Cyclocondensation of amidines with dimethyl acetylenedicarboxylate: A convenient entry into tetramic acids

Article abstract of DOI:10.1002/jhet.5570430220

Amidines undergo cyclocondensations with dimethyl acetylenedicarboxylate (DMAD) to give highly functionalized 5-dialkylamino-4-pyrrolin-3-ones. The products are crystalline, highly colored compounds that are uniquely functionalized and represent advanced

Full text of DOI:10.1002/jhet.5570430220

Mar-Apr 2006
395
Cyclocondensation of Amidines with Dimethyl
Acetylenedicarboxylate: A Convenient Entry into Tetramic Acids
Ihsan Erden*, Galip Ozer, Christophe Hoarau, Weiguo Cao
San Francisco State University, Department of Chemistry and Biochemistry, 1600 Holloway Avenue,
San Francisco, CA 94132
Received July 12, 2005
Amidines undergo cyclocondensations with dimethyl acetylenedicarboxylate (DMAD) to give highly
functionalized 5-dialkylamino-4-pyrrolin-3-ones. The products are crystalline, highly colored compounds
that are uniquely functionalized and represent advanced intermediates in the construction of several other
heterocyles, in particular the biologically active tetramic acids. The synthetic transformations of these com-
pounds to tetramic acids are also described.
J. Heterocyclic Chem., 43, 395 (2006).
Dimethyl acetylenedicarboxylate (DMAD) combines
fied by the characteristic singlets for the olefinic hydrogen
with electron-rich alkenes to give 2+2 cycloadducts that
may expand to seven membered rings; enamines, guani-
dines and related compounds have been reported to
undergo cycloadditions with DMAD to give nitrogen hete-
rocycles [1-8]. Diaminomethylenehydrazones have been
reported to give imidazolinone and 1,6-dihydroxypyrimi-
dine derivatives [9]. We report here the cyclocondensation
of amidines [10] with DMAD resulting in highly function-
alized five-membered nitrogen heterocycles that show
excellent promise as versatile intermediates in the synthe-
sis of tetramic acids [11]. These latter compounds, e.g.
aurentoside and ancorinoside are of considerable interest
due to their potent antibiotic, antiviral and antiulcerative
properties, as well as their cytotoxicity and mycotoxicity,
and inhibition of tumors.
atoms on the exocyclic double bond at either ca. 6 ppm
(Z), or 5 ppm (E), respectively, in the H NMR spectrum.
1
The resulting 5-dialkylamino-4-pyrrolin-3-ones were
purified by chromatography on silica gel (5%
MeOH/CH Cl ) followed by recrsytallization. In order to
2
2
gain access to the tetramic acid skeleton, the vinylogous
amide moiety was hydrolytically removed by heating with
NaOH in i-propyl alcohol. Attempts to hydrolyze the
enaminoketone functionality under acidic conditions, even
through initial N-alkylation by treatment with MeI, were
unsuccessful [13]. Under basic conditions the ester group
was saponified as well. The unsubstituted parent system 20
did not seem to enolize in chloroform at room temperature.
Catalytic hydrogenation of 20a on Pd/C gave the tetramic
acid 21 in quantitative yield. Since various tetramic acids
are not alkylated or arylated at the ring nitrogen, we took
advantage of the reductive removal of the benzyl group in
The DMAD-amidine cyclocondensations proceed read-
ily at low temperatures in CH Cl solution to give 5-
2
2
dialkyl(or alkylaryl)amino-4-pyrrolin-3-ones as highly
colored crystalline compounds in moderate to good yields
(Table I ) [12].
The mechanism starts with initial conjugate attack at the
propargyl system, followed by proton transfer to give 4;
the subsequent intramolecular condensation delivers a
five-membered ring (5) rather than a six-membered hete-
rocycle (Scheme 1). The E or Z isomers were easily identi-

396
I. Erden, G. Ozer, C. Hoarau, and W. Cao
Vol. 43
Table 1
Amidine-DMAD Cyclocondensation Products
18a and 18b (R=H, or Me; R'=Bn) to give 19a and 19b,
respectively (Scheme 2).
Catalytic hydrogenation of 19 using Adam’s catalyst in
methanol at atmospheric pressure and room temperature
resulted in the selective hydrogenation of the exocyclic
double bond (the vinylogous amide double bond was not
touched under a variety of conditions and using different
catalysts). Under the conditions the N-benzyl group was
not reduced. On Pd/C, the reduction yielded an 8:1 mixture
of 18 and 19. Complete reduction of both the exocyclic
double bond and the N-benzyl group was achieved upon
prolonged hydrogenation (4 days at r.t.) with Pd/C in
MeOH in the presence of Na CO .
2
3
Treatment of 20 with excess CH N in ether resulted in
2
2
the esterification as well trapping of the 1,3-dione moiety
as its enol ether, to give 22 in excellent yield.
The tetramic acids so obtained as well as the N-
debenzylated vinylogous amides also represent advanced
precursors of pyrrolizidine and indolizidine ring systems

Mar-Apr 2006
Cyclocondensation of Amidines with Dimethyl Acetylenedicarboxylate
397
1
Dark yellow crystal, mp: 130-131 °C, yield: 53%. H NMR
(CDCl , 300 MHz): δ 7.28-6.95 (m, 5H, ArH), 5.98 (s, 1H), 4.99
3
(s, 2H, CH ), 4.94 (s, 1H), 3.75 (s, 3H, OCH ), 3.08 (s, 6H, N-
2
3
13
CH ) ppm; C NMR (CDCl , 75 MHz): δ 183.2, 176.7, 166.3,
3
3
150.4, 135.5, 128.6, 127.7, 127.6, 99.6, 89.2, 53.0, 51.8, 40.9
ppm; IR (KBr): ν 3062, 3027, 2965, 2934, 2832, 2806, 1695,
1673, 1651, 1598, 1571, 1494, 1450, 1434, 1408, 1366, 1348,
-1
1326, 1273, 1200, 1162, 1089, 1953, 1029, 1009, 936, 896 cm .
Anal. Calcd. For: C
H N O : C, 67.12; 6.34; N, 9.78.
16 18 2 3
Found: C, 67.09; H, 6.31; N, 9.80.
that should be accessible by way of N-CH CO and N-
2
3
(Z)-Methyl 2-(5-(dimethylamino)-3-methyl-1-phenyl-3-oxo-1H-
pyrrol-2(3H)-ylidene)acetate (9).
CH CH CO Me derivatives of 21 and subsequent
2
2
2
Dieckmann condensations, respectively. These aspects of
the 4-pyrrolin-3-one methodology, as well as the total syn-
theses of several naturally occurring 3-acylated tetramic
acid antibiotics, in particular streptolydigin, ery-
throskyrine, ancorinoside, and auronthoside are underway.
1
Yellow crystals, mp: 162-3 °C, yield: 75%; H NMR (CDCl ,
3
300 MHz): δ 7.28 (5H, m, ArH), 5.99 (1H, s), 3.42 (3H, s,
13
OCH ), 2.90 (6H, s, N-CH ), 1.99 (3H, s, CH ) ppm; C NMR
3
3
3
(CDCl , 75 MHz): δ 184.8, 174.2, 166.3, 150.0, 143.5, 129.8,
3
129.4, 128.6, 100.9, 98.4, 51.9, 41.7, 9.3 ppm; IR (KBr): ν 3044,
3025, 3002, 2946, 2865, 2806, 1723, 1679, 1655, 1583, 1486,
1441, 1414, 1371, 1351, 1318, 1269, 1211, 1174, 1095, 1045,
EXPERIMENTAL
-1
992, 936, 917 cm .
Melting points were determined in open class capillary tubes
Anal. Calcd. for C
H N O : C, 67.12; H, 6.34; N, 9.78.
16 18 2 3
1
13
and are uncorrected. The H and C NMR spectra were recorded
on a General Electric QE-Plus 300 MHz and Bruker Avance
Found: C, 67.31; H, 6.32; N, 9.80.
(Z)-Methyl 2-(5-dimethylamino-1-benzyl-3-methyl-3-oxo-1H-
pyrrol-2(3H)-ylidene)acetate (11).
DRX 300 MHz spectrometers, using CDCl as solvent and TMS
3
as internal standard, unless specified otherwise. IR spectra were
obtained on a Nicolet Avanta 370 DTGS FT-IR spectrometer.
Column chromatographic separations were carried out with
Davison 6-200 Mesh silica gel. For preparative TLC, Merck sil-
1
Light yellow crystals, mp: 120-1 °C, yield: 55%; H NMR
(CDCl , 300 MHz): δ 7.2 (3H, m, ArH), 6.95 (2H, m, ArH), 6.0
3
(1H, s), 4.89 (2H, s), 3.76 (3H, s, OCH ), 3.08 (6H, s, N-CH ),
3
3
ica gel (grade 60 PF ) was used. All reactions were conducted
13
254
1.84 (3H, s, CH ) ppm; C NMR (CDCl , 75 MHz): δ 185.3,
3
3
under an atmosphere of dry nitrogen or argon. Non-deuterated
solvents were dried and distilled prior to use. Amidines 1, 6 and
10 were prepared according to the procedure reported by Haug
and Kantlehner [12a], whereas amidines 8, 13 and 15 were syn-
thesized using Weintraub et al.’s method [12b].
174.1, 167.0, 150.4, 136.4, 128.9, 128.4, 127.9, 99.4, 99.3, 53.2,
52.3, 41.4, 8.8 ppm; IR (KBr): ν 3036, 2948, 2923, 2899, 2864,
2803, 1720, 1697, 1666, 1573, 1488, 1452, 1413, 1357, 1319,
1263, 1241, 1215, 1202, 1176, 1162, 1123, 1100, 1080, 1055,
-1
1017, 953, 914 cm .
Anal. Calcd. for C
Found: C, 67.94; H, 6.68; N, 9.35.
H N O : C, 67.98; H, 6.71; N, 9.33.
17 20 2 3
General Procedure for the Cyclocondensation of Amidines with
DMAD.
(E)-Methyl 2-(5-dimethylamino-1-benzyl-3-methyl-3-oxo-1H-
pyrrol-2(3H)-ylidene)acetate (12).
To a solution of N,N-dimethyl-N'-methylacetamidine (1 g, 10
mmol) in 10 mL of dry CH Cl that was cooled to -20 °C, a solu-
2
2
tion of DMAD (1.42 g, 10 mmol) in 5 mL of dry CH Cl was
1
2
2
Brown crystals, mp: 93-4 °C, yield: 18%; H NMR (CDCl ,
3
added dropwise with stirring. The mixture was allowed to warm
up and was stirred for two hours after having removed the cold
bath. The solvent was then removed in vacuo (rotovapped), and
the residue purified by preparative TLC on silica gel, eluting with
300 MHz): δ 7.29-7.19 (5H, m, ArH), 5.20 (1H, s), 4.48 (2H, s),
3.71 (3H, s, OCH ), 2.95 (6H, s, N-CH ), 1.80 (3H, s, CH ) ppm;
CNMR (CDCl , 75 MHz): δ 181.7, 171.05, 167.2, 147.4,
136.5, 129.0, 127.5, 125.7, 101.5, 97.1, 52.2, 51.4, 41.4, 8.0 ppm;
IR (KBR): ν 3060, 3032, 2940, 2886, 2802, 1694, 1671, 1579,
1484, 1442, 1410, 1351, 1320, 1246, 1215, 1201, 1163, 1100,
3
3
3
13
3
5% MeOH/CH Cl . It was then crystallized from CH Cl /ether.
2
2
2
2
(Z)-Methyl 2-(5-(dimethylamino)-1-methyl-3-oxo-1H-pyrrol-
2(3H)-ylidene)acetate (5).
-1
1073, 1009, 957, 883 cm .
Anal. Calcd. for C
H N O : C, 67.98; H, 6.71; N, 9.33.
17 20 2 3
1
Bright yellow crystals, mp: 136-7 °C, yield: 77%. H NMR
Found: C, 67.96; H, 6.69; N, 9.37.
(CDCl , 300 MHz): δ 5.96 (1H, s), 4.84 (1H, s), 3.76 (3H, s,
3
13
OCH ), 3.19 (3H, s, N-CH ), 3.09 (6H, s, N-CH ) ppm;
C
(E)-Methyl 2-(5-Dimethylamino-1-benzyl-3-phenyl-3-oxo-1H-
pyrrol-2(3H)-ylidene)acetate (14).
3
3
3
NMR (CDCl , 75 MHz): δ 182.8, 177.5, 166.2, 153.2, 97.5, 86.4,
3
51.8, 40.9, 40.2 ppm; IR (KBr): ν 3128, 3108, 2950, 2926, 2910,
2891, 2847, 1716, 1705, 1667, 1616, 1591, 1463, 1429, 1416,
1396, 1354, 1338, 1276, 1230, 1205, 1172, 1159, 1063, 1036,
1
Dark yellow crystals, mp: 138-140 °C, yield: 68%; H NMR
(CDCl , 300 MHz): δ 7.45-7.20 (10H, m, ArH), 5.39 (1H, s),
4.67 (2H, s), 3.78 (3H, s, OCH ), 2.79 (6H, s, N-CH ) ppm.
NMR (CDCl , 75 MHz): δ 180.9, 170.4, 167.6, 147.1, 136.9,
3
13
C
3
3
-1
972, 901, 880 cm .
3
Anal. Calcd. for C
H N O : C, 57.13; H, 6.71; N, 13.33.
10 14 2 3
132.5, 130.2, 129.7, 128.4, 128.2, 126.6, 126.3, 103.6, 103.0,
52.9, 52.0, 42.7 ppm. IR (KBr): ν 3432, 3054, 3020, 2945, 2917,
2796, 1727, 1667, 1641, 1576, 1560, 1507, 1456, 1404, 1359,
Found: C, 57.09; H, 6.70; N, 13.36.
(Z)-Methyl 2-(5-(dimethylamino)-1-benzyl-3-oxo-1H-pyrrol-
2(3H)-ylidene)acetate (7).
-1
1327, 1277, 1249, 1209, 1167, 1082, 1026, 1003, 964 cm .

398
I. Erden, G. Ozer, C. Hoarau, and W. Cao
Vol. 43
Anal. Calcd. for C
Found: C, 72.89; H, 6.14; N, 7.76.
H
N O : C, 72.91; H, 6.12; N, 7.73.
13
22 22
2
3
Hz, B part of ABX system) ppm; C-NMR (CDCl 75 MHz): δ
3,
194.4, 713.5, 172.6, 81.9, 60.4, 52.3, 51.0, 37.6 ppm; IR
(CDCl ): ν 2950, 2922, 2855, 1734, 1635, 1588, 1437, 1401,
3
(Z)-Methyl 2-(5-Dimethylamino-1-benzyl-3-phenyl-3-oxo-1H-
pyrrol-2(3H)-ylidene)acetate (16).
-1
1358, 1263, 1235, 1203, 1168, 1065, 986 cm .
Anal. Calcd. for C H N O : C, 54.53; H, 7.12; N, 14.13.
9
14 2 3
1
Yellow crystals, m.p.138-140 °C, yield: 66%; H-NMR
Found: C, 54.54; H, 7.12; N, 14.10.
(CDCl , 300 MHz): δ 7.30 (5H, m, ArH), 5.98 (1H, s), 5.04 (1H,
1
3
19b: H-NMR (CDCl , 300 MHz): δ 5.5 (1H, s, NH), 4.0 (1H,
3
s), 3.38 (3H, s, OCH ), 2.84 (6H, s, N-CH ) ppm;
3
3
dd, J=11 and 2.6 Hz, X part of ABX system), 3.71 (3H, s, OCH ),
3
13
C-NMR (CDCl , 75 MHz): δ 182.8, 174.8, 166.2, 150.1,
3
3.1 (6H, s, N-CH ), 3.0 (1H, dd, J=17.2 and 2.6 Hz, A part of
3
132.3, 130.0, 129.6, 129.0, 101.0, 88.4, 52.0, 41.6 ppm; IR
(KBr): ν 2995, 2883, 2811, 1719, 1680, 1654, 1604, 1575, 1493,
1454, 1418, 1403, 1334, 1269, 1198, 1179, 1168, 1156, 1086,
ABX system), 2.26 (1H, dd, J=17.2 and 11.0 Hz, B part of ABX
13
system), 1.87 (3H, s, CH ) ppm; C-NMR (CDCl 75 MHz): δ
3
3,
193.9, 173.2, 171.2, 90.1, 63.6, 51.9, 39.2, 37.2, 8.9 ppm; IR
-1
1067, 1039, 1000, 940, 919 cm .
(CDCl ): ν 2989, 2953, 2927, 1802, 1730, 1681, 1596, 1440,
3
Anal. Calcd. for C
H N O : C, 66.16; H, 5.92; N, 10.29.
-1
15 16 2 3
1407, 1374, 1198, 1165, 1073, 957, 919 cm .
Found: C, 66.13; H, 5.94; N, 10.26.
Anal. Calcd. for C
H N O : C, 56.59; H, 7.60; N, 13.20.
10 16 2 3
Found: C, 56.55; H, 7.59; N, 13.16.
General Procedure for the Hydrogenation of 7 and 11.
A solution of 0.47 mmol of 7 (or 11) was dissolved in 10 mL of
(Z)-2-(1-Methyl-3,5-dioxopyrrolidin-2-ylidene)acetic acid (20).
methanol, 20 mg of PtO was added and the mixture was hydro-
2
A solution of 0.4 g of 5 (0.19 mmol) and 1 mL of a 2 M aque-
ous solution of NaOH in 1 mL of isopropyl alcohol was heated at
reflux for 24 h. The reaction mixture was cooled to room temper-
ature, and partitioned between 2 M HCl (5 mL) and ethyl acetate
(5 mL). The aqueous layer was extracted with 5 mL of EtOAc
and the combined organic extracts washed with 7 mL of brine.
genated at atmospheric pressure for 1.5 h (or until H uptake
2
ceased). The catalyst was filtered off, the solvent removed in
vacuo, leaving behind a quantitative yield of 18a (or 18b).
Methyl 2-(1-Benzyl-5-(dimethylamino-4-methyl-3oxo-2,3-dihy-
dro-1H-pyrrol-2-yl) acetate (18a).
After drying over MgSO , the solvent was evaporated in vacuo to
1
4
Yellow oil: H-NMR (CDCl , 300 MHz): δ 7.35-7.20 (5H, m,
3
give 300 mg (93%) of white crystals, mp 153-4 °C (from ethyl
ArH), 4.75 (1H, s), 4.50 (1H, d, J=16 Hz, B part of AB system),
4.40 (1H, d, J=16 Hz, A part of AB system), 3.89 (1H, dd, J=8.8
and 3.3 Hz, X part of ABX system), 3.58 (3H, s, OCH ), 3.0 (6H,
s, N-CH ), 2.90 (1H, dd, J=16.6 and 3.3 Hz, A part of ABX sys-
tem), 2.48 (1H, dd, J=16.6 and 8.8 Hz, B part of ABX system)
ppm; C NMR (CDCl 75 MHz): δ 195.8, 179.6, 172.7, 136.9,
129.2, 128.3, 128.1, 89.9, 66.5, 54.4, 52.1, 41.2, 38.0 ppm; IR
(CDCl ): ν 3062, 3026, 2947, 2925, 2909, 2808, 1768, 1733,
1654, 1572, 1493, 1453, 1431, 1409, 1357, 1257, 1221, 1161,
1
acetate-hexane). H NMR (acetone-d6, 300 MHz): δ 3.2 (s, 2H),
13
3.4 (s, 3H), 5.6 (s, 1H), 11.0 (br s, 1H) ppm; C NMR (CDCl ,
3
3
75 MHz): δ 206.8, 171.3, 166.2, 145.8, 93.9, 38.2, 29.9 ppm.
3
Anal. Calcd. for C H NO : C, 49.71; H, 4.17; N, 8.28. Found:
7
7
4
C, 49.74; H, 4.16; N, 8.24.
13
3,
2-(1-Methyl-3,5-dioxopyrrolidin-2-yl)acetic Acid (21).
3
To a 170 mg (10 mmol) solution of 20 in 50 mL of methanol,
100 mg of Pd/C was added, and the mixture was stirred under
hydrogen atmosphere until hydrogen uptake stopped. The solu-
tion was filtered, the solvent was removed in vacuo, and the oily
-1
1061, 1031, 990 cm .
Anal. Calcd. for C
Found: C, 66.62; H, 7.02; N, 9.70.
H N O : C, 66.65; H, 6.99; N, 9.72.
16 20 2 3
1
residue dried overnight to give 168 mg (98%) of 21. H NMR
Methyl 2-(1-Benzyl-5-(dimethylamino-3oxo-2,3-dihydro-1H-
pyrrol-2-yl)acetate (18b).
(CD OD, 300 MHz): δ 4.1 (m, 1H); 3.05 (d, A part of an AB sys-
3
2
tem, J= 21.3 Hz, 1H), 2.9 (d, B part, 1H); 2.8 (m, 2H), 2.7 (s,
13
1
3H); C NMR (CD OD, 75 MHz): δ 207.2, 171.4, 169.4, 64.2,
Yellow oil: H-NMR (CDCl , 300 MHz): δ 7.31-7.14 (5H, m,
3
3
40.8, 33.65, 26.6 ppm.
ArH), 4.40 (1H, d, J=15.7 Hz, B part of AB system), 4.30 (1H, d,
J=15.7 Hz, A part of AB system), 3.85 (1H, dd, J=8.6 and 3.6 Hz,
Anal. Calcd. for C H NO : C, 49.12; H, 5.30; N, 8.18. Found:
7
9
4
C, 49.10; H, 5.31; N, 8.17.
X part of ABX system), 3.62 (3H, s, OCH ), 3.08 (6H, s, N-
3
CH ), 2.85 (1H, dd, J=16.5 and 3.6 Hz, A part of ABX system),
3
(Z)-Methyl 2-(3-methoxy-1-methyl-5-oxo-1H-pyrrol-2-(5H)-yli-
dene)acetate (22).
2.40 (1H, dd, J=16.5 and 8.6 Hz, B part of ABX system), 1.79
13
(3H, s, CH ) ppm; C NMR (CDCl 75 MHz): δ 196.7, 177.0,
3
3,
To a solution of 0.5 g (3 mmol) in 10 mL of methanol was
added dropwise at 0 °C an ether solution of a 10 fold excess of
diazomethane, previously generated from diazald with KOH
[14], and the mixture was stirred at room temperature for 3 h. The
solvent was removed in vacuo to give a yellow oil, which was
purified by preparative TLC (2% MeOH/CH Cl ) to give 0.4 g
172.8, 136.9, 129.2, 128.3, 128.2, 98.5, 64.5, 54.0, 52.2, 41.3,
38.2, 9.1 ppm; IR(CDCl ): ν 2949, 2923, 1731, 1646, 1555,
3
-1
1492, 1454, 1436, 1408, 1359, 1230, 1165 cm .
Anal. Calcd. for C
H N O : C, 67.53; H, 7.33; N, 9.26.
17 22 2 3
Found: C, 67.50; H, 7.34; N, 9.22.
For the reduction of 18a and 18b, the same procedure was used
except Pd/C was used in the presence of 200 mg of Na CO
2
2
1
(80% yield) of 22. H NMR (CDCl , 300 MHz): δ 5.1 (s, 1H),
4.4 (dd, J= 5.4, 5.7 Hz, 1H), 3.8 (s, 3H), 3.7 (s, 3H), 2.9 (s, 3H),
2.9 (dd, A part of an AB system, J= 5.4Hz, J= 21.3 Hz, 1H), 2.8
(dd, B part, J= 5.7 Hz, 1H); C NMR (CDCl , 75 MHz): δ
171.1, 166.9, 165.2, 144.2, 94.4, 92.4, 58.5, 51.7, 29.1 ppm.
3
2
3
instead of PtO , and the hydrogenation was carried out for 4
2
3
2
days.
3
13
1
19a: H-NMR (CDCl , 300 MHz): δ 5.98 (1H, s, NH), 4.53
3
3
(1H, s), 4.05 (1H, dd, J=10.9 and 2.5 Hz, X part of ABX system),
Anal. Calcd. for C H NO : C, 54.82; H, 5.62; N, 7.10. Found:
3.71 (3H, s, OCH ), 3.1 (1H, dd, J=17.1 and 2.5 Hz, A part of
9
11
4
3
ABX system), 3.0 (6H, s, N-CH ), 2.32 (1H, dd, J=17.1 and 10.9
C, 54.81; H, 5.60, N, 7.13.
3

Mar-Apr 2006
Cyclocondensation of Amidines with Dimethyl Acetylenedicarboxylate
399
[6] B. De Ancos, M. C. Maestro, M. R. Martin, A. I. Mateo,
Tetrahedron, 50, 13857 (1994), and references cited therein.
[7] S. Jiang, Z. Janousek, H. G. Viehe, Tetrahedron Lett., 35, 1185
(1994).
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Acetylenes, in Chemistry of Acetylenes, H. G. Viehe, ed, Marcel Dekker,
New York, 1969; Ch. 8, pp 425-595.
[9] Y. Miyamoto, C. Yamazaki, J. Heterocyclic Chem., 31, 1445
(1994).
[10] S. Sandler, W. Karo, in Organic Functional Group
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Acknowledgments.
This work was supported by the National Institutes of Health,
MBRS-SCORE Program-NIGMS (Grant No. GM52588). This
work was supported in part by funding from a grant (P20
MD000262) from the Research Infrastructure in Minority
Institutions Program, NCMHD, NIH.
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[12] The requisite amidines were prepared by either of two meth-
ods: [a] E. Haug, W. Kantlehner, Synth. Comm., 13, 35 (1983); [b] L.
Weintraub, S. R. Oles, N. Kalish, J. Org. Chem., 33, 1679 (1968).
[13] G. Stork, A. Brizzolora, H. Landesman, J. Szmuszkovicz, R.
Terrell, J. Am. Chem. Soc., 85, 207 (1963).
(1971).
[3] L. Ma, D. Dolphin, J. Chem. Soc., Chem. Comm., 2251
(1995).
[4] Q. Lin, G. E. Ball, R. Bishop, Tetrahedron, 53, 10899 (1997).
[5] V. S. Berseneva, A. V, Tkachev, Y. Y. Morzherin, W. Dehaen,
I. Luyten, S. Toppet, V. A. Bakulev, J. Chem. Soc., Perkin Trans. 1, 2133
(1998).
[14] The procedure described in Aldrich Technical Bulletin AL-
180, 2003 was used to generate diazomethane from Diazald.