General preparation of primary, secondary, and tertiary aryl amines by the oxidative coupling of polyfunctional aryl and heteroaryl amidocuprates

Article abstract of DOI:10.1002/anie.200603089

(Chemical Equation Presented). A tolerant reaction: Functionalized tertiary amines have been prepared by the oxidative coupling of amidocuprates with chloranil used as the oxidant (see Scheme). A high tolerance of functional groups and insensitivity to steric hindrance characterize this general amination reaction.

Full text of DOI:10.1002/anie.200603089

Communications
Amination
DOI: 10.1002/anie.200603089
General Preparation of Primary, Secondary, and
Tertiary Aryl Amines by the Oxidative Coupling
of Polyfunctional Aryl and Heteroaryl
Amidocuprates**
Vicente del Amo, Srinivas Reddy Dubbaka,
Arkady Krasovskiy, and Paul Knochel*
Aromatic and heterocyclic amines are important target
molecules in organic synthesis because of their potential
applications as biologically active compounds and as precur-
sors for polymers or materials.[1] Besides several electrophilic
amination methods,[2] the palladium-catalyzed amination of
aromatic halides and related electrophiles have become a
widely used method for the preparation of aryl amines.[3]
However, this latter reaction has some limitations, such as
long reaction times for sterically hindered systems[4] and the
necessity to carefully choose the appropriate phosphine or
carbene ligand to obtain optimum yields. Also, the prepara-
tion of triaryl amines can usually not be performed by this
method.[5] Furthermore, some functional groups such as
iodides (and bromides) are not compatible with this Pd-
catalyzed amination procedure.
Recently, we reported a new transition-metal-free oxida-
tive coupling procedure for organomagnesium and organo-
zinc reagents using diphenoquinone or chloranil (1) as the
oxidative agents.[6] Inspired by the pioneering work of
Yamamoto and Marouka,[7] Ricci and co-workers,[8] Lipshutz
et al.,[9] and others,[10] who described the oxidative coupling of
amidocuprates or organo(cyano)cuprates using oxygen or 1,3-
dinitrobenzene derivatives as oxidants, we have now exam-
ined the oxidative amination reaction of various polyfunc-
tional amidocuprates and developed an experimental proce-
dure that allows the preparation of primary, secondary, as well
as tertiary aromatic and heterocyclic amines.
In preliminary experiments, we treated PhMgCl·LiCl[11a]
with various copper salts of the type CuX·nLiCl.[12,13] This was
followed by the addition of Et2NLi (3equiv) and one of three
representative quinones (1.2 equiv): 3,3’,5,5’-tetra-tert-butyl-
diphenoquinone,[6]
2,3-dichloro-5,6-dicyano-1,4-benzoqui-
[*] Dr. V. del Amo, Dr. S. R. Dubbaka, Dr. A. Krasovskiy,
Prof. Dr. P. Knochel
Ludwig-Maximilians-Universität München
Department Chemie und Biochemie
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)892-1807-7680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie and Merck Research
Laboratories (MSD) for financial support. V.d.A. and S.R.D. thank
the Alexander von Humboldt Foundation for fellowships. We also
thank Chemetall GmbH (Frankfurt) and BASF AG (Ludwigshafen)
for the generous gift of chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
7838
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 7838 –7842

Angewandte
Chemie
none (DDQ), and 2,3,5,6-tetra-
chloro-1,4-benzoquinone (1, chlor-
anil), with addition at À788C and
then 12 h at À408C. The combina-
tion of 1 with CuCl·2LiCl gave the
best results and allowed the isola-
tion of PhNEt2 in 84% yield.[13]
We have extended and adapted
this procedure to the preparation
of various primary, secondary, and
tertiary amines. Thus, for the syn-
thesis of primary amines, the die-
ster 2a was magnesiated with
TMPMgCl·LiCl[14] (1.1 equiv, 08C,
1 h) which led to the aryl magne-
sium derivative 3a[15] (TMP =
2,2,6,6-tetramethylpiperidyl). This
was treated with CuCl·2LiCl[12,13]
(1.2 equiv) at À508C followed by
the addition of bis[2-(N,N-dime-
thylamino)ethyl]ether
Scheme 1. Preparation of primary amines through an oxidative amination with a magnesiated polyfunctional
aryl derivative such as 3a and LiHMDS using 1. Boc=tert-butoxycarbonyl, TBAF=tetrabutylammonium
fluoride, TMS=trimethylsilyl.
Table 1: Synthesis of amines by the oxidative coupling of aryl and heteroaryl amidocuprates.
(1.2 equiv)[16] and lithium hexame-
thyldisilazide (LiHMDS (2 equiv);
À508C, 90 min) to afford the ami-
docuprate 5a. Treatment of 5a
with 1 (1.2 equiv, À78 to À508C,
12 h) led to the N,N-bis(trimethyl-
silyl)amine derivative 6a in 76%
yield. A facile desilylation was
achieved with TBAF (2.5 equiv,
258C, 10 min) to give the aryl
Entry
Grignard reagent
Lithium amide
Product
Yield [%][a]
LiHMDS
1
2
3
4
3b: R=CN
3c: R=CO2Et
3d: R=OMe
3e: R=I
7b: R=CN
7c: R=CO2Et
7d: R=OMe
7e: R=I
86[b]
84[b]
88[b]
60[b]
amine
7a
in
94%
yield
LiHMDS
LiHMDS
(Scheme 1). This method has been
used to prepare various primary
amines (7b–f) bearing electron-
withdrawing substituents such as a
nitrile, an ester, or a nitro group
(entries 1, 2, and 5, Table 1) or
5
3 f
7 f
61[c]
6
7
3g: X=CH,R=OBoc
3h: X=N, R=OBoc
6b: X=CH, R=OBoc
6c: X=N, R=OBoc
78[d]
72[d]
electron-donating
substituents
LiHMDS
such as a methoxy or an iodide
(entries 3and 4, Table 1). In all
these cases, the Grignard reagents
were prepared by an I/Mg or Br/
Mg exchange reaction.[11] Highly
functionalized aryl magnesium
reagents such as 3g, which can be
conveniently obtained by deproto-
nation with TMPMgCl·LiCl,[14,15]
can be aminated (entry 6 (78%),
Table 1). This procedure can also
be used with heterocyclic Grignard
reagents such as the pyridine deriv-
ative 3h, the benzothiophene 3i,
8
9
3i: X=CH
3j: X=N
7g: X=CH
7h: X=N
69[d]
80[d]
10
11
3b
3k
10b
10c
12b
12c
65[b]
70[b]
and
entries 7–9, Table 1). The resulting
primary amines of type are
benzothiazole
3j
(see
7
12
3l
10d
12d
70[b]
obtained in 69–80% yield, after
cleavage of the corresponding N,N-
Angew. Chem. Int. Ed. 2006, 45, 7838 –7842
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7839

Communications
Table 1: (Continued)
LiCl (1.1 equiv, 258C, 20 min), followed by
the addition of CuCl·2LiCl (1.1 equiv,
À508C, 30 min) in the presence of
(iPr)2NH (1.1 equiv). The resulting lithium
Entry
Grignard reagent
Lithium amide
Product
Yield [%][a]
amidocuprate 11a was treated with
1
(1.2 equiv, À78 to À508C, 12 h) to provide
the silyl-protected diaryl amine 12ain 72%
yield (Scheme 2).
13
3m
10e
12e
60[d]
This reaction proved to be quite general
and a number of functionalized Grignard
reagents such as 3b and 3k,l bearing a
cyano, trifluoromethyl, or bromine substitu-
ent undergo a smooth oxidative amination
with lithiated N-TBS-anilines (10b–d) bear-
ing various functional groups such as a
chloride, an ester, or a methoxy group. The
resulting TBS-protected secondary amines
12b–d are obtained in 65–70% overall yield
(entries 10–12, Table 1). The TBS-protected
secondary amine 12c (entry 11, Table 1)
was readily desilylated with TBAF
(1.1 equiv, 258C, 10 min).[17] Interestingly,
the heterocyclic copper derivative prepared
14
15
3o: R=H
3d
14b
14b
16b: R=H
16c: R=OMe
63[b]
58[b]
16
17
3p
3e
14c
14d
16d
16e
57[b]
66[b]
from
3,5-dibromo-2-pyridylmagnesium
chloride (3m) reacts equally as well with
lithiated 4-methoxyaniline (10e) to provide
the corresponding 2-aminopyridine deriva-
tive 12e in 60% yield (entry 13, Table 1).
Finally, the preparation of polyfunc-
tional triaryl amines can be performed
using the same approach. Thus, the lithia-
tion of the secondary amine 13a with
[a] Yield of analytically pure product. [b] The aryl magnesium reagent was formed through an I/Mg
exchange reaction with iPrMgCl·LiCl. [c] The aryl magnesium reagent was prepared through an I/Mg
exchange reaction with PhMgCl. [d] The aryl magnesium reagent was prepared through deprotonation
using TMPMgCl·LiCl (1.1 equiv).
bis(trimethylsilyl) group with TBAF (2.5 equiv, 258C,
10 min).
lithium diisopropylamide (LDA; 1.05 equiv, À408C, 1 h) in
the presence of an additional equivalent of (iPr)2NH provides
the lithium amide 14awhich reacted with the copper reagent
4n to afford the lithium amidocuprate 15a. This copper
reagent 4n was prepared by an I/Mg exchange on 1,3-
diiodobenzene (2n) with iPrMgCl·LiCl (1.1 equiv, 08C,
15 min) to give the Grignard reagent 3n, followed by a
transmetalation with CuCl·2LiCl (1.1 equiv, À408C, 30 min).
The resulting lithium amidocuprate 15a was treated with 1
(1.2 equiv, À78 to À408C, 12 h) to provide the triaryl amine
16a in 71% yield (Scheme 3).[13] This sequence can be
performed with several aryl magnesium reagents (3d, 3e,
Secondary amines can also be prepared from an aniline
derivative such as 8a (Scheme 2). Its in situ protection with a
TBS group can be achieved by lithiation with MeLi (1.1 equiv,
À508C, 10 min) followed by the addition of TBSCl (1.2 equiv,
À50 to 258C, 0.5 h) to give the N-silylaniline 9a. Further
treatment with MeLi (1.1 equiv, À508C, 10 min) provides the
lithium amide 10a which was treated with the aryl copper
species 4d for 2 h at À508C. This copper reagent was
prepared from 4-iodoanisole (2d) by an I/Mg exchange with
iPrMgCl·
Scheme 2. Preparation of TBS-protected secondary amines through an oxidative amination with a functionalized aryl magnesium reagent (3d)
and a lithium amide (10a) using 1. TBS=tert-butyldimethylsilyl.
7840 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 7838 –7842

Angewandte
Chemie
period of 45 min. The reaction mixture was then allowed to reach
À508C and stirred for 12 h. Et2O (10 mL) was poured into the crude
reaction mixture and the reaction mixture then filtered through celite
and the residue washed with Et2O (ca. 100 mL). The organic phase
was washed with 2 ” 10 mL portions of aqueous NH4OH (2.0m) and
extracted with Et2O. The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure. This
crude material was dissolved in Et2O (3mL) before TBAF (2 mL,
1.0m in THF, 2 mmol) was added in one portion. The mixture was
stirred at room temperature for 10 min, poured into EtOAc (10 mL),
and washed with water (3” 10 mL). The combined organic extracts
were dried (MgSO4), filtered, and concentrated in vacuum. Purifica-
tion by flash chromatography (pentane/Et2O; 4:1) yielded the
aromatic amine 7a (254 mg, 72%) as a white crystalline solid
(m.p. 86.7–88.18C).
Scheme 3. Preparation of a tertiary amine through an oxidative amina-
tion with a magnesiated aryl derivative (3n) and a functionalized
lithium amide (14a) using 1.
3o, and 3p) bearing various functional groups such as a
methoxy, an iodide, and an amide group, as well as with
various lithium amides bearing functional groups such as a
bromide, a nitrile, and an ester group (14b–d) to afford the
tertiary amines 16b–e in 57–66% yield (entries 14–17,
Table 1).
Remarkably, this amination reaction can be extended to
the preparation of very sterically hindered amines using
either sterically hindered copper reagents such as 4q and 4g
with the lithium amide 17 or a sterically hindered lithium
amide such as 18 by the oxidative coupling of the lithium
amidocuprates 19a,b and 20. The expected tertiary amines
(21a,b and 22) are obtained in 61–70% yield (Scheme 4).
In summary, we have developed a new general amination
procedure using readily available lithium amidocuprates. The
scope of the method is quite broad and is not hampered by
steric hindrance. It is a useful complement to the Pd-catalyzed
amination reactions. Further applications are currently being
investigated.
Scheme 4. Preparation of sterically hindered tertiary amines through
an oxidative amination with sterically hindered copper reagents (4q
and 4g) or lithium amide (18) with 1.
Received: July 31, 2006
Published online: October 31, 2006
Experimental Section
Typical procedure (synthesis of 7a; see Scheme 1): A dry and argon-
flushed Schlenk flask, equipped with a magnetic stirring bar and a
septum, was charged with a solution of 2a (338 mg, 1.0 mmol) in dry
THF (3mL). After cooling the mixture to 0 8C, TMPMgCl·LiCl
(0.92 mL, 1.20m in THF, 1.1 mmol) was added dropwise and stirred
for 1 h to afford the corresponding Grignard reagent 3a. This
organomagnesium reagent was added dropwise to a solution of
CuCl·2 LiCl (1.2 mL, 1.0m in THF, 1.2 mmol) and bis[2-(N,N-
dimethylamino)ethyl]ether (192 mg, 1.2 mmol) at À508C under
argon, and the mixture was stirred for 45 min. LiHMDS (2.0 mL,
1.0m in THF, 2.0 mmol) was added dropwise to the resulting aryl
cuprate (5a), and the mixture was further stirred for 90 min at À508C.
The reaction mixture was cooled to À788C, then a solution of 1
(295 mg, 1.2 mmol) in dry THF (7 mL) was added slowly over a
À
Keywords: amination · amines · C N bond formation ·
cuprates · Grignard reagents
.
[1] a) A. Zapf, M. Beller, Top. Catal. 2002, 19, 101; b) J. G. de Vries,
Can. J. Chem. 2001, 79, 1086, and references therein; c) appli-
cations in the preparation of biologically active compounds: M.
Prashad, Top. Organomet. Chem. 2004, 6, 181; d) applications in
polymer synthesis: C. Desmarets, B. Champagne, A. Walcarius,
C. Bellouard, R. Omar-Amrani, A. Ahajji, Y. Fort, R. Schneider,
J. Org. Chem. 2006, 71, 1351; e) applications as materials: P.
Bordat, R. Brown, Chem. Phys. Lett. 2000, 331, 439; f) applica-
Angew. Chem. Int. Ed. 2006, 45, 7838 –7842
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7841

Communications
tions in electrical devices: S. Miao, C. G. Bangcuyo, M. D. Smith,
[12] P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem.
1988, 53, 2390.
[13] See the Supporting Information.
U. H. F. Bunz, Angew. Chem. 2006, 118, 667; Angew. Chem. Int.
Ed. 2006, 45, 661; g) applications in liquid crystals: R. S. Wright,
T. K. Vinod, Tetrahedron Lett. 2003, 44, 7129; h) photophysical
applications: Z. Liu, X. Zhang, R. C. Larock, J. Am. Chem. Soc.
2005, 127, 15716.
[14] A. Krasovskiy, V. Krasovskaya, P. Knochel, Angew. Chem. 2006,
118, 3024; Angew. Chem. Int. Ed. 2006, 45, 2958.
[15] W. Lin, O. Baron, P. Knochel, Org. Lett. 2006, submitted.
[16] This additive improves the yield of the amination reaction; for
other uses, see: X.-J. Wang, X. Sun, L. Zhang, Y. Xu, D.
Krishnamurthy, C. H. Senanayake, Org. Lett. 2006, 8, 305.
[17] The corresponding secondary amine was obtained in 96% yield
upon deprotection.
[2] I. Sapountzis, P. Knochel, Angew. Chem. 2004, 116, 915; Angew.
Chem. Int. Ed. 2004, 43, 897.
[3] For selected reviews, see: a) J. F. Hartwig, Angew. Chem. 1998,
110, 2154; Angew. Chem. Int. Ed. 1998, 37, 2046; b) J. F. Hartwig,
Acc. Chem. Res. 1998, 31, 852; c) J. F. Hartwig, Pure Appl. Chem.
1999, 67, 805; d) B. H. Yang, S. L. Buchwald, J. Organomet.
Chem. 1999, 576, 125; e) J. P. Wolfe, S. L. Buchwald, Angew.
Chem. 1999, 111, 2570; Angew. Chem. Int. Ed. 1999, 38, 2413;
f) J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. L. Buchwald, Acc.
Chem. Res. 1998, 31, 805; g) A. R. Muci, S. L. Buchwald, Top.
Curr. Chem. 2002, 219, 131; h) H.-U. Blaser, A. Indolese, F.
Naud, U. Nettekoven, A. Schnyder, Adv. Synth. Catal. 2004, 346,
1583; i) B. Schlummer, U. Scholz, Adv. Synth. Catal. 2004, 346,
1599; j) J. F. Hartwig, Synlett 2006, 1283.
[4] The reaction between ortho-substituted aryl halides and
À
LiHMDS generally fails to form C N bonds because of the
steric hindrance of the two bulky silyl groups; for a discussion,
see: a) S. Lee, M. Jørgensen, J. F. Hartwig, Org. Lett. 2001, 3,
2729; b) X. Huang, S. L. Buchwald, Org. Lett. 2001, 3, 3417.
[5] For the synthesis of unfunctionalized triaryl amines, see: a) S.
Thayumanavan, S. Barlow, S. R. Marder, Chem. Mater. 1997, 9,
3231; b) T. Yamamoto, M. Nishiyama, Y. Koie, Tetrahedron Lett.
1998, 39, 2367; c) J. Louie, J. F. Hartwig, J. Am. Chem. Soc. 1997,
119, 11695; d) M. Watanabe, T. Yamamoto, M. Nishiyama,
Chem. Commun. 2000, 133; e) M. C. Harris, O. Geis, S. L.
Buchwald, J. Org. Chem. 1999, 64, 6019; f) G. N. Tew, M. U.
Pralle, S. I. Stupp, Angew. Chem. 2000, 112, 527; Angew. Chem.
Int. Ed. 2000, 39, 517; g) T. Braig, D. C. Muller, M. Gross, K.
Meerholz, O. Nuyken, Macromol. Rapid Commun. 2000, 21,
583; h) M. Thelakkhat, J. Hagen, D. Haarer, H. -W. Schmidt,
Synth. Met. 1999, 102, 1125; i) M. C. Harris, S. L. Buchwald, J.
Org. Chem. 2000, 65, 5327, and references therein.
[6] A. Krasovskiy, A. Tishkov, V. del Amo, H. Mayr, P. Knochel,
Angew. Chem. 2006, 118, 5132; Angew. Chem. Int. Ed. 2006, 45,
5010.
[7] H. Yamamoto, K. Maruoka, J. Org. Chem. 1980, 45, 2739.
[8] a) A. Casarini, P. Dembech, D. Lazzari, E. Marini, G. Reginato,
A. Ricci, G. Seconi, J. Org. Chem. 1993, 58, 5620; b) A. Alberti,
F. Canꢀ, P. Dembech, D. Lazzari, A. Ricci, G. Seconi, J. Org.
Chem. 1996, 61, 1677; c) F. Canꢀ, D. Brancaleoni, P. Dembech,
A. Ricci, G. Seconi, Synthesis 1997, 545; d) P. Bernardi, P.
Dembech, G. Fabbri, A. Ricci, G. Seconi, J. Org. Chem. 1999, 64,
641.
[9] a) B. H. Lipshutz, K. Siegmann, E. Garcia, Tetrahedron 1992, 48,
2579; b) B. H. Lipshutz, K. Siegmann, E. Garcia, F. Kayser, J.
Am. Chem. Soc. 1993, 115, 9276, and references therein.
[10] Homocoupling of organocuprates: a) D. S. Surry, X. Su, D. J.
Fox, V. Franckevicius, S. J. F. Macdonald, D. A. Spring, Angew.
Chem. 2005, 117, 1904; Angew. Chem. Int. Ed. 2005, 44, 1870;
b) Y. Miyake, M. Wu, M. J. Rahman, Y. Kuwatani, M. Iyoda, J.
Org. Chem. 2006, 71, 6110; c) for a review on the oxidation of
organocuprates, see: D. S. Surry, D. A. Spring, Chem. Soc. Rev.
2006, 35, 218.
[11] a) Br/Mg exchange: A. Krasovskiy, P. Knochel, Angew. Chem.
2004, 116, 3396; Angew. Chem. Int. Ed. 2004, 43, 3333; b) A.
Krasovskiy, B. Straub, P. Knochel, Angew. Chem. 2006, 118, 165;
Angew. Chem. Int. Ed. 2006, 45, 159; c) I/Mg exchange of o-
nitroaryl iodides: I. Sapountzis, P. Knochel, Angew. Chem. 2002,
114, 1680; Angew. Chem. Int. Ed. 2002, 41, 1610; d) A. E. Jensen,
W. Dohle, I. Sapountzis, D. M. Lindsay, V. A. Vu, P. Knochel,
Synthesis 2002, 565.
7842 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 7838 –7842