Cu(l)-catalyzed cycloguanidination of olefins

Article abstract of DOI:10.1021/ol702974s

This paper describes a novel cycloguanidination process using CuCl as catalyst and diaziridinimines as the nitrogen source. A variety of conjugated dienes, trienes, and terminal olefins can be effectively diaminated under mild reaction conditions. For dienes and trienes, the reaction occurs at the terminal double bond with high regioselectivity.

Full text of DOI:10.1021/ol702974s

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1087-1090
Cu(I)-Catalyzed Cycloguanidination of
Olefins
Baoguo Zhao, Haifeng Du, and Yian Shi*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
yian@lamar.colostate.edu
Received December 10, 2007
ABSTRACT
This paper describes a novel cycloguanidination process using CuCl as catalyst and diaziridinimines as the nitrogen source. A variety of
conjugated dienes, trienes, and terminal olefins can be effectively diaminated under mild reaction conditions. For dienes and trienes, the
reaction occurs at the terminal double bond with high regioselectivity.
Cyclic guanidines are present in a variety of biologically
active compounds,1 including massadine (geranylgeranyl-
transferase type I inhibitor),2 palau’amine (antibiotic, cyto-
toxic, and immunosuppressive agent),3 streptolidine lactam
(a component of the streptothricin antibiotics),4 and man-
nopeptimycins (antibiotic agents against drug-resistant bac-
teria).5 Cyclic guanidines are normally prepared1 by cycliza-
tion of vicinal diamines6 or guanidines,7 and by cycloaddition
of aziridines and carbodiimides.8 Cycloguanidination of
olefins provides a valuable approach to cyclic guanidines,
yet it needs to be further developed.9 Recently, we reported
a Pd(0)-10,11 and a Cu(I)-catalyzed12 regio- and stereoselective
diamination of conjugated dienes and trienes using di-tert-
butyldiaziridinone (2)13,14 as the nitrogen source (Scheme 1)
Scheme 1
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as well as Cu(I)-catalyzed15 diamination of activated terminal
olefins using di-tert-butylthiadiaziridine 1,1-dioxide as the
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10.1021/ol702974s CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/27/2008

nitrogen source.16,17-22 In an effort to expand the related
diamination processes, we have been investigating whether
diaziridinimines can be used as the nitrogen source to form
cyclic guanidines from olefins (Scheme 2). Herein we report
Pd(PPh3)4 as catalyst. When CuCl-P(n-Bu)3 was used as the
catalyst, no diamination reaction was observed with diaz-
Table 1. Catalytic Cycloguanidination of Olefinsa
Scheme 2
our preliminary efforts on this subject.
Initial studies were carried out using 1-phenyl-1,3-buta-
diene as the substrate and diaziridinimines 6a-c23 as the
nitrogen source. Little guanidine product was detected with
(7) For leading references, see: (a) Bu¨chi, G.; Rodriguez, A. D.;
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Ed. 2007, 46, 7125.
(10) (a) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762. (b)
Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688.
(11) For a related diamination of terminal olefins at allylic and homoal-
lylic carbons via C-H activation, see: Du, H.; Yuan, W.; Zhao, B.; Shi,
Y. J. Am. Chem. Soc. 2007, 129, 7496.
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Biol. Drug Des. 2006, 67, 101.
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Mn: (c) Fristad, W. E.; Brandvold, T. A.; Peterson, J. R.; Thompson, S. R.
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Barluenga, J.; Aznar, F. Synthesis 1974, 504.
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I. J. Am. Chem. Soc. 2005, 127, 7308.
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a All reactions were carried out with olefin (0.2 mmol), 1,2-di-tert-butyl-
3-(cyanimino)diaziridine (6c) (0.41 mmol), CuCl-PPh3 (1:2) (0.02 mmol)
in CDCl3 (0.1 mL) at 50 °C under argon for 24 h unless otherwise stated.
For entries 7-10, the reactions were carried out at 65 °C. b Isolated yield
based on olefin.
1088
Org. Lett., Vol. 10, No. 6, 2008

iridinimines 6a and 6b. However, good conversion was
obtained with 6c to give the desired cyclic guanidine product.
Under the reaction conditions, diaziridinimine 6a with an
electron-donating tert-butyl group remained unreacted, but
6b with a strong electron-withdrawing Ts group decomposed
rapidly. This indicates that the R substituent on iminodiaz-
iridines 6 has a significant impact on the reaction outcome,
and the cyano group appears to be an effective substituent
for the reaction. After additional optimization of conditions,
the reaction was further improved using 10 mol % of CuCl-
PPh3 (1:2) as catalyst at 50-65 °C in CDCl3. As shown in
Table 1, the reaction can be extended to additional olefins.24
Dienes and trienes are effective substrates, and the reaction
occurred highly regioselectively at the terminal double bond
(Table 1, entries 1-6). Other regioisomers were barely
detectable by 1H NMR of the crude reaction mixture. Enyne
and arylethylenes can also be guanidinated but with relatively
lower reactivity (the X-ray structure of 7ci is shown in Figure
1). However, terminal olefins such as 1-octene and ethyl
the previously proposed catalytic mechanism,12,15 proceeding
via the homolytic cleavage of the N-N bond of diaziridin-
imine 6c by CuCl, followed by the addition of the resulting
nitrogen radical 1025-28 to olefin 5 and the subsequent C-N
bond formation and regeneration of CuCl catalyst (Scheme
4).
Scheme 4. Proposed Catalytic Cycle for Cycloguanidination
The deprotection of the resulting cyclic guanidines was
investigated with compound 7ci (Scheme 5). Both the tert-
Scheme 5
Figure 1. X-ray structure of compound 7ci.
butyl and the cyano groups were smoothly removed with
HCl to give guanidine 12 in good overall yield after
neutralization with NaOH.29
In summary, a variety of conjugated dienes, trienes, and
terminal olefins have been effectively cycloguanidinated
acrylate are not effective substrates under the current reaction
conditions.
When deuterated diene 8 was subjected to the reaction
conditions, a mixture of two isomers (9a and 9b) was
(24) A representative diamination procedure (Table 1, entry 1): To
a 1.5 mL vial equipped with a stir bar was added CuCl (0.002 g, 0.02 mmol)
and triphenylphosphine (0.0104 g, 0.04 mmol). The sealed vial was
evacuated and filled with Ar three times, followed by addition of CDCl3
(0.05 mL). After the mixture was stirred at room temperature for 10 min,
1-phenyl-1,3-butadiene (5a) (0.026 g, 0.20 mmol) was added, followed by
a solution of 1,2-di-tert-butyl-3-(cyanimino)diaziridine (6c) (0.080 g, 0.41
mmol) in 0.05 mL of CDCl3 (for solid olefins, they were added together
with CuCl). The reaction mixture was stirred at 50 °C for 24 h and purified
by flash chromatography (silica gel, petroleum ether/ethyl acetate/triethy-
lamine ) 4:1:0.05 to 3:1:0.04) to give the diamination product 7ca as a
colorless oil (0.056 g, 86%).
Scheme 3
(25) For a leading review on metal-promoted radical reactions, see: Iqbal,
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Grimme, S.; Studer, A. J. Am. Chem. Soc. 2007, 129, 4498.
obtained (Scheme 3). While a precise reaction mechanism
awaits further study, the cycloguanidination is consistent with
Org. Lett., Vol. 10, No. 6, 2008
1089

using CuCl as catalyst and 1,2-di-tert-butyl-3-(cyanimino)-
diaziridine (6c) as nitrogen source under mild reaction
conditions, providing various cyclic guanidine derivatives
which are present in many biologically active compounds.1-7
For dienes and trienes, the reaction occurs regioselectively
at the terminal double bond. The cycloguanidination is likely
to proceed via a nitrogen radical intermediate. Further studies
on the reaction mechanism, different catalysts, and nitrogen
sources as well as expansion of the substrate scope and
development of an asymmetric process are currently under-
way.
Acknowledgment. We are grateful for the generous
financial support from the Camille and Henry Dreyfus
Foundation and the Monfort Foundation (CSU). We also
thank Wilmington PharmaTech for a gift of Pd(PPh3)4.
Supporting Information Available: The cycloguanidi-
nation and deprotection procedures, the characterization of
cyclic guanidine products, and the X-ray data of compound
(28) For leading references on Cu(I)-catalyzed homolytic cleavage of
N-O bonds of oxaziridines, see: (a) Aube´, J.; Peng, X.; Wang, Y.;
Takusagawa, F. J. Am. Chem. Soc. 1992, 114, 5466. (b) Aube´, J. Chem.
Soc. ReV. 1997, 26, 269. (c) Black, D. St. C.; Edwards, G. L.; Laaman, S.
M. Tetrahedron Lett. 1998, 39, 5853. (d) Black, D. St. C.; Edwards, G. L.;
Laaman, S. M. Synthesis 2006, 1981.
1
7ci along with the H and 13C NMR spectra of 7c, 9, and
12. This material is available free of charge via the Internet
at http://pubs.acs.org.
(29) Ishikawa, F.; Kosasayama, A.; Konno, T. Chem. Pharm. Bull. 1978,
26, 3666.
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