Coupling reactions with haloaromatic amines and alcohols for a practical synthetic route to 2-substituted aminophenyl and hydroxyphenyl pyridines

Article abstract of DOI:10.1016/j.tetlet.2009.09.160

A practical synthetic route to 2-substituted aminophenyl and hydroxyphenyl pyridines has been developed. It has been accomplished by the cross-coupling reactions of readily available 2-pyridylzinc bromides with haloaromatic amines and alcohols under mild

Full text of DOI:10.1016/j.tetlet.2009.09.160

Tetrahedron Letters 50 (2009) 6985–6988
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Tetrahedron Letters
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Coupling reactions with haloaromatic amines and alcohols for a practical
synthetic route to 2-substituted aminophenyl and hydroxyphenyl pyridines
*
Seung-Hoi Kim, Reuben D. Rieke
Rieke Metals, Inc., 1001 Kingbird Rd., Lincoln, NE 68521, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical synthetic route to 2-substituted aminophenyl and hydroxyphenyl pyridines has been devel-
oped. It has been accomplished by the cross-coupling reactions of readily available 2-pyridylzinc bro-
mides with haloaromatic amines and alcohols under mild conditions.
Received 4 September 2009
Revised 24 September 2009
Accepted 25 September 2009
Available online 1 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Recent developments in the preparation methods of 2-pyridyl
derivatives show the significance of their uses especially in natural
product synthesis, pharmaceutical, and material chemistry.1 To
this end, the transition metal-catalyzed cross-coupling reactions
of the corresponding 2-pyridylmetallic reagents have been inten-
sively used in spite of some difficulties such as instability and for-
mation of by-products.2,3
In order to avoid these difficulties of using 2-pyridylmetallic re-
agents, new synthetic methodologies utilizing the direct arylation
of pyridines have been developed.4
In our continuing study on the application of organozinc re-
agents, we found that a stable 2-pyridylzinc bromide was easily
prepared by the direct insertion of highly active zinc into 2-bromo-
pyridine and the subsequent coupling reactions of the resulting
organozinc reagent with several different types of electrophiles
afforded the desired products in good manner. All the coupling
reactions were easily carried out under very mild conditions.5
Including our study, most of the electrophiles used in aforemen-
tioned transition metal-catalyzed cross-coupling reactions of
2-pyridylmetallics contain relatively non-reactive functional
groups toward organometallics, such as ester, ketone, nitrile, halo-
gen, and ether.
For the preparation of a variety of 2-pyridyl derivatives, highly
functionalized electrophiles are necessary as the coupling partner
in the reactions. Here, we have performed the cross-coupling reac-
tions of 2-pyridylzinc bromides with haloaromatic compounds
containing relatively acidic protons. To this end, haloaromatic
amines, phenols, and alcohols are reasonable candidates as cou-
pling reactants. By utilizing this strategy, 2-substituted aminophe-
nyl and hydroxyphenyl pyridines have been successfully prepared
under mild conditions. To our best knowledge, it is the first general
example of the transition metal-catalyzed cross-coupling reactions
of 2-pyridylmetallic reagents providing pyridyl amines and pyridyl
phenols (Scheme 1).6
Since Pd(II)-catalysts along with an appropriate ligand have
been used in the coupling reactions of organozinc reagents with
haloaromatic amines and alcohols,7a it seemed reasonable to try
these conditions in our study. The coupling reactions worked well
with 2-pyridylzinc bromide (1a) and the results are summarized in
Table 1.
The reaction of 1a with 4-iodoaniline in the presence of 1 mol %
Pd(OAc)2 and 2 mol % SPhos gave rise to the cross-coupling prod-
uct, 2a, in 90% isolated yield (Table 1, entry 1). Two more reactions,
methyl substituted 2-pyridylzinc bromide (1c) with 4-iodoaniline
and 1a with 4-bromoaniline resulted in relatively low yields (Table
1, entries 2 and 3). However, a significantly improved yield was ob-
tained by the simple change of reaction temperature (Table 1, en-
try 4). An elevated reaction temperature also worked well for the
reaction of 1c with 3-iodoaniline leading 2c in 85% isolated yield
(Table 1, entry 5). As described in the previous report,7a we also
found that the presence of an extra ligand (SPhos) was critical for
the completion of the coupling reaction.
At this point, even though the similar conditions with the pre-
vious work7a were used, it should be emphasized that a more prac-
tical procedure, especially for the large scale synthesis, has been
demonstrated in our study. For example, the organozinc solution
was added into the flask containing Pd(II)-catalyst, ligand (SPhos)
and electrophile at a steady-stream rate at rt. A very slow addition
or
1% Pd(0)
+
R
X
R
N
ZnBr
Y
Z
1% Pd(II)/2% L
N
Ar
X: I, Br
Y: CH, N
Z: OH, NH2
PCy2
OMe
R: H, CH3, OMe
L;
SPhos
MeO
* Corresponding author.
E-mail address: sales@riekemetals.com (R.D. Rieke).
Scheme 1. Coupling reactions with haloaromatic amines and alcohols.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.160

6986
S.-H. Kim, R. D. Rieke / Tetrahedron Letters 50 (2009) 6985–6988
Table 1
Coupling reaction with haloanilines
X
conditions
THF
NH2
X
+
Y
N
ZnBr
NH2
Y : I, Br
0.8eq
N
X : H, CH3, MeO
1.0 eq
Entry
1
X
Y
Conditionsa
Product
Yieldb (%)
90
NH2
H(1a)
4-l
A
A
N
2a
H3C
2b
NH2
2
4-CH3(1c)
4-l
50
N
2a
3
4
H(1a)
4-Br
4-Br
A
B
2a
50
89
H(1a)
2a
H3C
NH2
2c
5
4-CH3(1c)
3-l
B
85
N
2a
6
7
H(1a)
H(1a)
4-l
3-l
C
C
2a
89
64
NH2
2d
N
N
H2N
8
H(1a)
2-l
C
74
2e
CH3
9
3-CH3(1b)
4-l
D
D
68
2f
NH2
N
NH2
2g
10
6-OMe(1d)
4-Br
Tracec
N
MeO
a
b
c
A: 1% Pd(OAc)2/2% SPhos/rt/24 h; B: 1% Pd(OAc)2/2% SPhos/reflux/24 h; C: 1% Pd[P(Ph)3]4/rt/24 h; D: 1% Pd[P(Ph)3]4/reflux/24 h.
Isolated yield (based on aniline).
By GC–MS.
of organozinc reagent into the reaction flask was crucial in order to
obtain high yields.8
try 9) was achieved from a sterically hindered 3-methyl-2-pyridyl-
zinc bromide (1b), resulting in 68% isolated yield with the
formation of 2f. Unfortunately, no satisfactory coupling reaction
occurred with 4-bromoaniline using the Pd(0)-catalyst (Table 1,
entry 10).
Interestingly, unsymmetrical amino-bipyridines were produced
from the coupling reactions of 2-pyridylzinc bromides with halo-
genated aminopyridines under the conditions used above.10 As
shown in Scheme 2, 2-amino-5-iodopyridine reacted with 1a to af-
ford 2,3-bipyridine (3a) in 59% isolated yield in the presence of
Pd[P(Ph)3]4 (1 mol %) catalyst. However, in the case of 2-amino-
5-bromo-pyridine, the Pd(II)-catalyst was more useful for the
coupling reaction and the reaction proceeded smoothly to give
2,3-bipyridine (3b) in 37% yield (B, Scheme 2). It is of interest that
the bipyridyl amines can be used as intermediates for the synthesis
of highly functionalized molecules after transformation of the ami-
no group to a halogen.11
As mentioned above, the extra ligand (SPhos) was necessary
when using the Pd(II)-catalysts for the coupling reactions in our
study as well as others. From an economic point of view as well
as ease of work-up, a ligand-free reaction conditions would be
highly beneficial. Thus, with the preliminary results (Table 1, en-
tries 1–5) in hand, we have investigated the SPhos-free Pd-cata-
lyzed coupling reactions of 2-pyridylzinc bromides with
haloanilines. They were performed by employing a Pd(0)-catalyst
and the results are summarized in Table 1. Significantly, the
Pd(0)-catalyzed coupling reactions were not affected by the pres-
ence of acidic protons (NH2).9
The reaction of 1a with 4-iodoaniline in the presence of 1 mol %
Pd[P(Ph)3]4 provided 2-(4-aminophenyl)pyridine (2a) with a com-
patible result (Table 1, 89% isolated yield, entry 6). 3-Iodoaniline
and 2-iodoaniline were also coupled with 1a under the same con-
ditions (condition C, Table 1) affording the aminophenyl pyridines
(2d and 2e) in 64% and 74% isolated yields, respectively (Table 1,
entries 7 and 8). Another successful coupling reaction (Table 1, en-
With the results obtained from the coupling reactions with
haloaromatic amines, it can be concluded that Pd(0)-catalyzed
reaction of 2-pyridylzinc bromides works effectively with iodoaro-

S.-H. Kim, R. D. Rieke / Tetrahedron Letters 50 (2009) 6985–6988
6987
an acidic proton. Encouraged by the results described above, the
coupling reactions with iodophenols were carried out in the pres-
ence of Pd(0)-catalyst.
I
1% Pd[P(Ph)3]4
N
+
A:
B:
THF/reflux/24h
59%
N
ZnBr
N
NH2
3a
As shown in Table 2, 4-iodophenol and 3-iodophenol were cou-
pled with 1a affording the corresponding hydroxyphenyl pyridine
products (4a and 4b) in excellent yields (Table 2, entries 1 and 2).
A slightly disappointing result (25%) was obtained from 2-iodophe-
nol (Table 2, entry 3). The reason is not clear, but it is presumably be-
cause the coupling was next to the hydroxy group. A similar
outcome has also been reported in another study.12 In the case of
bromophenolic alcohols, no coupling reaction took place with the
Pd(0)-catalyst. Instead, the Pd(II)-catalyst was more efficient for
the coupling reaction. 4-Bromophenol and 6-bromo-2-naphthol
were nicely coupled with 1a resulting in the coupling products (4a
and 4e) in 86% and 92% (Table 2, entries 5 and 6). Unlike the reactions
with bromophenols, it is of interest that the coupling products (4f
and 4g) of 1d and 1a were efficiently achieved from the Pd(0)-cata-
lyzed reactions with 4-bromobenzyl alcohol and 3-bromo-5-
methoxybenzyl alcohol (Table 2, entries 7 and 8), respectively.
N
NH2
1a,1.0eq
0.8eq
CH3
CH3
Br
1% Pd(OAc)2/2% L
THF/reflux/24h
37%
+
N
N
ZnBr
N
NH2
N
NH2
3b
1c,1.0eq
0.8eq
Scheme 2. Preparation of aminobipyridine.
matic amines and also the relatively more reactive bromoaromatic
amines.
Another interesting reaction of 2-pyridylzinc bromides would
be the coupling reaction with phenols or alcohols, which also have
Table 2
Coupling reaction with haloaromatic alcohols
conditions
X
+
Haloalcohol
0.5eq
Ar OH
THF/reflux/24h
N
ZnBr
X
N
1.0 eq
Entry
1
X
Alcohol
Conditionsa
Product
Yieldb (%)
I
H(1a)
I
95
4a
N
OH
OH
OH
I
OH
2
3
H(1a)
H(1a)
I
I
80
25
N
4b
OH
OH
I
N
4c
CH3
I
4
5
4-CH3(1b)
H(1a)
I
54
4d
N
OH
OH
Br
I
4a
0c
OH
II
86
Br
Br
Br
6
7
H(1a)
II
I
92
60
N
4e
OH
OH
6-CH3(1d)
4f
H3C
N
OH
OH
OH
N
OH
8
H(1a)
I
65
OCH3
OCH3
4g
a
b
c
I: 1% Pd[P(Ph)3]4; II: 1% Pd(OAc)2/2% SPhos.
Isolated yield (based on alcohol).
No coupling observed by GC.

6988
S.-H. Kim, R. D. Rieke / Tetrahedron Letters 50 (2009) 6985–6988
2. For selective examples for Suzuki: (a) Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.;
OH
Kurihara, H.; Dreher, S. D.; Weissman, S. A.; Stauffer, S. R.; Burgey, C. S. Org. Lett.
2009, 11, 345; (b) Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.; Li, G. Y.; Shen, H.
C. Org. Lett. 2009, 11, 381; (c) Voisin-Chiret, A. S.; Bouillon, A.; Burzicki, G.;
Celant, M.; Legay, R.; El-Kashef, H.; Rault, S. Tetrahedron 2009, 65, 607; (d)
Billingsley, K. L.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 4695; For Stille:
(e) Schwab, P. F. H.; Fleischer, F.; Michl, J. J. Org. Chem. 2002, 67, 443; (f) Zhang,
N.; Thomas, L.; Wu, B. J. Org. Chem. 2001, 66, 1500; (g) Schubert, U. C.;
Eschbaumer, C.; Heller, M. Org. Lett. 2000, 2, 3373; For Grignard: (h) Sugimoto,
O.; Yamada, S.; Tanji, K. J. Org. Chem. 2003, 68, 2054; (i) Song, J. J.; Yee, N. K.;
Tan, Z.; Xu, J.; Kapadia, S. R.; Senanayake, C. H. Org. Lett. 2004, 6, 4905; (j) Duan,
X.-F.; Ma, Z.-Q.; Zhang, F.; Zhang, Z.-B. J. Org. Chem. 2009, 74, 939; For Negishi:
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Lutzen, A.; Hapke, M.; Staats, H.; Bunzen, J. Eur. J. Org. Chem. 2003, 3948.
3. For more examples of the coupling reactions of 2-pyridylmetallics, see: Li, J. J.;
Gribble, G. W. Palladium in Heterocyclic Chemistry, 2nd ed.; Elsevier, 2006.
4. (a) Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2008, 130, 14926; (b) Li, M.; Hua, R. Tetrahedron Lett. 2009, 50, 1478; (c) Cho, S.
H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254; (d) Campeau, L.-C.;
Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020; (e) Andersson, H.;
Almqvist, F.; Olsson, R. Org. Lett. 2007, 9, 1335.
+
1% Pd[P(Ph)3]4
N
N
ZnBr
Br
N
THF/reflux/24h
51%
N
OH
1a,1.0eq
0.5eq
5a
Scheme 3. Preparation of hydroxy 2,20-bipyridine.
Treatment of 2-pyridylzinc bromide with a halopyridine bear-
ing a hydroxyl group provided another functionalized bipyridine.
Interestingly, the relatively reactive bromopyridyl alcohol, 2-bro-
mo-5-hydroxypyridine, was coupled with 1a using Pd(0)-catalyst.
As a result, the corresponding hydroxyl 2,20-bipyridine (5a) was
obtained in 51% isolated yield (Scheme 3). The hydroxyl group on
2,20-bipyridine can also be converted to halogen to make halobi-
pyridines by using several different methods.13
In conclusion, a practical synthetic procedure for the prepara-
tion of 2-substituted aminophenyl and hydroxyphenyl pyridines
has been demonstrated utilizing readily available 2-pyridylzinc
bromides with haloaromatic amines, phenols, and alcohols. Reac-
tions have been carried out in the presence of either a Pd(0)-cata-
lyst or a Pd(II)-catalyst under mild conditions. Further applications
of 2-pyridylzinc bromides are currently under way.
5. Kim, S.-H.; Rieke, R. D. Tetrahedron Lett. 2009, 50, 5329.
6. For an example of the coupling reaction of 2-pyridylzinc bromide with
bromoaromatic amine, see: Charifson, P. S.; Grillot, A.-L.; Grossman, T. H.;
Parsons, J. D.; Badia, M.; Bellon, S.; Deininger, D. D.; Drumm, J. E.; Gross, C. H.;
LeTiran, A.; Liao, Y.; Mani, N.; Nicolau, D. P.; Perola, E.; Ronkin, S.; Shannon, D.;
Swenson, L. L.; Tang, Q.; Tessier, P. R.; Tian, S.-K.; Trudeau, M.; Wang, T.; Wei,
Y.; Zhang, H.; Stamos, D. J. Med. Chem. 2005, 51, 5243.
7. (a) Manolikakes, G.; Schade, M. A.; Hernandez, C. M.; Mayr, H.; Knochel, P. Org.
Lett. 2008, 10, 2765; For scattered examples of Suzuki coupling, see: (b) Parry,
P. A.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B. J. Org. Chem. 2002,
67, 7541; (c) Jiang, B.; Wang, Q.-F.; Yang, C.-G.; Xu, M. Tetrahedron Lett. 2001,
42, 4083. and more examples, see: Ref. 3 references cited therein.
8. Slow cannulation (over 90 min) of organozinc (2.4 mmol) via syringe pump
was required, see: Ref. 12.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.160.
9. pKa Values; range between 15 and 20 for phenols, 20 and 30 for anilines, source
from http://www.chem.wisc.edu/areas/reich/pkatable/index.htm.
10. For a review of bipyridine chemistry, see: Kaes, C.; Katz, M.; Hosseini, M. W.
Chem. Rev. 2000, 100, 3553. and references cited therein.
11. (a) Eweiss, N. F.; Katritzky, A. R.; Nie, P. L.; Ramsden, C. R. Synthesis 1997, 634;
(b) Boyer, J. H.; McCane, D. I.; McCarville, W. J.; Tweedie, A. T. J. Am. Chem. Soc.
1953, 75, 5298.
12. Manolikakes, G.; Hernandez, C. M.; Schade, M. A.; Metzger, A.; Knochel, P. J.
Org. Chem. 2008, 73, 8422.
13. (a) Kato, Y.; Okada, S.; Tomimoto, K.; Mase, T. Tetrahedron Lett. 2001, 42, 4849;
(b) Sugimoto, O.; Mori, M.; Tanji, K.-I. Tetrahedron Lett. 1999, 40, 7477.
References and notes
1. For examples, see: (a) Bagley, M. C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459;
(b) Fang, A. G.; Mello, J. V.; Finney, N. S. Org. Lett. 2003, 5, 967; For recent
specific applications of 2-pyridyl derivatives, see: (c) Deprez, N. R.; Sanford, M.
S. J. Am. Chem. Soc. 2009, 131, 11234; (d) Chen, X.; Dobereiner, G.; Hao, X.-S.;
Giri, R.; Maugel, N.; Yu, J.-Q. Tetrahedron 2009, 65, 3085.