An unusual dehalogenation in the Suzuki coupling of 4-bromopyrrole-2-carboxylates

Article abstract of DOI:10.1016/S0040-4039(02)02615-1

An unusual dehalogenation of 4-bromopyrrole-2-carboxylates under Suzuki coupling conditions has been observed. This dehalogenation can be suppressed by protection of the pyrrole nitrogen. Using a BOC protecting group, not only is dehalogenation suppressed

Full text of DOI:10.1016/S0040-4039(02)02615-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 427–430
An unusual dehalogenation in the Suzuki coupling of
4-bromopyrrole-2-carboxylates
Scott T. Handy,* Howard Bregman, Jennifer Lewis, Xiaolei Zhang and Yanan Zhang
Department of Chemistry, State University of New York at Binghamton, Binghamton, NY 13902, USA
Received 16 September 2002; revised 18 November 2002; accepted 19 November 2002
Abstract—An unusual dehalogenation of 4-bromopyrrole-2-carboxylates under Suzuki coupling conditions has been observed.
This dehalogenation can be suppressed by protection of the pyrrole nitrogen. Using a BOC protecting group, not only is
dehalogenation suppressed, but the protecting group is also removed under the reaction conditions. © 2002 Elsevier Science Ltd.
All rights reserved.
Pyrroles are an important family of heterocyclic com-
pounds. In particular, modified pyrroles and
polypyrroles are the basis of a wide range of biologi-
cally important natural products.1 Not surprisingly,
there are a considerable number of methods available
for the preparation of substituted pyrroles. Interest-
ingly, many of these methods involve the final forma-
tion of the pyrrole nucleus from functionalized
precursors. Far fewer approaches take pyrrole itself and
elaborate this core. In part this is doubtless due to the
greater difficulties associated with the regiocontrolled
functionalization of pyrrole when compared to furan
and thiophene.2
Although dehalogenation is not an uncommon side
reaction in Stille couplings, it is unusual for it to be the
dominant reaction pathway.4 Indeed, Stille couplings
have been employed by Banwell and co-workers in their
synthesis of Lamellarins O and Q.5 Similarly, Scott and
co-workers have used a 4-stannylpyrrole carboxalde-
hyde in the preparation of a number of arylated pyrrole
carboxaldehydes.6 In all of these cases, the yields were
>66%.
Faced with this problem, the first alternative that we
explored was to change the type of cross-coupling
reaction. Our choice was a Suzuki-type coupling, since
dehalogenation is far less common in these reactions.7
As can be seen in Scheme 2, coupling with phenyl-
boronic acid did lead to some improvement in terms of
the preparation of the desired coupling adduct 2. Still,
the best result that was obtained was 55% of compound
2 along with 28% of debrominated compound 3. This
ratio proved to be highly variable, with the ratio of
these two compounds often times being closer to 1:1,
although with good mass recovery (>80%).
As part of a program directed at the preparation of
members of the lamellarin family of natural products,
we were interested in developing a method to install
three separate aryl substituents in a regiocontrolled
manner on a pyrrole-2-carboxylate ester.3 Our plan was
based on the ability to control the regiochemistry of
halogenation of the pyrrole core and using this selectiv-
ity to control the location of the three aryl subunits.
The beginning of these studies involved the coupling of
4-bromopyrrole-2-carboxylate ethyl ester 1 (Scheme 1).
Much to our surprise, the attempted Stille coupling of 1
with tributylphenyltin under standard conditions led to
the generation of the desired coupling product 2 as the
minor product (<35%), with debrominated compound 3
being the major isolated product (>50%).
Keywords: Suzuki coupling; pyrroles; dehalogenation; protecting
group.
* Corresponding author. Tel.: 607-777-4825; fax: 607-777-4478;
e-mail: shandy@binghamton.edu
Scheme 1. Dehalogenation in the Stille coupling reactions of
4-bromopyrrole-2-carboxylate 1.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02615-1

428
S. T. Handy et al. / Tetrahedron Letters 44 (2003) 427–430
Table 2. Suzuki couplings with BOC-protected systems
Scheme 2. Dehalogenation in the Suzuki couplings of 4-bro-
mopyrrole-2-carboxylate 1.
Entry
Ar
%Yielda
1
2
3
4
3,4-Dimethoxyphenyl
4-Fluorophenyl
3-Isopropoxy-4-methoxyphenyl
2,3,4-Trimethoxyphenyl
80 (58)b
68
82
Although the two products could be readily separated
by chromatography, the presence of such a significant
degree of dehalogenation was troubling. In examining
the major differences between our couplings and those
reported in the literature, it was noted that in most
cases the previous syntheses involve the use of N-pro-
tected pyrrole esters.8 To see if the free NH moiety was
indeed the source of the problem, protection of the
pyrrole amine was explored.9 The four protecting
groups seen in Table 1 were prepared using standard
methods. The TIPS group, although ideal due to the
ease of its deprotection, failed to survive the reaction
conditions required for the coupling (entry 1). Indeed,
the TIPS group appeared to be removed at a rate
competitive with the coupling reaction, since a nearly
1:1 mixture of coupling product 2 and debrominated
product 3 was obtained.
84 (65)
a Isolated yield.
b 1.2 equiv. of boronic acid.
With these improved conditions in hand, a series of
couplings with BOC-protected pyrrole 1 were explored
(Table 2).11 As can be seen, these reactions afford
uniformly good results. Although the use of only slight
excess of the boronic acid (1.2 equiv.) afforded the
coupling products in 58–65% yield, these yields could
be further improved by using a larger excess of the
boronic acid (2–3 equiv.). In this way, 68–84% yields of
the 4-arylated products 4 can be readily obtained with
only trace amounts (<5%) of the dehalogenation
product 3.
Alkyl protecting groups were more stable to the reac-
tion conditions (Table 1, entries 2 and 3) and did
indeed suppress any dehalogenation. This observation
supported our concerns regarding the free NH group
being the factor leading to dehalogenation. At the same
time, these alkyl protecting groups could be difficult to
remove following the coupling reaction. From this per-
spective, a BOC group appeared to be ideal. Indeed, the
Suzuki coupling of BOC-protected 1 with phenyl
boronic acid led to almost exclusive preparation of
compound 2 in which the protecting group has been
removed under the reaction conditions, but presumably
only after coupling has occurred (entry 4).10
With respect to the dehalogenation reaction, the exact
combination of electronic and regiochemical effects
required for it to occur are not yet clear. Examining
first 4-halopyrrole esters, good yields have been
reported for the coupling of an unprotected 5-alkyl-3,4-
dibromopyrrole ester,12 3,5-dialkyl-4-bromopyrrole
ester,12 and 3,4-dibromopyrrole ester.5 Seemingly, all of
these reports are at variance with our observations with
pyrrole ester 1, although in every case the exact elec-
tronics and substitution pattern are different. We have
also noted that 4,5-dibromopyrrole ester 5 exhibits
dehalogenation, but only at C4, affording a mixture of
bis-coupling product 6 and mono-coupling product 7
(Scheme 3).
Table 1. Influence of pyrrole protecting group on the
degree of dehalogenation
For 5-halopyrrole esters, very little information is avail-
able. The only substrates that have been reported are
not protected (compound 8 and a 3,4-extended 5-bro-
mopyrrole ester reported by Murashima).13 In all cases,
no significant dehalogenation was reported.
Finally, for 3-halopyrrole esters, the reports again are
conflicting. We have observed no dehalogenation in the
Suzuki coupling of an unprotected substrate such as 10.
Similarly, a 1,4,5-trialkylated-3-trifloxypyrrole ester is
reported to afford an excellent yield of the desired
coupling product.14 On the other hand, Ghosez has
noted significant dehalogenation in the coupling of an
N-tosylated 2-vinyl-iodopyrrole.15 This dehalogenation
can be controlled by modification of the palladium
catalyst.
Entry
Ra
%2/%3b
1
2
3
4
TIPS
Me
Bn
48/35c
75/–
72/–
BOC
68/5c
a Pd(Ph3P)4 (2 mol%), aq. Na2CO3/DMF, 110°C.
b Isolated yield.
c Protecting group lost, R=H in products

S. T. Handy et al. / Tetrahedron Letters 44 (2003) 427–430
429
H.; Fenical, W. J. Org. Chem. 1997, 62, 3254–3262 and
references cited therein.
4. For a discussion of dehalogenations in Stille couplings,
see: Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic
Reactions; John Wiley & Sons: New York, 1997; Vol. 50.
5. Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C.
R. Chem. Commun. 1997, 207–208.
6. Wang, J.; Scott, A. I. Tetrahedron Lett. 1996, 37, 3247–
3250.
7. Remarkably few reports provide any details regarding
dehalogenations in Suzuki coupling reactions, although a
few comment simply that dehalogenation is observed as a
secondary product. Two major exceptions are: Haseltine,
J.; Wang, D. J. Heterocyclic Chem. 1994, 31, 1637–1639
and Ref. 15.
8. For references to cross-coupling reactions with pyrroles,
see Refs. 5, 10, 12–15 and: Liu, J.-H.; Yang, Q.-C.; Mak,
T. C. W.; Wong, H. N. C. J. Org. Chem. 2000, 65,
3587–3595; Zhou, X.; Tse, M. K.; Wan, T. S. M.; Chan,
K. S. J. Org. Chem. 1996, 61, 3590–3593; Alvarez, A.;
Guzman, A.; Ruiz, A.; Velarde, E.; Muchowski, J. M. J.
Org. Chem. 1992, 57, 1653–1656; Banwell, M.; Edwards,
A.; Smith, J.; Hamel, E.; Verdier-Pinard, P. J. Chem.
Soc., Perkin Trans. 1 2000, 1497–1499; Dupont, C.;
Guenard, D.; Thal, C.; Thoret, S.; Gueritte, F. Tetra-
hedron Lett. 2000, 41, 5853–5856.
Scheme 3. Couplings with 3-halo, 5-halo, and 4,5-dihalo
pyrrole esters.
In light of these results, there are still a number of
questions concerning the electronic and regiochemical
features that facilitate the dehalogenation reaction of
halopyrrole esters. What can be stated with assurance is
that the 4 position of unsubstituted pyrrole-2-carboxyl-
ates is particularly prone to dehalogenation under
cross-coupling conditions. This dehalogenation can be
avoided by use of a protecting group on the pyrrole
nitrogen. With a BOC group, the protecting group is
also cleaved under the coupling conditions, thereby
avoiding a separate deprotection step. The mechanism
of this facile dehalogenation and its implications for
Suzuki couplings of halopyrroles in general is currently
under investigation and will be reported in due course.
9. Interestingly, as we were pursuing these investigations,
Dr. Cai of Hoffmann-La Roche informed us of a similar
observation that they have made in the coupling of
3-bromoindoles in which protection of the indole nitro-
gen is required to avoid extensive dehalogenation.
10. This deprotection appears to be a thermal reaction. We
have noted that simply heating a solution of pyrrole ester
1 in DMF to 120°C for 6 h is sufficient to completely
remove the BOC group. Lower temperatures (100°C) do
not cleave the BOC group. For similar observations, see:
(BOC removal), Fuerstner, A.; Grabowski, J.; Lehmann,
C. W. J. Org. Chem. 1999, 64, 8275–8280. (BOC
retained), Johnson, C. K.; Stemp, G.; Anand, N.;
Stephen, S. C.; Gallagher, T. Synlett 1998, 1025–1027.
11. General procedure for the coupling reaction: To a round-
bottom flask was added 100 mg (0.32 mmol) of BOC-pro-
tected pyrrole ester 1. DMF (2.5 mL) was added and the
mixture stirred under argon. To this solution was then
added sequentially 33 mg (0.016 mmol) of palladium
tetrakis-triphenylphosphine and 167 mg (0.79 mmol) of
2,3,4-trimethoxyphenylboronic acid. The mixture was
heated to 70°C and 540 mg (2.88 mmol) of sodium
carbonate dissolved in minimal water added. The reac-
tion was then heated to 110°C for 14 h. After cooling to
rt, the reaction was diluted with water (15 mL) and
extracted with diethyl ether (3×15 mL). The organic
layers were dried with magnesium sulfate, filtered, and
concentrated in vacuo. Chromatography (20% ethyl ace-
tate/hexanes) afforded 82.0 mg (84%) of ethyl 4-(2%,3%,4%-
trimethoxyphenyl)pyrrole-2-carboxylate as a white solid.
1H NMR (360 MHz, CDCl3) 9.16 (br s, 1H), 7.41 (m,
1H), 7.20 (m, 1H), 7.18 (d, 7.2 Hz, 1H), 6.70 (d, J=7.2
Hz, 1H), 4.33 (q, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.81 (s,
3H), 1.37 (t, 3H); 13C NMR (90 MHz, CDCl3) 161.14,
152.11, 150.87, 142.77, 122.66, 122.15, 122.09, 121.60,
121.40, 113.69, 107.69, 60.86, 60.34, 60.24, 55.98, 14.43.
Spectral data for other coupling products: ethyl 4-(4%-iso-
Acknowledgements
The authors thank the State University of New York at
Binghamton and the Research Foundation for financial
support of this work. The authors also thank Dr.
Jianping Cai at Hoffmann-La Roche for comments and
suggestions regarding the dehalogenation results.
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430
S. T. Handy et al. / Tetrahedron Letters 44 (2003) 427–430
propoxy-3%-methoxyphenyl)pyrrole-2-carboxylate:
1H
1
4-(3%,4%-dimethoxyphenyl)pyrrole-2-carboxylate: H NMR
(360 MHz, CDCl3) 9.13 (br s, 1H), 7.16–7.13 (m, 2H),
7.09 (s, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.86 (d, J=8.2 Hz,
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Hz, 1H), 4.52 (septet, 1H), 4.26 (q, 2H), 4.33 (s, 3H), 1.37
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CDCl3) 160.55, 150.00, 146.30, 126.63, 125.33, 123.52,
119.90, 115.42, 115.24, 111.60, 102.80, 71.31, 60.81, 55.89,
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1
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126.69 (d, J(C,F)=7.2 Hz), 125.81, 123.67, 119.21,
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