One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from α,β-unsaturated diazoketones and amines. Application in the synthesis of barmumycin

Article abstract of DOI:10.1016/j.tet.2017.05.040

A simple and one-pot way to prepare substituted 2- and 3-pyrrolidinones is described. The method uses unsaturated diazoketones (obtained from aldeydes in a single step) and amines, and provide an easy access to these important classes of nitrogen heterocycles. Furthermore, application of this methodology to the synthesis of the natural product barmumycin is achieved in 3 steps from these diazoketones.

Full text of DOI:10.1016/j.tet.2017.05.040

Tetrahedron xxx (2017) 1e10
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One-step syntheses of substituted 2-pyrrolidinones and 3-
pyrrolidinones from a,b-unsaturated diazoketones and amines.
Application in the synthesis of barmumycin
Rafael M.P. Dias, Patrícia B. Momo, Antonio C.B. Burtoloso*
~
~
~
Instituto de Química de Sao Carlos, Universidade de Sao Paulo, CEP 13560-970, Sao Carlos, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and one-pot way to prepare substituted 2- and 3-pyrrolidinones is described. The method uses
unsaturated diazoketones (obtained from aldeydes in a single step) and amines, and provide an easy
access to these important classes of nitrogen heterocycles. Furthermore, application of this methodology
to the synthesis of the natural product barmumycin is achieved in 3 steps from these diazoketones.
© 2017 Elsevier Ltd. All rights reserved.
Received 1 February 2017
Received in revised form
3 May 2017
Accepted 10 May 2017
Available online xxx
Keywords:
Pyrrolidines
Wolff rearrangement
Diazo compounds
Michael addition
Barmumycin
1. Introduction
For many years, our research group has been involved with the
chemistry of a,b-unsaturated a’-diazoketones. This class of com-
Pyrrolidines are an important class of 5-membered nitrogen
heterocycles, being one of the most abundant in nature among
nitrogenated compounds.1 In addition, many molecules of this class
exhibit broad biological and pharmaceutical activity, putting them
in a special position when compared to the 3-, 4- and 6-membered
ring homologous.2 Fig. 1 gives some examples of natural products,
as well as popular pharmaceutical drugs, containing the pyrrolidine
ring (Fig. 1).
pounds can be prepared in just one step from aldehydes and have
Due to the vast importance of pyrrolidines, many different
synthetic strategies for its preparation appeared in the literature.3
The most described strategies are: 1) intramolecular cyclization
via nucleophilic substitution4; 2) olefin metathesis5; and 3)
reductive amination from 1,4-diketones or iminium ions.6 Despite
the existence of these three main synthetic strategies, as well as of
many other methods to synthesize pyrrolidines, only a few can lead
to a great structural variety of pyrrolidines starting from a single
common intermediate. This type of strategy, a divergent synthesis,
becomes very attractive in medicinal chemistry as a tool for
obtaining a large number of analogs from the same intermediate.
* Corresponding author.
Fig. 1. Example of natural products and important pharmaceutical molecules, con-
E-mail address: antonio@iqsc.usp.br (A.C.B. Burtoloso).
taining a pyrrolidine scaffold.
http://dx.doi.org/10.1016/j.tet.2017.05.040
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Dias RMP, et al., One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from
a,b-
unsaturated diazoketones and amines. Application in the synthesis of barmumycin, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.05.040

2
R.M.P. Dias et al. / Tetrahedron xxx (2017) 1e10
been employed as useful platforms in the divergent synthesis of
several compounds, including heterocycles.7 Herein, we would like
Table 1
Optimization study for the aza-Michael addition from
ketones.
a,b-unsaturated diazo-
to show how we could use
a,b-unsaturated a’-diazoketones to
construct several 2- and 3-pyrrolidinones in a one pot reaction.
Moreover, a three-step synthesis of the alkaloid barmumycin is
demonstrated from these intermediates. To accomplish that, we
employed these building blocks as aza-Michael acceptors in two
different ways: 1) in the presence of amines and light; 2) in the
presence of amines and rhodium or copper salts. We envisaged that
after the formation of the aza-Michael adduct, a Wolff rearrange-
ment would be prone to happen in the presence of light, leading
directly to 2-pyrrolidinones (case 1). In a similar way, an intra-
molecular NeH insertion reaction would led to 3-pyrrolidinones
(case 2) if these adducts were formed in the presence of rhodium
or copper catalysts (Scheme 1).
Entry
Amine (equiv.)
Solvent
Concentration
Yield %a
18
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4
3
3
3
3
3
3
3
2
1
2
3
3
3
10
10
Ethyl Ether
Ethyl Ether
DCM
Benzene
THF
MeCN
Ethanol
DMF
0,3 M
0,5 M
0,5 M
0,5 M
0,5 M
0,5 M
0,5 M
0,5 M
0,5 M
0,5 M
0,5 M
1 M
64b
89
88
80
90
56
73
75
71
32
53
88
93
90c
0
THF
THF
Ethyl Ether
THF
Ethyl Ether
Ethyl Ether
THF
1 M
1 M
0,1 M
0,1 M
THF
73d
a
Yields determined by NMR with 1,2,4,5-tetramethylbenzene as an internal
standard.
b
c
Scheme 1. One-pot synthesis of pyrrolidinones from unsaturated diazoketones and
total synthesis of barmumycin.
48 h.
Isolated yield by column chromatography.
30 mol% of DBU was used.
d
2. Results/discussion
of 10 equivalents of amine) unless DBU is added (entries 15e16).10
From all these optimization studies it is clear that at least 3
equivalents of amine and diazoketone concentration of 0.5e1.0 M
in DCM, THF or Et2O should be employed to guarantee the best
yields. Using the optimized conditions, described in entry 13
(Table 1), several Michael adducts could be prepared from struc-
turally different amines and unsaturated diazoketones in 71e94%
isolated yields (Fig. 2).
We started our work by first optimizing the reaction conditions
to perform the Michael reaction, before trying the one-pot trans-
formation (Table 1).
Although Michael reactions with amines are well-described for
many types of substrates, it is not in the case of a,b-unsaturated a’-
diazoketones. In fact, before our studies,7 only one single example
was described by Clark8 where the authors used a simple unsatu-
rated
amines. This indicates that the aza-Michael reaction from unsatu-
rated ’-diazoketones is still extremely limited with respect to
a’-diazoketone (1-diazopent-3-en-2-one) and two different
We next, started the evaluation of the one-pot formation of 3-
pyrrolidines directly from diazoketone 1 (Table 2).
a
Intramolecular NeH insertion reactions are well-known in the
literature11 and rhodium and copper salts are generally the cata-
lysts of choice, being Rh2(OAc)4 the most used. Considering that,
our first attempt consisted in employing conditions in entry 13,
Table 1, in the presence of Rh2(OAc)4. As shown in entry 1 (Table 2)
no reaction was observed, Michael adduct 2 being the only
observed product. Performing the reaction with pure isolated 2 also
didn't furnish any of 3-pyrrolidine 22. The same trend was
observed when copper(II) acetylacetonate Cu(acac)2 was employed
(entry 2). We next turned our attention to dichloromethane (DCM)
and benzene as solvents, since they also provided very good yields
in the Michael addition optimization studies. According to litera-
ture11 these solvents are also the most employed in insertion re-
actions. Reaction of Rh2(OAc)4 and Cu(acac)2 in DCM furnished 10%
and 0% of 3-pyrrolidinone 22, being practically all the aza-Michael
adduct 2 recovered (entries 3e4). On the other hand, employing the
more reactive copper (II) hexafluoroacetylacetonate Cu(hfacac)2, a
complex mixture of products was observed. Probably, formation of
the metal carbene from the diazo function was faster than the aza-
Michael addition, leading to other reactions (including intermo-
lecular NeH insertion from benzylamine). From this point, we
decided to add the catalyst in the flask only after all the diazoketone
substrates and deserves more attention.9 Beginning our studies, we
choose diazoketone 1 and benzylamine as the model substrates. As
a first attempt using Clark's conditions (4.0 equivalents of the
amine, 0.3 M in Et2O, 48 h) we could already obtain a 64% yield for
Michael adduct 2 (entry 1, Table 1). In view of the moderate yield
and long reaction period, we decided to optimize the yield of this
reaction by studying different reaction conditions. For that, other
parameters such as solvent, concentration and number of equiva-
lents for the amine were evaluated. Almost doubling the concen-
tration in Clark's condition to 0.5 M furnished 2 in 89% (entry 2,
Table 1), even in a lower period of time (24 h). Using this condition,
several solvents with different dielectric constant were evaluated
next (entries 3e8). In general, less polar solvents proved to be
better for the studied aza-Michael addition (THF, Et2O and DCM
being the best and giving basically the same yield). Reducing the
amount of amine to two and one equivalents (entries 9e11) drop-
ped the yield from 90% to 71% and 32%, respectively (THF) and from
89% to 53% (Et2O). Performing the reaction in a higher concentra-
tion (entries 12e14), maintaining the amount of amine, didn't
cause any substantial change in the yield. It is important to note
that very diluted solutions gives no product (even in the presence
Please cite this article in press as: Dias RMP, et al., One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from
a,b-
unsaturated diazoketones and amines. Application in the synthesis of barmumycin, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.05.040

R.M.P. Dias et al. / Tetrahedron xxx (2017) 1e10
3
Scheme 2. One-pot conversion of unsaturated diazoketones to 2-pyrrolidinones.
was converted to the Michael adduct 2. Although the formation of
3-pyrrolidinone 22 could be detected (entry 6), better yields (50%,
entry 7) were observed when the reaction was diluted in the same
solvent to 0.05 M prior to the addition of the catalyst. This modi-
fication did not work well for Rh2(OAc)4 and low yields of 22,
together with recovery of 2, were obtained. This scenario changed
drastically when the same reaction was performed in benzene
under reflux, furnishing 22 in 55% yield (entry 9). From Table 2,
conditions in entries 7 and 9 proved to be the best for the one pot
transformation. To carry out further studies we selected conditions
in entry 7 as the best, since it uses a non-expensive copper catalyst,
dichloromethane instead of benzene and the reaction can be per-
formed at room temperature. Attempts to carry out this best con-
dition in ether as solvent provided lower yields.
Fig. 2. Aza-Michael adducts prepared from unsaturated diazoketones after the opti-
mization studies.
With respect to the one pot reaction in the presence of light,
aiming the synthesis of 2-pyrrolidinones,12
a less extended
screening was necessary. As already observed in our research
group, the Wolff rearrangement from unsaturated diazoketones is
too fast and probably would occur before the aza-Michael addition
Table 2
Optimization studies for the one-pot conversion of unsaturated diazoketones to 3-
pyrrolidinones.
reaction, leading to b,g-unsaturated amides as the main product. In
view of that, the reaction was only irradiated with light after all
diazoketone 1 was converted to 2. Repeating condition in entry 13
(Table 1) and then exposing the reaction flask to a 300 W xenon
lamp (after dilution to 0.05 M with the same solvent), furnished 2-
pyrrolidinone 23 in 80% (Scheme 2) in the first attempt.
Secured with two new protocols for the direct transformation of
unsaturated diazoketones into 2- and 3- pyrrolidines, we then
extended it to the preparation of other pyrrolidines. Using condi-
tions described in Table 2 and Scheme 2, sixteen pyrrolidinones
were prepared in 42e81% isolated yield from five types of diazo-
ketones in the presence of different types of amine (Fig. 3). More-
over, to demonstrate the applicability of this protocol, the total
synthesis of the natural product barmumycin13 was accomplished
in 2 steps from pyrrolidinone 36 Scheme 3. Installation of the
exocyclic double bond was carried out using Julia-Kocienski olefi-
nation13a,14 to provide olefin 38 in 54% yield in a 3:1 diastereomeric
ratio in favor of the desired E isomer. Attempts to improve this ratio
were fruitless. Next, removal of both PMB and TBS protecting
groups was performed in the presence of 1-chloroethyl chlor-
oformate,15 furnishing the crude alcohol which was used directly in
the next step. Coupling the free amine with vanilic acid (or its
fenolic TBS ether) in the presence of PyBOP and DIPEA gave bar-
mumycin 39 in approximately 30% overall yield from 38 after three
transformations. All the data for 39 are in complete accordance
Entry
Catalyst (mol%)
Solvent
Temp.
Time
Yield %
1a
Rh2(OAc)4 (5)
Cu(acac)2 (10)
Rh2(OAc)4 (5)
Cu(acac)2 (10)
Cu(hfacac)2 (10)
Cu(hfacac)2 (10)
Cu(hfacac)2 (10)
Rh2(OAc)4 (5)
Rh2(OAc)4 (5)
Cu(acac)2 (10)
Et2O
Et2O
DCM
DCM
DCM
DCM
DCM
DCM
C6H6
C6H6
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
25 ꢀC
80 ꢀC
80 ꢀC
24 h
24 h
24 h
24 h
24 h
25 h
25 h
25 h
25 h
5 min
0
0
10
0
0
15
50
10
55
35
2a
3a
4a
5a
6b,c
7b,c,d
8b,c,d
9b,d,e
10b,d,f
a
1.0 M solution, 24 h, all reagents mixed together.
b
Addition of the catalyst only after complete formation of the Michael adduct 2
(24 h).
c
Stirred by 1 h after addition of the catalyst.
Diluted to 0.05 M with the same solvent before the addition of the catalyst.
Stirred by 30 min after addition of the catalyst.
d
e
f
Stirred by 5 min after addition of the catalyst.
Please cite this article in press as: Dias RMP, et al., One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from
a,b-
unsaturated diazoketones and amines. Application in the synthesis of barmumycin, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.05.040

4
R.M.P. Dias et al. / Tetrahedron xxx (2017) 1e10
with those reported in the literature.13
3. Conclusion
Pyrrolidines are well distributed in nature and are found in
many important pharmaceutical drugs. Herein, we described for
the first time the application of unsaturated diazoketones, as useful
building blocks to prepare 2- and 3-pyrrolidinones in a divergent
and one-pot fashion. The experimental setup is simple and the
method permits the synthesis of a library of pyrrolidinones in a
direct way and with very good yields. Additionally, we showed an
application of this methodology to the short synthesis of the
alkaloid barmumycin.
4. Experimental section
4.1. General information
All solvents were dried and distilled prior to use by standard
procedures. Reagents were purchased at the highest commercial
quality and used without further purification, unless otherwise
stated. Reactions were monitored by thin layer chromatography
(TLC), carried out on 0.25 mm silica gel plates using UV light as
visualizing agent and potassium permanganate in aqueous KOH for
staining. Column chromatography was performed using silica gel
60 (particle size 0.063e0.210 mm). Unless stated otherwise, all the
yields refer to isolated products after flash column chromatog-
raphy. The solvent mixtures employed in TLC analysis and in flash
column chromatography purifications are reported as volume by
volume and in percentages. Proton nuclear magnetic resonance (1H
NMR) spectra were recorded using 400 and 500 MHz equipment.
For 1H NMR spectra, chemical shifts (
d) are referenced from TMS
(0.00 ppm). Coupling constants (J) are reported in Hz. For multi-
plicities the following abbreviations were used: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet; bs;
broad singlet; dt, double triplet. Carbon nuclear magnetic reso-
nance (13C NMR) spectra were recorded using a NMR spectrometer
at 100 or 125 MHz. For 13C NMR spectra, chemical shifts (
d) are
given from CDCl3 (77.0 ppm) or (CD3)2SO (39.5 ppm). Photo-
chemical reactions were carried out using UV light generated by an
Osram 150 Xenon lamp accommodated in an Oriel Model 8500
Universal arc lamp source with focusing quartz lens, a water-filled
infrared filter, and a thermostated cell holder. Infrared spectra were
obtained using FT-IR at 4.0 cmꢁ1 resolution and are reported in
wavenumbers. Melting points were determined using a digital
melting point apparatus and were not corrected. High resolution
mass spectra (HRMS) were recorded using electron spray ionization
(ESI) (Hybrid linear ion trape orbitrap FT-MS and QqTOF/MS e
Microtof e QII models).
Fig. 3. One-pot synthesis of 2- and 3-pyrrolidinones from unsaturated diazoketones.
4.2. General procedure for the Horner-Wadsworth-Emmons
reactions
To
a solution of diethyl 3-diazo-2-oxopropylphosphonate
(400 mg, 1.81 mmol, 1 equiv.) in EtOH (5 mL) was added 185
mL
of benzaldehyde (1.81 mmol, 1 equiv.) at room temperature. Thus,
3.6 mL of 0.5 M NaOH solution (water:EtOH 1:1) was added during
a period of 1 h (using a syringe pump). After this time, the mixture
was stirred and maintained at this temperature for more 30 min.
The reaction was finished by the addition of saturated NaCl (20 mL),
extracted using CH2Cl2 (3 ꢂ 20 mL) and dried over MgSO4. Purifi-
cation by flash column chromatography (10% EtOAc/hexanes)
afforded unsaturated diazoketone 1 (233.7 mg,1.36 mmol, 75%) as a
yellow solid.
Scheme 3. Application in the Barmumycin synthesis.
Please cite this article in press as: Dias RMP, et al., One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from
a,b-
unsaturated diazoketones and amines. Application in the synthesis of barmumycin, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.05.040

R.M.P. Dias et al. / Tetrahedron xxx (2017) 1e10
5
4.3. (E)-1-Diazo-4-phenylbut-3-en-2-one (1)
EtOAc/hexanes). 1H NMR (200 MHz, CDCl3)
d
7.44 (d, J ¼ 15.9 Hz,
1H), 6.97 (td, J ¼ 2.2, 8.9 Hz, 2H), 6.80 (td, J ¼ 1.9, 8.6 Hz, 2H), 6.03
Yield: 75%. Yellow solid, m.p. ¼ 63e65 ꢀC. Rf ¼ 0.25 (20% EtOAc/
(d, J ¼ 15.6 Hz, 1H), 4.40 (s, 1H) ppm. 13C NMR (50 MHz, CDCl3)
hexanes). 1H NMR (500 MHz, CDCl3)
d
7.59 (d, J ¼ 15.8 Hz, 1H),
d 183.9,136.3,132.9,129.3 (2C),129.2 (2C),127.2, 123.9, 56.4 ppm. IR
7.55e7.51 (m, 2H), 7.39e7.37 (m, 3H), 6.60 (d, J ¼ 15.8 Hz, 1H), 5.45
nmax (cmꢁ1): 3068, 2100, 1637, 1577, 1490, 1373, 1089, 821.
(s, 1H) ppm. 13C NMR (126 MHz, CDCl3)
d 184.3, 140.7, 134.4, 130.3,
128.9, 128.2, 123.7, 56.2 ppm. IR nmax (cmꢁ1): 3072, 3026, 2098,
1637, 1585, 1495, 1448, 1371, 1202, 1149, 1117, 974, 851, 758, 679,
573, 507.
4.10. (E)-1-Diazo-4-(4-nitrophenyl)but-3-en-2-one (9)
Yield: 74%. Yellow solid, m.p. ¼ 135e137 ꢀC. Rf ¼ 0.13 (30%
EtOAc/hexanes). 1H NMR (400 MHz, CDCl3)
d
8.24 (d, J ¼ 8.9 Hz, 2H),
7.69e7.62 (m, 3H), 6.69 (d, J ¼ 15.8 Hz, 1H), 5.51 (s, 1H) ppm. 13
C
4.4. (E)-1-Diazohept-3-en-2-one (3)
NMR (126 MHz, CDCl3)
d 183.1, 148.4, 140.7, 137.7, 128.8 (2C), 127.4,
Yield: 54%. Yellow oil. Rf ¼ 0.20 (20% EtOAc/hexanes). 1H NMR
124.2 (2C), 57.2 ppm. IR nmax (cmꢁ1): 3105, 2924, 2853, 2102, 1645,
1603, 1589, 1514, 1416, 1364, 1342, 1151, 1111, 978, 843, 750, 669,
569.
(500 MHz, CDCl3)
d
6.81 (dt, J ¼ 15.3, 7.0 Hz,1H), 5.99 (d, J ¼ 15.3 Hz,
1H), 5.29 (s,1H), 2.18 (dq, J ¼ 7.3, 1.5 Hz, 2H),1.59e1.38 (m, 2H), 0.94
(t, J ¼ 7.3 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3)
d 184.8, 145.1,
127.3, 55.0, 34.3, 21.4, 13.7 ppm. IR nmax (cmꢁ1): 2959, 2930, 2872,
2102, 1653, 1597, 1464, 1367, 1308, 1202, 1153, 1099, 1032, 974, 876,
750, 608, 476.
4.11. General procedure for the aza Michael addition
To a 4 mL vial equipped with a magnetic stir-bar and contained
an ethereal solution of diazo ketone 1 (20.0 mg, 0.116 mmol,. 1.0
equiv with 0.116 mL of ethyl ether) was added 38 mL of benzylamine
4.5. (E)-5-((tert-butyldimethylsilyl)oxy)-1-diazopent-3-en-2-one
(4)
(37.3 mg, 0.348 mmol, 3.0 equiv.) at room temperature. The reac-
tion was stirred at room temperature for 24 h. The crude mixture
was purified by flash column chromatography [silica gel (230e400
mesh)] using hexanes:AcOEt:TEA (gradient elution 85:10: 5 to
55:40:5) as eluent system to afford the Michael adduct of 2 in 90%
yield (29.2 mg, 0.105 mmol) as an orange oil.
Yield: 74%. Yellow oil. Rf ¼ 0.28 (20% EtOAc/hexanes). 1H NMR
(500 MHz, CDCl3)
d
6.88 (d, J ¼ 15.0 Hz, 1H), 6.27 (d, J ¼ 14.9 Hz,1H),
5.33 (s, 1H), 4.36 (2d, J ¼ 3.5 Hz, 2H), 0.92 (s, 9H), 0.04 (s, 6H) ppm.
13C NMR (126 MHz, CDCl3)
d 184.5, 143.4, 125.2, 62.3, 55.6, 25.9
(3C), 18.4, ꢁ5.4 (2C) ppm. IR nmax (cmꢁ1): 2953, 2928, 2883, 2856,
2106, 1661, 1614, 1539, 1472, 1362, 1256, 1138, 1007, 939, 837, 608,
4.12. 4-(benzylamino)-1-diazo-4-phenylbutan-2-one (2)
501. HRMS (ESI-TOF) calculated for
241.13668, found 241.13622.
C
11H21N2O2Si [MþHþ]
Yield: 90%. Yellow oil. Rf ¼ 0.21 (30% EtOAc/hexanes). 1H NMR
(400 MHz, CDCl3)
d
7.36e7.22 (m, 10H), 5.13 (s, 1H), 4.14 (dd, J ¼ 8.0,
4.6. (E)-1-Diazo-4-(pyridin-3-yl)but-3-en-2-one (5)
4.8 Hz, 1H), 3.63 (d, J ¼ 13.4 Hz, 1H), 3.54 (d, J ¼ 13.4 Hz, 1H),
2.70e2.58 (m, 2H), 2.07 (s, 1H) ppm. 13C NMR (101 MHz, CDCl3)
Yield: 72%. Yellow solid, m.p. ¼ 188e190 ꢀC. Rf ¼ 0.25 (30%
d
193.2, 142.8, 140.3, 128.8 (2C), 128.5 (2C), 128.3 (2C), 127.6, 127.3
EtOAc/hexanes). 1H NMR (500 MHz, CDCl3)
d
8.77 (d, J ¼ 2.0 Hz,1H),
(2C), 127.0, 59.3, 55.4, 51.6, 49.3 ppm. IR nmax (cmꢁ1): 3325, 3084,
3063, 3026, 2953, 2928, 2856, 2102, 1641, 1495, 1470, 1360, 1256,
1099, 1028, 1006, 970, 937, 837, 779, 698, 613, 492.
8.60 (dd, J ¼ 4.8, 1.6 Hz, 1H), 7.84 (d, J ¼ 8.0 Hz, 1H), 7.59 (d,
J ¼ 15.8 Hz,1H), 7.33 (dd, J ¼ 7.9, 4.8 Hz,1H), 6.66 (d, J ¼ 15.8 Hz,1H),
5.50 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3)
d 183.5, 150.9, 149.8,
137.0, 134.5, 130.3, 128.9, 123.8, 56.7 ppm. IR nmax (cmꢁ1): 3094,
3063, 3021, 2104,1651,1595,1564,1477,1373,1314,1182,1124,1103,
1024, 980, 876, 768, 683, 582, 494. HRMS (ESI-TOF) calculated for
C9H8N3O [MþHþ] 174.06619, found 174.06580.
4.13. 4-(allylamino)-1-diazo-4-phenylbutan-2-one (10)
Yield: 90%. Yellow oil. Rf ¼ 0.22 (30% EtOAc/hexanes). 1H NMR
(500 MHz, CDCl3)
d 7.33e7.24 (m, 5H), 5.89e5.81 (m, 1H), 5.18 (s,
1H), 5.13e5.09 (m, 1H), 5.07e5.04 (m, 1H), 4.17e4.14 (m, 1H), 3.09
(ddt, J ¼ 14.1, 5.5, 1.5 Hz, 1H), 3.02 (ddt, J ¼ 14.1, 5.6, 1.5 Hz, 1H),
2.72e2.68 (m, 1H), 2.61e2.58 (m, 1H), 1.93 (s, 1H) ppm. 13C NMR
4.7. (E)-1-Diazo-4-(furan-2-yl)-but-3-en-2-one (6)
Yield: 60%. Yellow solid, m.p. ¼ 66e68 ꢀC. TLC: Rf ¼ 0.26 (30%
EtOAc/hexanes). 1H NMR (500 MHz, CDCl3)
d
7.47 (d, J ¼ 1.7 Hz, 1H),
(126 MHz, CDCl3)
d 193.1, 142.6, 136.6, 128.6 (2C), 127.5, 127.1 (2C),
116.0, 59.0, 55.3, 49.9, 49.1 ppm. IR nmax (cmꢁ1): 3325, 3084, 3028,
2976, 2924, 2849, 2104, 1637, 1493, 1454, 1371, 1144, 1117, 1074,
1028, 995, 922, 764, 702, 628, 603, 538. HRMS (ESI-TOF) calculated
for 230.12879 [MþHþ] 223,18049, found 230.12779.
7.39 (d, J ¼ 15.4 Hz, 1H), 6.64 (d, J ¼ 3.4 Hz, 1H), 6.56e6.42 (m, 2H),
5.38 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3)
d 183.8, 151.1, 144.6,
127.1,121.0,115.6,112.5, 56.5 ppm. IR vmax (cmꢁ1): 3099, 2106,1645,
1583, 1552, 1477, 1371,1261, 1151, 1099, 1000, 825.
4.8. (E)-1-Diazo-4-(4-methoxyphenyl)but-3-en-2-one (7)
4.14. 4-(butylamino)-1-diazo-4-phenylbutan-2-one (11)
Yield: 50%. Yellow solid, m.p. ¼ 128e129 ꢀC. Rf ¼ 0.20 (30%
Yield: 71%. Yellow oil. Rf ¼ 0.27 (30% EtOAc/hexanes). 1H NMR
EtOAc/hexanes). 1H NMR (200 MHz, CDCl3)
d
7.70 (d, J ¼ 15.9, 1H),
(500 MHz, CDCl3)
d
7.33e7.25 (m, 5H), 5.17 (s, 1H), 4.10 (dd, J ¼ 8.1,
7.10 (d, J ¼ 8.9, 2H), 6.6 (d, J ¼ 8.9, 2H), 6.2 (d, J ¼ 15.9, 1H), 4.4 (s,
5.0 Hz, 1H), 2.67e2.69 (m, 1H), 2.59e2.57 (m, 1H), 2.46e2.38 (m,
2H), 1.42 (q, J ¼ 7.3 Hz, 2H), 1.30e1.26 (m, 2H), 0.86 (t, J ¼ 7.3 Hz,
1H), 3.2 (s, 3H) ppm. 13C NMR (50 MHz, CDCl3)
d 183.1, 161.7, 140.1,
130.1 (2C), 127.7, 122.1, 114.5 (2C), 58.8, 54.5 ppm. IR nmax (cmꢁ1):
3H). 13C NMR (126 MHz, CDCl3)
d 193.2, 143.1, 128.6 (2C), 127.4,
3062, 2090, 1643, 1587, 1512, 1421, 1367, 1551, 1172, 1093, 977, 827.
127.0 (2C), 59.9, 55.3, 49.2, 47.4, 32.3, 20.4, 14.0 ppm. IR nmax
(cmꢁ1): 3327, 3084, 3063, 3028, 2957, 2928, 2872, 2858, 2104,1639,
1493, 1454, 1367, 1144, 1074, 1028, 980, 945, 914, 762, 702, 631, 592.
HRMS (ESI-TOF) calculated for C14H20N3O [MþHþ] 246.1606, found
246.1589.
4.9. (E)-4-(4-chlorophenyl)-1-diazobut-3-en-2-one (8)
Yield: 83%. Yellow solid, m.p. ¼ 110e112 ꢀC. Rf ¼ 0.25 (30%
Please cite this article in press as: Dias RMP, et al., One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from
a,b-
unsaturated diazoketones and amines. Application in the synthesis of barmumycin, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.05.040

6
R.M.P. Dias et al. / Tetrahedron xxx (2017) 1e10
4.15. 4-(benzylamino)-1-diazoheptan-2-one (12)
4.20. 4-(benzylamino)-4-(4-chlorophenyl)-1-diazobutan-2-one
(17)
Yield: 94%. Yellow oil. Rf ¼ 0.28 (30% EtOAc/hexanes). 1H NMR
(500 MHz, CDCl3)
d
7.36e7.23 (m, 5H), 5.30 (s, 1H), 3.78 (s, 2H), 3.05
Yield: 85%. Yellow oil. Rf ¼ 0.20 (30% EtOAc/hexanes). 1H NMR
(q, J ¼ 6.0 Hz, 1H), 2.44 (s, 2H), 1.48e1.33 (m, 4H), 0.91 (t, J ¼ 7.2 Hz,
(400 MHz, CDCl3) d 7.36e7.23 (m, 9H), 5.14 (s, 1H), 4.15e4.12 (m,
3H) ppm. 13C NMR (126 MHz, CDCl3)
d
194.2,140.6, 128.4 (2C),128.2
1H), 3.61 (d, J ¼ 13.2 Hz, 1H), 3.52 (d, J ¼ 13.2 Hz, 1H), 2.66e2.65 (m,
(2C), 126.9, 55.1, 54.5, 51.2, 45.7, 36.7, 19.0, 14.2 ppm. IR nmax (cmꢁ1):
3325, 3086, 3073, 3028, 2959, 2930, 2872, 2102, 1636, 1495, 1454,
1362, 1202, 1149, 1072, 1038, 980, 910, 737, 700, 584, 495. HRMS
1H), 2.56e2.54 (m,1H), 2.00 (s,1H) ppm. 13C NMR (126 MHz, CDCl3)
d
192.6, 141.2, 140.0, 133.1, 128.8 (2C), 128.6 (2C), 128.4 (2C), 128.1
(2C),127.0, 58.4, 55.4, 51.4, 49.0 ppm. HRMS (ESI-TOF) calculated for
(ESI-TOF) calculated for
246.1602.
C
14H20N3O [MþHþ] 246.1606, found
C
17H17ClN3O [MþHþ] 314.1060, found 314.1053.
4.21. 4-(benzylamino)-1-diazo-4-(4-methoxyphenyl)butan-2-one
(18)
4.16. 4-(allylamino)-1-diazoheptan-2-one (13)
Yield: 82%. Yellow oil. Rf ¼ 0.22 (30% EtOAc/hexanes). 1H NMR
Yield: 91%. Yellow oil. Rf ¼ 0.29 (30% EtOAc/hexanes). 1H NMR
(500 MHz, CDCl3)
d 7.30e7.26 (m, 5H), 7.26e7.24 (m, 2H), 6.89 (d,
(400 MHz, CDCl3)
d 5.93e5.83 (m, 1H), 5.35 (s, 1H), 5.20e5.15 (m,
J ¼ 8.7 Hz, 2H), 5.13 (s, 1H), 4.09 (dd, J ¼ 8.2, 5.1 Hz, 1H), 3.81 (s, 3H),
1H), 5.10e5.06 (m, 1H), 3.24 (dt, J ¼ 6.0, 1.3 Hz, 2H), 3.12e2.97 (m,
3.62 (d, J ¼ 13.2 Hz, 1H), 3.53 (d, J ¼ 13.2 Hz, 1H), 2.72e2.67 (m, 1H),
1H), 2.41 (s, 2H), 1.46e1.32 (m, 4H), 0.92 (t, J ¼ 7.1 Hz, 3H) ppm. 13
C
2.59e2.56 (m, 1H) ppm. 13C NMR (126 MHz, CDCl3)
d 193.2, 159.0,
NMR (101 MHz, CDCl3)
d 194.2, 137.0, 115.9, 55.2, 54.3, 49.7, 45.6,
140.3,134.6,128.3 (2C),128.2 (2C),128.2 (2C),126.9,114.0 (2C), 58.5,
55.3, 51.4, 49.4 ppm. HRMS (ESI-TOF) calculated for C18H20N3O2
[MþHþ] 310.1556, found 310.1556.
36.6, 19.0, 14.2 ppm. IR nmax (cmꢁ1): 3325, 3080, 2959, 2930, 2872,
2104, 1636, 1466, 1367, 1148, 995, 920, 748, 702, 635, 576. HRMS
(ESI-TOF) calculated for
196.1445.
C
10H18N3O [MþHþ] 196.1450, found
4.22. 4-(benzylamino)-1-diazo-4-(4-nitrophenyl)butan-2-one (19)
Yield: 90%. Yellow oil. Rf ¼ 0.17 (30% EtOAc/hexanes). 1H NMR
4.17. 4-(butylamino)-1-diazoheptan-2-one (14)
(500 MHz, CDCl3)
d
8.21 (d, J ¼ 8.7 Hz, 2H), 7.57 (d, J ¼ 8.7 Hz, 2H),
Yield: 71%. Yellow oil. TLC: Rf ¼ 0.10 (60% EtOAc/hexanes). 1H
7.32e7.29 (m, 2H), 7.26e7.23 (m, 3H), 5.18 (s, 1H), 4.29 (dd, J ¼ 8.5,
4.8 Hz, 1H), 3.61 (d, J ¼ 13.2 Hz, 1H), 3.54 (d, J ¼ 13.2 Hz, 1H),
2.72e2.67 (m, 1H), 2.59e2.56 (m, 1H), 2.07 (s, 1H) ppm. 13C NMR
NMR (500 MHz, CDCl3)
d 5.38 (s, 1H), 3.01e2.96 (m, 1H), 2.57 (td,
J ¼ 7.0, 2.9 Hz, 2H), 2.40 (s, 2H), 1.47e1.41 (m, 4H), 1.36e1.32 (m,
4H), 0.93e0.90 (m, 6H) ppm. 13C NMR (126 MHz, CDCl3)
d
194.4,
(126 MHz, CDCl3) d 191.9, 150.6, 147.4, 139.6, 128.5 (2C), 128.2 (2C),
55.0, 46.8, 36.8 (2C), 32.6 (2C), 20.6, 19.1, 14.2, 14.0 ppm. IR vmax
128.1 (2C), 127.2, 124.0 (2C), 58.5, 55.6, 51.6, 48.4 ppm. IR nmax
(cmꢁ1): 3327, 3105, 3065, 3028, 2924, 2851, 2104, 1636, 1605, 1520,
1495, 1454, 1371, 1346, 1200, 1178, 1143, 1109, 1028, 1014, 982, 945,
856, 752, 737, 700, 644, 584, 496. HRMS (ESI-TOF) calculated for
(cmꢁ1): 3318, 3081, 2957, 2928, 2873, 2098, 1632, 1465, 1360, 1144,
977, 746. HRMS (ESI-TOF) calculated for
212.1763, found 212.1762.
C
11H22N3O [MþHþ]
C
17H17N4O3 [MþHþ] 325.1301, found 325.1291.
4.18. 5-((tert-butyldimethylsilyl)oxy)-4-((4-methoxybenzyl)amino)
-1-diazopentan-2-one (15)
4.23. 4-(allylamino)-1-diazo-4-(pyridin-3-yl)butan-2-one (20)
Yield 84%. Yellow oil. Rf ¼ 0.15 (50% EtOAc/hexanes). 1H NMR
Yield: 79%. Yellow oil. TLC: Rf ¼ 0.20 (30% EtOAc/hexanes). 1H
(500 MHz, CDCl3)
d
8.57 (d, J ¼ 2.0 Hz, 1H), 8.52 (dd, J ¼ 4.8, 1.6 Hz,
NMR (400 MHz, CDCl3)
d
7.23 (d, J ¼ 8.8 Hz, 2H), 6.85 (d, J ¼ 8.7 Hz,
1H), 7.71 (dt, J ¼ 7.8, 1.9 Hz, 1H), 7.29e7.26 (m, 1H), 5.87e5.79 (m,
1H), 5.23 (s, 1H), 5.14e5.07 (m, 2H), 4.23 (dd, J ¼ 8.5, 4.9 Hz, 1H),
3.11e3.00 (m, 2H), 2.76e2.71 (m, 1H), 2.62e2.59 (m, 1H), 2.19 (s,
2H), 5.31 (s, 1H), 3.79 (s, 3H), 3.73 (s, 2H), 3.64 (dd, J ¼ 10.0, 5.2 Hz,
1H), 3.57 (dd, J ¼ 10.0, 5.1 Hz, 1H), 3.18e3.06 (m, 1H), 2.46 (s, 2H),
1.80 (s, 1H), 0.89 (s, 9H), 0.05 (d, J ¼ 1.7 Hz, 6H) ppm. 13C NMR
1H) ppm. 13C NMR (101 MHz, CDCl3)
d 192.3, 149.3, 149.1, 138.1,
(126 MHz, CDCl3)
d 194.1, 158.8, 132.7, 129.4 (2C), 113.9 (2C), 64.3,
136.2, 135.0, 123.7, 116.5, 56.6, 55.7, 50.0, 48.5 ppm. IR nmax (cmꢁ1):
3317, 3078, 3036, 2976, 2922, 2818, 2104, 1634, 1477, 1425, 1373,
1144, 1026, 995, 924, 808, 715, 633, 613, 553, 504, 490. HRMS (ESI-
TOF) calculated for C12H15N4O [MþHþ] 231.12404, found 231.12311.
56.2, 55.4, 51.0, 26.0 (3C), 18.4, ꢁ5.3 (2C) ppm. IR vmax (cmꢁ1): 3325,
3093, 2951, 2928, 2899, 2854, 2102, 1637, 1612, 1585, 1512, 1466,
1360, 1300, 1248, 1176, 1105, 1038, 1007, 837, 779. HRMS (ESI-TOF)
calculated for C19H31N3O3Si [MþHþ] 378.2213, found 378.2206.
4.24. 4-(Furan-2-yl)-4-((4-methoxybenzyl)amino)-1-diazobutan-
4.19. 4-(benzylamino)-5-((tert-butyldimethylsilyl)oxy)-1-
2-one (21)
diazopentan-2-one (16)
Yield: 74%. Yellow oil. TLC: Rf ¼ ¼ 0.10 (35% EtOAc/hexanes). 1H
Yield: 79%. Yellow oil. Rf ¼ 0.25 (20% EtOAc/hexanes). 1H NMR
NMR (500 MHz, CDCl3)
d
7.38 (dd, J ¼ 1.8, 0.8 Hz, 1H), 7.22e7.15 (m,
(500 MHz, CDCl3)
d
7.33e7.31 (m, 4H), 7.25e7.23 (m, 1H), 5.29 (s,
2H), 6.89e6.80 (m, 2H), 6.33 (dd, J ¼ 3.2, 1.8 Hz, 1H), 6.20 (d,
J ¼ 3.2 Hz, 1H), 5.21 (s, 1H), 4.20 (dd, J ¼ 7.3, 6.3 Hz, 1H), 3.79 (s, 3H),
3.67 (d, J ¼ 12.9 Hz, 1H), 3.54 (d, J ¼ 12.9 Hz, 1H), 2.85e2.64 (m, 2H),
1H), 3.80 (s, 2H), 3.65 (dd, J ¼ 10.0, 5.2 Hz, 1H), 3.58 (dd, J ¼ 10.0,
5.2 Hz, 1H), 3.12 (q, J ¼ 6.0 Hz, 1H), 2.47 (s, 2H), 1.86 (s, 1H), 0.89 (s,
9H), 0.05 (s, 6H) ppm. 13C NMR (126 MHz, CDCl3)
d
193.9, 140.4,
1.89 (s, 1H) ppm. 13C NMR (126 MHz, CDCl3)
d 192.5, 158.7, 154.9,
128.4 (2C), 128.1 (2C), 126.9, 64.2, 56.1, 55.0, 51.5, 43.1, 25.9 (3C),
18.2, ꢁ5.4 (2C) ppm. IR nmax (cmꢁ1): 3327, 3084, 3063, 3026, 2953,
2928, 2895, 2856, 2103, 1641, 1495, 1470, 1360, 1256, 1099, 1028,
1007, 937, 837, 814, 779, 735, 698, 611, 490. HRMS (ESI-TOF)
calculated for C18H30N3O2Si [MþHþ] 348.2107, found 348.2096.
141.8, 132.0 (2C), 129.4, 113.8 (2C), 110.1, 107.1, 55.3 (2C), 52.2, 50.6,
46.5 ppm. IR vmax (cmꢁ1): 3314, 3099, 2955, 2928, 2836, 2098,1642,
1612, 1593, 1511, 1463, 1360, 1300, 1245, 1177, 1148, 1032, 1016, 814,
742. HRMS (ESI-TOF) calculated for C16H18N3O3 [MþHþ] 300.1348,
found 300.1343.
Please cite this article in press as: Dias RMP, et al., One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from
a,b-
unsaturated diazoketones and amines. Application in the synthesis of barmumycin, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.05.040

R.M.P. Dias et al. / Tetrahedron xxx (2017) 1e10
7
4.25. General procedure for one-pot NeH insertion
4.9 Hz, 1H), 2.77 (d, J ¼ 17.5 Hz, 1H), 2.73e2.68 (m, 2H), 2.41 (dd,
J ¼ 18.2, 10.6 Hz, 1H) ppm. 13C NMR (126 MHz, CDCl3)
d 212.5, 140.6,
To a 10 mL round-bottom flask equipped with a magnetic stir-
bar and contained the diazoketone 1 (20.0 mg, 0.116 mmol,. 1.0
134.4, 128.8 (2C), 128.0, 127.4 (2C), 117.6, 66.6, 61.6, 56.1, 48.0 ppm.
IR nmax (cmꢁ1): 3065, 3030, 2978, 2922, 2799, 2766, 1761, 17151
1697, 1690, 1607, 1495, 1456, 1420, 1369, 1287, 1200, 1179, 1134,
1074, 995, 758, 702, 581. HRMS (ESI-TOF) calculated for C13H16NO
[MþHþ] 202.12264, found 202.12192.
equiv) and 232 mL of DCM, was added 38
mL of benzylamine
(37.3 mg, 0.348 mmol, 3.0 equiv) at room temperature. The reaction
was stirred at room temperature for 24 h. After this time, 2.0 mL of
DCM and 5.5 mg Cu(hfacac)2 (0.0116 mmol,. 0.1 equiv) were added
to this solution at room temperature. The reaction mixture was
stirred at this temperature for 30 min (the reaction proceeded with
N2 release). After the reaction time, the solvent was partially
removed under reduced pressure in a rotary evaporator and the
crude material was purified by flash chromatography employing an
eluent system 9:1 hexanes:EtOAc and the 3-pyrrolidinone 22 was
obtained in 50% yield (14.6 mg, 0.058 mmol) as an orange oil.
4.30. 5-(Furan-2-yl)-1-(4-methoxybenzyl)pyrrolidin-3-one (30)
Yield: 44%. Yellow oil. TLC: Rf ¼ 0.45 (30% EtOAc/hexanes). 1H
NMR (500 MHz, CDCl3)
d
7.44 (dd, J ¼ 1.8, 0.8 Hz, 1H), 7.20e7.13 (m,
2H), 6.90e6.76 (m, 2H), 6.38 (dd, J ¼ 3.2, 1.8 Hz, 1H), 6.33 (dd,
J ¼ 3.2, 0.8 Hz, 1H), 4.10 (t, J ¼ 7.5 Hz, 1H), 3.82 (d, J ¼ 13.1 Hz, 1H),
3.79 (s, 3H), 3.35 (d, J ¼ 13.1 Hz,1H), 3.31 (d, J ¼ 17.3 Hz,1H), 2.86 (d,
J ¼ 17.3 Hz, 1H), 2.70 (d, J ¼ 7.5 Hz, 2H). 13C NMR (126 MHz, CDCl3)
4.26. 1-Benzyl-5-phenylpyrrolidin-3-one (22)
d
212.2, 158.9, 153.0, 142.5, 130.0, 129.5, 129.3, 114.4, 113.8, 110.2,
Yield: 50%. Yellow oil. Rf ¼ 0.27 (10% EtOAc/hexanes). 1H NMR
108.4, 60.2, 58.3, 56.4, 55.3, 43.8 ppm. IR vmax (cmꢁ1): 3137, 2998,
2953, 2932, 2836, 1758, 1612, 1593, 1513, 1463, 1346, 1300, 1249,
1177,1150,1034, 820, 744. HRMS (ESI-TOF) calculated for C16H18N3O
[MþHþ] 272.1287, found 272.1283.
(500 MHz, CDCl3) d 7.54e7.52 (m, 2H), 7.41e7.38 (m, 2H), 7.33e7.23
(m, 6H), 3.96 (d, J ¼ 13.2 Hz, 1H), 3.86 (dd, J ¼ 10.6, 6.3 Hz, 1H), 3.45
(d, J ¼ 17.5 Hz, 1H), 3.16 (d, J ¼ 13.2 Hz, 1H), 2.75e2.70 (m, 2H), 2.44
(dd, J ¼ 17.5, 10.6 Hz, 1H) ppm. 13C NMR (126 MHz, CDCl3)
d 212.4,
140.9, 137.9, 129.0 (2C), 128.6 (2C), 128.5 (2C), 128.1, 127.6 (2C),
127.4, 66.9, 61.6, 57.7, 48.2 ppm. IR nmax (cmꢁ1): 3086, 3063, 3030,
2918, 2833, 2795, 1757, 1672, 1603, 1495, 1454, 1429, 1400, 1364,
1310, 1234, 1198, 1178, 1136, 1074, 1028, 970, 893, 860, 758, 700,
636, 582, 484, 459.
4.31. 1-Butyl-5-propylpyrrolidin-3-one (32)
Yield: 49%. Yellow oil. TLC: Rf ¼ 0.40 (20% EtOAc/hexanes). 1H
NMR (500 MHz, CDCl3)
d
3.49 (d, J ¼ 17.4 Hz, 1H), 3.00e2.94 (m,
1H), 2.71e2.67 (m, 1H), 2.61 (d, J ¼ 17.4 Hz, 1H), 2.46 (dd, J ¼ 18.0,
4.27. 1-Benzyl-5-(((tert-butyldimethylsilyl)oxy)methyl) pyrrolidin-
3-one (24)
6.2 Hz,1H), 2.14e2.07 (m, 2H),1.83e1.80 (m,1H),1.49e1.34 (m, 7H),
0.97e0.92 (m, 6H) ppm. 13C NMR (126 MHz, CDCl3)
d 214.1, 62.6,
62.3, 53.5, 43.8, 35.1, 30.3, 20.6, 19.3, 14.3, 13.9 ppm. IR vmax (cmꢁ1):
2959, 2930, 2873, 1760, 1667, 1459, 1379, 1253, 1187, 1144, 746.
HRMS (ESI-TOF) calculated for C11H22NO [MþHþ] 184.1701, found
184.1699.
Yield: 51%. Yellow oil. Rf ¼ 0.26 (10% EtOAc/hexanes). 1H NMR
(500 MHz, CDCl3)
d
7.33e7. 25 (m, 5H), 4.19 (d, J ¼ 13.2 Hz, 1H), 3.84
(dd, J ¼ 10.5, 4.5 Hz, 1H), 3.78 (dd, J ¼ 10.4, 4.2 Hz, 1H), 3.57 (d,
J ¼ 13.2 Hz, 1H), 3.28 (d, J ¼ 17.4 Hz, 1H), 3.24e3.20 (m, 1H), 2.84 (d,
J ¼ 17.4 Hz, 1H), 2.55 (dd, J ¼ 18.2, 7.2 Hz, 1H), 2.29 (dd, J ¼ 18.2,
7.3 Hz,1H), 0.90 (s, 9H), 0.07 (s, 6H) ppm. 13C NMR (126 MHz, CDCl3)
4.32. 1-Benzyl-5-(4-chlorophenyl)pyrrolidin-3-one (34)
d
213.6, 138.3, 128.5 (2C), 128.4 (2C), 127.2, 65.1, 62.0, 61.8, 58.1, 41.7,
25.8 (3C), 18.2, ꢁ5.4, ꢁ5.5 ppm. IR nmax (cmꢁ1): 3063, 3030, 2955,
2930, 2897, 2857, 1759, 1716, 1682, 1495, 1472, 1458, 1443, 1362,
1256,1186,1096,1009, 839, 779, 742, 700, 669, 636, 517. HRMS (ESI-
Yield: 47%. Yellow oil. TLC: Rf ¼ 0.27 (20% EtOAc/hexanes). 1H
NMR (500 MHz, CDCl3)
d
7.48 (d, J ¼ 8.5 Hz, 2H), 7.38 (d, J ¼ 8.5 Hz,
2H), 7.32e7.29 (m, 2H), 7.26e7.22 (m, 3H), 3.92 (d, J ¼ 13.2 Hz, 1H),
3.85 (dd, J ¼ 10.5, 6.4 Hz, 1H), 3.45 (d, J ¼ 17.5 Hz, 1H), 3.17 (d,
J ¼ 13.2 Hz, 1H), 2.76e2.69 (m, 2H), 2.38 (dd, J ¼ 17.5, 10.5 Hz, 1H)
TOF) calculated for
320.2043.
C
18H30NO2Si [MþHþ] 320.2046, found
ppm. 13C NMR (126 MHz, CDCl3)
d 211.7, 139.5, 137.5, 133.7, 129.1
4.28. 1-Benzyl-5-propylpyrrolidin-3-one (26)
(2C), 128.8 (2C), 128.5 (2C), 128.4 (2C), 127.4, 66.0, 61.4, 57.5,
47.9 ppm. IR vmax (cmꢁ1): 2978, 2953, 2852, 1758, 1671, 1462, 1231,
1198, 1022, 891, 701. HRMS (ESI-TOF) calculated for C17H17NOCl
[MþHþ] 286.0999, found 286.0999.
Yield: 51%. Yellow oil. Rf ¼ 0.25 (10% EtOAc/hexanes). 1H NMR
(500 MHz, CDCl3)
d
7.32e7.24 (m, 5H) 4.22 (d, J ¼ 13.1 Hz, 1H),
3.26e3.23 (m, 2H), 2.90e2.86 (m, 1H), 2.62 (d, J ¼ 17.5, 1H), 2.48
(dd, J ¼ 17.5, 6.3 Hz, 1H), 2.16 (dd, J ¼ 18.0, 10.1 Hz, 1H), 1.98e1.90
(m, 1H), 1.51e1.32 (m, 3H), 0.98 (t, J ¼ 7.3 Hz, 3H) ppm. 13C NMR
4.33. 5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-
methoxybenzyl)pyrrolidin-3-one (36)
(126 MHz, CDCl3)
d
213.7, 138.2, 128.8 (2C), 128.6 (2C), 127.4, 62.2,
62.0, 57.7, 43.8, 35.1, 19.2, 14.5 ppm. IR nmax (cmꢁ1): 3086, 3063,
3030, 2959, 2932, 2872, 2797, 1757, 1495, 1454, 1402, 1371, 1337,
1296, 1252, 1186, 1148, 1070, 1028, 953, 741, 700, 638, 521. HRMS
Yield: 50%. Yellow oil. TCC: Rf ¼ 0.20 (15% EtOAc/hexanes). 1H
NMR (500 MHz, CDCl3)
d
7.23 (d, J ¼ 8.7 Hz, 2H), 6.86 (d, J ¼ 8.7 Hz,
(ESI-TOF) calculated for
218.15306.
C
14H20NO [MþHþ] 218.15394, found
2H), 4.12 (d, J ¼ 13.1 Hz, 1H), 3.84e3.77 (m, 5H), 3.52 (d, J ¼ 13.1 Hz,
1H), 3.26 (d, J ¼ 17.4 Hz, 1H), 3.28e3.18 (m, 1H), 2.82 (d, J ¼ 17.4 Hz,
1H), 2.54 (dd, J ¼ 18.2, 7.2 Hz,1H), 2.28 (dd, J ¼ 18.2, 7.3 Hz,1H), 0.90
(s, 9H), 0.07 (d, J ¼ 7.5 Hz, 6H) ppm. 13C NMR (126 MHz, CDCl3)
4.29. 1-Allyl-5-phenylpyrrolidin-3-one (28)
d
213.6, 158.8, 130.2, 129.7 (2C), 113.8 (2C), 65.1, 61.9, 61.7, 57.4, 55.3,
Yield: 47%. Yellow oil. Rf ¼ 0.24 (10% EtOAc/hexanes). 1H NMR
41.7, 25.8 (3C), 18.2, ꢁ5.4 (2C) ppm. IR vmax (cmꢁ1): 2955, 2930,
2899, 2857, 1759, 1612, 1514, 1472, 1464, 1362, 1302, 1252, 1180,
1105, 1038, 1010, 939, 839, 779, 702, 636, 584. HRMS (ESI-TOF)
calculated for C19H32NO3Si [MþHþ] 350.2151, found 350.2144.
(500 MHz, CDCl3)
d 7.44e7.42 (m, 2H), 7.38e7.29 (m, 3H),
5.84e5.76 (m, 1H), 5.19e5.15 (m, 1H), 5.13e5.10 (m, 1H), 3.77 (dd,
J ¼ 10.6, 6.3 Hz, 1H), 3.64 (d, J ¼ 17.4 Hz, 1H), 3.37 (dd, J ¼ 13.7,
Please cite this article in press as: Dias RMP, et al., One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from
a,b-
unsaturated diazoketones and amines. Application in the synthesis of barmumycin, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.05.040

8
R.M.P. Dias et al. / Tetrahedron xxx (2017) 1e10
4.34. General procedure for the one-pot photochemical Wolff
rearrangement
0.89 (t, J ¼ 7.3 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3)
d 175.2,
136.8, 128.6 (2C), 128.0 (2C), 127.4, 56.8, 44.1, 35.0, 30.3, 24.0, 17.7,
14.1 ppm. IR nmax (cmꢁ1): 3063, 3030, 2961, 2932, 2872, 1688, 1495,
1454, 1420, 1371, 1313, 1254, 1204, 1177, 1084, 1030, 920, 704, 633,
606, 511.
To a vial of 4 mL contained an ethereal solution of diazoketone 1
(15.0 mg, 0.087 mmol, 1.0 equiv. in 87
mL of anhydrous ethyl ether)
was added 29 L of benzylamine (28.5 mg, 0.261 mmol, 3.0 equiv)
m
at room temperature. The reaction was stirred at this temperature
for 24 h. Then, 3.2 mL of anhydrous ethyl ether was added and the
solution was transferred to a quartz cuvette of 1 cm light path. The
reaction mixture was irradiated with an Osram 150 Xenon arc lamp
for five hours under magnetic stirring at room temperature (gas
evolution was observed during the first four hours). Then, the
solvent was removed under reduced pressure in a rotary evaporator
and the crude material was purified by flash chromatography
employing as eluent system a mixture of hexanes:EtOAc (gradient
elution - 8:2 to 6:4). The pyrrolidinone 19 was obtained in 80%
(17.5 mg, 0.069 mmol) yield as a yellow oil. Osram 150 Xenon arc
lamp can also be replaced by an 18 W white LED lamp. In this case,
irradiation for 3 days is necessary.
4.39. 5-(((tert-butyldimethylsilyl)oxy)methyl)-1-(4-
methoxybenzyl)pyrrolidin-2-one (31)
Yield: 48%. Yellow oil. TCC: Rf ¼ 0.25 (30% EtOAc/hexanes). 1
H
NMR (400 MHz, CDCl3)
d
7.18 (d, J ¼ 8.6 Hz, 2H), 6.84 (d, J ¼ 8.6 Hz,
2H), 4.94 (d, J ¼ 14.8 Hz, 1H), 3.97 (d, J ¼ 14.8 Hz, 1H), 3.79 (s, 3H),
3.67 (dd, J ¼ 10.4, 3.7 Hz,1H), 3.55e3.48 (m, 2H), 2.57e2.48 (m, 1H),
2.38e2.30 (m, 1H), 2.04e1.98 (m, 1H), 1.91e1.86 (m, 1H), 0.88 (s,
9H), 0.03 (s, 6H) ppm. 13C NMR (101 MHz, CDCl3)
d 175.7, 159.1,
129.5 (2C), 129.2, 114.1 (2C), 63.6, 58.3, 55.4, 44.1, 30.6, 26.0 (3C),
21.6, 18.3, ꢁ5.4 (2C). ppm. IR vmax (cmꢁ1): 2953, 2930, 2856, 1682,
1612, 1513, 1461, 1418, 1247, 1177, 1113, 1032, 837, 777. HRMS (ESI-
TOF) calculated for C19H32NO3Si [MþHþ] 350.2151, found 350.2144.
4.35. 1-Benzyl-5-phenylpyrrolidin-2-one (23)
4.40. 1-Benzyl-5-(4-chlorophenyl)pyrrolidin-2-one (33)
Yield: 80% (68% using the LED lamp). Yellow oil. Rf ¼ 0.30 (30%
Yield: 42%. Yellow oil. TLC: Rf ¼ 0.30 (40% EtOAc/hexanes). 1H
EtOAc/hexanes). 1H NMR (500 MHz, CDCl3)
d
7.38e7.26 (m, 6H),
NMR (400 MHz, CDCl3)
d
7.35 (d, J ¼ 8.5 Hz, 2H), 7.28e7.26 (m, 3H),
7.15e7.13 (m, 2H), 7.13e7.07 (m, 2H), 5.12 (d, J ¼ 14.6 Hz, 1H), 4.41
7.08e7.04 (m, 4H), 5.10 (d, J ¼ 14.6 Hz, 1H), 4.37 (dd, J ¼ 8.0, 5.7 Hz,
(dd, J ¼ 8.1, 5.5 Hz, 1H), 3.48 (d, J ¼ 14.6, 1H), 2.68e2.61 (m, 1H),
1H), 3.47 (d, J ¼ 14.6 Hz, 1H), 2.66e2.59 (m, 1H), 2.54e2.37 (m, 2H),
2.53e2.48 (m, 1H), 2.44e2.36 (m, 1H), 1.93e1.86 (m, 1H) ppm. 13
C
1.89e1.82 (m, 1H). ppm. 13C NMR (101 MHz, CDCl3)
d 175.2, 139.4,
NMR (126 MHz, CDCl3)
d
175.3, 140.9, 136.4, 129.0 (2C), 128.5 (2C),
136.1, 133.9, 129.2 (2C), 128.6 (2C), 128.5 (2C), 128.1 (2C), 127.6, 60.7,
44.4, 30.2, 28.2 ppm. IR vmax (cmꢁ1): 3029, 2955, 2924, 2854, 1688,
1492, 1407, 1269, 1253, 1152, 1088, 1014, 822, 703. HRMS (ESI-TOF)
calculated for C17H17NOCl [MþHþ] 286.0999, found 286.0995.
128.5 (2C),128.1, 127.5, 126.7 (2C), 61.3, 44.3, 30.3, 28.3 ppm. IR nmax
(cmꢁ1): 3063, 3026, 3005, 2970, 2941, 2897, 1680, 1634, 1495, 1456,
1437, 1412, 1371, 1356,1306, 1288, 1256, 1217, 1200, 1167, 1153, 1078,
1028, 970, 708, 677, 596, 555.
4.41. 5-(Furan-2-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one (35)
Yield: 46%. Yellow oil. TLC: Rf ¼ 0.15 (30% EtOAc/hexanes). 1H
4.36. 1-Allyl-5-phenylpyrrolidin-2-one (25)
Yield: 55%. Yellow oil. Rf ¼ 0.29 (30% EtOAc/hexanes). 1H NMR
NMR (400 MHz, CDCl3)
d
7.39 (dd, J ¼ 1.8, 0.7 Hz, 1H), 7.10 (d,
(400 MHz, CDCl3)
d
7.51e7.00 (m, 5H), 5.71e5.61 (m, 1H), 5.12e5.10
J ¼ 8.6 Hz, 2H), 6.83 (d, J ¼ 8.6 Hz, 2H), 6.34 (dd, J ¼ 3.2, 1.9 Hz, 1H),
6.19 (dd, J ¼ 3.2, 0.5 Hz, 1H), 4.94 (d, J ¼ 14.6 Hz, 1H), 4.48 (dd,
J ¼ 8.3, 4.9 Hz, 1H), 3.79 (s, 3H), 3.53 (d, J ¼ 14.6 Hz, 1H), 2.71e2.64
(m, 1H), 2.50e2.42 (m, 1H), 2.27e2.16 (m, 2H) ppm. 13C NMR
(m, 1H), 4.99e4.95 (m, 1H), 4.65e4.62 (m, 1H), 4.40 (dd, J ¼ 15.2,
4.6 Hz,1H), 3.10e3.04 (m,1H), 2.63e2.46 (m, 3H),1.96e1.88 (m,1H)
ppm. 13C NMR (101 MHz, CDCl3)
d 175.2, 141.0, 132.0, 129.0 (2C),
128.1, 126.6 (2C), 118.1, 61.6, 43.3, 30.2, 28.3 ppm. IR nmax (cmꢁ1):
3082, 3065, 3030, 2970, 2922, 2855, 1693, 1547, 1495, 1456, 1439,
1410, 1366, 1285, 1258, 1246, 1150, 1078, 993, 928, 829, 770, 704,
(100 MHz, CDCl3) d 174.6, 159.0, 152.7, 142.8, 129.7 (2C), 128.6, 113.9
(2C), 110.2, 108.3, 55.3, 54.4, 43.8, 30.3, 24.5 ppm. IR vmax (cmꢁ1):
2955, 2926, 2838, 1682, 1612, 1513, 1440, 1414, 1245, 1175, 1152,
1032, 1012, 905, 818, 744. HRMS (ESI-TOF) calculated for
636, 584. HRMS (ESI-TOF) calculated for
202.12264, found 202.12184.
C
13H16NO [MþHþ]
C
16H17N3ONa [MþNaþ] 294.1106, found 294.1110.
4.37. 1-Benzyl-5-(((tert-butyldimethylsilyl)oxy)methyl) pyrrolidin-
4.42. 1-Butyl-5-propylpyrrolidin-2-one (37)
2-one (27)
Yield: 54%. Yellow oil. TLC: Rf ¼ 0.25 (30% EtOAc/hexanes). 1H
Yield: 65%. Yellow oil. Rf ¼ 0.29 (30% EtOAc/hexanes). 1H NMR
NMR (500 MHz, CDCl3)
d
3.65e3.56 (m, 2H), 2.89 (ddd, J ¼ 13.8, 8.8,
(500 MHz, CDCl3)
d
7.31e7.24 (m, 5H), 5.00 (d, J ¼ 15.0 Hz, 1H), 4.04
5.0 Hz, 1H), 2.39e2.26 (m, 2H), 2.16e2.04 (m, 1H), 1.69e1.64 (m,
(d, J ¼ 15.0 Hz, 1H), 3.68e3.66 (m, 1H), 3.54e3.49 (m, 2H),
2.57e2.50 (m, 1H), 2.40e2.33 (m, 1H), 2.06e2.01 (m, 1H), 1.92e1.86
(m, 1H), 0.88 (s, 9H). 0.03 (s, 6H) ppm. 13C NMR (126 MHz, CDCl3)
2H), 1.52e1.29 (m, 7H), 0.98e0.91 (m, 6H) ppm. 13C NMR (101 MHz,
CDCl3)
d 174.9, 57.4, 39.9, 35.4, 30.4, 29.5, 24.2, 20.2, 18.0, 14.2,
13.8 ppm. IR vmax (cmꢁ1): 2957, 2928, 2873, 1667, 1457, 1422, 1375,
1315,1284,1261,1193,1131,1113, 917, 820, 742, 661. HRMS (ESI-TOF)
calculated for C11H22NO [MþHþ] 184.1701, found 184.1700.
d
175.6,137.0,128.6 (2C),128.0 (2C),127.4, 63.5, 58.4. 44.6, 30.4, 25.8
max (cm-1): 3030, 2955, 2930,
(3C), 21.5, 18.2, ꢁ5.52 (2C) ppm. IR
n
2895, 2857, 1694, 1497, 1472, 1445, 1418, 1360, 1254, 1180, 1115,
1078, 1030, 1007, 974, 939, 883, 814, 779, 702, 650, 507.
4.43. General procedure for the Julia-Kocienski olefination
4.38. 1-Benzyl-5-propylpyrrolidin-2-one (29)
To a 25 mL round-bottom flask equipped with a magnetic stir-
bar and containing a solution of 5-(ethylsulfonyl)-1-phenyl-1H-
tetrazole (0.69 mmol, 1.2 equiv., 198.0 mg in 5.0 mL of THF)
at ꢁ78 ꢀC, was added dropwise a solution of LDA (1.5 M in THF,
0.69 mmol, 0.46 mL). The mixture was stirred at ꢁ78 ꢀC for 10 min.
After this time, a solution of pyrrolidin-3-one (36) (0.69 mmol, 1.0
Yield: 81%. Yellow oil. Rf ¼ 0.32 (30% EtOAc/hexanes). 1H NMR
(500 MHz, CDCl3)
d
7.33e7.22 (m, 5H), 4.98 (d, J ¼ 15.0 Hz, 1H), 3.96
(d, J ¼ 15.0 Hz,1H), 3.44e3.40 (m,1H), 2.51e2.35 (m, 2H), 2.12e2.05
(m, 1H), 1.71e1.64 (m, 2H), 1.35e1.27 (m, 2H), 1.22e1.17 (m, 1H),
Please cite this article in press as: Dias RMP, et al., One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from
a,b-
unsaturated diazoketones and amines. Application in the synthesis of barmumycin, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.05.040

R.M.P. Dias et al. / Tetrahedron xxx (2017) 1e10
9
equiv., 240.0 mg in 0.7 mL of THF) was added and the reaction
mixture was stirred at this temperature for 1 h. The mixture was
quenched with saturated NH4Cl (20 mL), extracted using CH2Cl2
(3 ꢂ 20 mL) and dried over MgSO4. The crude material was purified
1.60 (bs, 3H) ppm. 13C NMR (101 MHz, CDCl3)
134.5, 128.1, 120.9, 117.4, 113.9, 110.7, 67.0, 60.1, 56.0, 34.2, 29.7,
14.6 ppm. HRMS (ESI-TOF) calculated for C15H19NO4 [MþNaþ]
300.1212, found 300.1210.
d
171.7, 147.6, 146.5,
by flash chromatography employing
a mixture of 9:1 hex-
anes:EtOAc as eluent. The ethylidene pyrrolidine 38 was obtained
in an inseparable 3:1 E/Z ratio (135.0 mg, 0.37 mmol, 54%) as a
yellow oil.
Acknowledgements
We would thank FAPESP (Research Supporting Foundation of
the State of Sao Paulo) for financial support (2013/25504-1; 2013/
18009-4) and fellowship to P. B. M. (2015/22003-7). We also thank
CNPq for a research fellowship to A.C.B.B. (303437/2015-4) and a
fellowship to R.M.P.D. (2011/160522-0). We also thank IQSC-USP for
facilities and FAPESP (2013/50228-8; 2009/54040-8) for HRMS
multiuser equipment.
4.44. (E)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-ethylidene-1-
(4-methoxybenzyl)pyrrolidine (38)
Yield: 54%. Yellow oil. TLC: Rf ¼ 0.30 (20% EtOAc/hexanes). Ratio
3:1 E/Z. E isomer: 1H NMR (400 MHz, CDCl3)
d 7.25e7.23 (m, 2H),
6.84e6.82 (m, 2H), 5.23e5.21 (m, 1H), 4.15 (d, J ¼ 12.8 Hz, 1H),
3.85e3.80 (m, 1H), 3.79 (s, 3H), 3.62e3.58 (m, 1H), 3.37e3.30 (m,
1H) 3.23 (d, J ¼ 12.8 Hz, 1H), 2.85e2.75 (m, 1H), 2.58e2.53 (m, 1H),
2.25e2.11 (m, 1H), 1.56e1.53 (m, 3H), 1.47 (d, J ¼ 6.8 Hz, 1H), 0.90 (s,
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.05.040.
9H), 0.06 (s, 6H) ppm. 13C NMR (101 MHz, CDCl3)
d 158.5, 137.5,
131.6, 130.0 (2C), 114.4, 113.6 (2C), 67.0, 65.5, 60.1, 59.0, 55.2, 36.3,
32.5, 26.0 (3C), 18.3, 14.3, ꢁ5.3 (2C) ppm. Z isomer: 1H NMR
References
(400 MHz, CDCl3)
d 7.27e7.24 (m, 2H), 6.86e6.84 (m, 2H),
5.23e5.21 (m, 1H), 4.15 (d, J ¼ 12.8 Hz, 1H), 3.85e3.80 (m, 1H), 3.80
(s, 3H), 3.59e3.49 (m, 2H), 3.37e3.32 (m, 1H), 2.85e2.75 (m, 1H),
2.58e2.53 (m, 1H), 2.22e2.11 (m, 1H), 1.47e1.45 (m, 3H), 0.89 (s,
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m
m
m
reaction mixture was stirred at this temperature for 30 min. After
the solvent was removed, the residue containing the chloridrate
was dissolved in MeOH and refluxed for 2 h. The reaction was
finished by the addition of saturated K2CO3 (10 mL), extracted using
CH2Cl2 (20 ꢂ 10 mL) and dried over Na2SO4. After removal of the
solvent, the crude alcohol was dissolved in dry THF (2.40 mL) and
added to the activated vanilic acid [to a solution of vanilic acid
(57.5 mg, 0.332 mmol, 1.5 equiv.) and PyBOP (176 mg, 0.332 mmol,
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0.664 mmol, 3.0 equiv.). The mixture was stirred at ambient tem-
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60 ꢀC for 24 h. The solvent was then removed under reduced
pressure and the crude material dissolved in DCM and washed with
saturated NaHCO3 and NH4Cl. After concentration, purification by
flash column chromatography with EtOAc afforded barmumycin 39
(16.5 mg, 0.06 mmol, 27% overall yield) as a colorless oil and as an
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12a
ꢀ
rated only by HPLC as described by Alvarez.
Yield: 27%. Yellow oil. TLC: Rf ¼ 0.33 (5% MeOH/DCM). Ratio
3:1 E/Z. E isomer: 1H NMR (400 MHz, CDCl3)
7.09 (s, 1H), 7.04 (d,
(d) Ye T, Mckervey MA. Chem Rev. 1994;94:1091e1160;
d
(e) Doyle MP, Mackervey MA, Ye T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds: From Cyclopropanes to Ylides. New York:
Wiley; 1998 (For pyrrolidine synthesis from diazocompounds, see:);
(f) Shanahan CS, Fuller NO, Ludolph B, Martin SF. Tetrahedron Lett. 2011;52:
4076e4079;
J ¼ 8.0 Hz, 1H), 6.91 (d, J ¼ 8.0 Hz, 1H), 6.12 (bs, 1H), 5.34 (bs, 1H),
4.66 (bs, 1H), 4.07e4.20 (m 2H), 3.90 (s, 3H), 3.74 (bs, 2H),
2.69e2.76 (m, 1H), 2.23e2.34 (m, 1H), 1.63 (3H, d, J ¼ 6.8 Hz) ppm.
13C NMR (101 MHz, CDCl3)
d 171.7, 147.6, 146.5, 134.5, 128.1, 120.8,
(g) Dong C, Mo F, Wang J. J Org Chem. 2008;73:1971e1974;
(h) Moyer MP, Feldman PL, Rapoport H. J Org Chem. 1985;50:5223e5230.
12. (a) Dong C, Deng G, Wang J. J Org Chem. 2006;71:5560e5564;
(b) Mo F, Li F, Qui D, Wang J. Tetrahedron. 2010;66:1274e1277;
(c) Dong C, Mo F, Wang J. J Org Chem. 2008;73:1971e1974.
117.4, 113.8, 110.4, 67.0, 60.4, 56.1, 54.9, 29.9, 14.3 ppm. Z isomer: 1H
NMR (400 MHz, CDCl3)
d
7.09 (s, 1H), 7.04 (d, J ¼ 8.0 Hz, 1H), 6.91 (d,
J ¼ 8.0 Hz, 1H), 5.34e5.42 (m, 1H), 4.64 (bs, 1H), 4.07e4.20 (m 2H),
ꢀ
~
3.90 (s, 3H), 3.74 (bs, 2H), 2.69e2.76 (m, 1H), 2.27e2.40 (m, 1H),
13. (a) Lorente A, Pla D, Canedo LM, Albericio F, Alvarez M. J Org Chem. 2010;75:
Please cite this article in press as: Dias RMP, et al., One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from
a,b-
unsaturated diazoketones and amines. Application in the synthesis of barmumycin, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.05.040

10
R.M.P. Dias et al. / Tetrahedron xxx (2017) 1e10
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955e968.
tion of tertiary amines using
1993;1993(03):195e196.
a-chloroethyl chloroformate. Synlett.
ꢀ
Please cite this article in press as: Dias RMP, et al., One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from
a,b-
unsaturated diazoketones and amines. Application in the synthesis of barmumycin, Tetrahedron (2017), http://dx.doi.org/10.1016/
j.tet.2017.05.040