N,N,N′,N′-tetramethylchloroformamidinium chloride-mediated cyclizations of β-oxo amides: facile and divergent one-pot synthesis of substituted 2H-pyrans, 4H-pyrans and pyridin-2(1H)-ones

Article abstract of DOI:10.1002/adsc.200900310

An efficient and divergent one-pot synthesis of substituted 2H-pyrans, 4H-pyrans and pyridin-2(1H)-ones from β-oxo amides based on the selection of the reaction conditions is reported. Mediated by N,N,N′,N′- tetramethylchloroformamidinium chloride, β-oxo

Full text of DOI:10.1002/adsc.200900310

FULL PAPERS
DOI: 10.1002/adsc.200900310
N,N,N’,N’-Tetramethylchloroformamidinium Chloride-Mediated
Cyclizations of b-Oxo Amides: Facile and Divergent One-Pot
Synthesis of Substituted 2H-Pyrans, 4H-Pyrans and Pyridin-
2(1H)-ones
Yan Wang,a,b Xin Xin,a,b Yongjiu Liang,a Yingjie Lin,b,* Haifeng Duan,b
and Dewen Donga,*
a
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, Peopleꢀs Republic of China
Fax : (+86)-431-8569-3057; e-mail: dwdong@ciac.jl.cn
Department of Chemistry, Jilin University, 130012 Changchun, Peopleꢀs Republic of China
b
Received: May 3, 2009; Published online: September 11, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900310.
Abstract: An efficient and divergent one-pot synthe- which could be converted into substituted 4H-pyrans
sis of substituted 2H-pyrans, 4H-pyrans and pyridin- in the presence of sodium hydroxide in ethanol at
2(1H)-ones from b-oxo amides based on the selec- room temperature, or into substituted pyridin-2-
tion of the reaction conditions is reported. Mediated
by N,N,N’,N’-tetramethylchloroformamidinium chlo-
ride, b-oxo amides underwent intermolecular cycliza-
ACHTUNGERTN(NUNG 1H)-ones under reflux.
tions in the presence of triethylamine at room tem- Keywords: cyclization; iminium salts; b-oxo amides;
perature to give substituted 2H-pyrans in high yields, 2H-pyrans; 4H-pyrans; pyridin-2(1H)-ones
Introduction
amides towards the iminium salt,[9] N,N,N’,N’-tetrame-
thylchloroformamidinium chloride (TMC),[10] which
The pyridin-2(1H)-one ring makes up the core struc- possesses a similar structure to Vilsmeier reagent
ture of numerous pharmaceutically active compounds, POCl3-DMF (Figure 1).[11] In this research, we devel-
such as elfamycin and ilicolicin.[1,2] As an important oped efficient and divergent one-pot synthesis of sub-
class of heterocycles, functionalized pyridin-2(1H)- stituted 2H-pyrans, 4H-pyrans and pyridin-2(1H)-ones
ones have been utilized as versatile intermediates in from b-oxo amides based on a selection of the reac-
the synthesis of a wide range of nitrogen-containing tion conditions. Herein, we wish to report our experi-
heterocycles, such as pyridine, piperidine, quinolizi- mental results and present a proposed mechanism in-
dine, and indolizidine alkaloids.[3,4] The development volved in the cyclizations.
of efficient synthetic approaches for such nitrogen-
containing heterocycles has been the focus of much
research for many decades and continues to be an
active area of research today. Recently, we reported a
facile and efficient synthesis of substituted pyridin-
2(1H)-ones via the Vilsmeier–Haack reactions of a
variety of b-oxo amide derivatives, such as 1-acyl-1-
carbamylcyclopropanes,[5] 5,6-dihydro-4H-pyrans,[6] a- Figure 1.
mono- and a-unsubstituted b-oxo amides,[7] and a-(di-
methylamino)methylene b-oxo amides.[8] Inspired by
these results and in continuation of our research inter- Results and Discussion
est in the synthesis of highly valuable heterocycles
from b-oxo amide derivatives, we examined the reac- The reaction of 3-oxo-N-phenylbutanamide 1a with
tion behavior of the commercially available b-oxo TMC was initially attempted. Thus, 1a and TMC was
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subjected to CH2Cl2 at room temperature, then
Under the optimal conditions, we carried out a
triethylACHTUNGTRENNUNGamine (Et3N) was loaded under stirring. The series of reactions of 1 to determine its scope with re-
reaction mixture quickly turned yellowish. However, spect to the amide moiety. As shown in Table 1, the
as monitored by TLC, some of the substrate could cyclization reaction proved to be suitable for b-oxo
not be consumed even after a prolonged reaction amides 1b–g bearing varied arylamide groups, afford-
time (48 h). Then the reaction was halted, a product ing the corresponding substituted 2H-pyrans 2b–g in
was obtained after work-up and subsequent purifica- good to high yields (Table 1, entries 2–7). However,
tion by column chromatography of the resulting mix- no reaction was observed when N-alkyl b-oxo amide
ture. The product was characterized as the six-mem- was subjected to the above conditions. It is worth
bered oxaheterocyclic compound, 3-acetyl-6-methyl-4- mentioning that the structure of 2c was elucidated by
(phenylamino)-2-(phenylimino)-2H-pyran 2a (37%), means of an X-ray single crystal analysis (Figure 2),
on the basis of its spectral and analytical data and further confirmed by its NMR spectra.
(Scheme 1).
Scheme 1. Reaction of 1a with TMC and triethylamine.
To optimize the yield of 2a, the reaction of 1a was
Figure 2. ORTEP drawing of 2c.
then carried out under various conditions. No reaction
was observed when 1a was treated with TMC in
CH2Cl2 at room temperature without Et3N, as indicat-
Therefore, we have provided a simple and efficient
ed by TLC. The reaction of 1a could not proceed with one-pot synthesis of substituted 2H-pyrans under very
a Lewis acid, such as TiCl4 and SnCl4, and Et3N. To mild conditions. Actually, 2H-pyran derivatives repre-
our delight, the reaction of 1a, TMC and Et3N was sent an important class of six-membered oxaheterocy-
significantly speeded up when DMF was used as sol- cles possessing useful biological activities.[12,13] It
vent instead of CH2Cl2. A series of experiments re- should be noted that the richness of the functionality,
vealed that 1.0 equiv. of TMC/Et3N was effective for for example, acetyl, amino, and arylimino groups, on
the synthesis of 2a, and the optimal results were ob- the 2H-pyrans of type 2 may render them extremely
tained when the reaction of 1a with 1.2 equiv. of TMC versatile as synthons in further synthetic transforma-
and 1.5 equiv. of Et3N was performed in DMF at tions.
room temperature for 15 min, whereby the yield of 2a
reached 83% (Table 1, entry 1).
Encouraged by this, we selected 2e as a model com-
pound to examine its behavior under basic conditions.
Thus, 2e was treated with NaOH (3.0 equiv.) in etha-
nol at room temperature for 5.0 h. The reaction fur-
nished a white solid, which was characterized as N-(2-
methoxyphenyl)-4-(2-methoxyphenylimino)-2,6-di-
methyl-4H-pyran-3-carboxamide 3e (94% yield), an-
other type of six-membered oxaheterocyclic com-
pound (Scheme 2). The structure of 3e was estab-
lished by means of an X-ray single crystal analysis
(Figure 3), and further confirmed by its NMR spectra.
Table 1. Synthesis of substituted 2H-pyrans 2.[a]
Entry
1
Ar
Time [min]
2
Yield[b] [%]
1
2
3
4
5
6
7
1a Ph
15
15
20
15
20
15
2a 83
2b 86
2c 81
2d 82
2e 80
2f 92
2g 75
1b 4-MeC6H4
1c 4-MeOC6H4
1d 2-MeC6H4
1e 2-MeOC6H4
1f 2,4-Me2C6H3
1g 5-Cl-2-MeOC6H3 30
[a]
Reagents and conditions: 1a (5.0 mmol), TMC
(6.0 mmol), DMF (10.0 mL), Et3N (7.5 mmol), room tem-
perature.
Isolated yields.
[b]
Scheme 2. Reaction of 2e with NaOH/EtOH.
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N,N,N’,N’-Tetramethylchloroformamidinium Chloride-Mediated Cyclizations
Table 3. Synthesis of pyridin-2(1H)-ones 4 from 2.[a]
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Entry
2
Ar
Time [h]
4
Yield[b] [%]
1
2
3
4
5
6
7
2a Ph
3.0
3.5
3.0
3.5
3.0
2.5
4a 91
4b 94
4c 89
4d 91
4e 88
4f 96
4g 87
2b 4-MeC6H4
2c 4-MeOC6H4
2d 2-MeC6H4
2e 2-MeOC6H4
2f 2,4-MeC6H3
Figure 3. ORTEP drawing of 3e.
2g 2-MeO-5-ClC6H3 4.0
[a]
Under the identical conditions, a series of the
newly synthesized 2H-pyrans 2 were converted into
the corresponding substituted 4H-pyrans 3 in high
yields (Table 2). The 4H-pyran derivatives are impor-
tant six-membered oxaheterocycles due to their pres-
ence in numerous natural products and synthetic or-
Reagents and conditions:
(6.0 mmol), EtOH (5.0 mL), reflux.
Isolated yields.
2
(2.0 mmol), NaOH
[b]
Moreover, we attempted one-pot synthesis of sub-
ganic compounds along with diverse bio- and pharma- stituted 4H-pyrans 3 and pyridin-2(1H)-ones 4 direct-
cological activities.[12,14] We have provided a novel ly from b-oxo amides 1. In a representative experi-
entry to the synthesis of 4H-pyrans.
ment, 1a was treated with TMC (1.2 equiv.) and Et3N
(1.5 equiv.) in DMF at room temperature for 15 min,
then NaOH (4.5 equiv.) in ethanol were loaded. The
reaction mixture was stirred at room temperature for
further 5.0 h to afford 3a, whereas stirring at 758C for
4.0 h gave 4a (Scheme 3).
Table 2. Synthesis of 4H-pyrans 3 from 2H-pyrans 2.[a]
Entry
2
Ar
Time [h]
3
Yield[b] [%]
1
2
3
4
5
6
7
2a Ph
4.5
4.5
5.0
4.5
5.0
4.5
3a 93
3b 92
3c 90
3d 91
3e 94
3f 95
3g 92
2b 4-MeC6H4
2c 4-MeOC6H4
2d 2-MeC6H4
2e 2-MeOC6H4
2f 2,4-Me2C6H3
2g 5-Cl-2-MeOC6H3 5.5
[a]
Reagents and conditions:
2
(2.0 mmol), NaOH
Scheme 3. One-pot synthesis of 4H-pyran 3a and pyridin-2-
AHCTUNGTRENGN(UN 1H)-ones 4a from b-oxo amide 1a.
(6.0 mmol), EtOH (5.0 mL), room temperature.
Isolated yields.
[b]
It was interesting to note that when the reaction of
On the basis of all the results obtained, a plausible
2e and NaOH (3.0 equiv.) was conducted in ethanol mechanism for the cyclization of b-oxo amides to 2H-
under reflux, we obtained a single product instead of pyrans, 4H-pyrans and pyridin-2(1H)-ones is present-
3e. The product was characterized as 3-acetyl-1-(4- ed in Scheme 4. In the presence of Et3N, the attack of
methoxyphenyl)-4-(4-methoxyphenylamino)-6-meth-
oxygen of the carbamoyl group of 1 on the electron-
ylpyridin-2(1H)-one 4e (88% yield). Under the identi- deficient carbon of TMC generates iminium salt
cal conditions, a series of the newly synthesized 2H- A,[9a–d] which undegoes intermolecular addition-elimi-
pyrans 2 were converted into the corresponding sub- nation reaction to give iminium salt B. The intramo-
stituted pyridin-2(1H)-ones 4 in high yields (Table 3). lecular cyclization of B leads the formation of 2H-
It should be mentioned that treatment of 3e with pyran 2 via the intermediate C. In the presence of
NaOH (1.5 equiv.) in ethanol under reflux for 4.0 h NaOH/EtOH, a ring-opening reaction of 2H-pyran 2
could also afford 4e in 90% yield.
occurs to give intermediates D and D’, as a pair of
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Scheme 4. Proposed mechanism for the reaction of 1 with TMC and triethylamine.
Z/E isomers, at different temperatures, which then Experimental Section
undergo intramolecular cyclizations to afford 4H-
pyrans 3 and pyridin-2(1H)-ones 4, respectively.[15]
General
All reagents were purchased from commercial sources and
used without treatment, unless otherwise indicated.
1H NMR and 13C NMR spectra were recorded at 258C at
300 MHz and 75 MHz, respectively, using TMS as internal
standard. IR spectra (KBr) were recorded on an FT-IR
spectrophotometer in the range of 400–4000 cmÀ1. Mass
spectra were recorded on an LCMsD mass spectrometer.
Conclusions
In summary, the intermolecular cyclization of b-oxo
amides 1 mediated by TMC/Et3N in DMF is disclosed
for the first time, and thus a novel and divergent one-
pot synthesis of substituted 2H-pyrans 2, 4H-pyrans 3
and pyridin-2(1H)-ones 4 from b-oxo amides 1 has
been developed based on a selection of the reaction
conditions. The one-pot protocol features commercial-
ly available starting materials, mild conditions, high
yields and rich functionality of the products. Further
work on the potential utilization of the products 2–4
as synthetic scaffolds and the evaluation of their bio-
logical activity is currently underway in our laborato-
ry.
Typical Procedure for the Preparation of 2H-Pyrans 2
(2a as an Example)
To a solution of 1a (0.89 g, 5.0 mmol) and N, N, N’, N’-tetra-
methylchloroformamidinium chloride (1.03 g, 6.0 mmol) in
dry DMF (10 mL) at room temperature was added Et3N
(1.04 mL, 7.5 mmol) in one portion. The mixture was stirred
at room temperature for 15 min and then poured into satu-
rated aqueous NaCl (20 mL), which was extracted with di-
chloromethane (3ꢂ20 mL). The combined organic phase
was washed with water (3ꢂ20 mL), dried over MgSO4, fil-
tered and concentrated under vacuum. The crude product
was purified by flash chromatography (silica gel, petroleum
ether:diethyl ether=10:1) to give 2a; yield: 0.66 g (83%).
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76.98, H 7.00, N 7.48; found: C 76.83, H 7.05, N 7.39: MS:
m/z=375.2, calcd. for [M+ +1]: 374.2.
Physical Data of Compounds Isolated
1
2g: Yellow solid; mp 192–1938C; 1H NMR (300 MHz,
CDCl3): d=1.94 (s, 3H), 2.76 (s, 3H), 3.79 (s, 3H), 3.84 (s,
3H), 5.68 (s, 1H), 6.80 (d, J=6.3 Hz, 1H), 6.92 (t, J=
7.2 Hz, 3H), 7.16–7.23 (m, 2H), 12.90 (s, 1H); 13C NMR
(75 MHz, CDCl3): d=19.8, 32.8, 56.0, 94.9, 97.1, 112.2,
112.6, 122.3, 122.6, 125.2, 125.3, 126.2, 127.3, 138.2, 150.0,
152.4, 156.8, 162.6, 200.5; anal. calcd. for C22H20Cl2N2O4: C
59.07, H 4.51, N 6.26; found: C 58.89, H 4.57, N 6.36.
2a: Yellowish oil; H NMR (300 MHz, CDCl3): d=1.94 (s,
3H), 2.76 (s, 3H), 5.70 (s, 1H), 7.04 (t, J=7.2 Hz, 3H), 7.17
(d, J=7.2 Hz, 2H), 7.30 (t, J=7.5 Hz, 3H), 7.42 (t, J=
7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=19.7, 32.8,
94.8, 96.6, 122.3, 122.4, 125.8, 126.8, 128.5, 129.4, 137.1,
147.0, 149.7, 157.0, 162.5, 200.2; anal. calcd. for C20H18N2O2:
C 75.45, H 5.70, N 8.80; found: C 75.68, H 5.72, N, 8.62.
1
2b: Yellowish solid; mp 170–1728C; H NMR (300 MHz,
CDCl3): d=1.93 (s, 3H), 2.32 (s, 3H), 2.37 (s, 3H), 2.74 (s,
3H), 5.66 (s, 1H), 6.96 (d, J=8.1 Hz, 2H), 7.03–7.11 (q, J=
8.1 Hz, 4H), 7.20 (d, J=7.8 Hz, 2H), 13.02 (s, 1H);
13C NMR (75 MHz, CDCl3) d =19.7, 20.8, 21.0, 32.7, 94.8,
96.5, 122.3, 125.8, 129.1, 130.0, 131.6, 134.5, 136.7, 144.3,
157.1, 162.4, 200.1; IR (KBr): n=826, 966, 1018, 1269, 1548,
1637, 1676 cmÀ1; anal. calcd. for C22H22N2O2: C 76.28, H
6.40, N 8.09; found: C 76.43, H 6.50, N, 8.11.
Typical Procedure for the Preparation of 4H-Pyrans 3
(3a as an Example)
To a solution of 2a (0.64 g, 2.0 mmol) in EtOH (5.0 mL) at
room temperature was added NaOH (0.24 g, 6.0 mmol) in
one portion. The mixture was stirred at room temperature
for 4.5 h and then poured into saturated aqueous NaCl
(20 mL), which was extracted with dichloromethane (3ꢂ
20 mL). The combined organic phase was washed with
water (3ꢂ 20 mL), dried over MgSO4, filtered and concen-
trated under vacuum. The crude product was purified by
flash chromatography (silica gel, petroleum ether:diethyl
ether=10: 3) to give 3a; yield: 0.59 g (93%).
2c: Yellow solid; mp 128–1308C; 1H NMR (300 MHz,
CDCl3): d=1.95 (s, 3H), 2.74 (s, 3H), 3.80 (s, 3H), 3.83 (s,
3H), 5.59 (s, 1H), 6.84 (d, J=9.0 Hz, 2H), 6.92 (d, J=
7.8 Hz, 2H), 7.06 (t, J=9.6 Hz, 4H), 12.92 (s, 1H);
13C NMR (75 MHz, CDCl3): d=19.7, 32.6, 55.3, 55.4, 94.8,
96.4, 113.8, 114.5, 123.5, 127.3, 129.8, 140.0, 149.3, 155.1,
157.4, 158.3, 162.2, 199.8; anal. calcd. for C22H22N2O4: C
69.83, H 5.86, N 7.40; found: C 70.02, H 5.78, N 7.27. Crystal
data for 2c: C22H22N2O4, yellow crystal, M=346.42, mono-
clinic, P21/c, a=10.9714(13) ꢃ, b=20.036(2) ꢃ, c=
9.5699(12) ꢃ, b=112.140(2)8. CCDC 719422 contains the
supplementary crystallographic data for this compound.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Physical Data of Compounds Isolated
3a: White solid; mp 165–1668C; 1H NMR (300 MHz,
CDCl3): d=2.08 (s, 3H), 2.77 (s, 3H), 6.04 (s, 1H), 6.87 (d,
J=8.1 Hz, 2H), 7.05 (t, J=7.2 Hz, 1H), 7.12 (t, J=8.1 Hz,
1H), 7.30 (d, J=8.1 Hz, 2H), 7.37 (t, J=8.1 Hz, 2H), 7.62
(d, J=8.1 Hz, 2H), 13.29 (s, 1H); 13C NMR (75 MHz,
CDCl3): d =19.3, 21.7, 103.8, 122.7, 120.6, 121.4, 123.5,
123.7, 128.8, 129.4, 138.9, 148.9, 154.2, 159.4, 163.2, 169.2; IR
(KBr): n=695, 702, 761, 1169, 1388, 1486, 1555, 1572,
1689 cmÀ1; anal. calcd. for C20H18N2O2: C 75.45, H 5.70, N
8.80; found: C 75.28, H 5.65, N 8.99.
2d: Yellow solid; mp 133–1348C; 1H NMR (300 MHz,
CDCl3): d=1.85 (s, 3H), 2.23 (s, 3H), 2.28 (s, 3H), 2.79 (s,
3H), 5.45 (s, 1H), 6.92 (q, J=4.2 Hz, 2H), 7.11 (t, J=
4.5 Hz, 2H), 7.17 (d, J=7.2 Hz, 1H), 7.23 (t, J=5.1 Hz,
3b: White solid; mp 165–1678C; 1H NMR (300 MHz,
CDCl3): d=2.07 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 2.76 (s,
3H), 6.07 (s, 1H), 6.77 (d, J=7.2 Hz, 2H), 7.08 (d, J=
7.8 Hz, 2H), 7.18 (d, J=7.8 Hz, 2H), 7.51 (d, J=7.5 Hz,
2H), 13.31 (s, 1H); 13C NMR (75 MHz, CDCl3): d=19.2,
20.8, 21.6, 103.7, 112.7, 120.5, 121.2, 129.2, 129.9, 132.9,
133.1, 136.4, 146.2, 154.2, 159.1, 163.1, 168.9; IR (KBr): n=
2H), 7.28 (d, J=4.5 Hz, 1H), 13.07ACHTUNGTRNEUNG
(s, 1H); 13C NMR
(75 MHz, CDCl3): d=17.7, 18.4, 19.5, 32.9, 94.4, 95.7, 121.0,
121.9, 125.7, 126.5, 126.6, 127.1, 129.2, 129.7, 130.9, 134.2,
135.6, 146.1, 149.0, 157.3, 162.4, 199.8; IR (KBr): n=727,
759, 964, 1010, 1268, 1349, 1534, 1667 cmÀ1; anal. calcd. for
C22H22N2O2: C 76.28, H 6.40, N 8.09; found: C 76.63, H 6.47,
N, 8.21.
827, 1166, 1318, 1381, 1507, 1561, 1602, 1653, 1685 cmÀ1
;
2e: Yellow solid; mp 166–1688C; 1H NMR (300 MHz,
CDCl3): d=1.87 (s, 3H), 2.80 (s, 3H), 3.81 (s, 3H), 3.85 (s,
3H), 5.65 (s, 1H), 6.89–6.99 (m, 6H), 7.15 (d, J=7.2 Hz,
1H), 7.23 (m, 1H), 12.88 (s, 1H); 13C NMR (75 MHz,
CDCl3): d =19.7, 32.6, 55.7, 55.8, 94.9, 96.8, 111.5, 111.7,
120.4, 120.6, 122.6, 122.8, 126.1, 126.6, 127.7, 137.1, 151.1,
153.7, 157.0, 162.1, 200.1; IR (KBr): n=756, 1020, 1248,
1492, 1547, 1584, 1675 cmÀ1; anal. calcd. for C22H22N2O4: C
69.83, H 5.86, N 7.40; found: C 69.99, H 5.79, N 7.52.
2f: Yellow solid; mp 150–1528C; 1H NMR (300 MHz,
CDCl3): d=1.87 (s, 3H), 2.20 (s, 3H), 2.23 (s, 3H), 2.29 (s,
3H), 2.35 (s, 3H), 2.78 (s, 3H), 5.43 (s, 1H), 6.83 (d, J=
8.1 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 7.00 (m, 3H), 7.10 (s,
1H), 12.96 (s, 1H); 13C NMR (75 MHz, CDCl3): d=17.9,
18.6, 19.8, 20.8, 21.0, 33.1, 94.7, 96.0, 121.1, 126.4, 126.8,
127.3, 129.5, 130.8, 131.3, 131.7, 133.3, 134.2, 137.2, 143.6,
149.1, 157.8, 162.5, 200.1; IR (KBr): n=789, 963, 1018, 1269,
1318, 1540, 1588, 1674 cmÀ1; anal. calcd. for C24H26N2O2: C
anal. calcd. for C22H22N2O2: C 76.28, H 6.40, N 8.09; found:
C 76.59, H 6.28, N 8.23.
3c: White solid; mp 144–1468C; 1H NMR (300 MHz,
CDCl3): d=2.04 (s, 3H), 2.75 (s, 3H), 3.75 (s, 3H), 3.80 (s,
3H), 6.08 (s, 1H), 6.79–6.84 (m, 4H), 6.91 (d, J=8.4 Hz,
2H), 7.54 (d, J=8.4 Hz, 2H), 13.35 (s, 1H); 13C NMR
(75 MHz, CDCl3): d=19.1, 21.5, 55.26, 55.3, 103.5, 113.8,
113.9, 114.5, 121.9, 122.1, 132.2, 141.9, 156.4, 155.7, 155.9,
159.0, 162.8, 168.6; anal. calcd. for C22H22N2O4: C 69.83, H
5.86, N 7.40; found: C 69.64, H 5.90, N 7.47.
3d: White solid; mp 157–1598C; 1H NMR (300 MHz,
CDCl3): d=2.01 (s, 3H), 2.09 (s, 3H), 2.20 (s, 3H), 2.78 (s,
3H), 5.77 (s, 1H), 6.71 (d, J=7.5 Hz, 1H), 7.00 (q, J=
7.5 Hz, 2H), 7.11 (d, J=6.9 Hz, 1H), 7.15–7.22 (m, 3H),
8.19 (d, J=8.1 Hz, 1H), 13.12 (s, 1H); 13C NMR (75 MHz,
CDCl3): d=17.9, 18.9, 19.2, 21.7, 104.0, 112.9, 120.7, 122.4,
123.5, 124.0, 126.3, 126.8, 128.9, 129.0, 130.2, 130.7, 137.5,
147.8, 154.0, 159.2, 163.4, 169.2; IR (KBr): n=758, 1029,
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Yan Wang et al.
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1114, 1169, 1246, 1388, 1484, 1590, 1691 cmÀ1; anal. calcd.
for C22H22N2O2: C 76.28, H 6.40, N 8.09; found: C 76.44, H
6.43, N 8.00.
4b: White solid; mp 204–2058C; 1H NMR (300 MHz,
CDCl3): d=1.83 (s, 3H), 2.39 (s, 6H), 2.69 (s, 3H), 5.84 (s,
1H), 7.06 (d, J=7.5 Hz, 2H), 7.13 (d, J=8.1 Hz, 2H), 7.21–
7.30 (m, 4H), 12.54 (s, 1H); 13C NMR (75 MHz, CDCl3):
d=21.0, 21.2, 22.3, 33.4, 95.5, 102.2, 125.9, 128.1, 130.1,
130.3, 135.2, 136.1, 136.4, 138.5, 150.4, 158.4, 164.6, 202.4; IR
(KBr): n=800, 952, 1021, 1257, 1408, 1510, 1553, 1623,
1655 cmÀ1; anal. calcd. for C22H22N2O2: C 76.28, H 6.40, N
8.09; found: C 76.55, H 6.26, N 8.15.
3e: White solid; mp 154–1568C; 1H NMR (300 MHz,
CDCl3): d=2.07 (s, 3H), 2.76 (s, 3H), 3.65 (s, 3H), 3.77 (s,
3H), 5.83 (s, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.89 (d, J=
7.5 Hz, 1H), 6.94–6.97 (m, 4H), 7.07(d, J=7.2 Hz, 1H), 8.50
(d, J=8.1 Hz, 1H), 13.46 (s, 1H); 13C NMR (75 MHz,
CDCl3): d=19.1, 21.4, 55.67, 55.7, 104.6, 110.3, 112.0, 113.4,
120.7, 121.1, 122.5, 123.1, 123.9, 129.2, 138.2, 149.4, 150.3,
154.3, 158.3, 163.2, 168.3; anal. calcd. for C22H22N2O4: C
69.83, H 5.86, N 7.40; found: C 70.13, H 5.90, N 7.31. Crystal
data for 3e: C22H22N2O2, white crystal, M=346.42, mono-
clinic, P-1, a=10.334(3) ꢃ, b=10.420(3) ꢃ, c=11.131(3) ꢃ,
a=64.783(4)8, b=71.969(4)8, g=65.832(4)8. CCDC 719427
contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
4c: White solid; mp 200–2028C; 1H NMR (300 MHz,
CDCl3): d =1.84 (s, 3H), 2.69 (s, 3H), 3.84 (s, 6H), 5.76 (s,
1H), 6.94 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 7.10
(d, J=8.7 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 12.45 (s, 1H);
13C NMR (75 MHz, CDCl3): d =22.3, 33.5, 55.4, 95.4, 102.0,
114.6, 114.8, 127.5, 129.3, 130.4, 131.2, 150.6, 158.1, 158.8,
159.3, 164.7, 202.4; IR (KBr): n=802, 832, 1023, 1250, 1402,
1511, 1544, 1622, 1654 cmÀ1; anal. calcd for C22H22N2O4: C
69.83, H 5.86, N 7.40; found: C 69.69, H 5.91, N, 7.34.
4d: White solid; mp 164–1668C; 1H NMR (300 MHz,
CDCl3): d=1.75 (s, 3H), 2.14 (s, 3H), 2.32 (s, 3H), 2.72 (s,
3H), 5.68 (s, 1H), 7.11 (t, J=4.5 Hz, 1H), 7.25–7.34 (m,
7H), 12.52 (s, 1H); 13C NMR (75 MHz, CDCl3): d=17.5,
18.1, 21.8, 33.4, 95.5, 102.1, 126.8, 126.9, 127.1, 127.3, 128.3,
128.9, 131.2, 134.6, 135.7, 136.5, 137.9, 150.3, 158.7, 163.8,
202.4; IR (KBr): n=752, 1258, 1328, 1402, 1544, 1617,
1651 cmÀ1; anal. calcd. for C22H22N2O2: C 76.28, H 6.40, N
8.09; found: C 76.33, H 6.32, N 8.15; MS: m/z=347.2, calcd.
for [M+ +1]: 346.2.
3f: White solid; mp 157–1598C; 1H NMR (300 MHz,
CDCl3): d=2.04 (s, 6H), 2.17 (s, 3H), 2.27 (s, 3H), 2.32 (s,
3H), 2.77 (s, 3H), 5.80 (s, 1H), 6.60 (q, J=7.5 Hz, 1H),
6.95–7.04 (m, 4H), 8.02 (d, J=8.1 Hz, 1H), 13.09 (s, 1H);
13C NMR (75 MHz, CDCl3): d=17.8, 18.8, 19.1, 20.8, 21.6,
103.9, 112.8, 120.4, 122.3, 126.7, 127.3, 128.6, 128.9, 130.9,
131.3, 132.7, 133.3, 134.8, 145.1, 154.0, 158.9, 163.4, 168.8;
anal. calcd. for C24H26N2O2: C 76.98, H 7.00, N 7.48; found:
C 77.05, H 7.03, N 7.39; MS: m/z=375.2, calcd. for [M+ +1]:
374.2.
4e: White solid; mp 149–1528C; 1H NMR (300 MHz,
CDCl3): d=1.81 (s, 3H), 2.71 (s, 3H), 3.82 (s, 3H), 3.88 (s,
3H), 5.94 (s, 1H), 6.96–7.08 (m, 4H), 7.15 (d, J=7.2 Hz,
1H), 7.22 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.32
(d, J=8.1 Hz, 1H), 12.48 (s, 1H); 13C NMR (75 MHz,
CDCl3): d=21.5, 33.4, 55.7, 95.4, 102.8, 111.8, 112.1, 120.5,
121.2, 126.2, 126.9, 127.1, 129.9, 130.1, 150.9, 153.7, 154.9,
158.1, 164.1, 202.3; anal. calcd. for C22H22N2O4: C 69.83, H
5.86, N 7.40; found: C 69.71, H 5.83, N 7.49.
3g: White solid; mp 247–2498C; 1H NMR (300 MHz,
CDCl3): d=2.11 (s, 3H), 2.77 (s, 3H), 3.66 (s, 3H), 3.75 (s,
3H), 5.80 (s, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.88 (q, J=
8.7 Hz, 2H), 6.94 (t, J=5.7 Hz, 1H), 7.03 (m, 1H), 8.60 (d,
J=2.4 Hz, 1H), 13.40 (s, 1H); 13C NMR (75 MHz, CDCl3):
d=19.3, 21.6, 55.97, 56.0, 92.7, 95.1, 104.7, 110.8, 112.9,
120.4, 122.6, 123.5, 125.7, 130.0, 139.1, 147.1, 149.1, 154.9,
159.0, 163.2, 169.2; anal. calcd. for C22H20Cl2N2O4: C 59.07,
H 4.51, N 6.26; found: C 58.93, H 4.41, N 6.11.
4f: White solid; mp 128–1308C; 1H NMR (300 MHz,
CDCl3): d=1.74 (s, 3H), 2.08 (s, 3H), 2.25 (s, 3H), 2.35 (s,
6H), 2.70 (s, 3H), 5.63 (s, 1H), 6.96 (d, J=8.1 Hz, 1H),
7.03–7.12 (m, 5H), 12.38 (s, 1H); 13C NMR (75 MHz,
CDCl3): d=17.3, 17.8, 20.9, 21.0, 21.6, 33.3, 95.2, 101.9,
126.8, 127.3, 127.8, 127.9, 131.7, 131.8, 133.8, 134.3, 135.0,
135.1, 136.8, 138.6, 150.3, 158.8, 163.9, 202.4: IR (KBr): n=
803, 825, 1226, 1404, 1539, 1621, 1651 cmÀ1; anal. calcd. for
C24H26N2O2: C 76.98, H 7.00, N 7.48; found: C 76.27, H 6.93,
N 7.54.
Typical Procedure for the Pyridin-2(1H)-ones 4 (4a as
an Example)
To a flask equipped with a condenser were added 2a (0.64 g,
6.0 mmol), NaOH (0.24 g, 6.0 mmol) and EtOH (10 mL).
The mixture was heated to reflux and stirred for about 3.0 h
and then poured into saturated aqueous NaCl (20 mL),
which was extracted with dichloromethane (3ꢂ20 mL). The
combined organic phase was washed with water (3ꢂ
20 mL), dried over MgSO4, filtered and concentrated under
vacuum. The crude product was purified by flash chroma-
tography (silica gel, petroleum ether: diethyl ether=10: 3)
to give 4a; yield: 0.62 g (91%).
4g: White solid; mp 228–2308C; 1H NMR (300 MHz,
CDCl3): d=1.86 (s, 3H), 2.69 (s, 3H), 3.82 (s, 3H), 3.88 (s,
3H), 5.94 (s, 1H), 6.93 (q, J=9.0 Hz, 2H), 7.18 (d, J=
9.0 Hz, 2H), 7.31 (s, 1H), 7.37 (d, J=8.7 Hz, 1H), 12.53 (s,
1H); 13C NMR (75 MHz, CDCl3): d=21.5, 33.4, 56.0, 95.4,
102.8, 112.5, 113.0, 125.0, 125.6, 125.7, 126.6, 127.9, 129.8,
130.1, 150.8, 152.2, 153.7, 157.7, 163.7, 202.3; anal. calcd. for
C22H20Cl2N2O4: C 59.07, H 4.51, N 6.26; found: C 59.15, H
4.47, N 6.40.
Physical Data of Compounds Isolated
4a: White solid; mp 198–2008C; 1H NMR (300 MHz,
CDCl3): d=1.83 (s, 3H), 2.70 (s, 3H), 5.90 (s, 1H), 7.18–7.31
(m, 5H), 7.41–7.51 (m, 5H), 12.65 (s, 1H); 13C NMR
(75 MHz, CDCl3): d=22.3, 33.4, 95.5, 102.4, 125.9, 126.5,
128.4, 128.6, 129.5, 129.7, 137.9, 138.7, 150.3, 158.3, 164.5,
202.5; anal. calcd. for C20H18N2O2: C 75.45, H 5.70, N 8.80;
found: C 75.77, H 5.65, N 8.39.
2222
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Adv. Synth. Catal. 2009, 351, 2217 – 2223

N,N,N’,N’-Tetramethylchloroformamidinium Chloride-Mediated Cyclizations
FULL PAPERS
Salts in Organic Chemistry, in Advances in Organic
Chemistry, (Eds.: H. Bçhme, H. G. Viehe), John Wiley,
New York, 1976, Vol. 9, Part I, p 225.
Acknowledgements
Financial support of this research by the National Natural
Science Foundation of China (20572013 and 20872136) is
greatly acknowledged.
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