Substrate- and base-dependent reactivities of acylketene toward aryl aldimines derived from 2-amino-4-methylpyridine

Article abstract of DOI:10.1016/j.tetlet.2015.09.157

Acylketene, generated from 2,2,6-trimethyl-4H-1,3-dioxin-4-one reacts with aryl aldimines derived from 4-methyl-2-aminopyridine to give a variety of products, depending on the substituent on the C-aryl group, base used, and hydrolytic stability of the starting aldimine. Also the presence of the N-(2-pyridyl) group plays an important role in the fate of the reaction course, frequently participating in intramolecular conjugate additions, giving rise to interesting heterocycles.

Full text of DOI:10.1016/j.tetlet.2015.09.157

Tetrahedron Letters 56 (2015) 6468–6471
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Tetrahedron Letters
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Substrate- and base-dependent reactivities of acylketene toward aryl
aldimines derived from 2-amino-4-methylpyridine
a
b,
Nuket Ocal a, , Necla Mor , Ihsan Erden
⇑
⇑
a Yildiz Technical University, Faculty of Art and Sciences, Department of Chemistry, Davutpasa Campus, 34220 Esenler-Istanbul, Turkey
b San Francisco State University, Department of Chemistry and Biochemistry, 1600 Holloway-Avenue, San Francisco 94132, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Acylketene, generated from 2,2,6-trimethyl-4H-1,3-dioxin-4-one reacts with aryl aldimines derived from
4-methyl-2-aminopyridine to give a variety of products, depending on the substituent on the C-aryl
group, base used, and hydrolytic stability of the starting aldimine. Also the presence of the N-(2-pyridyl)
group plays an important role in the fate of the reaction course, frequently participating in intramolecular
conjugate additions, giving rise to interesting heterocycles.
Received 11 September 2015
Revised 29 September 2015
Accepted 30 September 2015
Available online 3 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Aldimines
Acylketene
2,2,6-Trimethyl-4H-1,3-dioxin-4-one
Schiff base
3,4-Dihydro-2H-pyrido[1,2-a]pyrimidin-2-
one
Introduction
emerged concerning the product structures under various reaction
conditions.5–8
Acylketenes, a class of exceptionally reactive and synthetically
useful intermediates, are accessible mainly by three methods:
dehydrochlorination of acetoacetyl chloride with NEt3, from dike-
tene 1 in the presence of amine bases, and most conveniently ther-
mally from the commercially available and inexpensive 2,2,
6-trimethyl-4H-1,3-dioxin-4-one (diketene-acetone adduct) 2.
Whether they are derived from diketene or dioxin-4-ones,
acetylketenes are excellent acetoacetylation agents for a variety
of nucleophiles, as well as synthetic building blocks for a diverse
spectrum of carbocycles and heterocycles depending on the nucle-
ophile or cycloaddend. There appears to be, however, considerable
reactivity difference between diketene and 2, in particular as
Acylketene, thermally generated at 120–135 °C without solvent,
gave with N-benzylideneaniline the oxazin-4-one derivative, while
prolonged heating also produced 2-benzylideneacetoacetamide
(Scheme 1).
When the above reaction was repeated in the presence of NEt3,
a small amount of the corresponding azetidinone (a b-lactam)
along with mostly 5, but no 6 was formed. The formation of 5
was ascribed to a hetero-Diels–Alder reaction between acylketene
3 and the imine, whereas 6 is believed to stem from nucleophilic
attack of the imine at the ketene carbon, attack by a second
equivalent of imine and subsequent cyclization to a 6-memberd
cyclic aminal and fragmentation of the latter. The azetidinone
was postulated to stem from a 2+2 cycloaddition of 3 onto the
imine C@N bond.
acetylating agents for amides,
2 being the superior reagent
(Fig. 1).1–4
There is a considerable variety of reactions acylketenes can
undergo with Schiff bases, and indeed, a number of products have
been reported from these reactions, depending on the reaction
conditions (solvent or neat, base present or absent).
In several cases conflicting results have also been reported, and
thanks to a thorough study by Kato et al. a consistent picture
In the course of our studies on the synthesis of nitrogen
heterocycles9–11 and reactions of azomethines with reactive acyl
groups, we decided to study the effect of the pyridine nitrogen,
incorporated into the arylamino component of the imine, on the
fate of imine-acylketene reactions.
Results and discussion
⇑
Corresponding authors. Tel.: +90 212 4834214; fax: +90 212 4834106 (N.O.);
tel.: +1 415 338 1627; fax: +1 415 338 2384 (I.E.).
We are pleased to report that the systems we chose helped
unravel hitherto unknown facets of the aforementioned reactions,
E-mail addresses: nocal@yildiz.edu.tr (N. Ocal), ierden@sfsu.edu (I. Erden).
http://dx.doi.org/10.1016/j.tetlet.2015.09.157
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

N. Ocal et al. / Tetrahedron Letters 56 (2015) 6468–6471
6469
O
The formation of 12 from 7 in the presence of NEt3 is unexcep-
tional and deserves no further comment. However, the unexpected
formation of the diastereomeric b-aminoketones 13a and b was
not observed in imine-acylketene cycloadditions in previously
published work. Here the use of imidazole instead of NEt3 appears
to have changed the course of the reaction. In the presence of NEt3,
the reaction commences with nucleophilic attack of the imine
nitrogen at the ketene carbonyl of the acylketene. The resulting
zwitterionic intermediate then cyclizes via the enolate intermedi-
ate to give 12 (or 17).13,14 However, in the presence of imidazole,
the NH of the heterocyclic base is the most nucleophilic species
in the mixture, and therefore attacks the ketene carbonyl first
(Scheme 2).15
O
O
H
O
C
O
O
O
2
1
3
Figure 1. Diketene 1, diketene-acetone adduct 2, acylketene 3.
O
O
O
Bn
Ph
N
Ph
heat
N
2
+
NHBn
+
Ph
CHPh
6
O
5
4
The process outlined in Scheme 2 represents a three component
reaction between imidazole, acylketene, and an imine.
Scheme 1. Products from N-benzylidenealdimine with 2.
The reaction of imidazole with 3 generates 21, a synthetic
equivalent of acetone enolate. After the nucleophilic attack on
the imine the imidazolide is readily hydrolyzed to the 2-substi-
tuted acetoacetic acid which decarboxylates during the workup.
Product 14 in entry 3 presumably stems from the fact that the
starting imine exhibits lower hydrolytic stability as compared to
the counterparts 7 and 8 carrying strong powerful electron-
withdrawing groups such as NO2 and CN on the N-aryl ring.
Adventitious water might have partially led to the starting amine
which would have undergone N-acylation with acylketene to give
14. Products similar to 15 have previously been isolated
from imine-acylketene reactions and have been ascribed to a 2:1
imine-acylketene addition leading to a cyclic aminal that collapses
alongside known transformations. From our results it has become
apparent that product compositions in imine-acylketene addi-
tions/cycloadditions are indeed quite dependent on a variety of
factors, such as temperature, solvent, substitution pattern in the
imine component, and added base. The results from the reaction
of 2 with selected Schiff bases derived from 2-aminopyridines
are depicted in Table 1. The requisite imines were prepared by
the reaction of 2-amino-4-methylpyridine with substituted aro-
matic aldehydes at 110 °C without solvent. Products 8, 10, 11 are
new compounds and were characterized by NMR spectroscopy
and correct HRMS data.12
Table 1
Reactions of azomethines derived from 2-amino-4-methylpyridine 24 with 2,2,6-trimethyl-1,3-dioxin-4-one 2
Entry
Substrate
Conditions
Products and yields
NO2
O
N
N
N
N
N
N
1
Toluene, 110 °C, NEt3
7
8
9
O
12
NO2
+
68%
CN
H
H
N
H
H
N
O
N
N
O
N
O
2
3
Toluene, 110 °C, imidazole
42%
31%
O
CN
CN
O
13a
13b
Ar
O
N
N
N
N
O
N
+
+
N
N
Toluene, 110 °C, NEt3
Cl
Cl
N
H
H
Ar
Ar
14
13%
15
35%
16
50%
Ar = p-ClPh
Cl
O
O
N
N
N
+
Cl
10
4
5
Toluene, 110 °C, NEt3
O
Cl
Ar = 2,4- dichlorophenyl
35%
18
17
50%
Br
O
H
N
N
N
N
11
O
Toluene, 110 °C, NEt3
19
62%
Br

6470
N. Ocal et al. / Tetrahedron Letters 56 (2015) 6468–6471
N
Ar
O
Ar1
N
O
C
H
N
O
N
3
N
NH +
O
+
11
N
Ar2
H
O
20
3
O-
21
28
Ar = p-BrPh
Ar1 = Py; Ar2 = p-CNPh
O-
8
N
O
OH
O
N
Ar
O
Ar
-CO2
H2O
COCH3
H
N
H
N
H
13a+13b
Ar1
O
O
N
N
N
Ar2
HN
Ar1
Ar2
22
O
O
O
23
19
29
Scheme 2. Three-component reaction between imidazole acylketene and imine:
formation of 13a and 13b.
Scheme 5. Mechanism for the formation of 19 from 11.
Finally, the unprecedented formation of the cyclohexen-2-one
derivative 19 (entry 5)19 can also be traced to an intermediate like
16 in entry 3. In this case, however, the preferred course of reaction
is an intermolecular Michael attack at the arylidene carbon by
N
NH2
N
N
Ar
H2O
H
Ar
+
O
20
acetone enolate (acetone is
a byproduct from the thermal
24
9
decomposition of 2) (Scheme 5).
Ar= o-ClPh
3
Conclusion
Ar
H
H
N
20
N
N
N
In conclusion, we have uncovered new facets of cycloadditions
of acylketenes onto arylimines. While we isolated compounds of
the type 5 and 6 which have been observed previously, we
observed considerable influence of substituents on the C-aryl
groups of the starting imine on the product composition, as well
as the choice of base. Thus, products 13a and b (entry 2), 16 and
18 (entries 3 and 4, respectively) as well as 19 (entry 5) have not
been isolated previously in acylketene-imine cycloadditions. We
have shown that the N-aryl group may participate in follow-up
reactions after product formation via intramolecular Michael
attack, resulting in a new synthesis of 3,4-dihydro-2H-pyrido
[1,2-a]pyrimidin-2-ones.
O
O
O
O
15
14
Scheme 3. Mechanism for the formation of 14 and 15 from 9.
O
N
O
O
N
Ar
O
H
Ar
O
Ar
O
conjugate
attack
N+
N
NH
N
B:
15
24
25
O-
Acknowledgments
21
NH
Ar= o-ClPh
N
N.O. gratefully acknowledges financial support of this work by
the Scientific and Technological Research Council of Turkey (TUBI-
TAK, project no. 112T880). I.E. acknowledges financial support of
this work by funds from the National Institutes of Health (Grant
No. SC1GM082340). We also thank Mr. Omer Tahir Gunkara for
technical support.
Ar
O
H
N
N
+
Ar
O
N
N
O
N
N
27
16
26
Scheme 4. Mechanism for the formation of 16.
Supplementary data
to 15 via a fragmentation reaction. Though this mechanism satis-
factorily explains the formation of 15, an aldol condensation of
14 with p-chlorobenzaldehyde from the imine cleavage could also
account for 15 (see Scheme 3).16
Supplementary data (Characterization data (listing of NMR and
HRMS data), 1H, 13C NMR20 and selected UV and FTIR spectra of
compounds 7–19) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
157.
Products 16 (entry 3) and 18 (entry 4), however, have not pre-
viously been observed/reported in imine-acylketene reactions and
obviously stem from participation of the pyridine ring in the reac-
tions. We postulate that 8-methyl-4-aryl-3,4-dihydro-2H-pyrido
[1,2-a]pyrimidin-2-one (16 or 18) are formed from 15 (and its
2,4-dichloro analog) by intramolecular conjugate addition fol-
lowed by deacetylation, presumably initiated by 2-aminopyridine
attack at the acetyl carbonyl (Scheme 4). The hydrolytic instability
of the starting imines 9 and 10 appears to be responsible for the
unusual course of reaction in these cases. Compounds 1617 and
1818 were readily identified by means of their characteristic NMR
spectra, correct HRMS data, and also their UV spectra, since both
compounds are fluorescent.
References and notes
1. Jager, G.; Wenzelburger, J. Leibigs Ann. Chem. 1976, 1689–1712.
2. Shaabani, A.; Seyyedhamzeh, M.; Maleki, A.; Hajishaabanha, F. Tetrahedron
2010, 66, 4040–4042.
3. Freier, B.; Wentrup, C. J. Org. Chem. 1991, 56, 2286–2289.
4. Kollenz, G.; Ebner, S. Sci. Synth. 2006, 23, 271–439.
5. Moazami, Y.; Pierce, J. G. Synthesis 2015, 47, A–H.
6. Sato, M.; Ogasawara, H.; Yoshizumi, E.; Kato, T. Chem. Pharm. Bull. 1983, 31,
1902–1909.
7. Morita, Y.; Kaneko, M.; Matsuzawa, S.; Yamamoto, Y. J. Heterocyclic Chem. 1997,
34, 515–519.
8. Kato, T.; Katagiri, N.; Yamamoto, Y. Heterocycles 1980, 14, 1333–1403.

N. Ocal et al. / Tetrahedron Letters 56 (2015) 6468–6471
6471
9. Ocal, N.; Aydogan, F.; Yolacan, C.; Turgut, Z. J. Heterocyclic Chem. 2003, 40, 721–
(Cq), 115.2 (CAr), 118.7 (Cq) 127.2 (2 Â CAr), 132.5 (2 Â CAr), 146.2 (CAr),
148.1 (Cq), 149.6 (Cq), 156.9 (Cq), 206.2 (C = O) ppm; LCMS (ESI-QTOF) m/z: [M
+H]+ calcd for C17H17N3O 279.1369; Found 280.1441; (13b): Colorless oil
724.
10. Aydogan, F.; Ocal, N.; Turgut, Z.; Yolacan, C. Bull. Korean Chem. Soc. 2001, 22,
476–479.
11. Mendez, L. Y. V.; Kouznetsov, V.; Poveda, J. C.; Yolacan, C.; Ocal, N.; Aydogan, F.
Heterocycl. Commun. 2001, 7, 129–134.
(31%); Rf = 0.24 (2:1, ethyl acetate/n-hexane); FTIR (ATR):
m = 3376, 3011, 2922,
2227, 1713, 1655, 1565, 1505, 1482, 1414, 1359, 1290, 1163, 1096, 801 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d = 2.07 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.20 (br s, 1H,
NH), 2.88 (dd, J = 5.36; 17.02 Hz, 1H, CH2), 3.02 (dd, J = 6.93; 17.02 Hz, 1H, CH),
5.28 (dd, J = 6.62; 12.61 Hz, 1H, CH), 6.10 (s, 1H, ArH), 6.36 (d, J = 5.36 Hz, 1H,
ArH), 7.43 (d, J = 8.51 Hz, 2H, ArH), 7.54 (d, J = 8.51 Hz, 2H, ArH), 7.78 (d,
J = 5.36 Hz, 1H, ArH) ppm; 13C NMR (CDCl3, 100 MHz): d = 21.2 (CH3), 30.7
(CH3), 49.7 (CH2), 51.3 (CH), 108.2 (CAr), 115.3 (CAr), 118.7 (Cq), 127.1
(2 Â CAr), 132.5 (2 Â CAr), 133.4 (Cq), 145.1 (Cq), 146.5 (CAr), 148.0 (Cq), 149.4
(Cq), 192.4 (C@O) ppm; LCMS (ESI-QTOF) m/z: [M+H]+ calcd for C17H17N3O
279.1369; Found 280.1441.
12. General procedure for the synthesis of aldimines (8, 10, 11):
A solution of
2-amino-4-methylpyridine (1 mmol, 108 mg) and p-cyanobenzaldehyde (or
2,4-dichlorobenzaldehyde or p-bromobenzaldehyde) (1 mmol) was refluxed at
110 °C for 6–7 h. The reaction mixture was filtered and the residue was washed
with diethyl ether then crystallized from suitable solvent. (8): Colorless solid
(74%); mp 162–164 °C; Rf = 0.52 (1:1, ethyl acetate/n-hexane); FTIR (ATR):
m
= 3171, 3051, 2913, 2226, 1606, 1558, 1500, 1469, 1440, 1344, 839 cmÀ1 1H
;
NMR (CDCl3, 500 MHz): d = 2.34 (s, 3H, CH3), 6.98 (d, J = 5.04 Hz, 1H, ArH), 7.12
(s, 1H, ArH), 7.68 (d, J = 8.19 Hz, 2H, ArH), 8.00 (d, J = 8.19 Hz, 2H, ArH), 8.29 (d,
J = 4.73 Hz, 1H, ArH), 9.13 (s, 1H, CH) ppm; APT (CDCl3, 125 MHz): d = 21.3
(CH3), 115.2 (Cq), 119.3 (CAr), 121.2 (CAr), 126.4 (CAr), 130.0 (CAr), 137.7 (Cq),
138.4 (Cq), 148.1 (CAr), 149.3 (Cq), 158.8 (CH), 160.3 (Cq) ppm; GC–MS (EI,
70 eV): m/z = 221 [M+]. (10): Tan solid (75%); mp 120–123 °C; Rf = 0.36 (1:5,
16. (15): Colorless oil (35%); Rf = 0.80 (3:1, ethyl acetate/methanol); FTIR (ATR):
m
= 3207, 3020, 2921, 2852, 1694, 1614, 1574, 1539, 1466, 1423, 1328, 1186,
1119, 816, 752 cmÀ1 1H NMR (DMSO-d6, 500 MHz): d = 2.34 (s, 3H, CH3), 2.51
;
(s, 3H, CH3), 6.97 (d, J = 5.04 Hz, 1H, ArH), 7.08 (d, J = 15.76 Hz, 1H, ArH), 7.44–
7.46 (m, 1H, ArH), 7.56 (t, J = 3.46 Hz, 1H, ArH), 7.74 (t, J = 4.72 Hz, 1H, ArH),
7.92 (d, J = 15.44 Hz, 1H, ArH), 8.09 (s, 1H, CH), 8.20 (d, J = 5.04 Hz, 1H, ArH),
10.72 (s, 1H, NH) ppm; APT (DMSO-d6, 125 MHz): d = 20.9 (2xCH3), 114.1 (CAr),
120.6 (CAr), 125.0 (CAr), 127.6 (CAr), 127.8 (CAr), 130.0 (CAr), 131.3 (CAr),
132.3 (Cq), 133.5 (Cq), 135.9 (CAr), 147.7 (CAr), 148.9 (CAr), 152.0 (Cq), 163.5
(C@O), 198.9 (C@O) ppm; GC–MS (EI, 70 eV): m/z = 315 [M+].
ethyl acetate/n-hexane); FTIR (ATR):
m = 3091, 3058, 2992, 1600, 1582, 1548,
1469, 1382 866, 823, 751 cmÀ1 1H NMR (CDCl3, 500 MHz): d = 2.40 (s, 3H,
;
CH3), 7.03 (d, J = 4.41 Hz, 1H, ArH), 7.15 (s, 1H, ArH), 7.34 (d, J = 8.19 Hz, 1H,
ArH), 7.45 (s, 1H, ArH), 8.26 (d, J = 8.51 Hz, 1H, ArH), 8.36 (d, J = 5.04 Hz, 1H,
ArH), 9.50 (s, 1H, CH) ppm; APT (CDCl3, 125 MHz): d = 20.9 (CH3), 120.6 (CAr),
123.4 (CAr), 127.6 (CAr), 129.7 (CAr), 129.8 (CAr), 131.7 (Cq), 137.4 (Cq), 138.1
(Cq), 148.6 (CAr), 149.5 (Cq), 158.2 (CH), 160.7 (Cq) ppm; GC–MS (EI, 70 eV):
m/z = 263 [M+]. (11): Colorless solid (70%); mp 100–104 °C; Rf = 0.57 (1:2, ethyl
17. (16): Colorless oil (50%); Rf = 0.36 (20:1, ethyl acetate/methanol); FTIR (ATR):
m
= 3002, 2923, 2852, 1661, 1620, 1573, 1541, 1466, 1339, 1178, 1165,
770 cmÀ1 1H NMR (CDCl3, 500 MHz): d = 2.29 (s, 3H, CH3), 2.94 (dd, J = 3.91;
;
acetate/n-hexane); FTIR (ATR):
m
= 3054, 2957, 2917, 2855, 1601, 1565, 1404,
16.13 Hz, 1H, CH2), 3.13 (dd, J = 7.82; 16.13 Hz, 1H, CH2), 5.81 (dd, J = 3.91;
7.33 Hz, 1H, CH), 6.41 (d, J = 6.35 Hz, 1H, ArH), 6.92 (d, J = 7.82 Hz, 1H, ArH),
6.99 (s, 1H, ArH), 7.12 (d, J = 6.84 Hz, 1H, ArH), 7.17 (t, J = 7.33 Hz, 1H, ArH),
7.24 (t, J = 7.33 Hz, 1H, ArH), 7.38 (d, J = 7.82 Hz, 1H, ArH) ppm; 13C NMR
(CDCl3, 125 MHz): d = 20.6 (CH3), 33.8 (CH), 59.9 (CH2), 114.6 (CAr), 120.8
(CAr), 126.4 (CAr), 127.2 (CAr), 129.4 (CAr), 129.5 (CAr), 131.0 (Cq), 133.1 (Cq),
135.4 (CAr), 152.5 (Cq), 155.9 (Cq), 170.8 (C = O) ppm; GC–MS (EI, 70 eV): m/
z = 273 [M+-C2H2O]. LCMS (ESI-QTOF) m/z: calcd for C15H13ClN2O 272.0712;
Found 273.0782 [M+H]+; UV (methanol): kmax = 219, 267, 338 nm.
1305, 800 cmÀ1 1H NMR (CDCl3, 500 MHz): d = 2.31 (s, 3H, CH3), 7.01 (d,
;
J = 5.04 Hz, 1H, ArH), 7.18 (s, 1H, ArH), 7.48 (d, J = 8.19 Hz, 2H, ArH), 7.80 (d,
J = 8.19 Hz, 2H, ArH), 8.25 (d, J = 4.73 Hz, 1H, ArH), 8.89 (s, 1H, CH) ppm; APT
(CDCl3, 125 MHz): d = 21.8 (CH3), 120.8 (CAr), 121.4 (CAr), 126.8 (CAr), 132.1
(CAr), 135.7 (Cq), 136.4 (Cq), 147.8 (CAr), 149.3 (Cq), 158.8 (CH), 161.3 (Cq)
ppm; GC–MS (EI, 70 eV): m/z = 275 [M+].
13. (12): Colorless oil (68%); Rf = 0.36 (1:1, ethyl acetate/n-hexane); FTIR (ATR):
m
= 3113, 3024, 2986, 2919, 2851, 1674, 1609, 1566, 1518, 1481, 1415, 1395,
1294, 1145, 787 cmÀ1 1H NMR (CDCl3, 500 MHz): d = 1.93 (s, 3H, CH3), 2.33 (s,
;
18. (18): Yellow solid (35%); mp 206-207 °C; Rf = 0.12 (20:1, dichloromethane/
3H, CH3), 5.22 (s, 1H, CH), 6.84 (d, J = 5.04 Hz, 1H, ArH), 7.51 (d, J = 8.19 Hz, 2H,
ArH), 7.59 (s, 1H, ArH), 7.87 (s, 1H, ArH), 8.05 (d, J = 5.04 Hz, 1H, ArH), 8.13 (d,
J = 8.19 Hz, 2H, ArH) ppm; APT (CDCl3, 125 MHz): d = 19.7 (CH3), 21.2 (CH3),
84.7 (CH), 102.2 (CAr), 117.8 (CAr), 121.0 (Cq), 122.0 (Cq), 123.6 (2 Â CAr),
127.6 (CAr), 145.1 (Cq), 147.4 (CAr), 149.2 (Cq), 151.5 (Cq), 161.9 (C@O) ppm;
LC–MS (ESI): 326 [M+].
methanol); FTIR (ATR):
m
= 3078, 2961, 2919, 2851, 1680, 1615, 1539, 1470,
1334, 1167, 867, 825, 810 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d = 2.37 (s, 3H,
CH3), 2.95 (d, J = 2.93; 15.65 Hz, 1H, CH2), 3.19 (dd, J = 7.82; 16.13 Hz, 1H, CH2),
5.85 (dd, J = 3.42; 7.33 Hz, 1H, CH), 6.52 (d, J = 6.84 Hz, 1H, ArH), 6.92 (d,
J = 8.31 Hz, 1H, ArH), 7.08 (s, 1H, ArH), 7.22 (t, J = 8.31 Hz, 2H, ArH), 7.47 (d,
J = 1.95 Hz, 1H, ArH) ppm; 13C NMR (CDCl3, 125 MHz): d = 21.7 (CH3), 34.7
(CH), 60.6 (CH2), 116.1 (CAr), 121.6 (CAr), 127.4 (CAr), 128.3 (CAr), 128.5 (CAr),
130.4 (CAr), 132.7 (Cq), 136.0 (Cq), 136.4 (Cq), 154.1 (Cq), 156.5 (Cq), 171.3
(C = O) ppm; LCMS (ESI-QTOF) m/z: calcd for C15H12Cl2N2O 306.0312; Found
307.0383 [M+H]+; UV (methanol): kmax = 218, 270, 320 nm.
14. (17): Yellow solid (50%); mp 146–147 °C; Rf = 0.54 (1:3, ethyl acetate/n-
hexane); FTIR (ATR):
m
= 3114, 3076, 3028, 2955, 2920, 2850, 1681, 1604, 1585,
1561, 1466, 1386, 1354, 1268, 1243, 1159, 824, 794 cmÀ1
;
1H NMR (CDCl3,
500 MHz): d = 1.82 (s, 3H, CH3), 2.30 (s, 3H, CH3), 5.28 (s, 1H, CH), 6.77 (d,
J = 5.04 Hz, 1H, ArH), 7.09 (d, J = 1.89 Hz, 1H, ArH), 7.11 (s, 1H, ArH), 7.39 (d,
J = 1.89 Hz, 1H, ArH), 7.56 (s, 1H, ArH), 7.81 (s, 1H, ArH), 7.99 (d, J = 5.04 Hz, 1H,
ArH) ppm; APT (CDCl3, 125 MHz): d = 19.6 (CH3), 29.7 (CH3), 84.0 (CH), 100.6
(CH), 118.4 (CAr), 118.6 (CAr), 121.9 (Cq), 126.1 (CAr), 129.6 (CAr), 130.0 (Cq),
130.5 (CAr), 132.7 (Cq), 135.8 (Cq), 147.1 (CAr), 148.7 (Cq), 162.8 (Cq), 165.4
(C@O) ppm; LC–MS (ESI): 349 [M+].
19. (19): Colorless solid (62%); mp 136–137 °C; Rf = 0.29 (1:1, ethyl acetate/n-
hexane); FTIR (ATR):
m
= 3278, 3024, 2953, 2922, 2852, 1660, 1611, 1567, 1532,
1488, 1431, 1179, 1074, 817 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d = 1.96 (s, 3H,
CH3), 2.30 (s, 3H, CH3), 2.62 (dd, J = 11.65; 16.39 Hz, 1H, CH2), 2.68 (dd, J = 4.73;
16.40 Hz, 1H, CH2), 3.36 (d, J = 9.14 Hz, 1H, CH), 3.65 (ddd, J = 4.73; 11.65;
16.39 Hz, 1H, CH), 6.07 (s, 1H, CH), 6.83 (d, J = 5.04 Hz, 1H, ArH), 7.06 (d,
J = 8.51 Hz, 2H, ArH), 7.34 (d, J = 8.51 Hz, 2H, ArH), 7.93 (s, 1H, ArH) 7.97 (d,
J = 5.04 Hz, 1H, ArH), 8.47 (br s, 1H, NH) ppm; 13C NMR (CDCl3, 100 MHz):
d = 21.4 (CH3), 22.4 (CH3), 29.7 (CH), 42.2 (CH2), 57.0 (CH), 114.6 (CAr), 121.4
(CAr), 123.8 (Cq), 128.8 (2 Â CAr), 129.3 (@CH), 132.1 (2 Â CAr), 139.8 (Cq),
147.1 (Cq), 150.2 (Cq), 155.9 (Cq), 169.0 (C@O), 196.7 (C@O) ppm; LCMS (ESI-
QTOF) m/z: calcd for C20H19BrN2O2 399.0693; Found 401.0675.
15. (13a): Colorless oil (42%); Rf = 0.36 (2:1, ethyl acetate/n-hexane); FTIR (ATR):
m
= 3377, 2953, 2921, 2227, 1713, 1658, 1564, 1505, 1482, 1414, 1359, 1290,
1162, 1018, 801 cmÀ1 1H NMR (CDCl3, 500 MHz): d = 2.07 (s, 3H, CH3), 2.11 (s,
;
3H, CH3), 2.50 (br s, 1H, NH), 2.88 (dd, J = 5.36; 17.02 Hz, 1H, CH2), 3.04 (dd,
J = 6.93; 17.02 Hz, 1H, CH2), 5.25 (dd, J = 6.62; 12.61 Hz, 1H, CH), 6.09 (s, 1H,
ArH), 6.36 (d, J = 5.36 Hz, 1H, ArH), 7.44 (d, J = 8.51 Hz, 2H, ArH), 7.53 (d,
J = 8.51 Hz, 2H, ArH), 7.77 (d, J = 5.36 Hz, 1H, ArH) ppm; 13C NMR (CDCl3,
100 MHz): d = 21.3 (CH3), 30.8 (CH3), 49.8 (CH2), 51.4 (CH), 108.2 (CAr), 111.0
20. In several cases, APT spectra in lieu of 13C NMR spectra are posted in the
Supplementary Material file.