Dihydroquinazoline/Olefin Coupling by Rh(I)/PR3
Tricyclohexylphosphonium Hydrogen Dichloride (PCy3‚
2HCl). The reaction was carried out according to a modified
literature procedure that was believed to provide PCy3‚HCl.4g In a
round-bottom flask under N2, PCy3 (1.08 g, 3.85 mmol) was
dissolved in diethyl ether (25 mL). A solution of HCl (1 N in ether,
7.1 mL) was added dropwise with stirring. After 20 min the white
precipitate was filtered under N2 through a glass frit, washed with
ether (2 × 10 mL), and dried under vacuum over P2O5. The resulting
white powder (1.12 g, 82%) was stored under N2. IR (Figure S-2f,
Supporting Information): 2933, 2853, 2393 (P-H), 1451, 765 (vbr,
vs, Cl-H-Cl) cm-1. 1H NMR: δ 7.59 (br s, 1H, ClHCl), 7.22 (br
d, 1H, JP-H ) 482 Hz, PH), 2.54 (m, 3H, PCH), 2.2-1.2 (m, 30H).
13C NMR (100 MHz): δ 28.4 (d, JP-C ) 39.3 Hz), 27.9 (d, JP-C
) 3.4 Hz), 26.3 (d, JP-C ) 12.6), 25.1. 31P NMR (160 MHz): δ
23.0. Anal. Calcd for C18H35Cl2P: C, 61.18; H, 9.98. Found: C,
61.11; H, 10.20.
SO4, filtered, and concentrated under vacuum. The resulting cloudy,
light yellow liquid was distilled (89-91 °C, 0.01 mmHg) (lit. 105-
107 °C, 0.5 mmHg)56 to give 18 as a clear colorless liquid (7.4 g,
1
96%). IR: 3313 (br), 1470, 1440, 1010, 965, 745 cm-1. H NMR
(300 MHz): δ 7.54 (dd, 1H, J ) 7.3, 2.0 Hz), 7.36 (dd, 1H, J )
7.6, 1.7 Hz), 7.20 (m, 2H), 7.01 (d, 1H, J ) 15.9 Hz), 6.35 (dt,
1H, J ) 15.9, 5.6 Hz), 4.37 (dd, 2H, J ) 5.6, 1.4 Hz), 1.62 (br s,
1H). 13C NMR (75 MHz): δ 134.8, 133.1, 131.1, 129.7, 128.7,
127.1, 126.9, 126.8, 63.6. Anal. Calcd for C9H9ClO: C, 64.11; H,
5.38. Found: C, 64.43; H, 5.63.
Mixture of 1-[(E)-3-Bromoprop-1-enyl]-2-chlorobenzene (19)
and 1-(1-Bromoallyl)-2-chlorobenzene (20) (94:6). In a round-
bottom flask 18 (6.0 g, 36 mmol) was dissolved in CCl4 (7 mL)
under N2 and the solution was cooled to 0 °C. PBr3 (3.9 g, 14 mmol)
was added dropwise with stirring over 10 min. The reaction mixture
was stirred for an additional 30 min and then pipetted onto ice
water (40 mL). After an additional 10 min, CH2Cl2 (15 mL) was
added and the resulting organic phase removed. The aqueous phase
was further extracted with CH2Cl2 (20 mL). The combined organic
phases were washed with saturated NaHCO3 (15 mL) then brine
(15 mL), filtered, and concentrated under vacuum. The resulting
light yellow liquid (7.9 g, 96%) was found to contain 19 and 20 in
Tricyclohexylphosphonium Chloride (PCy3‚HCl). In a N2
atmosphere glovebox, PCy3 (500 mg, 1.78 mmol) and diethyl ether
(10 mL) were added to a glass-walled vessel equipped with a
vacuum stopcock. A solution of HCl (1 N in ether, 0.445 mL) was
added dropwise under N2. After being stirred for 2 h the reaction
suspension was filtered and washed with ether (2 × 10 mL) under
N2. The filtrate was concentrated under vacuum to afford unreacted
tricyclohexylphosphine (227 mg, 45%). The filter cake was dried
under vacuum to give PCy3‚HCl as a white powder (268 mg, 48%,
87% based on recovered PCy3). IR (Figure S-2g, Supporting
1
a 94:6 ratio by H NMR analysis. This material was used without
further purification. IR: 1469, 1435, 1200, 1033, 961, 747, 696
cm-1. 19: 1H NMR (300 MHz) δ 7.55 (dd, 1H, J ) 7.3, 2.1 Hz),
7.35 (dd, 1H, J ) 7.3, 2.0 Hz), 7.23 (m, 2H), 7.05 (d, 1H, J )
15.6 Hz), 6.39 (dt, 1H, J ) 15.6, 7.8 Hz), 4.18 (dd, 2H, J ) 7.8,
0.7 Hz). 20: 1H NMR (300 MHz) δ 7.61 (d, 1H, J ) 7.6 Hz), 7.31
(d, 1H, J ) 8.4 Hz), 7.22 (m, 2H), 6.28 (m, 1H), 6.08 (d, 1H, J )
7.5 Hz), 5.35 (d, 1H, J ) 16.7 Hz), 5.24 (d, 1H, 10.0 Hz). 19: 13C
NMR (75 MHz) δ 133.8, 133.3, 130.3, 129.8, 129.3, 127.8, 127.0,
126.9, 32.9. 20: 13C NMR (75 MHz) not detected.
Information): 2935, 2852, 2345 (P-H), 1439, 1299, 931, 884 cm-1
.
1H NMR (400 MHz): δ 8.01 (br d, 1H, JP-H ) 490 Hz, PH), 2.46
(m, 3H, PCH), 2.2-1.2 (m, 30H). 31P NMR (160 MHz): δ 20.6.
Anal. Calcd for C18H34ClP: C, 68.22; H, 10.81. Found: C, 68.17;
H, 11.08.
(E)-3-(2-Chlorophenyl)acrylic Acid Methyl Ester.55 A slurry
prepared from (E)-3-(2-chlorophenyl)acrylic acid (9.1 g, 50 mmol),
concentrated H2SO4 (5.8 g, 59 mmol), and MeOH (100 mL) was
dissolved by heating to reflux (85 °C). Reflux was continued 2 h,
then 80 mL of solvent was removed by distillation (68 °C, 1 atm).
After cooling, 80 mL of fresh MeOH was added and the reaction
was further refluxed overnight. Most of the solvent was removed
by distillation (85 mL, 68 °C, 1 atm) and the remaining cloudy,
biphasic material was treated with ether (100 mL) and ice water
(100 mL). The ether phase was removed, and the aqueous phase
was washed with ether (50 mL). The combined ethereal phases
were washed once with water (50 mL), twice with aqueous Na2-
CO3 (1M, 50 mL), and once with brine (50 mL), then dried over
Na2SO4, filtered, and concentrated under vacuum to give (E)-3-
(2-chlorophenyl)acrylic acid methyl ester as a clear liquid (9.2 g,
94%). IR: 1716, 1635, 1434, 1318, 1171, 758 cm-1. 1H NMR (300
MHz): δ 8.08 (d, 1H, J ) 15.9 Hz), 7.59 (m, 1H), 7.39 (m, 1H),
7.26 (m, 2H), 6.41 (d, 1H, J ) 16.2 Hz), 3.80 (s, 3H). 13C NMR
(125 MHz): δ 166.8, 140.6, 134.9, 132.6, 131.0, 130.1, 127.5,
127.0, 120.4, 51.8. Anal. Calcd for C10H9ClO2: C, 61.08; H, 4.61.
Found: C, 61.14; H, 4.52.
(E)-3-(2-Chlorophenyl)prop-2-en-1-ol (18). In a two-neck
round-bottom flask fitted with an addition funnel and a N2 inlet,
(E)-3-(2-chlorophenyl)acrylic acid methyl ester (9.0 g, 46 mmol)
was dissolved in CH2Cl2 (200 mL). After the reaction solution was
cooled to -78 °C DIBAl-H (1M in toluene, 135 mL) was added
dropwise over 30 min. The reaction mixture was warmed to 0 °C
over 1 h then MeOH (40 mL) was added dropwise, maintaining a
steady rate of gas evolution. The reaction mixture was warmed to
room temperature and stirred for 30 min before adding Rochelle’s
salt (saturated aqueous, 150 mL). The resulting layers were stirred
vigorously until the solution was clear. The organic phase was
removed and the aqueous phase was washed (3 × 150 mL of CH2-
Cl2). The combined organic phases were washed with saturated
Na2SO4 (150 mL) and brine (150 mL) and then dried over Na2-
3-[(E)-3-(2-Chlorophenyl)allyl]-3,4-dihydroquinazoline (21).
In a round-bottom flask, 2 (2.6 g, 20 mmol) was dissolved in DMF
(40 mL) with stirring under N2. After the mixture was cooled to 0
°C, K2CO3 (5.5 g, 40 mmol) and a solution of 19 and 20 (94:6)
(4.6 g, 20 mmol) in DMF (5 mL) were added to the reaction vessel.
The reaction mixture was stirred an additional 1 h at 0 °C and then
overnight at 25 °C. The resulting suspension was then diluted with
THF (120 mL), filtered, and concentrated under vacuum. Analysis
of the crude reaction mixture by 1H NMR indicated a >20:1 ratio
of 3,4-dihydro- to 1,4-dihydroquinazoline products. Column chro-
matography (6:3.5:0.5 f 4.75:4.75:0.5 EtOAc/actone/Et3N) af-
forded 21 (3.7 g, 65%) as a pale yellow powder, which was stored
under nitrogen until use. IR: 1609, 1593, 1569, 1486, 1165, 971,
1
762, 746 cm-1. H NMR (300 MHz): δ 7.52 (m, 1H), 7.37 (m,
1H), 7.27-6.97 (m, 7H), 6.86 (d, 1H, J ) 7.5 Hz), 6.11 (dt, 1H,
1
J ) 15.8, 6.5 Hz), 4.56 (s, 2H), 3.94 (d, 2H, J ) 6.5 Hz). H
NOESY: Figure S-2h, Supporting Information. 13C NMR (75
MHz): δ 149.9, 141.6, 134.1, 133.1, 131.0, 129.8, 129.2, 128.4,
127.0 (2C), 126.1, 125.7, 124.9, 124.6, 120.3, 55.0, 46.5. Anal.
Calcd for C17H15ClN2: C, 72.21; H, 5.35; N, 9.91. Found: C, 72.04;
H, 5.56; N, 9.77.
3-(2-Chlorophenyl)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazo-
line (23). The reaction was carried out according to the general
procedure for intramolecular olefin coupling reactions of DHQs
with 21 (1.13 g, 4.00 mmol), [RhCl(coe)2]2 (143 mg, 0.200 mmol),
and ca. 2:1 mixture of Cy-[3.3.1]-Phoban and exo-Cy-[4.2.1]-
Phoban (135 mg, 0.600 mmol) in 1,2-dichlorobenzene. The reaction
1
tube was heated to 150 °C for 10 h until H NMR indicated that
21 had been completely consumed. Column chromatography eluting
with CH2Cl2 containing 3.3% of a mixture of 15% NH4OH in
MeOH gave 23 as a tan powder (673 mg, 60%), which was stored
under nitrogen until use. If contaminated with trace quinazoline,
23 could be further purified by crystallization (slow vapor diffusion
of hexanes into THF). IR: 1625, 1588, 1568, 1479, 1438, 1167,
1037, 760, 721 cm-1. 1H NMR (300 MHz, C6D6): δ 7.39 (d, 1H,
(55) Terrian, D. L.; Mohammad, T.; Morrison, H. J. Org. Chem. 1995,
60, 1981.
(56) Cignarella, G.; Occelli, E.; Testa, E. J. Med. Chem. 1965, 8, 326.
J. Org. Chem, Vol. 71, No. 5, 2006 1975