Metalated aziridines for cross-coupling with aryl and alkenyl halides via palladium catalysis

Article abstract of DOI:10.1021/ol101904a

The palladium-catalyzed coupling of an aziridinylzinc chloride intermediate with alkenyl and aryl halides has been demonstrated. The method provides products with retention of aziridine stereochemistry. The utility of the coupling procedure is illustrated

Full text of DOI:10.1021/ol101904a

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5085-5087
Metalated Aziridines for Cross-Coupling with
Aryl and Alkenyl Halides via Palladium
Catalysis
John M. Nelson and Edwin Vedejs*
Department of Chemistry, UniVersity of Michigan,
Ann Arbor, Michigan 48109, United States
edVed@umich.edu
Received August 12, 2010
ABSTRACT
The palladium-catalyzed coupling of an aziridinylzinc chloride intermediate with alkenyl and aryl halides has been demonstrated. The method
provides products with retention of aziridine stereochemistry. The utility of the coupling procedure is illustrated in the synthesis of structures
related to L-furanomycin.
Lithiated aziridines 1 (Scheme 1, Prot ) SO2R, CO2R, alkyl)
are useful intermediates for the preparation of functionalized
Scheme 1
aziridines 4.1 However, transition-metal-catalyzed coupling
reactions involving 1-3 have not been reported to our
knowledge. Prior work in our laboratory showed that
stannylated aziridine 5 lacks sufficient reactivity, while
lithiated aziridine 6 produces complex reaction mixtures
under palladium-catalyzed conditions. Herein, we show that
Negishi coupling can be achieved in good yields using the
protected aziridinylzinc chloride 7 and an improved pal-
ladium catalyst.
Initial attempts to couple 7 with methyl 4-bromobenzoate
using Pd(PPh3)4 (THF, 25 °C, 18 h) produced only traces of
the desired product. The source of difficulties became clear
when a control experiment was conducted under identical
conditions but without any palladium catalyst. Quenching
the control with CH3OD gave a complex mixture containing
the deuterated aziridine 9 (37%) as the major component
along with variable yields and ratios of imine 10 and the
known acrolein imine 112 (ca. 10-30% of 10 + 11
combined) and, more consistently, the enol ether 12 (33%).
Yet another product was sometimes isolated from this
reaction, apparently resulting from a dimerization pathway,
but this product was not formed reproducibly, and the yield
(1) (a) Vedejs, E.; Moss, W. O. J. Am. Chem. Soc. 2002, 115, 1607. (b)
Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett. 2005, 7, 1153.
10.1021/ol101904a  2010 American Chemical Society
Published on Web 10/14/2010

never exceeded 10%.3,4 Imines 10 and 11 are thought to arise
from intramolecular ring opening of 7 to produce an
intermediate 8, with subsequent protonation or elimination
of a benzyloxy group to form 10 or 11, respectively.5
Because 10 was obtained without any significant deuterium
incorporation after chromatographic purification, we suspect
that the initial product of CH3OD quenching is 8 with M )
D and that deuterium/proton exchange as well as conversion
to 10 and 11 take place during workup. The origin of the
enol ether 12 was also somewhat perplexing, but the reason
for the apparent incorporation of methanol became more clear
when freshly prepared 7 was quenched with CH3OD at -78
°C. This afforded 9 and 12 without any of the other products
(ca. 1:1 9:12, 75% combined yield after chromatography).
Therefore, the other products (10, 11, dimer) result from the
thermal decomposition of 7, whereas 9 and 12 reflect
deuteration or methanolysis directly from 7 without prior
decomposition.
1.2 equiv of ZnCl2, 1.5 equiv of halide, 2.5 mol % Pd2(dba)3,
and 10 mol % [(tBu)3PH]BF4 (Table 1).
Table 1. Scope of the Negishi Coupling Procedurea
Although details of the methanolysis step were not
investigated, the conversion to 12 can be understood as an
example of zinc-assisted leaving group displacement by
CH3OD to generate 13, followed by 1,2-elimination. Prior
examples of analogous displacement have been noted, but
they are limited to simple structures such as XZnCH2X (X
) halide) and have not been investigated in depth.6 In the
present example, we suggest that CH3OD adds to 7 to
generate a transient zincate intermediate, followed by
deuterium transfer to nitrogen and internal methoxide transfer
to carbon as the aziridine C-N bond is cleaved.
Fortunately, the complex background reactions resulting
from the thermal decomposition of 7 at 25 °C could be
suppressed by using the more reactive catalyst Pd2(dba)3/
[(tBu)3PH]BF4 in place of Pd(PPh3)4 in the Negishi coupling.
This simple variation was so effective that none of the
undesired products 9-12 were detected if sufficient time was
allowed for complete conversion of 7 (ca. 3 h, rt). The scope
of coupling was evaluated in several representative examples
using a stoichiometry of 1 equiv of 5, 1.1 equiv of nBuLi,
a Reaction conditions: 1 equiv of 5, 1.1 equiv of nBuLi, THF, -60 to
-20 °C; 1.2 equiv of ZnCl2, -78 °C; 1.5 equiv of halide, 2.5 mol %
Pd2(dba)3, and 10 mol % [(tBu)3PH]BF4, 25 °C.
The aromatic halides iodobenzene (entry 1) and methyl
4-bromobenzoate (entry 2) gave satisfactory yields of 15 and
17, respectively. The alkenyl halides vinyl bromide (entry
3) or iodoacrylate 20 (entry 4) also afforded coupled products
under the standard conditions. Similarly, iodoindole 22
reacted with 7 to produce the desired aziridine 23, although
in moderate yield.
(2) Mizota, I.; Matsuda, Y.; Hachiya, I.; Shimizu, M. Org. Lett. 2008,
10, 3977
.
(3) The dimeric product is tentatively assigned structure ii on the basis
of NMR and MS data (see Supporting Information). By analogy to
Hodgson’s lithiated N-Bus aziridines,4 intermediate i may be formed by
reaction of 7 with the carbene resulting from R-elimination, but elimination
of the NTrM fragment to produce ii contrasts with the N-Bus aziridine where
the aziridine C-N eliminates to give the symmetrical dimer. The trans
stereochemistry of ii follows from J2,3 ) ca. 3 Hz and remains unexplained.
To demonstrate the synthetic potential of aziridinylzinc
chloride 7, we have studied the conversion of aziridine 21
(Table 1, entry 4) into structures related to the antibacterial
agent L-furanomycin 24 and the analogue 25 (Scheme 2).7
We planned to assemble the dihydrofuranyl moiety of 25
by manipulation of the appended acrylate of 21 via Grignard
addition and intramolecular ring opening of the aziridine.
Thus, 21 was treated with CH3MgBr to afford the tertiary
alcohol 26, and subsequent acid-catalyzed aziridine cleavage
gave 27 (55% from 21). Reductive cleavage of the trityl
(4) Hodgson, D. M.; Humphreys, P. G.; Miles, S. M.; Brierley, C. A. J.;
Ward, J. G. J. Org. Chem. 2007, 72, 10009
.
(5) (a) Florio, S. Tetrahedron 2003, 59, 9683. (b) Luisi, R.; Capriati,
V.; Florio, S.; Ranaldo, R. Tetrahedron Lett. 2003, 44, 2677. (c) Troisi, L.;
Granito, C.; Carlucci, C.; Bona, F.; Florio, S. Eur. J. Org. Chem. 2006,
2006, 775. (d) Capriati, V.; Florio, S.; Luisi, R.; Mazzanti, A.; Musio, B.
J. Org. Chem. 2008, 73, 3197. (e) Florio, S.; Luisi, R. Chem. ReV. 2010,
110, 5128.
(7) (a) Zimmermann, P. J.; Blanarikova, I.; Ja¨ger, V. Angew. Chem.,
Int. Ed. 2000, 39, 910. (b) Zimmermann, P. J.; Young, J. L.; Hlobilova, I.;
Endermann, R.; Ha¨bich, D.; Ja¨ger, V. Eur. J. Org. Chem. 2005, 3450.
(6) (a) Wittig, G.; Wingler, F. Liebigs Ann. Chem. 1962, 656, 18. (b)
Hoberg, H. Liebigs Ann. Chem. 1962, 656, 15.
5086
Org. Lett., Vol. 12, No. 22, 2010

of the primary alcohol to the corresponding aldehyde using
Dess-Martin periodinane, followed by Pinnick oxidation,
gave the protected amino acid 30 (86%). The relative
stereochemistry and substitution pattern of 30 was established
by comparing NMR data with the enantiomeric structure used
earlier as an intermediate in the synthesis of 25,7 while the
absolute configuration follows from the configuration of 5
and is confirmed by optical rotation comparison at the stage
of 30.1,7
Scheme 2
In summary, we have demonstrated that aziridinylzinc
chloride 7 is a useful intermediate for palladium couplings
with aryl and alkenyl halides. The thermal decomposition
of 7, resulting in complex background reactions, can be
suppressed by using the more reactive catalyst Pd2dba3/
[(tBu)3PH]BF4. The synthetic utility of the coupling proce-
dure was demonstrated by stereospecific synthesis of the
protected dihydrofuranyl amino acid 30.
Acknowledgment. This work was supported by the
National Institutes of Health (CA17918).
Note Added after ASAP Publication. This paper was
published ASAP on October 14, 2010. Changes were made
to the yield values of 27 and 28. The revised paper was
reposted on October 18, 2010.
protecting group of 27 with TFA/Et3SiH8 produced the
corresponding amine, which was protected as the Boc
derivative 28 (49% over the two steps). To avoid the risk of
hydrogenating the double bond under H2/Pd/C conditions,
benzyl deprotection of 28 was accomplished using Na/NH3
reduction to produce the alcohol 29 in 97% yield.9 Oxidation
Supporting Information Available: Experimental details
and copies of 1H NMR and 13C NMR spectra of representa-
tive compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL101904A
(9) Wang, X. J.; Hart, S. A.; Xu, B.; Mason, M. D.; Goodell, J. R.;
Etzkorn, F. A. J. Org. Chem. 2003, 68, 2343.
(8) Pickersgill, I. F.; Rapoport, H. J. Org. Chem. 2000, 65, 4048.
Org. Lett., Vol. 12, No. 22, 2010
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