Fast Pd- and Pd/Cu-catalyzed direct C - H arylation of cyclic nitrones. Application to the synthesis of enantiopure quaternary α-amino esters

Article abstract of DOI:10.1021/jo301114k

Cocatalysis by pivalic acid or copper bromide allows a very fast, clean, and high-yielding palladium-catalyzed coupling of a large array of aryl, thienyl, and pyridyl halides with cyclic nitrones, including DMPO. The study of the reaction conditions, scope, and mechanism is presented. Applied to the chiral nitrone MiPNO, this transformation provides a straightforward access to enantiopure a-methyl α-arylglycine esters.

Full text of DOI:10.1021/jo301114k

Article
pubs.acs.org/joc
Fast Pd- and Pd/Cu-Catalyzed Direct C−H Arylation of Cyclic
Nitrones. Application to the Synthesis of Enantiopure Quaternary
α‑Amino Esters
Emilien Demory,† Daniel Farran,† Benoit Baptiste,‡ Pierre Y. Chavant,*,† and Veronique Blandin*,†
́
‡
†Dep
́
artement de Chimie Molec
́
ulaire, Equipe SeRCO and Service de Cristallographie, UMR-5250, ICMG FR-2607, CNRS,
́
Universite Joseph Fourier, BP-53, 38041 Grenoble Cedex 9, France
S
* Supporting Information
ABSTRACT: Cocatalysis by pivalic acid or copper bromide allows a very fast, clean, and high-yielding palladium-catalyzed
coupling of a large array of aryl, thienyl, and pyridyl halides with cyclic nitrones, including DMPO. The study of the reaction
conditions, scope, and mechanism is presented. Applied to the chiral nitrone MiPNO, this transformation provides a
straightforward access to enantiopure α-methyl α-arylglycine esters.
MiPNO is conveniently stable to heat, and we assumed that it
could be a worthy substrate for the study of direct coupling
reactions with aromatic halides. We hypothesized that cyclic
nitrones should behave like pyridine N-oxide, which is an
excellent substrate for Pd-catalyzed direct arylation.8,9 Indeed,
aromatic amine N-oxides share common reactivity features with
nitrones: for instance, they undergo addition of Grignard
reagents at the ortho position10 and cycloaddition reactions
with dipolarophiles.11 The same idea was independently
explored by Zhao and Wang, who very recently reported on
the Pd-catalyzed direct arylation of imidazolone N-oxides with
aryl bromides.12 Our own investigations led us to the
development of two catalytic systems: indeed, the use of
cocatalysts allows a very fast and efficient Pd-catalyzed direct
C−H arylation of cyclic nitrones 1−3 (Figure 1) with a large
array of aryl and heteroaryl halides. We present herein our
study of the reaction conditions, scope, and mechanism. The
obtained products still present a reactive nitrone function which
renders them valuable intermediates.13 As a first example, we
show that direct arylation of the chiral nitrone MiPNO,
followed by a totally diastereoselective Grignard addition,
provides a straightforward access to enantiopure α-methyl α-
arylglycine esters.
INTRODUCTION
■
In the past decade, a rapidly increasing number of methods for
the direct arylation of arenes and heteroarenes has been
developed.1 In this regard, nitrogen-containing heteroaromatic
compounds have been the subject of extensive research,1,2
whereas scarce examples of direct arylation involving non-
aromatic nitrogen heterocycles are found. The arylation of 4,4-
dimethyloxazoline was investigated by Bergman and Ellman
with Rh catalysts,3 and Ackermann reported very recently a Pd-
catalyzed version.4 Finally, the Daugulis Cu-catalyzed direct
arylation1f was applied to the synthesis of 5-arylbenzotriaze-
pines.5
Our continued interest in the preparation and reactivity of
nitrones6 led us to the design of the chiral cyclic nitrone 1
(MiPNO; Figure 1) as a versatile precursor of α-amino acids.7
Received: June 4, 2012
Published: September 4, 2012
Figure 1. Nitrones referred to in this study.
© 2012 American Chemical Society
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makes the Cu cocatalyst less robust than the Pd-PivOH system,
since self-condensation of the nitrone could compete with the
coupling. Therefore, we selected conditions A: 2 mol % Pd, 2
mol % PPh3 (from Pd2(dba)3 + PPh3),17 and 20 mol % PivOH
to investigate the scope of the direct arylation of nitrones.
Although the reaction can be performed efficiently at 100 °C
(entry 23), it remains very clean at 150 °C and we found no
drawback in developing our examples at this temperature so
that most of the reactions are complete in 1 h. Several literature
reports hint that higher temperatures allow reduced catalyst
loading.18 Actually, with only 0.1 mol % Pd, the model reaction
is complete within 3 h at 150 °C (entry 25). In contrast, with
0.2 mol % Pd at 100 °C, the product was still contaminated
with starting 1 (8%) after 2 days (entry 24).
RESULTS AND DISCUSSION
■
Pd- and Pd/Cu-Catalyzed Direct Arylation of Nitrones.
We first studied the reaction of nitrone 1 with 4-bromotoluene
6 in the presence of a Pd catalyst (Scheme 1); representative
Scheme 1. Palladium-Catalyzed Direct Arylation of Nitrone
1 vs Copper-Catalyzed Self-Condensation
The substrate scope is outlined in Figure 2. To our delight,
the reaction could in particular be extended to DMPO 2,19
notwithstanding the potentially labile H atoms in positions α to
the double bond.8c Using conditions A, nitrones 1−320 reacted
cleanly with various aryl and pyridyl bromides to give
ketonitrones 7a−m, 9a−d, and 10a−c, respectively.21 Com-
plete conversion was generally achieved in 0.5−2 h; the isolated
yields reflect only purification issues. In a sole instance the
formation of byproduct was noticeable: the coupling of 5-
bromo-2,4-dimethoxybenzaldehyde (68% yield in 7h) was
accompanied by some hydrodebromination.
results are gathered in Table 1. We started with experiments
conducted in closed vessels under microwave irradiation. Using
conditions based on Fagnou’s work (toluene, Pd(OAc)2 2 mol
%, SPhos 2 mol %, K2CO3, 150 °C, 1.5 h; entry 1), we found
that nitrone 1 and 4-bromotoluene 6 reacted remarkably
cleanly to give adduct 7a in 40−50% conversions. Moreover,
the addition of pivalic acid14 (PivOH, 20 mol %, entry 2)
dramatically improved the result: complete conversion (92%
isolated yield in 7a) was achieved in 1.5 h. At this point we
decided to proceed with conventional heating at atmospheric
pressure; we chose anisole as the solvent, so that temperatures
up to 150 °C could be reached. The reaction proved slower
under these conditions (compare entries 3 vs 2). However, if
the PdII precursor and the ligand are premixed in anisole
beforehand (entry 5), or if a Pd0 precursor is used (entry 7), a
high activity is regained. One equivalent of phosphine per Pd is
required (compare entries 3, 4, and 6). The positive effect of
the PivOH additive was confirmed (compare entries 8 and 7).
We next investigated the nature of the phosphine ligand
(entries 9−14). In comparison to SPhos, XPhos and tri-tert-
butylphosphine ligands gave similar results; however, in the
latter case the experimental protocol could be misleading
(compare entries 12 vs 11). Finally, the simple, inexpensive
triphenylphosphine proved to be the ligand of choice for this
reaction: complete conversion of MiPNO 1 into ketonitrone 7a
(95% isolated yield) is achieved in 1 h using triphenylphos-
phine in combination with Pd2(dba)3 (entries 13 and 14) or
PdCl2(PPh3)2 (entry 15). The absence of the PivOH additive
was detrimental (compare entries 16 vs 13) and could not be
entirely compensated by the use of Pd(OAc)2 as the Pd source
(entries 17 and 18).
Whereas compounds 1−3, representative of three classes of
cyclic nitrones, turned out to be excellent substrates for this Pd-
catalyzed direct arylation, all attempts to extend the reaction to
acyclic nitrones (Z configuration)22 such as 4 and 5 failed: PBN
4 was recovered intact and glyoxylic nitrone 5 underwent
degradation. The Pd-PivOH conditions also failed with some
nitrogen-containing aryl bromides.23 Whereas 3-bromopyridin-
e
8e and 4-bromopyridine could be easily coupled with nitrone 1
under conditions A (leading to compounds 7k,l, respectively),
2-bromopyridine,9a 2,5-dibromopyridine, and bromoanilines
remained unchanged. In such case, Cu cocatalysis comes as
an efficient solution: the coupling of MiPNO 1 with nitrogen-
containing aryl bromides using a Pd/Cu cocatalysis (2 mol %
Pd, 2 mol % PPh3, 5 mol % CuBr·DMS, 5 mol % 1,10-
phenanthroline, no PivOH; conditions B in Figure 2) provided
the expected adducts 7n−p in excellent yields. The action of
Cu salts as counter-poisons has been marginally mentioned in
the case of pyridine N-oxide.8d,e
The case of dibromides deserves attention. Reaction of o-
and m-dibromobenzenes (conditions A) and 2,6-dibromopyr-
idine and 2,5-dibromothiophene (conditions B) with 2 equiv of
enantiopure (S)-1 led in high yields to the bis-nitrone products
7i,j and 7q,r, respectively, uncontaminated by monocoupling or
hydrodebromination products.24 This illustrates further the
efficiency and cleanness of each coupling step. The possibility
of grafting several cyclic nitrones on one aromatic structure
offers an easy access not only to new families of conjugated
polynitrones with unexplored properties but also, since
reduction of nitrones to imines12 is easy, to new enantiopure
C2-symmetric diimine ligands.
In addition, recent work indicates that Cu could be a
cocatalyst8d,e,15 or a catalyst.16 Indeed, if PivOH was replaced
by CuBr·DMS and 1,10-phenanthroline (5 mol % each), the
model reaction of 1 and 6 proceeded even more quickly than
the PivOH-catalyzed version (compare entries 19 and 20 vs
entry 13). PivOH and Cu showed no synergetic effect
(compare entries 21 and 20). On the other hand, without the
cooperation of Pd (entry 22), Cu causes extensive self-
condensation of nitrone 1 to furnish 8 (Scheme 1). This
In addition, we investigated the reactivity of other aryl
halides12 in the present coupling. Methyl 4-chlorobenzoate was
unreactive under conditions A (<15% nitrone 1 conversion
after 72 h) or B (conversion of nitrone 1 was complete in 1 h
but self-condensation of the nitrone competed with the
arylation: a 1/1 ratio of 7f and 8 was obtained). Changing
triphenylphosphine for XPhos25 under conditions A brought
about success: methyl 4-chlorobenzoate was totally converted
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a
Table 1. Direct Arylation of Nitrone 1 with 4-Bromotoluene 6
b
c
entry
Pd source
ligand
SPhos
additive
additional information
time
conversion (%)
d
e
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
toluene (solvt), μw
1.5 h
1.5 h
1.5 h
16 h
40−50
100 (92)
50
d
e
f
f
SPhos
SPhos
PivOH
PivOH
toluene (solvt), μw
100 (85)
50
4
Pd(OAc)2
SPhos
SPhos
SPhos
PivOH
4 mol % SPhos
1.5 h
24 h
100
94
g
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
PivOH
PivOH
PivOH
preformed complex
1 h
16 h
0
15 min
1 h
50
85
17 h
100
27
8
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
SPhos
XPhos
XPhos
1 h
18 h
90
9
PivOH
PivOH
30 min
2 h
50
85
g
10
preformed complex
15 min
1 h
70
85
2 h
100
15
11
12
Pd2(dba)3
Pd2(dba)3
PtBu3,HBF4
PtBu3,HBF4
PivOH
PivOH
18 h
g
preformed complex
5 min
15 min
1 h
7
30
72
2 h
100
50
13
14
15
Pd2(dba)3
PPh3
PPh3
PivOH
PivOH
PivOH
7 min
1 h
f
100 (95)
50
Pd2(dba)3
4 mol % PPh3
7 min
1 h
100
39
PdCl2(PPh3)2
5 min
7 min
10 min
1 h
50
60
100
40
16
17
Pd2(dba)3
Pd(OAc)2
PPh3
PPh3
1 h
18 h
95
25 min
50 min
1.5 h
18 h
19
38
62
100
25
g
18
Pd(OAc)2
PPh3
preformed complex
20 min
50 min
1.5 h
30 min
18 h
56
79
19
20
21
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
PPh3
PPh3
PPh3
CuBr·DMS
50
100
50
CuBr·DMS Phen
4 min
20 min
4 min
18 min
1 h
100
50
CuBr·DMS Phen PivOH
100
h
22
23
24
CuBr·DMS Phen
PivOH
product: 8 (95)
Pd2(dba)3
PPh3
100 °C
2 h
100
40
PdCl2(PPh3)2
PivOH
0.2 mol % Pd, 100 °C
4 h
48 h
92
120 h
30 min
3 h
93
25
PdCl2(PPh3)2
PivOH
0.1 mol % Pd
50
f
100 (90)
a
Conditions unless otherwise stated: MiPNO 1 (1 mmol), 4-bromotoluene (1.1 equiv), K2CO3 (1.5 equiv), Pd (2 mol %), phosphine ligand (2 mol
%), anisole (0.5 M), 150 °C (preheated oil bath). The Pd source, the ligand, and all other reagents were charged into the vessel, the solvent was
b
added, and the vessel was plunged in the hot bath. Conditions: PivOH (20 mol %), CuBr·DMS (5 mol %), 1,10-phenanthroline (Phen, 5 mol %).
c
d
e
1
Conversion evaluated by H NMR analysis of reaction aliquots. solvt: reaction solvent, if not anisole. μw: reaction performed under microwave
f
g
irradiation. Isolated yield (%) in 7a. Preformed complex: Pd source, ligand, and K2CO3 were mixed at room temperature in anisole prior to
addition of substrates. Isolated yield (%) in 8.
h
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Figure 2. Ketonitrones 7, 9, and 10 prepared by Pd-catalyzed direct arylation of nitrones 1−3 with aryl bromides. General conditions: ArBr (1.1
equiv), K2CO3 (1.5 equiv), anisole (0.5 M), 150 °C, 0.5−2 h. Conditions A: Pd (2 mol %), PPh3 (2 mol %), PivOH (20 mol %). Conditions B: Pd
(2 mol %), PPh3 (2 mol %), CuBr·DMS (5 mol %), 1,10-phenanthroline (5 mol %). Legend: (a) 2 equiv of nitrone (S)-1; (b) run performed with 5
mol % Pd/PPh3.
in less than 30 min (91% isolated yield), and the less reactive 4-
chlorotoluene required only 2 h (94% isolated yield). As for
aryl iodides, the arylation reaction was sluggish under
conditions A (methyl 4-iodobenzoate: 49% nitrone 1
conversion after 2 h) and the degradation of the catalyst was
visible. Conditions B were the solution, however, providing
arylation products 7a,b,f in excellent yields (92%, 95%, and
85%, respectively) within 2 h.
Figure 3. Postulated intermediates in the case of a Heck-like
mechanism (I) and a deprotonation/metalation mechanism (II).
Mechanistic Considerations. In terms of mechanism,
many features of the present reaction are analogous to those
met in Fagnou’s azine N-oxide direct arylation, such as
importance of carboxylate base, weak influence of the nature
of the aryl bromide, and kinetic isotopic effect (KIE).26 With
regard to the latter, we compared in separate experiments27 the
relative rate of reaction of nitrone 1 and deuterated analogue d-
1 (aryl bromide 6, PdCl2(TPP)2 (0.2 mol %), 150 °C) and
found a kH/kD ratio of 3. Thus, the C−H bond cleavage occurs
during the turnover-limiting step.
this hypothesis, to account for the primary KIE, the elimination
step should be turnover-determining. Then, since intermediate
I would accumulate, decomposition byproduct could be
present. We have studied earlier7b the addition of aryl Grignard
reagents to nitrone 1 and noted that the corresponding
hydroxylamine adducts were prone to dehydration in basic
media, to produce the corresponding imines. Neither hydroxyl-
amine nor imine byproducts were ever detected in the crude
products of the present coupling. Moreover, this hypothesis
does not explain the absence of reaction of acyclic Z nitrones.
Hence, the possibility of a Heck-like mechanism was discarded.
A common hypothesis for the C−H arylation of (hetero)-
aromatic substrates is a deprotonation/metalation mechanism,
leading to intermediate II (Figure 3).29 The deuteration
The possibility of an addition−elimination process, where
the C−C bond is formed prior to the rupture of the C−H bond
(usually referred to as “Heck-like” in discussions on C−H
activation),28 could be considered (Figure 3, intermediate I). In
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experiments gathered in Table 2 suggest that such a
This modeling also provides an explanation for the non-
reactivity of linear, Z nitrones: in the case of 1′, 2′, and PNO,
the metalated intermediates II (Figure 4) are stabilized by a
strong Pd−O interaction (N−C−Pd angles 94−96°, O−Pd
distances 2.3−2.4 Å), making the transformation reasonably
endothermic (ΔG298 K = 11.8−16.5 kcal mol−1). In contrast, the
calculated deprotonation of the Z model 4′ is highly
endothermic: ΔG298 K = +29.1 kcal mol−1, which is higher
than the highest transition state of the series.
Thus, a metalation−deprotonation model is reasonable. It
can be considered concerted insofar as it takes place in the
coordination sphere of Pd. The exact nature of the species
(inner- or outer-sphere approach of the carboxylate,26 precise
nature of the Pd ligands34) was not sought further in the
present study.
deprotonation is relatively easy.30 Qualitatively, nitrone 1 is
a
Table 2. Deuterium Exchange with d6-Acetone
base
compd
K2CO3
KOH
tBuOK
1
deuteration (98%)
no reaction
b
2
decomposition
no reaction
4
no reaction
PNO
no reaction
deuteration (91%)
a
The compound was heated in d6-acetone (140 °C, 30 min,
b
microwave irradiation) with >1 equiv of base. Compound 2
decomposed also at 20 °C with substoichiometric KOH.
more acidic than nitrone 2 and pyridine N-oxide PNO, which
are both inert in the presence of K2CO3. The decomposition of
2 in the presence of KOH illustrates the general sensitivity of
cyclic nitrones;31 in contrast, the linear Z nitrone 4 is inert
Application to the Synthesis of Enantiopure α-Methyl
α-Arylglycine Esters. MiPNO 1 is a chiral glycine
equivalent,7 and the present direct arylation of nitrones can
be easily applied to the preparation of enantiopure quaternary
α-arylglycines which have been developed in particular for their
restricted conformational flexibility.35 To demonstrate this, we
submitted adducts 7a,b,k prepared from enantiopure samples of
(S)- and (R)-1 to excess MeMgCl in THF (Scheme 3). The
corresponding hydroxylamines 11a,b,k were obtained in
quantitative yields. The diastereoselectivity of the addition
was excellent: only one diastereomer was detected by 1H NMR
analysis of the crude reaction mixtures. The relative
configuration of 11a was confirmed by X-ray analysis:36 as
expected, the methyl group was transferred anti to the bulky
isopropyl group.37 Reduction of the N−O bond was performed
using zinc in acetic acid, under sonication. Hydrolysis of the
imidazolidinone ring required harsh conditions: a p-anisyl
group was deprotected. The obtained amino acids were
esterified for purification, providing the methyl esters of α-
methyl-α-arylglycines 12a,b,k in 43−66% overall yields from
7a,b,k (four steps) with an excellent enantiomeric purity
t
toward KOH and BuOK. On the other hand, heating 1 with
tBuOK in d8-toluene (140 °C, 30 min, microwave irradiation)
produced the self-condensation product 8, whereas nitrone 1
remained unchanged under the coupling conditions (K2CO3,
anisole, 150 °C) when Pd was omitted.
When Cu is used as the sole catalyst (Table 1, entry 22),
product 8 is obtained. This proves that Cu-assisted
deprotonation of 1 can take place, the organocopper species
reacting with excess 1 (Scheme 2). In the Pd-catalyzed direct
Scheme 2. Possible Pathways for the Direct Arylation of
Nitrones
38
1
(>98%, H NMR analysis).
CONCLUSION
■
Thus, we have disclosed two sets of conditions for the direct
arylation of cyclic nitrones. The acceleration effect of the
cocatalysts allows the reaction to be very fast and suitable for
substrates such as DMPO 2. We are currently investigating the
broadening of this new direct C−H arylation reaction to other
cyclic nitrones. A wide range of aryl and heteroaryl halides
reacted smoothly under our conditions, giving access to highly
functionalized compounds. Beyond the possible applications of
this reaction to the synthesis of non-natural amino acids or new
ligands,39 the present work contributes to indicate that Pd-
catalyzed arylation of heterocyclic C(sp2)−H bonds is not
intrinsically limited to aromatic systems.
arylation, CuBr accelerates the coupling: under these
conditions B, the deprotonation of the nitrone probably occurs
in the coordination sphere of Cu (Scheme 2), and a
transmetalation from Cu to Pd would provide intermediate
II. Conversely under conditions A, the fact that no self-
condensation product was observed in the absence of Pd
indicates that the nitrone is presumably coordinated to Pd in
the deprotonation step.
The hypothesis of a concerted metalation−deprotonation
(CMD) mechanism,26,29,32 proposed for the Pd-catalyzed direct
arylation of (hetero)arenes including azine N-oxides, was next
considered. Gorelsky33 and others30a performed extended DFT
calculations over a large variety of substrates and met good
agreement with experimental data. In order to find out how
nitrones are positioned among other C−H arylation substrates,
we reproduced Gorelsky’s calculations26 on three simplified
models of nitrones, 1′, 2′, and 4′ (Figure 4). It appeared that
the calculated free energies of activation (ΔG⧧298 K, kcal mol−1)
for 1′ (19.4) and 2′ (22.2) were among the lowest reported.
EXPERIMENTAL SECTION
■
General Methods. All experiments were carried out under a
nitrogen atmosphere in oven-dried glassware equipped with a
magnetic stir bar. Standard inert-atmosphere techniques were used
in handling all air- and moisture-sensitive reagents. Anisole was washed
with 10% aqueous NaOH and water, dried over magnesium sulfate,
distilled, stored, and handled under a N2 atmosphere. HPLC grade
THF, Et2O, toluene, and CH2Cl2 were dried and purified in a solvent
purification system. Palladium sources were stored in a desiccator and
were weighed out in air. All other reagents and solvents were
purchased from commercial sources and used as received. Product
purifications by dry column vacuum chromatography40 were
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Figure 4. Free Gibbs energy profile (kcal mol−1) calculated for carboxylate-assisted CMD processes (DFT, B3LYP, basis set DZVP for Pd and TZVP
for others).
Scheme 3. Preparation of α-Methyl α-Arylglycine Esters 12
performed using Macherey Nagel silica gel 60 (0.015−0.04 mm) and
gradient elution: cyclohexane/ethyl acetate (10/0 to 0/10), then ethyl
acetate/ethanol (10/0 to 9/1).
introduced the crude sulfonamide (13.5 g, 45 mmol), dimethoxy-
methane (100 mL), and BF3·OEt2 (25 mL). The solution was stirred
overnight. The reaction mixture was quenched with water (100 mL)
and diluted with dichloromethane (50 mL), and the two phases were
separated. The organic layer was washed with a saturated aqueous
NaHCO3 solution (2 × 50 mL) and then dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude material was
recrystallized from ethanol to afford 3,3-dimethyl-2-tosyl-1,2,3,4-
tetrahydroisoquinoline (4.7 g, 33%). In a 250 mL three-necked flask
equipped with an ammonia condenser was added the N-tosylamine
(4.7 g, 15 mmol). The flask and condenser were cooled to −50 °C,
and ammonia (50 mL) was condensed to give a suspension of the N-
tosylamine in ammonia. Lithium (740 mg, 105 mmol) was then added
to the suspension to give a dark blue solution. The cold bath was
removed so that the flask temperature rose to −33 °C (reflux of
ammonia), the condenser being maintained at −50 °C. The solid N-
tosylamine was consumed. When the solution turned yellow with solid
still present, fresh lithium was added until total consumption of the N-
tosylamine. The condenser was removed, and ammonia was
evaporated by flushing the flask with nitrogen. Dichloromethane (30
mL) and ice (30 g) were added. The mixture was stirred for 20 min.
The aqueous phase was extracted with diethyl ether (2 × 70 mL) and
dichloromethane (50 mL). The combined organic phases were dried
over MgSO4, filtered, and concentrated under reduced pressure to
afford 3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (2.5 g, quantitative).
In a 250 mL flask, the crude amine (2.5 g, 15 mmol) was dissolved in
methanol (50 mL) and water (50 mL). An aqueous solution of
Na2WO4 (500 mg, 1.5 mmol in 5 mL of water) was added. Hydrogen
Melting points (mp) are given uncorrected. For optical rotations
[α], the corresponding concentration is given in g per 100 cm−3.
Infrared spectra (IR) were recorded using ATR (attenuated total
reflection); wavenumbers are reported in reciprocal centimeters
(cm−1). The chemical shifts (δ) of the NMR spectra are given in
ppm using TMS as internal reference. Multiplicities are declared as
follows: s (singlet), d (doublet), hept (heptuplet), m (multiplet), q
(quadruplet); br (broad). Coupling constants (J) are given in hertz.
Nitrones. Racemic and enantiopure MiPNO 1 (2-isopropyl-1,2-
dimethyl-5-oxo-2,5-dihydro-1H-imidazole 3-oxide) was prepared
according to ref 7; DMPO 2 (2,2-dimethyl-3,4-dihydro-2H-pyrrole
1-oxide) is commercially available.
3,3-Dimethyl-3,4-dihydroisoquinoline 2-Oxide 3.20 The title
compound was synthesized from 2-methyl-1-phenylpropan-2-
amine,41 with slight modifications from the literature protocols.20
A
250 mL flask was charged with 2-methyl-1-phenylpropan-2-amine (8.4
g, 50 mmol) and dichloromethane (50 mL). To the solution was
added Et3N (12 mL, 86 mmol) and p-toluenesulfonyl chloride (11.5 g,
60 mmol). The solution was stirred overnight at room temperature.
The reaction mixture was quenched with a saturated aqueous Na2CO3
solution (50 mL). The organic layer was washed with a saturated
aqueous Na2CO3 solution (50 mL) and then with brine (50 mL). The
organic layer was dried over MgSO4, filtered, and concentrated under
reduced pressure to afford 4-methyl-N-(2-methyl-1-phenylpropan-2-
yl)benzenesulfonamide (13.5 g, 90%). In a 250 mL flask were
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peroxide (4.2 mL of a 30 wt % solution in water, 45 mmol) was added
dropwise. The reaction was followed by TLC. After completion, MnO2
(200 mg) was added cautiously to the reaction mixture. The
suspension was then filtered over Celite, and methanol was removed
under reduced pressure. The aqueous layer was extracted with
dichloromethane (2 × 40 mL). The crude product was purified over
silica gel to yield nitrone 3 (1.2 g, 46%). 1H NMR (400 MHz, CDCl3):
δ 7.69 (s, 1H), 7.29−7.24 (m, 2H), 7.21−7.14 (m, 1H), 7.12−7.07 (m,
1H), 3.07 (s, 2H), 1.46 (s, 6H). 13C NMR (101 MHz, CDCl3): δ
132.7, 129.9, 129.1, 128.4, 127.6, 127.4, 124.7, 66.9, 41.8, 24.7.
Direct Arylation of Nitrones. General Procedure A. A 10 mL
Schlenk flask under an N2 atmosphere was charged with nitrone, aryl
bromide (1.1 equiv), Pd2(dba)3 (1 mol %; i.e. 2 mol % Pd),
triphenylphosphine (2 mol %),17 pivalic acid (0.2 equiv), and K2CO3
(1.5 equiv). The flask was evacuated and purged with N2, and anisole
was added to give a 0.5 M solution. The Schlenk flask was plunged
into a 150 °C preheated oil bath, and the reaction was monitored by
1H NMR spectroscopy of small aliquots. After completion of the
reaction, the crude solution was purified over silica gel to give the
arylnitrone.
2-Isopropyl-1,2-dimethyl-4-(4-nitrophenyl)-5-oxo-2,5-dihydro-
1H-imidazole 3-Oxide (7d). The title compound was prepared
according to general procedure A from MiPNO (170 mg, 1.0
mmol) and 4-bromonitrobenzene (223 mg, 1.1 mmol): 1 h; colorless
crystals (245 mg, 89%). Mp: 155−156 °C. 1H NMR (400 MHz,
CDCl3): δ 9.04 (d, J = 9.3, 2H), 8.30 (d, J = 9.3, 2H), 3.12 (s, 3H),
2.43 (qq, J = 7.1, 6.8, 1H), 1.76 (s, 3H), 1.03 (d, J = 7.1, 3H), 0.99 (d,
J = 6.8, 3H). 13C NMR (75 MHz, CDCl3): δ 162.3, 148.2, 131.6,
128.1, 123.4, 92.2, 35.2, 26.6, 21.6, 16.2, 15.5. IR: 3110, 2989, 2970,
1703, 1544, 1506, 1338, 1110, 863. HRMS (ESI+): m/z calcd for
C14H17N3O4Na+ 314.111 13; found 314.110 87. Data for the crystal
structure have been deposited at the Cambridge Crystallographic Data
Centre, reference no. CCDC 871602.
2-Isopropyl-1,2-dimethyl-4-(4-methyl-3-nitrophenyl)-5-oxo-2,5-
dihydro-1H-imidazole 3-Oxide (7e). The title compound was
prepared according to general procedure A from MiPNO (170 mg,
1.0 mmol) and 4-bromo-2-nitrotoluene (238 mg, 1.1 mmol): 2 h;
white solid (300 mg, 98%). An analytical sample was obtained by
1
recrystallization from tert-butyl methyl ether. Mp: 106−107 °C. H
NMR (400 MHz, CDCl3): δ 9.52 (d, J = 1.7, 1H), 8.95 (dd, J = 8.2,
1.7, 1H), 7.44 (d, J = 8.2, 1H), 3.10 (s, 3H), 2.64 (s, 3H), 2.43 (qq, J =
7.1, 6.8, 1H), 1.74 (s, 3H), 1.02 (d, J = 7.1, 3H), 0.98 (d, J = 6.8, 3H).
13C NMR (75 MHz, CDCl3): δ 162.4, 149.3, 135.7, 132.6, 131.0,
General Procedure B. A 10 mL Schlenk flask under an N2
atmosphere was charged with nitrone, aryl bromide (1.1 equiv),
Pd2(dba)3 (1 mol %; i.e. 2 mol % Pd), triphenylphosphine (2 mol
%),17 CuBr·DMS (5 mol %), 1,10-phenanthroline (5 mol %), and
K2CO3 (1.5 equiv). The flask was evacuated and purged with N2, and
anisole was added to give a 0.5 M solution. The Schlenk flask was
plunged into a 150 °C heated oil bath, and the reaction was monitored
128.7, 125.0, 123.1, 91.8, 35.0, 26.5, 21.5, 20.5, 16.2, 15.5. IR: 3113,
2978, 2882, 1702, 1566, 1514, 1343, 1154, 843. Anal. Calcd for
C15H19N3O4: C, 59.01; H, 6.28; N, 13.77. Found: C, 59.36; H, 6.57;
N, 13.96.
1
by H NMR spectroscopy of small aliquots. After completion of the
2-Isopropyl-4-(4-(methoxycarbonyl)phenyl)-1,2-dimethyl-5-oxo-
2,5-dihydro-1H-imidazole 3-Oxide (7f). The title compound was
prepared according to general procedure A from MiPNO (170 mg, 1.0
mmol) and methyl 4-bromobenzoate (240 mg, 1.1 mmol): 1 h; white
solid (260 mg, 85%). An analytical sample was obtained by
recrystallization from tert-butyl methyl ether. Mp: 96−97 °C. 1H
NMR (400 MHz, CDCl3): δ 8.88 (d, J = 8.2, 2H), 8.12 (d, J = 8.2,
2H), 3.94 (s, 3H), 3.10 (s, 3H), 2.43 (qq, J = 7.1, 6.7, 1H), 1.74 (s,
3H), 1.03 (d, J = 7.1, 3H), 0.98 (d, J = 6.7, 3H). 13C NMR (75 MHz,
CDCl3): δ 166.5, 162.7, 131.5, 129.8, 129.3, 127.2, 91.7, 52.2, 35.1,
26.6, 21.5, 16.2, 15.5 (one quaternary C remained undetected). IR:
2945, 2883, 1718, 1699, 1549, 1364, 1280, 1110, 859. Anal. Calcd for
C16H20N2O4: C, 63.15; H, 6.63; N, 9.21. Found: C, 63.30; H, 6.83; N,
9.30.
2-Isopropyl-4-(2-(methoxycarbonyl)phenyl)-1,2-dimethyl-5-oxo-
2,5-dihydro-1H-imidazole 3-Oxide (7g). The title compound was
prepared according to general procedure A from MiPNO (170 mg, 1.0
mmol) and methyl 2-bromobenzoate (240 mg, 1.1 mmol): 1 h; white
solid (281 mg, 92%). An analytical sample was obtained by
recrystallization from tert-butyl methyl ether. Mp: 97−98 °C. 1H
NMR (400 MHz, CDCl3): δ 7.95 (dd, J = 7.8, 1.1, 1H), 7.80 (dd, J =
7.8, 1.0, 1H), 7.61 (td, J = 7.6, 1.4, 1H), 7.52 (td, J = 7.7, 1.3, 1H), 3.84
(s, 3H), 3.09 (s, 3H), 2.43 (qq, J = 7.2, 6.8, 1H), 1.74 (s, 3H), 1.08 (d,
J = 7.2, 1H), 1.04 (d, J = 6.8, 3H). 13C NMR (101 MHz, CDCl3): δ
167.1, 162.3, 133.7, 131.7, 131.6, 130.2, 130.1, 130.1, 124.4, 92.0, 52.5,
34.62, 26.6, 21.4, 16.3, 15.6. IR: 3375, 3072, 2975, 2939, 1728, 1697,
1560, 1361, 1255, 1127, 774. Anal. Calcd for C16H20N2O4: C, 63.15;
H, 6.63; N, 9.21. Found: C, 63.52; H, 6.60; N, 9.20.
reaction, the crude solution was purified over silica gel to give the
arylnitrone.
2-Isopropyl-1,2-dimethyl-5-oxo-4-(p-tolyl)-2,5-dihydro-1H-imida-
zole 3-Oxide (7a). The title compound was prepared according to
general procedure A starting from MiPNO (170 mg, 1.0 mmol) and 4-
bromotoluene (188 mg, 1.1 mmol): 1 h; colorless crystals (242 mg,
1
92%). Mp: 75−76 °C. H NMR (400 MHz, CDCl3): δ 8.70 (d, J =
8.3, 2H), 7.28 (d, J = 8.3, 2H), 3.08 (s, 3H), 2.48−2.35 (m, 4H), 1.72
(s, 3H), 1.02 (d, J = 7.1, 3H), 0.96 (d, J = 6.7, 3H). 13C NMR (101
MHz, CDCl3): δ 163.1, 141.3, 130.6, 129.0, 127.5, 123.2, 90.8, 35.0,
26.5, 21.7, 21.5, 16.3, 15.6. IR: 3370, 3079, 2971, 2879, 1690, 1556,
1356, 826. Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76.
Found: C, 69.58; H, 7.58; N 10.83.
(+)-7a (1.30 g, quantitative) was obtained from (S)-MiPNO (850
25
mg, 5.0 mmol) as a yellow solid. [α]D = +91.6° (c 1.87, CHCl3).
2-Isopropyl-4-(4-methoxyphenyl)-1,2-dimethyl-5-oxo-2,5-dihy-
dro-1H-imidazole 3-Oxide (7b). The title compound was prepared
according to general procedure A starting from MiPNO (170 mg, 1.0
mmol) and 4-bromoanisole (248 mg, 1.1 mmol): 1.5 h; yellow oil
(267 mg, 95%). 1H NMR (400 MHz, CDCl3): δ 8.85 (d, J = 9.2, 2H),
6.98 (d, J = 9.2, 2H), 3.86 (s, 3H), 3.08 (s, 3H), 2.42 (qq, J = 7.2, 6.8,
1H), 1.71 (s, 3H), 1.02 (d, J = 7.2, 3H), 0.96 (d, J = 6.8, 3H). 13C
NMR (75 MHz, CDCl3): δ 163.2, 161.3, 130.2, 129.4, 118.8, 113.6,
90.5, 55.3, 34.9, 26.5, 21.4, 16.3, 15.6. IR: 3085, 2968, 2838, 1695,
1604, 1557, 1506, 1356, 1252, 1180, 1028, 837.
(+)-7b (1.31 g, 95%) was obtained from (S)-MiPNO (850 mg, 5.0
25
mmol) as a yellow solid. Mp: 122−123 °C. [α]D = +93.5° (c 1.5,
CHCl3). Anal. Calcd for C15H20N2O3: C, 65.20; H, 7.30; N, 10.14.
Found: C, 65.14; H, 7.40; N, 9.97.
4-(5-Formyl-2,4-dimethoxyphenyl)-2-isopropyl-1,2-dimethyl-5-
oxo-2,5-dihydro-1H-imidazole 3-Oxide (7h). The title compound
was prepared according to general procedure A from MiPNO (170
mg, 1.0 mmol) and 5-bromo-2,4-dimethoxybenzaldehyde (273 mg, 1.1
mmol): 2.7 h; white solid (227 mg, 68%). An analytical sample was
obtained by washing the solid with diethyl ether under sonication. Mp:
2-Isopropyl-4-(2-methoxyphenyl)-1,2-dimethyl-5-oxo-2,5-dihy-
dro-1H-imidazole 3-Oxide (7c). The title compound was prepared
according to general procedure A from MiPNO (170 mg, 1.0 mmol)
and 2-bromoanisole (208 mg, 1.1 mmol): 18 h; white solid (245 mg,
89%). An analytical sample was obtained by recrystallization from tert-
butyl methyl ether. Mp: 107−108 °C. 1H NMR (400 MHz, CDCl3): δ
7.46−7.40 (m, 2H), 7.04 (td, J = 7.5, 0.9, 1H), 7.01−6.96 (m, 1H),
3.85 (s, 3H), 3.08 (s, 3H), 2.40 (qq, J = 7.1, 6.8, 1H), 1.74 (s, 3H),
1.07 (d, J = 7.1, 3H), 1.04 (d, J = 6.8, 3H). 13C NMR (75 MHz,
CDCl3): δ 162.9, 158.3, 132.9, 131.9, 130.8, 120.6, 113.9, 111.8, 92.0,
55.9, 34.7, 26.6, 21.5, 16.2, 15.4. IR: 3066, 2965, 2841, 1690, 1564,
1361, 1282, 753. Anal. Calcd for C15H20N2O3: C, 65.20; H, 7.30; N,
10.14. Found: C, 64.95; H, 7.36; N, 10.15.
1
289−290 °C. H NMR (400 MHz, CDCl3): δ 10.28 (s, 1H), 7.94 (s,
1H), 6.50 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.07 (s, 3H), 2.38 (qq, J
= 7.1, 6.8, 1H), 1.72 (s, 3H), 1.05 (d, J = 7.1, 3H), 1.02 (d, J = 6.8,
3H). 13C NMR (101 MHz, CDCl3): δ 187.5, 165.2, 164.4, 162.6,
132.7, 131.8, 118.7, 107.2, 95.0, 92.1, 56.2, 55.9, 34.7, 26.7, 21.6, 16.2,
15.5. IR: 3123, 2977, 2853, 1699, 1670, 1607, 1570, 1359, 1283, 1022,
821. Anal. Calcd for C17H22N2O5: C, 61.07; H, 6.64; N, 8.38. Found:
C, 60.92; H, 6.86; N, 8.25.
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(2S,2′S)-4,4′-(1,2-Phenylene)bis(2-isopropyl-1,2-dimethyl-5-oxo-
2,5-dihydro-1H-imidazole 3-oxide) (7i). The title compound was
prepared according to general procedure A from (S)-MiPNO (189 mg,
1.11 mmol) and 1,2-dibromobenzene (132 mg, 0.56 mmol): 2 h;
yellow solid (183 mg, 79%). An analytical sample was obtained by
washing the solid with diethyl ether under sonication. Mp: 224−226
°C. [α]D25 = +293° (c 0.99, CDCl3). 1H NMR (400 MHz, CDCl3): δ
8.04−7.97 (m, 2H), 7.62−7.55 (m, 2H), 3.09 (s, 6H), 2.31 (qq, J =
7.1, 6.8, 2H), 1.74 (s, 6H), 1.00 (d, J = 7.1, 6H), 0.89 (d, J = 6.8, 6H).
13C NMR (75 MHz, CDCl3): δ 162.1, 134.7, 130.2, 129.9, 123.9, 91.6,
34.8, 26.8, 21.8, 16.3, 15.5. IR: 3082, 2974, 2876, 1694, 1571, 1571,
1430, 1356, 1223, 1123, 789. Anal. Calcd for C22H30N4O4: C, 63.75;
H, 7.30; N, 13.52. Found: C, 64.00; H, 7.49; N, 13.18.
(S)-4-(2-Bromophenyl)-2-isopropyl-1,2-dimethyl-5-oxo-2,5-dihy-
dro-1H-imidazole 3-Oxide (7i′). 1H NMR (400 MHz, CDCl3): δ
7.72−7.63 (m, 1H), 7.45−7.37 (m, 2H), 6.93−6.81 (m, 1H), 3.11 (s,
3H), 2.51−2.36 (m, 1H), 1.77 (s, 1H), 1.16−1.00 (m, 6H).
bromopyridine (174 mg, 1.1 mmol): 1.5 h; orange oil (238 mg, 96%).
1H NMR (400 MHz, CDCl3): δ 8.86 (d, J = 4.8, 1H), 8.43 (d, J = 7.9,
1H), 7.81 (td, J = 7.9, 1.8, 1H), 7.33 (ddd, J = 7.6, 4.9, 0.7, 1H), 3.11
(s, 3H), 2.44 (qq, J = 7.1, 6.8, 1H), 1.76 (s, 3H), 1.05 (d, J = 7.1, 3H),
1.02 (d, J = 6.8, 3H). 13C NMR (101 MHz, CDCl3): δ 161.9, 150.1,
145.4, 136.2, 131.0, 124.5, 124.4, 92.1, 35.0, 26.6, 21.6, 16.2, 15.5. IR:
3573, 3060, 2968, 2879, 1698, 1549, 1361, 1283, 789. HRMS (ESI+):
m/z calcd for C13H17N3O2Na+ 270.121 30; found 270.121 16.
4-(4-(Dimethylamino)phenyl)-2-isopropyl-1,2-dimethyl-5-oxo-
2,5-dihydro-1H-imidazole 3-Oxide (7o). The title compound was
prepared according to general procedure A from MiPNO (170 mg, 1.0
mmol) and 4-bromo-N,N-dimethylaniline (225 mg, 1.1 mmol): 0.75
h; yellow solid (285 mg, 99%). An analytical sample was obtained by
washing the solid with diethyl ether under sonication. Mp: 158−159
°C. 1H NMR (400 MHz, CDCl3): δ 8.83 (d, J = 9.3, 2H), 6.73 (d, J =
9.3, 2H), 3.07 (s, 3H), 3.04 (s, 6H), 2.42 (qq, J = 7.2, 6.8, 1H), 1.70 (s,
3H), 1.01 (d, J = 7.2, 3H), 0.95 (d, J = 6.8, 3H). 13C NMR (101 MHz,
CDCl3): δ 163.6, 151.6, 130.6, 129.0, 114.0, 111.0, 89.8, 40.0, 34.9,
26.5, 21.4, 16.4, 15.6. IR: 3370, 3085, 2968, 2923, 1693, 1603, 1521,
1357, 1303, 1216, 947, 824. Anal. Calcd for C16H23N3O2: C, 66.42; H,
8.02; N, 14.53. Found: C, 66.29; H, 7.87; N, 14.43.
4-(4-Aminophenyl)-2-isopropyl-1,2-dimethyl-5-oxo-2,5-dihydro-
1H-imidazole 3-Oxide (7p). The title compound was prepared
according to general procedure B from MiPNO (170 mg, 1.0
mmol) and 4-bromoaniline (190 mg, 1.1 mmol): 1 h; brown solid
(200 mg, 77%). An analytical sample was obtained by washing the
solid with diethyl ether under sonication. Mp: 146−147 °C. 1H NMR
(400 MHz, CDCl3): δ 8.74 (d, J = 8.0, 2H), 6.71 (d, J = 8.0, 2H), 3.06
(s, 3H), 2.41 (qq, J = 7.1, 6.7, 1H), 1.69 (s, 3H), 1.01 (d, J = 7.1, 3H),
0.95 (d, J = 6.7, 3H). 13C NMR (75 MHz, CDCl3): δ 163.4, 130.5,
129.3, 116.3, 114.0, 90.0, 34.9, 26.5, 21.4, 16.3, 15.6 (one quaternary C
remained undetected). IR: 3453, 3344, 3217, 2974, 2879, 1683, 1627,
1601, 1558, 1508, 1353, 1294, 1187, 838. Anal. Calcd for C14H19N3O2:
C, 64.35; H, 7.33; N, 16.08. Found: C, 64.43; H, 7.49; N, 15.92.
(2S,2′S)-4,4′-(Pyridine-2,6-diyl)bis(2-isopropyl-1,2-dimethyl-5-
oxo-2,5-dihydro-1H-imidazole 3-oxide) (7q). The title compound
was prepared according to general procedure B from (S)-MiPNO (175
mg, 1.1 mmol) and 2,6-dibromopyridine (120 mg, 0.5 mmol): 1 h;
white solid (175 mg, 84%). Mp: 218−219 °C. [α]D25 = +119° (c 1.97,
CDCl3). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 7.9, 2H), 7.84 (t,
J = 7.9, 1H), 3.03 (s, 6H), 2.37 (qq, J = 7.0, 6.7, 2H), 1.66 (s, 6H),
0.98 (d, J = 7.0, 6H), 0.93 (d, J = 6.7, 6H). 13C NMR (101 MHz,
CDCl3): δ 161.5, 145.9, 136.6, 130.8, 124.8, 92.1, 35.1, 26.6, 21.5, 16.4,
15.7. IR: 3069, 2960, 2933, 1710, 1566, 1357, 1229, 812. Anal. Calcd
for C21H29N5O4·1/3H2O: C, 59.84; H, 7.09; N, 16.62. Found: C,
60.00; H, 7.05; N, 16.39.
(2S,2′S)-4,4′-(1,3-Phenylene)bis(2-isopropyl-1,2-dimethyl-5-oxo-
2,5-dihydro-1H-imidazole 3-oxide) (7j). The title compound was
prepared according to general procedure A from (S)-MiPNO (476 mg,
2.8 mmol) and 1,3-dibromobenzene (340 mg, 1.4 mmol): 0.5 h; white
solid (497 mg, 86%). An analytical sample was obtained by washing
25
the solid with diethyl ether under sonication. Mp: 159−162 °C. [α]D
= +174° (c 1.17, CDCl3). 1H NMR (400 MHz, CDCl3): δ 10.33 (t, J =
1.6, 1H), 8.88 (dd, J = 8.1, 1.7, 2H), 7.58 (t, J = 8.1, 1H), 3.10 (s, 6H),
2.44 (qq, J = 7.1, 6.8, 2H), 1.73 (s, 6H), 1.03 (d, J = 7.1, 6H), 0.97 (d,
J = 6.8, 6H). 13C NMR (75 MHz, CDCl3): δ 162.8, 130.0, 129.4,
128.2, 126.5, 126.1, 91.3, 35.0, 26.6, 21.6, 16.3, 15.6. IR: 3101, 3082,
2977, 2885, 1694, 1548, 1354, 1279, 1040, 808, 691. Anal. Calcd for
C22H30N4O4: C, 63.75; H, 7.30; N, 13.52. Found: C, 63.82; H, 7.65;
N, 13.56.
(R)-2-Isopropyl-1,2-dimethyl-5-oxo-4-(pyridin-3-yl)-2,5-dihydro-
1H-imidazole 3-Oxide (7k). The title compound was prepared
according to general procedure A from (R)-MiPNO (850 mg, 5.0
mmol) and 3-bromopyridine (869 mg, 5.5 mmol): 2 h; yellow oil
(1.05 g, 85%). [α]D25 = −85.5° (c 0.93, CDCl3). 1H NMR (400 MHz,
CDCl3): δ 9.97 (d, J = 1.6, 1H), 9.08 (dd, J = 8.2, 1.6, 1H), 8.67 (dd, J
= 4.9, 1.6, 1H), 7.39 (ddd, J = 8.2, 4.9, 0.7, 1H), 3.09 (s, 3H), 2.41 (qq,
J = 7.1, 6.8, 1H), 1.73 (s, 3H), 1.02 (d, J = 7.1, 3H), 0.98 (d, J = 6.8,
3H). 13C NMR (101 MHz, CDCl3): δ 162.6, 151.2, 148.6, 134.2,
128.9, 123.2, 122.8, 92.0, 35.2, 26.7, 21.7, 16.3, 15.6. IR: 3378, 3092,
2978, 2877, 1697, 1553, 1378, 1364, 1287, 1113, 809, 703. HRMS
(ESI+): m/z calcd for C13H17N3O2Na+ 270.121 30; found 270.121 37.
2-Isopropyl-1,2-dimethyl-5-oxo-4-(pyridin-4-yl)-2,5-dihydro-1H-
imidazole 3-Oxide (7l). The title compound was prepared according
to general procedure A from MiPNO (170 mg, 1.0 mmol) and 4-
bromopyridine (213 mg, 1.1 mmol): 1 h; white solid (249 mg,
quantitative). An analytical sample was obtained by recrystallization
(2S,2′S)-4,4′-(Thiophene-2,5-diyl)bis(2-isopropyl-1,2-dimethyl-5-
oxo-2,5-dihydro-1H-imidazole 3-oxide) (7r). The title compound was
prepared according to general procedure B from (S)-MiPNO (196 mg,
1.1 mmol) and 2,5-dibromothiophene (121 mg, 0.5 mmol): 1 h; the
crude product was filtered over Celite, and 7r was recrystallized from
1
from tert-butyl methyl ether. Mp: 127−128 °C. H NMR (400 MHz,
CDCl3): δ 8.76 (dd, J = 4.7, 1.6, 2H), 8.63 (dd, J = 4.7, 1.7, 2H), 3.10
(s, 3H), 2.41 (qq, J = 7.1, 6.8, 1H), 1.74 (s, 3H), 1.02 (d, J = 7.1, 3H),
0.98 (d, J = 6.8, 3H). 13C NMR (75 MHz, CDCl3): δ 162.3, 150.3,
132.6, 120.2, 92.3, 35.1, 26.6, 21.6, 16.2, 15.5. IR: 3110, 2970, 2939,
1696, 1555, 1399, 1365, 1319, 992, 829. HRMS (ESI+): m/z calcd for
ethyl acetate; orange crystals (160 mg, 76%). Same experiment with
25
general procedure A: 52% after 19 h. Mp: 203−204 °C. [α]D
=
+120° (c 1.03, CDCl3). 1H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H),
3.10 (s, 3H), 2.47−2.33 (m, 1H), 1.73 (s, 3H), 0.99 (d, J = 6.8, 3H),
0.97 (d, J = 7.1, 3H). 13C NMR (101 MHz, CDCl3): δ 161.5, 129.3,
129.3, 128.5, 91.0, 35.0, 26.4, 21.4, 16.1, 15.5. IR: 3113, 3094, 2971,
2939, 1703, 1560, 1427, 1353, 1236, 1126, 1045, 907, 821. Anal. Calcd
for C20H28N4O4S: C, 57.13; H, 6.72; N, 13.33. Found: C, 57.12; H,
6.65; N, 13.47.
+
C13H18N3O2 248.139 35; found 248.139 34.
4-(Anthracen-9-yl)-2-isopropyl-1,2-dimethyl-5-oxo-2,5-dihydro-
1H-imidazole 3-Oxide (7m). The title compound was prepared
according to general procedure A from MiPNO (170 mg, 1.0 mmol)
and 9-bromoanthracene (283 mg, 1.1 mmol): 3 h; yellow crystals (240
mg, 70%). Mp: 243−244 °C. 1H NMR (400 MHz, CDCl3): δ 8.61 (s,
1H), 8.09−8.01 (m, 2H), 7.83−7.76 (m, 1H), 7.56−7.41 (m, 5H),
3.24 (s, 3H), 2.56 (qq, J = 7.0, 1H), 2.00 (s, 3H), 1.24 (m, 6H). 13C
NMR (75 MHz, CDCl3): δ 163.4, 134.6, 131.5, 131.4, 131.2, 131.0,
130.0, 129.3, 129.1, 127.1, 127.0, 125.4, 125.4, 125.1, 124.7, 117.6,
93.1, 34.5, 26.8, 22.8, 16.6, 16.0. IR: 3047, 3025, 2971, 2870, 1691,
1557, 1366, 741. Anal. Calcd for C22H22N2O2: C, 76.28; H, 6.41; N,
8.09. Found: C, 76.36; H, 6.46; N, 8.28.
2,2′-Diisopropyl-1,1′,2,2′-tetramethyl-5,5′-dioxo-2,2′,5,5′-tetra-
hydro-1H,1′H-[4,4′-biimidazole] 3-Oxide (8). The title compound
was prepared according to general procedure B, except that Pd and
triphenylphosphine were omitted, starting from rac-MiPNO (170 mg,
1.0 mmol) and 4-bromotoluene (181 mg, 1.1 mmol): 1 h; white solid
(153 mg, 95%, ca. 1/1 mixture of diastereomers). Mp: 201−202 °C.
1H NMR (400 MHz, CDCl3): δ 3.06 (s, 3H), 2.93 (s, 3H), 2.46−2.29
(m, 1H), 2.28−2.10 (m, 1H), 1.76 and 1.72 (s, 3H), 1.57 (s, 3H), 1.21
and 1.19 (d, J = 6.8, 3H), 1.11−1.05 (m, 6H), 0.65 and 0.64 (d, J =
6.8, 3H). 13C NMR (101 MHz, CDCl3): δ 156.8, 127.8, 94.1, 91.2,
2-Isopropyl-1,2-dimethyl-5-oxo-4-(pyridin-2-yl)-2,5-dihydro-1H-
imidazole 3-Oxide (7n). The title compound was prepared according
to general procedure B from MiPNO (170 mg, 1.0 mmol) and 2-
7908
dx.doi.org/10.1021/jo301114k | J. Org. Chem. 2012, 77, 7901−7912

The Journal of Organic Chemistry
Article
35.0, 34.5, 26.6, 26.1, 22.0, 21.5, 17.6, 16.1, 15.5, 15.3. IR: 2970, 2939,
1698, 1557, 1434, 1381, 1256, 1119, 1082, 1051, 931, 711. Anal. Calcd
for C16H26N4O3: C, 59.61; H, 8.13; N, 17.38. Found: C, 59.29; H,
7.98; N, 17.28.
= 7.6, 1H), 6.72 (s, 1H), 3.90 (s, 2H), 3.84 (s, 3H), 3.17 (s, 1H), 2.04
(s, 1H), 1.52 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 153.2, 140.9,
138.5, 130.9, 130.6, 128.5, 127.6, 127.4, 127.0, 126.5, 107.4, 67.2, 60.9,
56.3, 41.9, 24.7. IR: 3063, 2965, 2933, 2834, 1584, 1451, 1410, 1355,
1233, 1120, 1002, 761. HRMS (ESI+): m/z calcd for C20H23NO4Na+
364.151 93; found 364.151 89.
5-(Anthracen-9-yl)-2,2-dimethyl-3,4-dihydro-2H-pyrrole 1-Oxide
(9a). The title compound was prepared according to general
procedure A from DMPO (48 mg, 0.42 mmol) and 9-bromoan-
thracene (148 mg, 0.55 mmol): 1.5 h; orange crystals (115 mg, 95%).
Mp: 160−161 °C. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 8.03
(d, J = 8.1, 2H), 7.68 (d, J = 8.4, 2H), 7.57−7.41 (m, 4H), 3.12 (t, J =
7.2, 2H), 2.45 (t, J = 7.2, 2H), 1.73 (s, 6H). 13C NMR (101 MHz,
CDCl3): δ 139.0, 131.5, 129.4, 129.1, 128.9, 126.8, 125.4, 124.6, 124.5,
74.8, 33.6, 30.5, 25.9. IR: 3047, 2967, 2866, 1576, 1361, 1238, 1179,
888, 786, 731. Anal. Calcd for C20H19NO: C, 83.02; H, 6.62; N, 4.85.
Found: C, 82.82; H, 6.68; N, 4.89.
1-(4-(Methoxycarbonyl)phenyl)-3,3-dimethyl-3,4-dihydroisoqui-
noline 2-Oxide (10c). The title compound was prepared according to
general procedure A from 3 (85 mg, 0.50 mmol) and methyl 4-
bromobenzoate (118 mg, 0.55 mmol); 2 h; colorless crystals (117 mg,
1
76%). Mp: 128−129 °C. H NMR (400 MHz, CDCl3): δ 8.18−8.10
(m, 2H), 7.63−7.56 (m, 2H), 7.31−7.20 (m, 2H), 7.20−7.10 (m, 1H),
6.75 (d, J = 7.8, 1H), 3.95 (s, 3H), 3.18 (s, 2H), 1.52 (s, 6H). 13C
NMR (101 MHz, CDCl3): δ 166.7, 140.1, 136.9, 130.8, 130.3, 130.3,
130.1, 129.5, 128.7, 127.7, 127.1, 125.9, 67.4, 52.2, 41.8, 24.6. IR: 3183,
3050, 2974, 2889, 1711, 1660, 1481, 1363, 1278, 1177, 1110, 761.
HRMS (ESI+): m/z calcd for C19H19NO3Na+ 332.125 71; found
332.125 33.
5-(4-Methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrrole 1-
Oxide (9b). The title compound was prepared according to general
procedure A from DMPO (56 mg, 0.50 mmol) and 4-bromoanisole
(100 mg, 0.55 mmol): 1 h; white solid (93 mg, 85%). An analytical
sample was obtained by recrystallization from tert-butyl methyl ether.
Preparation of Deuterated MiPNO: 4-Deuterio-2-isopropyl-
1,2-dimethyl-5-oxo-2,5-dihydro-1H-imidazole 3-Oxide (d-1). In
a CEM Discover 10 mL vial, racemic MiPNO 1 (0.543 g, 3.2 mmol)
was dissolved in 1 mL of d6-acetone. The sealed vial was heated at 140
°C for 30 min under microwave irradiation in a CEM Discover S-class
apparatus (external surface sensor, maximum power 140 W, 2 min to
reach set temperature, maximum pressure 6 bar), and then the solvent
1
Mp: 122−123 °C. H NMR (400 MHz, CDCl3): δ 8.37 (d, J = 8.4,
2H), 6.95 (d, J = 8.4, 2H), 3.85 (s, 3H), 3.00 (t, J = 7.2, 2H), 2.09 (t, J
= 7.2, 2H), 1.48 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 160.7, 137.4,
129.1, 122.8, 113.7, 75.18, 55.3, 31.9, 26.8, 25.6. IR: 3091, 2974, 2838,
1601, 1545, 1509, 1367, 1239, 1024, 831. Anal. Calcd for C13H17NO2:
C, 71.21; H, 7.82; N, 6.39. Found: C, 71.33; H, 8.08; N, 6.47. Data for
the crystal structure have been deposited at the Cambridge
Crystallographic Data Centre, reference no. CCDC 871603.
1
was evaporated to yield 0.545 g of pure d-1 (pale yellow solid). H
NMR (400 MHz, CDCl3): δ 3.00 (s, 3H), 2.31 (hept, J = 7.0, 1H),
1.67 (s, 3H), 1.01 (d, J = 7.1, 3H), 0.99 (d, J = 6.8, 3H). 13C NMR (75
MHz, CDCl3): δ 162.55, 124.48 (t, J = 33), 93.88, 34.16, 26.19, 21.27,
15.89, 15.25. IR: 2972, 2803, 2300 (νC−D), 1701, 1542, 1265. HRMS
5-(2-(Methoxycarbonyl)phenyl)-2,2-dimethyl-3,4-dihydro-2H-
pyrrole 1-Oxide (9c). The title compound was prepared according to
general procedure A from DMPO (56 mg, 0.50 mmol) and methyl 2-
bromobenzoate (113 mg, 0.55 mmol): 1.5 h; yellow oil (97 mg, 79%).
1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 7.7, 1H), 7.54 (t, J = 7.5,
+
(ESI+): m/z calcd for C8H14DN2O2 172.119 08; found 172.119 18.
Kinetic Isotope Effect Experiments. Two experiments were
conducted separately, one with nitrone 1 (1 mmol) and one with the
deuterated analogue d-1 (1 mmol). Both reactions were performed
according to general procedure A, using 4-bromotoluene 6 and
PdCl2(PPh3)2 (0.2 mol %). The corresponding rate constants kH and
kD were thus determined, and a kH/kD ratio of 3 was found.38
Ab Initio Calculations. These calculations were performed using
the same functional and basis set as Gorelsky and Fagnou26 in order to
have comparable data and accordingly a fruitful discussion. Density
functional theory (DFT) calculations were performed using the
Gaussian 03 program.42 The structures of all species were optimized at
the B3LYP exchange-correlation (XC) level43,44 using the mixed
double-/triple-ζ basis set (DZVP45 on Pd and TZVP46 on all other
atoms). Tight SCF convergence criteria (10−8 au) were used for all
calculations. Harmonic frequency calculations with the analytic
evaluation of force gradients were used to determine the nature of
the stationary points i.e. minima and transition states. See the
Supporting Information for detailed results.
Synthesis of Enantiopure α-Methyl α-Arylglycine Esters.
General Procedure. Methylation. The aryl nitrone 7 was dissolved in
anhydrous THF (20 mL) and cooled to 0 °C, and methylmagnesium
chloride in THF (22 wt %, 3 equiv) was added. The mixture was then
kept at room temperature. After 1 h, a saturated aqueous solution of
NH4Cl (15 mL) was added, followed by ethyl acetate (60 mL) and
water (15 mL). The aqueous layer was separated and extracted with
ethyl acetate (60 mL). The gathered organic layers were washed with
brine (60 mL), dried over anhydrous MgSO4, and filtered. The
solvents were removed under reduced pressure to furnish the desired
hydroxylamine product 11, which was used in the next step without
further purification.
1H), 7.46−7.34 (m, 2H), 3.87 (s, 3H), 3.00 (t, J = 7.1, 2H), 2.18 (t, J
= 7.1, 2H), 1.47 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 167.3, 139.0,
131.4, 131.4, 130.2, 129.8, 129.2, 128.5, 74.4, 52.5, 32.8, 28.4, 25.2. IR:
3063, 2974, 2949, 1723, 1558, 1362, 1290, 113, 916, 722. HRMS
(ESI+): m/z calcd for C14H17NO3Na+ 270.110 06; found 270.110 03.
5-(4-(Methoxycarbonyl)phenyl)-2,2-dimethyl-3,4-dihydro-2H-
pyrrole 1-Oxide (9d). The title compound was prepared according to
general procedure A (run performed with 5 mol % Pd/PPh3) from
DMPO (56 mg, 0.5 mmol) and methyl 4-bromobenzoate (124 mg, 0.6
mmol): 1 h; white solid (113 mg, 90%). An analytical sample was
obtained by recrystallization from tert-butyl methyl ether. Mp: 102−
103 °C. 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 8.0, 2H), 8.09 (d,
J = 8.0, 2H), 3.93 (s, 3H), 3.07 (t, J = 7.3, 2H), 2.15 (t, J = 7.3, 2H),
1.50 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 166.5, 136.8, 133.7,
130.7, 129.6, 126.8, 76.3, 52.2, 31.9, 26.7, 25.6. IR: 3094, 2984, 2949,
1714, 1534, 1364, 1274, 1102, 1016, 855, 767. Anal. Calcd for
C14H17NO3·1/3H2O: C, 66.39; H, 7.03; N, 5.53. Found: C, 66.36; H,
6.93; N, 5.54.
3,3-Dimethyl-1-(p-tolyl)-3,4-dihydroisoquinoline 2-Oxide (10a).
The title compound was prepared according to general procedure A
from 3 (175 mg, 1.0 mmol) and 4-bromotoluene (187 mg, 1.1 mmol):
1.5 h; white solid (195 mg, 74%). An analytical sample was obtained
by recrystallization from tert-butyl methyl ether. Mp: 110−111 °C. 1H
NMR (400 MHz, CDCl3): δ 7.40 (d, J = 7.6, 2H), 7.30−7.18 (m, 4H),
7.14 (t, J = 7.2, 1H), 6.85 (d, J = 7.8, 1H), 3.15 (s, 2H), 2.40 (s, 3H),
1.50 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 140.9, 138.7, 130.9,
130.7, 130.0, 129.1, 128.9, 128.3, 127.5, 126.9, 126.4, 66.9, 41.9, 24.7,
21.5. IR: 3050, 3031, 3005, 2972, 2939, 1479, 1235. Anal. Calcd for
C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.26; H, 7.20; N,
4.95. Data for the crystal structure have been deposited at the
Cambridge Crystallographic Data Centre, reference no. CCDC
871604.
Reduction. The crude hydroxylamine 11 was suspended in glacial
acetic acid (20 mL), and zinc dust (30 equiv) was added. The reaction
mixture was heated for 3−7 h at 80 °C under sonication. The excess
zinc was then filtered off and rinsed with ethyl acetate. The filtrate was
concentrated under reduced pressure. A saturated aqueous solution of
Na2CO3 (30 mL) was added and extracted with ethyl acetate (50 mL).
The organic layer was dried over anhydrous MgSO4, filtered,
concentrated, and evaporated under reduced pressure to yield the
3,3-Dimethyl-1-(3,4,5-trimethoxyphenyl)-3,4-dihydroisoquinoline
2-Oxide (10b). The title compound was prepared according to general
procedure A from 3 (175 mg, 1.0 mmol) and 1-bromo-3,4,5-
trimethoxybenzene (272 mg, 1.1 mmol): 1.5 h; orange oil (330 mg,
97%). 1H NMR (300 MHz, CDCl3): δ 7.31−7.12 (m, 3H), 6.89 (d, J
7909
dx.doi.org/10.1021/jo301114k | J. Org. Chem. 2012, 77, 7901−7912

The Journal of Organic Chemistry
Article
imidazolidinone 13, which was used in the next step without further
purification.
174.7, 158.5, 137.1, 127.2, 113.4, 78.9, 63.0, 55.3, 35.1, 31.5, 26.2, 25.8,
17.0, 16.9.
(R)-2-Amino-2-(4-hydroxyphenyl)propanoic acid hydrochloride
Hydrolysis. In a 20 mL pressure vessel were introduced the
imidazolidinone 13 and a 6 N aqueous solution of hydrochloric acid (5
mL). The reaction mixture was heated for the indicated time at 160
°C. After evaporation under reduced pressure, an equimolar mixture of
amino acid hydrochloride 14 and methylamine hydrochloride was
obtained, which was directly used in the next step.
Esterification. The mixture of amino acid hydrochloride 14 and
methylamine hydrochloride was dissolved in MeOH (10 mL). Thionyl
chloride (1.5 mL) was added at room temperature without cooling,
and then the reaction mixture was heated for 3 h at reflux. The solvent
was removed under reduced pressure, and ethyl acetate (10 mL) was
added. The organic layer was washed with a saturated aqueous
solution of Na2CO3 (10 mL), dried over anhydrous MgSO4, filtered,
and evaporated under reduced pressure. The crude product was
purified by column chromatography (silica gel, eluent cyclohexane/
AcOEt 10/0 to 0/10) to yield the amino ester 12.
1
(14b). H NMR (400 MHz, D2O): δ 7.02 (d, J = 8.8, 2H), 6.57 (d,
J = 8.8, 2H), 1.59 (s, 3H). 13C NMR (101 MHz, D2O): δ 173.1, 156.5,
127.3, 127.1, 126.5, 115.8, 61.1, 20.8.
(S)-Methyl 2-Amino-2-(pyridin-3-yl)propanoate (12k). The title
compound was prepared according to the general procedure from 7k
(1.018 g, 4.1 mmol): yellow oil (317 mg, 43%). [α]D25 = +32° (c 1.9,
1
MeOH). H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 2.2, 1H), 8.52
(dd, J = 4.8, 1.6, 1H), 7.85 (ddd, J = 8.0, 2.2, 1.6, 1H), 7.27 (dd, J =
8.0, 4.8, 1H), 3.73 (s, 3H), 1.72 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 175.9, 148.7, 147.3, 139.5, 133.1, 123.1, 59.4, 52.8, 27.6.
HRMS (ESI+): m/z calcd for C9H13N2O2+ 181.097 15; found 181.097
14.
Characterization Data for Intermediates. (2R,5S)-1-Hydroxy-2-
isopropyl-2,3,5-trimethyl-5-pyridin-3-ylimidazolidin-4-one (11k): yel-
1
low oil. H NMR (400 MHz, CDCl3): δ 9.74−9.31 (br m, 1H), 8.72
(br s, 1H), 8.64−8.35 (br m, 1H), 8.12 (br. d, J = 7.8, 1H), 7.48−7.28
(br m, 1H), 3.82 (s, 3H), 2.81 (s, 3H), 1.93 (hept, J = 6.8, 1H), 1.72
(s, 3H), 1.64 (s, 3H), 1.13 (d, J = 6.9, 3H), 0.82 (d, J = 6.5, 3H). 13C
NMR (101 MHz, CDCl3): δ 171.6, 147.3, 147.2, 139.6, 136.0, 123.6,
84.5, 68.2, 36.1, 25.8, 21.6, 18.8, 17.3, 17.2. HRMS (ESI+): m/z calcd
(R)-Methyl 2-Amino-2-p-tolylpropanoate (12a). The title com-
pound was prepared according to the general procedure from 7a
25
(1.136 g, 4.4 mmol): yellow oil (560 mg; 66%). [α]D1 = −18.1° (c
5.1, MeOH) (lit.47 [α]20 = −19.8° (c 0.5, MeOH)). H NMR (400
D
MHz, CDCl3): δ 7.36 (d, J = 8.3, 2H), 7.15 (d, J = 8.0, 2H), 3.70 (s,
3H), 2.33 (s, 3H), 1.68 (s, 3H). 13C NMR (101 MHz, CDCl3): δ
176.8, 141.3, 137.1, 129.2, 125.0, 60.5, 52.6, 27.5, 21.0. HRMS (ESI+):
+
for C14H22N3O2 264.170 65; found 264.170 73.
(2R,5S)-2-Isopropyl-2,3,5-trimethyl-5-pyridin-3-ylimidazolidin-4-
1
one (13k): colorless oil. H NMR (400 MHz, CDCl3): δ 9.06 (d, J =
+
m/z calcd for C11H16NO2 194.117 56; found 194.117 48.
2.2, 1H), 8.46 (dd, J = 4.6, 1.5, 1H), 8.17 (ddd, J = 8.2, 2.2, 1.5, 1H),
7.20 (dd, J = 8.2, 4.6, 1H), 2.78 (s, 3H), 1.79 (hept, J = 6.7, 1H), 1.65
(s, 3H), 1.60 (broad s, 1H), 1.50 (s, 3H), 0.97 (d, J = 6.7, 3H), 0.47
(d, J = 6.8, 3H). 13C NMR (101 MHz, CDCl3): δ 173.4, 148.2, 148.1,
140.2, 133.8, 122.8, 79.2, 61.9, 35.2, 32.2, 26.5, 25.8, 17.0, 16.9.
(S)-2-Amino-2-(pyridin-3-yl)propanoic acid hydrochloride (14k).
1H NMR (400 MHz, D2O): δ 8.80 (d, J = 2.3, 1H), 8.65 (d, J = 5.6,
1H), 8.53 (ddd, J = 8.4, 2.3, 1.3, 1H), 7.95 (dd, J = 8.4, 5.9, 1H), 1.84
(s, 3H). 13C NMR (101 MHz, D2O): δ 170.3, 144.8, 142.3, 139.8,
135.6, 128.0, 59.9, 21.7.
Characterization Data for Intermediates. (2S,5R)-1-Hydroxy-2-
isopropyl-2,3,5-trimethyl-5-p-tolyl-imidazolidin-4-one (11a): pale yel-
low solid. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 8.2, 2H), 7.16
(d, J = 8.0, 2H), 4.37 (s, 1H), 2.81 (s, 3H), 2.33 (s, 3H), 1.92 (hept, J
= 6.8, 1H), 1.72 (s, 3H), 1.57 (s, 3H), 1.10 (d, J = 6.9, 3H), 0.84 (d, J
= 6.6, 3H). 13C NMR (101 MHz, CDCl3): δ 172.3, 140.3, 137.0,
129.9, 126.6, 84.2, 69.3, 36.3, 25.8, 21.2, 20.3, 18.3, 18.0, 17.1. Anal.
Calcd for C16H24N2O2: C, 69.54; H, 8.76; N, 10.14. Found: C, 69.59;
H, 8.85; N, 10.13. Data for the crystal structure have been deposited at
the Cambridge Crystallographic Data Centre, reference no. CCDC
871605.
ASSOCIATED CONTENT
■
(2S,5R)-2-Isopropyl-2,3,5-trimethyl-5-p-tolyl-imidazolidin-4-one
1
S
* Supporting Information
(13a): yellow oil. H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.2,
Figures, tables, and CIF files giving H and 13C NMR spectra
1
2H), 7.12 (d, J = 8.0, 2H), 2.79 (s, 3H), 2.31 (s, 3H), 1.85 (hept, J =
6.8, 1H,), 1.75 (broad s, 1H), 1.64 (s, 3H), 1.47 (s, 3H), 0.96 (d, J =
6.8, 3H), 0.54 (d, J = 6.7, 3H). 13C NMR (101 MHz, CDCl3): δ 174.6,
141.8, 136.3, 128.7, 125.8, 78.8, 63.1, 35.0, 31.4, 26.1, 25.7, 21.0, 16.9,
16.8.
for all new compounds, determination of optical purity for 12a,
KIE experiments, results of DFT calculations, and crystallo-
graphic data for compounds 7d, 9b, 10a, and 11a. This material
is available free of charge via the Internet at http://pubs.acs.org.
(R)-2-Amino-2-p-tolylpropanoic acid hydrochloride (14a). 1H
NMR (400 MHz, D2O): δ 7.33 (d, J = 8.1, 2H), 7.22 (d, J = 8.0,
2H), 2.21 (s, 3H), 1.91 (s, 3H). 13C NMR (101 MHz, D2O): δ 173.5,
140.4, 132.2, 130.0, 125.6, 61.6, 21.1, 20.2.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Pierre-Yves.Chavant@ujf-grenoble.fr (P.Y.C.);
Veronique.Blandin@ujf-grenoble.fr (V.B.).
■
(R)-Methyl 2-Amino-2-(4-hydroxyphenyl)propanoate (12b). The
title compound was prepared according to the general procedure from
25
7b (1.232 g, 4.5 mmol): yellow oil (421 mg, 48%). [α]D = −36° (c
Notes
1
0.4, MeOH). H NMR (400 MHz, CDCl3): δ 7.26 (d, J = 8.7, 2H),
6.69 (d, J = 8.8, 2H), 3.70 (s, 3H), 1.70 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 177.0, 155.8, 135.1, 126.5, 115.8, 60.2, 52.8, 26.9. HRMS
The authors declare no competing financial interest.
+
(ESI+): m/z calcd for C10H14NO3 196.096 82; found 196.096 74.
ACKNOWLEDGMENTS
■
Characterization Data for Intermediates. (2S,5R)-1-Hydroxy-2-
We thank Marta Carbo
́
Lop
́
ez and Dr. Maryse Thiverny for
isopropyl-5-(4-methoxyphenyl)-2,3,5-trimethylimidazolidin-4-one
their support and Dr. Christian Philouze and Prof. Anne Milet
for their assistance in X-ray analysis and ab initio calculations,
1
(11b): yellow solid. H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8.9,
2H), 6.88 (d, J = 8.9, 2H), 4.46 (s, 1H), 3.79 (s, 3H), 2.81 (s, 3H),
1.90 (hept, J = 6.7, 1H), 1.70 (s, 3H), 1.56 (s, 3H), 1.10 (d, J = 6.8,
3H), 0.84 (d, J = 6.6, 3H). 13C NMR (101 MHz, CDCl3): δ 172.3,
158.9, 135.5, 127.9, 113.7, 84.1, 69.1, 55.4, 36.3, 25.8, 20.3, 18.3, 17.9,
́
respectively. We are grateful to Universite Joseph Fourier and
the CNRS for financial support.
+
17.1. HRMS (ESI+): m/z calcd for C16H25N2O3 293.185 97; found
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