Novel Tandem S
N
Ar Reactions of 2-Halobenzonitriles
J . Org. Chem., Vol. 66, No. 6, 2001 2003
borane-dimethyl sulfide (10 mL, 10 M, 100 mmol) was added
dropwise via syringe. After stirring at 0 °C for 1 h, an aliquot
was taken and analyzed by 11B NMR spectroscopy. B NMR
analysis (80.25 MHz, THF) showed the solution to be pyrro-
lidine-borane δ ) -18.0 ppm (q, J ) 96 Hz). If commercial
amine-borane is used, the previous step is modified so as to
dissolve the complex in the appropriate volume of dry THF.
At 0 °C, n-butyllithium in hexanes (40 mL, 2.5 M, 100 mmol)
was added dropwise via syringe. After stirring at 0 °C for 1 h,
noborohydride (7.5 mmol, 15 mL, 0.5 M) produced 3e as a light
1
yellow oil (0.77 g, 81%); H NMR (500 MHz, CDCl
3
) δ 2.92-
11
2.94 (t, J ) 5 Hz, 4H), 3.84-3.86 (t, J ) 5 Hz, 4H), 3.91 (s,
2H), 7.10-7.14 (m, 2H), 7.24-7.27 (m, J ) 2 Hz, J ) 9 Hz,
1H), 7.31-7.32 (d, J ) 7 Hz, 1H); 13C NMR (125 MHz, CDCl
)
3
δ 43.09, 53.26, 67.20, 120.33, 124.63, 127.89, 128.78, 138.78,
+
138.63, 150.98; HRMS (70 eV) m/z (M + 1), calcd 193.1335,
found 193.1345.
2-(1-Hexa m eth ylen eim in o)ben zyla m in e (3f). Reaction
of 2-fluorobenzonitrile (1c), (1.21 g, 10 mmol) and lithium
homopiperidinoborohydride (15 mmol, 15 mL, 1 M) produced
3f as a light yellow oil (1.53 g, 75%); 1H NMR (500 MHz,
1
1
an aliquot was taken and analyzed by B NMR spectroscopy.
1
1
B NMR analysis (80.25 MHz, THF) showed the solution to
be lithium pyrrolidinoborohydride (2c) δ ) -20.6 ppm (q, J )
5 Hz). LAB reagents may be transferred to an oven-dried,
8
CDCl
3
) δ 1.69 (bs, 4H), 3.03-3.06 (t, J ) 6 Hz, 4H), 3.86 (s,
nitrogen-cooled ampule via a cannula and stored under
nitrogen for up to six months without undergoing decomposi-
tion.
Gen er a l P r oced u r e for t h e Ta n d em Am in a t ion -
Red u ction Rea ction of Ha loben zon itr iles. The following
procedure for the reduction of 2-fluorobenzonitrile (1c) with
LiH Bpyrr (2c) is representative. A dry 50-mL round-bottom
3
flask equipped with a magnetic stirring bar was sealed with
a rubber septum and was charged with 2-fluorobenzonitrile
2H), 6.98-7.01 (t, J ) 8 Hz, 1H), 7.10-7.11 (d, J ) 8 Hz, 1H),
1
3
7.15-7.18 (t, J ) 8 Hz, 1H), 7.21-7.22 (d, J ) 8 Hz, 1H);
C
NMR (125 MHz, CDCl ) δ 27.16, 29.85, 44.22, 57.26, 122.28,
3
+
123.69, 127.80, 128.56, 138.78, 154.85; HRMS (70 eV) m/z (M
+ 1), calcd 205.1699, found 205.1699.
3-Meth ylben zyla m in e (10).11 A 100 mL, round-bottom
flask equipped with a magnetic stirring bar and fitted with a
rubber septa was charged with lithium dimethylaminoboro-
hydride (30 mmol, 30 mL, 1 M) and cooled under nitrogen to
0 °C. At °C, m-tolunitrile (0.58 g, 5 mmol) was added via
syringe. The reaction was heated to reflux (65 °C) under
nitrogen and quickly became blood red in color. After 12 h,
TLC analysis indicated the absence of starting material. The
reaction mixture was then cooled under nitrogen to 0 °C. At
°C, deionized water (4 mL) and then 12 M HCl (10 mL, 120
mmol) were added [Caution: Hydrogen evolution!]. The aque-
ous layer was extracted with 2 × 50 mL portions of diethyl
ether/THF. At 0 °C, the aqueous layer was made strongly basic
to litmus (pH ) 12 with solid NaOH. The aqueous layer was
extracted with 2 × 50 mL portions of diethyl ether/THF. The
(
(
10 mmol, 1.21 g). At 0 °C, 1 M lithium pyrrolidinoborohydride
15 mmol) was added dropwise via syringe. The flask was fitted
with a water-cooled reflux condenser and the reaction mixture
heated to reflux under nitrogen. After 2 h, the reaction was
cooled under N gas. At 0 °C, the reaction was quenched by
2
the slow addition of 25 mL of 3 M HCl [Caution: Hydrogen
evolution!]. The aqueous fraction was extracted with diethyl
ether (4 × 20 mL). Solid sodium hydroxide was added to the
aqueous fraction until strongly basic to litmus. The aqueous
layer was extracted with diethyl ether/THF 1:1 (4 × 20 mL).
4
The combined ethereal fractions were dried over MgSO and
filtered. The solvents were removed in vacuo (25 °C, 1 Torr)
4
organic layers were combined, dried over anhydrous MgSO ,
to yield 2-(1-pyrrolidino)benzylamine (3c) as a light yellow oil
and filtered. The solvent was removed under vacuum (35 °C,
30 Torr and then 25 °C, 1 Torr). The 3-methylbenzylamine
1
(
2
6
1.48 g, 84%). H NMR (500 MHz, CDCl
.29 (s, 2H), 3.18-3.21 (t, J ) 7 Hz, 4H), 3.92 (s, 2H), 6.92-
.95 (t, J ) 8 Hz, 1H), 6.98-6.99 (d, J ) 8 Hz, 1H), 7.17-7.20
3
) δ 1.87-1.97 (m, 4H),
product was obtained as (1.87 g, 77% yield) a light yellow oil.
1
H NMR (300 MHz, CDCl ) δ 1.62 (brd. S, 2H), 2.37 (s, 3H),
3
3.84 (s, 2H), 7.07-7.27 (mult., 4H); 13C NMR (75 MHz, CDCl
δ 21.42, 46.58, 1247.14, 127.54, 127.90, 128.50, 138.18, 143.45.
)
(
td, J ) 1 Hz, J ) 8 Hz, 1H), 7.26-7.28 (dd, J ) 1 Hz, J ) 8
3
1
3
Hz, 1H); C NMR (125 MHz, CDCl
3
) δ 25.06, 29.81, 54.38,
4-Meth oxyben zyla m in e (11).12 80% yield; H NMR (300
1
1
17.21. 121.30, 127.88, 129.54, 130.68, 148.66; HRMS (70 eV)
+
m/z (M + 1), calcd 177.1386, found 177.1363.
-(N,N-Dim et h yla m in o)ben zyla m in e (3a ). Reaction of
-fluorobenzonitrile (1c) (0.606 g, 5 mmol) and lithium di-
methylaminoborohydride (7.5 mmol, 7.5 mL, 1 M) produced
MHz, CDCl ) δ 1.43 (s, 2H), 3.78 (s, 5H), 6.68 (d, 2H), 7.22 (d,
3
2H); 13C NMR (75 MHz, CDCl
135.74, 158.60.
) δ 45.98, 55.32, 114.0, 128.26,
2
3
2
Attem p ted Bor a n e Sca ven gin g Usin g 1-Hexen e. A dry
100-mL round-bottom flask equipped with a magnetic stirring
bar was sealed with a rubber septum and was charged with
2-fluorobenzonitrile (5 mmol, 0.545 mL) and 1-hexene (22.5
mmol, 5.66 mL). At 0 °C, lithium dimethylaminoborohydride
(7.5 mmol, 7.5 mL, 1 M) was added dropwise via syringe. The
flask was fitted with a water-cooled reflux condenser, and the
reaction mixture heated to reflux under nitrogen. After 2 h,
1
3
a as a light yellow oil (0.61 g, 81%); H NMR (500 MHz,
CDCl
3
) δ 2.71 (s, 6H), 3.93 (s, 2H), 7.05-7.08 (td, J ) 1 Hz, J
)
7 Hz, 3H), 7.12-7.14 (d, J ) 8 Hz, 1H), 7.21-7.25 (td, J )
2
Hz, J ) 8 Hz, 1H), 7.31-7.32 (d, J ) 8 Hz, 1H); 13C NMR
3
(125 MHz, CDCl ) δ 43.45, 45.10, 119.57, 123.65, 127.63,
+
1
1
28.66, 138.07, 152.47; HRMS (70 eV) m/z (M + 1), calcd
51.1230, found 151.1182.
1
1
2
-(N,N-Dieth yla m in o)ben zyla m in e (3b). Reaction of 2-
the reaction was monitored by B NMR, and no peaks
indicating an alkylborane were present. A TLC analysis at this
time showed no indication of starting material. The reaction
fluorobenzonitrile (1c), (1.21 g, 10 mmol) and lithium dieth-
ylaminoborohydride (15 mmol, 15 mL, 1 M) produced 3b as a
1
light yellow oil (1.24 g, 70%); H NMR (500 MHz, CDCl
0
3
3
) δ
was cooled under N gas. At 0 °C, the reaction was quenched
2
.98-1.02 (td, J ) 2 Hz, J ) 8 Hz, 6H), 1.76 (bs, 2H), 2.95-
by the slow addition of 25 mL of 3 M HCl [Caution: Hydrogen
evolution!]. The aqueous fraction was extracted with diethyl
ether (4 × 20 mL). Solid sodium hydroxide was added to the
aqueous fraction until strongly basic to litmus. The aqueous
layer was extracted with diethyl ether/THF 1:1 (4 × 20 mL).
.00 (qd, J ) 2 Hz, J ) 8 Hz, 4H), 3.88 (s, 2H), 7.05-7.09 (tt,
J ) 1 Hz, J ) 7 Hz, 1H), 7.13-7.15 (d, J ) 8 Hz, 1H), 7.19-
7
.22 (tt, J ) 2 Hz, J ) 8 Hz, 1H), 7.27-7.29 (d, J ) 8 Hz, 1H);
1
3
C NMR (125 MHz, CDCl ) δ 12.84, 43.74, 48.35, 122.93,
3
+
1
1
24.30, 140.83, 149.59; HRMS (70 eV) m/z (M + 1), calcd
The combined ethereal fractions were dried over MgSO and
4
filtered. The solvents were removed in vacuo (25 °C, 1 Torr)
to yield 2-(N,N-dimethylamino)benzylamine 3c as a light
yellow oil in 71% yield.
79.1519, found 179.1543.
2
-(1-P ip er id in o)ben zyla m in e (3d ). Reaction of 2-fluo-
robenzonitrile (1c), (0.606 g, 5 mmol) and lithium piperidi-
noborohydride (7.5 mmol, 7.5 mL, 1 M) produced 3d as a light
Attem p ted Activa tion of 2-F lu or oben zon itr ile w ith
LiCl. A dry 100-mL, round-bottom flask equipped with a
sidearm and a magnetic stirring bar was charged with LiCl
(15 mmol, 0.63 g) and sealed with a rubber septum. Dry THF
(7.5 mL), 2-fluorobenzonitrile (10 mmol, 1.09 mL), and piper-
dine (15 mmol, 1.49 mL) were introduced to the flask via the
1
yellow oil (0.89 g, 94%); H NMR (500 MHz, CDCl
3
) δ 1.57-
1
(
.60 (quint. J ) 6 Hz, 4H), 2.85-2.87 (t, J ) 5 Hz, 4H), 3.90
s, 2H), 7.04-7.07 (t, J ) 7 Hz, 1H), 7.10-7.12 (d, J ) 8 Hz,
H), 7.20-7.23 (t, J ) 8 Hz, 1H), 7.27-7.29 (d, J ) 8 Hz, 1H);
1
1
3
C NMR (125 MHz, CDCl
3
) δ 24.40, 26.90, 43.61, 54.40,
1
20.41, 123.90, 127.68, 128.55, 138.81, 152.69; HRMS (70 eV)
+
m/z (M + 1), calcd 191.1543, found 191.1526.
-(4-Mor p h olin o)ben zyla m in e (3e). Reaction of 2-fluo-
robenzonitrile (1c), (0.606 g, 5 mmol) and lithium morpholi-
(11) Harada, H.; Marie, T.; Suzuki, T.; Yoshida, T.; Kato, S.
2
Tetrahedron 1998, 54, 10671.
(12) LopeZ, F. J .; Nitzan, D. Tetrahedron Lett. 1999, 40, 2071.