2,5-dimethylpyrrole protection facilitates copper(I)-mediated methoxylations of aryl iodides in the presence of anilines

Article abstract of DOI:10.1055/s-1998-2189

Converting iodoanilines to the corresponding 2,5-dimethylpyrroles was found to facilitate CuCI-mediated methoxide substitution. Examples with ortho-, meta-, or para-relationships between the iodide and aniline are presented. Several other aniline blocking groups were investigated and found not to be successful in this sequence.

Full text of DOI:10.1055/s-1998-2189

PAPERS
1599
2,5-Dimethylpyrrole Protection Facilitates Copper(I)-Mediated Methoxylations of Aryl
Iodides in the Presence of Anilines
John A. Ragan,* Teresa W. Makowski, Michael J. Castaldi, Paul D. Hill
Process Research and Development, Pfizer Central Research, Eastern Point Road, Groton, CT 06340, USA
Fax +1(860)441-5445
Received 19 January 1998; revised 31 March 1998
Abstract: Converting iodoanilines to the corresponding 2,5-
dimethylpyrroles was found to facilitate CuCl-mediated methox-
ide substitution. Examples with ortho-, meta-, or para-relation-
pared the benzophenone imine (ArN=CPh2). This group
ships between the iodide and aniline are presented. Several other
aniline blocking groups were investigated and found not to be suc-
cessful in this sequence.
group was found to be unstable to the basic reaction con-
ditions. Turning to a base-stable blocking group, we pre-
was stable to the reaction conditions, but led to a 1:1 mix-
ture of methoxide displacement at the fluorine and iodine,
apparently due to the anion stabilizing properties of the
benzophenone imine.
Key words: Ullman, methoxylation, aryl ether, 2,5-dimethyl-
pyrrole, aniline
We finally turned to the 2,5-dimethylpyrrole derivative 3
(Scheme 2),8 reasoning that it should retain the base-sta-
bility of the benzophenone imine, but would not be as ac-
tivating towards SNAr displacement of the ortho fluorine.
Condensation of 2-fluoro-4-iodoaniline (2) with acetonyl-
acetone (Acac) in refluxing toluene (1 mol% TsOH,
Dean–Stark removal of water) led to a quantitative yield
of pyrrole 3. Exposure of this material to NaOMe
(3 equiv) and either CuI or CuCl (15 mol%) in MeOH/
DMF (3:1) at 80°C for 4 hours led to a 62% recrystallized
yield of the desired methoxide substitution product 4.
Cleavage of the pyrrole was then effected with hydroxyl-
amine hydrochloride (10 equiv) and Et3N in aq EtOH at
reflux, which provided a 70% recrystallized yield of 2-
fluoro-4-methoxyaniline (1) on 50 gram scale. The over-
all yield for the three step sequence was 43%.
We recently required a practical, multigram synthesis of
2-fluoro-4-methoxyaniline (1). The published synthesis
of this compound1 involves a nonselective nitration of 3-
fluorophenol,2 which was unacceptable for our purposes
due to both safety considerations and the difficulty of sep-
arating the resulting mixture of regioisomers. Presented
herein is a practical, regiospecific synthesis of 1 which
also provides access to a variety of other methoxyanilines.
Copper-mediated alkoxide substitution of aryl halides is a
well-precedented method for the preparation of ani-
soles.3–5 For the case at hand, the commercial availability
of 2-fluoro-4-iodoaniline (Aldrich catalog #30,660-6,
$73/100 g) made this an attractive route. The influence of
an unprotected aniline in this reaction was unclear; a sin-
gle literature report found that free NH2 or OH groups on
the aryl halide had a deleterious effect (yields of 35–50%,
vs 75–100% yields for nonacidic substrates).6 Indeed,
when unprotected 2-fluoro-4-iodoaniline was exposed to
NaOMe (3 equiv) and CuI (0.20 to 2.0 equiv) in MeOH/
DMF or pyridine, no substitution products were observed
(Scheme 1, R1 = R2 = H).
Scheme 2
As shown in the Table, this sequence represents a general
method for the conversion of iodoanilines into the corre-
sponding methoxyanilines. The condensation of the io-
doaniline with acetonylacetone proceeded smoothly with
a variety of anilines in 86–100% yield (see Experimental
Section for details). The Cu(I)-mediated methoxylation
was substrate dependent, with several trends worth not-
ing:
Scheme 1
We next examined several blocking groups for the
aniline.7 With either acetamide (ArNHCOCH3) or methyl
carbamate (ArNHCO2Me), no methoxide coupling was
observed (prolonged reaction times led to cleavage of the
blocking groups). Reasoning that the acidic NH might be 1. Couplings were largely independent of the regiochem-
problematic, we prepared the phthalate derivative; this
istry between the aniline nitrogen and the iodine,

SYNTHESIS
1600
Table.
Entry
Yield
(%)
Entry
6
Yield
(%)
1a
62
49
96
94
97
0
2
7
8
3
–
–
4
5
95
92
9b
0
10c
34
a Methoxylation conditions: NaOMe (3 equiv), CuCl (15 mol%), MeOH/DMF (3:1 v/v), 80°C.
b Ester 17 was prepared from acid 16 via treatment with K2CO3/MeI in THF (65%).
c Methyl 3-amino-5-iodobenzoate was prepared from 3-iodo-5-nitrobenzoic acid by the sequence: (1) HCl/MeOH (62%), (2) Fe/AcOH (88%).9
whether para (entries 1 and 3), meta (entries 4 and 5), Removal of the pyrrole blocking group with hydroxyl-
or ortho (entries 6 and 7).
amine hydrochloride (10 equiv) and Et3N in aq EtOH pro-
2. Substituting bromide for iodide reduced the efficiency ceeded smoothly with all substrates (70–98% yield; see
of the methoxylation (entry 2); the desired product did Experimental Section for details).
slowly form by GC/MS and HPLC, but was contami-
A survey of several aniline blocking groups showed that
nated with 30–40% of several other byproducts after
the 2,5-dimethylpyrrole moiety was uniquely suited for
prolonged reaction times.
Cu(I)-mediated methoxylations. This sequence allows for
3. The source of copper(I) was not found to be critical:
the regiospecific conversion of iodoanilines into the cor-
99.999% CuI and 98% CuCl worked equally well.
responding methoxyanilines. The method led to an im-
Substrates bearing a carboxy substituent were less suc- proved synthesis of 2-fluoro-4-methoxyaniline, which
cessful (entries 8–10). A free carboxylic acid completely avoids the nonselective nitration reported earlier.
suppressed the methoxylation (entry 8). With a methoxy-
carbonyl substituent, the substitution pattern proved to be
critical, for reasons which remain unclear. For example,
methyl 2-amino-5-iodobenzoate (entry 9) failed to under-
go methoxylation under our standard reaction conditions.
However, the pyrrole derived from methyl 3-amino-5-io-
dobenzoate (entry 10) behaved as expected in the methox-
ylation, albeit in lower yield (34%) than the less electron-
deficient substrates (entries 1–6).
All chemicals were used as purchased. DMF and THF were pur-
chased in anhydrous form from Aldrich in Sure-Seal glass bottles; all
other solvents were reagent grade. Reactions were run under a posi-
tive pressure of N2 unless otherwise stated. 400 MHz 1H (and
100 MHz 13C) NMR spectra were obtained on a Varian Unity+400
spectrometer equipped with two RF channels, indirect detection, and
pulsed-field gradients (z-axis only). H spectra were acquired using
45˚ acquisition pulses, 3.0 s recycle delay, and 16 scans at a resolution
of 0.2 Hz/point. The acquisition window was typically 6800 Hz, and
1

November 1998
1601
processing used 0.1 Hz line broadening. 13C spectra were acquired
using 45˚ acquisition pulses, 0.7 s recycle delay, and 512 scans at a
resolution of 0.8 Hz/point. Proton decoupling was applied at 3 watts
of power during acquisition, and 2 Hz line broadening was used dur-
ing processing. MS data was collected on either a Hewlett–Packard
GC/MS (electron impact ionization), or a Micromass (Fisons) Plat-
form II mass spectrometer (atmospheric pressure chemical ioniza-
tion). HRMS data was obtained from M-Scan, Inc. (606 Brandywine
Parkway, West Chester, Pennsylvania). TLC was performed on pre-
coated sheets of 60 F254 (Merck Art. 5719). Mps are uncorrected.
13C NMR (CDCl3): δ = 140.0, 137.1, 136.7, 130.4, 128.6, 127.6,
106.1, 93.7, 12.9.
MS (EI): m/z (%) = 297 (100).
1-(2-Iodophenyl)-2,5-dimethyl-1H-pyrrole (12):
From 2-iodoaniline (10.0 g, 45.7 mmol) was obtained 13.3 g (98%) of
12 as a purple oil.
1H NMR (CDCl3): δ = 7.95 (d, J = 8 Hz, 1H), 7.45 (t, J = 3 Hz, 1H),
7.27 (d, J = 8 Hz, 1H), 7.15 (t, J = 3 Hz, 1H), 5.90 (s, 2H), 1.95 (s, 6H).
13C NMR (CDCl3): δ = 139.5, 129.9, 129.7, 129.2, 129.1, 128.3,
105.8, 100.6, 12.9.
1-(2-Fluoro-4-iodophenyl)-2,5-dimethyl-1H-pyrrole (3); Typical
Procedure:
MS (EI): m/z (%) = 297 (100).
A 500-mL round-bottom flask was charged with 2-fluoro-4-iodo-
1-(2-Fluoro-6-iodo-4-methylphenyl)-2,5-dimethyl-1H-pyrrole (14):
From 2-fluoro-6-iodo-4-methylaniline (4.0 g, 16 mmol) was obtained
4.57 g (87%) of 14 as a brown oil.
•
aniline (53.3 g, 220 mmol), toluene (250 mL), TsOH H2O (0.43 g,
2.3 mmol, 1 mol%), and acetonylacetone (30.8 g, 270 mmol, 1.2
equiv). The solution was warmed to reflux under Dean–Stark condi-
tions for 1 h, at which point GC/MS and TLC analysis indicated com-
plete conversion to the pyrrole. The solution was cooled to r.t.,
washed with aq NaHCO3, dried (MgSO4), filtered, and concentrated
to provide a dark brown oil which crystallized upon standing; crude
yield: 72.8 g (103%). This material was homogeneous by HPLC and
1H NMR, and was suitable for use in the next reaction. An analytical
sample was prepared by dissolving in hot hexanes (210 mL), cooling,
then concentrating to 50% of the original volume. Cooling in an ice
bath with rapid stirring provided 35.5 g (49% recovery) of a brown,
granular solid; mp 68–70°C.
1H NMR (CDCl3): δ = 7.53 (d, J = 1 Hz, 1H), 6.99 (dd, J = 1, 8 Hz,
1H), 5.92 (s, 2H), 2.36 (s, 3H), 1.93 (s, 6H).
MS (EI): m/z (%) = 329 (100).
HRMS (FAB) calcd for C13H13NFI (M + H) 330.0155, found
330.0153.
1-(2-Carboxy-4-iodophenyl)-2,5-dimethyl-1H-pyrrole (16):
From 2-amino-5-iodobenzoic acid (5.0 g, 19 mmol) was obtained
6.40 g (97%) of 16 as a brown solid.
1H NMR (CDCl3): δ = 8.37 (d, J = 2 Hz, 1H), 7.94 (dd, J = 2, 8 Hz,
1H), 6.96 (d, J = 8 Hz, 1H), 5.86 (s, 2H), 1.90 (s, 6H).
13C NMR (CD3OD) (9 of 10 lines observed): δ = 166.2, 141.2, 139.1,
138.1, 132.2, 128.2, 105.4, 92.6, 11.6.
1H NMR (CDCl3): δ = 7.43 (t, J = 27 Hz, 2H), 7.13 (t, J = 20 Hz, 1H),
5.94 (s, 2H), 2.02 (s, 6H).
13C NMR (CDCl3): δ = 158.3 (d, J = 254 Hz), 131.6, 128.9, 127.8 (d,
J = 3 Hz), 122.0, 120.3 (d, J = 23 Hz), 106.4, 12.4.
MS (CI): m/z (%) = 342 (M + H, 100).
HRMS (FAB) calcd for C13H12NIO2 (M + H) 341.9991, found
341.9979.
MS (EI): m/z (%) = 268 (100).
HRMS (FAB) calcd for C12H11NFI (M+) 315.9999, found 315.9995.
1-(4-Iodo-2-methoxycarbonylphenyl)-2,5-dimethyl-1H-pyrrole (17):
Carboxylic acid 16 (0.90 g, 2.6 mmol) was dissolved in THF (9 mL)
and treated with K2CO3 (0.43 g, 3.1 mmol) and MeI (0.18 mL,
2.9 mmol) at 55°C. After 9 h, the solution was cooled, diluted with
EtOAc, and washed with two portions of water and once with brine.
After drying (MgSO4), the organic phase was evaporated to provide
0.60 g (65%) of 17 as a brown solid.
1-(2-Fluoro-4-bromophenyl)-2,5-dimethyl-1H-pyrrole (5):
From 2-fluoro-4-bromoaniline (7.33 g, 38.6 mmol) was obtained
8.94 g (86%) of 5 as a tan solid.
1H NMR (CDCl3): δ = 7.43 (t, J = 11 Hz, 2H), 7.13 (t, J = 10 Hz, 1H),
5.94 (s, 2H), 2.02 (s, 6H).
13C NMR (CDCl3) (8 of 9 lines observed): δ = 158.3 (d, J = 254 Hz),
131.6, 128.9, 127.8 (d, J = 3 Hz), 122.0, 120.3 (d, J = 23 Hz), 106.4,
12.4.
1H NMR (CDCl3): δ = 8.27 (s, 1H), 7.92 (dd, J = 2, 8 Hz, 1H), 7.01
(dd, J = 2, 8 Hz, 1H), 5.89 (s, 2H), 3.67 (s, 3H), 1.91 (s, 6H).
13C NMR (CDCl3): δ = 165.0, 141.4, 139.5, 138.0, 132.5, 132.0,
128.7, 105.9, 93.0, 52.6, 12.6.
MS (EI): m/z (%) = 268 (100).
1-(3-Chloro-4-iodophenyl)-2,5-dimethyl-1H-pyrrole (6):
From 3-chloro-4-iodoaniline (5.30 g, 20.9 mmol) was obtained 6.90 g
(98%) of 6 as a dark red oil.
MS (CI): m/z (%) = 356 (M + H, 100).
1-(3-Iodo-5-methoxycarbonylphenyl)-2,5-dimethyl-1H-pyrrole (18):
From methyl 3-amino-5-iodobenzoate9 (1.84 g, 6.64 mmol) was ob-
tained 1.88 g (80%) of 18 as a tan solid (product was isolated via flash
chromatography, eluting with hexane/EtOAc 5:1).
1H NMR (CDCl3): δ = 8.38 (s, 1H), 7.84 (s, 1H), 7.74 (s, 1H), 5.87 (s,
2H), 3.91 (s, 3H), 2.00 (s, 6H).
1H NMR (CDCl3): δ = 7.93 (d, J = 8 Hz, 1H), 7.32 (d, J = 2 Hz, 1H),
6.84 (dd, J = 8, 2 Hz, 1H), 5.90 (s, 2H), 2.04 (s, 6H).
13C NMR (CDCl3): δ = 140.5, 140.2, 139.1, 129.1, 128.6, 127.9,
106.6, 97.0, 13.0.
MS (EI): m/z (%) = 334 (100).
13C NMR (CDCl3): δ = 164.7, 141.2, 140.2, 137.6, 132.6, 128.7,
106.6, 93.3, 52.6, 12.9.
MS (EI): m/z (%) = 355 (100).
1-(5-Iodo-2-methylphenyl)-2,5-dimethyl-1H-pyrrole (8):
From 5-iodo-2-methylaniline (5.00 g, 21.5 mmol) was obtained
6.28 g (94%) of 8 as a brown solid.
1H NMR (CDCl3): δ = 7.60 (dd, J = 2, 8 Hz, 1H), 7.49 (d, J = 2 Hz,
1H), 7.00 (d, J = 8 Hz, 1H), 5.87 (s, 2H), 1.90 (s, 6H), 1.85 (s, 3H).
13C NMR (CDCl3): δ = 139.5, 137.6, 137.3, 137.0, 132.2, 128.0,
105.7, 90.0, 16.7, 12.5.
1-(2-Fluoro-4-methoxyphenyl)-2,5-dimethyl-1H-pyrrole (4);
Typical Procedure:
1-(2-Fluoro-4-iodophenyl)-2,5-dimethyl-1H-pyrrole (3) (70.0 g,
222 mmol) was dissolved in MeOH (230 mL) and DMF (70 mL). To
this solution was added NaOMe (35.9 g, 666 mmol, 3.0 equiv) and
CuCl (3.3 g, 31 mmol, 15 mol%). The resulting mixture was warmed
to reflux for 4 h. After cooling to r.t., i-Pr2O (500 mL), 5% aq NH4Cl
(220 mL), and water (350 mL) were added, and the mixture was
stirred overnight. The mixture was then filtered through Celite, the
layers were separated, and the aqueous layer extracted with i-Pr2O
(350 mL). The combined organic extracts were then washed with 10%
MS (EI): m/z (%) = 311 (100).
1-(3-Iodophenyl)-2,5-dimethyl-1H-pyrrole (10):
From 3-iodoaniline (10.0 g, 45.7 mmol) was obtained 12.2 g (90%) of
10 as a purple solid.
1H NMR (CDCl3): δ = 7.70 (m, 1H), 7.56 (s, 1H), 7.17 (m, 2H), 5.86
(s, 2H), 2.00 (s, 6H).

SYNTHESIS
1602
aq NH4OH (200 mL), and passed through a pad of silica gel (100 g).
Concentration provided a brown oil, which crystallized upon standing
(45.2 g, 93% yield). Recrystallization from hot hexane (135 mL) pro-
vided 30.1 g (62% yield) of 4 as a brown solid; mp 67–69°C.
1H NMR (CDCl3): δ = 7.12 (t, J = 8 Hz, 1H), 6.75 (d, J = 8 Hz, 1H),
6.73 (s, 1H), 5.89 (s, 2H), 3.82 (s, 3H), 1.97 (s, 6H).
13C NMR (CDCl3) (9 of 10 lines observed): δ = 159.1 (d, J = 260 Hz),
130.7, 129.5, 109.9 (d, J = 3 Hz), 106.0, 105.6, 102.3 (d, J = 25 Hz),
55.7, 12.4.
1H NMR (CDCl3): δ = 7.60 (s, 1H), 7.50 (s, 1H), 6.96 (s, 1H), 5.90 (s,
2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.04 (s, 6H).
13C NMR (CDCl3): δ = 166.3, 160.0, 140.2, 132.1, 128.7, 121.8,
119.1, 113.7, 106.1, 55.8, 52.4, 13.0.
MS (EI): m/z (%) = 259 (100).
2-Fluoro-4-methoxyaniline (1); Typical Procedure:
(Caution! This reaction should be performed behind a suitable blast
shield due to the potential thermal hazard of hydroxylamine hydro-
chloride, as cited in Organic Functional Group Preparations; Vol. 3;
Academic Press: New York, 1986; p 490): A 2-L round-bottom flask
was charged with 1-(2-fluoro-4-methoxyphenyl)-2,5-dimethyl-1H-
pyrrole (4) (60.0 g, 271 mmol), hydroxylamine hydrochloride (188 g,
2.71 mol, 10 equiv), EtOH (600 mL), water (300 mL), and Et3N (76
mL, 0.54 mol), then warmed to reflux for 16 h. After cooling to r.t.,
the mixture was slowly poured into ice-cold 1 N HCl (1.7 L), and
washed with i-Pr2O (2 × 500 mL). The aqueous phase was then
brought to pH 10 by careful addition of 6 N NaOH, and extracted with
i-Pr2O (2 × 500 mL). The organic extracts were concentrated to pro-
vide an oily solid, which was filtered, rinsing with additional i-Pr2O
(the solid was not related to the aniline product by 1H NMR analysis,
and is presumably some acetonylacetone related byproduct of the
deprotection). Further concentration of the i-Pr2O solution provided a
brown oil (36 g, 98% yield), which was recrystallized from hot i-Pr2O
(200 mL), to provide 26.8 g (70% yield) of 1 as a brown solid; mp 46–
47°C (lit. 47–48°C).1 Spectral data (1H NMR, MS) were identical to
that reported,1 as well as to samples prepared by the nitration of 3-
fluorophenol followed by methylation and reduction.1
MS (EI): m/z (%) = 219 (100).
HRMS (FAB) calcd for C13H14NFO (M + H) 220.1138, found
220.1127.
1-(3-Chloro-4-methoxyphenyl)-2,5-dimethyl-1H-pyrrole (7):
From iodide 6 (2.89 g, 8.72 mmol) was obtained 1.97 g (96%) of 7 as
a dark brown oil.
1H NMR (CDCl3): δ = 7.22 (d, J = 3 Hz, 1H), 7.08 (dd, J = 3, 5 Hz,
1H), 6.96 (dd, J = 3, 5 Hz, 1H), 5.85 (s, 2H), 3.92 (s, 3H), 1.98 (s, 6H).
13C NMR (CDCl3): δ = 154.5, 129.9, 128.9, 127.5, 122.5, 119.7,
111.8, 105.6, 56.3, 12.9.
MS (EI): m/z (%) = 235 (100).
1-(5-Methoxy-2-methylphenyl)-2,5-dimethyl-1H-pyrrole (9):
From iodide 8 (2.0 g, 6.4 mmol) was obtained 1.31 g (95%) of 9 as a
brown oil.
1H NMR (CDCl3): δ = 7.17 (d, J = 8 Hz, 1H), 6.86 (dd, J = 3, 8 Hz,
1H), 6.70 (d, J = 3 Hz, 1H), 5.88 (s, 2H), 3.76 (s, 3H), 1.90 (s, 6H),
1.80 (s, 3H).
13C NMR (CDCl3): δ = 158.0, 138.5, 131.1, 128.8, 128.2, 114.4,
113.9, 105.2, 55.4, 16.2, 12.5.
3-Chloro-4-methoxyaniline:
From pyrrole 7 (0.89 g, 3.8 mmol) was obtained 0.54 g (89%) of prod-
uct as a brown solid. Spectral data (1H NMR, MS) were identical to a
commercially available sample.
MS (EI): m/z (%) = 215 (100).
1-(3-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole (11):
From iodide 10 (6.00 g, 20.2 mmol) was obtained 3.74 g (92%) of 11
as a brown oil.
5-Methoxy-2-methylaniline:
From pyrrole 9 (1.30 g, 6.05 mmol) was obtained 0.62 g (75%) of
product as a brown solid. Spectral data (1H NMR, MS) were identical
to a commercially available sample.
1H NMR (CDCl3): δ = 7.35 (t, J = 8 Hz, 1H), 6.90 (d, J = 8 Hz, 1H), 6.80
(d, J = 8 Hz, 1H), 6.75 (s, 1H), 5.89 (s, 2H), 3.80 (s, 3H), 2.00 (s, 6H).
13C NMR (CDCl3): δ = 159.9, 140.0, 129.5, 128.5, 120.5, 113.8,
113.4, 105.5, 55.3, 12.9.
3-Methoxyaniline:
MS (EI): m/z (%) = 201 (100).
From pyrrole 11 (3.0 g, 15 mmol) was obtained 1.4 g (76%) of prod-
uct as a brown liquid. Spectral data (1H NMR, MS) were identical to
a commercially available sample.
1-(2-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole (13):
From iodide 12 (6.00 g, 20.2 mmol) was obtained 3.81 g (94%) of 13
as a brown oil.
2-Methoxyaniline:
1H NMR (CDCl3): δ = 7.35 (t, J = 8 Hz, 1H), 7.12 (d, J = 8 Hz, 1H),
6.99 (m, 2H), 5.88 (s, 2H), 3.75 (s, 3H), 1.94 (s, 6H).
13C NMR (CDCl3): δ = 156.0, 130.1, 129.3, 128.5, 127.4, 120.5,
111.9, 105.1, 55.6, 12.4.
From pyrrole 13 (3.00 g. 14.9 mmol) was obtained 1.56 g (85%) of
product as a brown liquid. Spectral data (1H NMR, MS) were identi-
cal to a commercially available sample.
MS (EI): m/z (%) = 201 (100).
2-Fluoro-6-methoxy-4-methylaniline:
From pyrrole 15 (1.0 g, 4.3 mmol) was obtained 0.61 g (91%) of prod-
uct as a brown oil.
1-(2-Fluoro-6-methoxy-4-methylphenyl)-2,5-dimethyl-1H-pyrrole
(15):
1H NMR (CDCl3): δ = 6.48 (d, J = 10.4 Hz, 1H), 6.41 (s, 1H), 3.83 (s,
3H), 3.58 (br s, 2H), 2.24 (s, 3H).
From iodide 14 (4.0 g, 12 mmol) was obtained 2.74 g (97%) of 15 as
a brown oil.
13C NMR (CDCl3): δ = 151.6 (d, J = 235 Hz), 148.5, 126.9 (d, J =
9 Hz), 108.4 (d, J = 74 Hz), 107.0, 105.5, 55.8, 20.9.
MS (CI): m/z (%) = 155 (100).
1H NMR (CDCl3): δ = 6.66 (d, J = 9 Hz, 1H), 6.61 (s, 1H), 5.91 (s,
2H), 3.76 (s, 3H), 2.40 (s, 3H), 1.96 (s, 6H).
MS (CI): m/z (%) = 233 (100).
HRMS (FAB) calcd for C14H16NFO (M + H) 234.1294, found
234.1299.
3-Methoxy-5-methoxycarbonylaniline:
From pyrrole 19 (0.43 g, 1.7 mmol) was obtained 0.31 g (100%) of
product as a tan solid.
1H NMR (CDCl3): δ = 6.95–6.93 (m, 2H), 6.37 (br s, 1H), 3.98–3.82
(br s, 2H), 3.84 (s, 3H), 3.75 (s, 3H).
1-(3-Methoxy-5-methoxycarbonylphenyl)-2,5-dimethyl-1H-pyrrole
(19):
From iodide 18 (1.85 g, 5.21 mmol) was obtained 0.454 g (34%) of
19 as a tan solid (product was isolated via flash chromatography, elut-
ing with hexane/EtOAc 6:1).
13C NMR (CDCl3): δ = 160.6, 147.8, 132.0, 109.2, 105.7, 104.3, 55.3,
52.1.
MS (EI): m/z (%) = 181 (100).

November 1998
1603
The authors would like to thank Dave am Ende and Pamela Clifford
for calorimetry measurements on several intermediates, Alex Grod-
ski and Gary Berg for a sample of 1 prepared by the published
route,1 and Keith DeVries for several helpful discussions.
(4) Keegstra, M. A.; Peters, T. H. A.; Brandsma, L. Tetrahedron
1992, 48, 3633.
(5) Lindley, J. Tetrahedron 1984, 40, 1433.
(6) Bacon, R. G. R.; Rennison, S. C. J. Chem. Soc. (C) 1969, 312.
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