Palladium(0)-catalyzed enantioselective C-H arylation of cyclopropanes: Efficient access to functionalized tetrahydroquinolines

Article abstract of DOI:10.1002/anie.201207959

Activated: The title reaction proceeds efficiently with 1 mol % of palladium and gives tetrahydroquinolines in excellent enantioselectivities (see scheme). The enantiodiscriminating concerted metalation-deprotonation step occurs via a rare seven-membered palladacycle. The cyclopropyl-substituted tetrahydroquinolines can be regioselectively and enantiospecifically reduced to chiral tetrahydrobenzoazepines. Copyright

Full text of DOI:10.1002/anie.201207959

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Angewandte
Communications
DOI: 10.1002/anie.201207959
À
C H Activation
À
Palladium(0)-Catalyzed Enantioselective C H Arylation of
Cyclopropanes: Efficient Access to Functionalized
Tetrahydroquinolines**
Tanguy Saget and Nicolai Cramer*
Cyclopropanes have been in the center of interest for both
theoretical and practical purposes. As structural motifs, they
are found in many natural products and bioactive com-
pounds,[1] and as highly strained cycloalkanes they are
versatile synthetic intermediates for ring-expansion or ring-
opening reactions.[2] Moreover, cyclopropanes are used as
molecular tools to constrain conformation[3] and to study
reaction mechanisms.[4] Classical, robust methods that pro-
ceed via carbene or carbenoid intermediates, such as the
Simmons–Smith reaction and transition-metal-catalyzed
decomposition of stabilized diazoalkanes or Michael-type
additions, have greatly facilitated synthetic access to this
compound class.[5] However, the catalytic enantioselective
construction of unfunctionalized cyclopropanes remote from
functional groups remains problematic.
noline scaffold.[12] The tetrahydroquinoline core is an omni-
present and important structural subunit of natural products
and synthetic compounds that display a vast range of relevant
biological activities (Figure 1).[13]
In stark contrast to the formation of cyclopropane rings,
the direct functionalization of an existing cyclopropyl unit is
largely underdeveloped. Mainly, such functionalization has
been limited to metalations with stoichiometric amounts of
strong bases, such as organo–magnesium or organo–lithium
Figure 1. Tetrahydroquinoline-containing natural products and pharma-
ceuticals.
reagents.[6] Cyclopropane C H bonds display enhanced acid-
À
3
À
ity because of the orbital rehybridization that is imposed by
the geometry of the cyclopropane ring,[7] and an adequate
directing group is required in analogy to directed ortho
metalations of arenes.[8] Stoichiometric amounts of sparteine
as chiral modifier allowed an enantioselective deprotona-
tion.[9] Recently, Yu and co-workers reported a directed
palladium(II)-catalyzed process[10] that uses protected chiral
In this respect, a palladium(0)-catalyzed direct C(sp ) H
arylation of unbiased cyclopropanes 1 would give direct
access to the tetrahydroquinoline scaffold 3, which bears
a quaternary stereogenic center (Scheme 1). These intra-
3
À
molecular C(sp ) H functionalizations are strictly limited by
a) the ring size of the intermediary palladacycle (five- or six-
membered), and b) by substrates with a Thorpe–Ingold bias
that requires substrate branching.[14] In addition, asymmetric
À
amino acid derivatives as ligands for enantioselective C H
arylations of N-aryl cyclopropyl carboxamides.[10a]
À
Our interest to develop synthetic tools for asymmetric C
H functionalizations,[11] aiming to streamline the synthesis of
complex molecules, drew our attention to the tetrahydroqui-
[*] T. Saget, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis
EPFL SB ISIC LCSA, BCH 4305
1015 Lausanne (Switzerland)
E-mail: nicolai.cramer@epfl.ch
Homepage: http://isic.epfl.ch/lcsa
T. Saget
Laboratory of Organic Chemistry, ETH Zurich
Wolfgang-Pauli-Strasse 10, 8093 Zurich (Switzerland)
[**] This work was supported by the European Research Council under
the European Community’s Seventh Framework Program (FP7
2007–2013)/ERC Grant agreement no. 257891. We thank Dr. R.
Scopelliti for X-ray crystallographic analysis of compound 3e.
Scheme 1. Enantioselective synthesis of tetrahydroquinolines by palla-
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207959.
dium(0)-catalyzed C H functionalization. L=ligand, PG=protecting
group.
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Angew. Chem. Int. Ed. 2012, 51, 12842 –12845

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versions are often impeded by high reaction temperatures and
the use of a monodentate ligand imposed by the concerted
metalation–deprotonation (CMD) mechanism.[15] The pro-
cess we envisioned would require the enantioselective
formation of a rare seven-membered palladacycle[16] of an
unbranched substrate (2), thus significantly expanding the
boundaries of the current methodology. Among the very few
reported catalytic asymmetric processes, all examples are
limited to six-membered palladacyclic intermediates.[17]
however, the enantioselectivity is modest (Table 1, entry 2).
In contrast, SagePhos (L2), a ligand we previously introduced
À
for related C H functionalizations of aryl triflates leading to
indolines,[17c] showed a very low reactivity with aryl bromides
(Table 1, entry 3). We then turned our attention toward less-
electron-rich phosphoramidites. While binol-based ligand L3
did not promote the reaction at all (Table 1, entry 4), taddol-
derived ligand L4 gave excellent reactivity and selectivity,
providing 3a in 88% yield and e.r. = 94.5:5.5 (Table 1,
entry 5). A careful choice of aromatic substituents on the
taddol backbone is critical for reactivity and selectivity.[19]
Whereas the reactivity was very low with simple phenyl
groups (L5; Table 1, entry 6), bulky 3,5-di-tert-butylphenyl
groups (L6) are detrimental to the enantioselectivity
(entry 7). In conjunction with a dimethylamino group, the
3,5-xylyl backbone (L8) gave 3a almost quantitatively with
e.r. = 96:4 (Table 1, entry 9). As we have previously demon-
strated,[17c] the carboxylic acid co-catalyst plays a critical role
on the enantioselectivity of the activation by relaying the
chiral information of the phosphine ligand during the
selectivity-determining CMD step. Without acid additive,
the reaction proceeds sluggishly and with reduced selectivity
(Table 1, entry 11). Contrasting our previous findings with
aryl triflate substrates, bulky acids that bear aromatic groups
are not as efficient, leading to incomplete conversions with
2 mol% of palladium catalyst (Table 1, entries 12–15),
whereas aliphatic acids give rise to excellent yields (entries 16
and 17). Among them, pivalic acid displays the best enantio-
selectivity. Without affecting the reaction outcome negatively,
the catalyst loading could be reduced to 1 mol% (Table 1,
entry 18). Notably, such a low catalyst loading is quite
The general feasibility of our hypothesis for the cyclo-
3
À
propane C(sp ) H bond functionalization was proven using
aryl bromide 1a and tricyclohexylphosphine as achiral ligand
(Table 1, entry 1). The desired tetrahydroquinoline 3a was
obtained in excellent yield at 1308C. For the development of
an efficient asymmetric version, we first investigated related
chiral and electron-rich monodentate phosphines. P-Alkyl
phospholane L1[18] worked well with 2 mol% catalyst loading,
[a]
À
Table 1: Optimization of the enantioselective C H arylation of 3a.
À
uncommon in the field of C H functionalization and dem-
onstrates the efficiency of our catalytic system.
To explore the generality of the optimized process, we
evaluated different substitution patterns on the cyclopropane
ring. Several aliphatic and functional groups are tolerated
(Table 2, entries 1–3). The yields and selectivities are consis-
Entry Carboxylic acid
L
Yield [%][b]
e.r.[c]
[d,e]
1
2
3
4
5
6
7
8
pivalic acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
no acid
PCy3
L1[e]
L2
L3
L4
L5
L6
L7
L8
95
95
–
tently excellent. A phenyl and a benzyl group do not react in
35.5:64.5
–
–
94.5:5.5
–
62:38
94.5:4.5
96:4
2
À
a competing C(sp ) H activation (Table 2, entries 4 and 5).
<5[f]
<5[f]
88
With the unsubstituted cyclopropane 1g, exclusively methine
À
C H activation occurs and gives rise to spirocycle 4 (Table 2,
<5[f]
91
entry 6). The better accessibility of the six-membered palla-
dacycle clearly overrides the preference for the less-substi-
97
98
À
tuted C Pd bond. In contrast, silyl-substituted cyclopropane
9
1h cleanly gives 3h, offering further opportunities for
functionalization (Table 2, entry 7). The aromatic portion of
the substrates tolerates the most common electron-donating
and electron-withdrawing groups (Table 2, entry 7–14). Both
meta and para substitution with respect to the bromine atom
have little influence on the reaction efficiency. Notably,
tetrasubstituted substrate 1p with a fluorine atom in ortho
position to the nitrogen atom that disturbs the proper
orientation of the cyclopropyl moiety most, is also tolerated
(Table 2, entry 15). However, a somewhat lower enantiose-
lectivity is observed for 3p.
10
11
12
13
14
15
16
17
18
L9
L8
86[f]
58[f]
59[f]
75[f]
62[f]
38[f]
92
95:5
82:18
84.5:15.5
84:16
88.5:11.5
90:10
91.5:8.5
95:5
9H-xanthene-9-carboxylic acid L8
triphenylacetic acid
L8
L8
L8
L8
2,2-diphenylpropanoic acid
anthracene-9-carboxylic acid
cyclohexylcarboxylic acid
adamantylcarboxylic acid
pivalic acid
L8
94
95
L8[g]
96:4
[a] Reaction conditions: 1a (0.10 mmol), carboxylic acid (30.0 mmol),
[Pd(dba)2] (2.00 mmol), L (3.00 mmol), Cs2CO3 (1.5 equiv), 0.30m in p-
xylene at 1308C for 12 h. [b] Yields of isolated products. [c] Determined
by GC on a chiral stationary phase. [d] With Pd(OAc)2 (5 mol%) and PCy3
(10 mol%). [e] Used as HBF4 salt. [f] Incomplete conversion. [g] With
[Pd(dba)2] (1 mol%). Cy=cyclohexyl, dba=trans,trans-dibenzylidenea-
cetone.
To showcase the practicality of the process, we carried out
a gram-scale reaction using substrate 1e and a catalyst loading
of 1 mol% palladium (Scheme 2). The desired product 3e was
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Angewandte
Communications
isolated in slightly higher yield of 93% and with the same
selectivity (e.r. = 97:3).[20]
Table 2: Scope of the enantioselective tetrahydroquinoline synthesis.[a]
Scheme 2. Gram-scale synthesis of tetrahydroquinoline 3e.
To prove the utility of our methodology, the triflyl group
was removed under reductive conditions with Red-Al,
affording the corresponding free aniline 5 virtually quantita-
tively (Scheme 3). Furthermore, the cyclopropyl moiety is
Entry
Aryl bromide 1
Product 3
Yield
[%][b]
e.r.[c]
1
2
91
90
96:4
97:3
3
4
5
6
7
90
89
99
95
80
95.5:4.5
97:3
96:4
–
Scheme 3. Modifications of the tetrahydroquinoline scaffold by depro-
tection and regioselective enantiospecific cyclopropane cleavage. Red-
Al=sodium bis(2-methoxyethoxy)aluminum hydride.
96:4
amenable to modifications. For instance, treatment of 3e with
H2 and 10% Pd/C in ethyl acetate selectively reduces the
À
highest-substituted C C bond of the cyclopropane to give the
8
93
91
94
95
93
96:4
92:8
ring-enlarged highly valuable benzazepine scaffold[21]
(Scheme 3). Most notably, this reaction is completely stereo-
specific and the corresponding tetrahydrobenzoazepine 6 is
obtained with an almost unchanged e.r. = 96.5:3.5.
9
In summary, we reported an enantioselective palla-
dium(0)-catalyzed direct arylation of unbranched cyclopro-
pylmethyl anilines, giving an efficient access to the valuable
tetrahydroquinoline scaffold with excellent selectivities. The
enantioselective CMD step occurs via a rare seven-membered
palladacycle. We showed that the cooperative effect between
the chiral phosphine ligand and the carboxylate base is a great
handle to tune the selectivity. The reaction proceeds with
catalyst loadings as low as 1 mol% and is well suited for gram-
scale reactions. In addition, enantiospecific reduction of the
cyclopropyl group provides a convenient access to the highly
valuable chiral tetrahydrobenzoazepines.
10
11
12
94.5:5.5
92:8
95.5:4.5
13
90
96:4
Received: October 2, 2012
Published online: November 19, 2012
14
15
86
89
95:5
93:7
À
Keywords: asymmetric catalysis · C H activation ·
.
cyclopropanes · palladium · tetrahydroquinolines
[a] Reaction conditions: 1 (0.10 mmol), [Pd(dba)2] (2.00 mmol), L8
(3.00 mmol), PivOH (30.0 mmol), Cs2CO3 (1.5 equiv), 0.30m in p-xylene
at 1308C for 12 h. [b] Yields of isolated products. [c] Determined by
HPLC or GC on a chiral stationary phase. Bn=benzyl, Piv=pivaloyl,
Tf =trifluoromethanesulfonyl.
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3
À
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