Chemo- And diastereoselective synthesis of pyrrolidines from aroylformates and δ-tosylamino enones via P(NMe2)3-mediated reductive amination/base-catalyzed michael addition cascade

Article abstract of DOI:10.1021/acs.orglett.0c02453

A novel P(NMe2)3-mediated tandem (1 + 4) annulation between aroylformates and δ-tosylamino enones has been developed that affords a facile synthesis of functionalized pyrrolidines in moderate to excellent yields with exclusive chemoselectivity and high diastereoselectivity. Mechanistic investigation reveals that the reaction proceeds through an unprecedented P(NMe2)3-mediated reductive amination/base-catalyzed Michael addition cascade. The reaction herein also represents the first study of the reactivity patterns of the Kukhtin-Ramirez adducts toward ambiphilic nucleophile-electrophiles.

Full text of DOI:10.1021/acs.orglett.0c02453

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Letter
Chemo- and Diastereoselective Synthesis of Pyrrolidines from
Aroylformates and δ‑Tosylamino Enones via P(NMe2)3‑Mediated
Reductive Amination/Base-Catalyzed Michael Addition Cascade
Rongfang Liu,∥ Jialin Liu,∥ Jilei Cao, Ruifeng Li, Rong Zhou,* Yan Qiao, and Wen-Chao Gao*
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ABSTRACT: A novel P(NMe2)3-mediated tandem (1 + 4)
annulation between aroylformates and δ-tosylamino enones has
been developed that affords a facile synthesis of functionalized
pyrrolidines in moderate to excellent yields with exclusive
chemoselectivity and high diastereoselectivity. Mechanistic inves-
tigation reveals that the reaction proceeds through an unprece-
dented P(NMe2)3-mediated reductive amination/base-catalyzed
Michael addition cascade. The reaction herein also represents the
first study of the reactivity patterns of the Kukhtin−Ramirez
adducts toward ambiphilic nucleophile−electrophiles.
he pyrrolidines are ubiquitous structural motifs that
construct the core of a wide range of naturally occurring
especially through (1 + 4) annulation, therefore arouses our
interest in view of the diversity-oriented synthesis.
T
compounds, bioactive molecules, and pharmaceuticals (Figure
The Kukhtin−Ramirez adducts, a type of 1,1-dipoles which
are readily generated from 1,2-dicarbonyl compounds and
three coordinate phosphorus reagents, have served as versatile
intermediates in organic synthesis in recent years (Scheme 1,
top).7 The pioneering work from Radosevich and co-workers
disclosed that the Kukhtin−Ramirez adducts could react with
nucleophiles to undergo X−H (X = O, C, N) bond insertions,
affording a novel synthesis of α-functionalized carbonyl
derivatives in a metal-free manner (Scheme 1, bottom, a).8
Mechanistically, the insertion reactions proceed through a
deprotonation-SN2 substitution sequence. Moreover, the
Kukhtin-Ramirez adducts were also reported by our group,9
He,10 Ashfeld,11 and others12 to participate in (1 + 2) and (1 +
4) annulation reactions with electrophiles to bring about three-
and five-membered cyclic compounds, respectively (Scheme 1,
bottom, b). Generally, these annulation reactions were
believed to occur in a tandem Michael addition/intramolecular
substitution sequence. Inspired by these preceding studies and
also as part of our continuous research efforts in exploring the
reactivity patterns of the Kukhtin−Ramirez adducts, we
envisioned that employing an ambiphilic compound tethered
with both a nucleophile and an electrophile would lead to a
new reaction model when interacting with the Kukhtin−
1).1 Furthermore, they can also function as ligands2 and
Figure 1. Representative natural products containing a pyrrolidine
core.
organocatalysts3 in organic synthesis to affect many useful
transformations. This class of compounds has therefore
attracted intensive efforts from chemists owing to their
biological importance and utilities. As a result, a plethora of
synthetic methods have been established in the past few
decades for efficient preparation of pyrrolidines.4 Among them,
the (3 + 2) cycloaddition reactions, particularly the (3 + 2)
cycloaddition of azomethine ylides with activated olefins and
the (3 + 2) cycloaddition of donor−acceptor cyclopropanes
with imines, are demonstrated to be powerful tools to prepare
functionalized pyrrolidines.1b,c,4c,d As an alternative to (3 + 2)
cycloaddition, the (1 + 4) annulation of one carbon unit with
nitrogen-containing four-atom conjugated systems provides a
complementary access to five-membered N-heterocycles.5
Nevertheless, synthesis of pyrrolidines via (1 + 4) annulation
is still underdeveloped, although it has manifested its
effectiveness in preparation of pyrrolines.6 The development
of other complementary synthetic methods to pyrrolidines,
Received: July 23, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02453
© XXXX American Chemical Society
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A

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a
Scheme 1. Reactivity Patterns of the Kukhtin−Ramirez
Adducts toward Nucleophiles, Electrophiles, and
Nucleophile−Electrophiles
Table 1. Screening of the Model Reaction Conditions
b
entry
1
2
solvent
PR3
yield of 3a (%)
CH2Cl2
CHCl3
DCE
P(NMe2)3
P(NMe2)3
P(NMe2)3
P(NMe2)3
P(NMe2)3
P(NMe2)3
P(NMe2)3
P(NEt2)3
P(OMe)3
PPh3
PMePh2
PMe2Ph
PBu3
P(NMe2)3
P(NMe2)3
P(NMe2)3
27
50
35
5
32
12
15
38
c
3
4
5
THF
Toluene
CH3CN
Ethanol
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
d
6
7
8
9
10
11
12
13
8
32
80
81
19
e
14
f
15
g h
,
Ramirez adducts. Herein, we report the first exploration of the
reactivity patterns of the Kukhtin−Ramirez adducts toward
ambiphilic nucleophile−electrophiles such as δ-tosylamino
enones, which leads to a chemo- and diastereoselective
synthesis of pyrrolidines via a tandem (1 + 4) annulation
model (Scheme 1, bottom, c). Mechanistic investigation
unveils that the reaction proceeds through a P(NMe2)3-
mediated reductive amination/base-catalyzed Michael addition
cascade.
16
a
Reaction conditions: ethyl benzoylformate 1a (0.22 mmol), δ-
tosylamino enones 2a (0.2 mmol), PR3 (0.22 mmol), solvent (2.0
b
mL), −78 °C to rt, 15 h. Isolated yield based on 2a, and 3a was
c
d
isolated with dr of 95:5. The initial temperature was −60 °C. The
e
initial temperature was −40 °C. Ethyl benzoylformate 1a (0.3 mmol)
f
and P(NMe2)3 (0.3 mmol) were used. Ethyl benzoylformate 1a (0.4
g
mmol) and P(NMe2)3 (0.4 mmol) were used. Water (2.0 mmol) was
added. The amination product 4a was concomitantly formed in 23%
yield.
h
The δ-tosylamino enone 2a bearing both a nucleophilic
amino group and an electrophilic enone moiety was
synthesized and used as the ambiphilic substrate to probe
the possible reaction with the Kukhtin−Ramirez adduct
derived from ethyl benzoylformate 1a. Gratifyingly, in the
presence of P(NMe2)3 (0.22 mmol), the model reaction of 1a
(0.22 mmol) with 2a (0.2 mmol) in CH2Cl2 smoothly afforded
the pyrrolidine 3a in 27% yield with excellent diastereose-
lectivity (95:5 dr) (Table 1, entry 1). This result therefore
represents a new reactivity pattern of the Kukhtin−Ramirez
adducts toward ambiphilic compounds and also affords a rare
synthesis of functionalized pyrrolidines via a formal (1 + 4)
annulation model. A systematic survey on the model reaction
conditions was subsequently conducted in order to improve
the reaction efficiency. Solvent screening indicated that CHCl3
was the optimal reaction medium, while other common
solvents such as CH2Cl2, DCE, THF, toluene, and CH3CN
resulted in decreased yields, with a majority of the starting
material remaining (entries 1−6). Remarkably, the protic
ethanol could also furnish the desired product in low yield
(entry 7).8c Employing CHCl3 as the solvent, several three-
coordinate phosphorus reagents were investigated, in which
P(NMe2)3 still outperformed all others tested. The structurally
analogous P(NEt2)3 afforded the product 3a in a decreased
yield (entry 8), whereas phosphites such as P(OMe)3 and
phosphines including PPh3 and PMePh2 were completely
detrimental to this reaction (entries 9−11). The phosphines
with relatively strong nucleophilicity such as PMe2Ph and PBu3
could promote the annulation reaction but with inferior results
(entries 12 and 13). Of note, increasing the amounts of both
the ethyl benzoylformate 1a and P(NMe2)3 to 1.5 equiv led to
a remarkable improvement of the yield of 3a, but further
increasing their amounts to 2.0 equiv did not get significantly
enhanced efficiency (entries 14 and 15). Interestingly, when
water was introduced into the reaction as an additive, both the
pyrrolidine 3a and the amination product 4a, obtained from
the N−H insertion reaction,8c were generated in 19% and 23%
yields, respectively, suggesting that the product 4a might be a
possible intermediate in the annulation reaction (entry 16).
Having indentified the optimal reaction conditions, the
generality of this formal (1 + 4) annulation was explored
(Table 2). When δ-tosylamino enone 2a was employed as a
representative substrate, different substituted ethyl aroylfor-
mates 1 were first investigated. For an array of ethyl
aroylformates 1 bearing either an electron-neutral, electron-
donating, or electron-withdrawing substituent on their aryl
groups, their (1 + 4) annulation reactions with 2a smoothly
occurred to furnish the corresponding pyrrolidines 3 in
moderate to excellent yields with good to excellent
diastereoselectivity (entries 1−8). Notably, the substituents
located at both the para- and meta-positions of the aromatic
ring of the aroylformates were readily accommodated in the
annulation reaction (entries 2 vs 3 and 6 vs 7). A heteroaryl
such as thienyl on aroylformates 1 was well tolerated as well,
which readily delivered its product 3i in moderate yield and
diastereoselectivity (entry 9). However, ethyl pyruvate 1j (R1 =
B
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a
of DBU (20 mol %) was required as an additive to accompany
P(NMe2)3 in some cases listed in Table 2 to ensure high
reaction efficiency (entries 3, 5, 9, 11, 13−15, 18, and 19).13
Remarkably, although a reductive N−H insertion of
aroylformates into the nucleophilic tosylamino moiety of 2,8c
a cyclopropanation, and a (1 + 4) annulation of aroylformates
with the electrophilic enone unit of 2 could be envisaged under
the standard reaction conditions,9d,e only the desired
pyrrolidines 3 were generated, highlighting a highly chemo-
selective annulation model. The structures of the pyrrolidines 3
were identified by a combination of 1H, 13C NMR and HRMS-
ESI measurements and further confirmed by X-ray crystallo-
graphic analysis of representative compound 3b (CCDC
2011834; also see the Supporting Information). The stereo-
chemistry assignments for other compounds were made by
analogy with representative 3b.
Table 2. Synthesis of Pyrrolidines 3 from 1 and 2
b
time
(h)
yield
(%)
c
entry
R1 in 1
R2, R3 in 2
dr
1
2
C6H5 (1a)
4-MeOC6H4
(1b)
3-MeOC6H4
(1c)
C6H5, Ts (2a)
2a
15
15
3a, 80
3b, 75
95:5
92:8
d
3
2a
15
3c, 64
90:10
4
5
4-MeC6H4 (1d) 2a
15
24
24
15
15
24
24
15
3d, 80
3e, 90
3f, 73
3g, 55
3h, 58
3i, 74
92:8
d
4-FC6H4 (1e)
4-ClC6H4 (1f)
2a
2a
89:11
87:13
92:8
86:14
87:13
6
7
8
The synthetic utilities of this methodology were further
demonstrated by gram-scale synthesis. As illustrated in Scheme
2, the representative annulation between 1a and 2a was
3-ClC6H4 (1g) 2a
4-BrC6H4 (1h) 2a
d
9
thienyl (1i)
Me (1j)
1a
2a
2a
10
11
Scheme 2. Synthetic Applications of the (1 + 4) Annulation
d
4-MeOC6H4, Ts
(2b)
3j, 77
3k, 76
88:12
90:10
12
1a
4-MeC6H4, Ts
15
(2c)
d
13
1a
1a
1a
1a
4-ClC6H4, Ts (2d)
3-ClC6H4, Ts (2e)
4-BrC6H4, Ts (2f)
2-naphthyl, Ts
(2g)
15
15
15
15
3l, 75
87:13
85:15
86:14
89:11
d
14
3m, 65
3n, 72
3o, 75
d
15
16
17
1a
1a
1a
1a
1a
CH3, Ts (2h)
Et, Ts (2i)
OEt, Ts (2j)
C6H5, Ns (2i)
C6H5, Boc (2j)
15
15
24
15
24
3p, 52
3q, 80
3r, 67
3s, 70
92:8
d
18
19
90:10
86:14
80:20
d
20
21
a
Reaction conditions: ethyl aroylformate 1a (0.3 mmol), δ-
tosylamino enones 2 (0.2 mmol), P(NMe2)3 (0.3 mmol), CHCl3
b
c
amenable to scale-up to gram quantities in good efficiency
(Scheme 2a). Furthermore, the annulation product 3a could
be selectively reduced by NaBH4 to obtain the hydroxy-
substituted pyrrolidine 5a for further elaboration of complex
structures (Scheme 2b).14
To gain insight into the mechanism of this formal (1 + 4)
annulation reaction, the following experiments were deliber-
ately conducted. When the amination product 4a, collected
from the model reaction conditions survey, was treated with a
basic catalyst DBU, the corresponding pyrrolidine 3a was
afforded in 85% yield (Scheme 3, right). Furthermore, when 4a
(2.0 mL), −60 °C to rt. Isolated yield based on 2. Determined by
d
1H NMR assay and referring to the ratio of trans-3/cis-3. P(NMe2)3
(0.22 mmol) and DBU (0.04 mmol) were used.
Me) did not give the desired annulation product under the
standard conditions (entry 10). Experiments probing the scope
of δ-tosylamino enone 2 revealed that both aryl- and alkyl-
substituted enones (R2 = aryl, alkyl) were compatible with this
annulation reaction. In the examined cases, aryl-substituted
enones bearing either an electron-rich or an electron-poor R2
aryl group enabled the formation of their corresponding
pyrrolidines in generally high yields and good diastereose-
lectivity (entries 11−15). A sterically bulky naphthyl-
substituted enone 2g was also a suitable substrate, which
uneventfully produced its annulation product 3o with the
representative aroylformate 1a in 75% yield and 89:11 dr
(entry 16). Alkyl groups such as a methyl or an ethyl group as
the substituent R2 resulted in moderate to good yields with
high diastereoselectivity (entries 17 and 18). Furthermore, the
incorporation of an ester group instead of a carbonyl group on
2 was readily accommodated (entry 19). The influence of the
protecting group R3 attached to the nitrogen atom was
investigated as well. Replacement of the Ts (4-methylbenze-
nesulfonyl) group with an Ns (4-nitrobenzenesulfonyl) group
was feasible, whereas further changing it to a Boc (tert-
butoxycarbonyl) group blocked the annulation completely
(entries 20 and 21). It is worth noting that a catalytic amount
Scheme 3. Mechanistic Investigation
was treated with a catalytic amount of P(NMe2)3, the
annulation product 3a was also smoothly furnished in 74%
yield (Scheme 3, left). These results strongly indicated that the
amination product 4a is an active intermediate of the
annulation reaction and the cyclization of 4a most likely
proceeds in a base-catalyzed intramolecular Michael addition
process.9c,15
C
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Accession Codes
On the basis of the experimental results and the above
mechanistic investigation, a proposed mechanism for the
annulation reaction is exemplified in Scheme 4. The reaction is
CCDC 2011834 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.
Scheme 4. Proposed Mechanism
AUTHOR INFORMATION
Corresponding Authors
■
Rong Zhou − College of Chemistry and Chemical Engineering,
Taiyuan University of Technology, Taiyuan 030024, P.R.
China; orcid.org/0000-0002-0322-9199;
Email: zhourong@tyut.edu.cn
Wen-Chao Gao − College of Biomedical Engineering, Taiyuan
University of Technology, Taiyuan 030024, P.R. China;
orcid.org/0000-0002-1382-6210; Email: gaowenchao@
tyut.edu.cn
Authors
Rongfang Liu − College of Chemistry and Chemical Engineering,
Taiyuan University of Technology, Taiyuan 030024, P.R.
China
Jialin Liu − College of Chemistry and Chemical Engineering,
Taiyuan University of Technology, Taiyuan 030024, P.R.
China
Jilei Cao − College of Chemistry and Chemical Engineering,
Taiyuan University of Technology, Taiyuan 030024, P.R.
China
Ruifeng Li − College of Chemistry and Chemical Engineering,
Taiyuan University of Technology, Taiyuan 030024, P.R.
China; orcid.org/0000-0002-3158-6337
Yan Qiao − The State Key Laboratory of Coal Conversion,
Institute of Coal Chemistry, Chinese Academy of Sciences,
Taiyuan 030001, P.R. China
believed to be initiated with the in situ formation of the
Kukhtin−Ramirez adduct A/B from aroylformate such as 1a
and P(NMe2)3. The Kukhtin−Ramirez adduct then engages in
an N−H insertion into the δ-tosylamino enone such as 2a
through its dipolar form B to give the amination product 4a.8c
In the presence of a base such as DBU or P(NMe2)3, 4a is
deprotonated, affording intermediate C.15,16 Due to the lower
steric hindrance and the possible π−π stacking interaction
between the phenyl groups, the intermediate C prefers to
adopt its favorable conformation C′ instead of the unfavorable
conformation C′′ to participate in an intramolecular Michael
addition, resulting in formation of intermediate D.17 Finally,
intermediate D is protonated to furnish the product trans-3a.
In summary, the reactivity patterns of the Kukhtin−Ramirez
adducts toward ambiphilic nucleophile−electrophiles have
been studied for the first time, which leads to the development
of a novel P(NMe2)3-mediated tandem (1 + 4) annulation of
aroylformates with δ-tosylamino enones. The annulation
reaction tolerates a broad range of substrates and enables a
facile synthesis of functionalized pyrrolidines in moderate to
excellent yields with exclusive chemoselectivity and high
diastereoselectivity. Mechanistic investigation indicates that
the annulation proceeds through an unprecedented P(NMe2)3-
mediated reductive amination/base-catalyzed intramolecular
Michael addition cascade. This reaction also represents a rare
synthesis of structurally diverse pyrrolidines via a (1 + 4)
annulation model, which complements the well established (3
+ 2) cycloaddition reactions. Efforts to investigate the
reactivity patterns of the Kukhtin−Ramirez adducts toward
other types of ambiphilic compounds are currently in progress
in our laboratory, and the relevant results will be reported in
due course.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02453
Author Contributions
∥R.L. and J.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation
of China (Grant Nos. 21502135, 21901179), the Natural
Science Foundation of Shanxi (Grant No. 201901D111081),
the Scientific and Technological Innovation Programs of
Higher Education Institutions in Shanxi (Grant No.
201802024), and the Fund Program for the Scientific Activities
of Selected Returned Overseas Professionals in Shanxi
Province is gratefully acknowledged.
REFERENCES
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02453.
■
̃
́
(1) (a) Tamariz, J.; Burgueno-Tapia, E.; Vazquez, M. A.; Delgado, F.
In The Alkaloids: Chemistry and Biology; Knolker, H.-J., Ed.; Academic
sı
̈
Press, 2018; Vol. 80, pp 1−314. (b) Li, J.; Ye, Y.; Zhang, Y. Org.
Chem. Front. 2018, 5, 864. (c) Kumar, I. RSC Adv. 2014, 4, 16397.
(d) Majik, M. S.; Tilve, S. G. Synthesis 2012, 44, 2673.
(2) (a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem.
Rev. 2000, 100, 2159. (b) Sweet, J. A.; Cavallari, J. M.; Price, W. A.;
Ziller, J. W.; McGrath, D. V. Tetrahedron: Asymmetry 1997, 8, 207.
Experimental procedures, analytical data, crystal struc-
ture of 3b, and NMR spectra of all new compounds
(PDF)
D
https://dx.doi.org/10.1021/acs.orglett.0c02453
Org. Lett. XXXX, XXX, XXX−XXX

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pubs.acs.org/OrgLett
Letter
(3) (a) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.
(b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726.
(4) (a) Ratmanova, N. K.; Andreev, I. A.; Leontiev, A. V.;
Momotova, D.; Novoselov, A. M.; Ivanova, O. A.; Trushkov, I. V.
̈
Tetrahedron 2020, 76, 131031. (b) Dondas, H. A.; Retamosa, M. G.;
́
Sansano, J. M. Synthesis 2017, 49, 2819. (c) Najera, C.; Sansano, J. M.
Pure Appl. Chem. 2019, 91, 575. (d) Pandey, G.; Banerjee, P.; Gadre,
S. R. Chem. Rev. 2006, 106, 4484.
(5) (a) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Chem. Rev.
2015, 115, 5301. (b) Zhang, H.; Zhou, R. Eur. J. Org. Chem. 2020,
2020, 4098.
(6) Synthesis of pyrrolidines via formal (1 + 4) annulation reactions,
see: (a) Bott, T. M.; Vanecko, J. A.; West, F. G. J. Org. Chem. 2009,
74, 2832. (b) Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem.
Soc. 2007, 129, 12928. (c) Shi, M.; Liu, L.-P.; Tang, J. Org. Lett. 2006,
8, 4043.
(7) (a) Liu, Y.; Sun, F.; He, Z. Tetrahedron Lett. 2018, 59, 4136.
(b) Osman, F. H.; El-Samahy, F. A. Chem. Rev. 2002, 102, 629.
(c) Ramirez, F. Acc. Chem. Res. 1968, 1, 168. (d) Ramirez, F. Pure
Appl. Chem. 1964, 9, 337. (e) Kukhtin, V. A. Dokl. Akad. Nauk SSSR
1958, 121, 466.
(8) (a) Zhao, W.; Yan, P. K.; Radosevich, A. T. J. Am. Chem. Soc.
2015, 137, 616. (b) Zhao, W.; Fink, D. M.; Labutta, C. A.;
Radosevich, A. T. Org. Lett. 2013, 15, 3090. (c) Miller, E. J.; Zhao,
W.; Herr, J. D.; Radosevich, A. T. Angew. Chem., Int. Ed. 2012, 51,
10605.
(9) (a) Zhou, R.; Zhang, H.; Liu, J.; Liu, R.; Gao, W.-C.; Qiao, Y.;
Li, R. J. Org. Chem. 2018, 83, 8272. (b) Zhou, R.; Han, L.; Zhang, H.;
Liu, R.; Li, R. Adv. Synth. Catal. 2017, 359, 3977. (c) Zhou, R.; Zhang,
K.; Han, L.; Chen, Y.; Li, R.; He, Z. Chem. - Eur. J. 2016, 22, 5883.
(d) Zhou, R.; Zhang, K.; Chen, Y.; Meng, Q.; Liu, Y.; Li, R.; He, Z.
Chem. Commun. 2015, 51, 14663. (e) Zhou, R.; Yang, C.; Liu, Y.; Li,
R.; He, Z. J. Org. Chem. 2014, 79, 10709.
(10) Liu, Y.; Li, H.; Zhou, X.; He, Z. J. Org. Chem. 2017, 82, 10997.
(11) (a) Eckert, K. E.; Lepore, A. J.; Ashfeld, B. L. Helv. Chim. Acta
2019, 102, No. e1900192. (b) Eckert, K. E.; Ashfeld, B. L. Org. Lett.
2018, 20, 2315. (c) Rodriguez, K. X.; Vail, J. D.; Ashfeld, B. L. Org.
Lett. 2016, 18, 4514. (d) Wilson, E. E.; Rodriguez, K. X.; Ashfeld, B.
L. Tetrahedron 2015, 71, 5765.
(12) (a) Jiang, J.; Liu, H.; Lu, C.-D.; Xu, Y.-J. J. Org. Chem. 2017, 82,
811. (b) Yin, D.; Liu, H.; Lu, C.-D.; Xu, Y.-J. J. Org. Chem. 2017, 82,
3252. (c) Zhang, L.; Lu, H.; Xu, G.-Q.; Wang, Z.-Y.; Xu, P.-F. J. Org.
Chem. 2017, 82, 5782.
(13) In the case of substrate 2j, the presence of DBU is essential for
the success of the (1 + 4) annulation reaction. Using P(NMe2)3 alone
led to the predominant formation of the reductive amination product
4b in 60% yield, and only trace amount of the annulation product 3r
was detected. For details, see the Supporting Information.
(14) The Ts group on the nitrogen atom of pyrrolidine could be
deprotected by employing a known procedure with PhOH/HBr,
although the corresponding deprotecting product 6a was isolated in
inferior yield. For details, see the Supporting Information.
(15) For basicity of three-coordinate phosphorus compounds, see:
̈
Bunten, K. A.; Moreno, C.; Poe, A. J. Dalton Trans. 2005, 1416.
(16) A phosphine-triggered general base catalysis and a sequential
nucleophilic addition-SN2 substitution for the cyclization of 4a are
also feasible in the case of P(NMe2)3. For phosphine-triggered general
base catalysis, see: Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am.
Chem. Soc. 2003, 125, 8696.
(17) As for the δ-tosylamino enone 2 without a phenyl group such as
entries 17−19 in Table 2, the steric hindrance and the possible
interaction of the phenyl group with the keto/ester-carbonyl group in
intermediate C are believed to govern the stereochemical results.
E
https://dx.doi.org/10.1021/acs.orglett.0c02453
Org. Lett. XXXX, XXX, XXX−XXX