Unexpected pathway of the reaction of N-[(β-halogeno-α-tosyl) alkyl]ureas with β-oxoester enolates. Synthesis of ethyl 5-ureido-4,5-dihydrofuran-3-carboxylates and N-carbamoylpyrrole-3-carboxylates

Article abstract of DOI:10.1016/j.tetlet.2010.10.162

Reaction of β-halogeno-α-tosyl-substituted N-alkylureas with sodium enolates of β-oxoesters proceeds predominantly via nucleophilic substitution of the halogen rather than the tosyl group followed by spontaneous cyclization to give ethyl 5-ureido-4,5-dihy

Full text of DOI:10.1016/j.tetlet.2010.10.162

Tetrahedron Letters 52 (2011) 88–91
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected pathway of the reaction of N-[(b-halogeno-a-tosyl)alkyl]ureas with
b-oxoester enolates. Synthesis of ethyl 5-ureido-4,5-dihydrofuran-3-
carboxylates and N-carbamoylpyrrole-3-carboxylates
Nikolay N. Kurochkin a, Anastasia A. Fesenko a, Dmitry A. Cheshkov b, Musa M. Davudi a,
Anatoly D. Shutalev a,
⇑
a Department of Organic Chemistry, Moscow State Academy of Fine Chemical Technology, 86 Vernadsky Ave., 119571 Moscow, Russian Federation
b State Scientific Research Institute of Chemistry and Technology of Organoelement Compounds, 38 Entuziastov shosse, 111123 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of b-halogeno-a-tosyl-substituted N-alkylureas with sodium enolates of b-oxoesters proceeds
Received 1 September 2010
Revised 18 October 2010
Accepted 29 October 2010
Available online 4 November 2010
predominantly via nucleophilic substitution of the halogen rather than the tosyl group followed by spon-
taneous cyclization to give ethyl 5-ureido-4,5-dihydrofuran-3-carboxylates. The latter are transformed
into ethyl N-carbamoylpyrrole-3-carboxylates under acidic conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
b-Halogeno-a-tosyl-substituted N-
alkylureas
Nucleophilic substitution
-Halogeno N-acylimines
a
Dihydrofurans
Pyrroles
Biginelli compounds (e.g., 1; Fig. 1) are readily available hetero-
dro-1H-1,3-diazepin-2-ones. Herein, we describe the preliminary
results of our investigation of this synthetic process.
The starting materials, ureas 6a,b, were prepared by the reac-
tion of urea with 2-chloroethanal (7a) or 2-bromopropanal (7b)
cycles1 with a wide range of biological activity.2 In contrast, the
biological activity of their seven-membered analogs (e.g., 2) hith-
erto remains almost unknown because of their limited availability,
and only for some examples of compounds 2 has cardiovascular
activity been described.3
The reported approach to diazepinones 2 involves reaction of 1
(R = CH2Cl; R1 = Me, Et) with nucleophiles.3,4 However, this proce-
dure suffers from poor availability of the starting materials. Indeed,
only three 4-chloromethyl-substituted pyrimidines 1 (R1 = R2 =
Me; R1 = Et; R2 = Me; R1 = Et; R2 = Ph) have been obtained in low
to moderate yields (2–65%).4b,c
Recently, we described a general synthesis of 5-functionalized
1,2,3,4-tetrahydropyrimidin-2-ones/thiones 3 based on reaction
Figure 1. Structures of Biginelli compounds 1 and seven-membered analogs 2.
of
a-tosyl-substituted N-alkylureas and N-alkylthioureas 4 with
enolates of
a-substituted ketones followed by acid-catalyzed dehy-
dration of the obtained 4-hydroxyhexahydropyrimidin-2-ones/thi-
ones 5 (Scheme 1).5
We hypothesized that the use of b-halogeno-a-tosyl-substituted
alkyl ureas (4, X = O, R = CH(Hal)R0) in this synthesis might give
access to various 4-(1-halogenoalkyl)-1,2,3,4-tetrahydropyrimi-
din-2-ones, which could then be transformed into 2,3,4,5-tetrahy-
⇑
Corresponding author. Tel.: +7 495 936 8908; fax: +7 495 936 8909.
E-mail address: shutalev@orc.ru (A.D. Shutalev).
Scheme 1. General synthesis of 5-functionalized 1,2,3,4-tetrahydropyrimidin-
2-ones/thiones 3.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.162

N. N. Kurochkin et al. / Tetrahedron Letters 52 (2011) 88–91
89
(5.49–6.22 ppm; doublet of doublets of doublets in 10a,b and a
doublet of doublets of doublets in 11) and the C5 carbon (84.32–
90.53 ppm) in the 1H and 13C NMR spectra in DMSO-d6. The loca-
tion of the urea moiety at C4 in 12 was clearly evident from its
1H and 13C NMR spectra. In particular, the signals for the C5 and
C4 carbons in the 13C NMR spectrum of 12 are shifted upfield
(78.32 ppm) and downfield (52.16 ppm) compared with those for
its regioisomer 11 (84.32 and 34.12 ppm, respectively). A feature
of the 1H NMR spectra of trans-10a, 11, and 12 were the long-range
couplings of 1.1–1.7 Hz between the 2-CH3 and 4-H proton (for
trans-10a and 12) and between 2-CH3 and each of the 4-H protons
(for 11).
Formally, compounds 10–11 result from nucleophilic substitu-
tion of the halogen in 6a,b with the b-oxoester enolates 13a,b fol-
lowed by intramolecular nucleophilic substitution of the tosyl
group. However, direct substitution of the halogen in 6a,b seems
unlikely because the reaction of 6a,b with 13a,b proceeds under
mild conditions. One possible explanation for the formation of
10–12 is presented in Scheme 4. The principal stage of this path-
Scheme 2. Synthesis of b-halogeno-a-tosyl-substituted alkyl ureas 6a,b.
and p-toluenesulfinic acid (8) (3:1:1 molar ratio) in water at room
temperature for 15–16 h in 84–86% yields (Scheme 2).6 Compound
6b was obtained as a mixture of two diastereomers in a ratio of
67:33.
Ureas 6a,b possess electrophilic centers at the
a- and b-posi-
tions with respect to the nitrogen. Hence, these compounds could
react with nucleophiles to give products of halogen or tosyl group
substitution. However, based on our experience,5 we assumed that
substitution of the tosyl group, especially in the case of b-chloro-
substituted ethyl urea 6a, would be preferable.
way involves reaction of 13a,b with
a-halogeno acylimines A
which result from the base-induced elimination of p-toluenesulfi-
nic acid from starting ureas 6a,b according to an E1cB mechanism
(via B).10,11 Transformation of 6a,b into acylimines A leads to a sig-
Unexpectedly, we found that treatment of 6a,b with enolates of
ethyl acetoacetate (9a) or ethyl benzoylacetate (9b) in MeCN at
room temperature failed to give the products of tosyl group substi-
tution, 6-(1-halogenoalkyl)-4-hydroxyhexahydropyrimidin-2-ones
(or their acyclic precursors). Thus, reaction of 6b with 2 equiv of
sodium enolates 9a,b led to the formation of ethyl 5-ureido-4,5-
dihydrofuran-3-carboxylates 10a,b in 69–80% yields (Scheme 3).7
Reaction of 6a with the sodium enolate of 9a (2 equiv, MeCN, rt)
proceeded in a more complex manner and gave a regioisomeric
mixture of 5-ureidodihydrofuran 11 and 4-ureidodihydrofuran 12
in a ratio of 80:20 (71%).8 Pure 11 was obtained after crystallization
of the mixture from MeCN. The yields of dihydrofurans 10 were re-
duced significantly when 1 equiv of enolate 9a,b was used instead
of 2 equiv.
nificant increase of the electrophilicity of the b-carbon. a-Halogeno
acylimines A react further with 13a,b to give predominantly the
products of nucleophilic substitution of the halogen, acylimines
C. The products of nucleophilic addition to the C@N bond of A,
compounds D, partly form only in the case of 6a containing a rel-
atively poor chlorine leaving group. According to this mechanism
2 equiv of the nucleophile are necessary for the full conversion of
6a,b in agreement with the experimental data.
An interesting structural feature of the obtained 5-ureido-4,5-
dihydrofurans 10a,b and 11 is their ability to give acyclic isomeric
forms C (Scheme 4). Indeed, according to 1H NMR spectroscopy,
gradual formation of cis-10a was observed upon prolonged storage
of a DMSO-d6 solution of trans-10a.12 The molar ratios of cis- to
trans-10a after 3, 31, and 55 days were 2:98, 6:94, and 10:90,
respectively. Obviously, the transformation of trans-10a into cis-
10a proceeds via the respective acyclic form. However, this form
According to 1H NMR data, dihydrofurans 10a,b were formed
with high diastereoselectivity. Compound 10a was obtained as a
single isomer with trans-configuration as evidenced by a 1H, 1H-
NOESY experiments. NOEs were observed between 4-CH3 and
5-H, and between the N–H and 4-H protons. Compound 10b was
obtained as a mixture of trans- and cis-isomers in a ratio of
85:15. The structural assignment in this case was based on the
close values of the vicinal coupling constants J4-H,5-H for the major
isomer of 10b and trans-10a (4.2 and 4.6 Hz, respectively). The value
of J4-H,5-H for the minor diastereomer of 10b was 8.6 Hz.
The structures of dihydrofurans 10–12 were confirmed unam-
biguously by IR, 1H, and 13C NMR data7–9 including 2D NMR spec-
tral data (1H, 1H-COSY, 1H, 13C-HSQC, 1H, 13C-HMBC) for trans-10a.
The presence of the N,O-acetal functionality in compounds 10a,b
and 11 was proved by the downfield resonances of the 5-H proton
Scheme 4. Plausible pathways for the reactions of 6a,b with the sodium enolates of
9a,b.
Scheme 3. Reaction of b-halogeno-
a-tosyl-substituted alkyl ureas 6a,b with the
sodium enolates of b-oxoesters 9a,b.
Scheme 5. Synthesis of ethyl N-carbamoyl-1H-pyrrole-3-carboxylates 14a,b.

90
N. N. Kurochkin et al. / Tetrahedron Letters 52 (2011) 88–91
(amide-I), 1594 m (m CCarom), 1539 s (amide-II), 1493 w (m CCarom), 1287 s (mas
SO2), 1145 s ( s SO2). Anal. Calcd for C10H13ClN2O3S: C, 43.40; H, 4.74; N, 10.12.
m
Found: C, 43.49; H, 4.88; N, 10.32.
Compound 6b (13.860 g, 84%) was prepared as a mixture of two diastereomers
(67:33) in the same way as 6a from 2-bromopropanal (6.779 g, 49.49 mmol), p-
toluenesulfinic acid (7.730 g, 49.49 mmol), and urea (8.917 g, 148.48 mmol) in
H2O (50 mL). Mp 109–109.5 °C (decomp., acetone). 1H NMR of the major
isomer (300.13 MHz, DMSO-d6) d: 7.69–7.75 (2H, m, AA0 part of an AA0XX0 spin
system, C(2)H and C(6)H in 4-MeC6H4), 7.39–7.45 (2H, m, XX0 part of an AA0XX0
3
spin system, C(3)H and C(5)H in 4-MeC6H4), 6.93 (1H, d, JNH,CH = 10.5 Hz, N–
3
3
H), 6.03 (2H, s, NH2), 5.26 (1H, dd, JCH,NH = 10.5, JCH,CH = 2.6 Hz, CH–N), 4.89
(1H, dq, JCH,CH3 = 6.8, 3JCH,CH = 2.6 Hz, CH–Br), 2.39 (3H, s, CH3 in Ts), 1.63 (3H,
3
d, JCH3,CH = 6.8 Hz, CH3). 1H NMR of the minor isomer (300.13 MHz, DMSO-d6)
3
Scheme 6. Plausible pathway for the transformation of trans-10a and 11 into 14a,b.
3
d: 7.37 (1H, d, JNH,CH = 10.9 Hz, N–H), 5.84 (2H, s, NH2), 5.36 (1H, dd,
3JCH,NH = 10.9, 3JCH,CH = 2.6 Hz, CH–N), 5.00 (1H, dq, 3JCH,CH3 = 6.9,
3JCH,CH = 2.6 Hz, CH–Br), 2.40 (3H, s, CH3 in Ts), 1.79 (3H, d, JCH3,CH = 6.9 Hz,
3
was not detected by 1H NMR spectroscopy, possibly due to its pres-
ence in low concentration.
We found that dihydrofurans trans-10a and 11 on being treated
with TsOH in EtOH under reflux readily gave N-carbamoylpyrroles
14a,b in 69–87% yields (Scheme 5).13
This reaction can also be explained by the intermediate forma-
tion of the respective acyclic forms D followed by their recycliza-
tion into 14a,b (Scheme 6).
CH3). Signals of aromatic protons overlap with signals of the analogous protons
of the major isomer. 13C NMR of the major isomer (75.48 MHz, DMSO-d6) d:
156.60 (C@O), 144.51 (C(4) in 4-MeC6H4), 135.22 (C(1) in 4-MeC6H4), 129.60
(C(3) and C(5) in 4-MeC6H4), 128.69 (C(2) and C(6) in 4-MeC6H4), 72.58 (N–
CH), 45.43 (CH–Br), 23.94 (CH3), 21.11 (CH3 in Ts). 13C NMR of the minor
isomer (75.48 MHz, DMSO-d6) d: 156.43 (C@O), 144.84 (C(4) in 4-MeC6H4),
134.66 (C(1) in 4-MeC6H4), 129.77 (C(3) and C(5) in 4-MeC6H4), 128.69 (C(2)
and C(6) in 4-MeC6H4), 73.90 (N–CH), 44.49 (CH–Br), 21.14 (CH3 in Ts), 21.02
(CH3). IR (Nujol)
m
, cmꢀ1: 3473 s, 3375 s, 3281 s, 3198 m (
CCarom), 1529 s (amide-II),
m NH), 3060 w, 3045
w ( CHarom), 1698 m, 1665 s (amide-I), 1588 m (
m
m
1289 s (mas SO2), 1156 s (ms SO2). Anal. Calcd for C11H15BrN2O3S: C, 39.41; H,
4.51; N, 8.36. Found: C, 39.75; H, 4.87; N, 8.41.
In summary, the reaction of the readily available b-halogeno-a-
tosyl-substituted N-alkylureas with sodium enolates of b-oxoest-
ers proceeds via predominant nucleophilic substitution of the
halogen to give previously unknown ethyl 5-ureido-4,5-dihydrofu-
ran-3-carboxylates. This unexpected reaction pathway has been
7. Synthesis of trans-10a: To a stirred and cooled (ice bath) suspension of NaH
(0.402 g, 16.75 mmol) in anhydrous MeCN (15 mL) was added dropwise a
solution of ethyl acetoacetate (2.178 g, 16.74 mmol) in anhydrous MeCN
(9 mL). After 10 min, sulfone 6b (2.550 g, 7.61 mmol) was added and then
anhydrous MeCN (3 mL). The obtained suspension was stirred at rt for 5 h
10 min and the solvent was removed under vacuum. To the white solid residue
was added a saturated aqueous solution of NaHCO3 (7 mL). The obtained
mixture was left at rt for 12 h. After cooling to 0 °C, the precipitate was filtered,
washed with ice-cold water, light petroleum ether, and dried to give 1.195 g
(69%) of trans-10a. Mp 176.5–177 °C (MeCN). 1H NMR (600.13 MHz, DMSO-d6)
explained in terms of the intermediate formation of
a-halogeno
acylimines. The obtained dihydrofurans are rare representatives
of 3-acyl-substituted 4,5-dihydrofurans possessing
a C(5)–N
bond.14 They are of interest as versatile precursors in heterocycle
syntheses. This was demonstrated by their transformation into
ethyl N-carbamoyl-1H-pyrrole-3-carboxylates under acidic
conditions.
3
d: 7.36 (1H, d, JNH,5-H = 9.8 Hz, N–H), 5.75 (2H, s, NH2), 5.49 (1H, dd,
3J5-H,NH = 9.8, 3J5-H,4-H = 4.6 Hz, 5-H), 4.12 (1H, dq, 2JCH(A),CH(B) = 10.9, 3JCH(A),CH3
=
2
3
7.1 Hz, CH(A) in OCH2), 4.07 (1H, dq, JCH(B),CH(A) = 10.9, JCH(B),CH3 = 7.1 Hz,
CH(B) in OCH2), 2.81 (1H, dqq, 3J4-H,4-CH3 = 6.8, 3J4-H,5-H = 4.6, 5J4-H,2-CH3 = 1.3 Hz,
5
3
4-H), 2.12 (3H, d, J2-CH3,4-H = 1.3 Hz, 2-CH3), 1.21 (3H, t, JCH3,CH(A)
=
3JCH3,CH(B) = 7.1 Hz, CH3 in COOEt), 1.13 (3H, d, 3J4-CH3,4-H = 6.8 Hz,
4-CH3). 13C NMR (150.91 MHz, DMSO-d6) d: 166.01 (C(2)), 164.77 (C@O in
COOEt), 157.06 (N–C@O), 105.78 (C(3)), 90.53 (C(5)), 58.81 (OCH2), 41.59
(C(4)), 18.61 (4-CH3), 14.29 (CH3 in COOEt), 14.27 (2-CH3). IR (Nujol)
3437 s, 3355 m, 3305 m, 3208 s, 3067 m ( NH), 1681 s ( C@O in COOEt), 1651
s (amide-I), 1619 s ( C@C), 1546 s (amide-II), 1282 s, 1213 s, 1147 s, 1076 s (
Supplementary data
m :
, cmꢀ1
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.162.
m
m
m
m
C–O). Anal. Calcd for C10H16N2O4: C, 52.62; H, 7.07; N, 12.27. Found: C, 52.71;
H, 7.01; N, 12.23.
References and notes
Compound 10b (1.313 g, 80%) was prepared as a mixture of trans- and cis-
isomers (85:15, respectively) in the same way as trans-10a from sulfone 6b
(1.891 g, 5.64 mmol), ethyl benzoylacetate (2.382 g, 12.39 mmol), and NaH
(0.298 g, 12.42 mmol) in anhydrous MeCN (20 mL) at rt in 7 h. Mp 168.5–
169 °C (MeCN). 1H NMR of the trans-isomer (600.13 MHz, DMSO-d6) d: 7.63–
1. For reviews, see: (a) Kappe, C. O. Tetrahedron 1993, 49, 6937–6963; (b) Kappe,
C. O. Acc. Chem. Res. 2000, 33, 879–888.
2. For reviews, see: Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043–1052.
3. Baldwin, J. J.; McClure, D. E.; Claremon, D. A. U.S. Patent 4,677,102, 1987; Chem.
Abstr. 1988, 109, 54794.
3
7.66 (2H, m, C(2)H and C(6)H in Ph), 7.54 (1H, d, JNH,5-H = 9.8 Hz, N–H), 7.39–
4. (a) Ashby, J.; Griffiths, D. J. Chem. Soc., Chem. Commun. 1974, 607–608; (b)
Ashby, J.; Griffiths, D. J. Chem. Soc., Perkin Trans. 1 1975, 657–662; (c) Bullock,
E.; Garter, R. A.; Cochrane, R.; Gregory, B.; Shields, D. C. Can. J. Chem. 1977, 55,
895–905; (d) Claremon, D. A.; Rosenthal, S. A. Synthesis 1986, 664–665.
5. (a) Shutalev, A. D.; Kuksa, V. A. Chem. Heterocycl. Compd. 1997, 33, 91–95; (b)
Shutalev, A. D. Chem. Heterocycl. Compd. 1997, 33, 1469–1470; (c) Shutalev, A.
D.; Kishko, E. A.; Sivova, N. V.; Kuznetsov, A. Y. Molecules 1998, 3, 100–106; (d)
Fesenko, A. A.; Shutalev, A. D. Tetrahedron Lett. 2007, 48, 8420–8423; (e)
Fesenko, A. A.; Cheshkov, D. A.; Shutalev, A. D. Mendeleev Commun. 2008, 18,
51–53.
7.48 (3H, m, C(3)H, C(4)H and C(5)H in Ph), 5.79 (2H, s, NH2), 5.64 (1H, dd,
3
3J5-H,NH = 9.8, J5-H,4-H = 4.2 Hz, 5-H), 4.01–4.10 (2H, m, OCH2), 3.03 (1H, dq,
3
3
3J4-H,4-CH3 = 6.9, J4-H,5-H = 4.2 Hz, 4-H), 1.25 (3H, d, J4-CH3,4-H = 6.9 Hz, 4-CH3),
1.12 (3H, t, JCH3,CH2 = 7.1 Hz, CH3 in COOEt). 1H NMR of the cis-isomer
3
(600.13 MHz, DMSO-d6) d: 7.59–7.62 (2H, m, C(2)H and C(6)H in Ph), 7.09 (1H,
3
3
3
d, JNH,5-H = 11.0 Hz, N–H), 6.25 (1H, dd, J5-H,NH = 11.0, J5-H,4-H = 8.6 Hz, 5-H),
5.95 (2H, s, NH2), 3.31 (1H, dq, 3J4-H,5-H = 8.6, 3J4-H,4-CH3 = 7.1 Hz, 4-H), 1.18 (3H, d,
3J4-CH3,4-H = 7.1 Hz, 4-CH3), 1.10 (3H, t, 3JCH3,CH2 = 7.1 Hz, CH3 in COOEt). Signals for
C(3)H, C(4)H, C(5)H of Ph and OCH2 overlap with the signals for the analogous
protons of the trans-isomer. 13C NMR of the trans-isomer (150.91 MHz, DMSO-d6)
d: 164.02 (C@O in COOEt), 162.56 (C(2)), 157.07 (N–C@O), 130.25 (C(4) in Ph),
130.07 (C(1) in Ph), 129.01 (C(3) and C(5) in Ph), 127.57 (C(2) and C(6) in Ph),
106.50 (C(3)), 89.89 (C(5)), 59.09 (OCH2), 43.16 (C(4)), 18.60 (4-CH3), 13.96 (CH3
6. Synthesis of 6a: To
a stirred solution of chloroethanal (7a) (6.094 g,
77.63 mmol) in H2O (56 mL) was added p-toluenesulfinic acid (12.123 g,
77.61 mmol) and the resulting suspension was stirred at rt for 5 min, then urea
(13.993 g, 233.00 mmol) and H2O (50 mL) were added. The obtained
suspension was stirred at rt for 15 h 45 min, and the resulting solid was
filtered, washed with ice-cold water, light petroleum ether, and dried to give
18.465 g (86%) of 6a, which was used without further purification. An
analytically pure sample was obtained by recrystallization from MeCN. Mp
126–127 °C (decomp., MeCN). 1H NMR (300.13 MHz, DMSO-d6) d: 7.70–7.75
(2H, m, AA0 part of an AA0XX0 spin system, C(2)H and C(6)H in 4-MeC6H4), 7.41–
7.47 (2H, m, XX0 part of an AA0XX0 spin system, C(3)H and C(5)H in 4-MeC6H4),
in COOEt). IR (Nujol)
1688 s ( C@O in COOEt), 1667 s (amide-I), 1616 m (
1553 s (amide-II), 1490 m ( CCarom), 1295 s, 1266 s, 1199 s, 1093 s (
m
, cmꢀ1: 3455 s, 3343 s, 3277 s, 3217 m, 3082 m (
C@C), 1595 m ( CCarom),
C–O), 770 s,
m NH),
m
m
m
m
m
699 s (d CHarom). Anal. Calcd for C15H18N2O4: C, 62.06; H, 6.25; N, 9.65. Found: C,
61.83; H, 6.13; N, 9.84.
8. Synthesis of 11: To a stirred and cooled (ice bath) suspension of NaH (0.208 g,
8.67 mmol) in anhydrous MeCN (5 mL) was added dropwise a solution of ethyl
acetoacetate (1.137 g, 8.74 mmol) in anhydrous MeCN (6 mL). After 5 min,
sulfone 6a (1.143 g, 4.13 mmol) was added and then anhydrous MeCN (4 mL).
The obtained suspension was stirred at rt for 9 h and the solvent was removed
under vacuum. To the white solid residue was added a saturated aqueous
solution of NaHCO3 (3 mL). The obtained mixture was left at 35 °C for 1 h. Upon
cooling to 0 °C, the precipitate was filtered, washed with ice-cold water, light
petroleum ether, and dried to give a mixture of dihydrofurans 11 and 12 in a
ratio of 80:20 (0.628 g, 71%). Pure 11 was obtained after crystallization of the
mixture from MeCN. Mp 177.5–178 °C (decomp., MeCN). 1H NMR (300.13 MHz,
3
7.17 (1H, d, JNH,CH = 10.2 Hz, N–H), 5.86 (2H, s, NH2), 5.26 (1H, ddd,
3JCH,NH = 10.2, 3JCH,CH(B) = 8.5, 3JCH,CH(A) = 3.6 Hz, CH–N), 4.10 (1H, dd,
2JCH(A),CH(B) = 11.8, 3JCH(A),CH = 3.6 Hz, CH(A) in OCH2), 3.88 (1H, dd,
3
2JCH(B),CH(A) = 11.8, JCH(B),CH = 8.5 Hz, CH(B) in OCH2), 2.41 (3H, s, CH3). 13C
NMR (75.48 MHz, DMSO-d6) d: 156.49 (C@O), 144.91 (C(4) in 4-MeC6H4),
134.12 (C(1) in 4-MeC6H4), 129.80 (C(3) and C(5) in 4-MeC6H4), 128.94 (C(2)
and C(6) in 4-MeC6H4), 70.58 (N–CH), 41.16 (CH2–Cl), 21.19 (CH3). IR (Nujol)
m,
cmꢀ1: 3464 s, 3437 s, 3358 s, 3300 s, 3211 m (
m
NH), 3009 w ( CHarom), 1668 s
m

N. N. Kurochkin et al. / Tetrahedron Letters 52 (2011) 88–91
91
3
3
DMSO-d6) d: 7.35 (1H, d, JNH,5-H = 9.8 Hz, N–H), 6.00 (1H, ddd, J5-H,NH = 9.8,
ether, and dried to give (0.206 g, 87%) of 14a. Mp 214–215 °C (EtOH). 1H NMR
(300.13 MHz, DMSO-d6) d: 7.61 (2H, br s, NH2), 6.94 (1H, q, 4J5-H,4-CH3 = 1.2 Hz,
3J5-H,4-H(A) = 9.5, J5-H,4-H(B) = 6.0 Hz, 5-H), 5.78 (2H, s, NH2), 4.08 (2H, q,
3
3JCH2,CH3 = 7.1 Hz, OCH2), 3.02 (1H, ddq, J4-H(A),4-H(B) = 15.1, J4-H(A),5-H = 9.5,
5-H), 4.18 (2H, q, JCH2,CH3 = 7.1 Hz, OCH2), 2.62 (3H, s, 2-CH3), 2.10 (3H, d,
2
3
3
5J4-H(A),2-CH3 = 1.7 Hz, 4-H(A)), 2.49 (1H, ddq, J4-H(B),4-H(A) = 15.1, J4-H(B),5-H
=
=
4J4-CH3,5-H = 1.2 Hz, 4-CH3), 1.27 (3H, t, JCH3,CH2 = 7.1 Hz, CH3 in OEt). 13C NMR
2
3
3
6.0, 5J4-H(B),2-CH3 = 1.6 Hz, 4-H(B)), 2.11 (3H, dd, J2-CH3,4-H(A) = 1.7, J2-CH3,4-H(B)
(75.48 MHz, DMSO-d6) d: 164.86 (C@O in COOEt), 152.06 (NH2–C@O), 137.20
5
5
1.6 Hz, 2-CH3), 1.19 (3H, t, JCH3,CH2 = 7.1 Hz, CH3 in COOEt). 13C NMR
(75.48 MHz, DMSO-d6) d: 166.25 (C(2)), 164.89 (C@O in COOEt), 157.01 (N–
C@O), 99.96 (C(3)), 84.32 (C(5)), 58.93 (OCH2), 34.12 (C(4)), 14.40 (CH3 in
(C(2)), 119.65 (C(4)), 117.81 (C(5)), 114.13 (C(3)), 59.03 (OCH2), 14.20 (CH3 in
3
COOEt), 13.27 (2-CH3), 12.44 (4-CH3). IR (Nujol)
m, 3197 s ( NH), 1720 s ( C@O in COOEt), 1672 s (amide-I), 1622 s (amide-II),
1588 m, 1531 m ( C@C), 1309 s, 1257 s, 1132 c ( C–O). Anal. Calcd for
10H14N2O3: C, 57.13; H, 6.71; N, 13.33. Found: C, 57.17; H, 6.61; N, 13.44.
m
, cmꢀ1: 3433 s, 3337 m, 3243
m
m
COOEt), 13.97 (2-CH3). IR (Nujol)
C@O in COOEt), 1657 s (amide-I), 1613 s (
1202 s, 1130 s ( C–O). Anal. Calcd for C9H14N2O4: C, 50.46; H, 6.59; N, 13.08.
m
, cmꢀ1: 3425 s, 3317 s, 3218 s (
m
NH), 1683 s
m
m
(m
m
C@C), 1558 s (amide-II), 1273 s,
C
m
Compound 14b (0.390 g, 69%) was prepared in the same way as 14a from 11
(0.618 g, 2.88 mmol) and TsOHꢁH2O (0.168 g, 0.88 mmol) in EtOH (31 mL)
(reflux, 1 h 20 min). Mp 185–186.5 °C (EtOH). Mp lit.4b,4c 186–187 °C (H2O–
EtOH). 1H NMR (300.13 MHz, DMSO-d63) d: 7.76 (2H, br s, NH2), 7.13 (1H, d,
3J5-H,4-H = 3.4 Hz, 5-H), 7.13 (1H, d, J4-H,5-H = 3.4 Hz, 4-H), 4.18 (2H, q,
Found: C, 50.57; H, 6.58; N, 13.21.
9. Spectral characteristics of 12: 1H NMR (300.13 MHz, DMSO-d6) d: 6.17 (1H, d,
3JNH,4-H = 6.3 Hz, NH), 5.42 (2H, s, NH2), 4.82 (1H, dddq, J4-H,5-H(A) = 8.0,
3
3J4-H,NH = 6.3, 3J4-H,5-H(B) = 3.0, 5J4-H,CH3 = 1.1 Hz, 4-H), 4.40 (1H, dd, 2J5-H(A),5-H(B)
=
=
=
3
2
3
3
10.1, J5-H(A),4-H = 8.0 Hz, 5-H(A)), 4.12 (1H, dd, J5-H(B),5-H(A) = 10.1, J5-H(B),4-H
3JCH2,CH3 = 7.1 Hz, OCH2), 2.66 (3H, s, 2-CH3), 1.25 (3H, t, JCH3,CH2 = 7.1 Hz,
3
5
3.0 Hz, 5-H(B)), 4.09 (2H, q, JCH2,CH3 = 7.1 Hz, OCH2), 2.18 (3H, d, JCH3,4-H
CH3 in OEt). 13C NMR (75.48 MHz, DMSO-d6) d: 164.24 (C@O in COOEt), 152.11
(NH2–C@O), 136.95 (C(2)), 119.44 (C(5)), 114.38 (C(3)), 109.97 (C(4)), 59.26
1.1 Hz, 2-CH3), 1.20 (3H, t, JCH3,CH2 = 7.1 Hz, CH3 in COOEt). 13C NMR
(75.48 MHz, DMSO-d6) d: 170.97 (C(2)), 164.47 (C@O in COOEt), 158.09 (N–
C@O), 103.47 (C(3)), 78.32 (C(5)), 58.96 (OCH2), 52.16 (C(4)), 14.23 (CH3 in
COOEt), 13.12 (2-CH3).
3
(OCH2), 14.35 (CH3 in COOEt), 12.97 (2-CH3). IR (Nujol)
m, 3258 m, 3208 s ( NH), 1741 s ( C@O in COOEt), 1686 s (amide-I), 1628 s
(amide-II), 1574 m, 1519 m ( C@C), 1309 s, 1205 s ( C–O). Anal. Calcd for
m
, cmꢀ1: 3418 s, 3342
m
m
m
m
10. It has been reported,15 that N-acylimines form as intermediates in the
amidoalkylation reactions of various nucleophiles in basic media with amido
alkylating reagents derived from primary amides.
C9H12N2O3: C, 55.10; H, 6.16; N, 14.28. Found: C, 55.21; H, 6.29; N, 14.43.
14. (a) Sopowa, A. S.; Perekalin, V. V.; Bobowitsch, Ya. S. Zh. Obshch. Khim. 1961, 31,
1528–1531 [J. Gen. Chem. USSR (Engl. Trans.) 1961, 31, 1417–1419]; (b) Sopowa,
A. S.; Perekalin, V. V.; Yurchenko, O. I. Zh. Obshch. Khim 1964, 34, 1188–1189 [J.
Gen. Chem. USSR (Engl. Trans.) 1964, 34, 1180–1181]; (c) Gomez-Sanchez, A.;
Stiefel, B. M.; Fernandez-Fernandez, R.; Pascual, C.; Bellanato, J. J. Chem. Soc.,
Perkin Trans. 1 1982, 441–447; (d) Boberg, F.; Garburg, K.-H.; Görlich, K.-J.;
Pipereit, E.; Redelfs, E.; Ruhr, M. J. Heterocycl. Chem. 1986, 23, 1853–1859; (e)
Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S. Eur. J. Org. Chem. 2003, 14, 2635–
2644; (f) Trukhin, E. V.; Sheremet, E. A.; Masalovich, M. S.; Berestovitskaya, V.
M. Russ. J. Org. Chem. 2004, 40, 1823–1825.
15. (a) Zaugg, H. E. Synthesis 1970, 49–73; (b) Kobayashi, T.; Ishida, N.; Hiraoka, T. J.
Chem. Soc., Chem. Commun. 1980, 736–737; (c) Zaugg, H. E. Synthesis 1984, 85–
110; (d) Zaugg, H. E. Synthesis 1984, 181–212; (e) Hamon, D. P. G.; Massy-
Westropp, R. A.; Razzino, P. Tetrahedron 1992, 48, 5163–5178; (f) Petrini, M.;
Torregiani, E. Synthesis 2007, 159–186; (g) Pizzuti, M. G.; Minnaard, A. J.;
Feringa, B. L. J. Org. Chem. 2008, 73, 940–947; (h) Mazurkiewicz, R.;
Pazdz´ierniok-Holewa, A.; Orlin´ ska, B.; Stecko, S. Tetrahedron Lett. 2009, 50,
4606–4609.
11. For reviews on
a-halogenated imino compounds, see: (a) De Kimpe, N.;
Schamp, N. Org. Prep. Proceed Int. 1979, 11, 115–199; (b) De Kimpe, N.; Verhé,
R.; De Buyck, L.; Schamp, N. Org. Prep. Proceed Int. 1980, 12, 49–180.
12. 1H NMR spectrum of cis-10b (300.13 MHz, DMSO-d6) d: 6.93 (1H, d, JNH,5-H
=
3
3
3
11.0 Hz, N–H), 6.09 (1H, dd, J5-H,NH = 11.0, J5-H,4-H = 8.7 Hz, 5-H), 5.94 (2H, s,
NH2), 3.06 (1H, dqq, 3J4-H,5-H = 8.7, 3J4-H,4-CH3 = 7.0, 5J4-H,2-CH3 = 1.2 Hz, 4-H), 2.09
5
3
(3H, d, J2-CH3,4-H = 1.2 Hz, 2-CH3), 1.05 (3H, d, J4-CH3,4-H = 7.0 Hz, 4-CH3). The
signals of the OEt protons overlap with the signals of the analogous protons of
the trans-isomer. The cis-configuration was determined via a 1H, 1H-NOESY
experiment. An NOE was observed between the 4-CH3 and N–H protons, while
there was no NOE between the 4-CH3 and 5-H protons.
13. Synthesis of 14a: A solution of trans-10a (0.256 g, 1.12 mmol) and TsOHꢁH2O
(0.067 g, 0.35 mmol) in EtOH (5 mL) was heated at reflux for 33 min with
stirring and the solvent was removed under vacuum. To the white solid residue
was added a saturated aqueous solution of NaHCO3 (1 mL). Upon cooling to
0 °C, the precipitate was filtered, washed with ice-cold water, light petroleum