Palladium-Catalyzed Carbonylative Cyclization of Amines via γ-C(sp3)-H Activation: Late-Stage Diversification of Amino Acids and Peptides

Article abstract of DOI:10.1021/acscatal.6b01987

The selective γ-C(sp³)-H carbonylation of N-(2-pyridyl)sulfonyl (N-SO₂Py)-protected amines has been accomplished by using palladium catalysis and Mo(CO)₆ as carbonyl source. The reaction provides a powerful approach for derivatization of amine-based moieties, including amino acids, into richly functionalized γ-lactams. Not only methyl groups, but also methylene C-H bonds of cyclopropanes and conformationally biased molecules can be activated to provide ring-fused γ-lactam derivatives. This carbonylation protocol is also amenable to the late-stage diversification of more-complex multifunctional molecules such as dipeptides and tripeptides, demonstrating the key role of the N-SO₂Py as directing group and its capacity to override other inherent substrate coordinating elements. In addition to providing an attractive solution to the difficulties in handling hazardous CO gas, the use of Mo(CO)₆ as an air-stable solid source of CO in substoichiometric amount (0.33 equiv) ensures Pd^II-catalytic activity by preventing its decomposition or deactivation under excess of CO via reduction of Pd^II to Pd⁰ or saturation of the metal coordination sphere. Indeed, significantly lower efficiency is observed when the reactions are carried out under CO atmosphere (1 atm), or in the presence of increased amounts of Mo(CO)₆. A series of experimental and DFT mechanistic studies provide important insights about the reaction mechanism.

Full text of DOI:10.1021/acscatal.6b01987

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Article
3
Palladium-Catalyzed Carbonylative Cyclization of Amines via ##C(sp)-H
Activation: Late Stage Diversification of Amino Acids and Peptides
Elier Hernando, Julia Villalva, Angel Manu Martínez, Inés Alonso,
Nuria Rodríguez, Ramon Gomez Arrayas, and Juan C. Carretero
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01987 • Publication Date (Web): 31 Aug 2016
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ACS Catalysis
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Palladium-Catalyzed Carbonylative Cyclization of Amines via
γ‑C(sp3)−H Activation: Late Stage Diversification of Amino
Acids and Peptides
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Elier Hernando, Julia Villalva, Ángel Manu Martínez, Inés Alonso, Nuria Rodríguez*, Ramón Gómez
Arrayás* and Juan C. Carretero*
Departamento de Química Orgánica, Universidad Autónoma de Madrid (UAM). Cantoblanco 28049 Madrid (Spain)
ABSTRACT: The selective γꢀC(sp3)−H carbonylation of Nꢀ(2ꢀpyridyl)sulfonyl (NꢀSO2Py)ꢀprotected amines has been accomꢀ
plished by using palladiumꢀcatalysis and Mo(CO)6 as carbonyl source. The reaction provides a powerful approach for derivatization
of amineꢀbased moieties, including amino acids, into richly functionalized γꢀlactams. Not only methyl groups, but also methylene
C−H bonds of cyclopropanes and conformationally biased molecules can be activated to provide ringꢀfused γꢀlactam derivatives.
This carbonylation protocol is also amenable to the lateꢀstage diversification of more complex multifunctional molecules such as diꢀ
and tripeptides, demonstrating the key role of the NꢀSO2Py as directing group and its capacity to override other inherent substrate
coordinating elements. In addition to providing an attractive solution to the difficulties in handling hazardous CO gas, the use of
Mo(CO)6 as an airꢀstable solid source of CO in substoichiometric amount (0.33 equiv) ensures PdIIꢀcatalytic activity by preventing
its decomposition or deactivation under excess of CO via reduction of PdII to Pd0 or saturation of the metal coordination sphere.
Indeed, significantly lower efficiency is observed when the reactions are carried out under CO atmosphere (1 atm), or in the presꢀ
ence of increased amounts of Mo(CO)6. A series of experimental and DFT mechanistic studies provide important insights about the
mechanism of the reaction.
KEYWORDS: C
−
H carbonylation, Palladiumꢀcatalysis,
γꢀLactam, Amino acid, 2ꢀPyridylsulfonyl, Aliphatic amine, Peptide
INTRODUCTION
tion as it allows installing a synthetically valuable carbonyl
functional group into the desired target molecule.13ꢀ22 Howevꢀ
er, the paucity of catalytic direct carbonylation of C(sp3)−H
bonds highlights the challenging nature of this task.
Despite the direct functionalization of inert C−H bonds is one
of the most prevalent technologies for rapidly introducing
complexity and diversity on a core molecule,1 few methods
have demonstrated to be amenable to lateꢀstage diversification
of complex multifunctional molecules.2 This is particularly
true in the functionalization of C(sp3)−H bonds which, comꢀ
pared to activation of C(sp2)−H bonds, continues to be highly
challenging due to their lower acidity and the absence of π
orbitals causing stabilizing interaction with the transition
metal.3
The use of removable (bidentate) directing groups and Pd
catalysis has emerged as the preferred strategy to promote
both reactivity and selectivity in C(sp3)−H activation.4 In
2004, Sanford et al. pioneered the Pdꢀcatalyzed directed funcꢀ
tionalization (acetoxylation) of aliphatic C−H bonds using
oxime and/or pyridine as directing groups,5 while Daugulis et
al. demonstrated in 2005 the ability of a removable picoꢀ
linamide group to facilitate the Pdꢀcatalyzed C–H arylation at
remote positions of aliphatic amine derivatives.6,7 Shortly
after, Corey et al. expanded this reactivity to the diastereoseꢀ
lective βꢀC(sp3)−H arylation of αꢀamino acid derivatives.8
Since these breakthrough reports, the direct functionalization
of nitrogenꢀcontaining compounds, especially amino acid
derivatives given their prevalence in medicinal chemistry9and
organic synthesis,10,11 stands at the forefront in this field.12
Among the number of applications in various C−C and C−X
bondꢀforming reactions reported, the direct carbonylation of
C(sp3)−H bonds represents a powerful strategy for derivatizaꢀ
At the turn of the 21st century, long after the proof of concept
provided by Fujiwara in 1989,15 the groups of Yu16 and
Chatani17 reported the first effective catalytic carbonylations
of unactivated C(sp3)−H bonds.18,19 Both methods involve βꢀ
carbonylation of aliphatic amides followed by cyclization to
give succinimides under Pd and Ru catalysis, respectively.
Gaunt devised a method for the synthesis of βꢀlactams via
carbonylation of βꢀC(sp3)−H of secondary amines involving
an unusual fourꢀmembered ring cyclopalladation.5h While the
current work was in progress, the groups of Yao and Zhao20
and Wang21 independently disclosed a Pdꢀcatalyzed γꢀC(sp3)–
H carbonylation of aliphatic amines holding a bidentate picoꢀ
linamide or oxalylꢀamide directing group, respectively, thus
providing an efficient access to functionalized γꢀlactams.
In spite of these important recent accomplishments, many
challenges remain unsolved. For example, structurally new
bidentate directing motifs are needed for improving reactivity
and selectivity.23 Indeed, constraints in terms of selectivity
have hampered the development of efficient methods for the
lateꢀstage functionalization of small peptides, which is highly
desirable for peptidomimetic chemistry.24 On the other hand,
carbon monoxide gas is required for most of the reported
procedures, in some cases at high pressure. Although the CO
represents an ideal carbonylation reagent in terms of atom
efficiency, its hazardous nature limits its application on laꢀ
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boratoryꢀscale. Additionally, key obstacles that often limit
catalytic C−H carbonylation under excess of CO stem from: (i)
the reducing ability of CO might induce the reduction of PdII
species to Pd0, and (ii) the excess of CO could inhibit the C−H
activation event by competitively occupying coordination sites
in the PdII center.13,16a,25 Consequently, broadly applicable
alternative approaches superseding the need for gaseous CO
can potentially contribute to further advance.26 However, to
our knowledge, only recently has appeared in the literature the
first example of catalytic C(sp3)−H carbonylation relying on
the use of CO surrogates. Ge et al. have described βꢀ
carbonylationꢀcyclization of aliphatic amides to succinimides
via Ni/Cu synergistic catalysis using DMF as the source of
CO.27
the expected γꢀlactam (+)ꢀ2 was observed, with (+)ꢀ2 being the
only detected reaction product by H NMR in the crude mixꢀ
ture (Table 1, entry 1).
1
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Speculating that this moderate conversion could be caused by
deactivation of the catalytic Pd active species under excess of
CO released from Mo(CO)6, we reasoned that lowering the
amount of Mo(CO)6 could be beneficial to the reaction. A
study of the dependency of reaction efficiency upon the
amount of Mo(CO)6 revealed that this was indeed a crucial
parameter (Table 1). In accordance with our hypothesis, lowꢀ
ering the amount of Mo(CO)6 positively influenced the reacꢀ
tion outcome, guiding us to a substantial and consistent inꢀ
crease in conversion when decreasing the amount of Mo(CO)6
from 1.0 equiv (43% conversion, entry 1) to 0.5 equiv (67%
conversion, entry 2) and 0.33 equiv (95% conversion, entry 3).
However, further decrease of the amount of Mo(CO)6 hold a
negative impact, with 53% conversion being observed with
0.20 equiv (entry 4). Not unexpectedly, an attenuation of the
catalytic activity was consistently observed by increasing the
amount of Mo(CO)6 over 1.0 equiv (entries 5 and 6). Moreoꢀ
ver, when the reaction of (+)ꢀ1 was carried out under gaseous
CO (1 atm, sealed tube), the expected lactam (+)ꢀ2 was obꢀ
tained in a low 37% conversion (entry 7).
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We report herein the development of a practical and reliable
Pdꢀcatalyzed γꢀselective C(sp3)−H carbonylation/cyclization of
NꢀSO2Pyꢀprotected aliphatic amines leading to γꢀlactams. The
use of a substoichiometric amount of Mo(CO)6 (0.33 equiv) as
a nonhazardous, airꢀstable solid source of CO not only avoids
the difficulties in handling CO gas, but also enables slow in
situ release of CO, thus preventing PdIIꢀcatalyst deactivation.
Indeed, the in situ COꢀreleasing ability of Mo(CO)6 has been
previously demonstrated in a range of Pd0ꢀcatalyzed carbonylꢀ
ations of C(sp2)−X bonds.28
Table 1. Influence of the amount of Mo(CO)6 on reaction
efficiency and screening of other sources of COa
RESULTS AND DISCUSSION
Proofꢀofꢀconcept stoichiometric experiment. We recently
reported the (2ꢀpyridyl)sulfonyl (SO2Py)ꢀdirected Pdꢀ
catalyzed arylation of γꢀC(sp3)−H bonds of aliphatic side
chains in αꢀamino esters with iodoarenes.23e In our studies, a
bimetallic PdIIꢀcomplex A derived from the tertꢀleucine derivꢀ
ative (+)ꢀ1 was isolated and structurally characterized by Xꢀ
ray diffraction analysis, thus highlighting the role as bidentate
directing group of the NꢀSO2Py unit (Scheme 1). We decided
to use this complex as an ideal platform to test carbon monoxꢀ
ide insertion leading to carbonylative cyclization products.
The reaction of complex A with Mo(CO)6 (1.5 equiv) using
1,1,1,3,3,3ꢀhexafluoroꢀ2ꢀpropanol (HFIP) as solvent at 70 °C
for 3 hours, resulted in the clean formation of the expected γꢀ
lactam (+)ꢀ2, which was isolated in 69% yield (Scheme 1),
along with a significant amount of decomplexated tertꢀleucine
derivative (+)ꢀ1 (26%, not shown).
Entry
CO source (equiv)
Yield (%)b
1
Mo(CO)6 (1.00)
Mo(CO)6 (0.50)
Mo(CO)6 (0.33)
Mo(CO)6 (0.20)
Mo(CO)6 (2.00)
Mo(CO)6 (4.00)
gaseous CO (1 atm)
Cr(CO)6 (1.00)
Cr(CO)6 (0.33)
Co2(CO)8 (1.00)
Co2(CO)8 (0.33)
ꢀ
43
2
67
3
95 (93)c (77)d,e
4
53
5
42
6
36
7
37
Scheme 1. Proof of concept experiment
8
14
9
20
10
11
12
<10
<10
n.d.
a Reaction
conditions:
tertꢀleucine
derivative
(+)ꢀ1
(0.10 mmol), Pd(OAc)2 (0.01 mmol), AgOAc (0.15 mmol), BQ
Importance of the nature and the amount of the “CO”
source. Encouraged by this proofꢀofꢀconcept result, we next
embarked on the challenging task of developing a catalytic,
rather than stoichiometric, version. On the basis of literature
precedents on Pdꢀcatalyzed C(sp3)‒H arylation of simple
carboxylic acids29 and our previous work,23e we started our
investigations by subjecting the tertꢀleucine derivative (+)ꢀ1 to
carbonylation with Mo(CO)6 (1.0 equiv) in the presence of a
catalytic amount of Pd(OAc)2 (10 mol%) and a combination of
AgOAc (1.5 equiv) and 1,4ꢀbenzoquinone (BQ, 2.0 equiv)30 as
oxidants in HFIP (0.5 M) at 110 °C for 18 h. Under these
reaction conditions, an encouraging 43% conversion towards
(0.20 mmol), CO source (n equiv), HFIP (2 mL), 110 °C, 18 h in a
1
sealed tube. b Conversion yield determined by H NMR of the
d
crude reaction mixture. c Isolated yield. Isolated yield when
e
reaction is scaledꢀup to gramꢀscale ((+)ꢀ1, 1 g, 3.50 mmol)
Identical results were obtained when the reaction (at both 0.1 and
3.5 mmol scale) was performed under air.
We also explored alternative carbon monoxide sources that
could enhance the reactivity. However, a screen of metalꢀ
carbonyl complexes different from Mo(CO)6 typically used as
carbon monoxide sources26 led to worse reaction efficiency.
For example, the use of Cr(CO)6 (either 1.0 equiv or 0.33
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ACS Catalysis
omer could be isolated in 75% yield with no appreciable loss
equiv) provided the desired γꢀlactam (+)ꢀ2 in a much poorer
1
2
3
4
of enantiopurity (97% ee) upon standard chromatography.
Although the structure of the bimetallic complex of γꢀ
cyclopalladation of tertꢀleucine derivative (+)ꢀ1 (complex A)
strongly suggested that the NHꢀSO2Py directing group is cruꢀ
cial for this transformation, we were interested in confirming
this issue by screening other potentially coordinating Nꢀ
protecting groups. For this purpose, a set of Lꢀvaline derivaꢀ
tives (substrates 4ꢀ8) were examined in the carbonylation
reaction under the optimized conditions and the results are
summarized in Table 2. While Lꢀvaline methyl ester hydroꢀ
chloride decomposed under the reaction conditions (entry 2),
the NHꢀTs derivative 5 and the NHꢀ(2ꢀthienyl)sulfonyl derivaꢀ
tive 6 were recovered unaltered without detecting any carꢀ
bonylation product (entries 3 and 4, respectively). The reaction
of the (8ꢀquinolyl)sulfonyl and (2ꢀpyridyl)carbonyl derivatives
(7 and 8, respectively) led to a complex mixture of products in
low conversion (<10%) (entries 5 and 6). Interestingly, the
lack of reaction efficiency observed for the NHꢀCOPyꢀ
protected substrate 8 emphasizes the cooperative directing role
of both the sulfonylꢀtethering group and the 2ꢀpyridyl moiety
in the C‒H activation process.
conversion (≤20%, entries 8 and 9), whereas the Co2(CO)8 was
even less effective, providing only traces of the product (+)ꢀ2
(<10% conversion, entries 10 and 11). Finally, as expected, a
control experiment omitting any CO source determined that γꢀ
lactam (+)ꢀ2 is not produced (entry 12).
5
Importantly, simply adjusting the amount of Mo(CO)6 to
0.33 equiv led us to find conditions for the efficient transforꢀ
mation of tertꢀleucine derivative (+)ꢀ1 into the pyroglutamic
acid derivative (+)ꢀ2, which could be isolated in 93% yield
after purification by column chromatography (entry 3). These
results seem to indicate that each molecule of Mo(CO)6 releasꢀ
es three molecules of CO under the reaction conditions.28c,d
Furthermore, we successfully performed an experiment on a
larger gramꢀscale to demonstrate the practicality of this methꢀ
odology, which afforded product (+)ꢀ2 in 77% isolated yield
after an extended reaction time of 24 h (entry 3). Finally, it
was found that performing the reaction under air had no influꢀ
ence on the reaction (virtually the same results were obtained
at both 0.1 and 3.5 mmol scale), thus eliminating the need for
inert atmosphere (entry 3).
Carbonylation of Lꢀvaline derivative and confirmation of
the directing role of the SO2Py group. Our attention was
shifted to the Pdꢀcatalyzed carbonylative cyclization of the
derivative of the natural amino acid Lꢀvaline ((+)ꢀ3), having a
kinetically less favourable isopropyl group (rather than a tertꢀ
butyl group). Additionally, since the isopropyl unit contains
two diastereotopic methyl groups, this substrate would also
allow testing the diastereoselectivity of the reaction.
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Screening of a handful of other reaction parameters (see Supꢀ
porting Information) revealed the superiority of Pd(OAc)2 over
other Pd sources (no product was detected in the absence of
Pd) and that the combination of AgOAc and benzoquinone
was also essential to reach high catalytic activity. HFIP and
CH3CN were identified as the optimal solvents.
Structural versatility: γꢀCarbonylation of amino acid deꢀ
rivatives. We next set out to investigate the versatility of the
reaction with regard to structural modifications in the amino
acid moiety (Scheme 2). The reaction of the alloꢀisoleucine
derivative (±)ꢀ10a, having two sterically distinct primary and
secondary γꢀC(sp3)‒H bonds, selectively produced the cyꢀ
clized product (±)ꢀ11a (66%), indicating that primary (methyl)
γꢀC(sp3)‒H bonds are more reactive in comparison with secꢀ
ondary (methylene) ones. In contrast, the isoleucine diastereꢀ
omer (+)ꢀ10b was unreactive when exposed to identical cataꢀ
lytic conditions, with no cisꢀ11b detected. This result is in
agreement with the previously observed preference for C‒H
activation of the proꢀS methyl group of the Lꢀvaline derivative
(+)ꢀ3.23e Derivative (±)ꢀ12 bearing a quaternary center at the αꢀ
position did also participate in the reaction, yielding the exꢀ
pected cyclized compound (±)ꢀ13 as a separable 1.5:1 mixture
of diastereoisomers in good yield (87% overall yield).
The tertꢀleucine derivative (+)ꢀ14, bearing a free COOH
group, proved also to be suitable, thus expanding the functionꢀ
al group tolerance. The 5ꢀoxopyrrolidinoneꢀ2ꢀcarboxylic acid
derivative (+)ꢀ15 was obtained in good yield (81%). However,
the threonine derivative (−)ꢀ16, having a free hydroxyl group
at the βꢀposition, failed to provide the C−H carbonylation
product, affording instead the cyclic carbamate (−)ꢀ18 (85%
yield), as a result of a hydrocarboxylation process. More unꢀ
expected was that the protected Oꢀtertꢀbutyl threonine derivaꢀ
tive (−)ꢀ17 led to the same carbamate (−)ꢀ18 under identical
reaction conditions (95% yield).
Table 2. Carbonylative cyclization of valine derivatives:
effect of the protecting/directing groupa
Yield
(%)b
87 (75)e
trans/cisc ee
Entry DG (substrate)
(product) (%)d
1
2
3
4
5
6
(2ꢀpyridyl)SO2 ((+)ꢀ3)
− (4)f
5.7:1 (9) 97
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(pꢀTol)SO2 (5)
(2ꢀthienyl)SO2 (6)
(8ꢀquinolyl)SO2 (7)
(2ꢀpyridyl)CO (8)
ꢀ
ꢀ
<10
<10
a Identical reaction conditions to those in Table 1 (under air).
b Conversion yield determined by H NMR of the crude reacꢀ
1
tion mixture. Determined by 1H NMR. Enantiomeric excess
c
d
of the major product transꢀ9. e Isolated yield of the major
f
product (−)ꢀtransꢀ9. Lꢀvaline methyl ester hydrochloride was
used as substrate, adding 1.0 equiv of Et3N to the reaction.
To our delight, the reaction of (+)ꢀ3 with Mo(CO)6 (0.33
equiv) proceeded smoothly under the optimized conditions,
affording the expected amidocarbonylation product (−)ꢀ9 as an
5.7:1 mixture of trans/cis diastereoisomers (Table 2, entry 1).
This good transꢀdiastereoselectivity is remarkable, revealing a
marked preference for C‒H activation of the proꢀS methyl
group of (+)ꢀ3.23e Importantly, the major (−)ꢀtransꢀ9 diastereꢀ
This method was extended to βꢀamino acid derivatives, as
exemplified by the clean cyclocarbonylation of βꢀamino ester
(±)ꢀ19, affording the product (±)ꢀ20 as a separable 3.8:1 mixꢀ
ture of trans/cis diastereoisomers in good overall yield (76%).
Scheme 2. Carbonylative cyclization of amino acid derivaꢀ
tives
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Mo(CO)6 (0.33 equiv)
Pd(OAc)2 (10 mol%)
BQ (2.0 equiv)
H
N
SO2Py
CO2Me
CO2Me
1
2
3
4
SO2Py
N
O
´
AgOAc (1.5 equiv)
H
H
HFIP, 110 ºC, air, 18 h
(±)-10a
(±)-trans-11a, 66%
5
6
7
8
SO2Py
H
CO2Me
N
CO2Me
N
SO2Py
SO2Py
,,
O
<5% conversion
( )-10b
cis-11b
9
H
N
10
11
12
13
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SO2Py
N
SO2Py
CO2Me
To our delight, when (−)ꢀ21 was subjected to the optimized
N
,,
,,
+
O
O
O
catalytic reaction conditions, the pyrrolidinone (+)ꢀ22 was
cleanly obtained in 89% yield. Moreover, the reaction can be
scaled up to 10 times (1.0 gram scale) in a similarly yield
(85%), thus emphasizing the robustness of this method
(Scheme 4). Also important to take full advantage of the preꢀ
parative potential of this method is the facile removal of the
directing functionality. This was demonstrated upon treatment
of (+)ꢀ22 with magnesium turnings in MeOH at rt under soniꢀ
cation overnight, which afforded the unprotected γꢀlactam
derivative (−)ꢀ23 in 90% yield.32
CO2Me
, 37%
CO2Me
(±)-12
13a
13b
(±)-
(±)-
, 50%
O
SO2Py
H
N
CO2H
N
SO2Py
SO2Py
OH
14
( )-
( )-15, 81%
SO2Py
H
N
CO2Me
CO2Me
N
,,
O
RO
( )-16, R = H
17, R = t-Bu
O
Scheme 4. Catalytic carbonylative cyclization of amine (−)ꢀ
21 and subsequent Nꢀdeprotection
from ( )-16: ( )-18, 85%
from ( )-17: ( )-18, 95%
( )-
SO2Py
HN
SO2Py
SO2Py
N
N
,,
CO2Me
CO2Me
CO2Me
O
O
+
(±)-19
(±)-trans-20, 58%
(±)-cis-20, 18%
Extension of the method to simple aliphatic amines. The
broad substrate scope displayed by this reaction with αꢀamino
acid derivatives prompted us to explore the extension of this
method to simple aliphatic amine derivatives. We first tested if
compound (−)ꢀ21, analogue to tertꢀleucine derivative 1 but
lacking the methyl ester moiety, could undergo γꢀ
cyclometallation. The stoichiometric reaction of (−)ꢀ21 with
Pd(OAc)2 (1.0 equiv) in acetonitrile at 60 °C for 3.5 h, cleanly
provided, after simple recrystallization, the expected bimetalꢀ
lic complex B in 91% yield (unambiguously determined by
single crystal XꢀRay diffraction analysis, Scheme 3), which
presents an analogous structure to complex A.31
This result demonstrated that the ester group at the αꢀposition
of the previously studied αꢀamino ester derivatives was not
essential for the C‒H activation step. Furthermore, the reaction
of this complex with 1.5 equiv of Mo(CO)6 at 70 °C in HFIP
for 3 h afforded the expected γꢀlactam product (+)ꢀ22 in 95%
yield, evidencing that simple Nꢀ(2ꢀpyridyl)sulfonylꢀprotected
aliphatic amines are suitable substrates for the γꢀC(sp3)‒H
carbonylative cyclization protocol (Scheme 3).
An examination of the scope of carbonylation of various simꢀ
ple aliphatic amine derivatives was undertaken to test the
versatility of the reaction with regard to steric modifications of
the reactive γꢀC(sp3)‒H bond (Scheme 5). The product of
trans configuration was again formed predominantly (trans/cis
= 5.6:1) in the reaction of (−)ꢀ24, possessing two diastereotopꢀ
ic βꢀmethyl groups, allowing the isolation of (+)ꢀtransꢀ26 in
78% yield. In sharp contrast, the 2ꢀbutanamide derivative (±)ꢀ
25, without branching at the βꢀposition, was recovered unalꢀ
tered even when increasing the catalyst loading to 20 mol% of
Pd(OAc)2. When the achiral substrate 27 was tested, the correꢀ
sponding pyrrolidinone derivative (±)ꢀtransꢀ28 having two
contiguous stereogenic centers was obtained in good yield
(71%) as a single diastereoisomer. These results suggest that
branching at the βꢀposition is an essential biasing structural
element for the reaction to proceed.
We were pleased to find, however, that branching at the αꢀ
position was not a required structural feature for this transforꢀ
mation (substrates 29 and 31), even though this type of substiꢀ
tution is often necessary as turning elements maximizing the
conformation that leads to C‒H activation. Nevertheless, the
reaction proved to be more difficult, requiring an increased
catalyst loading of 20 mol% to achieve synthetically useful
yields (Scheme 5). For instance, the carbonylative cyclization
of the 2,2ꢀdimethylpropanamine derivative 29 afforded the 2ꢀ
pyrrolidinone derivative 30 in good yield (71%). On the other
hand, the less conformationally restrained derivative 31 was
found to be significantly less reactive, providing the correꢀ
sponding 4ꢀmethylꢀ2ꢀpyrrolidinone 32 in an acceptable 42%
Scheme 3. Stoichiometric γꢀC(sp3)−H cyclopalladation and
carbonylation of aliphatic amine derivative (−)ꢀ21
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ACS Catalysis
yield under identical reaction conditions. In accordance with for the strong dependence of reactivity on the degree of substiꢀ
1
2
3
4
these observations, the linear Nꢀ(SO2Py)sulfonyl propanamine
derivative 33 (see structure in Scheme 6), having unbranched
both αꢀ and βꢀpositions, was unreactive towards the C‒H
carbonylation (not shown).
tution (branching) of the substrate.
Scheme 6. Formation of bisꢀamide Pdꢀcomplex C from
linear sulfonamide 33
5
6
7
Scheme 5. Effect of branching at α− and β−position in
aliphatic amine derivatives
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22
23
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25
26
27
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48
49
50
51
52
53
54
55
56
57
58
59
60
Carbonylation at γꢀmethylene groups of aliphatic amine
derivatives. At this point, we wondered whether it might
enable activation at the more challenging (less reactive)
γꢀmethylene C‒H bonds.33 In particular, cyclopropane derivaꢀ
tives are attractive because of their prominence in natural
products and pharmaceuticals,34 along with the relative scarciꢀ
ty of methods enabling their C‒H activation.35 Additionally,
the rigidity of the cyclopropyl ring and the more sp2ꢀlike charꢀ
acter for its carbon atom should facilitate C‒H functionalizaꢀ
tion processes.
As shown in Scheme 7, compound 34 could be smoothly
transformed into the expected cyclopropaneꢀfused pyrroliꢀ
dinone36 derivative 35 in 97% yield as a 1.9:1 mixture of diaꢀ
stereoisomers, although it required increased catalyst loading
(20 mol%). This result shows that not only this method is
effective for the carbonylation of methylene C‒H bonds in
cyclopropylmethylamine derivatives, but it also reveals that
cyclopropyl C(sp3)‒H methylene groups can be selectively
carbonylated over a methyl γꢀC(sp3)‒H bond. The less conꢀ
formationally biased substrate 36, lacking the βꢀmethyl subꢀ
stituent did also participate in the reaction, providing the corꢀ
responding bicyclic lactam with increased diastereoselectivity
(37, 98% yield, cis/trans = 9:1), although a higher 30 mol% of
Pdꢀcatalyst was needed for achieving complete conversion.
Intrigued by the strong dependence of the reactivity on the
steric properties imposed by the substitution pattern of the
substrates and the appearance of an unknown product in the
reaction of amine derivatives lacking any substituent at the βꢀ
position (starting compounds 25 and 33), we decided to study
in more detail the cause behind this effect. In a recent report
by Gaunt on Pdꢀcatalyzed C−H activation of unprotected
aliphatic amines to give strained nitrogen heterocycles, hinꢀ
dered secondary amines were used to overcome the propensity
of these amines to form very stable, coordinatively saturated
and catalytically inactive, squareꢀplanar bisꢀamine palladiꢀ
um(II) complexes.5h It was suggested by the authors that the
steric hindrance around the PdII center should facilitate dissoꢀ
ciation of an amine ligand to create the essential vacant coorꢀ
dination site required for the C−H activation to take place. In
fact, this could be a primary reason for the scarcity of studies
involving aliphatic amines in C–H bond functionalization.
Accordingly, we found reasonable to assume the formation of
this type of bisꢀamine complexes in the reaction of the secondꢀ
ary sulfonamides. In the present case, the N,Nꢀbidentate nature
of these substrates imparted by the NꢀSO2Py directing group
should strengthen the interaction of the substrate to the metal,
thereby compensating the weakened coordination ability of a
sulfonamide compared to amine ligands, leading to more
stable complexes. To test this hypothesis, the linear propanaꢀ
mide derivative 33 was treated with a stoichiometric amount
of Pd(OAc)2. After 3 h of reaction in HFIP at 60 °C, we obꢀ
Scheme 7. Carbonylation at γꢀmethylene groups
1
served by H NMR the clean formation of the mononuclear
airꢀstable palladium complex C, which was isolated in 85%
yield (Scheme 7). XꢀRay diffraction analysis of suitable crysꢀ
tals revealed a slightly distorted squareꢀplanar N,N,N,Nꢀ
tetracoordinated palladium complex in which the PdII atom
coordinates two molecules of 33 through the deprotonated
amide and the pyridyl nitrogen atoms.31 The formation of this
type of stable Pdꢀcomplex provides a reasonable explanation
The conformationally biased exoꢀnorbornylamine derivative
38, lacking a marked sp2 character, afforded the expected
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C(sp2)−H versus C(sp3)−H carbonylation selectivity. The
lactam 39 with 75% conversion (50% yield) when subjected to
suitability of this method for both C(sp3)‒H and C(sp2)‒H
bond activation led us to examine site selectivity in substrates
containing both types bonds. For this purpose, the 2ꢀmethylꢀ1ꢀ
phenylpropanamine derivative 50, containing both γꢀC(sp2)‒H
and γꢀC(sp3)‒H bonds, was next tested (Scheme 9). Not unexꢀ
pectedly, the carbonylation reaction occurred at the site of the
more acidic C(sp2)−H, leading to the isoindolinone derivative
51 in 92% yield. The same preference for aryl activation was
still maintained even when the C(sp2)−H bond was located at
δꢀposition, as demonstrated in the reaction of derivative 52,
which afforded exclusively the 3,4ꢀdihydroisoquinolinone 53
in 82% isolated yield. Interestingly, opposite site selectivity
(i.e., complete preference for γꢀC(sp3)‒H activation) was atꢀ
tained in the case of the derivative 54 having the phenyl group
1
2
3
4
5
6
7
8
the general catalytic reaction conditions using 20 mol% of
Pd(OAc)2 (Scheme 7). Likewise, the functionalization of the
1ꢀ[adamantanꢀ1ꢀyl)ethanamine derivative 40 under similar
conditions turned out to be viable, albeit with a lower yield
(41, 33%). Despite the modest yield, the result is remarkable
considering the scarcity of C−H activation reactions in nonꢀ
activated methylene groups.33,37
C(sp2)‒H carbonylationꢀcyclization reactions. To test
whether this method would be also effective for the C(sp2)‒H
carbonylation, the dibenzylic sulfonamide derivative 42, havꢀ
ing four C(sp2)‒H bonds at the γꢀposition, was submitted to
the carbonylation reaction. Unfortunately, however, only 38%
of the corresponding 3ꢀphenylisoindolinone 43 was isolated
along with the (2ꢀpyridyl)sulfonamide in 40% yield (Scheme
8).38 In fact, the NꢀSO2Pyꢀbenzylamine derivative 44, which is
less prone to benzylic elimination, underwent cyclocarbonylaꢀ
tion to afford the corresponding isoindolinone derivative 45 in
a synthetically useful yield (52% isolated).39
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26
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55
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58
59
60
one bond further away from the directing group [
bond], even though the same customized conditions previously
optimized for the
ꢀC(sp2)‒H carbonylation/cyclization of
ε
ꢀC(sp2)‒H
ε
derivative 48 were employed. In this case, the selective forꢀ
mation of the γꢀlactam 55 (75% yield) over the corresponding
benzo[c]azepineꢀ1ꢀone product is likely caused by the much
more kinetically disfavored sevenꢀmembered ring formation
compared with a five membered ring, thereby overriding the
higher reactivity of the aromatic C−H bond.
Importantly, this method can be extended to phenethylamine
derivatives. For example, the δꢀcarbonylation of the pheneꢀ
thylamine derivative 46 afforded the 3,4ꢀdihydroisoquinolinꢀ
1(2H)ꢀone 47 in very high yield. This result suggests the parꢀ
ticipation of a sevenꢀmembered palladacycle intermediate
prior to CO insertion.40 Even the direct functionalization of the
ε
ꢀC(sp2)‒H bond of the 3ꢀphenylpropylamine derivative 48
Scheme 9. C(sp3)‒H versus C(sp2)‒H selectivity
turned out to be viable, yet using customized reaction condiꢀ
tions with increased catalyst loading and oxidants [Pd(OAc)2
(25 mol%), AgOAc (2.0 equiv) and BQ (3.0 equiv)], providꢀ
ing the benzo[c]azepineꢀ1ꢀone derivative 49 in 57% yield.
This structural flexibility is remarkable since very often the
precise tether length of the directing group is found to be
crucial for reactivity in C−H activation.41 A further point to
note is that, compared to the plethora of methods for the conꢀ
struction of fiveꢀ or sixꢀmembered Nꢀheterocyclic systems,
there are very few reports on the direct synthesis of sevenꢀ
membered rings by Pdꢀcatalyzed oxidative cyclization.42
Scheme 8. C(sp2)‒H carbonylation of amine derivatives
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ACS Catalysis
1
2
Scheme 10. Sequential C−H arylation and carbonylative cyclization for introducing structural diversity and complexity on
tertꢀleucine derivative (+)ꢀ1
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Monoarylation conditions: AgOAc (1.5 equiv), 4ꢀiodotoluene (1.5 equiv). b Diarylation:AgOAc (1.5 equiv), 4ꢀiodotoluene (2.5 equiv).
c Triarylation: AgOAc (3.5 equiv), 4ꢀiodotoluene (3.5 equiv). Ar = pꢀTol. SO2Py = 2ꢀPySO2. For further details, see SI.
On the basis of these results, and taking advantage of our
previously reported Pdꢀcatalyzed γ-C−H arylation of αꢀamino
acid derivatives with iodoarenes,23e we envisaged that a seꢀ
quential two C−H functionalization processes (i.e. arylation
followed by carbonylative cyclization) could provide an effiꢀ
cient strategy for rapidly introducing complexity and diversity
on a core amine molecule. We chose the tertꢀleucine derivaꢀ
tive (+)ꢀ1 as an ideal platform to test this possibility. As shown
in Scheme 10, our previously developed C−H arylation methꢀ
od23e enabled the selective preparation of the monoꢀ, diꢀ and
triꢀarylated derivatives (+)ꢀ56, (+)ꢀ58 and (+)ꢀ60, respectively,
in good yields (73ꢀ93%) by simply adjusting the excess of
iodoarene and oxidant. Subsequently, each of these tertꢀ
leucine derivatization products was subjected to the optimized
conditions for the Pdꢀcatalyzed carbonylative cyclization. The
reaction outcome proved to be strongly dependent on the
substitution pattern at the starting amine derivative. For inꢀ
induce siteꢀspecific reactivity on complex molecules at otherꢀ
wise unreactive sites, the estrone derivative 62,43 having a
variety of sterically distinct primary and secondary C−H
bonds, as well as a potentially reactive aryl sulfonate, was
chosen (Scheme 11). We were delighted to find that the C−H
carbonylation/cyclization reaction of 62 afforded cleanly the
pentacyclic γꢀlactam product 63, resulting from γꢀ
functionalization at the methyl group, in 40% yield. This result
also illustrates the capacity of the bidentate NꢀSO2Py directing
group to act in the presence of the potentially coordinating Oꢀ
SO2Py unit.
Scheme 11. Lateꢀstage carbonylation of the estrone derivaꢀ
tive
stance, the
with complete γꢀC(sp3)‒H site selectivity but low stereocontrol
(dr = 1.5:1) to afford the ꢀlactam (+)ꢀ57a in 38% yield,
γꢀmonoarylated compound (+)ꢀ56 smoothly reacted
γ
accompanied by (+)ꢀ57b in 28% yield. In contrast, the diaꢀ
rylated compound (+)ꢀ58 delivered exclusively the
corresponding benzazepineꢀ1ꢀone derivative (+)ꢀ59 in 80%
yield and high diastereoselectivity (no other diasteromer was
detected). The γꢀlactam product was not detected by 1H NMR
of the crude reaction mixture, revealing that the presence of
two aryl substituents (four orthoꢀC−H bonds against three γꢀ
C(sp3)−H bonds) kinetically favors aryl activation. Not unexꢀ
pectedly, the triarylated derivative (+)ꢀ60, having six equivaꢀ
lent orthoꢀC−H bonds, provided the benzo[c]azepineꢀ3ꢀ
carboxylate (+)ꢀ61 in good yield (67%). It is important to note
that up to four new C−C bond and one new C−N bond are
formed in this twoꢀstep derivatization protocol.
Carbonylation/cyclization of diꢀ and triꢀpeptides. Motivated
by the great significance of postꢀsynthetic modification of
small peptides as a means of optimizing their molecular funcꢀ
tion or discovering new biologically active candidates, we
sought to expand the substrate scope of this reaction to diꢀ and
triꢀpeptides. The increased complexity of this class of moleꢀ
cules represents a demanding test due to the possible forꢀ
mation of competing N,Nꢀ or N,Oꢀbisꢀcoordinated complexes
with PdII that could either inhibit the reaction or compromise
the desired pathway in terms of selectivity. Indeed, Yu has
recently demonstrated that the native amino acid moiety of
peptides can coordinate with PdII via N,Nꢀ or N,Oꢀbisdentate
coordination and promote the functionalization of proximate
C(sp3)−H bonds such as arylation or acetoxylation reactions.5i
We were delighted to see that the carbonylative cyclization of
both tertꢀleucineꢀglycine ((+)ꢀ64) and valineꢀglycine [(+)ꢀ66]
Lateꢀstage diversification of functional molecules
Derivatization of a derivative of the steroid strone. Addiꢀ
tionally, to further demonstrate the potential of this method to
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dipeptide derivatives took place efficiently providing the corꢀ
MeO2C
O
1
2
3
4
5
6
7
8
N
O
responding modified dipeptides (−)ꢀ65 and (−)ꢀ67 in good
yields (87% and 77%, respectively) and complete siteꢀ
selectivity control (Scheme 12). In the case of the valineꢀ
containing dipeptide, the product (−)ꢀ67 was obtained with
good transꢀdiastereoselectivity (trans/cis = 6.7:1). Encouraged
by this outstanding reactivity, we questioned whether this
carbonylation protocol could be applied to the more challengꢀ
ing tripeptide derivatives. We chose the valineꢀglycineꢀvaline
derivative (−)ꢀ68 as substrate because it contains two valine
moieties, one at the Nꢀterminus and another one at the Cꢀ
terminus, thus being well suited to test the capability of the Nꢀ
SO2Py directing group in controlling siteꢀselectivity. To our
delight, the carbonylation of tripeptide (−)ꢀ68 under the optiꢀ
mized reaction conditions proceeded smoothly to afford the
expected modified tripeptide (+)ꢀ69 as the only isolated prodꢀ
uct in 71% yield after chromatographic purification. Imꢀ
portantly, the C‒H activation occurred with complete siteꢀ
selectivity control at the Nꢀterminus, thus highlighting the
capacity of the bidentate NꢀSO2Py directing group to override
other inherent substrate coordinating elements. Also remarkaꢀ
ble is that the reaction occurred with nearly complete
transꢀdiastereoselectivity (trans/cis = >20:<1), presumably
due to the bulky peptide chain attached to C(5) of the 2ꢀ
pyrrolidinone cyclic system (Scheme 12).
Pd
Pd
SO2
N
N
S
N
CD3CN
O
CO2Me
N
Pd
S O
N
N
D3C
CO2Me
A
A´
(monomeric)
(dimeric)
This assumption was initially based on the fact that the 1Dꢀ
selective nOe spectrum in CD3CN obtained by inversion of the
signal corresponding to the proton ortho to the nitrogen of the
pyridine ring (H1, 8.38 ppm) showed a weak nOe interaction
(<0.05%) with the methylene protons (H2 and H2', 2.12 and
1.94 ppm, respectively, Figure 1). In fact, a similar 1Dꢀ
selective nOe spectrum of A in DCEꢀd4 (an apolar nonꢀ
coordinating solvent) shows an important nOe interaction
(4.7% and 5%).45
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 12. Lateꢀstage carbonylation of diꢀ and tripeptides
CO
Mo(
)
6 (0.33 equiv)
SO2Py
O
O
Pd(OAc)2 (10 mol%)
BQ (2.0 equiv)
CO2Me
H
N
N
SO2Py
N
CO2Me
N
O
H
H
AgOAc (1.5 equiv)
HFIP, 110 ºC, air, 18 h
H
γ
+
( )-
64
−
65
( )- , 87%
SO2Py
O
O
H
N
N
,,
SO2Py
N
H
CO2Me
N
CO2Me
66
O
H
H
γ
+
( )-
67
(−)- , 77%
(trans/cis = 6.7:1)
O
SO2Py
CO2Me
O
H
H
N
H
N
N
CO2Me
,,
N
SO2Py
N
H
N
H
H1
H2
H2’
O
O
γ
O
H
68
(−)-
H
(+)-69, 71%
(trans/cis = >20:<1)
1D- NOE
4.70%
5.00%
Mechanistic insights
Nuclearity of complex A in solution. In order to gain insights
into the reaction mechanism, we first sought to identify the
catalytically active species. Previous studies performed in our
group suggested that the dimer is not the predominant species
in solution of CD3CN,44 but rather this complex is mainly
present as a monomer (most likely A´), in which the weakly
coordinating CD3CN reversibly coordinates the active catalyst
(A´) (Scheme 13).
0.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
f1 (ppm)
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.
Figure 1. 1Dꢀselective nOe spectrum of A in two solvents
with different coordinating ability. Upper: 1Dꢀselective nOe
spectrum of A in CD3CN at 5° C. Lower: 1Dꢀselective nOe
spectrum of A in DCEꢀd4.
Scheme 13. Behaviour of complex A in a CD3CN solution
To add more light to this hypothesis, we performed an analysis
by positive electrospray high resolution mass spectroscopy
(ESIꢀHRMS) of two separate solutions of complex A, one in
the weakly coordinating CH3CN as solvent and another one in
the nonꢀcoordinating solvent CH2Cl2. The ESIꢀHRMS specꢀ
trum of complex A in MeCN is shown in Figure 2. The main
feature of this spectrum is that it shows intense peaks correꢀ
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ACS Catalysis
sponding to monomeric PdII complexes. In fact, the monomerꢀ
ic complex A´ was detected as the most intense peak [m/z
1
2
3
4
5
6
7
8
(M+H)+: 432.0198], while the corresponding monomeric
complex A´´, resulting from A´ by loss of CH3CN ligand, was
detected in lower abundance [m/z (M+H)+: 390.9872]. Instead,
the dimeric form of this complex (complex A), easily attributꢀ
able to the peak at m/z (M+H)+: 780.9782, was detected with a
very low intensity. In comparison with the previous results,
the ESIꢀHRMS analysis of a solution of complex A in CH2Cl2
showed the dinuclear species (A) with the highest intensity,
clearly indicating that this complex becomes predominant in
nonꢀcoordinating solvents (Figure 3). No mononuclear species
associated with this complex was detected in this case.
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. HRMS spectrum of complex A in CH2Cl2
These observations are in accordance with the much higher
catalyst activity encountered in coordinating solvents such as
HFIP or CH3CN (≥87% conversion in the model reaction of
3→9), compared to the low outcome when using the nonꢀ
coordinating DCE (17% conversion, see Supporting Inforꢀ
mation for solvent screening studies).
Monitoring stoichiometric carbonylation of complex A.
1
Next, we monitored by H NMR in CD3CN as solvent (much
less expensive than deuteratedꢀHFIP) the stoichiometric reacꢀ
tion of complex A with Mo(CO)6 (0.33 equiv) at rt. This exꢀ
periment led us to find a fast and clean formation of an interꢀ
mediate (D) which reached its highest concentration after 2.5 h
(roughly complex A/intermediate D ratio = 1:1), as shown in
Figure 4 (vide infra for characterization of intermediate D).
The resulting mixture remained almost unaltered for a period
of further 2.0ꢀ2.5 h and suddenly, a relatively fast conversion
of intermediate D into the final γꢀlactam (+)ꢀ2 was observed,
with a complete disappearance of characteristics signals of
intermediate D upon 7.5 h. Remarkably, a 60% conversion
towards (+)ꢀ2 was achieved after 9.5 h of reaction. Nevertheꢀ
less, full conversion of complex A into the γꢀlactam 2 was
reached under extended reaction times (24 h). Figure 5 shows
the complete reaction kinetic profile from a measure of conꢀ
version (%) versus time (hours).
Figure 2. HRMS spectrum of complex A in CH3CN
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SO2
N
SO2Py
SO2
N
1
2
3
4
O
N
N
N
Mo(CO)6 (0.33 equiv)
CD CN,
CO2Me
Pd
+
CO2Me
CO2Me
Pd
N
OC
rt
3
γ
γ
D
2
(+)-
A'
intermediate
complex
5
(from a solution of
6
A
complex in CD3CN)
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. 1H NMRꢀMonitoring the reaction of complex A with Mo(CO)6 (0.33 equiv) in CD3CN at rt.
by decomposition of intermediate D, likely through CO ligand
displacement by CD3CN (the signal for the CD3 group of this
CD3CN ligand would appear overlapped with the signal of the
solvent).47
Importantly, monomeric intermediate D was detected as the
highest intensity peak upon analysis by ESIꢀHRMS of a
CD2Cl2 solution [m/z (M+CO+H)+: 418.9893] accompanied by
the corresponding C‒H activation complex A´´ after loss of
CO [m/z (MꢀCO+H)+: 390.9943] (Figure 6).48
2
A'
D
Figure 5. Complete kinetic reaction profile of complex A with
Mo(CO)6 (0.33 equiv) in CD3CN at rt
Structural characterization of intermediate D. The 1H
NMR spectra of intermediate D in CD3CN was very similar to
that of complex A, providing little structural information (just
very small differences in chemical shifts). However, the 13C
NMR spectrum in CD3CN (at −20 °C to minimize decomposiꢀ
tion) showed two extra peaks compared to the 13C NMR specꢀ
trum of complex A. While one of them at 179.0 ppm, was
assigned to a CO bonded to the Pd center,46 the other one, at
125.4 ppm, with a very low intensity, was tentatively assigned
to the nitrile carbon of the CD3CN ligand bonded to the Pd
center in the monomeric complex A´ which is slowly formed
Figure 6. HRMS spectrum of intermediate D in CD2Cl2.
Finally, the presence of a CO molecule as external ligand in
the structure of intermediate D was corroborated by IR specꢀ
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being formed as the Pd‒CO bond is being cleaved [TS(VIIꢀ
troscopy. A very representative peak at 2095 cm−1 (observed
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6
VIII)a, 10.4(6.9) kcal/mol)] yielding the cyclized intermediate
VIIIa [−10.2(−14.3) kcal/mol)] where the ester moiety adopts
a pseudoecuatorial conformation. However, a more stabilized
intermediate was found in which the ester group presents a
pseudoaxial conformation, IXa [−13.4(−17.7) kcal/mol)]. In
this first route, both C‒H activation and the CO insertion steps
present transition states very similar in energy (19.7 and 19.1
kcal·mol−1, respectively) and thus both could act as reaction
limiting steps (having the C‒H activation step a slightly higher
energy barrier).
both in CD3CN and CD2Cl2) was very characteristic and perꢀ
fectly matches with previously reported data for similar pallaꢀ
diumꢀcarbonyl complexes (typically in the range of 1900ꢀ2100
cm−1).46 The stretch vibration corresponding to the carbonyl
group of the methyl ester moiety appeared, as expected, at
1742 cm−1 (See Supporting Information).
Computational studies. To shed more light on the carbonylaꢀ
tion/cyclization reaction mechanism, a complete energy proꢀ
file for the reaction of the Nꢀ(2ꢀpyridyl)sulfonylꢀtertꢀleucine
derivative 1 was calculated (Figure 7). The first considered
step was the C−H activation. It may occur by several potential
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This energy profile did not provide an explanation for the
observed negative role of an excess of CO in the reaction
medium since a more energy demanding insertion step would
be expected in this case. Thus, in order to evaluate the effect
of CO as a ligand in these intermediates route b was also studꢀ
ied. However, as shown in Figure 7, all the intermediates and
transition states found were much more stable, indicating the
C‒H activation step could be the reaction limiting one and
once the required energy to overcome this step was available,
the process should be favourable. Therefore, the possible
influence of CO before the C−H activation step was explored
(Figure 8). The coordination of a CO molecule in complex I
afforded a much more stable complex Ib. A conformational
change on this complex gave rise to complex IIb, from which
the located transition state for the C‒H activation step [TSIIbꢀ
CHact, 22.8 (23.8) kcal·mol−1] was less stable than that proꢀ
posed without coordination of CO [Figure 7, TSIIꢀIII,
19.7 (18.3) kcal·mol−1]. This suggests that the limiting C‒H
activation step becomes more difficult when an excess of CO
is present. Additionally, from complex IIb a more favourable
pathway for the insertion of CO into the Pd−N bond was
found. A change in the coordination mode of the acetate ligꢀ
and promotes the displacement of the pyridine one affording
complex IIIb from which the insertion process takes place
[TS(IIIꢀIV)b, 19.5 (21.8) kcal·mol−1] to give a quite stable
sixꢀmembered amide type complex IVb. From this intermediꢀ
ate, the C−H activation process would be extremely difficult
[TSIVbCHact, 39.8 (39.4) kcal·mol−1], promoting the entire
catalytic cycle to stop. This competitive offꢀcycle nonꢀ
productive pathway could explain the empirically observed
negative role of an excess of CO.
mechanisms. Among them,
a
concerted metalationꢀ
deprotonation (CDM) pathway has often been found to be the
most favourable.49 Based on our previous studies,44 model
complex I was used as starting point.50 A change in the conꢀ
formation of this complex affords complex II that shows an
agostic interaction between the Pd atom and the C‒H bond
that is going to be cleaved. The most stable transition state
found for this C‒H activation was TS(IIꢀIII), in which the sixꢀ
membered cycle formed by Pd, N and the rest of the amino
acid moiety, including the C‒H bond being cleaved, adopts a
distorted chairꢀlike conformation. After the C‒H activation
process, a bicyclic fiveꢀfiveꢀmembered palladium intermediate
III is formed which could suffer a ligand exchange between
the acetic acid and an acetonitrile solvent molecule, thus genꢀ
erating intermediate IV [model structure of the proposed inꢀ
termediate D, −1.2(−7.1) kcal·mol−1] as a stable palladium(II)
complex stabilized by the pyridine ring and the acetonitrile
molecule. In the presence of CO ligands, another ligand exꢀ
change can take place between the acetonitrile and the CO
ligand, generating an even more stable intermediate V
[−10.2(−15.4) kcal·mol−1] in which the sulfonamide nitrogen
and the CO adopt a transꢀarrangement.
If palladium atom coordinates another molecule of solvent or
carbon monoxide, the pyridine ring could be displaced out of
the coordination plane achieving different intermediates VI
from which two similar routes a (L=CH3CN) and b (L=CO)
have been studied. While VIa and VIb differ in the nature of
the ligand (L) but both keep the sulfonamide nitrogen and one
CO ligand in a transꢀarrangement, in VI’a these groups show
a cisꢀconfiguration.
We first studied route a. The CO insertion could just be
achieved from VIa via a high energetic transition state TS(VIꢀ
VII)a [19.1(16.4) kcal·mol−1] that shows a pentaꢀcoordinated
palladium structure. In this transition state, the Pd‒C bond is
being cleaved while the C‒CO‒Pd bond is being formed (inꢀ
sertion) by a three memberedꢀring in a concerted way, yielding
VIIa as a bicyclic sixꢀfiveꢀmembered palladium(II) intermediꢀ
ate in which the other vacancies are occupied by an acetoniꢀ
trile ligand and the pyridine ring. All the attempts to find an
analogous insertion transition state from VI´a failed, probably
due to an important electronic repulsion between CO and SO2
groups as they get closer. These results finally suggest that the
CO insertion probably takes place into the C−Pd bond (via
intermediate C‒CO‒Pd), dismissing other alternative hypotheꢀ
sis which proceeded via the CO insertion on the N‒Pd bond
(intermediate, N‒CO‒Pd). Complex VIIa evolves through a
reductive elimination transition state where the N‒CO bond is
Working mechanistic hypothesis. Based on these mechanisꢀ
tic insights gained from both experimental and theoretical
studies, we propose the simplified catalytic cycle presented in
Scheme 14. We reasoned that the reaction might proceed
through initial PdIIꢀcatalyzed γꢀC‒H activation via a concerted
metalationꢀdeprotonation (CMD) mechanism assisted by the
acetate ion, thus leading to the bimetallic complex A, which is
in equilibrium with an active monomeric complex A´. The
latter might undergo solvent ligand displacement by CO to
afford intermediate D. Carbonyl insertion across the Pd‒C
bond (intermediate VII), energetically favoured over the inserꢀ
tion across the Pd‒N bond), followed by reductive elimination
would yield the carbonylative cyclization product. The so
formed reduced Pd0 species would then reoxidize back to the
active PdII species via the combined action of BQ and AgOꢀ
Ac.51
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Figure 7. A complete energy profile for the reaction of the Nꢀ(2ꢀpyridyl)sulfonylꢀtertꢀleucine derivative 1 in the gas phase. Relative
G values are reported at 298 K (kcal·mol−1). Single point solvation energy corrections (CH3CN, CPCM model) are indicated in
parentheses.
298 K (kcal·mol−1). Single point solvation energy corrections
(CH3CN, CPCM model) are indicated in parentheses.
TSIVCHact
39.8(39.4)
Scheme 14. Tentative mechanistic rationalization
O
O
O
Me
N
S
O
MeO
Me
H
Pd
N
MeO
H
O
O
MeO
H
O
O
S
O
H
O
C
O
O
O
S
Me
N
N
Me
Me
TSIIbCHact
Me
CO
Pd
Pd
N
Me
22.6 23.8)
(
Me
H
N
O
O
O
TS(III-IV)b
19.5 21.8)
O
(
Me
Me
G
O
MeO
O
S
O
OC
MeO
N
O
H
O
S
IIIb
Me
CO
CO
O
Pd
N
Me
H
Me
N
O
4.6(7.5)
Me
Me
O
Pd
O
N
I
Me
CO2Me
Me
O
O
O
0
S
IVb
H
IIb
-4.5(-4.2)
Me
Me
N
Me
-2.3(-4.3)
Pd
N
O
O
O
Me
Ib
OMe
H
Me
Me
Me
O-6.4(-5.3)
O
S
N
Me
N
Pd
C
O
O
O
O
Me
Figure 8. A possible competitive route in the presence of an
excess of carbon monoxide. Relative G values are reported at
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AUTHOR INFORMATION
CONCLUSIONS
1
In conclusion, a practical and reliable Pdꢀcatalyzed procedure
for the siteꢀselective γꢀC(sp3)−H carbonylation/cyclization of
aliphatic amine derivatives, including αꢀ and βꢀamino acid
derivatives, has been developed, thus leading to the correꢀ
sponding γꢀlactams in good yields through a twoꢀfold carꢀ
bonylation [at both C(γ)−H and N−H bonds]. This protocol
strongly relies on the excellent directing ability displayed by
the NꢀSO2Py protecting group, which also proved to be easily
removed under mild conditions. In addition to γꢀmethyl
groups, the reaction proved to be also effective for the activaꢀ
tion of γꢀmethylene C−H bonds of cyclopropanes and conforꢀ
mationally biased molecules. This carbonylation protocol also
allows lateꢀstage modifications of more complex, functional
compounds such as diꢀ or tripeptides, thereby illustrating the
capacity of the bidentate NꢀSO2Py directing group to override
other inherent substrate coordinating elements, as well as
broad functional group tolerance. Importantly, the use of a
substoichiometric amount of Mo(CO)6 (0.33 equiv) as a solid
source of CO circumvents the problem of handling toxic gaseꢀ
ous CO and also enables slow in situ generation of CO, thus
preventing PdII catalyst deactivation under excess of CO, as
suggested by both experimental and computational studies.
Corresponding Author
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n.rodriguez@uam.es; ramon.gomez@uam.es; juancarꢀ
los.carretero@uam.es.
ACKNOWLEDGMENT
We thank the Spanish Ministerio de Economía y Competitividad
(MINECO, Project CTQ2012ꢀ35790), and MINECO/FEDER, UE
(Project CTQ2015ꢀ66954ꢀP) for financial support. E.H. thanks the
Gobierno Vasco for a predoctoral fellowship. N.R. thanks the
MICINN for a Ramón y Cajal contract and the European Comꢀ
mission for a Marie Curie Foundation (CIG: CHAASꢀ304085).
We also thank the Centro de Computación Científica de la UAM
for generous allocation of computer time.
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REFERENCES
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EXPERIMENTAL SECTION
General methods. All reactions were carried out in anhydrous
solvents taken from PureSolv MD purification system. Pallaꢀ
dium precatalysts, metal carbonyls and silver salts were purꢀ
chased from commercial sources and used without further
purification.
Computational methodology. Geometries were optimized
with B3LYP and the SDD basis set for Pd and the 6ꢀ31G(d)
basis set for other atoms. Single point energies were calculated
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Typical procedure for the Pdꢀcatalyzed carbonylative
cyclization of aliphatic amines. Synthesis of (S)ꢀmethylꢀ3,3ꢀ
dimethylꢀ5ꢀoxoꢀ1ꢀ(pyridinꢀ2ꢀylsulfonyl)ꢀpyrroledineꢀ2ꢀ
carboxylate [(+)ꢀ2]. An oven dried pressure tube was charged
with Pd(OAc)2 (2.33 mg, 0.010 mmol), AgOAc (26.04 mg,
0.156 mmol), benzoquinone (22.48 mg, 0.208 mmol),
Mo(CO)6 (9.06 mg, 0.034 mmol), tertꢀleucine derivative (+)ꢀ1
(29.78 mg, 0.104 mmol) and HFIP (0.2 mL). The pressure
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placed in a preheated oil bath at 110 °C for 18 h. Then, the
mixture was removed from the oil bath and allowed to cool to
room temperature. The reaction mixture was then diluted with
EtOAc, filtered through a pad of Celite and concentrated. The
residue was purified by flash chromatography (cyclohexꢀ
ane/EtOAc 6:1 to 3:1) to afford γꢀlactam (+)ꢀ2 as a yellow oil;
yield: 26.96 mg (83%), [α]D298= +5 (c = 0.2, CH2Cl2).
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ASSOCIATED CONTENT
Experimental and computational details, optimization studies as
well as spectroscopic and analytical data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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(24) For the late stage C(sp3)−H functionalization of diꢀ, triꢀ and
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(36) For the synthesis of cyclopropaneꢀfused γꢀlactams by intramoꢀ
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(37) For Pdꢀcatalyzed methylene activation of the adamantyl scafꢀ
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(38) This outcome can be explained by competitive dehydrogenaꢀ
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pyridyl)sulfonamide (see, for instance: (a) Kim, D.–S.; Park, J. –W.;
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Alternatively, direct 2ꢀpyridylsulfonamide displacement leading to
theformation of the highly stabilized carbocation intermediate could
also take place under the harsh reaction conditions (see, for instance:
(c) Alonso, I.; Esquivias, J.; Gómez Arrayás, R.; Carretero, J. C. J.
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(39) Yu and coꢀworkers have reported the intramolecular C‒H
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(27) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2015, 137,
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(28) For examples on the use of Mo(CO)6 as CO surrogate in Pd0ꢀ
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transformed into trisubstitued molybdenum carbonyls. For instance,
on refluxing Mo(CO)6 in excess acetonitrile under nitrogen, a near
quantitive yield of [Mo(CO)3(MeCN)3] is obtained with evolution of
3 moles of gas: (c) Abel, E. W.; Bennett, M. A.; Wilkinson, G. J.
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Stahl S. S. Top. Organomet. Chem. 2007, 22, 149−190.
(31) For Xꢀray crystallographic data of this compound, see the SI.
CCDC 1485593ꢀ1485594 (for complex B) and 1485578 (for complex
C) contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crysꢀ
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(32) For further examples on the use of the NꢀSO2Py directing
group in C−H functionalization showing its easy removal, see: (a)
GarcíaꢀRubia, A.; Gómez Arrayás, R.; Carretero, J. C. Angew. Chem.
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(40) The proposal of sevenꢀmembered cyclopalladation intermediꢀ
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(41) For examples of PdIIꢀcatalyzed olefination protocols featuring
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(42) For examples of construction of benzazepine skeleton through
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(43) Compound 62 was setereoselectively prepared from commerꢀ
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(45) In accordance with the different behaviour of complex A in
CD2Cl2, a marked difference in the reactivity profile was noticed
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when monitoring by 1H NMR the stoichiometric carbonylation of
Instead, the Ag salt is likely acting as an oxidant for the palladium
complex A with Mo(CO)6 (0.33 equiv) using CD2Cl2 as solvent (see
Supporting Information).
center. However, silver salts could also be involved in the formation
of heteroꢀbimetallic PdꢀAg species, which could participate in the C‒
H activation step. See: (a) Yang, Y.ꢀF.; Cheng, G.ꢀJ.; Liu, P.; Leow,
D.; Sum, T.ꢀY.; Chen, P.; Zhang, X.; Yu, Y.ꢀQ.; Wu, Y.ꢀD.; Houk, K.
N. J. Am. Chem. Soc. 2014, 136, 344−355. (b) Anand, M.; Sunoj, R.
B.; Schaefer, III, H. F. J. Am. Chem. Soc. 2014, 136, 5535−5538. (c)
Anand, M.; Sunoj, R. B.; Schaefer, III, H. F. ACS Catal. 2016, 6,
696−708. We have also tried to shed light on this point by calculating
the possible heterobimetallic PdꢀAg intermediates and transition states
that could be involved in our C−H activation process but we could not
find any more favourable pathway (see SI for details). For a recent
investigation of the role of silver carboxylate salts in Pdꢀcatalyzed
arene C−H functionalization, see: (d) Lotz, M. D.; Camasso, N. M.;
Canty, A. J.; Sanford, M. S. Organometallics 2016, DOI:
10.1021/acs.organomet.6b00437.
(52) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
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P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montꢀ
gomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.;
Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Norꢀ
mand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.;
Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J.
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1
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(46) This chemical shift is consistent with values previously reꢀ
ported for similar Pdꢀcarbonyl complexes (160ꢀ180 ppm). For selectꢀ
ed publications on the characterization of palladium carbonyl comꢀ
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Llamas, I.; Bautista, D.; Vicente, J. Organometallics 2013, 32,
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(47) A very similar result was achieved in CD3CN: Intermediate D;
[m/z (M+CO+Na)+: 440.9712] and complex A´´; [m/z (MꢀCO+Na)+:
412.9762] (see Supporting Information for details).
(48) Diffusionꢀordered NMR spectroscopy (DOSY) experiments
carried out on a 58:42 mixture of monomeric complex A´ (monomerꢀ
ic) and intermediate D (in CD3CN at 5 °C) and on a 40:60 mixture of
complex A (dimeric) and intermediate D (in CD2Cl2 at rt) further
supported the monomeric nature of the intermediate D (see Supportꢀ
ing Information for details).
(49) (a) Sanhueza, I. A.; Wagner, A. M.; Sanford, M. S.; Schoeneꢀ
beck, F. Chem. Sci. 2013, 4, 2767−2775. (b) GarcíaꢀCuadrado, D.; de
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(50) The model structures I, TS(IIꢀIII), III and IV were also proꢀ
posed to be involved in the C−H activation step during the γꢀarylation
process (see ref. 45 for details).
(51) Since in the stoichiometric reaction, the formation of complex
I and its reaction with Mo(CO)6 take place without AgOAc, providing
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the Ag salt is necessary for the C‒H activation step to take place.
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Figure 6
Figure 6
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Figure 3
Figure 3
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