Synthesis of mono- and diaza-'pyridones' via stille coupling of alkoxystannanes

Article abstract of DOI:10.1055/s-0034-1378331

Various alkoxy-substituted heterocyclic stannanes provide access to the corresponding substituted 'pyridone' moieties via Stille cross-coupling. Both pyridyl and a series of diazinyl stannanes are prepared, and options for unmasking (via demethylation or debenzylation) of the pyridone unit are evaluated. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0034-1378331

1904▌
LETTER
lSetyternthesis of Mono- and Diaza-‘Pyridones’ via Stille Coupling of Alkoxystannanes
Synthesis of Mono- and Diaza-‘Pyridones’
Charlotte L. Smith, Christoph Hirschhäuser, Georgia K. Malcolm, Daniel J. Nasrallah, Timothy Gallagher*
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Fax +44(117)9298611; E-mail: t.gallagher@bristol.ac.uk
Received: 02.05.2014; Accepted after revision: 23.05.2014
HO
OH
O
O
Abstract: Various alkoxy-substituted heterocyclic stannanes pro-
vide access to the corresponding substituted ‘pyridone’ moieties via
Stille cross-coupling. Both pyridyl and a series of diazinyl stan-
nanes are prepared, and options for unmasking (via demethylation
or debenzylation) of the pyridone unit are evaluated.
N
H
OH
NH
pyridovericin 1
Key words: pyridine, heterocyclic stannane, Stille coupling
F3CCO2
N
+
NH
NH
2-Pyridones and the related diazines (e.g., pyrazinone and
pyrimidinone) are important motifs (Figure 1) found in bi-
ologically active compounds, such as pyridovericin (1)
(kinase inhibitor),1 dragmacidin D (2) (indication: Parkin-
son’s and Alzheimer’s disease),2 raltegravir (3) (antiretro-
N
Br
N
H
O
HO
HN
dragmacidin D 2
viral),3
and
lamivudine
(4)
(antiretroviral).4
O
Consequently, and due to a number of physiochemical at-
tributes, including polarity, low molecular weight (high
heteroatom index), and in particular the condensed array
of hydrogen bond donor/acceptor functionality, the ability
to incorporate an intact mono and diaza ‘pyridone’ into a
more complex scaffold is of interest, alongside methods
for elaborating these core heterocyclic units.5
NH2
N
OH
F
N
H
N
N
O
N
O
HN
O
O
H
O
N
S
N
OH
H
Our interest in substituted 2-pyridones stems from recent
synthetic studies linked to cytisine (an α4β2 nicotinic par-
tial agonist)6 and, more pertinently, the development of
core-modified variants in which alkoxystannanes 5a and
6a served as effective precursors to substituted (via Stille-
based couplings) pyridones and pyrazinones, respectively
(Figure 2).7,8
lamivudine 4
raltegravir 3
Figure 1 Biologically active mono and diaza ‘pyridones’
Y
Y
Y
X
Z
X
Z
X
Z
O
N
H
N
H
Ar
O
MeO
N
SnBu3
While Suzuki couplings with electron-deficient heteroaryl
boronates are often difficult and 2-pyridyl organoboro-
nates readily undergo protodeboronation,9 the corre-
sponding stannanes 5a and 6a are both readily accessible
and exhibit a higher degree of stability (when stored at
5 °C), and provide a new and versatile set of ‘pyridone’
(both mono and diaza) building blocks.
5–8
Desirable
scaffold
X, Y, Z = CH or N
N
N
RO
N
SnBu3
RO
SnBu3
R = Me 5a
Bn 5b
R = Me 6a
Bn 6b
N
N
In this communication, we describe the synthesis of a se-
ries of stannanes 5–8, together with the application of
these reagents to: (i) Stille cross-coupling, and (ii) subse-
quent dealkylation (via demethylation or debenzylation)
to generate 6-arylated variants of 2-pyridones, 2-pyrazi-
nones and 2-pyrimidinones, and 2-aryl 4-pyrimidinones.
We report on the accessibility of the stannane reagents
and, using a selected group of substrates, explore the
scope and limitations of this chemistry.
MeO
N
SnBu3
MeO
N
SnBu3
7
8
Figure 2 Heterocyclic stannanes as ‘pyridone’ precursors
In general, access to heteroaryl stannanes is achieved ei-
ther by lithiation and subsequent (or in situ) quenching
with R3SnCl,8 nucleophilic aromatic substitution using
R3SnLi, or transition-metal-catalyzed stannylation using
R6Sn2.10 Procedures for the synthesis of 6-methoxy
stannanes 5a and 6a have been reported.7,8,11 Furthermore,
pyrimidine variant 7 has been described by Plé, via nu-
SYNLETT 2014, 25, 1904–1908
Advanced online publication: 08.07.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378331; Art ID: st-2014-d0367-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Mono- and Diaza-‘Pyridones’
1905
cleophilic aromatic substitution of chloride 9 with (tribu-
tylstannyl)lithium (Bu3SnLi) (Scheme 1).
BnOH, KOH
18-crown-6
toluene, 130 °C
n-BuLi, Bu3SnCl
THF, –78 °C to r.t.
We were unable to reproduce the 70% yield reported by
Plé, and at best we isolated pyrimidine 7 in 7% yield. Con-
sequently, a more robust protocol has been developed and
iodination of 9 to give 10 (89%) followed by slow addi-
tion of n-butyllithium (n-BuLi) to a mixture of 10 and tri-
butyltin chloride (Bu3SnCl) in tetrahydrofuran at –78 °C
provided stannane 7, reliably, in 70% isolated yield after
flash chromatography. It should be noted that, although
commercially available, 7 was (in our hands) the least sta-
ble reagent of those discussed here; even under nitrogen at
5 °C, stannane 7 degraded after 14 days.
70%
71%
BnO
Br
N
5b
SnBu3
SnBu3
Br
Cl
N
15
Br
BnO
N
16
BnOH, NaH
toluene, 50 °C
NaH, Bu3SnH
THF, –78 °C to r.t.
N
N
N
85%
89%
BnO
Cl
N
N
Cl
BnO
N
17
18
6b
Scheme 3 Synthesis of stannanes 5b and 6b
Stille coupling reactions of stannanes 5–8 with a range of
aryl bromides led to adducts 19–24, which are summa-
rized in Schemes 4 and 5. Cross-couplings were conduct-
ed under well-established Stille conditions by heating
stannanes 5–8 with an appropriate aryl bromide, tetra-
kis(triphenylphosphine)palladium(0) [Pd(PPh3)4] (10
mol%), lithium chloride (LiCl) (1.1 equiv) and copper(I)
chloride (CuCl) (1.1 equiv) in tetrahydrofuran for 18
hours.8 Generally, reactions proceeded in good yield, al-
though electron-rich aryl halides were less efficient, and
purification by flash chromatography was sufficient to
give the coupled product with minimal tin contamination.
N
Bu3SnLi
N
MeO
N
SnBu3
MeO
N
9
Cl
THF, –78 °C to r.t.
(Plé13 reported 70%)
7 (7%)
HI
N
N
Bu3SnCl, n-BuLi
THF, –78 °C
this work
MeO
N
I
MeO
N
SnBu3
10 (89%)
7 (70%)
In both series, couplings to 4-bromoanisole gave signifi-
cantly lower yields (see Schemes 4 and 5) and phenyl-
containing by-products derived from ligand transfer from
triphenylphosphine (Ph3P) were isolated.14 3-Bromopyri-
dine also highlighted a significant reactivity difference:
reaction with pyridyl stannane 5b was efficient, but at-
tempts to couple to the pyrazine variant 6b failed.
Scheme 1 Synthesis of pyrimidinyl stannane 7
The 2-methoxypyrimidinyl stannane 8 was prepared from
commercially available pyrimidine 11 via iodide 12,12
lithiation of which followed by an in situ quench gave
stannane 13. Oxidation of 13 gave sulfone 14,12 which un-
derwent subsequent displacement with sodium methoxide
to give 8 in 39% overall yield on a 3 g scale (Scheme 2).
Releasing the masked pyridone by acidic hydrolysis (us-
ing HCl) was not successful. Representative substrates
(pyridine 19a and pyrimidine 22a) were used and both
failed to react. Consequently, several alternative proce-
dures for demethylation and debenzylation (Tables 1 and
2) were examined, but in practice we could not identify a
single, generally applicable dealkylation method.
Bu3SnCl, n-BuLi
N
N
THF, –78 °C
70%
MeS
N
X
MeS
N
SnBu3
11 X = Cl
12 X = I
HI
72%
13
mCPBA, CH2Cl2
88%
0 °C, 24 h
Using pyridine 19a, chlorotrimethylsilane (TMSCl) and
sodium iodide (NaI)15 gave pyridone 25 in 85% yield, but
application of these conditions to 19b and 20a failed to
give the desired products; we observed recovered 19b and
decomposition of 20a. Similarly, lithium iodide (LiI) and
sym-collidine16 gave mixed results: demethylation of
19a,d,e proceeded in moderate yields, however 19c, 20a
and 22a were unreactive. Sodium ethanethiolate (NaS-
Et)17 successfully converted pyridine 19a, pyrazine 20a
and pyrimidine 21a, however, this reagent failed with the
isomeric pyrimidine 22a.
NaOMe
N
N
MeOH, 0 °C
89%
MeO
N
8
SnBu3
MeO2S
N
SnBu3
14
Scheme 2 Synthesis of 2-methoxy-4-(tributylstannyl)pyrimidine (8)
The benzyloxy variants 5b and 6b were synthesized as
shown in Scheme 3. Halides 15 and 17 were transformed
into 1613 and 18, respectively. Lithiation of 16 followed
by in situ quenching with Bu3SnCl gave stannane 5b, and
6b was obtained via chloride displacement in 18 with (tri-
butylstannyl)sodium (Bu3SnNa). Stannanes 5b and 6b
were both stable over extended periods of time when
stored at 5 °C.
Generally, debenzylation via hydrogenolysis was easier to
affect. Pyridyl substrates 23a,b,d provided the corre-
sponding pyridones in moderate to good yields. The 3-
pyridyl variant 23c was, however, unreactive and is pre-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1904–1908

1906
C. L. Smith et al.
LETTER
Pd(PPh3)4 (10 mol%)
LiCl (1.1 equiv), CuCl (1.1 equiv)
Y
N
Y
X
Z
X
Z
Stannane
Ar–Br
+
THF, 70 °C
MeO
Ar
MeO
N
SnBu3
5–8
19–22
OMe
OMe
S
5a
6a
MeO
MeO
N
MeO
MeO
N
MeO
MeO
N
MeO
N
MeO
N
OMe
OMe
CF3
19b 67%
19c 56%
19d 79%
19e 76%
19a 95%
N
N
N
N
N
S
S
N
MeO
MeO
MeO
N
N
N
MeO
MeO
N
CF3
20a 78%
20b 17%a
20c 16%
20d 54%
20e 62%
OMe
OMe
N
N
N
N
N
N
N
N
7
8
MeO
MeO
MeO
MeO
N
MeO
MeO
N
OMe
CF3
21a 59%
21b 27%
21c 10%
21d 69%
21e 70%
N
N
N
N
N
N
S
N
N
N
MeO
N
OMe
CF3
22a 26%
22b 32%
22c 30%
22d 46%
22e 39%
Scheme 4 Stille couplings of stannanes 5–8 with representative aryl bromides. a Reaction of 6a and 4-bromoanisole to give 20b also gave 20a
in 40% yield reflecting competitive aryl ligand exchange from Ph3P. All yields shown are those for isolated products following purification by
chromatography
Pd(PPh3)4 (10 mol%)
LiCl (1.1 equiv), CuCl (1.1 equiv)
X
X
Ar–Br
+
Stannane
THF, 70 °C
BnO
N
Ar
BnO
BnO
N
SnBu3
23, 24
5b and 6b
5b
S
S
N
BnO
N
BnO
N
BnO
N
OMe
OMe
N
N
23a 93%
23b 11%
23c 80%
23d 76%
N
N
N
N
6b
BnO
N
BnO
N
BnO
N
BnO
N
24a 32%
24b 12%a
24c 0%
24d 25%
Scheme 5 Stille couplings of stannanes 5b and 6b with representative aryl bromides. a Reaction of 6b and 4-bromoanisole to give 24b also
gave 24a in 10% yield reflecting competitive aryl ligand exchange from Ph3P. All yields shown are those for isolated products following puri-
fication by chromatography
sumed to have poisoned the catalyst. Pyrazines 24a and pyrimidine congeners, are suitable substrates for (general-
24d were also (and surprisingly) unreactive. Deben- ly) efficient Stille cross-coupling reactions. These re-
zylation using boron tribromide (BBr3) was also a viable agents serve as vehicles for the introduction of pyridone,
option and converted both 23c and 24a into the desired pyrazinone and pyrimidinone units where the carbonyl
products in good yields.
moiety is released via demethylation or debenzylation, al-
beit under substrate-dependent conditions.18
In conclusion, 2-methoxy- and 2-benzyloxy-6-stannylat-
ed pyridines, as well as the corresponding pyrazine and
Synlett 2014, 25, 1904–1908
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Mono- and Diaza-‘Pyridones’
1907
Table 1 Demethylation Conditions Evaluated and the ‘Pyridone’ Products
Substrate
Conditions
Yielda
2-Pyridone
TMSCl (10 equiv), NaI (3 equiv), MeCN, 80 °C, 1.5 h
85%
LiI (2 equiv), sym-collidine, reflux, 6 h
51% (28%)
O
O
N
H
MeO
MeO
N
NaSEt (1.2 equiv), DMF, 140 °C, 48 h
63%
19a
25
N
N
H
LiI (2 equiv), sym-collidine, reflux, 6 h
38% (42%)
CF3
CF3
19d
26
S
S
O
O
O
N
H
MeO
MeO
MeO
N
LiI (2 equiv), sym-collidine, reflux, 6 h
28% (50%)
19e
27
N
N
TMSCl (10 equiv), NaI (3 equiv), MeCN, 80 °C, 48 h
no reaction
no reaction
LiI (2 equiv), sym-collidine, reflux, 48 h
N
N
H
NaSEt (1.2 equiv), DMF, 140 °C, 4 h
66%
20a
28
N
TMSCl (10 equiv), NaI (3 equiv), MeCN, 80 °C, 48 h
LiI (2 equiv), sym-collidine, reflux, 48 h
NaSEt (1.2 equiv), DMF, 140 °C, 4 h
no reaction
no reaction
75%
N
N
N
H
21a
29
a Yields shown in parentheses refer to those of recovered starting material.
Table 2 Debenzylation Conditions and Debenzylation Products
Substrate
2-Pyridonea
Substrate
2-Pyridonea
S
S
BnO
BnO
N
O
O
N
H
O
N
H
BnO
BnO
N
23d
27 80%
23a
25 90%
N
N
N
N
H
N
O
N
H
OMe
OMe
23b
30 36%
24a
28 95%
O
N
H
BnO
N
–
–
N
N
23c
31 52%
a Conditions used for 23a, 23b and 23d: H2 (1 atm), Pd/C (5 mol%), MeOH–EtOAc (0.08 M), r.t., 4–24 h. Conditions used for 23c and 24a:
BBr3 (1 equiv), CH2Cl2 (0.02 M), r.t., 2–16 h.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1904–1908

1908
C. L. Smith et al.
LETTER
(13) Fang, A. G.; Mello, J. V.; Finney, N. S. Org. Lett. 2003, 5,
967.
Acknowledgment
Funding from the EPSRC (to C.L.S.), the Rotary Foundation (to
C.H.) and the National Science Foundation (Grant 0966420, to
D.J.N.) is acknowledged.
(14) Grushin V. V.; Organometallics; 2000, 19: 1888; a screen of
alternative phosphines [XPhos, PCy3, P(o-Tol)3, P(o-furanyl)]
was conducted (using 6a and 4-bromoanisole), but none
offered a significant advantage (in % yield) over Ph3P.
(15) Demers, S.; Stevenson, H.; Candler, J.; Bashore, C. G.;
Arnold, E. P.; O’Neill, B. T.; Coe, J. W. Tetrahedron Lett.
2008, 49, 3368.
References and Notes
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(18) Representative 1H NMR Data
2-Methoxy-6-(2-methoxyphenyl)pyridine (19c)
1H NMR (400 MHz, CDCl3): δ = 7.97 (dd, J = 7.5, 2.0 Hz, 1
H), 7.61 (t, J = 7.5 Hz, 1 H), 7.55 (dd, J = 7.5, 1.0 Hz, 1 H),
7.37 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.09 (td, J = 7.5, 1.0 Hz,
1 H), 7.01 (dd, J = 8.5, 1.0 Hz, 1 H), 6.68 (dd, J = 7.5, 1.0
Hz, 1 H), 4.01 (s, 3 H), 3.89 (s, 3 H).
4-Methoxy-2-(4-methoxyphenyl)pyrimidine (21b)
1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J = 5.5 Hz, 1 H),
8.40 (d, J = 9.0 Hz, 2 H), 6.98 (d, J = 9.0 Hz, 2 H), 6.56 (d,
J = 5.5 Hz, 1 H), 4.07 (s, 3 H), 3.88 (s, 3 H).
2-(Benzyloxy)-6-(thien-2-yl)pyrazine (24d)
1H NMR (400 MHz, CDCl3): δ = 8.53 (br s, 1 H), 8.13 (br s,
1 H), 7.66 (dd, J = 4.0, 1.0 Hz, 1 H), 7.53 (d, J = 7.5 Hz, 2
H), 7.46 (dd, J = 5.0, 1.0 Hz, 1 H), 7.31–7.42 (m, 3 H), 7.14
(dd, J = 5.0, 4.0 Hz, 1 H), 5.48 (s, 2 H).
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6-(Thien-2-yl)pyridin-2(1H)-one (27)
1H NMR (400 MHz, CDCl3): δ = 12.82 (br s, 1 H), 7.98 (d,
J = 3.5 Hz, 1 H), 7.43 (t, J = 8.5 Hz, 1 H), 7.38 (d, J = 5.0
Hz, 1 H), 7.16 (dd, J = 5.0, 3.5 Hz, 1 H), 6.52 (d, J = 8.5 Hz,
2 H).
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2-Phenylpyrimidin-4(3H)-one (29)
1H NMR (400 MHz, CDCl3): δ = 8.19 (dd, J = 8.0, 1.5 Hz, 2
H), 8.15 (d, J = 6.5 Hz, 1 H), 7.52–7.61 (m, 3 H), 6.46 (d,
J = 6.5 Hz, 1 H).
Synlett 2014, 25, 1904–1908
© Georg Thieme Verlag Stuttgart · New York

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