Reduction of pyrrolyl- and indolylamides with BH3·THF: Cyclodeoxygenation versus deoxygenation

Article abstract of DOI:10.1021/jo801627z

(Chemical Equation Presented) Herein we report that borane reductions of acylpyrroles and acylindoles that contain a pendant phenol take two different paths. Acylpyrroles undergo a reductive cyclization to make unusual chromanyl pyrroles. Treatment of related acylindoles under identical conditions results in deoxygenation without cyclization. The results are interpreted in terms of relative rates of cyclization and reduction of intermediate carbenium ions, where cyclization of the indole-stablized carbenium ion is slower.

Full text of DOI:10.1021/jo801627z

SCHEME 1
Reduction of Pyrrolyl- and Indolylamides with
BH3 ·THF: Cyclodeoxygenation versus
Deoxygenation
Kelin Li and Jon A. Tunge*
Department of Chemistry, 1251 Wescoe Hall DriVe,
2010 Malott Hall, The UniVersity of Kansas, Lawrence,
Kansas 66045-7582, and the KU Chemical Methodologies
and Library DeVelopment Center of Excellence, The
UniVersity of Kansas, 2121 Simons DriVe, SBC III,
Lawrence, Kansas 66047
SCHEME 2
tunge@ku.edu
ReceiVed July 23, 2008
arenes. Herein we report an interesting bifurcation in the
pathway of reductive deoxygenation of heteroaromatic amides
with a pendant phenol.
To begin, we synthesized dihydrocoumarin 1a using our acid-
catalyzed hydroarylation of phenols.1 Next, we investigated the
ring opening of the lactone with pyrrolyl lithium.6 Overall, the
two-step process provided acylpyrrole 6a in 88% yield (Scheme
2).
With these conditions in hand, we extended the ring opening
to the reaction of pyrrolyllithium with several different dihy-
drocoumarins. The results of the ring opening are summarized
in Table 1.
The yields of the ring-opening products seem quite dependent
on the substituents on the dihydrocoumarin core but are
generally acceptable and can be quite high. In addition,
performing the acyl substitution with indolyl lithium reagents
gives yields that are comparable to those obtained using pyrrolyl
lithium (7a,b, Table 1).7 It is interesting that 1H NMR
spectroscopic analysis shows that these products all exist
primarily as the open-chain phenolic amides 6. This is in contrast
to the analogous benzenoid ketones (2), which exist in equi-
librium with the cyclic hemiacetal (eq 1).2 It is perhaps even
more surprising in light of the remarkable stability exhibited
by tetrahedral intermediates derived from acylpyrroles and
acylindoles.8
Herein we report that borane reductions of acylpyrroles and
acylindoles that contain a pendant phenol take two different
paths. Acylpyrroles undergo a reductive cyclization to make
unusual chromanyl pyrroles. Treatment of related acylindoles
under identical conditions results in deoxygenation without
cyclization. The results are interpreted in terms of relative
rates of cyclization and reduction of intermediate carbenium
ions, where cyclization of the indole-stablized carbenium ion
is slower.
Previously, we have reported that 2,4-diaryl chromans 3 can
be conveniently obtained from phenols by a three-step procedure
involving hydroarylation of cinnamic acids,1 nucleophilic ring
opening of the resulting lactone, and diastereoselective reduction
using BF3 ·OEt2/R3SiH.2,3 While the reductive deoxygenation
of the phenolic ketone 2 proceeds via a cyclodeoxygenation
path, the reductive deoxygenation of the related amides provides
the open-chain amines exclusively.4 Given our interest in
exploring the biological activity of these derivatives,5 we became
interested in extending this protocol to the use of heteroaromatic
(1) Li, K.; Tunge, J. A. J. Org. Chem. 2005, 70, 2881–2883.
(2) Li, K.; Tunge, J. A. Org. Lett. 2006, 8, 4711–4714.
(3) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976–4978. (b) Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992, 57,
468–481. (c) Ellsworth, B. A.; Doyle, A. G.; Patel, M.; Caceres-Cortes, J.; Meng,
W.; Deshpande, P. P.; Pullockaran, A.; Washburn, W. N. Tetrahedron:
Asymmetry 2003, 3242–3247. (d) Terauchi, M.; Abe, H.; Matsuda, A.; Shuto,
S. Org. Lett. 2004, 6, 3751–3754.
Next, we subjected the N-acylpyrrole 6a to the conditions
that we had used previously for the reductive deoxygenation of
aliphatic amides (4).4a To our surprise, the major product of
(4) (a) Li, K.; Tunge, J. A. J. Comb. Chem. 2008, 10, 170–174. (b) Bussolari,
J. C.; Rehborn, D. C.; Combs, D. W. Tetrahedron Lett. 1999, 40, 1241–1244.
10.1021/jo801627z CCC: $40.75
Published on Web 10/08/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8651–8653 8651

TABLE 1. Synthesis of Acylpyrroles and Acylindoles
TABLE 2. Reductive Cyclization of Acylpyrroles
the reduction was that of reductive cyclization to form the
chroman derivative 8a as a 1:0.9 mixture of diastereomers (eq
2).
to give chromanyl pyrroles, and the yields are generally good,
ranging from 60% to 86%.9 Unfortunately, the diastereoselec-
tivities are generally poor, and the pattern of substituents on
the arene rings has little effect on the diastereomeric ratios.
Nonetheless, (pyrrolyl)tetrahyrdropyrans of this type are quite
rare in the literature,10,11 yet they may find uses similar to those
found for the more common (indolyl)tetrahydropyrans.12
With the goal of accessing the (indolyl)benzopyrans through
the same methodology, we treated the acylindole species (7)
under the same conditions that gave rise to reductive cyclization
Given that we had previously shown that aromatic ketones
undergo reductive cyclization under typical BF3 ·OEt2/R3SiH
deoxygenation conditions,2,3 we hypothesized that acylpyrroles
behave more like aromatic ketones than amides. However,
treatment of substrate 6a with BF3 ·OEt2/Et3SiH, which effected
the reductive cyclization of related aromatic ketones, led to a
complex mixture that did not contain any of the reductive
cyclization product 8a. Similarly, the arylketone substrates (2)
do not give cyclized products when treated with BH3. These
results indicate that the reduction of arylketones and acylpyrroles
proceed via different mechanisms.
(7) (a) Nakagawa, M.; Sodeoka, M.; Yamaguchi, K.; Tohru, H. Chem. Pharm.
Bull. 1984, 32, 1373–1384. (b) Katritzky, A. R.; Robinson, R. J. Chem. Soc.
1955, 2481–2485.
(8) (a) Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T. Tetrahedron
Lett. 1998, 39, 71. (b) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2002, 41, 3188–3191.
(9) For the synthesis of chromenylpyrroles, see: (a) Nahas, N. M.; Abdel-
Hafez, A. A. Heterocycl. Commun. 2005, 11, 263–272.
(10) (a) Kawana, M.; Sakae, E. Bull. Chem. Soc. Jpn. 1969, 42, 3539–3546.
(b) Kawana, M.; Sakae, E. Bull. Chem. Soc. Jpn. 1968, 41, 2552.
(11) For related tetrahydrofuran derivatives, see: (a) Kawana, M. Chem. Lett.
1981, 1541–1542. (b) Kawana, M.; Sakae, E. Bull. Chem. Soc. Jpn. 1969, 42,
3539–3546.
(12) (a) Reyes, F.; Fernandez, R.; Rodriguez, R.; Santiago, B.; de Eguilior,
C.; Francesch, A.; Cuevas, C. J. Nat. Prod. 2008, 71, 1046–1048. (b) Bouchikhi,
F.; Anizon, F.; Moreau, P. Eur. J. Med. Chem. 2008, 43, 755–762. (c) Mukherjee,
D.; Sarkar, S. K.; Chowdhury, U. S.; Taneja, S. C. Tetrahedron Lett. 2007, 48,
663–667. (d) Libnow, S.; Hien, M.; Michalik, D.; Langer, P. Tetrahedron Lett.
2006, 47, 6907–6909.
Next, we briefly investigated the generality of the reductive
cyclization; the results are shown in Table 2. All substrates react
(5) Chromans are biologically “privileged” structures: Horton, D. A.; Bourne,
G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893–930.
(6) Nicolaou, K. C.; Papahatjis, D. P.; Claremon, D. A.; Magolda, R. L.;
Dolle, R. E. J. Org. Chem. 1985, 50, 1440–1456.
8652 J. Org. Chem. Vol. 73, No. 21, 2008

SCHEME 3
of the acylpyrroles (eq 3). Interestingly, these substrates react
to provide the open-chain indole derivatives (9) that are aromatic
derivatives of the antimuscarinic pharmaceutical tolterodine.13,14
Thus, the reactivity that is observed for the acylindoles is that
expected for the “standard” reductive deoxygenation of amides
with BH3 ·THF.15
In conclusion, we have developed a reductive cyclization of
acylpyrroles that gives rise to chromanyl pyrroles. Evaluation
of the biological activities of compounds having this uncommon
scaffold is ongoing.
Experimental Section
General Procedure for the Addition of Lithium Pyrrol-1-
ide to Dihydrocoumarins. Pyrrole (0.48 mL, 0.96 mmol) was
dissolved in THF (2 mL) and cooled to -78 °C, and LDA (0.48
mL, 0.96 mmol) was added. The resulting solution of pyrrolyl
lithium was added dropwise to a suspension of dihydrocoumarin 1
(0.64 mmol) in toluene (15 mL) at -78 °C. The reaction mixture
was allowed to warm to room temperature, and stirring was
continued for 16 h. At this point, the reaction was quenched by
addition of saturated NaHCO3 (10 mL) and extracted with EtOAc
(50 mL). The resulting organic layer was dried (MgSO4) and
concentrated on a rotary evaporator. The residue was purified by
flash column chromatography.
General Procedure for the Borane Reduction of Subs-
trates 6 and 7. The heteroaromatic amide 6 or 7 (0.15 mmol) was
dissolved in THF (2 mL), and BH3 ·THF (1 M, 2 equiv) was added
dropwise. The resulting solution was heated to 60 °C for 16 h. At
this point the reaction was quenched with methanol (1 mL), and
the solvents were removed under vacuum. The remaining residue
was purified by flash column chromatography.
Finally, we would like to explain the interesting bifurcation
in reaction paths taken by acylindoles and acylpyrroles. Our
failure to achieve reductive cyclization of acylpyrroles using
Et3SiH/BF3 suggests that the cyclization does not take place
via lactol and oxocarbenium ion intermediates.2 Thus, the
mechanism for reduction of acylpyrroles and acylindoles likely
proceeds through free carbenium ion intermediates. The stabi-
lized carbenium ions can form after hydride reduction of the
carbonyl followed by ionization of the resulting borate (Scheme
3). At this point, the pyrrole stabilized carbenium ion is expected
to be more reactive and more sterically accessible than the
indole-stabilized carbenium ion.16 Thus, intramolecular trapping
of the carbenium ion by the phenol is rapid. In contrast, the
more stabilized and sterically larger indolyl carbenium ion does
not cyclize; rather it reacts with the small borane reducing agent.
Acknowledgment. We acknowledge support of this work by
the National Institutes of Health (KU Chemical Methodologies
and Library Development Center of Excellence, P50 GM069663).
WearegratefulfortheanalyticalassistanceofBenNeuenswander.
Supporting Information Available: General experimental,
complete compound characterization data, and copies of NMR
spectra and chromatograms. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) (a) Appell, R. A. Urology 1997, 50, 90–96. (b) Modiri, A. R.; Alberts,
P.; Gillberg, P. G. Urology 2002, 59, 963–968.
(14) Related acylaniline derivatives also undergo reductive deoxygenation
without cyclization.
(15) Brown, H. C.; Heim, P. J. Org. Chem. 1978, 38, 912–916.
(16) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem. Eur. J. 2003, 9,
2209–2218.
JO801627Z
J. Org. Chem. Vol. 73, No. 21, 2008 8653