Synthesis of functionalized arylpyridines and -pyrimidines by domino [4+2]/retro [4+2] cycloadditions of electron-rich dienes with alkynylpyridines and -pyrimidines

Article abstract of DOI:10.1039/c0ob00755b

Aryl-substituted pyridines and pyrimidines were prepared by [4+2] cycloadditions of alkynyl-substituted pyridines and -pyrimidines with electron-rich dienes. The reactions proceed by formation of a bridged cycloadduct and subsequent thermal extrusion of ethylene. The pyridine moiety plays a crucial role for the success of the reaction.

Full text of DOI:10.1039/c0ob00755b

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PAPER
Synthesis of functionalized arylpyridines and -pyrimidines by domino
[4+2]/retro [4+2] cycloadditions of electron-rich dienes with alkynylpyridines
and -pyrimidines
Obaid-ur-Rahman Abid,a Muhammad Nawaz,a Muhammad Farooq Ibad,a Rasheed Ahmad Khera,a
Viktor Iaroshenkoa and Peter Langer*a,b
Received 21st September 2010, Accepted 21st October 2010
DOI: 10.1039/c0ob00755b
Aryl-substituted pyridines and pyrimidines were prepared by [4+2] cycloadditions of
alkynyl-substituted pyridines and -pyrimidines with electron-rich dienes. The reactions proceed by
formation of a bridged cycloadduct and subsequent thermal extrusion of ethylene. The pyridine moiety
plays a crucial role for the success of the reaction.
to symmetric molecules, catalyzed by Pd(OAc)2, have also been
Introduction
reported.10 Syntheses of arylpyridines have been achieved by
Biaryls and their heterocyclic analogues are of considerable im-
direct cross-coupling of pyridyl halides and boronic acids. This
portance, specifically with respect to their occurrence in bioactive
strategy has been effectively applied to the use of both pyridyl
halides as well as pyridine boronic acids as coupling partners.11
Despite the great utility of these methods, the synthesis of more
complex, highly functionalized derivatives can be difficult by
these methods because the starting materials are not readily
available.
natural products and to their applications in medicinal chemistry
and as ligands in metal catalysis.1–3 Heterocyclic biaryls have been
shown to possess activity in a wide range of therapeutic assays and
show, for example, antifungal, anti-inflammatory, antirheumatic,
antitumor and antihypertensive activity.3 They have been shown
to be useful as antibacterial agents by inhibiting Gram-positive
and Gram-negative bacteria4 and as anti-inflammatory agents.
Owing to their heterocyclic structure, 4-phenylpyridines have
been reported as a novel class of selective glucagon antagonists.5
Particular 4-aryl-1,4-dihydropyridines are already in use for the
treatment of a number of cardiovascular disorders, such as
hypertension, cardiac arrhythmias or angina.6,7 (Pyrid-2-yl)arenes
are also present, hidden in a cyclic framework, in natural 4-
azafluorenones (e.g. kinabaline, darienine and onychine) which
exhibit a strong antimicrobial activity.8
Because of the significant importance of biaryls possessing
a heterocyclic aromatic ring in natural products, as well as in
molecular recognition phenomena and in asymmetric synthesis,3
the development of new and selective synthetic strategies, which
overcome obstacles of known methods, is an important area
of research. For the synthesis of arylpyridines a number of
palladium-catalyzed reactions have been developed. This includes
particularly the use of palladium-mediated strategies, such as
the Kharasch, Negishi, Stille and Suzuki reactions.9 Homo-
coupling reactions of heterocyclic aromatic bromides, leading
An alternative strategy for the synthesis of arylpyridines relies
on the application of a building block strategy. Recently, we
reported the synthesis of 6-(pyridyl)salicylates based on a building
block approach. The products were formed by formal [3+3]
cyclizations of 1,3-bis(silyl enol ethers) with 3-pyridyl-3-silyloxy-
2-en-1-ones.12 Diels–Alder reactions constitute a very important
method for the assembly of complex molecules.13 In recent years,
[4+2] cycloaddition reactions of alkynes have been widely used for
the synthesis of biaryls.14 However, the synthesis of arylpyridines
by cycloaddition reactions of pyridylacetylenes has, to the best
of our knowledge, not been reported to date. Recently, Carter
and co-workers have reported the synthesis of nitro-substituted
biaryls by Diels–Alder reaction of (nitrophenyl)acetylenes with
electron-rich dienes.15 It is important to note that the presence
of the nitro group played an important role for the success of
these reactions. The corresponding reactions of phenylacetylene
proceeded in low yields or not at all. It occurred to us that
the use of pyridyl- and pyrimidyl-substituted acetylenes in [4+2]
cycloaddition reactions should be equally successful as the use of
(ortho-nitrophenyl)acetylenes because pyridines possess a strong
electron withdrawing character. Herein, we report the results of
our studies related to [4+2] cycloaddition reactions of pyridyl-
and pyrimidyl-substituted acetylenes with electron-rich dienes.
These transformations provide a convenient approach to various
functionalized arylpyridines and -pyrimidines.
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059,
Rostock, Germany. E-mail: peter.langer@uni-rostock.de; Fax: +381
4986412
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-
Einstein-Str. 29a, 18059, Rostock, Germany
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Table 1 Synthesis of 2a–c and 4a–c
Diene Acetylene
Conditions
140 ◦C, 4 h
Product Yielda (%)
A
B
1
1
2a
63
57
1) 140 ◦C, 4 h; 2) K2CO3, 2b
MeOH, 15 min
C
1
1) 140 ◦C, 4 h; 2) K2CO3, 2c
MeOH, 15 min
55
A
B
3
3
140 ◦C, 16 h
4a
52
44
1) 140 ◦C, 6 h; 2) K2CO3, 4b
MeOH, 15 min
C
3
1) 140 ◦C, 6 h; 2) K2CO3, 4c
MeOH, 15 min
42
a Yields of isolated products.
Results and discussion
Cyclic dienes A and B are commercially available (Chart 1), while
C was prepared by a known procedure.15a Danishefsky’s diene (D)
is commercially available. Brassard’s diene (E)16 and Chan’s diene
(F)17 are available by known methods.
Scheme 2 Diels–Alder reactions of A–C with pyridyl acetylenes 1 and 3.
of 2a–c. In addition, better yields were obtained for 2a–c as
compared to 4a–c. This can be explained by the higher electron-
withdrawing effect of the 2-pyridyl compared to the 3-pyridyl
substituent which plays a role because all cycloadditions are
of normal electron demand. The reactions were carried out by
heating of the neat mixture of the starting materials. The yields
decreased when the reactions were carried out in a solution of
toluene or xylene. The yields also decreased when the temperature
was lowered or when the reaction time was shortened. Products 2a
and 4a were isolated by directed chromatographic purification of
the reaction mixture. In case of 2b,c and 4b,c a MeOH suspension
of potassium carbonate was added to the mixture to cleave the
silyl groups. The reaction of 2 with open-chain dienes D–F proved
to be unsuccessful. This can be explained by decomposition of
the dienes due to the high temperatures required. Carter et al.
reported that the corresponding reactions of D–F with (ortho-
nitrophenyl)acetylene also failed.
The experiments show that our hypothesis was correct and
pyridyl-substituted acetylenes indeed represent useful starting
materials for cycloaddition reactions with electron rich dienes.
The presence of the electron-withdrawing pyridine moiety plays,
as expected, a crucial role for the success of the reaction. The
corresponding reaction of A and C with phenylacetylene has been
reported by Carter and co-workers to proceed sluggishly in only 26
and 38% yields.15e The reaction of phenylacetylene with B failed.
In contrast, the yields of the reactions of (2-nitrophenyl)acetylene
with dienes A–C (ca. 80%)15e are higher than the yields of 2a–c.
With these promising results in hand, we further studied
the preparative scope of the methodology. Alkynes 618 and 919
were prepared, following known procedures, by Sonogashira
cross coupling reaction of 5 and 8 with TMS-acetylene and
subsequent removal of the TMS group using TBAF, respectively
(Scheme 3, Table 2). The reactions of acetylenes 6 and 9 with dienes
A–C afforded the cycloadducts 7a–c and 10a–c in good yields,
Chart 1 Dienes used in this study.
The [4+2] cycloaddition of (2-pyridyl)acetylene (1) with dienes
A–C afforded the 2-arylpyridines 2a–c in 55–63% yield (Schemes 1
and 2, Table 1). Likewise, 3-arylpyridines 4a–c were prepared
in 42–52% yield by reaction of (3-pyridyl)acetylene (3) with
dienes A–C. Products 2a–c and 4a–c were formed with excellent
regioselectivity. Their formation can be explained by formation
of a bridged cycloadduct and subsequent thermal extrusion
of ethylene by a retro Diels–Alder reaction (Schemes 1). The
syntheses of 4a–c required longer reaction times than the syntheses
Scheme 1 Diels–Alder reactions of A with pyridyl acetylene 1.
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Table 2 Synthesis of 7a–c and 10a–c
Diene Acetylene Conditions
Product Yielda (%)
A
B
6
6
140 ◦C, 2 h
7a
69
62
1) 140 ◦C, 3 h; 2) K2CO3, 7b
MeOH, 15 min
C
6
1) 140 ◦C, 3 h; 2) K2CO3, 7c
MeOH, 15 min
62
A
B
9
9
140 ◦C, 4 h
10a
55
43
1) 140 ◦C, 6 h; 2) K2CO3, 10b
MeOH, 15 min
C
9
1) 140 ◦C, 6 h; 2) K2CO3, 10c
MeOH, 15 min
48
Scheme 4 Diels Alder reactions of dienes A–C with acetylene 11.
a Yields of isolated products.
In conclusion, the [4+2] cycloaddition of pyridyl- and pyrimidyl-
substituted acetylenes with electron-rich dienes provide a con-
venient approach to aryl-substituted pyridines and pyrimidines
which are not readily available by other methods. The presence of
the electron-withdrawing pyridine moiety plays a crucial role for
the success of the reaction. Our present work is directed towards
exploring the scope and applications of the reactions reported
herein.
Experimental section
General procedure for the synthesis of biaryls
To a pressure tube containing the acetylene (1.0 equiv.) was added
the diene (1.5 or 3.0 equiv.). The reaction mixture was stirred at
140 ◦C for 2–16 h. In the case of diene A the reaction mixture was
directly then subjected to purification by chromatography over
silica gel eluting with EtOAc–heptane to give the product. In case
of dienes B and C, MeOH (5 mL) and K2CO3 (5 mmol) was added
at 20 ◦C. After stirring for 15 min, the solution was quenched with
a saturated aqueous solution of NH4Cl (30 mL). The mixture was
extracted with dichloromethane (2 ¥ 50 mL). The aqueous and the
organic layers were separated and the latter was dried (MgSO4),
filtered and concentrated in vacuo. The residue was purified by
chromatography over silica gel eluting with EtOAc–heptane to
give the product.
Scheme 3 Diels Alder reactions of A–C with acetylenes 6 and 9.
respectively. The presence of a weak electron-donating group in
the pyridyl ring of 9 resulted in a slight decrease of the yields of
cycloadducts 10a–c as compared to 2a–c.
2-(2-Methoxyphenyl)pyridine (2a)
Acetylene 11 was prepared by deprotonation of acetylene 3
with LDA followed by addition of 2-chlorobenzoyl chloride. The
cycloaddition of acetylene 11 with dienes A–C resulted in the
formation of the highly functionalized products 12a–c in 55–61%
yields (Scheme 4, Table 3). The yields of 12a–c are higher than
those of products 4a–c. This is remarkable because alkyne 11 is
more sterically hindered than alkyne 3. On the other hand, the 2-
chlorobenzoyl group has a strong electron withdrawing character.
Starting with 2-ethynylpyridine 1 (0.13 mL, 2.0 mmol) and diene
A (0.35 mL, 3.0 mmol), 2a was isolated as a colorless viscous
liquid (233 mg, 63%); 1H NMR (300 MHz, CDCl3): d 3.77 (s, 3H,
OCH3), 6.93 (d, J = 8.3 Hz, 1H, ArH), 7.01 (dt, J = 7.5, 1.0 Hz,
1H, ArH), 7.12 (dd, J = 7.4, 4.9, Hz, 1H, ArH), 7.27–7.33 (m,
1H, ArH), 7.61 (dt, J = 7.9, 1.9 Hz, 1H, ArH), 7.70 (dd, J = 7.6,
1.8 Hz, 1H, ArH), 7.74 (td, J = 8.0, 1.1 Hz, 1H, ArH), 8.63 (d, J =
4.8 Hz, 1H, ArH); 13C NMR (75.46 MHz, CDCl3): d 55.5 (OCH3),
111.3 (CH), 120.9 (CH), 121.5 (CH), 125.0 (CH), 129.0 (C), 129.8
Table 3 Synthesis of 12a–c
(CH), 131.0 (CH), 135.5 (CH), 149.3 (CH), 156.0 (C), 156.8 (C);
-1
˜
IR (ATR, cm ): n = 3049 (w), 2834 (w), 1599 (m), 1580 (s), 1563
Diene Conditions
Product Yielda (%)
(m), 1492 (s), 1459 (s), 1422 (s), 1300 (m), 1237 (s), 1160 (m), 1021
(s), 987 (m), 852 (w), 791 (m), 745 (s), 611 (m); MS (GC, 70 eV):
m/z (%): 186 (M+ + 1, 9), 185 (M+, 76), 184 (81), 156 (41), 155
(53), 154 (100), 141 (14), 128 (12), 127 (13), 115 (11), 89 (8), 80
(24), 78 (12), 51 (9); HRMS (ESI+): calc. for C12H12NO [M + H]+
186.0913; found 186.0916.
A
B
C
140 ◦C, 2 h
12a
61
51
55
1) 140 ◦C, 3 h; 2) K2CO3, MeOH, 15 min 12b
1) 140 ◦C, 3 h; 2) K2CO3, MeOH, 15 min 12c
a Yields of isolated products.
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4-(Pyrid-2-yl)phenol (2b)
4b was isolated as colorless crystals (75 mg, 44%), mp 198–199 ◦C;
1H NMR (300 MHz, d6-DMSO): d 6.90 (d(br), J = 8.5 Hz, 2H,
ArH), 7.39 (dd, J = 7.8, 4.8 Hz, 1H, ArH), 7.54 (d(br), J = 8.5 Hz,
2H, ArH), 7.94 (d(br), J = 8.1 Hz, 1H, ArH), 8.48 (d, J = 4.0 Hz, 1H,
ArH), 8.82 (s, 1H), 9.71 (s(br), 1H, OH); 13C NMR (75.46 MHz,
d6-DMSO): d 116.0 (2CH), 123.7 (CH), 127.7 (C), 128.0 (2CH),
Starting with 2-ethynylpyridine 1 (103 mg, 1.0 mmol), diene B
(505 mg, 3.0 mmol), MeOH (5 mL) and K2CO3 (0.69 g, 5 mmol),
2b was isolated as colorless crystals (97 mg, 57%), mp 151–153 ◦C;
1H NMR (300 MHz, d6-DMSO): d 6.87 (td, J = 8.8, 1.9 Hz, 2H,
ArH), 7.20–7.24 (m, 1H, ArH), 7.77–7.83 (m, 2H, ArH), 7.93 (td,
J = 8.8, 1.9 Hz, 2H, ArH), 8.58 (d(br), J = 4.8 Hz, 1H, ArH), 9.73
(s(br), 1H, OH); 13C NMR (75.46 MHz, d6-DMSO): d 115.4 (2CH),
119.0 (CH), 121.4 (CH), 127.9 (2CH), 129.6 (C), 136.9 (CH), 149.2
(CH), 156.1 (C), 158.5 (C); IR (ATR, cm ): n = 3180–2481 (br),
1592 (s), 1561 (m), 1523 (m), 1467 (s), 1422 (s), 1268 (s), 1246 (s),
1181 (s), 1098 (m), 998 (s), 837 (s), 776 (s), 743 (s), 576 (m); MS
(GC, 70 eV): m/z (%): 172 (M+ + 1, 11), 171 (M+, 100), 170 (30),
154 (9), 142 (11), 117 (8), 115 (9), 63 (3), 39 (2); HRMS (ESI+):
calc. for C11H10NO [M + H]+ 172.0757; found 172.0756.
133.2 (CH), 135.6 (C), 147.0 (CH), 147.4 (CH), 157.7 (C); IR
-1
˜
(ATR, cm ): n = 3170–2480 (br), 1698 (w), 1591 (m), 1580 (m),
1454 (m), 1385 (w), 1271 (m), 1232 (m), 1176 (m), 1062 (m), 1022
(m), 840 (s), 809 (s), 697 (s), 549 (s); MS (GC, 70 eV): m/z (%):
172 (M+ + 1, 14), 171 (M+, 100), 170 (19), 142 (10), 117 (12), 115
(11), 89 (5), 32 (4); HRMS (ESI+): calc. for C11H10NO [M + H]+
172.0757, found 172.0756.
-1
˜
3-Ethoxy-4-(pyrid-3-yl)phenol (4c)
Starting with 3-ethynylpyridine 3 (103 mg, 1.0 mmol), diene C
(636 mg, 3.0 mmol), MeOH (5 mL) and K2CO3 (0.69 g, 5 mmol),
4c was isolated as colorless crystals (90 mg, 42%), mp 168–170 ◦C;
1H NMR (300 MHz, d6-DMSO): d 1.27 (t, J = 6.9 Hz, 3H, CH3),
4.01 (q, J = 6.9 Hz, 2H, OCH2), 6.49 (dd, J = 8.2, 2.1 Hz, 1H,
ArH), 6.54 (d, J = 2.0 Hz, ArH), 7.18 (d, J = 8.2 Hz, 1H, ArH),
7.40 (dd, J = 7.8, 4.8 Hz, 1H, ArH), 7.87 (d(br), J = 7.9 Hz, 1H,
3-Ethoxy-4-(pyrid-2-yl)phenol (2c)
Starting with 2-ethynyl pyridine 1 (103 mg, 1.0 mmol), diene C
(636 mg, 3.0 mmol), MeOH (5 mL) and K2CO3 (0.69 g, 5 mmol), 2c
was isolated as colorless crystals (118 mg, 55%), m.p 142–143 ◦C;
1H NMR (300 MHz, CDCl3): d 1.21 (t, J = 7.0 Hz, 3H, CH3), 3.66
(q, J = 7.0 Hz, 2H, OCH2), 6.22–6.24 (m, 1H, ArH), 6.26 (d, J =
2.2 Hz, 1H, ArH), 7.11 (dt, J = 6.2, 1.3 Hz, 1H, ArH), 7.37 (d,
J = 8.1 Hz, 1H, ArH), 7.63 (dt, J = 8.0, 1.8 Hz, 1H, ArH), 7.71
(d, J = 7.9 Hz, 1H, ArH), 8.51–8.53 (m, 1H, ArH), 10.91 (s(br), 1H,
OH); 13C NMR (62.89 MHz, CDCl3): d 14.6 (CH3), 63.5 (OCH2),
100.3 (CH), 108.2 (CH), 118.9 (C), 121.2 (CH), 125.5 (CH), 131.8
(CH), 136.5 (CH), 147.9 (CH), 156.4 (C), 157.4 (CH), 160.0 (C);
ArH), 8.45 (d, J = 3.7 Hz, 1H, ArH), 8.68 (s, 1H, ArH), 9.69 (s(br)
,
1H, OH); 13C NMR (62.89 MHz, d6-DMSO): d 14.6 (CH3), 63.5
(OCH2), 100.4 (CH), 108.0 (CH), 117.1 (C), 123.3 (CH), 131.1
(CH), 134.3 (C), 136.5 (CH), 146.7 (CH), 149.3 (CH), 156.7 (C),
-1
-1
˜
159.1 (C); IR (ATR, cm ); IR (ATR, cm ): n = 3110–2390 (b),
1598 (m), 1513 (w), 1453 (s), 1385 (m), 1301 (m), 1257 (m), 1198
(s), 1120 (m), 1042 (m), 997 (m), 899 (w), 808 (s), 707 (s), 636 (s);
MS (GC, 70 eV): m/z (%): 216 (M+ + 1, 14), 215 (M+, 100), 187
(83), 186 (60), 160 (16), 158 (9), 131 (8), 130 (11), 77 (7), 51 (3);
HRMS (ESI+): calc. for C13H14NO2 [M + H]+ 216.1019; found
216.1018.
-1
-1
˜
IR (ATR, cm ): IR (ATR, cm ): n = 3220–2550 (br), 1613 (w),
1575 (s), 1454 (s), 1295 (m), 1180 (s), 1128 (s), 1035 (m), 991 (m),
774 (s), 632 (m), 563 (m); MS (GC, 70 eV): m/z (%): 216 (M+ + 1,
9), 215 (M+, 63), 214 (55), 201 (13), 200 (92), 187 (12), 186 (55),
172 (23), 171 (100), 170 (23), 130 (31), 117 (12), 80 (11), 63 (7),
51 (5), 29 (4); HRMS (EI): calc. for C13H13NO2 [M+]: 215.09408,
found 215.09396.
2-(2-Methoxyphenyl)pyrimidine (7a)
Starting with 2-ethynylpyrimidine 6 (208 mg, 2.0 mmol) and diene
A (0.35 mL, 3.0 mmol), 7a was isolated as a yellowish viscous
liquid (257 mg, 69%); H NMR (300 MHz, CDCl3): d 3.79 (s,
3-(2-Methoxyphenyl)pyridine (4a)
1
Starting with 3-ethynylpyridine 3 (206 mg, 2.0 mmol) and diene
A (0.35 mL, 3.0 mmol), 4a was isolated as a colorless viscous
liquid (192 mg, 52%); 1H NMR (300 MHz, CDCl3): d 3.72 (s, 3H,
OCH3), 6.92 (d, J = 8.3 Hz, 1H, ArH), 6.97 (dt, J = 7.5, 1.0 Hz,
1H, ArH), 7.21–7.31 (m, 3H, ArH), 7.77 (td, J = 8.0, 2.0 Hz, 1H,
ArH), 8.47 (d, J = 3.7 Hz, 1H, ArH), 8.70 (s(br), 1H, ArH); 13C
NMR (62.89 MHz, CDCl3): d 55.4 (OCH3), 111.2 (CH), 120.9
(CH), 122.8 (CH), 126.9 (C), 129.4 (CH), 130.5 (CH), 134.1 (C),
3H, OCH3), 6.96 (d, J = 8.3 Hz, 1H, ArH), 6.99 (dt, J = 7.5,
0.9 Hz, 1H, ArH), 7.13 (t, J = 4.9 Hz, 1H, ArH), 7.32–7.38 (m,
1H, ArH), 7.64 (dd, J = 7.5, 1.8 Hz, 1H, ArH), 8.77 (d, J = 4.9 Hz,
2H, ArH); 13C NMR (62.89 MHz, CDCl3): d 56.0 (OCH3), 111.9
(CH), 118.6 (CH), 120.7 (CH), 128.3 (C), 131.0 (CH), 131.7 (CH),
-1
˜
157.0 (2CH), 157.6 (C), 165.9 (C); IR (ATR, cm ): n = 3033 (w),
2937 (w), 2834 (w), 1714 (w), 1600 (m), 1566 (s), 1552 (s), 1494
(m), 1460 (m), 1412 (s), 1275 (m), 1238 (s), 1179 (m), 1127 (m),
1057 (m), 1021 (s), 803 (m), 750 (s), 633 (s); MS (GC, 70 eV): m/z
(%): 187 (M+ + 1, 12), 186 (M+, 100), 185 (50), 169 (34), 158 (12),
157 (39), 156 (29), 155 (13), 130 (29), 104 (13), 103 (44), 90 (15);
HRMS (ESI+): calc. for C11H11N2O [M + H]+ 187.0866, found
187.0866.
136.6 (CH), 147.8 (CH), 150.2 (CH), 156.5 (C); IR (ATR, cm-1):
-1
˜
IR (ATR, cm ): n = 3025 (w), 2936 (w), 2833 (w), 1598 (w), 1496
(s), 1462 (s), 1405 (s), 1333 (w), 1264 (s), 1235 (s), 1179 (m), 1121
(m), 1024 (s), 997 (s), 800 (m), 710 (s); MS (GC, 70 eV): m/z
(%): 186 (M+ + 1, 13), 185 (M+, 100), 184 (10), 170 (49), 141 (5),
115 (23), 89 (5), 63 (4); HRMS (EI): calc. for C12H11NO [M+]:
185.08352, found 185.08289.
4-(Pyrimidin-2-yl)phenol (7b)
Starting with 2-ethynylpyrimidine 6 (104 mg, 1.0 mmol), diene B
(505 mg, 3.0 mmol), MeOH (5 mL) and K2CO3 (0.69 g, 5 mmol),
7b was isolated as colorless crystals (107 mg, 62%), mp 183–185 ◦C;
1H NMR (300 MHz, d6-DMSO): d 6.89 (td, J = 8.8, 2.1 Hz, 2H,
4-(Pyrid-3-yl)phenol (4b)
Starting with 3-ethynylpyridine 3 (103 mg, 1.0 mmol), diene B
(505 mg, 3.0 mmol), MeOH (5 mL) and K2CO3 (0.69 g, 5 mmol),
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ArH), 7.31 (t, J = 4.9 Hz, 1H, ArH), 8.26 (td, J = 8.8, 2.1 Hz, 2H,
ArH), 8.81 (d, J = 4.9 Hz, 2H, ArH), 9.97 (s(br), 1H, OH); 13C NMR
(62.89 MHz, d6-DMSO): d 115.6 (2CH), 118.8 (CH), 128.3 (C),
129.6 (2CH), 157.6 (2CH), 160.2 (C), 163.6 (C); IR (ATR, cm-1):
127.7 (2CH), 129.8 (C), 130.5 (C), 137.4 (CH), 149.6 (CH), 153.7
-1
˜
(C), 158.3 (C); IR (ATR, cm ): n = 3080–2470 (br), 1704 (w), 1672
(w), 1601 (s), 1593 (s), 1522 (w), 1472 (s), 1374 (m), 1266 (s), 1234
(s), 1176 (m), 1111 (m), 1043 (m), 819 (s), 759 (m), 651 (m); MS
(GC, 70 eV): m/z (%): 186 (M+ + 1, 14), 185 (M+, 100), 184 (30),
157 (11), 141 (3), 131 (5), 128 (5), 63 (3), 39 (2); HRMS (ESI+):
calc. for C12H12NO [M + H]+ 186.0913; found 186.0913.
˜
n = 3129–2354 (b), 1704 (w), 1609 (m), 1550 (s), 1519 (m), 1407 (s),
1317 (m), 1283 (s), 1204 (s), 1166 (s), 1100 (m), 993 (m), 783 (s),
646 (s), 630 (s); MS (GC, 70 eV): m/z (%): 173 (M+ + 1, 12), 172
(M+, 100), 171 (12), 144 (2), 119 (55), 91 (4), 64 (5), 39 (2); HRMS
(EI): calc. for C10H8N2O [M+]: 172.06311, found 172.06280.
3-Ethoxy-4-(5-methylpyrid-2-yl)phenol (10c)
Starting with 2-ethynyl-5-methylpyridine 9 (117 mg, 1.0 mmol),
diene C (636 mg, 3.0 mmol), MeOH (5 mL) and K2CO3 (0.69 g,
5 mmol), 10c was isolated as colorless crystals (110 mg, 48%), mp
189–191 ◦C; 1H NMR (300 MHz, d6-DMSO): d 1.34 (t, J = 6.9 Hz,
3H, CH3), 2.29 (s, 3H, CH3), 4.04 (q, J = 6.9 Hz, 2H, OCH2), 6.45–
6.50 (m, 2H, ArH), 7.55 (dd, J = 8.2, 1.8 Hz, 1H, ArH), 7.66 (d,
J = 8.3 Hz, 1H, ArH), 7.78 (d, J = 8.2 Hz, 1H, ArH), 8.42 (s, 1H,
ArH), 9.66 (s(br), 1H, OH); 13C NMR (62.89 MHz, d6-DMSO):
d 14.7 (CH3), 17.7 (CH3), 63.6 (OCH2), 100.1 (CH), 107.8 (CH),
3-Ethoxy-4-(pyrimidin-2-yl)phenol (7c)
Starting with 2-ethynylpyrimidine 6 (104 mg, 1.0 mmol), diene C
(636 mg, 3.0 mmol), MeOH (5 mL) and K2CO3 (0.69 g, 5 mmol),
7c was isolated as colorless crystals (134 mg, 62%), mp 185–186 ◦C;
1H NMR (300 MHz, d6-DMSO): d 1.25 (t, J = 6.9 Hz, 3H, CH3),
4.00 (q, J = 6.9 Hz, 2H, OCH2), 6.47 (dd, J = 8.3, 1.8 Hz, ArH),
6.51 (d, J = 1.5 Hz, ArH), 7.31 (t, J = 4.8 Hz, 1H, ArH), 7.49
(d, J = 8.3 Hz, 1H, ArH), 8.81 (d, J = 4.8 Hz, 2H, ArH), 9.81
(s(br), 1H, OH); 13C NMR (62.89 MHz, d6-DMSO): d 14.7 (CH3),
64.0 (OCH2), 101.1 (CH), 107.5 (CH), 118.5 (CH), 120.2 (C),
119.5 (C), 123.5 (CH), 130.0 (C), 131.5 (CH), 136.2 (CH), 149.3
-1
˜
(CH), 152.7 (C), 157.3 (C), 159.2 (C); IR (ATR, cm ): n = 3120–
132.6 (CH), 157.0 (2CH), 158.4 (C), 160.1 (C), 165.4 (C); IR
2528 (br), 1613 (w), 1579 (m), 1455 (s), 1362 (w), 1300 (s), 1182 (s),
1124 (m), 1040 (s), 899 (w), 818 (s), 724 (w), 589 (m); MS (GC, 70
eV): m/z (%): 230 (M+ + 1, 6), 229 (M+, 47), 228 (36), 214 (82), 200
(26), 186 (26), 185 (100), 184 (28), 144 (21), 115 (9), 94 (12), 65 (5),
32 (4); HRMS (ESI+): calc. for C14H16NO2 [M + H]+ 238.1176;
found 230.1178.
-1
˜
(ATR, cm ): n = 3134–2606 (br), 1599 (m), 1571 (s), 1552 (s),
1468 (w), 1407 (s), 1321 (m), 1277 (s), 1235 (s), 1085 (m), 992
(m), 820 (m), 771 (m), 638 (s); MS (GC, 70 eV): m/z (%): 217
(M+ + 1, 11), 216 (M+, 100), 215 (26), 201 (42), 199 (13), 188 (15),
173 (18), 172 (74), 171 (11), 135 (18), 131 (25), 119 (29), 79 (6),
52 (6); HRMS (EI): calc. for C12H12N2O2 [M+]: 216.08933, found
216.08890.
(2-Chlorophenyl)(3-methoxy-2-(pyrid-3-yl)phenyl)methanone
(12a)
2-(2-Methoxyphenyl)-5-methyl-pyridine (10a)
Starting with 1-(2-chlorophenyl)-3-(pyrid-3-yl)prop-2-yn-1-one
Starting with 2-ethynyl-5-methylpyridine 9 (234 mg, 2.0 mmol)
and diene A (0.35 mL, 3.0 mmol), 10a was isolated as colorless
greenish viscous liquid (219 mg, 55%); 1H NMR (300 MHz,
CDCl3): d 2.28 (s, 3H, CH3), 3.76 (s, 3H, OCH3), 6.91 (d, J =
8.3 Hz, 1H, ArH), 7.00 (dt, J = 7.5, 1.0 Hz, 1H, ArH), 7.24–7.30
(m, 1H, ArH), 7.42 (dd, J = 8.1, 2.2 Hz, 1H, ArH), 7.63 (d, J =
11 (121 mg, 0.5 mmol) and diene A (0.18 mL, 1.5 mmol), 12a
was isolated as brown viscous liquid (98 mg, 61%); H NMR
1
(300 MHz, CDCl3): d 3.70 (s, 3H, OCH3), 6.89 (d, J = 7.7 Hz, 1H,
ArH), 6.95 (d, J = 8.2 Hz, 1H, ArH), 7.04–7.10 (m, 2H, ArH),
7.19–7.21 (m, 2H, ArH), 7.36 (d(br), J = 7.7 Hz, 1H, ArH), 7.42
(t, J = 8.1 Hz, 1H, ArH), 7.52 (td, J = 7.8, 1.9 Hz, 1H, ArH),
8.36 (d(br), J = 4.0 Hz, 1H, ArH), 8.41 (s, 1H, ArH); 13C NMR
(75.46 MHz, CDCl3): d 56.0 (OCH3), 111.0 (CH), 122.5 (CH),
122.7 (CH), 126.4 (CH), 129.6 (C), 130.9 (CH), 131.1 (CH), 131.6
(CH), 132.5 (CH), 132.9 (C), 135.4 (C), 136.3 (CH), 137.3 (C),
8.0 Hz, 1H, ArH), 7.68 (dd, J = 7.6, 1.8 Hz, 1H, ArH), 8.46 (s(br)
,
1H, ArH); 13C NMR (75.46 MHz, CDCl3): d 18.0 (CH3), 55.4
(OCH3), 111.2 (CH), 120.8 (CH), 124.3 (CH), 129.0 (C), 129.4
(CH), 130.8 (CH), 130.9 (C), 136.0 (CH), 149.6 (CH), 153.2 (C),
-1
-1
˜
156.7 (C); IR (ATR, cm ): IR (ATR, cm ): n = 2997 (w), 2920
(w), 2834 (w), 1599 (m), 1581 (m), 1495 (s), 1462 (s), 1434 (s), 1357
(m), 1240 (s), 1178 (m), 1121 (m), 1056 (m), 1022 (s), 832 (m), 750
(s); MS (GC, 70 eV): m/z (%): 200 (M+ + 1, 13), 199 (M+, 100),
198 (99), 170 (46), 169 (63), 168 (60), 167 (14), 154 (22), 142 (10),
141 (29), 128 (15), 115 (12), 94 (34), 84 (11). HRMS (EI): calc. for
C13H13NO [M+]: 199.09973, found 199.09890.
138.1 (C), 148.5 (CH), 149.3 (CH), 157.5 (C), 194.6 (CO); IR
-1
˜
(ATR, cm ): n = 3049 (w), 2937 (w), 2834 (w), 1600 (m), 1580 (s),
1492 (s), 1459 (s), 1422 (s), 1300 (m), 1256 (s), 1237 (s), 1179 (m),
1122 (m), 1021 (s), 987 (m), 745 (s), 729 (s), 611 (m); MS (GC,
70 eV): m/z (%): 325 (M+, 37Cl, 17), 323 (M+, 35Cl, 40), 322 (11),
294 (22), 289 (20), 288 (90), 272 (13), 260 (22), 213 (20), 212 (100),
207 (26), 183 (13), 169 (19), 141 (19), 139 (33), 111 (22), 75 (12);
HRMS (ESI+): calc. for C19H1535ClNO2 [M + H]+ 324.0786; found
324.0786.
4-(5-Methylpyrid-2-yl)phenol (10b)
Starting with 2-ethynyl-5-methylpyridine 9 (117 mg, 1.0 mmol),
diene B (505 mg, 3.0 mmol), MeOH (5 mL) and K2CO3 (0.69 g,
5 mmol), 10b was isolated as colorless crystals (80 mg, 43%), mp
173–175 ◦C; 1H NMR (300 MHz, d6-DMSO): d 2.30 (s, 3H, CH3),
6.85 (td, J = 8.8, 2.1 Hz, 2H, ArH), 7.61 (dd, J = 8.2, 2.2 Hz, 1H,
ArH), 7.72 (d, J = 8.1 Hz, 1H, ArH), 7.90 (td, J = 8.8, 2.1 Hz,
2H, ArH), 8.42 (s(br), 1H, ArH), 9.67 (s(br), 1H, OH); 13C NMR
(62.89 MHz, d6-DMSO): d 17.7 (CH3), 115.5 (2CH), 118.6 (CH),
(2-Chlorophenyl)-(5-hydroxy-2-(pyrid-3-yl)phenyl)methanone
(12b)
Starting with 1-(2-chlorophenyl)-3-(pyrid-3-yl)prop-2-yn-1-one
11 (121 mg, 0.5 mmol), diene B (252 mg, 1.5 mmol), MeOH
(2.5 mL) and K2CO3 (0.34 g, 2.5 mmol), 12b was isolated
as colorless crystals (79 mg, 51%), mp 98–100 ◦C; 1H NMR
(300 MHz, d6-DMSO): d 6.79 (d, J = 2.4 Hz, 1H, ArH), 6.93
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(dd, J = 8.5, 2.4 Hz, 1H, ArH), 7.28–7.41 (m, 5H, ArH), 7.45 (d,
J = 8.5 Hz, 1H, ArH), 7.65 (td(br), J = 8.0, 1.9 Hz, 1H, ArH), 8.42–
8.44 (m, 2H, ArH), 10.67 (s(br), 1H, OH); 13C NMR (75.46 MHz,
d6-DMSO): d 114.8 (CH), 118.3 (CH), 122.9 (CH), 127.0 (CH),
128.1 (C), 129.9 (CH), 130.1 (CH), 130.3 (C), 131.8 (CH), 134.1
5 G. H. Ladouceur, J. H. Cook, E. M. Doherty, W. R. Schoen, M. L.
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Y. Chen, F.-R. Chang, Y.-C. Shih, T.-J. Hsieh, Y.-C. Chia, H.-Y.
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(CH), 135.7 (CH), 136.3 (C), 138.8 (C), 141.5 (C), 148.0 (CH),
-1
˜
148.5 (CH), 161.1 (C), 193.9 (CO); IR (ATR, cm ): n = 3143–
2425 (br), 1651 (w), 1587 (m), 1462 (w), 1291 (s), 1218 (s), 1124
(m), 1053 (w), 929 (m), 758 (s), 710 (s), 605 (s); MS (GC, 70 eV):
m/z (%): 311 (M+, 37Cl, 9), 310 (M+ + 1, 35Cl, 13), 309 (M+, 35Cl,
29), 308 (26), 280 (23), 274 (52), 246 (15), 207 (18), 199 (66), 198
(100), 139 (18), 115 (14), 111 (13), 44 (6); HRMS (EI): calc. for
C18H12NO235Cl [M+]: 309.05511, found 309.05438.
9 (a) D. J. Madar, H. Kopecka, D. Pireh, J. Pease, M. Pliushchev, R. J.
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Tolomeo, Tetrahedron Lett., 2003, 44, 3005; (o) Y.-Q. Fang and G. S.
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Chem., 1988, 53, 386; (q) N. M. Simkovsky, M. Ermann, S. M. Roberts,
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and R. P. Volante, J. Org. Chem., 2004, 69, 8723; (u) V. Bonnet, F.
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45, 1282; (b) K. L. Billingsley, K. W. Anderson and S. L. Buchwald,
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(2-Chlorophenyl)-(3-ethoxy-5-hydroxy-2-(pyridin-3-
yl)phenyl)methanone (12c)
Starting with 1-(2-chlorophenyl)-3-(pyridin-3-yl)prop-2-yn-1-one
11 (121 mg, 0.5 mmol), diene C (318 mg, 1.5 mmol), MeOH
(2.5 mL) and K2CO3 (0.34 g, 2.5 mmol), 12c was isolated as
colorless crystals (97 mg, 55%), mp 154–156 ◦C; 1H NMR
(300 MHz, d6-DMSO): d 0.82 (t, J = 6.9 Hz, 3H, CH3), 3.82
(q, J = 6.9 Hz, 2H, OCH2), 6.40 (d, J = 2.1 Hz, 1H, ArH), 6.50
(d, J = 2.0 Hz, 1H, ArH), 7.32–7.50 (m, 5H, ArH), 7.66 (td(br)
,
J = 7.9, 2.0 Hz, 1H, ArH), 8.45 (d, J = 1.8 Hz, 1H, ArH), 8.47
(dd, J = 4.8, 1.4 Hz, 1H, ArH), 10.37 (s(br), 1H, OH); 13C NMR
(62.89 MHz, d6-DMSO): d 13.9 (CH3), 63.9 (OCH2), 99.7 (CH),
110.4 (CH), 120.0 (C), 123.2 (CH), 127.2 (CH), 130.3 (CH), 130.4
(CH), 131.1 (C), 132.2 (CH), 135.9 (CH), 136.4 (C), 140.0 (C),
140.7 (C), 148.2 (CH), 148.7 (CH), 159.5 (C), 160.9 (C), 193.6
-1
˜
(CO); IR (ATR, cm ): n = 3151–2580 (br), 1667 (m), 1558 (m),
1435 (m), 1291 (m), 1178 (s), 1137 (m), 1035 (s), 928 (m), 762
(s), 742 (s), 623 (s); MS (GC, 70 eV): m/z (%): 355 (M+, 37Cl,
5), 354 (M+ + 1, 35Cl, 10), 353 (M+, 35Cl, 24), 308 (42), 242 (18),
214 (100), 199 (32), 198 (43), 139 (3), 115 (94), 111 (7), 44 (21);
HRMS (ESI+): calc. for C20H1735ClNO3 [M + H]+ 354.0894; found
354.0891.
Acknowledgements
Financial support by the State of Pakistan (HEC scholarships for
O.-u.-R. A., M. N., and R. A. K.) and by the DAAD (scholarships
for O.-u.-R. A., M. N., R. A. K., and M. F. I.) is gratefully
acknowledged. Funding for Dr. V. O. I. by the German Ministry
of Education and Research (BMBF) is gratefully acknowledged
(grant No. 03IS2081A).
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©