Preparation of 1-substituted tetrahydro-β-carbolines by lithiation-substitution

Article abstract of DOI:10.1021/acs.joc.5b00725

A method to prepare 1-substituted N-Boc-tetrahydro-β-carbolines was developed by lithiation followed by electrophilic substitution. The deprotonation to give the organolithium was optimized by in situ IR spectroscopy and showed that the Boc group rotates slowly at low temperature. The chemistry was applied to the synthesis of 9-methyleleagnine (N-methyltetrahydroharman) and 11-methylharmicine.

Full text of DOI:10.1021/acs.joc.5b00725

Note
pubs.acs.org/joc
Preparation of 1‑Substituted Tetrahydro-β-carbolines by Lithiation−
Substitution
Edward J. Cochrane,† Lorraine A. Hassall,‡ and Iain Coldham*,†
†Department of Chemistry, University of Sheffield, Sheffield S3 7HF, United Kingdom
‡AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
S
* Supporting Information
ABSTRACT: A method to prepare 1-substituted N-Boc-
tetrahydro-β-carbolines was developed by lithiation followed by
electrophilic substitution. The deprotonation to give the
organolithium was optimized by in situ IR spectroscopy and
showed that the Boc group rotates slowly at low temperature.
The chemistry was applied to the synthesis of 9-methyleleagnine
(N-methyltetrahydroharman) and 11-methylharmicine.
he prevalence of substituted saturated nitrogen hetero-
Tcycles in natural products and medicinal drug compounds
has encouraged us in our studies of the preparation of such
compounds using lithiation−substitution chemistry. Lithiation
can be achieved adjacent to the nitrogen atom with various N-
substituted cyclic amines, of which the N-tert-butoxycarbonyl
(Boc) group has proven to be one of the most popular.1 We
have applied this chemistry to the formation of substituted
pyrrolidines,2 piperidines,2b,3 piperazines,4 imidazolidines,5 and
tetrahydroisoquinolines.6 Another important ring system found
in many natural products and drug molecules is tetrahydro-β-
carboline.7 This ring system is present in alkaloids, such as
eleagnine, isolated from Chrysophyllum albidum,8 and harmi-
cine, isolated from Kopsia griffithii (Figure 1).9
out to give a selection of substituted derivatives 2a−e (Table
1). In each case, high yields of the product were obtained using
NaH as the base followed by addition of the electrophile RX.
Table 1. Preparation of Substrates 2a−e
entry
RX
R
product
yield (%)
1
2
3
4
5
MOMCl
Boc2O
BnBr
MOM
Boc
2a
2b
2c
2d
2e
93
82
94
92
90
Bn
TsCl
SO2Tol
Me
MeI
Initially, we studied tetrahydro-β-carboline 2a, and in situ IR
spectroscopic monitoring indicated that lithiation was complete
after ∼4 min in Et2O/TMEDA at −50 °C (see the Supporting
Information (SI)). However, the addition of iodomethane gave
only byproducts rather than the desired 1-methylated product,
and we found that the starting material 2a was unstable upon
standing at room temperature. Therefore, we selected to study
derivatives 2b−e.
We had similar problems upon using substrates 2c and 2d
bearing an indole N-benzyl or N-tosyl group, respectively. Only
decomposition products were obtained upon treatment of these
compounds with n-BuLi in Et2O/TMEDA at −50 °C. Using
Figure 1. Structures of some tetrahydro-β-carboline natural products.
Tetrahydro-β-carboline can be lithiated at the 1-position
when the indole nitrogen is protected as an alkyl group and the
nitrogen atom in the 6-membered ring is part of a formamidine
or amide.10 However, the more common Boc group has not, as
far as we are aware, been used for this chemistry. We report
here the successful lithiation−substitution of this type of
compound.
We prepared the Boc-protected tetrahydro-β-carboline 1
from tryptamine and paraformaldehyde in acetic acid and
MeOH followed by the addition of Boc2O using a known
procedure.11 Protection of the indole nitrogen atom was carried
Received: April 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00725
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
tetrahydro-β-carboline 2b, the reaction with n-BuLi under the
same conditions followed by the addition of iodomethane gave
an approximately equal mixture of recovered tetrahydro-β-
carboline 2b, tetrahydro-β-carboline 1, and its N-methylated
analogue (2e); we did not observe any product from Boc
migration.12 We also attempted lithiation of tetrahydro-β-
carboline 1 using two equivalents of n-BuLi in Et2O/TMEDA
at −50 °C followed by the addition of iodomethane; however,
the only product was tetrahydro-β-carboline 2e (isolated in
78% yield), and no products from lithiation at C-1 were
obtained.
Fortunately, indole N-methyl analogue 2e behaved much
better in this chemistry. This compound was not very soluble in
Et2O, so THF was initially used as the cosolvent. Under these
conditions, a good yield of desired product 3a was obtained
(Scheme 1).
tetrahydro-β-carboline 2e (see SI). Coalescence of the signals
(ratio 1.3:1) for the N-CH3 group in D8-THF occurred at 10
°C. Line shape analysis indicated that the approximate
activation parameters for Boc rotation are ΔH‡ = 59.6 kJ/
mol and ΔS‡ = −9.8 J K−1 mol−1. The half-life for rotation can
therefore be determined to be t1/2 = ∼45 s at −50 °C and ∼85
min at −78 °C.
The optimized lithiation conditions were used to prepare a
selection of 1-substituted tetrahydro-β-carboline products 3a−f
after electrophilic quenching (Scheme 2, Figure 3). Addition of
Scheme 2. Preparation of Tetrahydro-β-carbolines 3a−f
Scheme 1. Initial Lithiation−Methylation of Tetrahydro-β-
carboline 2e
The use of several solvents and an additive (TMEDA) as
outlined in Scheme 1 is not ideal, so we screened a selection of
solvents with and without TMEDA (Table 2). The simplest
Table 2. Optimization of Lithiation of 2e
Figure 3. Structures and yields of tetrahydro-β-carboline products 3a−
f.
entry
solvent
temp (°C)
time (min)
yield 3a (%)
1
2
3
4
5
THF, TMEDA
THF
−78
−78
−50
−78
−50
10
10
4
60
51
90
69
95
iodomethane gave product 3a in 90% yield, showing that
neither Et2O nor TMEDA are required for successful reaction.
The carbonyl electrophiles MeOCOCl and acetone gave
products 3b and 3c, respectively, the latter being formed by
cyclization of the intermediate alkoxide onto the Boc group.
The reaction was amenable to allyl bromide or benzyl bromide
as the electrophile to give products 3d and 3e, respectively. In
addition, the electrophile PhS−SO2Ph provided the 1-phenyl-
thio tetrahydro-β-carboline product 3f in good yield. However,
the use of TMSCl or Bu3SnCl gave only recovered starting
material 2e, and it is unclear why these were unsuccessful.
An attempt was made to carry out an asymmetric lithiation−
substitution in the presence of the chiral ligand (−)-sparteine.
To avoid competing solvation by THF, we used toluene as the
THF
PhMe, TMEDA
PhMe, TMEDA
10
4
conditions were to carry out the lithiation in THF at −50 °C. If
the reaction was conducted at −78 °C, then the yields were
generally lower (50−69% after 10 min reaction time),
indicating that the rate of rotation of the Boc group was slow
at this temperature. Following the reaction in THF at −50 °C
by in situ IR spectroscopy showed that lithiation was complete
within a few minutes (Figure 2).13 In contrast, partial lithation
followed by slow further lithiation occurs at −78 °C (see SI).
Variable temperature NMR spectroscopy was carried out with
Figure 2. Monitoring the lithiation of tetrahydro-β-carboline 2e in THF at −50 °C (blue line represents the intensity of the CO stretching
frequency of 2e (1698 cm−1) and green line of lithiated 2e (1638 cm−1) over time (in h:min:sec).
B
DOI: 10.1021/acs.joc.5b00725
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The Journal of Organic Chemistry
Note
solvent. Following the lithiation by in situ IR spectroscopy
showed rapid but partial (∼50%) lithiation at −78 °C
(corresponding to lithiation of the rotamer with the carbonyl
group pointing toward the benzylic position) followed by slow
further lithiation over the course of ∼1 h (corresponding to
slow rotation of the Boc group and subsequent lithiation) (see
SI). Addition of iodomethane gave product 3a (84% yield) but
with poor enantioselectivity (56:44 er). It is possible that
iodomethane quenches only slowly after warming;14 thus, to
further investigate the potential for any asymmetric induction,
we added tetrahydro-β-carboline 2e to a solution of premixed
n-BuLi and chiral ligand (+)-sparteine-surrogate at −78 °C,
which can be used in THF,15 followed by trapping after only 5
min with the electrophile acetone. These conditions do not
promote full lithiation due to slow rotation of the Boc group,
but acetone should trap any enantioenriched organolithium at
−78 °C. Product 3c was formed in 24% yield as a racemic
mixture. It is likely that the intermediate organolithium is
configurationally unstable at this temperature (as found for the
related tetrahydroisoquinoline),6a and if so, then the lack of
asymmetric induction presumably arises from poor kinetic
selectivity on reaction of the diastereomeric organolithium−
(−)-sparteine complexes with the electrophile.16
suitable for Boc-directed lithiation at C-1. By using this
compound, a range of different 1-substituted tetrahydro-β-
carbolines can be prepared. The use of in situ IR spectroscopy
revealed that the Boc group rotates slowly at −78 °C, and the
lithiation is conducted better at −50 °C, where the Boc group is
rotating more quickly. No significant asymmetric induction was
obtained with this tetrahydro-β-carboline, (−)-sparteine or
(+)-sparteine-surrogate as the chiral ligand, and iodomethane
or acetone as the electrophile, although it may be possible to
develop an asymmetric substitution with other chiral ligands
and electrophiles. The chemistry was applied to a short
synthesis of two indole-N-methylated natural products,
eleagnine and harmicine.
EXPERIMENTAL SECTION
■
tert-Butyl-2,3,4,9-tetrahydro-1H-β-carboline-2-carboxylate
(1).11 To a 0.25 M solution of tryptamine (10 g, 62 mmol) in a
mixture of AcOH:MeOH (10:1) was added paraformaldehyde (2 g, 74
mmol). The mixture was heated to 80 °C for 1 h and then cooled to
room temperature. The mixture was basified to pH 9−10 using
NH4OH(aq) and was extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried (MgSO4), and filtered, and the
solvent was evaporated to give the crude amine, which was added to
Boc2O (13.5 g, 62 mmol) in THF at 0 °C. The mixture was allowed to
warm to room temperature over 16 h, and saturated aqueous NaHCO3
was added. The mixture was extracted with Et2O, and the combined
organic extracts were washed with brine and dried (MgSO4), and the
solvent was evaporated. Purification by column chromatography on
silica gel gave the product, which was recrystallized from MeCN to
give carbamate 1 (13.8 g, 82%) as needles; mp 148−150 °C, lit.11 151
°C; Rf = 0.50 [petrol−EtOAc (75:25)]; FT-IR νmax film 3295, 2800,
Treatment of tetrahydro-β-carboline product 3a with
trifluoroacetic acid (TFA) promoted deprotection of the Boc
group to give 9-methyleleagnine17 (Scheme 3). In addition, we
Scheme 3. Removal of the Boc Group from 3a
1
1670, 1395, 1370, 1150, 1095 cm−1; H NMR (400 MHz, CDCl3,
rotamers) δ 8.60 (0.65H, br s), 8.00 (0.35H, br s), 7.51 (1H, d, J = 7.5
Hz), 7.34 (1H, d, J = 7.5 Hz), 7.23−7.09 (2H, m), 4.70 (1.3H, br s),
4.65 (0.7H, br s), 3.80 (2H, br), 2.84 (2H, br), 1.57 (9H, br s); 13C
NMR (101 MHz, CDCl3, rotamers) δ 155.6 (br), 136.3, 130.8 (br),
127.0, 121.5, 119.3, 117.9, 111.0, 108.1 (br), 80.3, 42.7, 42.0, and 41.5
(br), 28.6, 21.5 (br); HRMS (ES) [M + H]+ calcd for C16H21N2O2
273.1603, found 273.1591. Data is in accordance with the literature.11
tert-Butyl-9-(methoxymethyl)-2,3,4,9-tetrahydro-1H-β-car-
boline-2-carboxylate (2a). Carbamate 1 (6.6 g, 24 mmol) in THF
was added to NaH (700 mg, 60 wt % mineral oil suspension, 29
mmol) in THF (0.25 M) at 0 °C. The mixture was warmed to room
temperature, and MOMCl (2.7 mL, 36 mmol) was added. After 30
min, water was added, and the mixture was extracted with Et2O. The
combined organic extracts were washed with brine, dried (MgSO4),
filtered, and evaporated. Purification by column chromatography on
silica gel, eluting with petrol−EtOAc (90:10), gave carbamate 2a (7.1
g, 93%) as an oil; Rf = 0.30 [petrol−EtOAc (90:10)]; FT-IR νmax film
2970, 2925, 1685, 1465, 1410, 1160, 1100 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.51 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.24 (1H,
t, J = 8.0 Hz), 7.19−7.13 (1H, m), 5.38 (2H, s), 4.72 (2H, br s), 3.80
(2H, br), 3.28 (3H, s), 2.83 (2H, br), 1.55 (9H, s); 13C NMR (101
MHz, CDCl3, one C not observable) δ 155.2, 137.3, 132.1 (br), 127.2,
121.9, 120.0, 118.1, 109.2, 80.1, 74.1, 55.8, 42.3 (br), 40.8 (br), 28.5,
21.4 (br); HRMS (ES) [M + Na]+ calcd for C18H24N2O3Na 339.1685,
found 339.1690.
treated tetrahydro-β-carboline 2e with n-BuLi in THF at −50
°C for 2 min followed by the addition of 1,3-dibromopropane
to give product 3g (Scheme 4). This reaction was conducted at
Scheme 4. Preparation of 11-Methylharmicine
Di-tert-butyl-2,3,4,9-tetrahydro-1H-β-carboline-2,9-dicar-
boxylate (2b). In the same manner as carbamate 2a, carbamate 1
(272 mg, 1 mmol), NaH (60 mg, 60 wt % mineral oil suspension, 1.5
mmol), and Boc2O (240 mg, 1.1 mmol) gave, after flash column
chromatography on silica gel eluting with petrol−EtOAc (90:10),
carbamate 2b (306 mg, 82%) as an amorphous solid; mp 106−108 °C;
Rf = 0.45 [petrol−EtOAc (90:10)]; FT-IR νmax film 2975, 2930, 1725,
lower concentration to help reduce any double alkylation.
Product 3g was then treated with TFA to give 11-
methylharmicine.18 These products are indole-N-methylated
analogues of the natural products; it would be useful to be able
to N-demethylate, although we have not attempted this
transformation and related demethylations of indoles are rare
in organic chemistry.19
1
1695, 1375, 1360, 1140, 1115 cm−1; H NMR (400 MHz, CDCl3) δ
8.21 (1H, d, J = 8.0 Hz), 7.43 (1H, d, J = 8.0 Hz), 7.35−7.22 (2H, m),
4.84 (2H, br s), 3.76 (2H, br), 2.76 (2H, br), 1.70 (9H, s), 1.53 (9H,
s); 13C NMR (101 MHz, CDCl3, two C not observable) δ 155.0,
We have shown that, of a range of tetrahydro-β-carbolines, only
a simple alkyl (methyl) group on the indole nitrogen atom is
C
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Note
150.0, 135.9 (br), 128.9, 124.0, 122.7, 117.7, 115.4, 83.9, 80.0, 44.4
(br), 40.2 (br), 28.5, 28.3, 21.2 (br); HRMS (ES) [M + H]+ calcd for
C21H29N2O4 373.2127, found 373.2110.
mg, 0.84 mmol) in PhMe at −78 °C was added a solution of
carbamate 2e (200 mg, 0.70 mmol) in PhMe. After 1 h, MeI (0.07 mL,
1.05 mmol) was added, and the mixture was warmed to room
temperature over 16 h. Purification as above gave carbamate 3a (176
mg, 84%) as an oil; 56:44 er, as determined by chiral stationary phase
HPLC (the resolution between the enantiomers of carbamate 3a was
achieved using a Beckman system fitted with a Phenomenex Lux
Cellulose-2 column (250 mm × 4.60 nm i.d.) as the stationary phase
with a mixture of n-hexane and iPrOH (99:1 v/v) as the mobile phase
at a flow rate of 1 mL min−1 at ambient temperature and detected by
UV absorbance at 254 nm). Injection volume of 20 μm of sample was
prepared in a 2 g L−1 solution of the eluent. Under these conditions,
the two components were eluted at 10.5 and 12.0 min with an analysis
time of 15 min.
1-Methyl 2-tert-butyl-9-methyl-2,3,4,9-tetrahydro-1H-β-car-
boline-1,2-dicarboxylate (3b). In the same manner as carbamate
3a, carbamate 2e (200 mg, 0.70 mmol), n-BuLi (0.34 mL, 0.84 mmol,
2.5 M in hexanes), and MeOCOCl (0.08 mL, 1.05 mmol) gave, after
flash column chromatography on silica gel eluting with petrol−EtOAc
(90:10), carbamate 3b (145 mg, 60%) as an oil; Rf = 0.25 [petrol−
EtOAc (90:10)]; FT-IR νmax film 2970, 2930, 1745, 1690, 1365, 1290,
1165 cm−1; 1H NMR (400 MHz, CDCl3, rotamers) δ 7.56−7.46 (1H,
m), 7.37−7.31 (1H, m), 7.30−7.21 (1H, m), 7.18−7.11 (1H, m), 5.98
(0.6H, s), 5.71 (0.4H, s), 4.44−4.24 (1H, m), 3.82 (3H, br s), 3.78
(3H, br s), 3.58−3.44 (1H, m), 2.97−2.74 (2H, m), 1.54 (9H, br s);
13C NMR (101 MHz, CDCl3, rotamers) δ 170.2 and 170.0, 155.5 and
tert-Butyl-9-benzyl-2,3,4,9-tetrahydro-1H-β-carboline-2-car-
boxylate (2c).20 In the same manner as carbamate 2a, carbamate 1
(272 mg, 1.0 mmol), NaH (60 mg, 60 wt % mineral oil suspension, 1.5
mmol), and BnBr (0.18 mL, 1.5 mmol) gave, after flash column
chromatography on silica gel eluting with petrol−EtOAc (90:10),
carbamate 2c (341 mg, 94%) as an oil; Rf = 0.55 [petrol−EtOAc
(90:10)]; FT-IR νmax film 2980, 2930, 2850, 1695, 1410, 1365, 1235,
1160, 1110 cm−1; 1H NMR (400 MHz, CDCl3, rotamers) δ 7.56 (1H,
d, J = 7.5 Hz), 7.35−7.23 (4H, m), 7.22−7.17 (2H, m), 7.09−7.02
(2H, m), 5.25 (2H, br s), 4.56 (2H, br s), 3.77 (2H, br), 2.87 (2H, br),
1.52 (5H, br s), 1.45 (4H, br s); 13C NMR (101 MHz, CDCl3) δ
155.3, 137.4, 137.0, 132.0 (br), 128.9, 127.5, 126.8, 126.3, 121.5, 119.4,
118.1, 109.2, 108.2 (br), 80.1, 46.8, 42.4 (br), 40.9 (br), 28.4, 21.7
(br); HRMS (ES) [M + H]+ calcd for C23H27N2O2 363.2073, found
363.2070. Data is in accordance with the literature.20
tert-Butyl-9-tosyl-2,3,4,9-tetrahydro-1H-β-carboline-2-car-
boxylate (2d). In the same manner as carbamate 2a, carbamate 1 (2.0
g, 7.3 mmol), NaH (360 mg, 60 wt % mineral oil suspension, 15.0
mmol), and TsCl (1.7 g, 8.8 mmol) gave, after flash column
chromatography on silica gel eluting with petrol−EtOAc (90:10),
carbamate 2d (2.9 g, 92%) as an amorphous solid; mp 148−150 °C; Rf
= 0.25 [petrol−EtOAc (90:10)]; FT-IR νmax film 2980, 2935, 2845,
1
1695, 1425, 1370, 1170, 1145 cm−1; H NMR (400 MHz, CDCl3) δ
8.15 (1H, d, J = 8.5 Hz), 7.74 (2H, br s), 7.37 (1H, d, J = 7.5 Hz),
7.34−7.16 (4H, m), 4.93 (2H, br s), 3.73 (2H, br), 2.70 (2H, br), 2.34
(3H, s), 1.53 (9H, s); 13C NMR (101 MHz, CDCl3, two C not
observable) δ 154.7, 144.9, 136.1, 135.6, 129.9, 129.6, 126.5, 124.5,
123.5, 118.3, 114.3, 80.2, 43.4 (br), 40.3 (br), 28.5, 21.5, 21.2 (br);
HRMS (ES) [M + H]+ calcd for C23H27N2O4S 427.1692, found
427.1678.
tert-Butyl-9-methyl-2,3,4,9-tetrahydro-1H-β-carboline-2-car-
boxylate (2e). In the same manner as carbamate 2a, carbamate 1
(272 mg, 1 mmol), NaH (60 mg, 60 wt % mineral oil suspension, 1.5
mmol), and MeI (0.1 mL, 1.5 mmol) gave, after flash column
chromatography on silica gel eluting with petrol−EtOAc (90:10),
carbamate 2e (258 mg, 90%) as an amorphous solid; mp 100−102 °C;
Rf = 0.30 [petrol−EtOAc (90:10)]; FT-IR νmax film 2980, 2910, 1685,
1395, 1230, 1150 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.53 (1H, d, J
= 7.5 Hz), 7.35−7.29 (1H, m), 7.23 (1H, t, J = 7.5 Hz), 7.16−7.10
(1H, m), 4.68 (2H, br s), 3.80 (2H, br), 3.65 (3H, s), 2.84 (2H, br),
1.56 (9H, s); 13C NMR (101 MHz, CDCl3) δ 155.2, 137.1, 132.1 (br),
126.5, 121.2, 119.1, 118.0, 108.7, 107.4 (br), 80.1, 42.5 (br), 41.1 (br),
29.3, 28.5, 21.7 (br); HRMS (ES) [M + H]+ calcd for C17H23N2O2
287.1760, found 287.1762.
154.7, 137.9 and 137.8, 129.3 and 128.5, 126.0 and 125.9, 122.2 and
122.1, 119.4 and 119.3, 118.6 and 118.4, 109.3, 109.1 and 109.0, 80.8,
54.4 and 53.0, 52.7 and 52.6, 40.5 and 39.5, 30.7, 28.4, 21.1 and 20.7;
HRMS (ES) [M + Na]+ calcd for C19H24N2O4Na 367.1634, found
367.1648.
3,3-Dimethyl-16-methyl-4-oxa-6.16-diazatetracyclo-
[7.7.0.02,6.010,15]hexadeca-1(9),10(15),11,13-tetraen-5-one (3c).
In the same manner as carbamate 3a, carbamate 2e (200 mg, 0.70
mmol), n-BuLi (0.34 mL, 0.84 mmol, 2.5 M in hexanes), and acetone
(0.08 mL, 1.05 mmol) gave, after flash column chromatography on
silica gel eluting with petrol−EtOAc (80:20), carbamate 3c (184 mg,
97%) as an amorphous solid; mp 140−143 °C; Rf = 0.39 [petrol−
EtOAc (50:50)]; FT-IR νmax film 2985, 2930, 1740, 1415, 1265 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.57 (1H, d, J = 8.0 Hz), 7.38−7.25
(2H, m), 7.22−7.15 (1H, m), 5.01 (1H, s), 4.34−4.26 (1H, m), 3.73
(3H, s), 3.06−2.94 (1H, m), 2.92−2.87 (2H, m), 1.87 (3H, s), 1.11
(3H, s); 13C NMR (101 MHz, CDCl3) δ 156.2, 137.8, 130.0, 126.4,
122.5, 119.8, 118.7, 110.9, 109.2, 82.9, 61.6, 39.7, 31.4, 27.9, 23.7, 21.7;
HRMS (ES) [M + H]+ calcd for C16H19N2O2 271.1447, found
271.1437.
Attempted Asymmetric Reaction. To a 0.25 M solution of n-
BuLi (0.12 mL, 0.30 mmol, 2.4 M in hexanes) and (+)-sparteine-
surrogate (57 mg, 0.30 mmol) in THF (3 mL) at −78 °C was added a
solution of carbamate 2e (70 mg, 0.25 mmol) in THF (2 mL). After 5
min, acetone (0.06 mL, 0.87 mmol) was added, and the mixture was
warmed to room temperature over 16 h. Purification as above gave
carbamate 3c (16 mg, 24%) as an amorphous solid; 50:50 er, as
determined by chiral stationary phase HPLC (the resolution between
the enantiomers of carbamate 3c was achieved using a Beckman
system fitted with a Daicel ChiralPak AD column (250 mm × 4.60 nm
tert-Butyl-1-methyl-9-methyl-2,3,4,9-tetrahydro-1H-β-car-
boline-2-carboxylate (3a). n-BuLi (0.34 mL, 0.84 mmol, 2.5 M in
hexanes) was added to carbamate 2e (200 mg, 0.70 mmol) in THF
(0.25 M) at −50 °C. After 2 min, MeI (0.07 mL, 1.05 mmol) was
added, and the mixture was allowed to warm to room temperature
over 16 h. Saturated aq NH4Cl was added, and the mixture was
extracted with Et2O. The combined organic extracts were washed with
brine, dried (MgSO4), filtered, and evaporated. Purification by column
chromatography on silica gel, eluting with petrol−EtOAc (90:10),
gave carbamate 3a (189 mg, 90%) as an oil; Rf = 0.40 [petrol−EtOAc
i
i.d.) as the stationary phase with a mixture of n-hexane and PrOH
1
(90:10)]; FT-IR νmax film 2980, 2930, 1685, 1410, 1165 cm−1; H
(97:3 v/v) as the mobile phase at a flow rate of 1 mL min−1 at ambient
temperature and detected by UV absorbance at 254 nm). Injection
volume of 25 μm of sample was prepared in a 2 g L−1 solution of the
eluent. Under these conditions, the two components were eluted at
52.6 and 58.7 min with an analysis time of 75 min.
NMR (400 MHz, CDCl3, rotamers) δ 7.57−7.49 (1H, m), 7.35−7.30
(1H, m), 7.25 (1H, t, J = 7.5 Hz), 7.19−7.11 (1H, m), 5.52 (0.6H, q, J
= 6.5 Hz), 5.28 (0.4H, q, J = 6.5 Hz), 4.54 (0.4H, br dd, J = 13.0, 5.5
Hz), 4.34 (0.6H, br dd, J = 13.0, 5.5 Hz), 3.70 (3H, s), 3.36−3.15 (1H,
m), 2.95−2.70 (2H, m), 1.55 (9H, br s), 1.53 (3H, d, J = 6.5 Hz); 13C
NMR (101 MHz, CDCl3, rotamers) δ 154.6 and 154.3, 137.3 and
137.2, 136.9 and 136.1, 126.4, 121.5 and 121.3, 119.2 and 119.1, 118.3
and 118.1, 108.9, 107.5 and 106.8 (br), 79.9, 46.6 and 45.5, 37.9 and
36.6, 29.8, 28.6, 21.6 and 21.3, 19.3 and 19.2; HRMS (ES) [M + H]+
calcd for C18H25N2O2 301.1916, found 301.1902.
tert-Butyl-1-allyl-9-methyl-2,3,4,9-tetrahydro-1H-β-carbo-
line-2-carboxylate (3d). In the same manner as carbamate 3a,
carbamate 2e (200 mg, 0.70 mmol), n-BuLi (0.34 mL, 0.84 mmol, 2.5
M in hexanes), and allyl bromide (0.09 mL, 1.05 mmol) gave, after
flash column chromatography on silica gel eluting with petrol−EtOAc
(90:10), carbamate 3d (153 mg, 67%) as an oil; Rf = 0.45 [petrol−
EtOAc (90:10)]; FT-IR νmax film 2975, 2930, 1680, 1410, 1370, 1165,
Attempted Asymmetric Reaction. To a 0.25 M solution of n-
BuLi (0.34 mL, 0.84 mmol, 2.5 M in hexanes) and (−)-sparteine (197
1
905 cm−1; H NMR (400 MHz, CDCl3, rotamers) δ 7.58−7.49 (1H,
D
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The Journal of Organic Chemistry
Note
m), 7.36−7.31 (1H, m), 7.29−7.22 (1H, m), 7.20−7.13 (1H, m),
6.07−5.90 (1H, m), 5.54 (0.6H, dd, J = 10.0 Hz, 4.0 Hz), 5.32 (0.4H,
t, J = 6.5 Hz), 5.24−5.11 (2H, m), 4.58 (0.4H, dd, J = 13.5, 5.5 Hz),
4.35 (0.6H, dd, J = 13.5, 5.5 Hz), 3.73 (1.2H, s), 3.71 (1.8H, s), 3.37−
3.17 (1H, m), 2.99−2.84 (1H, m), 2.83−2.71 (1H, m), 2.69−2.52
(2H, m), 1.55 (4H, br s), 1.54 (5H, s); 13C NMR (101 MHz, CDCl3,
rotamers) δ 155.5 and 154.6, 137.4 and 137.3, 135.8 and 135.2, 134.5,
126.6 and 126.5, 121.6 and 121.4, 119.3 and 119.2, 118.3 and 118.1,
117.6 and 117.2, 108.95 and 108.9, 108.1 and 107.5, 80.1 and 79.8,
50.4 and 49.2, 39.0 and 38.7, 38.0 and 36.6, 30.1, 28.5, 21.4 and 21.1;
HRMS (ES) [M + H]+ calcd for C20H27N2O2 327.2073, found
327.2075.
tert-Butyl-1-benzyl-9-methyl-2,3,4,9-tetrahydro-1H-β-carbo-
line-2-carboxylate (3e). In the same manner as carbamate 3a,
carbamate 2e (200 mg, 0.70 mmol), n-BuLi (0.34 mL, 0.84 mmol, 2.5
M in hexanes), and BnBr (0.12 mL, 1.05 mmol) gave, after flash
column chromatography on silica gel eluting with petrol−EtOAc
(90:10), carbamate 3e (187 mg, 71%) as an oil; Rf = 0.45 [petrol−
EtOAc (90:10)]; FT-IR νmax film 2975, 2930, 1690, 1410, 1370, 1165
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.61−7.53 (1H, m), 7.43−7.21
(7H, m), 7.20−7.14 (1H, m), 5.70 (0.4H, dd, J = 8.5, 5.5 Hz), 5.45
(0.6H, dd, J = 10.0, 4.0 Hz), 4.64 (0.6H, dd, J = 13.5, 5.5 Hz), 4.32
(0.4H, dd, J = 13.5, 5.5 Hz), 3.78 (1.8H, s), 3.59 (1.2H, s), 3.43−3.30
(1H, m), 3.27−2.72 (4H, m), 1.44 (3.6H, s), 1.21 (5.4H, s); 13C NMR
(101 MHz, CDCl3, rotamers, one C not observable) δ 154.7 and
154.2, 138.1, 137.6 and 137.4, 135.8 and 135.2, 129.5, 128.3 and 128.1,
126.7 and 126.5, 121.7 and 121.4, 119.4 and 119.2, 118.3 and 118.1,
109.0 and 108.9, 108.2, 79.7, 52.5 and 50.7, 40.4, 38.2 and 36.5, 30.0
and 29.9, 28.5 and 28.0, 21.4 and 21.2; HRMS (ES) [M + H]+ calcd
for C24H29N2O2 377.2229, found 377.2239.
1-Methyl-9-methyl-2,3,4,9-tetrahydro-1H-β-carboline (9-
methyleleagnine).17 TFA (0.25 mL, 3.3 mmol) was added to
carbamate 3a (100 mg, 0.33 mmol) in CH2Cl2 (0.25 M), and the
mixture was heated under reflux. After 1 h, the mixture was cooled to
room temperature. Water was added, and the mixture was basified to
pH 9−10 with aq NaOH (2 M). The mixture was extracted with
CH2Cl2, and the combined organic extracts were dried (MgSO4),
filtered, and evaporated. Purification by column chromatography on
silica gel, eluting with CH2Cl2−MeOH (90:10), gave 9-methyleleag-
nine (65 mg, 98%) as an oil; Rf = 0.55 [CH2Cl2−MeOH (90:10)]; FT-
IR νmax film 3315, 3040, 2920, 2845, 1615, 1470, 1375, 1125, 1100
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.51 (1H, d, J = 8.0 Hz), 7.33−
7.26 (1H, m), 7.26−7.20 (1H, m), 7.16−7.10 (1H, m), 4.24 (1H, q, J
= 6.5 Hz), 3.63 (3H, s), 3.52 (1H, br s), 3.31−3.26 (2H, m), 2.89−
2.82 (2H, m), 1.59 (3H, d, J = 6.5 Hz); 13C NMR (101 MHz, CDCl3)
δ 137.2, 136.7, 126.6, 121.5, 119.2, 118.2, 108.8, 106.9, 46.4, 38.8, 29.9,
21.7, 20.3; HRMS (ES) [M + H]+ calcd for C13H17N2 201.1392, found
201.1384. Data is in accordance with the literature.17
11-Methyl-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]-
indole (11-methylharmicine).18 In the same manner as 9-
methyleleagnine, carbamate 3g (60 mg, 0.15 mmol) and TFA (0.11
mL, 1.5 mmol) gave, after flash column chromatography on silica gel
eluting with CH2Cl2−MeOH (90:10), 11-methylharmicine (33 mg,
95%) as an oil; Rf = 0.50 [CH2Cl2−MeOH (90:10)]; FT-IR νmax film
3045, 2910, 2845, 1470, 1375, 1320, 1185, 1130 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.53 (1H, d, J = 7.5 Hz), 7.33−7.27 (1H, m), 7.23−
7.19 (1H, m), 7.16−7.11 (1H, m), 4.27 (1H, t, J = 7.5 Hz), 3.69 (3H,
s), 3.31−3.22 (1H, m), 3.09−2.88 (4H, m), 2.79−2.70 (1H, m), 2.51−
2.40 (1H, m), 2.02−1.81 (3H, m); 13C NMR (101 MHz, CDCl3) δ
137.4, 137.1, 126.7, 121.0, 118.9, 118.1, 108.7, 106.7, 56.3, 51.0, 46.6,
30.4, 30.2, 23.8, 18.8; HRMS (ES) [M + H]+ calcd for C15H19N2
227.1548, found 227.1553. Data is in accordance with the literature.18
tert-Butyl-9-methyl-1-(phenylthio)-2,3,4,9-tetrahydro-1H-β-
carboline-2-carboxylate (3f). In the same manner as carbamate 3a,
carbamate 2e (200 mg, 0.70 mmol), n-BuLi (0.34 mL, 0.84 mmol, 2.5
M in hexanes), and PhSSO2Ph (263 mg, 1.05 mmol) gave, after flash
column chromatography on silica gel eluting with petrol−EtOAc
(95:5), carbamate 3f (226 mg, 82%) as an oil; Rf = 0.70 [petrol−
EtOAc (99:1)]; FT-IR νmax film 2915, 2850, 1695, 1615, 1475, 1160,
1125 cm−1; 1H NMR (400 MHz, CDCl3, rotamers) δ 7.71−7.63 (2H,
m), 7.57 (0.6H, d, J = 8.0 Hz), 7.54 (0.4H, d, J = 8.0 Hz), 7.46−7.33
(4H, m), 7.32−7.26 (1H, m), 7.21−7.13 (1H, m), 6.97 (0.4H, s), 6.67
(0.6H, s), 4.60 (0.6H, dd, J = 13.0, 5.5 Hz), 4.36 (0.4H, dd, J = 13.0,
5.5 Hz), 3.97 (1.8H, s), 3.90 (1.2H, s), 3.86 (0.4H, td, J = 13.0, 5.0
Hz), 3.83 (0.6H, td, J = 13.0, 5.0 Hz), 3.04−2.77 (2H, m), 1.42 (3.6H,
s), 1.18 (5.4H, s); 13C NMR (101 MHz, CDCl3, rotamers) δ 153.9
and 153.1, 137.5, 135.6 and 133.9, 133.2 and 133.1, 131.5 and 131.1,
129.2 and 129.0, 128.9 and 128.2, 126.1 and 126.0, 122.5 and 122.3,
119.5, 118.7 and 118.5, 110.5 and 109.8, 109.2 and 109.2, 80.5, 61.6
and 59.6, 37.8 and 36.3, 30.0, 28.3 and 27.9, 21.4 and 21.0; HRMS
(ES) [M + Na]+ calcd for C23H26N2O2SNa 417.1627, found 417.1613.
tert-Butyl-1-(3-bromopropyl)-9-methyl-2,3,4,9-tetrahydro-
1H-β-carboline-2-carboxylate (3g). In the same manner as
carbamate 3a (but at half concentration), carbamate 2e (200 mg,
0.70 mmol), n-BuLi (0.34 mL, 0.84 mmol, 2.5 M in hexanes), and 1,3-
dibromopropane (0.11 mL, 1.05 mmol) gave, after flash column
chromatography on silica gel eluting with petrol−EtOAc (90:10),
carbamate 3g (217 mg, 76%) as an amorphous solid; mp 74−75 °C; Rf
= 0.30 [petrol−EtOAc (90:10)]; FT-IR νmax film 2960, 2900, 1675,
ASSOCIATED CONTENT
* Supporting Information
Additional information, in situ IR spectra, and NMR spectra.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b00725.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: i.coldham@sheffield.ac.uk.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC, the University of Sheffield, and
AstraZeneca for funding. We are grateful to Nicholas Carter
for conducting the (+)-sparteine surrogate experiment and to
Susan Bradshaw for help with the NMR spectroscopic studies.
REFERENCES
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1405, 1250, 1175 cm−1; H NMR (400 MHz, CDCl3, rotamers) δ
7.57−7.47 (1H, m), 7.36−7.30 (1H, m), 7.28−7.20 (1H, m), 7.18−
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DOI: 10.1021/acs.joc.5b00725
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The Journal of Organic Chemistry
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