Phosphine-catalyzed heine reaction

Article abstract of DOI:10.1021/ol202410v

Aziridines are important synthetic intermediates which readily undergo ring-opening reactions. It is demonstrated that electron-rich phosphines are efficient catalysts for the regioselective rearrangement of N-acylaziridines to oxazolines. The reactions o

Full text of DOI:10.1021/ol202410v

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5444–5447
Phosphine-Catalyzed Heine Reaction
Allen Martin, Kathleen Casto, William Morris, and Jeremy B. Morgan*
Department of Chemistry and Biochemistry, University of North Carolina Wilmington,
Dobo Hall, Wilmington, North Carolina 28403, United States
morganj@uncw.edu
Received August 2, 2011
ABSTRACT
Aziridines are important synthetic intermediates which readily undergo ring-opening reactions. It is demonstrated that electron-rich phosphines
are efficient catalysts for the regioselective rearrangement of N-acylaziridines to oxazolines. The reactions occur in excellent yield under neutral
conditions. Evidence is provided for an addition/elimination mechanism by generation of a phosphonium intermediate. Similar intermediates may
be useful for the development of alternate aziridine ring-opening processes and stereoselective synthesis with enantiopure phosphines.
Aziridines have a rich history as versatile intermediates
in organic synthesis.1 The strained three-membered ring is
highly activated for ring-opening nucleophilic addition by
a range of nucleophiles.2 Upon functionalization by ring-
opening, advanced amine synthons are produced for
applications in the fine chemical industry and bioactive mole-
cule synthesis. The aziridine structure is often chiral offer-
ing opportunities to access enantiopure intermediates.
Nucleophilic derivatization is also proposed to play an im-
portant role in the biological activity of aziridine-containing
natural products.
The aziridine ring-opening reaction with nucleophiles
primarily serves to introduce new functionality; however,
the potential of employing nucleophiles to catalyze azir-
idine transformations is well-known. Heine originally re-
ported a series of intramolecular aziridine rearrangements
that take place in the presence of nucleophilic inorganic
salts, such as sodium iodide.3 Specifically, the rearrangement
of N-acylaziridines tooxazolines is known tooccur under a
range of Lewis acid4 and Lewis base-catalyzed5 conditions.
Recently, organic catalysts, such asamines,6 N-heterocyclic
carbenes,7 and phosphines,8 have been investigated for
intermolecular aziridine opening reactions with a variety
of nucleophiles. However, phosphines have not been
(4) (a) Thyrum, P.; Day, A. R. J. Med. Chem. 1965, 8, 107–111. (b)
Heine, H. W.; Kaplan, M. S. J. Org. Chem. 1967, 32, 3069–3074. (c)
Lown, J. W.; Itoh, T.; Ono, N. Can. J. Chem. 1973, 51, 856–869. (d)
Eastwood, F. W.; Perlmutter, P.; Yang, Q. J. Chem. Soc., Perkin Trans.
1 1997, 35–42. (e) Bonini, B. F.; Fochi, M.; Comes-Franchini, M.; Ricci,
A.; Thijs, L.; Zwanenburg, B. Tetrahedron: Asymmetry 2003, 14, 3321–
3327.
(5) (a) Heine, H. W.; Proctor, Z. J. Org. Chem. 1958, 23, 1554–1556.
(b) Nishiguchi, T.; Tochio, H.; Nabeya, A.; Iwakura, Y. J. Am. Chem.
Soc. 1969, 91, 5835–5841. (c) Nishiguchi, T.; Tochio, H.; Nabeya, A.;
Iwakura, Y. J. Am. Chem. Soc. 1969, 91, 5841–5846. (d) Hori, K.;
Nishiguchi, T.; Nabeya, A. J. Org. Chem. 1997, 62, 3081–3088. (e)
Ferraris, D.; Drury, W. J.; Cox, C.; Lectka, T. J. Org. Chem. 1998, 63,
4568–4569. (f) Cardillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli, A.
Tetrahedron 2001, 57, 2807–2812.
(6) (a) Minakata, S.; Okada, Y.; Oderaotoshi, Y.; Komatsu, M. Org.
Lett. 2005, 7, 3509–3512. (b) Wu, J.; Sun, X.; Li, Y. Eur. J. Org. Chem.
2005, 4271–4275.
(7) (a) Liu, Y. K.; Li, R.; Yue, L.; Li, B. J.; Chen, Y. C.; Wu, Y.; Ding,
L. S. Org. Lett. 2006, 8, 1521–1524. (b) Sun, X.; Ye, S.; Wu, J. Eur. J.
Org. Chem. 2006, 4787–4790. (c) Wu, J.; Sun, X.; Ye, S.; Sun, W.
Tetrahedron Lett. 2006, 47, 4813–4816.
(8) (a) Hou, X.-L.; Fan, R.-H.; Dai, L.-X. J. Org. Chem. 2002, 67,
5295–5300. (b) Fan, R. H.; Hou, X. L. Tetrahedron Lett. 2003, 44, 4411–
4413. (c) Wu, J. Y.; Luo, Z. B.; Dai, L. X.; Hou, X. L. J. Org. Chem. 2008,
73, 9137–9139. (d) Matsukawa, S.; Tsukamoto, K. Org. Biomol. Chem.
2009, 7, 3792–3796.
(1) (a) McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365. (b)
Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247–258. (c) Sweeney, J. B. In
Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, 2006.
(2) For recent reviews, see: (a) Hu, X. E. Tetrahedron 2004, 60, 2701–
2743. (b) Lu, P. Tetrahedron 2010, 66, 2549–2560.
(3) (a) Heine, H. W.; Fetter, M. E.; Nicholson, E. M. J. Am. Chem.
Soc. 1959, 81, 2202–2204. (b) Heine, H. W.; Bender, H. S. J. Org. Chem.
1960, 25, 461–463. (c) Heine, H. W.; King, D. C.; Portland, L. A. J. Org.
Chem. 1966, 31, 2662–2665.
r
10.1021/ol202410v
Published on Web 09/29/2011
2011 American Chemical Society

reported as catalysts for the rearrangement of aziridines to
oxazolines.
Table 1. Identification of Phosphine Catalysts for the Rearran-
gement of Aziridine 4a
Scheme 1. Nucleophile-Catalyzed Rearrangement of Aziridines
entry
catalyst
yield (%)b
5:6
1
PPh3
0
0
;
2
P(OPh)3
;
We considered that phosphines may be active catalysts
for the intramolecular rearrangement of aziridines by the
mechanism outlined in Scheme 1. Nucleophile attack on
the least hindered carbonofaziridine 1 should result in ring
expansion by cyclization on the amide oxygen forming
oxazoline 3. If successful, the proposed intermediate (2)
might beengineeredtofurnish a range of interesting hetero-
cycles by modifying the nature of the aziridine protecting
group. If phosphines could be designed to operate via this
addition/elimination mechanism, we envisioned the develop-
ment of novel asymmetric reactions employing enantio-
enriched phosphines. Herein, we describe the application
of nucleophilic phosphine catalysis to the rearrangement
of N-acylaziridines, also recognized as the Heine reaction.9
Identification of an adequate phosphine catalyst began
with conversion of aziridine 4, activated for nucleophilic
ring openning, to a mixture of oxazolines 5 and 6 (Table 1).
Phosphine catalysts were chosen to represent varying
degrees of Lewis basicity and steric encumberance around
the phosphorus atom.10 Catalysts were screened at 70 °C in
THF to minimize thermal aziridine decomposition.11 Yield
and regioselectivity trends based on phosphine structure
quickly emerged. When 4 was heated in the presence of
10 mol % of PPh3, only unchanged starting material was
observedby 1H NMR after24h(entry1). While alessbasic
phosphite led to the same result (entry 2), a slight increase
in basicity resulted in a dramatic enhancement in yield
(entry 3). For the first time a phosphine-catalyzed rearrange-
ment of aziridines to oxazolines had been realized. A further
increase in phosphine basicity by employing tricyclohexyl-
phosphine (PCy3) was not tolerated (entry 4). Two tethered
diphosphines with similar basicity to PCyPh2 were investi-
gated but, for unknown reasons, failed to give any rearran-
gement product (entries 5À6).
c
3
PCyPh2
88
11
0
10:1
1.5:1
;
c
4
PCy3
5
dppec
dppbc
7
6
0
;
7
68
7
12:1
1.3:1
>20:1
11:1
>20:1
8
8
9
9
8
10
11
10
85
35
11
a Conditions: 4 (0.1 mmol), catalyst (0.01 mmol), THF (0.2 M), 70 °C,
24 h. b Yield determined by 1H NMR of the crude reaction mixture with
1,3,5-trimethoxybenzene as internal standard. c Cy = cyclohexyl, dppe =
bis(diphenylphosphino)ethane, dppb = bis(diphenylphosphino)butane.
Experiments to better understand the catalyst structural
effects were continued with a series of phosphines developed
by Buchwald and co-workers12 for transition metal catalysis
(Figure 1). The basic, sterically congested phosphines, which
are generally air-stable,13 were utilized in the rearrangement
(Table 1, entries 7À11). All exhibited some reactivity; how-
ever, sterics played a vital role in reaction yield and regios-
electivity. While the sterically hindered biaryl phosphine 7
resulted in good conversion, replacement of the tert-buyl
groups with cyclohexyl substituents (8) was detrimental14
(entries 7À8). The structure of the phenyl ring ortho to
phosphorus also played an important role in catalytic activity.
Adding substituents to the adjacent biaryl ring resulted in
lower yields but higher selectivities (entries 9 and 11). We were
intrigued to find that cyclohexyl-derived catalysts were viable
if the ortho-aryl ring was bulkier (10, entry 10). The increased
steric bulk in X-Phos15 (10) likely prevents a catalyst decom-
position pathway available to other cyclohexyl phosphines.
€
ꢀ
(9) Kurti, L.; Czako, B. In Strategic Applications of Named Reactions
in Organic Synthesis; Hayhurst, J., Ed.; Elsevier Academic Press: USA,
2005; pp 198À199.
(10) Tolman, C. A. Chem. Rev. 1977, 77, 313–348.
(11) N-Acylaziridines are reported to undergo thermal rearrange-
ment to allylamides. We have observed that 4 begins to undergo the same
rearrangement at 90 °C in DME and 1,4-dioxane. (a) Fanta, P. E.;
Walsh, E. N. J. Org. Chem. 1966, 31, 59–62. (b) Szeimies, G.; Mannhardt,
K.; Junius, M. Chem. Ber. 1977, 110, 1792–1803.
(12) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722–9723. (b) Tomori, H.; Fox, J. M.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 5334–5341. For general reviews, see: (c) Muci,
A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–209. (d)
Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599–1626.
Figure 1. Structurally diverse phosphine catalysts.
Org. Lett., Vol. 13, No. 20, 2011
5445

The effect of varying the benzoyl substituent on reaction
yield and selectivity was investigated. A series of protected
aziridines with varying sterics and electronics were synthe-
sized and subjected to optimized conditions (Table 2).
A collection of terminal, DNB-protected aziridines
(entries 1À6, Table 3) were prepared16 and reacted under
Table 3. Substrate Scope for the Phosphine-Catalyzed Rear-
rangementa,e
Table 2. Effect of Aryl Substitution on Catalytic Rearrange-
ment with 10a
a Conditions: aziridine (0.3 mmol), 10 (0.03 mmol), THF (0.2 M),
70 °C, 24 h. b Average isolated yield from two or more runs. c Regioiso-
meric ratio (rr) = 4-methyl:5-methyl.
Upon reaction scale-up, reactivity was inconsistent for
PCyPh2 and 7. Fortunately, X-Phos (10)-catalyzed reac-
tions were reproducible on a 0.3 mmol scale, and 10 became
the catalyst of choice. Though all aziridines underwent
some level of rearrangement, benzoyl rings substituted with
electron-withdrawing groups were superior. The low yields
in entries 1À3 are the result of low conversion, but longer
reaction times did not improve the yields. Complete con-
sumption of aziridine was observed for entries 4À8. With
the best mix of yield and regioselectivity, we settled on the
3,5-dinitrobenzoyl (DNB) protecting group (entry 5) for
further investigations into substrate scope.
a Conditions: aziridine (0.3 mmol), 10 (0.03 mmol), THF (0.2 M),
70 °C, 24 h. b Average isolated yield from two or more runs. c Only the
depicted regioisomer was observed following isolation. d Only the start-
ing aziridine was observed by 1H NMR. e DNP = 3,5-dinitrophenyl.
the X-Phos-catalyzed rearrangement conditions. The 3,
5-dinitrophenyl (DNP) derived oxazolines were isolated
with good to excellent yields as a single regioisomer in all
cases. A remote alkene (entry 2) and ethers (entries 5À6)
are tolerated under the neutral rearrangement conditions.
For terminal aziridines, increasing the steric bulk of the
substituent on the carbon backbone had no detrimental
effect on the reaction yield (entries 3À4). However, the
lone disubstituted aziridine did not undergo rearrange-
ment (entry 7).
Terminal aziridines contain a chiral center which is
retained in the product oxazolines. To ascertain if chirality
transfer was occurring, aziridine 12 was synthesized with
>99% ee and subjected to the optimized rearrangement
conditions. Oxazoline 13was isolatedin 94% yield without
loss of enantiopurity (Scheme 2). The stereospecificity of
the rearrangement not only is important for synthetic
application in asymmetric synthesis but also sheds light
on the reaction mechanism.
(13) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
5096–5101.
(14) The poor regioselectivity exhibited by some cyclohexyl-derived
phosphine catalysts is attributed to catalyst decomposition since low
yields were also observed (Table 1, entries 4, 8).
(15) Commercially available from Strem Chemicals. For seminal
publications, see: (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653–6655.
(b) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 11818–11819.
(16) A desirable substrate class is 2-aryl aziridines; however, we have
found that such substrates readily rearrange to the 5-aryl oxazolines.
This undesirable rearrangement occurs at 70 °C in THF in the absence of
phosphine catalyst, is promoted by silica gel (as seen during the
attempted purification of the substrate), and presumably involves
rearrangement at the activated benzylic CÀN bond.
5446
Org. Lett., Vol. 13, No. 20, 2011

Scheme 2. Phosphine-Catalyzed Rearrangement of an Enan-
tioenriched Aziridine
Scheme 3. Proposed Catalytic Cycle
We propose a catalytic cycle similar to that orginially
suggested by Heine3a (Scheme 3). Terminal aziridine 14 is
susceptible to attack at the least hindered carbon by a
nucleophilic phosphine (15). The intermolecular reaction
would be rate limiting with a certain Lewis basicity at pho-
sphorus required for reactivity based on data in Table 1.
The balanced steric requirement for an optimal phosphine
catalyst can be explained by initial phosphine attack
coupled with the stability of intermediate 16. The phos-
phine catalyst must be small enough to efficiently open the
aziridine, but added steric bulk around phosphorus may
prevent nonproductive decomposition of 16. Following
collapse of 16 on oxygen, the correct regioisomer of oxazo-
line (17) is predicted and the stereochemical integrity is
maintained.
array of commercially available enantioenriched phos-
phines should also facilitate the development of an azir-
idine kinetic resolution.
Acknowledgment. We would like to thank Research
Corporation (Cottrell College Science Award) and UNCW
(Cahill Award) for funding.
A novel phosphine-catalyzed rearrangement of aziri-
dines has been described. Future experiments will be aimed
at developing intermolecular reactions that take advantage
of the proposed phosphonium intermediate. The diverse
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all unknown
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 20, 2011
5447