Synthesis of substituted 2-aminoimidazoles via Pd-catalyzed alkyne carboamination reactions. Application to the synthesis of preclathridine natural products

Article abstract of DOI:10.1021/ol502471x

A new method for the synthesis of 2-aminoimidazole products is described. The heterocyclic products are generated in good yields via Pd-catalyzed carboamination reactions of N-propargyl guanidines and aryl triflates. This methodology generates both a C-N

Full text of DOI:10.1021/ol502471x

Letter
pubs.acs.org/OrgLett
Open Access on 09/08/2015
Synthesis of Substituted 2‑Aminoimidazoles via Pd-Catalyzed Alkyne
Carboamination Reactions. Application to the Synthesis of
Preclathridine Natural Products
Blane P. Zavesky, Nicholas R. Babij, and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1005, United States
S
* Supporting Information
ABSTRACT: A new method for the synthesis of 2-aminoimidazole products is described. The heterocyclic products are
generated in good yields via Pd-catalyzed carboamination reactions of N-propargyl guanidines and aryl triflates. This
methodology generates both a C−N and C−C bond during the annulation step and facilitates the rapid construction of 2-
aminoimidazole products with different aryl groups. The utility of this methodology was demonstrated in the total synthesis of
preclathridine A, preclathridine B, and dorimidazole B from a single intermediate.
yclic guanidine natural products have garnered wide-
spread attention due to their wide-ranging biological
guanidines was reported as a useful means for generating
substituted 2-aminoimidazoles.8
C
properties.1 One interesting subclass of cyclic guanidines are
Although these strategies have proven to be highly valuable
for the construction of 2-aminoimidazole-containing alkaloids,
none involve C−C bond formation during the ring-closing step,
and as a result, the synthesis of closely related alkaloids such as
1−3 cannot currently be accomplished from a single
intermediate. Rather, different substrates are required to access
compounds that differ in the nature of the 4-(arylmethyl)
group. A more attractive synthetic approach to these
compounds would be one that facilitates the conversion of a
single, simple, starting material to any of these derivatives via
installation of an appropriate aryl group, which could be
obtained from a readily available compound such as an aryl
halide or triflate.
substituted 2-aminoimidazole derivatives (1−5) (Figure 1).
We recently reported a method for the construction of
saturated cyclic guanidines via Pd-catalyzed carboamination
reactions between N-allyl guanidines 6 and aryl or alkenyl
halides (Scheme 1a).9 These cross-coupling reactions led to the
formation of both a C−N bond and a C−C bond and afforded
the products 7 in good yields.10,11 We envisioned that this
methodology could be employed for the synthesis of 2-
aminoimidazole-containing products by simply using N-
propargyl guanidine substrates 8 in place of the N-allyl
substrates 6 (Scheme 1b). These transformations should
generate products 9 bearing an exocyclic alkene, which would
then isomerize either under the reaction conditions or during a
workup step to afford the desired 2-aminoimidazole products
Figure 1. 2-Aminoimidazole natural products.
These compounds display a myriad of potentially useful
biological activities. Members of this family of alkaloids have
been shown to be human β-secretase (BACE1) inhibitors,2
tubulin-binding agents,3 and epidermal growth factor receptor
inhibitors,4 and also exhibit interesting antimicrobial5 and
antibiotic activity.6 Classical methods for the construction of 2-
aminoimidazoles generally involve either condensation reac-
tions of α-amino- or α-haloketones or functionalization of
imidazole derivatives.7 More recently, the metal-catalyzed
hydroamination of acyclic terminally substituted N-propargyl
Received: August 20, 2014
Published: September 8, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
aminopalladation pathways under appropriate conditions,
which leads to significantly improved chemical yields for
transformations of these types of substrates.15,16 Thus, we
reasoned that altering the reaction conditions to favor an anti-
aminopalladation mechanistic pathway might promote the
desired transformations of 8a to 2-aminoimidazoles 10.
Scheme 1. Synthesis of Cyclic Guanidines via Pd-Catalyzed
Carboamination Reactions
To probe the hypothesis outlined above, N-propargyl
guanidine substrate 8a was subjected to the reaction conditions
that had provided optimal results for Pd-catalyzed carboami-
nation reactions of N-allyl sulfamides.15a As shown in Table 1,
a
Table 1. Ligand Optimization
10.8a,c Importantly, these transformations would effect
installation of a C4′ aryl group during the ring-closing step.
This would allow for straightforward introduction of different
groups at the C4′ position, which cannot currently be
accomplished using other existing methods. Herein we describe
our initial findings on this new approach to the construction of
2-aminoimidazoles and the application of this method to the
synthesis of three different alkaloid natural products (1−3)
from a single intermediate.
In our original studies on the synthesis of saturated
guanidines, we utilized substrates 6 bearing two PMP
protecting groups. Despite the utility of these transformations,
we were not able to develop conditions to remove both PMP
aryl groups from the carboamination products. As such, in the
present studies we elected to examine substrates bearing N-
sulfonyl protecting groups, as these compounds can be
prepared in a straightforward manner, and cleavage of N-
sulfonyl groups from 2-aminoimidazoles has previously been
demonstrated.12
At the outset of this project we decided to explore the
reactivity of N-tosyl-N-propargyl guanidine substrate 8a, which
was prepared in four steps (63% overall yield) from
commercially available materials (N-methylallylamine,
trimethylsilylacetylene, and formaldehyde). Unfortunately
efforts to couple 8a with aryl bromide 3-bromophenyl-1,3-
dioxolane using conditions previously employed for reactions of
6 were unsuccessful (eq 1). The desired 2-aminoimidazole was
not obtained, and instead a mixture of hydroamination
products 11a−b was generated.
a
Reaction conditions: 1.0 equiv of 8a, 1.2 equiv of 12, 2.4 equiv of
LiOtBu, 4 mol % Pd(OAc)2, 8 mol % ligand, PhCF3 (0.1 M), 100 °C,
16 h.
the coupling of 8a with aryl triflate 12 to afford 2-
aminoimidazole 10a was successfully achieved when Pd(OAc)2
was employed as the palladium source along with the base
LiOtBu and the solvent PhCF3. Significant amounts of desired
product were obtained with several different phosphine ligands,
including Nixantphos17 and a variety of different Buchwald-type
biarylphosphines (entries 1−5).18 The primary side products
generated in these reactions resulted from competing hydro-
amination of the alkyne (11a and 11b), but this side reaction
was less problematic than with the conditions shown in eq 1.
Ultimately the RuPhos ligand was found to provide the best
results (entry 5), affording the desired product 10a in 80%
isolated yield while only trace amounts of hydroamination side
products were generated.
It seemed likely that the failure of 8a to undergo successful
carboamination was due to the decreased nucleophilicity of the
N-tosyl guanidine as compared to the bis-PMP-protected
guanidine present in 6. This decreased nucleophilicity likely
disfavors the key syn-aminopalladation step in the catalytic
cycle;13 previously reported cases of reactions that proceed via
alkyne syn-aminopalladation involve relatively nucleophilic
amines.14 Our group has recently discovered that Pd-catalyzed
carboamination reactions of relatively weak nitrogen nucleo-
philes (N-allylsulfamides) can be induced to proceed via anti-
With optimized conditions in hand, the scope of these
transformations was examined by coupling 8a with a variety of
aryl triflates (Table 2). Gratifyingly, aryl triflates bearing
electron-donating, electron-neutral, and electron-withdrawing
groups (entries 1−5) afforded the corresponding 2-amino-
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Organic Letters
Letter
a
Table 2. Scope of Carboamination Reactions
Scheme 2. Synthesis of 2-Aminoimidazole Natural Products
carboamination reactions as a synthetic strategy for the
construction of 2-aminoimidazole products and illustrates the
potential to generate several different alkaloid derivatives from
one intermediate (8a).
The rapid isomerization of putative intermediate 9 prevents
us from making definitive statements about the mechanism of
these reactions, as the stereochemistry of addition to the alkyne
cannot be unambiguously established. However, given our prior
observations that reaction conditions such as those employed in
these transformations tend to favor anti-aminopalladation
pathways, we suggest the mechanism illustrated in Scheme 3
a
Reaction conditions: 1.0 equiv of 8a or 8b, 2.0 equiv of Ar−OTf, 2.4
equiv of LiOtBu, 4 mol % Pd(OAc)2, 8 mol % RuPhos, PhCF3 (0.1
b
c
M), 100 °C, 3 h. Isolated yield. The reaction was conducted using
1.2 equiv of Ar−OTf. The reaction was conducted using 5 equiv of
Ar−OTf.
d
Scheme 3. Catalytic Cycle
imidazole derivatives in good yields. Moreover, an ortho-methyl
substituted aryl triflate also underwent smooth coupling with 8a
to generate product 10f in high yield (entry 4). However, it was
necessary to employ 2 equiv of most aryl triflates due to
competing base-mediated cleavage of the triflate to the
corresponding phenol. In most instances products bearing
TMS-groups were stable under these conditions, and it was not
necessary to rigorously monitor reactions to determine the
exact time of completion; reactions could be conducted for up
to 16 h with no product degradation (although efforts to
optimize reaction times indicated most were complete in ca. 3
h). However, a relatively short reaction time (3 h) and
somewhat careful monitoring of reaction progress were
required for the coupling of substrate 8a with 4-benzoylphenyl
trifluoromethanesulfonate in order to prevent conversion of
product 10e to the corresponding desilylated compound (entry
5). Related transformations of substrate 8b, which contains a
phenyl-substituted alkyne, also provided the desired 2-amino-
imidazole products. However, yields were lower than those in
analogous transformations of 8a due to competing hydro-
amination of the substrate.
To demonstrate the utility of this methodology we
undertook the total synthesis of 2-aminoimidazole alkaloids
1−3. As shown in Scheme 2, N-tosyl protected substrate 8a was
coupled with three different aryl triflates using the optimized
reaction conditions from above. However, in the synthesis of
1−3 the TMS-substituted products of these reactions were not
isolated but, instead, were treated with 4 M HCl in dioxane to
effect protodesilyation.19 The N-tosyl groups were then cleaved
from the resulting intermediates using Li/naphthalene, thereby
providing alkaloids preclathridine A, preclathridine B, and
dorimidazole B.20,21 Overall, the three 2-aminoimidizole natural
products 1−3 were synthesized in just six steps and good
overall yields (40−48%) from commercially available materials.
Importantly, this work highlights the power of Pd-catalyzed
may be in operation.15 Oxidative addition of the aryl triflate to
palladium(0) generates cationic palladium complex 15.22
Coordination of the Pd-catalyst to the alkyne produces 16
and facilitates outer-sphere attack of the guanidine nucleophile
onto the alkyne (anti-aminopalladation). Reductive elimination
from Pd-alkenyl intermediate 17 affords the exocyclic product
9, which then undergoes double-bond isomerization to give the
desired 2-aminoimidazole product 10.
In summary, we have developed a new strategy for the
construction of 2-aminoimidazoles via the Pd-catalyzed alkyne
carboamination of tosyl-protected N-propargyl guanidines and
aryl triflates. The N-tosyl-2-aminoimidazole products are
generated in good yields, and the N-tosyl group can be
reductively cleaved in a single step. Notably, this strategy
generates a C−C bond during the annulation event, thus
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Letter
(9) Zavesky, B. P.; Babij, N. R.; Fritz, J. A.; Wolfe, J. P. Org. Lett.
2013, 15, 5420−5423.
(10) For reviews on Pd-catalyzed carboamination reactions, see:
(a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571−582. (b) Wolfe, J. P.
Synlett 2008, 2913−2937. (c) Schultz, D. M.; Wolfe, J. P. Synthesis
2012, 44, 351−361. (d) Wolfe, J. P. Top. Heterocycl. Chem. 2013, 32,
1−38.
facilitating late-stage derivitization as illustrated through the
total synthesis of preclathridine A, preclathridine B, and
dorimidazole B in just two steps from a common intermediate.
Continued studies on the use of Pd-catalyzed carboamination
reactions of alkynes and alkenes in the synthesis of guanidine
alkaloids are currently underway.
(11) For Pd-catalyzed carboamination reactions utilized in the
synthesis of polycyclic guanidine alkaloids, see: Babij, N. R.; Wolfe, J.
P. Angew. Chem., Int. Ed. 2012, 51, 4128−4130. (b) Babij, N. R.;
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2540−2544.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data for all new
compounds, descriptions of stereochemical assignments, and
1
copies of H and 13C NMR spectra for all new compounds
(13) (a) Neukom, J. D.; Perch, N. S.; Wolfe, J. P. J. Am. Chem. Soc.
reported in the text. This material is available free of charge via
the Internet at http://pubs.acs.org.
́
2010, 132, 6276−6277. (b) Hanley, P. S.; Markovic, D.; Hartwig, J. F.
J. Am. Chem. Soc. 2010, 132, 6302−6303. (c) Neukom, J. D.; Perch, N.
S.; Wolfe, J. P. Organometallics 2011, 30, 1269−1277. (d) Hanley, P.
S.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 15661−15673.
(e) White, P. B.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 18594−
18597.
AUTHOR INFORMATION
■
Corresponding Author
(14) For selected examples of reactions that involve alkyne syn-
aminopalladation, see: (a) Karstens, W. F. J.; Stol, M.; Rutjes, F. P. J.
T; Kooijman, H.; Spek, A. L.; Hiemstra, H. J. Organomet. Chem. 2001,
624, 244−258. (b) Jacobi, P. A.; Liu, H. Org. Lett. 1999, 1, 341−344.
(c) Piou, T.; Neuville, L.; Zhu, J. Tetrahedron 2013, 69, 4415−4420.
(d) Tang, S.; Peng, P.; Pi, S.-F.; Liang, Y.; Wang, N.-X.; Li, J.-H. Org.
Lett. 2008, 10, 1179−1182. (e) Liu, J.; Shen, M.; Zhang, Y.; Li, G.;
Khodabocus, A.; Rodriguez, S.; Qu, B.; Farina, V.; Senanayake, C. H.;
Lu, B. Z. Org. Lett. 2006, 8, 3573−3575.
*E-mail: jpwolfe@umich.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the NIH-NIGMS (GM-071650) and the
University of Michigan Associate Professor Support Fund for
financial support of this work. B.Z. acknowledges the University
of Michigan Department of Chemistry for a Summer
Undergraduate Research Fellowship.
(15) (a) Fornwald, R. M.; Fritz, J. A.; Wolfe, J. P. Chem.Eur. J.
2014, 20, 8782−8790. (b) Babij, N. R.; McKenna, G. M.; Fornwald, R.
M.; Wolfe, J. P. Org. Lett. 2014, 16, 3412−3415.
(16) For selected recent examples of other transformations that
proceed through alkyne anti-aminopalladation, see: (a) Shen, Z.; Lu,
X. Tetrahedron 2006, 62, 10896−10899. (b) Han, X.; Lu, X. Org. Lett.
2010, 12, 3336−3339. (c) Liu, Q.; Chen, P.; Liu, G. ACS Catal. 2013,
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Chem. Rev. 2006, 106, 4644−4680. (f) Zeni, G.; Larock, R. C. Chem.
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