Radical-based regioselective C-H functionalization of electron-deficient heteroarenes: Scope, tunability, and predictability

Article abstract of DOI:10.1021/ja406223k

Radical addition processes can be ideally suited for the direct functionalization of heteroaromatic bases, yet these processes are only sparsely used due to the perception of poor or unreliable control of regiochemistry. A systematic investigation of fact

Full text of DOI:10.1021/ja406223k

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Article
Radical-Based Regioselective C-H Functionalization of Electron-
Deficient Heteroarenes: Scope, Tunability, and Predictability
Fionn O'Hara, Donna G Blackmond, and Phil S. Baran
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja406223k • Publication Date (Web): 17 Jul 2013
Downloaded from http://pubs.acs.org on July 23, 2013
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Radical'Based+Regioselective+C−H+Functionalization+of+Electron'
Deficient+Heteroarenes:+Scope,+Tunability,+and+Predictability+
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Fionn O’Hara, Donna G. Blackmond* and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United
States
ABSTRACT: Radical addition processes can be ideally suited for the direct functionalization of heteroaromatic bases, yet these
processes are only sparsely used due to the perception of poor or unreliable control of regiochemistry. A systematic investigation of
factors affecting the regiochemistry of radical functionalization of heterocycles using alkylsulfinate salts revealed that certain types
of substituents exert consistent and additive effects on the regioselectivity of substitution. This allowed us to establish guidelines
for predicting regioselectivity on complex π-deficient heteroarenes, including pyridines, pyrimidines, pyridazines and pyrazines.
Since the relative contribution from opposing directing factors was dependent on solvent and pH, it was sometimes possible to tune
the regiochemistry to a desired result by modifying reaction conditions. This methodology was applied to the direct, regioselective
introduction of isopropyl groups into complex, biologically active molecules, such as diflufenican (44) and nevirapine (45).
Introduction
that regioselectivity can be tuned according to solvent and pH,
and establishes useful, substituent-based reactivity patterns.
These studies culminate in the presentation of a hierarchical
set of empirically derived, practical guidelines allowing for
both prediction and tunability of regioselectivity (Figure 1B).
These guidelines provide the framework for further mechanis-
tic studies that promise to increase fundamental understanding
of radical-mediated heteroarene functionalization.7.
Aromatic heterocycles are essential structures in a large
proportion of small molecule drugs. Structural optimization of
bioactive leads through systematic chemical alteration is es-
sential for selecting a clinical candidate, and methods to syn-
thesize or elaborate key pharmacophores hold particular sig-
nificance in the drug discovery process. However, the produc-
tion of such libraries of compounds can be very challenging,
as electron-deficient heteroaromatic bases such as pyrim-
idines, pyrazines, pyridazines and pyrimidines are often diffi-
cult to derivatize directly with standard reactions (Figure
1A).1-4 As a result, the development of mild, direct functional-
ization methods for the selective late-stage modification of
complex heteroarene structures remains an important practical
goal.
A. Regioselective direct functionalization of electron-deficient heterocycles
SEAr
(often requires EDG)
SNAr
(e.g. NH2-, Grignards, RLi)
Het
Het
R
metallation
(e.g. Knochel, Schlosser, Snieckus)
A universal, but perhaps underappreciated, tendency of a
heteroarene (electron-rich or electron-poor) is to react with
radical species. Functionalization methods that proceed via
radical addition would therefore be expected to be a conven-
ient method for elaborating aromatic heterocycles, yet meth-
odology exploiting this innate reactivity is seldom employed.5
There is a perception that direct radical functionalization pro-
cesses are frequently low yielding, have unpredictable regiose-
lectivity, and give intractable mixtures of products. Although
this reputation is sometimes justified, the problem is com-
pounded because the factors governing the reactivity and se-
lectivity of radical addition to heteroarenes are not widely
known or understood.
C-H functionalization
(e.g. Pd, Rh, Ir)
B. Predictable, regioselective radical functionalization of heterocycles
[this work]
Zn(SO2R)2, TBHP
R
R1 Het
R1 Het
solvent, 50 °C
R = CF3, CF2H, i-Pr
•
•
predictable based on functional groups
tunable based on solvent
•
may be applied to simple
and complex systems
Figure 1. Regioselective radical functionalization of heteroarenes.
In our ongoing studies into the functionalization of het-
eroarenes using alkylsulfinate-derived radicals,6 we have be-
gun to observe certain trends pertaining to regiocontrol that –
based upon the similarity to patterns observed in various other
radical-mediated functionalization reactions – could be useful
in a more general manner. In this full report, an extensive
study of the reactivity trends of heteroarene functionalizations
employing alkylsulfinate-derived radicals is presented. This
work further defines the scope of these reactions, demonstrates
Background
A major objective at the outset of our studies was to under-
stand the reasons behind seemingly diverse regiochemical
results, both in our own work and in studies reported in the
literature, with the goal of establishing trends that would allow
the prediction of results. One broad conclusion that can be
drawn from a variety of different radical-mediated heteroarene
functionalization studies8 dating back thirty years or more is
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that regioselectivity is dominated by the inherent reactivity of
investigations of the factors regulating regiochemical out-
the substrate,9 for example the strong preference for pyridines
to react at the α and γ positions. Regulating regioselectivity is
therefore challenging, but as summarized in Figure 2, there is
precedent for innate regiochemical preferences to be influ-
enced by acid (Figure 2A), solvent (Figure 2B), substituents
on the heterocycle (Figure 2C), and nature of the radical (Fig-
ure 2D).10-18
comes with the aim to delineate generalizable effects leading
to a practical approach to predicting regioselectivity in the
radical functionalization of heteroarenes.
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8
R
NaSO2CF3 or
R
Zn(SO2CF3)2 (TFMS)
CF3
(1)
ref. 6a, 6c
N
N
A. Influence of acid additives: e.g. Lynch, 1964 (ref. 10)
R = CN, CO2Et, Ac: C2>C3 (CH2Cl2/water)
C3>C2 (DMSO/water)
Ph
9
Ph
(PhCO2)2
R = Bpin, CH2CO2H: C2 only
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N
N
N
Ph
N
Results and Discussion
Experimental Design. In-depth study of the regioselectivity of
the direct alkylation and fluoroalkylation of heteroarenes using
radicals derived from alkylsulfinate salts was initiated, with 1H
NMR spectroscopy employed as the primary tool for both
no additive:
AcOH:
62
80
:
:
38
20
B. Influence of solvent: e.g. Minisci, 1974 (ref. 11)
t-Bu
1
product identification and analysis. The H NMR spectra of
t-Bu
the crude reaction mixtures were exceptionally clean and the
aromatic region typically contained only peaks corresponding
to starting material and the different product regioisomers. As
a result, it was possible to identify products and determine the
regioisomeric ratio from these spectra (Figure 3A). Product
regiochemistry derived from these spectra was supported by
structural assignment after isolation.
solvent
N
N
t-Bu
N
H+
benzene:
water:
71
23
:
:
29
77
C. Influence of functional groups: e.g. Minisci,1986 (ref. 13)
k3 : k2
R
R
R
N
Preliminary studies identified reaction conditions optimal
for regiochemical studies. This entailed limiting the occur-
rence of multiple substitution, which was responsible for the
most significant side products observed at higher conversions,
and which could alter conclusions about primary reactivity and
selectivity. The yields reported below therefore represent in-
tentionally limited values, and not optimized reaction condi-
tions. Temporal profiles of conversion and regioselectivity
were monitored in a number of cases, and regioselectivity was
found to be constant over the course of the reaction (Figures
3B and 3C). A reasonable mass balance was observed in most
cases (Figure 3C). This confirms that selective product degra-
dation that could alter regioselectivity was not significant and
that the experimental protocol provides results that accurately
reflect the regiochemical preferences in each reaction. (Further
experimental details are given in the Supporting Information.)
(PhCO2)2
Cu2+
CN
OMe
Cl
2.8 : 1
1.7 : 1
1.5 : 1
1.1 : 1
0.6 : 1
3
2
Ph
Me
H
N
D. Influence of nature of radical: e.g. Minisci, 1974 (ref. 11)
R
R
water
N
N
R
N
H+
R = Me
R = n-Pr
R = t-Bu
62
58
23
:
:
:
38
42
77
Figure 2. Factors influencing regioselectivity in reports of homo-
lytic substitution reactions of heteroarenes (Refs. 10-18).
Reactivity patterns for alkylsulfinate-derived radicals. As a
first example, we studied the alkylation of 4-substituted pyri-
dines by radicals derived from alkylsulfinate salts. Figure 4A
shows the results of examination of the effect of solvent and
pH on the substitution ratio in the isopropylation of 4-
cyanopyridine, revealing a pattern reminiscent of that previ-
ously observed in Gomberg-Bachmann10 and Minisci8,11-14
chemistry: (i) addition of acid strongly favors reaction at the α
position;20 (ii) changing solvent could affect the regioselectivi-
ty.
Comparison of these literature results with regiochemical
perferences observed in our previous studies using radicals
derived from alkylsulfinate salts6 revealed some of the same
trends as well as some contrasting observations (Equation 1).
Substitution at the α and γ positions of pyridine is generally
preferred, although some C3 substitution was observed on
pyridines with CN, CO2Et or Ac groups at C4. Intriguingly,
however, the ratio of products for these substrates could be
altered to favor either C2 or C3 substitution simply by chang-
ing the solvent.12b, 15b, 19 Pyridines substituted with CH2COOH
or Bpin groups at C4 were fully selective for C2,6c an observa-
tion that could not be explained by steric effects, and is in
contrast to Minisci’s proposal that both electron-donating and
electron-withdrawing groups at C4 stabilize the radical adduct
arising from attack at C3.14a
The influence of functional group on regioselectivity was
probed by determining the C3:C2 ratio in the isopropylation of
C4-substituted pyridines in DMSO (Figure 4B). C3 substituted
products were observed only when a C4 π-conjugating, elec-
tron-withdrawing group was present, with the C3:C2 ratio
roughly corresponding to the electron-withdrawing power of
the functionality, as indicated by σ- values21 for these substitu-
ents.22 The importance of π-conjugation of the electron-
withdrawing group is underlined by the fact that while C3
substitution was observed for the CONH2 derivative, only C2
substitution occurred for the sterically hindered CON(i-Pr)2
Our analysis of the literature underlined the similarity of the
trends in regioselectivity observed in a number of different
radical functionalization systems, but also revealed examples
that were difficult to explain using established knowledge.
These considerations led us to undertake further systematic
group, which cannot act as
a
conjugating electron-
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conjugating electron-withdrawing groups is referred to as
withdrawing group, as it must adopt a conformation orthogo-
1
2
3
nal to the pyridine ring. Non-conjugating groups – such as
phenyl, t-butyl, or strongly σ-withdrawing CF3 – did not give
C3 products, nor did the conjugating π-donating OMe group.
“conjugate reactivity” because of the similarity of favored
regiochemistry to that which would be obtained by a formal
“conjugate” or Michael addition at the pyridine ring.
4
5
6
7
8
9
The electronic reasons for the directing effect is under fur-
ther investigation, but presumably it is due to the ability of the
π-conjugating electron-withdrawing group to stabilize the rad-
ical intermediate arising from attack at the ortho and para
positions. The strong directing effect of π-conjugating elec-
tron-withdrawing groups contrasts with the weak or negligible
directing effect of π-conjugating electron-donating groups
such as OMe, which might also be expected to stabilize the
intermediate radical adduct. This may be attributed to the addi-
tional captodative stabilization of radicals that can be stabi-
lized by both an electron accepting (such as CN), and an elec-
tron donating (the pyridyl nitrogen) group.23
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R1
R1
Zn(SO2R)2, TBHP
solvent, 50 °C
3
2
3
2
R
N
N
regiochemistry?
(A) solvent/pH effect: (R = i-Pr, R1 = CN)
solvent
DMSO
DMF
MeCN
CHCl3/H2O
DMSO/1 eq. H2SO4
C-3 : C-2
4.3 : 1
2.7 : 1
1 : 2.3
1 : 3.0
1 : 3.9
addition of acid
reduces influence of
conjugate reactivity
CHCl3/H2O/excess TFA 1 : 5.0
DMSO/excess H2SO4 1 : 6.6
(B) nature of substituent R1: (R = i-Pr, solvent = DMSO)
σ
R1
π-conjugating EWG
C-3 : C-2
0.66
0.50
0.45
0.43
0.36
4.3 : 1
1.4 : 1
1.3 : 1
1.3 : 1
1 : 4.3
CN
Ac
CO2Me
Bz
CONH2
influence of conjugate
reactivity decreases with
decreasing electrophilicity
of π−conjugating EWG
non π-conjugating EWG and other groups
0.54
-
0.0
-0.01
-0.20
-0.27
C2 only
C2 only
C2 only
C2 only
C2 only
C2 only
CF3
CON(i-Pr)2
H
Ph
t-Bu
no C3 products observed
in the absence of a
π−conjugating EWG
35
1
30
C3 Product
OMe
0.8
C4 product
C5 product
mass balance
25
20
15
10
5
(C) nature of radical R: (R1 = CN, solvent = DMSO)
0.6
0.4
0.2
0
R
C-3 : C-2
4.3 : 1
3.2 : 1
2.5 : 1
2.4 : 1
1 : 1.8
1 : 3.9
i-Pr
CF2H
CF3
CF3 (+ 1 eq. H2SO4)
CF2H (+ 1 eq. H2SO4)
i-Pr (+ 1 eq. H2SO4)
effect of protonation
increases with radical
nucleophilicity
0
20
40
60
80
100
120
Figure 4. Factors controlling the regiochemistry of radical addi-
tion to pyridines. Reagent and conditions: pyridine (0.125 mmol),
zinc sulfinate reagent (1 eq.), TBHP (1.5 eq.), 50 °C, 1.5-2 h. See
Supporting Information for more details.
time (min)
Figure 3. 1H NMR analysis of the crude reaction mixture allowed
ratios of regioisomeric products and starting material to be quanti-
fied (A) and tracked as the reaction progressed (B). The regioiso-
meric ratio remained constant throughout the reaction (C).
As the nucleophilicity of the radical species decreases24 on
moving from i-Pr to CF2H to CF3, the influence of “conjugate
reactivity” also decreases, as indicated by the C3:C2 ratio
(Figure 4C). This effect also correlates with a decreasing in-
fluence of protonation; isopropylation in DMSO showed a
complete reversal of selectivity when acid was added, whereas
the results with CF3 were virtually unchanged. The more nu-
Figure 4 reveals an ortho directing effect of π-conjugating
electron-withdrawing groups at C4, reminiscent of ortho-para
effects suggested by other systems,15 and this pattern was sup-
ported by further screening. For brevity, in Figure 4 and else-
where, this ortho-para directed reactivity induced by π-
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A. Innate reactivity: activated at inherently reactive positions of parent heterocycle
cleophilic i-Pr radical was also more sensitive to solvent
change than either CF3 or CF2H.6a, 6b For i-Pr radical, a striking
regioselectivity switch from reaction strongly favoring C2
substitution to strongly favoring C3 substitution could be ef-
fected simply by changing solvent (Figure 4A). These results
were broadly in line with prior observations.11-14
1
2
3
4
5
6
7
8
innate reactivity at α and γ positions
influence dependent on overall electron density
reactivity accentuated by H+
OMe
CN
N
δ+
The relative nucleophilicity of the free radical is implicated
in the case of the OMe substrate. While the reactivity trends
for the substrates described in Figure 4B for the i-Pr radical
were mostly very similar for the CF3 radical, a significant dif-
ference was observed for OMe, with a C3:C2 ratio of 1:2 ob-
tained for CF3 compared to C2 only for i-Pr. This result may
be rationalized by considering the electrophilic nature of the
CF3 radical. It is known that nucleophilic radicals react well
with protonated pyridines, but do not react with benzene, and
that electrophilic radicals are reactive with arenes, but are un-
reactive with protonated pyridines.25 Extending this concept to
regioselectivity preferences, nucleophilic radicals react at elec-
tron-poor sites and electrophilic radicals react at electron-rich
sites. Thus, the C3 product arises from the CF3 radical inter-
acting with the substrate as an electrophile at this position.
δ+
electron rich
increasingly reactive with nucleophilic radicals
δ+
δ+
δ+
δ+
δ+
N
N
electron poor
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B. Conjugate reactivity: activated at positions in conjugation with a π-EWG
conjugate reactivity ortho-para to π-EWG
influence dependent on solvent
CN
δ+
δ+
δ+
CN
δ+
δ+
δ+
δ+
N
CN
N
N
C. Radical electrophilicity and nucleophilicity: reactivity at δ+ and δ− sites
OMe
CF3
CN
All the alkyl or fluoroalkyl radicals generated from the al-
kylsulfinate salts are to a certain extent nucleophilic, as evi-
denced by their facile reaction with pyridines, but the CF3
radical is the most electrophilic of the examples studied.24
Radical polarity is not always an intrinsic factor, and the be-
havior can vary between nucleophilic, electrophilic or nonpo-
lar depending on the reaction and substrate involved.8 The
nucleophilic i-Pr radical only has useful reactivity when at-
tacking electron-poor sites, but the CF3 radical can give signif-
icant conversion when behaving as either a nucleophile or an
electrophile. As an example, in Langlois’s trifluoromethyla-
tion of electron-rich arenes with CF3SO2Na,26 the CF3 radical
behaved as an electrophile, yet the same reagent behaves as a
nucleophile in the functionalization of pyridines.6a
δ−
δ−
δ+
δ+
N
N
N
σ-withdrawing
π-donor
σ-withdrawing
π-withdrawing
δ+ at C3
δ− at C3
non-polar at C3
unreactive at C3
reacts with electrophilic
radicals at C3
reacts with nucleophilic
radicals at C3
Figure 5. Three major factors controlling regiochemistry of ho-
molytic aromatic substitution of pyridines. Green circles highlight
positions activated to attack by nucleophilic radicals; blue circles
highlight positions activated to attack by electrophilic radicals.
Working model to explain regioselectivity. Although the
mechanisms by which the factors discussed above regulate
regiochemistry are not fully understood, the experimentally
determined patterns in regiochemistry are observed with suffi-
cient consistency to make it possible to devise a set of empiri-
cal guidelines to predict the regioselectivity of substitution.
We present here a simple method for explaining regioselectivi-
ty on heteroarenes that forms the basis of a surprisingly robust
model for predicting reaction outcome.
Innate reactivity (Figure 5A). Pyridines are inherently reactive
with nucleophiles at the α and γ positions, which carry δ+
charge. The relative intensity of this factor appears to be relat-
ed to the total π-electron density of the pyridine: electron-rich
pyridines such as 4-methoxypyridine are less reactive than the
parent pyridine, and electron-poor pyridines such as 4-
cyanopyridine have enhanced reactivity. Protonation of the
pyridine under acidic conditions will reduce the overall π-
electron density of the pyridine ring and therefore increase the
relative intensity of the innate reactivity.
Our model assumes that regioselectivity of substitution is
governed by three major factors (Figure 5): (A) the inherent
reactivity of the parent heterocycle (innate reactivity); (B) the
reactivity induced by the presence of π-conjugating electron-
withdrawing functional groups (“conjugate reactivity”), and
(C) the electronic properties of the radical. In addition, we also
discuss the role of solvent and acid in determining the relative
significance of these factors as well as the importance of a
number of “reactivity-modifying factors.”
Conjugate reactivity (Figure 5B). The presence of π-
conjugating electron-withdrawing groups may be thought of as
inducing δ+ charge at the ortho and para sites, which are cor-
respondingly activated to attack by nucleophilic radicals. The
relative intensity of this factor appears to be related to solvent.
Radical electrophilicity and nucleophilicity (Figure 5C). In the
majority of cases discussed in this paper the radical, whether
trifluoromethyl or isopropyl, behaves as a nucleophile to at-
tack electrophilic (δ+) sites on a heteroarene. Nevertheless,
some issues of regiocontrol are best explained by considering
the relative nucleophilicity of the radical. Trifluoromethyl
radicals are capable of reacting as electrophiles to attack elec-
tron-rich (δ-) positions. This usually occurs where there is an
electron rich benzenoid ring also present in the molecule, as
was previously described for the trifluoromethylation of hy-
droquinine.6a Occasionally this effect is also seen to influence
the regioselectivity on electron deficient heterocycles such as
pyridines. The C3 reactivity of a series of C4 substituted pyri-
Since the alkylsulfinate-derived radicals discussed here pri-
marily react with pyridines as nucleophiles, to an approxima-
tion, the “reactive” sites can be identified by identifying those
sites with partial positive (δ+) charge, highlighted with green
circles in Figure 5 and all subsequent figures.27 However, as
discussed below, in a few cases the trifluoromethyl radical
may also be able to react as an electrophile with δ- sites; these
are highlighted in blue. Circles of different sizes are used to
represent differences in reactivity within the same molecule,
with the larger circle representing the preferred site.
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dines (Figure 4B) illustrates this trend: (i) the π-donating OMe
radical is more strongly affected than the CF3 radical by elec-
group induces δ- charge at C3, and the pyridine is reactive with
CF3 (behaving as an electrophile) at this position; (ii) the π-
withdrawing CN group induces δ+ charge at C3, and the pyri-
dine is reactive with i-Pr and CF3 (behaving as a nucleophile)
at this position; (iii) the σ-withdrawing CF3 group does not
induce significant charge at C3 and the pyridine is effectively
unreactive at this position, despite the CF3 group presumably
being able to stabilize the radical adduct arising from attack at
C3. The consequences of the electrophilicity of trifluorome-
thyl radical will be revisited later when the regioselectivity of
complex structures containing a number of aromatic and het-
eroaromatic rings are considered, but in general, for the vast
majority of small heterocyclic substrates described in this pa-
per, both CF3 and i-Pr radicals show similar regioselectivity
trends. The main difference that is observed is that CF3 is
more reactive than i-Pr with electron-rich pyridines and that i-
Pr radical is more reactive than CF3 radical with the very elec-
tron-deficient diazines.
tronic differences between regioisomeric sites.28
1
2
3
4
5
6
7
8
The reason for the change in influence of innate and conju-
gate reactivity with solvent is unclear. Although it is possible
that some component of the solvent dependence is related to
the differing pKa of a protonated pyridine in different solvents
(pyridine protonation is typically less favorable in DMSO than
in water, for example),29 it is likely that a solvent effect unre-
lated to pKa alters the balance between innate and conjugate
reactivity. Minisci observed that the ratio of C2:C4 substitu-
tion of protonated pyridines showed a distinct solvent effect,11,
9
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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
55
56
57
58
59
60
and it is known that many other radical reactions exhibit
large solvent effects.31 Calculations have also shown that the
nucleophilicity and chemical hardness of a radical can vary
depending on solvent, either of which could impact the bal-
ance between innate and conjugate reactivity.32
A. Influence of acid and solvent on C2:C3 ratio
CHCl3/H2O
DMSO
Solvent and acid effects. Attack on a pyridine by a nucleo-
philic radical may occur at any of the identified δ+ “reactive”
sites. If there are no π-conjugating electron-withdrawing
groups, only the pyridine α and γ positions will be activated. If
there are π-conjugating electron-withdrawing groups present,
the relative strengths of innate and conjugate reactivity will
determine the ratios of products obtained. In chlorinated sol-
vent/water mixtures, the innate reactivity is typically the dom-
inant factor, and reaction primarily occurs at the α and γ posi-
tions, which have higher δ+ charge than the β positions. In
DMSO, the balance between conjugate and innate reactivity is
altered, such that the “effective” δ+ activation felt by the in-
coming radical is greatest at the positions ortho and para to
the π-conjugating electron-withdrawing group; thus reaction
primarily occurs at these sites. In either solvent system, the
addition of acid emphasizes the influence of innate reactivity
to the extent that it exceeds the influence of conjugate reactivi-
ty, even in DMSO (Figure 6A).
CN
CN
N
CN
CN
N
N
N
H+
H+
enhanced
δ+ at C2
more δ+
more δ+
"effectively"
more δ+ at C3
at C2
at C2
C2>>C3
C2>C3
C2>>C3
C3>>C2
B. Reduced sensitivity of C2:C3 ratio to solvent change for CF3 radical
(i) i-Pr radical: nucleophilic
CN
reactive at most
CN
OMe
too electron
rich to be
reactive at δ+
site
δ+ site
reactive at
most δ+ site
N
N
N
H+
unreactive
C2 >> C3
C3 >> C2
~
C2 C3
~
(ii) CF3-radical: less nucleophilic, can behave as electrophile
Using these concepts, the regioselectivity outcomes from
our previous work in alkylsulfinate-derived radical addition to
C4 substituted pyridines (Equation 1)6a-6c that were not initially
straightforward to explain are now easily rationalized. Pyri-
dines with a C4 π-conjugating electron-withdrawing group,
such as Ac, CO2Et or CN, are activated to attack by nucleo-
philic radicals (δ+ charge) at both the C2 and C3 positions,
thereby yielding a regioisomeric mixture. In contrast, the Bpin
or CH2CO2H group do not induce either δ+ or δ- charge at C3,
so the pyridine is unreactive at this position; as a result exclu-
sive C2 substitution is observed.
most reactive
also reactive
reactive as
electrophile at
δ- site
at most δ+ site
at less δ+ site
CN
CN
OMe
N
N
remains
reactive at
electron rich δ+
site
N
H+
most reactive
also reactive
at less δ+ site
at most δ+ site
~
C3 ~ C2
C2 > C3
C3 > C2
Figure 6. Regioselectivity modifying effect of solvent and radical
electrophilicity. Green circles highlight positions activated to
attack by nucleophilic radicals; blue circles highlight positions
activated to attack by electrophilic radicals. The size of the circle
represents relative degree of activation within the same molecule.
The lower susceptibility of CF3 radical to regioselectivity
change induced by π-conjugating electron-withdrawing groups
or protonation can also be rationalized using this model. The
reactivity of the more nucleophilic i-Pr radical can be consid-
ered strongly dependent on the δ+ charge of the reactive site, so
there is high regioselectivity for the most activated site,
whereas the CF3 radical is less dependent on the δ+ charge for
reactivity, and therefore retains more reactivity with the less δ+
activated site (Figure 6B). A possible electronic rationale for
this preference may be extended from a frontier molecular
orbital argument for the increased selectivity of t-butyl radical
relative to methyl radical for reaction with electron-poor 4-
cyanopyridine compared with electron-rich 4-methoxy-
pyridine. The SOMO of the trifluoromethyl radical is lower in
energy than the SOMO of the isopropyl radical, so the SOMO-
LUMO distance is larger for CF3 than i-Pr. As a result, the i-Pr
Reactivity-modifying factors. While the previous section fo-
cused on identifying which sites were capable of reacting, an
important factor in predicting regioselectivity is accurately
assessing the relative reactivity of multiple “activated” sites.
The factors illustrated in Figure 7 and discussed below are
termed “reactivity-modifying” because although they can dis-
criminate between activated (δ+) sites, they cannot in general
give rise to useful levels of reactivity at a position that is not
already activated.
The influence of a variety of functional groups on the reac-
tivity of already activated sites was tested by measuring sub-
stitution patterns in otherwise symmetrical (C4-substituted)
pyridines.C4 substituted pyridines are reactive at C2 under
5
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Page 6 of 14
CHCl3/water conditions that promote innate reactivity. Intro- Predicting the site of radical addition to pyridines. The regi-
1
2
3
4
5
6
7
8
ducing a C3 group allows the effect of this group on the C2:C6
substitution ratio to be determined. Accordingly, methyl, halo-
gen and methoxy groups were found to function as ortho-
activators (Figure 7A). The reason for this is unclear, but pos-
sibly relates to a neighboring functional group being able to
help stabilize a radical intermediate or transition state. Halo-
gen and methoxy also function as meta-deactivators (high-
lighted in red), with the effect being particularly strong at the
pyridine β and γ positions. Again, the reason for this is unclear
but may be due to the π-donor capabilities of these groups.
oselectivity trends described above operated consistently and
reliably across pyridines bearing numerous different functional
groups and substitution patterns. Furthermore, the relative
importance of each factor followed a consistent hierarchy for
each solvent system. Consequently, it is possible to assess
whether a pyridine is likely to be reactive at a desired position
by considering each of the factors above in turn and combin-
ing the activating or deactivating factors. To simplify the
thought process for predicting regioselectivity by considera-
tion of the above factors we have designed a flowchart (Figure
8A, with an example35 illustrated in Figure 8B) which guides
the reader through the relevant factors in order of importance.
9
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
55
56
57
58
59
60
Substitution at C2 has a particularly strong effect on the re-
activity at C6. Electron-withdrawing functionality at C2 typi-
cally shut down reaction at C6, a fact that is well illustrated by
the exclusive production of mono-substituted products in the
trifluoromethylation or difluoromethylation of symmetrical
C4-substituted pyridines (Figure 7B).6c In contrast, attempted
C2 isopropylation in CHCl3/water/TFA resulted in mono-
alkylation being accompanied by concurrent dialkylation; as a
result electron-donating functionality at C2 is proposed to be
activating at C6.33
In Step 1, the innate sites of the heterocycle are identified.
Step 2 considers those sites that are reactive because of their
orientation relative to a π-conjugating electron withdrawing
group. The sites identified in these two steps may be consid-
ered “activated” and are highlighted in green. A further level
of analysis (Step 3) considers other factors that may modify
the reactivity of these “activated sites” but will not usually
alter the regioselectivity preferences of an unactivated site.
These modifying factors may reinforce an existing preference,
or exert a deactivating effect (highlighted in red) on an other-
wise activated site – in this case the “activated” site will have
reduced or negligible reactivity (highlighted in yellow).
A. Me, X, OMe groups: affects reactivity of ortho and meta positions
R
R
π-EWG
OMe
Me
Br
The final level of prediction (Step 4) considers the solvent
system being used for the reaction, and how this affects the
relative importance of innate reactivity (Step 1) and conjugate
reactivity (Step 2). In general, in CHCl3/water or
CH2Cl2/water solvent systems (with or without acid), or in
DMSO/acid the significantly reactive sites are the innate sites
identified in Step 1, and in DMSO (neutral) the significantly
reactive sites are the “conjugate” sites identified in Step 2.
N
N
N
ortho activating
meta-deactivating
ortho-activating
meta-deactivating
ortho-activating
B. C2 substitution: affects reactivity at C6
CO2Et
CO2Et
CO2Et
An example of how this analysis might be used to predict
the regioselectivity is illustrated for the case of methyl 3-
methylpicolinate as shown in Figure 8B (further details of the
regioisomeric ratio of this reaction are given in Figure 10).35
Proceeding through the steps of our model, we find that the
analysis correctly predicts the trend of the C4 product being
preferred in CHCl3/water, and increased preference for C5
reactivity in DMSO.
N
CF3
C2 EWG
N
CF2H
i-Pr
N
i-Pr
C2 EDG
exclusive mono-substitution
C6-deactivating
concurrent mono and di-substitution
C6-activating
C. Sterics: a fairly minor effect for the radicals studied
CN
i-Pr
These guidelines are based upon regioselectivity ratios ob-
tained in reactions with the set of commercially available pyr-
idines tested, but the trends observed have proven to be appli-
cable to unfamiliar substrates and functional groups (vide in-
fra, for example, 43-46 in Figure 12). In general, the predic-
tions of regioselectivity obtained by this method closely
matched the experimental results, although there are some
cases where the predicted values fit less closely, reflecting the
fact that guidelines seeking to be general will necessarily sim-
plify information concerning the relative contributions of dif-
ferent factors. For example, the result shown in Figure 8B
shows that the increased preference for conjugate reactivity in
DMSO for isopropyl radical is not sufficient to fully outweigh
the innate reactivity in the case of this substrate. It is interest-
ing to compare this result with that for the nitrile analog 16
(see Figure 9B). The CN group is a more strongly electron-
withdrawing π-conjugating group than is CO2Me, which en-
hances the influence of conjugate reactivity (see Figure 4B).
Isopropylation of 3-methylpicolinonitrile in DMSO gave an
enhanced preference for the C5 product compared to methyl 3-
methylpicolinate (C5:C4 = 2.6:1 for 16 compared to 1:1 for 3).
N
π-EWG
N
Cl
1
single product by 1H NMR
electronic preference outweighs sterics
para-substitution usually
favored over ortho-substitution
Figure 7. Regioselectivity-modifying effects of functional groups.
Green circles highlight sites activated to nucleophilic attack, red
circles represent a site with a functional group induced deactivat-
ing effect. The size of the circle represents relative degree of acti-
vation/deactivation within the same molecule.
Sterics are known to be a significant factor in Minisci reac-
tions34 but appeared to be a secondary consideration in deter-
mining regiochemistry for the alkylsulfinate-derived radicals
employed in our studies. The preference for para over ortho
substitution in “conjugate reactivity” is attributed to steric
effects, and the bulky i-Pr radical usually had a stronger pref-
erence for para-substitution than CF3 radical. Nevertheless, as
shown in Figure 7C, steric effects did not overturn the regiose-
lectivity preference set by functional groups, even when this
required substitution in a position with steric crowding.
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A. A simple method to predict and control regioselectivity on pyridines
B. Example: methyl 3-methylpicolinate
1
2
3
4
STEP 1: identify innate sites
STEP 2: identify conjugate sites
STEP 1: identify innate sites
innate reactivity
STEP 2: identify conjugate sites
innate reactivity
Me
conjugate reactivity
Me
conjugate reactivity
π-EWG = CN, CO2R, Ac
π-EWG
5
π-EWG
N
CO2Me
N
CO2Me
6
7
activated positions:
ortho-para to conjugating EWG
activated positions:
C2, C4 and C6
π-EWG
N
N
N
N
activated positions:
α and γ
activated positions:
ortho-para to conjugating EWG
8
9
STEP 3: consider factors that modify reactivity of activated sites
C2 EWG
Me
methyl
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
55
56
57
58
59
60
STEP 3: consider factors that modify reactivity of activated sites
Me
halide, alkoxy
C2 EWG
N
CO2Me
activate ortho, deactivate meta
N
CO2Me
X
deactivate C6
X
C2 ester deactivates C6
methyl activates ortho
STEP 4: add effects and decide on conditions
Me
N
N
EWG
N
N
X
N
methyl
C2 EDG
activate C6
Me
activate ortho
Me
N
CO2Me
Me
N
N
N
EDG
promote innate reactivity
reduce conjugate reactivity
reduce innate reactivity
promote conjugate reactivity
STEP 4: add effects and decide on conditions
promote innate reactivity
reduce conjugate reactivity
reduce innate reactivity
solvent + acid
Me
DMSO
Me
promote conjugate reactivity
N
CO2Me
N
CO2Me
solvent + acid
DMSO
innate reactivity promoted
conjugate reactivity promoted
increase reactivity for
electron-rich systems
increase reactivity for
electron-poor systems
predict C4 preferred
predict C5 preferred
using CHCl3/water/TFA:
R
solvent usually CHCl3/water
DMSO/acid mixtures useful for
substrates with limited solubility
Me
R
Me
N
CO2Me
N
CO2Me
activating
influence
deactivating
influence
activated site also
subject to deactivation
CF3 2 (C4 major product)
i-Pr 3 (C4 major product)
CF3 2 (C5 major product)
i-Pr 3 (1:1 C5:C4 products)
Figure 8. Flowchart for the prediction of regioselectivity of alkylsulfinate-derived radical functionalization of pyridines. Color code: green
circles, sites activated to nucleophilic attack; red circles, sites subject to a functional group induced deactivating influence; yellow circles,
otherwise activated sites that have reduced or negligible activity due to substituent-induced deactivation. The size of the circle represents
relative degree of activation within the same molecule. Further examples of regioselectivity prediction are in the Supporting Information.
Testing the model. A selection of substrates used to develop
and test these guidelines is shown in Figure 9. Regioselectivity
was examined with both IPS (i-Pr radical) and TFMS (CF3
radical) to represent both the most nucleophilic and the most
electrophilic from our alkylsulfinate salts. Where a result is
listed for only one radical species or solvent, this usually re-
flects a lack of reactivity, or product instability.36 This study
focused on two different reaction conditions: (i) CHCl3/water
(with the addition of TFA to enhance reactivity for the i-Pr
examples), and (ii) DMSO without addition of acid.37 Typical-
ly CHCl3/water38 solvent gave higher yields for electron-rich
pyridines, and DMSO gave higher yields for electron-poor
pyridines.
yields (albeit with the same general regioselectivity pattern) on
the most electron-rich pyridines (7−9 and 13, Fig 9A) as ex-
pected for a nucleophilic radical; (iv) neither position in 12
(Fig 9B) is very activated under the reaction conditions, result-
ing in low yield and selectivity – the C5 position has little
reactivity when not in DMSO solvent, and the C4 position has
limited reactivity due to the meta-deactivating methoxy group,
even under acidic conditions. Importantly, these results show
that it is possible to predict which substrates are likely to fail
or be reluctant to react.
As described previously, the relative contribution of innate
and conjugate reactivity is dependent on solvent and pH. As a
consequence, in examples where the innate and conjugate
reactivities activate different sites, it is sometimes possible to
tune the reactivity to favor a specific site, simply by changing
solvent, as shown in Figure 10. Note the slightly lower selec-
tivity for C5 over C4 substitution in 29 relative to 18 and 20,
reflecting the absence of a group that meta-deactivates the C4
position.
Particular points of note include: (i) an interesting example
of the meta-deactivating effect of chlorides may be seen by
comparing the unreactive 26 (Fig 9C) with the successful
functionalization of the methyl analogue (15 and 16, Fig 9B);
(ii) methoxy proved to be a stronger ortho-activator than bro-
mide on 10 (Fig 9A), in keeping with the high electronegativi-
ty of oxygen relative to bromine;17 (iii) i-Pr gave very low
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A. Predictable selectivity in CHCl3/H2O or CHCl3/H2O/TFA: innnate reactivity dominates
1
2
3
4
5
6
39%
48% 46%
10
58%
64% 10%
KEY
CO2Me
OMe
Me
1
total yield
Br
1.6
CO2Me
Me
Me
1.5
1.4
1.1
1
1
1
R
R
R
1
R
36%
1
0
6
2
6
2
Me
N
N
N
N
C6 C4
C6 C4 C6 C4
C2 C6 C2 C6
C2 C6
CF3
i-Pr 9
8
ratio
1
1
CF3
i-Pr 6
5
CF3
4
CF3 7
CF3
i-Pr
CF3
i-Pr
CF3
CF3
7
8
9
regioisomer
C4 C5
27%
Me
53%
4
20%
43%
5
4
R
Me
Br
Br
OMe
Br
5
2.3
1
2.1
R
radical
R
R
R
1.3
1
1
1
2
6
2
MeO
N
CO2Me
6
N
N
N
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
55
56
57
58
59
60
C2 C6 C4
C6 C4
C4 C5
C2 C6
CF3
CF3
i-Pr
CF3 10
CF3 11
CF3 13
CF3
i-Pr 12
B. Predictable selectivity in DMSO: conjugate reactivity dominates
30%
1
26%
52%
28% 40%
7
37% 37%
13
5
5
1
1
5
R
Me
CN
R
5
2.6
4
R
R
1
1
MeO
N
CO2Me
1
Me
N
CN
N
Cl
N
CN
1
0
1
0
0
CF3 17
i-Pr 18
CF3 15
i-Pr 16
CF3 19
i-Pr 20
C5 C3
C5 C4 C6 C5 C4
C5 C3 C5 C3
C5 C3 C5 C3
CF3 14
CF3
CF3
i-Pr
CF3
i-Pr
CF3
i-Pr
C. Predict poor reactivity or need for forcing conditions
34%
37%
40% 34%
OMe
1
1
NC
CN
Cl
5
Br
Cl
CO2Me
2.3
1.7
1
R
R
1
0
0
R
N
Cl
N
6
N
Ac
N
CN
N
CO2Me
6
Cl
N
C5 C3
C6 C4
C6 C4 C6 C4
CF3 23
i-Pr 24
CF3 22
CF3 21
25
26
CF3
CF3
i-Pr
27
CF3
Figure 9. Substrates tested to assess combined directing effects on complex pyridines. (For key to highlighting circles see Figures 6 and 7.)
Reagents and conditions: pyridine (0.125 mmol), zinc sulfinate reagent (TFMS or IPS) (2 eq.), TBHP (3 eq.), 50 oC, 12–16 h. See Support-
ing Information for more details.
Extension of regioselectivity trends to diazines. The regiose-
lectivity of radical isopropylation of various functionalized
and unfunctionalized diazines was examined to assess whether
DMSO
CHCl3/H2O/TFA
the functional group-dependent regioselectivity observed in
pyridines could be extended to other heteroarene systems
(Figure 11).39 DMSO was used as solvent to achieve syntheti-
cally useful conversions of products on these substrates. The
pattern observed with the diazines was similar to that for pyri-
dines: (i) the parent heterocycle had an innate regioselectivity
preference for a particular position; (ii) π-conjugating, elec-
tron-withdrawing groups induced a preference for reaction at
the ortho and para-positions, and could allow functionaliza-
tion at otherwise unreactive sites; (iii) halides and methyl
groups did not activate the para position, but did exert an or-
tho-directing effect. The influence of conjugate reactivity on
the innate preference is weaker compared with the pyridines,
and the preference of the functional group typically influ-
enced, but did not override, the innate preference.
conjugate reactivity
innate reactivity
R
Me
Me
R
Me
N
CO2Me
N
CO2Me
N
CO2Me
53%
2
60%
20%
17%
CF3
2
10
i-Pr 3
3
1
1
2.7
1.6
1
1
1
1
0
C4 C6 C5 C4 C6 C5
C4 C6 C5 C4 C6 C5
i-Pr
CF3
CF3
i-Pr
i-Pr
25%
29%
4
10
i-Pr
4
5
2-Acylpyrazine derivatives gave the para-substituted prod-
ucts as a single regioisomer both for isopropyl (33), and the
trifluoromethyl6a and difluoroethyl6d examples reported previ-
ously. Similar regioselectivity effects have also been seen in
Minisci alkylations and acylations of 2-acyl pyrazines.40 Pyri-
dazines had an innate reactivity at the C4/C5 (β) positions.
One of these two activated positions could be favored over the
other with an ortho-directing functional group in the α posi-
tion. The innate reactivity preference was by far the dominant
factor, with even a strongly electron withdrawing nitrile group
(37) having a limited capability to activate the para C6 posi-
tion. Pyrimidines had an innate reactivity for C4, which could
be partially overridden to give significant quantities of the C2
or C5 products with a π-conjugating electron-withdrawing
group in the para-position (cf. 39 with 40; 41 with 42).
1
1
Me
N
CN Me
N
CN
Me
N
CN
C4 C5
C4 C5
i-Pr 28
i-Pr 29
i-Pr
i-Pr
24%
1
28%
3.7
CO2Et
CO2Et
N
CO2Et
slow
Cy
5
1
6
0
Cy
N
CF2H
CF2H
N
CF2H
C6 C5
C6 C5
Cy
30
Cy
31
Figure 10. Tuning regioselectivity with solvent choice. (For key
to highlighting circles see Figures 6 and 7.) Reagents and condi-
tions: standard conditions as previously described. Forcing condi-
tions for compound 30.6c See Supporting Information for details.
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B. Pyridazines:
A. Pyrazines:
1
2
3
4
5
6
7
8
71%
51%
36%
51%
10
4
i-Pr
i-Pr
N
i-Pr
N
N
Ac
i-Pr
1
4
5
CO2Me
2.5
i-Pr
N
N
3.2
N
3
2.4
N
Me
N
i-Pr
N
1
N
CN
N
1
1
0
0
0
N
C4 C5 C6
C3 C5 C6
C4 C5 C6
C3 C4
33 (29%)
C5 only
(<10% isolated)
32 (36%)
i-Pr
34
i-Pr
i-Pr
i-Pr
35
36
37
(11% isolated)
conjugating EWG can direct ortho-para
direction para to
conjugating EWG
innate preference for β (C4/C5)
direction can allow α (C3/C6)
9
C. Pyrimidines:
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
55
56
57
58
59
60
46%
Br
41
29%
5
CO2Et
42%
1.3
40%
30%
i-Pr
i-Pr
1
9
i-Pr
4
i-Pr
1.7
N
N
N
N
N
N
i-Pr
1
1
N
N
N
N
1
2
1
0
0
CN
40
Me
39
C4 C5
C4 C2
C4 C2
C4 C2 C5
C4 C5
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
38
42
(14% isolated)
innate preference for C4
direction can allow C2 or C5
conjugating C2 EWG can direct C5
conjugating C5 EWG can direct C2
Figure 11. Extension of regioselectivity study to diazines: the same general principles apply, although the innate preference of the parent
heterocycle is harder to overcome. (For key to highlighting circles, see Figures 6 and 7.) Reagents and conditions: heterocycle (0.125
mmol), IPS (2 eq.), TBHP (3 eq.), DMSO, 50 °C, 12−16 h. See Supporting Information for more details.
The innate sites of reactivity to radical functionalization for
pyrimidines and pyridazines identified here are not unique to
the alkylsulfinate-derived radical system; the same preferences
have been observed in Minisci-type alkylations and acylations
of diazine substrates.40a, 41
at C2 on the electron-rich pyridine. This illustrates two im-
portant points: (i) the strong preference of the nucleophilic i-Pr
radical to react with the polar, electron-deficient pyridine ring,
instead of the electron-rich pyridine; (ii) the ability to predict
regioselectivity for a molecule bearing the previously unex-
amined amine group, based on the reasoning that this σ-
withdrawing, π-donating functionality should function as an
ortho-activator and meta-deactivator, as do methoxy and hal-
ide functionalities.
Testing on complex biologically active substrates. An im-
portant goal of our predictive model is to demonstrate general-
ity for more complex heteroarenes such as those that might be
encountered in pharmaceutical or agrochemical research. The-
se compounds are often difficult to elaborate due to problems
of solubility, the presence of other reactive functional groups,
or steric crowding. Several small heterocyclic drugs, herbi-
cides, pesticides, and natural products were identified as sub-
strates likely to give good reactivity and regiocontrol based
upon the previously described guidelines. It was intended that
these would provide a simulation of the size and complexity of
the kind of molecules that the alkylsulfinate reagents might be
used to functionalize.
The exclusive regioselectivity of substitution of ethyl β-
carboline-3-carboxylate (46) shows the very strong deactiva-
tion of a pyridine C2 position by a strongly electron-
withdrawing group at C6. The reason for the amine failing to
act as a meta-deactivator, as predicted in this case, is under
further investigation. It is likely that the meta deactivation
effect is dependent on the π-donor capability of the functional
group, and that this is reduced by participation of the nitrogen
lone-pair in the indole system.
Figure 12 shows that isopropylation of these compounds in
DMSO solvent gave products that very closely followed the
expected results. In all cases the predicted product was the
major regioisomer obtained, with a ratio of at least 9:1; in
most cases the reaction was fully selective for the predicted
product.
Voriconazole (47), an anti-fungal medicine, is isopropylated
exclusively at the pyrimidine C4 position. One position is se-
lected over three other open heterocyclic sites α to nitrogen.
The sensitivity of regiocontrol that is possible in radical func-
tionalization processes is underlined by the fact that the C2
position of a pyrimidine is also reactive to radicals. Indeed,
C2 substitution occurred exclusively for fenarimol (47), where
the C4 position is too sterically crowded to react.
The pesticide picolinafen (43) isopropylates exclusively at
C5, closely following the precedent set by simple pyridines 18
and 20. The elucidation of the regioselectivity guidelines fo-
cused on a limited selection of functional groups such as es-
ters, nitriles and methoxy for which a wide variety of disubsti-
tuted pyridines are commercially available, but the trends ob-
served are generalizable to other functional groups in the same
class. Thus the π-conjugating electron-withdrawing amide
group functions as an ortho-para director, and the aryl ether
behaves as an ortho-activator. The exclusive regioselectivity
of radical isopropylation of the herbicide diflufenican (44) is
also explained in this manner, bearing in mind that like the
methoxy group, an aryl ether can function as a meta-
deactivator.
Influence of the electrophilic character of CF3 radical. Our
guidelines for predicting regioselectivity identify the sites on
heteroarenes that are most reactive towards attack by radicals
acting as nucleophiles. This works well for simple het-
eroarenes because despite their different electronic properties,
both trifluoromethyl and isopropyl radicals primarily behave
as nucleophiles when attacking electron-deficient substrates
such as pyridines and diazines. A limitation of this prediction
method may arise when considering more complex structures
with several potentially reactive arenes and heteroarenes. In
these cases, the site of reaction may be dependent on the prop-
erties of both the radical and (hetero)arene. In the examples
shown in Figure 12, the nucleophilic i-Pr radical invariably
reacted with the most electron-deficient ring, whereas regiose-
Nevirapine (45), an anti-retroviral drug, shows 9:1 selectivi-
ty for substitution at C9 on the nicotinamide ring, rather than
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Journal of the American Chemical Society
Page 10 of 14
lectivity for the more electrophilic trifluoromethyl radical was ing with a very reactive trimethoxybenzene, is trifluromethyl-
1
2
3
4
5
6
7
8
more subtly controlled.
ated almost exclusively on the arene. The previously reported
results on differing sites of reactivity for difluoromethylation
and trifluoromethylation of varenicline and dihydroquinine
can be explained by using a similar argument.6b
A. Ability to predict is retained on complex, biologically active substratesa
F
O
Further investigations aim towards predicting the point at
which trifluoromethyl radical will switch from nucleophilic to
electrophilic behavior, but our investigations so far suggest
that the analysis described in Figure 8 generally provides a
good model for predicting the regioselectivity of alkyl-
sulfinate-mediated radical addition to electron-deficient het-
eroarenes. Nevertheless, an important caveat is that when con-
sidering trifluoromethylation of molecules containing elec-
tron-rich arenes, or electron-deficient heterocycles that are
fused to benzenoid or five-membered heteroaromatic rings, the
possibility of the trifluoromethyl radical behaving as an elec-
trophile to attack nucleophilic sites should also be considered.
i-Pr
N
H
N
H
F
F3C
O
N
i-Pr
N
O
O
F
9
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
55
56
57
58
59
60
CF3
25%
18%
picolinafen 43
diflufenican 44
herbicide
pesticide
EtO2C
i-Pr
O
N
Me
NH
Generalization to the borono-Minisci radical arylation. Exam-
ination of substitution patterns in literature examples of homo-
lytic substitution of heteroarenes suggested that the principles
of predicting and controlling regiochemistry for alkylsulfinate-
derived radicals might be generalizable to other radical-
mediated C−H functionalizations. A preliminary study was
undertaken to assess the extent to which the findings in this
report could be generalized to direct arylation of heteroarenes.
i-Pr
N
N
NH
N
28%
51%
nevirapine 45
anti-retroviral drug
ethyl β-carboline-3-carboxylate 46
natural product
Cl
N
OH
N
Arylboronic acids or alkyltrifluoroborates can be used for
the direct functionalization of electron-deficient heteroarenes
via a radical substitution process.42 The observed regiochemis-
try is broadly in line with that for typical for Minisci-type re-
actions (i.e., an overwhelming preference for the α and γ posi-
tions). However, in the “borono-Minisci” arylation42a of heter-
ocycles there were unexplained regiochemical results. The
direct arylation of C4-substituted pyridines gave mixtures of
C2 and C3 products for the 4-cyano and 4-chloro derivatives,
yet the 4-trifluoromethyl and 4-(1,3-dioxolan-2-yl) derivatives
were substituted only at the C2 position (Figure 13A). These
results are understandable based upon the model described
earlier (Figures 5 and 6), noting that aryl radicals are slightly
more nucleophilic than trifluoromethyl radicals, and may also
react as weakly electrophilic or nonpolar species.24
The original reaction conditions42a used a 1:1 CH2Cl2:H2O
solvent in the presence of TFA. By increasing the reaction
temperature from room temperature to 50 °C, we were able to
get appreciable conversions without the presence of acid.
NMR studies of the regioselectivity of direct arylation of 4-
cyanopyridine showed a familiar trend: (i) using DMSO rather
than a chlorinated solvent38 increased the proportion of “con-
jugate reactivity” to give the C3 product; (ii) as seen with CF3,
addition of acid showed only a slight increase in production of
the “innate” C2 product (Figure 13B). The regioselectivity of
arylation of a selection of more complex pyridines were as-
sessed and similar regioselectivity patterns to those found for
alkylsulfinate-derived radicals were observed (Figure 13C).
N
Me
F
OH
i-Pr
Cl
4
N
N
N
N
2
i-Pr
F
57%
21%
voriconazole 47
anti-fungal drug
fenarimol 48
fungicide
(C4 sterically blocked)
B. In the absence of a reactive heterocycle, CF3 may substitute on arenes
F
O
NH2
N
CF3
N
OMe
OMe
H
N
F
F3C
N
O
H2N
OMe
CF3
11%
35%
diflufenican 49a
trimethoprim 50b
herbicide
antibiotic
heterocycle electrophilic
arenes poorly nucleophilic
heterocycle poorly electrophilic
arene nucleophilic
CF3 behaves as nucleophile
CF3 behaves as electrophile
Figure 12. Regioselectivity remains predictable on complex sub-
strates. (For key to highlighting circles see Figures 6-8.) Reagents
and conditions: standard conditions as previously described. All
a
These preliminary results provide a precedent that the regi-
oselectivity guidelines that we developed may be generally
useful for other radical-mediated direct functionalization pro-
cesses, and they show that it may be possible to apply infor-
mation from the solvent dependence of regioselectivity in the
alkylsulfinate system to tune regioselectivity in the functional-
ization of heteroarenes by other types of radicals.
examples gave >9:1 selectivity for the regioisomer shown. D-
MSO solvent. bCHCl3/H2O solvent mixture.
In diflufenican (49) there is a reactive pyridine that com-
petes with the relatively unreactive arenes bearing electron-
withdrawing groups. Thus, trifluoromethylation occurred ex-
clusively at the pyridine C6 position, analogously to the i-Pr
radical. On the other hand, trimethoprim (50), which has an
unreactive, electron-deficient heterocycle (neither amine can
donate electron density to the unsubstituted position) compet-
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Journal of the American Chemical Society
A. Previously unexplained regiochemistry in "borono-Minisci" direct arylation
tionalization processes in modern pharmaceutical and agricul-
tural chemistry.
Ar = C6H4Me
1
O
O
2
3
4
Cl
N
CF3
CN
Supporting Information. Experimental procedures and analyti-
1
cal data for all new compounds, including H, 13C, and 19F NMR
Ar
Ar
N
N
Ar
N
Ar
5
files. This material is available free of charge via the Internet at
C2 only
C2 only
3.2:1 C2:C3
2.7:1 C2:C3
http://pubs.acs.org.
!
6
7
8
9
B. Solvent effects are generalizable to direct arylation
Corresponding!Author!
pbaran@scripps.edu, blackmond.scripps.edu
CN
CN
N
p-MeC6H4B(OH)2
AgNO3, K2S2O8
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
55
56
57
58
59
60
Ar
solvent, 50 °C
ACKNOWLEDGMENT!!
N
"borono-Minisci"
We thank L. Pasternack and D.-H. Huang for NMR spectroscopic
assistance, B. Maryanoff for advice on a draft of this manuscript,
and M. R. Collins (Pfizer), A. G. O’Brien, R. D. Baxter, Y. Ishi-
hara, W. R. Gutekunst and H. Lundberg for advice and useful
discussion. We are grateful to M. R. Collins (Pfizer) and the Yu,
Shenvi and Boger labs for loan of chemicals, and M. Eastgate
(BMS) for samples of nevirapine and diflufenican. Financial sup-
port for this work was provided by US NIH/NIGMS (GM-
073949) and the US-UK Fulbright Commission (postdoctoral
fellowship for F.O.).
solvent
C-3 : C-2
1 : 3.0
1 : 2.8
1 : 1.7
CH2Cl2/H2O/TFA
CH2Cl2/H2O
DMSO/H2O
C. Ability to predict regioselectivity using the same guidelines
DMSO/H2O:
CHCl3/H2O:
Me
12%
1
49%
3
34%
Me
2.4
Br
!
Ar
Me
Ar
1
1
Ar
0
N
CN
N
CO2Me
ABBREVIATIONS!!
N
C5 C3
C4 C6
C2 C6
51
52
53
Bpin,
4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;
DFMS,
Tol
Tol
Tol
bis(((difluoromethyl)sulfinyl)oxy)zinc; DMSO, dimethylsulfox-
ide; EDG, electron-donating group; EWG, electron-withdrawing
group; IPS, bis(((isopropyl)sulfinyl)oxy)zinc; TBHP, tert-butyl
Figure 13. Extension of regioselectivity prediction to “borono-
Minisci” direct arylation. Reagents and conditions: heterocycle
(0.125 mmol), p-tolylboronic acid (1.5 eq.), AgNO3 (20 mol%),
K2S2O8 (3 eq.), 50 °C, 3−16 h.
hydroperoxide;
TFA,
trifluoroacetic
acid;
TFMS,
bis(((trifluoromethyl)sulfinyl)oxy)zinc.
REFERENCES!
(1) For an overview of standard functionalization methods, see
Joule, J. A.; Mills. K. Heterocyclic Chemistry, 5th ed; Wiley: Chich-
ester, 2010.
(2) For some recent examples of SNAr chemistry, see: (a) Chen, Q.;
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Chem. Rev. 2012, 112, 2642-2713.
Conclusions
Factors affecting the regioselectivity of radical functionali-
zation of pyridines were investigated systematically with a
view to understanding, predicting and tuning the regiochemi-
cal outcome. A hierarchical model to rationalize the observed
regioselectivity is proposed based upon experimental results
and literature reports of related reactions. The principles of
this model for regiocontrol have been distilled into a set of
guidelines that summarize the stepwise process for predicting
the regioselectivity of direct C–H functionalization of elec-
tron-deficient heteroarenes using radicals derived from alkyl-
sulfinate salts. An advantage of alkylsulfinate salts as a means
for radical generation compared with more traditional tech-
niques is the facile ability to modify solvent and pH to influ-
ence the regioselectivity of substitution. This empirical model
provides a method of explaining and predicting regiochemistry
that closely fits with experimental observations.
(3) For examples of functionalization via heteroarene metallation,
see: (a) Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel, P.
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man, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926-14927;
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The regioselectivity trends observed for pyridines were rep-
licated for other heteroarenes, including pyrimidines and pyri-
dazines. The results obtained with alkylsulfinate salts corre-
spond with published data describing other radical direct func-
tionalizations of heterocycles, such as Minisci chemistry. The
potential general applicability of these observations was illus-
trated by similar regioselectivity effects with the “borono-
Minisci” radical arylation. The guidelines established for sim-
ple pyridines proved to be equally valid for more complex
heterocyclic drugs and agrochemicals.
Further studies to investigate the regioselectivity principles
described in this report are ongoing and will be reported in due
course. Application of the guidelines described here should aid
in the increased application of radical-mediated direct func-
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(5) For a review on applications of Minisci chemistry in medicinal
by Palla, see reference 12b. Very low yields of selective C3
chemistry see: (a) Duncton, M. A. J. MedChemComm 2011, 2, 1135-
1161. Intramolecular examples of homolytic aromatic substitutions on
heterocycles are more commonly used in synthesis, see for example:
(b) Bowman, W. R.; Storey, J. M. D. Chem. Soc. Rev. 2007, 36, 1803-
1822; (c) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Org. Biomol.
Chem. 2003, 1, 4047-4057.
(6) (a) Ji, Y.; Brückl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.;
Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A.
2011, 108, 14411-14415; (b) Fujiwara, Y.; Dixon, J. A.; Rodriguez,
R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.;
Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494-1497; (c) Fujiwara,
Y.; Dixon, J. A.; O'Hara, F.; Funder, E. D.; Dixon, D. D.; Rodriguez,
R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.; Ishihara, Y.;
Baran, P. S. Nature 2012, 492, 95-99; (d) Zhou, Q.; Ruffoni, A.;
Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. An-
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hara, Y.; Baran, P. S. Nat. Protoc. 2013, 8, 1042-1047.
(7) The zinc sulfinate reagents used in this report, and other related
alkylsulfinate salts, are commercially available from Aldrich, with the
following catalog numbers: TFMS (trifluoromethylation reagent)
771406; DFMS (difluoromethylation reagent) 767840; IPS
(isopropylation reagent) L511161.
(8) For a comprehensive review of the Minisci reaction, which is
the most widely studied system, see: Punta, C.; Minisci, F. Trends
Heterocycl. Chem. 2008, 13, 1-68.
substitution were reported for the reaction of 4-cyanoquinoline with
dioxanyl and α-amidoalkyl radicals generated from solvent. This was
attributed to the CN group activating homolytic substitution more
than the nuclear nitrogen.
(16) For an example of radical methylation of 3-picoline showing a
strong preference for C2 substitution, see: Abramovitch, R. A.; Ke-
naschuk, K. Can. J. Chem. 1967, 45, 509-513.
(17) For an example of substituent effects in the Minisci alkylation
of unsymmetrical 3,6-disubstituted pyridines, see: Cowden, C. J. Org.
Lett. 2003, 5, 4497-4499. The regioselectivity was attributed to a
preference for reaction ortho to the more electronegative substitutent.
(18) Studies into the regioselectivity of radical substitution of
arenes has also shown substituent effects, see: Shelton, J. R.; Uzel-
meier, C. W. J. Am. Chem. Soc. 1966, 88, 5222-5228.
(19) The previous reports describing the production of C3 products
involve altering the means of radical generation to in situ hydrogen
abstraction from a vast excess of solvent. Alkylsulfinate salts may be
1
2
3
4
5
6
7
8
9
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
55
56
57
58
59
60
used to append
a variety of alkyl and fluoroalkyl groups to
heterocycles, including several which would not be plausible to
generate from solvent excess, such as the pharmaceutically valuable
CF3 and CF2H groups.
(20) All the reactions appeared to become acidic during the reac-
tion, and addition of base (calcium carbonate) hindered reaction pro-
gress. Nevertheless, addition of stoichiometric quantities of strong
acid had a significant effect on rate and regioselectivity.
(21) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-
195.
(22) Sterics will also play a role in determining the observed C3:C2
ratio, but this appears to be a relatively minor affect.
(23) (a) Viehe, H. G.; Janousek, Z.; Merényi, R.; Stella, L. Acc.
Chem. Res. 1985, 18, 148-154; (b) Viehe, H. G.; Merényi, R.; Stella,
L.; Janousek, Z. Angew. Chem. Int. Ed. Engl. 1979, 18, 917-932; (c)
we thank a referee for this suggestion.
(9) Brückl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem.
Res. 2012, 45, 826-839.
(10) For an example of use of an acid additive to induce a regio-
chemical preference in Gomberg-Bachmann phenylation of pyridine,
and calculations that showed that this selectivity correlated with the
localization energy, see: (a) Lynch, B. M.; Chang, H. S. Tetrahedron
Lett. 1964, 5, 2965-2968; (b) Dou, H. J. M.; Lynch, B. M. Tetrahe-
dron Lett. 1965, 6, 897-901; (c) Brown, R. D. J. Chem. Soc. 1956,
272-275.
(11) For a study on the solvent effect in the α to γ regioselectivity
of substitution of protonated pyridines for a variety of radicals, see:
Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.; Serravalle, M.;
Giordano, C. J. Org. Chem. 1987, 52, 730-736.
(24) De Vleeschouwer, F.; Van Speybroeck, V.; Waroquier, M.;
Geerlings, P.; De Proft, F. Org. Lett. 2007, 9, 2721-2724.
(25) Minisci, F. In NATO Advanced Research Workshop on
Substituent Effects in Radical Chemistry; Viehe, H. G., Janousek, Z.,
Merényi, R., Eds.; D. Reidel Publishing Company: Louvain-la-Neuve,
Belgium, 1986; Vol. 189, p 391-434.
(12) The more pronounced solvent effect observed for more nucle-
ophilic radicals was attributed to the enhanced contribution from polar
forms of the intermediate radical adduct, see: (a) Minisci, F.; Ber-
nardi, R.; Bertini, F.; Galli, R.; Perchinummo, M. Tetrahedron 1971,
27, 3575-3579; (b) Palla, G. Tetrahedron 1981, 37, 2917-2919.
(13) For a study of the substituent effect on the rate of C2 exclusive
substitution of C4-substituted pyridines, see: (a) Minisci, F.;
Mondelli, R.; Gardini, G. P.; Porta, O. Tetrahedron 1972, 28, 2403-
2413. The rate of C2 substitution of C4-substituted pyridines closely
followed the electron density, with the exception of the OMe and Cl
substrates. This was attributed to the “enhanced electron-releasing
effects” associated with the C4 substituent lone pair interacting with
the pyridine nitrogen, see: (b) Belli, M. L.; Illuminati, G.; Marino, G.
Tetrahedron 1963, 19, 345-355.
(14) For a study of substituent effect on the rate of radical phenyla-
tion of C4 substituted pyridines, see: (a) Minisci, F.; Vismara, E.;
Fontana, F.; Morini, G.; Serravalle, M.; Giordano, C. J. Org. Chem.
1986, 51, 4411-4416. The rate at C3 was generally higher than that at
C2 under neutral conditions, but when protonated, the rate at C2 far
exceeded that at C3. See also a similar result showing that the in-
crease in reactivity of pyridine on protonation is due to enhanced rate
at the C2 and C4 positions, while the rate at C3 shows little change:
(b) Bonnier, J.-M.; Court, J. Compt. Rend. 1967, 265, C, 133-136.
(15) For an observation of an apparent ortho-para directing effect
in the cyclohexylation or dioxanylation of acetyl, ester or cyano sub-
stituted pyridines under neutral conditions, which was attributed to a
preference for reactivity at positions where the unpaired electron can
be delocalized into the substituent for additional stability, see: (a)
Tiecco, M. In NATO Advanced Research Workshop on Substituent
Effects in Radical Chemistry; Viehe, H. G., Janousek, Z., Merényi, R.,
Eds.; D. Reidel Publishing Company: Louvain-la-Neuve, Belgium,
1986; Vol. 189, p 435-442; (b) Chianelli, D.; Testaferri, L.; Tiecco,
M.; Tingoli, M. Tetrahedron 1982, 38, 657-663. For a related result
(26) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett.
1991, 32, 7525-7528.
(27) It is important to note that the δ+ sites identified in this manner
indicate only that the position may be capable of reacting with a nu-
cleophilic radical, not that it must do so. Furthermore, the magnitude
of the δ+ charge on a position does not generally relate to relative
reactivity in any straightforward manner. Simple calculations of
Hückel charges failed to adequately predict regioselectivity, as did
examination of the proton and carbon NMR spectra of substrates.
Although more sophisticated calulations may be able to better model
the reaction, our aim was to provide a method of predicting
regioselectivity and reaction outcome in a quick and simple manner.
(28) (a) Fleming, I. Frontier Orbitals and Organic Chemical
Reactions, 1st ed, Wiley: London, 1976, p. 192-193; (b) Fleming, I.
Molecular Orbitals and Organic Chemical Reactions: Reference
Edition, 1st ed, Wiley: London, 2010, p. 284-285; (c) The ionization
potential of trifluoromethyl radical is reported as 9.05 eV in Asher, R.
L.; Ruscic, B. J. Chem. Phys. 1997, 106, 210-221, corresponding to a
SOMO energy of -9.05 eV. The SOMO energy of a secondary alkyl
radical (s-Bu) is given as -7.4 eV in (a).
(29) Chmurzyński, L. J. Heterocycl. Chem. 2000, 37, 71-74.
(30) Minisci, F.; Vismara, E.; Morini, G.; Fontana, F.; Levi, S.;
Serravalle, M.; Giordano, C. J. Org. Chem. 1986, 51, 476-479.
(31) Litwinienko, G.; Beckwith, A. L. J.; Ingold, K. U. Chem. Soc.
Rev. 2011, 40, 2157-2163.
(32) De Vleeschouwer, F.; Geerlings, P.; Proft, F. Theor. Chem.
Acc. 2012, 131, 1-13.
(33) This does not address the overwhelming preference for
production of 2,5-dialkylated products in DMSO, or the similar
pattern observed under non-protonative conditions by Tiecco and
Testaferri.
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(34) For a clear example of the impact of steric effects on the regi-
oselectivity of the Minisci reaction, see: Pfleger, K.; Fuchs, W.;
Pailer, M. Monatsh. Chem. 1978, 109, 597-602.
Veldhuizen, A. Recl. Trav. Chim. Pays-Bas 1980, 99, 267-270; (g)
Togo, H.; Aoki, M.; Kuramochi, T.; Yokoyama, M. J. Chem. Soc.,
Perkin Trans. 1 1993, 2417-2427; (h) Togo, H.; Ishigami, S.; Fujii,
M.; Ikuma, T.; Yokoyama, M. J. Chem. Soc., Perkin Trans. 1 1994,
2931-2942; (i) Heinisch, G.; Lötsch, G. Heterocycles 1984, 22, 1395-
1402; (j) Danter, W. R.; Lau, C. K.. Compounds and method for the
treatment of cancer. International Patent PCT/CA2008/00229. (k)
Heinisch, G.; Matuszczak, B.; Mereiter, K.; Soder, J. Heterocycles
1995, 41, 1461-1470; (l) Haider, N.; Mavrokordatou, E.; Steinwender,
A. Synth. Commun. 1999, 29, 1577-1584; (m) Ruggiero, A.; Fuchter,
M. J.; Kokas, O. J.; Negru, M.; White, A. J. P.; Haycock, P. R.;
Hoffman, B. M.; Barrett, A. G. M. Tetrahedron 2009, 65, 9690-9693.
(42) (a) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.;
Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132,
13194-13196; (b) Molander, G. A.; Colombel, V.; Braz, V. A. Org.
Lett. 2011, 13, 1852-1855; (c) Singh, P. P.; Aithagani, S. K.; Yadav,
M.; Singh, V. P.; Vishwakarma, R. A. J. Org. Chem. 2013, 78, 2639-
2648; (d) Wang, J.; Wang, S.; Wang, G.; Zhang, J.; Yu, X.-Q. Chem.
Commun. 2012, 48, 11769-11771; (e) Presset, M.; Fleury-Brégot, N.;
Oehlrich, D.; Rombouts, F.; Molander, G. A. J. Org. Chem. 2013, 78,
4615-4619.
1
2
3
4
5
6
7
8
(35) Further examples of the prediction and explanation of
regiochemistry for 1, 11, 12, 15, 16, 17, 18, 28 and 29 may be found
in the Supporting Information.
(36) NMR analysis of the reaction mixture for the 2-chloro
derivatives 1 and 22 both showed only starting material and products
for i-Pr substitution, but when purification was attempted after
workup, numerous products were obtained. It is possible that the 2-
chloro functionality is unstable on silica with electron-rich alkyl
pyridine derivatives.
(37) Although DMSO/H2SO4 had given a promising C2:C3 ratio in
early testing (Figure 3), there was a reduction in yield associated with
removal of DMSO by aqueous washing from small, water soluble
pyridine products. As a result the use of DMSO was limited to cases
where "conjugate reactivity" was specifically needed. The use of
DMSO/acid solvent mixtures may, however, be useful if the molecule
under consideration has poor solubility in chlorinated solvent/water
mixtures.
(38) Chloroform was substituted for dichloromethane to
accommodate the increase in reaction temperature and facilitate NMR
studies. This substitution did not make a significant difference in the
results obtained.
9
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
55
56
57
58
59
60
(39) Trifluoromethyl radical did not show synthetically useful
reactivity with many of these electron-poor diazines; therefore,
although the same regioselectivity trends as described for i-Pr radical
were observed, these results were not reported in this study.
Electrophilic radicals were generally less regioselective for the most
polar (C4) site on pyridazines and pyrimidines, although the same
preference was still followed. Examination of the literature also
showed that, for the limited range of examples showing substitution
of a diazine with a somewhat electrophilic radical, a similar pattern to
that observed with pyridines was seen.
(40) (a) Rao, C. J.; Agosta, W. C. J. Org. Chem. 1994, 59, 2125-
2131; (b) Sato, N.; Kadota, H. J. Heterocycl. Chem. 1992, 29, 1685-
1688; (c) Opletalová, V.; Patel, A.; Boulton, M.; Dundrová, A.;
Lacinová, E.; Převorová, M.; Appeltauerová, M.; Coufalová, M.
Collect. Czech. Chem. Commun. 1996, 61, 1093-1101; (d) Tada, M.;
Totoki, S. J. Heterocycl. Chem. 1988, 25, 1295-1299.
(41) (a) Heinisch, G.; Lötsch, G. Tetrahedron 1985, 41, 1199-
1205; (b) Altenbach, R. J.; Adair, R. M.; Bettencourt, B. M.; Black, L.
A.; Fix-Stenzel, S. R.; Gopalakrishnan, S. M.; Hsieh, G. C.; Liu, H.;
Marsh, K. C.; McPherson, M. J.; Milicic, I.; Miller, T. R.; Vortherms,
T. A.; Warrior, U.; Wetter, J. M.; Wishart, N.; Witte, D. G.; Honore,
P.; Esbenshade, T. A.; Hancock, A. A.; Brioni, J. D.; Cowart, M. D. J.
Med. Chem. 2008, 51, 6571-6580; (c) Sakamoto, T.; Ono, T.; Sakasai,
T.; Yamanaka, H. Chem. Pharm. Bull. 1980, 28, 202-207; (d)
Sakamoto, T.; Sakasai, T.; Yamanaka, H. Chem. Pharm. Bull. 1980,
28, 571-577; (e) Brumfield, M. A.; Agosta, W. C. J. Am. Chem. Soc.
1988, 110, 6790-6794; (f) Kos, N. J.; van der Plas, H. C.; van
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amine deactivates
meta
amide activates
ortho-para
O
O
analyze based on:
9
Me
•
•
•
•
heterocycle
functionality
radical
Me
2
NH
NH
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
55
56
57
58
59
60
9
N
i-Pr
N
N
N
N
N
solvent and pH
e- deficient
pyridine activates
e- rich pyridine
deactivates
>9:1 C9 selectivity
[predictable, regioselective direct C-H functionalization of heterocycles]
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