Tetrabutylammonium fluoride promoted lntramolecular Nucleophilic attack of a carbodimide group on an α,β-unsaturated ester group

Article abstract of DOI:10.1055/s-1998-2032

(N-Aryl, N'-aryl/alkyl) carbodiimides bearing an α,βunsaturated ester moiety in the ortho position undergo cyclization in the presence of tetrabutylammonium fluoride under mild conditions to give dihydroquinazoline derivatives in synthetically useful yields.

Full text of DOI:10.1055/s-1998-2032

March 1998
SYNTHESIS
283
Tetrabutylammonium Fluoride Promoted Intramolecular Nucleophilic Attack
a b
of a Carbodiimide Group on an , -Unsaturated Ester Group
P. Molina,* E. Aller, A. Lorenzo
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, E-30071 Murcia, Spain
Received 30 June 1997
Abstract: (N-Aryl, N¢-aryl/alkyl) carbodiimides bearing an a,b- Aza-Wittig reaction of iminophosphorane 11 with alipha-
unsaturated ester moiety in the ortho position undergo cyclization
in the presence of tetrabutylammonium fluoride under mild condi-
tions to give dihydroquinazoline derivatives in synthetically useful
2, which were used for the next step without further puri-
yields.
tic and aromatic isocyanates in dry tetrahydrofuran at
room temperature gave the corresponding carbodiimides
fication. When compounds 2 were treated with a solution
of TBAF in tetrahydrofuran (1:4 molar ratio) at room tem-
perature for a short period of time (10 min) the dihydro-
Key words: carbodiimide, tetrabutylammonium fluoride, Michael
Addition, dihydroquinazolines, aza Wittig reaction
quinazoline derivatives 6 were obtained in yields ranging
from 56 to 88% (Scheme 1). When a 1:1 molar ratio was
We have reported1 that N,N¢ -diarylcarbodiimides bearing
used, the reaction proceeded very slowly and the yields
one o-vinyl substituent undergo a thermally induced 6p-
were lower. The best results were obtained when the reac-
electrocyclization to give quinoline derivatives. In this
tions were carried out in the presence of a mixture of an-
context, the so-called tandem aza-Wittig/carbodiimide
hydrous MgSO4/Na2SO4. When the reaction was carried
mediated electrocyclization methodology is successfully
out in the absence of this dehydrating agent the correspon-
utilized in heterocyclic synthesis.2 We report here the di-
ding ureas derived from 2 were found to be the major pro-
rect conversion of carbodiimides 2, readily available from
duct along with a small amount of 5.
iminophosphorane 1, into dihydroquinazoline derivatives
5 promoted by tetrabutylammonium fluoride (TBAF) in Iminophosphorane 1, also reacted with several vinyl iso-
synthetically useful yields. Formally, this conversion in- cyanates 7 to give the expected carbodiimides 8 (as evi-
volves an intramolecular N-conjugate addition to an a,b- denced by IR) which by treatment with TBAF under the
unsaturated ester moiety. In contrast to the various Micha- same reaction conditions afforded the corresponding 3-
el addition methods, there are few examples of hetero- vinyl-3,4-dihydroquinazoline derivatives 9 in yields ran-
conjugated addition of nitrogen compounds such as ging from 57 to 65%. Attempts to cyclize compounds 9 by
amines,3 amides,4 thiolactam,5 and guanidines.6 To the the action of TBAF/THF at reflux temperature failed, ex-
best of our knowledge no examples dealing with hetero- cept for compound 9c which under the above conditions
conjugate addition of carbodiimides to a,b-unsaturated provided, after dehydrogenation, the tricyclic compound
esters have been previously reported.
10 in 60% yield (Scheme 2).
Scheme 1

284
Papers
SYNTHESIS
Table 1. Dihydroquinazolines 6, 9, 10, and 13 Prepared
Prod-
ucta
R1
R2
mp (°C)
Yieldb
(%)
MS (70 eV)
m/z (%)
6a
6b
6c
6d
6e
6f
n-C3H7
–
–
–
–
–
–
172–173
133–134
130–131
205–206
167–168
170–171
64
72
88
75
73
77
262 (M+, 10), 219 (8), 189 (100),
147 (86), 129 (11), 91 (7), 77 (10)
iPr-C3H7
262 (M+, 3), 189 (64), 147 (100),
129 (7)
C6H5–CH2
C6H5
429 (M+, 1), 237 (59), 219 (12),
91 (100), 65 (25)
296 (M+, 5), 223 (100), 117 (13),
104 (22), 91 (12), 77 (53)
4-H3C–C6H4
4-H3CO–C6H4
310 (M+, 8), 237 (100), 118 (16),
91 (33), 65 (16)
326 (M+, 6), 253 (100), 181 (6),
162 (7), 149 (9), 134 (32), 117
(26), 107 (14), 92 (27), 77 (43)
6g
6h
9a
9b
4-Cl–C6H4
4-F–C6H4
H
–
211–212
179–180
128–129
229–230
56
40
60
57
332 (M+ +2, 2), 330 (M+, 6), 257
(100), 138 (24), 111 (36), 90 (20)
–
314 (M+, 4), 241 (100), 122 (27),
117 (14), 95 (38), 90 (12), 75 (12)
H
H
260 (M+, 10), 187 (100), 147 (31),
118 (7), 57 (7)
C6H5
322 (M+, 17), 249 (100), 204 (18),
147 (16), 132 (18), 117 (22), 103
(18), 91 (17), 77 (31)
9c
4-H3CO-C6H4
4-Cl–C6H4
H
H
208–210
213–214
60
59
352 (M+, 40), 279 (100), 132 (22),
117 (14), 89 (14), 59 (6)
358 (M+, + 2, 9), 356 (M+, 27), 283
(100), 162 (16), 147 (29), 132
(24), 102 (41), 89 (38), 77 (18)
9d
9e
10
C6H5
CH3
H
157–158
160–161
65
60
336 (M+, 10), 263 (37), 219 (19),
117 (40), 91 (45), 77 (24), 592
(22)
349 (M+ + 1, 1), 336 (17), 263 (50)
247 (18), 219 (25), 147 (100), 132
(10), 128 (22), 117 (35), 115 (55),
91 (33)
4-H3CO–C6H4
13
–
–
234–235
40
380 (M+, 17), 321 (8), 26 (15), 247
(100), 234 (10), 128 (33), 115
(11), 77 (8)
a Satisfactory microanalyses obtained: C ± 0.30, H + 0.28, N + 0.29.
b Yield of isolated pure product after chromatographic separation.
Scheme 2

March 1998
SYNTHESIS
285
Table 2. Spectral Data of Compounds 6, 9, 10, and 13
Prod-
uct
IR (Nujol)
1H NMR (300 MHz) (CDCl3/
TMS) d, J (Hz)
13C NMR (75 Hz) (CDCl3/TMS) d
n (cm–1)
6a
6b
6c
3194, 1728,
1669, 1471,
1297, 749
9.22 (s, 1H, NH), 7.10 (m, 1H),
6.99 (d, 1H, 3J = 7.1), 6.78 (m,
2H), 4.76 (dd, J = 8.2, 5.2, H4),
3.90 (m, 1H), 3.54 (s, 3H,
CH3O), 2.85 (m, 1H), 2.63 (m,
2H, CH2–COO), 1.57 (m, 2H),
0.83 (t, 3H, 3J = 7.1, CH3)
170.97 (q, COO), 155.11 (q, C2),
136.80 (q, C8a), 128.43, 125.17,
121.62, 120.98 (q, C4a), 114.15, 55.84
(C4), 51.70 (CH3O), 47.17 (CH2),
39.52 (CH2–COO), 21.39 (CH2), 11.09
(CH3-CH2)
3194, 1737,
1666, 1601,
1453, 1291,
1203, 746
9.04 (s, 1H, NH), 7.10 (m, 2H),
6.82 (m, 2H), 4.83 (dd, 1H, 3J =
8.2, 5.1, H4), 4.53 [m, 1H, 3J =
6.8, CH(CH3)2], 3.51 (s, 3H,
CH3O), 2.61 (m, 2H), 1.28 (d,
3H, 3J = 6.8, CH3), 1.18 (d, 3H,
3J = 6.8, CH3)
170.81 (q, COO), 155.28 (q, C2),
136.82 (q, C8a), 128.35, 124.92, 122.11
(q, C4a), 121.55, 114.07, 51.60 (CH3O)
51.12 (C4), 47.01 [CH(CH3)2], 41.25
(CH2), 21.33 (CH3), 20.70 (CH3)
3211, 1732,
1681, 1602,
1504, 1454,
1292, 1149,
756
9.25 (s, 1H, NH), 7.11 (m, 7H),
6.79 (m, 2H), 5.18 (d, 1H 3J =
15.4 H4), 4.73 (dd, 1H, 3J = 7.4,
5.4), 4.15 (d, 1H, 3J = 8.2, 5.1),
3.49 (s, 3H, CH3O), 2.59 (m, 2H,
CH2–COO)
170.78 (q, COO), 155.28 (q, C2),
137. 10 (q, Ci–Ph), 136.52 (q, C8a),
128.59, 128.53, 127.66, 127.41, 125.27,
121.87, 120.86 (q, C8a), 114.27, 55.11
(C4), 51.72 (CH3O), 48.59 (CH2-Ph),
39.40 (CH2–COO)
6d
6e
3190, 1736,
1673, 1440,
1417, 1216,
1149, 753
8.69 (s, 1H, NH), 7.34 (m, 5H),
7.21 (m, 2H), 6.87 (m, 1H), 6.72
(d, 1H, 3J = 7.9), 5.21 (dd, 1H, 3J
= 8.2, 5.1, H4), 3.42 (s, 3H,
170.38 (q, COO), 153.73 (q, C2),
140.73 (q, Ci–Ph), 136.48 (q, C8a),
129.15, 128.76, 127.41, 126.85, 125.53,
122.12, 121.04 (q, C4a), 114.44, 59.88
(C4), 51.65 (CH3O), 39.78 (CH2)
CH3O), 2.70 (m, 2H, CH2–COO)
3187, 1734,
1674, 1595,
1455, 1293,
1146, 763
8.62 (s, 1H, NH), 7.13 (m, 6H)
6.86 (m, 1H), 6.72 (d, 1H, 3J = 1
7.9), 5.15 (dd, 1H, 3J = 8.2, 5.1,
H4), 3.42 (s, 3H, CH3O), 2.73
(m, 2H, CH2), 2.28 (s, 3 H, CH3–
Ar)
170.39 (q, COO), 153.72 (q, C2),
40.69 (q, Ci–Ar), 136.72 (q), 136.49
(q), 129.17 (Cm–Ar), 128.78, 127.42
(C0–Ar), 126.89, 125.55, 122.16,
121.03 (q, C4a), 114.15, 59.87 (C4),
51.69 (CH3O), 39.76 (CH2–COO),
20.98 (CH3-Ar)
6f
3220, 1730,
1679, 1602,
1515, 1454
1298, 1247
8.96 (s, 1H, NH), 7.31 (d, 2H, 3J
= 8.7), 7.14 (m, 2H), 6.95 (m,
3H), 6.78 (d, 1H, 3J = 7.8), 5.20
(dd, 1H, 3J = 8.2, 5.1, H4), 3.81
(s, 3H, CH3O), 3.51 (s, 3H,
CH3O), 2.80 (m, 2H, CH2)
170.40 (q, COO), 158.21 (q, Cp–Ar),
153.93 (q, C2), 136.56 (q, C8a), 133.36
(q, C0–Ar), 128.91, 128.62, 125.40,
121.91, 120.82 (q, C4a), 114.44,
114.34, 60.11 (C4), 55.35 (CH3O–Ar),
51.60 (CH3O), 39.69 (CH2)
6g
6h
3187, 1731,
1673, 1595,
1462, 1293,
1152, 769
9.04 (s, 1H, NH), 7.30 (s, 4H)
7.10 (m, 2H), 6.89 (m, 1H), 6.71
(d, 1H, 3J = 7.9), 5.18 (dd, 1H, 3J
= 8.2, 5.2, H4), 3.44 (s, 3H,
CH3O), 2.66 (m, 2H, CH2)
170.25 (q, COO), 153.66 (q, C2),
139.21 (q), 136.24 (q, C8a), 132.35 (q),
129.24, 128.85, 128.70, 125.45, 122.28,
120.75 (q, C4a), 114.54, 59.80 (C4),
51.74 (CH3O), 39.78 (CH)2
170.30 (q, COO), 161.10 (q,1JF = 246.6
Cp–Ar), 153.85 (q, C2), 136.58 (q,
4JF = 3.2, Ci–Ar), 136.37 (q, C8a),
129.44 (3JF = 8.5), 128.78, 128.78,
125.43, 122.18, 120.71 (C4a), 115.97
(2JF = 22.65), 114.53 (CH3O) 60.06
(C4), 51.70 (CH3O), 39.77 (CH2)
3216, 1734,
1680, 1604,
1506, 1458,
1296, 1155,
841, 760
9.07 (s, 1H, NH), 7.31 (m, 2H),
7.08 (m, 4H), 6.87 (m, 1H), 6.70
(d, 1H, 3J = 7.9), 5.14 (dd, 1 H, 3J
= 5.2, 5.1, H4), 3.43 (s, 3H,
CH3O), 2.66 (m, 2H, CH2)
9a
9b
3204, 1740,
1679, 1604,
1295, 1217,
1200, 993,
953, 760
9.40 (s, 1H, NH), 7.15 (m, 1H),
7.02 (d, 1H, 3J = 7.2), 6.85 (m,
2H), 5.77 (m, 1H), 5.14 (m, 2H),
4.73 (dd, 1H, 3J = 8.1, 4.6, H4),
4.45 (m, 1H), 3.61 (m, 1H), 3.51
(s, 3H, CH3), 2.79 (dd, 1H, 2J =
14.6, 4.6), 2.52 (dd, 1H, 2J =
14.6, 8.1)
170.00 (q, COO), 153.20 (C2), 137.29
(q, C8a), 134.23, 128,34, 125.44,
121.21, 120.92 (q, C4a), 116.94 (CH2),
113.76, 54.50 (C4), 51.52 (CH3O),
46.56 (CH2), 39.09 (CH2–COO)
3207, 1728,
1693, 1682,
1644, 1609,
1506, 1454,
1326, 1134,
950, 755
10.05 (s, 1H, NH), 7.80 (d, 1H,
3J = 15.3), 7.28 (m, 7H), 6.95 (m,
2H), 6.19 (d, 1H, 3J = 15,3), 5.55
(dd, 1H, 3J = 7.5, 4.9, H4), 3.52
(s, 3H, CH3), 2.76 (m, 2H, CH2)
169.98 (q, COO), 150.65 (C2), 136.90
(q, Ci–Ph), 135.66 (q, C8a), 128.70,
125.94, 125.45, 125.12, 121.86, 119.96
(q, C4a), 114.04, 108.04, 52.26 (C4),
51.54 (CH3O), 38.56 (CH2)

286
Papers
SYNTHESIS
Table 2. (continued)
Prod-
uct
IR (Nujol)
1H NMR (300 MHz) (CDCl3/
TMS) d, J (Hz)
13C NMR (75 Hz) (CDCl3/TMS) d
n (cm–1)
9c
9d
9e
3198, 1729,
1682, 1602,
1507, 1247,
1178, 1035,
950, 839,
749
10.00 (s, 1H, NH), 7.67 (d, 1H,
3J = 15.2), 7.26 (m, 4H), 6.92 (m,
4H, 3J = 7.4), 6.14 (d, 1H, 3J =
15.2), 5.52 (d, 1H,3J = 7.1, 4.4,
H4), 3.72 (s, 3H, CH3O), 3.51 (s,
3H, CH3), 2.74 (m, 2H, CH2)a
70.09 (q, COO), 157.86 (q, Cp–Ar),
150.80 (q, C2), 135.82 (q), 129.39,
128.67 (q), 126.36, 125.92, 123.83,
121.85, 120.03 (q), 114.24, 114.10,
108.03, 55.05 (CH3), 52.38, 51.56
(CH3), 38.62 (CH2)a
3190, 1732,
1689, 1424,
1324
10.06 (s, 1H, NH), 7.80 (d, 1H,
3J = 15.2), 7,34 (m, 3H), 7.21 (d,
2H, 3J = 7.4), 6.95 (m, 2H), 6.16
(d, 1H,3J = 15.2), 5.53 (dd, 1H,
3J = 7.3, 4.8, H4), 3.51 (s, 3H,
CH3), 2.75 (m, 2H, CH2)a
170.05 (q, COO), 150.70 (C2), 136.07
(q, Ci–Ph), 135.71 (q, C8a), 130.22 (q)
128.71, 126.83, 126.31, 126.01, 122.00,
120.03 (q, C4a), 114.20, 106.88, 52.39
(C4), 51.63 (CH3O), 38.63 (CH2)a
3192, 1735,
1166, 1597,
1285, 1168,
1035, 977,
750, 696
9.56 (s, 1H, NH), 7.39 (m, 3H),
7.19 (m, 4H), 6.89 (m, 2H), 6.56
(s, 1H, PhCH=), 5.18 (dd, 1H, 3J
= 7.2, 4.8, H4), 3.48 (s, 3H,
170.25 (q, COO), 151.76 (q, C2),
138.05 (q), 137.01 (q), 136.00 (q, C8a),
128.81, 128.39, 128.33, 126.89, 126.51,
125.55, 121.30, 121.20 (q, C4a),
113.79, 57.99 (C4), 51.47 (CH3O),
40.60 (CH2), 18.34 (CH3)a
CH3O), 2.92 (dd, 1H, 2J = 14.6,
3J = 4.8), 2.70 (dd, 1H, 2J = 14.6,
3J = 7.2), 2.09 (s, 3H, CH3)a
10
13
3211, 1731,
1660, 1602,
1418, 1288,
1235, 1207,
1149, 914,
771, 726,
700
12.21 (s, 1H, NH), 8.52 (s, 1H),
7.86 (d, 1H, 3J = 7.9), 7.57 (m,
2H), 7.39 (d, 2H, 3J = 8.6), 7.25
(m, 2H), 7.05 (d, 2H, 3J = 8.6),
3.87 (s, 3H, CH3), 3.81 (s, 3H,
CH3)a
168.18 (q, COO), 158.91 (q, Cp–Ar),
151.11 (q), 147.00, 139.81 (q), 131.98
(q), 129.81, 129.62 (q), 127.53 (CH),
125.17 (q), 121.85, 120.06, 118.51 (q),
114.36, 111.83, 110.5 (q), 55.24 (CH3),
52.78 (CH3)a
3191, 1734,
1680, 1593,
1169, 1127,
763
9.02 (s, 1H, NH), 7.65 (d, 1H, 3J
= 7.8), 7.24 (m, 2H), 7.11 (m,
1H), 6.95 (m, 2H), 5.02 (d, 1H,
3J = 10.5, H6b), 3.82 (m, 1H,
H8), 3.54 (dd, 1H,3J=10.5, 4.4,
H7), 2.78 (m, 2H, CH2)
171.93 (q, COO), 154.45 (Cl), 136.96
(q), 136.37 (q), 131.09 (q), 128.70,
127.46, 127.03, 124.42, 123.81, 123.64,
122.58, 55.05, 52.41 (CH3), 51.78,
(CH3), 47.98, 35.58, 35.03 (CH2)
a Recorded in DMSO-d6.
Finally, the reaction of iminophosphorane 1 with solid
carbon dioxide in a sealed tube at 110°C yielded the car-
bodiimide 11, which was isolated without further purifi-
cation for the next step. Reaction of compound 11 with the
system TBAF/THF under standard conditions (Scheme 3)
gave the tetracyclic compound 13 as the sole reaction
product in 41% yield. It is worth noting that the conver-
sion 11 ® 13 implies the formation of three stereogenic
centers in only one-step. The structure 13 is assigned on
the basis of the coupling pattern of the tetrahydropyridine
ring protons in the 1H NMR spectrum: it shows both axial-
axial and axial-equatorial H-H relationships between the
neighboring H-6b, H-7 and H-8 protons.
As far as the mechanism of the conversion 2®6 is con-
cerned, it must be pointed out that ureas derived from 2
were recovered unchanged after further treatment with
TBAF/THF at room temperature. Hence, it is thought that
the TBAF strongly increases the nucleophilic character of
the nitrogen atom of the carbodiimide7 2 to give, presum-
ably, an intermediate like 3, which by attack of the nitro-
gen atom on the o-vinyl side chain in a Michael-type
addition leads to the cyclized product 4. Eventually, com-
pound 4 by the action of the water present in the TBAF/
THF solution affords tetrabutylammonium hydroxide and
the fluoropyrimidine derivative 5, which is hydrolyzed
Scheme 3
under the reaction conditions8 to the final product 6. Con-
version 11 ® 13 could be rationalized by initial formation
of the intermediate 12 which undergoes intramolecular
Michael addition with concomitant hydrolysis of the re-
sulting fluoropyrimidine derivative as described above to
give the final product 13.

March 1998
SYNTHESIS
287
bodiimide 11 was dissolved in dry THF (15 mL). To the resultant so-
lution anhyd MgSO4 (1.5 g), anhyd Na2SO4 (1.5 g) and 1 M TBAF in
THF (4.6 mL, 4.6 mmol) were added. The resultant mixture was
stirred at r.t. for 2 h, then extracted with EtOAc (3 ´ 15 mL). The
combined organic layers were dried (MgSO4), filtered and concen-
trated to dryness. The crude product was chromatographed on a silica
gel column (40 ´ 3.5 cm, 70–230 mesh) using Et2O as eluent to give
13 (Table 1).
In conclusion, this work shows, for the first time, that the
intramolecular addition of a carbodiimide group to an
a,b-unsaturated ester moiety, which represents the formal
addition of a urea group, can be efficiently achieved by
using TBAF as cyclization agent.
Dihydroquinazoline Derivatives 6 and 9; Geueral Procedure:
To a mixture of the iminophosphorane 1 (0.498 g, 1. 14 mmol), anhyd
THF (20 mL), anhyd MgSO4 (1.5 g) and anhyd Na2SO4 (1.5 g), was
added the corresponding isocyanate (1.14 mmol) under N2. The re-
sultant mixture was stirred at r.t. for 1 h. 1 M TBAF in THF (4.6 mL,
4.6 mmol) was added and stirring was continued for 10 min. The mix-
ture was poured into Na2HPO4 buffer (pH 7, 20 mL) and extracted
with EtOAc (2 ´ 10 mL). The organic layers were washed with sat.
brine (2 ´ 10 mL), water (2 ´ 10 mL) and finally dried (MgSO4). Af-
ter filtration the solution was concentrated to dryness and the crude
product was chromatographed (silica gel column, Et2O) to give 6 or 9
which were recrystallized from Et2O/hexane.
We gratefully acknowledge the financial support of the Dirección
General de Investigación Científica y Técnica (project number
PB95-I0I9).
(1) Molina, P.; Alajarín, M.; Vidal, A.; Sánchez-Andrada, P. J. Org.
Chem. 1992, 57, 929.
(2) For a review: Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197.
(3) Cabral, J.; Laszlo, P.; Mahé, L.; Montanfier, M. T.; Randriama-
hefa, S. L. Tetrahedron Lett. 1989, 30, 3969.
Pyrrolo[1,2-c]quinazoline Derivative 10:
(4) Ahn, K. M.; Lee, S. J. Tetrahedron Lett. 1994, 35, 1875.
(5) Fang, F. G.; Prato, M.; Kim, G.; Danishefsky, S. J. Tetrahedron
Lett. 1989, 30, 3625.
To a solution of dihydroquinazoline 9c (0.25 g, 0.7 mmol) in anhyd
THF (20 mL) was added 1 M TBAF in THF (4.6 mL, 4.6 mmol). The
resultant mixture was stirred at reflux temperature for 24 h. Workup
was similar to the preparation of compounds 6 and 9 (Table 1).
Maggini, M.; Prato, M.; Ranelli, M.; Scorrano, G. Tetrahedron
Lett. 1992, 33, 6537.
(6) Saito, T.; Tsuda K.; Saito, Y. Tetrahedron Lett. 1996, 37, 209.
(7) Molina, P.; Aller, E.; Ecija, A.; Lorenzo, A. Synthesis 1996, 690.
(8) Clark, H. R.; Beth, L. D.; Burton, R. M.; Garret, O. L.; Miller, A.
L.; Muscio Jr., O. J. J.Org.Chem. 1981, 46, 4363.
Dihydroquinazoline Derivative 13:
A mixture of iminophosphorane 1 (0.498 g, 1.14 mmol), excess of
solid CO2 and dry THF (20 mL) was heated at 110°C for 4 h in a
sealed tube. After cooling, the solvent was removed and the crude car-