Sequential Nucleophilic Arylation/Ring-Contractive Rearrangement of N-Alkoxylactams

Article abstract of DOI:10.1021/acs.orglett.0c03821

A nucleophilic addition/ring-contractive rearrangement of α-bromo N-alkoxylactams with organometallic reagents was developed, providing an efficient access to α-acylpyrrolidines incorporating various C(sp2) units such as aryl, heteroaryl, and alkenyl groups. The sequential reaction proceeds through a five-membered chelate formation using nucleophilic addition followed by ring contraction via the formation of N,O-hemiaminal with good yields and a broad substrate scope. Moreover, a preliminary result with the use of the chiral N-alkoxylactam for the diastereoselective reaction is described.

Full text of DOI:10.1021/acs.orglett.0c03821

pubs.acs.org/OrgLett
Letter
Sequential Nucleophilic Arylation/Ring-Contractive Rearrangement
of N‑Alkoxylactams
Norihiko Takeda, Yukiko Kobori, Kohei Okamura, Motohiro Yasui, and Masafumi Ueda*
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ABSTRACT: A nucleophilic addition/ring-contractive rearrange-
ment of α-bromo N-alkoxylactams with organometallic reagents
was developed, providing an efficient access to α-acylpyrrolidines
incorporating various C(sp2) units such as aryl, heteroaryl, and
alkenyl groups. The sequential reaction proceeds through a five-
membered chelate formation using nucleophilic addition followed
by ring contraction via the formation of N,O-hemiaminal with good
yields and a broad substrate scope. Moreover, a preliminary result
with the use of the chiral N-alkoxylactam for the diastereoselective reaction is described.
Scheme 1. Representative Examples of the Favorskii and
Other Types of Favorskii Rearrangements, Including the
Inspiration for This Work
n synthetic organic chemistry, the ring-contraction reaction
is one of the most elegant transformations because it allows
I
the skeletal reorganization with a high level of selectivity in
several cases, affording products not easily accessible by other
approaches.1 In particular, the ring-contraction reaction
involving the migration of carbonyl group is an attractive
and useful reaction due to the further introduction of a
nucleophile to the migrated carbonyl group. This reaction
proceeds via the rearrangement of several C−C bonds, and
representative examples include the pinacol rearrangement,2
Wolff rearrangement,3 Favorskii rearrangement,4 and benzylic
acid rearrangement.5 Therefore, these ring contraction
strategies are applied for the synthesis of biologically active
and natural products.6 The Favorskii rearrangement is a base-
induced ring contraction of α-halo cyclic ketones (1: Y = CH2)
that enables the migration of the endocyclic carbonyl group as
well as the incorporation of N- and O-nucleophiles (ROH,
R2NH, RNH2) to afford ring-contracted carboxylic acid
derivatives (1 → A → 2: Y = CH2) (Scheme 1, eq 1).7 In
contrast, the Favorskii rearrangement accompanied by
introduction of C-nucleophiles has received little attention.8
Moreover, available C-nucleophiles are limited to stabilized
enolates. The reaction utilizing lactones and lactams would
construct ring-contracted cyclic ethers and amines. For
example, the oxy-Favorskii rearrangement of α-halo lactones
(1: Y = O) proceeds through the ring-opening and
intramolecular SN2-type cyclization of alkoxide intermediate
B to provide α-acylated cyclic ethers (2: Y = O).9 However,
the aza-Favorskii rearrangement of α-halo lactams is scarce.10
Therefore, systematic studies were not conducted due to the
poor electrophilicity of the amide carbonyl group. For example,
Henning and co-worker reported that the ring-contraction
reaction of α-chloro lactam 3 followed by the introduction of
an O-nucleophile under basic conditions afforded the α-
carboxylated pyrrolidine derivative 4 (Scheme 1, eq 2).10a To
Received: November 18, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03821
© XXXX American Chemical Society
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the best of our knowledge, there are no studies on the
incorporation of C-nucleophiles in the aza-Favorskii rearrange-
ment of α-halo lactams, even though the carbonyl group
migrating in the reaction can serve as an effective proxy for a
wide variety of other functional groups. Therefore, the C−C
bond forming ring contraction of lactam remains a major
synthetic challenge.11 Herein, we present the sequential
nucleophilic arylation/ring contraction of δ-lactam for the
synthesis of α-acylpyrrolidines.12
noted that this is the first example for a nucleophilic
phenylation of lactam and sequential ring contraction.
Pleasingly, the phenylation/ring contraction of 7a provided
the desired compound 8aA in excellent yield with 2 equiv of
PhMgBr (entry 2). Phenyl lithium (PhLi) was also suitable for
this sequential reaction, whereas using other organometallic
reagents was not effective (entry 3 and data not shown).16 The
effects of the α-leaving group on the sequential reaction were
then examined. The sequential reaction of α-iodo N-
benzyloxylactam 11 with PhMgBr afforded the α-benzaldehyde
adduct 9 via the aldol-type addition of enolate E to
benzaldehyde, which was generated by retro-ene fragmentation
of enolate E (entry 4 and Scheme 2).13i In contrast, the use of
To introduce a C-nucleophile into an amide carbonyl group,
using the Weinreb amide is one of the most reliable and
powerful methods.13 The N-alkoxy group of a Weinreb amide
increases the electrophilicity of the amide carbonyl group and
then allows the nucleophilic addition under mild conditions.
Therefore, we surmised that the α-halo N-alkoxylactam 5
would act as a good acylating agent to introduce C-
nucleophiles, such as organometallic reagents (Scheme 1, this
work). The nucleophilic addition of organometallic reagents to
lactam 5 leads to the formation of the five-membered chelated
intermediate C. The acidic workup of the chelated
intermediate C results in the generation of the N,O-
hemiaminal D, which rapidly undergoes a 1,2-rearrangement
through the overlap of an antibonding orbital on the C−X
bond (σ*C−X) and a bonding orbital on the C−N of the
hemiaminal group (σC−N) to obtain α-acylpyrrolidines 6.14
The α-bromo N-alkoxylactam 5 (X = Br) was used to
investigate the possibility of the nucleophilic arylation/ring
contraction with an organometallic reagent because the α-
bromo group as a leaving group has the requisite reactivity for
the ring contraction and would be tolerant in the nucleophilic
addition to the amide carbonyl group without halogen−metal
exchange.15
Scheme 2. Proposed Reaction Pathway of α-Iodo Lactam 11
with PhMgBr
12 carrying an α-chloro group furnished the chloroenamine 10,
which was produced by nucleophilic phenylation and
dehydration (entry 5). The sequential reaction of 13 with
the α-tosyloxy group afforded α-benzoylpyrrolidine 8aA, but in
low yield (entry 6). Therefore, the α-bromo group as a leaving
group of 7a plays an important role in the nucleophilic
phenylation/ring-contraction reaction. Additionally, it is noted
that the reaction could also be carried out in 1 mmol scale
without any problem (97% yield, entry 7).
The nucleophilic addition/ring contraction of α-bromo N-
benzyloxylactam 7a as a model substrate was initially
investigated (Table 1). The model substrate 7a was readily
Table 1. Optimization of Nucleophilic Addition/Ring
Contraction
To demonstrate the synthetic utility of the ring-contracted
products, α-benzoyl N-(benzyloxy)pyrrolidine 8aA was used to
derive various pyrrolidinyl compounds (Scheme 3). The
Scheme 3. Transformations of N-Alkoxypyrrolidine 8aA
entry
substrate
PhM(X) (equiv)
yield (%)
b
1
2
3
4
5
6
7a (X = Br)
7a (X = Br)
7a (X = Br)
11 (X = I)
12 (X = Cl)
13 (X = OTs)
7a (X = Br)
PhMgBr (1)
PhMgBr (2)
PhLi (2)
PhMgBr (2)
PhMgBr (2)
PhMgBr (2)
PhMgBr (2)
8aA: 67
8aA: 97
8aA: 71
8aA: ND , 9: 46
8aA: ND , 10: 73
8aA: 30
8aA: 97
c
d
c
e
7
a
b
Yield of the chromatographically pure product. Lactam 7a was
c
d
e
recovered in 25% yield. Not detected. dr = 1:1. Lactam 7a (1.24
transformation of 8aA into pyrrolidinyl alcohols 14 and 15
by the nucleophilic phenylation with PhMgBr and reduction
with NaBH4 was successful. The synthesis of pyrrolidinyl
alkene 16 was achieved through C−C bond formation using
the Wittig reaction. Moreover, the benzyloxy moiety of 8aA
was removed by t-BuOK to afford pyrroline 17 via the E1cB
reaction.
After the optimal conditions for the nucleophilic addition/
ring contraction were established, the reaction of α-bromo N-
benzyloxylactam 7a with a variety of aryl Grignard reagents
mmol) was used.
prepared by α-bromination of 5-bromovaleryl chloride
followed by amidation and cyclization. The nucleophilic
phenylation of 7a was performed with phenylmagnesium
bromide (PhMgBr, 1 equiv) in THF at −78 °C and then
quenched with 1 M HCl. The phenylation/ring contraction
proceeded smoothly to give α-benzoylpyrrolidine 8aA in good
yield along with recovered 7a (Table 1, entry 1). It should be
B
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was investigated (Scheme 4). The electronic nature of the
substituents on the benzene ring had a moderate effect on the
and m,m-dimethoxy groups was also successful (8aJ−aM).
Heteroaryl groups, including thiophene, furan, benzothio-
phene, benzofuran, and indole, were also introduced into N-
alkoxylactam 7a using the sequential reaction. For example, the
heteroarylation of 7a with heteroaryl lithium reagents
proceeded under optimized conditions to afford the corre-
sponding products 8aN−aT in moderate to good yields.
Furthermore, the scope of the sequential reaction using several
alkenyl Grignard reagents was investigated and products 8aU
and 8aV carrying α,β-unsaturated ketone moieties were
obtained in moderate yields.17
Scheme 4. Nucleophilic Addition/Ring Contraction of 7a
a b
,
with Various ArMgBr, HetArLi, and Alkenyl MgBr
To elucidate the reaction pathway, we indirectly confirmed
the formation of chelate intermediate G by trapping an
electrophile (Scheme 5). By reacting 7a with PhMgBr followed
Scheme 5. Control experiments
by quenching with acetyl chloride at −78 °C, the O-acetylated
N,O-aminal 18 was obtained (eq 1).18 This result indicates
that chelate intermediate G is generated in situ.19 To
demonstrate the effect of the alkoxy group, the sequential
reaction of other lactam types was examined under optimized
conditions. The use of N-phenethyl lactam 19, which lacked an
oxygen atom compared to N-benzyloxylactam 7a, gave
diphenylated N,O-aminal 20 without the formation of α-
benzoylpyrrolidine 21 (eq 2). This result shows that the
adjacent nitrogen and oxygen atoms are critical for this
nucleophilic addition/ring contraction.20,21
Next, the substituent effects of various α-bromo N-
alkoxylactams with aryl magnesium and heteroaryl lithium
reagents were studied (Scheme 6). The sequential reaction of
α-bromo lactams 7b−d with methoxy, allyloxy, and prop-
argyloxy groups at the lactam nitrogen atom provided the
desired ring-contracted products 8bA−cN, 8dA in good to
high yields (entries 1−7). Moreover, the nucleophilic
arylation/ring contraction of disubstituted N-benzyloxylactams
7e−g was also examined. The β-methyl group of 7e
significantly affected the reaction, resulting in low yields of
the ring-contracted product 8eA (entry 8). However, when γ-
and δ-methyl α-bromo lactams 7f and 7g were used, α-
acylpyrrolidines 8fA−gN with various incorporated aryl and
heteroaryl groups were obtained in good yields (entries 9−14).
Lastly, the diastereoselective version of this nucleophilic
phenylation/ring contraction was investigated by employing a
(−)-cis-N-benzyloxylactam 7g (Scheme 7). As a result,
sequential reaction with PhMgBr proceeded in a stereo-
selective manner, and desired ring-contracted product 8gA was
obtained with high diastereoselectivity without loss of
enantiopurity, thereby indicating that the present method is
potentially promising for the synthesis of optically active α-
acylpyrrolidines at this stage.
a
Reaction conditions: 7a (0.15 mmol), organometallic reagent (0.30
b
mmol), THF (2 mL), − 78 °C 1−2 h, then 1 M HCl. Yield of the
chromatographically pure product. The reaction was carried out at 0
°C. ArMgCl was used. ArLi was in situ prepared from ArH and n-
BuLi (See Supporting Information). The reaction was quenched by
c
d
e
f
AcOH.
reaction efficacy. Higher yields of the desired α-acylpyrroli-
dines 8aB−aF were observed, when aryl Grignard reagents
with an electron-donating group on the benzene ring, such as
the p-methoxy, p-dimethylamino, p-methyl, p-tert-butyl, and p-
phenyl group, were used. Moreover, the sequential reaction of
7a with aryl Grignard reagents which have an electron-
withdrawing group on the benzene ring, such as the p-chloro,
p-trifluoromethoxy, and p-ethoxycarbonyl group, proceeded
under optimized conditions to give products 8aG−aI in
moderate to good yields.
In summary, we have successfully developed a nucleophilic
arylation and alkenylation/ring contraction of N-alkoxylactams.
A variety of Grignard and organolithium reagents including
Additionally, the sequential reaction of 7a with aryl Grignard
reagents which have m-methoxy, o-methoxy, m,p-dimethoxy,
C
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Scheme 6. Substituent Effects of 7b−g with ArMgBr and
Scheme 7. Diastereoselective Phenylation/Ring Contraction
of (−)-cis-7g
a
HetArLi
Further studies to demonstarate the synthtic utility of the
developed methodology, including in the synthesis of bio-
logically active compounds, are now in progress.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03821.
Experimental procedures, and spectroscopic and ana-
1
lytical data for new compounds, including H and 13C
NMR spectra (PDF)
Accession Codes
CCDC 2021279 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Masafumi Ueda − Kobe Pharmaceutical University, Kobe 658-
8558, Japan; orcid.org/0000-0002-8003-2971;
Email: masa-u@kobepharma-u.ac.jp
Authors
Norihiko Takeda − Kobe Pharmaceutical University, Kobe
658-8558, Japan; orcid.org/0000-0003-2330-0201
Yukiko Kobori − Kobe Pharmaceutical University, Kobe 658-
8558, Japan
Kohei Okamura − Kobe Pharmaceutical University, Kobe
658-8558, Japan
Motohiro Yasui − Kobe Pharmaceutical University, Kobe 658-
8558, Japan; orcid.org/0000-0001-9324-3463
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03821
Notes
a
The authors declare no competing financial interest.
Reaction conditions: 7b−g (0.15 mmol), organometallic reagent
b
(0.30 mmol), THF (2 mL), −78 °C 1−2 h, then 1 M HCl. Yield of
the chromatographically pure product. ArLi was in situ prepared from
ArH and n-BuLi (see Supporting Information). The reaction was
quenched by AcOH.
c
ACKNOWLEDGMENTS
■
d
This work was supported by JSPS KAKENHI (Grant Numbers
JP19K05467, N.T.; JP18K06590, M.U.; JP19K23815, M.Y.)
and the Hoansha Foundation (M.U.). N.T. is grateful to the
Mitsubishi Tanabe Pharma Award in Synthetic Organic
Chemistry, Japan (2016).
aryl, heteroaryl, and alkenyl groups could be utilized in the
sequential reaction. As a result, various C(sp2) units could be
introduced to N-alkoxylactams, providing various 2-acylpyrro-
lidines via ring contraction. This protocol is a simple procedure
in a two-step, one-pot process. This nucleophilic arylation and
alkenylation/ring-contractive rearrangement presents a new
platform for ring contraction of lactam in organic synthesis.
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(20) Although the ring-opening product has not been obtained to
date, the possibility that ring-opening and intramolecular SN2-type
cyclization in the reaction pathway cannot be excluded.
(21) One of the possibilities is that the difference in the reactivities
of 7a and 19 would be attributed to the pyramidalization of the amide
functional group.
(10) For ring contraction of α-halo δ-lactam, see: (a) Henning, R.;
Urbach, H. Tetrahedron Lett. 1983, 24, 5339. (b) Kariyone, K. Chem.
Pharm. Bull. 1960, 8, 1110. (c) Francis, W. C.; Thornton, J. R.;
Werner, J. C.; Hopkins, T. R. J. Am. Chem. Soc. 1958, 80, 6238.
(d) Hino, K.; Nagai, Y.; Uno, H. Chem. Pharm. Bull. 1988, 36, 2386.
(11) For other types of ring contraction of lactam, see: (a) Drouin,
A.; Lessard, J. Tetrahedron Lett. 2006, 47, 4285. (b) Drouin, A.;
Winter, D. K.; Pichette, S.; Aubert-Nicol, S.; Lessard, J.; Spino, C. J.
Org. Chem. 2011, 76, 164. (c) Pichette, S.; Aubert-Nicol, S.; Lessard,
J.; Spino, C. Eur. J. Org. Chem. 2012, 2012, 1328. (d) Pichette, S.;
Aubert-Nicol, S.; Lessard, J.; Spino, C. J. Org. Chem. 2012, 77, 11216.
For ring contraction of N-activated lactams, see: (e) Farran, D.;
E
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