Microwave-assisted trans-halogenation reactions of various chloro-, bromo-, trifluoromethanesulfonyloxy- and nonafluorobutanesulfonyloxy-substituted quinolines, isoquinolines, and pyridines leading to the corresponding iodinated heterocycles

Article abstract of DOI:10.1021/jo9008386

(Chemical Equation Presented) Microwave irradiation of certain chloro-, bromo-, trifluoromethanesulfonyloxy- and nonafluorobutanesulfonyloxy-substituted quinolines in the presence of acetic anhydride and sodium iodide leads, via a trans-halogenation process, to the corresponding iodides in high yield. Related conversions involving pyridines and isoquinolines can also be achieved under similar conditions.

Full text of DOI:10.1021/jo9008386

pyridine could be prepared in quantitative yield by heating its
dichloro-analogue with hydroiodic acid.4 Variations on this sort
of approach have been introduced over the intervening years
wherein the ring nitrogen in pyridines has been activated through
protonation,5 silylation,6 or acylation7 and thereby facilitating
a nucleophilic addition/elimination reaction (SNAr reaction)
involving iodide ion that leads to the target aryl halide.8 The
proton activation approach has been applied to quinolines7,9
although Newkome10 has shown that such conditions can lead
to reductive dehalogenation when very electron-deficient py-
ridines are involved. Nickel- and copper-promoted trans-
halogenation processes have been introduced over the last two
decades11 while, in 2002, Buchwald reported12 a copper-
catalyzed method for the conversion of aryl bromides into the
corresponding iodides. Various relevant extensions of Buch-
wald’s chemistry have since been introduced by his group.13
Despite the useful advances involved, high reaction temperatures
(i.e. >100 °C), extended reactions times (g24 h), and/or strongly
acidic conditions are often required and thus precluding the
application of such techniques to substrates containing sensitive
functionalities.
Microwave-Assisted Trans-Halogenation
Reactions of Various Chloro-, Bromo-,
Trifluoromethanesulfonyloxy- and
Nonafluorobutanesulfonyloxy-Substituted
Quinolines, Isoquinolines, and Pyridines Leading
to the Corresponding Iodinated Heterocycles†
Alex C. Bissember and Martin G. Banwell*
Research School of Chemistry, Institute of AdVanced Studies,
The Australian National UniVersity,
Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
ReceiVed April 23, 2009
In connection with work directed toward the total synthesis
of the alkaloid quinine, we recently reported a short and efficient
synthesis of 4-iodo-6-methoxyquinoline.14 The final step in the
reaction sequence was the trans-halogenation of the correspond-
ing bromide. The best conditions we could establish for effecting
this conversion involved treating a solution of the substrate
bromide in acetonitrile with sodium iodide and acetic anhydride
and then subjecting the resulting mixture to microwave irradia-
tion for 3 h at 80 °C. In this manner the desired iodo-compound
was obtained in 94% yield. Since these sorts of conditions are
much milder and involve shorter reaction times than those
employed in many of the above-mentioned trans-halogenation
protocols, we sought to investigate the scope of this method
Microwave irradiation of certain chloro-, bromo-, trifluo-
romethanesulfonyloxy- and nonafluorobutanesulfonyloxy-
substituted quinolines in the presence of acetic anhydride
and sodium iodide leads, via a trans-halogenation process,
to the corresponding iodides in high yield. Related conver-
sions involving pyridines and isoquinolines can also be
achieved under similar conditions.
The ready participation of aryl iodides in metalation processes
and metal-catalyzed cross-coupling reactions has made them
particularly valuable building blocks in medicinal chemistry,
in materials science, and in total synthesis.1 However, such
compounds are often difficult to obtain, especially if the halogen
is attached to a nitrogen-containing heteroaromatic framework.2
Trans-halogenation protocols (sometimes characterized as aro-
matic Finkelstein reactions) involving a bromo- or chloro-
precursor to the target iodide have been introduced in an effort
to overcome such difficulties although many limitations still
apply.3 In 1947 Bruce demonstrated that a 2,4-di-iodinated
(4) Bruce, W. F.; Perez-Medina, L. A. J. Am. Chem. Soc. 1947, 69, 2571.
(5) See, for example: (a) Camparini, A.; Ponticelli, F.; Tedeschi, P.
J. Heterocycl. Chem. 1977, 14, 435. (b) Newkome, G. R.; Roper, J. M. J.
Organomet. Chem. 1980, 186, 147. (c) Seton, A. W.; Stevens, M. F. G.; Westwell,
A. D. J. Chem. Res. (S) 2001, 546. (d) Liu, J.; Janeba, Z.; Robins, M. J. Org.
Lett. 2004, 6, 2917.
(6) Schlosser, M.; Cottet, F. Eur. J. Org. Chem. 2002, 4181.
(7) See, for example: (a) Corcoran, R. C.; Bang, S. H. Tetrahedron Lett.
1990, 31, 6757. (b) Turner, S. C.; Zhai, H.; Rapoport, H. J. Org. Chem. 2000,
65, 861. (c) Lennox, J. R.; Turner, S. C.; Rapoport, H. J. Org. Chem. 2001, 66,
7078.
(8) In certain instances no activation is required: Klingsberg, E. J. Am. Chem.
Soc. 1950, 72, 1031.
(9) Wolf, C.; Tumambac, G. E.; Villalobos, C. N. Synlett 2003, 1801.
(10) Newkome, G. R.; Moorfield, C. N.; Sabbaghian, B. J. Org. Chem. 1986,
51, 953.
† Strictly speaking, of course, the conversions of the title trifluoromethane-
sulfonyloxy- and nonafluorobutanesulfonyloxy-substituted systems into the
corresponding iodides do not represent trans-halogenation processes, but since
such substrates incorporate pseudohalogens it seems legitimate to apply this term
to these cases as well as those true trans-halogenation processes detailed herein.
(1) See, for example: (a) Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem.
Commun. 2006, 583, and references cited therein. (b) Fu, G. C. Acc. Chem.
Res. 2008, 41, 1555, and references cited therein.
(2) See, for example: (a) Merkushev, E. B. Synthesis 1988, 923. (b) Barluenga,
J.; Gonza´lez, J. M.; Garc´ıa-Mart´ın, M. A.; Campos, P. J.; Asensio, G. J. Org.
Chem. 1993, 58, 2058. (c) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2008,
1487.
(11) (a) Yang, S. H.; Li, C. S.; Cheng, C. H. J. Org. Chem. 1987, 52, 691
(nickel powder-promoted reaction). (b) Clark, J. H.; Jones, C. W. Chem. Commun.
1987, 1409 (alumina or charcoal supported CuI-promoted reaction). (c) Lovell,
J. M.; Joule, J. A. Synth. Commun. 1997, 27, 1209 (copper-bronze-promoted
reaction). (d) Kosaka, Y.; Yamamoto, H. M.; Nakao, A.; Tamura, M.; Kato, R.
J. Am. Chem. Soc. 2007, 129, 3054 (CuI-promoted reaction).
(12) (a) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844.
For an extension of this chemistry to the synthesis of an iodinated quinoline
see: (b) Uchiyama, M.; Furuyama, T.; Kobayashi, M.; Matsumoto, Y.; Tanaka,
K. J. Am. Chem. Soc. 2006, 128, 8404.
(13) (a) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 2890. (b) McNeill, E.; Barder, T. E.; Buchwald, S. L. Org. Lett. 2007, 9,
3785.
(14) Bissember, A. C.; Banwell, M. G. Org. Prep. Proced. Int. 2008, 40,
557.
(3) Smalley, R. K. In Quinolines; Jones, G., Ed.; The Chemistry of
Heterocyclic Compounds, Vol. 32, Part 1; John Wiley & Sons: London, UK,
1977; pp 418-426 and 679.
10.1021/jo9008386 CCC: $40.75  2009 American Chemical Society
Published on Web 05/29/2009
J. Org. Chem. 2009, 74, 4893–4895 4893

TABLE 1. Outcomes of the Trans-Halogenation Reactions of
Certain Substituted Quinolines, Isoquinolines, and Pyridines
for preparing a range of iodinated nitrogen-containing hetero-
cyclic systems. The outcomes of such studies are reported here.
The successful trans-halogenation reactions are presented in
Table 1 and involved treating acetonitrile solutions of quinolines
1, 3, 5, 7, 8, 10, 12, 13, 15, 16, and 17, the isoquinolines 19
and 21, as well as the pyridines 22, 24, 25, and 27 with sodium
iodide and either acetic anhydride or acetyl chloride then
subjecting the resulting mixture to microwave irradiation at 80
°C for the specified period. The substrates used for these studies
were either commercially available or readily prepared by
applying standard procedures to commercially available precur-
sors. The yields of the substrates prepared by such means were
not optimized.
The results presented in Table 1 reveal that quinolines
carrying a leaving group at C-2 and/or C-4 readily engage in
the desired trans-halogenation reaction(s) and thereby afford the
corresponding iodides in generally excellent yield. Significantly,
compounds 5, 7, 10, 16, and 17 carrying potential leaving groups
at C-6, C-7, or C-8 do not undergo iodination at these positions
while additional results presented below also reveal (in keeping
with expectations) a lack of reaction at C-3 and C-5 when these
sites bear halogen substituents. In some instances it was found
that using acetic anhydride as the activating agent (procedure
A) provided better yields of product than when acetyl chloride
was used for the same purpose (procedure B). This situation is
attributed to coproduction of the corresponding aryl chloride
when the latter activating agent was employed. Nevertheless,
there were other cases where the latter procedure proved
superior.
As expected, isoquinolines 19 and 21 carrying a potential
leaving group at C-1 engage in the trans-halogenation reaction
to give iodide 20 in excellent yield. Studies outlined below have
established that C-1 is likely to be the only position on the
isoquinoline framework where such a process can take place.
Pyridines bearing a leaving group at C-2 or C-4 also participate
in trans-halogenation reactions under the specified conditions,
thus affording the anticipated iodinated products in generally
good yield. The origins of the rather poor yield (33%) associated
with the conversion of triflate 22 into iodide 23 remain unclear
but can, seemingly, be addressed by using the corresponding
nonaflate (24) as substrate. A further interesting observation is
that when 1-chloroisoquinoline, rather than isoquinolin-1-yl
trifluoromethanesulfonate (19), was used as the substrate for
the trans-halogenation reaction then the yield of the correspond-
ing iodide was only 45% and this was accompanied by
significant quantities of a byproduct tentatively identified as an
unsymmetrical 1,X′-biisoquinoline.
The success of these reactions is clearly dependent upon the
acylation of the ring-nitrogen and the resulting activation of
the halogenated (or pseudohalogenated) carbon toward a SNAr
reaction involving iodide as nucleophile. To ensure complete
reaction, a 3-fold excess of sodium iodide was employed under
those conditions involving acetic anhydride (procedure A) as
the activating agent. When acetyl chloride was used for the same
purpose (procedure B) then a 10-fold excess of sodium iodide
was used so as to ensure a much higher iodide than chloride
ion concentration in the reaction mixture. It is noteworthy that
in all instances where an isoquinoline or pyridine was a substrate
then the more vigorous conditions defined by procedure B were
required to achieve good conversions into the target iodide.
a The substrates used were either commercially available materials or
readily prepared by conventional methods (see the SI). b Details of
procedures A and B are provided in the SI. c All yields cited are of
isolated and chromatographically purified materials.
conditions defined by procedure A or B. The lack of reaction
of substrate 36 at C-2 is a little surprising given the successful
trans-halogenation of 2-chloropyridine (see entry 17 of Table
1) but clearly attributable to the presence of the C-3 chlorine.
In keeping with expectations, substrates 29-35 all failed to
engage in trans-halogenation reactions when subjected to the
4894 J. Org. Chem. Vol. 74, No. 13, 2009

mg, 3.78 mmol) in acetonitrile (2 mL) maintained at 18 °C. The
ensuing reaction mixture was heated, for 3 h, at 80 °C in a
microwave reactor then cooled and treated with potassium carbonate
(1.5 mL of a 10% aqueous solution), sodium sulfite (1.5 mL of a
5% w/v aqueous solution), sodium thiosulfate (1.5 mL of a saturated
aqueous solution), and dichloromethane (10 mL). The phases were
separated, the aqueous layer was extracted with dichloromethane
(3 × 5 mL), and the combined organic phases were then dried
(MgSO4), filtered, and concentrated under reduced pressure. The
ensuing residue was subjected to flash chromatography.15
Trans-Halogenation Studies: Procedure B. Acetyl chloride
(134 µL, 1.89 mmol) was added to a magnetically stirred suspension
of the appropriate pyridine, quinoline, or isoquinoline (1.26 mmol)
and sodium iodide (1.88 g, 12.6 mmol) in acetonitrile (2 mL)
maintained at 18 °C. The ensuing reaction mixture was heated, for
3 h, at 80 °C in a microwave reactor then cooled and treated with
potassium carbonate (3 mL of a 10% w/v aqueous solution), sodium
sulfite (3 mL of a 5% w/v aqueous solution), sodium thiosulfate (3
mL of a saturated aqueous solution), and dichloromethane (20 mL).
The phases were separated, the aqueous layer was extracted with
dichloromethane (3 × 10 mL), and the combined organic phases
were then dried (MgSO4), filtered, and concentrated under reduced
pressure. The ensuing residue was subjected to flash chromatog-
raphy.15
It seems possible that the two chlorines attached to the pyridine
ring in compound 36 inhibit the initial N-acylation process, thus
precluding trans-halogenation under the conditions we report
here. Of course, steric effects exerted by the two chlorines may
also contribute to the lack of reactivity of compound 36.
We have undertaken a brief investigation of the capacity of
other aromatic nitrogen heterocycles to participate in the title
process but no useful outcomes have been observed. Thus, for
example, attempts to effect trans-halogenation of the com-
mercially available compounds 37 and 38 under either of the
specified conditions have failed and only the starting compounds
were recovered.
4-Iodo-6-methoxyquinoline (2)sFrom Substrate 1 via Proce-
dure A. The previously reported iodide 214 was prepared in 94%
yield from starting material 2 according to procedure A as specified
above and isolated by, flash chromatography, as a colorless,
crystalline solid, mp 126 °C (lit.14 mp 126 °C) (Rf 0.2 in 4:1 v/v
hexane/ethyl acetate). 1H NMR (300 MHz) δ 8.29 (br s, 1H),
7.99-7.89 (complex m, 2H), 7.65 (dd, J ) 9.0 and 2.7 Hz, 1H),
7.21 (d, J ) 9.0 Hz, 1H), 3.95 (s, 3H); 13C NMR (75 MHz) δ
158.9, 146.9, 143.7, 132.4, 131.4, 131.3, 122.9, 110.2, 109.2, 55.4;
IR νmax 3344, 2953, 1617, 1555, 1498, 1452, 1423, 1350, 1264,
1232, 1159, 1028 cm-1; EI-MS m/z 285 (M+•,100%); HRMS m/z
M+• calcd for C10H8127INO 284.9651, found 284.9651. Anal. Calcd
for C10H8INO: C, 42.13; H, 2.83; I, 44.51; N, 4.91. Found: C, 42.45;
H, 3.19; I, 44.22; N, 4.96.
A final aspect of the present investigation was concerned with
establishing if nucleophiles other than iodide could be induced
to participate in SNAr reactions under the conditions developed.
However, upon exposing compound 6 to either acetic anhydride
or acetyl chloride in the presence of various sources of fluoride,
chloride, cyanide, and nitrite anions no evidence for the
formation of the hoped-for substitution products could be
obtained.
The protocols defined here provide a useful means for
effecting the rather rapid trans-halogenation of various chlori-
nated, brominated, or pseudohalogenated quinolines, isoquino-
lines, and pyridines under mild conditions. The reaction
pathways involved mean that the regioselectivities of these
processes are entirely predictable. As such they should find use
in the preparation of a range of iodinated aromatic nitrogen
heterocycles.
Acknowledgment. We thank the Institute of Advanced Studies
at the Australian National University and the Australian Research
Council for generous financial support.
Supporting Information Available: Detailed procedures and
1
full characterization data for all compounds and H and 13C
NMR spectra for compounds 8, 9, 10, 11, 16, 17, 18, 21, and
24 (new compounds). This material is available free of charge
via the Internet at http://pubs.acs.org.
Experimental Section
JO9008386
Trans-Halogenation Studies: Procedure A. Acetic anhydride
(300 µL, 3.15 mmol) was added to a magnetically stirred suspension
of the appropriate quinoline (1.26 mmol) and sodium iodide (565
(15) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
J. Org. Chem. Vol. 74, No. 13, 2009 4895