Site-Selective C-H Alkylation of Diazine N-Oxides Enabled by Phosphonium Ylides

Article abstract of DOI:10.1021/acs.orglett.9b02365

The synthesis of alkylated diazine derivatives is important for their practical utilization as pharmaceuticals and for other purposes. Herein, we describe the metal-free site-selective C-H alkylation of diazine N-oxides using phosphonium ylides that affords a variety of alkylated diazine derivatives with broad functional group tolerance. The utility of this method is showcased by the late-stage functionalization of a commercially available drug such as varenicline. Notably, the sequential C-H alkylation of pyrazine N-oxides for the total synthesis of a pyrazine-containing natural product, paenibacillin A, highlights the importance of this method.

Full text of DOI:10.1021/acs.orglett.9b02365

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Site-Selective C−H Alkylation of Diazine N‑Oxides Enabled by
Phosphonium Ylides
Prithwish Ghosh,† Na Yeon Kwon,† Sangil Han, Saegun Kim, Sang Hoon Han, Neeraj Kumar Mishra,
Young Hoon Jung, Sang J. Chung,* and In Su Kim*
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
S
* Supporting Information
ABSTRACT: The synthesis of alkylated diazine derivatives is
important for their practical utilization as pharmaceuticals and
for other purposes. Herein, we describe the metal-free site-
selective C−H alkylation of diazine N-oxides using phospho-
nium ylides that affords a variety of alkylated diazine
derivatives with broad functional group tolerance. The utility
of this method is showcased by the late-stage functionalization
of a commercially available drug such as varenicline. Notably,
the sequential C−H alkylation of pyrazine N-oxides for the
total synthesis of a pyrazine-containing natural product,
paenibacillin A, highlights the importance of this method.
However, the direct installation of these alkyl groups on
diazine rings has been rarely explored. The classical approach
for the synthesis of alkylated diazines is the transition metal-
mediated cross-coupling reaction between functionalized
diazines and organometallic reagents (Scheme 1).3
The metal-mediated Minisci-type alkylation of diazines in
the presence of radical sources has been reported.4a,b In
addition, the metal-free Minisci-type alkylations of various N-
heterocycles were also disclosed.4c−e However, the generation
of residual metal wastes and regioisomeric impurities remains
he development of effective synthetic methods is
Timportant for advancing medicinal, agrochemical, and
other chemical industries. The ability to synthesize substituted
diazines is of great significance because these motifs are
commonly found in biologically relevant molecules.1 In
particular, alkylated diazines are of paramount interest in
medicinal chemistry due to their remarkable therapeutic
potential. For instance, methoxymethylated, cyclopropylated,
and cyclobutylated pyrazine frameworks have been recognized
as essential units with potent pharmacological activity (Figure
1).2
Scheme 1. Site-Selective Alkylation of Diazine Heterocycles
Received: July 9, 2019
Figure 1. Selected examples of alkylated diazines.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02365
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
an obstacle for the pharmaceutical application of alkylated
diazines. Therefore, an efficient method for the formation of
alkylated diazines under mild and metal-free conditions is
highly desirable.
Having determined the optimal reaction conditions, we
examined the scope of the reaction with a variety of pyrazine
and quinoxaline N-oxides and phosphonium salts (Scheme 2).
Scheme 2. Substrate Scope of Pyrazine N-Oxides and
Diazine N-oxides have been used as precursors in the
synthesis of functionalized diazine derivatives.5 Halogenation,
cyanation, and olefination have been described previously.6
Additionally, direct lithiation and subsequent alkylation or
acylation of pyrazine N-oxides were investigated.7 Phospho-
nium ylides are conventionally utilized for olefination reaction
with carbonyl compounds.8 Moreover, phosphonium salts have
been employed in Michael additions,9 organocatalytic Mannich
reactions,10 and other alkylation reactions.11 Recently, our
group first demonstrated the metal-free site-selective C−H
alkylation of pyridine and quinoline N-oxides using Wittig
reagents.12a Other alkyl sources were also utilized for the
metal-free C−H alkylations of heterocyclic N-oxides.12b−d Due
to the widespread relevance of diazine molecules in recent drug
discovery, we herein describe the metal-free site-selective
alkylation of diazine N-oxides using phosphonium ylides to
furnish alkylated diazines. Notably, the sequential trans-
formation of diazine N-oxides leading to the formation of
highly substituted diazines highlights the applicability of the
developed methodology.
a
Phosphonium Salts
This investigation was initiated by examining the optimal
reaction conditions for the coupling of pyrazine N-oxide 1a
with methoxymethyltriphenylphosphonium chloride (2a), as
shown in Table 1. Screening of various reaction conditions
showed that the use of KOtBu (3 equiv) in a THF solvent at
80 °C with a reaction time of 7 h afforded C2-alkylated
pyrazine 3a in 78% yield (Table 1, entry 2). It should be noted
that this reaction was scaled up to 1 g (8.06 mmol) to give 0.95
g of 3a in 77% yield (Table 1, entry 14).
a
Table 1. Selected Optimization of Reaction Conditions
b
entry
base (equiv)
2a (equiv)
solvent
THF
THF
THF
THF
THF
THF
THF
THF
1,4-dioxane
CPME
MTBE
toluene
THF
yield
a
Reaction conditions: 1 (0.2 mmol), 2 (0.7 mmol, 3.5 equiv), KOtBu
KOtBu (2)
KOtBu (3)
KOtBu (3)
NaOtBu (3)
LiOtBu (3)
KOMe (3)
KHMDS (3)
DBU (3)
KOtBu (3)
KOtBu (3)
KOtBu (3)
KOtBu (3)
KOtBu (3)
KOtBu (3)
2
3.5
5
25
78
76
8
b
1
2
3
4
5
6
7
8
(3 equiv), THF (2 mL) at 80 °C for 7 h. Reaction conditions: 1 (0.2
mmol), 2 (0.7 mmol, 3.5 equiv), KOtBu (3.5 equiv), CPME (2 mL)
c
at 90 °C for 10 h. Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol, 3
d
equiv), KOtBu (2.5 equiv), THF (2 mL) at 80 °C for 6 h. Reaction
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
conditions: 1 (0.2 mmol), 2 (0.7 mmol, 3.5 equiv), KOtBu (3.5
trace
e
equiv), THF (2 mL) at 80 °C for 10 h. Reaction conditions: 1 (0.2
6
10
mmol), 2 (0.6 mmol, 3 equiv), KOtBu (2.5 equiv), THF (2 mL) at 80
f
°C for 4 h. Reaction conditions: 1 (0.2 mmol), 2 (0.7 mmol, 3.5
no reaction
equiv), KOtBu (3.5 equiv), THF (2 mL) at 80 °C for 6 h.
9
20
72
70
74
51
77
10
11
12
As anticipated, 2,3-dimethylpyrazine N-oxide (1a) was
smoothly coupled with EtPPh3Br (2b) and cyclopropyl
PPh3Br (2c) to afford alkylated pyrazines 3b (53%) and 3c
(72%), respectively.
c
13
d
14
THF
To evaluate the steric effect in this process, 2,5-
dimethylpyrazine N-oxide (1b) was coupled with branched
or linear alkylphosphonium salts 2d−2f. Under the modified
reaction conditions, the corresponding adducts 3d−3f were
formed in moderate to good yields. In addition, C3-aryl- and
C3-oxyaryl-substituted pyrazine N-oxides 1c−1h exclusively
underwent C−H alkylation at the less hindered site, affording
a
Reaction conditions: 1a (0.2 mmol), 2a (quantity noted), base
(quantity noted), solvent (2 mL) at 80 °C for 7 h under a N2
atmosphere in pressure tubes. Abbreviations: KHMDS, potassium
bis(trimethylsilyl)amide; CPME, cyclopentyl methyl ether; MTBE,
b
tert-butylmethyl ether. Isolated percent yield determined by flash
c
column chromatography. The reaction was carried out at 60 °C.
d
Gram-scale experiment.
B
DOI: 10.1021/acs.orglett.9b02365
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Organic Letters
Letter
the desired products 3g−3n. Moreover, C2-aryl-substituted
pyrazine N-oxides 1i−1p also participated in the C6 alkylation
reaction to furnish the corresponding products 3o−3v,
respectively. The tolerance of this reaction system for NO2
and CN groups was of interest, as these moieties provide
versatile synthetic handles in the products. This reaction
proceeded readily with unsubstituted pyrazine N-oxide (1q) to
furnish 3w in 61% yield. The chloro-substituted pyrazine N-
oxide 1r was also compatible, affording the desired product 3x,
which can be further functionalized by nucleophilic aromatic
substitution reactions.13 Furthermore, quinoxaline N-oxide
(1s) also reacted with MePPh3I (2g) to give 3y in 78% yield. It
is known that phosphonium ylide (CH3CO2CHPPh3) and
phosphonium salts (phenyl PPh3Br and pyridinyl PPh3Br)
were unsuccessful in this coupling reaction, presumably due to
the lower nucleophilicity of the delocalized carbanion and the
lack of formation of (hetero)aryl carbanions under the current
reaction conditions. Notably, this protocol allows direct
incorporation of the cyclobutyl moiety on the diazine
frameworks. For example, pyrazine N-oxide 1a was smoothly
coupled with 4-bromobutylPPh3Br (2i) to provide the C2-
cyclobutylated pyrazine adduct 4a in 41% yield (Scheme 3).
intramolecular deuterium migration can be excluded in the
reaction pathway. Moreover, 3% incorporation of deuterium at
the benzyl position was detected after 6 h, indicatve of rapid
proton exchange of benzylic deuterium under basic reaction
conditions. Furthermore, the deuterium labeling experiment
was conducted by using deuterio-1s and 2i, resulting in 15%
deuterium incorporation. It should be noted that no exchange
of deuterium at the C3 position was observed in any
experiment. On the basis of the deuterium labeling experi-
ments, a plausible reaction mechanism was proposed, as
outlined in Scheme 4. The initial formation of phosphonium
ylide and subsequent intramolecular cyclization afforded
cyclobutyl phosphonium salt A, which further generated the
second ylide intermediate B in the presence of KOtBu. The
intermolecular [3+2] annulation reaction between quinoxaline
N-oxide deuterio-1s and phosphonium ylide B furnished
intermediate C, leading to the formation of the C2-cyclo-
butylated quinoxaline deuterio-4b through aromatization by
an external base.
Pyrimidine and pyridazine N-oxides 5a−5d were also
employed in the reaction with 2a and 2c, as shown in Scheme
5. To our delight, C2-substituted pyrimidine N-oxides 5a and
Scheme 5. Substrate Scope of Pyrimidine and Pyridazine N-
Oxides
Scheme 3. Synthesis of the C2-Cyclobutylated Pyrazine
Adduct
To gain mechanistic insight into this process, we first
performed a deuterium labeling experiment using deuterio-1s
and 2g for 2 and 6 h, respectively, under otherwise identical
reaction conditions (Scheme 4). Partial deuterium incorpo-
ration (10% D) at the benzyl position of the product deuterio-
3y was observed after reaction for 2 h. This result reveals that
a
Reaction conditions: 5a−5c (0.2 mmol), 2a or 2c (0.6 mmol, 3
equiv), KOtBu (3 equiv), THF (2 mL) at 80 °C for 6 h under N2 in
reaction tubes. Reaction conditions: 5d (0.2 mmol), 2a (0.4 mmol, 2
equiv), KHMDS (1.8 equiv), THF (2 mL) at room temperature for 4
h under N2 in reaction tubes.
b
Scheme 4. Deuterium Labeling Experiments and Plausible
Reaction Mechanism
5b reacted with phosphonium salts 2a and 2c, affording
products 6a and 6b, respectively. However, the C2-
unsubstituted substrate, 5-phenyl pyrimidine N-oxide, did
not produce any coupling product under the current reaction
conditions (data not shown). Moreover, pyridazine N-oxide 5c
also participated in the coupling reaction to give 6c, albeit with
slightly decreased reactivity. Phthalazine N-oxide (5d) was also
coupled with 2a in the presence of KHMDS as a base to
furnish phthalazine derivative 6d in 55% yield. To investigate
the relative reactivity of pyrazine N-oxides versus pyrimidine
N-oxides, a competitive intermolecular experiment was
performed (see the Supporting Information for details).
Exposure of 2a to equimolar quantities of 1c and 5a under
otherwise identical conditions provided a mixture of 3g (60%)
and 6a (31%).
This protocol allows late-stage functionalization and
sequential alkylation of complex diazine molecules bearing an
N-oxide group (Scheme 6). For example, N-oxide derivative
7a, derived from varenicline, a commercial smoking cessation
agent, was selectively reacted with 2a to provide desired
product 7b (32%), with recovery of starting material 7a (40%).
C
DOI: 10.1021/acs.orglett.9b02365
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Letter
Scheme 6. Late-Stage Functionalization and Sequential
Alkylations
Scheme 8. Synthetic Transformations of Alkylated Diazines
arylation of methoxymethyl pyrazine 3g was performed to
furnish 10d in 27% yield (eq 3).
In conclusion, a highly efficient protocol for the formation of
alkylated diazine derivatives via the metal-free site-selective C−
H alkylation of diazine N-oxides using phosphonium ylides was
developed. The method affords a wide substrate scope, high
site selectivity, and broad functional group tolerance. In
particular, the sequential C−H alkylation of diazine N-oxides
and gram-scale reaction demonstrate the utility of the
developed method. Furthermore, the late-stage C−H function-
alization of a complex molecule and total synthesis of a natural
product highlight the great potential of this method for
application in drug discovery.
Meanwhile, the sequential alkylation of pyrazine N-oxide 8a
furnished 2,3-bis-alkylated pyrazine adduct 8d.
To highlight the utility of this protocol, we first report the
total synthesis of racemic paenibacillin A, isolated from
Paenibacillus sp. XY-2 in 2015,14 based on the sequential C−
H alkylation of pyrazine N-oxides (Scheme 7). Treatment of 2-
Scheme 7. Total Synthesis of Racemic Paenibacillin A
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02365.
1
Experimental procedures, characterization data, and H,
13C, and 19F NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: sjchung@skku.edu.
*E-mail: insukim@skku.edu.
methoxypyrazine N-oxide (9a)15 with 2d under the developed
conditions provided C6-isopropylated pyrazine 9b in 43%
yield, which was subsequently oxidized by m-CPBA to afford
pyrazine N-oxide 9c in 72% yield. Site-selective alkylation of 9c
was performed using s-butylPPh3Br (2j), furnishing 3,6-
dialkylated pyrazine 9d (31%), with recovery of starting
material 9c (41%). Hydrolysis of 9d with concentrated HCl
gave racemic paenibacillin A in 80% yield. The spectroscopic
data for paenibacillin A were in full agreement with the
reported literature values.
To illustrate the applicability of the alkylated diazines, we
performed a series of synthetic transformations, as shown in
Scheme 8. Benzylic bromination of 3k and subsequent
amination using imidazole afforded 10a in 70% yield, which
is recognized as a pivotal scaffold of a Cushing’s syndrome
agent (eq 1).16 The Ni-catalyzed C−H functionalization of 3k
with benzyl alcohol gave alkylated product 10b (49%) and
olefinated product 10c (12%) (eq 2). Finally, direct C−H
ORCID
Sang J. Chung: 0000-0002-3501-212X
In Su Kim: 0000-0002-2665-9431
Author Contributions
†P.G. and N.Y.K. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research
Foundation of Korea (NRF) funded by the Korea government
(MSIP) (2017R1A2B2004786 and 2019R1A4A2001451).
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