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

Article abstract of DOI:10.1016/j.tetlet.2009.11.087

A broad survey of aromatic compounds with halogens positioned both ortho and para to activating groups was studied in S_NAr reactions with piperidine. Regioselectivities varied with the substituent group and the polarity of the solvent. Many act

Full text of DOI:10.1016/j.tetlet.2009.11.087

Tetrahedron Letters 51 (2010) 641–644
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Tetrahedron Letters
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Ortho selectivity in SNAr substitutions of 2,4-dihaloaromatic compounds.
Reactions with piperidine
*
Michael D. Wendt , Aaron R. Kunzer
Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064 6101, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A broad survey of aromatic compounds with halogens positioned both ortho and para to activating groups
was studied in SNAr reactions with piperidine. Regioselectivities varied with the substituent group and
the polarity of the solvent. Many activating groups exhibited an overall bias toward ortho-substitution,
and this led in nonpolar solvents to very high ortho selectivity. More polar solvents uniformly shifted
the product ratio toward para substitution. Evidence is presented that argues for coordination via hydro-
gen bonding as a driver of much of the ortho selectivity observed. The data presented show ample evi-
dence of the generality and synthetic utility of the ortho-directing ability of several common activating
groups for this reaction type.
Received 12 October 2009
Revised 16 November 2009
Accepted 20 November 2009
Available online 26 November 2009
Keywords:
SNAr
Regiochemistry
Fluoroaromatic
Regioselectivity
Coordination
Hydrogen bonding
Ó 2009 Elsevier Ltd. All rights reserved.
In the course of our drug discovery work, we recently targeted a
4-amino-substituted-2-fluorobenzoate. We first tried a Buchwald–
Hartwig coupling of piperazine with the 4-bromo-2-fluoroester 1a,
but found that under the reaction conditions, simple SNAr displace-
ment of the fluorine was much faster, and 2a was formed in near-
quantitative yield. Assuming that the corresponding 2,4-dif-
luorobenzoate would result in predominant reaction at the 4-posi-
tion, we ran 1b under identical conditions, minus the palladium
catalyst. However, these conditions again provided a nearly quan-
titative yield of the ortho-product 2b, with only a trace amount of
the product resulting from reaction at the 4-fluorine.
We were unaware of other examples of such high ortho-selec-
tivity in similar substrates. Upon examination of the literature,
we found no examples of esters directing SNAr reactions preferen-
tially ortho, though a few related reactions had been studied. Over
50 years ago, Bunnett and co-workers reported on the ortho-direct-
ing ability of nitro1 and carboxylate2 groups in SNAr reactions with
piperidine. In the former case, they also noted a solvent effect on
the observed regioselectivity, with more polar solvents increasing
the relative amount of para-derived product. They also argued that
the preponderance of ortho product likely arose from more favor-
able electrostatic interactions between the incoming nucleophile
and the directing group, rather than hydrogen bonding.
in fact, we were only able to find a few unequivocal examples con-
cerning nitrobenzenes in the patent literature. Among SNAr reac-
tions in general, several other examples of high ortho/para ratios
exist, but they exclusively concern anionic nucleophiles.3,4 Many
of these involve pentafluoroaromatic substrates, and are largely
confined to the Russian literature.5 There seems, then, to be a
gap in the understanding of both the regioselective outcomes of
this reaction and of the drivers of these outcomes.
We wanted to determine the extent of the generality of the ex-
treme ortho selectivity of reactions exemplified by the one shown
in Figure 1. As there seemed to be no systematic study of the ef-
fects of directing groups on the selectivity profile of amine reac-
tions with 2,4-difluoroaromatic compounds, we decided to look
at the behavior of several substrates in reactions with piperidine.
The collected data from these reactions are shown in Table 1. In
most cases, reaction sets for a given substrate were run at a tem-
perature that allowed complete or nearly complete reaction over
H
N
tBuO2C
tBuO2C
NH
F
N
N
H
DME, K3PO4
90 οC 24 h
X
X
Other cases of amines adding with high regioselectivity to 2,4-
dihaloaromatic or closely related compounds are exceedingly rare;
1
2
1a, 2a X = Br, reaction w/Pd cat.
1b, 2b X = F, reaction w/o Pd cat.
* Corresponding author. Tel.: +1 847 937 9305; fax: +1 847 938 1004.
E-mail address: mike.d.wendt@abbott.com (M.D. Wendt).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.087

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M. D. Wendt, A. R. Kunzer / Tetrahedron Letters 51 (2010) 641–644
Table 1
Reaction of piperidine with 2,4-disubstituted aromatic compounds
EWG
N
H
N
EWG
X
EWG
X
X
N
1.05 eq
+
1.1 eq TEA
X
X = F, Cl, or NO2
the allotted time for the least polar solvent used, unless boiling
point considerations intervened. Reactions were profiled by NMR
spectra of the crude product mixture. Product mixtures were
remarkably clean in all cases; there was virtually no presence of
bis-substitution products or unknown side products. In cases
where reactions did not go to completion, yields are estimated
based on the amount of starting material in the crude product mix-
ture, as determined by NMR integration.
In particular, dipolar aprotic solvents with high polarizability, for
example, DMF and DMSO, favored para substitution much more
than other solvents.6 Similar reaction sets run with other sub-
strates show the same effect, though this is superimposed on the
individual regiochemical preferences of the substrates. There is
no correlation between these regiochemical preferences and the
Hammett values
r
or
r
À.7 However, it is clear that those substrates
which display a strong preference for ortho-substitution in nonpo-
lar solvents (1b, 3–9) all possess functionalities that can coordinate
to the incoming amine, biasing it toward ortho attack via a hydro-
gen bond. Substrates unable to form an attractive interaction with
The collected reactions of the original ester 1b show a clear
relationship between solvent polarity and regioselectivity, with
increasing solvent polarity progressively favoring para reaction.

M. D. Wendt, A. R. Kunzer / Tetrahedron Letters 51 (2010) 641–644
643
the incoming nucleophile (10–15) almost always provide predom-
inantly para-substituted products. In addition, the spread of prod-
uct ratios over a full span of solvent polarities is correspondingly
greater for those substrates that may be expected to provide ener-
getic stabilization to the ortho transition state.
The data for the cyano compounds 10 and 11 seem particularly
instructive in this regard. The electron-rich nitrile functionality is
capable of an electrostatic interaction with the incipient positive
charge on the incoming amine, but is incapable of hydrogen bond-
ing in the transition state, and 10 and 11 show less of an ortho-bias
in nonpolar solvents than those capable of hydrogen bonding; in
fact their selectivities are instead comparable to the pyridine 13
or the bromide 14. On the other hand, if one imagines that the acti-
vating group is required to be still nearer to the incoming piperi-
dine in order to provide meaningful electrostatic stabilization,
then it is difficult to imagine why the two groups would fail to
form a hydrogen bond, given their close proximity and the conse-
quent extremely low entropic barrier to doing so. Thus it seems
reasonable to speak of hydrogen bonding as being operative in
these reactions. Finally, we note that it is unclear as to whether a
hydrogen bonding event takes place before or during the C(2)–N
bond forming process.
Finally, for SNAr additions of anionic nucleophiles, it is generally
accepted that coordination is operative for many directing groups.
Coordination has been implicated in ortho-substitutions of anions
to aromatic compounds, though much of this work has been per-
formed on perfluoroarenes.5 Pentafluoropyridine appears to add
metal salts to the 2-position via coordination in nonpolar solvents;
addition of a crown ether or changing to a polar solvent results in
4-substitution.10 Di-4 and pentafluorobenzoic11 acids are known to
react regioselectively with alkoxides or hydroxide at the ortho po-
sition, even in polar solvents.
The natural tendency to choose polar solvents in which to run
SNAr reactions has no doubt served to at least partially obscure
the ortho-directing ability of some activating substituents, which
may also help to maintain the common assumption among organic
chemists that the para position is normally favored over an ortho
position when a competition between the two is possible. This in
turn is probably based mostly on the correct view that reactions
of pyridines (such as 12 and 13) proceed preferentially at the para
position.12 In addition, quite a bit of work has been reported on the
regioselectivity of pentafluoropyridine13 and other pentafluoroaro-
matic compounds,5,14 which overwhelmingly give para substitu-
tion in the absence of coordination.
It is hoped that the foregoing discussion provides sufficient
rationalization of the observed product data. We also expect that
the data provided should provide guidance as to both the manner
of regioselectivity to be expected in SNAr reactions of amines, and
the ability to choose conditions to maximize the desired regio-
chemical product for reactions of this type.
Additionally, reactions in less polar solvents proceeded more
slowly, as expected. Qualitatively, overall reaction rates seemed
to increase in polar solvents by an amount roughly commensurate
with a rate increase of the para-oriented reaction, in keeping with
the observations of Bunnett and others. Solvent effects on rates of
reactions involving ionic transition states from uncharged sub-
strates are well understood, and are commonly explained as being
driven primarily by an increase in the entropy of activation with
increasing solvent polarity, leading to faster reactions in polar sol-
vents.1,2,8 This is due to more effective solvation of the ionic tran-
sition state compared to the neutral substrate and nucleophile. In
the cases of substrates such as 1b and 3–9, interactions with the
directing group can be thought of as internal, ‘built-in’ solvation
for the ortho transition state. This interaction thus provides a basis
for excellent ortho selectivity in nonpolar solvents, and also re-
duces the capacity for stabilization by polar solvents, so upon
increasing the solvent polarity, the rate of ortho reaction changes
very little, while the rate of reaction at the para center undergoes
a large increase.
For compounds such as 14 and 15, there is still a small shift in
regioselectivity toward the para product in polar solvents, which
can be rationalized as coming from a small steric effect on solva-
tion, or on small differences in charge separation in the ortho and
para transition states. This is again accompanied by a rate increase
for reaction in polar solvents. The other non-pyridyl compounds in
Table 1 will bear more of the transition state negative charge on
their electron-withdrawing substituents, leading to greater charge
separation and a larger potential for transition state stabilization
by polar solvents, which, together with internal stabilization of
the ortho transition state, generates the larger ranges of regioselec-
tivities seen for these compounds.
A comparison of F and Cl as leaving groups (1b vs 4, 8 vs 9, 10 vs
11, 12 vs 13), indicates that Cl tends to favor ortho-substitution rel-
ative to F, albeit by a small amount. In particular, the near 1:1 ratio
of ortho to para products for 13 in dioxane is surprising, given the
general para preference of pyridines. A possible explanation for
this relates to the superior capacity of fluorine substituents to both
increase the susceptibility of the adjacent carbon center toward
nucleophilic attack and to stabilize the negative charge on the ring
of the intermediate structure. This should result in an earlier tran-
sition state for difluoro compounds relative to their dichloro coun-
terparts, and a consequent reduction in the attractive interaction
between directing group and nucleophile in the transition state.
If possible, then, when ortho selectivity is required, employment
of chloride precursors may be warranted if the elevated tempera-
tures necessary for reaction are acceptable.
Acknowledgments
We are grateful to Jeffery Cross for NMR confirmation of struc-
tures, and to Kent Stewart for helpful discussions.
The question of whether ortho-substitution is favored through
electrostatic interactions or through actual coordination via a
hydrogen bond is still not entirely clear. Bunnett argued for the for-
mer, citing a paper disclosing a lack of an isotope effect in the reac-
tion of N-deuteropiperidine with o- and p-chloronitrobenzenes.9
However, this seems an odd result, since there should be a small
positive secondary isotope effect regardless of mechanism. If, in
addition, a hydrogen bond was present in the transition state,
the primary isotope effect relating to the weakening of the N–
H(D) bond should be small and positive, while any effect relating
to the forming NO2–H(D) hydrogen bond would be expected to
be small and negative. It may be that the individual or combined
isotope effects were too small to be measured, but a rate ratio of
1.0 does not seem to argue forcefully for an absence of hydrogen
bonding in the rate-determining step.
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.2009.11.087.
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