Synthesis of amino-substituted indoles using the Bartoli reaction

Article abstract of DOI:10.1039/c2ob25256b

We report herein the concise preparation of a range of functionalised aminoindoles via a new application of the Bartoli reaction. Scope and limitations of the methodology have been extensively studied to reveal the importance of protecting groups and subs

Full text of DOI:10.1039/c2ob25256b

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PAPER
Synthesis of amino-substituted indoles using the Bartoli reaction†
Laura Wylie,a Paolo Innocenti,a Daniel K. Whelligana,b and Swen Hoelder*a
Received 3rd February 2012, Accepted 11th April 2012
DOI: 10.1039/c2ob25256b
We report herein the concise preparation of a range of functionalised aminoindoles via a new application
of the Bartoli reaction. Scope and limitations of the methodology have been extensively studied to reveal
the importance of protecting groups and substitution patterns. The use of amino substituted nitroanilines
for the Bartoli reaction is to our knowledge unprecedented. Our work thus represents a novel entry into
substituted aminoindoles which are relevant building blocks for both the fine chemical and
pharmaceutical industry.
We hypothesised that the Bartoli reaction of suitably N-pro-
Introduction
tected bromo-nitroanilines would give easy access to the desired
substituted aminoindoles. The aminoindoles would also be
amenable for easy derivatisation at positions N-1 through C-3,
for example using alkylations at N-1, and exploiting the natural
reactivity of the indole ring to install groups at C-3.9 To the best
of our knowledge, direct synthesis of aminoindoles using this
method has not been reported.
The indole ring system is found in many pharmaceuticals and
natural products motifs,1 and numerous approaches have been
published for the formation of this heteroaromatic core.2
The Bartoli indole synthesis involves the reaction of a nitroar-
ene with a vinyl Grignard reagent, providing quick access to sub-
stituted indoles (Scheme 1).3
This reaction is generally known to give moderate yields that
are rarely higher than 60% and can be as low as 10–15% in
more complex cases. Moreover, these transformations can be
very substrate dependent and often no clear reactivity trends can
be observed.3,4 That said, the conciseness of this reaction often
outweighs the moderate yields as demonstrated by the recent
publications on the expeditious synthesis of azaindoles and on
the synthesis of indoles on solid support.4,5
Despite these recent advances in widening the scope of the
Bartoli reaction, some indole substitutions have not yet been
tackled. In the context of a medicinal chemistry program, we
wished to quickly access an aminoindole scaffold with an
additional halogen functionality for further synthetic manipula-
tions. We were surprised to find that a concise approach to such
aminoindoles had not been published. Current methods involve
late stage modification of the indole ring, such as reduction of a
nitro group,6 or metal-catalysed coupling reactions.7 These
approaches can be lengthy, can have uncontrollable regioselec-
tivity,8 and pose a limit to the number and type of functional
groups present on the arene ring.7
Results and discussion
We initially attempted the reaction of Boc-protected 4-bromo-3-
nitroaniline 1 under commonly applied conditions using 3
equivalents of vinylmagnesium bromide 2 as required according
to the accepted Bartoli reaction mechanism.10 However, this
reaction was not successful and we hypothesised that an
additional equivalent of reagent 2 was required to compensate
for the deprotonation of the carbamate group. Use of 4 equiva-
lents of vinylmagnesium bromide indeed led to the formation of
the desired indole 3 in 28% yield (Table 1, entries 1 and 2).
Next, we investigated the effect of the solvent, as we observed
that the reaction was heterogeneous. It has previously been
shown that adding a second ethereal solvent to the reaction can
improve the yield by increasing the solubility of Grignard
reagent 2 at low temperatures.11 Diethyl ether was chosen due to
its low boiling point and relatively low toxicity compared to
aCancer Research UK Cancer Therapeutics Unit, Division of Cancer
Therapeutics, The Institute of Cancer Research, Haddow Laboratories,
15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK. E-mail: swen.hoel-
der@icr.ac.uk
bDepartment of Chemistry, Faculty of Health and Medical Sciences,
University of Surrey, Guildford, GU2 7HX, UK.
†Electronic supplementary information (ESI) available: Experimental
1
Scheme 1 Reaction of vinyl Grignard reagents with nitroarenes in the
Bartoli reaction.
procedures for the synthesis of starting substrates and copies of H and
13C NMR spectra available. See DOI: 10.1039/c2ob25256b
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Table 1 Optimisation of reaction conditions
Table 2 Examination of suitable protecting groups
Starting
Entry material
Method A Method B
Grignard reagent
Entry equiv.
Solvent% Et2O in
THFa
Conc.
(M)
Yield
(%)
R1
R2
Product yield (%)
yield (%)
1
2
3
4
5
6
7
8
4a
1
4b
4c
4d
4e
4f
4g
4h
4i
H
Boc
Bn
PMB
Cbz
Alloc
Ac
Bz
Ts
Boc
Cbz
Boc
Boc
H
H
H
H
H
H
H
H
5a
3
5b
5c
5d
5e
5f
0
64
0
0
7
6
4
0
17
34a
0a
—
—
—
41
0
1
2
3
4
5
6
3
0
0
25
57
57
75
0.1
0.1
0.1
0.1
0.06
0.06
0
4b
4b
4b
4b
4b
28
41
64
48
56
0
13
10
0
a Solvent ratio and concentration listed are those reached after complete
addition of all reagent solutions. b When using 4 equivalents of 2, the
dissolved substrate was added to the stirring Grignard mixture in a so
called “inverse addition” in order to maintain a constant excess of 2 in
the reaction (see experimental procedure).12
5g
5h
5cb
5j
6
9
H
16
47a
0a
30a
0a
10
11
12
13
PMB
PMB
Et
4j
4k
4l
5kb
CH2– 5lb
C3H5
Method A: 57% (v/v) Et2O in THF. Method B: 25% (v/v) Et2O in
THF.a 3 equivalents of Grignard used. b Boc group removed in reaction
conditions.
other ethers. Although it did not completely solve the problem of
a heterogeneous mixture, addition of diethyl ether to the reaction
mixture proved beneficial and allowed indole 3 to be formed in a
41% yield (entry 3) as the major product. Systematic variation of
the THF : Et2O ratio further improved the yield to 64% by
increasing the ratio of ether relative to THF from 25% to 57%
(entry 4). A decrease in concentration from 0.1 M to 0.06 M led
to a decrease in yield of indole 3 (64 to 48%, Table 1, entries 4
and 5), which was partially countered by increasing the pro-
portion of diethyl ether (Table 1, entries 5 and 6).
Entries 3 and 4 were chosen as the optimal conditions in order
to keep solvent levels down at larger scales (Table 1, entry 4,
method A; entry 3 method B) and were both used throughout
this study. In all cases in this paper where the reaction was
unsuccessful, significant amounts of starting material were
recovered.
Next, a selection of commonly used protecting groups were
introduced onto 4-bromo-3-nitroaniline and the resulting nitro
compounds 4a–j were subjected to methods A and B to deter-
mine the role of the N-protecting group (Table 2).13 In all cases
except unprotected 4a, Bn protected 4b and PMB protected 4c
(entries 1, 3 and 4), the expected product was formed to some
extent and isolated along with substantial amounts of starting
material. Boc derivative 1 gave by far the best yield (entry 2).
Cbz derivative 4d, allyl carbamate 4e (entries 5 and 6) and tosyl
amide 4h (entry 9) were found to be lower yielding, with only
carboxyamides 4f and 4g (entries 7 and 8) producing very small
amounts of indole product. Method B gave comparable yields to
method A except in the case of Boc derivative 1 where the yield
was somewhat lower.
equivalents of Grignard 2. In order to test whether this double
protection method could be applied using PMB with other carba-
moyl protecting groups, we prepared starting material 4j, where
the Boc group is replaced by a Cbz group. Interestingly and in
sharp contrast, treatment of 4j with either method A or B did
not yield any product and only starting material was recovered
(entry 11).
In addition to these double protection experiments, we wanted
to test whether it was possible to install alkyl groups on the
nitrogen atom. As stated previously, starting materials were pre-
pared by alkylation of 4-bromo-3-nitroaniline and subsequent
Boc protection. Both ethyl and cyclopropylmethyl groups were
explored (entries 12 and 13),14 though only the former took part
in the Bartoli reaction and showed the formation of a significant
amount of indole (5k). Again, as seen in previous examples, a
significant amount of starting material was recovered when
cyclopropylmethyl derivative 4l was used. Cyclopropyl groups
contain π character in their carbon–carbon bonds and the differ-
ence in electronic properties compared to ethyl may at least in
part explain the lack of reactivity.15
Two conclusions can be drawn from testing different protect-
ing groups. Firstly, the Boc group proved to give the best results.
Secondly, it can be employed either alone or in conjunction with
a PMB group. Some simple alkyl groups can also be installed
using this method.
The key feature distinguishing the Boc protecting group from
the other carbamoyl group is the steric bulk exerted by the ter-
tiary butyl residue. In order to find out whether steric factors are
responsible for the yields achieved with 1, we performed a series
of experiments (Table 3). Firstly we replaced the Boc protecting
group with the pivaloyl amide protecting group (6a) which
We hypothesised that the reaction could be more successful by
using a second protecting group to prevent deprotonation of the
carbamate nitrogen. Interestingly, using the doubly protected
starting material 4i, featuring both Boc and PMB groups on the
nitrogen atom, led to a product containing only the PMB group
(5c) with yields comparable to indole 3 (entry 10) using 3
4442 | Org. Biomol. Chem., 2012, 10, 4441–4447
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shows similar steric properties. Secondly, the tertiary butyl group
was truncated to the isopropyl (6b) and ethyl groups (6c) in
order to establish whether changing the steric properties would
affect the yields of the reaction.
Reaction of starting materials 6a–c gave modest yields of
around 20% in every case and thus significantly below the 61
and 41% yields achieved with 1. These results show that the
tert-butyl group as well as the carbamoyl moiety are critical for
good yields, suggesting that the Boc group exerts electronic and
steric effects that are crucial for the success of the reaction.
After establishing Boc as the most efficient protecting group
for the reaction to proceed, different Grignard reagents and sub-
strates were examined to assess the scope of the reaction
(Table 4). Nitroarene 1 (entries 1 to 4) was reacted with four
different commercially available alkenyl Grignard reagents. As
reported for other Bartoli reactions, we found that the yield
strongly depended on the nature of the Grignard reagent. For
example, when 1-methyl-1-propenylmagnesium bromide was
employed in the reaction with nitroaniline 1, only starting
material was recovered (entry 4). Also, substitution of Br with
Me at C-7 of 1 (8a, entry 5) resulted in an unsuccessful reaction.
We next tested protected 3-bromo-4-nitroaniline 8b (entries 6
to 9). In this case higher substituted Grignard reagents generally
led to an increase in yields. Also, as seen with the 4-NHBoc sub-
strate 8a, substituting the Br at C-7 for a Me group did not give
any product (8c, entry 10).
Table 3 Investigation of Boc group importance
Starting
Entry material
Method A
Product yield (%)
Method B
yield (%)
R1
Surprisingly, moving the amino group further round the arene
ring (entries 11–14) did not yield indole product for any of the
Grignard reagents. Interestingly, however, substituting the C-7
Br for a Me group in 8k led to some product being formed with
both methods (entry 15).
1
1
3
64
17
41
2
6a
7a
16
Again, in the cases where no product was formed, significant
amounts of starting material were recovered. As shown in
Table 4, substrate 1 produced the highest yields of indole
product, with substrate 8g (6-NHBoc derivative) being comple-
tely unreactive. The reason for this variance in reactivities is
unclear.
3
4
6b
6c
7b
7c
22
26
13
16
It has previously been established that the first step in the
mechanism is a reduction of the nitro group to the corresponding
nitroso compound (Fig. 1) through a single electron transfer
Method A: 57% (v/v) Et2O in THF. Method B: 25% (v/v) Et2O in THF.
Table 4 Reactions to determine substrate scope
Entry
Starting material
R1
R2
R3, R4
Product
Method A yield (%)
Method B yield (%)
1
2
3
4
5
6
7
8
1
1
1
1
4-NHBoc
4-NHBoc
4-NHBoc
4-NHBoc
4-NHBoc
5-NHBoc
5-NHBoc
5-NHBoc
5-NHBoc
5-NHBoc
6-NHBoc
6-NHBoc
6-NHBoc
6-NHBoc
6-NHBoc
Br
Br
Br
Br
Me
Br
Br
Br
Br
Me
Br
Br
Br
Br
Me
H, H
3
64
44
0
0
0
0
13
0
15
0
0
41
43
22
0
0
0
19
33
22
0
0
0
H, Me
Me, H
Me, Me
H, H
3a
3b
3c
9a
9b
9ca
9d
9e
9f
9g
9h
9i
9j
9k
8a
8b
8b
8b
8b
8c
8g
8g
8g
8g
8k
H, H
H, Me
Me, H
Me, Me
H, H
9
10
11
12
13
14
15
H, H
H, Me
Me, H
Me, Me
H, H
0
0
0
22
0
0
27
a Product quickly decomposes upon storage. Method A: 57% (v/v) Et2O in THF. Method B: 25% (v/v) Et2O in THF.
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(SET) mechanism.10 Retrieval of starting material suggests that
this first step does not take place as none of the nitroso inter-
mediates 10 were isolated or observed in all the reactions per-
formed. The reason for this stalling in the first step is not clear,
but could be related to the inability of the nitro group to be
reduced by the Grignard reagent. 5-NHBoc nitrobenzenes have a
para relationship between the nitro and carbamate groups which
would put more electron density on the nitro group when the car-
bamate is deprotonated. This may render it less reactive to the
reducing processes. However, this does not explain entries
11–14 (Table 4) where the relationship is meta and yet no reac-
tion occurs.
In order to confirm that the first step of the mechanism is
likely to pose an obstacle to the reaction progression, we decided
to synthesise a nitroso compound through an alternative method
and react it under our set of conditions. In this case, only 3
equivalents of Grignard reagent would be necessary as the initial
reduction of the nitro group is no longer needed.
is consistent with previous literature studies.3,4 However, the
general lack of reactivity trends highlights the importance of sys-
tematic explorations like this one to identify substrates that can
successfully be prepared and utilised as starting materials.
Further studies on the employment of such highly functiona-
lised building blocks in medicinal chemistry will be reported in
due course.
Experimental section
General information
Starting materials, reagents and solvents for reactions were
reagent grade and used as purchased. Chromatography solvents
were HPLC grade and were used without further purification.
Thin layer chromatography (TLC) analysis was performed using
silica gel 60 F-254 thin layer plates. Flash column chromato-
graphy was carried out using columns pre-packed with
40–63 μm silica. LC yield determination, LCMS and HRMS
analyses were performed on a HPLC system with diode array
We decided to produce the nitroso version of 8a as this sub-
strate did not produce any indole product under our conditions
(Table 4, entry 5), and it did not contain a Br atom which could
be lost in the reduction step of the synthesis (Scheme 2).16 We
found that indole product 9a was formed, although in a low
yield of 9%.
This result suggests that the first step of the mechanism (SET)
could well be preventing the reaction from proceeding, as some
product was formed when this step was circumvented.
Conclusions
We have discovered and developed a new application of the
Bartoli reaction for the synthesis of substituted aminoindoles
with yields comparable to those of other substitution patterns
previously reported in the literature. Different N-protecting
groups for bromo-nitroanilines were investigated, leading to the
conclusion that the Boc group is the most effective; a combi-
nation of protecting groups can also be employed to produce
PMB-protected aminoindoles in useful yields.
The results presented here reveal no clear trend for the reactiv-
ity of amino-nitrobenzenes with vinyl Grignard reagents, which
Scheme 2 Synthesis and reaction of a nitroso derivative in the Bartoli
reaction.
Fig. 1 Proposed mechanism of the Bartoli reaction.
4444 | Org. Biomol. Chem., 2012, 10, 4441–4447
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Benzyl 7-bromo-1H-indol-4-ylcarbamate (5d). Off-white crys-
talline residue, 19 mg (13%); Rf = 0.58 (30% EtOAc in cyclo-
hexane); H NMR (500 MHz, CDCl3) δ 5.27 (2H, s), 6.56 (1H,
dd, J = 3, 2), 6.86 (1H, br s), 7.22–7.24 (1H, m), 7.33 (1H, d,
J = 8), 7.37 (1H, ddd, J = 7, 3.5, 1.5), 7.37–7.41 (2H, m),
7.43–7.46 (2H, m), 7.57 (1H, br s), 8.43 (1H, br s); 13C NMR
(126 MHz, CDCl3) δ 67.3, 99.3, 99.8, 111.2, 124.2, 124.9,
128.4, 128.6–128.7, 129.6, 134.9, 136.0, 153.4; IR (film) 3272,
1676, 1225; HRMS (ESI) m/z calcd for C16H14BrN2O2 [M +
H]+ 345.0233, found [M + H]+ 345.0235; HPLC purity >90%.
detector operating at 254 nm, fitted with a reverse-phase 50 ×
4.6 mm column at a temperature of 22 °C, connected to a Quad-
rupole Time of Flight (QToF) or Time of Flight (ToF) mass
spectrometer (simultaneous ESI and APCI or ESI respectively).
The following solvent system, at a flow rate of 2 mL min−1, was
used: solvent A: methanol; solvent B: 0.1% formic acid in water.
Gradient elution was as follows: 1 : 9 (A : B) to 9 : 1 (A : B) over
2.5 min, 9 : 1 (A : B) for 1 min, then reversion back to 1 : 9
(A : B) over 0.3 min, 1 : 9 (A : B) for 0.2 min IR analyses were
carried out on NaCl plates. NMR data are given as follows:
chemical shift (δ) in ppm, referenced to residual CHCl3 at
7.26 ppm, integration, multiplicity, coupling constants (J) given
in Hz.
1
Allyl 7-bromo-1H-indol-4-ylcarbamate (5e). Clear oil, 15 mg
(10%); Rf = 0.52 (30% EtOAc in cyclohexane); 1H NMR
(500 MHz, CDCl3) δ 4.73 (2H, d, J = 6), 5.31 (1H, d, J = 10, 1),
5.41 (1H, d, J = 17, 1), 6.02 (1H, ddd, J = 17, 10, 6), 6.58 (1H,
dd, J = 3, 2), 6.82 (1H, br s), 7.23–7.26 (1H, m), 7.33 (1H, d,
J = 8), 7.56 (1H, br s), 8.43 (1H, br s); 13C NMR (126 MHz,
CDCl3) δ 66.1, 99.2, 99.8, 111.1, 118.5, 120.6, 124.2, 124.9,
129.5, 132.4, 134.9, 153.2; IR (film) 3291, 1729, 1617, 1248,
995, 918; HRMS (ESI) m/z calcd for C12H12BrN2O2 [M + H]+
295.0077, found [M + H]+ 295.0073; HPLC purity >95%.
General procedure for synthesis of indoles
Method A. Vinylmagnesium bromide ([1 M] in THF, 4
equiv.) and Et2O (2.5 ml mmol−1) were mixed in an oven dried
flask and cooled to −40 °C under N2 with stirring. Aniline was
dissolved in THF (2.5 ml mmol−1) and added dropwise to the
Grignard mixture. The solution was stirred at −40 °C for 4 h,
then quenched with sat. aq. NH4Cl. The aqueous layer was sep-
arated and extracted using EtOAc, the organic layer was dried
over MgSO4 and concentrated in vacuo. The crude material was
purified by silica column chromatography (0–15% EtOAc in
cyclohexane) to yield the title compound.
N-(7-Bromo-1H-indol-4-yl)acetamide (5f). Clear oil, 6 mg
(4%); Rf = 0.31 (30% EtOAc in cyclohexane); 1H NMR
(500 MHz, CDCl3) δ 2.27 (3H, s), 6.56 (1H, br s), 7.26 (1H, s
(under CDCl3 peak)), 7.31 (1H, d, J = 8), 7.34 (1H, br s), 7.68
(1H, d, J = 8), 8.45 (1H, br s); 13C NMR (126 MHz, CDCl3) δ
24.7, 99.9, 100.1, 113.1, 121.3, 124.3, 124.8, 129.4, 134.9,
168.4; IR (film) 3419, 3264, 1654, 1530; HRMS (ESI) m/z
calcd for C10H10BrN2O [M + H]+ 252.9971, found [M + H]+
252.9979; HPLC purity >95%.
Method B. Vinylmagnesium bromide (1 M in THF, 4 equiv.)
and Et2O (2.5 ml mmol−1) were mixed in an oven dried flask
and cooled to −40 °C under N2 with stirring. Aniline was dis-
solved in additional Et2O (2.5 ml mmol−1) and added dropwise
to the Grignard mixture. The solution was stirred at −40 °C for
4 h, then quenched with sat. NH4Cl. The aqueous layer was sep-
arated and extracted using EtOAc, the organic layer was dried
over MgSO4 and concentrated in vacuo. The crude material was
purified by silica column chromatography (0–15% EtOAc in
cyclohexane) to yield the title compound.
N-(7-Bromo-1H-indol-4-yl)benzamide (5g). Off-white residue,
1
9 mg (6%); Rf = 0.32 (30% EtOAc in cyclohexane); H NMR
(500 MHz, CDCl3) δ 6.64 (1H, dd, J = 3, 2), 7.28–7.30 (1H, m),
7.38 (1H, d, J = 7.5), 7.54 (2H, ddd, J = 9, 6.5, 3.5), 7.58–7.60
(1H, m), 7.84 (1H, d, J = 7.5), 7.95 (2H, dd, J = 5, 3.5), 8.03
(1H, br s), 8.49 (1H, br s); 13C NMR (126 MHz, CDCl3) δ
100.0, 100.4, 113.2, 120.8, 121.3, 124.4, 124.9, 127.1, 128.9,
129.6, 131.9, 135.1, 165.5; IR (film) 3288, 1731; HRMS (ESI)
m/z calcd for C15H12BrN2O [M + H]+ 315.0128, found [M +
H]+ 315.0143; HPLC purity >95%.
tert-Butyl 7-bromo-1H-indol-4-ylcarbamate (3). Pale yellow
1
oil, 4.87 g (67%); Rf = 0.47 (20% cyclohexane in DCM); H
NMR (500 MHz, CDCl3) δ 1.57 (9H, s), 6.58 (1H, dd, J = 1.0,
2.5), 6.65 (1H, br s), 7.24 (1H, t, J = 2.5), 7.31 (1H, d, J = 8.5),
7.55 (1H, br d, J = 8.5), 8.39 (1H, br s); 13C NMR (126 MHz,
CDCl3) δ 28.4, 80.7, 98.6, 99.9, 110.8, 120.3, 123.9, 124.9,
130.2, 134.9, 152.8; IR (film) 3210, 2955, 1756; HRMS (ESI)
m/z calcd for C13H15BrN2O2Na [M + Na]+ 333.0215, found [M
+ Na]+ 333.0210; HPLC purity >95%.
N-(7-Bromo-1H-indol-4-yl)-4-methylbenzenesulfonamide
(5h). Clear oil, 25 mg (17%); Rf = 0.48 (30% EtOAc in cyclo-
1
hexane); H NMR (500 MHz, Acetone-d6) δ 2.32 (3H, s), 6.80
(1H, d, J = 3), 7.04 (1H, d, J = 8), 7.23 (1H, d, J = 8), 7.26 (2H,
d, J = 8), 7.32 (1H, d, J = 3), 7.69 (2H, d, J = 8), 8.87 (1H, br
s), 10.45 (1H, br s); 13C NMR (126 MHz, Acetone-d6) δ 20.4,
100.5, 100.7, 113.5, 123.6, 124.0, 125.3, 125.5, 127.1, 129.4,
135.3, 137.6, 143.4; IR (film) 3389, 3261, 1156; HRMS (ESI)
m/z calcd for C15H14BrN2O2S [M + H]+ 364.9954, found [M +
H]+ 364.9967; HPLC purity >95%.
7-Bromo-N-(4-methoxybenzyl)-1H-indol-4-amine (5c). Pale
yellow oil/glass, 54 mg (47%); Rf = 0.52 (30% EtOAc in cyclo-
1
hexane); H NMR (500 MHz, CDCl3) δ 3.78 (3H, s), 4.82 (2H,
s), 6.41 (1H, dd, J = 3, 2), 6.67 (1H, br s), 6.80 (2H, d, J = 8.5),
7.12–7.14 (2H, m), 7.17–7.19 (1H, m), 7.22 (1H, d, J = 8), 8.36
(1H, br s); 13C NMR (126 MHz, CDCl3) δ 53.1, 55.2, 102.2,
102.7, 113.6, 120.1, 124.2, 124.6, 126.6, 129.5, 130.9, 134.5,
135.4, 158.8; IR (solid) 3248, 1659, 1244, 1038; HRMS (ESI)
m/z calcd for C16H16BrN2O [M + H]+ 331.0441, found [M +
H]+ 331.0444; HPLC purity >95%.
7-Bromo-N-ethyl-1H-indol-4-amine
(5k). Off-white
oil,
21 mg (30%); Rf = 0.38 (20% EtOAc in cyclohexane); 1H NMR
(500 MHz, CDCl3) δ 1.12 (3H, t, J = 7), 3.74 (2H, q, J = 7),
6.50 (1H, t, J = 3), 6.82 (1H, br s), 7.23 (1H, t, J = 3), 7.29 (1H,
d, J = 8), 8.40 (1H, br s); 13C NMR (126 MHz, CDCl3) δ 14.1,
44.9, 102.3, 120.1, 124.4, 124.9, 127.1, 134.4, 135.5, 154.8; IR
(film) 2976, 1699, 1536, 1366, 1146; HRMS (ESI) m/z calcd for
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C10H12BrN2 [M + H]+ 241.0158, found [M + H]+ 241.0155;
HPLC purity >98%.
HRMS (ESI) m/z calcd for C14H18N2O2Na [M + Na]+ 269.1260,
found [M + Na]+ 269.1262; HPLC purity >98%.
tert-Butyl 7-bromo-2-methyl-1H-indol-5-ylcarbamate (9c).
Brown oil, 29 mg (19%), decomposes upon storage; Rf = 0.19
(20% EtOAc in cyclohexane); H NMR (500 MHz, CDCl3) δ
N-(7-Bromo-1H-indol-4-yl)pivalamide (7a). Off-white crystal-
line solid, 25 mg (17%); m.p = 190 °C (decomp); Rf = 0.26
(20% EtOAc in cyclohexane); H NMR (500 MHz, CDCl3) δ
1
1
1.43 (3H, d, J = 9), 6.27 (1H, br s), 6.72 (1H, d, J = 9), 7.04
(1H, d, J = 8), 7.55 (1H, br s); 13C NMR (126 MHz, CDCl3) δ
25.4, 28.4, 80.4, 109.3, 111.7, 115.8, 120.1, 123.7, 130.2, 140.2,
148.3, 153.1; IR (film) 3321, 2977, 1693, 1506, 1152; HRMS
(ESI) m/z calcd for C14H17BrN2O2Na [M + Na]+ 347.0366,
found [M + Na]+ 347.0366; HPLC purity >80%.
1.41 (9H, s), 6.54 (1H, dd, J = 3, 2), 7.26–7.29 (1H, m), 7.34
(1H, d, J = 8), 7.62 (1H, br s), 7.77 (1H, d, J = 8), 8.47 (1H, br
s); 13C NMR (126 MHz, CDCl3) δ 27.8, 39.9, 99.5, 99.8, 112.8,
121.0, 124.3, 124.9, 129.7, 134.9, 176.5; IR (solid) 3270, 2969,
1633, 1501; HRMS (ESI) m/z calcd for C13H15BrN2ONa [M +
Na]+ 317.0260, found [M + Na]+ 317.0256; HPLC purity >95%.
tert-Butyl 7-bromo-3-methyl-1H-indol-5-ylcarbamate (9d).
Yellow/orange wax, 43 mg (33%); Rf = 0.56 (30% EtOAc in
cyclohexane); H NMR (500 MHz, CDCl3) δ 1.55 (9H, s), 2.30
(3H, d, J = 1), 6.49 (1H, s), 7.02 (1H, d, J = 1), 7.39 (1H, s),
7.54 (1H, s), 7.99 (1H, s); 13C NMR (126 MHz, CDCl3) δ 9.3,
27.9, 103.7, 108.4, 112.5, 115.3, 117.2, 122.6, 123.2, 129.7,
131.6, 152.9; IR (film) 3328, 2977, 2918, 1669, 1580; HRMS
(ESI) m/z calcd for C14H17BrN2O2Na [M + Na]+ 347.0367,
found [M + Na]+ 347.0385; HPLC purity <80% (decomposed
upon storage).
Isopropyl 7-bromo-1H-indol-4-ylcarbamate (7b). Clear oil,
33 mg (22%); Rf = 0.29 (20% EtOAc in cyclohexane); 1H NMR
(500 MHz, CDCl3) δ 1.33 (6H, s), 5.07 (1H, h, J = 6), 6.56 (1H,
dd, J = 3, 2), 6.74 (1H, br s), 7.23 (1H, dd, J = 3, 2.5), 7.30 (1H,
d, J = 8), 7.56 (1H, br s), 8.44 (1H, br s); 13C NMR (126 MHz,
CDCl3) δ 22.3, 69.1, 99.0, 99.9, 110.9, 120.5, 124.2, 125.0,
130.0, 135.0, 153.4; IR (film) 3388, 2978, 1699, 1502; HRMS
(ESI) m/z calcd for C12H14BrN2O2 [M + H]+ 297.0233, found
[M + H]+ 297.0225; HPLC purity >95%.
1
Ethyl 7-bromo-1H-indol-4-ylcarbamate (7c). Pale tan resin,
38 mg (26%); Rf = 0.25 (20% EtOAc in cyclohexane); 1H NMR
(500 MHz, CDCl3) δ 1.36 (3H, t, J = 7), 4.29 (2H, q, J = 7),
6.57 (1H, dd, J = 3, 2.5), 6.81 (1H, br s), 7.24 (1H, dd, J = 3,
2.5), 7.32 (1H, d, J = 8), 7.56 (1H, br s), 8.47 (1H, br s); 13C
NMR (126 MHz, CDCl3) δ 14.6, 61.5, 99.0, 99.8, 111.0, 120.5,
124.2, 124.9, 129.7, 134.9, 153.7; IR (film) 3309, 1670, 1525;
HRMS (ESI) m/z calcd for C11H11BrN2O2Na [M + Na]+
304.9896, found [M + Na]+ 304.9888; HPLC purity >95%.
tert-Butyl 7-bromo-2,3-dimethyl-1H-indol-5-ylcarbamate (9e).
Brown oil, 35 mg (22%); Rf = 0.41 (30% EtOAc in cyclo-
hexane); H NMR (500 MHz, CDCl3) δ 1.56 (9H, s), 2.19 (3H,
s), 2.39 (3H, s), 6.44 (1H, br s), 7.30 (1H, s), 7.42 (1H, s), 7.77
(1H, br s); 13C NMR (126 MHz, CDCl3) δ 8.2, 11.1, 27.9, 79.7,
102.7, 107.7, 108.0, 115.9, 129.9, 130.4, 130.7, 132.1, 152.8; IR
(film) 3324, 2977, 2921, 1699; HRMS (ESI) m/z calcd for
C15H20BrN2O2 [M + H]+ 339.0703, found [M + H]+ 339.0708;
HPLC purity >95%.
1
tert-Butyl 7-bromo-2-methyl-1H-indol-4-ylcarbamate (3a).
Yellow/brown oil, 68 mg (44%); Rf = 0.55 (30% EtOAc in
cyclohexane); H NMR (500 MHz, CDCl3) δ 1.56 (9H, s), 2.47
(3H, s), 6.25 (1H, dd, J = 2, 1), 6.57 (1H, br s), 7.21 (1H, d, J =
8), 7.46 (1H, d, J = 8), 8.09 (1H, br s); 13C NMR (126 MHz,
CDCl3) δ 13.7, 28.4, 80.6, 97.8, 98.0, 111.0, 121.4, 123.7,
129.2, 134.9, 135.1, 152.8; IR (film) 3323, 1708, 1509, 1150;
HRMS (ESI) m/z calcd for C14H17BrN2O2Na [M + Na]+
347.0366, found [M + Na]+ 347.0361; HPLC purity >95%.
tert-Butyl 7-methyl-1H-indol-6-ylcarbamate (9k). Pale yellow
oil, 39 mg (27%); Rf = 0.25 (20% EtOAc in cyclohexane); H
1
1
NMR (500 MHz, CDCl3) δ 1.56 (9H, s), 2.30 (3H, s), 6.30 (1H,
br s), 6.49 (1H, dd, J = 3, 2), 7.05–7.07 (1H, m), 7.21 (1H, br s),
7.44 (1H, d, J = 8), 8.31 (1H, br s,); 13C NMR (126 MHz,
CDCl3) δ 11.8, 28.4, 80.0, 102.8, 114.5, 117.9, 118.1, 124.5,
125.4, 129.5, 135.8, 154.4; IR (film) 3313, 2976, 1688, 1243,
1155; HRMS (ESI) m/z calcd for C14H18N2O2Na [M + Na]+
269.1260, found [M + Na]+ 269.1253; HPLC purity >90%.
tert-Butyl 7-bromo-3-methyl-1H-indol-4-ylcarbamate (3b).
Pale yellow solid, 29 mg (22%); Rf = 0.43 (30% EtOAc in cyclo-
hexane); H NMR (500 MHz, CDCl3) δ 1.57 (9H, s), 2.54 (3H,
Acknowledgements
1
s), 6.94 (1H, br s), 6.97 (1H, d, J = 1), 7.27 (1H, d, J = 8), 7.44
(1H, d, J = 8), 8.08 (1H, br s); 13C NMR (126 MHz, CDCl3) δ
11.9, 27.9, 79.9, 99.2, 110.8, 112.7, 121.9, 124.2, 130.8, 135.5,
138.3, 152.8; IR (film) 3355, 1674, 1507; HRMS (ESI) m/z
calcd for C14H18BrN2O2 [M + H]+ 325.0546, found [M + H]+
325.0538; HPLC purity >90%.
This work was supported by Cancer Research UK (grant number
C309/A8274). We are thankful to Prof. Keith Jones and Prof.
Julian Blagg for useful discussions. We also thank Dr Amin
Mirza, Mr Meirion Richards, and Dr Maggie Liu for their help
with LC, NMR, and mass spectrometry.
Notes and references
tert-Butyl 7-methyl-1H-indol-4-ylcarbamate (9a). Brown oil,
9 mg (9%); Rf = 0.23 (20% EtOAc in cyclohexane); H NMR
1
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123.2, 128.5, 135.9, 153.2; IR (film) 3317, 2943, 1449, 1022;
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4446 | Org. Biomol. Chem., 2012, 10, 4441–4447
This journal is © The Royal Society of Chemistry 2012

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This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4441–4447 | 4447