Synthesis of novel trisubstituted imidazolines

Article abstract of DOI:10.1055/s-0029-1216784

Imidazolines substituted at the 1- and either the 4-, or 5-position with phenyl and at the 2-position with alkyl or phenyl have been prepared in racemic form. They appear to be fairly stable compounds and potentially useful as scaffolds in medicinal chemistry. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216784

PAPER
1987
Synthesis of Novel Trisubstituted Imidazolines
Synthesis of
N
r
ovel
T
ri
e
substituted
dImidazolineserick J. Lakner, Matthew A. Parker, Boris Rogovoy, Alexander Khvat,* Alexander Ivachtchenko
Department of Chemistry, ChemDiv Inc, 6605 Nancy Ridge Dr., San Diego, CA 92121, USA
Fax +1(858)7944931; E-mail: AK@chemdiv.com
Received 12 December 2008; revised 19 February 2009
Abstract: Imidazolines substituted at the 1- and either the 4-, or 5-
position with phenyl and at the 2-position with alkyl or phenyl have
been prepared in racemic form. They appear to be fairly stable com-
pounds and potentially useful as scaffolds in medicinal chemistry.
N
N
R
N
N
Key words: dihydroimidazole, imidazoline, reductive amination,
ring-closure, acylation
R
B
A
Figure 1
2-Substituted imidazolines are well represented in medic-
inal chemistry, particularly the class of adrenergic drugs
related to clonidine and tetrahydrozoline. It is rare, how-
ever, for drugs to take advantage of the sp3 character of the
ethylene bridge. Because substitution at this position pro-
vides chirality and non-planarity – and thus has unique
potential for fine-tuning target selectivity – we have un-
dertaken a study of such structures.1 In particular, we are
interested in 2-substituted 1,5- and 1,4-diarylimidazolines
as illustrated by the model phenyl substitution systems A
and B, respectively (Figure 1). A general and versatile
synthetic approach to both systems is presented herein.
proceeded efficiently to provide ketoamides 1, which
were subjected to reductive amination with aniline.
Yields of the requisite anilinoamides 2 obtained were fair
using sodium cyanoborohydride, with the main side prod-
uct being the corresponding alcohol formed through re-
duction of the ketone. Reduction using aniline under H2–
Pd/C or HCO2H–Pd/C systems generated relatively more
alcohol and less of the desired product. Finally, cyclode-
hydration using phosphorus oxychloride produced imida-
zolines 3.
Three 1,5-diphenyl substituted imidazolines were pre-
pared. These compounds were substituted at the 2-posi-
tion with methyl, isopropyl, or phenyl groups through a
three-step synthesis starting from 2-aminoacetophenone
(Scheme 1, path A). Acylation of the amino functionality
Somewhat more eventful was the preparation of three 1,4-
diphenylimidazolines (Scheme 1, path B). Anilinoace-
tophenone 4 was easily prepared and acylated to provide
ketoamides 5. Reduction with sodium cyanoborohydride
NaBH3CN
AcOH
aniline
RCOCl
NaHCO3
POCl3
A
N
H
O
CH2Cl2
H2O
O
O
MeOH
DCE
N
O
HN
HN
N
NH2
R
R
R
3
2
1
N
H
NH
O
NaBH3CN
NH4OAc
6
PhNH2
MeCN
R
RCOCl
DCE
POCl3
DCE
B
+
N
Br
N
H
MeOH
O
O
O
O
R
4
5
N
R
N
7
Scheme 1 Synthetic routes to trisubstituted imidazoles: (a) R = Me; (b) R = i-Pr; (c) R = Ph.
SYNTHESIS 2009, No. 12, pp 1987–1990
x
x.
x
x
.
2
0
0
9
Advanced online publication: 27.04.2009
DOI: 10.1055/s-0029-1216784; Art ID: M07608SS
© Georg Thieme Verlag Stuttgart · New York

1988
F. J. Lakner et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 2.11 (s, 3 H), 4.78 (d, J = 4 Hz,
2 H), 6.60 (br s, 1 H), 7.51 (t, J = 8 Hz, 2 H), 7.63 (t, J = 8 Hz, 1 H),
7.99 (d, J = 7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 23.1, 46.5, 127.9, 128.9, 134.2,
134.3, 170.2, 194.2.
and ammonium acetate, however, did not stop at simple
ammoniation.
The two products isolated were anilinoamides 6 and imi-
dazolines 7. Evidently, acyl migration from the aniline ni-
trogen to the primary amine of the putative intermediate 8
(Scheme 2) occurred rapidly.2 However, because both 6
and 7 are stable under the reaction conditions, it is pro-
posed that they both derive from a common cyclic inter-
mediate 9. Ratios of 6 to 7 were 73:27 (R = Me), 18:82
(R = i-Pr), and 85:15 (R = Ph). The crude mixture of 6 and
7 was treated with phosphorous oxychloride to complete
the synthesis.
1b (R = i-Pr)
CH2Cl2 (25 mL) and sat. NaHCO3 (50 mL) were stirred vigorously
and chilled in an ice bath. Isobutyryl chloride (1.5 mL, 14.5 mmol)
was added, followed immediately by aminoacetophenone hydro-
chloride (1.67 g, 9.71 mmol). Stirring was continued while warming
to r.t. over a period of 2 h. The organic layer was then separated,
dried with Na2SO4, and the solvent was evaporated.
Yield: 1.92 g (96%); white solid; mp 94–95 °C.
1H NMR (400 MHz, CDCl3): d = 1.22 (d, J = 7 Hz, 6 H), 2.53 (m,
1 H), 4.76 (d, J = 4 Hz, 2 H), 6.61 (br s, 1 H), 7.50 (t, J = 8 Hz, 2 H),
7.63 (t, J = 8 Hz, 1 H), 7.98 (d, J = 7 Hz, 2 H).
5
6 + 7
13C NMR (100 MHz, CDCl3): d = 19.5, 35.5, 46.3, 127.9, 128.9,
134.1, 134.4, 177.0, 194.5.
1c (R = Ph)
Benzoyl chloride was used as described for the synthesis of 1b in-
stead of isobutyryl chloride.
Yield: 2.32 g (100%); white solid; mp 124–125.5 °C (Lit.4 124–
125 °C).
N
N
HN
H2N
O
R
R
OH
8
9
1H NMR (400 MHz, CDCl3): d = 4.96 (d, J = 3 Hz, 2 H), 7.32 (br s,
1 H), 7.47 (t, J = 8 Hz, 2 H), 7.51–7.55 (overlapping m, 3 H), 7.65
(t, J = 8 Hz, 1 H), 7.89 (d, J = 8 Hz, 2 H), 8.04 (d, J = 8 Hz, 2 H).
Scheme 2
13C NMR (100 MHz, CDCl3): d = 46.8, 127.1, 127.9, 128.6, 129.0,
131.7, 133.9, 134.2, 134.3, 167.3, 194.2.
Imidazoline derivatives 3 and 7 were all examined for
acid and base stability by applying an informal assay.
Thus, each was dissolved in sodium hydroxide–methanol
(0.67 N) and also in HCl/methanol (0.34 N) and allowed
to stand at 22 °C for 24 hours. In no case was significant
decomposition observed. Furthermore, no air oxidation to
corresponding imidazoles was seen to occur either.
N-(2-Phenyl-2-phenylamino)ethylacylamides 2; General Proce-
dure
Amidoketone 1 (10.0 mmol) in MeOH (33 mL) was treated with
aniline (4.5 mL, 5.0 equiv), AcOH (2.8 mL) and finally NaBH3CN
(3.1 g, 5.0 equiv). The mixture was heated for 6 h at 60 °C then, af-
ter cooling, the solution was extracted with H2O (2 × 50 mL), then
with sat. NaHCO3 (50 mL), and brine (25 mL). The organic layer
was dried with Na2SO4, decanted, and the solvent was evaporated to
provide the product.
With reliable and facile preparations of both imidazoline
scaffolds in place, it is now our intention to exploit this
chemistry for the development of molecular libraries and
subsequent biological testing.
2a (R = Me)
Yield: 57%; mp 103–104 °C.
NMR data were obtained using a Varian Unity 400 spectrometer
and chemical shifts are given relative to internal TMS set at 0 ppm.
ESI-TOF high accuracy mass data were provided by the Scripps
Center for Mass Spectrometry. Preparative HPLC was performed
using a binary solvent system at 60 mL/min; H2O containing 0.1%
HCO2H and MeCN, starting at 10% MeCN and continuing linearly
to 90% over 16 min. A C-12 column was utilized, specifically a
Synergi 4m Max-RP, 100 mm × 300 mm model. Uncorrected melt-
ing ranges were obtained with a MelTemp. Solvents used were
HPLC grade throughout the experiments. Neither solvents nor com-
mercially obtained reagents were purified prior to use.
1H NMR (400 MHz, CDCl3): d = 1.98 (s, 3 H), 3.58 (overlapping m,
2 H), 4.46 (dd, J1 = 5 Hz, J2 = 7 Hz, 1 H), 4.95 (br s, 1 H), 5.80 (br
s, 1 H), 6.50 (d, J = 7 Hz, 2 H), 6.64 (t, J = 7 Hz, 1 H), 7.07 (t, J = 7
Hz, 2 H), 7.25–7.4 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 23.2, 46.3, 59.5, 113.2, 117.3,
126.5, 127.6, 128.8, 129.1, 141.0, 147.3, 171.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H18N2O: 255.1492;
found: 255.1491.
2b (R = i-Pr)
Crystallized from MeOH–H2O.
Amidoacetophenone 1a (R = Me)
Aminoacetophenone hydrochloride (1.67 g, 9.71 mmol) was sus-
pended in Ac2O (3.0 mL) and anhydrous NaOAc (1.5 g) was grad-
ually added. After 0.5 h, H2O (12 mL) was added and the mixture
was stirred vigorously for 1 h. The resulting solution was diluted
with EtOAc (60 mL) and extracted with sat. aq NaHCO3 (2 × 25
mL), then brine (25 mL). The organic layer was dried (Na2SO4) and
the solvent evaporated to give the product.
Yield: 40%; mp 141–142 °C.
1H NMR (400 MHz, CDCl3): d = 1.13 (d, J = 7 Hz, 3 H), 1.15 (d,
J = 7 Hz, 3 H), 2.36 (m, 1 H), 3.67 (overlapping dd, J1 = 6 Hz,
J2 = 6 Hz, 2 H), 4.51 (dd, J1 = 6 Hz, J2 = 6 Hz, 1 H), 6.60 (d, J = 7
Hz, 2 H), 6.73 (t, J = 7 Hz, 1 H), 7.10 (t, J = 7 Hz, 2 H), 7.23–7.35
(m, 5 H).
13C NMR (100 MHz, CDCl3): d = 19.4, 35.5, 45.0, 61.4, 115.7,
120.1, 127.0, 128.0, 128.8, 129.2, 138.8, 144.2, 178.9.
Yield: 1.42 g (83%); white solid; mp 86–87 °C (Lit.3 85–87 °C).
Synthesis 2009, No. 12, 1987–1990 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Trisubstituted Imidazolines
1989
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H22N2O: 283.1805;
found: 283.1808.
filtered through a pad of silica gel, and the solvent was evaporated
to yield the product.
Yield: 6.8 g (93%); yellow solid; mp 94–95 °C (Lit.5 98 °C).
2c (R = Ph)
1H NMR (400 MHz, CDCl3): d = 4.60 (s, 2 H), 6.70 (d, J = 8 Hz,
2 H), 6.75 (t, J = 8 Hz, 1 H), 7.22 (t, J = 8 Hz, 2 H), 7.50 (t, J = 8
Hz, 2 H), 7.61 (t, J = 8 Hz, 1 H), 7.80 (d, J = 8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 50.3, 113.0, 117.8, 127.7, 128.8,
129.3, 133.8, 147.0, 195.0.
Triturated with hot MeOH, then cooled to r.t. and filtered.
Yield: 40%; mp 189–190.5 °C.
1H NMR (400 MHz, CDCl3): d = 3.84 (overlapping m, 2 H), 4.61
(dd, J1 = 5 Hz, J2 = 7 Hz, 1 H), 6.37 (br s, 1 H), 6.54 (d, J = 8 Hz,
2 H), 6.64 (t, J = 7 Hz, 1 H), 7.08 (t, J = 7 Hz, 2 H), 7.25–7.52 (m,
8 H), 7.71 (d, J = 8 Hz, 2 H).
N-(2-Oxo-2-phenylethyl)-N-phenylacylamides (or N-phenyl-
amidoacetophenones) 5; General Procedure
13C NMR (100 MHz, CDCl3): d = 46.6, 59.5, 113.3, 117.4, 126.5,
126.9, 127.6, 128.6, 128.9, 129.0, 131.7, 134.0, 140.9, 147.2, 168.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H20N2O: 317.1648;
found: 317.1647.
Aminoketone 4 (10.0 mmol) was dissolved in DCE (25 mL) and re-
fluxed for 1 h with the appropriate acid chloride (2.0 equiv). Vola-
tiles were evaporated and the residue was recrystallized from the
indicated solvent.
2-Alkyl-1,5-diphenylimidazolines 3; General Procedure
5a (R = Me)
Amide 2 (0.5 M in DCE) was refluxed with POCl3 (1.0 equiv) for 6
h. Upon cooling, the solution was extracted sequentially with sat.
NaHCO3, H2O, and brine. The organic layer was dried with Na2SO4,
decanted, and the solvent was evaporated to provide the product.
Yield: 1.31 g (52%); mp 134–135 °C (EtOAc) (Lit.6 131.5–133 °C).
1H NMR (400 MHz, DMSO-d6): d = 1.87 (s, 3 H), 5.15 (s, 2 H),
7.45 (m, 5 H), 7.54 (t, J = 8 Hz, 2 H), 7.67 (t, J = 8 Hz, 1 H), 7.99
(d, J = 8 Hz, 2 H).
3a (R = Me)
Yield: 85%; oil.
13C NMR (100 MHz, CDCl3): d = 22.2, 56.1, 127.9, 128.1, 128.6,
129.6, 133.5, 135.1, 143.5, 170.8, 193.5.
1H NMR (400 MHz, CDCl3): d = 2.28 (s, 3 H), 4.12 (dd, J1 = 9 Hz,
J2 = 12 Hz, 1 H), 4.55 (dd, J1 = 12 Hz, J2 = 12 Hz, 1 H), 5.42 (dd,
J1 = 9 Hz, J2 = 12 Hz, 1 H), 6.99 (m, 2 H), 7.27 (m, 3 H), 7.36 (m,
5 H).
13C NMR (100 MHz, CDCl3): d = 12.8, 51.8, 68.8, 126.7, 127.6,
129.4 (2 × C), 129.8, 130.1, 134.0, 136.2, 167.1.
5b (R = i-Pr)
Yield: 2.05 g (73%); mp 142–143.5 °C (EtOH–H2O).
1H NMR (400 MHz, CDCl3): d = 1.09 (d, J = 7 Hz, 6 H), 2.64 (m,
1 H), 5.07 (s, 2 H), 7.26–7.41 (m, 5 H), 7.46 (t, J = 7 Hz, 2 H), 7.57
(t, J = 7 Hz, 1 H), 7.95 (d, J = 7 Hz, 2 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H16N2: 237.1386;
13C NMR (100 MHz, CDCl3): d = 19.5, 30.8, 56.2, 127.9, 128.0,
found: 237.1388.
128.2, 128.6, 129.6, 133.4, 135.3, 143.2, 177.6, 193.8.
3b (R = i-Pr)
Yield: 100%; oil.
1H NMR (400 MHz, CDCl3): d = 1.25 (d, J = 7 Hz, 3 H), 1.31 (d,
J = 7 Hz, 3 H), 2.61 (m, 1 H), 3.88 (dd, J1 = 9 Hz, J2 = 14 Hz, 1 H),
4.46 (dd, J1 = 11 Hz, J2 = 14 Hz, 1 H), 5.30 (dd, J1 = 9 Hz, J2 = 11
Hz, 1 H), 6.96 (d, J = 8 Hz, 2 H), 7.2–7.4 (m, 8 H).
5c (R = Ph)
Yield: 2.19 g (70%); mp 156–157 °C (EtOH–H2O) (Lit.7 156.5–
157.5 °C).
1H NMR (400 MHz, DMSO-d6): d = 5.41 (s, 2 H), 7.1–7.3 (m,
10 H), 7.57 (t, J = 8 Hz, 2 H), 7.70 (t, J = 8 Hz, 1 H), 8.05 (d, J = 8
Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 18.9, 19.5, 26.9, 51.7, 69.1, 127.3,
13C NMR (100 MHz, CDCl3): d = 57.1, 126.7, 127.5, 127.7, 128.0,
127.5, 129.4, 129.7, 129.8, 130.1, 134.4, 136.7, 173.9.
128.7, 128.8, 129.0, 129.7, 133.6, 135.2, 135.3, 144.0, 170.7, 193.4.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H20N2: 265.1699;
found: 265.1700.
2-Alkyl-1,4-diphenylimidazolines 7; General Procedure
Ketoamide 5 (2.0 mmol) was dissolved in anhydrous MeOH (6 mL)
and NH4OAc (0.77 g, 5.0 equiv) was added followed by NaBH3CN
(0.63 g, 5.0 equiv). The mixture was heated to 60 °C for 24 h before
cooling to r.t. and removing solvent under reduced pressure. The
residue was partitioned between H2O (60 mL) and CH2Cl2 (60 mL),
then sat. Na2CO3 was added until the aqueous phase became basic.
After shaking well in a separatory funnel, the organic phase was tak-
en and the aqueous solution was extracted with CH2Cl2 (2 × 60
mL). The combined organic layers were dried (Na2SO4) and the sol-
vent was evaporated. LC/MS and NMR revealed the product to be
a mixture of the amide 6 and imidazoline 7. This mixture was treat-
ed with POCl3 as described for the synthesis of 3 in order to obtain
7. The samples were subjected to reverse-phase preparative HPLC
in order to obtain analytically pure samples of both.
3c (R = Ph)
Yield: 96%; oil.
1H NMR (400 MHz, CDCl3): d = 4.09 (dd, J1 = 7 Hz, J2 = 14 Hz,
1 H), 4.65 (dd, J1 = 11 Hz, J2 = 14 Hz, 1 H), 5.28 (dd, J1 = 7 Hz,
J2 = 11 Hz, 1 H), 6.77 (d, J = 8 Hz, 2 H), 7.1 (m, 3 H), 7.3–7.5 (m,
8 H), 7.65 (d, J = 8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 52.1, 69.6, 122.2, 126.6, 127.6,
129.0, 129.4, 129.6, 129.7, 133.8, 135.9, 137.1, 165.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H18N2: 299.1543;
found: 299.1548.
N-Phenylaminoacetophenone (4)
Aniline (6.5 mL, 70 mmol) and bromoacetophenone (6.7 g, 35
mmol) were combined in MeCN (70 mL) and allowed to stand at r.t.
for 24 h. Solid aniline-HBr was filtered off and the filtrate was con-
centrated under vacuum. The residue was dissolved in EtOAc (100
mL) and extracted sequentially with H2O (50 mL), 5% citric acid
(50 mL), and brine (25 mL). The organic layer was dried (Na2SO4),
7a (R = Me)
Yield: 0.40 g (86%); oil.
1H NMR (400 MHz, CDCl3): d = 2.42 (s, 3 H), 4.11 (dd, J1 = 9 Hz,
J2 = 11 Hz, 1 H), 4.67 (dd, J1 = 11 Hz, J2 = 11 Hz, 1 H), 5.55 (dd,
J1 = 9 Hz, J2 = 11 Hz, 1 H), 7.26–7.54 (m, 10 H).
Synthesis 2009, No. 12, 1987–1990 © Thieme Stuttgart · New York

1990
F. J. Lakner et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 12.7, 59.0, 60.8, 125.2, 125.5,
6.68 (d, J = 7 Hz, 2 H), 6.76 (t, J = 7 Hz, 1 H), 7.19 (t, J = 7 Hz,
129.0, 129.4, 129.7, 130.3, 130.4, 138.0, 167.0.
2 H), 7.3–7.4 (m, 5 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H16N2: 237.1386;
13C NMR (100 MHz, CDCl3): d = 19.5, 35.6, 49.8, 52.7, 113.8,
found: 237.1389.
118.8, 126.5, 128.0, 129.0, 129.4, 139.6, 147.0, 177.3.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H22N2O: 283.1805;
found: 283.1805.
7b (R = i-Pr)
Yield: 0.52 g (92%); oil.
1H NMR (400 MHz, CDCl3): d = 1.38 (d, J = 7 Hz, 3 H), 1.41 (d,
J = 7 Hz, 3 H), 2.79 (m, 1 H), 4.06 (dd, J1 = 8 Hz, J2 = 11 Hz, 1 H),
4.67 (dd, J1 = 11 Hz, J2 = 11 Hz, 1 H), 5.63 (dd, J1 = 8 Hz, J2 = 11
Hz, 1 H), 7.25–7.55 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 19.0, 19.7, 26.6, 58.4, 61.5, 125.8,
126.1, 128.8, 129.3, 130.0, 130.6, 135.5, 138.7, 173.9.
6c (R = Ph)
Mp 157–158.5 °C (EtOH).
1H NMR (400 MHz, CDCl3): d = 3.61 (dd, J1 = 5 Hz, J2 = 13 Hz,
1 H), 3.68 (dd, J1 = 7 Hz, J2 = 13 Hz, 1 H), 5.47 (m, 1 H), 6.89 (d,
J = 7 Hz, 2 H), 6.76 (t, J = 7 Hz, 1 H), 6.79 (br d, 1 H), 7.19 (t, J = 7
Hz, 2 H), 7.3–7.5 (m, 8 H), 7.74 (d, J = 7 Hz, 2 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H20N2: 265.1699;
13C NMR (100 MHz, CDCl3): d = 49.4, 53.6, 113.5, 118.3, 126.6,
found: 265.1699.
127.0, 127.9, 128.5, 129.0, 129.4, 131.6, 134.0, 139.6, 147.5, 167.5.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H20N2O: 317.1648;
found: 317.1651.
7c (R = Ph)
Yield: 0.56 g (94%); oil.
1H NMR (400 MHz, CDCl3): d = 4.25 (dd, J1 = 8 Hz, J2 = 11 Hz,
1 H), 4.93 (dd, J1 = 11 Hz, J2 = 11 Hz, 1 H), 5.75 (dd, J1 = 8 Hz,
J2 = 11 Hz, 1 H), 7.08 (d, J = 7 Hz, 2 H), 7.3–7.5 (m, 10 H), 7.56 (t,
J = 7 Hz, 1 H), 7.61 (d, J = 7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 58.8, 61.7, 122.0, 125.0, 126.1,
128.7, 129.0, 129.1, 129.4, 129.9, 130.1, 134.0, 137.3, 138.4, 164.6.
References
(1) (a) von Rauch, M.; Busch, S.; Gust, R. J. Med. Chem. 2005,
48, 466. (b) Acharya, A. N.; Ostresh, J. M.; Houghten, R. A.
J. Org. Chem. 2001, 66, 8673. (c) Concellón, J. M.; Riego,
E.; Suárez, J. R.; García-Granda, S.; Díaz, M. R. Org. Lett.
2004, 6, 4499. (d) Ishihara, M.; Togo, H. Synthesis 2007,
1939. (e) Vassilev, L. T.; Vu, B. T.; Graves, B.; Carvajal, D.;
Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs,
C.; Klein, C.; Fotouhi, N.; Liu, E. A. Science 2004, 303, 844.
(2) Evidence for acyl migration comes mainly from 1H NMR
spectra of isolated 6. In particular, two broad singlets of
D2O-exchangeable protons were observed rather than the
one singlet integrating to 2 H expected for amide 8.
(3) Myers, M. C.; Wang Jin, L.; Iera, J. A.; Bang, J.-k.; Hara, T.;
Saito, S.; Zambetti, G. P.; Appella, D. H. J. Am. Chem. Soc.
2005, 127, 6152.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H18N2: 299.1543;
found: 299.1546.
6a (R = Me)
Mp 129–130 °C (EtOH).
1H NMR (400 MHz, CDCl3): d = 2.00 (s, 3 H), 3.46 (dd, J1 = 8 Hz,
J2 = 13 Hz, 1 H), 3.61 (dd, J1 = 8 Hz, J2 = 13 Hz, 1 H), 5.32 (m,
1 H), 6.81 (d, J = 7 Hz, 2 H), 6.87 (t, J = 7 Hz, 1 H), 7.22 (t, J = 7
Hz, 2 H), 7.3–7.4 (m, 5 H).
13C NMR (100 MHz, CDCl3): d = 23.1, 50.9, 52.5, 115.3, 120.6,
(4) Moriya, T.; Takabe, S.; Maeda, S.; Matsumoto, K.;
Takashima, K.; Mori, T.; Takeyama, S. J. Med. Chem. 1986,
29, 333.
(5) (a) Brown, D. S.; Elliott, M. C.; Moody, C. J.; Mowlem,
T. J.; Marino, J. P.; Padwa, A. J. Org. Chem. 1994, 59,
2447. (b) Barton, D. H. R.; Chern, C.-Y.; Tachdjian, C.
Heterocycles 1994, 37, 793.
(6) (a) Crowther, A. F.; Mann, F. G.; Purdie, D. J. Chem. Soc.
1943, 58. (b) Wang, J.; Hou, Y.; Wu, P. J. Chem. Soc.,
Perkin Trans. 1 1999, 16, 2277.
126.5, 128.0, 129.0, 129.5, 139.2, 145.0, 170.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H18N2O: 255.1492;
found: 255.1492.
6b (R = i-Pr)
Mp 149–150 °C (EtOH).
1H NMR (400 MHz, CDCl3): d = 1.14 (d, J = 7 Hz, 3 H), 1.56 (d,
J = 7 Hz, 3 H), 2.38 (m, 1 H), 3.49 (dd, J1 = 5 Hz, J2 = 13 Hz, 1 H),
3.58 (dd, J1 = 7 Hz, J2 = 13 Hz, 1 H), 5.28 (m, 1 H), 6.06 (br d, 1 H),
(7) Yates, P. J. Am. Chem. Soc. 1952, 74, 5376.
Synthesis 2009, No. 12, 1987–1990 © Thieme Stuttgart · New York