Pd-catalyzed stereoselective tandem ring-opening amination/cyclization of vinyl γ-lactones: Access to caprolactam diversity

Article abstract of DOI:10.1039/d0sc03647a

A stereoselective amination/cyclization cascade process has been developed that allows for the preparation of a series of unsaturated and substituted caprolactam derivatives in good yields. This conceptually novel protocol takes advantage of the easy access and modular character of vinyl γ-lactones that can be prepared from simple precursors. Activation of the lactone substrate in the presence of a suitable Pd precursor and newly developed phosphoramidite ligand offers a stereocontrolled ring-opening/allylic amination manifold under ambient conditions. The intermediate (E)-configured ?-amino acid can be cyclized using a suitable dehydrating agent in an efficient one-pot, two-step sequence. This overall highly chemo-, stereo- and regio-selective transformation streamlines the production of a wide variety of modifiable and valuable caprolactam building blocks in an operationally attractive way. This journal is

Full text of DOI:10.1039/d0sc03647a

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DOI: 10.1039/D0SC03647A
EDGEARTICLE
Pd-catalyzed stereoselective tandem ring-opening amination/
cyclization of vinyl -Lactones: Access to caprolactam diversity
a
a
ab
Received 00th January 20xx,
Accepted 00th January 20xx
Jianing Xie, Xuetong Li and Arjan W. Kleij*
A stereoselective amination/cyclization cascade process has been developed that allows for the preparation of a series of
unsaturated and substituted caprolactam derivatives in good yields. This conceptually novel protocol takes advantage over
the easy access and modular character of vinyl -lactones that can be prepared from simple precursors. Activation of the
lactone substrate in the presence of a suitable Pd precursor and newly developed phosphoramidite ligand offers a
stereocontrolled ring-opening/allylic amination manifold under ambient conditions. The intermediate (E)-configured -
amino acid can be cyclized using a suitable dehydrating agent in an efficient one-pot, two-step sequence. This overall highly
chemo-, stereo- and regio-selective transformation streamlines the production of a wide variety of modifiable and valuable
caprolactam building blocks in an operationally attractive way.
DOI: 10.1039/x0xx00000x
functional and modular seven-membered analogues remains
surprisingly limited. Therefore, designing new synthetic
procedures that can streamline the preparation of such
Introduction
Lactam derivatives play an important role in the development
of new pharmaceuticals and are useful as a starting point for
synthetic polyamides, with caprolactam being the most
prominent monomer known to date. Classic synthesis of
lactams is achieved using methods such as the Beckmann
rearrangement of oximes, the Schmidt reaction between an
azide and a carbonyl compound, and through cyclization of
caprolactam building blocks can create new incentives for their
use as synthons in drug-development programs and the
creation of new polyamide monomers. With this challenge in
mind, we decided to contemplate on combining our expertise
1
2
3
1
4
in the area of allylic substitution chemistry and merging this
4
5
O
6
HO2C
amino acids or similar precursors. Apart from the easy
HO
O
N
availability of stoichiometric methodologies, catalytic formation
of lactams has materialized as a more sustainable alternative
within the synthetic community fueled by the need for a higher
O
7
NH
EtO2C
7
N
O
Ph
O
7
Benzepril, ACE inhibitor
Cephalofortunone
atom and resource economy. Efficient methodologies have
anti-hypertensive drug
natural product
been developed by Fujita, Yamaguchi et al. who reported on a
Rh-catalyzed oxidative N-heterocyclization of amino alcohols
giving primarily access to five- and six-membered lactams,
X
OH OMe
O
H
N
NH
8
7
OH OH
O
whereas Hong and coworkers showed that direct lactam
synthesis can be achieved using lactones and amines as
reagents under Ir-catalysis. Other approaches that rely on the
use of prefunctionalized substrates have also been recently
disclosed.10
Bengamides,antitumor/antibiotic potential
R
9
R1 = aryl: (E)
CO2H
O
CO2
R1
stereo
--
R1 PdL
R NH2 R1
2
[
Pd], L
O
PdL
desired
Caprolactams represent key motifs of many natural
products and other biologically active compounds (Scheme 1,
top),11 and often serve as versatile synthetic intermediates for
R1
2
O C
NHR2
vinyl lactone
regio
R1
dehydrating
agent
1
2
chemo
over-allylation
bicyclic amino compounds and azepane ring systems. Despite
the recent progress noted for the catalytic synthesis of the more
2
R N
2 2 2
CH CH CO H
2
4
b,8,9,10,13
O
common five- and six-membered lactams,
the scope of
THIS CONTRIBUTION:
importance of ligand engineering
NR2
streamlined synthesis of 7-membered lactams
stereoselective domino approach
amplified diversity through modular reagents
a. Institute of Chemical Research of Catalonia (ICIQ), the Barcelona Institute of
Science and Technology, Av. Països Catalans 16, 43007 - Tarragona, Spain. E-mail:
R1
akleij@iciq.es
b.
Catalan Institute of Research and Advanced Studies (ICREA), Pg. Lluís Companys
Scheme 1 Approach towards the stereoselective domino synthesis of
caprolactams.
2
3, 08010 Barcelona, Spain.
†
2
Electronic supplementary information (ESI) available. CCDC 1998235 (3) and CCDC
001102 (53). For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/x0xx00000x
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PleaseC dh oe mn oi ct a al dS cj ui es nt cme argins
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EDGE ARTICLE
Chemical Science
with vinyl -lactones as modular substrates as outlined in substituents (entries 15-18). Cyclopentyl and i-Bu substituted
View Article Online
DOI: 10.1039/D0SC03647A
ligands L9 and L12 provided productive and rather selective
Scheme 1.
Non-strained, stable -lactones have so far only sporadically catalysts for the formation of 3 though with slightly lower yields
emerged as versatile and readily accessible substrates under and stereoselectivity as compared to L8. The reaction did not
1
5
suitable catalytic conditions. More specifically, the use of vinyl proceed with ligands comprising of cycloheptyl or i-Pr groups
1
6

-lactones (Scheme 1) may offer a tangible way to prepare - (L10 and L11). These results indicate that steric modulation of
amino acid intermediates through allylic amination under Pd the N-substituent of the ligand is key to the success of the
1
7
catalysis. In the overall manifold, proper ligand engineering is formation of caprolactam 3. From all ligands studied, the novel
crucial to control simultaneously the chemo-, regio- and stereo- ligand L8 (entry 14) provided the best combination of yield (for
selectivity under ambient conditions in order to generate the 1 and 3) and selectivity features.
(
E)-configured -amino acid intermediate (Scheme 1) en route
1
8
to the caprolactam target. Here we present a general and Table 1 Screening and optimization studies towards the stereoselective conversion of
practically attractive approach for the preparation of a library substrate A into caprolactam 3 using aniline as reagenta
of functional caprolactams through a novel and formal tandem
Ph
ring-opening allylic amination/cyclization process, which is
PhHN
PhN
O
3
O
controlled by
a
newly developed, readily accessible
Pd (dba) ·CHCl
2
3
3
COOH
Ph
E/Z-1
Ligand
EDC (1.5 equiv)
rt, 1 h
N
O
A
phosphoramidite-based Pd catalyst.
+
Solvent, rt, 12 h
PhNH2
(1.5 equiv)
Ph
Ph
Ph
CH2CH2CO2H
2
Results and discussion
(E/Z)2-2
At the onset of the screening studies, we considered to use
Ph
N
1
4,17
R
Me
Me
previously reported successful phosphorus ligands
to
Me
O
O
O
O
O
O
P
N
P
P N
examine their efficacy to generate Pd-catalysts derived from
R
Ph
†
Ph
Pd
2
(dba)
3
·CHCl
3
(see the ESI ). We were pleased to find that the
Ph
presence of phosphoramidite ligand L1 proved to be highly
beneficial for the ring-opening allylic amination step under
ambient conditions. Furthermore, the in situ rapid cyclization of
the intermediate (E)--amino acid towards the lactam target
L1: R = Me
L2: R,R = -(CH ) - L4: R = i-Pr
L3: R = Ph
L5 (rac)
L6
2
5
L8: R = c-Hex
L9: R = c-Pent
L10: R = c-Hept
L11: R = i-Pr
R
R
O
O
O
O
L7
P N
P
N
1
9
using the well-known reagent EDC was combined in a one-pot
two step sequence. Our screening then focused on producing
the intermediate -amino acids 1 in the most efficient way from
lactone A using phosphoramidite L1 (Table 1, entries 1-6) as to
L12: R = CH i-Pr
2
Entry
L
Solvent
Yield of 1
E:Z-1c
1/2c
Yield of 3
%)b
(%)b
(
2
0
favor the formation of the desired lactam 3. The type of
solvent has a significant effect on the outcome of the tandem
process. The use of both DCM and MeOH gave access to
moderate yields of 3 while minimizing the formation of the
double allylated byproduct 2. The presence of highly polar
solvents such as DMSO and DMF or THF, however, resulted in
unproductive processes, whereas the utilization of ACN lowered
the chemo-selectivity of the process. It is important to note that
in the absence of L1 (entry 7), there was no formation of any
product pointing at the crucial role of the ligand.
1
2
3
4
5
6
7
8
9
L1
L1
L1
L1
L1
L1
‒
DCM
THF
ACN
83
0
67
78
0
0
0
85
82
<1
0
82:18
‒
89:11
82:18
‒
16:1
‒
5:1
17:1
‒
66
‒
59
64
‒
MeOH
DMF
DMSO
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
‒
‒
‒
‒
‒
‒
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L12
L8
L8
77:23
61:39
‒
16:1
>20:1
‒
‒
‒
10:1
10:1
13:1
‒
65
53
‒
1
0
1
2
3
4
1
1
1
1
‒
‒
‒
‒
A variety of phosphoramidite ligands L2‒L12 (entries 8-18)
were then scrutinized under the conditions of entry 1,
illustrating the critical influence of the N-substitution and biaryl
backbone on the chemo-, regio- and stereoselectivity of this
catalytic process. For instance, too bulky N-substituents (L4‒L6,
entries 10-12) do not permit the formation of 3, whereas ligands
equipped with piperidine and phenyl (L2 and L3) provided good
yields of intermediate 1 with high chemoselectivity and
moderate E/Z ratios (entries 8-9). To our delight, the
introduction of cyclohexyl groups (L7, entry 13) further
0
79
80
79
<1
0
82
88
86
96:4
97:3
94:6
‒
76
77
74
‒
15
16
17
‒
‒
‒
1
9
0d-f
8
91:9
93:7
98:2
15:1
>20:1
>20:1
75
82
84
d,e
1
2
a
Lactone A (0.20 mmol), PhNH2 (0.30 mmol, 1.5 equiv), solvent (0.20 mL),
b
increased the E-stereoselective formation of 1 and thus the Pd
2
(dba)
3 3
·CHCl (2.0 mol%), L (8.0 mol%), rt, 12 h; then EDC (0.30 mmol), 1 h.
1
c
Determined by H NMR analysis in CDCl
Determined by H NMR analysis. PhNH
L1 (12.0 mol%). Solvent (0.30 mL).
3
using CH
(2.0 equiv). Pd
2
Br
2
as an internal standard.
(dba) ·CHCl (3.0 mol %),
yield of 3 while retaining good chemo-selectivity. Interestingly,
a binaphthyl ligand backbone was not essential to achieve high
selectivity, which became clear from studying the biphenyl
based ligands L8‒L12 and the steric effect of their N-
1
d
e
2
2
3
3
f
2
| Chem. Sci., 2020, 11, 1-6
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Chemical Science
EDGE ARTICLE
A further increase in the yield of 3 in the presence of L8 was of the tandem process, and the desired products coViuewldArbtiecleeOansliinlye
finally obtained by increasing the amount of catalyst, aniline formed and isolated. Larger aromatic suDrOfaI:c1e0s.10s3u9c/Dh0aSCs0t3h6o4s7Ae
and solvent (entries 19 and 20) providing the caprolactam present in lactam products 16 and 17 are also tolerated, while
product in 84% yield and with high stereo- (E/Z = 98:2) and this new protocol furthermore allows the introduction of
chemo-selectivity (1:2>20:1).
heteroaromatic fragments (18‒22) in the final products.
In the case of 20 and 22 bearing a 2-thienyl and 3-furyl group,
With the optimized conditions of entry 20 in Table 1, we
then set out to examine the scope of this new transformation respectively, the observed stereoselectivity was significantly
Scheme 2, compounds 3‒28) focusing first on variation of the lower which may be ascribed to the potential of these groups to
(
vinyl lactone reagent. Lactones with para-substituted aryl interact with the Pd-catalyst while affecting the 
substituents were productive substrates giving the caprolactam equilibrium as depicted in Scheme 1. Finally, introducing other
derivatives 3‒10 in high isolated yields (>80% in most cases) and -substituents in the lactam product such as different alkyl
2
2
with excellent stereo- (typically with E/Z ratios >95:5), regio- substituents (2325; 54-75%), and the introduction of
and chemo-selectivity control. The presence of meta-, additional -positioned groups (26, 81%; 27, 52%) were also
ortho,para-di- or 3,5-di-substituted aryl groups (11‒15; 71-90%, feasible preserving excellent stereoselectivity. The methylidene
E/Z  96:4) did not have any significant effect on the outcome
substituted product 27 could act as potential Michael acceptor
for late-stage modification towards the formation of
biologically active compounds. The preparation of 28 (63%)
additionally demonstrates that also lactones with substituted
.
1
. Pd2(dba)3 CHCl3
L8, PhNH2
O
O
Ph
DCM, rt, 12 h
N
O
5
7
2
3
2
. Then: EDC (1.5 equiv)
rt, 1 h
vinyl groups are productive substrates.
R
R
.
O
1. Pd2(dba)3 CHCl3
L8, RNH2
O
R
8. R´ = p-OMe, 70%, E/Z = 93:7a
. R´ = p-tBu, 91%, E/Z>99:1
10. R´ = p-Ph, 80%, E/Z = 97:3
Ph
O
R´
O
N
DCM, rt, 12 h
N
5
9
7
2
. Then: EDC (1.5 equiv)
A
Ph
rt, 1 h
a
1
1
1
1. R´ = m-tBu, 74%, E/Z = 97:3
2. R´ = m-Cl, 90%, E/Z = 96:4
Ph
3
4
5
6
7
. R´ = p-H, 82%, E/Z = 98:2
. R´ = p-Me, 81%, E/Z = 96:4
. R´ = p-SMe, 82%, E/Z = 90:10
. R´ = p-Br, 84%, E/Z = 97:3
. R´ = p-F, 90%, E/Z = 97:3
2
3
3
3
3
3
3
3
3
3
3
9. Y = p-OMe, 80%, E/Z = 97:3
0. Y = o-OMe, 91%, E/Z>99:1
1. Y = m-OMe, 86%, E/Z = 99:1
2. Y = m-Me, 74%, E/Z = 92:8
3. Y = p-F, 93%, E/Z = 98:2
4. Y = p-Ph, 75%, E/Z = 97:3a
5. Y = p-OH, 58%, E/Z>99:1
3. R´ = m-CF , 85%, E/Z = 97:3
3
14. R´ = o,p-F , 77%, E/Z = 99:1
2
15. R´ = m,m-Me , 71%, E/Z>99:1
O
2
N
Y
X-ray of 3
a
6. Y = p-CH CH OH, 62%, E/Z = 94:6
2
2
Ph
7. Y = m-CO Et, 68%, E/Z = 96:4
2
8. Y = 3,5-di-Me, 83%, E/Z = 94:6
9. Y = 3-OMe-4-Br, 73%, E/Z = 99:1
Ph
O
Ph
N
N
H
N
O
O
O
R´
O
O
O
O
O
N
Me
O
N
H
N
N
1
1
6. R´ = OMe, 65%, E/Z>99:1a
7. R´ = H, 77%, E/Z = 99:1
18. 85%, E/Z = 98:2
Me
Ph
Ph
Ph
4
0. 71%
41. 60%
E/Z>99:1
42. 74%
E/Z = 95:5
O
N
E/Z>99:1
O
Ph
O
Ph
O
N
21. 80%, E/Z = 99:1a
1
9. 73%, E/Z = 93:7
O
CO2Et
O
O
N
N
O
O
N
N
R
S
20. 67%, E/Z = 78:22
22. 72%, E/Z = 87:13
43. 81%
44. 71%
Ph
E/Z = 95:5
Ph
E/Z>99:1
23. R = Bn, X = Y = H: 75%, E/Z>99:1b
24. R = -CH2CH2Ph, X = Y = H: 51%, E/Z = 26:74
O
O
c
X
Ph
N

d

25. R = -CH iPr, X = Y = H : 54%, E/Z = 62:38
2
26. R = X = Ph, Y = H: 81%, E/Z = 97:3
4
5. 69%
Y

O
Me
Ph
O
2
7. R = Ph, X = CH , Y = H: 52%, E/Z>99:1
2
R
e
O
28. R = Ph, X = H, Y = Me: 63%, E/Z>99:1
N
N
X
N
Scheme 2 Scope in vinyl-substituted -lactone substrates. All reactions were
performed under the optimized conditions (Table 1, entry 20). Isolated yields are
reported, and the reported E/Z ratios for the intermediate -amino acids were
Ph
6. 55%[a]
E/Z>99:1
Ph
49. 58%a
E/Z>99:1
4
1
determined by H NMR; the inset shows the molecular structure determined for 3
Ph
a
by X-ray analysis, see footnote 21. Scheme notes: Using DCM/EtOH (1:1 v/v) as
a
b
c
47. X = Bn, 48%, E/Z>99:1
48. X = c-hex, 37%, E/Z>99:1a
solvent. L1 (12.0 mol %), MeOH (0.30 mL), 24 h. Using L1 (12.0 mol%), MeOH,
2
4 h, 30 ºC; note that the same stereoisomer is formed though with a different
E/Z priority assignment, and thus in this case the Z isomer is required towards
d
e
lactam formation. Using P(OPh)
3
(12.0 mol%), MeOH, 24 h. L1 (12.0 mol%),
Scheme 3 Scope in amine reagents. All reactions were performed under the
optimized conditions (Table 1, entry 20). Isolated yields are reported, and the E/Z
MeOH, 60 ºC.
1
ratios for the intermediate -amino acids were determined by H NMR, though in
the preparation 45, the E/Z selectivity could not be determined accurately.
Scheme note: a Using DCM/EtOH (1:1 v/v) as solvent.
This journal is © The Royal Society of Chemistry 2020
Chem. Sci., 2020, 11, 1-6 | 3
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EDGE ARTICLE
Our attention was then on further widening the scope of
Chemical Science
Lastly, we tested several, more nucleophilic alipVhieawtAicrticalme Oinnlienes
caprolactam products by combining vinyl lactone A and various to challenge the chemo-selectivity of ouDrOdIe: 1v0e.1lo03p9e/dD0pSrCo0t3o6c4o7Al.
amine reaction partners (Scheme 3, compounds 29‒49). A As may be expected, substantially lower yields for 46‒49 were
range of substituted anilines could be coupled to ring-opened obtained (37-58%) though under excellent stereocontrol (E/Z
lactone A under the optimized conditions providing overall >99:1) in a mixed solvent system consisting of DCM/EtOH. The
1
good to excellent yields of caprolactams 29‒40 under high
H NMR analysis of the crude products indeed indicated that
stereocontrol. The use of larger (hetero)aromatic amines larger amounts of bis-allylated amines of type 2 had been
2
4
(41‒44) gave access to lactam products with N-indole, N-1,3- formed.
benzodioxole, N-benzofuran and N-naphthyl groups. The di-
In order to examine whether the stereoselectivity indeed
lactam derivative 45 could be prepared in appreciable yield plays an important role prior to the cyclization step (Scheme 1),
69%) despite the more challenging nature of this formal we compared the yield of lactam 3 attained from a
tandem bis allylic amination/cyclization process. configurationally pure sample of 1 (E/Z>99:1) and one being a
9:31 E/Z mixture (Scheme 4a). From the results, it may be
(
6
O
concluded that the maximum yield unquestionably depends on
the amount of E-1 that is initially formed, and also molecular
models strongly suggest that the (Z) isomer of 1 is unable to
cyclize towards a lactam product. These results reinforce the
assumption that stereocontrol in the first step is vital to the
success of the overall manifold. The use of a simple ligand
structure (cf., L8) shows that the presence of a chiral ligand is
not a requisite. This is demonstrated by the fact that both (rac)-
and enantiopure (S)-L1 give virtually the same stereocontrol (for
(
a) HOOC
Ph
EDC (1.5 equiv)
NHPh
N
DCM (1 M), rt, 1 h
(0.2 mmol scale)
Ph
H
1
Ph
3
with E/Z >99:1: 98% NMR yield versus E/Z = 69:31: 60% NMR yield
O
(
b)
HOOC
standard
conditons
NHPh
O
PhNH2
Ph
E/Z-1
Ph
1
) and lead to a similar yield of 3 (Scheme 4b), thus being
Me
N
Me
consistent with the results described in Table 1.
O
O
(rac)-L1: 83%, E/Z = 82:18
(S)-L1: 82%, E/Z = 82:18
P
The practicality of this new procedure for the preparation of
functional seven-membered lactams is illustrated by the scale-
up of compound 3 (Scheme 4c), and product diversification
studies using 3 and 29 were also initiated (Scheme 4d). After
establishing that scaling up does not influence the stereo-
outcome or yield of the product (cf., Scheme 2, 3), several post-
modifications were carried out. Triflic acid mediated double
bond isomerization in 3 was feasible to produce 50 in good
yield, whereas epoxidation afforded 51 with excellent
diastereoselectivity. The latter compound could be reduced by
using Pd-catalyzed hydrogenation leading to 52 in high yield.
L1
O
(
c)
d)
3
. 80% yield
A.
standard conditons
Ph
1.16 g
N
5
.50 mmol, 1.04 g
PhNH2
E/Z = 97:3
Ph
(
O
O
O
3
Ph
N
Ph
Ph
N
N
TfOH
DCM, rt
mCPBA
DCM, rt
Ph
O
Ph
0, 77%
Ph
5
51, 85%, dr>99:1
Dibromination of 3 gives 53 (83%, with its molecular structure
DCM
rt
Br2
Pd/C
H2, rt
DCM
0 ºC
[21]
PCC
confirmed by X-ray analysis, see Scheme 4),
whereas
MeOH
4
pyridinium chlorochromate (PCC) assisted oxidation of 3
furnished the conjugated, bis-unsaturated caprolactam
derivative 54. In order to provide free lactams potentially useful
as a new type of monomer for polyamide synthesis or
pharmaceutical precursors, compound 29 was treated with
cerium ammonium nitrate (CAN) to afford 55 in 40% yield.
Alternatively, standard hydrogenation of 29 (56, 90%) followed
by deprotection gave easy access to free lactam 57 in 75% yield.
Finally, six-membered vinyl lactone 58 could be transformed
into eight-membered lactam 59 (54%) with high stereocontrol,
and this implies that the developed cascade process may be
suitable for the preparation of an even wider range of larger
O
O
Ph
Ph
N
N
Ph
Ph
OH
5
4, 56%
52, 92%, dr>99:1
O
5
3, 83%, dr>99:1
O
CAN
PMP
2
9
N
NH 55, 40%
ACN/H2O, 0 ºC
Ph
Ph
O
O
Pd/C, H2
MeOH, rt
PMP
N
CAN
NH
ACN/H O
2
2
5
0
ºC
ring lactams.
Ph
Ph
5
6, 90%
57, 75%
Ph
O
N
59
,
54%
E/Z>99:1
O
Ph standard conditons
.01 M, PhNH2
O
Conclusions
58
6
8
0
Ph
In summary, this work provides a new, efficient and practical
approach for valuable caprolactam scaffolds that involves (after
ring-opening of vinyl -lactones) a Pd-mediated stereo- and
regio-selective allylic amination followed by a cyclization step
Scheme 4. (a-b) Control experiments. (c) Gram-scale preparation of 3. (d) Product
†
diversification studies based on 3 and 29. For details, see the ESI .
4
| Chem. Sci., 2020, 11, 1-6
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PleaseC dh oe mn oi ct a al dS cj ui es nt cme argins
Chemical Science
EDGE ARTICLE
González-Tototzin, J. Aviña, O. Muñoz-Muñiz aVniedwEA.rtiJculeaOrnislitnie,
affording the lactam target. This formal tandem process relies
on the use of a new, easily prepared phosphoramidite ligand
Tetrahedron, 2011, 57, 1883; (d) O. David, W. J. Meester, H.
DOI: 10.1039/D0SC03647A
Bieraugel, H. E. Schoemaker, H. Hiemstra and J. H. van
Maarseveen, Angew. Chem. Int. Ed., 2003, 42, 4373.
(a) M. Szostak and J. Aubé, Chem. Rev., 2013, 113, 5701; (b) S.
Hosseyni and A. Jarrahpour, Org. Biomol. Chem., 2018, 16,
(L8) that allows to control the various process selectivity
features and, as such, the yield of the final product under
ambient conditions. The scale-up and diversification studies
show that more functional scaffolds may be created that can be
of great value to build up molecular complexity from this new
library of readily accessible caprolactam building blocks.
7
6
840; (c) C. R. Pitts and T. Lectka, Chem. Rev., 2014, 114, 7930;
(
d) A. G. Collar, C. Trujillo, B. Lockett-Walters, B. Twamley and
S. J. Connon, Chem. Eur. J., 2019, 25, 7275.
8
9
K.-I. Fujita, Y. Takahashi, M. Owaki, K. Yamamoto and R.
Yamaguchi, Org. Lett., 2004, 6, 2785.
K. Kim and S. H. Hong, J. Org. Chem., 2015, 80, 4152.
Conflicts of interest
There are no conflicts to declare.
10 (a) H. F. Motiwala, C. Fehl, S.-W. Li, E. Hirt, P. Porubsky and J.
Aubé, J. Am. Chem. Soc., 2013, 135, 9000; (b) X. Liu, Z. Han, Z.
Wang and K. Ding, Angew. Chem. Int. Ed., 2014, 53, 1978; (c)
B. H. Yang and S. L. Buchwald, Org. Lett., 1999, 1, 35; (d) B. El
Ali, K. Okuro, G. Vasapollo and H. Alper, J. Am. Chem. Soc.,
1996, 118, 4264; (e) L. Wu, S. Qiu and G. Liu, Org. Lett., 2009,
Acknowledgements
We thank the CERCA Program/Generalitat de Catalunya, ICREA,
and the Spanish MINECO (CTQ-2014–60419-R) and AGAUR
1
1, 2707; (f) N. Wang, Q. S. Gu, Z. L. Li, Z. Li, Y. L. Guo, Z. Guo
and X. Y. Liu, Angew. Chem. Int. Ed., 2018, 57, 14225; (g) M.
Peña-López, H. Neumann and M. Beller, ChemCatChem, 2015,
7
, 865; Using ring-closing metathesis: (h) H. M. A. Hassan,
(
2017-SGR-232) for financial support. Dr. Eduardo C. Escudero-
Adán is thanked for measuring the X-ray molecular structures of
and 53. J.X. and X.L. thank the Chinese Research Council (CSC)
for funding their predoctoral fellowships (2016-06200061 and
019-06870036).
Chem. Commun., 2010, 46, 9100; (i) A. Deiters and S. F.
Martin, Chem. Rev., 2004, 104, 2199, and references therein.
1 For examples: (a) H. Hotoda, M. Furukawa, M. Daigo, K.
Murayama, M. Kaneko, Y. Muramatsu, M. M. Ishii, S.-I.
Miyakoshi, T. Takatsu, M. Inukai, M. Kakuta, T. Abe, T.
Harasaki, T. Fukuoka, Y. Utsui and S. Ohya, Bioorg. Med. Chem.
Lett., 2003, 13, 2829; (b) X. Liu, Y. Jin, W. Cai, K. D. Green, A.
Goswami, S. Garneau-Tsodikova, K. Nonaka, S. Baba, M.
Funabashi, Z. Yang and S. G. van Lanen, Org. Biomol. Chem.,
2016, 14, 3956; Caprolactam can be used to prepare
meptazinol: (c) B. Holmes and A. Ward, Drugs, 1985, 30, 285.
See also references 1c and 1d.
3
1
2
Notes and references
1
For reviews of different ring-size, pharma-relevant lactams:
a) R. Fernandes, P. Amador and C. Prudêncio, Rev. Med.
Microbiol., 2013, 24, 7; (b) U. Nubbemeyer, Top. Curr. Chem.,
(
2
001, 216, 125; For original examples: (c) L. Edvinsson and M. 12 (a) Amide Linkage: Selected Structural Aspects in “Chemistry,
Linde, Lancet, 2010, 376, 645; (d) G. Liu, Y.-M. Ma, W.-Y. Tai,
C.-M. Xie, Y.-L. Li, J. Li and F.-J. Nan, ChemMedChem, 2008, 3,
Biochemistry, and Materials Science”, Eds. A. Greenberg, C.
M. Breneman, J. F. Liebman, Wiley, New York 2000; (b) S. J.
Lee and P. Beak, J. Am. Chem. Soc., 2006, 128, 2178; (c) J. T.
Bagdanoff, D. C. Behenna, J. L. Stockdill and B. M. Stoltz, Eur.
J. Org. Chem., 2016, 2101.
7
4; (e) Y. Oshiro, Y. Sakurai, S. Sato, N. Kurahashi, T. Tanaka,
T. Kikuchi, K. Tottori, Y. Uwahodo, T. Miwa and T. Nishi, J.
Med. Chem., 2000, 43, 177; (f) Z. Feng, F. Chu, Z. Guo and P.
Sun, Bioorg. Med. Chem. Lett., 2009, 19, 2270; (g) J. E. H. Day, 13 (a) G. A. Molander, Acc. Chem. Res., 1998, 31, 603; (b) L. Yet,
S. Y. Sharp, M. G. Rowlands, W. Aherne, A. Hayes, F. I.
Raynaud, W. Lewis, S. M. Roe, C. Prodromou, L. H. Pearl, P.
Workman and C. J. Moody, ACS Chem. Biol., 2011, 6, 1339.
Chem. Rev., 2000, 100, 2963; (c) M. Driowya, A. Saber, H.
Marzag, L. Demange, K. Bougrin and R. Benhida, Molecules,
2016, 21, 1032.
2
3
(a) M. Winnacker, Biomater. Sci., 2017, 5, 1230; (b) K. 14 For a selection of stereo- and enantio-selective allylic
Marchildon, Macromol. React. Eng., 2011, 5, 22; (c) I. Sibikin
and J. Karger-Kocsis, Adv. Ind. Engin. Polym. Res., 2018, 1, 48;
aminations: (a) A. Cai, W. Guo, L. Martínez-Rodríguez and A.
W. Kleij, J. Am. Chem. Soc., 2016, 138, 14194; (b) W. Guo, L.
Martínez-Rodríguez, R. Kuniyil, E. Martin, E. C. Escudero-
Adán, F. Maseras and A. W. Kleij, J. Am. Chem. Soc., 2016, 138,
11970; (c) W. Guo, A. Cai, J. Xie and A. W. Kleij, Angew. Chem.
Int. Ed., 2017, 56, 11797; (d) J. Xie, S. Xue, E. C. Escudero-Adán
and A. W. Kleij, Angew. Chem. Int. Ed., 2018, 57, 16727; (e) J.
Xie, C. Qiao, M. Martínez Belmonte, E. C. Escudero-Adán and
A. W. Kleij, ChemSusChem, 2019, 12, 3152.
(
d) J. Zhang, S. H. Gellman and S. S. Stahl, Macromolecules,
2
010, 43, 5618.
(a) R. Kumar, S. Shah, P. P. Das, G. G. Bhabavanbhai, A. Al
Fatesh and B. Chowdhury, Cat. Rev. Sci. Engin., 2019, 61, 516;
(
b) R. Beerthuis, G. Rothenberg and N. R. Shiju, Green Chem.,
015, 17, 1341; (c) S. Naumann, S. Epple, C. Bonten and M. R.
Buchmeiser, ACS Macro Lett., 2013, 2, 609; (d) Y. Tao, X. Chen,
2
F. Jia, S. Wang, C. Xiao, F. Cui, Y. Li, Z. Bian, X. Chen and X. 15 (a) W. Guo, J. E. Gómez, L. Martínez-Rodríguez, N. A. G.
Wang, Chem. Sci., 2015, 6, 6385.
Bandeira, C. Bo and A. W. Kleij, ChemSusChem, 2017, 10,
1969; (b) J. E. Gómez, W. Guo, S. Gaspa and A. W. Kleij, Angew.
Chem. Int. Ed., 2017, 56, 15035; (c) X.-L. Xu and Z. Li, Org. Lett.,
2019, 21, 5078; (d) R. Zhu, J.-L. Jiang, X.-L. Li, J. Deng and Y. Fu,
ACS Catal., 2017, 7, 7520. See also reference 8.
4
5
6
(a) A. H. Blatt, Chem. Rev., 1933, 12, 215; (b) J. L. Kenwright,
W. R. J. D. Galloway, L. Wortmann and D. R. Spring, Synth.
Commun., 2013, 1508; (c) X. Mo, T. D. R. Morgan, H. T. Ang
and D. G. Hall, J. Am. Chem. Soc., 2018, 140, 5264.
(a) S. Lang and J. A. Murphy, Chem. Soc. Rev., 2006, 35, 146; 16 (a) B. M. Trost and T. P. Klun, J. Am. Chem. Soc., 1979, 101,
(
b) A. Wrobleski, T. C. Coombs, C. W. Huh, S.-W. Li and J. Aubé,
Org. React., 2012, 78, 1; (c) H. Wolff, Org. React., 2011, 77,
07.
6756. See also for a more recent example: (b) J. L. Nallasivam
and R. A. Fernandes, J. Am. Chem. Soc., 2016, 138, 13238.
17 For the crucial role of the ancillary ligand in Pd-catalyzed allylic
substitution: (a) L. Hu, A. Cai, Z. Wu, A. W. Kleij and G. Huang,
Angew. Chem. Int. Ed., 2019, 58, 14694; (b) A. Cai and A. W.
Kleij, Angew. Chem. Int. Ed., 2019, 58, 14944.
3
For some examples: (a) C. Xie, J. Song, H. Wu, Y. Hu, H. Liu, Z.
Zhang, P. Zhang, B. Chen and B. Han, J. Am. Chem. Soc., 2019,
1
41, 4002; (b) J. Qi, C. Sun, Y. Tian, X. Wang, G. Li, Q. Xiao and
D. Yin, Org. Lett., 2014, 16, 190; (c) J. Escalante, M. A.
This journal is © The Royal Society of Chemistry 2020
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Page 6 of 7
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Chemical Science
1
8 The chemo-selectivity issue here is related to the occurrence
View Article Online
DOI: 10.1039/D0SC03647A
of over-allylation of the primary amine reagent as indicated in
Scheme 1. As for the stereoselectivity, the (E) configuration of
the intermediate -amino acid is deemed favorable for
intramolecular dehydration affording the caprolactam
product whereas the (Z) intermediate will likely follow an
intermolecular dehydrative pathway.
1
2
9 EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, was
selected as it represents a practical and standard dehydrative
reagent/carboxylic acid activator. See for instance: J.
Sheehan, P. Cruickshank and G. Boshart, J. Org. Chem., 1961,
2
6, 2525.
0 For more extensive data from the screening phase, please
†
refer to the ESI . In these reactions the virtual complete linear
regio-selectivity in the allylic amination step was unexpected
as phosphoramidite ligands have recently been shown to
direct allylic amination and sulfonation towards the branched
products, see references 14b-c and 17b. A further control
experiment using L8 in a previously reported allylic amination
reaction (reference 14a) indeed shows that a 15:85
regioisomeric mixture of branched and linear allylic amine is
†
obtained, see the ESI for details.
2
2
1 For more details, see CCDC 1998235 (3) and CCDC 2001102
(53).
2 Martin et al. reported previously a Pd-catalyzed allylic
alkylation process involving an -alkyl--vinyl substituted
lactone and a carbon based nucleophile affording the allylic
alkylation product with a 1:1 E/Z ratio, see: B. L. Ashfeld and
S. F. Martin, Org. Lett., 2005, 7, 4535. We recently reported
that also for related vinyl substituted cyclic carbonates a
decrease in stereo-induction is noted when “aryl” groups are
replaced by “alkyl” ones. We ascribe this to hyper-conjugation
effects (in the case of aryl substituents) stabilizing the allyl-Pd
intermediate towards undesirably fast  isomerization
that would favor the formation of a mixture of stereoisomers.
See: W. Guo, L. Martínez-Rodríguez, E. Martín, E. C. Escudero-
Adán and A. W. Kleij, Angew. Chem. Int. Ed., 2016, 55, 11037.
3 The use of a lactone substrate devoid of additional
2
2
1
substitution (R , Scheme 1) was also tried but failed to
produce the caprolactam product under the optimized
†
conditions. See details and comments in the ESI .
4 Bis-allylation of primary aliphatic amines has been observed
before, see: (a) A. Trowbridge, S. M. Walton and M. J. Gaunt,
Chem. Rev., 2020, 120, 2613; For original examples: (b) M.
Kimura, M. Futamata, K. Shibata and Y. Tamaru, Chem.
Commun., 2003, 234; (c) F. Ozawa, H. Okamoto, S. Kawagishi,
S. Yamamoto, T. Minami and M Yoshifuji, J. Am. Chem. Soc.,
2
002, 124, 10968.
2
4 Attempts to prepare a nine-membered lactam derivative gave
†
only access to low yield (<10%) of product, see the ESI for
details.
6
| Chem. Sci., 2020, 11, 1-6
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Page 7 of 7
Chemical Science
View Article Online
DOI: 10.1039/D0SC03647A
TOC graphic and text:
O
O
CO2
R2
4
NR4
R2
[Pd], L
rt
R NH
2
O
R2
5
PdL
7
rt, EDC
R3
R1
one-pot
R1
R3
R1
R3
stereoselective tandem synthesis of caprolactams
8 examples, high diversity, yield up to 93%, typical E/Z >95:5
4
A Pd-mediated stereoselective tandem process has been developed towards a large variety
of functional caprolactam synthons.