Synthesis of hindered anilines: Copper-catalyzed electrophilic amination of aryl boronic esters

Article abstract of DOI:10.1002/anie.201200480

No longer a hindrance: Copper-catalyzed electrophilic amination of aryl boronic esters is accomplished under mild reaction conditions using 2.5-5.0 mol % of a catalyst derived from copper tert-butoxide and Xantphos ligand (see scheme). The reaction tolerates a wide range of functional groups and can be used to prepare some of the most hindered anilines made to date. Copyright

Full text of DOI:10.1002/anie.201200480

Angewandte
Chemie
DOI: 10.1002/anie.201200480
Synthetic Methods
Synthesis of Hindered Anilines: Copper-Catalyzed Electrophilic
Amination of Aryl Boronic Esters**
Richard P. Rucker, Aaron M. Whittaker, Hester Dang, and Gojko Lalic*
The synthesis of aromatic and heteroaromatic amines has
attracted considerable attention in the last two decades as
a result of the numerous applications of these compounds in
the pharmaceutical industry and medicinal chemistry.[1] The
development of several transition-metal-catalyzed couplings
of aryl halides with amines[2] has provided a practical method
for the preparation of a wide range of anilines.[3] However,
some important challenges remain. For example, bromo- and
iodo-substituted anilines cannot be prepared directly using
these methods. More importantly, the preparation of hindered
anilines is still a major challenge,[4] as illustrated by problems
recently encountered by Baran et al. in the total synthesis of
(+)-psychotetramine.[5]
Currently available methods for the synthesis of hindered
anilines require the formation of highly reactive intermedi-
ates, such as benzynes[6] or organometallic reagents.[7,8] The
most general of these reactions was reported by Knochel and
co-workers, and involves oxidative coupling of organometallic
reagents with hindered lithium amides in the presence of
stoichiometric amounts of copper.[7b] In a rare instance of
catalytic synthesis of hindered anilines, Berman and Johnson
reported three examples of the electrophilic amination of aryl
zinc reagents by hindered electrophiles.[7a,9] A common
feature of the procedures reported by the groups of Johnson
and Knochel is that a significant excess (ꢀ 2 equivalents) of
one of the coupling components is necessary. Furthermore,
both methods use a stoichiometric amount of an aryl
Grignard or an aryl lithium reagent.
describe a catalytic method for the synthesis of hindered
anilines from aryl and heteroaryl boronic esters compatible
with a wide variety of functional groups, including aryl iodides
and bromides [Eq. (1); Bz = benzoyl].
In an initial experiment, we explored the reactivity of aryl
boronic ester 3 and 4-benzoyloxymorpholine (1), in the
presence of sodium tert-butoxide and IMesCuOtBu as
a catalyst.[16] Upon full conversion of the electrophile, the
desired aniline was obtained in less than 5% yield (Table 1,
entry 1).
Table 1: Developing the electrophilic amination of aryl boronic esters.
Entry[a] BzONR2
ArB(OR’)2
L
M
Solvent
Yield
[%][b]
1
2
3
3
4
5
5
6
6
6
IMes
IMes
IMes
Na THF
Na THF
Na THF
<5
16
72
99
8
Aryl boronic acids and their derivatives offer significant
advantages over the organometallic reagents currently used in
the synthesis of hindered anilines. They are stable, readily
available, and compatible with a wide range of functional
groups. However, previous attempts by Berman and John-
son[7a] and others[10] to develop electrophilic amination of
these compounds have been unsuccessful. A related oxidative
amination of organoboron reagents developed by the groups
of Lam,[11] Chan,[12] Evans,[13] and others[14] is highly sensitive
to the steric properties of amine substrates and cannot be
used for the synthesis of hindered anilines.[15] Herein, we
4[c]
5
Xantphos Na 1,4-dioxane
Xantphos Na 1,4-dioxane
Xantphos Li 1,4-dioxane
Xantphos Li toluene
6
7
56
74
8[d]
9[e]
6
6
Xantphos Li toluene
Xantphos Li toluene
81
94
[a] ArB(OR’)2 (1.2 equiv), BzONR2 (1.0 equiv), MOtBu (1.0 equiv), 258C,
12 h. [b] Determined by GC analysis of the crude reaction mixture.
[c] Catalyst was formed in situ from Xantphos and (CuOtBu)4. [d] Reac-
tion performed at 458C. [e] 608C, 1.0m. toluene used to prepare the
catalyst.
[*] R. P. Rucker, A. M. Whittaker, H. Dang, Prof. G. Lalic
Department of Chemistry, University of Washington
Box 351700, Seattle, WA 98105 (USA)
E-mail: lalic@chem.washington.edu
[**] The University of Washington is gratefully acknowledged for the
financial support. Prof. Forrest Michael and Prof. Dustin Maly are
gratefully acknowledged for their help in preparation of the
manuscript.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200480.
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Table 2: The scope of electrophilic amination.[a]
We speculated that the low yield of the aniline was
a consequence of slow transmetalation of the aryl boronic
ester. Indeed, reactions with ethylene glycol (4) and neopen-
tyl glycol (5) esters, which are known to undergo trans-
metalation faster than the corresponding pinacol esters,[17]
provided the aniline product in 16 and 72% yield, respectively
(Table 1, entries 2 and 3),
In a catalyst screen performed with boronic ester 5 and
electrophile 1,[18] we identified XantphosCuOtBu, a complex
prepared from Xantphos ligand and (CuOtBu)4,[19] as the best
catalyst. In a reaction performed in 1,4-dioxane, the desired
aniline was obtained in 99% yield (Table 1, entry 4).
Unfortunately, a reaction with the more hindered boronic
ester 6 resulted in the formation of the desired aniline in only
8% yield, together with 83% yield of tert-butyl benzoate
(Table 1, entry 5).
In fact, a control experiment revealed that tert-butyl
benzoate forms in nearly quantitative yield in a reaction of
1 with sodium tert-butoxide after only 10 minutes at room
temperature. We found that the decomposition of the
electrophile can be suppressed if lithium tert-butoxide is
used in a noncoordinating solvent.[18] Consistent with these
findings, a reaction with the boronic ester 6 and electrophile
1 performed in toluene in the presence of lithium tert-
butoxide afforded the desired aniline in 74% yield (Table 1,
entry 7). The same reaction conditions could also be used to
prepare highly hindered N,N-diisopropyl-2,6-dimethyl aniline
from boronic ester 6 and electrophile 2 (Table 1, entry 8).
Finally, the best result (94% yield) was obtained when this
reaction was performed in a concentrated isooctane solution
using a catalyst prepared from Xantphos and (CuOtBu)4 in
toluene (Table 1, entry 9).
The optimized reaction conditions proved to be remark-
ably general. We found that reactions with the diisopropyl-
amine-derived electrophile 2 could be performed in the
presence of a number of functional groups, including formyl,
carbomethoxy, nitro, methoxy, trifluormethyl, iodo, and
bromo groups (Table 2, 7–14). As the synthesis of anilines
16 and 17 suggests, hindered boronic esters are well tolerated
in the reaction. In addition, a variety of heteroaromatic
boronic esters, including 2-chloropyridine-3-boronic ester,
can also be used as nucleophiles (18–21). In most reactions,
2.5 mol% of the catalyst was sufficient to accomplish the full
conversion in less than 12 hours, whereas the sterically
hindered boronic esters required a higher catalyst loading
(5 mol%). Finally, as the synthesis of 8 demonstrates, the
reaction can be successfully performed on a 5 mmol scale.
To establish the full scope of the amination reaction, we
explored the reactivity of various electrophiles. O-benzoyl
hydroxylamines derived from common cyclic amines, such as
pyrrole, piperidine, morpholine, and piperazine can be used in
the reaction (Table 1, 23–25 and 31). Electrophiles bearing
functionality, such as nitro, carbomethoxy, bromo, and chloro
groups are also viable substrates and provide the aniline
products in excellent yields. The steric properties of an
electrophile have no significant effect on the outcome of the
reaction. Both 2-methylpyrrole- and decahydroquinoline-
derived electrophiles provide the expected anilines in high
yield (30 and 31). Even a highly hindered electrophile derived
[a] Reactions performed on a 0.5 mmol scale. Yields of isolated products
are reported. Catalyst was added as a 0.1m solution in toluene.
[b] 5 mol% of the catalyst was used. [c] The reaction was performed on
a 5.0 mmol scale. [d] 2.5 mol% of the catalyst was used at 458C.
Boc=tert-butoxycarbonyl, neop=neopentyl glycol.
from 2,2,6,6-tetramethylpiperidine could be coupled with
nitrophenyl boronic ester in 87% yield (32), and the 2-
methylphenyl boronic ester provided 33 in 60% yield.
An extension of the substrate scope could be achieved if
lithium tert-butoxide is replaced with CsF. This change was
particularly beneficial in coupling ortho-substituted boronic
esters with less hindered electrophiles (Scheme 1a).[20] Fur-
thermore, CsF allowed the reaction to be performed in the
presence of acidic functional groups, as demonstrated by the
reaction of the 4-hydroxypiperidine-derived electrophile
shown in Scheme 1b. Finally, the extremely hindered aniline
33 could be prepared in 89% yield using this procedure
(Scheme 1c).
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and methoxy groups. Overall, an exceptionally broad scope
and reliability of this new procedure, together with the
availability of a wide variety of aryl boronic esters, make it
a significant addition to the existing methods for aniline
synthesis.
See the Supporting Information for full experimental
details, including full characterization for new compounds.
Received: January 18, 2012
Published online: March 7, 2012
Keywords: amination · boron · copper · homogeneous catalysis ·
.
synthetic methods
Scheme 1. Reactions with CsF as an additive. a) ArBneop (1.2 equiv),
R2NOBz (1.0 equiv), Xantphos (5 mol%), CuOtBu (5 mol%), CsF
(5.0 equiv), toluene, 608C, 72 h.
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We propose that the amination reaction proceeds accord-
ing to the mechanism shown in Scheme 2. The reaction
involves transmetalation from boron to copper, with subse-
quent electrophilic amination of the aryl copper intermediate.
Finally, the reactive copper alkoxide is regenerated with
lithium alkoxide.
[4] For example, the 20% yield reported by Sattar et al. is the
highest yield reported for the coupling of aryl halides with
diisopropylamine. S. Iyer, G. M. Kulkarni, C. Ramesh, A. K.
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Scheme 2. Proposed reaction mechanism.
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With the transmetalation of aryl boronic esters to copper
well documented in the literature,[16,21d–e] we focused our
attention on the electrophilic amination of the putative aryl
copper intermediate (Scheme 1). A reaction of electrophile 2
with the IMes-supported copper aryl complex 37[16] resulted in
a 73% yield of aniline 38, in less than 30 minutes, at room
temperature. In addition, when used as a catalyst, 37 provided
results indistinguishable from those obtained with IMes-
CuOtBu catalyst.[22]
In conclusion, we have developed a mild copper-catalyzed
reaction for the synthesis of sterically hindered anilines from
aryl and heteroaryl boronic esters. The new method is
compatible with a wide range of fuctionalities, including
chloro, bromo, iodo, carbomethoxy, nitro, hydroxyl, formyl,
[13] D. A. Evans, J. L. Katz, T. R. West, Tetrahedron Lett. 1998, 39,
2937.
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amines, results in lower yields of the coupling products (37%
yield in a reaction with tert-butyl amine and phenyl boronic
acid). In a rare example of a reaction with acyclic secondary
amines reported by Miyaura (Ref. [14b]), diethylamine was
coupled with tolyl triolborate in 55% yield.
[20] Under the standard reactions conditions used in Table 2,
products 34 and 35 were obtained in less than 20% yield.
While not confirmed with all substrates presented in Table 2,
reactions performed with 5 equivalents of CsF provide yields of
the amination products that compare favorably with the yields
presented in Table 2.
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[18] For more details, see the Supporting Information.
[19] T. H. Lemmen, G. V. Goeden, J. C. Huffman, R. L. Geerts, K. G.
Caulton, Inorg. Chem. 1990, 29, 3680.
[22] IMesCuOtBu provides results comparable to those obtained
with Xantphos-based catalyst (XantphosCuOtBu) with less
hindered boronic esters. See the Supporting Information for
further information.
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