Reactions of 2- and 3-acetyl-1-methylpyrrole enolate ions with iodoarenes and neopentyl iodides by the S(RN)1 mechanism

Full text of DOI:10.1021/jo990327m

J . Org. Chem. 1999, 64, 6487-6489
6487
Sch em e 1
Rea ction s of 2- a n d
3-Acetyl-1-m eth ylp yr r ole En ola te Ion s w ith
Iod oa r en es a n d Neop en tyl Iod id es by th e
S
RN1 Mech a n ism
Mar´ıa T. Baumgartner, Adriana B. Pierini,* and
Roberto A. Rossi*
INFIQC, Departamento de Quı´mica Orga´nica, Facultad de
Ciencias Quı´micas, Universidad Nacional de Co´rdoba,
Ciudad Universitaria, 5000 Co´rdoba, Argentina
Received February 22, 1999
Carbanions are among the nucleophiles more widely
utilized in SRN1 reactions. Haloarenes, haloheteroarenes,
and alkyl halides (neopentyl, 1-adamantyl, and norcaran-
yl iodides) react with enolate ions of aromatic ketones in
DMSO under irradiation. Ferrous ion (usually FeSO4 in
liquid ammonia or FeCl2 or FeBr2 in DMSO) can provide
an alternative and efficient method to initiate reactions
of carbanions with iodobenzene and other aryl halides
to give R-substituted ketones.6,8,9 The enolate ions of
2-acetylfuran and 2-acetylthiophene did not react with
iodobenzene under irradiation10 but reacted with highly
electrophilic substrates.11 The difference in reactivity is
due to their low efficiency in the photoinitiation step. This
situation can be overcome by performing the reaction in
the presence of added nucleophiles that are better
electron donors or by addition of FeBr2 in the dark.8
Under these conditions and by competition experiments,
2-acetylfuran enolate ion was determined to be ca. 0.8
times as reactive as acetophenone enolate ion toward
iodobenzene whereas 2-acetylthiophene is ca. 0.5 as
reactive.10
There are several methods for synthesizing aromatic
or heteroaromatic ketones. Friedel-Crafts acylations
catalyzed by Lewis acids have the drawback that some
substituents are incompatible with the catalyst and the
reaction is often accompanied by rearrangement.1 The
regiochemistry depends on the presence of substituents
or the nature of the heteroaromatic compounds; often a
mixture of isomers is formed. The palladium-catalyzed
coupling of organotin compounds with acyl chlorides gives
the ketones with variable yields.2 Few examples of the
reactions of N-methylpyrrolyltrialkylstannanes with acyl
chlorides are known; they afford ketones in yields of 65-
72%.3
Another approach is the reaction of alkyl and aryl
halides with enolate ions of ketones by different proce-
dures including catalysis by Pd4,5 or the SRN1 reaction.6
Many substituents are compatible with the SRN1 mech-
anism, such as OR, OAr, SAr, CF3, CO2R, NH2, NHCOR,
NHBoc, SO2R, CN, COAr, NR2, and F. Even though the
reaction is not inhibited by the presence of negatively
charged carboxylate ions, other charged groups such as
oxyanions hinder the process.6 Substituents such as NO2
are not suitable, except with arylazo phenyl sulfide as
substrates.7 The mechanism is a chain process, whose
main steps are presented in Scheme 1.
To obtain R-substituted acetylpyrroles, we studied the
reactions of enolate ions of 2-acetyl (1) and 3-acetyl (6)
1-methylpyrroles with some aryl and alkyl iodides under
different reaction conditions; this is the first report on
the reactivity of these nucleophiles in SRN1 reactions.
Few systems are known to react through a thermal (or
spontaneous) SRN1 reaction. Most systems need to be
initiated by other means. Photostimulation is the most
frequently used technique. However, other methods such
as initiation by Fe2+ salts have also been reported.8
Resu lts
E n ola t e Ion s of 2-Acet yl (1) a n d 3-Acet yl (6)
1-Meth ylp yr r oles. The photostimulated reaction of the
enolate ion of 2-acetyl-1-methylpyrrole (1) with iodoben-
zene yields 98% of substitution product 212 (eq 5).
† Fax: 54-351-433-3030. E-mail: adriana@dqo.fcq.unc.edu.ar.
(1) Carey, F. A.; Sundberg, R. J . Advanced Organic Chemistry, Part
B, 3rd ed.; Plenum Press: New York, 1990; p 575 and references
therein.
(2) For reviews, see: Mitchell, T. N. Synthesis 1992, 803. Farina,
V.; Krishnamurthy, V.; Scott, W. J . In The Stille Reaction. Org. React.
1997, 50 (Paquette, L. A., Ed.).
(3) (a) Gaare, K.; Repstad, T.; Benneche, T.; Undheim, K. Acta Chem.
Scand. 1993, 47, 57. (b) J ousseaume, B.; Kwon, H.; Verlhac, J .-B.;
Denat, F.; Dubac, J . Synlett 1993, 117.
(4) House, H. O. Modern Synthetic Reactions; W. A. Benjamin Inc.,
California, 1972.
(5) (a) Blake, C. H.; Hartwing, J . F. J . Am. Chem. Soc. 1997, 119,
12382. (b) Ahman, J .; Wolfe, J . P.; Trouton, M. V.; Paluki, M.;
Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 1918.
(8) (a) Galli, C.; Bunnett, J . F. J . Org. Chem. 1984, 49, 3041. (b)
Galli, C.; Gentili, P. J . Chem. Soc., Perkin Trans. 2 1993, 1135. (c)
van Leeuwen, M.; McKillop, A. J . Chem. Soc., Perkin Trans. 1 1993,
2433. (d) Nazareno, M. A.; Rossi, R. A. J . Org. Chem. 1996, 61, 1645.
(e) Murgu´ıa, M. C.; Rossi, R. A. Tetrahedron Lett. 1997, 38, 1355.
(9) Beugelmans, R.; Bois-Choussy, M. Heterocycles 1987, 26, 1863.
(10) Baumgartner, M. T.; Gallego, M. H.; Pierini, A. B. J . Org. Chem.
1998, 63, 6394.
(11) Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron
1993, 49, 235. Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C.
Phosphorus, Sulfur Silicon 1993, 7.
(12) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1997, 119,
12382.
(6) For reviews, see: (a) Rossi, R. A., de Rossi, R. H. Aromatic
Substitution by the SRN1 Mechanism; ACS Monograph 178; American
Chemical Society: Washington, D.C., 1983. (b) Bowman, W. R. Chem.
Soc. Rev. 1988, 17, 283. (c) Norris, R. K. Compr. Org. Synth. 1991, 4,
451 (Trost B. M. Ed.). (d) Rossi, R. A.; Pierini, A. B.; Pen˜e´n˜ory, A. B.
The Chemistry of Functional Groups; Patai, S., Rappoport, Z., Ed.;
Wiley: Chichester, 1995; Supl. D2, Chapter 24, p 1395.
(7) (a) Petrillo, G.; Novi, M.; Garbarino, G.; Dell′Erba, C. Tetrahe-
dron 1987, 43, 4625. (b) Petrillo, G.; Novi, M.; Dell′Erba, C.; Tavani,
C.; Berta, G. Tetrahedron 1990, 46, 7977. (c) Dell′Erba, C.; Novi, M.;
Petrillo, G.; Tavani, C.; Bellandi, P. Tetrahedron 1991, 47, 333.
10.1021/jo990327m CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/29/1999

6488 J . Org. Chem., Vol. 64, No. 17, 1999
Notes
Ta ble 1. Rea ction of Ar yl a n d Neop en tyl Iod id es w ith
th e En ola te Ion s 1 a n d 6 in DMSOa
substn
nucleophile
substrate
t-BuOK
product
expt (M × 103)
(M × 103)
(M × 103) X-b
(%)c
1
1, 83.7
1, 62.2
1, 73.8
1, 76.8
1, 69.1
1, 90.8
1, 79.0
1, 76.6
1, 76.6
PhI, 27
PhI, 27
PhI, 27
PhI, 22.5
1-IC10H7, 27.4
1-IC10H7, 27.4
1-IC10H7, 22.9
(CH3)3CCH2I, 42.5
PhCH2(CH3)2CCH2I,
30.2
98
107
104
41
41
69
81
125
125
100 2, 98
<7
2d,e
3e,f
4g
5
<5
2, 53
Com p etition Exp er im en ts. The relative reactivities
of 1, 6, and the enolate ion of acetophenone (8) toward
iodobenzene under photoinitiation were determined in
competition experiments.15 It was found that 1 is 2.6
times more reactive than 8. On the other hand, 6 and 8
have similar reactivity (Table 2).
The present experimental evidence leads us to conclude
that enolate ions 1 and 6 react with aryl and neopentyl
iodides to afford good yields of substitution products by
the SRN1 mechanism. The higher reactivity of these
anions under photoinitiation shows that they are able to
participate in initiation in contrast to the enolate ions of
the five-membered-ring analogues 2-acetylthiophene (9)
or 2-acetylfuran (10). Although all these carbanions react
with iodobenzene in the presence of FeBr2, only carban-
ions 1 and 6 react under irradiation, and even spontane-
ous initiation occurs with carbanion 6.
106 3, 78
6g
7f
8
3, 17h
15 3, 7
100 4, 85
82 5, 45
9
10
6, 84.3
6, 84.3
6, 84.3
6, 84.3
6, 84.3
PhI, 27
PhI, 27
PhI, 27
PhI, 27
80
67
90
99
92
99 7, 89
26 7, 23
46 7, 34
23 7, 18
7, 14
11d
12f
13f,d
14g
PhI, 27
a
Photostimulated reactions (unless indicated) carried out under
nitrogen at 40 °C in 20 mL of DMSO with an excess of t-BuOK to
b
avoid condensation products. Irradiation time: 180 min. Deter-
mined potentiometrically. c Quantified by GLC and the internal
d
standard method. p-Dinitrobenzene (30 mol %) was added.
e More than 90% of substrate was recovered. f Dark reaction.
g Dark reaction in the presence of FeBr2 (90 mol %). Reaction time
h
30 min, 25 °C. Naphthalene was quantified (<5%).
Since the SRN1 mechanism is a chain process, overall
reactivity depends on the step under consideration. Thus
while carbanion 6 seems to be a better initiator than 1,
it has a lower reactivity in the coupling reaction toward
phenyl radicals, as determined by the competition experi-
ments (Table 3).
These reactions open an alternative route to R-substi-
tuted acetylpyrroles, even by reaction with neopentyl
iodides, which are largely unreactive under polar sub-
stitution reactions. They also demonstrate that carban-
ions 1 and 6 are efficient nucleophiles in the different
steps of the reaction, giving good yields of substitution
without the need of added initiators (entrainment condi-
tions).
The reaction was inhibited by p-dinitrobenzene (p-
DNB), a good radical anion scavenger.6 No substitution
product was formed in the absence of light stimulation.
The dark reaction in the presence of FeBr2 gives 53% of
product (Table 1, experiments 1-4).
The reaction of 1 with 1-iodonaphthalene yields 78%
of substitution product 3 under irradiation (eq 6). The
reaction is sluggish in the dark, even in the presence of
FeBr2 (Table 1, experiments 5-7).
Exp er im en ta l Section
Gen er a l Meth od s.10 Column chromatography was performed
on silica gel (70-270 mesh ASTM). Radial TLC was performed
using silica gel 60 PF-254 with calcium. Distillation at reduced
pressure was performed in a Ku¨gelrohr apparatus. Irradiation
was conducted in a reactor equipped with two 400-W lamps
emitting maximally at 350 nm (Philips Model HPT, air and
water refrigerated). Potentiometric titration of halide ions was
performed in a pH meter using a Ag/Ag+ electrode.
Ma ter ia ls. PhI, FeBr2, 1-iodonaphthalene, neopentyl iodide,
and t-BuOK were commercially available and used as received.
DMSO was distilled under vacuum and stored under molecular
sieves (4 Å). 2,2-Dimethyl-1-iodo-3-phenylpropane was synthe-
sized as reported.16 Acetophenone was distilled and stored with
molecular sieves (4 Å). 2- and 3-acetyl-1-methylpyrroles were
distilled.
Neopentyl iodide reacts with acetophenone enolate ion
under irradiation in DMSO but is unable to react with
acetone enolate ion; instead reduction mainly occurs.13
On the other hand, the photostimulated reactions of
neopentyl iodide and a related substrate, 2,2-dimethyl-
1-iodo-3-phenylpropane, with the anion 1 afford 85% and
45% of substitution products 4 and 5, respectively (eq 7)
(Table 1, experiments 8-9).
(15) The equation used in the relative reactivity determination of
pairs of nucleophiles vs a radical is shown below,
The enolate ion of 3-acetylmethylpyrrole 6 reacted with
iodobenzene under irradiation to afford 89% of product
714 (eq 8). Lower yields were found in the presence of
p-DNB or in dark conditions, with or without FeBr2
(Table 1, experiments 10-14).
k1 ln([Nu1]0/[Nu1]t)
)
k2
ln([Nu2]0/[Nu2]t)
where [Nu1]0 and [Nu2]0 are initial concentrations and [Nu1]t and [Nu2]t
are concentration at time t of both nucleophiles. This equation is based
on a first-order reaction of both anions with the phenyl radicals, see:
Bunnett, J . F. In Investigation of Rates and Mechanisms of Reactions,
3rd ed.; Lewis, E. S., Ed.; Wiley-Interscience: New York, 1974; Part
1, p 159.
(13) Pen˜e´n˜ory, A. B.; Rossi, R. A. Gazz. Chim. Ital. 1995, 125, 605.
(14) Massa, S.; Di Santo, R.; Artico, M. Synth. Commun. 1989, 19,
2721.
(16) Yuan, K.; Scott, W. J . J . Org. Chem. 1990, 55, 6188.

Notes
J . Org. Chem., Vol. 64, No. 17, 1999 6489
Ta ble 2. Com p etition Exp er im en ts betw een Ca r ba n ion s
1, 6, a n d 8 tow a r d Iod oben zen e
7.22-7.17 (dd, 1H), 6.86-6.78 (dd, 1H), 6.21-6.13 (dd, 1H), 4.54
(s, 2H), 3.89 (s, 3H). 13C NMR δ 188.5 (c), 133.9 (c), 132.5 (c),
132.1 (c) 131.4, 130.4, 128.7, 128.1, 127.6, 126.2, 125.6, 125.4,
124.2, 119.4, 108.1, 43.3, 37.6. HRMS (MH+) calcd 249.115364,
found 249.115811.
substitution product
Nu1
Nu2
(M × 103)
(M × 103) (M × 103)
kNu1/kNu2
P en tan on e, 1-(1-Meth yl-1H-pyr r ole-2-yl)-4,4-dim eth yl (4).
Purified by radial TLC (eluted with petroleum ether/diethyl
ether 95:5). MS m/e: 193 (9.3), 136 (11.2), 108 (100). 1H NMR δ
6.91-6.99 (dd, 1H), 6.76-6.82 (dd, 1H), 6.08-6.16 (dd, 1H), 3.93
(s, 3H), 2.80-2.66 (m, 2H), 1.52-1.69 (m, 2H), 0.94 (s, 9H). 13C
NMR δ 192.4, 130.7, 118.8, 107.7, 105.0, 39.4, 37.7, 34.5, 30.3,
29.2. HRMS (MH+) calcd 194.154489, found 194.153649.
1 (0.610) 6 (0.783) 2 (0.132) 7 (0.084)
k1/k6 2.1 ( 0.2
k1/k6 2.9 ( 0.2
k1/k6 2.5 ( 0.4
1 (0.578) 6 (1.29)
2 (0.120) 7 (0.097)
average:
1 (0.607) 8 (0.783) 2 (0.155) Ph-8a (0.085) k1/k8 2.6 ( 0.4b
6 (0.560) 8 (1.20)
6 (0.576) 8 (0.721) 7 (0.034) Ph-8a (0.063) k6/k8 0.67 ( 0.06
average: k6/k8 0.73 ( 0.08
7 (0.027) Ph-8a (0.073) k6/k8 0.79 ( 0.06
P en ta n on e, 1-(1-Meth yl-1H-p yr r ole-2-yl)-4,4-d im eth yl-5-
p h en yl (5). Isolated by radial TLC (eluted with petroleum ether/
diethyl ether 90:10). The liquid isolated was distilled in the
Ku¨gelrohr. MS m/e: 269 (7.5), 178 (84.6), 136 (36.1), 108 (100).
1H NMR δ 7.34-7.09 (m, 5H), 7.00-6.91 (dd, 1H), 6.83-6.75
(m, 1H), 6.16-6.08 (dd, 1H), 3.93 (s, 3H), 2.84-2.73 (m, 2H),
2.55 (s, 2H), 1.74-1.60 (m, 2H), 0.90 (s, 6H). 13C NMR δ 192.0,
138.9, 130.8, 130.6, 127.6, 125.8, 118.8, 107.8, 43.4, 37.7, 37.4,
34.3, 34.1, 26.7. HRMS (MH+) calcd 270.185790, found
270.185647.
a
b
R-Phenylacetophenone. Duplicate run.
Ta ble 3. Rea ctivities of Ar om a tic Keton e En ola tes
tow a r d Iod oben zen e in DMSO
Ack n ow led gm en t. This work was supported in part
by the Consejo de Investigaciones de la Provincia de
Co´rdoba (CONICOR), the Consejo Nacional de Investi-
gaciones Cient´ıficas y Te´cnicas (CONICET), and Secyt,
Universidad Nacional de Co´rdoba, Argentina. We thank
Prof. Pelayo Camps of the University of Barcelona,
Spain, for his help in recording the HRMS in the
Laboratorio de Espectrometr´ıa de Masas, CSIC.
P h otostim u la ted Rea ction . The procedure was as previ-
ously reported.10 The reaction mixture was extracted with
methylene chloride and water. The methylene chloride was
removed under reduced pressure. The substitution products were
isolated by column chromatography on silica gel and eluted with
petroleum ether/diethyl ether (90:10). The reaction of iodoben-
zene with carbanions 1 and 6 afforded ethanone, 1-(1-methyl-
1H-pyrrole-2-yl)-2-phenyl (2)12 and ethanone, 1-(1-methyl-1H-
pyrrole-3-yl)-2-phenyl (7),14 respectively.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 3-5. This material is available free of
charge via the Internet at http://pubs.acs.org.
E t h a n on e, 1-(1-Met h yl-1H -p yr r ole-2-yl)-2-(1-n a p h t h yl)
(3). Purified by radial TLC (eluted with petroleum ether/diethyl
1
ether 95:5). MS m/e: 249 (9.34), 141 (7.88), 108 (100). H NMR
δ 8.05-7.94 (m, 1H), 7.89-7.70 (m, 2H), 7.53-7.35 (dd, 4H),
J O990327M