New method for the synthesis of pyrromethanes

Article abstract of DOI:10.1016/S0040-4020(01)00088-6

Coupling reaction of 2-mercaptobenzothiazolylmethylpyrrole with α-free pyrrole in the presence of silver(I) triflate proceeds smoothly at room temperature to give a pyrromethane in excellent yield. The azafulvenium ion, an active form that reacts with α-f

Full text of DOI:10.1016/S0040-4020(01)00088-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2127±2131
New method for the synthesis of pyrromethanes
Kunisuke Okada,p Kiyoshi Saburi, Keishi Nomura and Hideo Tanino
Faculty of Pharmacy, Meijo University, Tenpaku, Nagoya 468-8503, Japan
Received 12 December 2000; accepted 15 January 2001
AbstractÐCoupling reaction of 2-mercaptobenzothiazolylmethylpyrrole with a-free pyrrole in the presence of silver(I) tri¯ate proceeds
smoothly at room temperature to give a pyrromethane in excellent yield. The azafulvenium ion, an active form that reacts with a-free pyrrole,
also reacts with pyrromethane rapidly under similar neutral conditions to afford an equilibrated mixture of pyrromethanes in good yield.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction1
copper(I) catalyst to yield the required azafulvene inter-
mediate 3b, as shown in Scheme 1.
Pyrromethane 1a is usually synthesized by coupling reac-
tion of a-acetoxymethylpyrrole 4a with a-free pyrrole 2a in
the presence of protonic acids (p-TsOH, TFA, AcOH) and
Lewis acid (SnCl4) as catalyst.2 Montmorillonite clay has
also been shown to be useful for the synthesis of pyrro-
methane3 and bilane.4 The azafulvenium ion 3a, generated
from 4a under these conditions, is a key intermediate in the
coupling reaction with 2a. In 1991, Battersby et al. reported
a new method for pyrromethane synthesis involving treat-
ment of a-free pyrrole 2b and phenylselenomethylpyrrole
4b in dry degassed dichloromethane containing the benzene
complex of copper(I) tri¯ate in the presence of calcium car-
bonate. The coupling reaction was rapid and product 1b was
isolated after 5 min at 2238C in 91% yield.5 In this reaction,
4b eliminates the phenylseleno-group with the aid of the
At this laboratory, attention has been directed to the chem-
istry of pyrromethane synthesis, particularly to develop a
method for the effective synthesis of bilanes4,6 and oligo-
pyrroles7 related to the biosynthetic mechanism of uropor-
phyrinogen III.8 A few preliminary experiments to generate
3a from 10 were made by using several activating reagents
of hydroxy group as follows: treatment of 10 with carbonyl-
diimidazole or triphenylphosphine±CCl4 in the presence of
2c did not produce any pyrromethane, however, reaction of
10 with 2c by the aid of diethylaminosulfur tri¯uoride
(2788C to rt, in CH2Cl2; 1.5 h) or 2-chloro-1-methylpyri-
dinium iodide (re¯uxed with triethylamine in CH3CN; 5 h),
produced the desired pyrromethane 1c in unsatis®ed 55 or
64% yield, respectively. While continuing the synthesis of
Scheme 1.
Keywords: pyrromethanes; 2-mercaptobenzothiazole; silver tri¯ate; azafulvenium ion; cross coupling reaction.
Corresponding author. Tel.: 181-52-832-1781, ext. 250; fax: 181-52-834-8780; e-mail: kokada@meijo-u.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00088-6

2128
K. Okada et al. / Tetrahedron 57 (2001) 2127±2131
Scheme 2. Reagents: (a) SO2Cl2, then H2O; (b) CCl3CH2OH/DCC-DMAP; (c) H2/Pd±C; (d) I2/KI, NaHCO3; (e) H2/Pd±C; (f) Pb(OAc)4/AcOH; (g) 0.5N
KOH±MeOH; (h) RSH/p-TsOH, CH2Cl2.
pyrromethanes under mild and neutral conditions, coupling
reaction between a-free pyrrole 2c and 2-mercapto-
benzothiazolyl-(S-BT)-methylpyrrole derivative 4c was
found to proceed smoothly at room temperature using a
thiophile reagent such as silver(I) tri¯ate in excellent
yield. This paper reports the detail results and experimental
conditions for the coupling reaction of a-free pyrroles with
2-mercaptomethylpyrrole derivatives in the presence of
thiophile reagents such as Ag(I) or Hg(II) salts, which
may catalyze the formation of azafulvenium ion 3a from
4c, the same key intermediate, as shown in Scheme 1.
4c±4e (0.10 mmol) and a-free pyrrole 2c (0.12 mmol) in
dry benzene (5 ml) was stirred with thiophile reagent
(0.15 mmol) in the presence of Na2HPO4 (0.35 mmol) at
room temperature. After dilution with benzene, the mixture
was ®ltered through celite and the ®ltrate was concentrated
under reduced pressure. The residue was puri®ed by ¯ash
column chromatography on silica gel to give pyrromethane
1c. Yields of pyrromethane as determined from the amounts
4c±4e under the various conditions are summarized in
Table 1. 2-Mercaptobenzothiazolylmethylpyrrole 4c was
clearly found to be the most promising substrate, compared
with phenylmercaptomethyl- and tert-butylmercaptomethyl-
pyrrole derivatives and the most ef®cient thiophile reagent
was CF3SO3Ag compared to other reagents such as
CF3COOAg and (CF3COO)2Hg. As shown in entry 4,
coupling reaction of 2c with 4c with the aid of CF3SO3Ag
proceeded quite rapidly (10 min) and yield of the desired
pyrromethane was excellent (98%).
2. Results and discussions
Reactions of three different mercaptomethylpyrrole deriva-
tives with three thiophile reagents were examined. Required
substrates 2c and 4c±4e were prepared from the known
benzyl 5-methylpyrrole-2-carboxylate 59 in the conven-
tional way as shown in Scheme 2.
It is of interest to note that reaction of excess 4c (1.2 equiv.)
with 2c (1 equiv.), in contrast to the amount of substrates
under similar conditions, gave symmetric pyrromethane 11
(10% yield) as a minor product along with the desired pyrro-
methane 1c. Cross coupling reaction 1c with azafulvenium
ion 3a may generate bis-(pyrrolylmethyl)pyrrolenine inter-
mediate 12, followed by cleavage of C±C bond to yield 11
or 1c. As shown in Scheme 3, symmetrical pyrromethane 11
should be produced by rapid equilibration through inter-
mediate 12. When pyrromethane 1c (10 mg, 13 mmol)
a-Free pyrrole 2c was prepared from 5 by the method
reported by Battersby as follows.10 Treatment of 5 with
SO2Cl2 in dichloromethane at 08C followed by hydrolysis
in boiling H2O±acetone yielded 5-carboxylic acid pyrrole
derivative 6 in 73% yield. Esteri®cation of 6 with 2,2,2-
trichloro-ethanol-DCC-DMAP produced trichloroethyl
ester 7 (85%), which was then converted to 2-carboxylic
acid pyrrole derivative 8 by the usual catalytic hydrogeno-
lysis in 94% yield. Iodination of 8 with I2/KI in a mixture of
dichloromethane±H2O±NaHCO3 gave 9 (86%), and sub-
sequent reductive deiodination (H2/10% Pd±C in dichloro-
methane; 97%) yielded the desired a-free pyrrole 2c. The
other substrates, 2-mercaptomethylpyrrole derivatives 4c±
4e were prepared by treatment of a-acetoxymethylpyrrole
4a, derived from 5 in the usual way (Pb(OAc)4/AcOH, rt),
with three mercapthanes, 2-mercaptobenzothiazole, thio-
phenol and tert-butylmercapthane in the presence of a cata-
lytic amount of p-toluenesulfonic acid in dry
dichloromethane for 16 h at room temperature in good
yields.
Table 1. Synthesis of pyrromethane 1c by coupling reaction of mercapto-
methylpyrrole derivatives 4c±4e with a-free pyrrole derivative 2c
Entry
Reagent
Substrate
Time
Yield of 1c (%)
1
2
3
CF3COOAg
4c
4d
4e
1 h
6 h
12 h
67
60
51
4
5
6
CF3SO3Ag
4c
4d
4e
10 min
6 h
12 h
98
83
58
7
8
9
(CF3COO)2Hg
4c
4d
4e
6 h
6 h
6 h
10
23
49
A general procedure for coupling reaction between 2c and
4c±4e is as follows: a solution of mercaptomethylpyrrole

K. Okada et al. / Tetrahedron 57 (2001) 2127±2131
2129
Scheme 3.
was reacted with four equiv. of 4c (28 mg, 52 mmol) under
similar conditions, 11 (7.5 mg) was obtained as the major
product in addition to recovered 1c (2.0 mg) from the reac-
tion mixture. Application of this method to the synthesis of
oligopyrrole derivative is now being studied.11
3.61 (3H, s), 3.67 (3H, s), 3.89 (2H, s), 5.33 (2H, s), 7.38±7.40
(5H, m), 9.67 (1H, brs); 13C NMR: 20.15, 30.04, 34.60, 51.55,
52.15, 66.77, 121.54, 122.38, 124.02, 128.47, 128.56, 128.65,
130.41, 135.41, 160.21, 164.93, 172.61, 173.38.
3.1.2. 2,2,2-Trichloroethyl 5-benzyloxycarbonyl-4-(2-
methoxycarbonylethyl)-3-methoxycarbonylmethyl-
pyrrole-2-carboxylate (7). To a solution of 6 (3.5 g,
3. Experimental
3.1. General
8.68 mmol)
and
2,2,2-tri-chloroethanol
(4.16 ml,
43.4 mmol) in CH2Cl2 (125 ml) were added N,N0-dicyclo-
hexylcarbodiimide (3.58 g, 17.35 mmol) and 4-dimethyl-
aminopyridine (0.53 g, 4.38 mmol) and the mixture was
stirred at room temperature for 15 h. After dilution with
ether (125 ml), the mixture was ®ltered through celite
column. The ®ltrate and washings (ether, 20 ml) of the
column were combined and concentrated under reduced
pressure. The residue was puri®ed by ¯ash column chroma-
tography on silica gel (hexane±AcOEtˆ5:1) to give 7
(3.94 g; 85.0% yield). Mp 92±948C (crystallized from
MeOH±hexane); IR (KBr): 3300, 1730, 1710, 1665, 1438,
1375, 1343, 1275, 1125 cm21; EIMS m/z: 535 and 533
(M1), 501, 410, 382; 1H NMR (CDCl3) d: 2.53 (2H,
t, Jˆ7.4 Hz), 3.00 (2H, t, Jˆ7.4 Hz), 3.62 (3H, s), 3.67
(3H, s), 3.94 (2H, s), 4.92 (2H, s), 5.35 (2H, s), 7.36±7.40
(5H, m), 9.70 (1H, brs); 13C NMR: 20.04, 30.01, 34.45,
51.58, 52.09, 66.99, 74.15, 94.60, 121.16, 123.00, 124.45,
128.59, 128.65, 128.75, 130.89, 135.20, 158.57, 159.83,
171.26, 173.23; Anal. Calcd for C22H22NO8Cl3: C, 49.41;
H, 4.15; N, 2.62%. Found: C, 49.34; H, 4.24; N, 2.69%.
Melting points were not corrected. IR spectra were deter-
mined on JASCO IR-810 spectrometer. H NMR and 13C
1
NMR spectra were recorded on a JEOL JNM-GX 270 or
JNM-GX 400 spectrometer. The chemical shifts (d) are
given relative to TMS (d: 0.00) or CDCl3 (dH: 7.26 and
dC: 77.03) as internal standard and coupling constants (J)
in Hz. Mass spectra were obtained with a Hitachi M-80 (EI)
or JEOL HX-110 (FAB) spectrometers. Column chroma-
tography was performed on Kanto Chemical silica gel
(over 100 mesh) or Wakogel C-300 (¯ash column chroma-
tography). TLC was carried out on Kieselgel 60F254 plates
(Art. 5744, Merck). Unless otherwise noted, all reaction
mixtures were dried after work up over anhydrous Na2SO4.
3.1.1. 5-Benzyloxycarbonyl-4-(2-methoxycarbonylethyl)-
3-methoxycarbonylmethylpyrrole-2-carboxylic acid (6).
To a solution of benzyl 3-(2-methoxycarbonylethyl)-4-meth-
oxycarbonylmethyl-5-methylpyrrole-2-carboxylate 5 (5.0 g,
13.40 mmol) in CH2Cl2 (50 ml) was added sulfuryl chloride
(3.4 ml, 42.32 mmol) dropwise at 08C. After being stirred for
2 h at room temperature, the mixture was added slowly to a
mixture of boiling acetone±water (2:1 v/v; 200 ml) and
allowed to stand at the same temperature for 15 min. After
cooling, the acetone was evaporated under reduced pressure
and the product was extracted with CH2Cl2 (50 ml£3). The
combined extracts were evaporated and the residue was
dissolved in ether (200 ml) and then the carboxylic acid was
transferred into 10% aqueous NaHCO3 solution (75 ml£3).
After the combined aqueous solution had been washed with
ether (50 ml), it was carefully acidi®ed with conc. HCl at 08C,
and the liberated carboxylic acid was extracted with CH2Cl2
(50 ml£3). The combined organic phase was washed with
brine, dried and then concentrated to dryness. The residue
was re-precipated from MeOH±H2O to give 6 (3.94 g,
73.0% yield) as an amorphous solid. EIMS m/z: 403 (M1),
402, 373, 341, 314, 282; IR(KBr): 3250 (br), 1730, 1710,
1560, 1438, 1345, 1270, 1168, 1125 cm21; 1H NMR
(CDCl3): d 2.52 (2H, t, Jˆ7.4 Hz), 2.99 (2H, t, Jˆ7.4 Hz),
3.1.3. 3-(2-Methoxycarbonylethyl)-4-methoxycarbonyl-
methyl-5-(2,2,2-trichloroethoxycarbonyl) pyrrole-2-
carboxylic acid (8). To a solution of 7 (3.5 g, 6.54 mmol)
in MeOH (50 ml) was added 10% Pd±C (3.5 g) and the
mixture was stirred vigorously at 358C for 4 h under hydro-
gen atmosphere. After ®ltration of the reaction mixture
through celite and washing of the column with MeOH, the
combined MeOH solution was evaporated under reduced
pressure. The residue was crystallized from MeOH±hexane
to give 8 (2.75 g, 94.5% yield). Mp 143±1458C; IR (KBr):
3250 (br), 1730, 1715, 1665, 1438. 1372, 1343, 1260, 1205,
1175, 1130 cm21; EIMS m/z: 445 and 443 (M1), 411, 383,
309, 281, 249, 222; 1H NMR (CDCl3) d: 2.63 (2H, t,
Jˆ7.4 Hz), 3.06 (2H, t, Jˆ7.4 Hz), 3.67 (3H, s), 3.70 (3H,
s), 3.98 (2H, s), 4.95 (2H, s), 9.82 (1H, br s); 13C NMR:
19.96, 30.04, 34.34, 51.74, 52.20, 74.20, 94.53, 122.01,
122.40, 124.59, 132.17, 158.55, 164.31, 171.41, 173.55;
Anal. Calcd for C15H16NO8Cll3: C, 40.52; H, 3.63; N,
3.15%. Found: C, 40.89; H, 3.77; N, 3.17%.

2130
K. Okada et al. / Tetrahedron 57 (2001) 2127±2131
3.1.4. 2,2,2-Trichloroethyl 5-iodo-4-(2-methoxycarbonyl-
ethyl)-3-methoxycarbonylmethylpyrrole-2-carboxylate
(9). To a solution of the foregoing carboxylic acid 8 (2.62 g,
5.89 mmol) in the mixture of CH2Cl2 (30 ml) and H2O
(20 ml) was added NaHCO3 powder (1.5 g) under vigorous
stirring at 508C. The aqueous solution (10 ml) of I2 (1.73 g,
6.81 mmol) and KI (1.76 g, 10.60 mmol) was added to the
above mixture at 508C during 5 min. Re¯uxing was contin-
ued with vigorous stirring, for further 25 min and then the
mixture was cooled. After addition of aqueous solution of
NaHSO3 to destroy the excess of iodine, the reaction
mixture was extracted with CH2Cl2 (30 ml£3). The
combined organic phase was washed with brine, dried and
concentrated. The residual solid was puri®ed by ¯ash column
chromatography on silica gel (hexane±AcOEtˆ6:1) to give
the iodopyrrole 9 which was crystallized from CH2Cl2-hexane
(2.67 g, 86.0% yield). Mp 134±1368C; IR (KBr): 3270,
2.01 (3H, s), 2.51 (2H, t, Jˆ7.4 Hz), 3.01 (2H, t, Jˆ7.4 Hz),
3.51 (2H, s), 3.57 (3H, s), 3.63 (3H, s), 5.02 (2H, s), 5.26
(2H, s), 7.30±7.34 (5H, m), 9.35 (1H, brs); 13C NMR: 20.40,
20.84, 29.38, 34.66, 51.48, 52.12, 56.85, 66.18, 116.96,
119.12, 128.33, 128.41, 128.62, 128.79, 129.99, 135.89,
160.42, 171.43, 171.85, 173.54; Anal. Calcd for
C22H25NO8: C, 61.24; H, 5.80; N, 3.25%. Found: C,
61.49; H, 5.74; N, 3.41%.
3.1.7. Benzyl 5-(2-mercaptobenzothiazolylmethyl)-3-(2-
methoxycarbonylethyl)-4-methoxycarbonylmethylpyr-
role-2-carboxylate (4c). To a solution of 2-acetoxymethyl-
pyrrole 10 (2.0 g, 4.64 mmol) and p-TsOH (0.080 g,
0.42 mmol) in CH2Cl2 (100 ml) was added 2-mercaptoben-
zothiazole (1.16 g, 6.95 mmol) under nitrogen atmosphere
and stirred at room temperature for 16 h in the dark. After
dilution with CH2Cl2 (50 ml), the mixture was washed with
saturated aq. solution of NaHCO3, brine, dried and then
concentrated to dryness. The residue was puri®ed by ¯ash
column chromatography on silica gel (hexane±AcOEtˆ3:1)
to give 4c (2.40 g, 96.1% yield): mp 93±958C (crystallized
from MeOH); IR (KBr) 3300, 1735, 1700, 1575, 1503,
1458, 1427, 1260, 1170 cm21; EIMS m/z: 538 (M1), 372,
1730, 1710, 1560, 1410, 1340, 1230, 1175, 1120 cm21
;
1
EIMS m/z: 527 (M1), 496, 468, 400, 350, 250; H NMR
(CDCl3) d: 2.49 (2H, t, Jˆ7.4 Hz), 2.72 (2H, t, Jˆ7.4 Hz),
3.68 (3H, s), 3.69 (3H, s), 3.95 (2H, s), 4.90 (2H, s), 9.20
(1H, brs); 13C NMR; 21.79, 30.71, 31.12, 51.74, 52.10,
73.94, 94.85, 123.19, 124.20, 124.23, 129.69, 158.12,
171.28, 173.03; Anal. calcd for C14H15NO6Cl3I: C, 31.94;
H, 2.87; N, 2.66%. Found: C, 31.67; H, 2.87, N, 2.63%.
1
298, 167, 91; H NMR (CDCl3) d: 2.56 (2H, t, Jˆ7.4 Hz),
3.04 (2H, t, Jˆ7.4 Hz), 3.54 (2H, s), 3.62 (3H, s), 3.69 (3H,
s), 4.49 (2H s), 5.25 (2H, s), 7.30±7.34 (7H, m), 7.64±7.75
(2H, m), 10.92 (1H, brs); 13C NMR: 20.39, 27.87, 29.68,
34.72, 51.45, 52.19, 65.89, 115.05, 118.42, 121.03, 121.31,
124.56, 126.44, 128.23, 128.43, 128.58, 130.12, 130.72,
135.39, 136.08, 152.48, 160.27, 167.83, 171.90, 173.65;
Anal. Calcd for C27H26N2O6S2: C, 60.21; H, 4.87; N,
5.20%. Found: C, 60.10; H, 4.88; N, 5.20%.
3.1.5. 2,2,2-Trichloroethyl 4-(2-methoxycarbonylethyl)-
3-methoxycarbonylmethylpyrrole-2-carboxylate (2c). A
solution of iodo pyrrole 9 (1.21 g, 2.30 mol) in MeOH
(12 ml) was vigorously stirred with 10% Pd±C (0.12 g)
and NaOAc (0.69 g) under hydrogen atmosphere until the
uptake of gas ceased. The catalyst was removed by ®ltration
through celite and the ®ltrate was evaporated under reduced
pressure. The residue was partitioned between CH2Cl2
(80 ml) and 5% aqueous Na2CO3 solution (20 ml). The
organic phase was dried over anhydrous MgSO4 and
concentrated to give an amorphous solid which was crystal-
lized from the mixture of CH2Cl2-hexane, giving colorless
prisms of 2c (0.895 g, 97.0% yield). Mp: 94±958C; IR
(KBr): 3340, 1735, 1710, 1573, 1510, 1418, 1410, 1340,
1273, 1170, 1115 cm21; EIMS m/z: 401 and 399 (M1),
In the same way, 4d and 4e were synthesized in high yield,
respectively.
4d. Mp 95±978C (crystallized from MeOH), IR (KBr):
3350, 1738, 1700, 1580, 1455, 1437, 1267, 1168 cm21
;
EIMS m/z: 481 (M1), 422, 372, 298; H NMR (CDCl3) d:
2.51 (2H, t, Jˆ7.4 Hz), 2.99 (2H, t, Jˆ7.4 Hz), 3.37 (2H, s),
3.61 (3H, s), 3.63 (3H, s), 4.05 (2H, s), 5.26 (2H, s), 7.22±
7.27 (5H, m), 7.34±7.39 (5H, m), 8.89 (1H, brs); 13C NMR:
20.48, 29.36, 30.37, 34.70, 51.46, 52.06, 66.03, 115.44,
117.99, 127.39, 128.29, 128.39, 128.60, 129.13, 130.42,
130.63, 131.04, 134.71, 135.98, 160.30, 171.83, 173.54;
Anal. Calcd for C26H27NO6S; C, 64.85; H, 5.65; N,
2.91%. Found C, 64.64; H, 5.68; N, 2.96%.
1
1
367, 341, 307, 268, 224; H NMR (CDCl3) d: 2.49 (2H, t,
Jˆ7.4 Hz), 2.69 (2H, t, Jˆ7.4 Hz), 3.60 (3H, s), 3.61 (3H,
s), 3.86 (2H, s), 4.82 (2H, s), 6.77 (1H, brs), 9.02 (1H, brs);
13C NMR: 20.11, 30.30, 34.68, 51.68, 52.02, 73.79, 95.08,
118.62, 121.66, 123.65, 124.97, 158.94, 171.60, 173.36;
Anal. Calcd for C14H16NO6Cl3: C, 41.97; H, 4.03; N,
3.50%. Found: C, 41. 86; H, 4.05; N, 3.52%.
4e. Mp 87±888C (crystallized from MeOH), IR (KBr):
3300, 1735, 1700, 1580, 1500, 1455, 1438, 1365, 1267,
1168 cm21; EIMS m/z: 461 (M1), 404, 372, 344, 314,
282; 1H NMR (CDCl3) d: 1.30 (9H, s), 2.52 (2H, t,
Jˆ7.4 Hz), 3.00 (2H, t, Jˆ7.4 Hz), 3.50 (2H, s), 3.61 (3H,
s), 3.67 (3H, s), 5.29 (2H, s), 7.32±7.40 (5H, m), 9.06 (1H,
brs); 13C NMR: 20.53, 65.95, 114.47, 117.52, 128.22,
128.34, 128.59, 130.88, 131.38, 136.12, 160.45, 171.95,
173.59; Anal. Calcd for C24H31NO6S; C, 62.45; H, 6.77,
N, 3.03%. Found: C, 62.31; H, 6.81; N, 3.03%.
3.1.6. Benzyl 5-acetoxymethyl-3-(2-methoxycarbonyl-
ethyl)-4-methoxycarbonylmethylpyrrole-2-carboxylate
(4a). a-Methylpyrrole derivative 5 (2.25 g, 6.03 mmol) was
stirred at rt for 16 h with lead tetraacetate (3.24 g,
7.31 mmol) in AcOH (180 ml) under nitrogen atmosphere.
The residue, obtained from evaporation of the solvent, was
partitioned between CH2Cl2 (200 ml) and saturated aq.
NaHCO3 (100 ml) and the aqueous layer was extracted
with fresh CH2Cl2 (50 ml£3). The combined CH2Cl2
extracts were dried and concentrated to dryness. The residue
was crystallized from CH2Cl2±hexane to give 4a (2.38 g,
91.7% yield); Mp 106±1088C; IR (KBr) 3295, 1740, 1670,
1472, 1438, 1370, 1350, 1287, 1240, 1188 cm21; EIMS m/z:
3.1.8. Benzyl 5-hydroxymethyl-3-(2-methoxycarbonyl-
ethyl)-4-methoxycarbonylmethylpyrrole-2-carboxylate
(10). A solution of 4a (431 mg, 1.00 mmol) in degassed
0.5N KOH±MeOH (10 ml) was allowed to stand at 08C
1
431 (M1), 400, 372, 340, 280, 266; H NMR (CDCl3): d:

K. Okada et al. / Tetrahedron 57 (2001) 2127±2131
2131
for 30 min. After dilution with AcOEt (100 ml), the mixture
was washed with brine, dried and concentrated. The residue
was puri®ed by ¯ash column chromatography on silica gel
(hexane±AcOEtˆ1:1) to give 10 (280 mg, 72% yield). Mp
116±1188C (crystallized from MeOH±hexane); IR (KBr):
3310, 1738, 1690, 1440, 1268, 1175, 1083 cm21; EIMS m/z:
389 (M1), 371, 330, 298, 280, 266, 238; 1H NMR (CDCl3):
d 2.52 (2H, t, Jˆ7.4 Hz), 3.01 (2H, t, Jˆ7.4 Hz), 3.52 (2H,
s), 3.61 (3H, s), 3.70 (3H, s), 4.55 (2H, s), 5.29 (2H, s),
7.32±7.43 (5H, m); 13C NMR: 20.28, 29.41, 34.82, 51.49,
52.43, 56.10, 66.13, 114.66, 118.02 128.32, 128.42, 128.62,
130.27, 134.14, 135.93, 160.59, 173.39, 173.56; Anal.
Calcd for C20H23NO7: C, 61.69; H, 5.95; N, 3.60%.
Found: C, 61.34; H, 5.97; N, 3.65%.
(about 10% yield) along with major product 1c. 11: Mp
144±1468C (crystallized from MeOH); IR (KBr): 3320
(br), 1730, 1700, 1580, 1500, 1438, 1255, 1170 cm21
;
1
FABMS m/z: 731 (MH1): H NMR (CDCl3) d: 2.50 (4H,
t, Jˆ7.4 Hz), 3.01 (4H, t, Jˆ7.4 Hz), 3.56 (4H, s), 3.59
(12H, s), 3.82 (2H, s), 5.24 (4H, s), 7.28±7.39 (10H, m);
13C NMR: 20.42, 22.54, 29.35, 34.82, 51.45, 52.49, 65.75,
113.78, 118.25, 128.02, 128.38, 128.43, 129.95, 132.11,
136.23, 160.37, 173.69, 174.07; Anal. Calcd for
C39H42N2O12: C, 64.09; H, 5.80; N, 3.84. Found: C, 64.13;
H, 5.82; N, 3.83%.
References
1. Preliminary communication about this paper was reported by
Okada, K.; Saburi, K.; Nomura, K.; Tanino, H. Tetraheron
Lett. 1998, 39, 2365±2366.
3.1.9. Synthesis of pyrromethane (1c). To a solution of
a-free pyrrole 2c (48.1 mg, 0.12 mmol) and 5-mercaptoben-
zothiazothiazolylmethylpyrrole-2-carboxylate derivative 4c
(53.8 mg, 0.10 mmol) in dry degassed benzene (5 ml) were
added CF3SO3Ag (38.5 mg, 0.15 mmol) and powdered
Na2HPO4 (49.7 mg, 0.35 mmol). The mixture was stirred
under nitrogen atmosphere at room temperature for
10 min. After dilution with benzene, the mixture was
®ltered through celite and the ®ltrate was concentrated
under reduced pressure. The residue was puri®ed by ¯ash
column chromatography on silica gel (hexane±AcOEtˆ2.1)
to give pyrromethane 1c as a colorless crystal (75.66 mg,
98% yield); Mp 119±1228C (crystallized from MeOH±
hexane); IR (KBr): 3350, 1730, 1700, 1579, 1505, 1438,
1251, 1172 cm21; FABMS m/z 773 (MH1); 1H NMR
(CDCl3) d: 2.48 (2H, t, Jˆ7.4 Hz), 2.59 (2H, t,
Jˆ6.7 Hz), 2.79 (2H, t, Jˆ6.7 Hz), 3.00 (2H, t,
Jˆ7.4 Hz), 3.54 (3H, s), 3.59 (2H, s), 3.62 (3H, s), 3.66
(3H, s), 3.79 (3H, s), 3.87 (2H, s), 3.97 (2H, s), 4.86 (2H,
s), 5.25 (2H, s), 7.29±7.35 (5H, m), 9.95 (1H, brs), 10.35
(1H, brs); 13C NMR: 18.61, 20.60, 22.35, 29.42, 30.98,
34.09, 34.84, 51.49, 52.01, 52.02, 52.80, 65.83, 73.74,
95.21, 114.74, 118.05, 118.36, 120.28, 121.55, 123.65,
128.27, 128.55, 129.96, 131.76, 133.00, 136.15, 158.98,
160.62, 171.71, 173.59, 174.02, 174.55; Anal. Calcd for
C34H37N2O12Cl13: C, 52.90; H, 4.83; N, 3.63%. Found C,
52.69; H, 4.87; N, 3.61%. The reaction of slightly excess 4c
(1.2 equiv.) with 2c (1 equiv.) under the similar conditions
produced a symmetric pyrromethane 11 as a minor product
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