Stereoselective radical cyclizations of N-(2-halobenzoyl)-cyclic ketene-N,X(X=O, S)-acetals

Article abstract of DOI:10.1016/j.tet.2006.02.018

2-Alkyloxazolines and 2-alkylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,O-acetals and N-(2-halobenzoyl)-cyclic ketene-N,S-acetals in excellent yields, respectively. These ketene acetals readily undergo stereoc

Full text of DOI:10.1016/j.tet.2006.02.018

Tetrahedron 62 (2006) 4093–4102
Stereoselective radical cyclizations of N-(2-halobenzoyl)-cyclic
ketene-N,X(XZO, S)-acetals
*
Aihua Zhou, Moses N. Njogu, and Charles U. Pittman, Jr.
*
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
Received 22 September 2005; revised 24 January 2006; accepted 3 February 2006
Available online 10 March 2006
Abstract—2-Alkyloxazolines and 2-alkylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,O-
acetals and N-(2-halobenzoyl)-cyclic ketene-N,S-acetals in excellent yields, respectively. These ketene acetals readily undergo
stereocontrolled aryl radical cyclizations to afford the central six-membered rings of substituted-2,3,10,10a-tetrahydrooxazolo[3,2-
b]isoquinolin-5-ones and their 2,3,10,10a-tetrahydrothiazolo[3,2-b]isoquinolin-5-one analogs. The tertiary N,O- and N,S-radicals formed
upon aryl radical reaction at the ketene-N,X(XZO, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in
hydrogen abstractions by these intermediate radicals from both Bu3SnH and (Me3Si)3SiH was investigated. The N,S-heterocyclic fused ring
products may have potential medical value.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
converted to N-(2-halobenzoyl)-cyclic ketene-N,O-acetals 3
or N-(2-halobenzoyl)-cyclic ketene-N,S-acetals 4, respect-
ively, in excellent yields (O95%), when treated with
1 equiv of 2-halobenzoyl (halogenZBr, I) chlorides and
Et3N in benzene (Scheme 1). Herein, we show that N-(2-
halobenzoyl)-cyclic ketene-N,X(XZO, S)-acetals 3 and 4
are good precursors for intramolecular aryl radical
cyclization. When a stereogenic center was inserted at the
C-3 position of the 2-alkyloxazolines 1 or 2-alkylthiazolines
2, the resulting N-(2-halobenzoyl)-cyclic ketene-N,X(XZ
O, S)-acetals 3 or 4 formed upon N-benzoylation directly
underwent stereocontrolled radical cyclization without need
for further purification of 3/4.
Radical cyclization is an important route to synthesize
heterocyclic compounds and many such methods have been
reported.1–4 Normally radical cyclizations generate a
mixture of five- and six-membered-ring products. The
product ratio obtained depends on the reagents, solvents,
radical initiators and other reaction conditions employed.5–7
Radical initiators commonly employed in these cyclizations
include R3SnH/AIBN,8 RSH/AIBN,9 R3SiH/AIBN,10
R3SnSnR3 and Et3B.12
11
Despite extensive previous studies, radical cyclizations using
electron-rich cyclic ketene-N,X(XZO, S)-acetals as a route to
make N,S heterocycles were only recently reported by our
group.13 N,S Heterocycles, which have important medicinal
properties appear to be available through such routes.13,14
Cyclic ketene-N,X(XZO, S)-acetals are very reactive,
electron-rich, nucleophilic compounds because they share
enamine and vinyl ether (thioether) structures simul-
taneously. These compounds and their O,O-analogs have
been under active investigation in our laboratory.15 They are
very sensitive to acids, water or acidic surfaces and are
easily protonated. They undergo ready cationic polymer-
ization,15a–d but tend to resist radical polymerization.
2-Alkyloxazolines 1 or 2-alkylthiazolines 2 are readily
Scheme 1. Reactions of 2-alkyloxazolines 1 and 2-alkylthioazolines 2 with
2-halobenzoyl chlorides.
2. Results and discussions
Keywords: Cyclizations; Acetals; Diastereomer; Ketene acetals; Ketene-N,
O-acetals; Ketene-N,S-acetals.
The syntheses of 1 and 2 with a stereogenic center at C-3
position proceed as shown in Table 1. Natural amino acids 5
*
Corresponding authors. Tel.: C1 662 325 7616; fax: C1 662 325 7611;
e-mail addresses: zhou_aihua@yahoo.com; cpittman@ra.msstate.edu
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.018

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A. Zhou et al. / Tetrahedron 62 (2006) 4093–4102
Table 1. The synthesis of 2-alkyloxazolines 1 and 2-alkylthiazolines 2
Entry
R1 in 5
R2
Product 1/2
Yield (%)a
1
2
3
4
5
6
7
8
9
–CH(CH3)2
–CH2CH(CH3)2
–CH(CH3)2
–CH2CH(CH3)2
–CH3
–CH2Ph
–CH2Ph
–CH(CH3)2
–CH2CH(CH3)2
–H
–H
–CH3
–CH3
–Ph
–H
–Et
–CH3
–CH3
O
O
O
O
O
O
O
S
1a
1b
1c
1d
1e
1f
1g
2a
2b
68
63
60
66
60
67
63
60
63
S
a All are isolated yields, based on 5, over the entire three-step sequence.
(S-configuration) were reduced by NaBH4–I2 in THF for
18 h to give amino alcohols 6.16 Refluxing 6 in chloro-
benzene with excess nitrile and ZnCl2 (5%), affords 1 in
good isolated yields.17 Reacting 6 with acid chlorides and
Et3N in CH2Cl2 afforded hydroxyamides 7, which gave 2
upon treatment with P2S5 in mineral oil.18 Treating 1 and 2
with 2-halobenzoyl chloride, filtration and the removal of
excess triethylamine and solvent afforded crude 3 and 4
(Scheme 1), which were directly used for aryl radical
cyclizations without further purification.
Two aryl radical cyclization pathways appeared possible
(Scheme 2). Radical 8, formed upon halogen atom abstraction
byBu3Sn%, couldcyclizetoeithersecondaryradical9, forming
in a new five-membered ring, or to tertiary radical 12,
generating a new six-membered ring. Radicals 9 and 12 would
abstract a hydrogen atom from Bu3SnH, forming 10/11 or 13/
14, respectively. But hydrogen abstraction from Bu3SnH will
be sterically influenced by the location of R1, R2 and the
stereostructure of the fused ring system. If R2 stabilizes a
radical center, this might facilitate formation of radical 9
Scheme 2.

A. Zhou et al. / Tetrahedron 62 (2006) 4093–4102
4095
relative to radical 12, leadingto five-membered ring formation
and affording 10/11 with –CH2R2 either cis or trans to R1.
Secondary radical 9 might isomerize to form tertiary radical
12, however, formation of 9 was never observed. Radical 8
might also abstract hydrogen from HSnBu3 to generate N-acyl
cyclic ketene acetals 15/16, which can no longer cyclize. Ring
systems 13 (XZO) or 14 (XZS) would form by hydrogen
abstraction from Bu3SnH. Compounds 13 and 14 could exist
asfourpossiblediastereomericstructures.Theconfigurationat
C-3is(S),buttheC-10andC-11positionsmaybeeitherSorR.
No ring closure to generate 10 was detected. However, small
amounts of the ring-opened amidoesters 17a–d (5–9%) were
isolated. These were produced by aryl radical hydrogen
abstraction to give the corresponding N-acyl cyclic ketene-
N,O-acetal 15 (see Table 2). These very acid sensitive ketene
acetals were protonated to generate cations 16, either on silica
gel during column separation or during work-up. Attack by
wateratC-5of16was followed by ring-openingto afford 17a–
d. No attack by water occurred at C-4, adjacent to nitrogen on
16, during this ring-opening. Cyclization of 8 to 12
predominates, in accord with the greater stability of tertiary
radical 12 versus secondary radical 9. Furthermore, more
strain is present in radical 9, which contains two fused five-
membered rings.
To study the cyclization’s stereoselectivity, the R1 group
was varied (isopropyl, isobutyl, benzyl and methyl) and
different R2 groups were also employed (H, methyl, ethyl
and phenyl). Aryl radical cyclizations of N-(2-halobenzoyl)-
cyclic ketene-N,X(XZO, S)-acetals 3 and 4 proceeded
smoothly in dry refluxing benzene with Bu3SnH/AIBN
under argon using 3 (or 4)/Bu3SnH/AIBN mole ratios of
1:1:0.2 in dry benzene. After refluxing 10 h, benzene was
removed and flash chromatography (hexane/ethyl acetate
eluent) of the product mixtures afforded two main products
and one minor product (Table 2) from 3 and two major
products (Table 3) from 4. These findings were also verified
The stereochemistries of 13a and 13b were established
by NOESY experiments (Scheme 3) and coupling
constants. Products 13a1 and 13b1 (where R1Zi-Pr,
R2ZCH3) are given here as representative examples.
Large coupling constants (10.5 Hz) were observed
between Ha and Hf for 13a1, indicating the dihedral
angle (Hf–C–C–Ha) is near 1808. No cross-peak existed
between Ha and He. A weak cross-peak between Hf and
He indicated that Hf and He are located on the same side
of the molecule while Ha and He are on opposite sides.
In contrast to 13a1, an intense cross-peak between Ha
and He was observed for 13b1, demonstrating that He and
Ha are on the same side. Furthermore, a small coupling
constant (4.5 Hz) was observed between Ha and Hf.
There are no correlations from Hg to He for 13a1 and
by HPLC. Product structures were determined by a
combination of GC–MS, FT-IR, H/13C NMR, DEPT135
1
,
HETCOR and NOESY methods. Cyclizations of 3 are
summarized in Table 2 and Scheme 3.
Cyclization of 3 (R2Z–CH3, Table 2) to six-membered
rings predominated, generating 2,3,10,10a-tetrahydrooxa-
zolo-[3,2-b]isoquinolin-5-one ring systems 13a and 13b.
Table 2. Aryl radical cyclizations of N-2-halobenzoyl cyclic ketene-N,O-acetals
Entry
R
R1
R2
X
Product yields (%)a
13a
13b
17
1
2
3
4
5
6
7
8
H
H
H
H
p-CH3
p-CH3
H
–CH(CH3)2
–CH(CH3)2
–CH2CH(CH3)2
–CH2CH(CH3)2
–CH(CH3)2
–CH(CH3)2
–CH2Ph
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
Br
I
Br
I
Br
I
Br
I
44 (13a1)
42 (13a1)
41 (13a2)
44 (13a2)
42 (13a3)
40 (13a3)
38 (13a4)
37 (13a4)
29 (13b1)
28 (13b1)
33 (13b2)
31 (13b2)
28 (13b3)
29 (13b3)
34 (13b4)
35 (13b4)
7 (17a)
9 (17a)
6 (17b)
7 (17b)
8 (17c)
6 (17c)
8 (17d)
8 (17d)
H
–CH2Ph
a All yields are isolated yields based on 3. R2ZCH3 for each case listed.

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A. Zhou et al. / Tetrahedron 62 (2006) 4093–4102
Table 3. Aryl radical cyclizations of N-2-halobenzoyl cyclic ketene-N,S-acetals
Entry
R
R1 in 4
X
Product yields (%)a
14a
14b
1
2
3
4
5
6
7
H
H
H
H
–CH(CH3)2
–CH(CH3)2
–CH2CH(CH3)2
–CH2CH(CH3)2
–CH(CH3)2
Br
I
Br
I
Br
I
Br
46 (14a1)
49 (14a1)
37 (14a2)
38 (14a2)
36 (14a3)
37 (14a4)
46 (14a5)
32 (14b1)
33 (14b1)
33 (14b2)
30 (14b2)
31 (14b3)
30 (14b4)
33 (14b5)
p-CH3
p-CH3
m-OCH3
–CH2CH(CH3)2
–CH(CH3)2
a All yields are isolated yields based on 4.
13b1, but correlations from He to Hc and from He to Hd
were evident for both structures.
when R1Z–CH2Ph, R2Z–Et, 13b7 was isolated in yields of
40–43% and when R1Z–CH3, R2Z–Ph, 13b8 was isolated in
58–61%. In these cases, no product could be isolated where
the 10a hydrogen was up (e.g., cis to R2). The combined
steric effects of R1 and R2 clearly control the selectivity of
hydrogen abstraction from Bu3SnH by radical 12.
Of the 4 possible diastereomers of 13, only two, 13a and
13b, were isolated for each example in Table 2. Traces of
the other two diastereomers could be present, but we could
not separate or identify them. Radical 8 attacks the
intramolecular double bond from above stereoselectively
(e.g., trans to R1), resulting in radical 12 where R2 is trans to
R1. The steric effect from R1 favors H abstraction from
above while R2 favors abstraction from below, leading to
the lower 13a/13b selectivity observed.
The use of a phenyl group for R2 (in 3 or 4) is of special
interest because it could favor cyclization of 8 to radical 9
due to benzylic radical resonance stabilization. However, no
trace of 10 (or 11 when XZS) (Scheme 2) could be detected
when R2Z–Ph. It is unlikely that 9 (R2Z–Ph) ever formed,
suggesting that tertiary radical 12 is favored kinetically and,
possibly, thermodynamically.
The inherent hydrogen abstraction step’s selectivity
was probed by replacing the C-10 methyl group (R2) with
R2Z–H, –Ph, and –Et (Scheme 4). When R1Z–CH(CH3)2,
R2Z–H, 13a5 was isolated in yields of 60–63%, while
the yield of its diastereomer 13b5 is only 16–18%. When
R1Z–CH2Ph, R2Z–H, 13a6 was isolated in 49–52% yields,
while its (3S,10aS) diastereomer, 13b6, was isolated in 22–
25% yields. Clearly, the neighboring C-10 methyl group in
radical 12 lowers 13a/13b ratio obtained on hydrogen
abstraction versus when the CH3 is replaced by R2Z–H.
Upon replacing this C-10 CH3 group in 12 by R2Z–Et or
–Ph, hydrogen abstraction trans to R2 and cis to R1
predominates, producing 13b as the major product. Thus,
Aryl radical cyclizations of seven example N-(2-halobenz-
oyl)-cyclic ketene-N,S-acetals 4 were also conducted under
similar reaction conditions to generate the five pairs of
substituted-2,3,10,10a-tetrahydrooxazolo[3,2-b]isoqui-
nolin-5-ones 14a and 14b (Table 3). After cyclization and
flash chromatography purification (hexane/ethyl acetate
eluent), product structures were characterized by GC–MS,
1H/13C NMR, DEPT135, HETCOR and NOESY methods
(Table 3). These cyclizations were similar to those of 3, except
for the absence of acyclic amidothioester formation (analo-
gousto17)viaarylradicalhydrogenabstraction/ring-opening.
Scheme 3. Selected NOESY correlations for compounds 13a1 and 13b1.

A. Zhou et al. / Tetrahedron 62 (2006) 4093–4102
4097
Scheme 4.
Only six-membered ring formation occurred to produce 14a
and 14b in each case. No formation of ring system 11
could be detected. This favors the higher relative stability of
N,S-tertiary radical 12 versus 9.
this stereochemistry in both 14a and 14b as with 13a and
13b. The methyl group at C-10 on the central ring was trans
to the R2 functional groups of the thiazolidine ring in every
case. After cyclization, radical 12 (XZS) abstracted
hydrogen from Bu3SnH both trans and cis to the isopropyl
group to generate 14a/14b (Scheme 2) with the selectivities
given in Table 3. Various N,S heterocyclic analogs exhibit
Both 14a and 14b were formed by aryl radical attack trans to
R1 (i-Pr, or sec-Bu). NOESY experiments again confirmed
Scheme 5.

4098
A. Zhou et al. / Tetrahedron 62 (2006) 4093–4102
potential biological activity,14 hence this route may be
further exploited to prepare libraries of candidates.
‘singlet, doublet, triplet, quartet, and multiplet’, respect-
ively. GC–MS instruments were used. All reactions were
carried out under a dried argon atmosphere. Acetonitrile and
triethylamine were distilled from calcium hydride under
nitrogen. Dichloromethane and nitromethane were pre-dried
with CaCl2 and then distilled from calcium hydride under
nitrogen. Tetrahydrofuran (THF) was distilled from Na
metal/benzophenone ketyl. All other commercially obtained
reagents were used as received. The silica gel used for the
column chromatography was purchased from Aldrich
Company (70–230 mesh).
To improve the selectivity in the hydrogen abstraction step
by radical 12, sterically bulky tris(trimethylsilyl)silane was
used as the hydrogen atom source in place of tributyltin
hydride, This silane is known to react with radicals more
slowly than stannanes.19 The reactions were conducted at
80 8C in refluxing benzene for 8 h, using tris(trimethyl-
silyl)silane/AIBN/N-acyl cyclic ketene-N,X-acetals mole
ratios of 1.2:1.0:0.2. Half of the AIBN was added at the
beginning of the reaction, and the second half was added
after 2 h. Example results are summarized in Scheme 5.
Using bulky tris(trimethylsilyl)silane as the hydrogen atom
donor increases the yields and the selectivities for hydrogen
abstraction trans to R1 to form products 13a and 14a (57–
78%). The yields of 13b and 14b from hydrogen abstraction
cis to R1 decrease to 5–18% in all these reactions. Increasing
the steric bulk of the hydrogen atom donor enhances
hydrogen abstraction selectivity trans to R1. Interestingly,
unlike Bu3SnH, the ring-opened products 17 were not found
in these reactions, even at only a slight excess of
tris(trimethylsilyl)silane over the N-acyl cyclic ketene-
N,X(XZO, S)-acetals. Thus, hydrogen abstraction by aryl
radical 8 (Scheme 2) is slowed relative to the use of
Bu3SnH. Cyclization to form the five-membered ring
(radical 9, products 10, 11) was also not observed in these
reactions. Tris(trimethylsilyl)silane provides higher selec-
tivities than tributylstannane hydride.
4.1.1. (3S,10R,10aS)-3-Isopropyl-10-methyl-2,3,10,10a-
tetrahydrooxazolo[3,2-b]isoquinolin-5-one (13a1). 2-Bro-
mobenzoyl chloride (220 mg, 1.00 mmol) was added
dropwise to a stirred solution of 2-ethyloxazoline 1a
(157 mg, 1 mmol) and triethylamine (130 mg, 1.20 mmol)
in benzene 60 mL at room temperature. Then this solution
was stirred for 3 h. The product mixture was filtered and the
solvent was removed on a rotary evaporator. Dry benzene
(60 mL) was added to the crude residue. Then Bu3SnH
(0.36 mL, 1 mmol) and AIBN (34 mg, 0.2 mmol) were also
added. The mixture was refluxed for 10 h and then the
solvent was removed by rotary evaporation. The crude
product was subjected to flash chromatography on silica gel
to afford (3S,10R,10aS)-3-alkyl-10-methyl-2,3,10,10a-tet-
rahydrooxazolo[3,2-b]isoquinolin-5-one (13a1, 44%,
107 mg), (3S,10R,10aR)-3-alkyl-10-methyl-2,3,10,10a-tet-
rahydrooxazolo[3,2-b]isoquinolin-5-one (13b1, 29%,
70 mg) and propionic acid 2-benzoylamino-3-methylbutyl
ester (17a, 7%, 17 mg). The same procedure was applied to
aryl radical cyclizations of all the N-acyl cyclic ketene-N,O-
acetals and N-acyl cyclic ketene-N,S-acetals employed in
this work.
3. Conclusions
In conclusion, 2-alkyloxazolines 1 and 2-alkylthiazolines 2
react with 2-halobenzoyl chlorides to form N-(2-halobenz-
oyl)-cyclic ketene-N,O-acetals 3 and N-(2-halobenzoyl)-
cyclic ketene-N,S-acetals 4 in excellent yields, respectively.
Both 3 and 4 can then readily undergo stereocontrolled
intramolecular aryl radical cyclizations to afford N,O- and
N,S-heterocycles via six-membered ring formation. These
results suggest reasonable stability of N,O- and N,S-tertiary
radicals, 12. In contrast, the difficulty encountered in radical
initiated polymerizations of 2-methylene-1,3-dioxolanes
and 2-methylene-1,3-dioxanes15a indicated the correspond-
ing O,O-tertiary radicals are either formed sluggishly or
cannot readily add to a double bond. The selectivity in the
hydrogen abstraction step by radical 12 is improved by
replacing Bu3SnH with more bulky (Me3Si)3SiH.
Mp 113–115 8C. 1H NMR (300 MHz, CDCl3): d 8.12–7.28
(m, 4H), 4.63 (d, JZ10.5 Hz, 1H), 4.19 (overlap m, 1H),
4.17 (overlap m, 1H), 3.87 (dd, JZ7.5, 9.3 Hz, 1H), 3.13
(m, 1H), 2.71 (m, 1H), 1.50 (d, JZ6.6 Hz, 3H), 0.97 (d, JZ
6.9 Hz, 3H), 0.88 (d, JZ6.9 Hz, 3H). 13C NMR (75 MHz,
CDCl3): d 161.6, 139.3, 132.3, 129.8, 127.7, 127.1, 124.9,
91.6, 66.6, 60.4, 37.7, 27.3, 19.5, 15.9, 12.9. MS (EI) m/z
(%): 245 (MC), 202 (100), 158, 132, 104, 77, 51. IR (neat):
2960, 2874, 1658, 1466, 1423, 1352, 1200, 1058, 742 cmK1
.
Anal. Calcd for C15H19O2N: C, 73.44; H, 7.81; N, 5.71;
Found: C, 73.25; H, 7.91; N, 5.86.
4.1.2. (3S,10R,10aR)-3-Isopropyl-10-methyl-2,3,10,10a-
tetrahydrooxazolo[3,2-b]isoquinolin-5-one (13b1). Mp
113–115 8C. 1H NMR (300 MHz, CDCl3): d 8.00–7.22
(m, 4H), 5.37 (d, JZ4.5 Hz, 1H), 4.34 (dd, JZ5.4, 10.8 Hz,
1H), 4.13 (dd, JZ5.4, 7.8 Hz, 1H), 4.00 (dd, JZ4.5, 7.8 Hz,
1H), 3.22 (m, 1H), 2.54 (m, 1H), 1.11 (d, JZ6.9 Hz, 3H),
0.96 (d, JZ6.9 Hz, 3H), 0.93 (d, JZ6.9 Hz, 3H). 13C NMR
(75 MHz, CDCl3): d 161.3, 140.7, 132.1, 128.9, 127.9,
127.6, 127.5, 88.6, 67.7, 60.0, 38.6, 29.2, 18.9, 16.8, 15.3.
MS (EI) m/z (%): 245 (MC), 202 (100), 158, 132, 104, 77,
51. IR (neat): 2962, 2874, 1657, 1465, 1421, 1355, 1207,
4. Experimental
4.1. General methods
Melting points were recorded with a Mel-Temp apparatus
and were uncorrected (a heating rate of 2 8C/min was used
near the mp). The IR spectra were recorded on FT infrared
spectrometer as films on KBr plates. The 1H and 13C NMR
spectra were recorded using a 300 MHz spectrometer
operating at 300 MHz for proton and 75 MHz for carbon.
Chemical shifts were reported in parts per million downfield
from Me4Si used as the internal standard. Splitting patterns
are designated as ‘s, d, t, q, and m’; these symbols indicate
1055, 740 cmK1
.
4.1.3. Propionic acid 2-benzoylamino-3-methylbutyl
ester (17a). Mp 118–120 8C. 1H NMR (300 MHz,
CDCl3): d 7.78–7.44 (m, 5H), 6.51 (d, JZ8.4 Hz, 1H),

A. Zhou et al. / Tetrahedron 62 (2006) 4093–4102
4099
4.39 (dd, JZ6.9, 11.1 Hz, 1H), 4.34 (m, 1H), 4.13 (dd, JZ
3.6, 11.1 Hz, 1H), 2.33 (q, JZ7.2 Hz, 2H), 1.94 (m, 1H),
1.10 (t, JZ7.2 Hz, 3H), 1.02 (d, JZ7.8 Hz, 3H), 1.00 (d,
JZ7.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 174.7,
167.3, 134.6, 131.4, 128.5, 126.8, 64.3, 53.9, 29.8, 27.4,
19.2, 18.6, 9.0. MS (EI) m/z (%): 263 (MC), 189, 146, 105
(100), 86, 77, 51. IR (neat): 3308 (broad), 3030, 2978, 2944,
1738, 1640, 1538, 1183, 1084, 1028, 700 cmK1. Anal.
Calcd for C15H21O3N: C, 68.42; H, 8.04; N, 5.32; Found: C,
68.70; H, 7.83; N, 5.18.
4.1.8. (3S,10R,10aR)-3-Isopropyl-8,10-dimethyl-
2,3,10,10a-tetrahydrooxazolo[3,2-b]isoquinolin-5-one
1
(13b3). Mp 116–118 8C. H NMR (300 MHz, CDCl3): d
7.89–7.03 (m, 3H), 5.34 (d, JZ4.2 Hz, 1H), 4.31 (dd, JZ
4.5, 6.8 Hz, 1H), 4.11 (dd, JZ6.6, 8.7 Hz, 1H), 4.00 (dd,
JZ4.5, 8.4 Hz, 1H), 3.16 (m, 1H), 2.53 (m, 1H), 2.38 (s,
3H), 1.09 (d, JZ7.2 Hz, 3H), 0.95 (d, JZ7.2 Hz, 3H), 0.92
(d, JZ7.2 Hz, 3H). 13C NMR (CDCl3): d 161.4, 142.6,
140.7, 128.2, 127.9, 126.2, 121.3, 88.6, 67.7, 60.0, 39.3,
38.6, 29.2, 21.4, 18.9, 16.7, 15.3. MS (EI) m/z: 259 (MC),
216, 172, 146 (100), 117, 91, 77, 51. IR (neat): 2968, 2878,
1656, 1461, 1418, 1345, 1200, 1054, 740 cmK1
.
4.1.4. (3S,10R,10aS)-3-Isobutyl-10-methyl-2,3,10,10a-
tetrahydrooxazolo[3,2-b]isoquinolin-5-one (13a2). Mp
115–117 8C. 1H NMR (300 MHz, CDCl3): d 8.09–7.27
(m, 4H), 4.62 (d, JZ10.5 Hz, 1H), 4.26 (m, 1H), 4.10 (m,
1H), 3.96 (dd, JZ6.0, 7.8 Hz, 1H), 3.04 (m, 1H), 2.04 (m,
1H), 1.67 (m, 1H), 1.51 (d, JZ6.9 Hz, 3H), 1.01 (d, JZ
6.9 Hz, 3H), 0.96 (d, JZ6.9 Hz, 3H). 13C NMR (CDCl3): d
161.2, 139.2, 132.3, 130.0, 127.7, 127.3, 124.9, 91.3, 70.9,
54.4, 41.7, 38.7, 26.0, 23.6, 21.7, 12.8. MS (EI) m/z: 259
(MC), 244, 203 (100), 132, 104, 77, 63, 51. IR (neat): 2962,
4.1.9. Propionic acid 3-methyl-2-(4-methylbenzoyl-
amino)-butyl ester (17c). Mp 123–125 8C. 1H NMR
(300 MHz, CDCl3): d 7.68–7.25 (m, 4H), 6.25 (d, JZ
8.2 Hz, 1H), 4.39 (dd, JZ6.6, 11.1 Hz, 1H), 4.24 (m, 1H),
4.13 (dd, JZ3.3, 11.1 Hz, 1H), 2.40 (s, 3H), 2.32 (q, JZ
7.5 Hz, 2H), 1.93 (m, 1H), 1.10 (t, JZ7.2 Hz, 3H), 1.00 (d,
JZ6.3 Hz, 6H). 13C NMR (CDCl3): d 161.4, 142.6, 140.7,
128.2, 128.1, 121.3, 88.6, 67.7, 60.0, 39.3, 38.6, 29.2, 18.9,
16.7, 15.3. MS (EI) m/z: 278 (MCCH), 262, 203, 161, 146,
119 (100), 91, 77. IR (neat): 3306 (broad), 3029, 2976,
2947, 1739, 1650, 1534, 1187, 1082, 1026, 704 cmK1. Anal.
Calcd for C16H23O3N: C, 69.29; H, 8.36; N, 5.05; Found: C,
69.21; H, 8.42; N, 4.93.
2878, 1657, 1470, 1421, 1350, 1204, 1057, 741 cmK1
.
4.1.5. (3S,10R,10aR)-3-Isobutyl-10-methyl-2,3,10,10a-
tetrahydrooxazolo[3,2-b]isoquinolin-5-one (13b2). Mp
115–117 8C. 1H NMR (300 MHz, CDCl3): d 8.07–7.29
(m, 4H), 5.43 (d, JZ4.5 Hz, 1H), 4.50 (m, 1H), 4.36 (dd,
JZ6.6, 8.1 Hz, 1H), 3.89 (dd, JZ4.5, 8.1 Hz, 1H), 3.32 (m,
1H), 2.18 (m, 1H), 1.71 (m, 1H), 1.49 (m, 1H), 1.10 (d, JZ
7.2 Hz, 3H), 1.09 (d, JZ6.3 Hz, 3H), 0.99 (d, JZ6.3 Hz,
3H). 13C NMR (CDCl3): d 160.9, 140.7, 132.0, 128.9, 127.7,
127.6, 121.3, 87.2, 72.0, 53.8, 41.0, 38.1, 25.6, 23.4, 21.9,
15.3. MS (EI) m/z: 259 (MC), 244, 202 (100), 132, 104, 77,
63, 51. IR (neat): 2960, 2874, 1658, 1466, 1423, 1352, 1200,
4.1.10. (3S,10R,10aS)-3-Benzyl-10-methyl-2,3,10,10a-
tetrahydrooxazolo[3,2-b]isoquinolin-5-one (13a4). Mp
128–130 8C. 1H NMR (300 MHz, CDCl3): d 8.23–7.35
(m, 9H), 4.73 (d, JZ10.5 Hz, 1H), 4.51 (m, 1H), 4.23 (m,
1H), 3.91 (dd, JZ6.3, 8.1 Hz, 1H), 3.68 (m, 1H), 3.06 (m,
1H), 2.81 (dd, JZ10.2, 12.9 Hz, 1H), 1.57 (d, JZ6.9 Hz,
3H). 13C NMR (CDCl3): d 161.4, 139.2, 137.9, 132.4, 129.6,
128.7, 128.6, 127.7, 127.3, 126.6, 124.9, 91.6, 69.6, 57.0,
38.4, 38.1, 12.8. MS (EI) m/z: 293 (MC), 278, 202 (100),
174, 158, 132, 115, 104, 91, 77, 65, 51. IR (neat): 2978,
1058, 742 cmK1
.
4.1.6. Propionic acid 2-benzoylamino-4-methylpentyl
ester (17b). Mp 121–123 8C. 1H NMR (300 MHz,
CDCl3): d 7.77–7.41 (m, 5H), 6.42 (d, JZ7.8 Hz, 1H),
4.51 (m, 1H), 4.24 (dd, JZ6.3, 11.1 Hz, 1H), 4.13 (dd, JZ
3.3, 11.1 Hz, 1H), 2.33 (q, JZ7.5 Hz, 2H), 1.69 (m, 1H),
1.50 (m, 1H), 1.43 (m, 1H), 1.11 (t, JZ7.2 Hz, 3H), 0.96 (d,
JZ6.3 Hz, 3H), 0.94 (d, JZ6.3 Hz, 3H). 13C NMR
(CDCl3): d 174.5, 167.0, 134.4, 131.3, 128.4, 126.8, 66.1,
47.2, 40.6, 27.4, 24.8, 22.9, 22.2, 9.0. MS (EI) m/z: 277
(MC), 203, 146, 105 (100), 77, 63, 57, 51. IR (neat): 3303
(broad), 3035, 2983, 2940, 1735, 1642, 1539, 1188, 1080,
1021, 695 cmK1. Anal. Calcd for C16H21O2N: C, 69.29; H,
8.36; N, 5.05; Found: C, 69.11; H, 8.42; N, 5.16.
2902, 2884, 1676, 1466, 1398, 1352, 1225, 1057, 727 cmK1
.
4.1.11. (3S,10R,10aR)-3-Benzyl-10-methyl-2,3,10,10a-
tetrahydrooxazolo[3,2-b]isoquinolin-5-one (13b4). Mp
128–130 8C. 1H NMR (300 MHz, CDCl3): d 8.14–7.30
(m, 9H), 5.31 (d, JZ3.9 Hz, 1H), 4.69 (m, 1H), 4.19 (t, JZ
6.9 Hz, 1H), 4.00 (dd, JZ5.4, 7.8 Hz, 1H), 3.58 (dd, JZ1.2,
11.7 Hz, 1H), 3.29 (m, 1H), 2.97 (dd, JZ10.2, 12.6 Hz, 1H),
1.18 (d, JZ6.9 Hz, 3H). 13C NMR (CDCl3): d 161.3, 140.9,
137.2, 132.3, 129.5, 128.7, 128.6, 127.8, 127.7, 127.5,
126.67, 87.9, 70.6, 56.1, 38.2, 37.2, 15.3. MS (EI) m/z: 293
(MC), 278, 202 (100), 174, 158, 115, 103, 91, 77, 65, 51. IR
(neat): 2979, 2904, 2887, 1674, 1464, 1396, 1355, 1228,
1064, 724 cmK1. Anal. Calcd for C19H19O2N: C, 77.79; H,
6.53; N, 4.77; Found: C, 77.70; H, 6.46; N, 4.58.
4.1.7. (3S,10R,10aS)-3-Isopropyl-8,10-dimethyl-2,3,10,10a-
tetrahydrooxazolo[3,2-b]isoquinolin-5-one (13a3). Mp
116–118 8C. 1H NMR (300 MHz, CDCl3): d 8.00–7.17
(m, 3H), 4.60 (d, JZ10.8 Hz, 1H), 4.18 (overlap m, 1H),
4.16 (overlap m, 1H), 3.85 (dd, JZ7.2, 9.3 Hz, 1H), 3.09
(m, 1H), 2.65 (m, 1H), 2.42 (s, 3H), 1.48 (d, JZ6.6 Hz, 3H),
0.96 (d, JZ6.9 Hz, 3H), 0.88 (d, JZ6.9 Hz, 3H). 13C NMR
(CDCl3): d 161.9, 142.8, 139.4, 127.9, 127.2, 125.6, 91.8,
66.7, 60.4, 37.7, 27.4, 21.7, 19.5, 15.9, 12.9. MS (EI) m/z:
259 (MC), 216, 172, 146 (100), 117, 91, 77, 51. IR (neat):
4.1.12. Propionic acid 2-benzoylamino-3-phenylpropyl
ester (17d). Mp 138–140 8C. 1H NMR (300 MHz, CDCl3):
d 7.80–7.32 (m, 10H), 6.82 (d, JZ7.5 Hz, 1H), 4.69 (m,
1H), 4.27 (overlap m, 1H), 4.22 (overlap m, 1H), 3.10 (dd,
JZ6.0, 13.5 Hz, 1H), 2.96 (dd, JZ7.5, 13.5 Hz, 1H), 2.41
(q, JZ7.5 Hz, 2H), 1.19 (d, JZ6.9 Hz, 3H). 13C NMR
(CDCl3): d 174.6, 167.0, 136.9, 134.2, 131.3, 129.1, 128.6,
128.5, 126.8, 126.6, 64.5, 50.2, 37.3, 27.3, 8.9. MS (EI) m/z:
312 (MC), 238 (100), 191, 146, 118, 105, 91, 77, 51. IR
(neat): 3345 (broad), 3030, 2967, 2904, 1767, 1643, 1524,
2970, 2880, 1654, 1463, 1420, 1349, 1203, 1056, 738 cmK1
.
Anal. Calcd for C16H21O2N: C, 74.10; H, 8.16; N, 5.40;
Found: C, 73.91; H, 8.03; N, 5.38.

4100
A. Zhou et al. / Tetrahedron 62 (2006) 4093–4102
1145, 1037, 1015, 711 cmK1. Anal. Calcd for C19H21O3N:
C, 73.29; H, 6.80; N, 4.50; Found: C, 73.57; H, 6.56;
N, 4.31.
1H), 2.90 (d, JZ12.30 Hz, 1H), 2.54 (m, 1H), 1.45 (d, JZ
6.90 Hz, 3H), 1.01 (d, JZ6.90 Hz, 3H), 1.00 (d, JZ
6.90 Hz, 3H). 13C NMR (CDCl3): d 163.6, 142.0, 132.2,
129.8, 128.4, 127.1, 124.1, 69.5, 66.0, 38.9, 30.6, 29.8, 20.0,
18.1 and 15.7. MS (EI) m/z: 261 (MC), 218 (100), 159, 132.
IR (neat): 2961, 2928, 2873, 1641, 1380 cmK1. Anal. Calcd
for C15H19OSN: C, 68.93; H, 7.33; N, 5.36; S, 12.27; Found:
C, 68.76; H, 7.41; N, 5.51; S, 12.12.
4.1.13. (3S,10aS)-3-Isopropyl-2,3,10,10a-tetrahydro-
oxazolo[3,2-b]isoquinolin-5-one (13a5). Mp 110–112 8C.
1H NMR (300 MHz, CDCl3): d 8.08–7.39 (m, 4H), 5.06 (dd,
JZ3.6, 11.7 Hz, 1H), 4.19 (overlap m, 1H), 4.17 (overlap
m, 1H), 3.88 (dd, JZ7.8, 9.3 Hz, 1H), 3.26 (dd, JZ3.6,
15.0 Hz, 1H), 3.09 (m, 1H), 2.70 (m, 1H), 1.62 (s, 3H), 0.97
(d, JZ6.9 Hz, 3H), 0.88 (d, JZ6.9 Hz, 3H). 13C NMR
(CDCl3): d 161.4, 139.3, 132.1, 129.8, 127.9, 127.5, 124.9,
87.1, 66.9, 60.0, 37.7, 27.2, 15.9, 12.9. MS (EI) m/z (%): 231
(MC), 188 (100), 144, 132, 104, 77, 51. IR (neat): 2960,
2874, 1658, 1466, 1423, 1352, 1200, 1058, 742 cmK1. Anal.
Calcd for C14H17O2N: C, 72.70; H, 7.41; N, 6.06; Found: C,
72.88; H, 7.27; N, 6.23.
4.1.18. 4(3S,10R,10aR)-3-Isopropyl-10-methyl-2,3,10,10a-
tetrahydrothiazolo[3,2-b]isoquinolin-5-one (14b1). Mp
142–144 8C. 1H NMR (300 MHz, CDCl3): d 8.01–7.17
(m, 4H), 5.21 (d, JZ3.90 Hz, 1H), 4.79 (dd, JZ5.70,
8.40 Hz, 1H), 3.07 (dd, JZ5.70, 10.80 Hz, 1H), 2.99 (m,
1H), 2.87 (d, JZ10.80 Hz, 1H), 2.24 (m, 1H), 1.26 (d, JZ
7.20 Hz, 3H), 1.03 (d, JZ7.20 Hz, 3H), 0.98 (d, JZ
6.90 Hz, 3H). 13C NMR (CDCl3): d 162.1, 142.7, 131.8,
128.3, 128.1, 127.1, 126.4, 65.6, 63.6, 39.0, 32.0, 30.6, 23.2,
19.5 and 15.7. MS (EI) m/z: 261 (MC), 218 (100), 159, 132.
4.1.14. (3S,10aS)-3-Benzyl-2,3,10,10a-tetrahydrooxa-
zolo[3,2-b]isoquinolin-5-one (13a6). Mp 125–127 8C. H
IR (neat): 2959, 2928, 2871, 1645, 1380 cmK1
.
1
NMR (300 MHz, CDCl3): d 8.15–7.33 (m, 9H), 5.19 (dd,
JZ4.8, 10.8 Hz, 1H), 4.72 (m, 1H), 4.24 (dd, JZ6.9,
8.7 Hz, 1H), 3.93 (dd, JZ6.0, 8.4 Hz, 1H), 3.57 (dd, JZ3.3,
13.2 Hz, 1H), 3.26 (m, 1H), 3.08 (m, 1H), 2.99 (m, 1H). 13C
NMR (CDCl3): d 161.5, 137.1, 133.5, 132.1, 129.5, 128.6,
128.1, 127.7, 127.6, 126.7, 86.2, 70.1, 55.8, 37.2, 34.6. MS
(EI) m/z: 279 (MC), 188 (100), 160, 144, 118, 103, 91, 65,
50. IR (neat): 2960, 2874, 1658, 1466, 1423, 1352, 1200,
1058, 742 cmK1. Anal. Calcd for C18H17O2N: C, 77.40; H,
6.13; N, 5.01; Found: C, 77.31; H, 6.30; N, 5.13.
4.1.19. (3S,10R,10aS)-3-Isobutyl-10-methyl-2,3,10,10a-
tetrahydrothiazolo[3,2-b]isoquinolin-5-one (14a2). Mp
144–146 8C. 1H NMR (300 MHz, CDCl3): d 8.10–7.27
(m, 4H), 4.72 (d, JZ12.00 Hz, 1H), 4.67 (m, 1H), 3.15 (m,
1H), 3.15 (m, 1H), 2.85 (d, JZ12.00 Hz, 1H), 1.82–1.67 (m,
2H), 1.64 (m, 1H), 1.46 (d, JZ6.80 Hz, 3H), 1.06 (d, JZ
6.34 Hz, 3H), 0.96 (d, JZ6.30 Hz, 3H). 13C NMR (CDCl3):
d 162.4, 141.5, 132.1, 130.0, 128.0, 127.2, 123.9, 68.9, 60.0,
42.6, 39.3, 33.4, 26.3, 23.8, 21.5 and 15.6. MS (EI) m/z: 275
(MCCH), 260, 219 (100), 132, 104. IR (neat): 2960, 2928,
2869, 1650, 1456, 1385, 752 cmK1
.
4.1.15. (3S,10R,10aR)-3-Benzyl-10-ethyl-2,3,10,10a-
tetrahydrooxazolo[3,2-b]isoquinolin-5-one (13b7). Mp
130–133 8C. 1H NMR (300 MHz, CDCl3): d 8.06–7.26
(m, 9H), 5.26 (d, JZ3.6 Hz, 1H), 4.58 (m, 1H), 4.11 (dd,
JZ6.9, 8.1 Hz, 1H), 3.90 (dd, JZ5.4, 8.1 Hz, 1H), 3.49 (dd,
JZ2.4, 13.2 Hz, 1H), 2.89 (overlap m, 1H), 2.85 (overlap
m, 1H), 1.87 (m, 1H), 1.25 (m, 1H), 0.77 (t, JZ7.5 Hz, 3H).
13C NMR (CDCl3): d 161.4, 138.5, 137.2, 131.4, 129.4,
129.2, 129.0, 128.5, 127.7, 127.6, 126.6, 88.3, 70.7, 55.9,
44.9, 39.3, 37.1, 23.3, 21.1, 11.0. MS (EI) m/z: 308 (MCC
H), 278, 216 (100), 198, 172, 165, 131, 115, 91, 77, 65, 51.
IR (neat): 2960, 2874, 1658, 1466, 1423, 1352, 1200, 1058,
4.1.20. (3S,10R,10aR)-3-Isobutyl-10-methyl-2,3,10,10a-
tetrahydrothiazolo[3,2-b]isoquinolin-5-one (14b2). Mp
144–146 8C. 1H NMR (300 MHz, CDCl3): d 8.03–7.17
(m, 4H), 5.23 (d, JZ3.80 Hz, 1H), 5.08 (m, 1H), 3.13 (dd,
JZ5.80, 10.80 Hz, 1H), 2.99 (m, 1H), 2.78 (d, JZ10.80 Hz,
1H), 1.66–1.63 (m, 2H), 1.38 (m, 1H), 1.27 (d, JZ6.90 Hz,
3H), 1.06 (d, JZ5.70 Hz, 3H), 0.96 (d, JZ5.70 Hz, 3H).
13C NMR (CDCl3): d 162.2, 143.5, 132.5, 130.5, 128.8,
127.7, 127.1, 63.5, 59.1, 41.3, 39.4, 34.1, 26.4, 23.9, 22.3
and 15.8. MS (EI) m/z: 275 (MCCH), 260, 219 (100), 132,
104. IR (neat): 2956, 2928, 2869, 1651, 1457, 1385,
752 cmK1. Anal. Calcd for C16H21OSN: C, 69.78; H,
7.69; N, 5.09; S, 11.64; Found: C, 69.48; H, 7.84; N, 5.22; S,
11.38.
742 cmK1
.
4.1.16. (3S,10R,10aR)-3-Methyl-10-phenyl-2,3,10,10a-
tetrahydrooxazolo[3,2-b]isoquinolin-5-one (13b8). Mp
122–125 8C. 1H NMR (300 MHz, CDCl3): d 8.15–6.98
(m, 9H), 5.63 (d, JZ4.8 Hz, 1H), 4.44 (d, JZ4.8 Hz, 1H),
4.18 (m, 1H), 3.47 (dd, JZ3.3, 8.1 Hz, 1H), 3.25 (dd, JZ
6.3, 7.8 Hz, 1H), 1.36 (d, JZ6.3 Hz, 3H). 13C NMR
(CDCl3): d 161.4, 136.8, 136.1, 132.6, 130.5, 129.5, 129.0,
128.2, 128.1, 127.6, 127.2, 87.3, 72.7, 50.5, 49.1, 17.8. MS
(EI) m/z: 280 (MCCH), 194, 165 (100), 139, 115, 86, 77,
51. IR (neat): 2960, 2874, 1658, 1466, 1423, 1352, 1200,
1058, 742 cmK1. Anal. Calcd for C18H17O2N: C, 77.40; H,
6.13; N, 5.01; Found: C, 77.46; H, 6.02; N, 5.24.
4.1.21. (3S,10R,10aS)-3-Isopropyl-8,10-dimethyl-2,3,10,10a-
tetrahydrothiazolo[3,2-b]isoquinolin-5-one (14a3). Mp
147–149 8C. 1H NMR (300 MHz, CDCl3): d 8.03–7.12
(m, 3H), 4.75 (d, JZ12.00 Hz, 1H), 4.52 (m, 1H), 3.19 (m,
1H), 3.07 (dd, JZ7.21, 12.23 Hz, 1H), 2.90 (d, JZ
12.23 Hz, 1H), 2.51 (m, 1H), 2.42 (s, 3H), 1.45 (d, JZ
6.80 Hz, 3H), 1.00 (d, JZ6.80 Hz, 6H). 13C NMR (CDCl3):
d 163.8, 142.8, 142.0, 128.5, 127.9, 127.3, 124.8, 69.6, 65.9,
38.8, 30.7, 29.9, 21.8, 20.0, 18.2 and 15.7. MS (EI) m/z: 275
(MCCH), 232 (100), 173, 146. IR (neat): 2960, 2928, 2873,
1642, 1381 cmK1
.
4.1.17. (3S,10R,10aS)-3-Isopropyl-10-methyl-2,3,10,10a-
tetrahydrothiazolo[3,2-b]isoquinolin-5-one (14a1). Mp
142–144 8C. 1H NMR (300 MHz, CDCl3): d 8.14–7.32
(m, 4H), 4.77 (d, JZ11.70 Hz, 1H), 4.45 (dd, JZ6.00,
6.20 Hz, 1H), 3.22 (m, 1H), 3.07 (dd, JZ7.20, 12.30 Hz,
4.1.22. (3S,10R,10aR)-3-Isopropyl-8,10-dimethyl-
2,3,10,10a-tetrahydrothiazolo[3,2-b]isoquinolin-5-one
1
(14b3). Mp 146–148 8C. H NMR (300 MHz, CDCl3): d

A. Zhou et al. / Tetrahedron 62 (2006) 4093–4102
4101
7.90–6.99 (m, 3H), 5.20 (d, JZ3.80 Hz, 1H), 4.78 (dd, JZ
Acknowledgements
6.20, 8.20 Hz, 1H), 3.06 (dd, JZ7.21, 10.96 Hz, 1H), 2.93
(m, 1H), 2.87 (d, JZ10.96 Hz, 1H), 2.39 (s, 3H), 2.23 (m,
1H), 1.25 (d, JZ7.00 Hz, 3H), 1.03 (d, JZ6.70 Hz, 3H),
0.98 (d, JZ6.70 Hz, 3H). 13C NMR (CDCl3): d 162.8,
143.3, 142.9, 129.0, 128.5, 127.5, 126.1, 66.0, 64.3, 39.4,
32.6, 31.2, 21.9, 20.1, 20.0 and 16.2. MS (EI) m/z: 275
(MCCH), 232 (100), 173, 146. IR (neat): 2960, 2928, 2873,
Partial support of this work by the National Science
Foundation, Grant No. EPS 012618 and by Mississippi
State University is acknowledged. Dr. E.A. Alley is thanked
for obtaining the mass spectra in the supplementary data.
1650, 1377 cmK1
.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2006.02.
018.
4.1.23. (3S,10R,10aS)-3-Isobutyl-8,10-dimethyl-2,3,10,10a-
tetrahydrothiazolo[3,2-b]isoquinolin-5-one (14a4). Mp
145–147 8C. 1H NMR (300 MHz, CDCl3): d 8.00–7.10
(m, 3H), 4.71 (d, JZ12.00 Hz, 1H), 4.68 (m, 1H), 3.14 (m,
1H), 3.10 (m, 1H), 2.84 (d, JZ12.00 Hz, 1H), 2.41 (s, 3H),
1.78 (m, 2H), 1.64 (m, 1H), 1.44 (d, JZ6.80 Hz, 3H), 1.05
(d, JZ6.80 Hz, 3H), 0.96 (d, JZ6.40 Hz, 3H). 13C NMR
(CDCl3): d 162.9, 143.0, 141.9, 128.5, 128.3, 127.5, 125.0,
69.3, 60.3, 43.1, 39.6, 33.8, 26.7, 24.2, 22.0, 21.8 and 16.0.
MS (EI) m/z: 289 (MCCH), 274, 233, 200, 174, 146 (100),
References and notes
1. (a) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon–Carbon Bonds; Pergamon: Oxford, 1986. (b) Curran,
D. P. In Trost, B. M., Fleming, I., Eds.; Comprehensive
Organic Synthesis; Pergamon: Oxford, 1991; Vol. 4, p 715. (c)
Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in
Organic Synthesis; Academic: London, 1992.
117. IR (neat): 2956, 2932, 2869, 1650, 1456, 1385 cmK1
.
Anal. Calcd for C17H23OSN: C, 70.55; H, 8.01; N, 4.84; S,
11.08; Found: C, 70.67; H, 7.91; N, 4.68; 11.32.
2. (a) Leffler, J. E. An Introduction to Free Radicals; Wiley-
interscience: New York, 1995. (b) Fossey, J.; Lefort, D.;
Sorba, J. Free Radicals in Organic Chemistry; Wiley: New
York, 1995. (c) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: Weinheim, 1998.
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4.1.24. (3S,10R,10aR)-3-Isobutyl-8,10-dimethyl-2,3,10,10a-
tetrahydrothiazolo[3,2-b]isoquinolin-5-one (14b4). Mp
145–147 8C. H NMR (300 MHz, CDCl3): d 7.91–6.99 (m,
1
3H), 5.20 (d, JZ3.60 Hz, 1H), 5.06 (m, 1H), 3.12 (dd, JZ5.80,
10.80 Hz, 1H), 2.92 (m, 1H), 2.76 (d, JZ10.80 Hz, 1H), 2.39 (s,
3H), 1.71–1.59 (m, 2H), 1.37 (m, 1H), 1.25 (d, JZ7.00 Hz, 3H),
1.03 (d, JZ6.40 Hz, 3H), 0.98 (d, JZ6.40 Hz, 3H). 13C NMR
(CDCl3): d 161.9, 143.1, 142.6, 128.4, 128.1, 127.3, 125.6, 63.2,
58.6, 40.9, 39.1, 33.7, 26.0, 23.5, 21.9, 21.5 and 15.4. MS (EI)
m/z: 288 (MC), 274, 233, 200, 174, 146 (100), 117. IR (neat):
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2960, 2932, 2869, 1654, 1456, 1385 cmK1
.
4.1.25. (3S,10R,10aS)-3-Isopropyl-7-methoxy-10-
5. (a) Basak, A.; Bag, S. S.; Rudra, K. R. Chem. Lett. 2002, 710.
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methyl-2,3,10,10a-tetrahydrothiazolo[3,2-b]isoquinolin-
5-one (14a5). Mp 138–140 8C. 1H NMR (300 MHz,
CDCl3): d 7.66–7.04 (m, 3H), 4.74 (d, JZ12.00 Hz, 1H),
4.52 (t, JZ6.10 Hz, 1H), 3.85 (s, 3H), 3.17 (m, 1H), 3.09
(dd, JZ7.31, 12.23 Hz, 1H), 2.91 (d, JZ12.23 Hz, 1H),
2.51 (m, 1H), 1.43 (d, JZ6.80 Hz, 3H), 1.00 (d, JZ6.80 Hz,
6H). 13C NMR (CDCl3): d 163.6, 158.8, 134.4, 131.0, 125.4,
119.4, 111.8, 69.8, 66.1, 55.5, 38.3, 30.7, 30.0, 20.1, 18.2
and 15.9. MS (EI) m/z: 291 (MCCH), 248 (100), 189, 162,
134, 119, 91. IR (neat): 2961, 2932, 2873, 1653, 1379, 1286,
6. (a) Nugent, B. M.; Williams, A. L.; Johnston, J. N.
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1033 cmK1
.
9. (a) Miyata, O.; Muroya, K.; Kobayashi, T.; Yamanaka, R.;
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4.1.26.
(3S,10R,10aR)-3-Isopropyl-7-methoxy-10-
methyl-2,3,10,10a-tetrahydrothiazolo[3,2-b]isoquinolin-
5-one (14b5). Mp 137–139 8C. 1H NMR (300 MHz,
CDCl3): d 7.51–6.97 (m, 3H), 5.18 (d, JZ12.00 Hz, 1H),
4.77 (t, JZ6.10 Hz, 1H), 3.83 (s, 3H), 3.06 (dd, JZ7.31,
12.23 Hz, 1H), 2.92 (m, 1H), 2.85 (d, JZ12.23 Hz, 1H),
2.22 (m, 1H), 1.21 (d, JZ6.80 Hz, 3H), 1.00 (d, JZ6.80 Hz,
3H), 0.96 (d, JZ6.80 Hz, 3H). 13C NMR (CDCl3): d 162.3,
159.0, 135.1, 129.4, 127.7, 119.5, 111.9, 65.8, 64.1, 55.6,
38.2, 32.2, 30.8, 19.7, 19.6 and 15.9. MS (EI) m/z: 291
(MCCH), 248 (100), 189, 162, 134, 119, 91. IR (neat):
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2960, 2931, 2873, 1653, 1380, 1285, 1031 cmK1
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