1,4-Palladium Shift/C(sp3)-H Activation Strategy for the Remote Construction of Five-Membered Rings

Article abstract of DOI:10.1021/acs.orglett.9b00187

1,n-Metal shift is an elegant alternative approach enabling the functionalization of remote C-H bonds from simple precursors. In this work, we report a novel and simple Pd⁰-catalyzed domino reaction involving 1,4-palladium shift and C(sp³)-H activation and leading to (fused) five-membered rings. This method allowed access to a broad range of valuable arylidene γ-lactams and indanones and was applied to the formal synthesis of (-)-pyrrolam.

Full text of DOI:10.1021/acs.orglett.9b00187

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
1,4-Palladium Shift/C(sp3)−H Activation Strategy for the Remote
Construction of Five-Membered Rings
Ronan Rocaboy and Olivier Baudoin*
University of Basel, Department of Chemistry, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
S
* Supporting Information
ABSTRACT: 1,n-Metal shift is an elegant alternative approach enabling
the functionalization of remote C−H bonds from simple precursors.
In this work, we report a novel and simple Pd0-catalyzed domino reac-
tion involving 1,4-palladium shift and C(sp3)−H activation and leading
to (fused) five-membered rings. This method allowed access to a broad
range of valuable arylidene γ-lactams and indanones and was applied to
the formal synthesis of (−)-pyrrolam.
he last two decades witnessed impressive developments in
the formation of carbon−carbon and carbon−heteroatom
Scheme 1. 1,4-Pd Shift/C−H Activation and Synthesis of
γ-Lactams
T
bonds by transition-metal-catalyzed C−H activation, generally
affording improved atom- and step-economy compared to
traditional cross-coupling methods.1 In addition to direct C−H
functionalization methods, strategies based on 1,n-metal shift
allow the functionalization of distal C−H bonds which may be
otherwise difficult to access.2 Since the initial observation of
1,4-palladium shift by Heck in 1972,3 a number of 1,n-Pd migra-
tions occurring between a wide range of C(sp2)- or C(sp3)-
hybridized carbon atoms have been reported.2 In 2003, Larock
and co-workers showed the first example of Pd0-catalyzed
domino reaction4 involving oxidative addition, 1,4-Pd shift,
and C(sp2)−H arylation, resulting in the construction of
complex polycyclic molecules (Scheme 1a).5 Later, they
reported a domino reaction involving 1,4-Pd shift, carbopalla-
dation, and C(sp3)−H activation to form a fused cyclo-
propane.6 A few years later, Zhu and co-workers described a
general method to access fused oxindoles by combining
carbopalladation, 1,4-Pd shift, and activation of benzylic
C(sp3)−H bonds (Scheme 1b).7 However, to the best of our
knowledge, there is no example of a method simply combining
oxidative addition, 1,4-Pd shift, and C(sp3)−H activation
without an intermediate carbopalladation step. In the past
years, our group has developed a set of Pd0-catalyzed methods
for the direct functionalization of C(sp3)−H bonds from
precursors containing a C(sp2)−X bond (X = leaving group).8
In particular, we reported the synthesis of (fused) γ-lactams
from alkenyl bromides (Scheme 1c).9 To extend the scope of
this reaction, we hypothesized that the organopalladium
intermediate arising from C−Br oxidative addition might be
also generated by 1,4-Pd shift from a more remote C−X bond.
Such an indirect strategy would allow the use of less congested,
easily accessible substrates.
mechanism10 affords the 5-membered palladacycle B. The
latter is too strained to undergo reductive elimination and
should readily open by proton transfer from the coordinated
carboxylic acid, according to previous experimental observa-
tions11 and mechanistic studies,12 to give intermediate C.
These two steps from A to C result in the net aryl to vinyl 1,4-Pd
shift.13,14 Organopalladium C is the same intermediate formed
during the previous direct C(sp3)−H activation reaction (see
Scheme 1c).9 Hence, base-mediated C(sp3)−H activation from
A mechanistic blueprint for this domino process is depicted
in Scheme 2. Oxidative addition from aryl bromide 1 followed
by bromide−carboxylate exchange leads to organopalladium
intermediate A. Subsequent C(sp2)−H activation through the
carboxylate-mediated concerted metalation−deprotonation
Received: January 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00187
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Mechanistic Hypothesis
a
The ligand has been omitted for clarity.
a
Scheme 3. Scope of the Synthesis of α-Arylidene γ-Lactams
a
b
c
All reactions were performed on a 0.1 mmol scale unless otherwise noted. Performed on a 1 mmol scale. Using additional PCy3 (10 mol %).
Thermal ellipsoids shown at 50% probability. TMB = 2,4,6-trimethoxybenzyl.
d
B
DOI: 10.1021/acs.orglett.9b00187
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
C and reductive elimination from the resulting 6-membered
palladacycle D would lead to γ-lactam 2. At this point, we were
aware of potential pitfalls resulting from the lack of precedence
for (1) 1,4-Pd shift onto the α-position of an α,β-unsaturated
system and (2) the combination of 1,4-Pd shift with the
activation of nonactivated C(sp3)−H bonds. Herein, we report
the development of such a domino reaction to access a wide
range of arylidene γ-lactams and indanones.
Scheme 4. Formal Synthesis of (−)-Pyrrolam A
We started our investigations with the synthesis of γ-lactams
2 (Scheme 3). The optimization of reaction conditions was
performed on the TMB-protected15 isopropylamide 1a derived
from 2-bromocinnamic acid (Table S1). The desired product
2a was obtained in 94% yield on a 0.1 mmol scale using the
well-defined complex Pd(PCy3)2 as the catalyst,16 co-catalytic
pivalic acid, and Rb2CO3 as the stoichiometric base in
mesitylene at 160 °C. This high temperature was required,
similar to our previous study on the direct reaction,9 to favor
the formation of the strained α-arylidene γ-lactam and avoid
the protodebromination side reaction. The reaction also
proceeded satisfyingly on a 10-fold (1 mmol) scale, giving
rise to 2a in 85% yield. With the optimized conditions in hand,
we studied the scope of the reaction. Addition of free PCy3
(10 mol %) was found to be beneficial in some cases, pre-
sumably to avoid catalyst decomposition. Using the aryl
chloride instead of the bromide also furnished 2a, albeit in
lower yield (55%). The influence of the alkyl group undergoing
C−H activation was first studied on amides containing the
TMB group (Scheme 3a). Average to good yields were
achieved for ethyl (2b), tert-butyl (2c), as well as cyclopropyl
(2d) groups. The former is a challenging case due to the lesser
number of methyl groups and the lack of a Thorpe−Ingold
effect favoring the C(sp3)−H activation step. Expectedly, the
competition between C(sp2)−H and C(sp3)−H activation was
clearly in favor of the former, giving rise to the interesting
(fused) oxindoles 2e,f. Substrates bearing two potentially
reactive substituents on the amide nitrogen were next
examined (Scheme 3b). Average to very good yields were
observed, together with a high site-selectivity for the primary
positions of the isopropyl group vs equidistant secondary
positions (2i, 2k−n), including much more acidic ones
adjacent to nitrile, sulfone, and ester groups (2l−n). It should
be noted that the β-lactam arising from C−H activation at the
α-position to the nitrogen atom9,17 was never observed (e.g.,
2b, 2d, 2h). Next, the effect of substituents on the aromatic
ring was studied (Scheme 3c). Electron-withdrawing or
-donating groups at the meta- or para-position to the bromine
atom were well tolerated, furnishing the corresponding
products with good to excellent yields (2o−u). Interestingly,
such α-arylidene γ-lactams have been shown to exhibit
antifungal activities toward Colletotrichum orbiculare.18 Finally,
we turned our attention to the synthesis of bicyclic γ-lactams
(Scheme 3d). The fused pyrrolidine 2v and azepane 2x,
relevant to the synthesis of pyrrolizidine19a and Stemona
alkaloids,19b respectively, were obtained from easily available
precursors in 40−51% yield. In contrast, the fused piperidine
2w was obtained in much higher yield (98%). This result was
successfully extended to bicyclic 5,6-fused γ-lactams containing
heteroatoms, such as oxazinanes 2y−z and the enantiopure
N-Boc-protected piperazine 2aa. Of note, olefin isomerization
of the reaction products was never observed.
a
Reaction conditions: (a) (COCl)2 (1.5 equiv), Et3N (2 equiv),
CH2Cl2, 20 °C, quant; (b) Pd(PCy3)2 (10 mol %), PCy3 (10 mol %),
PivOH (30 mol %), Rb2CO3 (1.5 equiv), mesitylene (c = 0.025M),
160 °C, 18 h, 50%.
(Scheme 4). Standard amide formation from (S)-2-methyl-
pyrrolidine and 2-bromocinnamic acid, both commercially
available, gave the precursor for the key 1,4-Pd shift/C(sp3)−H
activation reaction (1v). The latter was reacted under standard
conditions to afford the enantiopure γ-lactam 2v in 50% yield.
Compound 2v was previously converted to (−)-pyrrolam A in
three steps;21 hence, the current approach allows for the syn-
thesis of pyrrolam A in only five steps.
Next, we turned our attention toward the extension of the
current method to other α,β-unsaturated carbonyl substrates
for which the direct C(sp3)−H activation reaction is not
known. In particular, we examined the reactivity of readily
available chalcones 3 containing benzylic C(sp3)−H bonds
(Scheme 5).22 The reaction proceeded remarkably well under
a
Scheme 5. Synthesis of Arylidene Indanones
a
b
Reaction conditions: see Scheme 3. Using additional PCy3 (10 mol %).
the standard conditions, thereby furnishing a range of arylidene
indanones 4. The reaction was compatible with electron-rich
and electron-deficient substituents (4b−f), and even with a
free aniline (4g), giving rise to the corresponding products in
average to excellent yields (50−89%).23 Of note, such com-
pounds possess a variety of interesting biological properties.24
To gain mechanistic insights, we performed experiments
with fully and partially deuterated substrate 1a, bearing deute-
rium atoms on the key C(sp2) and C(sp3) positions under-
going C−H activation (Scheme S1). We observed an
Its application to the short formal synthesis of (−)-pyrrolam
A, a pyrrolizidine alkaloid isolated from Streptomyces olivaceus
strains,20 illustrates the simplicity of the current method
C
DOI: 10.1021/acs.orglett.9b00187
Org. Lett. XXXX, XXX, XXX−XXX

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unexpectedly strong intermolecular D−H exchange,12b pre-
venting us from analyzing the 1,4-Pd shift, but indicating that
the C(sp3)−H activation step (Scheme 2, C → D) is reversible
and faster than the final reductive elimination leading to the
strained α-arylidene γ-lactam ring.9,16c
7305. (g) Wang, M.; Zhang, X.; Zhuang, Y.-X.; Xu, Y.-H.; Loh, T.-P. J.
Am. Chem. Soc. 2015, 137, 1341.
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Chem., Int. Ed. 2013, 52, 12385.
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In conclusion, we reported a simple, step-economical
method to construct (fused) five-membered rings through a
novel Pd0-catalyzed domino reaction involving 1,4-palladium
shift and C(sp3)−H activation. The generality of this method
was demonstrated on a broad range of arylidene γ-lactams and
indanones, and its applicability was illustrated through the
formal synthesis of (−)-pyrrolam. This work opens the way to
the development of C(sp3)−H functionalization reactions that
are difficult to achieve through direct methods.
(9) Holstein, P.; Dailler, D.; Vantourout, J.; Shaya, J.; Millet, A.;
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00187.
Supplementary tables and figures; procedural and
spectral data (PDF)
Accession Codes
CCDC 1884100 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
(c) Rocaboy, R.; Dailler, D.; Zellweger, F.; Neuburger, M.; Salome,
C.; Clot, E.; Baudoin, O. Angew. Chem., Int. Ed. 2018, 57, 12131.
(17) Dailler, D.; Rocaboy, R.; Baudoin, O. Angew. Chem., Int. Ed.
2017, 56, 7218.
(18) Delong, W.; Lanying, W.; Yongling, W.; Shuang, S.; Juntao, F.;
Xing, Z. Eur. J. Med. Chem. 2017, 130, 286.
(19) (a) Robertson, J.; Stevens, K. Nat. Prod. Rep. 2014, 31, 1721.
(b) Pilli, R. A.; Rosso, G. B.; de Oliveira, M. C. F. Nat. Prod. Rep.
2010, 27, 1908.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: olivier.baudoin@unibas.ch.
ORCID
̈
(20) Grote, R.; Zeeck, A.; Stumpfel, J.; Zahner, H. Liebigs Ann.
̈
Chem. 1990, 1990, 525.
(21) Aoyagi, Y.; Manabe, T.; Ohta, A.; Kurihara, T.; Pang, G.-L.;
Yuhara, T. Tetrahedron 1996, 52, 869.
(22) Nonaromatic α,β-unsaturated ketone reactants failed to give the
corresponding arylidene pentanones.
(23) Park, S.; Kadayat, T. M.; Jun, K.-Y.; Magar, T. B. T.; Bist, G.;
Shrestha, A.; Lee, E. S.; Kwon, Y. Eur. J. Med. Chem. 2017, 125, 14.
(24) Menezes, J. C. J. M. D. S. RSC Adv. 2017, 7, 9357.
Olivier Baudoin: 0000-0002-0847-8493
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the University of Basel.
■
̈
We thank Dr. D. Haussinger, University of Basel, for NMR
experiments, Dr. Alessandro Prescimone, University of Basel,
for X-ray diffraction analysis and Dr. M. Pfeffer, University of
Basel, for MS analyses.
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D
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