A chemoselective microwave-assisted one-pot cross-stille reaction of benzylic halides with 2(1H)-pyrazinones using simultaneous cooling

Article abstract of DOI:10.1055/s-2006-941607

This manuscript reports the chemoselective one-pot cross-Stille coupling of benzylic halides with 3,5-dichloro-2(1H)-pyrazinones, which avoids the purification and handling of toxic stannylated intermediates. Significant improvements in yields were established when microwave irradiation was performed with simultaneous cooling. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-941607

LETTER
1491
A Chemoselective Microwave-Assisted One-Pot Cross-Stille Reaction of
Benzylic Halides with 2(1H)-Pyrazinones Using Simultaneous Cooling
M
icrowave-En
r
hanced
a
C
ross-Stille
s
R
eaction
a
s
d Appukkuttan,a Mofazzal Husain,a,b,c Rajinder K. Gupta,c Virinder S. Parmar,b Erik Van der Eycken*a
a
Department of Chemistry, University of Leuven, Celestijnenlaan 200 F, 3001 Leuven, Belgium
Fax +32(16)327990; E-mail: erik.vandereycken@chem.kuleuven.be
b
c
Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 100 007, India
School of Biotechnology, GGSIP University, Delhi 100 006, India
Received 23 February 2006
According to our approach it is clear that the nature of the
functional group at the C-3 position of the original 2(1H)-
pyrazinone scaffold has a critical role for constructing the
turn mimics, as the i+1 residue of the adapted side chain
Abstract: This manuscript reports the chemoselective one-pot
cross-Stille coupling of benzylic halides with 3,5-dichloro-2(1H)-
pyrazinones, which avoids the purification and handling of toxic
stannylated intermediates. Significant improvements in yields were
established when microwave irradiation was performed with simul- is a direct outcome of the C-3 substituent, e.g., a benzyl
taneous cooling.
group at the C-3 position constitutes a Phe mimic in the
APC system (Figure 1). For the purpose of biological
screening, it is therefore important to elaborate an easy
and flexible protocol for the incorporation of various alkyl
and benzyl moieties at the C-3 position of the 2(1H)-
pyrazinone scaffold, in view of generating APC systems
incorporating unnatural amino acids at the i+1 position.
We have recently demonstrated the use of Grignard re-
agents for the introduction of benzyl and alkyl groups at
the C-3 position of the 2(1H)-pyrazinone system.5 How-
ever, this reaction is rather harsh and known to demand
sensitive conditions. Even though the Stille reaction6 was
successfully carried out on the C-3 position of the pyrazi-
none for this purpose,7 this protocol was solely restricted
for the introduction of (hetero)aryl moieties. Syntheses of
the corresponding benzyl and alkyl stannanes are known
to be cumbersome due to the toxicity of these compounds
and the tedious purification procedures. During search for
an easier and straightforward approach, we found that
the cross-coupling can be effected by a microwave-
enhanced one-pot reaction applying a dedicated mono-
mode instrument (Scheme 1). The reactions proceed with
high chemoselectivity and high yields, avoiding the
process of isolation (or purification) of any stannous inter-
mediates during the reaction. Even though transition-met-
Key words: microwave, 2(1H)-pyrazinone, Stille, cross-coupling,
simultaneous cooling
In the course of the last two decades our laboratory
explored 3,5-dichloro-2(1H)-pyrazinones as interesting
starting materials for a gateway to the elaboration of dif-
ferent types of biologically active compounds. This valu-
able scaffold allows an easy introduction of a wide range
of pharmacologically active groups with the ability to
address the diverse set of biological targets.1 We have pre-
viously demonstrated that the 2(1H)-pyrazinones, upon
Diels–Alder reaction2 with ethylene followed by suitable
manipulations, could furnish the invaluable 5-aminopipe-
ridinone-2-carboxylate (APC) unit, mimicking the b-turn3
of the type VI with a conformationally restricted cis-pep-
tide bond. This concept has since been used in the synthe-
sis of a number of b-turn mimics with diversity at the i+1
and i+2 positions, generating pharmacologically interest-
ing molecules such as b-turn mimics for modifying the C-
terminus of substance P4 (an undecapeptide neurotrans-
mitter implicated in several diseases including arthritis
and asthma).
amino acid 2
amino acid 3
residue i+1
residue i+2
O
O
R1
N
R6
N
O
NH
R3
R6
N
R1
R6
O
O
1)
2)
HN
HN
H2O
Cl
N
R3
R3
O
2(1H)-pyrazinone
conformationally restricting
cis-peptide bond
APC-based β-turn mimics
Figure 1 2(1H)-pyrazinone and the APC-based b-turn mimics
SYNLETT 2006, No. 10, pp 1491–1496
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941607; Art ID: G03506ST
© Georg Thieme Verlag Stuttgart · New York

1492
P. Appukkuttan et al.
LETTER
R1
R1
N
R1
N
R6
N
O
R6
O
R
R6
O
Sn2Bu6, PhMe or DMF
Pd(PPh3)4, MW
X
+
+
Cl
N
Cl
Cl
N
Cl
N
Bu
R
1a–g
2a–j
3a–n
4a–n traces
no stannylation or dimerization
100% chemoselective
Scheme 1 The microwave-enhanced cross-Stille reaction
al-catalyzed one-pot cross-coupling reactions are known, cavity of a monomode microwave apparatus at a pre-
albeit rarely, in the literature,8 these reactions generally selected temperature of 150 °C for 15 minutes, using a
furnish the homocoupled products. In this contribution, maximum irradiation power of 200 W. After the chro-
we wish to delineate the outcome of our investigations.
matographic separation, the required target compound, 3-
benzyl-5-chloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one
(3a), was isolated in a good yield of 71% (Table 1, entry
1). A high chemoselectivity was obtained during reaction
and no traces of homodimerized or stannylated products
of either the 2(1H)-pyrazinone or benzyl bromide (2a)
were observed. The only by-product that was isolated dur-
ing the course of the reaction was 3-butyl-5-chloro-1-(4-
methoxybenzyl)pyrazin-2(1H)-one (4a), which is typical
We started our experiments by choosing the cross-
coupling reaction between benzyl bromide 2a and 3,5-
dichloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (1a).
Pyrazinone 1a and bromide 2a (1.2 equiv) were sus-
pended in toluene (2 mL) in a 10 mL microwave vial
together with hexabutyldistannane (Sn2Bu6, 1.1 equiv)
and Pd(PPh3)4 (5 mol%). The vial was irradiated in the
Table 1 Optimization of the Cross-Stille Reaction under Microwave Irradiationa
PMB
N
PMB
N
Sn2Bu6,
PhMe or DMF
O
O
Br
+
Pd(Ph3P)4,
MW
Cl
N
Cl
Cl
N
2a
1a
3a
PMB = 4-OMe-Bn
Entry
1
Catalyst
Solvent
Temp (°C)
150
Time (min)
Yield (%)
71
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)2Cl2
Pd(dppf)Cl2
Ni(dppe)Cl2
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
Pd(Ph3P)4
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
DMF
DMF
DMF
DMF
15
15
15
15
10
20
10
10
10
10
10
10
10
10
2
175
79
3
130
67
4
110
58
5
175
79
6
175
79
7
175
69
8
175
55
9
175
41
10
11
12
13
14
175
79
150
79
150
79b
79c
74d
150
150
a All reactions were carried out on a 0.25 mmol scale with 1.2 equiv of BnBr, 1.1 equiv of Sn2Bu6 and 5 mol% of Pd(Ph3P)4 in 2.0 mL of solvent.
Reactions were run at 200 W (toluene) and 150 W (DMF) maximum power.
b Reaction was performed with 1.5 equiv of Sn2Bu6.
c Reaction was performed with 2.0 equiv of Sn2Bu6.
d Reaction was performed with 1.1 equiv of BnCl.
Synlett 2006, No. 10, 1491–1496 © Thieme Stuttgart · New York

LETTER
Microwave-Enhanced Cross-Stille Reactions
1493
for reactions applying Sn2Bu6 at high temperatures. The Sn2Bu6 (Table 1, entries 12, 13) failed to improve the
optimum conditions were found to be the use of Pd(Ph3P)4 yields, and resulted in the formation of several unidenti-
as the catalyst in toluene, while the reaction was run at fied side products. We then investigated the cross-Stille
175 °C for 10 minutes (Table 1, entry 5) at 200 W maxi- reaction of 1a with BnCl (2b), being cheaper and compar-
mum power.
atively less hazardous than its bromo counterpart. The
reaction was found to proceed smoothly under the already
optimized microwave-enhanced conditions in DMF and
cross-coupled compound 3a was isolated in 74% yield
(Table 1, entry 14).
The 3-benzyl derivative 3a was obtained in 79% yield.
When the reactions were carried out at lower temperatures
inferior yields were observed (Table 1, entries 1, 3, 4).
Furthermore, Pd(Ph3P)4 was found to be the catalyst of
choice, as the application of alternative catalysts resulted Thus, after optimizing the reaction conditions, we decided
in lower yields (Table 1, entries 7–9). However, switching to investigate the scope and limitation of the cross-Stille
the solvent from toluene to DMF afforded the product in reaction applying a number of differently substituted
a similar yield of 79% in 10 minutes, but a lower temper- pyrazinones. In view of scaling up the reactions, we
ature of 150 °C could be applied at 150 W maximum decided to apply a dedicated multimode microwave
power (Table 1, entries 10, 11). Increasing the amount of apparatus designed for large-scale reactions. To maintain
Table 2 Cross-Stille Reaction of Various Pyrazinones 1b–g with Benzylic Halides 2a–ja
R1
N
R1
N
R1
N
R6
O
R6
O
R6
O
Sn2Bu6, Pd(Ph3P)4, MW
+
+
R3–X
DMF, 170 °C, 120 W, 10 min
Cl
N
Cl
Cl
N
R3
Cl
N
Bu
traces
4b–n
1b–g
2a–j
3b–n
Entry
1
Pyrazinone
1b
R1
R6
H
Halide
R3
X
Product
3b
3b
3c
Yield (%)
71
(CH2)3Ph
(CH2)3Ph
CH2C6H11
CH2C6H11
C6H11
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2c
2d
2d
2e
2f
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Cl
2
1b
H
68
3
1c
H
71
4
1c
H
3c
65
5
1d
H
3d
3d
3e
74
6
1d
C6H11
H
66
7
1e
CH2Ph
CH2Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
H
69
8
1e
3e
65
9
1f
3f
81
10
11
12
13
14
15
16
17
18
19
1f
Ph
3f
73
1g
Ph
(4-MeO)Bn
(4-MeO)Bn
(4-MeO)Bn
3g
3g
3h
3i
79
1g
Ph
75
1b
(CH2)3Ph
(CH2)3Ph
(CH2)3Ph
(CH2)3Ph
(CH2)3Ph
(CH2)3Ph
(CH2)3Ph
58
1b
H
(3,4,5-MeO)Bn Cl
57
1b
H
(2-F)Bn
Br
Cl
Br
Br
Br
3j
72
1b
H
2g
2h
2i
(2-NO2)Bn
(4-NO2)Bn
Allyl
3k
3l
0b
1b
H
0b
1b
H
3m
3n
94
1b
H
2j
Propargyl
0b
a All reactions were carried out on a 1.0 mmol scale with 1.2 equiv of the corresponding halide and 1.1 equiv of Sn2Bu6 and 5 mol% of Pd(Ph3P)4
in 12.0 mL of solvent at a preselected temperature of 170 °C for 10 min, using a maximum irradiation power of 120 W.
b Only starting material was recovered.
Synlett 2006, No. 10, 1491–1496 © Thieme Stuttgart · New York

1494
P. Appukkuttan et al.
LETTER
the same rates and yields of our optimized procedure, we (Table 2, entries 16, 17). Surprisingly, allylbromide 2i un-
found that the ceiling temperature of the reactions had to derwent the coupling reaction in a remarkably cleaner
be raised from 150 °C to 170 °C. A variety of 2(1H)- fashion and the product 3m was isolated in an excellent
pyrazinones 1b–f was chosen to react with 2a as well as 94% yield (Table 2, entry 18). On the contrary, propargyl
2b according to these new conditions (Table 2, entries 1– bromide 2j failed to promote the reaction and the starting
10). The reactions were found to proceed smoothly, fur- pyrazinone remained untouched (Table 2, entry 19).
nishing the required 3-benzyl analogues 3b–f in 65–81%
Recently, it has been demonstrated that simultaneous
yield. Once again, optimal chemoselectivity was obtained
cooling by passing a jet of air over the reaction vial during
during the reaction and no traces of dimers or stannanes
irradiation can result in higher yields and can provide nov-
were isolated as by-products, albeit with the presence of
el pathways that are otherwise unattainable,9 as it allows
traces of butylated compounds 4b–f.
higher intake of microwave energy.10 We have investigat-
Our next goal was to incorporate diversity at the C-3 po- ed our microwave-enhanced cross-Stille reaction under
sition of the pyrazinone scaffold by varying the benzyl ha- simultaneous cooling, in view of obtaining possible im-
lide component. As can be viewed from Table 2, the provements. We expected an advantageous effect as the
highly electron-rich 4-methoxybenzyl bromide (2c) and palladium catalyst, which is strongly absorbing the micro-
4-methoxybenzyl chloride (2d) furnished the required 3- wave energy, will be activated much stronger if a higher
benzyl analogues 3g–h in 58–79% yields, (Table 2, en- power could be maintained during the reaction by the air-
tries 11–13). The ortho-fluorobenzyl bromide (2f) reacted jet cooling. The temperature of the reaction mixture was
equally well and the product 3j was isolated in 72% yield monitored using external IR as well as fiberoptic tem-
(Table 2, entry 15). However, the ortho- and para-ni- perature measurement, as the former is known to indicate
trobenzyl halides 2g,h failed to promote the cross-Stille too low temperatures due to the stream of air passed over
reaction, and only starting pyrazinone 1b was isolated the vial. Under simultaneous cooling, the microwave
together with unidentified decomposition products energy intake of the reaction was found to increase up to
Table 3 Comparison of Experiments Performed under Simultaneous Coolinga
R1
N
R1
N
R1
N
R6
O
R6
O
R6
O
Sn2Bu6, Pd(Ph3P)4, MW
DMF, 170 °C, 10 min
+
R3–X
+
Cl
N
R3
Cl
N
Bu
Cl
N
Cl
1b–f
2b–d
3b–f,h,i
4b–f,h,i traces
Entry
1
Pyrazinone R1
R6
H
Halide
R3
Product11,12 Cooling
Power (W)b
84
Yield (%)
68
1b
1b
1c
1c
1d
1d
1e
1e
1f
(CH2)3Ph
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2c
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
3b
3b
3c
3c
3d
3d
3e
3e
3f
No
2
(CH2)3Ph
CH2C6H11
CH2C6H11
C6H11
H
Yes
No
113 (135%)
86
72
3
H
65
4
H
Yes
No
140 (163%)
74
74
5
H
66
6
C6H11
H
Yes
No
111 (150%)
65
74
7
CH2Ph
CH2Ph
Ph
Me
Me
Ph
Ph
H
65
8
Yes
No
127 (195%)
77
69
9
73
10
11
12
13
14
1f
Ph
3f
Yes
No
123 (160%)
75
75
1b
1b
1b
1b
(CH2)3Ph
(CH2)3Ph
(CH2)3Ph
(CH2)3Ph
(4-MeO)Bn
(4-MeO)Bn
3h
3h
58
H
2c
Yes
No
120 (160%)
84
74
H
2d
2d
(3,4,5-MeO)Bn 3i
(3,4,5-MeO)Bn 3i
57
H
Yes
123 (146%)
69
a All reactions were carried out on a 1.0 mmol scale with 1.1 equiv of the corresponding benzyl chloride, 1.1 equiv of Sn2Bu6 and 5 mol% of
Pd(Ph3P)4 in 3.0 mL of DMF at a preselected temperature of 170 °C for 10 min at a preselected maximum power of 350 W.
b The power values indicated in the table are the total power input values in each case; between brackets is given the percentage of power input
compared to the experiment without simultaneous cooling.
Synlett 2006, No. 10, 1491–1496 © Thieme Stuttgart · New York

LETTER
Microwave-Enhanced Cross-Stille Reactions
1495
A.; Stevens, A. M.; Stallings, W. C.; Kurumbail, R. G.;
South, M. S. J. Med. Chem. 2003, 46, 4050.
135–195% in most cases (Table 3). As can be viewed
from Table 3, the cross-Stille reactions clearly benefit
from the simultaneous cooling during the microwave irra-
diation resulting in higher yields. The reaction of 2b with
different pyrazinones 1b–f furnished slightly improved
yields in the range of 2–9% (Table 3, entries 1–10).
(2) (a) Kaval, N.; Ermolat’ev, D.; Appukkuttan, P.; Dehaen, W.;
Kappe, C. O.; Van der Eycken, E. J. Comb. Chem. 2005, 7,
490. (b) Kaval, N.; Dehaen, W.; Kappe, C. O.; Van der
Eycken, E. Org. Biomol. Chem. 2004, 2, 154. (c) Van der
Eycken, E.; Appukkuttan, P.; De Borggraeve, W.; Deahen,
W.; Dallinger, D.; Kappe, C. O. J. Org. Chem. 2002, 67,
7904.
(3) De Borggraeve, W. M.; Rombouts, F. J. R.; Van der Eycken,
E. V.; Toppet, S. M.; Hoornaert, G. J. Tetrahedron Lett.
2001, 42, 5693.
(4) Pawar, V. G.; De Borggraeve, W. M.; Maes, V.; Tourwe, D.
A.; Compernolle, F.; Hoornaert, G. J. Tetrahedron Lett.
2005, 46, 1707.
(5) De Borggraeve, W. M.; Verbist, B. M. P.; Rombouts, F. J.
R.; Pawar, V. G.; Smets, W. J.; Kamoune, L.; Alen, J.; Van
der Eycken, E. V.; Compernolle, F.; Hoornaert, G. J.
Tetrahedron 2004, 60, 11597.
However, important yield enhancements of 12–16% were
observed when pyrazinone 1b was cross-coupled with the
electron-rich benzyl halides like 2c and 2d (Table 3,
entries 11–14). These results indeed indicate that simulta-
neous cooling during microwave irradiation could be a
very useful tool to obtain higher product yields in certain
cases. Further experiments to extend this cross-Stille
reaction to other heterocyclic systems are under current
investigation.
In conclusion, we have developed a practical microwave-
enhanced one-pot cross-Stille protocol for the 3-chloro-
2(1H)-pyrazinones which avoids the purification and
handling of any toxic stannylated intermediates while
introducing benzyl and alkyl moieties via conventional
Stille coupling. Even though one-pot Stille reactions are
documented in the literature, they mostly focus on the
coupling of (hetero)aromatic molecules and often tend to
provide homodimerization products. A high chemoselec-
tivity was obtained during the course of the reaction,
while no stannous byproducts or homocoupling was ob-
served. A number of otherwise difficultly obtainable 3-
benzylated and allylated 2(1H)-pyrazinones was generat-
ed according to the protocol. The microwave-enhanced
cross-Stille reactions were investigated under simulta-
neous cooling and improved yields were obtained during
reactions.
(6) (a) Stille, J. K. Angew. Chem. 1986, 98, 504. (b) Stille, J.
K.; Simpson, J. H. J. Am. Chem. Soc. 1987, 109, 2138.
(c) Farina, V. Pure Appl. Chem. 1996, 68, 73. (d) Bedford,
R. B.; Hazelwood, S. L.; Limmert, M. E.; Albisson, D. A.;
Draper, S. M.; Scully, P. N.; Coles, S. J.; Hursthouse, M. B.
Chem. Eur. J. 2003, 9, 3216; and references cited therein.
(7) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der
Eycken, E. Mol. Diversity 2003, 7, 125.
(8) (a) Iyoda, M.; Miura, M.; Sasaki, S.; Kabir, S. M. H.;
Kuwatani, Y.; Yoshida, M. Tetrahedron Lett. 1997, 38,
4581. (b) Corsico, B. M.; Rossi, R. A. Synlett 2000, 230.
(c) Broutin, P.-E.; Čerňa, I.; Companiello, M.; Leroux, F.;
Colbert, F. Org. Lett. 2004, 6, 4419. (d) Cahiez, G.;
Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M. Org. Lett.
2005, 7, 1943. (e) Micozzia, A.; Ottaviania, M.; Giardinaa,
G.; Riccia, A.; Pizzoferratob, R.; Zillerb, T.; Compagnone,
D.; Lo Sterzoc, C. Adv. Synth. Catal. 2005, 347, 143.
(9) Arvela, R. K.; Leadbeater, N. E. Org. Lett. 2005, 7, 2101.
(10) (a) Chen, J. J.; Deshpande, S. V. Tetrahedron Lett. 2003, 44,
8873. (b) Humphrey, C. E.; Easson, M. A. M.; Tierney, J. P.;
Turner, N. J. Org. Lett. 2003, 5, 849. (c) Katritzky, A. R.;
Zhang, Y.; Singh, S. K.; Steel, P. J. Arkivoc 2003, (xv), 47.
(11) Representative Experimental Procedure Using a
Dedicated Multimode Microwave Apparatus – Synthesis
of 1,3-Dibenzyl-5-chloro-6-methylpyrazin-2 (1H)-one
(3e).
Acknowledgment
The authors wish to thank the F.W.O. [Fund for Scientific Research
– Flanders (Belgium)], Research Fund of the University of Leuven,
Research Fund of the University of Delhi and the C.S.I.R. (Council
for Scientific and Industrial Research – India) for financial support
to the laboratories. P.A. and M.H. are grateful to the University of
Leuven for providing postdoctoral and visiting researcher scholar-
ships, respectively.
Pyrazinone 1e (0.324 g, 1.0 mmol), bromide 2a (0.205 g, 1.2
mmol, 1.2 equiv), hexabutyldistannane (0.649 g, 1.1 mmol,
1.1 equiv) and Pd(Ph3P)4 (0.058 g, 5 mol%) were suspended
in DMF (12 mL) in a 50 mL glass vial equipped with a small
magnetic stirring bar. The mixture was irradiated in the
cavity of a Milestone-MYCROSYNTH multimode oven at a
preselected maximum temperature of 170 °C for 10 min,
using a maximum irradiation power of 120 W. The mixture
was then cooled to r.t., poured into crushed ice, diluted with
Et2O and the contents were stirred at r.t. for 2 h. It was then
extracted with Et2O and dried over MgSO4. The solvent was
removed under reduced pressure and the crude residue was
subjected to column chromatography (silica gel, PE–EtOAc,
3:1) as eluent to afford analytically pure product 3e (0.224 g,
69%) as a viscous oil. 1H NMR (300 MHz, CDCl3): d =
7.17–7.35 (m, 10 H), 5.38 (s, 2 H), 4.12 (s, 2 H), 2.49 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): d = 158.2, 153.3,
136.1, 134.1, 133.9, 129.2, 129.0, 128.5, 127.2, 127.0,
126.4, 123.2, 50.2, 39.1, 16.9 ppm. MS (CI): m/z (%) = 325
(100) [MH+]. HRMS (EI): m/z calcd for C19H17N2ClO:
324.1029; found: 324.1034.
References and Notes
(1) (a) Hoornaert, G. Bull. Soc. Chim. Belg. 1994, 103, 583.
(b) Kaval, N.; Van der Eycken, J.; Caroen, J.; Dehaen, W.;
Strohmeier, G. A.; Kappe, C. O.; Van der Eycken, E. J.
Comb. Chem. 2003, 5, 560. (c) Kaval, N.; Dehaen, W.; Van
der Eycken, E. J. Comb. Chem. 2005, 7, 90; and references
cited therein. (d) Jiang, B.; Yang, C.-G.; Wang, J. J. Org.
Chem. 2001, 66, 4865. (e) Heeres, J.; de Jonge, M. R.;
Koymans, L. M. H.; Daeyaert, F. F. D.; Vinkers, M.; Van
Aken, K. J. A.; Arnold, E.; Das, K.; Kilonda, A.; Hoornaert,
G. J.; Compernolle, F.; Cegla, M.; Azzam, R. A.; Andries,
K.; de Bethune, M.-P.; Azijn, H.; Pauwels, R.; Lewi, P. J.;
Janssen, P. A. J. J. Med. Chem. 2005, 48, 1910. (f) Parlow,
J. J.; Case, B. L.; Dice, T. A.; Fenton, R. L.; Hayes, M. J.;
Jones, D. E.; Neumann, W. L.; Wood, R. S.; Lachance, R.
M.; Girard, T. J.; Nicholson, N. S.; Clare, M.; Stegeman, R.
Synlett 2006, No. 10, 1491–1496 © Thieme Stuttgart · New York

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LETTER
(12) 3-Benzyl-5-chloro-1-(4-methoxybenzyl)-2(1H)-
pyrazinone (3a).
10 H), 7.49 (d, 2 H, J = 8.29 Hz) ppm. 13C NMR (75 MHz,
CDCl3): d = 39.8, 55.3, 114.0, 125.6, 128.2, 128.7, 129.0,
129.2, 130.0, 130.8, 131.3, 136.4, 137.2, 155.1, 158.3, 159.5
ppm. MS (CI): m/z (%) = 403 (100) [MH+]. HRMS (EI):
m/z calcd for C24H19N2ClO2: 402.1135; found: 402.1142.
5-Chloro-3-(4-methoxybenzyl)-1-(3-phenylpropyl)-
2(1H)-pyrazinone (3h).
Mp 102–103 °C. 1H NMR (300 MHz, CDCl3): d = 3.8 (s, 3
H), 4.12 (s, 2 H), 4.93 (s, 2 H), 6.9 (d, 2 H, J = 8.7 Hz), 7.01
(s, 1 H), 7.30–7.35 (m, 5 H), 7.44 (d, 2 H, J = 7.0 Hz) ppm.
13C NMR (75 MHz, CDCl3): d = 39.8, 51.8, 55.2, 114.4,
124.3, 125.7, 125.8, 126.5, 128.3, 129.3, 130.2, 136.3,
154.4, 158.8, 159.8 ppm. MS (CI): m/z (%) = 341 [MH+],
121 (100). HRMS (EI): m/z calcd for C19H17N2ClO2:
340.0978; found: 340.0972.
Mp 113–114 °C. 1H NMR (300 MHz, CDCl3): d = 2.03–2.08
(m, 2 H), 2.66 (t, J = 7.32 Hz, 2 H), 3.75 (s, 3 H), 3.82 (t,
J = 7.32 Hz, 2 H), 4.03 (s, 2 H), 6.83 (d, J = 8.22 Hz, 2 H),
6.99 (s, 1 H), 7.14 (d, J = 6.39 Hz, 2 H), 7.19–7.28 (m, 5 H)
ppm. 13C NMR (75 MHz, CDCl3): d = 29.7, 32.7, 39.1, 49.8,
55.2, 113.9, 125.2, 125.7, 126.7, 128.2, 128.5, 128.6, 130.5,
140.0, 154.6, 158.5, 159.2 ppm. MS (CI): m/z = 369 (100)
[MH+]. HRMS (EI): m/z calcd for C21H21N2ClO2: 368.1291;
found: 368.1287.
3-Benzyl-5-chloro-(3-phenylpropyl)-2(1H)-pyrazinone
(3b).
Mp 98–100 °C. 1H NMR (300 MHz, CDCl3): d = 2.03–2.19
(m, 2 H), 2.68 (t, J = 7.35 Hz, 2 H), 3.84 (t, J = 7.35 Hz, 2
H), 4.12 (s, 2 H), 6.92 (s, 1 H, C-6H), 7.15–7.44 (m, 10 H)
ppm. 13C NMR (75 MHz, CDCl3): d = 29.6, 32.7, 39.9, 49.8,
125.3, 125.6, 126.3, 126.7, 128.2, 128.3, 128.4, 128.6,
136.0, 139.0, 154.5, 158.9 ppm. MS (CI): m/z (%) = 339
(100) [MH+]. HRMS (EI): m/z calcd for C20H19N2ClO:
338.1185; found: 338.1194.
5-Chloro-1-(3-phenylpropyl)-3-(3,4,5-trimethoxy-
benzyl)-2(1H)-pyrazinone (3i).
Mp 104–105 °C. 1H NMR (300 MHz, CDCl3): d = 2.05–2.10
(m, 2 H), 2.67 (t, J = 7.44 Hz, 2 H), 3.80–3.88 (m, 11 H),
4.03 (s, 2 H), 6.67 (s, 2 H), 7.02 (s, 1 H), 7.15–7.30 (m, 5 H)
ppm. 13C NMR (75 MHz, CDCl3): d = 29.8, 32.8, 40.1, 50.0,
56.2, 56.3, 55.4, 106.5, 125.5, 125.7, 126.5, 128.3, 128.7,
132.3, 136.8, 140.0, 153.2, 153.3, 154.7, 158.7 ppm. MS
(CI): m/z (%) = 429 (100) [MH+]. HRMS (EI): m/z calcd for
C23H25N2ClO4: 428.1502; found: 428.1499.
3-Benzyl-5-chloro-1-cyclohexylmethyl-2(1H)-
pyrazinone (3c).
Mp 107–108 °C. 1H NMR (300 MHz, CDCl3): d = 1.13–1.90
(m, 11 H), 3.78 (d, J = 7.41 Hz, 2 H), 4.10 (s, 2 H), 7.21 (s,
1 H), 7.12–7.18 (m, 3 H), 7.32 (d, J = 7.32 Hz, 2 H) ppm. 13
NMR (75 MHz, CDCl3): d = 25.5, 26.1, 30.6, 36.8, 40.2,
C
57.4, 122.4, 126.2, 126.7, 128.4, 129.3, 136.5, 154.1, 158.7
ppm. MS (CI): m/z (%) = 317 (100) [MH+]. HRMS (EI):
m/z calcd for C18H21N2ClO: 316.1342; found: 316.1344.
3-Benzyl-5-chloro-1-cyclohexyl-2(1H)-pyrazinone (3d).
Mp 139–140 °C. 1H NMR (300 MHz, CDCl3): d = 1.37–1.91
(m, 10 H), 4.10 (s, 2 H), 4.68–4.76 (m, 1 H), 7.12 (s, 1 H),
5-Chloro-3-(2-fluorobenzyl)-1-(3-phenylpropyl)-2(1H)-
pyrazinone (3j).
Mp 97–98 °C. 1H NMR (300 MHz, CDCl3): d = 2.03–2.13
(m, 2 H), 2.67 (t, J = 7.40 Hz, 2 H), 3.85 (t, J = 7.47 Hz, 2
H), 4.15 (s, 2 H), 7.01 (s, 1 H), 7.02–7.31 (m, 9 H) ppm. 13
C
NMR (75 MHz, CDCl3): d = 29.8, 32.8, 33.2, 49.9, 115.6,
124.0, 125.5, 125.8, 126.5, 128.3, 128.5, 128.7, 131.5,
131.6, 140.1, 154.5, 158.7, 162.9 ppm. MS (CI): m/z (%) =
357 (100) [MH+]. HRMS (EI): m/z calcd for C20H18N2FClO:
356.1092; found: 356.1098.
7.18–7.30 (m, 3 H), 7.41 (d, J = 7.32 Hz, 2 H) ppm. 13
C
NMR (75 MHz, CDCl3): d = 25.2, 25.6, 30.0, 40.3, 55.5,
121.8, 126.2, 126.7, 128.5, 129.6, 136.7, 154.2, 158.6 ppm.
MS (CI): m/z 303 (100) [MH+]. HRMS (EI): m/z calcd for
C17H19N2ClO: 302.1185; found: 302.1184.
3-Allyl-5-chloro-1-(3-phenylpropyl)-2(1H)-pyrazinone
(3m).
3-Benzyl-5-chloro-1,6-diphenyl-2(1H)-pyrazinone (3f).
Mp 180–181 °C. 1H NMR (300 MHz, CDCl3): d = 4.12 (s, 2
H), 6.96–7.84 (m, 15 H) ppm. 13C NMR (75 MHz, CDCl3):
d = 40.2, 125.6, 126.87, 128.2, 128.2, 28.6, 128.7, 129.0,
129.1, 129.8, 130.0, 130.7, 131.2, 136.7, 137.2, 155.5, 158.3
ppm. MS (CI): m/z (%) = 373 (100) [MH+]. HRMS (EI):
m/z calcd for C23H17N2ClO: 372.1029; found: 372.1020.
5-Chloro-3-(4-methoxybenzyl)-1,6-diphenyl-2(1H)-
pyrazinone (3g).
Viscous oil. 1H NMR (300 MHz, CDCl3): d = 2.05–2.13 (m,
2 H), 2.22 (dd, J = 1.83, 5.49 Hz, 2 H), 2.71 (t, J = 7.34 Hz,
2 H), 3.89 (t, J = 7.30 Hz, 2 H), 6.83 (dd, J = 1.88, 14.16 Hz,
2 H), 6.99 (s, 1 H), 7.17–7.33 (m, 6 H) ppm. 13C NMR (75
MHz, CDCl3): d = 30.1, 31.9, 33.1, 50.2, 124.6, 124.5,
125.8, 126.8, 128.6, 129.1, 139.3, 140.5, 152.3, 154.7 ppm.
MS (CI): m/z (%) = 289 (100) [MH+]. HRMS (EI): m/z calcd
for C16H17N2ClO: 288.1029; found: 288.1034. Anal. Calcd
for C16H17N2ClO: C, 66.55; H, 5.93; N, 9.70. Found: C,
66.60; H, 5.97; N, 9.68.
Mp 194–195° °C. 1H NMR (300 MHz, CDCl3): d = 3.80 (s,
3 H), 4.16 (s, 2 H,), 6.89 (d, 2 H, J = 8.47 Hz), 6.96–7.29 (m,
Synlett 2006, No. 10, 1491–1496 © Thieme Stuttgart · New York