Direct synthesis of bicyclic guanidines through unprecedented palladium(II) catalysed diamination with copper chloride as oxidant

Article abstract of DOI:10.1039/b719479j

Palladium catalysed intramolecular guanidine transfer to alkenes can be accomplished with copper chloride as the oxidant to give bicyclic guanidines with complete selectivity and in high yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/b719479j

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Direct synthesis of bicyclic guanidines through unprecedented
palladium(II) catalysed diamination with copper chloride as oxidantwz
¨
Claas H. Hovelmann, Jan Streuff, Lydia Brelot and Kilian Muniz*
Received (in Cambridge, UK) 19th December 2007, Accepted 11th February 2008
First published as an Advance Article on the web 14th March 2008
DOI: 10.1039/b719479j
Palladium catalysed intramolecular guanidine transfer to al-
kenes can be accomplished with copper chloride as the oxidant to
give bicyclic guanidines with complete selectivity and in high
yields.
To this end, either Boc or Cbz substituents12 in precursors
such as 1 were preferred for the major reason that these would
provide only a single regioisomer and after oxidation should
be easily removed to give free guanidines. An initial attempt to
implement the copper bromide oxidation mode9 into the
desired guanidine transfer already met with success. Several
substrates underwent formation of the desired cyclic guani-
dines in moderate to very good yields in the presence of 3
equivalents of CuBr2 (Scheme 1).
Cyclic guanidines constitute important functional molecules.
For example, they are widely present in the fascinating struc-
tural world of marine natural products,1 and employed as
organocatalysts,2 for metal ligation3 or in anion recognition.4
As a consequence, the general demand for the facile accessi-
bility of cyclic guanidines is of synthetic interest. However,
their respective synthesis can be challenging and usually
requires multi-step condensation events from prefabricated
amine and diamine precursors.1–3 On the other hand, their
introduction through oxidation processes is a rarely observed
approach. The development of tethered guanidines for intra-
molecular C–H amination represents a noteworthy exception
to this end.5
However, it was noted that the reaction time had to be
optimized carefully, as prolonged exposure of the cyclic
guanidine products 2 to copper bromide salts led to gradual
conversion to the respective urea compounds. This undesired
reaction was observed as dominant pathway in the cyclisation
under concommitant six-membered ring annelation, where the
urea 4 was obtained as the major product.
To our delight, a simple change in oxidant to copper
chloride generated reaction conditions that led to mild con-
struction of the bicyclic guanidines 2a–f within a completely
chemo- and regioselective 1,2-diamination reaction (Scheme
2). Work-up of the reaction can be carried out by the addition
of aqueous thiosulfate solution followed by extraction with
dichloromethane. This gives the bicyclic guanidine as sole
product in an analytically pure form.
We recently reported the first catalysis protocols for intra-
molecular diamination of unfunctionalised alkenes, which
employed ureas and sulfamides as the respective nitrogen
sources.6–8 This previous work employed high oxidation pal-
ladium and nickel catalyst states derived from iodosobenzene
diacetate as stoichiometric oxidant. Recently, an alternative
protocol for cyclisation of urea molecules was elaborated9 that
relies on copper bromide as the terminal oxidant and hence
provides a more sustainable method than PhI(OAc)2.10,11
Motivated by these results, we considered the construction
of cyclic guanidines by direct catalytic alkene oxidation as an
attractive synthetic alternative to successive multiple-step
synthesis:
A range of cyclic guanidines bearing either Boc or Cbz
protecting groups could be constructed under these condi-
tions, in some cases within reaction times of just one hour. In
all cases, DMF as solvent provided the best conditions con-
cerning reaction time and conversion. Both the amount of
´
Institut de Chimie, UMR 7177, Universite Louis Pasteur, 4 rue Blaise
Pascal, F-67000 Strasbourg Cedex, France. E-mail:
muniz@chimie.u-strasbg.fr
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation, spectral reproduction for new com-
pounds and crystallographic data in CIF or other electronic format for
CCDC 671505 & 677355. See DOI: 10.1039/b719479j
z Dedicated to Prof. Dr Irina Beletskaya on the occasion of her 75th
birthday.
Scheme 1 Diamination of alkenes with copper bromide as reoxidant.
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Scheme 3 Examples for generation of free guanidines 6 and 7 from
Boc-disubstituted oxidation products 2c and 5c, respectively.
observed beneficial effect of the copper chloride over the copper
bromide is noteworthy, especially where reaction time and
prevention of guanidine degradation are concerned.13 Secondly,
the complete selectivity in pyrrolidine and piperidine annelation
compares favorably to related aminopalladation reactions.14
While the exact nature of the successful pairing of a palladiu-
m(II) catalyst with copper chloride is unknown to date, several
additional observations help to gain a broader understanding.
Apparently, copper chloride concentration is of key impor-
tance as attempts to run the reaction under aerobic conditions
with only 0.2 equivalents of CuCl2 resulted in significantly
reduced rate (Scheme 2, footnote b), and Wacker oxidation
under aqueous conditions did not work at all for the present
transfomation. In agreement with the stereochemical path-
ways from previous diamination reactions,6 guanidine forma-
tion proceeds with syn-diastereoselectivity for oxidation of
(E)-configured alkenes such as 1a-d1 (eqn (7)).
Scheme 2 Palladium-catalysed guanidine transfer to alkenes: pyrro-
lidine- and piperidine annelation. a5 mol% palladium diacetate.
bOxygen (1 atm), 20 mol% CuCl2.
palladium acetate (10 mol%) and the copper chloride concen-
tration are important. As determined for substrate 1a, low-
ering the palladium catalyst to 5 mol% led to a reaction with
still complete chemoselectivity, albeit under incomplete con-
version (Scheme 2, footnote a).
In particular, the efficient oxidation to six-membered bicyc-
lic products 5a–f is without precedence in all currently avail-
able alkene diamination protocols.6,8 The reactions proceed at
room temperature, under comparably low catalyst loading
and with complete selectivity. The structure of compounds
5a–f was unambiguously secured from an X-ray analysis of
compound 5d.w
Subsequent manipulation of the biscarbamate theme under
standard deprotection conditions gives rise to the free guani-
dines for five- and six-membered annelated compounds 6 and
7 (Scheme 3, eqn (5) and (6)). The latter structure was also
established via an X-ray analysis of compound 7.w
The unprecedented role of copper chloride represents the
These facts suggest the absence of traditional Pd(0)/Pd(II)
catalysis and the direct involvement of copper chloride already
most important feature from the present work. First, the
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in the final amination. We have previously disclosed a syn-
aminopalladation15,16 for related urea groups6 that should be
even more pronounced for the present guanidines with their
high metal-coordination ability.3 Such a resulting alkyl palla-
dium(II) intermediate has been suggested to undergo reductive
C–N bond formation upon transient palladium oxidation17
(Fig. 1).
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mez, J. Barluenga, J.
¨
Since the reductive amination proceeds via nucleophilic
displacement, this step requires an inversion of configuration
as noted from eqn (7). This mechanistic proposal is strongly
supported by the observation that the carbamate groups are
essential for this second amination to proceed, as free guani-
dine with its less nucleophilic nitrogen atoms leads exclusively
to aminochlorination product 9 (eqn (8)). Finally, a stronger
oxidant such as PhI(OAc)2 induces aminoacetoxylation pro-
duct 10 (eqn (9))18 from a discrete Pd(IV) intermediate19 as
previously observed for related sulfamide groups.8 Hence, only
the palladium(II)/copper chloride pairing provides the required
balanced conditions that allow palladium oxidation and nu-
cleophilic amination to proceed with complete chemoselectivity
for catalytic room-temperature guanidination of alkenes.
In summary, we have accomplished an oxidative guanidine
transfer to alkenes with significant operational simplicity that
closes a methodological gap in the synthesis of cyclic guani-
dines. This reaction also represents the first practical synthesis
of piperidine-annelation in catalytic diamination reactions. It
further enlarges the available oxidative diamination protocols
to environmentally benign copper chloride reoxidation condi-
tions with unprecedented selectivity.
10.1002/asia.200700373.
10 For a copper-catalysed diamination: B. Zhao, W. Yuan, H. Du
and Y. Shi, Org. Lett., 2007, 9, 4943.
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R. Chemler, J. Am. Chem. Soc., 2005, 127, 11250; T. P. Zabawa
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Feichtinger, C. Zapf, H. L. Sings and M. Goodman, J. Org. Chem.,
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13 We are currently investigating the influence of anion nature on
Pd(II)/Cu(II) combined systems in diamination reactions. Prelimin-
ary results showed no influence on the hydration grade of the
copper salt as use of unhydrous and hydrated copper chloride led
to identical reaction outcome (we thank a referee for drawing this
possibility to our attention).
14 A. Lei, X. Lu and G. Liu, Tetrahedron Lett., 2004, 45, 1785;
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17 For the conceptual introduction of transient palladium oxidation
with CuCl2: H. Stangl and R. Jira, Tetrahedron Lett., 1970, 11,
3589; O. Hamed and P. M. Henry, Organometallics, 1998, 17,
5184Palladium Catalyzed Oxidation of Hydrocarbons, ed. P. M.
Henry, Reidel, Dordrecht, 1980.
This work was supported by the Fonds der Chemischen
Industrie and by the Agence Nationale de la Recherche.
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2005, 127, 7690.
19 A. J. Canty, Acc. Chem. Res., 1992, 25, 83; A. R. Dick,
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Notes and references
1 Selected reviews and accounts: R. G. S. Berlinck and M. H.
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