Formal [3 + 2] Cycloaddition Reaction of [1,4]Oxazin-2-ones and α-Alkynyl Ketones via a Tandem Mukaiyama-Aldol Addition/Aza-Cope Rearrangement

Full text of DOI:10.1021/jo9902695

J . Org. Chem. 1999, 64, 6891-6895
6891
Sch em e 1
F or m a l [3 + 2] Cycloa d d ition Rea ction of
[1,4]Oxa zin -2-on es a n d r-Alk yn yl Keton es
via a Ta n d em Mu k a iya m a -Ald ol Ad d ition /
Aza -Cop e Rea r r a n gem en t
Daniel Obrecht,*,† Cornelia Zumbrunn,‡ and
Klaus Mu¨ller
F. Hoffmann-La Roche AG, Pharma Research,
CH-4070 Basel, Switzerland
Received February 12, 1999
In tr od u ction
In the course of our investigations on carbonyl-alkyne-
exchange (CAE) reactions,1-7 we were interested in the
use of [1,4]oxazin-2-ones81 as precursors for cyclic het-
erodienes for the synthesis of vitamin B6 analogues 5
starting from 1 and acetylenic ketones9 3 as depicted in
Scheme 1. Silyl enol ether formation would give cyclic
aza dienes 2, which should react in a [4 + 2] cycloaddition
with acetylenic ketones 3 to give bicyclic adducts 4.
Electrocyclic extrusion of acetone finally should lead to
3-hydroxypyridines 5. An alternative strategy starting
from 5-trimethylsiloxy oxazoles and olefins described by
Takagaki et al.10 leading to vitamin B6 analogues of type
5 constituted further motivation for this approach.
Sch em e 2
Resu lts a n d Discu ssion
Although we were aware of the inherent difficulties of
Diels-Alder reactions with aza dienes,11,12 we expected
a similar increase of reactivity of cyclic as compared to
acyclic aza dienes as has been observed in CAE reactions
of the parent all-carbon dienes.7
of the silyl enol ether 2 to the carbonyl group of acetylenic
ketones 3 to form adducts 6 as shown in Scheme 2.
Products of type 6 turned out to be relatively unstable.
After some days, transformation of 6a into bicyclic
derivative 7a had taken place as confirmed by 2D NMR
experiments and X-ray crystallography. An ORTEP ste-
reoplot of 7a (R1 ) R2 ) Me; R3 ) CO2Me; R4 ) Ph) is
depicted in Figure 1 of the Supporting Information. The
bicyclic pyrrolidine 7a actually corresponds to the product
of a formal [3 + 2] cycloaddition of 1a and 3a . This
finding was astonishing inasmuch as during our inves-
tigations of [3 + 2] cycloadditions of [1,4]oxazin-2-ones
we discovered that acetylenic ketones are poor dipolaro-
philes due to numerous side reactions.16 Under standard
reaction conditions for [3 + 2] cycloaddition reactions
(Ag(I) catalysis17), 7a could be isolated in 19% yield only.
Thus, treatment of, e.g., 1a (R1 ) R2 ) Me) with 3a
(R3 ) CO2Me, R4 ) Ph), trimethylsilyl triflate (TMS-OTf),
and 2,6-di-tert-butylpyridine (DTBP) in CH2Cl2 at -30
°C resulted in formation of a new product with the same
molecular weight as 4 (Scheme 1). Analysis of 2D NMR
spectra, however, revealed that not a [4 + 2] cycloaddition
had taken place but rather a Mukaiyama-aldol13-15addition
† Present address: POLYPHOR Ltd., Winterthurerstr. 190, CH-8057
Zu¨rich, Switzerland.
‡ Part of the Ph.D. Thesis of C.Z., University of Zu¨rich, 1998.
(1) Effenberger, F.; Ziegler, T. Chem. Ber. 1987, 120, 1339-1346.
(2) Escudero, S.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Tetrahedron Lett.
1997, 38, 5375-5378.
(3) Kozikowski, A. P.; Schmiesing, R. Tetrahedron Lett. 1978, 44,
4241-4244.
(4) Tam, T. F.; Coles, P. Synthesis 1988, 383-386.
(5) Tanyeli, C.; Tarhan, O. Synth. Commun. 1989, 19, 2453-2460.
(6) Ziegler, T.; Effenberg, F. Chem. Ber. 1987, 120, 1347-1355.
(7) Obrecht, D. Helv. Chim. Acta 1991, 74, 27-45.
(8) Schulz, G.; Steglich, W. Chem. Ber. 1977, 110, 3615-3623.
(9) Obrecht, D. Helv. Chim. Acta 1989, 72, 447-456. Masquelin, T.;
Obrecht, D. Tetrahedron Lett. 1994, 35, 9387-9390. Masquelin, T.;
Obrecht, D. Synthesis 1995, 276-284. Masquelin, T.; Obrecht, D.
Tetrahedron 1997, 53, 641-646. Obrecht, D.; Gerber, F.; Sprenger, D.;
Masquelin, T. Helv. Chem. Acta 1997, 80, 531-537.
(10) Takagaki, H.; Yasuda, N.; Asaoka, M.; Takei, H. Chem. Lett.
1979, 183-186.
(11) Boger, D. L. Tetrahedron 1983, 39, 2869-2939.
(12) Ghosez, L.; Bayard, P.; Nshimyumukiza, P.; Gouverneur, V.;
Sainte, F.; Beaudegnies, R.; Rivera, M.; Frisque-Hesbain, A.-M.;
Wynants, C. Tetrahedron 1995, 51, 11021-11042.
(13) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1977, 16, 817-
826.
To elucidate the mechanism of this unusual rearrange-
ment, we studied the influence of substituents R2 and
R3 on product formation. Optimized reaction conditions
for the Mukaiyama-aldol reaction were found by using
2.2 equiv of TMS-OTf and 2.5 equiv of 2,6-di-tert-
(14) Murata, S.; Suzuki, M.; Noyori, R. J . Am. Chem. Soc. 1990,
102, 3248-3249.
(15) Mukai, C.; Hashizume, S.; Nagami, K.; Hanaoka, M. Chem.
Pharm. Bull. 1990, 38, 1509-1512.
(16) Zumbrunn, C. Studies on the Synthesis of Aromatic Compounds
via Carbonyl-Alkyne-Exchange (CAE) Reaction. Ph.D. Thesis, Univer-
sity of Zu¨rich, 1998
(17) Grigg, R.; Kemp, J .; Malone, J . F. Tetrahedron 1988, 44, 5361-
5374.
10.1021/jo9902695 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/18/1999

6892 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
Ta ble 1. Sequ en tia l Mu k a iya m a -Ald ol/Rea r r a n gem en t
Sch em e 3
Rea ction s
Mukaiyama
rearrangement
(yield, %)a
entry R1 R2
R3
R4 aldol (yield, %)a
a
b
c
d
e
Me Me CO2Me Ph
Me Me CO2Et Arb
Me Me SiMe3 Ph
Me Ph CO2Me Ph
Me Ph SiMe3 Ph
6a (90)
6b (60)c
6c (95)d
6d (44)c
6e (92)e
7a (88)
7b (94)
7c (59)
7d (50)
7e (55)
a
c
Isolated yields. b3,4,5-trimethoxyphenyl. Ratio of diastereo-
mers not determined. d2:1 mixture of diastereoisomers. e3:2
mixture of diastereoisomers.
butylpyridine in CH2Cl2 at temperatures ranging be-
tween -40 and -25 °C. At temperatures above -20 °C,
Michael addition of the silyl enol ether to the acetylenic
ketone became an important side reaction. The experi-
mental results are summarized in Table 1.
formation of 11 via a retro-aldol reaction and subsequent
1,4-addition to the alkyne followed by addition of MeOH.
Product 11 was also obtained by treatment of 1a and 3c
with K2CO3 in MeOH. At room temperature, Michael
adducts (E)-12 and (Z)-12 were isolated in a ratio of 7.5:
1. At 40 °C, however, addition of methanol and thus
formation of 11 was observed.
Interestingly, treatment of 6c with tetrabutylammo-
nium fluoride in THF at -78 °C led again to the
formation of (Z)-12 and (E)-12, however, in favor of the
thermodynamically less stable cis-olefin (Z)-12 in a Z/E
ratio of 5:1.
In summary, neither basic or acidic conditions nor the
addition of a Ag(I) salt enhanced the rate of the aza-Cope
rearrangement. The best reaction conditions giving sat-
isfactory yields of rearranged products 7 were found by
heating the intermediate adducts 6 in dioxane/water (40:
1) at 90 °C.
For the conversion of the Mukaiyama-aldol adducts 6
into 7 two mechanisms can be postulated. The first
possibility is depicted in eq 1 and involves a 2-aza-Cope
rearrangement to yield the allenic silyl enol ether 13
followed by an intramolecular Mukaiyama aldol addition
to the resulting imine. Analogous oxy-Cope rearrange-
ments have been reported in the literature.19-21
1,2-Addition of the silyl enol ether of oxazinones 2 to
acetylenic ketones 3 and concomitant silyl transfer to
yield the tertiary alcohols 6 as mixtures of diastereomers
(Table 1) proceeded usually in good yields. Products 6
were stable enough to be isolated and purified by chro-
matography on SiO2. The ratio of diastereoisomer forma-
tion could be determined by NMR in cases where the
silylated alkyne 3c (R3 ) SiMe3, R4 ) Ph) was used (Table
1, entries c and e). The NMR spectra of 6a , however,
indicated the formation of only one diastereomer. Rear-
rangement to the formal [3 + 2] adducts 7 was achieved
by heating solutions of these primary adducts.
The nature of substituents R3 attached to the alkyne
seemed to have no major effect on the rearrangement.
Compared to the carbomethoxy-substituted compounds
6a ,b,d it was observed that the rearrangement of the
TMS-substituted derivatives 6c and 6e proceeded more
slowly (see the Experimental Section) and that the
diastereomers rearranged at slightly different rates as
qualitatively observed by TLC.
The polarity of the solvent appeared to play only a
minor role since rearrangements proceeded at similar
rates in chloroform, 1,2-dichloroethane, or 1,4-dioxane/
H2O.
In two cases, the originally targeted nicotinic acid
derivatives 5a and 5b could be isolated, however, only
as byproducts in low and irreproducible yields (see
Scheme 3).
A number of experiments were carried out in an
attempt to determine the factors that influence the rate
and the course of the rearrangements. Thus, adduct 6c
was exposed to several different reaction conditions as
summarized in Scheme 4.
Addition of pyridinium p-toluenesulfonate (PPTS) in
a variety of solvents regenerated 1a and the hydrolyzed
alkyne probably via a retro-aldol reaction. Treatment of
6c with silver nitrate in a mixture of ethanol and water
and trapping of the silver complex with sodium cyanide18
gave 9 where the trimethylsilyl group was replaced by a
hydrogen. This adduct underwent rearrangement to 10
under thermal conditions. The bicyclic derivative 10 could
also be obtained by treatment of rearranged product 7c
with tetrabutylammonium fluoride (TBAF) in THF at
room temperature.
This two-step mechanism would also offer an alterna-
tive pathway to the one shown in Scheme 1 for the
On the other hand, exposure of 6c to a catalytic amount
of potassium carbonate in MeOH resulted in the clean
(19) Onishi, T.; Fujita, Y.; Nishida, T. Synthesis 1980, 651-654.
(20) Bluthe, N.; Gore, J .; Malachria, M. Tetrahedron 1986, 42, 1333-
1344.
(21) Viola, A.; MacMillan, J . H. J . Am. Chem. Soc. 1970, 92, 2404-
2410.
(18) Schmidt, H. M.; Arens, J . F. Recueil 1967, 68, 1138-1142.

Notes
J . Org. Chem., Vol. 64, No. 18, 1999 6893
Sch em e 4a
a
Reagents and conditions: (i) TMS-Tf, DTBP, CHCl2; (ii) H3O+; (iii) dioxane/H2O, ∆; (iv) TBAF, THF, rt; (v) AgNO3, NaCN, EtOH; (vi)
cat. K2CO3, MeOH, rt; (vii) cat. K2CO3, MeOH, 40 °C; (viii) TBAF, THF, -78 °C.
formation of the observed nicotinic acid derivatives 5a
and 5b. Thus, rearrangement of 13 into bicyclic inter-
mediate 14, the intermediate of the corresponding CAE
reaction (Scheme 1), elimination of acetone, and aroma-
tization would explain the formation of 5a and 5b (cf. eq
2).
the occasionally occurring pyridine side products, and the
transformations described in Scheme 4. The fact that the
hydrolysis product of 13 was never detected might
suggest that the 2-aza-Cope rearrangement rather than
the aldol addition constitutes the rate-determining step.
Unfortunately, so far no reaction conditions have been
found that would favor the formation of the desired
pyridine derivatives.
Su m m a r y
In summary, we have found a novel reaction between
silyl enol ethers derived from [1,4]oxazin-2-ones 1 and
acetylenic ketones 3 yielding interesting bicyclic pyrro-
lidine derivatives 7 in good yields. Compounds of type 7
correspond to the regiochemically less favored products
obtained from a [3 + 2] cycloaddition reaction between
the two starting materials. A putative mechanism involv-
ing a Mukaiyama-aldol reaction followed by a 2-aza-Cope
rearrangement rationalizes the formation and the regio-
chemical outcome of bicyclic pyrrolidine derivatives 7 as
well as the formation of nicotinic acid derivatives 5a and
5b, which were formed as byproducts. The structures of
the novel compounds of type 7 were confirmed by an
X-ray structure of 7a .
An alternative possibility for the formation of the
bicyclic pyrrolidine derivatives would involve a concerted
mechanism in which in intramolecular migration of the
trimethylsilyl group from oxygen to nitrogen would be
accompanied by a simultaneous [1,2]-C-C bond migra-
tion of the oxazinone moiety to the adjacent triple bond.
From the experimental results, it is difficult to rule
out one of these two mechanisms. Nevertheless, we favor
the first mechanism because it offers a consistent rational
for the observation of both the main bicyclic products,
Exp er im en ta l Section
Gen er a l Meth od s. Thin-layer chromatography (TLC) was
performed using E. Merck silica gel 60 F254 0.25 mm plates.
Visualization was accomplished using ultraviolet light or the
following stain: (a) 1% KMnO4, 2% NaHCO3 in H2O, or (b)
o-toluidine (320 mg), acetic acid (60 mL), and KI (2 g) dissolved
in H2O (1 l). Chromatography was performed using E. Merck

6894 J . Org. Chem., Vol. 64, No. 18, 1999
Notes
silica gel 60 (230-400 mesh). Solvent systems are reported as
volume percent mixtures. Chloroform was filtered over alox prior
to use, and CH2Cl2 was distilled from CaH and stored under
Ar. Liquid reagents were distilled prior to use. All other reagents
were purchased from Fluka or Aldrich and used without further
purification.
Gen er a l P r oced u r e for Mu k a iya m a Ald ol Rea ction s. To
a stirred solution of oxazinone 1 (0.5 mmol) in dry CH2Cl2 (2
mL) at -30 °C under Ar were added ynone 3 (1.2 equiv) and
di-tert-butylpyridine (2.5 equiv). TMS-OTf (2.2 equiv) was added
dropwise, and the reaction mixture was stirred between -30 and
-20 °C. After completion of the reaction, the mixture was poured
onto saturated aqueous NaHCO3 and extracted with ether. The
organic layer was dried (MgSO4), and the solvents were evapo-
rated.
µL, 2.5 equiv), and TMS-OTf (256 µL, 2.2 equiv) (5 h at -30 °C
and overnight at -20 °C). Chromatography on SiO2 (15 g,
hexane/ether 2:1 f 1:1) gave 263 mg (95%) of 6c as a 2:1 (A:B)
mixture of diastereomers.
A 350 mg (0.81 mmol) portion of 6c was dissolved in dioxane/
water (40:1) and heated to 95 °C for 3 d. Evaporation of the
solvent and chromatography on SiO2 gave 171 mg (59%) of 7c.
Spectroscopic data of diastereomeric mixture of 6c:
1H NMR (250 MHz, CDCl3): δ 7.6-7.5 (m, 2 arom. H); 7.3-
7.2 (m, 3 arom. H); 2.07 (s, A, CH3); 1.95 (s, B, CH3); 1.56 (s, B,
CH3); 1.53 (s, A, CH3); 1.44 (s, A CH3); 1.42 (s, B CH3); 1.30 (s,
A CH3); 1.25 (s, B CH3); 0.24 (s, 9H, B, OSiMe3); 0.22 (s, 9H, A,
OSiMe3); 0.09 (s, 9H, A, SiMe3); 0.07 (s, B, 9H, SiMe3).
Spectroscopic data of 7c:
1H NMR (250 MHz, CDCl3): δ 7.8-7.75 (m, 2 arom H); 7.65-
7.55 (m, 1 arom H); 7.5-7.35 (m, 3 arom H); 2.29 (br, NH); 1.63
(s, CH3); 1.49 (s, CH3); 1.44 (s, CH3); 1.29 (s, CH3); 0.11 (s, 9H,
SiMe3).
4-P h en yl-4-(3,5,6,6-t et r a m et h yl-2-oxo-3,6-d ih yd r o-2H -
[1,4]oxa zin -3-yl)-4-t r im et h ylsila n yloxyb u t -2-yn oic Acid
Meth yl Ester (6a ). Treatment of 1a (500 mg, 3.22 mmol) with
3a (728 mg, 1.2 equiv), di-tert-butylpyridine (1.59 mL, 2.5 equiv),
and TMS-OTf (1.28 mL, 2.2 equiv) (24 h at -20 °C) according
to the general procedure gave after chromatography on SiO2 (90
g, hexane/ether 2:3, ether, ether/EtOAc) 1.2 g (90%) of 6a
(containing traces of 7a ) and 125 mg (10%) of the Michael-
addition product.
IR (KBr): 1730s; 1654s; 1595m; 1127s; 841s.
MS (ISP): 375 (65, [M + NH4]+); 358 (100, [M + H]+).
4-P h en yl-4-(3,6,6-tr im eth yl-2-oxo-5-p h en yl-3,6-d ih yd r o-
2H-[1,4]oxa zin -3-yl)-4-tr im eth ylsila n yloxybu t-2-yn oic Acid
Met h yl E st er (6d ), Met h yl (1S*,5R*)-7-Ben zoyl-1,4,4-t r i-
m eth yl-2-oxo-5-p h en yl-3-oxa -8-a za bicyclo [3.2.1]oct-6-en e-
6-ca r boxyla te (7d ), a n d 4-Ben zoyl-5-h yd r oxy-6-m eth yl-2-
p h en yln icotin ic Acid Meth yl Ester (5b). 1b (109 mg, 0.5
mmol) was treated according to the general procedure with 3a
(94 mg, 1.2 equiv), di-tert-butylpyridine (280 µL, 2.5 equiv), and
TMS-OTf (199 µL, 2.2 equiv) (3.5 h at -40 °C). Chromatography
on SiO2 (20 g, hexane/EtOAc 5:1 f 2:1) gave 105 mg (44%) of
6d together with 40 mg (20%) of 1,4-adduct.
1H NMR (400 MHz, CDCl3): δ 7.5-7.45 (m, 2 arom. H); 7.35-
7.25 (m, 3 arom. H); 3.83 (s, 3 H, COOCH3); 1.97 (s, 3H, C(9)-
H3); 1.61 (s, C(3)H3); 1.48 (s, C(11)H3); 1.19 (s, C(12)H3); 0.12 (s,
9H, SiMe3).
13C NMR (100 MHz, CDCl3): δ 167.52 (1); 167.40 (8); 153.68
(7); 139.42 (arom C); 128.38 (arom C); 127.94 (arom C); 127.26
(arom C); 87.78; 83.66 (10); 80.29 (6); 79.86 (4); 67.48 (2); 52.78
(COOMe); 28.16 (11); 26.60 (12); 23.87 (3); 22.16 (9); 1.24 (SiMe3).
IR (film): 1736s; 1717s; 1685m; 1066m.
6d (105 mg, 0.22 mmol) was dissolved in dichloroethane and
heated to 70 °C overnight. Evaporation of the solvent and
chromatography on SiO2 gave 44 mg (50%) of 7d and 8 mg (10%)
of 5b.
MS (EI): 415 (1, M+); 400 (2, [M - CH3]+); 342 (3), 261 (100);
227 (22); 105 (40).
(1S*,5R*)-7-Ben zoyl-1,4,4,5-t et r a m et h yl-2-oxo-3-oxa -8-
a za bicyclo[3.2.1]oct-6-en e-6-ca r boxylic Acid Meth yl Ester
(7a ). 6a was dissolved in CHCl3 and heated to reflux for 5 h.
Crystallization from hexane/EtOAc gave 730 mg (66%) of pure
7a (plus 150 mg from mother liquor).
Spectroscopic data of diastereomeric mixture of 6d :
1H NMR (250 MHz, CDCl3): δ 7.6-7.2 (m, 10 arom H); 3.82
(s, A, OCH3); 3.80 (s, B, OCH3); 1.71 (s, A, CH3); 1.63 (s, B, CH3);
1.60 (s, B, CH3); 1.58 (s, A, CH3); 1.55 (s, A + B, CH3); 1.45 (s,
B, CH3); 1.29 (s, A, CH3); 0.15 (s, 9H, A, OSiMe3); 0.10 (s, 9H,
A, OSiMe3).
1H NMR (400 MHz, CDCl3): δ 7.8-7.75 (m, 2 arom. H); 7.65-
7.55 (m, 1 arom. H); 7.5-7.4 (m, 2 arom. H); 3.45 (s, 3H,
COOCH3); 2.48 (br, NH); 1.66 (s, C(10)H3); 1.60 (s, C(9)H3); 1.44
(s, C(12)H3); 1.43 (s, C(11)H3).
MS (ISP): 495 (60, [M + NH4]+); 478 (100, [M + H+]).
Spectroscopic data of 7d :
1H NMR (250 MHz, CDCl3): δ 7.8-7.75 (m, 4 arom H); 7.65-
7.55 (m, 1 arom H); 7.5-7.3 (m, 5 arom H); 3.27 (s, 3H,
COOCH3); 3.05 (br, NH); 1.81 (s, CH3); 1.62 (s, CH3); 1.43 (s,
CH3).
13C NMR (100 MHz, CDCl3): δ 192.74 (13); 166.87 (2); 162.93
(14); 159.91 (7); 140.78 (6); 135.37; 134.28; 128.99; 128.70; 90.06
(4); 71.18 (1); 71.01 (5); 51.99 (COOCH3); 24.96 (10);23.87 (11);
19.64 (9); 16.96 (12).
IR (MIR): 1735s; 1651m; 1250m.
IR (KBr): 1729s; 1653s; 1594m.
MS (EI): 373 (5, [M - CH3OH]+); 346 (36, [M - COOCH3]+);
319 (58); 286 (100); 230 (14); 105 (14).
MS (EI): 343 (5, M+); 248 (100, [M - C3H6O]+); 256 (48); 225
(72); 162 (10); 105 (28).
Spectroscopic data of 5b:
4-(3,5,6,6-Tetr a m eth yl-2-oxo-3,6-d ih yd r o-2H-[1,4]oxa zin -
3-yl)-4-(3,4,5-tr im eth oxyp h en yl)-4-tr im eth ylsila n yloxybu t-
2-yn oic Acid Eth yl Ester (6b) a n d (1S*,5R*)-7-(3,4,5-Tr i-
m et h oxyb en zoyl)-1,4,4,5-t et r a m et h yl-2-oxo-3-oxa -8-a za -
bicyclo[3.2.1]oct-6-en e-6-ca r boxylic Acid Eth yl Ester (7b).
1a (100 mg, 0.644 mmol) was treated according to the general
procedure with 3b (282 mg, 1.5 equiv), di-tert-butylpyridine (360
µL, 2.5 equiv), and TMS-OTf (247 µL, 2.2 equiv) (3 h at -20 °C)
to give after chromatography on SiO2 (20 g, hexane/EtOAc 2:1
f 1:1, EtOAc) 25 mg (9%) of 7b, 198 mg (∼60%) of 6b (containing
traces of 7b), and 90 mg (30%) of 1,4-adduct.
1H NMR (400 MHz, CDCl3): δ 8.5 (br, OH); 7.75-7.65 (m, 2
arom H); 7.6-7.5 (m, 1 arom H); 7.5-7.3 (m, 7 arom H); 3.00 (s,
3 H, COOCH3); 2.67 (s, 3H, CH3).
13C NMR (63 MHz, CDCl3): δ 198.55 (CdO); 167.27 (COOMe);
152.10; 149.05; 148.27; 139.31; 137.20; 133.72; 129.20; 128.50;
128.32; 128.28; 125.58; 123.97; 51.92 (OMe); 19.81 (Me).
MS (ISN): 464 (10, [M + OAc]+); 346 (100, [M - H+]).
3,6,6-Tr im eth yl-5-p h en yl-3-(1-p h en yl-3-tr im eth ylsila n yl-
1-tr im eth ylsila n yloxyp r op -2-yn yl)-3,6-d ih yd r o[1,4]oxa zin -
2-on e (6e) an d (1S*,5R*)-7-Ben zoyl-5-ph en yl-1,4,4-tr im eth yl-
6-t r im e t h ylsila n yl-3-oxa -8-a za b icyclo[3.2.1]oct -6-e n -2-
on e (7e). 1b (140 mg, 0.644 mmol) was treated according to the
general procedure with 3c (165 mg, 1.2 equiv), di-tert-butylpy-
ridine (318 µL, 2.5 equiv), and TMS-OTf (256 µL, 2.2 equiv) (5
h at -30 °C and overnight at -20 °C). Chromatography on SiO2
(15 g, hexane/ether 2:1 f 1:1) gave 292 mg (92%) of 6e as a 2:3
mixture of diastereoisomers.
6b was dissolved in CHCl3 and heated to reflux for 5 h.
Filtration over SiO2 gave 160 mg (94%) of pure 7b as a white
foam.
1H NMR (250 MHz, CDCl3): δ 7.04 (s, 2 arom. H); 4.1-3.9
(m, OCH2CH3); 3.92 (s, 3 H, OCH3); 3.88 (s, 6 H, 2 OCH3); 2.5
(br, NH); 1.67 (s, CH3); 1.58 (s, CH3); 1.46 (s, CH3); 1.45 (s, CH3);
0.92 (t, 3H, OCH2CH3, J ) 7.1).
A 60 mg (0.12 mmol) portion of 6e was dissolved in dichlo-
roethane and heated to reflux overnight to give after chroma-
tography 28 mg (55%) of 7e.
Spectroscopic data of diastereomeric mixture of 6e:
1H NMR (250 MHz, CDCl3): δ 7.7-7.5 (m, 4 arom H); 7.5-
7.15 (m, 6 arom H); 1.69 (s, A, CH3); 1.67 (s, B, CH3); 1.59 (s, B,
CH3); 1.56 (s, A, CH3); 1.48 (s, A CH3); 1.30 (s, B CH3); 0.26 (s,
9H, B, OSiMe3); 0.23 (s, 9H, A, OSiMe3); 0.12 (s, 9H, B, SiMe3);
0.07 (s, A, 9H, SiMe3).
IR (KBr): 1743s; 1721s; 1660m; 1416s; 1335s; 1128s.
MS (ISP): 465 (25, [M + NH4]+); 448 (100, [M + H]+).
3,5,6,6-Tetr a m eth yl-3-(1-p h en yl-3-tr im eth ylsila n yl-1-tr i-
m et h ylsila n yloxyp r op -2-yn yl)-3,6-d ih yd r o[1,4]oxa zin -2-
on e (6c) a n d (1S*,5R*)-7-Ben zoyl-1,4,4,5-tetr a m eth yl-6-
tr im eth ylsilan yl-3-oxa-8-azabicyclo[3.2.1]oct-6-en -2-on e (7c).
1a (100 mg, 0.644 mmol) was treated according to the general
procedure with 3c (165 mg, 1.2 equiv), di-tert-butylpyridine (318

Notes
Spectroscopic data of 7e:
J . Org. Chem., Vol. 64, No. 18, 1999 6895
product was purified by chromatography on SiO2 (20 g, hexane/
EtOAc 1:1) to give 50 mg (68%) of 11.
1H NMR (250 MHz, CDCl3): δ 7.85-7.8 (m, 2 arom H); 7.6-
7.3 (m, 5 arom H); 7.3-7.2 (m, 1 arom H); 7.1-7.05 (m, 2 arom
H); 2.9 (br., NH); 1.88 (s, CH3); 1.81 (s, CH3); 1.40 (s, CH3); 0.02
(s, 9H, SiMe3).
1H NMR (250 MHz, CDCl3): 8.0-7.9 (m, 2 arom H); 7.6-7.4
(m, 3 arom H); 4.51 (dd, 1 aliph H, J ) 2.6, 6.3 Hz); 3.75 (s, 3 H,
OMe); 3.18 (dd, 1 aliph H, J ) 16.6, 6.3 Hz); 3.03 (dd, 1 aliph H,
J ) 2.6, 16.6 Hz); 1.99 (s, CH3); 1.44 (s, CH3); 1.37 (s, CH3); 1.31
(s, CH3).
MS (ISP): 437 (100, [M + NH4]+); 420 (95, [M + H]+).
3,5,6,6-Tet r a m et h yl-3-(1-p h en yl-1-t r im et h ylsila n yloxy-
p r op -2-yn yl)-3,6-d ih yd r o[1,4]oxa zin -2-on e (9). To a solution
of 6c (100 mg, 0.23 mmol) in EtOH (1 mL) was added at rt under
Ar a solution of AgNO3 (104 mg, 0.61 mmol) in EtOH/water (3:
1). The mixture was stirred at rt for 1 h. NaCN (30 mg, 0.61
mmol) was added, and the white suspension was stirred for
another 30 min. The mixture was poured on brine and extracted
with ether. The organic layer was dried (MgSO4), and the
solvents were evaporated. The product was purified by chroma-
tography on SiO2 (20 g, hexane/EtOAc 1:1) to give 30 mg (37%)
of 9 as a mixture of diastereomers.
MS (ISP): 635 (20, [2M + H]+); 318 (100, [M + H]+).
(E)- a n d (Z)-3,5,6,6-Tetr a m eth yl-3-(3-oxo-3-p h en ylp r o-
p en yl)-3,6-d ih yd r o[1,4]oxa zin -2-on e ((E)- a n d (Z)-12). To a
solution of 1a (100 mg, 0.23 mmol) and 3c (156 mg, 1.2 equiv)
in MeOH (1 mL) was added at rt. under Ar K2CO3 (3-4 crystals).
The mixture was stirred at rt for 2 h, poured on brine, and
extracted with ether. The organic layer was dried (MgSO4), and
the solvents were evaporated. The product was purified by
chromatography on SiO2 (10 g, hexane/EtOAc 1:1) to give 130
mg (71%) of a 7.5:1 mixture of (E)-12 and (Z)-12. The isomers
were not separated.
1H NMR (250 MHz, CDCl3): 7.45-7.4 (m, 2 arom H); 7.25-
7.15 (m, 3 arom H); 2.79 (s, 1 acetylene H); 1.87 (s, CH3); 1.53
(s, CH3); 135 (s, CH3); 1.11 (s, CH3); 0.0 (s, 9 H, OSiMe3).
MS (ISP): 358 (100, [M + H]+).
(1S*,4R*)-7-Ben zoyl-1,4,4,5-t et r a m et h yl-3-oxa -8-a za b i-
cyclo[3.2.1]oct-6-en -2-on e (10). To a solution of 6c (14 mg, 39
µmol) in THF was added at rt under Ar TBAF (1 M solution in
THF, two drops). The mixture was stirred at rt for 1 h, poured
on brine, and extracted with ether. The organic layer was dried
(MgSO4), and the solvents were evaporated. The product was
purified by chromatography on SiO2 (2 g, hexane/EtOAc 1:1) to
give 10 mg (89%) of 10.
Spectroscopical data for (E)-12:
1H NMR (250 MHz, CDCl3): 7.95-7.9 (m, 2 arom H); 7.65-
7.4 (m, 3 arom H); 7.13 (d, 1 olef H, J ) 15.6 Hz); 7.01 (d, 1 olef
H, J ) 15.6 Hz); 2.18 (s, CH3); 1.74 (s, CH3); 1.61 (s, CH3); 1.52
(s, CH3).
MS (ISP): 303 (100, [M + NH4]+); 286 (25, [M + H]+).
Ack n ow led gm en t. We thank our colleagues from
Pharma Research, F. Hoffmann-La Roche Ltd., for IR
(Mr. A. Bubendorf), NMR (Dr. W. Arnold), and MS (Mr.
W. Meister) data. We also thank Profs. J .E. Baldwin
(Oxford) and H.-J . Hansen and H. Heimgartner (Zu¨rich)
for their valuable advice and fruitful discussions.
1H NMR (250 MHz, CDCl3): 7.85-7.75 (m, 2 arom H); 7.65-
7.55 (m, 1 arom H); 7.5-7.4 (m, 2 arom H); 6.76 (s, 1 olef H); 2.3
(br, NH); 2.04 (s, CH3); 1.64 (s, CH3); 1.58 (s, CH3); 1.46 (s, CH3).
MS (ISP): 571 (15, [2M + H]+); 286 (100, [M + H]+).
3-(1-Meth oxy-3-oxo-3-p h en ylp r op yl)-3,5,6,6-tetr a m eth yl-
3,6-d ih yd r o[1,4]oxa zin -2-on e (11). To a solution of 6c (100
mg, 0.23 mmol) in MeOH (1 mL) was added at rt under Ar K2-
CO3 (3-4 crystals). The mixture was stirred at rt overnight,
poured on brine, and extracted with ether. The organic layer
was dried (MgSO4), and the solvents were evaporated. The
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and 2D
NMR spectra of compounds 6a and 7a , and an ORTEP
diagram (Figure 1) and X-ray structure data for compound 7a .
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J O9902695