Irradiation-Induced Palladium-Catalyzed Decarboxylative Heck Reaction of Aliphatic N-(Acyloxy)phthalimides at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.8b00023

It is reported that Pd(PPh₃)₂Cl₂ in combination with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) under irradiation of blue LEDs efficiently catalyzes a decarboxylative Heck reaction of vinyl arenes and vinyl heteroarenes with aliphatic N-(acyloxy)phthalimides at room temperature. A broad scope of secondary, tertiary, and quaternary carboxylates, including α-amino acid derived esters, can be applied as amenable substrates with high stereoselectivity. The experimental observation was explained by excitation-state reactivity of the palladium complex under irradiation to induce single-electron transfer to activate N-(acyloxy)phthalimides, and to suppress undesired β-hydride elimination of alkyl palladium intermediates.

Full text of DOI:10.1021/acs.orglett.8b00023

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Irradiation-Induced Palladium-Catalyzed Decarboxylative Heck
Reaction of Aliphatic N‑(Acyloxy)phthalimides at Room Temperature
Guang-Zu Wang,† Rui Shang,*,†,‡ and Yao Fu*,†
†Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Urban Pollutant Conversion, Anhui
Province Key Laboratory of Biomass Clean Energy, iChEM, Department of Chemistry, University of Science and Technology of
China, Hefei 230026, China
‡Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: It is reported that Pd(PPh3)2Cl2 in combination
with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xant-
phos) under irradiation of blue LEDs efficiently catalyzes a
decarboxylative Heck reaction of vinyl arenes and vinyl
heteroarenes with aliphatic N-(acyloxy)phthalimides at room
temperature. A broad scope of secondary, tertiary, and
quaternary carboxylates, including α-amino acid derived esters,
can be applied as amenable substrates with high stereoselectivity. The experimental observation was explained by excitation-state
reactivity of the palladium complex under irradiation to induce single-electron transfer to activate N-(acyloxy)phthalimides, and
to suppress undesired β-hydride elimination of alkyl palladium intermediates.
the stabilization of alkyl palladium species4 is incompatible with
he use of carboxylic acids as a coupling partner in cross-
the harsh condition required for decarboxylation (Figure 1b).5
Tcoupling reactions continues to attract the interest of
The activation group strategy using N-hydroxyphthalimide ester
in decarboxylative cross-couplings6 reinvigorated interest in
using aliphatic carboxylic acid as an alkyl donor under mild
reactions, as demonstrated elegantly by Baran et al.,7 in Ni- or Fe-
catalyzed cross-couplings with various organometallic reagents8
and heteroatoms.9 However, decarboxylative coupling of
aliphatic N-(acyloxy)phthalimides with styrene to deliver the
Heck type product remains challenging because of the difficulty
in reconciling the activation of carboxylate with selective β-H
elimination. Nickel catalysts are much less effective in Heck
processes because of the reluctance of the system to undergo β-H
elimination10 and catalyst regeneration.11 To achieve a
decarboxylative Heck reaction between aliphatic N-(acyloxy)-
phthalimides and styrene, efficient activation of the carboxylate
and selective control of β-H elimination after decarboxylation
and insertion are considered two key factors. We recently
discovered that a Pd catalyst in combination with two types of
phosphine ligands under irradiation effectively catalyzes
Mizoroki−Heck reaction between a range of alkyl bromides
with styrenes at rt.12 Recent elegant work by Gevorgyan et al. also
demonstrated irradiation-induced Pd-catalyzed alkyl Heck
reaction of functionalized alkyl halides.13 The key enabler for
the success of these transformations was the effect of irradiation,
which excited the Pd catalyst14 to facilitate a single-electron-
transfer type of oxidative addition; furthermore, the irradiation-
induced excitation of the alkyl palladium complex formed after
synthetic chemists because of the abundant and environmentally
benign nature of these compounds.1 A decarboxylative
Mizoroki−Heck reaction to deliver olefin products using
aromatic carboxylic acids represents the archetypal example of
the synthetic utility of carboxylic acids in Pd-catalyzed cross-
couplings2 (Figure 1a). Although under development for years,
extending the general scope of the reaction to include aliphatic
carboxylic acids as alkyl donor in Heck-type reactions remains
challenging because of the lack of d−π interaction in the
transition state of redox-neutral decarboxylation3 and because
Figure 1. Challenge of using alkyl carboxylates in ground-state Pd-
catalyzed decarboxylative Heck reaction (a, b) and possible solution by
applying irradiation excited Pd catalysis (c).
Received: January 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00023
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Study of Controlling Parameters
Scheme 2. Substrate Scope with Respect to Vinyl
(Hetero)arenes
a
a
Yields of isolated products. The ratio of stereoisomers was
1
determined by H NMR analysis. The reactions were conducted in
front of a cooling fan in a room of constant temperature (t = 25
3
°C).
of both photoactivation and C−C bond formation proceeding
with a single metal catalyst.18
a
The optimized reaction conditions are shown in Scheme 1,
entry 1. The selectivity of this reaction is remarkable given that
alkyl Heck reactions deliver product as an E/Z mixture
accompanied by a double insertion byproduct.19 The key results
obtained by studying the parameters of this reaction are
summarized in Scheme 1 (see the Supporting Information for
details). Both PPh3 and Xantphos are essential for this reaction.
The reaction did not proceed when Pd(Xantphos)Cl2 was used
alone without PPh3. Various photoredox catalysts20 were
ineffective (entries 4−6), revealing that a simple radical redox
pathway is not feasible. The wavelength of the irradiation source
was crucial. White LEDs were less effective (entry 14). Green
LEDs of a lower energy (wavelength 520−525 nm) were
completely ineffective (entry 15). Purple LEDs (wavelength
395−405 nm) with higher irradiation energy than blue LEDs
(wavelength 450−455 nm) resulted in a lower yield (entry 16).
The use of high-energy UV light (254 nm) disturbed the desired
reaction, and none of the desired product was detected. Ligand
screening revealed the unique efficacy of Xantphos as a ligand
and suggested the ligand structure may be related to the
excitation of the Pd catalyst (Scheme 1b). The dual ligand system
may play an essential role to facilitate single-electron transfer
from a Pd catalyst to activate a redox active ester. Testing other
activation groups on the redox active ester revealed N-
hydroxyphthalimide to be uniquely effective (Scheme 1c). The
reaction did not continue after the irradiation source was
removed, showing that irradiation is not only for Pd(0)
generation.13 Aromatic N-(acyloxy)phthalimide was ineffective
under the established condition.
Styrene (0.2 mmol), aliphatic carboxylate (0.3 mmol), Pd(PPh3)2Cl2
(5 mol %), Xantphos (6 mol %), K2CO3 (120 mol %), H2O (100 mol
%) in DMA (2 mL), irradiation by 36 W blue LEDs at room
temperature for 24 h under an Ar atmosphere. Yield and ratio of
stereoisomers were determined by gas chromatography using biphenyl
as an internal standard.
oxidative addition suppressed undesired β-H elimination before
insertion.12
We envisioned that the irradiation-excited Pd complex may
also be suitable for activation of N-(acyloxy)phthalimide through
single-electron transfer because alkyl bromide (e.g., for n-BuBr,
E1/2 = −1.22 V vs SCE)15 and N-(acyloxy)phthalimide (E1/2
=
−1.26 to −1.37 V vs SCE) have similar redox potential,16 even
though the activation mode should be different (Figure 1c). In
this work, we discovered that, upon irradiation by blue LEDs,
commercially available Pd(PPh3)2Cl2 in combination with
Xantphos efficiently catalyzes a decarboxylative Heck reaction
between N-(acyloxy)phthalimide and a range of styrene
derivatives. The reaction enables the use of aliphatic carboxylates
as an alkyl source in Heck type reactions. The method also
demonstrates a new activation mode of N-(acyloxy)phthalimide
by using a photoexcited Pd catalyst, thereby offering new
opportunities to apply aliphatic N-(acyloxy)phthalimide in Pd-
catalyzed coupling reactions. Although it is known that redox
active esters can be activated by a low-valent transition-metal
catalyst (e.g., Ni or Fe)7,8 and photoredox catalyst,17 the Pd
catalytic system demonstrated herein represents a rare example
B
DOI: 10.1021/acs.orglett.8b00023
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope with Respect to Aliphatic
a
Carboxylates
Figure 3. Mechanistic studies: (a) A radical clock experiment; (b)
intermolecular kinetic isotope experiment; (c) UV−vis absorption
spectrum of reaction mixture using stoichiometric amount of Pd-
(PPh3)2Cl2 and Xantphos.
unlikely. Several unreactive substrates are also reported at the
bottom of Scheme 2.
We then established the substrate scope of the reaction
regarding aliphatic carboxylates (Scheme 3). Gratifyingly, a
variety of quaternary, tertiary, and secondary aliphatic carbox-
ylates could be used as tertiary, secondary, and primary alkyl
donors. Even for substrates delivering tertiary alkyl groups with
eliminable β-hydrogen, the reactions still proceeded in excellent
yield (17, 18, 21). The successful coupling of these tertiary alkyls
demonstrates that β-H elimination on the Pd center is
suppressed by the irradiation excitation.12 The stereoselectivity
of coupling with tertiary alkyl is excellent. For the products of
coupling with tertiary and secondary carboxylates, the stereo-
selectivity was slightly decreased, but remained high (E/Z = 92:8
in the lowest case). α-Amino acid and α-alkoxy acid-derived
redox esters were also suitable substrates, generating allylic amine
and allylic ether derivatives (25, 26, 27, 28). Notably, both
terminal aliphatic alkene (30) and aliphatic alkyne (32) were well
tolerated. When a chlorinated aliphatic carboxylate was used, the
alkyl chloride moiety remained intact after the reaction and could
be used for further cross-coupling (33).21
a
Yields of isolated products. The ratio of stereoisomers was
1
determined by H NMR analysis. The reactions were conducted in
front of a cooling fan in a room of constant temperature (t = 25
°C). Aliphatic carboxylates (0.4 mmol), time = 36 h.
3
b
Several competition reactions were conducted to gain
mechanistic information on this reaction. First, competition
among quaternary, tertiary, and secondary carboxylates revealed
that the carboxylate delivering a more stable alkyl radical reacts
faster, which is consistent with a radical decarboxylation
mechanism (Figure 2a). The competition experiment between
styrene and 1-octene showed the overwhelming selectivity of
styrene. We did not detect any side product of the 1-octene
trapping cyclohexyl radical (Figure 2b). This reactivity may be
associated with the alkyl-palladium species in its excited state as a
Pd-intercepted alkyl radical. The radical properties of the alkyl-
coupling partner are further evidenced by the results of radical
clock experiments (Figure 3a).22
Figure 2. Competition experiments. Standard conditions: Pd-
(PPh3)2Cl2 (5 mol %), Xantphos (6 mol %), K2CO3 (120 mol %) in
DMA (2 mL), after 36 h under an Ar atmosphere at room temperature.
GC yields using biphenyl as an internal standard.
The substrate scope with respect to an alkene coupling partner
is demonstrated in Scheme 2. A variety of vinyl arenes and vinyl
heteroarene (14) were amenable substrates. Both electron-rich
and -deficient styrenes reacted well, and a variety of functional
groups such as halide (4, 5, 6, 9, 12), amine (7), boronate (8),
acetal (11), ketone (16), and esters (16) could be well tolerated.
Besides vinyl arenes, 1-phenyl styrene was also an amenable
substrate (15). Notably, 1,2,3,4,5-pentafluoro-6-vinylbenzene
(12) and 2-vinylpyridine (14) were amenable substrates,
suggesting that the involvement of benzylic carbenium is
The results of intermolecular kinetic isotope effect (KIE)
experiments showed that β-H elimination is not the product-
determining step (Figure 3b). Similar to our recently reported
Heck reaction with alkyl bromide, we also observed a UV−vis
C
DOI: 10.1021/acs.orglett.8b00023
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.; Kim, S.; Ackerman,
L. K. G.; Weix, D. J. J. Am. Chem. Soc. 2016, 138, 5016. (c) Xue, W.;
Oestreich, M. Angew. Chem., Int. Ed. 2017, 56, 11649.
absorption onset of the mixture of stoichiometric reaction
around 450 nm (Figure 3c).12 The absorption is affected by the
absence of Xantphos, but not affected by the absence of
substrates. N-(Acyloxy)phthalimide itself has no absorption in
the wavelength range of blue LED irradiation. The UV−vis
absorption experiments show that the Pd intermediate is indeed
excited by photoirradiation of blue LEDs.23
In summary, we discovered a Pd catalyst that can be
photoexcited by irradiation with blue LEDs to enable the
decarboxylative alkyl Heck reaction of N-(acyloxy)phthalimide
with vinyl (hetero)arenes at rt. With this reaction in hand, a
broad scope of aliphatic carboxylic acids can now be used as alkyl
donors in alkyl Heck type reactions. We also discovered a new
activation mode of aliphatic N-(acyloxy)phthalimide by a
photoexcited Pd catalyst to generate alkyl palladium species.
These new discoveries, along with the irradiation effect to
suppress undesired β-H elimination, are expected to inspire the
exploration of new alkylation reactions catalyzed by palladium,
such as C−H alkylation and alkylation of heteroatoms.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00023.
■
S
(13) Kurandina, D.; Parasram, M.; Gevorgyan, V. Angew. Chem., Int. Ed.
2017, 56, 14212. It should be mentioned that n-decyl iodide and
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Chuentragool, P.; Sarkar, D.; Gevorgyan, V. J. Am. Chem. Soc. 2016, 138,
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Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: rui@chem.s.u-tokyo.ac.jp.
*E-mail: fuyao@ustc.edu.cn.
6025.
(17) (a) Schnermann, M. J.; Overman, L. E. Angew. Chem., Int. Ed.
2012, 51, 9576. (b) Cheng, W.-M.; Shang, R.; Fu, Y. ACS Catal. 2017, 7,
907. (c) Cheng, W.-M.; Shang, R.; Fu, M.-C.; Fu, Y. Chem. - Eur. J. 2017,
23, 2537.
ORCID
Rui Shang: 0000-0002-2513-2064
Yao Fu: 0000-0003-2282-4839
(18) For irradiation-induced copper-catalyzed C−N bond and C−S
bond formation, see: (a) Creutz, S. E.; Lotito, K. J.; Fu, G. C.; Peters, J.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the NSFC (21325208, 21572212),
MOST (2017YFA0303500), FRFCU, and PCSIRT.
■
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DOI: 10.1021/acs.orglett.8b00023
Org. Lett. XXXX, XXX, XXX−XXX