Kinetic acidity of iminium ions. 2-Alkynyl- and 2,5-dialkynyl-pyrrolidines via the iminium ion route to azomethine ylides

Article abstract of DOI:10.1016/S0040-4020(02)00129-1

Condensation of carboxaldehydes with appropriate secondary propargylamines furnishes iminium ions which undergo regioselective deprotonation at the propargylic methylene group to generate azomethine ylides. Interception of the latter by N-methyl or N-phenyl maleimide furnishes 2- and 2,5-dialkynyl-pyrrolidines.

Full text of DOI:10.1016/S0040-4020(02)00129-1

TETRAHEDRON
Pergamon
Tetrahedron 58 42002) 2627±2640
Kinetic acidity of iminium ions. 2-Alkynyl- and 2,5-dialkynyl-
pyrrolidines via the iminium ion route to azomethine ylides
Ronald Grigg,p Visuvanathar Sridharan, Mark Thornton-Pett, Jun Wang, Juan Xu and Jin Zhang
Molecular Innovation, Diversity and Automated Synthesis ꢀMIDAS) Centre, School of Chemistry, The University of Leeds,
Leeds LS2 9JT, UK
Received 5 November 2001; revised 2 January 2002; accepted 31 January 2002
AbstractÐCondensation of carboxaldehydes with appropriate secondary propargylamines furnishes iminium ions which undergo regio-
selective deprotonation at the propargylic methylene group to generate azomethine ylides. Interception of the latter by N-methyl or N-phenyl
maleimide furnishes 2- and 2,5-dialkynyl-pyrrolidines. q 2002 Elsevier Science Ltd. All rights reserved.
We have developed several variants of the iminium ion
route to azomethine ylides involving either condensation
of aldehydes and ketones with acyclic or cyclic a-amino
acids1 or condensation of a-dicarbonyl compounds 4or
carbonylimines) with secondary amines.2 In the former
case the iminium ion intermediate generates the azomethine
ylide by decarboxylation 1!2 whilst in the later case
deprotonation occurs either via a 1,5-H shift 3!4 or by
interaction of an external base 4Scheme 1).
Whilst exploring aspects of 3!4 in which the R substituent
contained benzylic a-protons we observed synthetically
useful regiospeci®c azomethine ylide formation involving
deprotonation at the site bearing the less acidic protons, e.g.
5!6, i.e. the regioselectivity of azomethine ylide formation
was controlled by kinetic acidity and, moreover, the chiral
centre in 5 was not racemised 4Scheme 2).3
We now report further synthetically useful examples where
kinetic acidity controls the regioselectivity of azomethine
ylide formation involving imines of secondary propargyl-
amines.
1. Secondary propargylamines as azomethine ylide
precursorss
Several related series of azomethine ylides have been
generated in situ by condensation of secondary propargyl-
amines with carboxaldehydes. In the ®rst series the chiral
propargylamines 7a, b derived from S-amino esters and
7c derived fromthe
R-amino ester were reacted
4toluene, 1008C, 24 h) with 4trimethylsilyl) propynal 8 and
N-methyl- or N-phenyl-maleimide 12a, b 4Scheme 3). The
initial mixture of four diastereomers simpli®ed to two, 13
Scheme 1.
Scheme 2.
Keywords: iminium ions; azomethine ylide; 1,3-dipolar cycloaddition; regioselective deprotonation.
Corresponding author. Tel.: 144-113-233-6501; fax: 144-113-233-6501; e-mail: r.grigg@chem.leeds.ac.uk
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020402)00129-1

2628
R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
Scheme 3.
and 14, on removal 4TBAF, rt, 1 h) of the TMS group and
then were separated by ¯ash column chromatography on
silica 4Table 1).
The stereochemistry of the cycloadducts was established
fromn.O.e. data and con®rmed in some cases by X-ray
crystal structures. Typical n.O.e. enhancements for vicinal
cis-protons were 10.3±12.0% whilst for vicinal trans-
protons enhancements were 4.3±7.4% 4see Section 2).
The X-ray crystal structure of 13b is shown in Fig. 1. Based
on the known absolute con®guration of 7b, this established
the con®guration of the new chiral centres in 13b as C14R),
Table 1.
R
R0
Ratio 413/14)
Yield 4%)
a
b
c
d
Bn
Bn
Me
Ph
Me
Ph
Me
Me
64:36
60:40
75:25
67:33
66
50
54
42a
a
Product comprises a 47:23:30 mixture of 13d, 14d and 15d.
Figure 1. The X-ray crystal structure of 13b.

R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
2629
Scheme 4.
Cycloadducts 17a±d again arise from anti-dipole 10a and/
or 10b via an endo-transition state. In the case of the
iminium ion 18 derived from 16d none of the alternative
cycloadduct derived fromazomethine ylide 19, requiring
deprotonation at the allylic methylene group, was observed
4Scheme 6).
An analogous series of reactions was carried out between
16a±d, aryl/heteroaryl aldehydes 20 and dipolarophiles
12a, b. In all cases the products 4Table 2) comprised 1:1
mixtures of diastereomers 21 and 22.
Scheme 5.
The 1:1 mixtures of 21 and 22 were separated by ¯ash
chromatography on silica and the stereochemistry of
21a±q and 22a±q was assigned fromn.O.e. data and
coupling constants and con®rmed in the case of one pair
of isomers, 21n and 22n by X-ray crystal structures 4Fig. 2).
C34R), C3a4R), C6a4S) 4see numbering on formula in Fig. 1).
The absolute con®gurations of 13a±d and 14a±d are
assigned by analogy with 13b.
It is clear fromthe cycloadduct structures that the products
protons of the inter-
mediate iminium ion 9. Moreover since the cycloadducts
13a±d and 14a±d are optically active we can rule out
equilibria involving azomethine ylide 11 which would
arise fromremoval of one of the H
Typical n.O.e. enhancements for the cis-vicinal protons in
21a±q and 22a±q were 6.6±12.0% whilst for trans-vicinal
protons the enhancements were 1.7±5.6%. Isomers 21 and
22 can be distinguished by the coupling constants JHaHb and
JHcHd 4Scheme 7). Thus JHaHb is 8.7±9.2 Hz and JHcHd is
0 Hz for 21a±q whilst JHaHb is 3.5±6.5 Hz and JHcHd is
7.9±8.4 Hz for 22a±q.
A
arise fromremoval of the H proton in 9. Additionally we
B
have previously shown that the highly reactive maleimide
dipolarophiles trap the azomethine ylide4s) formed under
kinetic control.4 However, in the case of the N-propargyl
phenylglycine ester 7c the reaction affords a 47:23:30
mixture of 13d, 14d and 15d 4Scheme 4). Thus in this
case there is competitive formation of the corresponding
azomethine ylides 10 and 11. However, since both 13d
[4a)Dˆ116] and 14d [4a)Dˆ16] are optically active,
equilibration of azomethine ylides A and B 4Scheme 4) is
ruled out. The stereochemistry of the cycloadducts impli-
cates the anti-dipole 10a and/or 10b and an endo-transition
state for the cycloaddition.
2. Experimental
Melting points were determined on a Reichert hot-stage
apparatus and are uncorrected. H Nuclear magnetic reso-
1
nance spectra were recorded at 300 MHz on a Bruker DPX
300 instrument, at 250 MHz on a Bruker AC 250 instrument
or at 500 MHz on a Bruker DRX 500 instrument. Deutero-
chloroformwas used as solvent unless otherwise stated, and
chemical shifts are given in parts per million 4d) down®eld
fromtetramethylsilane. 1H spectra are referenced to tetra-
methylsilane or residual protonated solvent. Assignments of
1H signals were made with the aid of 2D COSY spectra
where necessary. Microanalyses were obtained using a
Carlo Erba Elemental Analyser MOD 1106 instrument.
When achiral secondary propargylamines 16a±c were
reacted 4toluene, 1008C, 24 h) with 8 and 12a, b followed
by removal of the TMS group 4TBAF, rt, 1 h) single
cycloadducts 17a±d were obtained in 50±70% yield
4Scheme 5).
Scheme 6.

2630
R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
Table 2. Reaction of 16a±d, 20 and 12a, b to give cycloadducts 21a±q and 22a±q
R
Ar
R0
Yield 4%)a,b
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
CH2CuCH
CH2CuCH
CH2CuCH
CH2CHvCH2
CH2CHvCH2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2-Thienyl
2-Thiazolyl
Ph
2-Thienyl
Ph
2-Furyl
2-Thienyl
2-Thiazolyl
Ph
2-Pyridyl
6-Me-2-pyridyl
4-MeOC6H4
2-Furyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
59
88
67
61
50
85
58
80
62
53
56
46
44
43
76
55
52
2-Thienyl
2-Thiazolyl
Ph
Ph
Ph
Ph
Ph
6-Me-2-pyridyl
All reaction carried out in toluene at 1008C 4bath temperature) for 24 h.
Isolated yields.
All reaction afforded 1:1 mixtures of diastereomers 21 and 22.
a
b
Infrared spectra were recorded as nujol mulls on a Nicolet
FTIR spectrophotometer. Mass spectra were recorded on a
VG-AutoSpec using electron impact 4EI) at 70 eV or fast
atom bombardment 4FAB), as speci®ed. Flash column chro-
matography was performed on silica gel 60 4Merk 230±400
mesh). Ether refers to diethyl ether and petroleum ether refers
to the fraction with boiling point 40±608C. All reagents and
solvents were puri®ed according to literature procedures.5
Figure 2. The X-ray crystal structures of 21n and 22n.

R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
2631
2.1. General method for the preparation of chiral
secondary amines 7a±c
70.9, H, 6.45, N, 6.9%.); d 2.11 4bs, 1H, NH), 2.26 4t,
Jˆ2.4 Hz, 1H, CuCH), 3.27 and 3.47 42£dd, Jˆ2.4 and
17.2 Hz, 2£H, NCH2), 3.70 4s, 3H, Me), 4.64 4s, 1H NCH)
and 7.31±7.42 4m, 5H, ArH); m/z 4%): 4FAB) 204 4M111,
67), 188 47), 159 49), 144 448), 131 413), 121 417), 109 432),
97 458), 83 463) and 69 4100).
Propargyl bromide 410.5 mmol) was added to a solution of
the a-amino acid ester hydrochloride 410 mmol) and potas-
sium carbonate 421 mmol) in dry DMF 4or acetone) at room
temperature under N2. The mixture was stirred for 1±3 d,
the solvent evaporated under reduced pressure and the
residue partitioned between water 450 ml) and DCM
430 ml). The organic phase was separated and the aqueous
phase was extracted with DCM 42£30 ml). The organic
phases were combined, dried 4MgSO4), ®ltered and the
solvent evaporated under reduced pressure. The residue
was puri®ed by column chromatography to give secondary
amines 7a±c.
2.2. General method for the preparation of cycloadducts
13a±d, 14a±d and 17a±e
Secondary amine 7a±c 41.5 mmol) or 16a±d 41.5 mmol)
were added to a solution of 3-4trimethylsilyl)propynal 86
41.5 mmol) and dipolarophile 12 41.8 mmol) in toluene
45 ml). The mixture was stirred and heated at 1008C under
N2 for 24 h. The solvent was then removed under reduced
pressure, THF 45 ml) and TBAF 4Tetra-n-butylammonium
¯uoride, 1 M soln in THF; 3 ml) added and the mixture
stirred at room temperature for 1 h when EtOAc 450 ml)
was added. The mixture was washed with water
43£30 ml), the organic phase collected, dried 4MgSO4),
®ltered and the solvent evaporated under reduced pressure.
The residue was puri®ed by column chromatography to give
the cycloadducts.
2.1.1. Methyl N-02-propynyl)-S-phenylalaninate 7a
This compound is prepared by the general procedure from
S-phenylalaninate methyl ester hydrochloride 42.16 g,
10 mmol), propargyl bromide 41.56 g, 80% in toluene solu-
tion, 10.5 mmol) and potassium carbonate 42.9 g, 21 mmol)
in dry DMF 4100 ml) for 3 d. Flash column chromatography
eluting with 3:1 v/v petroleumether±ether afforded 7a
41.79 g, 82%) as a pale yellow liquid. Bp 2068C/0.3 mm
2.2.1. Methyl 02S)-2-[01R,3R,3aR,6aS)-1,3-diethynyl-5-
methyl-4,6-dioxohexahydro-pyrrolo[3,4-c]pyrrol-201H)-
yl]-3-phenylpropanoate 13a and methyl 02S)-2-[01S,
3S,3aR,6aS)-1,3-diethynyl-5-methyl-4,6-dioxohexahydro-
pyrrolo[3,4-c]pyrrol-201H)-yl]-4-phenyl-propanoate 14a.
Chiral amine 7a 4434 mg, 2 mmol), 3-4trimethylsilyl)-
propynal 8 4252 mg, 2 mmol) and N-methylmaleimide 12a
4222 mg, 2 mmol) were reacted by the general procedure
in toluene 45 ml) for 24 h. Flash column chromatography
of the 1.8:1 mixture of 13a and 14a eluting with 1:3 v/v
25
4Kugelrohr distillation). [a]D ˆ116.0 41.0, CHCl3).
4Found: C, 71.9, H, 6.9, N, 6.6, C13H15NO2 requires: C,
71.85, H, 6.95, N, 6.45%); d 1.68 4br, 1H, NH), 2.18 4t,
1H, Jˆ2.4 Hz, CuCH), 2.95 4dd, 1H, Jˆ6.2 and 13.6 Hz,
ArCHH), 3.03 4dd, 1H, Jˆ7.3 and 13.6 Hz, ArCHH), 3.36
and 3.44 42£dd, 2£1H, Jˆ2.4 and 17.0 Hz, NCH2), 3.68 4s,
3H, OCH3), 3.76 4dd, 1H, Jˆ6.3 and 7.2 Hz, NCHCO2Me)
and 7.18±7.33 4m, 5H, ArH); d 413C): 37.2, 39.8, 52.2, 61.5,
72.2, 81.6, 127.3, 128.9, 129.6, 137.3 and 174.7; m/z 4%):
217 4M1, 2), 162 4100), 158 48), 91 482) and 77 410); nmax
3284, 2948, 1734 and 1446 cm21
:
petroleumether±ether afforded two distereoisomers
4208 mg, 29%) and 14a 487 mg, 12%).
13a
.
2.1.2. Methyl N-02-propynyl)-S-alaninate 7b
Major isomer 13a. Colourless plates fromether mp 79±
25
818C. [a]D ˆ1165 41.0, CHCl3). 4Found: C, 69.3, H,
This compound is prepared by the general procedure from
S-alanine methyl ester hydrochloride 41.396 g, 10 mmol),
propargyl bromide 41.56 g, 10.5 mmol) and potassium
carbonate 42.9 g, 21 mmol) in dry DMF for 3 d. Flash
column chromatography eluting with 1:1 v/v petroleum
ether±ether afforded the product 7b 4324 mg, 23%) as a
5.45, N, 7.85, C21H20N2O4 requires: C, 69.2, H, 5.55, N,
7.7%). d 4500 Hz): 2.52 4d, Jˆ2.2 Hz, 1H, CuCH), 2.61
4d, Jˆ2.3 Hz, 1H, CuCH), 2.99 4s, 3H, NCH3), 3.07 4dd,
Jˆ9.9 and 12.9 Hz, 1H, PhCHH), 3.28 4dd, Jˆ5.9 and
12.9 Hz, 1H, PhCHH), 3.31 4dd, Jˆ1.8 and 8.2 Hz, 1H,
Hc), 3.44 4t, Jˆ8.2 Hz, 1H, Hb), 3.50 4s, 3H, OCH3), 3.75
4dd, Jˆ5.9 and 9.9 Hz, 1H, NCHCO2Me), 4.34 4t, Jˆ
1.8 Hz, 1H, Hd), 4.40 4dd, Jˆ2.3 and 8.2 Hz, 1H, Ha),
7.14±7.16 4m, 2H, ArH), 7.20 4m, 1H, ArH) and 7.24±
7.27 4m, 2H, ArH). m/z 4%): 364 4M1, 2), 305 43), 273
25
pale yellow gum. [a]D ˆ262.0 41.0, CHCl3). 4Found: C,
59.4, H, 7.75, N, 9.6, C7H11NO2 requires: C, 59.55, H, 7.85,
N, 9.9%.); d 1.33 4d, Jˆ7.0 Hz, 3H, NCHMe), 2.23 4t,
Jˆ2.5 Hz, 1H, CuCH), 3.44 4dd, Jˆ2.5 and 6.7 Hz, 2H,
NCH2), 3.56 4q, Jˆ7.0 Hz, 1H, NCH) and 3.74 4s, 3H,
CO2Me); m/z 4%): 4FAB) 140 4M121, 25), 126 4100), 120
421), 115 410) and 109 410).
4100), 188 46) and 91 419). nmax: 3273, 1707 and 1431 cm21
.
n.O.e. 4500 MHz, CDCl3) of 13a:
2.1.3. Methyl N-02-propynyl)-R-phenylglycinate 7c
Proton
irradiated
Enhancement 4%)
This compound is prepared by the general procedure from
R-phenylglycine methyl ester hydrochloride 43.025 g,
15 mmol), propargyl bromide 41.78 g, 15 mmol) and potas-
sium carbonate 44.354 g, 31.5 mmol) in dry DMF 4100 ml)
for 62 h. Flash column chromatography eluting with 2:1 v/v
petroleumether±ether afforded the product 7c 42.537 g,
Ha
Hb
Hc
Hd
±
Ha
Hb
Hc
Hd
±
11.1 3.3
9.6
2.9
±
±
2.6
±
3.5
±
8.3
6.5
±
25
83%) as a pale yellow gum. [a]D ˆ2110.0 41.0, CHCl3).
4Found: C, 70.75, H, 6.25, N, 6.6, C12 H13NO2 requires: C,

2632
R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
Minor isomer 14a. Colourless prisms from ether, mp 110±
Minor isomer 14b. Evaporation of the mother liquors and
puri®cation of the residue by chromatography over Kiesel-
gel eluting with 1:1 v/v ether±petroleumether afforded 14b
which crystallised fromether as colourless needles. Mp
25
1208C. [a]D ˆ2250 41.0, CHCl3). 4Found: C, 69.05, H,
5.65, N, 7.8. C21H20N2O4 requires: C, 69.2, H, 5.55, N,
7.7%). d 4500 MHz): 2.39 4d, Jˆ2.1 Hz, 1H, CuCH),
2.55 4d, Jˆ2.3 Hz, 1H, CuCH), 2.73 4s, 3H, NCH3), 2.91
4dd, Jˆ10.5 and 14.9 Hz, 1H, PhCHH), 3.18 4dd, Jˆ5.8 and
14.9 Hz, 1H, PhCHH), 3.20 4dd, Jˆ1.0 and 7.8 Hz, 1H, Hb),
3.27 4dd, Jˆ7.8 and 8.0 Hz, 1H, Hc), 3.69 4s, 3H, OCH3),
4.26 4dd, Jˆ5.8 and 10.5 Hz, 1H, NCHCO2Me), 4.47 4dd,
Jˆ1.0 and 2.1 Hz, 1H, Ha), 4.49 4dd, Jˆ2.3 and 8.0 Hz, 1H,
Hd), 7.08±7.09 4m, 2H, ArH), 7.14 4m, 1H, ArH) and 7.19±
7.23 4m, 2H, ArH). m/z 4%): 364 4M1, 2), 305 43), 273 4100),
25
156±1588C. [a]D ˆ2156 41.0, CHCl3). 4Found: C,
73.05, H, 5.15, N, 6.6. C26H22N2O4 requires: C, 73.25, H,
5.2, N, 6.55%). d 4500 MHz): 2.43 4d, Jˆ2.0 Hz, 1H,
CuCH), 2.54 4d, Jˆ2.2 Hz, 1H, CuCH), 2.94 4dd, Jˆ
10.2 and 14.9 Hz, 1H, PhCHH), 3.23 4dd, Jˆ5.7 and
14.9 Hz, 1H, PhCHH), 3.42 4dd, Jˆ1.0 and 8.0 Hz, 1H,
Hb), 3.47 4dd, Jˆ8.0 and 8.4 Hz, 1H, Hc), 3.70 4s, 3H,
OCH3), 4.31 4dd, Jˆ5.7 and 10.2 Hz, 1H, NCHCO2Me),
4.63 4dd, Jˆ2.2 and 8.4 Hz, 1H, Hd), 4.65 4dd, Jˆ1.0 and
2.0 Hz, 1H, Ha), 6.93±6.95 4m, 2H, ArH), 7.04±7.12 4m,
5H, ArH) and 7.36±7.42 4m, 3H, ArH). m/z 4%): 426 4M1,
3), 367 455), 335 4100) and 91 463). nmax: 3266, 1715, 1495
188 45) and 91 423). nmax: 3262, 1700 and 1439 cm21
.
n.O.e. 4500 MHz, CDCl3) of 14a:
and 1382 cm21
.
Proton
irradiated
Enhancement 4%)
2.2.3. Methyl 02S)-2-[01R,3R,3aR,6aS)-1,3-diethynyl-5-
methyl-4,6-dioxohexahydro-pyrrolo[3,4-c]pyrrol-201H)-
yl]-propanoate 13c and methyl 02S)-2-[01S,3S,3aR,6aS)-
1,3-diethynyl-5-methyl-4,6-dioxohexahydropyrrolo[3,4-c]-
pyrrol-201H)-yl]-propanoate 14c. Chiral amine 7b
4141 mg, 1 mmol), 3-4trimethylsilyl)propynal 8 4126 mg,
1 mmol), and N-methylmaleimide 12a 4133 mg, 1.2mmol)
were reacted by the general procedure in toluene 45 ml) for
24 h. Flash column chromatography of the 3:1 mixture of
13c and 14c eluting with 1:3 v/v petroleumether±ether
afforded 13c 4102 mg) and a mixture of 13c and 14c
455 mg) in 54% combined yield.
Ha
Hb
Hc
Ha
Hb
Hc
±
5.6
15.46
4.6 8.0
±
±
±
±
2.2.2. Methyl 02S)-2-[01R,3R,3aR,6aS)-1,3-diethynyl-4,6-
dioxo-5-phenylhexahydro-pyrrolo[3,4-c]pyrrol-201H)-yl]-
3-phenylpropanoate 13b and methyl 02S)-2-[01S,3S,
3aR,6aS)-1,3-diethynyl-4,6-dioxo-5-phenylhexahydro-
pyrrolo[3,4-c]pyrrol-201H)-yl]-4-phenyl-propanoate 14b.
Chiral amine 7a 4434 mg, 2 mmol), 3-4trimethylsilyl)pro-
pynal 8 4252 mg, 2 mmol) and N-phenylmaleimide 12b
4346 mg, 2 mmol) were reacted by the general procedure
in toluene 45 ml) for 24 h. Flash column chromatography
of the 1.5:1 mixture of 13b and 14b eluting with 1:2 v/v
petroleumether±ether afforded the separated isomers 13b
and 14b 4428 mg, 50%).
Major isomer 13c. Colourless prisms from CH2Cl2/ether/
25
petroleumether, mp 117±118 8C. [a]D ˆ2266 41.09,
CHCl3). 4Found: C, 62.65, H, 5.55, N, 9.65, C15 H16N2O4
requires: C, 62.5, H, 5.6, N, 9.7%). d 4500 Hz) 1.36 4d,
Jˆ7.2 Hz, 3H, NCHMe), 2.38 4d, Jˆ2.0 Hz, 1H, CuCH),
2.55 4d, Jˆ2.2 Hz, 1H, CuCH), 3.00 4s, 3H, NMe), 3.30
4dd, Jˆ2.0 and 7.9 Hz, 1H, Hc), 3.41 4dd, Jˆ7.9 and 8.3 Hz,
1H, Hb), 3.67 4s, 3H, CO2Me), 3.98 4q, Jˆ7.2 Hz, 1H,
CHCO2Me), 4.44 4t, Jˆ2.0 Hz, 1H, Hd) and 4.57 4dd,
Jˆ2.2 and 8.3 Hz, 1H, Ha). m/z 4%): 4FAB) 289 4M11,
69), 263 415), 229 4100), 144 47), 118 49) and 80 45).
Major isomer 13b. Colourless rods from methanol mp 129±
25
1318C. [a]D ˆ1136 41.0, CHCl3). 4Found: C, 73.0, H, 5.1,
N, 6.5, C26H22N2O4 requires: C, 73.25, H, 5.2, N, 6.55%). d
4500 MHz): 2.54 4d, Jˆ2.0 Hz, 1H, CuCH), 2.64 4d, Jˆ
2.3 Hz, 1H, CuCH), 3.11 4dd, Jˆ10 and 13.0 Hz, 1H,
PhCHH), 3.33 4dd, Jˆ5.7 and 13.0 Hz, 1H, PhCHH), 3.50
4dd, Jˆ2.0 and 8.3 Hz, 1H, Hc), 3.51 4s, 3H, OCH3), 3.61 4t,
Jˆ8.3 Hz, 1H, Hb), 3.83 4dd, Jˆ5.7 and 10 Hz, 1H,
NCHCO2Me), 4.46 4t, Jˆ2.0 Hz, 1H, Hd), 4.53 4dd, Jˆ2.3
and 8.3 Hz, 1H, Ha), 7.17±7.28 4m, 7H, ArH), 7.40 4m, 1H,
ArH) and 7.46±7.49 4m, 2H, ArH). m/z 4%): 426 4M1, 2),
367 418), 335 499) and 91 4100).
n.O.e. 4500 MHz, CDCl3) of 13c:
Proton
irradiated
Enhancement 4%)
Ha
Hb
Hc Hd
Ha
Hb
Hc
Hd
±
12.95
±
11.59
±
3.53
±
±
3.87
±
±
±
4.85
±
n.O.e. 4500 MHz, CDCl3) of 13b:
±
4.57
Proton
irradiated
Enhancement 4%)
Minor isomer 14c. Colourless plates fromCH Cl2/ether/
2
25
petroleumether, pm 134±136
8C. [a]D ˆ199 41.04,
Ha
Hb
Hc
±
CHCl3). 4Found: C, 62.45, H, 5.7, N, 9.85, C15 H16N2O4
requires: C, 62.5, H, 5.6, N, 9.7%.). d 4300 Hz) 1.43 4d,
Jˆ6.9 Hz, 3H, NCHMe), 2.47 4d, Jˆ2.0 Hz, 1H, CuCH),
2.54 4d, Jˆ2.3 Hz, 1H, CuCH), 3.02 4s, 3H, NMe), 3.32
4dd, Jˆ2.0 and 8.2 Hz, 1H, Hb), 3.45 4t, Jˆ8.2 Hz, 1H, Hc),
3.55 4q, Jˆ6.9 Hz, 1H, NCHMe), 3.67 4s, 3H, CO2Me), 4.19
Ha
Hb
Hc
±
11.5
±
11.7
1.4
4.3

R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
2633
4dd, Jˆ2.3 and 8.2 Hz, 1H, Hd) and 4.39 4t, Jˆ2.0 Hz, 1H,
Ha). m/z 4%): 287 4M21, ,1), 229 4100), 201 411), 144 49),
91 45) and 80 48).
4m, 5H, ArH). m/z 4%): 351 4M11, 75), 325 410), 291
4100) and 206 46).
2.2.5. 0^)03aR,4R,6R,6aS)-4,6-Diethynyl-2-methyl-5-02-
propynyl)tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 17a. N,N-Di42-propynyl)amine 16a 4186 mg,
2 mmol), 3-4trimethylsilyl) propynal 8 4252 mg, 2 mmol)
and N-methylmaleimide 12a 4267 mg, 2.4 mmol) were
reacted by the general procedure in toluene 45 ml) for
24 h. Flash column chromatography eluting with 1:2 v/v
petroleumether±ether afforded a single stereoisomer 17a
4317 mg, 66%) which crystallised as colourless needles
n.O.e. 4500 MHz, CDCl3) of 14c:
Proton
irradiated
Enhancement 4%)
Ha Hb
Hc
Hd
Ha
Hb
Hc
Hd
±
4.32
±
4.37
±
5.43
±
±
2.94
±
±
±
fromCH 2Cl2/ether/petroleumether, pm 157±158
8C.
10.83
±
4Found: C, 70.05, H, 5.10, N, 11.70, C14H12N2O2, requires:
C, 70.00, H, 5.05, N, 11.65%). d 4500 Hz) 2.24 4t,
Jˆ2.6 Hz, 1H, CuCH), 2.50 4d, Jˆ2.0 Hz, 1H, CuCH),
2.57 4d, Jˆ2.2 Hz, 1H, CuCH), 3.02 4s, 3H, Me), 3.24 4dd,
Jˆ2.6 and 16 Hz, 1H, NCHH), 3.35 4dd, Jˆ2.0 and 8.1 Hz,
1H, Hc), 3.42 4t, Jˆ8.1 Hz, 1H, Hb), 3.81 4dd, Jˆ2.6 and
16 Hz, 1H, NCHH), 3.87 4dd, Jˆ2.2 and 8.1 Hz, 1H, Ha)
and 4.52 4t, Jˆ2.0 Hz, 1H, Hd). m/z 4%): 239 4M21, 13),
182 45), 154 4100), 129 456), 116 47), 102 423), 90 487), 77
417), 63 465), 56 49), 51 423) and 39 455).
±
10.77
2.2.4. Methyl 02R)-[01R,3R,3aR,6aS)-1,3-diethynyl-5-
methyl-4,6-dioxohexahydropyrrolo-[3,4-c]pyrrol-201H)-
yl]-0phenyl)ethanoate 13d and methyl 02R)-[01S,3S,
3aR,6aS)-1,3-diethynyl-5-methyl-4,6-dioxohexahydro-
pyrrolo[3,4-c]pyrrol-201H)-yl]-0phenyl)ethanoate 14d.
The chiral amine 7c 4203 mg, 1 mmol), 3-4trimethylsilyl)-
propynal 8 4120 mg, 1 mmol), and N-methylmaleimide 12a
4133 mg, 1.2 mmol) were reacted by the general procedure
in toluene 45 ml) for 24 h. Flash column chromatography
eluting with 1:1 v/v petroleumether±ether afforded a
2:1:1.3 mixture of three distereoisomers 13d, 14d and 15d
4147 mg, 42%).
2.2.6. 0^)03aR,4R,6R,6aS)-4,6-Diethynyl-2,5-dimethyl-
tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-dione 17b.
N-Methyl-N-42-propynyl)amine 16b 4104 mg, 1.5 mmol),
3-4trimethylsilyl)propynal
8 4189 mg, 1.5 mmol) and
N-methylmaleimide 12a 4200 mg, 1.8 mmol) were reacted
by the general procedure in toluene 45 ml) for 24 h. Flash
column chromatography eluting with 1:1 v/v petroleum
ether±ether afforded a single stereoisomer 17b 4190 mg,
59%) which crystallised as colourless prisms from
CH2Cl2/ether/petroleumether, mp 138±139 8C. 4Found: C,
66.65, H, 5.7, N, 13.2, C12H12N2O2, requires: C, 66.65, H,
5.6, N, 12.95%). d 4300 Hz) d 2.44 4s, 3H, Me), 2.48 4d,
Jˆ2.1 Hz, 1H, CuCH), 2.55 4d, Jˆ2.3 Hz, 1H, CuCH),
3.02 4s, 3H, Me), 3.32 4dd, Jˆ1.0 and 8.0 Hz, 1H, Hc), 3.40
4t, Jˆ8.0 Hz, 1H, Hb), 3.75 4dd, Jˆ2.3 and 8.0 Hz, 1H, Ha)
and 4.20 4dd, Jˆ1.0 and 2.1 Hz, 1H, Hd). m/z 4%): 215
4M21, 16), 130 434), 105 4100), 90 419), 77 421), 66 463),
56 414), 51 431) and 39 436). nmax 4nujol): 2923, 2853, 2953,
1696, 1460, 1377 and 3280.
Stereoisomer 13d. Colourless prisms from CH2Cl2/ether/
petroleumether, pm 163±165
25
8C [a]D ˆ116 41.0,
CHCl3). 4Found: C, 68.85, H, 5.2, N, 7.8. C20H18N2O4
requires: C, 68.55, H, 5.20, N, 8.00%). d 4500 Hz) 4C6D6)
1.74 4d, Jˆ2.0 Hz, 1H, CuCH), 2.09 4d, Jˆ2.4 Hz, 1H,
CuCH), 2.48 4dd, Jˆ2.0 and 8.2 Hz, 1H, Hc), 2.61 4s,
3H, NMe), 2.69 4t, Jˆ8.2 Hz, 1H, Hb), 3.22 4s, 3H,
CO2Me), 3.96 4dd, Jˆ2.4 and 8.2 Hz, 1H, Ha), 4.29 4t,
Jˆ2.0 Hz, 1H, Hd), 4.51 4s, 1H, PhCH) and 6.99±7.63 4m,
5H, ArH). m/z 4%): 351 4M11, 100), 291 438), 201 46), 149
48) and 121 411).
Stereoisomer 14d. Colourless prisms from CH2Cl2/ether/
25
petroleumether, mp 114±116 8C [a]D ˆ16 41.0, CHCl3).
2.2.7.
0^)03aR,4R,6R,6aS)-4,6-Diethynyl-5-methyl-2-
4Found: C, 68.3, H, 5.3, N, 8.05. C20H18N2O4 requires: C,
68.55, H, 5.20, N, 8.00%). d 4500 Hz) 4C6D6) 1.85 4d,
Jˆ2.3 Hz, 1H, CuCH), 1.86 4d, Jˆ2.0 Hz, 1H,
CuCH), 2.60 4s, 3H, NMe), 2.67 4dd, Jˆ2.3 and
8.4 Hz, 1H, Hb), 2.76 4t, Jˆ8.4 Hz, 1H, Hc), 3.19 4s,
3H, CO2Me), 4.35 4dd, Jˆ2.0 and 8.4 Hz, 1H, Hsd),
4.69 4t, Jˆ2.3 Hz, 1H, Ha), 4.73 4s, 1H, PhCH) and
7.00±7.53 4m, 5H, ArH). m/z 4%): 351 4M11, 68), 325
411), 291 4100), 206 416) and 167 46).
phenyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 17c. N-Methyl-N-42-propynyl)amine 16b 4104 mg,
1.5 mmol), 3-4trimethylsilyl)propynal
8 4189 mg, 1.5
mmol) and N-phenylmaleimide 12b 4312 mg, 1.8 mmol)
were reacted by the general procedure in toluene 45 ml)
for 24 h. Flash column chromatography eluting with 1:1
v/v petroleumether±ether afforded a single stereoisomer
17c 4149 mg, 54%) which crystallised as colourless needles
fromCH 2Cl2/ether/petroleumether, pm 118±119
8C.
4Found: C, 73.3, H, 5.1, N, 10.1, C17H14N2O2 requires: C,
73.35, H, 5.1, N, 10.05%). d 2.48 4s, 3H, Me), 2.50 4d,
Jˆ2.1 Hz, 1H, CuCH), 2.56 4d, Jˆ2.2 Hz, 1H, CuCH),
3.50 4dd, Jˆ1.1 and 7.9 Hz, 1H, Hc), 3.55 4t, Jˆ7.9 Hz, 1H,
Hb), 3.86 4dd, Jˆ2.2 and 7.9 Hz, 1H, Ha) 4.29 4d, Jˆ1.1 Hz,
1H, Hd) and 7.26±7.50 4m, 5H, ArH). m/z 4%): 4FAB) 279
4M11, 100), 253 414), 154 415), 136 411), 130 47), 105 414)
and 77 48). nmax 4nujol): 2923, 1710, 2953, 2853, 1204,
1455, 1731, 1393, 3293 and 3207.
Stereoisomer 15d. Colourless prisms from CH2Cl2/ether/
petroleumether, mp 119±121 8C. 4Found: C, 68.65, H,
5.25, N, 7.85. C20H18N2O4 requires: C, 68.55, H, 5.20, N,
8.00%). d 2.25 4t, Jˆ2.4 Hz, 1H, CuCH), 2.54 4d,
Jˆ2.1 Hz, 1H, CuCH), 3.03 4s, 3H, Me), 3.30 4d, Jˆ
10.5 Hz, 1H, COCH), 3.55 4dd, Jˆ7.5 and 10.5 Hz, 1H,
COCH), 3.67 4dd, Jˆ2.5 and 18.1 Hz, 1H, NCHH), 3.68
4s, 3H, Me), 4.06 4dd, Jˆ2.5 and 18.1 Hz, 1H, NCHH),
4.31 4dd, Jˆ2.1 and 7.5 Hz, 1H, NCH), and 7.31±7.53

2634
R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
2.2.8.
0^)03aR,4R,6R,6aS)-5-Benzyl-4,6-diethynyl-2-
v/v petroleumether±ethyl ether afforded the two separated
stereoisomers 21a and 22a 4262 mg, 59% combined yield).
methyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 17d. N-Benzyl-N-42-propynyl)amine 16c 4291 mg,
2 mmol), 3-4trimethylsilyl)propynal 8 4253 mg, 2 mmol)
and N-methylmaleimide 12a 4267 mg, 2.4 mmol) were
reacted by the general procedure in toluene 45 ml) for
24 h. Flash column chromatography eluting with 2:3 v/v
petroleumethyl±ether afforded 17d 4408 mg, 70%) which
crystallised as colourless prisms from CH2Cl2/ether/petro-
leumether, mp 129±131 8C. 4Found: C, 73.65, H, 5.6, N, 9.9.
C18H16N2O2, requires: C, 73.95, H, 5.50, N, 9.60%). d
4500 Hz) 2.49 4d, Jˆ2.0 Hz, 1H, CuCH), 2.57 4d, Jˆ
2.3 Hz, 1H, CuCH), 3.03 4s, 3H, Me), 3.30 4dd, Jˆ2.0
and 8.0 Hz 1H, Hc), 3.42 4dd, Jˆ8.0 and 8.3 Hz, 1H, Hb),
3.47 4d, Jˆ13 Hz, 1H, PhCHH), 3.95 4dd, Jˆ2.3 and 8.3 Hz,
1H, Ha), 4.00 4t, Jˆ2.0 Hz, 1H, Hd), 4.27 4d, Jˆ13 Hz, 1H,
PhCHH) and 7.23±7.31 4m, 5H, ArH). m/z 4%): 293 4M11,
100), 267 49), 181 49) and 91 434).
Stereoisomer 21a. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 144±146 8C. 4Found: C, 64.25, H, 4.6,
N, 9.2, S, 10.7. C16H14N2O2S requires: C, 64.4, H, 4.75, N,
9.4, S, 10.75%). d 4300 Hz): 2.23 4t, Jˆ2.6 Hz, 1H,
CuCH), 2.52 4d, Jˆ2.0 Hz, 1H, CuCH), 2.95 4s, 3H,
Me), 3.19 4dd, Jˆ2.6 and 16 1 Hz, 1H, NCHH), 3.39 4d,
Jˆ8.0 Hz, 1H, Hc), 3.42 4dd, Jˆ2.6 and 16.1 Hz, 1H,
NCHH), 3.53 4dd, Jˆ8.0 and 9.0 Hz, 1H, Hb), 4.42 4d,
Jˆ9.0 Hz, 1H, Ha), 4.80 4d, Jˆ2.0 Hz, 1H, Hd) and 6.99±
7.30 4m, 3H, ArH). m/z 4%): 299 4M11, 100), 273 413), 215
451), 187 411) and 148 412).
Stereoisomer 22a. Colourless plates fromCH 2Cl2/ether/
petroleumether, mp 131±132 8C. 4Found: C, 64.6, H, 5.0,
N, 9.50, S, 10.8. C16H14N2O2S requires: C, 64.4, H, 4.75, N,
9.4, S, 10.75%). d 2.23 4t, Jˆ2.5 Hz, 1H, CuCH), 2.49 4d,
Jˆ2.1 Hz, 1H, CuCH), 3.02 4s, 3H, Me), 3.15 4dd, Jˆ2.5
and 16 Hz, 1H, NCHH), 3.36 4dd, Jˆ5.5 and 9.1 Hz, 1H,
Hb), 3.43 4dd, Jˆ2.5 and 16 Hz, 1H, NCHH), 3.74 4dd,
Jˆ8.1 and 9.1 Hz, 1H, Hc), 4.38 4d, Jˆ5.5 Hz, 1H, Ha),
4.65 4dd, Jˆ2.1 and 8.1 Hz, 1H, Hd), 7.00 4dd, Jˆ3.5 and
5.1 Hz, 1H, ArH), 7.14 4dd, Jˆ0.6 and 3.5 Hz, 1H, ArH) and
7.32 4dd, Jˆ0.6 and 5.1 Hz, 1H, ArH). m/z 4%): 299 4M11,
100), 289 46), 273 413), 215 430), 187 411), 148 411), 121
46), 107 48), 89 48) and 77 49).
2.2.9.
0^)03aR,4R,6R,6aS)-4,6-Diethynyl-2-methyl-5-
vinyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-dione
17e. N-Allyl-N-42-propynyl)amine 16d 4240 mg, 2 mmol),
3-4trimethylsilyl)propynal
N-methylmaleimide 12a 4267 mg, 2.4 mmol) were reacted
by the general procedure in toluene 45 ml) for 24 h. Flash
column chromatography eluting with 1:1 v/v petroleum
ethyl±ether afforded 17e 4239 mg, 50%) which crystallised
8
4253 mg, 2 mmol) and
as colourless needles fromCH Cl2/ether/petroleumether,
2
mp 144±1468C. 4Found: C, 69.1, H, 5.85, N, 11.75.
C14H14N2O2, requires: C, 69.4, H, 5.8, N, 11.55%). d
4500 Hz) 2.46 4d, Jˆ2.2 Hz, 1H, CuCH), 2.54 4d, Jˆ
2.3 Hz, 1H, CuCH), 2.99 4dd, Jˆ7.8 and 13.2 Hz, 1H,
NCHH), 3.01 4s, 3H, Me), 3.32 4d, Jˆ8.0 Hz, 1H, Hc),
3.39 4dd, Jˆ8.0 and 8.2 Hz, 1H, Hb), 3.69 4dd, Jˆ4.3 and
13.2 Hz, 1H, NCHH), 3.85 4dd, Jˆ2.3 and 8.2 Hz, 1H, Ha),
4.25 4d, Jˆ2.2 Hz, 1H, Hd), 5.16 4dtd, Jˆ0.8, 1.8 and
10.1 Hz, 1H, CvCHH), 5.27 4dtd, Jˆ0.8, 1.8 and Jˆ
17.1 Hz, 1H, CvCHH) and 5.73±5.81 4m, 1H,
HCvCH2). m/z 4%): 241 4M21, 36), 215 412), 184 47),
156 455), 142 413), 131 489), 104 419), 90 4100), 77 428),
63 451), 51 425) and 39 460).
2.3.2. 0^)03aR,4R,6R,6aS)-4-Ethynyl-2-methyl-5-02-pro-
pynyl)-6-01,3-thiazol-2-yl)tetrahydropyrrolo[3,4-c]-
pyrrole-1,302H,3aH)-dione 21b and 03aR,4S,6S,6aS)-4-
ethynyl-2-methyl-5-02-propynyl)-6-01,3-thiazol-2-yl)tetra-
hydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-dione 22b. N,N-
Di42-propynyl)amine 16a 4140 mg, 1.5 mmol), 2-thiazole
carboxaldehyde 20b 4170 mg, 1.5 mmol) and N-methyl-
maleimide 12a 4200 mg, 1.8 mmol) were reacted by the
general procedure in toluene 45 ml) over 24 h. Flash column
chromatography of the 1:1 mixture of 21b and 22b eluting
with 1:3 v/v petroleumether±ethyl ether afforded the two
separated stereoisomers 21b and 22b 4368 mg, 80%
combined yield).
2.3. General method for the preparation of cycloadducts
21a±q and 22a±q
Stereoisomer 21b. Colourless prisms from CH2Cl2/ether/
petroleumether, mp 164±165 8C. 4Found: C, 60.25, H,
4.55, N, 14.3, S, 10.65. C15H13N3O2S, requires: C, 60.2,
H, 4.4, N, 14.05, S, 10.7%). d 2.26 4t, Jˆ2.5 Hz, 1H,
CuCH), 2.56 4d, Jˆ2.1 Hz, 1H, CuCH), 2.93 4s, 3H,
Me), 3.32 and 3.43 42£dd, Jˆ2.5 and 16.1 Hz, 2£1H,
NCH2), 3.46 4d, Jˆ8.1, 1H, Hc), 3.73 4dd, Jˆ8.1 and
9.1 Hz, 1H, Hb), 4.64 4d, Jˆ9.1 Hz, 1H, Ha), 4.82 4d,
Jˆ2.1 Hz, 1H, Hd) and 7.38 and 7.81 42£d, Jˆ3.3 Hz,
2£1H, ArH). m/z 4%): 300 4M111, 100), 274 45), 215
435) and 130 46).
The achiral secondary amine 16a±d 41.5 mmol) was added
to a solution of aldehyde 20 41.5 mmol) and dipolarophile
12a, b 41.8 mmol) in toluene 45 ml). The mixture was stirred
and heated at 1008C under N2 for 24 h. The solvent was
evaporated under reduced pressure and the residue was
puri®ed by column chromatography to give the cyclo-
adducts 21a±q and 22a±q.
2.3.1. 0^)03aR,4R,6R,6aS)-4-Ethynyl-2-methyl-5-02-pro-
pynyl)-6-02-thienyl)tetrahydropyrrolo[3,4-c]pyrrole-
1,302H,3aH)-dione 21a and 03aR,4S,6S,6aS)-4-ethynyl-2-
methyl-5-02-propynyl)-6-02-thienyl)tetrahydropyrrolo-
[3,4-c]pyrrole-1,302H,3aH)-dione 22a. N,N-Di42-pro-
pynyl)amine 16a 4140 mg, 1.5 mmol), thiophene-2-carboxy-
aldehyde 20a 4168 mg, 1.5 mmol) and N-methylmaleimide
12a 4200 mg, 1.8 mmol) were reacted by the general pro-
cedure in toluene 45 ml) over 24 h. Flash column chroma-
tography of the 1:1 mixture of 21a and 22a eluting with 5:2
Stereoisomer 22b. Colourless prisms from CH2Cl2/ether/
petroleumether, mp 157±159 8C. 4Found: C, 60.25, H,
4.65, N, 14.1, S, 10.7. C15H13N3O2S requires: C, 60.2, H,
4.4, N, 14.05, S, 10.7%). d 2.20 4t, Jˆ2.5 Hz, 1H, CuCH),
2.53 4d, Jˆ2.2 Hz, 1H, CuCH), 3.06 4s, 3H, Me), 3.15 4dd,
Jˆ2.5 and 16.5 Hz, 1H, NCHH), 3.56 4dd, Jˆ2.6 and
8.4 Hz, 1H, Hb), 3.62 4dd, Jˆ2.5 and 16.5 Hz, 1H,
NCHH), 3.78 4t, Jˆ8.4, 1H, Hc), 4.49 4dd, Jˆ2.2 and

R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
2635
8.4 Hz, 1H, Hd), 4.88 4d, Jˆ2.6 Hz, 1H, Ha) and 7.37 and
7.81 42£d, Jˆ3.2 Hz, 2£1H, ArH). m/z 4%): 300 4M111,
100), 289 45), 274 46), 215 423), 154 49) and 136 410).
and 6.98±7.26 4m, 3H, ArH); d 413C): 25.58 4Me), 49.74
and 51.05 42£COCH), 51.61 4NCH2), 53.73 and 63.53
42£NCH), 76.39 4CuCH), 78.29 4CuCH), 118.33
4CHvCH2), 126.29, 126.96 and 127.39 43£ArC), 134.54
4CHvCH2) and 175.70 and 176.99 42£CvO); m/z 4%):
323 4M123, 100).
2.3.3. 0^)03aR,4R,6R,6aS)-4-Ethynyl-2-methyl-6-phenyl-
5-02-propynyl)tetrahydropyrrolo[3,4-c]pyrrole-1,302H,
3aH)-dione 21c and 03aR,4S,6S,6aS)-4-ethynyl-2-methyl-
6-phenyl-5-02-propynyl)tetrahydropyrrolo[3,4-c]pyrrole-
1,302H,3aH)-dione 22c. N,N-Di42-propynyl) amine 16a
4140 mg, 1.5 mmol) benzaldehyde 20c 4159 mg, 1.5
mmol) and N-methylmaleimide 12a 4200 mg, 1.8 mmol)
were reacted by the general procedure in toluene 45 ml)
over 24 h. Flash column chromatography of the 1:1 mixture
of 21c and 22c eluting with 2:1 v/v petroleumether±ethyl
ether afforded the two separated stereoisomers 21c and 22c
4296 mg, 67% combined yield).
Stereoisomers 22d. Colourless plates fromCH Cl2/ether/
2
petroleumether, mp 97±99 8C. 4Found: C, 63.95, H, 5.5,
N, 9.6, S, 10.5. C16H16N2O2S requires: C, 64.0, H, 5.35,
N, 9.35, S, 10.65%). d 41H) 2.45 4d, Jˆ2.0 Hz, 1H,
CuCH), 3.00 4s, 3H, Me), 3.01 4d, Jˆ11 Hz, 1H,
NCHH), 3.25 4m, 1H, NCHH), 3.31 4dd, Jˆ5.7 and
8.8 Hz, 1H, Hb), 3.69 4dd, Jˆ8.1 and 8.8 Hz, 1H, Hc),
4.32 4d, Jˆ5.7 Hz, 1H, Ha), 4.42 4dd, Jˆ2.0 and 8.1 Hz,
1H, Hd), 5.13 4d, Jˆ10.0 Hz, 1H, CvCHH), 5.27 4d, Jˆ
17 Hz, 1H, CvCHH), 5.68±5.81 4m, 1H, CHvCH2), 6.98
4m, 1H, ArH), 7.12 4m, 1H, ArH) and 7.28 4m, 1H, ArH); d
413C): 29.17 4Me), 48.51 and 54.01 42£COCH), 51.36
4NCH2), 54.04 and 62.95 42£NCH), 76.37 4CuCH),
78.00 4CuCH), 118.75 4CHvCH2), 126.15, 127.02 and
127.37 43£ArC), 134.44 4CHvCH2), 144.41, 175.0 and
177.0 42£CvO); m/z 4%): 323 4M123, 100).
Stereoisomer 21c. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 129±131 8C. 4Found: C, 74.05, H,
5.55, N, 9.65. C18H16N2O2 requires: C, 73.95, H, 5.50, N,
9.60%). d 2.22 4t, Jˆ2.4 Hz, 1H, CuCH), 2.52 4d, Jˆ
2.0 Hz, 1H, CuCH), 2.91 4s, 3H, Me), 3.13 and 3.21
42£d, Jˆ2.4 Hz, 2£1H, NCH2), 3.40 4d, Jˆ7.8 Hz, 1H,
Hc), 3.52 4dd, Jˆ7.8 and 8.9 Hz, 1H, Hb), 4.08 4d, Jˆ
8.9 Hz, 1H, Ha), 4.84 4d, Jˆ2.0 Hz, 1H, Hd) and 7.19±
7.46 4m, 5H, ArH). m/z 4%): 293 4M11, 100), 267 417),
215 410), 206 47), 181 49), 142 413) and 115 48).
2.3.5. 0^)03aR,4R,6R,6aS)-5-Allyl-4-ethynyl-2-methyl-6-
phenyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 21e and 03aR,4S,6S,6aS)-5-allyl-4-ethynyl-2-methyl-
6-phenyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 22e. N-Allyl-N-42-propynyl)-amine 16d 4240 mg,
2 mmol), benzaldehyde 20c 4212 mg, 2 mmol) and
N-methylmaleimide 12a 4267 mg, 2.4 mmol) were reacted
by the general procedure in toluene 45 ml) over 24 h. Flash
column chromatography of the 1:1 mixture of 21e and 22e
eluting with 2:1 v/v petroleumether±ethyl ether afforded
the two separated stereoisomers 21e and 22e 4298 mg, 50%
combined yield).
Stereoisomers 22c. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 150±151 8C. 4Found: C, 73.90, H, 5.60,
N, 9.50. C18H16N2O2 requires: C, 73.95, H, 5.50, N, 9.60%).
d 2.22 4t, Jˆ2.3 Hz, 1H, CuCH), 2.48 4d, Jˆ2.0 Hz, 1H,
CuCH), 3.01 4s, 3H, Me), 3.19 4dd, Jˆ2.3 and 6.0 Hz, 2H,
NCH2), 3.25 4dd, Jˆ6.5 and 9.1 Hz, 1H, Hb), 3.75 4dd, Jˆ8.0
and 9.1 Hz, 1H, Hc), 3.88 4d, Jˆ6.5 Hz, 1H, Ha), 4.81 4dd,
Jˆ2.0 and 8.0 Hz, 1H, Hd) and 7.31±7.46 4m, 5H, ArH). m/z
4%): 291 4M21, 29), 253 412), 215 421), 206 412), 181 419),
167 45), 150 47), 142 465), 130 480), 115 4100), 103 413), 91
425), 77 426), 63 422), 51 422) and 39 448).
Stereoisomer 21e. Colourless prisms from CH2Cl2/ether/
petroleumether, mp 118±120 8C. 4Found: C, 73.4, H, 6.25,
N, 9.65, C18H18N2O2 requires: C, 73.45, H, 6.15, N, 9.50%).
d 41H) 2.47 4d, Jˆ2.0 Hz, 1H, CuCH), 2.90 4s, 3H, Me),
2.93±3.12 4m, 2H, NCH2), 3.37 4d, Jˆ7.7 Hz, 1H, Hc), 3.50
4dd, Jˆ7.7 and 9.0 Hz, 1H, Hb), 4.15 4d, Jˆ9.0 Hz, 1H, Ha),
4.55 4d, Jˆ2.0 Hz, 1H, Hd), 5.12 4d, Jˆ10.2 Hz, 1H,
CvCHH), 5.22 4d, Jˆ17.2 Hz, 1H, CvCHH), 5.69±5.75
4m, 1H, CHvCH2) and 7.19±7.36 4m, 5H, ArH); m/z 4%):
293 4M21, 57), 253 48), 217 428), 208 415), 183 435), 142
4100), 115 452), 104 416), 91 421), 77 417) and 66 49).
2.3.4. 0^)03aR,4R,6R,6aS)-5-Allyl-4-ethynyl-2-methyl-6-
02-thienyl)tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 21d and 03aR,4S,6S,6aS)-5-allyl-4-ethynyl-2-methyl-
6-02-thienyl)tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 22d. N-Allyl-N-42-propynyl)-amine 16d 4240 mg,
2 mmol), thiophene-2-carboxyaldehyde 20a 4224 mg,
2 mmol) and N-methylmaleimide 12a 4267 mg, 2.4 mmol)
were reacted by the general procedure in toluene 45 ml) over
24 h. Flash column chromatography of the 1:1 mixture of
21d and 22d eluting with 2:1 v/v petroleumether±ethyl
ether afforded the two separated stereoisomers 21d and
22d 4305 mg, 61% combined yield).
Stereoisomer 22e. Colourless prisms from CH2Cl2/ether/
petroleumether, mp 104±106 8C. 4Found: C, 73.45, H,
6.05, N, 9.45, C18H18N2O2 requires: C, 73.45, H, 6.15, N,
9.50%). d 41H) 2.44 4d, Jˆ2.0 Hz, 1H, CuCH), 3.00 4s, 3H,
Me), 3.02±3.12 4m, 2H, NCH2), 3.21 4dd, Jˆ6.5 and 9.2 Hz,
1H, Hb), 3.68 4dd, Jˆ8.0 and 9.2 Hz, 1H, Hc), 3.92 4d,
Jˆ6.5 Hz, 1H, Ha), 4.50 4dd, Jˆ2.0 and 8.0 Hz, 1H, Hd),
5.12 4dd, Jˆ1.1 and 10.1 Hz, 1H, CvCHH), 5.23 4dd, Jˆ
1.1 and 17.2 Hz, 1H, CvCHH), 5.66±5.80 4m, 1H,
CHvCH2) and 7.28±7.47 4m, 5H, ArH); m/z 4%): 295
4M11, 100), 208 412), 193 411), 142 437) and 133 411).
Stereoisomer 21d. Colourless prisms from CH2Cl2/ether/
petroleumether, mp 105±107 8C. 4Found: C, 63.95, H,
5.55, N, 9.40, S, 10.55. C16H16N2O2S requires: C, 64.0, H,
5.35, N, 9.35, S, 10.65%). d 41H) 2.47 4d, Jˆ2.0 Hz, 1H,
CuCH), 2.93 4s, 3H, Me), 3.00 4dd, Jˆ7.1 and 12.4 Hz, 1H,
NCHH), 3.26 4dd, Jˆ7.1 and 12.4 Hz, 1H, NCHH), 3.36 4d,
Jˆ7.7 Hz, 1H, Hc), 3.50 4dd, Jˆ7.7 and 9.1 Hz, 1H, Hb),
4.47 4d, Jˆ9.1 Hz, 1H, Ha), 4.50 4d, Jˆ2.0 Hz, 1H, Hd), 5.13
4dd, Jˆ1.6 and 10.1 Hz, 1H, CvCHH), 5.23 4dd, Jˆ1.6 and
17.2 Hz, 1H, CvCHH), 5.68±5.80 4m, 1H, CHvCH2)
2.3.6. 0^)03aR,4R,6R,6aS)-4-Ethynyl-6-02-furyl)-2,5-di-
methyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-

2636
R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
dione 21f and 03aR,4S,6S,6aS)-4-ethynyl-6-02-furyl)-2,5-
dimethyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 22fN-Methyl-N-42-propynyl)amine 16b 4104 mg,
1.5 mmol), 2-furaldehyde 20d 4144 mg, 1.5 mmol) and
N-methylmaleimide 12a 4200 mg, 1.8 mmol) were reacted
by the general procedure in toluene 45 ml) over 24 h. Flash
column chromatography of the 1:1 mixture of 21f and 22f
eluting with 2:3 v/v petroleumether±ethyl ether afforded
the two separated stereoisomers 21f and 22f 4330 mg, 85%
combined yield).
10.2, S, 11.7%). d 2.29 4s, 3H, Me), 2.48 4d, Jˆ2.1 Hz, 1H,
CuCH), 2.93 4s, 3H, Me), 3.35 4d, Jˆ7.7 Hz, 1H, Hc), 3.49
4dd, Jˆ7.7 and 9.1 Hz, 1H, Hb), 4.34 4d, Jˆ9.1 Hz, 1H, Ha),
4.43 4d, Jˆ2.1 Hz, 1H, Hd) 6.98±7.04 4m, 2H, ArH)
and 7.27±7.28 4m, 1H, ArH). m/z 4%): 275 4M11, 100).
nmax 4nujol): 3271, 2923, 2853, 2954, 1696, 1460, 1378
and 716.
n.O.e. 4500 MHz, CDCl3) of 21g:
Proton
irradiated
Enhancement 4%)
Stereoisomer 21f. Colourless needles fromCH Cl2/ether/
2
Ha Hb Hc ArH
petroleumether, mp 134±136 8C. 4Found: C, 65.05, H,
5.45, N, 11.0. C14H14N2O3 requires: C, 65.10, H, 5.45, N,
10.85%). d 2.22 4s, 3H, Me), 2.49 4d, Jˆ2.1 Hz, 1H,
CuCH), 2.98 4s, 3H, Me), 3.36 4d, Jˆ7.8 Hz, 1H, Hc),
3.47 4dd, Jˆ7.8 and 8.7 Hz, 1H, Hb), 4.09 4d, Jˆ8.7 Hz,
1H, Ha), 4.41 4d, Jˆ2.1 Hz, 1H, Hd), 6.30 4d, Jˆ2.8 Hz,
1H, ArH), 6.36 4dd, Jˆ1.8 and 3.2 Hz, 1H, ArH) and 7.40
4d, Jˆ1.8 Hz, 1H, ArH). m/z 4%): 257 4M121, 11), 172 48),
147 4100), 132 428), 118 444), 108 430), 91 48), 78 418), 66
413), 51 418) and 42 428). nmax 4nujol): 2923, 2853, 2953,
1698, 1455, and 3231.
Ha
Hb
Hc
Hd
±
7.93
3.56 3.27
±
9.21
±
±
3.71
±
3.29
±
±
±
±
3.25
Stereoisomer 22g. Colourless prisms from CH2Cl2/ether/
petroleumether, mp 134±136 8C. 4Found: C, 61.2, H, 5.1,
N, 10.05, S, 11.5. C14H14N2O2S requires: C, 61.3, H, 5.15,
N, 10.2, S, 11.7%). d 2.27 4s, 3H, Me), 2.46 4d, Jˆ2.1 Hz,
1H, CuCH), 3.01 4s, 3H, Me), 3.32 4dd, Jˆ5.5 and 9.1 Hz,
1H, Hb), 3.71 4dd, Jˆ8.0 and 9.1 Hz, 1H, Hc), 4.25 4d, Jˆ
5.5 Hz, 1H, Ha), 4.32 4dd, Jˆ2.1 and 8.0 Hz, 1H, Hd) 6.99
4dd, Jˆ3.5 and 5.1 Hz, 1H, ArH), 7.10±7.11 4m, 1H, ArH)
and 7.27±7.31 4m, 1H, ArH). m/z 4%): 274 4M1, 20), 188
49), 163 4100), 148 432), 135 46), 124 446), 115 46), 106 414),
97 418), 91 412), 82 48), 77 413), 69 48), 63 418), 58 48), 51
412) and 42 435). nmax 4nujol): 3271, 2923, 2853, 2953,
1696, 1460 and 716.
n.O.e. 4500 MHz, CDCl3) of 21f:
Proton
irradiated
Enhancement 4%)
Ha Hb Hc Hd
Ha
Hb
Hc
Hd
±
8.20
±
8.12
±
1.07
±
±
2.97
±
±
3.46
±
±
3.24
n.O.e. 4500 MHz, CDCl3) of 22g:
Stereoisomer 22f. Colourless plates fromCH 2Cl2/ether/
petroleumether, mp 114±116 8C. 4Found: C, 64.95, H, 5.5,
N, 10.80. C14H14N2O3 requires: C, 65.10, H, 5.45, N,
10.85%). d 2.23 4s, 3H, Me), 2.48 4d, Jˆ2.2 Hz, 1H,
CuCH), 3.03 4s, 3H, Me), 3.49 4dd, Jˆ3.9 and 8.5 Hz,
1H, Hb), 3.70 4t, Jˆ8.5 Hz, 1H, Hc), 4.15 4dd, Jˆ2.2 and
8.5 Hz, 1H, Hd), 4.21 4d, Jˆ3.9 Hz, 1H, Ha), 6.35 4dd, Jˆ0.8
and 3.2 Hz, 1H, ArH), 6.37 4dd, Jˆ1.8 and 3.2 Hz, 1H, ArH)
and 7.42 4d, Jˆ1.0 Hz, 1H, ArH). m/z 4%): 4FAB) 259
4M111, 100%). nmax 4nujol): 1698, 2923, 1702, 2951,
2853, 1682 and 3281.
Proton
irradiated
Enhancement 4%)
Ha Hb Hc Hd
Ha
Hb
Hc
Hd
±
1.57
±
1.71 0.91
±
±
6.52
±
±
7.25
±
6.24
±
6.71
±
2.3.8. 0^)03aR,4R,6R,6aS)-4-Ethynyl-2,5-dimethyl-6-01,3-
thiazol-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 21h and 03aR,4S,6S,6aS)-4-ethynyl-2,5-dimethyl-
6-01,3-thiazol-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3-
02H,3aH)-dione 22h. N-Methyl-N-42-propynyl)amine 16b
4104 mg, 1.5 mmol), 2-thiazole carboxaldehyde 20b 4170
mg, 1.5 mmol) and N-methylmaleimide 12a 4200 mg, 1.8
mmol) were reacted by the general procedure in toluene 45 ml)
over 24 h. Flash column chromatography 41:4 v/v petroleum
ether±ether) afforded the two separated stereoisomers 21h
and 22h 4329 mg, 80% combined yield) in a 1:1 ratio.
2.3.7. 0^)03aR,4R,6R,6aS)-4-Ethynyl-2,5-dimethyl-6-02-
thienyl)tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 21g and 03aR,4S,6S,6aS)-4-ethynyl-2,5-dimethyl-
6-02-thienyl)tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 22g. N-Methyl-N-42-propynyl) amine 16b 4104 mg,
1.5 mmol), thiophene-2-carboxyaldehyde 20a 4159 mg, 1.5
mmol) and N-methylmaleimide 12a 4200 mg, 1.8 mmol)
were reacted by the general procedure in toluene 45 ml)
over 24 h. Flash column chromatography of the 1:1 mixture
of 21g and 22g eluting with 1:1 v/v petroleumether-ethyl
ether afforded the two separated stereoisomers 21g and 22g
4238 mg, 58% combined yield).
Stereoisomer 21h. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 139±141 8C. 4Found: C, 56.7, H, 4.6,
N, 15.5, S, 11.75. C13H13N3O2S requires: C, 56.7, H, 4.75,
N, 15.25, S, 11.65%). d 2.37 4s, 3H, Me), 2.53 4d, Jˆ1.9 Hz,
1H, CuCH), 2.92 4s, 3H, Me), 3.42 4d, Jˆ7.8 Hz, 1H, Hc),
3.69 4dd, Jˆ7.8 and 9.2 Hz, 1H, Hb), 4.46 4d, Jˆ1.9 Hz, 1H,
Stereoisomer 21g. Colourless plates fromCH 2Cl2/ether/
petroleumether, mp 126±128 8C. 4Found: C, 61.1, H, 5.2,
N, 10.5, S, 11.5. C14H14N2O2S requires: C, 61.3, H, 5.15, N,

R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
2637
Hd), 4.55 4d, Jˆ9.2 Hz, 1H, Ha) and 7.35 and 7.80 42£d, Jˆ
n.O.e. 4500 MHz, CDCl3) of 22i:
3.2 Hz, 2£1H, ArH). m/z 4%): 276 4M111, 100). nmax 4nujol):
1688, 1706, 1698, 2934, 2855, 2957, 1121, 1280 and
3264.
Proton
irradiated
Enhancement 4%)
Ha Hb Hc Hd
Stereoisomer 22h. Colourless prisms from CH2Cl2/ether/
petroleumether, mp 126±128 8C. 4Found: C, 56.6, H, 4.7,
N, 15.15, S, 11.85. C13H13N3O2S, requires: C, 56.7, H, 4.75,
N, 15.25, S, 11.65%). d 2.31 4s, 3H, Me), 2.50 4d, Jˆ2.2 Hz,
1H, CuCH), 3.04 4s, 3H, Me), 3.54 4dd, Jˆ3.5 and 8.6 Hz,
1H, Hb), 3.76 4dd, Jˆ8.2 and 8.6 Hz, 1H, Hc), 4.30 4dd,
Jˆ2.2 and 8.2 Hz, 1H, Hd), 4.57 4d, Jˆ3.5 Hz, 1H, Ha)
and 7.35 and 7.82 42£d, Jˆ3.3 Hz, 2£1H, ArH). m/z 4%):
276 4M111, 95) and 191 4100). nmax 4nujol): 1694, 1698,
1702, 1781, 3291, 2924, 3112 and 2851.
Ha
Hb
Hc
Hd
±
1.75
±
2.59
±
9.01
±
±
7.85
±
1.04
±
8.78
±
±
8.05
2.3.10. 0^)03aR,4R,6R,6aS)-4-Ethynyl-2,5-dimethyl-6-
02-pyridinyl)tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 21j and 03aR,4S,6S,6aS)-4-ethynyl-2,5-dimethyl-6-
02-pyridinyl)tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 22j. N-Methyl-N-42-propynyl)amine 16b 4107 mg,
1.5 mmol), pyridine-3-carboxaldehyde 20e 4161 mg, 1.5
mmol) and N-methylmaleimide 12a 4200 mg, 1.8 mmol)
were reacted by the general procedure in toluene 45 ml)
over 24 h. Flash column chromatography 41:2 v/v petroleum
ether±ether) afforded the two separated stereoisomers 21j
and 22j 4214 mg, 53% combined yield) in a 1:1 ratio.
2.3.9.
0^)03aR,4R,6R,6aS)-4-Ethynyl-2,5-dimethyl-6-
phenyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 21i and 03aR,4S,6S,6aS)-4-ethynyl-2,5-dimethyl-6-
phenyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 22i. N-Methyl-N-42-propynyl)amine 16b 4104 mg,
1.5 mmol), benzaldehyde 20c 4159 mg, 1.5 mmol) and
N-methylmaleimide 12a 4200 mg, 1.8 mmol) were reacted
by the general procedure in toluene 45 ml) over 24 h. Flash
column chromatography 43:2 v/v petroleum ether±ether)
afforded the two separated stereoisomers 21i and 22i
4251 mg, 62% combined yield) in a 1:1 ratio.
Stereoisomer 21j. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 137±139 8C. 4Found: C, 66.7, H, 5.65,
N, 15.9. C15H15N3O2 requires: C, 66.90, H, 5.60, N, 15.6%). d
2.25 4s, 3H, Me), 2.50 4d, Jˆ2.1 Hz, 1H, CuCH), 2.92 4s,
3H, Me), 3.41 4d, Jˆ7.8 Hz, 1H, Hc), 3.63 4dd, Jˆ7.8 and
8.9 Hz, 1H, Hb), 4.21 4d, Jˆ8.9 Hz, 1H, Ha), 4.48 4d, Jˆ
2.1 Hz, 1H, Hd), 7.19±7.27 4m, 2H, ArH), 7.68 4dt, Jˆ1.8
and 7.7 Hz, 1H, ArH) and 8.61±8.63 4m, 1H, ArH). m/z 4%):
268 4M121, 56), 254 430), 240 426), 211 48), 191 445), 183
445), 169 439), 157 479), 143 463), 131 432), 117 462), 106
4100), 92 440), 78 482), 63 440), 56 415), 51 461) and 39
448). nmax 4nujol): 2923, 1689, 2853, 2955, 1441, 1285 and
3256.
Stereoisomer 21i. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 137±139 8C. 4Found: C, 71.65, H,
6.15, N, 10.5. C16H16N2O2 requires: C, 71.65, H, 6.0, N,
10.45%). d 2.19 4s, 3H, Me), 2.48 4d, Jˆ2.1 Hz, 1H,
CuCH), 2.90 4s, 3H, Me), 3.36 4d, Jˆ7.7 Hz, 1H, Hc),
3.49 4dd, Jˆ7.7 and 8.9 Hz, 1H, Hb), 4.02 4d, Jˆ8.9 Hz,
1H, Ha), 4.46 4d, Jˆ2.1 Hz, 1H, Hd) and 7.18±7.36 4m,
5H, ArH). m/z 4%): 268 4M, 36), 191 425), 182 414), 167
47), 157 4100), 142 422), 128 411), 115 483), 106 434), 91
433), 82 47), 77 456), 63 436), 58 413), 51 444) and 42 462).
nmax 4nujol): 2923, 1694, 2853, 3231, 1441 and 698.
Stereoisomer 22j. Colourless plates fromCH 2Cl2/ether/
petroleumether, mp 132±134 8C. 4Found: C, 66.7, H, 5.75,
N, 15.85. C15H15N3O2, requires: C, 66.90, H, 5.60, N, 15.6).
d 2.21 4s, 3H, Me), 2.48 4d, Jˆ2.2 Hz, 1H, CuCH), 3.03 4s,
3H, Me), 3.66 4dd, Jˆ5.1 and 9.0 Hz, 1H, Hb), 3.84 4dd,
Jˆ8.1 and 9.0 Hz, 1H, Hc), 4.07 4d, Jˆ5.1 Hz, 1H, Ha), 4.42
4dd, Jˆ2.2 and 8.1 Hz, 1H, Hd), 7.24±7.29 4m, 1H, ArH),
7.35 4d, Jˆ7.7 Hz, 1H, ArH), 7.71 4dt, Jˆ1.8 and 7.7 Hz,
1H, ArH), and 8.66±8.68 4m, 1H, ArH). m/z 4%): 270
4M11, 100), 244 46), 191 48) and 157 45). nmax 4nujol):
2923, 2853, 2954, 1696, 1460, 716, 1378 and 3271.
n.O.e. 4500 MHz, CDCl3) of 21i:
Proton
irradiated
Enhancement 4%)
Ha Hb Hc Hd
Ha
Hb
Hc
Hd
±
7.26
±
8.38
±
3.58
±
±
3.91
±
±
±
3.84
±
±
3.00
2.3.11. 0^)03aR,4R,6R,6aS)-4-Ethynyl-2,5-dimethyl-6-
06-methyl-2-pyridinyl)tetrahydropyrrolo[3,4-c]pyrrole-
1,302H,3aH)-dione 21k and 03aR,4S,6S,6aS)-4-ethynyl-
2,5-dimethyl-6-06-methyl-2-pyridinyl)tetrahydropyrrolo-
[3,4-c]pyrrole-1,302H,3aH)-dione 22k. N-Methyl-N-42-
propynyl)amine 16b 4104 mg, 1.5 mmol), 6-methyl-2-pyri-
dine-carboxaldehyde 20f 4182 mg, 1.5 mmol) and
N-methylmaleimide 12a 4200 mg, 1.8 mmol) were reacted
by the general procedure in toluene 45 ml) over 24 h. Flash
column chromatography 41:4 v/v petroleum ether±ether)
afforded the two separated stereoisomers 21k and 22k
4330 mg, 56% combined yield) in a 1:1 ratio.
Stereoisomer 22i. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 132.5±134.5 8C. 4Found: C, 71.55, H,
6.1, N, 10.65. C16H16N2O2 requires: C, 71.65, H, 6.0, N,
10.45%). d 2.19 4s, 3H, Me), 2.45 4d, Jˆ2.1 Hz, 1H,
CuCH), 3.01 4s, 3H, Me), 3.23 4dd, Jˆ6.4 and 9.3 Hz,
1H, Hb), 3.72 4dd, Jˆ8.0 and 9.3 Hz, 1H, Hc), 3.82 4d,
Jˆ6.4 Hz, 1H, Ha), 4.41 4dd, Jˆ2.1 and 8.0 Hz, 1H, Hd)
and 7.29±7.45 4m, 5H, ArH). m/z 4%): 267 4M21, 39),
191 429), 182 418), 167 48), 157 4100), 142 422), 128 49),
118 456), 106 424), 91 422), 77 425), 63 416), 51 418) and 42
431).

2638
R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
Stereoisomer 21k. Colourless needles fromCH Cl2/ether/
2
6.05, N, 9.3. C17H18N2O3 requires: C, 68.45, H, 6.1, N,
9.4%). d 2.17 4s, 3H, Me), 2.44 4d, Jˆ2.1 Hz, 1H,
CuCH), 3.00 4s, 3H, Me), 3.20 4dd, Jˆ6.5 and 9.2 Hz,
1H, Hb), 3.70 4dd, Jˆ8.1 and 9.2 Hz, 1H, Hc), 3.76
4d, Jˆ6.5 Hz, 1H, Ha), 3.82 4s, 3H, Me), 4.39 4dd, Jˆ2.1
and 8.1 Hz, 1H, Hd), 6.91 and 7.33 42£dd, Jˆ2.1 and
6.7 Hz, 2£2H, ArH). m/z 4%): 297 4M21, 13), 212 45),
187 4100), 172 476), 157 48), 148 441), 133 46), 121 48),
115 411), 105 49), 91 48), 77 413), 63 410), 51 48) and 42
414). nmax 4nujol): 1703, 3267, 1694, 1249, 1515, 2847,
2953 and 2903.
petroleumether, mp 153±155 8C. 4Found: C, 67.9, H, 6.0,
N, 14.6. C16H17N3O2, requires: C, 67.85, H, 6.05, N, 14.85).
d 2.24 4s, 3H, Me), 2.47 4d, Jˆ2.0 Hz, 1H, CuCH), 2.57
and 2.92 42£s, 2£3H, 2£Me), 3.39 4d, Jˆ7.9 Hz, 1H, Hc),
3.63 4dd, Jˆ7.9 and 8.8 Hz, 1H, Hb), 4.18 4d, Jˆ8.8 Hz, 1H,
Ha), 4.46 4d, Jˆ2.0 Hz, 1H, Hd), 6.97 and 7.08 42£d, Jˆ
7.7 Hz, 2£1H, ArH) and 7.54 4t, Jˆ7.7 Hz, 1H, ArH). m/z
4%): 284 4M111, 100%). nmax 4nujol): 1698, 1288, 1439,
1593, 2923 and 3243.
n.O.e. 4500 MHz, CDCl3) of 21k:
2.3.13. 0^)03aR,4R,6R,6aS)-4-Ethynyl-6-02-furyl)-5-methyl-
2-phenyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-dione
21m and 03aR,4S,6S,6aS)-4-ethynyl-6-02-furyl)-5-methyl-2-
phenyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-dione
22m. N-Methyl-N-42-propynyl)amine 16b 4104 mg,
1.5 mmol), 2-furaldehyde 20d 4144 mg, 1.5 mmol) and N-
phenylmaleimide 12b 4312 mg, 1.8 mmol) were reacted by
the general procedure in toluene 45 ml) over 24 h. Flash
column chromatography 41:1 v/v petroleum ether±ether)
afforded the two separated stereoisomers 21m and 22m
4212 mg, 44% combined yield) in a 1:1 ratio.
Proton
irradiated
Enhancement 4%)
Ha Hb Hc Hd
Ha
Hb
Hc
Hd
±
9.08
±
8.70
±
5.61
±
±
6.84
±
±
±
3.24
±
±
3.15
Stereoisomer 22k. Colourless needles frompreparative
HPLC, mp 134±1368C. 4Found: C, 67.8, H, 6.0, N, 15.15.
C16H17N3O2, requires: C, 67.85, H, 6.05, N, 14.85). d 2.20
4s, 3H, Me), 2.46 4d, Jˆ2.2 Hz, 1H, CuCH), 2.56 and 3.03
42£s, 2£3H, 2£Me), 3.72 4dd, Jˆ4.7 and 8.9 Hz, 1H, Hb),
3.83 4dd, Jˆ8.0 and 8.9 Hz, 1H, Hc), 4.07 4d, Jˆ4.7 Hz, 1H,
Ha), 4.43 4dd, Jˆ2.2 and 8.0 Hz, 1H, Hd), 7.11 4dd, Jˆ3.6
and 7.7 Hz, 2H, ArH) and 7.58 4t, Jˆ7.7 Hz, 1H, ArH). m/z
4%): 283 4M1, 69), 268 444), 255 425), 225 47), 211 45), 197
438), 191 458), 183 433), 171 450), 157 472), 145 451), 131
458), 118 414), 106 4100), 92 441), 77 432), 65 455), 51 421)
and 39 450). nmax 4nujol): 2923, 1699, 2361, 668, 2343, 2853
and 2954.
Stereoisomer 21m. Colourless plates fromCH Cl2/ether/
2
petroleumether, mp 136±138 8C. 4Found: C, 71.05, H,
4.95, N, 8.70. C19H16N2O3 requires: C, 71.25, H, 5.05, N,
8.75%). d 2.27 4s, 3H, Me), 2.50 4d, Jˆ2.0 Hz, 1H, CuCH),
3.52 4d, Jˆ8.0 Hz, 1H, Hc), 3.61 4dd, Jˆ8.0 and 8.8 Hz, 1H,
Hb), 4.20 4d, Jˆ8.8 Hz, 1H, Ha), 4.50 4d, Jˆ2.0 Hz, 1H, Hd),
6.36 4d, Jˆ1.2 Hz, 2H, ArH) and 7.27±7.47 4m, 6H, ArH).
m/z 4%): 320 4M1, 11), 173 49), 147 4100), 132 424), 118
436), 108 424), 91 416), 77 418), 64 413), 51 416) and 42 424).
n.O.e. 4500 MHz, CDCl3) of 21m:
2.3.12.
0^)03aR,4R,6R,6aS)-4-Ethynyl-6-04-methoxy-
Proton
irradiated
Enhancement 4%)
phenyl)-2,5-dimethyltetrahydropyrrolo[3,4-c]pyrrole-
1,302H,3aH)-dione 21l and 03aR,4S,6S,6aS)-4-ethynyl-6-
04-methoxyphenyl)-2,5-dimethyltetrahydropyrrolo[3,4-c]-
pyrrole-1,302H,3aH)-dione 22l. N-Methyl-N-42-propynyl)-
amine 16b 4104 mg, 1.5 mmol), 4-methoxybenzaldehyde
20g 4204 mg, 1.5 mmol) and N-methylmaleimide 12a
4200 mg, 1.8 mmol) were reacted by the general procedure
in toluene 45 ml) over 24 h. Flash column chromatography
41:1 v/v petroleumether±ether) afforded the two separated
stereoisomers 21l and 22l 4205 mg, 46% combined yield) in
a 1:1 ratio.
Ha
Hb
Hc Hd
Ha
Hb
Hc
Hd
±
12.24
±
11.72
±
3.53
±
±
3.36
±
±
±
6.41
±
±
4.80
Stereoisomer 22m. Colourless plates fromCH Cl2/ether/
2
petroleumether, mp 139±141 8C. 4Found: C, 71.25, H, 5.2,
N, 8.80. C19H16N2O3 requires: C, 71.25, H, 5.05, N, 8.75%).
d 2.28 4s, 3H, Me), 2.55 4d, Jˆ2.0 Hz, 1H, CuCH), 3.69
4dd, Jˆ4.48 and 8.9 Hz, 1H, Hb), 3.86 4dd, Jˆ8.2 and
8.9 Hz, 1H, Hc), 4.26 4d, Jˆ4.48 Hz, 1H, Ha), 4.31 4dd,
Jˆ2.0 and 8.2 Hz, 1H, Hd), 6.39 4d, Jˆ2.3 Hz, 2H, ArH)
and 7.31±7.50 4m, 6H, ArH). m/z 4%): 321 4M111, 100),
295 412), 253 440), 172 47), and 147 442).
Stereoisomer 21l. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 189±191 8C. 4Found: C, 68.25, H, 6.2,
N, 9.6. C17H18N2O3 requires: C, 68.45, H, 6.1, N, 9.4%). d
2.16 4s, 3H, Me), 2.47 4d, Jˆ2.1 Hz, 1H, CuCH), 2.91 4s,
3H, Me), 3.34 4d, Jˆ7.7 Hz, 1H, Hc), 3.44 4dd, Jˆ7.7 and
8.8 Hz, 1H, Hb), 3.80 4s, 3H, Me), 3.97 4d, Jˆ8.8 Hz, 1H, Ha),
4.44 4d, Jˆ2.1 Hz, 1H, Hd), 6.87 4d, Jˆ8.9 Hz, 2H, ArH) and
7.09 4d, Jˆ8.5 Hz, 2H, ArH). m/z 4%): 297 4M21, 23), 212
47), 187 4100), 172 466), 157 49), 148 450), 131 410), 115 411),
106 414), 91 49), 77 415), 63 411), 51 49) and 42 425).
2.3.14. 0^)03aR,4R,6R,6aS)-4-Ethynyl-5-methyl-2-phenyl-
6-02-thienyl)tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 21n and 03aR,4S,6S,6aS)-4-ethynyl-5-methyl-2-
phenyl-6-02-thienyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3-
02H,3aH)-dione 22n. N-Methyl-N-42-propynyl) amine 16b
Stereoisomer 22l. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 177±179 8C. 4Found: C, 68.55, H,

R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
2639
4104 mg, 1.5 mmol), thiophene-2-carboxyaldehyde 20a
4168 mg, 1.5 mmol) and N-phenylmaleimide 12b 4312 mg,
1.8 mmol) were reacted by the general procedure in toluene
45 ml) over 24 h. Flash column chromatography 41:1 v/v
petroleumether±ether) afforded the two separated stereo-
isomers 21n and 22n 4218 mg, 43% combined yield) in a 1:1
ratio.
phenyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 21p and 03aR,4S,6S,6aS)-4-ethynyl-5-methyl-2,6-
diphenyltetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-
dione 22p. N-Methyl-N-42-propynyl)amine 16b 4104 mg,
1.5 mmol), benzaldehyde 20c 4159 mg, 1.5 mmol) and
N-phenylmaleimide 12b 4312 mg, 1.8 mmol) were reacted
by the general procedure in toluene 45 ml) over 24 h. Flash
column chromatography 41:2 v/v petroleum ether±ether)
afforded the two separated stereoisomers 21p and 22p
4182 mg, 55% combined yield) in a 1:1 ratio.
Stereoisomer 21n. Colourless prismfromCH 2Cl2/ether/
petroleumether, mp 151±152 8C. 4Found: C, 67.8, H, 4.95,
N, 8.25, S, 9.3. C19H16N2O2S requires: C, 67.85, H, 4.8, N,
8.35, S, 9.55%). d 2.36 4s, 3H, Me), 2.51 4d, Jˆ2.1 Hz, 1H,
CuCH), 3.54 4d, Jˆ7.9 Hz, 1H, Hc), 3.64 4dd, Jˆ7.9 and
9.1 Hz, 1H, Hb), 4.45 4d, Jˆ9.1 Hz, 1H, Ha), 4.54 4d,
Jˆ2.1 Hz, 1H, Hd) and 6.98±7.43 4m, 8H, ArH). m/z 4%):
337 4M111, 100), 311 416), 253 465), 188 416), 163 458)
and 148 45).
Stereoisomer 21p. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 155±157 8C. 4Found: C, 76.1, H, 5.6,
N, 8.45. C21H18N2O2 requires: C, 76.35, H, 5.5, N, 8.5%). d
2.26 4s, 3H, Me), 2.51 4d, Jˆ2.1 Hz, 1H, CuCH), 3.54
4d, Jˆ8.0 Hz, 1H, Hc), 3.63 4dd, Jˆ8.0 and 9.0 Hz, 1H,
Hb), 4.13 4d, Jˆ9.0 Hz, 1H, Ha), 4.57 4d, Jˆ2.1 Hz, 1H,
Hd) and 7.17±7.44 4m, 10H, ArH). m/z 4%): 330 4M1, 47),
253 415), 182 421), 173 49), 157 4100), 142 419), 129 410),
115 445), 106 420), 91 428), 77 425), 64 416), 51 417) and 42
423).
Stereoisomer 22n. Colourless prisms from CH2Cl2/ether/
petroleumether, mp 156±158 8C. 4Found: C, 67.7, H, 4.95,
N, 8.4, S, 9.5. C19H16N2O2S requires: C, 67.85, H, 4.8, N,
8.35, S, 9.55%. d 2.34 4s, 3H, Me), 2.57 4d, Jˆ2.1 Hz, 1H,
CuCH), 3.50 4dd, Jˆ5.8 and 9.4 Hz, 1H, Hb), 3.86 4dd,
Jˆ8.1 and 9.4 Hz, 1H, Hc), 4.35 4d, Jˆ5.8 Hz, 1H, Ha),
4.47 4dd, Jˆ2.1 and 8.1 Hz, 1H, Hd) and 6.98±7.50 4m,
8H, ArH). m/z 4%): 337 4M11, 100), 311 47), 253 428),
188 46) and 163 419).
Stereoisomer 22p. Colourless needles fromCH Cl2/ether/
2
petroleumether, mp 148±150 8C. 4Found: C, 76.1, H, 5.55,
N, 8.6. C21H18N2O2 requires: C, 76.35, H, 5.5, N, 8.5%). d
2.23 4s, 3H, Me), 2.56 4d, Jˆ2.0 Hz, 1H, CuCH), 3.36 4dd,
Jˆ6.4 and 9.5 Hz, 1H, Hb), 3.80 4dd, Jˆ7.9 and 9.5 Hz, 1H,
Hc), 3.93 4d, Jˆ6.4 Hz, 1H, Ha), 4.50 4dd, Jˆ2.0 and 7.9 Hz,
1H, Hd) and 7.16±7.47 4m, 10H, ArH). m/z 4%): 331 4M11,
100).
2.3.15. 0^)03aR,4R,6R,6aS)-4-Ethynyl-5-methyl-2-phenyl-
6-01,3-thiazol-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3-
02H,3aH)-dione 21o and 03aR,4S,6S,6aS)-4-ethynyl-5-
methyl-2-phenyl-6-01,3-thiazol-2-yl)tetrahydropyrrolo-
[3,4-c]pyrrole-1,302H,3aH)-dione 22o. N-Methyl-N-42-
propynyl)amine 16b 4104 mg, 1.5 mmol), 2-thiazole
carboxaldehyde 20b 4170 mg, 1.5 mmol) and N-phenyl-
maleimide 12b 4312 mg, 1.8 mmol) were reacted by the
general procedure in toluene 45 ml) over 24 h. Flash column
chromatography 41:1 v/v petroleum ether±ether) afforded
the two separated stereoisomers 21o and 22o 4384 mg,
76% combined yield) in a 1:1 ratio.
n.O.e. 4500 MHz, CDCl3) of 22p:
Proton
irradiated
Enhancement 4%)
Hb Hc Hd
Ha
Ha
Hb
Hc
Hd
±
2.17 ±
9.06 ±
10.64
9.64 ±
±
1.81 ±
±
±
11.15 ±
±
Stereoisomer 21o. Colourless prisms from CH2Cl2/ether/
petroleumether, mp 179±182 8C. 4Found: C, 64.05, H, 4.5,
N, 12.75, S, 9.45. C18H15N3O2S requires: C, 64.10, H, 4.5,
N, 12.45, S, 9.5%). d 2.43 4s, 3H, Me), 2.55 4d, Jˆ2.0 Hz,
1H, CuCH), 3.61 4d, Jˆ8.1 Hz, 1H, Hc), 3.85 4dd, Jˆ8.1
and 9.2 Hz, 1H, Hb), 4.57 4d, Jˆ2.0 Hz, 1H, Hd), 4.66 4d,
Jˆ9.2 Hz, 1H, Ha), 7.23±7.46 4m, 6H, ArH).and 7.81 4d,
Jˆ3.3 Hz, 1H, ArH). m/z 4%): 338 4M111, 19), 253 47),
181 415), 91 4100) and 73 417).
2.3.17.
0^)03aR,4R,6R,6aS)-4-Ethynyl-5-methyl-6-06-
methyl-2-pyridinyl)-2-phenyltetrahydropyrrolo[3,4-c]-
pyrrole-1,302H,3aH)-dione 21q and 03aR,4S,6S,6aS)-4-
ethynyl-5-methyl-6-06-methyl-2-pyridinyl)-2-phenyl-
tetrahydropyrrolo[3,4-c]pyrrole-1,302H,3aH)-dione 22q.
N-Methyl-N-42-propynyl)amine 16b 4104 mg, 1.5 mmol),
6-methyl-2-pyridine-carboxaldehyde 20f 4182 mg, 1.5
mmol) and N-phenylmaleimide 12b 4312 mg, 1.8 mmol)
were reacted by the general procedure in toluene 45 ml)
over 24 h. Flash column chromatography 41:2 v/v petroleum
ether±ether) afforded the two stereoisomers 21q and 22q
4271 mg, 52% combined yield) in a 1:1 ratio. But we only
Stereoisomer 22o. Colourless plates fromCH 2Cl2/ether/
petroleumether, mp 146±149 8C. 4Found: C, 63.85, H,
4.55, N, 12.7, S, 9.6. C18 H15N3O2S requires: C, 64.10, H,
4.50, N, 12.45, S, 9.50%). d 2.38 4s, 3H, Me), 2.57 4d,
Jˆ2.1 Hz, 1H, CuCH), 3.72 4dd, Jˆ4.0 and 8.9 Hz, 1H,
Hb), 3.93 4dd, Jˆ8.2 and 8.9 Hz, 1H, Hc), 4.43 4dd, Jˆ2.1
and 8.2 Hz, 1H, Hd), 4.64 4d, Jˆ4.0 Hz, 1H, Ha), 7.32±7.51
4m, 6H, ArH) and 7.84 4d, Jˆ3.2 Hz, 1H, ArH). m/z 4%):
338 4M111, 100), 312 46), 253 437), 189 47), 165 46), 136
413), 106 413) and 77 47).
got pure stereoisomer 21q: colourless plates fromCH Cl2/
2
ether/petroleumether, mp 145±147 8C. 4Found: C, 72.75, H,
5.5, N, 12.45. C21H19N3O2 requires: C, 73.05, H, 5.55, N,
12.15%). d 2.30 4s, 3H, Me), 2.50 4d, Jˆ2.0 Hz, 1H,
CuCH), 2.56 4s, 3H, Me), 3.57 4d, Jˆ8.0 Hz, 1H, Hc),
3.80 4dd, Jˆ8.0 and 9.1 Hz, 1H, Hb), 4.31 4d, Jˆ9.1 Hz,
2.3.16. 0^)03aR,4R,6R,6aS)-4-Ethynyl-5-methyl-2,6-di-

2640
R. Grigg et al. / Tetrahedron 58 ꢀ2002) 2627±2640
1H, Ha), 4.56 4d, Jˆ2.0 Hz, 1H, Hd) and 7.06±7.58 4m, 8H,
ArH). m/z 4%): 346 4M111, 100), 320 46), 253 46), 197 46),
171 46), 147 46) and 106 46).
Data collection. 6.7,2u,52.08, 17028 data collected 3335
of which were unique [Rintˆ0.054]. There 2954 re¯ections
with Fo.4.0 s4Fo).
2.4. Single-crystal X-ray diffraction analysis of 13b, 21n
and 22n
Structure re®nement. Number of parametersˆ219, good-
ness of ®t, sˆ1.032; weighting parameters x, yˆ0.0847,
1.4702; wR2ˆ0.1567, R1ˆ0.0532.
Crystallographic data for all three compounds were
collected on a Nonius KappaCCD area-detector diffracto-
meter using graphite monochromated Mo Ka radiation
Crystallographic data 4excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 172752 4compound 13b),
CCDC 172753 4compound 21n) and CCDC 172754
4compound 22n). Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2) 1EZ, UK [fax: 14440)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
Ê
4lˆ0.71073 A) and a mixture of a 18 area-detector v- and
f-scans. All three structures were solved by direct methods
using SHELXS-867 and were re®ned by full-matrix least
squares 4based on F2) using SHELXL-97.8 The weighting
schemes used in all three re®nements was wˆ[s24Fo )1
2
4xP)21yP]21 where Pˆ4Fo 12Fc )/3. In all cases all non-
hydrogen atoms were re®ned with anisotropic displacement
parameters whilst hydrogen atoms were constrained to
predicted positions using a riding model with free rotation
for methyl groups. The re®nements of 13b and 21n includ0ed
an isotropic extinction parameter, x, so that Fc ˆ
2
2
Acknowledgements
kFc[110.001xFc l3]21/4 where k is the overall scale factor.
2
We thank the ORS and Tetley and Lupton for Scholarship
4to J. X. and J. Z.) and Leeds University and the EPSRC for
support.
The residuals wR2 and R1, given below, are de®ned as
P
2
wR2ˆ4S[w4Fo 2Fc2)2]/ [wFo2]2)1/2 and R1 ˆ SiFou 2 uFci=
P
iFoi.
References
Crystal data for 13b. C26H22N2O4, 0.57£0.15£0.06 mm3,
Mˆ426.46, monoclinic, space group P21, aˆ8.028344),
1. 4a) Aly, M. F.; Grigg, R.; Thianpatanagul, S.; Sridharan, V.
J. Chem. Soc., Perkin Trans. 1 1988, 949±955. 4b) Grigg, R.;
Sivagnanasundram, S.; Thianpatanagul, S.; Vipond, D. J. Chem.
Soc., Perkin Trans. 1 1988, 2693±2701. 4c) Grigg, R.; Idle, J.;
McMeekin, P.; Sivagnanasundram, S.; Vipond, D. J. Chem.
Soc., Perkin Trans. 1 1988, 2703±2713. 4d) Ardill, H.; Grigg,
R.; Sridharan, V.; Sivagnanasundram, S. Tetrahedron 1988, 44,
4953±4966. 4e) Grigg, R.; Henderson, D.; Hudson, A. J.
Tetrahedron Lett. 1989, 30, 2841±2844.
Ê
bˆ6.216444),
cˆ22.79842) A,
bˆ96.81044)8,
Uˆ
,
1129.74412) A , Zˆ2, Dcˆ1.254 mg m23, mˆ0.09 mm21
F4000)ˆ448, Tˆ150 K.
Ê 3
Data collection. 6.8,2u,52.08, 9815 data collected 3805
of which were unique [Rintˆ0.084]. There 3503 re¯ections
with Fo.4.0s4Fo).
Structure re®nement. Number of parametersˆ291, isotropic
extinction parameter, xˆ0.0942), goodness of ®t, sˆ1.089;
weighting parameters x, yˆ0.0327, 0.4211; wR2ˆ0.1273,
R1ˆ0.0531.
2. 4a) Ardill, H.; Dorrity, M. J. R.; Grigg, R.; Leon-Ling, M. S.;
Malone, J. F.; Sridharan, V.; Thianpatanagul, S. Tetrahedron
1990, 46, 6433±6448. 4b) Ardill, H.; Fontaine, X. L. R.;
Grigg, R.; Henderson, D.; Montgomery, J.; Sridharan, V.;
Sivagnanasundram, S. Tetrahedron 1990, 46, 6449±6466.
3. 4a) Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Somasundaram,
A. Tetrahedron 1993, 49, 8679±8690. 4b) Grigg, R.
Tetrahedron: Asymmetry 1995, 6, 2475±2486.
Crystal data for 21n. C19H16N2O2S, 0.40£0.17£0.10 mm3,
Mˆ336.40, monoclinic, space group P21/n, aˆ13.479947),
Ê
bˆ5.729841), cˆ21.7238410) A, bˆ92.74842)8, Uˆ
1672.13412) A , Zˆ4, Dcˆ1.34 mg m23, mˆ0.21 mm21
,
Ê 3
4. Grigg, R.; Sridharan, V. Advances in Cycloaddition; Curran,
D. P., Ed.; JAI Press: London, 1993; Vol. 3, pp 161±204.
5. 4a) Cooper, D. M.; Grigg, R.; Hargreaves, S.; Kennewell, P.;
Redpath, J. Tetrahedron 1995, 51, 7791±7808. 4b) Amornraksa,
K.; Grigg, R.; Gunaratne, H. Q. N.; Kemp, J.; Sridharan, V.
F4000)ˆ704, Tˆ150 K.
Data collection. 6.6,2u,52.08, 11484 data collected 3270
of which were unique [Rintˆ0.045]. There 2621 re¯ections
with Fo.4.0s4Fo).
J. Chem. Soc., Perkin Trans.
1
1987, 2285±2296.
4c) Ankersmit, H. A.; Witte, P. T.; Kooijman, H.; Lakin,
M. T.; Spek, A. L.; Goubitz, K.; Vrieze, K.; van Koten, G.
Inorg. Chem. 1996, 35, 6053±6063. 4d) Undheim, K.; Gacek,
M. Acta Chem. Scand. 1969, 23, 2488±3500.
Structure re®nement. Number of parametersˆ219, isotropic
extinction parameter, xˆ0.01242), goodness of ®t, sˆ1.025;
weighting parameters x, yˆ0.0494, 0.9388; wR2ˆ0.1274,
R1ˆ0.0481.
6. Harris, N. J.; Gajewski, J. J. J. Am. Chem. Soc. 1994, 116,
6121±6129.
Crystal data for 22n. C19H16N2O2S, 0.60£0.40£0.27 mm3,
7. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467±473.
8. Sheldrick, G. M. SHELX-97. Program for Re®nement of Crystal
È
Structures; University of Gottingen: Germany, 1997.
Mˆ336.40, monoclinic, space group P21/c, aˆ12.911344),
Ê
bˆ12.123343), cˆ10.965043) A, bˆ93.23142)8, Uˆ
1713.6048) A , Zˆ4, Dcˆ1.30 mg m23, mˆ0.20 mm21
,
Ê 3
F4000)ˆ704, Tˆ150 K.