Formation of functionalized 2H-azirines through phio-mediated trifluoroethoxylation and azirination of enamines

Article abstract of DOI:10.1021/ol4030716

A variety of enaminones and enamine carboxylic esters were converted to trifluoroethoxylated 2H-azirines through reactions with PhIO in trifluoroethanol (TFE). The cascade reaction is postulated to proceed via a PhIO-mediated oxidative trifluoroethoxylation and a subsequent azirination of the α-trifluoroethoxylated enamine intermediates.

Full text of DOI:10.1021/ol4030716

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Formation of Functionalized 2H‑Azirines
through PhIO-Mediated Trifluoroethoxylation
and Azirination of Enamines
Xiaoqian Sun,† Youran Lyu,† Daisy Zhang-Negrerie,† Yunfei Du,*,‡,† and Kang Zhao*,†
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of
Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China, and
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin
300072, China
duyunfeier@tju.edu.cn; kangzhao@tju.edu.cn
Received October 24, 2013
ABSTRACT
A variety of enaminones and enamine carboxylic esters were converted to trifluoroethoxylated 2H-azirines through reactions with PhIO in
trifluoroethanol (TFE). The cascade reaction is postulated to proceed via a PhIO-mediated oxidative trifluoroethoxylation and a subsequent
azirination of the R-trifluoroethoxylated enamine intermediates.
2H-Azirines, the smallest unsaturated nitrogen heterocycles,1
represent a highly valuable class of compounds found in
several natural products. For example, azirinomycin,2 iso-
lated from Streptomyces aureus, wasfoundtoexhibitabroad
range of antibiotic activities in vitro against both gram-po-
sitive and gram-negative bacteria.3 Other azirine-containing
natural products include (R)-(ꢀ)- and (S)-(þ)-dysidazirine
and (S)-(þ)-antazirine, isolated from dysidea fragilis.4
predominant strategiesadoptedfor the construction of this
interesting class of compounds include the classic Neber
rearrangement of proper imine substrates,6 azirination of
vinyl azides,7 elimination or oxidation of aziridines,8 ring
contraction of isoxazoles,9 oxazaphosphole derivatives,10
and coupling reactions between nitriles and carbenes11 or
(5) For selected examples, see: (a) Wendling, L. A.; Bergman, R. G.
J. Org. Chem. 1976, 41, 831–836. (b) Claus, P.; Doppler, T.; Gakis, N.;
Georgarakis, M.; Giezendanner, H.; Gilgen, P.; Helmgartner, H.;
Jackson, B.; Marky, M.; Narasimhan, N. S.; Rosenkranz, H. J.;
Wunderli, A.; Hansen, H. J.; Schmid, H. Pure Appl. Chem. 1973, 33, 339–
362. (c) Pinho e Melo, T. M. V. D.; Rocha Gonsalves, A. M. d’A. Curr. Org.
Synth. 2004,1, 275–292. (d) Pinho e Melo, T. M. V. D.; Lopes, C. S. J.; Rocha
Gonsalves, A. M. d’A.; Storr, R. C. Synthesis 2002, 605–608.
In addition, the characteristic high ring strain of this
particular functional group has rendered 2H-azirines
widely applicable in the synthesis of substituted allenes,
alkynes, heterocycles, and other important synthetic
intermediates.5 A survey of the literature reveals that the
(6) (a) Neber, P. W.; Huh, G. Justus Liebigs Ann. Chem. 1935, 283–
296. (b) Neber, P. W.; Burgard, A. Justus Liebigs Ann. Chem. 1932, 281–
294. (c) LaMattina, J. L. J. Heterocycl. Chem. 1983, 20, 533–538. (d)
Cram, D. J.; Hatch, M. J. J. Am. Chem. Soc. 1953, 75, 33–38. (e) Eguchi,
S.; Ishii, Y. Bull. Chem. Soc. Jpn. 1963, 36, 1434–1437. (f) Chaabouni, R.;
Laurent, A. Synthesis 1975, 464–467. (g) Sato, S. Bull. Chem. Soc. Jpn.
1968, 41, 1440–1444.
† Tianjin University.
‡ Collaborative Innovation Center of Chemical Science and Engineering.
(1) For selected examples, see: (a) Zhu, Z.; Wei, Y.; Shi, M. Chem.
Soc. Rev. 2011, 40, 5534–5563. (b) Pinho e Melo, T. M. V. D.; Lopes,
C. S. J.; Cardoso, A. L.; Rocha Gonsalves, A. M. d’A. Tetrahedron 2001,
57, 6203–6208. (c) Padwa, A.; Dharan, M.; Smolanoff, J.; Wetmore,
S. L., Jr. Pure Appl. Chem. 1973, 33, 269–284. (d) Skepper, C. K.;
Molinski, T. F. J. Org. Chem. 2008, 73, 2592–597.
(2) Miller, T. W.; Tristram, E. W.; Wolf, F. J. J. Antibiot. 1971, 24,
48–50.
€
(7) (a) Njar, V. C. O.; Duerkop, J.; Hartmann, R. W. Steroids 1996,
61, 138–143. (b) Hassner, A.; Alexanian, V. J. Org. Chem. 1979, 44,
3861–3864. (c) Smolinsky, G. J. Org. Chem. 1962, 27, 3557–3559. (d)
Smolinsky, G. J. Am. Chem. Soc. 1961, 83, 4483–4484. (e) Brown, D.;
Brown, G. A.; Andrews, M.; Large, J. M.; Urban, D.; Butts, C. P.; Hales,
N. J.; Gallagher, T. J. Chem. Soc., Perkin Trans 1 2002, 2014–2021. (f)
Hassner, A.; Fowler, F. W. J. Org. Chem. 1968, 33, 2686–2691. (g) Pinho
e Melo, T. M. V. D.; Lopes, C. S. J.; Cardoso, A. L.; Rocha Gonsalves,
M. d. A. Tetrahedron 2001, 57, 6203–6208. (h) Hortmann, A. G.;
Robertson, D. A.; Gillard, B. K. J. Org. Chem. 1972, 37, 322–324.
(3) Stapley, E. O.; Hendlin, D.; Jackson, M.; Miller, A. J. J. Antibiot.
1971, 24, 42–47.
(4) (a) Molinski, T. F.; Ireland, C. M. J. Org. Chem. 1988, 53, 2103–
2105. (b) Salomon, C. E.; Williams, D. H.; Faulkner, D. J. J. Nat. Prod.
1995, 58, 1463–1466.
r
10.1021/ol4030716
XXXX American Chemical Society

Table 1. Optimization of Reaction Conditionsa
Scheme 1. Formation of 2H-Azirines via I(III)-Mediated
Oxidative Azirination of Enamines
temp
time
entry
oxidant
(°C)
(min)
additive
none
yieldb
1
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PIDA
PIFA
IBX
25
0
30
60%c
50%c
77%
30%d
66%
ND
2
60
none
3
4
25
25
25
25
25
25
25
25
30
30
none
none
5
45
NaOAce
6
30
BF3 Et2Oe
3
7
20
none
none
none
none
35%
ND
8
10
9
180
180
NR
10
DMP
NR
Scheme 2. Discovery of the Formation of Trifluoroethoxylated
2H-Azirines
a Reaction conditions: all reactions were carried out by mixing the
oxidant (2.1 mmol) in TFE (5 mL) at rt for 15 min and then adding 1a
(1 mmol in 5 mL of TFE) dropwise at rt unless otherwise stated. b Isolated
yields. c PhIO (2.1 mmol) was added to a solution of 1a in TFE (10 mL) in
one portion. d The reaction was conducted in the presence of 2 equiv of TFE
in DCM (5 mL). e 2 equiv of additive was used.
by reacting with carboxylic acids in the presence of iodoso-
benzene (PhIO) and give β-acyloxy enamines D (Scheme 2,
eq 1).14 Inspired by the results of this work, we set out to see if
a parallel reaction would take place between enamine 1a and
an alcohol compound which could result in the C(sp2)ꢀO
bond formation via the expected intermolecular oxidative
coupling reaction. To our delight, the test result was positive
such that the reaction of enamine 1a (1 mmol) with trifluor-
oethanol as the solvent provided β-trifluoroethoxylated
2H-azirine compound 2a, in a good yield of 81% (brsm)
(Scheme 2, eq 2). It is obvious that the reaction sequence
involves not only the C(sp2)ꢀO bond formation but also a
subsequent intramolecular azirination process. Undoubt-
edly, this new finding led us to the establishing of a new
protocol for accessing functionalized 2H-azirines, namely,
from R-unsubstituted enaminones through a cascade reac-
tion involving oxidative trifluoroethoxylation ensued by the
intramolecular azirination of the generated R-trifluoroetho-
xylated enamine intermediate.
Enaminone 1awas used asthe model substrate in further
screening tests in search of the optimal conditions for this
newly discovered tandem reaction. Results show that the
addition of PhIO to a solution of enaminone 1a in TFE
(0.1 M) in a one-portion manner at room temperature
afforded 2a in 60% yield, while the same reaction con-
ductedat0 °C becamerelativelysluggish and the yield of 2a
was decreased by over 15%. On the other hand, a satisfac-
tory yield of 77% was obtained when enaminone 1a was
added to a solution of PhIO in TFE (0.1 M), premixed and
between nitrenes and acetylenes.12 In 2009, we reported
that various enamine compounds A could be oxidized by a
hypervalent iodine reagent, i.e., phenyliodine(III) diace-
tate, into a series of 2-functionalized 2H-azirine derivatives
B via direct intramolecular azirination (Scheme 1a).13 This
method is in general well suitable for the synthesis of
R-substituted enamine compounds. In this communica-
tion, we report a similar type of reactions where a series of
R-unsubstituted enamine compounds 1 are directly con-
verted to trifluoroethoxylated 2H-azirines 2 by reacting
with PhIO in trifluoroethanol (TFE) as solvent, a process
involving an intermolecular oxidative CꢀO bond forma-
tion followed by a subsequent intramolecular oxidative
azirination (Scheme 1b).
Quite recently, we reported that the R-unsubstituted en-
aminone compounds Ccould undergo direct β-acyloxylation
(8) (a) Davis, F. A.; Liang, C. H.; Liu, H. J. Org. Chem. 1997, 62,
3796–3797. (b) Davis, F. A.; Reddy, G. V.; Liu, H. J. Am. Chem. Soc.
1995, 117, 3651–3652. (c) Legters, J.; Thijs, L.; Zwanenburg, B. Recl.
Trav. Chim. 1992, 111, 75–78. (d) Gentilucci, L.; Grijzen, Y.; Thijs, L.;
Zwanenburg, B. Tetrahedron Lett. 1995, 36, 4665–4668.
(9) Auricchio, S.; Bini, A.; Pastormerlo, E.; Truscello, A. M. Tetra-
hedron 1997, 53, 10911–10920.
(10) (a) Sauers, R. R.; Hadel, L. M.; Scimone, A. A.; Stevenson, T. A.
J. Org. Chem. 1990, 55, 4011–4019. (b) Lipshutz, B. H.; Reuter, D. C.
Tetrahedron Lett. 1988, 29, 6067–6070. (c) Wentrup, C.; Fisher, S.;
€
Berstermann, H. M.; Kuzaj, M.; Luerssen, H.; Burger, K. Angew.
Chem., Int. Ed. Engl. 1986, 25, 85–86.
(11) (a) Alcaraz, G.; Wecker, U.; Baceiredo, A.; Dahan, F.; Bertrand,
G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1246–1248. (b) Moerdyk, J. P.;
Bielawski, C. W. J. Am. Chem. Soc. 2012, 134, 6116–6119.
(12) Andersson, D. J.; Gilchrist, T. L.; Gymer, G. E.; Rees, C. W.
J. Chem. Soc., Perkin Trans. 1 1973, 550–555.
(13) Li, X.; Du, Y.; Liang, Z.; Li, X..; Pan, Y.; Zhao, K. Org. Lett.
2009, 11, 2643–2646.
(14) Liu, X.; Cheng, R.; Zhao, F.; Zhang-Negrerie, D.; Du, Y.; Zhao,
K. Org. Lett. 2012, 14, 5480–5483.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Synthesis of 2-Trifluoroethoxyl-2H-azirine Derivatives through PhIO-Mediated Trifluoroethoxylation and Azirination of
Enaminesa
a General conditions: PhIO (2.1 mmol) in TFE (5 mL) was stirred at rt for 15 min, and then substrate 1 (1 mmol in 5 mL of TFE) was added dropwise.
b Isolated yields. c The structure of 2c was determined by X-ray crystallography.
stirred at room temperature for 15 min. Carrying out the
same reaction by applying 2 equiv of TFE and using DCM
as the solvent only afforded the desired product in 30%
yield (Table 1, entry 4). Attempts to further increase the
35% yield in the case of PIDA (Table 1, entry 7), no desired
product of PIFA (Table 1, entry 8), and no reaction at all of
either IBX or DMP (Table 1, entries 9ꢀ10).
Under the optimal conditions, various enamines were
prepared and examined to probe the scope and generality
of this method. For the enaminone substrates with both R
and R1 being aryl groups, the reaction proceeded smoothly
to afford the corresponding 2-trifluoroethoxyl-2H-azirine
products (Table 2, entries 1ꢀ3). The method was shown to
be also well applicable to the enaminone substrates with R
yield by adding additives, such as NaOAc and BF3 Et2O,
3
were found unsuccessful in either case, specifically, with a
decreased yield of 66% for the former, and no desired product
in the latter case (Table 1, entries 5ꢀ6). Other hypervalent
iodine reagents including PIDA, PIFA, IBX, and DMP were
also tested for the conversion. The results indicated that a
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Conversion of 2-Trifluoroethoxyl-2H-azirine 2i to
Isoxazole 3 via FeCl2-Mediated Intramolecular Ring Expansion
Scheme 5. Further Probe on the Reaction Mechanism
corresponding isoxazole 3 in excellent yields through an
intramolecular rearrangement (Scheme 3).15
A plausible mechanistic pathway for the above trifluor-
oethoxylation and azirination process is described in
Scheme 4. Initially, the reaction between PhIO and TFE
undergoes condensation to give the PhI(OCH2CF3)2 inter-
mediate 4,16 which reacts with the enamine substrate 1 to give
the R-iodo imine E. The reductive removal of PhI from E
affords R-triflouroethoxy imine F, which tautomerizes into its
enamine isomer G. Further reaction with the second molecule
of PhI(OCH2CF3)2 provides intermediate H, which under-
goes intramolecular azirination to give the title compound 2.
In order to gain further insights into the reaction me-
chanism, we undertook the task of isolating and verifying
the structure of the proposed enamine intermediate G.
When the amount of PhIO was decreased to 1.0 equiv, the
reaction regarding substrate 1i afforded a 55% yield of the
R-triflouroethoxy enaminone 5, in addition to the cyclized
2H-azirine 2i. After separating the two compounds, ex-
posure of enaminone 5 to1.0 equiv of PhIO in TFE at rt led
to the formation of the azirinated product in nearly
quantitative yield (Scheme 5). This result indisputably
supports the reaction sequence proposed above.
In conclusion, we have reported a novel method for the
synthesis of the trifluoroethoxylated 2H-azirines through
reactions between the R-unsubstituted enamines and PhIO
in trifluoroethanol (TFE). The process features a cascade
reaction of a metal-free intermolecular oxidative CꢀO
bond formation and a subsequent intramolecular oxida-
tive azirination. The significance of the method is tied
together with the unique features of the products formed,
in that they possess not only the biologically important
2H-azirine skeleton3,17 but also the biologically interesting
trifluoroethoxyl moiety.18 Further study on the reaction
mechanism is in progress in our lab.
Scheme 4. Proposed Mechanistic Pathway
being an aryl group and R1 being an alkyl group, including
a relatively long-chained propyl group and a bulky iso-
butyl group (Table 2, entries 4ꢀ12). Additional experi-
ments show that this method is applicable to a broad range
of enaminones containing a variety of R or R1 groups,
yields are between 45 and 85%, R can be an ester group
(Table 2, entries 14ꢀ17), and R1 can be a terminally dibromo
substituted alkyl group (Table 2, entry 13) or even an
R-ethoxycarbonyl group (Table 2, entry 18).
One important application of the obtained 2-trifluoro-
ethoxyl-2H-azirine derivatives 2 is their potential to be
transformed into various isoxazole compounds via intra-
molecular ring expansion. For example, upon treatment
with FeCl2 in refluxing 1,4-dioxane at 101 °C, 2-trifluoro-
ethoxyl-2H-azirine 2i could be efficiently turned into the
(15) Zheng, Y.; Yang, C.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.
Tetrahedron Lett. 2013, 54, 6157–6160.
(16) In our control experiment, PhI(OCH2CF3)2 was isolated and
characterized from the reaction of PhIO and TFE (see Supporting
Information for details). For the previous proposed in situ formation
of PhI(OCH2CF3)2, see: (a) Kajiyama, D.; Inoue, K.; Ishikawa, Y.;
Nishiyama, S. Tetrahedron 2010, 66, 9779–9784. (b) Kidwai, M.; Sapra,
P. Org. Prep. Proced. Int. 2001, 33, 381–386. (c) Bell, R.; Morgan, K. J. J.
Chem. Soc. 1960, 1209–1214. (d) Baker, G. P.; Mann, F. G.; Sheppard,
M. N.; Tetlow, A. J. J. Chem. Soc. 1965, 3721–3728. (f) Leffler, J. E.;
Ward, D. C.; Burduroglu, A. J. Am. Chem. Soc. 1972, 94, 5339–5341.
(17) For selected examples, see: (a) Stapley, E. O.; Hendlin, D.;
Jackson, M.; Miller, A. J. J. Antibiot. 1971, 24, 42–47. (b) Molinski,
T. F.; Ireland, C. M. J. Org. Chem. 1988, 53, 2103–2105. (c) Davis, F. A.;
Reddy, G. V.; Liu, H. J. Am. Chem. Soc. 1995, 117, 3651–3652. (d)
Davis, F. A.; Liu, H.; Liang, C. H.; Reddy, G. V.; Zhang, Y.; Fang, T.;
Titus, D. D. J. Org. Chem. 1999, 64, 8929–8935.
Acknowledgment. Y.D. acknowledges the National Nat-
ural Science Foundation of China (#21072148), Foundation
(B) for Peiyang Scholar ꢀ Young Core Faculty of Tianjin
University (2013XR-0144), and the Innovation Foundation
of Tianjin University (2013XJ-0005) for financial support.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds and
X-ray structural data of 2c. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) For selected examples, see: (a) Jeschke, P. ChemBioChem. 2004,
5, 570–589. (b) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44,
214–231. (c) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–
1886. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320–330.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX