Concerning the preparation of 6-bromotryptamine

Article abstract of DOI:10.1016/j.tet.2021.132055

Most of the previous syntheses of the marine natural product 6-bromotryptamine have almost certainly led to partial debromination resulting in an impure product containing tryptamine. We show that loss of bromine occurs when lithium aluminum hydride is employed as a reducing agent in the final reaction step leading to 6-bromotryptamine. Reductive-debromination is also likely to intrude during some of the syntheses of 6-bromoindole, the typical precursor to 6-bromotryptamine. None of the seven described syntheses of 6-bromotryptamine that involve a reduction sequence from 6-bromoindole have reported elemental analyses as a measure of purity.

Full text of DOI:10.1016/j.tet.2021.132055

Tetrahedron 85 (2021) 132055
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Concerning the preparation of 6-bromotryptamine
*
P. Scott Wiens, Jerry L. Johnson, Gordon W. Gribble
Department of Chemistry, Dartmouth College, Hanover, NH, 03755, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 November 2020
Received in revised form
Most of the previous syntheses of the marine natural product 6-bromotryptamine have almost certainly
led to partial debromination resulting in an impure product containing tryptamine. We show that loss of
bromine occurs when lithium aluminum hydride is employed as a reducing agent in the final reaction
step leading to 6-bromotryptamine. Reductive-debromination is also likely to intrude during some of the
syntheses of 6-bromoindole, the typical precursor to 6-bromotryptamine. None of the seven described
syntheses of 6-bromotryptamine that involve a reduction sequence from 6-bromoindole have reported
elemental analyses as a measure of purity.
16 February 2021
Accepted 23 February 2021
Available online 27 February 2021
Keywords:
©
2021 Elsevier Ltd. All rights reserved.
6
6
-bromotryptamine
-bromoindole
Indole
Reductive-debromination
6-bromoindole-3-carbaldehyde
Bromination
1. Introduction
2. Results and discussion
Of more than 2000 extant brominated marine natural products
1], the 6-bromoindole and 6-bromotryptamine entities are ubiq-
The reductive-dehalogenation of alkyl and aryl halides by
lithium aluminum hydride has been known since at least 1948 [4],
and is particularly rapid in refluxing tetrahydrofuran [4d]. In 1977
we employed this reductive-debromination on 5- and 6-
bromoindoles using lithium aluminum deuteride to give 5- and
6-deuterioindoles, respectively, for a (pre-2D NMR) validation of
[
uitous in alkaloids found in marine life e dating from Tyrian Purple
in 1909 [2] to myriad examples in sponges, algae, tunicates, gor-
gonians, bryozoa, and molluscs. Members of the flustramine [3a],
aplysinopsin [3b], chartelline [3c], eudistomin [3d], topsentin [3e],
tryptamine [3f], arborescidine [3g], hamacanthin [3h], securamine
1
13
the H and C chemical shifts of indole [5].
[
3i], didemnoline [3j], dragmacidin [3k], meridianin [3l], herdma-
Several methods are available for the synthesis of 6-
bromoindole. The inaugural synthesis of 6- (and 4-) bro-
moindoles featured a Reissert indole synthesis [6] via the initial
bromination of 2-nitrotoluene (3) (Scheme 1) as reported by Plie-
ꢀ
nine [3 m], opacaline [3n], purpuroine [3 ], similisine [3p], tan-
jungide [3q], and aspidostomide [3r] families of marine alkaloids all
contain the 6-bromoindole and/or the 6-bromotryptamine unit
rooted in many of their metabolites.
ꢀ
ninger [7]. The 6-bromoindole (1) was isolated as a solid (mp 94 C)
Pursuant to a project on the synthesis of marine natural prod-
ucts embedded with 6-bromoindole (1) and/or 6-bromotryptamine
from the mixture that also contained 4-bromoindole (oil). Pappa-
lardo and Vitali reported a similar preparation of 1 (mp 93.5e94 C)
ꢀ
(
2), we discovered that reductive-debromination in the final step
[8].
leading to 6-bromotryptamine hitherto fore has been unrecog-
nized. We now describe our studies in this regard, and we preface
our work with a comparative review of previous syntheses of 1 and
Higa and Scheuer described the synthesis of 1 via the nitration
of 4-aminotoluene (4) followed by the sequence shown in Scheme
2 [9]. No reaction conditions were reported and the overall yield
was 5%.
2
.
Whereas direct bromination of indole is not a feasible route to 1,
in unpublished work [5] we found that indoline (5) can be bromi-
nated in concentrated sulfuric acid and silver sulfate to give 6-
bromoindoline (6) as the major product in low yield, along with
some 4-bromoindoline [5]. Oxidation of 6-bromoindoline with
chloranil in refluxing xylene gave 1 in good yield (Scheme 3).
*
Corresponding author.
E-mail address: ggribble@dartmouth.edu (G.W. Gribble).
https://doi.org/10.1016/j.tet.2021.132055
040-4020/© 2021 Elsevier Ltd. All rights reserved.
0

P. Scott Wiens, J.L. Johnson and G.W. Gribble
Tetrahedron 85 (2021) 132055
Scheme 4. Kikugawa synthesis of 6-bromoindole [10].
Scheme 1. Plieninger synthesis of 6-bromoindole (7).
Scheme 5. Sargent synthesis of 6-bromoindole [11].
of 4-amino-2-nitrotoluene affords 4-bromo-2-nitrotoluene in 89%
yield. Notably, 4-bromo-2-nitrotoluene (7) can also be accessed by
the nitration of 4-bromotoluene [21]. For our preparation of 6-
bromotryptamine (2) (vide infra) we repeated the syntheses of 1
described in Scheme 6 and we found that the reduction of the
enamine intermediates was best performed with either Zn/HOAc or
Scheme 2. Scheuer synthesis of 6-bromoindole (9).
3 4
TiCl /NH OAc (see Experimental). To verify the bromine content of
our 6-bromoindole (1) we prepared 6-bromo-1-(phenylsulfonyl)
indole in excellent yield and with the expected bromine content (cf.
Experimental). This reaction was also reported by Janosik and
Bergman [22], and earlier by Sasaki et al. [23], but without spectral
or physical data in the latter report. We also synthesized 6-bromo-
Scheme 3. Johnson synthesis of 6-bromoindole (5).
3
-(2-methylaminoacetyl)indole and 2-(6-bromoindol-3-yl)-N-
Subsequently, Kikugawa et al. reported a similar synthesis of 1
from indoline (5), but they employed an azasulfonium salt oxida-
tion of the 6-bromoindoline (6) (Scheme 4) [10]. Whereas the
mixture of C-6 and C-4 bromoindolines could not be separated, the
methyl-2-oxoacetamide to reconfirm the bromine level in our 6-
bromoindole starting material (cf. Experimental).
Virtually all of the reported syntheses of 6-bromotryptamine (2)
originate from 6-bromoindole (1). The one exception involves the
Japp-Klingmann (Grandberg) variation of the Fischer indole syn-
thesis [24] on 3-aminobromobenzene (9) (Scheme 7) [25]. This first
synthesis of 2 provided spectral data (NMR, IR, MS), elemental
corresponding
bromoindoles
could
be
separated
by
chromatography.
Sargent et al. also employed a Sandmeyer reaction to access 4-
bromo-2-nitrotoluene (7) from 4-amino-2-nitrotoluene. The
former compound was heated with N,N-dimethylformamide
ꢀ
analysis, and melting point (120e120.5
C). Interestingly, this
foundational synthesis of 6-bromotryptamine (2) preceded its
isolation from the marine tunicate Didemnum candidum by seven
years [3f].
dimethyl acetal to afford
b-dimethylamino-2-nitrostyrene (8),
which was reduced with Raney Ni to afford 1 (Scheme 5) [11]. This
sequence became known as the Leimgruber-Batcho indole syn-
thesis [12], and has been used and modified by Rapoport [13],
Rinehart [14], Carrera [15], Davidson [16], Rawal [17], and Zhang
Reductive-debromination was noticed by both Rinehart [14] and
Carrera [15] as a likely side reaction in their studies involving the
synthesis of 6-bromotryptamine (2). Rinehart: “Attempted reduc-
tion of 6-bromoindole-3-glyoxylamide to 6-bromotryptamine with
lithium aluminum hydride gave a mixture of largely debrominated
products” [14]. Carrera: “Overreduction [of 6-bromoindole with
Raney Nickel] to unsubstituted indole was observed to a small
degree (ꢁ5% as determined by NMR), but this impurity is removed
[
18] to prepare 6-bromoindole (1) (Scheme 6).
As noted above, the key starting material in these syntheses of
6
-bromoindole (1) is 4-bromo-2-nitrotoluene (7) as prepared in a
Sandmeyer reaction from 4-amino-2-nitrotoluene [19], which has
been known since 1884 [20]. In our hands the Sandmeyer reaction
2

P. Scott Wiens, J.L. Johnson and G.W. Gribble
Tetrahedron 85 (2021) 132055
Scheme 6. Rapoport [13], Rinehart [14], Carrera [15], and Davidson [16] syntheses of 6-bromoindole
Scheme 8. Rinehart synthesis of 6-bromotryptamine [14].
(Scheme 8).
Koomen and co-workers [26] synthesized 6-bromotryptamine
(2) from indole-3-glyoxylamide (11) by a sequence of C-6 bromi-
nation to give a 1:1 mixture with C-5 bromination, reduction with
borane-dimethyl sulfide (avoiding lithium aluminum hydride),
carbamate formation, isomer separation, and deprotection to form
2
, which was isolated as the hydrochloride (characterized by HRMS
but not elemental analysis) (Scheme 9).
A popular and efficient route to 6-bromotryptamine (2) was
pioneered by Davidson (Scheme 10) [16]. This approach involved
converting 6-bromoindole (1) to 6-bromo-3-(2-nitrovinyl)indole
Scheme 7. Christophersen synthesis of 6-bromotryptamine [25].
(12) with 1-dimethylamino-2-nitroethylene (DMANE) (13), the
Büchi reagent [27]. Reduction with sodium borohydride/boron
trifluoride etherate afforded 6-bromotryptamine (2) in excellent
overall yield. The physical state of 2 was not described nor was an
elemental analysis or melting point reported (HRMS only). Rawal
et al. utilized the Davidson synthesis of 2 and claimed it “to be the
most efficient” [17]. The 6-bromotryptamine was also not analyzed
in this report.
during recrystallization” [15]. In addition to his synthesis of 2 via a
conventional Fischer indolization (3-bromophenylhydrazine and 4-
aminobutanal diethyl acetal with zinc chloride) to give a 1.5:1
mixture of 6-bromotryptamine and 4-bromotryptamine, Rinehart
employed the reaction between 6-bromoindole (1) and aziridinium
tetrafluoroborate (10) to give 6-bromotryptamine (2) in one step
3

P. Scott Wiens, J.L. Johnson and G.W. Gribble
Tetrahedron 85 (2021) 132055
The Davidson route to 6-bromotryptamine (2) was adopted by
Lindsley [28], Shi [29], and Andersen [30] (Scheme 11). In no case
was the product analyzed for purity.
Another route to 6-bromotryptamine (2) involved a Henry re-
action of 6-bromoindole-3-carbaldehyde (16) (which is also a ma-
rine natural product [31]). 6-Bromoindole-3-carbaldehyde (16) was
first synthesized by Da Settimo et al. in 1967 [32] from the
bromination of indole-3-carbaldehyde (15) to give in very low yield
a mixture of 16 (3%) and 5-bromoindole-3-carbaldehyde (17) (6%).
However, these workers found that treatment of 6-bromoindole (1)
3
with POCl /DMF gives 16 in 92% yield (Scheme 12).
A Henry reaction of 6-bromoindole-3-carbaldehyde (16) to give
-bromotryptamine (2) was first described by Zhang [18], followed
Scheme 9. Koomen synthesis of 6-bromotryptamine hydrochloride [26].
6
by Kobayashi [33], and Jiang [34] (Scheme 13). In no case was an
analysis of the 6-bromotryptamine product reported.
4
In summary, (1) the use of LiAlH in refluxing THF in the final
reduction step leading to 6-bromotryptamine (2) (cf. Schemes 11
and 13), (2) the description of product 2 as anything other than a
colorless solid, and (3) the complete absence of elemental analytical
data (except for HRMS in some cases) prompted our present
investigation in the synthesis of 6-bromotryptamine.
We initially repeated several of the aforementioned
Leimgruber-Batcho 6-bromoindole syntheses as summarized in
Scheme 14. As noted earlier, we verified the bromine content in our
6-bromoindole via three derivatives (vide supra). .
Our synthesis of 6-bromotryptamine (2) is depicted in Scheme
15. We used the Henry reaction with nitromethane on 6-
Scheme 10. Davidson synthesis of 6-bromotryptamine [16].
bromoindole-3-carbaldehyde (16) to form 3, and by selective
Scheme 11. Lindsley [28], Shi [29], and Andersen [30] syntheses of 6-bromotryptamine
Scheme 12. Da Settimo syntheses of 6-bromoindole-3-carbaldehyde [32].
4

P. Scott Wiens, J.L. Johnson and G.W. Gribble
Tetrahedron 85 (2021) 132055
Scheme 13. Zhang [18]. Kobayashi [33], and Jiang [34] syntheses of 6-bromotryptamine
Scheme 14. Our syntheses of 6-bromoindole via a Leimgruber-Batcho reaction.
ꢀ
ꢀ
reduction of the double bond to give 14. Direct reduction of 12 with
119e119.5 C, consistent with Gr o€ n and Christophersen, mp
LiAlH
4
gives 6-bromotryptamine (2) as previously reported by
120e120.5 C [25].
several groups (cf. Schemes 11 and 13). Unlike previous workers we
obtained melting points and elemental analyses of 12, 14, and 2.
Our data clearly show that reductive debromination is occurring in
3. Conclusion
the LiAlH
4
step to the extent of 5e10% at a minimum, as cleared evi-
Our examination of the several syntheses of 6-bromoindole
denced by the bromine analysis. Proton NMR is also consistent with
the presence of tryptamine (5e10%). This concurs with the quali-
tative observations of Rinehart and Carrera cited earlier. After
recrystallization to remove tryptamine (5e10%) our 6-
bromotryptamine (2) is a white solid having a melting point
(vide supra) indicates the most efficient and cost effective synthe-
ses is the 4-bromo-2-nitrotoluene/Leimgruber-Batcho (TiCl or Zn)
3
synthesis. Based on the known propensity of LiAlH to reductively
4
debrominate aryl bromides in refluxing THF [4d] and the elemental
analysis of our 6-bromotryptamine that shows erosion of bromine
5

P. Scott Wiens, J.L. Johnson and G.W. Gribble
Tetrahedron 85 (2021) 132055
Scheme 15. Our synthesis of 6-bromotryptamine.
using LiAlH
4
(Scheme 15), we urge caution in future syntheses of
is involved in
1 H), 6.69 (s, 1 H), 3.72 (br s, 1 H), 3.53 (t, J ¼ 8.4, 2 H), 2.93 (t, J ¼ 8.4,
13
any bromotryptamine and their derivatives if LiAlH
4
3
2 H); C NMR (CDCl ) d 153.1, 128.2, 125.6, 120.9, 120.5, 112.0, 47.6,
ꢃ1
their syntheses. Moreover, reductive-dehalogenation in general has
been observed during catalytic hydrogenation [35], and even with
sodium hydride in refluxing THF [36]. Accordingly, we recommend
that elemental analyses be performed to verify the purify of both 6-
bromoindole and 6-bromotryptamine, as well as derivatives if a
reduction operation is involved in their syntheses. The sole reliance
on high-resolution mass spectra is no evidence of purity.
29.1; IR (film) 3497 cm . This product was characterized as the N-
acetyl derivative (below).
4.3. N-acetyl-6-bromoindoline
To 0.374 g (1.89 mmol) of 6-/4-bromoindoline was added acetic
ꢀ
anhydride (70 mL). The reaction was heated briefly to 130 C,
cooled to rt, and poured onto crushed ice (75 mL). Filtration gave
0
.336 g of crude product (74%). Recrystallization from EtOH affor-
4
. Experimental
ꢀ
1
ded needles of N-acetyl-6-bromoindoline, mp 134e134.5 C;
H
NMR (CDCl
3
)
d
8.30 (s, 1 H), 7.22e6.90 (m, 2 H), 4.10e3.68 (m, 2 H),
4.1. Indoline
ꢃ1
3.20e2.87 (m, 2 H), 2.10 (s, 3 H); IR (nujol) 1660 cm . Anal. Calcd
for C10H10NOBr: C, 50.02; H, 4.20; N, 5.83. Found: C, 49.75; H, 4.09;
N, 5.76.
To a solution of indole (1.33 g, 11.4 mmol) in glacial HOAc
ꢀ
(
20 mL) cooled to 15 C in a H
2
O ice bath was added in one portion
NaBH
3
CN (1.89 g, 35.0 mmol). After 2 h the solution was poured
O (150 mL), cooled in an ice bath, made basic by addition of
NaOH pellets, and extracted with Et
O (4 ꢂ 75 mL). The combined
organic layers were washed with H
O (2 ꢂ 100 mL), brine
), and evaporated to yield indoline
into H
2
4
.4. 6-Bromoindole (1) by oxidation of 6- and 4-bromoindoline
2
2
To a solution of 6-/4-bromoindoline (0.44 g, 2.2 mmol) in xy-
(
2 ꢂ 100 mL), dried (Na
2 4
SO
lenes (25 mL) was added p-chloranil (0.93 g, 3.8 mmol) in one
portion. The dark green solution was heated to reflux for 5 h. The
mixture was cooled and filtered, rinsing the filter cake with an
aqueous solution of NaOH (6.0 M, 15 mL) and of H O (15 mL). The
2
combined organic phases were concentrated in vacuo to 10 mL of a
1
(
1.26 g, 93%) as a light yellow oil: H NMR (CDCl
3
)
d
7.10e7.05 (m,
1
3
H), 7.02e6.94 (m, 1 H), 6.70e6.63 (m, 1 H), 6.60e6.55 (m, 1 H),
13
.68 (br s, 1 H), 3.44 (t, J ¼ 8.5, 2 H), 2.95 (t, J ¼ 8.5, 2 H); C NMR
151.4, 129.0, 126.7, 124.3, 118.4, 109.1, 47.6, 29.6; IR (neat)
(
CDCl
3
)
d
ꢃ1
cm 3375, 3046, 3029, 2932, 2849, 1606, 1486, 1467, 1406, 1322,
brown slurry. Steam distillation afforded 6-bromoindole (1) (0.32 g,
7
ꢃ1
1244, 1167, 1153, 1092, 1056, 1022 cm
.
ꢀ
ꢀ
3%) as a white solid: mp 93e94 C (lit [7]. mp 94 C). The product
ꢀ
may also be recrystallized from petroleum ether (mp 92.5e94 C);
1
H NMR (CDCl
.25e7.16 (m, 1 H), 7.14e7.06 (m, 1 H), 6.54e6.46 (m, 1 H); C NMR
(CDCl 136.5, 126.7, 124.8, 123.1, 121.9, 115.4, 113.9, 102.7; IR
nujol) 3394, 1606, 1568, 1495, 1398, 1335, 1315, 1230, 1095, 1052,
3
) d 8.10e7.92 (br s, 1 H), 7.52e7.44 (m, 2 H),
4.2. 6-Bromoindoline/4-bromoindoline
13
7
ꢀ
3
) d
Freshly distilled indoline (0.48 g, 4.0 mmol) (bp 46e47 C/
.35 Torr) was dissolved in 97% H SO (5 mL) and Ag SO (0.61 g,
(
8
0
2
4
2
4
ꢃ1
93, 866, 808, 761, 731 cm .
mmol) was added in one portion. The mixture was stirred for
0 min, at which time Br (0.20 mL, 8 mmol) was added via syringe.
The mixture was stirred for 30 min, at which time it was poured
into H O (30 mL) and cooled in an ice bath, made basic with an
aqueous solution of NaOH (6.0 M, 45 mL), diluted with benzene
20 mL) and filtered. The phases were separated and the aqueous
layer was extracted with benzene (2 ꢂ 20 mL). The combined
organic layers were washed with brine (3 ꢂ 30 mL), dried (Na SO ),
and evaporated to yield a brown oil (0.72 g). Flash chromatography
3
2
4.5. 4-Bromo-2-nitrotoluene (7)
2
2
4-Amino-2-nitrotoluene (15.24 g, 99 mmol) was slurried in H O
(
(125 mL) in a 500 mL 3-necked flask equipped with a condenser,
addition funnel and stopper. The suspension was heated to reflux
and HBr (48%, 51.5 mL) was added dropwise. The mixture was
2
4
ꢀ
maintained at reflux for 20 min then cooled to 0 C. A solution of
(
(
(
CH
2
Cl
2
) gave a mixture of 6- (major) and 4-bromoindoline (minor)
NaNO
2
(6.45 g, 93 mmol) in H
2
O (40 mL) was added dropwise with
ꢀ
ꢀ
0.23 g, 29%) as a light brown oil; distillation gave bp 117e118
C
rapid stirring while maintaining the temperature at 0 C. The
resulting diazonium solution was stirred at 0 C for 15 min and then
0.53 Torr); 1H NMR (CDCl
d
6.94e6.89 (m, 1 H), 6.79e6.74 (m,
ꢀ
3
)
6

P. Scott Wiens, J.L. Johnson and G.W. Gribble
Tetrahedron 85 (2021) 132055
ꢀ
added dropwise to a mechanically stirred mixture of CuBr (15.44 g,
(lit [7]. mp 94 C). The spectroscopic data match that of authentic 1
ꢀ
108 mmol) in H
2
O (75 mL) and HBr (48%, 33 mL) cooled to 0e5 C
as prepared above.
with an ice bath. The thick suspension was stirred at rt for 20 min,
heated on a steam bath for an additional 20 min and let stand
overnight. Steam distillation afforded 4-bromo-2-nitrotoluene
4.9. 6-Bromo-1-(phenylsulfonyl)indole
ꢀ
(
4
1
1
17.79 g, 89%) as yellow prisms: mp 45e45.5 C (lit [20]. mp
ꢀ
1
7 C); H NMR (CDCl
3
)
d
8.10 (d, J ¼ 2.0, 1 H), 7.62 (dd, J ¼ 2.0, 8.2,
Benzenesulfonyl chloride (2.2 g, 1.6 mL, 28 mmol) was added
dropwise over 10 min to an ice cold mixture of 6-bromoindole (1)
(1.369 g, 6.90 mmol), powdered NaOH (0.90 g, 23 mmol) and
13
H), 7.24 (d, J ¼ 8.2, 1 H), 2.55 (s, 3 H); C NMR (CDCl
3
) d 149.5,
36.0, 134.1, 132.6, 127.5, 119.6, 20.1; IR (CDCl ) 3019, 1526, 1350,
3
ꢃ1
1215 cm
.
4 4 2 2
nBu NHSO (63 mg, 0.19 mmol) in CH Cl (35 mL). After 1 h, the
mixture was removed from the ice bath and stirred for an addi-
tional 2 h. The solids were removed by filtration and the solution
was evaporated to an oil which was tritrated in MeOH to give the
4
.6. 6-Bromoindole (1) (raney nickel reduction)
ꢀ
A solution of 4-bromo-2-nitrotoluene (7) (0.80 g, 3.7 mmol) in
title compound (2.20 g, 95%) in two crops: mp 98e99 C (lit [22].
ꢀ
1
N,N-dimethylformamide dimethyl acetal (1.40 mL, 10.5 mmol) was
heated to reflux (110 C) for 5.5 h. The bright red solution was
mp 100e101 C); H NMR (CDCl ) d 8.19 (m, 1 H), 7.88 (m, 2 H),
3
ꢀ
13
3
7.60e7.35 (m, 5 H), 6.63 (m, 1 H); C NMR (CDCl ) d 138.0, 134.1,
allowed to cool to rt, diluted with benzene (50 mL) and shaken in a
129.5, 129.4, 126.7, 122.5, 118.3, 116.6, 109.0. The elemental analysis
Parr apparatus with Raney nickel under 50 psi of H
light yellow solution was filtered, washed with H
O (3 ꢂ 30 mL),
SO ), and evaporated to give a brown
oil. Flash chromatography (hexanes/CH
2
for 26 h. The
showed no erosion of bromine within experimental error: Anal.
Calcd for C14H10NO SBr: C, 50.01; H, 3.00; N, 4.17; S, 9.52; Br, 23.77.
2
Found: C, 50.09; H, 3.08; N, 4.11; S, 9.62; Br, 23.86.
2
brine (3 ꢂ 30 mL), dried (Na
2
4
2
ꢀ
Cl
2
(1:1)) gave 1 (0.29 g,
ꢀ
4
0%) as a white powder: mp 92.5e93 C (lit [7]. mp 94 C). The
spectroscopic data match that of authentic 1 as prepared above.
4.10. 6-Bromo-3-(2-methylaminoacetyl)indole
4
.7. 6-Bromoindole (1) (zinc reduction)
To a stirred solution of AlCl
50 mL) was added ClCH COCl (1.56 mL, 20.0 mmol) and the
mixture was stirred for 15 min. A solution of 6-bromoindole (1.30 g,
6.63 mmol) in CH Cl (50 mL) was added dropwise and the mixture
was stirred for 1 h, then quenched with crushed ice. The resulting
precipitate was collected, washed with H O, and recrystallized from
3 2 2
(5.35 g, 40.2 mmol) in CH Cl
(
2
To a solution of 4-bromo-2-nitrotoluene (7) (14.0 g, 65.0 mmol)
in DMF (110 mL) was added DMF dimethyl acetal (17.3 mL,
30 mmol) and pyrrolidine (5.4 mL, 65 mmol). The solution was
2
2
1
ꢀ
heated with an oil bath to 105e110 C for 21 h. The bright red so-
lution was allowed to cool to rt, diluted with Et O (400 mL) and
extracted with H
O (4 ꢂ 150 mL). The combined aqueous layers
were extracted with Et O (100 mL). The combined organic layers
2
2
MeCN to give 0.89 g (44%) of 6-bromo-3-(2-chloroacetyl)indole as
ꢀ
2
an off-white solid: mp 297.5e298 C: IR (KBr) 1650, 1753,
ꢃ1
1
2
1513,1479, 1440, 1417, 1330 cm ; H NMR (DMSO‑d
6
) d 12.22 (br s,
were concentrated in vacuo to a red oil which crystallized on
standing. The red solid was taken up in 80% HOAc (500 mL) and
1H), 8.45 (s,1H), 8.08 (d, J ¼ 8.4 Hz,1 H), 7.69 (d, J ¼ 1.5 Hz,1 H), 7.36
13
(dd, J ¼ 8.7, 1.5 Hz, 1 H), 4.88 (s, 2 H); C NMR (DMSO‑d
6
) d 186.3,
ꢀ
heated to 70 C on an oil bath. Zinc dust (80 g, 1.2 mol) was added in
137.5, 135.6, 125.1, 124.4, 122.8, 115.8, 115.1, 113.5, 46.4. This product
was used as described below.
ꢀ
four portions over 1 h and the mixture was heated to 85e90 C for
2
h, at which time the solution was cooled and filtered. The filtrate
was extracted with Et
O (4 ꢂ 150 mL), washed with saturated
aqueous NaHCO ),
(6 ꢂ 200 mL), brine (3 ꢂ 100 mL), dried (MgSO
and evaporated to give xx as a green solid. Flash chromatography
hexanes/CH Cl (1:1)) afforded 1 as a light blue solid (8.43 g, 65%).
Recrystallization from hexanes gave 1 (6.59 g, 51%) as a white solid:
Methylamine (8.0 M) in EtOH (50 mL) was added to 6-bromo-3-
(2-chloroacetyl)indole (3.81 g, 19.6 mmol). The solution was stirred
2
3
4
for 4 h. The white precipitate was removed by filtration, washed
ꢀ
with H
2
O and dried (50 C, 1 Torr) to give the title compound
ꢀ
(
2
2
(2.05 g, 56%) as a white solid, mp 206e207 C; IR (KBr) 3314, 3069,
2938, 2878, 2793, 1643, 1606, 1570, 1520, 1445, 1424, 1329, 1246,
ꢀ
ꢀ
ꢃ1 1
mp 92e93 C (lit [7]. mp 94 C). Concentration of the mother liquor
afforded a second crop (0.60 g, 5%). The spectroscopic data match
that of authentic 1 as prepared above.
1141, 1100, 1049, 925, 884, 809 cm ; H NMR (DMSO‑d
6
) d 8.39 (s,
1 H), 8.11 (m, 1 H), 7.66 (s, 1 H), 7.31 (m, 1 H), 3.82 (s, 2 H), 2.33 (s,
13
2 H); C NMR (DMSO‑d
15.4, 114.8, 114.7, 57.3, 36.0; MS m/e 266/268 (Mþ), 237/239, 222/
224 (100). The elemental analysis showed no erosion of bromine
within experimental error: Anal. Calcd for C11 OBr: C, 49.46; H,
6
) d 193.9, 137.4, 134.3, 124.6, 124.4, 122.9,
1
4.8. 6-Bromoindole (1) (titanium(III) chloride reduction)
11 2
H N
To
a
solution of 4-bromo-2-nitrotoluene (7) (2.097 g,
4.15; N, 10.49; Br, 29.91. Found: C, 49.32; H, 4.06; N, 10.41; Br, 30.03.
9
.70 mmol) in DMF (25 mL) was added DMF dimethyl acetal
(
3.90 mL, 29.3 mmol) and pyrrolidine (0.84 mL, 10 mmol). The
ꢀ
solution was heated with an oil bath to 110e115 C for 135 min. The
4.11. 2-(6-Bromoindol-3-yl)-N-methyl-2-oxoacetamide
bright red solution was cooled to rt, diluted with Et
extracted with H
O (5 ꢂ 50 mL). The combined aqueous layers were
extracted with Et
O (2 ꢂ 30 mL). The combined organic layers were
), and evaporated to a
red oil which crystallized on standing. The resulting enamines were
dissolved in a minimal amount of acetone and placed in a separa-
2
O (100 mL) and
2
To a solution of oxalyl chloride (0.44 mL, 0.71 g, 5.6 mmol) in
O (25 mL) at 0 C was added 6-bromoindole (1.00 g, 5.1 mmol) in
O (40 mL). The solution was allowed to warm to rt and stirred for
ꢀ
2
Et
Et
2
washed with brine (2 ꢂ 50 mL), dried (MgSO
4
2
4 h. To this mixture was added a solution of 40% aqueous methyl-
amine in EtOH (30 mL) and the mixture was stirred at rt overnight.
The resulting precipitate was collected to give 1.08 g of the title
compound as a solid. The filtrate gave an additional 0.21 g for a total
tory funnel, shaken with an aqueous solution of NH
4
OAc (4 M,
(19% in 20% HCl, 40 mL) for 10 min, and extracted
O (4 ꢂ 35 mL). The combined organic layers were washed
8
5 mL) and TiCl
3
ꢀ
with Et
2
of 1.29 g (90%). Recrystallization from EtOH gave mp 247 C. The
with saturated aqueous NaHCO
3
(2 ꢂ 30 mL), brine (2 ꢂ 30 mL),
elemental analysis showed no erosion of bromine within experi-
dried (MgSO
CH Cl
4
), and evaporated. Flash chromatography (hexanes/
mental error: Anal. Calcd for C11
9 2 2
H N O Br: C, 47.00; H, 3.23; N, 9.97;
ꢀ
2
2
(1:1)) gave 1 (1.176, 62%) as a white powder: mp 92e93 C
Br, 28.42. Found: C, 46.89; H, 3.24; N, 9.98; Br, 28.35.
7

P. Scott Wiens, J.L. Johnson and G.W. Gribble
Tetrahedron 85 (2021) 132055
4.12. 6-Bromoindole-3-carbaldehyde (16)
4.15. 6-Bromo-3-(2-nitroethyl)indole (14)
Phosphorus oxychloride (3.3 mL, 36 mmol) was added slowly
To a slurry of 12 (2.58 g, 9.67 mmol) in EtOH (200 mL) heated to
ꢀ
via syringe to ice-cold dry DMF (10 mL). The solution, under N
stirred for 10 min at 0e5 C. A solution of 6-bromoindole (1) (4.95 g,
2
, was
45 C by an oil bath was added NaBH
mixture was cooled to rt over 1 h, the excess NaBH
4
4
(7.5 g, 0.20 mol) over 2 h. The
was quenched
with glacial HOAc, and the solution was concentrated in vacuo. The
resulting solid was partitioned between CH Cl (100 mL) and H
(100 mL). The layers were separated and the aqueous layer was
extracted with CH Cl
(2 ꢂ 50 mL). The combined organic layers
were washed with saturated aqueous NaHCO
(3 ꢂ 50 mL), brine
), and passed through a plug of silica gel
ꢀ
2
2
1
5 mmol) in DMF (10 mL) was added dropwise via syringe over
ꢀ
min and the solution was stirred at rt for 1 h, heated to 40 C for
2
2
2
O
.5 h, and poured into ice. A solution of NaOH (30 mL, 6 M) was then
ꢀ
added dropwise and the yellow mixture was heated to 98 C for
2
2
2
min, cooled to rt, and the precipitate that formed was collected by
3
ꢀ
filtration, washed with H
2
O, and dried (50 C, 1 Torr) to give 16
(3 ꢂ 50 mL), dried (MgSO
4
(
5.60 g, 100%) as a yellow solid. Recrystallization from 95% EtOH
to remove a baseline impurity. The solution was evaporated to give
ꢀ
ꢀ
gave mp 202.5e204 C (lit [32]. mp 203e204 C); IR (KBr) 3420
broad), 3156, 3035, 2910, 2791, 1635, 1573, 1523 1448, 1425, 1385,
14 as an oil (1.72 g, 66%) that solidified on standing. Recrystalliza-
(
1
2
tion from Et O/petroleum ether gave the analytical sample as clear
ꢃ1
1
ꢀ
ꢀ
243, 1128, 1049, 896, 842, 806, 746, 672 cm ; H NMR (DMSO‑d
6
)
yellow prisms: mp 64.5e65.5 C (lit [29]. mp 57e57.5 C); IR (KBr)
d
12.25 (br s, 1 H), 9.92 (s, 1 H), 8.13 (s, 1 H), 8.01 (d, J ¼ 8.4 Hz, 1 H),
3123, 2930, 1614, 1544, 1472, 1457, 1445, 1425, 1383, 1331, 1296,
1222, 1132, 1106, 1086, 896, 806, 774 cm ; H NMR (CDCl ) d 8.12
3
13
ꢃ1 1
7
.71 (d, J ¼ 1.8 Hz, 1 H), 7.35 (dd, J ¼ 8.4, 1.8 Hz, 1 H); C NMR
(
DMSO‑d 185.2, 139.2, 137.9, 125.1, 123.2, 122.5, 118.0, 115.9,
6
)
d
(br s, 1 H), 7.46 (d, J ¼ 1.5 Hz, 1 H), 7.39 (d, J ¼ 8.7 Hz, 1 H), 7.22 (dd,
115.2; MS m/e 225/223 (Mþ) (100), 196/194, 169/167, 143.
J ¼ 8.7, 1.5 Hz, 1 H), 6.96 (m, 1 H), 4.62 (t, J ¼ 7.2 Hz, 2 H), 3.42 (t,
1
3
J ¼ 7.2 Hz, 2 H); C NMR (CDCl
3
) d 136.9, 125.5, 123.2, 123.0, 119.3,
1
15.9, 114.3, 110.1, 75.6, 23.3; MS m/e 268/270 (Mþ), 221/223, 210/
2
08, 195, 143 (100%), 115. The elemental analysis showed no erosion
Br:
C, 44.63; H, 3.37; N, 10.41; Br, 29.69. Found: C, 44.83; H, 3.40; N,
0.44; Br, 29.65.
4
.13. 6-Bromo-3-(2-nitrovinyl)indole (12)
9 2 2
of bromine within experimental error: Anal. Calcd for C10H N O
4
A solution of 16 (0.935 g, 4.17 mmol) and NH OAc (0.250 g,
.25 mmol) in nitromethane (15 mL) was refluxed for 2 h, cooled to
1
3
rt, allowed to stand for 16 h. The resulting precipitate was collected
ꢀ
Declaration of competing interest
by filtration, washed with H
2
O and dried (50 C, 1 Torr) to give 12
ꢀ
(
0.820 g, 73%) as an orange solid, mp 113e114 C. A second crop was
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
obtained by concentration of the mother liquor (0.207 g, 18%). The
analytical sample was crystallized from EtOHeH
2
O: mp
ꢀ
1
13.5e114.5 C (dec.); IR (KBr) 3240 (broad), 1610, 1568, 1520, 1476,
ꢃ1
1
1293, 1221, 1130, 1053, 963, 894, 806 cm
;
H NMR (DMSO‑d
6
)
Acknowledgments
d
1
12.28 (br s, 1 H), 8.39 (d, J ¼ 13.8 Hz, 1 H), 8.26 (s, 1 H), 8.03 (d, J ¼
13
3.5 Hz, 1 H), 7.97 (d, J ¼ 8.7 Hz, 1 H), 7.72 (m, 1 H), 7.34 (m, 1 H);
C
We thank Dartmouth College for support of this work.
6
NMR (DMSO‑d ) d 138.5,139.7,134.0,131.9,124.5,123.7,122.2,115.9,
1
15.4, 108.2; MS m/e 268/266 (Mþ), 221/219, 141, 114 (100). The
elemental analysis showed no erosion of bromine within experi-
mental error: Anal. Calcd for C10 Br: C, 44.97; H, 2.64; N,
0.49; Br, 29.92. Found: C, 45.07; H, 2.68; N, 10.39; Br, 30.01.
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7 2 2
H N O
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9
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2
2
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1
give a mixture of 2 and tryptamine (2.04 g, 77%) (10:1 by NMR): H
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3
)
d
8.15 (br s, 1 H), 7.51 (d, J ¼ 1.8 Hz, 1 H), 7.47 (d,
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3
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m, 4 H), 1.35 (br s, 2 H); C NMR (CDCl
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6924e6928;
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20e120.5 C). The elemental analysis showed obvious loss of
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11 2
H N Br: C, 50.23; H, 4.64; N, 11.72; Br,
3
3.42. Found: C, 51.70; H, 4.81; N, 11.94; Br, 31.39.
8

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9