Model construction for the A-B-C ring system of lysergic acid via Vilsmeier-Haack-type cyclization of 1H-indole-4-propanoic acid derivatives

Article abstract of DOI:10.1002/hlca.200790058

Vilsmeier-Haack-type cyclization of 1H-indole-4-propanoic acid derivatives was examined as model construction for the A-B-C ring system of lysergic acid (1). Smooth cyclization from the 4 position of 1H-indole to the 3 position was achieved by Vilsmeier-H

Full text of DOI:10.1002/hlca.200790058

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Helvetica Chimica Acta – Vol. 90 (2007)
Model Construction for the A – B – C Ring System of Lysergic Acid via
Vilsmeier – Haack-Type Cyclization of 1H-Indole-4-propanoic Acid
Derivatives
by Masayuki Kurokawa, Toshiko Watanabe, and Tsutomu Ishikawa*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
(phone: þ 81-43-290-2910; fax: þ 81-43-290-2910; e-mail: benti@p.chiba-u.ac.jp)
Vilsmeier– Haack-type cyclization of 1H-indole-4-propanoic acid derivatives was examined as
model construction for the A – B – C ring system of lysergic acid (1). Smooth cyclization from the 4
position of 1H-indole to the 3 position was achieved by Vilsmeier– Haack reaction in the presence of
K2CO3 in MeCN, and the best substrate was found to be the N,N-dimethylcarboxamide 9 (Table 1). The
modified method can be successfully applied to an a-amino acid derivative protected with an N-acetyl
function, i.e., to 27 (Table 2); however, loss of optical purity was observed in the cyclization when a chiral
substrate (S)-27 was used (Scheme 5). On the other hand, the intramolecular Pummerer reaction of the
corresponding sulfoxide 20 afforded an S-containing tricyclic system 22, which was formed by a
cyclization to the 5 position (Scheme 3).
1. Introduction. – Lysergic acid (1), a tetracyclic indole derivative with two
stereogenic centers, is the core unit of ergot alkaloids showing wide spectra of
biological activities [1] such as prolactin inhibition, anti-Parkinsonian effect, and
depression of hypertension. The total synthesis of racemic 1 has been reported by nine
research groups [2], and two groups have successfully achieved the asymmetric
synthesis [3].
Recently, we have explored a novel aziridination from guanidinium ylides and
aromatic (or unsaturated) aldehydes, applicable to asymmetric synthesis [4], and
designed the atom-economical synthesis of bioactive N-containing compounds using
the formed aziridine as a key synthetic intermediate. Our retro-synthetic strategy of
lysergic acid (1) is shown in Scheme 1, in which all the C- and the N-units of the
aziridine 2, derived from guanidinium ylide 3 and 1H-indole-4-carboxaldehyde 4, are
incorporated in the lysergic acid structure during the synthesis. One of the key reactions
is the construction of ring C via cyclization from the 4 position of the 1H-indole
skeleton 2 to its 3-position. Such cyclizations had already been examined by four groups
[2i][5], among which Nedelec and Raincy [5a] reported the application of the
Vilsmeier – Haack reaction to 1H-indole-4-propanamide in their patent. Thus, we
extensively examined the cyclization based on their methodology and, in this paper,
describe experimental results obtained by using varieties of 1H-indole-4-propanoic
acid derivatives.
2. Results and Discussion. – 2.1. Cyclizations with 1H-Indole-4-propanamides. First
we tried to trace the Vilsmeier – Haack reaction of N,N-dimethyl-1H-indole-4-
ꢀ 2007 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 90 (2007)
575
Scheme 1. retro-Synthesis of Lysergic Acid (1) with Aziridine Derivative 2 as KeyIntermediate
propanamide (9) under the conditions reported in [5a]. The needed N,N-dimethyl-
propanamide 9 was prepared from the known N-Boc-1H-indole-4-carboxaldehyde 5
(Boc ¼ (tert-butoxy)carbonyl) [6] in four steps via 6b, 7b, and 8 (Scheme 2) and
subjected to the cyclization reaction with phosphoric trichloride (POCl3) in THF at 658
for 6h to give the desired product 10 in 38% yield (Entry1 , Table 1). Although no
improvement was observed when CHCl3 was used as solvent in place of THF (Entry2 ),
the use of MeCN resulted in the formation of 10 not only in higher yield but also with
shorter reaction time (Entry3 ). Some time ago, we have reported the efficiency of
K2CO3 as an additive in the intramolecular Friedel – Crafts reaction of 2,4-diaryl-
butanoic acids using POCl3 to give 2-aryl-3,4-dihydronaphthalen-1(2H)-one deriva-
tives [7]. In the Vilsmeier – Haack reaction with 9, addition of K2CO3 is also effective
(Entries 4 – 6), and the best yield (74%) was achieved under the conditions shown in
Entry5 .
Table 1. Vilsmeier– Haack Reaction of N,N-Dimethyl-1H-indole-4-propanamide (9)
Solvent
POCl3 [mol]
K2CO3 [mol]
Time [h]
Yielda) [%] of 10
Entry
1
2
3
4
5
6
THF
6.3
6.4
6.3
6.2
3.62.7
3.8
none
none
none
2.5
6
2
2
2
74
4
38
40
58
56
CHCl3
MeCN
MeCN
MeCN
MeCN
3
3.8
64
a) Non-optimized yield of isolated material.
Further trials for the Vilsmeier – Haack reaction by using different kinds of
carboxamides, i.e., N-methyl-N-phenyl-1H-indole-4-propanamide (13), N-methoxy-N-
methyl-1H-indole-4-propanamide (15), and N,N-dimethyl-1H-indole-4-propanethioa-
mide (16), which were prepared as shown in Scheme 2 from 7a via 11 and 12, via 11 and 14,
and from 7b via 8 and 9, respectively, only resulted in the formation of complex mixtures.

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Scheme 2. Preparation of 1H-Indole-4-propanamides for the Vilsmeier– Haack Reaction
Sano and co-workers [8] reported the acid-mediated cyclization of 2-(benzylami-
no)ethyl phenyl sulfoxide for the construction of the isoquinoline skeleton. Thus, we
prepared the 3-(1H-indol-4-yl)propyl phenyl sulfoxide (20) from ethyl 1-Boc-1H-
indole-4-propanoate 7b in four steps via 17 – 19 and subjected it to a Pummerer-type
cyclization under the reported conditions [8], with the objective to obtain the tricyclic
compound 21 (Scheme 3). Although a reaction occurred, the product obtained was an
S-containing tricyclic system 22, which was formed in 38% yield by a cyclization to the 5
position of the 1H-indole skeleton. Comparable results dependent upon the substrates
used were observed in the cyclization of other 4-substituted 1H-indoles.
2.2. Cyclizations with a-Amino-N,N-dimethyl-1H-indole-4-propanamides. Next, the
Vilsmeier – Haack reaction was applied to a-amino-N,N-dimethyl-1H-indole-4-prop-
anamides with different kinds of N-protecting groups. The desired propanamides 27

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577
Scheme 3. Preparation of 3-(1H-Indol-4-yl)propyl Phenyl Sulfoxide (20) and a Trial for a Pummerer-
type Cyclization
and 32 – 36 were prepared from the known methyl (2Z)-2-(acetylamino)-3-(1-tosyl-1H-
indol-4-yl)prop-2-enoate (23) [9] via 24 – 26 and from the known methyl (2Z)-2-(Cbz-
amino)-3-(1-Boc-1H-indol-4-yl)prop-2-enoate 28 [6] via 29 – 31, as shown in Scheme 4.
These propanamides were treated under the optimized Vilsmeier – Haack reaction
conditions mentioned above (Table 2).
The desired Vilsmeier – Haack cyclization gave the amino ketone 37 (R ¼ Ac) in
34% yield by using the (acetylamino)derivative 27 as a starting material (Entry1 ,
Table 2). Simple N-phosphorylation occurred when N-unprotected carboxamide 33
was used (Entry3 ). However, replacement of the (acetylamino) by the (benzoyla-
mino) group prevented the cyclization and, instead, hydrolysis of the carboxamide
function occurred (Entry4 ). The (ethoxycarbonyl)-protected 35 led to the cyclized
product in 11% yield (Entry5 ), whereas the reactions with the (benzyloxy)carbony-
lated and the tosylated derivatives 32 and 36, respectively, resulted in the formation of a
complex mixture (Entries 2 and 6).
Thus, as the desired cyclization was observed in the Vilsmeier – Haack reaction of a-
(acetylamino)-N,N-dimethyl-1H-indole-4-propanamide (27), although not satisfacto-
rily, we attempted to carry out the reaction with the corresponding optically active
substrate. (2S)-Methyl 2-(Cbz-amino)-3-(1-Boc-1H-indol-4-yl)propanoate (S)-29 with
99% ee was prepared by asymmetric hydrogenation of the Wittig – Horner – Emmons
reaction product 28 according to the reported method [6]. Successive alkaline
hydrolysis (!(S)-30), 2-chloro-1,3-dimethyl-1H-imidazolium chloride (DMC)-assist-
ed amidation [10] with Me2NH (!(S)-31), deprotection of the 1H-indole N-atom
(!(S)-32), and displacement of the Cbz by the Ac function under reductive conditions
afforded (S)-27 in a total yield of 70% (Scheme 5). The high retention of optical
activity during the reaction sequence was confirmed by the formation of 2-(Cbz-

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Helvetica Chimica Acta – Vol. 90 (2007)
Scheme 4. Preparation of Different 2-Amino-N,N-dimethyl-1H-indole-4-propanamides
amino)-N,N-dimethyl-1H-indole-4-propanamide (S)-32 with 99% ee. Unfortunately,
racemization of (S)-27 occurred in the Vilsmeier – Haack reaction to give the cyclized
product (S)-37 with only 4% ee.

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579
Table 2. Vilsmeier– Haack Reaction of Different a-Amino-N,N-dimethyl-1H-indole-4-propanamides 27
and 32 – 36
Substrate (R)
Time [h]
Results
Entry
1
2
3
4
5
6
27 (Ac)
32 (Cbz)
33 (H)
34 (Bz)
35 (CO2Et)
36 (Ts)
1
3
3
4
37 (R ¼ Ac) (34%)
complex mixture
N-phosphorylation (44%)
C-hydrolysis (36%)
37 (R ¼ CO2Et) (11%)
4
6complex mixture
Scheme 5. Preparation of OpticallyActive ( aS)-a-(Acetylamino)-N,N-dimethyl-1H-indole-4-propana-
mide ((S)-27) and Subsequent Vilsmeier– Haack Reaction

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3. Conclusions. – In summary, smooth cyclization from the 4 position of 1H-indole
to the 3 position was achieved by the Vilsmeier – Haack reaction of N,N-dimethyl-1H-
indole-4-propanamide (9) in the presence of K2CO3 in MeCN. The optimized
conditions can be successfully applied to the a-amino acid derivative 27 N-protected
by an acetyl function; however, the loss of optical purity was observed in the cyclization
when the enantiomerically pure substrate (S)-27 was used. On the other hand, the
intramolecular Pummerer reaction of the corresponding sulfoxide 20 afforded a
cyclized product at the 5 position but not at the 3 position.
Experimental Part
General. Anh. THF and CH2Cl2 were purchased from Wako and Kanto Chemicals, resp. DMF, Et3N,
MeCN, benzene, and EtOH were distilled from CaH2. MeOH was distilled from Mg turnings. Org. solns.
obtained by extraction were dried over Na2SO4. Column chromatography (CC): silica gel 60 (spherical,
70 – 230 mesh) from Kanto Chemicals. M.p.: Yanaco MP-S3 apparatus; uncorrected. [a]D: Jasco P-1020.
IR Spectra: Jasco FT/IR-300E spectrophotometer; ATR ¼ attenuated total reflexion; in cmꢀ1. NMR
Spectra: CDCl3 soln.; Jeol JNM-ECP-400 (400 (1H) and 100 (13C) MHz) or ALPHA-500 (500 (1H) and
1
125 (13C) MHz) instrument; SiMe4 as an internal standard for H, unless otherwise stated, and central
resonance of CDCl3 (d 77.0) as an internal standard for 13C; d in ppm, J in Hz. MS: Jeol GC-Mate
spectrometer with direct inlet for EI; Jeol JMS-HX-110A spectrometer with 3-nitrobenzyl alcohol as a
matrix for HR-FAB; in m/z (rel. %).
Methyl (2E)-3-{1-[(tert-Butoxy)carbonyl]-1H-indol-4-yl}prop-2-enoate (6a). To a suspension of
NaH (60%; 139 mg, 1.56 mmol) in dry THF (8 ml) under Ar was added dropwise methyl (dimethoxy-
phosphinyl)acetate (0.52 ml, 3.61 mmol) at 08, and the mixture was stirred at r.t. for 1 h. Then, a soln. of 5
(519 mg, 2.12 mmol) in dry THF (8 ml) was added dropwise at 08, the mixture was stirred at r.t. for 3 h,
and the reaction was quenched with sat. aq. NH4Cl soln. (3.5 ml). After the precipitate was dissolved in
H2O (4 ml), the mixture was stirred at r.t. for 10 min and extracted with hexane/AcOEt 2 :1 (3 ꢁ 20 ml).
The combined extract was washed with sat. aq. NaHCO3 soln. (10 ml) and brine (12 ml), dried, and
concentrated and the residue purified by CC (hexane/AcOEt 24 :1 to 18 :1): 6a (615 mg, 96%). Colorless
prisms. M.p. 103.5 – 1048. IR (ATR): 1722, 1703 (CO). 1H-NMR (400 MHz): 1.68 (s, Me3C); 3.84 (s,
MeO); 6.57 (d, J ¼ 16.1, HꢀC(2)); 6.85 (d, J ¼ 3.7, arom. H); 7.33 (dd, J ¼ 8.0, 8.0, arom. H); 7.50 (d, J ¼
8.0, arom. H); 7.69 (d, J ¼ 3.7, arom. H); 8.07 (d, J ¼ 16.1, HꢀC(3)); 8.22 (d, J ¼ 8.0, arom. H).
13C-NMR (125 MHz): 28.2; 51.8; 84.1; 105.1; 117.0; 118.5; 121.4; 124.3; 126.7; 127.1; 130.1; 135.6; 142.1;
149.5; 167.6. EI-MS: 302 (4, [M þ H]þ), 301 (23, Mþ), 245 (84), 201 (64), 170 (47), 115 (32), 57 (100).
Anal. calc. for C17H19NO4: C 67.76, H 6.36, N 4.65; found: C 67.66, H 6.32, N 4.54.
Ethyl (2E)-3-{1-[(tert-Butoxy)carbonyl]-1H-indol-4-yl}prop-2-enoate (6b). As described for 6a,
from 5: 6b (96%). Colorless prisms. M.p. 128.5 – 1298. IR (KBr): 1720, 1698 (CO). 1H-NMR (400 MHz):
1.36( t, J ¼ 7.1, MeCH2); 1.68 (s, Me3C); 4.30 (q, J ¼ 7.1, MeCH2); 6.57 (d, J ¼ 15.9, HꢀC(2)); 6.86 (d,
J ¼ 3.7, arom. H); 7.33 (dd, J ¼ 8.0, 8.0, arom. H); 7.50 (d, J ¼ 8.0, arom. H); 7.69 (d, J ¼ 3.7, arom. H);
8.06( d, J ¼ 15.9, HꢀC(3)); 8.21 (d, J ¼ 8.0, arom. H). 13C-NMR (100 MHz): 14.4; 28.2; 60.5; 84.1; 105.2;
116.9; 119.0; 121.4; 124.3; 126.8; 127.0; 130.1; 135.7; 141.9; 149.5; 167.2. FAB-MS: 316 ([M þ H]þ), 315
(Mþ). Anal. calc. for C18H21NO4: C 68.55, H 6.71, N 4.44; found: C 68.60, H 6.68, N 4.28.
Methyl 1-[(tert-Butoxy)carbonyl]-1H-indole-4-propanoate (7a). A mixture of 6a (1.525 g,
5.06mmol) in dry benzene (28 ml) and dry CH 2Cl2 (14 ml) was hydrogenated over 5% Pd/C (410 mg)
under H2 at r.t. for 50 min. After removal of the catalyst by filteration through a Celiteꢁ pad followed by
washing with AcOEt, the filtrate was evaporated. Purification of the residue by CC (hexane/AcOEt 20 :1
to 17:1) afforded 7a (1.472 g, 96%). Colorless oil. IR (ATR): 1735 (CO). 1H-NMR (400 MHz): 1.67 (s,
Me3C); 2.71 (t, J ¼ 7.9, CH2(a)); 3.20 (t, J ¼ 7.9, CH2(b)); 3.67 (s, MeO); 6.64 (d, J ¼ 3.7, arom. H); 7.05
(d, J ¼ 7.7, arom. H); 7.24 (dd, J ¼ 7.7, 7.7, arom. H); 7.61 (d, J ¼ 3.7, arom. H); 8.02 (d, J ¼ 7.7, arom. H).
13C-NMR (125 MHz): 28.2; 35.1; 51.6; 83.7; 105.2; 113.5; 122.0; 124.4; 125.7; 129.6; 132.8; 135.2; 149.8;
173.4. HR-FAB-MS: 303.1473 (Mþ, C17H21NO4þ ; calc. 303.1471).

Helvetica Chimica Acta – Vol. 90 (2007)
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Ethyl 1-[(tert-Butoxy)carbonyl]-1H-indole-4-propanoate (7b). As described for 7a, from 6b: 7b
(95%). Colorless oil. IR (neat): 1735 (CO). 1H-NMR (400 MHz): 1.24 (t, J ¼ 7.1, MeCH2); 1.67 (s,
Me3C); 2.69 (t, J ¼ 7.9, CH2(a)); 3.19 (t, J ¼ 7.9, CH2(b)); 4.13 (q, J ¼ 7.1, MeCH2); 6.64 (d, J ¼ 3.8,
arom. H); 7.06( d, J ¼ 8.0, arom. H); 7.24 (dd, J ¼ 8.0, 8.0, arom. H); 7.60 (d, J ¼ 3.8, arom. H); 8.02 (d,
J ¼ 8.0, arom. H). 13C-NMR (100 MHz): 14.2; 28.1; 28.2; 35.3; 60.5; 83.7; 105.2; 113.4; 122.0; 124.4;
125.7; 129.6; 132.8; 135.2; 149.8; 173.0. HR-FAB-MS: 317.1629 ( Mþ, C18H23NO4þ ; calc. 317.1627).
1-[(tert-Butoxy)carbonyl]-N,N-dimethyl-1H-indole-4-propanamide (8). To a suspension of Me2NH ·
HCl (268 mg, 3.29 mmol) in dry benzene (5.5 ml) under Ar was added dropwise at 08 2m Me3Al in
heptane (1.6ml, 3.20 mmol), and the mixture was stirred at r.t. for 1 h. Then a soln. of 7b (504 mg,
1.59 mmol) in dry benzene (7 ml) was added at 08. The mixture was stirred at 658 for 7 h, and the reaction
was quenched with H2O (8 ml) at 08. After addition of 10% HCl aq. soln. (2.4 ml), the mixture was
extracted with AcOEt (3 ꢁ 15 ml), the combined org. extract washed with sat. aq. NaHCO3 soln. (10 ml)
and brine (12 ml), dried, and concentrated, and the residue purified by CC (benzene/AcOEt 6:1 to 4 :1):
8 (471 mg, 94%). Colorless oil. IR (neat): 1734, 1653 (CO). 1H-NMR (400 MHz): 1.67 (s, Me3C); 2.68 (t,
J ¼ 7.9, CH2(a)); 2.86, 2.94 (each s, MeN); 3.22 (t, J ¼ 7.9, CH2(b)); 6.66 (d, J ¼ 3.7, arom. H); 7.07 (d,
J ¼ 7.1, arom. H); 7.24 (dd, J ¼ 7.1, 7.7, arom. H); 7.60 (d, J ¼ 3.7, arom. H); 8.03 (d, J ¼ 7.7, arom. H).
13C-NMR (100 MHz): 28.1; 28.5; 34.4; 35.4; 37.1; 83.6; 105.3; 113.2; 122.1; 124.3; 125.6; 129.6; 133.7;
135.1; 149.7; 172.2. HR-FAB-MS: 317.1872 ([M þ H]þ, C18H25N2O3þ ; calc. 317.1865).
N,N-Dimethyl-1H-indole-4-propanamide (9). A soln. of 8 (707 mg, 2.23 mmol) in AcOH (29 ml,
507 mmol) was stirred at 1008 for 22 h, and the solvent was evaporated. The residue was purified by CC
(benzene/AcOEt 4 :1 to 2 :1): 9 (420 mg, 87%). Colorless prisms. M.p. 117 – 1188 ([5a]: 117 – 1188). IR
(ATR): 3208 (NH), 1631 (CO). 1H-NMR (400 MHz, CD3OD): 2.75 (t, J ¼ 7.8, CH2(a)); 2.78, 2.87 (each
s, MeN); 3.16( t, J ¼ 7.8, CH2(b)); 6.50 (dd, J ¼ 3.1, 0.9, arom. H); 6.83 (dd, J ¼ 7.6, 0.9, arom. H); 7.01
(dd, J ¼ 7.6, 7.6, arom. H); 7.21 (d, J ¼ 3.1, arom. H); 7.23 (d, J ¼ 7.6, arom. H). 13C-NMR (100 MHz,
CD3OD): 29.1; 34.5; 35.5; 37.2; 100.7; 109.3; 119.1; 122.1; 123.9; 127.1; 133.5; 135.8; 172.8. FAB-MS: 217
([M þ H]þ), 216( Mþ). HR-FAB-MS: 216.1249 (Mþ, C13H16N2Oþ; calc. 216.1263).
1-[(tert-Butoxy)carbonyl]-1H-indole-4-propanoic Acid (11). A mixture of 7a (157 mg, 0.518 mmol)
and LiOH · H2O (330 mg, 7.87 mmol) in THF (2.4 ml) and H2O (2.4 ml) was stirred at r.t. for 5 h,
acidified with 6n aq. HCl (pH 2), and extracted with AcOEt (3 ꢁ 9 ml). The combined extract was
washed with brine (5 ml), dried, and concentrated and the residue purified by CC (hexane/AcOEt 10 :1
to 10 :3): 11 (150 mg, 100%). Colorless prisms. M.p. 131.5 – 1328. IR (ATR): 3200 – 2600 (OH); 1726,
1693 (CO). 1H-NMR (400 MHz): 1.67 (s, Me3C); 2.77 (t, J ¼ 7.9, CH2(a)); 3.21 (t, J ¼ 7.9, CH2(b)); 6.64
(d, J ¼ 3.8, arom. H); 7.07 (d, J ¼ 7.8, arom. H); 7.25 (dd, J ¼ 7.8, 7.8, arom. H); 7.61 (d, J ¼ 3.8, arom. H);
8.03 (d, J ¼ 7.8, arom. H). 13C-NMR (125 MHz): 27.8; 28.0; 34.9; 83.7; 105.1; 113.6; 122.0; 124.4; 125.8;
129.5; 132.3; 135.2; 149.7; 178.9. FAB-MS: 290 ([M þ H]þ), 289 (Mþ). Anal. calc. for C16H19NO4: C
66.42, H 6.62, N 4.84; found: C 66.37, H 6.63, N 4.73.
1-[(tert-Butoxy)carbonyl]-N-methyl-N-phenyl-1H-indole-4-propanamide (12). A mixture of 11
(100 mg, 0.346mmol), N-methylbenzenamine (75 ml, 0.692 mmol), DCC (142 mg, 0.688 mmol), and
DMAP (11 mg, 90.0 mmol) in CH2Cl2 (2.5 ml) was stirred at r.t. for 6h, and the reaction was quenched
with sat. aq. NH4Cl soln. (3 ml). Then the precipitates were dissolved with H2O (3 ml). The mixture was
extracted with CH2Cl2 (2 ꢁ 12 ml), the combined extract washed with brine (6ml), dried, and
concentrated, and the residue purified by CC (hexane/AcOEt 5 :1 to 3 :1): 12 (112 mg, 86%). Colorless
oil. IR (ATR): 1724, 1649 (CO). 1H-NMR (400 MHz): 1.67 (s, Me3C); 2.44 (t, J ¼ 7.8, CH2(a)); 3.14 (t,
J ¼ 7.8, CH2(b)); 3.25 (s, MeN); 6.40 (d, J ¼ 3.7, arom. H); 6.91 (d, J ¼ 7.6, arom. H); 6.97 (d, J ¼ 7.0, 2
arom. H); 7.17 (dd, J ¼ 7.6, 7.6, arom. H); 7.27 – 7.33 (m, 3 arom. H); 7.51 (d, J ¼ 3.7, arom. H); 7.97 (d,
J ¼ 7.6, arom. H). 13C-NMR (125 MHz): 28.2; 29.1; 35.2; 37.4; 83.6; 105.3; 113.2; 122.3; 124.3; 125.5;
127.3; 127.7; 129.6; 129.7; 133.5; 135.1; 144.0; 149.8; 172.4. HR-FAB-MS: 379.2023 ([M þ H]þ,
C23H27N2Oþ3 ; calc. 379.2022).
N-Methyl-N-phenyl-1H-indole-4-propanamide (13). A soln. of 12 (398 mg, 1.05 mmol) in AcOH
(13.2 ml, 231 mmol) was stirred at 1008 for 12 h, and the solvent was evaporated. The residue was
dissolved with AcOEt (25 ml), the org. soln. washed with 5n NaOH (3 ml) and brine (7 ml), dried, and
concentrated, and the residue purified by CC (hexane/AcOEt 3 :1 to 2 :1): 13 (266 mg, 91%). Yellow oil.
IR (ATR): 3282 (NH), 1633 (CO). 1H-NMR (400 MHz): 2.51 (t, J ¼ 8.1, CH2(a)); 3.20 (t, J ¼ 8.1,

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Helvetica Chimica Acta – Vol. 90 (2007)
CH2(b)); 3.27 (s, MeN); 6.36 (br. s, arom. H); 6.80 (d, J ¼ 7.6, arom. H); 7.01 (d, J ¼ 7.1, 2 arom. H); 7.06
(dd, J ¼ 7.6, 7.6, arom. H); 7.13 (dd, J ¼ 2.7, 2.6, arom. H); 7.23 (d, J ¼ 7.6, arom. H); 7.27 – 7.33 (m, 3
arom. H); 8.15 (br. s, NH). 13C-NMR (100 MHz): 29.6; 35.1; 37.4; 100.8; 109.1; 119.1; 122.1; 123.6; 127.1;
127.3; 127.6; 129.6; 133.3; 135.7; 144.1; 172.8. HR-FAB-MS: 279.1498 ([ M þ H]þ, C18H19N2Oþ; calc.
279.1497).
1-[(tert-Butoxy)carbonyl]-N-methoxy-N-methyl-1H-indole-4-propanamide (14). To a soln. of 11
(399 mg, 1.38 mmol), N,O-dimethylhydroxylamine hydrochloride (385 mg, 3.95 mmol), and Et3N
(1.6ml, 11.5 mmol) in dry MeCN (10.3 ml) was added a soln. of 1m 2-chloro-1,3-dimethyl-1H-
imidazolium chloride (DMC) in CH2Cl2 (3.20 ml, 3.20 mmol) over 20 min at ꢀ 158. The mixture was
stirred at ꢀ 108 for 4 h and then at 08 for 1 h. The reaction was quenched with sat. aq. K2CO3 soln.
(10 ml). Then the precipitate was dissolved with H2O (10 ml), the mixture extracted with AcOEt (2 ꢁ
30 ml), the combined extract washed with brine (15 ml), dried, and concentrated, and the residue
purified by CC (benzene/AcOEt 10 :1): 14 (417 mg, 91%). Colorless oil. IR (ATR): 1732, 1662 (CO).
1H-NMR (400 MHz): 1.67 (s, Me3C); 2.81 (t, J ¼ 8.0, CH2(a)); 3.18 (s, MeN); 3.20 (t, J ¼ 8.0, CH2(b));
3.57 (s, MeO); 6.67 (d, J ¼ 3.8, arom. H); 7.09 (d, J ¼ 7.8, arom. H); 7.24 (dd, J ¼ 7.8, 7.8, arom. H); 7.60
(d, J ¼ 3.8, arom. H); 8.01 (d, J ¼ 7.8, arom. H). 13C-NMR (100 MHz): 27.9; 28.2; 32.2; 33.2; 61.2; 83.7;
105.4; 113.3; 122.2; 124.4; 125.6; 129.6; 133.6; 135.2; 149.8; 173.8. HR-FAB-MS: 333.1798 ([ M þ H]þ,
C18H25N2Oþ4 ; calc. 333.1814).
N-Methoxy-N-methyl-1H-indole-4-propanamide (15). A soln. of 14 (84 mg, 0.254 mmol) in AcOH
(3.2 ml, 56.0 mmol) was stirred at 1008 for 21 h, and the solvent was evaporated. The residue was purified
by CC (benzene/AcOEt 8 :1 to 4 :1): 15 (53 mg, 89%). Yellow oil. IR (ATR): 3400 – 3286(NH), 1637
1
(CO). H-NMR (400 MHz): 2.87 (t, J ¼ 8.1, CH2(a)); 3.20 (s, MeN); 3.26( t, J ¼ 8.1, CH2(b)); 3.58 (s,
MeO); 6.63 (ddd, J ¼ 3.0, 2.2, 1.1, arom. H); 6.98 (dd, J ¼ 7.6, 1.1, arom. H); 7.14 (dd, J ¼ 7.6, 7.6, arom.
H); 7.22 (dd, J ¼ 3.0, 2.8, arom. H); 7.28 (dd, J ¼ 7.6, 1.1, arom. H); 8.20 (br. s, NH). 13C-NMR
(100 MHz): 28.4; 32.2; 33.0; 61.2; 100.9; 109.2; 119.1; 122.2; 123.8; 127.1; 133.4; 135.8; 174.2. HR-FAB-
MS: 233.1283 ([M þ H]þ, C13H17N2O2þ ; calc. 233.1290).
N,N-Dimethyl-1H-indole-4-propanethioamide (16). A mixture of 9 (128 mg, 0.592 mmol) and
Lawessonꢂs reagent (167 mg, 0.413 mmol) in THF (1.8 ml) was stirred at r.t. for 24 h. After addition of
MeOH (2.5 ml), the mixture was stirred at r.t. for 5 min, and the reaction was quenched with sat. aq.
NH4Cl soln. (2 ml) followed by H2O (3 ml). The mixture was extracted with AcOEt (2 ꢁ 13 ml), the
combined extract washed with brine (6ml), dried, and concentrated, and the residue purified by CC
(benzene/AcOEt 1:0 to 20 :1): 16 (127 mg, 93%). Colorless plates. M.p. 89.5 – 90.58. IR (ATR): 3400 –
3200 (NH), 1522 (CS). 1H-NMR (400 MHz): 3.05, 3.46(each s, MeN); 3.21 (dd, J ¼ 10.3, 8.4, CH2(a));
3.41 (dd, J ¼ 10.3, 8.4, CH2(b)); 6.67 (ddd, J ¼ 3.1, 2.2, 0.9, arom. H); 6.97 (d, J ¼ 7.6, arom. H); 7.13 (dd,
J ¼ 7.6, 7.6, arom. H); 7.23 (dd, J ¼3.1, 2.6, arom. H); 7.29 (dd, J ¼ 7.6, 0.9, arom. H); 8.20 (br. s, NH).
13C-NMR (100 MHz): 33.5; 41.6; 44.2; 44.6; 100.9; 109.5; 119.3; 122.2; 124.0; 127.2; 132.8; 135.7; 203.7.
HR-FAB-MS: 232.1047 (Mþ, C13H16N2S; calc. 232.1034).
Intramolecular Vilsmeier– Haack Reaction of Amide 9 (Entry1 , Table 1): 4,5-Dihydrobenz[cd]in-
dol-3(1H)-one (10). A soln. of 9 (45 mg, 0.209 mmol), K2CO3 (75 mg, 0.546mmol), and POCl 3 (70 ml,
0.751 mmol) in dry MeCN (0.6ml) was stirred at 65 8 for 3 h. Then the reaction was quenched with H2O
(3 ml) and the mixture washed with AcOEt (2 ꢁ 4 ml). After the aq. soln. was basified with 5n NaOH to
pH 12, the mixture was extracted with AcOEt (3 ꢁ 11 ml), the combined extract washed with brine
(10 ml), dried, and concentrated, and the residue purified by CC (benzene/AcOEt 7:1 to 9 :2): 10
(27 mg, 74%). Yellow prisms. M.p. 183.5 – 1848 ([5a]: 1848). IR (ATR): 3500 – 3250 (NH), 1650 (CO).
1H-NMR (500 MHz): 2.90 (t, J ¼ 7.0, CH2(5)); 3.37 (t, J ¼ 7.0, CH2(4)); 7.11 (dd, J ¼ 7.5, 0.9, arom. H);
7.25 (dd, J ¼ 7.5, 7.5, arom. H); 7.31 (dd, J ¼ 7.5, 0.9, arom. H); 7.75 (d, J ¼ 2.7, arom. H); 9.09 (br. s, NH).
13C-NMR (125 MHz): 27.7; 39.9; 109.2; 114.3; 118.5; 123.8; 124.3; 129.1; 129.3; 133.6; 194.5. HR-FAB-
MS: 172.0770 ([M þ H]þ, C11H10NOþ; calc. 172.0762).
1-[(tert-Butoxy)carbonyl]-1H-indole-4-propanol (17). A mixture of 7b (209 mg, 0.66 mmol) and
LiBH4 (95%, 34.3 mg, 1.50 mmol) in dry THF (3.2 ml) and EtOH (0.8 ml) under Ar was stirred at r.t. for
1.5 h. Then the reaction was quenched with sat. aq. NH4Cl soln. (5 ml) and H2O (2 ml) at 08, the mixture
extracted with AcOEt (3 ꢁ 10 ml), the combined extract washed with brine (5 ml), dried, and
concentrated, and the residue purified by CC (hexane/AcOEt 9 :2): 17 (167 mg, 92%). Colorless oil. IR

Helvetica Chimica Acta – Vol. 90 (2007)
583
1
(neat): 3368 (OH), 1735 (CO). H-NMR (400 MHz): 1.67 (s, Me3C); 1.72 (br. s, OH); 2.00 (tt, J ¼ 7.6,
6.4, CH2(b)); 2.96( t, J ¼ 7.6, CH 2(g)); 3.68 (t, J ¼ 6.4, CH2(a)); 6.64 (dd, J ¼ 3.7, 0.7, arom. H); 7.06( dd,
J ¼ 7.7, 0.7, arom. H); 7.23 (dd, J ¼ 7.7, 7.7, arom. H); 7.59 (d, J ¼ 3.7, arom. H); 8.00 (d, J ¼ 7.7, arom. H).
13C-NMR (100 MHz): 28.2; 29.1; 33.5; 62.3; 83.6; 105.4; 113.0; 122.2; 124.3; 125.5; 129.7; 134.2; 135.1;
149.8. HR-FAB-MS: 275.1540 (Mþ, C16H21NO3þ ; calc. 275.1522).
3-{1-[(tert-Butoxy)carbonyl]-1H-indol-4-yl}propyl Phenyl Sulfide (¼1-[(tert-Butoxy)carbonyl]-4-
[3-(phenylthio)propyl]-1H-indole; 18). To an ice-cooled mixture of 17 (116mg, 0.423 mmol) and
PhSSPh (185 mg, 0.848 mmol) in dry MeCN (3.5 ml) under Ar was added Bu3P (0.21 ml, 0.843 mmol),
and the mixture was stirred at r.t. for 1 h. Then the reaction was quenched with 5% aq. NaOH soln.
(3.5 ml) at 08, the mixture extracted with Et2O (3 ꢁ 8 ml), the combined extract washed with 10% aq.
HCl soln. (2.7 ml), sat. aq. NaHCO3 soln. (2 ꢁ 6ml), and brine (2 ꢁ 5 ml), dried, and concentrated, and
the residue purified by CC (hexane/AcOEt 120 :1 to 110 :1): 18 (147 mg, 95%). Colorless oil. IR (neat):
1735 (CO). 1H-NMR (400 MHz): 1.67 (s, Me3C); 2.04 (tt, J ¼ 7.3, 7.3, CH2(b)); 2.94 (t, J ¼ 7.3, CH2(g));
3.00 (t, J ¼ 7.3, CH2(a)); 6.59 (dd, J ¼ 3.7, 0.9, arom. H); 7.03 (dif. d, J ¼ 7.8, arom. H); 7.16( m, arom. H);
7.23 – 7.31 (m, 5 arom. H); 7.57 (d, J ¼ 3.7, arom. H); 8.00 (d, J ¼ 7.8, arom. H). 13C-NMR (100 MHz):
28.2; 29.9; 31.7; 33.0; 83.6; 105.3; 113.1; 122.4; 124.3; 125.5; 125.8; 128.8; 129.0; 129.7; 133.6; 135.1; 136.5;
149.7. HR-FAB-MS: 367.1596 (Mþ, C22H25NO2Sþ; calc. 367.1606).
3-{1-[(tert-Butoxy)carbonyl]-1H-indol-4-yl}propyl Phenyl Sulfoxide (¼1-[(tert-Butoxy)carbonyl]-
4-[3-(phenylsulfinyl)propyl]-1H-indole; 19). A mixture of 18 (265 mg, 0.721 mmol) and NaIO4 (237 mg,
1.11 mmol) in MeOH (5.5 ml) and H2O (1.1 ml) was stirred at r.t. for 7 h. Then the reaction was
quenched with H2O (10 ml), the mixture extracted with AcOEt (3 ꢁ 13 ml), the combined extract
washed with sat. aq. NaHCO3 soln. (5 ml) and brine (2 ꢁ 5 ml), dried, and concentrated, and the residue
1
purified by CC (hexane/AcOEt 7:2): 19 (266 mg, 96%). Colorless oil. IR (neat): 1735 (CO). H-NMR
(400 MHz): 1.67 (s, Me3C); 2.04, 2.20 (each dtt, J ¼ 15.2, 7.6, 7.6, CH2(b)); 2.79 (t, J ¼ 7.6, CH 2(g)); 2.99
(t, J ¼ 7.6, CH 2(a)); 6.56 (d, J ¼ 3.9, arom. H); 6.99 (d, J ¼ 7.9, arom. H); 7.22 (dd, J ¼ 7.9, 7.9, arom. H);
7.46– 7.51 ( m, 3 arom. H); 7.55 – 7.59 (m, 2 arom. H); 8.01 (d, J ¼ 7.9, arom. H). 13C-NMR (100 MHz):
22.9; 28.1; 31.5; 56.2; 83.7; 105.1; 113.4; 122.3; 123.9; 124.2; 125.6; 129.1; 129.6; 130.8; 132.6; 135.1; 143.7;
149.6. HR-FAB-MS: 384.1632 ([M þ H]þ, C22H26NO3Sþ; calc. 384.1633).
3-(1H-Indol-4-yl)propyl Phenyl Sulfoxide (¼4-[3-(Phenylsulfinyl)propyl]-1H-indole; 20). A soln. of
19 (138 mg, 0.36mmol) in AcOH (4.5 ml, 78.7 mmol) was stirred at 100 8 for 19 h, and the solvent was
evaporated. Then, the residue was dissolved with AcOEt (20 ml), the org. soln. washed with sat. aq.
NaHCO3 soln. (8 ml) and brine (9 ml), dried, and concentrated, and the residue purified by CC (hexane/
AcOEt 3 :1 to 2 :1): 20 (88 mg, 87%). Yellow oil. IR (neat): 3400 – 3160 (NH). 1H-NMR (400 MHz): 2.10
(dtt, J ¼ 13.9, 7.5, 7.5, CH2(b)); 2.83 (t, J ¼ 7.5, CH2(g)); 3.05 (t, J ¼ 7.5, CH2(a)); 6.53 (ddd, J ¼ 2.9, 2.0,
0.9, arom. H); 6.88 (dd, J ¼ 7.4, 0.9, arom. H); 7.11 (dd, J ¼ 7.4, 7.4, arom. H); 7.20 (dd, J ¼ 2.9, 2.7, arom.
H); 7.27 (d, J ¼ 7.4, arom. H); 7.46– 7.52 ( m, 3 arom. H); 7.55 – 7.59 (m, 3 arom. H); 8.23 (br. s, NH).
13C-NMR (100 MHz): 22.7; 31.9; 56.5; 100.3; 109.5; 119.0; 121.7; 123.9; 124.0; 127.0; 129.1; 130.8; 132.2;
135.8; 143.5. HR-FAB-MS: 284.1117 ([M þ H]þ, C17H18NOSþ; calc. 284.1109).
Pummerer-Type Cyclization of Sulfoxide 20: 3,7,8,9-Tetrahydro-6-phenylthiopyrano[3,2-e]indolium
Trifluoroacetate (22). A soln. of 20 (45 mg, 0.159 mmol) and (CF3CO)2O (70 ml, 0.496mmol) in dry
benzene (3.0 ml) was stirred at r.t. for 1 h, and the solvent was evaporated. Purification of the residue by
prep. TLC (CHCl3/MeOH 10 :3) gave 22 (23 mg, 38%). Light red prisms. M.p. 133.5 – 134.58. IR (KBr):
1684 (CO). 1H-NMR (500 MHz, CD3OD): 2.15, 2.48 (2m, HꢀC(5)); 3.32, 3.59 (2m, CH2(4)); 3.93, 4.20
(2m, CH2(6)); 6.84 (d, J ¼ 3.2, arom. H); 7.33 (d, J ¼ 8.5, arom. H); 7.54 (m, 2 arom. H); 7.59 (d, J ¼ 3.2,
arom. H); 7.64 (m, 2 arom. H); 7.69 (m, 2 arom. H). 13C-NMR (125 MHz, CD3OD): 15.9; 24.9; 42.0;
101.9; 112.7; 124.4; 125.2; 128.8; 128.9; 130.1; 130.8; 131.3; 131.9; 133.7; 134.0; 139.4; 162.9. HR-FAB-MS:
266.1022 (Mþ, C17H16NSþ; calc. 266.1003).
Methyl a-(Acetylamino)-1H-indole-4-propanoate [6] (24). A mixture of 23 (483 mg, 1.17 mmol) and
Mg turnings (249 mg, 10.2 mmol) in dry MeOH (16.0 ml) under Ar was stirred at r.t. for 2 h with
sonication. Then the reaction was quenched with sat. aq. NH4Cl soln. (9.0 ml) followd by H2O (9.0 ml)
and AcOEt (5.0 ml). The mixture was extracted with AcOEt (3 ꢁ 40 ml), the combined extract washed
with sat. aq. NaHCO3 soln. (20 ml) and brine (30 ml), dried, and concentrated, and the residue purified
by CC (benzene/AcOEt 3 :1 to 2 :1): 24 (274 mg, 90%). Yellow oil. IR (ATR): 3288 (NH); 1736, 1653

584
Helvetica Chimica Acta – Vol. 90 (2007)
(CO). 1H-NMR (400 MHz): 1.93 (s, MeCO); 3.38 (dd, J ¼ 13.9, 5.6, 1 HꢀC(b)); 3.46( dd, J ¼ 13.9, 5.9,
1 HꢀC(b)); 3.70 (s, MeO); 5.00 (ddd, J ¼ 8.0, 5.9, 5.6, HꢀC(a)); 5.92 (d, J ¼ 8.0, NH); 6.57 (ddd, J ¼
3.2, 2.2, 1.1, arom. H); 6.83 (d, J ¼ 7.2, arom. H); 7.12 (dd, J ¼ 7.2, 7.2, arom. H); 7.23 (dd, J ¼ 3.2, 2.5,
arom. H); 7.32 (d, J ¼ 7.2, arom. H); 8.24 (br. s, NH). EI-MS: 261 (20, [M þ H]þ), 260 (100, Mþ), 201
(100), 170 (65), 159 (51), 131 (100), 130 (100).
Methyl a-(Acetylamino)-1-[(tert-butoxy)carbonyl]-1H-indole-4-propanoate [6] (25). A soln. of 24
(266 mg, 1.02 mmol), DMAP (14 mg, 0.112 mmol), and (Boc)2O (281 mg, 1.29 mmol) in dry THF
(7.5 ml) under Ar was stirred at r.t. for 1 h, and the solvent was evaporated. The residue was purified by
CC (benzene/AcOEt 4 :1 to 2 :1): 25 (357 mg, 97%). Colorless oil. IR (ATR): 3379 (NH); 1732, 1657
(CO). 1H-NMR (400 MHz): 1.67 (s, Me3C); 1.95 (s, MeCO); 3.35 (dd, J ¼ 13.9, 5.2, 1 HꢀC(b)); 3.41 (dd,
J ¼ 13.9, 6.0, 1 HꢀC(b)); 3.69 (s, MeO); 4.97 (ddd, J ¼ 6.8, 6.0, 5.2, HꢀC(a)); 5.93 (d, J ¼ 6.8, NH); 6.61
(dd, J ¼ 3.8, 0.5, arom. H); 6.93 (dd, J ¼ 7.8, 7.8, arom. H); 7.23 (d, J ¼ 7.8, arom. H); 7.60 (d, J ¼ 3.8,
arom. H); 8.07 (dd, J ¼ 7.8, arom. H). FAB-MS: 361 ([M þ H]þ), 360 (Mþ).
a-(Acetylamino)-1-[(tert-butoxy)carbonyl]-N,N-dimethyl-1H-indole-4-propanamide (26). Under
Ar, 2m Me3Al in heptane (2.2 ml, 4.40 mmol) was added dropwise to a soln. of Me2NH · HCl (136mg,
1.67 mmol) in dry CH2Cl2 (3.0 ml) at 08, and the mixture was stirred at r.t. for 1 h. After addition of a soln.
of 25 (305 mg, 0.85 mmol) in dry CH2Cl2 (4.5 ml) at 08, the mixture was stirred at 308 for 26h, and the
reaction was quenched with sat. aq. NH4Cl soln. (8.0 ml) at 08, followed by H2O (5.0 ml) and 10% aq.
HCl soln. (2.4 ml). The mixture was extracted with CH2Cl2 (3 ꢁ 25 ml), the combined extract washed
with sat. aq. NaHCO3 soln. (15 ml) and brine (25 ml), dried, and concentrated, and the residue purified
by CC (AcOEt/EtOH 1:0 to 12 :1): 26 (207 mg, 66%). Colorless oil. IR (ATR): 3294 (NH); 1732, 1630
(CO). 1H-NMR (500 MHz): 1.68 (s, Me3C); 2.01 (s, MeCO); 2.27, 2.76(2 s, MeN); 3.13 (dd, J ¼ 13.0, 9.8,
1 HꢀC(b)); 3.37 (dd, J ¼ 13.0, 4.4, 1 HꢀC(b)); 5.23 (ddd, J ¼ 9.8, 7.9, 4.4, HꢀC(a)); 6.57 (d, J ¼ 7.9,
NH); 6.83 (d, J ¼ 3.7, arom. H); 7.01 (d, J ¼ 7.6, arom. H); 7.22 (dd, J ¼ 7.6, 7.6, arom. H); 7.60 (d, J ¼ 3.7,
arom. H); 8.05 (d, J ¼ 7.6, arom. H). 13C-NMR (125 MHz): 23.3; 28.2; 35.5; 36.7; 37.7; 49.8; 83.8; 105.5;
114.1; 123.6; 124.3; 126.0; 128.6; 130.6; 135.1; 149.7; 169.4; 171.3. HR-FAB-MS: 374.2082 ([ M þ H]þ,
C20H28N3Oþ4 ; calc. 374.2080).
a-(Acetylamino)-N,N-dimethyl-1H-indole-4-propanamide (27). A soln. of 26 (217 mg, 0.582 mmol)
in AcOH (7 ml, 122.4 mmol) was stirred at 1008 for 22 h, and the solvent was evaporated. The residue
was purified by CC (AcOEt/EtOH 1:0 to 9 :1, followed by 4 :1): 27 (147 mg, 92%). Yellow prisms. M.p.
176– 177 8. IR (ATR): 3300 – 3200 (NH), 1620 (CO). 1H-NMR (400 MHz, (D6)DMSO): 1.78 (s, MeCO);
2.57, 2.67 (2s, MeN); 3.00 (dd, J ¼ 13.3, 6.9, 1 HꢀC(b)); 3.11 (dd, J ¼ 13.3, 7.8, 1 HꢀC(b)); 5.05 (ddd,
J ¼ 8.4, 7.8, 6.9, HꢀC(a)); 6.53 (br. s, arom. H); 6.77 (d, J ¼ 7.6, arom. H); 6.96 (dd, J ¼ 7.6, 7.6, arom. H);
7.23 (d, J ¼ 7.6, arom. H); 7.31 (dd, J ¼ 2.9, 2.6, arom. H); 8.30 (d, J ¼ 8.4, NH); 11.1 (br. s, NH).
13C-NMR (125 MHz, (D6)DMSO): 22.3; 35.0; 36.2; 36.3; 48.8; 99.3; 109.9; 119.2; 120.7; 124.9; 127.4;
128.6; 135.6; 168.7; 171.2. HR-FAB-MS: 274.1547 ([ M þ H]þ, C15H19N3O2þ ; calc. 274.1556).
Methyl a-{[(Benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]-1H-indole-4-propanoate [6]
(29). Under Ar, a mixture of 28 (180 mg, 0.400 mmol) and Mg turnings (62 mg, 2.55 mmol) in dry
MeOH (5.1 ml) was stirred for 2 h at r.t. with sonication. After further addition of Mg turnings (21 mg,
0.864 mmol), the mixture was stirred at r.t. for 1 h under the same conditions. The reaction was quenched
with sat. aq. NH4Cl soln. (4.0 ml), H2O (4.0 ml), and 4% aq. HCl soln. (1.5 ml), the mixture extracted
with AcOEt (20 ml, 2 ꢁ 14 ml), the combined extract washed with sat. aq. NaHCO3 soln. (7 ml) and brine
(7 ml), dried, and concentrated, and the residue purified by CC (hexane/AcOEt 7:1): 29 (161 mg, 89%).
Colorless oil. IR (ATR): 3348 (NH), 1728 (CO). 1H-NMR (400 MHz, CD3OD): 1.67 (s, Me3C); 3.18 (dd,
J ¼ 13.9, 8.8, 1 HꢀC(b)); 3.39 (dd, J ¼ 13.9, 5.7, 1 HꢀC(b)); 3.66 (s, MeO); 4.53 (dd, J ¼ 8.8, 5.7,
HꢀC(a)); 4.97, 5.02 (2d, J ¼ 12.2, PhCH2); 6.69 (dd, J ¼ 3.8, arom. H); 7.03 (d, J ¼ 7.8, arom. H); 7.19
(dd, J ¼ 7.8, 7.8, arom. H); 7.22 – 7.33 (m, 5 arom. H); 7.58 (d, J ¼ 3.8, arom. H); 8.01 (d, J ¼ 7.8, arom.
H). EI-MS: 453 (16, [M þ H]þ), 452 (55, Mþ), 396(25), 245 (100), 220 (28), 201 (91), 174 (94), 130
(100), 91 (100), 57 (92).
a-{[(Benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]-1H-indole-4-propanoic Acid (30). A
mixture of 29 (369 mg, 0.816 mmol) and LiOH · H2O (481 mg, 11.5 mmol) in THF (4.1 ml) and H2O
(4.1 ml) was stirred at r.t. for 1 h, and the reaction was quenched with 6n aq. HCl (! pH 2). The mixture
was extracted with AcOEt (20 ml, 2 ꢁ 15 ml), the combined extract washed with brine (10 ml), dried, and

Helvetica Chimica Acta – Vol. 90 (2007)
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concentrated, and the residue purified by CC (hexane/AcOEt 4 :1 to 3 :1): 30 (360 mg, quant.). Colorless
oil. IR (ATR): 3400 – 2800 (OH), 1726(CO). 1H-NMR (400 MHz): 1.67 (s, Me3C); 3.35 (dd, J ¼ 13.9,
6.3, 1 HꢀC(b)); 3.48 (dd, J ¼ 13.9, 5.9, 1 HꢀC(b)); 4.77 (ddd, J ¼ 8.2, 6.3, 5.9, HꢀC(a)); 5.08, 5.11 (2d,
J ¼ 12.2, PhCH2); 5.19 (d, J ¼ 8.2, NH); 6.61 (d, J ¼ 3.7, arom. H); 7.00 (d, J ¼ 7.8, arom. H); 7.22 (dd,
J ¼ 7.8, 7.8, arom. H); 7.29 – 7.38 (m, 5 arom. H); 7.55 (d, J ¼ 3.7, arom. H); 8.07 (d, J ¼ 7.8, arom. H).
13C-NMR (125 MHz): 28.2; 35.1; 54.5; 67.1; 83.8; 105.1; 114.4; 123.5; 124.4; 126.1; 127.8; 128.1; 128.2;
128.5; 130.5; 135.3; 136.1; 149.7; 155.8; 175.7. HR-FAB-MS: 438.1758 (Mþ, C24H26N2O6; calc. 438.1791).
a-{[(Benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]-N,N-dimethyl-1H-indole-4-propana-
mide (31). To an ice-cooled soln. of 30 (171 mg, 0.391 mmol) and Me2NH2 · HCl (88 mg, 1.08 mmol) in
dry MeCN (3.4 ml) was added Et3N (0.55 ml, 3.95 mmol) over 5 min, and the mixture was cooled to ꢀ
158. To the soln. was added 1m DMC in CH2Cl2 (1.10 ml, 1.10 mmol) over 10 min. The mixture was stirred
at ꢀ 108 for 1.5 h and then at 08 for 1.5 h, and the reaction was quenched with sat. aq. NaHCO3 soln.
(4 ml). Then the prepicitate was dissolved with H2O (3.0 ml), the mixture extracted with AcOEt (3 ꢁ
13 ml), the combined extract washed with sat. aq. K2CO3 soln. (4 ml) and brine (7 ml), dried, and
concentrated, and the residue purified by CC (hexane/AcOEt 4 :1 to 3 :1): 31 (170 mg, 93%). Colorless
1
oil. IR (ATR): 3273 (NH); 1726, 1637 (CO). H-NMR (400 MHz): 1.68 (s, Me3C); 2.26, 2.75 (each s,
MeN); 3.16( dd, J ¼ 13.0, 9.8, 1 HꢀC(b)); 3.37 (dd, J ¼ 13.0, 4.8, 1 HꢀC(b)); 4.97 (ddd, J ¼ 9.8, 8.2, 4.8,
HꢀC(a)); 5.12 (s, PhCH2); 5.84 (d, J ¼ 8.2, NH); 6.79 (d, J ¼ 3.5, arom. H); 7.02 (d, J ¼ 7.7, arom. H);
7.22 (dd, J ¼ 7.7, 7.7, arom. H); 7.29 – 7.36( m, 5 arom. H); 7.59 (d, J ¼ 3.5, arom. H); 8.05 (d, J ¼ 7.7, arom.
H). 13C-NMR (125 MHz): 28.2; 35.1; 36.7; 38.0; 51.3; 66.8; 83.8; 105.4; 114.1; 123.6; 124.3; 126.0; 127.0;
128.0; 128.1; 128.5; 130.5; 135.1; 136.4; 149.7; 155.7; 171.2. HR-FAB-MS: 466.2338 (Mþ, C26H32N3O5þ ;
calc. 466.2342).
a-{[(Benzyloxy)carbonyl]amino}-N,N-dimethyl-1H-indole-4-propanamide (32). A soln. of 31
(268 mg, 0.576 mmol) in AcOH (6.6 ml, 115 mmol) was stirred at 1008 for 16h, and the solvent was
evaporated. The residue was purified by CC (hexane/AcOEt 2 :1 to 3 :2): 32 (196mg, 93%). Yellow oil.
IR (ATR): 3292 (NH); 1703, 1630 (CO). 1H-NMR (400 MHz): 2.21, 2.73 (2s, MeN); 3.19 (dd, J ¼ 12.8,
9.9, 1 HꢀC(b)); 3.42 (dd, J ¼ 12.8, 4.9, 1 HꢀC(b)); 5.06( ddd, J ¼ 9.9, 8.2, 4.9, HꢀC(a)); 5.12 (s,
PhCH2); 5.85 (d, J ¼ 8.2, NH); 6.75 (br. s, arom. H); 6.90 (d, J ¼ 7.5, arom. H); 7.09 (dd, J ¼ 7.5, 7.5,
arom. H); 7.22 (dd, J ¼ 2.7, 2.7, arom. H); 7.29 (d, J ¼ 7.5, arom. H); 7.31 – 7.37 (m, 3 arom. H); 8.22 (br. s,
NH). 13C-NMR (125 MHz): 35.5; 36.6; 38.5; 51.2; 66.7; 100.8; 110.1; 120.5; 121.8; 124.3; 127.9; 128.0;
128.1; 128.5; 128.6; 135.7; 136.5; 155.7; 171.7. HR-FAB-MS: 366.1812 ([M þ H]þ, C21H24N3O3þ ; calc.
366.1818).
a-Amino-N,N-dimethyl-1H-indole-4-propanamide (33). A mixture of 32 (132 mg, 0.361 mmol) and
5% Pd/C (27.4 mg) in MeOH (3.0 ml) was stirred at r.t. for 2 h under H2 (1 atm). After filtration, the
filtrate was evaporated. The residue was purified by CC (CHCl3/MeOH 30 :1 to 8 :1): 33 (80 mg, 96%).
Yellow oil. IR (ATR): 3600 – 3100 (NH), 1620 (CO). 1H-NMR (400 MHz): 2.60, 2.86 (each s, MeN); 3.09
(dd, J ¼ 13.2, 7.5, 1 HꢀC(b)); 3.22 (dd, J ¼ 13.2, 7.0, 1 HꢀC(b)); 4.12 (dd, J ¼ 7.5, 7.0, HꢀC(a)); 6.60
(ddd, J ¼ 3.1, 2.2, 0.9, arom. H); 6.94 (dd, J ¼ 7.6, 0.9, arom. H); 7.13 (dd, J ¼ 7.6, 7.6, arom. H); 7.23 (dd,
J ¼ 3.1, 2.7, arom. H); 7.30 (d, J ¼ 7.6, arom. H); 8.29 (br. s, NH). 13C-NMR (125 MHz): 35.7; 36.6; 40.8;
52.0; 100.8; 109.7; 120.5; 122.1; 124.1; 127.8; 129.8; 135.8; 175.0. HR-FAB-MS: 232.1460 ([M þ H]þ,
C13H18N3Oþ; calc. 232.1450).
a-(Benzoylamino)-N,N-dimethyl-1H-indole-4-propanamide (34).
A soln. of 32 (110 mg,
0.301 mmol) and 5% Pd/C (23.5 mg) in MeOH (2.4 ml) was stirred at r.t. for 2.5 h under H2 (1 atm).
After filtration, the filtrate was evaporated. The residue was dissolved in dry THF (2.5 ml), and K2CO3
(252 mg, 1.82 mmol) and benzoyl chloride (60 ml, 0.517 mmol) were added at 08. After being stirred at r.t.
for 1 h, the reaction was quenched with H2O (3 ml). The mixture was extracted with AcOEt (3 ꢁ 6ml),
the combined extract washed with sat. aq. NaHCO3 soln. (5 ml) and brine (7 ml), dried, and
concentrated, and the residue was purified by CC (hexane/AcOEt 1:1): 34 (95 mg, 94% over 2 steps).
Colorless prisms. M.p. 197 – 1988. IR (ATR): 3350 – 3250 (NH), 1620 (CO). 1H-NMR (500 MHz,
(D6)DMSO): 2.74, 2.77 (each s, MeN); 3.20 (dd, J ¼ 13.4, 7.7, 1 HꢀC(b)); 3.26( dd, J ¼ 13.4, 7.0,
1 HꢀC(b)); 5.21 (dd, J ¼ 7.7, 7.0, HꢀC(a)); 6.60 (m, arom. H); 6.91 (d, J ¼ 7.6, arom. H); 6.97 (dd, J ¼
7.6, 7.6, arom. H); 7.23 (d, J ¼ 7.6, arom. H); 7.32 (dd, J ¼ 2.7, 2.7, arom. H); 7.43 (dd, J ¼ 7.4, 7.4, 2 arom.
H); 7.51 (dd, J ¼ 7.4, 1.5, arom. H); 7.84 (dd, J ¼ 7.4, 1.5, 2 arom. H); 8.74 (d, J ¼ 7.9, NH); 11.07 (br. s,

586
Helvetica Chimica Acta – Vol. 90 (2007)
NH). 13C-NMR (125 MHz, (D6)DMSO): 35.2; 35.3; 36.4; 49.9; 99.3; 109.9; 119.5; 120.7; 124.9; 127.5
(C ꢁ 3); 128.1; 128.9; 131.3; 133.8; 135.7; 165.8; 171.3. HR-FAB-MS: 336.1685 ([M þ H]þ, C20H22N3O2þ ;
calc. 336.1712).
a-[(Ethoxycarbonyl)amino]-N,N-dimethyl-1H-indole-4-propanamide (35). A soln. of 32 (60 mg,
0.164 mmol) and 5% Pd/C (12 mg) in MeOH (1.5 ml) was stirred at r.t. for 2.5 h under H2 (1 atm). After
filtration, the filtrate was evaporated. The residue was dissolved in dry THF (1.4 ml), and K2CO3
(74.5 mg, 0.539 mmol) and ethyl carbonochloridate (35 ml, 0.366 mmol) were added at 08. After being
stirred at r.t. for 0.5 h, the reaction was quenched with H2O (3 ml). The mixture was extracted with
AcOEt (3 ꢁ 7 ml), the combined extract washed with brine (4 ml), dried, and evaporated, and the
residue purified by CC (hexane/AcOEt 3 :1 to 1:1): 35 (48 mg, 96% over 2 steps). Colorless oil. IR
1
(ATR): 3294 (NH); 1697, 1632 (CO). H-NMR (400 MHz): 1.25 (t, J ¼ 7.1, MeCH2); 2.21, 2.73 (each s,
MeN); 3.18 (dd, J ¼ 13.0, 9.7, 1 HꢀC(b)); 3.41 (dd, J ¼ 13.0, 4.9, 1 HꢀC(b)); 4.13 (q, J ¼ 7.1, MeCH2);
5.04 (ddd, J ¼ 9.7, 8.4, 4.9, HꢀC(a)); 5.72 (d, J ¼ 8.4, NH); 6.75 (br. s, arom. H); 6.90 (d, J ¼ 7.6, arom.
H); 7.09 (dd, J ¼ 7.6, 7.6, arom. H); 7.22 (dd, J ¼ 2.7, 2.7, arom. H); 7.29 (d, J ¼ 7.6, arom. H); 8.31 (br. s,
NH). 13C-NMR (125 MHz): 14.6; 35.5; 36.6; 38.5; 51.0; 60.9; 101.0; 110.0; 120.5; 122.0; 124.2; 128.0;
128.4; 135.6; 156.0; 171.8. HR-FAB-MS: 304.1672 ([M þ H]þ, C16H21N3O3þ ; calc. 304.1661).
N,N-Dimethyl-a-{[(4-methylphenyl)sulfonyl]amino}-1H-indole-4-propanamide (36). A mixture of
32 (110 mg, 0.301 mmol) and 5% Pd/C (24.7 mg) in MeOH (2.4 ml) was stirred at r.t. for 2 h under H2
(1 atm), and the catalyst was filtered off. After concentration of the filtrate, the residue was dissolved in
dry THF (2.7 ml) and, to the soln. at 08 was added K2CO3 (189.5 mg, 1.37 mmol) and TsCl (90 mg,
0.472 mmol). The mixture was stirred at r.t. for 3 h, and the reaction was quenched with H2O (3 ml). The
mixture was extracted with AcOEt (3 ꢁ 7 ml), the combined extract washed with sat. aq. NaHCO3 soln.
(5 ml) and brine (7 ml), dried, and evaporated, and the residue purified by CC (CHCl3/MeOH 35 :1): 36
(93 mg, 81% over 2 steps). Light green prisms. M.p. 223 – 2248. IR (ATR): 3500 – 3200 (NH), 1620 (CO).
1H-NMR (500 MHz, (D6)DMSO): 2.24, 2.38 (2s, MeN); 2.34 (s, MeC); 2.88 (dd, J ¼ 13.0, 5.8,
1 HꢀC(b)); 3.02 (dd, J ¼ 13.0, 8.9, 1 HꢀC(b)); 4.44 (dd, J ¼ 8.9, 5.8, HꢀC(a)); 6.20 (br. s, arom. H);
6.64 (d, J ¼ 7.6, arom. H); 6.92 (dd, J ¼ 7.6, 7.6, arom. H); 7.22 (d, J ¼ 7.6, arom. H); 7.27 – 7.29 (m, 3
arom. H); 7.57 (d, J ¼ 8.2, 2 arom. H); 8.15 (br. s, NH); 11.05 (br. s, NH). 13C-NMR (125 MHz,
(D6)DMSO): 20.9; 34.9; 36.0; 36.8; 51.9; 98.7; 110.1; 119.4; 120.7; 125.0; 126.4; 127.2; 127.4; 129.1; 135.6;
138.1; 142.4; 169.9. HR-FAB-MS: 386.1526 ([M þ H]þ, C20H24N3O3Sþ; calc. 386.1538).
Intramolecular Vilsmeier– Haack Reaction of Amide 27 (Entry1 , Table 2): N-(1,3,4,5-Tetrahydro-3-
oxobenz[cd]indol-4-yl)acetamide (37). A suspension of 27 (40 mg, 0.146mmol), K 2CO3 (53 mg,
0.383 mmol), and POCl3 (53 ml, 0.569 mmol) in dry MeCN (0.65 ml) was stirred at 658 for 1 h, and the
reaction was quenched with H2O (3 ml). The aq. soln. was washed with AcOEt (2 ꢁ 6ml), basified with
5n NaOH to pH 12, and extracted with AcOEt (3 ꢁ 12 ml). The combined extract was washed with brine
(6ml), dried, and concentrated, and the residue purified by CC (benzene/AcOEt 1:1 to 0 :1): 37
1
(11.5 mg, 34%). Yellow prisms. M.p. 231.5 – 2328. IR (ATR): 3294 (NH); 1650, 1620 (CO). H-NMR
(500 MHz, (D6)acetone): 2.02 (s, MeCO); 3.20 (dd, J ¼ 15.8, 12.2, 1 HꢀC(5)); 3.68 (dd, J ¼ 15.8, 6.6,
1 HꢀC(5)); 4.90 (ddd, J ¼ 12.2, 6.6, 5.2, HꢀC(4)); 7.06( d, J ¼ 7.6, arom. H); 7.21 (dd, J ¼ 7.6, 7.6, arom.
H); 7.37 (d, J ¼ 7.6, arom. H); 7.44 (br. s, NH); 7.88 (d, J ¼ 2.4, arom. H); 11.30 (br. s, NH). 13C-NMR
(125 MHz, (D6)acetone): 22.9; 35.4; 57.3; 110.8; 113.6; 119.1; 124.7; 125.9; 128.6; 129.7; 134.8; 170.4;
190.2. HR-FAB-MS: 229.0989 ([M þ H]þ, C13H12N2O2þ ; calc. 229.0977).
Methyl (aS)-a-{[(Benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]-1H-indole-4-propanoate
[6] ((S)-29). (S)-29 was prepared by asymmetric hydrogenation of 28 according to [6]. [a]2D4 ¼ ꢀ15.5
(c ¼ 0.5, MeOH) ([6]: [a]2D5 ¼ ꢀ13.4 (c ¼ 0.685, MeOH)). Chiral HPLC (Daicel Chiralcel OD-H, hexane/
iPrOH 24 :1, 1 ml/min, 254 nm): tR 25.5 (S; 99% ee) and 27.9 min (R).
(aS)-a-{[(Benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]-1H-indole-4-propanoic Acid
((S)-30). As described for racemic 30, from (S)-29: (S)-30. [a]2D5 ¼ þ32.5 (c ¼ 0.67, CHCl3).
(aS)-a-{[(Benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]-N,N-dimethyl-1H-indole-4-prop-
anamide ((S)-31). As described for racemic 31, from (S)-30: (S)-31. [a]2D4 ¼ þ24.9 (c ¼ 0.56, CHCl3).
(aS)-a-{[(Benzyloxy)carbonyl]amino}-N,N-dimethyl-1H-indole-4-propanamide ((S)-32). As de-
scribed for racemic 32, from (S)-31: (S)-32. [a]2D4 ¼ þ38.2 (c ¼ 0.56, CHCl3). Chiral HPLC (Daicel
Chiralcel OJ-H, hexane/iPrOH 9 :1, 0.7 ml/min, 230 nm): tR 57.5 (S; 99% ee) and 64.4 min (R).

Helvetica Chimica Acta – Vol. 90 (2007)
587
(aS)-a-(Acetylamino)-N,N-dimethyl-1H-indole-4-propanamide ((S)-27). A mixture of (S)-32
(164 mg, 0.449 mmol), 5% Pd/C (49.0 mg), and Ac2O (0.300 ml, 3.17 mmol) in MeOH (3.7 ml) was
stirred at r.t. for 5.5 h under H2 (1 atm). After removal of the catalyst by filtration, the filtrate was
concentrated. The residue was purified by CC (AcOEt/EtOH 1:0 to 20 :1): (S)-27 (105 mg, 85%). Light
orange prisms. M.p. 174 – 1758. [a]2D4 ¼ þ84.0 (c ¼ 0.43, MeOH).
Intramolecular Vilsmeier– Haack Reaction of (S)-27: N-[(4S)-1,3,4,5-Tetrahydro-3-oxobenz[cd]in-
dol-4-yl]acetamide ((S)-37). As described for racemic 37, from (S)-27: (S)-37. M.p. 231.4 – 232.38. [a]D20
ꢀ3.1 (c ¼ 0.22, MeOH). Chiral HPLC (Daicel Chiralpak AD-H, hexane/EtOH 4 :1, 0.7 ml/min, 247 nm):
tR 16.8 (S: 4% ee) and 19.7 min (R).
¼
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Received November 7, 2006