Rhodium(III)-Catalyzed Imidoyl C-H Activation for Annulations to Azolopyrimidines

Article abstract of DOI:10.1021/acs.orglett.8b00816

Azolopyrimidines are efficiently prepared by direct imidoyl C-H bond activation. Annulations of N-azolo imines with sulfoxonium ylides and diazoketones under redox-neutral conditions and alkynes under oxidizing conditions provide products with various arrangements of nitrogen atoms and carbon substituents. We have also probed the mechanism of this first example of Rh(III)-catalyzed direct imidoyl C-H activation by structural characterization of a catalytically competent rhodacycle obtained after C-H activation and by kinetic isotope effects.

Full text of DOI:10.1021/acs.orglett.8b00816

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium(III)-Catalyzed Imidoyl C−H Activation for Annulations to
Azolopyrimidines
Kim Søholm Halskov, Michael R. Witten, Gia L. Hoang, Brandon Q. Mercado, and Jonathan A. Ellman*
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
S
* Supporting Information
ABSTRACT: Azolopyrimidines are efficiently prepared by
direct imidoyl C−H bond activation. Annulations of N-azolo
imines with sulfoxonium ylides and diazoketones under redox-
neutral conditions and alkynes under oxidizing conditions
provide products with various arrangements of nitrogen atoms
and carbon substituents. We have also probed the mechanism of
this first example of Rh(III)-catalyzed direct imidoyl C−H
activation by structural characterization of a catalytically
competent rhodacycle obtained after C−H activation and by kinetic isotope effects.
ridgehead N-fused [5,6]-bicyclic heterocycles are privileged
would allow for rapid and convenient access to a wide range of N-
Bpharmacophores increasingly found in drug leads, clinical azolo imine substrates. However, while imidoyl C−H activation
candidates and approved drugs. We recently reported the
synthesis of azolopyridines by annulations of C-alkenyl azoles
with alkynes or diazoketones as mediated by alkenyl C(sp2)−H
functionalization (Scheme 1a).1 Other researchers had also
previously reported on annulations to give tricyclic N-fused
heterocycles by C(sp2)−H functionalization of C-aryl azoles with
alkynes.2,3
has been reported,5 to the best of our knowledge, it has not been
applied to annulations to give nitrogen heterocycles. Moreover,
while Rh(III) and Co(III) are particularly effective catalysts for
nitrogen heterocycle annulations,3 neither has been reported for
imidoyl C−H activation. Herein, we disclose the first heterocycle
formation by catalytic, direct imidoyl C−H activation.
Specifically, Rh(III)-catalyzed annulation of N-azolo imines
with sulfoxonium ylides, diazoketones, and alkynes generate
azolopyrimidines with a wide variety of substitution patterns. We
have obtained a crystal structure of a catalytically competent
rhodacycle C−H activation intermediate, which together with
kinetics and deuterium isotope studies, allow us to posit a
catalytic mechanism.
Scheme 1. Catalytic C(sp2)−H Functionalization for the
Preparation of Bridgehead N-Fused [5,6]-Bicyclic
Heterocycles
Initially, we focused on Rh(III)-catalyzed annulations of N-
azolo imines with sulfoxonium ylides. These reagents are
typically well-behaved crystalline solids that demonstrate high
stability and serve as carbene precursors that do not generate
gases as byproducts, which can cause safety issues in large scale
6
̈
processes. Recently the groups of Li, Aissa, and Cheng have
shown that these reagents are very effective for Rh(III)-catalyzed
acyl methylations7 and annulations8 of arenes. We envisioned
that azolopyrimidines could be obtained by imidoyl C−H acyl
methylation followed by intramolecular condensation.
After identification of optimal reaction conditions for the
desired coupling (see Table S1 in the Supporting Information),
the reactivities of several N-azolo imines with sulfoxonium ylide
2a were assessed (Scheme 2). Imines derived from 2-amino-
imidazole and various benzaldehydes provided imidazopyrimi-
dines in generally high yields (3a−3f). These substrates included
electron-rich (3b) and electron-deficient (3c and 3d)
benzaldimines. Bromide (3e) and chloride (3f) substituents
Azolopyrimidines are another class of bridgehead N-fused
[5,6]-bicyclic heterocycles found in many drugs and drug
candidates.4 We envisioned that annulations of N-azolo imines
might provide efficient entry to these compounds (Scheme 1b).
An attractive aspect of such a strategy would be that many
commercial aminoazoles and, in particular, aldehyde inputs
Received: March 13, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b00816
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Letter
Scheme 2. Rh(III)-Catalyzed C−H Functionalization of
Scheme 3. Rh(III)-Catalyzed C−H Functionalization of
a
a
Azoloaldimines 1 with Sulfoxonium Ylide 2a
Azolobenzaldimines 1 with Sulfoxonium Ylides 2
a
b
Reactions performed on 0.3 mmol scale. Reaction performed with
tetrahydrofuran as solvent.
Table S2 in the Supporting Information). Thus, we observed
coupling of diazoketone 4 with several imines (Scheme 4). In
addition to the parent imine (5a), reactions proceeded well with
electron-rich (5b) and electron-deficient (5c and 5d) imines.
Imines derived from 3-bromobenzaldehyde (5e), furfural (5f),
and cinnamaldehyde (5g) also participated in moderate to high
a
b
Reactions performed on 0.3 mmol scale. Reaction performed with
c
tetrahydrofuran as solvent. Reaction performed with 4.0 equiv of
PivOH at 120 °C. Reaction performed on 1 mmol scale on the
benchtop under an inert atmosphere.
d
are also compatible with the reaction conditions, affording
products capable of subsequent cross-coupling. The chloro
derivative (3f) additionally establishes that ortho-substituted
benzaldimines undergo reaction with only a modest reduction in
yield. Reaction of a furfural-derived imine also provided
heterocycle 3g. Moreover, imines derived from aminopyrazole
starting materials proceeded to pyrazolopyrimidines 3h−3j in
good to excellent yields. Preparation of N-azolo imines from
enolizable aldehydes proved difficult, and therefore, annulation
of this class of substrates was not studied. Finally, preparation of
3a was achieved outside the glovebox on 1 mmol scale in
comparable (82%) isolated yield.
Scheme 4. Rh(III)-Catalyzed C−H Functionalization of
a
Azoloaldimines 1 with Diazoketone 4
We next investigated the scope of this new transformation with
respect to other sulfoxonium ylides (Scheme 3). Although an
electron-rich aryl ylide coupled efficiently (3k), the reaction of an
electron-deficient ylide proceeded less favorably (3l). Sulfoxo-
nium ylides with bromophenyl (3m) and thiophene (3n)
substituents also successfully participated in these couplings. In
addition to aromatic ylides, aliphatic ylides can undergo
couplings (3o−3q), with carbamate 3q primed for further
functionalization following Boc-deprotection. Finally, N-pyrazo-
lo imines afforded products bearing electron-rich aryl (3r),
electron-deficient aryl (3s), and alkyl (3t) substituents in
excellent yields.
Next, we expanded this reaction protocol to include the
stabilized diazoketone 4. Like, sulfoxonium ylides, diazoketones
are redox-neutral carbene equivalents, and they have seen
extensive use in Rh(III)-catalyzed C−H functionalization
chemistry.9 An initial screen revealed that the conditions used
for sulfoxonium ylides were also optimal for diazoketone 4 (see
a
b
Reactions performed on 0.3 mmol scale. Reaction performed with
4.0 equiv of PivOH at 120 °C.
B
DOI: 10.1021/acs.orglett.8b00816
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Letter
yields. N-Pyrazolo imines also demonstrated good reactivity with
this coupling partner (5h−5j).
We also evaluated N-azolo imines 1 in oxidative annulation
processes, and for this purpose, studied oxidative couplings with
alkynes 6 (Scheme 5). Preliminary experiments (see Table S3 in
provided the first structure of a complex obtained by Rh(III)-
imidoyl activation.10
Scheme 6. Formation and Reaction of Rhodacycle 8
Scheme 5. Rhodium(III)-Catalyzed C−H Functionalization
a
of Azoloaldimines 1 with Alkynes 6
We confirmed the catalytic activity of this proposed
intermediate in both a redox-neutral and an oxidative coupling.
Reaction of imine 1a with ylide 2a in the presence of 10 mol % of
rhodacycle 8 and AgSbF6 provided a 58% isolated yield of
heterocycle 3a (Scheme 6b).11 Likewise, the oxidative coupling
of imine 1a with 3-hexyne 6a afforded a 78% isolated yield of
imidazopyrimidine 7a (Scheme 6c). These experiments
substantiate the likelihood of the cationic variant of rhodacycle
8 as an intermediate along the catalytic pathway.
To better understand the fundamental C−H activation step,
we submitted deuteroimine 1a-D and ylide 2a to the standard
reaction conditions, then halted the coupling at 33% yield of
product 3a (Scheme 7a). Remaining imine was analyzed for
a
b
Reactions performed on 0.3 mmol scale. Reaction conditions:
[Cp*RhCl2]2 (5 mol %), AgOAc (2.2 equiv), PivOH (4.0 equiv),
THF, 100 °C, 18 h.
Scheme 7. Deuterium Isotope Studies with 1a-D
the Supporting Information) revealed 2,2,2-trifluoroethanol
(TFE) to be the optimal solvent with copper(II) acetate as the
terminal oxidant. Under these conditions, 3-hexyne reacted with
the standard suite of electronically and sterically differentiated N-
imidazo imines (7a−7f). Coupling also proceeded in 93% yield
starting from an imine prepared from 2-aminobenzimidazole
(7g). Additionally, furfural- (7h) and cinnamaldehyde-derived
(7i) imines engaged in effective couplings with 3-hexyne. Use of
diphenylacetylene as the alkyne resulted in isolation of
imidazopyrimidine 7j in 75% yield, and use of 1-phenyl-1-
butyne provided a separable 2.8:1 mixture of regioisomers 7k. As
in the redox-neutral reactions, pyrazolopyrimidines were also
obtained, with 7l and 7m isolated in 46% and 83% yields,
respectively. However, for these pyrazolopyrimidines, AgOAc
needed to be used as the stoichiometric oxidant, with Cu(OAc)2
resulting in considerable decomposition and <5% yield of the
desired products.
We next turned our attention to the mechanism. To assess the
viability of the proposed rhodacyclic intermediate (i.e., Scheme
1b), we set out to isolate and characterize this key C−H activated
species by X-ray crystallography. Treatment of imine 1a with
stoichiometric (based on metal) [Cp*RhCl2]2 and NaOAc
cleanly afforded rhodacycle 8 (Scheme 6a) in nearly quantitative
yield. Single crystals of 8 were characterized by X-ray analysis and
hydrogen incorporation, revealing less than 4% conversion of
deuteroimine 1a-D to protioimine 1a. This low level of
scrambling is indicative of a slightly reversible C−H activation
step. Given the limited reversibility of this step, we investigated
the initial rates of reactions of 1a and deuterated 1a-D with 2a to
reveal a primary KIE of 1.5 0.09 (Scheme 7b). This result is
consistent with rate-limiting C−H activation and rules out
alternative nucleophilic addition to the imine, as this would result
in rehybridization and a secondary KIE.
We propose the catalytic mechanism depicted in Scheme 8.
Based on the findings in Scheme 7, we suggest concerted
metalation/deprotonation of imine 1a to form rhodacycle 8a is
rate determining. According to the results in Scheme 6, we
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DOI: 10.1021/acs.orglett.8b00816
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ORCID
Scheme 8. Proposed Mechanism of Rhodium(III)-Catalyzed
C−H Functionalizations of N-Azolo Imines
Jonathan A. Ellman: 0000-0001-9320-5512
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (R35GM122473 to J.A.E.
and F32GM114880 to M.R.W.) and the Villum Foundation
(VKR023371 to K.S.H.).
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believe this intermediate lies on the active catalytic pathway and
undergoes carbene insertion to rhodacycle 9 with sulfoxonium
ylide 2, resulting in the extrusion of DMSO.7a Protonolysis
releases ketone 10 and regenerates free Rh(III) catalyst. Finally,
cyclodehydration of imidazole 10 results in the formation of
heterocycle 3. The related catalytic cycle for couplings with
diazoketone 4 and the catalytic cycle for oxidative couplings with
alkynes 6 are provided in the Supporting Information (Schemes
S2 and S3).
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(10) Rhodacycles obtained by Rh(I) imidoyl C−H oxidative addition
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The modular and regiospecific nature of annulation by imidoyl
C−H activation is worth noting. For example, condensation of an
aminoazole with a 1,3-diketone also proceeds by cyclodehydra-
tion of an intermediate analogous to 10. However, differently
substituted 1,3-diketones must first be obtained and generally
condense with poor regiocontrol.12
In conclusion, Rh(III)-catalyzed direct imidoyl C−H
activation and coupling with sulfoxonium ylides, diazoketones,
and alkynes provide varied azolopyrimidines. We have probed
the unique imine C−H activation pathway by isolating and
characterizing by X-ray crystallography a catalytically active
rhodacycle intermediate and by obtaining a primary kinetic
isotope effect consistent with rate limiting C−H activation. The
reported methodology should find utility in the pharmaceutical
sector, where azolopyrimidines are frequently employed.4
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00816.
insertion of isocyanides: (b) Werner, H.; Heinemann, A.; Windmuller,
̈
Experimental details, characterization data, and NMR
spectra (PDF)
B.; Steinert, P. Chem. Ber. 1996, 129, 903. (c) Vicente, J.; Chicote, M. T.;
́
Vicente-Hernandez, I.; Bautista, D. Inorg. Chem. 2007, 46, 8939.
(11) [Cp*RhCl2]2 (5 mol %) and AgSbF6 (20 mol %) as the catalytic
system resulted in 66% yield (see Table S1 in the Supporting
Information).
Accession Codes
CCDC 1585355, 1585369, and 1585370 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(12) Maquestiau, A.; Taghret, H.; Vanden Eynde, J.-J. Bull. Soc. Chim.
Belg. 1992, 101, 131.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jonathan.ellman@yale.edu.
D
DOI: 10.1021/acs.orglett.8b00816
Org. Lett. XXXX, XXX, XXX−XXX