A Modular Formal Total Synthesis of (±)-Cycloclavine

Article abstract of DOI:10.1021/acs.joc.5b02815

Cycloclavine is a clavine-type Ergot alkaloid noteworthy for its unique pentacyclic skeleton featuring a 3-azabicyclo[3.1.0]hexane substructure. A short convergent route to the racemic alkaloid is described which comprises only eight linear steps and requires only four chromatographic purifications. The two key building blocks can be prepared in high yield from commercially available starting materials. Two consecutive coupling reactions, namely a selective alkylation of a dienolate and a Heck reaction, are the key steps of the reaction sequence. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02815

Note
pubs.acs.org/joc
A Modular Formal Total Synthesis of ( )-Cycloclavine
Natalie Netz and Till Opatz*
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: Cycloclavine is a clavine-type Ergot alkaloid
noteworthy for its unique pentacyclic skeleton featuring a 3-
azabicyclo[3.1.0]hexane substructure. A short convergent route
to the racemic alkaloid is described which comprises only eight
linear steps and requires only four chromatographic purifica-
tions. The two key building blocks can be prepared in high yield
from commercially available starting materials. Two consecutive
coupling reactions, namely a selective alkylation of a dienolate
and a Heck reaction, are the key steps of the reaction sequence.
he Ergot alkaloids are an important group of indole-
derived mycotoxins which exhibit strong biological
antimicrobial and cytostatic effects.4−10 The first total synthesis
of cycloclavine was published in 2008 by Szan
tay;11 further
reports came from Wipf,12 Cao,13 and Brewer.14
The construction of the ergoline skeleton is often effected
using Uhle’s ketone15 as it already contains three of the
required rings. However, to avoid problems emerging from the
oxidative sensitivity of the 1,3,4,5-tetrahydrobenzo[cd]indole
framework,16 we chose a modular approach to ( )-cycloclavine
(1) using indole and pyrrolinone-type building blocks and to
connect them to establish ring C at a late stage (Scheme 1).
T
́
activities illustrated, for example, by St. Anthony’s fire or
ergotism, a life-threatening disease caused by chronic ingestion
of toxic foodborne fungal secondary metabolites. Ergot alkaloids
primarily target serotonin (5-HT) receptors but also α-
adrenergic and dopamine receptors, and some natural or
semisynthetic ergoline derivatives are used as drugs against
migraine or Parkinson’s disease.1 Cycloclavine (1) belongs to
the subclass of clavine-type alkaloids and was first isolated in
1969 from seeds of Ipomoea hildebrandtii VATKE by Hofmann,
who also determined the absolute configuration as 5R,8S,10S.2
Cycloclavine is an isomer of agroclavine, but instead of having
an 8,9-double bond, the metabolite contains a cyclopropane
ring formed by the C atoms 8, 9, and 10 and represents the
only fused pentacyclic clavine alkaloid known to date (Figure
1).
Scheme 1. Retrosynthesis of ( )-Cycloclavine
The biosynthetic pathway for cycloclavine was investigated
by Naesby and O’Connor3 who identified chanoclavine-1 as an
intermediate and the oxidase EasH as the key enzyme
responsible for the formation of the cyclopropyl moiety.
Besides their action on receptors for biogenic amine neuro-
transmitters, biological activities of clavine alkaloids also include
The pyrrolinone unit was chosen to be 1,3-dimethyl-1,5-
dihydro-2H-pyrrol-2-one (3), while the bifunctional indole
+
building block 4 was derived from gramine (Y = N(CH3)3 ) or
another 3-methyleneindolenine precursor bearing a halogen
substituent at C-4.
The synthesis of building block 3 started from allylamine (5)
by an N-formylation using neat ethyl formate (Scheme 2).
Lithium aluminum hydride reduction of 6 yielded N-allyl-
methylamine, which was directly transformed into the
Received: December 11, 2015
Figure 1. Structures of clavine alkaloids.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02815
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The Journal of Organic Chemistry
Note
Scheme 2. Three-Step Synthesis of Pyrrolinone 3
Scheme 4. Coupling of Silyl Dienolether 14 under
Microwave Conditions
(10) or gramine methiodide (15) and triphenylphosphine
under microwave irradiation (300 W, 125 °C)21,22 to give the
desired γ-isomer 16 along with the α-isomer 13 and
regenerated pyrrolinone 3. Remarkably, compound 16 was
found to isomerize to enamide 17 during workup and
purification. Compound 16 and the rearranged γ-isomer 17
were both isolated in up to 17% yields (multiple runs).
Since a γ-selective coupling of 3 with the gramine derived
indole building block did not seem viable, a protected 3-
bromomethyl-1H-indole was synthesized as an alternative
electrophile. It was anticipated that the less reactive and
“softer” bromide would show a larger preference for the
sterically less hindered γ-position in the alkylation compared to
the reactive 3-methyleneindolenine. 3-Bromomethyl-1H-indole
22 could be readily prepared from indole (18) in 91% overall
yield through Vilsmeier formylation, Boc-protection, NaBH4-
reduction, and bromination (Scheme 5).23−25 Its reaction with
methacryloyl amide 8 without isolation. Subsequent ring
closing metathesis of 8 using catalyst 9 (catMETium RF1)17
afforded pyrrolinone 3 in 54% yield over three steps.
At first, we attempted coupling 3 with N-triisopropylsilyl-
protected gramine methiodide (12),18 which is easily prepared
from gramine (10) via reaction with lithium diisopropylamide
(LDA) and triisopropylsilyl chloride (TIPSCl), followed by
treatment with iodomethane (Scheme 3). Unfortunately,
Scheme 3. TBAF Induced Coupling of 3 with Gramine
Methiodide 12
Scheme 5. Coupling of Model Electrophile 22 with
Pyrrolinone 3
deprotonation of pyrrolinone 3 with sodium hydride and
reaction with methiodide 12 in the presence of tetrabutyl-
ammonium fluoride (TBAF) through the reactive 3-methylene-
indolenine intermediate did not afford the desired γ-alkylation
product. The isomeric α-coupling product 13 was formed
instead. The deprotonation of 3 was also carried out with LDA,
but the same unfavorable regioselectivity was observed.
To form the desired γ-isomer, the synthesis of silyl dienol
ethers of 3 was attempted. However, reaction with various
bases (2,6-lutidine, triethylamine, sodium hydride, and LDA)
and TMS and TBDMS chlorides and triflates did not afford the
desired silyloxypyrroles. On the other hand conversion to the
trimethylsilyloxypyrrole 14 could be effected with the
combination of zinc(II) chloride, triethylamine, and TMSCl
(Scheme 4).19,20 The highly moisture-sensitive compound 14
was not isolated but rather immediately reacted with gramine
B
DOI: 10.1021/acs.joc.5b02815
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The Journal of Organic Chemistry
Note
Scheme 6. Route to ( )-Cycloclavine
deprotonated pyrrolinone 3 led to a mixture of both isomers 23
and 24 in a 1:1 ratio (as judged by H NMR, isolated yields
26% and 27%). Furthermore, the doubly alkylated compounds
25 and 26 were obtained in 18% and 11% yield, respectively.
The application of KHMDS as an alternative base led to an
identical product distribution.
Lactam 36 was easily reduced to amine 38 by lithium
aluminum hydride, completing the formal total synthesis of
( )-cycloclavine (1) as the final cyclopropanation step has
1
́ ́
previously been reported by Szan tay
tay.11 Since the Szan
group11 had reported low yields for this step (32%, brsm), we
tried to cyclopropanate amide precursor 36 instead of the
free amine. However, treatment of 36 with diazomethane
did not give any conversion to 39 while trimethylsulfoxonium
ylide only led to undesired oxidative side reactions.
Reaction of 36 with diazomethane and several transition
metal catalysts (Pd(OAc)2, Rh2(OAc)4, CuCl, Cu(OTf)2,
[[CH3(CH2)6CO2]2Rh]2) in diethyl ether or dichloromethane
either gave unidentified side products or no conversion, while
Simmons−Smith conditions (ZnEt2, CH2I2, THF or Zn/Cu,
CH2I2, THF) led to the loss of the Boc protecting group.
Application of the aforementioned conditions to the depro-
tected compound resulted in a low conversion (HPLC-MS)
which could not be improved, and reproducibility was low.
The samarium/diiodomethane system, which was demon-
strated to cyclopropanate α,β-unsaturated amides,27 gave the
best results to date, but the reaction rate was very low. The
activation of samarium with mercury(II) chloride resulted in an
improved conversion (HPLC-MS) while the addition of TMS
chloride28 or the use of chromium(II) chloride/diiodo-
methane29 or samarium/iodoform under ultrasonication30
showed no improvement. A gradual increase in the conversion
was observed by addition of the carbene precursor with a
syringe pump and by replacing diiodomethane with chloroiodo-
methane. Higher reaction temperatures also appeared to be
beneficial in terms of conversion although the selectivity was
reduced (HPLC-MS). Nevertheless, an analytically pure sample
of the cyclopropane derivative 39 could not be obtained.
Since this was the most promising result obtained so far, the
4-bromo-compound 31 was prepared from commercially
available 4-bromoindole (27) over four steps in 78% overall
yield (Scheme 6).24,26 Reaction of 31 with deprotonated
pyrrolinone 3 led to a surprisingly high selectivity for the
desired γ-isomer 32. Presumably, the γ-position receives a
higher preference due to the steric demand of the bromine
substituent in the SN2 transition state. From experiments on
larger scales, α-isomer 33 and the doubly alkylated byproduct
34 were identified (yields of 5% and 3%, respectively). The
varying percentages of side products formed are probably due
to minor variations of base equivalents and different batch sizes.
Double bond isomerization on lactam 32 led to the conjugated
isomer 35 and was found to take place under slightly acidic
conditions (coevaporation with CHCl3 containing traces of
HCl). Further transformation of 32 via intramolecular Heck
reaction led to tetracyclic lactam 36 in 74% yield. Notably, the
exomethylene isomer 37 was formed as the major product next
to 36 when palladium(II) acetate/triphenylphosphine with
triethylamine in DMF or toluene was used as the catalytic
system. Addition of silver(I) carbonate led to the desired
selectivity (as reported by Cao)13 in the β-hydride elimination
step. Exomethylene compound 37 was difficult to separate from
36; attempts to isomerize 37 to 36 were unsatisfactory,
although partial isomerization could be achieved (see
Experimental Section).
C
DOI: 10.1021/acs.joc.5b02815
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The Journal of Organic Chemistry
Note
the residue afforded 3 (3.15 g, 79%) as a colorless liquid: bp 60 °C
(0.4 mbar); Rf = 0.09 (cyclohexane/EtOAc, 1:1); IR (ATR) ν (cm−1)
= 2923, 1709, 1670, 1642, 1450, 1400, 1247, 1072, 1021, 976, 814; 1H
NMR (400 MHz, CDCl3) δ (ppm) = δ 6.62 (dq, J = 1.8 Hz, 1H, H-4),
3.81−3.78 (m, 2H, H-5), 3.04−3.00 (m, 3H, NCH3), 1.88 (dd, J = 3.1,
1.8 Hz, 3H, CH3); 13C NMR, COSY, HSQC, HMBC (100.6 MHz,
CDCl3) δ (ppm) = 172.6 (CO), 136.4 (Cq3), 135.0 (C4), 53.0
(C5), 29.8 (NCH3), 11.8 (CH3); FD-MS (C6H9NO): 111.2. The
analytical data are in accordance with the literature.35−37
In summary, a convergent formal total synthesis of
( )-cycloclavine was developed which involves eight steps in
the longest linear sequence. Both key building blocks,
pyrrolinone 3 and 3-(bromomethyl)indole 31, were prepared
from simple, commercially available starting materials. Inter-
mediates 6, 8, and 3 could easily be purified by distillation while
intermediates 28−31 were obtained in high purity and were
used without further purification.
1-(N-Triisopropylsilyl-1H-indol-3-yl)-N,N-dimethylmethana-
mine (11). Gramine (4.75 g, 27.3 mmol) was dissolved in dry THF
(40 mL) under an argon atmosphere and cooled to −78 °C. LDA (2
M in THF/heptane/ethylbenzene; 15 mL, 30 mmol) was added. After
stirring for 30 min at −78 °C, triisopropylsilyl chloride (6.4 mL, 30
mmol) was added. The cooling bath was removed, and the reaction
was stirred overnight. The reaction mixture was quenched with
saturated NaHCO3 solution (100 mL) and extracted with dichloro-
methane (3 × 100 mL). The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated to afford 10.84 g
crude of 11. Thereof 8.89 g were purified by flash column
chromatography (cyclohexane/EtOAc, 3:1 → 1:1 + 1% TEA) to
yield 11 (7.22 g, 98%) as a yellow oil: Rf = 0.51 (cyclohexane/EtOAc,
1:1 + 1% TEA); IR (ATR) ν (cm−1) = 2945, 2866, 1450, 1150, 1137,
EXPERIMENTAL SECTION
■
All reactions involving air- or moisture-sensitive reagents or
intermediates were performed under an inert atmosphere of argon
in oven-dried glassware. All reagents and solvents were obtained from
commercial suppliers and used without further purification, if not
mentioned otherwise. Anhydrous toluene, THF, and diethyl ether
were distilled from sodium/benzophenone under argon. Triethylamine
was distilled from calcium hydride under argon. NMR spectra were
recorded with a 300 MHz (300 MHz H and 75.5 MHz 13C), 400
1
1
MHz (400 MHz H and 100.6 MHz 13C), or 600 MHz spectrometer
1
(600 MHz H and 151 MHz 13C) with digital architecture equipped
with 5 mm probes. The δ values were referenced to the residual
solvent signal (CHCl3, 7.26 ppm).31 IR spectra were recorded using a
diamond ATR. ESI-HRMS spectra were recorded on a Q-TOF
instrument with a dual source and a suitable external calibrant. Thin-
layer chromatography (TLC) was carried out on 0.25 mm silica gel
plates with a fluorescence indicator. Flash chromatography was
performed on 35−70 μm silica gel using the solvent systems indicated.
Allylformamide (6). A protocol of Christensen32 was applied to
yield 6 as a colorless liquid (93%): bp 102 °C (22 mbar) (Lit.33 104−
107 °C, 14 Torr); Rf = 0.10 (CH2Cl2/MeOH, 1:2); IR (ATR) ν
(cm−1) = 3282, 3086, 2872, 1655, 1643, 1532, 1383, 1232, 992, 919,
1
1015, 963, 882, 738, 688, 660, 645; H NMR (300 MHz, CDCl3) δ
(ppm) = 7.70−7.66 (m, 1H, H-7), 7.50−7.45 (m, 1H, H-4), 7.17−
7.09 (m, 3H, H-2, H-5, H-6), 3.63 (s, 2H, CH2), 2.28 (s, 6H, NCH3),
1.70 (h, J = 7.5 Hz, 3H, CH(CH3)2), 1.21 (d, J = 7.5 Hz, 18H,
CH(CH3)2). The analytical data are in accordance with the
literature.38
(N-Triisopropylsilyl-1H-indol-3-yl)-N,N,N-trimethyl-
methanaminium Iodide (12).18 Methyl iodide (0.45 mL, 7.2
mmol) was added to a solution of 11 (1.19 g, 3.60 mmol) in benzene
(20 mL). After 21 h of stirring at rt, diethyl ether was added and the
resulting precipitate was filtered and washed with diethyl ether to yield
12 (1.4 g, 83%) as an off-white solid: mp 178.2−179.4 °C; Rf = 0.38
(CH2Cl2/MeOH, 9:1); IR (ATR) ν (cm−1) = 3455, 2948, 2868, 1469,
1454, 1170, 1154, 960, 882, 749, 691, 659; 1H NMR (400 MHz,
CDCl3) δ (ppm) = 7.89−7.84 (m, 1H, H-4), 7.80 (s, 1H, H-2), 7.53
(dd, J = 5.8, 3.3 Hz, 1H, H-7), 7.21 (dd, J = 6.0, 3.0 Hz, 2H, H-5,6),
5.17 (s, 2H, CH2), 3.43 (s, 9H, N+(CH3)3), 1.73 (sept, J = 7.5 Hz, 3H,
CH(CH3)2), 1.13 (d, J = 7.5 Hz, 18H, CH(CH3)2); 13C NMR, HSQC,
HMBC (100.6 MHz, CDCl3) δ (ppm) = 141.1 (Cq7a), 137.1 (C2),
130.4 (Cq3a), 122.6 (C6), 121.5 (C5), 119.2 (C4), 114.5 (C7), 104.7
(Cq3), 62.2 (CH2), 52.7 (N+(CH3)3), 18.1 (CH(CH3)2), 12.6
(CH(CH3)2).
1
761; H NMR (400 MHz, CDCl3) δ (ppm) = 8.10 (s, 1H, CHO),
7.94 (dd, J = 12.0, 2.2 Hz, 0.14H, CHO), 6.81 (sbr, 1H, NH), 6.44 (sbr,
0.14H, NH), 5.83−5.68 (m, 1.14H, CHCH2), 5.20−5.01 (m, 2.3H,
CH2), 3.80 (t, J = 4.6 Hz, 2H, CH2), 3.78−3.73 (m, 0.3H, CH2);
FD-MS (C4H7NO): 85.2. The analytical data are in accordance with
the literature.33,34
1,3-Dimethyl-1,5-dihydro-2H-pyrrol-2-one (3). Lithium alumi-
num hydride (9.0 g, 0.24 mol) was added to dry diethyl ether (500
mL). A solution of 6 (20.0 g, 0.235 mol) in dry diethyl ether (100 mL)
was slowly added within 30 min. The reaction mixture was heated at
reflux for 1 h. The reaction mixture was cooled to 0 °C and carefully
quenched with (9.0 mL) water, 15% NaOH (9.0 mL), and water (27
mL). The resulting colorless solid was removed by filtration and
thoroughly washed with diethyl ether. To the resulting solution of N-
allyl-N-methylamine in diethyl ether (ca. 700 mL) was added an
aqueous sodium hydroxide solution (17.0 g, 425 mmol in 170 mL).
The reaction mixture was cooled to 0 °C, and methacryloyl chloride
(27 mL, 0.28 mol) was slowly added within 10 min. The mixture was
stirred for 30 min at 0 °C and for 1.5 h at rt. The organic layer was
separated, and the aqueous layer was extracted with diethyl ether (3 ×
50 mL). The combined organic layers were washed with a saturated
NaHCO3 solution and brine and dried over MgSO4. Diethyl ether was
removed by distillation, and further distillation of the residue yielded
N,N-allyl-methyl-2-methacryloylamide (8, 25.71 g, 79%) as a colorless
liquid: bp 60 °C (2.9 mbar); Rf = 0.49 (cyclohexane/EtOAc, 1:2); IR
(ATR) ν (cm−1) = 3083, 2922, 1684, 1647, 1617, 1456, 1396, 1296,
1204, 1088, 991, 914; 1H NMR, COSY (400 MHz, CDCl3) δ (ppm) =
5.75 (ddt, J = 16.1, 10.4, 5.4 Hz, 1H, CHCH2), 5.27−5.10 (m, 3H,
CHCH2, CqCH2A), 5.04 (sbr, 1H, CqCH2B), 3.97 (s, 2H, CH2),
2.93 (s, 3H, NCH3), 1.95 (t, J = 1.4 Hz, 3H, CH); 13C NMR, HSQC,
HMBC (100.6 MHz, CDCl3) δ (ppm) = 172.9, 172.1 (CO), 140.6
(CqCH2), 133.2, 132.6 (CHCH2), 117.3 (CHCH2), 115.4,
114.8 (CqCH2), 53.3, 49.1 (CH2), 35.9, 32.2 (NCH3), 20.6, 20.3
(CH3); FD-MS (C8H13NO): 139.2. Amide 8 (5.0 g, 36 mmol) and
catMETium (9, 340 mg, 0.036 mmol, 1 mol %) were put in a Schlenk
flask, dry and degassed toluene (250 mL) was added, and the reaction
mixture was degassed (three freeze−pump−thaw cycles) and heated at
reflux for 45 min. The solvent was removed in vacuo, and distillation of
3-[(1H-Indol-3-yl)methyl]-1,3-dimethyl-1,3-dihydro-2H-pyr-
rol-2-one (13). Compound 3 (33 mg, 0.30 mmol) was placed in a
Schlenk flask under argon, dissolved in DMF (2 mL), and cooled to 0
°C. Sodium hydride (60% dispersion in mineral oil, 14 mg, 0.35
mmol) was added under an argon counter flow. After stirring at 0 °C
for 30 min, a 1 M solution of TBAF in THF (0.35 mL, 0.35 mmol)
and a solution of 12 (140 mg, 0.30 mmol) in DMF (1.1 mL) were
simultaneously added within 5 min. After stirring at 0 °C for 5 min the
cooling bath was removed and the reaction mixture was stirred for 2.5
h at rt. The mixture was quenched with water and extracted with ethyl
acetate. The organic layer was washed with brine, dried over MgSO4,
and concentrated in vacuo. Purification by flash column chromatog-
raphy (cyclohexane/EtOAc, 2:1 + 0.5% TEA) yielded 13 (28 mg,
40%) as a colorless oil: Rf = 0.21 (cyclohexane/EtOAc, 1:1); IR (ATR)
ν (cm−1) = 3265, 2960, 2927, 1673, 1454, 1395, 1332, 1248, 1231,
1
1055, 743; H NMR, COSY (400 MHz, CDCl3) δ (ppm) = 8.12 (s,
1H, NH), 7.60−7.57 (m, 1H, H-4′), 7.33 (app.-dt, J = 8.1, 1.0 Hz, 1H,
H-7′), 7.19−7.14 (m, 1H, H-6′), 7.10 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H, H-
5′), 7.00 (d, J = 2.4 Hz, 1H, H-2′), 6.16 (d, J = 4.9 Hz, 1H, H-5), 5.32
(d, J = 4.9 Hz, 1H, H-4), 3.00 (AB-system, Japp = 14.1 Hz, 2H, CH2),
2.95 (s, 3H, NCH3), 1.24 (s, 3H, CH3); 13C NMR, HSQC, HMBC
(100.6 MHz, CDCl3) δ (ppm) = 182.7 (CO), 136.0 (Cq7′a), 131.2
(C5), 128.3 (Cq3′a), 123.4 (C2′), 121.8 (C6′), 119.5 (C4′), 119.3
(C5′), 116.4 (C4), 111.9 (Cq3′), 111.1 (C7′), 51.9 (Cq3), 32.6 (CH2),
D
DOI: 10.1021/acs.joc.5b02815
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The Journal of Organic Chemistry
Note
29.0 (NCH3), 21.8 (CH3); ESI-HRMS calcd for [C15H16N2O + Na]+
263.1160, found 263.1161.
1H-Indole-3-carbaldehyde (19). The title compound was
prepared from 1H-indole according to the protocol of Cuny.23 Light
brown solid: mp 193.9−196.2 °C (Lit.40 196−197 °C); Rf = 0.49
(CH2Cl2/MeOH, 9:1); IR (ATR) ν (cm−1) = 3166, 1631, 1613, 1576,
Gramine Methiodide (15). The title compound was prepared in
89% yield from gramine (10) according to the protocol of Lown and
Weir.39 Colorless solid: mp 157.6−157.9 °C (Lit.39 168−170 °C); IR
(ATR) ν (cm−1) = 3208, 1483, 1460, 1428, 1416, 1342, 1104, 979,
873, 750, 674, 619; 1H NMR (400 MHz, DMSO) δ (ppm) = 11.64 (s,
1H, NH), 7.83 (d, J = 7.7 Hz, 1H, H-7), 7.69 (d, J = 2.5 Hz, 1H, H-2),
7.48 (d, J = 7.9 Hz, 1H, H-4), 7.20−7.11 (m, 2H, H-5,6), 4.69 (s, 2H,
CH2), 3.04 (s, 9H, N+(CH3)3). The analytical data are in accordance
with the literature.39
1
1520, 1443, 1393, 1243, 1124, 787, 759, 640; H NMR (400 MHz,
CDCl3) δ (ppm) = 9.91 (s, 1H, CHO), 8.14 (s, 1H), 8.12 (s, 1H),
8.09 (dd, J = 6.9, 1.5 Hz, 1H, H-7), 7.47 (dd, J = 7.5, 1.4 Hz, 1H, H-4),
7.23−7.15 (m, 2H, H-5,6). The analytical data are in accordance with
the literature.41
tert-Butyl 3-Formyl-1H-indole-1-carboxylate (20). The title
compound was prepared from 19 according to the protocol of
Pelcman24 (quantitative yield). Off-white solid: mp 123.4−124.8 °C
(decomposition) (Lit.42 121−123 °C); Rf = 0.34 (cyclohexane/EtOAc,
2:1); IR (ATR) ν (cm−1) = 2980, 2816, 1743, 1679, 1398, 1359, 1242,
1155, 1134, 1102, 760, 751; 1H NMR (400 MHz, CDCl3) δ (ppm) =
10.10 (s, 1H, CHO), 8.29 (dd, J = 7.0, 1.3 Hz, 1H, H-7), 8.24 (s, 1H,
H-2), 8.15 (d, J = 8.0 Hz, 1H, H-4), 7.42 (ddd, J = 8.3, 7.8, 1.6 Hz,
1H), 7.37 (app.-td, J = 7.5, 1.3 Hz, 1H), 1.71 (s, 9H, Boc). The
analytical data are in accordance with the literature.43
5-[(1H-Indol-3-yl)methyl]-1,3-dimethyl-1,5-dihydro-2H-pyr-
rol-2-one (16). Following the protocol of Danishefsky and Kitahara19
1
3 was transformed into crude 14: H NMR (400 MHz, CDCl3) δ
(ppm) = 6.09 (d, J = 3.2 Hz, 1H), 5.77 (d, J = 3.2 Hz, 1H), 3.34 (s,
3H, NCH3), 1.91 (s, 3H, CH3), 0.24 (s, 9H, Si(CH3)3). Since the
TMS ether 14 showed high moisture sensitivity it was not purified, but
the crude product was immediately subjected to the subsequent
transformation. Gramine (222 mg, 1.27 mmol) and triphenylphos-
phine (134 mg, 0.511 mmol) were placed in a microwave reaction
vessel (10 mL volume) under an argon atmosphere and dissolved in
MeCN (2 mL). A solution of silyl enol ether 14 (crude, from 140 mg
of 3, 1.26 mmol) in MeCN (0.9 mL) was added, and the tube was put
in the microwave at 140 °C and 300 W for 2 × 1 h. Dichloromethane
and saturated NaHCO3 solution were added. The organic layer was
washed with NaHCO3 solution and brine and dried over MgSO4. The
crude product contained 3 as well as the α- and γ-substitution product
(ratio 3:0.4:1.6). Purification of the mixture by flash column
chromatography (cyclohexane/EtOAc, 1:1 + 1% TEA) yielded the
title compound (50 mg, 17%) as a light yellow oil: Rf = 0.10
(cyclohexane/EtOAc, 1:1); IR (ATR) ν (cm−1) = 3273, 2922, 1668,
1642, 1457, 1436, 1402, 1342, 1236, 1102, 1070, 745; 1H NMR,
COSY (400 MHz, CDCl3) δ (ppm) = 8.55 (s, 1H, NH), 7.54 (d, J =
8.1 Hz, 1H, H-7′), 7.38 (d, J = 8.1 Hz, 1H, H-4′), 7.26−7.16 (m, 1H,
H-6′), 7.14 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H, H-5′), 7.00 (d, J = 2.3 Hz,
1H, H-2′), 6.58 (dq, J = 1.8 Hz, 1H, H-4), 4.15 (ddt, J = 9.0, 4.5, 1.8
Hz, 1H, H-5), 3.36 (dd, J = 14.2, 4.5 Hz, 1H, CH2A), 3.07 (s, 3H,
NCH3), 2.74 (dd, J = 14.2, 9.0 Hz, 1H, CH2B), 1.83 (t, J = 1.8 Hz, 3H,
CH3); 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) =
172.3 (CO), 140.7 (C4), 136.3 (Cq7a′), 135.0 (Cq3), 127.5 (Cq3a′),
122.7 (C2′), 122.2 (C6′), 119.6 (C5′), 118.5 (C4′), 111.5 (C7′), 110.5
(Cq3′), 63.0 (C5), 27.7 (NCH3), 27.2 (CH2), 11.4 (CH3); ESI-HRMS
calcd for [C15H16N2O + Na]+ 263.1160, found 263.1172.
N-Methyl-3-methyl-5-(3-methinyl-indolyl)-pyrrolidin-2-one
(17). Gramine (42 mg, 0.24 mmol) and triphenylphosphine (25 mg,
0.095 mmol) were placed in a microwave reaction vessel (10 mL
volume) under an argon atmosphere and dissolved in acetonitrile (1
mL). A solution of silyl enol ether 14 (crude, from 25 mg of 3, 0.22
mmol) in acetonitrile (0.5 mL) was added, and the tube was put in the
microwave at 140 °C and 300 W for 1 h. Dichloromethane and
saturated NaHCO3 solution were added. The organic layer was
washed with NaHCO3 solution and brine and dried over MgSO4. The
solvent was removed in vacuo to yield a crude product (101 mg, yellow
oil) which contained 3 as well as rearranged γ-product 17, together
with traces of the α- and γ-substitution product. Purification by flash
column chromatography (cyclohexane/EtOAc, 2:1) yielded the title
compound (9.0 mg, 17%) as a yellow oil: Rf = 0.24 (cyclohexane/
EtOAc, 1:1); IR (ATR) ν (cm−1) = 3272, 2967, 2928, 1698, 1650,
1457, 1429, 1327, 1227, 1011, 740, 697; 1H NMR, COSY (400 MHz,
CDCl3) δ (ppm) = 8.23 (sbr, 1H, NH), 7.70−7.66 (m, 1H, H-4′), 7.39
(app.-dt, J = 8.1, 0.9 Hz, 1H, H-7′), 7.27−7.20 (m, 1H, H-6′), 7.17
(ddd, J = 8.0, 6.9, 1.1 Hz, 1H, H-5′), 7.10 (d, J = 2.5 Hz, 1H, H-2′),
5.96 (t, J = 2.3 Hz, 1H, = CH), 3.21−2.12 (m, 1H, CH2A), 3.15 (s, 3H,
NCH3), 2.79−2.69 (m, 1H, H-3), 2.50 (ddd, J = 16.5, 5.8, 2.3 Hz, 1H,
CH2B), 1.32 (d, J = 7.3 Hz, 3H, CH3); 13C NMR, HSQC, HMBC
(100.6 MHz, CDCl3) δ (ppm) = 178.3 (CO), 139.6 (Cq5), 135.7
(Cq7a′), 127.2 (Cq3a′), 122.7 (C6′), 120.1 (C2′), 119.8 (C5′), 118.8
(C4′), 113.0 (Cq3′), 111.2 (C7′), 92.8 (CH), 35.5 (C3), 33.1 (C4),
27.1 (NCH3), 17.5 (CH3); ESI-HRMS calcd for [C15H16N2O + Na]+
263.1160, found 263.1159.
tert-Butyl 3-(Hydroxymethyl)-1H-indole-1-carboxylate (21).
The title compound was prepared from 20 according to the protocol
of Pelcman24 (quantitative yield). Light brown oil: Rf = 0.60
(cyclohexane/EtOAc, 1:1); IR (ATR) ν (cm−1) = 3377, 2979, 1733,
1
1453, 1369, 1308, 1269, 1257, 1159, 1088, 767, 746; H NMR (400
MHz, CDCl3) δ (ppm) = 8.14 (d, J = 7.8 Hz, 1H, H-7), 7.65 (ddd, J =
7.8, 1.2, 0.8 Hz, 1H), 7.58 (s, 1H, H-2), 7.34 (ddd, J = 8.5, 7.2, 1.2 Hz,
1H), 7.28−7.24 (m, 1H), 4.84 (d, J = 0.8 Hz, 2H, CH2), 1.67 (s, 9H,
Boc). The analytical data are in accordance with the literature.43
tert-Butyl 3-(Bromomethyl)-1H-indole-1-carboxylate (22).
The title compound was synthesized from 21 by a modification of
the protocol of Schollkopf.25 Triphenylphosphine (3.21 g, 12.2 mmol)
̈
was dissolved in cyclohexane (90 mL), and bromine (0.67 mL, 13
mmol) was slowly added. After stirring for 15 min, 21 (3.03 g, 12.3
mmol) was added, and the reaction mixture was stirred overnight.
Filtration over Celite and concentration of the filtrate yielded 22 (3.43
g, 91%) as a light yellow solid: mp 116.0−116.3 °C (decomposition)
(Lit.44 106−107 °C); Rf = 0.56 (cyclohexane/EtOAc, 2:1); IR (ATR)
ν (cm−1) = 2979, 1735, 1453, 1366, 1271, 1258, 1205, 1154, 1114,
1083, 764, 746; 1H NMR (400 MHz, CDCl3) δ (ppm) = 8.16 (d, J =
8.1 Hz, 1H, H-7), 7.71−7.68 (m, 2H), 7.41−7.30 (m, 2H), 4.69 (s,
2H, CH2), 1.68 (s, 9H, Boc). The analytical data are in accordance
with the literature.44
Alkylation of Pyrrolinone 3 with 3-Bromomethylindole 22.
In a Schlenk flask, compound 3 (38 mg, 0.34 mmol) was dissolved in
DMF (2 mL) under an argon atmosphere and cooled to 0 °C. Sodium
hydride (60% dispersion in mineral oil, 14 mg, 0.35 mmol) was added
under an argon counter flow. After stirring at 0 °C, a solution of 22
(100 mg, 0.322 mmol) in DMF (1 mL) was added. After 15 min, the
cooling bath was removed, and the reaction mixture was left to stir at
ambient temperature for 21 h. The reaction mixture was quenched
with water and extracted with ethyl acetate. The organic layers were
thoroughly washed with brine, dried over MgSO4, and concentrated in
vacuo to afford the crude product (101 mg) as a light yellow oil, from
which the γ-substitution product 23 (28 mg, 26%), the α-substitution
product 24 (29 mg, 27%), and compounds 25 (13 mg, 18%) and 26
(8 mg, 11%) were isolated by repeated flash chromatography (vide
infra).
tert-Butyl 3-[(1,4-Dimethyl-5-oxo-2,5-dihydro-1H-pyrrol-2-
yl)methyl]-1H-indole-1-carboxylate (23). Purification by flash
column chromatography (cyclohexane/EtOAc, 3:1 + 1% TEA) yielded
the title compound as a colorless oil (28 mg, 26%): Rf = 0.22
(cyclohexane/EtOAc, 1:1); IR (ATR) ν (cm−1) = 2978, 2928, 1730,
1
1683, 1453, 1369, 1256, 1156, 1085, 768, 746; H NMR, COSY (400
MHz, CDCl3) δ (ppm) = 8.14 (d, J = 8.2 Hz, 1H, H-7), 7.48−7.45 (m,
1H, H-4), 7.43 (sbr, 1H, H-2), 7.34 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H, H-6),
7.29−7.24 (m, 1H, H-5), 6.58 (dq, J = 1.7 Hz, 1H, H-4′), 4.17−4.11
(m, 1H, H-5′), 3.29 (ddd, J = 14.3, 4.9, 1.0 Hz, 1H, CH2A), 3.06 (s,
3H, NCH3), 2.63 (ddd, J = 14.3, 9.7, 0.7 Hz, 1H, CH2B), 1.86 (t, J =
1.7 Hz, 3H, CH3), 1.68 (s, 9H, Boc); 13C NMR, HSQC, HMBC
(100.6 MHz, CDCl3) δ (ppm) = 172.0 (CO), 149.7 (COOtBu),
E
DOI: 10.1021/acs.joc.5b02815
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
140.0 (C4′), 135.5 (2C: Cq8, Cq3′), 130.4 (Cq3a), 124.8 (C6), 123.9
(C2), 122.8 (C5), 118.8 (C4), 115.6 (C7), 115.5 (Cq3), 84.0
(C(CH3)3), 62.2 (C5′), 28.4 (C(CH3)3), 27.7 (NCH3), 27.2 (CH2),
11.4 (CH3); ESI-HRMS calcd for [C20H24N2O3 + H]+ 341.1865,
found 341.1870.
tert-Butyl 3-[(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-pyrrol-3-
yl)methyl]-1H-indole-1-carboxylate (24). Purification by flash
column chromatography (cyclohexane/EtOAc, 10:1 + 1% TEA)
yielded the side product 24 as a colorless oil (29 mg, 27%): Rf = 0.26
(cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1) = 2962, 2926, 2854,
1731, 1703, 1453, 1369, 1258, 1158, 1078, 767, 747; 1H NMR, COSY
(400 MHz, CDCl3) δ (ppm) = 8.09 (d, J = 7.5 Hz, 1H, H-7), 7.52
(ddd, J = 7.7, 1.2, 0.7 Hz, 1H, H-4), 7.35 (s, 1H, H-2), 7.31−7.25 (m,
1H, H-6), 7.24−7.19 (m, 1H, H-5), 6.21 (d, J = 4.9 Hz, 1H, H-5′),
5.29 (d, J = 4.9 Hz, 1H, H-4′), 2.97 (s, 3H, NCH3), 2.93 (AB-system,
Japp = 14.2, 0.9 Hz, 2H, CH2), 1.66 (s, 9H, Boc), 1.25 (s, 3H, CH3);
13C NMR, HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 182.3
Hz, 1H, H-5). The analytical data are in accordance with the
literature.26,45
tert-Butyl 4-Bromo-3-formyl-1H-indole-1-carboxylate (29).
The title compound was prepared from 28 in quantitative yield
according to the protocol of Pelcman.24 Off-white solid: mp 118.0−
118.6 °C (Lit.46 117−119 °C); Rf = 0.51 (cyclohexane/EtOAc, 2:1);
IR (ATR) ν (cm−1) = 2980, 1747, 1672, 1529, 1424, 1364, 1252, 1139,
1
1090, 1017, 854, 777, 735; H NMR (400 MHz, CDCl3) δ (ppm) =
10.93 (s, 1H, CHO), 8.36 (s, 1H, H-2), 8.25 (dd, J = 8.4, 0.7 Hz, 1H,
H-7), 7.52 (dd, J = 7.8, 0.7 Hz, 1H, H-5), 7.22 (app.-t, J = 8.1 Hz, 1H,
H-6), 1.68 (s, 9H, Boc); 13C NMR, COSY, HSQC, HMBC (100.6
MHz, CDCl3) δ (ppm) = 186.9 (CHO), 148.4 (CO), 137.3 (Cq7a),
132.0 (C2), 128.6 (C5), 126.9 (Cq3a), 126.1 (C6), 121.1 (Cq3), 114.9
(C7), 113.5 (Cq4), 86.2 (C(CH3)3), 28.1 (3 × CH3). Anal. Calcd for
C14H14BrNO3: C, 51.87; H, 4.35; N, 4.32. Found: C, 51.76; H, 4.50;
N, 4.43. The analytical data are in accordance with the literature.46
tert-Butyl 4-Bromo-3-(hydroxymethyl)-1H-indole-1-carbox-
ylate (30). The title compound was prepared from 29 in 92% yield
according to a protocol by Pelcman.24 Off-white solid: mp 107.5−
108.7 °C; Rf = 0.22 (cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1) =
3372, 2979, 2933, 1732, 1421, 1367, 1278, 1253, 1152, 1095, 772, 736;
1H NMR, COSY (400 MHz, CDCl3) δ (ppm) = 8.17 (d, J = 8.3 Hz,
(CO), 149.9 (COOtBu), 135.2 (C7a), 131.67 (C5′), 131.31 (Cq3a),
124.4 (C2), 124.2 (C6), 122.4 (C5), 119.7 (C4), 116.6 (Cq3), 115.7
(C4′), 115.1 (C7), 83.7 (C(CH3)3), 51.0 (Cq3′), 32.2 (CH2), 29.1
(NCH3), 28.4 (C(CH3)3), 22.0 (CH3); ESI-HRMS calcd for
[C20H24N2O3 + Na]+ 363.1685, found 363.1694.
1H, H-7), 7.64 (s, 1H, H-2), 7.38 (dd, J = 7.8, 0.8 Hz, 1H, H-5), 7.15
tert-Butyl 3-[(4-{[1-(tert-Butoxycarbonyl)-1H-indol-3-yl]-
methyl}-1,4-dimethyl-5-oxopyrrolidin-2-ylidene)methyl]-1H-
indole-1-carboxylate (25). Purification by flash column chromatog-
raphy (cyclohexane/EtOAc, 10:1 + 1% TEA) yielded the side product
25 as a colorless oil (13 mg, 18%): Rf = 0.41 (cyclohexane/EtOAc,
2:1); IR (ATR) ν (cm−1) = 2976, 2930, 1724, 1656, 1453, 1369, 1255,
1154, 1081, 762, 745; 1H NMR, COSY (400 MHz, CDCl3) δ (ppm) =
8.13−8.01 (m, 2H, H-7/7″), 7.52−7.49 (m, 1H, H-4), 7.46 (ddd, J =
7.8, 1.2, 0.7 Hz, 1H, H-4″), 7.35−7.27 (m, 3H, H-2/2″, H-6″), 7.25−
7.20 (m, 2H, H-6, H-5″), 7.12 (ddd, J = 8.2, 7.3, 1.2 Hz, 1H, H-5),
5.59 (s, 1H, = CH), 3.15−3.10 (m, 1H, CH2A), 3.02 (dd, J = 16.3, 1.9
Hz, 1H, H-3A), 2.95 (s, 3H, NCH3), 2.85 (d, J = 14.5 Hz, 1H, CH2B),
2.62 (dd, J = 16.3, 1.9 Hz, 1H, H-3B), 1.68 (s, 9H, Boc), 1.53 (s, 9H,
Boc), 1.39 (s, 3H, CH3); 13C NMR, HSQC, HMBC (100.6 MHz,
CDCl3) δ (ppm) = 179.8 (CO), 150.0, 149.6 (2 × COOtBu), 141.6
(Cq2′), 135.3, 134.8 (Cq7a, Cq7a″), 131.1 (Cq3a), 130.5 (Cq3a″), 124.8
(C6″), 124.4 (2C, C6, C2″), 122.7 (C5″), 122.5 (C5), 120.7 (C2),
119.3 (C4), 118.8 (C4″), 116.8 (Cq3a), 116.1 (Cq3a″), 115.3 (C7″),
115.2 (C7), 91.1 (CH), 83.9, 83.5 (2 × C(CH3)3), 44.9 (Cq4′), 37.6
(C3′), 33.5 (CH2), 28.4, 28.2 (2 × C(CH3)3), 27.1 (NCH3), 24.9
(CH3); ESI-HRMS calcd for [C34H39N3O5 + Na]+ 592.2787, found
592.2773.
5,5-Bis[(1-tert-butyloxycarbonyl-1H-indol-3-yl)methylene]-
1,3-dimethyl-1,5-dihydro-2H-pyrrol-2-one (26). Purification by
flash column chromatography (cyclohexane/EtOAc, 3:1 + 1% TEA)
yielded the side product 26 as a colorless oil (8 mg, 11%): Rf = 0.38
(cyclohexane/EtOAc, 1:1); IR (ATR) ν (cm−1) = 2978, 2927, 1732,
1682, 1453, 1369, 1309, 1257, 1157, 1086, 768, 746; 1H NMR, COSY
(400 MHz, CDCl3) δ (ppm) = 8.09 (d, J = 7.3 Hz, 2H, H-7), 7.37
(ddd, J = 7.8, 1.2, 0.7 Hz, 2H, H-4), 7.33−7.27 (m, 4H, H-2, H-6),
7.24−7.19 (m, 2H, H-5), 6.59 (q, J = 1.6 Hz, 1H, H-2′), 3.27 (dd, J =
14.6, 1.0 Hz, 2H, CH2A), 3.08−3.03 (m, 2H, CH2B), 3.00 (s, 3H,
NCH3), 1.66 (s, 18H, 2 × Boc), 1.65 (d, J = 1.6 Hz, 3H, CH3); 13C
NMR, HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 171.5
(CO), 149.7 (COOtBu), 143.7 (C3′), 135.2 (2C, Cq4′, Cq7a), 130.9
(Cq3a), 124.6, 124.5 (C2, C6), 122.6 (C5), 118.9 (C4), 115.5 (C7),
114.4 (Cq3), 84.0 (C(CH3)3), 68.2 (Cq2′), 31.2 (2 × CH2), 28.4
(C(CH3)3), 25.0 (NCH3), 10.9 (CH3); ESI-HRMS calcd for
[C34H39N3O5 + Na]+ 592.2787, found 592.2786.
(app.-t, J = 8.1 Hz, 1H, H-6), 4.96 (s, 2H, CH2), 1.65 (s, 9H, Boc); 13
C
NMR, HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 149.2
(CO), 137.4 (Cq7a), 128.0 (Cq3a), 126.9 (C5), 126.0 (C2), 125.5
(C6), 120.7 (Cq3), 114.7 (C7), 113.5 (Cq4), 84.4 (C(CH3)3), 57.3
(CH2), 28.2 (3 × CH3); ESI-HRMS calcd for [C14H1679BrNO3 + Na]+
348.0211, found 348.0210. Anal. Calcd for C14H16BrNO3: C, 51.55; H,
4.94; N, 4.29. Found: C, 51.82; H, 4.74; N, 4.32.
tert-Butyl 4-Bromo-3-[(1,4-dimethyl-5-oxo-2,5-dihydro-1H-
pyrrol-2-yl)methyl]-1H-indole-1-carboxylate (32). Triphenyl-
phosphine (3.35 g, 12.8 mmol) was dissolved in cyclohexane (100
mL), and bromine (0.68 mL, 13 mmol) was slowly added. After
stirring for 15 min, 30 (4.11 g, 12.6 mmol) was added, and the
reaction mixture was stirred overnight. Filtration over Celite and
concentration of the filtrate in vacuo yielded tert-butyl 4-bromo-3-
(bromomethyl)-1H-indole-1-carboxylate (31) (4.53 g, 93%) as a light
red oil: Rf = 0.38 (cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1) =
2979, 2933, 1740, 1420, 1370, 1354, 1295, 1256, 1158, 1123, 1091,
744; 1H NMR, COSY (400 MHz, CDCl3) δ (ppm) = 8.18 (d, J = 8.3
Hz, 1H, H-7), 7.74 (s, 1H, H-2), 7.44 (dd, J = 7.8, 0.8 Hz, 1H, H-5),
7.18 (app.-t, J = 8.1 Hz, 1H, H-6), 4.94 (d, J = 0.5 Hz, 2H, CH2), 1.66
(s, 9H, Boc); 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3) δ
(ppm) = 148.7 (CO), 137.0 (Cq7a), 127.8 (C2), 127.7 (C5), 126.6
(Cq3a), 125.9 (C6), 117.8 (Cq3), 114.7 (C7), 113.9 (Cq4), 84.8
(C(CH3)3), 28.2 (3 × CH3), 25.8 (CH2); FD-MS (C14H15Br2NO2):
389.0. Pyrrolinone 3 (159 mg, 1.43 mmol) was placed in a Schlenk
flask under argon, dissolved in DMF (6 mL), and cooled to 0 °C.
Sodium hydride (60% dispersion in mineral oil, 56 mg, 1.4 mmol) was
added under an argon counter flow. After stirring at 0 °C for 30 min, a
solution of bromide 31 (500 mg, 1.29 mmol) in DMF (4 mL) was
added. After 10 min, the cooling bath was removed and the reaction
mixture was left to stir at ambient temperature for 1 h. The reaction
mixture was quenched with water and extracted with ethyl acetate. The
organic layers were thoroughly washed with brine, dried over MgSO4,
and concentrated in vacuo. Purification by flash column chromatog-
raphy (cyclohexane/EtOAc, 9:1 + 1% TEA) yielded 32 (276 mg, 52%)
as a light yellow oil; Rf = 0.19 (cyclohexane/EtOAc, 1:1); IR (ATR) ν
(cm−1) = 2980, 2927, 1736, 1687, 1421, 1370, 1278, 1256, 1148, 1094,
1
846, 776, 732. H NMR, COSY (400 MHz, CDCl3) δ (ppm) = 8.19
(d, J = 8.3 Hz, 1H, H-7), 7.44 (s, 1H, H-2), 7.41 (dd, J = 7.8, 0.8 Hz,
1H, H-5), 7.16 (app.-t, J = 8.1 Hz, 1H, H-6), 6.63 (dq, J = 1.7 Hz, 1H,
H-4′), 4.41−4.22 (m, 1H, H-5′), 3.78 (dd, J = 13.8, 4.5 Hz, 1H,
CH2A), 3.08 (s, 3H, N−CH3), 2.58 (dd, J = 13.8, 10.3 Hz, 1H, CH2A),
1.89 (t, J = 1.7 Hz, 3H, CH3), 1.68 (s, 9H, Boc); 13C NMR, HSQC,
HMBC (100.6 MHz, CDCl3) δ (ppm) = 172.0 (CO), 149.1
(COOtBu), 139.8 (C4′), 137.1 (Cq7a), 135.4 (Cq3′), 128.1 (Cq3a),
127.5 (C5), 126.4 (C2), 125.6 (C6), 116.1 (Cq3), 114.8 (C7), 113.9
(Cq4), 84.7 (C(CH3)3), 62.5 (C5′), 28.4 (CH2), 28.3 (C(CH3)3), 27.8
4-Bromo-1H-indole-3-carbaldehyde (28). The title compound
was prepared from 27 in 91% yield according to the protocol of
Dixon.26 Off-white solid: mp 178.4−182.2 °C (MeOH/H2O) (Lit.45
185−187 °C); Rf = 0.18 (cyclohexane/EtOAc, 2:1); IR (ATR) ν
(cm−1) = 3212, 3170, 2936, 2872, 1639, 1512, 1487, 1388, 1333, 1295,
1190, 775, 735; 1H NMR (400 MHz, CDCl3) δ (ppm) = 10.93 (s, 1H,
CHO), 9.20 (s, 1H, NH), 8.11 (d, J = 3.2 Hz, 1H, H-2), 7.51 (dd, J =
7.7, 0.8 Hz, 1H), 7.45 (dd, J = 8.2, 0.8 Hz, 1H), 7.15 (app.-t, J = 7.9
F
DOI: 10.1021/acs.joc.5b02815
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(NCH3), 11.5 (CH3). ESI-HRMS calcd for [C20H23N2O379Br + H]+
419.0970, found 419.0971. tert-Butyl 4-bromo-3-[(E)-(1,4-dimethyl-5-
oxopyrrolidin-2-ylidene)methyl]-1H-indole-1-carboxylate (35) was
obtained by rearrangement of compound 32 during coevaporation
(Cq5a), 84.1 (C(CH3)3), 60.9 (C6a), 28.3 (C(CH3)3), 27.5 (NCH3),
26.7 (C6), 10.1 (CH3); ESI-HRMS calcd for [C20H22N2O3 + Na]+
361.1528, found 361.1526.
tert-Butyl 7-Methyl-9-methylidene-8-oxo-6,6a,7,8,9,9a-
hexahydro-4H-indolo[6,5,4-cd]indole-4-carboxylate (37).
Palladium(II) acetate (1.3 mg, 5.8 μmol, 12 mol %) and
triphenylphosphine (2.6 mg, 9.9 μmol, 21 mol %) were placed in a
Schlenk flask under an argon atmosphere. A solution of bromoarene
32 (20 mg, 0.048 mmol) in dry dimethylformamide (0.3 mL) and dry
triethylamine (50 μL) were added. The medium was degassed (four
freeze−pump−thaw cycles) and then heated to 100 °C (oil bath) for 7
h to yield 37 and 36 in a 1:0.15 ratio (1H NMR). Purification by
repeated column chromatography (cyclohexane/EtOAc, 3:1) yielded
an analytically pure sample. Orange oil, Rf = 0.17 (cyclohexane/
EtOAc, 1:1); IR (ATR) ν (cm−1) = 2928, 1728, 1692, 1441, 1392,
1349, 1301, 1258, 1149, 1117, 757, 732; 1H NMR (600 MHz, CDCl3)
δ (ppm) = 7.86 (sbr, 1H, H-3), 7.38−7.31 (m, 2H, H-2, H-5), 7.18 (d,
J = 7.4 Hz, 1H, H-1), 6.06 (d, J = 2.8 Hz, 1H, CH2A), 5.34 (d, J =
2.8 Hz, 1H, CH2B), 4.27 (dt, J = 6.3, 2.8 Hz, 1H, H-9a), 4.02 (ddd, J
= 8.8, 6.3, 5.6 Hz, 1H, H-6a), 3.34 (ddd, J = 15.8, 5.6, 1.0 Hz, 1H, H-
6A), 3.05 (s, 3H, NCH3), 2.58 (ddd, J = 15.8, 8.8, 1.9 Hz, 1H, H-6B),
1.67 (s, 9H, Boc); 13C NMR, COSY, HSQC, HMBC (151 MHz,
CDCl3) δ (ppm) = 168.0 (CO), 142.1 (Cq9), 133.7 (Cq3a,
resonance located by HBMC), 128.2 (Cq9c), 127.3 (Cq9b), 125.6
(C2), 121.6 (C1), 120.2 (C5), 116.1 (CH2), 113.9 (C3), 113.4
(Cq5a), 83.8 (C(CH3)3), 57.4 (C6a), 41.5 (C9a), 28.4 (NCH3), 28.3
(C(CH3)3), 24.6 (C6); the resonance of COOtBu could not be found;
ESI-HRMS calcd for [C20H22N2O3 + H]+ 339.1709, found 339.1703.
Partial isomerization to 36 occurred by treatment with toluene/
triethylamine (1:1) at 110 °C or with palladium(II) acetate in toluene
at 110 °C.
1
with CHCl3 containing traces of acid. H NMR, COSY (400 MHz,
CDCl3) δ (ppm) = 8.14 (dbr, J = 8.1 Hz, 1H, H-7), 7.47 (sbr, 1H, H-2),
7.40 (d, J = 7.7 Hz, 1H, H-5), 7.13 (app.-t, J = 8.1 Hz, 1H, H-6), 6.50
(sbr, 1H, CH), 3.17−3.05 (m, 1H, CH2A), 3.12 (s, 3H, NCH3),
2.75−2.64 (m, 1H, H-3′), 2.45 (ddd, J = 16.5, 6.0, 2.0 Hz, 1H, CH2B),
1.68 (s, 9H, Boc), 1.29 (d, J = 7.3 Hz, 3H, CH3); 13C NMR, HSQC,
HMBC (100.6 MHz, CDCl3) δ (ppm) = 178.4 (CO), 149.3
(COOtBu), 141.4 (Cq5′), 136.5 (Cq7a), 128.2 (Cq3a), 127.7 (C5),
125.4 (C6), 123.4 (C2), 117.2 (Cq3), 114.7 (C7), 114.6 (Cq4), 93.6
(CH), 84.6 (C(CH3)3), 35.3 (C3′), 32.6 (CH2), 28.3 (C(CH3)3),
27.1 (NCH3), 17.2 (CH3).
tert-Butyl 4-Bromo-3-[(1,3-dimethyl-2-oxo-2,3-dihydro-1H-
pyrrol-3-yl)methyl]-1H-indole-1-carboxylate (33). The title
compound was obtained as a side product of the reaction of 32 and
3 (7.2 mmol scale) as a colorless solid (160 mg, 5%): mp 121.7−126.2
°C; Rf = 0.31 (cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1) = 2977,
1734, 1694, 1419, 1369, 1356, 1276, 1255, 1157, 1088, 1055, 730; 1H
NMR, COSY (400 MHz, CDCl3) δ (ppm) = 8.15 (d, J = 8.2 Hz, 1H,
H-7), 7.35 (dd, J = 7.8, 0.9 Hz, 1H, H-5), 7.31 (s, 1H, H-2), 7.08 (app.-
t, J = 8.1 Hz, 1H, H-6), 6.07 (d, J = 4.9 Hz, 1H, H-5′), 5.54 (d, J = 4.9
Hz, 1H, H-4′), 3.71 (d, J = 14.6 Hz, 1H, CH2A), 3.10 (d, J = 14.6 Hz,
1H, CH2B), 2.95 (s, 3H, N−CH3), 1.63 (s, 9H, Boc), 1.31 (s, 3H,
CH3); 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) =
182.4 (CO), 149.14 (COOtBu), 136.7 (Cq7a), 131.6 (C5′), 128.7
(Cq3a), 127.7 (C5), 125.7 (C2), 124.8 (C6), 117.0 (C3), 115.1 (C4′),
114.5 (C7), 114.2 (Cq4), 84.1 (C(CH3)3), 51.8 (Cq3′), 32.0 (CH2),
28.9 (NCH3), 28.3 (C(CH3)3), 22.56 (CH3); ESI-HRMS calcd for
[C20H2379BrN2O3 + H]+ 419.0970, found 419.0980.
5,5-Bis[(4-bromo-1-tert-butyloxycarbonyl-1H-indol-3-yl)-
methylene]-1,3-dimethyl-1,5-dihydro-2H-pyrrol-2-one (34).
The title compound was obtained as a side product of the reaction
of 32 and 3 (7.9 mmol scale) as a colorless oil (180 mg, 3%): Rf = 0.15
(cyclohexane/EtOAc, 2:1); IR (ATR) ν (cm−1) = 2979, 2931, 1738,
1687, 1421, 1370, 1278, 1256, 1156, 1098, 1056, 733; 1H NMR,
COSY (400 MHz, CDCl3) δ (ppm) = 8.15 (d, J = 8.3 Hz, 2H, H-7′),
7.35 (dd, J = 7.8, 0.8 Hz, 2H, H-5′), 7.28 (s, 2H, H-2′), 7.09 (app.-t, J
= 8.1 Hz, 2H, H-6′), 6.84 (q, J = 1.6 Hz, 1H, H-4), 3.92 (d, J = 15.0
Hz, 2H, CH2A), 3.31 (d, J = 15.0 Hz, 2H, CH2B), 3.08 (s, 3H, N−
CH3), 1.65 (s, 18H, Boc), 1.58 (d, J = 1.6 Hz, 3H, CH3); 13C NMR,
HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 171.9 (CO), 149.0
(COOtBu), 143.3 (C4), 136.7 (Cq7a′), 135.5 (Cq3), 128.2 (Cq3a′),
127.9 (C5′), 126.4 (C2′), 125.2 (C6′), 114.7 (2C, Cq3′, C7′), 113.9
(Cq4′), 84.6 (C(CH3)3), 68.6 (Cq5), 30.1 (2xCH2), 28.3 (C(CH3)3),
25.0 (NCH3), 11.0 (CH3); ESI-HRMS calcd for [C34H3779Br2N3O5 +
Na]+ 748.0998, found 748.1006.
tert-Butyl 7,9-Dimethyl-8-oxo-6,6a,7,8-tetrahydro-4H-
indolo[6,5,4-cd]indole-4-carboxylate (36). Palladium(II) acetate
(45.5 mg, 0.20 mmol), triphenylphosphine (173 mg, 0.66 mmol), and
silver(I) carbonate (677 mg, 2.46 mmol) were placed in a Schlenk
flask under an argon atmosphere. A solution of bromoarene 32 (460
mg, 1.10 mmol) in dry toluene (40 mL) and dry triethylamine (40
mL) were added. The reaction mixture was degassed (three freeze−
pump−thaw cycles) and then heated to 110 °C (oil bath) for 13 h.
After cooling to rt, the reaction mixture was filtered over Celite and
concentrated in vacuo. Purification by flash column chromatography
(cyclohexane/EtOAc, 3:1 + 1% TEA) yielded the title compound (274
mg, 74%) as a light yellow oil: Rf = 0.10 (cyclohexane/EtOAc, 2:1); IR
(ATR) ν (cm−1) = 2978, 2936, 1730, 1684, 1438, 1388, 1353, 1300,
1147, 1116, 784, 752; 1H NMR, COSY (400 MHz, CDCl3) δ (ppm) =
7.91 (sbr, 1H, H-3), 7.43−7.34 (m, 3H, H-1, H-2, H-5), 4.13 (ddd, J =
12.1, 6.3, 1.8 Hz, 1H, H-6a), 3.49 (dd, J = 14.5, 6.3 Hz Hz, 1H, H-6A),
3.10 (s, 3H, N−CH3), 2.52 (ddd, J = 14.5, 12.1, 2.2 Hz, 1H, H-6B),
2.20 (dd, J = 1.8, 0.9 Hz, 1H, CH3), 1.67 (s, 9H, Boc); 13C NMR,
HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 172.6 (CO), 149.8
(COOtBu), 145.0 (Cq9a), 133.6 (Cq3a), 129.7 (Cq9c), 128.2 (Cq9),
125.7 (C2), 124.3 (Cq9b), 121.4 (C5), 119.1 (C1), 115.7 (C3), 114.2
7,9-Dimethyl-6,6a,7,8-tetrahydro-4H-indolo[6,5,4-cd]indole
(38). Lactam 36 (41 mg, 0.12 mmol) was placed in a Schlenk flask,
lithium aluminum hydride (2 M solution in THF, 2 mL, 4 mmol) was
added, and the reaction mixture was heated to reflux for 17 h. The
reaction mixture was cooled to 0 °C, and a 1 N NaOH solution was
carefully added. The resulting colorless solid was removed by filtration,
and the filtrate was extracted with ethyl acetate. The combined organic
layers were washed with brine, dried over K2CO3, and concentrated.
Purification by flash column chromatography (CHCl3/MeOH, 6:1 +
1% TEA) yielded 38 (15 mg, 56%) as an off-white to light brown oil;
Rf = 0.21 (CHCl3/MeOH, 5:1); IR (ATR) ν (cm−1) = 3199, 2934,
1
2854, 2769, 1590, 1575, 1446, 1380, 1364, 1337, 786, 752; H NMR,
COSY (400 MHz, CDCl3) δ (ppm) = 8.17 (s, 1H, NH), 7.28−7.15
(m, 3H, H1,2,3), 6.91 (t, J = 1.8 Hz, 1H, H-5), 3.99 (ddd, J = 13.8, 3.6,
1.2 Hz, 1H, H-8A), 3.82−3.73 (m, 1H, H-6a), 3.59−3.526 (m, 1H, H-
8B), 3.36 (dd, J = 14.4, 6.2 Hz, 1H, H-6A), 2.78 (ddd, J = 14.4, 11.0, 1.8
Hz, 1H, H-6B), 2.66 (s, 3H, NCH3), 2.14 (sbr, 3H, CH3); 13C NMR,
HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 134.2 (Cq3a), 130.0
(Cq9b), 129.9 (Cq9), 127.4 (Cq9c), 125.4 (Cq9a), 123.2 (C2), 118.7
(C5), 115.0 (C1), 111.6 (Cq5a), 109.7 (C3), 72.7 (C6a), 67.7 (C8),
40.5 (NCH3), 28.5 (C6), 13.7 (CH3); ESI-HRMS calcd for [C15H16N2
+ H]+ 225.1392, found 225.1383. The analytical data are in accordance
with the literature.11
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02815.
1H and 13C NMR spectra of all synthesized compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: opatz@uni-mainz.de.
Notes
The authors declare no competing financial interest.
G
DOI: 10.1021/acs.joc.5b02815
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(32) Christensen, B. G.; Leanza, W. J.; Wildonger, K. J. Substituted
N-methylene derivatives of thienamycin U.S. Patent No. 4,194,047, 18
Mar. 1980.
ACKNOWLEDGMENTS
■
We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopy
and Dr. N. Hanold (Mainz) for HR-mass spectrometry. This
work was supported by the Rhineland Palatinate Center for
Natural Products Research and by BASF SE.
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