Synthesis of vinylindoles and vinylpyrroles by the Peterson olefination or by use of the Nysted reagent

Article abstract of DOI:10.1002/jhet.313

Vinylindoles and vinylpyrroles were prepared from their corresponding aldehydes or ketones using the Peterson olefination, or by use of the Nysted reagent, a commercially available gem-dimetallic compound. The two methods provide efficient and convenient

Full text of DOI:10.1002/jhet.313

March 2011
Synthesis of Vinylindoles and Vinylpyrroles by the Peterson
Olefination or by Use of the Nysted Reagent
381
Wayland E. Noland,* Christopher L. Etienne, and Nicholas P. Lanzatella
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455
*E-mail: nolan001@umn.edu
Received September 2, 2009
DOI 10.1002/jhet.313
Published online 30 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
Vinylindoles and vinylpyrroles were prepared from their corresponding aldehydes or ketones using
the Peterson olefination, or by use of the Nysted reagent, a commercially available gem-dimetallic com-
pound. The two methods provide efficient and convenient access to these useful heterocyclic 1,3-diene
systems.
J. Heterocyclic Chem., 48, 381 (2011).
INTRODUCTION
by subsequent trapping [15], Michael addition with elec-
tron-deficient acetylenes and ethylenes [16], and Pd-cat-
alyzed vinylation [17]. However, some of the drawbacks
that may be encountered using these reagents and meth-
ods include low yields, harsh reaction conditions, and
tedious workup procedures. Therefore, it is desirable to
develop additional practical methods for the synthesis of
these heterocyclic 1,3-diene systems.
There is great interest in the chemistry of indoles and
carbazoles [1] as some of these compounds, both natural
and synthetic [2], exhibit pharmacological activity. Vinyl-
indoles and vinylpyrroles have been shown to act as
dienes in regio- and stereo-controlled [4þ2]-cycloaddi-
tions with electron-deficient alkenes or alkynes, and,
therefore, represent valuable synthons for highly function-
alized indole and carbazole ring systems [3].
The Peterson olefination involves generation of b-
hydroxysilanes from carbonyl compounds and a-silylcar-
banions, followed by exposure to either acidic or basic
conditions to give alkenes, the driving force of the reac-
tion being formation of the strong SiAO bond [18].
Although there is an example of the generation of 2-(3-
indolyl)vinyltributylphosphonium salts [19] and also of
the generation of 3-(2-(trimethylsilyl)vinyl)indoles [20]
using the Peterson olefination, there is only a single
example of the synthesis of a vinylindole with an unsub-
stituted olefin using this procedure [21], and to the best
of our knowledge there are zero examples of the synthe-
sis of vinylindoles with alkyl-substituted olefins or of
any vinylpyrrole using this procedure.
The methylenation of carbonyl compounds is an im-
portant reaction in organic synthesis and various
reagents have been used for this transformation, namely,
phosphorus ylides [4], transition metal-carbene com-
plexes [5], the Tebbe complex and related compounds
[6], and gem-dimetallic compounds [7]. In addition to
these reagents, combinations of gem-dihaloalkanes and
low-valent metal salts have been used in the alkylidena-
tion of aldehydes, ketones, and esters [8–10], although
the reactive species generated by the above reagent sys-
tems have not been completely clarified. Among the
synthetic methods available for making vinylindoles and
vinylpyrroles, reliable standard methods are the Knoeve-
nagel, Perkin, and Aldol condensations [11], the Cram
modification of the Cope reaction [12], Wittig and
Horner-Wadsworth-Emmons olefinations [13], reduction/
dehydration [3i,14], base-mediated enolization followed
The Nysted reagent 1 (Fig. 1) [22] is a commercially
available reagent possessing two gem-dimetallic meth-
ylenating units in one molecule, and its utility for the
methylenation of carbonyl compounds and also toward
C
V
2010 HeteroCorporation

382
W. E. Noland, C. L. Etienne, and N. P. Lanzatella
Vol 48
examples of methylenation with the Nysted reagent 1
during target-driven syntheses [25]. Although there is
an example of the formation of a 3-vinylfuran using 1
[26], to the best of our knowledge there are no exam-
ples of the use of 1 to generate vinylindoles or
vinylpyrroles.
We present here several examples using the Peterson
olefination to make vinylindoles and vinylpyrroles in
which the vinyl group is either unsubstituted or has an
alkyl substituent. We also give what we believe to be
the first examples of vinylindole and vinylpyrrole for-
mation using the Nysted reagent.
Figure 1. Nysted reagent 1.
the methylenation of ketones using TiCl4-mediated con-
ditions were demonstrated soon after its introduction
[23]. The precise reactivity of the Nysted reagent and
the mechanistic role of TiCl4 still remain to be clarified.
Matsubara et al. have reported the use of 1 for the olefi-
nation of aldehydes and ketones [24]. They found that
the reagent is suitable for the chemoselective methylena-
tion of aldehydes under BF3ꢀOEt2-mediated conditions,
whereas ketones require TiCl4, TiCl3, or a combination
of TiCl2 and BF3ꢀOEt2. There are numerous recent
RESULTS AND DISCUSSION
The Peterson olefination. Vinyl compounds 4a–g, i–
m, and o–q were successfully formed from carbonyl
compounds 2a–g, i–m, and o–q using the Peterson olefi-
nation at 75% average yield over two steps. The results
are summarized in Scheme 1. Aldehyde 2h was con-
verted to the b-silanol 3h, but, upon subsequent treatment
Scheme 1. Vinylindoles and vinylpyrroles from the Peterson olefination.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Synthesis of Vinylindoles and Vinylpyrroles by the Peterson Olefination or by
Use of the Nysted Reagent
383
Scheme 2. Methylenation of aldehyde 2a with 1 and BF3ꢀOEt2.
Scheme 3. Methylenation of aldehydes 2a–e, o, p, and r.
with either aqueous 1M HCl or aqueous 48% HF only a
putative cycloadduct was observed by TLC, and the vinyl-
indole 4h was not isolated. It can be rationalized that the
unshared electron pair on the unprotected nitrogen
allowed elimination of the silylol, which was followed by
acid-catalyzed dimerization of two of the resulting vinyl-
indole molecules [33]. Problems were also experienced in
attempting to synthesize 4n by this strategy, which is not
surprising as it is well-known that 2-vinylindoles dimerize
under either acidic or thermal conditions [34]. The steric
presence of a methyl group at the 3-position of the indole
nucleus, however, allowed facile preparation of the
2-vinylindole 4o as a stable crystalline solid.
Even in sterically demanding cases, the Peterson ole-
fination performs quite admirably, although extended
reaction times are required. Additionally, the elimination
seems to occur more efficiently in the presence of aque-
ous 48% HF than aqueous 1M HCl [35]. For example,
the b-silanol 3j with aqueous 1M HCl was recovered
unchanged even after prolonged exposure (48 h),
whereas with aqueous 48% HF it gave the 3-vinylindole
4j within 30 min at room temperature.
Aldehydes 2b–e, o, p, and r were methylenated using
the most efficient reaction conditions described above
for 2a. Good to excellent yields were obtained for all of
the aldehydes studied (Scheme 3). In addition, it was
confirmed that the use of excess Nysted reagent (2
equiv.) for the olefination of 2a did not significantly
improve the yield of 4a.
The methylenation of ketones with the Nysted reagent
was also examined (Scheme 4). In the cases where
BF3ꢀOEt2 or no mediator was used to catalyze the
methylenation of 2i, no olefin was obtained. In the pres-
ence of TiCl4, however, olefins 4i and 4m were obtained
from the corresponding ketones in fair to good yields,
depending on the amount of Nysted reagent and TiCl4
used.
As BF3ꢀOEt2 mediated methylenation of aldehyde 2a,
but not ketone 2i, the chemoselectivity of the Nysted re-
agent 1 was studied briefly (see Scheme 4, last two
The practical advantages of this approach to vinylin-
doles and vinylpyrroles are high yields so long as an
appropriate protecting group is used to attenuate the
reactivity of the electron-rich heterocycle, easy workup
conditions and purification (the main by-products are
volatile silanols), gentle reaction conditions, and insensi-
tivity to steric hindrance.
Scheme 4. Methylenation using 1 in the presence of TiCl4.
The Nysted reagent. Methylenation of aldehyde 2a
was examined first (Scheme 2). The reaction conditions
were optimized by varying the amount of BF3ꢀOEt2 and
keeping the amount of Nysted reagent fixed at 1 equiv.,
as it has previously been demonstrated that the use of
excess Nysted reagent does not dramatically improve
yields of methylenated product [24]. An improvement in
yield was observed with increasing amounts of added
BF3ꢀOEt2; however, as found by Matsubara et al. [24],
the gains in yield seemed to plateau around 0.5 equiv.
BF3ꢀOEt2.
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W. E. Noland, C. L. Etienne, and N. P. Lanzatella
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mixture was poured into water (100 mL) and extracted with
CH2Cl2 (3 ꢁ 100 mL). The combined organic extracts were
washed with saturated aq NaHCO3 (2 ꢁ 100 mL), brine (100
mL), dried over MgSO4, and the solvents were removed using
a rotating evaporator, giving a brown oil. Addition of cold
EtOH (10 mL) caused the brown oil to crystallize, giving 2f
(3.01 g, 65%) as a tan solid: mp 129–131ꢂC; 1H NMR (300
MHz, DMSO-d6) d 10.04 (s, 1H), 8.84 (s, 1H), 8.08 (dd, J ¼
7.5, 1.5 Hz, 2H), 7.89 (d, J ¼ 7.2 Hz, 1H), 7.75–7.59 (m, 4H),
7.44–7.25 (m, 5H), 7.11 (dd, J ¼ 9.0, 2.4 Hz, 1H), 5.09 (s,
2H); 13C NMR (75 MHz, DMSO-d6) d 187.25, 156.83,
139.45, 137.32, 136.78, 135.85, 130.66, 129.44, 128.90,
128.33, 123.12, 127.63, 127.36, 122.05, 116.30, 114.66,
105.69, 104.99, 70.14; HR-EI MS: C22H17NO4S [M]þ, calcd.
391.0878, found 391.0876. Anal. Calcd. for C22H17NO4S: C,
67.50; H, 4.38; N, 3.58; S, 8.19. Found: C, 67.61; H, 4.21; N,
3.69; S, 8.25.
2,2-Dimethyl-1-(3-(1-phenylsulfonyl-1H-indolyl))-1-propanone
(2j). Aqueous 50% KOH (25 mL) and phenylsulfonyl chloride
(8.83 g, 0.050 mol) were added sequentially to a solution of 3-
pivaloylindole [40] (5.00 g, 0.025 mol) and tetrabutylammo-
nium hydrogen sulfate (0.11 g, 0.3 mmol) in benzene (100
mL) at rt. After being stirred for 1.5 h, the mixture was poured
into water (200 mL) and extracted with CH2Cl2 (3 ꢁ 100
mL), washed with brine (100 mL), dried over MgSO4, and the
solvents were removed using a rotating evaporator, giving a
golden yellow oil. Trituration with EtOH (10 mL) followedꢂby
drying gave 2j as white crystals (7.24 g, 85%): mp 93–95 C;
1H NMR (300 MHz, DMSO-d6) d 8.50 (s, 1H), 8.16 (dd, J ¼
6.9, 1.0 Hz, 2H), 7.96 (d, J ¼ 8.1 Hz, 1H), 7.69–7.57 (m, 3H),
7.39–7.31 (m, 2H), 1.31 (s, 9H); 13C NMR (75 MHz, DMSO-
d6) d 202.58, 136.98, 135.69, 133.84, 130.86, 130.56, 129.40,
127.71, 126.36, 125.18, 123.36, 117.64, 113.31, 44.68, 28.25;
HR-EI MS: C19H19NO3S [M]þ, calcd. 341.1086, found
341.1080. Anal. Calcd. for C19H19NO3S: C, 66.84; H, 5.61; N,
4.10; S, 9.39. Found: C, 66.96; H, 5.55; N, 4.08; S, 9.34.
3-(4-Fluorobenzoyl)-1-phenylsulfonyl-1H-indole (2l). 3-(4-
Fluorobenzoyl)indole [40] (5.98 g, 0.025 mol) was treated
with phenylsulfonyl chloride (8.83 g, 0.050 mol) as in the pro-
cedure described above for 2j, with recrystallization from
EtOH giving 2l as tan crystals (8.55 g, 90%): mp 108–110ꢂC;
1H NMR (300 MHz, DMSO-d6) d 8.32 (s, 1H), 8.15 (d, J ¼
7.2 Hz, 3H), 8.00–7.95 (m, 3H), 7.70 (dd, J ¼ 7.5, 7.2 Hz,
1H), 7.58 (dd, J ¼ 8.1, 7.2 Hz, 2H), 7.41 (m, 4H); 13C NMR
(75 MHz, DMSO-d6) d 189.03, 166.84, 163.51, 136.79,
135.77, 135.71, 135.67, 134.63, 134.56, 132.36, 132.24,
130.54, 128.49, 127.92, 126.56, 125.38, 122.87, 119.66,
116.42, 116.13, 113.55; 19F (282 MHz, DMSO-d6) d -117.19;
HR-EI MS: C21H14FNO3S [M]þ, calcd. 379.0678, found
379.0680. Anal. Calcd. for C21H14FNO3S: C, 66.48; H, 3.72;
N, 3.69; O, 12.65; S, 8.45. Found: C, 66.39; H, 3.75; N, 3.71;
O, 12.64; S, 8.33.
entries). Thus, an equimolar mixture of 2a and 2i was
allowed to react with 1 equiv. 1 and 0.5 equiv.
BF3ꢀOEt2. After 2 h at room temperature, 4a was iso-
lated in 75% yield, whereas 2i was recovered
unchanged. In contrast, when TiCl4 (1.0 equiv.) was
used instead of BF3ꢀOEt2 to mediate the reaction, 4a
was isolated in 61% yield, whereas 4i was isolated in
80% yield.
CONCLUSIONS
In summary, we have developed convenient and effi-
cient procedures for the preparation of vinylpyrroles and
vinylindoles from the corresponding ketones and alde-
hydes in good to excellent yields by using either the
Nysted reagent or the Peterson olefination. The Nysted
reagent is chemoselective for the methylenation of alde-
hydes in the presence of ketones when the appropriate
reaction mediator (BF3ꢀOEt2) is used. The Peterson ole-
fination performs well under sterically demanding condi-
tions. The mild conditions, relatively short reaction
times, and convenient workup procedures make these
particular routes to vinylpyrroles and vinylindoles an
attractive alternative to other olefination procedures.
Moreover, as vinylpyrroles and vinylindoles represent
useful synthons to highly functionalized indoles and car-
bazoles, the application of this methodology to the syn-
thesis of indole and carbazole alkaloids is currently
under investigation.
EXPERIMENTAL
General methods. Reagents were purchased from Aldrich
Chemical Company and were used as received, unless other-
wise noted. Tetrahydrofuran (THF) was dried by distillation
from sodium/benzophenone. Brine refers to saturated aqueous
NaCl solution. TLC analyses were performed on plastic-
backed plates precoated with 0.2 mm silica with F254 indicator.
Column chromatography was performed with silica gel (230-
400 mesh). Solvent ratios used in TLC and column chromatog-
raphy are reported by volume. Melting points are uncalibrated.
For 1H and 13C NMR spectra, chemical shifts (d) were refer-
enced to the solvent, and for 19F NMR spectra, they were ref-
erenced to CFCl3. 13C NMR spectra were proton-decoupled.
Infrared spectra were recorded on a 4000 FT-IR spectrometer;
only the most intense and/or diagnostic peaks are reported.
Elemental analyses were performed at M-H-W Laboratories,
Phoenix, AZ. Aldehydes and ketones were prepared according
to published procedures [36].
5-Benzyloxy-1-phenylsulfonyl-1H-indole-3-carboxaldehyde
(2f). Aqueous 50% potassium hydroxide (12 mL) and phenyl-
sulfonyl chloride (4.2 g, 23.8 mmol) were added to a solution
of 5-benzyloxyindole-3-carboxaldehyde (3.0 g, 11.9 mmol,
prepared by formylation [37] of 5-benzyloxyindole [38,39])
and tetrabutylammonium hydrogen sulfate (0.05 g, 0.14 mmol)
in benzene (40 mL) at rt. After being stirred for 2.5 h, the
3-Ethenyl-1-phenylsulfonyl-1H-indole (4a) (General procedures
for the synthesis of compounds 4a–q (Peterson Olefination)
and 4a–e,o,p,r (Nysted)) [13b,17a,27]. Using the Peterson
olefination. Formation of the b-silanol 3a: (Trimethylsilyl)me-
thylmagnesium chloride (3.0 mmol, 1M solution in Et2O, 1.5
equiv.) diluted with THF (5 mL) was added dropwise to a so-
lution of 1-phenylsulfonylindole-3-carboxaldehyde 2a (0.571
g, 2.0 mmol) in THF (10 mL) at rt under N2. The reaction
was monitored by TLC (SiO2, CH2Cl2) and was shown to be
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Synthesis of Vinylindoles and Vinylpyrroles by the Peterson Olefination or by
Use of the Nysted Reagent
385
complete when 2,4-DNP stain (for preparation, see ref. 41)
indicated the absence of the aldehyde, in 2–48 h (typically in
no more than 2 h). The reaction solution was quenched with
saturated aqueous NH4Cl (15 mL) and stirred at rt for 30 min.
It was extracted with Et2O (3 ꢁ 10 mL), and the combined or-
ganic extracts were washed with water (10 mL), brine (10
mL), and dried over MgSO4. The solution was filtered, and the
solvents were evaporated using a rotating evaporator, giving
the crude b-silanol 3a (0.725 g, 97 %) as a viscous, yellow
oil, which was carried on to the dehydration/desilylation step
without further purification. Formation of the olefin 4a: For
method A, aqueous 1M HCl (10 mL) was added to a solution
of the crude 3a (0.725 g, 1.9 mmol) in THF (10 mL) and the
two liquid phases were stirred at rt. After 0.5–48 h, TLC
(SiO2, CH2Cl2) indicated the elimination to be complete (typi-
cally in no more than 2 h). The reaction solution was poured
slowly into saturated aqueous NaHCO3 (30 mL) and extracted
with Et2O (3 ꢁ 10 mL). The combined organic extracts were
washed with water (10 mL) and brine (10 mL), dried over
MgSO4, and the solvents were removed using a rotating evap-
orator giving the crude vinylindole 4a as a pale golden-yellow
oil. Flash chromatography (SiO2, hexanes/CH2Cl2 3:1) gave
analytically pure 4a as a white crystalline solid (0.45 g, 82%):
(s, 1H), 7.30 (ddd, J ¼ 7.8, 7.2, 1.2 Hz, 1H), 7.25 (ddd, J ¼
8.7, 7.2, 1.2 Hz, 1H), 7.20 (dd, J ¼ 8.4, 1.0 Hz, 2H), 6.77 (dd,
J ¼ 18.0, 11.1 Hz, 1H), 5.78 (dd, J ¼ 18.0, 1.0 Hz, 1H), 5.35
(dd, J ¼ 11.1, 1.0 Hz, 1H), 2.31 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 145.09, 135.54, 135.14, 129.96, 129.06, 127.60,
126.89, 124.97, 124.14, 123.57, 121.01, 120.49, 115.39,
113.78, 21.59; IR (KBr) cmꢃ1 1670, 1630, 1598, 1448, 1372,
1178, 960; HR-EI MS: C17H15NO2S [M]þ, calcd. 297.0823,
found 297.0826. Anal. Calcd. for C17H15NO2S: C, 68.66; H,
5.08; N, 4.71; S, 10.78. Found: C, 68.61; H, 4.99; N, 4.74; S,
10.96.
1-Benzoyl-3-ethenyl-1H-indole (4c). Preparation using the
Peterson and Nysted procedures was as described for 4a. Data
for 4c: golden yellow oil (Peterson: 0.351 g, 71% over two
1
steps; Nysted: 0.878 g, 71%); Rf 0.75 (silica gel, CH2Cl2); H
NMR (300 MHz, DMSO-d6) d 8.30 (dd, J ¼ 6.9, 1.2 Hz, 1H),
7.93 (d, J ¼ 8.1 Hz, 1H), 7.75 (d, J ¼ 7.2 Hz, 2H), 7.73–7.32
(m, 6H), 6.82 (dd, J ¼ 18.0, 11.4 Hz, 1H), 5.85 (d, J ¼ 18.0
Hz, 1H), 5.30 (d, J ¼ 11.4 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) d 168.58, 136.75, 134.43, 132.58, 129.55, 129.47,
129.23, 128.98, 128.69, 127.13, 125.62, 124.72, 120.79,
119.92, 116.53, 115.64; IR (neat NaCl plates) cmꢃ1 3054,
1683, 1633, 1601, 1580, 1548, 1451, 1417, 1351, 1255, 1225;
HR-EI MS: C17H13NO [M]þ, calcd. 247.0997, found
247.0988. Anal. Calcd. for C17H13NO: C, 82.57; H, 5.30; N,
5.66. Found: C, 82.44; H, 5.35; N, 5.77.
1,1-Dimethylethyl 3-ethenyl-1H-indole-1-carboxylate (4d)
[13d,28,29]. Preparation using the Peterson and Nysted proce-
dures was as described for 4a. Data for 4d: pale yellow oil
(Peterson: 0.487 g, 82% over two steps; Nysted: 1.034 g,
85%); Rf 0.73 (silica gel, CH2Cl2); 1H NMR (300 MHz,
DMSO-d6) d 8.09 (d, J ¼ 8.1 Hz, 1H), 7.82 (dd, J ¼ 7.2, 1.0
Hz, 1H), 7.77 (s, 1H), 7.32 (ddd, J ¼ 8.4, 7.2, 1.2 Hz, 1H),
7.24 (ddd, J ¼ 8.7, 7.8, 1.2 Hz, 1H), 6.82 (dd, J ¼ 18.0, 11.4
Hz, 1H), 5.83 (dd, J ¼ 18.0, 1.2 Hz, 1H), 5.27 (dd, J ¼ 11.4,
1.2 Hz, 1H), 1.57 (s, 9H); 13C NMR (75 MHz, DMSO-d6) d
149.37, 135.79, 128.61, 128.56, 125.10, 124.95, 123.50,
120.59, 119.08, 115.38, 114.91, 84.29, 28.06; HR-EI MS:
C15H17NO2 [M]þ, calcd. 243.1259, found 243.1259. Anal.
Calcd. for C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: C,
74.21; H, 7.01; N, 5.65.
3-Ethenyl-5-methoxy-1-phenylsulfonyl-1H-indole (4e)
[30]. Preparation using the Peterson and Nysted procedure
was as described for 4a. Data for 4e: pale yellow solid (Peter-
son: 0.483 g, 77% over two steps; Nysted 1.347 g, 86%); mp
127–129ꢂC; 1H NMR (300 MHz, DMSO-d6) d 7.97-7.92 (m,
3H), 7.84 (d, J ¼ 9 Hz, 1H), 7.65 (dd, J ¼ 8.7, 1.2 Hz, 1H),
7.55 (dd, J ¼ 8.4, 8.1 Hz, 2H), 7.27 (d, J ¼ 2.4 Hz, 1H), 6.97
(dd, J ¼ 9.0, 2.4 Hz, 1H), 6.82 (dd, J ¼ 18.0, 11.4 Hz, 1H),
5.86 (dd, J ¼ 18.0, 1.0 Hz, 1H), 5.31 (dd, J ¼ 11.4, 1.0 Hz,
1H), 3.76 (s, 3H); 13C NMR (75 MHz, DMSO-d6) d 156.95,
137.29, 135.09, 130.30, 130.12, 129.74, 127.81, 127.11,
125.88, 121.30, 116.11, 114.72, 114.35, 103.73, 55.99; IR
(KBr) cmꢃ1 3107, 3067, 1610, 1593, 1566, 1473, 1448, 1373,
1292, 1222, 1174, 1119, 1095, 1036, 984; HR-EI MS:
C17H15NO3S [M]þ, calcd. 313.0773, found 313.0774. Anal.
Calcd. for C17H15NO3S: C, 65.16; H, 4.82; N, 4.47; S, 10.23.
Found: C, 64.98; H, 4.75; N, 4.58; S, 10.17.
1
mp 64–65ꢂC; H NMR (300 MHz, DMSO-d6) d 8.01 (m, 4H),
7.88 (d, J ¼ 7.8 Hz, 1H), 7.70 (m, 1H), 7.60 (dd, J ¼ 8.1, 7.2
Hz, 2H), 7.40 (ddd, J ¼ 8.1, 7.5, 1.2 Hz, 1H), 7.32 (ddd, J ¼
7.8, 7.2, 1.2 Hz, 1H), 6.86 (dd, J ¼ 17.7, 11.4 Hz, 1H), 5.93
(dd, J ¼ 18.0, 1.0 Hz, 1H), 5.37 (dd, J ¼ 11.4, 1.0 Hz, 1H);
13C NMR (75 MHz, DMSO-d6) d 137.34, 135.24, 135.17,
130.35, 128.90, 127.95, 127.20, 125.69, 125.48, 124.40,
121.20, 121.10, 116.24, 113.83; HR-EI MS: C16H13NO2S
[M]þ, calcd. 283.0667, found 283.0668. Anal. Calcd. for
C16H13NO2S: C, 67.82; H, 4.62; N, 4.94; S, 11.32. Found: C,
67.64; H, 4.67; N, 5.01; S, 11.29.
Using the Nysted reagent. Nysted reagent 1 [22] (11.5 g of
a 20 wt % suspension in THF, 5.0 mmol, 1 equiv.) was added
under N2 to THF (15 mL) at 0ꢂC. A solution of BF3ꢀEt2O
(0.35 g, 2.5 mmol, 0.5 equiv.) in THF (5 mL) was added drop-
wise and the milky gray suspension was stirred at 0ꢂC for 10
min. A solution of 1-phenylsulfonylindole-3-carboxaldehyde
2a (1.43 g, 5.0 mmol) in THF (15 mL) was added by syringe
and the mixture was warmed slowly to room temperature and
kept there for 3 h after which the milky gray suspension had
turned gray-black. TLC (silica gel, CH2Cl2) indicated comple-
tion of the reaction, so the mixture was poured into a beaker
containing aq 1M HCl (50 mL). The resulting dark gray sus-
pension was stirred until the HCl dissolved all of the Nysted
reagent zinc metal. The layers were separated and the aqueous
layer was extracted with Et2O (3 ꢁ 100 mL). The combined
organic extracts were washed with water (100 mL), saturated
aq NaHCO3 (100 mL), and brine (100 mL), dried over
MgSO4, filtered, and the solvents were removed using a rotat-
ing evaporator, giving an amber oil. Purification by column
chromatography (silica gel, hexanes/CH2Cl2, 3:1, v/v) gave the
3-ethenylindole (4a) as a white crystalline solid (1.12 g, 79%).
Analytical data matched that listed above for 4a.
3-Ethenyl-1-(4-methylphenylsulfonyl)-1H-indole (4b) [13c]. Prep-
aration using the Peterson and Nysted procedures was as
described for 4a. Data for 4b: white crystalline solid (Peterson:
0.488 g, 82% over two steps; Nysted: 1.115 g, 75%); mp 97–
98ꢂC; 1H NMR (300 MHz, CDCl3) d 8.01 (d, J ¼ 8.4 Hz,
1H), 7.77 (d, J ¼ 8.4 Hz, 2H), 7.74 (d, J ¼ 7.8 Hz, 1H), 7.62
5-Benzyloxy-3-ethenyl-1-phenylsulfonyl-1H-indole (4f). Prep-
aration using the Peterson procedure was as described for 4a.
Data for 4f: white crystals (0.709 g, 91% over two steps); mp
142–143ꢂC; 1H NMR (300 MHz, DMSO-d6) d 7.95 (m, 2H),
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7.86 (d, J ¼ 9.0 Hz, 1H), 7.69–7.54 (m, 3H), 7.45–7.27 (m,
6H), 7.05 (dd, J ¼ 9.0, 2.4 Hz, 1H), 6.80 (dd, J ¼ 18.0, 11.4
Hz, 1H), 5.85 (d, J ¼ 18.0 Hz, 1H), 5.31 (d, J ¼ 11.7 Hz,
1H), 5.11 (s, 2H); 13C (75 MHz, DMSO-d6) d 156.01, 137.57,
137.29, 135.12, 130.33, 130.02, 129.86, 128.91, 128.33,
128.23, 127.83, 127.13, 126.06, 121.24, 116.13, 114.99,
114.75, 105.01, 70.22; HR-EI MS: C23H19NO3S [M]þ, calcd.
389.1086, found 389.1060. Anal. Calcd. For C23H19NO3S: C,
70.93; H, 4.92; N, 3.60; S, 8.23. Found: C, 71.05; H, 4.99; N,
3.44; S, 8.19.
(Method A: 0.431 g, 60% over two steps; Method B: 0.589 g,
82% over two steps): Rf 0.69 (SiO2, CH2Cl2); mp 111–112ꢂC;
1H NMR (300 MHz, DMSO-d6) d 8.02 (dd, J ¼ 7.8, 1.2 Hz,
2H), 7.98 (d, J ¼ 8.4 Hz, 1H), 7.76 (s, 1H), 7.66 (dd, J ¼ 7.2,
1.2 Hz, 1H), 7.56 (ddd, J ¼ 7.8, 7.2, 1.2 Hz, 2H), 7.38–7.26
(m, 5H), 7.13 (m, 2H), 5.61 (s, 1H), 5.60 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) 140.69, 140.35, 137.28, 135.22, 135.13,
130.35, 129.61, 128.98, 128.70, 127.71, 127.32, 125.70,
125.55, 124.14, 123.78, 121.45, 116.61, 113.96; HR-EI MS:
C22H17NO2S [M]þ, calcd. 359.0980, found 359.0981. Anal.
Calcd. For C22H17NO2S: C, 73.51; H, 4.77; N, 3.90; S, 8.92.
Found C, 73.62; H, 4.92; N, 3.96; S, 8.74.
3-Ethenyl-1-methanesulfonyl-1H-indole (4g). Preparation
using the Peterson procedure was as described for 4a. Data for
4g: off-white solid (0.341 g, 77% over two steps); Rf 0.70
3-(1-(4-Fluorophenyl)ethenyl)-1-phenylsulfonyl-1H-indole
(4l). Preparation using the Peterson procedure was conducted
in two ways: as described for 4a, with the use of method A,
and as described for 4a but with the exception that method B
was used, as described for 4j. Data for 4l: white crystalline
solid (Method A: 0.393 g, 52% over two steps; Method B:
0.377 g, 50% over two steps); Rf 0.82 (SiO2, CH2Cl2); mp 98–
99ꢂC; 1H NMR (300 MHz, DMSO-d6) d 8.02 (dd, J ¼ 7.5,
1.5 Hz, 2H), 7.97 (d, J ¼ 8.4, 1H), 7.73–7.67 (m, 2H), 7.56
(dd, J ¼ 7.8, 7.2 Hz, 2H), 7.35–7.28 (m, 3H), 7.19–7.10 (m,
4H), 5.59 (s, 2H); 13C NMR (75 MHz, DMSO-d6) d 164.16,
160.91, 139.60, 137.27, 136.80, 136.75, 135.24, 135.11,
130.37, 129.82, 129.71, 129.47, 127.34, 125.78, 125.58,
124.20, 123.59, 121.40, 116.68, 115.98, 115.69, 113.97; 19F
1
(SiO2, CH2Cl2); mp 57–59ꢂC; H NMR (300 MHz, DMSO-d6)
d 7.93 (d, J ¼ 7.8 Hz, 1H), 7.87 (d, J ¼ 8.4 Hz, 1H), 7.77 (s,
1H), 7.41 (dd, J ¼ 8.7, 7.8 Hz, 1H), 7.34 (dd, J ¼ 8.1, 7.5 Hz,
1H), 6.88 (dd, J ¼ 17.7, 11.1 Hz, 1H), 5.90 (dd, J ¼ 18.0, 1.0
Hz, 1H), 5.34 (dd, 11.4, 1.0 Hz, 1H), 3.42 (s, 3H); 13C NMR
(75 MHz, DMSO-d6) d 135.46, 128.58, 128.27, 125.45,
125.38, 124.00, 121.10, 119.69, 115.55, 113.57, 41.38; IR
(neat, NaCl plates) 1636, 1604, 1448, 1362, 1269, 1219, 1173,
1124, 970 cmꢃ1; HR-EI MS: C11H11NO2S [M]þ, calcd.
211.0510, found 211.0491. Anal. Calcd. for C11H11NO2S: C,
59.71; H, 5.01; N, 6.33; S, 14.49. Found: C, 59.77; H, 5.22;
N, 6.39; S, 14.38.
3-(1-Methylethenyl)-1-phenylsulfonyl-1H-indole (4i) [13a,b]. Prep-
aration using the Peterson procedure was the same as
described for 4a. The Nysted procedure and molar quantities
used for the synthesis of compound 4a was followed, except
that: (1) The BF3ꢀEt2O solution in THF was replaced by TiCl4
(0.55 mL, 0.95 g, 5.0 mmol) which was added by syringe; and
(2) The reaction mixture was kept at rt for 4 h instead of 3 h.
The product 4i was obtained as a white crystalline solid (Peter-
son: 0.321 g, 54% over two steps; Nysted: 1.130 g, 76%): Rf
0.71 (silica gel, CH2Cl2); mp 97–98ꢂC; 1H and 13C NMR
(CDCl3) data matched those in the literature[13a,b]; HR-EI
MS: C17H15NO2S [M]þ, calcd. 297.0824, found 297.0839.
Anal. Calcd for C17H15NO2S: C, 68.66; H, 5.08; N, 4.71; S,
10.78. Found: C, 68.49; H, 5.05; N, 4.58; S, 10.69.
3-(2,2-Dimethyl-1-methylenepropyl)-1-phenylsulfonyl-1H-indole
(4j). Preparation using the Peterson procedure described for
4a, with the exception that method B was used in which
48% aqueous HF (8 drops) was added in place of HCl, and
rather than THF the crude 3j was dissolved in CH3CN (5
mL). Data for 4j: white crystalline solid (0.577 g, 85% over
two steps); mp 59–61ꢂC; 1H NMR (300 MHz, DMSO-d6) d
7.97–7.93 (m, 3H), 7.59 (dd, J ¼ 7.5, 1.5 Hz, 1H), 7.54–
7.49 (m, 3H), 7.36–7.29 (m, 2H), 7.20 (ddd, J ¼ 8.1, 7.8,
1.0 Hz, 1H), 5.35 (d, J ¼ 1.2 Hz, 1H), 4.83 (d, J ¼ 1.2 Hz,
1H), 1.00 (s, 9H); 13C (75 MHz, DMSO-d6) d 149.42,
137.41, 134.99, 134.35, 132.19, 130.20, 127.10, 125.31,
124.22, 124.11, 123.29, 121.09, 115.07, 113.66, 36.36,
29.52; HR-EI MS: C20H21NO2S [M]þ, calcd. 339.1293,
found 339.1292. Anal. Calcd. for C20H21NO2S: C, 70.77; H,
6.24; N, 4.13; O, 9.43; S, 9.45. Found: C, 70.71; H, 6.09; N,
3.98; S, 9.41.
NMR (282 MHz, DMSO-d6)
d
ꢃ124.17; HR-EI MS:
C22H16FNO2S [M]þ, calcd. 377.0886, found 377.0898. Anal.
Calcd. for C22H16FNO2S: C, 70.01; H, 4.27; F, 5.03; N, 3.71;
S, 8.50. Found: C, 70.19; H, 4.38; F, 5.15; N, 3.77; S, 8.45.
3-(1-Methylethenyl)-1-phenylsulfonyl-1H-pyrrole (4m). Prep-
aration using the Peterson procedure was the same as
described for 4a. The Nysted procedure and molar quantities
used for the synthesis of compound 4a were used, with the
exceptions noted above for compound 4i, giving 4m (Peterson:
0.247 g, 50% over two steps; Nysted: 0.841 g, 68%) as a
white crystalline solid: Rf 0.68 (silica gel, CH2Cl2); mp 58–
1
60ꢂC; H NMR (300 MHz, CDCl3) d 7.88 (m, 2H), 7.64–7.46
(m, 3H), 7.11 (m, 2H), 6.45 (m, 2H), 5.51 (dd, J ¼ 1.5, 1.2
Hz, 1H), 5.19 (dd, J ¼ 1.5, 1.2 Hz, 1H), 2.14 (s, 3H); HR-EI
MS: C13H13NO2S [M]þ, calcd. 247.0667, found 247.0691.
Anal. Calcd. for C13H13NO2S: C, 63.13; H, 5.30; N, 5.66; S,
12.97. Found: C, 63.26; H, 5.24; N, 5.78; S, 12.85.
2-Ethenyl-3-methyl-1-phenylsulfonyl-1H-indole (4o). Prep-
aration using the Peterson and Nysted procedure was as
described for 4a. Data for 4o: pale yellow solid (Peterson:
0.500 g, 84% over two steps; Nysted: 1.323 g, 89%); mp 131–
1
133ꢂC; H NMR (300 MHz, DMSO-d6) d 8.17 (d, J ¼ 8.1 Hz,
1H), 7.80 (dd, J ¼ 8.1, 1.2 Hz, 2H), 7.70 (m, 1H), 7.61–7.56
(m, 3H), 7.45 (ddd, J ¼ 8.1, 6.9, 1.2 Hz, 1H), 7.36 (ddd, J ¼
8.7, 7.5, 0.9 Hz, 1H), 7.17 (dd, J ¼ 17.7, 11.7 Hz, 1H), 5.79
(dd, J ¼ 11.7, 1.8 Hz, 1H), 5.58 (dd, J ¼ 17.7, 1.8 Hz, 1H),
2.28 (s, 3H); 13C NMR (75 MHz, DMSO-d6) d 137.73,
135.99, 135.08, 134.81, 131.97, 130.25, 127.58, 126.92,
126.15, 124.71, 121.72, 120.40, 119.51, 115.19, 10.70; HR-EI
MS: C17H15NO2S [M]þ, calcd. 297.0823, found 297.0819.
Anal. Calcd. for C17H15NO2S: C, 68.66; H, 5.08; N, 4.71; S,
10.78. Found: C, 68.85; H, 5.14; N, 4.69; S, 10.87.
3-(1-Phenylethenyl)-1-phenylsulfonyl-1H-indole (4k) [13e,
31]. Preparation using the Peterson procedure was conducted
in two ways: as described for 4a, with the use of method A,
and also as described for 4a but with the exception that
method B was used, as described for 4j. Recrystallization from
MeOH gave the analytical sample of 4k as a white solid
2-Ethenyl-1-phenylsulfonyl-1H-pyrrole (4p) [3i]. Prepara-
tion using the Peterson and Nysted procedures was as described
for 4a. Data for 4p: white crystalline solid (Peterson: 0.378 g,
Journal of Heterocyclic Chemistry
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Synthesis of Vinylindoles and Vinylpyrroles by the Peterson Olefination or by
Use of the Nysted Reagent
387
1
81% over two steps; Nysted: 1.015 g, 87%); mp 67–68ꢂC; H
NMR data (300 MHz, CDCl3) matched those in the literature
[3i]; 13C NMR (75 MHz, DMSO-d6) d 139.06, 134.13, 133.85,
129.22, 126.81, 125.44, 123.26, 115.21, 112.44, 111.89; HR-EI
MS: C12H11NO2S [M]þ, calcd. 233.0510, found 233.0506.
1,1-Dimethylethyl 2-Ethenyl-1H-pyrrole-1-carboxylate (4q)
[13g,29,32]. Preparation using the Peterson procedure was as
described for 4a, giving 4q as a yellow oil (0.332 g, 86% over
two steps): spectral data for 4q matched those in the
literature[13g].
3-Ethenyl-1-phenylsulfonyl-1H-pyrrole (4r) [3i]. Prepara-
tion using the Nysted procedure was as described for 4a. Data
for 4r: white crystalline solid (0.933 g, 80%); mp 40–41ꢂC;
1H NMR data (CDCl3) matched those in the literature [3i];
13C NMR (75 MHz, DMSO-d6) d 138.91, 133.66, 129.42,
128.20, 127.79, 126.83, 121.77, 118.45, 113.52, 111.06; HR-EI
MS: C12H11NO2S [M]þ, calcd. 233.0510, found 233.0513.
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Acknowledgment. C.L.E. and N.P.L. thank the Wayland E.
Noland Research Fellowship Fund for generous financial support
of this project.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet