Ortho-selectivity in SNAr substitutions of 2,4-dihaloaromatic compounds. Reactions with anionic nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2010.03.124

The nucleophilic addition of organic anions to aromatic compounds with halogens positioned both ortho and para to activating groups was studied in a variety of solvents. Substrates showed strong preferences for ortho substitution in most cases. Evidence is presented for activating group-dependent coordination, which contributes to very high ortho-selectivity in nonpolar solvents. This also drives the overall reaction rate in these solvents, and is of close to the same magnitude of rate increase derived from polar solvents. para-Products are maximized by using crown ethers in protic solvents. Solvent effects overall are very different from corresponding reactions with amine nucleophiles due primarily to the different charges present in the transition states, and to solvation of the nucleophile.

Full text of DOI:10.1016/j.tetlet.2010.03.124

Tetrahedron Letters 51 (2010) 3041–3044
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ortho-selectivity in SNAr substitutions of 2,4-dihaloaromatic compounds.
Reactions with anionic nucleophiles
*
Michael D. Wendt , Aaron R. Kunzer
Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The nucleophilic addition of organic anions to aromatic compounds with halogens positioned both ortho
and para to activating groups was studied in a variety of solvents. Substrates showed strong preferences
for ortho substitution in most cases. Evidence is presented for activating group-dependent coordination,
which contributes to very high ortho-selectivity in nonpolar solvents. This also drives the overall reaction
rate in these solvents, and is of close to the same magnitude of rate increase derived from polar solvents.
para-Products are maximized by using crown ethers in protic solvents. Solvent effects overall are very
different from corresponding reactions with amine nucleophiles due primarily to the different charges
present in the transition states, and to solvation of the nucleophile.
Received 4 March 2010
Revised 29 March 2010
Accepted 30 March 2010
Available online 3 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
We recently reported on a study of regioselectivity in SNAr addi-
tions of amines to activated 2,4-dihaloaromatic compounds.1 We
found that this extremely underutilized reaction displayed strong
ortho-selectivity under most conditions, and that this was almost
certainly driven by a coordination effect. Additionally, the choice
of solvent had a large bearing on regioselectivity, with highly
polarizable solvents such as DMF and DMSO shifting the product
distribution toward the para product. Parallel to this work, we be-
gan to look at the regioselectivity of alkoxides and other anionic
nucleophiles with the same substrates.
Similar to the situation with regard to amine nucleophiles,
examples of SNAr additions of alkoxides or other organic anions
to activated 2,4-dihaloaromatic compounds are surprisingly diffi-
cult to find in the literature.2–6 Additionally, for the majority of
examples it is not clear what selectivity was observed, and most
reports concern additionally substituted ring systems, usually per-
fluoroaromatic compounds,7 which are known to display different
regioselectivities.8 Additionally, there is almost nothing in the way
of studies comparing solvents or activating groups. For these rea-
sons we sought a broader understanding of this reaction.
In the course of our work, it quickly became apparent that,
unsurprisingly, anions do not add as cleanly to the various dihaloa-
renes as do amines. In the latter case, just over 1 equiv of nucleo-
phile assured complete reaction without generating any impurity
due to bis-addition. However, because of the lesser degree of ring
deactivation resulting from the substitution of a single alkoxide,
conditions necessary to completely consume starting material of-
ten resulted in significant amounts of bis-addition product along
with the usual regioisomeric product mixture. For this reason, we
chose to first look at the reactions of methyl 2,4-difluorobenzoate
(1) with exactly 1 equiv of alkali metal methoxides in a variety of
solvents (Table 1).
In keeping with recent results of alkoxide SNAr additions,2 our
data show extraordinary ortho-selectivity for this reaction when
run in either dioxane or toluene. Additionally, the reaction rate
in dioxane, while slower than in DMSO, was surprisingly fast,
and much faster than the reactions run in methanol. This stands
in sharp contrast to the set of reactions we recently described using
piperidine as the nucleophile.1 In that study, rates consistently var-
ied in the order dioxane < alcohol < DMSO. This was a result of
ortho reaction rates remaining roughly constant while para rates
increased dramatically with solvent polarizability, in line with
expectations.9 It has long been known that SNAr rates are faster
in dipolar aprotic solvents such as DMSO than in alcoholic sol-
vents.10 However, nonpolar solvents were for obvious reasons
not usually included in these studies. Moreover, the conclusions
reached were based on studies of reactants with one possible site
of attack; thus the issue of competing coordination-assisted reac-
tion rates did not normally enter into an assessment of rates. The
data here does not offer anything approximating a quantitative
assessment of relative rates; nevertheless it is clear from both Ta-
bles 1 and 2 given below that overall reaction rates for alkoxide
nucleophiles with these substrates increase in the order
alcohol < dioxane < DMSO.
Interestingly, para substitution is favored more by using meth-
anol as a solvent than by using DMSO. This again differs from the
results found with piperidine as a nucleophile,1 but here the tran-
sition state, nucleophile, and leaving group are all anionic, whereas
with amine nucleophiles a zwitterionic transition state derives
from uncharged reactants. For both reaction types highly polariz-
able solvents are most effective at stabilizing the transition states.
* Corresponding author. Tel.: +1 847 937 9305; fax: +1 847 938 1004.
E-mail address: mike.d.wendt@abbott.com (M.D. Wendt).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.124

3042
M. D. Wendt, A. R. Kunzer / Tetrahedron Letters 51 (2010) 3041–3044
Table 1
Solvent dependence of rate and regioselectivity for the reaction of 1 with alkali metal methoxides
CO2Me
F
CO2Me
OMe
CO2Me
F
CO2Me
OMe
1.0 eq MOMe
+
+
F
F
OMe
OMe
1
Reagent
NaOMe
Solvent
Temp/time
Productsa (% of recovered material)
SM
ortho-subst
para-subst
Bis-subst
Toluene
Dioxane
Dioxane
Dioxaneb
MeOH
90 °C 24 h
rt 24 h
90 °C 24 h
90 °C 24 h
rt 24 h
60 °C 24 h
rt 24 h
60 °C 24 h
rt 5 h
12
9
5
17
89
18
78
3
85
91
95
61
3
25
2
8
48
29
74
32
57
91
20
20
3
—
—
18
8
55
20
87
32
44
—
58
29
2
—
—
—
4
—
2
—
2
11
8
—
4
5
—
2
17
MeOH
MeOHb
MeOHb
DMSO
9
DMSOb
Dioxane
MeOH
rt 24 h
19
26
6
9
9
LiOMe
KOMe
90 °C 24 h
70 °C 24 h
90 °C 24 h
90 °C 24 h
70 °C 24 h
90 °C 24 h
DMSO
Dioxane
MeOH
13
31
65
32
DMSO
a
Determined by NMR integration of crude product.
Reaction carried out with 2 equiv of 18-crown-6.
b
In this case, though, the additional factor of the solvation of reac-
tant alkoxides increases dramatically in the order diox-
ane < DMSO < methanol.10 This reactant stabilization provides a
basis for the slower reaction rate in methanol. Additionally, it re-
sults in weaker coordination to the directing group, which further
specifically retards the ortho reaction rate, increasing the relative
amount of para product.
Thus, as coordination of primary or secondary amines occurs via
the amine hydrogen atom and is not destroyed by polar solvents,
the amine hydrogen will coordinate with the available directing
groups regardless of solvent, and para reaction only outcompetes
the coordination-assisted ortho reaction by virtue of a polar sol-
vent-assisted rate increase. However, with alkoxides or other anio-
nic nucleophiles, the ‘carrier’ of coordination is the counterion, and
protic solvents can effectively outcompete directing groups for sol-
vation of the cation. Thus alcohol solvents provide the most para
product by reducing the ortho reaction rate, and thereby also the
overall reaction rate.
The ortho selectivity in dioxane can be eroded to some extent by
the use of 18-crown-6, indicative of the crown ether binding the
Na+ counterion and consequently reducing the importance of the
directing effect of transition state coordination by the ester group.
This is again commensurate with an overall rate decrease. Addi-
tionally, combining 18-crown-6 with polar solvents further in-
creases the relative amount of para product, indicating that
DMSO or even methanol alone does not maximally stabilize the
Na+ cation. Finally, there appears to be a hint of a counterion effect
on the product distribution, with the amount of para product
increasing in the order Li+ < Na+ < K+, as would be expected from
relative solvation energies. Unfortunately, additional experiments
(data not shown) indicate that K+ counterions also tend to promote
the production of bis-substitution products, reducing the attrac-
tiveness of this counterion. The lithium salt, on the other hand, suf-
fered from solubility limitations in dioxane, contributing to a
slower rate of reaction.
reactions were for the most part run with 1.05 equiv of nucleo-
phile. As para products are more difficult to obtain in high yield,
we increased the amount of nucleophile in some cases in an at-
tempt to drive the reactions to completion without producing a
large amount of bis-substitution product.
The data show that ortho products are in general simple to ob-
tain in good yield regardless of the nature of the nucleophile, as
long as the directing group is capable of coordination. Overall,
the dominance of ortho product for a given nucleophile and sol-
vent, particularly dioxane, correlates well with the hydrogen-bond
acceptor strength of the directing group.11 The fully deprotonated
2 produces only a trace of para product under all conditions stud-
ied. Using NaOEt fails to give any product in ethanol either with or
without added crown ether. The more soluble bidentate Mg(OEt)2
does produce ortho product in ethanol, so even in alcoholic solvent,
para product is difficult to access.
The amides 3 and 4 and nitro 5 all display excellent ortho-selec-
tivity in dioxane; 5 does not react cleanly with alkoxides in diox-
ane due to competing reduction.12 Even the benzonitrile 6, which
is unable to maintain coordination with the attacking nucleophile
as it attacks the ortho carbon atom, provides only a small amount
of para product in dioxane. Only the pyridine 7 shows a lack of
ortho-selectivity in dioxane. As in our earlier report, compound 8,
the dichloro version of 7, provides much more ortho product than
its difluoro counterpart in dioxane,1 though this preference once
again disappears in ethanol or dipolar aprotic solvents. The differ-
ence between the two substrates may be due to reduced electron
density in the nitrogen lone pair in 7 due to inductive effects of
the fluorine atoms.
It is difficult to find additional examples of activating groups
that are incapable of coordinating metal ions. It is known that hal-
ogens direct aromatic metallation ortho,13 and recent work has
shown that halogens effectively ortho-direct SNAr alkoxide substi-
tutions.2 We thus chose to look at the trifluoromethyl group. En-
tries 40–43 show that the trifluoromethyl group of 9 provides
relatively poor ortho-selectivity in dioxane, as is expected when
the activating group affords little stabilization of the ortho transi-
With the Table 1 results in hand, we extended the study to in-
clude other activating groups and nucleophiles; these results are
contained in Table 2. Again, we sought to identify trends and con-
ditions that would maximize individual regioisomeric products, so
tion state. Compound
9 also displays a more typical diox-
ane ꢀ alcohol ꢁ DMSO rate progression. Nevertheless, there is

M. D. Wendt, A. R. Kunzer / Tetrahedron Letters 51 (2010) 3041–3044
3043
Table 2
Reactions of anionic nucleophiles with 2,4-disubstituted aromatic compounds
EWG
OR
EWG
OR
EWG
EWG
X
X
OR
X
OR
1.05 eq ROM
+
+
X = F or Cl
X
aDetermined by NMR integration of crude product.
bReaction carried out with 2.0 equiv of nucleophile.
cReaction carried out with 2.0 equiv of 18-crown-6.
dReaction carried out with 1.2 equiv of nucleophile.
eProduct isolated as pyridone.
fReactions followed by LC–MS, substrate evaporates on workup.

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M. D. Wendt, A. R. Kunzer / Tetrahedron Letters 51 (2010) 3041–3044
still a broad range of product ratios, and entry 41, which adds
crown ether to dioxane, indicates that coordination may still play
a small role in the weak ortho-selectivity seen.14
In summary, when coordination to a directing group is possible,
a variety of anionic nucleophiles prefer ortho products more
strongly than amine nucleophiles,1 and it is for this broad substrate
type a simple matter to achieve high regioselectivities and yields if
one is targeting ortho products. In line with recently reported re-
sults,2 we also found that an excess of alkoxide in dioxane did
not result in bis-substitution products and produced outstanding
ortho regioselectivities. In addition, phenoxide and even thiophen-
oxide additions produced excellent results under these conditions.
The difficulty is in achieving good yields and regioselectivities for
para products. Normally, when the nucleophile is a simple alkox-
ide, reactions are run in the corresponding alcohol. While we have
shown here that this is the best choice, we have also shown that
addition of a crown ether can further improve product ratios. Alco-
hol solvents are also amenable to thiol additions, but for these, as
well as for both alkoxides whose conjugate alcohols cannot be em-
ployed as solvent, and other anionic nucleophiles, dipolar aprotic
solvents such as DMSO, or better still, even more powerful solvents
in this class such as HMPA should be used. In spite of this change,
the yields and product ratios are not likely to be as satisfactory as
when one desires ortho product. It is hoped that the data and anal-
ysis presented provide an expectation of the regioselectivity to be
encountered in these reactions, and sufficient background to allow
one to choose conditions to maximize the amount of the desired
regiochemical product.
Overall, reactions with NaOEt produce results similar to those
in Table 1, with ethanol producing the most para product, and 18-
crown-6 further improving the product ratio. Addition of crown
ether to DMSO also shifted ratios toward para products, as in
Table 1, but the result was again inferior to that produced when
the alcohol/18-crown-6 combination was employed (data not
shown). The still more polarizable aprotic solvent HMPA (entries
14 and 29) produces results similar to those with ethanol alone.
While the qualitative shift in product ratios upon changing sol-
vent is entirely consistent and predictable, the degree of the shift
varies between substrates in a manner that does not accord with
the degree of hydrogen bonding capacity, and the maximally
para-favoring product ratios probably reflect additional factors
such as the relative electrophilicity of the relevant ring carbon
atoms, secondary solvent interactions with the directing groups,
and the polarizability and solvent stabilization of the anionic
intermediate structures. Thus, 4, which has a relatively strong
directing group, provides a surprising amount of para product
in ethanol both with and without added crown ether, while the
weaker ortho-directing 5 and 6 evince a smaller shift toward para
products.
For a given substrate, the bias toward ortho products decreases
in the order ROÀ > ArOÀ > ArSÀ. The increasing nucleophilicity of
these anions should dampen the regiochemical preferences as-
serted by the directing groups, and the strongly increasing polariz-
ability across this set makes them progressively less well solvated
by alcohols relative to DMSO. While NaOPh in protic solvents
unfortunately produces mixtures of phenoxide and alkoxide addi-
tion products (data not shown), comparisons of NaSPh additions in
alcohol and DMSO (entries 8, 9, 23 and 24) show similar product
ratios; thus the relative advantage of protic solvents is greatly re-
duced if not completely eliminated for this nucleophile. Still, both
phenoxides and thiophenoxides produce much more para product
in DMSO than in dioxane.
Acknowledgment
We are grateful to Jeffery Cross for NMR confirmation of struc-
tures for compounds.
Supplementary data
Supplementary data (representative procedures and NMR spec-
tra of products) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2010.03.124.
As the pairs of entries 19, 20, 31, and 32 show, the addition of
18-crown-6 to DMSO does not dramatically shift the product ra-
tio toward more para product for phenoxide additions, indicating
that for this anion, DMSO alone may be close to optimally effec-
tive in disrupting transition state coordination. Nevertheless, an
alternate strategy for maximizing para product is to use the more
powerful aprotic solvent HMPA; entry 33 shows a meaningful
improvement in the yield of para product. The fact that crown
ether does not improve the yield of para product for the 6/phen-
oxide combination, while HMPA does, probably indicates that fac-
tors other than transition state coordination are being affected.
HMPA is known to be particularly effective at stabilizing SNAr
intermediate ions; differential stabilization of ortho and para
intermediates or transition states may be responsible for the
additional shift toward para products. We note that in entry 21,
HMPA fails to produce the same effect for the 5/phenoxide
combination.
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