A novel base-mediated intramolecular hydroamination to build fused heteroaryl pyrazinones

Article abstract of DOI:10.1016/j.tetlet.2008.10.116

Functionalized fused heteroaryl pyrazinones were built up through a novel DBU-catalyzed intramolecular hydroamination reaction of aryl(prop-2-yn-1-yl)-1H-heteroaryl-2-carboxamides. The nucleophilic addition afforded three isomers; two with an exo-cyclic d

Full text of DOI:10.1016/j.tetlet.2008.10.116

Tetrahedron Letters 50 (2009) 172–177
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel base-mediated intramolecular hydroamination
to build fused heteroaryl pyrazinones
*
Laura Llauger , Costanza Bergami, Olaf D. Kinzel, Samuele Lillini,
Giovanna Pescatore, Caterina Torrisi, Philip Jones
Department of Medicinal Chemistry, IRBM-MRL Rome, Via Pontina Km 30,600, Rome 00040, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalized fused heteroaryl pyrazinones were built up through a novel DBU-catalyzed intramolecular
hydroamination reaction of aryl(prop-2-yn-1-yl)-1H-heteroaryl-2-carboxamides. The nucleophilic addi-
tion afforded three isomers; two with an exo-cyclic double bond [cis (Z), trans (E)], and a third one with
an endo-cyclic double bond. After the carboxamide deprotection, isomerization of the mixture under
acidic conditions resulted in a unique isomer.
Received 2 October 2008
Revised 20 October 2008
Accepted 22 October 2008
Available online 30 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Intramolecular hydroamination
Pyrrolopyrazinones
Fused-heteroaryl pyrazinones
DBU-mediated cyclisation
Isomerisation
The catalytic hydroamination of C–C multiple bonds has been
extensively explored in organic chemistry for being a very power-
ful and atom-efficient method to create C–N bonds.1 The intramo-
lecular version of this reaction generates, in a straightforward
manner, nitrogen-containing heterocycles, which are key interme-
diates for the syntheses of biologically active substances, dyes, and
fine chemicals. The wide number of methods (catalytic and non-
catalytic ones) reported in the literature for this transformation re-
flects its synthetic value.2 In general, they involve the presence of
alkali metals (Li, K), early or late transition metals (Sc,3 Ti, Zr,
Pd,4 Au,5 Ru,6 Zn7), and lanthanide complexes.8 Non-metal assisted
procedures have been published as well, intermolecular hydroam-
inations were described with strong inorganic bases (e.g., CsOH,
hydroamination/cyclization reaction using a Pd(II) catalyst to syn-
thesize the N-alkyl-pyrrolo[1,2-a]pyrazinone skeleton from N-al-
kyl-N-allyl-pyrrolo-2-carboxamides (Scheme 1).4d However, their
reaction worked only with N-substituted compounds.
Following the same procedure, the synthesis of the simple 4-
benzylpyrrolo[1,2-a]pyrazinone from the precursor I (Scheme 1)
was attempted. In our hands, the reaction gave the reduced 3,4-
dihydropyrrolo[1,2-a]pyrazinone system (II) in modest yield. In or-
der to obtain the desired pyrrolo[1,2-a]pyrazinone scaffold, several
oxidative conditions were tried on the unprotected adduct without
any success (i.e., MnO2, DMP, DDQ). Similar negative results were
obtained from the protected material (II). At that point, we decided
to circumvent the need for the oxidation reaction by incorporating
an alkyne in the starting material (III) (Scheme 2). Due to cleavage
problems of the p-methoxyphenyl and benzyl protecting groups,
2,4-dimethoxybenzyl (DMB) was chosen, as it is easily removed
under acidic conditions.
Pleasingly, the cyclization reaction of the propynyl derivative
(III) gave the desired product in a 63% yield. Microwave heating
was employed to shorten the reaction time to some minutes com-
pared to the 3-day reaction of Becalli. The reaction did not work
when the carboxamide moiety was unprotected.
When the set conditions were applied to our carboxamide
of interest, 1a, the yield dropped drastically to 12%. Furthermore,
an isomeric mixture was obtained: two isomers were identified
as 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one, with an exo-
cyclic double bond [cis (Z), trans (E)], and a third one was a
KOH),9a,b while TBAF has been used to synthesize
c-lactams from
carboxamides containing electron-deficient triple bonds.9c
All these synthetic approaches are substrate-dependent, and a
general and simple method is lacking. Herein, we present a novel
and robust methodology to obtain new 5,6-bicyclic systems by a
simple base-catalyzed intramolecular hydroamination of a wide
range of NH-heterocycle-containing alkynes.
As part of a medicinal chemistry project, we needed a general
and rapid synthetic method amenable to synthesize diversely
substituted 4-benzylpyrrolo[1,2-a]pyrazin-1(2H)-ones. The only
literature precedent was by Becalli et al., who described
a
* Corresponding author. Tel.: +39 069109 3754; fax: +39 069109 3654.
E-mail addresses: laura_llauger@merck.com, lllauger@pcb.ub.cat (L. Llauger).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.116

L. Llauger et al. / Tetrahedron Letters 50 (2009) 172–177
173
O
O
Pd(OAc)2 (10 mol%)
R
R
NaOAc, NBu4Cl
N
N
NH
N
DMSO, 120 °C, 72 h
57-89%
R= Me, allyl, Ph, cHex, cPentyl
O
O
O
O
PMP
PMP
NH
N
N
NH
Ph
[Ox]
Becalli's
37%
CAN
N
NH
N
N
MeCN:H2O
3 h, RT
Ph
Ph
Ph
I
II
62%
PMP= p-methoxyphenyl
Scheme 1.
O
O
O
DMB
DMB
N
Pd(OAc)2 (10 mol%)
NaOAc, NBu4Cl
N
NH
N
N
NH
DMSO, 120 °C
20 min (m.w.)
III
63%
pyrrolopyrazinone
scaffold
DMB= 2,4-dimethoxybenzyl
O
O
O
DMB
CN
DMB
Pd(OAc)2 (10 mol%)
NaOAc, NBu4Cl
N
NH
N
N
Cl
Cl
Cl
N
NH
DMSO, 5 min
120 °C (m.w.)
Cl
Cl
Cl
1a
F
12%
F
F
CN
2a
CN
Scheme 2.
pyrrolo[1,2-a]pyrazin-1(2H)-one with an endo-cyclic double bond.
The stereochemical assignments for isomers exo-E and exo-Z were
based on 1H–1H NOESY analysis.10
This result prompted us to investigate other synthetic ap-
proaches that could allow a wide range of substituents to be toler-
ated on the scaffold. Given the precedent for base-catalyzed
addition of 5-membered heterocycles onto alkynes, we focused
on non-metal conditions (Table 1).10
Unsurprisingly under neutral condition, the cyclization of car-
boxamide 1a was poor and resulted in a complex mixture of prod-
ucts (entry 1). We then decided to attempt the base-mediated
activation of the pyrrolic nitrogen to induce the cyclization. The
Table 1
Hydroamination/cyclization reaction with carboxamide 1a
O
O
O
O
DMB
DMB
DMB
CN
N
N
N
DMB
Cl
N
Cl
N
N
N
NH
Cl
Cl
F
F
F
F
CN
CN
CN
2a-exo in cursive-Z
1a
2a-exo in cursive-E
2a-endo in cursive
Entry
Reaction conditions
Results
1
2
3
4
5
6
7
DMF, 120 °C, 20 min (m.w.)
Et3N, DCM, reflux, 2 days
KOH (1 equiv), DMSO, rt, 2 h
DBU (1 equiv), DCM, rt, 2 h
DBU (0.3 equiv), DCM, rt, 2 h
Complex mixture
20% conversion
Complex mixture
Complete conversion (2a-exo-Z only)
Complete conversion (2a-exo-Z only)
Complete conversion (2a-exo-Z only)
2a-exo-Z:2a-endo (10:1)
DBU (0.3 equiv), DCM, reflux, 30 min
TBAF (1 equiv), THF, rt, 1 h

174
L. Llauger et al. / Tetrahedron Letters 50 (2009) 172–177
reaction with Et3N was slow, and after 48 h there was only a 20%
conversion (entry 2). With KOH, the reaction was much faster
but it was not efficient (entry 3). To our delight, the hydroamina-
tion/cyclization of 1a proceeded cleanly and smoothly with DBU
as base (entries 4–6). Complete conversion to 2a-exo-Z isomer
was seen within 2 h using 1 equiv of DBU in DCM at rt (entry 4).
Considering that this reaction is a rearrangement, a sub-stoichiom-
etric amount of DBU (0.3 equiv) was used and complete conversion
was seen in the identical timeframe (entry 5). The reaction could
be accelerated by heating at reflux, whereby complete conversion
was observed in 30 min (entry 6). When TBAF was used as base,
although 2a-exo-Z was the major product, 10% of the 2a-endo iso-
mer was obtained (entry 7).
To study the relevance of the NH-containing heterocycle on the
reaction, we held the 3-cyano-4-fluorophenyl-substituted alkyne
constant. Carboxamides 1a–h were synthesized by amide coupling
reaction of the DMB-protected amine 311 with a series of hetero-
aryl-carboxylic acids.12 The amide coupling reactions proceeded
in good yields using TBTU or HATU as coupling reagents. Carbox-
amides 1a–h were then treated with a substoichiometric amount
of DBU (30 mol %) to afford the desired heteroarylpyrazinone ana-
logues (2a–h),13,14 as summarized in Table 2. In general, the hydro-
amination/cyclization reaction took place under mild conditions
(method A, entries 1, 2, 4–7).
The microwave heating accelerated the reaction compared to
the conventional refluxing method (method A vs B, entry 1). Com-
plete cyclization of carboxamide 1a was achieved in 3 min under
microwave heating in DMF, while it required 30 min under reflux-
ing of dichloromethane. Furthermore, similar yields (67% and 71%,
Based on this promising result with
a sub-stoichiometric
amount of DBU, we were interested in further understanding the
scope of this reaction.
Table 2
Amide coupling reaction of 3 with RCO2H, hydroamination/cyclization of carboxamides 1a–h and deprotection/isomerization
O
O
O
O
O
DMB
DMB
DMB
DMB
DMB
HN
N
N
NH
R
N
N
iPr3SiH (6 eq)
R
R
R
R
DBU (30 mol%)
RCO2H
F
N
N
N
N
TFA, 110°C, 17 min
(microwave)
F
F
F
F
F
CN
CN
CN
2-exo in cursive-
CN
CN
CN
3
4a-h
1a-h
Z
2-exo in cursive-E 2-endo in cursive
Isomeric mixture (mol/mol %)f
2-exo-E
e
Entry
1
R
1a (%)b
Methodc (%)d
tR
4 (%)
2-exo-Z
2-endo
A (67)
B (71)
30 min
3 min
100
63
—
—
—
37
Cl
a (50)g
70
94
NH
Cl
2
3
b (65)
c (30)
A (80)
3 h 30 min
10 min
27
10
5
5
68
85
NH
A (0)
Degradation
NH
Cl
B (85)
d (56)g
e (55)
A (69)
A (85)
2 h
1 h
60
42
12
8
28
50
75
54
Cl
4
5
NH
NH
Cl
6
7
f (42)g
g (68)g
A (18)
A (34)
30 min
2 h
89
—
11
—
—
83
85
N
NH
NH
100
N
h (42)g
A (0)
B (85)
10 min
—
—
100
Degradation
N
8
NH
N
a
Coupling conditions: RCO2H (1 equiv), 3 (1 equiv), TBTU (1 equiv), TEA (2 equiv), DMF, rt.
Isolated yields.
Method A: DBU (30 mol %), DCM, reflux. Method B: DBU (30 mol %), DMF, 120 °C (microwave).
Isolated yield of the isomeric mixture.
The reaction time of the hydroamination/cyclization (tR) was the time when there was no more presence of 1 (monitored by UPLC/MS).
Ratio (mol/mol %) calculated from 1H NMR, COSY and NOESY spectra on purified product.
HATU as coupling reagent.
b
c
d
e
f
g

L. Llauger et al. / Tetrahedron Letters 50 (2009) 172–177
175
the cyclization rate. In the case of the trichloro-substituted pyrrole
1d, the reaction rate was decreased, probably due to a counteract-
ing steric effect.
With regard to the dimethyl-substituted 1c, microwave heating
(method B) was required to drive the reaction to completion, since
no conversion was seen after 12 h at reflux (method A). Both the
hindered dimethylpyrrole and the electron-donating nature of
the methyl groups, significantly deactived the pyrrolic N–H for
intramolecular cyclization.
O
O
DMB
DMB
DMB
HN
a
b
N
N
CO2H
R:
+
NH
NH
NH
6
5
1i-o
R
OMe
This cyclization reaction also worked well with other NH-con-
taining heterocycles (entries 5–8), although the triazole 1h (entry
8) required harsh conditions (10 min at microwave, method B).
In all the cases, the cyclization reaction resulted into a mixture of
up to three isomers, except for dichloropyrrole 1a, pyrazole 1g,
and triazole 1h.15
CN
OMe
F
CN
1m
1i
(58%)
1j
1k
1l
1n
(10%)
(62%)
(70%)
(91%)
(63%)
Scheme 3. Reagents and conditions: (a) TBTU, TEA, DMF, ON, rt (56%); (b) RI,
Pd(PPh3)4 (10 mol %), CuI (20 mol %), TEA, DMF, rt, ON (10–91%).
Attempts to isomerize these mixture to a unique isomer under
the basic conditions, even after longer reaction times, failed. Fortu-
nately, a solution was found under acidic conditions, sulfuric acid
converted all the isomers into the thermodynamically most stable
4-endo isomer with the concomitant DMB-cleavage; however,
nitrile hydrolysis was observed as well (50% H2SO4, 110 °C, 24 h,
Y = 22%). This side-reaction was successfully suppressed in neat
TFA (RT, 20 h, 50% conversion). The addition of 6 equiv of triisopro-
pylsilane and microwave heating at 110 °C gave full deprotection
and complete conversion to the endo-isomer in excellent yields.16
respectively) were obtained in both cases but while the thermal
reaction gave only the 2a-exo-Z, the microwave one gave a ratio
2:1 of 2a-exo-Z:2a-endo isomers.
As expected, the substitution of the pyrrole ring played an
important role on the cyclization reaction. While the presence of
electron-withdrawing groups accelerated the reaction (1a,d, en-
tries 1 and 4), the absence of substituents (1b, entry 2) or even
the presence of electron-donating ones (1c, entry 3) slowed down
Table 3
Hydroamination/cyclization of carboxamides 1i–n and deprotection/isomerization reaction
O
O
O
O
O
DMB
DMB
DMB
DMB
NH
R
N
N
N
R
N
R
iPr3SiH (6 eq)
DBU (30 mol%)
N
NH
N
R
N
N
TFA, 110 °C, 17 min
(microwave)
R
1i-n
2-exo in cursive-Z 2-exo in cursive-E 2-endo in cursive
4i-n
8 (R= H)
7-exo in cursive (R= H)
7-exo in cursive (R= H)
Methoda (%)b
tR
Isomeric mixture (mol/mol %)d
4 (%)
c
Entry
R
Carboxamides
2-exo-Z
2-exo-E
2-endo
1
2
H
6
B (78)e
B (94)e
25 min
10 min
75
—
25
62
1i
60
65
80
73
—
40
30
7
78
87
55
68
82
70
94
3
4
5
6
7
1j
B (66)e
B (88)e
B (60)e
A (67)
A (91)
A (80)
10 min
10 min
10 min
3 h
5
OMe
1k
1l
13
27
—
MeO
—
F
1m
1n
1b
100
62
68
CN
CN
5 h
—
38
5
CN
F
8
3 h 30 min
27
a
Method A: DBU (30 mol %), DCM, reflux. Method B: DBU (30 mol %), DMF, 120 °C (microwave).
Isolated yield of the isomeric mixture.
The reaction time of the hydroamination/cyclization (tR) was the time when there was no more presence of 1 (monitored by UPLC/MS).
Ratio (mol/mol %) calculated from 1H NMR, COSY and NOESY spectra on purified product.
No reaction after 12 h at reflux (method A).
b
c
d
e

176
L. Llauger et al. / Tetrahedron Letters 50 (2009) 172–177
O
O
R1
DMB
R1
DMB
N
N
N
N
C
Base
D
O
R2
R2
R1
DMB
N
Isomerisation
NH
O
O
R2
R1
DMB
C
R1
DMB
N
N
N
N
R2
R2
Scheme 4.
This reaction was applicable to a broad range of substituents,
thereby enabling the acyclic substrates (1a–h) to be converted into
a single desired bicyclic system by two simple high-yielding
reactions.
In summary, we have developed an entirely novel procedure for
the synthesis of polyfunctionalized 4-(arylmethyl)pyrrolo[1,2-a]-
pyrazinones by DBU-mediated hydroamination/cyclization of
aryl(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide. The resulting iso-
meric mixture was isomerized to a unique isomer (4-endo) and
concomitant DMB-cleavage under acidic conditions. The cycliza-
tion rate was demonstrated to be influenced by both the electronic
nature of the pyrrole ring and the substituted alkyne. This method-
ology has been shown to be applicable to a wide range of other
bicyclic frameworks and substituents.
The exploration on the alkyne substituent was carried out keep-
ing the unsubstituted pyrrole constant. Carboxamides 1i–o were
obtained by Sonogashira coupling of diverse aryl iodides and acet-
ylene 6, resulting from the reaction of acetylene 511 and 2-pyrrole
carboxylic acid using TBTU as coupling reagent (Scheme 3). In the
optimization of the Sonogashira cross-coupling reaction, several
Pd(0) and Pd(II) catalysts [Pd(PPh3)2Cl2, Pd2(dba)3, Pd(PPh3)4],
and Cu(I) co-catalysts [CuI, CuBr] were tried. The best results were
obtained with a mixture of a 10 mol % Pd(PPh3)4 and 20 mol % CuI.
The reaction worked well with aryl iodides, but failed with aryl
bromides. Modest to high conversions were observed in both elec-
tron-rich and electron-poor aryl groups.
Acknowledgments
We thank Renzo Bazzo for NMR support.
References and notes
Carboxamides 1i–n were subjected to cyclization conditions.
The results were summarized in Table 3.
1. (a) Beller, M.; Breindl, C.; Eichberger, M.; Hartung, C. G.; Seayad, J.; Thiel, O. R.;
Tillack, A.; Trauthwein, H. Synlett 2002, 1579–1593 and references cited
therein; (b) Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1407–1420 and
references cited therein.
2. Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079–3159 and
references cited therein.
The cyclization reaction of acetylene 6 (entry 1) required harsh
conditions (method B) and longer reaction time compared to the
rest of the analogues. Despite being a completely deactivated sys-
tem (terminal acetylene), the reaction occurred in good yield. Elec-
tron-rich alkynes (entries 2 and 3), which bore o/p-substituted aryl
with electron-donating groups, needed microwave heating (meth-
od B) to get total conversion but good yields were still obtained. On
the other hand, electron-poor alkynes (entries 6–8) proceeded in
milder conditions (method A). The cyano-derivatives 1m and 1n
(entries 6 and 7) confirmed that the para-substitution with an elec-
tron-withdrawing group accelerated the cyclization reaction com-
pared to meta-one [tR (para, 1m) = 3h vs tR (meta, 1n) = 5h]. With
regard to the fluoro-derivative 1l (entry 5), the cyclization required
microwave condition (method B). However, the introduction of cy-
ano group in meta position (1b, entry 8) activated the alkyne, and
cyclization took place at lower temperature (method A). The cycli-
zation reaction afforded up to three isomers (exo-Z, exo-E, and
endo), except for 1m (entry 6), which gave 2m-endo as unique iso-
mer. The DMB-removal and isomerization of the isomeric mixtures
(2b,i–n and 7) were achieved in high yields.
3. Lauterwasser, F.; Hayes, P. G.; Bräse, S.; Piers, W. E.; Schafer, L. L.
Organometallics 2004, 23, 2234–2237.
4. (a) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30, 2581–2584; (b)
Cacchi, S.; Fabrizi, G.; Carangio, A. Synlett 1997, 959–961; (c) Gabriele, B.;
Salerno, G.; Fazio, A. J. Org. Chem. 2003, 68, 7853–7861; (d) Becalli, E. M.;
Broggini, G.; Martinelli, M.; Paladino, G. Tetrahedron 2005, 61, 1077–1082.
5. Kadzimirsz, D.; Hildebrandt, D.; Merz, K.; Dyker, G. Chem. Commun. (Camb.)
2006, 661–662.
6. Chang, S.; Lee, M.; Jung, D. Y.; Yoo, E. J.; Cho, S. H.; Han, S. K. J. Am. Chem. Soc.
2006, 128, 12366–12367.
7. Zulys, A.; Dochnahl, M.; Hollmann, D.; Lohnwitz, K.; Herrmann, J. S.; Roesky, P.
W.; Blechert, S. Angew. Chem., Int. Ed. 2005, 44, 7794–7798.
8. (a) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 9295–9306; (b) Motta, A.;
Fragalà, I. L.; Marks, T. J. Organometallics 2006, 25, 5533–5539.
9. (a) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40, 6193–6195; (b)
Trofimov, B. A.; Tarasova, O. A.; Shemetova, M. A.; Afonin, A. V.; Klyba, L. V.;
Baikalova, L. V.; Mikhaleva, A. I. Russ. J. Org. Chem. 2003, 39, 408–414; (c)
Fustero, S.; Fernandez, B.; Bello, P.; Pozo, C. D.; Arimitsu, S.; Hammond, G. B.
Org. Lett. 2007, 9, 4251–4253.
10. It was detected the NOEs between H5/H1 and H5/H3 for the E conformation, and
the key NOE between H5 and H4 for the Z conformation.
O
O
No mechanistic studies were performed but two possible path-
ways could be considered (Scheme 4).
DMB
DMB
H5
H1
N
N
Cl
Cl
N
H5
N
The first would involve the nucleophilic addition of a pyrrolide
onto the alkyne, as precedented by the intermolecular reactions of
Tzalis and Trofimov10a,b followed by DBU-mediated double bond
isomerization to give the isomeric product mixture (pathway ‘C’,
Scheme 4). The second conceivable pathway would involve DBU-
mediated alkyne–allene isomerization, where there is a growing
body of evidence in several intramolecular cyclization reactions,17
followed by 6-exo-dig or 6-endo-dig processes, and any subsequent
double bond migration (pathway ‘D’, Scheme 4).
H5
H5
Cl
Cl
H4
NC
F
CN
H3
2a-exo-
F
E
2a-exo-Z
11. Jones, P.; Kinzel, O. D.; Llauger Bufi, L.; Muraglia, E.; Pescatore, G.; Torrisi, C.
WO 2007/138355, 2007.
12. A typical procedure is as follows: A mixture of pyrrole-2-carboxylic acid (0.3 g,
3 mmol), TBTU (0.96 g, 3 mmol), and TEA (0.3, 3 mmol) in dry DMF (6 mL) was

L. Llauger et al. / Tetrahedron Letters 50 (2009) 172–177
177
stirred for 15 min at rt. A solution of 3 (1 g, 3 mmol) and TEA (0.3 g, 3 mmol) in
DMF (4 mL) was then added, and the mixture was left for 6 h. The reaction
mixture was diluted with DCM and washed sequentially with a saturated
aqueous NaHCO3 solution and brine. The pooled organics were dried
over anhydrous Na2SO4, and solvent was evaporated under reduced pressure.
Compound 1b was isolated by silica gel chromatography (biotage system,
eluent: petroleum ether/EtOAc, 7:3) as a yellow powder. Yield, 65% (0.81 g).
1H NMR (400 MHz, DMSO-d6) d 11.64 (br s, 1H, NH), 7.94–7.93 (m, 1H),
7.79–7.76 (m, 1H), 7.55 (dd, 1, H, J = 9.0 Hz), 7.17 (d, 1H, J = 8.3 Hz), 6.97 (s, 1H),
6.63 (s, 1H), 6.56 (d, 1H, J = 8.3 Hz), 6.53–6.48 (m, 1H), 6.14 (s, 1H), 4.82 (s, 2H,
CH2), 4.54 (s, 2H, CH2), 3.82 (s, 3H, OCH3), 3.79 (s, 3H, OCH3). 13C NMR
(100 MHz, DMSO-d6) d 38.0, 46.6, 56.1, 56.4, 81.0, 88.8, 99.3, 101.9, 105.5,
109.7, 112.8, 114.1, 117.6, 118.1, 118.3, 120.7, 122.8, 124.7, 129.5, 137.5, 139.7,
159.0, 161.0, 163.2, 164.1. MS (ES) C24H20FN3O3 required: 417, found: 418
(M+H)+.
CH2), 3.77 (s, 3H, OCH3), 3.74 (s, 3H, OCH3)]. 19F NMR (500 MHz, DMSO-d6) d
À110.8 (2b-exo-Z), -112.3 (2b-endo). MS (ES) C24H20FN3O3 required: 417,
found: 418 (M+H)+.
14. Method B:
A mixture of carboxamide 1c (100 mg, 0.22 mmol) and DBU
(10.2 mg, 0.067 mmol) in dry DMF (0.75 mL) was sealed in a microwave tube
and irradiated in a microwave reactor (Emrys Optimizer) for 10 min at 120 °C.
The solution was concentrated under reduced pressure and the crude diluted
with DCM. The solution was washed with 0.5 N HCl solution and brine. The
organic extracts were dried over anhydrous Na2SO4, and solvent was
evaporated under reduced pressure. After purification by silica gel
chromatography (biotage system, eluent: petroleum ether/EtOAc, 7:3), the
three isomers (
a:b:c) were quantified (10:5:85 mol/mol %, respectively). Yield,
85% (85 mg). The major isomer, 2c-endo, was characterized. 1H NMR
(600 MHz, DMSO-d6)
1HAr), 7.54 (dd, 1HAr
d
,
7.76 (dd, 1HAr
J = 8.9 Hz), 7.05 (d, 1HAr
,
J = 6.1 and 2.1 Hz), 7.61–7.58 (m,
J = 8.3 Hz), 6.57 (d, 1HAr,
,
13. Method A: To a solution of carboxamide 1b (100 mg, 0.24 mmol) in dry DCM
(0.8 mL) was added DBU (11 mg, 0.072 mmol). The mixture was heated at
reflux for 5 h. The reaction solution was diluted in DCM, and then washed with
0.5 N HCl solution and brine. The organic extracts were dried over anhydrous
Na2SO4, and solvent was evaporated under reduced pressure. After purification
by silica gel chromatography (biotage system, eluent: petroleum ether/EtOAc,
J = 2.5 Hz), 6.50 (dd, 1HAr, J = 8.3 and 2.5 Hz), 6.12 (s, 1Hpyr), 6.06 (s, CH), 4.76 (s,
2H, CH2), 4.27 (s, 2 H, CH2), 3.80 (s, 3 H, OCH3), 3.76 (s, 3H, OCH3)]. MS (ES)
C26H24FN3O3 required: 445, found: 446 (M+H)+.
15. The molar ratio of the three isomers remained the same before and after silica
gel purification (confirmed by 19F NMR spectra).
16. A typical procedure is as follows: A mixture of 2b (65 mg, 0.15 mmol), iPr3SiH
(0.19 mL, 0.93 mmol) and TFA (0.7 mL) was irradiated in a microwave reactor
(Emrys Optimizer) for 17 min at 110 °C. After cooling down to room
temperature, the mixture was purified by silica gel chromatography (biotage
system, eluent: petroleum ether/EtOAc, 3:2) to afford 4b as a white powder.
Yield, 94% (42 mg). 1H NMR (300 MHz, DMSO-d6): d 10.51 (d, 1H, J = 2.1 Hz,
NH), 7.92–8.00 (m, 1HAr), 7.71–7.79 (m, 1HAr), 7.47 (t, 1HAr, J = 9 Hz), 7.29–7.32
(m, 1Hpyr), 6.89–6.92 (m, 1Hpyr), 6.43–6.53 (m, 2H, Hpyr and CH), 4.08 (s, 2H,
CH2). 13C NMR (75 MHz, DMSO-d6) d 32.0, 99.9, 109.4, 111.5, 113.2, 113.8,
116.4, 116.6, 117.0, 124.1, 133.5, 134.7, 135.9, 155.2, 161.2. MS (ES)
C15H10FN3O required: 267, found: 268 (M+H)+.
7:3), the three isomers
(a:b:c) were quantified (27:5:68 mol/mol %,
respectively). Yield, 80% (80 mg). The most relevant signals on the 1H NMR
(500 MHz, DMSO-d6) data were: 2b-exo-Z, d 11.64 (bs, 1H, NH), 7.81–7.78 (m,
1HAr), 7.60–7.58 (m, 1HAr), 7.55–7.52 (m, 1HAr), 7.18 (d, 1HAr, J = 8.4 Hz), 6.97
(s, 1H), 6.80 (dd, 1Hpyr, J = 3.8 and 1.5 Hz), 6.61 (d, 1HAr, J = 2.3 Hz), 6.58
(overlapped, 1Hpyr), 6.54 (dd, 1HAr, J = 8.3 and 2.5 Hz), 6.24–6.23 (m, 1Hpyr),
6.14 (s, 1H), 4.56 (s, 2H, CH2), 4.24 (s, 2H, CH2), 3.82 (s, 3H, OCH3), 3.74 (s, 3H,
OCH3)]; 2b-exo-E, d 7.70–7.68 (m, 1HAr), 7.11 (d, 1HAr, J = 8.3 Hz), 6.86 (dd,
1Hpyr, J = 3.8 and 1.5 Hz), 4.50 (s, 2H, CH2), 4.49 (s, 2H, CH2), 3.72 (s, 3H, OCH3),
3.66 (s, 3H, OCH3)]; 2b-endo, d 7.97 (dd, 1HAr, J = 6.2 and 2.1 Hz), 7.81–7.78 (m,
1HAr), 7.55–7.52 (m, 1HAr), 7.41–7.40 (m, 1Hpyr), 7.06 (d, 1HAr, J = 8.3 Hz), 6.96
(dd, 1Hpyr, J = 3.8 and 1.5 Hz), 6.62 (d, 1HAr, J = 2.3 Hz), 6.60 (overlapped, 1Hpyr),
6.58 (s, CH), 6.51 (dd, 1HAr, J = 8.3 and 2.5 Hz), 4.87 (s, 2H, CH2), 4.08 (s, 2H,
17. (a) Grigg, R.; Loganathan, V.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.;
Worakun, T. Tetrahedron 1996, 52, 11479–11502; (b) Le Strat, F.; Harrowven, D.
C.; Maddaluno, J. J. Org. Chem. 2005, 70, 489–498.