Improved synthesis of indolyl fulgides

Full text of DOI:10.1021/jo005722n

1914
J . Org. Chem. 2001, 66, 1914-1918
Sch em e 1. P h otoch r om ism of a n In d olyl F u lgid e
Im p r oved Syn th esis of In d olyl F u lgid es
Craig J . Thomas, Mason A. Wolak, Robert R. Birge, and
Watson J . Lees*
Department of Chemistry and W. M. Keck Center for
Molecular Electronics, Syracuse University,
Syracuse, New York 13244-4100
wjlees@syr.edu
Sch em e 2. F ir st Stobbe Con d en sa tion
Received November 6, 2000
In tr od u ction
Manipulation of the structure of photochromic mol-
ecules to control their optical properties is central to the
development of advanced materials.1,2 Photochromic or-
ganic compounds undergo reversible structural changes
upon illumination and currently find commercial success
as dyes and inks and in ophthalmic lenses. One impor-
tant potential application is utility as the photoactive
medium in an erasable rewriteable optical memory. In
the past decade, many dramatic strides in the engineer-
ing of such a device have been taken.3 A significant
hurdle that remains is the lack of a robust and efficient
photochromic medium. Requirements for a photochromic
molecule to be used for such a purpose include photo-
chemical but not thermal reversibility of the photoreac-
tion, ultrafast reaction rates, nondestructive readout, and
suitable quantum yields. Further, for long-term data
storage the material must have high photochemical and
thermal stability. Finally, the wavelength maxima must
match a commercially available light source and produc-
tion of large amounts of material must be uncomplicated
and cost-effective.
spectrum relative to other heteroaromatic fulgides.5
Yokoyama et al. recently reported that the trifluoro-
methyl derivative of an indolyl-based fulgide, 6 (R ) CF3),
possessed the most promising combination of photochro-
mic properties recorded to date.6 Among these properties
were a large increase in photochemical stability relative
to the methyl derivative (R ) CH3) and a red shift of the
absorption maximum which places the absorbance of the
E form further into the visible region (426 nm) than any
other fulgide. While the discovery of this robust fulgide
was of great importance, a simple and efficient method
to produce it in large quantity was not available. Limited
availability of 6 hinders photochemical characterization,
eliminates it as a viable candidate for optical memory,
and severely restricts the number of derivatives synthe-
sizable directly from the fulgide. Difficulties in the
synthesis of all fulgides, especially the most promising
indolyl fulgides, have plagued their realization as useful
and practical media for all manner of applications.
Herein, we describe an improved synthetic route to
Yokoyama’s indolyl fulgide, including modification of
reported techniques and development of new methodol-
ogy, which increases the overall synthetic yield. Ad-
ditionally, we have synthesized a number of novel
fulgides to explore structure-activity relationships.
Fulgides have been identified as viable photochromic
substances for a broad range of applications, including
optical memory, due to the thermal stability of both forms
of the molecule (Scheme 1).2,4 Indolyl fulgides are of
particular interest due to their enhanced photochemical
and thermal stability and the shift of their E form
wavelength maxima into the near visible region of the
(1) (a) Photochromism: Molecules and Systems; Durr, H., Bouas-
Laurent, H., Eds.; Elsevier: Amsterdam, 1990. (b) Organic Photochro-
mic and Thermochromic Compounds: Main Photochromic Families;
Crano, J . C., Guglielmetti, R. J ., Eds.; Plenum: New York, 1999; Vol.
1. (c) Organic Photochromic and Thermochromic Compounds: Phys-
icochemical Studies, Biological Application, and Thermochromisms;
Crano, J . C., Guglielmetti, R. J ., Eds.; Plenum: New York, 1999; Vol.
2. (d) Applied Photochromic Polymer Systems; McArdle, C. B., Ed.;
Blackie and Son Ltd.: Glasgow, U.K., 1991. (e) Berkovic, G.; Krongauz,
V.; Weiss, V. Chem. Rev. 2000, 100, 1741. (f) Delaire, J . A.; Nakatani,
K. Chem. Rev. 2000, 100, 1817. (g) Feringa, B. L.; van Delden, R. A.;
Koumura, N.; Geertsema, E. M. Chem. Rev. 2000, 100, 1789. (h)
Hampp, N. Chem. Rev. 2000, 100, 1755. (i) Ichimura, K. Chem. Rev.
2000, 100, 1847. (j) Irie, M. Chem. Rev. 2000, 100, 1683. (k) Irie, M.
Chem. Rev. 2000, 100, 1685. (l) Kawata, S.; Kawata, Y. Chem. Rev.
2000, 100, 1777. (m) Tamai, N.; Miyasaka, H. Chem. Rev. 2000, 100,
1875. (n) Feringa, B. L.; J ager, W. F.; Delange, B. Tetrahedron 1993,
49, 8267.
Resu lts a n d Discu ssion
The most versatile synthetic route to the fulgides
employs two Stobbe condensation reactions.7 The syn-
thetic strategies herein are based upon this sequence
employing modifications and new methods. The first
Stobbe condensation involves the reaction of diethyl
succinate with either acetone or adamantanone to form
isopropylidene (IPP, 1a ) or adamantylidene (ADD, 1b)
diethyl succinate derivatives,8 respectively (Scheme 2).
The succeeding Stobbe condensation combined either 1a
or 1b with a series of acylindoles. The acetylindole 2a
(2) Yokoyama, Y. Chem. Rev. 2000, 100, 1717.
(3) (a) Tsujioka, T.; Shimizu, Y.; Irie, M. J pn. J . Appl. Phys. 1994,
33, 1914. (b) Tsujioka, T.; Kume, M.; Irie, M. J pn. J . Appl. Phys. 1995,
34, 6439. (c) Tsujioka, T.; Kume, M.; Irie, M. J pn. J . Appl. Phys. 1996,
35, 4353.
(4) (a) Heller, H. G. Spec. Publ. - R. Soc. Chem. 1986, 60, 120. (b)
Whittal, J . In ref 1a; pp 467-492. (c) Whittal, J . In ref 1d; pp 80-120.
(d) Fan. M.-G.; Yu, L.; Zhao, W. In ref 1b; pp 141-206.
(5) Kaneko, A.; Tomoda, A.; Ishizuka, M.; Suzuki, H.; Matsushima,
R. Bull. Chem. Soc. J pn. 1988, 61, 3569.
(6) Yokoyama, Y.; Takahashi, K. Chem. Lett. 1996, 1037.
(7) (a) Stobbe, H. Ber. 1893, 26, 2312. (b) J ohnson, W. S.; Daub, G.
H. Org. React. 1951, 6, 1.
(8) Overberger, R. J . Am. Chem. Soc. 1949, 71, 3681.
10.1021/jo005722n CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/10/2001

Notes
J . Org. Chem., Vol. 66, No. 5, 2001 1915
Sch em e 3. Syn th esis of 3-Acylin d oles
Sch em e 5. Syn th esis of F u lgid es Usin g th e KOH
Meth od
Sch em e 4. Secon d Stobbe Con d en sa tion
Sch em e 6. Un w a n ted Decom p osition s of
cis-In d ole La cton es
Ta ble 1. Su m m a r y of F u lgid e Syn th esis
yield (%) of 6a -g
from lactones
In previous synthetic endeavors involving the CH3
analogue, only the trans lactone derivatives had been
carried on to the final product.11 In accordance with
previous efforts, treatment of trans indole lactones 4a -d
with aqueous ethanolic potassium hydroxide at 70 °C
opened the lactone via an elimination reaction and
afforded hydrolysis of the ethyl ester. The resulting
diacids 5a -d were dehydrated with acetic anhydride to
produce the corresponding fulgides (Scheme 5). Yields of
the combined elimination/hydrolysis of the trans indole
lactone to diacid and subsequent dehydration to fulgide
generally exceeded 70%. Under the same reaction condi-
tions for the opening of the trans isopropylidene indole
lactones 4a -d , the cis isopropylidene indole lactones 3a
and 3b decomposed to the starting acylindole or to
3-carboxyl-1,2-dimethylindole, respectively (Scheme 6).
Historically, the decomposition of the cis indole lactone
derivatives and low overall yields of fulgide were common
difficulties. For the fluorinated analogues, the cis indole
lactone comprised at least 75% of the product formed,
making these difficulties unmanageable. Additionally,
the ratio of cis to trans indole lactone for the adaman-
tylidene derivatives proved to be so great that it was not
feasible to isolate the trans derivatives. The cis adaman-
tylidene indole lactones were found to open to diacid via
the aqueous ethanolic potassium hydroxide method;
however, yields were consistently low. While production
of fulgide from the trans indole lactones occurred in
equivalent or better yields than previous reports, the
need for chemistry to make use of the cis isomer of the
lactones was imperative.
KOH
cis/trans method NaH + KOH % yield
compd
R
R′
ratio 3:4
only
methods
ratio
a
b
c
d
e
f
CH3 IPP
CF3 IPP
C2F5 IPP
C3F7 IPP
CF3 ADD
C2F5 ADD
C3F7 ADD
1:2
4:1
3:1
18.2a
15.0a
19.7a
14.6a
12.5d,e
42.7b
81.4c
63.0c
44.5c
56d
2.3
5.4
3.2
3
4.5
NA
NA
4:1
>10:1
>10:1
>10:1
NA
NA
28d
g
34d
a
After precipitating out the cis lactone, the resulting mixture
of cis and trans lactones was converted to fulgide with the KOH
method. Treatment of the initial mixture of lactones with ethanolic
b
KOH resulted in lower overall yields. The mixture of cis and
trans lactones was converted to fulgide with the NaH method.c A
combined yield from using the NaH and KOH methods on the cis
d
and trans lactones, respectively. Only the cis isomer was isolated
from the condensation reaction. e The cis lactone was converted
to fulgide with the KOH method.
was synthesized by refluxing 1,2-dimethylindole in neat
acetic anhydride (Scheme 3).9 The fluorinated acylindoles
2b-d were synthesized by quantitative acylation of 1,2-
dimethylindole with the corresponding perfluorinated
anhydride in 1,2-dichloroethane at 0 °C,10 an improve-
ment upon previous fulgide syntheses which used the
mixed anhydride of trifluoroacetic acid and trifluoro-
methanesulfonic acid.6 The second Stobbe condensation
was accomplished by enolization of the succinate deriva-
tives 1a and 1b and subsequent coupling with acylindoles
2a -d (Scheme 4).11 This reaction afforded a mixture of
the cis (3a -g) and trans (4a -g) indole lactone interme-
diates. The cis to trans ratios varied from 1:2 to greater
than 10:1 depending on the substrate (Table 1) as
determined by NMR spectroscopy.
Treatment of the cis indole lactones 3a -g with sodium
hydride in DMF at 0 °C followed by the addition of at
least 2 equiv of water resulted in the elimination of the
lactone and hydrolysis of the ethyl ester (Scheme 7). The
diacids 5a -g were then dehydrated as previously men-
tioned to form the fulgide. The ability to carry the cis as
(9) Borsche, W.; Groth, H. Ann. 1941, 549, 238.
(10) Cipiciani, A.; Clementi, S.; Giulietti, G.; Marino, G.; Savelli,
G.; Linda, P. J . Chem. Soc. Perkin Trans. 2 1982, 523.
(11) J anicki, S. Z; Schuster, G. B. J . Am. Chem. Soc. 1995, 117, 8524.

1916 J . Org. Chem., Vol. 66, No. 5, 2001
Notes
(39.6 g, 75%) as a clear colorless oil: 1H NMR (CDCl3) δ 4.07 (q,
J HH ) 7.1 Hz, 2H), 4.06 (q, J HH ) 7.1 Hz, 2H), 3.28 (s, 2H), 2.06
Sch em e 7. Syn th esis of F u lgid es Usin g th e Na H
Meth od
(s, 3H), 1.78 (s, 3H), 1.17 (t, J HH ) 7.1 Hz, 3H), 1.16 (t, J HH
)
7.1 Hz, 3H); 13C NMR (CDCl3) δ 171.2, 167.6, 148.6, 120.7, 60.4,
60.0, 35.3, 23.0, 14.0. Anal. Calcd for C11H18O4: C, 61.66; H, 8.47.
Found: C, 61.39; H, 8.66.
Ad a m a n tylid en e Dieth yl Su ccin a te (1b).8 Synthesis was
accomplished in a manner similar to that for 1a (54% yield): 1H
NMR (CDCl3) δ 4.13 (q, J HH ) 7.1 Hz, 2H), 4.08 (q, J HH ) 7.1
Hz, 2H), 3.63 (s, 1H), 3.31 (s, 2H), 2.78 (s, 1H), 1.98-1.75 (m,
12H), 1.23 (t, J HH ) 7.1 Hz, 3H), 1.21 (t, J HH ) 7.1 Hz, 3H); 13
C
NMR (CDCl3) δ 171.5, 168.6, 162.4, 114.3, 60.5, 60.1, 39.1, 38.9,
36.6, 35.0, 34.6, 34.5, 27.5, 14.2, 14.1.
Gen er a l P r ep a r a tion of Acylin d oles 2b-d .10 To a stirred
solution of fluorinated anhydride at 0 °C was added over 30 min
a solution of 1 equiv of 1,2-dimethylindole dissolved in dichloro-
ethane. After 2 h at room temperature, the now purple reaction
mixture was quenched with saturated aqueous NaHCO3 and
extracted with CH2Cl2 (3×). The combined organic layers were
dried (MgSO4) and filtered. The solvent was removed in vacuo
to afford the acylindole as a pale yellow solid.
well as the trans lactone on to fulgide improved the
overall yield of the initial CF3 isopropylidene fulgide 6b
to 29% from 1,2-dimethylindole. The previously reported
yield was 1.3%.6 Table 1 summarizes the yield enhance-
ments achieved by incorporation of this new methodology.
Use of aqueous sodium hydroxide with DMF as the
solvent in place of sodium hydride followed by water
produced similar results with slightly lower yields.
Replacing DMF with DMSO or acetonitrile achieved
elimination of the lactone but did not efficiently hydrolyze
the ester. The same reaction protocols gave little or no
reaction in THF or toluene. LDA and n-butyllithium in
THF or toluene provided no product.
In conclusion, we have developed a method to enhance
the overall synthetic yields of fulgides and demonstrated
that the procedure has broad applicability. The method
has been shown to improve the yields of both fluorinated
and nonfluorinated indole fulgide derivatives. It is ex-
pected that the scope of this reaction will include most,
if not all, cis lactone derivatives. The new methodology
will provide for the production of large quantities of
numerous derivatives of fluorinated and nonfluorinated
indolyl fulgides, including the robust trifluoromethyl
derivative. These advances will afford the materials
necessary to thoroughly study the photochromic proper-
ties of the fulgides, in turn making major progress toward
new and exciting applications.
1,2-Dim eth yl-3-tr iflu or oa cetylin d ole (2b):10 96% yield; 1H
NMR (CDCl3) δ 8.08-8.02 (m, 1H), 7.33-7.21 (m, 3H), 3.57 (s,
3H), 2.66 (s, 3H); 19F NMR (CDCl3) δ -74.5 (s); 13C NMR (CDCl3)
δ 174.8 (q, J CCF ) 36 Hz), 150.1, 136.8, 125.1, 123.1, 123.0, 120.6
(q, J CCCF ) 4 Hz), 117.3 (q, J CF ) 290 Hz), 109.8, 107.7, 29.7,
12.9. Anal. Calcd for C12H10F3NO: C, 59.75; H, 4.18; F, 23.63;
N, 5.81. Found: C, 59.59; H, 3.88; F, 23.32; N, 5.65.
1,2-Dim et h yl-3-p en t a flu or op r op ion ylin d ole (2c): 95%
yield; 1H NMR (CDCl3) δ 8.10-8.02 (m, 1H), 7.33-7.19 (m, 3H),
3.57 (s, 3H), 2.62 (s, 3H); 19F NMR (CDCl3) δ -82.8 (s), -118.8
(s); 13C NMR (CDCl3) δ 178.2 (t, J CCF ) 28 Hz), 150.2, 136.7,
125.0, 123.2, 123.1, 121.1 (t, J CCCF ) 7 Hz), 118.8 (qt, J CF ) 286
Hz, J CCF ) 35 Hz), 109.7, 108.7 (tq, J CF ) 270 Hz, J CCF ) 35
Hz), 108.4, 29.6, 13.0. Anal. Calcd for C13H10F5NO: C, 53.62;
H, 3.46; F, 32.62; N, 4.81. Found: C, 53.76; H, 3.28; F, 32.48; N,
4.76.
1,2-Dim eth yl-3-h ep ta flu or obu tyr ylin d ole (2d ): 93% yield;
1H NMR (CDCl3) δ 8.07-8.01 (m, 1H) 7.34-7.18 (m, 3H) 3.53
(s, 3H) 2.61 (s, 3H); 19F NMR (CDCl3) δ -80.1 (s), -116.0 (s),
-125.5 (s); 13C NMR (CDCl3) δ 178.6 (t, J CCF ) 28 Hz), 150.1,
136.7, 125.0, 123.1, 123.0, 121.0 (t, J CCCF ) 7 Hz), 118.1 (qt, J CF
) 288 Hz, J CCF ) 34 Hz), 109.7, 109.5 (t of sextet, J CF ) 254 Hz,
J CCF ) 33 Hz), 109.4, 109.3 (tt, J CF ) 260 Hz, J CCF ) 34 Hz),
29.6, 12.9. Anal. Calcd for C14H10F7NO: C, 49.28; H, 2.95; F,
38.97; N, 4.10. Found: C, 49.50; H, 3.02; F, 38.94; N, 4.11.
Gen er a l P r ep a r a tion of In d ole La cton es (3a -d /4a -g).11
To a stirred solution of either isopropylidene or adamantylidene
diethyl succinate in toluene at -78 °C was added 1.1 equiv of a
2.0 M solution of lithium diisopropylamide in toluene. The
resulting mixture was allowed to warm to 0 °C and then recooled
to -78 °C. The appropriate acylindole (1.0 equiv) was added,
and the mixture was allowed to warm to room temperature.
After 24 h, the reaction was quenched with a 10% H2SO4 solution
and extracted with ethyl acetate (3 × 40 mL). The combined
organic layers were dried (MgSO4) and filtered, and solvent was
removed in vacuo. Purification was accomplished via flash
chromatography (2:1 hexane/ethyl acetate or 1:1 hexane/ethyl
ether) and multiple crystallizations from ethanol to yield pure
cis indole lactone (3a -g) as a mixture of atropisomers. The trans
indole lactone (4a -d ) was isolated via supplementary flash
chromatography (CH2Cl2) as an oil, often containing a small
portion of the cis isomer. Note: the trans indole lactone was only
collected for the isopropylidene derivatives (3a -d ).
CF 3 isop r op ylid en e in d ole la cton e (3b/4b): 36% yield (80%
cis (3b), 20% trans (4b)). 4b (determined from mixture): 1H
NMR (CDCl3) δ 8.00 (d, J HH ) 8.3 Hz, 1H), 7.33-7.02 (m, 3H),
4.89 (s, 1H), 4.42-4.25 (m, 2H), 3.66 (s, 3H), 2.61 (s, 3H), 2.24
(s, 3H), 1.73 (s, 3H), 1.37 (t, J HH ) 7.0 Hz, 3H); 19F NMR (CDCl3)
δ -75.3 (s). 3b: 1H NMR (CDCl3) δ 8.27 (d, J HH ) 7.4 Hz, 0.3H),
7.60 (d, J HH ) 7.4 Hz, 0.7H), 7.22-7.04 (m, 3H), 4.81 (s, 0.7H),
4.62 (s, 0.3H), 3.75-3.68 (m, 1.4H), 3.58 (s, 2.1H), 3.54 (s, 0.9H),
3.52-3.43 (m, 0.6H), 2.65 (s, 2.1H), 2.42 (s, 0.9H), 2.33 (s, 3H),
2.07 (s, 2.1H), 2.02 (s, 0.9H), 0.59 (t, J HH ) 7.1 Hz, 2.1H), 0.35
(t, J HH ) 7.1 Hz, 0.9H); 19F NMR (CDCl3) δ -79.7 (s); 13C NMR
(CDCl3) δ 168.1, 167.9, 166.7, 166.6, 154.5, 153.8, 137.5, 136.7,
136.5, 133.7, 127.1, 125.0 (q, J CF ) 288 Hz), 124.2, 121.9, 121.5,
Exp er im en ta l Section
Gen er a l P r oced u r es a n d Ma ter ia ls. All commercially
available materials were used without further purification. NMR
spectra were recorded on a Bruker 300 MHz NMR spectrometer.
1H and 13C NMR samples were internally referenced to TMS
(0.00 ppm). 19F NMR samples were externally referenced to
fluorotrichloromethane (0.00 ppm). Flash chromatography was
performed with 230-400 mesh silica gel. E&R Microanalytical
Laboratory Inc. (Parsippany. NJ ) performed all elemental
analyses. Synthesis of 2a , 3a /4a , and 6a was accomplished in
accordance with previous reports.9,11
Isop r op ylid en e Dieth yl Su ccin a te (1a ).8 To a solution of
potassium tert-butoxide in tert-butyl alcohol (250 mL, 1.0 M) was
added diethyl succinate (43.0 g, 0.247 mol). After 5 min, acetone
(14.2 g, 0.245 mol) was added and the solution refluxed for 24
h. The reaction was then quenched with aqueous HCl (50 mL,
50% solution) and extracted with diethyl ether (2 × 100 mL).
The combined organic layers were dried (MgSO4) and filtered,
and solvent was removed in vacuo. The resulting brown syrup
was dissolved in ethanol (1 L) and acidified with conc HCl (20
mL). After 48 h the reaction mixture was quenched with
saturated aqueous NaHCO3 (100 mL) and extracted with diethyl
ether (3 × 200 mL). The combined organic layers were dried
(MgSO4) and filtered, and solvent was removed in vacuo.
Vacuum distillation afforded isopropylidene diethyl succinate

Notes
J . Org. Chem., Vol. 66, No. 5, 2001 1917
121.1, 120.4 (q, J CCCF ) 3 Hz), 120.2, 119.2, 118.5, 118.4, 108.9,
108.5, 103.2, 102.0, 83.3 (q, J CCF ) 30 Hz), 82.7 (q, J CCF ) 30
Hz), 61.2, 61.0, 58.1, 53.0, 51.8, 29.3, 29.2, 24.1, 20.4, 20.2, 12.9,
12.7, 11.9. Anal. Calcd for C21H22F3NO4: C, 61.61; H, 5.42; F,
13.92; N, 3.42. Found: C, 61.79; H, 5.73; F, 13.75; N, 3.41.
C2F 5 isop r op ylid en e in d ole la cton e (3c/4c): 21% yield
(76% cis (3c), 26% trans (4c)). 4c (determined from mixture):
1H NMR (CDCl3) δ 7.98-7.88 (m, 1H), 7.28-7.00 (m, 3H), 4.91
(s, 1H), 4.40 (q, J HH ) 7.0 Hz, 2H), 3.60 (s, 3H), 2.54 (s, 3H),
2.19 (s, 3H), 1.99 (s, 3H), 1.45 (t, J HH ) 7.0 Hz, 3H); 19F NMR
(CDCl3) δ -82.3 (s), -120.4 (m). 3c: 1H NMR (CDCl3) δ 8.24 (d,
J HH ) 7.8 Hz, 0.3H), 7.61 (t, J HH ) 7.8 Hz, 0.7H), 7.19-7.03 (m,
3H), 4.91 (s, 0.7H), 4.73 (s, 0.3H), 3.67-3.57 (m, 1.4H), 3.61 (s,
2.1H), 3.58 (s, 0.9H), 3.49-3.35 (m, 0.6H), 2.64 (s, 2.1H), 2.41
(d, J HH ) 2.9 Hz, 0.9H), 2.32 (s, 3H), 2.05 (s, 2.1H), 2.00 (s, 0.9H),
0.55 (t, J HH ) 7.0 Hz, 2.1H), 0.26 (t, J HH ) 7.0 Hz, 0.9H); 19F
NMR (CDCl3) δ -79.7 (s), -121.3 (m); 13C NMR (CDCl3) δ 168.1,
167.8, 166.5, 166.3, 154.0, 153.2, 137.0, 136.8, 136.4, 134.1, 126.9,
124.2, 122.1, 121.4, 121.2, 120.9, 120.7, 120.2, 119.1, 118.8, 118.7
(qt, J CF ) 289 Hz, J CCF ) 36 Hz), 118.6 (qt, J CF ) 289 Hz, J CCF
) 36 Hz), 114.2 (tq, J CF ) 266 Hz, J CCF ) 35 Hz), 114.1 (tq, J CF
) 266 Hz, J CCF ) 35 Hz), 108.7, 108.4, 103.0, 101.8, 83.5 (m),
83.0 (m), 61.2, 60.9, 53.3, 52.0, 29.4, 29.3, 24.1, 24.0, 20.4, 20.2,
13.6, 12.9, 12.5, 11.9. Anal. Calcd for C22H22F5NO4: C, 57.52;
H, 4.83; F, 20.68; N, 3.05. Found: C, 57.68; H, 4.98; F, 20.50; N,
3.03.
(m), 61.1, 60.9, 52.3, 51.0, 39.3, 39.2, 39.1, 39.0, 38.9, 37.2, 37.0,
36.3, 36.2, 31.9, 31.7, 29.5, 29.4, 27.3, 27.2, 13.7, 13.5, 13.1, 12.7,
12.0. Anal. Calcd for C29H30F5NO4: C, 63.15; H, 5.48; F, 17.22;
N, 2.54. Found: C, 62.97; H, 5.75; F, 17.51; N, 2.31.
C3F 7 a d a m a n tylid en e in d ole la cton e (3g): 24% yield (100%
cis (3g)); 1H NMR (CDCl3) δ 8.27 (d, J HH ) 7.8 Hz, 0.3H), 7.62-
7.58 (m, 0.7H), 7.26-7.01 (m, 3H), 4.96 (s, 0.7H), 4.77 (s, 0.3H),
4.34 (s, 1H), 3.63 (s, 2.1H), 3.61 (s, 0.9H), 3.60-3.50 (m, 1.4H),
3.48-3.35 (m, 0.6H), 2.97 (s, 0.7H), 2.84 (s, 0.3H), 2.66 (s, 2.1H),
2.41 (d, J HH ) 4.0 Hz, 0.9H), 2.02-1.60 (m, 12H), 0.58 (t, J HH
)
7.1 Hz, 2.1H), 0.31 (t, J HH ) 7.1 Hz, 0.9H); 19F NMR (CDCl3) δ
-122.3 (s), -176.5 (m), -187.2 (m); 13C NMR (CDCl3) δ 169.7,
169.0, 168.6, 168.5, 166.8, 166.7, 137.1, 136.7, 136.3, 134.1, 126.9,
124.3, 122.4, 121.4, 121.1, 120.9, 120.7, 120.2, 120.0, 119.0, 117.9
(qt, J CF ) 290 Hz, J CCF ) 34 Hz), 117.7 (qt, J CF ) 290 Hz, J CCF
) 34 Hz), 112.1, 111.8, 109.7 (t of sextet, J CF ) 271 Hz, J CCF
)
38 Hz), 109.6 (t of sextet, J CF ) 271 Hz, J CCF ) 38 Hz), 108.9
(tt, J CF ) 258 Hz, J CCF ) 34 Hz), 108.7 (tt, J CF ) 258 Hz, J CCF
) 34 Hz), 108.6, 108.3, 103.2, 101.9, 84.2 (m), 84.1 (m), 61.1,
60.9, 52.6, 51.3, 39.3, 39.2, 39.1, 39.0, 38.9, 37.2, 37.1, 36.3, 31.8,
31.7, 29.4, 29.3, 27.3, 27.2, 13.6, 13.5, 13.1, 12.7, 12.1, 12.0. Anal.
Calcd for C30H30F7NO4: C, 59.90; H, 5.03; F, 22.11; N, 2.33.
Found: C, 59.79; H, 4.99; F, 21.81; N, 2.26.
Gen er a l P r ep a r a t ion of F u lgid es 6a -d via KOH/H2O/
EtOH Meth od ology.11 To the cis/trans mixture of indole lactone
(3a -d /4a -d ) dissolved in ethanol was added
a saturated
C3F 7 isop r op ylid en e in d ole la cton e (3d /4d ): 10% yield
(83% cis (3d ), 17% trans (4d )). 4d (determined from mixture):
1H NMR (CDCl3) δ 7.81 (d, J HH ) 8.0 Hz, 1H), 7.32-7.01 (m,
3H), 4.91 (s, 1H), 4.42-4.27 (m, 2H), 3.64 (s, 3H), 2.63 (s, 3H),
2.31 (s, 3H), 1.84 (s, 3H), 1.34 (t, J HH ) 8.0 Hz, 3H); 19F NMR
(CDCl3) δ -80.9 (s), -113.0 (m), -124.8 (m). 3d : 1H NMR
(CDCl3) δ 8.24 (d, J HH ) 8.2 Hz, 0.3H), 7.60 (dd, J HH ) 8.2 Hz,
J HH ) 3.8 Hz, 0.7H), 7.26-7.03 (m, 3H), 4.90 (s, 0.7H), 4.71 (s,
0.3H), 3.66 (s, 2.1H), 3.62 (s, 0.9H), 3.61-3.49 (m, 1.4H), 3.48-
3.33 (m, 0.6H), 2.66 (s, 2.1H), 2.42 (d, J HH ) 4.0 Hz, 0.9H), 2.34
(s, 3H), 2.04 (s, 2.1H), 2.00 (s, 0.9H), 0.56 (t, J HH ) 7.1 Hz, 2.1H),
0.24 (t, J HH ) 7.1 Hz, 0.9H); 19F NMR (CDCl3) δ -81.3 (s), -115.0
(m), -122.5 (m); 13C NMR (CDCl3) δ 168.0, 167.7, 166.6, 166.4,
153.9, 153.2, 137.1, 136.8, 134.2, 127.0, 124.3, 122.3, 121.4, 121.1,
120.9, 120.8, 120.2, 119.2, 118.8, 118.7, 117.7 (qt, J CF ) 289 Hz,
J CCF ) 35 Hz), 117.6 (qt, J CF ) 289 Hz, J CCF ) 35 Hz), 109.1 (t
aqueous potassium hydroxide solution (4:1 ratio of ethanol to
base solution). The clear yellow solution immediately tinted
brown. After being stirred for 2 d at 70 °C, the solution was
allowed to cool to room temperature, diluted with water, and
extracted with ethyl ether (3 × 50 mL). The aqueous solution
was then acidified with a 20% H2SO4 solution and extracted with
ethyl acetate (3 × 50 mL). The combined ethyl acetate layers
were dried (MgSO4) and filtered, and solvent was removed in
vacuo producing a brown solid. The product was suspended in
toluene and allowed to stir. Acetic anhydride (2 equiv) was then
added. The solid immediately dissolved and the solution turned
dark orange. The solution was allowed to stir for at least 10 min
and then solvent was removed in vacuo. The resulting dark
slurry was purified by flash chromatography (2:1 hexane/ethyl
acetate). Fulgides 6a -d were recrystallized from 2-propanol.
Gen er a l P r ep a r a tion of F u lgid es 6a -g via Na H/DMF
Meth od ology. To a stirred solution of cis indole lactone 3a -g
dissolved in N,N-dimethylformamide at 0 °C was added sodium
hydride (at least 2 equiv). The solution was stirred and allowed
to warm to room temperature over 1 h. The mixture was recooled
to 0 °C, and 4-5 equiv of water was added to the mixture.
Hydrogen gas evolved, and the solution was allowed to warm to
room temperature and stirred overnight. The reaction was
carefully monitored by TLC to ensure complete elimination and
hydrolysis. Solvent was removed in vacuo to yield a white
powder. The product was suspended in toluene and stirred. At
least 3 equiv of acetic anhydride was then added. The solid
immediately dissolved, and the solution turned dark orange.
After the solution was stirred for 10 min, the solvent was
removed in vacuo. The resulting product was extracted from
water with dichloromethane (3 × 30 mL). The combined organic
layers were dried (MgSO4) and filtered, and solvent was removed
in vacuo. The product was purified via flash chromatography
(CH2Cl2 or 2:1 hexane/ethyl acetate). Crystallization of the
fulgides was accomplished using 2-propanol for isopropylidene
fulgides 6a -d and toluene/ligroin for adamantylidene fulgides
6e-g.
of sextet, J CF ) 231 Hz, J CCF ) 37 Hz), 108.9 (t of sextet, J CF
)
231 Hz, J CCF ) 37 Hz), 108.7, 108.4, 108.3 (tt, J CF ) 243 Hz,
J CCF ) 36 Hz), 108.1 (tt, J CF ) 243 Hz, J CCF ) 36 Hz), 103.0,
101.6, 84.2 (m), 84.1 (m), 61.2, 60.9, 53.6, 52.3, 29.3, 29.2, 24.0,
20.3, 20.1, 13.6, 13.4, 12.9, 12.4, 12.0. Anal. Calcd for C23H22F7-
NO4: C, 54.23; H, 4.35; F, 26.11; N, 2.75. Found: C, 54.65; H,
3.99; F, 26.33; N, 2.71.
CF 3 a d a m a n tylid en e in d ole la cton e (3e): 45% yield (100%
1
cis (3e)); H NMR (CDCl3) δ 8.27 (d, J HH ) 7.6 Hz, 0.3H), 7.55
(d, J HH ) 7.8 Hz, 0.7H), 7.24-7.02 (m, 3H), 4.81 (s, 0.7H), 4.61
(s, 0.3H), 4.34 (s, 1H), 3.73-3.66 (m, 1.4H), 3.65 (s, 2.1H), 3.62
(s, 0.9H), 3.60-3.47 (m, 0.6H), 3.01 (s, 0.7H), 2.86 (s, 0.3H), 2.67
(s, 2.1H), 2.42 (s, 0.9H), 2.07-1.83 (m, 12H), 0.64 (t, J HH ) 7.1
Hz, 2.1H), 0.41 (t, J HH ) 7.1 Hz, 0.9H); 19F NMR (CDCl3) δ
-120.2 (s); 13C NMR (CDCl3) δ 169.9, 169.3, 168.5, 168.4, 166.9,
166. 7, 137.4, 136.6, 136.4, 133.5, 127.1, 124.9 (q, J CF ) 289 Hz),
124.2, 122.0, 121.4, 120.9, 120.3, 120.1, 119.0, 111.8, 111.7, 108.7,
108.2, 103.5, 102.2, 83.2 (q, J CCF ) 30 Hz), 82.7 (q, J CCF ) 30
Hz), 60.96, 60.88, 52.0, 50.7, 39.4, 39.2, 39.1, 39.0, 37.1, 37.0,
36.3, 31.8, 31.7, 29.3, 27.3, 27.2, 13.4, 13.1, 12.8, 11.9. Anal. Calcd
for C28H30F3NO4: C, 67.05; H, 6.03; F, 11.36; N, 2.79. Found:
C, 66.91; H, 6.25; F, 11.30; N, 2.64.
CF 3 isop r op ylid en e fu lgid e (6b):6 KOH/H2O/EtOH method,
75% yield; NaH/DMF method, 83% yield; overall, fulgide 6b from
acylindole 2b, 29% yield; 1H NMR (CDCl3) δ 7.37-7.11 (m, 4H),
3.71 (s, 3H), 2.28 (s, 3H), 2.16 (s, 3H), 0.97 (s, 3H); 19F NMR
(CDCl3) δ -58.2 (s); 13C NMR (CDCl3) δ 161.8, 160.8 159.7, 138.0,
136.9, 132.8 (q, J CCF ) 36 Hz), 127.9, 124.6, 122.4, 122.0 (q, J CF
) 278 Hz), 121.3, 119.5, 119.4, 109.6, 106.9, 31.0, 26.7, 23.2,
12.2. Anal. Calcd for C19H16F3NO3: C, 62.81; H, 4.44; F, 15.69;
N, 3.86. Found: C, 62.58; H, 4.06; F, 15.52; N, 3.77.
C2F 5 isop r op ylid en e fu lgid e (6c): KOH/H2O/EtOH method,
76% yield; NaH/DMF method, 57% yield; overall; fulgide 6c from
acylindole 2c, 13% yield; 1H NMR (CDCl3) δ 7.35-7.12 (m, 4H),
3.69 (s, 3H), 2.24 (s, 3H), 2.12 (s, 3H), 1.09 (s, 3H); 19F NMR
(CDCl3) δ -80.9 (s), -103.4 (m); 13C NMR (CDCl3) δ 161.6, 161.3,
C2F 5 a d a m a n tylid en e in d ole la cton e (3f): 29% yield (100%
cis (3f)); 1H NMR (CDCl3) δ 8.24 (d, J HH ) 7.9 Hz, 0.3H), 7.59-
7.56 (m, 0.7H), 7.26-7.01 (m, 3H), 4.93 (s, 0.7H), 4.74 (s, 0.3H),
4.32 (s, 1H), 3.73-3.49 (m, 0.6H), 3.65 (s, 2.1H), 3.62 (s, 0.9H),
3.49-3.36 (m, 1.4H), 2.97 (s, 0.7H), 2.84 (s, 0.3H), 2.65 (s, 2.1H),
2.41 (d, J HH ) 3.5 Hz, 0.9H), 2.16-1.78 (m, 12H), 0.59 (t, J HH
)
7.1 Hz, 2.1H), 0.32 (t, J HH ) 7.1 Hz, 0.9H); 19F NMR (CDCl3) δ
-119.0 (s), -184.5 (m); 13C NMR (CDCl3) δ 169.9, 169.2, 168.7,
168.6, 166.8, 166.6, 137.0, 136.7, 136.3, 134.0, 126.4, 124.3, 122.2,
121.4, 121.2, 120.8, 120.7, 120.2, 119.0, 118.7 (qt, J CF ) 289 Hz,
J CCF ) 36 Hz), 118.6 (qt, J CF ) 289 Hz, J CCF ) 36 Hz), 114.4
(tq, J CF ) 265 Hz, J CCF ) 35 Hz), 114.3 (tq, J CF ) 265 Hz, J CCF
) 35 Hz), 112.1, 111.9, 108.7, 108.3, 103.2, 102.1, 83.5 (m), 83.2

1918 J . Org. Chem., Vol. 66, No. 5, 2001
Notes
158.9, 137.4, 137.0, 132.1 (t, J CCF ) 27 Hz), 124.9, 122.2, 121.4,
120.8, 119.5, 119.6, 119.3 (qt, J CF ) 289 Hz, J CCF ) 37 Hz), 113.0
(tq, J CF ) 273 Hz, J CCF ) 38 Hz), 109.4, 107.4, 30.1, 27.2, 23.1,
11.9. Anal. Calcd for C20H16F5NO3: C, 58.12; H, 3.90; F, 22.98;
N, 3.39. Found: C, 58.09; H, 3.60; F, 23.11; N, 3.31.
(CDCl3) δ 7.33-7.13 (m, 4H), 4.04 (s, 1H), 3.68 (s, 3H), 2.37 (s,
1H), 2.26 (s, 3H), 1.89 (dq, J HH ) 12.7 Hz, J HH ) 2.6 Hz, 1H),
1.77 (dq, J HH ) 12.7 Hz, J HH ) 2.7 Hz, 1H), 1.67-1.43 (m, 6H),
1.30 (d, J HH ) 12.8 Hz, 1H), 0.89 (d, J HH ) 12.5 Hz, 2H), 0.07
(d, J HH ) 12.6, 1H); 19F NMR (CDCl3) δ -121.3 (s), -154.8 (m);
13C NMR (CDCl3) δ 177.7, 161.5, 159.1, 137.1, 136.8, 131.0 (t,
J CCF ) 26.9 Hz), 125.8, 122.1, 121.3, 119.5, 119.4, 119.3 (qt, J CF
C3F 7 isop r op ylid en e fu lgid e (6d ): KOH/H2O/EtOH method,
86% yield; NaH/DMF method, 36% yield; overall, fulgide 6d from
1
acylindole 2d , 5% yield; H NMR (CDCl3) δ 7.35 (d, J HH ) 7.7
) 289 Hz, J CCF ) 39 Hz), 119.3, 112.9 (tq, J CF ) 259 Hz, J CCF
)
Hz, 1H), 7.29 (d, J HH ) 8.0 Hz, 1H), 7.25 (td, J HH ) 7.8 Hz, J HH
) 0.9 Hz, 1H), 7.12 (dt, J HH ) 7.8 Hz, J HH ) 0.9 Hz, 1H), 3.69
(s, 3H), 2.25 (s, 3H), 2.13 (s, 3H), 1.09 (s, 3H); 19F NMR (CDCl3)
δ -81.2 (s), -100.4 (m), -121.6 (s); 13C NMR (CDCl3) δ 161.7,
161.3, 159.0, 137.4, 137.0, 132.0 (t, J CCF ) 26 Hz), 124.9, 122.2,
121.4, 120.8, 119.8, 119.7, 117.9 (qt, J CF ) 287 Hz, J CCF ) 32
Hz), 115.2 (tt, J CF ) 260 Hz, J CCF ) 32 Hz), 109.4 (t of sextet,
J CF ) 267 Hz, J CCF ) 39 Hz), 109.3, 107.5, 30.1, 27.3, 23.1, 11.9.
Anal. Calcd for C21H16F7NO3: C, 54.44; H, 3.48; F, 28.70; N, 3.02.
Found: C, 54.36; H, 3.22; F, 28.65; N, 2.98.
38 Hz), 109.4, 107.0, 40.1, 39.6, 39.2, 38.3, 37.8, 35.5, 34.0, 30.0,
26.7, 26.6, 11.9. Anal. Calcd for C27H24F5NO3: C, 64.16; H, 4.79;
F, 18.79; N, 2.77. Found: C, 63.87; H, 4.74; F, 18.48; N, 2.56.
C3F 7 a d a m a n tylid en e fu lgid e (6g): NaH/DMF method, 34%
yield; overall, fulgide 6g from acylindole 2d , 8% yield; 1H NMR
(CDCl3) δ 7.34-7.13 (m, 4H), 4.06 (s, 1H), 3.67 (s, 3H), 2.39 (s,
1H), 2.28 (s, 3H), 1.90 (dq, J HH ) 12.7 Hz, J HH ) 2.6 Hz, 1H),
1.77 (dq, J HH ) 12.6 Hz, J HH ) 2.6 Hz, 1H), 1.68-1.49 (m, 6H),
1.29 (d, J HH ) 12.9 Hz, 1H), 0.88 (d, J HH ) 12.8 Hz, 2H), 0.07
(d, J HH ) 12.8 Hz, 1H); 19F NMR (CDCl3) δ -121.9 (s), -149.9
(m), -183.9 (s); 13C NMR (CDCl3) δ 177.8, 161.5, 159.1, 137.2,
137.0, 130.9 (t, J CCF ) 27 Hz), 125.8, 122.2, 121.3, 119.5, 119.4,
CF 3 a d a m a n tylid en e fu lgid e (6e): NaH/DMF method, 56%
yield; overall, fulgide 6e from acylindole 2b, 25% yield; 1H NMR
(CDCl3) δ 7.30-7.13 (m, 4H), 4.09 (s, 1H), 3.68 (s, 3H), 2.29 (s,
3H), 2.23 (s, 1H), 1.91 (dq J HH ) 12.7 Hz, J HH ) 2.6 Hz, 1H),
1.76 (dq J HH ) 12.7 Hz, J HH ) 2.6 Hz, 1H), 1.65-1.54 (m, 5H),
1.42 (dq J HH ) 12.4 Hz, J HH ) 2.4 Hz, 1H), 1.25 (dq J HH ) 12.7
Hz, J HH ) 2.7 Hz, 1H), 1.04 (dq J HH ) 12.7 Hz, J HH ) 2.6 Hz,
119.3, 117.7 (qt, J CF ) 288 Hz, J CCF ) 34 Hz), 115.1 (tt, J CF
259 Hz, J CCF ) 33 Hz), 109.7 (t of sextet, J CF ) 266 Hz, J CCF
)
)
39 Hz), 109.4, 107.2, 40.1, 39.6, 39.2, 38.3, 37.9, 35.5, 34.1, 29.9,
26.7, 26.6, 11.9. Anal. Calcd for C28H24F7NO3: C, 60.54; H, 4.35;
F, 23.94; N, 2.52. Found: C, 60.54; H, 4.01; F, 23.81; N, 2.38.
1H), 0.64 (d J HH ) 12.3 Hz, 1H), 0.39 (d J HH ) 12.6 Hz, 1H); 19
F
NMR (CDCl3) δ - 87.7 (s); 13C NMR (CDCl3) δ 177.8, 161.7,
159.8, 137.2, 137.0, 131.9 (q, J CCF ) 36 Hz), 125.2, 122.3, 121.9
(q, J CF ) 278 Hz), 121.8, 121.2, 120.9, 119.2, 109.5, 106.7, 40.5,
39.5, 38.8, 38.7, 38.1, 35.6, 34.1, 29.9, 26.7, 26.6, 12.0. Anal. Calcd
for C26H24F3NO3: C, 68.56; H, 5.31; F, 12.51; N, 3.08. Found:
C, 68.36; H, 5.25; F, 12.70; N, 3.07.
Ack n ow led gm en t. The financial support of the
Camille and Henry Dreyfus Foundation (NF-96-021)
and Syracuse University is gratefully acknowledged.
C2F 5 a d a m a n tylid en e fu lgid e (6f): NaH/DMF method, 28%
1
yield; overall, fulgide 6f from acylindole 2c, 8% yield; H NMR
J O005722N