PRACTICAL SYNTHETIC PROCEDURES
Tertiary Amines from Polyfunctional Amido(aryl)cuprates
1277
ture was stirred for 90 min to afford a 29:1 (average of three exper-
iments) regioisomeric ratio of magnesiated compounds in favor of
18, as determined by capillary GC analysis after iodolysis of a reac-
tion aliquot. This reagent, 18, was added dropwise to a solution of
1.0 M CuCl·2 LiCl in THF (1.2 mL, 1.2 mmol) and bis[2-(dimeth-
ylamino)ethyl] ether (192 mg, 1.2 mmol, distilled from CaH2 under
N2) at –50 °C and the mixture was stirred for 45 min. To the result-
ing arylcuprate 19, lithium morpholide (14) [2 mmol; prepared by
adding n-BuLi (2 mmol) to 0.5 M morpholine in THF (174 mg, 2
mmol), cooled to 0 °C and stirring for 30 min] was added dropwise
and the mixture was further stirred at –50 °C for 90 min. The mix-
ture was cooled to –78 °C, then chloranil (9, 295 mg, 1.2 mmol) in
anhyd THF (7 mL) was added slowly over a period of 30 min. The
mixture was allowed to reach –50 °C and was stirred for 12 h. Et2O
(10 mL) was added to the crude mixture and it was filtered through
Celite, washed with Et2O thoroughly (ca. 100 mL), and the filtrate
was washed with aq 2.0 M NH4OH (2 × 10 mL). The organic layer
was dried (MgSO4), filtered, and concentrated under reduced pres-
sure. Purification by flash chromatography (pentane–Et2O, 6:4) af-
forded the title amine 21 (116 mg, 50%) as a white crystalline solid;
mp 137.3–138.8 °C
N-[2-Chloro-5-(trifluoromethyl)phenyl]morpholine (27)
Prepared according to Procedure 1 from 1-chloro-2-iodo-4-(trifluo-
romethyl)benzene (306 mg, 1.0 mmol) (I/Mg exchange conditions:
i-PrMgCl·LiCl at 0 °C for 20 min) and lithium morpholide (14, 2
mmol; prepared as given in the typical procedure). Purification by
flash chromatography (pentane–CH2Cl2, 4:1) yielded 27 (183 mg,
69%) as a colorless oil.
IR (neat): 2962, 2858, 1603, 1418, 1310, 1298, 1113, 1084, 1041,
956, 820 cm–1.
3
1H NMR (300 MHz, CDCl3): d = 7.47 (dd, J = 4.4, 4.4 Hz, 1 H,
ArH), 7.23–7.26 (m, 2 H, ArH), 3.89 (t, 3J = 4.4, 4 H, 2 CH2), 3.09
(dd, 3J = 4.4, 4 H, 2 CH2).
13C NMR (75 MHz, CDCl3): d = 149.9, 131.6, 121.5, 120.8, 117.5,
67.3, 51.8.
19F NMR (280 MHz, CDCl3): d = –62.9 (s, 3 F, CF3).
MS (EI)+: m/z (%) = 265 (40) [M]+, 207 (100), 179 (16).
HRMS (EI): m/z calcd for C11H11NO35ClF3: 265.0481; found:
265.0460.
N-(2-Methylphenyl)morpholine (29)
IR (neat): 3118, 2971, 2919, 2855, 1585, 1542, 1428, 1234, 1170,
1118, 1040, 980, 930, 827, 808 cm–1.
Prepared according to Procedure 1 from 1.0 M 2-tolylmagnesium
chloride–lithium chloride (28) in THF (1.0 mL, 1.0 mmol) and lith-
ium morpholide (14, 2 mmol; prepared as given in the typical pro-
cedure). Purification by flash chromatography (pentane–Et2O, 9:1)
yielded 29 (103 mg, 58%) as a colorless oil. Spectroscopic data cor-
respond to those given in the literature.15
1H NMR (600 MHz, CDCl3): d = 6.57 (s, 2 H, ArH), 3.80 (t, 3J = 4.9
Hz, 4 H, 2 CH2), 3.29 (t, 3J = 4.9 Hz, 4 H, 2 CH2).
13C NMR (150 MHz, CDCl3): d = 158.3, 151.5, 106.5, 77.3, 46.4.
MS (EI, 70 eV): m/z (%) = 232 (75) [M]+, 231 (11), 216 (11), 177
1H NMR (300 MHz, CDCl3): d = 7.27–6.96 (m, 4 H, ArH), 3.86 (t,
3J = 4.6 Hz, 4 H, 2 CH2), 2.92 (t, 3J = 4.6 Hz, 4 H, 2 CH2), 2.33 (s,
3 H, CH3).
(12), 175 (62), 173 (100), 172 (21), 146 (10).
HRMS (EI): m/z calcd for C9H1035Cl2N2O: 232.0170; found:
232.0164.
N-(4-Methylphenyl)morpholine (31)
N-(4-Cyanophenyl)-N-ethylaniline (23)
Prepared according to Procedure 1 from 1.11 M 4-tolylmagnesium
chloride–lithium chloride complex (30) in THF (0.9 mL, 1.0 mmol)
and lithium morpholide (14, 2 mmol; prepared as given in the typi-
cal procedure). Purification by flash chromatography (pentane–
Et2O, 5:1) yielded 31 (125 mg, 71%) as a white solid. Spectroscopic
data correspond to those given in the literature.15
Prepared according to Procedure 1 from 4-bromobenzonitrile (11,
182 mg, 1.0 mmol) and lithium N-ethylanilide (22) (2.0 mmol, pre-
pared by adding n-BuLi to N-ethylaniline at –40 °C and stirring for
30 min, then the mixture was allowed to reach 0 °C and was stirred
for additional 15 min). Purification by flash chromatography (pen-
tane–Et2O, 9:1) yielded 23 (153 mg, 69%) as a yellow oil. Spectro-
scopic data correspond to those given in the literature.6d
1H NMR (300 MHz, CDCl3): d = 7.10 (d, J = 8.5 Hz, 2 H, ArH),
3
3
6.84 (d, 3J = 8.5 Hz, 2 H, ArH), 3.86 (t, J = 4.8 Hz, 4 H, 2 CH2),
1H NMR (300 MHz, CDCl3): d = 7.50–6.91 (m, 7 H, ArH), 6.66 (d,
3.11 (t, 3J = 4.8 Hz, 4 H, 2 CH2), 2.28 (s, 3 H, CH3).
3
3J = 9.0 Hz, 2 H, ArH), 3.78 (q, J = 7.2 Hz, 2 H, CH2), 1.24 (t,
3J = 7.2 Hz, 3 H, CH3).
N-(4-Methoxyphenyl)morpholine (33)
Prepared according to Procedure 1 from 4-iodoanisole (234 mg, 1.0
mmol) (I/Mg exchange conditions: i-PrMgCl·LiCl at 25 °C for 1 h)
and lithium morpholide (14, 2 mmol; prepared as given in the typi-
cal procedure). Purification by flash chromatography (pentane–
Et2O, 5:1) yielded 33 (107 mg, 55%) as a white solid. Spectroscopic
data correspond to those given in the literature.15
1H NMR (300 MHz, CDCl3): d = 6.99–6.85 (m, 4 H, ArH), 3.90 (t,
3J = 4.7 Hz, 4 H, 2 CH2), 3.80 (s, 3 H, CH3), 3.10 (t, 3J = 4.7 Hz, 4
H, 2 CH2).
N-Benzyl-N-(4-cyanophenyl)aniline (25)
Prepared according to Procedure 1 from 4-bromobenzonitrile (11,
182 mg, 1.0 mmol) and lithium N-benzylanilide (24) (2.0 mmol,
prepared by adding n-BuLi to N-benzylaniline at –40 °C and stir-
ring for 30 min before the mixture was allowed to reach 0 °C and
was then further stirred for additional 15 min). Purification by flash
chromatography (pentane–Et2O, 5:1) yielded 25 (202 mg, 71%) as
a brown oil.
IR (neat): 3059, 3028, 2924, 2853, 2215, 1603, 1591, 1509, 1495,
1452, 1378, 1350, 1259, 1222, 1176, 823, 730, 699 cm–1.
N-(4-Iodophenyl)morpholine (35)
1H NMR (300 MHz, CDCl3): d = 7.50–7.21 (m, 12 H, ArH), 6.77
Prepared according to Procedure 1 from 1,4-diiodobenzene (330
mg, 1.0 mmol) (I/Mg exchange conditions: i-PrMgCl·LiCl at
–20 °C for 2 h) and lithium morpholide (14, 2 mmol; prepared as
given in the typical procedure). Purification by flash chromatogra-
phy (pentane–Et2O, 5:1) yielded 35 (188 mg, 65%) as a white solid.
Spectroscopic data correspond to those given in the literature.16
(d, 3J = 9.1 Hz, 2 H, ArH), 5.02 (s, 2 H, CH2).
13C NMR (75 MHz, CDCl3): d = 56.7, 100.2, 114.8, 120.4, 126.5,
126.6, 126.8, 127.6, 129.1, 130.4, 133.5, 137.7, 146.4, 151.6.
MS (EI, 70 eV): m/z (%) = 284 (61) [M]+, 281 (14), 207 (55), 91
(100), 69 (13), 44 (13).
1H NMR (300 MHz, CDCl3): d = 7.56 (d, J = 8.2 Hz, 2 H, ArH),
3
HRMS (EI): m/z calcd for C20H16N2: 284.1313; found: 284.1275.
3
3
6.70 (d, J = 8.2 Hz, 2 H, ArH), 3.88 (t, J = 4.7 Hz, 4 H, 2 CH2),
3.15 (t, 3J = 4.7 Hz, 4 H, 2 CH2).
Synthesis 2007, No. 8, 1272–1278 © Thieme Stuttgart · New York