Palladium-Catalyzed Intramolecular Insertion of Alkenes into the Carbon-Nitrogen Bond of β-Lactams

Article abstract of DOI:10.1021/jacs.5b05308

The carbon-nitrogen bond of β-lactams is cleaved by palladium(0), and an alkene is intramolecularly inserted therein. The following reductive elimination produces nitrogen-containing benzo-fused tricycles in good to high yields.

Full text of DOI:10.1021/jacs.5b05308

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Intramolecular Insertion of Alkenes into the
Carbon−Nitrogen Bond of β‑Lactams
Akira Yada, Satoshi Okajima, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
S
* Supporting Information
cyclobutanone5 led us to study structurally related β-lactams as
ABSTRACT: The carbon−nitrogen bond of β-lactams is
cleaved by palladium(0), and an alkene is intramolecularly
inserted therein. The following reductive elimination
produces nitrogen-containing benzo-fused tricycles in
good to high yields.
potential-rich and readily accessible substrates for such a
purpose.6 In general, the lone-pair electrons of the nitrogen
atom of an amide linkage are delocalized onto the carbonyl
group, rendering the C−N bond stronger. However, the
double-bond character of the C−N bond of a β-lactam is
reduced as a result of the angle strain of the four-membered
ring.6i,7,8 Although various methods to activate C−N σ bonds
with transition metals have been developed,9 there have been
no reports on the cleavage of the carbonyl C−N bond of β-
lactams by transition metals leading to the “cut-and-sew”
approach.10 Herein we report a palladium-catalyzed intra-
molecular insertion of alkenes into carbonyl C−N bonds of β-
lactams to afford nitrogen-containing tricycles, benzoindolizi-
nediones (Scheme 1b), which are key motifs in many
pharmaceuticals and natural products, such as valmerins,11
nuevamine,12 and urotensin-II receptor antagonists.13
ransition-metal-catalyzed activation of unreactive non-
T
polar carbon−carbon1 and carbon−hydrogen2 σ bonds
has demonstrated its applicability to various synthetic trans-
formations in the past decades. In particular, insertion of
unsaturated functionalities into a C−C σ bond of cyclic
compounds offers an atom- and step-economical method to
construct ring-expanded products (Scheme 1a).3 This strategy,
Scheme 1. Transition-Metal-Catalyzed Alkene Insertion into
Unreactive σ Bonds
In order to test the proposed strategy, β-lactam 1a was
employed as the model substrate, and a variety of ligands for
palladium(0) were examined. The initial survey of ligands
revealed that electron-rich and bulky PCy3 afforded the desired
benzoindolizinedione 2a in ca. 20% yield along with vinyl
amide 3a (ca. 10%) (eq 1).
A plausible reaction mechanism is illustrated in Scheme 2.
The carbonyl C−N bond of the substrate 1 oxidatively adds to
palladium(0) to form the five-membered palladacycle A.
Subsequent intramolecular insertion of the alkene moiety into
the Pd−N bond14 forms the seven-membered palladacycle B.
The following reductive elimination furnishes 2 and palla-
dium(0). Another mechanistic pathway forming the ring-
opened vinyl amide 3 branches off after the first step.
Decarbonylation from A generates the four-membered pallada-
cycle C, and β-hydride elimination followed by reductive
elimination affords 3 and regenerates palladium(0).
recently coined as the “cut-and-sew” protocol,3c is especially
viable in intramolecular cases. It presents access to fused-ring
compounds that are synthetically important building blocks
and/or structural frameworks found in myriads of natural
products (Scheme 1a).4
Building on the C−C bond cleavage chemistry, we envisaged
that transition-metal-catalyzed activation of a carbon−nitrogen
σ bond of cyclic compounds followed by alkene insertion might
serve as the key step to furnish nitrogen-containing fused
heterocycles. Successful examples of alkene insertion into
To improve the yield of 2a as well as the selectivity (2a/3a),
a variety of parameters such as ligands, Pd precatalysts, solvents,
temperature, and concentration were then examined. The
selected optimization studies are summarized in Table 1.15
A
Received: May 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b05308
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 2. Plausible Reaction Mechanism
Table 2. Substrate Scope of Palladium-Catalyzed Reaction of
1
ab c
, ,
a
Table 1. Selected Optimization Studies
b
yield (%)
entry
ligand
2a
3a
1
2
3
4
5
PCy3
PMe3
PtBu3
IPr
35
3
0
4
0
39
0
a
1 (0.10 mmol), CpPd(π-allyl) (10 mol %), SIPr (20 mol %), toluene,
31
b
70 °C (for 1b and 1h−j) or 90 °C (1c−g). Isolated yields are shown.
c
SIPr
SIPr
81
0
The major diastereomer is depicted. Diastereomeric ratios (d.r.)
c
d
1
6
93 (91 )
0
determined by H NMR analysis of the crude reaction mixture are
shown. Run with CpPd(π-allyl) (5 mol %) and SIPr (10 mol %) for
21 h.
d
a
1a (0.10 mmol), CpPd(π-allyl) (10 mol %), ligand (20 mol %),
toluene, 70 °C. NMR yields. Run at 0.10 M. 0.50 mmol scale.
b
c
d
Isolated yield.
The diastereoselectivity observed with 2b may be ascribed to
the formation of the thermodynamically favored conformation
in which a benzyl substituent (R1) occupies an equatorial
position. On the other hand, the diastereoselectivities observed
with products 2c−e can be ascribed to the alkene insertion step
(A to B in Scheme 2), where the alkene coordinates to the
palladium center in a way that avoids the steric repulsion
between the methyl group on the alkene and the β-lactam
substituents (R2) (Figure 1). The substituents on the inserting
lower reaction temperature (70 °C) slightly improved the
product selectivity (2a, 35%; 3a, 3%) (entry 1). Other
trialkylphosphine ligands such as PMe3 and PtBu3 were not as
effective as PCy3 (entries 2 and 3). In contrast, N-heterocyclic
carbene (NHC) ligands, which are more electron-donating
than phosphine ligands, gave better results. 1,3-Bis(2,6-
diisopropylphenyl)imidazol-2-ylidene (IPr), for instance, sup-
pressed the formation of 3a, although almost the same level of
production of 2a was observed (entry 4). To our delight, the
use of 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene
(SIPr), the saturated analogue of IPr, significantly improved
the yield of 2a to 81% (entry 5). Although SIPr is regarded to
have a similar electron-donating ability as IPr,16 the conforma-
tional flexibility induced by saturation of the backbone might be
beneficial for the present reaction.17 Finally, dilution of the
reaction system improved the yield to 93% (entry 6).18
Various β-lactams 1 were then subjected to the ring-
expansion reaction under the optimized reaction conditions
(Table 2). Those bearing alkyl and aryl substituents at the 3-
and 4-positions successfully participated in the reaction, giving
the desired benzoindolizinediones in good to excellent yields
with diastereoselectivities ranging from 83:17 to >95:5 (2b−d).
The reaction of a β-lactam containing a cyclopentane ring (1e)
also proceeded well with 5 mol % palladium catalyst, though
the reaction required a prolonged reaction time (21 h).
Figure 1. Plausible transition state for alkene insertion.
alkene were also examined. Both propyl-substituted and
isopropyl-substituted alkenes inserted well (2f and 2g), whereas
the phenyl-substituted alkene led to a diminished yield of 54%
(2h). The attempted reactions of β-lactams bearing a
nonsubstituted vinyl group, monosubstituted vinyl group, or
1,2-disubstituted vinyl group (4−6 in Figure 2) were futile even
at elevated temperature.19 Methoxy and trifluoromethyl
substituents on the tethered benzene ring were also tolerated,
affording the desired tricyclic products in good yields (2i and
2j). Although we also examined the reaction of substrate 7
having an aliphatic chain as the tether, the desired
indolizinedione was not observed.20
B
DOI: 10.1021/jacs.5b05308
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Journal of the American Chemical Society
Communication
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by Grants-in-Aid for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” (22105005), Scientific
Research (S) (15H05756), and Challenging Exploratory
Research (26620083) from MEXT and the ACT-C Program
of the JST.
Figure 2. Other attempted β-lactams.
REFERENCES
■
(1) Reviews of C−C bond activation: (a) Rybtchinski, B.; Milstein,
D. Angew. Chem., Int. Ed. 1999, 38, 870. (b) Murakami, M.; Ito, Y. Top.
Organomet. Chem. 1999, 3, 97. (c) Takahashi, T.; Kotora, M.; Hara, R.;
Xi, Z. Bull. Chem. Soc. Jpn. 1999, 72, 2591. (d) Jun, C.-H. Chem. Soc.
Rev. 2004, 33, 610. (e) Miura, M.; Satoh, T. Top. Organomet. Chem.
2005, 14, 1. (f) Seiser, T.; Cramer, N. Org. Biomol. Chem. 2009, 7,
2835. (g) Aïssa, C. Synthesis 2011, 2011, 3389. (h) Murakami, M.;
Since many biologically active compounds and natural
products contain the indolizidinone skeleton, the deoxygenated
analogue of indolizinedione, the carbonyl group of the product
was converted into a methylene group (eq 2). Thus, treatment
̌ ̌
Matsuda, T. Chem. Commun. 2011, 47, 1100. (i) Korotvicka, A.; Necas,
D.; Kotora, M. Curr. Org. Chem. 2012, 16, 1170. (j) Ruhland, K. Eur. J.
Org. Chem. 2012, 2012, 2683. (k) Dong, G. Synlett 2013, 24, 1. (l) C−
C Bond Activation; Dong, G., Ed.; Topics in Current Chemistry, Vol.
346; Springer: Berlin, 2014.
(2) Recent reviews of C−H bond activation: (a) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (b) Lyons, T.
W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Newhouse, T.;
Baran, P. S. Angew. Chem., Int. Ed. 2011, 50, 3362. (d) Ackermann, L.
Chem. Rev. 2011, 111, 1315. (e) Engle, K. M.; Mei, T.-S.; Wasa, M.;
Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (f) Yamaguchi, J.; Yamaguchi,
A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (g) Wencel-
Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369.
(3) Representative examples of cleavage of cyclobutanones:
(a) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2005,
127, 6932. Of cyclobutenones: (b) Huffman, M. A.; Liebeskind, L. S.
J. Am. Chem. Soc. 1991, 113, 2771. Of benzocyclobutenones: (c) Xu,
T.; Dong, G. Angew. Chem., Int. Ed. 2012, 51, 7567. Of
benzocyclobutenols: (d) Ishida, N.; Sawano, S.; Masuda, Y.;
Murakami, M. J. Am. Chem. Soc. 2012, 134, 17502. Of 3-azetidinones
and 3-oxetanones: (e) Ho, K. Y. T.; Aïssa, C. Chem. - Eur. J. 2012, 18,
3486. Of cyclopropanes: (f) Koga, Y.; Narasaka, K. Chem. Lett. 1999,
705. Of biphenylene: (g) Edelbach, B. L.; Lachicotte, R. J.; Jones, W.
D. Organometallics 1999, 18, 4040. Of isatins: (h) Zeng, R.; Dong, G.
J. Am. Chem. Soc. 2015, 137, 1408.
(4) (a) South, M. S.; Liebeskind, L. S. J. Am. Chem. Soc. 1984, 106,
4181. (b) Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2014, 53, 10733.
(5) Rhodium-catalyzed reactions: (a) Murakami, M.; Itahashi, T.; Ito,
Y. J. Am. Chem. Soc. 2002, 124, 13976. (b) Matsuda, T.; Fujimoto, A.;
Ishibashi, M.; Murakami, M. Chem. Lett. 2004, 33, 876. (c) Parker, E.;
Cramer, N. Organometallics 2014, 33, 780. (d) Souillart, L.; Parker, E.;
Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 3001. (e) Ko, H. M.;
Dong, G. Nat. Chem. 2014, 6, 739. Nickel-catalyzed reactions:
(f) Murakami, M.; Ashida, S. Chem. Commun. 2006, 4599. (g) Liu, L.;
Ishida, N.; Murakami, M. Angew. Chem., Int. Ed. 2012, 51, 2485.
(6) Reviews of β-lactams: (a) Singh, G. S. Mini-Rev. Med. Chem.
2004, 4, 69. (b) Singh, G. S. Mini-Rev. Med. Chem. 2004, 4, 93.
(c) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11, 1921.
(d) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107,
4437. (e) Llarrull, L. I.; Testero, S. A.; Fisher, J. F.; Mobashery, S. Curr.
Opin. Microbiol. 2010, 13, 551. (f) Palomo, C.; Oiabide, M. Top.
Heterocycl. Chem. 2010, 22, 211. (g) Kamath, A.; Ojima, I. Tetrahedron
2012, 68, 10640. (h) Mack, D. J.; Njardarson, J. T. ACS Catal. 2013, 3,
272. (i) Pitts, C. R.; Lectka, T. Chem. Rev. 2014, 114, 7930.
of 2h with hydrazine and sodium in refluxing ethylene glycol11
allowed selective deoxygenation of the keto carbonyl group,
giving a 73% yield of 10, which is known as a non-nucleoside
HIV-1 reverse transcriptase inhibitor.21
Next, the significance of the ring carbonyl and tether
carbonyl groups was examined. At the outset of the project, the
seminal work reported by Matsubara and Kurahashi on the
nickel-catalyzed decarbonylative alkyne insertion reaction of
phthalimides9f,g led us to use imide-like β-lactams. In order to
observe the effect of the two carbonyl groups, substrates 8
lacking the ring carbonyl group and 9 lacking the tether
carbonyl group were synthesized (Figure 2). Both substrates
were treated under the same reaction conditions as before but
yielded no desired products even at elevated temperature.
These experiments showed that the presence of the both
carbonyl groups is requisite for the reactivity. We assume that
the tether carbonyl group also accepts electron density from the
nitrogen to further weaken the double-bond character between
the nitrogen and the ring carbonyl carbon.
In summary, we have developed a reaction involving
intramolecular alkene insertion into the carbonyl C−N bond
of β-lactams to access tricyclic nitrogen heterocycles. This
implies the possibility of activation of other carbon−
heteroatom σ bonds and insertion of unsaturated functionalities
therein, resulting in the construction of fused-ring heterocyclic
systems. An asymmetric version and other heteroatom variants
of this reaction are currently being investigated in this
laboratory.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectra data. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/jacs.5b05308.
■
S
(7) The Amide Linkage: Structural Significance in Chemistry,
Biochemistry, and Materials Science; Greenberg, A., Breneman, C. M.,
Liebman, J. F., Eds.; John Wiley & Sons: New York, 2003.
(8) Carbonyl stretching absorption is a convenient measure to
observe such a phenomenon. Although acyclic amides show a signal at
AUTHOR INFORMATION
Corresponding Author
*murakami@sbchem.kyoto-u.ac.jp
■
C
DOI: 10.1021/jacs.5b05308
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Journal of the American Chemical Society
Communication
around 1600 cm−1, β-lactams show a signal at around 1750 cm−1,
which is indicative of the inefficient resonance effect.
(9) Recent reviews of C−N bond activation by transition metals:
(a) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M. Chem. Rev.
̃
2006, 106, 4622. (b) Wan, X.-B. In Homogeneous Catalysis for
Unreactive Bond Activation; Shi, Z.-J, Ed.; John Wiley & Sons:
Hoboken, NJ, 2015. Representative examples of activation of C(sp3)−
N bonds and insertion of unsaturated bonds for vinylaziridines:
(c) Butler, D. C. D.; Inman, G. A.; Alper, H. J. Org. Chem. 2000, 65,
5887. (d) Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem.
2002, 67, 5977. (e) Hirner, J. J.; Roth, K. E.; Shi, Y.; Blum, S. A.
Organometallics 2012, 31, 6843. For vinylazetidines: (f) Inman, G. A.;
Butler, D. C. D.; Alper, H. Synlett 2001, 2001, 914. Of activation of
C(sp2)−N bonds for phthalimides: (g) Kajita, Y.; Matsubara, S.;
Kurahashi, T. J. Am. Chem. Soc. 2008, 130, 6058. (h) Shiba, T.;
Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2013, 135, 13636. Of
activation of C(sp)−N bonds for cyanoamides: (i) Miyazaki, Y.; Ohta,
N.; Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136, 3732.
(10) C−N bond activation of β-lactams based on rearrangements:
Liu, L.; Wang, Y.; Zhang, L. Org. Lett. 2012, 14, 3736 and references
therein .
(11) Boulahjar, R.; Ouach, A.; Matteo, C.; Bourg, S.; Ravache, M.;
Guevel, R. L.; Marionneau, S.; Oullier, T.; Lozach, O.; Meijer, L.;
́
Guguen-Guillouzo, C.; Lazar, S.; Akssira, M.; Troin, Y.; Guillaumet,
G.; Routier, S. J. Med. Chem. 2012, 55, 9589.
(12) (a) Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V.
Tetrahedron Lett. 1984, 25, 599. (b) Alonso, R.; Castedo, L.;
Domínguez, D. Tetrahedron Lett. 1985, 26, 2925.
(13) Luci, D. K.; Lawson, E. C.; Ghosh, S.; Kinney, W. A.; Smith, C.
E.; Qi, J.; Wang, Y.; Minor, L. K.; Maryanoff, B. E. Tetrahedron Lett.
2009, 50, 4958.
(14) Review of insertion of alkenes into metal−nitrogen bonds:
(a) Hanley, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2013, 52, 8510.
Mechanistic studies on intramolecular insertion of alkenes into Pd−N
bonds: (b) Neukom, J. D.; Perch, N. S.; Wolfe, J. P. J. Am. Chem. Soc.
2010, 132, 6276. (c) White, P. B.; Stahl, S. S. J. Am. Chem. Soc. 2011,
133, 18594. Intermolecular insertion of alkenes into Pd−N bonds:
(d) Hanley, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 15661
and references therein .
(15) See the Supporting Information for details.
(16) (a) Cavallo, L.; Correa, A.; Costabile, C.; Jacobsen, H. J.
Organomet. Chem. 2005, 690, 5407. (b) Droge, T.; Glorius, F. Angew.
̈
Chem., Int. Ed. 2010, 49, 6940. (c) Nelson, D. J.; Nolan, S. P. Chem.
Soc. Rev. 2013, 42, 6723.
(17) Such a phenomenon that a subtle structural difference plays a
critical role has been observed in many other catalytic reactions. For
instance, see: Cao, C.; Wang, L.; Cai, Z.; Zhang, L.; Guo, J.; Pang, G.;
Shi, Y. Eur. J. Org. Chem. 2011, 2011, 1570 and references therein. .
(18) We synthesized the saturated analogue of 1a and reacted it
under the optimized conditions, which resulted in recovery of the
starting material without the observation of any byproduct derived
from decarbonylation. This demonstrates that the alkene moiety also
serves as a directing group for oxidative addition of the C−N bond of
the β-lactam.
(19) Starting substrates were recovered.
(20) Partial isomerization of the double bond was observed (ca. 17%
conversion).
(21) Mertens, A.; Zilch, H.; Koenig, B.; Schaefer, W.; Poll, T.;
Kampe, W.; Seidel, H.; Leser, U.; Leinert, H. J. Med. Chem. 1993, 36,
2526.
D
DOI: 10.1021/jacs.5b05308
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX