Dynamic kinetic asymmetric cycloadditions of isocyanates to vinylaziridines

Article abstract of DOI:10.1021/ja037450m

The first examples of the use of racemic vinylaziridines in a Pd-catalyzed dynamic kinetic asymmetric transformation have been examined. Optimization studies of the Pd-catalyzed addition of vinylaziridines to isocyanates revealed that the chiral ligand be

Full text of DOI:10.1021/ja037450m

Published on Web 09/09/2003
Dynamic Kinetic Asymmetric Cycloadditions of Isocyanates to Vinylaziridines
Barry M. Trost* and Daniel R. Fandrick
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received July 21, 2003; E-mail: bmtrost@stanford.edu
Table 1. Representative Additive Effect for N-Benzylvinylaziridinea
The dynamic kinetic asymmetric transformations (DYKATs) of
7
racemic compounds in simple addition reactions provide an efficient
and atom economic synthesis of useful chiral compounds.1 In
particular, the highly enantioselective addition of alcohols, amines,
phthalimide, and acetoacetates to vinyl epoxides has recently been
reported with the Trost ligands 4 and 5.2 Although aziridines are
normally considerably less reactive toward nucleophilic additions,
their successful reaction with isocyanates in the presence of
Pd(O)3-5 led us to consider their ability to function in a DYKAT
process (eq 1). To obtain asymmetric induction for the palladium-
catalyzed DYKATs of vinylaziridines, the interconversion of the
diastereomeric π-allyl palladium intermediates via a η3-η1-η3
interconversion must occur faster than the subsequent nucleophilic
addition and be under Curtin-Hammett conditions. To initiate this
methodology, we chose isocyanates as the addition component to
circumvent regioselectivity issues.
Initial experiments were preformed with the parent aziridine (R1
) CH2C6H5, R2 ) H) and phenyl isocyanate using conditions
analogous to those of Alper et al.3c (eq 1). Using 4 mol % Pd-
(OAc)2 and 10 mol % (R,R) 4 in degassed THF at ambient
temperature, we synthesized the corresponding imidazolidinone in
29% yield and a modest 59% ee after 24 h. After optimization of
the palladium precatalyst, ligand, and solvent, the yield can be
increased to 98% with still a modest 41% ee using 2 mol % (η3-
C3H5PdCl)2 and 6 mol % (R,R) 5 in degassed methylene chloride
for 2 h at room temperature. Additionally, variation of the
temperature, concentration, or solvent showed little improvement
on the enantioselectivity, but at least 2 mol % (η3- C3H5PdCl)2
was necessary for complete conversion on a 1 mmol scale.
entry
additive (pK in H O )
timeb
convc
yieldd
eee
a
2
1
2f
3f
4f
5
6
7
8
9
none
none
4% TBAT
4% THACl
2 h
20 h
4 h
30 h
2 h
2 h
2 h
2 h
4 h
100%
83%
100%
83%
100%
100%
100%
100%
∼98%
100%
100%
∼50%
98%
62%
73%
42%
98%
99%
99%
98%
84%
96%
ND
41%
43%
35%
43%
77%
80%
82%
77%
70%
81%
72%
11%
6% pivalic acid (5.0)
6% AcOH (4.8)
10% AcOH (4.8)
6% formic acid (3.8)
6% TFA (0.5)
10
11
12
12% HOBt (4.6)
10% HOAt (3.5)
10% TBAOAc
2 h
2 h
20 h
ND
a Reactions were conducted with aziridine (R1 ) CH2C6H5, R2 ) H), 2
mol % (η3 C3H5PdCl)2, 6 mol % 5, 0.12 M in CH2Cl2, 1 equiv of PhNCO
at room temperature. b Time until complete consumption of aziridine or
until the indicated time. c Conversion based on ratio of product to SM by
1H NMR. d Isolated yield. e ee determined by chiral HPLC. f Reactions
conducted in THF. ND ) Not determined. TFA ) Trifluoroacetic acid.
HOAt ) 1-Hydroxy-7-azabenzotriazole. HOBt ) 1-Hydroxybenzotriazole.
TBAOAc ) Tetrabutylammonium acetate. THACl ) Tetrahexylammonium
chloride.
amine bases at various quantities in addition to TBAT and showed
little effect on the enantioselectivity disfavoring the decomposition
of TBAT as the source of the irreproducibility. On the other hand,
the adventitious water leading to acidic conditions may have
influenced the enantioselectivity. Therefore, we studied the effect
of an acid and a halide additive (Table 1).
Contrary to other Pd-AAA reactions requiring Curtin-Hammett
conditions, halide ions had little, if any, effect (entries 3 and 4),
and carboxylate had a deleterious effect (entry 12). On the other
hand, acid additives had a dramatic effect (entries 5-11). The effect
seems to be dependent upon the pKa, which, if translated to an
aqueous medium, would correspond to approximately 4.7. Varying
acetic acid from 4 to 25 mol % demonstrated that 8 or more mol
% acetic acid was necessary for optimal enantioselectivity. Addition
of acyl transfer catalysts such as DMAP showed no effect on the
enantioselectivity with or without acetic acid. More interestingly,
HOBt (entry 10) was as effective as acetic acid, and HOAt (entry
11) was somewhat inferior. It appears then that the role of HOBt
is more related to its pKa than to its ability to promote acyl transfer.
In accord with this interpretation, the more acidic HOAt gave lower
ee’s. A reasonable rationalization relates to the requirement that
equilibration of the diastereomeric π-allyl palladium intermediates
must be faster than cyclization to achieve high ee in a DYKAT.
By protonation of the nitrogen upon opening of the aziridine which
should slow its rate of addition to the isocyanate or the nitrogen of
the initial adduct between the ring opened aziridine and the
isocyanate which slows the cyclization rate, an η3-η1-η3 inter-
conversion of the π-allyl palladium intermediates can compete
effectively with product formation. Thus, a Curtin-Hammett
situation is created wherein the enantiodiscriminating event is the
cyclization.
The low enantioselectivity was attributed to the nucleophilic
addition competing with the rapid interconversion of the π-allyl
palladium intermediates. Halide additives have been shown to
increase the rate of this interconversion and lead to higher
enantioselectivities for the DYKAT of epoxides.2 Addition of 4-10
mol % TBAT (tetrabutylammonium triphenyl-difluorosilicate) to
reaction 1 initially increased the enantiomeric excess to ∼70% at
5 °C with 2 mol % (η3C3H5PdCl)2 and 6 mol % (R,R) 5 in degassed
THF after 24 h. Using different sources of TBAT led to irrepro-
ducibility of the results. Water may have contaminated the acid-
sensitive TBAT6 and in the presence of isocyanates furnished an
acidic solution. Experiments were performed with several tertiary
9
11836
J. AM. CHEM. SOC. 2003, 125, 11836-11837
10.1021/ja037450m CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Isocyanate and Aziridine Effect on Eq 1a
Scheme 2. Conversion of Imidazolidinone 8b to a SALEN Liganda
b
ee %
(yield % )
1
2
3
c
entry
R
R
R
1
2d
3f
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
o-NO2C6H4CH2
o-NO2C6H4CH2
p-CH3OC6H4
tosyl
H
Ph
COC6H5
p-CH3OC6H4
CH2C6H5
o,p-(CH3O)2C6H3
p-CH3SC6H4
Ph
Ph
82 (99)
13 (94)
90 (99)
95 (98)
91 (96)
85 (85)
80 (60)
83 (99)
82 (99)
74 (52)
65 (61)
H
H
H
H
H
CH3
H
H
4e
5e
6
a Reagents and conditions: (a) Pd(OH)2/C, 85 psi H2, MeOH, 26 h. (b)
Salicylaldehyde, MeOH, reflux 2 h (∼60% for two steps).
7
8
9
[R]D ) +223 (c ) 0.72 in CHCl3)) to establish the absolute
configuration for imidazolidin-2-one 6b as (S). By analogy, the
absolution configurations of the imidazolidinones in entries 1 and
3-11 (Table 2) were assigned accordingly.
In summary, these reactions report the first examples of the
asymmetric cycloaddition of isocyanates to vinyl aziridines. High
yields and enantioselectivity can be obtained for a broad array of
imidazolidin-2-ones through simple addition reactions. Also, chiral
diamines can be efficiently synthesized from the imidazolidin-2-
ones.
p-CH3OC6H4
Ph
Ph
10e
11
H
H
a Reactions were conducted with 2 mol % (η3 C3H5PdCl)2, 6 mol % 5
(R,R), 10 mol % AcOH, 1 equiv of of isocyanate, and 0.12 M in CH2Cl2
for 2 h. b ee determined by chiral HPLC. c Isolated yield. d 8 h. e 18 h.
f Reaction was conducted with 1 mol % (η3 C3H5PdCl)2, 3 mol % 5 (R,R),
5 mol % AcOH, 1 equiv of isocyanate, and 0.24 M in CH2Cl2.
Scheme 1. Conversion of Imidazolidinones to Diaminesa
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences
Institute (GM-13598) for their generous support of our programs.
Mass spectra were provided by the Mass Spectrometry Facility of
the University of California-San Francisco, supported by the NIH
Division of Research Resources.
a Reagents and conditions: (a) LiAlH4, Et2O, reflux 2-20 h. (b)
H2NOH‚HCl, 0.01% HCl aq 60 °C, 1 h (8a 91%, 8b 94% for two steps).
Supporting Information Available: Full experimental procedures,
synthesis of aziridines, and characterization data for all unknown
compounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Having developed highly enantioselective conditions for the
DYKAT of vinylaziridines, we examined the scope of the substrate
and isocyanate (Table 2). Generally, the cycloaddition furnished
the chiral imidazolidinone in high yield and enantiomeric excess
with electron-rich isocyanates. The enantioselectivity correlated with
the electrophilicity of the isocyanate. With the parent aziridine, the
enantiomeric excess ranged from 13% with benzoyl isocyanate to
95% with benzyl isocyanate (entries 1-6). Similarly, the more
electron-rich p-anisyl isocyanate (entry 3) gave higher ee’s than
phenyl isocyanate (entry 1). Substituents at the 2 position of the
vinyl aziridine, or ortho position of the benzyl moiety, and N-aryl
aziridine are all well tolerated in the DYKAT (entries 7-10). The
enantioselectivity was dramatically lower for N-tosyl aziridine (entry
11) than the parent aziridine. Interestingly, a tetrasubstituted carbon
by using a 1,1-disubstituted aziridine (entry 7) was created in about
the same ee as that for the parent vinylarizidine (entry 1), although
the reaction was somewhat less efficient as was reflected by the
lower yield.
Imidazolidinones 6 were efficiently converted to their corre-
sponding diamines 8 through the transformations shown in Scheme
1. LAH reduction provided the sensitive imidazolidines in high
yield. Typical hydrolyses utilize strong aqueous acidic conditions
that are not compatible with N-aryl or N-benzyl substituents.8,9 The
hydrolysis with hydroxylamine10 in weakly acidic conditions enables
the conversion to the diamines in >90% yield for the two steps.
The absolute configuration of the imidazolidinones was estab-
lished by conversion of 8b to the known SALEN ligand 10 (Scheme
2). The filtrate of the hydrogenation and hydrogenolysis of 8b (95%
ee from 6b) was directly subjected to salicyaldehyde to yield 10 in
reasonable purity with an [R]27D ) +174 (c ) 0.66 in CHCl3) (lit11
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