Oxidation of aminoalkyl and hydroxylaminoalkyl furans

Article abstract of DOI:10.1016/j.tetlet.2015.10.105

The oxidation reactions of amino and hydroxylamino substituted alkylfurans were explored for the synthesis of structurally complex compounds from simple starting materials. A novel photooxygenation of the furan derivatives gave an α,β-unsaturated dicarbonyl moiety which underwent subsequent conjugate addition to yield diastereomeric mixtures of the corresponding pyrrolidine and isoxazoline heterocycles. Oxidation of the α,β-unsaturated dicarbonyl using mCPBA gave epoxide intermediates, which were opened by nucleophilic attack of the amino groups, furnishing pyrrolidine and isoxazolidine heterocycles.

Full text of DOI:10.1016/j.tetlet.2015.10.105

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidation of aminoalkyl and hydroxylaminoalkyl furans
⇑
Mustafa Zahrittin Kazancioglu, Elif Akin Kazancioglu, Hasan Secen, Ramazan Altundas
Department of Chemistry, College of Sciences, Ataturk University, 25240 Erzurum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxidation reactions of amino and hydroxylamino substituted alkylfurans were explored for the
synthesis of structurally complex compounds from simple starting materials. A novel photooxygenation
Received 22 June 2015
Revised 21 October 2015
Accepted 29 October 2015
Available online xxxx
of the furan derivatives gave an
conjugate addition to yield diastereomeric mixtures of the corresponding pyrrolidine and isoxazoline
heterocycles. Oxidation of the ,b-unsaturated dicarbonyl using mCPBA gave epoxide intermediates,
a,b-unsaturated dicarbonyl moiety which underwent subsequent
a
which were opened by nucleophilic attack of the amino groups, furnishing pyrrolidine and isoxazolidine
heterocycles.
Keywords:
Aminoalkylfuran
Hydroxylaminofuran
Oxidation
Ó 2015 Elsevier Ltd. All rights reserved.
Substituted pyrrolidine
Substituted isooxazoline
Introduction
synthetic potential for forming complex multifunctional hetero-
cyclic ring systems by manipulating the reaction conditions. In
Nitrogen containing saturated heterocycles are an important
subclass of biologically active natural and synthetic products.
Substituted pyrrolidines are found in many natural products and
serve as building blocks for indolizidine and pyrrolizidine alkaloids.1
Moreover, naturally occurring polyhydroxylated pyrrolidines and
their synthetic derivatives have attracted much attention due to
their biological activities.2 Isoxazolidines, which can be considered
as pyrrolidine derivatives where the carbon attached to the
nitrogen atom has been replaced by an oxygen atom, are valuable
intermediates in synthetic organic chemistry3 and are commonly
used in drug discovery.4 Recently O-alkylhydroxylamines have been
used in the straightforward stereoselective syntheses of various
isoxazolidines.5
The oxidation of furan and its derivatives have been applied to
the discovery of structurally diverse compounds and the syntheses
of many biologically active compounds.6 Oxidation has been
achieved by either standard chemical oxidation7 or photooxygena-
tion using singlet oxygen.8 These two methods are selected accord-
ing to the substrate utilized and the desired end product. 2-Alkyl
furans containing hydroxyl or amine functional groups at different
positions on the alkyl chain have been intensively explored to help
understand the mechanism of oxidation and exploited in the
synthesis of many natural and synthetic heterocycles.9
addition, despite the well known synthetic utility of O-alkylhy-
droxylamines, to the best of our knowledge, hydroxylamine substi-
tuted alkylfurans have not yet been evaluated in this reaction.
Therefore, we have explored the oxidation of amine and hydroxy-
lamine substituted alkyl furans leading to
a straightforward
method for the synthesis of pyrrolidine and isoxazolidine
derivatives bearing consecutive stereocenters.
Results and discussion
The syntheses of starting materials (3, 4) were achieved by
epoxide ring opening of benzyl protected glycidol with furyllithi-
ums (from 1, 2) at ꢀ78 °C to give 3 and 4 in 68% yield. The alcohols
(3, 4) were converted to Boc protected amines (7, 8) in good yields
using a three step procedure including: azidation, reduction and
protection (Scheme 1).
With compounds 7 and 8 in hand, we began by exploring
oxidation conditions for the furan ring. Initially, a solution of 7 in
CH2Cl2 was illuminated with a sun lamp in the presence of TPP
(meso-tetraphenylporphyrin) at 0 °C while passing O2 gas through
the solution. Upon consumption of 7 (TLC), the reaction was trea-
ted with excess Me2S to furnish
10 via cleavage of the peroxide bond of the ozonide-like interme-
diate 9. Because the ,b-unsaturated unit of 10 could serve as a
a,b-unsaturated-1,4-dicarbonyl
Although, the oxidation of aminoalkylfurans have been
a
extensively reported in the literature,10 there is still unexplored
Michael acceptor for the intramolecular conjugate addition of the
amine, the solution of 10 in CH2Cl2 was stirred at rt for one week.
However, no cyclization took place, and only starting material was
recovered (Scheme 2).
⇑
Corresponding author. Tel.: +90 442 231 4386; fax: +90 442 231 4109.
E-mail address: ramazanaltundas@atauni.edu.tr (R. Altundas).
http://dx.doi.org/10.1016/j.tetlet.2015.10.105
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kazancioglu, M. Z.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.105

2
M. Z. Kazancioglu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
OH
OH Ha
i
N3
ii
O
3
4
H3C
H3C
HO
O
1'
O
OBn
5
i
Hb
R
OBn
R
R
4
O
2
1
O
O
2
1'
N
Boc
5
H3C
OBn
N
1
2
3
5
(83%)
R = H
R = H
(68%)
R = H
H
OBn
H
H
HO
R = CH3
R = CH3 4 (68%)
R = CH3 6 (83%)
Boc
18 (64%)
17
iii
Scheme 5. Reagents and conditions: (i) MeMgBr, THF, ꢀ55 °C, 11 h, 64%.
NHBoc
OBn
R
O
7
R = H
(62%)
i
ii
R = CH3 8 (92%)
H3C
H3C
R
R
O
O
H3C
O
OH
OPhth
Scheme 1. Reagents and conditions: (i) (a) n-BuLi, THF, ꢀ78 °C to ꢀ5 °C, 2 h; (b) 2-
((benzyloxy)methyl)oxirane in THF, ꢀ78 °C to rt, 1 d, 68% (3 and 4); (ii) (a) MsCl,
Et3N, 0 °C, 4 h; (b) NaN3, DMF, 70 °C, 24 h, 83% over two steps (5 and 6); (iii) (a) H2,
10% Pd/C, EtOH, rt, 10 h; (b) (Boc)2O, Et3N, THF, 0 °C to rt, 20 h, 62% over two steps
(7), and 92% over two steps (8).
2
R = CH3
R = CH2OBn 20 (78%)
19 (81%)
R = CH3
21 (80%)
R = CH2OBn22 (88%)
iii
iv
H3C
H3C
R
O
R
O
ONH2
23
R = CH2OBn 24
ONHBoc
O
NHBoc
OBn
OBn
25
R = CH3 (92%)
R = CH2OBn 26 (81%)
R = CH3
NHBoc
OBn
i
ii
O
O
O
HN
O
O
H
Boc
Scheme 6. Reagents and conditions: (i) (a) n-BuLi, THF, ꢀ78 °C to ꢀ5 °C, 2 h; (b)
3-(benzyloxy)propanal or propionaldehyde in THF, ꢀ78 °C to rt, 15 h, 81% (19) and
78% (20); (ii) DEAD, N-hydroxyphthalimide, THF, 0 °C, 19 h, 80% (21); 17 h, 88%
(22); (iii) NH2NH2.xH2O, CH2Cl2, 0 °C; (iv) (Boc)2O, Et3N, THF, 0 °C, 92% over two
steps (25) and 28 h, 81% over two steps (26).
7
9
10
O
O
O
OBn
or
HO
Boc
H
N
Boc
N
OBn
11
12
the desired cyclization products. Because aldehyde 10 was unsta-
ble and did not undergo conjugate addition under the examined
conditions, we turned our attention to furan 8 which upon oxida-
Scheme 2. Reagents and conditions: (i) O2, (0.4 mol %) TPP, 500 W lamp, CH2Cl2,
0 °C, 4 h; (ii) Me2S, CH2Cl2, rt, 7 d.
tion would provide
a,b-unsaturated ketone 14, and was expected
to be a better Michael acceptor. Pleasingly, the photooxygenation
of 8 under RB (Rose Bengal)-sensitized conditions furnished 15 in
85% yield as a 1:1 diastereomeric mixture after treatment with
p-TSA. Disappointingly, separation of the diastereomers was not
Next, aldehyde 10 was treated with either catalytic p-TSA, TFA
or NaH to effect cyclization (Scheme 2). However, 1H NMR spec-
troscopy revealed only decomposed material with no evidence of
O
O
NHBoc
NHBoc
HN
Boc
HN
Boc
OBn
OBn
ii
i
OBn
OBn
H3C
O
H3C
O
O
O
O
O
CH3
8
13
14a
14b
CH3
iii
O
O
OBn
H3C
N
Boc
(dr=1:1,85%)
15
Scheme 3. Reagents and conditions: (i) O2, (0.4 mol %) RB, 500 W lamp, MeOH, 0 °C; 2 h (ii) Me2S, CH2Cl2, rt, 6 d; (iii) p-TSA, CH2Cl2, 2 d, 85% (dr = 1:1).
CH3
O
O
H
O
O
O
O
NHBoc
OBn
i
OBn
HN
H3C
+
H
H
Boc
N
Boc
H3C
H3C
N
Boc
OBn
O
OH
OBn
17 (16%)
8
14
15 (46%)
ii
CH3
H
CH3
O
O
H
O
O
O
O
O
HN
HN
N
Boc
H3C
Boc
H
H
OBn
Boc
OH
OBn
OBn
14
16
17 (72%)
Scheme 4. Reagents and conditions: (i) mCPBA (1.2 equiv), CH2Cl2, 0 °C, 2 d, 46% (15) and 16% (17); (ii) mCPBA (2.5 equiv), CH2Cl2, 0 °C, 3 d, 72%.
Please cite this article in press as: Kazancioglu, M. Z.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.105

M. Z. Kazancioglu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
O
R
O
R
ii
i
O
H3C
H3C
O
HN
Boc
O
R
O
R
O
O
O
H3C
O
N
O
O
CH3
Boc
R = CH2OBn 29 (75%)
NHBoc
NHBoc
R = CH3
25
R = CH2OBn27
R = CH2OBn 28
R = CH2OBn 26
iii
O
R
O
O
R
O
R
O
H
O
O
HN
Boc
O
H3C
H3C
HN
H3C
N
O
O
OH
Boc
Boc
R = CH3 33 (80%)
R = CH2OBn 34 (60%)
30
31
R = CH3
R = CH2OBn 32
R = CH3
R = CH2OBn 28
Scheme 7. Reagents and conditions: (i) O2, (0.4 mol %) RB, 500 W lamp, MeOH, 0 °C, 1 h; (ii) Me2S, CH2Cl2, rt, 6 d, 75% (dr = 4:1); (iii) mCPBA (2.5 equiv), CH2Cl2, ꢀ40 °C, 8 h,
then rt, 8 h, 80% (33) and ꢀ40 °C, 12 h then rt, 12 h, 60% (34).
successful using column or preparative thin layer chromatography
(Scheme 3).
oxidation of 25 and 26 using mCPBA. Pleasingly, after tuning the
reaction conditions, the oxidation of 25 and 26 with mCPBA
(2.5 equiv) in CH2Cl2 at ꢀ40 °C furnished isoxazolidines 33 in
80% and 34 in 60% yield as single diastereomers (Scheme 7).
We envisioned that mCPBA mediated oxidation of furan 8
would only give the E-isomer of the intermediate alkene. The ini-
tially formed but less stable Z-alkene was assumed to isomerize
in situ to give the E-isomer under our mildly acidic mCPBA oxida-
tion conditions which would be followed by diastereoselective
cyclization. A solution of 8 in CH2Cl2 was treated with mCPBA
(1.2 equiv) at 0 °C for 2 d to give 15 in 46% yield as a diastereomeric
mixture along with a new compound 17 in 16% yield. Structural
elucidation of 17 was achieved using APT, HMBC and HMQC and
NOE experiments. In Scheme 4, we show that 17 could also be
obtained by epoxidation of unsaturated olefin 14. Excited by this
preliminary result, the reaction was optimized in order to increase
the yield of 17 by altering the amount of mCPBA. Gratifyingly,
2.5 equiv of mCPBA at 0 °C in CH2Cl2 furnished pyrrolidine deriva-
tive 17 as a single diastereomer in 72% yield (Scheme 4). We pre-
sume that the diastereoselective epoxidation of 14 was caused by
the directing ability of the amino group via hydrogen bonding with
mCPBA.
The relative configuration of 17 could not be determined by 2D
NMR spectroscopy techniques due to the fact that all the tertiary
hydrogens (H-10, H-2 and H-5) resonated in the same region
(4.30–4.20 ppm). Therefore, compound 17 was transformed to a
rigid compound that could be used to assign the relative configura-
tion of the stereocenters. Treatment of 17 with 1 equiv of MeMgBr
furnished hemiketal 18 as a single diastereomer (Scheme 5). NOE
measurements of H-4a showed an enhancement of the peaks in
compound 18, which clearly supported the syn relation of H-4a
with H-2.
Conclusions
The photooxygenation of amino and hydroxylamino substituted
alkylfurans yielded diastereomeric mixtures of pyrrolidines and
isoxazolidines, respectively. As opposed to the generally employed
oxidation of furans with mCPBA leading to
a,b-unsaturated-1,4-
diones, we harnessed the further reaction with mCPBA to provide
an epoxide intermediate which underwent nucleophilic opening
with amino groups to diastereoselectively give polyfunctionalized
pyrrolidine and isoxazolidine heterocycles. This work represents
the first example in which furan based hydroxylamine derivatives
have been used for the synthesis of structurally complex heterocy-
cles. We believe that these discoveries will find application in the
syntheses of polysubstituted pyrrolidine and isoxazolidine motifs.
Further work on the oxidation of furan derivatives to provide
access to other interesting structures will be reported in due
course.
Acknowledgments
This work was supported by TUBITAK (TBAG-107T838). We
would like to thank B. Altundas (Miami University, USA) for critical
reading of the manuscript and G. Bilsel (UME-TUBITAK) for
(HRMS).
After developing a successful method for the diastereoselective
synthesis of polysubstituted pyrrolidine 17 via the oxidation of
aminoalkylfuran 8, we next explored the oxidation of furans bear-
ing a hydroxylamine group on the alkyl chain. Starting materials
(19, 20) were prepared in excellent yields by the addition of 2-
methylfuryl lithium to the corresponding aldehyde, followed by a
Mitsunobu reaction using PPh3, DEAD and N-hydroxyphthalimide.
Subsequent treatments of the corresponding intermediates with
hydrazine monohydrate provided O-alkylhydroxylamines (23, 24)
which were subjected to Boc protection (Scheme 6).
With 25 and 26 in hand, we began by exploring whether
photooxygenation or mCPBA were the most suitable experimental
conditions. Photooxygenation of 25 using either RB or TPP for
30 min at 0 °C, and subsequent treatment with excess Me2S gave
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
105.
References and notes
1. (a) Rosset, I. G.; Dias, R. M. P.; Pinho, V. D.; Burtoloso, A. C. B. J. Org. Chem. 2014,
79, 6748; (b) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68,
1556; (c) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435; (d) Leclercq, S.; Braekman, J.
C.; Daloze, D.; Pasteels, J. M. Prog. Chem. Org. Nat. Prod. 2000, 79, 115.
2. (a) Davis, F. A.; Xu, H.; Wu, Y.; Zhang, J. Org. Lett. 2006, 8, 2273; (b) Zhou, X.; Liu,
W.-J.; Ye, J.-L.; Huang, P.-Q. J. Org. Chem. 2007, 72, 8904; (c) Murruzzu, C.; Riera,
A. Tetrahedron Asymmetry 2007, 18, 149; (d) Asano, N.; Ikeda, K.; Kasahara, M.;
Arai, Y.; Kizu, H. J. Nat. Prod. 2004, 67, 846; (e) Donohoe, T. J.; Headley, C. E.;
Cousins, R. P. C.; Cowley, A. Org. Lett. 2003, 5, 999.
a,b-unsaturated-1,4-dicarbonyl 28. The crude mixture was then
stirred in CH2Cl2 for 6 d to afford 29 as an inseparable 4:1 mixture
of diastereomers (Scheme 4). We then turned our attention to the
3. (a) Davis, F. A.; Zhang, J.; Qiu, H.; Wu, Y. Org. Lett. 2008, 10, 1433; (b)
Frederickson, M. Tetrahedron 1997, 53, 403.
Please cite this article in press as: Kazancioglu, M. Z.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.105

4
M. Z. Kazancioglu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
4. (a) Han, M.-Y.; Jia, J.-Y.; Wang, W. Tetrahedron Lett. 2014, 55, 784; (b) Minter, A.
8. Graziano, M. L.; Lesce, M. R.; Scarpati, R. J. Chem. Soc. Perkin 1955, I, 1980.
9. (a) Iesce, M. R.; Cermola, F.; De Lorenzo, F.; Orabona, I.; Graziano, M. L. J. Org.
Chem. 2001, 66, 4732; (b) Gollnick, K.; Griesbeck, A. Tetrahedron 1985, 41, 2057;
(c) Patil, S. N.; Stephens, B. E.; Liu, F. Tetrahedron 2008, 64, 10831; (d) Haukaas,
M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 3899; (e) Kouridaki, A.; Montagnon, T.;
Tofi, M.; Vassilikogiannakis, G. Org. Lett. 2012, 14, 2374; (f) Noutsias, D.;
Kouridaki, A.; Vassilikogiannakis, G. Org. Lett. 2011, 13, 1166; (g) Tofi, M.;
Koltsida, K.; Vassilikogiannakis, G. Org. Lett. 2009, 11, 313; (h) Pavlakos, E.;
Georgiou, T.; Tofi, M.; Montagnon, T.; Vassilikogiannakis, G. Org. Lett. 2009, 11,
4556; (i) Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc. Chem. Res. 2008,
1001, 41; (k) Zhu, L. Z.; Talukdar, A.; Zhang, G. S.; Kedenburg, J. P.; Wang, P. G.
Synlett 2005, 1547; (l) Teijeira, M.; Suárez, P. L.; Gómez, G.; Terán, C.; Fall, Y.
Tetrahedron Lett. 2005, 46, 5889; (m) Burke, M. D.; Berger, E. M.; Schreiber, S. L.
J. Am. Chem. Soc. 2004, 126, 14095; (n) Harris, J. M.; Keränen, M. D.; Nguyen, H.;
Young, V. G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17; (o) Abrams, J. N.;
Babu, R. S.; Guo, H.; Le, D.; Le, J.; Osbourn, J. M.; O’Doherty, G. A. J. Org. Chem.
1935, 2008, 73; (p) Montagnon, T.; Noutsias, D.; Alexopoulou, I.; Tofi, M.;
Vassilikogiannakis, G. Org. Biomol. Chem. 2011, 9, 2031; (r) 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, 2018, 16.
R.; Brennan, B. B.; Mapp, A. K. J. Am. Chem. Soc. 2004, 126, 10504; Palmer, G. C.;
Ordy, M. J.; Simmons, R. D.; Strand, J. C.; Radov, L. A.; Mullen, G. B.; Kinsolving,
C. R.; Georgiev, V. St.; Mitchell, J. T.; Allen, S. D. Antimicrob. Agents Chemother.
1989, 33, 895; (d) Burton, G.; Clarke, G. J.; Douglas, J. D.; Eglington, A. J.;
Frydrych, C. H.; Hinks, J. D.; Hird, N. W.; Hunt, E.; Moss, S. F.; Naylor, A.;
Nicholson, N. H.; Pearson, M. J. J. Antibiot. 1996, 49, 1266; (e) Rescifina, A.;
Chiacchio, M. A.; Corsaro, A.; De Clercq, E.; Iannazzo, D.; Mastino, A.; Piperno,
A.; Romeo, G.; Romeo, R.; Valveri, V. J. Med. Chem. 2006, 49, 709.
5. (a) Bates, R. W.; Sa-Ei, K. Org. Lett. 2002, 4, 4225; (b) Peng, J.; Lin, W.; Yuan, S.;
Chen, Y. J. Org. Chem. 2007, 72, 3145; (c) Lemen, G. S.; Giampietro, N. C.; Hay, M.
B.; Wolfe, J. P. J. Org. Chem. 2009, 74, 2533.
6. (a) Kobayashi, Y.; Matsuumi, M. J. Org. Chem. 2000, 65, 7221; (b) Kobayashi, Y.;
Kumar, G. B.; Kurachi, T.; Acharya, H. P.; Yamazaki, T.; Kitazume, T. J. Org. Chem.
2011, 2001, 66; (c) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J. Org.
Chem. 1998, 63, 7505; (d) Wu, B.; Feast, G. C.; Thompson, A. L.; Robertson, J. J.
Org. Chem. 2012, 77, 10623; (e) Cermola, F.; Iesce, M. R.; Buonerba, G. J. Org.
Chem. 2005, 70, 6503; (f) Kim, G.; Jung, S.-D.; Lee, E.-J.; Kim, N. J. Org. Chem.
2003, 68, 5395; (g) Hjelmgaard, T.; Persson, T.; Rasmussen, T. B.; Givskov, M.;
Nielsen, J. Bioorg. Med. Chem. 2003, 11, 3261; (h) Gómez, G.; Rivera, H.; García,
I.; Estévez, L.; Fall, Y. Tetrahedron Lett. 2005, 46, 5819.
7. (a) Kobayashi, Y.; Katsuno, H.; Sato, F. Chem. Lett. 1993, 1771; (b) Piancatelli, G.;
Scettri, A.; D’Auria, M. Tetrahedron 1980, 36, 661; (c) Clive, D. L. J.; Ou, L. J. Org.
Chem. 2005, 70, 3318; (d) Ngooi, T. K.; Scilimati, A.; Guo, Z. W.; Sih, J. C. J. Org.
Chem. 1989, 54, 911; (d) Couladouros, E. A.; Georgiadis, M. P. J. Org. Chem. 1986,
51, 2725.
10. (a) Cassidy, M. P.; Padwa, A. Org. Lett. 2004, 6, 4029; (b) Leverett, C. A.; Cassidy,
M. P.; Padwa, A. J. Org. Chem. 2006, 71, 8591; (c) Haukaas, M. H.; O’Doherty, G.
A. Org. Lett. 2001, 3, 401.
Please cite this article in press as: Kazancioglu, M. Z.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.105