Preparation of heterocyclic amines via a copper(i)-mediated oxidative cross-coupling of organozinc reagents with lithium amides

Article abstract of DOI:10.1055/s-0029-1220008

Functionalized heteroaromatic amines are readily prepared by the oxidative coupling of polyfunctional zinc amidocuprates using PhI(OAc)₂ as oxidant. Various sensitive heterocyclic organometallics undergo this oxidative cross-coupling reaction furnishing aminated heteroaromatics. A high functional group tolerance and relative insensibility to steric hindrance characterize this general amination reaction. A practical procedure for the preparation of protected primary and secondary as well as tertiary heteroaryl amines is described. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1220008

PRACTICAL SYNTHETIC PROCEDURES
2313
Preparation of Heterocyclic Amines via a Copper(I)-Mediated Oxidative
Cross-Coupling of Organozinc Reagents with Lithium Amides
H
eterocyclic Am
o
r
a
tive
C
r
a
oss-Coupling Dunst, Marcel Kienle, Paul Knochel*
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
Received 14 April 2010
Dedicated to Prof. Dr. Rolf Huisgen on the occasion of his 90th birthday
PSP
No188
Abstract: Functionalized heteroaromatic amines are readily prepared by the oxidative coupling of polyfunctional zinc amidocuprates using
PhI(OAc)2 as oxidant. Various sensitive heterocyclic organometallics undergo this oxidative cross-coupling reaction furnishing aminated
heteroaromatics. A high functional group tolerance and relative insensibility to steric hindrance characterize this general amination reaction.
A practical procedure for the preparation of protected primary and secondary as well as tertiary heteroaryl amines is described.
Key words: amination, amidocuprates, C–N bond formation, lithium amides, polyfunctional zinc reagents
Procedure 1:
1) CuCl·2LiCl
Br
Br
2
Br
PhI(OAc)2
(1.1 equiv)
1) TMP2Zn·2MgCl2·2LiCl
(0.6 equiv), THF
(1.1 equiv)
Br
TMS
N
N
N
N
N
TMS
–50 °C, 30 min
TMS
N
Br
Zn
Cu
Br
Br
S
S
S
25 °C, 45 min
Br
2) LiN(SiMe3)2 (3a)
(2.0 equiv)
–78 °C, 1 h
S
TMS
ZnX
1a
2a
4a
5a: 82%
–50 °C, 1 h
Procedure 2:
TBS
Mg (2.5 equiv)
ZnCl2 (1.0 equiv)
LiCl (2.5 equiv)
1) CuCl·2LiCl
(1.1 equiv)
Ph
XZn
N
N
Br
Ph
TBS
XZn
PhI(OAc)2
(1.1 equiv)
N
N
Cu
–50 °C, 30 min
O
O
N
–78 °C, 1 h
THF, 25 °C, 25 min
2) LiN(TBS)Ph (3b)
O
O
N
(2.0 equiv)
–50 °C, 1 h
1b
2b
4b
5b: 60%
Procedure 3:
1) i-PrMgCl·LiCl
1) CuCl·2LiCl
(1.1 equiv)
(1.1 equiv)
THF
0 °C to 25 °C, 1h
ZnX
Cu
TBS
N
PhI(OAc)2
(1.1 equiv)
Br
Zn
Br
Br
Br
–50 °C, 30 min
TBS
Br
N
Ph
2
2) ZnCl2
2) LiN(TBS)Ph (3b)
–78 °C, 1 h
Ph
N
N
N
(0.55 equiv)
(2.0 equiv)
–50 °C, 1 h
0 °C, 30 min
1c
2c
4c
5c: 55%
Scheme 1 Procedures for the oxidative amination of arylzinc reagents
Introduction
reaction3is widely used, these protocols still have some
limitations such as long reaction times and the require-
Functionalized aromatics and heteroaromatics are impor- ment of using strong bases. Furthermore, some functional
tant building blocks for the synthesis of pharmaceuticals, groups such as iodides and bromides are not compatible
polymers, and materials.1 Especially, amines containing with these amination procedures. Inspired by the works of
five-membered heteroaryl groups such as furans, Yamamoto4 and Ricci,5 we recently reported a Cu(I)-me-
thiophenes, thiazoles, and pyrazoles are found in various diated oxidative amination of magnesium reagents with
target molecules.2 Although the Pd-catalyzed amination lithium amides using chloranil as oxidant.6 However, this
protocol is limited due to the low stability of some het-
eroarylmagnesium reagents. Furthermore, functionalized
SYNTHESIS 2010, No. 13, pp 2313–2318
Advanced online publication: 20.05.2010
DOI: 10.1055/s-0029-1220008; Art ID: C02510SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0
heteroaromatics bearing halides often underwent halogen-
dance reactions7 and could not be employed in this proce-
dure. Finally, the scale-up of this reaction was difficult

2314
C. Dunst et al.
PRACTICAL SYNTHETIC PROCEDURES
(over 10 mmol) due to the formation of the corresponding tion of an organomagnesium reagent (Procedure 3;
homocoupling product. Therefore, we have recently re- Scheme 1). Thus, the direct zincation of 2,4-dibromothia-
ported an extension of this work using the more stable or- zole (1a) with TMP2Zn·2MgCl2·2LiCl10 (TMP = 2,2,6,6-
ganozinc reagents in an oxidative amination reaction, tetramethylpiperidyl)11 (0.55 equiv, 25 °C, 45 min) gave
8
which was mediated by PhI(OAc)2 as oxidation reagent.9 the diarylzinc species 2a. This compound was treated with
Beside a large tolerance towards functional groups, the the THF-soluble complex CuCl·2LiCl (1.1 equiv, –50 °C,
generated organozinc reagents showed a remarkable sta- 30 min) and LiN(SiMe3)2 (3a, 2.0 equiv, –50 °C, 1 h) af-
bility even at higher temperatures. The resulting organo- fording the corresponding zinc amidocuprate 4a. Subse-
zinc compounds reacted in a Cu(I)-mediated oxidative quent oxidation of 4a using PhI(OAc)2 (1.1 equiv, –78 °C,
cross-coupling with various lithium amides and furnished 1 h) afforded the heterocyclic amine 5a in 82% yield
the desired amines in moderate to good yields. Herein, we (Scheme 1, Procedure 1). The magnesium insertion12 in
wish to report typical practical procedures illustrating the the presence of LiCl and ZnCl2 into the heteroaryl bro-
preparation of functionalized organozinc reagents and mide 1b gave the corresponding zinc reagent 2b, which
subsequent reaction in an oxidative amination reaction.
reacted with CuCl·2LiCl and secondary TBS-protected
lithium amide to the amido cuprate 4b. Subsequent oxida-
tion with PhI(OAc)2 gave the protected secondary amine
5b in 60% yield. Finally, the organozinc reagent 2c, ob-
tained via a Br/Mg exchange13 on 3,5-dibromopyridine
Scope and Limitations
The required organozinc reagents can either by obtained (1c) and subsequent transmetalation, was reacted in the
by direct zincation (Procedure 1), by magnesium insertion same manner furnishing the triarylamine 5c in 82% yield
in the presence of ZnCl2 (Procedure 2) or by transmetala- (Procedure 3). The mild conditions of this oxidative ami-
Table 1 Oxidative Amination of Zinc Reagents with Various Lithium Amidesa
Entry
1
Zinc reagent
Lithium amide
LiNPh2
Product
Yield (%)b
60c
Ph
Ph
2d
2d
3c
5d
5e
Zn
N
N
S
S
S
2
2
3
3d
75c
73c
Zn
Li
N
O
O
S
2
TMS
S
S
S
Br
Br
Zn
2
S
2e
2e
2e
2f
3a
3d
3e
3a
LiN(SiMe3)2
5f
5g
5h
5i
Br
N
TMS
N
N
N
N
O
4
5
6
80c
65c
63c
Zn
2
S
S
Br
N
Li
N
O
N
N
i-Pr
Br
Zn
2
LDA
Br
N
i-Pr
TMS
S
PhS
Zn
S
LiN(SiMe3)2
LiNPh2
PhS
N
TMS
2
N
N
Ph
ZnBr
N
Ph
7
2g
3c
5j
66d
N
N
N
N
Me
Me
Ph
N
Br
Br
Zn
2
88e
54e
Br
Br
8
9
2c
2c
3c
3f
LiNPh2
5k
5l
Ph
N
N
N
C6H13
N
Zn
2
LiN(C6H13)2
C6H13
N
a Reactions were carried out on a 10 mmol scale.
b Yield of analytically pure products.
c Arylzinc reagent was obtained via direct metalation using TMP2Zn·2MgCl2·2LiCl.
d The arylzinc reagent was prepared by Mg insertion in the presence of LiCl and ZnCl2 into the corresponding aryl bromide.
e The zinc reagent was prepared from the corresponding Mg reagent by transmetalation with ZnCl2.
Synthesis 2010, No. 13, 2313–2318 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Heterocyclic Amines via Oxidative Cross-Coupling
2315
suppliers and used without further purification unless otherwise
stated. THF was continuously refluxed and freshly distilled from
sodium benzophenone ketyl under nitrogen. Yields refer to isolated
compounds estimated to be >95% pure as determined by 1H NMR
and capillary GC analysis.
nation are compatible with a wide range of functionalized
heterocycles (Scheme 1 and Table 1). Moreover, this
amination reaction is also suitable for large-scale reac-
tions, when the previously described organozinc reagents
are used.
Reagent i-PrMgCl·LiCl
Thus, the zincation of benzothiophene (10 mmol) with
TMP2Zn·2MgCl2·2LiCl (0.55 equiv, 25 °C, 24 h) afford-
ed the corresponding diarylzinc species 2d, which was re-
acted with the lithium amides 3c and 3d under the
conditions described above. The tertiary amines 5d and 5e
were obtained in yields of 60 and 75%, respectively
(Table 1, entries 1,2). 2-Bromothiazole was metalated us-
ing the same base. Thus, the reaction of 2-bromothiazole
(10 mmol) with TMP2Zn·2MgCl2·2LiCl (0.55 equiv,
25 °C, 2 h) furnished the zinc reagent 2e. After transmet-
alation (CuCl·2LiCl, 1.1 equiv) and addition of an appro-
priate lithium amide such as 3a, 3d,e, the resulting
amidocuprates of type 4 were treated with PhI(OAc)2 to
give the desired amines 5f–h in 65–80% yields (entries 3–
5). The zinc species 2f was obtained by direct zincation
of the corresponding thiazole derivative using
TMP2Zn·2MgCl2·2LiCl (0.55 equiv, 25 °C, 2 h). Amina-
tion with LiN(SiMe3)2 furnished the amine 5i in a yield of
63% (entry 6). (Phenylthio)thiazoles of this type are use-
Mg turnings (110 mmol) and anhyd LiCl (100 mmol) were placed
in a dried argon-flushed flask, and THF (50 mL) was added. A so-
lution of i-PrCl (100 mmol) in THF (50 mL) was slowly added at
r.t. The reaction starts within few minutes. After the addition was
complete, the reaction mixture was stirred for 12 h at r.t. The grey
solution of i-PrMgCl·LiCl was cannulated from the excess of mag-
nesium to a different flask under argon. A yield of ca. 95–98% of i-
PrMgCl·LiCl was obtained. The reagent was titrated prior to use by
the method of Paquette,15 or the method developed in our laborato-
ry.16
Reagent TMPMgCl·LiCl
A dry and N2-flushed 250 mL Schlenk flask, equipped with a mag-
netic stirring bar and a septum, was charged with freshly titrated i-
PrMgCl·LiCl (1.2 M in THF) (100 mL, 120 mmol). 2,2,6,6-Tetram-
ethylpiperidine (TMPH) (19.8 g, 126 mmol, 1.05 equiv) was added
dropwise at r.t. The reaction mixture was stirred at r.t. until gas evo-
lution was completed (ca. 24 h). The reagent was titrated with ben-
zoic acid prior to use [4-(phenylazo)diphenylamine as indicator].17
Reagent TMP2Zn·2MgCl2·2LiCl
ful intermediates since the phenylthio group can serve as In an argon-flushed Schlenk flask, ZnCl2 (53.0 mmol, 7.22 g) was
a leaving group in cross-coupling reactions.14
dried in vacuo at 140 °C for 4 h. After cooling to 25 °C, freshly ti-
trated TMPMgCl·LiCl (100 mmol, 1.00 M, 100 mL) was added
dropwise. The resulting mixture was stirred for 15 h at 25 °C. The
Treatment of 4-bromo-1,3,5-trimethyl-1H-pyrazole with
Mg turnings in the presence of LiCl and ZnCl2 at 25 °C re-
sulted in the formation of the zinc species 2g after a reac-
tion time of 25 minutes. Copper(I)-mediated oxidative
amination of 2g with lithium diphenylamide (3c) fur-
nished the triaryl amine 5j in 66% yield (entry 7).
freshly prepared TMP2Zn·2MgCl2·2LiCl solution was titrated prior
to use at 0 °C with benzoic acid using 4-(phenylazo)diphenylamine
as indicator. A concentration of 1.60–1.70 M in THF (concentration
of Zn) was obtained.
ZnCl2 (1 M in THF)
Finally, 3,5-dibromopyridine was treated with i-
PrMgCl·LiCl (1.1 equiv, 0 °C to 25 °C, 1 h) to give the
corresponding monomagnesium reagent. Subsequent
transmetalation with the THF-soluble salt ZnCl2 provided
the zinc species 2c. Oxidative amination with the lithium
amides 3c and 3f furnished the corresponding tertiary
amines 5k and 5l in 88 and 54% yield, respectively (en-
tries 8,9).
ZnCl2 (27.3 g, 200 mmol) (17.0 g, 400 mmol) was placed in a 500
mL Schlenk flask equipped with a magnetic stirring bar and a sep-
tum. The salt was heated at 150 °C in an oil bath for 4 h under high
vacuum. Then, after cooling to 25 °C, absolute THF (200 mL) was
added. Afterwards, the septum was replaced by a glass stopper and
the suspension was left stirring overnight at 25 °C. After 12 h, the
salt had completely dissolved, the stirring was stopped and the so-
lution was left for some more time to become completely clear (lit-
tle particles and insoluble impurities were allowed to settle down in
that way). The solution was stored under argon upon use.
It has to be highlighted that this oxidative amination reac-
tion is not very substrate-dependent and does not show
sensitivity to steric hindrance. Remarkably, all the com-
pounds reported herein were prepared according to the
standardized reaction conditions.
Reagent CuCl·2LiCl (1 M in THF)
A dry and argon-flushed 50 mL Schlenk flask, equipped with a
magnetic stirrer and a glass stopper, was charged with LiCl (1.7 g,
40 mmol) and heated up to 130 °C under high vacuum for 2 h. After
cooling to r.t. under argon, CuCl (1.98 g, 20 mmol, 99.5% Cu) was
added under inert atmosphere inside a glove-box. The Schlenk flask
was further heated to 130 °C for 5 h under high vacuum, cooled to
r.t. (ca. 1 h), charged with freshly distilled THF (20 mL) under ar-
gon and wrapped in aluminum foil to protect it from light. The mix-
ture was vigorously stirred until all solid went into solution (ca. 2
h). The reagent CuCl·2LiCl (1 M in THF) was obtained as a color-
less or slightly pink solution.
In summary, we have extended our previous work to more
heteroaromatics and optimized the scale-up for such ami-
nation reactions. These reactions could be performed with
standard laboratory glassware and did not require the use
of expensive chemicals or catalysts. Further studies are
under way in our laboratory for extending the scope of this
oxidative amination.
Procedure 1: 2,4-Dibromo-N,N-bis(trimethylsilyl)-1,3-thiazol-
5-amine (5a, Scheme 1)
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirring bar and a septum, was charged with 2,4-dibromo-1,3-thia-
zole (1a; 243 mg, 1.0 mmol) and THF (1 mL). To the resulting mix-
Procedures
All reactions were carried out under argon atmosphere in dried
glassware. All starting materials were purchased from commercial
Synthesis 2010, No. 13, 2313–2318 © Thieme Stuttgart · New York

2316
C. Dunst et al.
PRACTICAL SYNTHETIC PROCEDURES
ture was added dropwise (TMP)2Zn·2MgCl2·2LiCl (1.30 mL, 1.68
M in THF, 0.55 mmol) and stirred for 45 min. CuCl·2LiCl (1.1 mL,
1.0 M in THF, 1.1 mmol) was added dropwise to 2a at –50 °C under
argon and the mixture was stirred for 30 min. LiN(SiMe3)2 (3a, 2
mmol, 1 M in THF) was added dropwise to the resulting cuprate 4a,
and the mixture was stirred for 1 h at –50 °C. The reaction mixture
was cooled to –78 °C, then a solution of PhI(OAc)2 (354 mg, 1.1
mmol) in anhyd THF (10 mL) was added slowly over a period of 60
min. The mixture was then warmed to –50 °C and stirred for an
additional 3 h. Et2O (100 mL) was poured into the crude reaction
mixture. The organic phase was washed with aq 2 M NH4OH
(2 × 10 mL) and back-extracted with Et2O (2 × 50 mL). The com-
bined organic layers were dried (Na2SO4), filtered, and concentrated
under reduced pressure. Purification by flash chromatography (pen-
tane; Al2O3 III) yielded 5a (331 mg, 80%) as a colorless oil.
HRMS (EI): m/z calcd for C17H26N2OSi: 302.1814; found:
302.1822.
Procedure 3: (5-Bromopyridin-3-yl)-(tert-butyldimethyl-
silyl)phenylamine (5c, Scheme 1)
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirring bar and a septum, was charged with 3,5-dibromopyridine
(1c; 236 mg, 1.0 mmol). After cooling to 0 °C, i-PrMgCl·LiCl (0.90
mL, 1.24 M in THF, 1.1 mmol) was added dropwise and stirred for
30 min at this temperature and for a further 30 min at 25 °C. Then,
THF (1 mL) was added and the resulting solution was stirred for an
additional 10 min at 25 °C. After cooling to 0 °C, ZnCl2 (0.55 mL,
1.0 M in THF, 0.55 mmol) was added and the mixture was stirred
for 30 min at this temperature. CuCl·2LiCl (1.1 mL, 1.0 M in THF,
1.1 mmol) was added dropwise at –50 °C and the resulting mixture
was stirred for an additional 30 min at –50 °C. LiN(TBS)Ph [3b; 2.0
mmol, prepared by adding n-BuLi to a 0.5 M solution of
HN(TBS)Ph (414 mg, 2 mmol) in THF at –20 °C and stirring for 30
min] was added dropwise to the resulting cuprate, and the mixture
was stirred for 1 h at –50 °C. The reaction mixture was cooled to
–78 °C, then a solution of PhI(OAc)2 (354 mg, 1.1 mmol) in anhyd
THF (10 mL) was added slowly over a period of 60 min. The mix-
ture was then warmed to –50 °C and stirred for 3 h. Et2O (100 mL)
was poured into the crude reaction mixture. The organic phase was
washed with aq 2 M NH4OH (2 × 10 mL) and extracted with Et2O
(2 × 50 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. Purification by
flash chromatography (pentane–Et2O; 19:1) yielded 5c (200 mg,
55%) as a yellow solid; mp 85.5–87.1 °C.
IR (ATR): 2950, 1499, 1412, 1251, 1204, 1154, 1009, 909, 869,
837, 816, 790, 753, 684, 666, 632 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.17 (s, 18 H).
13C NMR (150 MHz, CDCl3): d = 147.3, 127.7, 119.8, 1.5.
MS (70 eV, EI): m/z (%) = 402 (18), 399 (18), 387 (32), 385 (14),
323 (15), 321 (14), 125 (12), 123 (11), 97 (11), 83 (11), 73 (100).
HRMS (EI): m/z calcd for C9H1879Br2N2SSi2: 399.9096; found:
399.9086.
Procedure 2: (tert-Butyldimethylsilyl)-(3,5-dimethylisoxazol-4-
yl)phenylamine (5b, Scheme 1)
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirrer and a septum, was charged with LiCl (104 mg, 2.5 mmol) and
dried under vacuum at 450 °C for 5 min. Then, ZnCl2 (135 mg, 1.0
mmol) was added and also dried under vacuum at 450 °C for 5 min.
After cooling to r.t., Mg turnings (61 mg, 2.5 mmol) and THF (5
mL) were added and activated with i-Bu2AlH (0.1 mL, 0.1 M in
THF, 0.01 mmol).18 4-Bromo-3,5-dimethylisoxazole (1b; 176 mg,
1.0 mmol) was added in one portion and the resulting mixture was
stirred for 25 min at 25 °C and then cannulated to a new Schlenk
flask for the reaction with an amine. CuCl·2LiCl (1.1 mL, 1.0 M in
THF, 1.1 mmol) was added dropwise to the generated zinc species
2b at –50 °C under argon and the mixture was stirred for 30 min.
LiN(TBS)Ph [3b, 2.0 mmol, prepared by adding n-BuLi to a 0.5 M
solution of HN(TBS)Ph (414 mg, 2 mmol) in THF at –20 °C and
stirring for 30 min] was added dropwise to the resulting cuprate, and
the mixture was stirred for 1 h at –50 °C. The reaction mixture was
cooled to –78 °C, then a solution of PhI(OAc)2 (354 mg, 1.1 mmol)
in anhyd THF (10 mL) was added slowly over a period of 60 min.
The mixture was then warmed to –50 °C and stirred for 3 h. Et2O
(100 mL) was poured into the crude reaction mixture. The organic
phase was washed with aq 2 M NH4OH (2 × 10 mL) and extracted
with Et2O (2 × 50 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated under reduced pressure. Purifi-
cation by flash chromatography (pentane–Et2O, 20:1) yielded 5b
(181 mg, 60%) as a yellow oil.
IR (ATR): 2957, 2949, 2929, 2857, 1567, 1542, 1486, 1471, 1462,
1443, 1413, 1318, 1267, 1257, 1230, 1208, 1168, 1103, 1002, 955,
936, 911, 902, 886, 857, 842, 833, 819, 808, 788, 772, 733, 699, 676
cm–1.
1H NMR (400 MHz, C6D6): d = 8.34 (d, 4JH,H = 2.35 Hz, 1 H, ArH),
4
4
8.31 (d, JH,H = 1.96 Hz, 1 H, ArH), 7.20 (t, JH,H = 2.35 Hz, 1 H,
ArH), 6.96–6.91 (m, 2 H, ArH), 6.85–6.81 (m, 2 H, ArH), 6.75–6.72
(m, 1 H, ArH), 0.77 (s, 9 H, t-C4H9), –0.06 [s, 6 H, Si(CH3)2].
13C NMR (100 MHz, C6D6): d = 147.9, 146.5, 142.5, 142.3, 130.6,
129.4, 128.9, 125.2, 120.2, 27.3, 20.0, –2.4.
MS (70 eV, EI): m/z (%) = 308 (17), 307 (98), 306 (17), 305 (100),
135 (14), 73 (12).
HRMS (EI): m/z calcd for C17H23BrN2Si: 362.0814; found:
362.0810.
Benzo[b]thiophen-2-yl-diphenylamine (5d, Table 1, entry 1)
Prepared according to Procedure 1 from benzothiophene (1.34 g,
10.0 mmol) [reaction conditions: deprotonation with
(TMP)2Zn·2MgCl2·2LiCl at 25 °C for 24 h] and LiNPh2 [20.0
mmol; prepared by adding n-BuLi (20.0 mmol) to a 1.0 M solution
of Ph2NH in THF (3.38 g, 20.0 mmol) at –20 °C and stirring for 5
min and further stirring at 0 °C for 30 min]. Purification by flash
chromatography (pentane; Al2O3 III) yielded 5d (18.1 g, 60%) as a
colorless solid; mp 134.0–136.3 °C.
IR (ATR): 2928, 2855, 1594, 1490, 1472, 1440, 1419, 1276, 1260,
1249, 1241, 1215, 1030, 948, 891, 876, 858, 836, 821, 802, 772,
746, 706, 691, 681, 633 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.16–7.14 (m, 2 H, ArH), 6.88–
6.83 (m, 3 H, ArH), 2.31 (s, 3 H, CH3), 2.09 (s, 3 H, CH3), 0.96 (s,
9 H, t-C4H9), 0.21 [s, 6 H, Si(CH3)2].
IR (ATR): 1586, 1562, 1530, 1518, 486, 1458, 1436, 1418, 1316,
1292, 1276, 1250, 1241, 1172, 1158, 761, 750, 726, 695, 688 cm–1.
1H NMR (400 MHz, C6D6): d = 7.37–7.30 (m, 2 H, ArH), 7.16–7.10
(m, 4 H, ArH), 7.05–6.98 (m, 6 H, ArH), 6.88–6.81 (m, 2 H, ArH),
6.63 (s, 1 H, ArH).
13C NMR (100 MHz, C6D6): d = 151.9, 147.6, 139.4, 136.1, 129.2,
124.3, 123.6, 123.5, 123.3, 122.3, 122.0, 114.5.
13C NMR (150 MHz, CDCl3): d = 164.7, 160.3, 148.7, 128.8,
123.6, 120.9, 120.4, 27.9, 19.9, 11.3, 9.9, –2.1.
MS (70 eV, EI): m/z (%) = 302 (23), 246 (20), 245 (96), 204/19),
161 (17), 137 (21), 126 (15), 111 (24), 109 (17), 103 (29), 101 (58),
99 (16), 97 (35), 95 (22), 85 (40), 83 (30), 73 (100), 71 (51), 69 (28),
56 (20), 55 (24), 37 (27).
MS (70 eV, EI): m/z (%) = 302 (23), 301 (100), 300 (18), 223 (12),
197 (29), 121 (13), 77 (10).
HRMS (EI): m/z calcd for C20H15NS: 301.0925; found: 301.0919.
Synthesis 2010, No. 13, 2313–2318 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Heterocyclic Amines via Oxidative Cross-Coupling
2317
4-Benzo[b]thiophen-2-ylmorpholine (5e, Table 1, entry 2)
Prepared according to Procedure 1 from benzothiophene (1.34 g,
10.0 mmol) [reaction conditions: deprotonation with
(TMP)2Zn·2MgCl2·2LiCl at 25 °C for 24 h] and N-lithium mor-
pholide [20.0 mmol; prepared by adding n-BuLi (20.0 mmol) to a
0.5 M solution of morpholine in THF (1.74 g, 20.0 mmol) at 0 °C
and stirring for 30 min]. Purification by flash chromatography (pen-
tane–Et2O; 20:1; Al2O3 III) yielded 5e (1.65 g, 75%) as a colorless
solid; mp 180.1–181.5 °C.
TMP2Zn·2MgCl2·2LiCl at 25 °C for 60 min] and LDA (20 mmol,
20 mL, 0.5 M in THF). Purification by flash chromatography (pen-
tane–Et2O; 100:1; Al2O3 III) yielded 5h (1.71 g, 65%) as a colorless
oil.
IR (ATR): 2968, 2930, 2871, 1538, 1518, 1446, 1416, 1382, 1365,
1328, 1271, 1240, 1204, 1178, 1149, 1122, 1101, 1089, 999, 907,
857, 840, 756, 719, 697, 635 cm–1.
1H NMR (300 MHz, C6D6): d = 6.83 (s, 1 H, ArH), 3.08 [sept,
3
3JH,H = 6.8 Hz, 2 H, 2 × CH(CH3)2], 0.84 [d, JH,H = 6.8 Hz, 12 H,
IR (ATR): 1556, 1528, 1454, 1437, 1375, 1316, 1303, 1264, 1250,
1220, 1211, 1187, 1166, 1117, 1065, 1032, 1024, 1013, 933, 901,
869, 781, 744, 723, 653 cm–1.
2 × CH(CH3)2].
13C NMR (75 MHz, C6D6): d = 150.6, 133.0, 126.1, 51.1, 20.6.
1H NMR (400 MHz, C6D6): d = 7.44–7.40 (m, 2 H, ArH), 7.18–7.14
MS (70 eV, EI): m/z (%) = 264 (24), 262 (13), 249 (37), 247 (54),
127 (38), 112 (38), 97 (46), 83 (40), 71 (37), 70 (36), 69 (62), 57
(100), 55 (51), 43 (75).
(m, 1 H, ArH), 6.97–6.93 (m, 1 H, ArH), 5.90 (s, 1 H, ArH), 3.33 (t,
3
3JH,H = 4.89 Hz, 4 H, CH2CH2), 2.70 (t, JH,H = 4.89 Hz, 4 H,
CH2CH2).
HRMS (EI): m/z calcd for C9H15BrN2S: 262.0139; found: 262.0136.
13C NMR (100MHz, C6D6): d = 157.7, 140.7, 132.9, 124.5, 121.6,
5-(1,1,1,3,3,3-Hexamethyldisilazan-2-yl)-2-phenylsulfanylthia-
zole (5i, Table 1, entry 6)
121.5, 121.0, 99.4, 65.7, 50.6.
MS (70 eV, EI): m/z (%) = 220 (12), 219 (100), 161 (50), 160 (14).
HRMS (EI): m/z calcd for C12H13NOS: 219.0718; found: 219.0712.
Prepared according to Procedure 1 from 2-(phenylthio)thiazole
(1.64 g, 10.0 mmol) [reaction conditions: deprotonation with
(TMP)2Zn·2MgCl2·2LiCl at 25 °C for 2 h] and LiN(SiMe3)2 (20.0
mmol, 20.0 mL, 1 M in THF). Purification by flash chromatography
(pentane–Et2O; 19:1; Al2O3 III) yielded 5i (2.22 g, 63%) as a yellow
oil.
2-Bromo-N,N-bis(trimethylsilyl)-1,3-thiazol-5-amine (5f, Table
1, entry 3)
Prepared according to Procedure 1 from 2-bromothiazole (1.64 g,
10.0 mmol) [reaction conditions: deprotonation with
(TMP)2Zn·2MgCl2·2LiCl at 25 °C for 60 min] and LiHMDS (20
mmol, 20 mL, 1 M in THF). Purification by flash chromatography
(pentane; Al2O3 III) yielded 5f (2.44 g, 75%) as a colorless oil.
IR (ATR): 2955, 1514, 1500, 1477, 1440, 1403, 1377, 1273, 1251,
1150, 1141, 1016, 922, 874, 840, 819, 739, 701, 686, 624 cm–1.
1H NMR (400 MHz, C6D6): d = 7.48–7.46 (m, 2 H, ArH), 7.06 (s, 1
H, ArH), 6.97–6.90 (m, 3 H, ArH), 0.00 [s, 18 H, 2 × Si(CH3)3].
13C NMR (75 MHz, C6D6): d = 156.6, 150.9, 138.1, 137.3, 133.5,
132.2, 129.9, 129.2, 128.1, 1.2.
IR (ATR): 2956, 1517, 1436, 1412, 1251, 1185, 1148, 1132, 1001,
919, 874, 840, 818, 756, 699, 686 cm–1.
1H NMR (400 MHz, C6D6): d = 6.76 (s, 1 H, ArH), –0.02 (s, 18 H).
13C NMR (100 MHz, C6D6): d = 152.3, 137.1, 128.0, 1.3.
MS (70 eV, EI): m/z (%) = 354 (18), 353 (28), 352 (100), 337 (23),
243 (32), 206 (11), 116 (22), 73 (84), 45 (10).
MS (70 eV, EI): m/z (%) = 324 (13), 322 (22), 309 (17), 307 (14),
244 (10), 243 (44), 227 (15), 116 (20), 73 (100).
HRMS (EI): m/z calcd for C9H1979BrN2SSi2: 321.9991; found:
HRMS (EI): m/z calcd for C15H24N2S2Si2: 352.0919; found:
352.0912.
321.9977.
Diphenyl(1,3,5-trimethyl-1H-pyrazol-4-yl)amine (5j, Table 1,
entry 7)
4-(2-Bromo-1,3-thiazol-5-yl)morpholine (5g, Table 1, entry 4)
Prepared according to Procedure 1 from 2-bromothiazole (1.64 g,
10.0 mmol) [reaction conditions: deprotonation with
(TMP)2Zn·2MgCl2·2LiCl at 25 °C for 60 min] and N-lithium mor-
pholide [20.0 mmol; prepared by adding n-BuLi (20.0 mmol) to a
0.5 M solution of morpholine in THF (1.74 g, 20.0 mmol) at 0 °C
and stirring for 30 min]. Purification by flash chromatography (pen-
tane–Et2O; 9:1; Al2O3 III) yielded 5g (1.99 g, 80%) as a colorless
solid; mp 145.3–147.0 °C.
Prepared according to Procedure 2 from 4-bromo-1,3,5-trimethyl-
1H-pyrazole (1.89 g, 10.0 mmol, stirring for 25 min) and LiNPh2
[20.0 mmol, prepared by adding n-BuLi to a 0.5 M solution of
Ph2NH (3.38 g, 20.0 mmol) in THF at –20 °C and stirring for 30 min
at 0 °C]. Purification by flash chromatography (pentane–Et2O, 1:1)
yielded 5j (1.80 g, 65%) as a yellow solid; mp 78.8–80.3 °C.
IR (ATR): 2919, 1584, 1482, 1457, 1448, 1386, 1373, 1322, 1287,
1276, 1198, 1170, 1153, 1116, 1075, 1037, 1025, 998, 983, 959,
916, 890, 831, 755, 712, 693, 644, 638, 628, 620, 605 cm–1.
IR (ATR): 1512, 1448, 1430, 1368, 1336, 1308, 1293, 1272, 1257,
1220, 1211, 1168, 1143, 1112, 1071, 1038, 991, 929, 893, 855, 842,
758, 728 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.25–7.20 (m, 4 H, ArH), 7.07–
7.03 (m, 4 H, ArH), 6.94–6.89 (m, 2 H, ArH), 3.76 (s, 3 H, CH3),
2.00 (s, 3 H, CH3), 1.98 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 146.9, 145.1, 136.1, 129.0, 123.8,
121.1, 120.2, 36.4, 11.5, 9.2.
1H NMR (400 MHz, C6D6): d = 6.51 (s, 1 H, ArH), 3.23 (t,
3
3JH,H = 4.9 Hz, 4 H, CH2CH2), 2.31 (t, JH,H = 4.9 Hz, 4 H,
CH2CH2).
MS (70 eV, EI): m/z (%) = 278 (18), 277 (100), 56 (14).
13C NMR (100 MHz, C6D6): d = 157.6, 122.4, 122.3, 65.7, 51.8.
HRMS (EI): m/z calcd for C18H19N3: 277.1579; found: 277.1574.
MS (70 eV, EI): m/z (%) = 250 (99), 249 (12), 248 (100), 192 (43),
190 (42), 169 (39), 111 (31).
5-Bromo-N,N-diphenylpyridin-3-amine (5k, Table 1, entry 8)
Prepared according to Procedure 3 from 3,5-dibromopyridine (2.36
g, 10.0 mmol) and LiNPh2 [20.0 mmol, prepared by adding n-BuLi
to a 0.5 M solution of Ph2NH (3.38 g, 20.0 mmol) in THF at –20 °C
and stirring for 30 min at 0 °C]. Purification by flash chromatogra-
phy (pentane–CH2Cl2, 1:1 to 1:2) yielded 5k (2.88 g, 88%) as a col-
orless solid; mp 118.4–119.9 °C.
HRMS (EI): m/z calcd for C7H9BrN2OS: 247.9619; found:
247.9616.
2-Bromo-N,N-diisopropyl-1,3-thiazol-5-amine (5h, Table 1, en-
try 5)
Prepared according to Procedure 1 from 2-bromothiazole (1.64 g,
10.0 mmol) [reaction conditions: deprotonation with
Synthesis 2010, No. 13, 2313–2318 © Thieme Stuttgart · New York

2318
C. Dunst et al.
PRACTICAL SYNTHETIC PROCEDURES
IR (ATR): 1586, 1570, 1557, 1544, 1485, 1456, 1438, 1424, 1329,
1276, 1270, 1232, 1191, 1098, 1069, 1005, 948, 903, 854, 844, 780,
758, 746, 702, 694, 665, 628, 620 cm–1.
(3) For selected reviews, see: (a) Surry, D. S.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2008, 47, 6338. (b) Hartwig, J. F.
Acc. Chem. Res. 2008, 41, 1534. For recent reports, see:
(c) Shekhar, S.; Ryberg, P.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 3584. (d) Strieter, E. R.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2006, 45, 925. (e) Surry, D. S.; Buchwald, S.
L. J. Am. Chem. Soc. 2007, 129, 10354. (f) Fors, B. P.;
Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 13552. (g) Fors, B. P.; Davis, N. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 5766.
(h) Schulz, T.; Torborg, C.; Enthaler, S.; Schäffner, B.;
Dumrath, A.; Spannenberg, A.; Neumann, H.; Börner, A.;
Beller, M. Chem. Eur. J. 2009, 15, 4528.
(4) Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45, 2739.
(5) (a) Casarini, A.; Dembech, P.; Lazzari, D.; Marini, E.;
Reginato, G.; Ricci, A.; Seconi, G. J. Org. Chem. 1993, 58,
5620. (b) Alberti, A.; Canè, F.; Dembech, P.; Lazzari, D.;
Ricci, A.; Seconi, G. J. Org. Chem. 1996, 61, 1677.
(c) Canè, F.; Brancaleoni, D.; Dembech, P.; Ricci, A.;
Seconi, G. Synthesis 1997, 545. (d) Bernardi, P.; Dembech,
P.; Fabbri, G.; Ricci, A.; Seconi, G. J. Org. Chem. 1999, 64,
641.
1H NMR (400 MHz, C6D6): d = 8.36 (dd, 3JH,H = 6.1 Hz, 4JH,H = 2.9
4
Hz, 2 H), 7.37 (t, JH,H = 2.2 Hz, 1 H), 6.97–6.91 (m, 4 H), 6.85–
6.76 (m, 6 H).
13C NMR (100 MHz, C6D6): d = 146.5, 145.6, 143.7, 142.9, 130.6,
129.9, 125.0, 124.5, 120.7.
MS (70 eV, EI): m/z (%) = 327 (19), 326 (87), 325 (48), 324 (100),
323 (30), 245 (14), 244 (38), 243 (18), 217 (12), 167 (14), 115 (13),
77 (23).
HRMS (EI): m/z calcd for C17H13BrN2: 324.0262; found: 324.0257.
(5-Bromopyridin-3-yl)dihexylamine (5l, Table 1, entry 9)
Prepared according to Procedure 3 from 3,5-dibromopyridine (2.36
g, 10.0 mmol) and LiN(C6H13)2 [20.0 mmol, prepared by adding n-
BuLi to a 0.5 M solution of (C6H13)2NH (3.71 g, 20.0 mmol) in THF
at –20 °C and stirring for 30 min at 0 °C]. Purification by flash chro-
matography (pentane–Et2O; 20:1) yielded 5l (1.85 g, 54%) as a yel-
low oil.
IR (ATR): 2954, 2926, 2870, 2856, 1572, 1533, 1465, 1428, 1368,
1255, 1242, 1228, 1213, 1176, 1164, 1135, 1106, 992, 837, 822,
797, 725, 697, 657 cm–1.
(6) (a) del Amo, V.; Dubbaka, S. R.; Krasovskiy, A.; Knochel,
P. Angew. Chem. Int. Ed. 2006, 45, 7838. (b) Kienle, M.;
Dubbaka, S. R.; del Amo, V.; Knochel, P. Synthesis 2007,
1272.
(7) Arzel, E.; Rocca, P.; Marsais, F.; Quéguiner, G. Tetrahedron
Lett. 1998, 39, 6465.
(8) For an excellent overview of hypervalent iodine compounds,
see: Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108,
5299.
(9) Kienle, M.; Dunst, C.; Knochel, P. Org. Lett. 2009, 11, 5158;
highlighted in Synfacts 2010, 213 and Angew. Chem. Int. Ed.
2010, 49, 2282.
1H NMR (400 MHz, C6D6): d = 8.24 (d, 4JH,H = 1.96 Hz, 1 H, ArH),
4
4
8.11 (d, JH,H = 2.74 Hz, 1 H, ArH), 6.97 (t, JH,H = 1.96 Hz, 1 H,
3
ArH), 2.81 (t, JH,H = 7.63 Hz, 4 H, CH2CH2), 1.30–1.16 [m, 8 H,
(CH2)4], 1.13–0.98 [m, 8 H, (CH2)4], 0.86 (t, 6 H, 3JH,H = 7.23 Hz,
2 × CH3).
13C NMR (100 MHz, C6D6): d = 144.8, 137.2, 133.1, 121.1, 119.4,
50.3, 31.5, 26.7, 26.5, 26.4, 22.6, 13.8.
MS (70 eV, EI): m/z (%) = 342 (15), 340 (16), 272 (12), 271 (88),
(10) (a) Wunderlich, S. H.; Knochel, P. Angew. Chem. Int. Ed.
2007, 46, 7685. (b) Wunderlich, S. H.; Knochel, P. Chem.
Commun. 2008, 6387.
270 (13), 269 (100), 201 (46), 199 (47), 187 (15), 185 (16), 43 (23).
HRMS (EI): m/z calcd for C17H29BrN2: 340.1514; found: 340.1509.
(11) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew.
Chem. Int. Ed. 2006, 45, 2958.
(12) Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.;
Gavryushin, A.; Knochel, P. Chem. Eur. J. 2009, 15, 7192.
(13) (a) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004,
43, 3333. (b) Krasovskiy, A.; Straub, B.; Knochel, P.
Angew. Chem. Int. Ed. 2006, 45, 159.
(14) (a) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801.
(b) Metzger, A.; Melzig, L.; Despotopoulou, C.; Knochel, P.
Org. Lett. 2009, 11, 4228. (c) Melzig, L.; Metzger, A.;
Knochel, P. J. Org. Chem. 2010, 75, 2131.
Acknowledgment
We thank the Fonds der Chemischen Industrie, the European Re-
search Council (ERC), and the Deutsche Forschungsgemeinschaft
(DFG) for the financial support. We also thank BASF AG
(Ludwigshafen), W. C. Heraeus GmbH (Hanau), and Chemetall
GmbH (Frankfurt) for the generous gift of chemicals.
References
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Synthesis 2010, No. 13, 2313–2318 © Thieme Stuttgart · New York