A one-pot three-component reaction for the preparation of highly functionalized tryptamines

Article abstract of DOI:10.1016/j.tet.2011.11.032

We have developed a general one-pot method to provide highly functionalized tryptamine derivatives, via a Fischer indole type pathway. In this article, we demonstrate optimal conditions for a one-pot indole synthesis, allowing for the synthesis of a broad scope of 2-methyl tryptamine derivatives and a precursor for the synthesis of the core structure of some akuammiline alkaloids. Additionally, further modification of the indole products is described.

Full text of DOI:10.1016/j.tet.2011.11.032

Tetrahedron 68 (2012) 813e818
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A one-pot three-component reaction for the preparation of highly functionalized
tryptamines
*
Se Jeong Yeo, Yongxiang Liu, Xiang Wang
Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 October 2011
Received in revised form 10 November 2011
Accepted 11 November 2011
Available online 19 November 2011
We have developed a general one-pot method to provide highly functionalized tryptamine derivatives,
via a Fischer indole type pathway. In this article, we demonstrate optimal conditions for a one-pot indole
synthesis, allowing for the synthesis of a broad scope of 2-methyl tryptamine derivatives and a precursor
for the synthesis of the core structure of some akuammiline alkaloids. Additionally, further modification
of the indole products is described.
Published by Elsevier Ltd.
Keywords:
Tryptamine derivatives
One-pot process
Multi-component reaction
Fischer indole type pathway
1. Introduction
derivatives have been used widely in both bio- and chemical syn-
theses of complex indole alkaloids.5,6
Tryptamine and associated analogues possess a variety of im-
portant biological activities.1e4 For example, 5-hydroxytryptamine
(1, Fig. 1) is a key signalling molecule found in a wide variety of
species, playing an important role in numerous fundamental pro-
cesses, including the regulation of mood, sleep and muscle con-
traction.2 Furthermore, melatonin (2, Fig. 1) is another natural
product that has a variety of functions in humans, such as regula-
tion of sleep, interactions with immune system, and antioxidant.3
Synthetic tryptamine derivatives bearing substitutions at the C2-
position of the indole have been reported as agonists of serotonine
or melatonine receptors.4 In addition, tryptamine comprises a main
structural unit in many indole alkaloid natural products. For ex-
ample, both the vinca alkaloids (e.g., vindoline 3, Fig. 1) and the
akuammiline alkaloids (e.g., minfiensine 4, Fig. 1) contain trypt-
amine as a core component. Hence, tryptamine and related
Currently, there are several major approaches for the chemical
synthesis of tryptamine derivatives. The first method begins with
functionalization of indoles via carbonecarbon bond formation.7
The second mode of construction assembles tryptamine by a pal-
ladium-catalyzed reaction from o-haloanilines.8 Recent studies by
Nicolaou and co-workers describe an alternative approach, which
employs readily available N-Boc-protected anilines and provides
a variety of highly functionalized tryptamines in three steps.9 An-
other tactic is perhaps the most familiar; a Fischer indole synthesis
utilizing functionalized aminoaldehyde or the equivalent provides
a breadth of tryptamine derivatives.10 Facile syntheses of complex
tryptamine derivatives from commercially available materials are
still in demand. The Fischer indole synthesis shows promise as an
avenue for the efficient synthesis of tryptamine derivatives. How-
ever, the necessary isolation or preparation of reactive in-
termediates, such as ketones leaves room for improvement.
2. Results and discussion
As part of our ongoing efforts to synthesize both simple and
complex indole alkaloids, we have developed a one-pot, three-
component synthesis for the rapid assembly of highly functional-
ized tryptamine derivatives.11 Herein, we report our optimized
conditions, scope and applications of this one-pot process.
Fig. 1. Tryptamine-containing natural products.
We propose a one-pot, cascade-based strategy for the con-
struction of tryptamine derivatives (Scheme 1). As it has been
demonstrated, cyclic imines, such as 5a, can be activated by acyl
* Corresponding author. Tel.: þ1 303 492 6266; fax: þ1 303 492 5894; e-mail
address: xiang.wang@colorado.edu (X. Wang).
0040-4020/$ e see front matter Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.11.032

814
S.J. Yeo et al. / Tetrahedron 68 (2012) 813e818
chloride in the presence of a mediator.10e Pyridine or other medi-
ator forms intermediate 7a, 7b, or 7c presumably in equilibrium.
From enamine 7a or N-acyliminium ion 7c, there are two possible
pathways to the desired product 11a. Under acidic conditions, 7a
may be hydrolyzed to amidoketone 8, the precursor to hydrazone
10. Alternatively, addition of phenylhydrazine to 7c might yield
hydrazone 10 through intermediate 9. As 10 is a standard in-
termediate in Fischer indole syntheses, it should be readily trans-
formed to produce tryptamine derivative 11a under acidic
conditions. Therefore, we hypothesized that this ketone 8 and/or
intermediate 9 can be generated in situ from the cyclic imine and
afford tryptamine derivative 11a under standard Fischer indole
synthesis condition in one-pot.
phenylhydrazone can be formed without isolation of the ketone
intermediate 8 towards the synthesis of tryptamine derivatives.
With the initial result in hand, a variety of optimization studies
were conducted. First, we optimized the mediator (e.g., DMAP, Et3N
and 2,6-lutidine) for the reaction. Without the mediator, the reaction
proceeds in only 14% yield (entry 2, Table 1). DMAP was found to be
the most effective mediatorand stoichiometric amounts are required
(entries 3 and 4, Table 1). We then screened numerous acids, such as
HCl, TsOH$H2O and HOAc. Both HCl and TsOH$H2O gave high yields
with DMF as a solvent. During the solvent optimization, it was found
that TsOH$H2O performs better in a variety of solvents. As a result,
TsOH$H2O and acetonitrile (entry 7, Table 1) were chosen as the
optimal acid and solvent. With optimized reagents, we also varied
temperatures and reaction times (see Supplementary data for de-
tailedconditions). We foundthat the best yieldcan be obtained when
the reaction is conducted using DMAP (1.2 equiv) and TsOH$H2O
(3 equiv) in CH3CN at 82 ꢀC for 20 h (entry 8, Table 1).
During optimization studies, we found that addition of acid,
followed by phenylhydrazine, gave higher isolated yields. This
suggests that reaction equilibrium lies towards intermediate 7a,
compared to 7b or 7c (Scheme 1). Additionally, we found that 70%
of the enamide 7a along with 20% of ketone 8 can be isolated
without aqueous workup before the addition of acid and phenyl-
hydrazine. Based on these experimental results, we assume that the
acid would open the enamide ring in the presence of water to yield
ketone 8, which reacts with phenylhydrazine to form indole
product. To clarify the detailed reaction process, under standard
conditions and without the addition of phenylhydrazine, we suc-
ceeded in the isolation of the ketone intermediate in nearly
a quantitative yield, further supporting our initial hypothesis. It is
also worth mentioning that compared with our one-pot process
that yielded 99% of 11a from imine 5, a traditional two-step ap-
proach using the same substrates has previously been reported. The
yields for these two steps are 75% and 77%, respectively;10e there-
fore, the total yield for the two-step approach was 58%.
Optimization of reaction conditions for the one-pot method
opened an avenue to synthesize numerous tryptamine derivatives.
Our method allows for variation of three different functional
groups on the tryptamine skeleton: functionalization of amine (R1,
Table 2), derivatization on the indole nitrogen (R2, Table 2) and
substitution on indole backbone (R3, Table 2).
Scheme 1. Proposed one-pot indole synthesis pathway.
We selected commercially available 2-methyl-1-pyrroline 5a,
acetyl chloride, phenylhydrazine, pyridine and HCl for the initial
attempt. This combination gave 62% yield of the desired product
(entry 1, Table 1). This primary result indicates that the
Initially, we used 2-methyl-1-pyrroline 5a (entries 1e20, Table
2) as the cyclic imine to produce tryptamine derivatives. By using
commercially available acyl chlorides, sulfonyl chlorides, anhy-
drides and methyl chloroformate, we synthesized a number of
tryptamine derivatives with different functional groups on the
amines in excellent yields (entries 1e9, Table 2). Next, we changed
phenylhydrazines with different functional groups on nitrogens to
achieve substitutions on the indole nitrogen and the yields
remained satisfactory (entries 10e12, Table 2). Additional modifi-
cations of the phenyl rings of phenylhydrazine introduced func-
tionality on the indole backbone to generate more complex
products (entries 13e20, Table 2). Also, we were able to utilize
a readily available six-membered cyclic imine 5b12 to produce
homotryptamine derivatives in good yields (entries 21 and 22,
Table 2). In these cases, slower reaction rates were observed in the
acyl transfer step. Overall, we prepared a variety of highly func-
tionalized tryptamine derivatives in good to excellent yields, from
commercially available materials in a single step.
Table 1
Optimization of one-pot indole synthesis conditions
Entry Mediator Acid
Solvent Temp (ꢀC) Time (h) Yielda (%)
1
2
3
4
5
6
7
8
Pyridine
d
HCl
HCl
HCl
HCl
DMF
DMF
DMF
DMF
82
82
82
82
82
82
82
82
3
3
3
3
3
3
20
20
62
14
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
73
23b
73
TsOH$H2O DMF
AcOH DMF
TsOH$H2O CH3CN
TsOH$H2O CH3CN
62
Next, we applied this method for the synthesis of alkynyl indole
14 (Eq. 1, Scheme 2) using a readily available alkynyl imine 5c.13 To
our delight, the desired product 14 was isolated in 70% yield, to-
gether with 14% of its regioisomer. Compound 14 can be readily
converted to the core structure of the akuammiline alkaloids, such
as minfiensine, using a previously developed gold(I)-catalyzed
tandem cyclization reaction.14
100c
100d
a
b
c
1H NMR yield determined using an internal standard.
DMAP (0.1 equiv) was used.
The isolated yield was 97%.
d
Stirred for 3 h after the addition of imine. Acid was added before PhNHNH2. The
isolated yield was 99%.

S.J. Yeo et al. / Tetrahedron 68 (2012) 813e818
815
Table 2
4. Experimental section
4.1. General experimental section
Scope of tryptamine derivatives synthesis
Unless otherwise noted, reagents were obtained commercially
from Sigma, Aldrich, GFS and used without further purification.
Thin-layer chromatography (TLC) analysis of reaction mixtures was
performed on Dynamic adsorbents silica gel F-254 TLC plates. Flash
chromatography was carried out on Cilicycle 60 ECO silica gel. 1H
and 13C NMR in CDCl3 spectra were recorded with Varian INOVA
400, and Bruker Avance-III 300 spectrometers. Mass spectral and
analytical data were obtained via the PE SCIEX/ABI API QSTAR
Pulsar i Hybrid LC/MS/MS, or SYNAPT G2 High Definition Mass
Spectrometry System From Waters, Applied Biosystems operated
by the Central Analytical Laboratory, University of Colorado at
Boulder. Infrared (IR) spectra were recorded on a Thermo Nicolet
Avatar 370 FT-IR spectrometer. Melting point (mp) determinations
were performed by using a Thomas Hoover capillary melting point
apparatus and are uncorrected.
Entry
n
R1
R2/R3
12
Yield (%)
Product
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
Ac
4-FeBz
Ts
Butyryl
MeOCO
Ms
TFA
Tf
Ns
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ts
Tf
4-FeBz
TFA
Ac
H/H
H/H
H/H
H/H
H/H
H/H
H/H
H/H
12a
12a
12a
12a
12a
12a
12a
12a
12a
12b
12c
12d
12e
12f
12g
12h
12i
99
96
88
85
82
83
92
11a
11b
11c
11d
11e
11f
11g
11h
11i
92a
75a,b
90
9
H/H
Me/H
10
11
12
13
14
15
16
17
18
19
20
21
22
11j
11k
11l
allyl/H
mFBn/H
H/2-Cl
H/4-MeO
H/4-Br
allyl/4-MeO
4-FBn/4-MeO
Me/H
85
82
83c
87
11m
11n
11o
11p
11q
11r
11s
11t
13a
13b
4.2. Typical procedure for the preparation of tryptamine
derivatives (11aet)
71
96
73
66
Acyl chloride (1.2 mmol, 1.2 equiv) was added to a solution of 4-
dimethylaminopyridine (DMAP) (1.2 mmol, 1.2 equiv) in acetoni-
trile (1.0 mL) at 0 ꢀC. The reaction was stirred at room temperature
for 15 min. A solution of the 5-methyl-3,4-dihydro-2H-pyrrole
(1.0 mmol) in acetonitrile (1.0 mL) was added and the reaction was
stirred at room temperature for 3 h. p-Toluenesulfonic acid mon-
ohydrate (3.0 mmol, 3.0 equiv) was added at 0 ꢀC under inert at-
mosphere. The reaction was then stirred at room temperature for
2 h. Arylhydrazine (1.5 mmol, 1.5 equiv) was added and stirred for
an addition 5 min at room temperature. The reaction was then
heated to 82 ꢀC for 20 h. The reaction cools down to room tem-
perature. The residue was then dissolved in ethyl acetate and
washed with brine and a saturated aqueous solution of NaHCO3.
The combined organic layers were dried over anhydrous Na2SO4,
filtered and concentrated in vacuo to give a crude solid, which was
purified by column chromatography on silica gel.
12b
12j
12f
12a
12b
Me/4-Br
H/4-MeO
H/H
90
70
71d
70d
Ac
Me/H
a
Stirred for 2 h after adding acid.
DMF was used as solvent.
b
c
DMF was used as solvent. Stirred at 140 ꢀC.
d
DMF was used as solvent. Stirred for 12 h after the addition of imine.
4.2.1. 4-Methyl-N-(2-(2-methyl-1H-indol-3-yl)ethyl)benzenesulfo-
namide (11c). Yield 88%; brown black solid; Rf 0.25 (hexanes/EtOAc
3:1); mp 135e137 ꢀC; IR (thin film):
n
3397, 3055, 2920, 1597, 1462,
1320, 1157, 1093, 910 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
7.80 (s, 1H),
Scheme 2. Applications of one-pot indole synthesis process.
7.65e7.59 (m, 2H), 7.32e7.27 (m, 2H), 7.22 (dd, J¼8.6, 0.7 Hz, 2H),
7.14e7.07 (m, 1H), 7.05e6.98 (m, 1H), 4.27 (t, J¼6.3 Hz, 1H), 3.22 (q,
J¼6.6 Hz, 2H), 2.90 (t, J¼6.7 Hz, 2H), 2.42 (s, 3H), 2.36 (s, 3H) ppm;
Furthermore, we demonstrated that the 2-methyl group of the
13C NMR (75 MHz, CDCl3)
d143.4, 136.9, 135.46, 132.7, 129.8, 128.3,
tryptamine derivative 11j can be selectively oxidized to aldehyde 16
under mild Swern oxidation conditions (Eq. 2, Scheme 2),15 a more
versatile chemical handle for further elaborations.5b,16 A variety of
well-documented methods for the functionalization of 2-methyl
group of indoles have also been reported by others,17,18 which
make the 2-methyl tryptamine derivative a useful synthon for
complex molecule synthesis.
127.2, 121.4, 119.6, 117.7, 110.6, 107.2, 43.4, 24.8, 21.7, 11.8 ppm;
HRMS (ESI): m/z: calcd for C18H21N2O2S [MþH]þ 329.1318, Found
329.1330.
4.2.2. N-(2-(2-Methyl-1H-indol-3-yl)ethyl)butyramide (11d). Yield
85%; yellowish oil; Rf 0.20 (hexanes/EtOAc 3:1); IR (thin film):
3400, 3283, 3058, 2962, 2873, 1721, 1649, 1527, 1463, 909 cmꢁ1; 1H
NMR (300 MHz, CDCl3) 7.86 (s, 1H), 7.53e7.47 (m, 1H), 7.32e7.27
n
3. Conclusion
d
(m, 1H), 7.11 (m, 2H), 5.46 (s, 1H), 3.52 (dd, J¼12.8, 6.6 Hz, 2H), 2.92
In summary, we describe the development of a facile synthesis
of highly functionalized tryptamine derivatives using a one-pot,
three-component process via Fischer indole type pathway. Using
this method, we were able to assemble a wide range of tryptamine
derivatives with good to excellent yields in a single step. A regio-
selective oxidation of the 2-methyl group allows for transformation
of the products into more useful synthons. Further applications of
this approach to the syntheses of complex indole alkaloids are in
progress and will be reported in due course.
(t, J¼6.7 Hz, 2H), 2.39 (s, 3H), 2.09e2.03 (m, 2H), 1.67e1.53 (m, 2H),
0.90 (t, J¼7.4 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3)
d 173.3, 135.4,
132.3, 128.5, 120.8, 119.0, 117.6, 110.6, 108.0, 40.0, 38.6, 24.2, 19.1,
13.8, 11.4 ppm; HRMS (ESI): m/z: calcd for C15H21N2O [MþH]þ
245.1637, Found 245.1637.
4.2.3. Methyl 2-(2-methyl-1H-indol-3-yl)ethylcarbamate (11e). Yield
82%; brown oil; Rf 0.30 (hexanes/EtOAc 3:1); IR (thin film):
n 3400,
2940, 1702, 1524, 1462, 1257, 1140 cmꢁ1; 1H NMR (300 MHz, CDCl3)

816
S.J. Yeo et al. / Tetrahedron 68 (2012) 813e818
d
7.80 (s, 1H), 7.50 (d, J¼7.0 Hz, 1H), 7.31e7.28 (m, 1H), 7.17e7.04 (m,
2H), 4.69 (s,1H), 3.66 (s, 3H), 3.50e3.35 (m, 2H), 2.91 (t, J¼6.7 Hz, 2H),
2.38(s, 3H)ppm;13C NMR (75 MHz, CDCl3)
157.3,135.5,132.3,128.6,
24.6, 23.6, 10.2 ppm; HRMS (ESI): m/z: calcd for C16H21N2O [MþH]þ
257.1648, Found 257.1645.
d
121.2, 119.4,117.9,110.5, 108.3, 52.2, 41.6, 24.7, 11.6 ppm; HRMS (ESI):
4.2.10. N-(2-(1-(3-Fluorobenzyl)-2-methyl-1H-indol-3-yl)ethyl)acet-
amide (11l). Yield 82%; black oil; Rf 0.25 (hexanes/EtOAc 3:1); IR
m/z: calcd for C13H17N2O2 [MþH]þ 233.1285, Found 233.1280.
(thin film):
n
3291, 3056, 2930, 1650, 1555, 1487, 1468, 1367, 1250,
4.2.4. N-(2-(2-Methyl-1H-indol-3-yl)ethyl)methanesulfonamide
1134, 925 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.59e7.53 (m, 1H),
(11f). Yield 83%; brown oil; Rf 0.25 (hexanes/EtOAc 3:1); IR (thin
7.25e7.16 (m, 2H), 7.16e7.08 (m, 2H), 6.97e6.87 (m, 1H), 6.78e6.73
(m, 1H), 6.64e6.58 (m, 1H), 5.52e5.42 (br, 1H), 5.30 (s, 2H), 3.51 (q,
J¼6.6 Hz, 2H), 2.98 (t, J¼6.7 Hz, 2H), 2.30 (s, 3H), 1.90 (s, 3H) ppm;
film):
CDCl3)
n
3393, 2929, 1463, 1313, 1147, 971 cmꢁ1; 1H NMR (300 MHz,
d
7.85 (s, 1H), 7.48 (dd, J¼8.2, 0.8 Hz, 1H), 7.32e7.27 (m, 1H),
7.16e7.05 (m, 2H), 4.20e4.11 (br, 1H), 3.42 (q, J¼6.5 Hz, 2H), 3.00 (t,
13C NMR (75 MHz, CDCl3)
d 170.2, 164.8, 161.6, 140.8, 140.7, 136.5,
J¼6.5 Hz, 2H), 2.81 (s, 3H), 2.43 (s, 3H) ppm; 13C NMR (75 MHz,
133.5, 130.5, 130.4, 128.0, 121.6, 121.3, 119.5, 118.0, 114.4, 113.1, 109.0,
109.0, 46.1, 46.1, 40.3, 24.5, 23.3, 10.2 ppm; HRMS (ESI): m/z: calcd
for C20H22FN2O [MþH]þ 325.1711, Found 325.1713.
CDCl3) d 135.4,132.8, 128.3, 121.2, 119.4, 117.7,110.7,107.2, 43.5, 39.8,
25.2, 11.6 ppm; HRMS (ESI): m/z: calcd for C12H17N2O2S [MþH]þ
253.1005, Found 253.0995.
4.2.11. N-(2-(7-Chloro-2-methyl-1H-indol-3-yl)ethyl)acetamide
(11m). Yield 83%; yellowish solid; The reaction was heated to
140 ꢀC for 20 h in DMF; Rf 0.25 (hexanes/EtOAc 3:1); mp
4.2.5. 2,2,2-Trifluoro-N-(2-(2-methyl-1H-indol-3-yl)ethyl) acetamide
(11g). Yield 92%; dark-brown solid; Rf 0.25 (hexanes/EtOAc 3:1); mp
98e102 ꢀC; IR (thin film):
n
3398, 2922, 1705, 1553, 1463, 1437, 1181,
119e121 ꢀC; IR (thin film):
n
3272, 2923,1651,1557,1450,1297,1199,
910 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
7.96 (s,1H), 7.49 (d, J¼7.4 Hz,
1130, 1082, 1048, 949 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
8.07 (s,
1H), 7.34e7.27 (m,1H), 7.21e7.08 (m, 2H), 6.50e6.35 (br,1H), 3.62 (q,
J¼6.5 Hz, 2H), 3.00 (t, J¼6.7 Hz, 2H), 2.37 (s, 3H) ppm; 13C NMR
(75 MHz, CDCl3) 158.2, 157.7, 157.2, 156.7, 135.5, 132.6, 128.3, 121.5,
119.6,117.6,110.7,107.2, 40.46, 23.6,11.4 ppm; HRMS(ESI): m/z: calcd
for C13H14F3N2O [MþH]þ 271.1053, Found 271.1064.
1H), 7.39 (d, J¼7.8 Hz, 1H), 7.12 (dd, J¼7.7, 1.0 Hz, 1H), 7.02 (t,
J¼7.7 Hz, 1H), 5.54e5.40 (br, 1H), 3.48 (dd, J¼12.9, 6.6 Hz, 2H), 2.90
(t, J¼6.7 Hz, 2H), 2.42 (s, 3H), 1.91 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3)
d 170.2, 133.0, 132.7, 130.3, 120.8, 120.5, 116.7, 116.1, 110.1,
40.2, 24.5, 23.6, 11.9 ppm; HRMS (ESI): m/z: calcd for C13H16ClN2O
[MþH]þ 251.0946, Found 251.0957.
4.2.6. 1,1,1-Trifluoro-N-(2-(2-methyl-1H-indol-3-yl)ethyl) methanesul
fonamide (11h). Yield 92%; dark-brown oil; Rf 0.30 (hexanes/EtOAc
4.2.12. N-(2-(5-Bromo-2-methyl-1H-indol-3-yl)ethyl)acetamide
3:1); IR (thin film):
n
3407, 3300, 2922, 1463, 1367, 1193, 1145,
7.90e7.85 (br, 1H), 7.47 (dd,
(11o). Yield 71%; yellowish oil; Rf 0.25 (hexanes/EtOAc 3:1); IR
1060 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
(thin film):
n
3273, 2928, 1651, 1536, 1433, 1364, 1304, 1097, 1047,
8.34 (s, 1H), 7.62e7.54 (m,
J¼8.1, 0.9 Hz, 1H), 7.32e7.27 (m, 1H), 7.21e7.09 (m, 2H), 4.85e4.70
909 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
(br, 1H), 3.55 (q, J¼6.4 Hz, 2H), 3.01 (t, J¼6.6 Hz, 2H), 2.41 (s, 3H)
1H), 7.22e7.05 (m, 2H), 5.63 (s, 1H), 3.44 (q, J¼6.7 Hz, 2H), 2.84 (t,
ppm; 13C NMR (75 MHz, CDCl3)
d 135.6, 133.0, 128.1, 121.8, 120.0,
J¼6.8 Hz, 2H), 2.39e2.31 (m, 3H), 1.92 (s, 3H) ppm; 13C NMR
117.7, 117.7, 110.8, 106.4, 44.6, 25.7, 11.8 ppm; HRMS (ESI): m/z: calcd
(75 MHz, CDCl3) d 170.4, 134.1, 133.8, 130.6, 123.9, 120.5, 112.7, 112.0,
for C12H14F3N2O2S [MþH]þ 307.0723, Found 307.0721.
108.4, 40.3, 24.2, 23.6, 11.8 ppm; HRMS (ESI): m/z: calcd for
C13H16BrN2O [MþH]þ 295.0441, Found 295.0450.
4.2.7. N-(2-(2-Methyl-1H-indol-3-yl)ethyl)-2-nitrobenzenesulfon-
amide (11i). Yield 75%; brown oil; Rf 0.25 (hexanes/EtOAc 2:1); mp
4.2.13. N-(2-(1-Allyl-5-methoxy-2-methyl-1H-indol-3-yl)ethyl)acet-
amide (11p). Yield 96%; black oil; Rf 0.30 (hexanes/EtOAc 3:1); IR
125e127 ꢀC; IR (thin film):
n
3399, 2921, 1538, 1302, 1242,
1063 cmꢁ1; 1H NMR (300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3)
8.03e7.94 (m, 1H), 7.76 (s, 1H), 7.68e7.53 (m, 3H), 7.22e7.15 (m,
d
(thin film):
n
3292, 3083, 2933, 2831, 1650, 1484, 1419, 1300, 1229,
d
1229, 1184, 1036, 923 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.12 (d,
2H), 7.07e7.02 (m,1H), 6.92e6.87 (m,1H), 5.26 (t, J¼5.5 Hz,1H), 3.39
J¼8.8 Hz, 1H), 6.98 (d, J¼2.4 Hz, 1H), 6.80 (dd, J¼8.8, 2.4 Hz, 1H),
5.91 (ddt, J¼17.0, 10.3, 4.6 Hz, 1H), 5.60 (s, 1H), 5.16e5.06 (m, 1H),
4.79 (ddd, J¼17.0, 3.0, 1.8 Hz, 1H), 4.64 (dt, J¼4.5, 1.8 Hz, 2H), 3.85 (s,
3H), 3.47 (q, J¼6.6 Hz, 2H), 2.91 (t, J¼6.7 Hz, 2H), 2.31 (s, 3H),1.90 (s,
(dd, J¼12.3, 6.7 Hz, 2H), 2.96 (t, J¼6.7 Hz, 2H), 2.38 (s, 3H). 13C NMR
(75 MHz, CDCl3) d 135.5,133.4,132.9,132.7,131.0,128.0,125.6,121.4,
119.6,117.6,110.5,106.9,100.2, 44.0, 24.6,11.9 ppm; HRMS (ESI): m/z:
calcd for C17H18N3O4S [MþH]þ 360.1013, Found 360.1008.
3H) ppm; 13C NMR (75 MHz, CDCl3)
d 170.2, 154.2, 134.2, 133.7,
131.5, 128.3, 116.2, 110.7, 109.9, 108.0, 100.3, 56.2, 45.7, 40.3, 24.6,
23.6, 10.2 ppm; HRMS (ESI): m/z: calcd for C17H22N2O2 [MþH]þ
287.1755, Found 287.1762.
4.2.8. N-(2-(1,2-Dimethyl-1H-indol-3-yl)ethyl)acetamide
(11j). Yield 90%; pink solid; Rf 0.25 (hexanes/EtOAc 1:2); mp
101e104 ꢀC; IR (thin film):
n
3289, 2932, 1650, 1553, 1370, 1294,
1184 cmꢁ1, 1H NMR (300 MHz, CDCl3)
d
7.53 (d, J¼7.7 Hz,1H), 7.27 (d,
4.2.14. N-(2-(1-(4-Fluorobenzyl)-5-methoxy-2-methyl-1H-indol-3-
J¼8.0 Hz, 1H), 7.22e7.15 (m, 1H), 7.14e7.06 (m, 1H), 5.80e5.73 (br,
1H), 3.66(s, 3H), 3.54e3.35(m, 2H), 2.95(t, J¼6.8 Hz,2H), 2.38(s, 3H),
yl)ethyl)-4-methylbenzenesulfonamide (11q). Yield 73%; white
solid; Rf 0.25 (hexanes/EtOAc 3:1); mp 130e132 ꢀC; IR (thin film):
n
1.90 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
d
170.2,136.7,133.9,127.8,
3284, 2936, 2832, 1603, 1509, 1484, 1325, 1229, 1157, 1094,
120.8,119.1,117.8,108.8,107.8, 40.4, 29.6, 24.5, 23.4,10.3 ppm; HRMS
907 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
7.71e7.56 (m, 2H), 7.25e7.17
(ESI): m/z: calcd for C14H19N2O [MþH]þ 231.1492, Found 231.1494.
(m, 2H), 7.06 (dd, J¼8.8, 0.4 Hz, 1H), 6.99e6.87 (m, 4H), 6.84 (d,
J¼2.2 Hz, 1H), 6.76 (dd, J¼8.8, 2.4 Hz, 1H), 5.20 (s, 2H), 4.45 (t,
J¼6.2 Hz, 1H), 3.80 (s, 3H), 3.20 (q, J¼6.7 Hz, 2H), 2.93 (t, J¼6.8 Hz,
2H), 2.40 (s, 3H), 2.24 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
4.2.9. N-(2-(1-Allyl-2-methyl-1H-indol-3-yl)ethyl)acetamide
(11k). Yield 85%; black solid; Rf 0.20 (hexanes/EtOAc 1:2); mp
90e93 ꢀC; IR (thin film):
n
3288, 2928, 1650, 1553, 1469, 1367, 1293,
d 163.8, 160.6, 154.3, 143.5, 137.0, 134.7, 133.7, 133.7, 131.8, 129.8,
1181, 922 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.54e7.51 (m, 1H),
128.0, 127.8, 127.7, 127.2, 116.0, 115.7, 111.1, 110.0, 107.1, 100.3, 56.1,
46.3, 43.4, 25.2, 21.7, 10.6 ppm; HRMS (ESI): m/z: calcd for
C26H28N2O3S [MþH]þ 467.1800, found 467.1790.
7.26e7.22 (m, 1H), 7.20e7.02 (m, 2H), 5.94 (ddt, J¼17.0, 10.3, 4.7 Hz,
1H), 5.77e5.50 (br, 1H), 5.16e5.07 (m, 1H), 4.89e4.73 (m, 1H), 4.69
(dt, J¼4.6,1.8 Hz, 2H), 3.56e3.43 (m, 2H), 2.95 (t, J¼6.7 Hz, 2H), 2.34
(s, 3H), 1.90 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
d
170.2, 136.3,
4.2.15. N-(2-(1,2-Dimethyl-1H-indol-3-yl)ethyl)-1,1,1-trifluoromethan
esulfonamide (11r). Yield 66%; brown oil; Rf 0.30 (hexanes/EtOAc
133.7, 133.6, 128.0, 121.1, 119.3, 117.9, 116.3, 109.2, 108.3, 45.6, 40.4,

S.J. Yeo et al. / Tetrahedron 68 (2012) 813e818
817
4:1); IR (thin film):
n
3300, 3054, 2944, 1614, 1567, 1063, 1013,
7.49e7.45 (m, 1H), 7.32e7.27
2.34 (s, 3H), 1.96e1.75 (m, 5H) ppm; 13C NMR (75 MHz, CDCl3)
170.2, 136.7, 133.0, 127.6, 120.7, 118.8, 117.9, 110.2, 108.7, 39.7, 30.5,
922 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
d
(m, 1H), 7.24e7.17 (m, 1H), 7.15e7.07 (m, 1H), 4.67 (s, 1H), 3.69 (s,
3H), 3.56 (q, J¼6.3 Hz, 2H), 3.05 (t, J¼6.5 Hz, 2H), 2.40 (s, 3H) ppm;
29.6, 23.3, 22.0, 10.3 ppm; HRMS (ESI): m/z: calcd for C15H21N2O
[MþH]þ 245.1649, found 245.1651.
13C NMR (75 MHz, CDCl3)
d 137.0, 134.8, 127.2, 122.0, 121.5, 119.7,
117.7, 117.6, 109.2, 105.5, 44.8, 29.9, 26.0, 10.5 ppm; HRMS (ESI): m/z:
4.4. Typical procedure for the preparation of substituted
arylhydrazines
calcd for C13H16F3N2O2S [MþH]þ 321.0880, found 321.0883.
4.2.16. N-(2-(5-Bromo-1,2-dimethyl-1H-indol-3-yl)ethyl)-4-
fluorobenzamide (11s). Yield 90%; white solid; Rf 0.25 (hexanes/
Arylhydrazine (10.0 mmol), fluorobenzyl bromide (10.5 mmol)
and triethylamine (1.5 mL, 11.0 mol) in toluene (30 mL) were
heated at 100 ꢀC for 3 h. The solution was cooled, diluted with ether
(50 mL), and the solid was removed by filtration through Celite.
After removal of the solvent, the residue was taken up in EtOAc
(100 mL) and washed with a saturated NaHCO3 solution. The or-
ganic layer was dried over anhydrous Na2SO4, filtered and con-
centrated in vacuo to give a crude solid, which was purified by
column chromatography on silica gel to afford the product.
EtOAc 4:1); mp 120e122 ꢀC; IR (thin film):
n
3379, 2937, 1643, 1541,
1501, 1372, 1319, 1234, 1162, 1099, 851 cmꢁ1 1H NMR (300 MHz,
CDCl3)
7.70e7.61 (m, 3H), 7.21 (dd, J¼8.6, 1.9 Hz, 1H), 7.14e6.97
(m, 3H), 6.35 (s, 1H), 3.66e3.52 (m, 5H), 2.98 (t, J¼6.7 Hz, 2H), 2.33
(s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
166.7, 166.4, 163.1, 135.5,
;
d
d
135.4, 130.9, 130.9, 129.6, 129.4, 129.3, 123.6, 120.3, 115.8, 115.6,
112.5, 110.4, 107.7, 41.1, 29.9, 24.3, 10.5 ppm; HRMS (ESI): m/z: calcd
for C19H18BrFN2ONa [MþNa]þ 411.0479, found 411.0476.
4.4.1. 1-(3-Fluorobenzyl)-1-phenylhydrazine
brown solid; Rf 0.20 (hexanes/EtOAc 10:1); mp 48e50 ꢀC; IR (thin
film): 3335, 3059, 3036, 2893, 2836, 2585, 1935, 1858, 1600, 1485,
1448, 1355, 1249, 1131, 1026, 955 cmꢁ1; 1H NMR (300 MHz, CDCl3)
7.35e7.24 (m, 3H), 7.14e6.93 (m, 5H), 6.86e6.80 (m, 1H), 4.60 (s,
2H), 3.65e3.61 (br, 2H) ppm; 13C NMR (75 MHz, CDCl3)
130.5,
130.3, 129.7, 129.4, 123.5, 123.4, 119.0, 115.0, 114.7, 114.6, 114.3, 113.6,
113.1, 60.2, 60.2 ppm; HRMS (ESI): m/z: calcd for C13H14FN2 [MþH]þ
217.1136, found 217.1133.
(12d). Yield
55%;
4.2.17. 2,2,2-Trifluoro-N-(2-(5-methoxy-2-methyl-1H-indol-3-yl)
ethyl)acetamide (11t). Yield 70%; white solid; Rf 0.30 (hexanes/
n
EtOAc 3:1); mp 130e131 ꢀC; IR (thin film):
n
3395, 2943, 1707, 1558,
1485, 1215, 1180, 1029 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.77 (s,
d
1H), 7.19 (dd, J¼8.7, 0.4 Hz, 1H), 6.92 (d, J¼2.4 Hz, 1H), 6.81 (dd,
J¼8.7, 2.4 Hz, 1H), 6.33 (s, 1H), 3.85 (s, 3H), 3.62 (q, J¼6.4 Hz, 2H),
2.96 (t, J¼6.6 Hz, 2H), 2.36 (s, 3H) ppm; 13C NMR (75 MHz, CD3OD)
d
d
159.8, 159.4, 158.9, 158.4, 155.1, 134.4, 132.4, 130.3, 112.1, 112.1,
111.3, 108.1, 101.0, 56.4, 41.7, 24.7, 11.5 ppm; HRMS (ESI): m/z: calcd
for C14H16F3N2O2 [MþH]þ 301.1159, found 301.1157.
4.4.2. 1-(4-Fluorobenzyl)-1-(4-methoxyphenyl)hydrazine (12i). Yield
81%; brown oil; Rf 0.25 (hexanes/EtOAc 10:1); IR (thin film):
3041, 2933, 2834, 1602, 1506, 1441, 1358, 1242, 1155, 1035 cmꢁ1; 1H
NMR (300 MHz, CDCl3) 7.32e7.26 (m, 2H), 7.08e6.99 (m, 4H),
6.88e6.82 (m, 2H), 4.41 (s, 2H), 3.78 (s, 3H), 3.46e3.41 (s, 2H) ppm;
13C NMR (75 MHz, CDCl3)
164.1, 160.8, 153.7, 146.4, 133.4, 133.4,
130.2, 130.1, 116.7, 115.8, 115.5, 114.6, 61.9, 55.9 ppm; HRMS (ESI): m/
z: calcd for C14H16FN2O [MþH]þ 247.1242, found 247.1243.
n 3346,
4.3. Typical procedure for the preparation of tryptamine
derivatives (13a, 13b)
d
Acetyl chloride (1.2 mmol, 1.2 equiv) was added to a solution of
4-dimethylaminopyridine (DMAP) (1.2 mmol, 1.2 equiv) in DMF
(1.0 mL) at 0 ꢀC. The reaction was stirred at room temperature for
15 min. A solution of the 6-methyl-2,3,4,5-tetrahydropyridine
(1.0 mmol) in DMF (1.0 mL) was added and the reaction was stir-
red at room temperature for 20 h. p-Toluenesulfonic acid mono-
hydrate (3.0 mmol, 3.0 equiv) was added at 0 ꢀC under inert
atmosphere. The reaction was then stirred at room temperature for
2 h. Arylhydrazine (1.5 mmol, 1.5 equiv) was added and stirred for
an addition 5 min at room temperature. The reaction was then
heated to 82 ꢀC for 20 h. The reaction was cooled down to room
temperature. The residue was then dissolved in ethyl acetate and
washed with brine and a saturated aqueous solution of NaHCO3.
The combined organic layers were dried over Na2SO4, filtered and
concentrated in vacuo to give a crude solid, which was purified by
column chromatography on silica gel.
d
4.4.3. Allyl-1-(4-methoxyphenyl)hydrazine (12h). To a solution of 4-
methoxyphenyl-hydrazine hydrochloride (1.75 g, 10 mmol) in THF
(20 mL) was added a solution of LiHMDS (11 mL, 11 mmol, 1.0 M in
THF) at 0 ꢀC. The resulting mixture was stirred at 0 ꢀC to room
temperature for 30 min, the reaction was cooled to 0 ꢀC, and then
allyl bromide (0.95 mL, 11 mmol) was added. The resulting mixture
was stirred at room temperature for 2 h. A saturated aqueous so-
lution of NH4Cl was added and the aqueous layer was extracted
with ethyl acetate, dried over anhydrous Na2SO4, filtered and
concentrated in vacuo to give a crude oil, which was purified by
column chromatography on silica gel (hexanes/ethyl acetate¼10:1)
to afford the product (1.15 g, 6.45 mmol) as a colourless oil in 65%
yield. IR (thin film):
n
3339, 3075, 2997, 2832, 1857, 1603, 1506,
7.08e6.98
4.3.1. N-(3-(2-Methyl-1H-indol-3-yl)propyl)acetamide (13a). Yield
1294, 1180, 1037, 882 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
71%; brown oil; Rf 0.25 (hexanes/EtOAc 1:2); IR (thin film):
2932, 2855, 1651, 1462, 4598, 1239, 1185, 1010 cmꢁ1 1H NMR
(300 MHz, CDCl3) 7.93 (s, 1H), 7.51e7.41 (m, 1H), 7.26e7.22 (m,
n 3398,
(m, 2H), 6.90e6.79 (m, 2H), 5.97e5.78 (m, 1H), 5.35e5.29 (m, 1H),
5.27e5.23 (m, 1H), 3.92 (dt, J¼6.2, 1.3 Hz, 2H), 3.77 (s, 3H),
;
d
3.55e3.46 (br, 2H) ppm; 13C NMR (75 MHz, CDCl3)
d 153.5, 146.2,
1H), 7.16e6.99 (m, 2H), 5.46 (s, 1H), 3.30e3.19 (m, 2H), 2.73 (t,
J¼7.2 Hz, 2H), 2.33 (s, 3H), 1.91e1.77 (m, 5H) ppm; 13C NMR
133.2, 119.3, 116.5, 114.6, 60.9, 55.9 ppm; HRMS (ESI): m/z: calcd for
C10H15N2O [MþH]þ 179.1179, found 179.1175.
(75 MHz, CDCl3) d 170.3, 135.5, 131.3, 128.6, 121.2, 119.3, 118.0, 110.9,
110.5, 39.8, 30.3, 23.5, 21.8, 11.8 ppm; HRMS (ESI): m/z: calcd for
C14H19N2O [MþH]þ 231.1492 found 231.1491.
4.5. N-(2-(3-(but-3-ynyl)-1H-indol-2-yl)ethyl)acetamide (140)
Yield 15%; brown oil; Rf 0.20 (hexanes/EtOAc 1:5); IR (thin film):
4.3.2. N-(3-(1,2-Dimethyl-1H-indol-3-yl)propyl)acetamide
(13b). Yield 70%; brown oil; Rf 0.25 (hexanes/EtOAc 1:2); IR (thin
n
3291, 3088, 2932, 1651, 1538, 1461, 1370, 1295, 1245, 1181,
film):
n
3287, 3053, 2933, 2854, 1650, 1472, 1370, 1331, 1294, 1247,
909 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
9.65 (s, 1H), 7.63 (d,
1199 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
7.49 (d, J¼7.7 Hz, 1H), 7.25
J¼7.7 Hz, 1H), 7.37 (d, J¼7.6 Hz, 1H), 7.16e7.09 (m, 2H), 3.64 (d,
J¼2.7 Hz, 2H), 3.34 (dd, J¼12.4, 6.3 Hz, 3H), 2.85e2.77 (m, 2H), 2.03
(t, J¼2.7 Hz, 1H), 1.99 (s, 3H), 1.86e1.76 (m, 2H) ppm; 13C NMR
(d, J¼6.7 Hz, 1H), 7.16 (t, J¼7.0 Hz, 1H), 7.08 (t, J¼7.4 Hz, 1H), 5.71 (s,
1H), 3.63 (s, 3H), 3.24 (dd, J¼13.5, 6.7 Hz, 2H), 2.76 (t, J¼7.3 Hz, 3H),

818
S.J. Yeo et al. / Tetrahedron 68 (2012) 813e818
4. (a) Stevenson, G. I.; Smith, A. L.; Lewis, S.; Michie, S. G.; Neduvelil, J. G.; Patel, S.;
(101 MHz, CDCl3) d 171.6, 135.4, 127.8, 121.4, 119.3, 118.1, 111.1, 105.5,
Marwood, R.; Patel, S.; Castro, J. L. Bioorg. Med. Chem. Lett. 2000, 10, 2697e2699;
(b) Glennon, R. A.; Lee, M.; Rangisetty, J. B.; Dukat, M.; Roth, B. L.; Savage, J. E.;
McBride, A.; Rauser, L.; Hufeisen, S.; Lee, D. K. H. J. Med. Chem. 2000, 43,
1011e1018; (c) Spadoni, G.; Bedini, A.; Rivara, S.; Mor, M. CNS Neurosci. Ther.
2010, 1e9; (d) Koike, T.; Hoashi, Y.; Takai, T.; Nakayama, M.; Yukuhiro, N.;
Ishikawa, T.; Hirai, K.; Uchikawa, O. J. Med. Chem. 2011, 54, 3436e3444.
5. Recent representative examples of total synthesis using tryptamine derivatives
as starting materials, see (a) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.;
Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10596e10612; (b) Jones, S. B.; Simmons,
B.; MacMillan, D. V. C. J. Am. Chem. Soc. 2009, 131, 13606e13607.
6. (a) Money, T.; Wright, I. G.; McCapra, F.; Hall, E. S.; Scott, A. I. J. Am. Chem. Soc.
1968, 90, 4144e4150; (b) Naotaka, N.; Martina, R.; Meinhart, H. Z. J. Chem. Soc.,
Perkin Trans. 1 1979, 2308e2312; (c) Vincenzo, D. L.; Jesus, A. F.; Douglas, C.;
Wolfgang, G.ˇ W. K. Plant Physiol. 1988, 86, 447e450; (d) Rocha, L. G.; Almeida, J.
R. G. S.; Macedo, R. O.; Barbosa-Filho, J. M. Phytomedicine 2005, 12, 514e535; (e)
O’Connor, S. E.; Maresh, J. Nat. Prod. Rep. 2006, 23, 532e547.
83.4, 68.2, 38.6, 30.1, 23.5, 22.4, 13.9 ppm; HRMS (ESI): m/z: calcd
for C16H19N2O [MþH]þ 255.1492, found 255.1491.
4.6. N-(2-(2-Formyl-1-methyl-1H-indol-3-yl)ethyl)acetamide
(16)
To a solution of oxalyl chloride (0.038 mL, 0.434 mmol) in dry
CH2Cl2 (1 mL), at ꢁ78 ꢀC under a nitrogen atmosphere, was added
DMSO (0.044 mL, 0.608 mmol). The solution was stirred for ca.
10 min, until effervescence ceased. A solution of indole (20 mg,
0.086 mmol) in dry CH2Cl2 (0.3 mL) was added dropwise, and the
red solution was stirred for 10 min at ꢁ78 ꢀC. Triethylamine
(0.122 mL, 0.868 mmol) was then added and the solution was left to
warm to room temperature for 20 min. The reaction mixture was
diluted with CH2Cl2 (20 mL) and washed with saturated aqueous
solution of NH4Cl. The organic layer was dried over anhydrous
Na2SO4, filtered and evaporated, and the residue was purified by
column chromatography on silica gel, eluting with 1:2 hexanes/
ethyl acetate to provide the product with a yield of 61%; mp
7. (a) Speeter, M. E.; Anthony, W. C. J. Am. Chem. Soc. 1954, 76, 6208e6210; (b)
Abramovitch, R. A.; Shapiro, D. J. Chem. Soc. 1956, 4589e4592; (c) Flaugh, M. E.;
Crowell, T. A.; Clemens, J. A.; Sawyer, B. D. J. Med. Chem. 1979, 22, 63e69; (d)
Repke, D. B.; Grotjahn, D. B.; Shulging, A. T. J. Med. Chem. 1985, 28, 892e896; (e)
Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T. J. Am. Chem. Soc. 1992,
ꢀ
ꢀ
114, 2175e2180; (f) Soti, F.; Incze, M.; Kardos-Balogh, Z.; Kajtar-Peredy, M.;
ꢀ
Szantay, C. Synth. Commun. 1993, 23, 1689e1698; (g) Koch, S. S. C.; Thoresen, L.
H.; Tikhe, J. G.; Maegley, K. A.; Almassy, R. J.; Li, J.; Yu, X. H.; Zook, S. E.; Kumpf,
R. A.; Zhang, C.; Boritzki, T. J.; Mansour, R. N.; Zhang, K. E.; Ekker, A.; Calabrese,
C. R.; Curtin, N. J.; Kyle, S.; Thomas, H. D.; Wang, L. Z.; Calvert, A. H.; Golding, B.
T.; Griffin, R. J.; Newell, D. R.; Webber, S. E.; Hostomsky, Z. J. Med. Chem. 2002,
45, 4961e4974; (h) Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
125e127 ꢀC; IR (thin film):
n
3274, 2923, 1652, 1555, 1471, 1431,
10.10 (s, 1H), 7.74 (d,
1297, 1065 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
€
11797e11810; (i) Friedrich, A.; Brase, S.; O’Connor, S. E. Tetrahedron Lett. 2009,
J¼7.6 Hz, 1H), 7.44 (t, J¼7.5 Hz, 1H), 7.37 (d, J¼8.4 Hz, 1H), 7.18 (t,
J¼7.0 Hz, 1H), 5.67 (s, 1H), 4.07 (s, 3H), 3.65e3.55 (br, 2H),
3.35e3.30 (br, 2H), 1.93 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3)
50, 75e76.
8. (a) Dong, Y.; Busacca, C. A. J. Org. Chem. 1997, 62, 6464e6465; (b) Aubart, K. M.;
Heathcock, C. H. J. Org. Chem. 1999, 64, 16e22; (c) Hua, C.; Qin, H.; Cui, Y.; Jia, Y.
Tetrahedron 2009, 65, 9075e9080.
d
182.0,170.7,139.9, 131.9,127.7,127.2,126.5,121.5,120.9, 110.6, 41.6,
9. (a) Nicolaou, K. C.; Krasovskiy, A.; Trepanier, V. E. D.; Chen, Y.-K. Angew. Chem.,
Int. Ed. 2008, 47, 4217e4220; (b) Nicolaou, K. C.; Krasovskiy, A.; Majumder, U.;
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31.8, 24.0, 23.8 ppm; HRMS (ESI): m/z: calcd for C14H17N2O2
[MþH]þ 245.1285, found 245.1281.
Acknowledgements
We are grateful to Dr. Richard Shoemaker (Department of
Chemistry and Biochemistry, University of Colorado at Boulder) for
NMR spectroscopic assistance and Dr. Rebecca Keller Friedman
(Department of Chemistry and Biochemistry, University of Colorado
at Boulder) for the preparation of this manuscript.
Supplementary data
11. For other examples of tryptamine derivatives synthesis involved cyclic imines
or enamides, see (a) Marais, W.; Holzapfel, C. W. Synth. Commun. 1998, 28,
3681e3691; (b) Zakurdaev, E. P.; Balenkova, E. S.; Nenajdenko, V. G. Russ. Chem.
Bull. 2005, 54, 1219e1228.
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13. Harrison, T. J.; Kozak, J. A.; Corbella-Pane, M.; Dake, G. R. J. Org. Chem. 2006, 71,
4525e4529.
Full table of condition screening and the spectroscopic data of all
new compounds are available. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tet.2011.11.032.
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