The Synthesis of 3,3-Dimethyl Aza- and Diazaindolines Using a Palladium-Catalysed Intramolecular Reductive Cyclisation

Article abstract of DOI:10.1055/s-0035-1560320

A range of azaindolines was prepared in three steps from heterocyclic amines using halogenation, alkylation with 3-bromo-2-methylpropene, and a palladium-catalysed reductive cyclisation. The chemistry proved applicable to a multigram-scale operation.

Full text of DOI:10.1055/s-0035-1560320

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©
Georg Thieme Verlag Stuttgart · New York
2015, 26, 2570–2574
2570
letter
Synlett
J. E. Day et al.
Letter
The Synthesis of 3,3-Dimethyl Aza- and Diazaindolines Using a
Palladium-Catalysed Intramolecular Reductive Cyclisation
James E. H. Day*a
Pd(OAc) (5 mol%)
2
Martyn Fredericksona
Colin Hoggb
Christopher N. Johnsona
Alistair Meekb
HCOONa (1.2 equiv)
TBACl (1.2 equiv)
Et3N (3.0 equiv)
Y
Z
Hal2
Y
Z
X
X
Hal1
N
R1
Hal1
N
R1
PhMe/H2O, 100 °C
39–89%
Julian Northernb
Michael Readera
Gary Reidb
X, Y, Z = CH, N
1
Hal = Cl, Br
2
Hal = Cl, I
a
R1 = H, Boc
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton
Road, Cambridge, CB4 0QA, UK
james.day@astx.com
Onyx Scientific Limited, Silverbriar, Enterprise Park East, Sun-
b
derland, Tyne & Wear, SR5 2TQ, UK
Received: 09.07.2015
Accepted after revision: 22.08.2015
Published online: 22.09.2015
4
Y
X
5
X, Y, Z = CH, N
Hal = Cl, Br
DOI: 10.1055/s-0035-1560320; Art ID: st-2015-d0527-l
6
Z
N
Hal
H
Abstract A range of azaindolines was prepared in three steps from
heterocyclic amines using halogenation, alkylation with 3-bromo-2-
methylpropene, and a palladium-catalysed reductive cyclisation. The
chemistry proved applicable to a multigram-scale operation.
7
1
Figure 1
Key words heterocycles, cyclisation, palladium, ring closure, catalysis
eral route providing access to 4- and 7-aza, as well as diaza
analogues. Methodology from the Larock group makes use
of an intramolecular palladium-catalysed reductive cyclisa-
Indolines and azaindolines are well-known motifs in
natural products and medicinal chemistry. Preparations
of 3,3-dimethylindolines and azaindolines include radical
1–6
tion to synthesise 3,3-dimethylindolines from iodinated an-
3
,7–10
5
15,18
cyclisation,
nucleophilic aromatic substitution, palla-
iline starting materials.
However, there have been very
11
dium-catalysed α-arylation cyclisation and reduction,
few reports of the application of such methodology to the
copper-catalysed intramolecular C–H amination,12 Fischer
indole synthesis with reduction of the initially formed ind-
synthesis of 3,3-dimethylaza- and diazaindolines. Further-
5
more, we required a method compatible with the presence
of a leaving group such as a halogen (as in 1) that could al-
low further elaboration. However, such substituents can
prove challenging for palladium-mediated chemistry.
This Letter reports the successful application of this
chemistry to synthesise a range of 3,3-dimethylindoline
and azaindolines (Scheme 2 and Table 1). Importantly, the
method proved compatible with the presence of a halogen
substituent allowing subsequent elaboration using
palladium-catalysed methods such as Negishi and Suzuki
reactions.1
13
olenine, alkylation of an oxindole with subsequent reduc-
5,6,14
tion,
and an intramolecular palladium-catalysed reduc-
tive cyclisation. The work in this paper extends and ex-
pands the examples from the seminal work done by Larock
15
15
on palladium-catalysed reductive cyclisation.
As part of our fragment-based drug-discovery16 efforts
in developing antagonists of inhibitor of apoptosis proteins
17
(
IAP) for the treatment of cancer, we required a general
and efficient route for the synthesis of 3,3-dimethylindo-
lines and azaindolines bearing a halogen atom 1 (Figure 1),
for use as core scaffold intermediates.
We initially focused on the 5-azaindolines (Scheme 1)
and our initial synthesis, based on commercially available
7,30
The required dihalogenated heterocyclic amines were
either commercially available (Table 1, entries 1, 4, and 7)
or prepared from the monohalogenated derivatives using
N-iodosuccinimide (NIS) in acetonitrile at reflux or NIS in
acetic acid. Iodination of the 2-halo-4-aminopyridines in
acetonitrile gave a mixture of regioisomers which could be
separated by column chromatography (Table 1, entries 2
and 3). The iodination of 5-bromopyridin-3-ylamine (Table
6
-chloro-1H-pyrrolo[3,2-c]pyridine, was low yielding and
not suitable for large-scale preparation because of a delayed
exotherm observed for the zinc reduction (step iii).17 In ad-
dition, the method was only suitable for the preparation of
5
-azaindolines 1 (X = N, Y = Z = CH), and we required a gen-
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J. E. Day et al.
Letter
1, entry 5) was done in acetic acid as the solvent and gave a
Initially, we attempted alkylation of 2-chloro-5-iodo-
mixture of monoiodinated and a di-iodinated product (42%
and 8% isolated yield, respectively) using 0.9 equivalents of
NIS.
pyridin-4-ylamine with 3-bromo-2-methylpropene (1.1
equiv) using sodium hydride (1.1 equiv) as base in DMF giv-
ing a 53% yield. However, upon scale-up of the reaction, a
significant amount of a dialkylated product was observed.
By screening different reaction conditions we found the use
Table 1 Preparation 3,3-Dimethylindolines and Azaindolinesa
Entry
1
Aniline
Yield (%)c
Alkene precursor
Yield (%)c,g
Cyclisation product
Yield (%)c,i,m
I
I
NAb
37h
60
Cl
Cl
Br
Cl
Br
Cl
Cl
N
H
Cl
NH2
I
N
Cl
H
I
N
N
N
N
2
3
4
5
6
7
36d
33d
NAb
42e
40f
76
71
79
75
57
52
89
39j
87
44
48
0k
N
H
Cl
Br
Cl
Br
Cl
Cl
NH2
Cl
N
H
I
I
N
N
N
H
NH2
N
Br
Cl
Br
Cl
H
I
I
N
N
N
H
N
N
NH2
I
N
N
N
H
I
N
H
NH2
I
N
H
I
N
N
N
N
N
N
N
N
N
N
H
N
N
NH2
N
H
N
N
Cl
Cl
NAb
N
H
NH2
N
H
Cl
Cl
N
Cl
N
N
N
8
84l
63
Cl
N
O
t-BuO
O
t-BuO
a
Reactions were done on multigram scale.
b
c
d
e
f
NA = not applicable; starting material commercially available.
Yields are isolated yields.
20
NIS (1.1 equiv), MeCN (0.25 M), 82 °C.
NIS (0.9 equiv), AcOH (0.18 M).
NIS (1.1 equiv), AcOH (0.18 M), r.t.
g
h
i
21
Alkene precursor (1.0 equiv), H
Product contained 25% dialkylated impurity, yield calculated from H NMR.
Cyclisation precursor (1.0 equiv), Et N (3.0 equiv), HCO Na (1.2 equiv), Pd(OAc)
2 3 2
C=C(CH )CH Br (1.2 equiv), KOt-Bu (1.2 equiv), THF (0.24 M), r.t.
1
, 100 °C.22
3
2
2
(5.0 mol%), n-Bu
4
NCl (1.2 equiv), PhMe (0.13 M), H
2
O (2.6 M), N
2
j
8.0 mol% catalyst used.
k
l
Dechlorination of starting material observed by mass spectroscopy.
Boc protection: alkylated pyridazine (1.0 equiv, Table 1, entry 7), DMAP (1.0 equiv), Boc
Compounds were >95% pure by LC–MS and H NMR.
2
O (1.0 equiv), THF, 60 °C, 2 h.
m
1
23–29
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Br Br
tion was highly tolerant to changes to the heterocycle and
presence of an unprotected nitrogen giving acceptable
yields. However, the bromo-5-azaindoline (Table 1, entry 3)
was isolated in lower yield than the chloro-5-azaindoline
N
i
N
ii
N
O
N
Cl
N
Cl
N
SEM
Cl
H
SEM
(Table 1, entry 2). Higher catalyst loadings (8 mol%), longer
reaction times and repeated addition of aliquots of catalyst,
sodium formate, phase-transfer reagent, and base were
needed for a complete reaction.
iii
Of all the heterocylic precursors only the chloro pyra-
zine, (Table 1, entry 7, X = Y = N, Z = CH) failed to undergo
palladium-catalysed reductive cyclisation; by mass spectro-
metric analysis there was evidence for protodehalogena-
tion. It has been reported that aryl chlorides are difficult
N
v
N
iv
N
O
O
O
N
N
N
Cl
Cl
Cl
H
SEM
SEM
vi
31
substrates for such palladium-catalysed cyclisations. tert-
Butyl carbamate protection of the nitrogen resulted in a
successful cyclisation giving the tert-butyl carbamate pro-
tected diazaindoline (Table 1, entry 8) in 63% yield. The tert-
butyl carbamate diazaindoline was deprotected using HCl
in ethyl acetate to give the the chloropyridazine (Table 1,
N
1
(X = N, Y = Z = CH)
N
Cl
H
Scheme 1 Original Synthesis of 5-aza indoline17. Reagents and condi-
tions: i) NaH, TMSCH CH OCH Cl, DMF, 0 °C (82%); ii) C H N·HBr·Br , diox-
29
entry 7, X = Y = N, Z = CH) in quantitative yield.
2
2
2
5
5
2
We were keen to develop this chemistry for use at larger
scale (>100 g) to synthesise the 5-azaindoline (Table 1, en-
try 2). The initial iodination was modified to use iodine
monochloride as a replacement for NIS, leading to reduced
cost (Scheme 3). The reaction run on 250 g input of 4-ami-
no-2-chloropyridine gave a 1:1 mixture of regioisomers
that could be separated by column chromatography to give
the desired 5-iodo aniline in 33% isolated yield.32
ane, r.t. (58%);19 iii) Zn, NH Cl (aq), THF, r.t. (75%); iv) LiHMDS, MeI,
19
4
THF, –78 °C (51%); v) TFA, CH Cl , r.t. (67%); vi) BH –Me S, THF, 68 °C
2
2
3
2
Y
Z
Y
Z
I
Y
Z
I
X
X
X
i
ii
NH2 Hal
Hal
NH2 Hal
N
H
for X = N, Y = Z = CH
Y = N, X = Z = CH
X = Z = N, Y = CH
Hal = Cl, Br
iii
I
N
i
N
ii, iii
N
Y
Z
X
N
Cl
NH2
Cl
NH2
Cl
see Table 1
H
N
H
Hal
Scheme 3 Synthesis of 5-azaindoline using iodine monochloride. Re-
agents and conditions: i) ICl, AcOH, 80 °C (33%); ii) a. H C=C(Me)CH Br,
1
2
2
Scheme 2 Preparation 3,3-dimethylindolines and azaindolines. Re-
agents and conditions: i) NIS, MeCN, 82 °C or NIS, AcOH, r.t. (36–48%); ii)
H C=C(Me)CH Br, KOt-Bu, THF, r.t. (37–79%); iii) Pd(OAc) , HCO Na,
KOt-Bu, THF, 0 °C to r.t., b. 5 M HCl (quant.); iii) Pd(OAc) , HCO Na,
2 2
33
n-Bu NCl, Et N, PhMe, H O, 100 °C (66%).
4
3
2
2
2
2
2
n-Bu NCl, Et N, PhMe, H O, 100 °C (39–89%).
4
3
2
The alkylation of the iodinated aniline (Table 1, entry 2)
using potassium tert-butoxide and 3-chloro-2-methylpro-
pene in THF gave a quantitative yield of the cyclisation pre-
cursor after isolation as the hydrochloride salt without
need for chromatography. This salt was then used directly
in the palladium-catalysed reductive cyclisation with addi-
tion of an extra equivalent of base. Using toluene as solvent,
the reaction gave 75 g of the 5-azaindoline (Table 1, entry
2) in 66% yield and by using an diethyl ether–water parti-
tion as workup, we were able to again avoid the need for
chromatography.33
In summary, we have developed a three-step procedure
for the synthesis of 3,3-dimethylaza- and diazaindolines
from heterocyclic amines using halogenation, alkylation,
and palladium-catalysed reductive cyclisation. The proce-
dure provides key building blocks for the synthesis of IAP
of potassium tert-butoxide and 3-bromo-2-methylpropene
in THF gave the cyclisation precursors in good yields over a
range of substrates with no appreciable dialkylation ob-
served upon scale-up (Table 1). The use of potassium tert-
butoxide was advantageous because it avoided the genera-
tion of flammable gas and the tert-butanol solvates the re-
sultant anion.
The reported conditions15,18 involved use of a polar sol-
vent (DMF) for the palladium-catalysed cyclisation. We
found that a toluene–water mixture was a suitable solvent
system for this process, with the advantage of more
straightforward workup and isolation. Using these modified
conditions, we successfully obtained a 3,3-dimethylindo-
line (Table 1, entry 1) and range of azaindolines with a halo-
gen substituent (Table 1, entries 2–6). In general, the reac-
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antagonists,17 and these compounds may be of general util-
ity for medicinal chemistry (e.g., as synthetic intermediates
or fragments ) and other applications.
(20) General Iodination Procedure
NIS (24.75 g, 110.0 mmol) was added to a solution of 2-chloro-
pyridin-4-ylamine (12.85 g, 100.0 mmol) in MeCN (400 mL),
and the mixture was stirred and held at reflux overnight. Upon
cooling to r.t. the solvent was removed in vacuo and the residue
partitioned between EtOAc (250 mL), sat. Na S O (100 mL), and
16
Acknowledgment
2
2
3
H O (250 mL). The organic layer was separated, washed with
2
The authors would like to thank Matt Sanders for analytical support
during the course of this work. In addition we would like to acknowl-
edge Manchester Organics for their support in the scale-up synthesis
of these compounds and other IAP project team members.
H O (2 × 250 mL), separated, and the solvent removed in vacuo
2
to afford an orange oil that was subjected to column chromatog-
raphy on silica gel. Elution with 30–50% EtOAc in PE afforded a
pale orange solid that was rinsed with 25% EtOAc in PE (80 mL).
The solids were collected by filtration and sucked dry to afford
2
-chloro-5-iodopyridin-4-ylamine (7.32 g) as an off-white solid.
References and Notes
The mother liquors were concentrated to dryness in vacuo and
the residues subjected to column chromatography on silica.
Elution with 30–50% EtOAc in PE afforded further pure material
(
(
1) Gribble, G. W. J. Chem Soc., Perkin Trans. 1 2000, 1045.
2) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake,
C. H. Chem. Soc. Rev. 2007, 36, 1120.
1
(1.90 g). Combined yield 9.22 g, 36%.
d ): δ = 8.20 (s, 1 H), 6.64 (s, 1 H), 6.50 (br s, 2 H). MS: m/z = 255,
H NMR (400 MHz, DMSO-
6
(
(
3) Wipf, P.; Maciejewski, J. P. Org. Lett. 2008, 10, 4383.
4) Gonzalez-Lopez de Turiso, F.; Shin, Y.; Brown, M.; Cardozo, M.;
Chen, Y. L.; Fong, D.; Hao, X.; He, X.; Henne, K.; Hu, Y. L. J. Med.
Chem. 2012, 55, 7667.
257 [M + H] .
+
(21) General Alkylation Procedure
KOt-Bu (4.56 g, 40.73 mmol) was added to a stirred solution of
2-chloro-5-iodopyridin-4-ylamine (8.62 g, 33.94 mmol) in
anhydrous THF (140 mL), and the mixture was stirred at r.t. for
15 min. 3-Bromo-2-methylpropene (5.51 g, 40.73 mmol) was
added, and the mixture was stirred at r.t. overnight. The solvent
was removed in vacuo and the residues partitioned between
CH Cl (100 mL) and H O (100 mL). The organic layer was sepa-
(
5) Qiao, J. X.; Wang, T. C.; Ruel, R.; Thibeault, C.; L’heureux, A.;
Schumacher, W. A.; Spronk, S. A.; Hiebert, S.; Bouthillier, G.;
Lloyd, J.; Pi, Z.; Schnur, D. M.; Abell, L. M.; Hua, J.; Price, L. A.; Liu,
E.; Wu, Q.; Steinbacher, T. E.; Bostwick, J. S.; Chang, M.; Zheng,
J.; Gao, Q.; Ma, B.; McDonnell, P. A.; Huang, C. S.; Rehfuss, R.;
Wexler, R. R.; Lam, P. Y. S. J. Med. Chem. 2013, 56, 9275.
6) Genin, M. J.; Chidester, C. G.; Constance, G.; Rohrer, D. C.;
Romero, D. L. Bioorg Med. Chem. Lett. 1995, 5, 1875.
2
2
2
rated, the solvent removed in vacuo, and the residues subjected
to column chromatography on silica. Elution with 5–20% EtOAc
in PE afforded (2-chloro-5-iodopyridin-4-yl)-(2-methylal-
(
(
7) Leroi, C.; Bertin, D.; Dufils, P. E.; Gigmes, D.; Marque, S.; Tordo,
P.; Courturier, J. L.; Guerret, O.; Ciufolini, M. A. Org. Lett. 2003, 5,
lyl)amine (7.93 g, 76%) as a pale yellow oil. H NMR (400 MHz,
1
DMSO-d ): δ = 8.23 (s, 1 H), 6.49 (t, J = 6.4 Hz, 1 H), 6.39 (s, 1 H),
6
4943.
4.84 (s, 1 H), 4.73 (s, 1 H), 3.82 (d, J = 5.7 Hz, 2 H), 1.69 (s, 3 H).
(8) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.; Prabhakaran, E.
N. Org. Lett. 2001, 3, 1009.
MS: m/z = 309, 311 [M + H] .
+
(22) General Palladium-Catalysed Cyclisation
(9) Mo, D.-L.; Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Chem. Asian J. 2011,
Pd(OAc)2 (300 mg, 1.34 mmol), sodium formate (2.40 g, 30.53
mmol), n-Bu NCl (8.48 g, 30.53 mmol), and Et N (10.6 mL, 76.32
6, 3200.
4
3
(10) Viswanathan, R.; Prabhakaran, E. N.; Plotkin, M. A.; Johnston, J.
mmol) were added to a solution of (2-chloro-5-iodopyridin-4-
yl)-(2-methylallyl)amine (7.85 g, 25.44 mmol) in toluene (200
N. J. Am. Chem. Soc. 2003, 125, 163.
(
(
11) Pfefferkorn, J. A.; Choi, C. Tetrahedron Lett. 2008, 49, 4372.
12) Takamatsu, K.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
mL) and H O (10 mL), and the mixture was stirred and held at
2
100 °C under a nitrogen atmosphere overnight. The mixture
was filtered whilst still hot and the solids rinsed with toluene
2015, 80, 3242.
(
(
13) Liu, K. G.; Lo, J. R.; Robichaud, A. J. Tetrahedron 2010, 66, 573.
14) Vu, A. T.; Cohn, S. T.; Zhang, P.; Kim, C. Y.; Mahaney, P. E.; Bray, J.
A.; Johnston, G. H.; Koury, E. J.; Cosmi, S. A.; Deecher, D. C.;
Smith, V. A.; Harrison, J. E.; Leventhal, L.; Whiteside, G. T.;
Kennedy, J. D.; Trybulski, E. J. J. Med. Chem. 2010, 53, 2051.
15) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291.
16) Jhoti, H.; Williams, G.; Rees, D. C.; Murray, C. W. Nat. Rev. Drug
Discovery 2013, 12, 644.
(50 mL), H O (50 mL), and EtOAc (50 mL). The organic solvent
2
was removed in vacuo, the aqueous residues were diluted with
H O (100 mL), and extracted with EtOAc (2 × 200 mL). The
2
organic layer was separated, the solvent was removed in vacuo,
and the residues subjected to column chromatography on silica.
Elution with 30–100% EtOAc in PE afforded 6-chloro-3,3-
dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (4.12 g, 89%)
(
(
1
as a colourless solid.
H), 6.75 (br s, 1 H), 6.33 (s, 1 H), 3.32 (s, 2 H,), 1.25 (s, 6 H). MS:
m/z = 183, 185 [M + H]
(23) Cyclisation Product (Table 1, Entry 1)
H NMR (400 MHz, DMSO-d ): δ = 6.94 (d, J = 7.8 Hz, 1 H), 6.57–
H NMR (400 MHz, DMSO-d ): δ = 7.72 (s, 1
6
(
17) Chessari, G.; Buck, I. M.; Day, J. E. H.; Day, P. J.; Iqbal, A.; Johnson,
C. N.; Lewis, E. J.; Martins, V.; Miller, D.; Reader, M.; Rees, D. C.;
Rich, S. J.; Tamanini, E.; Vitorino, M.; Ward, G. A.; Williams, P. A.;
Williams, G.; Wilsher, N. E.; Woolford, A. J.-A. J. Med. Chem.
+
.
1
6
2015, 58, 6574.
6.47 (m, 1 H), 6.44 (d, J = 2.0 Hz, 1 H), 5.74 (s, 1 H), 3.21 (d, J = 1.8
(18) Pd(OAc)2 (0.005 mmol, 2 mol%), Et N (0.625 mmol), substrate
Hz, 1 H), 1.20 (s, 6 H). MS: m/z = 182 [M + H]
(24) Cyclisation Product (Table 1, Entry 2)
+
.
3
(0.25 mmol), sodium formate (0.06 M), n-Bu NCl (0.25 mmol),
4
and DMF (0.06 M) at 80 °C.
1
H NMR (400 MHz, DMSO-d ): δ = 7.72 (s, 1 H), 6.75 (br s, 1 H),
6.33 (s, 1 H), 3.32 (s, 2 H), 1.25 (s, 6 H). MS: m/z = 183 [M + H]
(25) Cyclisation Product (Table 1, Entry 3)
6
(
19) Bell, I. M.; Gallicchio, S. N.; Wood, M. R.; Quigley, A. G.; Stump, C.
A.; Zartman, C. B.; Fay, J. F.; Li, C.-C.; Lynch, J. J.; Moore, E. L.;
Mosser, S. D.; Prueksaritanont, T.; Regan, C. P.; Roller, S.;
Salvatore, C. A.; Kane, S. A.; Vacca, J. P.; Selnick, H. G. ACS Med.
Chem. Lett. 2010, 1, 24.
+
.
1
H NMR (400 MHz, DMSO-d ): δ = 7.71 (s, 1 H), 6.74 (s, 1 H),
6.48 (s, 1 H), 3.31 (s, 1 H), 1.25 (s, 6 H). MS: m/z = 228 [M + H] .
6
+
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J. E. Day et al.
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(
26) Cyclisation Product (Table 1, Entry 4)
(32) 2-Chloro-3-iodopyridin-4-ylamine isolated in 33% yield. 1H
1
H NMR (270 MHz, CDCl ): δ = 7.09–7.06 (d, J = 8.0 Hz, 1 H),
NMR (400 MHz, DMSO-d ): δ = 7.75 (d, J = 5.5 Hz, 1 H), 6.53 (m,
3
6
+
6
.51–6.48 (d, J = 8.0 Hz, 1 H), 5.05 (br s, 1 H), 3.37 (s, 2 H), 1.28
3 H), MS: m/z = 255 [M + H] .
+
(
s, 6 H). MS: m/z = 183 [M + H] .
(33) Larger-Scale Palladium Cyclisation
(
27) Cyclisation Product (Table 1, Entry 5)
To a 10 L flange flask fitted with stirrer bar and nitrogen
inlet/outlet was added (2-chloro-5-iodopyridin-4-yl)-(2-meth-
ylallyl)amine hydrochloride (217 g, 0.629 mol), Pd(OAc)2 (7 g,
0.031 mol), sodium formate (51.3 g, 0.755 moles), TBACl (210 g,
0.755 mol), Et N (350 mL, 2.52 mol), toluene (4.9 L), and H O
1
H NMR (400 MHz, DMSO-d ): δ = 7.72–7.64 (m, 1 H), 6.87 (t, J =
6
2
2
.2 Hz, 1 H), 6.05 (s, 1 H), 3.30 (m, 2 H), 1.20 (s, 6 H). MS: m/z =
28 [M + H] .
+
(28) Cyclisation Product (Table 1, Entry 6)
3
2
1
H NMR (270 MHz, CDCl ): δ = 7.74 (s, 1 H), 5.79 (br s, 1 H), 3.46
(242 mL). The reaction mixture was heated at 100 °C (oil bath)
overnight after which time NMR confirmed no starting material
remaining, bulk material worked up. The reaction mixture was
cooled to r.t. and stood overnight. To the cooled reaction
mixture was added H O (500 mL) and Et O (2.5 L), organic layer
3
+
(s, 2 H), 1.35 (s, 6 H). MS: m/z = 184 [M + H] .
(29) Cyclisation Product from HCl Deprotection (Table 1, Entry 7)
1
H NMR (270 MHz, CD OD): δ = 6.92 (s, 1 H), 3.79 (s, 2 H), 1.44
3
+
(
s, 6 H). MS: m/z = 184 [M + H] .
2
2
(30) Negishi, E.-I. Handbook of Organopalladium Chemistry for
Organic Synthesis; Wiley-Interscience: New York, 2002.
removed and aqueous re-extracted with Et O (1.5 L). Organic
extracts combined, washed with sat. brine solution (1.5 L),
2
(
31) Liu, P.; Huang, L.; Lu, Y.; Dilmeghani, M.; Baum, J.; Xiang, T.;
Adams, J.; Tasker, A.; Larsen, R.; Faul, M. M. Tetrahedron Lett.
removed, dried over MgSO , filtered, and evaporated to dryness
4
at 40 °C to give 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyr-
rolo[3,2-c]pyridine (76.2 g, 66%) as a yellow solid, the analytical
data matched those from the smaller scale.
2007, 48, 2307.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2570–2574