Effective synthesis of chiral N-fluoroaryl aziridines through enantioselective aziridination of alkenes with fluoroaryl azides

Article abstract of DOI:10.1002/anie.201209599

The Co^II complex of a D₂-symmetric chiral porphyrin ([Co(D₂-Por*)], see scheme) is a highly effective catalyst for the enantioselective aziridination of alkenes with fluoroaryl azides. The reaction can be performed at RT w

Full text of DOI:10.1002/anie.201209599

Angewandte
Chemie
DOI: 10.1002/anie.201209599
Asymmetric Catalysis
Effective Synthesis of Chiral N-Fluoroaryl Aziridines through
Enantioselective Aziridination of Alkenes with Fluoroaryl Azides**
Li-Mei Jin, Xue Xu, Hongjian Lu, Xin Cui, Lukasz Wojtas, and X. Peter Zhang*
Catalytic aziridination of alkenes with nitrene sources
through “C2+N1” addition represents a general approach
for the direct synthesis of aziridines, the smallest three-
membered N-heterocycles.[1] The enantioselective version of
this catalytic process allows for efficient access to chiral
nonracemic aziridines, which are versatile synthetic inter-
mediates in asymmetric synthesis.[1,2] Several classes of
transition-metal-based chiral catalysts, such as Mn, Fe, Cu,
Scheme 1. Synthesis and transformations of N-fluoroaryl aziridines.
Rh, and Co complexes, are effective in catalyzing asymmetric
olefin aziridination with different nitrene sources.[1,3] Besides
iminoiodanes and haloamines, organic azides, which enjoy
several advantages, have been actively pursued as alternative
nitrene sources for metal-catalyzed aziridination.[3] While
sulfonyl and phosphoryl azides have been effectively
employed for metal-catalyzed asymmetric aziridination,[4]
catalytic processes based on the use of other types of azides,
such as aryl azides, are less developed. In addition to
generating environmentally friendly nitrogen gas as the only
by-product, the asymmetric catalytic aziridination with read-
ily available aryl azides provides an attractive approach for
the synthesis of valuable N-aryl aziridines through direct
introduction of N-aryl groups concurrently with the ring
formation.[5,6] This method would avoid two additional steps
of deprotection and N-arylation when other types of nitrene
sources such as sulfonyl azides are used for preparing N-aryl
aziridines.[7] However, few catalytic systems are effective for
the asymmetric olefin aziridination with aryl azides.[4d,6]
Fluoroaryl azides, which can be easily prepared from
commercially available fluoroanilines, are a class of common
aryl azides that have not been previously employed in
catalytic aziridination of alkenes.[8] A catalytic process for
the asymmetric aziridination with fluoroaryl azides would be
particularly attractive as the resulting enantioenriched N-
fluoroaryl aziridines could serve as effective chiral synthons
for the preparation of chiral fluoroarylamine-containing
compounds through various ring-opening and ring-expansion
transformations (Scheme 1).[2] Chiral fluoroarylamine deriv-
atives are useful in pharmaceutical and other important
applications.[9] To date, only a few metal complexes, including
Ru, Co, and Fe complexes, have been reported to catalyze the
aziridination of alkenes with aryl azides.[4d,6] None of them
involved the use of fluoroaryl azides as nitrene sources. These
existing catalytic aziridination systems typically required the
use of excess olefins and relatively high reaction temperatures
(70–908C) to achieve satisfactory yields. Furthermore, the
majority of these systems are non-asymmetric; the issue of
enantioselectivity is not addressed. To the best of our
knowledge, the only example of asymmetric aziridination
with aryl azides was that of a-methylstyrene with 4-nitro-
phenyl azide catalyzed by a Ru-based chiral catalyst, giving
the product in only 10% enantiomeric excess and in 35%
yield.[10] It is evident that asymmetric olefin aziridination with
aryl azides, including fluoroaryl azides, is an unsolved
problem and faces formidable challenges in both reactivity
and enantioselectivity.
As stable metalloradicals with a well-defined open-shell
doublet d7 electronic structure, cobalt(II) complexes of D2-
symmetric chiral amidoporphyrins, [Co(D2-Por*)], are effec-
tive catalysts for the asymmetric aziridination of various
olefin substrates with different classes of nitrene sources,
particularly with sulfonyl and phosphoryl azides.[4a,b] Results
from computational and experimental studies suggest a dis-
tinctive metalloradical mechanism for the CoII-catalyzed
aziridination, involving an unprecedented CoIII–nitrene rad-
ical intermediate and a stepwise radical addition–substitution
pathway.[11] In addition to serving as rigid spacers to support
and orient the chiral environments toward the cobalt center,
the amide units of the D2-symmetric amidoporphyrins were
shown to also function as potential donors to engage in
hydrogen-bonding interaction with acceptors located at the
nitrene moiety in the CoIII–nitrene radical intermediate,[12,13]
thus lowering the energy barrier of the transition state and
accelerating the reaction rate.[11a] Given that the fluorine atom
in organic fluorides can act as a potential hydrogen-bond
acceptor,[14] we hypothesized the possibility of a similar
hydrogen-bonding interaction in the corresponding CoIII–
nitrene radical intermediate from activation of fluoroaryl
azides (Figure 1). Depending on the number of fluorine atoms
[*] Dr. L. M. Jin, Dr. X. Xu, Dr. H. Lu, Dr. X. Cui, Dr. L. Wojtas,
Prof. Dr. X. P. Zhang
Department of Chemistry, University of South Florida
Tampa, FL 33620-5250 (USA)
E-mail: xpzhang@usf.edu
Homepage: http://chemistry.usf.edu/faculty/zhang/
[**] We are grateful for financial support by NSF (CHE-1152767) and
NIH (R01-GM098777. We thank the Advanced Photon Source at
Argonne National Lab, Chicago, IL for the measurement of the X-ray
structure of porphyrin P3.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209599.
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Table 1: Enantioselective aziridination by different [Co(D2-Por*)].[a]
Entry Catalyst
Ar
Solvent Yield [%][b] ee [%][c]
1[d]
2[d]
3[d]
4[d]
5
6
7
8
9
[Co(P1)]
[Co(TPP)] o-FC6H4 (2a)
o-FC6H4 (2a)
PhH
PhH
50[e]
trace
95
95
94
À47
–
[Co(P1)]
[Co(P2)]
[Co(P3)]
[Co(P3)]
[Co(P3)]
[Co(P3)]
–
2,4,6-F3C6H2 (2b) PhH
2,4,6-F3C6H2 (2b) PhH
2,4,6-F3C6H2 (2b) PhH
2,4,6-F3C6H2 (2b) PhCl
2,4,6-F3C6H2 (2b) PhF
À66
73
90
91
92
90
–
Figure 1. Hydrogen-bonding in postulated nitrene radical complex.
in the ortho position in fluoroaryl azides, formation of single
80
94
À
(Figure 1A) or double (Figure 1B) N H···F hydrogen bonds
2,4,6-F3C6H2 (2b) hexane 72
2,4,6-F3C6H2 (2b) PhH NR
À
between the amide N H elements of amidoporphyrins and
the F atoms in ortho position of fluoroaryl groups would be
attainable. On the basis of this hypothesis, we embarked on
a research project to study the catalytic asymmetric olefin
aziridination with fluoroaryl azides by [Co(D2-Por*)].
As an outcome of this effort, we report herein a highly
effective catalytic system that is based on a new generation of
chiral CoII metalloradical catalysts for asymmetric aziridina-
tion of alkenes with fluoroaryl azides. The CoII-catalyzed
aziridination is suitable for a wide range of aromatic olefins
and fluoroaryl azides, producing the corresponding N-fluo-
roaryl aziridines in high yields with excellent enantioselectiv-
ities. In addition to tolerating a wide variety of fluoroaryl
azides as nitrene sources, the new metalloradical aziridination
process features a practical protocol that operates at room
temperature without the need of excess olefin, generating N2
as the only by-product.
At the outset of our studies, we evaluated the catalytic
capability of different D2-symmetric chiral amidoporphyrins
[Co(D2-Por*)] in the aziridination of styrene (1a) with 2-
fluorophenyl azide (2a; Table 1). Catalyzed by [Co(P1)]
(2 mol%; P1 = 3,5-di-tert-butyl-ChenPhyrin),[15] the reaction
in benzene went smoothly even at room temperature, and
afforded the desired aziridine product in 50% yield and
47% ee (Table 1, entry 1). Subsequent experiments showed
that [Co(TPP)] (TPP = 5,10,15,20-tetraphenylporphyrin) was
an ineffective catalyst for the reaction under the same
conditions (Table 1, entry 2). The notable difference in
catalytic capability between [Co(P1)] and [Co(TPP)] is in
[a] Carried out with olefin (1 equiv, 0.2m), azide (1.2 equiv), and [Co(D2-
Por*)] (1 mol%). [b] Yields of isolated products. [c] Determined by HPLC
on a chiral stationary phase. [d] 2 mol% catalyst loading. [e] Yield
determined by 19F NMR spectroscopy. Product mixture contained 2a
(10%), azofluorobenzene (15%), fluoroaniline (10%), and unknown
components (15%). Entry in bold marks optimized reaction conditions.
chiral amidoporphyrin 3,5-di-tert-butyl-Xu(2’-Naph)Phyrin
(P3),[17] whose CoII complex [Co(P3)] was shown to be the
optimal catalyst for the process, giving the desired product in
94% yield and 90% ee even with only 1 mol% of catalyst
loading (Table 1, entry 5). Among various solvents that were
screened, fluorobenzene was found to be the solvent of
choice, giving the aziridine product in high yield (94%) and
excellent enantioselectivity (92% ee) at room temperature
(Table 1, entries 5–8). As expected, control experiments in
the absence of a catalyst gave no reaction (Table 1, entry 9).
Under the optimized reaction conditions, we then used
the aziridination of styrene as a model reaction to investigate
the scope and limitation of fluoroaryl azides as nitrene
sources (Table 2). As in the case of aryl azide 2b, which has
two F atoms in ortho position (Table 1), the use of the new
metalloradical catalyst, [Co(P3)], also led to significant
improvement in enantioselectivity for the aziridination reac-
tion with aryl azide 2a, which contains one F atom in ortho
position (Table 2, entry 1 versus Table 1, entry 1). The
[Co(P3)]-based catalytic aziridination system could effec-
tively employ other mono-ortho-fluoro-substituted aryl
azides as nitrene sources, as demonstrated by the use of
2,4,5-trifluorophenyl azide (2c) (Table 2, entry 2). In addition
to azide 2b, various other di-ortho-fluoro-substituted aryl
azides, including 2,6-difluoro-, 2,3,5,6-tetrafluoro-, and penta-
fluorophenyl azides (2d–f), were shown to be highly effective
nitrene sources for the CoII-based aziridination process,
yielding the corresponding aziridines in high yields with
excellent enantioselectivities (Table 2, entries 3–5). Presum-
À
line with our assumption about the possible role of N H···F
hydrogen-bonding interaction in activating the fluoroaryl
azide (Figure 1A). Further studies showed that 2,4,6-trifluor-
ophenyl azide (2b) also effectively aziridinated styrene under
[Co(P1)] catalysis, affording the corresponding aziridine in
95% yield and 66% ee (Table 1, entry 3). The observed
improvement in reactivity and stereoselectivity with azide 2b,
which contains two F atoms in ortho position, is ascribed to
À
the potential formation of the double N H···F hydrogen
bonds in the postulated CoIII–nitrene radical intermediate
(Figure 1B). Further improvement in enantioselectivity was
achieved for aziridination of styrene with azide 2b when
[Co(P2)] (P2 = 3,5-di-tert-butyl-QingPhyrin), a second-gener-
ation metalloradical catalyst that was previously shown to be
highly effective for asymmetric intramolecular cyclopropa-
nation,[16] was employed as a catalyst, reaching 73% ee and
the same high yield (Table 1, entry 4). Successive studies
resulted in the design and synthesis of a new D2-symmetric
À
ably as a result of additional N H···F hydrogen-bonding
interactions in the postulated CoIII–nitrene radical intermedi-
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Table 2: [Co(P3)]-catalyzed enantioselective aziridination of styrene with
Table 3: Enantioselective aziridination of different combinations of
olefins with azides catalyzed by [Co(P3)].[a,b,c]
various fluoroaryl azides.[a,b,c]
entry 1: 3ab;
entry 2: 3af;
entry 3: 3bf;
99% yield, 94% ee
99% yield, 92% ee
99% yield, 96% ee
entry 1:[e] 3aa;
entry 2: 3ac;
entry 3:[d] 3ad;
52% yield, 75% ee
64% yield, 80% ee
80% yield, 96% ee
entry 4: 3cb;
entry 5: 3cf;
entry 6: 3df;
99% yield, 92% ee
95% yield, 94% ee
99% yield, 87% ee
entry 4: 3ae;
entry 5: 3af;
entry 6: 3ag;
95% yield, 89% ee
99% yield, 92% ee
96% yield, 90% ee
entry 7: 3eb;
entry 8: 3 fb;
entry 9: 3gb;
85% yield, 92% ee
99% yield, 87% ee
77% yield, 92% ee
entry 7: 3ah;
entry 8: 3ai;
entry 9: 3aj;
95% yield, 80% ee
99% yield, 68% ee
no reaction
See Table 1 for footnotes [a], [b], [c], and [e]. [d] Determined by X-ray
diffraction.
entry 10:[d] 3gf;
91% yield, 85% ee
entry 11: 3hb;
80% yield, 92% ee
entry 12: 3ib;
93% yield, 95% ee
ate (Figure 1), di-ortho-fluoro-substituted aryl azides were
found to be more selective and effective aziridinating agents
than mono-ortho-fluoro-substituted aryl azides. Similarly, 4-
tetrafluoropyridinyl azide (2g) was found to be equally
effective in the aziridination of styrene, without complication
from potential coordination of the pyridine unit to [Co(P3)]
(Table 2, entry 6). Reactions with para-substituted fluoroaryl
azides, such as 4-bromotetrafluorophenyl azide (2h) and 4-
trifluoromethyltetrafluorophenyl azide (2i), produced the
desired products in excellent yields, albeit with slightly
lower enantioselectivities (Table 2, entries 7 and 8). It is
worth noting that 3,4,5-trifluorophenyl azide (2j), which
contains three F atoms but none of them in ortho position,
gave no reaction under the same conditions (Table 2, entry 9),
entry 13:[d] 3if;
90% yield, 91% ee
entry 14:[d] 3jb;
81% yield, 92% ee
entry 15: 3kb;
82% yield, 93% ee
entry 16: 3kf; 95%
yield, 89% ee
entry 17: 3lb; 80%
yield, 90% ee
entry 18: 3lf; 73%
yield, 98% ee
entry 19: 3mb; 74%
yield, 86% ee
entry 20: 3nf; 90%
yield, 85% ee
entry 21: 3ob; 80%
yield, 96% ee
See Table 1 for footnotes [a], [b], and [c]. [d] Determined by X-ray
diffraction.
À
again suggesting the important role the N H···F hydrogen
bond plays in the CoII-based metalloradical aziridination
process (Figure 1).[18]
The [Co(P3)]-catalyzed asymmetric aziridination was
found to be suitable for a wide range of aromatic olefins
with varied electronic and steric properties, as shown for
2,4,6-trifluorophenyl azide (2b) and pentafluorophenyl azide
(2 f) as representative fluoroaryl azides (Table 3).[19] Similar
to styrene, styrene derivatives with electron-donating sub-
stituents at various positions, including Me, tBu, and MeO
groups at the para, meta, and ortho positions, could be
aziridinated smoothly to form the corresponding N-fluoroaryl
aziridines in high yields and enantioselectivity (Table 3,
entries 1–8). In addition, enantioenriched N-fluoroaryl azir-
idines could be readily formed from aziridination reactions of
electron-deficient styrenes, such as para-CF3- and para-
CO2Me-substituted styrenes (Table 3, entries 9–11). More-
over, [Co(P3)] could effect aziridination of various halogen-
ated styrenes, such as fluorostyrenes and bromostyrenes,
producing the corresponding aziridines with high enantio-
meric excesses (Table 3, entries 12–16). The CoII-based asym-
metric aziridination could also be successfully applied to
extended aromatic olefins, including 2-vinylnaphthalene and
sterically demanding 1-vinylnaphthalene and 9-vinylanthra-
cene (Table 3, entries 17–20). Notably, heteroaromatic
alkenes such as Boc-protected 3-vinylindole could also be
aziridinated with fluoroaryl azides to generate the desired
aziridinylindole 3ob in high yield and excellent enantioselec-
tivity (Table 3, entry 21).
The demonstrated asymmetric olefin aziridination with
fluoroaryl azides by catalysis with CoII-based metalloradical
provides a practical method to access N-fluoroaryl-containing
chiral compounds in high enantiomeric purity, which may find
applications in asymmetric synthesis and pharmaceuticals.[9]
An initial exploration of further transformations of these
chiral N-fluoroaryl aziridines showed that the aziridine ring
could be readily opened in the presence of a Lewis acid
without apparent loss of the enantiomeric purity [Scheme 2,
Eqs. (1)–(3)].[20] For instance, N-fluoroaryl-containing chiral
aziridines 3ab and 3af readily underwent ring-opening
reactions with MeOH in the presence of Cu(OTf)2, thus
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respectively, in high yields and with high optical purity
[Eqs. (1) and (2)]. X-ray structural analysis showed the
absolute configuration of the carbon stereocenter in product
5 to be (R) (see the Supporting Information), thus indicating
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lective aziridination of alkenes with fluoroaryl azides. This
CoII-based process represents the first catalytic system for
asymmetric olefin aziridination with aryl azides as the nitrene
source. Among other attributes, the metalloradical aziridina-
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limiting reagent without the need of any additives, thus
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Received: November 30, 2012
Revised: February 17, 2013
Published online: && &&, &&&&
À
catalyzed C H amination, see: c) V. Lyaskovskyy, A. I. O.
Keywords: aziridines · aryl azides · asymmetric catalysis ·
cobalt · porphyrins
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Angewandte
Chemie
[15] Y. Chen, K. B. Fields, X. P. Zhang, J. Am. Chem. Soc. 2004, 126,
14718.
[19] The current catalytic system was found to be ineffective for
disubstituted alkenes. For substrates that contain secondary and
À
À
[16] X. Xu, H. Lu, J. V. Ruppel, X. Cui, S. Lopez de Mesa, L. Wojtas,
X. P. Zhang, J. Am. Chem. Soc. 2011, 133, 15292.
[17] Chiral porphyrin P3 was developed using an iterative approach
based on CoII-catalyzed asymmetric cyclopropanation.[16] For
details on its synthesis and X-ray crystal structure, see the
Supporting Information.
[18] a) No reactions were observed with phenyl azide and 2,6-
dichlorophenyl azide; b) an inverse kinetic isotope effect was
observed with deuterated catalyst.
allylic C H bonds, catalytic C H amination was observed
instead of olefin aziridination.
[20] a) M. K. Ghorai, K. Das, D. Shukla, J. Org. Chem. 2007, 72, 5859.
Preliminary results showed the possibility of further trans-
formations of these polyfluorinated aryl groups by SNAr
reactions, see related references: b) M. Bella, S. Kobbelgaard,
K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127, 3670; c) L. Qin, C.
Sheridan, J. Gao, Org. Lett. 2012, 14, 528; d) A. Rolfe, T. B.
Samarakoon, P. R. Hanson, Org. Lett. 2010, 12, 1216.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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.
Angewandte
Communications
Communications
Asymmetric Catalysis
L. M. Jin, X. Xu, H. Lu, X. Cui, L. Wojtas,
X. P. Zhang*
&&&& — &&&&
Effective Synthesis of Chiral N-Fluoroaryl
Aziridines through Enantioselective
Aziridination of Alkenes with Fluoroaryl
Azides
The CoII complex of a D2-symmetric chiral
porphyrin ([Co(D2-Por*)], see scheme) is
a highly effective catalyst for the enantio-
selective aziridination of alkenes with
fluoroaryl azides. The reaction can be
performed at RTwith low catalyst loading,
and the olefin is the limiting reagent.
Furthermore, the reaction is tolerant
toward different combinations of aro-
matic olefins and fluoroaryl azides.
6
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!