Expanding the substrate scope for C-H amination reactions: Oxidative cyclization of urea and guanidine derivatives

Article abstract of DOI:10.1021/ol052920y

Oxidative C-H amination of N-trichloroethoxysulfonyl-protected ureas and guanidines is demonstrated to proceed in high yield for tertiary and benzylic-derived substrates. The success of these reactions is predicated on the choice of the electron-withdrawn

Full text of DOI:10.1021/ol052920y

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1073-1076
Expanding the Substrate Scope for C
Amination Reactions: Oxidative
Cyclization of Urea and Guanidine
Derivatives
−H
Mihyong Kim, John V. Mulcahy, Christine G. Espino, and J. Du Bois*
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
jdubois@stanford.edu
Received December 1, 2005
ABSTRACT
Oxidative C
benzylic-derived substrates. The success of these reactions is predicated on the choice of the electron-withdrawn 2,2,2-trichloroethoxysulfonyl
(Tces) protecting group, the commercial catalyst Rh2(esp)2 (1 2 mol %), and toluene as solvent. The frequency with which the heterocyclic
−H amination of N-trichloroethoxysulfonyl-protected ureas and guanidines is demonstrated to proceed in high yield for tertiary and
−
imidazolidin-2-ones and 2-aminoimidazolines appear as structural elements in both natural products and therapeutically designed molecules
confers these methods with a large number of potential applications.
Direct methods for the amination of C-H bonds have been
established as tools for the assembly of nitrogen-based
heterocycles and related amine derivatives.1 Our laboratory
has delineated such processes, which enable the catalytic,
oxidative cyclization of both primary carbamate and sulfa-
mate esters to give the corresponding 5- and 6-membered
ring products, respectively (Figure 1).2,3 These value-added
Figure 1. Catalytic methods for C-H amination.
compounds may be readily transformed into 1,2- or 1,3-
(1) (a) Espino, C. G.; Du Bois, J. In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp 379-416.
(b) Halfen J. A. Curr. Org. Chem. 2005, 9, 657-669. (c) Mu¨ller, P.; Fruit,
C. Chem. ReV. 2003, 103, 2905-2920. (d) Dauban, P.; Dodd, R. H. Synlett
2003, 1571-1586.
(2) (a) Du Bois, J. CHEMTRACTS-Org. Chem. 2005, 18, 1-13. (b)
Fiori, K. W.; Fleming, J. J.; Du Bois, J. Angew. Chem., Int. Ed. 2004, 43,
4349-4352. (c) Wehn, P. M.; Lee, J.; Du Bois, J. Org. Lett. 2003, 5, 4823-
4826. (d) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935-6936. (e) Espino, C. G.; Du Bois, J. Angew. Chem.,
Int. Ed. 2001, 40, 598-600.
disubstituted amine derivatives. Although simple dirhodium
tetracarboxylate complexes (i.e., Rh2(OAc)4, Rh2(O2CCPh3)4)
have proven effective as catalysts in many instances, we have
recently demonstrated that a tethered carboxylate, Rh2(esp)2,
is superior in performance to all others.4,5 This new catalyst
has allowed us to expand the collection of substrates that
will engage in high-yielding C-H amination reactions
(3) For recent related studies, see: (a) Lebel, H.; Huard, K.; Lectard, S.
J. Am. Chem. Soc. 2005, 127, 14198-14199. (b) Cui, Y.; He, C. Angew.
Chem., Int. Ed. 2004, 43, 4210-4212. (c) Fruit, C.; Mu¨ller, P. Tetrahe-
dron: Asymmetry 2004, 15, 1019-1026. (d) Liang, J.-L.; Yuan, S.-X.;
Huang, J.-S.; Yu, W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2002, 41,
3465-3468. Also see: Yu, X.-Q.; Huang, J.-S.; Zhou, X.-G.; Che, C.-M.
Org. Lett. 2000, 2, 2233-2236.
(4) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc.
2004, 126, 15378-15379.
(5) Rh2(esp)2 is known by its chemical name as Rh2(R,R,R′,R′-tetra-
methyl-1,3-benzenedipropionate)2; see ref 4. This catalyst may be purchased
from Aldrich Chemical Co. or conveniently prepared on large scale (40 g)
in three steps: Fiori, K. W.; Du Bois, J. Manuscript in preparation.
10.1021/ol052920y CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/17/2006

(Figure 2). As a result of these efforts, we now report that
primary urea and guanidine derivatives function with general
Subsequent control experiments indicated that a rapid reac-
tion between 1 and PhI(OAc)2 ensues in the absence of Rh
catalyst and/or MgO.9 This process effectively out-competes
the Rh-mediated insertion pathway. As such, we considered
modifying the urea substrates with an electron-withdrawing
group so as to attenuate the unfavorable reaction with PhI-
(OAc)2. Both N-alkyl-N-acylurea 3 and N-alkyl-N-sulfonyl-
urea 4 substrates were synthesized and tested in this
capacity.10 Although the background reaction with oxidant
was indeed avoided, only the trichloroethoxysulfonyl (Tces)
substrate 5 proved effective for oxidative cyclization. The
resulting Tces-blocked imidazolidinone 6 was thus formed,
albeit in modest yield (12%), using 5 mol % of Rh2(O2C-
tBu)4, PhI(OAc)2, and MgO (eq 1).11
Figure 2. Oxidative cyclization of ureas and guanidines.
utility as substrates for this process. With the former class
of starting materials, the products of oxidation can be
elaborated to vicinal diamines.6 Additionally, heterocylic
ureas and guanidines are found as structural elements in a
growing number of complex, biologically efficacious targets,
including a spectacularly diverse family of bromopyrrole
metabolites (Figure 2).7,8 The demonstration that two new
substrate types can engage in C-H amination reactions
affirms the power of this methodology as a unified strategy
for the preparation of structurally disparate molecules.
With our initial success developing carbamate ester
insertion reactions, we anticipated that N-alkylureas would
perform as substrates in an analogous fashion. Phenethylurea
1 was tested under conditions that employed 5 mol % of
Rh2(OAc)4, PhI(OAc)2, and MgO (Figure 3). From this
Prior work from our lab has demonstrated the unique
effectiveness of Rh2(esp)2 for catalyzing both intra- and
intermolecular C-H amination reactions of sulfamate esters.4
We were therefore pleased to find that this complex was
equally adept at promoting high-yielding oxidation of Tces-
urea 5 (Table 1). Other Rh-tetracarboxylates examined, which
Table 1. Evaluating Reaction Conditions for Urea Oxidation
Figure 3. Control experiments and initial test substrates.
a A 5 mol % catalyst charge was employed. b Estimated product
conversion is based on integration of the 1H NMR spectrum of the unpurified
reaction mixture.
reagent mixture, multiple products were generated; none,
however, corresponded to the desired imidazolidin-2-one 2.
included Rh2(O2CCPh3)4 and Rh2(O2C-1-PhcHx)4, gave
reduced product conversions, particularly as the loading was
decreased from 5 to 1 mol %.12 Aside from the identification
of Rh2(esp)2 as an optimal catalyst for this process, the choice
of toluene as solvent was found to be another important factor
contributing to increased reaction yields. It is interesting to
(6) For a general review on vicinal diamine synthesis, see: Lucet, D.;
Le Gall, T.; Mioskowski, C.; Angew. Chem., Int. Ed. 1998, 37, 2580-
2627. Also, see: (a) Dunn, P. J.; Ha¨ner, R.; Rapoport, H. J. Org. Chem.
1990, 55, 5017-5025. (b) Jones, R. C. F.; Schofield, J. J. Chem. Soc.,
Perkin Trans. 1 1990, 375-383.
(7) (a) Shue, H.-J.; Chen, X.; Shih, N.-Y.; Blythin, D. J.; Paliwal, S.;
Lin, L.; Gu, D.; Schwerdt, J. H.; Shah, S.; Reichard, G. A.; Piwinski, J. J.;
Duffy, R. A.; Lachowicz, J. E.; Coffin, V. L.; Liu, F.; Nomeir, A. A.;
Morgan, C. A.; Varty, G. B. Biorg. Med. Chem. Lett. 2005, 15, 3896-
3899. (b) Berlinck, R. G. S.; Kossuga, M. H. Nat. Prod. Rep. 2005, 22,
516-550. (c) Brackeen, M. F.; Cowan, D. J.; Stafford, J. A.; Schoenen, F.
J.; Veal, J. M.; Domanico, P. L.; Rose, D.; Strickland, A. B.; Verghese,
M.; Feldman, P. L. J. Med. Chem. 1995, 38, 4848-4854.
(9) The mixture of unidentified products does not appear to contain any
derived from C-H functionalization.
(10) Espino, C. G. Ph.D. Thesis, Stanford University, Stanford, CA, 2004.
(11) When conducted with 5 mol % Rh2(OAc)4, the reaction of 5 gives
<10% of the desired product 6. With either catalyst, recovered starting
material accounts for the mass balance in these reactions.
(8) (a) Dembitsky, V. M. Russ. J. Bioorg. Chem. 2002, 28, 170-182.
(b) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237-243.
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Org. Lett., Vol. 8, No. 6, 2006

note that products derived from solvent oxidation have never
been obtained under these reaction conditions. A standard
protocol employing urea 5, 1 mol % of Rh2(esp)2, 1.5 equiv
of PhI(OAc)2, and 2.5 equiv of MgO in toluene at 40 °C
thus afforded 87% of the heterocyclic product 6.
Table 2. Oxidative Cyclization of N-Tces Urea Substrates
The ease by which Tces-protected ureas may be fashioned
further enhances the value of these substrates for C-H
amination (Figure 4). In a single operation, the commodity
Figure 4. Preparative method for Tces-urea assembly.
chemical ClSO2NCO can be transformed to N-(2,2,2-
trichloroethoxy)sulfonylurea 7.13 This compound reacts with
primary and secondary alcohols using Ph3P and DEAD to
furnish the N-alkylated materials. Accordingly, access to a
number of differentially substituted ureas is possible by
employing this straightforward protocol (Table 2).
As with reactions of carbamates, high-yielding amination
proceeds for Tces-ureas having tertiary and benzylic â-C-H
centers (entries 1-5, Table 2). Importantly, amination of
optically pure tertiary C-H bonds is stereospecific (entry
5), thereby giving access to tetrasubstituted amine products
with absolute stereochemical fidelity. Oxidative cyclization
of the homoallyl urea (entry 6) also occurs efficiently but
generates a nearly equal mixture of both insertion and
aziridine products. Similar chemoselectivites have been noted
for reactions of unsaturated carbamates and sulfamates.2 One
of the more difficult classes of substrates for amination is
represented by the straight chain, unsubstituted n-butylurea
(entry 7). Not surprisingly, product yields are reduced from
other entries even when higher catalysts loadings are
employed. Overall, the observed reactivity trends are quite
comparable to those of carbamates and sulfamates; as with
the former starting materials, five-membered ring formation
is highly favored.2e
a Reactions were performed with 1 mol % of Rh2(esp)2, 1.5 equiv of
PhI(OAc)2, and 2.5 equiv of MgO in toluene at 40 °C. b Isolated yield of
imidazolidin-2-one. The ratio of insertion/aziridine products is ∼1:1.3 based
on integration of the 1H NMR spectrum of the unpurified product. c The
starting urea is recovered in 50% yield.
group proved most effective. By employing Tces-guanidine
8 with 2 mol % Rh2(esp)2, PhI(OAc)2, and MgO in toluene,
74% yield of the cyclized product 9 was obtained (eq 2).
The ability to effect such a reaction at low catalyst loadings
given the polar, Lewis basic nature of the protected guanidine
is particularly striking and underscores the functional group
compatibility of these Rh-tetracarboxylate systems.
Motivated by the complex architectures of a number of
intriguing guanidine natural products, we wished to extend
the C-H amination methodology to include such substrates.
Again it was discovered that the reactivity of the N-
alkylguanidine needed to be tempered by the incorporation
of an electron-withdrawn protecting group. A focused screen
of N-carbamoyl and N-sulfonyl alkylguanidines afforded
results analogous to those of the urea reactions, as the Tces
Two methods have been developed for the efficient
synthesis of Tces-protected guanidines from primary amines.
Both of these protocols rely on imidodithionate 11, which
is easily prepared as a crystalline compound in a single step
from trichloroethylsulfamate 10.14,15 Subsequent conversion
of this reagent to either isothiourea 12 or imidochloride 13
is accomplished with NH3 and SO2Cl2, respectively (Figure
5).16 We have found that isothiourea 12 will react with most
primary amines in H2O at 100 °C (eq 3). Isolation by silica
gel chromatography affords the desired guanidines in high
(12) Rh2(O2CCPh3)4 is easily prepared from Rh2(OAc)4 and Ph3CCO2H;
see: Hashimoto, S.-i.; Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1992,
33, 2709-2712. Rh2(O2C-1-PhcHx)4 is prepared in an analogous fashion
from 1-phenylcyclohexane carboxylic acid.
(13) The reaction of Cl3CCH2OH with ClSO2NCO is precedented, see:
Lohaus, G. Chem. Ber. 1972, 105, 2791-2799.
Org. Lett., Vol. 8, No. 6, 2006
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Table 3. C-H Insertion of N-Tces Alkylguanidine Substrates
Figure 5. Reagents for the synthesis of N-Tces alkylguanidines.
yields. For certain, more functionalized amines, a second
strategy is utilized in which the desired amine is first
condensed with 13 (eq 4). The resulting pseudothiourea can
be transformed to the requisite guanidine using (Me3Si)2NH
as an ammonia source. In general, the guanidine starting
materials are highly crystalline materials and readily available
on preparative scales.
a Reactions were conducted with 2 mol % of Rh2(esp)2, 1.65 equiv of
PhI(OAc)2, and 2.5 equiv of MgO in toluene at 40 °C. b Product formed as
1
a single diastereomer based on H NMR analysis.
quantitatively using powdered Zn (5 equiv) in 1:1 AcOH/
MeOH to give the deprotected guanidinium salt (purified
by rp HPLC).18
The scope of the C-H amination reaction with Tces-
guanidines was examined, and the results are summarized
in Table 3. Substrates bearing tertiary â-C-H bonds are
clearly superior to those having benzylic or unactivated
secondary methylene centers. In contrast to our prior
experience with secondary-alcohol derived carbamates, cy-
clization of R-branched guanidines (entries 3 and 4) can be
promoted with reasonable success.17 Oxidation of N-pent-
ylguanidine (entry 5), although low yielding, gives only the
five-membered imidazoline product in keeping with results
from both carbamate and urea studies. Finally, it should be
noted that the Tces group serves as a useful, robust protecting
agent for the polar guanidine moiety. The insertion products
are easily purified by normal phase chromatography on silica
gel. Ultimately, the Tces group can be cleaved smoothly and
Selective and efficient C-H amination of urea- and
guanidine- derived substrates has been achieved with the
advent of Rh2(esp)2. This catalyst in combination with an
inexpensive oxidant, MgO, and toluene as solvent makes
possible the facile assembly of complex 1,2-diamine deriva-
tives in the form of imidazolidin-2-ones and 2-aminoimida-
zolines. Such heterocycles are ubiquitous structural elements
in natural and designed compounds, thus conferring these
oxidative methods with a large degree of practical value.
The expanding number of substrates that are now viable for
C-H amination reactions should promote further these
methods as essential tools for chemical synthesis.
Acknowledgment. This work was funded by grants from
the NSF and the Beckman Foundation and with generous
gifts from Abbott, Amgen, Boehringer Ingelheim, Bristol-
Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, Pfizer,
and Roche.
(14) 2,2,2-Trichloroethylsulfamate (TcesNH2) is now available from
Aldrich Chemical Co. It may also be readily prepared from Cl3CCH2OH
and ClSO2NCO in a single step. We have employed TcesNH2 for
Rh-catalyzed intermolecular C-H amination and alkene aziridination; see:
ref 4 and Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 13672-
13673, respectively.
Supporting Information Available: General experimen-
tal protocols and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) For a preparation of related N-arenesulfonyl imidodithionates, see:
Gompper, R.; Ha¨gele, W. Chem. Ber. 1966, 99, 2885-2899. For use of
these reagents in guanidine synthesis, see: Bosin, T. R.; Hanson, R. N.;
Rodricks, J. V.; Simpson, R. A.; Rapoport, H. J. Org. Chem. 1973, 38,
1591-1600.
(16) (a) Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel,
S. B.; Vyas, D. M. Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990. (b)
Neidlein, R.; Haussmann, W. Angew. Chem., Int. Ed. Engl. 1965, 4, 521-522.
(17) Many secondary alcohol-derived carbamates (e.g., cyclohexyl
carbamate) react with PhI(OAc)2 under Rh-catalysis to give ketone products
(cyclohexanone). We believe that this undesired reaction is the result of
either intramolecular C-H insertion or C-H abstraction at the R-center.
See refs 1a and 10 for details.
OL052920Y
(18) The analogous conditions when employed with Tces-protected
imidazolidin-2-ones failed to cleave the N-S bond, thus giving the product
as the N-sulfated cyclic urea. Preliminary investigations indicate that strongly
acidic conditions (e.g., 6 M HCl) may be needed to liberate the fully
deprotected urea product.
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Org. Lett., Vol. 8, No. 6, 2006