Novel preparation of functionalized iodotetrahydronaphthyridine, iodoazaindoline, and iodotetrahydropyridoazepine systems

Article abstract of DOI:10.1016/j.tetlet.2007.08.076

A novel method, which utilizes a key halogen dance step for the preparation of iodotetrahydronaphthyridine, iodoazaindoline, and iodotetrahydropyridoazepine ring-systems is described. A variety of transformations of the iodo-functional group are also repo

Full text of DOI:10.1016/j.tetlet.2007.08.076

Tetrahedron Letters 48 (2007) 7460–7463
Novel preparation of functionalized iodotetrahydronaphthyridine,
iodoazaindoline, and iodotetrahydropyridoazepine systems
Hanh Nho Nguyen* and Zhan J. Wangꢀ
Amgen Inc., Department of Medicinal Chemistry, One Kendall Square Bldg 1000, Cambridge, MA 02139, USA
Received 27 July 2007; accepted 20 August 2007
Available online 24 August 2007
Abstract—A novel method, which utilizes a key halogen dance step for the preparation of iodotetrahydronaphthyridine, iodoaza-
indoline, and iodotetrahydropyridoazepine ring-systems is described. A variety of transformations of the iodo-functional group are
also reported to demonstrate the utility of this method.
Published by Elsevier Ltd.
Pyridine, pyrimidine, quinoline, and quinazoline hetero-
cycles are common structural features in kinase inhibi-
tors, whereby the N engages as a key H-bond acceptor
with a backbone NH residing in the hinge region of
the kinase.1 This important interaction provides binding
affinity between an inhibitor and the kinase and is
present in the majority of protein kinases. Structure
activity relationships have shown that the amino group
of 2-methylaminopyridine donates a hydrogen bond to
backbone carbonyl also in the hinge region. This addi-
tional interaction provides further binding affinity,
which is generally reflected as a boost in inhibitory
potency for 2-methylaminopyridine compared to an
unsubstituted pyridine linker binding ring.2 It was
envisioned that ring-constrained versions such as
azaindoline (n = 1), tetrahydronaphthyridine (n = 2),
and tetrahydropyridoazepine (n = 3) should also pro-
vide two-point interaction with inhibitory properties
(Fig. 1). In order to prepare a fully elaborated kinase
inhibitor, a C4 substitution would be necessary. How-
ever, to our knowledge, these ring systems with halogen
at the C4-position of the pyridine are not known.
Herein, we describe a novel approach to the synthesis
of iodotetrahydronaphthyridine, iodoazaindoline, and
iodotetrahydropyridoazepine ring-systems, via a key
halogen dance step. These iodinated heterocycles serve
Hinge Region
N
H
O
Gate Keeper
H
N
H
N
N
N
X
External
Solvent
n
n
R
X = I, Br, Cl
n = 1, 2, 3
Hydrophobic
Pocket
Figure 1. New hinge binding rings.
as versatile precursors for the preparation of novel pro-
tein kinase inhibitors.
Initially, we tried to selectively hydrogenate the pyrrole
ring of 4-chloro-7-azaindole and its Boc-protected ana-
log in the presence of palladium (Scheme 1, conditions
1) or rhodium (Scheme 1, conditions 2)3 in order to
access 4-chloro-7-azaindoline. However, none of the de-
sired product was observed. Other reduction conditions
such as LAH, or BH3 (with or without TFA) also did
not provide the desired product.4 We then turned our
attention to a dianion approach that was previously re-
ported by Bishop et al. to prepare 6-chloro-7-azaindo-
line.5 However, Boc-protected 4-chloro-7-azaindoline
was not observed under similar reaction conditions.
Keywords: Halogen dance; Azaindoline; Tetrahydronaphthyridine;
Tetrahydropyridoazepine.
*
Corresponding author. Tel.: +1 617 444 5254; fax: +1 617 577
9822; e-mail: hanhn@amgen.com
ꢀ Current address: University of California, Berkeley, College of
Chemistry, Berkeley, CA 94720, USA.
Although the dianion approach failed to provide the de-
sired product, it provided us insight to a new method of
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.08.076

H. N. Nguyen, Z. J. Wang / Tetrahedron Letters 48 (2007) 7460–7463
7461
R
N
Li
R
N
H
N
n
-BuLi, TMEDA,
2) CuBr•SMe,
O
N
N
N
O
N
N
THF, -70 to -75 ºC
Conditions
R = H, Boc
Conditions
-65
ºC
O
O
3)
Li
I
Cl
Cl
1
Cl
3
2
4
Cl
Cl
R = Boc
1) H2, Pd/C (with or without TFA)
2) Rh(acac)(cod), DPPF, i-PA, 400 PSI H2
3) LAH
4) BH3•THF, TFA
5) BH3•SMe2, TFA
Scheme 1. Initial attempts.
obtaining the desired 4-halo-7-azaindoline system. We
envisioned that a halogen dance should provide a simi-
lar anion at the C3-position as provided by the dianion
approach while installing the required iodine at the C4-
position of the pyridine ring (Scheme 2, transformation
from 5 to 6).6 Attempted alkylation of the C3-anion
with 1-chloro-2-iodoethane provided 1-fluoro-2,3-
diiodopyridine (7) instead of the desired alkylation
product (8). In this case, 1-chloro-2-iodoethane behaved
as an iodinating reagent.6 Ring-opening of activated N-
tosylaziridine with the C3-anion provided the desired
product (9), albeit in 6% yield. Attempts to prepare cup-
rate reagents from the C3-anion with different copper
sources such as CuI, CuIÆSMe2, and CuCNÆ2LiCl prior
to adding the activated N-tosylaziridine did not provide
any desired product. We found that Boc and Bn-pro-
tected cyclic sulfamidates (10 and 11, respectively) were
compatible electrophiles.7 For example, ring-opening of
cyclic Boc-protected sulfamidate (10) with the halogen
dance anion (6) provided the desired sulfamic acid
(12). Hydrolysis of the sulfamic acid (12) with aqueous
HCl followed by Boc-deprotection with TFA provided
the desired precursor for 4-iodo-7-azaindoline that
underwent an intramolecular SNAr reaction in the pres-
ence of potassium carbonate to furnish 4-iodo-7-azain-
doline in high yield (16). Similarly, N-benzyl-4-iodo-7-
azaindoline (17) was prepared in a similar manner.
Iodotetrahydronaphthyridine and iodotetrahydropyrido-
azepine were prepared in a more straightforward man-
ner from the halogen dance approach due to the fact
that 1-chloro-3-iodopropane and 1-chloro-4-iodobutane
do not behave as iodinating reagents. Thus, alkylation
of the C3-anion (6) with 1-chloro-3-iodopropane and
1-chloro-4-iodobutane provided the precursors for
iodotetrahydronaphthyridine
and
iodotetrahydro-
pyridoazepine, respectively (Scheme 3, compounds 18
and 22). We found that ammonia, benzylamine, and
p-methoxybenzylamine first underwent the SN2 reaction
under Finkelstein conditions followed by SNAr reaction
to afford the cyclized tetrahydronapthyridines. Monitor-
ing the reaction progress by LCMS confirmed the initial
appearance of the iodo-intermediate with concurrent
formation of an SN2-product resulting from amine
displacement of the iodo-intermediate. A final intramo-
lecular
SNAr
cyclization
afforded
iodotetra-
hydronaphthyridines 19–21. For the formation of
iodotetrahydropyridoazepine (23), cyclization with
p-methoxybenzylamine worked best under microwave
conditions at 150 °C for 25 min. Both iodotetrahydro-
H
F
N
N
I
F
N
I
NH3
N
Cl
I
I
16
7 (74%)
8
not observed
I
Cl
ºC to rt
-78
Ts
N
Ts
N
F
N
I
N
I
F
I
N
F
N
LDA
TsHN
Halogen
dance
6%
Li
9
5
6
I
1) TFA, DCM, rt, 16 h
(79% yield)
H
O
N
O
N
I
N
R = Boc (10)
Bn (11)
S
2) K2CO3, DMF, 60
(84% yield)
ºC, 1 d
-78 ºC to rt
O
R
R = Boc
R = Bn
16
F
N
6 N HCl,
H2O, rt
F
N
R
N
Bn
N
R
H
N
N
I
K2CO3, DMF, 60
55%
ºC, 1 d
I
SO3H
I
14 R=Boc, 75% over two steps
15 R=Bn, 21% (unoptimized) over two steps
R = Boc (12), Bn (13)
17
Scheme 2. Halogen dance approach to 4-iodo-7-azaindoline.

7462
H. N. Nguyen, Z. J. Wang / Tetrahedron Letters 48 (2007) 7460–7463
R
N
N
I
RNH2, KI,
K2CO3, DMF
F
N
I
F
N
I
LDA, THF
-78 ºC, 1 h
F
I
N
I
Cl
Cl
19 R=PMB, 50%
20 R=Bn, 51%
Li
-78 ºC to rt
88%
18
6
5
H
I
Cl
NH4OH, NH4OAc
KI, K2CO3, DMF
60%
N
N
I
79%
F
-78 ºC to rt
PMB-NH2, KI, K2CO3,
DMF, Microwave,
150 ºC, 25 min
PMB
N
N
I
N
I
21
Cl
40%
22
23
Scheme 3. Halogen dance approach to iodotetrahydronaphthyridine, and iodotetrahydropyridoazepine.
naphthyridine and iodotetrahydropyridoazepine were
prepared in two steps.
inhibitors having the tetrahydronapthyridine pharmaco-
phore. The high reactivity of the iodo-group toward
metal-catalyzed coupling reactions allowed amida-
tion (21–24),8 Sonogashira (21–25 and 26), and Suzu-
ki–Miyaura (21–27 and 28) couplings9 to occur in high
yields (Scheme 4). In Scheme 5, PMB-protected
Next we turned our attention to functionalize
iodotetrahydronapthyridine (21) to demonstrate the
utility of this method in the preparation of the kinase
O
H
N
N
N
H
N
H
R
N
R
N
N
I
R
Yield
97%
91%
NH
PdCl2(PPh3)2, CuI
N
Et3N, DMF, rt
Pd(OAc)2, Xantphos
Cs2CO3, dioxane
100 ºC
25
O
21
24
TMS
26
62%
RB(OH)2
Pd(OAc)2, t-Bu3PH•BF4
Na2CO3, H2O, dioxane
H
R
Yield
N
N
R
94%
90%
27
F
N
28
Scheme 4. Functionalization of iodotetrahydronaphthyridine.
PMB
N
BnOH, CuI
1,10-Phenanthroline
Cs2CO3, 110 ºC
PMB
N
O
Zn(CN)2, Pd(PPh3)4,
DMF, 80 ºC
N
N
93%
61%
35
29
CN
PMB
N
PMB
N
HN
O
PMB
N
(Bu)3Sn
N
N
N
N
I
Pd(OAc)2, (+)-BINAP, Cs2CO3,
Toluene, 120 ºC, 30 h
Pd(PPh3)4,
Toluene, 110 ºC
92%
58%
N
O
19
N
34
30
R
Yield
70%
R2NH
Pd2(dba)3, (+)-BINAP,
18-Crown-6, NaOt-Bu,
THF, 60 ºC, 16 h
31
N
HN
68%
54%
32
PMB
N
N
R
N
N
Boc
33
Scheme 5. Functionalization of PMB-protected iodotetrahydronaphthyridine.

H. N. Nguyen, Z. J. Wang / Tetrahedron Letters 48 (2007) 7460–7463
7463
V. J.; Chaffee, S. C.; Coxon, A.; Emery, M.; Fretland, J.;
Gallant, P.; Gu, Y.; Hoffman, D.; Johnson, R. E.;
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iodotetrahydronapthyridine (19) also underwent a vari-
ety of coupling processes such as cyanation (19–29),
Stille (19–30), and Buchwald–Hartwig (19–31, 32, 33,
and 34) couplings,10 and C–O bond formation (19–35).11
In conclusion, we have demonstrated a novel approach
to synthesize functionalized hinge binding cores such
as iodotetrahydronaphthyridine, iodoazaindoline, and
iodotetrahydropyridoazepine ring-systems. The key step
involved a halogen dance that provided the penultimate
precursors to those rings. In addition, we have shown
that the iodo-functional group could be transformed
via a variety of metal-catalyzed coupling reactions.
These rings have the potential to provide entry to new
classes of kinase inhibitors.
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Acknowledgments
Z.W. thanks Amgen Inc. for a summer internship. We
would like to thank Dr. Steve Hollis for performing
some of the NMR analyses and Professor Eric Jacobsen
for insightful suggestions.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
08.076.
8. Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
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