One-pot iodination of hydroxypyridines

Article abstract of DOI:10.1021/jo900726f

(Chemical Equation Presented) A one-pot, high-yielding iodination of hydroxypyridines and hydroxyquinolines is described. The iodination proceeds under mild conditions, and the products are obtained in high yield without the need for chromatographic purif

Full text of DOI:10.1021/jo900726f

commercially available hydroxypyridines, we reasoned that
suitable activation followed by displacment with iodide would
serve as an attractive method for the construction of both 2-
and 4-iodopyridines. Although several methods exist for the
chlorination8 and bromination9 of hydroxypyridines, to the best
of our knowledge a direct method for the related iodination does
not exist. The most common method involves a two-step
sequence involving chlorination followed by iodide displace-
ment.10 Given the superior reactivity of iodides versus chlorides
and bromides, methods which provide rapid access to iodopy-
ridines and tolerate a wide range of functional groups are
important synthetic tools. Therefore, we set out to develop a
mild, one-pot, high-yielding iodination of 2- and 4-hydroxy-
pyridines. In this paper, we report a general synthesis of 2- and
4-iodopyridines and extend the methodology to the preparation
of both iodoquinolines and iodoisoquinolines.
One-Pot Iodination of Hydroxypyridines
Kevin M. Maloney,* Emily Nwakpuda, Jeffrey T. Kuethe,
and Jingjun Yin
Department of Process Research, Merck & Co., Inc., P.O.
Box 2000, Rahway, New Jersey 07065
keVin_maloney@merck.com
ReceiVed April 6, 2009
Our investigations began with hydroxypyridine 1 as shown
in eq 1. We envisioned that conversion of 1 to a sulfonate ester
would sufficiently activate the hydroxyl group for iodide
displacement under mild conditions.11 Sulfonate esters 2a-c
were prepared in excellent yield by reaction of 1 with the
corresponding sulfonic anhydride (Ms2O, Ts2O, and Tf2O) in
the presence of pyridine.
A one-pot, high-yielding iodination of hydroxypyridines and
hydroxyquinolines is described. The iodination proceeds
under mild conditions, and the products are obtained in high
yield without the need for chromatographic purification. In
addition, the iodination works on both 2- and 4-hydroxypy-
ridines and -hydroxyquinolines.
Iodopyridines are important and valuable intermediates for
the synthesis of both natural products and pharmaceutically
important compounds. Iodopyridines often serve as convenient
precursors for the generation of reactive organometallics such
as organomagnesium and organolithium reagents.1 Alternatively,
iodopyridines and iodoquinolines participate in carbon-carbon,
carbon-oxygen, and carbon-nitrogen bond formation via cross-
coupling reactions such as the Suzuki-Miyaira,2 Negishi,3 and
Buchwald-Hartwig4 reactions. Iodopyridines also undergo
substitution with (trifluoromethyl) copper reagents to give
trifluoromethyl-substituted heterocycles.5 While iodopyridines
are versatile intermediates, their limited commercial availability
requires that they be synthesized from readily available precur-
sors. One of the most common methods for the preparation of
iodopyridines involves lithiation of activated pyridines followed
by quenching with iodine.6 The major disadvantage of this
protocol is that sensitive functional groups are not well tolerated
leading to either competing side reactions or decomposition of
either the starting materials or products.7 Given the wealth of
With 2a,b in hand, efforts were focused on the iodination
reaction as shown in Table 1. For example, reaction of 2a,b
with 5 equiv of sodium iodide in refluxing acetonitrile for up
TABLE 1. Optimization Studies for the Iodination of Pyridine 2
(1) For reviews, see: (a) Schlosser, M. In Organometallics in Synthesis: A
Manual, 2nd ed.; Wiley: Chichester, 2002; pp 1-353. (b) Knochel, P.; Dohle,
W.; Gommermann, N.; Kneisel, F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V.
Angew Chem., Int. Ed. 2003, 42, 4302–4320. (c) Chinchilla, R.; Najera, C.; Yus,
M. Chem. ReV. 2004, 204, 2667–2722.
(2) For a review, see: Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–
2483.
(3) Negishi, A. Acc. Chem. Res. 1982, 15, 340–348.
(4) For reviews, see: (a) Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–
209. (b) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; De Meijere, A., Diederich, F., Eds.; Wiley-VCH: New York, 2004; pp
699-760.
(5) Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2002, 3277–330.
(6) For examples, see: (a) Gros, P.; Fort, Y. Eur. J. Org. Chem. 2002, 3375–
3383. (b) Taylor, S. L.; Lee, D. Y.; Martin, J. C. J. Org. Chem. 1983, 48, 4156–
4158.
a Determined by HPLC analysis.
10.1021/jo900726f CCC: $40.75  2009 American Chemical Society
Published on Web 06/01/2009
J. Org. Chem. 2009, 74, 5111–5114 5111

TABLE 2. One-Pot Iodination of 2-Hydroxypyridines to 2-Iodopyridines
a Isolated yields. b Reactions were carried out at room temperature using 1.1 equiv of concd HCl and 5 equiv of NaI in MeCN. c Reaction was carried
out at room temperature using 1.1 equiv of HCl (2 M solution in Et2O) and 5 equiv of NaI in MeCN. d Reactions were carried out at room temperature
using 1.1 equiv of HCl (2 M solution in Et2O) and 5 equiv of NaI in toluene.
to 24 h only afforded trace amounts (<5%) of the desired iodide
3. In each case, the starting material was recovered virtually
unchanged, despite the presence of the activating cyano group
present in the 3-position of the ring. In an attempt to further
activate the pyridine ring toward nucleophilic displacement, it
was decided to screen the effect of Brønsted acids in the reaction
of 2a with sodium iodide.12 As shown in Table 1, it was
discovered that concd HCl, MsOH, and TfOH led to 3 with
complete conversion when 2 was treated with 1 equiv of acid
in the presence of 5 equiv of NaI at room temperature in
acetonitrile. Interestingly, activation of 2a with TFA resulted
in no detectable reaction, suggesting that the pKa of the acid
employed for activation of the pyridine was crucial for success.13
We also observed that 1 equiv of acid (HCl, MsOH, or TfOH)
was needed for complete conversion. In the presence of less
than 1 equiv, conversion corresponded to the amount of acid
added.14 This confirmed that protonation of the pyridine nitrogen
was in fact activating the C-2 carbon of 2a for subsequent iodide
addition. Unfortunately, mesylate 2b and tosylate 2c were
completely unreactive under these conditions.
Having identified conditions for the iodination of sulfonate
ester 2a, we investigated the possibility of developing a one-
pot procedure for the direct conversion of 1 to 3 (eq 2). It was
discovered that treatment of crude triflate 2a with 5 equiv of
sodium iodide and 1.1 equiv of concd HCl afforded quantitative
conversion to 3 for the one-pot process. The workup of the
reaction involved a simple pH adjustment with 10 M NaOH,
extraction into toluene, and solvent removal to give 3 in 95%
isolated yield and excellent purity15 (>98%) avoiding the need
for further purification by chromatography.16
(7) For a review, see: Schlosser, M.; Mongin, F. Chem. Soc. ReV. 2007, 36,
1161–1172.
(8) See, for example: Sugimoto, O.; Mori, M.; Tanji, K. Tetrahedron Lett.
1999, 40, 7477–7478.
(9) See, for example: (a) Kato, Y.; Okada, S.; Tomimoto, K.; Mase, T.
Tetrahedron Lett. 2001, 42, 4849–4851. (b) Katritzky, A. Org. Prep. Proced.
Int. 1994, 26, 436–444.
(10) See, for example: Schlosser, M.; Cottet, F. Eur. J. Org. Chem. 2002,
4181–4184.
(11) For examples of the two-step transformation of phenols to aryl iodides
via sulfonate esters, see: (a) Wang, Z.; Shangguan, N.; Cusick, J. R.; Williams,
L. J. Synlett 2008, 213–216. (b) McClure, K. F.; Danishefsky, S. J. J. Am. Chem.
Soc. 1993, 115, 6094–6100. (c) Prugh, J. D.; Alberts, A. W.; Deana, A. A.;
Gilfillian, J. L.; Huff, J. W.; Wiggins, J. M. J. Med. Chem. 1990, 33, 758–765.
(12) For examples of Brønsted acid activation of pyridines, see: Comins,
D. L.; Joseph, S. P. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, F. V., McKillop, A., Eds.; Pergamon Press: New
York, 1996; Vol. 5, pp 37-86.
The scope and generality of the one-pot iodination procedure
was next examined. As shown in Table 2, the one-pot iodination
(14) With catalytic acid, the iodination could be pushed to completion with
increased temperature (reflux) and reaction time (>7 days).
(15) Purity determined by HPLC and NMR (1H and 13C) analysis.
(16) Attempts to conduct the one-pot iodination without pyridine were
unsuccessful due to incomplete triflate (2a) formation.
(13) The pKa of 2a was calculated to be-4.7 (pKa calculation program from
Advanced Chemistry Development, Inc., Version 11.01).
5112 J. Org. Chem. Vol. 74, No. 14, 2009

TABLE 3. One-Pot Bromination of Hydroxypyridines
SCHEME 1. Iodination of Hydroxyquinolines
SCHEME 2. Iodination of 4-Hydroxypyridines and
4-Hydroxyquinolines
a Isolated yields. b See ref.9a Reactions were carried out using TBAB
and P2O5 in refluxing toluene (entry 1) or refluxing 1,2-Cl2Ph (entry 2).
one-pot iodination procedure on pyridone 24 afforded iodide
28 in 85% yield. As expected, we were able to extend this
protocol to 4-hydroxyquinolines as demonstrated by the prepa-
ration of iodide 29 in 98% yield. Unfortunately, attempts to
extend this methodology to unhindered pyridones such as
4-hydroxypyridine were unsuccessful due to competing N-
triflation.17
Lastly, we explored the possibility of utilizing a similar
procedure for the bromination of hydroxypyridines. We envi-
sioned that simply replacing sodium iodide with lithium bromide
in our standard protocol would provide an efficient bromination
procedure. Although direct methods exist for the bromination
of hydroxypyridines,9 we felt our methodology would provide
a mild and high-yielding alternative. As shown in Table 3, we
were pleased to find that our modified conditions efficiently
converted pyridones 1 and 14 to the desired bromides 30 and
31 in 98% and 90% yield. This proved to be a substantial
improvement over current methodologies with regard to yield
(90-98% versus 75%) and reaction conditions (room temper-
ature versus 100-180 °C).9a It should also be mentioned that
both TfOH and HCl efficiently promoted the bromination;
however, trace amounts of 2-chloro products were seen in HCl-
promoted reactions.
In conclusion, we have developed an efficient one-pot
procedure for the iodination of hydroxypyridines and hydrox-
yquinolines. The iodination proceeds under mild conditions, and
the products are obtained in high yield without the need for
chromatographic purification. The reaction is also amenable to
large scale applications as exemplified in the Experimental
Section. In addition, the iodination works on both 2- and
4-hydroxypyridines and hydroxyquinolines.
of several electronically and structurally diverse hydroxypy-
ridines afforded the desired iodides in excellent yields. In
general, pyridines bearing electron-deficient groups (entries
1-5) reacted with sodium iodide within 1 h and gave the iodide
products in high yield. On the other hand, reaction of substrates
lacking electron-withdrawing substituents (entries 6-9) proved
sluggish. For example, reaction of the intermediate triflate of
pyridine 14 with sodium iodide in the presence of concd HCl
resulted in the formation of 15 in only 15% yield after 12 h at
room temperature. The mass balance of the reaction was
identified as remaining triflate and 14. Under the reaction
conditions, hydrolysis of the triflate intermediate back to
hydroxypyridine 14 was competitive with iodide displacemnt.
It was speculated that water from the conc. HCl was leading to
the formation of 14 and in order to circumvent this competitive
process, modified reaction conditions were investigated. It was
discovered that replacing acetonitrile with toluene and using
anhydrous acid (anhydrous HCl or TfOH) afforded 15 in 90%
yield. In a similar fashion, reaction of 16, 18, and 20 provided
access to iodides 17, 19, and 21 in 95%, 94%, and 90% yields,
respectively.
Next, we set out to explore the reactivity of hydroxyquino-
lines. As shown in Scheme 1, 2-hydroxyquinoline 22 and
isoquinoline 23 afforded the desired iodides 26 and 27 in 96%
and 97% yield. Interestingly, we noticed that HCl afforded a
mixture of the 2-chloro and 2-iodo products which was not seen
in the related hydroxypyridine cases. However, we found that
replacement of HCl with TfOH completely eliminated the
2-chloroquinoline byproduct.
As shown in Scheme 2, we were also interested in extending
this methodology to 4-hyrdoxypyridines. Historically, the
preparation of 4-iodopyridines has been fairly challenging, often
requiring several synthetic steps.11 However, utilization of our
Experimental Section
Representative Procedure: Preparation of 4-Chloro-3-cyano-2-
iodo-6-methylpyridine (7). A 100-L, three-necked, round-bottomed
flask equipped with a nitrogen inlet adapter, 5-L addition funnel,
thermocouple, and mechanical stirrer was charged with pyridine
(2.48 L, 30.7 mol) and 18 L of MeCN. Pyridone 6 (4.5 kg, 26.7
mol) was added in one portion, and the reaction mixture (brown
slurry) was cooled at 5 °C. Tf2O (4.96 L, 29.4 mol) was then added
via addition funnel over 1.5 h keeping the internal temperature
(17) Giudice, M. R.; Settimj, G. Tetrahedron 1984, 40, 4067–4080.
J. Org. Chem. Vol. 74, No. 14, 2009 5113

1
below 25 °C. After complete addition, the reaction mixture (black
solution) was stirred at 20-25 °C for 30 min and then charged
with NaI in five portions over 15 min keeping the internal
temperature below 40 °C. HCl was then added via addition funnel
over 15 min keeping the internal temperature below 40 °C. The
reaction mixture (orange slurry) was stirred for 1 h and then cooled
to 10 °C. The reaction mixture was diluted with 22.5 L of water
and slowly quenched with 10 M NaOH to reach a pH of ca. 10.
The resulting brown solution was transferred to a 100-L extractor
with the aid of toluene (45 L, 10 vol). The resulting organic layer
was separated and washed with 5% sodium thiosulfate (12 L), 1
M NaOH (12 L), and 20 L of water. The organic layer was dried
(azeotroped with 50 L of toluene) and concentrated to give 7.06
kg (95% yield) of yellow crystals: H NMR (400 MHz, CDCl3) δ
7.73 (s, 1 H), 2.70 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 162.1,
140.5, 131.5, 118.4, 116.7, 116.6, 23.1. Anal. Calcd for C7H4N2ClI:
C, 30.19; H, 1.45; N, 10.06. Found: C, 30.47; H, 1.14; N, 9.90.
Acknowledgment. E.N. was a recipient of an United Negro
Fund/Merck Science Initiative scholarship.
Supporting Information Available: Detailed experimental
procedures, characterization data, and copies of 1H and 13C NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO900726F
5114 J. Org. Chem. Vol. 74, No. 14, 2009