Unprecedented formation of stable ketene-N,O-acetals and their rearrangement under basic conditions

Article abstract of DOI:10.1016/j.tet.2006.11.033

Treatment of 2,4-disubstituted glutaryl dichlorides with benzimidic acid ethyl ester hydrochloride in the presence of triethylamine did not give the expected bis(acylbenzimidates), but delivered O-acyl-N-ethoxybenzylidene-ketene-N,O-acetals in good to exc

Full text of DOI:10.1016/j.tet.2006.11.033

Tetrahedron 63 (2007) 934–940
Unprecedented formation of stable ketene-N,O-acetals
and their rearrangement under basic conditions
*
Matthias Breuning and Tobias Hauser
€
Institute of Organic Chemistry, University of Wu€rzburg, Am Hubland, D-97074 Wu€rzburg, Germany
Received 5 October 2006; revised 9 November 2006; accepted 10 November 2006
Available online 29 November 2006
Dedicated to Professor M. Christl on the occasion of his 65th birthday
Abstract—Treatment of 2,4-disubstituted glutaryl dichlorides with benzimidic acid ethyl ester hydrochloride in the presence of triethylamine
did not give the expected bis(acylbenzimidates), but delivered O-acyl-N-ethoxybenzylidene-ketene-N,O-acetals in good to excellent yields.
These compounds, which are stable to moisture and chromatography on silica gel, underwent an unprecedented rearrangement to cyclic
enamides under stronger basic conditions. A mechanism for this rearrangement is proposed.
Ó 2006 Elsevier Ltd. All rights reserved.
Me2N
O
Ph
Ph
O
Ph
NH
1. Introduction
O
KOtBu
THF
N
HN
N
Acylimidates and -amidates are unsymmetric imide
derivatives1 that possess an electrophilic carbon atom in
the C]N moiety and, upon deprotonation, also a nucleo-
philic carbon atom in a-position to the carbonyl group.2,3
This bifunctional reactivity pattern was used by Closs
and Gompper in an elegant synthesis of the diazapentalene-
dione 2 (Scheme 1).4 Treatment of the succinyl bisamidate
1 with KOt-Bu in THF induced a 2-fold cyclization affording
2 in a single step and in quantitative yield. Since further
examples of such ring closure reactions are unknown, we
were interested in whether this principle can be extended
to other 1,n-diacid derived bis(acylimidates) or bis(acylami-
dates),5 which would allow a facile access to bridged
bicyclic diamides.6 Within these investigations we intended
to prepare the glutaryl bisimidates 5 from the corresponding
dichlorides 3 and benzimidic acid ethyl ester hydrochloride
(4). In this paper we report about the unexpected and
unprecedented formation of stable O-acyl-N-ethoxybenzyl-
idene-ketene-N,O-acetals, which occurred in the attempted
syntheses of 5b–d from the 2,4-disubstituted glutaryl
dichlorides 3b–d and 4, and their rearrangements upon treat-
ment with base.
Ph
NMe2
Ph
O
1
2
NH·HCl
O
O
O
O
R
OEt
4
N
N
Cl
Cl
R
OEt
R
EtO
R
Ph
Ph
5
3
3, 5
a
b
c
d
R
H
Me Et Bn
Scheme 1. Synthesis of the diazapentalenedione 2 from the succinyl bisami-
date 1 according to Closs and Gompper4 and our attempted preparation of
the glutaryl derived bis(acylimidates) 5.
2. Results and discussion
2.1. Preparation of the glutaryl dichlorides 3c and 3d
The 2,4-dialkylglutaryl dichlorides 3c and 3d were synthe-
sized from the tetramethyl ester 67 in a three-step sequence
(Scheme 2).8 Deprotonation of 6 with NaOMe in MeOH and
2-fold alkylation with ethyl iodide and benzyl bromide de-
livered the esters 7, which were hydrolyzed and decarboxy-
lated in refluxing half-concentrated H2SO4 to give the crude
diacids 8. Chromatographic purification and crystallization
from Et2O/n-pentane afforded analytically pure 8c9 and 8d
as mixtures of their dl- and meso-isomers.10 The desired di-
chlorides 3c (dl/meso¼36:64) and 3d (dl/meso¼44:56) were
Keywords: Acylimidate; Ketene-N,O-acetal; Rearrangement; Benzimidic
acid.
* Corresponding author. Tel.: +49 931 888 4761; fax: +49 931 888 4755;
e-mail: breuning@chemie.uni-wuerzburg.de
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.033

M. Breuning, T. Ha€user / Tetrahedron 63 (2007) 934–940
935
obtained by treatment with oxalyl chloride in CH2Cl2. The
overall yield for the preparation of 3c and 3d from 6 was
33% each.
generate a bis(acylimidate) of type 5 from 3b–d, e.g. by
treatment of 3b–d with an excess of 4, or a ketene-N,O-
acetal of type 9 from 3a, e.g. by reaction of 3a with a substoi-
chiometric amount of 4, failed.
EtI or BnBr
NaOMe
CO2Me
CO2Me
MeO2C
MeO2C
CO2Me
CO2Me
MeO2C
MeO2C
Exemplarily for the ketene-N,O-acetals 9 prepared, the
structure of 9b was established unambiguously by two-
dimensional NMR spectroscopy; some significant HMBC
correlations are depicted in Scheme 3. The configuration of
the C]N double bond is unknown. A mixture of cis and trans
isomers, however, is very unlikely since only a single set of
signals was detected in all NMR spectra. NOESY interac-
tions of the protons of the methyl group at C-3 were found
with those of the methylene unit of the ethoxy substituent as
well as with the ortho-protons of the phenyl group. Thus, the
2-aza-1,3-diene subunit cannot be aligned in plane, probably
due to steric interactions. As a consequence, the electronic
resonance stabilization within the 2-aza-1,3-diene system
has to be low.
Δ, 10 h
R
R
7c (61%), 7d (60%)
6
3, 7, 8
c
d
H2SO4
H2O
Δ, 3-5 d
R
Et Bn
O
O
(COCl)2, CH2Cl2
r.t., 18 h
HO2C
CO2H
Cl
Cl
R
R
R
R
3c (85%, dl/meso = 36:64)
3d (100%, dl/meso = 44:56)
8c (63%, dl/meso = 38:62)
8d (55%, dl/meso = 42:58)
Scheme 2. Preparation of the glutaryl dichlorides 3c and 3d.
2.2. Formation of the ketene-N,O-acetals 9
The combination of structural elements in 9—an O-acyl-
N-alkoxyalkylidene ketene-N,O-acetal function that is
not stabilized, e.g. by an aromatic system15—is unprece-
dented. The stability of 9b–d is also extraordinary: these
compounds show no tendency to decompose, neither by
exposure to moisture nor by column chromatography on
silica gel.
The synthesis of the glutaryl derived bis(acylbenzimidates) 5
was attempted in analogy to known standard procedures.11
Treatment of commercially available glutaryl dichloride
(3a) with benzimidic acid ethyl ester hydrochloride (4) in
the presence of triethylamine afforded, as expected, the glu-
taryl bisimidate 5a in 44% yield (Scheme 3).12 The analo-
gous reactions of 4 with the 2,4-disubstituted glutaryl
dichlorides 3b,13,14 3c, and 3d, in contrast, delivered the
ketene-N,O-acetals 9b–d as the sole products in high yields
(73–95%). Thus, the monoacylimidates 10 formed in the
first step did not undergo a second addition of 4, but an intra-
molecular cyclization. Most likely, a nucleophilic attack of
the carbonyl oxygen of the acylimidate group at the ketene
moiety of 11, as generated from the acyl chloride function
in the presence of base, occurred.
2.3. Rearrangement of the ketene-N,O-acetals 9
under basic conditions
Deprotonation of the ketene-N,O-acetals 9 will lead to the
corresponding ester enolates. A direct intramolecular attack
of the enolates at the electrophilic acylimidate function pres-
ent, however, seems to be unlikely due to the largely planar-
ized structures of 9. And indeed, skeletal rearrangements
were observed in refluxing THF upon treatment of 9b–d
with LiHMDS and, in the case of 9b, also with NaHMDS
and KOt-Bu, delivering the enamides 12b–d in 37–53%
yields (Scheme 4). The formation of 12, which requires
a cleavage of the C-6–C-5 bond of 9, can be explained by
The different reactivity of the 2,4-disubstituted glutaryl di-
chlorides 3b–d compared to 3a is probably the result of the
increased steric hindrance in the a-positions. All attempts to
O
O
N
N
Ph
OEt
EtO
Ph
for 3a
5a (44%)
O
O
NEt3 (6 equiv.)
CH2Cl2
NH·HCl
OEt
+
2
Cl
Cl
→
0 °C
r.t., 4 h
Ph
N
Ph
O
R
O
R
3a-d
R
9b: 95%
9c: 73%
9d: 84%
2
6
5
for 3b-d
3R
4
OEt
4
9b-d
+
- 2 HCl
O
4
H+
significant HMBC (
)
and NOESY (
)
correlations of 9b:
O
•
O
H
N
N
Ph
O
O1
OCH2CH3
CH3
2
H+
Cl
N
6
3
4
H OEt
- HCl
O
H
R
R
R
5
H2
3, 9-11
a
b
c
d
R
H3C
EtO
Ph
H
R
H
Me Et Bn
10b-d
11b-d
Scheme 3. Unexpected formation of the ketene-N,O-acetals 9b–d from 3b–d and 4 and significant HMBC and NOESY correlations of 9b.

936
M. Breuning, T. Ha€user / Tetrahedron 63 (2007) 934–940
O
O
base
yield [%]
R
3
O
H
O
N
R
Ph
OEt
2
base (1.4 equiv.), THF, Δ, 10 h
EtO
NH
6
5
KOtBu
NaHMDS
LiHMDS
LiHMDS
LiHMDS
53
37
52
44
42
12b
12b
12b
12c
12d
4
6
Ph
5
R
R
12b-d
9b-d
- H+
+ EtO- + H+
O
O
R
-O
R
O
●
-O
N
Ph
OEt
significant HMBC
- EtO-
N
N
correlations of 12b:
Ph
O
EtO
Ph
R
R
R
R
O
H
O
H
N
2
13
14
15
6
4
3
Ph
EtO
5
H
CH3
9, 12-15
b
c
d
H3C
Et
R
Me
Bn
Scheme 4. Base induced rearrangement of the ketene-N,O-acetals 9b–d to the enamides 12b–d and significant HMBC correlations of 12b.
a mechanism that involves all functional groups present. In
the first step, abstraction of the acidic proton of 9 is followed
by ring opening to give the acylimidate enolate 13, which is
the deprotonated analog of 11 (see Scheme 3). The reactive
ketene moiety concurrently created is trapped intramolecu-
larly by the amide enolate to deliver the strained cyclobuta-
none enolate 14, which attacks the C]N double bond of
the regenerated acylimidate function. Finally, the four-
membered ring of the resulting 3-azabicyclo[3.1.1]hept-
3-ene-2,6-dione 15 is cleaved by ethanolate, liberated in
the preceding step, in the sense of a retro-Claisen condensa-
tion to give the observed enamides 12 after protonation. The
driving force for the last step is probably the release of ring
strain.
MAT 8200 instrument and on a Bruker Daltonics micrOTOF
focus. IR spectra were recorded on a Jasco FT-IR-410 spec-
trometer.
4.2. Tetramethyl heptane-3,3,5,5-tetracarboxylate (7c)
The tetramethyl ester 6 (5.00 g, 18.1 mmol) was added at rt to
a methanolic solution of NaOMe, prepared from Na (1.00 g,
43.4 mmol) in MeOH (50 mL). After 30 min, EtI (5.61 mL,
8.47 g, 54.3 mmol) was added and the reaction mixture was
stirred at rt for 2 h and refluxed for 8 h. Most of the solvent
was removed under reduced pressure. The oily residue was
diluted with water (50 mL) and extracted with CH2Cl2
(2ꢀ50 mL). The combined organic layers were washed
with brine (20 mL), dried over MgSO4, and concentrated un-
der reduced pressure. Chromatographic purification on silica
gel (n-pentane/Et2O 5:1/1:1) delivered a colorless oil,
which started to crystallize upon standing. Crystallization
from Et2O/n-pentane gave 7c (3.67 g, 11.0 mmol, 61%)
3. Conclusion
Treatment of glutaryl dichloride (3a) with benzimidic acid
ethyl ester hydrochloride (4) in the presence of triethylamine
afforded the expected bis(acylimidate) 5a. The analogous
reactions with the 2,4-disubstituted glutaryl dichlorides
3b–d, however, delivered the O-acyl-N-ethoxybenzylidene-
ketene-N,O-acetals 9b–d, which were found to be stable to
moisture and chromatography on silica gel. Under stronger
basic conditions, 9b–d rearranged to give the enamides
12b–d.
1
as a colorless solid, mp 76–78 ꢁC; H NMR (400 MHz,
CDCl3) d 0.80 (t, J¼7.5 Hz, 6H), 1.89 (q, J¼7.5 Hz, 4H),
2.71 (s, 2H), 3.68 (s, 12H); 13C NMR (100 MHz, CDCl3)
d 9.1, 27.1, 35.5, 52.2, 56.7, 171.5; IR (film) 2979, 2958,
1736, 1438, 1298, 1240, 1210, 1130, 1105 cmꢂ1; HRMS
(ESI, MeCN/CHCl3) calcd for C15H24O8+Na 355.1363;
found 355.1370.
4.3. Tetramethyl 1,5-diphenylpentane-2,2,4,4-tetra-
carboxylate (7d)
4. Experimental
4.1. General
The tetramethyl ester 7d was prepared in analogy to the syn-
thesis of 7c described above. Deprotonation of 6 (2.00 g,
7.24 mmol) with NaOMe in MeOH and alkylation (6 h at
rt, 4 h reflux) with BnBr (2.60 mL, 3.71 g, 21.7 mmol)
yielded, after work up, column chromatography (n-pen-
tane/Et2O 2:1), and crystallization from Et2O, 7d (1.98 g,
All reactions were performed in flame-dried glassware
under a static argon atmosphere using dried solvents. Melt-
ing points were determined with a Kofler melting point
apparatus and are uncorrected. NMR spectra were recorded
on a Bruker AV 400 instrument operating at 400 MHz (1H)
and 100 MHz (13C) or on a Bruker DMX 600 instrument
operating at 600 MHz (1H) and 150 MHz (13C). Chemical
shifts are reported in d units using the deuterated solvent
as an internal reference. Elemental analyses were performed
in the Institute of Inorganic Chemistry, University of
1
4.34 mmol, 60%) as a colorless solid, mp 116–117 ꢁC; H
NMR (400 MHz, CDCl3) d 2.78 (s, 2H), 3.26 (s, 4H), 3.62
(s, 12H), 7.14–7.19 (m, 4H), 7.22–7.31 (m, 6H); 13C NMR
(100 MHz, CDCl3) d 39.8, 42.5, 52.0, 57.9, 127.0, 128.0,
130.4, 136.0, 170.8; IR (film) 2995, 2949, 1743, 1723,
1440, 1337, 1278, 1205, 1108 cmꢂ1; HRMS (ESI, MeCN/
CHCl3 1:1) calcd for C25H28O8+Na 479.1676; found
479.1677.
€
Wurzburg. Mass spectra were measured on a Finnigan

M. Breuning, T. Ha€user / Tetrahedron 63 (2007) 934–940
937
4.4. 2,4-Diethylglutaric acid (8c)9
(12) [M+ꢂCl], 161 (10) [M+ꢂCOCl], 125 (11), 97 (100),
83 (20); HRMS (EI, 70 eV) calcd for C9H14O2Cl (¼MꢂCl)
189.0677; found 189.0675.
A solution of 7c (3.00 g, 9.03 mmol) in half-concentrated
H2SO4 (40 mL) was refluxed for 3 d. The reaction mixture
was diluted with water (200 mL), carefully neutralized at
0 ꢁC with solid NaOH, slightly re-acidified with 2 N HCl,
and extracted with Et2O (2ꢀ200 mL). The combined
organic layers were washed with brine (50 mL), dried over
MgSO4, and concentrated under reduced pressure. Fast
column chromatography on silica gel (n-pentane/Et2O 2:1)
gave a colorless oil, which was crystallized from Et2O/
n-pentane to yield a 38:62-mixture of the dl-8c (A) and
meso-8c (B) (1.07 g, 5.69 mmol, 63%), mp 74–107 ꢁC;9
1H NMR (400 MHz, CDCl3) d 0.95 (t, J¼7.4 Hz, 6H A),
0.96 (t, J¼7.4 Hz, 6H B), 1.42–1.56 (m, 2H A, 2H B),
1.59 (dt, J¼14.0, 2.8 Hz, 1H B), 1.65–1.85 (m, 2H A, 2H
B), 2.02 (t, J¼5.8 Hz, 2H A), 2.08 (dt, J¼13.9, 11.6 Hz,
1H B), 2.34 (dddd, J¼11.4, 8.4, 5.6, 2.8 Hz, 2H B), 2.46
(m, 2H A), 12.5 (br s, 2H A, 2H B); 13C NMR (100 MHz,
CDCl3) d 11.6 (B), 11.8 (A), 24.5 (A), 26.6 (B), 32.4 (A),
34.7 (B), 43.3 (A), 47.1 (B), 182.3 (A), 182.7 (B);
IR (film) 3600–2400, 2971, 1710, 1458, 1279, 1238,
932 cmꢂ1; HRMS (ESI, MeCN/CHCl3 1:1) calcd for
C9H16O4+Na 211.0941; found 211.0941.
4.7. 2,4-Dibenzylglutaryl dichloride (3d)
(COCl)2 (804 mL, 1.17 g, 9.21 mmol) and a catalytic amount
of DMF were added to a solution of 8d (720 mg, 2.30 mmol)
in CH2Cl2 (13 mL). The reaction mixture was stirred for
18 h at rt and the solvent was removed under reduced pres-
sure. Drying at 50 ꢁC/0.5 mbar gave a 44:56-mixture of
the dichlorides dl-3d (A) and meso-3d (B) (804 mg,
2.30 mmol, 100%) as a slightly yellow oil; 1H NMR
(400 MHz, CDCl3) d 1.77 (m, 1H B), 1.94 (m, 2H A), 2.32
(m, 1H B), 2.85 (m, 2H A, 2H B), 3.13 (m, 4H A, 4H B),
7.08 (m, 4H B), 7.14 (m, 4H A), 7.20–7.35 (m, 6H A, 6H
B); 13C NMR (100 MHz, CDCl3) d 32.2 (B), 33.1 (A),
37.6 (B), 38.6 (A), 56.2 (B), 56.4 (A), 127.3 (2ꢀPhC),
128.8, 128.9 (3ꢀPhC), 136.1 (A), 136.2 (B), 175.7 (B),
175.8 (A); IR (KBr) 3063, 3030, 2927, 1801, 1765, 1497,
1455, 1041, 751, 700 cmꢂ1; MS (EI, 70 eV) m/z (%) 313
(12) [M+ꢂCl], 284 (8), 249 (12), 221 (11), 145 (21), 117
(52), 91 (100); HRMS (EI, 70 eV) calcd for C19H17O2Cl
(¼MꢂHCl) 312.0912; found 312.0910.
4.5. 2,4-Dibenzylglutaric acid (8d)
4.8. Glutaric acid bis(1-phenyl-1-ethoxymethylidene-
amide) (5a)
The glutaric acid derivative 8d was prepared in analogy to
the synthesis of 8c described above. Refluxing a solution
of 7d (1.81 g, 3.96 mmol) in half-concentrated H2SO4
(20 mL) for 5 d, work up, column chromatography (n-
pentane/Et2O 2:1/1:3), and crystallization from Et2O/
n-pentane delivered a 42:58-mixture of the dl-8d (A) and
meso-8d (B) (681 mg, 2.18 mmol, 55%) as a colorless solid,
mp 129–142 ꢁC; 1H NMR (400 MHz, CDCl3) d 1.67 (br d,
J¼13.9 Hz, 1H B), 1.98 (t, J¼5.6 Hz, 2H A), 2.09 (m, 1H
B), 2.57 (dd, J¼13.8, 8.4 Hz, 2H A), 2.66 (m, 4H B), 2.91
(m, 2H A), 3.02 (m, 2H B), 3.09 (dd, J¼13.8, 6.2 Hz, 2H
A), 7.05 (m, 4H A), 7.12 (m, 4H B), 7.17–7.29 (m, 6H A,
6H B), 12.5 (br s, 2H A, 2H B); 13C NMR (100 MHz,
CDCl3) d 30.3 (A), 33.1 (B), 36.6 (A), 38.9 (B), 43.3 (A),
46.9 (B), 126.5 (A), 126.6 (B), 128.5 (PhC A, PhC B),
128.9 (PhC A, PhC B), 138.1 (B), 138.4 (A), 181.9 (A),
182.0 (B); IR (KBr) 3600–2400, 3033, 2923, 1738, 1718,
1297, 1246, 1230, 1180, 697 cmꢂ1; HRMS (ESI, MeCN/
CHCl3 1:1) calcd for C19H20O4+Na 335.1254; found
335.1254.
Triethylamine (2.95 mL, 2.13 g, 21.0 mmol) was added to
a suspension of benzimidic acid ethyl ester hydrochloride
(4, 1.30 g, 7.00 mmol) in CH2Cl2 (10 mL). The reaction mix-
turewas stirred for 30 min at rt, cooled to 0 ꢁC, and a solution
of glutaryl dichloride (3a, 447 mL, 592 mg, 3.50 mmol) in
CH2Cl2 (5 mL) was added slowly. After 24 h at rt, the reac-
tion mixture was diluted with satd aq NH4Cl (50 mL) and
extracted with CH2Cl2 (2ꢀ30 mL). The combined organic
layers were washed with brine (50 mL), dried over MgSO4,
and concentrated under reduced pressure. Chromatographic
purification on silica gel (n-pentane/Et2O 100:0/50:50)
delivered 5a (612 mg, 1.55 mmol, 44%) as a yellow oil; 1H
NMR (400 MHz, CDCl3) d 1.39 (t, J¼7.1 Hz, 6H), 1.86
(quin., J¼7.3 Hz, 2H), 2.32 (t, J¼7.3 Hz, 4H), 4.25 (q,
J¼7.1 Hz, 4H), 7.36 (m, 4H, PhH), 7.45 (m, 2H, PhH),
7.60 (m, 4H, PhH); 13C NMR (100 MHz, CDCl3) d 14.0,
20.2, 38.2, 63.5, 128.3, 128.6, 131.3, 131.6, 156.2, 183.8;
IR (KBr) 3062, 2980, 2940, 2905, 1769, 1660, 1279, 1098,
698 cmꢂ1; MS (CI, CH4, 150 eV) m/z (%) 395 (31)
[M+H]+, 260 (8), 246 (100), 151 (29), 115 (32). Anal. Calcd
for C23H26N2O4: C 70.03; H 6.64; N 7.10; found: C 69.66;
H 6.59; N 7.00.
4.6. 2,4-Diethylglutaryl dichloride (3c)
To a suspension of 8c (376 mg, 2.00 mmol) in CH2Cl2
(11 mL) was added (COCl)2 (698 mL, 1.02 g, 8.00 mmol)
and a catalytic amount of DMF. After 18 h of stirring at rt,
the solvent was removed under reduced pressure. Drying
at 50 ꢁC/0.5 mbar gave a 36:64-mixture of the dichlorides
dl-3c (A) and meso-3c (B) (382 mg, 1.70 mmol, 85%) as
4.9. General procedure for the preparation of the
ketene-N,O-acetals 9b–d
A suspension of 4 (2.0 equiv) in CH2Cl2 (10 mL/mmol 3)
was treated with triethylamine (6.0 equiv). After 30 min, a
solution of the 2,4-disubstituted glutaryl dichlorides 3b–d
(1.0 equiv) in CH2Cl2 (5 mL/mmol 3) was added slowly at
0 ꢁC. After 5 h of stirring, the reaction mixture was diluted
with satd aq NH4Cl (40 mL/mmol 3) and extracted with
Et2O (2ꢀ40 mL/mmol 3). The combined organic layers were
washed with brine (20 mL/mmol 3), dried over MgSO4,
and concentrated under reduced pressure. Chromatographic
1
a slightly yellow oil; H NMR (400 MHz, CDCl3) d 0.98
(m, 6H A, 6H B), 1.76 (m, 4H A, 5H B), 1.93 (dd, J¼7.8,
6.5 Hz, 2H A), 2.25 (m, 1H B), 2.79 (m, 2H A, 2H B); 13C
NMR (100 MHz, CDCl3) d 10.8 (A, B), 24.7 (B), 25.9
(A), 32.2 (B), 33.0 (A), 55.5 (B), 56.3 (A), 176.2 (B),
176.5 (A); IR (KBr) 2971, 2937, 2880, 1801, 1764, 1709,
1460, 1056, 1027, 789 cmꢂ1; MS (EI, 70 eV) m/z (%) 189

938
M. Breuning, T. Ha€user / Tetrahedron 63 (2007) 934–940
Table 1. NMR spectroscopic data of 9ba
Position
13C (CDCl3) 1H (CDCl3) [ppm]
[ppm]
COSY HMBC
(CDCl3) (CDCl3)
INADEQUATEb 1H (C6D6) [ppm]
(CDCl3)
NOESY (C6D6)c
2
3
144.6
93.5
3 (93)
2 (87), 4 (43),
8 (43)
2,3,5,6,7,8 3 (37), 5 (37)
4
32.8
2.06 (m, 2H)
5,8
a: 1.46 (dd, J¼16.1,
7.3 Hz, 1H);
b: 1.57 (ddd, J¼16.1,
12.1, 1.3 Hz, 1H)
2.13 (dquin., J¼12.1,
6.9 Hz, 1H)
4b,5,7,8;
4a,5,7,8
4a,4b,7
5
34.0
2.54 (ddq, J¼11.1, 8.2, 4,7
4,6,7
4 (37), 6 (53),
7 (37)
5 (50)
6.9 Hz, 1H)
6
7 (5-Me)
8 (3-Me)
9 (6-N]C)
10 (OCH2CH3)
11 (OCH2CH3)
12 (ipso-Ph)
13 (ortho-Ph)
14 (meta-Ph)
15 (para-Ph)
172.0
15.2
15.7
164.8
63.1
14.1
132.4
127.5
128.1
130.5
1.22 (d, J¼6.9 Hz, 3H)
5
4
4,5,6
2,3,4
5 (37)
3 (45)
0.97 (d, J¼6.8 Hz, 3H) 4a,4b,5
1.41 (s, 3H)
1.36 (s, 3H)
4a,4b,(10),(13)
d
4.39 (q, J¼7.1 Hz, 2H) 11
9,11
10
11 (36)
10 (42)
9 (68), 13 (57)
12 (58), 14 (55)
13 (50), 15 (57)
14 (59)
4.26 (q, J¼7.1 Hz, 2H) (8),11,13
1.41 (t, J¼7.1 Hz, 3H)
10
1.12 (t, J¼7.1 Hz, 3H)
10
7.50 (m, 2H)
7.36 (m, 2H)
7.42 (m, 1H)
14
13,15
14
9,13,15
12,14
13
7.50 (m, 2H)
7.00 (m, 2H)
7.00 (m, 1H)
(8),10,14
13
Recorded at 400 MHz (1H, COSY, HMBC, NOESY) and 150 MHz (13C, INADEQUATE).
Coupling partner; in parentheses: coupling constant J (Hz).
In parentheses: weak interactions.
a
b
c
d
Signal too weak.
purification on silica gel (n-pentane/Et2O 100:0/60:40)
delivered the ketene-N,O-acetals 9b–d as slightly yellow
oils.
general procedure, 3d (50.1 mg, 143 mmol) was converted
1
into 9d (51.0 mg, 120 mmol, 84%); H NMR16 (400 MHz,
CDCl3) d 1.42 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.89 (dd,
J¼16.5, 9.5 Hz, 1H, 4-H), 1.99 (dd, J¼16.5, 6.7 Hz, 1H,
4-H), 2.53 (dd, J¼13.8, 9.7 Hz, 1H, 5-CHHPh), 2.68 (tdd,
J¼9.6, 6.7, 4.3 Hz, 1H, 5-H), 3.11 (d, J¼14.9 Hz, 1H,
3-CHHPh), 3.14 (dd, J¼13.7, 4.3 Hz, 1H, 5-CHHPh), 3.26
(d, J¼14.8 Hz, 1H, 3-CHHPh), 4.42 (q, 2H, J¼7.1 Hz,
OCH2CH3), 6.92 (m, 4H, PhH), 7.18 (m, 6H, PhH), 7.37
(m, 2H, PhH), 7.45 (m, 1H, PhH), 7.54 (m, 2H, PhH); 13C
NMR16 (100 MHz, CDCl3) d 14.2 (OCH2CH3), 26.9 (C-4),
35.6 (5-CH2Ph), 36.0 (3-CH2Ph), 40.9 (C-5), 63.4
(OCH2CH3), 97.2 (C-3), 126.2 (PhC), 126.4 (PhC), 127.8
(PhC), 128.3 (PhC), 128.4 (2ꢀPhC), 128.6 (PhC), 129.0
(PhC), 130.8 (PhC), 132.5 (PhC), 138.3 (PhC), 139.4 (PhC),
145.2 (C-2), 164.5 (C]N), 170.7 (C-6); IR (KBr)
3027, 2925, 2851, 1765, 1694, 1638, 1494, 1283, 1108,
699 cmꢂ1; HRMS (ESI, MeCN/CHCl3 1:1) calcd for
C28H27NO3+Na 448.1889; found 448.1886.
4.9.1. N-(3,5-Dimethyl-6-oxo-5,6-dihydro-4H-pyran-2-
yl)benzimidic acid ethyl ester (9b). According to the
general procedure, 3b (144 mg, 730 mmol) was converted
into 9b (190 mg, 695 mmol, 95%); IR (KBr) 2979, 2933,
1758, 1699, 1641, 1448, 1363, 1283, 1109, 701 cmꢂ1; MS
(CI, CH4, 150 eV) m/z (%) 547 (15) [2M+H]+, 501 (17)
[2MꢂOEt]+, 274 (100) [M+H]+, 228 (48). Anal. Calcd for
C16H19NO3: C 70.31; H 7.01; N 5.12; found: C 70.09; H
7.04; N 5.24; HRMS (ESI, MeCN) calcd for C16H19NO3+Na
296.1257; found 296.1251; the NMR spectroscopic data are
summarized in Table 1.
4.9.2. N-(3,5-Diethyl-6-oxo-5,6-dihydro-4H-pyran-2-yl)-
benzimidic acid ethyl ester (9c). As described in the
general procedure, the ketene-N,O-acetal 9c (49.1 mg,
163 mmol) was obtained from 3c (50.0 mg, 222 mmol) in
73% yield; 1H NMR16 (400 MHz, CDCl3) d 0.67 (t,
J¼7.5 Hz, 3H, 3-CH2CH3), 0.97 (t, J¼7.5 Hz, 3H, 5-
CH2CH3), 1.41 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.48 (dquin.,
J¼14.4, 7.2 Hz, 1H, 5-CHHCH3), 1.86 (m, 3H, 3-CH2CH3,
5-CHHCH3), 1.99 (dd, J¼16.1, 10.6 Hz, 1H, 4-H), 2.19 (dd,
J¼16.1, 6.7 Hz, 1H, 4-H), 2.35 (dq, J¼10.4, 6.8 Hz, 1H, 5-
H), 4.38 (q, J¼7.1 Hz, 2H, OCH2CH3), 7.32–7.44 (m, 3H,
PhH), 7.51 (m, 2H, PhH); 13C NMR16 (100 MHz, CDCl3)
d 11.4 (3-CH2CH3, 5-CH2CH3), 14.2 (OCH2CH3), 23.0
(3-CH2CH3, 5-CH2CH3), 27.3 (C-4), 40.6 (C-5), 63.1
(OCH2CH3), 98.7 (C-3), 127.8 (PhC), 128.1 (PhC), 130.6
(PhC), 132.3 (PhC), 143.9 (C-2), 164.5 (C]N), 171.3
(C-6); IR (KBr) 2964, 2927, 2852, 1763, 1698, 1640,
1281, 1109, 1031, 700 cmꢂ1; HRMS (ESI, MeCN/CHCl3
1:1) calcd for C18H23NO3+Na 324.1576; found 324.1575.
4.10. General procedure for the rearrangement of 9b–d
LiHMDS (1.0 M in hexanes, 1.4 equiv) was added at rt to a
solution of the ketene-N,O-acetals 9b–d (1.0 equiv) in THF
(20 mL/mmol 9). After refluxing for 10 h, satd aq NH4Cl
(40 mL/mmol 9) was added and the reaction mixture was
extracted with Et2O (2ꢀ40 mL/mmol 9). The combined or-
ganic layers were washed with brine (20 mL/mmol 9), dried
over MgSO4, concentrated under reduced pressure, and
chromatographed on silica gel (n-pentane/Et2O 100:0/
70:30) to give the enamides 12b–d as slightly yellow solids.
4.10.1. 3,5-Dimethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-
pyridine-3-carboxylic acid ethyl ester (12b). According
to the general procedure, 9b (78.0 mg, 285 mmol) was rear-
ranged to give 12b (40.5 mg, 148 mmol, 52%) as a slightly
yellow solid, mp 75 ꢁC; IR (KBr) 3210, 3102, 2983, 2932,
1728, 1683, 1669, 1386, 1260, 1180, 1109, 701; MS (EI,
4.9.3. N-(3,5-Dibenzyl-6-oxo-5,6-dihydro-4H-pyran-2-
yl)benzimidic acid ethyl ester (9d). According to the

M. Breuning, T. Ha€user / Tetrahedron 63 (2007) 934–940
939
Table 2. NMR spectroscopic data of 12ba
Position
13C [ppm]
1H [ppm]
COSY
HMBC
1 (NH)
6.81 (br s, 1H)
2
3
4
170.2
49.3
39.2
a: 2.46 (dd, J¼16.2, 1.2 Hz, 1H);
b: 2.80 (d, J¼16.2 Hz, 1H)
4b,8;
4a,8
2,3,5,6,7,8,9;
2,3,5,6,7,8,9
5
6
110.7
130.8
20.0
18.4
172.6
61.5
7 (3-Me)
8 (5-Me)
9 (3-CO)
10 (OCH2CH3)
1.50 (s, 3H)
1.77 (s, 3H)
2,3,4,9
4,5,6
4a,4b
a: 4.19 (dq, J¼10.7, 7.1 Hz, 1H);
b: 4.25 (dq, J¼10.7, 7.1 Hz, 1H)
1.26 (t, J¼7.1 Hz, 3H)
10b,11;
10a,11
10a,10b
9,11;
9,11
10
11 (OCH2CH3)
12 (Ph)
14.2
135.1, 128.4,
128.5, 128.6
b
7.20–7.45 (m, 5H)
6b
Recorded at 400 MHz (1H, COSY, HMBC) and 100 MHz (13C).
Further correlations were not assigned due to signal overlap.
a
b
70 eV) m/z (%) 273 (4) [M]+, 258 (12), 200 (100), 182 (6), 77
(14), 41 (7); HRMS (ESI, MeCN) calcd for C16H19NO3+Na
296.1257; found 296.1257; the NMR spectroscopic data are
summarized in Table 2.
(PhC), 128.3 (PhC), 128.5 (2ꢀPhC), 128.9 (2ꢀPhC),
130.7 (PhC), 132.3 (C-6), 134.8 (PhC), 136.2 (PhC), 139.0
(PhC), 168.6 (C]O), 171.4 (C]O); IR (film) 3210 (br),
2955, 2925, 2854, 1732, 1684, 1458, 1261, 799, 700 cmꢂ1
;
HRMS (ESI, MeCN) calcd for C28H27NO3+H 426.2064;
found 426.2073.
The analogous reactions of 9b with NaHMDS and KOt-Bu
as the bases gave 12b in 37% and 53% yields, respectively.
4.10.2. 3,5-Diethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-
pyridine-3-carboxylic acid ethyl ester (12c). As described
in the general procedure, the enamide 12c (18.8 mg,
62.4 mmol) was obtained from 9c (42.8 mg, 142 mmol) in
44% yield, mp 104–106 ꢁC; 1H NMR16 (400 MHz,
CDCl3) d 1.02 (t, J¼7.5 Hz, 3H, 5-CH2CH3), 1.05 (t,
J¼7.5 Hz, 3H, 3-CH2CH3), 1.27 (t, J¼7.2 Hz, 3H,
OCH2CH3), 2.00 (m, 2H, 3-CH2CH3), 2.08 (q, J¼7.5 Hz,
2H, 5-CH2CH3), 2.51 (d, J¼16.2 Hz, 1H, 4-H), 2.75 (d,
J¼16.2 Hz, 1H, 4-H), 4.18 (dq, J¼10.8, 7.1 Hz, 1H,
OCHHCH3), 4.25 (dq, J¼10.8, 7.1 Hz, 1H, OCHHCH3),
6.72 (br s, 1H, NH), 7.25 (m, 2H, PhH), 7.35 (m, 3H,
PhH); 13C NMR16 (100 MHz, CDCl3) d 9.2 (3-CH2CH3),
12.8 (5-CH2CH3), 14.3 (OCH2CH3), 25.0 (5-CH2CH3),
26.5 (3-CH2CH3), 33.2 (C-4), 53.2 (C-3), 61.4 (OCH2CH3),
116.4 (C-5), 128.3 (PhC), 128.5 (PhC), 128.7 (PhC), 130.4
(C-6), 135.1 (PhC), 169.4 (C]O), 171.9 (C]O); IR
(film) 3229 (br), 2958, 2925, 2853, 1731, 1684, 1462,
1259, 1028, 749, 700 cmꢂ1; HRMS (ESI, MeCN) calcd for
C18H23NO3+Na 324.1570; found 324.1571.
Acknowledgements
This work was supported by the Deutsche Forschungsge-
meinschaft DFG (Emmy-Noether fellowship to M.B.) and
the Fonds der Chemischen Industrie.
References and notes
1. (a) Perrin, C. L. The Chemistry of Amidines and Imidates; Patai,
S., Rappoport, Z., Eds.; Wiley: Chichester, UK, 1991; Vol. 2,
pp 147–230; (b) Neilson, D. G. The Chemistry of Amidines
and Imidates; Patai, S., Rappoport, Z., Eds.; Wiley:
Chichester, UK, 1991; Vol. 2, pp 425–484.
~
2. For reactions of acylimidates, see i.a. (a) Alves, M. J.; Duraes,
M. M.; Fortes, A. G. Tetrahedron 2004, 60, 6541–6553; (b)
~
Alves, M. J.; Duraes, M. M.; Fortes, A. G. Tetrahedron Lett.
2003, 44, 5079–5082; (c) Jnoff, E.; Ghosez, L. J. Am. Chem.
Soc. 1999, 121, 2617–2618; (d) Gouverneur, V.; Ghosez, L.
Tetrahedron 1996, 52, 7585–7598; (e) Gouverneur, V.;
Ghosez, L. Tetrahedron Lett. 1991, 32, 5349–5352; (f)
Yamamoto, Y.; Morita, Y.; Minami, K. Chem. Pharm. Bull.
ꢀ
1986, 34, 1980–1986; (g) Cuadrado, F. J.; Perez, M. A.; Soto,
J. L. J. Chem. Soc., Perkin Trans. 1 1984, 2447–2449; (h)
Perez, M. A.; Dorado, C. A.; Soto, J. L. Synthesis 1983, 6,
4.10.3. 3,5-Dibenzyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-
pyridine-3-carboxylic acid ethyl ester (12d). According
to the general procedure, 9d (41.1 mg, 96.6 mmol) was con-
verted into 12d (17.3 mg, 40.7 mmol, 42%), mp 166–168 ꢁC;
1H NMR16 (400 MHz, CDCl3) d 1.21 (t, J¼7.1 Hz, 3H,
OCH2CH3), 2.38 (d, J¼16.4 Hz, 1H, 4-H), 2.58 (d,
J¼16.4 Hz, 1H, 4-H), 3.18 (d, J¼13.6 Hz, 1H, 3-CHHPh),
3.33 (d, J¼15.4 Hz, 1H, 5-CHHPh), 3.39 (d, J¼15.4 Hz,
1H, 5-CHHPh), 3.40 (d, J¼13.6 Hz, 1H, 3-CHHPh), 4.06
(dq, J¼10.7, 7.1 Hz, 1H, OCHHCH3), 4.15 (dq, J¼10.7,
7.1 Hz, 1H, OCHHCH3), 6.83 (br s, 1H, NH), 7.08 (m,
2H, PhH), 7.19–7.31 (m, 11H, PhH), 7.37 (m, 2H, PhH);
13C NMR16 (100 MHz, CDCl3) d 14.1 (OCH2CH3), 33.6
(C-4), 37.9 (3-CH2Ph), 38.9 (5-CH2Ph), 54.5 (C-3), 61.7
(OCH2CH3), 112.9 (C-5), 126.3 (PhC), 126.9 (PhC), 128.1
ꢀ
483–486; (i) Nagasaka, T.; Hamaguchi, F.; Ozawa, N.;
Kosugi, Y.; Ohki, S. Heterocycles 1980, 14, 291–293; (j)
Nagasaka, T.; Hamaguchi, F.; Ozawa, N.; Ohki, S.
Heterocycles 1978, 9, 1375–1380; (k) Kumar, S.; Gupta,
C. M.; Anand, N. Indian J. Chem. 1976, 14B, 303–305.
3. For reactions of acylamidates, see i.a. (a) Chen, C.; Dagnino,
R.; McCarthy, J. R. J. Org. Chem. 1995, 60, 8428–8430; (b)
Prewo, R.; Bieri, J. H.; Widmer, U.; Heimgartner, H. Helv.
Chim. Acta 1981, 64, 1515–1521; (c) Widmer, U.;
Heimgartner, H.; Schmid, H. Helv. Chim. Acta 1978, 61,
815–821; (d) See Ref. 4.

940
M. Breuning, T. Ha€user / Tetrahedron 63 (2007) 934–940
4. (a) Closs, F.; Gompper, R. Angew. Chem. 1987, 99, 564–567;
Angew. Chem., Int. Ed. Engl. 1987, 26, 552–554; (b) Closs,
10. The dl/meso-ratios of pure 8c and 8d can vary depending on the
crystallization conditions. As observed for other 2,4-disubsti-
tuted glutaric acid derivatives,8b,9a the meso-isomers can be
enriched by fractional crystallization.
11. (a) Ghosez, L.; Bayard, P.; Nshimyumukiza, P.; Gouverneur,
V.; Sainte, F.; Beaudegnies, R.; Rivera, M.; Frisque-Hesbain,
A. M.; Wynants, C. Tetrahedron 1995, 51, 11021–11042;
(b) See Ref. 2a.
€
F.; Gompper, R.; Noth, H.; Wagner, H.-U. Angew. Chem.
1988, 100, 875–878; Angew. Chem., Int. Ed. Engl. 1988, 27,
842–845.
5. All known bis(acylamidate) and bis(acylimidate) derivatives
are heterocyclic compounds. There are only two exceptions,
the succinyl bis(benzamidate) 1 (Ref. 4) and N,N0-adipinyl-
bis(benzimidic acid methyl ester), a homolog to 5a: Inventa
12. According to NMR, the glutaryl bisimidate 5a is a stereochemi-
cally homogenous compound; the two C]N double bonds can
be either both cis or both trans configured.
€
AG fur Forschung und Patentverwaltung. Neth. Appl. NL
6615358, May 2, 1967.
6. The analogous cyclizations of 1,(n+4)-diacid derived bis(acyl-
amidates) and bis(acylimidates) would lead to functionalized
diazabicyclo[3.3.n]alkadiene derivatives.
7. Gogoll, A.; Johansson, C.; Axen, A.; Grennberg, H. Chem.—
Eur. J. 2001, 7, 396–403.
8. For the synthesis of 2,4-disubstituted glutaric acids from the
tetraethyl ester derivative of 6, see: (a) Guthzeit, M.; Dressel,
O. Liebigs Ann. Chem. 1890, 256, 171–201; (b) Evans,
D. W. S. J. Chem. Soc. 1962, 1096–1098.
9. (a) Auwers, K.; Singhof, W. Liebigs Ann. Chem. 1896, 292,
194–224; (b) See Ref. 8a.
13. Cason, J.; Reist, E. J. J. Org. Chem. 1958, 23, 1675–1678.
14. Glutaryl dichloride 3b is a 1:1-mixture of dl-3b and meso-3b.
15. Several compounds are known in which an O-acyl-N-alkoxy-
alkylidene ketene-N,O-acetal function is incorporated into a
hetarene (e.g., 6-alkoxypyridin-2-yl alkanoic acid esters) or a
heterocycle with aromatic character (e.g., 6-oxo-6H-1,3-
oxazin-4-yl alkanoic acid esters, 4-alkoxy-2-alkylidene-2H-
oxazol-5-ones). To the best of our knowledge, compounds
9b–d are the only examples of stable ketene-N,O-acetals
devoid of such an electronic stabilization.
16. The 1H and 13C NMR signals were assigned by 2D experiments.