An intramolecular N-arylation approach to 3-functionalized 4,9-dihydropyrrolo[2,1-b]quinazolines

Article abstract of DOI:10.1002/jhet.534

A series of 4,9-dihydropyrrolo[2,1-b]quinazolines containing electron withdrawing groups at the 3-position have been prepared by the palladium-catalyzed intramolecular N-arylation of some 2-aminopyrroles having a 2-bromobenzyl group at the N-1 position. I

Full text of DOI:10.1002/jhet.534

706
An Intramolecular N-Arylation Approach to 3-Functionalized
4,9-Dihydropyrrolo[2,1-b]quinazolines
Vol 48
Nisaraporn Suthiwangcharoen, Steven M. Pochini, Daniel P. Sweat,
and Chad E. Stephens*
Department of Chemistry and Physics, Augusta State University, Augusta, Georgia 30904
*E-mail: cstephe7@aug.edu
Received January 31, 2010
DOI 10.1002/jhet.534
Published online 4 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
A series of 4,9-dihydropyrrolo[2,1-b]quinazolines containing electron withdrawing groups at the 3-
position have been prepared by the palladium-catalyzed intramolecular N-arylation of some 2-aminopyr-
roles having a 2-bromobenzyl group at the N-1 position. Important for success of the reaction is the use
of X-phos, a biphenyl mono-phosphine ligand, instead of xantphos, a more standard diphosphine ligand,
and the use of t-BuOH as reaction solvent.
J. Heterocyclic Chem., 48, 706 (2011).
INTRODUCTION
Recently, we have described the palladium-catalyzed
N-arylation (Buchwald-Hartwig amination) of 3-func-
tionalized 2-aminopyrroles whereby the amino group is
coupled with various aryl bromides to give N-arylated
2-aminopyrrole analogues (1) [1]. All couplings in that
study were intermolecular. Considering recent reports of
various intramolecular N-arylations to yield nitrogen-
containing heterocycles [2], we have become interested
in exploring such cyclization approaches to certain pyr-
rolo-fused ring systems. As a result of our efforts, we
now wish to describe the palladium-catalyzed intramo-
lecular N-arylation of some 2-aminopyrroles having a 2-
bromobenzyl group at the N-1 position (2) to yield 3-
functionalized 4,9-dihydropyrrolo[2,1-b]quinazolines (3).
These tricyclic compounds are structurally related to a
number of partially reduced quinazoline-based alkaloids,
such as vasicine, (4) which possess interesting biologi-
cal properties, including anti-inflammatory, antimicro-
bial, antidepressant, and antitumor activities [3]. As
there is continued interest in these alkaloids, our work
here may complement recent efforts [4] to develop new
synthetic approaches to the pyrrolo[2,1-b]quinazoline
ring system.
RESULTS AND DISCUSSION
The 2-bromobenzyl-substituted pyrroles (2a-e) were
prepared in similar manner to other such 2-
a
C
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An Intramolecular N-Arylation Approach to 3-Functionalized 4,
9-Dihydropyrrolo[2,1-b]quinazolines
707
Scheme 1
aminopyrroles [5] by reaction of 2-bromobenzylamine
with acetoin (3-hydroxy-2-butanone), followed by reac-
tion of the intermediate a-aminoketone with a function-
alized acetonitrile, such as malononitrile (Scheme 1). As
a modification to the standard method, we simply heated
the amine and acetoin together for a short time without
solvent to form the intermediate. This approach is more
convenient, compared with azeotropic removal of water
with a Dean-Stark trap and eliminates the use of ben-
zene or toluene as reaction solvent. Subsequent reaction
of the intermediate with the functionalized acetonitrile
was conducted in the usual manner by refluxing in
EtOH for 2 h. Functional groups at the 3-position of
pyrroles 2 include cyano, t-butyl ester, and three differ-
ent sulfonyls (methyl, phenyl, and 4-fluorophenyl). Ben-
zylamine is often used in this pyrrole synthesis to give
N-benzyl pyrroles, [5] but this appears to be the first use
of 2-bromobenzylamine. Purified yields for these new 2-
aminopyrroles ranged from 38 to 56%.
and ligand combination [2a] (with K2CO3 as base in
DMF at 100ꢀC for 18 h) afforded cyclized product in
modest yield (ꢁ10%, W ¼ SO2Ph). However, much
improved yields were obtained upon returning to our
original conditions (Pd2dba3 as palladium source and
Cs2CO3 as base), but using X-phos, a sterically-hindered
mono-phosphine ligand, [7] in place of xantphos, a
bidentate ligand. A further improvement in yield, and in
purity of crude product, was realized upon changing the
reaction solvent from 1,4-dioxane to tert-butyl alcohol
[7c]. Under these optimized conditions, the reaction was
complete in just 4 h, with tricyclics 3a-e (Scheme 1)
being readily isolated as solids upon addition of water
to the reaction mixture. Recrystallization from MeOH or
DMF/MeOH gave pure crystalline samples in 49–84%
yield, with all products being characterized by NMR
(1H, 13C, and 19F when applicable), IR, combustion
analysis, and melting point.
Attempted cyclization of pyrroles 2 using our origi-
nally reported conditions for intermolecular N-arylation
of similar 2-aminopyrroles (Pd2dba3, xantphos, Cs2CO3,
1,4-dioxane, 100ꢀC, 18 h) was surprisingly unsuccessful
in giving tricyclics 3, with starting pyrrole primarily
being recovered. A change in reaction solvent to DMF
(100ꢀC) or to refluxing xylenes led to no noticeable
improvement. These results are consistent with observa-
tions that catalyst systems, which are useful for intermo-
lecular N-arylations may fail with cyclizations. [6] Pre-
liminary experiments using Pd(PPh3)4 as a palladium
CONCLUSIONS
In conclusion, a palladium-catalyzed intramolecular
N-arylation approach to a series of 4,9-dihydropyr-
rolo[2,1-b]quinazolines containing electron withdrawing
groups at the 3-position has been described. Precursors
for the cyclization reaction are 2-aminopyrroles contain-
ing a 2-bromobenzyl substituent at the N-1 position.
These pyrroles were prepared by a modified procedure
that eliminates the use of benzene or toluene as initial
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DOI 10.1002/jhet

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N. Suthiwangcharoen, S. M. Pochini, D. P. Sweat, and C. E. Stephens
Vol 48
121.1, 126.6, 128.1, 129.0, 132.4, 136.6, 146.9, 165.8. Analy-
sis for calcd for C18H23BrN2O2 (379.29): C, 57.00; H, 6.11; N,
7.39. Found: C, 56.89; H, 6.21; N, 7.30.
solvent. For the cyclization reaction, X-phos, a sterically
hindered mono-phosphine ligand, proved to be a much
better ligand compared to xantphos, a more standard
bidentate ligand. Also, tert-butyl alcohol was found to
be an excellent reaction solvent for the cyclization
reaction.
2-Amino-1-(2-bromobenzyl)-4,5-dimethyl-3-(methylsulfonyl)-
pyrrole (2c). Using (methylsufonyl)acetonitrile in place of
malononitrile, this compound was obtained in 40% yield as
course tan crystals, mp 155–157ꢀC (MeOH). IR (cmꢂ1): 3400,
1
3315, 2921, 1618, 1540, 1481, 1276, 1099, 1025, 943, 762. H
NMR (DMSO-d6): 1.81 (s, 3H), 2.01 (s, 3H), 2.97 (s, 3H),
4.96 (s, 2H), 5.60 (s, NH2), 6.34 (dd, J ¼ 7.7 and 1.5 Hz, 1H),
7.21–7.24 (m, 1H), 7.31–7.34 (m, 1H), 7.64 (dd, J ¼ 7.9 and
1.2 Hz, 1H). 13C NMR (DMSO-d6): 8.6, 9.6, 45.4, 45.5, 96.3,
109.9, 117.8, 121.1, 126.5, 128.2, 129.1, 132.5, 136.2, 142.8.
Anal. Calcd for C14H17BrN2O2S (357.27): C, 47.07; H, 4.80;
N, 7.84. Found: C, 46.95; H, 4.67; N, 7.76.
EXPERIMENTAL
General. Melting points were obtained using a Mel-Temp
apparatus and are uncorrected. IR spectra were obtained using
a Perkin–Elmer Spectrum 100 instrument using attenuated total
reflection. NMR were recorded on a Bruker 300 Avance
instrument, with signals referenced to residual DMSO-d6 sol-
vent (2.49 ppm for 1H NMR, 39.5 ppm for 13C NMR) or to
hexafluorobenzene (set to 0 ppm for 19F NMR). Elemental
analyses were performed by Atlantic Microlab in Norcross,
GA. 2-Bromobenzylamine, cesium carbonate (fine powder)
and Pd2dba3 [tris(dibenzylideneacetone)dipalladium(0)] were
obtained from Alfa Aesar. X-Phos (2-dicyclohexylphosphino-
20,40,60-triisopropylbiphenyl) was obtained from Aldrich.
(Methylsulfonyl)acetonitrile, (phenylsulfonyl)acetonitrile, and
(4-fluorophenylsulfonyl)-acetonitrile are commercially avail-
able. All reagents were weighed in open air.
2-Amino-1-(2-bromobenzyl)-4,5-dimethyl-3-(phenylsulfonyl)-
pyrrole (2d). Using (phenylsulfonyl)acetonitrile in place of
malononitrile, this compound was obtained in 56% yield as
light tan/colorless crystals, mp 186–187ꢀC (MeOH). IR
(cmꢂ1): 3458, 3360, 2911, 1616, 1541, 1482, 1440, 1275,
1
1126, 1077, 751, 726, 689. H NMR (DMSO-d6): 1.74 (s, 3H),
1.89 (s, 3H), 4.96 (s, 2H), 5.90 (s, NH2), 6.25 (d, J ¼ 7.4 Hz,
1H), 7.21–7.30 (m, 2H), 7.55–7.69 (m, 4H), 7.78–7.82 (m,
2H). 13C NMR (DMSO-d6): 8.6, 9.8, 45.5, 95.4, 109.9, 118.4,
121.2, 125.1, 126.3, 128.1, 129.1, 129.2, 132.0, 132.6, 136.1,
143.8, 145.5. Anal. Calcd for C19H19BrN2O2S (419.34): C,
54.42; H, 4.57; N, 6.68. Found: C, 54.26; H, 4.69; N, 6.64.
2-Amino-1-(2-bromobenzyl)-3-(4-fluorophenylsulfonyl)-4,5-
dimethylpyrrole (2e). Using (4-fluorophenylsulfonyl)acetoni-
trile in place of malononitrile, this compound was obtained in
51% yield as light tan/colorless crystals, mp 148–149ꢀC
(EtOH). IR (cmꢂ1): 3452, 3358, 3099, 3071, 2926, 2856,
1615, 1587, 1536, 1486, 1271, 1226, 1125, 1077, 844, 821,
752, 713, 663. 1H NMR (DMSO-d6): 1.75 (s, 3H), 1.89 (s,
3H), 4.97 (s, 2H), 5.92 (s, NH2), 6.25 (dd, J ¼ 7.6 and 1.5 Hz,
1H), 7.30–7.42 (m, 4H), 7.64 (dd, J ¼ 7.8 and 1.4Hz, 1H),
7.83–7.88 (m, 2H). 13C NMR (DMSO-d6): 8.6, 9.8, 45.5, 95.2,
109.8, 116.3 (d, J ¼ 22 Hz), 118.5, 121.1, 126.3, 128.0, 128.1,
129.1, 132.6, 136.0, 141.9 (d, J ¼ 3 Hz), 143.9, 163.9 (d, J ¼
249 Hz). 19F NMR (DMSO-d6): 54.9 (m). Anal. Calcd for
C19H18BrFN2O2S (437.32): C, 52.18; H, 4.15; N, 6.41. Found:
C, 52.19; H, 4.04; N, 6.36.
Representative procedure for synthesis of 2-aminopyr-
roles 2a-e.
2-Amino-1-(2-bromobenzyl)-3-cyano-4,5-dime-
thylpyrrole (2a). Acetoin (3-hydroxy-2-butanone, finely
ground) (3.52 g, 40 mmol) and 2-bromobenzylamine (7.44 g,
40 mmol) were combined in a 50 mL round-bottom flask and
heated with a heat gun or on a hotplate until the acetoin dis-
solved and a homogenous yellow liquid was obtained (ꢁ2–3
min of heating). The water vapor that condensed in the neck
of the flask was removed using a chemwipe. EtOH (5–10 mL)
was then added followed by malononitrile (2.64 g, 40 mmol)
and the solution was heated at reflux for 2 h. The solution was
then transferred to a beaker with addition of a small amount of
water to produce a crystalline yellow solid. After chilling, this
solid was filtered by suction and recrystallized from MeOH
(50 mL) to give course powdery crystals (4.60 g, 38%). An
analytical sample was obtained by recrystallization of a small
amount (1.0 g) from MeOH (15–20 mL) to give course yellow
crystals (0.69 g), mp 148–150ꢀC (MeOH). IR (cmꢂ1): 3452,
3405, 3336, 3300, 3223, 3185, 2915, 2858, 2187, 1637, 1558,
Representative procedure for synthesis of pyrrole[2,1-
b]quinazolines 3a-e.
3-Cyano-1,2-dimethyl-4,9-dihydropyr-
rolo[2,1-b]quinazoline (3a). A mixture of pyrrole 2a (3.65 g,
12.0 mmol), Pd2dba3 (0.197 g, 0.215 mmol, 3.6 mol% Pd), X-
phos (0.547 g, 1.15 mmol, 9.6 mol%) and Cs2CO3 (5.47 g,
16.8 mmol, 1.4 eq) in tert-butyl alcohol (75 mL) was heated at
gentle reflux under nitrogen for 4 h. The resulting burgundy
suspension was then diluted with excess water (ꢁ100 mL) to
give a tan solid which was filtered by suction and washed with
water. Recrystallization of the dried product from EtOH (ꢁ400
mL), with hot filtration to remove traces of Pd metal, gave
pinkish colored microneedles (1.75 g, 65%), mp 230–233ꢀC.
IR (cmꢂ1): 3281, 3226, 2913, 2851, 2197, 1622, 1581, 1531,
1493, 1417, 1307, 1256, 1037, 859, 750. 1H NMR (DMSO-
d6): 1.93 (s, 3H), 2.10 (s, 3H), 4.99 (s, 2H), 6.82–6.86 (m,
1H), 6.94 (d, J ¼ 7.6 Hz, 1H), 7.09–7.15 (m, 2H), 9.73 (s,
NH). 13C NMR (DMSO-d6): 8.7, 9.5, 42.7, 69.6, 112.6, 114.0,
114.2, 117.4, 117.7, 120.4, 127.0, 128.1, 135.7, 138.1. Anal.
Calcd for C14H13N3 (223.27): C, 75.31; H, 5.87; N, 18.82.
Found: C, 75.10; H, 5.91; N, 18.75.
1
1440, 1219, 1105, 1025, 751, 658. H NMR (DMSO-d6): 1.78
(s, 3H), 1.90 (s, 3H), 4.93 (s, 2H), 5.78 (s, NH2), 6.29 (d, J ¼
7.6 Hz, 1H), 7.20–7.23 (m, 1H), 7.29–7.32 (m, 1H), 7.63 (dd,
J ¼ 7.8 and 1.1 Hz, 1H). 13C NMR (DMSO-d6): 9.0, 9.8,
45.5, 71.3, 112.0, 116.9, 118.3, 121.1, 126.5, 128.1, 129.0,
132.5, 136.4, 146.8. Anal. Calcd for C14H14BrN3 (304.19): C,
55.28; H, 4.64; N, 13.81. Found: C, 55.30; H, 4.51; N, 13.71.
2-Amino-1-(2-bromobenzyl)-3-(tert-butoxycarbonyl)-4,5-dime-
thylpyrrole (2b). Using tert-butyl cyanoacetate in place of
malononitrile, this compound was obtained in 55% yield as
yellow/tan crystals, mp 134–135ꢀC (MeOH). IR (cmꢂ1): 3443,
3335, 2974, 2927, 1649, 1607, 1504, 1439, 1364, 1302, 1245,
1104, 1026, 753, 743. 1H NMR (DMSO–d6): 1.47 (s, 9H),
1.78 (s, 3H), 2.00 (s, 3H), 4.93 (s, 2H), 5.95 (s, NH2), 6.31
(dd, J ¼ 7.7 and 1.5 Hz, 1H), 7.20–7.23 (m, 1H), 7.28–7.31
(m, 1H), 7.63 (dd, J ¼ 7.8 and 1.3 Hz, 1H). 13C NMR
(DMSO-d6): 8.6, 11.6, 28.5, 45.1, 77.6, 92.3, 111.2, 116.6,
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An Intramolecular N-Arylation Approach to 3-Functionalized 4,
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709
1H), 7.38 (t, 2H), 7.92–7.97 (m, 2H), 8.59 (s, NH). 13C NMR
(DMSO-d6): 8.4, 9.3, 42.7, 95.7, 110.1, 114.3, 115.3, 116.2,
116.5, 119.4, 120.9, 126.9, 128.1, 128.5 (d, J ¼ 9 Hz), 135.0
(d, J ¼ 17 Hz), 141.3 (d, J ¼ 3 Hz), 163.9 (d, J ¼ 250 Hz).
19F NMR (DMSO-d6): 55.3 (m). Anal. Calcd for
C19H17FN2O2S (356.41): C, 64.03; H, 4.81; N, 7.86. Found: C,
63.87; H, 4.80; N, 7.80.
3-tert-Butoxycarbonyl-1,2-dimethyl-4,9-dihydropyrrolo[2,1-
b]quinazoline (3b). This compound was obtained in 84% yield
as gray microneedles, mp 142–143ꢀC (MeOH). IR (cmꢂ1):
3374, 3059, 3005, 2969, 2935, 2856, 1640, 1612, 1579, 1419,
1
1277, 1268, 1179, 1127, 1107, 1067, 779, 740, 706. H NMR
(DMSO-d6): 1.49 (s, 9H), 2.01 (s, 3H), 2.09 (s, 3H), 4.99 (s,
2H), 6.82–6.87 (m, 1H), 7.10–7.15 (m, 3H), 8.60 (s, NH). 13C
NMR (DMSO-d6): 8.4, 11.0, 28.4, 42.5, 78.1, 92.2, 111.5,
114.4, 114.9, 117.7, 120.5, 127.0, 128.0, 135.5, 137.9, 165.2.
Anal. Calcd for C18H22N2O2 (298.38): C, 72.46; H, 7.43; N,
9.39. Found: C, 72.20; H, 7.35; N, 9.28.
Acknowledgments. We thank our department and Pamplin Col-
lege of Arts and Sciences for funding of this work.
1,2-Dimethyl-3-(methylsulfonyl)-4,9-dihydropyrrolo[2,1-
b]quinazoline (3c). This compound was obtained in 76%
yield as pale orange/tan needles, mp 176–179ꢀC (MeOH). IR
(cmꢂ1): 3338, 3044, 2929, 2856, 1610, 1571, 1492, 1272,
REFERENCES AND NOTES
[1] Griswold, C. P.; Suthiwangcharoen, N.; Pochini, S. M.; Ste-
phens, C. E.; Synth Comm, in press.
1
1105, 943, 855, 754, 740, 712. H NMR (DMSO-d6): 2.02 (s,
3H), 2.18 (s, 3H), 3.02 (s, 3H), 5.03 (s, 2H), 6.84–6.91 (m,
1H), 7.10–7.16 (m, 3H), 8.26 (s, NH). 13C NMR (DMSO-d6):
8.4, 9.2, 42.6, 45.5, 96.3, 110.4, 114.2, 115.0, 118.6, 120.7,
126.9, 128.1, 134.2, 135.2. Anal. Calcd for C14H16N2O2S
(276.36): C, 60.85; H, 5.84; N, 10.14. Found: C, 60.87; H,
5.81; N, 10.08.
1,2-Dimethyl-3-(phenylsulfonyl)-4,9-dihydropyrrolo[2,1-
b]quinazoline (3d). This compound was obtained in 49%
yield as coral/orange microcrystals, mp 229–231ꢀC (DMF/
MeOH). IR (cmꢂ1): 3362, 3047, 2917, 2853, 1610, 1571,
1524, 1494, 1445, 1282, 1124, 1080, 854, 753, 723, 685. 1H
NMR (DMSO-d6): 1.91 (s, 3H), 2.05 (s, 3H), 5.01 (s, 2H),
6.88 (t, 1H), 7.10–7.18 (m, 2H), 7.28 (d, J ¼ 7.6 Hz, 1H),
7.51–7.58 (m, 3H), 7.86–7.89 (m, 2H), 8.57 (s, 1H). 13C NMR
(DMSO-d6): 8.4, 9.3, 42.7, 95.9, 110.2, 114.3, 115.3, 119.3,
120.9, 125.5, 126.9, 128.1, 129.2, 132.2, 134.9, 135.2, 144.9.
Anal. Calcd for C19H18N2O2S (338.42): C, 67.43; H, 5.36; N,
8.28. Found: C, 67.36; H, 5.39; N, 8.26.
[2] (a) Boganyi, B.; Kaman, J. J Heterocycl Chem 2009, 46,
33; (b) Loones, K. T. J.; Maes, B. U. W.; Herrebout, W. A.; Dom-
misse, R. A.; Lemiere, G. L. F.; Van der Veken, B. J. Tetrahedron
2007, 63, 3818; (c) Venkatesh, C.; Sundaram, G. S. M.; Ila, H.; Jun-
jappa, H. J Org Chem 2006, 71, 1280; (d) Kitamura, Y.; Hashimoto,
A.; Yoshikawa, S.; Odaira, J.; Furuta, T.; Kan, T.; Tanaka, K. Synlett
2006, 115; (e) Tietze, M.; Iglesias, A.; Merisor, E.; Conrad, J.;
Klaiber, I.; Beifuss, U. Org Lett 2005, 7, 1549; (f) van den Hoogen-
brand, A.; den Hartog, J. A. J.; Lange, J. H. M.; Terpstra, J. W. Tetra-
hedron Lett 2004, 45, 8535.
[3] (a) Liu, J.-F.; Ye, P.; Sprague, K.; Sargent, K.; Yohannes,
D.; Baldino, C. M.; Wilson, C. J.; Ng, S.-C. Org Lett 2005, 7, 3363;
(b) Mhaske, S. B.; Argade, N. P. J Org Chem 2001, 66, 9038.
[4] (a) Wiedmann, S. H.; Ellman, J. A.; Bergman, R. G. J Org
Chem 2006, 71, 1969; (b) Kamal, A.; Shankaraiah, N.; Devaiah, V.;
Reddy, K. L. Tetrahedron Lett 2006, 47, 9025.
[5] (a) Mattson, R. J.; Wang, L.-C.; Sowell, J. W. J. Sr. Hetero-
cycl Chem 1980, 17, 1793; (b) Stephens, C. E.; Sowell, J. W. Sr.
J Heterocycl Chem 1996, 33, 1615.
3-(4-Fluorophenylsulfonyl)-1,2-dimethyl-4,9-dihydropyr-
rolo[2,1-b]quinazoline (3e). This compound was obtained in
49% yield as coral/red microneedles, mp 222–223ꢀC (DMF/
MeOH). IR (cmꢂ1): 3379, 3103, 3069, 3043, 2918, 1609,
1571, 1491, 1281, 1222, 1128, 1079, 848, 818, 748, 710, 685,
661. H NMR (DMSO-d6): 1.91 (s, 3H), 2.05 (s, 3H), 5.01 (s,
2H), 6.88 (t, 1H), 7.10–7.15 (m, 2H), 7.28 (d, J ¼ 8.0 Hz,
[6] Lebedev, A. Y.; Khartulyari, A. S.; Voskoboynikov, A. Z.
J Org Chem 2005, 70, 596.
[7] (a) Charles, M. D.; Schultz, P.; Buchwald, S. L. Org Lett
2005, 7, 3965; (b) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman,
R. A.; Buchwald, S. L. Angew Chem Int Ed 2006, 45, 6523; (c)
Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapers, A.; Buch-
wald, S. L. J Am Chem Soc 2003, 125, 6653.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet