Palladium-Catalyzed Enantioselective Narasaka–Heck Reaction/Direct C?H Alkylation of Arenes: Iminoarylation of Alkenes

Article abstract of DOI:10.1002/anie.201705641

A palladium-catalyzed reaction of γ,δ-unsaturated oxime esters with oxadiazoles afforded dihydropyrroles in good to excellent yields through an intramolecular iminopalladation/intermolecular direct heteroarene C?H alkylation cascade. This unprecedented iminoarylation of alkenes was subsequently realized in an enantioselective manner in the presence of a chiral bidentate phosphine ligand (Synphos).

Full text of DOI:10.1002/anie.201705641

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Accepted Article
Title: Palladium-Catalyzed Enantioselective Narasaka-Heck/Direct C-H
Alkylation of Arene: Iminoarylation of Alkene
Authors: Xu Bao, Qian Wang, and Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705641
Angew. Chem. 10.1002/ange.201705641
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Palladium-Catalyzed Enantioselective Narasaka-Heck/Direct C-H
Alkylation of Arene: Iminoarylation of Alkene**
Xu Bao, Qian Wang, Jieping Zhu*
Abstract: Palladium-catalyzed reaction of g,d-unsaturated
oxime esters with oxadiazoles afforded dihydropyrroles in
good to excellent yields via an intramolecular iminopalladation/
intermolecular direct heteroarene C-H alkylation cascade. This
unprecedented iminoarylation of alkene was subsequently realized
in an enantioselective manner in the presence of a chiral bidentate
phosphine ligand (Synphos).
potentially coordinate to Pd, modifying consequently the
asymmetric environment created by chiral ligand. We report
herein the first examples of domino Narasaka-Heck
iminopalladation/direct heteroarene C-H alkylation sequence
as well as its catalytic enantioselective variant for the synthesis
of functionalized dihydropyrroles (Scheme 1c).
Narasaka-Heck: Initial discovery
Pd(PPh3)4
Et3N
PdX
OCOC6F5
Ph
N
N
N
Narasaka and co-workers reported in 1999 a palladium-
catalyzed cyclization of g,d-unsaturated oxime esters for the
synthesis of pyrroles (Scheme 1a).[1] The reaction was initiated
by oxidative addition of acyloxime to Pd(0) leading to
iminopalladium(II) complex which then underwent an
intramolecular iminopalladation with the tethered double bond.
In this process, nitrogen atom acted in the initiation step as an
electrophilic centre in sharp contrast to most of the other
palladium-catalyzed amination reactions wherein the nitrogen
(a)
(b)
Me
Ar
Ar
DMF, 80 °C
Bower and co-workers: Enantioselective Narasaka-Heck reaction
Pd2(dba)3, L*
OCOC6F5
Ar
Et3N, DMF, 120 °C
Me
N
N
Ar
CH2R
R
O
N
e.e. 80-90%
L * =
Ph
PAr2
Ar = 3,5-Me2C6H3
atom acted as a nucleophile.[2] Since this pioneer report,
[3]
various N-heterocycles including pyridine,
imidazole,[5] aziridine,[6] indole,[7]
azaazulene,[4]
This work: Racemic and enantioselective domino Narasaka-Heck/direct arene
C-H alkylation
phenanthridine,[8]
isoquinoline,[8,9] dihydropyrrole, [10,11] have been synthesized by
combining the iminopalladation process with Heck, Suzuki-
Miyuara, intramolecular C-H arylation and chlorination
reactions. Extensive investigation of Bower and coworkers
demonstrated that, by tuning the nature of the ligand and the
substrate structure, it was possible to generate
dihydropyrroles/perhydroindoles with concurrent generation of
a secondary or a tertiary stereogenic center.[11] This is of
significant importance in view of the wide spread presence of
chiral nitrogen containing heterocycles in natural products and
drugs.[12] Very recently, Bower has developed the first efficient
catalytic asymmetric Narasaka-Heck reaction leading to 2,5,5-
R
OCOC6F5
Pd(OAc)2, L*
O
R1
N
N
Ar
(c)
+
N
N
base, solvent
temp
N
N
Ar
O
R1
R
1
2
3
Scheme 1. Evolution of Narasaka-Heck reaction: from heteroarenes to
chiral heterocycles.
Pd(OAc)2 (0.1 equiv)
XPhos (0.4 equiv)
OCOC6F5
Ph
O
Me
N
Ph
N
(a)
(b)
+
Me
N
N
K2CO3, toluene, 100 °C
Ph
1a
2a
4 47%
Me
trisubstituted
dihydropyrrole
in
good
to
excellent
Ph
Pd(OAc)2 (0.1 equiv)
XPhos (0.4 equiv)
Me Me
N
enantioselectivities (Scheme 1b).[ 11b,13]
1a
2a
Me
Me
Me
+
Me
N
O
N
K2CO3, toluene
100 °C
Our group has been interested in developing domino
process initiated by carbopalladation reaction.[14] While
enantioselective Heck reaction has been well documented
over the years,[15] the development of enantioselective
carbopalladation/nucleophilic trapping of the transient C(sp3)-
Pd species is known to be challenging.[16-19] Indeed, the
presence of nucleophilic species, whether neutral or ionic, can
O
5
6 60%
Me Me
Scheme 2. Narasaka-Heck cyclization: a competitive radical pathway.
We began by investigating the reaction of 4-methyl-1-
phenylpent-4-en-1-one O-(pentafluorobenzoyl ester) oxime
(1a) with 2-phenyl-1,3,4-oxadiazole (2a). The projected
domino reaction involved a sequence of oxidative addition of
oxime ester to Pd(0), intramolecular iminopalladation and
direct heteroarene C-H alkylation with the transient s-C(sp3)-
Pd complex. The results of the initial experiments were
disappointing. For example, performing the reaction of 1a and
2a in the presence of Pd(OAc)2 and XPhos in toluene afforded
2,2-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrole (4) in 47% yield
(Scheme 2a). When the same reaction was carried out in the
presence of TEMPO (5), the radical trapping product 6 was
isolated in 60% yield (Scheme 2b). These results clearly
indicated that the radical mechanism could be operating under
this Pd-catalyzed reaction.11f Fortunately, it was found that
[*]
Dr. X. Bao, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
[**] Financial supports from EPFL (Switzerland), the Swiss National
Science Foundation (SNSF) are gratefully acknowledged. We thank
Dr. Rosario Scopelliti for performing X-ray structural analysis of
compound 3ag.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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solvent can effectively divert the reaction mechanism.
Performing the reaction of 1a and 2a in DMF under otherwise
identical conditions afforded the coupling product 3aa in 30%
yield together with the hydrolysis product 4-methyl-1-
phenylpent-4-en-1-one. Systematic survey of reaction
parameters varying the nature of ligands, the solvents, the
bases and the additives allowed us to identify following
optimum conditions: Pd(OAc)2 (0.1 equiv), (±)-BINAP (0.2
equiv), iPr2NEt (4.0 equiv), Cs2CO3 (3.0 equiv), DMSO, 120 °C
(See Supporting Information for detailed survey of reaction
conditions). Under these conditions, reaction of 1a and 2a
afforded compound 3aa in 90% isolated yield (Scheme 3).
carbopalladation/CH-functionalization,[18] inhibited completely
the occurrence of the desired process; b) Among the various
chiral ligands screened, biaryl-based bidentate phosphine
ligands such as BINAP, Segphos and Synphos provided good
enantioselectivities, with (S)-Synphos[21] being the best in
terms of both yield and e.r. of the product (Figure 1, see
Supporting Information for complete list of ligands screened).
To exploit the steric and electronic effects on the reaction
efficiency, Synphos analogues (L7 and L8) and (S)-
Solphos,[22]
an aza analogue of (S)-Synphos, were
synthesized. However, none of them provided product 3aa
with better e.r. than the Synphos itself. The reaction using tBu-
PHOX[23] as a supporting ligand afforded only a trace amount
of desired product; c) DMSO was the solvent of choice among
those screened (DMF, MeCN). Overall, under optimized
conditions [1a (0.2 mmol), 2a (0.1 mmol), Pd(OAc)2 (0.1
equiv), (S)-Synphos (0.2 equiv), K2CO3 (3.0 equiv), DMSO,
100 °C], reaction of 1a and 2a afforded 3aa in 90% yield with
an e.r. of 92:8.
OCOC6F5
R
Standard conditions[a]
N
N
N
N
+
N
N
Ar
Ar
R1
O
O
R
R1
3
2
1
N
N
Ar
N
N
N
N
O
R1
O
Ph
3aa Ar = Ph, 90%
O
3ab R1 = 4-Ph-C6H4, 67%
O
3ba Ar = 2-Me-C6H4, 86%
3ca Ar = 3-Me-C6H4, 92%
3da Ar = 4-Me-C6H4, 89%
3ea Ar = 3,4-Me2-C6H3, 73%
3fa Ar = 4-MeO-C6H4, 81%
3ga Ar = 4-Cl-C6H4, 84%
3ha Ar = 4-CF3O-C6H4, 69%
3ia Ar = 4-F-C6H4, 46%
3ja Ar = 2-Naphthyl, 80%
R
3ac R1 = 4-CF3O-C6H4, 71%
3ad R1 = 4-Me-C6H4, 81%
3ae R1 = 4-tBu-C6H4, 69%
3af R1 = 3-MeO-C6H4, 73%
3ag R1= 2-Naphthyl, 58%
3ah R1 = nBu, 42%
O
PAr2
PAr2
PPh2
PPh2
O
O
PPh2
PPh2
PPh2
PPh2
O
O
O
L4 Ar = 3,5-Me2C6H3
23%, e.r. 86.5:13.5[a]
L1 (R)-BINAP
36%, e.r. 17.5:82.5[a]
L3 (S)-SEGPHOS
26%, 78.5: 21.5[a]
O
L2 trace, e.r. n.d.
Me
N
O
3ka R = Et, 79%
N
O
O
PAr2
PAr2
3la R = nPr, 74%
3ma R = nBu, 70%
3na R = CH2OBn, 46%
N
N
O
O
PPh2
PPh2
O
O
PPh2
PPh2
O
O
PPh2
PPh2
O
Ph
O
O
N
Me
L7 Ar = 3,5-Me2C6H3
L6 (S)-Synphos 40%, e.r. 85:15[b]
Scheme 3. Substrate scope. [a] Standard conditions: 1a (0.2 mmol), 2a
(0.10 mmol), Pd(OAc)2 (0.1 equiv), (±)-BINAP (0.2 equiv), Cs2CO3 (0.3
mmol), iPr2NEt (0.4 mmol), DMSO (1.0 mL), 120 °C, 8 h.
L5 (R)-C3-Tunephos
17%, e.r. 14.5:85.5[a]
51%, e.r. 90:10[a]
90%, e.r. 92:8[b]
L9 (S)-Solphos
32%, e.r. 88.5:11.5[b]
L8 Ar = 3,5-(CF3)2C6H3
trace, e.r. n.d
Figure 1. Chiral biphosphine ligands screened for the enantioselective
synthesis of 3aa. [a] Standard conditions: 1a (0.1 mmol), 2a (0.12 mmol),
Pd(OAc)2 (0.025 equiv), Ligand (0.05 equiv), K2CO3 (0.2 mmol), DMF (1.0
mL), 100 °C, 8 h; [b] 1a (0.2 mmol), 2a (0.1 mmol), Pd(OAc)2 (0.1 equiv),
Ligand (0.2 equiv), K2CO3 (0.3 mmol), DMSO (1.0 mL), 100 °C, 8 h.
This novel iminopalladation/direct heteroarene C-H
alkylation protocol was applicable to a large set of substrates.
As shown in Scheme 3, substituents regardless of their
electronic nature and positions on the aryl group (Ar) of the
oxime ester were well tolerated (3aa-3ja). The same was true
for the C2 substituents of the oxadiazole (3ab-3ag) although
the 2-butyl oxadiazole afforded the coupling product 3ah in
diminished yield. Of note, the aryl chloride was stable under
our reaction conditions and chlorinated product 3ga was
isolated in excellent yield. Alkyl groups (Me, Et, nPr, nBu)
including functionalized one (CH2OBn) attached to the double
bond were well tolerated (3ka-3na, Scheme 3).
The scope of this enantioselective domino process was
next investigated (Scheme 4). In general, the conditions were
applicable to oxime esters having different aryl and alkyl
substituents (Ar and R groups in 1). Oxadiazoles with diverse
substituents at C2 were also tolerated. In most cases, the
2,5,5-trisubstituted dihydropyrroles 3 were isolated in good
yields with good to high enantioselectivities. The (S)-absolute
configuration of 3ag was determined by X-ray crystallographic
analysis.[24] Consequently, that of the other dihydropyrroles
was assigned accordingly. Unfortunately, other heterocycles
such as benzoxazole and benzothiazole failed to participate in
this reaction.[25]
We next turned our attention to the enantioselective
version of the Narasak-Heck/direct cross-coupling process.[20]
Using (R)-BINAP under otherwise standard conditions,
reaction of 1a and 2a afforded indeed 3aa in 57% yield with an
encouraging e.r. of 82.5:17.5. Conditions were therefore
further optimized by varying the Pd sources, ligands, bases
and solvents (cf Supporting Information for details) and
following observations were made: a) Potassium carbonate
and cesium carbonate were the bases of choice and the
former was used for the subsequent studies. Tertiary amine
bases (Et3N, iPr2NEt, Et2NPh, DBU, DABCO, MTBD) alone or
in combination with K2CO3 reduced the reaction efficiency.
Tetramethylguanidine (TMG), the base of significant
A possible reaction pathway is depicted in Scheme 5.
Oxidative addition of oxime ester to Pd(0) would afford
intermediate A that would most probably exist as a cationic
species as demonstrated previously by Bower and co-
workers.[11] Coordination of the electrophilic cation Pd(II)
complex to the tethered double bond followed by
intramolecular
syn-iminopalladation
would
afford
dihydropyrrole with concurrent generation of the chiral
quaternary stereocenter and the s-C(sp3)-Pd(II) species. In
importance
in
our
previous
enantioselective
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parallel, deprotonation of oxadiazole's C5-H with Cs2CO3 or
K2CO3 would generate the oxadiazole anion, which, upon
transmetallation with B, would afford C. Reductive elimination
from the latter would then furnish the observed product 3. In
line with the classic enantioselective Heck reaction, we
assumed that the cationic Pd(II) intermediate A is of utmost
importance to the desired asymmetric induction. Since this
species has a free coordination site available for the alkene,
the bidentate ligand can therefore remain chelated to Pd
creating therefore the chiral environment needed for the
efficient chirality transfer.[15]
the absence of good hydrogen donor, the radical E could
recombine with the Pd(I) species to generate the Pd(II)
complex F which could then alkylate the oxadiazole leading to
the racemic product
3
(Scheme 6a).[26]
To probe this
mechanistic possibility, the reaction of 1a and 2a was
performed in the presence of TEMPO under otherwise
identical conditions. As it is seen (Scheme 6b), the reaction
afforded indeed the radical trapping product 6 (7% yield)
together with compound 3aa in 53% yield with an e.r. of 65/35.
Since the presence of TEMPO could potentially provoke the
radical process,[27] the diminished enantioselectivity is
therefore understandable. Although the formation of 6 was not
a definitive evidence to support the radical mechanism in its
absence, the fact that 3aa was still produced was highly
indicative of the occurrence of the mechanism depicted in
Scheme 6a and that the radical recombination of E with Pd(I)X
was kinetically competitive with the TEMPO trapping process.
On the other hand, treatment of 7 under standard conditions,
afforded 8 in 36% yield, providing further evidence of the
radical mechanism (Scheme 6c). The concurrent occurrence
of the radical pathway would obviously render the
development of highly enantioseletive Narasaka-Heck type
reaction extremely difficult.
OCOC6F5
R
Standard conditions[a]
N
N
N
+
N
N
N
Ar
Ar
R1
O
R
O
R1
3
2
1
(S)-3aa Ar = Ph, 90%, 91.9:8.1 e.r.
(S)-3ca Ar = 3-Me-C6H4, 87%, 86.8:13.2 e.r.
(S)-3da Ar = 4-Me-C6H4, 82%, 90.4:9.6 e.r.
Me
(S)-3ea Ar = 3,4-Me-C6H3, 61%, 88.1:11.9 e.r.
(S)-3fa Ar = 4-MeO-C6H4, 50%, 89.9:10.1 e.r.
(S)-3ga Ar = 4-Cl-C6H4, 62%, 88.9:11.1 e.r.
(S)-3ha Ar = 4-CF3O-C6H4, 58%, 88.7:11.3 e.r.
(S)-3ja Ar = 2-Naphthyl, 67%, 86.8:13.2 e.r.
N
N
N
Ar
O
Ph
(S)-3ac R1 = 4-CF3O-C6H4, 56%, 89.0:11.0 e.r.
(S)-3ad R1 = 4-Me-C6H4, 62%, 88.8:11.2 e.r.
(S)-3ae R1 = 4-tBu-C6H4, 49%, 87.7:12.3 e.r.
(S)-3af R1 = 3-MeO-Ph, 53%, 89.4:10.6 e.r.
(S)-3ai R1 = 4-Cl-C6H4, 53%, 90.6:9.4 e.r.
Me
N
N
N
O
R1
Pd(0)
OCOC6F5
N
R
Ar
R
N
R
N
N
(S)-3la R = nPr, 61%, 87:13 e.r.
(S)-3ma R = nBu, 58%, 86.2:13.8 e.r.
(S)-3na R = CH2OBn, 41%, 87.5:12.5 e.r.
CH2
Ar
Pd(I)OCOC6F5
N
Ar
N
R
R
1
D
E
O
Ph
Ar
N
Ar
(a)
2
R
N
N
O
N
N
Pd(II)OCOC6F5
N
Ph
O
N
F
3 racemic
OCOC6F5
Ph
N
N
N
Me
N
Me Me
Standard
conditions[a]
(S)-3ag 54%, 88.5:11.5 e.r.
N
Ph
Ph
O
N
N
(b)
(c)
1a
+
Me
TEMPO
Scheme 4. Scope of the enantioselective iminopalladation/direct C-H
functionalization. [a] 1a (0.2 mmol), 2a (0.1 mmol), Pd(OAc)2 (0.1 equiv),
(S)-Synphos (0.2 equiv), K2CO3 (0.3 mmol), DMSO (1.0 mL), 100 °C, 8 h;
yield referred to isolated product; e.r. was determined by SFC on chiral
O
O
Ph
3aa 53%, e.r. 65/35
Me Me
Ph
6 7%
N
2a
OCOC6F5
Standard
conditions[a]
Ar
stationary
phase.
Abbrev.
Synphos
=
[(5,6),(5′,6′)-
Me
Me
N
N
bis(ethylenedioxy)biphenyl-2,2′ diyl]bis(diphenylphosphine).
Ph
N
O
Me
Me
TEMPO
Me
7
8 36%
Scheme 6. Possible competitive radical mechanism and results of control
experiments. [a] 1a (0.2 mmol), 2a (0.1 mmol), TEMPO (0.2 mmol),
Pd(OAc)2 (0.1 equiv), (S)-Synphos (0.2 equiv), K2CO3 (0.3 mmol), DMSO
(1.0 mL), 100 °C, 8 h.
R
OCOC6F5
N
Pd(0)L*
N
Ar
N
N
Ar
O
1
R
R1
3
R
R1
N
Pd(II)L*X
N
N
N
Ar
O
Ar
In summary, we have developed the first examples of
palladium-catalyzed Narasaka-Heck iminopalladation/direct
arene C-H alkylation cascade. The domino process produced
2,5,5-trisubstituted dihydropyrroles via formation of one N(sp2)-
C(sp3) bond and one C(sp3)-C(sp2) bond. One quaternary
stereocenter was generated in this process and an
enantioselective variant was developed leading to the
dihydropyrroles in good yields with good to high
Pd(II)L*
A
C
R
CsX
+
CsHCO
3
R
N
N
N
Ar
Cs2CO3
+
R1
Pd(II)L*X
O
B
2
Scheme 5. Possible reaction pathway.
enantioselectivities.
The
observed
solvent-dependant
mechanistic dichotomous (SET vs two electron process) and
possible concurrent occurrence of these two mechanisms in a
given set of conditions is unique in Pd-catalyzed
transformations which shed light on the difficulties associated
with the development of enantioselective Narasaka-Heck
reaction.
The development of enantioselective Narasaka-Heck type
reactions is known to be highly challenging due to the
mechanistic complexity. Indeed, if the reaction were initiated
by cyclization of the iminyl radical D to the pendant double
bond, then the intermediate E generated would be racemic. In
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