One-pot synthesis of 2-imidazolines via the ring expansion of imidoyl chlorides with aziridines

Article abstract of DOI:10.1021/jo200101q

We herein report a simple and convenient one-pot synthesis of highly substituted 2-imidazolines in a regiocontrolled and stereospecific matter through the ring expansion reaction of an imidoyl chloride with an aziridine, analogous to the Heine reaction.

Full text of DOI:10.1021/jo200101q

NOTE
pubs.acs.org/joc
One-Pot Synthesis of 2-Imidazolines via the Ring Expansion of Imidoyl
Chlorides with Aziridines
Michael R. Kuszpit, William D. Wulff, and Jetze J. Tepe*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48823, United States
S Supporting Information
b
ABSTRACT: We herein report a simple and convenient one-pot synthesis of
highly substituted 2-imidazolines in a regiocontrolled and stereospecific matter
through the ring expansion reaction of an imidoyl chloride with an aziridine,
analogous to the Heine reaction.
midazolines have attracted significant attention because
2-Iof their diverse pharmacological properties.1ꢀ4 The
stereochemistry of this privileged scaffold is capable of governing
its diverse biological characteristics, perhaps best illustrated by
the general NF-κB inhibitory scaffold 15ꢀ9 and p53 activator
scaffold 210ꢀ12 (Figure 1). To develop a stereospecific route to
2-imidazoline scaffolds, we investigated the scope of a Heine-
type ring expansion of aziridines. We anticipated aziridines to be
particularly valuable building blocks, as they can be readily
accessed enantiomerically pure.13ꢀ17 The Heine reaction was
first developed by Harold W. Heine, who reported the synthesis
of 2-imidazolines18 and 2-oxazolines19ꢀ21 by the isomerization of
an imidoyl aziridine and a benzoylated aziridine through NaI in
acetone (Scheme 1). Many examples have been reported for the
isomerization of acyl and benzoyl aziridines to 2-oxazolines by
Heine and others using NaI19ꢀ22 or Lewis acids.23ꢀ27
Even though there have been several reported syntheses of
2-imidazolines,28ꢀ31 reports of a Heine-type isomerization of
imidoyl aziridines have been scarce.18,32ꢀ34 A couple reports
employed the Heine reaction using the reaction of an aziridine
with an alkyne and sulfonyl azide32 and an N-arylketenimine.33
However, these reports were limited in scope and required the
isolation of the imidoyl aziridine prior to the subsequent
rearrangement to the 2-imidazolines. We herein report a simple
and convenient one-pot Heine reaction synthesis of tetrasubsti-
tuted 2-imidazolines in a regiocontrolled and stereospecific
matter through the ring expansion reaction of an imidoyl chloride
with an aziridine.
byproduct with ether. Intermediate 5 was then treated with either
1 equiv of NaI or Et3N HCl and was successfully transformed
3
into the 2-imidazoline 6 by refluxing in acetone, without the
formation of the 2-imidazoline 7 (Scheme 2). The regio- and
stereochemistry of compound 6 was verified by NOE.
The Brønsted acid isomerization of intermediate 5 into
compound 6 by Et3N HCl was consistent with the work by
3
Kohn and co-worker. They reported a Brønsted acid isomeriza-
tion of an ethyl aziridine carboximidate to the corresponding
2-ethoxyimidazoline.34 The exact role of the TEA in the reaction
was somewhat ambiguous. Excess TEA halted the reaction at the
intermediate 5 whereas isomerizaton occurred once the excess
TEA was removed leaving only Et3N HCl (Scheme 2). How-
3
ever, we hypothesized that the correct base would allow for a one-
pot synthesis of 2-imidazoline 6 without stalling at the inter-
mediate 5. Due to the instability of the intermediate 5 to
hydrolysis, we investigated the possibility of a one-pot sequence
using aziridine 3 and imidoyl chloride 4. To optimize this
reaction, compound 4 was isolated by reacting N- benzylbenza-
mide with (COCl)2 and 2,6-lutidine in CH2Cl2. The CH2Cl2 was
removed, followed by trituration of the 2,6-lutidine hydrogen
chloride salt in hexane and removal of any residual 2,6-lutidine in
vacuo.35 The imidoyl chloride 4 was treated with the aziridine 3
in toluene and multiple different bases were investigated in order
to optimize the conversion to compound 6. Initially, the reaction
conditions were optimized with respect to the base and included
DABCO, DMAP, H€unig’s base, Et3N, and 2,6-lutidine (Table 1).
Of these bases, 2,6-lutidine performed the best (Table 1, entry 5)
and rendered the product 6 in a moderate 20% overall yield.
Et3N and H€unig’s base resulted in the reaction stalling at
intermediate 5 (Table 1, entries 3 and 4), which did not cyclize
to compound 6, whereas 2,6-lutidine provided product 6. Although
We first attempted to synthesize 2-imidazoline 6 by reacting
aziridine 3 with imidoyl chloride 4 in a one-pot procedure via
intermediate 5. However, isomerization of the imidoyl aziridine
intermediate 5 into 2-imidazoline 6 did not occur in CH2Cl2 with
a 5:1 mixture of TEA:TEA HCl. Instead only unreacted inter-
mediate 5 was recovered from the reaction by removal of the
3
Received: January 24, 2011
Published: March 14, 2011
excess Et3N in vacuo followed by trituration of the Et3N HCl
3
r
2011 American Chemical Society
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|

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NOTE
Table 1. One-Pot Optimization of Compound 6
Figure 1. Anti and syn 2-imidazolines.
temp equiv
equiv
yields
entry solvent
base
(°C) of 4
of base
T (h)
(%)
1
2
3
4
5
6
7
8
9
toluene DABCO
toluene DMAP
80
80
80
80
80
80
80
rt
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
6.0
6.0
6.0
6.0
6.0
0.0
12
12
12
12
21
21
21
21
21
21
21
21
6
0
Scheme 1. Synthesis of 2-Imidazolines and 2-Oxazolines
0
toluene Et3N
0a
0a
20
37
44
10
38
47
39
50
52
0
toluene (iPr)2NEt
toluene 2,6 lutidine
acetone 2,6-lutidine
DMF
DMF
DMF
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
rt
10 DMF
80
80
55
55
55
11 DCM 2,6-lutidine
12 DMF
13 DMF
14 DMF
2,6-lutidine
2,6-lutidine
none
6
a The reaction stalled at the intermediate imidoyl aziridine 5.
optimization of this one-pot reaction resulted in an overall
yield of 52% of compound 6 based on the aziridine 3 (Table 1,
entry 13).
Considering that 2,6-lutidine was used both to synthesize the
imidoyl chloride 4 and for the ring expansion of aziridine 5 to the
2-imidazoline 6, the imidoyl chloride 4 did not have to be
isolated. Using this one-pot sequence, a range of different imidoyl
chlorides were treated with trans-2,3-diphenyl aziridine to yield
the trans imidazoline in useful yields (Table 2).
Scheme 2. Synthesis of 2-Imidazoline 6
The R1 position tolerated alkyl groups and electron-withdraw-
ing and electron-donating aryl groups, while the R2 position was
restricted to alkyl and benzyl groups. The structural identity was
supported by X-ray crystallography of compound 9j (see the
SupportingInformation). Thereactiondidnot provide thedesired
product when aryl groups were introduced at the R2 position or
when a p-NO2-C6H4ꢀ group was introduced at the R1 position.
The scope of the reaction was subsequently investigated with
respect to the R3, R4, and R5 positions of the aziridine. Electron-
withdrawing and electron-donating aryl groups, along with vinyl,
ketone, ester, and alkyl functionalities were readily tolerated at
these positions (Table 3).
It was important to note that it was not possible to have just a
hydrogen atom at the R4 and R5 positions (Table 3, entry 9). With
respect to the regiochemistry, only one regioisomer was produced in
all cases, except when a p-NO2-C6H4ꢀ group was introduced at
the R3 position or a benzyl group at the R4 position (Table 3,
entries 4 and 8). Side products in this Heine reaction often
included the 2-imidazole, due to oxidation of the imidazoline ring.
Of particular note is that this one-pot Heine reaction showed
an overall retention of stereochemistry. In comparing the cis and
trans stereoisomers of ethyl 3-phenylaziridine-2-carboxylate the
stereochemistry was preserved to yield the cis- and trans-2-
imidazolines, respectively (compounds 6 and Table 3, entry 2).
full mechanistic details have not been exhausted, we postulated that
the role of the base is to initially quench the HCl generated by
substitution of aziridine 3 with imidoyl chloride 4. Second, the
protonated base generated will subsequently act as a Brønsted acid
and is responsible for the isomerization of 5 to compound 6
(Table 1). This is consistent with our finding that unlike TEA
(Scheme 2), excess 2,6-lutidine (Table 1, entries 9ꢀ13) did not
halt the reaction at the intermediate 5, which could be reasoned by
the greater acidity of generated 2,6-lutidine HCl (pKa = 6.7) versus
3
Et3N HCl (pKa = 10.75). The choice of solvent also greatly
3
affected the overall yield of this two-step process and solvents
capable of producing a homogeneous solutions, such as DMF
and DCM, performed superior over solvents that only partially
solubilized the 2,6-lutidine HCl salts, such as toluene. Further
3
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NOTE
Table 2. Variation at R1 and R2
Scheme 3. Synthesis of Enantiopure 2-Imidazoline 6
entry
R1
R2
Bn
T (h)
9
yield (%)
1
2
p-MeO-C6H4
9
9
a
b
c
d
e
f
59
55
43
0
Scheme 4. Proposed Reaction Mechanism
Ph
Bn
3
pꢀF-C6H4
p-NO2ꢀC6H4
Bn
9
4
Bn
6
5
Cy
Me
Ph
Ph
Ph
Ph
Bn
6
60
48
0a
53
53
60
6
Bn
9
7
Ph
13
9
g
h
i
8
PMB
Cy
Me
9
12
9
10
j
a The reaction stalled at the intermediate imidoyl aziridine and did not
cyclize to the 2-imidazoline
Table 3. Variation at R3, R4, and R5
The synthesis of a 2-imidazoline with a quaternary carbon at
the C-5 position (11c) proceeded with complete retention of
stereochemistry (Table 3, entry 3). The identity of compound
11c was supported by X-ray crystallography (see the Supporting
Information). This retention of stereochemistry could be accom-
plished by SN2 attack of the chlorine anion at the 2-position of
the imidoyl aziridine ring carbon and then ring closure through a
second SN2.18ꢀ21 However, another possible mechanism could
involve attack of the imidoyl carbon atom by the chloride anion
followed by ring closure. This mechanism would be analogous to
the earlier proposed mechanism of attack of the imidoyl carbon
by the iodine anion from NaI and subsequent ring closure
(Scheme 4).18,32
entry
R3
R4
R5
T (h)
11
yield (%)
1
2
3
4
5
6
7
8
9
p-MeO-C6H4
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COPh
H
10
12
12
6
a
b
c
d
e
f
45
42
59
40a
41
40
41
40a
0
Ph
H
Ph
Me
H
p-NO2-C6H4
PhCHdCH
n-C6H13
Ph
H
20
12
12
12
12
H
H
g
h
i
Ph
Bn
H
Ph
H
a The compound was synthesized as a 2:1 mixture of regioisomers.
The latter mechanism would suggest that the imidoyl azir-
idines would undergo ring expansion by a 4-endo-tet ring closure.
Both a SNi or a stepwise process are plausible mechanisms;
evidence for these mechanisms has been supported by Tomasini
and co-workers36 via the ring expansion of N-tert-butoxycarbonyl
aziridines to oxazolidinones. These mechanisms would likely
involve activation of the imidoyl aziridine intermediate by the
The 2-imidazoline, compound 6, was synthesized from both
racemic aziridine 3 and enantiopure aziridine 3 (98% ee). This
would presumably yield the 2-imidazoline as a racemate or
enantiopure (98% ee) depending on the enantiopurity of the
starting aziridine 3. The racemate, compound 6, was treated with
(S)-Mosher’s acid, and analysis by 1HNMR showed a 1:1 ratio of
diasteromeric salts. However, the enantiopure compound 6 gave
only one diasteromeric salt by 1H NMR. Thus the enantiopurity
of compound 6 was preserved in the ring expansion reaction
therefore demonstrating the utility to access enantiopure 2-imi-
dazolines (Scheme 3).
Brønsted acid, 2,6-lutidine HCl. Nitrogenꢀcarbon bond forma-
3
tion occurred at the most electropositive carbon atom in the
imidoyl aziridine intermediate. This was the C-2 position of the
aziridine in all cases except when a p-NO2-C6H4ꢀ group was
introduced at the C-3 position or a benzyl group at the C-2
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NOTE
position. In this case the C-3 and C-2 positions of the aziridine
ring had similar electronics and resulted in a mixture of 2-imi-
dazoline regioisomers (Table 3, entries 4 and 8).
concentrated in vacuo to yield compound 5. To crude compound 5 were
added NaI (78 mg, 0.52 mmol) and acetone (5 mL) and the solution was
brought to reflux for 24 h. The reaction was worked up and purified by
the general procedure for synthesis of imidazolines (located below): oil;
65 mg, 32% yield.
In conclusion, we have developed a simple one-pot stereo-
specific synthesis of 2-imidazolines from the ring expansion
of an aziridine with an imidoyl chloride consistent with a
Heine reaction. The scope of the reaction indicated that the
reaction tolerated many diverse functional groups. The pur-
ification of imidoyl chlorides and imidoyl aziridine intermedi-
ates was not needed, therefore creating a simple one-pot
method to synthesize these biologically significant highly sub-
stituted 2-imidazolines.
General Procedure for the Synthesis of Imidazolines. The
reaction scale was based on 100 mg of the starting aziridine. To a 10-mL
round-bottomed flask under argon were added the desired amide (1.2
equiv), 2,6-lutidine (6 equiv), and DCM (4 mL). The solution was either
cooled to 0 °C or left at room temperature depending on the amide
(located below). Oxalyl chloride (1.2 equiv) was added to the round-
bottomed flask over 3 min with a syringe. The solution was reacted for the
desired time (located below) and then the DCM was removed under
reduced pressure at room temperature. This gave the crude product as a
mixture of the desired imidoyl chloride, excess 2,6-lutidine (bp 144 °C,
760 mmHg), and 2,6-lutidine hydrogen chloride. This round-bottomed
flask was then placed under argon again and the desired aziridine (100 mg,
1 equiv) and DMF (4 mL) were added. The solution was heated to 55 °C
for the desired time (see Table 2 or 3). An aliquot of the reaction solution
was taken and placed under vacuum (approximately 10 mmHg) at room
’ EXPERIMENTAL SECTION
General. Acetonitrile, Et3N, and DMF were distilled from calcium
hydride under nitrogen. Toluene and DCM were purified through a
column packed with dry alumina and were dispensed by a nitrogen
pressure delivery system. THF and ether were distilled from sodium
under nitrogen. Acetone, 1,2-dichloroethane, and chloroform were
distilled from calcium sulfate under nitrogen. All other reagents and
solvents were purchased from commercial sources and used without
further purification. All flasks were oven-dried overnight and cooled
under argon or nitrogen. All reactions were monitored by TLC with 0.25
μM precoated silica gel plates and UV light was used to visualize the
compounds. It some cases phosphomolybdic acid (PMA) stain or I2 was
used to visualize the compounds. Column chromatography silica gel was
provided by EM Science (230ꢀ400 mesh). All NMR spectra were
recorded on a 500 or 300 MHz spectrometer. Chemical shifts are
reported relative to the solvent peak of chloroform (δ 7.24 for 1H and δ
77.0 for 13C).
1
temperature and a H NMR was taken to determine the imidazoline
reaction times. The reactions could also be monitored by TLC 30:70
EtOAc:hexane (imidazoline HCl salt polar). The reaction solution was
3
then cooled to room temperature and poured into a separatory funnel
followed by an addition of equal volumes of sat. aq. NaHCO3 and water.
The product was extracted with EtOAC, and the combined organic
extracts were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The imidazolines were purified
by column chromatography on silica gel. In some cases the silica gel had to
be neutralized with TEA to avoid product decomposition.
Racemic or enantiopure ethyl 1-benzyl-2,4-diphenyl-4,5-
dihydro-1H-imidazole-5-carboxylate (6): Either racemic or en-
antiopure ethyl 3-phenylaziridine-2-carboxylate was used. The imidoyl
chloride reaction time was 1.25 h at 0 °C. The imidazoline reaction time
was 6 h. Silica gel chromatography; 50:50 EtOAc:hexane; Rf 0.35; oil;
General Procedure To Neutralize Silica Gel. Silica gel was
saturated with Et3N; the slurry was mixed for 5 min and then
concentrated under reduced pressure to remove the excess Et3N to give
a free-flowing powder once again.
1
105 mg; 52% yield; H NMR (500 MHz) (CDCl3) δ 0.8 (3H, t, J =
Racemic or enantiopure ethyl 1-benzyl-2,4-diphenyl-4,5-
dihydro-1H-imidazole-5-carboxylate (Scheme 2) (6): Benzyl
benzamide (200 mg, 0.95 mmol) and DCM (4 mL) were added to a 10-
mL round-bottomed flask under argon. The round-bottomed flask was
cooled to 0 °C and 2,6-lutidine (0.13 mL, 1.58 mmol) was added to the
round-bottomed flask via a syringe. Oxalyl chloride (0.10 mL, 1.14
mmol) was added dropwise to the reaction solution over the course of 2
min. Carbon monoxide and carbon dioxide bubbled out of the solution
and the reaction was stirred at 0 °C for 1.25 h. The DCM was removed
under reduced pressure at room temperature to give a yellow solid. The
round-bottomed flask was put under argon and hexane (4 mL) was
added via a syringe. The solution was mixed for 1 h at room temperature.
The salts were removed by vacuum filtration through a plug of Celite.
The hexane was removed under reduced pressure at room temperature
to give (Z)-N-benzylbenzimidoyl chloride 4: oil; 175 mg; 80% yield. The
product could not be purified any further due to rapid hydrolysis to
benzyl benzamide with water from the air. To another 10 mL of RBF
were added either racemic or enantiopure ethyl 3-phenylaziridine-2-
carboxylate (100 mg, 0.52 mmol), TEA (0.44 mL, 3.12 mmol), DCM
(6 mL), and (Z)-N-benzylbenzimidoyl chloride (143 mg, 0.62 mmol).
The solution was heated to reflux for 5 h and then cooled to room
temperature. The reaction solution was concentrated and the excess
TEA was removed in vacuo to yield crude compound 5 and 1 equiv of
7.0 Hz), 3.3ꢀ3.4 (2H, m), 4.2 (1H, d, J = 15.5 Hz), 4.4 (1H, d, J = 12.0 Hz),
4.7 (1H, d, J = 15.5 Hz), 5.6 (1H, d, J = 12.0 Hz), 7.1ꢀ7.3 (10H, m), 7.4
(3H, m), 7.7 (2H, m); 13C NMR and DEPT (125 MHz) (CDCl3) δ
13.4 (CH3), 49.9 (CH2), 60.4 (CH2), 67.0 (CH), 71.3 (CH), 127.3
(CH), 127.5 (CH), 127.6 (CH), 127.7 (CH), 128.0 (CH), 128.4 (CH),
128.6 (CH), 130.0 (CH), 130.5 (CH), 130.7 (C), 136.3 (C), 139.0 (C),
146.3 (C), 169.8 (C); IR (NaCl) 3075, 2980, 1738, 1496; HRMS calcd
for C25H25N2O2 (M þ H) 385.1916, found 385.1922.
Determination of Enantiomeric Excess of Compound 6 by
(S)-Mosher’s Acid. Racemic compound 6 and (S)-Mosher’s acid were
combined in equal molar quantities in an NMR tube along with CDCl3.
Analysis by 1H NMR revealed that the (S,R,R) and the (S,S,S)
diastereomeric salts were formed in a 50:50 mixture. Enantiopure
compound 6 and (S)-Mosher’s acid were combined in equal molar
1
quantities in an NMR tube along with CDCl3. Analysis by HNMR
revealed that only one of the (S,S,S) diastereomeric salt was detected. (S,
R,R) diastereomeric salt: 1H NMR (500 MHz) (CDCl3) δ 0.78 (3H, t, J
= 7.5 Hz), 3.34 (3H, s), 3.5ꢀ3.8 (2H, m), 4.33 (1H, d, J = 15.0 Hz), 4.62
(1H, d, J = 12.5 Hz), 4.94 (1H, d, J = 15.0 Hz), 5.86 (1H, d, J = 12.5 Hz),
7.2ꢀ7.9 (20H, m), 9.2 (1H, s, br). (S,S,S) diastereomeric salt: 1H NMR
(500 MHz) (CDCl3) δ 0.79 (3H, t, J = 7.5 Hz), 3.35 (3H, s), 3.5ꢀ3.8
(2H, m), 4.34 (1H, d, J = 15.0 Hz), 4.64 (1H, d, J = 12.5 Hz), 4.95 (1H, d,
J = 15.0 Hz), 5.90 (1H, d, J = 12.5 Hz), 7.2ꢀ7.9 (20H, m), 9.5 (1H, s, br).
1-Benzyl-2-(4-methoxyphenyl)-4,5-diphenyl-4,5-dihydro-
1H-imidazole (9a): The imidoyl chloride reaction time was 1.25 h
at 0 °C. The imidazoline reaction time was 9 h. Silica gel column
chromatography; 50:50 EtOAc:hexane; Rf 0.4; oil, 126 mg; 59% yield;
1H NMR (500 MHz) (CDCl3) δ 3.9 (3H, s), 4.0 (1H, d, J = 16.0 Hz),
Et3N HCl. To crude compound 5 was added acetone (5 mL) and the
3
solution was brought to reflux for 24 h. The reaction was worked up and
purified by the general procedure for synthesis of imidazolines (located
below): oil; 77 mg, 38% yield. Alternatively, the Et3N HCl could be
3
removed by the addition of ether (10 mL) and the solution was allowed
to sit for 15 min. The solution was then filtered through Celite and
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NOTE
4.4 (1H, d, J = 8.5 Hz), 4.8 (1H, d, J = 15.5 Hz), 5.0 (1H, d, J = 8.5 Hz),
68.0 (2H, dd, J1 = 7.5 Hz, J2 = 2.5 Hz), 7.1 (2H, d, J = 9.0 Hz), 7.2 (2H, d,
1-(4-Methoxybenzyl)-2,4,5-triphenyl-4,5-dihydro-1H-imi-
dazole (9h): The imidoyl chloride reaction time was 1.25 h at 0 °C.
The imidazoline reaction time was 9 h. Silica gel chromatography; 50:50
EtOAc:hexane; Rf 0.4; solid; mp 110ꢀ112 °C; 114 mg; 53% yield; 1H
NMR (500 MHz) (CDCl3) δ 3.8 (3H, s), 3.9 (1H, d, J = 15.0 Hz), 4.4
(1H, d, J = 9.0 Hz), 4.7 (1H, d, J = 15.5 Hz), 5.0 (1H, d, J = 8.5 Hz), 6.8
(2H, dd, J1 = 6.5 Hz, J2 = 2.0 Hz), 6.9 (2H, dd, J1 = 8.5 Hz, J2 = 2.0 Hz),
7.2 (2H, dd, J1 = 8.5 Hz, J2 = 1.5 Hz), 7.2ꢀ7.4 (8H, m), 7.5 (3H, m),
7.8ꢀ7.9 (2H, m); 13C NMR and DEPT (125 MHz) (CDCl3) δ 49.1
(CH2), 55.1 (CH3), 72.4 (CH), 77.9 (CH), 113.8 (CH), 126.8 (CH),
126.9 (CH), 127.1 (CH), 127.7 (CH), 128.3 (CH), 128.3 (C), 128.6
(CH), 128.7 (CH), 128.8 (CH), 129.2 (CH), 130.0 (CH), 131.4 (C),
141.9 (C), 143.9 (C), 158.9 (C), 166.0 (C); IR (NaCl) 3028, 2928,
1512; HRMS calcd for C29H27N2O (M þ H) 419.2123, found
419.2125.
1-Cyclohexyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole
(9i): The imidoyl chloride reaction time was 3 h at room temperature.
The imidazoline reaction time was 12 h. Silica gel column chromatog-
raphy; 50:50 EtOAc:hexane; Rf 0.33; 104 mg; 53% yield; solid; mp
138ꢀ140 °C; 1H NMR (500 MHz) (CDCl3) δ 0.7 (2H, m), 0.8ꢀ0.9
(2H, m), 1.3 (3H, m), 1.4ꢀ1.5 (3H, m), 3.4ꢀ3.5 (1H, m), 4.4 (1H, d, J =
7.0 Hz), 4.7 (1H, d, J = 7.0 Hz), 7.1 (4H, m), 7.3 (6H, m), 7.3 (3H, m),
7.7 (2H, m); 13C NMR and DEPT (125 MHz) (CDCl3) δ 25.5 (CH2),
25.7 (CH2), 26.3 (CH2), 30.4 (CH2), 33.8 (CH2), 56.9 (CH), 70.1
(CH), 78.9 (CH), 126.4 (CH), 126.8 (CH), 127.4 (CH), 127.5 (CH),
128.7 (CH), 128.9 (CH), 129.0 (CH), 130.4 (CH), 132.2 (CH), 145.0
(C), 146.5 (C), 165.8 (C), 167.6 (C); IR (NaCl) 3028, 2933, 1451;
HRMS calcd for C27H29N2 (M þ H) 381.2331, found 381.2330.
1-Methyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole (9j):
The imidoyl chloride reaction time was 1.25 h at 0 °C. The imidazoline
reaction time was 9 h. Silica gel chromatography; 50:50 EtOAc:hexane;
Rf 0.35; solid; mp 86ꢀ88 °C; 96 mg; 60% yield; 1H NMR (500 MHz)
(CDCl3) δ 2.7 (3H, s), 4.3 (1H, d, J = 10.0 Hz), 5.0 (1H, d, J = 10.0 Hz),
7.3ꢀ7.4 (10H, m), 7.5 (3H, m), 7.7 (2H, m); 13C NMR and DEPT (125
MHz) (CDCl3) δ 35.0 (CH3), 77.8 (CH), 78.6 (CH), 126.9 (CH),
127.1 (CH), 127.1 (CH), 127.8 (CH), 128.4 (CH), 128.5 (CH), 128.6
(CH), 128.9 (CH), 130.0 (CH), 131.3 (C), 141.9 (C), 144.1 (C), 167.0
(C); IR (NaCl) 3028, 2925, 1498; HRMS calcd for C22H21N2 (M þ H)
313.1705, found 313.1707.
Ethyl 1-benzyl-4-(4-methoxyphenyl)-2-phenyl-4,5-dihy-
dro-1H-imidazole-5-carboxylate (11a): The imidoyl chloride
reaction time was 1.25 h at 0 °C. The imidazoline reaction time was
10 h. Silica gel chromatography; 50:50 EtOAc:hexane; Rf 0.45; oil; 98
mg; 45% yield; 1H NMR (500 MHz) CDCl3: 1.3 (3H, t, J = 7.0 Hz), 3.9
(3H, s), 4.0 (1H, d, J = 16.0 Hz), 4.3 (2H, m), 4.6 (1H, d, J = 8.0 Hz), 4.6
(1H, d, J = 16.0 Hz), 4.9 (1H, d, J = 8.0 Hz), 6.9 (2H, m), 7.1 (2H, d J =
7.0 Hz), 7.2ꢀ7.3 (5H, m), 7.4ꢀ7.5 (3H, m), 7.7 (2H, m); 13C NMR
(500 MHz) (CDCl3) δ 14.4 (CH3), 40.0 (CH2), 55.6 (CH3), 61.5
(CH2), 66.1 (CH), 76.0 (CH), 114.6 (CH), 127.7 (CH), 127.7 (CH),
128.7 (CH), 128.7 (CH), 128.9 (CH), 128.9 (CH), 130.6 (CH), 130.7
(C), 132.8 (C), 136.6 (C), 159.8 (C), 167.2 (C), 172.2 (C); IR (NaCl)
3031, 2934, 1734, 1512, 1249; HRMS calcd for C26H27N2O3 (M þ H)
415.1977, found 415.2022.
Ethyl 1-benzyl-2,4-diphenyl-4,5-dihydro-1H-imidazole-5-
carboxylate (11b): The imidoyl chloride reaction time was 1.25 h at
0 °C. The imidazoline reaction time was 12 h. Silica gel column
chromatography; 50:50 EtOAc:hexane; Rf 0.4; solid; 78ꢀ80 °C; 85
mg; 42% yield; 1H NMR (500 MHz) (CDCl3) δ 1.3 (3H, t, J = 7.0 Hz),
4.0 (1H, d, J = 7.5 Hz), 4.1ꢀ4.3 (2H, m), 4.4 (1H, d, J = 15.5 Hz), 4.6
(1H, d, J = 15.5 Hz), 5.3 (1H, d, J = 7.5 Hz), 7.1 (2H, dd, J1 = 6.0 Hz, J2 =
1.5 Hz), 7.2ꢀ7.3 (10H, m), 7.5 (3H, m), 7.8 (2H, m); 13C NMR and
DEPT (500 MHz) (CDCl3) δ 14.1 (CH3), 51.3 (CH2), 61.3 (CH2),
69.9 (CH), 72.3 (CH), 126.6 (CH), 127.3 (CH), 127.7 (CH), 127.9
(CH), 128.4 (CH), 128.57 (CH), 128.58 (CH), 128.8 (CH), 130.3
J = 7.0 Hz), 7.4 (8H, m), 7.4ꢀ7.5 (3H, m), 7.8 (2H, d, J = 9.0 Hz); 13
C
NMR and DEPT (125 MHz) (CDCl3) δ 49.7 (CH2), 55.2 (CH3), 72.5
(CH), 76.5 (CH), 114.1 (CH), 122.3 (C), 126.5 (CH), 127.0 (CH),
127.1 (CH), 127.5 (CH), 127.8 (CH), 127.9 (CH), 128.4 (CH), 128.5
(CH), 128.8 (CH), 130.2 (CH), 136.0 (C), 141.2 (C), 143.3 (C), 161.3
(C), 165.7 (C); IR (NaCl) 3028, 2925, 1512; HRMS calcd for
C29H27N2O (M þ H) 419.2123, found 419.2123.
1-Benzyl-2,4,5-triphenyl-4,5-dihydro-1H-imidazole (9b):
The imidoyl chloride reaction time was 1.25 h at 0 °C. The imidazo-
line reaction time was 9 h. Silica gel column chromatography; 50:50
EtOAc:hexane; Rf 0.4; oil; 109 mg; 55% yield; 1H NMR (500 MHz)
(CDCl3) δ 4.0 (1H, d, J = 15.5 Hz), 4.4 (1H, d, J = 8.5 Hz), 4.8 (1H, d,
J = 15.5 Hz), 5.0 (1H, d, J = 8.5 Hz), 7.0 (2H, dd, J1 = 8.0 Hz, J2 = 2.0
Hz), 7.1 (2H, dd, J1 = 8.0 Hz, J2 = 1.5 Hz), 7.2ꢀ7.4 (11H, m), 7.5
(3H, m), 7.8ꢀ7.9 (2H, m); 13C NMR and DEPT (125 MHz)
(CDCl3) δ 49.5 (CH2), 72.5 (CH), 77.7 (CH), 126.6 (CH), 126.9
(CH), 127.0 (CH), 127.3 (CH), 127.6 (CH), 127.8 (CH), 128.2
(CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.7 (CH), 130.0
(CH), 131.1 (C), 136.2 (C), 141.6 (C), 143.7 (C), 165.8 (C); IR
(NaCl) 3028, 2922, 1495; HRMS calcd for C28H25N2 (M þ H)
389.2023, found 389.2023.
1-Benzyl-2-(4-fluorophenyl)-4,5-diphenyl-4,5-dihydro-1H-
imidazole (9c): The imidoyl chloride reaction time was 1.25 h at 0 °C.
The imidazoline reaction time was 9 h. Silica gel column chromatogra-
phy; 50:50 EtOAc:hexane; Rf 0.4; oil; 90 mg; 43% yield; 1H NMR (500
MHz) (CDCl3) δ 4.1 (1H, d, J = 15.5 Hz), 4.4 (1H, d, J = 8.5 Hz), 4.7
(1H, d, J = 15.5 Hz), 5.0 (1H, d, J = 8.5 Hz), 7.0 (2H, dd, J1 = 9.5 Hz, J2 =
3.5 Hz), 7.1ꢀ7.4 (15H, m), 7.8ꢀ7.9 (2H, m); 13C NMR and DEPT
(125 MHz) (CDCl3) δ 50.1 (CH2), 73.1 (CH), 78.2 (CH), 116.2
(d, 2JC/F = 86.5 Hz) (CH), 127.0 (CH), 127.4 (CH), 127.5 (CH), 127.8
(d, 4JC/F = 17 Hz) (C), 127.9 (CH), 128.1 (CH), 128.2 (CH), 128.7
(CH), 128.9 (CH), 129.2 (CH), 131.0 (d, 3JC/F = 33 Hz) (CH), 136.6
(C), 142.1 (C), 144.1 (C), 163.1 (C), 165.1 (d, 1JC/F = 119.5 Hz) (C);
IR (NaCl) 3030, 2957, 1512; HRMS calcd for C28H24FN2 (M þ H)
407.1929, found 407.1927.
1-Benzyl-2-cyclohexyl-4,5-diphenyl-4,5-dihydro-1H-imida-
zole (9e): The imidoyl chloride reaction time was 1.25 h at room
temperature. The imidazoline reaction time was 6 h. Silica gel column
chromatography; 50:50 EtOAc:hexane; Rf 0.35; oil; 122 mg; 60% yield;
1H NMR (500 MHz) (CDCl3) δ 1.2ꢀ1.3 (3H, m), 1.7ꢀ1.8 (2H, m),
1.8ꢀ1.9 (3H, m), 2.0ꢀ2.1 (2H, m), 2.4ꢀ2.5 (1H, m), 3.9 (1H, d, J =
16.5 Hz), 4.2 (1H, d, J = 8.0 Hz), 4.6 (1H, d, J = 16.0 Hz), 4.8 (1H, d, J =
8.0 Hz), 7.0ꢀ7.4 (15H, m); 13C NMR and DEPT (125 MHz) (CDCl3)
δ 26.0 (CH2), 26.2 (CH2), 26.4 (CH2), 30.6 (CH2), 31.9 (CH2), 36.6
(CH), 47.2 (CH2), 72.7 (CH), 76.8 (CH), 126.6 (CH), 126.9 (CH),
127.1 (CH), 127.1 (CH), 127.4 (CH), 127.7 (CH), 128.4 (CH), 128.6
(CH), 128.8 (CH), 137.0(C), 141.9 (C), 144.3 (C), 169.9 (C); IR
(NaCl) 3028, 2928, 1495; HRMS calcd for C28H31N2 (M þ H)
395.2487, found 395.2494.
1-Benzyl-2-methyl-4,5-diphenyl-4,5-dihydro-1H-imida-
zole (9f): The imidoyl chloride reaction time was 1.25 h at 0 °C. The
imidazoline reaction time was 9 h. Silica gel was neutralized with TEA by
the general procedure. Silica gel chromatography; 40:55:5 EtOAc:
hexane:TEA; Rf 0.4. oil; 81 mg; 48% yield; 1H NMR (500 MHz)
(CDCl3) δ 2.2 (3H, s), 3.9 (1H, d, J = 16.5 Hz), 4.3 (1H, d, J = 9.0 Hz),
4.5 (1H, d, J = 16.5 Hz), 4.8 (1H, d, J = 9.0 Hz), 7.1 (2H, d, J = 7.5 Hz),
7.1 (2H, m), 7.2ꢀ7.4 (11H, m); 13C NMR and DEPT (125 MHz)
(CDCl3) δ 14.8 (CH3), 47.8 (CH2), 73.0 (CH), 77.3 (CH), 126.6
(CH), 126.9 (CH), 127.1 (CH), 127.3 (CH), 127.4 (CH), 127.7 (CH),
128.3 (CH), 128.6 (CH), 128.7 (CH), 136.7 (C), 141.0 (C), 143.6 (C),
162.9 (C); IR (NaCl) 3028, 2924, 1495; HRMS calcd for C23H23N2
(M þ H) 327.1861, found 327.1867.
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NOTE
(CH), 130.6 (C), 136.3 (C), 143.2 (C), 165.8 (C), 172.1 (C); IR
(NaCl) 3030, 2980, 1734, 1497; HRMS calcd for C25H25N2O2 (M þ H)
385.2023, found 385.2027.
J = 7.0 Hz), 1.3ꢀ1.4 (8H, m), 1.5ꢀ1.6 (1H, m), 1.6ꢀ1.7 (1H, m), 3.7
(1H, d, J = 7.0 Hz), 4.1 (1H, m), 4.1ꢀ4.3 (2H, m), 4.3 (1H, d, J = 15.5
Hz), 4.6 (1H, d, J = 15.5 Hz), 7.1 (2H, d, J = 7.0 Hz), 7.3 (3H, m), 7.4
(3H, m), 7.7 (2H, m); 13C NMR and DEPT (500 MHz) (CDCl3) δ
14.1 (CH3), 14.2 (CH3), 22.6 (CH2), 25.0 (CH2), 29.1 (CH2), 31.7
(CH2), 36.8 (CH2), 51.0 (CH2), 61.1 (CH2), 66.8 (CH), 69.8 (CH),
127.7 (CH), 127.9 (CH), 128.6 (CH), 128.6 (CH), 128.7 (CH), 130.1
(CH), 130.7 (C), 136.7 (C), 164.7 (C), 172.6 (C); IR (NaCl) 3029,
2928, 1734, 1469, 1381; HRMS calcd for C25H33N2O2 (M þ H)
393.2542, found 393.2548.
1-Benzyl-2,4-diphenyl-4,5-dihydro-1H-imidazol-5-yl)(phenyl)-
methanone (11g): The imidoyl chloride reaction time was 1.25 h at
0 °C. The imidazoline reaction time was 12 h. Silica gel chromator-
graphy; 50:50 EtOAc:hexane; Rf 0.45; oil; 85 mg; 41% yield; 1H NMR
(500 MHz) (CDCl3) δ 4.3 (1H, d, J = 15.5 Hz), 4.7 (1H, d, J = 15.5 Hz),
4.9 (1H, d, J = 6.5 Hz), 5.1 (1H, d, J = 6.5 Hz), 7.1 (2H, m), 7.2 (2H, m),
7.2ꢀ7.4 (6H, m), 7.4 (2H, m), 7.5 (3H, m), 7.6 (1H, m), 7.7 (2H, d, J =
8.0 Hz), 7.8 (2H, m); 13C NMR and DEPT (500 MHz) (CDCl3) δ 51.1
(CH2), 73.2 (CH), 73.3 (CH), 127.3 (CH), 127.9 (CH), 128.0 (CH),
128.4 (CH), 128.8 (CH), 128.9 (CH), 128.9 (CH), 129.0 (CH), 129.0
(CH), 129.1 (CH), 130.6 (CH), 133.8 (CH), 135.0 (C), 136.7 (C),
143.0 (C), 165.8 (C), 166.3 (C), 197.7 (C); IR (NaCl) 3065, 2925,
1688, 1451; HRMS calcd for C29H25N2O (M þ H) 417.1967, found
417.1960.
1,5-Dibenzyl-2,4-diphenyl-4,5-dihydro-1H-imidazole and
1,4-dibenzyl-2,5-diphenyl-4,5-dihydro-1H-imidazole (11h):
The imidoyl chloride reaction time was 1.25 h at 0 °C. The imidazoline
reaction time was 12 h. Silica gel chromatorgraphy; 50:50 EtOAc:
hexane; Rf 0.45; oil; 87 mg; 41% yield; the compounds were isolated
as an inseparable mixture of regioisomers (2:1 ratio). Regioisomer 1: 1H
NMR (500 MHz) (CDCl3) δ 2.5 (1H, dd, J1 = 8.5 Hz, J2 = 5.5 Hz), 3.0
(1H, dd, J1 = 8.0 Hz, J2 = 6.0 Hz), 3.8 (1H, d, J = 16.0 Hz), 4.6 (1H, d, J =
11.0 Hz), 4.7 (1H, d, J = 16.0 Hz), 4.8 (1H, m), 6.8ꢀ7.9 (20H, m).
Regioisomer 2: 1H NMR (500 MHz) (CDCl3) δ 2.3 (1H, dd, J1 = 7.5
Hz, J2 = 6.0 Hz), 2.7 (1H, dd, J1 = 8.5 Hz, J2 = 5.5 Hz), 3.6 (1H, d, J = 16.0
Hz), 4.1 (1H, m), 4.5 (1H, d, J = 16.0 Hz), 5.3 (1H, d, J = 10.5 Hz),
6.8ꢀ7.9 (20H, m). Both Regioisomers: 13C NMR (500 MHz)
(CDCl3) δ 37.7, 39.0, 48.9, 51.3, 64.6, 66.9, 70.6, 72.8, 125.9, 126.4,
127.3, 127.7, 127.7, 127.8, 127.8, 127.8, 127.8, 128.1, 128.2, 128.2, 128.5,
128.6, 128.8, 128.8, 128.9, 128.9, 128.9, 129.1, 129.2, 129.4, 130.3, 130.6,
131.6, 131.7, 137.4, 137.8, 138.4, 139.3, 149.8, 140.0, 165.8, 167.7; IR
(NaCl) 3028, 2918, 1616, 1595; HRMS calcd for C26H27N2O2 (M þ H)
399.2073, found 399.2086.
Ethyl 1-benzyl-5-methyl-2,4-diphenyl-4,5-dihydro-1H-imi-
dazole-5-carboxylate (11c): The imidoyl chloride reaction time was
1.25 h at 0 °C. The imidazoline reaction time was 12 h. Silica gel column
chromatography; 50:50 EtOAc:hexane; Rf 0.3; solid; mp 100ꢀ102 °C;
125 mg; 59% yield; 1H NMR (500 MHz) (CDCl3) δ 1.0 (3H, s), 1.3
(3H, t, J = 7.0 Hz), 4.2 (2H, q, J = 7.0 Hz), 4.3 (1H, d, J = 17.5 Hz), 4.6
(1H, d, J = 17.5 Hz), 5.5 (1H, s), 7.2ꢀ7.4 (13H, m), 7.6 (2H, m); 13C
NMR and DEPT (500 MHz) (CDCl3) δ (one CH carbon not found)
14.4 (CH3), 18.4 (CH3), 48.4 (CH2), 61.9 (CH2), 73.7 (CH), 75.8 (C),
127.0 (CH), 127.3 (CH), 127.9 (CH), 128.3 (CH), 128.5 (CH), 128.5
(CH), 128.6 (CH), 128.7 (CH), 130.1 (CH), 131.6 (C), 138.4 (C),
139.3 (C), 167.0 (C), 175.2 (C); IR (NaCl) 3029, 2988, 1732, 1454;
HRMS calcd for C29H27N2 (M þ H) 403.2174, found 403.2185.
Ethyl 1-benzyl-4-(4-nitrophenyl)-2-phenyl-4,5-dihydro-1H-
imidazole-5-carboxylate (11d): The imidoyl chloride reaction
time was 1.25 h at 0 °C. The imidazoline reaction time was 13 h. Silica
gel column chromatography; 40:60 EtOAc:hexane; Rf 0.29; oil; 30 mg;
13% yield; the regiochemistry was confirmed by NOESY; 1H NMR (500
MHz) (CDCl3) δ 1.3 (3H, t, J = 7.5 Hz), 3.9 (1H, d, J = 7.5 Hz), 4.2ꢀ4.4
(2H, m), 4.4 (1H, d, J = 15.0 Hz), 4.7 (1H, d, J = 15.5 Hz), 5.4 (1H, d, J =
7.5 Hz), 7.0 (2H, m), 7.2 (3H, m), 7.4 (2H, d, J = 8.5 Hz), 7.5 (3H, m),
7.8 (2H, m), 8.2 (2H, d, J = 9.0 Hz); 13C NMR and DEPT (125 MHz)
(CDCl3) δ 14.5 (CH3), 51.5 (CH2), 62.0 (CH2), 69.3 (CH), 71.5
(CH), 124.0 (CH), 127.8 (CH), 128.2 (CH), 128.3 (CH), 129.0 (CH),
129.0 (CH), 129.1 (CH), 130.4 (C), 131.0 (CH), 136.1 (C), 147.5 (C),
150.8 (C), 167.1 (C), 171.8 (C); IR (NaCl) 3028, 2918, 1734, 1523,
1350; HRMS calcd for C25H24N3O4 (M þ H) 430.1767, found
430.1780.
Ethyl 1-benzyl-5-(4-nitrophenyl)-2-phenyl-4,5-dihydro-1H-
imidazole-4-carboxylate (11d): Silica gel column chromatogra-
phy; 40:60 EtOAc:hexane; Rf 0.2; oil; 60 mg; 27% yield; the regiochem-
istry was confirmed by NOESY; 1H NMR (500 MHz) (CDCl3) δ 1.3
(3H, t, 7.0 Hz), 4.0 (1H, d, J = 15.5 Hz), 4.2ꢀ4.3 (2H, m), 4.5 (1H, d, J =
8.0 Hz), 4.6 (1H, d, J = 15.5 Hz), 5.0 (1H, d, J = 15.5 Hz), 7.0 (2H, dd, J1
= 5.5 Hz, J2 = 2.0 Hz), 7.2ꢀ7.3 (4H, m), 7.5 (4H, m), 7.7 (2H, m), 8.2
(2H, d, J = 9.0 Hz); 13C NMR and DEPT (125 MHz) (CDCl3) δ 14.2
(CH3), 51.3 (CH2), 61.8 (CH2), 66.4 (CH), 76.5 (CH), 124.5 (CH),
128.0 (CH), 128.1 (CH), 128.2 (CH), 128.9 (CH), 129.0 (CH), 129.0
(CH), 130.3 (C), 131.0 (CH), 135.8 (C), 147.9 (C), 148.7 (C), 167.8
(C), 171.6 (C); IR (NaCl) 3029, 2984, 1742, 1523, 1350; HRMS calcd
for C25H24N3O4 (M þ H) 430.1767, found 430.1780.
Ethyl 1-benzyl-2-phenyl-4-styryl-4,5-dihydro-1H-imidazole-
5-carboxylate (11e): The imidoyl chloride reaction time was 1.25 h
at 0 °C. The imidazoline reaction time was 20 h. The silica gel was
neutralized by the general method. Silica gel column chromatography;
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures for all compounds synthesized, X-ray structure of com-
pounds 9j and 11c, as well as all spectroscopy data. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
40:60 EtOAc:hexane; Rf 0.48; oil; 92 mg; 41% yield; H NMR (500
MHz) (CDCl3) δ 1.2 (3H, t, J = 7.0 Hz), 4.1ꢀ4.2 (2H, m), 4.2 (1H, d, J
= 17.0 Hz), 4.5 (1H, d, J = 0.5 Hz), 4.5 (1H, d, J = 0.5 Hz), 4.5 (1H, d, J =
16.0 Hz), 6.1 (1H, m), 6.4 (1H, d, J = 16.0 Hz), 7.1 (2H, d, J = 5.0 Hz),
7.2ꢀ7.4 (11H, m), 7.6 (2H, m); 13C NMR and DEPT (125 MHz)
(CDCl3) δ 14.4 (CH3), 49.5 (CH2), 61.6 (CH2), 66.4 (CH), 77.1
(CH), 126.9 (CH), 127.7 (CH), 127.7 (CH), 127.8 (CH), 128.3 (CH),
128.8 (CH), 128.8 (CH), 128.9 (CH), 128.9 (CH), 130.5 (CH), 130.8
(C), 134.1 (CH), 136.4 (C), 137.1 (C), 167.4 (C), 172.1 (C); IR
(NaCl) 3154, 2984, 1733, 1469, 1381; HRMS calcd for C27H27N2O2
(M þ H) 411.2073, found 411.2086.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: tepe@chemistry.msu.edu.
’ ACKNOWLEDGMENT
The authors gratefully acknowledge financial support of this
work from the National Institutes of Health (CA142644-01). In
addition the authors thank Dr. Richard J. Staples for carrying out
the X-ray crystallography as well as Rahman Saleem and Nicole
Hewlett for HRMS analysis.
Ethyl 1-benzyl-4-hexyl-2-phenyl-4,5-dihydro-1H-imida-
zole-5-carboxylate (11f): The imidoyl chloride reaction time was
1.25 h at 0 °C. The imidazoline reaction time was 12 h. Silica gel
chromatography; 50:50 EtOAc:hexane; Rf 0.4; oil; 86 mg; 40% yield;
1H NMR (500 MHz) (CDCl3) δ 0.9 (3H, t, J = 6.5 Hz), 1.3 (3H, t,
2918
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The Journal of Organic Chemistry
NOTE
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