Chemical reactivity of dihydropyrazine derivatives. Cycloaddition behavior toward ketenes

Article abstract of DOI:10.1248/cpb.57.846

The cycloaddition behavior of dihydropyrazines toward ketenes was investigated using single-crystal X-ray structures of the cycloadducts and density functional theory (DFT) calculation data. The reaction proceeds via a stepwise pathway involving an orient

Full text of DOI:10.1248/cpb.57.846

846
Chem. Pharm. Bull. 57(8) 846—852 (2009)
Vol. 57, No. 8
Chemical Reactivity of Dihydropyrazine Derivatives. Cycloaddition
Behavior toward Ketenes
Kazuhide NAKAHARA, Koki YAMAGUCHI, Yasuyuki YOSHITAKE, Tadatoshi YAMAGUCHI, and
Kazunobu HARANO*
Faculty of Pharmaceutical Sciences, Sojo University; 4–22–1 Ikeda, Kumamoto 860–0082, Japan.
Received April 9, 2009; accepted May 7, 2009; published online May 12, 2009
The cycloaddition behavior of dihydropyrazines toward ketenes was investigated using single-crystal X-ray
structures of the cycloadducts and density functional theory (DFT) calculation data. The reaction proceeds via a
stepwise pathway involving an orientation complex prior to formation of the betaine intermediate. This is fol-
lowed by electrocyclization to afford the 1 : 1 and 1 : 2 adducts bearing b-lactam ring(s).
Key words dihydropyrazine; ketene; imine; cycloaddition; density functional theory; X-ray analysis
Dihydropyrazines (DHPs), which are derived from amino- DHPs, we studied the cycloaddition behavior of DHPs as
sugars, exhibit various properties such as specific DNA diazadienes or imines towards ketenes. The results are dis-
strand-breakage activity,1—3) facile dimerization,4—6) unique cussed in detail on the basis of molecular orbital (MO) calcu-
ESR spectral behavior,7—9) in vitro, induction of apoptosis10) lations on the cycloaddition pathways and the single crystal
and mutagenesis11,12) in vivo. It is thought that all these phe- X-ray analyses of the cycloadducts.
nomena originate from the two natural characteristics of
DHPs, i.e., their high chemical reactivity and radical genera- Results and Discussion
tion ability.4—9)
First, reactions of relatively stable 2,3-diphenyl DHP de-
As exemplified in Chart 1, less substituted DHPs such as rivatives (1a—c)13) with ketenes (2a—c) were performed
5,6-dimethyl-2,3-dihydropyrazine exhibit high chemical re- (Chart 2).
activity and readily transform to dimeric heterocyclic com-
pounds via aldol condensation or pericyclic ene reaction and two stereoisomeric 1:2 adducts (anti 4aa and syn 4aa).
(Chart 1).5,6)
The yields and product ratios for the reactions with 1a—c
The reaction of 1a with 2a provided the 1 : 1 adduct (3aa)
In order to clarify the inherent chemical reactivity of and 2a—c are summarized in Table 1.
Chart 1
Chart 2
∗ To whom correspondence should be addressed. e-mail: harano@ph.sojo-u.ac.jp
© 2009 Pharmaceutical Society of Japan

August 2009
847
Fig. 1. 500 MHz 1H-NMR Spectral Data for 1 : 2 Adducts
Table 1. Reaction Product (%) and Ratio (anti 4 : syn 4) for Dihydropy-
razine (1) with Ketene (2)
Product (%)
Product ratio
Starting substance
Reaction time
3
4
(anti 4 : syn 4)
1a
1b
1c
2a
2b
2c
2a
2b
2c
2a
2b
2c
40.1 (3aa)
—
52.6 (4aa)
90.2 (4ab)
—
36.7a) (4ba)
58.6a) (4bb)
—
3 : 2
7 : 2
—
21.5 h
24 h
18 h
17 h
24 h
17 h
16 h
24 h
22 h
90.3 (3ac)
2.3a) (3ba)
21.5 (3bb)
33.3 (3bc)
38.8 (3ca)
42.5 (3cb)
79.3 (3cc)
—
—
Fig. 2. ORTEP Drawings of the Cycloadducts (3ba, 3ac, 3bc, syn 4aa)
—
30.2 (4ca)
54.9 (4cb)
—
2 : 1
5 : 1
—
Table 2. Crystal and Analysis Data for the Adducts
Crystal data
3ba
3ac
3bc
syn 4aa
a) Mixture of stereoisomers.
Formula
C20H20N2O2
Monoclinic
C30H24N2O
Monoclinic
C31H26N2O
Monoclinic
C22H24N2O5
Crystal system
Lattice parameters
a (Å)
Orthorhombic
The structures of the adducts were established by MS, IR
and NMR spectral data, showing the formation of a b-lactam
ring. The 1H-NMR spectrum of 3aa exhibited a methoxy sig-
nal at 3.50 ppm, methylene signals at 3.21—4.17 ppm, a me-
thine signal at 4.63 ppm and aromatic proton signals at
7.34—7.85 ppm. The 13C-NMR spectrum exhibited seven
non-aromatic carbon signals, suggesting the presence of one
methyl (d 59.3), two methylenes (d 37.0, 45.2), one methine
(d 89.1), one quaternary (d 63.7) and two sp2 carbons (d
168.4, 171.0). The IR spectrum showed the characteristic ab-
sorption of a b-lactam carbonyl at 1769 cmꢀ1. The structure
of the adduct (3aa) was confirmed by comparison of the
spectral features with those of the analogous 1 : 1 adducts
(3ba, 3ac) whose structures were firmly established by single
crystal X-ray analysis (see Fig. 2, Table 2).
19.243(7)
8.149(4)
10.861(3)
99.00
11.656(5)
17.754(7)
10.810(3)
90.99(3)
2236(1)
P21/n
11.930(3)
18.068(7)
10.863(3)
94.09(2)
2335(1)
P21/n
14.549(5)
19.032(5)
14.218(5)
b (Å)
c (Å)
b (°)
V (Å3)
1682(1)
P21/n
3937(2)
Pbca
8
Space group
Z
4
4
4
Density (calcd.)
Density (obsd.)
1.265
1.272
1.259
1.338
1.335
4526
0.072
0.116
1.002
717629
1.266
1.272
1.258
Unique data used 3868
5117
5347
R
0.095
0.166
1.000
717626
0.083
0.088
Rw
0.108
0.089
Goodness of fit
CCDC number
1.001
1.270
717627
717628
Both 1 : 2 adducts showed similar spectral behaviors as ob- with 2c, four isomers were recognized, indicating that the re-
served in the 1 : 1 adducts. Comparison of the 1H-NMR spec- action was affected by site selectivity in addition to the steric
tra of the 1 : 2 adducts afforded a clue to the determination effect. Of those, the structure of 3bc was established by X-
of the syn/anti orientation. In the syn orientation, the two ray analysis (see Fig. 2, Table 2).
phenyl rings are in a face-to-face disposition which agrees
The ketene cycloaddition reaction has attracted much at-
with the observation that the phenyl hydrogens are shifted tention from both synthetic and theoretical chemists because
upfield (6.91—7.26 ppm) in comparison with those of the the [2ꢂ2] cycloaddition products of cyclic dienes and
anti adduct (7.25—7.52 ppm), whereas the methine proton ketenes are known to be formed via [3,3]-sigmatropic re-
[ꢁCH(OMe)–CO–] of the anti adduct resonates at ca. arrangement of the [4ꢂ2] cycloadduct in which the carbonyl
0.7 ppm higher field than that of the syn adduct. The assign- double bond of the ketene acts as a dienophile (Chart 3, entry
1
ment of the H-NMR spectra of the 1 : 2 adducts (anti 4aa b). This finding has caused a revolution in ketene chem-
and syn 4aa) is shown in Fig. 1. The structure of syn 4aa was istry.14)
confirmed by single crystal X-ray analysis (see Fig. 2, Table
2).
In this connection, we previously reported another cy-
cloaddition mechanism for the reaction of dihydropyridines
It is noted that the reaction of 1a—c with diphenylketene with ketenes on the basis of MO calculations,15) in which the
(2c) gave only the 1 : 1 adduct. The reaction of the mono- lactam ring formation does not proceed via a sequential peri-
methyl-substituted DHP (1b) with 2a—c gave mixtures of cyclic reaction mechanism but takes place by a stepwise re-
the stereoisomeric cycloadducts. Even in the reaction of 1b action mechanism (Chart 3, entry c).

848
Vol. 57, No. 8
Based on the results for dihydropyridines, we considered unfavorable19) in comparison with the reaction barrier for the
that the reaction of a ketene with an a,b-unsaturated cyclic intermediate formation in the stepwise cyclization reaction
imine does not fall into the new category but involves initial (see also Fig. 4).
nucleophilic attack of the imine nitrogen on the ketene sp-hy-
The energy profile for the model reaction of 1 with 2 is de-
bridized carbon, followed by 4p electrocyclic ring closure to picted in Fig. 4. The reaction is found to proceed via a be-
give the [2ꢂ2] cycloaddition product. This reaction behavior taine intermediate followed by electrocyclization.
is easily explained by frontier molecular orbital (FMO) the-
The energy profile for the reaction of 1a with 2a is de-
ory.16,17) The highest occupied molecular orbital (HOMO) of picted in Fig. 5. The betaine intermediate is more stable than
the dihydropyridine localizes on the lone pair of the nitrogen that for the model reaction using the parent molecules.
atom, 0.35 eV higher than p-NHOMO, and the resulting aza-
diene readily undergoes conrotatory electrocyclic ring clo- (Fig. 6). The energy profile is essentially the same as that for
sure (Chart 4). 1 : 1 cycloadduct formation. The calculations indicate that
The 1 : 2 cycloadduct formation pathway is also calculated
To confirm the reaction mechanism for the reaction of the syn approach of the methoxy group with respect to the
DHP and ketene, we calculated possible transition-state (TS) lactam ring is energetically favorable, inconsistent with the
structures using the density functional theory (DFT) method experimental results. Close inspection of the reaction path-
at the B3LYP/6-31G (d) level.18) The TS geometries of [4ꢂ2] way between GS and TS1 suggests the presence of an orien-
cycloadditions using parent molecules [DHP as 4p diene to- tation complex (OC)20—25) in which the reactants loosely
wards ketene (CꢃC or CꢃO) as 2p dienophile], the interact- combine with each other as compared with the intermediate
ing bond distances and energies (Hartree) are depicted in Fig. (IM). The calculation indicates that the syn OC is more sta-
3. As shown in Fig. 3, [4ꢂ2] cycloadditions are energetically ble than the anti OC. The reaction barrier based on the anti
OC is lower than that for the syn OC, implying dominant for-
mation of the anti adduct.
Fig. 3. B3LYP/6-31G (d) Calculated Transition Structures for Possible
Chart 3
[4ꢂ2]p Cycloadditions
Chart 4
Fig. 4. B3LYP/6-31G (d) Simulation for Model Reaction Pathway for DHP and Ketene Using Parent Addends

August 2009
849
Fig. 5. Reaction Profile for Cycloaddition of 1a with 2a Calculated by the B3LYP/6-31G (d) Method
Fig. 6. Energy Diagram for the Reaction of 2a and 3aa
Fig. 7. Possible OC and IM in the Reaction of 1a with 2c Used for the MOS-F CNDO/S Calculation
The reaction barrier of the electrocyclization process is necessarily correspond to the calculation prediction.
lower than that for 1 : 1 adduct formation. This may be due to
the difference in the stabilization energy between the ground color in the reaction mixture was observed. The MOS-F
states of the reactants.
CNDO/S calculations26) suggested the presence of a charge-
During the course of the cyclization reaction, a change of
As the reaction may take place in part via direct cycloaddi- transfer complex, presumably due to the OC and IM struc-
tion without the OC formation, the product ratio does not tures (see Fig. 7, Table 3).

850
Vol. 57, No. 8
(MꢂꢂH): 503.1971. Found: 503.2018.
Table 3. Calculated Absorption Wavelength and Oscillator Strength
3ac: Colorless prisms. mp 174—176 °C.30) IR (KBr) cmꢀ1: 3100—2800
(C–H), 1752 (CꢃO), 1601 (CꢃN), 1574, 1495 (Ph), 1446 (CꢃN). 1H-NMR
(500 MHz; CDCl3) d: 3.22—3.27 (1H, m, CH), 3.47—3.54 (1H, m, CH),
3.91—3.96 (1H, m, CH), 4.27—4.33 (1H, m, CH), 6.79—7.53 (20H, m,
aromatic-H). 13C-NMR (125 MHz; CDCl3) d: 34.8 (C2), 45.8 (C3), 68.9
(C6), 78.6 (C7), 127.0, 127.3, 127.4, 127.7, 127.8, 128.0, 128.3, 128.9,
129.2, 129.6, 135.6, 137.8, 138.2, 138.4 (aromatic-C), 169.84 (CꢃN),
170.51 (CꢃO). FAB-MS (m/z): 429 (Mꢂꢂ1). Anal. Calcd for C30H24N2O:
C, 84.08; H, 5.65; N, 6.54. Found: C, 84.18; H, 5.55; N, 6.54.
State
OC
Absorption wavelength (nm)
Oscillator strengtha)
373.33
389.26
854.75
367.23
355.49
482.42
0.00765
0.00489
0.00525
0.00657
0.00134
0.53804
TS-SW1
IM
TS-SW2
3ba: Colorless prisms. mp 189—191 °C. IR (KBr) cmꢀ1: 1750 (CꢃO).
1H-NMR (500 MHz; CDCl3) d: 1.29 (3H, d, Jꢃ7.3 Hz, CH3), 2.55 (1H, dd,
Jꢃ9.1, 13.4 Hz, CH), 3.62 (3H, s, OCH3), 3.86 (1H, dd, Jꢃ6.7, 13.4 Hz,
CH), 4.08—4.12 (1H, m, CH), 4.74 (1H, s, CH), 7.25—7.80 (10H, m, aro-
matic-H). 13C-NMR (125 MHz; CDCl3) d: 20.8 (C3-Me), 40.7 (C2), 51.8
(C3), 59.9 (C7-OMe), 61.5 (C6), 90.7 (C7), 127.5, 127.7, 128.0, 128.4,
128.6, 129.8, 130.5, 135.6, 136.2 (aromatic-C), 163.5 (CꢃN), 166.0 (CꢃO).
EI-MS (m/z): 320 (Mꢂ). Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N,
8.74. Found: C, 74.97; H, 6.25; N, 8.63.
a) MOS-F CNDO/S.
In summary, DHP shows a high cycloaddition reactivity
toward ketenes, in which a stepwise reaction takes place via
nucleophilic attack of the nitrogen lone pair of DHP on the
ketene central carbon, followed by electrocyclization of the
azadiene.
1
3ba-1: Recognized as a minor product in the H-NMR spectrum of 3ba.
1H-NMR (300 MHz; CDCl3) d: 1.78 (3H, d, Jꢃ6.6 Hz, CH3), 3.29 (3H, s,
OCH3), 3.60 (1H, m, CH), 3.92—3.96 (2H, m, CH), 5.03 (1H, s, CH),
6.86—7.25 (10H, m, aromatic-H).
Experimental
Melting points are uncorrected. The IR spectra were obtained with a Hi-
tachi 270-30 spectrophotometer. 1H- and 13C-NMR spectra were obtained
with JEOL JNM-AL 300 (300 MHz) and JNM-A 500 (500 MHz) spectrome-
ters using tetramethylsilane as an internal standard. Mass spectra were ob-
tained using a JMS-DX303HF instrument.
Materials The DHPs (1a—c) were prepared according to the litera-
ture.1,27) The ketenes (2a—c) were also synthesized by established meth-
ods.28,29)
General Procedure A solution of methoxyacetyl chloride (0.43 g,
4 mmol) in CH2Cl2 (5.5 ml) was added dropwise to a solution of 2,3-dihy-
dropyrazine derivative (2 mmol) in CH2Cl2 (7.0 ml) containing triethylamine
(0.55 ml). After stirring at room temperature overnight, aqueous NaHCO3
was added to neutralize the reaction mixture. The products were extracted
with CH2Cl2 three times and dried over anhydrous MgSO4. Evaporation of
the solvent gave crude products, which were purified by chromatography on
silica gel. Crystallization from n-hexane gave pure cycloadducts.
3aa: Colorless prisms. mp 126—128 °C. IR (KBr) cmꢀ1: 1769 (CꢃO).
1H-NMR (500 MHz; CDCl3) d: 3.21 (1H, m, CH), 3.35—3.41 (1H, m, CH),
3.46—3.52 (1H, m, CH), 3.50 (3H, s, OCH3), 4.13—4.17 (1H, m, CH), 4.63
(1H, s, CH), 7.34—7.85 (10H, m, aromatic-H). 13C-NMR (125 MHz;
CDCl3) d: 37.0 (C2), 45.2 (C3), 59.3 (C7-OMe), 63.7 (C6), 89.1 (C7),
127.5, 128.3, 128.4, 128.6, 128.7, 130.9, 134.8, 136.0 (aromatic-C), 168.4
(CꢃN), 171.0 (CꢃO). EI-MS (m/z): 306 (Mꢂꢂ1). Anal. Calcd for
C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C, 74.33; H, 5.70; N, 9.14.
anti 4aa: Colorless prisms. mp 212—214 °C. IR (KBr) cmꢀ1: 1760
4ba: Colorless prisms. mp 158—160 °C. IR (KBr) cmꢀ1: 1752 (CꢃO).
1H-NMR (300 MHz; CDCl3) d: 1.75 (3H, d, Jꢃ6.7 Hz, CH3), 3.07—3.18
(6H, m, OCH3), 3.09 (1H, s, CH), 3.84 (1H, m, CH), 4.10 (1H, dd, Jꢃ4.4,
12.8 Hz, CH), 4.19 (1H, s, CH), 4.43 (1H, s, CH), 7.25—7.52 (10H, m, aro-
matic-H). 13C-NMR (125 MHz; CDCl3) d: 16.2 (C7-Me), 44.6 (C6), 49.5
(C7), 58.2 (C3-OMe), 58.3 (C10-OMe), 70.5 (C1), 74.2 (C2), 85.5 (C3),
90.5 (C10), 127.0, 127.2, 127.5, 127.7, 127.8, 127.9, 128.0, 128.4, 128.7,
128.8, 129.1, 129.8, 130.5, 137.2, 137.3 (aromatic-C), 165.4 (CꢃO), 165.7
(CꢃO). EI-MS (m/z): 392 (Mꢂ). Anal. Calcd for C23H24N2O4: C, 70.39; H,
6.16; N, 7.14. Found: C, 70.11; H, 6.12; N, 7.10.
1
4ba-1: Recognized as a minor product in the H-NMR spectrum of 4ba.
1H-NMR (300 MHz; CDCl3) d: 1.46 (3H, d, Jꢃ 6.4 Hz, CH3), 3.00—3.09
(1H, m, CH), 3.29 (6H, s, OCH3), 4.05—4.12 (1H, m, CH), 4.18—4.24 (1H,
m, CH), 4.90 (1H, s, CH), 4.97 (1H, s, CH), 6.86—7.25 (10H, m, aromatic-
H).
3bb: Colorless prisms. mp 164—166 °C. IR (KBr) cmꢀ1: (CꢃO). 1H-
NMR (500 MHz; CDCl3) d: 1.46—1.47 (3H, s, CH3), 3.16—3.17 (1H, m,
CH), 3.30—3.31 (1H, m, CH), 3.51—3.52 (1H, m, CH), 5.30—5.31 (1H, s,
CH), 6.94—7.77 (15H, m, aromatic-H). 13C-NMR (125 MHz; CDCl3) d:
20.9 (CH3), 44.1 (C2), 50.7 (C3), 63.9 (C5), 86.1 (C8), 117.3, 123.0, 127.8,
128.5, 128.8, 129.1, 129.2, 129.6, 131.1, 134.8, 135.7 (aromatic-C), 157.4
(OPh), 167.6 (CꢃN), 169.5 (CꢃO). EI-MS (m/z): 382 (Mꢂ). HR-MS Calcd
for C25H23N2O2(MꢂꢂH): 383.1760. Found: 383.1723.
1
4bb: Colorless prisms. mp 204—205 °C. IR (KBr) cmꢀ1: 1757 (CꢃO).
1H-NMR (500 MHz; CDCl3) d: 1.55 (3H, d, Jꢃ6.7 Hz, CH3), 3.65 (1H, dd,
Jꢃ5.5, 12.8 Hz, CH), 3.87 (1H, dd, Jꢃ2.4, 12.8 Hz, CH), 4.51—4.54 (1H,
m, CH), 5.12 (1H, s, CH), 5.40 (1H, s, CH), 6.56—7.43 (20H, m, aromatic-
H). 13C-NMR (125 MHz; CDCl3) d: 19.3 (C7-Me), 42.6 (C6), 43.5 (C7),
71.3 (C1), 73.7 (C2), 87.0 (C3), 87.2 (C10), 116.7, 122.7, 122.8, 128.2,
128.4, 128.6, 128.7, 128.8, 129.3, 129.4, 136.5, 136.9, 156.9, 157.0 (aro-
matic-C), 166.2 (CꢃO), 166.7 (CꢃO). EI-MS (m/z): 516 (Mꢂ). Anal. Calcd
for C33H28N2O4: C, 76.73; H, 5.46; N, 5.42. Found: C, 76.64; H, 5.26; N,
5.42.
(CꢃO), 1740 (CꢃO). H-NMR (500 MHz; CDCl3) d: 3.07 (6H, s, OCH3),
3.44 (2H, d, Jꢃ7.9 Hz, CH2), 4.10 (2H, d, Jꢃ7.9 Hz, CH2), 4.32 (2H, s, CH),
7.40—7.52 (10H, m, aromatic-H). 13C-NMR (125 MHz; CDCl3) d: 36.6
(C6, C7), 58.2 (C3-OMe, C10-OMe), 71.3 (C1, C2), 90.5 (C3, C10),
127.22, 127.61, 127.75, 127.92, 128.11, 128.51, 137.11 (aromatic-C),
165.69 (CꢃO). FAB-MS (m/z): 379 (Mꢂꢂ1). Anal. Calcd for C22H22N2O4:
C, 69.83; H, 5.86; N, 7.40. Found: C, 69.58; H, 5.90; N, 7.22.
syn 4aa: Colorless prisms. mp 248—251 °C. IR (KBr) cmꢀ1: 1749
(CꢃO). 1H-NMR (500 MHz; CDCl3) d: 3.26 (6H, s, OCH3), 3.52 (2H, d,
Jꢃ7.3 Hz, CH2), 4.17 (2H, d, Jꢃ7.3 Hz, CH2), 5.01 (2H, s, CH), 6.91—7.26
(10H, m, aromatic-H). 13C-NMR (125 MHz; CDCl3) d: 37.9 (C6, C7), 58.1
(C3-OMe, C10-OMe), 70.7 (C1, C2), 88.0 (C3, C10), 127.62, 127.72,
127.78, 127.93, 136.51 (aromatic-C), 168.97 (CꢃO). EI-MS (m/z): 378
(Mꢂ). Anal. Calcd for C22H22N2O4: C, 69.83; H, 5.86; N, 7.40. Found: C,
69.95; H, 5.68; N, 7.50.
Continued fractional crystallization caused enrichment but the minor
products could not be isolated in pure form. The following products were
1
recognized in the H-NMR spectrum of the enriched fractions whose struc-
tures were determined by comparison of the 1H-NMR data with each other.
4bb-1: 1H-NMR (300 MHz; CDCl3) d: 1.81 (3H, d, Jꢃ6.8 Hz, CH3),
3.21—3.29 (1H, m, CH), 3.93—4.00 (1H, m, CH), 4.17—4.22 (1H, m, CH),
5.02 (1H, s, CH), 5.18 (1H, s, CH), 6.55—7.40 (20H, m, aromatic-H).
4bb-2: 1H-NMR (300 MHz; CDCl3) d: 1.41 (3H, d, Jꢃ6.6 Hz, CH3),
3.06—3.14 (1H, m, CH), 4.13—4.20 (1H, m, CH), 4.31—4.39 (1H, m, CH),
5.48 (1H, s, CH), 5.55 (1H, s, CH), 6.78—7.31 (20H, m, aromatic-H).
4bb-3: 1H-NMR (300 MHz; CDCl3) d: 1.84 (3H, d, Jꢃ6.6 Hz, CH3),
3.70—3.73 (1H, m, CH), 4.01—4.07 (2H, m, CH), 5.61 (1H, s, CH), 5.62
(1H, s, CH), 6.78—7.31 (20H, m, aromatic-H).
anti 4ab: Colorless prisms. mp 222—224 °C. IR (KBr) cmꢀ1: 1760
1
(CꢃO). H-NMR (500 MHz; CDCl3) d: 3.56 (2H, d, Jꢃ7.9 Hz, CH2), 4.20
(2H, d, Jꢃ7.9 Hz, CH2), 5.11 (2H, s, CH), 6.62—7.40 (20H, m, aromatic-
H). 13C-NMR (125 MHz; CDCl3) d: 36.7 (C6, C7), 71.8 (C1, C2), 87.1 (C3,
C10), 116.46, 122.68, 128.68, 128.76, 129.35, 136.37, 156.93 (aromatic-C),
164.9 (CꢃO). EI-MS (m/z): 502 (Mꢂ). Anal. Calcd for C32H26N2O4: C,
76.48; H, 5.21; N, 5.57. Found: C, 76.33; H, 5.18; N, 5.59.
syn 4ab: Colorless prisms. mp 118—120 °C. IR (KBr) cmꢀ1: 1754
1
3bc: Colorless prisms. mp 184—186 °C. IR (KBr) cmꢀ1: 1747 (CꢃO).
1H-NMR (500 MHz; CDCl3) d: 1.29 (3H, d, Jꢃ6.1 Hz, CH3), 2.79 (1H, dd,
Jꢃ10.9, 14.6 Hz, CH), 4.09—4.14 (1H, m, CH), 4.27 (1H, dd, Jꢃ6.1,
14.6 Hz, CH), 6.72—7.53 (20H, m, aromatic-H). 13C-NMR (125 MHz;
CDCl3) d: 19.8 (C3-Me), 43.9 (C3), 52.6 (C2), 69.9 (C6), 78.5 (C7), 126.9,
(CꢃO). H-NMR (500 MHz; CDCl3) d: 3.62 (2H, d, Jꢃ7.3 Hz, CH2), 4.29
(2H, d, Jꢃ7.3 Hz, CH2), 5.61 (2H, s, CH), 6.91—7.34 (20H, m, aromatic-
H). 13C-NMR (125 MHz; CDCl3) d: 38.1 (C6, C7), 71.2 (C1, C2), 84.7 (C3,
C10), 116.4, 123.1, 127.4, 127.9, 128.2, 129.7, 135.9, 157.0 (aromatic-C),
168.0 (CꢃO). FAB-MS (m/z): 503 (Mꢂꢂ1). HR-MS Calcd for C32H27N2O4

August 2009
851
127.3, 127.4, 127.5, 127.7, 127.8, 128.0, 128.2, 128.4, 128.5, 128.9, 129.1, flection data were measured on a RIGAKU AFC7R four-circle autodiffrac-
129.4, 129.5, 135.8, 138.4, 138.8, 138.9 (aromatic-C), 171.92 (CꢃN), tometer with a graphite monochromated MoKa radiation (50 kV–150 mA)
172.42 (CꢃO). EI-MS (m/z): 442 (Mꢂ). Anal. Calcd for C32H28N2O: C,
84.13; H, 5.92; N, 6.33. Found: C, 84.17; H, 5.99; N, 6.26.
and rotating anode generator. The data were collected at a temperature of
23ꢄ1 °C to a maximum 2q value of 55.0°. The structures were solved by di-
rect method (SIR-92),31) and hydrogen atoms were placed in the calculation.
3ca: Colorless prisms. mp 114—116 °C. IR (KBr) cmꢀ1: 1754 (CꢃO).
1H-NMR (500 MHz; CDCl3) d: 1.25 (3H, s, CH3), 1.33 (3H, s, CH3), 2.71 A full-matrix least-squares technique was used with anisotropic thermal pa-
(1H, d, Jꢃ13.4 Hz, CH), 3.63 (3H, s, OMe), 3.67 (1H, d, Jꢃ13.4 Hz, CH),
4.72 (1H, s, CH), 7.25—7.82 (10H, m, aromatic-H). 13C-NMR (125 MHz;
CDCl3) d: 28.6 (C3-Me), 30.3 (C3-Me), 45.4 (C2), 55.3 (C3), 59.9 (C7-
OMe), 61.3 (C6), 90.7 (C7), 127.6, 128.0, 128.4, 129.8, 130.3, 135.6, 136.3
(aromatic-C), 161.1 (CꢃN), 166.5 (CꢃO). EI-MS (m/z): 334 (Mꢂꢂ1).
rameters for non-hydrogen atoms and riding model for hydrogen atoms. All
calculations were performed using the Crystal Structure32) crystallographic
software package.
Acknowledgements We would like to thank Associate Professor S.
Anal. Calcd for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C, 75.51; H, Takechi and Associate Professor H. Kansui for useful discussions.
6.67; N, 8.32.
anti 4ca: Colorless prisms. mp 209—211 °C. IR (KBr) cmꢀ1: 1752 References and Notes
(CꢃO). 1H-NMR (500 MHz; CDCl3) d: 1.33 (3H, s, CH3), 1.79 (3H, s,
CH3), 2.96 (3H, s, OCH3), 3.19 (3H, s, OCH3), 3.21 (1H, d, Jꢃ12.8 Hz,
CH), 3.82 (1H, d, Jꢃ12.8 Hz, CH), 4.06 (1H, s, CH), 4.95 (1H, s, CH),
7.38—7.60 (10H, m, aromatic-H). 13C-NMR (125 MHz; CDCl3) d: 25.3
(C7-Me), 26.5 (C7-Me), 50.0 (C6), 55.2 (C7), 58.1 (C3-OMe), 58.5 (C10-
OMe), 69.4 (C1), 73.1 (C2), 89.8 (C3), 90.1 (C10), 128.0, 128.2, 128.4,
128.5, 128.9, 138.0, 138.1 (aromatic-C), 166.7 (CꢃO), 166.9 (CꢃO). EI-
MS (m/z): 406 (Mꢂ). Anal. Calcd for C24H26N2O4: C, 70.92; H, 6.45; N,
6.89. Found: C, 70.95; H, 6.49; N, 6.93.
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syn 4ca: Colorless prisms. mp 148—150 °C. IR (KBr) cmꢀ1: 1748
(CꢃO). 1H-NMR (300 MHz; CDCl3) d: 0.88 (3H, s, CH3), 1.62 (3H, s,
CH3), 2.91 (1H, d, Jꢃ14.3 Hz, CH), 3.29 (3H, s, OCH3), 3.61 (3H, s,
OCH3), 3.76 (1H, d, Jꢃ14.4 Hz, CH), 4.91 (2H, s, CH), 7.07—7.60 (10H,
m, aromatic-H). 13C-NMR (125 MHz; CDCl3) d: 26.3 (C7-Me), 26.6 (C7-
Me), 48.6 (C6), 55.4 (C7), 59.5 (C3-OMe), 59.7 (C10-OMe), 64.5 (C1),
74.1 (C2), 87.2 (C3), 90.4 (C10), 126.4, 127.4, 127.8, 128.1, 128.3, 128.4,
128.6, 128.7, 131.2, 135.6, 138.1 (aromatic-C), 166.2 (CꢃO), 173.8 (CꢃO).
EI-MS (m/z): 406 (Mꢂ). HR-MS Calcd for C24H27N2O4 (MꢂꢂH): 407.1971.
Found: 407.1982.
10) Yamaguchi T., Nomura H., Matsunaga K., Ito S., Takata J., Karube Y.,
Biol. Pharm. Bull., 26, 1523—1527 (2003).
3cb: Colorless prisms. mp 113—115 °C. IR (KBr) cmꢀ1: 1769 (CꢃO).
1H-NMR (500 MHz; CDCl3) d: 1.26 (3H, s, CH3), 1.37 (3H, s, CH3), 2.76 11) Takechi S., Yamaguchi T., Nomura H., Minematsu T., Nakayama T.,
(1H, d, Jꢃ13.4 Hz, CH), 3.72 (1H, d, Jꢃ13.4 Hz, CH), 5.41 (1H, s, CH),
6.99—7.81 (15H, m, aromatic-H). 13C-NMR (125 MHz; CDCl3) d: 28.5
(C3-Me), 30.3 (C3-Me), 45.5 (C2), 55.3 (C3), 61.2 (C6), 87.0 (C7), 117.2,
123.0, 127.6, 128.0, 128.3, 128.4, 128.5, 129.6, 130.1, 130.4, 135.4, 135.8
(aromatic-C), 157.6 (OPh), 160.6 (CꢃN), 165.3 (CꢃO). HR-MS Calcd for
C26H25N2O2 (MꢂꢂH): 397.1916. Found: 397.1925.
Mutat. Res., 560, 49—55 (2004).
12) Takechi S., Yamaguchi T., Nomura H., Minematsu T., Adachi M., Ku-
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123, 717—759 (2003).
14) Machiguchi T., Hasegawa T., Ishiwata A., Terashima S., Yamabe S.,
Minato T., J. Am. Chem. Soc., 121, 4771—4786 (1999).
anti 4cb: Colorless prisms. mp 193—195 °C. IR (KBr) cmꢀ1: 1753
(CꢃO). 1H-NMR (500 MHz; CDCl3) d: 1.43 (3H, s, CH3), 1.85 (3H, s, 15) Oiso S., Eto M., Yoshitake Y., Harano K., Chem. Pharm. Bull., 51,
CH3), 3.29 (1H, d, Jꢃ12.8 Hz, CH), 3.91 (1H, d, Jꢃ13.0 Hz, CH), 4.94 (1H,
s, CH), 5.58 (1H, s, CH), 6.49—7.50 (20H, m, aromatic-H). 13C-NMR
(125 MHz; CDCl3) d: 25.2 (C7-Me), 26.5 (C7-Me), 50.0 (C6), 55.5 (C7),
1068—1074 (2003).
16) Fukui K., “Kagaku Hanno to Densi no Kido (Chemical Reactions and
Electron Orbitals),” Maruzen, Tokyo, 1976.
69.9 (C1), 73.2 (C2), 87.2 (C3), 87.3 (C10), 116.9, 117.0, 122.6, 122.9, 17) Fleming I., “Frontier Orbitals and Organic Chemical Reactions,”
128.2, 128.3, 128.4, 128.8, 129.1, 129.4, 137.2, 137.7 (aromatic-C), 157.0
(OPh), 157.1 (OPh), 165.9 (CꢃO), 166.0 (CꢃO). FAB-MS (m/z): 530 (Mꢂ).
Anal. Calcd for C34H30N2O4: C, 76.96; H, 5.70; N, 5.28. Found: C, 76.81; H,
5.65; N, 5.24.
Wiley, London, 1976.
18) Gaussian 98, Revision A.7. Frisch M. J., Trucks G. W., Schlegel H. B.,
Scuseria G. E., Robb M. A., Cheeseman J. R., Montgomery J. A. Jr.,
Vreven T., Kudin K. N., Burant J. C., Millam J. M., Iyengar S. S.,
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R., Hasegawa J., Ishida M., Nakajima T., Honda Y., Kitao O., Nakai
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V., Adamo C., Jaramillo J., Gomperts R., Stratmann R. E., Yazyev O.,
Austin A. J., Cammi R., Pomelli C., Ochterski J. W., Ayala P. Y., Mo-
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syn 4cb: Recognized as a minor product in the 1H-NMR spectrum of anti
1
4cb. H-NMR (500 MHz; CDCl3) d: 1.64 (3H, s, CH3), 1.71 (3H, s, CH3),
2.99 (1H, d, Jꢃ14.4 Hz, CH), 3.84 (1H, d, Jꢃ14.4 Hz, CH), 5.43 (1H, s,
CH), 5.54 (1H, s, CH), 6.77—7.81 (20H, m, aromatic-H).
3cc: Colorless prisms. mp 176—178 °C. IR (KBr) cmꢀ1: 1757 (CꢃO).
1H-NMR (500 MHz; CDCl3) d: 1.15 (3H, s, CH3), 1.61 (3H, s, CH3), 2.60
(1H, d, Jꢃ13.5 Hz, CH), 3.93 (1H, d, Jꢃ13.5 Hz, CH), 6.81—7.54 (20H, m,
aromatic-H). 13C-NMR (125 MHz; CDCl3) d: 29.3 (C3-Me), 30.1 (C3-Me),
44.9 (C2), 55.0 (C3), 66.8 (C6), 78.6 (C7), 127.0, 127.2, 127.3, 127.4,
127.9, 128.2, 128.9, 129.0, 129.7, 130.4, 136.1, 137.3, 137.6, 138.4 (aro-
matic-C). FAB-MS (m/z): 456 (Mꢂ). Anal. Calcd for C32H28N2O: C, 84.18;
H, 6.18; N, 6.14. Found: C, 84.01; H, 6.08; N, 6.11.
Molecular Orbital (MO) Calculations Semi-empirical MO calcula-
tions were run through the CS Chem3D Pro interface and WINMOPAC3.5
using MOPAC200226) on an Intel personal computer and iBook Macintosh
G4 computer. The ab initio and density functional theory (DFT) computa-
tions18) were carried out on a HIT parallel computer (Itanium 2, 2 node-4
CPU). The AM1-optimized structures or PM5-optimized structures were
used as starting geometries for the ab initio and DFT calculations. The ener-
gies were corrected using zero point vibrational energy (scaled by a factor of
0.9804). The B3LYP/6-31G (d) calculated data are available upon request
through e-mail.
19) Tamura et al., reported13) that the reaction of 2,3-diphenyl-5,6-dihy-
dropyrazine (1a) with diethyl fumarate gave the diethyl 3,4-diphenyl-
2,5-diazabicyclo[2.2.2]oct-2-ene-7,8-dicarboxylate via the [4ꢂ2]-cy-
cloaddition of the [1,5]-sigmatropic rearrangement product (1a’) of
1a.
20) Yoshitake Y., Eto M., Harano K., Heterocycles, 45, 1873—1878
(1997).
21) Sustmann R., Sicking W., Huisgen R., J. Am. Chem. Soc., 117, 9679—
9685 (1995).
Single Crystal X-Ray Analysis of 3ba, 3ac, 3bc and syn 4aa The re-

852
Vol. 57, No. 8
22) Matsuoka T., Hasegawa T., Eto M., Harano K., Hisano T., J. Chem.
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Pharm. Bull., 38, 605—611 (1990).
25) Inspection of the geometries of the complexes calculated by the
27) Ishiguro T., Matsumura M., Yakugaku Zasshi, 78, 229—231 (1958).
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30) The compound 3ac has been synthesized, however the NMR spectral
data were not described.13)
B3LYP/6-31G(d) method indicates that the phenyl group is rotated by 31) SIR92: Altomare A., Burla M.C, Camalli M., Cascarano M., Giacova-
55° out of the plane of CꢃN bond in which the anti OC is less stable
by 5.14 kcal/mol than the syn OC.
26) MOS-F (V5.0A), AM1 and PM5 calculations were performed using
MOPAC2002 ver. 1.00, Fujitsu Ltd., Tokyo, Japan, 2001.
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32) teXsan: Crystal Structure Analysis Package, Version 1.11. Molecular
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