Sequential C3 and C5 direct C-H arylation of imidazo[1,2-a]pyrazines with (Hetero)aryl bromides

Article abstract of DOI:10.1002/ejoc.201301802

An efficient reaction manifold for the preparation of C3/C5- diarylimidazo[1,2-a]pyrazines through sequential C3 and C5 direct arylation is disclosed. The two distinct palladium catalyst systems showcased herein are compatible with a wide variety of aryl and heteroaryl bromides and are also operative in a one-pot, twofold C-H functionalization event. Copyright

Full text of DOI:10.1002/ejoc.201301802

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301802
Sequential C3 and C5 Direct C–H Arylation of Imidazo[1,2-a]pyrazines with
(Hetero)aryl Bromides
Brett M. Johnson[a] and Malcolm P. Huestis*[a]
Dedicated to the memory of Professor David Y. Gin (1967–2011)
Keywords: Arylation / C–H functionalization / Palladium / Biaryls / Cross-coupling
An efficient reaction manifold for the preparation of C3/C5-
diarylimidazo[1,2-a]pyrazines through sequential C3 and C5
lyst systems showcased herein are compatible with a wide
variety of aryl and heteroaryl bromides and are also opera-
direct arylation is disclosed. The two distinct palladium cata- tive in a one-pot, twofold C–H functionalization event.
ure 1.[6] Typically, 3-arylimidazo[1,2-a]pyrazines are ob-
tained from imidazo[1,2-a]pyrazines by electrophilic bromin-
Introduction
The assembly of functionalized biaryl molecules presents
an important challenge to synthetic chemists. At present,
when faced with the preparation of biaryl linkages, one
would undoubtedly call upon the powerful palladium(0)-
catalyzed cross-coupling technologies that were first investi-
gated in the 1970s and 1980s.[1,2] These methods rely on the
use of two prefunctionalized arenes that must be prepared
beforehand.
ation, followed by Suzuki–Miyaura cross-coupling with
A newer approach that has seen considerable advance-
ments in the last decade is direct arylation, whereby one
cross-coupling partner (usually the one adorned with an or-
ganometallic or organometalloid functional group) is re-
placed by the arene itself (C–H bond).[3,4] In many cases,
this obviates the need for additional synthetic steps to pre-
pare one of the arenes for the cross-coupling event. Al-
though direct arylation has been demonstrated on a wealth
of aromatic heterocycles so far, there still remains a multi-
tude of heteroaromatic ring systems that have not been in-
vestigated. Furthermore, studies in the literature describing
a distinct, second C–H arylation event are scant[5] but
would provide facile access to polyaromatic compounds
that would be far more laborious to obtain by conventional
methods.
Imidazo[1,2-a]pyrazine heterocycles have received little
attention from the field of C–H functionalization. A selec-
tion of ornamented imidazo[1,2-a]pyrazines born out of re-
cent medicinal chemistry campaigns is displayed in Fig-
[a] Discovery Chemistry, Genentech, Inc.,
1 DNA Way, South San Francisco, California 94080, USA
E-mail: huestis.malcolm@gene.com
malcolm.huestis@gmail.com
www.gene.com
Figure 1. Examples of C3- and C5-arylated imidazo[1,2-a]pyrazines
in medicinal chemistry.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301802.
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B. M. Johnson, M. P. Huestis
SHORT COMMUNICATION
Scheme 1. Literature precedent for the direct arylation of imidazo[1,2-a]pyrazines; Piv = pivaloyl, CyJohnPhos = 2-(dicyclohexylphos-
phino)biphenyl.
aryl boronic acids. For 5-arylimidazo[1,2-a]pyrazines, which C5 direct arylation event have not been forthcoming.[11] We
are also typically prepared by Suzuki–Miyaura cross-cou- now wish to record the establishment of robust and scalable
pling, the C5 halogen must either be installed before con- reaction conditions to expand the scope of the C3 direct
struction of the imidazo[1,2-a]pyrazine ring system or an arylation of imidazo[1,2-a]pyrazines, as well as conditions
additional functional group must be used to divert the halo- for a subsequent C5 direct arylation with aryl and het-
genation site to C5. In contrast to the biaryl architectures eroaryl bromides (Scheme 1).
depicted in Figure 1, C3/C5-diarylimidazo[1,2-a]pyrazines
are virtually unknown, most likely due to the inefficient and
lengthy synthetic sequences needed for their procurement.
Results and Discussion
In the current study, we sought to establish a procedure
to provide improved access to these types of motifs through
Under conditions similar to those for Fagnou’s hetero-
the direct arylation of imidazo[1,2-a]pyrazine C–H bonds. aryl direct arylation procedure,[12] we were pleased to ob-
Besides several unoptimized instances of C3 direct arylation serve that C3 direct arylation of imidazo[1,2-a]pyrazine
that can be found within the patent literature (27–60% with 4-bromo-1-ethylbenzene proceeded cleanly at 100 °C
yield),[7] palladium-catalyzed C–H arylation reactions with to provide biaryl 1a in 74% yield and in 78% yield on gram
imidazo[1,2-a]pyrazines have appeared in the chemical lit- scale (Table 1). Although we confirmed that reactions with
erature only recently (Scheme 1). In 2012, a single example 4-iodo- and 4-chloro-1-ethylbenzene were successful (77
of C3 direct arylation was described by Tobisu and Chatani and 49% yield, respectively), the remainder of our work
(iodobenzene, 99% yield).[8] Shortly thereafter, Guchhait focused on reactions with aryl bromides, as a result of their
demonstrated C6 direct arylation of 2-(aryl/alkyl)-3-N- stability and ease of preparation on the laboratory scale.
(aryl/alkyl)aminoimidazo[1,2-a]pyrazines with aryl brom- Thus, the current transformation is compatible with aryl
ides.[9] Finally, Gembus and Hoarau disclosed that 6- bromides possessing 4-trifluoromethyl (product 1b, 47%),
bromo-8-methoxyimidazo[1,2-a]pyrazine and 6-bromo-8- 4-ethylthio (product 1c, 56% on gram scale), and 3-cyano-
methylthioimidazo[1,2-a]pyrazine underwent one-pot Su- 4-methoxy functional groups (product 1d, 90% on gram
zuki–Miyaura/C3 direct arylation.[10] Studies describing a scale). Sterically encumbered 1-bromo-2,4-dimethylbenzene
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Sequential and Direct C–H Arylation of Imidazo[1,2-a]pyrazines
also reacted (product 1e, 75%), as did 5-bromoindole, Table 1. C3 direct arylation of imidazo[1,2-a]pyrazine and ethyl
imidazo[1,2-a]pyrazine-2-carboxylate.[a]
which bears a free N–H group (product 1f, 21%). Ethyl
imidazo[1,2-a]pyrazine-2-carboxylate underwent C3 direct
arylation as well to afford biaryl products with 1-bromo-3-
chloro-5-fluorobenzene (product 1g, 56%), methyl 4-
bromobenzoate (product 1h, 76%), and 4-bromo-3-fluoro-
benzaldehyde (product 1i, 61%). Notably, we did not ob-
serve any competitive side reactions with the chloride, ester,
or aldehyde functionalities. In terms of heteroaromatic cou-
pling partners, the scope of the C3 direct arylation is exten-
sive. Multiple bromoazines were compatible, including 2-
bromo-6-methoxypyridine (product 1k, 53%), 3-bromopyr-
idine (product 1j, 79%), and 4-bromo-2-methylpyridine
(product 1l, 86%). Also tolerated was 3-bromoquinoline
(product 1m, 84% on gram scale), 4-bromoisoquinoline
(product 1n, 79%), and 5-bromopyrimidine (product 1o,
60%). Additionally, successful couplings were achieved with
five-membered heterocyclic bromides such as 2-acetyl-5-
bromothiophene (product 1p, 46%), 4-bromo-1-methylpyr-
azole (product 1q, 63%), and 3-bromofuran (product 1r,
44% on gram scale). Some limitations to the scope of this
method exist for both the imidazo[1,2-a]pyrazine[13] and the
(hetero)aryl bromide[14] coupling partners; further optimi-
zation of the reaction conditions may be necessary in spe-
cific cases.
During our investigation, we sometimes detected small
amounts of diarylated product resulting from a second C–
H arylation event. This prompted us to examine the pos-
sibility of performing a second direct arylation reaction to
produce triaryl compounds. Reaction conditions based on
those from Table 1, as well as those reported by Guchhait
for the C6 arylation of 2-(aryl/alkyl)-3-N-(aryl/alkyl)amino-
imidazo[1,2-a]pyrazines[9] provided only trace conversion as
determined by HPLC–MS. Gratifyingly, conditions adapted
from Yu’s direct arylation of pyridines and 1H-indazoles
provided triaryl products in moderate yield, and the aryl
fragment was deposited exclusively at C5 (Table 2).[15,16] It
remains unclear why Guchhait’s conditions did not provide
useful levels of product, nor why we observed a change in
regioselectivity from C6 to C5 under our conditions. Al-
though our reactions did not go to completion, the triaryl
products were easily separated from the remaining starting
materials by using standard flash chromatography purifica-
tion; further optimization work may seek to address this
shortcoming and provide higher yields of the isolated prod-
ucts. The scope of the C5 direct arylation is shown in
[a] Conditions: A vial was charged with the imidazo[1,2-a]pyrazine
(0.55 mmol), the (hetero)aryl bromide (0.50 mmol), Pd(OAc)2
Table 2: electron-rich (product 2a, 50%), electron-neutral
(products 2b and 2c, 34 and 24%, respectively) as well as
(5 mol-%), PCy3·HBF4 (10 mol-%), PivOH (30 mol-%), and K2CO3
electron-poor (products 2d and 2e, 30% and 33%, respec-
tively) aryl bromides were compatible. In the reaction to
produce 2c, a product resulting from competitive pyrazole
arylation had to be removed by using preparative HPLC.[17]
For heteroaryl bromides, we were once again able to employ
(0.75 mmol). Under a flow of N2 gas, anhydrous DMF (0.3 m) was
added, the vial was sealed tightly, and the mixture was stirred at
100 °C. Cy = cyclohexyl. [b] Gram-scale reaction (4.8–13.6 mmol).
[c] 4-Iodo-1-ethylbenzene. [d] 4-Chloro-1-ethylbenzene. [e] Pd-
(OAc)2 (10 mol-%) and PCy3·HBF4 (20 mol-%) at 120 °C. [f] Iso-
lated compound was contaminated with 3–5% of the regioisomer,
multiple azine substitution patterns. Reactions with 2- which could be removed by preparative HPLC.
bromo-6-methoxypyridine (product 2f, 40%), 3-bromopyr-
idine (product 2g, 46%), and 4-bromo-2-methoxypyridine oline (product 2j, 50%). Notably, the C3/C5 arylation pro-
(product 2h, 26%) were successful, as were reactions with tocols can be conducted in a one-pot operation to afford 2j
4-bromoisoquinoline (product 2i, 35%) and 3-bromoquin- in 40% yield over two steps.
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B. M. Johnson, M. P. Huestis
SHORT COMMUNICATION
Table 2. C5 direct arylation of 3-arylimidazo[1,2-a]pyrazines.[a]
find use in materials and pharmaceutical research pro-
grams.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H NMR and 13C NMR spectra of all final products.
Acknowledgments
B. M. J. thanks the Genentech Undergraduate Summer Internship
Program. M. P. H. thanks Michael Siu for support and encourage-
ment, Yanzhou Liu for NMR spectroscopic assistance, Olivier
René and Amber Guillen for preparative HPLC support, and De-
sheng Wang for acquisition of the high-resolution mass spectro-
metric data.
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azo[1,2-a]pyrazine (0.275 mmol), the (hetero)aryl bromide
(0.25 mmol), Pd(OAc)2 (10 mol-%), 1,10-phenanthroline (phen,
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(200 mg). Dimethylacetamide (DMA, 0.3 m) was added, the vial
was sealed tightly, and the mixture was stirred at 140 °C. [b] Iso-
lated compound was contaminated with 2–5% of the regioisomer,
which could be removed by preparative HPLC. [c] Yield over two
steps from imidazo[1,2-a]pyrazine (one-pot reaction).
Conclusions
As established here, consecutive C3 and C5 direct C–H
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through the use of palladium catalysis. The broad substrate
scope should enable improved access to a range of bi- and
triaryl imidazo[1,2-a]pyrazine-based fragments that may
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Sequential and Direct C–H Arylation of Imidazo[1,2-a]pyrazines
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no reaction between 1-bromo-4-ethylbenzene and imidazo[1,2-
a]pyrazin-8-amine or 6,8-dibromoimidazo[1,2-a]pyrazine.
[14] According to HPLC–MS: no reaction for 4-bromopyrazole;
low conversion for 5-bromo-[1,2,4]triazolo[1,5-a]pyridine, 3-
bromoimidazo[1,2-a]pyrazine, 2-bromo-N-(p-tolylsulfonyl)pyr-
role, 6-bromothiochroman-4-one, 5-bromo-2-furaldehyde, and
3-bromo-4-chloro-7-methoxyquinoline; multiple reaction by-
products for 4-bromo-1-chloroisoquinoline, 5-bromo-8-nitro-
isoquinoline, and 4-bromo-2-fluoro-1-nitrobenzene.
[15] a) M. Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington,
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[16] 2D HMBC NMR experiments were corroborated by indepen-
dent synthesis of authentic 2a from 3-bromo-5-chloroimid-
azo[1,2-a]pyrazine through sequential Suzuki–Miyaura cross-
couplings. The authentic sample of 2a was an exact 1D 1H
NMR spectral match to our sample. Conversely, an authentic
sample of 6-(4-ethylphenyl)-3-(pyrimidin-5-yl)imidazo[1,2-a]-
pyrazine prepared from 6-chloroimidazo[1,2-a]pyrazine by Su-
zuki–Miyaura, C3 Friedel–Crafts bromination, and Suzuki–
Miyaura was not a match.
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has been shown to undergo C5 direct arylation if the C3 and
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[13] Although the desired product mass is detected, reaction of 1-
bromo-4-ethylbenzene with either 6-chloro- or 8-chloroimid-
azo[1,2-a]pyrazine affords complex mixtures, as determined by
HPLC–MS and isolation was not attempted. We also observed
[17] Reactions with furan-bearing 1r afforded an even more com-
plex spectrum of arylated products, and we did not attempt to
isolate the desired C5 product.
Received: December 4, 2013
Published Online: January 27, 2014
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