Tandem ring-opening/closing reactions of N-Ts aziridines and aryl propargyl alcohols promoted by T-BuOK

Article abstract of DOI:10.1021/ol802862p

T-BuOK was found to be an effective promoting reagent for tandem ring-opening/closing reactions of various N-Ts aziridines and aryl propargyl alcohols to afford dihydroxazine derivatives in moderate to good yields. A plausible reaction mechanism has been

Full text of DOI:10.1021/ol802862p

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1119-1122
Tandem Ring-Opening/Closing
Reactions of N-Ts Aziridines and Aryl
Propargyl Alcohols Promoted by t-BuOK
Liang Wang,†,‡ Qi-Bin Liu,† Duo-Sheng Wang,† Xin Li,† Xiu-Wen Han,†
Wen-Jing Xiao,*,‡ and Yong-Gui Zhou*,†
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China, and Key
Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal UniVersity, 152 Luoyu Road,
Wuhan, Hubei 430079, China
ygzhou@dicp.ac.cn; wxiao@mail.ccnu.edu.cn
Received December 11, 2008
ABSTRACT
t-BuOK was found to be an effective promoting reagent for tandem ring-opening/closing reactions of various N-Ts aziridines and aryl propargyl
alcohols to afford dihydroxazine derivatives in moderate to good yields. A plausible reaction mechanism has been proposed.
Aziridines were recognized as versatile building blocks and
widely applied in the synthesis of natural products and
medicinal reagents.1 Hitherto many excellent examples about
using aziridines for the construction of functionalized acyclic
molecules by ring-opening reactions have been reported.2
Due to ring constrain aziridines readily undergo ring-opening
reactions with nucleophiles to form amines.3 In the past
decades, tandem reactions of designed precursors brought
great attention to the construction of complicated com-
pounds.4 Owing to the advantages of greatly enhancing
synthetic efficiency, forming two or more bonds in one pot,
and avoiding the purification procedures of intermediates,
the tandem reaction played a very important role in modern
organic synthetic chemistry.5 Thus, the exploration of tandem
reactions of easily available aziridines was highly desirable.
† Dalian Institute of Chemical Physics.
(3) For selected examples, see: (a) Heinrich, M. R.; Martin, I. P.; Zard,
S. Z. Chem. Commun. 2005, 5928. (b) Sureshkumar, D.; Gunasundari, T.;
Saravanan, V.; Chandrasekaran, S. Tetrahedron Lett. 2007, 48, 623. (c)
Kim, Y.; Ha, H.-J.; Han, K.; Ko, S. W.; Yun, H.; Yoon, J. H.; Min, S. K.;
Lee, W. K. Tetrahedron Lett. 2005, 46, 4407. (d) Hou, X.-L.; Fan, R.-H.;
Dai, L.-X. J. Org. Chem. 2002, 67, 5295. (e) Sureshkumar, D.; Koutha,
S. M.; Chandrasekaran, S. J. Am. Chem. Soc. 2005, 127, 12760. (f) Han,
H.; Base, I.; Yoo, E. J.; Lee, J.; Do, Y.; Chang, S. Org. Lett. 2004, 6,
4109. (g) Wu, J.; Sun, X.; Xia, H.-G. Eur. J. Org. Chem. 2005, 4769. (h)
Wu, J.; Sun, X.; Li, Y. Eur. J. Org. Chem. 2005, 4271.
‡ Central China Normal University.
(1) For the recent reviews, see: (a) Pearson, W. H.; Lian, B. W.;
Bergmeier, S. C. Aziridines and Azirines: Monocyclic. In ComprehensiVe
Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon Press: Oxford, UK,
1996; Vol. 1A, p 1. (b) Tanner, D. Angew. Chem., Int. Ed. 1994, 33, 599.
(c) Ibuka, T. Chem. Soc. ReV. 1998, 27, 145. (d) Hu, X. E. Tetrahedron
2004, 60, 2701. (e) Rayner, C. M. Synlett 1997, 11. (f) McCoull, W.; Davis,
F. A. Synthesis 2000, 1347. (g) Sweeney, J. B. Chem. Soc. ReV. 2002, 31,
247. (h) Kasai, M.; Kono, M. Synlett 1992, 778. (i) Watson, I. D. G.; Yu,
L.; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194. (j) Hou, X. L.; Wu, J.;
Fan, R. H.; Ding, C. H.; Luo, Z. B.; Dai, L. X. Synlett 2006, 181.
(2) For selected recent examples, see:(a) Sun, X.; Ye, S. Q.; Wu, J.
Eur. J. Org. Chem. 2006, 4787. (b) Savoia, D.; Alvaro, G.; Fabio, R. D.;
Gualandi, A. J. Org. Chem. 2007, 72, 3859. (c) Li, P.; Forbeck, E. M.;
Evans, C. D.; Joullie´, M. M. Org. Lett. 2006, 8, 5105. (d) Diao, T.; Sun,
X.; Fan, R.; Wu, J. Chem. Lett. 2007, 36, 604. (e) Siebert, M. R.; Yudin,
A. K.; Tantillo, D. J. Org. Lett. 2008, 10, 57. (f) Wu, J.; Sun, X.; Sun, W.
Org. Biomol. Chem. 2006, 4, 4231. (g) Liu, H.; Pattabiraman, V. R.;
Vederas, J. C. Org. Lett. 2007, 9, 4211.
(4) For reviews, see:(a) Meijere, A. D.; Zezschwitz, P. V.; Bra¨se, S.
Acc. Chem. Res. 2005, 38, 413. (b) Hussain, M. M.; Walsh, P. J. Acc. Chem.
Res. 2008, 41, 883. (c) Sun, X. L.; Tang, Y. Acc. Chem. Res. 2008, 41,
937. (d) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed. 2004, 43, 3754.
(e) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354. (f) Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134. (g) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
2007, 46, 1570. (h) Wasike, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C.
Chem. ReV. 2005, 105, 1001. (i) Bur, S. K.; Padwa, A. Tetrahedron 2007,
63, 5341.
10.1021/ol802862p CCC: $40.75
Published on Web 02/03/2009
2009 American Chemical Society

In this letter, a novel tandem ring-opening/closing reaction
of azridines and arylpropargyl alcohols promoted by t-BuOK
is reported.
of temperature and bases on the reactivity and yield, chiral
aziridine 1a and phenyl propargyl alcohol 2a were chosen
as model substrates. The reaction could proceed smoothly
to afford 3a with 62% yield in the presence of 150 mol %
of t-BuOK in DMSO at 60 °C (Table 1, entry 3). However,
by increasing the reaction temperature to 80 °C, the yield
decreased from 62% to 30% (Table 1, entry 4). By decreasing
the reaction temperature from 60 to 40 °C, the yield was
slightly improved from 62% to 69% (Table 1, entry 2), while
low yield was obtained when the reaction was performed at
20 °C. Accordingly, 40 °C was selected as the optimal
reaction temperature for further examinations. Subsequently,
we examined the effect of various bases (Table 1, entries 2
and 5-7) in DMSO at 40 °C and found that the base had
significant influence on the reaction. The application of
t-BuONa to the reaction afforded 3a with slightly lower yield
(Table 1, entry 5 vs 2). Compared with t-BuOK, MeONa
afforded the product with only 43% yield. With the utilization
of organic base DABCO, no expected product was detected
(Table 1, entry 7). The reaction medium was also investi-
gated, and it was found that only DMSO gave good results.
With the optimal reaction conditions established, the scope
of these tandem ring-opening/closing reactions was then
studied. As revealed in Table 2, a wide range of aryl
propargyl alcohols were suitable for this transformation in
moderate to good yields regardless of electronic and steric
effects (Table 2, entries 1-6, 10, and 11). Propargyl alcohols
containing an electron-donating group on the benzene ring
(e.g., methyl at the meta position) gave 64% yield (Table 2,
entry 4). Replacement of the methyl group by the strong
electron-withdrawing trifluoromethyl at the meta position of
phenyl also afforded the corresponding product in 78% yield
(Table 2, entry 2). Other fused and heteroaromatic systems,
such as naphthyl and thiophen-2-yl-substituted propargylic
Table 1. Optimization of Reaction Conditionsa
entry
base
temp (°C)
yield (%)b
1
2
3
4
5
6
7
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
MeONa
DABCO
20
40
60
80
40
40
40
29
69
62
30
61
43
0
a Reaction conditions: 1a (0.55 mmol), 2a (0.5 mmol), base (1.5 equiv).
b Isolated yield based on 2a.
Recently, in the course of our research on the synthesis
of new functionalized olefins and asymmetric hydrogena-
tions, we needed the ring-opening product of N-Ts aziridine
1a with phenyl propargyl alcohol 2a.6 The studies com-
menced with the ring-opening reaction of N-Ts aziridine 1a
with phenyl propargyl alcohol 2a mediated by t-BuOK in
DMSO at 60 °C. Surprisingly, a new cyclic dihydroxazine
3a was obtained, instead of the expected simple ring-opening
product, via a tandem ring-opening/closing sequence. The
structure of compound 3a was assigned by 1H and 13C NMR,
DEPT, COSY, HMBC, and mass spectrocopy analysis (see
the Supporting Information), and further unambiguously
verified by X-ray diffraction of its analogue 3i (Figure 1).
This discovery represents a new method for the construction
of six-membered dihydroxazine derivatives.
Table 2. Reaction of N-Ts Aziridines 1 and Aryl Propargyl
Alcohols 2 Promoted by t-BuOK at 40 °Ca
entry
R1
R2
Ar
product
yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Me
i-Bu
Bn
Me
H
H
H
H
H
H
H
H
H
H
H
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
69
78
66
64
74
70
65
73
22
70
64
54
49
3-CF3C6H4
1-naphthyl
3-CH3C6H4
4-BrC6H4
thiophen-2-yl
Ph
Ph
Ph
3-CF3C6H4
3-CF3C6H4
Ph
3j
3k
3l
i-Bu
-(CH2)4-
H
Figure 1. X-ray structure of compound 3i.
H
1-naphthyl
3m
a Reaction conditions: 1 (0.55 mmol), 2 (0.5 mmol), t-BuOK (1.5 equiv).
b Isolated yield based on 2.
With this unexpected result in hand, optimization of the
reaction conditions was carried out. To evaluate the effect
1120
Org. Lett., Vol. 11, No. 5, 2009

alcohols (Table 2, entries 3 and 6), could be employed in
this reaction, and the corresponding products 3c and 3f were
obtained in 66% and 70% yields, respectively.
compound 8, as a precursor for the formation of intermediate
6 under the reaction condition, was synthesized by Cu-
catalyzed cyclization of compound 7, and then subjected
8
A broad range of chiral monosubstituted aziridines includ-
ing methyl, isopropyl, isobutyl, and benzyl (Table 2, entries
1 and 7-9) were investigated. Both methyl and isobutyl
aziridines worked well in the tandem process, gaving 65%
and 73% yield, respectively (Table 2, entries 7 and 8).
However, the reaction of benzyl-substituted aziridine gave
a lower yield probably because of its steric hindrance (Table
2, entry 9). Note that both the disubstituted and unsubstituted
aziridines were well tolerated (Table 2, entries 12 and 13).
to reaction under the same condition. However, no isomer-
ization occurs even with extended reaction time with 8 being
recovered quantitatively (eq 2). Therefore, path B could be
ruled out as a possible route.
To confirm the existence of intermediate 5, compound 7
and 150 mol % of t-BuOK were mixed in DMSO at 25 °C.
During the course of the reaction, the allene intermediate
5a could be detected by TLC. However, the isolation of
unstable 5a in its pure form was unsucessful. Alternatively,
we carried out the reaction (shown in eq 1) in d6-DMSO,
1
and the reaction was monitored by H NMR. As shown in
Figure 2, the changes in the 1H NMR spectra of intermediate
7 could be observed during the reaction process. The Ha and
Hb signals of 7 gradually weakened and completely disap-
peared after 90 min at 25 °C. Two new signals9 (δ 6.95 and
7.03), which were assigned as the character signals of allene,
were obsevered clearly. So, according to the above experi-
ments, path A should be the possible reaction route.
Scheme 1. Proposed Mechanism
On the basis of the above results, a possible mechanism
was proposed (Scheme 1). The aryl propargyl alcohol was
deprotonated by t-BuOK first to form the oxygen nucleophile,
which then attacked the N-Ts aziridine to generate a new
nucleophilic intermediate 4. To demonstrate this process,
compound 7, a neutral form of intermediate 4, was prepared
by a two-step procedure. 7 The reaction of 7 in the presence
of t-BuOK in DMSO at 40 °C did give the expected product
3a in 90% isolated yield (eq 1).
Figure 2.
Changes in 1H NMR spectra of compound 7 in d6-DMSO,
detection of allene intermediate.
The synthetic utility of this methodology was demonstrated
in a highly efficient route to morpholine derivatives by an
ionic hydrogenation, which was the important structural motif
of diverse pharmacologically active compounds (Table 3,
entries 1-5).10 To our surprise, for isopropyl-substituted
(5) For selected recent examples, see: (a) Ye, L.-W.; Sun, X.-L.; Wang,
Q.-G.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 5951. (b) Chen, J.-R.;
Li, C.-F.; An, X.-L.; Zhang, J.-J.; Zhu, X.-Y; Xiao, W.-J. Angew. Chem.,
Int. Ed. 2008, 47, 2489. (c) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc.
2006, 128, 3928. (d) Zu, L.; Wang, J.; Li, H.; Xie, H.; Jiang, W.; Wang,
W. J. Am. Chem. Soc. 2007, 129, 1036. (e) Shi, F.-Q.; Li, Xin.; Xia, Y.;
Zhang, L.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 15503. (f) Wang, Q.-
G.; Deng, X.-M.; Zhu, B.-H.; Ye, L.-W.; Sun, X.-L.; Li, C.-Y.; Zhu, C.-
Y.; Shen, Q.; Tang, Y. J. Am. Chem. Soc. 2008, 130, 5408. (g) Fan, R.;
Wang, W.; Pu, D.; Wu, J. J. Org. Chem. 2007, 72, 5905. (h) Enders, D.;
Hu¨ttl, M. R. M.; Grondal, C.; Rabbe, G. Nature 2006, 441, 861. (i) Ye,
L.-W.; Sun, X.-L.; Zhu, C.-Y.; Tang, Y. Org. Lett. 2006, 8, 3853. (j) Gao,
K.; Wu, J. Org. Lett. 2008, 10, 2251.
Afterward, there could be two pathways to form the target
molecule. Through path A, the intermediate 4 underwent the
isomerization of the triple bond to form the allene species
5. The intramolecular nucleophilic attack therefore forms the
product 3. Alternatively, path B involves the intermediate
6, which could be obtained via 6-exo-cyclization of 4.
Subsequent double bond isomerization results in the forma-
tion of product 3. To differentiate the two pathways,
Org. Lett., Vol. 11, No. 5, 2009
1121

4 and 5). The absolute configuration of product 9a was
confirmed by COSY, HMBC, and NOSY analysis (see the
Supporting Information). Noteworthy, the tosyl group of
morpholine derivatives 9a could be readily removed and
converted to chiral 3,5-disubstituted morpholine 10 in 65%
yield (Scheme 2).
Table 3. Synthesis of 3,5-Disubstituted Morpholine Derivatives
by Ionic Hydrogenation of 3a
Scheme 2. Deprotection of the Tosyl Group in 9a
In conclusion, an efficient and unprecedented route to
dihydroxazine derivatives via tandem ring-opening/closing
reactions of N-Ts aziridines with aryl proparglic alcohols
has been developed. This strategy offers a concise platform
for the construction of six-membered ring systems under mild
conditions with high atom economy. A plausible reaction
mechanism has been proposed to elucidate this novel tandem
process. Further investigation on the range of the current
reaction is in progress.
Acknowledgment. Financial support from National Natu-
ral Science Foundation of China (20621063 and 20672112)
and Dalian Institute of Chemical Physics (K2007F1), Chinese
Academy of Sciences.
a Reaction conditions: 3 (0.25 mmol), TFA (trifluoroacetic acid 1 mL),
Et3SiH (3.0 equiv), 50 °C. b Determined by 1H NMR. c Isolated yield based
on the 3.
Supporting Information Available: Experimental pro-
cedures and characterization data including X-ray diffraction
analysis data of compound 3i and full spectroscopic data for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
dihydroxazines, only cis morpholine derivatives were ob-
served in the hydrogenation by TFA/Et3SiH at 50 °C (Table
3 entries 1-3). However, for the methyl- and isobutyl-
substituted dihydroxazines, a diastereomeric mixture of the
desired morpholine derivatives was obtained (Table 3 entries
OL802862P
(10) For a review see: (a) Wijtmans, R.; Vink, M. K. S.; Schoemaker,
H. E.; van Delft, F. L. V.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis
2004, 641. For recent examples, see: (b) Yar, M; Mcgarrigle, E. M.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2008, 47, 3784. (c) Breuning, M.;
Winnacker, M.; Steiner, M. Eur. J. Org. Chem. 2007, 2100. (d) Dhooghe,
M.; Vanlangendonck, T.; To¨mroos, K. W.; Kimpe, N. D. J. Org. Chem.
2006, 71, 4678. (e) Pedrosa, R.; Andre´s, C.; Mendiguch´ıa, P.; Niero, J. J.
Org. Chem. 2006, 71, 8854. (f) Henegar, K. E. J. Org. Chem. 2008, 73,
3662. (g) Lanman, B. A.; Myers, A. G. Org. Lett. 2004, 6, 1054. (h)
Leijondahl, K.; Bore´n, L.; Braun, R.; Ba¨ckvall, J.-E. Org. Lett. 2008, 10,
2027. (i) Sladojevich, F.; Trabocchi, A.; Guarna, A. Org. Biomol. Chem.
2008, 6, 3328. (j) Zhang, P.; Cedilote, M.; Cleary, T. P.; Pierce, M. E.
Tetrahedron Lett. 2007, 48, 8659.
(6) (a) Zhou, Y.-G.; Yang, P.-Y.; Han, X.-W. J. Org. Chem. 2005, 70,
1679. (b) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357. (c) Wang, W.-B.;
Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003,
125, 10536. (d) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew.
Chem., Int. Ed. 2006, 45, 2260.
(7) See the Supporting Information.
(8) Kundu, N. G.; Chaudhuri, G.; Upadhyay, A. J. Org. Chem. 2001,
66, 20. See the Supporting Information.
(9) (a) Tius, M. A.; Hu, H.; Kawakami, J. K.; Petersen, J. B. J. Org.
Chem. 1998, 63, 5971. (b) Hu, H.; Smith, D.; Cramer, R. E.; Tius, M. A.
J. Am. Chem. Soc. 1999, 121, 9895.
1122
Org. Lett., Vol. 11, No. 5, 2009