Synthesis of new chiral bidentate (phosphinophenyl)benzoxazine P,N- ligands

Article abstract of DOI:10.1002/(SICI)1522-2675(19990908)82:9<1360::AID-HLCA1360>3.0.CO;2-V

Two new chiral bidentate (phosphinophenyl)benzoxazine P,N-ligands 2a and 2b were synthesized from highly enantiomer-enriched 2-(1-aminoalkyl)phenols 4. Ligand rac-2a was obtained on refluxing the t-Bu-substituted (aminomethyl)phenol 4a with 2-(diphenylpho

Full text of DOI:10.1002/(SICI)1522-2675(19990908)82:9<1360::AID-HLCA1360>3.0.CO;2-V

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Helvetica Chimica Acta ± Vol. 82 (1999)
Synthesis of New Chiral Bidentate (Phosphinophenyl)benzoxazine
P,N-Ligands
by E. Peter Kündig* and Peter Meier
Â
Â
Á
Á
Departement de Chimie Organique, Universite de Geneve, 1211 Geneve 4; fax: ‡ 41223287396; e-mail:
Peter.Kundig@chiorg.unige.ch
Two new chiral bidentate (phosphinophenyl)benzoxazine P,N-ligands 2a and 2b were synthesized from
highly enantiomer-enriched 2-(1-aminoalkyl)phenols 4. Ligand rac-2a was obtained on refluxing the t-Bu-
substituted (aminomethyl)phenol 4a with 2-(diphenylphosphino)benzonitrile in chlorobenzene in the presence
of anhydrous ZnCl2 followed by decomplexation (Scheme 2). This reaction, when carried out with (‡)-(S)-4a,
was accompanied by racemization at the stereogenic center of the alkyl side chain. The enantiomerically pure
ligands (‡)-(R)-2a and ( )-(S)-2a were obtained using a stepwise procedure via the amides ( )-(R)- and (‡)-
(S)-5b, respectively, followed by cyclization to benzoxazines (‡)-(R)- and ( )-(S)-7b, respectively, with triflic
anhydride and by F-atom substitution by diphenylphosphide (Schemes 3 and 5). In the case of the i-Pr analogue
2b, this last step resulted in racemization (Scheme 6). This was overcome by preparing the bromo derivative and
introducing the diphenylphosphine group via Br/Li exchange and reaction with chlorodiphenylphosphine
(Scheme 7). The first application of (‡)-(R)-2a in an asymmetric Heck reaction showed high enantioselectivity
(91%) (Scheme 8).
1. Introduction. ± Bidentate chiral dihydro(phosphinoaryl)oxazole ligands 1 are
readily obtained from 2-aminoalkan-1-ols. They have been applied highly successfully
in a number of catalytic reactions including allylic substitution [1], Heck reaction [2],
hydrogenation [3], hydrosilylation [4], and Diels-Alder reaction [5]. Given the success
and popularity of ligands 1, it is surprising that the use of the six-membered analogues is
scarce [6]. The prime reason would appear to be the lack of natural sources of the
requisite chiral 3-aminoalkan-1-ols, in marked contrast to the abundance of enantio-
merically pure 2-aminoalkan-1-ols derived from the chiral pool (amino acids,
ephedrins). In this article, we report the synthesis of the chiral ligands 2, which differ
from ligands 1 by having, in place of the five-membered dihydrooxazole ring, a benzo-
fused six-membered 4H-oxazine ring.
A two-dimensional drawing suggests that the group R at the stereogenic center
is closer to the metal in complex [M(2)] with the six-membered 5,6-dihydro-4H-
oxazine ligand than in complex [M(1)] with the five-membered dihydrooxazole
ligand and that R, therefore, could exert a larger influence on the stereochemical
outcome of reactions at the metal center. However, while the dihydrooxazoles
are almost flat, the 4H-oxazines have chair- and boat-like conformations, and
this flexibility may be detrimental to their use as chiral inductors. An efficient
way to reduce the number of conformations is ring fusion. This approach has
been used successfully by Evans and coworkers, who applied the pinene-
derived 4H-oxazine ligand 3 in Pd-catalyzed asymmetric allylic substitution reactions
[6].

Helvetica Chimica Acta ± Vol. 82 (1999)
1361
We chose fusion of the 4H-oxazine ring to an aromatic ring to render the
heterocyclic system rigid, and this required chiral enantiomerically pure 2-(1-amino-
alkyl)phenols 4 as starting materials (Scheme 1). Like the known 1-aminoethyl
analogue 4c [7], the chiral (aminoalkyl)phenols 4a and 4b were obtained via resolution
with mandelic acid (ˆa-hydroxybenzeneacetic acid) [8]. Alternatively, compounds 4
are accessible by diastereoselective syntheses from chiral imine precursors [8][9].
Scheme 1
In the following, we first describe the synthesis of 4-(tert-butyl)-2-[2-(diphenyl-
phosphino)phenyl]-4H-1,3-benzoxazine (2a) and then that of 2-[2-(diphenylphosphi-
no)phenyl]-4-isopropyl-4H-1,3-benzoxazine (2b).
2. Results and Discussion. ± According to a literature procedure for the analogous
dihydrooxazole ligands 1 [10], racemic (aminoalkyl)phenol rac-4a, 2-(diphenylphos-
phino)benzonitrile, and ZnCl2 were refluxed in chlorobenzene. The reaction was very
sluggish, and yielded, after 10 days reaction time and ligand exchange at the Zn-center
with 2,2'-bipyridine, the expected ligand rac-2a in 41% yield. The same reaction, when
carried out with highly enantiomer-enriched (‡)-(S)-4a (> 96% ee), again yielded 2a
in racemic form (Scheme 2).

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Helvetica Chimica Acta ± Vol. 82 (1999)
Scheme 2
Racemization at the stereogenic center of the alkyl side chain had thus occurred
under the harsh reaction conditions required for the oxazine-ring synthesis. A sample
of enantiomerically pure 2a was obtained by prep. HPLC with the chiral column
Chiralpak AD1). Preliminary tests of this ligand in the asymmetric Heck reaction gave
promising results (vide infra), and we therefore focused on milder, stepwise synthetic
procedures via the amides 5. Compounds 5 were readily obtained in nearly quantitative
yields (Scheme 3), but their cyclization to the oxazines 7 with thionyl chloride, a
procedure commonly used for the synthesis of dihydrooxazoles [11], failed to give
satisfactory results (Table, Entry 1). An alternative procedure, i.e., reaction with POCl3
and pyridine followed by NaOH treatment, gave better results, but was not satisfactory
with the 2-fluorobenzamide 5b (Entries 2 and 3). Not surprisingly, the cyclization
methods that work well for substrates containing a primary-alcohol group could not be
Scheme 3
1
)
The preparative-scale separation of the enantiomers of rac-2a was carried out at Novartis Inc. (separation
laboratories headed by E. Francotte).

Helvetica Chimica Acta ± Vol. 82 (1999)
1363
Table 1. Synthesis of 2-Aryl-4H-1,3-benzoxazines 7
R' Reaction conditions
Entry 5 (Yield [%])
R
7 (Yield [%])
7b (ꢀ 10)
1
2
3
4
5
6
5ba) (99)
5aa) (100)
5ba) (100)
5ba) (100)
5ca) (99)
5db) (86)
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
F
H
F
F
I
1) SOCl2, CH2Cl2, 208, 1 d; 2) NaOH
1) POCl3, CH2Cl2, 408, 1 h; 2) Py, 208, 20 h; 3) NaOH 7a (60)
1) POCl3, CH2Cl2, 408, 1 h; 2) Py, 208, 90 h; 3) NaOH 7b (32)
1) Tf 2O, CH2Cl2, 08, 0.3 h; 2) Et3N, 08 ! 208, 1 h
1) Tf 2O, CH2Cl2, 08, 0.3 h; 2) Et3N, 08 ! 208, 1 h
1) Tf 2O, CH2Cl2, 788 ! 08; 2) Et3N, 308 ! 08
7b (64)
7c (77)
7d (< 23)
F
a) Prepared from the corresponding chloride. b) Prepared from 2-fluoro-N-[1-(2-methoxyphenyl)-2-methyl-
propyl]benzamide, followed by demethylation with BBr3.
readily applied to the phenol derivatives 5. Whereas in the former case, hydroxy
activation is followed by nucleophilic displacement by the amide O-atom, cyclization of
5 involves the reverse mode of reaction: the phenolate moiety attacks at an imidate
intermediate 6 (Scheme 3). We, therefore, turned to triflic anhydride (ˆtrifluoro-
methanesulfonic anhydride), known to efficiently form the imidate triflate 6 (E ˆ Tf)
[12]. Indeed, treatment of the racemic amide rac-5b with triflic anhydride, followed by
addition of Et3N, afforded 2-(2-fluorophenyl)-1H-1,3-benzoxazine (rac-7b) in 64%
yield (Entry 4). This method was also used to prepare highly enantiomer-enriched
( )-(S)- and (‡)-(R)-7b and rac-7c (Entry 5).
Introduction of the PPh2 group at the phenyl substituent of 7 was first tried by the
ortho-lithiation procedure applied to 7a, analogously to the method used for phenyl-
dihydrooxazoles [13] (Scheme 4). This approach did not work though in the case at
hand, and we note a literature precedent of a similar example with a t-Bu substituent at
a dihydrooxazole ring [14].
Scheme 4
a) 1. BuLi (1.1 equiv.), TMEDA (1.1 equiv.), THF, 788, 2 h; 2. ClPPh2 (2 equiv.). b) Ph2HP ´ BH3 (3 equiv.),
K2CO3 (2 equiv.), [Pd(PPh3)4 (5 mol-%), MeCN/THF, reflux, 60 h. c) t-BuOK (1.1 equiv.), HPPh2
(1.1 equiv.), [18]crown-6 (1.3 equiv.), THF, 08 to r.t., 21 h.

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Helvetica Chimica Acta ± Vol. 82 (1999)
Pd(0)-Catalyzed coupling of 4-(tert-butyl)-2-(2-iodophenyl)-4H-1,3-benzoxazine
and HPPh2 ´ BH3 [15] gave a moderate yield of the borane complex of 2a. This route
was not further pursued since the product, a mixture of the N-borane and the P-borane
adduct of 2a, resisted borane removal by Et2NH or by HBF4, and because at that stage,
another route (see c in Scheme 4) had been successful.
Nucleophilic aromatic substitution of the F-atom in (2-fluorophenyl)dihydroox-
azole by either LiPPh2 or KPPh2 has been reported [16]. Accordingly, rac-7b was first
reacted with LiPPh2; but on finding that this afforded only traces of 2a, we turned to
the more reactive KPPh2. The latter was prepared in situ from t-BuOK and HPPh2, and
its reaction with rac-7b at room temperature gave rac-2a in 43% yield. The yield was
increased to 71% when 2 equiv. of KPPh2 were used, and to 79% with 1.1 equiv. of
KPPh2 in the presence of 1.3 equiv. of [18]crown-6 (Scheme 4). This procedure was also
applied to enantiomerically enriched (‡)-(R)-7b as shown in Scheme 5. HPLC Analysis
of the obtained (‡)-(R)-2a confirmed that no racemization had occurred in any of the
steps from the starting (aminoalkyl)phenol ( )-(R)-4a.
Scheme 5
In extension of the synthesis of ligand 2a, we undertook the preparation of the i-Pr
analogue 2b by the same methodology. However, cyclization of the i-Pr-substituted
amide 5d to the (2-fluorophenyl)benzoxazine 7d (Scheme 3) with triflic anhydride and
Et3N gave low yields (ꢀ 25%). This could be overcome by extending a recently
reported protocol for dihydrooxazole synthesis to the oxazines [17]. Refluxing 2-
fluorobenzoic acid triethyl orthoester 8 and the (aminoalkyl)phenol (‡)-(S)-4b in 1,2-
dichloroethane in the presence of AcOH afforded the benzoxazine ( )-(S)- 7d in 84%
yield (Scheme 6). The drawback here is the synthesis of the triethyl orthoester 8. Under
the same conditions that were reported for the synthesis of benzoic acid triethyl
orthoester (71% yield [18]), a,a,a-trichloro-2-fluorotoluene gave a product mixture
from which the triethyl orthoester 8 was isolated in only 7% yield. Shorter reaction
times led to incomplete Cl-substitution, while F-substitution became a problem at
longer reaction times.
We were dismayed, however, to find that the substitution of the F-atom of ( )-(S)-
7d by diphenylphosphine with potassium diphenylphosphide was accompanied by
racemization at the stereogenic center C(4). A number of other attempts to synthesize
highly enantiomer-enriched 2b, e.g., the synthesis of 2-(diphenylphosphino)benzoic
acid orthoester, Stille coupling of 4-isopropyl-2-(trimethylstannyl)-4H-1,3-benzoxazine
with 2-(bromodiphenylphosphino)benzene, and nucleophilic substitution of 2-ethoxy-

Helvetica Chimica Acta ± Vol. 82 (1999)
1365
Scheme 6
4-isopropyl-4H-1,3-benzoxazine by 2-(diphenylphosphino)phenyllithium, were all
unsuccessful. Finally it was found that Br/Li exchange in (R)-2-(2-bromophenyl)-4-
isopropylbenzoxazine (‡)-(R)-7e, followed by reaction with chlorodiphenylphosphine,
provided a viable route to (R)-2-[2-(diphenylphosphino)phenyl]-4-isopropylbenzox-
azine (‡)-(R)-2b (Scheme 7). No racemization occurred, but reaction conditions have
not yet been optimized. The oxazine (‡)-(R)-7e was synthesized from 2-bromobenz-
amide, Meerweinꢀs salt, and the (aminoalkyl)phenol ( )-(R)-4b [19].
Scheme 7
The first application of (‡)-(R)-2a in the asymmetric Heck reaction is promising:
2,3-dihydrofuran and phenyl triflate (ˆ phenyl trifluoromethanesulfonate) reacted in
the presence of 5 mol-% of (‡)-(R)-2a, 1.5 mol% of [Pd2(dba)3 ´ dba] (dba ˆ diben-
zylidene acetone) and 2 equiv. of (i-Pr)2EtN to give ( )-(S)-9 in 79% yield and with an
enantiomeric excess of 91% (Scheme 8).
3. Conclusions. ± Syntheses of the new chiral 4-(tert-butyl)- and 4-isopropyl-
substituted 2-[2-diphenylphosphino)phenyl]-4H-1,3-benzoxazine ligands 2a and 2b,
respectively, starting with highly enantiomer-enriched (aminoalkyl)phenols 4, have

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Helvetica Chimica Acta ± Vol. 82 (1999)
Scheme 8
been developed. The first application of the ligand (‡)-(R)-2a in the asymmetric Heck
reaction of 2,3-dihydrofuran and phenyl triflate led to product ( )-(S)-9 in 79% yield
and with 91% ee. Further applications in the areas of Heck reactions, Pd-catalyzed
allylic substitutions, iridium-catalyzed hydrogenation, hydrosilylation, and in Lewis-
acid-catalyzed Diels-Alder reactions are in progress, in collaboration with Prof. A.
Pfaltz, Basel.
Experimental Part
1. General. Reactions were carried out under purified N2 with an inert gas/vacuum double manifold and
standard Schlenk techniques. THF and Et2O were dried and distilled from Na/benzophenone, and CH2Cl2 and
chlorobenzene from CaH2 under N2 before use. All other chemicals were purchased from Aldrich or Fluka and
were purified following standard literature procedures. All glassware was flame-dried prior to use. TLC: Merck
SIL G/UV254; detection by UV/VIS or 2% KMnO4/4% NaHCO3 soln. Flash column chromatography (FC):
silica gel Merck 60. HPLC: Jasco PU-980; Chiralpak AD, 25 cm; detection at 254 nm; tR in min. GC: Hewlett-
Packard-HP-6890 instrument; FS-595-(t-Bu)Me2Si-b-CD/SE-54 capillary column [20]; tR in min. Melting
points: Büchi 510; uncorrected. Optical rotations: Perkin-Elmer-241 polarimeter; 10-cm cell. UV/VIS:
1
Uvikon 860; l in nm (log e). CD: Jasco J-715; l in nm ([De]). IR: Perkin-Elmer FT-IR 1650; nÄ in cm
.
NMR: Varian-XL-200 or Bruker 400 MHz, d in ppm rel. to internal SiMe4 or to the signal of the residual solvent
(19F: C6F6, external reference; 31P: H3PO4, external reference), J in Hz. MS: Varian CH4 or SM1; ionizing
voltage 70 eV; m/z (intensity in %). HR-MS: VG anal. 7070E (data system 11250, resolution 7000). Elemental
Â
analyses were performed by Dr. H.J. Eder, Service de Microchimie, Departement de Chimie Pharmaceutique,
Â
Á
Universite de Geneve.
2. rac-4-(tert-Butyl)-2-[2-(diphenylphosphino)phenyl]-4H-1,3-benzoxazine (rac-2a), using ZnCl2. (‡)-(S)-
4a (707 mg, 3.94 mmol), 2-(diphenylphosphino)benzonitrile (863 mg, 3.00 mmol), and freshly dried ZnCl2
(533 mg, 3.91 mmol) in chlorobenzene (10 ml) were refluxed for 10 d. The mixture was poured directly onto a
column (silica gel) and eluted with Et2O/hexane 1 :4 to give, after evaporation, a yellow solid (887 mg). The
solid was dissolved in CHCl3 (15 ml), 2,2'-bipyridine (247 mg, 1.58 mmol) added, and the soln. stirred for 1 h at
r.t. After filtration through a short column (silica gel, 3 Â 4 cm) and washing of the column with CHCl3 (100 ml),
the soln. was evaporated and the residue purified by FC (silica gel, AcOEt/hexane 1 : 2): 2a (551 mg, 41%).
White powder. M.p. 1308. TLC: Rf 0.6 (Et2O/hexane 1 : 2). UV (EtOH): 216 (2.80). IR (CHCl3): 3059w,
2961m, 2384m, 1674m, 1488m, 1215s. 1H-NMR (400 MHz, CDCl3): 0.94 (s, 9 H); 4.35 (s, 1 H); 6.52 (dd, J ˆ 7.6,
1.6, 1 H); 6.97 ± 7.47 (m, 16 H); 7.88 ± 8.02 (m, 1 H). 13C-NMR (100 MHz, CDCl3): 26.1; 38.2; 64.7; 115.4; 123.8;
127.6; 128.2; 128.3; 128.3; 128.4; 128.5; 129.7 (d, J ˆ 4.4); 130.2, 133.8 (d, J ˆ 19.8); 134.0 (d, J ˆ 20.3); 134.6;
134.7; 137.4 (d, J ˆ 21.9); 137.9 (d, J ˆ 11.2); 138.2 (d, J ˆ 11.3); 149.9; 153.5. 31P-NMR (162 MHz, CDCl3): 7.7
‡
(97%); 29.8 (3%, P-oxide of 2a). MS: 449 (36, M ), 434 (61), 392 (58), 372 (100), 286 (17), 208 (12), 183 (20),
‡
‡
77 (11), 51 (10). HR-MS: 449.19164 (M , C30H28NO2P ; calc. 449.19086). Anal. calc. for C30H28NO2P: C 80.15,
H 6.27, N 3.12; found: C 79.92, H 6.19, N 3.08.
3. rac-N-[1-(2-Hydroxyphenyl)-2,2-dimethylpropyl]benzamide (rac-5a). To rac-4a (896 mg, 5.0 mmol) in
CH2Cl2 (15 ml), benzoyl chloride (0.581 ml, 703 mg, 5.0 mmol) was added at 08. Et3N (0.760 ml, 555 mg,
5.48 mmol) was added slowly, and the soln. was stirred for 32 h at r.t. The mixture was poured onto a short silica
gel column (2 Â 7 cm). Elution with AcOEt and evaporation gave rac-5a (1.40 g, 99%). White solid. M.p. 90 ±
948. TLC (CH2Cl2/AcOEt 10 : 1): Rf 0.36. IR (CHCl3): 3278w, 2968m, 1652s, 1523s, 1487m, 1455w, 1357w, 1246w.
1H-NMR (400 MHz, (D6)DMSO): 0.90 (s, 9 H); 5.46 (s, 1 H); 6.74 (t, J ˆ 7.5, 1 H); 6.79 (d, J ˆ 8.0, 1 H); 7.03

Helvetica Chimica Acta ± Vol. 82 (1999)
1367
(td, J ˆ 7.1, J ˆ 1.3, 1 H); 7.38 ± 7.56 (m, 4 H); 7.76 (d, J ˆ 7.1, 2 H); 8.31 (d, J ˆ 8.4, 1 H); 9.52 (s, 1 H).
13C-NMR (100 MHz, (D6)DMSO): 26.7; 36.1; 53.9; 115.2; 118.3; 127.3; 127.5; 128.2; 129.1; 129.6; 130.9; 135.3;
‡
‡
154.8; 166.1. MS: 283 (7, M ), 226 (88), 147 (11), 121 (15), 105 (100), 77 (81), 51 (20). HR-MS: 283.1580 (M ,
‡
C18H21NO2 ; calc. 283.1572).
4. rac-2-Fluoro-N-[1-(2-hydroxyphenyl)-2,2-dimethylpropyl]benzamide (rac-5b). To rac-4a (358 mg,
2.0 mmol) in CH2Cl2 (3 ml), 2-fluorobenzoyl chloride (0.237 ml, 318 mg, 2.0 mmol) was added at 08. Et3N
(0.291 ml, 212 mg, 2.1 mmol) was added slowly, and the soln. was stirred for 24 h at r.t. The mixture was poured
onto a short silica gel column (2 Â 5 cm). Elution with AcOEt and evaporation gave rac-5b (601 mg, 100%).
White foam. M.p. 178 ± 1808. IR (CHCl3): 3301w, 2965m, 1655s, 1528vs, 1481m, 1455w, 1356w, 1292w, 1235w.
1H-NMR (400 MHz, CDCl3): 1.05 (s, 9 H); 5.36 (d, J ˆ 7.8, 1 H); 6.71 ± 7.53 (m, 6 H); 8.02 ± 8.17 (m, 2 H).
13C-NMR (100 MHz, CDCl3): 27.1; 36.6; 64.4; 116.5; 116.8; 117.3; 120.5; 125.5; 126.8; 128.9; 133.1; 134.0 (d, J ˆ
‡
9.2); 155.4; 160.5; 163.0; 164.0 (d, J ˆ 0.4). 19F-NMR (376 MHz, CDCl3): 49.9. MS: 244 (96, [M t-Bu] ), 226
‡
‡
(11), 123 (100), 95 (23), 57 (17). HR-MS: 301.1472 (M , C18H20FNO2 ; calc. 301.1478).
According to the procedure described for rac-5b, (‡)-(S)-4a (1.793 g, 10.0 mmol), 2-fluorobenzoyl chloride
(1.183 ml, 1.59 g, 10.0 mmol), and Et3N (1.46 ml, 1.07 g, 10.5 mmol) gave (‡)-(S)-5b (3.04 g, 100%). M.p. 187 ±
1908. [a]D21 ˆ‡ 61.6 (c ˆ 0.56, CHCl3).
According to the procedure described for rac-5b, ( )-(R)-4a (3.589 g, 20.0 mmol), 2-fluorobenzoyl
chloride (2.37 ml, 3.17 g, 20.0 mmol), and Et3N (2.91 ml, 2.12 g, 21.0 mmol) gave ( )-(R)-5b (6.01 g, 100%).
M.p. 185 ± 1928. [a]2D1
ˆ
62.3 (c ˆ 0.75, CHCl3).
5. rac-N-[1-(2-Hydroxyphenyl)-2,2-dimethylpropyl]-2-iodobenzamide (rac-5c). According to the proce-
dure described for rac-5b, rac-4a (539 mg, 3.01 mmol), 2-iodobenzoyl chloride (804 mg, 3.02 mmol), and Et3N
(0.437 ml, 319 mg, 3.15 mmol) gave rac-5c (1.222 g, 99%). M.p. 82 ± 838. TLC (AcOEt): Rf 0.8. IR (CHCl3):
3282w, 3003w, 2967m, 1742w, 1656s, 1586w, 1509s, 1458m, 1360w, 1290w, 1215s. 1H-NMR (200 MHz, CDCl3):
1.02 (s, 9 H); 5.17 (d, J ˆ 9.7, 1 H); 6.75 ± 6.87 (m, 2 H); 7.00 ± 7.16 (m, 3 H); 7.26 ± 7.36 (m, 2 H); 7.81 (d, J ˆ
8.0, 1 H). 13C-NMR (100 MHz, CDCl3): 27.3; 36.9; 60.4; 92.4; 116.7; 119.8; 128.1; 128.1; 128.2; 128.3; 131.0;
‡
‡
140.0; 142.5; 154.2; 169.1. MS: 409 (1, M ), 352 (55), 231 (100), 203 (13), 76 (13). HR-MS: 409.0537 (M ,
C18H20INO2 ; calc. 409.0539).
‡
6. rac-2-Fluoro-N-[1-(2-hydroxyphenyl)-2-methylpropyl]benzamide (rac-5d). At 08, 1-(2-methoxyphenyl)-
2,2-dimethylpropylamine (365 mg, 2.04 mmol) and 2-fluorobenzoyl chloride (0.237 ml, 318 mg, 2.00 mmol)
were stirred for 5 min. Et3N (0.291 ml, 212 mg, 2.10 mmol) was added, and the mixture was stirred for 21 h at r.t.
and then poured onto a silica gel column. Elution with AcOEt/hexane 1:2 and evaporation gave a colorless oil,
which was dissolved in CH2Cl2 (5 ml) and treated at 788 with BBr3 (0.580 ml, 1.51 g, 6.0 mmol). The yellow
soln. was allowed to warm to r.t. and then added to 1n NaOH (50 ml) at 08. Conc. HCl soln. was added until pH 6
was reached. The aq. layer was extracted wtih CH2Cl2 (3 Â 20 ml) and the combined org. layer dried (MgSO4)
and evaporated. rac-5d (491 mg, 86%). White solid. M.p. 138 ± 1408. IR (CHCl3) 3449w, 3180w, 3017s, 2964w,
1637s, 1528s, 1313w, 1281w, 1199m, 672s. 1H-NMR (400 MHz, CDCl3): 0.89 (d, J ˆ 6.9, 3 H); 1.20 (d, J ˆ 6.7,
3 H); 2.42 (sept. d, J ˆ 10.3, 6.9, 1 H); 4.93 ± 5.00 (m, 1 H); 6.86 ± 6.98 (m, 2 H); 7.08 ± 7.28 (m, 3 H); 7.38 ± 7.53
(m, 2 H); 8.05 ± 8.13 (m, 1 H). 13C-NMR (100 MHz, CDCl3): 20.2; 20.4; 30.9; 55.7; 115.9; 116.1; 118.2; 120.2;
120.5; 124.9; 127.3; 128.8; 132.3; 133.7; 133.8; 155.2; 159.6; 162.0; 164.2. 19F-NMR (376 MHz, CDCl3): 50.4. MS:
‡
‡
‡
287 (2, M ), 244 (40), 123 (100), 95 (16). HR-MS: 287.1329 (M , C17H18FNO2 , calc. 287.1322). Anal. calc. for
C17H18FNO2: C 71.06, H 6.31, N 4.87; found: C 70.47, H 6.39, N 4.66.
7. rac-4-(tert-Butyl)-2-phenyl-4H-1,3-benzoxazine (rac-7a). To a soln. of rac-5a (284 mg, 1.00 mmol) in
CH2Cl2 (10 ml) at 408, POCl3 (0.091 ml, 153 mg, 1.0 mmol) was added and the mixture stirred for 30 min.
Pyridine (0.480 ml, 470 mg, 6.0 mmol) was added next, and stirring was continued for 15 min at 408 and for
20 h at r.t. Then, 1n NaOH (20 ml) was added, the yellow mixture stirred for 15 min and extracted with Et2O
(3 Â 10 ml), and the combined org. phase dried (MgSO4) and evaporated. FC (AcOEt/hexane 1 : 20) yielded
rac-7a (160 mg, 60%). Colorless oil. IR (CHCl3): 2964s, 2873w, 1666s, 1584w, 1486m, 1457w, 1352w, 1245m,
1193m, 1094m, 1068w, 1025w, 909w, 697m. 1H-NMR (400 MHz, CDCl3): 1.01 (s, 9 H); 4.49 (s, 1 H); 7.08 ± 7.18
(m, 3 H); 7.26 ± 7.33 (m, 1 H); 7.43 ± 7.54 (m, 3 H); 8.14 (d, J ˆ 1.7, 2 H). 13C-NMR (100 MHz, CDCl3): 26.0,
38.7; 64.5; 115.4; 121.4; 123.9; 127.7; 127.7; 127.9; 128.3; 128.3; 128.5; 131.1; 132.0; 150.2; 152.5. MS: 265 (0.4,
‡
‡
‡
M ), 208 (100), 105 (16), 77 (30), 51 (27). HR-MS: 208.0758 ([M t-Bu] , C14H10NO ; calc. 208.0762).
8. rac-4-(tert-Butyl)-2-(2-fluorophenyl)-4H-1,3-benzoxazine (rac-7b). rac-5b (452 mg, 1.5 mmol) was
dissolved in CH2Cl2 (15 ml) at 08. Triflic anhydride (0.271 ml, 466 mg, 1.65 mmol) was added slowly, and the
soln. was stirred for 20 min at 08. Et3N (0.48 ml, 350 mg, 3.5 mmol) was added, and the soln. was stirred for 1 h at
r.t. Evaporation followed by FC (Et2O/pentane 1:10) gave rac-7b (274 mg, 64%). Colorless oil. TLC (Et2O/
hexane 1 :20): Rf 0.20. IR (CHCl3): 3018m, 2961s, 1672s, 1613w, 1488m, 1456m, 1352w, 1216s, 1115w. 1H-NMR

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Helvetica Chimica Acta ± Vol. 82 (1999)
(200 MHz, CDCl3): 1.02 (s, 9 H); 4.48 (s, 1 H); 6.99 ± 7.50 (m, 7 H); 7.80 ± 7.90 (m, 1 H). 13C-NMR (50 MHz,
CDCl3): 26.0; 38.6; 65.0; 115.4; 116.7 (d, J ˆ 21.7); 121.1; 123.9 (d, J ˆ 3.9); 124.1; 128.0; 128.5; 130.8 (d, J ˆ 1.7);
‡
132.3 (d, J ˆ 8.5); 150.2; 163.7. 19F-NMR (376 MHz, CDCl3): 51.6. MS: 284 (6, [M ‡ H] ), 226 (98), 123 (36),
‡
‡
105 (40), 95 (13), 91 (13), 77 (93), 57 (27), 51 (100). HR-MS: 283.1370 (M , C18H18FNO ; calc. 283.1372).
According to the procedure described for rac-7b, (‡)-(S)-5b (2.968 g, 9.85 mmol), triflic anhydride
(1.78 ml, 3.06 g, 10.8 mmol), and Et3N (3.14 ml, 2.29 g, 22.7 mmol) gave ( )-(S)-7b (2.15 g, 77%). [a]2D1
(c ˆ 1.53, CHCl3).
ˆ
41.6
According to the procedure described for rac-7b, ( )-(R)-5b (6.012 g, 20.0 mmol), triflic anhydride
(3.43 ml, 5.90 g, 20.9 mmol), and Et3N (6.07 ml, 4.43 g, 43.8 mmol) gave (‡-(R)-7b (4.45 g, 78%). [a]D21 ˆ‡ 45.9
(c ˆ 1.09, CHCl3).
9. rac-4-(tert-Butyl)-2-(2-iodophenyl)-4H-1,3-benzoxazine (rac-7c). According to the procedure described
for rac-7b, rac-5c (613 mg, 1.50 mmol), triflic anhydride (0.260 ml, 450 mg, 1.58 mmol), and Et3N (0.440 ml,
321 mg, 3.17 mmol) gave rac-7c (454 mg, 77%). M.p. 97 ± 998. TLC (Et2O/pentane 1:5): Rf 0.23. IR (CHCl3):
2967m, 1677m, 1486w, 1351w, 1294w, 1214s, 1190m, 1097w. 1H-NMR (400 MHz, CDCl3): 1.08 (s, 9 H); 4.55
(s, 1 H); 7.12 ± 7.24 (m, 4 H); 7.29 ± 7.36 (m, 1 H); 7.47 (t, J ˆ 7.4, 1 H); 7.70 (d, J ˆ 7.4, 1 H); 7.94 (d, J ˆ 7.9,
1 H). 13C-NMR (100 MHz, CDCl3): 26.2; 38.7; 64.7; 94.2; 116.0; 121.0; 125.1; 128.4; 128.8; 132.1; 132.3; 133.9;
‡
‡
‡
134.5; 139.8; 140.6; 150.2. MS: 391 (1, M ), 334 (100), 77 (11), 51 (15). HR-MS: 391.0404 (M , C18H18INO ;
calc. 391.0433). Anal. calc. for C18H18INO: C 55.26, H 4.64, N 3.58; found: C 55.32, H 4.65, N 3.44.
10. rac-4-(tert-Butyl)-2-[2-(diphenylphosphino)phenyl]-4H-1,3-benzoxazine (rac-2a) from rac-7b. To a
soln. of t-BuOK (120 mg, 1.07 mmol) and [18]crown-6 (332 mg, 1.26 mmol) in THF (6 ml) at 08, diphenyl-
phosphine (0.183 ml, 198 mg, 1.06 mmol) was added, and the resulting orange soln. was stirred for 1 h at 08. A
soln. of rac-7b (274 mg, 0.967 mmol) in THF (1 ml) was added slowly, and the mixture was stirred for 20 h at r.t.
After evaporation, MeOH (2 ml) was added, the resulting suspension stirred for 5 min and the evaporated, and
the residue purified by FC (CH2Cl2): rac-2a (342 mg, 79%). White solid. HPLC (Chiralpak AD; 25 cm; hexane/
i-PrOH 95 :5, 0.5 ml min 1; detection at 254 nm): tR 9.2 (S) and 12.4 (R).
According to the procedure described for rac-2a, t-BuOK (920 mg, 8.20 mmol), [18]crown-6 (2.563 g,
9.70 mmol), diphenylphosphine (1.41 ml, 1.52 g, 8.18 mmol), and ( )-(S)-7b (2.10 g, 7.41 mmol) gave ( )-(S)-
2a (2.22 g, 67%). M.p. 61 ± 638. [a]2D1
ˆ
111 (c ˆ 0.78, CHCl3; >98% ee by HPLC). CD (89.0 mm, EtOH): 226
(‡ 15.40, max.), 245 ( 2.39, min.), 287 ( 2.74, min.). HPLC (hexane/i-PrOH 95 : 5, 0.5 ml min 1): 9.3 (S) and
12.5 (R).
According to the procedure described for rac-2a, t-BuOK (1.93 mg, 17.2 mmol), [18]crown-6 (5.39 g,
20.4 mmol), diphenylphosphine (2.98 ml, 3.22 g, 17.3 mmol), and (‡)-(R)-7b (4.45 g, 15.7 mmol) gave (‡)-(R)-
2a (5.74 g, 81%). M.p. 60 ± 628. [a]D21 ˆ‡ 110 (c ˆ 0.87, CHCl3; >99% ee by HPLC). CD (91.2 mm, EtOH): 225
(
13.38, min.), 245 (‡ 1.57, max.), 289 (‡ 1.89, max.). HPLC (hexane/i-PrOH 95 : 5, 0.5 ml min 1): 12.7 (R);
the other enantiomer was not detected.
11. 2-Fluorobenzoic Acid Triethyl Orthoester (ˆ 1-Fluoro-2-(triethoxymethyl)benzene) (8). Small pieces of
Na (3.82 g, 166 mmol) were added to dry EtOH (40 ml). When all the Na had reacted, a,a,a-trichloro-2-
fluorotoluene (7.4 ml, 11 g, 50 mmol) was added, and the resulting soln. was heated to reflux for 20 h. The soln.
was allowed to cool to r.t. and filtered over Celite. The solvent was evaporated and the residue distilled twice to
afford 8 (854 mg, 7%). Colorless liquid. B.p. 65 ± 758/0.3 mbar. IR (CHCl3): 3019w, 2981w, 2933w, 2896w, 1615w,
1586w, 1485w, 1451m, 1392w, 1281m, 1241m, 1087s, 1060s. 1H-NMR (200 MHz, C6D6): 1.14 (t, J ˆ 7.2, 9 H); 3.51
(q, J ˆ 7.2, 6 H); 6.82 ± 7.00 (m, 3 H); 7.86 (td, J ˆ 7.0, 2.0, 1 H). 13C-NMR (50 MHz, C6D6): 15.1; 57.9; 113.1;
116.5 (d, J ˆ 22.1); 123.4 (d, J ˆ 3.8); 130.7 (d, J ˆ 6.7); 131.1 (d, J ˆ 3.1); 160.8 (d, J ˆ 253.0). 19F-NMR
‡
(376 MHz, C6D6): 51.8. MS: 242 (0.5, M ), 197 (92), 169 (309), 141 (100), 123 (62), 95 (16). HR-MS: 197.0978
‡
‡
([M OEt] , C11H14FO2 ; calc. 197.0987).
12. )-(S)-2-(2-Fluorophenyl)-4-isopropyl-4H-1,3-benzoxazine (( )-(S)-7d). (S)-4b ´ AcOH (454 mg,
(
2.02 mmol) and 8 (602 mg, 2.5 mmol) were heated under reflux for 22 h in 1,2-dichloroethane (10 ml). Sat.
NaHCO3 soln. (20 ml) was added at r.t. The aq. phase was extracted with CH2Cl2 (3 Â 15 ml), the combined org.
phase dried (Na2SO4) and evaporated, and the residue purified by FC (AcOEt/hexane 1 : 10): ( )-(S)-7d
(451 mg, 84%). Colorless oil. [a]2D1
(CHCl3): 3450w, 3018s, 2965s, 2875w, 1672s, 1615m, 1586w, 1525m, 1489s, 1456s, 1419w, 1359m, 1304m,
ˆ
68.1 (c ˆ 0.42, CHCl3). TLC (AcOEt/hexane 1 : 10): Rf 0.49. IR
1
1232s, 1193s, 1110m, 1061m, 908m, 783w, 729m, 666s. H-NMR (200 MHz, CDCl3): 0.91 (d, J ˆ 6.8, 3 H); 1.09
(d, J ˆ 6.8, 3 H); 2.15 (sept. d, J ˆ 6.8, 4.0, 1 H); 4.71 (d, J ˆ 4.0, 1 H); 6.97 ± 7.18 (m, 7 H); 7.76 (td, J ˆ 7.4, 1.5,
1 H). 13C-NMR (100 MHz, CDCl3): 17.0; 18.6; 36.3; 60.2; 115.3; 116.7 (d, J ˆ 5); 121.8; 123.9; 123.9;
124.8; 126.6; 128.0; 130.7; 149.6; 159.7; 162.3; 163.1 (d, J ˆ 257). 19F-NMR (376 MHz, CDCl3): 51.7. MS: 269

Helvetica Chimica Acta ± Vol. 82 (1999)
1369
‡
‡
‡
(1, M ), 226 (87), 121 (100), 105 (12), 94 (36), 84 (27), 57 (18). HR-MS: 269.1201 (M , C17H16FNO ; calc.
269.1216).
13. rac-2-(2-Bromophenyl)-4-isopropyl-4H-1,3-benzoxazine (rac-7e). At r.t., 1.0m triethyloxonium tetra-
fluoroborate in CH2Cl2 (1.0 ml) was added to a soln. of 2-bromobenzamide (201 mg, 1.0 mmol) in 1,2-
dichloroethane (10 ml), and the soln. was stirred for 14 h. After addition of rac-4b (154 mg, 0.93 mmol) in
CH2Cl2 (2 ml), the soln. was refluxed for 48 h. Sat. NaHCO3 soln. (20 ml) was added at r.t., the aq. layer
extracted with CH2Cl2 (2 Â 20 ml), the combined org. layer dried (Na2SO4) and evaporated, and the residue
purified by FC (Et2O/pentane 1 : 5): rac-7e (68 mg, 21%). Pale yellow oil. TLC (Et2O/hexane 1 : 5): Rf 0.4. IR
(CHCl3): 2965m, 1682m, 1589w, 1487m, 1462m, 1360w, 1298m, 1226m, 1192m, 1104m, 1033w, 909w, 762s, 730s.
1H-NMR (200 MHz, CDCl3): 0.96 (d, J ˆ 6.9, 3 H); 1.11 (d, J ˆ 6.9, 3 H); 2.18 (sept. d, J ˆ 6.9, 4.0, 1 H); 4.70
(d, J ˆ 4.0, 1 H); 6.95 ± 7.48 (m, 6 H); 7.60 ± 7.69 (m, 2 H). 13C-NMR (50 MHz, CDCl3): 17.2; 18.8; 36.3; 60.6;
‡
115.3; 121.4; 122.0; 124.8; 126.6; 127.2; 128.0; 131.1; 131.2; 133.5; 149.8. MS: 330 (1, M ), 288 (100), 286 (100),
‡
‡
148 (23), 133 (53), 105 (26), 77 (27), 51 (28). HR-MS: 287.9847 ([M i-Pr] , C14H9BrNO ; calc. 287.9846).
According to the procedure described for rac-7e, 2-bromobenzamide (600 mg, 3.0 mmol), triethyloxonium
tetrafluoroborate (3.0 ml, 3.0 mmol), and (R)-4b (497 mg, 3.0 mmol) gave (‡)-(R)-7e (320 mg, 32%). [a]2D1
‡ 136 (c ˆ 1.18, CHCl3).
ˆ
14. rac-2-[2-(Diphenylphosphino)phenyl]-4-isopropyl-4H-1,3-benzoxazine (rac-2b). At 788, 1.6m BuLi in
hexane (0.12 ml, 0.19 mmol) was added to rac-7e (62 mg, 0.19 mmol) in Et2O (5 ml). The resulting red soln. was
stirred for 15 min at 788, then ClPPh2 (60 mg, 0.27 mmol) was added dropwise. The yellowish soln. was stirred
for 1 h at 788 and then allowed to warm up to r.t. within 14 h. Sat. NaHCO3 soln. (20 ml) was added, the aq.
layer extracted with CH2Cl2 (3 Â 20 ml), the combined org. layer dried (Na2SO4) and evaporated, and the
residue purified by FC (CH2Cl2): rac-2b (36 mg, 44%). White solid. M.p. 118 ± 1208. TLC (CH2Cl2): Rf 0.6.
HPLC (hexane/i-PrOH 9 : 1, 1.0 ml min 1): tR 23.0 (S) and 29.9 (R). IR (CHCl3): 3060w, 2967s, 2873w, 1677m,
1
1587w, 1485m, 1462m, 1435w, 1363m, 1227s, 1203s, 1102m. H-NMR (400 MHz, C6D6): 0.90 (d, J ˆ 6.9, 3 H);
0.94 (d, J ˆ 6.9, 3 H); 1.98 (sept. d, J ˆ 6.9, 3.4, 1 H); 4.56 (d, J ˆ 3.4, 1 H); 6.68 (td, J ˆ 8.0, 1.5, 2 H); 6.77 ± 7.40
(m, 15 H); 8.16 ± 8.21 (m, 1 H). 13C-NMR (100 MHz, C6D6): 17.1; 19.2; 36.3; 60.3; 115.5; 122.5; 124.5; 126.7;
127.9; 128.3; 128.3; 128.4; 128.5; 129.3 (d, J ˆ 3.0); 130.3; 134.0 (d, J ˆ 19.7); 134.6 (d, J ˆ 20.5); 135.4; 138.1
(d, J ˆ 21.2); 138.8 (d, J ˆ 25.0); 139.9 (d, J ˆ 2.3); 140.0 (d, J ˆ 4.5); 150.3; 151.9. 31P-NMR (162 MHz, C6D6):
‡
6.7. MS: 435 (48, M ), 420 (66), 292 (29), 358 (199), 287 (32), 208 (14), 196 (12), 183 (25). HR-MS:
‡
‡
435.1739 (M , C29H26NOP ; calc. 435.1752). Anal. calc. for C29H26NOP: C 79.98, H 6.02, N 3.22; found: C 79.51,
H 6.25, N 3.06.
According to the procedure described for rac-2b, 1.6m BuLi in hexane (0.55 ml, 0.89 mmol) (‡)-(R)-7e
(289 mg, 0.875 mmol), and ClPPh2 (232 mg, 1.05 mmol) gave (‡)-(R)-2b (165mg, 43%). M.p. 42 ± 458. [a]D21 ˆ‡
80 (c ˆ 0.37, CHCl3; >99% ee by HPLC). HPLC (hexane/i-PrOH 9 : 1, 1.0 ml min 1): tR 29.8 (R); the other
enantiomer was not detected.
15. ( )-(S)-2,5-Dihydro-2-phenylfuran. (( )-(S)-9). [Pd2(dba)3 ´ dba] (17.5 mg, 15.2 mmol, 1.5 mol-%) and
(‡)-(R)-2a (22.8 mg, 50.7 mmol, 5.2 mol-%) were placed under Ar in a Carius tube equipped with a magnetic
stirring bar and a Young tap. THF (5 ml) was added and the resulting red soln. stirred for 20 min. Tridecane
(56.9 mg, 0.309 mmol) as internal GC standard, N,N-diisopropylethylamine (0.35 ml, 266 mg, 2.06 mmol), 2,3-
dihydrofuran (0.23 ml, 214 mg, 3.05 mmol), and phenyl triflate (222 mg, 0.982 mmol) were added, and the soln.
was stirred at 708 for 90 h. At r.t., pentane (8 ml) was added and the mixture filtered over silica gel. Evaporation
and FC (t-BuOMe/pentane 1 : 20) afforded ( )-(S)-9 (114 mg, 79%). Colorless oil. [a]2D1
CHCl3; 91% ee by GC). GC (FS-595-(t-Bu)Me2Si-b-CD/SE-54 capillary column [20], 25 m; 808, 1.58 min
ˆ
265 (c ˆ 0.925,
1
,
1308, 158 min 1, 1608; 90 kPa): tR 17.3 ((S)-9, 95.3%) and 18.8 ((R)-9, 4.7%). TLC (t-BuOMe/pentane 1 : 20).
Rf 0.30. IR (CHCl3): 3371w, 3062m, 3031m, 2954w, 2852s, 1600w, 1492m, 1452s, 1354m, 1264m, 1227m, 1081s,
1063s, 1028s, 841m, 760s, 700s. 1H-NMR (300 MHz, CDCl3): 4.77 (dddd, J ˆ 12.6, 4.2, 2.4, 1.5, 1 H); 4.85
(dddd, J ˆ 12.6, 6.0, 2.4, 1.5, 1 H); 5.76 ± 5.82 (dtd, J ˆ 6.0, 2.4, 1.5, 1 H); 6.03 (dtd, J ˆ 6.0, 2.4, 1.5, 1 H); 7.23 ±
7.39 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 76.2; 88.3; 126.3; 126.5; 127.7; 128.4; 129.9; 142.0. MS: 146 (50,
‡
M ), 127(12), 115 (64), 105 (100), 91 (24), 77 (40), 69 (14), 63 (10), 51 (18).
We thank E. Francotte, Novartis-Pharma Inc. for his help with the preparative HPLC (chiral phase)
separation of rac-2a and A. Pfaltz for welcoming P.M. in his group for one month. We are indebted to A. Pinto
Â
Á
and J.P. Saulnier, Universite Geneve, for obtaining the NMR spectra. Financial support by the Swiss National
Science Foundation (Chiral 2, project 2027-048319.96) is gratefully acknowledged.

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Helvetica Chimica Acta ± Vol. 82 (1999)
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Received May 20, 1999