into triazole F by two individual and consecutive
CꢀC bond cleavages of the furan. Obtainment of the usual
oxidation products, R,β-unsaturated-1,4-dione (3, 5, 24),
rather than the corresponding triazoles, could be attributed
to the difficulty of tetracyclic intermediate formation (C).
To summarize, we have discovered a new metal catalyst-
free triazole synthesis and a unique endoperoxide rearran-
gement pathway with two unusual CꢀC bond cleavages
from C-3 and C-4 azidoalkyl furans. Two new units,
triazole and carboxylic acid, were formed simply in one
single operation from azidoalkylfurans. However, C-1,
C-2, and C-5 azido derivatives only gave unsaturated-
1,4-diones probably due to geometric restriction in the
tetracyclic ring formation. Triazole yields are moderate to
high, and the crude reaction does not need tedious workup
or chromatographic separations. The simple trituration is
sufficient to obtain the pure product. Notably, enantio-
merically pure triazole derivatives (e.g., entries 2 and 3) can
also be achievable from the readily available epoxides (e.g.,
(R)-, and (S)-glycidols) by taking into account that the
stereocenter is not affected. We believe that this methodo-
logy could find application in the syntheses of a new class
of triazole derivatives containing multiple functional
groups such as carboxylic acid, hydroxyl, and alkyl groups.
The new endoperoxide rearrangement pathway could
also lead to the discovery of structurally diverse motifs
from the furan based methodology. Further studies in the
Scheme 3. Plausible Reaction Mechanism of Triazole Formation
photooxidation of azide-containing alkyl furans to discover
highly diverse product profiles are currently in progress,
and the results will be reported in due course.
Acknowledgment. This work was supported by
TUBITAK (TBAG-107T838). We would like to thank
Prof. Fraser F. Fleming (Duquesne University, USA), Dr.
Erin M. Skoda (University of Pittsburgh, USA), and Bilal
Altundas for helpful discussions and critical reading of
the manuscript and Gokhan Bilsel (UME-TUBITAK) for
HRMass.
Supporting Information Available. Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX