Synthesis and characterization of photoswitchable lipids containing hemithioindigo chromophores

Article abstract of DOI:10.1021/jo0056848

The synthesis of four lipids containing the hemithioindigo chromophore as part of the fatty acid is described. Heck reaction of bromophenyl thioacetate esters with acrylonitrile, followed by reduction, ester hydrolysis, and Friedel-Craft acylation-cyclization gave a substituted thioindoxyl that condensed with an alkoxy benzaldehyde to produce the hemithioindigo. "Solventless" nitrile hydrolysis followed by mixed anhydride coupling of the acid with glycerophosphocholine produced lipids bearing two hemithioindigo chromophores. The photochemistry of various hemithioindigo derivatives was studied to confirm the expected photoisomerization in both homogeneous organic solution, and in vesicle bilayer membranes. Characteristic changes in the UV-visible spectra are consistent with fully reversible Z-E photoisomerization. Chromatographic separation of the Z and E isomers of a compound containing a single hemithioindigo chromophore confirmed the spectroscopic analysis and provided a quantitative analysis of the compositions of Z-E isomer mixtures.

Full text of DOI:10.1021/jo0056848

2966
J . Org. Chem. 2001, 66, 2966-2977
Syn th esis a n d Ch a r a cter iza tion of P h otosw itch a ble Lip id s
Con ta in in g Hem ith ioin d igo Ch r om op h or es
Keetah Eggers, Thomas M. Fyles,* and Pedro J . Montoya-Pelaez
Department of Chemistry, University of Victoria, Victoria, B.C. Canada V8 W 3P6
tmf@uvic.ca
Received October 16, 2000
The synthesis of four lipids containing the hemithioindigo chromophore as part of the fatty acid is
described. Heck reaction of bromophenyl thioacetate esters with acrylonitrile, followed by reduction,
ester hydrolysis, and Friedel-Craft acylation-cyclization gave a substituted thioindoxyl that
condensed with an alkoxy benzaldehyde to produce the hemithioindigo. “Solventless” nitrile
hydrolysis followed by mixed anhydride coupling of the acid with glycerophosphocholine produced
lipids bearing two hemithioindigo chromophores. The photochemistry of various hemithioindigo
derivatives was studied to confirm the expected photoisomerization in both homogeneous organic
solution, and in vesicle bilayer membranes. Characteristic changes in the UV-visible spectra are
consistent with fully reversible Z-E photoisomerization. Chromatographic separation of the Z and
E isomers of a compound containing a single hemithioindigo chromophore confirmed the
spectroscopic analysis and provided a quantitative analysis of the compositions of Z-E isomer
mixtures.
The lipid composition of biomembranes varies dra-
The control of the lipid shape parameter provides a
potential mechanism to modulate membrane processes
such as transmembrane transport,7 transfection,8 or
bilayer fusion.9,10 Irreversible destabilization of bilayer
vesicles (liposomes) has been widely examined using pH
changes to alter headgroup repulsions,11-13 or light-
induced polymerizations to alter chain packing.14 Revers-
ible photochemical switching, e.g., Z/E photoisomeriza-
tion, is a particularly appealing option for controlling
lipid shape, and examples of retenoic acid,15 azoben-
zene,16,17 and spiropyran18-derived lipids have been ex-
amined as triggers for release of vesicle contents, pre-
sumably via defects in the bilayer. Similarly, vesicle
fusion can be irreversibly initiated photochemically by
photopolymerization processes that induce lipid phase
separation.19,20 The product vesicles of such a process are
matically between cells and subcellular components yet
is tightly regulated to preserve defined lipid composition
profiles in specific membranes.1,2 Moreover, most mem-
branes contain large amounts of lipids that alone do not
form planar bilayers.3 As a consequence, most biomem-
branes are actively maintained in a state of “curvature
stress” in which the tendency of each bilayer leaflet to
curl to a nonplanar conformation is opposed by hydro-
phobic interactions between the leaflets.4 Proteins em-
bedded in the lipid bilayer alter this balance by providing
additional hydrophobic interactions.5 This is a reciprocal
relationship: a “hydrophobic coupling” exists between the
curvature stress of the membrane and the conformational
state of the protein. Ultimately this can lead to a
regulation of protein function through control of the
physical properties of the membrane lipids.4
(7) Lundbaek, J . A.; Maer, A. M.; Andersen, O. S. Biochemistry 1997,
36, 5695-5701.
On a molecular level, curvature stress is directly
related to the shape of individual lipid molecules. A
“shape parameter” (s) has been described that relates the
hydrated headgroup area (a0), the overall length (l), and
the volume (v) of the alkyl chains to the phase preference
of pure lipids (s ) v/a0l).6 Lipids that are roughly
cylindrical (s ∼ 1) form lamellar bilayer phases. Increas-
ing the headgroup area, and/or decreasing the tail volume
decreases s and leads to micellar phases (s ∼ 0.5).
Conversely decreasing headgroup area and/or increasing
chain volume leads to “inverted” lipid phases (s >1) such
as reverse micelles.
(8) Koltover, I.; Salditt, T.; Radler, J . O.; Safinaya, C. R. Science
1998, 281, 78-81.
(9) Bentz, J .; Alford, D.; Ellens, H. In The Structure of Biological
Membranes; Yeagle, P., Ed.; CRC Press: Boca Raton, 1992; pp 915-
947.
(10) Lee, J . K.; Lentz, B. R. Biochemistry 1997, 36, 6251-6259.
(11) Thomas, J . L.; Tirrell, D. A. Acc. Chem. Res. 1992, 25, 336-
342.
(12) Maeda, M.; Kumano, A.; Tirrell, D. A. J . Am. Chem. Soc. 1988,
110, 7455-7479.
(13) Nayar, R.; Schroit, A. J . Biochemistry 1985, 24, 5967-5971.
(14) Lamparski, H.; Liman, U.; Barry, J . A.; Frankel, D. A.;
Ramaswami, V.; Brown, M. F.; O’Brien, D. F. Biochemistry 1992, 31,
685-694.
(15) Pidgeon, C.; Hunt, C. A. Photochem. Photobiol. 1983, 37, 491-
494.
(1) Dowhan, W. Annu. Rev. Biochem. 1997, 66, 199-232.
(2) Wieslander, A.; Karlsson, O. P. Curr. Top. Membr. 1997, 44,
517-540.
(3) Gruner, S. M. In The Structure of Biological Membranes; Yeagle,
P., Ed.; CRC Press: Boca Raton, 1992; pp 211-250.
(4) Hui, S. W. Curr. Top. Membr. 1997, 44, 541-563.
(5) Epand, R. M.; Epand, R. F. In The Structure of Biological
Membranes; Yeagle, P., Ed.; CRC Press: Boca Raton, 1992.
(6) Israelachvili, J . Intermolecular and Surface Forces; 2nd ed.;
Academic Press: London, 1992.
(16) Kano, K.; Tanaka, Y.; Ogawa, T.; Shimomura, M.; Kunitake,
T. Photochem. Photobiol. 1981, 34, 323-329.
(17) Sato, T.; Kijima, M.; Shiga, Y.; Yonezawa, Y. Langmuir 1991,
7, 2330-2335.
(18) Ohya, Y.; Okuyama, Y.; Fukunaga, A.; Ouchi, T. Supramol. Sci.
1998, 5, 21-29.
(19) Bennett, D. E.; O’Brien, D. F. J . Am. Chem. Soc. 1994, 116,
7933-7934.
(20) Ravoo, B. J .; Weringa, W. D.; Engberts, J . B. F. N. Biophys. J .
1999, 76, 374-386.
10.1021/jo0056848 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/05/2001

Photoswitchable Hemithioindigo Lipids
J . Org. Chem., Vol. 66, No. 9, 2001 2967
Sch em e 1. P r op osed Syn th esis of Ta r get Lip id 1
typically unstable and fusion is usually followed by
enhanced bilayer permeability.
substituents, thus a simple series of regioisomers can be
used to explore the multiple requirements of the target
lipid. This paper describes the design, synthesis, and
photochemical characterization of switchable lipids based
on the hemithioindigo chromophore (1). The use of these
lipids to influence membrane processes will be reported
separately.
Reversible control of membrane or transporter func-
tions, via reversible control of curvature stress, has not
been achieved, yet is highly desirable for some applica-
tions such as the initiation and control of bilayer fusion.
We envisage a reversibly photoisomerizable lipid that
would preserve the bilayer barrier in both forms, yet
would provide sufficient shape change on photoisomer-
ization to influence curvature stress and thence some
responsive membrane process. Photochemical reversibil-
ity in an oriented membrane medium is sometimes
limited relative to homogeneous solution as the aniso-
tropic environment inhibits some types of large structural
reorganizations.21 The ideal switch would also be freely
miscible in membrane lipids and resist aggregation and
phase separation. Aggregation of azobenzenes in lipids
leads to membrane disruption on photoisomerization,
while the same lipid dispersed as monomers does not
alter bilayer permeability.22 Good miscibility is essential,
given the importance of lateral mobility of lipids in the
dynamics of bilayer fusion.20
Hemithioindigos, although relatively little studied,23-28
are appealing candidates as components of photoswitch-
able lipids. They are reversibly photochromic and the
less-stable E-isomer is sufficiently stable to be isolated
by chromatography.29 They are photochemically robust,
resisting photofatigue over thousands of cycles.29 Most
importantly, a surfactant derivative has been shown to
be reversibly photoisomerized in dialkylammonium
vesicles.30 The structural changes accompanying isomer-
ization will vary depending on the positions of the
Resu lts a n d Discu ssion
Scheme 1 shows a general structure of the target lipids
prepared (1) together with an analysis of the proposed
synthesis. The lipid should be available from bis-esteri-
fication of phosphoglycerol by a hemithioindigo carboxylic
acid (2). The key intermediate 2 could be derived by
Knoevenagel condensation of a substituted thioindoxyl
(3) and a benzaldehyde derivative (4). The thioindoxyl
could be derived from a halo-substituted thiophenol
derivative (6) and an acrylate (5) by a Heck coupling and
reduction sequence, and a Friedel-Crafts acylation-
cyclization process. Other routes are possible, differing
only in the sequence of the various steps. The chemical
stability of thioindoxyl and hemithioindigo intermediates
to the proposed reactions was unknown at the outset, but
it was clear that selective differentiation of the esters in
5 and 6 would be required to ensure that the cyclization
process proceeded as desired.
Scheme 2 shows exploratory chemistry that refined the
synthetic plan of Scheme 1. p-Bromothiophenoxide was
alkylated with ethyl bromoacetate to give the thioether
6a that was hydrolyzed to the acid 7. Conversion to the
acid chloride was followed by AlCl3-catalyzed cyclization
to the bromothioindoxyl 8. In general, thoindoxyl deriva-
tives are unstable with respect to oxidation to thioindigos,
thus Knoevenagel condensation with benzaldehyde de-
rivatives was done with freshly prepared 8 to give the
hemithioindigos 9 or 10 in moderate yield (66 and 74%,
respectively). The phenol 9 could be alkylated to give 10
although the yield was modest,29 thus the one-step
process from alkylated benzaldehydes such as 4a is
superior.
(21) Fyles, T. M.; Zeng, B. J . Org. Chem. 1998, 63, 8337-8345.
(22) Song, X.; Perlstein, J .; Whitten, D. G. J . Am. Chem. Soc. 1997,
119, 9144-9159.
(23) Friedlaender, P. Monatsh. 1909, 30, 347-354.
(24) Mostoslavskii, M. A.; Izmail’skii, V. A. J . Gen. Chem. USSR
1961, 17, 21-31.
(25) Mostoslavskii, M. A.; Izmail’skii, V. A.; Shapkina, M. M. J . Gen.
Chem. USSR 1962, 32, 1731-1739.
(26) Mostoslavskii, M. A.; Izmail’skii, V. A. J . Gen. Chem. USSR
1963, 33, 727-731.
(27) Mostoslavskii, M. A.; Izmail’skii, V. A. J . Gen. Chem. USSR
1965, 35, 519-523.
In parallel, the bromo ester 6a or the bromo acid 7
underwent palladium-catalyzed coupling31 with acrylic
acid (5a ), or in somewhat better yield with methyl
(28) Reamonn, L. S. S.; O’Sullivan, W. I. J . Chem. Soc. Perkin Trans.
1 1977, 1009-1012.
(29) Yamaguchi, T.; Seki, T.; Tamaki, T.; Ichimura, K. Bull. Chem.
Soc. J pn. 1992, 65, 649-656.
(30) Seki, T.; Tamaki, T.; Yamaguchi, T.; Ichimura, K. Bull. Chem.
Soc. J pn. 1992, 65, 657-663.
(31) Meijere, d. A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379-2411.

2968 J . Org. Chem., Vol. 66, No. 9, 2001
Sch em e 2. Syn th eses of Hem ith ioin d igo In ter m ed ia tesa
Eggers et al.
a
Key: (i) NaOH, MeOH, reflux, 3 h; 93% (7), 85% (12); (ii) (a) SOCl2, reflux, 1 h, (b) AlCl3, (ClCH2)2, 0 °C to RT, 1 h; (iii) piperidine
(cat.), benzene, reflux, 2 h; 66% (9), 74% (10); (iv) KOH, DMSO, RT, 30 min; 16%; (v) Pd(OAc)2 (5 mol %), PPh3 (10 mol %), Et3N, 100 °C,
24 h; 27% (11), 10% (13), 27% (15); (vi) Rh(PPh3)3Cl (3 mol %), H2 (60 psi), benzene/EtOH, RT, 10 d; 95% (16), incomplete (17).
acrylate (5b), to give the expected trans-alkenes 11, 12,
and 13. The yields in all the Heck couplings discussed
are poor (generally less than 45%) and were resistant to
improvement over a range of changes in reaction condi-
tions, solvents, and catalysts. More serious is the failure
of the acids 12 or 13 to undergo cyclization and coupling
with aldehydes to produce the required hemithioindigos
such as 15. Alkene 15 could be produced in low yield from
10 using the conditions used previously with the thio-
ethers. Reduction of 15 to 17 either failed outright
(H2-Pd/C; H2-Pt gave unreacted starting material) or
was extremely sluggish (H2-Rh(PPh3)3Cl). Thus it ap-
pears that reduction must precede hemithioindigo forma-
tion, and a differentially protected form of the diacid 12
is required. Our initial choice was the phthalimidomethyl
ester, reported to be resistant to Friedel-Crafts acylation
conditions.32,33 In the event, the coupling of the phthal-
imidomethyl acrylate (5c) proceeded as expected to give
14, and the alkene was successfully reduced using
Wilkinson’s catalyst to give the diester 16. Attempts to
selectively deprotect the ethyl ester while preserving the
phthalimidomethyl ester failed (LiBr-pyridine; LiI-
DMF; TMSCl-NaI-CH3CN; KOiBu); the differential
reactivity differences are too small in this system.
Based on the initial findings, the synthesis of the
targets was completed as shown in Scheme 3. The
required differential protection of the diacid is achieved
via the nitrile that will be subsequently hydrolyzed to
expose the acid. The synthesis begins with the Heck
coupling of bromo esters 6a -c with acrylonitrile. For the
para and meta isomers, mixed isomers of the alkene
products 19a ,b were produced in acceptable yields.
Compound 19c from the ortho isomer was not produced,
but gave instead an isomeric compound lacking an olefin.
The structure of the isomeric product was assigned as
23 based on the following evidence. The compound is
isomeric with 19a ,b by mass spectrometry and retains a
disubstituted benzene, an ethyl ester, and a nitrile group
(IR, 13C NMR). The methylene adjacent to the sulfur
expected in 19c appears as a methine (DEPT), together
with a second methine having a very similar chemical
shift in the 1H NMR spectrum. A COSY spectrum
establishes the fragment S-CH-CH-CH2, and a de-
coupled 13C NMR spectrum of the product of base
hydrolysis (24) establishes both two- and three-bond
couplings in the fragment S-CH-CH-CH2-C(O)OH.
Compound 23 would form from 19c by a deprotonation
adjacent to the ester followed by intramolecular Michael
reaction and reprotonation.
The hemithioindigo synthesis proceeded from 19a ,b by
hydrogenation of the mixed alkenes to the saturated
nitriles 20a ,b. Hydrolysis of the ethyl ester then allowed
the hemithioindigos 22a -f to be formed via the proce-
dures previously discussed. Friedel-Crafts cyclization
from 21b results in two isomeric thioindoxyls, thus 22e
and 22f are formed as a mixture of regioisomers that was
subsequently separated by chromatography. The yields
of the hemithioindigo synthesis remain poor (20-45%).
The next step required the hydrolysis of the nitrile.
Basic conditions sufficient to achieve nitrile hydrolysis
(NaOH or KOH, alcohols or ethylene glycol)34-37 resulted
(32) Nefkens, G. H. L.; Tesser, G. I.; Nivard, R. J . F. Recl. Trav.
Chim. Pays-Bas 1963, 82, 941-953.
(33) Greene, T. Protecting Groups in Organic Synthesis; J ohn Wiley
& Sons: New York, 1981.

Photoswitchable Hemithioindigo Lipids
J . Org. Chem., Vol. 66, No. 9, 2001 2969
Sch em e 3. Syn th esis of Hem ith ioin d igo Lip id sa
a
Key: (i) Pd(OAc)2 (5 mol %), PPh3 (10 mol %), Et3N, 100 °C, 24 h; 78% (19a ), 60% (19b), 19c not formed, gave 23 (38%); (ii) Rh(PPh3)3Cl
(3 mol %), H2 (60 psi), benzene/EtOH, RT, 10 d; 65% (20a ), 64% (20b); (iii) NaOH, MeOH, reflux, 3 h; 90% (21a ), 84% (21b), 75% (21c);
(iv) (a) SOCl2, reflux, 1 h, (b) AlCl3, (ClCH2)2, 0 °C to RT, 1 h; (v) piperidine (cat.), benzene, reflux, 2 h; 45% (22a ), 34% (22b), 42% (22c),
19% (22d ), 34% (22e + 22f); (vi) 170 °C, 5 d; 90% (2a ), 71% (2b), 88% (2c), 86% (2d ), 83% (2e); (vii) t-BuCOCl, Et3N, CH2Cl2, RT, 30 h;
(viii) DMAP, CH2Cl2, RT, 24 h; 85% (1a ), 91% (1b), 87% (1c), 92% (1d ); (ix) CH2N2, Et2O, RT, 24 h; quant.
in destruction of the hemithioindigo core. The polar
products are uncharacterized; some samples suggest that
hydroxide attack occurred â to the carbonyl. The hemi-
thioindigo core readily resists acidic conditions (H2SO4/
H2O; HBr/AcOH),38 but so too does the nitrile. “Solvent-
less” hydrolysis employing CuCl2‚2H2O (240 °C, 1 h)
resulted in destruction of the hemithioindigo presumably
due to the generation of hydroxide.39 Fusion with phthalic
acids,40 particularly tetrafluorophthalic acid41 proved to
a suitable method to produce the required acids (2a -e)
in good yields. The lipid synthesis was completed follow-
ing a standard mixed anhydride coupling with the CdCl2
complex of glycerophosphocholine.22,42,43 The bis-hemi-
thioindigo lipids (1a -d ) were readily isolated and puri-
fied by size exclusion chromatography on lipophilic
Sephadex. Despite some poor-yielding steps, and some
steps that required long reaction times, the overall
synthesis is reasonably efficient (10% from bromothiophe-
nol).
The absorption spectra of the hemithioindigos prepared
show many of the features reported in previous work.24,25,29
Figure 1 shows sample spectra for nitrile hemithioindigos
(22), and Table 1 unites data for single hemithioindigo
compounds in a number of solvents. In hexanes, the
Z-isomer normally has two maxima between 410 and 490
nm depending on substituent.24 The E-isomer absorption
occurs as single band, usually 20-30 nm longer in
wavelength than the longer wavelength absorption of the
Z-isomer.29 Solvents other than hexanes give more poorly
resolved spectra in which the absorption peaks are
broader and lower in intensity. The exceptions are the
meta-substituted derivative 22d , illustrated in Figure 1C,
and the corresponding acid 2c. Even in hexanes the
absorption bands are broadened and of low intensity.
These are the first hemithioindigo derivatives with a
meta-substituent on the phenyl. It is not known if this is
a general property of this substitution pattern.
Photoisomerization is readily observed in most cases.
The Z-to-E conversion is achieved by irradiation at 406
nm, near the minimum absorbance of the E-isomer in
most solvents. E-to-Z conversion can be effected by
irradiation at 480 nm, near the maximum in the E-isomer
absorbance spectrum. Typical spectral changes are shown
in Figure 1. The meta-substituted derivatives 22d and
2c show very little spectral change on irradiation (Figure
1C). Similarly, the bromo-substituted derivative 9 resists
isomerization. All photoisomerizations show clear isos-
bestic points, and the process is apparently completely
(34) Newman, M. S.; Wise, R. M. J . Am. Chem. Soc. 1956, 78, 450-
454.
(35) Meek, J . S.; Dann, J . R.; Poon, B. T. J . Am. Chem. Soc. 1956,
78, 5413-5416.
(36) Aristoff, P. A.; J ohnson, P. D.; Harrison, A. W. J . Am. Chem.
Soc. 1985, 107, 7967-7974.
(37) Christopfel, W. C.; Miller, L. L. J . Org. Chem. 1986, 51, 4169-
4175.
(38) Barnes, R. A.; Miller, R. J . Am. Chem. Soc. 1960, 82, 4960-
4965.
(39) Chemat, F.; Poux, M.; Berlan, J . J . Chem. Soc., Perkin Trans.
2 1996, 1781-1784.
(40) Chemat, F.; Poux, M.; Berlan, J . J . Chem. Soc., Perkin Trans.
2 1994, 2597-2602.
(41) Rounds, W. D.; Eaton, J . T.; Urbanowicz, J . H.; Gribble, G. W.
Tetrahedron 1988, 29, 6557-6560.
(42) Gupta, C. M.; Radhakrishnan, R.; Khorana, H. G. Proc. Nat.
Acad. Sci. 1977, 74, 4315-4319.
(43) Sandhu, S. S.; Yianni, Y. P.; Morgan, C. G.; Taylor, D. M.; Zaba,
B. Biochim. Biophys. Acta 1986, 860, 253-262.

2970 J . Org. Chem., Vol. 66, No. 9, 2001
Eggers et al.
F igu r e 1. Absorption spectra of single chromophore hemithioindigos. A: 21f (4.8 × 10-5M) in hexanes; B: 21b (3.3 × 10-5M) in
CHCl3; C: 21d (1.7 × 10-5M) in hexanes. Solid line - sample from ambient light; dashed line - sample following irradiation at
406 nm; dotted line - sample following irradiation at 480 nm.
Ta ble 1. Absor p tion Sp ectr a of Hem ith ioin d igo
Com p ou n d s
ꢀo × 10-3
λmax (nm)
Z isomer
λmax (nm)
E isomer
(M-1 cm-1
)
compd
Z isomer
solvent
9
423, 446
451
422, 446
455
418, 441
452
b
b
22
23
22
16
26
28
hexanes
MeOH
hexanes
CH2Cl2
hexanes
CHCl3
10
362, 473
461
357, 467
459
22a
22b
22c
2a
2b
22d
2c
}
441
452
437
437
357, 467
c
455
455
17
11
9
8
7
hexanes
CHCl3
hexanes
hexanes
CHCl3
}
F igu r e 2. Chromatogram of an isomer mixture of 17 produced
by irradiation at 406 nm analyzed by reverse-phase HPLC (C18
column, acetonitrile-methanol-water 98:2:2, 1 mL/min, detect
at 465 nm). The inset shows the absorption spectra of the two
components, normalized to correct for the concentration ratio
(59:41 E:Z).
2c
446
c
22e
2d
2d
22f
22f
2e
1a
1a
1b
1c
447
444
453
422, 447
454
421, 444
356, 453
361, 460
310, 444
352, 445
351, 451
358, 471
467
c
358, 471
c
354, 468
d
462
d
d
25
20
11
25
20
20
30
28
10
26
19
hexanes
hexanes
CHCl3
hexanes
CHCl3
hexanes
CHCl3
CF3CH2OH
CHCl3
30 min, followed by concentration and chromatography
in red light produced E-22b in quantity sufficient for
spectroscopic characterization. The proton and carbon â
to the carbonyl show the largest NMR changes: 0.78 ppm
upfield shift in the 1H spectrum and 5 ppm downfield
shift in the 13C spectrum. The ortho-positions of the
phenyl substituent are also significantly perturbed,
CHCl3
CHCl3
1d
454
a
Calculated assuming 100% conversion to the Z-isomer in the
dark. Insensitive to photoisomerization. c Shoulder peak. No
b
d
1
apparent change.
undergoing a 0.43 ppm downfield shift in the H spec-
reversible over periods of several days involving many
hours of irradiation. This is consistent with previous
reports of high resistance of hemithioindigos to photo-
fatigue.29
As prepared, all hemithioindigos are predominantly in
the Z form. The 1H and 13C NMR spectra consistently
show a single isomer, with only minor amounts of the
E-isomer in a few samples. On a preparative scale,
irradiation of a chloroform solution of 22b at 350 nm for
trum. Smaller changes are evident throughout the hemi-
thioindigo core, particularly at the 4 position of the
thioindoxyl.
Quantitative analysis of the isomer mixture can be
achieved by liquid chromatography on a reverse phase
column (Figure 2). The data illustrated for 17 are
representative of chromatograms of compounds 9 and
22a -f. An isosbestic point for 17 in acetonitrile-
methanol-water (96:2:2) occurs at 465 nm, thus the

Photoswitchable Hemithioindigo Lipids
J . Org. Chem., Vol. 66, No. 9, 2001 2971
F igu r e 3. Absorption spectra of bis-hemithioindigo lipids. A: 1b (6.7 × 10-6M) in CHCl3; B: 1d (1.6 × 10-5M) in CHCl3; C:
thermal recovery of 1d (5.8 × 10-6 M) in CHCl3 under ambient light. Solid line - sample from ambient light; dashed line -
sample following irradiation at 406 nm; dotted line - sample following irradiation at 480 nm.
integrated areas of peaks detected at 465 nm can be used
to determine the isomer composition (59:41 E:Z in the
sample used for Figure 2). The assignment of isomers to
the two peaks in the chromatogram follows directly from
the spectra of the two components (inset to Figure 2).
The following features of the photoisomerization of
single hemithioindigo compounds are established. (1) The
Z isomer is the thermodynamically favored form. The
composition of mixtures held in the dark for prolonged
periods is 98 ( 2% Z: 2 ( 2% E (for 17). (2) Irradiation
at 406 nm, or 445 nm produces a photostationary state
enriched in the E-isomer. The composition varies some-
what with the compound, the irradiation conditions, and
the solvent. Compound 17 is typical: the photostationary
state is 65% E-17 after 10 min of irradiation in acetoni-
trile-methanol-water (96:2:2). The photostationary states
achieved with the compounds reported here, are signifi-
cantly less enriched in the E-isomer relative to previous
reports.29 (3) Similarly, irradiation at longer wavelength
(480 or 490 nm) produces a photostationary state en-
riched in the Z-isomer. This is not the thermodynamic
equilibrium mixture as there is still a significant amount
of the E-isomer present. For 17 in acetonitrile-methanol-
water (96:2:2), irradiation at 490 nm for 10 min produces
a stationary state that is 93% Z-17. If left in the dark,
this mixture reverts slowly to the equilibrium mixture.
(4) Ambient light (fluorescent, indirect daylight) is suf-
ficient to establish a mixture in stock solutions of the
compounds. The composition varies with the “conditions”,
but is typically between 60 and 70% Z-isomer a day after
the solution is prepared. (5) In the dark at room tem-
perature, solutions enriched in the E-isomer slowly revert
to the Z-isomer. The process is first-order with a half-
life of 8-9 h (k ≈ 2 × 10-5 s-1) for a range of compounds
and solvents. This is 2-3 orders of magnitude faster than
reported previously.29 (6) In ambient light the rate of
approach to the apparent photostationary state is also
first order with rate about 10-fold faster (t1/2 ≈ 50 min).
The experiments with single-chromophore hemithio-
indigos indicate that switching to the E-isomer will be
incomplete, and that once formed, the E-isomer will
revert to the Z isomer relatively quickly, even in the dark.
The bis-hemithioindigo lipids are therefore predicted to
consist of: a thermodynamically stable Z,Z-isomer, a pair
of E,Z- and Z,E-isomers, and an E,E-isomer. If a photo-
stationary state of 60% E-isomer per hemithioindigo is
assumed to follow from irradiation at 406 nm, the
mixture will be 16% Z,Z, 48% Z,E + E,Z, and 36% E,E.
This composition might be altered if chromophores do not
act independently. Figure 3 shows typical spectral changes
observed for the bis-hemithioindigo lipids 1a -d . Some
lipids and solvents show virtually no photochromism, as
illustrated by 1b in CHCl3 (Figure 3A). The apparent
bleaching of the peak centered at 465 nm is reversible
with a half-life in the dark of 8 h, consistent with previous
examples of E-to-Z thermal reversion of a hemithioindigo.
Other lipids show more pronounced changes following
irradiation at 406 nm, as exemplified by 1d (Figure 3B).
The broadening and longer wavelength shift of the band
at 460 nm is consistent with an increased proportion of
E-isomer. The changes in this case are reversible as well
(Figure 3C). Chromatographic conditions suitable for the
quantification of the isomer mixtures produced could not
be developed. Four partly overlapped components could
be separated, each of which had a hemithioindigo absorp-
tion spectrum. However, the four-component system is
too complex to provide a single isosbestic point, so the
quantitative analysis of this mixture requires a more
sophisticated approach than was possible with the single-
chromophore systems discussed above.

2972 J . Org. Chem., Vol. 66, No. 9, 2001
Eggers et al.
F igu r e 4. Absorption spectra of hemithioindigo lipids dispersed in phosphatidylserine vesicles (1:9 wt/wt). A: 1c, B: 1d . Solid
line - sample from ambient light; dashed line - sample following irradiation at 406 nm; dotted line - sample following irradiation
at 480 nm.
Hemithioindigo lipids 1a -d were readily incorporated
into phosphatidylserine (PS) vesicles. A mixed lipid film
was prepared by evaporation of a CHCl3 solution of PS
and 1a -d . Vesicles prepared from this film by a freeze-
thaw technique44 followed by sizing through an extruder45
and gel filtration showed incorporation of hemithioindigo
in the vesicle fraction. Pure 1a -d did not disperse into
aqueous buffers under the mild conditions used to form
the vesicles, forming rather platelets that clogged the
extruder filter. The proportion of 1a -d in PS could be
varied freely up to about 20 wt %. At higher proportions
of hemithioindigo lipid, platelets appeared on the ex-
truder filter indicating incomplete incorporation in the
PS vesicle formed. Typical absorption spectra of hemi-
thioindigo lipids in PS vesicles are shown in Figure 4.
No clear photochromism was found in any preparation.
However, the absorption band about 450 nm is reversibly
altered by irradiation at 406 and 480 nm in a manner
that is consistent with previous examples of hemithio-
indigo switching in homogeneous solution. Both the
apparent “bleaching” at 450 nm and the modest broaden-
ing to longer wavelength following irradiation at 406 nm
are consistent with a Z-to-E photoisomerization (Figure
4B). The rate of thermal return to the initial spectrum
under ambient light conditions was comparable to previ-
ous cases (t1/2 ≈ 45 min) as well. The results, while not
clear-cut, are consistent with the minor changes noted
in previous work with single hemithioindigos in vesicle
membranes.30 It is unlikely that the isomerized lipid is
ejected from the bilayer, as these, and previously reported
hemithioindigos,25 exhibit significant solvatochromism.
A significant red-shift of 15-20 nm would be expected if
the chromophore migrated to a more polar environment,
such as the surface of a vesicle.
they apparently undergo the same type of reversible
photoisomerization and slow thermal reversion reactions
as in homogeneous solution. These lipids thus offer the
potential for the reversible control of membrane processes
via control of curvature stress. Our progress in this area
will be reported separately.
Exp er im en ta l Section
Gen er a l P r oced u r e I: Eth er Syn th esis.46,47 A suspension
of KOH (132 mmol, 4 equiv) in 50 mL of DMSO was treated
with hydroxybenzaldehyde (33 mmol, 1 equiv) and an alkyl
halide (49.0 mmol, 1.5 equiv). This suspension was stirred
vigorously at room temperature for 30 min, and then quenched
with water (150 mL). The product was extracted with CH2Cl2
(2 × 75 mL), and then washed with water (3 × 75 mL), dried,
and concentrated to a yellow liquid. The crude product was
purified by distillation (Kugelrohr, 5 × 10-2 atm), affording a
clear liquid.
Gen er a l P r oced u r e II: Th ioeth er Syn th esis.48 A solu-
tion of bromothiophenol (230 mmol) and ethyl bromoacetate
(240 mmol, 1.05 equiv) in 60 mL of benzene was refluxed,
under N2. DBU (240 mmol, 1.05 equiv), in 60 mL of benzene,
was added over 10 min, and the solution was refluxed for 2 h.
The DBU salt precipitate was filtered, and the filtrate was
concentrated to yield a light yellow liquid. This crude product
was distilled, (Kugelrohr, 5 × 10-2 atm), yielding a clear liquid
(bp ca. 120 °C).
Gen er a l P r oced u r e III: Heck Rea ction s.49 A mixture
was prepared containing an aryl bromide (1 equiv), a freshly
distilled alkene (1.5 equiv), NEt3 (1.5 equiv), Pd(OAc)2 (0.05
equiv), and P(Ph)3 (0.10 equiv). The flask was purged with
argon, sealed with a septum, sonicated to a fine suspension,
and then heated at 100 °C for 24-72 h. The mixture was cooled
and filtered, and the solid was washed twice with ether.
Concentration of filtrate resulted in a golden solution. The
purification procedures varied with compound as described
below.
In conclusion, we have prepared a class of lipids
containing hemithioindigo chromophores in the acyl
chains. The isolated chromophore can be reversibly
switched between two geometric isomers in organic
solvents; however, the conversion to the less-stable
E-isomer is incomplete at the photostationary state.
Thermal reversion to the Z-isomer is slow in the dark,
but is accelerated in ambient light. The hemithioindigo
lipids are readily incorporated into PS vesicles where
Gen er a l P r oced u r e IV: Hem ith ioin d igo Syn th esis.29
A phenyl thioacetic acid (7.81 mmol) in an excess of SOCl2 (5
mL) was refluxed, under N2, for 1 h. The excess thionyl chloride
was removed under vacuum. The resultant acid chloride, in
15 mL of (ClCH2)2, was cooled in a salt ice bath to below 0 °C.
AlCl3 (9.4 mmol, 1.2 equiv) was added to the cooled solution,
under rapid stirring, over a 2 min period. The solution was
stirred with cooling for another 10 min, removed, and left
(46) J ohnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35, 2169-
2173.
(44) New, R. R. C. In Liposomes: a practical approach; New, R. C.
C., Ed.; IRL Press: Oxford, 1990.
(45) MacDonald, R. C.; MacDonald, R. I.; Menco, B. P. M.; Takeshita,
K.; Subbarao, N. K.; Hu, L. Biochim. Biophys. Acta 1991, 1061, 297-
303.
(47) Benedict, D. R.; Bianchi, T. A.; Cate, L. A. Synthesis 1979, 428.
(48) Ono, N.; Hideyoshi, M.; Saito, T.; Kaji, A. Synthesis 1980, 80,
952-953.
(49) Heck, R. F. In Palladium Reagents in Organic Synthesis;
Springer: Berlin, 1985; pp 276-287.

Photoswitchable Hemithioindigo Lipids
J . Org. Chem., Vol. 66, No. 9, 2001 2973
stirring at room temperature (23 °C), for a further 40 min.
The reaction was quenched with ice/water, and product was
extracted with CH2Cl2, dried, concentrated, and dried under
vacuum for 15 min. This yellow solid thioindoxyl slowly
decomposed and so was used as soon as possible. A solution
of the indoxyl, a benzaldehyde derivative (8.2 mmol, 1.05
equiv), and 2 drops of piperidine in 50 mL of benzene was
refluxed for 2 h. The course of the reaction and the purification
procedure varied with compound and is described individually.
Gen er a l P r oced u r e V: Nitr ile Hyd r olysis.41 The nitrile
(0.3 mmol, 1 equiv) and tetrafluorophthalic acid (1 equiv) were
added to a Carius tube and sealed under vacuum. The vessel
was heated at 170 °C for 5 days. The solid crude product was
dissolved in CHCl3/MeOH and was passed through a LH-20
column with CHCl3/MeOH, 4:3, as eluent, to give a yellow
solid.
mmol) in 100 mL of DMF was added over 10 min, and the
solution was stirred for a further 30 min. The ammonium salt
precipitate was filtered and the supernatant concentrated. The
crude product was recrystallized from toluene, yielding a white
solid (5.97 g, 25.8 mmol, 54%), mp ) 142-143 °C. 1H NMR
(CDCl3): δ ) 7.91 (AB, J ) 5.2, 3.0 Hz, 2H), 7.76 (AB, J )
5.2, 3.0 Hz, 2H), 7.42 (ABX, J ) 16.9, 1.5 Hz, 1H), 6.07 (ABX,
J ) 16.9, 10.3 Hz, 1H), 5.85 (ABX, J ) 10.3, 1.5 Hz, 1H), 5.78
(s, 2H). 13C NMR 75.47 MHz (CDCl3): δ ) 166.7, 164.8, 134.6,
132.2, 131.7, 127.4, 124.0, 60.8. CI MS m/z (%): 260, 232 (100),
176, 160. Anal. Calcd for C12H9O4N (%): C, 62.34; H, 3.92; N,
6.06. Found C, 62.49; H, 4.05; N, 5.82.
Eth yl [(4-br om op h en yl)th io]a ceta te (6a ) was prepared
by procedure II, from 4-bromothiophenol in 91% yield. 1H NMR
(CDCl3): δ ) 7.34 (d, J ) 8.4 Hz, 2H), 7.21 (d, J ) 8.4 Hz,
2H), 4.11 (q, J ) 7.2 Hz, 2H), 3.55 (s, 2H), 1.16 (t, J ) 7.3 Hz,
3H). 13C NMR 75.47 MHz (CDCl3): δ ) 169.1, 134.3, 132.0,
131.4, 120.8, 61.5, 36.3, 14.1. Anal. Calcd for C10H11O2SBr
(%): C 43.65; H 4.03; O 11.63; S 11.65; Br 29.04. Found: C
43.54; H 4.03; O 11.25; S 11.97; Br 29.21.
Eth yl [(3-Br om op h en yl)th io]a ceta te (6b) was prepared
by procedure II, from 3-bromothiophenol in 77% yield. 1H NMR
300 MHz (CDCl3): δ ) 7.49 (s, 1H), 7.27 (m, 2H), 7.09 (t, J )
8.1 Hz, 1H), 4.12 (q, J ) 7.4 Hz, 2H), 3.59 (s, 2H), 1.18 (t, J )
7.4 Hz, 3H). 13C NMR 75.47 MHz (CDCl3): δ ) 169.2, 137.5,
131.9, 130.3, 129.8, 128.0, 122.8, 61.7, 36.2, 14.1. Anal. Calcd
for C10H11O2SBr (%): C 43.65; H 4.03; O 11.63; S 11.65; Br
29.04. Found: C 44.06; H 4.07; O 11.14; S 11.96; Br 28.77.
Eth yl [(2-Br om op h en yl)th io]a ceta te (6c) was prepared
by procedure II, from 2-bromothiophenol in quantitative yield.
1H NMR 300 MHz (CDCl3): δ ) 7.52 (d, J ) 8.1 Hz, 1H), 7.34
(d, J ) 8.1 Hz, 1H), 7.23 (t, J ) 7.4 Hz, 1H), 7.03 (t, J ) 8.1
Hz, 1H), 4.14 (q, J ) 6.6 Hz, 2H), 3.64 (s, 2H), 1.20 (t, J ) 6.6
Hz, 3H). 13C NMR 75.47 MHz (CDCl3): δ ) 168.9, 136.2, 129.3,
127.8, 127.5, 123.9, 61.6, 35.4, 13.9. Anal. Calcd. for C10H11O2-
SBr (%): C 43.65; H 4.03; O 11.63; S 11.65; Br 29.04. Found:
C 43.87; H 4.10; O 11.07; S 12.09; Br 28.87.
Gen er a l P r oced u r e VI: Lip id Syn th esis.22 A solution of
hemithioindigo carboxylic acid (0.29 mmol), (CH3)3CCOCl (3.0
mmol, 10 equiv), and NEt3 (1.4 mmol, 5 equiv) in CH2Cl2 was
stirred, under N2, for 35 h. The reaction was monitored by TLC
(CHCl3/MeOH/H2O, 65:25:4). The crude mixed anhydride was
concentrated and dried under vacuum, for 8 h, to remove
unreacted (CH3)3CCOCl and NEt3. The mixed anhydride was
dissolved in 5 mL of CH2Cl2, added to a suspension of dried
GPC-CdCl2 complex (0.115 mmol, 0.4 equiv) and DMAP (0.230
mmol, 0.8 equiv) in CH2Cl2 (10 mL), and stirred for 23 h. The
solution was concentrated and eluted through an ion exchange
column of Rexyn-I-300 to remove the CdCl2 and DMAP (CHCl3/
MeOH/H2O, 65:25:4). The crude product was concentrated and
then redissolved in CHCl3/MeOH, 4:3, and passed through a
Sephadex LH-20 column to yield the pure lipid as a yellow
solid.
4-Hexyloxyben za ld eh yd e (4a )50 was prepared by proce-
dure I, from 1-bromo hexane and p-hydroxybenzaldehyde in
64% yield. Bp 120 °C. 1H NMR (CDCl3): δ ) 9.82 (s, 1H), 7.77
(d, J ) 8.8 Hz, 2H), 6.94 (d, J ) 8.8 Hz, 2H), 3.98 (t, J ) 6.6,
2H), 1.76 (qn, J ) 6.6 Hz, 2H), 1.43 (qn, J ) 6.6 Hz, 2H), 1.31
(m, 4H), 0.87 (t, J ) 7.4, 3H). 13C NMR (CDCl3): δ ) 190.7,
164.2, 131.9, 129.6, 114.6, 68.3, 31.4, 28.9, 25.5, 22.5, 13.9. CI
MS m/z (%): 247 (4), 235 (16), 207 (100).
[(4-Br om op h en yl)th io]a cetic Acid (7). Ester 6a (8.72 g,
32 mmol) was dissolved in 100 mL of MeOH containing NaOH
(1.52 g, 38.0, 1.2 equiv) and was stirred at reflux for 3 h. The
acid salt was concentrated and dried under vacuum. The
resultant solid was dissolved in H2O and acidified to pH < 1.
The white precipitate was filtered and dried (3.65 g, 15 mmol,
4-Bu toxyben za ld eh yd e (4b)50 was prepared by procedure
I, from 1-bromobutane and p-hydroxybenzaldehyde in 48%
yield. Bp 80 °C. 1H NMR (CDCl3): δ ) 9.85 (s, 1H), 7.80 (d,
J ) 8.1 Hz, 2H), 6.96 (d, J ) 8.1 Hz, 2H), 4.01 (t, J ) 6.6, 2H),
1.77 (qn, J ) 8.1 Hz, 2H), 1.48 (sx, J ) 7.4, 2H), 0.96 (t, J )
7.4, 3H). 13C NMR (CDCl3): δ ) 190.6, 164.1, 131.8, 129.6,
114.6, 67.9, 30.9, 19.0, 13.7. CI MS m/z (%): 219 (6), 207 (22),
179 (100).
3-Hexlyoxyben za ld eh yd e (4c) was prepared by procedure
I, from 1-bromohexane and m-hydroxybenzaldehyde in 83%
yield. 1H NMR (CDCl3): δ ) 9.94 (s, 1H), 7.42 (s, 1H), 7.40,
7.36, 7.15 (m, 1H), 3.98 (t, J ) 6.6, 2H), 1.77 (qn, J ) 6.6 Hz,
2H), 1.44 (m, 2H), 1.31 (m, 8H), 0.88 (t, J ) 7.4 Hz, 3H). 13C
NMR (CDCl3): δ ) 192.2, 159.7, 137.7, 129.9, 123.2, 121.9,
112.7, 68.3, 31.5, 29.0, 25.6, 22.5, 14.0. CI MS m/z (%): 235
(15), 207 (100).
1
39%), mp ) 117-119 °C. H NMR (CDCl3): δ ) 7.41 (d, J )
8.8 Hz, 2H), 7.27 (d, J ) 8.8 Hz, 2H), 3.63 (s, 2H). 13C NMR
MHz (CDCl3): δ ) 175.0, 133.6, 132.3, 131.7, 121.5, 36.5. CI
MS m/z (%): 249, 247 (50), 231, 229 (40), 203, 201 (100). Anal.
Calcd for C8H7O2Br (%): C 38.69; H 2.86. Found: C 38.18; H
2.85.
5-Br om oben zo[b]th iop h en -3(2H)-on e (8) was prepared
by the initial stages of procedure IV, from acid 7. The product
is unstable with respect to oxidation and was only character-
ized spectroscopically: 1H NMR (CDCl3): δ ) 7.86 (d, J ) 1.8
Hz, 1H), 7.61 (dd, J ) 8.5, 1.8 Hz, 1H), 7.29 (d, J ) 8.5 Hz,
1H), 3.81 (s, 2H). 13C NMR (CDCl3): δ ) 198.5, 153.0, 138.3,
132.6, 129.3, 125.9, 39.8. CI MS m/z (%): 271, 269 (5), 259,
257 (11), 231, 229 (100).
4-Octoylxyben za ld eh yd e (4d )50 was prepared by proce-
dure I, from 1-bromooctane and p-hydroxybenzaldehyde. Dis-
tillation (120 °C) gave an impure product. Chromatography
of the distillate (silica, 50 g, 1:3 ethyl acetate:hexanes) was
employed to yield a thick clear liquid (17% yield). 1H NMR
(CDCl3): δ ) 9.86 (s, 1H), 7.81 (d, J ) 8.8 Hz, 2H), 6.97 (d,
J ) 8.8 Hz, 2H), 4.02 (t, J ) 6.6, 2H), 1.79 (qn, J ) 6.6 Hz,
2H), 1.45 (m, 2H), 1.30 (m, 8H), 0.87 (t, J ) 7.4 Hz, 3H). 13C
NMR MHz (CDCl3): δ ) 190.8, 164.2, 132.0, 129.7, 114.7, 68.4,
31.8, 29.3, 29.2, 29.0, 25.9, 22.6, 14.1. CI MS m/z (%): 263 (20),
235 (100).
2-(4-Hyd r oxyp h en ylm eth ylen e)-5-br om oben zo[b]th io-
p h en -3(2H)-on e (9) was prepared from 8 and p-hydroxybenz-
aldehyde by the later stages of procedure IV. Upon cooling of
the reaction mixture a bright orange solid precipitated. The
suspension was washed with Na2S2O3 (5%, 25 mL × 2),
filtered, and dried under vacuum (1.72 g, 5.16 mmol, 66%).
The product was recrystallized from 95% EtOH, mp ) 282 °C.
1H NMR (DMSO): δ ) 10.46 (s, 1H), 7.90 (d, J ) 2.2 Hz, 1H),
7.86 (s, 1H), 7.84 (dd, J ) 8.8, 2.2 Hz, 1H), 7.74 (d, J ) 8.1
Hz, 1H), 7.64 (d, J ) 8.8 Hz, 2H), 6.94 (d, J ) 8.8 Hz, 2H). 13
C
NMR (DMSO): δ ) 186.0, 160.5, 144.0, 137.7, 134.8, 133.5,
132.0, 128.5, 126.4, 125.7, 124.5, 118.9, 116.4. CI MS m/z (%):
363, 361 (19), 335, 333 (100). Anal. Calcd for C15H9O2BrS:
(%): C, 54.07; H, 2.72. Found C, 53.65; H, 2.79.
(N-P h th a lim id o)m eth yl Acr yla te (5c). A solution of
acrylic acid (3.47, 48 mmol) and dicyclohexylamine, (8.71 g,
48 mmol,1 equiv) in 150 mL of DMF was heated to 65 °C, in
an inert atmosphere. N-Chloromethylphthalimide (9.41 g, 48
2-(4-Hexyloxyp h en ylm eth ylen e)-5-br om oben zo[b]th io-
p h en -3(2H)-on e (10) was prepared by procedure IV, from 7
(0.98 g, 4.3 mmol) and 4b. The solution was concentrated, and
the residue was recrystallized from CH2Cl2/hexanes to yield a
(50) Ndayikengurukiye, H.; J acobs, S.; Tachelet, W.; van der Looy,
J .; Pollaris, A.; Geise, H. J .; Claeys, M.; Kauffmann, J . M.; J anietz, S.
Tetrahedron 1997, 53, 13811-13828.

2974 J . Org. Chem., Vol. 66, No. 9, 2001
Eggers et al.
yellow solid (1.34 g, 3.2 mmol, 74%), mp ) 129-131 °C. 1H
NMR (CDCl3): δ ) 8.02 (d, J ) 2.2 Hz, 1H), 7.91 (s, 1H), 7.63
(d, J ) 8.1 Hz, 1H), 7.62 (d, J ) 8.8 Hz, 2H), 7.36 (d, J ) 8.1
Hz, 1H), 6.96 (d, J ) 8.8 Hz, 2H), 4.00 (t, J ) 6.6 Hz, 2H),
1.79 (qn, J ) 7.4 Hz, 2H), 1.45 (qn, J ) 7.4 Hz, 2H), 1.34 (m,
4H), 0.89 (t, J ) 6.6 Hz, 3H). 13C NMR (CDCl3): δ ) 187.2,
161.2, 144.6, 137.5, 134.9, 133.2, 132.5, 129.6, 127.2, 126.4,
125.2, 119.3, 115.2, 68.3, 31.5, 29.0, 25.6, 22.6, 14.0. +LSIMS
(mNBA) m/z (%): 419, 417 (M + H+, 100). Anal. Calcd for
127.4, 126.5, 126.0, 124.3, 118.5, 115.2, 68.3, 51.8, 31.5, 29.1,
25.6, 22.6, 14.0. +LSIMS (mNBA) m/z (%): 423 (60), 289 (100).
Anal. Calcd for C25H26O4S: (%): C, 71.06; H, 6.20; O, 15.15;
S, 7.57. Found C, 71.37; H, 6.16; O, 14.98.
(N-P h t h a lim id o)m et h yl 4-(1-Th ia -4-oxa -3-oxoh exyl)-
d ih yd r ocin n a m a te (16). Alkene 14 (2.00 g, 4.70 mmol) and
Rh(PPh3)3Cl (0.124 g, 0.134 mmol, 0.03 equiv) in 150 mL of
degassed 1:1 benzene/ethanol was hydrogenated at room
temperature, at 60 psi, for 10 days. The crude product was
purified on a silica column (1:1, ethyl acetate/hexanes) to give
a clear liquid (1.90 g, 4.45 mmol, 95%). 1H NMR (CDCl3): δ )
7.89 (AB, J ) 5.5, 2.9 Hz, 2H), 7.77 (AB, J ) 5.5, 2.9 Hz, 2H),
7.26 (d, J ) 8.1 Hz, 2H), 7.08 (d, J ) 8.1 Hz, 2H), 5.68 (s, 2H),
4.11 (q, J ) 6.6 Hz, 2H), 3.62 (s, 2H), 2.88 (t, J ) 7.4 Hz, 2H),
2.59 (t, J ) 7.4 Hz, 2H), 1.18 (t, J ) 6.6 Hz, 3H). 13C NMR
(CDCl3): δ ) 171.3, 169.5, 166.5, 139.0, 134.5, 132.4, 131.5,
130.4, 128.8, 123.8, 61.3, 60.6, 36.8, 35.1, 30.0, 13.9. +LSIMS
(mNBA) m/z (%): 427 (28), 354 (10), 280 (20), 267 (30), 209
(24), 160 (100). Anal. Calcd for C22H21O6NS (%): C, 61.82; H,
4.95; N, 3.28. Found C, 61.83; H, 4.96; N, 3.33.
Meth yl 2-(4-h exyloxyp h en ylm eth ylen e)ben zo[b]th io-
p h en -3(2H)-on e-5-(2-eth ylca r boxyla te) (17) was prepared
from 2a (150 mg, 0.37 mmol) in excess diazomethane in ether.
The mixture was stirred at room temperature for 1 h and then
evaporated and chromatographed on a silica column (CHCl3:
MeOH 9:1) to give a yellow solid (145 mg 0.34 mmol, 93%). 1H
NMR (CDCl3): δ ) 7.91 (s, 1H), 7.76 (s, 1H), 7.63 (d, J ) 8.8
Hz, 2H), 7.41 (m, 2H), 6.96 (d, J ) 8.8 Hz, 2H), 4.01 (t, J )
6.62 Hz, 2H), 3.66 (s, 3H), 2.99 (t, J ) 7.4 Hz, 2H), 2.65 (t,
J ) 7.4 Hz, 2H), 1.79 (qn, J ) 6.6 Hz, 2H), 1.33 (qn, J ) 6.6
Hz, 2H), 1.23 (m, 4H), 0.89 (t, J ) 6.6 Hz, 3H). 13C NMR
(CDCl3): δ ) 188.5, 172.9, 161.0, 143.0, 138.2, 135.6, 133.9,
133.0, 131.1, 128.5, 126.8, 126.3, 123.9, 115.1, 68.3, 51.7,
35.4, 31.5, 30.3, 29.4, 29.1, 25.7, 22.6, 14.0. +LSIMS (mNBA)
m/z (%) 425.0 (100). Exact mass Calculated for C25H29O4S
425.1779; found 425.1781
C
21H21O2BrS: (%): C, 60.43; H, 5.07. Found C, 60.97; H, 5.51.
Meth yl (2E)-3-[4-(1-Th ia-4-oxa-3-oxoh exyl)ph en yl]pr op-
2-en oa te (11) was prepared by procedure III, from 6a (30
mmol) and methyl acrylate (5b). The crude product was
purified by chromatography (flash silica, 200 g, 60:40 ether:
hexanes) and gave a white solid in 37% yield, mp ) 47-48
1
°C. H NMR(CDCl3): δ ) 7.62 (d, J ) 16.0 Hz, 1H), 7.43 (d,
J ) 8.3 Hz, 2H), 7.34(d, J ) 8.3 Hz, 2H), 6.38 (d, J ) 16.0 Hz,
1H), 4.16 (q, J ) 7.1 Hz, 2H), 3.78 (s, 3H), 3.66 (s, 3H), 1.22 (t,
J ) 7.1 Hz, 3H). 13C NMR 90.57 MHz (CDCl3): δ ) 169.3,
167.4, 143.9, 138.3, 132.5, 128.7, 128.5, 117.6, 61.8, 51.7, 35.7,
14.1. +LSIMS (mNBA) m/z (%): 280 (M+, 100), 249 (43), 207
(35), 175 (30). Anal. Calcd for C14H16O4S (%): C, 59.98; H, 5.75;
O, 22.83; S, 11.44. Found: C, 59.80; H, 5.77; O, 23.00; S, 11.43.
(2E)-3-[4-(Car boxym eth ylth io)ph en yl]pr op-2-en oic Acid
(12). NaOH (0.54 g, 13.6, 2.5 equiv), in 25 mL of MeOH, was
added to a solution of 11 (1.53 g, 5.44 mmol) in 50 mL of
MeOH, and the mixture was refluxed for 2 h. The acid salt
was concentrated and dried under vacuum. The resultant solid
was dissolved in H2O and then acidified to pH < 1. The white
precipitate was filtered and dried (1.10 g, 4.62 mmol, 85%),
1
mp ) 219-220 °C. H NMR MHz (DMSO): δ ) 12.63 (br s),
7.62 (d, J ) 8.8 Hz, 2H), 7.55 (d, J ) 15.4 Hz, 1H), 7.32 (d,
J ) 8.8 Hz, 2H), 6.50 (d, J ) 15.4 Hz, 1H), 3.88 (s, 2H). 13C
NMR MHz (DMSO): δ ) 170.5, 167.7, 143.3, 138.9, 131.5,
128.8, 127.0, 118.6, 34.2.
Met h yl (2E)-3-[4-(ca r b oxym et h ylt h io)p h en yl]p r op -2-
en oa te (13) was prepared by procedure III, from 7 (7.85 mmol)
and methyl acrylate (5b). The crude product was isolated by
ether extraction (2 × 25 mL) of the acidic aqueous reaction
medium, dried, and concentrated. Recrystallization from 95%
ethanol gave 13 as a white solid in 10% yield. 1H NMR
(DMSO): δ ) 12.9 (br s, 1H), 7.63 (d, J ) 8.3 Hz, 2H), 7.60 (d,
J ) 16.1 Hz, 1H), 7.32 (d, J ) 8.3 Hz, 2H), 6.58 (d, J ) 16.1
Hz, 1H), 3.88 (s, 2H), 3.70(s, 3H). 13C NMR (DMSO): δ ) 170.4,
166.7, 143.8, 139.3, 131.3, 128.8, 126.9, 117.1, 56.1, 34.1.
(N-P h t h a lim id o)m et h yl 4-(1-t h ia -4-oxa -3-oxoh exyl)-
cin n a m a te (14) was prepared by procedure III, from 6a (2.38
g, 8.66 mmol) and 5c(2.00 g, 8.66 mmol, 1 equiv). The crude
product was dissolved in CH2Cl2 (100 mL), and the solution
was washed with H2O (50 mL × 2) and then concentrated.
The crude product was recrystallized from ethyl acetate/
hexanes and purified further using centrifugal chromatogra-
phy (CHCl3) to give a white solid (1.66 g, 3.90 mmol, 45%),
mp ) 130 °C. 1H NMR (CDCl3): δ ) 7.91 (AB, J ) 5.9, 2.9 Hz,
2H), 7.76 (AB, J ) 5.9, 2.9 Hz, 2H), 7.62 (d, J ) 16.2 Hz, 1H),
7.42 (AB, J ) 8.1 Hz, 2H), 7.27 (AB, J ) 8.1 Hz, 2H), 6.32 (d,
J ) 16.2 Hz, 1H), 5.82 (s, 2H), 4.14 (q, J ) 6.6 Hz, 2H), 3.65
(s, 2H), 1.19 (t, J ) 6.6 Hz, 3H). 13C NMR (CDCl3): δ ) 169.2,
166.7, 165.5, 145.2, 138.8, 134.6, 132.1, 131.7, 128.6, 128.5,
123.9, 116.5, 61.7, 60.8, 35.5, 14.0. CI MS m/z (%): 459 (14),
426 (52), 408 (100), 160 (88). Anal. Calcd for C22H19O6NS (%):
C, 62.11; H, 4.50; N, 3.29. Found: C, 61.67; H, 4.50; N, 3.31.
2-(4-H exyloxyp h en ylm et h ylen e)-5-(m et h oxyca r b on -
yleth en yl)ben zo[b]th iop h en -3(2H)-on e (15) was prepared
by procedure III, from 10 (0.393 g, 0.94 mmol) and methyl
acrylate (5b). The product was purified by centrifugal chro-
matography (CHCl3), eluting unreacted 9, followed by 14
(0.090 g, 0.21 mmol, 22%), mp ) 179-181 °C. 1H NMR
(CDCl3): δ ) 8.05 (d, J ) 1.5 Hz, 1H), 7.95 (s, 1H), 7.69 (d,
J ) 15.4 Hz, 1H), 7.68 (d, J ) 8.1 Hz, 1H), 7.64 (d, J ) 8.8 Hz,
2H), 7.51 (d, J ) 8.1 Hz, 1H), 6.98 (d, J ) 8.8 Hz, 2H), 6.49 (d,
J ) 15.4 Hz, 2H), 4.01 (t, J ) 6.6 Hz, 2H), 3.80 (s, 3H), 1.79
(qn, J ) 7.4 Hz, 2H), 1.46 (qn, J ) 6.6 Hz, 2H), 1.33 (m, 4H),
0.90 (t, J ) 6.6 Hz, 2H). 13C NMR MHz (CDCl3): δ )187.9,
167.1, 161.2, 147.8, 143.2, 134.8, 134.0, 133.2, 132.1, 131.4,
Eth yl [(4-(2-cya n oeth en yl)p h en yl)th io]a ceta te (19a )
was prepared by procedure III, from 6a (6.37 g, 23.2 mmol)
and freshly distilled acrylonitrile (1.84 g, 34.8 mmol, 1.5 equiv).
The crude product (TLC, 1:1 ether:hexanes, Rf ) 0.33) was
purified by chromatography (silica, 100 g, 55:45 ether:hexanes)
to give a yellow liquid that solidified on standing. Kugelrohr
distillation (5 × 10-2 atm) gave a white solid between 140 and
165 °C (4.46 g, 18.0 mmol, 78%). The isomers could be
separated by repeated centrifugal chromatography (1:3 ether:
hexanes), trans mp ) 44-45 °C. 1H NMR (CDCl3): Trans δ )
7.30 (m, 3H), 5.78 (d, J ) 16.7 Hz, 1H), 4.12 (q, J ) 7.1, 2H),
3.64 (s, 2H), 1.17 (t, J ) 7.1 Hz, 3H). Cis δ ) 7.67 (d, J ) 8.4
Hz, 2H), 7.30 (m, 3H), 6.99 (d, J ) 12.1 Hz, 1H), 5.35 (d, J )
12.0 Hz, 1H), 4.12, (q, J ) 7.1, 2H), 3.65 (s, 2H), 1.17 (t, J )
7.1 Hz, 3H). 13C NMR (CDCl3): Trans δ ) 168.8, 149.2, 139.5,
131.0, 127.9, 127.5, 117.9, 95.6, 61.5, 34.9, 13.8. Cis. δ ) 168.8,
147.4, 139.3, 131.0, 129.2, 127.6, 117.1, 94.3, 61.5, 34.9, 13.8.
CI MS m/z (%): 288 (6), 276 (17), 248 (100), 174 (16). Anal.
Calcd for C13H13O2NS (%): C 63.14; H 5.30; N 5.67. Found C,
63.77; H, 5.27; N, 6.05.
Eth yl [(3-(2-cya n oeth en yl)p h en yl)th io]a ceta te (19b)
was prepared by procedure III, from 6b (3.16, 11.5 mmol) and
acrylonitrile (0.61 g, 11.5 mmol, 1equiv). The crude product
was fractionated on a column (silica, 60 g, 2:1 ether:hexanes),
followed by centrifugal chromatography (1:3 ether:hexanes),
yielding 1.71 g (6.92 mmol, 60%). Separation of isomers was
achieved by tedious centrifugal chromatography. 1H NMR
(CDCl3): Trans δ ) 7.46 (s, 1H), 7.42 (d, J ) 7.35 Hz, 1H),
7.29 (m, 2H), 5.86 (d, 16.9 Hz), 4.14 (q, J ) 6.7 Hz, 2H), 3.62
(s, 2H), 1.19 (t, J ) 6.6 Hz, 3H). Cis δ ) 7.71 (s, 1H), 7.66 (d,
J ) 8.1 Hz, 1H), 7.42 (d, 1H), 7.29 (m, 1H), 7.06 (d, J ) 11.8,
1H), 5.46 (d, J ) 12.5 Hz, 1H), 4.14 (q, J ) 6.7 Hz, 2H), 3.65
(s, 2H), 1.19 (t, J ) 6.6 Hz, 3H). 13C NMR (CDCl3): Trans δ )
169.2, 149.5, 136.6, 134.22, 131.7, 129.5, 127.8, 125.6, 117.7,
97.2, 61.6, 36.0, 13.9. Cis δ ) 169.2, 147.8, 136.3, 134.18, 131.5,
129.6, 129.4, 126.8, 116.9, 96.0, 61.5, 36.1, 13.9. CI MS m/z
(%): 288 (8), 276 (26), 248 (100). HRMS for C13H14O2NS, m/e:
248.0742, found 248.0763.

Photoswitchable Hemithioindigo Lipids
J . Org. Chem., Vol. 66, No. 9, 2001 2975
Eth yl [(4-(2-Cya n oeth yl)p h en yl)th io]a ceta te (20a ). The
alkene 19a (7.43 g, 30.1 mmol) and Rh(PPh3)3Cl (0.97 g, 1.05
mmol, 0.035 equiv), in 150 mL of degassed 1:1 benzene/ethanol,
was stirred under a pressure of 50 psi of hydrogen at room
temperature for 9 days. The solution was concentrated, and
the residue was triturated with ether, filtered and concen-
trated again. The crude product was distilled (Kugelrohr, 5 ×
10-2 atm) at 160-180 °C, to yield product as a yellowish liquid,
acceptably pure for the following step. For higher purity, 18a
+LSIMS (mNBA) m/z (%): 364.1 (100). HRMS (+LSIMS)
Calculated for C22H22O2NS+: 364.1366, found 364.1362.
2-(4-Hexyloxyp h en ylm eth ylen e)-5-(2-cya n oeth yl)ben -
zo[b]th iop h en -3(2H)-on e (22b) was prepared by method IV,
from acid 21a (0.600 g, 2.71 mmol) via the acid chloride and
cyclization, followed by coupling of the resultant thioindoxyl
with 4b (0.57 g, 2.8 mmol, 1 equiv). A yellow solid precipitated
from the cooled reaction mixture, which was filtered and dried
under vacuum to give a yellow solid (0.360 g, 0.92 mmol, 34%),
mp ) 129-131 °C. As isolated the product is the Z-isomer:
1H NMR (CDCl3): δ ) 7.93 (s, 1H), 7.76 (s, 1H), 7.64 (d, J )
8.8 Hz, 2H), 7.48, 7.45 (AB, J ) 8.5 Hz, 2H), 6.97 (d, J ) 8.8
Hz, 2H), 4.00 (t, J ) 6.6 Hz, 2H), 3.00 (t, J ) 7.4 Hz, 2H), 2.65
(t, J ) 7.4 Hz, 2H), 1.79 (qn, J ) 6.6 Hz, 2H), 1.44 (qn, J ) 6.6
Hz, 2H), 1.34 (m, 4H), 0.90 (t, J ) 6.6 Hz, 2H). 13C NMR
(CDCl3): δ ) 188.2, 161.1, 145.0, 135.2, 134.3, 133.1, 131.4,
127.7, 126.6, 126.3, 124.3, 118.8, 115.1, 68.3, 31.5, 31.0, 29.0,
25.6, 22.6, 19.2, 14.0. +LSIMS (mNBA) m/z (%): 392.0 100).
HRMS (+LSIMS) Calculated for C24H26O2NS+: 392.1684,
found 392.1670. Anal. Calcd for C24H25O2NS: (%): C, 73.63;
H, 6.44; N, 3.58. Found C, 73.20; H, 6.45; N, 3.61.
The E-isomer was synthesized by irradiating a chloroform
solution of Z-22b, in a Rayonet reactor, at 350 nm for 30 min.
The solution was concentrated, and the isomers were separated
by centrifugal chromatography (1:3 hexanes:chloroform), under
red light. 1H NMR (CDCl3): δ ) 8.19 (d, J ) 8.8 Hz, 2H), 7.68
(d, J ) 1.5 Hz, 1H), 7.44, 7.34 (AB, J ) 8.1 Hz, 2H), 7.15 (s,
1H), 6.91 (d, J ) 8.8 Hz, 2H), 4.00 (t, J ) 6.6 Hz, 2H), 2.98 (t,
J ) 6.6 Hz, 2H), 2.62 (t, J ) 6.6 Hz, 2H), 1.78 (qn, J ) 6.6 Hz,
2H). 1.45 (qn, J ) 6.6 Hz, 2H), 1.34 (m, 4H), 0.90 (t, J ) 6.6
Hz, 2H). 13C NMR (CDCl3): δ ) 185.4, 161.5, 144.4, 139.4,
134.8, 134.7, 133.9, 133.9, 133.1, 130.2, 127.0, 126.2, 123.8,
118.7, 114.1, 68.1, 31.5, 31.0, 29.0, 25.6, 22.6, 19.2, 14.0.
2-(4-Octyloxyp h en ylm eth ylen e)-5-(2-cya n oeth yl)ben -
zo[b]th iop h en -3(2H)-on e (22c) was prepared by method IV,
from acid 21a (0.29 g, 1.30 mmol) via the acid chloride and
cyclization, followed by coupling of the resultant thioindoxyl
with 4d (0.280 g, 1.20 mmol, 0.92 equiv). A yellow solid
precipitated from the cooled reaction mixture, which was
filtered and dried under vacuum to give a yellow solid (0.212
g, 0.506 mmol, 42%) with a complex melting behavior. 1H NMR
(CDCl3): δ ) 7.92 (s, 1H), 7.76 (s, 1H), 7.64 (d, J ) 8.8 Hz,
2H), 7.51, 7.42 (AB, J ) 8.5 Hz, 2H), 6.97 (d, J ) 8.8 Hz, 2H),
4.00 (t, J ) 6.6 Hz, 2H), 3.00 (t, J ) 7.4 Hz, 2H), 2.65 (t, J )
7.4 Hz, 2H), 1.79 (qn, J ) 6.6 Hz, 2H), 1.45 (m, 2H), 1.28 (m,
8H), 0.87 (t, J ) 6.6 Hz, 3H). 13C NMR (CDCl3): δ ) 188.2,
161.1, 145.0, 135.6, 135.2, 134.3, 133.1, 131.4, 127.7, 126.6,
126.3, 118.7, 115.2, 68.3, 31.8, 31.8, 31.0, 29.3, 29.2, 29.1, 26.0,
22.6, 19.3, 14.1. +LSIMS (mNBA) m/z (%): 420 (100). Anal.
Calcd for C26H29O2NS: (%): C, 74.43; H, 6.97; N, 3.34. Found
C, 73.88; H, 7.11; N, 2.96.
was passed through
a silica column (1:9, ethyl acetate/
toluene), giving a clear liquid (4.85 g, 19.5 mmol, 65%). 1H
NMR (CDCl3): δ ) 7.32 (d, J ) 8.3 Hz, 2H), 7.12 (d, J ) 8.3
Hz, 2H) 4.11 (qua., J ) 7.0 Hz, 2H), 3.57 (s, 2H), 2.86 (t, J )
7.3 Hz, 2H), 2.54 (t, J ) 7.3 Hz, 2H), 1.17 (t, J ) 7.0 Hz, 3H).
13C NMR (CDCl3): δ ) 169.4, 136.7, 133.7, 130.2, 128.8, 118.8,
61.3, 36.4, 30.8, 18.9, 13.8. CI MS m/z (%): 290 (5), 278 (19),
250 (100), 176 (25). HRMS for C13H15O2NS, m/e: 249.0824,
found 249.0823.
Eth yl [(3-(2-cya n oeth yl)p h en yl)th io]a ceta te (20b) was
prepared from 19b (1.71 g, 6.93 mmol) following the procedure
for 20a . The crude product was purified on a silica column
(1:1, ether:hexanes) to give a clear liquid (1.10 g, 4.42 mmol,
64%). 1H NMR (CDCl3): δ ) 7.25 (m, 3H), 7.06 (d, J ) 7.4 Hz,
1H), 4.14 (q, J ) 6.6 Hz, 2H), 3.62 (s, 2H), 2.90 (t, J ) 7.4 Hz,
2H), 2.58 (t, J ) 7.4 Hz, 2H), 1.20 (t, J ) 6.6 Hz, 3H). 13C
NMR (CDCl3): δ ) 169.5, 138.9, 135.8, 129.4, 129.3, 128.2,
126.7, 118.8, 61.6, 36.3, 31.2, 19.0, 14.0. CI MS m/z (%): 278
(28), 250 (85), 204 (37), 176 (100). Anal. Calcd for C13H15O2NS
(%): C, 62.60; H, 6.10; N, 5.60. Found C, 62.58; H, 6.05; N,
5.55.
[(4-(2-Cya n oeth yl)p h en yl)th io]a cetic Acid (21a ). Ester
20a (1.50 g, 6.01 mmol) was dissolved in 50 mL of MeOH
containing NaOH (0.29 g, 7.22 mmol, 1.2 equiv) and was
stirred at reflux for 3 h. The acid salt was concentrated and
dried under vacuum. The resultant solid was dissolved in H2O
and acidified to pH < 1. The white precipitate was filtered
and dried. The product was a white solid (1.20 g, 5.43 mmol,
1
90%), mp ) 106-107 °C. H NMR (CDCl3): δ ) 7.38 (d, J )
8.3 Hz, 2H), 7.17 (d, J ) 8.3 Hz, 2H), 3.64 (s, 2H), 2.92 (t, J )
7.3 Hz, 2H), 2.59 (t, J ) 7.3 Hz, 2H). 13C NMR (CDCl3): δ )
175.2, 137.2, 133.4, 130.6, 129.2, 118.9, 36.5, 31.1, 19.2. CI MS
m/z (%): 262 (10), 250 (26.), 222 (17), 204 (78), 176 (100). Anal.
Calcd for C8H11O2NS: (%): C 59.71; H 5.02; N 6.33. Found C,
59.92; H, 5.00; N, 6.48.
[(3-(2-Cya n oeth yl)p h en yl)th io]a cetic Acid . Ester 20b
(1.10 g, 4.39 mmol) was dissolved in 50 mL of MeOH contain-
ing NaOH (0.21 g, 5.38 mmol, 1.2 equiv) and was stirred at
reflux for 3 h. The acid salt was concentrated and dried under
vacuum. The resultant solid was dissolved in H2O and acidified
to pH < 1. After acidifying the aqueous salt solution, the
product was extracted with CH2Cl2, dried, and concentrated
to give a white solid (0.820 g, 3.71 mmol, 84%), mp ) 77-78
2-(3-Hexyloxyp h en ylm eth ylen e)-5-(2-cya n oeth yl)ben -
zo[b]th iop h en -3(2H)-on e (22d ) was prepared by method IV,
from acid 21a (0.450 g, 2.04 mmol) via the acid chloride and
cyclization, followed by coupling of the resultant thioindoxyl
with 4c (0.42 g, 2.04 mmol, 1 equiv). A yellow solid precipitated
from the cooled reaction mixture, which was filtered and dried
under vacuum to give a yellow solid (0.150 g, 0.384 mmol,
19%), mp ) 158 °C. 1H NMR (CDCl3): δ )7.91 (s, 1H), 7.77
(s, 1H), 7.47(AB,s, 2H), 7.36 (t, J ) 8.1 Hz, 1H), 7.26 (d, J )
9.6 Hz, 1H), 7.20 (t, J ) 2.2 Hz, 1H), 6.95 (dd, J ) 8.1, 1.5 Hz,
1H), 4.00 (t, J ) 6.6 Hz, 2H), 3.00 (t, J ) 7.4 Hz, 2H), 2.65 (t,
J ) 7.4 Hz, 2H), 1.81 (qn, J ) 6.6 Hz, 2H), 1.48 (qn, J ) 6.6
Hz, 2H), 1.34 (m, 4H), 0.90 (t, J ) 6.6 Hz, 3H). 13C NMR
(CDCl3): δ ) 188.3, 159.5, 145.2, 135.7, 135.6, 135.3, 134.1,
131.0, 130.5, 130.0, 126.4, 124.3, 123.6, 118.6, 117.1, 116.1,
68.2, 31.6, 30.9, 29.1, 25.7, 22.6, 19.2, 14.0. Anal. Calcd for
1
°C. H NMR (CDCl3): δ ) 10.5 (br s, 1H), 7.27 (m, 3H), 7.09
(d, J ) 6.6 Hz, 1H), 3.66 (s, 2H), 2.90 (t, J ) 7.4 Hz, 2H), 2.59
(t, J ) 7.4 Hz, 2H). 13C NMR (CDCl3): δ ) 175.3, 139.0, 135.2,
129.6, 129.5, 128.5, 127.1, 118.8, 36.2, 31.2, 19.1. CI MS m/z
(%): Calculated for C8H11O2NS: (%): C, 59.71; H, 5.02; N, 6.33.
Found C, 59.72; H, 5.05; N, 6.07.
2-(4-Bu tyloxyp h en ylm eth ylen e)-5-(2-cya n oeth yl)ben -
zo[b]th iop h en -3(2H)-on e (22a ) was prepared by method IV,
from acid 21a (0.293 g, 1.32 mmol) via the acid chloride and
cyclization, followed by coupling of the resultant thioindoxyl
with 4a (0.235 g, 1.32 mmol, 1 equiv). A yellow solid precipi-
tated from the cooled reaction mixture, which was filtered and
dried under vacuum (0.216 g, 0.595 mmol, 45%), mp ) 158
°C. Alternatively the reaction mixture was concentrated and
chromatographed (silica, 3:1, CHCl3/hexanes) to afford the
C
24H25O2NS: (%): C, 73.63; H, 6.44; N, 3.56. Found C, 73.45;
1
product. H NMR (CDCl3): δ ) 7.91 (s, 1H), 7.75 (s, 1H), 7.63
H, 6.50; N, 3.60.
(d, J ) 8.8 Hz, 2H), 7.45 (m, 2H), 6.97 (d, J ) 8.8 Hz, 2H),
4.01 (t, J ) 6.3 Hz, 2H), 2.99 (t, J ) 7.4 Hz, 2H), 2.65 (t, J )
7.4 Hz, 2H), 1.78 (qn J ) 7.4 Hz, 2H), 1.48 (sx, J ) 7.4 Hz,
2H), 0.97 (t, J ) 7.4 Hz, 3H). 13C NMR (CDCl3): δ ) 188.2,
161.0, 145.0, 135.5, 135.2, 134.3, 133.1, 131.3, 127.6, 126.6,
126.2, 124.2, 118.6, 115.1, 67.9, 31.1, 30.9, 19.2, 19.1, 13.8.
2-(4-Hexyloxyp h en ylm eth ylen e)-6-(2-cya n oeth yl)ben -
zo[b]th iop h en -3(2H)-on e (22e) a n d 2-(4-h exyloxyp h en -
ylm et h ylen e)-4-(2-cya n oet h yl)b en zo[b]t h iop h en -3(2H )-
on e (22f) were prepared as a mixture by method IV, from acid
21b (0.820 g, 3.71 mmol) via the acid chloride and cyclization,
followed by coupling of the resultant thioindoxyl with 4b (0.280

2976 J . Org. Chem., Vol. 66, No. 9, 2001
Eggers et al.
g, 1.20 mmol, 0.92 equiv). A yellow solid precipitated from the
cooled reaction mixture, which was filtered and dried under
vacuum. The regioisomers were separated by column chroma-
tography (silica, 3:1 CHCl3/hexanes). Compound 22e elutes
first followed closely by 22f in a combined yield of 34%.
2-(4-H exyloxyp h en ylm et h ylen e)-6-(2-ca r b oxyet h yl)-
ben zo[b]th iop h en -3(2H)-on e (2d ) was prepared by proce-
dure V, from 22e (184 mg, 0.469 mmol) and tetrafluorophthalic
acid (112 mg, 0.469 mmol, 1 equiv) heated at 140 °C for 4 days.
The product was a yellow solid (166 mg, 0.405 mmol, 86%),
mp ) 134-135 °C. 1H NMR(CDCl3): δ ) 7.90 (s, 1H), 7.84 (d,
J ) 8.1 Hz, 1H), 7.63 (d, J ) 8.8 Hz, 2H), 7.33 (s, 1H), 7.12 (d,
J ) 8.1 Hz, 1H), 6.97 (d, J ) 8.8 Hz, 2H), 4.00 (t, J ) 6.6 Hz,
2H), 3.03 (t, J ) 7.4 Hz, 2H), 2.73 (t, J ) 7.4 Hz, 2H), 1.79
(qn, J ) 6.6 Hz, 2H), 1.45 (qn, J ) 6.6 Hz, 2H), 1.33 (m, 4H),
0.89 (t, J ) 6.6 Hz, 3H). 13C NMR (CDCl3): δ ) 188.2, 177.4,
160.9, 148.3, 146.6, 133.9, 133.0, 129.4, 127.7, 127.1, 126.7,
126.0, 123.5, 115.1, 68.2, 34.7, 31.5, 30.8, 29.1, 25.6, 22.6, 14.0.
Anal. Calcd for C24H26O4S: (%): C, 70.22; H, 6.38. Found C,
69.76; H, 6.66.
2-(4-H exyloxyp h en ylm et h ylen e)-4-(2-ca r b oxyet h yl)-
ben zo[b]th iop h en -3(2H)-on e (2e) was prepared by proce-
dure V, from 22f (193 mg, 0.492 mmol) and tetrafluorophthalic
acid (118 mg, 0.492 mmol, 1 equiv) heated at 168 °C for 4 days.
The product was a yellow solid (168 mg, 0.410 mmol, 83%),
mp ) 142-144 °C. 1H NMR (CDCl3): δ )7.87 (s, 1H), 7.63 (d,
J ) 8.8 Hz, 2H), 7.41 (m, 2H), 7.09 (d, J ) 7.4 Hz, 1H), 6.97
(d, J ) 8.8 H, 2 Hz, 2H), 4.01 (t, J ) 6.6 Hz, 2H), 3.44 (t, J )
7.4 Hz, 2H), 2.73 (t, J ) 7.4 Hz, 2H), 1.77 (qn, J ) 6.6 Hz,
2H), 1.64 (qn, J ) 6.6 Hz), 1.34 (m, 4H), 0.90 (t, J ) 6.6 Hz,
3H). 13C NMR (CDCl3): δ ) 189.2, 178.1, 160.9, 147.4, 143.9,
134.3, 133.6, 133.0, 127.6, 127.5, 127.4, 126.8, 122.5, 115.1,
68.3, 34.5, 31.5, 29.1, 27.6, 25.7, 22.6, 14.0. +LSIMS (mNBA)
m/z (%): 411 (100), 393 (69).
22e: (0.240 g, 0.614 mmol), mp ) 98-99 °C. 1H NMR
(CDCl3): δ ) 7.86 (s, 1H), 7.82 (d, J ) 8.1 Hz, 1H), 7.59 (d,
J ) 8.8 Hz, 2H), 7.32 (s, 1H), 7.08 (d, J ) 8.1 Hz, 1H), 6.94 (d,
J ) 8.8 Hz, 2H), 3.96 (t, J ) 6.6 Hz, 2H), 2.97 (t, J ) 7.4 Hz,
2H), 2.65 (t, J ) 6.6 Hz, 2H), 1.76 (qn, J ) 6.6 Hz, 2H), 1.43
(qn, J ) 6.6 Hz, 2H), 1.32 (m, 4H), 0.88 (t, J ) 6.6 Hz, 3H).
13C NMR (CDCl3): δ ) 187.7, 160.9, 146.7, 145.5, 133.9, 132.9,
129.9, 127.4, 127.1, 126.4, 125.7, 123.4, 118.5, 115.0, 68.1, 31.6,
31.4, 29.0, 25.6, 22.5, 18.7, 13.9. +LSIMS (mNBA) m/z (%):
392 (100). Anal. Calcd for C24H25O2NS: (%): C, 73.63; H, 6.44;
N, 3.58. Found C, 73.44; H, 6.56; N, 3.61.
1
22f: (0.252 g, 0.644 mmol). H NMR (CDCl3): δ ) 7.81 (s,
1H), 7.60 (d, J ) 8.8 Hz, 2H), 7.42 (m, 2H), 7.09 (d, J ) 7.4
Hz, 1H), 6.95 (d, J ) 8.8 Hz, 2H), 3.98 (t, J ) 6.6 Hz, 2H),
3.40 (t, J ) 7.4 Hz, 2H), 2.75 (t, J ) 6.6 Hz, 2H), 1.78 (qn,
J ) 6.6 Hz, 2H), 1.45 (qn, J ) 6.6 Hz, 2H), 1.33 (m, 4H), 0.90
(t, J ) 6.6 Hz, 3H). 13C NMR (CDCl3): δ ) 189.0, 160.9, 147.6,
141.0, 134.4, 133.9, 132.9,0.127.7, 127.4, 127.2, 126.5, 123.3,
119.2, 115.0, 68.2, 31.5, 29.0, 28.3, 25.6, 22.5, 18.0, 14.0.
+LSIMS (mNBA) m/z (%): 392 (100). Anal. Calcd for C24H25O2-
NS: (%): C, 73.63; H, 6.44; N, 3.58. Found C, 73.29; H, 6.48;
N, 3.54.
2-(4-H exyloxyp h en ylm et h ylen e)-5-(2-ca r b oxyet h yl)-
ben zo[b]th iop h en -3(2H)-on e (2a ) was prepared by proce-
dure V, from 22b (129 mg, 0.323 mmol) and tetrafluorophthalic
acid (81 mg, 0.323 mmol, 1 equiv). The product was a yellow
solid (119 mg, 0.290 mmol, 90%), mp ) 109 °C. 1H NMR
(CDCl3): δ ) 7.91 (s, 1H), 7.77 (s, 1H), 7.63 (d, J ) 8.8 Hz,
2H), 7.41 (AB, s, 2H), 6.96 (d, J ) 8.8 Hz, 2H), 4.00 (t, J ) 6.6
Hz, 2H), 2.99 (t, J ) 7.4 Hz, 2H), 2.70 (t, J ) 7.4 Hz, 2H), 1.79
(qn, J ) 6.6 Hz, 2H), 1.45 (m, 2H), 1.33 (m, 4H), 0.89 (t, J )
6.6 Hz, 3H). 13C NMR (CDCl3): δ ) 188.5, 176.9, 161.0, 144.1,
137.8, 135.5, 134.0, 133.1, 131.1, 127.9, 126.7, 126.3, 123.9,
115.1, 68.3, 35.0, 31.5, 29.9, 29.1, 25.6, 22.6, 14.0.+LSIMS
(mNBA) m/z (%): 411.1 (65), 289 (100). -LSIMS: 409.1 (100).
HRMS (+LSIMS) Calculated for C24H27O4S+: 411.1630, found
411.1639.
1,2-Bis[2-(4-h exyloxyp h en ylm et h ylen e)b en zo[b]t h io-
p h en e-3-(2H)-on e-5-yleth a n oyl]p h osp h a tid ylch olin e (1a )
was prepared by procedure VI, from 2a (119 mg, 0.290 mmol)
as a yellow solid (61 mg, 0.059 mmol, 85%), with a complex
1
melting behavior. [R]D ) +16.6° cm2 g-1 (c 0.046, CHCl3). H
NMR (CDCl3): δ ) 7.77 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.63
(s, 1H), 7.56 (d, J ) 3.6 Hz, 2H), 7.54 (d, J ) 2.8 Hz, 2H), 7.33
(m, AB, 2H), 7.31 (br s, AB, 2H), 6.91 (d, J ) 3.6 Hz, 2H), 6.89
(d, J ) 2.8 Hz, 2H), 5.19 (m, 1H), 4.36 (m, 3H), 4.11 (dd, J )
12.1, 7.0 Hz, 1H), 3.96 (m, 6H), 3.86 (m, 2H), 3.38 (s, 9H), 2.86
(m, 4H), 2.61 (t, J ) 7.8 Hz, 2H), 2.54 (t, J ) 7.4 Hz, 2H), 1.75
(m, 4H), 1.41 (m, 4H), 1.32 (m, 8H), 0.89 (m, 6H). 13C NMR
(CDCl3): δ )188.2, 172.2, 171.9, 160.8, 143.7, 138.01, 137.97,
135.5, 135.4, 133.55, 133.51, 132.9, 130.9, 130.7, 127.8, 127.7,
126.6, 126.5, 126.0, 123.0, 114.9, 70.7 (d, J ) 6.1 Hz), 68.1,
66.2 (d, J ) 4.8 Hz), 63.5, 63.1, 59.5, 54.3, 35.1, 34.5, 31.5,
29.8, 29.1, 25.6, 22.6, 14.0. 31P NMR (CDCl3): δ ) -0.8.
+LSIMS (mNBA) m/z (%): 1042.4 (100). -LSIMS: 1041.3
2-(4-Octyloxyph en ylm eth ylen e)-5-(2-car boxyeth yl)ben -
zo[b]th iop h en -3(2H)-on e (2b) was prepared by procedure
V, from 22c (55 mg, 0.13 mmol) and tetrafluorophthalic acid
(32 mg, 0.13 mmol, 1 equiv) heated at 180 °C for 5 days. The
product was a yellow solid (40 mg, 9.3 × 10-2 mmol, 71%),
(100). HRMS (+LSIMS) Calculated for
1042.3999, found 1042.3993.
C
56H69NO12S2P+:
1
with a complex melting behavior. H NMR (CDCl3): δ ) 7.91
(s, 1H), 7.76 (s, 1H), 7.62 (d, J ) 8.8 Hz, 2H), 7.40 (AB, s, 2H),
6.95 (d, J ) 8.8 Hz, 2H), 3.99 (t, J ) 6.6 Hz, 2H), 2.97 (t, J )
7.4 Hz, 2H), 2.70 (t, J ) 7.4 Hz, 2H), 1.78 (qn, J ) 6.6 Hz,
2H), 1.44 (m, 2H), 1.28 (m, 8H), 0.87 (t, J ) 6.6 Hz, 2H). 13C
NMR (CDCl3): δ ) 188.5, 177.9, 161.0, 144.1, 137.9, 135.5,
134.0, 133.1, 127.9, 126.7, 126.3, 123.9, 115.1, 68.3, 35.2, 31.8,
29.9, 29.3, 29.2, 29.1, 26.0, 22.6, 14.1. +LSIMS (mNBA) m/z
(%): 439 (100). Anal. Calcd for C26H30O4S: (%): C, 71.20; H,
6.89; O, 14.59, S, 7.31. Found C, 70.97; H, 7.09; O, 12.73; S,
8.08.
2-(3-H exyloxyp h en ylm et h ylen e)-5-(2-ca r b oxyet h yl)-
ben zo[b]th iop h en -3(2H)-on e (2c) was prepared by proce-
dure V, from 22d (105 mg, 0.263 mmol) and tetrafluorophthalic
acid (66 mg, 0.263 mmol, 1 equiv) heated at 160 °C for 3 days.
The product was a yellow solid (95 mg, 0.232 mmol, 88%),
mp ) 116-117 °C. 1H NMR (CDCl3): δ ) 7.90 (s, 1H), 7.77 (s,
1H), 7.47, 7.38 (AB, J ) 8.5 Hz, 2H), 7.33 (t, J ) 8.1 Hz, 1H),
7.26 (d, J ) 8.1 Hz, 1H), 7.20 (s, 1H), 6.95 (d, J ) 8.1 Hz, 2H),
4.00 (t, J ) 6.6 Hz, 2H), 3.00 (t, J ) 7.4 Hz, 2H), 2.71 (t, J )
7.4 Hz, 2H), 1.80 (qn, J ) 6.6 Hz, 2H), 1.47 (m, 2H), 1.35 (m,
4H), 0.91 (t, J ) 6.6 Hz, 3H). 13C NMR (CDCl3): δ ) 188.6,
178.0, 159.5, 144.2, 138.0, 135.9, 135.4, 133.9, 130.7, 129.9,
126.5, 123.9, 123.5, 117.0, 116.1, 68.2, 35.1, 31.6, 29.8, 29.1,
25.7, 22.6, 14.0. +LSIMS (mNBA) m/z (%): 411 (100). Anal.
Calcd for C24H26O4S: (%): C, 70.22; H, 6.38. Found C, 70.10;
H, 6.46.
1,2-Bis[2-(3-h exyloxyp h en ylm et h ylen e)b en zo[b]t h io-
p h en e-3-(2H)-on e-5-yleth a n oyl]p h osp h a tid ylch olin e (1b)
was prepared by procedure VI, from 2c (70 mg, 0.171 mmol),
as a yellow solid (41 mg, 0.039 mmol, 91%), with complex
melting behavior. [R]D ) +7.0°cm2 g-1 (c 0.028, CHCl3). 1H
NMR (CDCl3): δ ) 7.76 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.63
(s, 1H), 7.31 (m, 6H), 7.18 (m, 2H), 7.11 (s, 2H), 6.89 (m, 2H),
5.19 (m, 1H), 4.38 (d, J ) 12.0 Hz, 1H), 4.31 (m, 2H), 4.11 (dd,
J ) 12.0, 7.1 Hz, 1H), 3.95 (m, 6H), 3.81 (m, 2H), 2.91 (s, 9H),
2.87 (m, 4H), 2.61 (t, J ) 7.3 Hz, 2H), 2.54 (t, J ) 7.6 Hz, 2H),
1.76 (m, 4H), 1.44 (m, 4H), 1.33 (m, 8H), 0.87 (m, 6H). 13C NMR
(CDCl3): δ ) 188.0, 171.8, 171.5, 159.1, 143.6, 137.89, 137.86,
135.6, 135.5, 135.00, 134.96, 133.24, 133.21, 130.29, 130.25,
130.18, 129.5, 125.9, 123.5, 123.1, 116.6, 115.7, 70.6 (d, J )
6.1 Hz), 67.7, 66.1 (d, J ) 6.1 Hz), 62.9, 59.0, 54.1, 34.8, 34.6,
31.2, 29.5, 28.8, 25.4, 25.3, 22.2, 13.7. 31P NMR (CDCl3): δ )
1.3. +LSIMS (mNBA) m/z (%): 2084.6 (5), 1042.3 (100). HRMS
(+LSIMS) Calculated for C56H69NO12S2P+: 1042.3999, found
1042.3993.
1,2-Bis[2-(4-h exyloxyp h en ylm et h ylen e)b en zo[b]t h io-
p h en e-3-(2H)-on e-6-yleth a n oyl]p h osp h a tid ylch olin e (1c)
was prepared by procedure VI, from 2d (114 mg, 0.278 mmol),
as a yellow solid (64 mg, 0.061 mmol, 87%), with complex
melting behavior. [R]D ) +7.3° cm2 g-1 (c 0.023, CHCl3). 1H
NMR (CDCl3): δ ) 7.722 (s, 1H), 7.715 (s, 1H), 7.69 (m, 2H),
7.48 (m, 4H), 7.21 (s, 1H), 7.17 (s, 1H), 7.02 (d, J ) 8.1 Hz,

Photoswitchable Hemithioindigo Lipids
J . Org. Chem., Vol. 66, No. 9, 2001 2977
1H), 6.96 (d, J ) 8.1 Hz, 1H), 6.85 (m, 4H), 5.16 (m, 1H), 4.36
(d, J ) 9.8 Hz, 2H), 4.24 (m, 2H), 4.08 (m, 3H), 3.88 (q, J )
6.6 Hz, 4H), 3.75 (m, 2H), 3.31 (s, 9H), 2.85 (m, 4H), 2.60 (m,
4H), 2.53 (t, J ) 7.6 Hz, 4H), 1.71 (m, 4H), 1.38 (m, 4H), 1.29
(m, 8H), 0.86 (t, J ) 6.6 Hz, 3H). 13C NMR (CDCl3): δ ) 187.71,
187.61, 172.0, 171.7, 160.8, 148.4, 148.3, 146.3, 146.2, 133.55,
133.47, 132.8, 129.0, 127.5, 127.4, 126.7, 126.46, 126.40, 125.8,
125.7, 123.36, 123.26, 114.9, 71.9 (d, J ) 7.4 Hz), 68.1, 66.1
(d, J ) 6.1 Hz), 63.2, 59.2 (d, J ) 4.9 Hz), 54.2, 34.7, 34.5,
31.5, 30.82, 30.76, 29.0, 25.5, 22.5, 13.9. 31P NMR (CDCl3):
δ ) 1.2. +LSIMS (mNBA) m/z (%): 2084.6 (10), 1042.3 (100).
HRMS (+LSIMS) Calculated for C56H69NO12S2P+: 1042.3999,
found 1042.4005.
(9), 276 (23), 248 (100). Anal. Calcd for C13H13O2NS (%): C,
63.14; H, 5.30; N, 5.67. Found C, 62.85; H, 5.21; N, 5.81.
2-Ca r boxy- 3-cya n eth yl-2H,3H-ben zo[b]th iop h en e (24)
was prepared from 22 (0.120 g, 0.486 mmol) and NaOH (0.1
g, excess) in 15 mL of MeOH. The mixture was refluxed for 3
h, cooled, acdified, extracted with CH2Cl2 (25 mL × 2), dried,
and concentrated to give a white solid (0.080 g, 0.365 mmol,
75%), mp ) 142-144 °C. 1H NMR 300 MHz (CDCl3): δ ) 9.14
(br s, 1H), 7.20 (m, 4H), 4.15 (d, J ) 2.9 Hz, 1H), 4.09 (dt, J )
6.6, 3.7 Hz, 1H), 2.72 (t, J ) 6.6 Hz, 2H). 13C NMR (CDCl3):
δ ) 175.9, 138.1, 137.7, 129.4, 125.7, 124.7, 122.4, 117.2, 52.8,
46.1, 21.8. +LSIMS (mNBA) m/z (%): 220 (36), 219 (97), 147
(100). Anal. Calcd for C8H11O2NS: (%): C, 59.71; H, 5.02; N,
6.33. Found C 59.92; H 5.00; N 6.48.
P h otoch em ica l Exp er im en ts. Photoisomerization reac-
tions were conducted using a super high pressure mercury
lamp (Ushio Inc.) installed in an illuminator (Oriel Corp.)
equipped with a shutter control for timing, and a variable
wavelength monchromator (PTI). Irradiations were conducted
in quartz cells (1 cm path length) held approximately 3 cm
from the exit slit of the monochromator. Typically, irradiation
times of 10 min of less were sufficient to establish the
photostationary states. Analysis of the photoproducts by HPLC
was done on a C18 reverse-phase column with 96:2:2 aceto-
nitrile:methanol:water as isocratic eluent. The mixtures were
quantified at the wavelength of the isosbestic points deter-
mined for the compounds (typically about 465 nm).
1,2-Bis[2-(4-h exyloxyp h en ylm et h ylen e)b en zo[b]t h io-
p h en e-3-(2H)-on e-4-yleth a n oyl]p h osp h a tid ylch olin e (1d )
was prepared by procedure VI, from 2e (124 mg, 0.302 mmol),
as a yellow solid (73 mg, 0.070 mmol, 92%), with a complex
melting behavior. [R]D ) +25.8° cm2 g-1 (c 0.0433, CHCl3). 1H
NMR (CDCl3): δ ) 7.65 (s, 1H), 7.61 (s, 1H), 7.48 (m, 4H),
7.24 (m, 4H), 6.97 (m, 2H), 6.85 (m, 4H), 5.22 (m, 1H), 4.33
(m, 3H), 4.12 (dd, J ) 12.0, 7.1 Hz, 1H), 3.91 (m, 6H), 3.83 (m,
2H), 3.37 (s, 9H), 3.30 (m, 4H), 2.61 (m, 4H), 1.73 (m, 4H),
1.41 (m, 4H), 1.31 (m, 8H), 0.87 (m, 6H). 13C NMR (CDCl3):
δ ) 188.7, 172.6, 172.3, 160.6, 147.0, 143.9, 143.8, 134.2, 133.0,
132.8, 127.4, 127.32, 127.28, 127.22, 127.17, 126.73, 126.67,
122.2, 114.9, 70.8 (d, J ) 7.3 Hz), 68.1, 66.3 (d, J ) 6.1 Hz),
63.3, 63.0, 59.3, 54.4, 34.4, 34.3, 31.5, 29.1, 27.4, 25.6, 22.6,
14.0. 31P NMR (CDCl3): δ ) -0.8. +LSIMS (mNBA) m/z (%):
2084.6 (15), 1042.3 (100). HRMS (+LSIMS) Calculated for
56H69NO12S2P+: 1042.3999, found 1042.3999.
Ack n ow led gm en t. Support of the Natural Sciences
and Engineering Research Council and of the University
of Victoria is gratefully acknowledged.
C
2-(Ca r boxyeth yl)-3-(cya n oeth yl)-2H,3H-ben zo[b]th io-
p h en e (23) was prepared by procedure III, from 5c (9.56 g,
34.8 mmol) and acrylonitrile (2.76 g, 52.2 mmol, 1.5 equiv).
The crude product was fractionated by chromatography (silica,
100 g, 2:1 ether:hexanes), followed by centrifugal chromatog-
raphy (1:3 ether:hexanes), yielding 3.27 g of product (13.2
mmol, 38%). 1H NMR(CDCl3): δ ) 7.18 (m, 4H), 4.19 (m, 4H),
7.76 (t, J ) 6.6 Hz, 2H), 1.27(d, J ) 8.8 Hz, 3H). 13C NMR
MHz (CDCl3): δ ) 170.4, 138.28, 138.24, 129.2, 125.5, 124.6,
122.3, 117.4, 62.2, 53.1, 46.2, 21.7, 14.0. CI MS m/z (%): 288
Su p p or tin g In for m a tion Ava ila ble: Tables of 1H and 13C
NMR chemical shifts of the hemithioindigo core of compounds
1
prepared, and H and 13C NMR spectra for compounds 1a -d ,
2a ,e, 8, 17, 19a , 20a , and 22a ,b,f. This material is available
free of charge via Internet at http://pubs.acs.org.
J O0056848