Diastereoselective Synthesis of 1,3-Oxazolidines via Cationic Iron Porphyrin-catalyzed Cycloaddition of Aziridines with Aldehydes

Article abstract of DOI:10.1021/acs.orglett.9b00560

An efficient iron porphyrin Lewis acid-catalyzed cycloaddition of aziridines with aldehydes has been developed to provide oxazolidines with high regio- and diastereoselectivity. The cycloaddition proceeds in toluene with 1 mol % of the iron catalyst at 25

Full text of DOI:10.1021/acs.orglett.9b00560

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Diastereoselective Synthesis of 1,3-Oxazolidines via Cationic Iron
Porphyrin-catalyzed Cycloaddition of Aziridines with Aldehydes
Satoru Teranishi, Kazuki Maeda, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
*
S Supporting Information
ABSTRACT: An efficient iron porphyrin Lewis acid-catalyzed
cycloaddition of aziridines with aldehydes has been developed to
provide oxazolidines with high regio- and diastereoselectivity. The
cycloaddition proceeds in toluene with 1 mol % of the iron catalyst
at 25 °C. A theoretical study and synchrotron-based X-ray
absorption fine structure measurements provided fundamental
insights into the aziridine−iron porphyrin complex, which is the
key intermediate for the generation of the 1,3-dipole synthon.
etalloporphyrins perform important biochemical func-
To prove our hypothesis, we initially examined the Gibbs
free energy change for the complexion of cationic iron(III)
porphyrin catalyst Fe[(TArP)]SbF (Ar = 1,3-tBu-C H ) CP1
with aziridine 1a by means of density functional theory
calculation (Scheme 2). It was found that the coordination of
M
tions in nature. Therefore, the related chemistry has
1
been a topic of great interest. Recently, we reported that
6
6
3
metalloporphyrins could perform as Lewis acid and catalyze
various reactions such as formal hetero-Diels−Alder reaction
2
and cycloisomerization. Herein, we report that iron porphyrin
can catalyze [3 + 2] cycloaddition of aziridines via formation of
Scheme 2. Gibbs Free Energy Change of 1,3-Dipole
Synthon Formation via Activation of Aziridine with Iron
Porphyrin Lewis Acid
1
,3-dipole synthon with carbonyl compounds to give 1,3-
oxazolidines diastereoselectively.
Aziridine is a valuable synthetic building block for various
nitrogen-containing cyclic compounds, as it readily reacts as a
3
1
,3-dipole synthon with various dipolarophiles, and the high
reactivity of aziridine is attributed to its facile formation of 1,3-
dipolar intermediate mediated by a Lewis acid. From the point
of Gibbs free energy change, the use of Lewis acid is
mandatory for activation of aziridine and stabilization of the
resulting 1,3-dipole since in the absence of Lewis acid this step
is highly endergonic as shown in Scheme 1. Thus, the use of
Scheme 1. Gibbs Free Energy Change of 1,3-Dipole
Synthon Formation without Stabilization by Lewis Acid
aziridine 1a to CP1 formed CP2 in an exergonic step. The
interaction between CP1 and 1a is further confirmed by using
noncovalent interaction plot (NCIPlot) and second-order
perturbation theory analysis of the Fock matrix in NBO (see
Supporting Information). The activated aziridine, i.e., 1,3-
dipole synthon, is also thermodynamically stabilized by
appropriate Lewis acid to activate aziridine and stabilize the
resulting 1,3-dipole synthon is key for the reaction. We
hypothesized that with its high Lewis acidity, the cationic iron
porphyrin complex would catalytically facilitate the activation
of aziridine to generate 1,3-dipole synthon, thereby promoting
the reaction with dipolarophiles to afford nitrogen-containing
cyclic compounds. Moreover, the steric hindrance of the
porphyrin ligand would promote the dissociation of the
product to achieve high turnover frequency.
Received: February 12, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00560
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
coordination to the cationic iron porphyrin to form CP3, with
a Gibbs energy change of 22.8 kcal/mol that is a reasonable
value for the reaction intermediate and rather small compared
to the case without the iron complex (36.9 kcal/mol in Scheme
Table 1. Cycloaddition of Aziridine 1a with Aldehyde 2a
1
). To gain further insight into the structure of CP2 in solution
phase, Fe K-edge X-ray absorption spectroscopy (XAS)
analysis was performed using a synchrotron radiation beamline,
where the ultrahigh brightness made solution-phase XAS
accessible for in situ structural investigation. Analysis of the
extended X-ray absorption fine structure (EXAFS) spectrum of
the solution of CP2 in toluene indicated good agreement with
the theoretically calculated model for the Lewis acid−base
b
c
entry
catalyst
yield (%)
3aa/3aa′
1
2
3
4
5
6
7
8
9
[Fe(TArP)]SbF6
[Fe(TPP)]SbF6
[Fe(TPP)]OTf
[Fe(TPP)]ClO4
[Fe(TPP)]BF4
[Fe(TPP)]Cl
[Mn(TPP)]SbF6
[Co(TPP)]SbF6
[Cr(TPP)]SbF6
Fe(OTf)3
97
87
30
18
24
<1
<1
52
59
69
90
79
91
73
82
99
<1
<1
<1
10/1
50/1
20/1
20/1
20/1
adduct with R = 3.0% (Figure 1).
f
7/1
20/1
1/1
5/1
1/1
3/1
1/1
1/1
1/1
10
11
12
13
14
15
16
17
18
AgSbF6
BF ·Et O
3
2
Zn(OTf)2
Sc(OTf)3
Cu(OTf)2
TfOH
FeCl3
FeCl2
Figure 1. Solution-phase Fe K-edge EXAFS analysis (Fourier
19
Fe(OAc)
2
3
−1
a
transform of k -weighted spectrum, Δk = 3.0−9.7 Å , ΔR = 1.1−
Reaction conditions: catalyst (1 mol %), aziridine 1a (0.1 mmol),
and aldehyde 2a (0.15 mmol, 1.5 equiv) in 1 mL of CH Cl for 1 h.
NMR yields are given. Ratio of diastereomers (3aa/3aa′).
3
.4 Å, spatial resolution δR = 0.162 Å, R = 3.0%): simulated spectrum
f
2
2
b
c
based on DFT structure CP2 (red line) and experimental spectrum
(
black line).
lectivity (3ac and 3ad). Not only aryl aldehydes but also
aliphatic aldehydes participated in the reaction to afford
cycloadducts in high yields. For example, cylcohexylcarbox-
aldehyde (2e) reacted with 1a in the presence of iron catalyst
to give cycloadducts in 97% yield with a diastereomer ratio of
17/1. We next applied the iron porphyrin catalyst to the
reaction with ketones. The cycloaddition of ketone 2j with 1a
gave bicyclic compound 3aj in 72% yield. The reaction also
proceeded with cyclohexanone 2m to provide 3am in 80%
yield. Of note, the asymmetrical ketone 2m also reacted with
1a to give 3am diastereoselectively. It is also remarkable that
Based on the theoretical study and X-ray spectroscopic
analysis of complexation between iron porphyrin and aziridine,
we envisioned that iron porphyrin may promote the 1,3-dipole
addition with dipolarophiles. Indeed, the reaction of aziridine
a with benzaldehyde (2a) in the presence of cationic iron(III)
porphyrin catalyst CP1 (1 mol %) in dichloromethane at 25
C for 1 h afforded 1,3-oxazolidine 3aa in 97% yield with a
1
°
diastereomer ratio of 10/1 (Table 1, entry 1). Upon
optimization of the iron porphyrin catalyst structure, [Fe-
(
TPP)]SbF showed improved diastereoselectivity (entry 2).
6
Among various counteranions such as SbF , OTf, ClO , BF ,
the [Fe(TPP)]SbF -catalyzed [3 + 2] cycloaddition is feasible
6
4
4
6
and Cl, the cationic iron porphyrin complex having SbF6
counteranion provided the cycloadduct in the highest yield
in the presence of water: an aqueous solution of formaldehyde
2n could react with 1a to obtain cycloadduct 3an in 64% yield.
In order to demonstrate the scope of this cycloaddition, we
next examined the reaction of various aziridines 1 with
benzaldehyde 2a (Chart 2). Under the optimized reaction
conditions, 2-arylaziridines possessing an electron-withdrawing
substituent and an electron-donating one on phenyl moiety
reacted with benzaldehyde 2a to afford the corresponding
substituted 1,3-oxazolidines in good yield diastereoselectively
(3ba and 3ca). Note that 2,2-dialkyl-substituted aziridine 1d
also participated in the reaction to give 3da in 82% yield.
It is possible for the present reaction to proceed via either a
concerted mechanism or a stepwise mechanism, as shown in
Figure 2. In order to determine which one is the case, the
chiral aziridine 1a (99% ee) was reacted with 2a in the
presence of iron porphyrin catalyst under the standard reaction
conditions (Scheme 3). The isolated cycloadduct from the
experiment was found to be almost racemic (11% ee).
Furthermore, it was found that chiral aziridine 1a racemized
in the presence of iron porphyrin catalyst under the standard
reaction conditions. Based on these results, it is proposed that
(
entries 2−5). The use of other cationic metalloporphyrin
complexes, such as [Mn(TPP)]SbF , [Co(TPP)]SbF , and
6
6
[
Cr(TPP)]SbF in place of [Fe(TPP)]SbF also resulted in the
6
6
formation of 1,3-oxazolidine 3aa in trace amount or much
lower yield. Furthermore, the reaction with conventional Lewis
acid catalysts such as Fe(OTf) , AgSbF , BF ·Et O, Zn(OTf) ,
3
6
3
2
2
Sc(OTf) , Cu(OTf) , and Brønsted acid TfOH also afforded
2
2
the cycloadduct 3aa in high yield but with far lower
diastereoselectivity (entries 10−16). Iron salts catalyst, such
as FeCl , FeCl , and Fe(OAc) did not afford cycloadduct 3aa
3
2
2
(
entries 17−19).
With the optimized reaction conditions in hand, we first
evaluated the cationic iron(III) porphyrin-catalyzed [3 + 2]
cycloaddition by using aziridine 1a with various carbonyl
compounds 2, and the results are summarized in Chart 1. The
reaction of anisaldehyde (2b) with 1a provided 3ab in 82%
yield. Cycloaddition of arylaldehydes having an electron-
donating substituent reacted with 1a to afford the correspond-
ing substituted oxazolidines in high yields with diastereose-
B
DOI: 10.1021/acs.orglett.9b00560
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chart 1. Diastereoselective Cycloaddition of Aziridine 1a
with Aldehydes
Chart 2. Diastereoselective Cycloaddition of Aziridines with
Aldehyde 2a
a
a
a
Reaction conditions: iron porphyrin catalyst (1 mol %), aziridine 1
(
0.1 mmol), and aldehyde 2a (0.15 mmol, 1.5 equiv) in 1 mL of
b c
CH Cl for 1 h. Isolated yields are given. Reaction time: 3 h.
2
2
a
Reaction conditions: iron porphyrin catalyst (1 mol %), aziridine 1a
(
0.1 mmol), and aldehyde 2 (0.15 mmol, 1.5 equiv) in 1 mL of
b c
CH Cl for 1 h. Isolated yields are given. Reaction time: 3 h.
2
2
d
e
f
Reaction time: 7 h. Reaction time: 4 h. Reaction time: 6 h.
Figure 2. Possible reaction paths for the cycloaddition.
g
h
Reaction temperature: 60 °C. Reaction time: 4 h. Reaction
temperature: 60 °C (CH Cl /water mixture in sealed tube). Reaction
time: 2 h.
2
2
Scheme 3. Cationic Iron Porphyrin-catalyzed Cycloaddition
of Chiral Aziridine 1a with Aldehyde 2a, and Racemization
of 1a
the reaction involves coordination of the aziridine to the iron
porphyrin, leading to the cleavage of C−N bond to produce a
discrete and stable 1,3-dipole synthon, which reacts with the
carbonyl compound in a stepwise fashion to afford the
cycloadduct. It should be noted that epimerization of 1,3-
oxazolidines was not observed under the reaction conditions
(Scheme 4), suggesting that the diastereoselectivity is mainly
due to the kinetics rather than thermodynamics, and the
cycloadduct 3aa and its diastereomer 3aa′ are stable enough to
tolerate the reaction conditions without opening the
oxazolidine ring.
In summary, we found that the Lewis acid-catalyzed
cycloaddition of aziridines with carbonyl compound provides
oxazolidines with high regio- and diastereoselectivity. The use
of cationic iron porphyrin complex as Lewis acid catalyst
facilitates the reaction under mild condition within a short
time. The cycloaddition proceeds in toluene with 1 mol % of
the iron catalyst at 25 °C within 1 h. The reaction occurs in a
stepwise mechanism involving ring opening of aziridine to
form a discrete stable 1,3-dipole synthon, which reacts with
various types of carbonyl compounds. The coordination of 1,3-
Scheme 4. Stability of 1,3-Oxazolidines 3aa/3aa′ Under the
Reaction Conditions
dipole synthon to the iron porphyrin catalyst was also
elucidated with Fe K-edge XAS analysis and density functional
C
DOI: 10.1021/acs.orglett.9b00560
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
theory calculation. Since the use of appropriate metal-
loporphyrin Lewis acid as a catalyst enables the [3 + 2]
cycloaddition of aziridines with both high diastereoselectively
and high turnover frequency, further study on these metal-
loporphyrin Lewis acid catalysts may reveal intrinsic catalytic
activity of first-row transition metals; these studies are
(2) (a) Fujiwara, K.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2
012, 134, 5512. (b) Wakabayashi, R.; Kurahashi, T.; Matsubara, S.
Org. Lett. 2012, 14, 4794. (c) Ozawa, T.; Kurahashi, T.; Matsubara, S.
Org. Lett. 2012, 14, 3008. (d) Ozawa, T.; Kurahashi, T.; Matsubara, S.
Synlett 2013, 24, 2763. (e) Teranishi, S.; Kurahashi, T.; Matsubara, S.
Synlett 2013, 24, 2148. (f) Shiba, T.; Kuroda, D.; Kurahashi, T.;
Matsubara, S. Synlett 2014, 25, 2005. (g) Maeda, K.; Terada, T.;
Kurahashi, T.; Matsubara, S. Org. Lett. 2015, 17, 5284. (h) Kuwano,
T.; Kurahashi, T.; Matsubara, S. Chem. Lett. 2013, 42, 1241.
4
−7
currently under investigation in our laboratory.
ASSOCIATED CONTENT
(3) For some selected examples of the use of aziridines as 1,3-dipole
synthon, see: (a) Yang, P. J.; Qi, L.; Liu, Z.; Yang, G.; Chai, Z. J. Am.
Chem. Soc. 2018, 140, 17211. (b) Kaicharla, T.; Jacob, A.; Gonnade,
R. G.; Biju, A. T. Chem. Commun. 2017, 53, 8219. (c) Wu, X. X.;
Zhou, W.; Wu, H. H.; Zhang, J. L. Chem. Commun. 2017, 53, 5661.
(d) Martinand-Lurin, E.; Gruber, R.; Retailleau, P.; Fleurat-Lessard,
P.; Dauban, P. J. Org. Chem. 2015, 80, 1414. (e) Li, X.; Yang, X. Q.;
Chang, H. H.; Li, Y. W.; Ni, B.; Wei, W. L. Eur. J. Org. Chem. 2011,
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00560.
Experimental procedures including spectroscopic and
analytical data of new compounds (PDF)
2011, 3122. (f) Maeda, R.; Ishibashi, R.; Kamaishi, R.; Hirotaki, K.;
Furuno, H.; Hanamoto, T. Org. Lett. 2011, 13, 6240. (g) Li, L.; Wu,
X. X.; Zhang, J. L. Chem. Commun. 2011, 47, 5049. (h) Attanasi, O.
A.; Davoli, P.; Favi, G.; Filippone, P.; Forni, A.; Moscatelli, G.; Prati,
F. Org. Lett. 2007, 9, 3461. (i) Kang, B. M.; Miller, A. W.; Goyal, S.;
Nguyen, S. T. Chem. Commun. 2009, 3928. (j) Craig, R. A.;
O’Connor, N. R.; Goldberg, A. F. G.; Stoltz, B. M. Chem. - Eur. J.
AUTHOR INFORMATION
■
*
*
Corresponding Authors
E-mail: kurahashi.takuya.2c@kyoto-u.ac.jp.
E-mail: matsubara.seijiro.2e@kyoto-u.ac.jp.
2
014, 20, 4806. (k) Gupta, A.; Yadav, V. K. Tetrahedron Lett. 2006,
47, 8043. (l) Ghorai, M. K.; Ghosh, K.; Das, K. Tetrahedron Lett.
ORCID
2
2
2
006, 47, 5399. (m) Wu, X. X.; Lia, L.; Zhang, J. L. Chem. Commun.
011, 47, 7824. (n) Ghorai, M. K.; Das, K.; Shukla, D. J. Org. Chem.
007, 72, 5859. (o) Li, L.; Zhang, J. L. Org. Lett. 2011, 13, 5940.
Takuya Kurahashi: 0000-0001-8417-7660
Seijiro Matsubara: 0000-0001-8484-4574
Notes
(p) Cardoso, A. L.; Melo, T.M.V.D.P.E. Eur. J. Org. Chem. 2012,
6
7
9
479. (q) Ghorai, M. K.; Kumar, A.; Tiwari, D. P. J. Org. Chem. 2010,
5, 137. (r) Dauban, P.; Malik, G. Angew. Chem., Int. Ed. 2009, 48,
026. (s) Gandhi, S.; Bisai, A.; Prasad, B. A. B.; Singh, V. K. J. Org.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Chem. 2007, 72, 2133. (t) Wender, P. A.; Strand, D. J. Am. Chem. Soc.
2
2
009, 131, 7528. (u) Yadav, V. K.; Sriramurthy, V. J. Am. Chem. Soc.
005, 127, 16366.
This work was supported by Advanced Catalytic Trans-
formation Program for Carbon Utilization (ACT-C No.
JPMJCR12YE) from Japan Science and Technology Agency
(
4) Johnson, E. R.; Keinan, S.; Mori-San
J.; Cohen, A. J.; Yang, W. J. Am. Chem. Soc. 2010, 132, 6498−6506.
5) (a) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys.
985, 83, 735−746. (b) Glendening, E. D.; Landis, C. R.; Weinhold,
F. J. Comput. Chem. 2013, 34, 1429−1437.
6) Tomifuji, R.; Maeda, K.; Takahashi, T.; Kurahashi, T.;
́
chez, P.; Contreras-García,
(
1
JST) and a Grant-in-Aid for Scientific Research (18H04253,
7KT0006, and 15H03809) from the Ministry of Education,
(
1
Culture, Sports, Science and Technology (Japan). T.K.
acknowledges the Asahi Glass Foundation. We thank Dr.
Hiroyasu Sato (Rigaku) for the valuable help in X-ray crystal
structural analysis. We are grateful to Prof. Tsunehiro Tanaka
(
Matsubara, S. Org. Lett. 2018, 20, 7474−7477.
(7) (a) Rehr, J. J.; Kas, J. J.; Prange, M. P.; Sorini, A. P.; Takimoto,
Y.; Vila, F. C. R. C. R. Phys. 2009, 10, 548−559. (b) Ravel, B.;
Newville, M. J. Synchrotron Radiat. 2005, 12, 537−541. (c) Newville,
M. J. Synchrotron Radiat. 2001, 8, 322−324.
(
Kyoto University), Prof. Masaharu Nakamura (Kyoto
University), Prof. Hikaru Takaya (Kyoto University), Dr.
Tetsuo Honma (JASRI), Dr. Hironori Ofuchi (JASRI), and
Dr. Masafumi Takagaki (JASRI) for valuable support in the X-
ray absorption fine structure analysis. Part of this study was
performed at the BL14B2 beamline of the SPring-8
synchrotron radiation facility with the approval of the Japan
Synchrotron Radiation Research Institute (Proposal Nos.
2
2
016A1549, 2016A1680, 2016B1766, 2017A1700,
017B1748, 2018A1690, and 2018B1594).
REFERENCES
■
(
1) For some examples of the use of metalloporphyrins in
nonoxidative bond formation, see: (a) Suda, K.; Baba, K.;
Nakajima, S.-I.; Takanami, T. Chem. Commun. 2002, 2570.
(
b) Suda, K.; Kikkawa, T.; Nakajima, S.-I.; Takanami, T. J. Am.
Chem. Soc. 2004, 126, 9554. (c) Suda, K.; Baba, K.; Nakajima, S.-I.;
Takanami, T. Tetrahedron Lett. 1999, 40, 7243. (d) Schmidt, J. A. R.;
Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2005, 127, 11426.
(
(
e) Zhou, C.-H.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2006, 8, 325.
f) Tachinami, T.; Nishimura, T.; Ushimaru, R.; Noyori, R.; Naka, H.
J. Am. Chem. Soc. 2013, 135, 50. (g) Ushimaru, R.; Nishimura, T.;
Iwatsuki, T.; Naka, H. Chem. Pharm. Bull. 2017, 65, 1000. (h) Liu, Y.;
Wei, J.; Che, C.-M. Chem. Commun. 2010, 46, 6926.
D
DOI: 10.1021/acs.orglett.9b00560
Org. Lett. XXXX, XXX, XXX−XXX