Stereoselective synthesis of densely functionalized pyrrolidin-2-ones by a conjugate addition/nitro-mannich/lactamization reaction

Article abstract of DOI:10.1021/jo301000r

Copper-catalyzed conjugate addition of diorgano zinc reagents to nitroacrylate 1 followed by a subsequent nitro-Mannich reaction and in situ lactamization leads to an efficient one-pot synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones (5). The versatility of the reaction is shown for a wide range of N-p-(methoxy)phenyl protected aldimines 3 derived from alkyl, aryl, and heteroaryl aldehydes. The densely functionalized pyrrolidin-2-ones 5 are isolated as single diastereoisomers (40 examples, 33-84% yield). An enantioselective copper-catalyzed conjugate addition of diethylzinc led to highly crystalline products that could be recrystallized to enantiopurity in high yield. A range of successful chemoselective transformations were investigated, which widens the applicability of the pyrrolidn-2-ones as stereochemically pure building blocks for further organic synthesis.

Full text of DOI:10.1021/jo301000r

Article
pubs.acs.org/joc
Stereoselective Synthesis of Densely Functionalized Pyrrolidin-2-
ones by a Conjugate Addition/Nitro-Mannich/Lactamization
Reaction
James C. Anderson,*,† Lisa R. Horsfall,† Andreas S. Kalogirou,† Matthew R. Mills,† Gregory J. Stepney,‡
and Graham J. Tizzard§
†Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K.
‡School of Chemistry, University of Nottingham, Nottingham NG7 2RD, U.K
§National Crystallography Service, School of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
S
* Supporting Information
ABSTRACT: Copper-catalyzed conjugate addition of diorga-
no zinc reagents to nitroacrylate 1 followed by a subsequent
nitro-Mannich reaction and in situ lactamization leads to an
efficient one-pot synthesis of 1,3,5-trisubstituted 4-nitro-
pyrrolidin-2-ones (5). The versatility of the reaction is
shown for a wide range of N-p-(methoxy)phenyl protected
aldimines 3 derived from alkyl, aryl, and heteroaryl aldehydes.
The densely functionalized pyrrolidin-2-ones 5 are isolated as
single diastereoisomers (40 examples, 33−84% yield). An enantioselective copper-catalyzed conjugate addition of diethylzinc led
to highly crystalline products that could be recrystallized to enantiopurity in high yield. A range of successful chemoselective
transformations were investigated, which widens the applicability of the pyrrolidn-2-ones as stereochemically pure building blocks
for further organic synthesis.
formation of the additional two new stereocenters from the
nitro-Mannich reaction. In addition we have also investigated
the addition of hydride nucleophiles in a similar protocol, which
lays the foundation for an alternative method for the
asymmetric synthesis of β-nitroamines.6 In this paper we
report a conjugate addition/nitro-Mannich/lactamization strat-
egy that forms pyrrolidin-2-ones in one pot. We have found
that conjugate addition of a diorgano zinc reagent to
nitroacrylate 1 and subsequent trapping of the resultant
nitronate anion 2 with an imine 3 leads to an intermediate β-
nitroamine 4, which cyclizes in situ to give a pyrrolidin-2-one 5
(Scheme 2).
The pyrrolidin-2-one structure is a significant heterocycle
found in many complex natural products7 and pharmaceutical
compounds (Figure 1).8 Currently, the synthesis of pyrrolidin-
2-ones relies on methods involving cyclization of previously
formed carbon skeletons such as cycloadditions,9 amide bond
formation,10 radical cyclizations,11 and expansion or contraction
of a previously formed ring,12 among many others.13 These
methods often involve toxic reagents and require a number of
steps to obtain the desired heterocycle.
INTRODUCTION
■
The nitro-Mannich (or aza-Henry) reaction has been
developed extensively in recent years, with highly diaster-
eoselective and enantioselective reactions being reported.1
Direct reduction of the β-nitroamine products allows for an
efficient synthesis of vicinal diamines,2 found in many natural
products and biologically active compounds,3 as well as ligands
for asymmetric catalysis.4 In order to broaden the scope of the
nitro-Mannich reaction we have been developing the conjugate
addition of nucleophiles to nitroalkenes with in situ trapping of
the nitronate anion with an imine (Scheme 1). This leads to a
wider access to acyclic β-nitroamines and does not require a
prerequisite synthesis of a nitroalkane (most often prepared
from a nitroalkene).
We have recently reported an enantioselective conjugate
addition nitro-Mannich protocol, initiated by asymmetric
copper-catalyzed dialkyl zinc additions, which affords anti- or
syn-β-nitroamines with exquisite control of stereochemistry
over three contiguous centers.5 The initial stereocenter from
the conjugate addition reaction effectively controls the
We are aware of only one other similar procedure specifically
related to the work presented here, which has been reported by
Dixon et al. (Scheme 2) and also generates densely substituted
pyrrolidin-2-ones with three contiguous stereocenters.14 Our
Scheme 1. Conjugate Addition Nitro-Mannich Reaction
Received: May 15, 2012
© XXXX American Chemical Society
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Scheme 2. Nitro-Mannich/Lactamization Strategies
Scheme 3. General Procedure for Conjugate Addition/
Nitro-Mannich/Lactamization Reaction and Stereochemical
Outcome
cyclizes to give 5. This assumption was later confirmed by
single crystal X-ray crystallography of two analogues of 5 (vide
infra).
With the PMP group identified as the optimum imine N-
protecting group, the scope of the reaction with respect to
imine substituents was investigated (Table 1). All products
were isolated as single diastereoisomers (except 5w). The
relative stereochemistry was confirmed by single crystal X-ray
analysis15 of 5r and a derivative of 5q (vide infra) and by
analogy of coupling constants around the pyrrolidin-2-one ring
(see Supporting Information).
With optimal conditions in hand, other N-protecting groups
of the imine of benzaldehyde were briefly investigated. A
similarly neutral N-o-methoxybenzyl (OMB) or N-butyl group
afforded the desired pyrrolidin-2-ones 5b and 5c in 57% and
46% yield, respectively (R2 = Ph, P = OMB and n-butyl,
respectively). The more electron-withdrawing N-Boc group
gave two acyclic, β-nitroamines 4 (R1 = Et, R2 = Ph, P = Boc)
with a diastereomeric ratio of 7:1 (syn,anti-:syn,syn-) in 64%
combined yield. We attribute that the lack of cyclization was
due to the decreased availability of the nitrogen loan pair in the
β-nitro-amine product.
Figure 1. Pyrrolidinone-containing natural products and pharmaceut-
ical compounds.
complementary results in contrast are made readily enantiose-
lective by the use of chiral ligand copper complexes that control
the asymmetry of the conjugate addition reaction. We have
focused on the use of imines with a removable N-protecting
group P, and the cyclization occurs spontaneously upon
warming from −78 °C. With acyclic imines we isolate a single
diastereoisomer, and we show that the product pyrrolidin-2-
ones can be transformed into a number of different products by
chemoselective reactions.
Aromatic groups substituted in the para and meta positions
consistently provided good yields (58−72%) across a range of
electron-donating and -withdrawing functionalities (5d−i),
with the exception of the p-methoxyphenyl analogue 5g
(49%). With ortho substituents the yields were reduced slightly
to around 50%, perhaps due to steric interactions around the
newly formed ring (5j−l). Two representative disubstituted
aromatics (5m, 5n) gave good to excellent yields. Hetero-
aromatic groups based on furan and thiophene gave good yields
(5o−q, 64−70%). Pyridines gave moderate yields (5r, 5s), but
2-pyrrole and 3-indene required N-tosyl protection (compare
5u and 5w with 5t and 5v). The N-Ts-2-pyrrole example (5v)
gave the lowest yield (33%) of those investigated and was the
only substrate that did not give a single diastereomer of
pyrrolidin-2-one product, giving instead an 85:15 mixture of
diastereoisomers presumably in favor of the diastereoisomer
observed for all other examples. The thiooxazolene (5x) and
oxazoline (5y) gave good yields of pyroolidin-2-one products
(58% and 53% yield, respectively). The reaction conditions are
also compatible with alkyl substituents (5z, 5aa−5cc), to give
the desired products in 38−62%. The lower yields for the
primary alkyl chains (5bb, 5cc) were due to the instability of
the imine. A methoxy acetal (5dd) and an ethyl-ester
substituent (5ee) gave good yields of desired products in
63% and 69% yield, respectively. To expand the scope further,
the one-pot reaction was carried out using cyclic imine 716 to
give the densely substituted polycyclic pyrrolidin-2-one 8 in
60% yield in an unseparable dr of 5:1 (eq 1). The major isomer
was assigned on the basis of NOESY data and by analogy of the
RESULTS AND DISCUSSION
■
As part of our studies into the enantioselective conjugate
addition/nitro-Mannich protocol, initiated by asymmetric
copper-catalyzed addition of dialkyl zincs,5 we observed that
treatment of 1 with diethyl zinc (1.1 equiv) at −78 °C gave the
intermediate nitronate anion upon warming to rt. Recooling of
the reaction to −78 °C, addition of N-p-methoxyphenyl (PMP)
imine of benzaldehyde (2.0 equiv) and trifluoroacetic acid
(TFA, 3.5 equiv), and allowing the reaction to warm to rt with
an overnight stir gave pyrrolidinone 5a (R2 = Ph, P = PMP) in
67% yield as a single diastereoisomer (Scheme 3). A small
solvent screen revealed that THF and diethyl ether were
equally effective and superior to other less polar solvents. We
have already seen that for this particular type of conjugate
addition/nitro-Mannich reaction two distinct stereochemical
outcomes are possible and are dependent upon the choice of
solvent, which dictates whether the reaction is homogeneous or
heterogeneous.5 The polarity of nitroalkene 1 is such that in
either THF or Et2O the reaction is homogeneous. From our
extensive studies, we would expect this reaction to form the
syn,anti-β-nitroamine 6, which in this reaction spontaneously
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a
Table 1. Scope of Reaction with Respect to PMP Imine Partner
a
b
c
Conditions as in Scheme 3 (P = PMP). Isolated yield of single diastereoisomers. Isolated as an 85:15 mixture of diastereoisomers.
Scheme 4. Use of Common Di-organo Zinc Nucleophiles
coupling constants around the pyrrolidinone ring compared to
compounds 5 (see Supporting Information).
The reaction was also compatible with other diorgano zinc
nucleophiles (Scheme 4). While the addition of alkyl groups
was efficient, the one-pot reaction protocol using diphenyl zinc
led to a complex mixture of unidentifiable products. A two -step
procedure involving isolation of the phenyl conjugate addition
product and then nitro Mannich reaction led to the isolation of
5hh in 51% yield. Functionalized diorgano zinc reagents can be
prepared using the tandem hydroboration/boron−zinc ex-
change method developed by Knochel,17 and we have shown
that they also participate in the conjugate addition nitro-
Mannich reaction sequence,5 which suggests they could also be
compatible here.
The asymmetric catalytic addition of dialkyl zinc to
nitroalkenes catalyzed by Cu-chiral ligand complexes is a
well-known reaction, giving a range of products in high
enantioselectivity.18 To show that this protocol can be used to
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prepare enantiomerically enriched pyrolidin-2-ones we repeated
the known asymmetric addition of diethyl zinc to methyl
nitroacrylate19 and intercepted the conjugate addition product
with our nitro-Mannich/lactamization reaction (Scheme 5).
Scheme 5. Enantioselective Conjugate Addition/Nitro-
Mannich/Lactamization Reactions
corresponds to the cyclization of the major syn,anti-10a
diastereoisomer.
The synthesis of 5a (Scheme 3) was repeated in d8-THF, and
1
aliquots were analyzed by H NMR at time intervals directly
after the removal of the −78 °C cooling bath (Table 2). After 5
a
1
Table 2. H NMR Studies
entry
time (min)
ratio 5a:syn,anti-10a
1
2
3
4
5
6
5
20
35
50
65
80
45:55
66:34
75:25
85:15
85:15
90:10
a
Conditions as in Scheme 3 (P = PMP) in d8-THF
This gave enantioenriched 5a and 5q in high yield and 89%
ee.20 Pyrrolidin-2-one 5a could be recrystallized from IPA/
hexane to give 5a in 71% yield and 99% ee. The absolute
stereochemistry was not defined in the original publication of
the asymmetric addition, so we attempted to grow suitable
crystals of 5q to use anomalous-dispersion effects in single
crystal X-ray diffraction measurements. Suitable crystals were
unfortunately not obtained, but reduction of 5q to the 1,2-
diamine and protection of the primary amine as the
trifluoroacetamide gave 9 in high yield; 9 was highly crystalline
and could be recrystallized to give a 73% yield of product with
99% ee. Anomalous-dispersion effects in the single crystal X-ray
crystallographic analysis of 9 confirmed the absolute sense of
chirality as depicted (Scheme 5).15
What is remarkable about this conjugate addition/nitro-
Mannich/lactamization reaction is that for acyclic imines a
single trans,trans-pyrrolidin-2-one diastereoisomer is isolated
(except for the low yielding synthesis of 5w). After addition of
the imine and TFA at −78 °C the reaction is stirred for 1 h
before the cooling bath is removed and the reaction is allowed
to slowly equilibrate to room temperature and stirred for a
nominal 16 h during which time both the nitro-Mannich and
lactamization reactions take place. Repeat of the synthesis of 5a
(Scheme 3), but quenching the reaction with saturated
NaHCO3 solution 5 min after removing the −78 °C cooling
bath, gave crude reaction material, which was trifluoroacetylated
under our standard conditions.5 Separation by column
chromatography gave pyrrolidinone 5a (16%), a mixture of
β-nitrotrifluoroacetamides 10a (37%) and the addition product
11 (23%, eq 2). The ratio of diastereoisomers of 10a was 65:35
(syn,anti-:syn,syn-), and we assume 11 originates from
degradation of other diastereoisomers of 10a as we have
previously seen during trifluoroacetamide protection of other β-
nitroamines of this type.5 The stereochemistry of 5a
min the spectrum showed only the formation of syn,anti-10a
with a nearly equal quantity of the single pyrrolidin-2-one
product 5a, along with baseline traces of what we presume are
other β-nitroamine diastereoisomers. Further analysis over 1.5
h revealed a gradual decrease in the proportion of β-nitroamine
in favor of a single diastereoisomer of the cyclized product 5a.
These observations suggest that lactamization is the slowest
step in this reaction sequence. We know from our previous
studies concerning the conjugate addition of diethyl zinc to
nitroalkenes and subsequent nitro-Mannich reaction that the
syn,anti-diastereoisomer is by far the major diastereoisomer in
homogeneous reactions.5 In addition we have previously shown
that β-nitroamines are susceptible to retro- and readdition.5
The nitro Mannich reaction proceeds with high diastereose-
lectivity, but it seems, at ambient temperature at least, that only
the syn,anti-β-nitroamine diastereoisomer cyclizes to give the all
equatorial product. Any other β-nitroamine diastereoisomers
formed could potentially equilibrate to the syn,anti-diaster-
eoisomer to allow cyclization. This reaction scenario is also in
line with Dixon’s analysis of some relative kinetic data that also
suggests the lactamization step is rate-determining in his closely
related cascade reaction (Scheme 2).14a However, in the Dixon
protocol they do see a minor pyrrolidin-2-one diastereoisomer
in many cases. As they rule out any post cyclization
epimerization, the minor diastereoisomer probably comes
from the cyclization of a minor β-nitroamine diastereoisomer.
This may be possible under their conditions of 70 °C in
toluene, but generally not under our ambient reaction
conditions.
To demonstrate the synthetic potential of these stereo-
chemically pure building blocks, we investigated some chemo-
selective reactions (Scheme 6). Deprotection of the PMP group
of 5a proceeded smoothly using CAN, giving the lactam 12 in
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Scheme 6. Chemoselective Functional Group
Interconversions
CONCLUSION
■
In line with our previous work5 the initial stereocenter formed
from the copper-catalyzed conjugate addition of diorgano zinc
reagents to nitroacrylate 1 controls the formation of two new
stereogenic centers formed from an in situ nitro-Mannich
reaction with added N-PMP protected imines. The major initial
product, syn,anti-β-nitroamine 6, exclusively cyclizes in a rate
determining lactamization to give a range of densely function-
alized pyrrolidin-2-ones 5 as single diastereoisomers. Any
alternate acyclic diastereoisomers of 6, formed in the reaction,
can potentially equilibrate to allow cyclization to diaster-
eoisomer 5. Control of the absolute stereochemistry of the
initial copper catalyzed conjugate addition reaction19 can lead
to the formation of highly crystalline, diastereomerically pure
pyrrolidin-2-ones, which can be recrystallized to enantiopurity
in high yield. The pyrrolidin-2-ones 5 and products generated
from chemoselective reactions have the potential to be useful
stereodefined building blocks for further asymmetric organic
synthesis.
74% yield. Reduction of the nitro group to the primary amine
13 was achieved using standard Zn/HCl conditions to give a
single compound in 91% crude yield as this material was
unstable to chromatography. Attempted deprotection of the
PMP group of 13 with CAN led to degradation under the
oxidizing conditions. Fortunately reduction of the nitro
function of 12 to give unprotected cyclic vicinal diamine 14
was possible in a moderate 49% yield. Removal of the carbonyl
group was possible with BH3·THF to give pyrrolidine 15 in
79% yield. Use of the Nef reaction to provide the
corresponding dicarbonyl compound could provide another
opportunity for further functional group addition. Attempts at
using standard conditions with TiCl3 led to no reaction under a
variety of different conditions.21 Treatment with chromium(II)
dichloride, prepared in situ from reaction of potassium
dichromate with 6 M HCl and zinc dust,22 led to pyrrolone
16 in only 38% yield.23 Unfortunately prolonged reaction did
not improve the yield of this stubborn transformation.
EXPERIMENTAL SECTION
Functionalization alpha to the carbonyl or nitro group would
create more functionality in the pyrrolidin-2-one core. However
treatment with a variety of bases and nucleophiles led to a
mixture of unidentified products. An optimized procedure using
nBuLi as base followed by the addition of allyl bromide led to
the isolation of 17, albeit in 32% yields (Scheme 7). A
■
General Procedure A for the Synthesis of Pyrrolidin-2-ones
5 (Table 1). To a solution of nitroalkene 1 (0.69 mmol) in THF (3
mL) under N2 was added Cu(OTf)2 (34.0 μmol, 5 mol %). The
mixture was cooled to −78 °C, and diethyl zinc (0.76 mmol, of a 1.0
M solution in hexanes, 1.1 equiv) was added quickly dropwise. The
orange mixture was stirred at this temperature for 10 min before being
warmed to rt and stirred for a further 1.5 h. The dark mixture was
recooled to −78 °C, and the corresponding imine (1.38 mmol, 2.0
equiv) in THF (2 mL) was added via cannula. The mixture was stirred
for 20 min before TFA (2.41 mmol, 3.5 equiv) in THF (0.5 mL) was
added via cannula. The mixture was stirred at this temperature for a
further 1 h before being warmed to rt for 16 h. Saturated aq NaHCO3
and Et2O were then added, and the layers were separated. The
aqueous phase was extracted with Et2O, and the combined organics
were washed with brine, dried (MgSO4), filtered, and concentrated in
vacuo to leave crude pyrrolidinone. The pyrrolidinone was then
purified further by column chromatography.
Scheme 7. Attempted α-Functionalization
General Procedure B for the Asymmetric Synthesis of
Pyrrolidinones 5a and 5q. A suspension of Cu(OTf)2 (8 mg, 22.0
μmol, 5 mol %) and BINOL derived catalyst L* (Scheme 5, 14.7 mg,
27.0 μmol, 5 mol %) in Et2O (3 mL) under N2 was stirred at rt for 1 h.
The mixture was cooled to −78 °C, and a solution of methyl
nitroacrylate (76 mg, 580 μmol) in Et2O (1 mL) was added, followed
by diethyl zinc (640 μL, 640 μmol of a 1 M soln in hexanes, 1.1 equiv)
quickly dropwise. The reaction then proceeded as for General
procedure A.
General Procedure C for the Reduction of the Nitro Group.
To a solution of pyrrolidinone (0.29 mmol) in EtOAc/MeOH (2:1, 6
mL) at 0 °C under N2 was added HCl (1.47 mL of an aqueous 6 M
sol, 8.82 mmol, 30.0 equiv). Zinc dust (1.15 g, 17.6 mmol, 60.0 equiv)
was added portionwise over 20 min. The mixture was then warmed to
rt and stirred for a further 15 h. NaHCO3 was added carefully,
followed by EtOAc. The layers were separated, the aqueous layer was
reasonable mechanism to account for the formation of 17 is β-
elimination of NO2 to give the pyrrolidinone. The unexpected
similarity in the acidic protons of the parent ring system 5a
seems to thwart selective functionalization in this manner.
Denitration with nBu3SnH and AIBN led to a complex
mixture of products with some evidence for the formation of
the oxime. A circuitous route involved formation of the
formamide from the reduced product 13 (Scheme 6), followed
by dehydration with POCl3 to give the isocyanate24 which was
smoothly removed with nBu3SnH in refluxing toluene and
AIBN to give 18 (eq 3).
A densely substituted proline like structure 19 could be
accessed from the hydrolysis of ester 5ee in high yield (eq 4).
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extracted with EtOAc, and the combined organics werewashed with
satd aq NaHCO3 and brine. The pH of the aqueous layer was tested,
and additional satd aq NaHCO3 was added as necessary to reach pH 9.
The organics were dried (MgSO4), filtered, and concentrated in vacuo
to give the product diamine.
CDCl3) δ 10.5 (CH3), 13.9 (CH3), 22.4 (CH2), 28.0 (3 × CH3), 47.4
(CH), 56.2 (CH), 61.1 (CH2), 80.3 (Cq), 91.7 (CH), 126.7 (2 × CH),
128.5 (CH), 128.7 (CH), 129.4 (CH), 136.6 (Cq), 154.3 (Cq), 171.8
t
(Cq); m/z (CI+) 381 (47%, M + H+), 234 (100%, M + H+ − CO2 Bu
− NO2); HRMS found 381.2034, C19H29N2O6 requires 381.2026.
Anal. Calcd for C19H28N2O6: C, 59.98, H, 7.42, N, 7.36. Found C,
59.90, H, 7.42, N 7.27%.
5a. (3R,4R,5S)-3-Ethyl-1-(4-methoxy-phenyl)-4-nitro-5-phenyl-
pyrrolidin-2-one (158 mg, 67%) as a pale yellow solid; prepared by
general procedure A; mp 134−136 °C; Rf 0.28 (20% Me2CO/
syn,syn-4 (R1 = Et, R2 = Ph, P = Boc). (2S*,3S*,4S*)-Ethyl-4-
(tert-butoxycarbonylamino)-2-ethyl-3-nitro-4-phenyl-butanoate (23
mg, 8%) as a white solid; prepared by general procedure A, except
using Et2O as the reaction solvent; mp 84−86 °C; Rf 0.33 (20%
1
hexanes); IR νmax (thin film) 3009, 2970, 1765, 1558, 1251 cm−1; H
NMR (500 MHz, CDCl3) δ 1.10 (3H, t, J = 7.5), 1.83 (1H, ddq, J =
14.3, 8.2, 7.5), 2.13 (1H, dqd, J = 14.3, 7.5, 4.8), 3.32 (1H, ddd, J = 8.4,
6.8, 4.8), 3.73 (3H, s), 4.81 (1H, dd, J = 6.8, 5.2), 5.61 (1H, d, J = 5.3),
6.80 (2H, m), 7.20−7.27 (4H, m), 7.31−7.34 (3H, m). 13C NMR
(100 MHz, CDCl3) δ 10.9 (CH3), 23.3 (CH2), 49.2 (CH), 55.3
(CH3), 65.8 (CH), 90.5 (CH), 114.2 (2 × CH), 124.9 (2 × CH),
126.6 (2 × CH), 129.2 (CH), 129.4 (2 × CH), 137.3 (Cq), 158.6
(Cq), 171.0 (Cq), one quaternary carbon could not be distinguished;
m/z (EI+) 363 (M + Na+, 100%); HRMS found 341.1484,
C19H21N2O4 requires 341.1501. Anal. Calcd for C19H20N2O4: C,
67.05, H, 5.92, N, 8.23. Found C, 66.99, H, 5.91, N, 8.23%.
Enantioenriched sample was prepared by general procedure B to
give (157 mg, 80%) as a pale yellow solid with identical spectral data
to the racemic sample; HPLC (chiralcel AD 0.46 cm × 25 cm column,
90:10 hexane/IPA, 1 mL min−1) 35.8 min (major), 45.0 min (minor)
measured 89% ee. Recrystallization of the sample with IPA/hexane
gave 5a (140 mg, 71% overall yield, near racemic compound was
isolated as solid, mother liquor contained enantiomerically enriched
material) as an identical pale yellow solid; [α]D −62.0 (c 0.98, CHCl3,
20 °C); HPLC measured 99% ee.
1
Me2CO/hexanes); H NMR (400 MHz, CDCl3) δ 0.96 (3H, t, J =
7.4), 1.32 (3H, t, J = 7.2), 1.47 (9H, s), 1.60−1.67 (2H, m), 3.20 (1H,
ddd, J = 11.3, 7.4, 5.4), 4.13−4.23 (1H, m), 4.24−4.33 (1H, m), 5.12
(1H, dd, J = 11.0, 3.8), 5.35 (1H, dd, J = 10.4, 3.6), 5.91 (1H, d, J =
10.4), 7.20−7.38 (5H, m); 13C NMR (100 MHz, CDCl3) δ 10.2
(CH3), 13.8 (CH3), 23.8 (CH2), 27.9 (3 × CH3), 46.8 (CH), 53.3
(CH), 61.3 (CH2), 80.0 (Cq), 92.4 (CH), 125.5 (2 × CH), 128.0
(CH), 128.6 (2 × CH), 136.7 (Cq), 154.6 (Cq), 170.8 (Cq); m/z
(CI+) 381 (17%, M + H+), 234 (100%, M + H+ − Boc − NO2);
HRMS found 381.2032, C19H29N2O6 requires 381.2026.
5d. (3S*,4S*,5R*)-3-Ethyl-1-(4-methoxy-phenyl)-4-nitro-5-p-
tolyl-pyrrolidin-2-one (23 mg, 8%) as a white solid; prepared by
general procedure A; mp 104−106 °C; Rf 0.27 (20% Me2CO/
hexanes); IR νmax (thin film) 2966, 1706, 1555, 1513, 1366, 1249
cm−1; 1H NMR (600 MHz, CDCl3) δ 1.09 (3H, t, J = 7.5), 1.83 (1H,
app tq, J = 14.4, 7.5), 2.14 (1H, dqd, J = 14.2, 7.5, 4.8), 2.31 (3H, s),
3.32 (1H, ddd, J = 8.5, 6.8, 4.8), 3.74 (3H, s), 4.79 (1H, dd, J = 6.8,
5.3), 5.57 (1H, d, J = 5.3), 6.79−6.81 (2H, m), 7.09−7.15 (2H, m),
7.24−7.28 (2H, m), 7.29−7.34 (2H, m); 13C NMR (125 MHz,
CDCl3) δ 10.5 (CH3), 20.8 (ArCH3), 23.0 (CH2), 48.9 (CH), 55.0
(CH3), 65.4 (CH), 90.3 (CH), 113.8 (2 × CH), 124.6 (2 × CH),
126.2 (2 × CH), 129.2 (Cq), 129.7 (2 × CH), 133.9 (Cq), 138.8 (Cq),
157.2 (Cq), 170.6 (Cq); m/z (ESI−) 353 (70%, M − H+); HRMS
found 353.1513, C20H21N2O4 requires 353.1501. Anal. Calcd for
C20H22N2O4: C, 67.78, H, 6.26, N, 7.90. Found C, 67.95, H, 6.18, N,
7.56%.
5b. (3S*,4S*,5R*)-3-Ethyl-1-(2-methoxy-benzyl)-4-nitro-5-phe-
nyl-pyrrolidin-2-one (140 mg, 57%) as a pale yellow oil, prepared
by general procedure A, except using Et2O as the reaction solvent and
1.1 equiv of imine; Rf 0.35 (20% Me2CO/hexanes); IR νmax (thin film)
1
2976, 2938, 1697, 1553, 1245 cm−1; H NMR (500 MHz, CDCl3) δ
1.04 (3H, t, J = 7.5), 1.75 (1H, ddq, J = 14.4, 8.3, 7.5), 2.07 (1H, dqd, J
= 14.2, 7.6, 4.6), 3.17 (1H, ddd, J = 8.4, 6.7, 4.7), 3.68 (3H, s), 3.78
(1H, d, J = 14.7), 4.67 (1H, dd, J = 6.6, 5.3), 4.80 (1H, d, J = 5.3), 5.03
(1H, d, J = 14.7), 6.76−6.89 (2H, m), 7.00 (1H, dd, J = 10.0, 2.4),
7.07−7.13 (2H, m), 7.21−7.29 (1H, m), 7.35−7.44 (3H, m); 13C
NMR (125 MHz, CDCl3) δ 10.9 (CH3), 23.1 (CH2), 40.6 (CH2), 48.7
(CH), 55.0 (CH3), 64.4 (CH), 90.8 (CH), 110.3 (CH), 120.6 (CH),
122.8 (Cq), 126.9 (CH), 129.1 (2 × CH), 129.2 (CH), 129.4 (CH),
129.5 (CH), 130.8 (CH), 137.5 (Cq), 157.6 (Cq), 171.8 (Cq); m/z
(ESI+) 355 (100%, MH+); HRMS found 355.1651, C20H23N2O4
requires 355.1658.
5c. (3S*,4R*,5R*)-1-Butyl-3-ethyl-4-nitro-5-phenyl-pyrrolidin-2-
one (92 mg, 46%) as a pale yellow oil; prepared by general procedure
A, except using Et2O as the reaction solvent; Rf 0.44 (20% Me2CO/
hexanes); IR νmax (thin film) 2963, 2933, 1696, 1557, 1458, 1421,
1368, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.86 (3H, t, J = 7.2),
1.02 (3H, t, J = 7.4), 1.17−1.33 (2H, m), 1.35−1.44 (2H, m), 1.72
(1H, ddq, J = 14.4, 8.2, 7.4), 2.05 (1H, dqd, J = 14.0, 7.6, 4.8), 2.58
(1H, ddd, J = 13.2, 7.6, 6.0), 3.14 (1H, ddd, J = 8.4, 6.8, 4.8), 3.78 (1H,
dt, J = 14.0, 8.0), 4.70 (1H, dd, J = 6.8, 5.4), 5.03 (1H, d, J = 5.4),
7.18−7.23 (2H, m), 7.38−7.46 (3H, m); 13C NMR (125 MHz,
CDCl3) δ 10.9 (CH3), 13.7 (CH3), 19.9 (CH2), 23.1 (CH2), 28.7
(CH2), 40.7 (CH2), 48.9 (CH), 64.3 (CH), 90.8 (CH), 126.9 (2 ×
CH), 129.5 (CH), 129.6 (2 × CH), 136.9 (Cq), 171.6 (Cq); m/z
(ESI+) 291 (M + H+, 40%), 244 (M+ − NO2, 100%); HRMS found
291.1709, C16H23N2O3 requires 291.1712.
5e. (3S*,4S*,5R*)-3-Ethyl-1-(4-methoxy-phenyl)-4-nitro-5-(4-
nitro-phenyl)-pyrrolidin-2-one (143 mg, 54%) as an off white
solid; prepared by general procedure A; mp 167−169 °C; Rf 0.16
(20% Me2CO/hexanes); IR νmax (thin film) 2968, 2950, 1701, 1610,
1
1555, 1510, 1343, 1246, 1032 cm−1; H NMR (400 MHz, CDCl3) δ
1.09 (3H, t, J = 7.6), 1.85 (1H, app dquint, J = 14.6, 7.4), 2.13 (1H,
dqd, J = 14.4. 7.6, 4.8), 3.38 (1H, app td, J = 7.8, 4.8), 3.72 (3H, s),
4.76 (1H, dd, J = 7.1, 5.8), 5.76 (1H, d, J = 5.8), 6.77−6.81 (2H, m),
7.20−7.24 (2H, m), 7.42−7.44 (2H, m), 8.61−8.20 (2H, m); 13C
NMR (125 MHz, CDCl3) δ 10.7 (CH3), 23.2 (CH2), 48.7 (CH), 55.4
(CH3), 64.7 (CH), 89.6 (CH), 114.6 (2 × CH), 124.7 (2 × CH),
124.9 (2 × CH), 127.0 (2 × CH), 128.8 (Cq), 144.4 (Cq), 148.4 (Cq),
157.9 (Cq), 170.7 (Cq); m/z (ES−) 384 (30%, M − H+), 366 (100%,
M − H+ − H2O); HRMS found 384.1178, C19H18N3O6 requires
384.1196. Anal. Calcd for C19H19N3O6: C, 59.22, H, 4.97, N, 10.90.
Found C, 58.88, H, 4.94, N, 10.75%.
5f. (3S*,4S*,5R*)-3-Ethyl-1-(4-methoxy-phenyl)-4-nitro-5-(4-tri-
fluoromethyl-phenyl)-pyrrolidin-2-one (196 mg, 70%) as a pale
yellow solid; prepared by general procedure A; mp 140−142 °C; Rf
0.20 (20% Me2CO/hexanes); IR νmax (thin film) 2969, 2939, 1704,
1555, 1512, 1323, 1248, 1166, 1122, 1112, 1067 cm−1; 1H NMR (600
MHz, CDCl3) δ 1.09 (3H, t, J = 7.5), 1.83 (1H, app tq, J = 14.4, 7.5),
2.12 (1H, dqd, J = 14.3, 7.5, 4.8), 3.36 (1H, app td, J = 7.6, 4.7), 3.73
(3H, s), 4.76 (1H, dd, J = 6.6, 5.5), 5.71 (1H, d, J = 5.7), 6.80 (2H, d, J
= 9.0), 7.24 (2H, d, J = 9.0), 7.34 (2H, d, J = 8.4), 7.60 (2H, d, J =
7.8); 13C NMR (125 MHz, CDCl3) δ 10.8 (CH3), 23.3 (CH2), 49.0
(CH), 55.4 (CH3), 65.1 (CH), 90.0 (CH), 114.5 (3 × CH), 123.7 (1C,
q, J = 270.9, CF3), 124.7 (2 × CH). 126.6 (CH), 127.2 (2 × CH),
129.1 (Cq), 131.4 (1C, q, J = 32.4, CCF3), 141.5 (Cq), 157.8 (Cq),
170.9 (Cq); 19F NMR (282 MHz, CDCl3) δ −63.2 (3F, s, CF3); m/z
(FAB+) 409 (100%, M + H+), 363 (35%, M + H+ − NO2); HRMS
found 409.1385, C20H20F3N2O4 requires 409.1375. Anal. Calcd for
syn,anti-4 (R1 = Et, R2 = Ph, P = Boc). (2S*,3S*,4R*)-Ethyl-4-
(tert-butoxycarbonylamino)-2-ethyl-3-nitro-4-phenylbutanoate
(146 mg, 56%) as a white solid, prepared by general procedure A,
except using Et2O as the reaction solvent; mp 122−124 °C; Rf 0.28
(20% Me2CO/hexanes); IR νmax (thin film) 2977, 2934, 1705, 1555,
1367, 1241, 1161, 1018 cm−1; NMR (400 MHz, CDCl3) δ 0.93 (3H, t,
J = 7.1), 1.33 (3H, t, J = 7.4), 1.42 (9H, s), 1.63 (2H, sept, J = 7.2),
2.99 (1H, app dt, J = 9.7, 6.7), 4.10−4.20 (1H, m), 4.24−4.31 (1H,
m), 4.95 (1H, d, J = 9.4), 5.23 (1H, t, J = 9.4), 5.12 (1H, t, J = 9.2),
7.20−7.27 (2H, m), 7.30−7.38 (3H, m); 13C NMR (100 MHz,
F
dx.doi.org/10.1021/jo301000r | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
C20H19F3N2O4: C, 58.82, H, 4.69, N, 6.86. Found C, 58.92, H, 4.65, N,
6.66%.
7.21 (3H, m), 7.26−7.28 (2H, m); 13C NMR (125 MHz, CDCl3) δ
11.4 (CH3), 19.3 (CH3), 23.9 (CH2), 50.3 (CH), 55.4 (CH3), 62.6
(CH), 89.6 (CH), 114.3 (2 × CH), 124.4 (3 × CH), 125.7 (Cq), 127.0
(CH), 128.9 (CH), 129.8 (Cq), 131.6 (CH), 135.7 (Cq), 157.6 (Cq),
171.5 (Cq); m/z (FAB+) 377 (15%, M + Na+), 176 (100%); HRMS
found 377.1464, C20H22N2O4Na requires 377.1472.
5g. (3S*,4S*,5R*)-3-Ethyl-1,5-bis(4-methoxy-phenyl)-4-nitro-
pyrrolidin-2-one (121 mg, 47%) as an off white solid; prepared by
general procedure A; mp 88−90 °C; Rf 0.23 (20% Me2CO/hexanes);
IR νmax (thin film) 2966, 2936, 2838, 1704, 1553, 1512, 1366, 1248,
1177, 1031 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.09 (3H, t, J = 7.5),
1.83 (1H, app dquint, J = 14.8, 7.5), 2.13 (1H, dqd, J = 14.2, 7.5, 4.7),
3.31 (1H, ddd, J = 8.2, 7.1, 4.7), 3.73 (3H, s), 3.76 (3H, s), 4.79 (1H,
dd, J = 7.0, 5.5), 5.53 (1H, d, J = 5.4), 6.78−6.80 (2H, m), 6.82−6.85
(2H, m), 7.11−7.13 (2H, m), 7.21−7.27 (2H, m); 13C NMR (125
MHz, CDCl3) δ 10.9 (CH3), 23.3 (CH2), 49.2 (CH), 55.3 (CH3), 55.4
(CH3), 65.6 (CH), 90.9 (CH), 114.2 (2 × CH), 114.8 (2 × CH),
125.2 (2 × CH), 128.0 (2 × CH), 129.0 (Cq), 129.5 (Cq), 157.6 (Cq),
160.1 (Cq), 170.9 (Cq); m/z (FAB+) 371 (100% MH+), 324 (30%,
M+ − NO2); HRMS found 371.1598, C20H23N2O5 requires 371.1607.
5h. (3S*,4S*,5R*)-5-(4-Chloro-phenyl)-3-ethyl-1-(4-methoxy-
phenyl)-4-nitro-pyrrolidin-2-one (191 mg, 74%) as an off-white
solid; prepared by general procedure A; mp 136−138 °C; Rf 0.34
(20% Me2CO/hexanes); IR νmax (thin film) 2967, 2936, 1702, 1554,
1510, 1246, 728 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.09 (3H, t, J =
7.4), 1.84 (1H, app dquint, J = 14.9, 7.5), 2.12 (1H, dqd, J = 14.3, 7.5,
4.7), 3.33 (1H, ddd, J = 8.1, 7.1, 4.7), 3.74 (3H, s), 4.77 (1H, dd, J =
7.0, 5.5), 5.59 (1H, d, J = 5.5), 6.78−6.82 (2H, m), 7.15−7.17 (2H,
m), 7.20−7.23 (2H, m), 7.29−7.34 (2H, m); 13C NMR (100 MHz,
CDCl3) δ 10.4 (CH3), 22.9 (CH2), 48.6 (CH), 55.2 (CH3), 64.8
(CH), 89.9 (CH), 113.9 (2 × CH), 124.6 (2 × CH), 127.7 (2 × CH),
128.7 (Cq), 129.4 (2 × CH), 134.8 (Cq), 135.4 (Cq), 157.4 (Cq),
170.5 (Cq); m/z (ESI−) 373 (78%, M-H+). Anal. Calcd for
C19H19N2O4Cl: C, 60.88, H, 5.11, N, 7.47. Found C, 60.76, H, 5.07,
N, 7.20%.
5l. (3S*,4S*,5R*)-5-(2-Bromo-phenyl)-3-ethyl-1-(4-methoxy-
phenyl)-4-nitro-pyrrolidin-2-one (162 mg, 56%) as an off white
solid; prepared by general procedure A, except using 1.1 equiv of
imine; mp 132−134 °C; Rf 0.23 (20% Me2CO/hexanes); IR νmax (thin
film) 2967, 2936, 2879, 2838, 1704, 1554, 1511, 1365, 1247, 1177,
1027 cm−1; 1H NMR (400 MHz, DMSO, 100 °C, signals at rt appear
broad due to atropisomerism) δ 1.00 (3H, t, J = 7.2), 1.73 (1H, app
dquint, J = 14.8, 7.6), 1.92 (1H, dqd, J = 12.0, 7.2, 5.6), 3.28 (1H, ddd,
J = 12.0, 8.0, 6.4), 3.63 (3H, s), 5.11 (1H, app t, J = 5.6), 6.00 (1H, d, J
= 5.2), 6.76−6.80 (2H, m), 7.14−7.23 (2H, m), 7.23−7.34 (2H, m),
7.53 (2H, m); 13C NMR (125 MHz, CDCl3) δ 11.6 (CH3), 24.4
(CH2), 51.2 (CH), 55.5 (CH3), 64.7 (CH), 88.5 (CH), 114.4 (2 ×
CH), 123.18 (Cq), 124.0 (CH), 127.5 (Cq), 128.3 (Cq), 129.7 (2 ×
CH), 130.6 (CH), 133.9 (CH), 136.3 (CH), 157.6 (Cq), 171.7 (Cq);
m/z (ESI+) 419 (5% M + H+), 372 (100%, M+ − NO2); HRMS found
419.0624, C19H20N2O4Br requires 419.0606. Anal. Calcd for
C19H19BrN2O4: C, 54.43, H, 4.57, N, 6.68. Found C, 54.67, H, 4.56,
N 6.65%.
5m. (3S*,4S*,5R*)-5-(3,5-Dichloro-phenyl)-3-ethyl-1-(4-me-
thyoxy-phenyl)-4-nitro-pyrrolidin-2-one (232 mg, 83%) as a white
solid; prepared by general procedure A; mp 70−72 °C, Rf 0.14 (20%
Me2CO/hexanes); IR νmax (thin film) 2968, 2838, 1707, 1557, 1513,
1
1440, 1386, 1366, 1249 cm−1; H NMR (400 MHz, CDCl3) δ 1.11
(3H, t, J = 7.4), 1.83 (1H, app dquint, J = 14.8, 7.4), 2.15 (1H, dqd, J =
15.1, 7.6, 4.9), 3.33 (1H, ddd, J = 8.2, 7.0, 4.8), 3.77 (3H, s), 4.74 (1H,
dd, J = 7.0, 5.4), 5.56 (1H, d, J = 5.5), 6.82−6.86 (2H, m), 7.11 (2H, d,
J = 2.0), 7.20−7.24 (2H, m), 7.31 (1H, t, J = 2.0); 13C NMR (125
MHz, CDCl3) δ 10.9 (CH3), 23.4 (CH2), 48.9 (CH), 55.5 (CH3), 64.7
(CH), 89.8 (CH), 114.6 (2 × CH), 124.9 (2 × CH), 125.3 (2 × CH),
128.8 (Cq), 129.7 (CH), 136.3 (2 × Cq), 140.9 (Cq), 158.0 (Cq),
170.8 (Cq); m/z (ESI+) 408 (100%, M+), 363 (78%, M+ − NO2);
HRMS found 408.0636, C19H18N2O4Cl2 requires 408.0638. Anal.
Calcd for C19H18N2O4Cl2: C, 55.76, H, 4.43, N, 6.84. Found C, 55.44,
H, 4.36, N, 6.74%.
5i. (3S*,4S*,5R*)-3-Ethyl-1-(4-methoxy-phenyl)-4-nitro-5-m-
tolyl-pyrrolidin-2-one (175 mg, 72%) as an off white solid; prepared
by general procedure A; mp 109−111 °C; Rf 0.32 (20% Me2CO/
hexanes); IR νmax (thin film) 2966, 2938, 1704, 1556, 1517, 1367,
1
1248, 1182, 1032, 830 cm−1; H NMR (400 MHz, CDCl3) δ 1.09
(3H, t, J = 7.4), 1.82 (1H, app dquint, J = 14.3, 7.5), 2.13 (1H, dqd, J =
14.2, 7.5, 4.8), 2.31 (3H, s), 3.31 (1H, ddd, J = 8.4, 6.8, 4.7), 3.74 (3H,
s), 4.79 (1H, dd, J = 6.8, 5.4), 5.56 (1H, d, J = 5.4), 6.78−6.82 (2H,
m), 7.08−7.15 (4H, m), 7.23−7.27 (2H, m); 13C NMR (125 MHz,
CDCl3) δ 10.5 (CH3), 20.8 (CH3), 23.0 (CH2), 48.9 (CH), 55.0
(CH3), 65.4 (CH), 90.3 (CH), 113.8 (2 × CH), 124.6 (2 × CH),
126.2 (2 × CH), 129.2 (Cq), 129.7 (2 × CH), 133.9 (Cq), 138.8 (Cq),
157.2 (Cq), 170.6 (Cq); m/z (ESI+) 355 (10%, M + H+), 308 (100%,
M − NO2); HRMS found 377.1471, C20H22N2O4Na requires
377.1477.
5j. (3S*,4S*,5R*)-3-Ethyl-1-(4-methoxy-phenyl)-5 (2-methoxy-
phenyl)-4-nitro-pyrrolidin-2-one (125 mg, 49%) as an off white
solid; prepared by general procedure A; mp 114−116 °C; Rf 0.27
(20% Me2CO/hexanes); IR νma1x (thin film) 2967, 2937, 2838, 1701,
1553, 1512, 1244, 1027 cm−1; H NMR (400 MHz, CDCl3) δ 1.06
(3H, t, J = 7.5), 1.69 (1H, ddq, J = 14.2, 9.1, 7.3), 2.09 (1H, dqd, J =
14.1, 7.8, 4.7), 3.15 (1H, app dt, J = 9.4, 4.9), 3.73 (3H, s), 3.84 (3H,
s), 4.89 (1H, app t, J = 4.4), 5.92 (1H, d, J = 4.0), 6.78−6.82 (2H, m),
6.89 (2H, d, J = 8.0), 7.05 (1H, dd, J = 7.6, 1.6), 7.25−7.29 (1H, m),
7.33−7.37 (2H, m); 13C NMR (125 MHz, CDCl3) δ 11.4 (CH3), 24.0
(CH2), 50.6 (CH), 55.5 (CH3), 55.5 (CH3), 62.3 (CH), 77.4 (Cq),
88.8 (CH), 111.0 (2 × CH), 114.2 (2 × CH), 120.9 (CH), 124.4
(CH), 124.9 (Cq), 128.5 (CH), 130.2 (CH), 156.7 (Cq), 157.4 (Cq),
171.7 (Cq); m/z (CI+) 370 (100%, M+), 370 (20%, M + H+); HRMS
found 370.1515, C20H22N2O5 requires 370.1523.
5n. (3S*,4S*,5R*)-5-(2-Bromo-5-fluoro-phenyl)-3-ethyl-1-(4-
methyoxy-phenyl)-4-nitro-pyrrolidin-2-one (169 mg, 56%) as a
white solid; prepared by general procedure A; mp 150−152 °C; Rf
0.20 (20% Me2CO/hexanes); IR νmax (thin film) 2968, 2838, 1709,
1
1558, 1513, 1466, 1387, 1367, 1250, 1031, 831 cm−1; H NMR (400
MHz, D6C2SO, 100 °C, at rt signals appeared broad due to
atropisomerism) δ 0.68 (3H, t, J = 7.5), 1.43 (1H, app dquint, J =
14.8, 7.4), 1.61 (1H, app dquint, J = 13.2, 6.5), 2.97 (1H app q, J =
6.8), 3.32 (3H, s), 4.87 (1H, app t, J = 6.3), 5.66 (1H, d, J = 5.5), 6.46
(2H, d, J = 8.8), 6.69−6.74 (1H, m), 6.87 (3H, d, J = 8.8), 7.24 (1H,
dd, J = 8.4, 5.2); 13C NMR (125 MHz, CDCl3) δ 11.6 (CH3), 24.5
(CH2), 51.0 (CH), 55.5 (CH3), 64.5 (CH), 88.3 (CH), 114.5 (2 ×
CH), 117.2 (Cq), 118.1 (2C, d, J = 22.0, CHCF), 124.0 (2 × CH),
129.3 (Cq), 135.3 (CH), 138.7 (Cq), 157.8 (Cq), 162.3 (1C, d, J =
248.5, CF), 171.5 (Cq); 19F NMR (282 MHz, CDCl3) δ −111.8 (1F,
s, CF); m/z (ESI+) 437 (100%, M + H+), 391 (86%, MH+ − NO2);
HRMS found 436.0424, C19H18N2O4BrF requires 436.0429, Anal.
Calcd for C19H18N2O4BrF: C, 52.19, H, 4.15, N, 6.41. Found C, 52.00,
H, 4.11, N, 6.25%.
5o. (3S*,4S*,5S*)-3-Ethyl-5-(furan-2-yl)-1-(4-methoxyphenyl)-
4-nitropyrrolidin-2-one (155 mg, 68%) as an off white solid;
prepared by general procedure A; mp 87−88 °C; Rf 0.33 (20%
Me2CO/hexanes); IR νmax (thin film) 2967, 2937, 1703, 1556, 1513,
1385, 1369, 1248 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.15 (3H, t, J
= 7.6), 1.93 (1H, ddq, J = 14.4, 8.5, 7.4), 2.17 (1H, dqd, J = 14.2, 7.6,
4.9), 3.24 (1H, ddd, J = 8.7, 5.9, 4.9), 3.77 (3H, s), 5.12 (1H, dd, J =
5.9, 4.9), 5.55 (1H, d, J = 4.7), 6.27−6.30 (2H, m), 6.83−6.85 (2H,
m), 7.07−7.10 (2H, m), 7.46 (1H, m); 13C NMR (125 MHz, CDCl3)
δ 11.0 (CH3), 23.3 (CH2), 49.3 (CH), 55.5 (CH3), 60.3 (CH), 86.7
(CH), 110.9 (CH), 111.5 (CH), 114.4 (2 × CH), 126.6 (2 × CH),
5k. (3S*,4S*,5R*)-3-Ethyl-1-(4-methoxy-phenyl)-4-nitro-5-o-
tolyl-pyrrolidin-2-one (112 mg, 46%) as an off white solid; prepared
by general procedure A; mp 102−104 °C; Rf 0.38 (20% Me2CO/
hexanes); IR νmax (thin film) 2968, 2935, 1705, 1555, 1513, 1367,
1
1249 cm−1; H NMR (400 MHz, CDCl3, 60 °C, signals at rt appear
broad due to atropisomerism) δ 1.08 (3H, t, J = 7.4), 1.77 (1H, ddq, J
= 14.3, 8.6, 7.3), 2.15 (1H, dqd, J = 14.3, 7.6, 5.2), 2.36 (3H, s), 3.25
(1H, app Dt, J = 8.7, 5.2), 3.75 (3H, s), 4.81 (1H, dd, J = 5.3, 4.3),
5.91 (1H, d, J = 4.3), 6.78−6.80 (2H, m), 7.11 (1H, d, J = 4.8), 7.14−
G
dx.doi.org/10.1021/jo301000r | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
128.8 (Cq), 143.8 (CH), 148.1 (Cq), 158.6 (Cq), 170.8 (Cq); m/z
(ESI+) 353 (100%, M + Na+), 331 (81%, M + H+), 284 (78%, M −
NO2); HRMS found 353.1125, C17H18N2O5Na requires 353.1113.
5p. (3S*,4S*,5R*)-3-Ethyl-5-furan-3-yl-1-(4-methoxy-phenyl)-4-
nitro-pyrrolidin-2-one (143 mg, 70%) as an orange solid; prepared by
general procedure A; mp 116−118 °C; Rf 0.25 (20% Me2CO/
hexanes); IR νmax (thin film) 2968, 2938, 2884, 1702, 1555, 1512,
1366, 1248, 1024 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.11 (3H, t, J
= 7.5), 1.85 (1H, app dquint, J = 14.8, 7.4), 2.13 (1H, dqd, J = 14.2,
7.4, 4.7), 3.29 (1H ddd, J = 8.2, 7.1, 4.8), 3.76 (3H, s), 4.84 (1H, dd, J
= 7.0, 5.6), 5.55 (1H, d, J = 5.5), 6.25 (1H, m), 6.81−6.86 (2H, m),
7.14−7.21 (2H, m), 7.33 (1H, s), 7.38 (1H, t, J = 1.6); 13C NMR (125
MHz, CDCl3) δ 10.8 (CH3), 23.3 (CH2), 49.0 (CH), 55.5 (CH3), 58.4
(CH), 89.5 (CH), 107.8 (CH), 114.6 (2 × CH), 122.4 (Cq), 125.8 (2
× CH), 129.0 (Cq), 141.4 (CH), 144.8 (CH), 158.1 (Cq), 170.6 (Cq);
m/z (CI+) 331 (100%, M + H+); HRMS found 331.1294, C17H19N2O5
requires 331.1291. Anal. Calcd for C17H18N2O5: C, 61.81, H, 5.49, N,
8.48. Found C, 61.62, H, 5.41, N, 8.35%.
5q. (3R,4R,5R)-3-Ethyl-1-(4-methoxy-phenyl)-4-nitro-5-thio-
phen-2-yl-pyrrolidin-2-one (152 mg, 64%) as an off white solid;
prepared by general procedure A; mp 90−92 °C; Rf 0.32 (20%
Me2CO/hexanes); IR νmax (thin film) 2967, 2936, 1701, 1553, 1511,
1362, 1246, 1030, cm−1; 1H NMR (400 MHz, CDCl3) δ 1.12 (3H, t, J
= 7.4), 1.91 (1H, app dquint, J = 15.0, 7.4), 2.16 (1H, dqd, J = 14.2,
7.5, 5.2), 3.29 (1H, ddd, J = 8.1, 6.8, 4.9), 3.75 (3H, s), 4.94 (1H, dd, J
= 6.4, 5.4), 5.89 (1H, d, J = 5.1), 6.83 (2H, app d, J = 8.8), 6.91 (1H,
dd, J = 4.0, 1.4), 7.01 (1H, d, J = 2.8), 7.23 (2H, app d, J = 9.2), 7.27
(1H, d, J = 4.4); 13C NMR (125 MHz, CDCl3) δ 10.8 (CH3), 23.5
(CH2), 49.2 (CH), 55.4 (CH3), 62.0 (CH), 90.6 (CH), 114.6 (2 ×
CH), 125.9 (2 × CH), 127.0 (CH), 127.3 (CH), 127.8 (CH), 129.0
(Cq), 140.6 (Cq), 158.1 (Cq), 170.5 (Cq); m/z (ESI+) 369 (90%, M +
Na+), 300 (100%, M+ − NO2); HRMS found 369.0888,
C17H18N2O4NaS requires 369.0885. Anal. Calcd for C17H18N2O4S:
C, 58.94, H, 5.24, N, 8.09. Found C, 58.84, H, 5.19, N, 8.04%.
Asymmetric sample prepared by general procedure B to give 5q
(149 mg, 74%) as a pale yellow solid identical to the racemic sample;
[α]D −48.1 (c 1, CHCl3, 20 °C); HPLC (chiralcel AD 0.46 × 25 cm
column, 90:10 hexane/IPA, 1 mL min−1) 38.8 min (major), 46.4 min
(minor) measured 89% ee.
5r. (3S*,4S*,5S*)-3-Ethyl-1-(4-methoxyphenyl)-4-nitro-5-(pyri-
din-2-yl)pyrrolidin-2-one (118 mg, 50%) as a white solid; prepared
by general procedure A; mp 115−117 °C (Et2O/pentane); Rf 0.08
(20% Me2CO/hexane); IR νmax (thin film) 3026, 2975, 1691, 1550,
1517, 1393, 1366, 1292, 1252, 1224, 1206, 1029, 755, cm−1; 1H NMR
(600 MHz, CDCl3) δ 1.11 (3H, t, J = 7.35), 1.89 (1H, ddq, 14.7, 9.0,
7.4), 2.15 (1H, dqd, J = 14.3, 7.6, 4.8), 3.27 (1H, ddd, J = 9.0, 5.8, 4.8),
3.73 (3H, s), 5.26 (1H, dd, J = 5.8, 4.4), 5.64 (1H, d, J = 4.4), 6.78
(2H, d, J = 9.1), 7.11 (1H, d, J = 7.8), 7.14 (2H, d, J = 9.1), 7.23 (1H,
ddd, J = 7.5, 4.5, 0.7), 7.60 (1H, td, J = 7.7, 1.7), 8.63 (1H, m); 13C
NMR (150 MHz, CDCl3) δ 11.3 (CH3), 23.6 (CH2), 49.5 (CH), 55.5
(CH3), 67.2 (CH), 87.9 (CH), 114.4 (2 × CH), 123.2 (2 × CH),
123.9 (CH), 126.0 (CH), 129.4 (Cq), 137.1 (CH), 150.7 (CH), 155.8
(CH), 158.1 (Cq), 171.6 (Cq).; m/z (CI+) 342 (100%, M + H+);
HRMS found 342.1450, C18H20N3O4 requires 342.1448. Anal. Calcd
for C18H19N3O4: C, 63.33, H, 5.61, N, 12.31. Found C, 63.04, H, 5.56,
N, 12.11%.
5s. (3S*,4S*,5R*)-3-Ethyl-1-(4-methoxyphenyl)-4-nitro-5-(pyri-
din-3-yl)pyrrolidin-2-one (99 mg, 42%) as a white solid; prepared by
general procedure A; mp 91−93 °C; Rf 0.05 (20% Me2CO/hexane);
IR νmax (thin film) 2963, 1709, 1550, 1511, 1362, 1252, 1184, 1035,
1025, 832, 712, cm−1; 1H NMR (600 MHz, CDCl3) δ 1.11 (3H, t, J =
7.7), 1.88 (1H, ddq, J = 14.4, 8.0, 4.9), 2.15 (1H, dqd, J = 14.1, 7.5,
4.8), 3.38 (1H, ddd, J = 8.0, 7.3, 4.7), 3.74 (3H, s), 4.80 (1H, dd, J =
7.2, 5.7), 5.65 (1H, d, J = 5.9), 6.80 (2H, d, J = 9.2), 7.20 (2H, m),
7.28 (1H, d, J = 9.2), 7.53 (1H, dt, J = 7.9, 1.9), 8.54 (1H, d, J = 2.1),
8.57 (1H, dd, J = 4.8, 1.4); 13C NMR (150 MHz, CDCl3) δ 10.7
(CH3), 23.2 (CH2), 48.8 (CH), 55.5 (CH3), 63.6 (CH), 89.9 (CH),
114.6 (2 × CH), 124.2 (2 × CH), 125.3 (CH), 128.7 (CH), 133.0
(Cq), 134.4 (CH), 148.8 (CH), 150.8 (CH), 158.0 (Cq), 170.7 (Cq).;
m/z (CI+) 342 (100%, M + H+), 295 (10%); HRMS found 342.1461,
C18H20N3O4 requires 342.1458. Anal. Calcd for C18H19N3O4: C, 63.33,
H, 5.61, N, 12.31. Found C, 63.36, H, 5.62, N, 12.24%.
5u. (3S*,4S*,5R*)-3-Ethyl-1-(4-methoxyphenyl)-4-nitro-5-(1-
tosyl-1H-indol-3-yl)pyrrolidin-2-one (206 mg, 56%) as a yellow
solid; mp 131−132 °C; Rf 0.08 (20% Me2CO/hexane); IR νmax (thin
film) 3104, 2935, 1709, 1553, 1511, 1445, 1363, 1350, 1244, 1174,
1
828, 746, 678 cm−1; H NMR (600 MHz, CDCl3) δ 1.08 (3H, t, J =
7.4), 1.82 (1H, ddq, J = 14.2, 8.5, 7.2), 2.15 (1H, dqd, J = 14.2, 7.6,
4.8), 2.43 (3H, s), 3.38 (1H, ddd, J = 8.5, 6.7, 4.8), 3.76 (3H, s), 4.97
(1H, dd, J = 6.7, 5.2), 5.83 (1H, d, J = 5.3), 6.76 (2H, d, J = 9.0), 7.13
(2H, d, J = 8.4), 7.25 (2H, d, J = 9.0), 7.29 (1H, m), 7.35 (1H, m),
7.46 (4H, m), 7.93 (1H, d, J = 8.4); 13C NMR (150 MHz, CDCl3) δ
11.1 (CH3), 21.7 (CH3), 23.6 (CH2), 49.2 (CH), 55.5 (CH3), 59.5
(CH), 88.2 (CH), 114.3 (2 × CH), 114.4 (CH), 118.3 (Cq), 119.2
(CH), 124.2 (CH), 124.8 (2 × CH), 125.8 (CH), 126.1 (CH), 126.8
(2 × CH), 127.5 (Cq), 129.3 (Cq), 130.0 (2 × CH), 134.5 (Cq), 135.7
(Cq), 145.4 (Cq), 157.8 (Cq), 170.7 (Cq).; m/z (ESI+) 534 (100%, M
+ H+); HRMS found 534.1674, C28H28N3O6S requires 534.1699.
5w. (3S*,4S*,5S*)-3-Ethyl-1-(4-methoxyphenyl)-4-nitro-5-(1-
tosyl-1H-pyrrol-2-yl)pyrrolidin-2-one (110 mg, 33%), as a yellow
solid; inseparable 85:15 mixture of diastereoisomers (diastereoisomer
ratio calculated by CHEt signal, δ major = 2.86, δ minor = 3.01);
prepared by general procedure A; mp 147−148 °C; Rf 0.18 (20%
Me2CO/hexane); IR νmax (thin film) 3004, 2994, 2878, 1699, 1550,
1512, 1368, 1248, 1172, 1154, 833, 816, 736, 703, 671 cm−1; 1H NMR
(600 MHz, CDCl3) δ 1.13 (3H, t, J = 7.4), 1.59 (1H, m), 2.12 (1H,
dqd, J = 14.8, 7.4, 4.8), 2.50 (3H, s), 2.86 (1H, m), 3.74 (3H, s), 4.94
(1H, s), 6.02 (1H, s), 6.10 (1H, s), 6.22 (1H, t, J = 3.4), 6.58 (2H, d, J
= 9.1), 6.91 (2H, d, J = 9.2), 7.38 (3H, m), 7.63 (2H, d, J = 8.2); 13C
NMR (150 MHz, CDCl3) δ 12.0 (CH3), 21.7 (CH3), 25.5 (CH2), 52.3
(CH), 55.3 (CH3), 59.4 (CH), 86.4 (CH), 111.7 (2 × CH), 113.9 (2 ×
CH), 114.9 (CH), 123.2 (2 × CH), 124.0 (CH), 126.9 (CH), 128.3
(CH), 129.8 (CH), 130.5 (2 × CH), 135.3 (Cq), 145.9 (Cq), 157.1
(Cq), 171.6 (Cq); m/z (EI+) 483 (20%, M+), 281 (24%), 155 (22%,
+
Ts+), 91 (100%, PhCH2 ); HRMS found 483.1451, C24H25N3O6S
requires 483.1464. Anal. Calcd for C24H25N3O6S: C, 59.61, H, 5.21, N,
8.69. Found C, 59.52, H, 5.20, N, 8.61.
1
Minor diastereomer: H NMR (600 MHz, CDCl3) δ 1.12 (3H, t, J
= 7.4), 1.33 (1H, m), 2.12 (1H, m), 2.47 (3H, s), 3.01 (1H, ddd, J =
9.6, 7.3, 4.6), 3.74 (3H, s), 5.73 (1H, s), 6.20 (1H, s), 6.22 (1H, s),
6.27 (1H, t, J = 3.4), 6.61 (2H, d, J = 9.1), 6.98 (2H, d, J = 9.0), 7.38
(3H, m), 7.60 (2H, d, J = 8.2); 13C NMR (150 MHz, CDCl3) δ
12.2(CH3), 18.9 (CH), 21.7 (CH3), 45.8 (CH), 55.3 (CH3), 60.0
(CH), 86.6 (CH), 112.0 (2 × CH), 113.9 (2 × CH), 114.6 (CH),
123.2 (CH), 124.4 (CH), 126.7 (2 × CH), 129.6 (CH), 130.3 (CH),
171.0 (Cq), 4 carbons missing.
5x. (3S*,4S*,5S*)-3-Ethyl-1-(4-methoxyphenyl)-4-nitro-5-(thia-
zol-2-yl)pyrrolidin-2-one (139 mg, 58%) as a yellow solid; prepared
by general procedure A; mp 121−122 °C; Rf 0.31 (30% EtOAc/
hexane); IR νmax (thin film) 2961, 1716, 1558, 1512, 1440, 1390, 1363,
1248, 1187, 1029, 833, 782, 752 cm−1; 1H NMR (600 MHz, CDCl3) δ
1.14 (3H, t, J = 7.1), 1.90 (1H, ddq, J = 14.3, 8.9, 7.1), 2.15 (1H, dqd, J
= 14.0, 7.6, 4.9), 3.25 (1H, dt, J = 9.0, 5.0), 3.78 (3H, s), 5.36 (1H, dd,
J = 5.1, 3.8), 6.02 (1H, d, J = 4.2), 6.87 (2H, d, J = 9.2), 7.25 (2H, d, J
= 9.2), 7.31 (1H, d, J = 3.0), 7.80 (1H, d, J = 3.4); 13C NMR (150
MHz, CDCl3) δ 11.2 (CH3), 23.7 (CH2), 49.7 (CH), 55.5 (CH3), 63.3
(CH), 87.4 (CH), 114.6 (2 × CH), 121.0 (CH), 126.4 (2 × CH),
128.7 (Cq), 143.6 (CH), 158.6 (Cq), 165.7 (Cq), 171.1 (Cq).; m/z
(EI+) 347 (100%, M+), 300 (55%, M+ − HNO2); HRMS found
347.0940, C16H17N3O4S requires 347.0934. Anal. Calcd for
C16H17N3O4S: C, 55.32, H, 4.93, N, 12.10. Found C, 55.23, H, 4.89,
N, 12.02%.
5y. (3S*,4S*,5S*)-3-Ethyl-1-(4-methoxyphenyl)-4-nitro-5-(oxa-
zol-2-yl)pyrrolidin-2-one (121 mg, 53%) as a white solid; prepared
by general procedure A; mp 97−98 °C; Rf 0.15 (20% Me2CO/
hexane); IR νmax (thin film) 3128, 2964, 1706, 1562, 1509, 1387, 1243,
1
1179, 1115, 1031, 834, 779.5 cm−1; H NMR (600 MHz, CDCl3) δ
1.17 (3H, t, J = 7.5), 1.96 (1H, ddq, J = 14.3, 8.7, 7.4), 2.19 (1H, dqd, J
= 14.3, 7.6, 4.9), 3.25 (1H, ddd, J = 8.7, 5.7, 4.9), 3.78 (3H, s), 5.28
(1H, dd, J = 5.6, 4.4), 5.79 (1H, d, J = 4.4), 6.86 (2H, d, J = 9.0), 7.11
H
dx.doi.org/10.1021/jo301000r | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(1H, s), 7.19 (2H, d, J = 9.0), 7.62 (1H, s); 13C NMR (150 MHz,
CDCl3) δ 11.1 (CH3), 23.4 (CH2), 49.2 (CH), 55.5 (CH3), 59.6
(CH), 85.6 (CH), 114.6 (2 × CH), 126.4 (2 × CH), 128.2 (CH),
128.6 (Cq), 140.5 (CH), 158.8 (Cq), 159.3 (Cq), 170.8 (Cq); m/z
(EI+) 331 (100%, M+), 284 (72%, M+ − HNO2); HRMS found
331.1155, C16H17N3O5 requires 331.1163. Anal. Calcd for
C16H17N3O5: C, 58.00, H, 5.17, N, 12.68. Found C, 57.97, H, 5.09,
N, 12.64%.
5z. (3S*,4S*,5R*)-5-Cyclohexyl-3-ethyl-1-(4-methoxy-phenyl)-4-
nitro-pyrrolidin-2-one (147 mg, 62%) as an off white solid; prepared
by general procedure A; mp 122−124 °C; Rf 0.35 (20% Me2CO/
hexanes); IR νmax (thin film) 2929, 2855, 1698, 1555, 1512, 1450,
1366, 1248, 1033 cm−1; 1H NMR (600 MHz, CDCl3) δ 0.81 (1H, dq,
J = 12.4, 3.3), 0.98 (1H, q, J = 12.6, 3.2), 1.10 (3H, t, J = 7.4), 1.05−
1.20 (3H, m), 1.51 (2H, d, J = 8.0), 1.64−1.74 (5H, m), 2.10 (1H,
dqd, J = 9.5, 7.6, 4.8), 3.11 (1H, ddd, J = 9.4, 6.0, 4.8), 3.83 (3H, s),
4.51 (1H, app t, J = 4.2), 4.81 (1H, app t, J = 5.4), 6.94 (2H, m), 7.23
(2H, m); 13C NMR (125 MHz, CDCl3) δ 11.2 (CH3), 23.4 (CH2),
25.6 (CH2), 25.8 (CH2), 26.1 (CH2), 26.2 (CH2), 28.5 (CH2), 38.1
(CH), 50.0 (CH), 55.6 (CH3), 66.8 (CH), 84.4 (CH), 114.7 (2 ×
CH), 126.6 (2 × CH), 129.0 (Cq), 158.4 (Cq), 171.0 (Cq); m/z
(FAB+) 369 (100% MNa+); HRMS found 369.1794, C19H26N2O4Na
requires 369.1790.
278.12611. Anal. Calcd for C14H18N2O4: C, 60.42, H, 6.52, N,
10.07. Found C, 60.31, H, 6.61, N, 9.77%.
5dd. (2S*,3S*,4S*)-3-Ethyl-5-(dimethoxymethyl)-1-(4-methoxy-
phenyl)-4-nitropyrrolidin-2-one (147 mg, 63%) as a white solid;
Prepared by general procedure A; mp 112−113 °C; Rf 0.41 (30%
EtOAc/hexanes); IR νmax (thin film) 2939, 1698, 1548, 1510, 1370,
1249, 1069, 1034, 834, 754 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.14
(3H, t, J = 7.4), 1.81 (1H, ddq, J = 14.0, 9.7, 7.2), 2.09 (1H, dqd, J =
14.0, 7.4, 4.3), 2.97 (1H, dt, J = 9.8, 4.6), 3.38 (3H, s), 3.40 (3H, s),
3.84 (3H, s), 4.24 (1H, d, J = 2.4), 4.76 (1H, dd, J = 3.2, 2.6), 5.07
(1H, dd, J = 4.9, 3.4), 6.97 (2H, d, J = 8.9), 7.30 (2H, d, J = 9.0); 13C
NMR (150 MHz, CDCl3) δ 11.3 (CH3), 23.1 (CH2), 50.2 (CH), 55.5
(CH3), 56.9 (CH3), 57.9 (CH3), 64.3 (CH), 82.1 (CH), 102.3 (CH),
114.7 (2 × CH), 126.2 (2 × CH), 128.8 (Cq), 158.3 (Cq), 171.7
(Cq).; m/z (EI+) 338 (75%, M+), 217 (85%, M+ − NO2
−CH(OMe)2), 114 (100%); HRMS found 338.1472, C16H22N2O6
requires 338.1478. Anal. Calcd for C16H22N2O6: C, 56.80, H, 6.55, N,
8.28. Found C, 56.70, H, 6.51, N, 8.11%.
5ee. (2S*,3S*,4S*)-4-Ethyl-1-(4-methoxy-phenyl)-3-nitro-5-oxo-
pyrrolidine-2-carboxylic Acid Ethyl Ester (160 mg, 69%) as an
orange oil; Prepared by general procedure A; Rf 0.35 (20% Me2CO/
hexanes); IR νmax (thin film) 2970, 2938, 2839, 1743, 1708, 1555,
1
1511, 1369, 1245, 1194, 1027 cm−1; H NMR (400 MHz, CDCl3) δ
5aa. (3S*,4S*,5R*)-3-Ethyl-5-isopropyl-1-(4-methoxy-phenyl)-4-
nitro-pyrrolidin-2-one (119 mg, 56%) as a white solid; prepared by
general procedure A; mp 116−118 °C; Rf 0.29 (20% Me2CO/
hexanes); IR νmax (thin film) 2966, 2937, 2878, 1702, 1557, 1513,
1.14 (3H, t, J = 7.5), 1.21 (3H, t, J = 7.3), 1.79 (1H, ddq, J = 14.7, 8.8,
7.3), 2.11 (1H, dqd, J = 15.2, 7.6, 5.1), 3.14 (1H, ddd, J = 9.2, 5.0, 4.3),
3.73 (3H, s), 4.21 (2H, dq, J = 7.1, 1.9), 4.99 (1H, dd, J = 4.2, 3.4),
5.21 (1H, d, J = 3.3), 6.93 (2H, m), 7.33 (2H, m); 13C NMR (125
MHz, CDCl3) δ 11.2 (CH3), 14.0 (CH3), 23.5 (CH2), 49.5 (CH), 55.5
(CH3), 61.5 (CH2), 62.9 (CH), 84.5 (CH), 114.5 (2 × CH), 125.9 (2
× CH), 129.2 (Cq), 158.6 (Cq), 168.5 (Cq), 171.3 (Cq); m/z (FAB+)
359 (100%, M + Na+); HRMS found 359.1223, C16H20N2O6Na
requires 359.1219.
1
1368, 1249, 1033, 836 cm−1; H NMR (400 MHz, CDCl3) δ 0.78
(3H, d, J = 6.8), 0.96 (3H, d, J = 6.8), 1.12 (3H, t, J = 7.3), 1.73 (1H,
ddq, J = 14.2, 9.0, 7.4), 2.04−2.18 (2H, m), 3.15 (1H, ddd, J = 9.1, 6.3,
4.6), 3.82 (3H, s), 4.56 (1H, dd, J = 5.1, 3.8), 4.76 (1H, dd, J = 6.3,
5.1), 6.93−6.96 (2H, m), 7.22−7.27 (2H, m); 13C NMR (125 MHz,
CDCl3) δ 11.1 (CH3), 14.9 (CH3), 17.7 (CH3), 23.3 (CH2), 27.7
(CH), 49.9 (CH), 55.6 (CH3), 66.9 (CH), 83.7 (CH), 114.2 (2 ×
CH), 126.3 (2 × CH), 128.8 (Cq), 158.4 (Cq), 170.9 (Cq); m/z (CI+)
307 (100%, MH+); HRMS found 307.1659, C16H23N2O4 requires
307.1658.
5ff. (3S*,4R*, 5R*)-1-(4-Methoxy-phenyl)-3-methyl-4-nitro-5-
phenyl-pyrrolidin-2-one (143 mg, 64%) as a white solid; prepared
by general procedure A, except dimethylzinc was used; mp 114−116
°C; Rf 0.23 (20% Me2CO/hexanes); IR νmax (thin film) 2938, 2837,
1
1702, 1552, 1500, 1244, 1779, 1031, 831 cm−1; H NMR (400 MHz,
5bb. (3S*,4S*,5R*)-3-Ethyl-1-(4-methoxy-phenyl)-4-nitro-5-
pentyl-pyrrolidin-2-one (88 mg, 38%) as an orange oil; prepared by
general procedure A; Rf 0.29 (20% Me2CO/hexanes); IR νmax (thin
CDCl3) δ 1.54 (3H, d, J = 7.3), 3.38 (1H, quint, J = 7.3), 3.73 (3H, s),
4.73 (1H, dd, J = 7.3, 5.8), 5.63 (1H, d, J = 5.9), 6.77−6.81 (2H, m),
7.22−7.37 (7H, m); 13C NMR (125 MHz, CDCl3) δ 15.1 (CH3), 42.6
(CH), 55.0 (CH3), 65.1 (CH), 92.4 (CH), 113.9 (2 × CH), 124.6 (2 ×
CH), 126.4 (2 × CH), 128.8 (CH), 129.0 (Cq), 129.1 (2 × CH),
136.6 (Cq), 157.2 (Cq), 171.0 (Cq); m/z (ESI+) 326 (100%, M+);
HRMS found 326.1255, C18H18N2O4 requires 326.1261. Anal. Calcd
for C18H18N2O4: C, 66.25, H, 5.56, N, 8.58. Found C, 66.07, H, 5.54,
N, 8.38%.
1
film) 2958, 2861, 1699, 1552, 1511 1247, 1032 cm−1; H NMR (600
MHz, CDCl3) δ 0.82 (3H, t, J = 6.9), 1.10 (3H, t, J = 7.4), 1.16−1.30
(6H, m), 1.44−1.50 (1H, m), 1.73−1.81 (2H, m), 2.09 (1H, dqd, J =
15.0, 7.6, 4.8), 3.19 (1H ddd, J = 8.7, 6.0, 5.0), 3.81 (3H, s), 4.48 (1H,
ddd, J = 8.5, 4.5, 3.5), 4.71 (1H, dd, J = 5.9, 5.2), 6.92−6.94 (2H, m),
7.20−7.21 (2H, m); 13C NMR (125 MHz, CDCl3) δ 11.0 (CH3), 13.9
(CH3) 22.4 (CH2), 23.6 (CH2), 23.7 (CH2), 31.4 (CH2), 32.5 (CH2),
49.5 (CH), 55.6 (CH3), 62.5 (CH), 87.4 (CH), 114.7 (2 × CH), 126.6
(2 × CH), 128.9 (Cq), 158.5 (Cq), 170.8 (Cq), m/z (CI+) 335 (100%,
MH+); HRMS found 335.1962, C18H27N2O4 requires 335.1971. Anal.
Calcd for C18H26N2O4: C, 58.00, H, 5.17, N, 12.68. Found C, 57.97,
H, 5.09, N, 12.64%.
5cc. (3S*,4S*,5R*)-3-Ethyl-1-(4-methoxyphenyl)-5-methyl-4-ni-
tropyrrolidin-2-one (78 mg, 40%) as a colorless oil. Prepared by
general procedure A, with the exception that acetaldehyde imine was
formed and used in situ. To a solution of acetaldehyde (77 μL, 1.38
mmol) in THF (3 mL) were added under N2 dried 4 Å molecular
sieves (1.4 g) and the mixture cooled at −78 °C. Then a solution of p-
anisidine (170 mg, 1.38 mmol) in THF (1 mL) was added and the
mixture stirred at this temperature for 1.5 h. The solution was then
transferred into the reaction via cannula while kept cold. Rf 0.22 (20%
EtOAc/hexanes); IR νmax (thin film) 2967, 1702, 1554, 1513, 1368,
1248, 1033, 834 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.07 (3H, t, J =
7.4), 1.35 (3H, d, J = 6.3), 1.79 (1H, m), 2.08 (1H, m), 3.26 (1H, ddd,
J = 8.3, 7.3, 4.7), 3.81 (3H, s), 4.49 (1H, app q, J = 6.2), 4.60 (1H, dd,
J = 7.2, 5.7), 6.93 (2H, app d, J = 8.9), 7.18 (2H, app d, J = 8.9); 13C
NMR (125 MHz, CDCl3) δ 10.6 (CH3), 19.3 (CH3), 23.1 (CH2),48.5
(CH), 55.4 (CH3), 58.0 (CH), 89.3 (CH), 114.5 (2 × CH), 126.6 (2 ×
CH), 128.4 (Cq), 158.4 (Cq), 170.4 (Cq), m/z (EI+) 278 (5%, M+),
91 (100%); HRMS found 278.12631, C14H18N2O4 requires
5gg. (3S*,4S*,5R*)-3-Isopropyl-1-(4-methoxyphenyl)-4-nitro-5-
phenylpyrrolidin-2-one (125 mg, 51%) as a white solid; prepared by
general procedure A, except diisopropylzinc was used; mp 140−141
°C; Rf 0.50 (20% EtAc/hexanes); IR νmax (thin film) 2962, 1708, 1557,
1
1513, 1369, 1249, 1032, 700 cm−1; H NMR (600 MHz, CDCl3) δ
1.07 (6H, dd, J = 8.3, 7.0), 2.55 (1H, m), 3.43 (1H, dd, J = 7.6, 4.5),
3.73 (3H, s), 4.88 (1H, dd, J = 7.6, 5.9), 5.52 (1H, d, J = 5.9), 6.79
(2H, app d, J = 9.1), 7.19 (2H, m), 7.23 (2H, app d, J = 9.1), 7.28−
7.35 (3H, m); 13C NMR (150 MHz, CDCl3) δ 18.3 (CH3), 19.6
(CH3), 28.0 (CH), 53.3 (CH), 55.3 (CH3), 65.9 (CH), 88.4 (CH),
114.1 (2 × CH), 125.0 (2 × CH), 126.6 (2 × CH), 129.1 (CH), 129.2
(Cq), 129.3 (2 × CH), 137.2 (Cq), 157.5 (Cq), 170.5 (Cq).; m/z
(ESI+) 355 (M + H+, 20%), 308 (M+ − NO2, 100%); HRMS found
355.1647, C20H23N2O4 requires 355.1658. Anal. Calcd for
C20H22N2O4: C, 67.78, H, 6.26, N, 7.90. Found C, 67.70, H, 6.22,
N, 7.84%.
5hh. (3S*,4S*,5R*)-1-(4-Methoxyphenyl)-4-nitro-3,5-diphenyl-
pyrrolidin-2-one. To a solution of nitroalkene 1 (100 mg, 0.69
mmol) in THF (3 mL) under N2 was added Cu(OTf)2 (12 mg, 34.0
μmol, 5 mol %). The mixture was cooled to −78 °C, and the
diphenylzinc solution (0.76 mmol, 1.1 equiv) was added quickly
dropwise. The orange mixture was stirred at this temperature for 10
min before being warmed to rt and stirred for a further 1.5 h. Saturated
aq NH4Cl and Et2O were then added, and the layers were separated.
I
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The Journal of Organic Chemistry
Article
The aqueous phase was extracted with Et2O, and the combined
organics were washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo to leave crude nitroalkane. Purification by flash
column chromatography (10% Et2O/hexanes) gave ethyl 3-nitro-2-
phenylpropanoate (92 mg, 60%) as a colorless oil; Rf 0.35 (10% Et2O/
3.6, 1.3), 7.12 (2H, app d, J = 8.9), 7.18 (1H, d, J = 5.0); 13C NMR
(150 MHz, CDCl3) δ 11.0 (CH3), 22.9 (CH2), 51.2 (CH), 55.1
(CH3), 61.1 (CH), 67.1 (CH), 113.7 (2 × CH), 125.6 (2 × CH),
125.8 (CH), 126.6 (CH), 126.8 (CH), 130.0 (Cq), 142.4 (Cq), 157.2
(Cq), 173.9 (Cq); m/z (ESI+) 317 (71%, M + H+), 206 (100%);
HRMS found 317.1321, C17H21N2O2S requires 317.1324. Anal. Calcd
for C17H20N2O2S: C, 64.53, H, 6.37, N, 8.85. Found C, 64.68, H, 6.56,
N, 8.77%.
25
1
hexanes); H NMR was in agreement with the literature.
A solution of ethyl 3-nitro-2-phenylpropanoate (121 mg, 0.54
mmol) in THF (3 mL), under N2 was cooled to −78 °C, and a
n
solution of BuLi (0.32 mL, 0.54 mmol, 1.0 equiv, 1.7 M solution in
To a solution of the diamine (3R, 4R, 5R)-4-amino-3-ethyl-1-(4-
methoxyphenyl)-5-(thiophen-2-yl)pyrrolidin-2-one (127 mg, 0.41
mmol) in DCM (4 mL) under N2 at 0 °C, was added trifluoroacetic
anhydride (0.28 mL, 2.05 mmol, 5 equiv) followed by pyridine (0.16
mL, 2.05 mmol, 5 equiv). The mixture was then warmed to rt and
stirred for a further 2 h. Then 2 M aq HCl and CH2Cl2 were added,
and the layers were separated. The aqueous layer was extracted with
CH2Cl2 and the combined organics washed with satd aq NaHCO3,
dried (MgSO4), filtered, and concentrated in vacuo to give crude
trifluoroacetamide 9. Purification by flash column chromatography
(30% Me2CO/hexanes) gave trifluoroacetamide 9 (136 mg, 82%) as a
white solid; mp 139−140 °C; Rf 0.46 (30% Me2CO/hexanes); HPLC
(chiralcel AD 0.46 × 25 cm column, 90:10 hexane/IPA, 1 mL min−1)
10.9 min (major), 20.4 min (minor) measured 87% ee; IR νmax (thin
film) 3257, 3089, 1720, 1672, 1515, 1254, 1212, 1168, 1030, 845, 693
cm−1; 1H NMR (600 MHz, CDCl3) δ 0.96 (3H, t, J = 7.4), 1.65 (1H,
m), 1.87 (1H, m), 2.25 (1H, dt, J = 8.7, 5.5), 3.74 (3H, s), 4.36 (1H,
app dt, J = 8.7, 5.3), 5.18 (1H, d, J = 4.7), 6.81 (2H, app d, J = 8.9),
6.85 (1H, m), 6.89 (1H, m), 7.15 (2H, app d, J = 8.9), 7.19 (1H, d, J =
5.0), 8.26 (1H, d, J = 8.7); 13C NMR (150 MHz, CDCl3) δ 11.2
(CH3), 23.7 (CH2), 49.4 (CH), 55.3 (CH3), 56.9 (CH), 65.0 (CH),
114.1 (2 × CH), 125.6 (CH), 115.7 (q, J = 288, CF3), 126.0 (2 × CH),
126.5 (CH), 126.9 (CH), 129.2 (Cq), 141.3 (Cq), 157.0 (q, J = 38,
CF3CO), 157.9 (Cq), 173.6 (Cq); 19F NMR (282 MHz, CDCl3) δ
−76.0 (3F, s, CF3); m/z (ESI+) 413 (100%, M + H+), 300 (30%, M+-
NHTFA); HRMS found 413.1139, C19H20F3N2O3S requires 413.1147.
Anal. Calcd for C19H19F3N2O3S: C, 55.33, H, 4.64, N, 6.79. Found C,
55.24, H, 4.59, N, 6.69%. Recrystallization of the sample with Et2O/
hexane gave 9 (111 mg, 73% overall yield) as an identical white solid;
[α]D +14.7 (c 1.00, CHCl3, 20 °C); HPLC measured 99% ee.
syn,anti-10a (2S*,3R*,4S*)-2-Ethyl-4[(4-methoxyphenyl-(2,2,2-
trifluoro-acetyl)-amino]-3-nitro-4-phenyl-butyric Acid Ethyl Ester
and syn,syn-10a (2S*,3R*,4R*)-2-Ethyl-4[(4-methoxyphenyl-(2,2,2-
trifluoro-acetyl)-amino]-3-nitro-4-phenyl-butyric Acid Ethyl Ester.
According to general procedure A but quenching the reaction with
saturated NaHCO3 solution 5 min after removing the −78 °C cooling
bath. After workup the crude mixture was dissolved in CH2Cl2 (10
mL) and cooled to −78 °C, and DIPEA (1.48 mmol, 0.25 mL) and
TFAA (1.48 mmol, 0.20 mL) were added. The reaction was warmed
to rt and stirred for 30 min. The organic solution was then washed
with 2 M HCl, H2O, dried (MgSO4), filtered, and evaporated to
dryness. Purification by column chromatography gave an inseparable
65:35 mixture of syn,anti-10a and syn,syn-10a as a yellow oil (120 mg,
37%). Analysis of the crude mixture after the nitro-Mannich step
showed the ratio of diastereoisomers to be 60:30:10:0. Rf 0.14 (10%
acetone/petrol); IR νmax (thin film) 2974, 2938, 2842, 1730, 1698,
hexanes) was added dropwise. The orange mixture was stirred at this
temperature for 10 min before being warmed to rt and stirred for a
further 30 min. The mixture was recooled to −78 °C, and the PMP-
protected imine (228 mg, 1.08 mmol, 2.0 equiv) in THF (2 mL) was
added via cannula. The mixture was stirred for 20 min before TFA
(104 μL, 1.35 mmol, 2.5 equiv) in THF (0.5 mL) was added via
cannula. The mixture was stirred at this temperature for a further 1 h
before being warmed to rt for 16 h. Saturated aq NaHCO3 (20 mL)
and Et2O (20 mL) were then added, and the layers were separated.
The aqueous phase was extracted with Et2O (3 × 20 mL), and the
combined organic phase was washed with brine (20 mL), dried
(MgSO4), filtered, and concentrated in vacuo to leave crude
pyrrolidinone 5hh. Purification by flash column chromatography
(20% EtOAc/hexanes) gave 5hh (106 mg, 51%) as a white solid; mp
136−137 °C; Rf 0.24 (20% EtOAc/hexanes); IR νmax (thin film) 1721,
1553, 1510, 1247, 1177, 1036, 847, 753, 714, 696 cm−1; 1H NMR (600
MHz, CDCl3) δ 3.73 (3H, s), 4.69 (1H, d, J = 8.0), 5.15 (1H, dd, J =
8.0, 6.3), 5.68 (1H, d, J = 6.2), 6.81 (2H, app d, J = 6.2), 7.23−7.45
(12H, m); 13C NMR (150 MHz, CDCl3) δ 53.3 (CH), 55.3 (CH3),
65.5 (CH), 93.0 (CH), 114.2 (2 × CH), 125.2 (2 × CH), 126.9 (2 ×
CH), 128.2 (2 × CH), 128.5 (CH), 129.1 (Cq), 129.3 (3 × CH),
129.4 (2 × CH), 134.9 (Cq), 157.7 (Cq), 169.1 (Cq).; m/z (CI+) 389
(M + H+, 6%), 342 (100%, M − NO2); HRMS found 389.15036,
C23H21N2O4 requires 389.15013. Anal. Calcd for C23H20N2O4: C,
71.12, H, 5.19, N, 7.21. Found C, 70.91, H, 5.17, N, 7.15%.
8. (1S*,2S*,10bR*)-2-Ethyl-1-nitro-1,5,6,10b-tetrahydro-2H-
pyrrolo[2,1-a]isoquinolin-3-one (107 mg, 60%) as a yellow oil;
prepared by general procedure A and isolated as a 5:1 mixture of
diastereoisomers (diastereoisomer ratio calculated by CHNO2 signal, δ
major = 4.83, δ minor = 5.24). Major diastereoisomer, (91 mg, 51%)
as a yellow oil; Rf 0.37 (20% Me2CO/hexanes); IR νmax (thin film)
2967, 2937, 2878, 1700, 1552, 1459, 1428, 1367; 1H NMR (600 MHz,
CDCl3) δ (0.91 (3H, t, J = 7.2), 1.68 (2H, app dquint, J = 14.4, 7.2),
1.94 (1H, dqd, J = 14.4, 7.8, 4.8), 2.77 (1H, dq, J = 16.2, 2.4), 2.92
(1H, ddd, J = 16.8, 11.4, 4.8), 3.14 (1H, dddd, J = 12.9, 10.2, 4.8, 1.8),
3.26 (1H, tdd, J = 8.4, 4.8, 1.2), 4.34 (1H, ddd, J = 8.4, 6.0, 2.4), 4.81
(1H, dd, J = 8.4, 6.6), 5.25, (1H, dd, J = 6.6), 7.12−7.17 (2H, m),
7.25−7.29 (2H, m); 13C NMR (150 MHz, CDCl3) δ 10.3 (CH3), 22.4
(CH2), 28.3 (CH2), 37.5 (CH2), 49.8 (CH), 58.9 (CH), 90.5 (CH),
124.8 (CH), 127.6 (CH), 128.3 (CH), 129.8 (CH), 133.6 (Cq), 134.0
(Cq), 169.3 (Cq); m/z (CI+) 261 (100%, MH+); HRMS found
261.1238, C14H17N2O3, requires 261.1239. Minor diastereoisomer
peaks: 1H NMR (400 MHz, CDCl3) δ 1.10 (3H, t, J = 7.2), 1.58−1.65
(1H, m), 1.85−1.92 (1H, m), 2.78 (1H, dd, J = 4.4, 2.4), 2.89−3.03
(1H, m), 3.13−3.22 (1H, m), 3.30 (1H, dddd, J = 12.8, 8.0, 4.8, 1.2),
4.37 (1H, ddd, J = 13.2, 6.0, 2.4), 5.24 (1H, dd, J = 9.2, 6.0), 5.47 (1H,
d, J = 6.0), 7.11−7.20 (2H, m), 7.26−7.33 (2H, m); 13C NMR (125
MHz, CDCl3) δ 11.7 (CH3), 20.3 (CH2), 28.1 (CH2), 37.5 (CH2),
47.3 (CH), 58.3 (CH), 88.5 (CH), 124.7 (CH), 124.8 (CH), 128.6
(CH), 129.9 (CH), 133.2 (Cq), 134.3 (Cq), 170.0 (Cq).
1
1557, 1510, 1254, 1205, 1180, 1156, 734, 701 cm−1; H NMR (500
MHz, CDCl3) syn,anti-10a δ 1.08 (3H, t, J = 7.4,), 1.29 (3H, t, J = 7.2),
1.78 (1H, dqd, J = 13.2, 7.4, 5.8), 2.02 (1H, ddq, J = 14.1, 9.1, 7.4),
3.01 (1H, ddd, J = 9.1, 5.6, 3.6), 3.79 (3H, s), 4.20−4.35 (2H, m), 5.61
(1H, m), 6.01 (1H, dd, J = 10.6, 3.2), 6.49−6.78 (2H, m), 6.91- 7.06
(2H, m), 7.18−7.32 (5H, m); syn,syn-10a δ 1.03 (3H, t, J = 7.3), 1.37
(3H, t, J = 7.2), 1.70 (1H, dqd, J = 11.3, 7.1, 4.2), 1.96 (1H, m), 2.96
(1H, m), 3.79, (3H, s), 4.20−4.35 (2H, m), 5.59 (1H, m), 6.04 (1H, d,
J = 9.5) remaining signals could not be distinguished; 13C NMR (125
MHz, CDCl3) syn,anti-10a δ 11.9 (CH3), 14.1 (CH3), 22.8 (CH2),
47.7 (CH), 55.5 (CH3), 61.8 (CH2), 66.0 (CH), 88.3 (CH), 113.5
(CH), 113.8 (CH), 113.9 (CH), 116.2 (q, J = 288.7, CF3), 128.9
(CH), 129.4 (CH × 2), 129.7 (CH), 130.6 (CH), 131.6 (CH), 136.1
(Cq), 138.1 (Cq), 158.1 (q, J = 35.7, CO), 160.4 (Cq), 171.4 (Cq);
syn, syn-10a δ 12.4 (CH3), 14.1 (CH3), 20.1 (CH2), 48.0 (CH), 61.9
(CH2), 87.1 (CH), 116.4 (q, J = 288.7, CF3), 130.7 (CH) remaining
9. N-((2R,3R,4R)-4-Ethyl-1-(4-methoxyphenyl)-5-oxo-2-(thio-
phen-2-yl)pyrrolidin-3-yl)-2,2,2-trifluoroacetamide. Reduction of
5q (0.40 mmol, 89% ee) by general procedure C gave diamine
(3R,4R,5R)-4-amino-3-ethyl-1-(4-methoxyphenyl)-5-(thiophen-2-yl)-
pyrrolidin-2-one (113 mg, 89%) as a yellow oil; Rf 0.25 (30% Me2CO/
hexanes); [α]D −22.2 (c 1.00, CHCl3, 20 °C); IR νmax (thin film)
1
3363, 2962, 1687, 1509, 1367, 1295, 1244, 1029, 830, 699 cm−1; H
NMR (600 MHz, CDCl3) δ 1.11 (3H, t, J = 7.5), 1.82 (1H, m), 1.96
(1H, dqd, J = 14.1, 7.6, 5.2), 2.17 (2H, br), 2.38 (1H, ddd, J = 9.4, 6.7,
5.1), 3.32 (1H, dd, J = 9.3, 7.2), 3.70 (3H, s), 4.88 (1H, d, J = 7.2),
6.76 (2H, app d, J = 9.0), 6.85 (1H, dd, J = 5.1, 3.6), 6.95 (1H, dd, J =
J
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Article
signals could not be distinguished; 19F (282 MHz, CDCl3) δ − 67.7
(3F, s, CF3); m/z (EI+) 482 (M+, 8%); HRMS C23H25F3N2O6 calcd.
482.16592 found 482.16656.
(2 × CH), 140.0 (Cq), 141.1 (Cq), 152.2 (Cq); m/z (ESI+) 326 (54%,
M+), 250 (100%, M + H+ − Ph); HRMS found 326.1626, C19H22N2O3
requires 326.1625. Anal. Calcd for C19H22N2O3: C, 69.92, H, 6.79, N,
8.58. Found C, 70.20, H, 6.86, N, 8.54%.
12. (3S*,4S*,5R*)- 3-Ethyl-4-nitro-5-phenyl-pyrrolidin-2-one.
To a solution of pyrrolidinone 5a (100 mg, 0.29 mmol) in MeCN
(4 mL) at 0 °C under N2 was added CAN (0.71 g, 1.18 mmol, 4.0
equiv) as a solution in H2O (4 mL) dropwise over 3 min. The solution
turned dark orange. The mixture was stirred at 0 °C for a further 2 h
over which time the solution became light orange. H2O was added,
and the layers were separated. The aqueous layer was extracted with
EtOAc, and the combined organics washed with satd aq NaHCO3,
dried (MgSO4), filtered, and concentrated in vacuo. Purification by
flash column chromatography (30% Me2CO/hexanes) gave pyrrolidi-
none 12 (50 mg, 74%) as a brown oil; Rf 0.44 (30% Me2CO/hexanes);
IR νmax (thin film) 2968, 2926, 2878, 1703, 1552, 1457, 1367, 698
cm−1; 1H NMR (400 MHz, CDCl3) δ 0.99 (3H, t, J = 7.4), 1.71 (1H,
app d quint, J = 14.5, 7.5), 1.96 (1H, dqd, J = 14.4, 7.5, 4.9), 3.17 (1H,
app td, J = 7.7, 4.8), 4.73 (1H, dd, J = 7.5, 6.0), 5.16 (1H, d, J = 5.9),
6.99 (1H, br, s), 7.31−7.33 (2H, m), 7.40−7.47 (3H, m); 13C NMR
(100 MHz, CDCl3) δ 10.2 (CH3), 22.0 (CH2), 44.3 (CH), 56.4 (CH),
91.8 (CH), 125.6 (3 × CH), 128.8 (2 × CH), 139 (Cq), 174 (Cq); m/
z (FAB) 257 (45%, M + Na+), 235 (30%, M + H+), HRMS: found
257.0905, C12H14N2O3Na requires 257.0902. Anal. Calcd for
C12H14N2O3: C, 61.53, H, 6.02, N, 11.96. Found C, 61.12, H, 5.99,
N 11.86%.
13. (3S*,4S*,5R*)-4-Amino-3-ethyl-1-(4-methyoxy-phenyl)-5-
phenyl-pyrrolidin-2-one (83 mg, 91%) as an off white solid; prepared
by general procedure C from pyrrolidinone 5a (0.29 mmol); mp >250
°C; Rf 0.22 (20% Me2CO/hexanes); IR νmax (thin film) 2961, 2932,
2876, 1689, 1510, 1456, 1370, 1246, 1031; 1H NMR (400 MHz,
CDCl3) δ 1.12 (3H, t, J = 7.4), 1.72 (2H, s, br), 1.82 (1H, app d quint,
J = 14.5, 7.3), 1.97 (1H, dqd, J = 14.9, 7.4, 5.2), 2.43 (1H, ddd, J =
11.8, 6.7, 5.3), 3.20 (1H, dd, J = 9.2, 7.1), 3.70 (3H, s), 4.66 (1H, d, J =
7.0), 6.71−6.75 (2H, m), 7.15−7.19 (2H, m), 7.20−7.24 (2H, m),
7.26−7.31 (2H, m); 13C NMR (125 MHz, CDCl3) δ 11.2 (CH3), 22.2
(CH2), 51.8 (CH), 55.3 (CH3), 60.9 (CH), 71.3 (CH), 113.9 (2 ×
CH), 124.9 (2 × CH), 127.1 (2 × CH), 128.1 (CH), 128.9 (2 × CH),
130.6 (Cq), 139.0 (Cq), 156.9 (Cq), 174.5 (Cq); m/z (FAB+) 333
(20%, M + Na+), HRMS found 333.1567, C19H22N2O2Na requires
333.1579.
14. (3S*,4S*,5R*)-4-Amino-3-ethyl-5-phenyl-pyrrolidin-2-one
(16 mg, 49%) as an off white solid; prepared by general procedure
C from pyrrolidinone 12 (0.16 mmol); mp 149−151 °C; Rf 0.27 (50%
Me2CO/hexanes); IR νmax (thin film) 3230, 2963, 2927, 2876, 1689,
1630, 1456, 1278 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.05 (3H, t, J
= 7.5), 1.71 (1H, ddq, J = 14.4, 7.6, 7.4), 1.84 (1H, ddq, J = 14.2, 7.5,
5.4), 2.06 (2H, br s), 2.30 (1H, ddd, J = 9.3, 6.3, 5.5), 3.15 (1H, app t,
J = 8.6), 4.24 (1H, d, J = 7.2), 6.03 (1H, br s), 7.32−7.42 (5H, m); 13C
NMR (125 MHz, CDCl3) δ 11.0 (CH3), 22.2 (CH2), 51.8 (CH), 62.2
(CH), 65.5 (CH), 127.6 (2 × CH), 129.4 (CH), 129.9 (2 × CH),
141.5 (Cq), 179.2 (Cq); m/z (CI+) 205 (100%, MH+); HRMS found
205.1338, C12H17N2O requires 205.1341.
15. (2R*,3S*,4R*)-4-Ethyl-1-(4-methoxy-phenyl)-3-nitro-2-phe-
nyl-pyrrolidine. To a solution of pyrrolidinone 5a (70 mg, 0.21
mmol) in THF (5 mL) under N2 at 0 °C was added BH3−THF
complex (0.72 mL, of a 1.0 M sol. in THF, 0.72 mmol, 3.5 equiv)
dropwise. The mixture was stirred at 0 °C until no more effervescence
was observed before being heated to reflux for 15 h. The mixture was
cooled to rt, and MeOH was added before being concentrated in vacuo
to give crude pyrrolidine 15. Purification by flash column
chromatography (20%Me2CO/hexanes) gave pyrrolidine 15 (53 mg,
79%) as a yellow solid; mp 50−52 °C; Rf 0.21 (20% Me2CO/
hexanes); IR δmax (thin film) 2964, 2932, 1548, 1510, 1358, 1241,
1180, 1038 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.97 (3H, t, J = 7.4),
1.58 (2H, app quintd, J = 7.4, 2.6), 2.85 (1H, m), 3.67 (1H, dd, J = 9.2,
5.6), 3.72 (3H, s), 3.85 (1H, dd, J = 9.2, 8.0), 4.76 (1H, app t, J = 5.3),
5.13 (1H, d, J = 4.8), 6.46−6.50 (2H, m), 6.74−6.78 (2H, m), 7.28−
7.34 (5H, m); 13C NMR (125 MHz, CDCl3) δ 12.1 (CH3), 25.6
(CH2), 45.2 (CH), 54.9 (CH2), 55.7 (CH3), 68.5 (CH), 97.8 (CH),
114.7 (2 × CH), 114.9 (2 × CH), 126.1 (2 × CH), 128.2 (CH), 129.2
16. 3-Ethyl-4-hydroxy-1-(4-methoxy-phenyl)-5-phenyl-1,5-dihy-
dro-pyrrol-2-one and 4-Ethyl-5-hydroxy-1-(4-methoxy-phenyl)-2-
phenyl-1,2-dihydro-pyrrol-3-one. To a solution of potassium
dichromate (0.26 g, 0.88 mmol, 6.0 equiv) in 6 M HCl (6.40 mL,
26.5 mmol, 180.0 equiv) at 0 °C under N2 was added Zn dust (480
mg, 7.35 mmol, 50.0 equiv) portionwise over 20 min. During the
addition, the solution turned from orange to dark blue. After complete
dissolution of the zinc the resulting CrCl2 solution was transferred to a
refluxing solution of pyrrolidinone 5a (50 mg, 0.15 mmol) in MeOH/
EtOAc (2.5:1, 7 mL). The solution was refluxed for 1 h before satd aq
NaHCO3 and CH2Cl2 were added, and the layers were separated. The
aqueous layer was extracted with CH2Cl2, and the combined organics
washed with brine, dried (MgSO4), filtered, and concentrated in vacuo
to give crude pyrrolones 16. Purification by flash column
chromatography (30% Me2CO/hexanes) gave pyrrolones 16 as an
inseparable 1:1 mixture of tautomers, (14 mg, 30%) as a yellow oil; Rf
0.09 (20% Me2CO/hexanes); IR νmax (thin film) 3367, 2971, 2937,
2839, 1776, 1689, 1512, 1250, 1031 cm−1; 1H NMR (600 MHz,
CDCl3) δ 0.93 (3H, t, J = 7.5), 1.07 (3H, t, J = 7.5), 1.77 (1H, app
quint, J = 7.2), 1.96 (1H, tq. J = 14.8, 7.5), 2.05−2.11 (2H, tq, J = 14.8,
7.5), 3.74 (3H, s), 3.77 (3H, s), 5.39 (1H, s), 5.52 (1H, s), 6.80−6.82
(2H, m), 6.84−6.86 (2H, m), 7.22−7.23 (2H, m), 7.29−7.35 (10H),
7.48−7.49 (2H, m); 13C NMR (125 MHz, CDCl3) δ 6.9 (CH3), 7.4
(CH3), 30.1 (CH2), 30.6 (CH2), 55.5 (2 × CH3), 69.2 (CH), 70.3
(CH), 75.7 (Cq), 75.9 (Cq), 114.3 (2 × CH), 114.5 (2 × CH), 123.4
(2 × CH), 125.2 (2 × CH), 126.2 (2 × CH), 128.0 (2 × CH), 128.9
(2 × CH), 128.9 (Cq), 129.2 (2 × CH), 129.3 (2 × CH), 129.7 (Cq),
132.6 (Cq), 133.6 (Cq), 157.5 (Cq), 157.9 (Cq), 171.7 (Cq), 172.1
(Cq), 203.6 (Cq), 205.5 (Cq); m/z (ESI+) 309 (20%, M+); HRMS
found 309.1368, C19H19NO3 requires 309.1368.
17. 4-Allyl-3-ethyl-1-(4-methoxyphenyl)-5-phenyl-1,5-dihydro-
pyrrol-2-one. A solution of pyrrolidinone 5a (84 mg, 0.25 mmol) in
THF (5 mL) was cooled to −78 °C and n-butyl lithium (200 μL, of a
2.5 M soln in THF, 0.50 mmol, 2.0 equiv) was added dropwise via
cannula under N2. The mixture was stirred at this temperature for 10
min before allyl bromide (65 μL, 0.75 mmol, 3.0 equiv) was added via
cannula. The mixture was warmed to rt and stirred for a further 2 h
before satd aq NH4Cl and Et2O were added, and the layers were
separated. The aqueous layer was extracted with Et2O, and the
combined organics washed with brine, dried (MgSO4), filtered, and
concentrated in vacuo to give crude pyrrolone 17. Purification by flash
column chromatography gave pyrrolone 17 (27 mg, 32%) as a yellow
oil; Rf 0.50 (20% Me2CO/hexanes); IR νmax 2928, 1720, 1512, 1446,
1370, 1292, 1249, 1168 cm−1; 1H NMR (400 MHz) δ 0.91 (3H, t, J =
7.2), 1.74 (1H, dq, J = 15.2, 7.6), 1.87 (1H, dq, J = 14.8, 7.6), 2.44−
2.55 (2H, m), 3.77 (3H, s), 5.06 (1H, app dt, J = 10.0, 1.0), 5.16 (1H,
dd, J = 17.2, 2.0), 5.42 (1H, s), 5.77 (1H, ddt, J = 16.8, 10.0, 7.4),
6.78−6.82 (2H, m), 6.92−6.96 (2H, m), 7.12−7.15 (2H, m), 7.20−
7.26 (3H, m); 13C NMR (125 MHz) δ 9.1 (CH3), 29.5 (CH2), 41.3
(CH2), 55.2 (CH3), 55.4 (Cq), 111.7 (CH), 114.0 (2 × CH), 118.3
(CH2), 127.8 (2 × CH), 128.2 (2 × CH), 128.3 (2 × CH), 128.5
(CH), 128.7 (Cq), 131.4 (Cq), 133.4 (CH), 144.5 (Cq), 158.3 (Cq),
181.8 (Cq); m/z (CI+) 334 (100%, MH+); HRMS found 334.1799,
C22H24NO2 requires 334.1807.
18. (3S*,5S*)-3-Ethyl-1-(4-methoxyphenyl)-5-phenylpyrrolidin-
2-one. To a solution of diamine 13 (250 mg, 0.81 mmol) in formic
acid (5 mL) at 0 °C was added dropwise acetic anhydride (0.81 mL,
8.06 mmol, 10 equiv). The mixture was then stirred at rt for 2 h. Then
water (20 mL) was added, and the mixture was extracted with DCM
(3 × 20 mL). The combined organics were washed with satd aq
NaHCO3 (2 × 20 mL) and brine (20 mL), dried (MgSO4), filtered,
and concentrated in vacuo to give crude formamide. Purification by
flash column chromatography (30%Me2CO/hexanes) gave N-
((2R*,3S*,4S*)-4-ethyl-1-(4-methoxyphenyl)-5-oxo-2-phenylpyrroli-
din-3-yl)formamide (246 mg, 90%) as a white crystalline solid, which
was found to be a 4:1 mixture of rotamers (rotamer ratio calculated by
K
dx.doi.org/10.1021/jo301000r | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CHNH signal, δ major = 4.24, δ minor = 3.67); mp 130−131 °C; Rf
0.16 (30% Me2CO/hexanes). Major rotamer: IR νmax (thin film) 3239,
3059, 2961, 1704, 1644, 1510, 1374, 1246, 1180, 1026, 834, 749, 737,
EtOAc (2 × 20 mL), and the combined organics were extracted with
satd aq NaHCO3 (2 × 10 mL). The combined aqueous extracts were
then acidified to pH = 1 with addition of 2 M HCl and then extracted
with EtOAc (3 × 20 mL), dried (MgSO4), filtered, and concentrated
in vacuo to give carboxylic acid 19 (265 mg, 86%) as a white solid; mp
155−156 °C; Rf 0.34 (10% MeOH/DCM); IR νmax (thin film) 2967,
2463, 1739, 1634, 1604, 1560, 1604, 1369, 1248, 1222, 1203, 1183,
1021, 792 cm−1; 1H NMR (600 MHz, CD3OD) δ 1.13 (3H, t, J = 7.4),
1.80 (1H, ddq, J = 14.2, 8.7, 7.4), 2.00 (1H, dqd, J = 14.1, 7.4, 5.5),
3.17 (1H, ddd, J = 8.9, 5.5, 3.7), 3.79 (3H, s), 5.29 (1H, t, J = 3.3),
5.34 (1H, d, J = 2.8), 6.95 (2H, app d, J = 8.9), 7.36 (2H, app d, J =
8.9); 13C NMR (150 MHz, CD3OD) δ 11.5 (CH3), 24.5 (CH2), 51.0
(CH), 55.9 (CH3), 66.1 (CH), 85.4 (CH), 115.3 (2 × CH), 127.1 (2 ×
CH), 130.9 (Cq), 160.0 (Cq), 171.4 (Cq), 174.4 (Cq); m/z (CI+) 309
(100%, M + H+), 218 (40%, M+ −CO2 − NO2); HRMS found
309.10666, C14H17N2O6 requires 309.10872. Anal. Calcd for
C14H16N2O6: C, 54.54, H, 5.23, N, 9.09. Found C, 54.21, H, 5.19,
N, 8.96%.
1
698 cm−1; H NMR (600 MHz, CDCl3) δ 1.03 (3H, t, J = 7.5), 1.62
(1H, m), 1.91 (1H, m), 2.53 (1H, m), 3.73 (3H, s), 4.24 (1H, dt, J =
7.8, 5.7), 5.05 (1H, d, J = 4.9), 6.37 (1H, d, J = 8.4), 6.75 (2H, app d, J
= 9.2), 7.10−7.31 (7H, m), 8.18 (1H, d, J = 1.2); 13C NMR (150
MHz, CDCl3) δ 11.5 (CH3), 23.4 (CH2), 50.3 (CH), 55.3 (CH3), 56.0
(CH), 68.6 (CH), 114.0 (2 × CH), 124.3 (2 × CH), 126.7 (2 × CH),
128.2 (CH), 128.9 (2 × CH), 130.4 (Cq), 138.3 (Cq), 157.0 (Cq),
160.9 (CH), 174.1 (Cq); m/z (CI+) 339 (M + H+, 30%), 294 (100%,
M+ − NHCOH); HRMS found 339.1699, C20H23N2O3 requires
339.1709. Minor rotamer: 1H NMR (600 MHz, CDCl3) δ 1.10 (3H, t,
J = 7.4), 1.62 (1H, m), 1.91 (1H, m), 2.53 (1H, m), 3.67 (1H, m),
3.71 (3H, s), 4.76 (1H, d, J = 7.7), 6.30 (1H, t, J = 10.8), 6.78 (2H,
app d, J = 9.2), 7.10−7.31 (7H, m), 7.62 (1H, d, J = 11.5); 13C NMR
(150 MHz, CDCl3) δ 10.8 (CH3), 21.6 (CH2), 48.8 (CH), 55.3
(CH3), 60.9 (CH), 68.4 (CH), 113.9 (2 × CH), 124.9 (2 × CH),
127.0 (2 × CH), 128.7 (CH), 129.2 (2 × CH), 129.7 (Cq), 136.7
(Cq), 157.2 (Cq), 163.7 (CH), 172.5 (Cq).
To a solution of the formamide formed above (441 mg, 1.31 mmol)
in THF (4 mL) under N2 at −78 °C was added Et3N (0.92 mL, 6.53
mmol, 5 equiv) followed by a solution of POCl3 (0.16 mL, 1.55 mmol,
1.18 equiv) in THF (1 mL) dropwise. The mixture was then warmed
to 0 °C and stirred for a further 1 h. Then ice−water (20 mL) was
added, and the mixture extracted with EtOAc (4 × 30 mL). The
combined organics were washed with brine (20 mL), dried (MgSO4),
filtered, and concentrated in vacuo to give crude isocyanide.
Purification by flash column chromatography (20%Me2CO/hexanes)
gave (3S*,4S*,5R*)-3-ethyl-4-isocyano-1-(4-methoxyphenyl)-5-phe-
nylpyrrolidin-2-one (261 mg, 63%) as a white crystalline solid; mp
168−169 °C; Rf 0.26 (20% Me2CO/hexanes); IR νmax (thin film)
2970, 2141, 1707, 1509, 1458, 1365, 1247, 1223, 1193, 1179, 1039,
830, 78, 742, 700 cm−1; 1H NMR (600 MHz, CDCl3) δ 1.16 (3H, t, J
= 7.5), 1.83 (1H, m), 2.12 (1H, dqd, J = 12.4, 7.6, 4.7), 2.92 (1H, ddd,
J = 9.4, 7.9, 4.7), 3.71 (3H, s), 3.79 (1H, dd, J = 9.4, 7.6), 5.10 (1H, d,
J = 7.6), 6.77 (2H, app d, J = 9.0), 7.15 (2H, app d, J = 9.0), 7.22−7.35
(5H, m); 13C NMR (150 MHz, CDCl3) δ 10.7 (CH3), 22.5 (CH2),
50.0 (CH), 55.2 (CH3), 59.9 (CH), 67.4 (CH), 114.0 (2 × CH), 125.0
(2 × CH), 126.8 (2 × CH), 129.0 (CH), 129.2 (2 × CH), 129.2 (Cq),
136.4 (Cq), 157.3 (Cq), 160.2 (Cq), 171.2 (Cq); m/z (EI+) 320 (M+,
100%); HRMS found 320.15222, C20H20N2O2 requires 320.15193.
Anal. Calcd for C20H20N2O2: C, 74.98, H, 6.29, N, 8.74. Found C,
74.94, H, 6.27, N, 8.68%.
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental details, X-ray representations, copies of
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: j.c.anderson@ucl.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Martin P. Green for discussions; the EPSRC,
Pfizer. and University College London for funding; Mr. T.
Hollingworth, Mr. D. Hooper, and Dr. L. Harris for mass
spectra; and Dr. T. Liu and Ms. J. Maxwell for microanalytical
data.
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E.; Linden, A.; Lopez, R.; Mugica-Mendiola, I.; Oiarbe, M.; Palomo, C.
MHz, CDCl3) δ 1.03 (3H, t, J = 7.5), 1.59 (1H, ddq, J = 14.0, 9.2, 7.3),
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M
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