Synthesis and application of oxadiazines as chiral ligands for the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2010.09.010

A series of oxadiazines derived from l-phenylalanine bearing phenolic substituents have been synthesized in a multistep, one pot process. This process involves the reaction of a mixed anhydride with a β-hydrazino alcohol, methanesulfonylation of the alcohol moiety, and base induced cyclization. The resultant oxadiazines were employed in the asymmetric addition of diethylzinc to aldehydes.

Full text of DOI:10.1016/j.tetasy.2010.09.010

Tetrahedron: Asymmetry 21 (2010) 2471–2478
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and application of oxadiazines as chiral ligands
for the enantioselective addition of diethylzinc to aldehydes
⇑
Melissa A. Dean, Shawn R. Hitchcock
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of oxadiazines derived from L-phenylalanine bearing phenolic substituents have been synthe-
Received 16 August 2010
Accepted 21 September 2010
Available online 26 October 2010
sized in a multistep, one pot process. This process involves the reaction of a mixed anhydride with a
b-hydrazino alcohol, methanesulfonylation of the alcohol moiety, and base induced cyclization. The
resultant oxadiazines were employed in the asymmetric addition of diethylzinc to aldehydes.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
6 using the synthetic route previously established by our research
group.18 The synthesis was effected by reductive alkylation with
Chiral, non-racemic oxadiazines 1 were first prepared by Trepa-
nier et al. in the 1960s (Fig. 1).1–6 These compounds were of interest
because of their central nervous system activity but were not fully
pursued to a significant degree after their introduction. These com-
pounds are structurallyrelated to the oxadiazinones 2 that were pio-
neered by Trepanier et al.7,8 and later applied in the asymmetric
aldol reaction by Hitchcock et al.9–12 We recently disclosed our
efforts in developing syntheses for a series of oxadiazines derived
acetone and sodium borohydride, N-nitrosation, and lithium alumi-
num hydride reduction (Scheme 1). With the hydrazine in hand, the
carboxylic acid component was then pursued. The first carboxylic
acid that was employed in the oxadiazine synthesis was acetylsali-
cylic acid 9 (Scheme 2). Thus, the carboxylic acid was treated with
from Ephedra alkaloids as well as L
-phenylalanine.13 We became
R
O
interested in further developing oxadiazines for asymmetric applica-
tions. Oxazolines 3 are structurally related to oxadiazines and have
been used in the asymmetric addition of diethylzinc to alde-
hydes.14–17 Allen and Williams17 synthesized an oxazoline bearing
a phenolic substituent at the 2-position and used this compound as
a ligand for the asymmetric addition reaction. This served as a moti-
vation for the synthesis of oxadiazines bearing phenolic positions 4
for application in the diethylzinc addition process with aldehydes.
OH
N3
N 4
OH
N3
3
H
1
1 O
N 3
N 4
O
N
N 4
1O
1O
4
R'
R'
R'
R'
oxadiazine
oxadiazinone
R'
oxazoline
1
2
3
4
We opted to create the oxadiazines from
had previously developed a preparative method based on this
-amino acid and had also demonstrated that the related -phenyl-
L-phenylalanine as we
Figure 1. Structural relationship between oxadiazines, oxadiazinones, and oxazo-
lines.
a
L
alanine based oxadiazinones could serve as effective chiral auxilia-
ries for the aldol reaction (Fig. 2).18 We report herein on our efforts
to prepare oxadiazines possessing phenolic substituents and their
application in the asymmetric addition reaction with diethylzinc
and aldehydes.
R
R
OH
NH2
N
OH
2. Results and discussion
OPg
O
N
N
CH2Ph
HO
O
The preparation of chiral, non-racemic oxadiazines was initiated
by the synthesis of the L-phenylalaninol derived b-hydrazinoalcohol
7
6
CH2Ph
5
⇑
Corresponding author. Tel.: +1 309 438 7854.
E-mail address: hitchcock@ilstu.edu (S.R. Hitchcock).
Figure 2. Synthesis plan for the phenolic oxadiazines.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.09.010

2472
M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 2471–2478
functionalized carboxylic acid 17a (Scheme 3). Other related
OH NH2
N
1. (CH3)2CO; NaBH4
2. NaNO2, HCl
OH
derivates were sought and so protection of the phenolic oxygen
of 1-hydroxy-2-naphthoic acid was also accomplished using this
synthetic route, thus providing compound 17b. The introduction
of a tert-butyl group onto the aromatic ring was also of interest.
Thus, 3-tert-butylsalicylaldehyde was used in this process as the
corresponding carboxylic acid was not commercially available.
The phenolic oxygen was protected by methylation and the alde-
hyde was oxidized with potassium permanganate to afford carbox-
ylic acid 17c.
NH2
3. LiAlH4, THF
CH2Ph
CH2Ph
(ref. 18)
6
8
Scheme 1. Synthesis of b-hydrazinoalcohol 6.
methanesulfonyl chloride and the resultant mixed anhydride was
added dropwise to a solution of b-hydrazinoalcohol 6.
With the carboxylic acids in hand, the synthesis of the phenolic
oxadiazine ligands was pursued. The multistep process of hydra-
zide formation, methanesulfonylation, and cyclization was em-
ployed and this led to the formation of oxadiazines 21a–c in
varying yields. The overall yield for the conversion of carboxylic
acid 17a into the desired oxadiazine 21a through intermediate
b-hydrazidoalcohol 20a was 32% (Scheme 4). In like fashion, car-
boxylic acid 17b was reacted with methanesulfonyl chloride to
form 20b which ultimately underwent cyclization to afford 21b
in 68% isolated yield after chromatography. Finally, the tert-butyl-
salicylic acid derivative was taken through the same process. The
carboxylic acid was treated with methanesulfonyl chloride to form
20c. Cyclization of the hydrazide gave a yield of 13% yield. The low
yield is attributed to the steric volume of the tert-butyl group on
the phenolic ring interfering with the cyclization. Finally, the
methyl ethers were deprotected using the method of McOmie
and West19 employing boron tribromide (BBr3) in a dichlorometh-
ane solution.
The collected oxadiazines were then employed in the asymmet-
ric addition of diethylzinc to 2-naphthaldehyde to yield 1-(2-naph-
thyl)-1-propanol (Table 1). The observed enantioselectivities were
determined by CSP HPLC to range from 17% to 55% ee with isolated
chemical yields ranging from 76% to 93%. Oxadiazines 13a and 22a
yielded the same level of enantioselection suggesting that the pres-
ence of the methyl group on 22a was not of enough steric volume
to make a difference. Changing the number of equivalents of
diethylzinc (cf. entries 2 and 3) did not alter the level of enantiose-
lection, but did produce the reduction byproduct 2-naphthylmeth-
anol in addition to the addition product.20 The oxadiazine bearing
the naphthyl group led to a decrease in the enantioselection of the
addition process. It is proposed that the naphthyl substituent does
This process created b-hydrazidoalcohol 11a which proved dif-
ficult to isolate in pure form without significant decomposition. In
order to obviate this problem, 11a was not isolated, but was trea-
ted directly with a second equivalent of methanesulfonyl chloride
and triethylamine leading to the formation of oxadiazine 12a in
29% yield for the three step process (hydrazide formation, meth-
anesulfonate formation, and cyclization). It should be noted that
an excess of methanesulfonyl chloride could not be added at the
beginning of the reaction sequence as this might lead into the for-
mation of the sulfonamide of 6 which would not undergo the cycli-
zation process.
There was also an interest in the use of substituted derivatives
of salicylic acid. To this end, 3-methylsalicylic acid 13a was acety-
lated with acetic anhydride in 75% chemical yield and then em-
ployed in the synthesis of b-hydrazidoalcohol 11b (Scheme 2).
Cyclization with methanesulfonyl chloride and triethylamine
afforded oxadiazine 12b in 29% isolated yield after chromatogra-
phy. With oxadiazines 12a and 12b in hand, an effort was made
to deprotect the phenolic position. Saponification of 12a with
potassium hydroxide led to the formation of the desired oxadiazine
13a in 45% yield. Oxadiazine 12b did not readily undergo saponifi-
cation perhaps due to steric hindrance inhibiting the formation of
the tetrahedral intermediate necessary for the hydrolysis process.
Treatment of 12b with lithium aluminum hydride led to the forma-
tion of phenolic oxadiazine 13b in 68% yield.
An alternate approach was pursued in order to circumvent the
use of lithium aluminum hydride. To this end, 3-methylsalicylic
acid was esterified with methanol and catalytic sulfuric acid, meth-
ylated at the phenolic oxygen with potassium carbonate and iodo-
methane, and then hydrolyzed under basic conditions to yield
R
CH3
R
OH
OAc
OAc
Ac2O, DMAP
TEA
1a. MsCl, TEA, CH2Cl2
2. MsCl, TEA
1b. add to solution
OH HN
N
O
CO2H
CO2H
of 6
9
10a: R = -H
10b: R = -CH3
CH2Ph
11a: R = -H
11b: R = -CH3
R
CH3
OH
OAc
OH
KOH, H2O
THF
LiAlH4, THF
12b
O
N
N
O
N
N
O
N
N
68%
CH2Ph
CH2Ph
CH2Ph
13b
12a: R = -H, (29%)
13a
12b: R = -CH3, (29%)
Scheme 2. Synthesis of oxadiazines 13a and 13b.

M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 2471–2478
2473
R
R
R'
OH
R'
OH
CH3I, K2CO3
DMF
MeOH
cat. H2SO4
CO2CH3
CO2H
15a (95%)
15b (79%)
9/a: R = -CH3, R' = -H
14/b: R = R' = (-CH=CH-)2
R
R
R'
OCH3
R'
OCH3
CO2H
KOH, H2O
THF
CO2CH3
16a (88%)
17a (67%)
17b (69%)
16b (93%)
C(CH3)3
C(CH3)3
OH
C(CH3)3
OCH3
OCH3
CH3I, K2CO3
DMF
KMnO4, acetone
H2O
55%
CHO
CHO
CO2H
95%
18
17c
19
Scheme 3. Preparation of functionalized carboxylic acids.
R'
R'
R
R
R
OCH3
OCH3
R'
OCH3
CO2H
1a. MsCl, TEA, CH2Cl2
2. MsCl, TEA
O
N
N
OH HN
N
O
1b. add to solution of 6
17a-c
CH2Ph
CH2Ph
20a-c
21a (32%)
21b (68%)
21c (13%)
a: R = -CH3; R' = -H
b: R = R' = (-CH = CH-)2
c: R = -C(CH3)3; R' = -H
R'
R
OH
BBr3, CH2Cl2
21a-c
O
N
N
CH2Ph
22a (13b) (32%)
22b (74%)
22c (54%)
Scheme 4. Synthesis of oxadiazines 22a–c.
not provide a steric environment conducive to the production of
high enantioselectivities.
lated oxadiazinones demonstrated that this position was effective
in the asymmetric aldol reaction.18 However, in this case, the iso-
propyl group does not provide the same level of stereoselectivity.
The tert-butyl containing oxadiazine 22c yielded the best
enantioselectivity but presented a challenge in terms of its synthe-
sis (vide supra). Oxadiazine 22a was employed in the asymmetric
addition of diethylzinc to a variety of aldehydes (Table 2). The ob-
served enantioselectivities ranged from 12% to 36% ee. Again, the
argument is made that the stereocontrol element of the N4-isopro-
pyl group was not sufficient in generating enantioselectivities that
would be synthetically useful.
The use of oxadiazine 22c bearing the tert-butyl substituent
gave the best enantioselectivity in the formation of the addition
product, presumably due to the projection of steric volume of the
tert-butyl group into the region where the aldehyde potentially
resides during the course of the asymmetric induction process
(Fig. 3). Overall, the low enantioselectivity may be due to a variety
of factors, primary amongst which might be the proximity of the
stereocontrol element of the oxadiazine ring, namely, the N4-posi-
tion which bears an isopropyl group. Previous research with the re-

2474
M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 2471–2478
Table 1
Table 2
Enantioselective addition of diethylzinc with 2-naphthaldehyde with oxadiazine
Enantioselective additions of diethylzinc with aldehydes with oxadiazine 22a
ligands 13a and 22a–c
OH
O
Et
H
O
oxadiazine 22a
OH
Et2Zn, (2 equiv.)
R
R
H
H
oxadiazines 13a, 22a-c
26
25
H
Et
Et2Zn, toluene
Entry
R
Yielda
80
er (R:S), (% ee)b
Config.c
23
24
er (R:S), (% ee)b
1
2
3
4
5
1-C6H5
63.4:37.6, (25)
38.0:62.0, (24)
56.1:43.9, (12)
59.8:40.2, (20)
32.3:67.7, (36)
(R)
(R)
(R)
(R)
(R)
2-C10H7 (-2-naphthyl)
-trans-CH@CHC6H5
p-C6H4OCH3
91
74
63
84
Entry
Oxadiazine
Et2Zn (equiv)
Yielda
Config.c
1
2
3
4
5
13a
22a
22a
22b
22c
2
2
3
2
2
93
91
76
91
90
38.1:61.9, (24)
37.8:62.2, (24)
38.1:61.9, (24)
41.5:58.5, (17)
22.7:77.3, (55)
(R)
(R)
(R)
(R)
(R)
-1-C10H7(-1-naphthyl)
a
b
c
The yield was calculated after flash column chromatography.
The enantiomeric ratios were determined via CSP HPLC using a Chiralcel-OD.
The configuration was determined by comparison of literature values.21
a
The yield was calculated after flash column chromatography.
The enantiomeric ratios were determined via CSP HPLC using a Chiralcel-OD
b
are measured either as Nujol mull or a neat liquid. Melting points
wererecordedona Mel-Tempapparatus andareuncorrected. Optical
activities were measured using at 589 nm using digital polarimeter.
Enantiomeric ratioofthe catalysis was determined usingchiralphase
HPLC using AD, AS, or OD column. High resolution mass spectra were
obtained from the mass Spectrometry laboratory, School of Chemical
Science, University of Illinois, Urbana-Champaign. Anhydrous
toluene was used for the catalysis reaction.
column.
c
The configuration was determined by comparison of literature values.21
R'
R'
R
R
Et
Et
Zn
Zn
Et
Et
H
2-nap
H
O
O
4.2. 2-Acetoxy-3-methylbenzoic acid 10b
O
O
Zn
Zn
2-nap
O
N
N
O
N
N
In a nitrogen purged, flame dried round bottomed flask was
placed 3-methylsalicylic acid (10.0 g, 65.7 mmol), CH2Cl2
(366 mL), triethylamine (27.5 mL, 197 mmol), acetic anhydride
(6.5 mL, 69 mmol), and dimethyaminopyridine (2.00 g, 16.4 mmol).
The reaction mixture was stirred overnight before being quenched
with 1 M HCl (100 mL). The organic layer was extracted with CH2Cl2
(2 ꢁ 100 mL) and washed with brine (75 mL). The organic layer was
dried over MgSO4 and the solvent was removed by rotary evapora-
tion. The title compound was isolated by recrystallization (EtOAc,
hexanes). White solid (75%). Mp = 187–189 °C. 1H NMR (400 MHz,
CDCl3) d: 2.24 (s, 3H), 2.37 (s, 3H), 7.24 (t, J = 7.7 Hz, 1H), 7.48 (d,
J = 6.6 Hz, 1H) 7.96 (d, J = 6.6 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3) d: 16.1, 20.8, 122.1, 125.8, 130.1, 132.4, 136.4, 169.3,
170.3 ppm. IR (Nujol mull): 3328, 1698, 1592 cmꢀ1. ESI-HRMS calcd
for C10H10O4Na (M+Na+): 217.0477. Found: 217.0473.
Et
Et
favored
disfavored
CH2Ph
CH2Ph
Et
Et
HO
HO
H
H
(R)-24
(S)-24
Figure 3. Proposed favored and disfavored transition states.
3. Conclusion
4.3. General procedure for formation of b-hydrazido alcohols
11a and 11b
The oxadiazines were used in the asymmetric addition of dieth-
ylzinc with aldehydes; the enantiomeric excesses that were ob-
served ranged from 12% to 55% ee. It is believed that the N4-
isopropyl oxadiazines 13a and 22a-c did not effectively impose
stereoselectivity for the 1,2-addition reactions with diethylzinc
and aldehydes. Consequently, we are exploring other applications
that may prove to be more amenable to the oxadiazine structure.
In a 250 mL flamed dried, nitrogen purged round bottomed flask
functionalized carboxylic acid (2.00 g, 11.1 mmol), CH2Cl2 (110 mL),
triethylamine (1.63 mL, 11.7 mmol), and methanesulfonyl chloride
(0.85 mL, 11 mmol) were placed and the solution was allowed to stir
for 90 min before being transferred to an addition funnel. The solu-
tion was added dropwise to a solution made of L-phenyalanine
4. Experimental
derived b-hydrazino alcohol 3.16 (2.31 g, 11.1 mmol), CH2Cl2
(65 mL), and triethylamine (1.63 mL, 11.7 mmol). After the addition,
the reaction mixture was allowed to stir overnight before being
quenched with a saturated solution of NH4Cl (75 mL). The organic
layer was extracted with CH2Cl2 (2 ꢁ 75 mL) and washed with brine
(75 mL). The organic layer was dried over MgSO4 and the solvent
was removed by rotary evaporation.
4.1. General remarks
Toluene was purchased as an anhydrous reagent and was used
without further purification. Diethylzinc was directly purchased
from Aldrich. All reactions were run under a nitrogen atmosphere.
Unless otherwise noted, all 1H and 13C NMR spectra were recorded
in CDCl3 using NMR spectrometer operating at 400 or 100 MHz
respectively. Chemical shifts were reported in parts per million
(d scale), and coupling constants (J values)are listedinhertz (Hz). Tet-
ramethylsilane (TMS) was used as internal standard (d = 0 ppm).
Infrared spectra are reported in reciprocal centimeters (cmꢀ1) and
4.3.1. (S)-2-(2-(1-Hydroxy-3-phenyl-2-propyl)-2-isopropylhydra-
zinecarbonyl)phenyl acetate 11a
Using acetylsalicylic acid 10a, the title compound was not iso-
lated and was directly carried out in the cyclization. ESI-HRMS
calcd for C21H27N2O4 (M+H+): 371.1971. Found: 371.1966.

M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 2471–2478
2475
4.3.2. (S)-2-(2-(1-Hydroxy-3-phenyl-2-propyl)-2-isopropylhyd-
razinecarbonyl)-6-methyl phenyl acetate 11b
Using 9, the title compound was not isolated and was directly
carried out in the cyclization. ESI-HRMS calcd for C22H29N2O4
(M+H+): 385.2127. Found: 385.2116.
J = 10.4, 5.0 Hz, 1H), 6.74–7.51 (m, 4H), 11.83 (s, 1H) ppm. 13C
NMR (CDCl3, 100 MHz) d: 17.2, 20.9, 34.6, 52.0, 53.9, 66.6, 114.8,
116.4, 118.4, 125.2, 126.8, 128.7, 129.3, 130.4, 137.2, 145.6,
147.2, 157.3 ppm. IR (neat): 3492, 1622, 1448 cmꢀ1
.
4.6. (S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadia-
4.4. General procedure for one-pot synthesis of oxadiazines 12a
and 12b
zin-2-yl)-6-methylphenol 13b
Oxadiazine 12b (0.130 g, 0.350 mmol) was added to a solution of
LiAlH4 (0.010 g, 0.17 mmol) in THF (5 mL). The reaction mixture was
allowed to stir for 45 min before being quenched with H2O (50 mL).
THF was removed by rotary evaporation and the organic layer was
extracted with CH2Cl2 (2 ꢁ 50 mL) and washed with brine (50 mL).
The organic layer was dried over MgSO4 and the solvent was re-
moved by rotary evaporation. The title product was isolated by flash
column chromatography (hexanes/EtOAc, 98:2). Yellow oil (68%).
In a 250 mL flamed dried, nitrogen purged round bottomed flask
functionalized carboxylic acid (0.97 g, 4.8 mmol) was placed.
CH2Cl2 (48 mL), triethylamine (0.80 mL, 5.8 mmol), and methane-
sulfonyl chloride (0.40 mL, 4.8 mmol) were added and the solution
was allowed to stir for 90 min before being transferred to an addi-
tion funnel. The solution was added dropwise to a solution com-
posed of L-phenyalanine derived b-hydrazino alcohol 3.16 (1.00 g,
4.80 mmol), CH2Cl2 (24 mL), and triethylamine (0.80 mL,
5.8 mmol). After the addition the reaction mixture was allowed
to stir overnight before the addition of triethylamine (1.35 mL,
9.60 mmol) and methanesulfonyl chloride (0.40 mL, 5.0 mmol).
The reaction mixture was allowed to stir for an additional 48 h be-
fore being quenched with a saturated solution of NH4Cl (75 mL).
The organic layer was extracted with CH2Cl2 (2 ꢁ 75 mL) and
washed with brine (75 mL). The organic layer was dried over
MgSO4 and the solvent was removed by rotary evaporation.
½
a 2D4
ꢂ
¼ þ157:1 (c 1.24, CHCl3). 1H NMR (400 MHz, CDCl3) d: 1.13
(d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 2.28 (s, 3H), 2.65
(dd, J = 13.6, 9.6 Hz, 1H), 3.04 (dd, J = 13.6, 5.0 Hz, 1H), 3.42–3.47
(m, 1H), 4.06 (dd, J = 10.4, 2.8 Hz, 1H), 4.16 (dd, J = 10.4, 5.0 Hz,
1H), 6.74 (t, J = 7.6 Hz, 1H), 7.04–7.45 (m, 8H), 12.11 (s, 1H) ppm.
13C NMR (CDCl3, 100 MHz) d: 15.9, 17.2, 21.0, 34.5, 52.1, 53.9, 66.7,
114.2, 117.9, 123.0, 125.2, 126.7, 128.6, 129.2, 131.5, 137.2, 147.5,
155.5 ppm. IR (neat): 3492, 1622, 1448 cmꢀ1. ESI-HRMS calcd for
C
20H25N2O2 (M+H+): 325.1916. Found: 325.1907.
4.4.1. (S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-
4.7. Methyl 2-hydroxy-3-methylbenzoate 15a
oxadiazin-2-yl)phenyl acetate 12a
Yellow oil (41%),
½
a 2D4
ꢂ
¼ þ153:0 (c 1.78, CHCl3). 1H NMR
In a round bottomed flask were placed 3-methylsalicylic acid 9
(15.0 g, 98.6 mmol), methanol (300 mL), and concentrated H2SO4.
The reaction mixture was allowed to stir at reflux for 48 h. The sol-
vent was then removed by rotary evaporation. The reaction mix-
ture was then neutralized with NaHCO3. The organic layer was
extracted with EtOAc (2 ꢁ 100 mL) and washed with brine
(100 mL). The organic layer was dried over MgSO4 and the solvent
was removed by rotary evaporation. The title compound was iso-
lated by flash column chromatography (hexanes/EtOAc, 99:1).
Clear liquid (97%). 1H NMR (400 MHz, CDCl3) d: 2.27 (s, 3H), 3.94
(s, 3H), 6.78 (t, J = 7.6 Hz, 1H), 7.31 (m, 1H), 7.67–7.70 (m, 1H),
11.01 (s, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d: 15.6, 52.2,
111.6, 118.5, 126.6, 127.4, 136.4, 160.0, 171.0 ppm. IR (neat):
3483, 1738, 1589 cmꢀ1. ESI-HRMS calcd for C9H11O3 (M+H+):
167.0618. Found: 167.0619.
(400 MHz, CDCl3) d: 1.12 (d, J = 6.4 Hz, 3H), 1.27 (d, J = 6.4 Hz,
3H), 2.25 (s, 3H), 2.71 (dd, J = 13.5, 9.8 Hz, 1H), 2.95 (dd, J = 13.5,
8.4 Hz, 1H), 3.37–3.45 (m, 1H), 3.90 (dd, J = 10.2, 2.7 Hz, 1H), 4.06
(dd, J = 10.2, 3.5 Hz, 1H), 6.99–7.79 (m, 4H) ppm. 13C NMR (CDCl3,
100 MHz) d: 18.5, 20.3, 21.0, 34.6, 53.1, 53.6, 65.2, 123.2, 125.6,
125.9, 126.4, 128.4, 128.7, 129.2, 137.8, 141.6, 147.5, 169.4 ppm.
IR (neat): 1686, 1622, 1448 cmꢀ1. ESI-HRMS calcd for C21H25N2O3
(M+H+): 353.1865. Found: 353.1862.
4.4.2. (S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-
oxadiazin-2-yl)-6-methylphenyl acetate 12b
Yellow oil (68%).
½
a 2D4
ꢂ
¼ þ124:0 (c 1.31, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 1.12 (d, J = 6.4 Hz, 3H), 1.26 (d, J = 6.4 Hz,
3H), 2.18 (s, 3H), 2.28 (s, 3H), 2.71 (dd, J = 13.5, 9.9 Hz, 1H), 2.96
(dd, J = 13.5, 5.0 Hz, 1H), 3.38–3.46 (m, 1H), 3.90 (dd, J = 10.2,
2.6 Hz, 1H), 4.08 (dd, J = 10.2, 3.5 Hz, 1H), 7.10–7.34 (m, 7H),
7.58–7.61 (m, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d: 16.5, 18.7,
20.5, 21.0, 34.7, 53.3, 53.7, 65.5, 125.6, 126.1, 126.6, 126.8, 128.6,
129.4, 131.1, 131.4, 138.1, 142.2, 146.5, 169.0 ppm. IR (neat):
4.8. Methyl 1-hydroxy-2-naphthoate 15b
In a round bottomed flask were placed 1-hydroxy-2-naphthoic
acid 14b (10.0 g, 53.1 mmol), methanol (200 mL), and concentrated
H2SO4 (10 mL). The reaction mixture was allowed to stir at reflux
for 48 h. The organic layer was then extracted with EtOAc
(2 ꢁ 100 mL) and washed with brine (100 mL). The organic layer
was dried over MgSO4 and the solvent was removed by rotary
evaporation. The title compound was isolated by flash column
chromatography (hexanes/EtOAc, 99:1). White solid (79%).
Mp = 217–220 °C. 1H NMR (400 MHz, CDCl3) d: 3.98 (s, 3H), 7.26
(d, J = 4.3 Hz, 1H), 7.51 (ddd, J = 7.5, 6.9, 1.3, 1H), 7.59 (ddd,
J = 7.5, 6.9, 1.3 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 8.40 (d, J = 7.9 Hz,
1H), 11.98 (s, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d: 52.3, 105.6,
118.6, 123.8, 124.2, 124.7, 125.7, 127.4, 129.4, 137.2, 160.9,
171.4 ppm. IR (Nujol mull): 3483, 1738, 1589 cmꢀ1. ESI-HRMS
calcd for C12H11O3 (M + H+): 203.0630. Found: 203.0629.
1686, 1622, 1448 cmꢀ1
.
4.5. (S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-
oxadiazin-2-yl)phenol 13a
Oxadiazine 12a (0.705 g, 2.00 mmol), THF (4 mL), and KOH
(1 M, 4 mL) were combined in a 50 mL round bottomed flask. The
reaction mixture was stirred for 24 h before the solvent was re-
moved by rotary evaporation. The reaction mixture was diluted
with a saturated solution of ammonium chloride (50 mL) and the
organic layer was extracted with CH2Cl2 (2 ꢁ 50 mL) and washed
with brine (50 mL). The organic layer was dried over (MgSO4)
and the solvent was removed by rotary evaporation. The title com-
pound was isolated by flash column chromatography (hexanes/
EtOAc, 95:5). Yellow oil (45%), ½a D23
ꢂ
¼ þ164:7 (c 0.16, CHCl3). 1H
4.9. Methyl 2-methoxy-3-methylbenzoate 16a
NMR (400 MHz, CDCl3) d: 1.07 (d, J = 6.4 Hz, 3H), 1.27 (d,
J = 6.4 Hz, 3H), 2.60 (dd, J = 13.6, 9.6 Hz, 1H), 2.99 (dd, J = 13.6,
5.0 Hz, 1H), 3.38 (m, 1H), 4.00 (dd, J = 10.4, 2.8 Hz, 1H), 4.10 (dd,
To a flame dried, nitrogen purged flask were added 15a (15.0 g,
90.3 mmol), DMF (90 mL), and K2CO3 (37.40 g, 270.8 mmol). The

2476
M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 2471–2478
reaction mixture was allowed to stir for 45 min before the addition
of iodomethane (5.90 mL, 94.8 mmol). The reaction mixture was
allowed to stir overnight before being quenched with HCl (1 M,
100 mL). The organic layer was extracted with CH2Cl2
(2 ꢁ 50 mL) and washed with brine (50 mL). The solvent was re-
moved by rotary evaporation. The title compound was isolated
by flash column chromatography (hexanes/EtOAc, 95:5). Clear
liquid (72%). 1H NMR (400 MHz, CDCl3) d: 2.31 (s, 3H), 3.82
(s, 3H), 3.90 (s, 3H), 7.03 (t, J = 7.6 Hz, 1H), 7.31–7.33 (m, 1H),
7.61–7.61 (m, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d: 16.0, 52.1,
61.4, 123.3, 124.4, 128.9, 132.5, 134.9, 158.4, 166.8 ppm. IR (neat):
1729, 1590, 1293. ESI-HRMS calcd for C10H12O3Na (M+Na+):
203.0684. Found: 203.0683.
4.13. 3-tert-Butyl-2-methoxybenzaldehyde 19
In a nitrogen purged, round bottomed flask 3-tert-butyl-2-
hydroxybenzaldehyde 18 (4.20 mL, 24.5 mmol), DMF (25 mL),
and K2CO3 (10.2 g, 73.5 mmol) were placed. The reaction mixture
was stirred for 45 min before the addition of iodomethane
(2.30 mL, 36.8 mmol). The reaction mixture was stirred overnight
before being quenched with 1 M HCl (150 mL). The organic layer
was extracted with CH2Cl2 (2 ꢁ 75 mL) and washed with brine
(75 mL). The solvent was removed by rotary evaporation. The title
compound was isolated by flash column chromatography (hex-
anes/EtOAc, 95:5). Clear liquid (95%). 1H NMR (400 MHz, CDCl3)
d: 1.42 (s, 9H), 3.95 (s, 3H), 7.14 (t, J = 7.8 Hz, 1H), 7.57 (dd,
J = 7.8, 1.8 Hz, 1H), 7.70 (dd, J = 7.8, 1.8 Hz, 1H), 10.3 (s, 1H) ppm.
13C NMR (CDCl3, 100 MHz) d: 30.7, 35.1, 66.0, 123.7, 128.0, 129.7,
133.2, 143.6, 163.3, 190.3 ppm. IR (neat): 2749, 1698, 1596,
4.10. Methyl 1-methoxy-2-naphthoate 16b
To a flame dried, nitrogen purged flask were added 15b (6.90 g,
40.0 mmol), DMF (40 mL), and K2CO3 (16.5 g, 120 mmol). The reac-
tion mixture was allowed to stir for 45 min before the addition of
iodomethane (3.75 mL, 60.1 mmol). The reaction mixture was al-
lowed to stir overnight before being quenched with 1 M HCl
(100 mL). The organic layer was extracted with CH2Cl2 (2 ꢁ 75 mL)
and washed with brine (75 mL). The organic layer was dried over
MgSO4 and the solvent was removed by rotary evaporation. The title
compound was isolated by flash column chromatography (hexanes/
EtOAc, 9:1). Clear liquid (93%). 1H NMR (400 MHz, CDCl3) d: 3.94
(s, 3H), 4.03 (s, 3H), 7.48–7.56 (m, 3H), 7.76–7.83 (m, 2H), 8.23–8.26
(m, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d: 52.0, 63.1, 118.9, 123.4,
126.3, 126.4, 127.6, 128.1, 128.3, 136.5, 158.1, 166.4 ppm. IR (neat):
1729, 1590, 1293 cmꢀ1. ESI-HRMS calcd for C13H12O3 (M+Na+):
239.0684. Found: 239.0689.
1199 cmꢀ1 ESI-HRMS calcd for C12H15O2 (M+H+): 191.1072.
.
Found: 191.1071.
4.14. 3-tert-Butyl-2-methoxybenzoic acid 17c
In a flame dried, nitrogen purged flask 19 (4.47 g, 23.3 mmol),
acetone (232 mL), H2O (211 mL), and KMnO4 (9.18 g, 58.1 mmol)
dissolved in H2O (93 mL) were placed. The reaction mixture was al-
lowed to stir overnight before the reaction mixture was filtered
through Celite. The filtrate was then removed of solvent by rotary
evaporation. The organic layer was made basic with 3 M NaOH
(75 mL) and the organic layer was removed with EtOAc
(2 ꢁ 75 mL). The water layer was acidified with 3 M HCl (100 mL).
The organic layer was extracted with EtOAc (2 ꢁ 75 mL) and washed
withbrine (75 mL). The organic layer was then dried over MgSO4 and
the solvent was removed by rotary evaporation. The title product
was isolated by flash column chromatography (hexanes/EtOAc,
85:15). Yellow solid (55%). Mp = 167–169 °C. 1H NMR (400 MHz,
CDCl3) d: 1.42 (s, 9H), 3.9 (s, 3H), 7.09 (t, J = 7.8 Hz, 1H), 7.55 (dd,
J = 7.8, 1.5 Hz, 1H), 7.83 (dd, J = 7.8, 1.5 Hz, 1H) ppm. 13C NMR (CDCl3,
100 MHz) d: 30.8, 35.3, 63.1, 123.0, 123.2, 130.8, 132.3, 143.9, 160.9,
171.9 ppm. IR (Nujol mull): 3328, 1686, 1293 cmꢀ1. ESI-HRMS calcd
for C12H17O3 (M+H+): 209.1178. Found: 209.1173.
4.11. 2-Methoxy-3-methylbenzoic acid 17a
Ester 16a (2.63 g, 14.6 mmol), THF (12 mL), and KOH (6 M,
12 mL) were combined in a round bottomed flask and the solution
was stirred overnight. The solvents were removed by rotary evap-
oration. The reaction mixture was acidified by 3 M HCl and the or-
ganic layer was extracted with CH2Cl2 (2 ꢁ 50 mL) and washed
with brine (50 mL). The organic layer was dried over MgSO4 and
the solvent was removed by rotary evaporation. The title com-
pound was recrystallized with EtOAc and hexanes. White solid
(77%). Mp = 194–197 °C. 1H NMR (400 MHz, CDCl3) d: 2.37 (s,
3H), 3.93 (s, 3H), 7.17 (t, J = 7.6 Hz, 1H), 7.42–7.44 (m, 1H), 7.94–
7.96 (m, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d: 16.0, 62.1,
122.1, 124.9, 130.7, 131.7, 137.0, 158.0, 167.1 ppm. IR (Nujol mull):
3276, 1691, 1281 cmꢀ1. ESI-HRMS calcd for C9H10O3Na (M+Na+):
189.0528. Found: 189.0524.
4.15. General procedure for one-pot synthesis of oxadiazines
In a 250 mL flamed dried, nitrogen purged round bottomed flask
was placed the functionalized carboxylic acid (0.97 g, 4.8 mmol).
Then CH2Cl2 (48 mL), triethylamine (0.80 mL, 5.8 mmol), and
methanesulfonyl chloride (0.40 mL, 4.8 mmol) were added and
the solution was allowed to stir for 90 min before being transferred
to an addition funnel. The solution was added dropwise to a solu-
tion made of the L-phenyalanine derived b-hydrazino alcohol
4.12. 1-Methoxy-2-naphthoic acid 17b
(1.00 g, 4.80 mmol), CH2Cl2 (24 mL), and triethylamine (0.80 mL,
5.8 mmol). After the addition the reaction mixture was allowed
to stir overnight before the addition of triethylamine (1.35 mL,
9.60 mmol) and methanesulfonyl chloride (0.40 mL, 5.0 mmol).
The reaction mixture was allowed to stir for an additional 48 h be-
fore being quenched with a saturated solution of NH4Cl (75 mL).
The organic layer was extracted with CH2Cl2 (2 ꢁ 75 mL) and
washed with brine (75 mL). The organic layer was dried over
MgSO4 and the solvent was removed by rotary evaporation. The
target compound was isolated by flash column chromatography
(hexanes/EtOAc, 95:5) and contained <5% impurities.
Ester 16b (6.10 g, 32.8 mmol) was dissolved in THF (27 mL) and
6 M KOH (27.0 mL, 164 mmol) was added cautiously. The reaction
mixture was stirred at reflux overnight and the solvent was re-
moved by rotary evaporation. The reaction mixture was acidified
by 3 M HCl (100 mL) and the organic layer was extracted with
CH2Cl2 (2 ꢁ 50 mL) and washed with brine (50 mL). The organic
layer was dried over MgSO4 and the solvent was removed by rotary
evaporation. The title compound was recrystallized with EtOAc
and hexanes. White solid (79%). Mp = 198–199 °C. 1H NMR
(400 MHz, CDCl3) d (ppm): 4.17 (s, 3H), 7.60–7.67 (m, 2H), 7.72
(d, J = 8.6 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H),
8.19–8.21 (m, 1H). 13C NMR (CDCl3, 100 MHz) d (ppm): 64.3,
117.7, 123.1, 125.1, 126.9, 127.0, 127.1, 128.4, 129.0, 137.6,
157.8, 166.8. IR (Nujol mull): 3276, 1691, 1281 cmꢀ1. ESI-HRMS
calcd for C12H10O3 (M+Na+): 225.0528. Found: 225.0525.
4.15.1. (S)-5-Benzyl-4-isopropyl-2-(2-methoxy-3-methylphenyl)-
5,6-dihydro-4H-1,3,4-oxadiazine 21a
Yellow oil (32%).
(400 MHz, CDCl3) d: 1.17 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.4 Hz,
½
a 2D4
ꢂ
¼ þ179:6 (c 0.98, CHCl3). 1H NMR
3H), 2.32 (s, 3H), 2.76 (dd, J = 13.4, 9.9 Hz, 1H), 3.02 (dd, J = 13.4,

M. A. Dean, S. R. Hitchcock / Tetrahedron: Asymmetry 21 (2010) 2471–2478
2477
4.8 Hz, 1H), 3.42–3.48 (m, 1H), 3.86 (s, 3H), 4.01 (dd, J = 10.4,
2.7 Hz, 1H), 4.14 (dd, J = 10.4, 4.0 Hz, 1H), 6.97–7.43 (m, 7H),
7.80–7.82 (m, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d: 16.2, 18.3,
20.7, 34.5, 52.6, 53.6, 61.0, 66.0, 123.5, 126.5, 127.1, 127.9, 128.6,
129.3, 131.8, 138.1, 144.1, 156.4 ppm. IR (neat): 1686, 1448,
1213 cmꢀ1. ESI-HRMS calcd for C21H27N2O2 (M+H+): 339.2073.
Found: 339.2072.
124.9, 125.1, 126.8, 127.1, 127.3, 128.7, 129.3, 134.7, 137.3,
148.3, 154.6 ppm. IR (neat): 3490, 1618, 1456 cmꢀ1. ESI-HRMS
calcd for C23H25N2O2 (M+H+): 361.1802. Found: 361.1816.
4.16.2. (S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-
oxadiazin-2-yl)-6-tert-butylphenol 22c
In
a flame dried, nitrogen purged flask 21c (0.211 g,
0.555 mmol) and CH2Cl2 (5 mL) were placed. The reaction mixture
was cooled to 0 °C before the dropwise addition of 1 M BBr3 in tol-
uene (1.0 mL, 1.0 mmol). The reaction mixture was stirred over-
night and then quenched with H2O (50 mL). The organic layer
was extracted with ether (2 ꢁ 50 mL) and washed with brine
(50 mL). The organic layer was dried over MgSO4 and the solvent
was removed by rotary evaporation. The title compound was iso-
lated by flash column chromatography (hexanes/EtOAc, 98:2). Yel-
4.15.2. (S)-5-Benzyl-4-isopropyl-2-(1-methoxynaphthalen-2-
yl)-5,6-dihydro-4H-1,3,4-oxadiazine 21b
Yellow oil (24%).
½
a 2D4
ꢂ
¼ þ191:3 (c 1.21, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 1.17 (d, J = 6.4 Hz, 3H), 1.36 (d, J = 6.4 Hz,
3H), 2.78 (dd, J = 13.5, 9.8 Hz, 1H), 3.05 (dd, J = 13.5, 4.8 Hz, 1H),
3.45–3.51 (m, 1H), 4.01 (s, 3H), 4.05 (dd, J = 10.3, 2.8 Hz, 1H),
4.20 (dd, J = 10.3, 4.2 Hz, 1H), 7.20–7.33 (m, 1H), 7.42–7.49
(m, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.79–7.87
(m, 1H), 8.20–8.22 (m, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d:
18.3, 20.9, 34.8, 52.7, 53.8, 62.6, 66.2, 121.8, 122.8, 123.3, 125.9,
126.5, 126.6, 127.6, 128.5, 128.7, 129.3, 135.0, 138.0, 143.8,
154.3 ppm. IR (neat): 1686, 1448, 1213 cmꢀ1. ESI-HRMS calcd for
low oil (54%). ½a D24
ꢂ
¼ þ146:9 (c 1.03, CHCl3). 1H NMR (400 MHz,
CDCl3) d (ppm): 1.15 (d, J = 6.4 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H),
1.44 (s, 3H), 2.69 (dd, J = 13.6, 9.7 Hz, 1H), 3.04 (dd, J = 13.6,
5.0 Hz, 1H), 3.42–3.52 (m. 1H), 4.04 (dd, J = 10.4, 2.8 Hz, 1H), 4.15
(dd, J = 10.4, 4.6 Hz, 1H), 6.77 (t, J = 4.2 Hz, 1H), 7.19–7.29 (m,
7H), 7.49 (dd, J = 7.9, 1.75 Hz, 1H), 12.3 (s, 1H). 13C NMR (CDCl3,
100 MHz) d (ppm): 17.5, 21.0, 29.5, 34.5, 34.9, 52.3, 53.9, 66.4,
114.8, 117.4, 123.5, 126.7, 127.7, 128.7, 129.3, 136.7, 137.4,
147.8, 156.7. IR (neat): 3489, 1617, 1443 cmꢀ1. ESI-HRMS calcd
for C23H31N2O2 (M+H+): 367.2318. Found: 367.2314.
C
24H27N2O2 (M+H+): 375.2073. Found: 375.2066.
4.15.3. (S)-5-Benzyl-2-(3-tert-butyl-2-methoxyphenyl)-4-
isopropyl-5,6-dihydro-4H-1,3,4-oxadiazine 21c
Yellow oil (13%).
½
a 2D4
ꢂ
¼ þ156:1 (c 1.11, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 1.13 (d, J = 6.4 Hz, 3H), 1.30 (d, J = 6.4 Hz,
3H), 1.38 (s, 9H), 2.70 (dd, J = 13.5, 9.8 Hz, 1H), 3.05 (dd, J = 13.5,
4.8, 1H), 3.40–3.53 (m, 2H), 3.84 (s, 3H), 4.03 (dd, J = 11.4, 2.8 Hz,
1H), 4.18 (dd, J = 10.4, 4.8 Hz, 1H), 6.98 (t, J = 7.7 Hz, 1H), 7.20–
7.41 (m, 7H) ppm. 13C NMR (CDCl3, 100 MHz) d: 17.9, 20.6, 30.8,
35.1, 35.3, 52.4, 53.5, 60.7, 66.4, 122.5, 126.6, 127.0, 127.8, 128.6,
129.4, 129.5, 137.9, 142.8, 145.1, 158.0 ppm. IR (neat): 1686,
4.17. General procedure for the diethylzinc addition with
aldehydes
A chiral ligand of choice (0.313 mmol) was added to a flame
dried round bottomed flask with toluene (4.1 mL) in an inert atmo-
sphere. To the flask was added a solution of diethylzinc in hexanes
(1 M, 9.4 mL) and the mixture was allowed to stir at room temper-
ature for 25 min. An aldehyde of choice (3.13 mmol) was then
added and allowed to stir at room temperature for 24 h. The reac-
tion was quenched with HCl (1 M, 50 mL) and extracted with
CH2Cl2 (2 ꢁ 50 mL). The organic solution was washed with brine,
dried over (MgSO4), gravity filtered, and concentrated under re-
duced pressure to afford enantiomerically enriched alcohol. The
enantioselectivity of this process was immediately determined by
chiral stationary phase HPLC.
1448, 1213 cmꢀ1
.
ESI-HRMS calcd for C24H33N2O2 (M+H+):
381.2542. Found: 381.2537.
4.16. (S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-
oxadiazin-2-yl)-6-methylphenol 22a
In a flame dried, nitrogen purged flask were placed 21a (1.10 g,
3.25 mmol) and CH2Cl2 (32 mL). The reaction mixture was cooled
to 0 °C before the dropwise addition of 1 M BBr3 in toluene
(5.5 mL, 5.5 mmol). The reaction mixture was stirred overnight
and then quenched with H2O (75 mL). The organic layer was ex-
tracted with ether (2 ꢁ 50 mL) and washed with brine (50 mL).
The organic layer was dried over MgSO4 and the solvent was re-
moved by rotary evaporation. The title compound was isolated
by flash column chromatography (hexanes/EtOAc, 95:5). See 13b
for characterization data.
Acknowledgments
The authors acknowledge support for this work by the donors of
the Petroleum Research Fund as administered by the American
Chemical Society (PRF 48367-B1).
References
4.16.1. (S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-
oxadiazin-2-yl)naphthalen-1-ol 22b
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a flame dried, nitrogen purged flask 21b (0.147 g,
0.376 mmol) and CH2Cl2 (5 mL) were placed. The reaction mixture
was cooled to 0 °C before the dropwise addition of 1 M BBr3 in tol-
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ꢂ
¼ þ176:6 (c 0.89, CHCl3). 1H NMR (400 MHz, CDCl3)
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8.43 (m, 1H), 13.01 (s, 1H) ppm. 13C NMR (CDCl3, 100 MHz) d:
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