N-Amination of Pyrrole and Indole Heterocycles with Monochloramine (N H2Cl)

Article abstract of DOI:10.1021/jo035587p

A survey of several electrophilic ammonia reagents for the N-amination of indole- and pyrrole-containing heterocycles revealed that monochloramine (NH₂Cl) is an excellent reagent for this transformation. Pyrroles and indoles containing a variety of substitution were aminated on nitrogen with isolated yields ranging from 45% to 97%.

Full text of DOI:10.1021/jo035587p

N-Am in a tion of P yr r ole a n d In d ole
Heter ocycles w ith Mon och lor a m in e
(
2
NH Cl)
J ohn Hynes, J r.,*,† Wendel W. Doubleday,‡
+
F IGURE 1. Common reagents for NH
onto heterocyclic nitrogens.
2
transfer reactions
†
‡
Alaric J . Dyckman, J ollie D. Godfrey, J r.,
12
‡
§
†
J ohn A. Grosso, Susanne Kiau, and Katerina Leftheris
TABLE 1. Su r vey of NH2+ Tr a n sfer Rea gen ts for th e
Con ver sion of 2a to 3a
Departments of Discovery Chemistry and Process Research
&
Development, Bristol-Myers Squibb Co., Pharmaceutical
Research Institute, Princeton, New J ersey 08543, and
Department of Process Research & Development,
Bristol-Myers Squibb Co., Pharmaceutical Research
Institute, New Brunswick, New J ersey 08903
john.hynes@bms.com
Received October 29, 2003
Abstr a ct: A survey of several electrophilic ammonia re-
agents for the N-amination of indole- and pyrrole-containing
heterocycles revealed that monochloramine (NH2Cl) is an
excellent reagent for this transformation. Pyrroles and
indoles containing a variety of substitution were aminated
on nitrogen with isolated yields ranging from 45% to 97%.
Safe, efficient, and economical processes for the intro-
2
duction of pendant NH functionality onto carbon and
nitrogen anions are limited in practicality by the require-
a
Isolated. b HPLC conversion after 1 h at room temperature
(
YMC S5 ODS-A, 4.6 mm × 50 mm; 10% MeOH/water/0.2% H3PO4
ment of stoichiometric electrophilic nitrogen transfer
gradient to 90% MeOH/water/0.2% H3PO4, 4 mL/min, 8 min
+
reagents. Until improved processes for the direct NH
2
c
gradient, 220 nm). Bu4NBr added as phase transfer catalyst.
HPLC conversion after 3 days.
d
transfer onto carbon and nitrogen centers is discovered,
such reagents (Figure 1) will remain the most widely
used for reactions of this type. The varying availability,
high cost, and potentially dangerous properties of many
of these reagents preclude their utility in scaleable
reports reveal that the generality of the common re-
agents is limited. For example, early work identified
hydroxylamine-O-sulfonic acid (HOSA)3 as a capable
reagent for reactions of this type, but it failed for
substrates containing base-sensitive functionality. Ad-
ditionally, heterocycle N-amination with HOSA suffers
from poor substrate conversion requiring chromato-
graphic separation of the products from the starting
materials. O-(2,4-Dinitrophenyl)-hydroxylamine (Dnp-
ONH , 1) has been utilized as an electrophilic source of
2
nitrogen for various types of reactions including hetero-
cycle N-aminations. Previous studies have demonstrated
that reaction of pyrrole 2a with 1 affords 1-aminopyrrole
3a in 85-90% yield (Table 1, entry 1) on a multigram
scale. However, 1 is not readily available and has the
reaction processes. In fact, two recent reports highlight
+
the continued interest in novel NH
2
transfer reagents
whose improved physical and chemical properties make
them more amenable to widespread use in organic
synthesis.1
,2
Heterocycle N-aminations have been reported using
various methods and reagents, primarily those derived
3
-7
from hydroxylamine (Figure 1), but inspection of these
4
†
Department of Discovery Chemistry, Princeton, NJ .
Department of Process Research and Development, Princeton, NJ .
Department of Process Research and Development, New Bruswick,
‡
§
NJ .
(
8
1) Boyles, D. C.; Curran, T. T.; Partlett, R. V., III. Org. Proc. Res.
9
Dev. 2002, 6, 230.
potential for detonation. Additionally, the reaction waste
(2) Shen, Y.; Friestad, G. K. J . Org. Chem. 2002, 67, 6236.
(
3) (a) Raap, R. Can. J . Chem. 1969, 47, 3677. (b) Somei, M.;
Natsume, M. Tetrahedron Lett. 1974, 5, 461. (c) Zeiger, A. V.; J oullie,
M. M. Synth. Commun. 1976, 6, 457. (d) Somei, M.; Matsubara, M.;
Kanda, Y.; Natsume, M. Chem. Pharm. Bull. 1978, 26, 2522. (e)
Wallace, A. G. Org. Prep. Proc. Intl. 1982, 14, 265. (f) Neunhoeffer,
H.; Clausen, M.; V o¨ tter, H.-D.; Ohl, H.; Kr u¨ ger, C.; Angermund, K.
Liebig. Ann. Chem. 1985, 1732. (g) Nagai, S.; Kato, N.; Ueda, T.; Oda,
N.; Skakakibara, J . Heterocycles 1986, 24, 907. (h) Ruxer, J . M.;
Lachoux, C.; Ousset, J . B.; Torregrossa, J . L.; Mattioda, G. J .
Heterocycl. Chem. 1994, 31, 1561. (i) Patil, S. A.; Otter, B. A.; Klein,
R. S. J . Heterocycl. Chem. 1994, 31, 781. (j) Hoechst-Roussel Pharma-
ceuticals Inc.: U.S. Patent 5,459,274, 1995; Chem. Abstr. 1995, 124,
(4) (a) Sheradsky, T. Tetrahedron Lett. 1968, 16, 1909. (b) Sherad-
sky, T.; Salemnick, G.; Nir, Z. Tetrahedron 1972, 28, 3833. (c) Bellettini,
J . R.; Olson, E. R.; Teng, M.; Miller, M. J . In Encyclopedia of Reagents
for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995;
Vol. 3, pp 2189-2190.
(5) (a) Tamura, Y.; Minamikaw, J .; Ikeda, M. Synthesis 1977, 1. (b)
Lee, C.-S.; Ohta, T.; Shudo, K.; Okamoto, T. Heterocycles 1981, 16,
1081. (c) Boche, G. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 5, pp 3277-3281.
(6) (a) Sosnovsky, G.; Purgstaller, K. Z. Naturforsch., B: Chem Sci.
1989, 44, 482. (b) Boche, G. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 4, pp
2240-2242.
1
45914. (k) Klein, J . T.; Davis, L.; Olsen, G. E.; Wong, G. S.; Huger, F.
P.; Smith, C. P.; Petko, W. W.; Cornfeldt, M.; Wilker, J . C.; Blitzeer,
R. D.; Landau, E.; Haroutunian, V.; Martin, L. L.; Effland, R. C. J .
Med. Chem. 1996, 39, 570. (l) Belley, M.; Scheigetz, J .; Dub e´ , P.;
Dolman, S. Synlett 2001, 2, 222.
(7) (a) Carpino, L. A. J . Org. Chem. 1965, 30, 321. (b) Carpino, L.
A. J . Org. Chem. 1965, 30, 736.
(8) Hunt, J . Unpublished results.
1
0.1021/jo035587p CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/17/2004
1
368
J . Org. Chem. 2004, 69, 1368-1371

TABLE 2. N-Am in o Heter ocycles P r ep a r ed w ith NH 2Cl
a
Method A: 1.2 equiv of NaH as base. Method B: 2.0 equiv of KOtBu as base. b Isolated. c HPLC conditions: (YMC S5 ODS-A,
d
4
.6 mm × 50 mm; 10% MeOH/water/0.2% H3PO4 gradient to 90% MeOH/water/0.2% H3PO4, 4 mL/min, 8 min gradient, 220 nm). 3l
decomposed rapidly in air.
stream contains the highly toxic 2,4-dinitrophenol,10
which is also potentially explosive.11 Finally, only 8.1%
We were intrigued by several communications report-
2
ing the amination of amides with monochloramine (NH -
(NH
2
content by mass) of 1 is used in the reaction,
Cl) for the synthesis of acylhydrazines.15 By modifying
making the overall process inefficient. We now report our
this method, we found that treatment of 2a with NaH or
KOtBu (1.2 equiv) followed by anhydrous ethereal NH -
2
+
efforts to identify optimal NH
2
transfer reaction pro-
cesses for the preparation of N-amino heterocycles,
specifically, 1-aminopyrroles and 1-aminoindoles.
Cl (1.2 equiv) produced 3a in greater than 93% conversion
and 89% isolated yield on 1-mmol scale (Table 1, entries
9 and 10). To our knowledge, this represents the first
Utilizing diethyl 3-methylpyrrole-2,4-dicarboxylate (2a )
+
as a test substrate, we surveyed several NH
2
transfer
application of NH
tions. Ethereal NH
NH
OH, and bleach,16 and the reaction byproducts are
2
Cl for aromatic heterocycle N-amina-
reagents for the synthesis of 3a (Table 1). Under similar
conditions as those using 1, the commercially available
HOSA gave moderate conversion of 2a to 3a (entry 2).
Phase transfer catalyzed reactions (entries 5 and 6) gave
poor yields of 3a , as did 3,3′-di-tert-butyloxaziri-
2
Cl is readily prepared from NH Cl,
4
4
enviromentally benign. Furthermore, this transformation
is highly efficient: 31% of the reagent is consumed in
the reaction as compared to 8.1% for 1.
Following this discovery, we sought to apply this
reaction to other heterocyclic systems containing an
acidic NH. As detailed in Table 2, this reaction works
well for pyrroles (entries 1-4) containing a variety of
functional groups. Diethyl 3-methoxypyrrole-2,4-dicar-
boxylate (2b) and diethyl 3-trifluoromethylpyrrole-2,4-
dine13 (entry 8). O-(Mesitylenesulfonyl)-hydroxylamine
5
(
(
MtsONH
DppONH
2
) and O-(diphenylphosphinyl)-hydroxylamine
6
2
) did not offer a synthetic advantage over 1
1
4
and were not pursued for large-scale reactions.
(9) Compound 1 has a reported decomposition onset temperature
of 90-110 °C with an energy of 2308 J /g; see ref 1. Subsequent studies
in our laboratories confirmed these results, although a lower energy
of decomposition was observed: 1269 J /g, onset 105 °C.
(15) (a) Metlesics, W.; Tavares, R. F.; Sternbach, L. H. J . Org. Chem.
1965, 30, 1311. (b) Karady, S.; Ly, M. G.; Pines, S. H.; Sletzinger, M.
J . Org. Chem. 1971, 36, 1949. (c) Khatib, A. A.; Sisler, H. H. Inorg.
Chem. 1990, 29, 309.
(16) (a) J affari, G. A.; Nunn, A. J . J Chem. Soc. C 1971, 823. (b)
Goehring, R. R. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 2, pp 1052-1053.
(c) See also: Theilacker, W.; Wegner, E. Angew. Chem. 1960, 72, 127.
(
(
10) Rat oral LD50 ) 30 mg/kg.
11) Detonation of a reaction using 1 and KH has been reported:
Radhakrishna, A. S.; Loudon, G. M. J Org. Chem. 1979, 44, 4836.
12) We have adopted the annotation of Friestad for the compounds
in Figure 1; see ref 2.
(
(
(
13) Choong, I. C.; Ellman, J . A. J . Org. Chem. 1999, 64, 6528.
14) DppONH has given similar results as 1.
2
J . Org. Chem, Vol. 69, No. 4, 2004 1369

SCHEME 1. Rea ction s of N-Am in op yr r ole 3a
TABLE 3. Rela tion sh ip Betw een Ba se a n d
Ch lor op yr r ole (4) F or m a tion
NH2Cl
(equiv)
KOtBu
(equiv)
yield 3a
(%)
yield 4
(%)
entry
pH
1
2
1.2
1.2
1.0
2.0
3-4
11
75
95
25
<5
to the problem of poor conversion for indole and indoles
j-l, we found that by using 2 equiv of KOtBu and
freshly prepared NH Cl, N-amination of these molecules
was instantaneous with no additional conversion after 2
min. Additionally, reaction concentration had a signifi-
cant effect for the synthesis of 3i. Reduced initial
concentration in DMF led to higher conversion levels
2
2
dicarboxylate (2c, entries 1 and 2) were aminated in 88%
yield, whereas 2-cyanopyrrole (entry 3) was N-aminated
3
i
with high conversion (>95% HPLC) to afford 3d , albeit
in low isolated yield.17 Chemoselective pyrrole N-amina-
tion in the presence of a pendant monosubstituted amide
(entries 8b-d) as a result of increased solubilization of
a
was anticipated on the basis of pK differences of the
the formed indole anion. These improved conditions
allowed for a 72% isolated yield of 3i.
pyrrole18 and amide NH. As shown in entry 4, N-
amination of 2e afforded 3e in high yield; amination of
the C-2 amide nitrogen was not observed.
Having demonstrated the generality of this reaction,
we next turned to multigram-scale reactions. The pre-
Indoles containing electron-withdrawing groups were
N-aminated in high yield (entries 5-7) under the stan-
dard conditions. Of noteworthy importance, 3-acetyl
indole (2h ), previously reported to be inert to N-amina-
tion using HOSA,3d underwent rapid conversion in high
yield to 3h using this method. Indole (2i, entry 8a)
reacted to 50% conversion using NaH as base. Similarly,
2Cl in ether was reevaluated
ferred solvent system of NH
along with alternatives to CaCl as a drying agent for
2
the NH Cl preparation. The solubility of NH Cl in THF,
2
2
MTBE, ethyl acetate, toluene, and water was determined
to be 0.17, 0.09, 0.12, 0.05, and 0.04 M, respectively.
20
Evaluation of these solutions for the conversion of 2a to
3a revealed that MTBE solutions gave conversion levels
equivalent to ether/NH Cl solutions. Ethyl acetate/NH -
5
-cyanoindole (2j, entry 9a), 7-aza-indole (2k , entry 10a),
2
2
and 5-fluoroindole (2l, entry 11a) also halted at moderate
levels of conversion. Although these levels of conversion
are comparable to aminations of indoles using HOSA or
Cl solutions proceeded to a maximal 40-45% conversion,
whereas THF, toluene, and water solutions of NH Cl
2
failed to give substantial conversion to 3a . K CO was
2
3
3
d,6a
DppONH
2
,
demonstration of this reagent as a supe-
found to be an equivalent drying agent to CaCl , giving
2
solutions with <0.03% water.21 The concentration of NH2-
rior alternative to the existing methods would require
higher levels of conversion and isolated yields. We
therefore focused our efforts on the amination of indole
Cl routinely obtained in MTBE dried with K CO was
2
3
0.12M.
(
2i) to demonstrate the generality of this methodology.
Attempts were made to enhance conversion with ad-
ditional NH Cl and/or NaH; however, these all failed.
On a 5-g scale, amination of 2a proceeded rapidly with
95% HPLC conversion to 3a . However, following a water
quench, extractive workup, and concentration, the start-
ing pyrrole 2a was recovered. Assessment of the stability
of 3a under the reaction conditions revealed that 3a
2
Extended reaction times (16 h) did not increase the
overall conversion nor did extended exposure to NaH
before NH
2
2
Cl addition. We initially theorized that poor
differences of
reacts with excess NH
which can be reverted to the aminopyrrole by treatment
with aqueous Na (Scheme 1). Accordingly, a modi-
fied quenching procedure utilizing aqueous Na was
2
Cl to give an oxidation product,
2
conversion could be explained by the pK
a
indole and the substituted indoles in Table 1. However,
another possibility is that 1-aminoindole under these
conditions is not stable,19 and in the case of a slowly
reacting substrate, N-deamination becomes a competitive
process. This reverse process is not unprecedented. In
two separate reports, Somei and Belley have observed
the deamination of 1-aminoindoles in the presence of base
or for extended reaction times.3 N-Deamination has also
been observed for 3a . When exposed to 2 equiv of KOtBu
in DMF, 3a decomposes almost quantitatively to pyrrole
2 2 3
S O
2
2 3
S O
employed allowing for isolation of 3a in 86% yield and
99.5% purity.
Subsequent studies also revealed that in the presence
2
of an excess of NH Cl relative to base (Table 3, entry 1)
lower yields of 3a were achieved and a new product,
diethyl 2-chloro-4-methylpyrrole-3,5-dicarboxylate (4,
Scheme 1), was observed. Control experiments with
aqueous HCl confirmed our hypothesis that 3a was
degraded under the acidic reaction conditions to chloro-
pyrrole 4 (Scheme 1). Final modifications using 2.0 equiv
d,l
2
a within 15 min at room temperature (Scheme 1).
Although the mechanism of this reverse process is not
known, this may account for the poor yields associated
with N-aminations of heterocycles with HOSA. Returning
of KOtBu with 1.2-1.4 equiv of NH
2
Cl while maintaining
Cl addition
efficient stirring and N sparge during NH
2
2
were found to be optimal (entry 2), allowing for the
preparation 3a in 90% yield on a 75-g scale.
(
17) Aminopyrrole 3d had significant water solubility contributing
to the poor isolated yield due to losses on workup.
18) The pK of 2a was determined to be 8.7 ( 0.2 using the
spectrophotometric titration method.
19) Aminoindoles 3i and 3l were noticeably less stable than
(
a
(20) The concentration of NH
iodometric titration.
2
Cl in solution was determined by
(
(21) Water content was determined using a Karl Fischer titration
instrument.
(22) This oxidation product was observed by LCMS. Interestingly,
aminoindoles containing electron-withdrawing groups. Extended reac-
tion times were accompanied with significant degradation of product.
This was also observed upon aqueous workup and careful attention
was made to exclude oxygen from the workup process.
amines and alcohols can be oxidized upon prolonged exposure to NH
Cl: 2PhNH + 2NH Cl f PhNdNPh + 2NH Cl; see ref 16a.
2
-
2
2
4
1
370 J . Org. Chem., Vol. 69, No. 4, 2004

In summary, we have discovered and developed a
simplified and practical procedure for the electrophilic
amination of heterocycles using NH Cl, a reagent that
2
3.83 (s, 3 H), 1.32 (t, J ) 7.1 Hz, 3H), 1.27 (t, J ) 7.1 Hz, 3H);
3
1
C NMR (100 MHz, CDCl
05.8, 63.3, 61.0, 60.3, 14.7, 14.7; MS (ESI) m/z 257.0 (M + H),
calcd for C11 256.1.
Dieth yl 1-Am in o-3-tr iflu or om eth ylp yr r ole-2,4-d ica r box-
3
) δ 162.9, 161.7, 151.8, 130.3, 113.3,
1
16 2 5
H N O
is easily prepared from inexpensive precursors. We
believe this alternative N-amination reaction process is
1
yla te (3c). 88% yield; H NMR (400 MHz, CDCl
3
) δ 7.28 (s, 1H),
+
superior to those utilizing HOSA or other synthetic NH
2
4.45 (br s, 2H), 4.23 (q, J ) 7.2 Hz, 2H), 4.12 (q, J ) 7.2 Hz,
1
3
transfer reagents, offering a safer and more economical
synthesis of N-amino heterocycles.
2H), 1.22 (t, J ) 7.2 Hz, 3H), 1.17 (t, J ) 7.2 Hz, 3H); C NMR
100 MHz, CDCl ) δ 162.6, 161.1, 131.2, 123.3, 122.2 (CF , J )
80 Hz), 112.7, 62.5, 61.3, 14.5, 14.1; MS (DCI) m/z 293.9 (M ),
calcd for C11 294.1.
-Am in o-2-cya n op yr r ole (3d ). 44% yield.
Eth yl 1-Am in o-2-(n -p r op ylca r boxa m id o)-3-m eth ylp yr -
(
3
3
+
2
13 2 4 3
H N O F
Exp er im en ta l Section
3i
1
All starting materials were commercial grade and used
1
3
r ole-4-ca r boxyla te (3e). 89% yield; H NMR (400 MHz, CDCl )
2
3
24
without further purification. Pyrroles 2a -e and indole 2g
δ 7.33 (s, 1H), 6.05 (br s, 1H), 4.18 (q, J ) 7.1 Hz, 2H), 3.33 (q,
J ) 6.4 Hz, 2H), 2.47 (s, 3H), 1.57 (m, 2H), 1.26 (t, J ) 7.1 Hz,
are available using known synthetic procedures.
P r ep a r a tion of An h yd r ou s Eth er ea l Mon och lor a m in e.16
13
3
1
H), 0.93 (t, J ) 7.3 Hz, 3H); C NMR (100 MHz, CDCl
3
) δ 164.9,
NH
4
Cl (3 g, 56 mmol) in ether (110 mL) was cooled to -5 °C,
62.6, 130.5, 123.8, 123.1, 111.4, 60.0, 41.5, 23.4, 14.8, 12.2, 11.9;
253.1. Anal.
: C, 56.90; H, 7.56; N, 16.59. Found: C,
7.07; H, 7.50; N, 16.36.
E t h yl 1-Am in o-2-m et h ylin d ole-3-ca r boxyla t e (3f). 88%
and concentrated NH
4
OH (4.7 mL) was added via pipet. Com-
MS (ESI) m/z 254.1 (M + H), calcd for C12
19 3 3
H N O
mercial bleach (Clorox, 72 mL) was then added via addition
funnel over 15 min. The mixture was stirred for 15 min, the
layers were separated, and the organic layer was washed with
brine (1 × 35 mL). The organic layer was dried over powdered
Calcd for C12
5
19 3 3
H N O
1
yield; H NMR (400 MHz, CDCl
H), 4.15 (br s, 2H), 4.29 (q, J ) 7.1 Hz, 2H), 2.61 (s, 3H), 1.36
3
) δ 8.01 (m, 1H), 7.22-7.13 (m,
CaCl in a freezer for 1 h and stored at -40 °C. Approximate
2
3
(
1
concentration is 0.15 M.
13
t, J ) 7.1 Hz, 3H); C NMR (100 MHz, CDCl
36.9, 124.9, 122.5, 122.3, 121.6, 108.6, 102.0, 59.8, 15.0, 11.6;
MS (ESI) m/z 219.1 (M + H), calcd for C12 218.1. Anal.
Calcd for C12 : C, 66.04; H, 6.47; N, 12.84. Found: C,
5.79; H, 6.22; N, 12.57.
Met h yl 1-Am in o-2-m et h yl-7-m et h oxyin d ole-3-ca r b ox-
3
) δ 166.4, 146.8,
Gen er a l Am in a tion P r oced u r e. Dieth yl 1-Am in o-3-m eth -
ylp yr r ole-2,4-d ica r boxyla te (3a ). Meth od A. To a solution
of pyrrole 2a (1 mmol) in DMF (2 mL) was added NaH (1.2
mmol), and the reaction was stirred for 45 min at room
temperature. NH Cl (8 mL, ca. 0.15 M in ether) was added via
2
syringe while maintaining a nitrogen sparge. The reaction was
monitored by HPLC until completion. The reaction was then
14 2 2
H N O
14 2 2
H N O
6
1
yla te (3g). 88% yield; H NMR (400 MHz, CDCl
.1 Hz, 1H), 7.00 (t, J ) 8.1 Hz, 1H), 6.55 (d, J ) 7.9 Hz, 1H),
.25 (br s, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 2.62 (s, 3H); C NMR
) δ 166.8, 146.9, 146.7, 127.2, 125.2, 122.5,
14.4, 103.3, 101.6, 55.8, 51.0, 11.5; MS (ESI) m/z 235.1 (M +
234.1. Anal. Calcd for C12 : C,
1.53; H, 6.02; N, 11.96. Found: C, 61.49; H, 5.85; N, 11.78.
-Am in o-3-a cetylin d ole (3h ). 95% yield; H NMR (400 MHz,
DMSO-d ) δ 8.22 (s, 1H), 8.16 (d, J ) 7.9 Hz, 1H), 7.54 (d, J )
.1 Hz, 1H), 7.27 (t, J ) 8.0 Hz, 1H), 7.20 (t, J ) 7.6 Hz, 1H),
3
) δ 7.62 (d, J )
8
4
quenched with saturated aqueous Na
2
S
2
O
3
, diluted with water,
13
and extracted into ether. The ether layer was dried, filtered, and
(100 MHz, CDCl
3
concentrated in vacuo to give diethyl 1-amino-3-methylpyrrole-
1
1
2
,4-dicarboxylate (3a ) in 89% yield. H NMR (400 MHz, CDCl
3
)
H), calcd for C12
6
H
14
N
2
O
3
14 2 3
H N O
δ 7.57 (s, 1H), 4.85 (br s, 2H), 4.35 (q, J ) 7.1 Hz, 2H), 4.26 (q,
J ) 7.1 Hz, 2H), 2.57 (s, 3H), 1.39 (t, J ) 7.1 Hz, 3H), 1.33 (t,
1
1
1
3
3
J ) 7.1 Hz, 3H); C NMR (100 MHz, CDCl ) δ 164.7, 162.9,
6
1
32.4, 130.7, 120.0, 111.9, 60.8, 60.0, 14.8, 14.7, 14.4; HRMS
8
6
1
+
(
ESI) m/z 240.1200 (M ), calcd for C11
Calcd for C11 : C, 54.99; H, 6.71; N, 11.66. Found: C,
4.65; H, 6.54; N, 11.85. Meth od B. Substitute 2.0 equiv KOtBu
for NaH.
5-g P r oced u r e. Pyrrole 2a (75 g, 0.33 mol) and KOtBu (75
H
16
N
2
O
4
240.1100. Anal.
13
.26 (s, 2 H), 2.42 (s, 3H); C NMR (100 MHz, CDCl
38.0, 137.7, 124.2, 122.9, 122.4, 121.6, 113.2, 110.7, 27.6; MS
O 174.1. Anal. Calcd
O: C, 68.95; H, 5.79; N, 16.08. Found: C, 68.68; H,
3
) δ 192.4,
16 2 4
H N O
5
(
10 2
ESI) m/z 175.1 (M + H), calcd for C10H N
for C10
10 2
H N
7
5
.62; N, 15.92.
g, 0.67 mol) were dissolved in DMF (1.5 L) and stirred for 2 h at
room temperature. While vigorously sparging with nitrogen,
NH Cl (3.3 L, 0.15 M in MTBE) was added in portions of 300
2
mL over 20 min, and the reaction mixture was stirred for 5 min.
HPLC analysis indicated <1% of residual 2a . The reaction was
then added to 2.0 L of aqueous Na S O (100 g/L) while
2 2 3
maintaining the temperature at less than 25 °C. After stirring
overnight, the reaction mixture was allowed to phase split, and
the layers were separated. The aqueous layer was back-extracted
with 1.0 L of MTBE and the combined organic layers were
washed water (2 × 1.0 L). The organic layer was distilled to a
volume of 750 mL to give (3a ) as 95.5 g/L solution in MTBE
3d
1
-Am in oin d ole (3i). 73% yield.
-Am in o-5-cya n oin d ole (3j). 89% yield; H NMR (400 MHz,
) δ 7.93 (s, 1H), 7.52 (d, J ) 8.3 Hz, 1H), 7.46 (dd, J ) 8.4,
.4 Hz, 1H), 7.28 (d, J ) 3.3 Hz, 1H), 6.49 (d, J ) 3.3, 1H), 4.75
1
1
CDCl
1
3
13
(
1
(
6
br s, 2H); C NMR (125 MHz, CDCl
26.0, 124.8, 120.7, 109.7, 102.8, 100.3; MS (ESI) m/z 158.0
M + H), calcd for C 157.1. Anal. Calcd for C : C,
8.77; H, 4.48; N, 26.73. Found: C, 68.10; H, 4.41; N, 26.65.
3
) δ 138.3, 131.7, 126.5,
9
H
7
N
3
9 7 3
H N
3h
1
1
H-P yr r olo[2,3-b]p yr id in e-1-a m in e (3k ). 97% yield.
-Am in o-5-flu or oin d ole (3l). 45% yield; H NMR (400 MHz,
1
DMSO-d
6
) δ 7.45 (q, J ) 4.7 Hz, 1H), 7.33 (d, J ) 3.2 Hz, 1H),
7
6
.27 (dd, J ) 10.0, 2.4 Hz, 1H), 6.99 (dt, J ) 9.3, 2.5 Hz, 1H),
(90% yield).
13
.29 (d, J ) 5.0 Hz, 1H), 5.98 (s, 2H); C NMR (100 MHz,
) δ 157.3, 133.6, 132.0, 126.1, 110.9, 109.7, 105.0, 97.8;
MS (ESI) m/z 151.1 (M + H), calcd for C F 150.1.
Diet h yl 1-Am in o-3-m et h oxyp yr r ole-2,4-d ica r b oxyla t e
DMSO-d
6
1
(
(
3b). 88% yield; H NMR (400 MHz, CDCl
3
) δ 7.30 (s, 1 H), 4.75
8
7 2
H N
br s, 2H), 4.28 (q, J ) 7.1 Hz, 2H), 4.20 (q, J ) 7.1 Hz, 2H),
Ack n ow led gm en t. We gratefully acknowledge the
Department of Discovery Analytical Sciences for HRMS
and pKa determinations and Francis J . Okuniewicz for
thermal evaluations of 1.
(
23) (a) 2a : Suzuki, M.; Miyoshi, M.; Matsumoto, K. J . Org. Chem.
1
974, 39, 1980. (b) 2b: Rappaport, H.; Holden, K. G. J . Am. Chem.
Soc. 1962, 84, 635. (c) 2c: Uno, H.; Tanaka, M.; Inoue, T.; Ono, N.
Synthesis 1999, 3, 471. (d) 2d : see ref 3i. (e) 2e: prepared by EDCI/
HOBt-mediated coupling of n-propylamine with 3-methylpyrrole-2,4-
dicarboxylic acid-4-ethyl ester. See: Corwin, A. H.; Viohl, P. J . Am.
Chem. Soc. 1944, 66, 1137.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 3b,c,j,l and 4 and characterization data for 3d ,i,k
and 4. This material is available free of charge via the Internet
at http://pubs.acs.org.
(24) Hynes, J ., J r.; Leftheris, K.; Wu, H.; Pandit, C.; Chen, P.; Norris,
D. J .; Chen, B.-C.; Zhao, R.; Kiener, P. A.; Chen, X.; Turk, L. A.; Patil-
Koota, V.; Gillooly, K. M.; Shuster, D. J .; McIntyre, K. W. Bioorg. Med.
Chem. Lett. 2002, 12, 2399.
J O035587P
J . Org. Chem, Vol. 69, No. 4, 2004 1371