Two-Step Synthesis of Polysubstituted 6-Nitroindoles under Flow Chemical and Microwave Conditions

Article abstract of DOI:10.1002/adsc.201700790

A new simple and efficient synthesis of 6-nitroindoles, starting from N-carboxylalkylpyrrole-2-carboxaldehydes and protected β-nitro ketones, has been developed. The method involves two distinct domino processes, respectively performed under flow chemical conditions and microwave irradiation. 6-Nitroindoles were produced in good to excellent overall yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201700790

Title: Two-step Synthesis of Polysubstituted 6-Nitroindoles under Flow
Chemical and Microwaves conditions
Authors: Alessandro Palmieri, Serena Gabrielli, Roberto Ballini, and
Susanna Sampaolesi
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10.1002/adsc.201700790
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Two-step Synthesis of Polysubstituted 6-Nitroindoles under
Flow Chemical and Microwaves conditions
Susanna Sampaolesi,a Serena Gabrielli,a Roberto Ballinia and Alessandro Palmieria,*
a
Green Chemistry Group, School of Sciences and Technology, Chemistry Division, University of Camerino, Via S.
Agostino n. 1, 62032 Camerino (MC), Italy.
Phone: (+39)-0737-402262; Fax: (+39)-0737-402297; e-mail: alessandro.palmieri@unicam.it
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A new simple and efficient synthesis of 6- 6-Nitroindoles were produce from good to excellent overall
nitroindoles, starting from N-carboxylalkyl pyrrole-2- yields.
carboxaldehydes and protected β-nitro ketones, has been
developed. The method involves two distinct domino
processes, respectively performed under flow chemical
conditions and microwaves irradiations.
Keywords: heterocycles; flow chemistry; microwaves;
nitro compounds; domino reactions.
ex-novo synthesis of heterocycles,[11] we developed a
new general, simple and efficient protocol for
synthesizing 6-nitroindoles starting from β-protected
Introduction
The indole nucleus is probably the most ubiquitous
heterocyclic system in nature.[1] It is widely present in
many biological active molecules,[2] is extensively
used as synthetic precursor of strategic targets,[3] as
well as investigated in agrochemistry, essential oils,
material science, pigments and dyes.[4] For all these
reasons, since its discovery in 1866 by Adolf von
Baeyer,[5] the preparation and derivatization of
functionalized indoles are the research focus of many
chemists.[6] In this context, the nitro functionalized
indoles are valuable precursors of other important 6-
substituted derivatives,[7] due to the possibility to
convert the nitro group into many other
functionalities.[8]
nitro ketones
1
and N-protected pyrrolyl-2-
carboxaldehydes 2 (Scheme 2).
However, although their importance, only few
synthetic procedures are present in the literature for
their preparation, which can be classified in two main
approaches: (i) direct nitration of the indole nucleus,
and (ii) the ex-novo indole nucleus construction
starting from nitro functionalized arenes (Scheme 1).
The former approach often requires harsh reaction
conditions and provides good results only with
specific substituted indoles, shows a low functional
group tolerance and generally produces a mixture of
nitroindole isomers.[9] The second approach is based
on the reactivity of nitro arenes (mainly m-nitro
anilines and their derivatives) in combination with
carbonyl compounds, it involves the assembly of the
pyrrole moiety, providing the target compounds in
moderate yields, as a mixture of nitroindole
regioisomers as well.[10]
Scheme 1. Some synthetic examples of 6-nitroindoles
In this regard, with the aim to overcome these
limitations and following our studies concerning the
1
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10.1002/adsc.201700790
Advanced Synthesis & Catalysis
The method involves two distinct steps: (i) a base
promoted flow chemical nitroaldol-
transesterification-decarboxylation domino process,
which presumably passes via the intermediate A (as
analogously reported for Grignard reagents),[12] that
species can be continuously removed from the
reaction system, thus minimizing its interaction with
2a and preventing the formation of 5.
provides the adduct
3
by an elimination-
decarboxylation process; and (ii) a microwave
assisted
deprotection-cyclization-aromatization
cascade process, achieved under acidic conditions.
Scheme 3. Competitive N-decarboxylation
For this aim, we implemented a flow equipment
constituted of two different reservoirs, respectively
containing 1a and 2a (Reservoir A), and a base
(Reservoir B), a T-mixing piece (T1), a PTFE coil
reactor (R1, 20 mL, I.D. = 0.8 mm, O.D. = 1.58 mm),
and a back pressure regulator (Scheme 4).
Scheme 4. Flow Chemical approach
The solutions were pumped through the system by
two HPLC pumps and, after a deep screening in
terms of base, stoichiometry, temperature,
concentration and solvent (Table 1), the best yield of
3a (entry i, 61%) was obtained using a 0.15 M
dioxane solution of 1a and 2c, a 0.15 M dioxane
solution of DBU (1,5-diazabiciclo[5.4.0]undec-5-ene),
a flow rate of 2 mL/h for each pump (residence time
5 hours), at room temperature and in the presence of a
back pressure regulator (BPR) set at 2 atmospheres.
In order to confirm the generality of our approach,
we extended the reaction conditions used in entry i to
a wide range of β-protected nitro ketones and N-ethyl
carboxylate pyrrole-2-carboxaldehydes (Table 2).
In all cases, adducts 3 were obtained, as single E
diastereoisomer, in good yields. In particular, the 5-
Scheme 2. Two-step approach
Results and Discussion
In order to optimize the whole process, we firstly
focused our efforts to the first step (Scheme 3). In this
context, due to the low reactivity of 1a with the
unprotected pyrrole derivative 5,[13] we moved our
attention to the N-BOC protected derivative 2a (R1=H,
R2=t-Bu).
Unfortunately, even after a wide series of tests (for
more details see SI), the adduct 3a was isolated only
in 39% yield. This unsatisfactory result is probably
due to the competitive decarboxylation of 2a (giving
5), promoted by the tert-butoxyde (t-BuO-) generated
during the reaction.[14]
substituted
aldehydes
2g-j
furnished
the
corresponding adducts 3b, 3d, 3f-h and 3j in an
excellent range of yields from 70 to 95%.
At this point, with the purpose to remedy this
problem, we switched from batch to flow chemical
conditions (FCC). In this regard, exploiting the
peculiarity of flow chemistry,[15] the tert-butoxyde
2
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10.1002/adsc.201700790
Advanced Synthesis & Catalysis
Table 1. Optimization of the step I under FCC.
Entry
2 (eq.)
(1)
Base(eq.)
Solvent (M)
Total Flow Rate (mL/h)
Yield (%) of 3aa)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
TMG (1)
TBD (1)
DBU (1.5)
DBU (1)
DBU (1)
DBU (1)
2-MeTHF (0.1 M)
CPME (0.1 M)
DMF (0.1 M)
5
5
5
5
5
5
44
38
31
37
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
2c
2c
2c
2c
2c
2c
2c
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
MeCN (0.1 M)
Dioxane (0.1 M)
Dioxane (0.15 M)
Dioxane (0.2 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
Dioxane (0.15 M)
48
51
---
5
---b)
11
5
5
5
5
5
5
5
4
61
---c)
---c)
27
42
46
54
56
6.6
5
58
42d)
s
DBU (1)
5
35e)
a)
b)
c)
Yield of pure isolated products. Clogging of the reactor coil due to precipitate formation. Recovery of starting
materials d) Reaction performed at 0°C. e) Reaction performed at 50°C
Table 2. Synthesis of adducts 3a-j.
mg/mmol) as acid promoter, and using 2-MeTHF as
the solvent.
Table 3. Optimization studies of the step II.
Yield (%)
R
n
R1
of 3a)
Me
Me
Et
Et
1
1
1
1
1
1
1
1
2
2
H
61
70
54
90
55
95
89
79
52
88
1a
1a
1b
1b
1c
1d
1e
1e
1f
2c
2g
2c
2h
2c
2h
2i
2j
2c
2g
3a
3b
3c
3d
3e
3f
3g
3h
3i
Entry Acidic species
(mg/mmol)
Solvent
Time Yield
CH3(CH2)8
H
Ph(CH2)4
H
Ph(CH2)4
Cl(CH2)6
CH3(CH2)3
H
(min) of 4aa)
a
b
c
d
e
f
Amberlyst 15 (400) EtOAc
Amberlyst 15 (200) EtOAc
Amberlyst 15 (100) EtOAc
30
30
30
58b)
57b)
42b)
66b)
44b)
40b)
45b)
---b)
69c)
68d)
52e)
64c)
74c)
72c)
p-tBu-C6H4
p-Me-C6H4
Ph(CH2)2
Ph(CH2)2
H
Amberlyst 15 (200) 2-MeTHF 30
Amberlyst 15 (200) iPrOH
Amberlyst 15 (200) Dioxane
30
30
g
h
i
j
k
l
p-TsOH·H2O (190) 2-MeTHF 30
AcOH (1000) --- 30
H
CH3(CH2)8
1f
3j
a) Yield of pure isolated products.
Amberlyst 15 (200) 2-MeTHF 30
Amberlyst 15 (200) 2-MeTHF 30
Amberlyst 15 (200) 2-MeTHF 30
Amberlyst 15 (200) 2-MeTHF 15
Amberlyst 15 (200) 2-MeTHF 45
Once confirmed the goodness of the first step, we
moved our attention to optimize the conversion of
adducts 3a-j into the title targets 4a-j. Hence, based
on our previous experiences,[16] we investigated the
transformation of 3a into 4a under a variety of acidic
conditions. As shown in Table 3, we found the best
result (entry m, 74%), under microwave irradiation, at
100°C, in the presence of Amberlyst 15 (200
m
n
Amberlyst 15 (200) 2-MeTHF 60
a)
b)
Yield of pure isolated products. Reaction performed at
c)
80°C, MW irradiation.
Reaction performed at 100°C,
Reaction performed at 120°C, MW
irradiation. e) Batch reflux conditions.
d)
MW irradiation.
3
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10.1002/adsc.201700790
Advanced Synthesis & Catalysis
simultaneously pumped with a flow rate of 2 mL/h for each
pump into the T-connector before passing through a 20 mL
reactor coil pressurised by back pressure regulator set at 2
atm. The outflow was collected and, after the removal of
the solvent under vacuum, the crude adducts 3a-j were
Finally, we extended the method to all adducts 3,
always obtaining very good results (Table 4).
Table 4. Synthesis of 6-nitroindoles 4a-j.
purified
by
flash
column
chromatography
(toluene:EtOAc=98:2).
Compound 3a. Yellow waxy solid; IR (neat):  = 756, 948,
1042, 1273, 1491, 1626, 2977, 3299 cm-1; 1H-NMR
(400MHz, CDCl3): δ = 1.5 (s, 3H), 3.47 (bs, 2H), 3.86-3.94
(m, 2H), 3.95-4.02 (m, 2H), 6.36-6.38 (m, 1H), 6.67 (m,
1H), 7.07 (bs, 1H), 8.13 (s, 1H), 10.75 (bs, 1H); 13C-NMR
(100MHz, CDCl3): δ = 25.1, 37.6, 65.3, 110.5, 112.1, 120.2,
125.3, 125.5, 128.0, 140.0; EI-MS (70eV): m/z = 238 ([M+],
2%), 105 (7%), 104 (11%), 87 (100%), 43 (32%); Anal.
Calcd. for C11H14N2O4 (238.24): C, 55.46; H, 5.92; N,
11.76; Found: C, 55.51; H, 5.95; N, 11.73.
R
R1
n
Yield (%) of 4a)
Me
Me
Et
Et
H
1
1
1
1
1
1
1
1
2
2
74
77
87
78
67
62
75
81
70
68
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
CH3(CH2)8
H
Ph(CH2)4
H
Ph(CH2)4
Cl(CH2)6
CH3(CH2)3
H
Compound 3b. Yellow waxy solid; IR (neat):  = 916,
p-tBu-C6H4
p-Me-C6H4
Ph(CH2)2
Ph(CH2)2
H
1038, 1187, 1251, 1274, 1477, 1501, 1626, 2854, 2924,
1
3266 cm-1; H-NMR (400MHz, CDCl3): δ = 0.88 (t, 3H, J
= 6.8 Hz), 1.27-1.39 (m, 12H), 1.50 (s, 3H), 1.56-173 (m,
2H), 2.66 (t, 2H, J = 7.3 Hz), 3.47 (bs, s, 2H), 3.88-3.96 (m,
2H), 3.96-4.03 (m, 2H), 6.11 (t, 1H, J = 2.99 Hz), 6.62 (t,
1H, J = 2.99 Hz), 8.12 (s, 1H), 10.58 (bs, s, 1H); 13C-NMR
(100MHz, CDCl3): δ = 14.2, 22.8, 24.9, 28.5, 29.2, 29.4,
29.5, 29.6, 32.0, 37.8, 65.1, 110.3, 110.8, 122.1, 124.4,
128.3, 137.9, 142.2; EI-MS (70eV): m/z = 364 ([M+], 1%),
118 (18%), 87 (100%), 43 (14%). Anal. Calcd. for
C20H32N2O4 (364.49): C, 65.91; H, 8.85; N, 7.69; Found: C,
65.86; H, 8.82; N, 7.72.
H
CH3(CH2)8
3j
4j
a) Yield of pure isolated products.
Conclusion
Compound 3c. Yellow solid; mp 127-129°C; IR (neat):  =
In conclusion, we have developed a new, general,
convenient and mild synthetic protocol for the
preparation of 6-nitroindoles, which are key
intermediates for synthesizing more complex
biologically active molecules. The method is based on
the peculiarity of the flow chemistry and the
effectiveness of the microwave technology. By our
approach it has been possible to synthesize a large
variety of title targets in satisfactory to good overall
yields, hardly obtainable by the conventional batch
synthesis. Moreover, the accurate selection of starting
materials gave the opportunity to introduce specific
substituents in 2- and 4-positions, avoiding any
problem due to the formation of a mixture of
nitroindole isomers, which, as reported in the
literature, is very common about the preparation of
these derivatives.
1
754, 945, 1041, 1275, 1493, 1628, 2976, 3294 cm-1; H-
NMR (400MHz, CDCl3): δ = 1.05 (t, 3H, J = 7.3 Hz), 1.82
(q, 2H, J = 7.5 Hz), 3.44 (bs, 2H), 3.85-3.98 (m, 4H), 6.37
(dd, 1H, J = 2.6, 6.0 Hz), 6.65-6.67 (m, 1H), 7.06-7.07 (m,
1H), 8.10 (s, 1H), 10.75 (bs, 1H); 13C-NMR (100MHz,
CDCl3): δ = 8.3, 32.2, 35.7, 65.8, 112.0, 112.7, 120.0,
125.2, 125.5, 127.8, 140.4; EI-MS (70eV): m/z = 252 ([M+],
1%), 104 (9%), 102 (5%), 101 (100%), 57 (26%), 29 (5%).
Anal. Calcd. for C12H16N2O4 (252.27): C, 57.13; H, 6.39; N,
11.10. Found: C, 57.18; H, 6.36; N, 11.13.
Compound 3d. Yellow waxy solid; IR (neat):  = 700, 734,
785, 951, 1039, 1186, 1265, 1476, 1498, 1562, 1627, 2858,
1
2934, 3263 cm-1; H-NMR (400MHz, CDCl3): δ = 1.04 (t,
3H, J = 7.3 Hz), 1.69-1.73 (m, 4H), 1.80 (t, 2H, J = 7.3 Hz),
2.64-2.72 (m, 4H), 3.41 (bs, s, 2H), 3.79-3.92 (m, 4H), 6.11
(t, 1H, J = 2.6 Hz), 6.6 (dd, 1H, J = 2.6, 3.4 Hz), 7.16-7.20
(m, 3H), 7.25-7.30 (m, 2H), 8.08 (s, 1H), 10.58 (bs, s, 1H);
13C-NMR (100MHz, CDCl3): δ = 8.5, 28.4, 28.8, 31.2, 32.2,
35.7, 35.9, 65.7, 110.5, 112.8, 121.9, 124.6, 126.1, 128.3,
128.5, 128.6, 138.2, 141.8, 142.3. EI-MS (70eV): m/z =
118 (10%), 101 (100%), 57 (19%), 29 (6%). Anal. Calcd.
for C22H28N2O4 (384.48): C, 68.73; H, 7.34; N, 7.29.
Found: C, 68.69; H, 7.36; N, 7.32.
Experimental Section
Compound 3e. Yellow solid; mp 42-44°C; IR (neat):  =
753, 972, 1042, 1281, 1473, 1500, 1629, 2861, 2935, 3287
cm-1; 1H-NMR (400MHz, CDCl3): δ = 1.34 (s, 9H), 3.65 (s,
bs, 2H), 3.82-3.86 (m, 2H), 3.98-4.01 (m, 2H), 6.41 (dt, 1H,
J = 2.6, 3.4 Hz), 6.7 (q, 1H, J = 1.7 Hz), 7.14-7.16 (m, 1H),
7.42-7.44 (m, 2H), 7.51-7.55 (m, 2H), 8.18 (s, 1H), 10.87
(s, bs, 1H); 13C-NMR (100MHz, CDCl3): δ = 31.6, 34.9,
38.6, 65.1, 110.4, 112.1, 120.3, 125.3, 125.4, 125.6, 128.1,
138.5, 139.7, 151.9; EI-MS (70eV): m/z = 206 (17%), 205
(100%), 190 (5%), 161 (21%), 118 (6%), 105 (6%); Anal.
Calcd. for C20H24N2O4 (356.42): C, 67.40; H, 6.79; N, 7.86;
Found: C, 67.45; H, 6.82; N, 7.90.
General remarks. 1H-NMR analyses were recorded at 400
MHz on a Varian Mercury Plus 400. 13C-NMR analyses
were recorded at 100 MHz. IR spectra were recorded with
a PerkineElmer FT-IR spectrometer Spectrum Two UATR.
Microanalyses were performed with a CHNS-O analyzer
Model EA 1108 from Fisons Instruments. GS-MS analyses
were obtained by a Hewlett-Packard GC/MS 6890N that
works with the EI technique (70 eV). Microwave
®
+
irradiations were performed by Biotage Initiator .
General procedure for the synthesis of compounds 3a-j.
The flow equipment was set up according to Scheme 3.
Protected β-nitro ketones 1a-j (1.5 mmol) and N-ethyl
carboxylate 2-pyrrole carboxaldehydes 2c, 2g-h (1.5 mmol)
were taken up in dioxane (10 mL) and filled into the
reservoir A. DBU (1.5 mmol) was taken up in dioxane (10
mL) and filled into reservoir B. The two solutions were
Compound 3f. Yellow waxy oil; IR (neat):  = 751, 971,
1
1038, 1278, 1476, 1498, 1626, 2858, 2931, 3283 cm-1; H-
NMR (400MHz, CDCl3): δ = 1.75-1.77 (m, 4H), 2.37 (s,
3H), 2.69 (t, 2H, J = 6.6Hz), 2.76 (t, 2H, J = 6.6Hz), 3.61
(bs, 2H), 3.70-3.79 (m, 2H), 3.85-3.96 (m, 2H), 6.13 (bs,
1H), 6.63 (bs, 1H), 7.19 (t, 4H, J = 7.3Hz), 7.23-7.29 (m,
4
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10.1002/adsc.201700790
Advanced Synthesis & Catalysis
3H), 7.39 (m, 2H), 8.12 (s, 1H), 10.68 (bs, 1H); 13C-NMR Compound 4a. Yellow solid; mp 145-147°C; IR (neat):  =
(100MHz, CDCl3): δ = 21.4, 28.5, 28.8, 31.2, 35.9, 38.7, 727, 745, 770, 866, 1064, 1293, 1314, 1482, 1509, 3338
1
64.8, 110.5, 110.6, 122.1, 124.7, 125.6, 126.1, 128.4, 128.6, cm-1; H-NMR (400MHz, CDCl3): δ = 2.61 (s, 3H), 6.65-
128.7, 129.4, 137.5, 138.3, 138.8, 141.8, 142.2; EI-MS 6.67 (m, 1H), 7.50 (t, 1H, J = 2.4 Hz), 7.83 (d, 1H, J = 0.87
(70eV): m/z = 163 (100%), 119 (25%), 91 (14%), 65 (3%); Hz), 8.25 (s, 1H), 8.77 (bs, s, 1H); 13C-NMR (100MHz,
Anal. Calcd. for C27H30N2O4 (446.55): C, 72.62; H, 6.77; N, CDCl3): δ = 19.0, 102.4, 106.3, 115.4, 129.6, 131.1, 133.1,
6.27; Found: C, 72.66; H, 6.81; N, 6.24.
134.0, 143.5; EI-MS (70eV): m/z = 176 ([M+], 100%), 146
(20%), 130 (55%), 128 (16%), 118 (12%), 103 (24%), 102
(16%), 91 (8%), 77 (28%), 63 (5%), 51 (6%); Anal. Calcd.
for C9H8N2O2 (176.17): C, 61.36; H, 4.58; N, 15.90;
Found: C, 61.41; H, 4.55; N, 15.87.
Compound 3g. Orange oil; IR (neat):  = 700, 1039, 1185,
1275, 1476, 1497, 1626, 2858, 2932, 3266 cm-1; H-NMR
1
(400MHz, CDCl3): δ = 1.37-1.45 (m, 2H), 1.45-1.54 (m,
2H), 1.66-1.81 (m, 4H), 2.10-2.16 (m, 2H), 2.70 (t, 2H, J =
7.7 Hz), 2.81-2.87 (m, 2H), 3.50-3.54 (m, 4H), 3.90-3.94 Compound 4b. Yellow solid; mp 66-68°C; IR (neat):  =
(m, 2H), 3.98-4.02 (m, 2H), 6.12 (dd, 1H, J = 2.1, 3.4 Hz), 747, 780, 1073, 1310, 1331, 1259, 1466, 1513, 1537, 2851,
6.62 (dd, 1H, J = 2.3, 3.6 Hz), 7.19-7.25 (m, 3H), 7.27-7.33 2921, 3360 cm-1; H-NMR (400MHz, CDCl3): δ= 0.88 (t,
1
(m, 2H), 8.10 (s, 1H), 10.54 (bs, 1H); 13C-NMR (100MHz, 3H, J = 6.8Hz), 1.26-1.42 (m, 12H), 1.71-1.81 (m, 2H),
CDCl3): δ = 26.8, 28.3, 28.7, 29.0, 30.4, 32.6, 36.3, 41.1, 2.55 (s, 3H), 2.82 (t, 2H, J = 7.3 Hz), 6.34 (t, 1H, J = 0.9
45.2, 65.8, 110.5, 112.2, 122.1, 124.5, 126.3, 128.3, 128.5, Hz), 7.79-7.81 (m, 1H), 8.16 (s, 1H), 8.62 (bs, s, 1H); 13C-
128.8, 138.0, 141.5, 141.9; EI-MS (70eV): m/z = 446 ([M+], NMR (100MHz, CDCl3): δ = 14.4, 18.9, 22.9, 28.8, 29.2,
0.1%), 217 (12%), 177 (87%), 112 (73%), 104 (24%), 91 29.4, 29.5, 29.6, 29.7, 32.1, 99.6, 105.6, 115.4, 129.6,
(100%), 77 (17%), 68 (26%); Anal. Calcd. for 134.0, 134.3, 142.4, 146.6; EI-MS (70eV): m/z = 302
C24H31ClN2O4 (446.97): C, 64.49; H, 6.99; N, 6.27; Found: (21%), 203 (30%), 190 (100%), 157 (15%), 143 (42%),
C, 64.45; H, 7.03; N, 6.30.
131 (15%), 115 (15%), 41 (9%); Anal. Calcd. for
C18H26N2O2 (302.42): C, 71.49; H, 8.67; N, 9.26; Found: C,
71.44; H, 8.63; N, 9.28.
Compound 3h. Orange oil; IR (neat):  = 733, 1039, 1185,
1263, 1284, 1476, 1498, 1626, 2929, 2956, 3266 cm-1; H-
1
NMR (400MHz, CDCl3): δ = 0.98 (t, 3H, J = 7.3 Hz), 1.42 Compound 4c. Red solid, mp 114-117°C; IR (neat):  =
(tq, 2H, J = 7.3, 7.7 Hz), 1.62-1.76 (m, 2H), 2.12-2.17 (m, 665, 726, 742, 756, 975, 1057, 1118, 1297, 1481, 1504,
2H), 2.71 (t, 2H, J = 7.7 Hz), 2.83-2.88 (m, 2H), 3.51 (bs, 2905, 2977, 3341 cm-1; H-NMR (400MHz, CDCl3): δ =
1
2H), 3.89-4.05 (m, 4H), 6.14 (dd, 1H, J = 2.6, 3.4 Hz), 6.64 1.37 (t, 3H, J = 7.7 Hz ), 2.97 (q, 2H, J = 7.7 Hz), 6.65-
(dd, 1H, J = 2.6, 3.0 Hz), 7.20-7.34 (m, 5H), 8.12 (s, 1H), 6.67 (m, 1H), 7.50 (t, 1H, J = 2.8 Hz), 7.85-7.86 (m, 1H),
10.57 (bs, 1H); 13C-NMR (100MHz, CDCl3): δ = 14.1, 22.6, 8.28-8.29 (m, 1H), 9.02 (bs, s, 1H). 13C-NMR (100MHz,
28.1, 30.4, 31.3, 36.4, 41.1, 65.8, 110.5, 112.2, 122.2, CDCl3): δ = 14.5, 26.4, 102.1, 106.5, 113.5, 129.9, 132.6,
124.4, 126.3, 128.4, 128.5, 128.8, 137.8, 141.5, 142.4; EI- 134.3, 137.2, 143.6; EI-MS (70eV): m/z = 190 ([M+],
MS (70eV): m/z = 384 ([M+], 0.1%), 177 (100%), 118 100%), 176 (8%), 175 (80%), 160 (6%), 144 (22%), 143
(18%), 91 (47%); Anal. Calcd. for C22H28N2O4 (384.48): C, (24%), 130 (9%), 129 (34%), 128 (13%), 117 (35%), 115
68.73; H, 7.34; N, 7.29; Found: C, 68.68; H, 7.30; N, 7.32.
(28%), 102 (12%), 89 (10%), 75 (7%), 63 (9%), 51 (6%);
Anal. Calcd. for C10H10N2O2 (190.20): C, 63.15; H, 5.30; N,
14.73; Found: C, 63.19; H, 5.33; N, 14.77.
Compound 3i. Yellow waxy solid; IR (neat):  = 782, 974,
1019, 1036, 1269, 1479, 1499, 1628, 2858, 2921, 3292 cm-
1
1; H-NMR (400MHz, CDCl3): δ = 1.38-1.49 (m, 1H), Compound 4d. Orange waxy solid; IR (neat):  = 699, 749,
2.11-2.16 (m, 1H), 3.2 (d, 2H, J = 5.1 Hz), 3.87 (dt, 2H, J = 879, 1073, 1301, 1447, 1485, 1512, 1540, 2858, 2932,
2.6, 12.4 Hz), 4.18 (dd, 2H, J = 1.3, 5.1 Hz), 4.91 (t, 1H, J 3361 cm-1; H-NMR (400MHz, CDCl3): δ = 1.38 (t, 3H, J
1
= 5.1 Hz), 6.35-6.39 (m, 1H), 6.67-6.71 (m, 1H), 7.05-7.09 = 7.3 Hz), 1.73-1.86 (m, 4H), 2.7 (t, 2H, J = 7.7 Hz), 2.85
(m, 1H), 8.19 (s, 1H), 10.48 (s, bs, 1H); 13C-NMR (t, 2H, J = 7.7Hz), 2.93 (q, 2H, J = 7.7 Hz), 6.36 (s, 1H),
(100MHz, CDCl3): δ = 25.8, 34.5, 67.4, 100.5, 112.2, 120.2, 7.19-7.23 (m, 3H), 7.29-7.33 (m, 2H), 7.85-7.86 (m, 1H),
120.8, 125.4, 125.7, 129.0, 138.3; EI-MS (70eV): m/z = 8.17 (s, 1H), 8.63 (bs, s, 1H); 13C-NMR (100MHz, CDCl3):
238 ([M+], 6%), 105 (14%), 104 (21%), 87 (100%), 77 δ = 14.5, 26.4, 28.6, 28.7, 31.2, 35.9, 99.5, 105.8, 113.7,
(6%), 59 (22%), 41 (8%), 31 (13%); Anal. Calcd. for 126.1, 128.6, 128.7, 133.6, 134.3, 135.9, 142.4, 142.6,
C11H14N2O4 (238.24): C, 55.46; H, 5.92; N, 11.76; Found: 146.2; EI-MS (70eV): m/z = 322 (45%), 217 (42%), 204
C, 55.50; H, 5.96; N, 11.72.
(100%), 171 (20%), 157 (45%), 142 (19%), 130 (27%),
115 (27%), 91 (54%), 65 (12%); Anal. Calcd. for
C20H22N2O2 (322.41): C, 74.51; H, 6.88; N, 8.69; Found: C,
74.46; H, 6.85; N, 8.67.
Compound 3j. Yellow waxy oil; IR (neat):  = 780, 976,
1016, 1039, 1266, 1477, 1498, 1627, 2854, 2924, 3288 cm-
1; 1H-NMR (400MHz, CDCl3): δ = 0.88 (t, 3H, J = 6.8Hz),
1.27-1.40 (m, 12H), 1.46 (dt, 1H, J = 1.2, 13.7 Hz), 1.62- Compound 4e. Yellow solid; mp 61-63°C; IR (neat):  =
1.72 (m, 2H) 2.10-2.22 (m, 1H), 2.66 (t, 2H, J = 7.7 Hz), 751, 836, 1070, 1311, 1327, 1492, 2961, 3374 cm-1; H-
1
3.20 (t, 2H, J = 5.1Hz), 3.87 (td, 2H, J = 2.1, 12.4 Hz), 4.17 NMR (400MHz, CDCl3): δ = 1.40 (s, 9H), 6.85-6.86 (m,
(dd, 2H, J = 6.0, 11.1 Hz), 4.9 (t, 1H, J = 5.1 Hz), 6.09- 1H), 7.53-7.56 (m, 3H), 7.64-7.67 (m, 2H), 8.11 (d, 1H, J =
6.11 (m, 1H), 6.62-6.64 (m, 1H), 8.15 (s, 1H), 10.35 (bs, s, 2.1 Hz), 8.36-8.37 (m, 1H), 8.84 (s, bs, 1H); 13C-NMR
1H); 13C-NMR (100MHz, CDCl3): δ = 14.4, 22.9, 25.9, (100MHz, CDCl3): δ = 31.6, 34.9, 103.7, 106.9, 115.0,
28.5, 29.1, 29.5, 29.6, 29.7, 32.1, 34.7, 67.4, 100.7, 110.6, 126.0, 128.6, 130.2, 131.3, 134.9, 135.0, 136.5, 143.8,
122.6, 124.4, 129.2, 136.1, 142.8; EI-MS (70eV): m/z = 151.3; EI-MS (70eV): m/z = 294 ([M+], 49%), 279 (100%),
364 ([M+], 1%), 118 (10%), 87 (100%), 59 (8%), 31 (6%); 251 (11%), 233 (11%), 217 (10%), 204 (9%), 191 (9%),
Anal. Calcd. for C20H32N2O4 (364.49): C, 65.91; H, 8.85; N, 165 (6%), 139 (5%), 125 (5%), 111 (7%), 102 (8%), 161
7.69; Found: C, 65.96; H, 8.88; N, 7.66.
(21%), 118 (5.9%), 105 (5.9%); Anal. Calcd. for
C18H18N2O2 (294.35): C, 73.45; H, 6.16; N, 9.52; Found: C,
73.48; H, 6.19; N, 9.49.
General procedure for the synthesis of compounds 4a-j.
Compound 4f. Yellow solid; mp 154-156°C; IR (neat):  =
753, 828, 1071, 1291, 1317, 1500, 1535, 2933, 3367 cm-1;
1H-NMR (400MHz, CDCl3): δ = 1.69-1.83 (m, 4H), 2.45 (s,
3H), 2.69 (t, 2H, J = 7.5 Hz), 2.76 (t, 2H, J = 7.5 Hz), 6.50
(s, 1H), 7.15-7.22 (m, 3H), 7.25-7.34 (m, 4H), 7.58 (dt, 2H,
J = 1.7, 8.1 Hz), 8.06 (d, 1H, J = 1.7 Hz), 8.22 (dd, 1H, J =
0.8, 2.1 Hz), 8.49 (bs,1H); 13C-NMR (100MHz, CDCl3): δ
= 21.5, 28.6, 28.7, 31.2, 35.8, 101.0, 106.2, 115.0, 126.1,
128.6, 128.7, 128.7, 129.7, 132.4, 133.7, 134.9, 136.7,
A solution of the intermediate 3a-j (1 mmol) in 2-MeTHF
(10 mL) was treated with Amberlyst 15 (0.200 g) and
irradiated by Biotage® Initiator+ at 100°C for 45 minutes.
Then, the Amberlyst 15 was filtered off washing with fresh
2-MeTHF (10 mL) and, after the removal of the solvent at
reduced pressure, the crude products 4a-j were purified by
flash chromatography column (toluene).
5
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10.1002/adsc.201700790
Advanced Synthesis & Catalysis
137.9, 142.2, 142.9, 146.7; EI-MS (70eV): m/z = 384 ([M+],
100%), 341 (12%), 179 (33%), 219 (54%), 208 (45%), 204
(37%), 91 (46%), 65 (11%); Anal. Calcd. for C25H24N2O2
(384.48): C, 78.10; H, 6.29; N, 7.29; Found: C, 78.14; H,
6.26; N, 7.27.
[2]a) B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo,
R. M.; Freidinger, W. L. Whitter, G. F. Lundell, D. F.
Verber, P. S. Anderson, R. S. L. Chang, V. J. Lotti, D.
H. Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel, J. P.
Springer, J. Hirhfield, J. Med. Chem. 1988, 31, 2235-
2246; b) D. A. Horton, G. T. Bourne, M. L. Smythe,
Chem. Rev. 2003, 103, 893-930.
Compound 4g. Orange solid; mp 65-66°C; IR (neat):  =
698, 751, 1069, 1301, 1446, 1476, 1510, 1541, 2859, 2935,
1
3351 cm-1; H-NMR (400MHz, CDCl3): δ = 1.39-1.57 (m,
4H), 1.75-1.84 (m, 4H), 2.83 (t, 2H, J = 7.7 Hz), 3.02-3.08
(m, 2H), 3.17-3.23 (m, 2H), 3.52 (t, 2H, J = 6.6 Hz), 6.34
(d, 1H, J = 0.86 Hz), 7.19-7.26 (m, 3H), 7.27-7.33 (m, 2H),
7.83 (d, 1H, J = 1.7 Hz), 8.15 (d, 1H, J = 1.3 Hz), 8.40 (bs,
1H); 13C-NMR (100MHz, CDCl3): δ = 26.8, 28.6, 28.7,
[3] G. W. Gribble in Indole Ring: Synthesis from Natural
Products to Drug Discovery, 1st ed., Wiley, Chichester,
2016.
29.0, 32.6, 35.4, 36.6, 45.2, 99.5, 105.8, 114.8, 126.4, [4] a) J. Bergman, Studies in Natural Products Chemistry,
128.6, 128.7, 133.5, 133.7, 134.3, 141.7, 142.7, 146.0; EI-
MS (70eV): m/z = 384 ([M+], 25%), 293 (100%), 188
(12%), 142 (60%), 115 (14%), 91 (39%); Anal. Calcd. for
C22H25ClN2O2 (384.90): C, 68.65; H, 6.55; Cl, 9.21; N,
7.28; Found: C, 68.61; H, 6.52; N, 9.23.
Vol. 1, Part A (Ed.; A. Rahman), Elsevier, New York,
1988, pp 3-30; b) K. S. J. Stapleford, The Indole
Alkaloids; Chemistry of Carbon Compounds, Vol. 4,
Part B (Ed.; S. Coffey), Elsevier, New York, 1977, pp
63-163.
Compound 4h. Orange solid; mp 148-149°C; IR (neat):  =
575, 697, 748, 883, 1286, 1312, 1447, 1495, 1540, 2858, [5] a) A. Baeyer, Justus Liebigs Ann. Chem. 1866, 140,
1
2926, 3334 cm-1; H-NMR (400MHz, CDCl3): δ = 0.99 (t,
295-296; b) A. Baeyer, A. Emmerling, Chem. Ber. 1869,
2, 679-682.
3H, J = 7.3 Hz), 1.40-1.49 (m, 2H), 1.70-1.82 (m, 2H),
2.83 (t, 2H, J = 7.7 Hz), 3.03-3.09 (m, 2H), 3.18-3.23 (m,
2H), 6.35 (m, 1H), 7.20-7.35 (m, 5H), 7.84 (d, 1H, J = 1.7
[6] M. Inman, C. J. Moddy, Chem. Sci. 2013, 4, 29-41.
Hz), 8.17 (m, 1H), 8.55 (bs, 1H); 13C-NMR (100MHz,
CDCl3): δ = 14.1, 22.7, 28.5, 31.2, 35.4, 36.6, 99.4, 105.9,
[7] a) F. J. Brown, L. A. Cronk, D. Aharony, D. W. Snyder,
114.7, 126.4, 128.6, 128.7, 133.4, 133.8, 134.3, 141.8,
142.6, 146.6; EI-MS (70eV): m/z = 322 ([M+], 17%), 231
(100%), 185 (11%), 142 (36%), 115 (10%), 91 (20%);
Anal. Calcd. for C20H22N2O2 (322.41): C, 74.51; H, 6.88; N,
8.69; Found: C, 74.55; H, 6.91; N, 8.66.
J. Med. Chem. 1992, 35, 2419-2439; b) H. Deng, A. N.
Gifford, A. M. Zvonok, G. Cui, X. Li, P. Fan, J. R.
Deschamps, J. L. Flippen-Anderson, S. J. Gatley, A.
Makriyannis, J. Med. Chem. 2005, 48, 6386-6392; c) I.
Borza, É. Bozo´, G. Barta-Szalai, C. Kiss, G. Tárkányi,
Á. Demeter, T. Gáti, V. Háda, S. Kolok, A. Gere, L.
Fodor, J. Nagy, K. Galgóczy, I. Magdó, B. Ágai, J.
Fetter, F. Bertha, G. M. Keserü, C. Horváth, S. Farkas, I.
Greiner, G. Domány, J. Med. Chem. 2007, 50, 901-914;
d) Y. Jia, M. Bois-Choussy, J. Zhu, Org. Lett. 2007, 9,
2401-2404; e) S. C. Annedi, S. P. Maddaford, G.
Mladenova, J.Ramnauth, S. Rakhit, J. S. Andrews, D.
K. H. Lee, D. Zhang, F. Porreca, D. Bunton, L. Christie,
J. Med. Chem. 2011, 54, 7408-7416.
Compound 4i. Yellow solid; mp 141-143°C; IR (neat):  =
725, 747, 773, 867, 1061, 1298, 1318, 1485, 1512, 3335
1
cm-1; H-NMR (400MHz, CDCl3): δ = 6.67-6.68 (m, 1H),
7.52 (t, 1H, J = 2.7 Hz), 7.68 (d, 1H, J = 9.0 Hz), 8.03 (dd,
1H, J = 2.14, 9.0 Hz), 8.40 (d, 1H, J = 2.1 Hz), 8.73 (bs, s,
1H); 13C-NMR (100MHz, CDCl3): δ = 103.9, 108.2, 115.6,
120.8, 130.0, 133.0, 134.5, 143.7; EI-MS (70eV): m/z =
162 ([M+], 100%), 132 (39%), 116 (82%), 104 (29%), 89
(70%), 77 (9%), 63 (30%), 51 (10%), 39 (8%), 30 (9%);
Anal. Calcd. for C8H6N2O2 (162.04): C, 59.26; H, 3.73; N,
17.28; Found: C, 59.22; H, 3.75; N, 17.31.
Compound 4j. Orange solid; mp 59-61°C; IR (neat):  =
[8] a) N. Ono, The nitro group in organic synthesis, Wiley-
VCH, New York, 2001; b) R. Ballini, S. Gabrielli, A.
Palmieri, M. Petrini, Curr. Org. Chem. 2011, 15, 1482-
1506; c) R. Ballini, M. Petrini, Adv. Synth. Catal. 2015,
357, 2371-2402.
733, 779, 819, 1061, 1293, 1464, 1501, 1540, 1592, 2851,
1
2926, 2953, 3358 cm-1; H-NMR (400MHz, CDCl3): δ =
0.88 (t, 3H, J = 6.8Hz), 1.18-1.44 (m, 12H), 1.72-1.80 (m,
2H), 2.82 (t, 2H, J = 7.7 Hz), 6.36 (s, 1H), 7.53 (d, 1H, J =
9.0 Hz), 7.99 (dd, 1H, J = 2.1, 8.5 Hz), 8.29 (d, 1H, J = 2.1
Hz), 8.48 (bs, s, 1H); 13C-NMR (100MHz, CDCl3): δ =
14.4, 22.9, 28.7, 29.1, 29.5, 29.6, 29.7, 32.1, 101.1, 107.5,
115.7, 119.5, 134.3, 134.4, 142.5, 147.2; EI-MS (70eV):
m/z = 288 ([M+], 13%),189 (30%), 176 (100%), 175 (50%),
143 (15%), 129 (37%), 115 (15%), 41 (15%); Anal. Calcd.
for C17H24N2O2 (288.39): C, 70.80; H, 8.39; N, 9.71;
Found: C, 70.84; H, 8.42; N, 9.68.
[9] a) W. E. Noland, K. R. Rush, L. R. Smith, J. Org.
Chem. 1966, 31, 65-69; b) W. E. Noland, K. R. Rush, J.
Org. Chem. 1966, 31, 70-77; c) O. Ottoni, R. Cruz, N.
H. Krammer, Tetrahedron Lett. 1999, 40, 1117-1120;
d)
[10] a) N. Moskalev, M. Makosza, Tetrahedron Lett. 1999,
40, 5395-5398; b) J. Bergman, P. Sand, Tetrahedron
1990, 46, 6085-6112; c) A. R. Katritzky, S. Rachwal, S.
Bayyuk, Org. Prep. Proced. Int. 1991, 23, 357-363; d)
B. Narayana, B. V. Ashalatha, K. K. Vijaya Raj, J.
Fernandes, B. K. Sarojini, Bioorg. Med. Chem. 2005, 13,
4638-4644;
Acknowledgements
The authors thank the University of Camerino for the financial
support.
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10.1002/adsc.201700790
Advanced Synthesis & Catalysis
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7
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Advanced Synthesis & Catalysis
FULL PAPER
Two-step Synthesis of Polysubstituted 6-
Nitroindoles under Flow Chemical and
Microwaves conditions
Adv. Synth. Catal. Year, Volume, Page – Page
Susanna Sampaolesi, Serena Gabrielli, Roberto
Ballini and Alessandro Palmieri*
8
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