Aziridinyl vinyl ketones from the asymmetric catalytic aziridination reaction

Article abstract of DOI:10.1002/ejoc.200601126

Under the aegis of boron Lewis acids, prepared from either the vanol or vapol ligand, vinyl aziridinyl ketones can be obtained with a high degree of asymmetric induction from the catalytic asymmetric aziridination reaction (AZ) of imines and vinyl diazome

Full text of DOI:10.1002/ejoc.200601126

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200601126
Aziridinyl Vinyl Ketones from the Asymmetric Catalytic Aziridination Reaction
Yonghong Deng,[a] Young Rok Lee,[a] Cory A. Newman,[a] and William D. Wulff*[a]
Keywords: Aziridines / Asymmetric catalysis / Lewis acids
Under the aegis of boron Lewis acids, prepared from either
the vanol or vapol ligand, vinyl aziridinyl ketones can be ob-
tained with a high degree of asymmetric induction from the
catalytic asymmetric aziridination reaction (AZ) of imines
and vinyl diazomethyl ketones. The products have potential
as synthons for five-carbon chiral amines.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Asymmetric entry to optically pure aziridinyl vinyl
ketones was envisioned from vinyl diazomethyl ketone 2
and benzhydryl imine 3 (Scheme 1) by the catalytic asym-
metric aziridination reaction (AZ) that we have recently de-
veloped in our laboratories.[2,3] Catalysts prepared from
either the vapol or vanol ligand and triphenylborate are
capable of inducing the highly enantioselective formation of
cis-3-substituted aziridine-2-carboxylate esters 10 from
ethyl diazoacetate and benzhydryl imines (Scheme 2).[2] It
was a surprise to find that the asymmetric inductions ob-
served for this AZ reaction with both the vanol- and vapol-
derived catalysts mirrored each other in a nearly perfect
fashion over a range of aryl- and alkyl-substituted imines.
This was not the case for aluminum catalysts employed in
Diels–Alder reactions or for imino–aldol reactions where
the vapol-derived catalysts were superior to those from
vanol.[4,5] In contrast, vanol-derived catalysts were found to
be superior to those from vapol in aluminum catalysts for
the Baeyer–Villiger reaction[6] and in boron catalysts for the
Diels–Alder reaction.[7]
Introduction
Vinyl aziridinyl ketones of type 4 (Scheme 1) have the
potential to provide a platform that could be pivotal in per-
mitting access to a diverse array of highly functionalized
five-carbon fragments. Options for the introduction of func-
tionality into the system could be exercised at C1 and C2
by ring-opening of the aziridine, at C3 by addition to the
ketone, or at C4 and C5 by 1,4-addition reactions to the
alkene or by sequential Michael addition/alkylation events.
Furthermore, it can be envisioned that in these processes,
the stereochemical information contained in the aziridine
could be transmitted to all five carbons of the vinyl aziridi-
nyl ketone. Despite this potential, a search of the literature
produced only a single report for the preparation of an acy-
clic 2-aziridinyl vinyl ketone.[1]
Scheme 1.
[a] Department of Chemistry, Michigan State University,
East Lansing, MI 48824, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 2.
2068
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2068–2071

Aziridinyl Vinyl Ketones from an Aziridination Reaction
SHORT COMMUNICATION
The results from the catalytic asymmetric aziridination and obtained as white solids. In order to ensure that the
of four different diazomethyl vinyl ketones and ten different enantiomeric purity of the formed cis-aziridine 4 was prop-
imines are presented in Table 1. Diazomethyl vinyl ketones erly measured, care was needed in its isolation; most of the
2 were prepared from the corresponding methyl vinyl cis-aziridines in Table 1 can be readily enhanced to greater
ketones 1 by a diazo transfer reaction following the pro- than 99% ee by crystallization or simple precipitation.
cedure of Danheiser.[8] The imines were prepared from the
Most of the reactions in Table 1 were carried out with a
corresponding aldehyde and benzhydrylamine and purified catalyst prepared from the vapol ligand, but in two cases
by crystallization prior to use. The catalyst was prepared the corresponding reaction with the vanol-derived catalyst
by the reaction of either vanol or vapol with 3 equiv. of was examined, and it was found that similar asymmetric
triphenylborate in CH2Cl2 heated at 55 °C for 30 min fol- inductions were observed for both ligands (Table 1, En-
lowed by the removal of the volatiles at 55 °C under high tries 1, 2 and 18, 19). This mirrors the observation made
vacuum. The catalyst (10 mol-%) was then transferred to for the asymmetric aziridination with ethyl diazoacetate for
a flask containing a solution of imine in CH2Cl2 at room these two ligands. It was shown that ethyl diazoacetate adds
temperature, and after 5 min, 1.2 equiv. of the diazo com- to the si face of the imine when the aziridination reaction
pound was added. After 24 h, the reaction was stopped and is performed in the presence of (S)-vapol and (S)-vanol,[2]
the cis-aziridines were purified by silica gel chromatography and the same facial selectivity is assumed for the addition of
Table 1. Asymmetric aziridination of vinyl diazoketones.[a]
Entry
Imine
R4
Aziridine
Yield of cis 4[b]
ee of cis 4[c]
cis 4/trans 4[d]
Yield of 13[d]
[%]
[%]
[%]
Diazoketone 2a
Ph
Ph
1
2
3
4
5
6
7
8
3a
3a
3b
3c
3d
3e
3f
4a
4a
4b
4c
4d
4e
4f
79
61
45
55
64
78
71
51
80
84
90
95
92[e]
91
93
95
94
99.7
96
95
98.3
93
Ն50:1
Ն50:1
Ն50:1
12:1
15
9
2-MeC6H4
2-BrC6H4
2-F-5-BrC6H3
3-NO2C6H4
4-MeC6H4
4-BrC6H4
4-NO2C6H4
2-naphthyl
c-C6H11
17
18
12
16
17
20
8
14:1
Ն50:1
Ն50:1
14:1
Ն50:1
Ն50:1
5:1
3g
3h
3i
4g
4h
4i
9
10
11
8
3
3j
4j
Diazoketone 2b
Ph
4-MeC6H4
4-BrC6H4
4-NO2C6H4
c-C6H11
12
13
14
15
16
3a
3f
3g
3h
3j
4k
4l
4m
4n
4o
76
83
76
67
75
98.1
96.1
98.5
95.7
94.4
15:1
Ն50:1
20:1
7:1
15
12
15
13
15
10:1
Diazoketone 2c
Ph
17
3a
4p
85
95.7
25:1
11
Diazoketone 2d
Ph
Ph
18
19
3a
3a
4q
4q
40
35
82[f]
81[e]
6:1
6:1
26
43
[a] The catalyst was prepared from (S)-vapol and B(OPh)3 as described in the text and the Supporting Information. All reactions were
performed with imine (0.5 ) and diazo compound 2 (1.2 equiv.) in CH2Cl2 heated at 25 °C for 24 h. [b] Isolated yields after silica gel
chromatography. [c] Measured by chiral HPLC with chromatographed cis-aziridine. [d] Measured by 1H NMR spectroscopy with the
crude reaction mixture. [e] This reaction was performed with a catalyst prepared from (S)-vanol. [f] With one batch of 2d a 93% ee for
4q was obtained.
Eur. J. Org. Chem. 2007, 2068–2071
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2069

Y. Deng, Y. R. Lee, C. A. Newman, W. D. Wulff
SHORT COMMUNICATION
diazomethyl vinyl ketones. With the exception of the diazo syn,anti-aminodiol 15 and syn,syn-aminodiol 17, respec-
compound obtained from cyclohexenyl methyl ketone tively.
(Table 1, Entries 18 and 19), all of the reactions investigated
In conclusion, we have shown that the asymmetric cata-
in this work gave cis-aziridine 4 in greater than 90% ee. This lytic aziridination reaction (AZ) can be extended to di-
includes aziridines derived from alkyl imines and aryl im- azomethyl vinyl ketones with high degrees of asymmetric
ines that have both electron-withdrawing and electron-do- induction. The aziridinyl vinyl ketone products can be read-
nating groups in the para, meta, and ortho positions. The ily and stereoselectively transformed into chiral five-carbon
yields of the cis-aziridines are generally good to excellent, amine units. The further development of aziridinyl vinyl
except for diazo methyl ketone 2d, which gave nearly equal ketones as synthons for polyfunctionalized amines will be
amounts of enamine product 5. This vinyl diazo methyl reported in due course.
ketone is the only one examined that has a substituent on
the vinyl group alpha to the ketone. The cis to trans selectiv-
Experimental Section
ity is generally good to excellent and does vary a bit but
does not seem to correlate with the electron density on the
aryl ring or the position of the substituent on the aryl ring.
As an initial foray into a study aimed at the development
of aziridinyl vinyl ketones 4 as synthons for the asymmetric
(S)-vapol (27 mg, 0.05 mmol) in dry dichloromethane (1 mL) was
added to a flame-dried 25-mL single-necked round-bottomed flask
which had the 14/20 joint replaced with a threaded high-vacuum
telfon stopcock. After the addition of triphenylborate (43.5 mg,
synthesis of five-carbon amine fragments, we examined the 0.15 mmol), the stopcock was sealed, and the flask was heated at
55 °C for 1 h, and then a high vacuum was applied for 30 min with
the temperature maintained at 55 °C. The catalyst was then dis-
solved in dichloromethane (0.5 mL) and transferred by syringe to
a 25-mL flame-dried flask, which had been previously charged with
the requisite imine (0.50 mmol) in dichloromethane (0.5 mL). After
diastereoselectivity of the reduction of the ketone unit in
vinyl diazomethyl ketone 4a (Scheme 3). The reduction of
aziridinyl ketones is known to be highly stereoselective un-
der chelation-controlled conditions with bidentate Lewis
acids.[9] Thus, the reduction of 4a was first examined with
zinc borohydride. Despite our concerns with the presence
of the large benzhydryl substituent on the nitrogen which
might prevent coordination of zinc, it proved possible to
reduce the ketone moiety in 4a with zinc borohydride with
stirring for 10 min, the desired vinyl diazomethyl ketone
2
(0.6 mmol) was added. The reaction was monitored by TLC and
was found to be complete after 24 h at 25 °C. The reaction mixture
was diluted with dichloromethane (5 mL) and then saturated aque-
ous sodium hydrogencarbonate (5 mL) was added. The organic
Ͼ50:1 selectivity for diastereomer 14, which would be the layer was separated and then washed with brine (3 mL), dried with
resulting product from a chelation-controlled reduction.[10]
magnesium sulfate, filtered, and concentrated under vacuum to give
the crude product. The cis/trans ratio of aziridine 4 was determined
Nonchelation-controlled reduction of the ketone function-
ality in 4a could be effected with -Selectride in 99% yield
and with a 5:1 selectivity for diastereomer 16, which could
be readily separated from 14. Hydrolytic opening of the az-
by the relative integration of the 1H NMR spectroscopic signals for
the methine protons on the three-membered ring in the spectrum
of the crude reaction mixture. For most aziridines, these protons
appear as doublets between δ = 2 and 4 ppm and have coupling
iridine ring in both 14 and 16 could be achieved in high
constants of 7 Hz for the cis-aziridines and ca. 2 Hz for the trans-
yield and with complete inversion at the C3 position to give
aziridines. Purification by flash chromatography on silica gel (hex-
anes/ethyl acetate) gave the pure cis-aziridines as white solids. The
asymmetric induction was measured by chiral HPLC on the puri-
fied cis-aziridines. Care is required in the accurate determination
of the induction because the pure enantiomers of 4 are less soluble
than the racemate. The amount of enamine side product was calcu-
lated from the isolated yield of the cis-aziridine and the relative
integration of the NH signal of the enamine and the three-mem-
bered ring methine proton of the cis-aziridine in the crude reaction
mixture. The enamine side product is often formed as a mixture of
isomers and the NH absorption for both generally appear between
δ = 11.5 and 12.5 ppm. For each different substrate, a sample of
the racemic aziridine was prepared by the reaction of the appropri-
ate imine and vinyl diazomethyl ketone catalyzed by boron trifluo-
ride etherate. The racemic aziridine was utilized in the determi-
nation of the retention time of each enantiomer in the chiral HPLC
analysis. The absolute configuration of the cis-aziridine product
was assumed to result from si face addition to the imine by the
catalyst derived from (S)-vapol as was shown to be the case for the
reaction with ethyl diazoacetate.[2] Aziridine 4a: 79% yield, 95% ee,
cis/trans Ն50:1, [α]2D0 = +109.2 (c = 1, CH2Cl2). White solid, m.p.
150 °C, Rf = 0.33 (hexanes/ethyl acetate, 8:2). 1H NMR (300 MHz,
CDCl3): δ = 2.91 (d, J = 7.1 Hz, 1 H), 3.38 (d, J = 7.1 Hz, 1 H),
3.99 (s, 1 H), 6.81 (d, J = 16.2 Hz, 1 H), 7.08–7.41 (m, 17 H), 7.51–
7.55 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 49.8, 52.4,
Scheme 3.
2070
78.3, 123.6, 127.2, 127.3, 127.4, 127.5, 127.60, 127.63, 128.0, 128.3,
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2068–2071

Aziridinyl Vinyl Ketones from an Aziridination Reaction
SHORT COMMUNICATION
128.6, 128.7, 130.3, 134.6, 135.1, 142.2, 142.3, 142.5, 194.8 (one sp2
d) A. P. Patwardan, V. R. Pulgam, Y. Zhang, W. D. Wulff, An-
gew. Chem. Int. Ed. 2005, 44, 6169.
C not located) ppm. IR (KBr): ν = 3062, 3029, 1683, 1657, 1610,
˜
[3] a) For solid-state structures of the vapol ligand, see: C. P. Price,
A. J. Matzger, J. Org. Chem. 2005, 70, 1; b) For platinum com-
plexes of vanol and vapol, see: J. J. Becker, J. J. P. S. White,
M. R. Gagné, Organometallics 2003, 22, 3245.
[4] a) J. Bao, W. D. Wulff, A. L. Rheingold, J. Am. Chem. Soc.
1993, 115, 3814; b) D. P. Heller, D. R. Goldberg, W. D. Wulff,
J. Am. Chem. Soc. 1997, 119, 10551; c) D. P. Heller, D. R.
Goldberg, H. Wu, Hongqiao, W. D. Wulff, Can. J. Chem. 2006,
84, 0000.
1494, 1452, 1206, 1099, 764 cm–1. MS (EI): m/z (%) = 415 (1)
[M]+, 248 (77), 167 (100), 131 (40), 115 (42), 103 (34). C30H25NO
(415.5): calcd. C 86.71, H 6.06, N 3.37; found C 86.44, H 5.97, N
3.38. HPLC (chiralcel OD, hexanes/iPrOH = 90:10, flow rate =
1.0 mLmin–1): tR = 8.0 min (major enantiomer), tR = 11.2 min
(minor enantiomer).
Supporting Information (see footnote on the first page of this arti-
cle): Procedures for the preparation and catalytic asymmetric azir-
idination of ketones 4, including spectroscopic data. Procedure for
the reduction of 4a with -Selectride or with zinc borohydride. For-
mation of derivative 18, procedure for the ring-opening reaction of
the aziridines with aqueous trifluoroacetic acid, and preparation of
derivative 19.
[5] S. Xue, S. Yu, Y. Deng, W. D. Wulff, Angew. Chem. Int. Ed.
2001, 40, 2271.
[6] C. Bolm, J.-C. Frison, Y. Zhang, W. D. Wulff, Synlett 2004,
1619.
[7] J. Bao, W. D. Wulff, Tetrahedron Lett. 1995, 36, 3321.
[8] R. L. Danheiser, R. F. Miller, R. G. Brisbois, Org. Synth. 1996,
73, 134.
[9] J. M. Yun, T. B. Sim, H. S. Hahm, W. K. Lee, J. Org. Chem.
2003, 68, 7675.
[10] The relative stereochemistry of 14 was determined by X-ray
diffraction analysis on its para-nitrobenzoyl derivative, see Sup-
porting Information.
[1] H. A. Albar, Journal of King Abdulaziz University 1999, 11, 65;
Chem. Abstr. 2001, 134, 340471.
[2] a) J. C. Antilla, W. D. Wulff, J. Am. Chem. Soc. 1999, 121,
5099; b) J. C. Antilla, W. D. Wulff, Angew. Chem. Int. Ed. 2000,
39, 4518; c) C. Loncaric, W. D. Wulff, Org. Lett. 2001, 3, 3675;
Received: December 26, 2006
Published Online: March 14, 2007
Eur. J. Org. Chem. 2007, 2068–2071
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2071