Synthesis of aziridines by palladium-catalyzed reactions of allylamines with aryl and alkenyl halides: evidence of a syncarboamination pathway

Full text of DOI:10.1002/anie.200903178

Communications
DOI: 10.1002/anie.200903178
Synthetic Methods
Synthesis of Aziridines by Palladium-Catalyzed Reactions of
Allylamines with Aryl and Alkenyl Halides: Evidence of a syn-
Carboamination Pathway**
Sayuri Hayashi, Hideki Yorimitsu,* and Koichiro Oshima*
Palladium-catalyzed intramolecular carboetherification or
carboamination reactions of alkenes with organic halides
Table 1: Scope of the aryl and alkenyl halides in the palladium-catalyzed
aziridination/arylation or aziridination/alkenylation with 1a.
emerged as an attractive method to construct heterocycles,
forming both carbon–heteroatom and carbon–carbon bonds
in a single operation.[1] A number of five-membered hetero-
cycles have been synthesized by this methodology,[2,3] how-
ever, the preparation of strained three-membered hetero-
cycles has remained a challenge. We have previously reported
À
Entry
R X
2
Yield [%][a]
palladium-catalyzed carboetherification reactions of tertiary
allyl alcohols with aryl or alkenyl halides, which provide
multisubstituted epoxides.[4] We expected that the reaction
could be extended to carboamination for the synthesis of
aziridines starting from allylamines. Herein we present our
preliminary results of the carboamination along with evidence
for a plausible reaction mechanism.
Our investigation began with a reaction of N-phenylallyl-
amine 1a bearing two phenyl groups at the allylic position
(Table 1). Treatment of 1a with bromobenzene in the
presence of sodium tert-butoxide under palladium catalysis
1
2
3
4
5
6
7
8
C6H5Br
C6H5Cl
1-C10H7Br
2-MeOC6H4Br
4-MeOC6H4Br
4-Me2NC6H4Br
4-F3CC6H4Cl
4-(tBuO2C)C6H4Cl
4-(Et2NOC)C6H4Cl
2a
2a
2b
2c
2d
2e
2 f
2g
2h
2i
98
98
90
83
97
88
99
81
81
94
90
9
10
11
=
(CH3)2C CHCl
(E)-n-C5H11CH CHCl
=
2j
[a] Yield of isolated product. Cy=cyclohexyl, dba=dibenzylideneace-
À
led to aziridination and C C bond formation, providing the
tone.
corresponding arylated aziridine 2a in 98% yield (Table 1,
entry 1). In contrast to our previous epoxidation reactions, the
aziridination reaction did not suffer from a competitive
Mizoroki–Heck reaction.[4] Awide range of aryl bromides and
chlorides were incorporated into the corresponding aziridines
2a–2h in excellent yields (Table 1, entries 2–9). Alkenyl
chlorides also proved to be suitable substrates for the
aziridination reactions (Table 1, entries 10 and 11).
Table 2: Reactions with various N-arylallylamines with bromobenzene.
Entry
R
Ar
1
3
Yield [%][a]
The reactions of several N-arylallylamines with bromo-
benzene were then examined (Table 2). The electronic nature
of aryl substituents on the nitrogen atom did not affect the
efficiency of the reaction (Table 2, entries 1 and 2). Gratify-
ingly, alkyl-substituted allylamines 1d and 1e also underwent
the reaction in satisfactory yields (Table 2, entries 3 and 4).
1
2
3
4
Ph
Ph
n-C3H7
-(CH2)5-
4-MeOC6H4
4-FC6H4
Ph
1b
1c
1d
1e
3a
3b
3c
3d
92
96
92
76
Ph
[a] Yield of isolated product.
Next, we turned our attention to reactions of allylamines
bearing a stereogenic center at the aminated carbon atom, in
which two diastereomers could be obtained (Table 3). It was
found that the larger substituent, RL, and the benzyl moiety
were oriented in a cis configuration in the major diastereo-
mer.[5] Interestingly, the major diastereomer obtained in the
aziridination reaction possessed a configuration opposite to
that of the epoxides.[4] For instance, the reaction with 1 f
afforded 4a as a single diastereomer in 90% yield (Table 3,
entry 1). Moreover, allylamine 1g bearing a trifluoromethyl
group also took part in the reaction with high diastereoselec-
tivity (Table 3, entry 2). However, both yield and diastereo-
[*] S. Hayashi, Prof. Dr. H. Yorimitsu, Prof. Dr. K. Oshima
Department of Material Chemistry
Graduate School of Engineering, Kyoto University
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2438
E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp
oshima@orgrxn.mbox.media.kyoto-u.ac.jp
[**] This work was supported by Grants-in-Aid for Scientific Research
from MEXTand JSPS. S.H. acknowledges JSPS for financial support.
H.Y. acknowledges financial support from Eisai and Kyoto Univer-
sity.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903178.
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Chemie
Table 3: Diastereoselective synthesis of aziridines.
hydrogen atom at the alkene terminus, and the other is 1,2-
pseudoequatorial repulsion between the phenyl group
attached to the nitrogen atom and either RL or RS. Generally,
TS1 would be more favorable because of its smaller repulsion
energy relative to that of TS2, which involves a larger
repulsive interaction between RL and the phenyl group
(Table 3, entries 1 and 2). However, as RL becomes much
bulkier (Table 3, entry 3), the 1,3-allylic interaction cannot be
negligible in TS1. As a result, the difference of the energy
between the two transition states would be smaller, leading to
the lower diastereoselectivity in the case of the reaction with
1h.
Entry
RL
RS
1
4
Yield [%][a]
d.r.
1
Ph
Ph
tBu
Me
CF3
Me
1 f
1g
1h
4a
4b
4c
90
90
42
>99:1
93:7
59:41
2
3[b]
[a] Yield of isolated product. [b] Xylene was used instead of toluene. An
amount of 47% of 1h was recovered .
As described above, we hypothesize that the reaction
proceeds through syn aminopalladation of the palladium
amide intermediate B. However, an intermolecular anti-
aminopalladation pathway[8] is also conceivable. To confirm
syn aminopalladation, we performed the reaction of (Z)-
[D]1i with 1,2-dichlorobenzene (Scheme 3a). As a conse-
selectivity diminished when the more bulky tert-butyl-sub-
stituted allylamine 1h was used as a substrate (Table 3,
entry 3).
A mechanism of the reaction based on related prece-
dent[1,2,4] is proposed as shown in Scheme 1. Initial oxidative
Scheme 1. Plausible reaction mechanism.
addition of aryl halide to zerovalent palladium occurs to
provide arylpalladium halide A. Subsequent ligand exchange
between A and allylamine in the presence of sodium tert-
butoxide affords palladium amide B. It seems likely that B
would undergo reductive elimination to give the N-arylated
product under the reaction conditions.[6] However, intramo-
lecular coordination of the alkene moiety of B to the
palladium center would prevent such a reductive elimination.
The coordination and subsequent syn aminopalladation then
furnishes alkylpalladium intermediate C.[7] Finally, reductive
elimination from C takes place to give the corresponding
aziridine and to regenerate Pd0.
The observed diastereoselectivity in Table 3 could be
explained as follows (Scheme 2). There are two presumable
chair-like transition states, TS1 and TS2, in the aminopalla-
dation step, in which diastereoselectivity would be deter-
mined. Two sets of steric interactions should be considered in
each of the two transition states: one is 1,3-allylic interaction
between the pseudoaxial substituent, RL or RS, and the
Scheme 3. Validation of the reaction mechanism. a) Ce(NH4)2(NO3)6,
MeCN/H2O, 08C, 65%; b) cat. [Pd2(dba)3]/SPhos, K3PO4, toluene,
reflux, 28%. b) 1H NMR coupling constant analysis of both 6 and [D]6.
quence, aziridine [D]5 bearing three stereogenic centers was
obtained as a single diastereomer. The relative configuration
of 5 on the aziridine ring would be erythro, the same as 4a.[9]
The other relative configuration between the secondary
aminated carbon atom and the deuterium-substituted
carbon center (2,3-position) was not known at this stage and
was determined after further derivatization. Oxidative
removal of the 4-methoxyphenyl group and subsequent
intramolecular amination of the aryl chloride gave an
azabicyclo[3.1.0]hexane derivative [D]6. The corresponding
nondeuterated analogue 6 was prepared in the same manner.
The rigid conformation of 6 gave us characteristic coupling
1
constants in the H NMR spectrum, allowing assignment of
the signals corresponding to HA, HB, and HC (Scheme 3b,
left).[10] In contrast, the HB signal was not observed in the
1H NMR spectrum of [D]6 (Scheme 3b, right). Thus, the
Scheme 2. The transistion states leading to each of the two diastereo-
mers of 4.
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Communications
cetone)]dipalladium (6.9 mg, 0.0075 mmol) and 2-dicyclohexylphos-
phino-2’,6’-dimethoxybiphenyl (SPhos, 6.2 mg, 0.015 mmol) were
added to the flask, and the flask was filled with argon by using the
standard Schlenck technique. Toluene (1.0 mL) was then added to the
reaction mixture at room temperature. After the suspension was
stirred for 10 min, 1a (0.0856 g 0.30 mmol) and bromobenzene
(0.0942 g, 0.60 mmol) were dissolved in toluene (2.0 mL) and then
added to the flask at ambient temperature. The mixture was heated at
reflux for 15 h with an oil bath. After the flask was cooled to room
temperature, water (20 mL) was added to quench the reaction. The
mixture was extracted with n-hexane/AcOEt = 5:1 three times. The
combined organic layer was dried over sodium sulfate and concen-
trated under reduced pressure. The resulting brown residue was
purified by silica gel column chromatography under basic conditions
(silica gel 60N was used with an eluent (n-hexane/AcOEt/triethyl-
amine = 30:1:0.1)) to provide 3-benzyl-1,2,2-triphenylaziridine 2a
(0.106 g, 0.294 mmol, 98%).
relative stereochemistry of the newly created stereogenic
centers of [D]6 was assigned as erythro. Therefore, [D]5
should have a 1,2-erythro, 2,3-erythro configuration.
Suppose that the aminopalladation reaction proceeds in a
syn fashion, (1,2-erythro, 2,3-erythro)-[D]5 would be pro-
duced [Eq. (1)]. In contrast, the anti-aminopalladation path-
way would result in the formation of (1,2-erythro, 2,3-threo)-
[D]5 [Eq. (2)]. Therefore, the experimental result is consis-
tent with our hypothesis.
Received: June 12, 2009
Published online: August 28, 2009
Keywords: allylamines · aziridines · carboamination · palladium
.
In addition, the reaction of 1j, bearing a benzyl moiety on
the nitrogen atom, provided a mixture of the aziridinated
product 3e and imine 7, which would be generated from b-
hydride elimination from the palladium amide intermediate
corresponding to B in Scheme 1 [Eq. (3); Bn = benzyl].
Moreover, the reaction of 1k gave aziridine 3 f along with
the N-arylated allylamine 8 [Eq. (4)]. The results are also
suggestive of the existence of the palladium amide inter-
mediate.
[1] For reviews, see: a) J. P. Wolfe, Eur. J. Org. Chem. 2007, 571 –
582; b) J. P. Wolfe, Synlett 2008, 2913 – 2937.
[2] Recent work reported by Wolfe and co-workers: a) A. F. Ward,
J. P. Wolfe, Org. Lett. 2009, 11, 2209 – 2212; b) G. S. Lemen, N. C.
Giampietro, M. B. Hay, J. P. Wolfe, J. Org. Chem. 2009, 74, 2533 –
2540; c) M. B. Bertrand, J. D. Neukom, J. P. Wolfe, J. Org. Chem.
2008, 73, 8851 – 8860.
[3] Representative examples reported by other groups: a) D. Jiang,
J. Peng, Y. Chen, Org. Lett. 2008, 10, 1695 – 1698; b) K. G.
Dongol, B. Y. Tay, Tetrahedron Lett. 2006, 47, 927 – 930.
[4] S. Hayashi, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2009,
131, 2052 – 2053.
[5] The relative configuration of 4 was assigned by X-ray crystallo-
graphic analysis and NOE experiments. See the Supporting
Information for details.
[6] Palladium amide intermediates bearing a bulky monophosphine
ligand are known to undergo rapid reductive elimination to
produce N-arylated products: a) D. S. Surry, S. L. Buchwald,
Angew. Chem. 2008, 120, 6438 – 6461; Angew. Chem. Int. Ed.
2008, 47, 6338 – 6361; b) M. Yamashita, J. F. Hartwig, J. Am.
Chem. Soc. 2004, 126, 5344 – 5345.
[7] We cannot exclude another possibility in which
the reaction proceeds through syn carbopalla-
In conclusion, we have found a new synthetic method for
the preparation of aziridines by palladium-catalyzed reactions
of allylamines with aryl or alkenyl halides. The reaction
proceeds through syn aminopalladation, producing carbon–
nitrogen bond with concomitant carbon–carbon bond forma-
tion. Synthesis of other strained hetero- and carbocycles by
the methodology are currently under investigation in our
laboratory.
dation, yielding azapalladacyclobutane C’.
However, examples of reductive elimination
À
to form an Csp3 N bond are rare. In contrast,
syn aminopalladation and subsequent reduc-
tive elimination from C is a prevailing pathway as shown in
reference [1].
[8] Although anti aminopalladation of olefin has been well studied,
the reactions of amines tend to suffer from catalyst deactivation
by the strong coordination of amine to the palladium center,
except for the reaction of a substrate bearing a electron-
withdrawing group on the nitrogen center. For leading reviews:
a) L. S. Hegedus, Tetrahedron 1984, 40, 2415 – 2434; b) T. E.
Mꢀller, M. Beller, Chem. Rev. 1998, 98, 675 – 704.
[9] For the unambiguous erythro/threo nomenclature, see: R.
Noyori, I. Nishida, J. Sakata, J. Am. Chem. Soc. 1981, 103,
2106 – 2108.
Experimental Section
Typical procedure for palladium-catalyzed reactions of allylamines
with aryl or alkenyl halides: The reaction of N-(1,1-diphenyl-2-
propenyl)aniline (1a) with bromobenzene (Table 1, entry 1) is
representative. Sodium tert-butoxide (0.058 g, 0.60 mmol) was
added to a 30 mL two-necked reaction flask equipped with a Dimroth
condenser and was dried by heating for 1 min. [Tris(dibenzylidenea-
[10] See the Supporting Information for more details.
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