Palladium-catalyzed stereoretentive olefination of unactivated C(sp3)-H bonds with vinyl iodides at room temperature: Synthesis of β-vinyl α-amino acids

Article abstract of DOI:10.1021/ol503248f

A method is reported for palladium-catalyzed N-quinolyl carboxamide-directed olefination of the unactivated C(sp³)-H bonds of phthaloyl alanine with a broad range of vinyl iodides at room temperature. This reaction represents the first example of the stereoretentive installation of multisubstituted terminal and internal olefins onto unactivated C(sp³)-H bonds. These methods enable access to a wide range of challenging β-vinyl α-amino acid products in a streamlined and controllable fashion, beginning from simple precursors.

Full text of DOI:10.1021/ol503248f

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Stereoretentive Olefination of Unactivated
C(sp3)−H Bonds with Vinyl Iodides at Room Temperature: Synthesis
of β‑Vinyl α‑Amino Acids
Bo Wang, Chengxi Lu, Shu-Yu Zhang, Gang He, William A. Nack, and Gong Chen*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
ABSTRACT: A method is reported for palladium-catalyzed
N-quinolyl carboxamide-directed olefination of the unactivated
C(sp3)−H bonds of phthaloyl alanine with a broad range of
vinyl iodides at room temperature. This reaction represents the
first example of the stereoretentive installation of multi-
substituted terminal and internal olefins onto unactivated
C(sp3)−H bonds. These methods enable access to a wide
range of challenging β-vinyl α-amino acid products in a
streamlined and controllable fashion, beginning from simple
precursors.
Scheme 1. Pd-Catalyzed Olefination of Unactivated C(sp3)−
ver the past decade, metal-catalyzed C−H functionaliza-
H Bonds of Alkyl Carboxamides
O
tion has emerged as a powerful strategy for the formation
of C−C bonds in organic synthesis.1 In contrast to C−H
arylation2 methods, methods for the functionalization of C−H
bonds with nonaromatic coupling partners have been less
developed.3 In particular, the development of olefination
reactions of unactivated C(sp3)−H bonds, providing multi-
substituted olefins, has lagged far behind.4−12 Compared with
aryl and alkyl groups, vinyl groups can readily undergo further
transformations, providing unique flexibility and versatility in
synthesis planning. However, unlike C−H arylation and
alkylation reactions, the inherent reactivity and metal-binding
properties of the olefin products can interfere with and even
inhibit metal-catalyzed C−H functionalization processes.5 In
2010, Yu reported Pd-catalyzed fluoroarylcarboxamide-directed
functionalization of primary C(sp3)−H bonds with terminal
olefins bearing electron withdrawing substituents (e.g.,
acrylates) (Scheme 1A).6,7 However, the expected trans C−H
olefination products (e.g., 3) cannot be isolated, as they
immediately undergo intramolecular Michael addition to give
diastereomeric N-aryl substituted γ-lactams in this reaction
system. Unlike olefinated products, the resulting saturated
lactams should not interfere with the reaction. Complementary
to Yu’s approach using terminal olefins under oxidative
conditions, C−H olefination can also be achieved with vinyl
halide reagents in the absence of external oxidants, analogous to
the use of aryl halides in many metal-catalyzed C−H
arylations.9,10 Sporadic examples from Baran and our own
laboratory have demonstrated the feasibility of such a Pd-
catalyzed C(sp3)−H olefination, albeit with limited scope.11
Herein, we report an efficient method for the palladium-
catalyzed N-quinolyl carboxamide-directed olefination of the β-
C(sp3)−H bonds of alanine with vinyl iodides at room
temperature. For the first time, the stereoretentive installation
of multisubstituted olefin precursors in either a cis or trans
configuration onto unactivated C(sp3)−H bonds has been
achieved. This method enables the synthesis of a wide range of
challenging β-vinyl α-amino acid products from simple
precursors in a streamlined and controllable fashion.
Our research in C−H functionalization chemistry stems from
an interest in synthetic and biological studies of peptide
compounds. Building upon earlier work by Daugulis13 and
Received: November 8, 2014
Published: November 20, 2014
© 2014 American Chemical Society
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Letter
Corey,14 we have developed methods to prepare complex β-
and γ-substituted α-amino acids (AAs) through carboxamide-
directed Pd-catalyzed C−H arylation, alkylation, amidation, and
alkoxylation of simple α-AA precursors.15−17 To further expand
this synthetic strategy, we proceeded to investigate C−H
olefination to provide α-AAs bearing various vinyl side groups,
which are valuable and difficult-to-access building blocks for
natural product and complex molecule synthesis.18,19
We commenced our study with the reaction of aminoquino-
line (AQ) carboxamide-coupled phthaloyl alanine substrate 4
with methyl trans-3-iodoacrylate 5 (2 equiv) under the catalysis
of Pd(OAc)2 (eq 1, Table 1).9 Reaction of 4 under our
Under the room temperature conditions A with AgOAc/
TFA in dioxane (entry 7, Table 1), we proceeded to evaluate
the scope of vinyl iodides amenable to β-C(sp3)−H olefination
of Ala 4 (Scheme 2).22 trans-3-Iodoacrylates bearing various
ester or amide appendants (e.g., 9, 11, and 23) gave the
corresponding trans olefin products in good to excellent yields
with exclusive trans-specificity. While less reactive than the trans
isomer 5, methyl cis-3-iodoacrylate 13 afforded cis-olefin 14 in
10% yield with exclusive cis-specificity. A 51% yield of 14 was
obtained at 65 °C under biphasic conditions C (AgTFA, TCE/
a
Scheme 2. Scope of Vinyl Iodides
Table 1. AQ-Directed β C(sp3)−H Olefination of Ala with 5
a
yield (%)
t (°C)/
entry
reagents (equiv)
AgOAc (3)
solvents
DCE
time (h)
6
7/8
1
2
100/24
100/24
<2
<2
<2
<2
KHCO3 (2),
DCE
oPBA (0.2)
b
3
4
5
6
AgTFA (2.5)
DCE
DCE
TCE
TCE
100/24
65/24
rt/24
∼5
∼5
48
∼5
24
<2
<2
AgTFA (2.5)
AgTFA (2.5)
AgTFA (2.5),
TFA (2)
rt/24
19
c
7
AgOAc (3),
TFA (2)
dioxane
THF
rt/24
rt/24
65/24
rt/24
rt/24
65/24
65/24
71(68)
62
<2
<2
28
<2
<2
<2
<2
8
AgOAc (3),
TFA (2)
9
AgOAc (3),
TFA (2)
dioxane/H2O
(9:1)
59
10
11
12
13
AgOAc (3),
AcOH (3)
dioxane
<2
AgTFA (2)
TCE/H2O
(1:1)
51
AgTFA (2)
TCE/H2O
(1:1)
80
d
AgTFA (2.5)
TCE/H2O
(1:1)
53
a
1
Yields are based on H NMR analysis on a 0.2 mmol scale, ambient
b
atmosphere. Complete consumption of 4; complex product mixture
formed. Isolated yield. 10 mol % of Pd(TFA)2 was used as catalyst.
c
d
previously developed conditions for the ortho- C(sp2)−H
olefination of benzylpicolinamides with vinyl iodides (ortho-
phenylbenzoic acid (oPBA) additive and KHCO3 base in 1,2-
dichloroethane (DCE) at 100 °C) gave little conversion (entry
2).10c Interestingly, use of silver trifluoroacetate (AgTFA)
considerably improved the conversion of Ala 4, but gave a very
complex mixture of products including γ-lactam Michael
cyclization products 7 and 8 (entry 3). To our delight, the
reaction of 4 at room temperature (rt) with AgTFA in 1,1,2,2-
tetrachloroethane (TCE) gave a much cleaner transformation,
forming only small amounts of cyclized side products (entry
5).20 The combination of 3 equiv of AgOAc and 2 equiv of
TFA in dioxane at rt gave further improved olefination results,
affording a 68% isolated yield of 6 with excellent retention of
chiral integrity at Cα (>98% ee, entry 7).21 Moisture and air are
well tolerated. A biphasic solvent system of TCE/H2O (1:1)
also gave good results (entries 11 and 12).
a
(a) Conditions A: 0.2 mmol scale, isolated yields, ambient
atmosphere. (b) Conditions B: AgTFA, TCE/H2O, rt, 24 h; see
entry 11 of Table 1. (c) Conditions C: same as B except at 65 °C; see
entry 12 of Table 1.
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Letter
H2O; see entry 12 of Table 1). Methyl 2-iodoacrylate 21 gave
terminal olefin 22 in good yield and with complete stereo-
retention under room temperature conditions A. More densely
substituted vinyl iodides, either cyclic or acyclic, e.g. 17, 19, 25,
29, and 33, gave tri- and even tetrasubstituted olefins with
complete stereoretention. It is worth noting that this level of
stereochemical control is not seen in Fujiwara-type oxidative
C−H olefination using terminal olefins, which forms the
thermodynamically favored trans olefin product.8 As exempli-
fied by 5, 13, and 21, the use of vinyl halide coupling partners
in this reaction system allows us to regio- and stereospecifically
construct complex olefins of any desired substitution pattern. In
general, vinyl iodides bearing moderately electron-withdrawing
substituents performed well under rt conditions A; vinyl
bromides, e.g. methyl trans-3-bromoacrylate 37, and electron-
rich vinyl iodides, e.g. 38, are considerably less reactive under
the rt conditions.23 For instance, while trans-3-iodoallyl
benzoate 27 gave product 28 in 75% yield, the corresponding
more electron-rich benzyl ether analogue 39 gave a much lower
yield (∼20%) at rt. C−H alkynylation of Ala 4 with TIPS-
protected acetylene bromide 35 proceeded smoothly under the
biphasic conditions B at rt to give product 36 in good yield.24
As shown in Scheme 3A, olefination product 6 can cleanly
undergo intramolecular Michael addition to form γ-lactam 7 in
excellent yield and diastereoselectivity (>15/1) upon treatment
with 1.2 equiv of 4-dimethylaminopyridine (DMAP) in MeOH
at rt for 4 h. Similarly, compound 30 cyclized following
treatment with DMAP, providing spirolactams 40 and 41 as
separable diastereomers in excellent yield and 1/5.5 diaster-
eoselectivity. Interestingly, a reversed diastereoselectivity (2.3/
1) was obtained following treatment of 30 with 1.2 equiv of 1,8-
diazabicycloundec-7-ene (DBU) at rt. The AQ group of the
olefinated or alkynylated products can be removed to give the
corresponding carboxylic acid under mild conditions using our
previously reported Boc activation and amide cleavage
procedure (Scheme 3B).15d
The olefination reaction of Ala 4 likely starts with AQ-
directed C−H palladation, forming a 5-membered palladacycle
intermediate (see 50, Scheme 4).25 A primary KIE (kH/D ∼3.5)
was observed for the rt C−H olefination of Ala 4 with vinyl
iodide 5.26
Scheme 4. KIE Experiments
Scheme 3. Further Transformations
In summary, we have developed a new set of synthetic
methods which provide β-olefinated α-amino acids via the
palladium-catalyzed olefination of the β C(sp3)−H bonds of
aminoquinoline-coupled phthaloyl alanine. For the first time, a
broad range of vinyl iodides bearing various substitution
patterns can be incorporated in a stereoretentive fashion under
mild conditions at room temperature. Notably, our protocol
allows the isolation of olefinated products, enabling further
useful transformations. A wide range of challenging β-olefinated
α-amino acid products can be prepared from simple precursors
in a streamlined and controllable fashion.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, X-ray crystallographic analysis, and
1H and 13C NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: guc11@psu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully thank the Pennsylvania State University, NSF
(CAREER CHE-1055795), and ACS-PRF (51705-DN11) for
financial support of this work.
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