Palladium-catalyzed cross-couplings of lithium arylzincates with aromatic halides: Synthesis of analogues of isomeridianin G and evaluation as GSK-3β inhibitors

Article abstract of DOI:10.1055/s-0029-1217003

Several analogues of isomeridianin G have been synthesized using palladium-catalyzed cross-coupling reactions of lithium triorganozincates as a key step. The latter have been prepared by deprotonative lithiation followed by transmetalation using ZnCl

Full text of DOI:10.1055/s-0029-1217003

PAPER
3617
Palladium-Catalyzed Cross-Couplings of Lithium Arylzincates with Aromatic
Halides: Synthesis of Analogues of Isomeridianin G and Evaluation as GSK-3b
Inhibitors
C
ross-Couplings
o
n
f
L
ithium
A
r
n
ylzincates/Sy
e
nthesis of Isome
S
ridianin G A
n
e
alogues ggio,a,b Ghislaine Priem,b Floris Chevallier,a Florence Mongin*a
a
Chimie et Photonique Moléculaires, UMR CNRS 6510, Université de Rennes 1, Bâtiment 10A, Case 1003, Campus Scientifique de
Beaulieu, 35042 Rennes Cedex, France
Fax +33(2)23236955; E-mail: florence.mongin@univ-rennes1.fr
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow CM19 5AW, UK
b
Received 9 July 2009
whole study, as well as the use of the deprotonation–trans-
metalation–coupling sequence as a key step for the syn-
thesis of molecules of biological interest.
Abstract: Several analogues of isomeridianin G have been synthe-
sized using palladium-catalyzed cross-coupling reactions of lithium
triorganozincates as a key step. The latter have been prepared by
deprotonative lithiation followed by transmetalation using
ZnCl2·TMEDA (0.33 equiv).
For this present study, numerous lithioaromatics obtained
by deprotonation were transmetalated using 0.33 equiva-
lent of ZnCl2·TMEDA. The lithium triarylzincates gener-
ated were then involved in cross-coupling reactions with
aromatic halides using catalytic amounts of palladium(II)
chloride and 1,1¢-bis(diphenylphosphino)ferrocene (dppf)
(2 mol% each).13
Key words: cross-coupling, heterocycles, palladium, zinc, lithium
The importance of heterobiaryls in compounds of biolog-
ical interest have stimulated tremendous efforts for the de-
velopment of synthetic methods in the area of aryl–aryl
bond formation.1 Like the Suzuki–Miyaura2 and Stille3 re-
actions, the Negishi4 cross-couplings between organo-
zincs and aryl halides are known to tolerate numerous
functional groups. When compared with the first reac-
tions, the latter become attractive when heteroaryl boronic
acids cannot be prepared; furthermore they do not require
highly toxic starting materials.
Diverse 4-substituted bromobenzenes14 were used
(Table 1). Thiophene was lithiated using butyllithium in
tetrahydrofuran (THF) at –75 °C,15 before the transmeta-
lation step to generate lithium tri(2-thienyl)zincate. The
subsequent palladium-catalyzed cross-coupling was per-
formed with 4-bromoanisole, 4-bromonitrobenzene,
methyl 4-bromobenzoate, and 4-bromobenzonitrile at
55 °C to afford the corresponding derivatives 1a–d in
yields ranging from 10%16 to 79% (entries 1–4). It was no-
ticed that reactions performed with the corresponding
chlorobenzenes, which have higher carbon–halogen bond
dissociation energies,17 failed. N-Boc-indole was deproto-
nated upon treatment with lithium 2,2,6,6-tetramethylpip-
eridide (LiTMP) in THF at –90 °C,18,19 and then treated
similarly to provide the expected substituted N-Boc-2-
phenylindoles 2a–c (entries 5–7). These conditions also
proved suitable for the functionalization of 5-fluoro and 5-
bromo N-Boc-indoles (compounds 3, 4a,b, entries 8–10).
Activated heteroaryl chlorides20 were also used to prepare
bis(heterocycles) (Table 2). The 2-lithiobenzo[b]furan
derivative was prepared using butyllithium in THF at
–15 °C,21 and converted to the corresponding lithium
arylzincate. Subsequent cross-coupling with 2,4-dichloro-
pyrimidine and 2-chloropyridine provided the expected
bis(heterocycles) 5a,b in satisfying yields (entries
1,2).22,23 The furylpyrimidine 6 was prepared similarly
(entry 3).24 Benzo[b]thiophene, thiophene, and 2-chloro-
thiophene were deprotonated using butyllithium at –75 °C,15
and the lithio derivatives gave the corresponding coupled
products 7a,b, 1e, and 8 (entries 4–7). N-Boc-pyrrole was
deprotonated upon treatment with LiTMP in THF at
–75 °C25 to give the pyrimidyl and pyridyl derivatives
9a,b after subsequent transmetalation-coupling reactions
(entries 8,9). The syntheses of the 2-indolylpyridine 2e
The organozincs are often prepared by reacting the corre-
sponding lithium or magnesium compounds with zinc ha-
lides.5 A drawback of the Negishi coupling procedure lies
in the fact that anhydrous zinc chloride or zinc bromide is
required.
Miller and Farrell reported the use of a catalytic amount
of zinc chloride to perform nickel- or palladium-catalyzed
couplings of aryl Grignard reagents with aryl halides.6
Other studies avoided the use of a zinc salt by generating
lithium zincates either by iodine–metal exchange7 or by
deprotonation.8 In 2002, Gauthier and co-workers docu-
mented an approach through lithium zincates using only
one third equivalent of zinc chloride for the synthesis of
5-aryl-2-furaldehydes from 5-lithio-2-furaldehyde diethyl
acetal.9 In addition, Mutule and Suma described in 2005 a
one-pot Grignard formation–transmetalation–Negishi re-
actions using the less hygroscopic TMEDA-chelated zinc
chloride.10
We have recently published palladium-catalyzed Negishi
reactions11 for which the lithium triarylzincates were gen-
erated by transmetalation of the corresponding lithio com-
pounds using ZnCl2·TMEDA.12 Herein, we report the
SYNTHESIS 2009, No. 21, pp 3617–3632
x
x.
x
x
.
2
0
0
9
Advanced online publication: 08.09.2009
DOI: 10.1055/s-0029-1217003; Art ID: Z14909SS
© Georg Thieme Verlag Stuttgart · New York

3618
A. Seggio et al.
PAPER
Table 1 Coupling Reactions of Lithium Triarylzincates with Sub-
stituted Phenyl Bromides (continued)
and -pyrimidines 2d,10–13 were performed from differ-
ent 2-lithiated N-Boc-indoles generated by deprotonation
using LiTMP at –90 °C (entries 10–15). Anisole was sim-
ilarly ortho-functionalized after direct lithiation at 25 °C26
to afford the 2-pyridyl derivative 14 (entry 16). The reac-
tion also proved convenient for the functionalization of a
p-deficient substrate, 2-fluoropyridine, which was con-
verted into the unsymmetrical bipyridine 15 (entry 10) af-
ter lithiation using LiTMP in THF at –75 °C,27 followed
by transmetalation and cross-coupling steps.
1) base, THF, temp, 1 h
2) ZnCl2•TMEDA (0.33 equiv), r.t., 1 h
3)
Br
Ar
R
Ar
H
R
PdCl2 (2 mol%), dppf (2 mol%)
55 °C, 12 h
4) hydrolysis
En- Substrate
try
Base,
Temp
(°C)
Product
Yield
(%)
Table 1 Coupling Reactions of Lithium Triarylzincates with Sub-
stituted Phenyl Bromides
Br
Br
1) base, THF, temp, 1 h
2) ZnCl2•TMEDA (0.33 equiv), r.t., 1 h
LiTMP,
–90
9
66
31
3)
Br
N
N
Ar
CO2Me
R
Boc
Boc
Ar
H
R
PdCl2 (2 mol%), dppf (2 mol%)
55 °C, 12 h
4) hydrolysis
4a
Br
Br
LiTMP,
–90
En- Substrate
try
Base,
Temp
(°C)
Product
Yield
(%)
10
N
Boc
N
CF3
Boc
4b
BuLi,
–75
a Coupling step performed in the presence of DME (5 equiv).14g
1
S
S
10
OMe
NO2
S
1a
1b
1c
1d
Meridianins are a family of compounds isolated and char-
acterized from the south atlantic tunicate Aplidium merid-
ianum.28 Some of them proved to inhibit GSK-3
(Glycogen Synthase Kinase),29 a kinase involved in the
abnormal phosphorylation of tau protein and the produc-
tion of b-amyloid – two processes implicated in Alz-
heimer’s disease30 (Figure 1).
BuLi,
–75
38
2
76a
S
BuLi,
–75
3
41
79
S
CO2Me
S
N
R1
R
BuLi,
–75
NH2
4
S
N
CN
S
NH2
N
R2
N
N
H
N
R3
meridianin B (R1 = OH, R2 = Br,
3 = H): 0.5 μM
meridianin E (R1 = OH, R2 = H,
3 = Br): 2.5 μM
H
LiTMP,
–90
5
48
61
60
isomeridianin C (R = Br): >1000 μM
isomeridianin G (R = H): 420 μM
N
R
N
CO2Me
Boc
Boc
R
2a
Figure 1 Inhibition Activities (IC50) at GSK-3b of meridianins B
and E, and isomeridianins C and G.
LiTMP,
–90
6
7
N
N
CN
Boc
Boc
2b
2c
The method we developed proved suitable to prepare iso-
meridianin G as well as different analogues.31 The re-
placement of the indole ring by other five-membered
aromatic heterocycles was first considered. To this pur-
pose, the chloro group of 2-chloropyrimidyl compounds
2d, 9a, 5a, 6, 7a, and 1e was substituted with allylamine
to afford the derivatives 16–21 after subsequent cleavage
of the allyl group under classical conditions32 (Table 3).
LiTMP,
–90
N
N
CF3
Boc
Boc
F
F
LiTMP,
–90
8
36
N
N
CF3
Boc
Boc
3
Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York

PAPER
Cross-Couplings of Lithium Arylzincates/Synthesis of Isomeridianin G Analogues
3619
Table 2 Coupling Reactions of Lithium Triarylzincates with Het-
eroaryl Chlorides
Table 2 Coupling Reactions of Lithium Triarylzincates with Het-
eroaryl Chlorides (continued)
1) base, THF, Temp, 1 h
1) base, THF, Temp, 1 h
2) ZnCl2•TMEDA (0.33 equiv), r.t., 1 h
3)
2) ZnCl2•TMEDA (0.33 equiv), r.t., 1 h
3)
Cl
N
R
Cl
N
R
R
R
N
N
Ar
Ar
X
X
X
Ar
H
X
Ar
H
PdCl2 (2 mol%), dppf (2 mol%)
55 °C, 12 h
4) hydrolysis
PdCl2 (2 mol%), dppf (2 mol%)
55 °C, 12 h
4) hydrolysis
Entry Substrate
Base,
Temp
(°C)
Product
Yield
(%)
Entry Substrate
Base,
Temp
(°C)
Product
Yield
(%)
Cl
N
BuLi,
–15
LiTMP,
–90
N
1
56
11
27
O
N
N
N
O
Boc
2e
Boc
5a
OMe
OMe
N
N
BuLi,
–15
61
2
3
76a
O
LiTMP,
–90
Cl
12
13
18b
N
O
N
N
5b
Boc
Cl
Boc
N
10
BuLi,
–15
61
O
N
Br
Br
O
6
LiTMP,
–90
17b
Cl
N
N
Cl
N
N
BuLi,
–75
N
4
5
29b
Boc
Boc
S
N
11
S
S
NC
7a
NC
Cl
LiTMP,
–90
14
15
21b
N
BuLi,
–75
N
N
81
N
N
S
Boc
Boc
12
7b
1e
8
O2N
O2N
Cl
N
BuLi,
–75
Cl
LiTMP,
–90
20b
6
7
8
56
N
S
N
N
S
N
N
N
Boc
Boc
13
BuLi,
–75
OMe
Cl
85
S
Cl
OMe
S
BuLi,
25c
N
16
17
64
62
Cl
N
LiTMP,
–75
25b
14
F
N
N
N
N
Boc
Boc
N
F
9a
9b
LiTMP,
–75
N
N
LiTMP,
–75
9
61
N
N
15
Boc
Boc
a Coupling step performed in presence of DME (5 equiv).14g
b Since 2,4-dichloropyrimidine rapidly reacts with damp air, lower
yields can be partly attributed to the presence of pyrimidinone in the
starting heteroaryl chloride.
Cl
N
LiTMP,
–90
10
25b
c Reaction time: 2 h instead of 1 h.
N
Boc
N
N
Boc
2d
Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York

3620
A. Seggio et al.
PAPER
Table 3 Synthesis of Isomeridianin G and Pyrimidine Analogues
Table 4 Synthesis of Indole Analogues
Cl
NH2
TFA, CH2Cl2
r.t., 2 h (A)
N
N
Ar
Ar
MeSO3H, 10% Pd/C
EtOH, reflux, 3 d
H2N
N
N
reflux, 2 h
Ar
Ar
or
N
Boc
N
H
2d, 9a, 5a, 6, 7a, 1e
TBAF, THF
reflux, 10 h (B)
16–21
2a–c,e, 3, 4a, b
22–28
Entry Substrate
Product
Yield (%) (2 steps)
Entry Sub- Method
strate
Product
Yield
(%)
NH2
N
1
2
2d
9a
48a
N
N
H
16 (isomeridianin G)
1
2
3
2a
2b
2c
A
A
B
52
N
H
NH2
CO2Me
N
70a
55
26
58
29
N
22
23
24
N
H
17
46
55
N
NH2
H
CN
N
3
4
5
6
5a
6
O
N
18
NH2
N
N
H
CF3
O
N
F
19
NH2
4
5
3
A
A
46
31
N
7a
1e
N
S
H
CF3
CO2Me
CF3
N
25
26
20
Br
NH2
N
S
4a
N
N
H
21
a Cleavage of the Boc protection occurred during the first step.
Br
The replacement of the pyrimidine group by other six-
membered ring aromatics was then considered. This was
achieved by cleavage of the Boc protective group of cou-
pled compounds using either trifluoroacetic acid (TFA) in
dichloromethane at room temperature33 or tetrabutylam-
monium fluoride (TBAF) under reflux of THF34 to pro-
vide the indole analogues 22–28 (Table 4).
6
7
4b
2e
A
B
30
67
N
H
27
28
N
N
H
Finally, analogues containing both indole and pyrimidine
rings with diverse amino groups on the 2-position of the
pyrimidyl ring were synthesized from the chloro com-
pound 2d. The substitution of the chloro group was per-
formed using a large range of amines under microwave
irradiation35 after initial Boc cleavage using TFA.
cross-coupling between an aromatic halide and a lithium
triorganozincate which has been prepared by deproto-
lithiation followed by transmetalation using ZnCl2·TMEDA
(1/3 equiv). As compared with isomeridianin G (IC50 =
420 mM), the inhibition activity at GSK-3b has been great-
ly improved, with an IC50 value of 4.9 mM for the best
compound 44. It would be interesting to make further an-
alogues of compound 44 containing an hydroxy group at
the 4-position or/and a bromo group at the 6- or 7-posi-
tion, such as meridianin templates.
The GSK-3b inhibition activity (IC50 values) of the iso-
meridianin G analogues 16–47 was evaluated. While most
of the compounds showed a weak activity (IC50 >27 mM),
analogues 29, 31, 33, 44, and 46 were, however, found to
inhibit GSK-3b in the 5–25 mM range (Table 5).
In conclusion, several analogues of isomeridianin G have
been synthesized and evaluated as GSK-3b inhibitors.
The key step of their synthesis is a palladium-catalyzed
Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York

PAPER
Cross-Couplings of Lithium Arylzincates/Synthesis of Isomeridianin G Analogues
3621
Table 5 Synthesis of both Pyrimidine and Indole Analogues of Iso-
meridianin G, and Inhibition Activities at GSK-3b
Table 5 Synthesis of both Pyrimidine and Indole Analogues of Iso-
meridianin G, and Inhibition Activities at GSK-3b (continued)
NHR
NHR
TFA
RNH2
TFA
RNH2
N
N
2d
Entry
1
2d
N
N
H
CH2Cl2
r.t., 2 h
pyridine–EtOH
MW, 150 °C, 20 min
CH2Cl2
pyridine–EtOH
N
N
H
r.t., 2 h MW, 150 °C, 20 min
29–47
29–47
Product
Yield (%) IC50
(2 steps) (mM)
Entry
Product
Yield (%) IC50
(2 steps) (mM)
OMe
H
N
N
44
48
20.4
>27
H
N
H
9
42
>27
N
N
N
N
29
N
H
37
H
N
N
2
3
N
H
N
H
N
10
11
12
36
10
12
>27
>27
>27
N
30
Cl
N
N
H
H
N
N
38
59
45
11.5
>27
N
H
N
H
N
Cl
31
N
N
N
H
H
N
N
4
5
39
CF3
Cl
N
N
H
32
H
N
N
N
N
H
H
CF3
N
N
33
49
24.5
>27
40
N
N
H
33
H
N
13
14
41
43
>27
>27
N
CF3
F
N
N
H
H
N
N
6
41
N
N
H
34
H
N
N
H
N
N
N
N
7
8
50
43
>27
>27
H
OMe
N
42
N
H
MeO
OMe
35
H
OMe
15
37
>27
H
OMe
N
N
N
N
N
N
N
H
N
H
43
36
Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York

3622
A. Seggio et al.
PAPER
N-Boc-Protected Indoles; General Procedure19
Table 5 Synthesis of both Pyrimidine and Indole Analogues of Iso-
meridianin G, and Inhibition Activities at GSK-3b (continued)
To a stirred solution of the required indole (35 mmol) in CH2Cl2 (70
mL) were successively added pyridine (3.7 mL, 45 mmol), Boc2O
(9.9 g, 45 mmol), and DMAP (0.43 g, 3.5 mmol). The mixture was
stirred for 24 h at r.t. before addition of sat. aq NH4Cl (50 mL) and
extraction with EtOAc (3 × 50 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The residue was purified by chromatography on silica gel (the
eluent is given in the product description).
NHR
TFA
RNH2
N
2d
N
CH2Cl2
pyridine–EtOH
N
H
r.t., 2 h MW, 150 °C, 20 min
29–47
Entry
Product
Yield (%) IC50
(2 steps) (mM)
N-Boc-indole
Eluent: heptane–CH2Cl2 (50:50); yield: 5.1 g (67%); colorless oil.
1H NMR (200 MHz, CDCl3): d = 1.67 (s, 9 H), 6.56 (d, J = 3.5 Hz,
1 H), 7.17–7.40 (m, 2 H), 7.56 (m, 1 H), 7.60 (d, J = 3.5 Hz, 1 H),
8.19 (d, J = 8.1 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 28.3 (3 C), 83.7, 107.4, 115.3,
121.1, 122.8, 124.3, 126.0, 130.7, 135.3, 149.9.
H
N
N
16
17
73
65
4.9
N
44
N
N
H
N
N
The spectral data were identical to those of a commercial sample.
O
N-Boc-5-nitroindole38
Eluent: hexane–CH2Cl2 (95:5 to 50:50); yield: 9.0 g (99%); white
powder; mp 115 °C.
1H NMR (400 MHz, CDCl3): d = 1.65 (s, 9 H), 6.71 (d, J = 4.0 Hz,
1 H), 7.73 (d, J = 4.0 Hz, 1 H), 8.19 (dd, J = 9.2, 2.4 Hz, 1 H), 8.26
(d, J = 9.2 Hz, 1 H), 8.48 (d, J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 28.3 (3 C), 85.4, 108.1, 115.5,
117.5, 119.7, 129.1, 130.5, 138.5, 143.9, 149.2.
H
N
>27
N
H
45
H
N
N
18
19
70
50
13.8
>27
N
N
H
ESCI MS: m/z = 206.77, 262.81 [M + H]+.
46
Anal. Calcd for C13H14N2O4 (262.26): C, 59.54; H, 5.38; N, 10.68.
Found: C, 59.53; H, 5.33; N, 10.44.
H
N
N
N
Me
N
N-Boc-5-cyanoindole
N
H
Eluent: hexane–CH2Cl2 (95:5 to 50:50); yield: 8.2 g (97%); white
powder, mp 128 °C (Lit.39 mp 128–129 °C).
47
1H NMR (400 MHz, CDCl3): d = 1.68 (s, 9 H), 6.62 (dd, J = 3.9, 0.9
Hz, 1 H), 7.56 (dd, J = 8.5, 1.7 Hz, 1 H), 7.70 (d, J = 3.9 Hz, 1 H),
7.89 (dd, J = 1.7, 0.9 Hz, 1 H), 8.25 (d, J = 8.5 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 28.3 (3 C), 85.2, 106.3, 107.2,
116.2, 120.1, 126.0, 127.6, 128.3, 130.7, 137.3, 149.3.
Metalation reactions were performed under argon atmosphere. THF
was distilled over sodium/benzophenone. LiTMP was prepared in
situ in THF at 0 °C from 2,2,6,6-tetramethylpiperidine and BuLi
(1.6 M solution in hexanes). ZnCl2·TMEDA was prepared as de-
scribed previously.36 Column chromatography separations were
achieved on silica gel (40–63 mm). Mass-Directed AutoPreparative
HPLC (MDAP) analyses were performed using a Waters ZQ instru-
ment with H2O–MeCN as gradient. Melting points were measured
on a Kofler apparatus. 1H and 13C NMR spectra were recorded on a
Bruker ARX-200 spectrometer at 200 and 50 MHz, respectively, on
a Bruker Avance III spectrometer at 300 and 75 MHz, respectively,
or on a Bruker AC-400 spectrometer at 400 and 100 MHz, respec-
tively. 1H chemical shifts (d) are given in ppm relative to the solvent
residual peak, and 13C chemical shifts relative to the central peak of
the solvent signal.37 Low-resolution mass spectra measurements
were performed using a Waters ZQ instrument in ElectroSpray
Chemical Ionization (ESCI) mode. High-Resolution Mass Spectra
(HRMS) measurements and elemental analyses were performed at
the CRMPO (Centre Régional de Mesures Physiques de l’Ouest) of
Rennes using a Micromass MS/MS ZABSpec TOF instrument in EI
mode and a Thermo-Finnigan Flash EA 1112 CHNS analyzer, re-
spectively. The reactions under microwave irradiation were per-
formed in a Biotage Initiator instrument. Kinase inhibition activity
at GSK-3b of isomeridianin G and analogues was measured at
GlaxoSmithKline R & D Harlow from an in vitro assay, following
an in-house procedure.
ESCI MS: m/z = 186.90, 242.92 [M + H]+.
Anal. Calcd for C14H14N2O2 (242.27): C, 69.41; H, 5.82; N, 11.56.
Found: C, 69.38; H, 5.79; N, 11.58.
The spectral data were identical to those previously described.39
N-Boc-4-methoxyindole
Eluent: hexane–CH2Cl2 (95:5 to 50:50); yield: 7.5 g (88%); color-
less oil.
1H NMR (400 MHz, CDCl3): d = 1.67 (s, 9 H), 3.94 (s, 3 H), 6.67
(d, J = 7.9 Hz 1 H), 6.69 (dd, J = 3.9, 0.9 Hz, 1 H), 7.23 (dd, J = 8.3,
7.9 Hz, 1 H), 7.50 (d, J = 3.9 Hz, 1 H), 7.75 (d, J = 8.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 28.4 (3 C), 55.6, 83.9, 103.2,
104.5, 108.5, 121.0, 124.6, 125.3, 136.7, 150.1, 153.1.
Anal. Calcd for C14H17NO3 (247.29): C, 68.00; H, 6.93; N, 5.66.
Found: C, 67.99; H, 6.87; N, 5.64.
N-Boc-4-bromoindole
Eluent: hexane–CH2Cl2 (100:0 to 50:50); yield: 9.4 g (91%); color-
less oil.
1H NMR (400 MHz, CDCl3): d = 1.67 (s, 9 H), 6.64 (d, J = 3.9 Hz,
1 H), 7.16 (dd, J = 8.3, 7.9 Hz, 1 H), 7.39 (dd, J = 7.9, 0.9 Hz, 1 H),
7.64 (d, J = 3.9 Hz, 1 H), 8.11 (d, J = 8.3 Hz, 1 H).
Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York

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Cross-Couplings of Lithium Arylzincates/Synthesis of Isomeridianin G Analogues
3623
13C NMR (100 MHz, CDCl3): d = 28.3 (3C), 84.5, 107.3, 114.4,
2-(4-Cyanophenyl)thiophene (1d)
114.9, 125.3, 125.7, 126.7, 131.3, 135.8, 149.7.
Prepared from thiophene (0.32 mL) using BuLi at –75 °C and 4-
bromobenzonitrile (0.73 g); eluent: heptane–CH2Cl2 (100:0 to
80:20); yield: 0.54 g (79%); white powder; mp 88 °C.
1H NMR (200 MHz, CDCl3): d = 7.13 (dd, J = 4.9, 3.7 Hz, 1 H),
7.40 (dd, J = 5.1, 1.2 Hz, 1 H), 7.43 (dd, J = 3.7, 1.2 Hz, 1 H), 7.66
(d, J = 8.8 Hz, 2 H), 7.70 (d, J = 8.5 Hz, 2 H).
Anal. Calcd for C13H14BrNO2 (296.16): C, 52.72; H, 4.76; N, 4.73.
Found: C, 52.70; H, 4.66; N, 4.72.
N-Boc-5-fluoroindole
Eluent: heptane–CH2Cl2 (60:40); yield: 5.7 g (70%); colorless oil.
1H NMR (200 MHz, CDCl3): d = 1.67 (s, 9 H), 6.52 (d, J = 3.7 Hz,
1 H), 7.03 (ddd, J = 9.2, 9.0, 2.5 Hz, 1 H), 7.21 (dd, J = 9.2, 2.5 Hz,
1 H), 7.63 (d, J = 3.7 Hz, 1 H), 8.09 (dd, J = 9.0, 4.5 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 110.3, 118.7, 125.0, 125.9, 127.0,
128.4 (2 C), 132.6 (2 C), 138.5, 141.9.
The spectral data were identical to those previously described.44
These data were identical to those previously described.40
N-Boc-2-(4-methoxycarbonylphenyl)indole (2a)45
Prepared from N-Boc-indole (0.81 mL) using LiTMP at –90 °C and
methyl 4-bromobenzoate (0.86 g); eluent: heptane–CH2Cl2 (70:30);
yield: 0.68 g (48%); white powder; mp 190 °C.
13C NMR (50 MHz, CDCl3): d = 28.4 (3 C), 84.1, 106.5 (d, J = 23
Hz), 107.1 (d, J = 3.9 Hz), 112.2 (d, J = 25 Hz), 116.2 (d, J = 9.3
Hz), 127.6 (2 C), 131.6 (d, J = 10 Hz), 149.7, 159.4 (d, J = 239 Hz).
N-Boc-5-bromoindole
Eluent: heptane–CH2Cl2 (60:40); yield: 10 g (97%); brown-purple
powder; mp 56 °C.
1H NMR (300 MHz, acetone-d6): d = 1.29 (s, 9 H), 3.92 (s, 3 H),
6.68 (s, 1 H), 7.16–7.41 (m, 2 H), 7.49–7.62 (m, 3 H), 8.08 (m, 2 H),
8.26 (d, J = 7.5 Hz, 1 H).
1H NMR (200 MHz, CDCl3): d = 1.67 (s, 9 H), 6.51 (d, J = 3.5 Hz,
1 H), 7.39 (dd, J = 9.1, 2.0 Hz, 1 H), 7.59 (d, J = 3.5 Hz, 1 H), 7.68
(d, J = 2.0 Hz, 1 H), 8.02 (d, J = 9.1 Hz, 1 H).
13C NMR (75 MHz, acetone-d6): d = 28.6 (3 C), 53.3, 85.3, 112.5,
116.8, 122.6, 124.8, 126.4, 130.5 (2 C), 130.7 (2 C), 130.9 (2 C),
139.5, 141.0, 141.1, 151.4, 167.8.
13C NMR (50 MHz, CDCl3): d = 28.3 (3 C), 84.3, 106.7, 116.2,
116.8, 123.7 (2 C), 127.2, 132.4, 134.1, 149.6.
Anal. Calcd for C21H21NO4 (351.40): C, 71.78; H, 6.02; N, 3.99.
Found: C, 71.96; H, 6.14; N, 4.13.
These data were identical to those previously described.41
N-Boc-2-(4-cyanophenyl)indole (2b)
Prepared from N-Boc-indole (0.81 mL) using LiTMP at –90 °C and
4-bromobenzonitrile (0.73 g); eluent: heptane–CH2Cl2 (70–30);
yield: 0.78 g (61%); white powder; mp 121 °C.
1H NMR (300 MHz, acetone-d6): d = 1.35 (s, 9 H), 6.80 (s, 1 H),
7.22–7.44 (m, 2 H), 7.64 (dd, J = 7.5, 1.1 Hz, 1 H), 7.72 (m, 2 H),
7.88 (m, 2 H), 8.22 (d, J = 8.5 Hz, 1 H).
Deprotonation–Cross-Coupling Sequence; General Procedure
To a stirred and cooled solution (temperature given in the product
description) of the appropriate reagent (4.0 mmol) in anhyd THF (5
mL) under argon were added the required base (4.0 mmol) and, 1 h
later, ZnCl2·TMEDA35 (0.33 g, 1.3 mmol). The mixture was slowly
warmed to r.t. (1 h) before addition of the appropriate aromatic ha-
lide (4.0 mmol), PdCl2 (14 mg, 80 mmol), and dppf (44 mg, 80
mmol), and heated at 55 °C for 12 h. The mixture was cooled before
addition of H2O (0.5 mL). Extraction with EtOAc (2 × 25 mL), dry-
ing (Na2SO4), and removal of the solvents under reduced pressure
afforded a crude compound, which was purified by chromatography
on silica gel (the eluent is given in the product description)
(Tables 1 and 2).
These data were identical to those previously described.46
13C NMR (75 MHz, acetone-d6): d = 28.7 (3 C), 85.8, 112.8, 113.1,
117.0, 117.6, 122.8, 125.1, 126.8, 131.0, 131.4 (2 C), 133.6 (2 C),
139.6, 140.5, 141.3, 151.5.
HRMS: m/z calcd for C20H18N2O2 (M+): 318.1368; found:
318.1391.
Anal. Calcd for C20H18N2O2 (318.37): C, 75.45; H, 5.70; N, 8.80.
Found: C, 75.46; H, 5.80; N, 8.72.
2-(4-Methoxyphenyl)thiophene (1a)
Prepared from thiophene (0.32 mL) using BuLi at –75 °C and 4-
bromoanisole (0.50 mL); eluent: heptane–CH2Cl2 (100:0 to 95:5);
yield: 67 mg (10%); beige powder; mp 104 °C.
1H NMR (200 MHz, CDCl3): d = 3.84 (s, 3 H), 6.92 (d, J = 8.8 Hz,
2 H), 7.05 (dd, J = 5.0, 3.5 Hz, 1 H), 7.21 (m, 2 H), 7.55 (d, J = 8.8
Hz, 2 H).
N-Boc-2-(4-trifluoromethylphenyl)indole (2c)
Prepared from N-Boc-indole (0.81 mL) using LiTMP at –90 °C and
1-bromo-4-(trifluoromethyl)benzene (0.55 mL); eluent: heptane–
toluene (80:20 to 40:60); yield: 0.86 g (60%); white powder; mp
104 °C.
13C NMR (50 MHz, CDCl3): d = 55.3, 114.2 (2 C), 122.0, 123.8,
1H NMR (300 MHz, acetone-d6): d = 1.34 (s, 9 H), 6.62 (s, 1 H),
7.29 (dd, J = 7.5, 1.5 Hz, 1 H), 7.37 (ddd, J = 8.3, 7.5, 1.5 Hz, 1 H),
7.51–7.61 (m, 3 H), 7.67 (d, J = 8.3 Hz, 2 H), 8.21 (d, J = 8.3 Hz, 1
H).
127.2 (2 C), 127.4, 127.9, 144.3, 159.1.
The spectral data were identical to those previously described.42
13C NMR (75 MHz, acetone-d6): d = 27.6 (3 C), 83.9, 111.0, 115.3,
120.7, 123.2, 124.2 (q, J = 272 Hz), 124.7, 124.8 (2 C), 128.9 (2 C),
129.0, 129.6 (q, J = 32 Hz), 137.5, 138.5, 138.8, 149.9.
Methyl 4-(2-Thienyl)benzoate (1c)
Prepared from thiophene (0.32 mL) using BuLi at –75 °C and
methyl 4-bromobenzoate (0.86 g); eluent: heptane–CH2Cl2 (100:0
to 80:20); yield: 0.36 g (41%); white powder; mp 134 °C.
1H NMR (300 MHz, CDCl3): d = 3.94 (s, 3 H), 7.12 (dd, J = 4.9, 3.6
Hz, 1 H), 7.36 (dd, J = 5.1, 1.1 Hz, 1 H), 7.42 (dd, J = 3.6, 1.3 Hz,
1 H), 7.67 (d, J = 8.8 Hz, 2 H), 8.04 (d, J = 8.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 53.8, 124.4, 125.5 (2 C), 126.2,
128.4, 129.1, 130.2 (2 C), 138.5, 143.1, 166.7.
The spectral data were identical to those previously described.43
These data were identical to those previously described.47
N-Boc-5-fluoro-2-(4-trifluoromethylphenyl)indole (3)
Prepared from N-Boc-5-fluoroindole (0.59 g) using LiTMP at
–90 °C and 1-bromo-4-(trifluoromethyl)benzene (0.34 mL); eluent:
heptane–CH2Cl2 (100:0 to 70:30); yield: 0.34 g (36%); yellow pow-
der; mp 117 °C.
1H NMR (300 MHz, acetone-d6): d = 1.32 (s, 9 H), 6.75 (s, 1 H),
7.16 (ddd, J = 9.0, 8.3, 3.0 Hz, 1 H), 7.35 (dd, J = 8.3, 3.0 Hz, 1 H),
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A. Seggio et al.
PAPER
7.72 (d, J = 8.3 Hz, 2 H), 7.82 (d, J = 8.3 Hz, 2 H), 8.22 (dd, J = 9.0,
3.0 Hz, 1 H).
1H NMR (200 MHz, CDCl3): d = 6.60 (dd, J = 3.5, 1.5 Hz, 1 H),
7.38 (dd, J = 3.5, 1.0 Hz, 1 H), 7.51 (d, J = 5.2 Hz, 1 H), 7.63 (m, 1
H), 8.57 (d, J = 5.2 Hz, 1 H).
The 1H NMR spectrum was identical to that previously described.23
13C NMR (50 MHz, CDCl3): d = 113.1, 113.1, 114.5, 146.2, 150.4,
158.1, 159.9, 161.7.
13C NMR (75 MHz, acetone-d6): d = 28.6 (3 C), 85.9, 107.9 (d,
J = 24 Hz), 112.2 (d, J = 4.4 Hz), 114.1 (d, J = 25 Hz), 118.3 (d,
J = 9.9 Hz), 126.6 (2 C), 128.1 (q, J = 214 Hz), 131.1 (q, J = 31 Hz),
131.3 (2 C), 131.9 (d, J = 11 Hz), 135.9, 140.5, 142.4, 151.3, 161.2
(d, J = 238 Hz).
HRMS: m/z calcd for C20H17F4NO2 (M+): 379.1195; found:
4-(2-Benzo[b]thienyl)-2-chloropyrimidine (7a)
379.1183.
Prepared from benzo[b]thiophene (0.54 g) using BuLi at –75 °C and
2,4-dichloropyrimidine (0.60 g); eluent: heptane–EtOAc (100:0 to
70:30); yield: 0.29 g (29%); pale yellow powder; mp 198 °C.
1H NMR (200 MHz, CDCl3): d = 7.38–7.46 (m, 2 H), 7.59 (d,
J = 5.5 Hz, 1 H), 7.82–7.92 (m, 2 H), 8.12 (s, 1 H), 8.60 (d, J = 5.5
Hz, 1 H).
The 1H NMR spectrum was identical to that previously described.23
13C NMR (50 MHz, CDCl3): d = 114.5, 122.9, 125.2, 125.3, 126.3,
126.9, 139.8, 140.1, 141.8, 159.7, 161.9, 162.3.
N-Boc-5-bromo-2-(4-methoxycarbonylphenyl)indole (4a)
Prepared from N-Boc-5-bromoindole (1.2 g) using LiTMP at
–90 °C and methyl 4-bromobenzoate (0.86 g); eluent: heptane–
CH2Cl2 (50:50 to 40:60); yield: 1.1 g (66%); beige powder; mp
154 °C.
1H NMR (300 MHz, acetone-d6): d = 1.31 (s, 9 H), 3.92 (s, 3 H),
6.74 (s, 1 H), 7.49 (dd, J = 8.5, 2.0 Hz, 1 H), 7.65 (d, J = 8.6 Hz, 2
H), 7.81 (d, J = 2.0 Hz, 1 H), 8.10 (d, J = 8.6 Hz, 2 H), 8.15 (d,
J = 8.5 Hz, 1 H).
13C NMR (75 MHz, acetone-d6): d = 28.6 (3 C), 53.4, 86.1, 111.5,
117.6, 118.7, 125.1, 129.1, 130.7 (2 C), 130.9, 131.4 (2 C), 132.8,
138.3, 140.7, 142.5, 151.2, 167.9.
HRMS: m/z calcd for C21H2079BrNO4 (M+): 429.0576; found:
429.0543.
2-(2-Benzo[b]thienyl)pyridine (7b)
Prepared from benzo[b]thiophene (0.54 g) using BuLi at –75 °C and
2-chloropyridine (0.38 mL); eluent: heptane–CH2Cl2 (50:50 to
30:70); yield: 0.69 g (81%); white powder; mp 126 °C.
1H NMR (200 MHz, CDCl3): d = 7.21 (m, 1 H), 7.36 (m, 2 H), 7.73
(dt, J = 8.0, 1.6 Hz, 1 H), 7.81 (m, 4 H), 8.64 (d, J = 5.0 Hz, 1 H).
Anal. Calcd for C21H20BrNO4 (430.29): C, 58.62; H, 4.69; N, 3.26.
Found: C, 58.59; H, 4.89; N, 3.29.
13C NMR (50 MHz, CDCl3): d = 119.6, 121.1, 122.6 (2 C), 124.1,
124.5, 125.0, 136.6, 140.5, 140.6, 144.8, 149.7, 152.5.
The spectral data were identical to those of a commercial sample.
HRMS: m/z calcd for C13H9NS (M+): 211.0456; found: 211.0461.
N-Boc-5-bromo-2-(4-trifluoromethylphenyl)indole (4b)
Prepared from N-Boc-5-bromoindole (1.2 g) using LiTMP at
–90 °C and 1-bromo-4-(trifluoromethyl)benzene (0.54 mL); eluent:
heptane–CH2Cl2 (100:0 to 60:40); yield: 0.54 g (31%); white pow-
der; mp 104 °C.
1H NMR (300 MHz, acetone-d6): d = 1.31 (s, 9 H), 6.70 (s, 1 H),
7.46 (dd, J = 9.1, 2.0 Hz, 1 H), 7.59–7.85 (m, 5 H), 8.15 (d, J = 9.1
Hz, 1 H).
2-Chloro-4-(2-thienyl)pyrimidine (1e)
Prepared from thiophene (0.32 mL) using BuLi at –75 °C and 2,4-
dichloropyrimidine (0.60 g); eluent: heptane–EtOAc (100:0 to
80:20); yield: 0.44 g (56%); white powder; mp 124 °C.
The physical data were identical to those previously described.48
13C NMR (75 MHz, acetone-d6): d = 28.5 (3 C), 86.0, 111.6, 117.7,
118.7, 125.1, 125.8 (q, J = 271 Hz), 126.6 (q, J = 3.9 Hz, 2 C),
129.1, 130.6 (q, J = 32 Hz), 131.3 (2 C), 132.7, 138.1, 140.1 (q,
J = 1.6 Hz), 141.9, 151.1.
HRMS: m/z calcd for C20H1779BrF3NO2 (M+): 439.0394; found:
439.0401.
1H NMR (200 MHz, acetone-d6): d = 7.17 (dd, J = 7.5, 5.7 Hz, 1 H),
7.46 (d, J = 7.8 Hz, 1 H), 7.59 (dd, J = 7.5, 1.5 Hz, 1 H), 7.82 (dd,
J = 5.7, 1.5 Hz, 1 H), 8.53 (d, J = 8.1 Hz, 1 H).
13C NMR (50 MHz, acetone-d6): d = 113.7, 128.8, 129.2, 131.8,
140.5, 159.5, 161.7, 162.0.
2-(5-Chlorothienyl)pyridine (8)
4-(2-Benzo[b]furyl)-2-chloropyrimidine (5a)
Prepared from 2-chlorothiophene (0.37 mL) using BuLi at –75 °C
and 2-chloropyridine (0.38 mL); eluent: heptane–EtOAc (100:0 to
80:20); yield: 0.67 g (85%); pale yellow powder; mp 67 °C.
1H NMR (200 MHz, CDCl3): d = 6.91 (d, J = 3.8 Hz, 1 H), 7.15
(ddd, J = 7.1, 4.9, 1.5 Hz, 1 H), 7.33 (d, J = 3.8 Hz, 1 H), 7.56 (dt,
J = 8.1, 1.0 Hz, 1 H), 7.66 (ddd, J = 9.1, 7.6, 2.0 Hz, 1 H), 8.53 (dq,
J = 4.9, 1.0 Hz 1 H).
13C NMR (50 MHz, CDCl3): d = 117.2, 121.5, 122.9 (CH), 126.7,
131.4, 135.9, 143.0, 148.7, 150.8.
The spectral data were identical to those previously described.49
Prepared from benzo[b]furan (0.44 mL) using BuLi at –15 °C and
2,4-dichloropyrimidine (0.60 g); eluent: CH2Cl2–MeOH (100:0 to
80:20); yield: 0.52 g (56%); pale yellow powder; mp 186 °C.
1H NMR (200 MHz, acetone-d6): d = 7.37 (t, J = 7.8 Hz, 1 H), 7.51
(t, J = 7.8 Hz, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1
H), 7.90 (s, 1 H), 7.97 (d, J = 5.2 Hz, 1 H), 8.86 (d, J = 5.2 Hz, 1 H).
The 1H NMR spectrum was identical to that previously described.23
13C NMR (50 MHz, acetone-d6): d = 110.9, 112.4, 114.5, 123.5,
124.7, 127.8, 128.5, 152.2, 156.5, 158.6, 161.8, 162.1.
HRMS: m/z calcd for C12H735ClN2O (M+): 230.0247; found:
230.0238.
N-Boc-2-(2-chloro-4-pyrimidyl)indole (9a)
Prepared from N-Boc-indole (0.82 mL) using LiTMP at –75 °C and
2,4-dichloropyrimidine (0.60 g); eluent: hexane–CH2Cl2 (70:30 to
30:70; yield: 0.33 g (25%); beige powder; mp 114 °C.
Anal. Calcd for C12H7ClN2O (230.65): C, 62.49; H, 3.06; N, 12.15.
Found: C, 62.75; H, 3.13; N, 12.35.
1H NMR (400 MHz, CDCl3): d = 1.47 (s, 9 H), 7.02 (d, J = 0.9 Hz,
1 H), 7.28 (ddd, J = 7.9, 7.0, 0.9 Hz, 1 H), 7.43 (ddd, J = 8.3, 7.0,
1.3 Hz, 1 H), 7.45 (d, J = 5.3 Hz, 1 H), 7.62 (ddd, J = 7.9, 1.3, 0.9
Hz 1 H), 8.17 (dd, J = 8.3, 0.9 Hz, 1 H), 8.64 (d, J = 5.3 Hz, 1 H).
2-Chloro-4-(2-furyl)pyrimidine (6)
Prepared from furan (0.29 mL) using BuLi at –15 °C and 2,4-
dichloropyrimidine (0.60 g); eluent: heptane–EtOAc (100:0 to
80:20); yield: 0.45 g (61%); white powder; mp 88 °C.
Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York

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Cross-Couplings of Lithium Arylzincates/Synthesis of Isomeridianin G Analogues
3625
13C NMR (100 MHz, CDCl3): d = 27.9 (3 C), 84.9, 115.1, 115.4,
117.9, 122.0, 123.7, 126.9, 128.4, 135.6, 138.9, 149.7, 159.4, 161.1,
163.0.
N-Boc-4-bromo-2-(2-chloro-4-pyrimidyl)indole (11)
Prepared from N-Boc-4-bromoindole (1.2 g) using LiTMP at
–90 °C and 2,4-dichloropyrimidine (0.60 g); eluent: hexane–
CH2Cl2 (40:60 to 0:100); yield: 0.28 g (17%); beige powder; mp
125–126 °C.
1H NMR (400 MHz, CDCl3): d = 1.45 (s, 9 H), 7.06 (d, J = 0.9 Hz,
1 H), 7.29 (dd, J = 8.3, 7.9 Hz, 1 H), 7.45 (dd, J = 7.9, 0.9 Hz, 1 H),
7.50 (d, J = 4.8 Hz, 1 H), 8.12 (ddd, J = 8.3, 1.2, 0.9 Hz, 1 H), 8.68
(d, J = 4.8 Hz, 1 H).
Anal. Calcd for C17H16ClN3O2 (329.78): C, 61.91; H, 4.89; N,
12.74. Found: C, 61.90; H, 4.86; N, 12.69.
N-Boc-2-(2-pyridyl)pyrrole (9b)
Prepared from N-Boc-pyrrole (0.67 mL) using LiTMP at –75 °C
and 2-chloropyridine (0.38 mL);
eluent: heptane–CH2Cl2 (70:30 to 0:100); yield: 0.60 g (61%); yel-
low oil.
1H NMR (200 MHz, CDCl3): d = 1.31 (s, 9 H), 6.18 (t, J = 3.2 Hz,
1 H), 6.36 (dd, J = 3.5, 1.5 Hz, 1 H), 7.07–7.19 (m, 1 H), 7.29–7.39
(m, 2 H), 7.61 (ddd, J = 9.6, 7.5, 1.5 Hz, 1 H), 8.56 (d, J = 4.5 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 27.8 (3 C), 85.4, 114.3, 114.5,
115.7, 118.0, 126.5, 127.6, 129.2, 136.0, 139.0, 149.3, 159.7, 161.2,
162.6.
ESCI MS: m/z = 307.85, 309.82 [M + H – Boc]+, 353.76, 355.79
[M + H – t-Bu]+.
N-Boc-2-(2-chloro-4-pyrimidyl)-5-cyanoindole (12)
The spectral data were identical to those previously described.50
Prepared from N-Boc-5-cyanoindole (0.97 g) using LiTMP at
–90 °C and 2,4-dichloropyrimidine (0.60 g); eluent: hexane–
CH2Cl2 (50:50 to 0:100); yield: 0.29 g (21%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.42 (s, 9 H), 6.98 (s, 1 H), 7.50
(d, J = 4.8 Hz, 1 H), 7.60 (dd, J = 8.7, 1.7 Hz, 1 H), 7.91 (dd,
J = 1.7, 0.9 Hz, 1 H), 8.21 (d, J = 8.7 Hz, 1 H), 8.69 (d, J = 4.8 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 27.6 (3 C), 85.9, 106.9, 113.3,
116.2, 118.0, 119.4, 126.7, 128.1, 129.2, 137.4, 140.0, 148.6, 159.9,
161.0, 162.0.
N-Boc-2-(2-chloro-4-pyrimidyl)pyrrole (2d)
Prepared from N-Boc-pyrrole (0.67 mL) using LiTMP at –90 °C
and 2,4-dichloropyrimidine (0.60 g); eluent: heptane–CH2Cl2
(50:50 to 0:100); yield: 0.26 g (25%); beige powder; mp 102 °C.
1H NMR (200 MHz, CDCl3): d = 1.45 (s, 9 H), 6.25 (t, J = 3.5 Hz,
1 H), 6.69 (dd, J = 3.5, 2.0 Hz, 1 H), 7.31 (d, J = 5.5 Hz, 1 H), 7.41
(dd, J = 3.5, 2.0 Hz, 1 H), 8.51 (d, J = 5.5 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 27.7 (3 C), 85.1, 111.4, 117.6,
120.0, 127.1, 130.5, 148.8, 158.9, 160.7, 161.9.
HRMS: m/z calcd for C13H1435ClN3O2 (M+): 279.0774; found:
279.0787.
ESCI MS: m/z = 254.87, 256.86 [M + H – Boc]+, 298.88, 300.88
[M + H – t-Bu]+.
N-Boc-2-(2-chloro-4-pyrimidyl)-5-nitroindole (13)
N-Boc-2-(2-pyridyl)indole (2e)51
Prepared from N-Boc-indole (0.81 mL) using LiTMP at –90 °C and
2-chloropyridine (0.38 mL); eluent: heptane–CH2Cl2 (60:40 to
0:100); yield: 0.32 g (27%); brown oil.
1H NMR (300 MHz, CDCl3): d = 1.33 (s, 9 H), 6.77 (s, 1 H), 7.22–
7.29 (m, 2 H), 7.36 (ddd, J = 8.3, 6.8, 1.5 Hz, 1 H), 7.51 (dt, J = 7.5,
1.5 Hz, 1 H), 7.59 (d, J = 8.3 Hz, 1 H), 7.74 (ddd, J = 8.3, 7.5, 1.5
Hz, 1 H), 8.19 (d, J = 7.5 Hz, 1 H), 8.67 (d, J = 6.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 27.6 (3 C), 83.4, 111.0, 115.0,
120.9, 122.2, 122.9, 123.3, 124.9, 128.8, 136.0, 137.7, 139.3, 148.9,
150.0, 153.3.
Prepared from N-Boc-5-nitroindole (1.05 g) using LiTMP at –90 °C
and 2,4-dichloropyrimidine (0.60 g); eluent: hexane–CH2Cl2 (50:50
to 0:100); yield: 0.30 g (20%); yellow powder; mp >260 °C.
1H NMR (400 MHz, CDCl3): d = 1.46 (s, 9 H), 7.09 (s, 1 H), 7.51
(d, J = 5.3 Hz, 1 H), 8.29–8.31 (m, 2 H), 8.56 (dd, J = 1.7, 0.9 Hz,
1 H), 8.73 (d, J = 5.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 27.8 (3 C), 86.4, 114.2, 115.8,
118.1, 118.3, 121.7, 128.0, 138.5, 141.1, 144.4, 148.8, 160.1, 161.3,
162.1.
ESCI MS: m/z = 274.78, 276.71 [M + H – Boc]+, 318.73, 320.73
[M + H – t-Bu]+.
HRMS: m/z calcd for C18H18N2O2 (M+): 294.1368; found:
294.1352.
2-(2-Methoxyphenyl)pyridine (14)
Anal. Calcd for C18H18N2O2 (294.35): C, 73.45; H, 6.16; N, 9.52.
Found: C, 73.14; H, 6.05; N, 9.30.
Prepared from anisole (0.44 mL) using BuLi at 25 °C and 2-chloro-
pyridine (0.38 mL); eluent: CH2Cl2; yield: 0.43 g (64%); colorless
oil.
N-Boc-2-(2-chloro-4-pyrimidyl)-4-methoxyindole (10)
Prepared from N-Boc-4-methoxyindole (1.0 g) using LiTMP at
–90 °C and 2,4-dichloropyrimidine (0.60 g); eluent: hexane–
CH2Cl2 (40:60 to 0:100); yield: 0.26 g (18%); yellow powder; mp
148 °C.
1H NMR (400 MHz, CDCl3): d = 1.46 (s, 9 H), 3.95 (s, 3 H), 6.69
(d, J = 7.9 Hz, 1 H), 7.16 (s, 1 H), 7.34 (dd, J = 8.3, 7.9 Hz, 1 H),
7.44 (d, J = 5.3 Hz, 1 H), 7.74 (d, J = 8.3 Hz, 1 H), 8.61 (d, J = 5.3
Hz, 1 H).
1H NMR (200 MHz, CDCl3): d = 3.87 (s, 3 H), 7.02 (d, J = 8.3 Hz,
1 H), 7.09 (t, J = 7.5 Hz, 1 H), 7.2 (m, 1 H), 7.37 (dt, J = 7.8, 1.7
Hz, 1 H), 7.7 (m, 3 H), 8.71 (dd, J = 4.3, 1.2 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 56.0, 111.7, 121.4, 122.0, 125.5,
129.5, 130.3, 131.5, 136.0, 149.8, 156.4, 157.2.
The spectral data were identical to those previously described.52
2-Fluoro-3-(2-pyridyl)pyridine (15)
Prepared from 2-fluoropyridine (0.34 mL) using LiTMP at –75 °C
and 2-chloropyridine (0.38 mL); eluent: heptane–CH2Cl2 (60:40 to
0:100); yield: 0.43 g (62%); beige powder; mp <50 °C.
1H NMR (200 MHz, CDCl3): d = 7.25–7.37 (m, 2 H), 7.72–7.91 (m,
2 H), 8.25 (d, J = 3.2 Hz, 1 H), 8.47–8.58 (m, 1 H), 8.72 (d, J = 4.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 27.9 (3 C), 55.7, 84.8, 103.5,
108.1, 112.5, 117.6, 119.2, 128.0, 134.1, 140.3, 149.8, 153.9, 159.3,
161.1, 162.9.
ESCI MS: m/z = 259.80, 261.73 [M + H – Boc]+, 303.79, 305.74
[M + H – t-Bu]+.
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13C NMR (50 MHz, CDCl3): d = 122.1 (d, J = 4.3 Hz), 122.6, 123.2,
124.3 (d, J = 10 Hz), 136.8, 141.6 (d, J = 3.8 Hz), 147.7 (d, J = 15
Hz), 150.0, 151.4 (d, J = 6.8 Hz), 160.9 (d, J = 241 Hz).
N-Allyl-4-(2-indolyl)-2-pyrimidinamine
1H NMR (200 MHz, CDCl3): d = 4.14–4.22 (m, 2 H), 5.19 (dq,
J = 11, 1.5 Hz, 1 H), 5.26 (s, 1 H), 5.31 (dq, J = 17, 1.5 Hz, 1 H),
5.96–6.11 (m, 1 H), 7.00 (d, J = 5.3 Hz, 1 H), 7.09–7.16 (m, 2 H),
7.27 (ddd, J = 8.3, 7.0, 1.5 Hz, 1 H), 7.44 (d, J = 8.3 Hz, 1 H), 7.66
(d, J = 7.5 Hz, 1 H), 8.29 (d, J = 5.3 Hz, 1 H), 9.36 (s, 1 H).
HRMS: m/z calcd for C10H7FN2 (M+): 174.0593; found: 174.0595.
Deprotonation/Cross-Coupling Sequence (Compounds 1b and
5b); General Procedure
13C NMR (50 MHz, CDCl3): d = 44.0, 103.6, 106.1, 111.5, 115.8,
120.4, 121.6 (2C), 128.7, 135.0, 135.1, 136.5, 157.4, 158.1, 162.1.
To a stirred and cooled solution (temperature given in the product
description) of the appropriate reagent (4.0 mmol) in anhyd THF (5
mL) under argon were added the required base (4.0 mmol) and, 1 h
later, ZnCl2·TMEDA34 (0.33 g, 1.3 mmol). The mixture was slowly
warmed to r.t. (1 h) before the addition of the appropriate aromatic
halide (4.0 mmol), PdCl2 (14 mg, 80 mmol), dppf (44 mg, 80 mmol),
and 1,2-dimethoxyethane (2.1 mL, 20 mmol), and heated at 55 °C
for 12 h. The mixture was cooled before the addition of H2O (0.5
mL). Extraction with EtOAc (2 × 25 mL), drying (Na2SO4), and re-
moval of the solvents under reduced pressure afforded a crude com-
pound, which was purified by chromatography on silica gel (the
eluent is given in the product description) (Tables 1 and 2).
Isomeridianin G (16)
Eluent: EtOAc–CH2Cl2 (70:30); yield: 0.10 g (2 steps, 48%); yel-
low powder; mp 225 °C.
1H NMR (300 MHz, CDCl3): d = 5.07 (s, 2 H), 7.07 (d, J = 5.3 Hz,
1 H), 7.09–7.16 (m, 2 H), 7.27 (td, J = 8.3, 1.5 Hz, 1 H), 7.43 (d,
J = 8.3 Hz, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 8.28 (d, J = 5.3 Hz, 1 H),
9.40 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 104.2, 106.9, 111.6, 120.5, 121.7,
124.5, 128.6, 134.2, 136.7, 157.5, 158.0, 162.9.
HRMS: m/z calcd for C12H10N4 (M+): 210.0905; found: 210.0884.
2-(4-Nitrophenyl)thiophene (1b)
The physical and spectral data were identical to those previously de-
scribed.31
Prepared from thiophene (0.32 mL) using BuLi at –75 °C and 1-
bromo-4-nitrobenzene (0.81 g); eluent: heptane–EtOAc (100:0 to
90:10); yield: 0.62 g (76%); yellow powder; mp 135 °C.
1H NMR (200 MHz, CDCl3): d = 7.15 (t, J = 4.4 Hz, 1 H), 7.44 (d,
J = 5.2 Hz, 1 H), 7.48 (d, J = 4.0 Hz, 1 H), 7.74 (d, J = 9.5 Hz, 2 H),
8.23 (d, J = 8.8 Hz, 2 H).
4-(2-Pyrryl)-2-pyrimidinamine (17)55
Precursor N-allyl-4-(2-pyrryl)-2-pyrimidinamine was prepared
from N-Boc-2-(2-chloro-4-pyrimidyl)pyrrole (9a; 0.28 g), and
identified by NMR spectroscopy.
13C NMR (50 MHz, CDCl3): d = 124.4, 125.7 (2 C), 126.0, 127.7,
N-Allyl-4-(2-pyrryl)-2-pyrimidinamine
128.7 (2 C), 140.6, 141.6, 146.6.
1H NMR (200 MHz, CDCl3): d = 4.06–4.16 (m, 2 H), 5.15 (dq,
J = 10, 1.5 Hz, 1 H), 5.27 (dq, J = 17, 1.5 Hz, 1 H), 5.30 (s, 1 H),
5.87–6.10 (m, 1 H), 6.30 (m, 1 H), 6.76 (d, J = 5.1 Hz, 1 H), 6.81
(ddd, J = 3.5, 2.5, 1.2 Hz, 1 H), 6.96 (ddd, J = 3.5, 2.5, 1.2 Hz, 1 H),
8.18 (d, J = 5.1 Hz, 1 H), 9.55 (s, 1 H).
The spectral data were identical to those previously described.53
2-(2-Benzo[b]furyl)pyridine (5b)
Prepared from benzo[b]furan (0.44 mL) using BuLi at –15 °C and
2-chloropyridine (0.38 mL); eluent: heptane–CH2Cl2 (60:40); yield:
0.60 g (76%); white powder; mp 88 °C.
1H NMR (200 MHz, CDCl3): d = 7.20–7.39 (m, 3 H), 7.43 (d,
J = 1.0 Hz, 1 H), 7.57 (dq, J = 8.1, 1.0 Hz, 1 H), 7.62–7.68 (m, 1 H),
7.78 (ddd, J = 9.3, 8.1, 1.5 Hz, 1 H), 7.91 (dt, J = 9.3, 1.0 Hz, 1 H),
8.69 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 43.9, 104.6, 110.3, 110.8, 115.6,
121.1, 129.7, 135.2, 157.0, 157.6, 161.8.
17
Eluent: EtOAc–CH2Cl2 (50:50); yield: 0.11 g (2 steps, 70%); beige
powder; mp 183 °C.
1H NMR (300 MHz, acetone-d6): d = 5.80 (s, 2 H), 6.18–6.24 (m, 1
H), 6.88 (d, J = 5.1 Hz, 1 H), 6.84–6.89 (m, 1 H), 6.97–7.01 (m, 1
H), 8.13 (d, J = 5.1 Hz, 1 H), 10.6 (s, 1 H).
13C NMR (75 MHz, acetone-d6): d = 106.6, 112.3, 112.7, 124.1,
132.5, 159.8, 160.9, 165.8.
The spectral data were identical to those previously described.54
Substitution of the Chloro Group of Compounds 2d, 9a, 5a, 6,
7a, and 1e with Allylamine and Subsequent Allyl Cleavage
(Compounds 16–21); General Procedure
A stirred solution of the aromatic chloride (1.0 mmol) in allylamine
(5 mL) was heated under reflux for 2 h. After concentration under
reduced pressure, H2O (10 mL) and aq 1 M NaOH (1 mL) were add-
ed before extraction with EtOAc (3 × 15 mL). The combined organ-
ic phases were washed with brine (10 mL), dried (Na2SO4), and the
solvents were removed under reduced pressure. After checking the
purity by NMR spectroscopy, the crude allylated compound was di-
rectly dissolved in EtOH (5 mL), and MeSO3H (85 mL, 1.3 mmol)
and 10% Pd/C (0.10 g) were added at r.t. The mixture was then heat-
ed under reflux for 3 days, filtrated over Celite, and the solvents
were removed under reduced pressure. Sat. aq NaHCO3 (10 mL)
was added to the residue before extraction with EtOAc (3 × 15 mL).
The combined organic phases were washed with brine (10 mL), and
dried (Na2SO4). The solvent was removed under reduced pressure
before purification by chromatography on silica gel (eluent given in
the product description) (Table 3).
HRMS: m/z calcd for C8H8N4 (M+): 160.0749; found: 160.0743.
4-(2-Benzo[b]furyl)-2-pyrimidinamine (18)
Precursor N-allyl-4-(2-benzo[b]furyl)-2-pyrimidinamine was pre-
pared from 4-(2-benzo[b]furyl)-2-chloropyrimidine (5a; 0.23 g),
and identified by NMR spectroscopy.
N-Allyl-4-(2-benzo[b]furyl)-2-pyrimidinamine
1H NMR (200 MHz, CDCl3): d = 4.11–4.20 (m, 2 H), 5.17 (dq,
J = 11, 1.5 Hz, 1 H), 5.30 (dq, J = 17, 1.5 Hz, 1 H), 5.35 (s, 1 H),
5.90–6.12 (m, 1 H), 7.10 (d, J = 5.1 Hz, 1 H), 7.26 (ddd, J = 8.6, 7.6,
1.0 Hz, 1 H), 7.37 (ddd, J = 8.6, 7.0, 1.5 Hz, 1 H), 7.52 (s, 1 H), 7.56
(d, J = 7.0 Hz, 1 H), 7.66 (dd, J = 7.6, 1.5 Hz, 1 H), 8.40 (d, J = 5.1
Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 43.8, 105.9, 107.4, 111.7, 115.7,
121.9, 123.3, 125.9, 128.2, 134.9, 153.7, 155.5, 156.3, 158.9, 162.2.
4-(2-Indolyl)-2-pyrimidinamine (Isomeridianin G, 16)
Precursor N-allyl-4-(2-indolyl)-2-pyrimidinamine was prepared
from N-Boc-2-(2-chloro-4-pyrimidyl)indole (2d; 0.33 g), and iden-
tified by NMR spectroscopy.
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18
Cross-Couplings of Lithium Arylzincates/Synthesis of Isomeridianin G Analogues
3627
N-Allyl-4-(2-thienyl)-2-pyrimidinamine
Eluent: EtOAc; yield: 0.12 g (2 steps, 55%); pale yellow powder;
mp 205 °C.
1H NMR (300 MHz, CDCl3): d = 5.24 (s, 2 H), 7.17 (d, J = 5.3 Hz,
1 H), 7.29 (t, J = 7.5 Hz, 1 H), 7.39 (ddd, J = 8.5, 7.5, 1.5 Hz, 1 H),
7.53 (s, 1 H), 7.58 (d, J = 8.5 Hz, 1 H), 7.66 (d, J = 7.6 Hz, 1 H),
8.39 (d, J = 5.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 106.9, 108.0, 111.8, 122.1, 123.5,
126.3, 128.2, 152.7, 155.1, 156.3, 158.9, 162.5.
HRMS: m/z calcd for C12H9N3O (M+): 211.0746; found: 211.0745.
1H NMR (200 MHz, CDCl3): d = 4.00–4.11 (m, 2 H), 5.08 (dq,
J = 10, 1.5 Hz, 1 H), 5.22 (dq, J = 17, 1.5 Hz, 1 H), 5.23 (s, 1 H),
5.82–6.03 (m, 1 H), 6.86 (d, J = 5.1 Hz, 1 H), 7.11 (dd, J = 5.0, 3.5
Hz, 1 H), 7.44 (dd, J = 5.0, 1.0 Hz, 1 H), 7.66 (dd, J = 3.5, 1.0 Hz,
1 H), 8.27 (d, J = 5.1 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 43.9, 104.6, 115.8, 126.9, 127.9,
129.5, 134.7, 140.5, 158.6, 159.4, 162.6.
21
Eluent: EtOAc–CH2Cl2 (50:50); yield: 51 mg (2 steps, 29%); pale
yellow powder; mp 181 °C (Lit.56 mp 174 °C).
4-(2-Furyl)-2-pyrimidinamine (19)55
Precursor N-allyl-4-(2-furyl)-2-pyrimidinamine was prepared from
4-(2-furyl)-2-chloropyrimidine (6; 0.18 g), and identified by NMR
spectroscopy.
1H NMR (300 MHz, acetone-d6): d = 6.06 (s, 2 H), 7.05 (d, J = 5.3
Hz, 1 H), 7.16 (dd, J = 5.3, 3.8 Hz, 1 H), 7.63 (dd, J = 5.3, 1.5 Hz,
1 H), 7.83 (dd, J = 3.8, 1.5 Hz, 1 H), 8.25 (d, J = 5.3 Hz, 1 H).
13C NMR (75 MHz, acetone-d6): d = 105.6, 127.9, 128.9, 130.2,
144.2, 159.6, 160.4, 164.8.
N-Allyl-4-(2-furyl)-2-pyrimidinamine
1H NMR (200 MHz, CDCl3): d = 4.07–4.17 (m, 2 H), 5.15 (dq,
J = 11, 1.5 Hz, 1 H), 5.28 (dq, J = 17, 1.5 Hz, 1 H), 5.30 (s, 1 H),
5.88–6.10 (m, 1 H), 6.54 (dd, J = 3.6, 1.5 Hz, 1 H), 6.90 (d, J = 5.1
Hz, 1 H), 7.16 (d, J = 3.6 Hz, 1 H), 7.57 (m, 1 H), 8.31 (d, J = 5.1
Hz, 1 H).
HRMS: m/z calcd for C8H7N3S (M+): 177.0361; found: 177.0373.
Deprotection of N-Boc-Indoles Using TFA (Compounds 22, 23,
25–27); General Procedure
Method A: To a stirred solution of the appropriate N-Boc-indole (2.0
mmol) in CH2Cl2 (10 mL) at r.t. was added TFA (30 mmol). After
2 h at r.t., sat. aq NaHCO3 (10 mL) was added. Extraction with
EtOAc (3 × 10 mL), washing with brine (10 mL), drying (Na2SO4),
and removal of the solvents under reduced pressure afforded a crude
product, which was purified by chromatography on silica gel (elu-
ent given in the product description) (Table 4).
13C NMR (50 MHz, CDCl3): d = 43.8, 104.9, 111.5, 112.1, 115.7,
135.0, 144.5, 152.2, 156.1, 158.5, 162.2.
19
Eluent: EtOAc; yield: 42 mg (2 steps, 26%); dark yellow powder
(degradation before melting).
1H NMR (300 MHz, CDCl3): d = 5.15 (s, 2 H), 6.54 (dd, J = 3.8, 2.2
Hz, 1 H), 6.96 (d, J = 5.1 Hz, 1 H), 7.14 (d, J = 3.8 Hz, 1 H), 7.57
(s, 1 H), 8.30 (d, J = 5.1 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 104.7, 110.9, 111.3, 143.5, 152.5,
156.2, 158.4, 162.6.
2-(4-Methoxycarbonylphenyl)indole (22)
Prepared from N-Boc-2-(4-methoxycarbonylphenyl)indole (2a;
0.71 g); eluent: CH2Cl2; yield: 0.27 g (52%,); yellow powder; mp
200 °C.
1H NMR (300 MHz, CDCl3): d = 3.92 (s, 3 H), 6.95 (dd, J = 2.5, 1.0
Hz, 1 H), 7.14 (ddd, J = 8.6, 7.5, 1.5 Hz, 1 H), 7.24 (ddd, J = 8.6,
8.0, 1.5 Hz, 1 H), 7.42 (dd, J = 8.0, 1.5 Hz, 1 H), 7.65 (d, J = 7.5 Hz,
1 H), 7.72 (dt, J = 8.6, 2.0 Hz, 2 H), 8.10 (dt, J = 8.6, 2.0 Hz, 2 H),
8.47 (s, 1 H).
HRMS: m/z calcd for C8H7N3O (M+): 161.0589; found: 161.0577.
4-(2-Benzo[b]thienyl)-2-pyrimidinamine (20)
Precursor N-allyl-4-(2-benzo[b]thienyl)-2-pyrimidinamine was
prepared from 4-(2-benzo[b]thienyl)-2-chloropyrimidine (7a; 0.22
g), and identified by NMR spectroscopy.
These spectral data were identical to those previously described.57
13C NMR (75 MHz, CDCl3): d = 52.2, 101.8, 111.1, 120.6, 121.0,
123.1, 124.6 (2 C), 128.8, 129.0, 130.3 (2 C), 136.4, 137.2, 141.3,
166.7.
N-Allyl-4-(2-benzo[b]thienyl)-2-pyrimidinamine
1H NMR (200 MHz, CDCl3): d = 4.04–4.14 (m, 2 H), 5.11 (dq,
J = 11, 1.5 Hz, 1 H), 5.26 (dq, J = 17, 1.5 Hz, 1 H), 5.25 (s, 1 H),
5.84–6.06 (m, 1 H), 6.95 (d, J = 5.1 Hz, 1 H), 7.27–7.35 (m, 2 H),
7.72–7.84 (m, 2 H), 7.88 (s, 1 H), 8.25 (d, J = 5.1 Hz, 1 H).
HRMS: m/z calcd for C16H13NO2 (M+): 251.0946; found: 251.0968.
Anal. Calcd for C16H13NO2 (251.28): C, 76.48; H, 5.21; N, 5.57.
Found: C, 76.27; H, 5.23; N, 5.54.
13C NMR (50 MHz, CDCl3): d = 43.9, 105.7, 115.9, 122.6, 123.7,
124.5, 124.6, 125.7 (2 C), 134.9, 139.9, 140.9, 158.3, 159.8, 162.2.
2-(4-Cyanophenyl)indole (23)
Prepared from N-Boc-2-(4-cyanophenyl)indole (2b; 0.64 g); eluent:
CH2Cl2; yield: 0.20 g (46%); yellow powder; mp 192 °C.
1H NMR (200 MHz, CDCl3): d = 6.94 (d, J = 2.2 Hz, 1 H), 7.10–
7.28 (m, 2 H), 7.42 (dd, J = 8.1, 7.5 Hz, 1 H), 7.65 (d, J = 7.5 Hz, 1
H), 7.68–7.74 (m, 2 H), 7.85–7.88 (m, 2 H), 8.37 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 101.1, 111.5, 112.7, 117.8, 120.7,
121.6, 123.2, 128.7, 131.5 (2 C), 133.3 (2 C), 136.1, 136.9, 141.3.
20
Eluent: EtOAc; yield: 0.13 g (2 steps, 58%); white powder; mp
230 °C.
1H NMR (300 MHz, CDCl3): d = 5.11 (s, 2 H), 7.08 (d, J = 5.3 Hz,
1 H), 7.34–7.43 (m, 2 H), 7.78–7.91 (m, 2 H), 7.96 (s, 1 H), 8.33 (d,
J = 5.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 105.2, 123.5, 124.4, 124.5, 125.6
(2 C), 139.8, 140.8, 143.4, 158.2, 159.9, 162.3.
HRMS: m/z calcd for C12H9N3S (M+): 227.0517; found: 227.0531.
HRMS: m/z calcd for C15H10N2 (M+): 218.0844; found: 218.0858.
These data were identical to those previously described.58
5-Fluoro-2-(4-trifluoromethylphenyl)indole (25)
Prepared from N-Boc-5-fluoro-2-(4-trifluoromethylphenyl)indole
(3; 0.77 g); eluent: heptane–CH2Cl2 (50:50); yield: 0.26 g (46%);
yellow powder; mp 162 °C.
4-(2-Thienyl)-2-pyrimidinamine (21)
Precursor N-allyl-4-(2-thienyl)-2-pyrimidinamine was prepared
from 4-(2-thienyl)-2-chloropyrimidine (1e; 0.20 g), and identified
by NMR spectroscopy.
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1H NMR (200 MHz, CDCl3): d = 6.88 (d, J = 1.5 Hz, 1 H), 6.98
(ddd, J = 11.6, 9.1, 2.5 Hz, 1 H), 7.24–7.38 (m, 2 H), 7.65–7.80 (m,
4 H), 8.36 (s, 1 H).
HRMS: m/z calcd for C15H9F4N (M+): 279.0671; found: 279.0652.
These data were identical to those previously described.59
These data were identical to those previously described.60
13C NMR (75 MHz, CDCl3): d = 100.6, 111.4, 119.8, 120.1, 121.1,
121.9, 123.1, 129.0, 136.5, 136.6, 136.7, 148.9, 150.3.
HRMS: m/z calcd for C13H10N2 (M+): 194.0844; found: 194.0851.
Deprotection of N-Boc-Indoles Using TFA Followed by the Sub-
stitution of the Chloro Group with Amines (Compounds 29–
47); General Procedure
5-Bromo-2-(4-methoxycarbonylphenyl)indole (26)
Prepared from N-Boc-5-bromo-2-(4-methoxycarbonylphenyl)in-
dole (4a; 0.88 g); eluent: heptane–CH2Cl2 (50:50); yield: 0.20 g
(31%); yellow powder; mp 204 °C.
1H NMR (200 MHz, CDCl3): d = 3.90 (s, 3 H), 6.88 (d, J = 2.0 Hz,
1 H), 7.25–7.33 (m, 2 H), 7.66–7.79 (m, 3 H), 8.12 (d, J = 8.6 Hz, 2
H), 8.46 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 52.2, 101.2, 112.5, 113.7, 123.4,
124.8 (2 C), 125.9, 129.3, 130.4 (2 C), 130.8, 135.8, 135.9, 137.9,
167.3.
To a stirred solution of N-Boc-2-(2-chloro-4-pyrimidyl)indole (2d;
0.33 g, 1.0 mmol) in CH2Cl2 (5 mL) at r.t. was added TFA (15
mmol). After 2 h at r.t., sat. aq NaHCO3 (5 mL) was added. Extrac-
tion with EtOAc (3 × 5 mL), washing with brine (5 mL), drying
(Na2SO4), and removal of the solvents under reduced pressure af-
forded crude 2-chloro-4-(2-indolyl)pyrimidine, which was further
dissolved in a mixture of pyridine (3 mL) and EtOH (3 mL). The re-
quired amine (3.0 mmol) was then added, and the reaction mixture
was heated at 150 °C for 20 min in the microwave oven. After re-
moval of the solvents under reduced pressure, the crude product was
purified by MDAP (Table 5).
HRMS: m/z calcd for C16H1279BrNO2 (M+): 329.0051; found:
329.0320.
4-(2-Indolyl)-N-propyl-2-pyrimidinamine (29)
Prepared using N-propylamine (0.25 mL); yield: 0.11 g (44%);
beige powder; mp 138 °C.
1H NMR (400 MHz, CDCl3): d = 1.02 (t, J = 7.5 Hz, 3 H), 1.68 (m,
2 H), 3.47 (dt, J = 7.5, 4.4 Hz, 2 H), 5.23 (s, 1 H), 6.97 (d, J = 5.2
Hz, 1 H), 7.09 (dd, J = 2.2, 0.9 Hz, 1 H), 7.12 (ddd, J = 7.9, 7.0, 0.9
Hz, 1 H), 7.26 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H), 7.43 (dd, J = 8.3, 0.9
Hz, 1 H), 7.66 (dd, J = 7.9, 1.3 Hz, 1 H), 8.29 (d, J = 5.2 Hz, 1 H),
9.47 (s, 1 H).
5-Bromo-2-(4-trifluoromethylphenyl)indole (27)
Prepared from N-Boc-5-bromo-2-(4-trifluoromethylphenyl)indole
(4b; 0.89 g); eluent: heptane–CH2Cl2 (60:40); yield: 0.20 g (30%);
yellow powder; mp 190 °C.
1H NMR (200 MHz, CDCl3): d = 6.78 (d, J = 2.0 Hz, 1 H), 7.23 (d,
J = 2.0 Hz, 2 H), 7.58–7.73 (m, 5 H), 8.34 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 101.3, 111.8, 114.7, 123.5, 124.5
(q, J = 253 Hz), 125.6 (q, J = 3.6 Hz, 2 C), 125.9, 127.7 (2 C),
129.3, 129.8 (q, J = 32 Hz), 135.7, 136.0, 140.8.
13C NMR (100 MHz, CDCl3): d = 11.5, 22.9, 43.4, 103.5, 105.7,
111.5, 120.4, 121.6, 124.1, 128.7, 135.0, 136.5, 157.4, 158.0, 162.3.
ESCI MS: m/z = 253.19 [M + H]+.
HRMS: m/z calcd for C15H979BrF3N (M+): 338.9870; found:
338.9893.
Deprotection of N-Boc-Indoles Using TBAF (Compounds 24,
28); General Procedure
Anal. Calcd for C15H16N4 (252.31): C, 71.40; H, 6.39; N, 22.21.
Found: C, 71.33; H, 6.38; N, 22.26.
Method B: To a stirred solution of the appropriate N-Boc-indole (2.0
mmol) in THF (5 mL) at r.t. was added TBAF (8.0 mmol). The mix-
ture was then heated under reflux for 10 h, and cooled at r.t. before
addition of brine (10 mL), extraction with EtOAc (3 × 10 mL), and
drying (Na2SO4). The solvents were removed under reduced pres-
sure before purification by chromatography over silica gel (eluent
given in the product description) (Table 4).
4-(2-Indolyl)-N-isobutyl-2-pyrimidinamine (30)
Prepared using isobutylamine (0.30 mL); yield: 0.13 g (48%); beige
powder; mp 129 °C.
1H NMR (400 MHz, CDCl3): d = 1.01 (d, J = 6.6 Hz, 6 H), 1.94 (m,
1 H), 3.34 (t, J = 6.6 Hz, 2 H), 5.29 (s, 1 H), 6.97 (d, J = 5.3 Hz, 1
H), 7.10–7.16 (m, 2 H), 7.26 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H), 7.42
(dd, J = 8.3, 0.9 Hz, 1 H), 7.66 (dd, J = 7.9, 1.3 Hz, 1 H), 8.28 (d,
J = 5.3 Hz, 1 H), 9.49 (s, 1 H).
2-(4-Trifluoromethylphenyl)indole (24)
Prepared from N-Boc-2-(4-trifluoromethylphenyl)indole (2c; 0.76
g); eluent: heptane–CH2Cl2 (50:50); yield: 0.29 g (55%); white
powder; mp 228 °C.
1H NMR (200 MHz, CDCl3): d = 6.93 (dd, J = 2.0, 1.0 Hz, 1 H),
7.10–7.29 (m, 2 H), 7.43 (d, J = 7.5 Hz, 1 H), 7.62–7.81 (m, 5 H),
8.39 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 101.5, 110.7, 110.8, 119.5, 120.2,
122.4, 123.9 (q, J = 226 Hz), 124.6 (2 C), 125.3 (q, J = 4.1 Hz, 2 C),
128.3 (q, J = 38 Hz), 135.5, 135.8, 137.4.
13C NMR (100 MHz, CDCl3): d = 20.3 (2 C), 28.5, 49.1, 103.5,
105.7, 111.5, 120.4, 121.6, 124.1, 128.7, 135.0, 136.5, 157.4, 158.0,
162.5.
ESCI MS: m/z = 267.24 [M + H]+.
Anal. Calcd for C16H18N4 (266.34): C, 72.15; H, 6.81; N, 21.04.
Found: C, 72.09; H, 6.80; N, 20.98.
4-(2-Indolyl)-N-neopentyl-2-pyrimidinamine (31)
Prepared using neopentylamine (0.35 mL); yield: 0.17 g (59%);
pale yellow powder; mp 134 °C.
1H NMR (400 MHz, CDCl3): d = 1.02 (s, 9 H), 3.36 (d, J = 6.1 Hz,
2 H), 5.22 (s, 1 H), 6.96 (d, J = 5.3 Hz, 1 H), 7.09–7.16 (m, 2 H),
7.26 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H), 7.44 (d, J = 8.3 Hz, 1 H), 7.66
(dd, J = 7.9, 1.3 Hz, 1 H), 8.27 (d, J = 5.3 Hz, 1 H), 9.43 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 27.5 (3 C), 32.0, 52.8, 103.5,
105.7, 111.6, 120.4, 121.7, 124.1, 128.8, 135.0, 136.5, 157.4, 158.0,
162.8.
HRMS: m/z calcd for C15H10F3N (M+): 261.0765; found: 261.0745.
These data were identical to those previously described.59
2-(2-Pyridyl)indole (28)
Prepared from N-Boc-2-(2-pyridyl)indole (2e; 0.60 g); eluent:
CH2Cl2; yield: 0.26 g (67%); beige powder; mp 153 °C.
1H NMR (300 MHz, CDCl3): d = 7.04 (d, J = 1.5 Hz, 1 H), 7.07–
7.28 (m, 3 H), 7.39 (dd, J = 8.1, 1.0 Hz, 1 H), 7.67 (dd, J = 7.5, 2.0
Hz, 1 H), 7.75 (dd, J = 8.1, 2.0 Hz, 1 H), 7.84 (td, J = 8.1, 1.5 Hz, 1
H), 8.59 (m, 1 H), 9.95 (s, 1 H).
ESCI MS: m/z = 281.03 [M + H]+.
Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York

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Cross-Couplings of Lithium Arylzincates/Synthesis of Isomeridianin G Analogues
3629
4-(2-Indolyl)-N-(2-trifluoromethylbenzyl)-2-pyrimidinamine
(32)
Prepared using 2-(trifluoromethyl)benzylamine (0.42 mL); yield:
0.17 g (45%); beige powder; mp 150 °C.
1H NMR (400 MHz, CDCl3): d = 4.96 (d, J = 6.1 Hz, 2 H), 5.69 (s,
1 H), 7.05 (d, J = 5.0 Hz, 1 H), 7.08–7.15 (m, 2 H), 7.26 (ddd,
J = 8.3, 7.0, 1.3 Hz, 1 H), 7.32–7.45 (m, 2 H), 7.48 (ddd, J = 8.1,
7.9, 1.3 Hz, 1 H), 7.60–7.73 (m, 3 H), 8.29 (d, J = 5.0 Hz, 1 H), 9.29
(s, 1 H).
13C NMR (100 MHz, CDCl3): d = 41.9, 103.6, 106.4, 111.6, 120.5
(2 C), 121.6, 123.9 (q, J = 225 Hz), 124.2, 126.2 (q, J = 3.6 Hz),
127.2, 128.8, 129.1 (q, J = 31 Hz), 132.2, 134.7, 136.5, 138.2,
157.4, 158.3, 161.9.
13C NMR (100 MHz, CDCl3): d = 41.1, 55.4, 103.4, 105.9, 110.4,
111.5, 120.4, 120.6, 121.6, 124.1, 127.3, 128.6, 128.8, 129.2, 135.0,
136.5, 157.3, 157.6, 158.1, 162.3.
ESCI MS: m/z = 330.91 [M + H]+.
Anal. Calcd for C20H18N4O (330.38): C, 72.71; H, 5.49; N, 16.96.
Found: C, 72.73; H, 5.57; N, 16.96.
4-(2-Indolyl)-N-(3-methoxybenzyl)-2-pyrimidinamine (36)
Prepared using 3-methoxybenzylamine (0.37 mL); yield: 0.14 g
(43%); white powder; mp 140 °C.
1H NMR (400 MHz, CDCl3): d = 3.79 (s, 3 H), 4.70 (d, J = 5.7 Hz,
2 H), 5.57 (s, 1 H), 6.82 (ddd, J = 8.3, 2.6, 0.9 Hz, 1 H), 6.95–7.02
(m, 2 H), 7.00 (d, J = 5.3 Hz, 1 H), 7.09–7.15 (m, 2 H), 7.23–7.31
(m, 2 H), 7.41 (dd, J = 8.3, 0.9 Hz, 1 H), 7.65 (dd, J = 7.9, 0.9 Hz,
1 H), 8.28 (d, J = 5.3 Hz, 1 H), 9.32 (s, 1 H).
ESCI MS: m/z = 368.99 [M + H]+.
Anal. Calcd for C20H15F3N4 (368.36): C, 65.21; H, 4.10; N, 15.21.
Found: C, 65.23; H, 4.21; N, 15.28.
13C NMR (100 MHz, CDCl3): d = 45.7, 55.2, 103.5, 106.2, 111.5,
112.6, 113.1, 119.6, 120.4, 121.6, 124.2, 128.7, 129.7, 134.8,
136.5, 141.1, 157.4, 158.2, 159.9, 162.1.
4-(2-Indolyl)-N-(3-trifluoromethylbenzyl)-2-pyrimidinamine
(33)
Prepared using 3-(trifluoromethyl)benzylamine (0.43 mL); yield:
ESCI MS: m/z = 330.91 [M + H]+.
Anal. Calcd for C20H18N4O (330.38): C, 72.71; H, 5.49; N, 16.96.
Found: C, 72.77; H, 5.54; N, 17.04.
0.12 g (33%); beige powder, mp 157 °C.
1H NMR (400 MHz, CDCl3): d = 4.79 (d, J = 6.1 Hz, 2 H), 5.59 (s,
1 H), 7.04 (d, J = 5.3 Hz, 1 H), 7.10–7.16 (m, 2 H), 7.26 (ddd,
J = 8.3, 7.0, 0.9 Hz, 1 H), 7.41 (dd, J = 8.3, 0.9 Hz, 1 H), 7.47 (t,
J = 7.5 Hz, 1 H), 7.54 (d, J = 7.5 Hz, 1 H), 7.60 (d, J = 7.5 Hz, 1 H),
7.66 (dd, J = 7.9, 0.9 Hz, 1 H), 7.68 (s, 1 H), 8.31 (d, J = 5.3 Hz, 1
H), 9.24 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 45.5, 104.0, 106.8, 111.8, 120.7,
121.9, 124.3 (q, J = 3.7 Hz, 2 C), 124.6 (q, J = 224 Hz), 124.6,
128.9, 129.4, 130.6 (q, J = 1.5 Hz), 130.9 (q, J = 32 Hz), 134.8,
136.8, 140.8, 157.7, 158.4, 162.3.
4-(2-Indolyl)-N-(4-methoxybenzyl)-2-pyrimidinamine (37)
Prepared using 4-methoxybenzylamine (0.39 mL); yield: 0.14 g
(42%); beige powder; mp 161 °C.
1H NMR (400 MHz, CDCl3): d = 3.80 (s, 3 H), 4.66 (d, J = 5.7 Hz,
2 H), 5.44 (s, 1 H), 6.89 (d, J = 8.8 Hz, 2 H), 7.01 (d, J = 5.3 Hz, 1
H), 7.10–7.15 (m, 2 H), 7.26 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H), 7.33
(d, J = 8.8 Hz, 2 H), 7.41 (dd, J = 8.3, 0.9 Hz, 1 H), 7.66 (dd,
J = 7.9, 0.9 Hz, 1 H), 8.28 (d, J = 5.3 Hz, 1 H), 9.33 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 45.2, 55.3, 103.5, 106.1, 111.5,
114.1 (2 C), 120.4, 121.6, 124.2, 128.7, 128.8 (2 C), 131.3, 134.9,
136.5, 157.4, 158.2, 158.9, 162.1.
ESCI MS: m/z = 369.04 [M + H]+.
Anal. Calcd for C20H15F3N4 (368.36): C, 65.21; H, 4.10; N, 15.21.
Found: C, 65.01; H, 4.10; N, 15.11.
ESCI MS: m/z = 330.91 [M + H]+.
Anal. Calcd for C20H18N4O (330.38): C, 72.71; H, 5.49; N, 16.96.
Found: C, 72.65; H, 5.47; N, 16.87.
4-(2-Indolyl)-N-(4-trifluoromethylbenzyl)-2-pyrimidinamine
(34)
Prepared using 4-(trifluoromethyl)benzylamine (0.43 mL); yield:
0.18 g (49%); beige powder; mp 131 °C.
N-(2-Chlorobenzyl)-4-(2-indolyl)-2-pyrimidinamine (38)
Prepared using 2-chlorobenzylamine (0.36 mL); yield: 0.12 g
(36%); white powder; mp 153 °C.
1H NMR (400 MHz, CDCl3): d = 4.83 (d, J = 6.1 Hz, 2 H), 5.66 (s,
1 H), 7.01 (d, J = 5.1 Hz, 1 H), 7.10 (dd, J = 1.7, 0.9 Hz, 1 H), 7.12
(ddd, J = 7.9, 7.0, 0.9 Hz, 1 H), 7.20–7.29 (m, 3 H), 7.38–7.50 (m,
3 H), 7.65 (dd, J = 7.9, 0.9 Hz, 1 H), 8.29 (d, J = 5.1 Hz, 1 H), 9.38
(s, 1 H).
1H NMR (400 MHz, CDCl3): d = 4.79 (d, J = 6.1 Hz, 2 H), 5.67 (s,
1 H), 7.04 (d, J = 5.2 Hz, 1 H), 7.10–7.16 (m, 2 H), 7.26 (ddd,
J = 8.3, 7.0, 1.3 Hz, 1 H), 7.39 (dd, J = 8.3, 0.9 Hz, 1 H), 7.50 (d,
J = 8.1 Hz, 2 H), 7.60 (d, J = 8.1 Hz, 2 H), 7.67 (dd, J = 7.9, 0.9 Hz,
1 H), 8.29 (d, J = 5.2 Hz, 1 H), 9.33 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 45.3, 103.9, 106.7, 111.6, 120.7,
121.8, 124.1 (q, J = 273 Hz), 124.5, 125.6 (q, J = 3.7 Hz, 2 C),
127.6 (2 C), 128.8, 129.5 (q, J = 32 Hz), 134.7, 136.7, 143.7, 157.6,
158.3, 162.1.
13C NMR (100 MHz, CDCl3): d = 43.5, 103.8, 106.6, 111.8, 120.7,
121.9, 124.4, 127.2, 128.8, 128.9, 129.5, 129.8, 133.6, 135.0, 136.8,
137.0, 157.7, 158.4, 162.3.
ESCI MS: m/z = 368.87 [M + H]+.
ESCI MS: m/z = 334.91, 336.85 [M + H]+.
Anal. Calcd for C20H15F3N4 (368.36): C, 65.21; H, 4.10; N, 15.21.
Found: C, 65.16; H, 4.18; N, 15.17.
Anal. Calcd for C19H15ClN4 (334.80): C, 68.16; H, 4.52; N, 16.73.
Found: C, 68.12; H, 4.62; N, 16.58.
4-(2-Indolyl)-N-(2-methoxybenzyl)-2-pyrimidinamine (35)
Prepared using 2-methoxybenzylamine (0.39 mL); yield: 0.17 g
(50%); beige powder; mp 149 °C.
1H NMR (400 MHz, CDCl3): d = 3.91 (s, 3 H), 4.73 (d, J = 6.1 Hz,
2 H), 5.64 (s, 1 H), 6.90–6.96 (m, 2 H), 6.98 (d, J = 5.3 Hz, 1 H),
7.09 (dd, J = 2.2, 0.9 Hz, 1 H), 7.12 (ddd, J = 7.9, 7.0, 0.9 Hz, 1 H),
7.23–7.30 (m, 2 H), 7.38 (dd, J = 7.5, 1.3 Hz, 1 H), 7.43 (dd, J = 8.3,
0.9 Hz, 1 H), 7.66 (dd, J = 7.9, 0.9 Hz, 1 H), 8.28 (d, J = 5.3 Hz, 1
H), 9.42 (s, 1 H).
N-(3-Chlorobenzyl)-4-(2-indolyl)-2-pyrimidinamine (39)
Prepared using 3-chlorobenzylamine (0.37 mL); yield: 33 mg
(10%); white powder; mp 160 °C.
1H NMR (400 MHz, CDCl3): d = 4.73 (d, J = 5.8 Hz, 2 H), 5.57 (s,
1 H), 7.02 (d, J = 5.3 Hz, 1 H), 7.11 (dd, J = 2.2, 0.9 Hz, 1 H), 7.13
(ddd, J = 7.9, 7.0, 0.9 Hz, 1 H), 7.24–7.33 (m, 4 H), 7.41–7.43 (m,
2 H), 7.66 (dd, J = 7.9, 0.9 Hz, 1 H), 8.30 (d, J = 5.3 Hz, 1 H), 9.24
(s, 1 H).
Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York

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A. Seggio et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 45.2, 103.8, 106.6, 111.7, 120.6,
121.8, 124.3, 125.5, 127.5 (2 C), 128.8, 130.0, 134.6, 134.8, 136.6,
141.7, 157.6, 158.3, 162.1.
Anal. Calcd for C22H22N4O3 (390.44): C, 67.68; H, 5.68; N, 14.35.
Found: C, 67.51; H, 5.72; N, 14.01.
4-(2-Indolyl)-N-(2-pyridylmethyl)-2-pyrimidinamine (44)
Prepared using 2-(aminomethyl)pyridine (0.31 mL); yield: 0.22 g
(73%); beige powder; mp 178 °C.
1H NMR (400 MHz, CDCl3): d = 4.84 (d, J = 5.7 Hz, 2 H), 6.22 (s,
1 H), 7.01 (d, J = 5.1 Hz, 1 H), 7.09 (dd, J = 2.2, 0.9 Hz, 1 H), 7.11
(ddd, J = 7.9, 7.0, 0.9 Hz, 1 H), 7.17–7.22 (m, 1 H), 7.26 (ddd,
J = 8.3, 7.0, 1.3 Hz, 1 H), 7.37 (d, J = 7.9 Hz, 1 H), 7.43 (ddd,
J = 8.3, 1.7, 0.9 Hz, 1 H), 7.63–7.68 (m, 2 H), 8.31 (d, J = 5.1 Hz, 1
H), 8.61 (ddd, J = 4.8, 1.8, 0.9 Hz, 1 H), 9.49 (s, 1 H).
ESCI MS: m/z = 334.99, 336.97 [M + H]+.
N-(4-Chlorobenzyl)-4-(2-indolyl)-2-pyrimidinamine (40)
Prepared using 4-chlorobenzylamine (0.37 mL); yield: 40 mg
(12%); beige powder; mp 162 °C.
1H NMR (400 MHz, CDCl3): d = 4.70 (d, J = 6.1 Hz, 2 H), 5.51 (s,
1 H), 7.03 (d, J = 5.3 Hz, 1 H), 7.12 (dd, J = 2.1, 0.9 Hz, 1 H), 7.13
(ddd, J = 7.9, 7.0, 0.9 Hz, 1 H), 7.26 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H),
7.30–7.36 (m, 4 H), 7.41 (dd, J = 8.3, 0.9 Hz, 1 H), 7.66 (dd, J = 7.9,
1.3 Hz, 1 H), 8.29 (d, J = 5.3 Hz, 1 H), 9.27 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 47.2, 103.7, 106.4, 111.8, 120.6,
121.7, 121.8, 122.4, 124.4, 128.9, 135.1, 136.8, 136.9, 149.3, 157.6,
158.3, 158.4, 162.3.
13C NMR (100 MHz, CDCl3): d = 45.2, 104.0, 106.7, 111.8, 120.7,
121.9, 124.5, 128.9, 129.0 (2 C), 129.1 (2 C), 133.2, 134.9, 136.8,
138.1, 157.7, 158.4, 162.3.
ESCI MS: m/z = 302.05 [M + H]+.
ESCI MS: m/z = 335.03, 337.02 [M + H]+.
Anal. Calcd for C18H15N5 (301.35): C, 71.74; H, 5.02; N, 23.24.
Found: C, 71.48; H, 4.98; N, 23.26.
N-(2-Fluorobenzyl)-4-(2-indolyl)-2-pyrimidinamine (41)
Prepared using 2-fluorobenzylamine (0.34 mL); yield: 0.13 g
(41%); white powder; mp 146 °C.
1H NMR (400 MHz, CDCl3): d = 4.78 (d, J = 6.1 Hz, 2 H), 5.71 (s,
1 H), 7.01 (d, J = 5.3 Hz, 1 H), 7.05–7.15 (m, 4 H), 7.22–7.29 (m, 2
H), 7.40–7.47 (m, 2 H), 7.66 (dd, J = 7.9, 0.9 Hz, 1 H), 8.28 (d,
J = 5.3 Hz, 1 H), 9.45 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 39.2, 103.8, 106.5, 111.8, 115.3
(d, J = 21 Hz), 120.6, 121.9, 124.4, 124.5 (d, J = 3.7 Hz), 126.3 (d,
J = 15 Hz), 129.0 (d, J = 8.1 Hz), 129.2, 129.9 (d, J = 4.4 Hz),
135.0, 136.8, 157.6, 158.4, 161.0 (d, J = 245 Hz), 162.3.
N-(3-Furylmethyl)-4-(2-indolyl)-2-pyrimidinamine (45)
Prepared using 3-furylmethylamine (0.26 mL); yield: 0.19 g (65%);
pale brown powder; mp 144 °C.
1H NMR (400 MHz, CDCl3): d = 4.72 (d, J = 5.7 Hz, 2 H), 5.53 (s,
1 H), 6.27–6.36 (m, 2 H), 7.03 (d, J = 5.3 Hz, 1 H), 7.12 (dd, J = 2.2,
0.9 Hz, 1 H), 7.13 (ddd, J = 7.9, 7.0, 0.9 Hz, 1 H), 7.27 (ddd, J = 8.3,
7.0, 1.3 Hz, 1 H), 7.38 (dd, J = 1.8, 0.9 Hz, 1 H), 7.43 (ddd, J = 8.3,
1.7, 0.9 Hz, 1 H), 7.66 (dd, J = 7.9, 0.9 Hz, 1 H), 8.30 (d, J = 5.3 Hz,
1 H), 9.41 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 39.1, 103.8, 106.6, 107.1, 110.7,
111.8, 120.7, 121.9, 124.5, 128.9, 135.0, 136.8, 142.2, 152.8, 157.6,
158.3, 162.1.
ESCI MS: m/z = 318.86 [M + H]+.
Anal. Calcd for C19H15FN4 (318.35): C, 71.68; H, 4.75; N, 17.60.
Found: C, 71.52; H, 4.83; N, 17.58.
ESCI MS: m/z = 291.05 [M + H]+.
N-Cyclohexyl-4-(2-indolyl)-2-pyrimidinamine (46)
Prepared using cyclohexylamine (0.34 mL); yield: 0.20 g (70%);
pale yellow powder; mp 114 °C.
4-(2-Indolyl)-N-(4-tert-butylbenzyl)-2-pyrimidinamine (42)
Prepared using 4-tert-butylbenzylamine (0.53 mL); yield: 0.15 g
(43%); white powder; mp 162 °C.
1H NMR (400 MHz, CDCl3): d = 1.18–1.35 (m, 2 H), 1.39–1.53 (m,
2 H), 1.60–1.72 (m, 2 H), 1.73–1.84 (m, 2 H), 2.01–2.14 (m, 2 H),
3.87–4.00 (m, 1 H), 5.08 (d, J = 7.9 Hz, 1 H), 6.95 (d, J = 5.3 Hz, 1
H), 7.10 (dd, J = 1.8, 0.9 Hz, 1 H), 7.13 (ddd, J = 7.9, 7.0, 0.9 Hz, 1
H), 7.26 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H), 7.43 (dd, J = 8.3, 0.9 Hz, 1
H), 7.66 (dd, J = 7.9, 1.3 Hz, 1 H), 8.27 (d, J = 5.3 Hz, 1 H), 9.36 (s,
1 H).
13C NMR (100 MHz, CDCl3): d = 25.1 (2 C), 26.0, 33.5 (2 C), 49.9,
103.7, 105.8, 111.7, 120.6, 121.8, 124.3, 129.0, 135.2, 136.7, 157.6,
158.3, 161.8.
1H NMR (400 MHz, CDCl3): d = 1.33 (s, 9 H), 4.71 (d, J = 5.7 Hz,
2 H), 5.54 (s, 1 H), 7.01 (d, J = 5.3 Hz, 1 H), 7.11 (dd, J = 2.2, 0.9
Hz, 1 H), 7.13 (ddd, J = 7.9, 7.0, 0.9 Hz, 1 H), 7.26 (ddd, J = 8.3,
7.0, 1.3 Hz, 1 H), 7.33–7.44 (m, 5 H), 7.66 (dd, J = 7.9, 1.3 Hz, 1
H), 8.28 (d, J = 5.3 Hz, 1 H), 9.34 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 31.6 (3 C), 34.7, 45.6, 103.7,
106.3, 111.8, 120.6, 121.7, 124.4, 125.8 (2 C), 127.4 (2 C), 128.9,
135.1, 136.5, 136.7, 150.6, 157.6, 158.4, 162.4.
Anal. Calcd for C23H24N4 (356.46): C, 77.50; H, 6.79; N, 15.72.
Found: C, 77.62; H, 6.97; N, 15.29.
ESCI MS: m/z = 292.89 [M + H]+.
4-(2-Indolyl)-N-(3,4,5-trimethoxybenzyl)-2-pyrimidinamine
(43)
Prepared using 3,4,5-trimethoxybenzylamine (0.51 mL); yield: 0.14
4-(2-Indolyl)-N-(N-methyl-4-piperidyl)-2-pyrimidinamine (47)
Prepared using 4-amino-N-methylpiperidine (0.34 g); yield: 0.15 g
(50%); pale yellow oil.
g (37%); beige powder; mp 143 °C.
1H NMR (400 MHz, CDCl3): d = 1.57–1.71 (m, 2 H), 2.07–2.16 (m,
2 H), 2.23 (t, J = 11 Hz, 2 H), 2.33 (s, 3 H), 2.82 (d, J = 11 Hz, 2 H),
3.95 (m, 1 H), 5.06 (d, J = 7.9 Hz, 1 H), 6.98 (d, J = 5.3 Hz, 1 H),
7.11 (dd, J = 1.8, 0.9 Hz, 1 H), 7.13 (ddd, J = 7.9, 7.0, 1.3 Hz, 1 H),
7.26 (ddd, J = 8.1, 7.0, 0.9 Hz, 1 H), 7.43 (d, J = 8.1 Hz, 1 H), 7.66
(dd, J = 7.9, 0.9 Hz, 1 H), 8.28 (d, , J = 5.3 Hz, 1 H), 9.36 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 32.6 (2 C), 46.5, 47.6, 54.7 (2 C),
103.8, 106.1, 111.8, 120.7, 121.9, 124.4, 130.0, 135.1, 136.7, 157.7,
158.3, 161.9.
1H NMR (400 MHz, CDCl3): d = 3.82 (s, 6 H), 3.84 (s, 3 H), 4.65
(d, J = 5.7 Hz, 2 H), 5.65 (s, 1 H), 6.62 (s, 2 H), 7.02 (d, J = 5.3 Hz,
1 H), 7.10–7.15 (m, 2 H), 7.25 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H), 7.39
(dd, J = 8.3, 0.9 Hz, 1 H), 7.66 (dd, J = 7.9, 0.9 Hz, 1 H), 8.29 (d,
J = 5.3 Hz, 1 H), 9.44 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 46.3, 56.3 (2 C), 61.1, 103.9,
104.5 (2 C), 106.5, 111.7, 120.7, 121.9, 124.5, 128.7, 134.7, 135.0,
136.6, 137.1, 153.4 (2C), 157.5, 158.1, 162.1.
ESCI MS: m/z = 391.04 [M + H]+.
ESCI MS: m/z = 292.89 [M + H]+.
Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York

PAPER
Cross-Couplings of Lithium Arylzincates/Synthesis of Isomeridianin G Analogues
3631
Gallagher, T. Synlett 2002, 808. (i) Balle, T.; Andersen, K.;
Vedsø, P. Synthesis 2002, 1509. (j) Kondolff, I.;Doucet, H.;
Santelli, M. Organometallics 2006, 25, 5219. (k) Akao, A.;
Tsuritani, T.; Kii, S.; Sato, K.; Nonoyama, N.; Mase, T.;
Yasuda, N. Synlett 2007, 31.
Acknowledgment
We gratefully acknowledge the financial support of Région
Bretagne, CNRS and GlaxoSmithKline (A.S.). We thank Michel
Vaultier for his contribution to this study.
(15) About the direct lithiation of thiophene and
benzo[b]thiophene, see also: (a) Jen, K.-Y.; Cava, M. P.
J. Org. Chem. 1983, 48, 1449. (b) Surry, D. S.; Fox, D. J.;
MacDonald, S. J. F.; Spring, D. R. Chem. Commun. 2005,
2589.
(16) The 10% yield obtained by using 4-bromoanisole could be
explained by the absence of an electron-withdrawing group
at the 4-position of the phenyl ring. The competitive
formation of 2,2¢-bisthiophene was also observed in 40–50%
yield.
(17) Legault, C. Y.; Garcia, Y.; Merlic, C. A.; Houk, K. N. J. Am.
Chem. Soc. 2007, 129, 12664.
(18) Use of N-Boc-indole under these conditions gave after
subsequent reaction with iodine the 2-iodo derivative in 68%
yield as a pale yellow oil [after purification by
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7.01 (s, 1 H), 7.22–7.30 (m, 2 H), 7.48 (dd, J = 7.8, 2.0 Hz,
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Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York

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Synthesis 2009, No. 21, 3617–3632 © Thieme Stuttgart · New York