A Suzuki cross-coupling route to substituted aziridines

Article abstract of DOI:10.1016/S0040-4039(01)01903-7

We have shown that the Suzuki cross-coupling reaction of olefinic aziridines is an effective route for the synthesis of substituted aziridines. This is the first example of a palladium coupling reaction applied to an aziridine-containing molecule. This method is complementary to other methods of aziridine synthesis utilizing organocuprate reagents.

Full text of DOI:10.1016/S0040-4039(01)01903-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8583–8586
A Suzuki cross-coupling route to substituted aziridines
David J. Lapinsky and Stephen C. Bergmeier*
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA
Received 17 September 2001; accepted 9 October 2001
Abstract—We have shown that the Suzuki cross-coupling reaction of olefinic aziridines is an effective route for the synthesis of
substituted aziridines. This is the first example of a palladium coupling reaction applied to an aziridine-containing molecule. This
method is complementary to other methods of aziridine synthesis utilizing organocuprate reagents. © 2001 Elsevier Science Ltd.
All rights reserved.
The Suzuki cross-coupling reaction provides an excel-
lent method for coupling sp3 hybridized carbons to sp2
hybridized carbons (as well as sp2 to sp2). This reaction
has been applied to the synthesis of a large variety of
compounds.1 Suzuki or similar types of reactions have
not been carried out with an aziridine ring present in
the molecule.2,3 Such a process in the presence of an
aziridine ring suggests a number of potential problems,
such as reaction of the organometallic portion (e.g. 4)
with the aziridine ring,4 palladium-catalyzed aziridine
ring opening,5 and hydrolysis of the aziridine ring
under the basic reaction conditions (Scheme 1).
This strategy could be very useful for the preparation of
substituted aziridines, especially those in which the
desired organometallic reagent (such as 2) is not readily
available or one in which the aziridine is not amenable
to the type of ring opening reaction we have typically
employed.6
The Suzuki cross-coupling reaction between an
aliphatic partner and a sp2-halide typically involves the
conversion of the aliphatic partner to an organoborane
via hydroboration. The appropriate olefin for hydrobo-
ration would be aziridine 9. Olefin 9 was conveniently
prepared from commercially available allylglycine (6).
Treatment of amino acid 6 with MeOH/HCl followed
by toluenesulfonyl chloride provided the diprotected
amino acid 78 in 80% yield from allylglycine. The ester
was then reduced with LiBH4 followed by a Mitsunobu
ring closure to yield the target aziridine 9 (Scheme 2).9
We were interested in preparing aziridine–allylsilanes
such as 3 using our previously reported method involv-
ing the reaction of an organocuprate reagent (e.g.
derived from 2) with the aziridine 1.6 Unfortunately,
the synthesis of the requisite organolithium reagent
proved troublesome.7 We thus began to explore the
possibility of using a Suzuki coupling between the
appropriately substituted aziridine (e.g. 4) and an sp2-
bromide (e.g. 5) to prepare the desired aziridines (3).
Olefin 9 was then treated with 9-BBN followed by
2-bromopropene (11) and PdCl2(dppf)·CH2Cl2 under
Suzuki cross-coupling conditions. We were pleased to
Ts
N
H
CuI, nBu3P
+
Me3Si
TsN
Me3Si
Me3Si
OTs
Li
H
2
1
3
Ts
N
H
Pd0
Me3Si
TsN
Br
H
5
BR2
3
4
Scheme 1.
Keywords: aziridines; Suzuki reactions; coupling reactions; palladium and compounds.
* Corresponding author. Fax: 740 593 0148; e-mail: bergmeis@ohio.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01903-7

8584
D. J. Lapinsky, S. C. Bergmeier / Tetrahedron Letters 42 (2001) 8583–8586
O
O
a, b
c
d
OH
OH
NHTs
OMe
NHTs
NTs
NH2
9
8
7
6
Scheme 2. (a) MeOH, AcCl (500 mol%), reflux, 24 h. (b) TsCl (110 mol%), Et3N (250 mol%), CH2Cl2, rt, 24 h, 80% (two steps).
(c) NaBH4 (300 mol%), LiCl (300 mol%), EtOH:THF, 2:1, rt, 24 h, 80% (d) Ph3P (110 mol%), DEAD (110 mol%), THF, rt, 16
h, 82%.
find that the coupling provided the desired coupling
product in 47% yield (Table 1, entry 1). We have
examined the coupling of 9 with a variety of vinylic and
aryl halides (Table 1). The yields reported in Table 1 are
of analytically pure material.9 As hoped, the bromoallyl-
silane 5 was an excellent cross-coupling partner provid-
ing 10b in 58% yield. Similar yields were obtained from
a number of other aryl halides (13, 14, 16, 17). The only
exception being 4-nitro-bromobenzene, which afforded
10f in only 28% yield. Some of the low yields observed
in the cross-coupling reactions can be attributed to
difficulties in purification. All of the cross-coupling
products (to some extent) co-eluted with 9-BBN by-prod-
ucts from the reaction and required additional purifica-
tion. We should note that for many of these examples the
organolithium reagent that might be required to prepare
aziridines 10a–h from aziridine 1 would not be readily
accessible. Thus, this method is an excellent complement
to the addition of an organometallic reagent to an
aziridine as a route to substituted aziridines (Scheme 3).
Table 1. Examples of Suzuki cross-coupling reactions of olefinic aziridines9,10
1) 9-BBN (120 mol%), THF, rt, 4 h
R
2) R-X (110 mol%), 3 M aq. K3PO4
NTs
NTs
10
(210 mol%), PdCl2(dppf)•CH2Cl2
9
(5 mol%), DMF, rt, 18 h
Entry
Product (yield)
R-X
1
NTs
Br
11
10a, (47%)
Me3Si
2
NTs
SiMe3
Br
10b, (58%)
5
CO2Et
CO2Et
I
3
4
5
12
NTs
NTs
10c, (51%)
10d, (42%)
Br
Ph
13
I
NTs
NTs
NTs
OH
10e, (60%)
HO
14
15
Br
Br
6
7
NO2
O2N
10f, (28%)
10g, (70%)
O
O
16
Br
8
NTs
CO2Me
MeO2C
10h, (65%)
17

D. J. Lapinsky, S. C. Bergmeier / Tetrahedron Letters 42 (2001) 8583–8586
8585
TBSO
f, g
c
a, b
RO
TsN
H
NTs
20
NHTs
19
H
18
SiMe3
TsN
H
21
d
e
f, g
No product observed
CO2Me
CHO
TsN
TsN
TsN
H
H
H
22
23
24
Scheme 3. (a) AllylMgCl (300 mol%), CuCN (50 mol%), Et2O:THF (1:1.5), −78 to 0°C, 45 h, R=Si(Me2)tBu, 75%. (b) nBu4NF
(110 mol%), THF, 0°C, 1 h, R=H, 88%. (c) Ph3P (110 mol%), DEAD (110 mol%), THF, 0°C to rt, 4 h, 93%. (d) DIBAL-H (160
mol%), CH2Cl2, −78°C, 3 h. (e) Ph3PCH2 (250 mol%), THF, −20°C, 1 h, 29% (two steps). (f) 9-BBN (120 mol%), THF, rt, 4 h.
(g) 5 (110 mol%), 3 M aq. K3PO4 (210 mol%), PdCl2(dppf)·CH2Cl2 (5 mol%), DMF, rt, 18 h, 21 (65%).
In an effort to extend this synthesis we prepared olefins
20 and 24. Olefin 20 was readily prepared from the
serine derived aziridine 18.6a Reaction of 18 with allyl-
magnesium chloride/CuCN followed by removal of the
silyl protecting group and Mitsunobu ring closure pro-
vided aziridine 2011 in excellent overall yield. Standard
cross-coupling conditions using bromoallylsilane 5 pro-
vided substituted aziridine 21 in 65% yield.9,10 We next
turned our attention to olefin 24. The known aziridine
ester 226a,12 can be reduced to aldehyde 23 by reaction
with DIBAL-H. Wittig reaction of the aldehyde pro-
duces the vinyl aziridine 2413 in 29% yield over two
steps. Unfortunately, hydroboration of 24, followed by
Suzuki coupling conditions did not provide any of the
desired product. We have examined a number of varia-
tions of the Suzuki cross-coupling protocol and all were
unsuccessful. No aziridine containing products were
obtained, and we believe that the aziridinyl borane
formed upon hydroboration of 24 is unstable.
3. An intramolecular Heck reaction has been used in the
presence of an aziridine ring, see: Schkeryantz, J. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 4722–
4723.
4. Pearson, W. H.; Liam, B. W.; Bergmeier, S. C. In Com-
prehensive Heterocyclic Chemistry II; Padwa, A., Ed.;
Pergamon: Oxford, 1996; Vol. 1, pp. 1–60.
5. See Baeg, J.-O.; Bensimon, C.; Alper, H. J. Am. Chem.
Soc. 1995, 117, 4700–4701 and references cited therein.
6. (a) Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1997, 62,
2671–2674; (b) Bergmeier, S. C.; Fundy, S. L.; Seth, P. P.
Tetrahedron 1999, 55, 8025–8038.
7. While the desired organolithium reagent (2) has been
prepared via a reductive lithiation of a phenylsulfide (see
Manteca, I.; Ardeo, A.; Osante, I.; Lete, E.; Etxarri, B.;
Arrasate, S.; Sotomayor, N. Tetrahedron 1998, 54,
12361–12378), we were hoping to carry out a metal
halogen exchange between the corresponding iodide and
t-BuLi. The synthesis of the alcohol needed for prepara-
tion of the iodide has been reported (see Ahmed-
Schafield, A.; Mariano, P. S. J. Org. Chem. 1985, 50,
5667–5677). However, we were unable to convert this
alcohol to the iodide using a number of different
methods.
In conclusion, we have shown that the Suzuki coupling
reaction of olefinic aziridines proceeds quite well. This
reaction should be useful for the preparation of a
variety of substituted aziridines.
8. (a) Varray, S.; Gauzy, C.; Lamaty, F.; Lazaro, R.; Mar-
tinex, J. J. Org. Chem. 2000, 65, 6787–6790; (b) Voigt-
mann, U.; Blechert, S. Synthesis 2000, 893–898; (c)
Witulski, B.; Gossmann, M. Chem. Commun. 1999, 1879–
1880; (d) Bolton, G. L.; Hodges, J. C.; Rubin, J. R.
Tetrahedron 1997, 53, 6611–6634.
Acknowledgements
We would like to thank the National Science Founda-
tion (CHE-9816208) for support of this work.
1
9. All new products showed satisfactory H, 13C NMR and
HRMS.
10. Typical procedure for the Suzuki cross-coupling reaction:
The desired aziridinyl alkene (9 or 20, 1.1 mmol) was
dissolved in dry THF (3.7 mL) and cooled to 0°C. A
solution of 9-BBN (2.5 mL of a 0.5 M solution in THF)
was added and the reaction was warmed to room temper-
ature and stirred until no alkene remained (TLC, 20%
EtOAc:hexanes, ca. 4 h). Distilled DMF (1.8 mL) was
added followed by careful addition (H2 evolution) of
degassed aq. K3PO4 (3 M, 210 mol%). This was followed
by a rapid addition of R-X (110 mol%, X=Br or I) and
PdCl2(dppf)·CH2Cl2 (5 mol%). The reaction was stirred
overnight at room temperature. The solvent was removed
in vacuo and the remaining DMF residue was partitioned
References
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2. Recently the Suzuki cross-coupling reaction has been
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bell, A. D.; Raynham, T. M.; Taylor, R. J. K. Tetra-
hedron Lett. 1999, 40, 5263–5266; (b) Sabat, M.; Johnson,
C. R. Org. Lett. 2000, 2, 1089–1092; (c) Collier, P. N.;
Campbell, A. D.; Patel, I.; Taylor, R. J. K. Tetrahedron
Lett. 2000, 41, 7115–7119.

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D. J. Lapinsky, S. C. Bergmeier / Tetrahedron Letters 42 (2001) 8583–8586
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with Et2O. The combined organic layers were dried
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12. We prepared ester 22 in 92% yield by the Mitsunobu ring