Synthesis and preliminary use of naphthyl quinazoline and isoquinoline oxazolines for asymmetric allylic oxidation

Article abstract of DOI:10.1002/jhet.5570380605

Four new oxazoline ligands, 4-naphthyl-2-phenylquinazoline 4 and 1-naphthylisoquinoline 5 were made using Suzuki coupling, a Pictet-Gams reaction, and S-amino alcohol. Preliminary use as ligands for asymmetric copper catalyzed allylic oxidation with cyclo

Full text of DOI:10.1002/jhet.5570380605

Nov-Dec 2001
Synthesis and Preliminary Use of Naphthyl Quinazoline and
Isoquinoline Oxazolines for Asymmetric Allylic Oxidation
Merritt B. Andrus* and B. B. V. Soma Sekhar
1265
Brigham Young University, Department of Chemistry and Biochemistry,
C100 BNSN, Provo, UT 84602-5700, USA
Received July 11, 2001
This paper is dedicated to Professor Jerald S. Bradshaw, undergraduate mentor of MBA,
with warmth and gratitude for his encouragement and outstanding leadership.
Four new oxazoline ligands, 4-naphthyl-2-phenylquinazoline 4 and 1-naphthylisoquinoline
5 were made using Suzuki coupling, a Pictet-Gams reaction, and S-amino alcohol.
Preliminary use as ligands for asymmetric copper catalyzed allylic oxidation with cyclohex-
ene and perester showed promise providing S-cyclohexenyl benzoate product in moderate
enantioselectivity (64%ee).
J. Heterocyclic Chem., 38, 1265 (2001).
Bisoxazoline and oxazoline ligands derived from non-
combined in ligands with sulfide and phosphine moieties,
[17] oxazoline-quinazoline and isoquinoline dual-domain
ligands have not been reported. The new oxazoline-quina-
zoline 4 was made using a Suzuki coupling and is obtained
in conformationally stable S form. The biaryl oxazoline-
isoquinoline 5, made using a Pictet-Gams reaction, is not
conformationally stable. Both were tested for use as lig-
ands for asymmetric allylic oxidation.
racemic amino alcohols continue to play an important role
as ligands for asymmetric processes. Metal complexes
with oxazoline ligands serve as catalysts for a variety of
asymmetric transformations including cyclopropanation
[1], aziridination [2], allylic displacement [3], imine addi-
tions [4], Diels-Alder [5] ,aldol [6],1,3-dipolar cycloaddi-
tion [7],reduction [8],and the ene reaction [9]. We and
Pfaltz independently reported [10] that malonyl-derived
bisoxazoline copper complexes of 1 and 2 (Scheme 1) give
high selectivities (80%ee) in the Kharasch copper cat-
alyzed allylic oxidation reaction [11], a significant
improvement over earlier approaches [12]. As the utility of
this class of ligands expands, efforts to improve reactivity
and selectivity will depend on the availability of synthetic
routes to modified bisoxazolines. While the majority of
bisoxazoline ligands remain methylene and pyridyl linked,
recently biaryl bisoxazoline ligands have been reported
and used as ligands in asymmetric reactions [13]. We syn-
thesized and used the S,S,S –bis-toluyl bisoxazoline 3 as
ligand for allylic oxidations and obtained products in the
70%ee range [14].
The synthesis of 4 began with the Suzuki coupling [18]
of commercially available 4-chloro-2-phenylquinazoline 6
(AM-ex-OL) with 2-methyl-1-naphthylboronic acid [19] 7
under palladium catalysis to give the biaryl adduct 8 in
85% isolated yield (Scheme 3). Functionalization of the
methyl group appended at the 2-position of the naphthyl
moiety was performed using benzylic bromination. The
dibromide 9 was formed using two equivalents of N-bro-
mosuccinide under photolytic conditions in quantitative
yield [20].
The dibromide 9 was converted to the 2-naphthaldehyde
10 silver nitrate in 70% yield following the protocol of
Walsh (Scheme 4) [20]. While many options are available
at this point to effect the conversion to the carboxylic acid,
only treatment with potassium permanganate in an ace-
tone-water mixture resulted in formation of 11. Problems
obtained with other reagents, N-oxide formation and ring
cleavage were not seen in this case. The final steps follow
well established routes to oxazolines form carboxylic acids
and amino alcohols. Treatment with thionyl chloride pro-
vided the intermediate acid chloride, which was taken on
In an effort to improve reactivity and selectivity, we now
report the synthesis and preliminary use of two new novel
ligands, 4-naphthyl-2-phenylquinazoline 4 and 1-naph-
thylisoquinoline 5 (Scheme 2). Brown and others have
recently produced and investigated biaryl isoquinoline-
phosphines and indoles [15]. Quinazoline-phosphines
have also been reported [16]. While oxazolines have been

1266
M. B. Andrus and B. B. V. Soma Sekhar
Vol. 38
in crude form to the amide. S-Phenylglycinol was added in
the presence of triethylamine to provide product in 82%
yield. As seen previously with the bitoluyl bisoxazolines
3, the diastereomeric atropisomers 13 formed were separa-
ble at this stage by simple silica gel chromatography. The
60:40 mixture was cleanly separated at this point and the
major isomer was taken on to the final reaction. Previous
quinazoline-phosphines have also been resolvable, but
have required enantiopure palladium co-ligand complexes
[16]. The major amide 13 was converted to naphthyloxa-
zolinyl quinazoline 4 using carbon tetrachloride and triph-
enylphosphine in high yield. A single crystal x-ray struc-
ture was solved for 4 and it was shown conclusively that it
possessed the S,S configuration shown. The crystal shows
the oxazoline oxygen pointing in toward the quinazoline
instead of the more basic nitrogen. Upon metal exposure,
this nitrogen should swing around pointing toward quina-
zoline N-2 to form a seven-ring chelate.
material was then converted to carboxylic acid 19 in 97%
yield using the previous silver nitrate reagent in the pres-
ence of base. Amide coupling with PyBrop and the amino
alcohols shown gave amides 20 in good yield [23].
Oxazoline formation occurred again using carbon tetra-
chloride and phosphine giving the target ligands 5. Both
compounds were found to exist as rapidly interconverting
atropisomers, which were not separable.
Preliminary asymmetric allylic oxidation reactions
were then performed using 4 and 5 as ligands for copper
complexes using cyclohexene as substrate to give ester
products. Two methods were used. One with copper(I)
hexafluorophosphate in acetonitrile follows previous
efforts with t-butyl p-nitroperbenzoate as oxidant and
the other the protocol of Singh with copper(II) triflate
and phenylhydrazine with t-butyl perbenzoate (Table 1).
In both cases only low yields were obtained. With lig-
and 4 the reactivity was very low, 7% with 32%ee, as
seen previously with some S,R,S –3 ligands (t-Bu in place
of Ph). With S,S,S- 3 the yield was 78% with 73%ee. In
contrast S,R,S –3 (Ph) gave ester in 76% yield and 0%ee.
Ligand 5 (R=Ph) gave only slightly improved results at
44% ee. Use of phenylhydrazine, a reducing additive,
gave much faster reaction times in this case with improved
selectivity, 64%ee. Previously, these conditions failed to
improve the reactivity of ligand 3. Other ligands, where
R=t-Bu, Bn, and i-Pr, together with other olefin substrates
and various conditions can now be performed in an effort
to improve reactivity and selectivity. The routes to these
novel ligands should also find application to other asym-
metric transformations involving metal complexes.
The synthesis of oxazolinylisoquinoline 5 began with
the treatment of racemic norephedrine 14 with 1-naph-
thoyl chloride 15 to give amide 16 (Scheme 5). The
Pictet-Gams reaction, direct isoquinoline formation from
a β-hydroxy-β-phenethylamide, was effected by treat-
ment with P O to give isoquinoline 17 in 62% isolated
yield [21]. Benzylic monobromination was performed
with NBS under photolysis conditions to provide 18.
Dibromide formation leading to an intermediate aldehyde
proved problematic from 17. Once monobromide 18 was
secure, the direct aldehyde formation conditions of
Ganem and Boeckman using silver tetrafluoroborate in
DMS were used with success in 77% yield [22]. This
2
5

Nov-Dec 2001 Synthesis and Preliminary Use of Naphthyl Quinazoline and Isoquinoline Oxazolines
1267
TLC analysis was conducted on silica gel 60 F , 0.25 mm pre-
254
1
coated glass plates. All H NMR spectra were obtained using
either a 300 or 500 MHz spectrometer employing chloroform
(7.26 ppm) or TMS (0.0 ppm) as an internal reference. Signals
are reported as: m (multiplet), s (singlet), d (doublet), t (triplet), q
(quartet), bs (broad singlet), bd (broad doublet), bt (broad triplet),
ABq (AB quartet); coupling constants (J) are reported in hertz
(Hz). Carbon spectra were obtained at 75 or 125 MHz and refer-
enced against deuterated CDCl . Infrared spectra were obtained
3
using a Varian FTIR spectrometer. Mass spectra were run by the
Brigham Young mass spectrometry facility. Generally, FAB or
CI analysis was performed. Optical rotations were obtained
using a polarimeter at rt employing the sodium D line.
Preparation of 4-(2-Methyl-naphthalen-1-yl)-2-phenyl-quinazo-
line (8).
®
AM-ex-OL 6 (4.25 g, 17.65 mmol) was added as a solid to a
solution of Pd(PPh ) (1.02 g, 0.88 mmol) in DME (100 mL) and
3 4
stirred (10 minutes) under nitrogen atmosphere to give a pale yel-
low solution. 2-Methyl-1-naphthylboronic acid 7 (3.94 g, 21.2
mmol) was transferred as a solid. This homogenized reaction
mixture turned to reddish brown by precipitation upon the addi-
Acknowledgment.
We are grateful for the support provided by the National
Science Foundation (Career Award, CHE-9501867), Brigham
Young University. We also thank Prof. N. Kent Dalley for X-ray
crystallography and Mr. Bruce Jackson for mass spectroscopy.
tion of aqueous K CO (2.0 M, 21 mL) which was subsequently
2
3
refluxed overnight. The reaction mixture was cooled, filtered
and concentrated. The red viscous concentrate was dissolved in
CH Cl (500 mL),and washed with brine (2 X100 mL). Usual
workup and purification by silica gel chromatography furnished
EXPERIMENTAL
2
2
8 as a fine crystalline solid (5.22 g, 85%). R = 0.52 (10%
f
Air-sensitive reactions were performed under nitrogen. Air
and moisture-sensitive reagents were introduced by syringe or
cannula through rubber septa. All reaction solvents were of
HPLC grade quality or distilled prior to use from an appropriate
drying agent. Methylene chloride and acetonitrile were distilled
1
EtOAc/Hexanes). mp 148-150 °C. H (300 MHz, CDCl ): δ
3
8.74 -8.67 (m, 2H), 8.24 (dt, 1H, J = 0.9 and 8.5 Hz), 7.99-7.84
(m 3H), 7.57-7.50 (m, 4H), 7.39 (dd, 2H, J = 0.9 and 6.8 Hz),
13
7.32-7.26 (m, 1H), 7.16 (d, 1H, J = 8.0 Hz), 2.21 (s, 3H).
C
(75 MHz, CDCl ): δ 169.74, 161.14, 151.46, 138.47, 134.26,
from CaH . DMSO was dried over 4 Å molecular sieves prior to
3
2
134.19, 133.12, 132.34, 132.11, 130.75, 129.31, 129.18, 129.03,
128.87, 128.76, 128.21, 127.48, 126.94, 126.75, 125.56, 125.43,
use. THF and diethyl ether were distilled from sodium ben-
zophenone ketyl. Starting materials and reagents were purchased
from Aldrich, Sigma and used without further purification.
Purification by flash chromatography was carried out in the indi-
cated solvent system using 70-230 mesh silica gel. Purification
by radial chromatography was performed using 1, 2, and 4 mm
plates loaded with 230-400 mesh PF-254 gypsum-bound silica.
+
123.77, 20.43. MS (EI) m/z (relative Intensity): 345 (M - H,
100), 266 (5), 241 (5), 173 (8), 84 (10). HRMS (EI) calcd for
+
C
H
N (M ) 346.1470, found 346.1460.
25 18
2
Anal. Calcd for C
H N : C, 86.68; H, 5.24; N, 8.09. Found:
25 18 2
C, 86.73; H, 5.33; N, 7.89.

1268
M. B. Andrus and B. B. V. Soma Sekhar
Vol. 38
Preparation of 4-(2-Dibromomethyl-naphthalen-1-yl)-2-phenyl-
quinazoline (9).
7.58 (t, 1H, J = 8.3 Hz), 7.47-7.46 (m, 3H), 7.34-7.18 (m, 4H).
13
C (125 MHz, CDCl ): δ 170.26, 160.62, 150.56, 138.70,
3
138.30, 135.78, 133.94, 131.94, 130.67, 129.68, 129.07,
128.96, 128.73, 128.70, 128.34, 127.58, 127.53, 127.37,
126.47, 126.33, 126.28, 124.05. MS (EI) m/z (relative
A mixture of 8 (1.23 g, 3.56 mmol), NBS (1.33 g, 7.47 mmol)
and dibenzoyl peroxide (0.086 g, 0.35 mmol) in CCl (125 mL)
4
was heated at reflux while being irradiated by flood lamp for 6
hours. The reaction mixture was cooled, filtered and washed
with benzene (100 mL). The filtrate was washed successively
+
Intensity): 360 (M + H, 60), 331 (100), 253 (13), 227(12), 165
+
(10), 77 (5). HRMS (EI) calcd for C
found 360.1263.
H
N O (M ) 360.1263,
25 16
2
with water (50 mL), saturated aqueous NaHCO (50 mL) and
3
Anal. Calcd for C
H N O: C, 83.31; H, 4.47; N, 7.77.
25 16 2
brine (50 mL). Organic layer was dried over anhydrous CaCl ,
2
Found: C, 82.98; H, 4.53; N, 7.92.
concentrated and dried under vacuum to provide the pale yellow
solid 9 in quantitative yield which was used without further
Preparation of Amide 13.
1
purification. R = 0.46 (10% EtOAc/hexanes). H (300 MHz,
f
Acid 11 (0.10 g, 0.26 mmol) was refluxed in SOCl (0.37 g,
0.23 mL, 3.15 mmol) for 3 hours. Reaction mixture was cooled
2
CDCl ): δ 8.73 -8.70 (m, 2H), 8.26 (d, 2H, J = 8.8 Hz), 8.17 (d,
3
1H, J = 8.8 Hz), 7.94 (m, 2H), 7.56-7.51 (m, 4H), 7.45 (m, 3H),
and excess SOCl removed under reduced pressure. The resul-
2
13
7.07 (d, 1H, J = 8.2 Hz), 6.44 (s, 1H). C (75 MHz, CDCl ): δ
3
tant glue was dried under high vacuum for 3 hours. The yellow
solid acyl chloride was dissolved in dry CH Cl at -78 °C, and
transferred via cannula to a stirring mixture of 2(S)-2-phenylgly-
cinol 12 (0.043 g, 0.31 mmol) and NEt (0.145 g, 0.20 mL, 1.43
166.59, 161.05, 151.53, 137.91, 137.42, 134.87, 134.50, 133.70,
134.87, 134.50, 133.70, 131.10, 130.99, 130.77, 129.42, 129.12,
128.88, 128.44, 127.90, 127.79, 127.72, 126.97, 126.94, 126.49,
123.66, 38.90.
2
2
3
mmol) at -78 °C in CH Cl . Reaction mixture was stirred at -78
2
2
Preparation of 1-(2-Phenyl-qunizolin-4-yl)-naphthalene-2-car-
baldehyde (10).
°C for 3 hours and allowed to warm slowly to room temperature
overnight. Reaction mixture was concentrated under reduced
pressure and dissolved in ethyl acetate (50 mL) and aqueous
To the solution of 9 (0.5 g, 0.99 mmol) in EtOH (5 mL) and
NaHCO (5 mL). Usual workup and purification by radial chro-
THF (3 mL) at reflux was treated with aqueous AgNO (0.5 g in
3
3
matography provided separable 13-(Sp, S) (0.065 g, 49%)(R =
0.54, 70% EtOAc/hexanes) and 13-(Rp, S) (0.043 g, 32%) (R =
1.4 mL of H O, 2.94 mmol) in dropwise addition. The reaction
f
2
mixture formed pale yellow precipitation. Upon reflux for a
period of 1 hour it turned to grayish yellow precipitate. The mix-
ture was filtered through a fritted disk funnel while hot and the
filter cake was washed with hot THF. The combined filtrates
were concentrated and subjected to gradient silica gel chro-
matography to provide the aldehyde 10 as a fine crystalline solid
f
0.40, 70% EtOAc/Hexanes) diastereomeric atropisomers as
white solid products. (Sp, S)-1-(2-Phenylquninazolin-4-yl)-naph-
thalene-2-carbox-[2(S)-2-hydroxy-1-pheynylethyl]amide (13):
1
H (300 MHz, CDCl ): 8.68-6.86 (aromatic hydrogens, 20H),
3
6.64 (d, 1H, amide NH, J = 5.8 Hz), 4.66 (dd, 1H, J = 5.8 and 5.6
13
Hz), 3.20 (m, 2 H). C (125 MHz, CDCl ): δ 168.97 (NHC=O),
(0.25 g, 70%). R = 0.53 (20% EtOAc/Hexanes). mp 179-180
3
f
1
aromatic signals, 66.08, 56.49. MS (EI) m/z (relative Intensity):
°C. H (300 MHz, CDCl ): δ 9.80 (s, 1H), 8.69 -8.65 (m, 2H),
3
+
+
495 (M , 3), 358 (100). HRMS (EI) calcd for C
H N O (M )
8.28-8.14 (m, 3H), 8.03 (d, 1H, J = 8.3 Hz), 7.93 (ddd, 1H, J =
33 25 3 2
495.1947, found 495.1956. (Rp, S)-1-(2-phenylquninazolin-4-
yl)-naphthalene-2-carbox-[2(S)-2-hydroxy-1-pheynylethyl]-
1.5, 6.8 and 8.3 Hz), 7.65 (ddd, 1H, J = 1.5, 6.8 and 8.3 Hz),
13
7.55-7.50 (m, 3H), 7.45 -7.34 (m, 4 H). C (75 MHz, CDCl ): δ
3
1
amide (13): H (500 MHz, CDCl ): 8.57-6.48 (aromatic H, 20H),
190.88, 166.38, 160.68, 151.20, 140.67, 137.90, 136.31, 134.70,
132.17, 131.84, 131.07, 130.26, 129.50, 129.39, 129.03, 128.85,
128.70, 128.03, 127.84, 127.27, 126.65, 124.71, 122.78. MS
3
6.72 (d, 1 H, amide NH, J =5.6 Hz), 4.72 (dd, 1H, J = 5.6 and
13
5.6 Hz), 3.56 (t, 2H, J = 5.6 Hz).
C (125 MHz, CDCl ): δ
3
+
168.98 (NHC=O), aromatic signals, 66.41, 56.68.
(EI) m/z (relative Intensity): 360 (M + H, 60), 331 (100), 253
(13), 227(12), 165 (10), 77 (5). HRMS (EI) calcd for
Procedure for the Synthesis of Oxazoline-quinazoline (4).
+
C
H
N O (M ) 360.1263, found 360.1263.
25 16
2
A solution of amide 13 (1 equivalent), PPh (1.2 equivalent),
Anal. Calcd for C
H N O: C, 83.31; H, 4.47; N, 7.77.
3
25 16 2
NEt (1.75 equivalent), and CCl (3.4 equivalent), in dry acetoni-
Found: C, 82.98; H, 4.53; N, 7.92.
3
4
trile were refluxed for 6 hours. After being cooled, the brown
reaction mixture was concentrated under reduced pressure. The
residue was extracted with EtOAc, washed with saturated aque-
Preparation of 1-(2-Phenyl-qunizolin-4-yl)-naphthalene-2-car-
boxylic Acid (11).
Aldehyde (10), (0.31 g, 0.86 mmol) in acetone (15 mL)
ous NaHCO and brine. Organic layer was dried over anhydrous
3
was heated to 60 °C and aqueous KMnO (0.237 g in 6 mL
Na SO and concentrated under reduced pressure. The concen-
4
2
4
water, 1.5 mmol) was added for 15 minutes followed by
refluxing the reaction mixture for 1 hour. The reaction mix-
ture was cooled and filtered through celite. The celite pad
was washed with hot acetone. Reaction mixture was concen-
trated and dissolved in 75 mL of ether and neutralized with 1 N
HCl (3 mL). Organic layer was separated , dried over anhy-
drous Na SO and concentrated. The concentrate was purified
trate was subjected to purification by radial chromatography to
furnish the desired oxazolines. (Sp, S) Oxazoline-4: (S)-2-
Phenyl-4-[(S)-2-(4(S)-phenyl-4,5-dihydro-oxazol-2-yl)-naph-
thalen-1-yl]quinazoline: R = 0.50 (25% EtOAc/hexanes). mp
f
1
190 °C. [α] -168 (c = 1.1, CHCl ). H (500 MHz, CDCl ): δ
D
3
3
8.70-7.76 (m, 2H), 8.28 (d, 1H, J = 8.8 Hz), 8.20 (d, 1H, J = 8.3
Hz), 8.12 (d, 1H, J =8.3 Hz), 8.01 (d, 1H, J = 8.3 Hz), 7.90(ddd,
1H, J = 1.4, 7.5, and 7.5 Hz), 7.60-7.57 (m, 1H), 7.53-7.45 (m,
4H), 7.42-7.36 (m, 3H), 7.16-7.08 (m, 3H), 6.86-8.64 (m, 2H),
2
4
by silica gel chromatography to furnished acid 11 as a fine
white powder (0.227 g ,70%). R = 0.59 (EtOAc). mp 249-250
f
1
°C. H (500 MHz, CDCl ): δ 13.7 (br s, 1H, D O) exchange-
5.07 (dd, 1H, J = 8.3 and 10.2 Hz), 4.17 (dd, 1H, J = 8.3 and
3
2
13
able), 8.57-8.56 (m, 2H), 8.15 (d, 2 H, J = 8.7 Hz), 8.06 (d, 1H,
J = 8.7 Hz), 7.97 (d, 1H, J = 8.3 Hz), 7.79 (t, 1H, J = 8.3 Hz),
10.2 Hz), 3.71 (t, 1H, J = 8.3Hz). C (125 MHz, CDCl ): δ
3
169.34, 164.72, 160.65, 150.99, 142.08, 138.44, 135.80, 134.90,

Nov-Dec 2001 Synthesis and Preliminary Use of Naphthyl Quinazoline and Isoquinoline Oxazolines
1269
133.78, 132.03, 130.71, 129.61, 129.21, 129.08, 128.75, 128.68,
128.43, 127.80, 127.47, 127.44, 127.28, 127.12, 126.71, 126.59,
126.41, 125.35, 124.40, 74.98, 70.11. MS (EI) m/z (relative
the ethereal layers were concentrated and the crude was once
again washed with brine, dried over anhydrous Na SO and con-
centrated. Silica gel column chromatographic purification of the
2
4
+
Intensity): 477 (M , 60), 447 (35), 359 (45), 246 (25). HRMS
concentrate gave 8 (2.73 g, 62%) as a reddish foam which was
+
(EI) calcd for C
H
N O (M ) 477.1841, found 477.1854. (Rp,
subsequently recrystallized in 10% ethyl acetate/hexanes. mp
33 23
3
1
S) Oxazoline-4: (R)-2-Phenyl-4-[-2-(4(S)-phenyl-4,5-dihydro-
125 °C. R = 0.55 (10% EtOAc/Hexanes). H (300 MHz,
f
oxazol-2-yl)-naphthalen-1-yl]quinazoline: R = 0.40 (25%
CDCl ): δ 8.02-7.98 (m, 1H), 7.95 (d, 1H, J = 8.3Hz), 7.82 (d,
f
3
1
EtOAc/hexanes). mp 182 °C. [α] + 8.2 (c = 1.1, CHCl ).
H
1H, J = 8.3 Hz), 7.65-7.41 (m, 7H), 7.35-7.26 (m, 2H), 2.82 (s,
D
3
13
(500 MHz, CDCl ): δ 8.71-8.68 (m, 2H), 8.27 (d, 1H, J = 8.7
3H). C (75 MHz, CDCl ): δ 160.04, 151.10, 137.25, 133.83,
3
3
Hz), 8.18 (d, 1H, J = 8.3 Hz), 8.11 (d, 1H, J = 8.7 Hz), 8.00 (d,
1H, J = 8.3 Hz), 7.86 (ddd, 1H, J = 1.4, 7.8, and 7.8 Hz), 7.59-
7.56 (m, 1H), 7.55-7.49 (m, 3H), 7.46 (dd, 1H, J = 0.9 and 7.8
Hz), 7.41-7.35 (m, 3H), 7.14-7.11 (m, 1H), 7.06 (t, 2H, J = 7.8
132.46, 130.24, 128.83, 128.31, 127.79, 127.70, 126.53, 126.35,
126.29, 126.18, 125.99, 125.39, 118.40, 24.62. MS (CI) m/z (rel-
+
ative Intensity): 270 (M + H, 100). HRMS (CI) calcd for
+
C
H
N (M + H) 270.1283, found 270.1264.
20 16
Hz), 6.87 (d, 2H, J = 7.8 Hz), 5.07 (dd, 1H, J = 8.3 and 10.2 Hz),
Preparation of 3-Bromomethyl-1-naphthalene-1-yl-isoquinoline
(18).
13
4.33 (dd, 1H, J = 8.3 and 10.2 Hz), 3.56 (t, 1H, J = 8.3 Hz).
C
(125 MHz, CDCl ): δ 169.34, 164.72, 160.65, 150.99, 142.08,
3
138.44, 135.80, 134.90, 133.78, 132.03, 130.71, 129.61, 129.21,
129.08, 128.75, 128.68, 128.43, 127.80, 127.47, 127.44, 127.28,
127.12, 126.71, 126.59, 126.41, 125.35, 124.40, 74.98, 70.11.
A mixture of 17 (3.53 g, 13.11 mmol), NBS (2.56 g, 14.38
mmol) and dibenzoyl peroxide (0.32 g, 1.32 mmol) in CCl (200
4
mL) was heated at reflux for 12 hours. Analogous workup as
described previously provided the crude bromide 18 (4.51, 99%)
+
MS (EI) m/z (relative Intensity): 477 (M , 100), 447 (25), 359
+
(55), 331 (100). HRMS (EI) calcd for C
477.1841, found 477.1857.
H
N O (M )
as a pale red solid which was used without further purification.
33 23
3
1
R = 0.55 (25% EtOAc/Hexanes). H (300 MHz, CDCl ): δ
f
3
8.05-7.91 (m 4H), 7.72-7.60 (m, 4H0, 7.53-7.33 (m, 4H), 4.88 &
Preparation of Naphthalene-1-carboxylic Acid (2-Hydoxy-1-
methyl-2-phenylethyl)-amide (16).
13
4.84 (d, AB q, J = 11.1 Hz). C (75 MHz, CDCl ): δ 160.95,
3
149.60, 137.14, 136.54, 133.93, 132.37, 130.80, 129.22, 128.43,
127.99, 127.91, 127.87, 127.74, 127.19, 126.61, 126.19, 126.08,
A solution of 1-naphthoyl chloride 15 in (2.78 g, 2.2 mL, 14.59
+
mmol) in CH Cl (20 mL) was added to a stirred mixture of
125.35, 119.80, 35.11. MS (EI) m/z (relative Intensity): 349 (M
2
2
+
norephedrine 14 (2.0 g, 13.22 mmol) in CH Cl (100 mL) and
+ 2, 10), 349 (M , 10), 302 (50), 268 (100). HRMS (EI) calcd for
2
2
+
5% aqueous NaOH (26 mL). Reaction was allowed to stir for 6
hours after the completion of the addition. The resultant white
solid formed was filtered, and the filter cake was washed with
water, i-PrOH and ether successively followed by drying under
C
H
BrN (M ) 347.0310, found 347.0294.
20 14
Preparation of 1-Naphthalen-1-yl-isoquinoline-3-carbaldehyde.
Dry DMSO (22 mL) was added to the mixture of 18 (5.0 g,
high vacuum in a dessicator containing anhydrous P O as a des-
14.35 mmol) and AgBF (4.52 g, 23.21 mmol), protected from
2
5
4
iccant to provide 16 (3.99 g, 99%). R = 0.49 (50%
light and stirred the yellow green slurry at room temperature.
f
1
EtOAc/Hexanes). mp 150-152 °C. H (300 MHz, CDCl ): δ
NEt (2.2 mL) was added to the reaction mixture and stirring was
3
3
8.28-8.25 (m, 1H), 7.91-7.84 (m, 2H), 7.54-7.51 (m, 4H), 7.44-
continued for an additional period of 30 minutes. The reaction
mixture was diluted with ether and filtered through celite by
decanting the ethereal layer. The black residue was extracted
with ether by swirling and filtering through celite. The filtrate
was concentrated and dried under high vacuum. The pure alde-
hyde (3.3 g, 77%) was obtained by subjecting the purification of
7.25 (m, 5H), 6.12 (d, 1H, J = 8.0 Hz), 4.98 (d, 1H, J = 2.9 Hz),
13
4.69-4.58 (m, 1H), 3.59 (br s, 1H), 1.16 (d, 3H, J = 7.1 Hz).
C
(75 MHz, CDCl ): δ 170.44, 140.79, 134.31, 133.88, 131.01,
3
130.27, 128.55, 128.51, 127.94, 127.44, 126.69, 126.65, 125.51,
125.21, 124.89, 51.82, 15.29. MS (CI) m/z (relative Intensity):
+
306 (M + H, 80), 288 (100), 199 (15), 155 (20), 107 (15).
the concentrate by silica gel column chromatography purifica-
+
1
HRMS (CI) calcd for C
306.1500.
H
NO (M + H) 306.1494, found
tion. R = 0.47 (25% EtOAc/hexanes). mp 170-172 °C. H (300
20 20
2
f
MHz, CDCl ): δ 10.35 (s, 1H), 8.53 (d, 1H, J = 1.0 Hz), 8.14 (d,
3
1H, J = 8.3 Hz), 8.05 (dd, 1H, J = 2.0 and 7.3 Hz), 7.98 (d, 1H, J
Anal. Calcd for C
H NO : C, 78.66; H, 6.27; N, 4.59.
20 19 2
= 7.3 Hz), 7.80 (ddd, 1H, J = 1.4, 7.1 and 8.3 Hz), 7.70-7.49 (m,
Found: C, 78.72; H, 6.29; N, 4.68.
13
5H), 7.36-7.34 (m, 2H).
C (75 MHz, CDCl ): δ 194.22,
3
Preparation of 3-Methyl-1-naphthalene-1-yl-isoquinoline (17).
161.62, 146.38, 136.22, 136.15, 133.92, 132.28, 131.39, 130.59,
130.25, 129.53, 129.27, 128.60, 128.26, 127.92, 126.77, 126.35,
125.85, 125.45, 120.78. MS (EI) m/z (relative Intensity): 283
A mixture of 16 (5.0 g, 0.016 mol) and P O (16.3 g, 0.114
2
5
mol) was refluxed in o-dichlorobenzene (125 mL) at 180 °C for
24 hours. The mixture was cooled and most of the solvent was
decanted. The black residual matter in the flask was washed with
benzene (3 x 20 mL) and water (50 mL) was added cautiously.
When the vigorous reaction stopped, it was made basic with 50%
aqueous NaOH by cooling the reaction mixture. The solid mate-
rial dissolves forming a dark reddish brown slurry after 2-3
hours. At this stage reaction mixture was diluted with excess
ether and solid NaCl was added to breakup the suspension. The
ether layer was decanted and the solid material was extracted
again with ether. This process was repeated several times till
there was no indication of the product in the extracted ether. All
+
(M , 70), 282 (100), 268 (40), 254 (30), 226 (8). HRMS (EI)
+
calcd for C
H
NO (M ) 283.0997, found 283.0988.
20 13
Anal. Calcd for C
H NO C, 84.78; H, 4.62; N, 4.94. Found:
20 13
C, 84.62; H, 4.73; N, 4.82.
Preparation of 1-Naphthalen-1-yl-isoquinoline-3-carboxylic
Acid (19).
To a solution of aldehyde (0.093 g, 0.33 mmol) in absolute
ethanol (2 mL) was added AgNO (0.167 g, 0.5 mL) in water (0.5
3
mL). To this stirring solution, NaOH (0.04 g, 1.0 mmol) in water
(0.5 mL) was added. After the addition was complete, the black

1270
M. B. Andrus and B. B. V. Soma Sekhar
Vol. 38
reaction slurry was filtered through celite and the filter cake was
125.39, 122.23 75.67 & 75.66, 70.44. MS (CI) m/z (relative
+
washed with Et O and then neutralized with 1 M HCl. The com-
Intensity): 401 (M + H, 100), 333 (15). HRMS (CI) calcd for
2
+
bined filtrates were mixed, ethereal layer separated and the aque-
ous layer was extracted with ether. Organic layer was dried over
C
H
N O (M + H) 401.1654, found 401.1659. 5 (R=t-Bu):
28 21
2
R = 0.64 (50% EtOAc/hexanes). [α] -84.3 (c = 2.6, CHCl ).
f
D
3
1
anhydrous Na SO and concentrated and dried under vacuum to
H (500 MHz, CDCl ): δ 8.68 (s, 1H), 8.03-7.97 (m, 2H), 7.92
2
4
3
1
give 19 (0.096 g, 97%) as a pale yellow solid. H (300 MHz,
(d, 1H, J = 8.3 Hz), 7.73-7.67 (m, 1H), 7.64-7.54 (m, 3H), 7.49-
7.40 (m, 2H), 7.35-7.25 (m, 2H), 4.52-4.45 (overlapped dd, 1H,
J = 8.8 and 10.3 Hz), 4.35 (overlapped t, 1H, J= 8.3 Hz), 4.17
CDCl ): δ 11.81 (br s, 1H), 8.75 (s, 1H), 8.22 (d, 1H, J = 8.3 Hz),
3
8.05 (d, 1H, J = 7.8 Hz), 7.98 (t, 1H, J = 7.3 Hz), 7.90 (d, 1H, J
13
= 8.3 Hz), 7.72-7.59 (m, 4H), 7.44 (t, 1H, J = 7.3 Hz), 7.28 (t,
(dd, 1H, J = 8.3 and 10.8 Hz). 1.03 (s, 9 H). C (125 MHz,
13
1H, J = 7.8 Hz), 7.16 (d, 1H, J = 8.3 Hz).
C (75 MHz,
CDCl ): δ 163.50, 160.81 & 160.78, 140.31 & 140.24, 136.85 &
3
CDCl ): δ 163.43, 159.54, 137.84, 135.82, 134.78, 133.56,
131.80, 131.68, 131.30, 130.83, 129.60, 129.51, 129.09, 128.82,
136.71, 136.30 & 136.22, 133.76 & 133.66, 132.59 & 132.55,
130.82, 129.22 & 129.20, 129.06, 128.69, 128.30, 128.16,
128.07, 127.92, 126.41& 126.36, 126.22 & 126.18, 126.01 &
125.97, 125.47 & 125.33, 121.81 & 121.77, 76.46 & 76.45,
69.63, 34.24, 26.19 & 26.17. MS (EI) m/z (relative Intensity):
3
127.65, 126.86, 125.42, 125.20, 124.69. MS (CI) m/z (relative
+
Intensity): 300 (M + H, 100). HRMS (CI) calcd for C
H NO
20 14 2
+
(M + H) 300.1024, found 300.1037.
+
380 (M , 30), 323 (100), 295 (60), 279 (17), 253 (35). HRMS
General Procedure for the Preparation of Amides 20.
+
(EI) calcd for C
H
N O (M + H) 380.1889, found 380.1896.
26 24
2
To the acid 19 (0.125 g, 0.41 mmol) in dry methylene chloride
(20 mL) at 0 °C, PyBrop (0.25 g, 0.530 mmol) was added under
nitrogen and stirred for 10 minutes. 2(S)-2-Phenylglycinol (0.067
g, 0.49 mmol) was added to this pale yellow clear solution and
Asymmetric Allylic Oxidation using the Ligands (4 ) and (5).
Degassed acetonitrile (2 mL) containing ligand (0.031 mmol)
and Cu(CH CN) PF (0.031 mmol) was stirred for 3hours.
3
4
6
Freshly distilled cyclohexene (1.04 mmol) and t-butyl p-nitro
perbenzoate (0.21 mmol) were added to the above bright yellow
reaction mixture, freeze-thawed under vacuum for three cycles
under nitrogen, and allowed to stir at -20 °C. The reaction
progress was monitored intermittently by TLC for the disappear-
ance of perester for 7 days. At this stage the reaction was con-
centrated under reduced pressure and dissolved in ether (20 mL)
and aqueous ammonia (3 mL). The ether layer was further
washed with aqueous ammonia until the disappearance of the
blue color of the aqueous layer. Organic layer was washed with
brine (3 mL), dried over anhydrous Na SO and concentrated.
allowed to stir for 10 min. i-Pr NEt (0.18 g, 0.24 mL, 1.37
2
mmol) was added dropwise for 7 minutes. The solution turned to
clear pale yellow after the addition was completed. Contents
were stirred at 0 °C for 3 hours followed by stirring overnight.
Reaction mixture was concentrated, diluted with EtOAc (50 mL)
and water (10 mL). Organic layer was separated and the aqueous
layer was back extracted with EtOAc (3 X 10 mL). The organic
layers were combined, washed with 1 N HCl (5 mL), aqueous
NaHCO (5 mL) and brine and dried over anhydrous Na SO .
3
2
4
Concentration followed by the purification gave 20 (0.14, 80%).
1
R = 0.53 (70% EtOAc/hexanes). H (500 MHz, CDCl ): δ 8.80
2
4
f
3
The concentrate was purified by radial chromatography to obtain
the 2-cyclohexenyl p-nitrobenzoate. See table 1 for yields and
selectivities.
& 8.74 (d, 1H, J = 7.3 Hz), 8.69 (d, 1H, J = 3.0 Hz), 8.05 (d, 1H,
J = 8.3Hz), 7.99 (d, 1H, J = 7.3Hz), 7.94 (t, 1H, J = 7.3 Hz),
7.72 (t, 1H, J = 7.8 Hz), 7.65-7.45 (m, 5H), 7.40-7.21 (m, 7H),
13
5.32-5.26 (m, 1H), 3.86 (br s, 2H), 3.21 & 3.09 (br s, 1H).
C
(125 MHz, CDCl ): δ. 165.75 & 165.64, 159.56 & 159.48,
REFERENCES AND NOTES
3
142.76, 139.21, 137.01 & 136.92, 136.61 & 136.51, 133.88 &
133.80, 132.43, 131.05, 129.68, 129.35 & 129.34, 129.05, 128.96
& 128.94, 128.74, 128.58 & 128.57, 128.16 & 128.13, 128.09 &
128.04, 127.92 & 127.89, 127.09 & 127.04, 126.71 & 126.64,
126.33 & 126.31, 126.05, 125.34 & 125.32, 120.62 & 120.52,
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Compound 5 was prepared following the procedure as
described for oxazoline 4; 5 (R=Ph): R = 0.58 (50%
f
1
EtOAc/hexanes). [α ] -27.2 (c = 3.4, CHCl ). H (500
D
3
MHz, CDCl ): δ 8.74 (s, 1H), 8.00 (d, 1H, J = 8.3 Hz), 7.98
3
(dd, 1H, J = 1.4 and 7.8 Hz), 7.92 (d, 1H, J = 7.8 Hz), 7.70
(t, 1H, J = 7.3 Hz), 7.63-7.57 (m, 3H), 7.46 (m, 2H), 7.39-
7.24 (m, 7H), 5.58 (t, 1H, J = 9.3 Hz), 4.93-4.88 (over lapped
dd, 1H, J = 9.3 and 8.3 Hz), 4.89 (overlapped t, 1H, J = 8.3
13
Hz).
C (125 MHz, CDCl ): δ. 164.82 & 164.80, 161.06 &
3
161.05, 142.30, 139.89 & 139.86, 136.71 & 136.67, 136.26 &
136.23, 133.73 & 133.69, 132.55, 130.97, 129.38, 129.11,
128.97, 128.91, 128.33, 128.20, 128.18, 128.06, 128.02,
127.82, 127.09, 126.44, 126.17, 126.03, 126.02, 125.43,

Nov-Dec 2001 Synthesis and Preliminary Use of Naphthyl Quinazoline and Isoquinoline Oxazolines
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