Titanium-mediated amination of Grignard reagents using primary and secondary amines

Article abstract of DOI:10.1002/anie.201103700

Make it, then break it: N-chlorosuccinimide (NCS) was employed as the oxidant in the synthesis of aniline derivatives using the title transformation (see scheme). Functionalization was well tolerated on both the amine and Grignard reagent. An androgen receptor agonist and several analogues were synthesized to demonstrate the utility of this method.

Full text of DOI:10.1002/anie.201103700

DOI: 10.1002/anie.201103700
Amination Reactions
Titanium-Mediated Amination of Grignard Reagents Using Primary
and Secondary Amines**
Timothy J. Barker and Elizabeth R. Jarvo*
Table 1: Optimization with Cyclohexylamine.
The synthesis of anilines through the formation of an aryl–
nitrogen bond is a powerful method for the preparation of
natural products and pharmaceutical targets.[1] Although
palladium catalysis has proven to be an expedient and
practical method for this type of bond construction,[1b–d] the
use of electrophilic aminating reagents with nucleophilic
organometallic reagents presents an alternative strategy.[2–4]
This approach typically requires synthesis and isolation of the
electrophilic nitrogen source; methods that use amines
directly increase the appeal of this strategy. Transition-
metal-catalyzed amination of organometallic reagents with
N-chloroamines has been demonstrated by a number of
research groups.[5] Although several of these methods were
amenable to generation of the N-chloroamines in situ, none
of these reports utilized the nonisolable primary N-chloro-
amines; thus establishing the need for a new method to
address these challenging substrates.[6] Herein, we report the
one-pot chlorination and titanium-mediated coupling of
Grignard reagents with amines, including primary amines.
Our investigations began with examination of the reaction
between N-chlorocyclohexylamine and Grignard or arylzinc
reagents in the presence of a series of catalysts or promoters
(Table 1). A one-pot procedure to prepare the electrophilic
N-chloroamines in situ was utilized. In the absence of
additive, no desired aniline was formed (Table 1, entry 1).
Notably, in the presence of either nickel catalyst or diamine
ligand, negligible to modest yields of desired product were
observed (Table 1, entries 2 and 3).[7] We hypothesized that an
aryltitanium intermediate may provide a suitably nucleophilic
reaction partner that could best decomposition of the N-
chloroamine (Scheme 1).[8–10] Use of [Ti(OiPr)4] with
Grignard reagent provided the best yield of the desired
product (Table 1, entry 6).[11]
Entry
M
Additive (equiv)
Ligand (equiv)
Yield [%]
1
2
3
4
5
6
Mg
Zn
Mg
Zn
Mg
Mg
none
[Ni(cod)2] (0.1)
none
[Ti(OiPr)4] (1)
[Ti(OiPr)4] (1)
[Ti(OiPr)4] (2.5)
none
<5
50
<5
29
56
74
bipyridine (0.1)
TMEDA (10)
none
none
none
cod=cycloocta-l,5-diene, NCS=N-chlorosuccinimide, THF=tetrahy-
drofuran, TMEDA=N,N,N’,N’-tetramethylethylenediamine, Tol=to-
luene.
Scheme 1. Titanium-mediated amination of Grignard reagents. [Ti-
(OiPr)4] with Grignard reagent provided the best yield of the desired
product (Table 1, entry 6).[11]
Configuration is conserved when starting with a chiral amine
(Table 2, entry 10).[12] The reaction conditions tolerate pro-
tected alcohols and amines as well as a terminal alkyne
(Table 2, entries 9–12). Use of unbranched primary amines
generally resulted in lower yields.[13]
A series of primary amines reacted smoothly under the
one-pot procedure (Table 2). Steric bulk on the adjacent
carbon atom is well-tolerated, with a,a-disubstituted amines
providing some of the best yields (Table 2, entries 5–7).
Next we turned our attention to functionalized secondary
amines, including the synthesis of the biologically active
biarylpiperazine substructure (Table 3). Functionalized cyclic
and acyclic secondary amines were found to be very effective
substrates under the reaction conditions. Diallylamine, a
substrate that shows potential for being part of a protecting
group strategy, gave the desired aniline in good yield (Table 3,
entry 2). Primary nitriles were well tolerated (Table 3,
entry 3), as were ethyl and benzyl carbamates (Table 3,
entries 5 and 9). Arylpiperazines that incorporate functional
groups including pyridine, nitrile, and 2-furanyl underwent
smooth cross-coupling under the reaction conditions and
provided biarylpiperazines (Table 3, entries 6–8). These types
of structures are of particular interest because of the myriad
of biological activities associated with the biarylpiperazine
pharmacophore.[14] The synthesis of an N-aryl homopipera-
zine was also examined (Table 3, entry 9), thus demonstrating
[*] T. J. Barker, Prof. E. R. Jarvo
Department of Chemistry
University of California, Irvine
Irvine, CA 92697 (USA)
E-mail: erjarvo@uci.edu
Homepage: http://chem.ps.uci.edu/~erjarvo/Jarvo_Group/
Home.html
[**] We thank Pfizer for financial support and Dr. John Greaves for mass
spectrometry analyses. T.J.B. acknowledges Allergan for a Graduate
Fellowship. We thank Sigma–Aldrich for donation of functionalized
amines.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103700.
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Table 2: Scope of primary amines.
Table 4: Coupling using functionalized Grignard reagents.
Entry
Amine
ArMgX
Product
Yield [%]
1
2
nBu2NH
CyNH2
4a
4b
80
59
Entry
R
Amine
Product
Yield [%]
1
2
3
4
5
6
7
H
H
CyNH2
sBuNH2
CyNH2
sBuNH2
tBuNH2
tAmNH2
tOctNH2
1a
1b
2a
2b
2c
2d
2e
74
70
66
64
73
64
67
3
4
nBu2NH
CyNH2
5a
5b
66
61
MeO
MeO
MeO
MeO
MeO
5
6
nBu2NH
nBu2NH
6
7
86
63
8
MeO
2 f
63
7
8
nBu2NH
nBu2NH
8
9
58
59
9
MeO
2g
61
10
11
12
MeO
MeO
MeO
2h
2i
55
55
59
2j
access to another substructure with application in medicinal
chemistry.[15]
Boc=tert-butoxycarbonyl, Cy=cyclohexyl, sBu=sec-butyl, tAm=tert-
amyl, TBS=tert-butyldimethylsilyl, tBu=tert-butyl, tOct=tert-octyl.
Examination of the scope with respect to the Grignard
reagent was then performed (Table 4). Grignard reagents
were prepared conventionally from aryl halides and magne-
sium turnings or by using the magnesium halogen exchange
procedure developed by Knochel and co-workers.[16,17] In
general, the highest yields were obtained when using secon-
dary amines as coupling partners (Table 4, entries 1–4).
Substitution in the para, meta, and ortho positions of the
aryl Grignard reagent was well tolerated (Table 4, entries 1–4,
7, and 8). Trifluoromethyl-, nitrile-, and ester-substituted as
well as thienyl-substituted Grignard reagents gave good
yields. o-Bromophenylmagnesium bromide, a reagent of
limited stability, provided the desired product, albeit in
modest yield (Table 4, entry 7).
Table 3: Coupling of functionalized secondary amines.
An androgen receptor modulator and two analogues were
prepared to demonstrate the synthetic utility of this method.
Androgen receptor agonist 10 has been previously prepared
by an SNAr reaction (Scheme 2).[18,19] Using our method,
aniline 10 was prepared from diallylamine and the suitably
functionalized Grignard reagent in 59% yield. To highlight
this method as a complementary approach for the synthesis of
electron-deficient anilines, we prepared two additional ana-
logues, 11 and 12, using our method. The synthesis of 11 and
Entry
Amine
Product
Yield [%]
1
2
nBu2NH
(allyl)2NH
3a
3b
78
76
3
4
5
3c
3d
3e
75
80
77
6
7
3 f
80
75
3g
8
3h
3i
66
72
9
Bn=benzyl.
Scheme 2. Androgen receptor antagonist and analogues.
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[6] Whereas primary N-chloramines are unstable, the corresponding
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The titanium-mediated amination of Grignard reagents
presents a method for the synthesis of secondary and tertiary
anilines. This electrophilic amination strategy for aniline
synthesis employs inexpensive, commercially available
reagents and provides a mild and convenient complement to
SNAr methodology. No prior isolation of the N-chloroamines
was necessary, thus allowing for a diverse substrate scope.
Further work in our laboratories will be focused on applying
the use of N-chloroamines to other practical carbon–nitrogen
bond-forming reactions.
Experimental Section
Representative procedure for the titanium-mediated amination of
Grignard reagents: Cyclohexylamine (45.7 mL, 0.40 mmol, 1.0 equiv),
N-chlorosuccinimide (53.4 mg, 0.40 mmol, 1.0 equiv) and toluene
(1 mL) were added to an oven-dried vial (7 mL) under N2. After
stirring for 20 min, to a separate oven-dried vial (7 mL) under N2, was
added 1 mL of toluene, a 0.7m solution of p-methoxyphenylmagne-
sium bromide in THF (1.43 mL, 1.0 mmol, 2.5 equiv), and [Ti(OiPr)4]
(296 mL, 1.0 mmol, 2.5 equiv). Then the titanium-Grignard mixture
was cooled to À408C while stirring. After five additional min, the N-
chloroamine was cooled to À408C and the titanium solution was
added by syringe. The bath temperature was allowed to warm slowly
to RT (over about 1 h). After 3 h, the reaction was quenched with of
aqueous saturated K2CO3 (2 mL). The reaction mixture was diluted
with EtOAc (10 mL) and filtered. The layers were separated and the
aqueous layer was extracted (2 ꢀ 10 mL EtOAc) and the combined
organic layers were dried over Na2SO4, filtered, and concentrated
in vacuo. Purification was performed by chromatography on silica gel
with a gradient from neat hexanes to (95:5) hexanes/EtOAc to afford
2a as a pale yellow oil (54 mg, 66% yield).
[7] Representative examples are shown in Table 1. See the Support-
ing Information for more detail. Using modified procedures of
methods reported in Ref. [5b] and [5c] provided unsatisfactory
yields of the desired product.
[8] Nucleophilic aryltitanium intermediates undergo addition to
aldehydes and ketones. Selected examples of enantioselective
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and ketones: a) S. Zhou, C.-R. Chen, H.-M. Gau, Org. Lett. 2010,
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[9] For titanium-catalyzed hydroamination: a) T. E. Mꢃller, K. C.
Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev. 2008, 108,
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for the synthesis of secondary amines: B. Ramanathan, A. L.
Odom, J. Am. Chem. Soc. 2006, 128, 9344 – 9345.
Representative Knochel procedure for Mg Br exchange[16]
:
À
iPrMgCl·LiCl (5.0 mL, 1.0m, 5 mmol) and 3-bromo-4-fluorobenzoni-
trile (1.00 g, 5 mmol) were added to a flame-dried flask (25 mL) that
had been cooled to 08C. The reaction was stirred for 3 h at 08C and
then titrated with I2. The Grignard reagent was then used in the
amination reaction as described above. For best results the iPrMgCl·-
LiCl should be freshly prepared from isopropyl chloride and
magnesium turnings in the presence of one equivalent of lithium
chloride. Commercially available iPrMgCl with LiCl (1 equiv) added
gave irreproducible results. The exchange could be monitored using
1H NMR spectroscopy by taking a small aliquot of the Grignard
reagent solution quenched with methanol and then analyzing the
sample for the disappearance of the starting aryl bromide. For
magnesium–iodine exchange, the exchange was performed at À408C
for 45 min with commercially available iPrMgCl.
[10] TiCl4 has been shown to promote oxidative coupling of anilines
at the 4-position: M. Periasamy, K. N. Jayakumar, P. Bharathi, J.
Org. Chem. 2000, 65, 3548 – 3550.
Received: May 31, 2011
[11] See the Supporting Information for details.
Published online: July 18, 2011
[12] See the Supporting Information for details.
[13] N-Butylamine gave desired product in 44% yield. Unbranched
N-chloroamines are prone to polymerization, see: J. C. Guille-
min, J. M. Denis, Synthesis 1985, 1131 – 1133.
Keywords: amination · anilines · Grignard reagents ·
N-chloroamines · titanium
.
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Communications
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[17] Use of 3-pyridylmagnesium bromide in the titanium-mediated
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pyridylmagnesium bromide did not afford any desired product
under the reaction conditions.
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[16] For the synthesis of anilines 1–4 and 6, the Grignard reagents
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