Expedient synthesis of α-(2-azaheteroaryl) acetates via the addition of silyl ketene acetals to azine- N -oxides

Article abstract of DOI:10.1021/ol501359r

A new and expedient synthesis of α-(2-azaheteroaryl) acetates is presented. The reaction proceeds rapidly under mild conditions via the addition of silyl ketene acetals to azine-N-oxides in the presence of the phosphonium salt PyBroP. This procedure affords diverse α-(2-azaheteroaryl) acetates which are highly desirable components/building blocks in molecules of pharmaceutical interest but are traditionally challenging to synthesize via contemporary methods. The reaction optimization and mechanism as well as a novel electronically enhanced PyBroP derivative are described.

Full text of DOI:10.1021/ol501359r

Letter
pubs.acs.org/OrgLett
Expedient Synthesis of α‑(2-Azaheteroaryl) Acetates via the Addition
of Silyl Ketene Acetals to Azine‑N‑oxides
Allyn T. Londregan,* Kristen Burford, Edward L. Conn, and Kevin D. Hesp
Pfizer Worldwide Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: A new and expedient synthesis of α-(2-
azaheteroaryl) acetates is presented. The reaction proceeds
rapidly under mild conditions via the addition of silyl ketene
acetals to azine-N-oxides in the presence of the phosphonium
salt PyBroP. This procedure affords diverse α-(2-azaheter-
oaryl) acetates which are highly desirable components/
building blocks in molecules of pharmaceutical interest but are traditionally challenging to synthesize via contemporary
methods. The reaction optimization and mechanism as well as a novel electronically enhanced PyBroP derivative are described.
he α-aryl carbonyl moiety is a ubiquitous feature in
Scheme 1. Direct Syntheses of α-(2-Azaheteroaryl) Acetates
T
molecules of pharmaceutical and biological interest. New
synthetic methods for the direct α-arylation of carbonyl and
enolate equivalents are important for strategic bond formation
and the introduction of heterocyclic diversity into molecules. In
recent years, there has been extensive research into the
intermolecular, transition metal-mediated reaction of enolates
with aryl halides to form the corresponding α-aryl carbonyl
derivatives.1 Palladium-catalyzed transformations are now
perhaps the most widely used for this type of C−C bond
construction. In their seminal works on the topic, Buchwald,2
Hartwig,3 and Miura4 demonstrated the direct arylation of
ketones with aryl iodides and aryl bromides in the presence of
catalytic palladium. Since those reports, there have been
continuous improvements made in yield, selectivity, and
substrate compatibility. Additionally, reaction conditions can
now be adapted to a variety of carbonyl reaction partners
including, esters,5 amides,6 and aldehydes.7 Despite these
advancements, the substrate scope of the aryl halide reaction
partner remains limited with respect to heterocyclic diversity.
Reported examples of α-heteroaryl carbonyl adducts are
infrequent and often low yielding.
carbonyl enolates have been introduced with success onto
azine-N-oxides in a C−C bond forming process. We
rationalized that, with the use of the appropriate carbon
nucleophile, our methodology might serve as an effective means
to directly synthesize the requisite α-(2-azaheteroaryl) acetates
in a single step under mild conditions.
We initiated a reaction optimization study with pyridine-N-
oxide and commercially available methyl tert-butyldimethylsilyl
ketene acetal 2 (Table 1). It was imperative to utilize either a
relatively acidic12 carbon nucleophile or an equivalent in neutral
form, as anionic bases are incompatible with our PyBroP-based
methodology. Using optimized conditions from our previous
work (entry 1), we were pleased to observe the formation of
desired product 3, but the yield was poor (27%), and the
product derived from overheteroarylation (4) was significant.
With further experimentation, we determined that this
transformation was remarkably sensitive to both solvent and
base. The solvent/base pair of THF/iPr2EtN appeared optimal
(entry 4). To diminish 4, we assessed reaction concentration
During the course of our research, we required a facile
synthesis of α-(2-azaheteroaryl) acetates (Scheme 1) for use as
versatile synthetic intermediates. We found that these were
among the most challenging substrates to synthesize via
transition metal catalysis. Direct metalation8 approaches are
known but severely limit reactant scope and compatibility. Our
laboratory was therefore interested in developing a new
protocol for the synthesis of α-(2-azaheteroaryl) acetates,
which would be more amenable to diverse heterocyclic
substrates and overcome some of the inherent limitations of
traditional methods.
In previous communications,9 we described the addition of
varied nucleophiles to azine-N-oxides with the phosphonium
salt PyBroP.10 We found that 1,3-dicarbonyl enolates11 were
suitable reaction partners in the transformation. Others have
reported similar results,11 but to our knowledge, no other
Received: May 12, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501359r | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Optimization for the Addition of Methyl
tert-Butyldimethlysilyl Ketene Acetal to Pyridine-N-oxide
Scheme 2. Substrate Scope for the Addition of Methyl tert-
Butyldimethlysilyl Ketene Acetal to Azine-N-oxides
a
a
b
entry
base
solvent
equiv 2
% yield 3/4
1
2
3
4
5
6
7
8
9
iPr2EtN
Et3N
CH2Cl2
CH2Cl2
THF
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
2.0
3.0
27
30
60
80
55
45
15
35
10
8
Et3N
iPr2EtN
(Cy)2MeN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
THF
THF
8
1,4-dioxane
DMSO
DMF
13
<10
20
−
−
10
20
−
toluene
THF
33
c
10
55
d
11
THF
15
e
12
THF
89(67)
89(81)
85
4
13
THF
3(1)
2
14
THF
a
Unless otherwise noted, all reactions were conducted in 2 dram vials
at 0.20 M concentration with 1 (1.00 equiv), base (3.00 equiv), and
b
PyBroP (1.10 equiv) at 25 °C for 15 h. Yield determined by 1H NMR
using 2,6-dimethoxytoluene as internal standard with isolated yields in
c
d
e
parentheses. 0.05 M concentration. iPr2EtN (1.00 equiv). iPr2EtN
a
(5.00 equiv).
Unless otherwise noted, all reactions were conducted in 2 dram vials
at 0.20 M concentration with 5 (1.00 equiv), 2 (2.00 equiv), iPr2EtN
b
(3.00 equiv), and PyBroP (1.10 equiv) at 25 °C. 45 °C for 2 h.
(entry 10), base equivalents (entries 11−12), and reagent
addition order. None of these parameters, however, were
effective. Ultimately, we determined that a second equivalent of
silyl ketene acetal (2) reduced side-product 4 to almost
undetectable levels, with a fortuitous increase in the yield of
desired product. Under optimized conditions (entry 13), we
were able to isolate 3 in 81% yield. Any impurities, including a
trace amount of 4, were easily removed by silica gel
chromatography.
As shown in Scheme 2, we applied the optimized reaction
conditions to a series of azine-N-oxides (5) and were pleased to
obtain a diverse array of α-(2-azaheteroaryl) acetates (6a−p) in
modest to high yields. The reactions were performed in capped
2-dram vials without atmospheric controls and were usually
complete within 2 h at room temperature. For each example,
we prepared a solution of 5 in THF and sequentially added
iPr2EtN, silyl ketene acetal 2, and PyBroP. A slight exotherm
and color change were usually noted after the addition of the
PyBroP. In general, electron-neutral/-rich azine-N-oxides
performed most effectively in the transformation. Certain
reactions were sluggish and required gentle heating to ensure
reaction completion.13 Pleasingly, most bromide-containing
substrates were well-tolerated under our reaction conditions
(6g, 6j−k). Substrates with polar functionality and multiple
heteroatoms all performed acceptably. Interestingly, the
majority of the reactions showed no evidence of over-
heteroarylation, which we observed in our original optimization
study with pyridine-N-oxide.
Figure 1. Proposed intermediate, PyBroP, and newly synthesized
PyBroP derivatives.
with silyl ketene acetals. When we utilized PyBroP variant 8,
which contains a bromide counteranion, we observed no
reactivity under our standard conditions. This suggests that the
hexafluorophosphate counteranion of PyBroP is an important
reaction component. Likely, equilibrium dissociation of fluoride
−
from PF6 initiates silicon−oxygen cleavage for ketene acetal
addition. In an effort to better understand the attenuated
reactivity of certain azine-N-oxides, particularly those with
electron-withdrawing groups, we prepared a novel PyBroP
derivative (9) containing tris-3,3-difluoropyrrolidine and
reassessed 4-trifluoromethylpyridine-N-oxide as a substrate
(6e, from Scheme 2). As hypothesized, the enhanced
electrophilic character of 9 significantly improved the yield of
6e at room temperature when compared with PyBroP as the
activator (51% vs 22% respectively).14 This suggests that facile
formation of intermediate 7 is critical to a robust outcome and
that “designed” PyBroP-type reagents may be an effective
means to enhance overall yields with substrates less inclined to
form intermediate 7.
In accord with our previous reports on the addition of
nucleophiles to azine-N-oxides activated by PyBroP, we
propose intermediate 7 (Figure 1) as the key mechanistic
feature in this transformation. The counteranion of the
phosphonium salt appears to be crucial for successful reactivity
B
dx.doi.org/10.1021/ol501359r | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
As shown in Scheme 3, we briefly assessed the competency
of several trimethylsilyl ketene acetals with varied substitution
azine-N-oxides with an emphasis on “designed” PyBroP
alternatives and stereochemical induction.
ASSOCIATED CONTENT
* Supporting Information
Scheme 3. Addition of Varied Trimethylsilyl Ketene Acetals
to Azine-N-oxides
■
a
S
Experimental procedures and characterization for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: allyn.t.londregan@pfizer.com.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Dr. Vincent Mascitti, Dr. Peter
Mikochik, Dr. David W. Piotrowski and Mr. Jason Ramsay of
Pfizer Inc. for their assistance in this research.
a
Unless otherwise noted, all reactions were conducted in 2 dram vials
at 0.20 M concentration with 5 (1.00 equiv), 10 (2.00 equiv), iPr2EtN
b
(3.00 equiv), and PyBroP (1.10 equiv) at 25 °C. Determined by
REFERENCES
■
1
integration of H NMR spectrum.
(1) (a) Johansson, C. C. C; Colacot, T. J. Angew. Chem., Int. Ed.
2010, 49, 676−707. (b) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110,
1082−1146.
(2) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108−
11109.
(3) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119,
12382−12383.
(4) (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew.
Chem., Int. Ed. 1997, 36, 1740−1742. (b) Satoh, T.; Inoh, J.;
Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71,
2239−2246.
(5) (a) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7996−8002. (b) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc.
2001, 123, 8410−8411. (c) Jorgensen, M.; Lee, S.; Liu, X.; Wolkowski,
J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 12557−12565.
(d) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 11176−11177. (e) Liu, X.; Hartwig, J. F. J. Am. Chem. Soc.
2004, 126, 5182−5191. (f) Hama, T.; Hartwig, J. F. Org. Lett. 2008,
10, 1545−1548. (g) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10,
1549−1552. (h) Biscoe, M. R.; Buchwald, S. L. Org. Lett. 2009, 11,
1773−1775. (i) Hama, T.; Ge, S.; Hartwig, J. F. J. Org. Chem. 2013, 78,
8250−8266. (j) Wong, B.; Linghu, X.; Crawford, J. J.; Drobnick, J.;
Lee, W.; Zhang, H. Tetrahedron 2014, 70, 1508−1515.
(6) (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org.
Chem. 1998, 63, 6546−6553. (b) Cossy, J.; deFilippis, A.; Pardo, D. G.
Org. Lett. 2003, 5, 3037−3039. (c) Hama, T.; Culkin, D. A.; Hartwig, J.
F. J. Am. Chem. Soc. 2006, 128, 4976−4985. (d) Zheng, B.; Jia, T.;
Walsh, P. J. Org. Lett. 2013, 15, 4190−4193.
at the nucleophilic carbon. When R2 and R3 were equal to
hydrogen and pyridine-N-oxide was utilized as a substrate, we
obtained the expected product (3) in 74% yield. Surprisingly,
when trimethylsilyl ketene acetals bearing methyl groups at the
R2 and R3 position were utilized in the same transformation, we
obtained a regioisomeric mixture of products (11a−b and
11c−d), resulting from addition to both the 2- and 4-postion of
pyridine-N-oxide. This loss of selectivity is contrary to the other
examples reported here, as well as to those from our previous
works, and is not fully understood. Nevertheless, these
preliminary results suggest that steric bulk at the nucleophilic
carbon may interfere with the critical charge association15 we
attribute to the usual regioselectivity. In further support of this
hypothesis, when we compared the reactivity of analogous tert-
butyldimethylsilyl ketene acetals (OTBS vs OTMS) in
examples 11a−d, we again obtained a mixture of isomers,
albeit in lower yield. Azine-N-oxide substrates with substitution
at the 4-position proceeded as expected and afforded single
products (11e−f). Lastly, we determined if a silyl ketene acetal
containing a chiral auxiliary might impart some degree of
stereoselectivity if utilized in this transformation. Indeed, as
demonstrated in example 11g, we obtained a 2:1 diastereomeric
ratio of products with an optically pure phenethyloxy-silyl
ketene acetal.
In conclusion, we have presented a novel procedure for the
synthesis of diverse α-(2-azaheteroaryl) acetates, which remains
a challenge by contemporary methods. Our procedure is
expedient, operationally simple, and tolerant of varied substrate
functionality, including reactive bromides. This methodology
should be of particular use in the synthesis of small molecule
chemotherapeutics, where the incorporation of polarity is
needed to control lipophilicity, increase beneficial drug/target
interactions, and optimize drug-like properties. Our laboratory
will continue to investigate the addition of silyl ketene acetals to
(7) (a) Terao, Y.; Fukuoka, T.; Satoh, M.; Miura, M.; Nomura, M.
Tetrahedron Lett. 2002, 43, 101−104. (b) Martin, R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2007, 46, 7236−7239. (c) Vo, G. D.; Hartwig, J.
F. Angew. Chem., Int. Ed. 2008, 47, 2127−2130. (d) Martin, R.;
Buchwald, S. L. Org. Lett. 2008, 10, 4561−4564.
(8) (a) Woodward, R. B.; Kornfeld, E. C. Org. Synth. 1949, 29, 44−
46. (b) Kofron, W. G.; Baclawski, L. M. Org. Synth. 1972, 52, 75−76.
(9) (a) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2010, 12,
5254−5257. (b) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett.
2011, 13, 1840−1843.
(10) Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate,
Castro, B.; Coste, J. PCT Int. Appl. WO/90/10009, 1990.
C
dx.doi.org/10.1021/ol501359r | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) (a) Funakoshi, K.; Sonoda, H.; Sonoda, Y.; Hamana, M. Chem.
Pharm. Bull. 1978, 12, 3504−3514. (b) Mieczkowski, J. B. Bull. Pol.
Acad. Sci., Chem. 1984, 32, 255−9. (c) Lecointre, B.; Azzouz, R.;
Bischoff, L. Tetrahedron Lett. 2014, 55, 1913−1915.
(12) From our previous experimentation, we determined that
competent nucleophiles were within a pKa range of ∼10−20.
(13) Azine-N-oxide (<10%) by LCMS analysis.
(14) Although not shown in Scheme 2, example 6e was prepared in
22% yield at room temperature utilizing PyBroP.
(15) A charge association of the incoming nucleophile with the
distributed cationic charge and/or lone pairs of the tris-pyrrolidino
moiety in 7 likely directs nucleophiles to the 2-position of the azine-N-
oxide exclusively. See ref 9a.
D
dx.doi.org/10.1021/ol501359r | Org. Lett. XXXX, XXX, XXX−XXX