Pd-Catalyzed C(sp3)-H Functionalization/Carbenoid Insertion: All-Carbon Quaternary Centers via Multiple C-C Bond Formation

Article abstract of DOI:10.1021/jacs.6b02867

A Pd-catalyzed C(sp³)-H functionalization/carbenoid insertion is described. The method allows for the rapid synthesis of bicyclic frameworks, generating all-carbon quaternary centers via multiple C-C bond formations in a straightforward manner.

Full text of DOI:10.1021/jacs.6b02867

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Communication
Pd-Catalyzed C(sp3)-H Functionalization/Carbenoid Insertion: All-
Carbon Quaternary Centers via Multiple C–C Bond-Formation
Alvaro Gutierrez-Bonet, Francisco Julia-Hernandez, Beatriz de Luis, and Ruben Martin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02867 • Publication Date (Web): 04 May 2016
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Pd-Catalyzed C(sp )-H Functionalization/Carbenoid Insertion: All-
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†
†
†
†§
Álvaro GutiérrezꢀBonet, Francisco JuliáꢀHernández, Beatriz de Luis and Ruben Martin *
†Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
§
Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluïs Companys, 23, 08010, Barcelona, Spain
Supporting Information Placeholder
3
yet powerful, technique for our synthetic arsenal, but
also a unique opportunity to improve our everꢀgrowing
knowledge in C–H functionalization. However, the diffiꢀ
ABSTRACT: A Pdꢀcatalyzed C(sp )ꢀH functionalizaꢀ
tion/carbenoid insertion is described. The method allows
for the rapid synthesis of bicyclic frameworks, generatꢀ
ing allꢀcarbon quaternary centers via multiple C–C
bondꢀformations in a straightforward manner.
3
culty for effecting C(sp )–H functionalization in the abꢀ
3
sence of directing groups and the inherent propensity of
5,6
carbenoids towards competitive dimerization constiꢀ
tute serious drawbacks to be overcome. To such end, we
hypothesized that the intermediacy of in situ generated
Over the last few years, there has been a growing conꢀ
sensus that C–H functionalization has profoundly
changed the landscape of organic synthesis while estabꢀ
lishing new paradigms in retrosynthetic analysis. While
spectacular advances have been realized, this area of
expertise primarily relies on the utilization of directing
groups, particularly via C(sp )–H functionalization. Inꢀ
deed, a close inspection into the literature data reveals
that the preparation of allꢀcarbon quaternary centers via
1
0
3
Pd-I via C(sp )–H functionalization would be critical
for success (Scheme 2). At the outset of our investigaꢀ
tions, it was unclear whether such scenario could ever be
1
conducted given the known proclivity of Pd-I towards
2
11,12
C–C reductive elimination (path b)
or competitive
1
3
[1,4]ꢀshifts en route to 4 (path a). Herein, we report a
2
3
mild catalytic C(sp )–H functionalization/carbenoid inꢀ
3
C(sp )–H functionalization in the absence of directing
sertion en route to indanes 3 bearing allꢀcarbon quaterꢀ
nary centers (path c). This protocol is distinguished by a
wide scope and excellent chemoselectivity profile, thus
constituting a unique tool to rapidly build up molecular
complexity.
3,4
groups still remains rather elusive.
3
Scheme 1. C(sp )–H Functionalization/Carbenoid Insertion.
Scheme 2. Intermediacy of Pd-I in C-H Functionalization.
While originally designed for cyclopropanation events,
carbenoid species have shown to be superb synthons in a
myriad of relevant transformations. Indeed, these reaꢀ
gents have successfully been employed in C–H funcꢀ
tionalization without the need for directing groups, alꢀ
lowing for installing secondary or tertiary carbon cen-
ters via single C–C bond-formation (Scheme 1, path a).
To the best of our knowledge, allꢀcarbon quaternary steꢀ
reocenters derived from the corresponding carbenoid
species are beyond reach in C–H functionalization.
Undoubtedly, the ability to promote multiple C–C bond-
5
6
We initiated our study by investigating the reaction of 1a
14
with 2a (Table 1). After considerable experimentation,
a protocol based on PdCl (SMe ) , L1, PivOH and
2
2 2
7,8
Cs CO in DMF at 80 ºC provided the best results (entry
2
3
1
). Although the structure of 3aa was evident by NMR
3
spectroscopy, we univocally assigned its structure by
formations initiated by C(sp )–H functionalization while
installing allꢀcarbon quaternary centers would be of parꢀ
ticular interest (Scheme 1, path b). If successful, such a
protocol would not only represent an unconventional,
comparison with 3aa’ derived from the hydrolysis of
14
9
3
aa by Xꢀray crystallography. Not surprisingly, the
ligand backbone had a critical impact on both reactivity
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and selectivity (entries 2ꢀ6). While the significant lower and 2h), ketones (2l) or acetals (2o) were all well acꢀ
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reactivity of L2 and L3 might suggest an intimate interꢀ
play of steric and electronic effects, care must be taken
when generalizing this since we found that L4 was
equally effective. The use of monodentate phosphines
commodated. Notably, nitrogenꢀcontaining heterocycles
posed no problems (2p). Particularly interesting was the
observation that the presence of alkene on the side chain
did not interfere, affording 3ad in high yields without
traces of intramolecular cyclopropanation being obꢀ
served in the crude mixtures. Gratifyingly, the diazo
(entries 5 and 6) had a deleterious effect; strikingly, the
utilization of PtBu resulted in a selectivity switch, obꢀ
3
11c
16
taining exclusively 5a. Similarly, the base and the solꢀ
compound derived from Isoxepac (2l), a nonstereoidal
vent exerted a profound influence on reactivity (entries
antiꢀinflammatory drug (NSID), could be employed with
equal ease. Notably, this transformation was not limited
to diazoester derivatives, as diaryldiazomethanes could
also be coupled, albeit in lower yields (2q-r). Unfortuꢀ
nately, donor/donor diazocompounds and monosubstiꢀ
tuted carbene precursors could not participate in the tarꢀ
geted reaction, recovering starting material unaltered.
7
ꢀ10), with toluene favoring the formation of 5a (entry
0
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). Interestingly, inferior results were found for protoꢀ
cols based on Pd(OAc) (entry 11). The higher reactivity
2
of PdCl (SMe) is tentatively attributed to its high soluꢀ
2
2
bility; at present, we cannot rule out that Me S facilitates
2
the reduction to Pd(0) while forming DMSO. Additionꢀ
ally, otherwise related aryl chlorides, iodides and triflate
congeners failed to deliver 3aa. As anticipated, control
experiments univocally revealed that all parameters were
a,b
Table 2. Scope of Diazo Compounds.
14,15
essential for the reaction to occur.
a
Table 1. Optimization of the Reaction Conditions
.
PhC(N )CO Me (2a)
2
2
Me Me
Me
PdCl (SMe ) (5 mol%)
2
2 2
Me
Me
Me
H
L1 (7.5 mol%)
+
PivOH (50 mol%)
Cs CO3 (1.30 equiv)
2
Br
CO Me
2
Ph
1a
DMF, 80 ˚C
3aa
5a
3aa (%)b
93 (80)c
5a (%)b
Entry Deviation from the standard conditions
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5
6
7
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9
none
0
0
using L2 as the ligand
using L3 as the ligand
Using L4 as the ligand
36
0
0
83
0
0
Using PtBu —HBF4 (15 mol%) as the ligand
58
0
3
Using PCy3 (15 mol%) as the ligand
Using CsOPiv (1.30 equiv) as the based
Using CsOAc as the base
0
43
38
15
49
73
0
0
Using PhMe instead of DMF
Using DMA instead of DMF
73
0
10
11
Using 5 mol% Pd(OAc)2
0
PR
2
PR
2
Me Me
PPh2
a
b
O
As Table 1 (entry 1), 0.50 mmol scale. Isolated yields,
c
average of at least two independent runs. PdCl (SMe) (10
mol%) at 100 ºC. PdCl (SMe) (10 mol%).
2
2
d
O
PPh2
3aa'
2
2
R = Cy, L1
R = Ph, L2
PPh2
PPh2
L3
L4
Next, we turned our attention to study the substitution
pattern on the aryl halide backbone (Table 3). As shown,
the preparative scope was rather general regardless of
whether electronꢀdonating or electronꢀwithdrawing
groups were present or not. Notably, a variety of aryl
fluorides (3da), aldehydes (3ea), esters (3fa), amines
a
1
a (0.10 mmol), 2a (0.18 mmol), PdCl (SMe ) (5 mol%),
2 2 2
L1 (7.50 mol%), PivOH (50 mol%), Cs CO (0.13 mmol),
DMF (0.25 M) at 80 ºC. GC yields using oꢀxylene as
standard. Isolated yield. No PivOH was added.
2
3
b
c
d
Prompted by these results, we sought to examine the
influence of the carbenoid species (Table 2). As shown,
the scope was insensitive to electronic changes at the
para and meta positions on the aromatic ring (2f-2l).
Likewise, the substitution pattern on the ester motif was
inconsequential to the reactivity profile (2a-2c), invariaꢀ
bly leading to the targeted products in high yields. The
chemoselectivity profile of our protocol is nicely illusꢀ
trated by the fact that a wide variety of diazoester deꢀ
rivatives bearing aryl halides (2f, 2j and 2m), esters (2e
(3ga and 3ha) or silyl ethers (3ka) could perfectly be
tolerated. Importantly, even free amines could be emꢀ
ployed as substrates, albeit in lower yields (3ga). Altꢀ
hough the presence of an ortho tꢀbutyl group statistically
3
17
accelerates the key C(sp )–H functionalization, we
found that a variety of ortho substituents other than t-
butyl groups could be equally accommodated (3ia-3na).
3
In all cases analyzed, the targeted C(sp )–H functionaliꢀ
3
zation occurred exclusively at the primary C(sp )–H
bonds of methyl groups, leaving the corresponding
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10b
methylene positions intact. In line with this notion, no
ing the methodology described by Cámpora, we preꢀ
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reaction occurred when employing 3ka’. Unfortunately,
no diastereoselection was observed in the presence of
gemꢀdimethyl groups (3ia-3ka), even in the presence of
pared 6 from 7 in high yield (Scheme 3, bottom), which
was fully characterized by Xꢀray structure analysis.
14
Interestingly, while 6 rapidly underwent reductive elimiꢀ
18
11
bulky silyl or aromatic motifs (3ja-3ka). Likewise,
nation en route to 5a in the absence of 2a, 3aa was
2
19,20
tertiary benzylic carbons (R =H) resulted in βꢀhydride
exclusively obtained with 2a (Scheme 3, bottom).
elimination, even with bulkier mesityl groups. Taken
together, the results in Tables 2 and 3 show the prospecꢀ
tive impact of our protocol for rapidly preparing indane
skeletons bearing allꢀcarbon quaternary centers.
Notably, 3aa was not obtained from 5a, thus ruling out
the possibility of a C–C cleavage event. We believe theꢀ
se results reinforce a scenario consisting of Pd-I via
concerted metallationꢀdeprotonation from II (Scheme
0
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11,21
4
).
While Pd-I might coexist in equilibrium with III
a,b
Table 3. Scope of Aryl Bromides.
upon protonolysis with PivOH, a 1,2ꢀinsertion of a diazo
1
0a,22,23
compound
might generate IV that ultimately deꢀ
livers the targeted product via reductive elimination. At
present, we cannot rule out the intermediacy of V via
2
4
rapid equilibration with III and Pd-I, as traces of cyꢀ
clopropane derivatives via reductive elimination from V
were detected in reactions of aryl bromides possessing
2
5
bulky groups at the geminal position.
Scheme 4. Mechanistic Hypothesis.
In conclusion, we have developed a mild and robust Pdꢀ
3
a
b
catalyzed C(sp )ꢀH functionalization/carbenoid insertion
As for Table 1 (entry 1), but at 0.50 mmol scale. Isolated
c
event. This technique represents a unique synthetic tool
yields, average of at least two independent runs. 1:1 diaꢀ
stereomeric ratio. PdCl (SMe) (10 mol%) at 100 ºC.
3
d
in the C(sp )–H functionalization arena for building up
2
2
bicyclic frameworks in which the allꢀcarbon quaternary
center is derived from carbenoid species.
Scheme 3. Mechanistic Experiments.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*
rmartinromo@iciq.es
Funding Sources
No competing financial interests have been declared.
Next, we decided to gather indirect evidence on the
mechanism by examining the reactivity of 1a with Pivꢀ
OD. Interestingly, a nonꢀnegligible deuteration at ortho
position of 3aa was observed, suggesting that Pd-I
ACKNOWLEDGMENT
We thank ICIQ, the European Research Council (ERCꢀ
277883), MINECO (CTQ2012ꢀ34054 & Severo Ochoa
Excellence Accreditation 2014ꢀ2018, SEVꢀ2013ꢀ0319) and
Cellex Foundation for support. Johnson Matthey, Umicore
and Nippon Chemical Industrial are acknowledged for a
(Scheme 2) might coexist in equilibrium with homobenꢀ
zylic Pd(II) intermediates generated upon protonolysis
10c,11c,13,14
with PivOD via [1,4]ꢀshift.
Next, we studied
the reactivity of the putative metallacycle Pd-I. Followꢀ
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gift of metal & ligand sources. We sincerely thank E. Esꢀ
cudero, E. Martin for XꢀRay crystallographic data and Prof.
E. GómezꢀBengoa for invaluable theoretical calculations.
E. Inorg. Chem. 2001, 40, 4116. (c) Cámpora, J.; López, J.
A.; Palma, P.; Valerga, P.; Spillner, E.; Carmona, E. Angew.
Chem. Int. Ed. 1999, 38, 147.
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(
11) (a) Kefalidis, C. E.; Davi, M.; Holstein, P. M.; Clot, E.;
Baudoin, O. J. Org. Chem. 2014, 79, 11903. (b) Rousseaux,
S.; Davi, M.; SofackꢀKreutzer, J.; Pierre, C.; Kefalidis, C. E.;
Clot, E.; Fagnou, K.; Baudoin, O. J. Am. Chem. Soc. 2010,
132, 10706. (c) Chaumontet, M.; Piccardi, R.; Audic, N.;
Hitce, J.; Peglion, J. –L.; Clot, E.; Baudoin, O. J. Am. Chem.
Soc. 2008, 130, 15157.
REFERENCES
(1) (a) Gutekunst, W. R.; Baran, P. L. Chem. Soc. Rev. 2011,
4
1
0, 1976. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
10, 1147. (c) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. ꢀ
–Q. Angew. Chem. Int. Ed. 2009, 48, 5094.
(2) Allꢀcarbon quaternary centers are defined as carbon atoms
to which four distinct carbon substituents are attached. (a)
Quasdorf, K. W.; Overman, L. E. Nature, 2014, 516, 181.
(12) For preparing otherwise related benzocyclobutenones: (a)
FloresꢀGaspar, A.; GutiérrezꢀBonet, A.; Martin, R. Org. Lett.
2012, 14, 5234. (b) ÁlvarezꢀBercedo, P.; FloresꢀGaspar, A.;
Correa, A.; Martin, R. J. Am. Chem. Soc. 2010, 132, 466.
(13) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. J. Am. Chem. Soc., 2005, 127, 4685. (b) Hoshi, T.;
Honma, T.; Mori, A.; Konishi, M.; Sato, T.; Hagiwara, H.;
Suzuki, T. J. Org. Chem., 2013, 78, 11513.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
b) Das, J. P.; Marek, I. Chem. Commun, 2011, 47, 4593.
3) (a) Li, H.; Li, B.ꢀJ.; Shi, Z.ꢀJ. Catal. Sci. Technol, 2011, 1,
91. (b) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofackꢀ
(
1
Kreutzer, J.; Baudoin, O. Chem. Eur. J. 2010, 16, 2654. (c)
Herrmann, P.; Bach, T. Chem. Soc. Rev. 2011, 40, 2022.
(4) (a) Pedroni, J.; Saget, T.; Donets, P. A.; Cramer, N. Chem.
Sci. 2015, 6, 5164. (b) Davies, H. M. L.; Hansen, T.;
Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063. (c)
Janody, S.; Jazzar, R.; Comte, A.; Holstein, P. M.; Vors, J. –
P.; Ford, M. J.; Baudoin, O. Chem. Eur. J. 2014, 20, 11084.
(14) See Supporting information for details.
(15) The use of tosyl hydrazones as carbenoid species resulted in
dehalogenation while not observing even traces of 3aa.
(16) Scott, J.; Huskinsson, E. C. Rheumatology, 1982, 21, 48
3
(17) For selected C(sp )ꢀH functionalization of ortho t-butyl
(d) Saget, T.; Cramer, N. Angew. Chem. Int. Ed. 2012, 51,
groups: (a) Yan, J.ꢀX.; Li, H.; Liu, X.ꢀW.; Shi, J.ꢀL.; Wang,
X.; Shi, Z.ꢀJ. Angew. Chem. Int. Ed. 2014, 53, 4945. (b)
Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem.
Soc. 2007, 129, 14570. (d) Desai, L. V.; Hull, K. L.; Sanꢀ
ford, M. S. J. Am. Chem. Soc. 2004, 126, 9542.
1
2842. (e) Martin, N.; Pierre, C.; Davi, M.; Jazzar, R.; Bauꢀ
doin, O. Chem. Eur. J. 2012, 18, 4480. (f) Holstein, P. M.;
Vogler, M.; Karini, P.; Pilet, G.; Clot, E.; Baudoin, O. ACS
Catal. 2015, 5, 4300. (g) Yu, S.; Liu, S.; Lan, Y.; Wan, B.;
Li, X. J. Am. Chem. Soc. 2015, 137, 1623.
(18) DFT calculations (B3LYP & M06) showed that the energy
difference of the transition states leading to the two possible
diastereoisomers (IV, Scheme 4) is negligible (0.3ꢀ2.3
(
5) (a) Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, A:
R.; McKervey, A. Chem. Rev. 2015, 115, 9981. For selected
carbenoid insertions into organopalladium intermediates: (b)
Kudirka, R.; Devine, S. K. J.; Adams, C. S.; VanVrankꢀ
en, D. L. Angew. Chem. Int. Ed. 2009, 48, 3677. (c) Premaꢀ
chandra, I. D.; Nguyen, T. A.: Shen, C.; Gutman, E. S.;
VanVranken, D. L. Org. Lett. 2015, 17, 5464. (d) Zhou, L.;
Ye, F.; Zhang, Y.; Wang, J. Org. Lett. 2012, 14, 922. (e)
Barluenga, J.; Escribano, M.; Aznar, F.; Valdes, C. Angew.
Chem. Int. Ed. 2010, 49, 6856.
ꢀ
1
kcal·mol ). Additionally, the overall energy barrier for
ꢀ
1
[1,2]ꢀinsertion was found to be 1.7ꢀ3.3 kcal·mol (ref.14).
(19) Although 6-L1 could be isolated and characterized by Xꢀray
crystallography (see ref. 14), its insolubility prevented its
characterization by NMR spectroscopy. Still, 6-L1 could be
converted into either 5a or 3aa in quantitative yields.
(20) 6 and 7 were found to be catalytically competent on the
conversion of 1a into 3aa. See ref. 14.
(
(
(
6) For selected reviews of C–H functionalization dealing with
diazoderivatives: (a) Caballero, A.; Pérez, P. J. Chem. Soc.
Rev., 2013, 42, 8809. (b) Davies, H. M. L.; Morton, D.
Chem. Soc. Rev. 2011, 40, 1857.
(21) (a) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118. (b)
Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 10848. (c) ref. 20c. (d) GarciaꢀCuadrado, D.; de
Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A.
M. J. Am. Chem. Soc. 2007, 129, 6880.
7) For selected syntheses of quaternary center not derived from
carbenoids via C–H activation: (a) Fuentes, M. A.; Muñoz,
B. K.; Jacob, K.; Vendier, L.; Caballero, A.; Etienne, M.;
Pérez, P. J. Chem. Eur. J. 2013, 19, 1327. (b) ref. 4c.
8) While this paper was under preparation, a functionalization
(22) We propose the intermediacy of Pd carbenoid species from
3
Pd-I prior 1,2ꢀinsertion at the C(sp )–C bond en route to IV.
Preliminar DFT calculations (B3LYP & M06) revealed that
2
1,2ꢀinsertion at C(sp )–C was less favorable by 12ꢀ15
3
ꢀ1
of activated C(sp )–H bonds using expensive Rh catalysts
kcal·mol (ref.14).
followed by carbenoid insertion was reported: Zhou, B.;
Chen, Z.; Yang, Y.; Ai, W.; Tang, H.; Wu, Y.; Zhu, W.; Li,
Y. Angew. Chem. Int. Ed. 2015, 54, 12121.
(23) (a) Hu, F.; Xia, Y.; Ma, C.; Zhang, Y.; Wang, J. Chem.
Commun. 2015, 51, 7986. (b) Xia, Y.; Zhang, Y.; Wang,
J. ACS Catal. 2013, 3, 2586.
(24) (a) Miyashita, A.; Ohyoshi, M.; Shitara, H.; Nohira, H. J.
Organomet. Chem. 1988, 338, 103. (b) Jennings P. W.;
Johnson L. L. Chem. Rev. 1994, 94, 2241.
(25) 0% ee was observed by reacting diethyl 2ꢀdiazomalonate
with aryl halides containing gemꢀdimethyl groups. See Supꢀ
porting information for a mechanistic rationale.
(
9) For syntheses of not all-carbon quaternary centers via
2
C(sp )–H/carbenoid insertion: (a) Ye, B.; Cramer, N. An-
gew. Chem. Int. Ed. 2014, 53, 7896. (b) Hyster, T. K.; Ruhl,
K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 5364.
(
10) For selected stoichiometric transformations of these Pd(II)
metallacycles: (a) Cámpora, J.; Palma, P.; del Río, D.; Lóꢀ
pez, J. A.; Valerga, P. Chem. Commun. 2004, 1490. (b)
Cámpora, J.; López, J. A.; Palma, P.; del Río, D.; Carmona,
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