378
E. L. Piatnitski Chekler et al. / Tetrahedron Letters 53 (2012) 377–379
Boc
N
the C4 O-Boc group can be removed using piperdine to give the
H
N
H
N
N
N
corresponding alcohol 15 which may then be converted to triflate
16 under standard conditions.11 Compound 16 could now undergo
cross-coupling chemistry at C4 followed by additional N-function-
alization after removal of the Boc group at N1.
N
N
OTf
Cl
CN
30
20
16
A shorter route to a 4-substitued-7-azaindoline scaffold is pre-
sented in Scheme 2. Commercially available 4-chloro-7-azaindole
17 can be directly reduced to the corresponding indoline 18 by
hydrogenation over Raney-Ni. It should be mentioned that the
same or similar reaction conditions failed to produce the desired
product in the case of 6-azaindoline 10. The C5 and N1 positions
are differentially functionalized in that N1 was protected as its tri-
fluoroacetamide 19 using TFAA and the 5-Cl group functionalized
to CN using PdCl2(dppf) and Zn(CN)2.12
We have also enabled a route to a 4-substituted diazaindoline
scaffold which is shown in Scheme 3. Initially 4,5-dichloropyrida-
zin-3(2H)-one 21 is protected as its PMB-amide 22. The 5-Cl group
can be selectively displaced with sodium diethylmalonate13 to give
23 which can be ethyl decarboyxlated on heating in DMSO to give
24. Reduction of the ethyl ester to alcohol 25 is accomplished with
NaBH4, alcohol 26 was converted to mesylate 27, and displacement
with PMB-NH2 was followed by cyclization to give the N-PMB pro-
tected 1H-pyrrolo[2,3-d]pyridazin-4(5H)-one 28. The PMB group
can be removed using TFA and aromatization of the pyridazinone
ring is accomplished using POCl3 to give the 4-Cl diazaindoline
30. It should be noted that the need to undertake an extensive pro-
tecting group manipulation (PMB) was justified by the unexpected
circumstances with this group’s deprotection. When the PMB
group was carried forward to produce intermediate 31, its removal
on pyridazinone nitrogen could not be achieved under an exhaus-
tive list of conditions. Therefore, we resorted to the sequential
deprotection strategy even if it forced us to proceed with unpro-
tected pyridazinone nitrogen going from 26 to 28.
Figure 2. Key indoline synthetic intermediates.
intermediates that could be used as synthetic intermediates 16, 20,
and 30 (Fig. 2).
The preparation of 2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl
trifluoromethanesulfonate 16 is presented in Scheme 1. Commer-
cially available 3-nitropyridin-4-ol 5 can be selectively bromi-
nated5 to give 3-bromo-5-nitropyridin-4-ol 6. Conversion to the
corresponding chloride 7 is accomplished by heating with POCl3
and Et2NH.6 Replacement of the chlorine in 7 with a Me group is
accomplished by a two step procedure where (1) the chlorine
was initially displaced with sodium diethylmalonate and (2) the
malonylpyridine intermediate is saponified and doubly decarbox-
ylated with aqueous HCl.7 Elaboration of 8 to enamine 9 is effected
with DMFÁDMA and the corresponding indole 10 is formed by heat-
ing with iron and HOAc.8 An attempt was made to selectively re-
duce the enamine double bond in 9 followed by a cyclization to
produce azaindoline, but various reaction conditions led to the ni-
tro group reduction without a subsequent cyclization. An alterna-
tive synthetic strategy is to selectively reduce the 2,3-indole
double bond in 10, but the reaction with various reducing agents
under multiple conditions fails to produce the desired product.9
Therefore, reduction of the 2,3-indole double bond requires pro-
tecting group manipulations and conversion of the 5-bromo to a
5-hydroxy moiety. Thus 10 is N-Boc protected under standard con-
ditions to produce 11. The bromine atom is converted to a hydroxyl
moiety with concomitant removal of the N-Boc group using an
aqueous CuSO4,10 and the resulting alcohol 12 is N-Boc protected
again to give 13. The key reduction step from azaindole 13 to aza-
indoline 14 was accomplished using hydrogenation over Pd/C.
Compound 14 is a useful intermediate in that the N1 and C4 sub-
stituents can be differentiated for future chemistry. For example,
We have highlighted the development of routes to 4-substi-
tuted azaindolines. This synthetic effort enables a viable strategy
for the replacement of indolines that contain an aniline structural
alert. These routes also allow for the preparation of intermediates
that can be used in future chemistry by derivatization at the N1
and C5 positions.
1. NaH
OH
OH
Cl
Me
diethyl malonate
O2N
Br2, H2O O2N
Br
O2N
Br
O2N
Br
DMF•DMA
POCl3
DMF, 0 oC, 1 h
50 oC, 2 h
74%
Et2NH
reflux, 5 h
81%
2. aq. HCl
reflux, 16 h
85%
DMF, 90 oC, 4 h
90%
N
N
N
N
5
6
7
8
NMe2
Fe
H
Boc
N
H
N
N
Boc2O
CuSO4, Cu-Sn
Boc2O, Et3N
THF, H2O
AcOH
O2N
Br
N
N
N
90 oC, 3 h
83%
Et3N, CH2Cl2
25 o
NaOH, H2O
160 oC
0 C
oC - 23 o
N
C
Br
Br
OH
12
80%
21% over 2 steps
9
10
11
Boc 10% Pd/C
Boc
N
Boc
Boc
N
N
N
Piperidine
PhN(OTf)2
MeOH
N
N
N
N
150 psi
24 h
CH2Cl2
23 °C, 3 h
68%
i-Pr2NEt
CH2Cl2
OBoc
80%
OBoc
OH
15
OTf
16
0 oC - 23 o
60%
C
13
14
Scheme 1. Preparation of 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-4-triflate.