Oxidation of azidoalkyl furans

Article abstract of DOI:10.1016/j.tetlet.2016.10.116

The oxidation reactions of various azidoalkyl furans were explored under different conditions to access structurally complex compounds from simple starting materials in an operationally simple, single step reaction. The strategically placed azide functional groups on the alkyl chain of the furan led to the discovery of a new and simple method for the synthesis of five-, six-, and seven-membered nitrogen heterocycles bearing prochiral centers and stereocenters.

Full text of DOI:10.1016/j.tetlet.2016.10.116

Accepted Manuscript
Oxidation of azidoalkyl furans
Mustafa Zahrittin Kazancioglu, Elif Akin Kazancioglu, Hasan Secen, Ramazan
Altundas
PII:
S0040-4039(16)31449-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.116
TETL 48286
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 September 2016
18 October 2016
31 October 2016
Please cite this article as: Zahrittin Kazancioglu, M., Akin Kazancioglu, E., Secen, H., Altundas, R., Oxidation of
azidoalkyl furans, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.10.116
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Graphical Abstract
Oxidation of azidoalkyl furans
Mustafa Zahrittin Kazancioglu, Elif Akin Kazancioglu, Hasan Secen, Ramazan Altundas*
Department of Chemistry, College of Sciences, Ataturk University, 25240 Erzurum, Turkey
Oxidation of azidoalkyl furans
Mustafa Zahrittin Kazancioglu, Elif Akin Kazancioglu, Hasan Secen and Ramazan Altundas∗
*
Department of Chemistry, College of Sciences, Ataturk University, 25240 Erzurum, Turkey
ramazanaltundas@atauni.edu.tr
Abstract
The oxidation reactions of various azidoalkyl furans were explored under different conditions to access structurally
complex compounds from simple starting materials in an operationally simple, single step reaction. The strategically
placed azide functional groups on the alkyl chain of the furan led to the discovery of a new and simple method for the
synthesis of five-, six-, and seven-membered nitrogen heterocycles bearing prochiral centers and stereocenters.
Key words: azidoalkyl furans, oxidation, pyrrolidine, piperidine, homopiperidine
Introduction
Nitrogen containing heterocycles are important natural and unnatural products possessing a wide range of
biological activities. A recent review by Njardarson and co-workers showed that 59% of the US FDA approved drugs
1
contain at least one nitrogen heterocycle, in which five- and six-membered nitrogen heterocycles are the most
2
abundant. These structures are present in natural products and synthetic biologically active motifs, and are considered
3
to be privileged structures in medicinal chemistry. Cyclic vicinal enamines possessing stereocenters and prochiral
4
centers are also highly versatile intermediates in the syntheses of many structurally complex nitrogen hetereocycles.
The furan ring has been harnessed as a building block in the syntheses of various natural products exhibiting
5
significant pharmaceutical interest. To unearth its hidden building block features, furans are oxidized either
*
1
Corresponding author. Tel.: +90 442 231 4386; fax: +90 442 231 4109; e-mail: ramazanaltundas@atauni.edu.tr
Permanent Address: Atatürk Vocational School of Health Science, Kafkas University, 36100 Kars, Turkey
Permanent Address: College of Pharmacy, Agri Ibrahim Cecen University, 04100 Agri, Turkey
2

6
chemically or photochemically with the preference for particular oxidation conditions strictly dependent on the
7
8
substrate and targeted product. The oxidation of alkyl furans possessing nucleophilic substituents such as hydroxyl
9
and amino groups, has been extensively implemented in the synthesis of structurally complex and pharmaceutically
important compounds. The azide group is also very common and usually functions as a precursor for both amines and
triazoles. Despite the interesting properties of the azide group, the oxidation of azidoalkyl furan derivatives is
1
0
surprisingly rare in the literature. Prior to this work, there have only been two reported studies, one of which was
conducted in our laboratory. In our previous study, we disclosed the TPP (meso-tetraphenylporphyrin) sensitized
photooxygenation of azidoalkyl furans giving triazoles via an unusual cycloaddition reaction and a new endoperoxide
1
0a
rearrangement pathway.
Currently, our group is focused extensively on furan-based strategies for the development of new methods for
9
h,10a
obtaining nitrogen heterocycles.
Herein, we report the oxidation of azidoalkyl furans leading to a straightforward
method for synthesizing 5-, 6- and 7-membered nitrogen heterocycles bearing prochiral centers.
Results and discussion
The syntheses of azidosubstituted alkyl furans at different positions of the alkyl chain was achieved by bond
1
0a
formation and functional group transformations.
Our investigation began with the model substrate 2-(1-
azidopentyl)furan 1. The RB (Rose Bengal) sensitized photooxygenation of 1 was carried out in MeOH at -78 °C using
a 500 W halogen lamp while oxygen was bubbled through the solution. Upon reaction completion (TLC), the reaction
1
S and left to warm slowly to room temperature. After solvent removal, H NMR
mixture was treated with excess Me
2
spectroscopy revealed neither the starting material nor the expected α,β-unsaturated-1,4-dione 3, the commonly
encountered oxidation product in furan chemistry. Under the same conditions the photooxygenation of furan 4, bearing
an azide group at C-2, also did not yield α,β-unsaturated dione 6. After these disappointing results using
photooxygenation, we surveyed commonly used chemical oxidants such as mCPBA and NBS. The oxidation of
compounds 1 and 4 did not provide any identifiable oxidation products or the returned starting material. In these
oxidation attempts, the consumption of starting materials clearly indicated that the employed oxidation conditions were
functioning but not in the desired manner. In this regard, the probable instability of the expected aldehydes 3, 6
resulted in discouraging results.

Scheme 1. Reagents and conditions: (i) O
2 2 2 2
, RB (0.4 mol%), 500 W lamp, MeOH, 0 °C, 0.5 h; (ii) Me S, CH Cl , rt,
overnight; (iii) mCPBA, CH Cl , rt, 5 h or NBS, acetone-H O (10:1), NaHCO , -40 °C, 10 min.
2 3
2
2
To avoid formation of the aldehyde functional group, we then explored 2-methyl furan derivatives which
would supposedly yield 1,4-diketones after oxidation. Initially, we examined the RB-sensitized photooxygenation of 2-
1
2-azidopentyl)methyl furan 7 (Scheme 2). The H NMR spectrum of the crude mixture showed no sign of the
(
expected unsaturated-1,4-dione, but a new structure which after purification provided 9 in 77% yield (Table 1, entry
). After this intriguing result using photooxygenation, additional chemical oxidants and reaction conditions were
1
screened for this new pyrrolidine ring formation method. Unfortunately, the oxidation of 7 using either NBS in MeCN
or mCPBA in DCM at both 0 °C and rt were ineffective (Scheme 2).
O
H
N
i
N3
Me
Me
N3
Me
O
O
O
O
7
8
9
2 2 2 2
Scheme 2. Reagents and conditions: (i) (a) O , RB (0.4 mol%), 500 W lamp, MeOH, 0 °C, 2 h; (b) Me S, CH Cl , rt,
1
2 h, 77%.
The discovery of this novel method for obtaining the pyrrolidine ring system from simple azidoalkyl furan
precursors motivated us to explore further substrates. Various reactions were performed by placing both the azide
functional group as well as additional substituents at different positions of the alkyl chain. In order to test the role of
steric effects around the azide during ring formation, the photooxygenation of furan 10 was carried out under the
developed conditions to yield 11 as a single product in 66% yield (Entry 2). To improve the yield our focus turned to
examining alternative oxidation conditions. Therefore, we first examined the efficiency of the mCPBA and NBS
1
mediated oxidation of 10 using the same conditions as described above for 7. Although the crude H NMR spectrum
from the NBS mediated oxidation did not show any product or starting material, pleasingly the mCPBA mediated
oxidation gave 11 in 53% yield. The stereochemistry of the alkene geometry was confirmed by an NOE experiment.
Irradiation of the olefinic proton at 5.60 ppm resulted in an enhancement of the NH signal at 9.69 ppm indicating that
the geometry of the double bond was the (E)-configuration. In order to test the generality of this reaction and whether
it could also be applied to form fused heterocycles, azidocyclopentyl furan 12 was oxidized using the established
oxidation conditions. To our delight, compound 13 was obtained using RB (65%) and NBS (86%) while mCPBA gave
no product (Entry 3).
We then turned our attention C-3 azidoalkyl furans. First, furan 14 was subjected to oxidation using either
photooxygenation, mCPBA or NBS. Only the NBS conditions gave 15 in 60% yield while photooxygenation and
mCPBA were unsuccessful (Entry 4). These findings clearly showed that the oxidants needed to be individually
screened for each substrate. Having established a new method for the formation of a piperidine ring system with an
unsubstituted alkyl chain, we further evaluated the reliability of this method with an additional substituent at C-3 or in
its close proximity. For this purpose, compound 16 with an OBn group at C-2, was examined, giving product 17 in
moderate yield using mCPBA (57%). Unfortunately, neither photooxidation nor NBS gave the desired piperidine

(
Entry 5). However, oxidation of 18 was achieved with both mCPBA and NBS to give 19 in 52% yield. Unfortunately,
the RB-sensitized photooxygenation did not form the desired piperidine derivative (Entry 6).
Following these results, an OBn group was installed at the C-1 position of compound 20. This was
envisioned to give an intermediate where the OBn group would be adjacent to the prochiral carbonyl group, paving the
way to constructing contiguous stereocenters. Despite significant effort with chemical oxidants and screening reaction
condition, neither of these led to formation of the piperidine ring system. On the other hand, both the RB-sensitized
10b
oxidation and TPP-sensitized photooxygenations of 20 furnished a triazole.
Based on our proposed reaction
mechanism, we then set out to eliminate triazole formation. Thiourea, as a peroxide cleavage reagent, was added at the
beginning of the reaction in order to immediately cleave the peroxide bond upon formation. This tactic eliminated
1
triazole formation, however, only trace amounts of the desired product 21 was observed in by H NMR spectroscopy.
Rapid separation of the crude material gave 21 in only 8% yield; we also found that this compound was unstable upon
storage, even in a refrigerator.
a
b
c
Entry
1
Substrate
Product
O
2
, RB, hν
mCPBA
NBS
77%
66%
-
-
-
2
53%
3
4
5
6
65%
-
86%
60%
-
-
-
-
-
57%
52%
52%
7
8
9
8%
-
-
-
-
60%
42%
62%
50%
-
-
-
10
Table 1. Reagents and conditions: (a) O
2
, RB (0.4 mol%), 500W lamp, MeOH, 0 °C; (ii) Me
2 2 2
S, CH Cl , rt; (b)
mCPBA, CH Cl , 0 °C; (c) NBS, acetone-H
2
2
2
O (10:1), NaHCO , -40 °C.
3
Encouraged by the oxidation of C-2 and C-3 azidoalkyl furans, enabling access to the pyrrolidine and
piperidine ring systems, respectively, we proceeded to examine whether this method could be applied to the

construction of homopiperidines. The RB-sensitized photooxygenation of 22 with an azide group at the C-4 position
gave homopiperidine 23 in 60% yield. However, oxidation with either mCPBA or NBS did not yield the desired
product (Entry 8). Furthermore, furan 24 bearing a functional group at C-3 was also screened to gain access to the
multifunctionalised homopiperidine 25 (Entry 9).
To determine the scope of this new furan based heterocycle formation, the azide functional group was
installed at the C-5 position in order to access eight membered heterocycles. Disappointingly, the oxidation of 26 did
not yield the cyclized product and instead 27 was obtained as the oxidation product (Entry 10). To accomplish the
3 2 3 3
cyclization, the crude material was treated with p-TSA, BF •OEt and Bi(NO ) in DCM at rt. Unfortunately, not even
1
trace amounts of the cyclization product were observed by crude H NMR spectroscopy. This result clearly showed
that C-4 is the last position where the azide can be placed for heterocycle formation.
Based on these results, a plausible reaction mechanism for ring formation was proposed (Scheme 3). The
oxidation of furan first provides the unsaturated-1,4-dione B which undergoes 3+2 cycloaddition to yield the bicyclic
intermediate C. Release of nitrogen from the five membered heterocyclic unit, results in intermediate D which
rearranges to E.
Scheme 3. Plausible reaction mechanism for the formation of five-, six- and seven-membered heterocycles
Conclusion
In conclusion, the oxidation of azidoalkyl furans employing different oxidants and reaction conditions was
explored to obtain structurally diverse compounds. Oxidation of azidoalkyl furans under either chemical or
photochemical conditions did not provide valuable material for further elaboration or use as intermediates in the
syntheses of more complex structures and was probably due to the instability of the aldehyde moiety in the oxidation
product. Pleasingly, oxidation of the azidoalkyl 5-methyl furan derivatives proceeded efficiently, affording five-, six-,
and seven-membered nitrogen containing heterocycles bearing prochiral centers and stereocenters in an operationally
simple, single step reaction. Although the C-5 azidoalkyl 5-methyl furan derivative did provide the unsaturated-1,4-
dione, it did not lead to the formation of an eight-membered ring.
Acknowledgements
This work was supported by TUBITAK (TBAG-107T838). The authors would like to thank B. Altundas (Miami
University) for the critical reading of the manuscript and G. Bilsel (UME-TUBITAK) for HRMS.
Supplementary Data

Supplementary data associated with this article can be found, in the online version, at htpp://
References
1
.
(a) Das, P.; Njardarson, J. T. Org. Lett. 2015, 17, 4030; (b) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J.
Med. Chem. 2014, 57, 10257.
2
3
.
.
Alonso, B.; Ocejo, M.; Carrillo, L.; Vicario, J. L.; Reyes, E.; Uria U. J. Org. Chem. 2013, 78, 614.
(a) Spangenberg, T.; Breit, B.; Mann A. Org. Lett. 2009, 11, 261; (b) Katoh, M.; Matsune, R.; Nagase, H.;
Honda T. Tetrahedron Lett. 2004, 45, 6221.
4
5
.
.
(a) Zhou, X.; Liu, W-J.; Ye, J-L.; Huang, P-Q. J. Org. Chem. 2007, 72, 8904; (b) Kim, J. H.; Shin, H.; and
Lee, S-g. J. Org. Chem. 2012, 77, 1560.
(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,
1
30, 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. (j) Kobayashi, Y.; Matsuumi,
M. J. Org. Chem. 2000, 65, 7221; (k) Kobayashi, Y.; Kumar, G. B.; Kurachi, T.; Acharya, H. P.; Yamazaki,
T.; Kitazume, T. J. Org. Chem. 2001, 66, 2011.
6
.
(a) Li, Z.; Tong, R. J. Org. Chem. 2016, 81, 4847; (b) Kobayashi, Y.; Katsuno, H.; Sato, F. Chem. Lett. 1993,
1
771; (c) Piancatelli, G.; Scettri, A.; D’Auria, M. Tetrahedron 1980, 36, 661; (d) Clive, D. L. J.; Ou, L. J.
Org. Chem. 2005, 70, 3318; (e) Ngooi, T. K.; Scilimati, A.; Guo, Z. W.; Sih, J. C. J. Org. Chem. 1989, 54,
11; (f) Couladouros, E. A.; Georgiadis, M. P. J. Org. Chem. 1986, 51, 2725.
9
7
8
.
.
Graziano, M. L.; Lesce, M. R.; Scarpati, R. J. Chem. Soc. Perkin 1955, 1, 1980.
(a) Achmatowicz, O, Jr.; Bukowski, P. ; Szechner, B.; Zwierzchowska, Z.; Zamojski, A. Tetrahedron 1971,
2
7, 1973; (b) Gollnick, K.; Griesbeck, A. Tetrahedron 1985, 41, 2057; (c) Iesce, M. R.; Cermola, F.; De
Lorenzo, F.; Orabona, I.; Graziano, M. L. J. Org. Chem. 2001, 66, 4732; (d) Erden, I.; Basada, J.; Poli, D.;
Cabrera, G.; Xu, F.; Gronert, S. Tetrahedron Lett. 2016, 57, 2190; (e) Burke, M. D.; Berger, E. M.;
Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 14095; (f) Wu, B.; Feast, G. C.; Thompson, A. L.; Robertson,
J. J. Org. Chem. 2012, 77, 10623; (g) Cermola, F.; Iesce, M. R.; Buonerba, G. J. Org. Chem. 2005, 70, 6503;
(
h) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 3899; (i) Harris, J. M.; Keränen, M. D.; Nguyen,
H.; Young, V. G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17; (j) Kouridaki, A.; Montagnon, T.;
Kalaitzakis, D.; Vassilikogiannakis, G. Org. Biomol. Chem. 2013, 11, 537; (k) Zhu, L. Z.; Talukdar, A.;
Zhang, G. S.; Kedenburg, J. P.; Wang, P. G. Synlett 2005, 1547; (l) Gómez, G.; Rivera, H.; García, I.;
Estévez, L.; Fall, Y. Tetrahedron Lett. 2005, 46, 5819; (m) Patil, S. N.; Stephens, B. E.; Liu, F. Tetrahedron
2
008, 64, 10831; (n) Hayes, S. J.; Knight, D. W.; Smith, A. W. T.; O’Halloran, M. J. Tetrahedron Lett. 2010,
1, 720; (o) Kouridaki, A.; Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Org. Lett. 2012, 14, 2374; (p)
5
Noutsias, D.; Kouridaki, A.; Vassilikogiannakis, G. Org. Lett. 2011, 13, 1166; (r) Tofi, M.; Koltsida, K.;
Vassilikogiannakis, G. Org. Lett. 2009, 11, 313; (s) Pavlakos, E.; Georgiou, T.; Tofi, M.; Montagnon, T.;
Vassilikogiannakis, G. Org. Lett. 2009, 11, 4556; (t) Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc.
Chem. Res. 2008, 41, 1001; (u) Teijeira, M.; Suárez, P. L.; Gómez, G.; Terán, C.; Fall, Y. Tetrahedron Lett.
2
005, 46, 5889.

9
.
(a) van der Pijl, F.; van Delft, F. L.; Rutjes, F. P. J. T. Eur. J. Org. 2015, 4811; (b) van der Pijl, F.; Harmel,
R. K.; Richelle, G. J. J.; Janssen, P.; van Delft, F. L.; Rutjes, F. P. J. T. Org. Lett. 2014, 16, 2038; (c)
Cassidy, M. P.; Padwa, A. Org. Lett. 2004, 6, 4029; (d) Leverett, C. A.; Cassidy, M. P.; Padwa, A. J. Org.
Chem. 2006, 71, 8591; (e) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401; (f) Kim, G.; Jung, S.-
D.; Lee, E.-J.; Kim, N. J. Org. Chem. 2003, 68, 5395; (g) 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; (h) Kazancioglu, M. Z.; Akin Kazancioglu,
E.; Secen, H.; Altundas, R. Tetrahedron Lett. 2015, 56, 6994.
1
0. (a) Akin Kazancioglu, E.; Kazancioglu, M. Z.; Fistikci, M.; Secen, H.; Altundas, R. Org. Lett. 2013, 15,
790; (b) García, I.; Pérez, M.; Gándara, Z.; Gómez, G.; Fall, Y. Tetrahedron Lett. 2008, 49, 3609.
4

Highlights
ꢀ
ꢀ
ꢀ
The oxidation of azidoalkyl furans was achieved with singlet oxygen, mCPBA and NBS.
Nitrogen heterocycles bearing a stereocenter and prochiral centers were obtained.
The reaction proceeded via furan oxidation, cycloaddition, and nitrogen release.