force for these reactions is the generation of the 2-lithiated
species: by HD in the series 4a-c and directly in the series
23a-b. Recent studies by Collum established the intramo-
lecularity of the AoF rearrangement.7d The classical HD
proceeds via a sequence of intermolecular lithium-halogen
exchange processes.16 As a mechanistic contribution, we
have established intramolecularity for the AoF component
of the present reaction, see SI.
Scheme 3. One-Pot Sequential HD-AoF Reactions
In conclusion, we have demonstrated the first HD process
of isomeric iodo pyridine O-carbamates, compounds that are
readily available by DoM chemistry. The DoM-HD-
electrophile quench sequence (Table 1), as well as subsequent
HD reactions of its products (Table 2), allows access to
diverse tri- and tetra-substituted pyridines that have valuable
functionalities for further manipulation and are difficult to
obtain by alternative available routes.17 In addition, we have
established the first DoM-double HD process of iodo
pyridine 2-O-carbamate (Scheme 2). Finally, we have found
the hitherto unobserved sequential HD-anionic ortho Fries
(AoF) rearrangement of conveniently synthesized DoM-
derived starting materials that lead to continuously substi-
tuted, difficult to access salicylamides (Scheme 3). The
conjunction of DoM-HD-AoF reactions reinforces the
value of DoM protocols, of continued interest in pyridines,18
from which the development and application of further new
synthetic aromatic and heteroaromatic chemistry may be
anticipated. On the basis of the present work, we note that
the HD reaction appears to be fast even at low temperatures
and therefore suggest giving due consideration to the
occurrence of potential HD reactions in the strong base
chemistry of halopyridines as well as haloaromatics.
expectation that the next deprotonation of 4b would be
followed by an AoF process to give the iodo salicylamides
6 (Scheme 3).15 Discouragingly, treatment of 4b with 1.1
equiv of LDA (-78 °C/THF/1 h) at 0.01-0.1 M concentra-
tion gave, in addition to unreacted starting material (23%
yield), deiodinated 3-methoxy N,N-diethyl phenyl O-car-
bamate (48% yield). Surprisingly, under highly concentrated
conditions (0.5 M) a new product was obtained (84% yield)
for which the assignment as 6b or 22 was insecure based on
1H NMR (δ ) 6.50 ppm, dd, 7.67 ppm, dd) and 13C NMR
(δ ) 76.2 ppm, 115.1 ppm) data and comparison with model
compounds (see Supporting Information). The uncertainty
in structural assignment forced an X-ray structure determi-
nation (see Supporting Information), which proved that the
product of the reaction of 4b is 6b, the result of a sequential
HD-AoF rearrangement reaction.
This delightful observation prompted application of similar
reaction conditions to the chloro and fluoro N,N-diethyl O-
carbamates 4a and 4c, which gave the analogous products 6a
and 6c, respectively, in good yields. Interestingly, in contrast
to the HD-AoF product 6b, the products 6a and 6c were
obtained in highest yields under dilute conditions (for X-ray
crystal structure verification as well as optimization and
temperature dependence studies, see Supporting Information).
The availability of dimethylamino and 1,3-dioxanyl N,N-
diethyl O-carbamates 23a and 23b from DoM reactions
allowed determination of 1,3-synergistic OCONEt2-DMG
effects on the AoF rearrangement. Despite the presence of
weak second DMG effects and undoubtedly as a consequence
of the sizeable iodo group that offers a steric enhancement,
23a and 23b underwent smooth AoF rearrangement to afford
the salicylamides 24a and 24b (for X-ray, see Supporting
Information), respectively, in good yields.
Acknowledgment. We are most grateful to NSERC
Canada Discovery Grant Program and the Graduiertenschule
Chemical Biology Konstanz for financial support and
scientific encouragement. We thank Michael Burgert (Uni-
versita¨t Konstanz) for expert X-ray assistance. R.M. is
grateful for a fellowship from the Studienstiftung des
Deutschen Volkes (German National Academic Foundation).
Supporting Information Available: Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
OL100493V
(12) Compatibility of LDA and TMSCl first established by Martin and
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G. J. Chem. Res., Miniprint 1982, 2863. A similar one-pot DoM-HD reaction
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