Site-Selective Switching Strategies to Functionalize Polyazines

Article abstract of DOI:10.1021/jacs.8b04530

Many drug fragments and therapeutic compounds contain multiple pyridines and diazines. Developing site-selective reactions where specific C-H bonds can be transformed in polyazine structures would enable rapid access to valuable derivatives. We present a study that addresses this challenge by selectively installing a phosphonium ion as a versatile functional handle. Inherent factors that control site-selectivity are described along with mechanistically driven approaches for site-selective switching, where the C-⁺PPh₃ group can be predictably installed at other positions in the polyazine system. Simple protocols, readily available reagents, and application to complex drug-like molecules make this approach appealing to medicinal chemists.

Full text of DOI:10.1021/jacs.8b04530

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Article
Site-Selective Switching Strategies to Functionalize Polyazines
Ryan D Dolewski, Patrick J Fricke, and Andrew McNally
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Site-Selective Switching Strategies to Functionalize Polyazines
Ryan D. Dolewski, Patrick J. Fricke and Andrew McNally*
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Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.
ABSTRACT: Many drug fragments and therapeutic compounds contain multiple pyridines and diazines. Developing site-selective
reactions where specific C–H bonds can be transformed in polyazine structures would enable rapid access to valuable derivatives.
We present a study that addresses this challenge by selectively installing a phosphonium ion as a versatile functional handle. Inher-
ent factors that control site-selectivity are described along with mechanistically driven approaches for site-selective switching,
where the C–+PPh3 group can be predictably installed at other positions in the polyazine system. Simple protocols, readily available
reagents and application to complex drug-like molecules make this approach appealing to medicinal chemists.
Examples of biologically relevant polyazines (1)
INTRODUCTION
Me
N
H
MeO
MeO
N
N
When molecules have multiple occurrences of the same
functional group or structural motif, site-selective reactions
give immediate access to valuable derivatives without requir-
ing prior synthesis from a simpler precursor.1 This superior
efficiency is particularly relevant for biologically active mole-
cules where structures are often complex and rapid access to
analogues for structure activity relationship (SAR) studies
expedites drug discovery.2 However, reaction development is a
significant challenge in this regime; reactivity differences be-
tween sites is often dependent on subtle steric and electronic
factors that must be recognized by the chemical entities in-
volved in the process.
N
NH
H
N
H
O
N
Cl
HN
N
H
H
Me
N
N
O
N
H
Gleevec – Myeloid
Leukemia
Previous work: Regioselective C–P bond formation and derivatization (2)
H
MK-1064 – Insomnia
C–C Bond Formation
H
PPh3
OTf
C–O/S Bond Formation
C–N Bond Formation
C–D/T Bond Formation
H
H
H
H
C–P Bond
Formation
R
R
Significant progress has been made in selective alcohol
functionalization of polyhydroxylated molecules and examples
of polyene and polyarene derivatization have emerged.3-5
While metal-catalyzed C–H activation reactions have shown
potential for site-selectivity between distinct classes of het-
eroaromatics, there are no general approaches to distinguish
between molecules containing multiple pyridines and dia-
zines.6-8 Polyazines are often found in therapeutic compounds
(eq 1), and they are also abundant in medicinal chemistry li-
braries as lead compounds and drug fragments.9 Given the
importance of polyazines in pharmaceuticals, site-selective
functionalization strategies would be highly desirable.10 We
herein report a study that addresses this challenge by selective-
ly installing a phosphonium ion as a generic functional handle
in polyazine structures. Furthermore, analyzing the reaction
mechanism for C–P bond-formation has revealed several dis-
tinct strategies for switching site-selective selectivity; simple
changes in reaction conditions allow the phosphonium ion to
be installed at different positions in the scaffold.11
Our laboratory has shown that pyridines and diazines can be
selectively converted into heterocyclic phosphonium salts
using simple reagents and reaction protocols.12 The process
has significant scope, including structures representative of
drug fragments, and can be used as a tool for late-stage func-
tionalization. C–P bond formation is exclusively selective for
the 4-position of pyridines in most cases, and the phosphoni-
um ion can be subsequently used as a functional handle to
N
N
This work: Switchable site-selectivity for polyazine functionalization (3)
OTf
N
H
PPh3
S
N
N
S
S
N
N
N
Inherent
Switch
Selectivity
Selectivity
OTf
PPh3
N
N
N
H
form C–C, C–O, C–S, C–N and C–D/T bonds (eq 2).13 During
our investigations, we observed that site-selective phosphoni-
um salt formation is possible, although the precise reasons for
the selective outcomes were not always clear. Our purpose in
this study is to systematically evaluate how substitution pat-
terns, steric and electronic effects determine the inherent site
of C–P bond formation and devise methods to predictably
switch site-selectivity to other positions in polyazines (eq 3).
Our hypothesis was that all three stages of the mechanism for
C–P bond-formation could influence site-selectivity (Scheme
1): first, nucleophilic attack by the heterocyclic nitrogen on
Tf2O; second, phosphine addition to the activated pyridinium
triflyl salt; third, base-mediated elimination to reform the aro-
matic system. Furthermore, reaction parameters, such as order
of reagent addition, were also envisioned to affect site-
selectivity.
Based
on
this
mecha
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Scheme 1. Mechanistic stages of phosphonium ion formation.
Page 2 of 8
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2
3
4
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1
2
3
4
Reaction with Tf2O
H
PPh3
H
PPh3
OTf
R’3N
PPh3
OTf
Factors influencing
regio- and
site-selectivity:
Phosphine addition selectivity
Base dependence
1
2
3
R
R
R
R
O
O
O
O
N
N
N
N
– R’3NHTf
S
S
OTf
Order of reagent addition
Tf
Tf
F3C
O
CF3
6
7
8
9
nistic approach, we herein present distinct strategies for
switchable control of C–P bond formation in polyazines.
moderate level on the chloro-substituted ring. A large number
of derivatives could subsequently be obtained using the C–P
and C–Cl bonds as functional handles. A derivative of an anti-
histamine, bepotastine,16 bearing a piperidine ring and ben-
zhydril stereocenter, is representative of a small molecule
drug, or drug fragment, where site-selectivity is challenging.
The inherent site of C–P bond formation shows a modest bias
towards the 3-substituted pyridine (2d). The acylation-
blocking strategy can be used to switch selectivity and provide
usable quantities of the phosphonium ion on the 2-substituted
ring.
An intermolecular competition reaction confirmed that
phosphonium ion formation selectively occurs on pyridine
over pyrazine, which reflects the significant difference in nu-
cleophilicity of these heterocycles (Table 1). Gratifyingly, the
selectivity trend can be reversed via the acylation-blocking
protocol. Two pyridine-diazine systems, linked by oxymeth-
ylene and thiomethylene groups, respectively, were tested for
the potential for site-selective switching. We were disappoint-
ed to observe that C–P bond formation in 2e did not match the
intermolecular experiment (vide infra), and an unbiased mix-
ture of salts was formed. However, acylation-blocking resulted
in C–P bond formation on the pyrazine ring as the only detect-
able isomer. The pyridine-pyrimidine system showed greater
reliability using both standard and switching conditions (2f);
single phosphonium salt isomers were detected in the crude
31P NMRs of the reaction mixtures and the salts were isolated
in good yields. A thiophene-linked system, containing pyri-
dine and pyrimidine rings, was moderately selective under
standard conditions (2g). Like 2b and bepotastine derivative
2d, a 2-position salt is a significant component of the reaction
mixture, and it is important to note that we have only seen
significant levels of 2-position selectivity in polyazines. Acyl-
ation-blocking was highly selective for the pyrimidine ring in
moderate yield with the remainder of the mass balance being
unreacted starting material.
Selecting between different 2-substituted pyridines is a chal-
lenge due to comparable steric effects. We examined an elec-
tronically biased system by competing 2-phenylpyridine with
2-chloropyridine; the preference for phenyl substitution indi-
cates that a carbon-bearing group is more favorable to an in-
ductively withdrawing substituent. A representative fragment,
containing a 2-aryl and 2-chloro motif was synthesized, and
under standard conditions selectivity for the 2-aryl pyridine
was observed (2h). In a 1H NMR study, only the 2-
arylpyridine ring protons were downshifted after adding Tf2O,
in line with the observed selectivity.17 Both pyridine rings
showed downfield shifts under the acylation-blocking condi-
tions, and this protocol results in a complete reversal of selec-
tivity towards the chloro-substituted pyridine in 2h. Notably,
P(p-OMePh)3 provided higher yields than PPh3 for this sys-
tem.18 Bipyridine 2i shows that a 2-acyloxypyridine is selec-
tively functionalized in a 2,4-substituted bipyridine
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RESULTS AND DISCUSSION
An Acylation-Blocking Strategy. We reasoned that stage 1
of C–P bond formation would be influenced by steric and elec-
tronic properties of the nucleophilic azines, and a site-selective
bias would occur when one azine is inherently more reactive
towards Tf2O. As shown in equation 4, PPh3 would selectively
add to one heterocycle in a polyazine (1) if a single triflyl salt
isomer forms (I). Furthermore, we envisioned a blocking strat-
egy for site-selective switching, where the more reactive het-
erocycle is acylated prior to adding Tf2O.11 In bis-salt (II),
PPh3 should add to the more electrophilic triflyl pyridinium
over the acyl pyridinium salt, resulting in a selectivity switch
between different sites in a polyazine system.
An acylation-blocking strategy for site-selective switching (4)
PPh3
Tf2O; PPh3
R1
R2
N
N
OTf
Tf
I
R1
R2
N
N
AcCl, AgOTf
then
Ph3P
1
R1
R2
Tf2O; PPh3
Inherent site-selectivity
Switched site-selectivity
N
N
OTf
O
OTf
Tf
Me
II
To rapidly identify inherent substrate biases and test the ac-
ylation-blocking strategy, we performed intermolecular com-
petition experiments between pairs of azines (Table 1). Distin-
guishing between pyridines with 2- vs. 3-substitution patterns
would apply to a large range of biologically relevant poylazine
structures. Under standard conditions, a competition between
2- vs. 3-methoxy pyridine shows a clear bias towards the 3-
substituted isomer, presumably due to the absence of steric
crowding at the pyridine nitrogen. To test the acylation-
blocking strategy, the pair of pyridines was first subjected to
acetyl chloride and AgOTf at 0 ºC in CH2Cl2, and stirred at
room temperature for 1 hour.14 The mixture is then cooled to –
78 ºC and the phosphonium salt forming protocol was con-
ducted as normal.15 The combined phosphonium salts were
isolated in good yield, with a significant reversal in selectivity
towards the 2-substituted isomer.
After validating the acylation-blocking strategy in an in-
termolecular system, we anticipated that this switchable selec-
tivity would translate into a set of bipyridines embedded with
2- and 3-substituents (Table 1). Phosphonium ion derivatives
of a bis-pyridyl ether can be obtained on either heterocycle
with good control of selectivity (2a). Bipyridine salt 2b shows
an expected site-selectivity bias under standard conditions;
surprisingly, a 2-position isomer is tentatively assigned as the
next significant phosphonium species (vide infra). 2-Chloro
substituents deter reactivity in the presence of 3-oxypyridines
as shown in 2c; selectivity can be switched in this case to a
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Table 1. Site-selective switching via an acylation-blocking strategy.a,b,c,d,e
1
2
3
4
5
6
7
8
B
Blocking conditions:
PPh3
x
H
H
PPh3
y
A
Standard conditions:
Tf2O; PPh3; DBU
x
y
OTf
R1
OTf
Z
AcCl, AgOTf, 0 ºC to rt then
Tf2O; PPh3; DBU
Z
Z
R2
R1
R2
R1
R2
N
N
N
N
N
N
CH2Cl2, –78 ºC to rt
CH2Cl2 or EtOAc, –78 ºC to rt
Intermolecular Competition Experiments
2
1
2
y
y
x
x
x
OMe
N
y
vs.
2- vs.
3-substituted
pyridines
vs.
Ph
vs.
2-aryl vs.
2-halopyridines
pyridines
vs. diazines
N
N
Cl
N
N
OMe
N
A
B
N
9
83% – 19:1 (x:y)
72% – 1:8 (x:y)
74% – >20:1 (x:y)
83% – 19:1 (x:y)
72% – 1:8 (x:y)
A
B
A
10
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19
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36% – 1:17 (x:y)
B
x
N
y
x
N
O
N
x
x
58% – 2:1
(x:mix. of 4 isomers)
A
O
y
N
y
Cl
O
N
N
N
B
50% – <1:20 (iso:y)
y
O
N
N
2e
2a
2b
2h
83% – >20:1 (x:y)
75% – 11.6:1:2.4 (x:y:iso)
A
B
A
B
y
88% – 19:<1:1 (x:y:iso)
63% – <1:20 (x:y)e
A
B
40% – 1:17:2
(x:y:mix. of 2 isomers)
36% – 1:11 (x:y)
N
N
x
83% – >20:1 (x:y)
75% – <1:20 (x:y)
A
B
S
N
y
N
y
Cl
N
N
N
y
x
2f
x
O
N
O
y
O
x
2- vs.
N
O
S
2c
N
53% – 5.6:1:3.1
(x:y:iso)
4-substituted
pyridines
A
B
N
N
2d
2i
CO2Et
84% – >20:1:1
(x:y:iso)
A
B
68% – >20:1 (x:y)d
43% – <1:20 (x:y)e
A
B
42% – <1:20 (iso:y)
73% – 5.9:1:2.2 (x:y:iso)
37% – <1:20 (x:y)
A
N
x
44% – 3:1
(y:mix. of 2 isomers)e
2g
B
aIsolated yields are reported of salt mixtures are reported. bRatios were calculated from crude 1H or 31P NMR spectra. Ratios of isolated
products can differ from the crude reaction mixture. ciso refers to an unidentified phosphonium salt isomer. dYields calculated by 1H NMR
using
1,3,5-trimethoxybenzene
as
an
internal
standard.
eP(p-OMePh)3
used.
and that selectively can again be reversed using the blocking
strategy. P(p-OMePh)3 was again superior to PPh3 in this
case.18
Base-Mediated Switching. The nature of the organic base
can be tuned to control site-selectivity by exploiting structural
differences during stage 3 of the reaction mechanism (Scheme
1). DBU and NEt3 are typically used, with DBU generally
providing higher yields for most substrates in the reaction
scope. We made an unexpected observation for certain 3-
substituted pyridines that suggested site-selectivity may be
controlled by base selection (Scheme 2A). Both DBU and
NEt3 are effective for 3-methoxypyridine, however no product
is obtained for 3-methyl and 3-phenylpyridine when NEt3 is
used as a base. We hypothesized that a difference in acidity, or
steric effects, preclude elimination of the triflyl anion in
dearomatized intermediate III when an alkyl or aryl group is
present. Scheme 2B illustrates the challenge for 3,3-bipyridine
systems such as 1j; an unselective outcome is observed under
standard conditions due to a similar proclivity of each pyridine
nitrogen to react with Tf2O (2j). A lack of steric and electronic
bias also precludes using the acylation-blocking strategy, so
we conceived of an approach using base dependent selectivity.
Using two equivalents each of Tf2O and PPh3, double-
dearomatized bis-salt IV is a putative intermediate where only
the oxy-substituted form is susceptible to elimination by NEt3.
Low temperature 31P NMR shows two major resonances at
21.93 ppm and 19.53 ppm in a 1:1 ratio indicating that a bis-
phosphonium salt is present. Adding NEt3 results in complete
C–P bond site-selectivity for the 3-oxypyridine, while the 3-
alkylpyridine is reformed under the reaction conditions.
Scheme 2. Effect of base on reactivity and site-selectivitya,b
A – Unexpected effect of base on C–P bond-formation
Tf2O; PPh3; DBU or NEt3, CH2Cl2, –78 ºC to rt
NEt3
Ph3P
OTf
H
PPh3
PPh3
PPh3
R
OTf
OTf
OTf
OMe
Me
Ph
N
N
N
N
Tf
III
No elimination
when R = alkyl
or aryl
DBU 78%b
DBU 87%
DBU 72%
90%b
0%b
0%b
NEt3
NEt3
NEt3
B – Base-controlled selectivity via double-dearomatized intermediates
Tf
N
N
NEt3
Tf2O; PPh3
(2 equiv)
x
O
Ph3P
OTf
H
O
y
1j
PPh3
OTf
N
CH2Cl2, –30 ºC
H
N
Standard conditions:
Tf
IV
77% – 2.9:2.2:2.8 (x:y:
mix. of 2 isomers)
DBU
31P NMR: 21.93 ppm
and 9.53 ppm (1:1)
N
PPh3
OTf
x
NEt3
O
y
–78 ºC to rt
2j 69% – >20:1 (x:y)
N
aYields and ratios reported as in Table 1. Yields calculated by
b
1H NMR spectroscopy of the crude reaction mixture.
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Table 2. A base-dependent protocol for site-selective switchinga,b
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3
4
5
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Standard conditions:
Tf2O; PPh3 (1 equiv);
DBU
Base-switch conditions:
Tf2O (2 equiv); PPh3 (2 equiv);
NEt3
PPh3
x
H
H
PPh3
y
x
y
OTf
R1
OTf
Z
Z
Z
R2
R1
R2
R1
R2
N
N
N
N
N
N
CH2Cl2, –78 ºC to rt
CH2Cl2 or EtOAc, –78 ºC to rt
2
1
2
y
N
y
N
N
y
N
y
N
x
y
x
x
x
O
O
O
O
N
Me
Br
S
N
x
N
2e
9
2k
Me
N
Me
N
Me
N
2l
2m
N
2f
83% – <1:20 (x:y)
58% – 2:1
10
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DBU
54% – 20:1:2.9
(x:y:mix. of 2 isomers)
n.d. – mix. of 4 isomers
56% – >20:1 (x:y)
68% – <1:20 (x:y)
55% – 13:1 (x:y)
DBU
NEt3
DBU
NEt3
DBU
DBU
(x:mix. of 4 isomers)
NMe2Cy
NEt3 74% – <1:20: (iso:y)
NEt3 68% – >20:1 (x:y)
65% – <1:20 (x:y)
Biologically relevant compounds
x
N
x
y
O
O
x
N
y
O
N
N
Cl
OMe
N
x
Me
N
N
y
N
2n
N
N
A-84543 analogue 2o
MK-1064 precursor 2p
83% – 10:1:3.1 (x:y:x+y)
NEt3 89% – <1: 20 (iso:y)
loratadine analogue 2q
67% – 1:2.2 (x:y)b
y
65% – <1:20 (x:y)
89% – 2.6:1.2:1 (x:y:x+y)
N
DBU
DBU
DBU
DBU
CO2Et
NEt3 54% – >20:1 (x:y)
NEt3 72% – >20:1 (x:y)
NEt3 82% – <1:20 (x:y)
aYields and ratios reported as in Table 1. bYield calculated by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard. cx+y rep-
resents bis-phosphonium salt.
a
A series of oxymethyl-linked bipyridine systems was first
selected to explore base effects on site-selectivity (Table 2).
Under standard conditions, the 3-substituted pyridine is pre-
ferred over the 2,5-system in 2k. Using NMe2Cy under base-
switch conditions results in phosphonium ion formation on the
opposite pyridine ring; NEt3 was also effective in this system
but in lower yield.19 Under standard conditions, the 3,5-
disubstituted pyridine ring is preferred in 2l and the crude ratio
improves to >20:1 after purification; base-switching condi-
tions give access to the 3-oxy pyridine case with excellent
selectivity. A bromo-containing bipyridine resulted in a com-
plex mixture of four phosphonium isomers under the standard
protocol (2m) but a site-selective outcome is observed using
base-switch conditions. The same base effect is also observed
between pyridines and diazines, as shown in examples 2e and
2f. As previously described in Table 1, standard conditions are
less effective for pyridine-pyrazine 2e, with several phospho-
nium isomers observed (vide infra). However, base-switching
conditions result in excellent selectivity for a single site on the
pyrazine ring. Pyridine-pyrimidine salt 2f is also amenable to
this base-switching strategy. A 3-aryl linker can be used as a
controlling element in site-selective phosphonium ion for-
mation (2n).
We next selected a set of biologically active complex pol-
yazines to test the base-switching strategy. An analogue of A-
84543,20 a nicotinic acetylcholine receptor agonist, can be
selectively converted into phosphonium ion derivatives on
each pyridine ring with complete control of regio- and site-
selectivity (2o). The tripyridine system in an MK-1064 precur-
sor is a challenging target for site selective functionalization.
Under standard conditions, moderate selectivity for the 3,5-
disubstituted ring is observed, along with a mixture of a bis-
phosphonium salt and substitution on the 2-substituted pyri-
dine (2p, vide infra). The 3,5-system can, however, be recog-
nized by NEt3 under the base-switching conditions resulting in
exclusive C–P bond formation on the 2-substituted ring. A
loratadine analogue shows poor selectivity under standard
conditions (2q), but the presence of a 2,3-fused carbocycle
enables NEt3 to distinguish between the two pyridines with
complete site-selectivity.
Order of Reagent Addition. Several examples in this study
are moderately site-selective under standard conditions and we
have found that the order that the reagents are added can sig-
nificantly affect these outcomes. Under the standard protocol,
the polyazine is stirred with Tf2O for 30 minutes at –78 ºC
before PPh3 is added. This order is chosen to minimize an
unwanted reaction between Tf2O and PPh3 that we have ob-
served results in Ph3P=O. We revisited phosphonium salt for-
mation on loratadine analogue (1q), where modest site-
selectivity was observed under standard conditions (Table 2
and Scheme 3A). When the order of addition is reversed, and
PPh3 is added before Tf2O, site-selectivity is significantly in-
creased and the product phosphonium salt is isolated in good
yield with minor amounts of Ph3P=O formed. This dichotomy
can be rationalized by an equilibrium mixture of pyridinium-
Tf salt isomers V, VI and VII formed under standard condi-
tions (Scheme 3B). When 1q is stirred with Tf2O, the 1H NMR
spectrum displays a downfield shift of all pyridine protons
indicating that a rapidly interconverting mixture of Tf salt
isomers is present (see Supporting Information for more de-
tails). Site-selectivity is then related to the relative populations
of V, VI and VII. When PPh3 is present before Tf2O is added,
we propose that site-selectivity reflects a kinetic regime where
pyridinium-Tf salt V forms fastest, and rapidly reacts with
PPh3.
Other substrates with moderate selectivity were retested, as
well as additional examples, to further assess the impact of
reagent order on site-selectivity (Scheme 3C). A bepotastine
analogue that produced a mixture of phosphonium salt isomers
can be significantly improved by reversing the order of addi-
tion (2d). Reaction efficiency and site-selectivity in pyridine-
pyridine and pyridine-diazine systems 2b, 2e and 2g are also
improved under these conditions. An MK-1064 precursor, that
resulted in a mixture of mono- and bis-phosphonium salts,
forms a single C–P bond isomer on the 3,5-disubstituted pyri-
dine in the crude 31P NMR (2p). Bipyridine salt 2l is an inter
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Journal of the American Chemical Society
Scheme 3. Impact of reagent order on site-selectivitya,b,c,d,e
1
2
3
4
5
6
7
8
A – Standard vs. reverse addition protocol
B – Standard conditions: N-Trifyl salt pre-equilibrium
x
Standard conditions:
Tf2O then PPh3
y
N
N
N
N
89% – 2.6:1.2:1 (x:y:x+y)
N
N
N
N
Tf
Tf
OTf
OTf
Tf
Tf
Modified conditions:
PPh3 then Tf2O
loratadine
analogue
OTf
V
VI
VII
OTf
N
N
N
N
72% – <1:20 (x:y)
1r
CO2Et
CO2Et
CO2Et
CO2Et
9
C – Moderately selective substrates revisited and additional examples
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
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59
60
N
N
N
N
y
N
y
Me
y
y
N
x
O
x
S
Me
N
O
O
y
x
Cl
OMe
N
N
x
x
N
2l
N
O
N
N
O
MK-1064
precursor
x
N
2e
2d
Tf2O then PPh3
Tf2O time:
bepotastine
analogue
N
2b
y
N
2g
2p
CO2Et
Tf2O then PPh3
15 mins, 44%b – 1.5:2:1 (x:y:isoe)
30 mins, 52%b – 3.3:1:1 (x:y:isoe)
60 mins, 72%b – 20:1:3 (x:y:isoe)
58% – 2:1
(x:mix of 4 isomers)
Tf2O then PPh3
Tf2O then PPh3
Tf2O then PPh3
Tf2O then PPh3
73% – 5.9:1:2.2 (x:y:iso)
75% – 11.6:1:2.4 (x:y:iso)
53% – 5.6:1:3.1 (x:y:iso)
83% – 10:1:3.1 (x:y:x+y)
PPh3 then Tf2O
PPh3 then Tf2O
PPh3 then Tf2O
PPh3 then Tf2O
PPh3 then Tf2O
52%b – 4.3:1:1 (x:y:isoe)
PPh3 then Tf2O
83% – 18.5:1:2
(x:y:mix. of 2 isomers) 77% – 17:<1:1 (x:y:iso)
81% – >20:1 (x:y)
99% – >20:1 (x:y)
93% – >20:1 (x:iso)
aYields and ratios reported as in Table 1. bYield calculated by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard. cx+y rep-
resents a bis-phosphonium salt. diso refers to an unidentified phosphonium salt isomer. eMixture of two undefinited isomers
aYields and ratios reported as in Table 1. Yields calculated by
b
esting case where reversing the order of Tf2O and PPh3 is det-
rimental to site-selectivity. Increasing stirring time with
1H NMR spectroscopy of the crude reaction mixture.
Tf2O,before adding PPh3, results in a stronger bias towards the
standard conditions is highly effective, however, applying the
3,5-disubstituted pyridine and presumably indicates more time
site-selective switching strategies described in this report have
is needed to establish a biased pyridinium-Tf salt equilibri-
proven challenging. Scheme 4A shows three representative
um.Adding PPh3 before Tf2O results in poor site-selectivity
cases of linked pyridine-pyridine and pyridine-diazine sys-
and suggests that kinetic Tf-salt formation is unselective. Giv-
tems. Phosphonium ion formation occurs with excellent levels
en the impact of reagent order on site-selectivity, we recom-
of site-selectivity and is in line with predisposed reactivity
mend alternating the order that Tf2O and PPh3 are added for
with Tf2O (2r-2t). Both acylation-blocking and base-switching
strategies resulted in no product formation for bipyridines 2r
and 2s. Our current hypothesis is that the adjacent pyridinium
substrates where site-selectivity is modest.
Initial Investigations of [m,n]-Bipyridines and Pyridine-
Diazines. Bis-azine biaryls are an important class of com-
salts formed in these cases have heightened electrophilicity
pounds that are encountered in numerous biologically active
molecules.21 Our initial investigations into site-selective C–P
such that PPh3 reacts with the Tf-portion of the salts, at sulfur,
and is oxidized; O=PPh3 is the major phosphorus species ob-
bond formation have shown that inherent selectivity under
served in the crude 31P NMR. Pyridine-diazine 2t shows that
the switching strategies can be effective, albeit in low yield.
Scheme 4B shows a 3,3’-bipyridine where site-selective
switching could be triggered by an alternative approach. Un-
der standard conditions, phosphine addition favors the 3,5-
disubstituted pyridine, with P(p-OMePh)3 proving superior to
PPh3 as a nucleophile (2u).22 This outcome is again expected
based on Tf-salt VIII forming selectively during the reaction.
As above, attempts to switch site-selectivity using the acyla-
tion-blocking strategy resulted in no formation of any phos-
phonium ion species. We envisioned that site-selectivity could
be controlled by selective phosphine addition to a bis-
pyridinium salt (Scheme 4B, VIII), where the less hindered
2,5-system would be the preferred site of attack. Adding 1.75
equivalents of PPh3 to a pre-stirred mixture of the bipyridine
and two equivalents of Tf2O resulted in a reversal in selectivi-
ty to the 2,5-disubstituted pyridine in 50% yield. As linked
bipyridines are important in the chemical sciences, we are
continuing to investigate site-selective processes involving
these systems.
Scheme 4. Phosphine-dependent site-selectivitya,b
y
y
A – Representative examples
N
y
of bis-azine biaryls
x
x
N
N
N
N
C–H
conditions:
C–+PPh3
N
N
x
2r
2s
2t
96% – >20:1 (x:y)
59% – >20:1 (x:y)
72% – >20:1 (x:y)
standard
acylation
0%
0%
0%
0%
21% – 7.7:1 (y:iso)
19% – 1:2 (x:y)b
base-switch
B – 3,3’-Bipyridine system: Standard conditions
Tf
PAr3
OTf
N
Me
N
Me
N
Me
x
Me
Me
Me
y
N
N
N
OTf
2u
VIII
IX
PPh3
OTf
Tf
Tf
Tf2O (1 equiv)
Tf2O (2 equiv)
50% – 1:9.6 (x:y)
Standard
Modified
conditions:
(Ar = p-OMePh)
Derivatization reactions. To show that site-selective phos-
phonium ion formation is useful for generating a range of ana-
conditions:
48% – >15:1 (x:y)
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Journal of the American Chemical Society
logue compounds, we performed a series of derivatization
Page 6 of 8
This study has established factors that control site-selective
phosphonium ion formation in poylazine systems. Steric and
electronic factors in pyridines and diazines dictate the inherent
site of C–P bond formation, which is predictable for complex
polyazine systems. Examining the reaction mechanism for C–
P bond formation allowed us to develop strategies for site se-
lective switching where phosphonium ion formation can be
directed to other positions in a polyazine scaffold. Acylation-
blocking, base-dependent selectivity and selective phosphine
addition enable control of selectivity in polyazines with dis-
tinct substitution patterns and electronic properties. The order
that reagents are added also has a significant impact on site-
selectivity in polyazine systems. We believe that this study
will be useful in applications such as medicinal and agrochem-
istry as well as applications such as ligand design. Further
studies into site-selectivity are ongoing in our laboratory and
will be reported in due course.
1
2
3
4
5
6
7
8
reactions (Scheme 5). Both isomers of pyridine-pyrimidine 1f
are accessible in high levels of site-selectivity using standard
and base-switching conditions (2f, Table 2). We first tested
carbon-heteroatom bond-forming reactions using our previ-
ously reported protocols;13 heteroaryl ethers 3a and 4a are
formed efficiently on both ring systems using alcohol 5. Simi-
larly, heteroaryl thioethers can be obtained using benzyl thio-
late as a nucleophile (3b and 4b). Heating with sodium azide,
followed by hydrolysis of the iminophosphorane products,
results in heteroaryl aniline isomers 3c and 4c. Hydrogen iso-
topes can be incorporated into different sites of 1m by subject-
ing the respective phosphonium salts to K2CO3 in the presence
of a mixture of CD3OD and D2O. Finally, a sequence of reac-
tions can be used to create drug-like scaffold 6. Selective
phosphonium salt formation on the pyrimidine ring of 1u is
followed by nickel-catalyzed cross-coupling to install a thio-
phene group. Second phosphonium ion formation selectively
occurs on the pyridine ring, and C–O bond formation using
azetidine-containing alcohol 5 forms compound 6.
9
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13
14
15
16
17
18
19
20
21
22
23
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27
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ASSOCIATED CONTENT
Supporting Information
Scheme 5. Derivatizations of phosphonium salt isomersa,b
The Supporting Information is available free of charge on the
ACS Publications website.
1) C–+PPh3 formation (see Table 2)
N
3a-3d
Experimental procedures and spectral data (PDF)
2) Derivatization
S
N
1) C–+PPh3 formation
AUTHOR INFORMATION
Corresponding Author
(base-switch, see Table 2)
N
4a-4d
1f
2) Derivatization
*Email: andy.mcnally@colostate.edu
ORCID
ROH (5) =
Na
N
N
N
HO
Ph
Ph
HS
DMSO, 120 ºC
then
N
Andrew McNally: 0000-0002-8651-163
DMF/H2O (9:1), 100 ºC
NaH, THF, 0 ºC to rt
NaH, THF, 0 ºC to rt
R
Bn
ACKNOWLEDGMENT
O
N
S
N
NH2
N
This work was supported by start-up funds from Colorado State
University and The National Institutes of Health under award
number R01 GM124094.
S
N
O
S
N
S
S
N
N
N
N
3a, 56%
3b, 53%
3c, 57%
R
Bn
NH2
REFERENCES
N
N
N
(1) (a) Mahatthananchai, J.; Dumas, A. M.; Bode, J. W. Angew.
Chem. Int. Ed. 2012, 51, 10954. (b) Huang, Z.; Dong, G. Acc. Chem.
Res. 2017, 50, 465.
(2) (a) Silverman, R. B.; Holladay, M. W. Lead Discovery and
Lead Modification. The Organic Chemistry of Drug Design and Drug
Action, 3rd Ed.; Elsevier: Waltman, MA, 2014; pp. 19–106. (b) Cer-
nak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W.
Chem. Soc. Rev. 2016, 45, 546−576.
(3) (a) Lewis, C. A.; Miller, S. J. Angew. Chem. Int. Ed. 2006, 45,
5616. (b) Wilcock, B. C.; Uno, B. E.; Bromann, G. L.; Clark, M. J.;
Anderson, T. M.; Burke, M. D. Nature Chem. 2012, 4, 996. (c) Jor-
dan, P. A.; Miller, S. J. Angew. Chem. Int. Ed. 2012, 51, 2907. (d)
Han, S.; Miller, S. J. J. Am. Chem. Soc. 2013, 135, 12414. (e) Sun, X.;
Lee, H.; Tan, K. L. Nature Chem. 2013, 5, 790. (f) Bastain, A. A.;
Marcozzi, A.; Herrmann, A. Nature Chem. 2012, 4, 789.
(4) (a) Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, 4, 990. (b)
Pathak, T. P.; Miller, S. J. J. Am. Chem. Soc. 2012, 134, 6120. (c)
Snyder, S. A.; Gollner, A.; Chiriac, M. I. Nature 2011, 474, 461.
(5) For an example of site-selective functionalization of sp3-rich
compounds see: Roiban, G-D.; Reetz, M. T. Chem. Commun. 2015,
51, 2208.
S
N
S
N
S
N
N
N
N
4a, 68%
4b, 81%
4c, 66%
Site-selective labeling with hydrogen isotopes
D
N
1) C–+PPh3
formation
(switch)
1) C–+PPh3
formation
D
N
N
1f
S
N
S
2) K2CO3
CD3OD/D2O
2) K2CO3
CD3OD/D2O
N
N
3d, 75%
4d, 74%
Sequential C–P and C–C bond-forming reactions
Ph
Ph
1) C–+PPh3 formation
S
N
(base-switch), 65%, >20:1
N
2) Ni-catalysis, 3-thienylboronic
acid, 50%
O
N
O
N
N
3) C–+PPh3 formation
N
1u
O
N
(standard conditions), 90%, 20:1b
4) 5, NaH, THF, 0ºC to 40 ºC, 50%
6
aIsolated yields are shown and ratios are reported as in Table 1.
bThe minor isomer is a 2-position pyridine phosphonium salt.
(6) (a) Kalyani, D.; Dick, A. R.; Anani, W, Q.; Sanford, M. S. Tet-
rahedron 2006, 62, 11483. (b) Lapointe, D.; Markiewicz, T.; Whipp,
C. J.; Toderian, A.; Fagnou, K. J. Org. Chem. 2011, 76, 749.
(7) Zoltewicz, J. A.; Cruskie Jr., M. P. Tetrahedron 1995, 51, 3103.
CONCLUSIONS
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Journal of the American Chemical Society
(8) For an example of site-selective functionalization of benzylic
(14) In the absence of AgOTf, we observe no product formation;
the presence of chloride ions appears to prevent phosphonium ion
formation.
(15) The acylpyridinium salt persists at the end of the reaction so
two equivalents of pyridine are added in the work up to release the
product via a transamination mechanism.
and heterobenzylic positions see: Cooper, J. C.; Luo, C.; Kameyama,
R.; Van Humbeck, J. F. J. Am. Chem. Soc. 2018, 140, 1243.
(9) (a) Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem.
2013, 9, 2265. (b) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med.
Chem. 2014, 57, 10257.
1
2
3
4
5
6
7
8
9
(10) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.;
Thomas, A. W.; Wilson, D. M.; Wood, A. Nature Chem. 2018, 10,
383.
(11) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B.
Chem. Rev. 2012, 112, 2642.
(12) (a) Hilton, M. C.; Dolewski, R. D.; McNally, A. J. Am. Chem.
Soc. 2016, 138, 13806. (b) Anders, E.; Markus, F. Tetrahedron Lett.
1987, 28, 2675. (c) Anders, E.; Markus, F. Chem. Ber. 1989, 122,
113. (d) Anders, E.; Markus, F. Chem. Ber. 1989, 122, 119. (e) Haas,
M.; Goerls, H.; Anders, E. Synthesis 1998, 195.
(13) (a) Zhang, X.; McNally, A. Angew. Chem. Int. Ed. 2017, 56,
9833. (b) Koniarczyk, J. L.; Hesk, D.; Overgard, A.; Davies, I. W.;
McNally, A. J. Am. Chem. Soc. 2018, 140, 1990. (c) Anderson, R. G.;
(16) Kato, M.; Nishida, A.; Aga, Y.; Kita, J.; Kudo, Y.; Endo, T.
Arzneimittelforschung 1997, 47, 1116.
(17) See the Supporting Information for more details.
1
(18) H NMR yields using 1,3,5-trimethoxybenzene as an internal
standard: 2h, PPh3 – 28%, P(p-OMePh)3 – 72%. For 2i, PPh3 resulted
in a mixture of 4 phosphonium species in the 31P NMR.
1
(19) H NMR yields for 2k using 1,3,5-trimethoxybenzene as an
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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internal standard: NMe2Cy – 68%,13:1 (x:y), NEt3 – 28%, 2.5:1 (x:y).
(20) Ogunjirin, A. E.; Fortunak, J. M.; Brown, L. L.; Xiao, Y.;
Dávila-García, M. I. Neurochem. Res. 2015, 40, 2131.
(21) Campeau, L.-C.; Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058-
1068.
1
(22) H NMR yields for 2w using 1,3,5-trimethoxybenzene as an
Jett,
B.
M.;
McNally,
A.
Tetrahedron.
internal standard: PPh3 – 27%, 3.5:1 (x:y), P(p-OMePh)3 – 60%, 15:1
(x:y). Tf2O was added after the phosphine in these reactions.
http://dx.doi.org/10.1016/j.tet.2017.12.040. (d) Patel, C.; Mohnike, M.
L.; Hilton, M. C.; McNally, A. Org. Lett. 2018, 20, 2607.
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Insert Table of Contents artwork here
1
2
3
4
5
6
7
Switched C–P
site-slectivity
<1:20
Inherent C–P
site-slectivity
>20:1
C–H
H
H
C–+PPh3
or
(
)
N
8
N
9
Loratadine
analogue
C–C C–O/S
C–D/T
10
11
12
13
14
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N
C–N
CO2Et
8
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