Synthesis of 4(5)-acyl-2-aminoimidazoles and vinylogues

Article abstract of DOI:10.1055/s-2007-990870

A convenient protocol for the preparation of 4(5)-acyl-2-aminoimidazoles and vinylogues is disclosed employing a crystalline imidazole-derived iminophosphorane as the coupling partner in Heck and Sonogashira reactions. For the first time, derivatives of u

Full text of DOI:10.1055/s-2007-990870

3620
PAPER
Synthesis of 4(5)-Acyl-2-aminoimidazoles and Vinylogues
4
(5)-Acyl-2-amin
h
oimidazolesristoph Pöverlein,a Nicolas Jacobi,b Peter Mayer,a Thomas Lindel*b
a
Department of Chemistry and Biochemistry, Faculty of Chemistry and Pharmacy, Ludwig Maximilian University,
Butenandtstr. 5-13, 81377 Munich, Germany
Institute of Organic Chemistry, Faculty of Life Sciences, TU Braunschweig, Hagenring 30, 38106 Brunswick, Germany
Fax +49(531)3917744; E-mail: th.lindel@tu-bs.de
b
Received 1 June 2007
Abstract: A convenient protocol for the preparation of 4(5)-acyl-2-
aminoimidazoles and vinylogues is disclosed employing a crystal-
line imidazole-derived iminophosphorane as the coupling partner in
Heck and Sonogashira reactions. For the first time, derivatives of
urocanic acid bearing a free amino group in the 2¢-position are de-
scribed.
Key words: aminoimidazole, iminophosphorane, cross coupling,
pyrrole-imidazole-alkaloids, alkyne hydration
2-Aminoimidazoles are of interest in the life sciences, be-
cause their guanidine partial structure is embedded in the
aromatic system of an imidazole. Compared to the argin-
ine side chain, the basicity of the guanidine unit of 2-ami-
noimidazole is diminished by 4–5 pKa units, while similar
interactions with biochemical targets can be expected.
Marine sponges make use of this technology.1 Recently,
we have synthesized the new amino acid 2¢-aminohomo-
histidine (2¢-Ahh) as a less basic analogue of arginine.2
Scheme 1 Crystalline iminophosphorane 2
intermediate azide (Scheme 1). We wondered whether 2
could serve as an easy-to-handle building block for the
synthesis of (4)5-substituted 2-aminoimidazoles.
Indeed, iminophosphorane 2 underwent Heck reactions
with acrylic acid derivatives 3, 6, and 9 giving convenient
access to derivatives of the hitherto unknown 2¢-amino-
urocanic acid (Scheme 2). Deprotection of the crude cou-
pling products 4, 7, and 10 proceeded smoothly on
treatment with trifluoroacetic acid providing 5-TFA, 8-
TFA, and 11-TFA, which were purified by reverse-phase
chromatography and constitute the first examples of uro-
canic acid derivatives bearing a free amino group in the 2¢-
position.
Surprisingly, 2-aminoimidazoles have not played an im-
portant role in medicinal chemistry, possibly due to limit-
tations regarding their synthesis. In particular, knowledge
regarding the chemical functionalization of free 2-ami-
noimidazole is still limited. With regard to the 4(5)-posi-
tion, Horne reported hydroxyalkylations in up to 40%
yields.3 In this study, we address the synthesis of 4(5)-
acyl-2-aminoimidazoles (n = 0, Figure 1) and of deriva-
tives of the physiologically important urocanic acid4
(n = 1) with an additional amino group in the imidazole 2-
position.
X
PdCl2(PPh3)2 (5 mol%), Et3N
+
2
O
DMF, 100 °C, 2 d
N
2'
3: X = OMe
6: X = OEt
9: X = NH2
NH2
X
N
n
H
O
X
n = 0,1
X
CF3CO2
N
TFA–H2O (5:1)
r.t., 3 d
Figure 1 Target structures and retrosynthetic cuts
O
O
H
CPh3
N
N
N
N
2'
H
NH2
Searching for a suitable synthetic equivalent of 2-ami-
noimidazole, we found that the crystalline5 iminophos-
phorane 2 can be obtained from 4-iodo-1-trityl-1H-
imidazole (1) in one step via Staudinger reduction of the
Ph3P
5-TFA: X = OMe (67%)
8-TFA: X = OEt (63%)
11-TFA: X = NH2 (73%)
4: X = OMe
7: X = OEt
10: X = NH2
Scheme 2 Synthesis of 2¢-aminourocanic acid derivatives (yields
over 2 steps)
SYNTHESIS 2007, No. 23, pp 3620–3626
Advanced online publication: 31.10.2007
x
x.
x
x
.
2
0
0
7
DOI: 10.1055/s-2007-990870; Art ID: T09007SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
4(5)-Acyl-2-aminoimidazoles
3621
We anticipated that alkynylation of 2 might provide indi- Formal addition of water to the triple bond was also ob-
rect access to 4(5)-acyl-2-aminoimidazoles, because served on hydrolysis of the putative dehydrooroidin pre-
metal-free hydration of triple bonds is facilitated if they cursor 18,5 prepared via Sonogashira reaction of 2 with
are conjugated to electron-rich aromatic systems.6 This propargylic amine 17. In fact, formation of the acyl com-
would be helpful, because alternative acylation with acid pound could not be avoided. Exclusive formation of the
chlorides is limited to weakly functionalized acyl compo- acyl compound 19-HCl, tautomer of hydroxyoroidin, was
nents.
achieved on hydrolysis of 18 with 6 N hydrochloric acid–
tetrahydrofuran (1:2).
Sonogashira reactions of 2 with model compounds phen-
ylacetylene and propargylic alcohol proceeded smoothly Hydration occurs also in the absence of the iminophos-
affording coupling products 12 and 14 in 62% and 78% phorane group and in the presence of an imidazole N-
yield, respectively (Scheme 3). Deprotection under acidic methyl group, as can be concluded from the behavior of
conditions (TFA–H2O, 5:1) led to immediate removal of the formate of bromodehydrokeramadine (24-HCO2H,
the trityl group. Hydrolysis of the N=P bond was complete prepared via azidation of 2-free imidazole 21 and reduc-
after 24 hours; in the absence of water, only the trityl tion of 22 with Na2S)7 (Scheme 4). On treatment of 24
group was cleaved. 4-(Phenylethynyl)-1H-imidazol-2- with water–ethanol at 95 °C, compound 26, a tautomer of
ylamine trifluoroacetic acid salt (13-TFA) was isolated as ‘hydroxybromokeramadine’, was obtained and converted
the sole, stable product. Even under harsher conditions into the free base by removing formic acid at 40 °C/
[H2O–EtOH (4:1), reflux, 24 h] no acyl compound was 1 mbar; intermediacy of allene 25 is likely. It should be
formed.
noted that under the same conditions the nonmethylated
natural product oroidin, containing an alkene instead of an
alkyne moiety, undergoes intramolecular nucleophilic at-
tack of the pyrrole nitrogen affording cyclooroidin.8
However, the major product obtained on hydrolysis of
propargylic alcohol 14 was acyl compound 16-TFA
(36%), accompanied by smaller amounts of alkyne 15-
TFA (9%). An alternative procedure [HCO2H–H2O (5:1), Compounds 19 and 26 proved to be surprisingly stable
reflux, 24 h] provided 16-HCO2H in higher yield (66%). and survived heating in water, ethanol, or N,N-dimethyl-
CPh3
H
TFA–H2O (5:1),
r.t., 24 h
CF3CO2
N
N
Ph
N
NH2
56% (2 steps)
N
N
PPh3
H
Ph
Ph
13-TFA
12
62%
H
PdCl2(PPh3)2 (5 mol%),
CuI (10 mol%),
i-Pr2NH, THF, r.t., 1–3 d
N
CF3CO2
NH2
N
HO
HO
CPh3
H
TFA–H2O (5:1),
r.t., 24 h
N
HO
15-TFA (9%)
N
+
2
H
N
78%
HO
PPh3
N
CF3CO2
NH2
14
N
HCO2H–H2O (5:1),
reflux, 24 h
H
O
16-TFA (36%)
16-HCO2H
66%
Br
CPh3
N
Br
H
Br
N
N
N
H
N
H
PPh3
Br
17
O
N
N
H
Sonogashira conditions
84%
O
18
Br
H
6 N HCl–THF (1:2),
reflux, 24 h
Cl
N
H
NH2
Br
N
52%
N
N
H
H
O
O
19-HCl
Scheme 3 Synthesis of 4(5)-acyl-2-aminoimidazoles via hydration of the corresponding alkynes
Synthesis 2007, No. 23, 3620–3626 © Thieme Stuttgart · New York

3622
C. Pöverlein et al.
PAPER
were measured with a Perkin-Elmer Lambda-16 UV spectrometer.
Chemicals were purchased from commercial suppliers and used
without further purification. Silica gel 60 (40–63 mm, Merck) and
LiChroprep RP-18 (Merck, 40–63 mm, 94 g, 3-cm column, regener-
ation: MeOH) were used for column chromatography.
N
Br
N
17
X
N
H
Sonogashira
Br
N
I
N
conditions
75%
Me
N
Me
H
O
20
21: X = H
LDA (4 equiv), THF, –78 °C,
30 min, then TsN3, 10 min
N-(4-Iodo-1-trityl-1H-imidazol-2-yl)triphenylphosphora-
nylideneamine (2)
65%
86%
22: X = N3
Na2S, MeOH
A 2.5 M soln of BuLi in hexane (30.0 mL, 75.0 mmol, 1.5 equiv)
was added to a soln of i-Pr2NH (11.3 mL, 80.0 mmol, 1.6 equiv) in
anhyd THF (50 mL) at 0 °C and the soln was stirred for 15 min. At
–78 °C, the LDA soln was added to a soln of 4-iodo-1-trityl-1H-im-
idazole (1, 21.80 g, 50.0 mmol, 1.0 equiv)14 in anhyd THF (300
mL). The mixture was stirred for 1 h and TsN3 (14.80 g, 75.0 mmol,
1.5 equiv)15 was added dropwise. After 10 min, the reaction was
quenched by the addition of aq buffer (pH 7, 50 mL). Solid Ph3P
(19.67 g, 75.0 mmol, 1.5 equiv) was added over 30 min and the mix-
ture was stirred for 24 h. A portion of 2 (usually 20–25%) was isol-
able in analytically pure form by filtration. To the filtrate was added
H2O (500 mL) and THF was removed in vacuo. The resulting sus-
pension was filtered and the solid product was washed with H2O
(200 mL) and aq 2 M HCl (100 mL) and dried in vacuo. To purify
the solid, Et2O (300 mL) was added and the suspension was stirred
for 2 h. The precipitate was filtered, washed (Et2O), and dried. Prod-
uct 2 (28.83 g, 81%) was obtained as a yellow powder; mp 208–209
°C; Rf = 0.30 (CHCl3–EtOAc, 10:1).
23: X = NH2
HCO2H,
quant.
H
H2O–EtOH (4:1),
Br
95 °C, sealed tube,
24 h, 90%
N
HCO2
NH2
N
H
N
Br
Me
N
H
O
24-HCO2H
O
HCO2
C
H
N
N
Br
NH
NH2
N
Me
Br
H
O
H
H
25
Br
IR (ATR): 3155, 3056, 3022, 1577, 1515, 1486, 1446, 1436, 1399,
1363, 1240, 1186, 1149, 1111, 1042, 1027, 999, 928, 904, 749, 730,
720, 691, 668, 639 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.52 (d, J = 2.4 Hz, 1 H, NCHCI),
7.14–7.34 (m, 27 H, Hphenyl), 7.37–7.45 (m, 3 H, Hphenyl).
N
H
N
Br
NH2
N
N
– HCO2H
H
Me
O
O
26
13C NMR (75.5 MHz, CDCl3): d = 74.2, 76.7, 121.5 (d, J = 1.7 Hz),
126.4, 127.2, 127.9 (d, J = 12.6 Hz), 129.6 (d. J = 101.4 Hz), 130.3,
131.3 (d, J = 2.9 Hz), 133.0 (d, J = 10.4 Hz), 143.3, 153.4.
Scheme 4 Hydration of bromodehydrokeramadine (23)
MS (ESI+): m/z (%) = 243 (100), 343 (52), 586 (77), 587 (63), 712
formamide up to 100 °C without degradation. We are cur-
rently exploring the conversion of 19 into the azepinone
stevensine, which would formally proceed via nucleo-
philic attack of the pyrrole carbon at the new carbonyl
group, followed by dehydration.
(16) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C40H32IN3P: 712.1379;
found: 712.1357.
UV/Vis (CHCl3): lmax (log e) = 266 (2.90), 295 nm (2.69).
Anal. Calcd for C40H31IN3P: C, 67.52; H, 4.39; N, 5.91. Found: C,
67.48; H, 4.37; N, 5.84.
Our new synthesis of 4(5)-acyl-2-aminoimidazoles via
iminophosphorane 2 appears to be superior to the two oth-
er approaches already described. Intramolecular ring
opening of N-(1,2,4-oxadiazol-3-yl)-b-enamino ketones9
yields 4-acyl-2-aminoimidazoles only as minor products
if they are 5-unsubstituted.10 Conversion of 4-acyl-2-ami-
nooxazoles into 4-acyl-2-aminoimidazoles occurs on
treatment with ammonia or primary or secondary amines
in 30–60% yields and with the formation of side prod-
ucts.11 Regarding the synthesis of oroidin or keramadine
derivatives, the amino group should be introduced after
the Sonogashira coupling12,13 of 2-free imidazoles 1 or 20
with alkyne 17.
Methyl 3-(2-Amino-1H-imidazol-4-yl)acrylate Trifluoroacetic
Acid Salt (5-TFA); Typical Procedure
Iminophosphorane
2 (712 mg, 1.00 mmol, 1.00 equiv),
PdCl2(PPh3)2 (35.0 mg, 0.05 mmol, 5 mol%), methyl acrylate (3,
0.45 mL, 5.00 mmol, 5.00 equiv), and Et3N (0.3 mL, 2.0 mmol, 2.0
equiv) were dissolved in DMF (40 mL). The mixture was heated in
a sealed tube at 120 °C for 48 h. Consumption was monitored by
TLC. All volatiles were removed. For characterization, a sample
was purified by column chromatography (silica gel, CHCl3–EtOAc,
5:1) yielding 4 as an orange solid; mp 231–232 °C; Rf = 0.42
(CHCl3–EtOAc, 4:1).
IR (ATR): 3150, 3058, 3024, 2948, 1702, 1703, 1621, 1576, 1545,
1514, 1491, 1435, 1374, 1354, 1292, 1266, 1246, 1233, 1216, 1189,
1149, 1125, 1107, 1020, 998, 974, 931, 906, 896, 880, 857, 747,
717, 690, 661, 643 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.67 (s, 3 H, CH3), 6.09 (d,
J = 15.1 Hz, 1 H, COCH), 6.76 (d, J = 2.6 Hz, 1 H, NCCHN), 7.17–
7.34 (m, 28 H, Hphenyl, CHCHCO), 7.37–7.43 (m, 3 H, Hphenyl).
Melting points were determined with a Büchi Melting Point B540
apparatus and are uncorrected. NMR spectra were taken with a
Varian NMR System 300 MHz, a Varian NMR System 400 MHz
Inova 400 and a Varian NMR System 600 MHz [300, 400, and 600
MHz for 1H, 75.7, 100.5, and 150.8 MHz for 13C (referenced to sol-
vent signals or TMS)]. All measurements were carried out at 300 K.
MS spectra were obtained with a Finnigan MAT95Q and a Thermo
Finnigan LTQ FT spectrometer. IR spectra were recorded with a
Perkin-Elmer PE 1600 FT-IR spectrophotometer. UV/Vis spectra
13C NMR (75.5 MHz, CDCl3): d = 50.1, 74.4, 111.1, 122.2, 126.5,
127.2, 127.9 (d, J = 12.4 Hz), 129.3 (d, J = 102.0 Hz), 130.2, 131.4
Synthesis 2007, No. 23, 3620–3626 © Thieme Stuttgart · New York

PAPER
4(5)-Acyl-2-aminoimidazoles
3623
(d, J = 2.5 Hz), 132.7, 133.0 (d, J = 10.2 Hz), 137.9, 143.2, 154.1
(d, J = 3.3 Hz), 168.8.
MS (ESI+): m/z (%) = 670 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C44H37N3O2P: 670.2623;
found: 670.2628.
1H NMR (400 MHz, CD3OD): d = 1.30 (t, J = 7.1 Hz, 3 H, CH3),
4.23 (q, J = 7.1 Hz, 2 H, CH2CH3), 6.27 (dd, J = 16.1, 0.6 Hz, 1 H,
COCH), 7.19 (br s, 1 H, NCHCN), 7.40 (dd, J = 16.1, 0.4 Hz, 1 H,
COCHCH).
13C NMR (100.5 MHz, CD3OD): d = 14.6, 61.9, 118.2, 118.6,
125.5, 130.5, 150.4, 167.9.
UV/Vis (CHCl3): lmax (log e) = 261 (3.11), 361 nm (3.21).
MS (ESI+): m/z (%) = 182 (100) [M + H]+.
The main portion of crude 4 was treated with TFA–H2O (5:1, 6 mL)
for 2 d (monitored by TLC). The mixture was concentrated in vacuo
and MeOH (20 mL) and H2O (20 mL) were added. The suspension
was filtered and purified by chromatography (RP-18, MeOH–H2O
+0.5% TFA, 1:6) yielding 5-TFA (189 mg, 67%) as a yellow solid;
mp 161–162 °C (dec.); Rf = 0.48 (CHCl3–MeOH–NH4OH,
40:10:1).
HRMS (ESI+): m/z [M + H]+ calcd for C8H12N3O2: 182.0930;
found: 182.0921.
3-(2-Amino-1H-imidazol-4-yl)acrylamide Trifluoroacetic Acid
Salt (11-TFA)
Following the typical procedure using iminophosphorane 2 (712
mg, 1.00 mmol, 1.00 equiv), PdCl2(PPh3)2 (35 mg, 0.05 mmol, 5
mol%), acrylamide (355 mg, 5.00 mmol, 5.00 equiv), Et3N (0.3 mL,
2.0 mmol, 2.0 equiv), and DMF (40 mL); time 48 h. For character-
ization, a sample was purified by column chromatography (silica
gel, EtOAc–EtOH–NH3, 10:1:0.1) yielding 10 as yellow solid; mp
162 °C (dec.); Rf = 0.41 (EtOAc–EtOH–NH3, 10:1:0.1).
IR (ATR): 3428, 3339, 3058, 3014, 2948, 2510, 2296, 1678, 1617,
1573, 1539, 1459, 1431, 1312, 1238, 1194, 1156, 1027, 951, 933,
844, 820, 800, 773, 740, 726, 632 cm–1.
1H NMR (400 MHz, CD3OD): d = 3.73 (s, 3 H, CH3), 6.02 (d,
J = 15.7 Hz, 1 H, COCH), 6.91 (s, 1 H, NCCHN), 7.39 (d, J = 15.7
Hz, 1 H, COCHCH).
IR (ATR): 3451, 3054, 1671, 1597, 1551, 1521, 1491, 1436, 1386,
1366, 1267, 1232, 1184, 1152, 1108, 1044, 1026, 999, 976, 936,
906, 882, 856, 812, 746, 717, 691, 666, 648, 614 cm–1.
13C NMR (100.5 MHz, CD3OD): d = 51.9, 111.2, 126.9, 129.7,
135.3, 154.2, 170.2.
1H NMR (600 MHz, CDCl3): d = 5.25 (br s, 2 H, NH2), 6.10 (d,
J = 15.0 Hz, 1 H, COCH), 6.72 (d, J = 2.4 Hz, 1 H, NCCHN), 7.11
(d, J = 15 Hz, 1 H, COCHCH), 7.18–7.19 (m, 9 H, Hphenyl), 7.23–
7.29 (m, 12 H, Hphenyl), 7.30–7.32 (m, 6 H, Hphenyl), 7.40–7.43 (m, 3
H, Hphenyl).
MS (ESI+): m/z (%) = 168 (100) [M +H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C7H10N3O2: 168.0773;
found: 168.0766.
UV/Vis (MeOH): lmax (log e) = 331 nm (3.24).
13C NMR (150.8 MHz, CDCl3): d = 74.3, 113.7, 121.6, 126.5,
127.2, 128.0 (d, J = 12.3 Hz), 129.5 (d, J = 104.5 Hz), 130.2, 131.4,
132.6, 132.9 (d, J = 10.2 Hz), 134.9, 143.3, 153.8, 169.5.
MS (ESI+): m/z (%) = 655 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C43H36N4OP: 655.2627;
Ethyl 3-(2-Amino-1H-imidazol-4-yl)acrylate Trifluoroacetic
Acid Salt (8-TFA)
Following the typical procedure using iminophosphorane 2 (712
mg, 1.00 mmol, 1.00 equiv), PdCl2(PPh3)2 (35 mg, 0.05 mmol, 5
mol%), ethyl acrylate (6, 0.54 mL, 5.00 mmol, 5.00 equiv), Et3N
(0.3 mL, 2.0 mmol, 2.0 equiv), and DMF (40 mL); time: 52 h. For
characterization, a sample was purified by column chromatography
(silica gel, CHCl3–EtOAc, 5:1) yielding 7 as a yellow solid; mp 237
°C; Rf = 0.40 (CHCl3–EtOAc, 4:1).
found: 655.2623.
UV/Vis (CHCl3): lmax (log e) = 267 (3.06), 352 nm (3.09).
The main portion of crude 10 was treated with TFA–H2O (5:1, 6
mL) for 2 d (monitored by TLC) following the typical procedure;
chromatography (RP-18, MeOH–H2O + 0.5% TFA, 1:6) gave 11-
TFA (194 mg, 73%) as a yellow solid; mp 143 °C; Rf = 0.18 (RP-
18, MeOH–H2O, 1:5).
IR (ATR): 3056, 2977, 1688, 1617, 1576, 1541, 1512, 1490, 1437,
1378, 1365, 1246, 1234, 1152, 1124, 1108, 1039, 1025, 999, 970,
933, 883, 816, 746, 719, 690, 667, 624 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.24 (t, J = 7.1 Hz, 3 H, CH3),
4.15 (q, J = 7.1 Hz, 2 H, CH2), 6.07 (d, J = 15.1 Hz, 1 H, COCH),
6.76 (d, J = 2.6 Hz, 1 H, NCCHN), 7.18–7.22 (m, 9 H, Hphenyl),
7.23–7.29 (m, 13 H, Hphenyl, COCHCH), 7.30–7.33 (m, 6 H, Hphenyl),
7.40–7.44 (m, 3 H, Hphenyl).
IR (ATR): 3392, 3311, 3199, 3053, 2795, 1777, 1676, 1638, 1582,
1401, 1186, 1133, 1022, 981, 965, 844, 788, 723, 705 cm–1.
1H NMR (400 MHz, CD3OD): d = 6.37 (d, 3J = 15.9 Hz, 1 H,
3
COCH), 7.12 (s, 1 H, NCHCN), 7.26 (d, J = 15.9 Hz, 1 H, CO-
CHCH).
13C NMR (150.8 MHz, CDCl3): d = 14.5, 59.5, 74.3, 111.6, 122.2,
126.5, 127.2, 127.9 (d, J = 12.4 Hz), 129.3 (d, J = 102.0 Hz), 130.2,
131.4 (d, J = 2.4 Hz), 132.8, 133.0 (d, J = 10.2 Hz), 137.7, 143.3,
154.1 (d, J = 4.3 Hz), 168.4.
MS (ESI+): m/z (%) = 684 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C45H39N3O2P: 684.2780;
13C NMR (100.5 MHz, CD3OD): d = 117.3, 120.9, 125.8, 127.4,
150.3, 169.9.
MS (ESI+): m/z (%) = 153 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C6H9N4O: 153.0776; found:
153.0770.
found: 648.2781.
Sonogashira Reactions
UV/Vis (CHCl3): lmax (log e) = 261 (3.17), 360 nm (3.24).
All reactions were carried out under argon. THF (p.a. quality) was
carefully degassed in a supersonic bath for at least 15 min before
use. The solns of iminophosphorane 2 and of the alkyne component
were degassed for additional 15 min.
The main portion of crude 7 was treated with TFA–H2O (5:1, 6 mL)
for 2 d (monitored by TLC) following the typical procedure; chro-
matography (RP-18, MeOH–H2O + 0.5% TFA, 1:6) gave 8-TFA
(185 mg, 63%) as yellow solid; mp 122–124 °C; Rf = 0.14 (RP-18,
MeOH–H2O, 1:5).
4-(Phenylethynyl)-2-(triphenylphosphoranylideneamino)-1-tri-
tyl-1H-imidazole (12) and 4-(Phenylethynyl)-1H-imidazol-2-
ylamine Trifluoroacetic Acid Salt (13-TFA)
IR (ATR): 3387, 3352, 3326, 3210, 3119, 1786, 1694, 1651, 1621,
1398, 1370, 1330, 1303, 1221, 1189, 1145, 1105, 1037, 1014, 991,
872, 809, 786, 705 cm–1.
Iminophosphorane
2 (712 mg, 1.00 mmol, 1.00 equiv),
PdCl2(PPh3)2 (35.0 mg, 0.05 mmol, 5 mol%), CuI (20.0 mg, 0.10
mmol, 10 mol%), and i-Pr2NH (0.3 mL, 2.0 mmol, 2.0 equiv) were
Synthesis 2007, No. 23, 3620–3626 © Thieme Stuttgart · New York

3624
C. Pöverlein et al.
PAPER
dissolved in THF (40 mL). Phenylacetylene (0.4 mL, 3.5 mmol, 3.5
equiv) in THF (10 mL) was added. After 48 h at r.t. the mixture was
filtered, EtOAc (100 mL) was added and the organic layer was
washed with aq NH4Cl (50 mL) and brine (2 × 50 mL). For charac-
terization of the coupling product 12, the organic layer was dried
(MgSO4), concentrated in vacuo, and purified by chromatography
(silica gel, CHCl3 to CHCl3–EtOAc, 4:1) to give 12 (426 mg, 62%)
as a pale yellow solid; mp 240 °C; Rf = 0.26 (CHCl3–EtOAc, 10:1).
13C NMR (100.5 MHz, DMSO-d6): d = 49.4, 73.7, 80.5, 87.8,
117.0, 120.9, 126.6, 127.2, 128.1 (d, J = 12.2 Hz), 129.0 (d,
J = 101.4 Hz), 129.5, 131.7 (d, J = 2.8 Hz), 132.2 (d, J = 10.2 Hz),
142.7, 152.1 (d, J = 4.3 Hz).
MS (ESI+): m/z (%) = 640 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C43H35N3OP: 640.2518;
found: 640.2492.
UV/Vis (DMSO): lmax (log e) = 267 nm (3.71).
IR (ATR): 3057, 2216, 1590, 1577, 1551, 1516, 1484, 1437, 1433,
1355, 1325, 1237, 1188, 1150, 1124, 1106, 1084, 1068, 1039, 1025,
999, 940, 916, 895, 880, 813, 769, 754, 748, 735, 718, 703, 687,
669, 647 cm–1.
1H NMR (600 MHz, CDCl3): d = 6.83 (d, J = 2.6 Hz, 1 H, NCH-
CN), 7.09–7.20 (m, 25 H, Hphenyl), 7.24–7.26 (m, 5 H, Hphenyl), 7.32–
7.36 (m, 5 H, Hphenyl).
13C NMR (150.8 MHz, CDCl3): d = 74.3, 86.4, 87.8, 117.4, 122.7,
124.2, 126.4, 127.1, 127.2, 127.9, 128.0 (d, J = 12.8 Hz), 129.8 (d,
J = 102.7 Hz), 130.3, 131.3, 131.3 (d, J = 2.5 Hz), 132.8 (d,
J = 10.3 Hz), 143.3, 152.4 (d, J = 5.0 Hz).
4,5-Dibromo-N-prop-2-ynyl-1H-pyrrole-2-carboxamide (17)
To a soln of 2,2,2-trichloro-1-(4,5-dibromo-1H-pyrrol-2-yl)ethan-
one (40.73 g, 0.110 mol, 1.0 equiv)16 in CH2Cl2 (30 mL) were added
Na2CO3 (13.60 g, 0.128 mol, 1.2 equiv) and a soln of propargyl-
amine hydrochloride (11.72 g, 0.128 mol, 1.2 equiv) in MeCN (200
mL). The mixture was stirred at 40 °C until the ketone had been con-
sumed (12 h). H2O (300 mL), aq 2 M HCl (50 mL), and Et2O (1 L)
were added and the phases were separated. The organic layer was
washed with aq 2 M HCl (100 mL) and brine (2 × 100 mL) and
dried (MgSO4). The solvent was removed in vacuo and the resulting
solid was dissolved in CHCl3 (50 mL) at 50 °C. After cooling to 4
°C for 1 h, filtration of the precipitate yielded 17 (26.95 g, 80%) as
a pale yellow solid; mp 184–185 °C (dec.); Rf = 0.88 (hexane–
EtOAc, 1:3).
MS (ESI+): m/z (%) = 686 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C48H37N3P: 686.2725; found:
686.2697.
For in situ deprotection of 12, the organic layer was concentrated in
vacuo and the residue was treated with TFA–H2O (5:1, 6 mL) for 24
h (monitored by TLC). The mixture was concentrated in vacuo and
MeOH (50 mL) and H2O (20 mL) were added. The suspension was
filtered and purified by chromatography (RP-18, MeOH–H2O +
0.5% TFA, 1:2) yielding 13-TFA (165 mg, 56%) as a yellow solid;
Rf = 0.42 (RP-18, MeOH–H2O + 0.5% AcOH, 4:3).
IR (ATR): 3417, 3288, 3148, 3110, 2982, 2938, 2857, 2651, 1632,
1556, 1514, 1432, 1400, 1393, 1347, 1316, 1240, 1216, 979, 914,
814, 762, 678, 638 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.13 (t, J = 2.5 Hz, 1 H,
C≡CH), 4.00 (dd, J = 5.6, 2.5 Hz, 2 H, CH2), 6.94 (d, J = 2.7 Hz,
BrCCH), 8.56 (t, J = 5.5 Hz, 1 H, NHC=O), 12.73 (br s, 1 H, NH-
CBr).
13C NMR (100.5 MHz, DMSO-d6): d = 27.8, 73.0, 81.0, 97.8,
104.9, 112.9, 127.5, 158.4.
MS (ESI–): m/z (%) = 303/305/307 (37/100/37) [M – H]–.
HRMS (ESI–): m/z [M – H]– calcd for C8H579Br81BrN2O: 304.8748;
IR (ATR): 3337, 3193, 1778, 1686, 1489, 1445, 1197, 1138, 1023,
787, 775, 753, 724, 702, 688 cm–1.
1H NMR (400 MHz, CD3OD): d = 7.09 (s, 1 H, NCHCN), 7.35–
7.41 (m, 3 H, Hphenyl), 7.47–7.51 (m, 2 H, Hphenyl).
13C NMR (100.5 MHz, CD3OD): d = 76.5, 94.9, 111.0, 118.6,
122.9, 129.8, 130.5, 132.5, 148.8.
found: 304.8758.
UV/Vis (CHCl3): lmax (log e) = 278 nm (3.75).
MS (ESI+): m/z (%) = 184 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C11H10N3: 184.0875; found:
184.0866.
4,5-Dibromo-N-{3-[2-(triphenylphosphoranylideneamino)-1-
trityl-1H-imidazol-4-yl]prop-2-ynyl}-1H-pyrrole-2-carbox-
amide (18)
UV/Vis (MeOH): lmax (log e) = 238 (4.02), 285 (4.10), 300 nm
(4.10).
Iminophosphorane 2 (3.56 g, 5.00 mmol, 1.00 equiv), PdCl2(PPh3)2
(175 mg, 0.25 mmol, 5 mol%), CuI (95 mg, 0.50 mmol, 10 mol%),
and i-Pr2NH (1.5 mL, 10 mmol, 2.0 equiv) were dissolved in THF
(200 mL). Alkyne 17 (2.14 g, 7.00 mmol, 1.4 equiv) in THF (50
mL) was added. After 48 h at r.t. the mixture was filtered, EtOAc
(250 mL) was added, and the organic layer was washed with aq
NH4Cl (250 mL), and brine (2 × 150 mL). The organic layer was
dried (MgSO4), concentrated in vacuo, and purified by chromatog-
raphy (silica gel, CHCl3 to CHCl3–EtOAc, 1:1) to give 18 (3.72 g,
84%) as a pale yellow solid; mp 187–188 °C; Rf = 0.29 (CHCl3–
EtOAc, 1:1).
3-[2-(Triphenylphosphoranylideneamino)-1-trityl-1H-imida-
zol-4-yl]prop-2-yn-1-ol (14)
Iminophosphorane 2 (3.56 g, 5.00 mmol, 1.00 equiv), PdCl2(PPh3)2
(175 mg, 0.25 mmol, 5 mol%), CuI (95 mg, 0.50 mmol, 10 mol%),
and i-Pr2NH (1.5 mL, 10 mmol, 2.0 equiv) were dissolved in THF
(200 mL). Propargyl alcohol (1.2 mL, 20 mmol, 4.0 equiv) in THF
(20 mL) was added. After 48 h at r.t. the mixture was filtered and
concentrated in vacuo (important: no aqueous workup!). To the res-
idue CHCl3 (50 mL) and EtOAc (50 mL) were added. The mixture
was stirred at 40–45 °C for 30 min, then cooled to 4 °C and the
brown precipitate was filtered. The solid was dissolved in THF (100
mL) and purified by filtration through a small pad of silica gel
(height, ca. 5 cm, diameter 4 cm) to give 14 (2.49 g, 78%) as a pale
yellow solid; mp 208 °C (dec.); Rf = 0.56 (EtOAc).
IR (ATR): 3117, 3053, 3028, 1639, 1576, 1565, 1517, 1491, 1444,
1392, 1362, 1322, 1246, 1156, 1140, 1108, 1044, 1025, 999, 976,
942, 843, 745, 718, 691, 650, 619 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 4.08 (d, J = 5.3 Hz, 2 H, CH2),
6.51 (d, J = 2.4 Hz, 1 H, NCCHN), 6.87 (s, 1 H, BrCCH), 7.16–7.25
(m, 21 H, Hphenyl), 7.29–7.36 (m, 6 H, Hphenyl), 7.45–7.51 (m, 3 H,
IR (ATR): 3165, 3059, 2994, 2837, 2226, 1736, 1577, 1558, 1513,
1491, 1436, 1390, 1366, 1311, 1236, 1184, 1163, 1142, 1112, 1056,
1041, 1023, 995, 934, 917, 883, 752, 735, 722, 691 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 4.08 (d, J = 5.8 Hz, 2 H,
CH2OH), 5.00 (t, J = 5.8 Hz, 1 H, OH), 6.51 (d, J = 2.5 Hz, 1 H,
NCCHN), 7.13–7.26 (m, 21 H, Hphenyl), 7.30–7.26 (m, 6 H, Hphenyl),
7.46–7.51 (m, 3 H, Hphenyl).
Hphenyl), 8.26 (t, J = 5.0 Hz, 1 H, NHCO), 12.46 (s, 1 H, BrCNH).
13C NMR (100.5 MHz, DMSO-d6): d = 28.5, 73.5, 78.7, 84.1, 97.5,
104.2, 112.7, 116.6, 120.9, 126.3, 126.8, 127.5, 127.7 (d, J = 12.2
Hz), 128.9 (d, J = 101.6 Hz), 129.2, 131.3, 131.9 (d, J = 10.2 Hz),
142.6, 151.8, 158.0.
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PAPER
4(5)-Acyl-2-aminoimidazoles
3625
MS (ESI+): m/z (%) = 888/890/892 (36/100/55) [M + H]+.
HRMS-ESI+: m/z [M + H]+ calcd for C48H3779Br2N5OP: 888.1102;
4,5-Dibromo-N-[3-(2-amino-1H-imidazol-4-yl)-3-oxopropyl]-
1H-pyrrole-2-carboxamide Hydrochloric Acid Salt (19-HCl)
A soln of 18 (445 mg, 0.50 mmol) in THF–6 M HCl (2:1, 30 mL)
was refluxed for 24 h (monitored by TLC). After cooling to r.t., H2O
(250 mL), MeOH (50 mL), and Et2O (400 mL) were added. The
phases were separated and the aqueous layer was washed with Et2O
(2 × 200 mL). The mixture was concentrated in vacuo and the resi-
due was dissolved in MeOH (20 mL) and H2O (20 mL). Purification
by chromatography (RP-18, H2O + 0.5% AcOH–MeOH, 2:1) gave
19-HCl (115 mg, 52%) as a pale yellow solid; mp 242–244 °C
(dec.); Rf = 0.33 (RP-18, MeOH–H2O + 0.5% AcOH, 4:3).
found: 888.1086.
UV/Vis (CHCl3): lmax (log e) = 274 nm (3.36).
1-(2-Amino-1H-imidazol-4-yl)-3-hydroxypropan-1-one Acid
Salts 16
Method 1: Alcohol 14 (538 mg, 0.84 mmol) was treated with TFA–
H2O (5:1, 6 mL) for 24 h (monitored by TLC). The mixture was
concentrated in vacuo and MeOH (50 mL), H2O (250 mL), and
Et2O (300 mL) were added. The phases were separated and the
aqueous layer was washed with Et2O (2 × 150 mL). The aqueous
layer was concentrated in vacuo and the residue was purified by
chromatography (RP-18, MeOH–H2O + 0.5% TFA, 1:8) to give 15-
TFA (20 mg, 9%) and acyl compound 16-TFA (82 mg, 36%) as yel-
low solids.
IR (ATR): 3301, 3116, 2897, 1699, 1657, 1612, 1578, 1533, 1420,
1396, 1339, 1243, 1202, 1082, 980, 947, 810, 750, 685 cm–1.
1H NMR (400 MHz, CD3OD): d = 3.05 (t, J = 6.7 Hz, 2 H, COCH2),
3.65 (t, J = 6.7 Hz, 2 H, CH2NH), 6.77 (s, 1 H, BrCCH), 7.79 (s, 1
H, NCCHN).
Method 2: Alcohol 14 (320 mg, 0.50 mmol) was heated with
HCO2H–H2O (5:1, 10 mL) under reflux for 24 h (monitored by
TLC). The mixture was concentrated in vacuo and MeOH (5 mL)
and H2O (20 mL) were added. The resulting suspension was filtered
and the residue was diluted with MeOH (5 mL) and H2O (20 mL)
once again. The filtrate was purified by RP-chromatography (RP-
18, MeOH–H2O + 0.5% HCO2H, 1:4) to give 16-HCO2H (66 mg,
66%).
13C NMR (100.5 MHz, CD3OD): d = 36.1, 38.9, 100.0, 106.2,
114.3, 122.6, 128.66, 128.68, 150.2, 161.8, 188.7.
MS (ESI+): m/z (%) = 404/406/408 (36/100/56) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C11H1279Br2N5O2: 403.9358;
found: 403.9340.
UV/Vis (MeOH): lmax (log e) = 280 nm (4.26).
4,5-Dibromo-N-[3-(2-amino-1H-imidazol-4-yl)-3-oxopropyl]-
1H-pyrrole-2-carboxamide
To obtain the free base, a small portion of 19 was purified by chro-
matography (silica gel, CH2Cl2–MeOH–NH4OH, 20:10:1).
1-(2-Amino-1H-imidazol-4-yl)-3-hydroxypropan-1-one
Trifluoroacetic Acid Salt (16-TFA)
Rf = 0.68 (RP-18, MeOH–H2O + 0.5% TFA, 1:5).
1H NMR (400 MHz, CD3OD): d = 3.00 (t, J = 6.7 Hz, 2 H, COCH2),
3.64 (t, J = 6.7 Hz, 2 H, CH2NH), 6.77 (s, 1 H, BrCCH), 7.66 (s, 1
H, NCCHN).
13C NMR (100.5 MHz, CD3OD): d = 36.5, 38.7, 100.0, 106.2,
114.4, 128.8, 129.3, 145.6, 147.4, 161.8, 188.7.
IR (ATR): 3310, 3149, 1787, 1698, 1654, 1614, 1428, 1392, 1308,
1177, 1123, 1044, 1020, 927, 830, 798, 721 cm–1.
1H NMR (600 MHz, CD3OD): d = 2.94 (t, J = 6.0 Hz, 2 H, CH2CO),
3.91 (t, J = 6.0 Hz, 2 H, CH2OH), 7.79 (s, 1 H, NCCHN).
13C NMR (150.8 MHz, CD3OD): d = 41.9, 58.5, 122.7, 129.1,
150.4, 189.2.
4,5-Dibromo-N-[3-(3-methyl-3H-imidazol-4-yl)prop-2-ynyl]-
1H-pyrrole-2-carboxamide (21)
MS (ESI+): m/z (%) = 156 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C6H10N3O2: 156.0773;
5-Iodo-1-methyl-1H-imidazole (20, 416 mg, 2.00 mmol, 1.0
equiv),17 PdCl2(PPh3)2 (70.0 mg, 0.10 mmol, 5 mol%), CuI (39.0
mg, 0.20 mmol, 10 mol%), and i-Pr2NH (0.6 mL, 4.3 mmol, 2
equiv) were dissolved in THF (50 mL). Alkyne 17 (857 mg, 2.80
mmol, 1.4 equiv) in THF (20 mL) was added. After 48 h at r.t. the
mixture was filtered, concentrated in vacuo, and purified by chro-
matography (silica gel, CHCl3–MeOH, 25:1) to give 21 (580 mg,
75%) as a colorless solid; mp 215 °C (dec.); Rf = 0.12 (EtOAc).
found: 156.0766.
1-(2-Amino-1H-imidazol-4-yl)-3-hydroxypropan-1-one (16)
To obtain the free base, a small portion of 16 was purified by chro-
matography (silica gel, CHCl3–MeOH–NH4OH, 40:10:1).
1H NMR (400 MHz, CD3OD): d = 2.86 (t, J = 6.3 Hz, 2 H, CH2CO),
3.88 (t, J = 6.3 Hz, 2 H, CH2OH), 7.51 (s, 1 H, NCCHN).
IR (ATR): 3148, 3108, 3060, 2950, 2851, 2769, 2653, 2357, 2335,
1652, 1568, 1530, 1487, 1429, 1416, 1402, 1347, 1310, 1281, 1240,
1223, 1117, 1059, 971, 919, 832, 760, 753 cm–1.
13C NMR (100.5 MHz, CD3OD): d = 41.6, 59.5, 130.5, 136.5,
155.5, 188.8.
3-(2-Amino-1H-imidazol-4-yl)prop-2-yn-1-ol Trifluoroacetic
Acid Salt (15-TFA)
Rf = 0.63 (RP-18, MeOH–H2O + 0.5% TFA, 1:5).
1H NMR (400 MHz, DMSO-d6): d = 3.61 (s, 3 H, NCH3), 4.32 (d,
J = 5.5 Hz, 2 H, CH2NH), 6.97 (s, 1 H, BrCCH), 7.20 (s, 1 H,
NCCHN), 7.72 (s, 1 H, NCHN), 8.69 (t, J = 5.5 Hz, 1 H, CH2NH),
12.78 (br s, 1 H, BrCNH).
13C NMR (100.5 MHz, DMSO-d6): d = 28.8, 31.5, 70.2, 93.8, 97.9,
105.0, 112.9, 114.9, 127.5, 133.3, 139.0, 158.5.
IR (ATR): 3288, 3154, 3025, 2769, 2238, 1788, 1667, 1435, 1356,
1187, 1133, 1043, 1008, 914, 839, 796, 721 cm–1.
1H NMR (600 MHz, CD3OD): d = 4.38 (s, 2 H, CH2), 7.01 (s, 1 H,
NCCHN).
MS (ESI+): m/z (%) = 385/387/389(38/100/50) [M + H]+.
13C NMR (150.8 MHz, CD3OD): d = 51.0, 72.1, 94.7, 110.6, 118.7,
148.7.
HRMS (ESI+): m/z [M + H]+ calcd for C12H1179Br2N4O: 384.9300;
found: 384.9285.
MS (ESI+): m/z (%) = 138 (100) [M + H]+.
UV/Vis (DMSO): lmax (log e) = 274 nm (3.23).
HRMS (ESI+): m/z [M + H]+ calcd for C6H8N3O: 138.0667; found:
138.0661.
N-[3-(2-Azido-3-methyl-3H-imidazol-4-yl)prop-2-ynyl]-4,5-di-
bromo-1H-pyrrole-2-carboxamide (22)
A 2.5 M soln of BuLi in hexane (1.6 mL, 4.0 mmol, 4.0 equiv) was
added to a soln of i-Pr2NH (0.59 mL, 4.2 mmol, 4.2 equiv) in anhyd
THF (5 mL) at 0 °C and the soln was stirred for 15 min. At –78 °C,
Synthesis 2007, No. 23, 3620–3626 © Thieme Stuttgart · New York

3626
C. Pöverlein et al.
PAPER
the LDA soln was added to a soln of 21 (386 mg, 1.00 mmol, 1.0
equiv) in anhyd THF (70 mL). The mixture was stirred for 0.5 h and
TsN3 (296 mg, 1.50 mmol, 1.5 equiv)15 was added dropwise. After
10 min, the reaction was quenched by addition of aq buffer (pH 7,
15 mL) and brine (20 mL). The mixture was extracted with EtOAc
(3 × 50 mL) and the combined organic layers were dried (MgSO4),
concentrated in vacuo, and purified by chromatography (silica gel,
CHCl3–EtOAc, 1:1) to give 22 (278 mg, 65%) as a yellow solid;
Rf = 0.76 (EtOAc).
1H NMR (400 MHz, DMSO-d6): d = 2.86 (t, J = 6.8 Hz, 2 H,
CH2CH2NH), 3.36 (br s, 2 H, NH2), 3.47 (dt, J = 5.6, 6.8 Hz, 2 H,
CH2CH2NH), 3.58 (s, 3 H, NCH3), 6.88 (s, 1 H, BrCCH), 7.72 (s, 1
H, NCCHN), 8.24 (t, J = 5.6 Hz, 1 H, CH2NH), 12.68 (s, 1 H, BrC-
NH).
13C NMR (100.5 MHz, DMSO-d6): d = 30.7, 35.3, 37.9, 97.7,
104.3, 112.5, 125.9, 128.0, 136.1, 153.7, 158.7, 185.9.
MS (ESI+): m/z (%) = 418/420/422 (42/100/52) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C12H1479Br2N5O2: 417.9514;
IR (ATR): 3122, 2950, 2851, 2653, 2357, 2138, 1628, 1555, 1563,
1407, 1385, 1308, 1210, 1152, 1084, 974, 823, 749 cm–1.
found: 417.9488.
1H NMR (400 MHz, DMSO-d6): d = 3.35 (s, 3 H, NCH3), 4.31 (d,
J = 5.5 Hz, 2 H, CH2NH), 6.96 (s, 1 H, BrCCH), 7.14 (s, 1 H,
NCCHN), 8.68 (t, J = 5.5 Hz, 1 H, CH2NH), 12.77 (br s, 1 H, BrC-
NH).
Acknowledgment
C. Pöverlein thanks Universität Bayern e.V. for a doctoral stipend.
13C NMR (100.5 MHz, DMSO-d6): d = 28.8, 29.8, 70.0, 94.1, 97.9,
105.1, 112.9, 114.4, 127.4, 131.5, 140.1, 158.5.
MS (ESI–): m/z (%) = 424/426/428 (47/100/45) [M – H]–.
References
(1) Reviews on the pyrrole-imidazole alkaloids, see:
(a) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001,
237. (b) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753.
(c) Jacquot, D. E. N.; Lindel, T. Curr. Org. Chem. 2005, 9,
1551.
HRMS (ESI–): m/z [M – H]– calcd for C12H879Br2N7O: 423.9157;
found: 423.9152.
UV/Vis (MeOH): lmax (log e) = 276 nm (3.33).
(2) Friedel, M.; Lindel, T. Tetrahedron Lett. 2004, 45, 2779.
(3) Xu, Y.; Yakushijin, K.; Horne, D. A. Tetrahedron Lett.
1993, 34, 6981.
(4) Walterscheid, J. P.; Nghlem, D. X.; Kazimi, N.; Nutt, L. K.;
McConkey, D. J.; Norval, M.; Ullrich, S. E. Proc. Natl.
Acad. Sci. U.S.A. 2006, 103, 17420; and references cited
therein.
(5) CCDC numbers: 644864 (2), 644865 (18).
(6) Hydration of phenylacetylenes: Le Bras, G.; Provot, O.;
Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron Lett.
2006, 47, 5497; and references cited therein.
(7) Belinka, B. A.; Hassner, A. J. Org. Chem. 1979, 44, 4712.
(8) Pöverlein, C.; Breckle, G.; Lindel, T. Org. Lett. 2006, 8, 819.
(9) (a) Ruccia, M.; Vivona, N.; Cusmano, G. Tetrahedron Lett.
1972, 13, 4959. (b) Ruccia, M.; Vivona, N.; Cusmano, G.
Tetrahedron 1974, 30, 3839. (c) Vivona, N.; Buscemi, S.;
Frenna, V.; Ruccia, M. J. Chem. Soc., Perkin Trans. 1 1986,
17.
N-[3-(2-Amino-3-methyl-3H-imidazol-4-yl)prop-2-ynyl]-4,5-di-
bromo-1H-pyrrole-2-carboxamide (23)
A soln of azide 22 (200 mg, 0.47 mmol, 1.0 equiv) and Na2S·9 H2O
(1.13 g, 4.7 mmol, 10 equiv) in MeOH (20 mL) was stirred at r.t. for
18 h. BuOH (150 mL) and brine (50 mL) were added. The organic
layer was separated, washed with brine (3 × 50 mL), concentrated
in vacuo, and purified by chromatography (silica gel, CHCl3–
MeOH–NH4OH, 70:10:1) to give 23 (162 mg, 86%) as a yellow sol-
id; mp 190–193 °C (dec.); Rf = 0.28 (CHCl3–MeOH–NH4OH,
70:10:1).
IR (ATR): 3411, 3148, 3104, 3049, 2945, 2851, 2665, 2356, 2330,
2214, 1644, 1559, 1516, 1432, 1405, 1396, 1350, 1309, 1241, 1215,
1056, 977, 922, 812, 752 cm–1.
1H NMR (400 MHz, CD3OD): d = 3.40 (s, 3 H, NCH3), 4.33 (s, 2
H, CH2NH), 6.81 (s, 1 H, BrCCH), 6.90 (s, 1 H, NCCHN).
13C NMR (100.5 MHz, CD3OD): d = 30.2, 30.3, 70.8, 94.4, 100.1,
106.6, 113.0, 114.7, 123.8, 128.4, 149.7, 161.4.
(10) Braun, M.; Büchi, G.; Bushey, D. F. J. Am. Chem. Soc. 1978,
100, 4208.
MS (ESI+): m/z (%) = 400/402/404(33/100/47) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C12H1279Br2N5O: 399.9409;
found: 399.9389.
(11) LaMattina, J. L.; Mularski, C. J. Tetrahedron Lett. 1984, 25,
2957.
(12) Breckle, G.; Polborn, K.; Lindel, T. Z. Naturforsch. B:
UV/Vis (MeOH): lmax (log e) = 275 nm (3.28).
Chem. Sci. 2003, 58, 451.
(13) (a) Lindel, T.; Hochgürtel, M. Tetrahedron Lett. 1998, 39,
2541. (b) Lindel, T.; Hochgürtel, M. J. Org. Chem. 2000, 65,
2806.
(14) Kirk, K. L. J. Heterocycl. Chem. 1985, 22, 57.
(15) Pollex, A.; Hiersemann, M. Org. Lett. 2005, 7, 5705.
(16) (a) Bailey, D. M.; Johnson, R. E.; Albertson, N. F. Org.
Synth. Coll. Vol. VI; John Wiley & Sons: London, 1988,
618. (b) Bailey, D. M.; Johnson, R. E. J. Med. Chem. 1973,
16, 1300.
N-[3-(2-Amino-3-methyl-3H-imidazol-4-yl)-3-oxopropyl]-4,5-
dibromo-1H-pyrrole-2-carboxamide (26)
To a soln of alkyne 23 (40 mg, 0.10 mmol) in MeOH (1 mL) was
added HCO2H (0.1 mL) and the soln was concentrated in vacuo.
The formate was dissolved in H2O–EtOH (4:1, 40 mL) and heated
for 24 h in a sealed tube. The mixture was filtered and concentrated
in vacuo to give 26 (38 mg, 90%) as a slightly brown solid; Rf = 0.30
(CHCl3–MeOH–NH4OH, 70:10:1).
(17) Holden, K. G.; Mattson, M. N.; Hoi Cha, K.; Rapoport, H. J.
Org. Chem. 2002, 67, 5913.
IR (ATR): 3114, 3039, 1713, 1680, 1655, 1560, 1519, 1390, 1318,
1235, 1191, 1135, 1096, 1000, 827, 758, 615 cm–1.
Synthesis 2007, No. 23, 3620–3626 © Thieme Stuttgart · New York