An efficient one-pot synthesis of annulated pyridines utilising a directed ortho-metallation/transmetallation approach

Article abstract of DOI:10.1016/j.tetlet.2003.12.096

The ortho-alkylation of Boc-protected aminopyridines with α,ω-dihaloalkanes followed by in situ cyclisation, resulted in the corresponding annulated pyridine derivatives in good to excellent yields. The effect of the alkylating and chelating agents, the transmetallation additives and the directing group was examined.

Full text of DOI:10.1016/j.tetlet.2003.12.096

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1721–1724
An efficient one-pot synthesis of annulated pyridines utilising a
directed ortho-metallation/transmetallation approach
Antony J. Davies,* Karel M. J. Brands, Cameron J. Cowden, Ulf-H. Dolling
and David R. Lieberman
Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon,
Hertfordshire EN11 9BU, UK
Received 14 November 2003; accepted 16 December 2003
Abstract—The ortho-alkylation of Boc-protected aminopyridines with a,x-dihaloalkanes followed by in situ cyclisation, resulted in
the corresponding annulated pyridine derivatives in good to excellent yields. The effect of the alkylating and chelating agents, the
transmetallation additives and the directing group was examined.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Substituted pyridines and their annulated derivatives
represent an important class of organic compounds,
being fully represented in a plethora of natural products1
and pharmaceutical applications.2 As part of an ongoing
research effort aimed at the preparation of avb3 integrin
antagonists,3 we recently required an efficient and robust
synthesis of compounds with the general structure 2.
Various methods for the preparation of 2,3-dihydro-1H-
strategy based on the directed ortho-metallation (DoM)
of compounds of type 1. Alkylation of deprotonated 1
with a,x-dihaloalkanes followed by in situ cyclisation
should furnish the desired bicyclic product 2 (Scheme 1).
The organic literature is replete with examples of the
DoM reaction on aromatic substrates.7 The methodol-
ogy has been less well utilised in p-deficient heteroaro-
matics, however, mainly due to side reactions involving
nucleophilic addition of the alkyllithium reagent to the
azomethine bond of the azine. Reed et al. have reported a
DoM approach, which provided 1,2,3,4-tetrahydro-1,6-
naphthyridines in low yield. The approach reportedly
failed, however, when applied to the preparation of the
1,2,3,4-tetrahydro-1,8-naphthyridine 2c, giving ꢀa num-
ber of unidentified productsꢁ.8
pyrrolo[2,3-b]pyridines,4
1,2,3,4-tetrahydro-1,8-naph-
thyridines5 and 2,3,4,5-tetrahydro-1H-pyrido[2,3-b]aze-
pines6 have been reported in the literature.
Unfortunately, most of these methods require several
steps and are inefficient. Obviously, a universal synthetic
method, which allows entry into these annulated systems
would be highly desirable. We envisaged a general
R
Cl
( )n
( )n
N
X
N
X
N
NHBoc
X
N
NLi
Boc
Boc
1a, X=H, R=H
1b, X=Cl, R=H
1c, X=H, R=Me
1d, X=Cl, R=Me
3
2a, X=H, n=1; 2b, X=Cl, n=1
2c, X=H, n=2; 2d, X=Cl, n=2
2e, X=H, n=3; 2f, X=Cl, n=3
Scheme 1.
Keywords: Ring annulation; Directed ortho-metallation; Transmetallation; Aminopyridines.
* Corresponding author. Tel.: +44-1992-452012; fax: +44-1992-452581; e-mail: tony_davies2@merck.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.096

1722
A. J. Davies et al. / Tetrahedron Letters 45 (2004) 1721–1724
Table 1.
R
Cl
( )n
( )n
N
X
N
X
N
NHBoc
X
N
NLi
Boc
Boc
1a, X=H, R=H
1b, X=Cl, R=H
1c, X=H, R=Me
1d, X=Cl, R=Me
3
2a, X=H, n=1; 2b, X=Cl, n=1
2c, X=H, n=2; 2d, X=Cl, n=2
2e, X=H, n=3; 2f, X=Cl, n=3
Substrate 1
R–Li
Additive
Copper(I) halide
Electrophile
Product 2
Yield%a
1a
1a
1a
1d
1c
1c
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
s-BuLi
s-BuLi
s-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
TMEDA
TMEDA
TMEDA
––
––
––
Cl(CH2)2I
Cl(CH2)3I
Cl(CH2)4I
Cl(CH2)2I
Cl(CH2)3I
Cl(CH2)2Br
Cl(CH2)4Br
Cl(CH2)3I
Cl(CH2)4I
MeI
2a
2c
2e
2d
2e
2c
2f
0
54
55
0
––
––
––
––
––
––
86
0
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
––
––
51
51
85
91
95
94
94
98
90 (86)
57
52
45
2d
2f
––
––
1d
2d
2d
2d
2d
2f
CuCl
Cl(CH2)3I
Cl(CH2)3I
Cl(CH2)3I
Cl(CH2)3I
Cl(CH2)4I
Cl(CH2)2I
Cl(CH2)2I
Cl(CH2)2I
CuBr
CuBrÆMe2S
CuI
CuBrÆMe2S
CuBr
CuBrÆMe2S
CuBrÆMe2S
2b
2b
2a
a Yield refers to HPLC assay yield, obtained by comparison with an isolated pure standard. Yield in parenthesis refers to isolated yield, obtained by
silica gel chromatography.
In this paper we disclose two complementary DoM
methodologies for the construction of annulated
pyridines 2 starting from the readily available Boc-
protected aminopyridines 1a–b or aminopicolines 1c–
d.9 Previously in these laboratories, we have utilised
DoM methodology for the construction of the 7-az-
aindole nucleus starting from picoline derivative 1c.10
Indeed, selective lateral metallation of 1c can be
achieved with 2.2 equiv of n-BuLi at 0 ꢁC in high
yield without the use of an additive such as TME-
DA. The dianion, thus formed, can be quenched with
simple electrophiles (MeI, DMF) in close to quanti-
tative yields. We were gratified to find that quenching
the resulting dianion at )78 ꢁC11 with 1-chloro-3-
iodopropane resulted in complete (>99:1) conversion
to the corresponding chlorobutyl intermediate 3.
Warming the reaction mixture to reflux effected clean
ring closure to give the pyrido[2,3-b]azepine 2e in
86% overall yield.12
BocHN
N
Br
N
4
NHBoc
N
NHBoc
5
BocHN
N
Cl
Cl
N
NHBoc
6
The latter two results led us to explore an approach
using Boc-aminopyridines 1a–b. The 3-H proton in 1a–b
is less acidic than the methyl protons in 1c–d. High
yielding lithiation could be achieved with a slight excess
(2.2 equiv) of an equimolar TMEDA/n-BuLi solution
for the more acidic 1b,13 whilst 1a required more forcing
conditions (TMEDA/n-BuLi at )10 ꢁC or TMEDA/
s-BuLi at )78 ꢁC). We found it beneficial in terms of
conversion to age the TMEDA/BuLi mixtures for
ꢀ30 min at )20 ꢁC prior to the addition of substrate 1.
Other potential chelating agents (A–E) and bases (LDA,
LiHMDS, i-PrMgCl) were screened, however,
none were as effective as the BuLi/TMEDA combina-
tion.14
Attempts to extend the reaction to the preparation of
3,4-dihydro-1,8-naphthyridine 2c starting from 1c and
1-chloro-2-bromoethane were thwarted by lithium/bro-
mine exchange, which led to subsequent alkylation by
the remaining benzyl anion to give dimer 5 in 63% yield.
The fleeting presence of 4 could be demonstrated via a
cold hydrolytic quench and LCMS analysis. In the case
of the related 1d, we were unable to control the selec-
tivity of the alkylation. A complex mixture ensued, in
which the major product was identified as dimer 6 by
LCMS.
The lithiation of 1b was cleaner than that of the
unsubstituted compound 1a, due to competing nucleo-

A. J. Davies et al. / Tetrahedron Letters 45 (2004) 1721–1724
1723
References and notes
Me2N
NMe2
N
N
N
N
N
N
1. Pertinent reviews: (a) Plunkett, O.; Sainsbury, M. In
Rodd’s Chem. Carbon Compd., 2nd ed.; 1998; Vol. 4(Part
F/Part G(partial)), p 365; (b) Bailey, T. D.; Goe, G. L.;
Scriven, E. F. V. Chem. Heterocycl. Compd. 1984, 14
(Pyridine Its Deriv., Pt. 5), 1; (c) Thummel, R. P. Chem.
Heterocycl. Compd. 1984, 14 (Pyridine Its Deriv., Pt. 5),
253; (d) Kumar, R.; Chandra, R. Adv. Heterocycl. Chem.
2001, 78, 269.
N
N
Me
A
B
C
Me
N
N
N
N
Me
2. (a) Selected articles: Ghisalberti, E. L. Phytomedicine
1998, 5, 147; (b) Pinder, A. R. Methods Plant Biochem.
1993, 8 (Alkaloids and Sulphur Compounds), 241; (c)
Bernofsky, C. Coenzymes Cofactors 1987, 2 (Pyridine
Nucleotide Coenzymes, Pt. B), 105; (d) Altomare, C.;
Summo, L.; Cellamare, S.; Varlamov, A. V.; Voskressen-
sky, L. G.; Borisova, T. N.; Carotti, A. Bioorg. Med.
Chem. Lett. 2000, 10, 581; (e) Da Settimo, F.; Marini, A.
M.; La Motta, C.; Simorini, F.; Luchetti, E.; Bertini, S.
Farmaco 1996, 51, 725.
3. Meissner, R. S.; Perkins, J. J.; Duong, L. T.; Hartman, G.
D.; Hoffman, W. F.; Huff, J. R.; Ihle, N. C.; Leu, C.-T.;
Nagy, R. M.; Naylor-Olsen, A.; Rodan, G. A.; Rodan, S.
B.; Whitman, D. B.; Wesolowski, G. A.; Duggan, M. E.
Bioorg. Med. Chem. Lett. 2002, 12, 25.
D
E
philic addition of n- or s-BuLi to give the corre-
sponding dihydropyridine derivative. We were
delighted to find that alkylation of dilithiated 1b with
1-chloro-4-iodobutane was facile (90–95% conversion
to 3). Subsequent in situ ring closure yielded the pyr-
ido[2,3-b]azepine 2f in 85% overall yield.
Surprisingly, when this reaction was performed with
1-chloro-3-iodopropane, the conversion to intermediate
3 was poor with approximately equal amounts of
protonation and alkylation. As expected, ring closure
of the N-lithio species was more facile for the six-
membered ring, occurring in the 0–25 ꢁC range and 2d
was isolated in 51% yield. We believe that the differ-
ence in performance between 1-chloro-3-iodopropane
and its methylene homologue, might have been due to
the higher acidity of the protons b to iodine in the
former. Since dilithiated 1b was also thought to be
more basic than dilithiated 1c, we decided to attenuate
the dianionꢁs basicity by transmetallation. Indeed,
transmetallation with any copper(I) halide (CuCl,
CuBr, CuBrÆMe2S and CuI proved to be equally
effective) followed by the addition of the a,x-dihalide,
resulted in excellent conversion of 1b (>99:1).15 Similar
results were seen in the unsubstituted series (70–80%
conversion of 1a). Subsequent in situ cyclisation gave
the desired annulated pyridines 2 in good to excellent
yields (Table 1).
4. Taylor, E. C.; Macor, J. E.; Pont, J. L. Tetrahedron 1987,
43, 5145.
5. (a) Keller, P. C.; Marks, R. L.; Rund, J. V. Polyhedron
1983, 2, 595; (b) Hawes, E. M.; Davis, H. L. J. Heterocycl.
Chem. 1973, 10, 39; (c) Armarego, W. L. F. J. Chem. Soc.
C 1967, 5, 377; (d) Trecourt, F.; Marsais, F.; Gungor, T.;
ꢀ
Queguiner, G. J. Chem. Soc., Perkin Trans. 1 1990, 9,
2409.
6. Jossang-Yanagida, A.; Gansser, C. J. Heterocycl. Chem.
1978, 15, 249.
7. For general reviews on the directed ortho-metallation
reaction, see: (a) Gschwend, H. W.; Rodriguez, H. R. Org.
React. 1979, 26, 1; (b) Snieckus, V. Chem. Rev. 1990, 90,
879; (c) For more focussed reviews on the metallation of
ꢀ
azines and diazines, see: Mongin, F.; Queguiner, G.
Tetrahedron. 2001, 57, 4059; (d) Turck, A.; Ple, N.;
ꢀ
Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4489; (e)
Epsztajn, J.; Marsais, F.; Queguiner, G.; Snieckus, V. Adv.
ꢀ
Heterocycl. Chem. 1991, 52, 187.
8. Reed, J. N.; Rotchford, J.; Strickland, D. Tetrahedron
Lett. 1988, 29, 5725.
9. Prepared via a modified literature method, see: Kelly,
T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35, 9003.
10. Hands, D.; Bishop, B. C.; Cameron, M.; Edwards, J. S.;
Cottrell, I. F.; Wright, S. H. B. Synthesis 1996, 877.
11. Cooling the dianion mixture to )78 ꢁC prior to alkylation
is necessary to prevent the formation of a dimeric species
analogous to compound 6.
12. The pivaloyl protecting group is equally effective in the
alkylation step, but failed to give any of the cyclisation
products on warming. Pivaloyl protected aminopyridines
have been used in DoM reactions previously, see: Turner,
J. A. J. Org. Chem. 1983, 48, 3401.
13. Compound 2f: To a stirred solution of TMEDA (22.4 g,
0.192 mol) in THF (200 mL) at )20 ꢁC was added n-BuLi
(77 mL, 0.192 mol, 2.5 M in hexanes) over 10 min. The
solution was stirred between )20 and 10 ꢁC for 30 min and
then cooled to )78 ꢁC. A solution of 1,1-dimethylethyl[6-
chloro-2-pyridinyl]carbamate 1b (20.0 g, 0.087 mol) in
THF (100 mL) was added over 15 min. The reaction
mixture was aged for 1 h and then CuI (16.7 g, 0.088 mol)
added in one portion. The reaction mixture was allowed to
warm to )50 ꢁC and aged at that temperature for 1 h.
1-Chloro-4-iodobutane (28.7 g, 0.131 mol) was added neat
In conclusion, we have demonstrated a facile and
general one-pot preparation of perhydro-1H-pyrido[2,3-
b]azacycloalkanes starting from either N-Boc amino-
picolines or pyridines. We have established that in
selected cases, transmetallation with Cu(I) halides can
overcome difficulties, which have previously been
observed in this area.8 Critically, the process performs
exceptionally well with a 6-chloro substituent in the
starting material, thus providing products, which can be
further functionalised via various coupling methods
(Suzuki, Sonogashira, Heck etc.).
Acknowledgements
Thanks are due to Dr. D. J. Kennedy for high temper-
ature 400 MHz NMR spectra.

1724
A. J. Davies et al. / Tetrahedron Letters 45 (2004) 1721–1724
over 1 min, the cooling bath removed and the reaction
DMSO-d6, 343 K): d 155.7, 153.8, 146.7, 142.8, 134.0,
123.3, 80.6, 47.1, 32.6, 29.5, 28.8, 25.7; Anal. Calcd for
C13H17ClN2O2: C, 59.47; H, 6.77; N, 9.91; Cl, 12.54.
Found: C, 59.57; H, 6.79; N, 9.85; Cl, 12.53.
mixture allowed to warm to ambient. The reaction mixture
was then refluxed for 9 h. The cooled reaction mixture was
quenched by the addition of saturated sodium bicarbonate
(100 mL). The aqueous layer was separated and extracted
with isopropyl acetate (100 mL). The combined organic
layers were washed sequentially with 20% w/w sodium
thiosulfate (3 · 100 mL) and water (100 mL) and then
concentrated to afford crude 2f. Yield by HPLC assay was
90%. Purification by silica gel chromatography (eluent,
hexanes:EtOAc 85:15), yielded 21.3 g of 2f (86%) mp 166–
168 ꢁC (EtOAc); Rf 0.15 (hexanes:EtOAc 85:15); 1H NMR
(400 MHz, DMSO-d6, 343 K): d 7.62 (d, J ¼ 7.9 Hz, 1H),
7.17 (d, J ¼ 7.9 Hz, 1H), 3.35 (m, 2H), 2.58 (m, 2H), 1.62
(m, 2H), 1.51 (m, 2H), 1.22 (s, 9H); 13C NMR (100 MHz,
14. The role of additives and the directing group in DoM
reactions is still the subject of intense research, see: (a)
Rutherford, J. L.; Hoffman, D.; Collum, D. B. J. Am.
Chem. Soc. 2000, 122, 8640; (b) Chadwick, S. T.; Rennels,
R. A.; Rutherford, J. L.; Collum, D. B. J. Am. Chem. Soc.
2000, 122, 8640.
15. For examples of DoM reactions followed by lithium–
copper transmetallation, see: (a) Kamila, S.; Chandrani,
M.; De, A. Tetrahedron Lett. 2001, 42, 5955; (b) Cambie,
R. C.; Hill, J. H. M.; Rutledge, P. S.; Stevenson, R. J.;
Woodgate, P. D. J. Organomet. Chem. 1994, 474, 31.