Domino Synthesis of α,β-Unsaturated γ-Lactams by Stereoselective Amination of α-Tertiary Allylic Alcohols

Article abstract of DOI:10.1002/anie.201810160

Tertiary allylic alcohols equipped with a carboxyl group can be smoothly aminated under ambient conditions by a conceptually new and stereoselective protocol under palladium catalysis. The in situ formed Z-configured γ-amino acid cyclizes to afford an α,β-unsaturated γ-lactam, releasing water as the only byproduct. This practical catalytic transformation highlights the use of a carboxyl group acting as an activating and stereodirecting functional group to provide a wide series of pharma-relevant building blocks. Various control reactions support the crucial role of the carboxyl group in the substrate to mediate these transformations.

Full text of DOI:10.1002/anie.201810160

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Accepted Article
Title: Domino Synthesis of Unsaturated Lactams via Stereoselective
Amination of Tertiary Allylic Alcohols
Authors: Arjan Willem Kleij, Eduardo C Escudero-Adán, Sijing Xue,
and Jianing Xie
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810160
Angew. Chem. 10.1002/ange.201810160
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10.1002/anie.201810160
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Domino Synthesis of -Unsaturated -Lactams via Stereo-
selective Amination of -Tertiary Allylic Alcohols
Jianing Xie,[a] Sijing Xue,[a] Eduardo C. Escudero-Adán,[a] and Arjan W. Kleij*[a][b]
Abstract: Tertiary allylic alcohols equipped with a carboxyl group can
be smoothly aminated under ambient conditions via a conceptually
new and stereoselective protocol under Pd catalysis. The in situ
formed (Z)-configured -amino acid cyclizes to afford an ,-
unsaturated -lactam releasing water as the only by-product. This
practical catalytic transformation highlights the use of a carboxyl
group acting as a hydrogen donor, stereodirecting and functional
group to provide a wide series of pharma-relevant building blocks.
Various control reactions support the crucial role of a carboxyl group
in the substrate to mediate these transformations.
of the terminal position of the Pd(allyl) species. These -
unsaturated -lactams are highly attractive scaffolds as they form
part of a wide range of bioactive compounds (Scheme 1, below)[12]
and are valuable precursors to pyrroles and -lactams.[13]
Allylic substitution reactions mediated by transition metal
catalysts are prominent in the area of synthetic chemistry
providing convenient access to more complex target molecules
via CC and CX (X = N, O, S) bond formation reactions.[1] More
recent focus in this area features allylic alcohols as relatively
unactivated and more ubiquitous substrates as to increase both
the atom and step economy of the allylic substitution process.[2]
Despite the attractiveness of using allylic alcohols as more
environmentally benign substrates, the poor leaving group ability
of the alcohol group renders the allylic substitution process more
challenging. As such, often the use of a protic solvent such as
MeOH or water, the presence of Lewis/Brøndsted additives
and/or elevated temperatures are required for efficient turnover.[3]
In the realm of allylic substitution chemistry, allylic amination[4]
has been intensively studied as the resultant amines are valuable
synthons in natural product synthesis and bioactive molecules.[5]
We have recently developed both stereo-[6] as well as
enantioselective protocols[7] for challenging highly substituted
allylic amines. Key to the success of these latter approaches was
the presence of an activated allylic surrogate. We wondered
whether direct amination of suitable allylic alcohol substrates
would be feasible via a conceptually novel activation approach
(Scheme 1) using a stereo-directing group. Inspired by previous
work on allylic amination from Ozawa[8a-b] and Samec[8c] revealing
a transient Pd hydride species, we hypothesized that an allylic
alcohol substrate with a carboxyl group (Scheme 1) could
generate a Pd hydride via oxidative addition to a suitable Pd(0)
precursor.[9] This should allow for the formation of a palladacyclic
intermediate that incorporates the requisite stereochemistry for
efficient cyclization towards a -lactam product[10] via amination[11]
Scheme 1. Conceptual design towards a domino process converting -tertiary
allylic alcohols into -unsaturated -lactams under Pd catalysis. Below
selected examples of bioactive compounds with an unsaturated--lactam core.
A few challenges in this envisioned manifold need to be
addressed, including the rarely developed stereocontrolled
conversion of -tertiary allylic alcohols,[14] and the use of mild
reaction conditions to reduce the intrinsic risk of parasitic
decarboxylative pathways. Here we demonstrate that such a
conceptual approach offers a novel and practical way for allylic
alcohol conversion into valuable synthetic building blocks under
ambient conditions.
First, the required substrates were designed and these could
be readily prepared from -keto acids and vinyl Grignard reagents
affording in good yields the desired vinyl glycolic acids (see the
Supporting Information, SI, for details). Allylic alcohol A was
selected towards screening of appropriate reaction conditions and
Pd/ligand combinations (Table 1) leading to the formation of -
lactam 1a. The use of a Pd(II) precursor (entries 12) proved to
be rather unproductive.
[a]
[b]
J. Xie, S. Xue, Dr. E. C. Escudero-Adán, Prof. Dr. A. W. Kleij,
Institute of Chemical Research of Catalonia (ICIQ), the Barcelona
Institute of Science and Technology, Av. Països Catalans 16, 43007
- Tarragona, Spain. E-mail: akleij@iciq.es
Prof. Dr. A. W. Kleij
Catalan Institute of Research and Advanced Studies (ICREA), Pg.
Lluís Companys 23, 08010 Barcelona, Spain
Supporting information for this article is given via a link at the end of
the document
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Table 1. Pd-mediated conversion of COOH-substituted -tertiary allylic
alcohol A under various conditions.[a]
turned out to be acetonitrile (entry 3; 45% yield, 1a:1b = 98:2).
The use of other solvents showed in several cases significant
formation of 1b that is formed after decarboxylation following an
aza-Michael addition (see SI for details). Other ligands (L2L10,
entries 1119) were then probed, and the use of L6 (dppf; entry
15) showed an encouraging increase in the yield of 1a to 79%.
The optimized conditions for the formation of 1a were achieved
by further increasing the amount of L6 to 5 mol% and reducing
the amount of aniline to 1.1 equiv (entry 21). The presence of a
Pd catalyst was crucial as no conversion of substrate A was noted
in its absence (entry 22). Under the optimized conditions, the
synthesis of 1a could be easily scaled up to gram quantities (see
SI for details).
Entry
L
[Pd]
Solv.
[1 M]
Yield
of 1a[b]
Sel.[c]
1a:1b
1
2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L6
L6
L6
Pd(OAc)2
CH3CN
CH3CN
CH3CN
THF
10
0
96/4

[allylPdCl]2
3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3
Pd2(dba)3·CHCl3

45
14
21
34
25
30
12
22
5
98/2
76/24
100/0
83/17
93/7
99/1
98/2
98/2

4
5
DMF
6
DMSO
MeOH
CH2Cl2
EtOAc
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
7
8
9
10
11
12
13
14
15
16
17
18
19
20[d]
21[d,e]
22
trace
7

79/21
87/13
98/2

18
79
trace
trace
8


5

95
95
0
97:3
97:3

Figure 1. Scope in -unsaturated -lactams using various (hetero)aromatic
amines as coupling partners.
[a] Conditions: 1a (0.15 mmol), aniline (0.23 mmol, 1.5 equiv), solvent (0.15
mL), Pd2(dba)3·CHCl3 (0.003 g, 2.0 mol%), L (4.0 mol%), 25 ºC. [b] By 1H
NMR (CDCl3) using toluene as internal standard. [c] By 1H NMR. [d] L6 (5
mol %). [e] Aniline (1.1 equiv).
With the optimized conditions in hand, we then examined the
scope in reaction partners and first varied the nature of the amine
The use of a Pd(0) precursor (entries 3) showed a significant
improvement in the yield of 1a at only 25 ºC, and the best solvent
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substrate (Figure 1).[15] Various anilines with para-, meta, and
ortho-substituents proved to be productive substrates giving clean
access to the -lactam products (1a, 2b2o; 1a characterized by
X-ray analysis)[16] in typically appreciable to high isolated yields.
The introduction of phenolic or aryl iodide groups in the lactam
product is tolerated as exemplified by the successful isolation of
product 2e and 2f, which have the potential for late stage
modification towards the formation of biologically active
compounds. Anilines with para electron-withdrawing groups or
with a double ortho-substitution gave, as expected, somewhat
lower yields (2h; 65% and 2m; 50%). Interestingly, the developed
protocol also tolerated the introduction of various other
aromatic/heterocyclic fragments as illustrated by the synthesis of
derivatives 2p2u, although in some of these latter cases a higher
reaction temperature (50 ºC) and/or longer reaction time was
required. Product 2s incorporates a useful 8-quinolyl fragment,
which is frequently utilized as a directing group in C-H
functionalization. Finally we also attempted the use of alkyl
amines, and while preliminary reactions showed that these easily
become protonated and formation of the desired lactam is
subsequently blocked,[15] addition of sub-stoichiometric amounts
of a Brøndsted acid (CF3COOH; 2v, 24%) allows for some
product formation.
(Figure 2; products 3a3q.[17] The installation of a bulky naphthyl
group (3j) or a heterocycle (3l) in the lactam was feasible, while
the conversion of the CF3-substituted allylic alcohol (cf., synthesis
of 3d) required a longer reaction time. In the case of the alkyl-
substituted substrate congeners (cf., preparation of 3m3o), the
use of DMF at elevated temperature was required to maintain a
homogeneous reaction medium. The use of a -substituted
tertiary allylic alcohol also afforded the desired lactam product (R1
= Ph, R2 = Me; 3p, 49%) though the use of a secondary allylic
alcohol (R1 = R2 = H; 3q) at rt showed no conversion. A higher
reaction temperature was needed (70 ºC), though a complex
mixture was obtained and the lactam derivative was formed in
only 6% yield.
In order to support the mechanistic scenario displayed in
Scheme 1, a number of control experiments were conducted
(Scheme 2). First, various substitutions were examined in the
allylic substrate (Scheme 2a), showing the crucial role of a
carboxyl group in A (Figure 1) to accommodate the conversion of
the allylic substrate under ambient conditions. The replacement
of the COOH for an ester, amide, methyl, alcohol or strong
electron-withdrawing CF3 group did not lead to any observable
conversion, whereas allylic alcohol protection still provided 60%
yield of the lactam derivative 1a. Further to this, in the presence
of 1 equiv of base (Scheme 2b; Cs2CO3) also no conversion of A
could be achieved, further affirming the key role of the free
carboxyl group within the substrate.
Figure 2. Scope in -unsaturated -lactams using various allylic alcohols as
coupling partners.
Scheme 2. Mechanistic control experiments to support the manifold proposed
in Scheme 1. The standard conditions relate to entry 21 in Table 1.
Upon variation of the substituent of the -tertiary allylic alcohol,
a further amplification of lactam products could be easily realized
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The influence of the presence of (sub)stoichiometric amounts
of a Brøndsted acid (Scheme 2c) using methyl-ester ACOOMe was
also examined. However, no conversion was noted in the
presence of 0.52 equiv HOAc as additive. An additional
competition experiment involving a 1:1 mixture of the methyl-ester
ACOOMe and the alcohol-protected substrate AOMe showed only
conversion of the latter: the ester derivative ACOOMe was
quantitatively recovered (Scheme 2d). Both reactions illustrate
that intermolecular COOH···OH hydrogen-bond activation does
not play any significant role in the conversion of the allylic
substrate.[18] Crystallographic analysis[16] of allylic substrate A
(see the SI for full details) revealed no productive H-bonding to
account for intramolecular allylic alcohol activation. Various
spectroscopic control experiments (see the SI) were conducted to
investigate intramolecular solution phase hydrogen bonding but
In summary, we here disclose a user-friendly, mild and
attractive protocol for direct and stereoselective amination of
allylic alcohols to afford synthetically useful -unsaturated -
lactams using readily available substrates. Key to the observed
and unique reactivity is the presence of a free, carboxyl group in
the substrate that allows for Pd-mediated activation of the allylic
alcohol under ambient conditions. This new activation mode
therefore holds great promise for a wider range of stereoselective
allylic substitutions reactions under sustainable reaction
conditions.
Acknowledgements
We thank the CERCA Program/Generalitat de Catalunya, ICREA,
the Spanish MINECO (CTQ2017-88920-P), and AGAUR (2017-
SGR-232). J.X. thanks the Chinese Scholarship Council (CSC-
2016-06200061) for a predoctoral fellowship.
no conclusive confirmation of
a requisite HO···HO-C(O)
interaction could be established.[19] Finally, a secondary aniline
(Scheme 2e) was tested in the allylic amination of B providing in
71% yield the unsaturated -amino acid (Z)-4 in support of the
proposed mechanism presented in Scheme 1.[20]
Keywords: allylic alcohols • amination • lactams • stereoselec-
tivity • palladium
We further explored the synthetic utility of these lactam
scaffolds through a series of site-selective post-modifications
(Scheme 3). A Rh-mediated oxidative CH functionalization[21] of
1a afforded 5 in 53% yield, and the identity of the product was
unambiguously confirmed by X-ray analysis.[16] Hydrogenation of
1a using Pd/C as catalyst gave clean access to 6 (92%), while the
use of a different reducing medium (NaBH4/BiCl3) for more
functional 2o provided 7 in 95% yield. Pyrrolidine 8 could be
prepared in 75% by reducing 1a in the presence of LiAlH4, and
finally deprotection of the N-PMP protected lactam 3n in the
presence of cerium ammonium nitrate (CAN) gave the free lactam
9 in good yield. It should be further noted that products 3n, 3k and
7 are considered useful entries towards the formation of bioactive
lactams Jatropham (Scheme 3),[21] the 5-HT2C-antogonist in
Scheme 1,[22] and therapeutic agents for neurological disorders,[23]
respectively.
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Scheme 3. Post-synthetic potential of the ,-unsaturated -lactam scaffolds.
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[6]
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for further details.
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[18] Benzoic acid was previously reported to act as an activator in the
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to Pd(0) can be rather challenging, see: g) B. M. Trost, Chem. Eur. J.
1998, 4, 2405-2412. See also reference 8b.
[19] The occurrence of some degree of requisite HO···HOOC hydrogen
bonding in solution cannot be fully ruled out, despite that such
interactions are not observed in the solid state. See the X-ray analysis of
A and related comments in the SI.
[20] Control experiments (see the SI) rule out that an (E)-configured product
is first formed, following equilibration to its (Z) isomer. (Allyl)Pd
complexes derived from -unsaturated ketones and esters and their
stoichiometric reactions with various nucleophiles were reported by
Jackson et al., see: W. R. Jackson, J. U. Strauss, Austr. J. Chem. 1977,
30, 553-562. Under Pd-catalysis, the ester derivatives showed
preference for the formation of (E)-configured products, in line with the
crucial role of the carboxyl group in our tertiary allylic alcohol substrates.
[21] L.-W. Liu, Z.-Z. Wang, H.-H. Zhang, W.-S. Wang, J.-Z. Zhang, Y. Tang,
Chem. Comm. 2015, 51, 9531-9534.
[10] a) J. Mathew, B. Alink, J. Org. Chem. 1990, 55, 3880-3886; b) B. M. Trost,
G. J. Roth, Org. Lett. 1999, 1, 67-70; c) X. del Corte, A. Maestro, J.
Vicario, E. Martinez de Marigorta, F. Palacios, Org. Lett. 2018, 20, 317-
320. Note that the (E)-isomers of the unsaturated -amino acids can be
isolated and need to be hydrogenated first before cyclization to their -
lactams can takes place, see: d) C. Xia, J. Shen, D. Liu, W. Zhang, Org.
Lett. 2017, 19, 4251-4254.
[22] N. J. Stam, P. Vanderheyden, C. van Alebeek, J. Klomp, T. de Boer, A.
M. van Delft, W. Olijve, Eur. J. Pharmacol.1994, 269, 339-348.
[23] B. Blass, ACS Med. Chem. Lett. 2015, 6, 1092-1094.
[11] As far as we are aware, stereoselective conversions using allylic alcohol
substrates are rare.
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10.1002/anie.201810160
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents:
COMMUNICATION
One, two, lactam!
A
domino
Jianing Xie, Sijing Xue, Eduardo C.
Escudero-Adán and Arjan W. Kleij*
synthesis of unsaturated -
lactams is reported via a Pd-
catalyzed amination of allylic
alcohols.
An
intramolecular
carboxyl group acts as
a
stereodirecting functional group,
enabling the formation of (Z)
configured -amino acids following
cyclization towards the targeted
lactam scaffolds. This protocol is
atom-efficient and mild, and
highlights a new way of allylic
alcohol activation under ambient
conditions.
Page No. – Page No.
Domino Synthesis of -
Unsaturated -Lactams via
Stereoselective Amination of -
Tertiary Allylic Alcohols
This article is protected by copyright. All rights reserved.