Sequential nucleophilic addition/1,2-rearrangement of N-iminolactam: A ring-contractive strategy for the synthesis of 2-acyl pyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2021.153098

A sequential nucleophilic addition/ring contraction of α-bromo N-iminolactam with organometallic reagents for the synthesis of 2-acyl pyrrolidines has been developed. The reaction allows facial construction of 2-acyl pyrrolidines incorporating not only ar

Full text of DOI:10.1016/j.tetlet.2021.153098

Tetrahedron Letters 73 (2021) 153098
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Sequential nucleophilic addition/1,2-rearrangement of N-iminolactam:
A ring-contractive strategy for the synthesis of 2-acyl pyrrolidines
Norihiko Takeda, Yukiko Kobori, Motohiro Yasui, Yuki Matsumoto, Kotomi Orihara, Yusaku Kido,
⇑
Masafumi Ueda
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A sequential nucleophilic addition/ring contraction of
a-bromo N-iminolactam with organometallic
Received 12 March 2021
Revised 12 April 2021
Accepted 16 April 2021
Available online 18 April 2021
reagents for the synthesis of 2-acyl pyrrolidines has been developed. The reaction allows facial construc-
tion of 2-acyl pyrrolidines incorporating not only aryl and heteroaryl groups, but alkenyl, alkynyl, and
alkyl groups. Moreover, 2-acyl pyrrolidine products can be further transformed into the pyrrolidinyl alco-
hol, epoxide, b-lactam, and pyrazole.
Ó 2021 Elsevier Ltd. All rights reserved.
This paper is dedicated to Professor Dr.
Ilhyong Ryu for the celebration of his 70th
birthday.
Keywords:
Ring contraction
Lactam
Nucleophilic addition
Pyrrolidine
Grignard reagent
Introduction
still of great importance and desired in the fields of organic chem-
istry and medicinal chemistry.
The pyrrolidine scaffold is present as a privileged structure in
many biologically active natural products and pharmaceuticals,
such as kainoids [1,2], lucentamycins [3], ABBV/GLPG-3221 [4],
and enalapril [5]. Among the many pyrrolidine groups reported
in the literature, 2-acyl pyrrolidines have attracted considerable
interest because they are potent inhibitors of dipeptidyl peptidase
IV (DPP IV) [6], serotonin, norepinephrine, and dopamine reuptake
[7]. Additionally, 2-acyl pyrrolidine moieties are synthesized as
partial structures at the C-terminus in the lipopeptides jahanyne
family [8] and kurahyne [9].
Our focus is on developing methods for the efficient formation
of 2-acyl pyrrolidines that would provide facial access to these
compounds and allow them to be used in further synthetic appli-
cations. We recently reported the sequential nucleophilic aryla-
tion/ring-contractive rearrangement of
a-bromo N-alkoxylactams
1 (Y = OBn) with Grignard or organolithium reagents (Scheme 1)
[14]. This Aza–Favorskii type rearrangement enables the nucle-
ophilic arylation of 1 followed by the migration of the lactam car-
bonyl group to afford ring-contracted 2-aroyl pyrrolidines
3
(Nu = Ar). When N-alkoxylactam 1 was used in the sequential reac-
tion, various aryl and heteroaryl groups could be introduced. How-
ever, the introduction of the alkyl group is challenging because the
reaction of 1 with alkyl magnesium bromide favors halogen-metal
exchange/retro-ene fragmentation (A ? B) over nucleophilic
alkylation to the lactam carbonyl group. To expand the range of
C-nucleophiles for this methodology, an increase in the elec-
trophilicity at the carbonyl moiety is desired to facilitate the nucle-
ophilic addition to the lactam over halogen–metal exchange.
Considering the 13C NMR spectra of N-acetyl hydrazones 5 [15]
and N-alkoxyamides 6 [16] in the literature, the C1 signal of 5
tends to shift downfield (Fig. 1). This tendency suggests that the
electrophilicity of the amide 5 is higher than that of 6. Therefore,
The common strategy for the synthesis of 2-acyl pyrrolidines
involves (i) the reaction of proline derivatives, such as Weinreb
amides [10] and activated esters [11], with organometallic
reagents and (ii) a-lithiation of N-protected pyrrolidine derivatives
and subsequent trapping by acylating agents [12]. Although a vari-
ety of other methods have been developed, studies focused on the
synthesis of 2-acyl pyrrolidines carrying various substituents are
scarce [13]. Therefore, the study of 2-acyl pyrrolidine synthesis is
⇑
Corresponding author.
E-mail address: masa-u@kobepharma-u.ac.jp (M. Ueda).
https://doi.org/10.1016/j.tetlet.2021.153098
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

N. Takeda, Y. Kobori, M. Yasui et al.
Previous work: Y = OR, Nu = Ar, Alkenyl
Tetrahedron Letters 73 (2021) 153098
Table 1
Optimization of nucleophilic phenylation-ring contraction.a
This study: Y = N=CPh2, Nu = Ar, Alkenyl, Alkynyl, Alkyl
O
O
Nu
NuMgBr or NuLi
then H
Br
Y
N
N
Y
1 (Y = OBn)
2 (Y = N=CPh2)
3 (Y = OBn)
4 (Y = N=CPh2)
NuMgBr
(Nu = alkyl)
(Y = OBn)
halogen-metal exchange
b
Entry
Substrate
PhM(X)
Yield (%)
1
2
3
4
2 (X = Br)
2 (X = Br)
7 (X = Cl)
8 (X = I)
PhMgBr
PhLi
PhMgBr
PhMgBr
99
64
63
8
H
N
Ph
retro-ene
fragmentation
MO
MO
O
N
+ PhCHO
a
Reaction conditions: lactam (0.15 mmol), organometallic reagent (0.30 mmol),
A
B
THF (2 mL), –78 °C, 1 h, then 1 M HCl.
b
Isolated yields.
Scheme 1. Nucleophilic addition/ring contraction of N-substituted lactams.
reaction of 2 with aryl Grignard reagents carrying both electron-
donating groups (p-methoxy, p-methyl, and p-tert-butyl group)
on the benzene ring and electron-withdrawing groups (p-chloro,
p-ethoxycarbonyl, and p-cyano group) afforded the desired 2-acyl
pyrrolidines 4b–g in good to high yields. These results indicate that
the electronic nature of the substituent on the benzene ring had no
impact on the reaction efficiency. Moreover, the sequential reac-
tion of 2 with aryl Grignard reagents, which have a variety of m-
and o-substituted groups, and m,p- and m,m-disubstituted groups,
worked well (4 h–l).
Fig. 1. 13C NMR chemical shifts of N-acetyl hydrazones
alkoxyamides 6.
5 and acetyl N-
Next, the introduction of heteroaryl groups to the N-iminolac-
tam 2 with heteroaryl lithium reagents was examined. As a result,
the corresponding products 4 m–r, which have various heteroaryl
groups, including thiophene, furan, benzothiophene, and benzofu-
ran, were obtained in high yields [17].
we envisioned that a-bromo lactam 2 possessing the diphenylim-
ino group (Y = N=CPh2) on the lactam nitrogen atom could be a
suitable substrate for the nucleophilic addition/ring-contractive
rearrangement. Consequently, the reaction of 2 with organometal-
lic reagents would lead to the formation of various 2-acyl pyrrolidi-
nes 4. Herein, we present the synthesis of 2-acyl pyrrolidines
through the nucleophilic addition/ring contraction of N-iminolac-
tam with a variety of Grignard or organolithium reagents. This
method can provide access to 2-acyl pyrrolidines incorporating
various C(sp2) units as well as C(sp), C(sp3) units, such as aryl, het-
eroaryl, alkenyl alkynyl, and alkyl groups. Moreover, the synthetic
utility of the reaction was further demonstrated by converting the
2-acyl pyrrolidine into pyrrolidinyl alcohol, epoxide, b-lactam, and
pyrazole.
As a more challenging task, we extended to the introduction of
alkenyl and alkynyl groups using a sequential reaction because the
corresponding products that incorporated
a,b-unsaturated car-
bonyl groups would convert to other functional groups and hetero-
cycles [18]. The reaction of 2 with alkenyl Grignard reagents
provided the desired products 4 s–v in moderate to good yields
[17]. Meanwhile, the use of various alkynyl lithium reagents led
to the formation of products bearing the conjugated ynone group
in high yields (4w–ac) [17]. Additionally, the scope of the sequen-
tial reaction using a variety of alkyl Grignard reagents, such as
methyl, ethyl, c-propyl, and dodecyl groups, was examined. As a
result, products 4ad, 4ae, 4ag, and 4ah were obtained [17]. In con-
trast, when i-propyl magnesium bromide was used, the debromi-
nated N-iminolactam 9 was obtained instead of the formation of
4af.
Results and discussion
We initially examined the nucleophilic phenylation/ring con-
To confirm the increased reactivity of N-iminolactam 2 com-
pared with that of N-alkoxylactam 1, we measured the 13C NMR
of the lactams in CDCl3 (Fig. 2). The 13C NMR spectrum of 2 showed
a chemical shift at 176.3 ppm (C2, C@O group). In comparison, the
traction of
(Table 1). According to our preceding communication [14], the
reaction of -bromo N-iminolactam 2 with phenylmagnesium bro-
a-halo N-iminolactam with organometallic reagents
a
mide (PhMgBr, 2 equiv.) in THF at –78 °C followed by quenching
with 1 M HCl produced an excellent yield of 2-benzoyl pyrroridine
4a (entry 1). Phenyllithium (PhLi) was also suitable for this sequen-
corresponding chemical shift for N-alkoxylactam 1 was at
163.9 ppm. The highly shifted C2 signal for 2 indicated that the
increased electrophilicity of 2 compared to 1, presumably due to
the pronounced electron-withdrawing effects of the diphenylimino
group. Therefore, a variety of C-nucleophiles, such as C(sp2), C(sp),
and C(sp3) units, could be introduced to N-iminolactam 2 because
the nucleophilic addition of 2 proceeded faster than halogen–metal
exchange.
tial reaction (entry 2). Moreover, the treatment of
nolactam with PhMgBr afforded the corresponding 4a in
moderate yield (entry 3). In contrast, the use of -iodo N-iminolac-
tam 8 with PhMgBr led to the formation of 4a in low yield (entry
4). Therefore, these results indicate that -bromo N-iminolactam
a-chloro N-imi-
7
a
a
2 is the optimal substrate for this sequential reaction.
We proceeded to examine the scope of the reaction with vari-
ous Grignard and organolithium reagents (Table 2). The sequential
A plausible reaction pathway for the formation of 2-acyl pyrro-
lidines 4 is depicted in Scheme 2. The nucleophilic addition of
organometallic reagents to N-iminolactam 2 leads to the formation
2

N. Takeda, Y. Kobori, M. Yasui et al.
Tetrahedron Letters 73 (2021) 153098
Table 2
Nucleophilic addition/ring contraction of 2 with various NuMgX and NuLi.a,b
O
O
R
RMgX or RLi
Br
N
Ph
N
N
N
THF, -78 °C
then 1 M HCl
or AcOH
Ph
Ph
Ph
2
4
(ArMgBr then 1 M HCl)
O
O
O
O
O
O
OMe
Me
t-Bu
Cl
CO2Et
CN
N
N
N
N
N
N
N
N
N
N
N
N
Ph
4b: 93%
OMe
Ph
Ph
Ph
Ph
4f: 98%
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4c: 88%
4d: 99%
MeO
4e: 91%
OMe
4g: 68%
OMe
OMe
CO2Et
O
O
O
O
O
OMe
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
4l: 91%c
Ph
4h: 89%
Ph
Ph
Ph
Ph
Ph
Ph
4j: 85%
4k: 88%
4i: 86%
(ArLi then 1 M HCl)
O
N
O
O
S
O
O
O
Me
Me
O
S
O
S
O
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4m: 99%
4n: 99%d
4o: 70%
4p: 93%
4r: 99%
4q: 99%
then AcOH)
Li
(alkenyl MgBr then AcOH)
(
Ar
Me
Me
Me
O
O
O
O
O
O
Me
Me
Me
OMe
Me
Me
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4s: 60%
4t: 82%
4u: 38%e
4v: 69%
4x: 70%
4w: 92%
Me
Me
O
N
O
O
O
O
OCF3
Me
CF3
N
N
N
N
N
N
N
N
N
Ph
Ph
4ac: 76%
Ph
Ph
Ph
4ab: 74%
Ph
Ph
Ph
Ph
Ph
4aa: 86%f
4y: 90%
4z: 70%
(alkyl MgBr then AcOH)
O
O
O
O
O
Me
Me
Me
O
Et
Me
N
Ph
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4ae: 80%
Ph
Ph
Ph
Ph
9: 90%
4ad: 73%
4ah: 54%e
4af: ND
4ag: 88%
aReaction conditions: 2 (0.15 mmol), organometallic reagent (0.30 mmol), THF (2 mL), –78 °C, 1 h, then 1 M HCl.
b
Isolated yields.
ArMgCl (3 equiv.) was used.
Reaction was quenched by AcOH.
RMgBr (4 equiv.) were used.
c
d
e
f
RLi (3 equiv.) was used.
of the five-membered chelated intermediate C. The acidic workup
of the chelated intermediate C resulted in the generation of the N,
O-hemiaminal D, which rapidly underwent 1,2-rearrangement of
the CAN bond to obtain 2-acyl pyrrolidines 4.
Notably, the scalable synthesis of 2-benzoyl pyrrolidine 4a was
performed under optimized conditions, and the desired 4a was
obtained in 98% yield when the amount of 2 was increased to
2.0 mmol (Scheme 3). The synthetic utility of the current methods
was demonstrated by applying it to the preparation of
Fig. 2. 13C NMR chemical shifts of lactams 2 and 1.
3

N. Takeda, Y. Kobori, M. Yasui et al.
Tetrahedron Letters 73 (2021) 153098
O
N
Acknowledgments
O
Nu
NuMgBr or NuLi
Br
N
Ph
N
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 for the Mitsubishi Tan-
abe Pharma Award in Synthetic Organic Chemistry, Japan (2016).
then 1 M HCl or AcOH
N
Ph
Ph
Ph
2
4
nucleophilic
addition
1,2-rearrangement
Appendix A. Supplementary data
M
Nu
O
Nu OH
N
H
Ph
Ph
Br
N
Br
N
Ph
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153098.
N
acidic work up
Ph
C
D
References
Scheme 2. The proposed reaction pathway.
[1] For selected reviews on the kainoid family: (a) Moloney M. G. Nat. Prod. Rep.
2002, 19, 597–616; (b) Moloney M. G. Nat. Prod. Rep. 1999, 16, 485–498; (c)
Moloney M. G. Nat. Prod. Rep. 1998, 15, 205–219; (d) Parsons A. F. Tetrahedron
1996, 52, 4149–4174
[2] (a) S. Murakami, T. Takemoto, Z. Shimizu, J. Pharm. Soc. Jpn. 73 (1953) 1026–
1028;
Ph
PhMgBr
HO
Ph
THF, -78 °C
then 1 M HCl
2 (0.71 g, 2.0 mmol)
(b) K. Daigo, J. Pharm. Soc. Jpn. 79 (1959) 350–353;
N
PhMgBr
O
N
98%
(c) T. Takemoto, K. Daigo, Chem. Pharm. Bull. 6 (1958) 578–580;
(d) J. Clayden, B. Read, K.R. Hebditch, Tetrahedron 61 (2005) 5713–5724.
[3] J.Y. Cho, P.G. Williams, H.C. Kwon, P.R. Jensen, W. Fenical, J. Nat. Prod. 70 (2007)
1321–1328.
[4] M.J.C. Scanio, X.B. Searle, B. Liu, J.R. Koenig, R. Altenbach, G.A. Gfesser, A.
Bogdan, S. Greszler, G. Zhao, A. Singh, Y. Fan, A.M. Swensen, T. Vortherms, A.
Manelli, C. Balut, Y. Jia, W. Gao, H. Yong, M. Schrimpf, C. Tse, P. Kym, X. Wang,
ACS Med. Chem. Lett. 10 (2019) 1543–1548.
[5] A.A. Patchett, E. Harris, E.W. Tristram, M.J. Wyvratt, M.T. Wu, D. Taub, E.R.
Peterson, T.J. Ikeler, J. ten Broeke, L.G. Payne, D.L. Ondeyka, E.D. Thorsett, W.J.
Greenlee, N.S. Lohr, R.D. Hoffsommer, H. Joshua, W.V. Ruyle, J.W. Rothrock, S.D.
Aster, A.L. Maycock, F.M. Robinson, R. Hirschmann, C.S. Sweet, E.H. Ulm, D.M.
Gross, T.C. Vassil, C.A. Stone, Nature 288 (1980) 280–283.
[6] D. Ferraris, Y.-S. Ko, D. Calvin, T. Chiou, S. Lautar, B. Thomas, K. Wozniak, C.
Rojas, V. Kalish, S. Belyakov, Bioorg. Med. Chem. Lett. 14 (2004) 5579–5583.
[7] M.C. Lucas, R.J. Weikert, D.S. Carter, H.-Y. Cai, R. Greenhouse, P.S. lyer, C.J. Lin, E.
K. Lee, A. Madera, M. Moore, A.K. Ozboya, R.C. Schoenfeld, S. Steiner, Y. Zhai, S.
M. Lynch, Bioorg. Med. Chem. Lett. 20 (2010) 5559–5566.
Ph
Ph
10: 96%
Ph
THF
0 °C
N
N
PhO
COCl
Et3N
Me3S I
t-BuOK
O
O
Ph
Ph
4a (0.70 g)
Ph
Ph
O
DMSO
rt
CH2Cl2
rt
N
N
N
N
Ph
OPh
Ph
Ph
Ph
11: 94%
12: 99%
Me
(dr = 2.5:1)
O
(dr = 6:1)
N
Ph
N
MeNHNH2
Ph
AcOH
N
N
N
N
[8] (a) A. Iwasaki, O. Ohno, S. Sumimoto, H. Ogawa, K.A. Nguyen, K. Suenaga, Org.
Lett. 17 (2015) 652–655;
(b) A. Iwasaki, H. Fujimura, S. Okamoto, T. Kudo, S. Hoshina, S. Sumimoto, T.
Teruya, K. Suenaga, J. Org. Chem. 83 (2018) 9592–9603.
[9] A. Iwasaki, O. Ohno, S. Sumimoto, S. Suda, K. Suenaga, RSC Adv. 4 (2014)
12840–12843.
EtOH, 60 °C
Ph
Ph
Ph
Ph
4w
13: 73%
Scheme 3. Scalable synthesis and synthetic modification of 4a and 4w.
[10] (a) S. Nahm, S.M. Weinreb, Tetrahedron Lett. 22 (1981) 3815–3818;
(b) M. Falorni, G. Giacomelli, A.M. Spanedda, Tetrahedron: Asymmetry
(1998) 3039–3046;
(c) L. De Luca, G. Giacomelli, M. Taddei, J. Org. Chem. 66 (2001) 2534–2537.
[11] (a) L. De Luca, G. Giacomelli, A. Porcheddu, Org. Lett. 3 (2001) 1519–1521;
(b) H. Tokuyama, S. Yokoshima, T. Yamashita, T. Fukuyama, Tetrahedron Lett.
39 (1998) 3189–3192.
9
pyrrolidine-containing derivatives (Scheme 3). The transformation
of 4a into pyrrolidinyl alcohol 10 by nucleophilic phenylation with
PhMgBr was successful. The Corey-Chaykovsky epoxidation and [2
+ 2] cycloaddition of 4a gave epoxide 11 and b-lactam 12 in high
yields, respectively [19,20]. Moreover, the treatment of 4w carry-
ing the ynone moiety with N-methylhydrazine afforded pyrazolo-
pyrrolidine 13 in good yield [21].
[12] (a) R.K. Dieter, R.R. Sharma, H. Yu, V.K. Gore, Tetrahedron 59 (2003) 1083–
1094;
(b) S. Monticelli, W. Holzer, T. Langer, A. Roller, B. Olofsson, V. Pace,
ChemSusChem 12 (2019) 1147–1154.
[13] (a) C. Le, D.W.C. MacMillan, J. Am. Chem. Soc. 137 (2015) 11938–11941;
(b) C.L. Joe, A.G. Doyle, Angew. Chem. Int. Ed. 55 (2016) 4040–4043;
(c) T.K. Beng, J. Garcia, M. Smith, A.O. Orellana, New J. Chem. 44 (2020) 15337–
15340.
Conclusion
[14] N. Takeda, Y. Kobori, K. Okamura, M. Yasui, M. Ueda, Org. Lett. 22 (2020) 9740–
9744.
[15] (a) P.-L. Wu, S.-Y. Peng, J. Magrath, Synthesis (1995) 435–438;
(b) L. Somogyi, Tetrahedron 41 (1985) 5187–5190.
[16] (a) X. Chen, J. Han, Y. Zhu, C. Yuan, J. Zhang, Y. Zhao, Chem. Commun. 52
(2016) 10241–10244;
(b) C. Torruellas, F.-L. Hsu, A.J. Walz, Synthesis 51 (2019) 2891–2896.
[17] When the reaction mixture was quenched with 1 M HCl, the yields of product
4n, 4s, 4w, and 4ad were decreased due to the deompositions of furan (4n),
enone (4s), and ynone (4w) moieties.
In conclusion, a sequential nucleophilic addition/ring contrac-
tion reaction for the conversion of N-iminolactam to 2-acyl pyrro-
lidines has been developed. The transformation tolerates the
introduction of a wide range of C-nucleophiles, such as Grignard
and organolithium reagents. Further applications of nucleophilic
addition/ring contraction of lactams are currently being investi-
gated in our laboratory.
[18] (a) G. Desimoni, G. Faita, P. Quadrelli, Chem. Rev. 115 (2015) 9922–9980;
(b) C. Nájera, L.K. Sydnes, M. Yus, Chem. Rev. 119 (2019) 11110–11244.
[19] Yu.G. Gololobov, A.N. Nesmeyanov, V.P. Lysenko, I.E. Boldeskul, Tetrahedron
43 (1987) 2609–2651.
Declaration of Competing Interest
[20] S.D. Sharma, S.B. Pandhi, J. Org. Chem. 55 (1990) 2196–2200.
[21] S. Barbey, L. Goossens, T. Taverne, J. Cornet, V. Choesmel, C. Rouaud, G. Gimeno,
S. Yannic-Arnoult, C. Michaux, C. Charlier, R. Houssin, J.-P. Hénichart, Bioorg.
Med. Chem. Lett. 12 (2002) 779–782.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
4