Synthesis of Polyfunctional Secondary Amines by the Reaction of Functionalized Organomagnesium Reagents with Tertiary Nitroalkanes

Article abstract of DOI:10.1055/s-0034-1378871

Addition of polyfunctionalized aryl, heteroaryl, and tertiary alkylmagnesium reagents to tertiary nitroalkanes at 25A"°C in tetrahydrofuran produces, after reductive workup with FeCl₂ and NaBH₄ in ethanol, the corresponding polyfunctional secondary amines in high yields.

Full text of DOI:10.1055/s-0034-1378871

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3246–3256
paper
3246
V. Dhayalan, P. Knochel
Paper
Synthesis
Synthesis of Polyfunctional Secondary Amines by the Reaction of
Functionalized Organomagnesium Reagents with Tertiary Nitro-
alkanes
Me
Vasudevan Dhayalan
Paul Knochel*
NO2
XMg
N
1) 25 °C, 12 h
+
N
2) FeCl2 (2 equiv)
NaBH4 (1 equiv)
EtOH, 25 °C, 15 h
Me
N
Department of Chemistry, Ludwig-Maximilians-Universität
München, Butenandtstr. 5-13, 81377 Munich, Germany
paul.knochel@cup.uni-muenchen.de
H
(2.5 equiv)
(1.0 equiv)
Cl
93%
OMe
MgX
1) –60 to 25 °C, 12 h
H
+
NO
N
2) FeCl2 (2 equiv)
NaBH4 (1 equiv)
EtOH, 25 °C, 15 h
MeO
(1.0 equiv)
(2.2 equiv)
OMe
76%
Received: 10.06.2015
Accepted after revision: 01.07.2015
Published online: 17.08.2015
Cu-catalyzed C–N cross-couplings of arylboronic acids with
adamantylamine have been described.8 Alternatively, the
reaction of inexpensive and less toxic main group organo-
metallics with electrophilic nitrogen reagents have been
used to prepare various amines.9
DOI: 10.1055/s-0034-1378871; Art ID: ss-2015-t0367-op
Abstract Addition of polyfunctionalized aryl, heteroaryl, and tertiary
alkylmagnesium reagents to tertiary nitroalkanes at 25 °C in tetrahy-
drofuran produces, after reductive workup with FeCl2 and NaBH4 in eth-
anol, the corresponding polyfunctional secondary amines in high yields.
A few years ago, we reported the preparation of diaryl-
amines through the addition of functionalized organomag-
nesium reagents to nitroso-arenes10 and nitro-arenes.11 Re-
cently, we reported that the addition of functionalized or-
ganozinc reagents12 to nitroso-arenes produces the
corresponding polyfunctional secondary amines in high
yields.13 However, adamantylzinc chloride reacts smoothly
only with electron-rich nitroso-arenes and furnishes the
corresponding adamantyl(aryl)amines in good yields only
with such substrates (Scheme 1). Nitroso-arenes substitut-
ed with an electron-withdrawing group do not react in sat-
isfactory yields (less than 20%) under these conditions.
Herein, we wish to report a mild synthesis of highly ste-
rically hindered polyfunctionalized adamantyl(aryl)- or
tertiary-alkyl(aryl)-amines as well as di-adamantylamine,
including aryl amines bearing electron-withdrawing sub-
stituents. Thus, we first prepared various aryl, heteroaryl,
Key words secondary amines, nitroalkanes, organomagnesium re-
agents, amination reactions, adamantane
The synthesis of arylamines is an important synthetic
goal because such amines are common functional groups
with useful properties in pharmaceuticals and material sci-
ence.1 Aminoadamantane derivatives, in particular, have
found several interesting applications in drug development
and medicinal chemistry.2 Palladium,3 nickel,4 copper,5 and
rhodium6 catalyzed aminations are excellent amination
methods, but they have the disadvantage of requiring both
expensive and toxic transition metals. Recently, Buchwald
and co-workers reported a palladium-catalyzed arylation of
hindered primary amines with aryl halides.7 Additionally,
1) THF, –20 °C, 1–2 h
MgX
+
NO/NO2
FG
R
FG
R
2) FeCl2 (2 equiv)
NaBH4 (1 equiv)
N
H
EtOH, –20 °C to r.t.
R
1) THF, 0–25 °C
2–3 h
NO
+
ZnCl
2) FeCl2 (2 equiv)
NaBH4 (1 equiv)
EtOH, 25 °C, 15 h
R
N
H
R = H, NMe2, OMe
Scheme 1 Previously reported aminations using nitroso- or nitro-arenes10,11,13
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256

3247
V. Dhayalan, P. Knochel
Paper
Synthesis
and tertiary alkyl magnesium reagents of type 2 from the
corresponding aryl halides (R1–X; X = Br, I) either by the di-
rect insertion of Mg in the presence of LiCl14 or by an I/Mg
exchange using iPrMgCl·LiCl.15 Thus, the reaction of
Grignard reagents of type 2 with tertiary nitroalkanes 3 at
25 °C in THF produced, after reductive workup with FeCl2
and NaBH4 in ethanol, the corresponding polyfunctional
secondary amines 4 in high yields (Scheme 2 and Table 1).
Table 1 Synthesis of Polyfunctional Adamantyl(aryl)amines of Type
4a–l by the Addition of Arylmagnesium Reagents 2a–l to 1-Nitroada-
mantane (3a) Followed by Reductive Workupa
Entry Grignard reagent (R1) Product
Yield
(%)b
Ph
PhMgCl
2a
1
95
N
H
1) R2NO2 (3)
4a
Mg, LiCl
THF, 25 °C
FG
THF, 25 °C, 12 h
R1X
R1-MgX·LiCl
R1 NH R2
MgX
or
2) FeCl2 (2 equiv)
NaBH4 (1 equiv)
EtOH, 25 °C, 15 h
i-PrMgCl·LiCl
THF, –20 °C
1
2
4 56–95%
FG
N
H
Scheme 2 Synthesis of polyfunctional secondary amines of type 4
through the addition of functionalized magnesium reagents 2 to tertia-
ry nitroalkanes 3 followed by reductive workup
2
3
4
5
6
7
8
2b FG = n-Bu
2c FG = SMe
2d FG = NMe2
2e FG = OTIPS
2f FG = Ph
4b
4c
4d
4e
4f
85
81
56
93
79
73
60
Thus, PhMgCl (2a; 2.5 equiv) reacted with 1-nitroada-
mantane (3a; 1.0 equiv)16 at 25 °C for 12 hours and pro-
duced, after reductive workup with FeCl2 (2.0 equiv) and
NaBH4 (1.0 equiv) in ethanol, the corresponding phenylada-
mantylamine 4a in 95% yield (Table 1, entry 1).8 A variety of
functionalized aryl, heteroaryl, or tertiary-alkylmagnesium
reagents bearing an amide, amine, silyl ether, thiomethyl
ether, or fluoro substituent were prepared by the direct in-
sertion of Mg (2.5 equiv) in the presence of LiCl (1.3 equiv)
in THF at 0–25 °C for 1–3 hours.14 Remarkably, all these
Grignard reagents reacted smoothly with 1-nitroadaman-
tane (3a) furnishing, after reductive workup, the corre-
sponding adamantyl(aryl)amines in 56–93% yield, allowing
the preparation of aryl(adamantyl)amines bearing elec-
tron-withdrawing substituents (entries 2–11) for the first
time.7,13 Additionally, the magnesiated indole reagent 2l re-
acted smoothly with 1-nitroadamantane (3a) to give het-
eroaryl(adamantyl)amine 4l in 93% yield (entry 12).
The scope of the reaction was extended to the prepara-
tion of sterically hindered17 di-tertiary-alkylamines using
tertiary alkylmagnesium reagents, such as commercially
available tert-butylmagnesium chloride (2m) and 1-ada-
mantylmagnesium bromide (2n).18 Their reaction with 1-
nitroadamantane (3a) produced the expected di-tertiary-
alkylamines 4m–n in 53–77% yield (Table 2, entries 1 and
2).19 Moreover, 2-methyl-2-nitropropane (3b) also reacted
efficiently with arylmagnesium reagents of type 2a, 2i, and
2f, furnishing the corresponding tert-butyl(aryl)amines
4o–q in 72–80% yield (entries 3–5).20
2g FG = F
4g
4h
2hc FG = CO2Et
MgX
9
10
11
90
82
70
N
H
2i
4i
4j
MgX
OCONEt2
N
H
OCONEt2
2j
O
MgX
O
O
O
2k
N
H
4k
Me
XMg
N
12
93
N
N
H
Me
2l
4l
a General reaction conditions: arylmagnesium reagent 2 (2.5 equiv), 1-ni-
troadamantane 3a (1.0 equiv), NaBH4 (1.0 equiv), FeCl2 (2.0 equiv).
b Isolated yield after purification by flash-column chromatography.
c Prepared by I/Mg exchange with iPrMgCl·LiCl.15
In the reaction of organomagnesium reagents with 1-ni-
troadamantane (3a) an excess of the magnesium reagent 2
(2.5 equiv) was necessary to achieve complete conversion.
The first equivalent of the organomagnesium reagent 2
adds at the oxygen of the nitro group of adamantane 3a,
producing an intermediate adamantylnitroso derivative 5
after elimination of magnesium alcoholate. The tertiary al-
kylnitroso compound 5 reacts with a second equivalent of
the magnesium reagent 2 leading to the formation of the
desired C–N bond, and affords the hydroxylamine deriva-
tive 6, which, after reductive workup, gives the correspond-
ing secondary amines 4 in excellent yields (Scheme 3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256

3248
V. Dhayalan, P. Knochel
Paper
Synthesis
Table 2 Synthesis of Polyfunctional Secondary Amines of Type 4m–q by the Addition of Aryl- and Alkylmagnesium Reagents 2 to Tertiary Nitroalkanes
3a and 3b Followed by Reductive Workupa
Entry
1
Grignard reagent
Electrophile (R2)
Product, yieldb
t-BuMgCl
2m
NH
t-Bu
NO2
3a
4m 77%c
H
N
2
NO2
MgBr
2n
3a
4n 53%c
NH
t-Bu
PhMgCl
2a
t-BuNO2
3b
3
4
4o 72%
4p 75%
MgX
NH
t-Bu
t-BuNO2
3b
2i
NH
MgX
t-Bu
t-BuNO2
5
3b
Ph
4q 80%
Ph
2f
a General reaction conditions: organomagnesium reagent 2 (2.5 equiv), 3a or 3b (1.0 equiv), NaBH4 (1.0 equiv), FeCl2 (2.0 equiv).
b Isolated yield after purification by flash-column chromatography.
c Reaction was performed at –60 °C to room temperature.
chlorosuccinimide in 90% yield. Similarly, 1-chloro-1-nitro-
socyclopentane 8b was obtained from 7b in 60% yield
(Scheme 4).21
R1MgX
THF, 25 °C
– R1OMgX
+
NO2
3a (1.0 equiv)
NO
Notably, an arylmagnesium reagent of type 2 (2.2 equiv)
reacted smoothly with 1-chloro-1-nitrosocyclohexane (8a;
1.0 equiv) at –60 °C to room temperature for 12 hours, pro-
ducing an intermediate nitrone 1022 after elimination of
chloride. Nitrone 10 then reacted with a second equivalent
of magnesium reagent 2, leading to a magnesiated hydrox-
ylamine of type 11, which, after reductive workup, led to
the corresponding double arylated amines 12a–c in 75–77%
yield. Similarly, 8b reacted with arylmagnesium reagents 2
to produce the cyclopentyl(aryl)amines 12d–e in 68–81%
yield (Scheme 5).
2 (2.5 equiv)
5
FeCl2 (2 equiv)
NaBH4 (1 equiv)
R1MgX (2)
R1
R1
N
N
H
12 h
EtOH, 25 °C, 15 h
OMgX
6
4
Scheme 3 Reaction pathway and mechanism for the synthesis of ada-
mantyl(aryl)amines
We also examined the addition of magnesium and zinc
organometallics to 1-chloro-1-nitrosocycloalkanes such as
8a and 8b. 1-Chloro-1-nitrosocyclohexane (8a) was ob-
tained by chlorination of cyclohexanone oxime with N-
Finally, the arylzinc reagents 13a–d14 (1.1 equiv) reacted
with 1-chloro-1-nitrosocyclohexane (8a; 1.0 equiv) at 0 °C
to room temperature (12 h) producing an intermediary ni-
OH
Cl
NO
N
NCS (1.1 equiv)
Cl
N
NCS (1.1 equiv)
OH
NO
CH2Cl2, 0 to 25 °C
4 h
CH2Cl2, 0 to 25 °C
3 h
7a
Scheme 4 Synthesis of 1-chloro-1-nitrosocycloalkanes 8a and 8b
8a 90%
7b
8b 60%
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256

3249
V. Dhayalan, P. Knochel
Paper
Synthesis
8a (1.0 equiv)
–60 to 25 °C
Cl
N
O
ArMgX
OMgX
N
ArMgX
– MgXCl
12 h
Ar
Ar
2 (2.2 equiv)
9
10
Ar
FeCl2 (2 equiv)
NaBH4 (1 equiv)
Ar
12a Ar = 4-FC6H4; 77%
12b Ar = 4-MeC6H4; 75%
12c Ar = 4-MeOC6H4; 76%
NH
OMgX
N
Ar
EtOH, 0–25 °C
15 h
Ar
11
12a–c
Ar
Cl
NO
same conditions
12d Ar = 4-MeC6H4; 68%
12e Ar = 4-MeOC6H4; 81%
ArMgX
NH
Ar
(2.2 equiv)
(1.0 equiv)
12d–e
2
8b
Scheme 5 Synthesis of secondary amines 12a–e by the reaction of arylmagnesium reagents of type 2 with 1-chloro-1-nitrosocycloalkanes 8a,b
Cl
Cl
N
O
0 to 25 °C
12 h
OZnX
N
NO
ArZnX
– ZnXCl
Ar
Ar
8a
13a–d
10
14
(1.0 equiv)
(1.1 equiv)
FeCl2 (2 equiv)
NaBH4 (1 equiv)
15a Ar = Ph; 46%
15b Ar = 4-MeC6H4; 41%
15c Ar = 4-n-BuC6H4; 41%
15d Ar = 3,4,5-(MeO)3C6H2; 49%
Ar HN
EtOH, 0–25 °C
15 h
15a–d
Scheme 6 Synthesis of secondary amines 15a–d by the reaction of arylzinc reagents 13 with 1-chloro-1-nitrosocyclohexane (8a)
trone, which, under our reaction conditions, did not react
further with arylzinc reagents and gave, after reductive
workup (Scheme 6),23 the corresponding secondary amines
15a–d in 41–49% yield.
let of triplet), and m (multiplet). Column chromatographic purifica-
tion was performed using SiO2 (0.040–0.063 mm, 230–400 mesh
ASTM) from Merck if not indicated. All reagents were obtained from
commercial sources.
In summary, we have developed a practical synthesis of
sterically hindered polyfunctionalized secondary amines by
the reaction of aryl, heteroaryl, or tertiary alkylmagnesium
reagents with 1-nitroadamantane or 2-methyl-2-nitropro-
pane as well as 1-chloro-1-nitrosocycloalkanes. Further ex-
tensions of this work are underway in our laboratories.
Preparation of ZnCl2 (1 M in THF)
A dry and argon-flushed 250 mL Schlenk flask equipped with a mag-
netic stirring bar and a septum was charged with ZnCl2 (13.6 g,
100 mmol). The salt was heated to 140 °C under high vacuum for
10 h. After cooling to 25 °C, anhydrous THF (100 mL) was added and
stirring was continued until the salt was dissolved completely (4 h).
Preparation of Functionalized Aryl and Heteroarylmagnesium Re-
agents (2)14 through LiCl-Mediated Magnesium Insertion in Aryl
and Heteroaryl Halides
All reactions were carried out under an argon atmosphere in flame-
dried glassware. Syringes that were used to transfer anhydrous sol-
vents or reagents were purged with argon prior to use. THF was con-
tinuously heated at reflux and freshly distilled from sodium benzo-
phenone ketyl under nitrogen. Yields refer to isolated yields of com-
pounds estimated to be >95% pure as determined by 1H NMR (25 °C)
and capillary GC analyses. Chemical shifts are reported as δ-values in
ppm relative to the solvent peak. NMR spectra were recorded in a
solution of CDCl3 (residual chloroform: δ = 7.25 ppm for 1H NMR and
δ = 77.0 ppm for 13C NMR). Signal multiplicities are abbreviated as: s
(singlet), d (doublet), t (triplet), q (quartet), dd (doublet of a doublet),
ddd (doublet of a doublet of a doublet), dt (doublet of triplet), tt (trip-
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with LiCl (1.3 equiv) and heated to
450 °C with a heat gun under high vacuum for 5 min. After cooling to
r.t., magnesium turnings (2.5 equiv) were added, followed by THF (2
mL/mmol). The magnesium turnings were activated using 1,2-dibro-
moethane (5 mol%) and trimethylsilyl chloride (5 mol%). The suspen-
sion was cooled to 0 °C, followed by addition of the aryl or heteroaryl
halide (1.0 equiv). The reaction mixture was stirred at 0 °C to r.t. until
GC analysis of hydrolyzed reaction aliquots showed full consumption
of the starting material. The solids were allowed to settle or the reac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256

3250
V. Dhayalan, P. Knochel
Paper
Synthesis
tion mixture was centrifuged (10 min, 2000 rpm). The yield of the in-
sertion reaction was determined by iodometric titration24 of the su-
pernatant solution.
(3s,5s,7s)-N-(4-Butylphenyl)adamantan-1-amine (4b)7b
The amination reaction of freshly prepared arylmagnesium reagent
2b (0.37 M in THF, 2.5 mmol, 6.75 mL) with 1-nitroadamantane 3a
(182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 88:12] furnished 4b.
Preparation of Functionalized Aryl and Heteroarylzinc Reagents
(13)14 through LiCl-Mediated Magnesium Insertion in the Pres-
ence of Zinc Chloride in Aryl and Heteroaryl Halides
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with LiCl (1.3 equiv) and heated to
450 °C with a heat gun under high vacuum for 5 min. After cooling to
r.t., magnesium turnings (2.5 equiv) were added, followed by THF (2
mL/mmol). The magnesium turnings were activated using 1,2-dibro-
moethane (5 mol%) and trimethylsilyl chloride (5 mol%). The suspen-
sion was cooled to 0 °C, ZnCl2 solution (1 M in THF, 1.1 equiv) was
added followed by addition of the aryl or heteroaryl halide (1.0
equiv). The reaction mixture was stirred until GC analysis of hydro-
lyzed reaction aliquots showed full consumption of the starting mate-
rial. The solids were allowed to settle or the reaction mixture was
centrifuged (10 min, 2000 rpm). The yield of the insertion reaction
was determined by iodometric titration24 of the supernatant solution.
Yield: 240 mg (85%); pale-yellow liquid.
IR (ATR): 3400, 2903, 2848, 1614, 1511, 1452, 1308, 1092, 812 cm–1
1H NMR (300 MHz, CDCl3): δ = 6.98 (d, J = 8.3 Hz, 2 H), 6.76 (d, J =
8.0 Hz, 2 H), 3.24 (br s, 1 H), 2.52 (t, J = 7.6 Hz, 2 H), 2.01–2.19 (m,
3 H), 1.75–1.99 (m, 6 H), 1.44–1.74 (m, 8 H), 1.25–1.43 (m, 2 H), 0.93
(t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 143.1, 134.4, 128.5, 120.5, 52.4, 43.6,
36.5, 34.8, 33.8, 29.8, 22.4, 14.0.
MS (EI): m/z (%) = 283 (100) [M+], 240 (34), 227 (20), 226 (97), 135
(87), 106 (17), 93 (21), 91 (12), 79 (21), 67 (11), 41 (13).
.
HRMS (EI): m/z calcd for C20H29N: 283.2300; found: 283.2294.
(3s,5s,7s)-N-[4-(Methylthio)phenyl]adamantan-1-amine (4c)7a
Preparation of Secondary Amines (4) by the Reaction of Function-
alized Magnesium Reagents (2) with Nitro-Electrophiles (3); Typi-
cal Procedure 1 (TP1)
The amination reaction of freshly prepared arylmagnesium reagent
2c (0.34 M in THF, 7.35 mL, 2.5 mmol) with 1-nitroadamantane 3a
(182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 80:20] furnished 4c.
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with freshly prepared organomagne-
sium reagent 2 (2.5 mmol. 2.5 equiv) in anhydrous THF (2 mL) and
cooled to 0 °C. The nitro substrate 3 (1.0 mmol, 1.0 equiv) was added
and the reaction mixture was stirred at 0 to 25 °C for 12 h until GC
analysis of a reaction aliquot showed full consumption of the starting
material. EtOH (1.0 mL), FeCl2 (2.0 mmol, 2.0 equiv), and NaBH4 (1.0
mmol, 1.0 equiv) were added and the reaction mixture was stirred at
r.t. for 15 h. After quenching the reaction with sat. aq NH4Cl (10 mL),
the mixture was neutralized with aq NaOH (2 M) and extracted with
EtOAc (6 × 25 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The crude residue was purified by
flash-column chromatography to give the analytically pure amine
product 4.
Yield: 220 mg (81%); pale-yellow solid; mp 67.1–67.5 °C.
IR (ATR): 3376, 2898, 2847, 1592, 1500, 1297, 1100, 814, 805, 671 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.14 (d, J = 8.4 Hz, 2 H), 6.72 (d, J =
8.6 Hz, 2 H), 3.32 (br s, 1 H), 2.40 (s, 3 H), 1.97–2.18 (m, 3 H), 1.76–
1.93 (m, 6 H), 1.54–1.76 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 144.4, 130.0, 126.5, 119.6, 52.3, 43.3,
36.4, 29.7, 18.4.
MS (EI): m/z (%) = 273 (100) [M+], 216 (39), 169 (19), 136 (10), 135
(65), 93 (12), 79 (13).
.
HRMS (EI): m/z calcd for C17H23NS: 273.1551; found: 273.1548.
(3s,5s,7s)-N-Phenyladamantan-1-amine (4a)8
N1-[(3s,5s,7s)-adamantan-1-yl]-N4,N4-dimethylbenzene-1,4-di-
The amination reaction of freshly prepared arylmagnesium reagent
2a14 (1.68 M in THF, 1.48 mL, 2.5 mmol) with 1-nitroadamantane 3a16
(182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 90:10] furnished 4a.
amine (4d)13
The amination reaction of freshly prepared arylmagnesium reagent
2d (0.30 M in THF, 8.33 mL, 2.5 mmol) with 1-nitroadamantane 3a
(182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 50:50] furnished 4d.
Yield: 215 mg (95%); pale-yellow solid; mp 80.6–82.3 °C.
IR (ATR): 3408, 2904, 2847, 1598, 1502, 1305, 1130, 1096, 741,
690 cm–1
.
Yield: 152 mg (56%); pale-yellow solid; mp 103.0–104.1 °C.
1H NMR (300 MHz, CDCl3): δ = 7.16 (dd, J = 8.7, 7.3 Hz, 2 H), 6.60–6.92
(m, 3 H), 3.25 (s, 1 H), 2.04–2.21 (m, 3 H), 1.81–2.01 (m, 6 H), 1.57–
1.79 (m, 6 H).
IR (ATR): 3295, 2901, 2842, 1616, 1511, 1243, 1124, 819, 689 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.83 (d, J = 8.3 Hz, 2 H), 6.66 (d, J =
8.3 Hz, 2 H), 2.89 (s, 6 H), 2.80 (br s, 1 H), 1.97–2.16 (m, 3 H), 1.50–
1.85 (m, 12 H).
13C NMR (75 MHz, CDCl3): δ = 146.0, 128.7, 119.2, 119.1, 52.2, 43.5,
36.5, 29.8.
13C NMR (75 MHz, CDCl3): δ = 146.6, 135.1, 125.0, 113.5, 52.6, 43.8,
41.3, 36.5, 29.8.
MS (ESI): m/z (%) = 228 (100) [M + H]+, 135 (37), 114 (1).
MS (EI): m/z (%) = 270 (100) [M+], 269 (5), 213 (14), 136 (13), 135
HRMS (ESI): m/z [M + H] calcd for C16H22N: 228.1752; found:
228.1746.
(34), 121 (12), 93 (7), 79 (6).
HRMS (EI): m/z calcd for C18H26N2: 270.2096; found: 270.2090.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256

3251
V. Dhayalan, P. Knochel
Paper
Synthesis
(3s,5s,7s)-N-{4-[(Triisopropylsilyl)oxy]phenyl}adamantan-1-
Ethyl 4-{[(3s,5s,7s)-Adamantan-1-yl]amino}benzoate (4h)
amine (4e)
The amination reaction of freshly prepared arylmagnesium reagent
2h (0.45 M in THF, 5.55 mL, 2.5 mmol) with 1-nitroadamantane 3a
(182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 75:25] furnished 4h.
The amination reaction of freshly prepared arylmagnesium reagent
2e (0.33 M in THF, 7.57 mL, 2.5 mmol) with 1-nitroadamantane 3a
(182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 85:15] furnished 4e.
Yield: 180 mg (60%); pale-yellow solid; mp 97.2–99.3 °C.
Yield: 372 mg (93%); pale-yellow liquid.
IR (ATR): 2904, 2866, 2849, 1503, 1463, 1240, 910, 882, 678 cm–1
IR (ATR): 3372, 2903, 1680, 1598, 1525, 1273, 1170, 1094, 836, 771,
.
700 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.61–6.85 (m, 4 H), 2.93 (s, 1 H), 1.96–
2.18 (m, 3 H), 1.42–1.92 (m, 12 H), 0.93–1.35 (m, 21 H).
13C NMR (75 MHz, CDCl3): δ = 150.9, 138.4, 123.9, 119.7, 52.6, 43.7,
36.5, 29.7, 17.9, 12.6.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.4 Hz, 2 H), 6.70 (d, J =
8.2 Hz, 2 H), 4.33 (q, J = 7.0 Hz, 2 H), 4.02 (br s, 1 H), 2.09–2.23 (m,
3 H), 1.90–2.07 (m, 6 H), 1.62–1.82 (m, 6 H), 1.37 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.9, 150.6, 131.1, 118.3, 114.5, 60.1,
52.1, 42.7, 36.4, 29.6, 14.5.
MS (EI): m/z (%) = 299 (27) [M+], 242 (26), 136 (13), 135 (100), 93
MS (EI): m/z (%) = 399 (100) [M+], 356 (14), 342 (16), 135 (74), 93
(18), 86 (14), 79 (17), 59 (13), 43 (15), 41 (20).
(20), 79 (19), 67 (10), 41 (9).
HRMS (EI): m/z calcd for C25H41NOSi: 399.2957; found: 399.2951.
HRMS (EI), m/z calcd for C19H25NO2 (299.1885): 299.1877.
(3s,5s,7s)-N-[(1,1′-Biphenyl)-4-yl]adamantan-1-amine (4f)
(3s,5s,7s)-N-(Naphthalen-2-yl)adamantan-1-amine (4i)
The amination reaction of freshly prepared arylmagnesium reagent 2f
(0.24 M in THF, 10.41 mL, 2.5 mmol) with 1-nitroadamantane 3a (182
mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and NaBH4
(38 mg, 1.0 mmol) was performed according to TP1. Flash-column
chromatographic purification [silica gel (pre-neutralized with Et3N);
i-hexane–EtOAc, 88:12] furnished 4f.
The amination reaction of freshly prepared arylmagnesium reagent 2i
(0.37 M in THF, 6.75 mL, 2.5 mmol) with 1-nitroadamantane 3a (182
mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and NaBH4
(38 mg, 1.0 mmol) was performed according to TP1. Flash-column
chromatographic purification [silica gel (pre-neutralized with Et3N);
i-hexane–EtOAc, 88:12] furnished 4i.
Yield: 240 mg (79%); pale-yellow solid; mp 117.2–117.9 °C.
Yield: 250 mg (90%); pale-yellow solid; mp 111.9–112.6 °C.
IR (ATR): 3396, 2903, 1629, 1525, 1399, 1226, 831, 812, 744 cm–1
.
IR (ATR): 3393, 2909, 1610, 1598, 1522, 1490, 1451, 1302, 1096, 813,
759, 696 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.55 (d, J = 7.5 Hz, 2 H), 7.33–7.49 (m,
4 H), 7.21–7.32 (m, 1 H), 6.87 (d, J = 8.3 Hz, 2 H), 3.59 (br s, 1 H), 2.0–
2.23 (m, 3 H), 1.83–2.04 (m, 6 H), 1.58–1.81 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 145.3, 141.1, 131.6, 128.6, 127.4, 126.3,
126.2, 118.7, 52.4, 43.3, 36.5, 29.7.
1H NMR (300 MHz, CDCl3): δ = 7.51–7.75 (m, 3 H), 7.37 (t, J = 7.3 Hz,
1 H), 7.19–7.29 (m, 1 H), 7.14 (s, 1 H), 6.98 (dd, J = 8.7, 1.8 Hz, 1 H),
3.64 (br s, 1 H), 2.08–2.25 (m, 3 H), 1.84–2.08 (m, 6 H), 1.54–1.83 (m,
6 H).
13C NMR (75 MHz, CDCl3): δ = 143.4, 134.6, 128.4, 128.1, 127.5, 126.2,
126.1, 122.5, 122.0, 111.9, 52.6, 43.3, 36.5, 29.7.
MS (EI): m/z (%) = 277 (100) [M+], 221 (18), 220 (86), 143 (15), 135
MS (EI): m/z (%) = 303 (85) [M+], 246 (78), 169 (26), 136 (26), 135
(100), 93 (29), 79 (31), 67 (19), 44 (47), 43 (41), 41 (21).
(61), 127 (13), 115 (17), 93 (17), 79 (17), 43 (13).
HRMS (EI): m/z calcd for C22H25N: 303.1987; found: 303.1988.
HRMS (EI): m/z calcd for C20H23N: 277.1830; found: 277.1814.
(3s,5s,7s)-N-(4-Fluorophenyl)adamantan-1-amine (4g)
3-{[(3s,5s,7s)-Adamantan-1-yl]amino}phenyl Diethylcarbamate
(4j)
The amination reaction of freshly prepared arylmagnesium reagent
2g (0.55 M in THF, 4.54 mL, 2.5 mmol) with 1-nitroadamantane 3a
(182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 80:20] furnished 4g.
The amination reaction of freshly prepared arylmagnesium reagent 2j
(0.31 M in THF, 8.1 mL, 2.5 mmol) with 1-nitroadamantane 3a (182
mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and NaBH4
(38 mg, 1.0 mmol) was performed according to TP1. Flash-column
chromatographic purification [silica gel (pre-neutralized with Et3N);
i-hexane–EtOAc, 75:25] furnished 4j.
Yield: 180 mg (73%); colorless solid; mp 64.3–65.1 °C.
IR (ATR): 3338, 2896, 1502, 1354, 1240, 1205, 1090, 836, 753, 700 cm–1
.
Yield: 280 mg (82%); pale-yellow solid; mp 55.9–59.9 °C.
1H NMR (300 MHz, CDCl3): δ = 6.68–6.97 (m, 4 H), 3.19 (br s, 1 H),
1.96–2.24 (m, 3 H), 1.48–1.90 (m, 12 H).
13C NMR (75 MHz, CDCl3): δ = 157.9 (d, J = 237.0 Hz), 141.2, 122.6 (d,
J = 7.5 Hz), 115.1 (d, J = 21.7 Hz), 52.7, 43.5, 36.4, 29.7.
19F NMR (282 MHz, CDCl3): δ = –124.1 (s, 1 F).
IR (ATR): 3363, 2904, 1698, 1613, 1421, 1269, 1176, 1156, 753,
686 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.09 (t, J = 8.0 Hz, 1 H), 6.34–6.74 (m,
3 H), 3.14–3.61 (m, 5 H), 2.01–2.18 (m, 3 H), 1.76–1.99 (m, 6 H), 1.54–
1.76 (m, 6 H), 1.05–1.34 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 154.2, 152.1, 147.0, 129.0, 115.1, 111.8,
52.3, 43.2, 42.1, 41.9, 36.4, 29.7, 14.2, 13.4.
MS (EI): m/z (%) = 245 (100) [M+], 216 (6), 202 (10), 189 (17), 188 (97),
135 (36), 110 (6).
HRMS (EI): m/z calcd for C16H20FN: 245.1580; found: 245.1560.
MS (EI): m/z (%) = 342 (57) [M+], 285 (37), 135 (46), 100 (100), 79 (14),
72 (40), 44 (20).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256

3252
V. Dhayalan, P. Knochel
Paper
Synthesis
HRMS (EI): m/z calcd for C21H30N2O2: 342.2307; found: 342.2303.
N-[(3s,5s,7s)-Adamantan-1-yl]benzo[d][1,3]dioxol-5-amine (4k)
(3s,5s,7s)-Di[(3s,5s,7s)-adamantan-1-yl]amine (4n)19
The amination reaction of freshly prepared tertiary-alkylmagnesium
reagent 2n (0.10 M in THF, 25.0 mL, 2.5 mmol) with 1-nitroadaman-
tane 3a (182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol),
and NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-
column chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 60:40) furnished 4n.
The amination reaction of freshly prepared arylmagnesium reagent
2k (0.43 M in THF, 5.8 mL, 2.5 mmol) with 1-nitroadamantane 3a
(182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 75:25] furnished 4k.
Yield: 150 mg (53%); pale-yellow solid; mp 165.5–175.1 °C.
IR (ATR): 2896, 2846, 1744, 1448, 1350, 1158, 1097, 820 cm–1
.
Yield: 190 mg (70%); pale-yellow solid; mp 90.1–90.6 °C.
IR (ATR): 3365, 2900, 1495, 1478, 1194, 1180, 1035, 934, 821 cm–1
1H NMR (300 MHz, CDCl3): δ = 1.94–2.07 (m, 6 H), 1.68–1.94 (m,
12 H), 1.40–1.66 (m, 13 H).
.
1H NMR (300 MHz, CDCl3): δ = 6.63 (d, J = 8.0 Hz, 1 H), 6.46 (s, 1 H),
6.21–6.37 (m, 1 H), 5.88 (s, 2 H), 3.08 (br s, 1 H), 1.96–2.16 (m, 3 H),
1.49–1.84 (m, 12 H).
13C NMR (75 MHz, CDCl3): δ = 147.5, 142.4, 139.7, 115.0, 107.8, 104.7,
100.8, 52.9, 43.6, 36.4, 29.7.
13C NMR (75 MHz, CDCl3): δ = 52.9, 46.3, 36.6, 30.0.
MS (EI): m/z (%) = 285 (40) [M+], 229 (21), 228 (100), 191 (17), 135
(72), 93 (20), 79 (20), 67 (11), 41 (13).
HRMS (EI): m/z calcd for C20H31N: 285.2457; found: 285.2440.
MS (EI): m/z (%) = 271 (100) [M+], 214 (45), 184 (15), 137 (18), 135
(96), 93 (21), 79 (18), 77 (15).
N-(tert-Butyl)aniline (4o)20a
The amination reaction of freshly prepared arylmagnesium reagent
2a (1.68 M in THF, 1.48 mL, 2.5 mmol) with 2-methyl-2-nitropropane
3b (104 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); pentane–Et2O, 80:20] furnished 4o.
HRMS (EI): m/z calcd for C17H21NO2: 271.1572; found: 271.1561.
N-[(3s,5s,7s)-Adamantan-1-yl]-1-methyl-1H-indol-5-amine (4l)
The amination reaction of freshly prepared heteroarylmagnesium re-
agent 2l (0.25 M in THF, 10.0 mL, 2.5 mmol) with 1-nitroadamantane
3a (182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 50:50] furnished 4l.
Yield: 108 mg (72%); yellow liquid.
IR (ATR): 3406, 2958, 2924, 2855, 1484, 1363, 1189, 1081, 965, 763,
685 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.05–7.25 (m, 2 H), 6.48–6.93 (m, 3 H),
3.44 (br s, 1 H), 1.36 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 146.8, 128.9, 118.4, 117.5, 51.5, 30.1.
MS (ESI): m/z (%) = 150 (100) [M + H]+, 135 (29).
Yield: 260 mg (93%); pale-yellow solid; mp 91.4–93.0 °C.
IR (ATR): 3302, 2897, 2843, 1498, 1237, 1154, 787, 754, 717 cm–1
1H NMR (600 MHz, CDCl3): δ = 7.09–7.21 (m, 2 H), 6.98 (d, J = 2.7 Hz,
1 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.37 (d, J = 2.5 Hz, 1 H), 3.74 (s, 3 H), 2.88
(br s, 1 H), 1.97–2.15 (m, 3 H), 1.72–1.85 (m, 6 H), 1.52–1.70 (m, 6 H).
.
HRMS (ESI): m/z [M + H] calc. for C10H16N: 150.1283; found:
150.1277.
13C NMR (150 MHz, CDCl3): δ = 133.6, 128.9, 128.6, 120.4, 115.5,
108.7, 100.2, 52.9, 43.8, 36.5, 32.9, 29.8.
MS (EI): m/z (%) = 280 (92) [M+], 223 (100), 146 (18), 145 (18), 135
N-(tert-Butyl)naphthalen-2-amine (4p)20b
The amination reaction of freshly prepared arylmagnesium reagent 2i
(0.31 M in THF, 8.1 mL, 2.5 mmol) with 2-methyl-2-nitropropane 3b
(104 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 93:7] furnished 4p.
(29), 131 (20), 93 (17), 79 (17).
HRMS (EI): m/z calcd for C19H24N2: 280.1939; found: 280.1933.
(3s,5s,7s)-N-(tert-Butyl)adamantan-1-amine (4m)
The amination reaction of freshly prepared tertiary-alkylmagnesium
reagent 2m (1.18 M in THF, 2.1 mL, 2.5 mmol) with 1-nitroadaman-
tane 3a (182 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol),
and NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-
column chromatographic purification [silica gel (pre-neutralized with
Et3N); EtOH] furnished 4m.
Yield: 150 mg, (75%); red solid; mp 35.2–35.8 °C.
IR (ATR): 3408, 3328, 2960, 1628, 1596, 1360, 1213, 1184, 858, 818,
748 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.54–7.78 (m, 3 H), 7.18–7.45 (m, 2 H),
7.08 (s, 1 H), 6.94 (d, J = 8.8 Hz, 1 H), 3.79 (br s, 1 H), 1.46 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 144.3, 134.9, 128.6, 127.7, 127.5, 126.1,
122.3, 121.0, 109.6, 51.7, 29.9.
MS (EI): m/z (%) = 199 (51) [M+], 185 (17), 184 (96), 143 (100), 127
Yield: 160 mg (77%); pale-yellow solid; mp 265–275 °C.
IR (ATR): 2912, 2850, 2781, 2441, 1497, 1375, 1189, 1073, 918,
758 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.49 (br s, 1 H), 2.22–2.47 (m, 6 H),
2.01–2.19 (m, 3 H), 1.45–1.85 (m, 15 H).
13C NMR (75 MHz, CDCl3): δ = 62.4, 60.8, 40.9, 35.5, 29.6,
(11), 116 (11), 115 (31), 41 (7).
HRMS (EI): m/z calcd for C14H17N: 199.1361; found: 199.1361.
MS (EI): m/z (%) = 207 (9) [M+], 192 (72), 150 (42), 135 (100), 94 (86),
57 (14), 41 (34).
N-(tert-Butyl)-[1,1'-biphenyl]-4-amine (4q)20c
The amination reaction of freshly prepared arylmagnesium reagent 2f
(0.28 M in THF, 8.92 mL, 2.5 mmol) with 2-methyl-2-nitropropane 3b
(104 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
HRMS (EI): m/z calcd for C14H25N: 207.1987; found: 207.1993.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256

3253
V. Dhayalan, P. Knochel
Paper
Synthesis
NaBH4 (38 mg, 1.0 mmol) was performed according to TP1. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 90:10] furnished 4q.
FeCl2 (2.0 mmol, 2.0 equiv), and NaBH4 (1.0 mmol, 1.0 equiv) were
added and the reaction mixture was stirred at 0 °C to r.t. for 15 h. Af-
ter quenching the reaction with sat. aq NH4Cl (10 mL), the mixture
was neutralized with aq NaOH (2 M) solution and extracted with
EtOAc (6 × 25 mL). The combined organic phases were dried over
Na2SO4 and concentrated in vacuo. The crude residue was purified by
flash-column chromatography to give the analytically pure amine
product 12a–e.
Yield: 180 mg (80%); pale-yellow solid; mp 37.1–38.3 °C.
IR (ATR): 3404, 2973, 1607, 1519, 1484, 1220, 1204, 826, 756, 694 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.56 (d, J = 7.5 Hz, 2 H), 7.35–7.49 (m,
4 H), 7.22–7.32 (m, 1 H), 6.85 (d, J = 8.3 Hz, 2 H), 3.99 (br s, 1 H), 1.40
(s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 145.8, 141.1, 131.2, 128.6, 127.6, 126.3,
4-Fluoro-N-[1-(4-fluorophenyl)cyclohexyl]aniline (12a)
126.2, 117.5, 51.8, 30.0, 29.9.
MS (EI): m/z (%) = 225 (52) [M+], 211 (16), 210 (100), 170 (14), 169
(98), 168 (12), 152 (13), 115 (10), 41 (7).
The amination reaction of freshly prepared arylmagnesium reagent
2g (0.49 M in THF, 4.48 mL, 2.2 mmol) with 1-chloro-1-nitrosocyclo-
hexane 8a (148 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0
mmol), and NaBH4 (38 mg, 1.0 mmol) was performed according to
TP2. Flash-column chromatographic purification [silica gel (pre-neu-
tralized with Et3N); i-hexane–Et2O, 85:15] furnished 12a.
HRMS (EI): m/z [M – CH3] calcd for C15H16N: 210.1283; found:
210.1228.
Yield: 220 mg (77%); pale-yellow liquid.
IR (ATR): 3436, 2936, 2859, 1606, 1506, 1221, 1159, 905, 822, 727 cm–1
1-Chloro-1-nitrosocyclohexane (8a)21
.
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with cyclohexanone oxime 7a (20.0 g,
177.0 mmol. 1.0 equiv) in anhydrous CH2Cl2 (350 mL) and cooled to
0 °C. N-Chlorosuccinimide (26.0 g, 194.0 mmol, 1.1 equiv) was then
added and the reaction mixture was stirred at 0 to 25 °C for 3 h until
GC analysis of reaction aliquots showed full consumption of the start-
ing material. Removal of the solvent followed by addition of n-pen-
tane (200 mL) to the crude mixture led to the precipitation of succin-
imide. This succinimide was filtered off then washed with n-pentane
(50 mL) and the filtrate was evaporated. The crude residue was puri-
fied by flash-column chromatography (silica gel; n-pentane) to fur-
nish 8a.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.50 (m, 2 H), 6.95 (t, J = 8.6 Hz,
2 H), 6.65 (t, J = 8.6 Hz, 2 H), 6.21 (dd, J = 8.1, 4.2 Hz, 2 H), 4.02 (br s,
1 H), 1.89–2.16 (m, 2 H), 1.39–1.82 (m, 7 H), 1.09–1.36 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 161.5 (d, J = 244.0 Hz), 155.8 (d, J =
231.0 Hz), 144.0, 141.4, 127.5 (d, J = 8.0 Hz), 116.5, 115.4 (d, J =
8.0 Hz), 115.1 (d, J = 10.0 Hz), 57.5, 36.2, 25.4, 21.9.
19F NMR (376 MHz, CDCl3): δ = –117.1 (s, 1 F), –128.0 (s, 1 F).
MS (EI): m/z (%) = 287 (6) [M+], 177 (26), 135 (7), 111 (56), 109 (100),
81 (8), 55 (8).
HRMS (EI): m/z calcd for C18H19F2N: 287.1486; found: 287.1469.
Yield: 23.4 g (90%); greenish blue liquid.
1H NMR (400 MHz, CDCl3): δ = 2.29–2.74 (m, 2 H), 1.21–2.05 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 117.7, 33.4, 24.7, 21.8.
4-Methyl-N-[1-(p-tolyl)cyclohexyl]aniline (12b)
The amination reaction of freshly prepared arylmagnesium reagent
2o (0.51 M in THF, 4.31 mL, 2.2 mmol) with 1-chloro-1-nitrosocyclo-
hexane 8a (148 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0
mmol), and NaBH4 (38 mg, 1.0 mmol) was performed according to
TP2. Flash-column chromatographic purification [silica gel (pre-neu-
tralized with Et3N); i-hexane–Et2O, 99:1] furnished 12b.
1-Chloro-1-nitrosocyclopentane (8b)21
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with cyclopentanone oxime 7b (6.2 g,
62.2 mmol. 1.0 equiv) in anhydrous CH2Cl2 (150 mL) and cooled to
0 °C. N-Chlorosuccinimide (9.2 g, 68.9 mmol, 1.1 equiv) was added
and the reaction mixture was stirred at 0 to 25 °C for 3 h until GC
analysis of reaction aliquot showed full consumption of the starting
material. Removal of solvent followed by addition of n-pentane (100
mL) to the crude mixture led to the precipitation of succinimide. This
succinimide was filtered off then washed with n-pentane (50 mL) and
the filtrate was evaporated. The crude residue was purified by flash-
column chromatography (silica gel; n-pentane) to furnish 8b.
Yield: 210 mg (75%); pale-yellow liquid.
IR (ATR): 3425, 2928, 2855, 1615, 1513, 1448, 1300, 1252, 806,
720 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 8.0 Hz, 2 H), 7.08 (d, J =
7.8 Hz, 2 H), 6.77 (d, J = 8.2 Hz, 2 H), 6.25 (d, J = 7.4 Hz, 2 H), 4.01 (br s,
1 H), 2.28 (s, 3 H), 1.97–2.18 (m, 5 H), 1.4–1.87 (m, 7 H), 1.15–1.36
(m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 145.7, 143.2, 135.8, 129.2, 129.2,
125.8, 115.7, 57.4, 36.2, 25.6, 22.0, 21.0, 20.4.
Yield: 5.0 g (60%); greenish blue liquid.
1H NMR (400 MHz, CDCl3): δ = 2.64–3.12 (m, 2 H), 1.57–2.33 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 122.9, 38.2, 25.5.
MS (EI): m/z (%) = 279 (31) [M+], 236 (17), 173 (38), 157 (19), 129
(17), 115 (15), 107 (85), 105 (100).
HRMS (EI): m/z calcd for C20H25N: 279.1987; found: 279.1973.
Preparation of Secondary Amines (12a–e) by the Reaction of Func-
tionalized Arylmagnesium Reagents (2) with 1-Chloro-1-nitroso-
cycloalkanes (8); Typical Procedure 2 (TP2)
4-Methoxy-N-[1-(4-methoxyphenyl)cyclohexyl]aniline (12c)
The amination reaction of freshly prepared arylmagnesium reagent
2p (0.51 M in THF, 4.31 mL, 2.2 mmol) with 1-chloro-1-nitrosocyclo-
hexane 8a (148 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0
mmol), and NaBH4 (38 mg, 1.0 mmol) was performed according to
TP2. Flash-column chromatographic purification [silica gel (pre-neu-
tralized with Et3N); i-hexane–EtOAc, 60:40] furnished 12c.
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with nitroso substrate 8 (1.0 mmol, 1.0
equiv) in anhydrous THF (4 mL) and cooled to –60 °C. Freshly pre-
pared arylmagnesium reagent 2 (2.2 mmol. 2.2 equiv) was then added
and the reaction mixture was stirred at –60 to 25 °C for 12 h until GC
analysis of reaction aliquots showed full consumption of the starting
material. The reaction mixture was cooled to 0 °C, then EtOH (1.0 mL),
Yield: 236 mg (76%); pale-yellow solid; mp 59.3–62.2 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256

3254
V. Dhayalan, P. Knochel
Paper
Synthesis
IR (ATR): 3428, 2933, 2857, 1605, 1504, 1215, 1158, 819, 770 cm–1
.
starting material. The reaction mixture was cooled to 0 °C, then EtOH
(1.0 mL), FeCl2 (2.0 mmol, 2.0 equiv), and NaBH4 (1.0 mmol, 1.0 equiv)
were added and the reaction mixture was stirred at 0 °C to r.t. for 15
h. After quenching with sat. aq NH4Cl (10 mL), the mixture was neu-
tralized with aq NaOH (2 M) solution and extracted with EtOAc
(6 × 25 mL). The combined organic phases were dried over Na2SO4
and concentrated in vacuo. The crude residue obtained was purified
by flash-column chromatography to give the analytically pure amine
product 15a–d.
1H NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 8.8 Hz, 2 H), 6.81 (d, J =
8.8 Hz, 2 H), 6.54 (d, J = 8.9 Hz, 2 H), 6.25 (d, J = 8.8 Hz, 2 H), 3.84 (br s,
1 H), 3.74 (s, 3 H), 3.61 (s, 3 H), 2.02 (d, J = 13.1 Hz, 2 H), 1.60–1.78 (m,
3 H), 1.42–1.59 (m, 4 H), 1.21–1.31 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 158.0, 151.9, 140.9, 139.6, 127.0,
117.1, 114.3, 113.8, 57.2, 55.6, 55.2, 36.3, 25.6, 22.1.
MS (EI): m/z (%) = 311 (10) [M+], 189 (82), 188 (21), 160 (10), 123
(51), 121 (100), 108 (18).
HRMS (EI): m/z calcd for C20H25NO2: 311.1885; found: 311.1884.
N-Cyclohexylaniline (15a)23a
The amination reaction of freshly prepared arylzinc reagent 13a (1.68
M in THF, 0.65 mL, 1.1 mmol) with 1-chloro-1-nitrosocyclohexane 8a
(148 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP3. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–Et2O, 96:4] furnished 15a.
4-Methyl-N-[1-(p-tolyl)cyclopentyl]aniline (12d)
The amination reaction of freshly prepared arylmagnesium reagent
2o (0.47 M in THF, 4.68 mL, 2.2 mmol) with 1-chloro-1-nitrosocyclo-
pentane 8b (134 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0
mmol), and NaBH4 (38 mg, 1.0 mmol) was performed according to
TP2. Flash-column chromatographic purification [silica gel (pre-neu-
tralized with Et3N); i-hexane–EtOAc, 99:1] furnished 12d.
Yield: 80 mg (46%); pale-yellow liquid.
IR (ATR): 3401, 2926, 2852, 1600, 1502, 1319, 1255, 744, 690 cm–1
.
Yield: 180 mg (68%); pale-yellow liquid.
1H NMR (400 MHz, CDCl3): δ = 7.09–7.22 (m, 2 H), 6.66 (tt, J = 7.3,
1.1 Hz, 1 H), 6.55–6.62 (m, 2 H), 3.52 (br s, 1 H), 3.21–3.31 (m, 1 H),
2.02–2.11 (m, 2 H), 1.73–1.81 (m, 2 H), 1.62–1.69 (m, 1 H), 1.32–1.42
(m, 2 H), 1.11–1.27 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 147.4, 129.2, 116.8, 113.1, 51.7, 33.5,
25.9, 25.0.
IR (ATR): 3414, 2953, 2869, 1615, 1512, 1448, 1302, 1256, 1183, 1019,
806 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 7.8 Hz, 2 H), 7.07 (d, J =
7.8 Hz, 2 H), 6.79 (d, J = 8.0 Hz, 2 H), 6.26 (d, J = 8.2 Hz, 2 H), 3.91 (br s,
1 H), 2.28 (s, 3 H), 1.94–2.19 (m, 7 H), 1.70–1.89 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 143.8, 143.7, 135.6, 129.2, 129.1,
MS (EI): m/z (%) = 175 (41) [M+], 132 (100), 118 (11), 77 (17), 61 (12),
126.0, 125.9, 115.3, 66.9, 40.8, 24.2, 21.0, 20.4.
44 (43), 43 (92).
MS (EI): m/z (%) = 265 (17) [M+], 159 (85), 143 (12), 115 (11), 107
HRMS (EI): m/z calcd for C12H17N: 175.1361; found: 175.1355.
(100), 105 (74), 67 (10).
HRMS (EI): m/z calcd for C19H23N: 265.1830; found: 265.1817.
N-Cyclohexyl-4-methylaniline (15b)23b
The amination reaction of freshly prepared arylzinc reagent 13b (0.51
M in THF, 2.15 mL, 1.1 mmol) with 1-chloro-1-nitrosocyclohexane 8a
(148 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP3. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–Et2O, 70:30] furnished 15b.
4-Methoxy-N-[1-(4-methoxyphenyl)cyclopentyl]aniline (12e)
The amination reaction of freshly prepared arylmagnesium reagent
2p (0.48 M in THF, 4.58 mL, 2.2 mmol) with 1-chloro-1-nitrosocyclo-
pentane 8b (134 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0
mmol), and NaBH4 (38 mg, 1.0 mmol) was performed according to
TP2. Flash-column chromatographic purification [silica gel (pre-neu-
tralized with Et3N); i-hexane–EtOAc, 70:30] furnished 12e.
Yield: 78 mg (41%); pale-yellow liquid.
IR (ATR): 3382, 2924, 2854, 2480, 2429, 1618, 1515, 1464, 1021, 809,
788 cm–1
.
Yield: 240 mg (81%); pale-yellow solid; mp 90.9–91.2 °C.
IR (ATR): 3407, 2966, 1606, 1508, 1243, 1170, 1024, 821, 799 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.91 (d, J = 8.2 Hz, 2 H), 6.52 (d, J =
8.2 Hz, 2 H), 3.01–3.26 (m, 1 H), 2.17 (s, 3 H), 1.89–2.06 (m, 2 H),
1.47–1.78 (m, 3 H), 0.95–1.38 (m, 6 H).
1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 8.6 Hz, 2 H), 6.79 (d, J =
8.6 Hz, 2 H), 6.56 (d, J = 8.8 Hz, 2 H), 6.28 (d, J = 8.6 Hz, 2 H), 3.73 (s,
4 H), 3.62 (s, 3 H), 1.91–2.10 (m, 4 H), 1.67–1.85 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 144.2, 129.8, 127.0, 114.2, 52.8, 33.3,
13C NMR (100 MHz, CDCl3): δ = 158.0, 151.9, 140.1, 138.9, 127.1,
25.9, 25.1, 20.4.
MS (EI): m/z (%) = 189 (49) [M+], 147 (17), 146 (100), 133 (16), 131
116.8, 114.3, 113.6, 67.0, 55.7, 55.2, 40.4, 23.9.
MS (EI): m/z (%) = 297 (9) [M+], 176 (12), 175 (100), 134 (8), 123 (41),
(13), 120 (13), 106 (14), 91 (15), 77 (11).
121 (43), 108 (10).
HRMS (EI): m/z calcd for C13H19N: 189.1517; found: 189.1506.
HRMS (EI): m/z calcd for C19H23NO2: 297.1729; found: 297.1725.
4-Butyl-N-cyclohexylaniline (15c)
Preparation of Secondary Amines 15a–d by the Reaction of Func-
tionalized Arylzinc Reagents 13a–d with 1-Chloro-1-nitrosocyclo-
hexane (8a): Typical Procedure 3 (TP3)
The amination reaction of freshly prepared arylzinc reagent 13c (0.27
M in THF, 4.07 mL, 1.1 mmol) with 1-chloro-1-nitrosocyclohexane 8a
(148 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP3. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–Et2O, 96:4] furnished 15c.
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with freshly prepared arylzinc reagent
13a–d (1.1 mmol. 1.1 equiv) in anhydrous THF (2 mL) and cooled to
0 °C. Then 1-chloro-1-nitrosocyclohexane 8a (1.0 mmol, 1.0 equiv)
was added and the reaction mixture was stirred at 0 to 25 °C for 12 h
until GC analysis of reaction aliquots showed full consumption of the
Yield: 95 mg (41%); pale-yellow liquid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256

3255
V. Dhayalan, P. Knochel
Paper
Synthesis
IR (ATR): 3399, 2925, 2852, 1616, 1515, 1450, 1316, 1304, 1254,
816 cm–1
1H NMR (400 MHz, CDCl3): δ = 6.92 (d, J = 8.2 Hz, 2 H), 6.49 (d, J =
8.20 Hz, 2 H), 3.46 (br s, 1 H), 3.06–3.25 (m, 1 H), 2.43 (t, J = 7.7 Hz,
2 H), 1.87–2.10 (m, 2 H), 1.42–1.76 (m, 5 H), 1.00–1.40 (m, 7 H), 0.86
(t, J = 7.32 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.1, 131.6, 129.1, 113.5, 52.2, 34.8,
34.1, 33.6, 26.0, 25.1, 22.4, 14.0,
MS (EI): m/z (%) = 231 (46) [M+], 230 (9), 189 (17), 188 (100), 132
(15), 106 (18).
Wakimoto, T.; Imai, K.; Shirota, Y. Mol. Cryst. Liq. Cryst. 1996,
280, 331. (h) D’Aprano, G.; Leclerc, M.; Zotti, G.; Schiavon, G.
Chem. Mater. 1995, 7, 33.
.
(2) (a) Wanka, L.; Iqbal, K.; Schreiner, P. R. Chem. Rev. 2013, 113,
3516. (b) Shokova, E. A.; Kovalev, V. V. Russ. J. Org. Chem. 2012,
48, 1007. (c) Liu, J.; Obando, D.; Liao, V.; Lifa, T.; Codd, R. Eur. J.
Med. Chem. 2011, 46, 1949. (d) Lamoureux, G.; Artavia, G. Curr.
Med. Chem. 2010, 17, 2967. (e) Valente, S.; Conte, M.; Tardugno,
M.; Massa, S.; Nebbioso, A.; Altucci, L.; Mai, A. ChemMedChem
2009, 4, 1411. (f) Geldenhuys, W. J.; Malan, S. F.; Bloomquist, J.
R.; Marchand, A. P.; Van der Schyf, C. J. Med. Res. Rev. 2005, 25,
21. (g) Spasov, A. A.; Khamidova, T. V.; Bugaeva, L. I.; Morozov, I.
S. Pharm. Chem. J. 2000, 34, 1.
HRMS (EI): m/z calcd for C16H25N: 231.1987; found: 231.1967.
(3) (a) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423.
(b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576,
125. (c) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. (d) Hartwig, J. F. Angew. Chem. Int.
Ed. 1998, 37, 2046. (e) Driver, M. S.; Hartwig, J. F. J. Am. Chem.
Soc. 1996, 118, 7217. (f) Wagaw, S.; Buchwald, S. L. J. Org. Chem.
1996, 61, 7240. (g) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am.
Chem. Soc. 1996, 118, 7215.
(4) (a) Ackermann, L.; Sandmann, R.; Song, W. Org. Lett. 2011, 13,
1784. (b) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett.
2001, 42, 247. (c) Lipshutz, B. H.; Ueda, H. Angew. Chem. Int. Ed.
2000, 39, 4492.
(5) (a) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc.
2010, 132, 6900. (b) Klapars, A.; Antilla, J. C.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (c) Wolter, M.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803. (d) Shen, R.;
Porco, J. A. Jr. Org. Lett. 2000, 2, 1333. (e) Kalinin, A. V.; Bower, J.
F.; Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986.
N-Cyclohexyl-3,4,5-trimethoxyaniline (15d)23c
The amination reaction of freshly prepared arylzinc reagent 13d (0.23
M in THF, 4.78 mL, 1.1 mmol) with 1-chloro-1-nitrosocyclohexane 8a
(148 mg, 1.0 mmol), EtOH (1.0 mL), FeCl2 (254 mg, 2.0 mmol), and
NaBH4 (38 mg, 1.0 mmol) was performed according to TP3. Flash-col-
umn chromatographic purification [silica gel (pre-neutralized with
Et3N); i-hexane–EtOAc, 50:50] furnished 15d.
Yield: 130 mg (49%); greenish liquid.
IR (ATR): 3377, 2927, 2851, 1609, 1594, 1506, 1231, 1123, 1012, 801,
776 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 5.81 (s, 2 H), 3.80 (s, 6 H), 3.74 (s, 3 H),
3.40 (br s, 1 H), 3.13–3.22 (m, 1 H), 1.99–2.09 (m, 2 H), 1.71–1.79 (m,
2 H), 1.59–1.67 (m, 1 H), 1.30–1.40 (m, 2 H), 1.09–1.26 (m, 3 H).
13C NMR (150 MHz, CDCl3): δ = 154.0, 144.1, 129.8, 90.8, 61.1, 55.9,
52.1, 33.6, 25.9, 25.0.
MS (EI): m/z (%) = 265 (34) [M+], 251 (16), 250 (100), 168 (41), 140 (9),
(6) Kim, M.; Chang, S. Org. Lett. 2010, 12, 1640.
55 (8), 43 (16).
(7) (a) Castillo, P. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2015, 137, 3085. (b) Fors, B. P.; Buchwald, S. L. J. Am. Chem.
Soc. 2010, 132, 15914.
HRMS (EI): m/z calcd for C15H23NO3: 265.1678; found: 265.1669.
(8) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397.
Acknowledgment
(9) (a) Corpet, M.; Gosmini, C. Synthesis 2014, 46, 2258. (b) Sinha,
P.; Kofink, C. C.; Knochel, P. Org. Lett. 2006, 8, 3741. (c) Sinha, P.;
Knochel, P. Synlett 2006, 3304. (d) Rucker, R. P.; Whittaker, A.
M.; Dang, H.; Lalic, G. Angew. Chem. Int. Ed. 2012, 51, 3953.
(e) Barker, T. J.; Jarvo, E. R. Angew. Chem. Int. Ed. 2011, 50, 8325.
(f) He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu, W.; Li, Q.; Lei, A. Angew.
Chem. Int. Ed. 2008, 47, 6414. (g) Berman, A. M.; Johnson, J. S.
J. Org. Chem. 2006, 71, 219. (h) Berman, A. M.; Johnson, J. S.
J. Org. Chem. 2005, 70, 364. (i) Narasaka, K.; Kitamura, M. Eur. J.
Org. Chem. 2005, 4505. (j) Berman, A. M.; Johnson, J. S. Synlett
2005, 1799. (k) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc.
2004, 126, 5680. (l) Kitamura, M.; Suga, T.; Chiba, S.; Narasaka,
K. Org. Lett. 2004, 6, 4619. (m) Yu, Y.; Srogl, J.; Liebeskind, L. S.
Org. Lett. 2004, 6, 2631.
The research leading to these results has received funding from the
European Research Council under the European Community’s Sev-
enth Framework Programme (FP7/2007−2014) ERC grant agreement
no. 227763. We thank the Fonds der Chemischen Industrie for finan-
cial support. We also thank Heraeus Holding GmbH (Hanau), Rock-
wood Lithium (Frankfurt), and BASF SE (Ludwigshafen) for the
generous gift of chemicals.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378871.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(10) (a) Kopp, F.; Sapountzis, I.; Knochel, P. Synlett 2003, 885.
(b) Waters, W. L.; Marsh, P. G. J. Org. Chem. 1975, 40, 3344.
(11) For the reaction of nitroarenes with Grignard reagents, see:
(a) Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124, 9390.
(b) Windler, G. K.; Pagoria, P. F.; Vollhardt, K. P. C. Synthesis
2014, 2383. (c) Gao, H.; Xu, Q. L.; Yousufuddin, M.; Ess, D. H.;
Kürti, L. Angew. Chem. Int. Ed. 2014, 53, 2701. (d) Gao, H.; Ess, D.
H.; Yousufuddin, M.; Kürti, L. J. Am. Chem. Soc. 2013, 135, 7086.
(e) Wylie, L.; Innocenti, P.; Whelligan, D. K.; Hoelder, S. Org.
Biomol. Chem. 2012, 10, 4441. (f) Dobbs, A. J. Org. Chem. 2001,
66, 638. (g) Dobbs, A. P.; Voyle, M.; Whittall, N. Synlett 1999,
1594. (h) Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.;
Petrini, M. J. Chem. Soc., Perkin Trans. 2 1991, 657. (i) Barboni, L.;
References
(1) (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337. (b) Schlummer, B.; Scholz, U. Adv.
Synth. Catal. 2004, 346, 1599. (c) Thomas, G. Medicinal Chemis-
try; Wiley-VCH: Weinheim, 2000. (d) Liu, S.; Jiang, X.; Ma, H.;
Liu, M. S.; Jen, A. K.-Y. Macromolecules 2000, 33, 3514. (e) Yu,
W.-L.; Pei, J.; Huang, W.; Heeger, A. J. Chem. Commun. 2000, 681.
(f) Bellmann, E.; Shaheen, S. E.; Thayumanavan, S.; Barlow, S.;
Grubbs, R. H.; Marder, S. R.; Kippelen, B.; Peyghambarian, N.
Chem. Mater. 1998, 10, 1668. (g) Inada, H.; Yonemoto, Y.;
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256

3256
V. Dhayalan, P. Knochel
Paper
Synthesis
Bartoli, G.; Marcantoni, E.; Petrini, M.; Dalpozzo, R. J. Chem. Soc.,
Perkin Trans. 1990, 2133. (j) Bartoli, G.; Petrini, M.;
(17) (a) Druzhinin, S. I.; Dubbaka, S. R.; Knochel, P.; Kovalenko, S. A.;
Mayer, P.; Senyushkina, T.; Zachariasse, K. A. J. Phys. Chem. A
2013, 117, 9113. (b) Druzhinin, S. I.; Dubbaka, S. R.; Knochel, P.;
Kovalenko, S. A.; Mayer, P.; Senyushkina, T.; Zachariasse, K. A.
J. Phys. Chem. A 2008, 112, 2749.
(18) (a) Molle, G.; Bauer, P.; Dubois, J. E. J. Org. Chem. 1982, 47, 4120.
(b) Dubois, J. E.; Bauer, P.; Molle, G.; Daza, J. C. R. Seances Acad.
Sci., Ser. C 1977, 284, 146.
1
Marcantoni, E.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1990,
31, 6089. (k) Inagaki, Y.; Okazaki, R.; Inamoto, N. Bull. Chem. Soc.
Jpn. 1975, 48, 3727. (l) Yost, Y.; Gutmann, H. R.; Muscoplat, C. C.
J. Chem. Soc. C 1971, 2119. (m) Bartoli, G.; Palmieri, G.; Bosco,
M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129. (n) Curtin, D.
Y.; Kauer, J. C. J. Am. Chem. Soc. 1953, 75, 6041.
(12) (a) Sämann, C.; Dhayalan, V.; Schreiner, P. R.; Knochel, P. Org.
Lett. 2014, 16, 2418. (b) Dagousset, G.; François, C.; León, T.;
Blanc, R.; Dagousset, E. S.; Knochel, P. Synthesis 2014, 46, 3133.
(c) Sidduri, A.; Tilley, J. W.; Fotouhi, N. Synthesis 2014, 46, 430.
(13) Dhayalan, V.; Sämann, C.; Knochel, P. Chem. Commun. 2015, 51,
3239.
(14) (a) Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.;
Gavryushin, A.; Knochel, P. Chem. Eur. J. 2009, 15, 7192.
(b) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.;
Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 6802.
(19) Sarker, H.; Greer, M. L.; Blacktock, S. C. J. Org. Chem. 1996, 61,
3177.
(20) (a) Arnauld, T.; Barton, D. H. R.; Doris, E. Tetrahedron 1997, 53,
4137. (b) Cortright, S. B.; Huffman, J. C.; Yoder, R. A.; Coalter, J.
N. III; Johnston, J. N. Organometallics 2004, 23, 2238. (c) Cran, J.
W.; Vidhani, D. V.; Krafft, M. E. Synlett 2014, 25, 1550.
(21) (a) Hawthorne, M. F.; Strahm, R. D. J. Am. Chem. Soc. 1957, 79,
2515. (b) Muller, E.; Metzger, H.; Fries, D. Chem. Ber. 1954, 87,
1449. (c) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005,
3514.
(15) (a) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu, V.
A.; Knochel, P. Synthesis 2002, 565. (b) Sapountzis, I.; Dohle, W.;
Knochel, P. Chem. Commun. 2001, 2068. (c) Rottländer, M.;
Boymond, L.; Bérillon, L.; Leprêtre, A.; Varchi, G.; Avolio, S.;
Laaziri, H.; Quéguiner, G.; Ricci, A.; Cahiez, G.; Knochel, P. Chem.
Eur. J. 2000, 6, 767. (d) Abarbri, M.; Thibonnet, J.; Bérillon, L.;
Dehmel, F.; Rottländer, M.; Knochel, P. J. Org. Chem. 2000, 65,
4618. (e) Boymond, L.; Rottländer, M.; Cahiez, G.; Knochel, P.
Angew. Chem. Int. Ed. 1998, 37, 1701.
(22) (a) Schenk, C.; Beekes, M. L.; Van der Drift, J. A. M.; de Boer, T. J.
Recl. J. R. Neth. Chem. Soc. 1980, 99, 278. (b) Schenk, C.; Beekes,
M. L.; de Boer, T. J. Recl. J. R. Neth. Chem. Soc. 1980, 99, 246.
(23) (a) Kawakami, T.; Sugimoto, T.; Shibata, I.; Baba, A.; Matsuda,
H.; Sonoda, N. J. Org. Chem. 1995, 60, 2677. (b) Viciu, M. S.; Kelly,
R. A. III; Stevens, E. D.; Naud, F.; Studer, M.; Nolan, S. P. Org. Lett.
2003, 5, 1479. (c) Razzuk, A.; Biehl, E. R. J. Org. Chem. 1987, 52,
2619.
(24) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890.
(16) Schwertfeger, H.; Würtele, C.; Schreiner, P. R. Synlett 2010, 493.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3246–3256