Ligand-controlled β-selective C(sp3)-H arylation of N-Boc-piperidines

Article abstract of DOI:10.1039/c3sc50428j

We report a general palladium-catalyzed β-arylation of Boc-piperidines, which yields a variety of valuable 3-arylpiperidines in a simple and direct manner. The β- vs. α-arylation selectivity was controlled by the ligand, with flexible biarylphosphines providing mainly the desired β-arylated products whereas more rigid biarylphosphines mainly furnished the more classical α-arylated products. The computed reaction mechanism (DFT), studied from the common α-palladated intermediate, indicated that the reductive elimination steps leading to the α- and β-arylated products are selectivity-determining. Moreover, the experimental trend obtained with different ligands was well reproduced by the calculations.

Full text of DOI:10.1039/c3sc50428j

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3
Ligand-controlled b-selective C(sp )–H arylation of
N-Boc-piperidines†
Cite this: DOI: 10.1039/c3sc50428j
a
a
b
a
Anthony Millet, Paolo Larini, Eric Clot and Olivier Baudoin*
We report a general palladium-catalyzed b-arylation of Boc-piperidines, which yields a variety of
valuable 3-arylpiperidines in a simple and direct manner. The b- vs. a-arylation selectivity was
controlled by the ligand, with flexible biarylphosphines providing mainly the desired b-arylated products
whereas more rigid biarylphosphines mainly furnished the more classical a-arylated products. The
computed reaction mechanism (DFT), studied from the common a-palladated intermediate, indicated
that the reductive elimination steps leading to the a- and b-arylated products are selectivity-
determining. Moreover, the experimental trend obtained with different ligands was well reproduced by
the calculations.
Received 13th February 2013
Accepted 7th March 2013
DOI: 10.1039/c3sc50428j
www.rsc.org/chemicalscience
2
-arylpiperidines, via transmetalation to zinc and Negishi
Introduction
coupling with aryl electrophiles (Scheme 1a, R ¼ H). This
3
-Arylpiperidines are important building blocks for drug principle was initially implemented on Boc-pyrrolidine by
5
discovery, as shown by the structures of preclamol, a dopami- Campos et al., and subsequently transposed to Boc-piperi-
nergic autoreceptor agonist, and MK-4827, a poly(ADP-ribose)- dine by Coldham and co-workers. Recently, Knochel and
polymerase (PARP) inhibitor (Fig. 1). Their synthesis usually co-workers reported a study on the diastereoselective aryla-
6,7
1
involves the construction of the piperidine ring or the partial tion of substituted Boc-piperidines, which occurred at the
2
reduction of a 3-arylpyridine precursor, since the inert char-
acter of C–H bonds in a b position to the nitrogen atom seems to
preclude direct functionalization.
usual a position to the nitrogen atom, except with 2-methyl-
piperidine, which unexpectedly underwent b-arylation
8
(
Scheme 1a, R ¼ Me). In this work, the arylation site-selec-
In contrast, the well-established directed lithiation of Boc- tivity was substrate-controlled, since a-arylated products where
piperidines (Boc ¼ tert-butyloxycarbonyl) a to the nitrogen obtained with the same ligand (Buchwald's RuPhos) from
3,4
atom
provides an efficient and direct entry into piperidines lacking a 2-Me substituent. We recently described
the Pd-catalyzed b C–H-arylation of ester enolates, for which
site-selectivity (i.e. a- vs. b-arylation) was controlled both by
9,10
the reactants and the ligand. This reaction, the mechanism
of which was investigated in detail, involves Pd migration
Fig. 1 Examples of bioactive 3-arylpiperidines.
a
Universit ´e Claude Bernard Lyon 1, CNRS UMR 5246 – Institut de Chimie et Biochimie
Mol ´e culaires et Supramol ´e culaires, CPE Lyon, 43 Boulevard du 11 Novembre 1918,
6
9622 Villeurbanne, France. E-mail: olivier.baudoin@univ-lyon1.fr
b
Institut Charles Gerhardt, CNRS UMR 5253, Universit ´e Montpellier 2, case courrier
1
501, Place Eug `e ne Bataillon, 34095 Montpellier, France
†
Electronic supplementary information (ESI) available: Procedural, spectral and
X-ray crystallographic (CIF) data. CCDC 924289–924291. For ESI and
crystallographic data in CIF or other electronic format see DOI:
1
0.1039/c3sc50428j
Scheme 1 Substrate vs. ligand-controlled arylation of Boc-piperidines.
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along the alkyl chain by a b-H elimination/rotation/insertion
Results and discussion
Experimental results
9b
sequence. By extension, we envisioned that the b-arylation
of 2-methylpiperidine observed by Knochel et al., which
8
presumably involves the same Pd migration mechanism,
We rst examined the arylation of the organozinc reagent,
might be extended to other piperidines, including those generated in situ by a-lithiation of Boc-piperidine 1a and
5
lacking a C-2 substituent, by a proper choice of the ligand. transmetalation with ZnCl
2
,
with p-triuoromethylbromo-
The development of such a ligand-controlled b-arylation of benzene (Table 1). This aryl bromide was chosen because the
Boc-piperidines (Scheme 1, bottom) is the focus of the triuoromethyl group should not introduce a strong electronic
current report.
bias for the control of the arylation site-selectivity, in light of our
9
b
1
11a
previous studies. In the presence of DavePhos (L ) as the
ligand and toluene as the solvent, i.e. under conditions similar
to those developed in our initial work on the b-selective aryla-
9
a
a
tion of ester enolates, a ca. 3 : 2 mixture of a- and b-arylated
products 2a and 3a was isolated in 68% yield (entry 1). By using
Table 1 Optimization of the b-arylation of piperidine
2
11b
3
11c
SPhos (L ) or RuPhos (L ) as the ligand as in the previous
8
work of Knochel et al., the a-arylated product 2a was obtained
as expected with more than 90% selectivity (entries 2–3). We
next studied the effect of the directing group (R) on the piper-
12
idine ring, which was expected to have an inuence on the a/b
selectivity by virtue of electronic and steric effects (entries 4–7).
Indeed, this turned out to be the case, but none of the amides
and carbamates that were examined resulted in an increase in
the selectivity in favor of the b-arylated product. The effect of
other solvents was also analyzed (see entries 8–11 for repre-
sentative examples), but toluene was found to provide the best
combination of b-selectivity and yield (entry 1). Next, we turned
our attention to the modication of the ligand (entries 12–16).
b
c
Entry R
Ligand Solvent
2/3
Yield (%)
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
Boc (1a)
Boc (1a)
Boc (1a)
Piv (1b)
CO(2-pyridinyl) (1c)
CO
CO(2,4,6-i-Pr-C
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
L
L
L
L
L
L
Toluene
61 : 39 68
94 : 6 78
90 : 10 65
85 : 15 —
2
3
1
1
1
1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
—
—
0
0
2
i-Pr (1d)
4
d
Gratifyingly, analogues of DavePhos bearing an imidazole (L )
6
H
2
) (1e) L1
>98 : 2 68
59 : 41 55
71 : 29 68
64 : 36 62
5
13,14
or pyrrole (L ) ring,
which gave superior yields and selec-
L
1
9c
L
Me
4
THF
tivities to DavePhos in a previous study, reversed the selectivity
in favor of b-arylated product 3a (entries 12–13). Then, we found
that the dimethylamino group of these ligands was not required
to obtain good b/a selectivity, in contrast to previous work.
Indeed, ligand L provided a slightly enhanced selectivity (entry
1
0
1
2
3
4
5
6
7
L
MTBE
1
L
Mesitylene 73 : 27 54
4
L
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
17 : 83 57
17 : 83 65
9
b
5
L
6
6
L
10 : 90 44e
7
5
L
17 : 83 56
14) compared to L (entry 13), albeit with a low conversion and
8
e
L
9 : 91 59
yield. This could be somewhat improved by decreasing the
—
—
0
steric bulk at the phosphorus alkyl substituents (entries 15–16),
8
and diisopropylphosphinopyrrole L provided compound 3a
with a 91 : 9 selectivity and a 59% yield aer chromatographic
separation of the a and b isomers (entry 16). A control experi-
ment without added phosphine ligand (entry 17) gave a low
conversion and no arylated product, as expected. Finally, the
ꢀ
reaction temperature (60 C) was found to be optimal through a
ꢀ
screening of different temperatures from 20 to 100 C.
The scope of the b-arylation of Boc-piperidine 1a with
different aryl electrophiles was next evaluated (Scheme 2). The
8
optimized conditions using L as the ligand could be trans-
posed to a variety of aryl electrophiles, to give homogeneously
good b/a arylation ratios and isolated yields in the range 45–
7
0% aer chromatographic separation to remove the minor
a
Reaction conditions: piperidine (1.0 equiv.), s-BuLi (1.2 equiv.), TMEDA a-arylation isomer. As shown with product 3a, the inuence of
ꢀ
ꢀ
(1.2 equiv.), Et
2
O, ꢁ78 C, then ZnCl
2
(1.2 equiv.), ꢁ78 / 20 C, then
the aryl leaving group (X) was found to be relatively weak and
the usual halides (Cl, Br, I) and triate of the same arene could
ꢀ
0
C, 17 h. Determined from H NMR or GCMS analysis of the be employed with little difference in efficiency and selectivity.
c
2 3 3
removal of volatiles under vacuum, then solvent, Pd dba $CHCl (2.5
mol%), ligand (5 mol%), 4-triuoromethylbromobenzene (0.7 equiv.),
b
1
6
crude mixture. Combined yield of the isolated mixture of 2/3 unless
Moreover, the reaction tolerated a variety of electron-with-
drawing (3a–h) and donating (3j–l) substituents on the benzene
ring as well as other (hetero)arenes (3m–n), although the
d
e
otherwise stated. Yield of the isolated a-arylated product. Yield of
the isolated b-arylated product. Me THF 2,2,5,5-tetramethyl-
tetrahydrofuran; MTBE ¼ methyl tert-butyl ether.
4
¼
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Scheme 3 Formal synthesis of preclamol.
similar to 4, arising from the decoordination of intermediate
palladium p-complexes (vide infra), were also observed in the
9c,15
arylation of ester enolates.
The X-ray crystal structure of
product 3i could be obtained, showing the chair conformation
of the piperidine ring with the phenyl ring in the equatorial
position as expected from usual steric effects.† With aryl
bromides bearing a strongly electron-withdrawing substituent
8
(F or CF
3
) in the ortho position, ligand L proved completely
inefficient (3o–p). In contrast, excellent selectivities and satis-
1
fying yields were obtained with DavePhos L as the ligand. We
have already shown that ortho electron-withdrawing groups
introduce an electronic bias by disfavoring C–C reductive
9a,b
elimination. Indeed, large amounts of enecarbamate 4 (64%
8
yield based on aryl bromide) were obtained when ligand L was
employed, which might be consistent with this effect. However,
it is not yet clear why the use of DavePhos resulted in a coun-
terbalancing of this effect.
This method was applied to the gram-scale formal synthesis
of preclamol (Fig. 1, Scheme 3). Indeed, Boc-piperidine 1a
underwent b-selective arylation with 3-bromoanisole under the
optimized conditions to give product 3q in 71% yield. Subse-
quent cleavage of the Boc group with TFA followed by formation
1a
of the known hydrochloride salt 3r proceeded efficiently.
Next, we studied the b-arylation of substituted Boc-piperi-
dines (Scheme 4). The above reaction conditions were rst
applied to the coupling of 4-methylpiperidine 5a and bromo-
benzene, but only cis-congured a-arylated product 6a was
8
formed in low yield. In this case, b-arylation is highly dis-
favored, likely because this would involve the formation of an
organopalladium intermediate in the b-position cis to the
Scheme 2 Scope of the b-arylation of Boc-piperidine. Reaction conditions: see 4-methyl substituent. In contrast, cis-2,4-dimethylpiperidine 5b,
3
a
Table 1. Yields refer to the isolated b-arylated product. b/a Ratios were deter- which was obtained by directed lithiation/methylation of 5a,
mined from GCMS analysis of the crude mixture. Aryl bromides (X ¼ Br) were used
underwent exclusive b-arylation with bromobenzene to give
trisubstituted piperidine 7a in good yield as a single cis,trans
diastereoisomer. In this case, b-arylation is sterically allowed by
the trans relationship between the 4-methyl group and the
a
ꢀ
b
to obtain compounds 3f–p. Reaction performed at 80 C. Ellipsoids are drawn
at 50% probability; only H atoms of the piperidine ring are shown for clarity.
strongly electron-donating NMe
2
substituent (3l) led to some- incoming 5-phenyl group. Compared to unsubstituted piperi-
ꢀ
what decreased selectivity and reactivity. In addition, similar to dine 1a, a higher temperature (80 C) was required to achieve a
the more classical a-arylation of Boc-piperidines,
sensitive electrophilic groups could be introduced (3g–h). In as ligand instead of L , a-arylation occurred predominantly (b/a
most instances, the conversion of the aryl bromide was 40 : 60). These results show that the use of ligand L allows the
6,7b,8
3
relatively satisfying conversion. Of note, when RuPhos L was employed
8
8
incomplete and enecarbamate 4 was formed in variable inherent preference for substrate 5b to undergo a-arylation to
amounts, at the expense of the desired product. For instance, be overridden. Similarly, compounds 5b and 5c underwent
b-arylated product 3n was isolated in 61% yield, together with highly regio- and diastereoselective b-arylation with two
10% of a-arylated product, 6% of compound 4 and 2-bromo- different aryl bromides to give products 7b and 8a–b in
naphthalene (non-quantied). Dehydrogenated products moderate yields.
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Scheme 4 Diastereoselective b-arylation of 2,4-disubstituted Boc-piperidines.
Reaction conditions: see Table 1. Yields refer to the isolated b-arylated product. b/
a
a Ratios were determined from GCMS analysis of the crude mixture. Ellipsoids
are drawn at 50% probability; only H atoms of the piperidine ring are shown for
clarity.
The X-ray crystal structure of 8a revealed that in this case the Scheme 5 Diastereoselective b-arylation of trans-decahydroquinoline (a) and
reactivity of other N-heterocycles (b). Reaction conditions: see Table 1. Yields refer
piperidine ring adopts a twist-boat conformation, which avoids
1
to the isolated b-arylated product. b/a Ratios were determined from H NMR or
both the 1,3-allylic strain between the 2-Me and the Boc groups
and the 1,3-diaxial interaction between the 2-Me and the 4-Ph
a
GCMS analysis of the crude mixture. Ellipsoids are drawn at 50% probability;
b
only H atoms of the piperidine ring are shown for clarity. Yield of the isolated a-
3c,d
groups.† This twist-boat conformation is compatible with the arylated product.
Pd migration involved in the b-arylation mechanism (vide infra).
The reactivity of trans-decahydroquinoline 9 was also studied
8
(
Scheme 5a), to assess the applicability of the current approach despite the use of ligand L . These results indicate that the
16
to bicyclic systems. Under the same conditions as above b-arylation mechanism cannot accommodate the conforma-
Scheme 3), the arylation of 9 with three different aryl bromides tional constraints of these rings, at least under the current
proved both highly b-selective and diastereoselective (b/a $ conditions.
5 : 5, 1 observed diastereoisomer). However, the yields of the
(
9
corresponding products 10a–c were moderate, especially for 10c
3
Computational mechanistic study
bearing the sensitive acetyl group. With RuPhos L as the ligand
8
instead of L , a complete reversal of selectivity was obtained for We assumed that the current reaction involves the same overall
9
10a (b/a 7 : 93), consistent with the preceding results (Table 1, mechanism as previously reported with ester enolates. The
Scheme 4). The X-ray structure of compound 10a was obtained competition between a- and b-arylation in the reaction of
and showed again a twist-boat conformation for the piperidine 2-zincated Boc-piperidine with bromobenzene was addressed
ring, together with a cis relationship between the C-3 methylene computationally using DFT(B3PW91) calculations (Fig. 2–4, see
and C-5 phenyl substituents.† This conformation allows 1,3- also the ESI† for the geometries of all intermediates and tran-
17
8
allylic strain between the C-2 methylene substituent and the Boc sition states). In the initial palladium complex [Pd(L )(Ph)Boc-
group to be avoided while maintaining a diequatorial arrange- piperidine] Ia, which results from the Zn–Pd transmetalation
ment for the C2, C3-fused cyclohexane ring, and is again step, the Pd atom is attached to the piperidine ring in the
˚
compatible with the b-arylation mechanism.
equatorial position (Pd–C ¼ 2.060 A) and coordination of the
˚
Finally, the reactivity of saturated nitrogen heterocycles of Boc group to Pd (Pd/O 2.192 A) completes the square-planar
different ring size (5, 7, 8) was also examined (Scheme 5b). geometry around Pd (Fig. 3), in line with previous
II
5,6
8
However, in all cases a-arylation occurred predominantly calculations.
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#
Starting from intermediate Ia (Fig. 3), the a-arylated product b-H elimination from the agostic C–H bond via TS-Ib-IIa (DG ¼
ꢁ1
ꢀ
(
i.e. 2i still coordinated to Pd through the aromatic ring) is 9.2 kcal mol ) leading to p-complex IIa; (3) two subsequent 90
#
obtained by reductive elimination through TS-Ia-a associated rotations of the coordinated olen, via TS-IIa-IIb (DG ¼ 1.8 kcal
#
ꢁ1
ꢁ1
#
ꢁ1
with DG ¼ 31.2 kcal mol (Fig. 4). TS-Ia-a, in which the Pd mol ) and TS-IIb-IIc (DG ¼ 4.2 kcal mol ) leading to p-
atom is still coordinated to the oxygen atom of the Boc group, is complex IIc (Fig. 3); (4) insertion of the olen into the Pd–H bond
#
ꢁ1
reminiscent of a tetrahedral ML
forming C(sp )–C(sp ) bond (1.929 A) is associated with a the Pd–C
lengthening of both Pd–C bonds (Pd–C(sp ) from 1.996 A in Ia has ipped back to the chair conformation (intermediate III,
4
geometry. In addition, the through TS-IIc-III (DG ¼ 1.8 kcal mol ) with the formation of
2
3
˚
b
bond in an axial position of the piperidine ring which
2
˚
3
˚
˚
˚
to 2.040 A in TS-Ia-a; Pd–C(sp ) from 2.060 A in Ia to 2.273 A in Fig. 3); (5) reductive elimination to give the b-arylated product
2
3
#
ꢁ1
TS-Ia-a), and a concomitant decrease of the C(sp )–Pd–C(sp ) (3i) via TS-III-b (DG ¼ 15.9 kcal mol , Fig. 4). In TS-III-b, the Pd–
ꢀ
ꢀ
3
˚
angle from 87.7 (Ia) to 52.8 (TS-Ia-a). The Pd/O interaction C(sp ) bond has elongated to 2.275 A, a value similar to that
2
˚
˚
observed in Ia (2.192 A) is weakened in TS-Ia-a (2.524 A). obtained in TS-Ia-a. The Pd–C(sp ) bond is shorter in TS-III-b
˚
˚
However, this interaction is still sufficiently important to induce (2.025 A) compared to the value in TS-Ia-a (2.040 A) and the
2
3
˚
˚
an out-of-plane motion of the Pd-bound phenyl ring, as illus- forming C(sp )/C(sp ) bond is longer (1.984 A vs. 1.929 A). The
trated by the variation of the dihedral angle Cipso–P–Pd–C(sp ) essential difference between TS-Ia-a and TS-III-b is the lack of
from 118.2 in Ia to 152.4 in TS-Ia-a (Cipso: ipso carbon atom of Pd/O interaction in the latter, which is reminiscent of a T-
the phenyl ring in L ). This results in a geometry of TS-Ia-a shaped ML
2
ꢀ
ꢀ
8
3
geometry. Consequently, the Pd-bound phenyl ring
featuring the Pd-bound phenyl ring in a pseudo trans geometry does not experience the out-of-plane motion observed in TS-Ia-a.
8
2
with respect to the phenyl ring of L . Consequently, the shortest The Cipso–P–Pd–C(sp ) dihedral angle has even decreased
˚
ꢀ
ꢀ
Pd/C bond distance of 3.374 A in Ia between the phenyl ring of compared to the value in Ia (90.0 , TS-III-b; 118.2 , Ia). As a result,
L and Pd elongates to 3.556 A in TS-Ia-a.
8
8
˚
the interaction between the phenyl ring of L and Pd has
The b-arylation pathway involves the following sequential increased in TS-III-b with a shortest C/Pd distance of 3.304 A˚ .
steps: (1) decoordination of Pd/O, ring-ipping to the twist- This nal reductive elimination step furnishes the b-arylated
ꢁ
1
boat conformation Ib (DG ¼ 10.9 kcal mol ) and formation of a product with the phenyl group in the axial position of the
˚
˚
b-CH agostic interaction (C
b
–H1.143 A, H/Pd 2.034 A, Fig. 3); (2) piperidine ring inthe chair conformation, which interconverts to
8
Fig. 2 Comparison of the energy profiles for the a- and b-arylation pathways from complex Ia with L as the ligand.
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Table 2 Comparison of calculated and experimental a/b-arylation selectivities in
the reaction of 2-zincated Boc-piperidine with bromobenzene
#a
a
#a
b
#
b
c
Entry
Ligand
DG
DG
DDGcalcd
a/bcalcd
a/bexp
8
1
2
3
4
L
L
L
L
31.1
30.5
26.3
23.5
29.6
30.2
26.3
24.4
–1.5
–0.3
0.0
9 : 91
10 : 90
20 : 80
50 : 50
97 : 3
7
39 : 61
50 : 50
80 : 20
1
2
0.9
a
ꢁ1
Calculated values (kcal mol ) at 333 K, expressed relative to
b
#
#
#
intermediate Ia. DDG ¼ DG
b
ꢁ DG
a
. A negative value indicates that
c
the b-arylated product is kinetically preferred. Experimental ratios
1
(333 K), determined from H NMR analysis of the crude mixture. The
latter differ only slightly from those obtained with p-
triuoromethylbromobenzene (see Table 1).
9
b
in the b-arylation of ester enolates. A possible explanation
could be that both the a and the b carbons in Boc-piperidine are
secondary, while in the ester case the a carbon was tertiary and
the b carbon primary, thereby reducing the activation energy for
the Ar–C reductive elimination.
b
Finally, as the nature of the ligand proved to be crucial with
regard to the a/b selectivity, we computed the activation barriers
#
#
of the two rate-limiting steps, i.e. DG (TS-Ia-a) and DG (TS-III-
a
b
18
b), with selected ligands (Table 2). The trend observed experi-
Fig. 3 Selected intermediates in the a- (Ia) and b-arylation (Ib, IIc and III) mentally for the competition between a- and b-arylation was
pathways. Only H atoms of the piperidine ring are shown for clarity.
#
qualitatively well reproduced by the calculations (rDDGcalcd
ꢁ
#
ꢁ1
DDGexpr # 1.3 kcal mol ). In particular, imidazole- and pyrrole-
based ligands L –L (entries 1–2) give opposite selectivities
compared to DavePhos L and SPhos L (entries 3–4), as observed
experimentally. In addition, the comparison of DGa and DGb
7
8
put the phenyl group in the thermodynamically favored equa-
torial position (Fig. 2). The latter conformation was indeed found
1
2
#
#
ꢁ1
to be more stable by 3.2 kcal mol than the former, in line with
the above X-ray structure of 3i (Scheme 2).
values indicates that more exible and less sterically hindered
ligands such as L and L disfavor the reductive elimination at
the less crowded C to a lesser extent than at C , thus favoring the
b-arylated product. Conversely, the more bulky and rigid SPhos
ligand (L ) favors reductive elimination to a higher extent at the
7
8
From these calculations, the highest points in the a- and
b-arylation pathways are TS-Ia-a and TS-III-b, respectively
b
a
(Fig. 2), and therefore the C–C reductive eliminations are
2
ꢁ
1
selectivity-determining. Moreover, TS-Ia-a is 1.4 kcal mol
19
more sterically hindered C
a
compared to C .
b
higher than TS-III-b, and although intermediate Ia is more
ꢁ1
stable than Ib by 10.9 kcal mol , the b-arylated product is the
kinetically favored product by virtue of the Curtin–Hammett
principle. One should point out that the highest point in
Conclusions
In conclusion, we have reported a general palladium-catalyzed
b-arylation of Boc-piperidines, leading to a variety of valuable 3-
arylpiperidines in a regioselective and highly diastereoselective
manner. The b- vs. a-arylation selectivity was essentially
controlled by the ligand, with exible biarylphosphines
providing the desired b-arylated products whereas more rigid
biarylphosphines furnished the more classical a-arylated
products. The computed (DFT) reaction mechanism indicated
that the reductive elimination steps leading to the a- and b-
arylated products are selectivity-determining, and the experi-
mental trend obtained with different ligands was well repro-
duced by the calculations. The extension of these results and
mechanistic data to other synthetically relevant systems will be
reported in due course.
the b-arylation pathway is the Ar–C
present case, whereas it was found to be the insertion of the
olen into the Pd–H bond with the formation of the Pd–C bond
b
reductive elimination in the
b
Acknowledgements
Fig. 4 Transition states for the reductive elimination step in the a- (TS-Ia-a) and
b-arylation (TS-III-b) pathways. Only H atoms of the piperidine ring are shown for
clarity.
This work was nancially supported by the Agence Nationale de
la Recherche (programme blanc 2011 “EnolFun”) and Institut
Chem. Sci.
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Universitaire de France. We thank Dr E. Jeanneau (Universit´e
Claude Bernard Lyon 1) for crystallographic data collection,
structure solution, and renement.
E. Clot and O. Baudoin, Chem.–Eur. J., 2012, 18, 1932; (c)
S. Aspin, A.-S. Goutierre, P. Larini, R. Jazzar and
O. Baudoin, Angew. Chem., Int. Ed., 2012, 51, 10808.
3
1
1
0 For a review on the catalytic arylation of unactivated C(sp )–
H bonds, see: O. Baudoin, Chem. Soc. Rev., 2011, 40, 4902.
1 DavePhos: (a) D. W. Old, J. P. Wolfe and S. L. Buchwald, J.
Am. Chem. Soc., 1998, 120, 9722; SPhos: (b) S. D. Walker,
T. E. Barder, J. R. Martinelli and S. L. Buchwald, Angew.
Chem., Int. Ed., 2004, 43, 1871; RuPhos: (c) M. D. Charles,
P. Schultz and S. L. Buchwald, Org. Lett., 2005, 7,
3965.
Notes and references
1
(a) H. Wikstr ¨o m, D. Sanchez, P. Lindberg, U. Hacksell,
L.-E. Arvidsson, A. M. Johansson, S.-O. Thorberg,
J. L. G. Nilsson, K. Svensson, S. Hjorth, D. Clark and
A. Carlsson, J. Med. Chem., 1984, 27, 1030; (b) M. Amat,
M. Cant ´o , N. Llor, C. Escolano, E. Molins, E. Espinosa and
J. Bosch, J. Org. Chem., 2002, 67, 5343; (c) D. J. Wallace, 12 (a) P. Beak, W. J. Zajdel and D. B. Reitz, Chem. Rev., 1984, 84,
C. A. Baxter, K. J. M. Brands, N. Bremeyer, S. E. Brewer,
R. Desmond, K. M. Emerson, J. Foley, P. Fernandez,
471; (b) P. Beak and W. J. Zajdel, J. Am. Chem. Soc., 1984, 106,
1010.
W. Hu, S. P. Keen, P. Mullens, D. Muzzio, P. Sajonz, 13 (a) A. Zapf, R. Jackstell, F. Rataboul, T. Riermeier,
L. Tan, R. D. Wilson, G. Zhou and G. Zhou, Org. Process
Res. Dev., 2011, 15, 831.
M. G. P. Buffat, Tetrahedron, 2004, 60, 1701.
(a) P. Beak and W.-K. Lee, Tetrahedron Lett., 1989, 30, 1197;
A. Monsees, C. Fuhrmann, N. Shaikh, U. Dingerdissen and
M. Beller, Chem. Commun., 2004, 38; (b) F. Rataboul,
A. Zapf, R. Jackstell, S. Harkal, T. Riermeier, A. Monsees,
U. Dingerdissen and M. Beller, Chem.–Eur. J., 2004, 10,
2983; (c) T. Schulz, C. Torborg, B. Sch ¨a ffner, J. Huang,
A. Zapf, R. Kadyrov, A. B ¨o rner and M. Beller, Angew. Chem.,
Int. Ed., 2009, 48, 918.
2
3
(
b) P. Beak and W.-K. Lee, J. Org. Chem., 1990, 55, 2578; (c)
P. Beak and W.-K. Lee, J. Org. Chem., 1993, 58, 1109; (d)
T. A. Johnson, D. O. Jang, B. W. Slafer, M. D. Curtis and
P. Beak, J. Am. Chem. Soc., 2002, 124, 11689; (e) D. Stead, 14 D. Pingen, C. M u¨ ller and D. Vogt, Angew. Chem., Int. Ed.,
G. Carbone, P. O'Brien, K. R. Campos, I. Coldham and
2010, 49, 8130.
A. Sanderson, J. Am. Chem. Soc., 2010, 132, 7260; (f) 15 For the direct C-3 alkylation of cyclic amines involving a
N. S. Sheikh, D. Leonori, G. Barker, J. D. Firth,
K. R. Campos, A. J. H. M. Meijer, P. O'Brien and
I. Coldham, J. Am. Chem. Soc., 2012, 134, 5300.
similar intermediate, see: B. Sundararaju, M. Achard,
G. V. M. Sharma and C. Bruneau, J. Am. Chem. Soc., 2011,
133, 10340.
4
5
Selected reviews: (a) K. R. Campos, Chem. Soc. Rev., 2007, 36, 16 For the a-lithiation of this compound, see: A. I. Meyers and
1069; (b) E. A. Mitchell, A. Peschiulli, N. Lefevre, L. Meerpoel
G. Milot, J. Am. Chem. Soc., 1993, 115, 6652.
and B. U. W. Maes, Chem.–Eur. J., 2012, 18, 10092.
17 The extrema were located in the gas phase and the energies
given are polarizable continuum model (PCM) electronic
energy values (toluene) corrected by gas phase Gibbs free
energy contributions. For details, see the ESI.†
18 This is of course valid only if reductive elimination remains
the rate-limiting step for b-arylation regardless of the ligand.
We believe that the difference between TS-III-b and the
preceding TS in Fig. 2 is sufficiently high to support this
hypothesis.
(a) K. R. Campos, A. Klapars, J. H. Waldman, P. G. Dormer
and C.-y. Chen, J. Am. Chem. Soc., 2006, 128, 3538; (b)
G. Barker, J. L. McGrath, A. Klapars, D. Stead, G. Zhou,
K. R. Campos and P. O'Brien, J. Org. Chem., 2011, 76, 5936.
I. Coldham and D. Leonori, Org. Lett., 2008, 10, 3923.
See also: (a) R. K. Dieter and S. Li, J. Org. Chem., 1997, 62,
6
7
7726; (b) T. K. Beng and R. E. Gawley, Org. Lett., 2011, 13, 394.
8
9
S. Seel, T. Thaler, K. Takatsu, C. Zhang, H. Zipse, B. F. Straub,
P. Mayer and P. Knochel, J. Am. Chem. Soc., 2011, 133, 4774. 19 For discussions on biaryl-based phosphines, see: (a)
(a) A. Renaudat, L. Jean-G ´e rard, R. Jazzar, C. E. Kefalidis,
E. Clot and O. Baudoin, Angew. Chem., Int. Ed., 2010, 49,
D. S. Surry and S. L. Buchwald, Angew. Chem., Int. Ed.,
2008, 47, 6338; (b) D. S. Surry and S. L. Buchwald, Chem.
Sci., 2011, 2, 27.
7261; (b) P. Larini, C. E. Kefalidis, R. Jazzar, A. Renaudat,
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Chem. Sci.