Palladium nanoparticles: Chemoselective control for reductive Heck with aryl triflates and 2,3-dihydrofuran

Article abstract of DOI:10.1016/j.tet.2018.04.052

The reductive-Heck reaction offers a unique entry to formal Csp²-Csp³ cross-coupling reactions that proceed in the absence of a main group organometallic coupling partner. Consequently, further development of new variants would be transformative. Unfortunately, controlling the relative rates of the organopalladium intermediates has proven difficult with homogenous, single-site Pd catalysts. This work describes a selective reductive Heck reaction catalyzed by Pd-nanoparticles. The reaction works well with electron-deficient aryl triflates at room temperature in the absence of ligands. This work addresses some of the challenges found in the reductive-Heck literature.

Full text of DOI:10.1016/j.tet.2018.04.052

Tetrahedron xxx (2018) 1e4
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium nanoparticles: Chemoselective control for reductive Heck
with aryl triflates and 2,3-dihydrofuran
Daisy Rosas Vargas, Silas P. Cook*
Indiana University, Department of Chemistry, 800 East Kirkwood Avenue, Bloomington, IN 47405, United States
a r t i c l e i n f o
a b s t r a c t
The reductive-Heck reaction offers a unique entry to formal Csp2-Csp3 cross-coupling reactions that
proceed in the absence of a main group organometallic coupling partner. Consequently, further devel-
opment of new variants would be transformative. Unfortunately, controlling the relative rates of the
organopalladium intermediates has proven difficult with homogenous, single-site Pd catalysts. This work
describes a selective reductive Heck reaction catalyzed by Pd-nanoparticles. The reaction works well
with electron-deficient aryl triflates at room temperature in the absence of ligands. This work addresses
some of the challenges found in the reductive-Heck literature.
Article history:
Received 13 February 2018
Received in revised form
13 April 2018
Accepted 17 April 2018
Available online xxx
Keywords:
© 2018 Published by Elsevier Ltd.
Palladium catalysis
Reductive Heck
Nanoparticles
1. Introduction
Our interest in Pd nanoparticles began with our work on an
intramolecular reductive-Heck reaction en route to englerin A.20
The Mizoroki-Heck reaction maintains a privileged status in
synthesis due to its broad use in organic chemistry. Since the first
reports by Mizoroki and Heck, the ability to combine an aryl/vinyl
halide and an olefin to create a carbon-carbon bond has empow-
ered legions of chemists.1,2 The impact of this work culminated in a
share of the 2010 Nobel Prize award for Richard F. Heck. While
originally investigated as an intermolecular variant,3e9 the intra-
molecular Mizoroki-Heck enabled the construction of highly hin-
dered carbon atoms.10
Initial evaluation of reaction tactics revealed that Jeffery-type
conditions provided optimal selectivity for the reductive-Heck
product over the Heck product. Preliminary mechanistic in-
vestigations suggested that these conditions support the formation
of Pd nanoparticles in situ with Pd(OAc)2 and TBAC. While there
have been several reports of intramolecular reductive-Heck re-
actions and applications in total synthesis,19,21e32 our reaction was
unusual in that it provided an intramolecular reductive-Heck re-
action in the presence of
b
hydrogens.20 In spite of these advances,
In 1984, Jeffery reported unique conditions for the Heck reaction
that included tetrabutylammonium chloride (TBAC), Pd(OAc)2, and
NaHCO3 but notably lacked any ligands.11,12 Through the use of
‘solid-liquid phase transfer conditions’ Jeffery could lower Pd
loading and use milder conditions with several unstable vinylic
substrates as well as allylic alcohols. Since these early reports,
further investigations have implicated Pd nanoparticles as the
active catalysts that are responsible for the surprising differences in
reactivity relative to typical homogenous Pd-catalyzed Heck reac-
tions.13e19 For example, stabilized Pd nanoclusters led to improved
reactivity of chloro- and bromobenzene in Heck reactions before
modern ligands enabled the similar reactivity with single-site ho-
mogenous palladium.14
intermolecular reductive-Heck variants remain a challenge in cross
coupling chemistry.
Learning from our work on the intramolecular reductive-Heck
reaction, we sought to employ Pd-nanoparticle conditions to
create a viable intermolecular variant. During the course of this
research, Sekar and coworkers reported a Pd-nanoparticle reduc-
tive-Heck reaction between aryl iodides and enones.33 Notably, the
conditions required ligand-stabilized nanoparticles and heat but
did not investigate alternate electrophiles or olefin substrates
beyond enones. We were interested in the potential advantages of
Jeffery-type Pd nanoparticles for an intermolecular reductive-Heck
beyond conjugate-type addition reactions (Scheme 1). We postu-
lated that in the presence of a Pd precatalyst and alkyl ammonium
salts, a Pd nanoparticle pool will form,34 thereby allowing Pd to
undergo oxidative addition with an aryl pseudohalide followed by
syn migratory insertion of an alkene (Scheme 2). The resulting
* Corresponding author.
E-mail address: sicook@indiana.edu (S.P. Cook).
alkylpalladium species undergoes a hydride transmetallation,
https://doi.org/10.1016/j.tet.2018.04.052
0040-4020/© 2018 Published by Elsevier Ltd.
Please cite this article in press as: Rosas Vargas D, Cook SP, Palladium nanoparticles: Chemoselective control for reductive Heck with aryl
triflates and 2,3-dihydrofuran, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.052

2
D. Rosas Vargas, S.P. Cook / Tetrahedron xxx (2018) 1e4
Table 1
Optimization of the reductive-Heck reaction.
Entry
Deviation from above
% yield:a
A
Bb
C
1
2
3
4
5
6
7
no Pd
as above
TBAC (1.5 equiv)
Pd2dba3 (1 mol%)
Pd(OAc)2 (10 mol%) instead of Pd2dba3
(rac)-BINAP (20 mol%) added
KHCO2 instead of NaHCO2
0
0
0
36
58
22
13
<5
<5
20
18
36
37
0
38
<15
<40
50
0
19
60
a
Yield based on 1H NMR using trimethoxybenzene as internal standard.
Major alkene isomer. TBAC ¼ tetrabutylammonium chloride.
b
elimination, and b-hydride elimination (Scheme 2). Consequently,
preventing the formation of the side products from Heck (product
B) and reduction (product C) became paramount. Other hydride
sources, such as different formate salts or proton sponge,35 did not
improve the selectivity (see Supporting Information). Addition of a
ligand used previously in intermolecular Heck reactions,8,36,37
(rac)-BINAP inhibited the reaction (Table 1, entry 6). While phos-
phines have been used under special circumstances to prepare Pd
nanoparticles,13 they often adversely affect the formation of Pd
nanoparticles under similar conditions.17e19 Elevated temperatures
are detrimental to the target reaction (see SI). Pd2dba3 proved su-
perior than Pd(OAc)2 in the reaction, as it increased the reductive-
Heck yield and significantly decreased reduction product C (Table 1,
entry 5). Next, investigation of the alkyl chain length and coun-
terion demonstrated that tetrabutylammonium salts provide
higher yields and selectivity (see SI).
Scheme 1. Pd-nanoparticle reductive-Heck reaction.
outcompeting the traditional syn
b-H elimination, to provide a
hydridopalladium species. Then, reductive elimination provides the
reductive-Heck product to regenerate the Pd nanoparticles
(Scheme 2). Here, we describe ligand- and base-free conditions to
produce competent Pd nanoparticles that function in an intermo-
lecular reductive-Heck reaction.
2. Results and discussion
2.1. The reductive-Heck reaction
Furthermore, the chloride ion proved critical to reductive-Heck
formation within each alkyl ammonium group, thereby suggesting
an important role of chloride to stabilize the Pd nanoparticle pools
irrespective of the ammonium alkyl chain length.38 For example,
long alkyl chain ammonium salts like cetyl trimethylammonium
We began by testing our previously reported Pd conditions with
naphthyl triflate 1a, 2,3-dihydrofuran (DHF) and sodium formate
(NaHCO2) as the hydride source (Table 1, entry 2).20 The major
challenge with the intermolecular reductive-Heck reaction lies in
controlling the relative rates of migratory insertion, reductive
Scheme 2. Catalytic cycle of Pd-nanoparticle reductive-Heck reaction.
Please cite this article in press as: Rosas Vargas D, Cook SP, Palladium nanoparticles: Chemoselective control for reductive Heck with aryl
triflates and 2,3-dihydrofuran, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.052

D. Rosas Vargas, S.P. Cook / Tetrahedron xxx (2018) 1e4
3
bromide showed modest improvement in reductive-Heck forma-
tion relative to entry 2 (see SI). However, if the chloride is replaced
with a bulkier anion, such as an acetate, the reactivity shifts toward
Heck product B (See SI). We made tetrabutylammonium formate in
an attempt to simplify the system, but it proved inferior (see SI).
Decreasing the amount of TBAC increased the yield of the reaction
(Table 1, entry 3), which may be a result of the nanoparticle envi-
ronment dependent on the ammonium salt. Finally, the use of a
homogenous Pd system employing TBAC led to low conversion and
no reductive Heck formation (see SI).39 Lowering the Pd loading
decreased the reductive-Heck product and increased the Heck
product B (Table 1, entry 4). It is unknown whether the loading of
Pd affects nanoparticle formation or stability under these condi-
tions. To probe the existence of Pd nanoparticles in the reaction, we
added (rac)-BINAP and observed complete inhibition of the
reductive-Heck and Heck product B (Table 1, entry 6). This result is
consistent with several reports of the detrimental effects of phos-
phine ligands to the formation of certain pools of Pd
nanoparticles.11,12,16e18
beginning of the reaction inhibited the reaction.41 Addition of a
phosphine ligand (Table 1, entry 6) or CS2 (0.10 equiv) inhibited the
reaction. The lack of Pd nanoparticles under these conditions were
also confirmed by TEM (see SI).
Next, we turned to transmission electron microscopy (TEM) to
directly observe the presence of Pd nanoparticles under our reac-
tion conditions. Interestingly, TEM revealed nanoparticles in the
range of 4e8 nm with clusters about 12e70 nm in size (Fig. 1). In
the absence of TBAC in the reaction conditions, Pd nanoparticles
were not observed (Fig. 1). Taken together, these experiments
provide strong evidence that our intermolecular reductive-Heck
reaction is catalyzed by Pd nanoparticles. Whether this is accom-
plished through Pd leaching or “on-surface” remains an open
question worthy of further exploration.
3. Conclusion
In conclusion, we developed a mild Pd-nanoparticle reductive-
Heck reaction devoid of costly ligands. The methodology works
With the optimized conditions, we evaluated the substrate
scope of the reductive-Heck reaction (Table 2). The DHF reacted
with several aryl triflates to afford the corresponding reductive-
Heck product (39e67%). Electron-deficient aryl triflates provided
moderate yields and afforded little-to-no reduction of the aryl tri-
flates (Table 2, 2b-2f). Electron-rich aryl triflates did not provide the
reductive-Heck product (Table 2 and 2i). The lower yields observed
with electron-rich aryl triflates are consistent with a slow oxidative
addition that leaves significant quantities of unreacted aryl triflate.
The sterically hindered aryl triflate 1h was not an effective sub-
strate and led only to side product formation. The reaction tolerated
quinoline in the substrate to produce product 2g in reasonable
yield.
No one individual experiment or analytical technique can
establish the presence of nanoparticles in a catalytic reaction.40 To
probe the reaction for Pd nanoparticles, we used several experi-
ments and analytical methods. The addition of a drop of Hg at the
Fig. 1. TEM image of Pd-nanoparticles after reaction under standard conditions.
Table 2
Substrate scope.
Please cite this article in press as: Rosas Vargas D, Cook SP, Palladium nanoparticles: Chemoselective control for reductive Heck with aryl
triflates and 2,3-dihydrofuran, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.052

4
D. Rosas Vargas, S.P. Cook / Tetrahedron xxx (2018) 1e4
well with electron-deficient aryl triflates and is selective for
reductive-Heck relative to the Heck or simple aryl triflate reduction.
Preliminary investigations suggest the process is catalyzed by Pd
nanoparticles. While the possibility of homogenous, unligated Pd as
the catalytic agent remains, current evidence points toward a
nanoparticle-mediated process. Mechanistic and kinetic studies
with regards to nanoparticle formation for this reductive-Heck
reaction remain an active area of pursuit.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.04.052.
References
1. Heck RF, Nolley JP. J Org Chem. 1972;37:2320e2322.
2. Mizoroki T, Mori K, Ozaki A. Bull Chem Soc Jpn. 1971;44:581.
3. Carpenter NE, Kucera DJ, Overman LE. J Org Chem. 1989;54:5846e5848.
4. Sato Y, Sodeoka M, Shibasaki M. J Org Chem. 1989;54:4738e4739.
5. Shibasaki M, Boden C, Kojima A. Tetrahedron. 1997;53:7371e7395.
6. Nicolaou KC, Bulger PG, Sarlah D. Angew Chem Int Ed. 2005;44:4442e4489.
7. Beletskaya IP, Cheprakov AV. Chem Rev. 2000;100:3009e3066.
8. Cartney MD, Guiry PJ. Chem Soc Rev. 2011;40:5122e5150.
9. Johansson Seechurn CCC, Kitching MO, Colacot TJ, Snieckus V. Angew Chem Int
Ed. 2012;51:5062e5085.
10. Dounay AB, Overman LE. Chem Rev. 2003;103:2945e2964.
11. Jeffery T. J Chem Soc, Chem Commun. 1984:1287e1289.
12. Jeffery T. Tetrahedron. 1996;52:10113e10130.
13. Beller M, Fischer H, Kühlein K, Reisinger CP, Herrmann WA. J Organomet Chem.
1996;520:257e259.
4. Experimental
4.1. 2-(Naphthalen-2-yl)tetrahydrofuran (2a)
To a flame-dried, 0.5-dram vial fitted with a rubber septum and
equipped with a magnetic stir bar was added 2-naphthalen-2-yl
trifluoromethanesulfonate 1a (0.4 mmol, 1.0 equiv), Pd2dba3
(10 mol %), TBAC (1.5 equiv) and NaHCO2 (1.2 equiv). The contents
were evacuated and backfilled three times with argon. 2,3-
Dihydrofuran (DHF) (5.2 equiv) and DMF (0.7 M) was added via
syringe and the reaction vial was sealed with a screw-top cap. The
reaction mixture was stirred at room temperature for 14 h. The
reaction was diluted with Et2O (3 mL) and filtered through a 3 cm
pad of silica, flushing with 35 mL of Et2O. The solution was
concentrated via rotary evaporation. The reductive-Heck product
was isolated by flash chromatography (gradient 2e20% EtOAc/
hexanes over 400 mL), to give desired product 2-(naphthalen-2-yl)
tetrahydrofuran 2a (44 mg, 56% yield) as a colorless oil. 1H NMR:
14. Reetz MT, Lohmer G. Chem Commun. 1996:1921e1922.
15. Reetz MT, Westermann E, Lohmer R, Lohmer G. Tetrahedron Lett. 1998;39:
8449e8452.
16. Reetz MT, Westermann E. Angew Chem Int Ed. 2000;39:165e168.
17. de Vries AHM, Mulders JMCA, Mommers JHM, Henderickx HJW, de Vries JG.
Org Lett. 2003;5:3285e3288.
18. Reetz MT, de Vries JG. Chem Commun. 2004:1559e1563.
ꢀꢁ
19. Tobrman T, Dvorak D. Tetrahedron Lett. 2004;45:273e276.
20. Gao P, Cook SP. Org Lett. 2012;14:3340e3343.
21. Clayton SC, Regan AC. Tetrahedron Lett. 1993;34:7493e7496.
22. Lee K, Cha JK. J Am Chem Soc. 2001;123:5590e5591.
23. Trost BM, Thiel OR, Tsui H-C. J Am Chem Soc. 2003;125:13155e13164.
24. Dounay AB, Humphreys PG, Overman LE, Wrobleski AD.
2008;130:5368e5377.
25. Peng R, VanNieuwenhze MS. Org Lett. 2012;14:1962e1965.
26. Wu C, Zhou J. J Am Chem Soc. 2014;136:650e652.
27. Yue G, Lei K, Hirao H, Zhou JS. Angew Chem Int Ed. 2015;54:6531e6535.
28. Mannathan S, Raoufmoghaddam S, Reek JNH, de Vries JG, Minnaard AJ.
ChemCatChem. 2015;7:3923e3927.
(400 MHz, chloroform-d)
d 7.85e7.78 (m, 4H), 7.49e7.41 (m, 3H),
J Am Chem Soc.
5.07 (t, J ¼ 7.2 Hz, 1H), 4.22e4.12 (m, 1H), 4.06e3.95 (m, 1H),
2.47e2.32 (m, 1H), 2.12e1.99 (m, 2H), 1.96e1.82 (m, 1H). 13C NMR:
(126 MHz, chloroform-d):
d 141.05, 133.45, 132.93, 129.10, 128.22,
128.04, 127.79, 126.15, 125.72, 124.18, 80.93, 68.98, 34.76, 26.23.
TLC: Rf ¼ 0.22 (10% Et2O in hexanes).
29. Liu R-R, Xu Y, Liang R-X, et al. Org Biomol Chem. 2017;15:2711e2715.
30. Khalifa A, Conway L, Geoghegan K, Evans P. Tetrahedron Lett. 2017;58:
4559e4562.
31. Kim HS, Lee HS, Kim SH, Kim JN. Tetrahedron Lett. 2009;50:3154e3157.
32. Liu P, Huang L, Lu Y, et al. Tetrahedron Lett. 2007;48:2307e2310.
33. Parveen N, Saha R, Sekar G. Adv Synth Catal. 2017;359:3741e3751.
34. Eremin DB, Ananikov VP. Coord Chem Rev. 2017;346:2e19.
35. Minatti A, Zheng X, Buchwald SL. J Org Chem. 2007;72:9253e9258.
36. Ozawa F, Kubo A, Hayashi T. J Am Chem Soc. 1991;113:1417e1419.
37. Shibasaki M, Vogl EM. Adv Synth Catal. 2004;346:1533e1552.
38. Balanta A, Godard C, Claver C. Chem Soc Rev. 2011;40:4973e4985.
39. Murray PM, Bower JF, Cox DK, Galbraith EK, Parker JS, Sweeney JB. Org Process
Res Dev. 2013;17:397e405.
Acknowledgments
We acknowledge funds from Indiana University in partial sup-
port of this work. We also gratefully acknowledge the NSF CAREER
Award (CHE-1254783) and an AGEP supplement for DRV. Eli Lilly &
Co. and Amgen supported this work through the Lilly Grantee
Award and the Amgen Young Investigator Award. Finally, this
project was partially funded by the Vice Provost for Research
through the Research Equipment Fund. Jocelyn T.L. Gamler is
acknowledged for help with the TEM images in Fig. 1.
40. Widegren JA, Finke RG. J Mol Catal Chem. 2003;198:317e341.
41. Bhadra M, Sasmal HS, Basu A, et al. ACS Appl Mater Interfaces. 2017;9:
13785e13792.
Please cite this article in press as: Rosas Vargas D, Cook SP, Palladium nanoparticles: Chemoselective control for reductive Heck with aryl
triflates and 2,3-dihydrofuran, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.04.052