The first practical and efficient one-pot synthesis of 6-substituted 7-azaindoles via a Reissert-Henze reaction

Article abstract of DOI:10.1055/s-2007-1000853

A variety of 6-substituted 7-azaindoles (30 examples) were obtained via selective O-methylation of 7-azaindole-N-oxide m-chlorobenzoic acid salt and subsequent, base-catalyzed one-pot reaction with a range of N-, O-, S-nucleophiles or cyanide. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000853

PAPER
201
The First Practical and Efficient One-Pot Synthesis of 6-Substituted
7-Azaindoles via a Reissert–Henze Reaction
Efficient
O
ne-P
h
ot
S
ynthesis
o
of 6-Substitu
m
ted 7-Azaindoles as Storz,*a,1 Michael D. Bartberger,b Steven Sukits,b Chris Wilde,b Troy Soukupc
a
Chemical Process R & D, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
Fax +1(845)6025561; E-mail: storzt@wyeth.com
b
c
Molecular Structure & Modelling, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
Process Analytical Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
Received 19 June 2007
Dedicated to Professor Dr. Wolfgang Pfleiderer, Professor Emeritus, University of Konstanz, Germany,
on the occasion of his 80th birthday
nitrogen (N1) of 1 (amination,9 silylation,10 alkylation,
carbamoylation and sulfonation,11 acylation,12 arylation,13
vinylation,14 Michael addition,15 urea formation,16 or
glycosylation17),3g,h or the C3 position (formylation,18
acylation,12 aldol condensation,19 Mannich reaction,20
Michael addition,21 alkylation,21,22 halogenation,23 nitra-
tion,24 sulfide formation,25 or oxidation26).3g,h
Abstract: A variety of 6-substituted 7-azaindoles (30 examples)
were obtained via selective O-methylation of 7-azaindole-N-oxide
m-chlorobenzoic acid salt and subsequent, base-catalyzed one-pot
reaction with a range of N-, O-, S-nucleophiles or cyanide.
Key words: 7-azaindole, pyrrolo[2,3-b]pyridine, addition-elimina-
tion, oxidation, N-oxide, O-methylation
Only a few methods are known for the selective modifica-
tion at C4: from the 7-azaindole-N7-oxide (2),27a,b 4-chlo-
ro-7-azaindole27 and 4-bromo-7-azaindole28 have been
obtained in one synthetic step; whereas 4-amino-7-
azaindole29 and 4-nitro-7-azaindole29 have been made
from 2 in two, and 4-fluoro-7-azaindole28 in three synthet-
ic steps, respectively.30 The derivatization of 7-azaindole
at C5 is not straightforward31 and usually better accom-
plished by de novo-synthesis,3g,h,32 whereas derivatization
at C2 is regarded as more facile.33
Since its original discovery as a component of coal tar by
Kruber in 1943,2 derivatives of 7-azaindole3 (1H-pyrro-
lo[2,3-b]pyridine) (1) have emerged4 as an important and
promising class of bioisosteric pharmacophores5 for the
indole or purine ring system in both agrochemistry and
medicinal chemistry6 (e.g., see Figure 1).7
More recently, 7-azaindoles have attracted interest in ma-
terial sciences for biophysical and photophysical applica-
tions due to their optical and metal-ion binding
properties.8
De novo synthesis has traditionally also been the method
of choice for 7-azaindoles substituted at C6.3g,h Following
the early report of Robison et al.,34 only one further at-
tempt towards a selective derivatization at C6 was pub-
lished: Oshiro et al.35 reported the synthesis of 6-chloro-
and 6-bromo-7-azaindole via a Reissert–Henze type
reaction36a from the N-oxide 2. However, due to p-dona-
While a number of strategies for the de novo synthesis of
7-azaindole3a–d and its derivatives have been reported,3e–i
the available methods for site-selective derivatization of
the parent molecule remain relatively limited. In analogy
to known indole chemistry, they target either the pyrrole
N
N+
O–
N
O
H
N
H
2
1
N
N
N
NH2
OH
N
N
N
O
O
O
NH
O
N
O
N
N
N
N
N
N
N
H
H2N
H
BMS-378806
(HIV attachment
inhibitor) [ref. 6]
BRL 54504AX
(anxiety) [ref. 6,7]
DF 1012
(non-narcotic
antitussive) [ref. 6]
variolins (PharmaMar)
(antitumor) [ref. 6,7]
Figure 1 7-Azaindole (1), its N7-oxide 2, and 7-azaindole derivatives in clinical evaluation
SYNTHESIS 2008, No. 2, pp 0201–0214
x
x
.
x
x
.2
0
0
7
Advanced online publication: 18.12.2007
DOI: 10.1055/s-2007-1000853; Art ID: M04807SS
© Georg Thieme Verlag Stuttgart · New York

202
T. Storz et al.
PAPER
X
O
NaOH,
MeOH
HMDS,
benzene
N+
O–
N
N
X
N
N
X
N
H
H
O
2
4a X = Cl, 100%
4b X = Br, 99%
3a X = Cl, 60%
3b X = Br, 57%
Cl
O
+
TMSCN
THF
N
N
N
N
Cl
NC
O
O
6a 51%
5a 39%
Scheme 1 Selective halogenation and unselective cyanation/halogenation of 7-azaindole at C6 (Ohshiro et al.35)
tion from N1, electrophilicity at C6 is greatly diminished, To our surprise, O-alkylated derivatives of 7-azaindole-
so that access to 6-O- and especially 6-N-substituted 7- N7-oxide (2) have not been reported,41 perhaps because it
azaindoles via nucleophilic substitution usually is not was felt that, in analogy to the well-known reactivity of 1
practical.35b,36b,37 Interestingly, attempts by Oshiro et al. to towards alkylating agents (vide supra), the same undesir-
extend their Reissert–Henze reaction variant to the syn- able reaction channels would also predominate in the case
thesis of 6-cyano- or thiocyanato-7-azaindole met with of the corresponding N-oxide. Gratifyingly, a simple, un-
only limited success due to competing chloride attack at ambiguous NMR-tube experiment revealed that stoichio-
C6 (Scheme 1).35a
metric dimethyl sulfate in acetonitrile does not alkylate
the pyrrole nitrogen or C3 of the N-oxide MCBA (m-chlo-
robenzoic acid) salt 3,42 but, instead, leads to clean forma-
tion of O-methylated N-oxide methyl sulfate salt 4
(Scheme 2, Figure 2).43
In the context of a recent development project,27e,38 we
were interested in different syntheses of 4-cyano-39 and 6-
cyano-7-azaindole.23a Inspired by the results of Oshiro
(Scheme 1), we decided to reinvestigate different variants
of the Reissert–Henze reaction36 of 7-azaindole-N-ox-
ide.40
O
O
O
O
HO
O
S
Cl
4
N
CD3CN
N+
O
N
N+
O–
>95% by NMR
H
H
r.t. to 50 °C
(NMR tube)
Cl
O
O
–O
O
O
O
H3C
H+
–
S
3
O
OH
O
OH
+ B
O
OH
Nu-H
(MeO)2SO2
O-methylation
Nu
N
H
+ N
N
H
N
H
– BH+
N
+ N
O–
O
H
Cl
O
Cl
Cl
nucleophilic
addition
methanol
– MeOH
elimination
N
H
Nu
N
Scheme 2 Selective O-methylation of 7-azaindole-N7-oxide MCBA salt 3 followed by reaction with a nucleophile; a three-step, one-pot reaction
Synthesis 2008, No. 2, 201–214 © Thieme Stuttgart · New York

PAPER
Efficient One-Pot Synthesis of 6-Substituted 7-Azaindoles
203
as an O-methylating agent towards secondary, tertiary,
neopentylic alcohols, and phenols, respectively (usually
<30% desired product observed, mostly N-oxide 2 was
obtained back). Likewise, aliphatic thiolates gave the 6-S-
substituted 7-azaindole more cleanly than aromatic thi-
olates; and with heteroaromatic thiols (2-mercaptoazoles,
-diazoles and -diazines), S-methylation was again the
dominant reaction pathway (>60% formation of the S-me-
thylheterocycle and N-oxide 2 observed). With MCPBA,
the 6-thio-substituted 7-azaindole 10 underwent selective
oxidation to the corresponding sulfone (no N-oxidation
observed), a potentially interesting, stable building block
for introducing further functionality at C6 (Scheme 4).50,51
1) (MeO)2SO2, MeCN
75–80 °C
3
R
N
2) RONa, ROH
50–60 °C
O
N
H
one-pot
6 R = Me (81%)
7 R = Bn (85%)
8 R = All (73%)
1) (MeO)2SO2, MeCN
75–80 °C
3
R
2) RSNa, MeCN–
2-MeTHF
N
S
N
H
50–60 °C
9 R = 2-naphthyl (51%)
10 R = (CH2)11Me (63%)
Figure 2 1H-NOESY and 1H-15N-HMBC NMR data of in situ gene-
rated 4 (in CD3CN)
one-pot
MCPBA,
CH2Cl2
With the desired O-methyl-N-oxide salt 4 in hand, we ap-
plied a variant of the Okamoto–Tani cyanation
conditions44 known to be selective for the formation of 4-
cyano- over 2-cyanopyridine from O-methylpyridine-N-
oxide.36a,c The precipitated solid isolated in 76% yield by
a simple filtration from the aqueous ammonium chloride/
potassium cyanide reaction mixture was 95% pure by
HPLC, and turned out to be 6-cyano-7-azaindole (5)
(Scheme 3).45–47 No traces of the 4-cyano-regioisomer
were detected. To the best of our knowledge, this consti-
tutes the first direct and clean synthesis of a cyano-7-aza-
indole from the corresponding N-oxide and the most
practical synthesis of compound 5 to date23a (vide supra,
Scheme 1).48,49
R
N
S
N
H
O
O
11
R = (CH2)11Me (91%)
Scheme 4 Reaction of the O-methyl-N-oxide salt 4 with alcoholates
and thiolates
The reaction of 4 with a number of azoles gave predomi-
nantly the 6-substituted regioisomer and provides a mild
and quick route to previously inaccessible pharmaco-
phores 13–15; only the unsymmetrical (N1) coupling
product was obtained with 1,2,4-triazole (13)
(Scheme 5).51,52
1) (MeO)2SO2, n-BuOAc
75–80 °C
3
76%
1) (MeO)2SO2, MeCN
80%
N
2) KCN, aq NH4Cl
50 °C
NC
N
75–80 °C
N
H
N
N
N
3
H
2) K2CO3 or i-Pr2NEt
(3 equiv), azole (3 equiv)
95A% HPLC crude
13
N
one-pot
5
60%
75%
one-pot
Scheme 3 Reaction of in situ generated O-methyl-N-oxide salt 4
with aqueous potassium cyanide
N
N
N
H
14
N
Next we subjected 4 to a variety of oxygen and sulfur nu-
cleophiles and found that primary, allylic, and benzylic al-
cohols reacted cleanly and smoothly with 4 to give
exclusively the 6-O-substituted 7-azaindole in good
yields (Scheme 4).50,51 The N-oxide salt 4 behaved mainly
N
N
N
H
N
15
Scheme 5 Reaction of the O-methyl-N-oxide salt 4 with diazoles
and triazoles
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204
T. Storz et al.
PAPER
Table 1 6-Amino-Substituted 7-Azaindoles 16–27 Prepared from 3
(continued)
We found the new reaction to be most useful for the one-
pot conversion of the N-oxide salt 3 to 6-aminosubstituted
7-azaindoles. Direct regioselective introduction of nitro-
gen functionality at the 6-position of 7-azaindole was not
possible with previous synthetic methodology.37 Ammo-
nia, primary amines, a-branched and b-branched amines,
allylic amines, benzylic/heteroaromatic amines, propar-
gylic amines, secondary acyclic as well as secondary cy-
clic amines all reacted with in situ generated 4 to the
corresponding 6-amino-substituted 7-azaindoles 16–24
under mild conditions and in good yields.53 Furthermore,
both primary (1°, 2°) as well as secondary amino alcohols
were found to react in a completely chemoselective fash-
ion giving 25–27, respectively; concomitant O-arylation
was not observed (Table 1).
Nitrogen
nucleophile
Methoda Yield
(%)b
Product
N
B
63
N
N
O
NH
H
O
24
B
B
58
72
N
N
N
HO
NH2
H
H
OH
( )
25 ( )
Table 1 6-Amino-Substituted 7-Azaindoles 16–27 Prepared from 3
N
N
H
N
HO
NH2
H
OH
( )
Nitrogen
nucleophile
Methoda Yield
(%)b
Product
26 ( )
OH
N
H
B
73
N
N
NH
NH3
A
A
B
65
71
67
N
H2N
N
OH
(2S)
H
27 (2¢S)
15
a Method A: 1. 3 + dimethyl sulfate (1.05–1.10 equiv), MeCN, 50–
60 °C, 8–12 h; 2. NH3 (10 equiv, or MeNH2 in MeOH or EtOH),
50 °C, 8–12 h. Method B: 1. 3 + dimethyl sulfate (1.05–1.10 equiv),
MeCN, 50–60 °C, 8–12 h; 2. add 4–6 equiv of the corresponding
amine (in case of value-added amines: add 1.5 equiv of the amine +
3–4 equiv i-Pr2NEt) 40–60 °C; 8–12 h.
CF3COOH
x
MeNH2
N
H
N
H
N
17
18
b Isolated yields after flash chromatography on SiO2.
NH2
N
N
N
H
H
This mild reaction sequence also did not disappoint in the
one-pot conversion of 4-chloro-7-azaindole-N-oxide
MCBA salt 2854 to the corresponding 6-substituted deriv-
atives 30–32 (see Scheme 6): no SNAr product could be
detected.
O
B
B
83
70
NH2
N
N
N
H
O
H
19
Moreover, the same protocol allows the facile introduc-
tion of a- and w-amino acids as nitrogen substituents at C6
of 7-azaindole with full retention of optical purity. In this
way, the new, unnatural 7-azaindolyl amino acid deriva-
tives 33–37 (Table 2) were obtained, potentially useful
new building blocks for the construction of peptidomi-
metic drugs.55
NH2
N
N
N
H
H
20
N
B
B
77
68
N
N
H
N
NH2
N
H
In general, after aqueous workup, the crude 6-amino-sub-
stituted azaindoles were obtained ≥85% pure by HPLC
and only require minimal purification. This is remarkable,
considering that three separate reaction steps (O-methyla-
tion, nucleophilic addition, MeOH-elimination, see
Scheme 2) have to occur in this one-pot sequence. Ac-
cording to Katritzky56 and Abramovitch,57 the reaction of
N-alkoxypyridinium salts with nucleophiles can proceed
through a number of other reaction channels as well, such
as pyridine ring opening, alkylation of the nucleophile by
the R-group on the oxygen (vide supra), or deoxygenation
of the N-oxide with concomitant aldehyde formation.36a–d
21
NH2
N
N
N
H
H
22
N
Et2NH
B
87
N
N
H
23
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Efficient One-Pot Synthesis of 6-Substituted 7-Azaindoles
205
Cl
Cl
Cl
NaCN
aq NH4Cl
45 °C
1) (MeO)2SO2, MeCN
75–80 °C
Cl
Cl
30
31
N+
O–
N
N+
N
one-pot
H
H
O
OH–
N
H
NC
N
O
O–
O
O–
O
OMe
H+
28 [27b]
95%
Cl
S
O
NH3–EtOH
45 °C
29
one-pot
N
H
H2N
N
83%
Cl
NH2
r.t.
32
one-pot
N
N
N
H
H
55%
Scheme 6 Reaction of in situ generated 4-chloro-7-azaindole-O-methyl-N-oxide salt (28) with cyanide, ammonia, or propargylamine, respec-
tively
Table 2 6-Aminoacid-Substituted 7-Azaindoles 33–37 Prepared
a-Amino acid
Methoda
Yield (%)b
80
Productc
O
O
C
NH2
N
N
H
N
O
H
O
(Gly)
33
O
BnO
O
OBn
NH2
N
N
N
H
H
C
52
N
H
N
H
(D-Trp)
34
O
O
t-BuO
HO
HO
Ot-Bu
C
C
84
73
N
N
N
H
H
NH2
35
(L-Thr)
O
NH2
BnO
N
OBn
NH
N
N
H
N
H
H
BnO
O
BnO
O
O
(L-Lys)
36
NH2
N
N
O
N
H
C
67
O
NH2
NH
(L-Pro)
37
a Method C: 1. 3 + dimethyl sulfate (1.05 equiv), MeCN, 50–60 °C; 8–12 h; 2. amino acid (1.5–2.0 equiv) + i-Pr2NEt (2–3 equiv), MeCN, r.t.
–45 °C; 8–24 h.
b Yields are for isolated and chromatographed products.
c Optical purity: Amino acid 35 did not show any signs of erythro-diastereomer in the NMR and on achiral and chiral stationary phases. For
amino acids 34, 36 and 37, the opposite enantiomers were made and used as reference standards for chiral HPLC analysis; the enantiomeric
purities were in line with the optical purity of the commercial AA building blocks used: 34: er = 98.8:1.2; 36: er = 100:0; 37: er = 99.8:0.2.
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206
T. Storz et al.
PAPER
Erel (4-adduct)
Erel (6-adduct)
Nu
H
Nu
Nu
Nu–
+0.0
(favored)
NHMe
+2.1
N
+
N
+
H
H
N
N
N
N
OMe
H
H
OMe
OMe
+0.0
(favored)
OMe
CN
+3.1
4-adduct
6-adduct
+0.0
(favored)
+2.4
Nu
N
Erel (4-adduct)
+2.5
Erel (6-adduct)
Nu
+
+0.0
(favored)
NHMe
N
H
N
H
Nu
N
– MeOH
+0.0
(favored)
OMe
CN
+5.2
6-adduct
4-adduct
+0.0
(favored)
+0.5
R
+ MeOH
R
N
N
H
N
R
N
H
N
H
N
H
H
OMe
OMe
R
CN
∆Ea (kcal/mol)
+18.8
+21.0
+25.5
NHMe
OMe
Scheme 7 Relative energies (kcal/mol) of intermediate adducts and elimination products (B3LYP/6-31G* + ZPE)
As a rule, softer nucleophiles either react via the O-meth- trolled formation of the observed 6-cyano isomer to rapid
ylation pathway (phenols, heteroaromatic thiols) or tend 1,2-elimination of methanol from the disfavored 6-ad-
to give somewhat lower regioselectivities (aliphatic, aro- duct. B3LYP/6-31G* calculations locate a transition state
matic thiols, diazoles) than harder nucleophiles (amines, corresponding to a unimolecular, 1,2-syn-elimination of
aliphatic alcoholates), which give the 6-regioisomer al- MeOH, lying 18.8 kcal/mol in energy above the initial tet-
most exclusively. The observed regioselectivity, in accor- rahedral 6-cyano adduct. This pathway may constitute an
dance with that of the Reissert–Henze reaction of additional, thermally accessible avenue, not available to
thieno[2,3-b]- and furo[2,3-b]pyridine (a to the azine ring the 4-substituted species, to account for formation of the
nitrogen),58 is rationalized in part on the basis of the ther- observed 6-cyano product; however, medium effects,
modynamic stabilities of both the initial intermediates, such as general acid-base catalysis and/or hydrogen bond-
and final products after MeOH elimination (Scheme 7).59 ing may also lower the elimination barrier and override
B3LYP/6-31G* geometry optimizations were performed the thermodynamic stability in the cyano case.
on the 4- and 6-substituted intermediates and final prod-
ucts corresponding to addition of methylamine, methanol,
and cyanide.
In accord with experimental findings for nitrogen- and ox- sert–Henze intermediates60 en route to a variety of 6-sub-
ygen-based nucleophiles, formation of the 6-regioisomers stituted 7-azaindoles not readily accessible via previous
of both intermediate adduct and methanol elimination synthetic methodology.38
In summary, the newly discovered 7-O-methyl-N-oxides
of 7-azaindole and 4-chloro-7-azaindole, respectively,
lend themselves as versatile and convenient in situ Reis-
product are favored in
a
thermodynamic sense
(Scheme 7). Curiously, addition of cyanide at the 4-posi-
tion is predicted to be thermodynamically preferred, both
in terms of the initial adduct intermediate and final elimi-
nated product. We therefore attribute the kinetically-con-
All reactions were carried out under N2. All reagents were obtained
from Aldrich. TLC was performed on silica gel 60 F254 (Merck)
with detection by UV light and/or staining with anisaldehyde. Flash
chromatography (FC) was performed on silica gel 60 (EMD, 40–63
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Efficient One-Pot Synthesis of 6-Substituted 7-Azaindoles
207
mm). The 1H and 13C NMR spectra were recorded on a Bruker 400,
500 or 600 MHz spectrometer. IR spectra were recorded using a
universal ATR sampling unit. All yields are isolated yields for chro-
matographed (HPLC ≥ 95A%) products (HPLC purity = area% at
254 nm unless otherwise indicated).
6-Allyloxy-7-azaindole (8)
Yield: 650 mg (73%); off-white crystalline solid; mp (DSC)
69.3 °C.
1H NMR (500 MHz, DMSO-d6): d = 11.44 (br s, 1 H), 7.86 (d,
J = 8.3 Hz, 1 H), 7.20 (dd, J = 2.5, 3.3 Hz, 1 H), 6.55 (d, J = 8.3 Hz,
1 H), 6.35 (dd, J = 3.3, 1.9 Hz, 1 H), 6.12 (ddd, J = 17.2, 10.5, 5.3
Hz, 1 H), 5.39 (dq, J = 17.2, 3.2, 1.7 Hz, 1 H), 5.23 (dq,
J = 10.5, 3.2, 1.4 Hz, 1 H), 4.83 (dt, J = 5.3, 1.7, 1.4 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 159.2, 145.6, 134.2, 131.5,
122.6, 116.9, 113.8, 103.3, 100.1, 65.7.
HRMS (MALDI-TOF): m/z calcd for C10H11N2O [M + H+]:
175.08659; found: 175.08610.
6-Cyano-7-azaindole (5)
A suspension of N-oxide MCBA salt 327d (3.5 g, 12.04 mmol) and
dimethyl sulfate (1.38 mL, 14.45 mmol) in anhyd BuOAc (17.5
mL) was stirred under N2 at 75–80 °C overnight. After cooling to
4 °C, the upper BuOAc phase was separated and discarded. The
lower, purple phase was washed with cyclohexane (5 mL) and di-
luted with sat. aq NH4Cl (25 mL). KCN (2.4 g, 3.0 equiv) was added
and the purple mixture was stirred overnight at 50 °C, then cooled
to 4 °C and filtered. The filter cake was rinsed with aq sat. NaHCO3
(5 mL) and H2O (5 mL) and dried in vacuo to afford 5 (1.309 g,
76%) as a slightly yellowish crystalline solid (HPLC: 95A% [245
nm]); mp (DSC) 187.4 °C (Lit.23a mp 175–177 °C).
6-(2-Naphthylthio)-7-azaindole (9)
This compound was prepared via a similar procedure as for the al-
cohols 6–8, except that the sodium thiolate solution (5 equiv thiol +
5 equiv NaH) was generated in 2-methylteterahydrofuran; yield:
268 mg (51%); off-white crystalline solid; mp (DSC) 196.3 °C.
1H NMR (500 MHz, DMSO-d6): d = 11.67 (br s, 1 H), 8.14 (s, 1 H),
7.96–7.92 (m, 3 H), 7.88 (d, J = 8.2 Hz, 1 H), 7.58–7.55 (m, 2 H),
7.53 (dd, J = 8.6, 1.4 Hz, 1 H), 7.41 (br t, J = 3, 2 Hz, 1 H), 6.92 (d,
J = 8.2 Hz, 1 H), 6.42 (br d, J = 2 Hz, 1 H).
IR (KBr): 2229 cm–1 (C≡N).
1H NMR (500 MHz, DMSO-d6): d = 12.25 (br s, 1 H, NH), 8.18 (d,
3J4,5 = 8 Hz, 1 H, H-4), 7.83 (t, 3J2,3 = 3J2,NH = 3.2 Hz, 1 H, H-2), 7.62
(d, 3J5,4 = 8 Hz, 1 H, H-5), 6.63 (dd, 3J3,2 = 3.4 Hz, 4J3,NH = 1.9 Hz,
1 H, H-3).
13C NMR (125 MHz, DMSO-d6): d = 150.2, 148.4, 133.4, 132.3,
131.8, 130.4, 130.3, 129.4, 128.9, 127.6, 127.5, 126.7, 126.0, 117.8,
115.4, 100.1.
HRMS (MALDI-TOF): m/z calcd for C17H13N2S [M + H+]:
277.07940; found: 277.07957.
13C NMR (125 MHz, DMSO-d6): d = 148.3 (C7a), 131.7 (C2),
129.5 (C4), 124.2 (C6), 123.4 (C3a), 120.4 (C5), 119.5 (C≡N).
HRMS (MALDI-TOF): m/z calcd for C8H6N3 [M + H+]: 144.0564;
found: 144.0568.
6-Methoxy-7-azaindole (6); Typical Procedure
The procedure given below is not optimized.
6-Dodecylthio-7-azaindole (10)
Yield: 1.0 g (63%); slightly pinkish crystalline solid; mp (DSC)
77.3 °C.
A suspension of N-oxide MCBA salt 327d (1.69 g, 5.81 mmol) and
dimethyl sulfate (0.6 mL, 6.39 mmol) in anhyd MeCN (15 mL) was
stirred overnight under N2 at 60–65 °C. After cooling to r.t., a soln
of NaOMe in MeOH (25 wt%, Aldrich, 6.6 mL) was added, and the
turbid mixture was stirred overnight at 60–65 °C. After neutraliza-
tion with AcOH and diluting with MeOH, the mixture was evapo-
rated to dryness. The residue was taken up in CH2Cl2 (20 mL) and
washed with aq NaHCO3 (2 × 5 mL). The aqueous layers were ex-
tracted with EtOAc (10 mL). The combined organic phases were
dried (Na2SO4) and evaporated to dryness. Flash chromatography61
on SiO2 (hexanes–EtOAc) yielded 6 (695 mg, 81%) as a white crys-
talline solid; mp (DSC) 89.4 °C.
1H NMR (500 MHz, DMSO-d6): d = 11.40 (br s, 1 H, NH), 7.84 (d,
3J = 8.4 Hz, 1 H, H-4), 7.18 (dd, 3J = 3.3, 2.5 Hz, 1 H, H-2), 6.52 (d,
3J = 8.4 Hz, 1 H, H-5), 6.34 (dd, 3J = 3.3 Hz, 4J = 2.5 Hz, 1 H, H-3),
3.86 (s, 3 H, OCH3).
13C NMR (125 MHz, DMSO-d6): d = 160.4, 146.2, 131.8, 122.9,
114.1, 103.7, 100.6, 53.4.
1H NMR (400 MHz, DMSO-d6): d = 11.56 (br s, 1 H), 7.80 (d,
J = 8.2 Hz, 1 H), 7.31 (dd, J = 3.5, 2.5 Hz, 1 H), 6.92 (d, J = 8.2 Hz,
1 H), 6.37 (br dd, J = 2, 3.3 Hz, 1 H), 3.16 (t, J = 7.3 Hz, 2 H), 1.68–
1.61 (m, 2 H), 1.44–1.37 (m, 2 H), 1.32–1.16 (m, 16 H), 0.85 (t,
J = 6.8 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 150.5, 148.3, 128.8, 124.4,
116.4, 114.2, 100.0, 31.3, 29.6, 29.1, 29.0, 28.95, 28.7, 28.6, 28.3,
22.1, 14.0.
HRMS (MALDI-TOF): m/z calcd for C19H31N2S [M + H+]:
319.22025; found: 319.21952.
6-Dodecylsulfonyl-7-azaindole (11)
To a soln of the thioether 10 (860 mg, 2.69 mmol) in CH2Cl2 (30
mL) was added MCPBA (1.1 g, 5.40 mmol) at 0 °C. The resulting
lemon-yellow suspension was allowed overnight to reach r.t. and
quenched at 0 °C by adding aq 0.2 M Na2S2O3 (5 mL). After dilu-
tion with CH2Cl2 (30 mL), phases were separated and the organic
phase was washed with aq NaHCO3 (15 mL) and brine (15 mL).
The organic phases were dried (MgSO4) and evaporated to dryness
under reduced pressure. After FC on SiO2, 11 was obtained (855
mg, 91%) as a slightly yellowish crystalline solid; mp (DSC)
87.1 °C.
HRMS (MALDI-TOF): m/z calcd C8H9N2O [M + H+]: 149.07094;
found: 149.07122.
6-Benzyloxy-7-azaindole (7)
Yield: 980 mg (85%); slightly yellowish; amorphous solid.
1H NMR (500 MHz, DMSO-d6): d = 11.46 (br s, 1 H), 7.87 (d,
J = 8.4 Hz, 1 H), 7.45–7.30 (m, 5 H, C6H5), 7.19 (br d, J = 2.8 Hz,
1 H), 6.59 (d, J = 8.4 Hz, 1 H), 6.36 (br d, J = 3.2 Hz, 1 H), 5.38 (s,
2 H, OCH2).
13C NMR (125 MHz, DMSO-d6): d = 159.8, 146.0, 138.1, 132.0,
128.8, 128.3, 128.1, 123.1, 114.4, 103.9, 100.7, 67.1.
HRMS (MALDI-TOF): m/z calcd for C14H13N2O [M + H+]:
225.10237; found: 225.10250.
IR (KBr): 1324/1310, 1149/1110 cm–1 (O=S=O).
1H NMR (600 MHz, DMSO-d6): d = 12.32 (br s, 1 H), 8.26 (d,
J = 8.1 Hz, 1 H), 7.84 (br t, J = 3 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 1 H),
6.66 (br dd, J = 1.7, 3.2 Hz, 1 H), 3.41–3.37 (m, 2 H), 1.58–1.52 (m,
2 H), 1.32–1.10 (m, 18 H), 0.84 (t, J = 6.8 Hz, 3 H).
13C NMR (150 MHz, DMSO-d6): d = 149.1, 147.6, 131.6, 129.9,
123.5, 113.7, 101.1, 52.3, 31.8, 29.5, 29.3, 29.2, 29.1, 28.8, 27.9,
22.6, 22.5, 14.4.
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HRMS (MALDI-TOF): m/z calcd for C19H30N2O2SNa [M + Na+]:
373.19202; found: 373.19269.
55 °C. After cooling to r. t., the suspension was evaporated to dry-
ness, and the solid residue partitioned between CH2Cl2 (10 mL) and
10% aq Na2CO3 (2.5 mL). The aqueous phase was extracted with
CH2Cl2 (3 × 5 mL) and the combined organic layers were washed
with 10% aq Na2CO3 (3 mL), brine (3 mL), and H2O (3 mL). After
drying (MgSO4) and evaporating to dryness, flash chroma-
tography61 of the crude product (84A% HPLC) with toluene–
EtOAc afforded 1635b (373 mg, 65%) as an amber crystalline solid
(99.5A% HPLC, 230 nm). Anhyd MeNH2 in EtOH (33 wt%, 5.8
mL) was used for the preparation of 17 (860 mg, 71%, TFA-salt
[isolated by preparative RP-HPLC on a C18-phase, MeCN–H2O,
1% TFA]).
Procedure B: A suspension of N-oxide MCBA salt 327d (1.50 g, 5.15
mmol) and dimethyl sulfate (0.55 mL, 5.65 mmol) in anhyd MeCN
(10 mL) was stirred overnight under N2 at 55–60 °C. After cooling
to r.t., DL-2-aminopropan-1-ol (2.0 mL, 25.5 mmol) was added
slowly and the mixture was stirred overnight under N2 at 50–55 °C.
After cooling to r. t., the suspension was concentrated under re-
duced pressure, and the residue partitioned between CH2Cl2 (10
mL) and 10% aq Na2CO3 (2.5 mL). The aqueous phase was extract-
ed with CH2Cl2 (3 × 5 mL), and the combined organic layers were
washed with 10% aq Na2CO3 (3 mL), brine (3 mL), H2O (3 mL),
and dried (MgSO4). After concentrating to dryness, flash
chromatography61 of the crude evaporated residue (900 mg, 82A%
HPLC, 230 nm) with CH2Cl2–MeOH afforded 26 (710 mg, 72%) as
a caramel-colored solid. Similarly compounds 18–25 and 27 were
prepared using 3–6 equiv of the corresponding amine nucleophile.
6-(1,2,4-Triazol-2-yl)-7-azaindole (13); Typical Procedure
A suspension of N-oxide MCBA salt 327d (2.5 g, 8.60 mmol) and
dimethyl sulfate (1.0 mL, 10.32 mmol) in anhyd MeCN (15 mL)
was stirred under N2 at 60 °C overnight. The purple solution was di-
vided up into five equal aliquots. To one of the aliquots was added
1,2,4-triazole (360 mg, 5.2 mmol) and anhyd K2CO3 (1.2 g, 8.6
mmol). After stirring overnight at 60 °C and cooling to r.t., the sus-
pension was neutralized with aq AcOH and evaporated to dryness.
The solid residue was partitioned between CH2Cl2 (10 mL) and 10%
aq Na2CO3 (3 mL), and the combined organic layers washed with
brine (3 mL) and H2O (3 mL). After drying (MgSO4) and evaporat-
ing to dryness, flash chromatography61 of the crude product with
hexanes–EtOAc afforded 13 (255 mg, 80%) as an off-white crystal-
line solid; mp (DSC) 225.5 °C. Trace amounts of the 4-isomer are
readily removed during purification; purity: ≥95A% HPLC.
1H NMR (500 MHz, DMSO-d6): d = 11.95 (br s, 1 H, NH), 9.26 (s,
1 H), 8.27 (s, 1 H), 8.20 (d, J = 8.3 Hz, 1 H), 7.61 (d, J = 8.3 Hz, 1
H), 7.56 (br t, J = 3 Hz, 1 H), 6.55 (d, J = 3 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6) d: 152.5, 146.0, 143.4, 141.3,
131.4, 127.4, 119.7, 105.2, 100.5.
HRMS (MALDI-TOF): m/z calcd for C9H8N5 [M + H+]: 186.07742;
found: 186.07732.
6-(Benzimidazol-1-yl)-7-azaindole (14)
Prepared by adding benzimidazole (615 mg, 5.2 mmol) to one of the
aliquots obtained in the typical procedure described above; yield:
244 mg (60%); off-white crystalline solid; mp (DSC) 210.8 °C.
Trace amounts of the 4-isomer are readily removed during purifica-
tion; purity: ≥95A% HPLC.
1H NMR (500 MHz, DMSO-d6): d = 11.96 (br s, 1 H), 8.91 (s, 1 H),
8.33 (d, J = 8.0 Hz, 1 H), 8.22 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 7.9
Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 3.4 Hz, 1 H), 7.39
(m, 1 H), 7.33 (m, 1 H).
6-Amino-7-azaindole (16)
Yield: 373 mg (65%); crystalline solid; mp (DSC) 126.7 °C (Lit.35b
mp 118–119 °C).
1H NMR (600 MHz, DMSO-d6): d = 10.79 (br s, 1 H, NH), 7.54 (d,
3J4,5 = 8.4 Hz, 1 H, H-4), 6.91 (dd, 3J2,3 = 3.0 Hz, 3J2,NH = 2.4 Hz, 1
H, H-2), 6.25 (d, 3J5,4 = 8.4 Hz, 1 H, H-5), 6.16 (dd, 3J3,2 = 3.3 Hz,
4J3,NH = 2.4 Hz, 1 H, H-3), 5.56 (br s, 2 H, NH2).
13C NMR (150 MHz, DMSO-d6): d = 155.7, 147.5, 129.8, 119.9,
110.7, 102.7, 99.95.
13C NMR (125 MHz, DMSO-d6): d = 147.1, 144.5, 144.4, 142.8,
132.6, 131.6, 127.2, 123.9, 123.4, 120.2, 118.7, 114.0, 107.6, 100.8.
HRMS (MALDI-TOF): m/z calcd for C14H11N4 [M + H+]:
HRMS (MALDI-TOF): m/z calcd for C7H8N3 [M + H+]: 134.07127;
found: 134.07150.
235.09782; found: 235.09801.
6-Methylamino-7-azaindole Trifluoroacetic Acid Salt (17)
Yield: 860 mg (71%); off-white crystalline solid; mp (DSC)
99.6 °C.
(Indazol-1-yl)-7-azaindole (15)
Prepared by adding indazole (615 mg, 5.2 mmol) to one of the ali-
quots obtained in the typical procedure described above; yield: 302
mg (75%); white crystalline solid; mp (DSC) 215.2 °C. Trace
amounts of the 4-isomer are readily removed during purification;
purity: ≥95A% HPLC.
1H NMR (500 MHz, DMSO-d6): d = 11.81 (br s, 1H), 8.91 (dd,
J = 8.6, 0.6 Hz, 1 H), 8.41 (s, 1 H), 8.15 (d, J = 8.45 Hz, 1 H), 7.91
(d, J = 8 Hz, 1 H), 7.77 (d, J = 8.45 Hz, 1 H), 7.57 (m, 1 H), 7.48 (br
d, J = 3.3 Hz, 1 H), 7.32 (br t, J = 7.45 Hz, 1 H), 6.51 (d, J = 3.3 Hz,
1 H).
1H NMR (600 MHz, DMSO-d6): d = 11.79 (br s, 1 H), 8.04 (br d,
J = 8.85 Hz, 1 H), 7.10 (m, 1 H), 6.56 (br d, J = 8.85 Hz, 1 H), 6.44
(m, 1 H), 2.96 (br s, 3 H).
13C NMR (150 MHz, DMSO-d6): d = {159.1, 158.9, 158.7, 158.4}
(C=O [CF3COO–]), 151.4, 136.9, 136.4, 121.4, {119, 117, 115,
113} (CF3 [CF3COO–]), 111.3, 103.2, 102.2, 28.7.
HRMS (MALDI-TOF): m/z calcd for C8H9N3Na (free base) [M +
Na+]: 170.06887; found: 170.06837.
6-Cyclopropylamino-7-azaindole (18)
Yield: 542 mg (67%); brownish crystalline solid; mp (DSC)
115.3 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.0 (br s, 1 H), 7.60 (d, J = 8.4
Hz, 1 H), 6.94 (m, 1 H), 6.47 (br s, 1 H), 6.37 (d, J = 8.4 Hz, 1 H),
6.18 (m, 1 H), 2.56 (m, 1 H), 0.68 (m, 2 H), 0.42 (m, 2 H).
13C NMR (150 MHz, DMSO-d6): d = 156.0, 147.7, 129.5, 120.0,
110.9, 101.8, 99.8, 24.1, 6.8.
HRMS (MALDI-TOF): m/z calcd for C10H12N3 [M + H+]:
174.10257; found: 174.10205.
13C NMR (125 MHz, DMSO-d6): d = 148.6, 146.3, 138.3, 136.7,
131.4, 127.9, 126.0, 125.9, 122.6, 121.5, 117.3, 115.1, 106.2, 100.9.
HRMS (MALDI-TOF): m/z calcd for C14H11N4 [M + H+]:
235.09785; found: 235.09758.
Amino Adducts 16–27; Typical Procedures
Procedure A: A suspension of N-oxide MCBA salt 327d (1.23 g, 4.24
mmol) and dimethyl sulfate (0.45 mL, 4.63 mmol) in anhyd MeCN
(9 mL) was stirred under N2 at 55–60 °C for 14 h. After transferring
the mixture to a 25 mL glass pressure tube and cooling to 0–4 °C, a
soln of ammonia in MeOH (Aldrich, 7 M, anhyd, 10 mL) was added
slowly. The mixture was stirred overnight in the sealed tube at 50–
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Efficient One-Pot Synthesis of 6-Substituted 7-Azaindoles
209
6-(Tetrahydrofuran-2-ylmethyl)amino-7-azaindole (19)
Yield: 925 (83%); yellow amorphous solid.
6-(Morpholin-4-yl)-7-azaindole (24)
Yield: 416 mg (63%); yellowish crystalline solid; mp (DSC)
161.1 °C.
1H NMR (400 MHz, DMSO-d6): d = 11.09 (br s, 1 H), 7.75 (d,
J = 8.6 Hz, 1 H), 7.08 (dd, J = 2.4, 3.3 Hz, 1 H), 6.64 (d, J = 8.6 Hz,
1 H), 6.25 (dd, J = 2.0, 3.3 Hz, 1 H), 3.73 (m, 2 H), 3.41 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 155.9, 147.1, 130.0, 121.9,
112.1, 101.5, 99.7, 66.1, 46.4.
HRMS (MALDI-TOF): m/z calcd for C11H14N3O [M + H+]:
204.11314; found: 204.11319.
1H NMR (600 MHz, DMSO-d6): d = 10.91 (br s, 1 H), 7.52 (d,
J = 8.4 Hz, 1 H), 6.88 (dd, J = 2.4, 3.2 Hz, 1 H), 6.32 (d, J = 8.4 Hz,
1 H), 6.26 (t, J = 5.8 Hz, 1 H), 6.15 (dd, J = 2.0, 3.2 Hz, 1 H), 4.02
(m, 1 H), 3.79 (m, 1 H), 3.62 (m, 1 H), 3.38–3.30 (m, 2 H), 1.95–
1.55 (m, 4 H).
13C NMR (125 MHz, DMSO-d6): d = 155.3, 147.4, 129.5, 119.5,
110.1, 103.2, 100.0, 77.3, 67.0, 45.2, 28.8, 25.2.
HRMS (MALDI-TOF): m/z calcd for C12H16N3O [M + H+]:
218.12879; found: 218.12904.
( )-6-(Propan-2-ol-3-yl)amino-7-azaindole (25)
Yield: 510 mg (58%); brownish crystalline solid; mp (DSC)
160.2 °C.
IR (KBr): 3312, 3242 (s) cm–1 (O–H).
1H NMR (600 MHz, DMSO-d6): d = 10.90 (br s, 1 H, exch. D2O),
7.53 (d, J = 8.4 Hz, 1 H), 6.88 (t, J = 2.8 Hz, 1 H), 6.31 (d, J = 8.4
Hz, 1 H), 6.18 (br t, J = 5.6 Hz, exch. D2O, 1 H), 6.15 (br d, J = 1.9
Hz, 1 H), 4.82 (br s, 1 H, exch. D2O), 3.82 (m, 1 H), 3.25–3.17 (m,
2 H), 1.10 (d, J = 6.5 Hz, 3 H).
6-Allylamino-7-azaindole (20)
Yield: 625 (70%); slightly pinkish crystalline solid; mp (DSC)
71.2 °C.
1H NMR (600 MHz, DMSO-d6): d = 10.92 (br s, 1 H), 7.54 (d,
J = 8.3 Hz, 1 H), 6.89 (dd, J = 2.4, 3.3 Hz, 1 H), 6.38 (t, J = 5.75 Hz,
1 H), 6.31 (d, J = 8.3 Hz, 1 H), 6.15 (dd, J = 2.0, 3.3 Hz, 1 H), 5.96
(m, 1 H), 5.20 (m, 1 H), 5.05 (m, 1 H), 3.92 (m, 2 H).
13C NMR (150 MHz, DMSO-d6): d = 155.1, 147.5, 136.9, 129.6,
119.6, 114.6, 110.3, 103.1, 100.0, 43.4.
HRMS (MALDI-TOF): m/z calcd for C10H12N3 [M + H+]:
13C NMR (150 MHz, DMSO-d6): d = 155.6, 147.4, 129.6, 119.5,
110.1, 103.2, 100.0, 65.5, 49.2, 21.5.
174.10257; found: 174.10201.
15N NMR (60.8 MHz, DMSO-d6): d = 218.5, 137.1, 75.2.
HRMS (MALDI-TOF): m/z calcd for C10H14N3O [M + H+]:
192.11314; found: 192.11222.
6-(Pyridin-4-ylmethyl)amino-7-azaindole (21)
Yield: 890 mg (77%); reddish oil.
1H NMR (500 MHz, DMSO-d6): d = 10.94 (br s, 1 H), 8.46 (d,
J = 5.9 Hz, 2 H), 7.59 (d, J = 8.6 Hz, 1 H), 7.32 (d, J = 5.9 Hz, 1 H),
6.96 (br t, J = 8.1 Hz, 1 H), 6.90 (dd, J = 2.5, 3.2 Hz, 1 H), 6.38 (d,
J = 8.6 Hz, 1 H), 6.17 (dd, J = 2.0, 3.4 Hz, 1 H), 4.55 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 154.9, 150.6, 149.3, 147.4,
129.9, 122.2, 119.9, 110.7, 103.1, 100.1, 43.4.
( )-6-(Propan-1-ol-2-yl)amino-7-azaindole (26)
Yield: 634 mg (72%); yellowish crystalline solid; mp (DSC)
108.9 °C.
IR (KBr): 3377 (s) cm–1 (O–H).
1H NMR (600 MHz, DMSO-d6): d = 10.89 (br s, 1 H), 7.51 (d,
J = 8.5 Hz, 1 H), 6.88 (dd, J = 2.6, 3.1 Hz, 1 H), 6.27 (d, J = 8.5 Hz,
1 H), 6.14 (dd, J = 2.0, 3.3 Hz, 1 H), 5.94 (d, J = 7.7 Hz, 1 H), 4.72
(br s, 1 H), 3.96 (m, 1 H), 3.51 (m, 1 H), 3.33 (m, 1 H), 1.14 (d,
J = 6.5 Hz, 3 H).
13C NMR (150 MHz, DMSO-d6): d = 155.5, 147.9, 130.0, 119.9,
110.5, 103.9, 100.5, 65.5, 48.3, 18.2.
HRMS (MALDI-TOF): m/z calcd for C10H14N3O [M + H+]:
192.11314; found: 192.11259.
HRMS (MALDI-TOF): m/z calcd for C13H13N4 [M + H+]:
225.11347; found: 225.11397.
6-Propargylamino-7-azaindole (22)
Yield: 400 (68%); yellowish crystalline solid; mp (DSC) 104.7 °C.
IR (KBr): 2106 cm–1 (C≡C).
1H NMR (600 MHz, DMSO-d6): d = 11.05 (br s, 1 H), 7.59 (d,
J = 8.4 Hz, 1 H), 6.95 (dd, J = 2.5, 3.2 Hz, 1 H), 6.59 (br t, J = 5.9
Hz, 1 H), 6.33 (d, J = 8.4 Hz, 1 H), 6.18 (dd, J = 2.0, 3.2 Hz, 1 H),
4.06 (dd, J = 5.9, 2.5 Hz, 2 H), 2.98 (s, 1 H).
13C NMR (150 MHz, DMSO-d6): d = 154.3, 147.3, 129.7, 120.1,
110.8, 103.3, 100.0, 83.1, 72.1, 30.3.
(S)-6-(2-Hydroxymethylpyrrolidin-1-yl)-7-azaindole (27)
Yield: 840 mg (73%); light-yellow crystalline solid; mp (DSC)
118.4 °C.
IR (KBr): 3178 (s) cm–1 (O–H).
1H NMR (500 MHz, DMSO-d6): d = 11.04 (br s, 1 H), 7.67 (d,
J = 8.8 Hz, 1 H), 6.95 (dd, J = 2.4, 3.3 Hz, 1 H), 6.31 (d, J = 8.8 Hz,
1 H), 6.20 (dd, J = 1.8, 3.3 Hz, 1 H), 4.94 (br t, J = 4 Hz, 1 H, OH),
4.03 (m, 1 H), 3.62 (m, 1 H), 3.48 (m, 1 H), 3.35–3.20 (m, 2 H),
2.05–1.83 (m, 4 H).
13C NMR (125 MHz, DMSO-d6): d = 153.9, 147.6, 129.9, 120.4,
110.5, 101.1, 99.9, 62.1, 59.5, 48.0, 27.8, 23.0.
15N NMR (60.8 MHz, DMSO-d6): d = 222.7, 136.8, 92.5.
HRMS (MALDI-TOF): m/z calcd for C12H16N3O [M + H+]:
HRMS (MALDI-TOF): m/z calcd for C10H10N3 [M + H+]:
172.08692; found: 172.08679.
6-Diethylamino-7-azaindole (23)
Yield: 825 mg (87%); yellowish crystalline solid; mp (DSC)
67.4 °C.
1H NMR (500 MHz, DMSO-d6): d = 10.93 (br s, 1 H), 7.63 (d,
J = 8.6 Hz, 1 H), 6.93 (dd, J = 2.4 Hz, 1 H), 6.38 (d, J = 8.6 Hz, 1
H), 6.18 (dd, J = 2.0, 3.0 Hz, 1 H), 3.50 (q, J = 7.0 Hz, 4 H), 1.12 (t,
J = 7.0 Hz, 6 H).
13C NMR (125 MHz, DMSO-d6): d = 153.8, 147.9, 129.9, 120.1,
218.12879; found: 218.12874.
109.9, 100.0, 99.7, 42.0, 13.1.
4-Chloro-7-azaindole-7-oxide MCBA Salt 28
HRMS (MALDI-TOF): m/z calcd for C11H16N3 [M + H+]:
190.13387; found: 190.13359.
To a vigorously stirred suspension of 4-chloroazaindole27a (22.7 g,
148.77 mmol) in butyl acetate–heptane (3:5, 800 mL) was added
portionwise MCPBA (37.65 g, 163.65 mmol) under cooling in an
ice bath. The suspension was vigorously stirred and allowed over-
night to reach r.t. Suction filtration of the resulting white suspen-
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sion, followed by washing the filter cake with heptane (4 × 100 mL)
provided, after drying in vacuo, 28 as an off-white powdery solid
(42.72 g, 88%; 98.4% HPLC, 220 nm); mp (DSC) 151.9 °C.
1H NMR (600 MHz, DMSO-d6): d = 13.37 (br s, 1 H), 12.90 (br s,
1 H), 8.15 (d, J = 6.6 Hz, 1 H), 7.89 (m, 2 H) 7.68 (d, J = 8.0 Hz, 1
H), 7.56 (d, J = 3.1 Hz, 1 H), 7.52 (t, J = 8.1 Hz, 1 H), 7.20 (d, J =
6.6 Hz, 1 H), 6.58 (d, J = 3.1 Hz, 1 H).
13C NMR (150 MHz, DMSO-d6): d = 166.6, 133.8, 133.5, 133.1,
132.3, 131.1, 129.3, 128.4, 128.0, 123.9, 122.5, 116.5, 101.1.
HRMS (MALDI-TOF): m/z calcd for C7H6ClN2O [M + H+]:
169.01632; found: 169.01594.
suspension was concentrated under reduced pressure, and the resi-
due partitioned between CH2Cl2 (20 mL) and 10% aq Na2CO3 (5
mL). The aqueous phase was extracted with CH2Cl2 (3 × 5 mL), and
the combined organic layers were washed with 10% aq Na2CO3 (3
mL), brine (3 mL), H2O (3 mL), and dried (MgSO4). After concen-
trating to dryness, flash chromatography61 (toluene–EtOAc) of the
crude evaporated residue yielded 33 (600 mg, 80%) as a light yel-
low crystalline solid; mp (DSC) 114.4 °C.
Similarly compounds 34–37 were prepared at reaction temperatures
from r.t. to 45 °C. The yields given are isolated yields for chromato-
graphed (HPLC ≥94A%, 230 nm) products.
Optical purity was checked either via analytical HPLC on a Chiral-
cel OJ-H column (4.6 × 250mm, 5 mm, mobile phase: i-PrOH–hex-
ane), or via analytical SFC on a Chiralpak AD-H column [4.6 × 250
mm, 5 mm, mobile phase: MeOH (0.1% i-PrNH2)/scCO2], using the
opposite enantiomer as reference standards.
4-Chloro-6-cyano-7-azaindole (30)
Using the synthetic procedure for 5 (vide supra), 4-chloro-7-azain-
dole-N-oxide MCBA salt 28 (1.3 g, 3.98 mmol) gave 30 (675 mg,
95%) as slightly yellowish crystalline solid; mp (DSC) 213.0 °C.
IR (KBr): 3406 (NH), 1731 cm–1 (C=O).
IR (KBr): 2232 (C≡N).
1H NMR (500 MHz, DMSO-d6): d = 12.67 (br s, 1 H), 7.98 (d,
J = 3.4 Hz, 1 H), 7.89 (s, 1 H), 6.70 (d, J = 3.4 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 148.1, 134.4, 132.3, 124.3,
121.8, 119.5, 117.9, 99.0.
1H NMR (600 MHz, DMSO-d6): d = 10.95 (br s, 1 H), 7.57 (d,
J = 8.5 Hz, 1 H), 6.92 (m, 1 H), 6.65 (br t, J = 6.3 Hz, 1 H), 6.35 (d,
J = 8.5 Hz, 1 H), 6.18 (m, 1 H), 3.93 (d, J = 6.4 Hz, 2 H), 1.41 (s, 9
H).
13C NMR (150 MHz, DMSO-d6): d = 171.4, 155.2, 147.7, 130.1,
120.4, 111.1, 103.7, 100.4, 80.4, 44.0, 28.3.
HRMS (MALDI-TOF): m/z calcd for C8H5ClN3 [M + H+]:
178.01665; found: 178.01655.
15N NMR (60.8 MHz, DMSO-d6): d = 271.0, 188.1 (1JN,H = 90 Hz),
120.8 (1JN,H = 90 Hz).
6-Amino-4-chloro-7-azaindole (31)
Following the synthetic procedure for 16 [vide supra, using 2 M
NH3/EtOH (8 equiv) instead of NH3/MeOH], 4-chloro-7-azaindole-
N-oxide MCBA salt 28 (1.6 g, 4.92 mmol) gave 31 (690 mg, 83%)
as an amber crystalline solid; mp (DSC) 140.0 °C.
1H NMR (600 MHz, DMSO-d6): d = 11.14 (br s, 1 H), 7.02 (dd, J =
2.3, 3.3 Hz, 1 H), 6.36 (s, 1 H), 6.22 (dd, J = 3.3, 2.3 Hz, 1 H), 5.85
(br s, 2 H).
HRMS (MALDI-TOF): m/z calcd for C13H17N3O2Na [M + Na+]:
270.12130; found: 270.12192.
(S)-Na-(7-Azaindol-6-yl)tryptophan Benzyl Ester (34)
Reaction temperature: 45 °C; yield: 725 mg (52%); brownish vis-
cous oil.
IR (KBr): 3406 (s) (NH), 1728 (s) cm–1 (C=O).
13C NMR (150 MHz, DMSO-d6): d = 156.4, 148.3, 135.1, 121.0,
1H NMR (500 MHz, DMSO-d6): d = 10.95 (br s, 1 H), 10.88 (br s,
1 H), 7.59–7.53 (m, 2 H), 7.37 (d, J = 8.1 Hz, 1 H), 7.32–7.08 (m, 7
H), 7.00 (t, J = 7.1 Hz, 1 H), 6.92 (dd, J = 2.6, 3.1 Hz, 1 H), 6.77 (br
d, J = 8.2 Hz, 1 H), 6.40 (d, J = 8.6 Hz, 1 H), 6.18 (dd, J = 1.9, 3.3
Hz, 1 H), 5.07–5.00 (m, 2 H), 4.87 (q, J = 7.4 Hz, 1 H), 3.27 (dd, J =
6.3 Hz, 1 H), 3.19 (dd, J = 8.0, 14.1 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 174.5, 154.8, 147.5, 137.8,
136.7, 136.6, 130.1, 129.4, 128.7, 128.5, 128.1, 127.8, 127.6, 127.1,
126.9, 125.8, 124.3, 121.4, 120.5, 118.9, 118.6, 111.9, 111.3, 110.6,
103.9, 100.5, 65.9, 55.6, 28.4.
109.9, 101.7, 98.0.
HRMS (MALDI-TOF): m/z calcd for C7H7ClN3 [M + H+]:
168.03230; found: 168.03218.
4-Chloro-6-propargylamino-7-azaindole (32)
Applying the typical procedure B for 26 (vide supra, using 3 equiv
propargylamine overnight at r.t.), 32 was obtained from of 4-chloro-
7-azaindole-N7-oxide MCBA-salt 28 (vide supra, 925 mg, 2.84
mmol); yield: 320 mg (55%); slightly yellowish crystalline solid;
mp (DSC) 110.6 °C.
15N NMR (50.7 MHz, DMSO-d6): d = 320.8, 137.8, 131.4, 83.8.
HRMS (MALDI-TOF): m/z calcd for C25H23N4O2 [M + H+]:
IR (KBr): 2111 cm–1 (C≡C).
1H NMR (500 MHz, DMSO-d6): d = 11.44 (br s, 1 H), 7.06 (dd,
J = 3.4, 2.4 Hz, 1 H), 6.88 (br t, J = 2.3 Hz), 6.45 (s, 1 H), 6.25 (dd,
J = 2.3, 3.4 Hz, 1 H), 4.07 (dd, J = 5.7, 2.3 Hz), 3.05 (t, J = 2.3 Hz,
1 H).
13C NMR (125 MHz, DMSO-d6): d = 154.9, 148.0, 135.2, 121.3,
110.1, 102.3, 98.2, 82.6, 72.5, 30.4.
411.18155; found: 411.18202.
(S)-N-(7-Azaindol-6-yl)threonine tert-Butyl Ester (35)
Reaction temperature 45 °C; yield: 1.3 g (84%); brownish viscous
oil.
IR (KBr): 3383 (s/br) (OH/NH), 1727 cm–1 (C=O).
HRMS (MALDI-TOF): m/z calcd C10H9ClN3 [M + H+]: 206.04795;
found: 206.04778.
1H NMR (500 MHz, DMSO-d6): d = 10.90 (br s, 1 H, exch. D2O),
7.57 (d, J = 8.5 Hz, 1 H), 6.91 (br t, J = 2.8 Hz, 1 H), 6.47 (d, J = 8.5
Hz, 1 H), 6.17 (dd, J = 1.9, 3.3 Hz, 1 H), 6.10 (br d, J = 9.0 Hz, 1 H,
exch. D2O), 4.87 (d, J = 6.15 Hz, 1 H, exch. D2O), 4.37 (dd,
J = 3.7, 9.0 Hz, 1 H), 4.14 (m, 1 H), 1.38 (s, 9 H), 1.17 (d, J = 6.3
Hz, 3 H).
Chiral Amino Acid Adducts 33–37
N-(7-Azaindol-6-yl)glycine tert-Butyl Ester (33); Typical Proce-
dure
A suspension of N-oxide MCBA salt 3 (vide supra) (875 mg, 3.0
mmol) and dimethyl sulfate (0.303 ml, 3.16 mmol) in anhyd MeCN
(5 mL) was stirred overnight under N2 at 55–60 °C. After cooling
the resulting dark purple soln to r.t., glycine tert-butyl ester (790
mg, 6.0 mmol) and Hünig’s base (1.05 mL, 6.0 mmol) were added
slowly and the mixture was stirred overnight under N2 at r.t. The
13C NMR (125 MHz, DMSO-d6): d = 172.1, 155.4, 147.5, 130.1,
120.4, 111.2, 104.1, 100.4, 80.2, 67.6, 60.7, 28.2, 21.4.
15N NMR (50.7 MHz, DMSO-d6): d = 136.7 (NH), 75.1 (NH).
HRMS (MALDI-TOF): m/z calcd for C15H22N3O3 [M + H+]:
292.16557; found: 292.16619.
Synthesis 2008, No. 2, 201–214 © Thieme Stuttgart · New York

PAPER
Efficient One-Pot Synthesis of 6-Substituted 7-Azaindoles
211
(S)-Na-Cbz-Nw-(7-Azaindol-6-yl)lysine Benzyl Ester (36)
Reaction temperature: 30 °C; yield: 1.72 g (73%); brownish crystal-
line solid; mp (DSC) 95.7 °C.
1H NMR (500 MHz, DMSO-d6): d = 10.91 (br s, 1 H, exch. D2O),
7.82 (d, J = 7.7 Hz, 1 H, exch. D2O), 7.51 (d, J = 8.5 Hz, 1 H), 7.39–
7.23 (m, 10 H), 6.88 (dd, J = 2.5, 3.2 Hz, 1 H), 6.24 (d, J = 8.5 Hz,
1 H), 6.21 (br t, J = 5.5 Hz 1 H, exch. D2O), 6.14 (dd, J = 1.9, 3.3
Hz, 1 H), 5.13 (s, 2 H), 5.03 (AB system, 2 H), 4.11 (m, 1 H), 3.20
(AB system, 2 H), 1.76–1.61 (m, 2 H), 1.53 (m, 2 H), 1.40 (m, 1 H).
indole compounds in biological pathways: Kidder, G. W.;
Dewey, V. C. Biochim. Biophys. Acta 1955, 17, 288. (b)
For an early review on studies of biological activity of 7-
azaindoles, see: Yakhontov, L. N.; Prokopov, A. A. Russ.
Chem. Rev. (Engl. Transl.) 1980, 49, 428.
(6) Especially since the year 2000, the medicinal chemistry
literature on pharmaceutically active 7-azaindole derivatives
has increased exponentially; among others, their use has
been reported in the following categories: (a) As
constituents of anti-inflammatories: Saify, Z. N. Pakistan J.
Pharmacol. 1985, 2, 43. (b) See also: Henry, J. R.; Dodd, J.
H. Tetrahedron Lett. 1998, 39, 8763. (c) As anxiolytics:
Meade, E. A.; Beauchamp, L. M. J. Heterocycl. Chem. 1996,
33, 303. (d) As plant antifungals: Minakata, S.; Hamada, T.;
Komatsu, M.; Tsuboi, H.; Kikuta, H.; Ohshiro, Y. J. Agric.
Food Chem. 1997, 45, 2345. (e) As corticotropin releasing
hormone antagonists: Hodge, C. N.; Aldrich, P. E.;
Wasserman, Z. R.; Fernandez, C. H.; Nemeth, G. A.;
Arvanitis, A.; Cheeseman, R. S.; Chorvat, R. J.; Ciganek, E.;
Christos, T. E.; Gilligan, P. J.; Krenitsky, P.; Scholfield, E.;
Strucely, P. J. Med. Chem. 1999, 42, 819. (f) As
13C NMR (125 MHz, DMSO-d6): d = 172.9, 156.7, 155.9, 148.1,
137.4, 136.4, 129.9, 128.9, 128.8, 128.5, 128.3, 128.2, 119.9, 110.4,
103.6, 100.5, 66.4, 66.0, 54.6, 41.3, 31.0, 29.1, 23.7.
15N NMR (50.7 MHz, DMSO-d6): d = 269.4 (N7), 186.8 (N1),
138.0 (Lys-a-N), 128.9 (Lys-w-N).
HRMS (MALDI-TOF): m/z calcd for C28H31N4O4 [M + H+]:
487.23398; found: 487.23452.
(S)-Na-(7-Azaindol-6-yl)prolinecarboxamide (37)
Reaction temperature: 40 °C; yield: 690 mg (67%); yellowish vis-
cous oil.
antipsychotic agents: Kulagowski, J. J.; Broughton, H. B.;
Curtis, N. R.; Mawer, I. M.; Ridgill, M. P.; Baker, R.; Emms,
F.; Freedmann, S. B.; Marwood, R.; Patel, S.; Ragan, C. I.;
Leeson, P. D. J. Med. Chem. 1996, 39, 1941. (g) As
antitussive agents: Allegretti, M.; Anacardio, R.; Cesta, M.
C.; Curti, R.; Mantovanini, M.; Nano, G.; Topai, A.;
Zampella, G. Org. Process Res. Dev. 2003, 7, 209. (h) As
antivirals/anti-HIV agents: Soundararajan, N.; Benoit, S.;
Gingras, S. US Patent Appl. 2004/0044025, 2004. (i) See
also: Reeves, J. D.; Piefer, A. J. Drugs 2005, 65, 1747. (j)
See also: Yang, A.; Zadjura, L.; D’Arienzo, A. M.; Santone,
K.; Llunk, L.; Green, D.; Lin, P.-F.; Colonno, R.; Wang, T.;
Neanwell, N.; Hansel, S. Biopharm. Drug Dispos. 2005, 26,
387. (k) As PPARg modulators: Dropinski, J. F.; Akiyama,
T.; Einstein, M.; Habulihaz, B.; Doebber, T.; Berger, J. P.;
Meinke, P. T.; Shi, G. Q. Bioorg. Med. Chem. Lett. 2005, 15,
5035. (l) As inhibitors of various kinases (FAK, KDR, Tie2,
Aurora, JNK): Tabart, M.; Bacque, E.; Halley, F.; Ronan, B.;
Desmazeau, P.; Viviani, F.; Souaille, C. French Patent
2884821, 2006. (m) See also: Patel, V. F.; Askew, B.;
Booker, S.; Chen, G.; Dipietro, L. V.; Germain, J.; Habgood,
G. J.; Huang, Q.; Kim, T.; Li, A.; Nishimura, N.; Nomak, R.;
Riahi, B.; Yuan, C. C.; Elbaum, D. US Patent Appl. 2003/
3203922, 2003. (n) See also: Rodgers, J. D.; Wang, H.;
Combs, A. P.; Sparks, R. B. PCT Int. Appl. WO
1H NMR (600 MHz, DMSO-d6): d = 11.05 (br s, 1 H), 7.68 (d,
J = 8.5 Hz, 1 H), 7.26 (br s, 1 H), 6.97 (dd, J = 3.1, 2.5 Hz, 1 H),
6.94 (br s, 1 H), 6.24 (d, J = 8.5 Hz, 1 H), 6.21 (dd, J = 3.1, 1.9 Hz,
1 H), 4.25 (dd, J = 9.4, 10.2 Hz, 1 H), 3.68 (m, 1 H), 3.35 (m, 1 H),
2.14 (m, 1 H), 1.99–1.91 (m, 3 H).
13C NMR (150 MHz, DMSO-d6): d = 175.7, 153.4, 147.5, 129.7,
120.7, 110.9, 101.1, 99.8, 61.1, 47.9, 30.6, 23.7.
15N NMR (60.8 MHz, DMSO-d6): d = 223.6, 136.7, 103.2 (CONH2,
1JN,H = 87.9, 88.4 Hz), 91.6.
HRMS (MALDI-TOF): m/z calcd for C12H15N4O [M + H+]:
231.12404; found: 231.12440.
Acknowledgment
We are grateful to Dr. Paul Schnier for exact mass determinations.
Dr. J. Preston is thanked for DSC measurements and Mr. Milan Pet-
kovic for IR spectroscopic data.
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J. Org. Chem. 2002, 67, 6226. (e) Allegretti, M.;
Anacardio, R.; Cesta, M. C.; Curti, R.; Mantovanini, M.;
Nano, G.; Topai, A.; Zampella, G. Org. Process Res. Dev.
2003, 7, 209. (f) Helgen, C.; Bochet, C. G. Heterocycles
2006, 67, 797.
(13) (a) Wu, Q.; Hook, A.; Wang, S. Angew. Chem. Int. Ed. 2000,
39, 3933. (b) Tani, K.; Sakurai, H.; Fujii, H.; Hirao, T.
J. Organomet. Chem. 2004, 689, 1665.
(14) Reisch, J.; Dittmann, S. J. Heterocycl. Chem. 1993, 30, 379.
(15) (a) Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.;
Sacramento, J.; Sebastião, J. J. Chem. Soc., Perkin Trans. 1
2000, 3317. (b) Rolland-Fulcrand, V.; Haroune, N.;
Roumestant, M.-L.; Martinez, J. Tetrahedron: Asymmetry
2000, 11, 4719. (c) Huck, J.; Duru, C.; Roumestant, M.-L.;
Martinez, J. Synthesis 2003, 2165.
(26) (a) N1-Protected 7-azaindolin-3-one was obtained from
Bayer–Villiger oxidation of the corresponding 3-formyl
compound, see: Desarbre, E.; Mérour, J.-Y. Tetrahedron
Lett. 1994, 35, 1995. (b) N1-(Me, Et, Bn)-substituted 7-
azaisatin was obtained from the parent azaindole via
oxidation with NBS/DMSO, see: Tatsugi, J.; Zhiwei, T.;
Amano, T.; Izawa, Y. Heterocycles 2000, 53, 1145.
(27) (a) Clark, B. A. J.; Parrick, J. J. Chem. Soc., Perkin Trans. 1
1974, 2270. (b) Schneller, S. W.; Luo, J.-K. J. Org. Chem.
1980, 45, 4045. (c) Chen, C.-C.; Chang, C.-P.; Yu, W.-S.;
Hung, F.-T.; Liu, Y.-I.; Wu, G.-R.; Chou, P.-T. J. Phys.
Chem. A 2003, 107, 1459. (d) Soundararajan, N.; Benoit, S.;
Gingras, S. US Patent Appl. US 2004/0044025, 2004.
(e) Wang, X.; Zhi, B.; Baum, J.; Chen, Y.; Crockett, R.;
Huang, L.; Eisenberg, S.; Ng, J.; Larsen, R.; Martinelli, M.;
Reider, P. J. Org. Chem. 2006, 71, 4021.
(28) Thibault, C.; L’Heureux, A.; Bhide, R. S.; Ruel, R. Org. Lett.
2003, 5, 5023.
(29) Antonini, I.; Claudi, F.; Cristalli, G.; Franchetti, P.;
Grifantini, M.; Martelli, S. J. Med. Chem. 1982, 25, 1258.
(30) 4-Halo-7-azaindoles have been used as intermediates for
other 4-substituted and also polysubstituted 7-azaindoles,
for recent examples, see: (a) Allegretti, M.; Arcadi, A.;
Marinelli, F.; Nicolini, L. Synlett 2001, 609. (b)L’Heureux,
A.; Thibault, C.; Ruel, R. Tetrahedron Lett. 2004, 45, 2317.
(c) Thutewohl, M.; Schirok, H.; Bennabi, S.; Figueroa-
Pérez, S. Synthesis 2006, 629. (d) For a more
(16) Ahaidar, A.; Fernandez, D.; Danelon, G.; Cuevas, C.;
Manzanares, I.; Albericio, F.; Joule, J. A.; Alvarez, M.
J. Org. Chem. 2003, 68, 10020.
(17) Wang, K.; Stringfellow, S.; Dong, S.; Jiao, Y.; Yu, H.
Spectrochim. Acta, Part A 2002, 58, 2595.
(18) (a) Verbiscar, A. J. J. Med. Chem. 1972, 15, 149. (b) Oh,
S.-J.; Lee, K. C.; Lee, S.-Y.; Ryu, E. K.; Saji, H.; Choe, Y.
S.; Chi, D. Y.; Kim, S. E.; Lee, J.; Kim, B.-T. Bioorg. Med.
Chem. 2004, 12, 5505.
(19) Mewshaw, R. E.; Meagher, K. L.; Zhou, P.; Zhou, D.; Shi,
X.; Scerni, R.; Smith, D.; Schechter, L. E.; Andree, T. H.
Bioorg. Med. Chem. Lett. 2002, 12, 307.
comprehensive overview, see Refs. 3c,d.
(31) (a) 5-Bromo-7-azaindole (four steps from 1): Mazéas, D.;
Guillaumet, G.; Viaud, M.-C. Heterocycles 1999, 50, 1065.
(b) For a synthesis of 4,5-disubstituted 7-azaindoles from 4-
substituted 7-azaindoles via directed ortho-metalation, see
ref. 30b.
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PAPER
Efficient One-Pot Synthesis of 6-Substituted 7-Azaindoles
(44) (a) Ochiai and Nakayama were the first to report the
213
(32) See the recent comparison of synthetic routes for 5-amino-7-
azaindole: Pearson, S. E.; Nandan, S. Synthesis 2005, 2503.
(33) (a) Metalation and quenching with electrophiles of N1-
arylsulfonyl-protected 7-azaindole: Desarbre, E.; Coudret,
S.; Meheust, C.; Mérour, J.-Y. Tetrahedron 1997, 53, 3637.
(b) See also: Joseph, B.; Da Costa, H.; Mérour, J.-Y.;
Léonce, S. Tetrahedron 2000, 56, 3189. (c) Arylation of
N1-SEM-protected 7-azaindole: Touré, B. B.; Lane, B. S.;
Sames, D. Org. Lett. 2006, 8, 1979.
(34) Robison et al. had obtained 6-oxo-7-azaindole via
dehydrogenation, followed by acetyl group hydrolysis, of a
mixture of 5- and 6-acetoxy-1-acetyl-7-azaindoline:
Robison, M. M.; Robison, B. L.; Butler, F. P. J. Am. Chem.
Soc. 1959, 81, 743.
(35) (a) Minakata, S.; Komatsu, M.; Ohshiro, Y. Synthesis 1992,
661. The 6-halo-7-azaindoles described have been used as
starting materials for various transition metal-catalyzed C–C
coupling reactions, see: (b) Minakata, S.; Itoh, S.; Komatsu,
M.; Ohshiro, Y. Bull. Chem. Soc. Jpn. 1992, 65, 2992.
(c) See also ref. 30a. (d) Recently, a seven-step de novo
synthesis of a new cross coupling-reagent, N1-benzyl-6-
triflyloxy-7-azaindole, has been reported, see: Kerr, M.;
Zheng, X. Org. Lett. 2006, 8, 3777.
(36) (a) Henze, M. Ber. Dtsch. Chem. Ges. 1936, 69, 1566.
(b) Katritzky, A. R.; Lagowski, J. M. Chemistry of the
Heterocyclic N-Oxides; Academic Press: New York, 1971,
300–303. (c) Hayashi, E.; Higashino, T. Heterocycles 1979,
12, 837. (d) Fife, W. K.; Scriven, E. F. V. Heterocycles
1984, 22, 2375; and references cited therein.
formation of a cyanopyridine (2-cyano-4-chloropyridine)
from the reaction of cyanide with the corresponding O-alkyl
pyridinium salt: Ochiai, E.; Nakayama, I. Yakugaku Zasshi
1945, 65, 7; Chem. Abstr. 1945, 45, 49933. The reaction
was rediscovered and expanded independently by Okamoto/
Tani and Feely/Beavers: (b) Okamoto, T.; Tani, H. Chem.
Pharm. Bull 1959, 7, 130. (c) See also: Okamoto, T.; Tani,
H. Chem. Pharm. Bull 1959, 7, 925. (d) See also: Okamoto,
T.; Tani, H. Chem. Pharm. Bull 1959, 7, 930. (e) See also:
Feely, W. E.; Beavers, E. M. J. Am. Chem. Soc. 1959, 81,
4004. For later reports, see: (f) Matsumura, E.; Ariga, M.;
Ohfuji, T. Bull. Chem. Soc. Jpn. 1970, 43, 3210.
(g) Botteghi, C.; Schionato, A.; Chelucci, G.; Brunner, H.;
Kürzinger, A.; Obermann, U. J. Organomet. Chem. 1989,
370, 17. (h) Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.;
Fukaya, C.; Watanabe, M.; Yokoyama, K. Chem. Pharm.
Bull. 1990, 38, 2446. (i) Hibino, S.; Sugino, E. J.
Heterocycl. Chem. 1990, 27, 1751. (j) See also reviews
cited in ref. 36.
(45) A solvent screen for the O-methylation of 3 with dimethyl
sulfate (data not shown) revealed MeCN(homogeneous) and
butyl acetate(biphasic) as the most favorable solvents. In
MeCN, the O-methylation is very clean and proceeds at a
somewhat lower (55–60 °C) temperature than in butyl
acetate (85–90 °C). On the other hand, butyl acetate results
in a clear biphasic mixture with a lower, purple N-oxide salt
phase (‘ionic liquid layer’), that can be readily separated and
employed for reaction with nucleophiles in other solvents,
and a clear, upper phase (butyl acetate) containing most of
the m-chlorobenzoic acid. Although the cyanide reaction
also proceeds under nonaqueous conditions, NH4Cl-
buffered aqueous cyanide provides the cleanest reaction and
highest yield. A ‘blank reaction’ with NH4Cl alone did not
yield the 6-chloro product, in accordance with the
(e) Yakhontov, L. N.; Krasnokutskaya, D. M.; Akalaev, A.
N.; Palant, I. N.; Vainshtein, Yu. I. Khim. Geterotsikl.
Soedin. 1971, 789. (f) Fife, W. K.; Boyer, B. D.
Heterocycles 1984, 22, 1121. (g) Comins, D. L.; Joseph, S.
P. In Comprehensive Heterocyclic Chemistry II, Vol. 5;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: London, 1996, 70–78.
observations made with tetraalkylammonium halides under
(37) Indirect syntheses of 6-amino-substituted 7-azaindoles have
been achieved by: (1) reacting the corresponding 6-halo-7-
azaindole with ammonia or amines, but, as a rule, require
extended autoclaving at high temperatures/pressures,35a,b
and (2) by extended heating at high temperatures of the
corresponding 6-chloro-7-azaindoline with amines and
subsequent oxidation to the azaindole, see: (a) Yakhontov,
L. N.; Krasnokutskaya, D. M.; Akalaev, A. N. Dokl. Akad.
Nauk SSSR 1970, 192, 118. (b) See also: Yutilov, Yu. M.;
Svertilova, I. A. Khim. Geterotsikl. Soedin. 1986, 91. (c)
Oxidation/cyclization/elimination/decarboxylation of a 2,6-
diaminosubstituted pyridyl-3-b-keto ester: Sanders, W. J.;
Zhang, X.; Wagner, R. Org. Lett. 2004, 6, 4527.
(38) Germain, J.; Askew, B. C.; Bauer, D.; Choquette, D.;
Dipietro, L. V.; Graceffa, R.; Harmanage, J.-C.; Huang, Q.;
Kim, J. L.; La, D.; Li, A.; Nishimura, N.; Nomack, R.; Patel,
V.; Potashman, M.; Riahi, B.; Storz, T.; Van der Plas, S.;
Yang, K.; Yuan, C. PCT Int. Appl. WO 2007/048070, 2007.
(39) Cox, P. J.; Majid, T. N.; Lai, J. Y. Q.; Morley, A. D.;
Amendola, S.; Deprets, S.; Edlin, C. PCT Int. Appl. WO
2001047922, 2001.
forcing conditions (vide infra).48
(46) Increasing the steric bulk of the alkylating agent (EtI, i-PrI)
did not change the regioselectivity. Other cyanating reagents
[BzCN, TMSCN,62 (EtO)2P=O(CN)63] did not lead to
cyanated azaindole (data not shown).
(47) As clearly evidenced by 3J4,5 (8 Hz), which is the typical
coupling observed between the m-, and p-protons in ortho-
substituted pyridines.64
(48) Contrary to Ohshiro’s report35 (vide supra, Scheme 1), 6-
chloroazaindole was not observed as a side-product under
our conditions. In test reactions of 4 with TBACl, TBABr
and TBAI under forcing conditions (data not shown), no
reaction occurred with the chloride, whereas the bromide
and iodide reacted via the demethylation pathway
(formation of MeBr and MeI, respectively). Thus, it appears
the nature of the leaving group at N7 strongly determines the
site of nucleophilic attack at the ambident electrophile 4.
(49) (a) Vorbrüggen, H.; Krolikiewicz, K. Synthesis 1983, 316.
(b) Fife, W. K. J. Org. Chem. 1983, 48, 1375.
(50) In pyridine chemistry, 2-(alkyl/aryl)sulfonyl groups are
often used to introduce heteroatom substituents ortho to the
ring nitrogen; as a rule, they are more reactive than the
corresponding 2-halo compounds, see: Furukawa, N.;
Ogawa, S.; Kawai, T.; Oae, S. J. Chem. Soc., Perkin Trans.
1 1984, 1839.
(51) The reactivity of the O-methyl-7-azaindole-N-oxide salt 4
towards alcoholates, thiolates and azoles was somewhat
surprising considering the earlier unsuccessful attempts to
obtain the same types of addition products from Reissert–
Henze reactions of N-methoxypyridinium salts, see:
(40) Shiotani, S.; Taniguchi, K. J. Heterocycl. Chem. 1997, 34,
493.
(41) CAS & Beilstein online searches, June 2007.
(42) The MCBA salt 3 is the most practical way to isolate the N-
oxide 2 as it readily precipitates from a number of nonpolar
solvents during the oxidation of 1 with MCPBA (cf. refs.
27b,d,e). On the other hand, upon freebasing, 20%27d to
50%27e loss is typically incurred due to the high water
solubility of 2.
(43) Methyl ester formation of MCBA was also not observed.
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T. Storz et al.
PAPER
Kiselyov A. S., Strekowski L.; J. Heterocycl. Chem.; 1993,
30: 1361.
(59) For pyridinium salts, regioselectivity of nucleophilic attack
to yield either 1,2- or 1,4-dihydropyridines has been
explained by the formation of charge-transfer complexes,62
by Pearson’s HSAB-concept,66 and by kinetic versus
thermodynamic control;67 for a review, see: Poddubnyi, I. S.
Chem. Heterocycl. Comp. 1995, 31, 682.
(60) To the best of our knowledge, no other reports on Reissert–
Henze type reactions of 7-azaindole-N-oxide have appeared
in the literature (CAS/Beilstein searches June 2007). On the
other hand, Popp et al. had reported on a failed attempt to
obtain cyanated azaindole via the classical Reissert reaction
conditions: Veeraraghavan, S.; Popp, F. D. J. Heterocycl.
Chem. 1981, 18, 909.
(52) In the absence of a stronger base (typically Hünig base or
K2CO3), N-methylation of the azoles dominates (data not
shown). 6-N-(Heteroaromatic)-substituted 7-azaindoles
have not been reported (CAS/Beilstein, July 2007). Trace
amounts of the 4-isomer are readily removed during
purification; all yields are isolated yields for
chromatographed products (typically ≥95A% HPLC).
(53) Crude 6-amino adducts are typically ~85A% LC-pure
already and require minimal purification.
(54) It is more convenient to isolate the hitherto unknown MCBA
complex 28 of 4-chloro-7-azaindole-N-oxide than the free
base, since the isolation of the latter typically leads to
reduced yields.27b,28 A convenient protocol is given in the
experimental part (vide supra).
(61) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
(62) Kosower, E. M. J. Am. Chem. Soc. 1956, 78, 3497.
(63) Harusawa, S.; Hamada, Y.; Shioiri, T. Heterocycles 1981,
15, 981.
(55) Chiral N-(7-azaindolyl)-a-amino acids have not been
reported (CAS/Beilstein searches July 2007).
(56) Katritzky, A. R.; Lunt, E. Tetrahedron 1969, 25, 4291.
(57) Abramovitch, R. A.; Smith, E. M. Chem. Heterocycl. Comp.
1974, 14 (Suppl. 2), 1.
(58) Contrary to the behavior of the corresponding N,O- and
N,S-isosters of pyrrolo[2,3-b]pyridine, where both
thieno[2,3-b]-65 as well as furo[2,3-b]pyridine-N-oxide40
have been reported to give the a-cyanated product in good
yields in the Reissert–Henze reaction with benzoyl chloride
and cyanide.
(64) Pretsch, E.; Seibl, J.; Clerc, T.; Simon, W. Spectral Data for
Structure Determination of Organic Compounds; Springer-
Verlag: Heidelberg, 1989, 2nd ed., H275.
(65) Klemm, L. H.; Muchiri, D. R. J. Heterocycl. Chem. 1983,
20, 213.
(66) Lyle, R. E.; Gauthier, G. J. Tetrahedron Lett. 1965, 6, 4615.
(67) Damji, S. W. H.; Fyfe, C. A.; Smith, D.; Sharom, F. J. J. Org.
Chem. 1979, 44, 1761.
Synthesis 2008, No. 2, 201–214 © Thieme Stuttgart · New York