Solvent-free Heck-Jeffery reactions under ball-milling conditions applied to the synthesis of unnatural amino acids precursors and indoles

Article abstract of DOI:10.1055/s-2006-926371

The syntheses of various amino- and hydroxy-substituted dehydrophenylalanine derivatives using the Heck-Jeffery protocol under non-solvent conditions in a ball mill are presented. The influences of electron-withdrawing groups and of the location of the heteroatom substituent relative to the halide are discussed. Suitably substituted ortho-amino dehydrophenylalanine derivatives undergo a cyclization-elimination reaction to the corresponding 2-substituted indoles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926371

PAPER
1183
Solvent-Free Heck–Jeffery Reactions under Ball-Milling Conditions Applied
to the Synthesis of Unnatural Amino Acids Precursors and Indoles
a
b
c
a
S
E
ynthesis of
U
n
r
natural
A
i
mino
k
A
cids Precursors
a
T
s
ullberg, Felix Schacher, Dan Peters, Torbjörn Frejd*
a
Department of Organic Chemistry 1, Lund University, P. O. Box 124, 22100 Lund, Sweden
Fax +46(46)2224119; E-mail: Torbjorn.Frejd@organic.lu.se
b
c
Makromolecular Chemistry II, Naturwissenschaften II (NW II), 95440 Bayreuth, Germany
NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark
Received 29 September 2005; revised 10 November 2005
shorten the reaction times. This was achieved by ball-
milling in which the reaction was carried out under non-
solvent conditions. In that study we ascertained the cru-
cial importance of the tetraalkylammonium salt (in stoi-
Abstract: The syntheses of various amino- and hydroxy-substitut-
ed dehydrophenylalanine derivatives using the Heck–Jeffery proto-
col under non-solvent conditions in a ball mill are presented. The
influences of electron-withdrawing groups and of the location of the
1
2
heteroatom substituent relative to the halide are discussed. Suitably chiometric amounts) for the successful outcome of the
substituted ortho-amino dehydrophenylalanine derivatives undergo
a cyclization–elimination reaction to the corresponding 2-substitut-
ed indoles.
reaction. Aryl halides possessing electron-donating
groups or with no extra substitution, proved to be the best
coupling partners together with the amido acrylates. The
most successful amino aryl halide in that study was 4-io-
Key words: cyclizations, indoles, green chemistry, Heck reaction,
palladium
doaniline. This encouraged us to test the coupling of halo
anilines in general. In some cases the resulting substituted
a-amino dehydrophenylalanine derivatives spontaneously
The Heck reaction is a palladium-catalyzed coupling reac- cyclized to form 2-carboxy substituted indole derivatives
tion for the formation of a C–C bond between an aryl ha- under mildly acidic or thermal conditions. The literature
lide and an olefin. In the infancy of this transformation, describes many methods to cyclize unprotected ortho-
the catalytic species Pd(0) was often stabilized with phos- ethynyl anilines to 2-substituted indoles,1
3–19
but unpro-
1
phine ligands but in more recent years much effort has tected ortho-ethenyl counterparts are somewhat more
scarce.2 Syntheses of methyl-1H-indole-2-carboxylate
0,21
been devoted to the development of phosphine-free con-
2
,3
ditions, especially since it was observed that the addi-
tion of tetraalkylammonium salts to phosphine-free
derivatives in the literature include a Fischer synthesis, re-
ductive cyclization of methyl-2-nitro cinnamate and cy-
The compound itself, has
been used as starting material for the synthesis of HIV-1
3
22–24
reaction mixtures led to higher catalytic activities. Fur-
clization of azidoesters.
thermore, in some cases, a reduction of catalytic activity
4
integrase inhibitors.24
has been observed upon addition of phosphines. The ra-
tionale behind this behavior is that the tetraalkylammoni-
um salts stabilize the catalytic species, i.e. Pd(0)
nanoparticles, by forming a monomolecular layer around
the metal core and thereby preventing undesirable ag-
In this report we describe the coupling of various halo
anilines with an amido acrylate under solvent- and phos-
phine-free conditions and the subsequent cyclization of
suitably substituted coupling products to their corre-
sponding indole derivatives.
2
glomeration.
The existence of these Pd(0) nanoparticles has been ob-
served by in situ electron microscopy and the catalytic ac-
tivity of the tetraalkylammonium-encapsulated Pd(0) has
been verified by independent and conclusive experi-
Our results for the coupling reactions are summarized in
Table 1 and Scheme 1. As olefin for the reactions we se-
lected 2-tert-butoxycarbonylaminoacrylic acid methyl es-
ter which gave the best results in our previous study. It
will henceforth be abbreviated as AA. Aryl iodides were
12
2
ments. Among the phosphine-free Heck conditions, the
Heck–Jeffery protocol extends the scope of this reaction
to the synthesis of unnatural amino acids derived from
5
,6
phenylalanine. The reaction is carried out in N,N-di-
methylformamide with a stoichiometric amount of
tetrabutylammonium halide and sodium bicarbonate as
base. Unnatural amino acids derived from this methodol-
ogy have been the subject of a number of papers in our
Pd(OAc)2
NaHCO3
HCO2Na
R4
I
R4
CO2Me n-Bu NCl
CO2Me
NHBoc
4
+
NaCl
R3
R1
NHBoc
R3
R1
7
–11
group.
Recently, we further modified this methodolo-
R2
Ball milling
R2
AA
1
h
gy to avoid the use of N,N-dimethylformamide and to
1
–10
1
1–19
SYNTHESIS 2006, No. 7, pp 1183–1189
x
x
.
x
x
.2
0
0
6
Scheme 1 General reaction scheme for the coupling reactions under
ball-milling conditions
Advanced online publication: 08.03.2006
DOI: 10.1055/s-2006-926371; Art ID: T13805SS
Georg Thieme Verlag Stuttgart · New York
©

1
184
E. Tullberg et al.
PAPER
Table 1 Yields from Coupling Reactions
The above observation that electron-withdrawing substit-
uents on the aryl halide had a detrimental effect on the
yields in the coupling reactions, is consistent with obser-
vations in previous studies.6 The effect of the heteroat-
om substituents adjacent to the halide, can be rationalized
by increased steric hindrance to some extent but it could
also be an electronic effect due to coordination of nitrogen
to palladium. Indeed, in a recent study, 4-membered pal-
ladacycles were synthesized, isolated and subjected to X-
Ar–X
Product R1
R2
H
R3
H
R4
Yield (%)
29
,12
1
2
3
4
5
6
7
8
9
11
12
13
14
15
16
–
NH2
CN
NH2
H
H
CO CH 31
2 3
H
NH2
NH2
H
H
H
81
44
85
66
–
H
H
NH2
H
26
ray analysis. Moreover, a slight shortening of the ArC–
Pd bond length indicated that the presence of nitrogen in-
fluences the electronic properties of Pd(II) in the oxidative
addition complex. This, in turn, may slow down or com-
pletely stop subsequent steps in the Heck reaction. Indeed,
theoretical calculations on the strength of coordination of
ethylene to cationic methyl and ethyl palladium complex-
es, show that when ammonia ligands are introduced to the
system, the energy released upon coordination of ethylene
CH3
H
NH2
NH2
H
CH3
H
H
NH2
NH2
OH
H
F
17
18
19
H
CF3
H
H
43
31a
64
H
H
10
H
OH
H
27
drops significantly. Although the system studied in the
theoretical calculations is not comparable with our sys-
tem, it offers an insight into the influence exerted by nitro-
gen ligands on Pd (II) species.
a
Imino tautomer; see Figure 1.
the only substrates that coupled successfully; all aryl bro-
mides failed to give coupling products.
Nevertheless, 2-halo aniline substrates gave products re-
sulting from Heck-coupling but some of the primary cou-
pling products easily cyclized to give indole derivatives
The results shown in Table 1 show that poorer yields or no
products were obtained for iodoanilines carrying the elec-
tron-withdrawing groups (entries 1, 2, 7 and 8). Substrates
(
see Table 2, products 21, 24, 28, 31 and 32). During the
reaction of 2-iodoaniline (20) with the olefin TLC analy-
sis clearly indicated the formation of only one compound,
which upon chromatographic workup, was converted into
two new compounds. The crude product apparently un-
derwent a reaction in contact with the slightly acidic sili-
ca. When the reaction was repeated and the coupling
product was purified on a pre-neutralized silica column
1
and 2 are affected both by an electron-withdrawing sub-
stituent and by the proximity to the halide of a heteroatom
substituent; each affecting the poor outcome of the reac-
tion. It also transpired that the position of the amino- or
hydroxyl substituent relative to the iodine influenced the
yield. Thus, when the heteroatom substituent was in the
R or R positions (entries 3, 5, 6 and 10) the yields ob-
tained were significantly better than when it was in the R1
position (entries 1, 2, 8 and 9). The behavior of substrate
2
3
[
10% triethylamine in heptane–ethyl acetate (1:1)] this
behavior was not observed. In this case the expected prod-
uct was isolated and it could be analyzed by H NMR
1
4
was not consistent with this pattern, however. For rea-
spectroscopy if an acid free solvent was used. The initial
coupling product cyclized easily in refluxing acetic acid
or acetic anhydride to give the corresponding methyl-2-
indole carboxylate 21 in near quantitative yield. For the
coupling product between 22 and AA, the silica neutral-
ization was left out. This resulted in the serendipitous iso-
sons of comparison, we tried to couple 4 using conven-
tional Heck–Jeffery conditions as described by Carlström
6
et al. This substrate was particularly interesting because
to the best of our knowledge, there are no examples in the
literature of Heck couplings with substrates carrying two
amino groups. The only examples are Sonogashira type
1
lation of a substance that on H NMR analysis in CDCl3
2
5
couplings on related compounds. We found that 4 did
couple using the standard conditions but the yield was
slightly poorer (35%) than under ball-milling conditions
was shown to be 23 (see Figure 2).
CO2Me
(
44%).
N
NHBoc
Reaction products 11–17 and 19 showed the characteristic
structural features of dehydroamino acids. Product 18 tau-
tomerised, presumably after the coupling reaction, to form
the corresponding imino-derivative (see Figure 1).
H
Cl
23
Figure 2 Intermediate in the cyclization to form indole 24
CO2Me
When this material was treated with refluxing acetic anhy-
dride overnight, it exclusively gave indole derivative 24.
Dehydroindole derivatives such as 23 with a quaternary
carbon adjacent to the nitrogen are known from the litera-
NBoc
OH
Figure 1 Imino tautomer of coupling product 18
2
8
ture. Upon acidic treatment, this labile intermediate los-
es the equivalent of tert-butyl carbamate to form the
Synthesis 2006, No. 7, 1183–1189 © Thieme Stuttgart · New York

PAPER
Synthesis of Unnatural Amino Acids Precursors and Indoles
1185
indole. Upon searching the literature for other examples Table 2 Yields of Methyl-1H-indole-2-carboxylate Derivatives
of this type of cyclization–elimination, we could only find
one relevant reference (see Scheme 2). Acidic treatment
of 25 with HCl in refluxing methanol afforded the indole
2
9
ArX
Product R1
R2
H
H
H
H
Cl
H
H
H
R4
R5
H
Yield (%)
1
2
9
–
NH2
CN
–
2
6 in near quantitative yield. The authors did not comment
–
NH2
CO CH
H
–
on the mechanism.
2
3
–
OH
H
H
H
–
OBn
OBn
2
0
21
24
28
31
32
NH2
H
60
46
58
26
35
MeO
H2N
NHAc
MeO
H2N
HCl/MeOH
CO2Me
22
27
NH2
CH3
H
CO2Me
NH2
N
H
NH2
H
OCH3
H
25
26
2
9
0
NH2
Cl
Br
Scheme 2 Details from a known reaction sequence comprising a cy-
clization–elimination reaction forming an indole derivative
3
NH2
H
Those ortho-amino dehydrophenylalanine intermediates
prone to form indoles were so unstable that characterisa-
tion of these intermediates was not practical. In fact, the
onset of the cyclization–elimination was also observed in
neat samples after an overnight storage in an open flask.
Therefore, the entire reaction sequence depicted in
Scheme 3 was carried out without fully characterizing any
intermediates until products could be isolated as stable in-
doles. The results from these coupling–cyclization reac-
tions are shown in Scheme 3 and Table 2.
mildly electron-donating substituents gave the corre-
sponding indoles 24, 31 and 32, respectively, in more
modest yields. The yield-determining process in the reac-
tion sequence was invariably the coupling reaction as de-
termined by the weight of the residue remaining after a
short workup prior to cyclization, whereas the cycliza-
tion–elimination reaction was nearly quantitative. The
failure of aryl bromides to couple with AA enabled a
regioselective coupling of 30 followed by cyclization to
form indole 32 in modest yield. The indole derivative 32
has been used as starting material for Suzuki and Son-
agashira coupling reactions.3
The results in the Table 2 suggest that the cyclization–
elimination reaction was very sensitive to the nature of the
substituents. Thus, when the sequence was performed
with ortho-aminoaryl iodides containing electron-with-
drawing substituents such as 1 and 2, the intermediate
ortho-amino dehydrophenylalanine derivatives 11 and 12,
respectively, failed to form the indole even after several
days of refluxing in acetic anhydride. When the imino tau-
tomer 18 obtained from the coupling between 9 and AA
was subjected to cyclization conditions, in an attempt to
form the corresponding benzofuran derivative, no product
was formed either. The unsubstituted 2-iodoaniline (20)
and the electron-donating substituted substrate 27 both
gave the corresponding indole derivatives 21 and 28 in
fair yields, whereas substrates 22, 29 and 30 containing
0,31
Interestingly, in a further attempt to perform the coupling
between 2-iodoaniline (20) and AA under conventional
conditions, using N-methyl-2-pyrrolidone as solvent, no
coupling product was formed after 24 hours at 80 °C. This
is remarkable as the temperature attained in the ball mill
after one hour of milling seldom rises above this level but
it is sufficient to form product. However, heating to 130
°
C, gave the indole in 50% yield. This fact was puzzling
because the reaction mixture used for coupling, irrespec-
tive if performed in solvent or without solvent, is inherent-
ly basic. This suggested that the cyclization could be
performed simply by heating the coupled intermediate in
Pd(OAc)2
R5
NaHCO3
HCO2Na
R5
R4
I
CO2Me
NHBoc
n-Bu NCl
R4
4
CO2Me
+
NaCl
NHBoc
NH2
NH2
Ball milling, 1 h
R2
R2
AA
1
, 2, 9, 20,
22, 27, 29, 30
R5
R4
Ac2O
reflux
CO2Me
N
H
12 h
21, 24, 28,
R2
3
1, 32
Scheme 3 General reaction scheme for the formation of the indole derivatives
Synthesis 2006, No. 7, 1183–1189 © Thieme Stuttgart · New York

1
186
E. Tullberg et al.
PAPER
an appropriate solvent and indeed we found that the cy- AcOH (40 mL) and H
O (10 mL) over 30 min. The reaction mixture
was heated at 90 °C for 3 h and then cooled to 25 °C. The reaction
was quenched with a solution of sodium thiosulfate in water, ex-
2
clization could be effected thermally by refluxing in tolu-
ene but conversion was slower and the yields were poorer
than when the coupled intermediate was heated at reflux
in acetic acid or anhydride.
tracted with Et O (3 × 50 mL) and the combined organic phases
2
were dried with Na SO . After filtering and removal of the solvent
2
4
under reduced pressure the residue was purified by chromatograph-
ic workup using heptane–EtOAc (8:1) as eluent. The amine was ob-
tained as a pale brown liquid (1.29 g, 37%).
The coupling of amido acrylate AA with various iodo
anilines and iodo phenols under ball-milling conditions
proceeded in modest to good yields. The reaction was per- IR (NaCl): 3473, 3381, 3201, 2120, 1733, 1610, 1485 cm .
formed under solvent- and phosphine-free conditions and
has the added advantage of being rapid and easily worked 6.94 (s, 1 H, ArH), 6.71 (d, J = 8.2 Hz, 1 H, ArH), 4.30 (br, 2 H,
up. Suitably substituted ortho-aminoaryl dehydrophenyl-
alanine derivatives cyclized efficiently to the correspond-
ing methyl 1H-indole-2-carboxylates. This methodology Hz), 124.0 (q, J = 272.3 Hz), 116.1 (q, J = 3.8 Hz), 110.8 (q, J = 3.8
provides a useful and direct synthesis of some of these de-
rivatives.
–1
1
H NMR (300 MHz, CDCl ): d = 7.74 (d, J = 8.2 Hz, 1 H, ArH),
3
NH2).
1
3
C NMR (75 MHz, CDCl ): d = 147.2, 139.7, 132.0 (q, J = 32.4
3
Hz), 87.7.
+
HRMS (FAB ): m/z calcd for C H NF I: 286.9419; found:
7
5
3
2
86.9422.
It was not possible to obtain satisfactory elemental analysis for this
All reagents were used as delivered from Aldrich without further
1
compound. The H NMR data were in accordance with literature da-
purification. 2-tert-Butoxycarbonylaminoacrylic acid methyl ester
3
8
6
32
ta.
(
AA) and 2-iodo-3-nitrophenol was synthesized according to the
literature procedures. Inorganic salts were dried in an oven at 110
C overnight. Chromatographic workup was performed with Ma-
2
-Iodo-3-methoxyphenylamine (27)
°
Methyl iodide (0.32 mL, 3.8 mmol) was added to a suspension of 2-
iodo-3-nitrophenol (0.92 g, 3,5 mmol) and K CO (2.4 g, 17 mmol)
trex 60 Å 35–70 mesh silica. Ethyl acetate and pentane were sup-
plied by Fluka, heptane by Merck, and petroleum ether (bp 60–80
2
3
in DMF (5 mL). The mixture was stirred at r.t. overnight and then
M NaOH (5 mL) was added. The mixture was extracted with Et O
°
C) by VWR Prolabo. TLC analyses were performed on Merck sil-
2
ica gel 60-coated aluminum or glass plates. NMR spectra were re-
corded on a Bruker ARX 400 or a Bruker ARX 300 instrument.
Melting points were measured on a Gallenkamp Melting Point Ap-
paratus MFB-595 and are uncorrected. IR spectra were recorded on
a Shimadzu FTIR-8300 instrument and mass spectra were recorded
on a JEOL SX-102 mass spectrometer. Microanalyses were per-
formed by H. Kolbe Mikroanalytisches Laboratorium, Höhenweg
2
(
3 × 20 mL) and the combined organic phases were dried with
Na SO . After filtration and removal of the solvent under reduced
2
4
pressure 2-iodo-1-methoxy-3-nitrobenzene was obtained as a yel-
low powder. (0.9 g, 97%) The melting point (100.9–102.9 °C) was
3
9
in agreement with the literature data (Lit. 102.5–103.5 °C). This
compound was used directly in the next step without further purifi-
cation.
1
7, 45470, Mülheim an der Ruhr, Germany.
Iron powder (0.77 g, 14 mmol) was added to a solution of 2-iodo-1-
methoxy-3-nitrobenzene (0.9 g, 3.3 mmol) in a mixture of AcOH (8
mL) and EtOH (8 mL). The grey slurry thus obtained was heated at
reflux for 3.5 h and then left to cool. The mixture was diluted 1:1
with water, neutralized with solid Na CO and extracted with
Ball milling was performed using a Fritsch Planetary Micro Mill
model ‘Pulverisette 7’ housing two stainless steel cups containing
eight stainless steel balls each and sealed by a stainless steel lid fit-
ted with a Teflon gasket.
2
3
In our previous study, we determined that the coupling reactions
gave the Z-isomer.12 Some of the tested amino- or hydroxyl-substi-
tuted aryl iodides were commercially available: 3, 5, 6, 9, 10, 20 and
CH Cl (3 × 20 mL). The combined organic phases were dried with
2
2
Na SO . After filtration and removal of the solvent under reduced
2
4
pressure, the title compound 27 was obtained as a brown oil (0.51 g,
2
9; others: 1, 2, 4, 7, 22 and 30 were synthesized according to liter-
1
6
0%). The H NMR spectrum of this compound was in agreement
33–37
ature procedures
and finally substrates 8 and 27 were synthe-
40
with the literature data.
sized by the modified literature procedures described below. We
also tested a series of commercially available amino-substituted
aryl bromides under these conditions: 2-bromo-4-chloro-6-fluo-
rophenylamine, 2-bromo-4-fluorophenylamine, 2-bromo-4-trifluo-
romethylphenylamine, 3-bromophenylamine, 3-bromo-5-methyl-
pyrindin-2-ylamine, 2-bromo-4-methylphenylamine and 2-bromo-
Heck Couplings; General Procedure
The following components were added to the reaction vessels: aryl
halide (1.00 equiv), AA (1.05 equiv), NaHCO3 (2.50 equiv),
HCO Na (0.20 equiv), n-Bu NCl (1.20 equiv), Pd(OAc) (0.05
2
4
2
equiv) and NaCl (5 mg/mg aryl halide). Then, 8 steel balls were
added and the vessel was purged with argon and closed with lid and
gasket. To balance the rotor of the ball mill, two similarly loaded
vessels were always run at the same time. The ball mill was then run
at full speed for an hour. After the vessels had cooled down, the con-
tents were scraped out into a beaker and the vessel and the balls
were washed with acetone (200 mL). The acetone solution was then
poured into a round-bottomed flask together with silica and the sol-
vent was removed in vacuo. The solid residue absorbed on silica
was placed on a neutralized silica column (the appropriate eluent
4
-trifluoromethoxyphenylamine but these substrates failed to react
altogether. Attempts to remedy this complete lack of reactivity us-
ing 3-bromophenylamine as candidate by changing the pre-catalyst
from Pd(OAc) to Pd(O CCF ) and Pd (dba) with or without ad-
2
2
3
2
2
3
ditional triphenylphosphine or with Pd(PPh ) , did not help, neither
3
4
did changing the ionic liquid from tetrabutylammonium chloride to
BMIM·PF . The reaction time was also extended to four hours in-
6
stead of one hour (but at lower milling speed to avoid damaging the
vessels) using the standard conditions with and without added triph-
enylphosphine but to no avail.
containing 10% Et N was used to pack the column) and purified by
3
chromatographic workup with eluent system as indicated.
2
-Iodo-5-trifluoromethylphenylamine (8)
Reactions were typically run on a 0.5 mmol scale with regard to the
aryl halide. The total weight of the reaction mixture in the reaction
vessel was in the order of 1 g. The following compounds were pre-
pared using this procedure.
Warning! This is an extremely noxious substance with a very repug-
nant smell.
A solution of ICl (3.0 g, 18 mmol) in AcOH (10 mL) was added to
a solution of 3-trifluoromethylphenylamine (3.0 g, 18 mmol) in
Synthesis 2006, No. 7, 1183–1189 © Thieme Stuttgart · New York

PAPER
-(2-Amino-5-cyanophenyl)-2-tert-butoxycarbonylamino-
Synthesis of Unnatural Amino Acids Precursors and Indoles
1187
3
Anal. Calcd for C H N O : C, 58.62; H, 6.89; N, 13.67. Found: C,
1
5
21
3
4
acrylic Acid Methyl Ester (11)
58.69; H, 6.86; N, 13.61.
Eluent: pentane–EtOAc (3:2); pale yellow needles (pentane–
EtOAc); mp 151.8–152.2 °C.
3-(4-Amino-2-methylphenyl)-2-tert-butoxycarbonylamino-
acrylic Acid Methyl Ester (15)
Eluent: petroleum ether–EtOAc (3:2); yellow powder (pentane–
–
1
IR (KBr): 3409, 2222, 1716, 1624 cm .
1
H NMR (300 MHz, CDCl ): d = 7.52 (d, J = 1.8 Hz, 1 H, ArH),
3
EtOAc); mp 141.1–142 °C.
7
.35 (dd, J = 1.9, 8.4 Hz, 1 H, ArH), 7.03 (s, 1 H, HC=), 6.71 (d,
–
1
IR (KBr): 3419, 1716, 1645 cm .
J = 8.4 Hz, 1 H, ArH), 6.54 (br, 1 H, NH), 4.38 (br, 2 H, NH ), 3.87
2
1
(
s, 3 H, CO CH ), 1.35 [s, 9 H, C(CH ) ].
H NMR (400 MHz, CDCl ): d = 7.15 (s, 1 H, ArH), 7.01 (d, J = 8.1
2
3
3
3
3
1
3
Hz, 1 H, ArH), 6.82 (d, J = 2.2 Hz, 1 H, HC=), 6.59 (dd, J = 2.5, 8.1
C NMR (100 MHz, CDCl ): d = 165.2, 151.4, 148.2, 133.3, 133.1,
3
Hz, 1 H, ArH), 6.07 (br, 1 H, NH), 3.86 (s, 3 H, CO CH ), 3.33 (br,
2
3
1
26.9, 121.5, 120.3, 119.8, 116.0, 100.5, 81.6, 53.1, 28.1.
2
H, NH ), 2.21 (s, 3 H, ArCH ), 1.38 [s, 9 H, C(CH ) ].
2 3 3 3
+
HRMS (FAB ): m/z calcd for C H N O : 317.1376; found:
1
6
19
3
4
13
C NMR (100 MHz, CDCl ): d = 166.1, 152.4, 144.3, 133.7, 131.4,
3
3
17.1376.
1
27.6, 127.3, 126.2, 116.3, 114.7, 81.1, 52.7, 28.3, 19.2.
Anal. Calcd for C H N O : C, 60.56; H, 6.03; N, 13.24. Found: C,
1
6
19
3
4
+
HRMS (FAB ): m/z calcd for C H N O : 306.1580; found:
1
6
22
2
4
6
0.40; H, 5.96; N, 13.20.
3
06.1581.
4
-Amino-3-(2-tert-butoxycarbonylamino-2-methoxycarbonyl-
Anal. Calcd for C H N O : C, 62.73; H, 7.24; N, 9.14. Found: C,
62.61; H, 7.21; N, 9.08.
1
6
22
2
4
vinyl)benzoic Acid Methyl Ester (12)
Eluent: petroleum ether–EtOAC (3:2); yellow powder (pentane–
EtOAc); mp 185.2–186.1 °C.
3-(4-Amino-3-methylphenyl)-2-tert-butoxycarbonylamino-
acrylic Acid Methyl Ester (16)
Eluent: heptane–EtOAc (3:2); brown powder (pentane–EtOAc); mp
163.3–164.1 °C.
–
1
IR (KBr): 3419, 1733, 1716, 1652 cm .
1
H NMR (400 MHz, CDCl ): d = 7.96 (d, J = 1.8 Hz, 1 H, ArH),
3
7
.81 (dd, J = 1.9, 8.5 Hz, 1 H, ArH), 7.11 (s, 1 H, HC=), 6.71 (d,
–
1
IR (KBr): 3411, 1706, 1620 cm .
J = 8.5 Hz, 1 H, ArH), 6.47 (br, 1 H, NH), 4.25 (br, 2 H, NH ), 3.88
2
1
(
s, 3 H, CO CH ), 3.85 (s, 3 H, CO CH ), 1.36 [s, 9 H, C(CH ) ].
H NMR (300 MHz, CDCl ): d = 7.24 (s, 2 H, ArH), 7.14 (s, 1 H,
2
3
2
3
3 3
3
1
3
HC=), 6.54 (d, J = 8.4 Hz, 1 H, ArH), 6.02 (br, 1 H, NH), 3.82 (s, 3
C NMR (100 MHz, CDCl ): d = 167.0, 165.6, 152.4, 148.6, 131.7,
3
H, CO CH ), 3.65 (br, 2 H, NH ), 2.08 (s, 3 H, ArCH ), 1.39 [s, 9
2
3
2
3
1
31.6, 126.7, 123.3, 120.0, 119.2, 115.5, 81.3, 53.0, 51.9, 28.5.
H, C(CH ) ].
3
3
+
HRMS (FAB ): m/z calcd for C H N O : 350.1478; found:
1
7
22
2
6
13
C NMR (100 MHz, CDCl ): d = 166.9, 146.5, 133.1, 131.8, 130.1,
3
3
50.1482.
1
28.6, 124.2, 121.7, 118.9, 114.3, 81.0, 52.5, 28.5, 17.3.
Anal. Calcd for C H N O : C, 58.28; H, 6.33; N, 8.00. Found: C,
1
7
22
2
6
+
HRMS (FAB ): m/z calcd for C H N O : 306.1580; found:
1
6
22
2
4
5
8.20; H, 6.29; N, 7.88.
3
06.1577.
3
-(3-Aminophenyl)-2-tert-butoxycarbonylaminoacrylic Acid
Anal. Calcd for C H N O : C, 62.73; H, 7.24; N, 9.14. Found: C,
62.68; H, 7.32; N, 9.05.
1
6
22
2
4
Methyl Ester (13)
Eluent: heptane–EtOAc (3:2); white crystals (pentane–EtOAc); mp
1
34.9–135.6 °C.
3-(2-Amino-4-trifluoromethylphenyl)-2-tert-butoxycarbonyl-
aminoacrylic Acid Methyl Ester (17)
Eluent: petroleum ether–EtOAc (4:1); gray needles (pentane–
EtOAc); mp 129.5–131 °C.
–
1
IR (KBr): 3419, 1718, 1643 cm .
1
H NMR (400 MHz, CDCl ): d = 7.14 (m, 2 H, ArH), 6.93 (d, J =
3
7
.7 Hz, 1 H, ArH), 6.85 (s, 1 H, HC=), 6.66 (dd, J = 2.2, 7.9 Hz, 1
–
1
IR (KBr): 3425, 3323, 1693, 1604 cm .
H, ArH), 6.15 (br, 1 H, NH), 3.84 (s, 3 H, CO CH ), 3.48 (br, 2 H,
NH ), 1.41 [s, 9 H, C(CH ) ].
2
3
1
H NMR (400 MHz, CDCl ): d = 9.74 (br, 1 H, NH), 7.80 (d, J = 8.5
2
3 3
3
1
3
Hz, 1 H, ArH), 7.71 (s, 1 H, HC=), 7.39 (dd, J = 1.3, 8.5 Hz, 1 H,
C NMR (100 MHz, CDCl ): d = 166.4, 152.9, 146.5, 135.0, 130.3,
29.5, 124.8, 120.4, 116.2, 116.1, 81.0, 52.6, 28.2.
3
ArH), 7.25 (d, J = 1.3 Hz, 1 H, ArH), 4.59 (br, 2 H, NH ), 3.99 (s, 3
2
1
H, CO CH ), 1.48 [s, 9 H, C(CH ) ].
2
3
3 3
+
HRMS (FAB ): m/z calcd for C H N O : 292.1423; found:
2
1
5
20
2
4
13
C NMR (100 MHz, CDCl ): d = 162.4, 156.7, 135.9, 129.7, 127.5
3
92.1423.
(
q, J = 29.2 Hz), 126.3, 123.6, 123.4, 117.5 (q, J = 3.85 Hz), 110.0
Anal. Calcd for C H N O : C, 61.63; H, 6.90; N, 9.58. Found: C,
6
1
5
20
2
4
(q, J = 3.85 Hz), 108.6, 80.0, 52.5, 28.5.
1.56; H, 6.85; N, 9.45.
+
HRMS (FAB ): m/z calcd for C H F N O : 360.1297; found:
1
6
19
3
2
4
3
60.1357.
2
-tert-Butoxycarbonylamino-3-(3,5-diaminophenyl)acrylic
Acid Methyl Ester (14)
Eluent: pentane–EtOAc (1:1); amorphous white solid (pentane–
Anal. Calcd for C H F N O : C, 53.33; H, 5.31; N, 7.77. Found:
C, 53.29; H, 5.25; N, 7.68.
1
6
19
3
2
4
EtOAc); mp 127.5–128.5 °C.
–
1
2-tert-Butoxycarbonylamino-3-(2-hydroxyphenyl)acrylic Acid
Methyl Ester (18)
Eluent: petroleum ether–EtOAc (4:1); white needles (pentane–
EtOAc); mp 144.8–145.5 °C.
IR (KBr): 3410, 1716, 1647 cm .
1
H NMR (300 MHz, CDCl ): d = 6.99 (s, 1 H, ArH), 6.29 (d, J = 2.2
Hz, 2 H, ArH), 6.08 (br, 1 H, NH), 6.01 (s, 1 H, HC=), 3.83 (s, 3 H,
CO CH ), 3.62 (br, 4 H, NH ), 1.45 [s, 9 H, C(CH ) ].
3
2
3
2
3
3
IR (KBr): 3424, 3152, 1728, 1656 cm–1.
1
3
C NMR (100 MHz, CDCl ): d = 166.3, 152.2, 147.6, 135.8, 129.8,
25.1, 107.4, 102.9, 81.1, 52.6, 28.3.
3
1
H NMR (400 MHz, acetone-d ): d = 7.42 (br, 1 H, OH), 7.11–7.17
6
1
(
m, 2 H, ArH), 6.86 (t, J = 7.5 Hz, 1 H, ArH), 6.78 (d, J = 8.0 Hz, 1
+
HRMS (FAB ): m/z calcd for C H N O : 307.1532; found:
1
5
21
3
4
H, ArH), 3.74 (s, 3 H, CO CH ), 3.59–3.47 (m, 2 H, ArCH ), 1.39
2
3
2
3
07.1545.
[
s, 9 H, C(CH ) ].
3 3
Synthesis 2006, No. 7, 1183–1189 © Thieme Stuttgart · New York

1
188
E. Tullberg et al.
PAPER
1
3
C NMR (100 MHz, CDCl ): d = 169.5, 158.2, 153.6, 130.9, 128.5,
Anal. Calcd for C H ClNO : C, 59.07; H, 4.51; N, 6.26. Found: C,
58.97; H, 4.40; N, 6.12.
3
11 10
2
1
24.4, 121.5, 109.8, 92.6, 81.3, 53.6, 39.8, 28.2.
+
+
HRMS (FAB ): m/z [M + H ] calcd for C H NO : 294.1341;
1
5
20
5
4
-Methoxy-1H-indole-2-carboxylic Acid Methyl Ester (28)
found: 294.135.
4
2
White needles (toluene); mp 143.3–145.5 °C (Lit. 147–148 °C).
Anal. Calcd for C H NO : C, 61.42; H, 6.53; N, 4.78. Found: C,
15
19
5
1
The H NMR data of this compound were in accordance with the lit-
erature data.
6
1.35; H, 6.59; N, 4.66.
4
2
2
-tert-Butoxycarbonylamino-3-(4-hydroxyphenyl)acrylic Acid
5
-Chloro-1H-indole-2-carboxylic Acid Methyl Ester (31)
Methyl Ester (19)
Eluent: petroleum ether–EtOAc (2:1); white amorphous solid (pen-
tane–EtOAc); mp 145.2–146 °C.
White needles (toluene); mp 214–215 °C.
–
1
IR (KBr): 3333, 1693, 1551 cm .
–
1
1
IR (KBr): 3587, 3409, 1705, 1606 cm .
H NMR (300 MHz, CDCl ): d = 8.85 (br, 1 H, NH), 7.70 (d, J = 2
3
1
Hz, 1 H, ArH), 7.28 (d, J = 8.6 Hz, 1 H, ArH), 7.21 (dd, J = 2.0, 8.6
Hz, 1 H, ArH), 7.18 (s, 1 H, HC=), 3.88 (s, 3 H, CO CH ).
H NMR (400 MHz, CDCl ): d = 7.75 (br, 1 H, OH), 7.42 (d, J = 8.4
Hz, 2 H, ArH), 7.29 (br, 1 H, HC=), 6.72 (br, 2 H, ArH), 6.22 (br, 1
H, NH), 3.83 (s, 3 H, CO CH ), 1.44 [s, 9 H, C(CH ) ].
3
2
3
1
H NMR (400 MHz, DMSO-d ): d = 12.13 (br, 1 H, NH), 7.73 (d,
2
3
3 3
6
1
3
J = 1.7 Hz, 1 H, ArH), 7.45 (d, J = 8.8 Hz, 1 H, ArH), 7.26 (dd, J =
2
These data were in accordance with the literature data.41
1
C NMR (100 MHz, CDCl ): d = 166.7, 158.1, 155.0, 132.7, 132.2,
3
.0, 8.8 Hz, 1 H), 7.13 (s, 1 H, HC=), 3.87 (s, 3 H, CO CH ).
2
3
1
26.7, 116.3, 115.9, 82.0, 52.7, 28.4.
+
HRMS (FAB ): m/z calcd for C H NO : 293.1263; found:
1
5
19
5
3
2
93.1267.
C NMR (75 MHz, CDCl ): d = 162.9, 135.5, 129.2, 128.8, 126.9,
3
1
26.4, 122.2, 113.4, 108.5, 52.6.
Anal. Calcd for C H NO : C, 61.42; H, 6.53; N, 4.78. Found: C,
15
19
5
+
6
1.36; H, 6.59; N, 4.71.
HRMS (FAB ): m/z calcd for C H ClNO : 209.0244; found:
1
0
8
2
2
09.0268.
Cyclization of Coupled Intermediates to Form Indole Deriva-
tives; General Procedure
The above chromatographic workup was used to remove excess
starting materials after which the column was flushed with heptane–
EtOAc (1:1). The solvent was evaporated at reduced pressure and
5-Bromo-1H-indole-2-carboxylic Acid Methyl Ester (32)
White needles (toluene); mp 211.8–213.6 °C.
IR (KBr): 3325, 1695, 1523 cm–1.
1
H NMR (300 MHz, CDCl ): d = 8.97 (br, 1 H, NH), 7.83 (s, 1 H,
the residue was suspended in Ac O (2 mL/100 mg residue). The
3
2
ArH), 7.42 (dd, J = 1.9, 6.9 Hz, 1 H, ArH), 7.31 (d, J = 8.8 Hz, 1 H,
mixture was heated at reflux overnight and then the mixture was
ArH), 7.14 (s, 1 H, HC=), 3.95 (s, 3 H, CO CH ).
evaporated to dryness under reduced pressure. Residual Ac O was
2
3
2
removed by co-evaporation with toluene. The brownish white resi-
due was placed on a pad of silica and eluted with heptane–EtOAc
13
C NMR (75 MHz, CDCl ): d = 162.2, 135.4, 129.2, 128.6, 128.4,
3
1
25.1, 114.1, 113.5, 108.1, 52.4.
(1:1). Removal of the solvent under reduced pressure afforded the
+
HRMS (FAB ): m/z calcd for C H BrNO : 252.9738; found:
1
0
8
2
indole derivative that could be re-crystallised from EtOH or tolu-
ene. Intermediates prone to cyclization to the corresponding indoles
were not characterized.
2
97.9727.
Anal. Calcd for C10
7.25; H, 3.14; N, 5.41.
H BrNO : C, 47.27; H, 3.17; N, 5.51. Found: C,
8 2
4
1
H-Indole-2-carboxylic Acid Methyl Ester (21)
White needles (absolute EtOH); mp 148.1–148.5 °C (Lit. 145–147
C).
2
4
Acknowledgment
°
1
24
The H NMR data was in accordance with the literature data.
The authors would like to thank the Swedish Science Council, the
Royal Physiographic Society in Lund and the Lund University Re-
search School of Medicinal Sciences for financial support. Dr. Karl
Erik Bergkvist and Dr. Ola Wendt are thanked for their help in elu-
cidating the connectivity of certain substances.
2
1
-tert-Butoxycarbonylamino-7-chloro-5-methyl-2,3-dihydro-
H-indole-2-carboxylic Acid Methyl Ester (23)
This compound (white paste) was not stable enough to allow full
characterization.
1
H NMR (300 MHz, CDCl ): d = 6.86 (s, 1 H, ArH), 6.75 (s, 1 H,
3
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3
2
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–
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1
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1
1
10
2
(
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Synthesis 2006, No. 7, 1183–1189 © Thieme Stuttgart · New York

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Synthesis 2006, No. 7, 1183–1189 © Thieme Stuttgart · New York