Palladium-catalyzed γ-selective arylation of zincated Boc-allylamines

Article abstract of DOI:10.1021/ol5018257

The regio- and diastereoselective arylation of Boc-protected allylamines was performed via a one-pot lithiation/transmetalation to zinc/cross-coupling sequence, through an appropriate choice of a phosphine ligand. A variety of γ-arylated products were obtained in moderate to good yield, and the products could be directly transformed into valuable γ-arylamines and β-aryl aldehydes.

Full text of DOI:10.1021/ol5018257

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed γ‑Selective Arylation of Zincated Boc-
Allylamines
Anthony Millet and Olivier Baudoin*
́ ́ ́
Universite Claude Bernard Lyon 1, CNRS UMR 5246 - Institut de Chimie et Biochimie Moleculaires et Supramoleculaires, CPE
Lyon, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France
S
* Supporting Information
ABSTRACT: The regio- and diastereoselective arylation of Boc-protected
allylamines was performed via a one-pot lithiation/transmetalation to zinc/
cross-coupling sequence, through an appropriate choice of a phosphine
ligand. A variety of γ-arylated products were obtained in moderate to good
yield, and the products could be directly transformed into valuable γ-
arylamines and β-aryl aldehydes.
he Negishi coupling of α-zincated saturated Boc-amines,
obtained by directed α-lithiation and transmetalation to
Boc-allylamines was shown to depend on the nature of the
electrophile, with carbon-based electrophiles generally giving rise
to γ-functionalization, and the corresponding γ-functionalized
products were obtained as major Z geometrical isomers.4
However, to the best of our knowledge, the reactivity of the
corresponding allylzinc reagents has not been reported.5
T
zinc, has been established as a powerful method to access α-
arylated amines (Scheme 1a).1 By employing a less bulky and
Scheme 1. Site-Selective Arylation of Zincated Boc-Amines
We first studied the lithiation/transmetalation/Negishi
coupling of Boc-allylmethylamine 1a (Table 1). As shown by
quenching experiments with dimethyl sulfate,6 the initial
lithiation step was best performed with n-BuLi in THF at −78
°C as previously described (84% yield),4 but lithium amides such
as LDA could be also employed with similar results, which might
be useful for more sensitive substrates. After in situ trans-
metalation of the so formed allyllithium species with zinc(II)
chloride (1 equiv), the cross-coupling step was performed with p-
trifluoromethylbromobenzene as the electrophile under various
conditions (Table 1). Importantly, in all cases, the coupling
occurred exclusively at the γ-position. First, the influence of
various phosphine ligands was analyzed (entries 1−10).
Interestingly, monophosphines of different types (entries 1−4)
furnished coupling product 2a in a completely E-selective
manner albeit in low yield, with PCy3 being the most efficient
ligand (entry 3). In contrast, diphosphines such as dppf, dppe,
and BINAP provided a separable mixture of E and Z isomers,
with the Z isomer 2b being the major product (entries 5−7).
With Buchwald’s biarylphosphine ligands L1−L3 (entries 8−10),
2a was again obtained as the major diastereoisomer, with SPhos
L2 being optimal (entry 9). With this ligand, further improve-
ments in the yield were found with a lower excess of zincated 1a
(1.25 equiv) with regard to the aryl bromide (entry 11) and a
lower temperature of 60 °C (entries 12−13). The recently
introduced precatalyst 3 could be also employed instead of the
Pd2dba3/L2 in situ combination,7 albeit with slightly reduced
efficiency (entry 14). Finally, the catalyst loading could be
decreased to 2 mol % without detrimental effect on the yield
more flexible biarylphosphine ligand in the Pd-catalyzed step, we
have shown that the migrative Negishi coupling of the
intermediate α-zincated Boc-amine can be favored, giving rise
to β-arylated Boc-amines in a selective manner (Scheme 1a).1e,2
However, we were unable to selectively arylate homologous Boc-
protected n-propylamines at the γ-position. To access these
valuable γ-arylated amines3 in a site-selective manner, we thus
turned to a different strategy. Beak and co-workers have
described the lithiation of Boc-allylamines with the n-BuLi/
sparteine combination and have reacted the resulting configura-
tionally stable allyllithium species with a variety of electrophiles
to give enantiopure γ-functionalized allylamines.4 We thought
that these lithiated Boc-allylamines should be able to undergo
transmetalation with a zinc(II) halide to generate an allylzinc
species, which would then undergo one-pot Negishi coupling to
furnish the corresponding γ-arylated allylamines (Scheme 1b). In
turn, the latter should lead to γ-arylamines upon reduction of the
double bond. At this point, two potential issues were to be
addressed: the control of the γ- vs α-arylation selectivity and the
control of the E/Z configuration of the formed substituted
double bond. The γ- vs α-functionalization selectivity of lithiated
Received: June 24, 2014
Published: July 23, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 1. Optimization of the Negishi Coupling of Boc-
Allylmethylamine 1a
Scheme 2. Scope and Limitations of the γ-Arylation of Boc-
Allylamines
a
a
b
c
entry
ligand
PPh3
temp (°C)
E/Z
yield of 2a (%)
1
80
80
80
80
80
80
80
80
80
80
80
60
40
60
60
>95:5
>95:5
>95:5
>95:5
40:60
44:56
27:73
90:10
92:8
42
34
51
14
d
2
P(t-Bu)3
d
3
PCy3
d
4
PEt3
e
5
dppf
dppe
BINAP
L1
31(23)
e
6
27(28)
e
7
16(35)
8
57
57
49
9
L2
10
11
12
13
14
15
L3
80:20
93:7
f
L2
64
f
L2
95:5
75
f
L2
86:14
95:5
58
fg
L2
58 ,
fh
L2
96:4
73 ,
a
Reaction conditions: 1a (1.4 equiv), n-BuLi (1.4 equiv), TMEDA
(1.4 equiv), THF, −78 °C, 1 h, then ZnCl2 (1.4 equiv), −78 → 20 °C,
then removal of volatiles under vacuum, then toluene, Pd2dba3 (2.5
mol %), ligand (5 mol %), 4-trifluoromethylbromobenzene (1.0
b
equiv), 80 °C, 15 h. Determined by GCMS analysis of the crude
c
d
mixture. Yield of the isolated E isomer. Introduced as HBF4 salt.
e
f
Yield of the isolated Z isomer. With 1.25 equiv of 1a/n-BuLi/
g
TMEDA/ZnCl2 instead of 1.4 equiv. With precatalyst 3 (5 mol %)
h
instead of Pd2dba3/L2. With 2 mol % Pd/L2 instead of 5 mol %.
a
Reaction conditions: Boc-allylamine (1.25 equiv), n-BuLi (1.25
equiv), TMEDA (1.25 equiv), THF, −78 °C, 1 h, then ZnCl2 (1.25
equiv), −78 → 20 °C, then removal of volatiles, then toluene, Pd2dba3
(2.5 mol %), Sphos L2 (5 mol %), Ar−Br (1.0 equiv), 60 °C, 15 h.
Yields refer to the isolated E isomer unless otherwise stated. b Yield of
the E/Z mixture.
(18a−b), this can be ascribed to a more difficult lithiation step, as
indicated by the observation of large amounts of 1-(n-butyl)-4-
methylbenzene, whereas in the second case (19a) the cross-
coupling step is implicated, as indicated by the observation of
unreacted aryl bromide.
A plausible mechanism of the lithiation/transmetalation/
cross-coupling sequence based on previous literature elements is
shown in Scheme 3. The lithiation of a Boc-allylamine with n-
(entry 15). Under optimal conditions, E-configured coupling
product 2a was isolated in 75% yield (entry 12).8
The scope and limitations of this γ-arylation process were next
evaluated under the optimal conditions (Scheme 2). First, a
number of substituents were tolerated on the (hetero)aryl
electrophile, with homogeneously good E/Z ratios (92%−97%
of E isomer) and yields of the isolated E isomer in the range
48%−75% (Scheme 1a). Then the N-methyl group of 1a was
replaced with other substituents and the lithiation/trans-
metalation/arylation sequence was performed with p-bromoto-
luene as an unbiased electrophile (Scheme 1b). N-Aryl
substituents displayed good performances in this three-step
one-pot sequence (12a−13a). Allyl (14a), ethyl (15a), and
methylcyclopropyl (16a) groups furnished moderate yields of
the E isomer (51−58%), whereas the yield dropped with a
cyclohexyl substituent (17a). This lower yield of 17a can be
ascribed to a more difficult lithiation due to increased steric
hindrance,1e,4 as indicated by the observation of larger quantities
of the coupling product of n-BuZnCl (1-(n-butyl)-4-methyl-
benzene) by GCMS analysis. Further limitations were found in
the reaction of Boc-allylmethylamines bearing an additional Me
group at the β- or γ-position, which furnished the corresponding
γ-arylated products in low yield (Scheme 2c). In the first case
Scheme 3. Proposed Organometallic Intermediates in the
Lithiation/Transmetalation/Cross-Coupling Sequence
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Organic Letters
Letter
BuLi/TMEDA should lead to Boc-coordinated η3-allyllithium
compound A, on the basis of the X-ray diffraction and NMR
studies of the analogous sparteine complex isolated by Beak and
co-workers.9 In contrast, allylzinc compounds have been recently
shown to exhibit η1-allyl and not η3-allyl coordination.10 On this
basis, transmetalation of A with zinc chloride is proposed to give
rise to Boc-coordinated η1-allylzinc compound B and/or C, by
analogy with related organotin and organosilicon compounds.4c
Subsequent transmetalation with the organopalladium species
ArPdIIBrL, arising from oxidative addition of ArBr to
monoligated Pd0L,11 should furnish η3-allylpalladium complex
D.12 Reductive elimination from D at the least hindered γ-
position would furnish the observed γ-arylated product. The γ-
arylation selectivity and the E-diastereoselectivity observed in the
current reaction are both consistent with an η3-allylpalladium
intermediate D rather than an η1-allyl coordination mode
(analogous to B and C with Pd instead of Zn).
The α,β-unsaturated γ-arylated enecarbamates obtained
through the current method are isomeric to compounds obtained
by Heck-type reactions, in which the double bond is located at
the β,γ-position and the aryl group at the β- or γ-position,13 and
therefore both cross-coupling methods are complementary. In
the present case, the coupling products can be further derivatized
to access valuable organic intermediates (Scheme 4). First,
ASSOCIATED CONTENT
* Supporting Information
Full characterization of all new compounds, detailed exper-
imental procedures, and copies of NMR spectra for target
molecules. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: olivier.baudoin@univ-lyon1.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Agence Nationale de la Recherche (programme blanc
“EnolFun”) and Institut Universitaire de France for financial
support.
REFERENCES
■
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a
Yield for two steps (arylation and hydrolysis).
hydrogenation of the CC bond of 2a provided γ-aryl-Boc-
amine 21, thereby nicely complementing our previously
described α- and β-arylation of saturated acyclic Boc-amines.1e
In addition, acidic hydrolysis of the enecarbamate group of 2a
furnished β-arylated aldehyde 22a in 94% yield. The γ-arylation/
hydrolysis sequence could be also conducted without isolation of
the enecarbamate intermediate, as illustrated with the synthesis
of aldehydes 22a−d in 53%−62% overall yield from the
corresponding aryl bromides. Thus, the current method provides
a novel and rapid entry into this useful class of aldehydes.
In conclusion, we have developed a new method allowing the
selective γ-arylation of Boc-protected allylamines via a one-pot
lithiation/transmetalation/cross-coupling sequence. This meth-
od is complementary to previously reported α- and β-arylations
of Boc-amines. High E-stereoselectivity was achieved through the
proper choice of a phosphine ligand in the coupling step. A
variety of arylated products were obtained in moderate to good
yield, and the products could be easily transformed into valuable
γ-arylamines and β-aryl aldehydes.
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