Selective Palladium(II)-Catalyzed Carbonylation of Methylene β-C?H Bonds in Aliphatic Amines

Article abstract of DOI:10.1002/anie.201706303

Palladium(II)-catalyzed C?H carbonylation reactions of methylene C?H bonds in secondary aliphatic amines lead to the formation of trans-disubstituted β-lactams in excellent yields and selectivities. The generality of the C?H carbonylation process is aided by the action of xantphos-based ligands and is important in securing good yields for the β-lactam products.

Full text of DOI:10.1002/anie.201706303

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Selective Pd(II)-Catalyzed Carbonylation of Methylene beta-C-H
Bonds in Aliphatic Amines
Authors: Matthew James Gaunt, Jaime Cabrera-Pardo, Aaron
Trowbridge, Manuel Nappi, and Kyohei Ozaki
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706303
Angew. Chem. 10.1002/ange.201706303
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10.1002/anie.201706303
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b
Selective Pd(II)-Catalyzed Carbonylation of Methylene -C–H
Bonds in Aliphatic Amines
Jaime R. Cabrera-Pardo, Aaron Trowbridge, Manuel Nappi, Kyohei Ozaki and Matthew J. Gaunt*
the versatile b-lactam products will be of significant interest to
practitioners of synthetic and medicinal chemistry.
Abstract: Pd(II)-catalyzed C–H carbonylation of methylene C–H
bonds in secondary aliphatic amines leads to the formation trans-
disubstituted b-lactams in excellent yields and selectivities. The
generality of the C–H carbonylation process is aided by the action of
xantphos-based ligands and is important in securing good yields of
the b-lactam products.
(1) State of the art in amine-directed methylene C–H functionalization with Pd(II)
γ-C–H functionalization in amine/amide derivatives
auxiliary controlled – Daugulis, Chen, Yu, Sanford
H
N
β
γ
γ-C–H functionalization of primary amines
imine-based transient directing group – Dong, Ge, Yu
H
One of the most important developments in synthetic chemistry
over the last 20 years has been the advent of transition metal
catalyzed C–H activation reactions.1 While the majority of these
successful catalytic processes exploit the functionalization of
C(sp2)–H bonds, embracing C(sp3)–H bonds as reactive entities
remains a challenge to synthetic chemists and continues to
inspire intensive efforts.2 Arguably, the most successful
approaches to C(sp3)–H functionalization have exploited
processes based on functional group directed C–H cleavage at
methyl groups with electrophilic palladium(II) catalysts.3 Despite
this, selective Pd-catalyzed C–H functionalization at methylene
sites remains particularly challenging because the increased
steric interactions that result from engaging a mid-chain C–H
bond can preclude proximity-driven palladation. Although,
successful examples of Pd-catalyzed methylene activation
usually require the appendage of an auxiliary directing group to
facilitate the C–H bond cleavage, these advances have led to a
range of novel transformations across a variety of substrate
classes.4,5 In contrast, the use of native directing groups to
achieve related methylene C–H processes is less common.6,7
Given the prevalence of amines in biologically active molecules,8
we reasoned that a general strategy enabling selective activation
of methylene C–H bonds directed by the intrinsic unprotected
amine functionality would be of substantial utility in synthesis.
no examples of amine directed Pd(II)-catalyzed
methylene β-C–H functionalization
(2) β-functionality is a common feature in biologically relevant aliphatic amines
OH
MeO
O
R1
O
H
N
OH
N
H
N
H
R2
N
F
O
β-amino acids
methylphenidate
ezetimibe
F
(3) Pd(II)-catalyzed methylene C–H carbonylation of secondary aliphaitc amines
R
O
O
H
H
CH3
H
O
Pd
N
H3C
H
N
N
H
H
CH3
H
N
O
CH3
CH3
H
H3C
CH3
readily accessible
amine
disubstituted
β-lactam
10 mol% Pd(OAc)2, CO
AgOAc, benzoquinone, xantphos, PhMe, 80 ˚C
First, we benchmarked the C–H activation step by treating amine
1a with a stoichiometric amount of Pd(OAc)2. We found that 1a
underwent classical cyclopalladation at the g-C–H bond to form
the 5-membered ring complex, int-I (Scheme 1a).11 When this
complex was stirred under an atmosphere of CO, the expected g-
lactam 2a was observed. The pathway to 2a (via int-I) is
consistent with cyclopalladation, followed by CO insertion and
With respect to previous work on methylene C–H activation,
Daugulis,4a Chen,4b Yu,4f,7b and Sanford4g have reported directed
transformations with a range of aliphatic amine derivatives (eqn.
1). Each of these processes, however, requires the use of a pre-
installed auxiliary group to enable functionalization and additional,
often complicated, steps are always needed for its processing.
More recently, Dong,7a Yu7b and Ge7c have reported that
transiently formed catalytic auxiliaries (via imines) can be applied
to methylene C–H activation in some functionally simple primary
amines. In most of the aforementioned cases, auxiliary-controlled
methylene C–H activation takes place at the g-position to the
amine via ‘classical’ 5-membered ring cyclopalladation. To the
best of our knowledge, there is no direct functionalization process
that selectively targets a methylene C–H bond in the b-position to
an unprotected aliphatic amine;9,10 such a transformation would
give rise to a structural feature that is ubiquitous in biologically
relevant complex amines (eqn. 2).
reductive elimination.3h,3I,12 Next, we stirred
a mixture of
(bis)amine Pd(II) complex int-II (an established precursor to C–H
activation)3h under 1 atm. of CO/air. We were surprised to find the
reaction afforded a 1.3:1 mixture of g-lactam 2a and b-lactam 3a,
the later arising from methylene b-C–H carbonylation (Scheme
1b). We postulated that 3a could be formed via a competitive C–
H carbonylation pathway, recently outlined by our laboratory.13 If
CO is first activated by the Pd(OAc)2, it could engage the amine
to form a carbamoyl-Pd(II) species, from which C–H activation
can occur at the b-methylene position via a 5-membered ring
transition structure (eqn 3); reductive elimination from putative
palladacycle int-III would form b-lactam 3a. Notably, the
concentration of CO appears to control the pathway of the C–H
carbonylation process; only 3a is observed if int-II is stirred under
a purely CO atmosphere. The proposed pathway to 3a is further
supported by reaction of carbamoyl chloride 4 with Pd(PPh3)4,
which presumably passes through a related carbamoyl-Pd(II)
intermediate (int-IV) en route to the b-lactam (Scheme 1c).10a,13,14
Here we report
a general process for the Pd-catalyzed
functionalization of methylene C–H bonds at the b-position to an
unprotected aliphatic amine; no auxiliary group is required. By
exploiting a novel carbonylation pathway, precluding classical
cyclopalladation, the C–H functionalization process inserts CO
between the b-carbon and amine to selectively form trans-
disubstituted b-lactams (eqn. 3). The operationally simple reaction
produces b-lactams in good yields and works for a wide range of
functionally diverse and readily available amines. We believe that
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10.1002/anie.201706303
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COMMUNICATION
of AgOAc, 2 equiv. of BQ under 1 atm. of CO at 80 ˚C in PhMe
and gave 3a in 82% yield after isolation. Interestingly, we found
that reaction of 1a using CO diluted with air (c.f. Scheme 1b), but
otherwise optimal conditions, resulted in the formation of b- and g-
lactams in a 3:1 ratio, further supporting the dependence of the
pathway on CO concentration. The successful use of phosphines
in oxidative C–H carbonylation is surprising given their propensity
oxidize to phosphine oxides; the unique effect of xantphos,
compared to other phosphines, is also striking. Accordingly, we
found that reaction using xantphos mono-oxide gave almost the
same yield as the use of xantphos (entry 10),17a,b however the
yield drops dramatically when xantphos dioxide was used (entry
11, c.f. entry 9).16 Although unsure of its precise role, we believe
xantphos (or its mono-oxide) most likely stabilizes Pd(0) at the
end of the catalytic cycle prior to oxidation to the Pd(II) species
required for reaction.17c
CH3
(a)
H3C
H3C
O
H3C
H
N
Pd(OAc)2
CO
N
H3C
86%
PhMe, 50 ˚C
41%
CH3
H3C
2a
int-I
1a
(b)
Me
O
CH3
H3C
H3C
H
H
N
O
Pd
O
6.25% CO
in air
H3C
O
Et
H
H
O
Et
Et
Et
N
H
Me
N
N
H
PhMe, 50 ˚C
Me
Me
Me
CH3
H
H3C
H3C
O
Me
int-II
3a (15%) 1 : 1.3
2a (19%)
O
CH3
Et
H3C
C
H
Et
H3C
O
N
With the optimal conditions, we examined the scope of the
methylene b-C–H carbonylation process. As shown in Table 2,
structurally and functionally diverse amines undergo efficient b-
C–H carbonylation to trans-disubstituted b-lactams. Branching at
the a- and b-carbon atoms on the non-reacting side of the amine
is well tolerated to provide the b-lactams in good yields (Table 2a,
3a-f). Interestingly, we found that the use of hindered carboxylate
ligands were required for amines not containing a-branching, in
order to prevent the formation of the undesired N-acetylation
byproducts. A variety of functional groups, including alkene,
esters, arenes, alkenes, and oxetane moieties can be
accommodated by the reaction, forming b-lactams in good yields
(3g-p). Among these, we note that (a) a thioether motif neither
deactivates the catalyst nor succumbs to oxidation, and b-lactam
3h is produced in high yield, (b) the free NH-b-lactam could be
revealed through photochemical cleavage of an N-benzyl
derivative18 and (c) the reaction was amenable to being performed
on gram scale (3l). Linear substituents can be incorporated on the
non-reacting side of the amine (3q-t), and we observed that the
carbonylation is tolerant of Lewis basic heteroarenes (3s,t)
thereby enhancing the utility of this process towards medicinal
chemistry applications.8,19 A range of functional groups can also
be included on the reacting side of the amine (Table 2b, 3u-3ae).
Substrates derived from protected amino alcohols work well to
provide functionalized b-lactams in good yields and
diastereoselectivities (3w-z); interestingly, C–H carbonylation is
not observed at the b-position bearing the O-substituent, thereby
conveying useful selectivity in more heavily functionalized
systems. Selective carbonylation at the benzylic position in
phenylalanine- and tryptophan-derived substrates gave highly
100% CO
Pd
N
H
Et
Et
PhMe
50 ˚C
CH3
N
O
H3C
H
H3C
putative
palladacyle
int-III
Et
Et
exclusively 3a
31%
(c)
H3C
H3C
H3C
H3C
H3C
H3C
int-IV
CH3
O
O
PPh3
H3C
O
18%
PhMe
N
Cl
N
Pd
N
PPh3
Pd(PPh3)4
50 ˚C
Cl
CH3
H
3a
H3C
CH3
CH3
4
Scheme 1. Preliminary mechanistic experiments
Using amine 1a, we assessed a catalytic methylene b-C–H
carbonylation by testing the reaction conditions that were
successful for our methyl b-C–H carbonylation.13 Although the
reaction produced 3a in a capricious 23% assay yield, a
significant amount of N-acetylated amine byproduct (28%) was
observed. Cu(II) salts are known to catalyze N-acetylation,15 but
we found changing the oxidant from Cu(OAc)2 to AgOAc
increased the yield of 3a to 42%, and reduced the amount of
acetylated byproduct (Table 1, entry 1).
Table 1. Selected Optimization
CH3
CH3
10mol% Pd(OAc)2, CO (1 atm)
ligand
H3C
O
H3C
H3C
H
N
N
H
functionalized
a-aryl-b-hydroxymethyl-b-lactams
(3y-z);
CH3
1a
3 equiv. AgX, BQ
PhMe, 80 ˚C
importantly, no competitive C(sp2)–H carbonylation was observed
in these b-arene-containing amines. Unfortunately, reaction was
not observed when the amine was unbranched on the reacting
side,15 however C–H carbonylation onto cycloalkanes worked well
to reveal a useful class of fused ring b-lactams (3aa-ab). A
selection of heteroarenes on the reacting side of the amine are
compatible in the C–H carbonylation (3ac-2ae).
CH3
H3C
3a
H
Entry
Catalyst
AgX
BQ
Ligand
Yield %
(dr)
42 (12:1)
28 (12:1)
82 (12:1)
54 (12:1)
74 (12:1)
0
1
2
Pd(OAc)2
Pd(OAc)2
OAc
OAc
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
–
2 eq.
2 eq.
2 eq.
2 eq.
Li-quinoline
PPh3
3
4
5
6
7
8
9
10
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
OAc
OPiv
OBz
OAc
OAc
–
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
–
To test the limits of selectivity in this C–H carbonylation, we
prepared 1af, wherein four different b-C–H bonds are accessible
to the Pd-carboxamide activation (Scheme 2). Remarkably,
reaction was selective at one C–H bond (next to the ester,
possibly reflecting C–H acidity or importance of a Pd-enolate) to
form 3af.
0
0
OAc
OAc
23 (12:1)
80 (12:1)
XantphosO
11
Pd(OAc)2
OAc
2 eq.
Xantphos(O)2
23 (12:1)
Yields and diastereoselective ratios (dr) are determined by 1H NMR.
PivO
PivO
H3C
O
H3C
H
10 mol% Pd(OAc)2, xantphos
Prompted by the observation that a reaction using PPh3 as ligand
(instead of Li-quinoline) also formed 3a (entry 2), we examined a
series of phosphines and found that bidentate xantphos gave an
excellent yield of 3a (entry 3).16 The reaction of 1a using different
Ag-carboxylates also worked well (entries 3-5). Control
experiments highlighted essential roles for BQ, Pd(II)- and Ag(I)-
carboxylates (entries 6-8). Optimal conditions involved treatment
of amine 1a with 10mol% Pd(OAc)2, 10mol% xantphos, 3 equiv.
N
O
N
H
CO, AgOAc, BQ, PhMe, 80 ˚C
68% yield
> 20:1 3af to all other isomers
OEt
OEt
H3C
1af CH3
3af
O
Scheme 2. Regioselective C–H carbonylation
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10.1002/anie.201706303
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COMMUNICATION
Table 2 Scope of methylene C–H carbonylation
Me Me
10 mol% Pd(OAc)2 or Pd(OPiv)2, CO (1 atm)
10 mol% Xantphos
non-reacting
α
H
side
O
N
N
H
O
3 equiv AgOAc or AgOPiv, 2 equiv BQ
PhMe, 80 ˚C
reacting
side
P
P
Ph
Ph
Ph
Ph
H
readily prepared amines, 1
disubstituted β-lactam, 3
Xantphos
(a)
H3C
CH3
O
O
N
O
O
O
O
N
H
N
N
H
N
H
N
H
CH3
CH3
CH3
H
CH3
H
H3C
H3C
CH3
CH3
H3C
H3C
H3C
H3C
3b, 73%, 20:1 dr
3c, 67%, 12:1 dr
3d, 51%, 7:1 dr
3e, 82%, 10:1 dra
3f, 75%, >20:1 dra
3g, 59%, 20:1 drb
O
S
O
EtO
O
CH3
O
CH3
O2N
CH3
O
F
F
OPiv
O
O
O
N
O
O
N
H
N
H
N
H
N
H
N
CH3
CH3
CH3
CH3
CH3
H
H3C
CH3
H3C
H3C
H3C
H3C
H
H3C
3h, 60%, 12:1 dr
3i, 48%, 20:1 dra,b
3j, 60%, 12:1 dra,b
3k, 64%, >20:1 dra
3l, 75%, >20:1 dr, gram scalea
3m, 61%, 20:1 drb
CH3
F3C
CH3
H3C
O
TIPSO
N
O
CH3
CH3
O
N
O
N
O
N
O
N
O
N
O
N
H
CH3
CH3
CH3
H
H
H
H3C
CH3
H3C
H3C
CH3
CH3
H
H
H3C
H3C
H3C
3n, 85%, 15:1 dr
3o, 67%, 15:1 dra
3p, 80%, 12:1 dra
3q, 40%, >20:1 dra
3r, 78%, 9:1 dra
3s, 60%, >20:1 dra
CH3
H3C
CH3
H3C
(b)
N
O
CH3
H3C
CH3
H3C
H3C
CH3
CH3
CH3
CH3
O
N
H3C
O
N
N
O
N
O
N
O
N
O
N
H
CH3
H3C
H3C
CH3
H
O
H
H
CH3
CH3
PivO
CH3
H
H
H3C
PivO
TIPSO
H3C
3t, 52%, >20:1 dr
3u, 81%, >20:1 dr
3v, 65%, >20:1 dr
3w, 72%, >20:1 dr
3x, 51%, >20:1 dra
3y, 62%, 12:1 dr
CH3
CH3
H3C
CH3
H3C
CH3
H3C
CH3
H3C
CH3
H3C
CH3
H3C
CH3
CH3
CH3
CH3
CH3
O
O
N
O
N
O
N
O
N
H
O
N
N
H
H
H
H
H
CH3
CH3
CH3
N
PivO
H
O
H
O
O
N
N
N
N
Piv
Piv
3z, 62%, 12:1 dr
3aa, 66%
3ab, 51%
3ac, 61%, 15:1 dr
3ad, 60%, >20:1 dr
3ae, 63%, 15:1 dr
a
reaction with 10mol% Pd(OPiv)2, 3 equiv AgOPiv. b. product exists as a 1:1 mixture of diasteromers, each with diastereoselectivity across the b-lactam as stated
In conclusion, we have developed a C–H carbonylation of the
methylene b-C–H bonds in secondary aliphatic amines to form
trans-disubstituted b-lactams. We believe the reaction proceeds
via a carbamoyl–Pd(II) intermediate, from which C–H activation is
The b-lactams could be readily transformed into useful building
blocks. Acidic methanolysis formed the b-amino ester 5;
exhaustive reduction afforded the amino alcohol 6; and treatment
with alane delivered the azetidine 7 (Scheme 3).
selective for the b-C–H bond via
a
5-membered ring
cyclopalladation. The bis-phosphine, xantphos, was important for
achieving the high yields of the b-lactams. Given the broad
tolerance of this reaction to useful functional groups, we believe
that this C–H carbonylation process will be of significant interest
to practitioners of synthesis and medicinal chemistry.8
F
F
O
N
H
3l
CH3
H3C
LiAlH4
(1.25 equiv) reflux
MeOH
HCl
LiAlH4
AlCl3
Et2O
reflux
Et2O
Acknowledgements
Ar
Ar
NH
O
Ar
NH
N
H3C
H3C
OMe
OH
We are grateful to EPSRC (EP/100548X/1), ERC (ERC-
STG-259711) and the Royal Society (Wolfson Award) for
supporting this research (M.J.G.). We thank the Marie Curie
CH3
H
H3C
7, 98%
5, 90%
CH3
6, 90%
CH3
Scheme 3. Derivatization of b-lactams
Foundation (J.C.P.
& M.N.) and the Herchel Smith
Foundation (A.T.) for funding. Mass spectrometry data were
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10.1002/anie.201706303
Angewandte Chemie International Edition
COMMUNICATION
S. Li, G. Chen, C.-G. Feng, W. Gong, J.-Q. Yu, J. Am. Chem. Soc. 2014, 136,
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2015, 6, 4610; For examples of C(sp3)–H carbonylation at methylene groups,
see: e) P. Xie, Y. Xie; B. Qian; H. Zhou; C. Xia; H. Huang, J. Am. Chem. Soc.
2012, 134, 9902; e) P. Xie, C. Xia, H. Huang, Org. Lett. 2013, 15, 3370; For a
related study on methylene C–H carbonylation, see G. Liao; X.-S. Yin; K. Chen;
Q. Zhang; S.-Q. Zhang; B.-F. Shi, Nat. Commun. 2016, 7, 12901.
acquired at the EPSRC UK National Mass Spectrometry
Facility at Swansea University.
Keywords: C–H activation • methylene • aliphatic amines •
carbonylation • palladium catalysis
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(18) The nitrobenzyl group was removed using photochemical cleavage.
O2N
CH3
O
H
O
hv, NaHCO3(aq)
N
H
N
H
MeCN, 45 ˚C, 18 h
71%
CH3
H3C
(4) For auxiliary-controlled Pd-catalyzed methylene functionalization at
unactivated C–H bonds, see: Pyridine/quinoline-derived amides a) V. G.
Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2005, 127, 13154; b)
G. He, G. Chen, Angew. Chem. Int. Ed. 2011, 50, 5192; N-Aryl carboxamides
c) M. Wasa, K. S. L. Chan, X.-G. Zhang, J. He, M. Miura, J.-Q. Yu, J. Am. Chem.
Soc. 2012, 134, 18570; d) G. Chen, W. Gong, Z. Zhuang, M. S. Andrä, Y.-Q.
Chen, X. Hong, Y.-F. Yang, T. Liu, K. N. Houk, J.-Q. Yu, Science 2016, 353,
1023; e) R.-Y. Zhu, K. Tanaka, G.-C. Li, J. He, H.-Y. Fu, S.-H. Li, J.-Q. Yu, J.
Am. Chem. Soc. 2015, 137, 7067; Thiocarbamates f) J E. Spangler, Y.
Kobayashi, P. Verma, D.-H Wang, J.-Q. Yu, J. Am. Chem. Soc. 2015, 137,
11876; Amine derivatives g) J. J. Topczewski, P. J. Cabrera, N. I. Saper, M. S.
Sanford, Nature 2016, 531, 220. For a comprehensive review, see also
reference 2c.
CH3
3k H3C
8
(19) For a review on b-lactams, see: B. Alcaide, P. Almendros, C. Aragoncillo,
Chem. Rev. 2007, 107, 4437.
(5) For auxiliary-controlled Pd-catalyzed methylene functionalization at
activated C–H bonds, see: N-Aryl carboxamides, cyclopropyl C–H a) M. Wasa,
K. M. Engle, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 3680; benzylic C–H b) J.
He, S. Li, Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, A. Homs J.-Q. Yu,
Science 2014, 343, 1216; cyclobutyl C–H c) K.-J. Xiao, D. W. Lin, M. Miura, R.-
Y. Zhu, W. Gong, M. Wasa, J.-Q. Yu, J. Am. Chem. Soc. 2014, 136, 8138; d)
F.-L. Zhang, K. Hong, T.-J. Li, H. Park, J.-Q. Yu, Science 2016, 351, 252;
Sulfonamides, cyclopropyl C–H e) K. S. L. Chan, H.-Y. Fu, J.-Q. Yu, J. Am.
Chem. Soc. 2015, 137, 2042.
For a comprehensive review, see also reference 2c.
(6) G. Chen, Z. Zhuang, G. C. Li, T. G. Saint-Denis, Y. Xiao, C. L. Joe, J.-Q. Yu,
Angew. Chem. Int. Ed. 2017, 56, 1506.
(7) For examples of C–H activation of primary amines using transient directing
groups in C(sp3)–H activation with Pd(II) catalysts: a) Y. Xu, M. C. Young, C.
Wang, D. M. Magness, G. Dong, Angew. Chem. Int. Ed. 2016, 55, 9084; b) Y.
Wu, Y.-Q. Chen, T. Liu, M. D. Eastgate, J.-Q. Yu, J. Am. Chem. Soc. 2016, 138,
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(8) S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451.
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Huang, C. Wang, G. Dong Angew. Chem. Int. Ed. 2016, 55, 5299-5303; (b) N.
Gulia, O. Daugulis Angew. Chem. Int. Ed. 2017, 56, 3630-3634.
(10) For examples of indirect methods for proximity-driven C–H activation in the
b-position to amine derivatives, see: a) D. Dallier, R. Rocaboy, O. Baudoin,
Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201703109; b) J. Pedroni, N.
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(11) A. D. Ryabov, Chem. Rev. 1990, 90, 403.
(12) For examples of Pd-catalyzed C(sp3)–H carbonylation at methyl groups,
see: a) E. J. Yoo, M. Masa, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 17378; b)
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Selective Pd(II)-Catalyzed
Carbonylation of Methylene
Pd(II)-catalyzed C–H carbonylation of methylene C–H bonds in secondary aliphatic
amines leads to the formation trans-disubstituted b-lactams in excellent yields and
selectivities. The generality of the C–H carbonylation process is aided by the action
of xantphos-based ligands and is important in securing good yields of the b-lactam
products.
b
-C–H Bonds in Aliphatic
Amines
10 mol% Pd(OAc)2, CO (1 atm)
10 mol% Xantphos
H
O
N
N
H
AgOAc, benzoquinone
PhMe, 80 ˚C
H
readily prepared amine
32 examples, broad scope
trans-disubstituted β-lactam
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