The optimization for cyclization reaction of 2-(2-carbomethoxyethynyl) aniline derivatives and formal synthesis of pyrroloquinoline quinone and its analogue utilizing a sequential coupling-cyclization reaction

Article abstract of DOI:10.1016/j.tet.2005.09.084

The reaction conditions for the Pd-catalyzed cyclization reaction of 2-(2-carbomethoxyethynyl)aniline derivatives were investigated. The amounts of Pd(PPh₃)₄, methyl propiolate, and ZnBr₂ could be significantly reduced compared with those reported in our preliminary publication by careful tuning of the solvent and the reaction temperature. In addition to the above results, formal syntheses of pyrroloquinoline quinone (PQQ) and its analogue from 2-amino-5-nitrophenol using a Pd-complex-catalyzed sequential coupling-cyclization reaction between methyl propiolate and 2-iodoaniline derivatives are described.

Full text of DOI:10.1016/j.tet.2005.09.084

Tetrahedron 61 (2005) 12330–12338
The optimization for cyclization reaction of
2-(2-carbomethoxyethynyl)aniline derivatives and formal
synthesis of pyrroloquinoline quinone and its analogue utilizing
a sequential coupling-cyclization reaction
a
a
a
Kou Hiroya,a, Shigemitsu Matsumoto, Masayasu Ashikawa, Hitomi Kida and
*
Takao Sakamotoa,b
aGraduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980 8578, Japan
bTohoku University 21st Century COE Program ‘Comprehensive Research and Education Center for Planning of Drug Development and
Clinical Evaluation,’ Sendai 980 8578, Japan
Received 26 August 2005; revised 20 September 2005; accepted 21 September 2005
Available online 10 October 2005
Abstract—The reaction conditions for the Pd-catalyzed cyclization reaction of 2-(2-carbomethoxyethynyl)aniline derivatives were
investigated. The amounts of Pd(PPh3)4, methyl propiolate, and ZnBr2 could be significantly reduced compared with those reported in our
preliminary publication by careful tuning of the solvent and the reaction temperature. In addition to the above results, formal syntheses of
pyrroloquinoline quinone (PQQ) and its analogue from 2-amino-5-nitrophenol using a Pd-complex-catalyzed sequential coupling-
cyclization reaction between methyl propiolate and 2-iodoaniline derivatives are described.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 1, 1a/3a; 69% vs 1b/3b; 10%).2 However,
the cyclization reactions for the compound 2b can be
realized in almost perfect yield when both Pd(PPh3)4 and
methyl propiolate are present in the reaction medium
(Scheme 1, 2b/3b; 94%).2 These results suggest that the
coupling reaction rate for the electron-rich substrate is
slower than that for the electron-poor compound in the
sequential processes, and it seems likely that the catalyst
was deactivated during the long reaction time.
1.1. Cyclization reaction of 2-(2-carbomethoxylethynyl)-
aniline derivatives
In our continuing efforts to develop new methods of
synthesis for heterocyclic compounds, we have previously
discovered both Cu(II)-catalyzed synthesis of indoles from
2-ethynylaniline derivatives1 and Pd-complex-catalyzed
sequential coupling-cyclization reactions between methyl
propiolate and 2-iodoaniline derivatives, and the latter’s
application to duocarmycin SA synthesis.2,3 Although the
true catalytic species in the Pd-complex-catalyzed reactions
has not yet been identified, these reactions are an effective
method for the synthesis of indole-2-carboxylate deriva-
tives, which are commonly found in biologically active
compounds.
In our previous communication, we reported that methyl
propiolate is essential for the Pd-catalyzed cyclization
reactions of 2b.2 However, we did not optimize the reaction
conditions, including the amount of each reagent and the
solvent, reaction temperature, and ligand for Pd. In the first
half of this article, we describe the results of the
optimization for the Pd-catalyzed cyclization reaction
conditions (2b/3b).
Unfortunately, the substrates for the Pd-complex-catalyzed
sequential reaction are limited to compounds having at least
one electron-withdrawing group on the aromatic ring
1.2. Pyrroloquinoline quinone (PQQ) and its analogues
The characterization of pyrroloquinoline quinone (PQQ) (4)
from Pseudomonas TP14 was first reported in 1979 by
Salisbury. Initially, the role of PQQ in bacteria seemed to be
limited to that of a redox cofactor, but later it was found that
Keywords: Palladium; 2-Ethynylaniline; Methyl propiolate; Indole;
Cyclization reaction; Pyrroloquinoline quinone.
*
Corresponding author. Tel.: C81 22 795 6867; fax: C81 22 795 6864;
e-mail: hiroya@mail.tains.tohoku.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.084

K. Hiroya et al. / Tetrahedron 61 (2005) 12330–12338
12331
Scheme 1. Sequential coupling-cyclization reactions for 1a and 1b and cyclization reaction for 2b.
PQQ also acts as a growth factor and tissue-protective
agent.5 Quite recently, another important role for PQQ as
the 14th vitamin in mammals was established by Kasahara
and Kato.6,7
synthesized, including mono- and dicarboxylic acid deriva-
tives,11 6-deaza derivatives,12 benzo-,13a furo- (FQQ),13b
thieno- (TQQ),13b and imidazole13c analogues in place of the
pyrrole ring, and azaisomers involving both the pyrrole and
pyridine rings.14,15
ThefirsttotalsynthesisofPQQwasreportedbyCoreyin1981,
in11stepsstartingfromcommerciallyavailable2-methoxy-5-
nitroaniline.8a After this communication, seven articles on the
total synthesis of PQQ were published in the 1980s,8b–h and
three papers reported the preparation of PQQ and/or its
trimethyl ester in the 1990s.8i–k Interest in PQQ has recently
shifted toward understanding the mechanisms of its biological
activity9 and biosynthetic pathway.10 Thus, the synthetic
targetshavebeennotonlyPQQitself, butalsoPQQanalogues,
in order to understand the structure–activity relationships of
PQQ. Hence, many kinds of PQQ analogues have been
Our synthetic strategies for PQQ (4) and its analogue 5 are
shown in Figure 1. Briefly, the conversions from 9 via 7 and
6 to PQQ (4) and from 8 to PQQ analogue 5 had been
reported by Rees’s8g and Hudson’s14b research groups,
respectively. Thus, compound 8 can be synthesized from 10
by same pyridine ring formation reactions as for 9. Since
both 11 and 12 have the nitro group on the aromatic ring, we
planned to use our sequential coupling-cyclization
reaction2, followed by reduction of nitro group to form the
indoles 9 and 10, respectively. Iodides 11 and 12 may be
Figure 1. Retrosynthetic analysis for PQQ (4) and its analogue 5.

12332
K. Hiroya et al. / Tetrahedron 61 (2005) 12330–12338
Table 2. Optimization of the solvent and the reaction temperature
synthesized from 2-amino-5-nitrophenol (13) as the
common starting material by regioselective functional
group installations.
In the second half of this article, we describe a relatively
short synthesis of 78g and 8,14 which are intermediates for
the synthesis of PQQ (4) and its analogue 5 by Pd-complex-
catalyzed sequential coupling-cyclization reactions as the
key steps.
Entry
Solvent
Time (h)
Temperature (8C)
Yield (%)
1
2
3
THF
DMF
CH2Cl2
THF
DMF
17
65
76
12
12
12
6
Ambient
Ambient
Ambient
50
50
50
0
0
5
4
74
88
85
4a
5a
6a
7a
2. Results and discussion
Trifluorotoluene
CH2Cl2
2.1. Optimization of the reaction conditions
50
a Reactions were carried out in a sealed tube.
Since we have already established that both Pd(PPh3)4 and
methyl propiolate are essential for the cyclization
reactions,2 we first experimented with reducing the amounts
of the reagents. The results are summarized in Table 1.
When the amount of i-Pr2NEt was reduced from 2.0 to
1.0 equiv, the yield of 3b was markedly reduced compared
to that from the original conditions (Table 1, entry 1 [94%]
vs entry 2 [28%]). In contrast, the amount of methyl
propiolate could be reduced from 600 to 20 mol%, but not to
10 mol% (Table 1, entries 2–6). Since higher reaction
temperature was required for the reactions with less than
100 mol% of methyl propiolate, the reactions were carried
out in a sealed tube (Table 1, entry 4 vs entries 5–8). In the
presence of 20 mol% of methyl propiolate, the amount of
ZnBr2 could also be reduced from 300 to 20 mol% without
any loss of yield (Table 1, entry 5 [87%] vs entry 7 [88%]).
However, in the absence of ZnBr2, the yield of 3b decreased
from 88 to 35% (Table 1, entries 7 and 8). Presumably, the
role of ZnBr2 might be acceleration of the formation of the
catalyst, or its activation, or both.
(Table 2, entries 5 and 6). The fastest reaction was observed
in CH2Cl2 at 50 8C (Table 2, entry 7) and these reaction
conditions were included in the further optimizations
(Tables 3 and 4).
Because of the volatile nature of methyl propiolate, we were
worried that it might evaporate from the reaction mixture.
However, contrary to our speculation, the propiolates
possessingbulkierestermoietiestendedtoreducethereaction
rate. When benzylpropiolatewasused, there isadvantagethat
the reaction can be carried out without using a sealed tube.
However, since no difference in yield between the methyl and
benzyl esters was observed and the reaction rate with methyl
propiolate is much faster than that with benzyl propiolate
(Table 3, entry 1 vs 2), we chose commercially available
methyl propiolate in subsequent experiments. The other
acetylenes, which do not have an electron withdrawing group,
did not show any catalytic activities, even when reacted for
30 h (Table 3, entries 3 and 4).
Next, we examined the influence of the solvent and the
reaction temperature using optimized amounts of ZnBr2,
methyl propiolate, and i-Pr2NEt (Table 2). The reaction
barely proceeded in the tested solvents at ambient
temperature (ca. 20 8C, Table 2, entries 1–3). At 50 8C,
the yield of 3b was quite low under the original conditions2
(in THF, Table 2, entry 4) and reasonable yields were
observed in both DMF and trifluorotoluene at 50 8C
Finally, the effects of the ligand, using Pd2(dba)3 as the
palladium source, were investigated (Table 4). Pd2(dba)3
without any ligand did not have effective catalytic activity
(Table 4, entry 1). Surprisingly, the yield of 3b in the
reaction with PPh3 was much lower than that with Pd(PPh3)4
(Table 4, entry 2 [35%] vs Table 2, entry 7 [85%]). The
Table 1. The optimized amounts of the reagents for the cyclization reaction
Entry
ZnBr2 (mol%)
Methyl propiolate (mol%)
i-Pr2NEt (equiv)
Temperature (8C)
Time (h)
Yield (%)
1
2
3
4
300
300
300
300
300
300
20
600
600
100
50
20
10
2.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
65–67 (Reflux)
65–67 (Reflux)
65–67 (Reflux)
65–67 (Reflux)
100
100
100
100
17
17
17
22
17
17
4
94
28
100
56 (27)a
87
54
88
35
5b
6b
7b
8b
20
20
—
17
a The numbers in the parenthesis are the yields of the recovered 2b.
b Reactions were carried out in a sealed tube.

K. Hiroya et al. / Tetrahedron 61 (2005) 12330–12338
Table 3. The effect of the substituent of the acetylenes
12333
Alkaline hydrolysis of the carbamate moiety of 15 followed
by benzylation of the resulting phenol group afforded the
amine 17 in good overall yield (91% for two steps). The
amino group of 17 was converted to an iodine atom under
Sandmeyer conditions to provide 2-benzyloxy-1-iodo-4,6-
dinitrobenzene (18). It was difficult to reduce only the C6-
nitro group of 18; we tested several reaction conditions (e.g.,
H2, Pd/C; H2, PtO2; H2NNH2$H2O, etc.). However, the
reaction of 18 in the presence of metallic iron in a mixture of
AcOH–EtOH (1/1) at 100 8C16 gave 19 as the major
product. Next, the amino group of 19 was converted to the
corresponding mesylamide 11 via bis-mesylate 20, followed
by methanolysis, with 89% yield from 19 (Scheme 2).
Entry
R
Time (h)
Yield (%)
1a
2
CO2Me
CO2Bn
Ph
6
85
86
17.5
30
30
3a
4a
15 (85)b
16 (83)b
Bu
a Reactions were carried out in a sealed tube.
b The numbers in the parenthesis are the yields of the recovered 2b.
Having established the synthesis of the desired 2-iodo-
aniline derivative 11 in large quantities, we applied the
sequential coupling-cyclization reaction to 11 (Scheme 3).
The coupling reaction of 11 in the presence of methyl
propiolate, Pd(PPh3)4, ZnBr2, and i-Pr2NEt in THF as
previously reported,2 followed by cyclization, proceeded
smoothly to afford the indole 21 in 65% yield.17 Only the
cyclized compound 21 was isolated, and the 2-ethynyl-
aniline derivative produced in the first reaction was not
detected. Methanolysis of the mesylamide group on 21
followed by reduction of the nitro group was carried out to
produce the aniline 98g in reasonable yield (73%). The
pyridine ring was constructed using the procedure reported
by MacKenzie et al.8g [dimethyl (E)-2-oxoglutaconate,
CH2Cl2, room temperature 12 h, then cat. HCl in Et2O,
room temperature 12 h] to permit synthesis of the three-ring
ligands that have larger cone angles [P(o-tol)3 or PBn3] or
smaller one (PBu3) or more p-acid character [P(OPh)3] than
PPh3 also gave disappointing results (Table 4, entries 3–6).
The catalyst with bidentate ligands (BINAP or dppf) also
did not show any catalytic activity (Table 4, entries 6 and 7).
At this stage, we gave up investigating the reactions with the
other ligands and focused on reducing the catalyst
[Pd(PPh3)4] loading. The yield was essentially the same
between 3 and 1 mol% Pd(PPh3)4 (Table 4, entries 9 and
10). Consequently, the amount of the catalyst could be
reduced to 0.5 mol%, although the yield was decreased
slightly (Table 4, entry 11). From the above results, we
could establish the optimized conditions.
1
system of PQQ in 71% yield. The spectral data (IR, H
2.2. Synthesis of PQQ and its analogues
NMR, and MS) of 7 were identified with the reported data.8g
This compound was converted to PQQ (4) via ortho-
quinone 238a–c,g,i by four steps. Thus, we furnished formal
synthesis of PQQ (4) (Scheme 3).
Following the retro synthetic scheme (Fig. 1), we began
with the synthesis of PQQ. Both the amino and phenol
groups of commercially available 2-amino-5-nitrophenol
(13) were protected as cyclic carbamates by treatment with
1,10-carbonyldiimidazole in THF in 96% yield. Regio-
selective nitration was performed by standard reaction
conditions to yield dinitro compound 15 as the major
product (78%). The cyclic carbamate was essential as the
protecting group in achieving the regioselective nitration.
Synthesis of the PQQ analogue was started from the indole
derivative 24, which was synthesized from 13 via 12 in our
synthesis of duocarmycin SA.2 The selective removal of the
methanesulfonyl group under methanolysis conditions was
followed by reduction of the nitro group on 25 by
hydrogenation to provide 10. The third ring was constructed
using the same procedure as in the synthesis of PQQ, to
afford 26 (45% yield for two steps). Finally, the benzyl ether
of 26 was cleaved under hydrogenolysis conditions to give
8, which yielded spectral data that matched those previously
reported14b (Scheme 4).
Table 4. Palladium species and ligand effect
3. Conclusion
Entry
Pd source (mol%)
Ligand (mol%)
Yield (%)
1
2
3
4
5
6
7
8
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd2(dba)3 (3)
Pd(PPh3)4 (3)
Pd(PPh3)4 (1)
Pd(PPh3)4 (0.5)
—
8 (50)a
34 (50)a
Trace
12 (68)a
14 (51)a
Trace
0
In summary, we optimized the Pd-catalyzed cyclization
reaction of 2-(2-carbomethoxyethynyl)aniline derivatives.
Namely, the amounts of Pd(PPh3)4, methyl propiolate,
and ZnBr2 could be significantly reduced compared with
those reported in our previous communication. We also
successfully applied a Pd-complex-catalyzed sequential
coupling-cyclization reaction between methyl propiolate
and 2-iodoaniline derivatives to the synthesis of PQQ and its
analogues. The further application is currently underway in
our laboratory.
PPh3 (24)
P(o-tol)3 (24)
PBn3 (24)
PBu3 (24)
P(OPh)3 (24)
BINAP (6)
dppf (12)
—
Trace
85
87
9
10
11
—
—
76
a The numbers in the parentheses are the yields of recovered 2b.

12334
K. Hiroya et al. / Tetrahedron 61 (2005) 12330–12338
Scheme 2. Reagents and conditions: (i) (Imid)2CO, THF, rt, 2 h (96%); (ii) f. HNO3, concd H2SO4, 0 8C, 5 min (78%); (iii) NaOH, 50 8C, 22 h; (iv) BnBr,
K2CO3, acetone, reflux, 2 h (91% from 15); (v) NaNO2, H2SO4, AcOH, 5 8C, 5 min, then KI, rt, 2 h (54%); (vi) Fe, AcOH–EtOH (1/1), 100 8C, 1 h (55%); (vii)
MsCl, Et3N, CH2Cl2, rt, 5 min; (viii) K2CO3, MeOH, rt, 15 min (89% from 19).
Scheme 3. Reagents and conditions: (i) methyl propiolate, Pd(PPh3)4, ZnBr2, i-Pr2NEt, THF, 100 8C in a sealed tube, 11 h (65%); (ii) K2CO3, MeOH–THF (1/1),
rt, 15 min (78%); (iii) H2, PtO2, AcOEt–THF (1/1), rt, 2 h (73%); (iv) dimethyl (E)-2-oxoglutaconate, CH2Cl2, rt, 12 h, then cat. HCl in Et2O, rt, 12 h (71%).
Scheme 4. Reagents and conditions: (i) K2CO3, MeOH–THF (1/1), rt, 20 min (89%); (ii) H2, PtO2, AcOEt, rt, 2 h; (iii) dimethyl (E)-2-oxoglutaconate, CH2Cl2,
rt, 12 h, then cat. HCl in MeOH, rt, 10 h (45% from 25); (iv) H2, Pd/C, CHCl3–MeOH (1/3), rt, 1.5 h, (97%).
4. Experimental
shifts (d) are given from TMS (0 ppm) in CDCl3 and from
residual non-deuterated solvent peak in the other solvents
(acetone-d6:2.04 ppm, DMSO-d6:2.49 ppm, methanol-
d4:3.30 ppm, and THF-d8:3.58 ppm) as internal standards.
For 13C NMR spectra, chemical shifts (d) are given from
13CDCl3 (77.0 ppm), (13CD3)2CO (29.8 ppm), (13CD3)2SO
(39.7 ppm), and (13CD2-CD2)2O (25.2 ppm) as internal
standards. Standard and high-resolution mass spectra were
measured on JEOL JMS-DX303 and MS-AX500 instru-
ments, respectively. IR spectra were recorded on a
Shimadzu FTIR-8400.
4.1. General
All melting points were determined with a Yazawa Micro
Melting Point BY-2 and are uncorrected. H NMR spectra
1
(400 and 600 MHz) were recorded on JEOL JMN AL-400
and JEOL ECA-600 spectrometers, respectively. 13C NMR
spectra (100, 125, 150 MHz) were recorded on JEOL JMN
AL-400, JEOL ECP-500, and JEOL ECA-600 spec-
trometers, respectively. For 1H NMR spectra, chemical

K. Hiroya et al. / Tetrahedron 61 (2005) 12330–12338
12335
4.1.1. Methyl 1-methylsulfonyl-2-indolecarboxylate (3b)
(Table 4, entry 11). i-Pr2NEt (69 ml, 0.4 mmol), 2b
(50.0 mg, 0.2 mmol), methyl propiolate (4 ml, 0.04 mmol),
and Pd(PPh3)4 (1.4 mg, 0.001 mmol) were successively
added to a solution ZnBr2 (8.8 mg, 0.04 mmol) in CH2Cl2
(2.0 ml) and the mixture was stirred at 50 8C for 6 h in a
sealed tube. Saturated aqueous NH4Cl solution was added to
the mixture and the aqueous phase was extracted with
CHCl3. The combined organic solution was washed with
saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and concentrated. The residue was purified by
silica gel column chromatography [AcOEt–hexane (1/3)] to
afford 3b (38.2 mg, 76%) as a colorless solid. The spectral
data of 3b were identified with those of the authentic
sample.1a
with saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and the solvent was evaporated to afford the crude
16, which was used to the next reaction without further
purification.
K2CO3 (455 mg, 3.29 mmol) and benzyl bromide (454 mg,
2.65 mmol) were added successively to a solution of the
crude 16 in acetone (25 ml) and the mixture was refluxed for
2 h. After being cooled to room temperature, the inorganic
precipitate was filtered through a Celitee pad and the
filtrate was concentrated at the reduced pressure. The
resulting solid was recrystallized from AcOEt to afford 17
(557 mg) as yellow needles and the mother liquid was
chromatographed on silica gel [AcOEt–hexane (1/2)] to
afford 17 (110 mg) as a yellow solid (total yield of 17:
667 mg, 91%). Yellow needles from AcOEt; mp 187–
189 8C; IR (film, cmK1) 3489, 3369, 1624, 1541, 1328; 1H
NMR (400 MHz, CDCl3) d 5.23 (2H, s), 7.41–7.44 (5H, m),
7.81 (1H, d, JZ2.4 Hz), 8.81 (1H, d, JZ2.4 Hz); 13C NMR
(100 MHz, CDCl3) d 72.1, 108.1, 108.3, 115.6, 115.8,
128.1, 129.0, 129.1, 134.2, 141.2, 146.4; MS m/z 289 (MC,
4.1), 91 (100); HRMS Calcd C13H11N3O5: 289.0699.
Found: 289.0683. Anal. Calcd for C13H11N3O5: C, 53.98;
H, 3.83; N, 14.53. Found: C, 53.90; H, 3.87; N, 14.47.
4.1.2. 6-Nitro-3H-benzooxazol-2-one (14). 1,10-Carbonyl-
diimidazole (5.77 g, 35.6 mmol) was added to a solution of
13 (5.0 g, 32.4 mmol) in anhydrous THF (100 ml) at room
temperature and stirred for 2 h at the same temperature.
Diluted aqueous HCl solution (50 ml) was added to the
mixture and the aqueous phase was extracted with Et2O.
The organic solution was washed with saturated aqueous
NaCl solution, dried over anhydrous MgSO4, and concen-
trated. The resulting solid 14 (5.58 g, 96%) was essentially
pure and could be used to the following reaction. Analytical
sample was recrystallized from AcOEt–hexane to provide
colorless needles. Mp 254–255 8C; IR (film, cmK1) 1794,
4.1.5. 2-Benzyloxy-1-iodo-4,6-dinitrobenzene (18).
NaNO2 (65.4 mg, 0.948 mmol) was slowly added to concd
H2SO4 (1 ml) at 0 8C and the mixture was dropped to a
solution of 17 (203 mg, 0.702 mmol) in AcOH (10 ml) at
5 8C. After being stirred for 5 min, a solution of KI (157 mg,
0.946 mmol) in ice and H2O (10 ml) was added to the
reaction mixture and the mixture was stirred for another 2 h
at room temperature. The mixture was extracted with
AcOEt and the combined organic solution was washed with
saturated aqueous NaHCO3 solution and saturated aqueous
NaCl solution. The organic solution was dried over
anhydrous MgSO4 and concentrated. The residue was
purified by silica gel column chromatography [AcOEt–
hexane (1/9)] to afford 18 (157 mg, 54%) as a light yellow
solid. Light yellow plates from AcOEt–hexane; mp 152–
154 8C; IR (film, cmK1) 1527; 1H NMR (400 MHz, CDCl3)
d 5.34 (2H, s), 7.40–7.51 (5H, m), 7.83 (1H, d, JZ2.2 Hz),
8.14 (1H, d, JZ2.2 Hz); 13C NMR (125 MHz, CDCl3) d
72.7, 89.6, 108.3, 111.7, 127.3, 128.9, 129.0, 134.1, 148.8,
155.4, 159.7; MS m/z 400 (MC, 2.1), 91 (100); HRMS
Calcd C13H9IN2O5: 399.9556. Found: 399.9556. Anal.
Calcd for C13H9IN2O5: C, 39.02; H, 2.27; N, 7.00. Found:
C, 39.22; H, 2.45; N, 6.88.
1
1508, 1342; H NMR (400 MHz, methanol-d4) d 7.22 (1H,
d, JZ8.7 Hz), 8.11 (1H, d, JZ2.1 Hz), 8.17 (1H, dd, JZ
8.7, 2.1 Hz); 13C NMR (100 MHz, acetone-d6) d 105.3,
109.2, 120.5, 136.4, 142.8, 143.3, 153.6; MS m/z 180 (MC,
100), 134 (19.0), 106 (21.1); HRMS Calcd C7H4N2O4:
180.0171. Found: 180.0154.
4.1.3. 4,6-Dinitro-3H-benzooxazol-2-one (15). Concd
H2SO4 (0.83 ml) was slowly added to 1.52 M f. HNO3
solution (5.6 ml, 8.51 mmol) at 0 8C. After being stirred for
5 min at the same temperature, 14 (1.4 g, 7.77 mmol) was
added to the mixture. After the addition was completed, the
solution was poured into a mixture of ice and water. The
aqueous phase was extracted with AcOEt and the combined
organic solution was successively washed with saturated
aqueous NaHCO3 solution and saturated aqueous NaCl
solution. The organic solution was dried over anhydrous
MgSO4 and concentrated at the reduced pressure. The
residue was purified by silica gel column chromatography
[AcOEt–hexane (2/3)] to afford 15 (1.09 g, 78%) as a
colorless powder. Colorless powder from AcOEt–hexane;
mp 200–202 8C; IR (film, cmK1) 3099, 1790, 1634, 1541,
4.1.6. 3-Benzyloxy-2-iodo-5-nitroaniline (19). Fe (75 mg,
1.34 mmol) was added to a solution of 18 (135 mg,
0.337 mmol) in AcOH (3.4 ml) and EtOH (3.4 ml) and the
mixture was stirred for 1 h at 100 8C. H2O was added and
the mixture was filtered through a Celitee pad and the
filtrate was extracted with AcOEt. The combined organic
solution was washed with saturated aqueous NaCl solution,
dried over anhydrous MgSO4, and concentrated. The
residue was purified by silica gel column chromatography
[AcOEt–hexane (1/9)] to afford 19 (68.4 mg, 55%) as a
yellow solid. Yellow needles from AcOEt–hexane; mp 147–
148 8C; IR (film, cmK1) 3464, 3369, 1622, 1501, 1435,
1346; 1H NMR (400 MHz, CDCl3) d 4.58 (2H, s), 5.19 (2H,
s), 7.07 (1H, d, JZ1.6 Hz), 7.25–7.51 (6H, m); 13C NMR
1
1344; H NMR (400 MHz, acetone-d6) d 8.47 (1H, d, JZ
2.0 Hz), 8.80 (1H, d, JZ2.0 Hz); 13C NMR (100 MHz,
acetone-d6) d 109.7, 115.1, 130.1, 132.9, 141.5, 145.2,
152.9; MS m/z 225 (MC, 100), 209 (3.0), 179 (3.3); HRMS
Calcd C7H3N3O6: 225.0022. Found: 225.0000. Anal. Calcd
for C7H3N3O6: C, 37.35; H, 1.34; N, 18.67. Found: C,
37.15; H, 1.63; N, 18.66.
4.1.4. 2-Benzyloxy-4,6-dinitroaniline (17). A suspension
of 15 (570 mg, 2.53 mmol) in 0.2 N NaOH (50 ml) was
stirred for 22 h at 50 8C. The solution was neutralized with
3 N HCl (3.1 ml) at 0 8C and the aqueous phase was
extracted with AcOEt. The organic solution was washed

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K. Hiroya et al. / Tetrahedron 61 (2005) 12330–12338
(100 MHz, CDCl3) d 71.3, 83.5, 96.0, 101.8, 127.0, 128.1,
128.6, 135.5, 148.5, 149.5, 158.1; MS m/z 370 (MC, 29.8),
264 (7.7), 243 (14.3), 91 (100); HRMS Calcd C13H11IN2O5:
369.9814. Found: 369.9799. Anal. Calcd for C13H11IN2O5:
C, 42.18; H, 3.00; N, 7.57. Found: C, 42.27; H, 3.18; N,
7.32.
0.182 mmol) in a mixture of MeOH–THF (1/1, 2.0 ml) and
stirred for 15 min at room temperature. Saturated aqueous
NH4Cl solution was added to the mixture and the aqueous
solution was extracted with AcOEt. The organic solution
was washed with saturated aqueous NaCl solution, dried
over anhydrous MgSO4, and the solvent was evaporated at
reduced pressure. The residue was purified by silica gel
column chromatography [AcOEt–hexane (1/4)] to afford 22
(46.4 mg, 78%) as a yellow powder. Yellow powder from
AcOEt–hexane; mp 262–263 8C; IR (film, cmK1) 3296,
4.1.7. N-methanesulfonyl-3-benzyloxy-2-iodo-5-nitroani-
line (11). MsCl (0.23 ml, 2.97 mmol) was added to a
solution of 19 (432 mg, 1.17 mmol) and Et3N (0.49 ml,
3.52 mmol) in anhydrous CH2Cl2 (1.0 ml) at 0 8C and
stirred for 5 min at the same temperature. H2O was added to
the mixture and the aqueous phase was extracted with
CHCl3. The combined organic solution was washed with
saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and the solvent was evaporated to afford 20, which
was used to the next reaction without further purification.
1
1693, 1524; H NMR (400 MHz, THF-d8) d 3.89 (3H, s),
5.32 (2H, s), 7.29 (1H, s), 7.31 (1H, t, JZ7.2 Hz), 7.38 (2H,
t, JZ7.2 Hz), 7.49 (1H, s), 7.54 (2H, d, JZ7.2 Hz), 7.98
(1H, s), 11.8 (1H, s); 13C NMR (100 MHz, THF-d8) d 51.8,
70.8, 96.0, 102.9, 105.9, 123.5, 127.9, 128.3, 128.8, 131.6,
136.9, 137.1, 146.9, 153.8, 161.3; MS m/z 326 (MC, 23.0),
91 100); HRMS Calcd C17H14N2O5: 326.0903. Found:
326.0894.
K2CO3 was added to a solution of the crude 20 in a mixture
of MeOH–THF (1/1, 10 ml) and stirred for 15 min at room
temperature. Saturated aqueous NH4Cl solution was added
to the mixture and the aqueous phase was extracted with
AcOEt. The organic solution was washed with saturated
aqueous NaCl solution, dried over anhydrous MgSO4, and
concentrated. The resulting solid was recrystallized from
AcOEt–hexane to afford 11 (400 mg) as colorless needles
and mother liquor was chromatographed on silica gel
[AcOEt–hexane (1/2)] to afford 11 (68.9 mg) as colorless
solid (total yield of 11:468.9 mg, 89% from 19). Colorless
needles from AcOEt–hexane; mp 182–184 8C; IR (film,
cmK1) 3273, 1609, 1518, 1327, 1151; 1H NMR (400 MHz,
CDCl3) d 3.11 (3H, s), 5.27 (2H, s), 7.11 (1H, s), 7.37–7.50
(5H, m), 7.53 (1H, d, JZ3.2 Hz), 8.14 (1H, d, JZ3.2 Hz);
13C NMR (100 MHz, CDCl3) d 40.9, 72.0, 91.5, 102.4,
107.1, 127.2, 128.6, 128.8, 134.6, 140.0, 149.8, 158.3; MS
m/z 448 (MC, 5.5), 321 (2.6), 91 (100); HRMS Calcd
C14H13IN2O5S: 447.9590. Found: 447.9592.
4.1.10. Methyl 6-amino-4-benzyloxyindole-2-carboxylate
(9). PtO2 (3 mg, 0.0132 mmol) was added to a solution of 22
(45 mg, 0.138 mmol) in a mixture of AcOEt–THF (1/1,
2.0 ml) and the mixture was vigorously stirred under
hydrogen atmosphere for 2 h. PtO2 was filtered off and the
filtrate was concentrated in vacuo. The residue was purified
by silica gel column chromatography [AcOEt–hexane (1/1)]
to provide 9 (30 mg, 73%) as a tan solid. IR (film, cmK1
)
1
3352, 2924, 1682, 1634, 1520, 1279; H NMR (400 MHz,
CDCl3) d 3.83 (2H, br s), 3.91 (3H, s), 5.18 (2H, s), 6.06
(1H, d, JZ1.8 Hz), 6.28 (1H, s), 7.30 (1H, d, JZ1.8 Hz),
7.36–7.51 (5H, m), 8.54 (1H, s); 13C NMR (100 MHz, THF-
d8) d 50.7, 69.7, 88.0, 93.6, 107.0, 112.5, 123.8, 127.5,
127.8, 128.6, 138.3, 141.4, 148.6, 154.4, 162.2; MS m/z 296
(MC, 100), 264 (26.3), 205 (54.8), 173 (34.8); HRMS Calcd
C17H16N2O3: 296.1161. Found: 296.1154.
4.1.11. Trimethyl 4-benzyloxy-1H-pyrrolo[2,3-f]quino-
line-2,7,9-tricarboxylate (7). Dimethyl (E)-2-oxoglutaco-
nate (22.8 mg, 0.132 mmol) was added to a solution of 9
(26.2 mg, 0.0884 mmol) in anhydrous CH2Cl2 (0.5 ml) at
room temperature. After being stirred for 12 h at the same
temperature, one drop of hydrogen chloride in diethyl ether
was added to the mixture and stirred for another 12 h.
Saturated aqueous NaHCO3 solution was added to the
mixture and the aqueous phase was extracted with AcOEt.
The combined organic solution was washed with saturated
aqueous NaCl solution, dried over anhydrous MgSO4, and
concentrated. The residual solid was triturated with
methanol and dried to give 7 (28.3 mg, 71%) as a bright
yellow solid. Mp 211–213 8C (lit.8g 215–217 8C); IR (film,
cmK1) 3299, 2954, 1717, 1436, 1259; 1H NMR (400 MHz,
CDCl3) d 4.00 (3H, s), 4.10 (3H, s), 4.16 (3H, s), 5.35 (2H,
s), 7.37–7.55 (7H, m), 8.75 (1H, s), 12.56 (1H, s); 13C NMR
(100 MHz, CDCl3) d 52.2, 53.3, 53.9, 70.2, 102.0, 106.8,
113.1, 121.2, 122.0, 126.9, 127.3, 128.1, 128.5, 129.4,
131.4, 136.0, 144.7, 151.7, 155.6, 161.3, 165.3, 168.5; MS
m/z 448 (MC, 100), 416 (14.4), 388 (23.3); HRMS Calcd
C24H20N2O7: 448.1271. Found: 448.1254.
4.1.8. Methyl 4-benzyloxy-1-methanesulfonyl-6-nitroin-
dole-2-carboxylate (21). i-Pr2NEt (11 ml, 0.0631 mmol),
11 (14.5 mg, 0.0324 mmol), methyl propiolate (17 ml,
0.19 mmol), and Pd(PPh3)4 (5.6 mg, 4.8 mmol) were
successively added to a solution of ZnBr2 (22 mg,
0.098 mmol) in THF (1 ml) at room temperature and the
mixture was heated at 100 8C in a sealed tube for 11 h.
Saturated aqueous NH4Cl solution was added to the mixture
and the aqueous solution was extracted with AcOEt. The
combined organic solution was washed with saturated
aqueous NaCl solution, dried over anhydrous MgSO4, and
the solvent was evaporated at reduced pressure. The residue
was chromatographed on silica gel [AcOEt–hexane (1/4)] to
provide 21 (8.5 mg, 65%) as a colorless solid. Colorless
needles from AcOEt–MeOH; mp 173–175 8C; IR (film,
cmK1) 1732, 1522, 1371, 1335; 1H NMR (600 MHz,
CDCl3) d 3.80 (3H, s), 3.97 (3H, s), 5.28 (2H, s), 7.39–
7.49 (6H, m), 7.66 (1H, s), 8.63 (1H, s); 13C NMR
(150 MHz, CDCl3) d 43.9, 53.0, 71.0, 99.9, 105.1, 113.5,
123.0, 127.7, 128.6, 128.8, 133.0, 135.3, 137.8, 147.9,
153.0, 160.7; MS m/z 404 (MC, 11.2), 326 (3.9), 91 (100);
HRMS Calcd C18H16N2O7S: 404.0678. Found: 404.0692.
4.1.12. Methyl 7-benzyloxy-5-nitroindole-2-carboxylate
(25). K2CO3 (247 mg, 1.79 mmol) was added to a solution
of 242 (725 mg, 1.79 mmol) in a mixture of MeOH–THF
(1/1, 20 ml) and stirred for 20 min at room temperature.
4.1.9. Methyl 4-benzyloxy-6-nitroindole-2-carboxylate
(22). K2CO3 was added to a solution of 21 (73.5 mg,

K. Hiroya et al. / Tetrahedron 61 (2005) 12330–12338
12337
Saturated aqueous NH4Cl solution was added to the mixture
and the aqueous solution was extracted with AcOEt. The
organic solution was washed with saturated aqueous NaCl
solution, dried over anhydrous MgSO4, and concentrated.
The residue was triturated with diethyl ether to afford 25
(520 mg, 89%) as a light yellow solid. Light yellow needles
(61.9), 268 (89.0); HRMS Calcd C17H14N2O7: 358.0801.
Found: 358.0785.
from AcOEt–hexane; mp 165–167 8C; IR (film, cmK1
)
References and notes
3294, 1705, 1524; 1H NMR (400 MHz, CDCl3) d 3.94 (3H,
s), 5.26 (2H, s), 7.31 (1H, s), 7.42 (5H, m), 7.68 (1H, s), 8.31
(1H, s), 9.42 (1H, s); 13C NMR (100 MHz, CDCl3) d 52.4,
71.0, 100.3, 110.8, 113.1, 126.6, 128.1, 128.68, 128.73,
129.5, 130.7, 135.1, 143.0, 145.0, 161.2; MS m/z 326 (MC,
14.6), 91 (100); HRMS Calcd C17H14N2O5: 326.0903.
Found: 326.0891. Anal. Calcd C17H14N2O5: C, 62.57; H,
4.32; N, 8.59. Found: C, 62.71; H, 4.52; N, 8.46.
1. (a) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69,
1126–1136. (b) Hiroya, K.; Itoh, S.; Ozawa, M.; Kanamori, Y.;
Sakamoto, T. Tetrahedron Lett. 2002, 43, 1277–1280.
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3. The reaction condition for the coupling reaction between aryl
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4.1.13. Trimethyl 4-benzyloxy-3H-pyrrolo[3,2-f ]quino-
line-2,7,9-tricarboxylate (26). PtO2 (3.2 mg, 0.014 mmol)
was added to a solution of 25 (22.8 mg, 0.0699 mmol) in
AcOEt (2.3 ml) and the mixture was stirred under hydrogen
atmosphere for 2 h. PtO2 was filtered off and the filtrate was
concentrated in vacuo to afford the crude 10, which was
used to the next reaction without further purification.
4. Salisbury, S. A.; Forrest, H. S.; Cruse, W. B. T.; Kennard, O.
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5. For reviews see: (a) Duine, J. A. Chem. Rec. 2000, 1, 74–83.
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Dimethyl (E)-2-oxoglutaconate (14.4 mg, 0.0837 mmol)
was added to a solution of 10 in anhydrous CH2Cl2 (1 ml)
at room temperature. After being for 12 h at the same
temperature, anhydrous MeOH (6.2 ml) and AcCl (10 ml)
was added to the mixture and stirred for another 10 h.
Saturated aqueous NaHCO3 solution was added to the
mixture and the aqueous solution was extracted with CHCl3.
The combined organic solution was washed with saturated
aqueous NaCl solution, dried over anhydrous MgSO4, and
concentrated. The residue was purified by preparative TLC
[CH2Cl2–MeOH (95/5)] to afford 26 (14 mg, 45% from 25)
as a light yellow solid. Semi-opaque powder from Et2O–
hexane; mp 164 8C; IR (film, cmK1) 3287, 2951, 1717,
1252; 1H NMR (400 MHz, CDCl3) d 3.96 (3H, s), 4.08 (3H,
s), 4.15 (3H, s), 5.35 (2H, s), 7.41–7.63 (7H, m), 8.30 (1H,
s), 9.72 (1H, s); 13C NMR (100 MHz, CDCl3) d 52.1, 53.1,
53.2, 70.9, 105.9, 111.7, 118.1, 119.1, 119.8, 126.3, 128.0,
128.6, 128.7, 129.4, 135.2, 136.1, 144.4, 148.8, 149.2,
161.4, 165.4, 168.5; MS m/z 448 (MC, 58.9), 420 (14.3),
389 (18.4), 343 (12.9), 91 (100); HRMS Calcd C24H20N2O7:
448.1271. Found: 448.1277.
6. Kasahara, T.; Kato, T. Nature 2003, 422, 832.
7. (a) The role of PQQ as vitamin is under discussion. See:
Felton, L. M.; Anthony, C. Nature 2005, 433, E10. (b) Rucker,
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2005, 433, E10–E11. (c) Kasahara, T.; Kato, T. Nature 2005,
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J. Org. Chem. 1991, 56, 6857–6865. (b) Itoh, S.; Ogino, M.;
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4.1.14. Trimethyl 4-hydroxy-3H-pyrrolo[3,2-f ]quino-
line-2,7,9-tricarboxylate (8). Ten percentage Pd/C (3 mg)
was added to a solution of 26 (99.7 mg, 0.222 mmol) in a
mixture of CHCl3–MeOH (1/3, 4.0 ml) and the mixture was
stirred under hydrogen atmosphere for 1.5 h. Pd/C was
filtered off eluting with CHCl3 and the filtrate was
concentrated in vacuo to afford 8 (77.5 mg, 97%) as a
light yellow solid. Light yellow needles from
MeOH–CHCl3; mp 294 8C (decomposition) [lit.14b 276–
278 8C (decomposition)]; IR (film, cmK1) 3292, 2955,
1717, 1254; 1H NMR (400 MHz, DMSO-d6) d 3.88 (3H, s),
3.93 (3H, s), 4.05 (3H, s), 7.24 (1H, s), 7.39 (1H, s), 8.07
(1H, s), 11.17 (1H, s), 12.77 (1H, s); 13C NMR (100 MHz,
DMSO-d6) d 51.9, 52.5, 53.3, 106.6, 110.5, 115.5, 116.8,
119.1, 126.8, 129.8, 135.7, 143.8, 148.1, 149.0, 160.7,
164.8, 168.1; MS m/z 358 (MC, 100), 326 (24.9), 300
11. (a) Itoh, S.; Kato, J.-i.; Inoue, T.; Kitamura, Y.; Komatsu, M.;
Ohshiro, Y. Synthesis 1987, 1067–1071. (b) Itoh, S.; Inoue, T.;
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13. (a) Itoh, S.; Fukui, Y.; Haranou, S.; Ogino, M.; Komatsu, M.;
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P.; Winkler, T. Helv. Chim. Acta 1994, 77, 100–110. (c)
Fouchard, D. M. D.; Tillekeratne, L. M. V.; Hudson, R. A.
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17. Since the sequential coupling-cyclization reaction was
employed for the preparation of indole 21 from 2-iodoaniline
derivative 11, excess methyl propiolate (5.9 equiv) was used
and heating is essential for this reaction.
14. (a) Martin, P.; Winkler, T. Helv. Chim. Acta 1994, 77,
111–120. (b) Zhang, Z.; Tillekeratne, L. M. V.; Hudson, R. A.
Synthesis 1996, 377–382.