Pyrrolodiazines. 6. Palladium-catalyzed arylation, heteroarylation, and amination of 3,4-dihydropyrrolo[1,2-α]pyrazines

Article abstract of DOI:10.1021/jo048898o

The palladium-catalyzed Suzuki cross-coupling reaction of arylboronic acids and 6-bromo- and 6,8-dibromo-3,4-dihydropyrrolo[1,2-α]pyrazines afforded 6-substituted and 6,8-disubstituted 3,4-dihydropyrrolo[1,2-α]pyrazines in good yields. Stille and Negishi coupling reactions have been used to prepare 6-heteroaryl-substituted derivatives in moderate yields by employing heteroaryl halides and 6-metalated 3,4-dihydropyrrolo[1,2-α]pyrazines as reaction partners. A variety of cyclic secondary amines have also been incorporated at position C-6 of 6-bromo-1-phenyl-3,4-dihydropyrrolo[1,2-α]pyrazine in the presence of the palladium catalyst Pd₂(dba)₃ in conjunction with BINAP as ligand. This amination reaction is one of the few reported examples of such a palladium-catalyzed transformation on a pyrrole ring, although the reaction could not be extended to less nucleophilic amines.

Full text of DOI:10.1021/jo048898o

Pyrrolodiazines. 6. Palladium-Catalyzed Arylation,
Heteroarylation, and Amination of
3,4-Dihydropyrrolo[1,2-a]pyrazines†
Isabel Castellote,‡ Juan J. Vaquero,*,‡ Javier Ferna´ndez-Gadea,§ and Julio Alvarez-Builla*,‡
Departamento de Quı´mica Orga´nica, Universidad de Alcala´, 28871-Alcala´ de Henares, Madrid, Spain,
and Lab. Janssen-Cilag, C/Rı´o Jarama s/n, Pol´ıgono Industrial, 45007-Toledo, Spain
juanjose.vaquero@uah.es
Received June 30, 2004
The palladium-catalyzed Suzuki cross-coupling reaction of arylboronic acids and 6-bromo- and 6,8-
dibromo-3,4-dihydropyrrolo[1,2-a]pyrazines afforded 6-substituted and 6,8-disubstituted 3,4-dihy-
dropyrrolo[1,2-a]pyrazines in good yields. Stille and Negishi coupling reactions have been used to
prepare 6-heteroaryl-substituted derivatives in moderate yields by employing heteroaryl halides
and 6-metalated 3,4-dihydropyrrolo[1,2-a]pyrazines as reaction partners. A variety of cyclic
secondary amines have also been incorporated at position C-6 of 6-bromo-1-phenyl-3,4-dihydro-
pyrrolo[1,2-a]pyrazine in the presence of the palladium catalyst Pd2(dba)3 in conjunction with BINAP
as ligand. This amination reaction is one of the few reported examples of such a palladium-catalyzed
transformation on a pyrrole ring, although the reaction could not be extended to less nucleophilic
amines.
Introduction
The core structure of pyrrolodiazine 11 is present in a
variety of biologically active molecules including some
natural alkaloids such as hinckdentine2 and the variolin
family3 (Figure 1). In simple derivatives, the activity is
strongly associated with the tetrahydro form of the
diazine moiety. For example, 1,2,3,4-tetrahydropyrrolo-
[1,2-a]pyrazine derivatives 2 exhibit antihypertensive,
ischemic, anxiolytic, and equistomicidal activities.1b,4 To
date, compounds with the core structure 2 have been
* To whom correspondence should be addressed.
† Dedicated to the memory of the organic chemist Dr. Juan C.
del Amo, who was killed in the terrorist attack in Madrid, Spain, on
March 11, 2004.
‡ Universidad de Alcala´.
§ Lab. Janssen-Cilag.
(1) (a) Amarnath, V.; Madhav, R. Synthesis 1974, 837. (b) Kuhla,
D. E.; Lombardino, J. G. Adv. Heterocycl. Chem. 1977, 21, 1. (c) Blewitt,
H. L. Chem. Heterocycl. Compd. 1977, 30, 117. (d) Maury, G. Chem.
Heterocycl. Compd. 1977, 30, 179. (e) Terenin, V. I.; Kabanova, E. S.;
Feoktistova, E. S. Chem. Heterocycl. Compd. 1991, 10, 1037.
(2) (a) Blackman, A. J.; Hambly, T. W.; Picker, K.; Taylor, W. C.;
Thirasasana, N. Tetrahedron Lett. 1987, 28, 5561. (b) Billimoria, A.
D.; Cava, M. P. J. Org. Chem. 1994, 59, 6777. (c) Liu, Y.; McWhorter,
W. W. J. Am. Chem. Soc. 2003, 125, 4240. (d) McWhorter, W. W.; Liu,
Y. Curr. Opin. Drug Discovery Dev. 2003, 6, 930.
FIGURE 1. Structures of some natural alkaloids containing
a pyrrolodiazine core.
(3) (a) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro,
M. H. G.; Parkin, S.; Hope, H. Tetrahedron 1994, 50, 3987. (b)
Trimurtuhu, G.; Faulkner, D. J.; Perry, N. B.; Ettouati, L.; Litaudon,
M.; Blunt, J. W.; Munro, M. H. G.; Jameson, G. B. Tetrahedron 1994,
50, 3993. (c) Anderson, R. J.; Morris, J. C. Tetrahedron Lett. 2001, 42,
8697. (d) Molina, P.; Fresneda, P. M.; Delgado, S. J. Org. Chem. 2003,
68, 489. (e) Ahaidar, A.; Fernandez, D.; Danelon, G.; Cuevas, C.;
Manzanares, I.; Albericio, F.; Joule, J. A.; Alvarez, M. J. Org. Chem.
2003, 68, 10020.
(4) (a) Jirkovsky, I. L. U.S. Patent 4188389, 1980. (b) Romero, G.
S.; Franco, F.; Castaneda, A. C.; Muchowski, J. M.; U.S. Patent
5041442, 1991. (c) Rover, S. Eur. Patent 521368, 1993. (d) Seredenin,
S.; Voronina, T. A.; Likhosherstov, A. M.; Peresada, V. P.; Moladavkin,
G. M.; Halikas, J. A. U.S. Patent 5378846, 1995.
prepared from the corresponding fully oxidized precursors
or from the corresponding dihydro derivatives by stan-
dard reduction procedures.1
In connection with our recent studies on the chemistry
and biology of pyrrolodiazines,5 we needed to develop a
practical route to pyrrolo[1,2-a]pyrazine derivatives 6 and
this would involve the prior preparation of 5. Most of the
reported methods for the synthesis of 1-substituted 3,4-
dihydropyrrolo[1,2-a]pyrazines 5 are based on the con-
10.1021/jo048898o CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/11/2004
8668
J. Org. Chem. 2004, 69, 8668-8675

3,4-Dihydropyrrolo[1,2-a]pyrazines
SCHEME 1
SCHEME 2
densation reaction between appropriately substituted
furans or tetrahydrofurans and 1,2-diamino compounds
to give 1-(2-aminoethyl)pyrroles 3.1e Compounds 3 were
reacted with carboxylic acids to afford the amides 4,
which are transformed into 5 under acid conditions
(Scheme 1). In all cases, the R substituent on the pyrrole
is incorporated in the starting material, a situation that
limits the diversity in the pyrrole moiety and also suffers
from the drawback of low to moderate global yields
associated with this linear route.
Herein, we report an easy and convergent method for
the preparation of compounds 5 based on the use of
palladium-catalyzed reactions (Suzuki, Stille, and Negishi)
to introduce aryl, heteroaryl, and dialkylamino substit-
uents in 1-aryl-substituted 3,4-dihydropyrrolo[1,2-a]py-
razines 5.
morpholine/formaldehyde also failed to give the expected
substitution products (Scheme 2).
It was envisaged that a palladium-catalyzed coupling
reaction would not only provide an efficient method to
introduce substituents on the pyrrole ring but also
constitute an extension of a known methodology in this
field.7 Investigation of this alternative process was initi-
ated by studying the halogenation reaction of 5a. Iodi-
nation using iodine provided only traces of the 6-iodo
derivative. The reaction with N-iodosuccinimide (NIS),
on the other hand, gave an unexpected 1:1 addition
complex in equilibrium with starting materials.8
However, reaction of 5a and 1 equiv of N-bromosuc-
cinimide (NBS) afforded the 6-bromo-1-phenyl-3,4-dihy-
dropyrrole 7 in 86% yield along with 10% of the 7-bromo
compound 9 and traces of the 6,8-dibrominated derivative
8. Compound 8 was obtained as the major reaction
product when 2 equiv of NBS were used.
As palladium-promoted cross-coupling reactions have
been successfully employed in the functionalization of
some halopyrroles,9 we therefore decided to explore
various palladium-catalyzed C-C bond formation meth-
ods to achieve an efficient preparation of target com-
pounds 5. With this aim in mind, compound 7 was treated
with nBuLi, and the metalated intermediate 10 was
converted into the heteroarylboronic acid 11, the het-
eroaryltin 12, and the heteroarylzincate 13 to test the
well-known Suzuki,7,10 Stille,7,11 and Negishi7,12 reactions
with a variety of commercially available aryl and het-
eroaryl halides (Scheme 3).
Results and Discussion
Initial screening demonstrated the beneficial role, in
terms of activity, of aryl substituents at the C1 position
of compound 6, and so our first target was the prepara-
tion of 5a (R ) H; Ar ) Ph). This heterocycle was
prepared following the procedure previously reported by
us for an improved synthesis of 3,4-dihydropyrrolo[1,2-
a]pyrazine.5a First, pyrrole was alkylated with 2-chloro-
ethylamine under phase-transfer conditions,6 and the
resulting aminoethylpyrroles were treated with benzoyl
chloride to give the desired amide. The amide was heated
in the presence of POCl3 to afford the desired cyclization
product 5a with a global yield of 36%.
It is worth noting that the attempted formylation of
5a using Vilsmeier-Haack conditions resulted in recov-
ery of the starting material when the reaction was carried
out at room temperature and complex mixtures were
obtained under more forcing conditions. Similarly, Man-
nich reaction with dimethylamine, di-n-propylamine, or
(7) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Metal-
Catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998. (c) Cross-Coupling Reactions: A Practical
Guide; Miyaura, N., Ed.; Topics in Current Chemistry Series 219;
Springer-Verlag: New York, 2002. (c) Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-Inter-
science: New York, 2002.
(8) Analytical and spectral data are according with a NIS/5a (1:1)
adduct. The unstability of this adduct precluded to date its structure
determination by X-ray diffraction.
(9) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: New York, 2000.
(10) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979,
20, 3437. (b) Miura, N.; Suzuki, A. Chem. Commun. 1979, 866.
(5) (a) de Pablo, M. S.; Gandasegui, T.; Vaquero, J. J.; Garc´ıa Nav´ıo,
J. L.; Alvarez-Builla, J. Tetrahedron 1992, 32, 8793. (b) Minguez, J.
M.; Vaquero, J. J.; Garc´ıa Navio, J. L.; Alvarez-Builla, J. Tetrahedron
Lett. 1996, 37, 4263. (c) Minguez, J. M.; Castellote, I.; Vaquero, J. J.;
Garc´ıa Navio, J. L.; Alvarez-Builla, J.; Castan˜o, O.; de Andre´s, J. L. J.
Org. Chem. 1996, 61, 1655. (d) Minguez, J. M.; Castellote, I.; Vaquero,
J. J.; Garc´ıa Navio, J. L.; Alvarez-Builla, J.; Castan˜o, O.; de Andre´s,
J. L Tetrahedron 1997, 53, 9341. (e) Minguez, J. M.; Vaquero, J. J.;
Alvarez-Builla, J.; Castan˜o, O.; de Andre´s, J. L. J. Org. Chem. 1999,
64, 7788.
(6) Cuadro, A. M.; Matia, M. P.; Garc´ıa, J. L.; Vaquero, J. J.; Alvarez-
Builla, J. Synth. Commun. 1991, 21, 535.
J. Org. Chem, Vol. 69, No. 25, 2004 8669

Castellote et al.
SCHEME 3
SCHEME 4
Stannane 12 was obtained in an acceptable 65% yield,
but the boronic acid 11 was isolated in only 26% and 30%
yield depending on the borate employed [B(OMe)3 or B(O-
i-Pr)3]. These low yields are due to the low stability of
11, which is prone to decomposition sa situation that
precludes the use of this route as an efficient synthetic
method. We therefore decided to study the Suzuki
coupling reaction using halide 7 and commercially avail-
able arylboronic acids.
Initial attempts to couple 7 and representative aryl-
boronic acids using Pd(PPh3)3 as a catalyst in toluene/
K2CO3 gave the coupling product in low or moderate
yield. The replacement of toluene by a mixture of toluene/
EtOH led to a considerable improvement in the yields,
and the best results for arylboronic acids (Table 1, entries
1-3) were obtained with a toluene/EtOH ratio of 20:1.
When these conditions were applied to the coupling of
7 and thienylboronic acid, the coupled compound was
isolated in very low yield. Further attempts led to a
remarkable increase in the yield by using Ba(OH)2 as a
base in a 6:1 mixture of DME/H2O as solvent (Table 1,
entry 4).
The conditions established for the coupling reaction of
7 and aryl- or thienylboronic acids also proved to be
appropriate for a double-coupling reaction of the dibromo
derivative 8 and these boronic acids. In this way, disub-
stituted compounds 15 (Table 1, entries 5 and 6) were
obtained in high yields by using 2.5-3 equiv of the
boronic acid (Scheme 4).
a significant decrease in the yield of the monocoupled
compound 16 was found in comparison to the correspond-
ing coupling reaction of the monobromo compound 7. This
chemoselective coupling process allowed the preparation
of the disubstituted compound 17 bearing a 3-thienyl and
a phenyl substituents at C6 and C8 respectively by
employing consecutive coupling reactions with two dif-
ferent boronic acids (Scheme 4).
The reactivities of the C6 and C8 positions in the
dibromo compound 8 are different toward the palladium-
catalyzed coupling reaction. Evidence for this was pro-
vided by the fact that 8-aryl or heteroaryl subtitution
products were not detected when 1 equiv of the boronic
acid was reacted with 8. Under these conditions, however,
As anticipated, the low stability and yield of boronic
acid 11 precluded its use as a convenient partner in the
Suzuki reaction. This situation limited the preparation
of 6-heteroaryl-substituted derivatives to those derived
from commercially available heteroaryl halides. In con-
trast to 11, stannane 12 provides a good alternative for
an investigation into the Stille reaction using a variety
of heteroaryl halides such as those shown in Table 2.
Using conditions similar to those reported for the pal-
ladium-catalyzed coupling reaction of pyrrolestannanes
and aryl and heteroaryl halides,12 we successfully ob-
tained the coupled products using haloazines (Table 2,
entries 1-3) and haloazoles (Table 2, entries 4-11)
although moderate or low yields were obtained in all
(11) (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636.
(b) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992. (c)
Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (d) Farina,
V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction; John Wiley &
Sons: New York, 1998.
(12) See, inter alia: (a) Bailey, T. R. Tetrahedron Lett. 1986, 27,
4407. (b) Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. I.; Sapiro,
J. J. Org. Chem. 1990, 45, 5833. (c) Hoffmann, H. M. R.; Gerlach, K.;
Lattmann, E. Synthesis 1996, 164.
8670 J. Org. Chem., Vol. 69, No. 25, 2004

3,4-Dihydropyrrolo[1,2-a]pyrazines
TABLE 1. Suzuki Coupling of Aryl and Heteroarylboronic Acids and Halides 7 and 8
a Pd(Ph3)4 (0.05 mmol).
cases. It was found that a catalyst combination of 0.1
equiv of (PPh3)4Pd and 2.0 equiv of LiCl in THF as
solvent and heating at 80 °C generally provided the best
results, except in the case of 3-iodopyrazole (Table 2,
entry 4).
In an attempt to improve these yields, we turned our
attention to the Negishi methodology since there are
literature precedents for coupling reactions involving
pyrrolezincates that give high yields of coupled prod-
ucts.13,14 The required zincate 13 was generated in situ
by metalation of 7 with nBuLi followed by addition of
ZnCl2 in THF. A slight modification of the reported
conditions for the palladium-catalyzed arylation of pyr-
rolezincates gave no reaction with haloazoles, but bro-
mopyridines (Table 2, entries 9-11) provided the coupled
compounds with better yields than those obtained in the
Stille reaction using stannane 12. While 2-bromo-
pyridines reacted in the presence of (PPh3)4Pd to afford
moderate yields of the coupled products (Table 2, entries
9 and 10), the less reactive 3-bromopyridine could only
be coupled using Pd2(dba)3 dppf as palladium catalyst,
and in this case the yield was lower (Table 2, entry 11).
In a final attempt to improve the yields of compounds
14 (Table 2) by a Stille reaction, we also tested the
reaction between 7 and tributyl 2-pyridylstannane. Re-
sults obtained with different catalysts demonstrate that
although the coupling reaction did occur, isolated yields
were clearly disappointing when compared with those
obtained using the alternative combination of reactants
shown in Scheme 3. The coupling products and best yields
(13) (a) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977,
42, 1821. (b) Negishi, E.; Matsushita, H.; Kobayashi, M.; Rand, C. L.
Tetrahedron Lett. 1983, 24, 3823. (c) Negishi, E.; Owczarczyk, Z.
Tetrahedron Lett. 1991, 32, 6683. (d) Knochel, P.; Singer, R. D. Chem.
Rev. 1993, 93, 2117. (e) Organozinc Reagents, A Practical Approach;
Knochel, P., Jones, P., Eds.; Oxford: New York, 1999. (f) Erdik, E.
Organozinc Reagents in Organic Synthesis; CRC Press: Boston, 1996.
(g) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem.,
Int. Ed. 2000, 39, 4414-4435.
(14) (a) Luo, F.-T.; Wang, R.-T. Heterocycles 1990, 2181. (b) Taka-
hashi, K.; Gunji, A. Heterocycles 1996, 941.
J. Org. Chem, Vol. 69, No. 25, 2004 8671

Castellote et al.
TABLE 2. Stille and Negishi Coupling of Heteroaryl Halides 12 and 13
a Conditions: A ) Pd(Ph3P)4 (0.01 mmol), LiCl, THF; B ) Pd(PPh3)4 (0.05 mmol), THF; C ) Pd2(dba)3 (0.01 mmol), dppf (0.01 mmol),
THF.
achieved by Stille and/or Negishi reactions are sum-
marized in Table 2.
tBuONa as a base and toluene as the solvent at 100 °C.
These conditions proved to be general for the amination
of 7 with a variety of secondary cyclic amines (Table 3).
However, all our attempts to extend the scope of this
amination reaction to primary and secondary acyclic
amines such as 4-methoxybencilamine, n-propylamine,
cyclobutylamine and di-n-butylamine failed, and un-
altered 7 was recovered in most cases or the debromi-
nated compound was formed as the main reaction product
when Pd2(dba)3 was used in the presence of different
ligands such as dppf, PtBu3 and biphenylPtBu2.
Although the Pd-catalyzed amination of some azoles
have been reported,15 the amination of pyrroles had not
previously been reported until our recent publication16
describing the conditions for the amination of protected
2-acetyl-5-bromopyrrole with primary and cyclic second-
ary amines using Pd2(dba)3 as catalysts with BINAP as
the ligand. Under these conditions, morpholine was
successfully coupled with 7 to give the desired 6-mor-
pholino-1-phenyl-3,4-pyrrolo[1,2-a]pyrazine 18a by using
8672 J. Org. Chem., Vol. 69, No. 25, 2004

3,4-Dihydropyrrolo[1,2-a]pyrazines
SCHEME 5
rolo[1,2-a]pyrazine as reaction partners. Stille and Negishi
reactions gave rise to heteroaromatic substitution with
moderate yields on using heteroaryl halides and 1-phen-
yl-3,4-dihydro[1,2-a]pyrazine as the C6 metalated sub-
strate. Exceptions to this general applicability include
3-iodopyrazole, which did not react with either the
stannane or the zincate. Comparatively, the Stille reac-
tion produced better yields than the Negishi coupling
except in the cases of bromopyridines, which were the
only heterocycles that could be incorporated using this
latter reaction. The Pd-catalyzed amination of the pyrrole
ring was successfully achieved using BINAP as the ligand
and Pd2(dba)3 a catalysts, although this amination was
only successful with cyclic secondary amines.
TABLE 3. Palladium-Catalyzed Amination of 7 with
Cyclic Secondary Amines
Experimental Section
6-Bromo-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine
(7) and 7-bromo-1-phenyl-3,4-dihydropyrrolo[1,2-a]py-
razine (9). To a solution of 5a5a,17 (0.295 g, 1.5 mmol) in CH2-
Cl2 (6 mL) was added a solution of N-bromosuccinimide (0.267
g, 1.5 mmol) in CH2Cl2 (3 mL). After the mixture was stirred
at room temperature for 30 min, a 2% solution of NaOH was
added and the mixture extracted with CH2Cl2 (3 × 20 mL).The
combined organic extracts were dried over Na2SO4 and con-
centrated under reduced pressure, yielding a residue which
was purified by column chromatography (hexane/EtOAc, 3:7)
to yield 355 mg (86%) of compound 7 and 40 mg (10%) of
compound 9. 7: mp 84-86 °C (pale powder); 1H NMR (300
MHz, CDCl3) δ 7.72-7.69 (m, 2H), 7.43-7.40 (m, 3H), 6.37
(d, 1H, J ) 4.0 Hz), 6.23 (d, 1H, J ) 4.0 Hz), 4.04-3.92 (m,
4H); 13C NMR (50 MHz, CDCl3) δ 159.8, 137.5, 129.9, 128.4,
128.3, 125.8, 113.2, 110.8, 106.4, 48.0, 40.2; IR (KBr) νmax 2947,
1589, 1566, 1408, 1036 cm-1. Anal. Calcd for C13H11BrN2: C,
56.75; H, 4.03; N, 10.18. Found: C, 56.49; H, 4.23; N, 10.11.
9: mp 94-95 °C (pale powder); 1H NMR (300 MHz, CDCl3) δ
7.76-7.40 (m, 5H), 6.82 (d, 1H, J ) 1.5 Hz), 6.39 (d, 1H, J )
1.5 Hz), 4.06-3.96 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 159.5,
136.6, 130.4, 128.3, 128.2, 124.3, 123.5, 114.7, 96.8, 47.1, 42.0;
IR (KBr) νmax 1715, 1593, 1567, 1409, 1333 cm-1. Anal. Calcd
for C13H11BrN2: C, 56.75; H, 4.03; N, 10.18. Found: C, 56.49;
H, 4.24; N, 10.07.
a Conditions: Pd2(dba)3 (0.02 mmol), BINAP (0.04 mmol),
NaOtBu, toluene, 100 °C.
6,8-Dibromo-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyra-
zine (8). To a solution of 5a (0.295 g, 1.5 mmol) in CH2Cl2 (6
mL) was added a solution of N-bromosuccinimide (0.534 g, 3.0
mmol) in CH2Cl2 (6 mL). After the mixture was stirred at room
temperature for 1 h, a solution of NaOH 2% was added and
the mixture extracted with CH2Cl2 (3 × 20 mL) and dried over
Na2SO4. The solvent was evaporated under reduced pressure,
and the residue was purified by chromatography (hexane/
EtOAc, 2:8) yielding 418 mg (79%) of the title compound as a
Conclusions
The palladium-catalyzed arylation and heteroarylation
of 6-bromo-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine (7)
using aryl and heteroaryl halides has proven to be a
practical means for introducing aromatic and heteroaro-
matic diversity on the pyrrole ring. The Suzuki reaction
is particularly useful with aryl or 3-thienyl boronic acids
and 6-bromo- or 6,8-dibromo-1-phenyl-3,4-dihydropyr-
1
pale powder: mp 138-139 °C; H NMR (300 MHz, CDCl3) δ
7.70-7.66 (m, 2H), 7.45-7.41 (m, 3H), 6.45 (s, 1H), 4.02-3.95
(m, 4H); 13C NMR (50 MHz, CDCl3) δ 159.1, 136.8, 130.2, 128.4,
128.3, 125.9, 114.6, 108.2, 99.3, 47.6, 41.1; IR (KBr) νmax 2946,
1590, 1567, 1407, 1326 cm-1. Anal. Calcd for C13H10Br2N2: C,
44.10; H, 2.85; N, 7.91. Found: C, 43.97; H, 2.76; N, 8.06.
(1-Phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-6-yl)bo-
ronic Acid (11). To a -78 °C cooled solution of 5a (687 mg,
2.5 mmol) in dry THF (6 mL) was added nBuLi (1.72 mL, 2.75
mmol, 1.6 M in hexane) dropwise under argon. After the
mixture was stirred for 45 min at this temperature, B(OiPr)3
(0.63 mL, 2.75 mmol) was added, and the reaction mixture
was stirred for another 30 min at the same temperature and
then allowed to warm to room temperature. The reaction
mixture was treated with 20 mL of a solution of THF/HCl
(10%) (1/1) and H2O (10 mL) and extracted with CH2Cl2 (3 ×
20 mL). The aqueous layer was evaporated under reduced
pressure to obtain a solid that was treated with EtOH.
Filtration and evaporation of the solvent gave a residue that
(15) For aminations of thiophenes, see: (a) Watanabe, M.; Yama-
moto, T.; Nishiyama, M. Chem. Commun. 2000, 133. (b) Luker, T. J.;
Beaton, H. G.; Whiting, M.; Mete, A.; Cheshire, D. R. Tetrahedron Lett.
2000, 41, 7731. (c) Ogawa, K.; Radke, K. R.; Rothstein, S. D.;
Rasmussen, S. C. J. Org. Chem. 2001, 66, 9067. For amination of
thiazoles and imidazoles, see: (b) Hong, Y.; Tanoury, G. J.; Wilkinson,
S. H.; Bakale, R. P.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett.
1997, 38, 5607. (c) Wang, Z.; Rizzo, C. J. Org. Lett. 2001, 3, 565. (d)
Schoffers, E.; Olsen, P. D.; Means, J. C. Org. Lett. 2001, 3, 4221. For
amination five-membered heterocyclic halides, see: Hooper, M. W.;
Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003, 68, 2861.
(16) Castellote, I.; Vaquero, J. J.; Alvarez-Builla, J. Tetrahedron Lett.
2004, 45, 769-772
(17) Likhosherstov, A. M.; Peresada, V. P.; Vinokurov, V. G.;
Skoldinov, A. P. J. Org. Chem. USSR 1986, 22, 2341.
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Castellote et al.
was triturated with Et2O to yield 180 mg (30%) of the title
compound (yellow unstable powder). 1H NMR (300 MHz,
CDCl3): δ 7.84-7.61 (m, 5H), 7.03 (d, 1H, J ) 4.4 Hz), 6.82 (d,
1H, J ) 4.4 Hz), 4.65-4.61 (m, 2H), 4.03-3.98 (m, 4H).
was diluted with EtOAc (30 mL) and washed with saturated
NaHCO3 (10 mL) solution. The organic layer was dried over
Na2SO4, filtered, and evaporated under reduced pressure. The
residue was purified by flash chromatography (CHCl3/MeOH
satd NH3, 96:4).
General Procedure for Suzuki Coupling of Aryl- and
Heteroarylboronic Acids and Halides 8. Over a stirring
solution of 8 (354 mg, 1.0 mmol), the boronic acid (2.5 mmol),
and Ba(OH)2‚8H2O (1.10 g, 3.50 mmol) in DME/H2O (6/1, 14
mL) or toluene/EtOH (20:1, 21 mL) was added Pd(Ph3)4 (116
mg, 0.10 mmol) under argon. The reaction mixture was
refluxed for 24 h, cooled to rt, poured into a saturated NaCl
solution, and extracted with CH2Cl2 (3 × 30 mL). The organic
layer was dried over Na2SO4, the solvent was evaporated under
reduced pressure, and the residue obtained was triturated with
EtOAc to yield compounds 15a,b.
1-Phenyl-6,8-di(thiophen-3-yl)-3,4-dihydropyrrolo[1,2-
a]pyrazine (15a): yellow powder; 284 mg (79%); mp 235-
236 °C; 1H NMR (300 MHz, CDCl3) δ 7.84-7.80 (m, 2H), 7.50-
7.45 (m, 3H), 7.43 (dd, 1H, J ) 4.8, 2.9 Hz), 7.31 (dd, 1H, J )
2.9, 1.1 Hz), 7.20 (dd, 1H, J ) 4.8, 2.9 Hz), 7.07 (dd, 1H, J )
4.8, 1.1 Hz), 6.95 (dd, 1H, J ) 2.9, 1.1 Hz), 6.91 (dd, 1H, J )
4.8, 1.1 Hz), 6.62 (s, 1H), 4.05-3.90 (m, 4H); 13C NMR (50 MHz,
CDCl3) δ 160.5, 138.0, 135.8, 131.0, 129.9, 129.1, 128.5, 128.2,
127.6, 127.4, 126.0, 125.7, 124.9, 124.1, 119.6, 119.1, 111.9,
48.3, 39.7; IR (KBr) νmax 1589, 1564, 1461, 1418, 1349, 1332,
1286, 1168 cm-1. Anal. Calcd for C21H16N2S2: C, 69.97; H, 4.47;
N, 7.77. Found: C, 70.02; H, 4.61; N, 7.91.
1,6,8-Triphenyl-3,4-dihydropyrrolo[1,2-a]pyrazine
(15b): pale powder; 243 mg (70%); mp 233-234 °C; 1H NMR
(300 MHz, CDCl3) δ 7.86-7.83 (m, 2H), 7.47-7.38 (m, 6H),
7.34-7.30 (m, 2H), 7.22-7.10 (m, 5H), 6.66 (s, 1H), 4.02-3.91
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 160.6, 138.1, 135.4, 132.5,
130.8, 130.6, 129.9, 128.6, 128.5, 128.2, 128.2, 128.1, 128.1,
125.8, 124.3, 123.4, 111.5, 48.5, 40.0; IR (KBr) νmax 1586, 1562,
1457, 1436, 1415, 1181 cm-1 . Anal. Calcd for C25H20N2: C,
86.18; H, 5.79; N, 8.04. Found: C, 86.32; H, 5.77; N, 8.01.
1-Phenyl-6-tributylstannyl-3,4-dihydropyrrolo[1,2-a]-
pyrazine (12). To a -78 °C cooled solution of 5a (550 mg, 2.0
mmol) in dry THF (10 mL) was added nBuLi (1.54 mL, 2.2
mmol, 1.6 M in hexane). After the mixture was stirred for 45
min, a solution of tributyltin chloride (0.61 mL, 2.2 mmol) in
dry THF (2 mL) was added. The reaction mixture was stirred
at this temperature for another 45 min and then allowed to
warm to room temperature, treated with a saturated NaHCO3
(10 mL) solution, and extracted with CH2Cl2 (3 × 20 mL). The
organic layers were washed with aqueous KF (10 mL), dried
over Na2SO4, filtered, and evaporated under reduced pressure.
The crude product was purified by flash chromatography
(hexane/EtOAc, 8:2) to give 705 mg (66%) of 12 as a yellow
pale oil: 1H NMR (300 MHz, CDCl3) δ 7.80-7.71 (m, 2H),
7.48-7.41 (m, 3H), 6.38 (d, 1H, J ) 3.6 Hz), 6.24 (d, 1H, J )
3.6 Hz), 4.02-3.96 (m, 4H), 1.60-1.25 (m, 18H), 0.83 (t, 9H, J
) 8.1 Hz). Anal. Calcd for C25H38N2Sn: C, 61.88; H, 7.89; N,
5.77. Found: C, 62.02; H, 7.96; N, 5.99.
General Procedure for Suzuki Coupling of Aryl- and
Heteroarylboronic Acids and 7. Method A (Compounds
14a-c). To a suspension of 7 (1.00 mmol) and Pd(Ph3)4 (58
mg, 0.05 mmol) in a mixture of toluene/EtOH (20/1,16 mL)
under argon were added K2CO3 (152 mg, 1.10 mmol) and the
corresponding boronic acid (1.10 mmol). The reaction mixture
was refluxed for 24 h, and the cooled suspension was extracted
with CH2Cl2 (3 × 40 mL). The organic layer was washed with
a saturated solution of NaCl (20 mL), and the combined
organic extracts were dried over Na2SO4, filtered, and evapo-
rated under reduced pressure. The residue was purified by
flash chromatography. Compounds 14a and 14d were isolated
and identified as the oxalate salt.
Method B (Compound 14d). The reaction was carried out
as described in method A, but the mixture of solvents and the
base were changed to DME/H2O (6/1.7, 16 mL) and Ba(OH)2‚
8H2O (473 mg, 1.50 mmol). Compound 14d was isolated and
identified as the oxalate salt.
General Procedure for Stille Coupling of 12 and
Heteroaryl Halides (Compounds 14e-l). A solution of the
stannane 12 (242 mg, 0.50 mmol), the heteroaryl halide (0.75
mmol), LiCl (42 mg), and Pd(Ph3P)4 (12 mg, 0.01 mmol) in dry
THF (7 mL) was refluxed for 20 h. The mixture was cooled,
filtered over Celite, and evaporated under reduced pressure.
The residue was purified by flash chromatography on silica
gel.
General Procedure for Negishi Coupling of 13 and
Heteroaryl Halides. Method A (Compounds 14m,n). To
a solution of 7 (275 mg, 1.00 mmol) in dry THF (5 mL), under
an atmosphere of argon, was added nBuLi (0.69 mL, 1.6 M in
hexane, 1.10 mmol) at -78 °C. After the mixture was stirred
for 45 min, a solution of ZnCl2 (2.2 mL, 1.10 mmol, 0.5 M in
THF) was added, and stirring was continued while warming
up to rt. A solution of the halide (1.00 mmol) in THF (3 mL)
and Pd(PPh3)4 (58 mg, 0.05 mmol) were added, and the mixture
was heated at 55 °C until completion. After being cooled to rt,
the solution was diluted with EtOAc (30 mL) and washed with
saturated NaHCO3 (10 mL) solution. The organic layer was
dried over Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by flash chromatography
(CHCl3/MeOH satd NH3, 96:4).
Method B (Compound 14o). To a solution of 7 (275 mg,
1.00 mmol) in dry THF (5 mL), under argon, was added nBuLi
(0.69 mL, 1.10 mmol, 1.6 M in hexane) at -78 °C. After the
mixture was stirred for 45 min, a solution of ZnCl2 (2.2 mL,
1.10 mmol, 0.5 M in THF) was added, and stirring was
continued with warming to rt. A solution of the halide (1.00
mmol) in THF (3 mL), Pd2(dba)3 (9 mg, 0.01 mmol), and dppf
(10 mg, 0.01 mmol) were added, and the mixture was heated
at 55 °C for 10 h. After being cooled to rt, the reaction mixture
8-Bromo-1-phenyl-6-(thiophen-3-yl)-3,4-dihydropyrrolo-
[1,2-a]pyrazinium Oxalate (16). Over a stirring solution of
8 (354 mg, 1.0 mmol), thiophen-3-yl-boronic acid (128 mg, 1.0
mmol), and Ba(OH)2‚8H2O (1.50 mmol, 473 mg) in DME/H2O
(6/1, 7 mL) was added Pd(Ph3)4 (0.05 mmol, 58 mg) under
argon. The reaction mixture was refluxed for 24 h, cooled to
rt, poured into saturated NaCl solution, and extracted with
CH2Cl2 (3 × 20 mL). The organic layer was dried over Na2-
SO4, the solvent was evaporated under reduced pressure, and
the residue was purified by chromatography (CH2Cl2/acetone)
to give the coupling product 16 (168 mg, 47%) as a yellow oil
that was transformed into the corresponding oxalate: mp 174-
1
175 °C; H NMR (200 MHz, CD3OD) δ 7.90 (dd, 1H, J ) 4.2,
1.3 Hz), 7.87-7.77 (m, 3H), 7.75-7.64 (m, 3H), 7.47 (dd, 1H,
J ) 5.2, 1.3 Hz), 7.25 (s, 1H), 4.44 (t, 2H, J ) 6.3 Hz), 4.08 (t,
2H, J ) 6.3 Hz); IR (KBr) νmax 1713, 1597, 1540, 1436, 1338,
1230, 1131 cm-1. Anal. Calcd for C19H15BrN2O4S: C, 51.02;
H, 3.38; N, 6.26. Found: C, 51.23; H, 3.54; N, 6.17.
1,8-Diphenyl-6-(thiophen-3-yl)-3,4-dihydropyrrolo[1,2-
a]pyrazine (17). Over a stirring solution of 16 (178 mg, 0.50
mmol), phenylboronic acid (67 mg, 0.55 mmol), and K2CO3 (76
mg, 0.55 mmol) in toluene/EtOH (20/1, 12 mL) was added Pd-
(Ph3)4 (0.025 mmol, 30 mg) under argon. The reaction mixture
was refluxed for 24 h, cooled to rt, poured into a saturated
NaCl solution, and extracted with CH2Cl2 (3 × 20 mL). The
organic layer was dried over Na2SO4, the solvent was evapo-
rated under reduced pressure, and the residue was purified
by chromatography (hexane/EtOAc, 6:4) to give 17 (85 mg,
48%) as a yellow powder: mp 179-180 °C; 1H NMR (300 MHz,
CDCl3) δ 7.86-7.80 (dd, 2H, J ) 7.7, 1.8 Hz); 7.48-7.42 (m,
3H), 7.40-7.27 (m, 5H), 7.23 (dd, 1H, J ) 2.9, 1.1 Hz), 7.20-
7.11 (m, 2H), 6.99 (dd, 1H, J ) 5.1, 1.1 Hz), 6.58 (s, 1H), 3.99
(m, 4H); IR (KBr) νmax 1589, 1564, 1460, 1416, 1172 cm-1. Anal.
Calcd for C23H18N2S: C, 77.93; H, 5.12; N, 7.90. Found: C,
77.87; H, 5.21; N, 7.95.
8674 J. Org. Chem., Vol. 69, No. 25, 2004

3,4-Dihydropyrrolo[1,2-a]pyrazines
General Procedure for Palladium-Catalyzed Amina-
tions of 7. An oven-dried glass vial was charged with 7 (275
mg, 1.00 mmol), 1.2 equiv of the amine, NaOtBu (135 mg, 1.40
mmol), Pd2(dba)3 (19 mg, 0.02 mmol), and BINAP (25 mg, 0.04
mmol) in dry toluene (7 mL) under argon. The flask was
immersed in an oil bath, heated at 100 °C, and stirred
overnight. The solution was then allowed to cool to room
temperature, taken up in CH2Cl2 (10 mL), filtered over Celite,
and concentrated under reduced pressure. Column chroma-
tography of the residue on silica gel gave pure products 18.
Investigacio´n Cient´ıfica, Desarrollo e Innovacio´n Tec-
nolo´gica, Direccio´n General de Investigacio´n, Ministerio
de Ciencia y Tecnolog´ıa through projects BQU2002-
03578 and BQU2001-1508 and a grant from Lab.
Janssen (I.C.).
Supporting Information Available: Complete experi-
mental procedures for the synthesis and characterization data
for compounds 14 and 18. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We acknowledge support of this
work from Lab. Janssen and the Plan Nacional de
JO048898O
J. Org. Chem, Vol. 69, No. 25, 2004 8675