Synthesis of β-substituted tryptamines by regioselective ring opening of aziridines

Article abstract of DOI:10.1016/j.tet.2016.03.031

Functionalized tryptamines are targets of interest for development as small molecule therapeutics. The ring opening of aziridines with indoles is a powerful method for tryptamine synthesis if site selectivity can be controlled. 4-Nitrobenzyl carbamate (PN

Full text of DOI:10.1016/j.tet.2016.03.031

Accepted Manuscript
Synthesis of β-Substituted Tryptamines by Regioselective Ring Opening of Aziridines
Jesse Kidd, Kristen Maiden, Jeremy B. Morgan
PII:
S0040-4020(16)30150-8
10.1016/j.tet.2016.03.031
TET 27571
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 January 2016
Revised Date: 29 February 2016
Accepted Date: 3 March 2016
Please cite this article as: Kidd J, Maiden K, Morgan JB, Synthesis of β-Substituted Tryptamines by
Regioselective Ring Opening of Aziridines, Tetrahedron (2016), doi: 10.1016/j.tet.2016.03.031.
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ACCEPTED MANUSCRIPT
Synthesis of β-Substituted Tryptamines by Regioselective Ring
Opening of Aziridines
Jesse Kidd, Kristen Maiden, and Jeremy B. Morgan*
Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Dobo Hall, Wilmington,
North Carolina 28403, United States
Corresponding author. Email address: morganj@uncw.edu
Abstract
Functionalized tryptamines are targets of interest for development as small molecule
therapeutics. The ring opening of aziridines with indoles is a powerful method for tryptamine
synthesis if site selectivity can be controlled. 4-Nitrobenzyl carbamate (PNZ)-protected
aziridines undergo regioselective ring opening to produce β-substituted tryptamines for a series
of indoles. The PNZ-protected tryptamines can be further manipulated by PNZ removal under
mild conditions.
1

ACCEPTED MANUSCRIPT
The demand for nitrogen-containing small molecules facilitates the search for new
1
pathways to construct chiral amine building blocks. The ring opening of aziridines is a well-
2
-4
established method for incorporating nitrogen into organic molecules. Despite significant
history in the development of aziridine opening, new advances are continuing to provide unique
5
-9
bond constructions and product selectivities. The inherent ring strain in aziridines is sufficient
to initiate reactivity, but the nitrogen atom is often modified with an electron-withdrawing
1
0
(
protecting) group for increased activation. The resulting product retains this moiety as a
nitrogen protecting group which must be removed prior to nitrogen functionalization. Synthetic
design must account for the aziridine activation group to ensure its removal is compatible with
ancillary functional groups in the final product.
Sulfonamides stand out as the most commonly utilized aziridine protecting groups for
5
,7,10
ring opening reactions.
toluenesulfonamide (Ts) substrates, which are easy to generate from alkenes.
subsequent Ts deprotections can be challenging, and alternative sulfonamide-protected
A majority of these methodologies incorporate the p-
1
1-13
However, the
1
4-17
aziridines have been developed.
be removed under very mild conditions, but are less common as aziridine protecting groups since
Carbamates, such as benzyl (Cbz) and tert-butyl (Boc), can
1
8-21
rearrangement byproducts are possible.
The 4-nitrobenzyl carbamate (PNZ) had been
2
2-31
sparingly used as an aziridine activating group until recently.
The PNZ group is more
activating than Cbz and more resistant to cleavage under acidic conditions.
Our group has been interested in the development of novel aziridine ring opening
3
2,33
reactions, particularly for N-acylaziridines.
The addition of indoles to aziridines produces
3
4,35
tryptamine derivatives, which are known to possess extensive biological activity.
An initial
36
report of indoles adding to aziridinium ions was followed by methods for opening carbamate-
3
7,38
protected aziridines.
Extensive effort has been made to control the final tryptamine structure
2
1,39-41
in high yield,
where unsymmetrical aziridines, such as 1, can open at either backbone
carbon (Scheme 1). For carbamate-protected aziridines with a C2 ester substituent (R ), addition
1
of indole to the least hindered carbon produces the α-substituted tryptamine (2). Yields of 2 have
21
steadily improved as new Lewis acid catalysts are developed and side reactions are minimized.
The synthesis of a β-substituted tryptamine (3) from a mono-substituted aziridine has only been
21,42
reported in low yields for carbamate-protected aziridines;
however, limited examples with
2

ACCEPTED MANUSCRIPT
3
3,43
alternative nitrogen protecting groups are known.
This report details our discovery that PNZ-
protected, alkyl substituted aziridines (4) undergo selective ring opening by C2 attack with
7
,44,45
indoles to produce β-substituted tryptamines (5).
The tryptamine products can be readily
functionalized at nitrogen after PNZ removal under mild conditions.
Scheme 1: Synthesis of Tryptamines by Indole Addition to Aziridines
Aziridine 6 was synthesized in racemic and enantiopure form and subjected to ring
opening in the presence of 1-methylindole. The choice of BF as the Lewis acid promoter was
3
2
5-27,30,43
directed by previous reports
and unpublished data from our laboratory. The reaction
conditions were remarkably mild with complete consumption of 6 in 1 hour at -78 °C. The PNZ-
protected tryptamine (7) was isolated in 71% yield as a single enantiomer as confirmed by
4
6
33
HPLC. Excess indole was employed, based on previous data, to maximize tryptamine yield.
Scheme 2: Regioselective, Enantiospecific Ring Opening of Aziridine 6
3

ACCEPTED MANUSCRIPT
Optimized conditions for the BF -promoted tryptamine synthesis were applied for a
3
series of functionalized indoles (Table 1). The racemic aziridine 6 and a meso disubstituted PNZ-
aziridine (8) were chosen for the investigation. Reactions were performed in duplicate on a 1
mmol scale to generate sufficient tryptamine for further functionalization. The yield for ring
opening of rac-6 ranged from good to excellent with a variety of indole substitution patterns
(entries 1–7). Tryptamines were produced in high regioselectivity favoring attack at the more
substituted aziridine carbon. The 2, 5, and 6 positions of a 1H-indole were well-tolerated with
functional groups including an ether (entry 4) and halogens (entries 5–6). Slightly lower yields
were observed for aziridine 8, compared to rac-6, with similar indoles (entries 8–12). The
reactions with 2-methylindole (entries 2 and 9) produced the highest yields, indicating
unidentified byproducts from attack at the indole C2 may be reducing product yield in the
remaining examples.
a
Table 1: Substrate Scope for the Synthesis of β-Substituted Aziridines
4

ACCEPTED MANUSCRIPT
We envisioned access to PNZ-protected, β-substituted tryptamines would provide a
single intermediate for the synthesis of biologically relevant tryptamine derivatives. To this end,
the PNZ group of 9 was readily removed under standard hydrogenation conditions. Tryptamine
2
0 was formed as a mixture with toluidine from PNZ reduction in quantitative yield. With this
byproduct in mind, we employed literature methods to selectively functionalize the alkyl
4
7
48
nitrogen of 20. Dimethylation (21) and benzylation (22) were accomplished by reductive
amination in moderate yield. Site selective acylation led the melatonin-like tryptamine 23 in
4
9
modest yield. Studies are underway to functionalize each PNZ-tryptamine in Table 1 to
generate a library of molecules for biological activity screening.
Scheme 3: Deprotection and Functionalization of PNZ-Tryptamine 9
A general method for the synthesis of β-substituted tryptamines by the addition of indoles
to aziridines has been described. The PNZ protecting group functions to activate the aziridine for
selective addition and is removed from the tryptamine product under mild conditions. Future
5

ACCEPTED MANUSCRIPT
experiments will be directed toward expansion of our β-substituted tryptamine library, and
further development of ring opening reactions with underutilized PNZ-protected aziridines.
Acknowledgements
The authors are grateful to the National Institute of General Medical Sciences of the
National Institutes of Health (R15GM114766) for financial support. The HRMS data was
collected by using a Bruker MicrOTOF-Q II purchased with funds from the NSF (CHE-
1
039784) and UNCW.
Supplementary data
1
13
H and C NMR spectra for compounds 6−19 and 21−23 and HPLC data for compound
and 7. This material is available online at….
6
Disclaimer
The content is solely the responsibility of the authors and does not necessarily represent
the official views of the National Institutes of Health.
Experimental
1
General.
H NMR spectra were recorded on Bruker DRX (400 MHz) or Bruker Avance
(600 MHz) spectrometer. Chemical shifts are reported in ppm from tetramethylsilane with the
solvent resonance as the internal standard (CDCl : 7.27 ppm). Data are reported as follows:
3
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m =
1
3
multiplet), coupling constants (Hz), and integration. C NMR spectra were recorded on a Bruker
DRX 400 (100 MHz) or Bruker Avance 600 (151 MHz) spectrometer with complete proton
decoupling. Chemical shifts are reported in ppm from tetramethylsilane with the solvent as the
internal standard (CDCl : 77.1 ppm). High resolution mass spectrometry was acquired with a
3
Bruker MicrOTOF-Q II at the University of North Carolina Wilmington. Infrared (IR) spectra
were obtained using a Nicolet iS5 FT-IR.
Liquid chromatography was performed using forced flow (flash chromatography) on
silica gel (SiO , 32 to 63µm) purchased from Dynamic Absorbents Inc. Thin layer
2
6

ACCEPTED MANUSCRIPT
chromatography (TLC) was performed on EMD Chemicals 0.25 mm silica gel 60 plates.
Visualization was achieved UV light (254 nm) or basic potassium permanganate in water
followed by heating. High pressure liquid chromatography (HPLC) was performed on an HP
instrument equipped with an autosampler and a UV detector.
All reactions were conducted in oven and flame dried glassware under an inert
atmosphere of argon. All solvents were EMD Chemicals anhydrous solvents in Sure-Seal bottles
sold by VWR International, unless otherwise noted. 2-Methylaziridine (90%) was purchased
from Aldrich Chemical Company. 4-Nitrobenzyl chloroformate was purchased from the Acros
Chemical Company. All reagents were used as received.
Representative Procedure for Synthesis of Aziridine 6.
A 250 mL round bottom flask with a Teflon®-coated magnetic stir bar was charged with
5
0 mL of THF and 20 mL of H O. Solid sodium carbonate (6.36 g, 60 mmol) and 2-
2
methylaziridine (1.57 mL, 20 mmol) were added to the stirred suspension at room temperature
under argon. The flask was cooled to 0 °C where 4-nitrobenzyl chloroformate (4.67 g, 21 mmol)
in 10 mL of THF was added dropwise. The mixture was stirred at 0 ˚C for 1 hour and then
diluted with 30 mL of H O and 40 mL of ethyl acetate. The flask was warmed to room
2
temperature and the organic layer was taken. The aqueous layer was extracted twice with 25 mL
of ethyl acetate. The combined organics layer was then washed with 30 mL of brine and dried
over MgSO . The crude reaction was concentrated via rotary evaporation and further purified by
4
silica gel chromatography (4:1 hexanes/acetone) to yield rac-6 (3.23 g, 62% yield) as a white
50
solid. An enantioenriched sample of 6 was synthesized from (S)-2-methylaziridine.
1
4
-nitrobenzyl 2-methylaziridine-1-carboxylate. H NMR (400 MHz, Chloroform-d) δ
8
.23 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 5.27 – 5.18 (m, 2H), 2.61 − 2.53 (m, 1H), 2.38
1
3
(
d, J = 5.9 Hz, 1H), 2.02 (d, J = 3.9 Hz, 1H), 1.32 (d, J = 5.6 Hz, 3H). C NMR (151 MHz,
Chloroform-d) δ 163.0, 147.9, 143.3, 128.5, 124.0, 66.6, 34.3, 32.9, 17.6. HRMS: Calculated
+
+
+
for C H N NaO : 259.0689 (M+Na ), found 259.0697 (M+Na ). IR (diamond ATR crystal):
1
1
12
2
4
1
713, 1536, 2969, 2933, 3110, 3087.
Representative Procedure for Synthesis of Aziridine 8.
7

ACCEPTED MANUSCRIPT
In a flame-dried round bottom flask equipped with a Teflon®-coated magnetic stir bar the
lithium naphthalenide reagent was freshly prepared by vigorously stirring finely chopped lithium
metal (1.0 equiv) and naphthalene (1.1 equiv) in dry THF (1 M) under argon for 24 hours at
room temperature.
A flame-dried round bottom flask equipped with a Teflon®-coated magnetic stir bar was
1
1
charged with 3.77 g (15 mmol) of 7-tosyl-7-azabicyclo[4.1.0]heptane and 60 mL of THF. The
solution was cooled to -78 °C in a dry ice and acetone bath. The lithium naphthalenide reagent
was added dropwise until the dark green endpoint was observed (~40 mL of stock 1 M solution).
The reaction was quenched with 20 mL of aqueous saturated sodium bicarbonate and slowly
warmed to 0 °C. Solid 4-nitrobenzyl chloroformate (3.50 g, 16.2 mmol) was added all at once,
and the suspension was stirred for a total of 2 hours at 0 °C. After this time, the mixture was
diluted with 20 mL of H O and 30 mL of ethyl acetate. The flask was warmed to room
2
temperature and the organic layer was taken. The aqueous layer was extracted twice with 20 mL
of ethyl acetate. The combined organics layer was then washed with 30 mL of brine and dried
over MgSO . The crude reaction mixture was concentrated and further purified with silica gel
4
chromatography (4:1 hexanes/ethyl acetate) to yield 2.74 g (66% yield) of 8 as a white solid.
1
4
-nitrobenzyl 7-azobicyclo[4.1.0]heptane-7-carboxylate. H NMR (600 MHz,
Chloroform-d) δ 8.21 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 5.20 (s, 2H), 2.72 – 2.67 (m,
1
3
2
H), 1.99 – 1.91 (m, 2H), 1.85 – 1.78 (m, 2H), 1.46 – 1.37 (m, 2H), 1.29 − 1.21 (m, 2H).
C
NMR (151 MHz, Chloroform-d) δ 163.5, 147.7, 143.5, 128.4, 123.8, 66.3, 37.4, 23.7, 19.8.
+
+
+
HRMS: Calculated for C H NNaO : 299.1002 (M+Na ), found 299.1014 (M+Na ). IR
1
4
17
2
(diamond ATR crystal): 1348, 1534, 1709, 2854, 2934, 3316.
Enantiospecific Synthesis of β-Substituted Tryptamine 7
A 1 dram vial equipped with a Teflon®-coated magnetic stir bar was purged with argon.
The flask was charged with aziridine 6 (0.0236 g, 0.1 mmol) and 1-methylindole (0.0374 mL,
0
.3 mmol). Dry DCM (0.5 mL, 0.20 M) was added, and the solution was cooled to -78 °C with a
dry ice/acetone bath. A 1 M solution of BF ꢀOEt in DCM (0.1 mL, 0.1 mmol) was then added
3
2
dropwise. The reaction was stirred for a total of 1 hour at -78 °C and then quenched with 0.5 mL
of aqueous saturated sodium bicarbonate. After slowly warming to room temperature, the
mixture was extracted with 1 mL ethyl acetate three times and the combined organic layers were
8

ACCEPTED MANUSCRIPT
dried over MgSO . The crude reaction mixture was then filtered and concentrated via rotary
4
evaporation. The crude mixture was purified using silica gel chromatography (3:1 hexanes/ethyl
acetate) afforded tryptamine 7 as a viscous yellow oil in 71% yield (0.0260 g).
1
4
-nitrobenzyl (2-(1-methyl-1H-indol-3-yl)propyl) carbamate. H NMR (400 MHz,
Chloroform-d) δ 8.19 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.34
d, J = 8.1 Hz, 1H), 7.26 (t, J = 7.2 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H) 6.89 (s, 1H), 5.19 (d, J =
3.4 Hz, 1H), 5.16 (d, J = 13.4 Hz, 1H), 4.87 (br s, 1H), 3.77 (s, 3H), 3.59 − 3.52 (m, 1H), 3.52 −
(
1
3
1
4
3
1
3
.44 (m, 1H), 3.35 − 3.26 (m, 1H), 1.40 (d, J = 7.0 Hz, 3H). C NMR (151 MHz, CDCl ) δ
3
56.0, 147.6, 144.3, 137.3, 128.1, 127.1, 125.7, 123.8, 122.0, 119.3, 119.0, 117.0, 109.5, 65.1,
+
+
7.5, 32.8, 31.5, 18.9. HRMS: Calculated for C H N NaO : 390.1424 (M+Na ), found
2
0
21
3
4
+
90.1433 (M+Na ). IR (diamond ATR crystal): 1514, 1716, 2875, 2929, 2961, 3411.
Representative for the Synthesis of β-Substituted Tryptamines
A flame-dried round bottom flask equipped with a Teflon®-coated magnetic stir bar was
purged with argon. The flask was charged with the required aziridine (1 mmol) and indole (3
mmol). Dry DCM (5 mL, 0.20 M) was added, and the solution was cooled to -78 °C with a dry
ice/acetone bath. A 1 M solution of BF ꢀOEt in DCM (1 mL, 1 mmol) was then added
3
2
dropwise. The reaction was stirred for a total of 2 hours at -78 °C and then quenched with 5 mL
of aqueous saturated sodium bicarbonate. After slowly warming to room temperature, the
mixture was extracted with 10 mL ethyl acetate three times and the combined organic layers
were dried over MgSO . The crude reaction mixture was then filtered and concentrated via
4
rotary evaporation. The crude mixture was purified using silica gel chromatography yielding the
respective β-substituted tryptamine.
4
-nitrobenzyl (2-(1H-indol-3-yl)propyl)carbamate (9). Synthesized from 0.2362 g of
rac-6 and 0.3514 g of 1H-indole by the standard procedure. Purification by silica gel
1
chromatography (3:2 hexanes/ethyl acetate) afforded a yellow solid in 71% yield (0.2499 g). H
NMR (600 MHz, Chloroform-d) δ 8.20 (d, J = 8.4 Hz, 2H), 8.04 (br s, 1H), 7.66 (d, J = 8.0 Hz,
1
H), 7.45 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.13 (t, J = 7.5
Hz, 1H), 7.05 (s, 1H), 5.19 (d, J = 12.0 Hz, 1H), 5.15 (d, J = 12.0 Hz, 1H), 4.82 (br s, 1H), 3.60
1
3
−
3.46 (m, 2H), 3.36 − 3.26 (m, 1H), 1.41 (d, J = 7.0 Hz, 3H). C NMR (151 MHz,
Chloroform-d) δ 156.1, 147.6, 144.3, 136.7, 128.1, 126.7, 123.8, 122.4, 120.9, 119.6, 119.2,
9

ACCEPTED MANUSCRIPT
+
1
18.6, 111.5, 65.1, 47.3, 31.6, 18.7. HRMS: Calculated for C H N NaO : 376.1267
19 19 3 4
+
+
(
M+Na ), found 376.1275 (M+Na ). IR (diamond ATR crystal): 1509, 1715, 3313, 3405.
-nitrobenzyl (2-(2-methyl-1H-indol-3-yl)propyl) carbamate (10). Synthesized from
.2362 g of rac-6 and 0.3935 g of 2-methylindole by the standard procedure. Purification by
4
0
silica gel chromatography (1% acetone in DCM) afforded a yellow solid in 90% yield (0.3327 g)
1
H NMR (600 MHz, Chloroform-d) δ 8.18 (d, J = 8.6 Hz, 2H), 7.89 (s, 1H), 7.59 (d, J = 7.9 Hz,
1
H), 7.42 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5
Hz, 1H), 5.15 (s, 2H), 4.77 (br s 1H), 3.74 − 3.67 (m, 1H), 3.48 − 3.41 (m, 1H), 3.28 − 3.19 (m,
1
3
1
1
3
H), 2.36 (s, 3H), 1.44 (d, J = 7.1 Hz, 3H). C NMR (151 MHz, Chloroform-d) δ 155.8, 147.5,
44.2, 135.5, 131.6, 128.0, 127.0, 123.7, 123.7, 121.1, 119.2, 118.9, 112.5, 110.6, 64.9, 46.4,
+
+
1.7, 18.3, 12.0. HRMS: Calculated for C H N NaO : 390.1424 (M+Na ), found 390.1437
2
0
21
3
4
+
(
M+Na ). IR (diamond ATR crystal): 1514, 1701, 2926, 2959, 3333, 3398.
-nitrobenzyl (2-(5-methyl-1H-indol-3-yl)propyl) carbamate (11). Synthesized from
.2362 g of rac-6 and 0.3935 g of 5-methylindole by the standard procedure. Purification by
4
0
silica gel chromatography (3:2 hexanes/ethyl acetate) afforded a yellow solid in 65% yield
1
(
0.2431 g). H NMR (600 MHz, Chloroform-d) δ 8.18 (d, J = 8.7 Hz, 2H), 8.02 (br s, 1H), 7.44
d, J = 2.0 Hz, 2H), 7.43 (s, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.3Hz, 1H), 6.99 (s, 1H),
(
5
.17 (s, 2H), 4.85 (br s, 1H), 3.60 – 3.53 (m, 1H), 3.53 − 3.46 (m, 1H), 3.33 − 3.24 (m, 1H), 2.46
1
3
(
s, 3H), 1.40 (d, J = 7.0 Hz, 3H). C NMR (151 MHz, Chloroform-d) δ 156.0, 147.5, 144.2,
1
34.9, 128.7, 128.0, 126.8, 123.9, 123.7, 121.0, 118.8, 117.9, 111.0, 65.0, 47.1, 31.5, 21.6, 18.7.
+
+
+
Calculated for C H N NaO : 390.1424 (M+Na ), found 390.1422 (M+Na ). IR (diamond
2
0
21
3
4
ATR crystal): 1509, 1714, 2849, 2912, 2950, 3309, 3386.
-nitrobenzyl (2-(5-methoxy-1H-indol-3-yl)propyl) carbamate (12). Synthesized
4
from 0.2362 g of rac-6 and 0.4415 g of 5-methoxylindole by the standard procedure.
Purification by silica gel chromatography (1% THF in DCM) afforded an orange solid in 73%
1
yield (0.2951 g). H NMR (600 MHz, Chloroform-d) δ 8.18 (d, J = 8.9 Hz, 2H), 8.08 (br s, 1H),
7
1
2
1
.43 (d, J = 8.6 Hz, 2H), 7.28(d, J = 8.7 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 7.01 (d, J = 2.5 Hz,
H), 6.89 (dd, J = 8.8, 2.5 Hz, 1H), 5.18 (s, 2H), 4.90 (br s, 1H), 3.86 (s, 3H), 3.58 – 3.45 (m,
1
3
H), 3.33 − 3.21 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H). C NMR (151 MHz, Chloroform-d) δ 156.1,
54.0, 147.6, 144.3, 131.8, 128.1, 127.1, 123.8, 121.6, 118.3, 112.4, 112.2, 101.2, 65.1, 56.1,
10

ACCEPTED MANUSCRIPT
+
+
4
7.3, 31.5, 18.6. HRMS: Calculated for C H N NaO : 406.1373 (M+Na ), found 406.1386
2
0
21
3
5
+
(
M+Na ). IR (diamond ATR crystal): 1514, 1712, 2868, 2911, 2952, 3323, 3396.
-nitrobenzyl (2-(5-chloro-1H-indol-3-yl)propyl) carbamate (13). Synthesized from
.2362 g of rac-6 and 0.4548 g of 5-chloroindole by the standard procedure. Purification by
4
0
silica gel chromatography (3:2 hexanes/ ethyl acetate) afforded a yellow solid in 65% yield
1
(
0.2551 g). H NMR (600 MHz, Chloroform-d) δ 8.20 (br s, 1H), 8.18 (d, J = 8.3 Hz, 2H), 7.61
s, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.30(d, J = 8.6 Hz, 1H), 7.16 (d, J = 8.6, 1H), 7.06 (s, 1H), 5.17
s, 2H), 4.86 (br s, 1H), 3.59 − 3.48 (m, 1H), 3.48 – 3.38 (m, 1H), 3.29 − 3.21 (m, 1H), 1.38 (d, J
(
(
1
3
=
7.0 Hz, 3H). C NMR (151 MHz, Chloroform-d) δ 156.0, 147.5, 144.1, 134.8, 128.0, 127.8,
1
25.2, 123.7, 122.6, 122.1, 118.6, 118.4, 112.4, 65.1, 47.4, 31.4, 18. 6. HRMS: Calculated for
+
+
+
C H ClN NaO : 410.0878 (M+Na ), found 410.0886 (M+Na ). IR (diamond ATR crystal):
19
18
3
4
1
0
510, 1704, 2913, 3287, 3406.
4
-nitrobenzyl (2-(6-fluoro-1H-indol-3-yl)propyl) carbamate (14). Synthesized from
.2362 g of rac-6 and 0.4053 g of 6-fluoroindole by the standard procedure. Purification by
silica gel chromatography (3:2 hexanes/ethyl acetate) to afforded a yellow solid in 57% yield
1
(
0.2107 g). H NMR (600 MHz, Chloroform-d) δ 8.20 (d, J = 8.4 Hz, 2H), 8.02 (br s, 1H), 7.56
dd, J = 8.8, 5.3 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 9.6, 1H), 7.01 (s, 1H), 6.89 (t, J =
(
9
.1 Hz, 1H), 5.17 (s, 2H), 4.83 (br s, 1H), 3.50 (t, J = 6.4 Hz, 2H), 3.33 − 3.23 (m, 1H), 1.39 (d, J
1
3
=
7.0 Hz, 3H). C NMR (151 MHz, Chloroform-d) δ 160.0 (d, J = 237.9 Hz), 156.1, 147.5,
1
44.2, 136.5 (d, J = 12.4 Hz), 128.0, 123.7, 123.3, 121.1 (d, J = 3.5 Hz), 119.8 (d, J = 10.1 Hz),
18.6, 108.2 (d, J = 24.5 Hz), 97.7 (d, J = 25.8 Hz), 65.1, 47.3, 31.5, 18.5. HRMS: Calculated
1
+
+
+
for C H FN NaO : 394.1173 (M+Na ), found 394.1183 (M+Na ). IR (diamond ATR crystal):
1
9
18
3
4
1
708, 2954, 2914, 3284, 3397.
-nitrobenzyl (2-(1H-indol-3-yl)cyclohexyl)carbamate (15). Synthesized from 0.2763
g of 8 and 0.3514 g of 1H-indole by the standard procedure. Purification by silica gel
4
1
chromatography (2:1 hexanes/ethyl acetate) afforded a yellow solid in 73% yield (0.2903 g) H
NMR (400 MHz, Chloroform-d) δ 8.18 (br s, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 7.6 Hz,
1
H), 7.39 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.1 Hz, 2H), 7.09 (d, J = 7.1
Hz, 1H), 7.00 (s, 1H), 5.03 (d, J = 13.6 Hz, 1H), 4.90 (d, J = 13.6 Hz, 1H), 4.77 (br s, 1H), 3.92 –
3
2
.77 (m, 1H), 2.85 – 2.73 (m, 1H), 2.32 – 2.23 (m, 1H), 2.16 – 2.05 (m, 1H), 1.94 – 1.77 (m,
1
3
H), 1.65 – 1.31 (m, 4H). C NMR (151 MHz, Chloroform-d) δ 155.4, 147.3, 144.5, 136.2,
11

ACCEPTED MANUSCRIPT
1
27.4, 127.2, 123.6, 122.0, 120.8, 119.4, 118.7, 118.3, 111.4, 64.6, 55.2, 41.5, 34.7, 34.6, 26.3,
+
+
+
2
5.5. HRMS: Calculated for C H N NaO : 416.1581 (M+Na ), found 416.1586 (M+Na ). IR
2
2
23
3
4
(diamond ATR crystal): 1512, 1712, 2855, 2928, 3311, 3401.
4
-nitrobenzyl (2-(2-methyl-1H-indol-3-yl)cyclohexyl) carbamate (16). Synthesized
from 0.2763 g of 8 and 0.3935 g of 2-methylindole by the standard procedure. Purification by
silica gel chromatography (1% acetone in DCM) afforded a yellow solid in 78% yield (0.3112
1
g). H NMR (600 MHz, DMSO-d ) δ 10.65 (s, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 7.9 Hz,
6
1
1
1
1
H), 7.21 (d, J = 8.0 Hz, 2H), 7.18 – 7.01 (m, 2H), 7.01 − 6.79 (m, 2H), 4.99 (d, J = 14.5 Hz,
H), 4.87 (d, J = 14.5 Hz, 1H), 3.90 (m, 1H), 2.74 (m, 1H), 2.33 (s, 3H), 2.05 – 1.65 (m, 4H),
1
3
.54 – 1.20 (m, 4H). C NMR (151 MHz, DMSO-d ) δ 154.7, 146.6, 145.7, 135.2, 131.7, 127.2,
6
26.9, 123.3, , 119.3, 118.8, 117.6, 112.0, 110.2, 63.1, 52.8, 40.5, 34.1, 32.5, 26.1, 25.3. HRMS:
+
+
+
Calculated for C H N NaO : 430.1737 (M+Na ), found 430.1736 (M+Na ). IR (diamond
2
3
25
3
4
ATR crystal): 1508, 1708, 2854, 2912, 3339, 3399.
-nitrobenzyl (2-(5-methyl-1H-indol-3-yl) cyclohexyl) carbamate (17). Synthesized
4
from 0.2763 g of 8 and 0.3935 g of 5-methylindole by the standard procedure. Purification by
silica gel chromatography (3:2 hexanes/ethyl acetate) afforded a yellow solid in 59% yield
1
(
0.2422 g). H NMR (600 MHz, Chloroform-d) δ 8.05 (d, J = 8.1 Hz, 2H), 8.02 (br s, 1H), 7.40
s, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H),
(
5
2
1
1
.02 (d, J = 13.7 Hz, 1H), 4.91 (d, J = 13.7 Hz, 1H), 4.74 (br s, 1H), 3.88 – 3.76 (m, 1H), 2.82 −
.68 (m, 1H), 2.45 (s, 3H), 2.32 – 2.24 (m, 1H), 2.14 − 2.06 (m, 1H), 1.92 – 1.77 (m, 2H), 1.64 –
1
3
.30 (m, 4H). C NMR (151 MHz, Chloroform-d) δ 155.4, 147.3, 144.5, 134.6, 128.6, 127.4,
23.6, 121.0, 118.3, 117.8, 111.1, 64.6, 55.1, 41.5, 34.8, 34.6, 26.3, 25.5, 21.7. Calculated for
+
+
+
C H N NaO : 430.1737 (M+Na ), found 430.1735 (M+Na ). IR (diamond ATR crystal):
23
25
3
4
1
520, 1700, 2865, 2917, 3338, 3390, 3407.
-nitrobenzyl (2-(5-methoxy-1H-indol-3-yl) cyclohexyl) carbamate (18). Synthesized
4
from 0.2763 g of 8 and 0.4415 g of 5-methoxylindole by the standard procedure. Purification by
silica gel chromatography (2% acetone in DCM) afforded a yellow solid in 63% yield (0.2626
1
g). H NMR (400 MHz, Chloroform-d) δ 8.08 (d, J = 8.7 Hz, 2H), 7.87 (br s, 1H), 7.28 (d, J =
8.7 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 7.03 (s, 2H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 5.03 (d, J =
13.8 Hz, 1H), 4.93 (d, J = 13.8 Hz, 1H), 4.67 (br s, 1H), 3.86 (s, 3H), 3.87 – 3.73 (m, 1H), 2.78 –
2.65 (m, 1H), 2.31 – 2.21 (m, 1H), 2.16 – 2.06 (m, 1H), 1.92 – 1.76 (m, 2H), 1.61 – 1.29 (m,
12

ACCEPTED MANUSCRIPT
1
3
4
1
H). C NMR (151 MHz, Chloroform-d) δ 155.4, 154.0, 147.3, 144.5, 131.4, 127.7, 127.5,
23.7, 121.7, 118.0, 112.0, 111.9, 100.9, 64.6, 56.1, 55.2, 41.5, 34.7, 34.6, 26.3, 25.5. HRMS:
+
+
+
Calculated for C H N NaO : 446.1686 (M+Na ), found 446.1688 (M+Na ). IR (diamond
2
3
25
3
5
ATR crystal): 1515, 1692, 2849, 2913, 2935, 3322, 3409.
-nitrobenzyl (2-(1-methyl-1H-indol-3-yl) cyclohexyl) carbamate (19). Synthesized
4
from 0.2763 g of 8 and 0.375 mL of 1-methylindole by the standard procedure. Purification by
silica gel chromatography (3:2 hexanes/ethyl acetate) afforded a yellow solid in 63% yield
1
(
0.2607 g). H NMR (600 MHz, Chloroform-d) δ 8.07 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 7.8 Hz,
1
H), 7.33 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 8.3 Hz, 2H), 7.12 (t, J = 7.5
Hz, 1H), 6.90 (s, 1H), 5.05 (d, J = 13.9 Hz, 1H), 4.94 (d, J = 13.9 Hz, 1H), 4.74 (br s,1H), 3.86 –
3
1
1
3
.76 (m, 1H), 3.71 (s, 3H), 2.84 – 2.72 (m, 1H), 2.35 – 2.26 (m, 1H), 2.16 – 2.05 (m, 1H), 1.92 –
1
3
.78 (m, 2H), 1.65 – 1.28 (m, 4H). C NMR (151 MHz, Chloroform-d) δ 155.3, 147.3, 144.6,
37.0, 127.6, 127.5, 125.6, 123.6, 121.6, 118.9, 118.8, 116.9, 109.5, 64.6, 55.2, 41.4, 35.1, 34.6,
+
+
2.8, 26.3, 25.5. HRMS: Calculated for C H N NaO : 430.1737 (M+Na ), found 430.1737
2
3
25
3
4
+
(
M+Na ). IR (diamond ATR crystal): 1521, 1542, 1692, 2848, 2915, 3328.
Representative Procedure for the Tryptamine Functionalization
An oven-dried 1-dram vial equipped with a Teflon®-coated magnetic stir bar was purged
with argon. The vial was charged with 0.0706 g (0.2 mmol) of tryptamine 9 and 0.0400 g (0.02
mmol) of 10% palladium on carbon (activated, wet). Dry methanol (1.0 mL) was added under an
argon atmosphere. Hydrogen gas was bubbled into solution for 5 minutes, then the hydrogen
atmosphere was maintained under balloon pressure. The reaction was stirred for 4 hours after
which no starting material remained. The solution was filtered through a Celite© plug using
excess methanol, and the crude filtrate was concentrated via rotary evaporation. Unpurified
tryptamine 20 was used without purification for subsequent reactions.
2
-(1H-indol-3-yl)-N,N-dimethylpropan-1-amine (21). Synthesized from tryptamine 20
4
7
(
0.33 mmol) by a published procedure. Purification by silica gel chromatography (10%
1
methanol and 1% NH OH in DCM) afforded a white solid in 53% yield (0.0359 g). H NMR
4
(400 MHz, Chloroform-d) δ 8.03 (br s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.1, 1H), 7.22
−
7.16 (m, 1H), 7.15 − 7.09 (m, 1H), 7.00 (d, J = 2.4 Hz, 1H), 3.33 − 3.20 (m, 1H), 2.61 (dd, J =
13

ACCEPTED MANUSCRIPT
1
3
1
2.0, 5.7 Hz, 1H), 2.49 (dd, J = 12.0, 9.2 Hz, 1H), 2.30 (s, 6H), 1.41 (d, J = 6.8 Hz, 3H). C
NMR (151 MHz, CDCl ) δ 136.6, 126.9, 122.0, 121.0, 120.3, 119.3, 119.2, 111.4, 67.1, 46.1,
3
2
9.3, 19.7.
N-benzyl-2-(1H-indol-3-yl)propan-1-amine (22). Synthesized from tryptamine 20 (0.2
4
8
mmol) by a published procedure. Purification by silica gel chromatography (5-7.5% methanol
1
in DCM) afforded a yellow oil in 45% yield (0.0238 g). H NMR (400 MHz, Chloroform-d) δ
8
.17 (br s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.35 – 7.19 (m, 6H), 7.13 (t, J
8.0 Hz, 1H), 7.00 (s, 1H), 3.86 (d, J = 13.4, 1H), 3.81 (d, J = 13.4, 1H), 3.42 − 3.30 (m, 1H),
.04 (dd, J = 11.4, 7.9 Hz, 1H), 2.91 (dd, J = 11.4, 6.1 Hz, 1H), 2.17 (br s, 1H), 1.42 (d, J = 6.9
=
3
1
3
Hz, 3H). C NMR (151 MHz, CDCl ) δ 140.2, 136.7, 128.5, 128.2, 127.0, 126.7, 122.1, 120.9,
3
1
19.7, 119.5, 119.3, 111.4, 55.5, 53.8, 31.5, 19.8.
N-(2-(1H-indol-3-yl)propyl)acetamide (23). Synthesized from tryptamine 20 (0.2
4
9
mmol) by a published procedure. Purification by silica gel chromatography (2:1 ethyl acetate/
1
hexanes) afforded a white solid in 44% yield (0.0191 g). H NMR (400 MHz, Chloroform-d) δ
8
.25 (br s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 7.5, 1H), 7.14 (t, J
=
7.5, 1H), 7.05 (d, J = 2.4 Hz, 1H), 5.46 (br s, 1H), 3.73 − 3.64 (m, 1H), 3.45 (ddd, J = 13.2,
1
3
8
.2, 5.1 Hz, 1H), 3.35 − 3.24 (m, 1H), 1.89 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H). C NMR (151
MHz, CDCl ) δ 170.3, 136.7, 126.8, 122.4, 120.9, 119.6, 119.2, 118.9, 111.5, 45.8, 31.3, 23.5,
3
1
9.0.
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