Acid catalyzed halogen dance on deactivated pyrroles

Article abstract of DOI:10.1002/jhet.276

(Chemical Equation Presented) A study on the acid catalyzed halogen dance (ACHD) on deactivated bromopyrroles is reported. A different behavior is observed when considering singly deactivated pyrrole alkylcarboxamides, or doubly deactivated pyrroleketo-lactams (aldisines). Although less electron deficient pyrrole alkylcarboxamides suffer from ACHD, the double deactivation on keto-lactams disfavors pyrrole ring protonation thus preventing halogen scrambling. The mechanism involved in the rearrangement is hypothesized.

Full text of DOI:10.1002/jhet.276

112
Acid Catalyzed Halogen Dance on Deactivated Pyrroles
Federico Tutino,a Gianluca Papeo,b and Francesca Quartieria*
Vol 47
aDepartment of Chemical Core Technologies, Nerviano Medical Sciences, Nerviano,
Milan 20014, Italy
bDepartment of Medicinal Chemistry, Nerviano Medical Sciences, Nerviano, Milan 20014, Italy
*E-mail: francesca.quartieri@nervianoms.com
Received July 31, 2009
DOI 10.1002/jhet.276
Published online 5 January 2010 in Wiley InterScience (www.interscience.wiley.com).
A study on the acid catalyzed halogen dance (ACHD) on deactivated bromopyrroles is reported. A
different behavior is observed when considering singly deactivated pyrrole alkylcarboxamides, or doubly
deactivated pyrroleketo-lactams (aldisines). Although less electron deficient pyrrole alkylcarboxamides
suffer from ACHD, the double deactivation on keto-lactams disfavors pyrrole ring protonation thus pre-
venting halogen scrambling. The mechanism involved in the rearrangement is hypothesized.
J. Heterocyclic Chem., 47, 112 (2010).
INTRODUCTION
previously postulated for the isomerization of 2-acety-
lindoles [6]. Rearrangement as side-reaction, on the
contrary, was observed in the sulfinylation of pyrroles
with sulfinylchlorides: 2-sulfinylpyrroles were contami-
nated by 3-sulfinyl isomers, likely coming from an
acid-catalyzed migration of the substituent in 2-position
due to HCl released during the reaction [4]. Moreover,
PPA-mediated cyclization of 3-(2-pyrrolyl)propionic
acids afforded the expected products along with unde-
sired regioisomers arising from both alkyl and acyl
migration [3(a)]. Complex reaction mixtures were also
obtained when pyrrole was treated with molecular bro-
mine: beside the expected 2-bromopyrrole, products
deriving from both isomerization and disproportionation
of the brominated substrate were detected [5(a)]. The
mechanism of bromine isomerization and disproportio-
nation of N-benzyl-2-bromopyrrole in the presence of
TFA has been recently investigated by Park et al., who
suggested a 1,3-bromine shift to explain rearrangement
on the corresponding N-benzyl-2-bromo-5-deuterio pyr-
role [5(c)].
The first example of the well-known Halogen Dance
(HD, also named halogen scrambling, halogen migra-
tion, halogen isomerization, halogen shift) reaction dates
back to 1951, when Vaitiekunas isolated tetrabromothio-
phene instead of 2-ethynylthiophene by treating 2-bro-
mothiophene with sodium acetylide in liquid ammonia
[1]. The reaction was induced by the presence of the
base and since then it has been largely investigated.
Currently, the base catalyzed halogen dance (BCHD) is
considered a useful tool for the introduction of halogen
on aromatic and heteroaromatic substrates in positions
that could be hardly reached with other methods. A
recently published review thoroughly describes BCHD
with elucidations of the mechanism and description of
the factors that influence the reaction [2]. Among all the
heteroaromatic substrates, no examples on pyrrole have
been reported.
What is known in the literature referring to pyrroles
solely deals with the effect of acids on substituents in
the 2 position of the ring. In this context, acyl [3] and
sulfinyl [4] moieties as well as halogens (bromine and
chlorine) [5] have been considered. Rearrangement of
2-acylpyrroles aimed at the synthesis of 3-acyl isomers
has been studied in the presence of strong acids (PPA,
TFA). A [1,2]-acyl shift was hypothesized to rational-
ize the formation of the products [3(b)], as it was
Thus, if on one hand halogen dance may be useful
for the insertion of groups in specific positions of aro-
matic and heteroaromatic substrates, on the other hand
it could represent a parasitic reaction when the shift of
the halogen is unwanted. This is the case, for instance,
of 2-bromoaldisine 1 (common name of 2-Bromo-6,7-
C
V
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Acid Catalyzed Halogen Dance on Deactivated Pyrroles
113
Scheme 2. ACHD on bromopyrrolecarboxamides 7 and 9.
performing the synthesis of bromoaldisines 1 and 6,
prompted us to study in more detail the ACHD on vari-
ously deactivated bromopyrroles in a strong acidic
environment.
Figure 1. Bromopyrrole alkaloids derived from 2-bromoaldisine 1.
To this purpose we decided, at first, to confirm the
observations previously published for the synthesis of 2-
bromo (1) and 3-bromoaldisine (8), by using the same
reaction conditions (reagents, temperature, and reaction
time) in the cyclization of 7 and 9 [11] (Scheme 2). As
described, treatment of 7 with PPA/P2O5 at 105ꢀC for
1 h produced a mixture of 1 and 8 in a 43:57 ratio
dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), envis-
aged as the key-intermediate for the synthesis of some
bromopyrrole alkaloids, such as (Z)-hymenialdisine 2
[7], (Z)-axinohydantoin 3, and (E)-axinohydantoin 4 [8]
(Fig. 1).
The synthesis of 1 was reported for the first time by
Annoura by means of a PPA/P2O5-mediated cyclization
of the corresponding 2-bromopyrrole propionic acid
[7(a)]. The reaction suffered from bromine scrambling,
delivering a 1:1 mixture of hardly separable bromoaldi-
sine regioisomers. Interestingly, this was the first exam-
ple of acid catalyzed halogen dance (ACHD) on deacti-
vated pyrroles.
1
(measured by H NMR). On the contrary, in our hands
regioisomer 9 [12] gave rise to a 15:85 mixture of 1 and
8 under the same conditions, in contrast with the litera-
ture (1:1 ratio as for 7) [7(a)].
In these examples, PPA/P2O5 mediates both cycliza-
tion and scrambling of bromine atom. With the aim of
trying to understand whether halogen dance (HD) took
place before or after cyclization, the same acidic treat-
ment was performed directly on brominated aldisines 1
and 8. 2-Bromoaldisine 1 was synthesized as already
described [8], while 3-bromoaldisine 8 was successfully
isolated from the enriched mixture (15:85) deriving
from 9 (see Scheme 2) by means of preparative HPLC.
The two substrates have then been subjected to PPA/
P2O5 treatment. The results highlighted minor differen-
ces, namely 2-bromoaldisine 1 was not prone at all to
This side-reaction was later efficiently avoided by
exploiting a Friedel-Craft-type cyclization on the acyl
chloride intermediate in the presence of AlCl3, affording
1 as the sole product in 69% optimized yield [8]. The
same synthetic protocol allowed the preparation of
2,3-dibromoaldisine 6 [9] from the corresponding dibro-
moacid 5 [10] in 85% yield without any bromine rear-
rangement, differently from what previously reported in
the presence of PPA/P2O5 [10] (Scheme 1).
RESULTS AND DISCUSSION
Scheme 3. ACHD on aldisines 1 and 8.
The different reaction outcomes that a protic acid
(PPA/P2O5) versus a Lewis acid (AlCl3) displayed while
Scheme 1. Lewis acid-mediated synthesis of 6.
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F. Tutino, G. Papeo, and F. Quartieri
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Scheme 5. ACHD on 11 and 13.
Table 1
Results of ACHD on 1, 8, 7, and 9 (105ꢀC, 1 h).
Entry
Substrate
1 (%)a
8 (%)a
1
2
3
4
1
8
7
9
100
2
–
98
57
85
43
15
a Measured by integrating pyrrole CH signal in 1H NMR spectrum.
rearrangement, while 3-bromoaldisine 8 produced a
small percentage (2%) of 2-bromoisomer 1 (Scheme 3).
This means that these keto-lactams hardly undergo halo-
gen scrambling and HD occurs before cyclization.
The observations of ACHD on these substrates are
summarized in Table 1.
that pyrrole alkylcarboxamides (i.e., 7, 9, 11, and 13)
are more prone to halogen rearrangement (Table 1,
Entries 3 and 4; Table 2) than aldisines (Table 1, Entries
1 and 2). Second, scrambling of the halogen is faster
when involving a shift from 2- to 3-position at the pyr-
role ring (Table 1, Entry 3; Table 2, Entry 1) than vice
versa (Table 1, Entry 4; Table 2, Entry 2). The ratio of
2-bromo and 3-bromoaldisine generated from 7 and the
distribution of 2- and 3-regioisomers deriving from 11
(Table 1, Entry 3; Table 2, Entry 1) are the same. This
means that the two mixtures reach the equilibrium dur-
ing the reaction (thermodynamic conditions). Moreover,
considering that aldisines are insensitive to ACHD, it is
fair to assert that, for 7, V2S > V2C, where V2S repre-
sents the velocity of scrambling, and V2C the velocity of
cyclization (Scheme 6).
Intrigued by these outcomes, we decided to evaluate
the effect of PPA/P2O5 on bromopyrroles that: (a) were
singly deactivated, like pyrrole alkylcarboxamides 7 and
9, and (b) could not undergo cyclization, differently
from 7 and 9. Bromopyrrole methylcarboxamides 11
and 13 [11] have been chosen as the suitable substrates
to the purpose, having the same EWG as 7 and 9. Their
synthesis is reported in Scheme 4: treatment of 2-tri-
chloroacetylpyrrole with methylamine and subsequent
bromination of 10 with NBS in THF/MeOH (2:1)
afforded 11 (60% yield over two steps). The direct bro-
mination of the same starting material with Br2 in
CHCl3 and subsequent reaction of intermediate 12 with
methylamine yielded 13 [13] (70% yield over two
steps).
On the contrary, the same treatment on 9 and 13 did
not spring out analogous results. The ratios of the two
aldisines (products of 9) and of 2- and 3-regioisomers
arising from 13 measured in the experiments are differ-
ent, meaning that these reaction mixtures are under
kinetic conditions. It is possible to postulate that, for 9,
V3C ꢁ V3S, meaning that the velocity of cyclization and
of scrambling are competitive (see Table 1, Entry 4).
Furthermore, rearrangement from 2-position of 7 and 11
is faster than from carbon 3 of 9 and 13, that explains
the higher velocity with which 11 and 7 reach the equi-
librium (V2S > V3S, see Table 1, Entries 3 and 4, and
Table 2). Finally, disproportionation on 7 and 9 and on
aldisines 1 and 6 has never been observed, while for 11
and 13 only to a less extent, meaning that this side-reac-
tion is the slowest (VD << VS and VC, being VD ¼ ve-
locity of disproportionation).
Both bromopyrroles 11 and 13 underwent rearrange-
ment in different ratios, along with disproportionation
that generated des-bromo derivative 10 and 4,5-di-bro-
momethylamide 14 (Scheme 5, Table 2).
As previously mentioned, the amount of the products
has been determined by integrating isolated pyrrole CH
1
signals in the H NMR spectra of the reaction mixtures
[Fig. 2(a,b)].
These results allowed us to make some considerations
about the kinetics/thermodynamics of the ACHD on
deactivated pyrroles compared to cyclization and to
hypothesize a possible mechanism. First, it is evident
Scheme 4. Synthesis of pyrrolecarboxamides 11 and 13.
Table 2
Results of ACHD on 11 and 13 (105ꢀC, 1 h).
Entry Substrate
11 (%)a
13 (%)a
10 (%)a 14 (%)a
1
2
11
13
32 (46)b 38 (54)b
25 (34)b 49 (66)b
15
13
15
13
a Measured by integrating isolated pyrrole CH signals in 1H NMR
spectrum.
b In brackets the relative percentage of 11 and 13 is reported.
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Acid Catalyzed Halogen Dance on Deactivated Pyrroles
115
Figure 2. 1H NMR analysis of ACHD on 11 (2a: top) and 13 (2b: bottom). [Color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
lated) were recorded at 25ꢀC in DMSO-d6 on a Varian Inova
A
rearrangement mechanism was postulated to
500 spectrometer equipped with a 5 mm 1H{13C,15N} z-axis-
PFG indirect detection cold probe or at 28ꢀC on a Varian Mer-
cury 300 spectrometer equipped with a 5 mm switchable probe
15N-31P{1H,19F}. Residual solvent signal was used as
explain ACHD (Scheme 7). In strong acid media, 7 and
11 are subjected to protonation at the 2-position of the
pyrrole affording 7a and 11a, respectively, which
undergo a 1,2-bromine shift toward 9a and 13a, passing
through transient cyclic bromonium intermediate 15.
The same mechanism can be invoked for 9 and 13, that
are protonated at 3-position generating 9a and 13a,
respectively. A cyclic bromonium intermediate has been
hypothesized instead of free Brþ cation because statisti-
cally this would have generated a higher amount of
dibrominated pyrrole from 11 and 13 (see Table 2) and
the presence of dibromo/desbromo aldisines from 7 and
9 (see Table 1).
Scheme 6. Velocity of cyclization versus scrambling.
EXPERIMENTAL
General. Melting points were determined in open glass
capillaries with a Buchi 535 melting point apparatus, and are
uncorrected. NMR spectra (1D 1H and 2D H-C hetero corre-
Journal of Heterocyclic Chemistry
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116
F. Tutino, G. Papeo, and F. Quartieri
Vol 47
Scheme 7. ACHD mechanism hypothesized.
reference; chemical shifts and coupling constants are reported,
respectively, in d (ppm) and Hz. ESI(þ) high-resolution mass
spectra (HRMS) were obtained on a Waters Q-Tof Ultima
directly connected with micro HPLC 1100 Agilent [14].
pressure, the residue was dissolved in water, made alkaline by
addition of 2N sodium hydroxide and then acidified to pH 2
with conc. HCl. The precipitate was filtered, washed with
water, and dried under vacuum. 6 was isolated as white solid
1
(334 mg, 85%). mp: 270–272ꢀC. H NMR (400 MHz, DMSO-
d6) d ppm 2.76 (m, 2 H) 3.34 (m, 2 H) 8.47 (br. s., 1 H) 13.46
(br. s., 1 H). 13C NMR (125.7 and 75.4 MHz, DMSO-d6) d
36.0, 44.3, 99.0, 110.3, 120.5, 130.6, 161.5, 192.6. HRMS
calcd for C8H7Br2N2O2 [MþHþ] 320.8869 found 320.8853.
3-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione
(8). The general procedure for ACHD was performed on 9
(170 mg, 0.65 mmol). One hundred thirty milligram of crude
were purified by prep-HPLC (eluant 0,05% NH3 in H2O/Ace-
tonitrile 95:5 as a mobile phase A and Acetonitrile as mobile
phase B), affording 8 (102 mg, 64%) as a white solid. The
separation was achieved using a rapid gradient increasing 0–
25% B in 15 min followed by a hold at 100% B for 2 min at
a flow rate of 20 mL/min. mp: 248–250ꢀC. 1H NMR (400
MHz, DMSO-d6) d ppm 2.76 (m, 2 H, CH2CO) 3.35 (m, 2 H,
CH2NH) 7.20 (s, 1 H, CHNH) 8.45 (t, J ¼ 5.12 Hz, 1 H,
NHCH2) 12.52 (br. s., 1 H, NH). 13C NMR (125.7 MHz,
DMSO-d6) d 35.6, 44.6, 96.7, 118.9, 124.0, 128.8, 161.5,
193.8, HRMS calcd for C8H8BrN2O2 [MþHþ] 242.9764 found
242.9759.
CONCLUSION
In conclusion, a study on the ACHD on deactivated
bromopyrroles has been reported and an hypothetical
mechanism has been suggested. A different behavior
was observed when considering singly deactivated pyr-
role alkylcarboxamides, or doubly deactivated pyrrole-
keto-lactams (aldisines). While less electron deficient
pyrrole alkylcarboxamides suffered from ACHD, the
double deactivation on keto-lactams disfavored protona-
tion thus preventing halogen scrambling. Moreover, in
the carboxamides series, scrambling was faster when
bromine atom was in the 2-position rather than on 3-car-
bon. In addition, during the conversion of pyrrole alkyl-
carboxamides
7 and 9 into aldisines, cyclization
occurred, respectively, after scrambling and at a compet-
itive velocity.
1H-Pyrrole-2-carboxylic acid methyl amide (10). To a
solution of 2-trichloroacetylpyrrole (2.12 g, 9.98 mmol) in
40 mL of dry CH3CN, a 2M solution of MeNH2 in THF was
added (12.5 mL, 25 mmol). The mixture was stirred under
nitrogen, at room temperature for 48 h, until HPLC revealed
the disappearance of the starting material. The solvent was
removed under reduced pressure to give 10 as white solid. mp:
EXPERIMENTAL
General procedure for ACHD. P2O5 (2 eq) and PPA (28
eq) were mechanically stirred and heated at 120ꢀC for 50 min,
to obtain a clear solution. The substrate was then added and
the mixture was heated at 105ꢀC for 1 h. The mixture was
poured into ice water and stirred for 1 h. The solid was filtered
off, washed with water, and dried. A second aliquot of reaction
mixture was recovered from the aqueous phase as follow: the
water solution was cooled, neutralized with concentrated
sodium hydroxide, and extracted with CH2Cl2. The organic
phase was dried over anhydrous Na2SO4, concentrated, and
combined with the solid.
1
151–152ꢀC. H NMR (400 MHz, DMSO-d6) d ppm 2.72–2.74
(d, 3 H, J ¼ 5 Hz, CH3) 6.06 (dt, J ¼ 3.63, 2.40 Hz, 1 H,
CHCHCH) 6.70 (ddd, J ¼ 3.69, 2.41, 1.46 Hz, 1 H, CHCHC)
6.82 (td, J ¼ 2.69, 1.46 Hz, 1 H, CHCHN) 7.89 (br. s., 1 H,
NHCH3) 11.37 (br. s., 1 H, NH).
5-Bromo-1H-pyrrole-2-carboxylic
acid
methylamide
(11). To a stirred solution of 10 (500 mg, 4.03 mmol) in dry
MeOH (84 mL) and dry THF (168 mL) at 0ꢀC, N-bromosucci-
nimide (NBS) (323 mg, 1.81 mmol) was added. The cold bath
was removed and the reaction mixture was allowed to warm to
room temperature under stirring. After 3 h, a HPLC control
revealed a 50% conversion of 10–11. The mixture was
recooled to 0ꢀC and more NBS (323 mg, 1.81 mmol) was
added. The ice bath was removed and the reactants were
stirred for further 2 h at room temperature. The solvent was
then removed under vacuum and the residue was purified by
flash chromatography (eluant Et2O/Hexane 2:1) to give 11 in
mixture with 14 as side product. 11 was isolated as white solid
by reverse-phase chromatography (eluant 0.1% trifluoroacetic
2,3-Dibromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-
4,8-dione (6). To a suspension of 5 (414 mg, 1.21 mmol) in
dry CH2Cl2 (15 mL) oxalyl chloride (0.21 mL, 2.43 mmol)
and DMFcat (0.015 mL) were added. The mixture was stirred
under nitrogen until completion of gas evolution. The solvent
was removed under reduced pressure and the crude was dis-
˚
solved in 1,2-dichloroethane (40 mL). 4-A molecular sieves
and aluminium trichloride (0.65 g, 4.87 mmol) were subse-
quently added. The red solution was stirred at room tempera-
ture overnight. After removal of the solvent under reduced
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Acid Catalyzed Halogen Dance on Deactivated Pyrroles
117
REFERENCES AND NOTES
acid in H2O/acetonitrile 95/5 as mobile phase A and Acetoni-
trile as mobile phase B) (490 mg, 60%). mp: 173–175ꢀC. 1H
NMR (400 MHz, DMSO-d6) d ppm 2.71 (d, J ¼ 4.64 Hz, 3
H, CH3) 6.11 (dd, J ¼ 3.72, 2.38 Hz, 1 H, CHCHCBr) 6.69
(dd, J ¼ 3.78, 2.69 Hz, 1 H, CHCHC) 7.93 (q, J ¼ 3.99 Hz, 1
H, NHCH3) 12.15 (br. s., 1 H, NH). 13C NMR (125.7 MHz,
DMSO-d6) d 25.0, 102.1, 110.5, 111.2, 128.8, 160.5. HRMS
calcd for C6H8BrN2O [MþHþ] 202.9815 found 202.9821.
4-Bromo-2-(trichloroacetyl)pyrrole (12). 2-(Trichloroace-
tyl)pyrrole (10 g, 0.05 mol) in CHCl3 (50 mL) was treated
with Br2 (9.5 g, 0.06 mol) in CHCl3 (3 mL) at 5ꢀC. The ice
bath was removed and the reactants were stirred for 1 h at
room temperature. The mixture was diluted with CH2Cl2 and
washed with H2O, NaHCO3, and brine. The organic layer was
dried (over Na2SO4) and concentrated under vacuum. The
crude was then crystallized from hexane-CH2Cl2 affording 12
(11.3 g, 70%). 1H NMR (400 MHz, DMSO-d6) d ppm 7.34
(dd, J ¼ 2.68, 1.46 Hz, 1 H, CCHC) 7.56 (dd, J ¼ 3.29, 1.46
Hz, 1 H, CHN) 12.85 (br. s., 1 H).
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4-Bromo-1H-pyrrole-2-carboxylic
acid
methylamide
(13). Compound 12 (575 mg, 1.98 mmol) was treated with a
2M solution of MeNH2 in THF (2.45 mL, 4.95 mmol) deliver-
ing 13 (400 mg, quantitative) as white solid after removal of
the solvent. mp: 178–180ꢀC. 1H NMR (300 MHz, DMSO-d6)
d ppm 2.70 (d, J ¼ 4.69 Hz, 3 H, CH3) 6.75 (dd, J ¼ 2.64,
1.47 Hz, 1 H, CHCBr) 6.92 (dd, J ¼ 2.93, 1.47 Hz, 1 H,
CHN) 8.01 (q, 1 H, NHCH3) 11.75 (br. s., 1 H, NH).
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Acknowledgments. The authors acknowledge Dr. Maurizio
Pulici and Dr. Sergio Mantegani for helpful suggestions and
enlightening discussions, Dr. Daniela Borghi for NMR consulting.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet