Enantiopure trans -4,5-disubstituted 2-imidazolidinones via copper(I)-catalyzed ring opening of 1,1′-DiBoc-2,2′-biaziridine with grignard reagents

Article abstract of DOI:10.1021/acs.joc.5b00832

The copper-catalyzed ring opening of chiral-pool-derived 1,1′-diBoc-2,2′-biaziridine with Grignard reagents affords enantiopure 2-imidazolidinones in a desymmetrizing, cascade process involving the Boc protecting group. This divergent strategy provides re

Full text of DOI:10.1021/acs.joc.5b00832

Note
pubs.acs.org/joc
Enantiopure Trans-4,5-Disubstituted 2‑Imidazolidinones via
Copper(I)-Catalyzed Ring Opening of 1,1′-DiBoc-2,2′-Biaziridine with
Grignard Reagents
Matthew D. Kennedy,† Stephen J. Bailey,† Steven M. Wales,† and Paul A. Keller*
School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
S
* Supporting Information
ABSTRACT: The copper-catalyzed ring opening of chiral-
pool-derived 1,1′-diBoc-2,2′-biaziridine with Grignard reagents
affords enantiopure 2-imidazolidinones in a desymmetrizing,
cascade process involving the Boc protecting group. This
divergent strategy provides reaction-ready, N-differentiated
products and allows two C−C bond constructions concurrent
to imidazolidinone formation. A variety of alkyl, cyclic, and aryl
Grignard reagents are tolerated in reasonable to good yields.
2-Imidazolidinones are important heterocycles represented in
bioactive compounds1 and peptidomimetics,2 as well as chiral
ligands3 and auxiliaries4 in stereoselective synthesis (e.g., 1−4,
Figure 1). Additionally, these five-membered cyclic ureas are
precursors to other useful compound classes including vicinal
diamines,5 cyclic guanidines6 and imidazolidinethiones.7
from an unforeseen participation of the Boc protecting group
(Scheme 1).11 Although 5 is an easily synthesized,12 bench-
Scheme 1. Proposed Synthesis of 2-Imidazolidinones
stable solid, its reactivity has remained unexplored beyond this
example; thus, we were inspired to further investigate the ring
opening of 5 by Grignard reagents. As well as harboring the
potential to prepare enantiopure 2-imidazolidinones 6 in a
divergent manner, this approach would allow direct access to
reaction-ready, N-differentiated products, thus presenting
downstream opportunities for sequential, asymmetric N-
functionalization.13 Furthermore, this method would constitute
a useful addition to the limited existing synthetic strategies to
enantioenriched trans-4,5-disubstituted imidazolidinones, which
are specific to vinyl derivatives14 or require multistep routes
from amino acids15 or 1,3-dihydro-2-imidazolone.16
We began this investigation by examining the effect of
reaction parameters on the product ratio, in the search for
conditions favoring imidazolidinone formation (Table 1). We
were not concerned with pursuing a separate optimization of 7
in this study, as we have recently shown that the analogous
tosyl-biaziridine cleanly provides vicinal diamines of this type
upon ring opening.17 For convenience, we selected commer-
Figure 1. Exemplary 2-imidazolidinones.
Although the traditional route to this heterocycle involves
treatment of a vicinal diamine with an electrophilic carbonyl
source,8 an abundance of alternate methods are now available
which avoid the requirement for presynthesized diamines,
offering greater product diversity in modular fashion.9 Despite
these advances, however, there remains comparatively few
general methods which allow access to 4- and/or 5-substituted
2-imidazolidinones with control of absolute stereochemistry.10
Previously in our laboratory, as an intermediary step toward
the synthesis of 2,2′-biindoline, we attempted the ring opening
of tartaric acid derived biaziridine 5 with a Grignard reagent,
affording an imidazolidinone 6a as the major product arising
Received: April 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00832
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The Journal of Organic Chemistry
Note
a
silica gel flash chromatography and were observed to be stable
to these conditions.
Table 1. Reaction Optimization
Similarly to the isopropyl test substrate, clean C−C bond
formation took place with the cyclohexyl Grignard reagent, but
equimolar amounts of 6c and 7c were formed, resulting in a
46% yield of 6c (Table 2). Notably, all other Grignard reagents
surveyed provided higher ratios of 6:7 than observed with the
secondary carbanions (isopropyl and cyclohexyl). Primary alkyl
(nonmethyl) and aryl Grignard reagents were particularly good
performers in this regard, providing molar ratios of 6:7 in
excess of 90:10 in all cases. With aryl and vinyl Grignard
reagents, up to 3.6 equiv of the carbanion was required for
complete consumption of 5, although not at the expense of the
product ratio.
The method was revealed to be somewhat sensitive to
inductive effects: the electron-rich 2-methoxyphenyl Grignard
reagent furnished 6l in 80% yield (Table 2), whereas the
electron-deficient 3-chloro derivative provided 6p in a reduced
37% yield. In the latter case, a number of unidentified side
products were observed. The 2-bromophenyl Grignard reagent
was required in 4-fold excess for complete consumption of 5,
presumably due to nucleophile loss via decomposition to
benzyne.20 Under these conditions, 6a was obtained in 60%
yield, with, at most, a trace of 7a formed, representing a
significant improvement to our original lead result (Scheme 1).
Unsuccessful substrates under the standard conditions included
tert-butyl, ethynyl, and 2-thienyl Grignard reagents (products
not shown). In these cases, unreacted 5 was the predominant
component in the crude mixture after workup.
NMR analysis of the products revealed some notable general
characteristics. H4 was observed in all cases as an apparent
triplet (δ 3.14−3.63 ppm, J = 5.7−7.4 Hz), while H5 routinely
resonated further downfield as a doublet (δ 3.73−4.40 ppm, J =
7.8−10.8 Hz). These multiplicities were attributed to vicinal
coupling with their adjacent methylene protons (HA and HB),
as no correlations between H4 and H5 were observed by
gCOSY analysis. The diastereotopic methylene protons at HA,
as well as HB, were fully resolved as two distinct doublets of
doublets for some compounds derived from aryl Grignard
reagents (e.g., 6k, 6n). In regards to the 13C NMR spectra,
several products bearing pendant aryl moieties exhibited up to
two doubly degenerate signals (ArC’s), likely as a consequence
of the pseudo C2-symmetric nature of the compounds.
As anticipated, all evidence pertaining to the stereochemical
purity of the products pointed conclusively to a complete
chirality transfer from the biaziridine. The absence of
diastereoisomers in the NMR spectra of all crude materials
and purified products served as primary evidence against
epimerization under the basic ring-opening conditions. In
addition, representative ring-opening product ent-6l was
prepared and was found to have a specific rotation equal and
opposite to 6l (Table 2, insert). The optical purities of 6l and
ent-6l were further confirmed by analytical chiral HPLC.21
A divergent reaction mechanism is proposed in Scheme 2 to
account for the formation of 6 and side product 7. Initially,
nucleophilic addition of the organocuprate produces common
intermediate 8, which can either be attacked by a second
equivalent of the carbanion to give the fully ring-opened
diamine 7 (blue arrows, intermolecular pathway) or undergo an
intramolecular N-acylation22,23 to produce bicyclic intermediate
9 (red arrows, intramolecular pathway).24 Subsequent addition
of a second equivalent of the organocuprate to 9 ultimately
produces imidazolidinone 6. This mechanistic proposal is
equiv
mol % Cu
[5]0
ratio
b
entry
i-PrMgCl
(wrt i-PrMgCl)
(mol L−1
)
6b:7b
1
2
3
4
5
6
7
4.0
4.0
4.0
4.0
2.4
2.4
15
5
0.10
25:75
21:79
−
0.10
0
0.10
15
15
15
15
0.025
0.025
0.025
0.025
34:66
c
55:45
56:44
−
d
e
2.4
a
Reactions performed by premixing 5 and CuBr·SMe2 in THF at −40
°C, adding i-PrMgCl and allowing the cooling bath to warm to rt over
b
c
16 h. Determined by 1H NMR analysis of the crude mixture. Isolated
d
yields of 6b and 7b were 48% and 26%, respectively. Reaction time
was 96 h. i-PrMgCl added dropwise over 2 h to the reaction mixture
e
at −20 °C.
cially available i-PrMgCl as the model Grignard reagent. Our
initial experiment was performed under similar conditions to
those reported previously,11,17 affording a mixture of the
desired heterocycle 6b and vicinal diamine 7b in a 25:75 ratio
(entry 1). Immediately, we noted a clear dependency of the
product ratio on the Grignard reagent, given the reversal in
major product from the previous reaction (see Scheme 1).
Undeterred by this result, we examined variations in the
quantity of the catalyst: a reduction to 5 mol % gave a similar
outcome (Table 1, entry 2), while omitting the copper salt
completely resulted in neither product being observed (entry
3). Encouragingly, when the starting concentration of 5 was
reduced, the ratio of 6b:7b was increased favorably (entry 4
versus entry 1). Maintaining this concentration and removing
the excess Grignard reagent18 provided a further advantage,
enabling 6b to emerge as the major product in 48% isolated
yield (entry 5), along with 7b obtained in 26% yield, which was
easily separated from 6b by flash chromatography due to its
significantly lower polarity on silica gel. Subsequent experi-
ments proved unsuccessful in further optimizing the outcome;
increasing the reaction time (prior to NH4Cl quench) had a
negligible effect (entry 6), while performing slow addition of
the Grignard reagent at −20 °C returned mostly unreacted 5
(entry 7).19
Although the yield of 6b was affected by the persistent
formation of 7b, we remained optimistic that screening a
variety of Grignard reagents would provide more favorable
results, given the apparent dependency of the product ratio on
the Grignard reagent. Therefore, we proceeded to examine the
scope of the process under the newly established conditions
(Table 2). A range of structurally and electronically diverse
Grignard reagents such as cyclic, primary alkyl, and function-
alized benzylic and aryl carbanions, including ortho-substituted
substrates, were found to be accommodated, affording the
desired imidazolidinones 6a−6p in modest to good yields (37−
84%). With the majority of Grignard reagents examined, the
yield of 6 was notably lower than would be expected based on
the product ratio, indicating biaziridine decomposition as a
competing reaction pathway. The products were purified by
B
DOI: 10.1021/acs.joc.5b00832
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The Journal of Organic Chemistry
Note
a
Table 2. Grignard Substrate Scope
a
b
Reactions performed with 0.14 mmol of 5 and 10−15 mol % CuBr·SMe2 (wrt RMgX). The product ratio was determined by 1H NMR analysis of
c
the crude reaction mixture, and 6 was isolated by flash chromatography. Product ratio unable to be determined with more precision due to multiple
side products. 4 equiv of RMgX used; some unreacted 5 was returned. 8 equiv of RMgX used. ent-5 used. Red-colored bonds highlight new C−C
bond formation.
d
e
f
a
Scheme 2. Proposed Reaction Mechanism
consistent with our earlier data in that the resultant ratio of 6:7
was found to increase with higher dilution and lesser
equivalents of the carbanion, conditions which would be
expected to favor the intramolecular pathway. Furthermore, the
propensity for secondary alkyl and cyclic Grignard reagents to
produce greater quantities of 7 can be rationalized by the higher
reactivity of their derived organocuprates toward 8, as the rate
of competing cyclization to 9 is presumably independent of the
pendant R group. Notably, the possibility of an alternative entry
(or additional contribution) to 6 via cyclization of intermediate
10 can be ruled out on the basis that an extended stirring time
did not alter the final product ratio, although this mode of ring
closure has been reported for the lithium dianion of an aryl
ortho-dicarbamate.25
In an attempt to characterize the reaction products of
monocarbanion addition, we performed an experiment with a
limiting amount of i-PrMgCl and maintained the temperature
below −10 °C (Scheme 3). Interestingly, TLC and NMR
a
(MgX)+ counterions are omitted for clarity.
C
DOI: 10.1021/acs.joc.5b00832
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The Journal of Organic Chemistry
Note
according to a published procedure.12 Notably, 5 is a bench-stable
solid that can be stored indefinitely at ambient temperature without
decomposition. 2-Bromophenylmagnesium chloride was prepared
from 2-bromoiodobenzene via I/Mg exchange with i-PrMgCl.29 3-
Chlorophenylmagnesium chloride was prepared from 1-bromo-3-
chlorobenzene via Br/Mg exchange with i-PrMgCl·LiCl.30 Other
Grignard reagents were obtained commercially or prepared from
freshly acid-washed Mg turnings. All other reagents and solvents were
obtained reagent grade from commercial sources and used as received.
General Procedure for the Ring Opening of Biaziridine 5
with Grignard Reagents. To a suspension of 5 (40.0 mg, 0.14
mmol) and CuBr·SMe2 (10−15 mol % wrt the Grignard reagent) in
THF at −40 °C (liquid N2/MeCN slush bath) was added a Grignard
reagent (2.4−3.6 equiv) in THF (total volume of THF = 5.6 mL;
individual proportions vary depending on the Grignard concen-
tration). The resulting solution was allowed to warm to rt with stirring
over 16 h. The mixture was quenched with saturated NH4Cl (2 mL),
diluted with brine (10 mL), and extracted with EtOAc (20 mL). The
organic layer was dried (MgSO4) and concentrated under reduced
pressure. The residue was analyzed by 1H NMR spectroscopy to
determine the product ratio, before being subjected to flash
chromatography to isolate the desired imidazolidinone.
Scheme 3. Reaction of 5 with Limiting i-PrMgCl
analyses of the crude mixture did not reveal any new reaction
products; only the previously characterized diaddition products
6b and 7b were present, in addition to unreacted 5 as the major
component. The absence of 11 was not overly surprising, given
that there are presumably two modes for the consumption of its
anionic precursor 8 (see Scheme 2), but the lack of observation
of 9 is more difficult to rationalize. Essentially, if 9 is formed
during the ring opening process, its absence in the crude
mixture suggests either its instability to the aqueous workup
conditions26 or a significantly greater reactivity to ring opening
than 5, thereby being consumed more rapidly by the available
carbanion. In line with the latter, a number of related aziridine-
fused imidazolidinones27 and oxazolidinones26 have been
shown to undergo facile and regioselective nucleophilic ring
opening at the terminal methylene position, including by
organocuprates.26b,c,27b
(4S,5S)-2,7-Dimethyl-4,5-di(N-tert-butoxycarbonylamino)octane
(7b) and (4S,5S)-4,5-Diisobutyl-1-tert-butoxycarbonyl-2-imidazoli-
dinone (6b). The title compounds were prepared according to the
general procedure using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2
(10.8 mg, 0.053 mmol) in THF (5.4 mL) and a solution of i-PrMgCl
(1.8 M in THF, 0.19 mL, 0.34 mmol). Flash chromatography (2.4 g
silica, 5% EtOAc/hexanes) gave 7b (13.5 mg, 26%) as a white solid.
Mp 146−147 °C; TLC (15% EtOAc/pet ether) RF = 0.71; [α]D21
1
−65.9 (c 2.77, CH2Cl2); H NMR (300 MHz, CDCl3, major rotamer
only) δ 4.45 (bd, J = 9.1 Hz, 2H), 3.63−3.46 (m, 2H), 1.74−1.61 (m,
2H), 1.43 (s, 18H), 1.36−1.22 (m, 4H), 0.94−0.88 (m, 12H); 13C
NMR (75 MHz, CDCl3) δ 156.3, 79.0, 52.9, 42.4, 28.4, 24.9, 23.4,
21.9; IR (neat) v 3351, 2949, 1685, 1534, 1362, 1291, 1179, 1011
cm−1; HRMS (EI) calcd for C20H40N2O4 372.2988 [M]•+, found
372.3001. Further elution (5% to 20% EtOAc/hexanes) gave 6b (20.0
mg, 48%) as a colorless gum. TLC (30% EtOAc/pet ether) RF = 0.32;
[α]2D1 −5.4 (c 4.23, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 6.33 (bs,
1H), 3.77 (t, J = 7.2 Hz, 1H), 3.25 (t, J = 7.2 Hz, 1H), 1.53 (s, 9H),
1.74−1.32 (m, 5H), 1.30−1.22 (m, 1H), 0.97−0.91 (m, 12H); 13C
NMR (75 MHz, CDCl3) δ 155.7, 150.4, 82.0, 59.5, 52.1, 45.4, 42.4,
28.1, 24.3, 24.2, 23.9, 23.0, 22.0, 21.5; IR (neat) v 3289, 2952, 2866,
1787, 1711, 1370, 1336, 1254, 1164, 1131, 1102, 778 cm−1; HRMS
(EI) calcd for C16H30N2O3 298.2256 [M]•+, found 298.2259.
(4S,5S)-4,5-Di(cyclohexylmethyl)-1-tert-butoxycarbonyl-2-imida-
zolidinone (6c). This was prepared according to the general procedure
using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg, 0.053 mmol)
in THF (5.2 mL) and a solution of cyclohexylmagnesium chloride
(1.84 M in THF, 0.20 mL, 0.37 mmol). Flash chromatography (2.0 g
silica, 20% EtOAc/hexanes) gave 6c (24.3 mg, 46%) as an amorphous
solid. TLC (20% EtOAc/pet ether) RF = 0.14; [α]2D5 = −2.2 (c 1.20,
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 5.93 (s, 1H), 3.81 (d, J = 9.6
Hz, 1H), 3.28 (t, J = 7.0 Hz, 1H), 1.86−1.38 (m, 21H), 1.38−1.11 (m,
9H), 1.08−0.87 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 155.4,
150.4, 82.0, 58.9, 51.5, 43.9, 41.0, 34.4, 34.0, 33.9, 33.5, 33.0, 32.5,
28.2, 26.4, 26.3, 26.10, 26.07; IR (neat) v 3284, 2921, 2346, 1776,
1744, 1701, 1340, 1250, 1157, 857, 774, 733 cm−1; HRMS (ESI) calcd
for C22H38N2NaO3 401.2780 [M + Na]+, found 401.2765.
In summary, we have developed a new, enantiospecific route
to 2-imidazolidinones via the ring opening of Boc-protected
2,2′-biaziridine with Grignard reagents. As demonstrated, this
method has the potential to access a diverse range of
enantiopure 2-imidazolidinones in a single step from a
common, easily prepared chiral-pool precursor. This approach
can be considered as a variant of the classical ‘vicinal diamine +
carbonyl source’ imidazolidinone synthesis, whereby in this case
the latent diamine is embedded in the biaziridine. Further
elaboration of the products prepared herein toward new
catalysts and medicinally relevant materials can be readily
envisioned, taking advantage of the embedded halogen, alkoxy,
and olefin moieties, as well as the numerous methods available
for N-functionalization of 2-imidazolidinones.28
EXPERIMENTAL SECTION
■
General Methods and Materials. All reactions were carried out
in standard laboratory glassware with magnetic stirring under N2. Thin
layer chromatography (TLC) was performed on aluminum-backed
0.20 mm silica gel plates. Visualization was accomplished with UV light
or a solution of phosphomolybdic acid in ethanol. Flash chromatog-
raphy was performed under positive air pressure using Silica Gel 60 of
230−400 mesh (40−63 μm). Melting points (mp) are uncorrected.
Optical Rotations were measured in CH2Cl2 with a path length of 1.0
dm (λ = 589 nm). Proton and carbon magnetic resonance spectra (1H
NMR and 13C NMR) were recorded at 300 MHz, or at 500 MHz, as
specified. Spectra were aquired in CDCl3 and are reported relative to
tetramethylsilane (1H: δ = 0.00 ppm) and solvent resonance (13C: δ =
77.0 ppm). 1H NMR data are reported as follows: chemical shift,
multiplicity (abbreviations: s = singlet, bs = broad singlet, d = doublet,
bd = broad doublet, dd = doublet of doublets, t = triplet, q = quartet,
m = multiplet), coupling constant (Hz), and integration. High
resolution mass spectrometry (HRMS) was performed on a QTOF
ESI spectrometer or on a TOF EI spectrometer.
(4S,5S)-4,5-Di(cyclopropylmethyl)-1-tert-butoxycarbonyl-2-imi-
dazolidinone (6d). This was prepared according to the general
procedure using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg,
0.053 mmol) in THF (4.55 mL) and a solution of cyclopropyl-
magnesium bromide (0.5 M in THF, 0.85 mL, 0.42 mmol). Flash
chromatography (2.0 g silica, 30% EtOAc/hexanes) gave 6d (26.2 mg,
63%) as an amorphous solid. TLC (40% EtOAc/pet ether) RF = 0.40;
[α]2D5 = −6.8 (c 1.20, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 6.05 (s,
1H), 3.94 (d, J = 9.0 Hz, 1H), 3.49 (t, J = 5.7 Hz, 1H), 1.79−1.70 (m,
2H), 1.61−1.47 (m, 10H), 1.40−1.30 (m, 1H), 0.76−0.64 (m, 2H),
0.58−0.41 (m, 4H), 0.20−0.08 (m, 4H); 13C NMR (125 MHz,
Anhydrous tetrahydrofuran was obtained commercially. (2S,2′S)-
1,1′-Di-(tert-butoxycarbonyl)-2,2′-biaziridine 5 and its (R,R)-enan-
tiomer (ent-5) were prepared from D- and L-tartaric acid, respectively,
D
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The Journal of Organic Chemistry
Note
CDCl3) δ 155.6, 150.4, 82.0, 60.6, 54.1, 41.0, 38.0, 28.1, 6.8, 6.3, 5.0,
4.4, 3.9, 3.5; IR (neat) v 3303, 2987, 2335, 1772, 1701, 1343, 1251,
1162, 1018, 855, 824, 775, 756 cm−1; HRMS (ESI) calcd for
C16H26N2NaO3 317.1841 [M + Na]+, found 317.1826.
(40% EtOAc/pet ether) RF = 0.36; [α]2D5 = −13.4 (c 0.74, CH2Cl2);
1H NMR (500 MHz, CDCl3) δ 5.84 (bs, 1H), 5.77−5.64 (m, 2H),
5.19−5.11 (m, 4H), 3.87 (d, J = 8.4 Hz, 1H), 3.33 (t, J = 5.9 Hz, 1H),
2.56−2.48 (m, 1H), 2.46−2.38 (m, 1H), 2.30−2.18 (m, 2H), 1.53 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 155.3, 150.2, 132.2, 132.1,
119.41, 119.35, 82.4, 59.0, 52.0, 40.3, 37.7, 28.1; IR (neat) v 2913,
1771, 1704, 1343, 1251, 1158, 1103, 914, 855, 774, 756, 621 cm−1;
HRMS (ESI) calcd for C14H22N2NaO3 289.1528 [M + Na]+, found
289.1516.
(4S,5S)-4,5-Di(3-methyl-2-butenyl)-1-tert-butoxycarbonyl-2-imi-
dazolidinone (6j). This was prepared according to the general
procedure using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg,
0.053 mmol) in THF (4.55 mL) and a solution of 2-methylprop-1-en-
1-ylmagnesium bromide (0.5 M in THF, 0.84 mL, 0.42 mmol). Flash
chromatography (2.0 g silica, 20% EtOAc/hexanes) gave 6j (18.0 mg,
40%) as an amorphous solid. TLC (30% EtOAc/pet ether) RF = 0.31;
[α]2D5 = −17.6 (c 0.90, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 5.77
(s, 1H), 5.12−4.96 (m, 2H), 3.77 (d, J = 7.8 Hz, 1H), 3.18 (t, J = 6.4
Hz, 1H), 2.51−2.05 (m, 4H), 1.72 (s, 6H), 1.64 (s, 3H), 1.62 (s, 3H),
1.53 (s, 9H); 13C NMR (75 MHz, CDCl3, one doubly degenerate
CH3) δ 155.5, 150.4, 136.2, 136.0, 118.0, 117.7, 82.1, 59.8, 53.0, 34.7,
31.7, 28.1, 25.8, 18.1, 18.0; IR (neat) v 3287, 2979, 2360, 1769, 1340,
1249, 1157, 853, 774, 756 cm−1; HRMS (ESI) calcd for
C18H30N2NaO3 345.2154 [M + Na]+, found 345.2147.
(4S,5S)-4,5-Diethyl-1-tert-butoxycarbonyl-2-imidazolidinone
(6e). This was prepared according to the general procedure using 5
(41.5 mg, 0.15 mmol) and CuBr·SMe2 (14.2 mg, 0.069 mmol) in THF
(5.58 mL) and a solution of methylmagnesium chloride (1.8 M in
THF, 0.26 mL, 0.46 mmol). Flash chromatography (2.0 g silica, 30%
EtOAc/hexanes) gave 6e (21.0 mg, 59%) as a pale yellow gum. TLC
(40% EtOAc/pet ether) RF = 0.37; [α]2D5 = −2.0 (c 1.05, CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ 5.63 (bs, 1H), 3.73 (d, J = 8.3 Hz, 1H),
3.14 (t, J = 6.0 Hz, 1H), 1.84−1.57 (m, 4H), 1.53 (s, 9H), 0.98−0.88
(m, 6H); 13C NMR (75 MHz, CDCl3) δ 155.8, 150.5, 82.1, 61.2, 54.6,
29.2, 28.1, 26.4, 9.1, 8.5; IR (neat) v 2968, 1774, 1738, 1702, 1344,
1253, 1161, 1102, 855, 775, 757 cm−1; HRMS (ESI) calcd for
C12H22N2NaO3 265.1528 [M + Na]+, found 265.1530.
(4S,5S)-4,5-Di(4-pentenyl)-1-tert-butoxycarbonyl-2-imidazolidi-
none (6f). This was prepared according to the general procedure using
5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg, 0.053 mmol) in
THF (4.6 mL) and a solution of but-3-en-1-ylmagnesium bromide
(0.44 M in THF, 0.83 mL, 0.37 mmol). Flash chromatography (2.0 g
silica, 20% EtOAc/hexanes) gave 6f (31.6 mg, 68%) as an amorphous
solid. TLC (20% EtOAc/pet ether) RF = 0.10; [α]2D5 = −2.6 (c 1.60,
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 6.49 (bs, 1H), 5.84−5.71
(4S,5S)-4,5-Dibenzyl-1-tert-butoxycarbonyl-2-imidazolidinone
(6k). This was prepared according to the general procedure using 5
(40.0 mg, 0.14 mmol) and CuBr·SMe2 (14.2 mg, 0.069 mmol) in THF
(5.30 mL) and a solution of phenylmagnesium chloride (1.4 M in
THF, 0.33 mL, 0.46 mmol). Flash chromatography (2.0 g silica, 30%
EtOAc/hexanes) gave 6k (31.2 mg, 60%) as an amorphous solid. TLC
(m, 2H), 5.08−4.92 (m, 4H), 3.75 (d, J = 8.5 Hz, 1H), 3.19 (t, J = 6.5
Hz, 1H), 2.13−2.02 (m, 4H), 1.76−1.61 (m, 2H), 1.59−1.31 (m,
15H); 13C NMR (125 MHz, CDCl3) δ 155.6, 150.5, 137.93, 137.86,
115.2, 115.1, 82.1, 60.4, 53.7, 35.8, 33.4, 33.3, 33.0, 28.1, 24.1, 23.7; IR
(neat) v 3309, 2931, 2358, 1773, 1700, 1340, 1249, 1157, 909, 855,
775, 756, 638 cm−1; HRMS (ESI) calcd for C18H30N2NaO3 345.2154
[M + Na]+, found 345.2142.
(40% EtOAc/PE) RF = 0.38; [α]2D5 = −25.3 (c 1.12, CH2Cl2); H
1
NMR (500 MHz, CDCl3) δ 7.33−7.17 (m, 6H), 7.14 (d, J = 7.0 Hz,
2H), 6.92 (d, J = 7.1 Hz, 2H), 4.87 (bs, 1H), 4.13 (d, J = 10.0 Hz, 1H),
3.46 (t, J = 6.8 Hz, 1H), 3.26 (dd, J = 13.3, 3.6 Hz, 1H), 2.71 (dd, J =
13.3, 10.0 Hz, 1H), 2.59 (dd, J = 13.4, 8.7 Hz, 1H), 2.46 (dd, J = 13.4,
5.2 Hz, 1H), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 155.0,
150.1, 136.0, 135.8, 129.2, 128.9, 128.69, 128.65, 126.82, 126.79, 82.5,
60.7, 53.5, 42.0, 39.1, 28.1; IR (neat) v 1762, 1490, 1340, 1152, 1061,
1022, 847, 748, 701 cm−1; HRMS (ESI) calcd for C22H26N2NaO3
389.1841 [M + Na]+, found 389.1827. Note that ent-6k has been
previously synthesized in nine steps from a protected L-aspartic acid
derivative, although neither the specific rotation nor 13C NMR data
were reported.15c
(4S,5S)-4,5-Di(4-benzyloxybutyl)-1-tert-butoxycarbonyl-2-imida-
zolidinone (6g). This was prepared according to the general procedure
using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg, 0.053 mmol)
in THF (3.9 mL) and a solution of 3-benzyloxypropylmagnesium
bromide (0.24 M in THF, 1.53 mL, 0.37 mmol). Flash
chromatography (2.0 g silica, 30% EtOAc/hexanes) gave 6g (54.3
mg, 76%) as an amorphous solid. TLC (40% EtOAc/pet ether) RF =
0.23; [α]2D5 = −3.8 (c 2.70, CH2Cl2); H NMR (500 MHz, CDCl3) δ
1
7.38−7.24 (m, 10H), 5.65 (bs, 1H), 4.48 (s, 4H), 3.75 (d, J = 8.7 Hz,
1H), 3.46 (q, J = 5.8 Hz, 4H), 3.16 (t, J = 6.7 Hz, 1H), 1.77−1.57 (m,
6H), 1.54−1.31 (m, 16H); 13C NMR (125 MHz, CDCl3) δ 155.4,
150.4, 138.40, 138.36, 128.31, 128.30, 127.60, 127.56, 127.51, 127.48,
82.1, 72.90, 72.87, 69.8, 69.7, 60.4, 53.6, 36.2, 33.3, 29.5, 29.4, 28.1,
21.6, 21.1; IR (neat) v 3929, 2858, 2360, 1773, 1696, 1457, 1340,
1249, 1098, 855, 736, 697 cm−1; HRMS (ESI) calcd for
C30H42N2NaO5 533.2991 [M + Na]+, found 533.3013.
(4S,5S)-4,5-Di(2-bromobenzyl)-1-tert-butoxycarbonyl-2-imidazo-
lidinone (6a). This was prepared according to the general procedure
using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg, 0.053 mmol)
in THF (3.52 mL) and a solution of 2-bromophenylmagnesium
chloride (0.6 M in THF, 1.88 mL, 1.13 mmol). Flash chromatography
(2.0 g silica, 30% EtOAc/hexanes) gave 6a (44.3 mg, 60%) as a pale
yellow gum. Spectral data for 6a were consistent with those reported
previously.11
(4S,5S)-4,5-Di(2-methoxybenzyl)-1-tert-butoxycarbonyl-2-imida-
zolidinone (6l). This was prepared according to the general procedure
using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg, 0.053 mmol)
in THF (4.50 mL) and a solution of 2-methoxyphenylmagnesium
bromide (0.46 M in THF, 0.92 mL, 0.42 mmol). Flash
chromatography (2.0 g silica, 40% EtOAc/hexanes) gave 6l (48.1
mg, 80%) as a white solid. Mp 136−138 °C; TLC (40% EtOAc/pet
ether) RF = 0.33; [α]D25 −18.0 (c 0.61, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.20−7.10 (m, 2H), 7.00 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 7.4
Hz, 1H), 6.85−6.75 (m, 2H), 6.71 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 8.2
Hz, 1H), 5.26 (bs, 1H), 4.28 (dd, J = 10.1, 4.3 Hz, 1H), 3.68 (s, 3H),
3.59 (s, 3H), 3.55 (t, J = 7.2 Hz, 1H), 3.21 (dd, J = 13.0, 4.3 Hz, 1H),
2.71 (t, J = 10.7 Hz, 1H), 2.62 (dd, J = 13.2, 7.2 Hz, 1H), 2.55 (dd, J =
13.2, 6.8 Hz, 1H), 1.56 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
157.6, 157.3, 155.3, 150.4, 131.4, 130.9, 128.1, 128.0, 124.6, 124.5,
120.4, 120.3, 110.21, 110.18, 81.9, 59.0, 55.0, 54.9, 51.6, 37.1, 34.1,
28.2; IR (neat) v 2921, 1776, 1492, 1351, 1250, 1153, 1117, 1026, 754
cm−1; HRMS (EI) calcd for C24H30N2O5 426.2155 [M]•+, found
426.2163.
(4S,5S)-4,5-Di(2-(2-bromophenyl)ethyl)-1-tert-butoxycarbonyl-2-
imidazolidinone (6h). This was prepared according to the general
procedure using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg,
0.053 mmol) in THF (3.8 mL) and a solution of 2-bromobenzyl-
magnesium bromide (0.25 M in Et2O, 1.60 mL, 0.40 mmol). Flash
chromatography (2.0 g silica, 30% EtOAc/hexanes) gave 6h (47.4 mg,
61%) as an amorphous solid. TLC (30% EtOAc/pet ether) RF = 0.21;
[α]2D5 = −15.1 (c 2.35, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.52
(t, J = 8.9 Hz, 2H), 7.29−7.02 (m, 6H), 6.77 (bs, 1H), 3.99−3.93 (m,
1H), 3.44 (t, J = 5.7 Hz, 1H), 2.85−2.68 (m, 4H), 2.06−1.96 (m, 2H),
1.94−1.81 (m, 2H), 1.50 (s, 9H); 13C NMR (125 MHz, CDCl3, one
doubly degenerate ArC) δ 155.7, 150.2, 140.0, 139.9, 132.91, 132.88,
130.4, 130.2, 128.0, 127.9, 127.7, 127.6, 124.2, 82.3, 60.0, 53.0, 36.5,
33.7, 31.7, 31.2, 28.1; IR (neat) v 3298, 2966, 2360, 1772, 1472, 1340,
1249, 1154, 1022, 854, 749, 659 cm−1; HRMS (ESI) calcd for
C24H28(79Br)2N2NaO3 573.0364 [M + Na]+, found 573.0386.
(4S,5S)-4,5-Di(2-propenyl)-1-tert-butoxycarbonyl-2-imidazolidi-
none (6i). This was prepared according to the general procedure using
5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (14.2 mg, 0.069 mmol) in
THF (5.34 mL) and a solution of vinylmagnesium chloride (1.6 M in
THF, 0.29 mL, 0.46 mmol). Flash chromatography (2.0 g silica, 30%
EtOAc/hexanes) gave 6i (21.5 mg, 57%) as a pale yellow gum. TLC
E
DOI: 10.1021/acs.joc.5b00832
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(4R,5R)-4,5-Di(2-methoxybenzyl)-1-tert-butoxycarbonyl-2-imida-
zolidinone (ent-6l). This was prepared according to the general
procedure using ent-5 (40.6 mg, 0.14 mmol) and CuBr·SMe2 (14.2
mg, 0.069 mmol) in THF (4.78 mL) and a solution of 2-
methoxyphenylmagnesium bromide (0.46 M in THF, 0.92 mL, 0.42
mmol). Flash chromatography (2.0 g silica, 30% EtOAc/hexanes) gave
ent-6l (51.3 mg, 84%) as a white solid. Spectral data for ent-6l were
consistent with those reported above for 6l. [α]2D5 +18.3 (c 2.08,
CH2Cl2).
1H), 6.80 (d, J = 7.2 Hz, 1H), 5.69 (bs, 1H), 4.04 (d, J = 8.4 Hz, 1H),
3.42 (t, J = 7.0 Hz, 1H), 3.19 (dd, J = 13.2, 3.6 Hz, 1H), 2.70−2.59 (m,
2H), 2.48 (dd, J = 13.5, 7.0 Hz, 1H), 1.58 (s, 9H); 13C NMR (125
MHz, CDCl3, two doubly degenerate ArC’s) δ 154.6, 150.1, 137.8,
137.5, 134.53, 134.51, 129.9, 129.2, 129.0, 127.31, 127.29, 127.1, 82.9,
60.3, 53.5, 41.7, 38.8, 28.2; IR (neat) v 3302, 2328, 1762, 1574, 1424,
1337, 1198, 1148, 1050, 786, 689 cm−1; HRMS (ESI) calcd for
C22H24Cl2N2NaO3 457.1062 [M + Na]+, found 457.1079.
(4S,5S)-4,5-Di(3,5-dimethoxybenzyl)-1-tert-butoxycarbonyl-2-
imidazolidinone (6m). This was prepared according to the general
procedure using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg,
0.053 mmol) in THF (4.4 mL) and a solution of 3,5-dimethoxy-
phenylmagnesium bromide (0.49 M in THF, 1.0 mL, 0.49 mmol).
Flash chromatography (2.0 g silica, 40% EtOAc/hexanes) gave 6m
(40.8 mg, 60%) as an amorphous solid. TLC (50% EtOAc/pet ether)
ASSOCIATED CONTENT
* Supporting Information
NMR spectra and HPLC traces. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.joc.5b00832.
■
S
RF = 0.35; [α]2D5 = −15.0 (c 2.00, CH2Cl2); H NMR (500 MHz,
1
AUTHOR INFORMATION
Corresponding Author
*E-mail: keller@uow.edu.au.
■
CDCl3) δ 6.30 (s, 1H), 6.25 (s, 1H), 6.24 (s, 2H), 6.06 (s, 2H), 5.17
(bs, 1H), 4.08 (d, J = 9.5 Hz, 1H), 3.75 (s, 6H), 3.72 (s, 6H), 3.47 (t, J
= 7.2 Hz, 1H), 3.19 (dd, J = 13.2, 3.4 Hz, 1H), 2.62−2.52 (m, 2H),
2.41 (dd, J = 13.3, 6.1 Hz, 1H), 1.58 (s, 9H); 13C NMR (125 MHz,
CDCl3, two doubly degenerate ArC’s) δ 160.9, 154.7, 150.2, 138.2,
138.1, 107.2, 106.8, 98.8, 82.6, 60.8, 55.2, 55.1, 53.7, 42.6, 39.5, 28.2;
IR (neat) v 1772, 1607, 1595, 1458, 1429, 1340, 1293, 1205, 1148,
1064, 831, 691 cm−1; HRMS (ESI) calcd for C26H34N2NaO7 509.2264
[M + Na]+, found 509.2265.
(4S,5S)-4,5-Di(3,4-methylenedioxybenzyl)-1-tert-butoxycarbonyl-
2-imidazolidinone (6n). This was prepared according to the general
procedure using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg,
0.053 mmol) in THF (4.4 mL) and a solution of 3,4-(methylene-
dioxy)phenylmagnesium bromide (0.42 M in THF, 1.0 mL, 0.42
mmol). Flash chromatography (2.0 g silica, 40% EtOAc/hexanes) gave
6n (44.5 mg, 70%) as an amorphous solid. TLC (50% EtOAc/pet
ether) RF = 0.36; [α]D25 = +1.8 (c 0.80, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 6.66 (d, J = 7.7 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 6.50−6.45
(m, 2H), 6.38 (d, J = 7.9 Hz, 1H), 6.34 (s, 1H), 5.97−5.89 (m, 4H),
5.78 (bs, 1H), 3.99 (d, J = 9.7 Hz, 1H), 3.40 (t, J = 7.1 Hz, 1H), 3.12
(dd, J = 13.3, 3.3 Hz, 1H), 2.60 (dd, J = 13.5, 6.5 Hz, 1H), 2.52 (dd, J
= 13.2, 10.4 Hz, 1H), 2.40 (dd, J = 13.5, 7.5 Hz, 1H), 1.58 (s, 9H); 13C
NMR (125 MHz, CDCl3, one doubly degenerate ArC) δ 154.9, 150.2,
147.74, 147.69, 146.4, 129.6, 129.4, 122.3, 122.1, 109.2, 109.0, 108.20,
108.18, 101.01, 100.99, 82.6, 60.6, 53.7, 41.8, 38.8, 28.2; IR (neat) v
3285, 2331, 1769, 1490, 1341, 1242, 1188, 1037, 928, 854, 813, 773,
735 cm−1; HRMS (ESI) calcd for C24H26N2NaO7 477.1638 [M +
Na]+, found 477.1649.
Author Contributions
†M.D.K., S.J.B., and S.M.W. contributed equally.
Notes
The authors declare no competing financial interest.
REFERENCES
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lidinone (6o). This was prepared according to the general procedure
using 5 (40.0 mg, 0.14 mmol) and CuBr·SMe2 (10.8 mg, 0.053 mmol)
in THF (4.9 mL) and a solution of o-tolylmagnesium chloride (1.0 M
in THF, 0.47 mL, 0.47 mmol). Flash chromatography (2.0 g silica,
20% EtOAc/hexanes) gave 6o (30.7 mg, 55%) as an amorphous solid.
TLC (20% EtOAc/pet ether) RF = 0.10; [α]2D5 = −14.7 (c 1.55,
CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.16−6.92 (m, 7H), 6.76 (d,
J = 7.4 Hz, 1H), 6.28 (bs, 1H), 4.14 (dd, J = 10.8, 4.5 Hz, 1H), 3.46 (t,
J = 7.4 Hz, 1H), 3.27 (dd, J = 13.4, 4.5 Hz, 1H), 2.80−2.44 (m, 3H),
2.12 (s, 3H), 1.91 (s, 3H), 1.55 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 155.4, 150.3, 136.5, 136.1, 134.1, 134.0, 130.52, 130.48, 130.45,
129.6, 126.9, 126.8, 126.0, 125.9, 82.5, 58.3, 51.5, 39.0, 36.6, 28.1, 19.2,
18.9; IR (neat) v 3298, 2331, 1772, 1700, 1456, 1340, 1243, 1151, 854,
741 cm−1; HRMS (ESI) calcd for C24H30N2NaO3 417.2154 [M +
Na]+, found 417.2145.
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iterations were required: 2.0 g silica, 25% EtOAc/hexanes) gave 6p
(22.4 mg, 37%) as a colorless gum. TLC (30% EtOAc/pet ether) RF =
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DOI: 10.1021/acs.joc.5b00832
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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to unreactive RCu. Therefore, there is a negligible excess of reactive
carbanion under these conditions.
(19) TLC analysis had previously indicated very slow reaction rates at
−40 °C. Therefore, the mixing temperature was modified to −20 °C in
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(21) See the Supporting Information for full details.
(22) For a related example of intramolecular N-acylation involving an
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G
DOI: 10.1021/acs.joc.5b00832
J. Org. Chem. XXXX, XXX, XXX−XXX