Synthesis of N -Acyl-5-aminopenta-2,4-dienals via base-induced ring-opening of N -acylated furfurylamines: Scope and limitations

Article abstract of DOI:10.1021/jo100634z

N-Acylation of furfurylamines provided 1, which on double deprotonation with LDA led to the formation of N-acyl-5-aminopenta-2,4-dienals 2 via an isomerization involving opening of the furan ring. The scope and limitations of the procedure were examined by considering the influence of substituents on the carbonyl group and also on the heterocycle moiety. The efficacy of the reaction was shown to be very dependent on the nature of these groups.

Full text of DOI:10.1021/jo100634z

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SCHEME 1. Base-Induced Ring-Opening of N-Furfurylpyrrole-
2-carboxamide 4
Synthesis of N-Acyl-5-aminopenta-2,4-dienals via
Base-Induced Ring-Opening of N-Acylated
Furfurylamines: Scope and Limitations
ꢀ
Cecile Ouairy, Patrick Michel, Bernard Delpech,*
David Crich, and Christian Marazano†
Centre de Recherche de Gif, Institut de Chimie des Substances
Naturelles, CNRS, Avenue de la Terrasse,
91198 Gif-sur-Yvette Cedex, France
SCHEME 2. Formation of N-Acylaminopentadienals 6 from
N-Acylfurfurylamines 5
bernard.delpech@icsn.cnrs-gif.fr
Received April 2, 2010
glutaconaldehydes via Zincke salts,3c but their acylation is
expected to lead to the O- rather than the required N-acyl
derivatives.4 The ring-opening of pyridiniums salts with sodium
hydroxide likewise did not appear to be a convenient prepara-
tive method for the N-acylaminopentadienals.5,6 Therefore, we
were forced to search for alternative entries to these potentially
useful synthons and were attracted by the reported formation
of N-benzoylaminopentadienal on treatment of N-furfurylben-
zamide with 2.5-3.0 equiv of LDA in THF between -78 and
-30 °C.7 Here, we report on the scope and limitations of this
ring-opening isomerization procedure as it pertains to the
preparation of N-acylated aminopentadienals.
The ring-opening of N-acylfurfurylamines with a pyrrole-2-
carboxamide moiety was first envisaged to probe the feasibility
of the process. The amide 3 was prepared by acylation of
furfurylamine with N-benzyl-2-trichloroacetylpyrrole, and its
behavior in the presence of 2.9 equiv of LDA in THF was
examined. After deprotonation at -78 °C, increasing the
temperature of the reaction mixture from -78 to -45 °C,
and quenching with 1 N HCl, the (E,E)-N-acylated amino-
pentadienal 4 was obtained in 74% yield (Scheme 1).
N-Acylation of furfurylamines provided 1, which on double
deprotonation with LDA led to the formation of N-acyl-5-
aminopenta-2,4-dienals 2 via an isomerization involving
opening of the furan ring. The scope and limitations of the
procedure were examined by considering the influence of
substituents on the carbonyl group and also on the hetero-
cycle moiety. The efficacy of the reaction was shown to be
very dependent on the nature of these groups.
5-Aminopenta-2,4-dienals are regarded as key intermedi-
ates in the biomimetic schemes developed in the laboratory
toward the manzamine alkaloids.1 In an attempt to extend
these approaches to the pyrrole-imidazole alkaloids such as
oroidin,2 we required a facile entry into N-(pyrrole-2-carbonyl)-
5-aminopenta-2,4-dienals.
The success of this base-induced rearrangement with a
pyrrole-2-carboxamide prompted us to study this isomeriza-
tion method further and to probe the scope and limitations of
compatible N-acylfurfurylamines and their substituents.
The effect of the substituent R1 on the carbonyl group as
well as the possibility of extending the reaction to differently
(3) (a) For a review on aminopentadienals, see: Becher, J. Synthesis 1980,
589–612. (b) The parent compound is rather unstable: Reinehr, D.; Winkler,
T. Angew. Chem., Int. Ed. 1981, 20, 881–882. (c) Nguyen, T. M.; Peixoto, S.;
Existing literature methods for the synthesis of 5-amino-
penta-2,4-dienals appeared to be unsuitable for our purpose.3
For example, these compounds are usually obtained from
ꢀ ꢀ
Ouairy, C.; Nguyen, T. D.; Benechie, M.; Marazano, C.; Michel, P. Synthesis
2010, 103–109. (d) For a recent use of aminopentadienals in alkaloid
synthesis, see: Martin, D. B. C.; Vanderwal, C. D. J. Am. Chem. Soc.
2009, 131, 3472–3473.
(4) Nuhant, P.; Raikar, S. B.; Wypych, J.-C.; Delpech, B.; Marazano, C.
J. Org. Chem. 2009, 74, 9413–9421.
(5) N-Acylpyridiniums are acylating reagents, and to the best of our
knowledge, only a N,N-dimethylcarbamoyl derivative has been used for such
a reaction: (a) Johnson, S. L.; Rumon, K. A. Tetrahedron Lett. 1966, 1721–
1726. (b) Johnson, S. L.; Rumon, K. A. Biochemistry 1970, 9, 847–857.
(c) Colabroy, K. L.; Begley, T. P. J. Am. Chem. Soc. 2005, 127, 840–841.
(6) The N-benzoyl derivative of 5-aminopenta-2,4-dienal was formed via
a pyridinium salt in a colorimetric Fujiwara reaction (pyridine and R,R,R-
trichlorotoluene in aqueous sodium hydroxide): Uno, T.; Okumura, K.;
Kuroda, Y. J. Org. Chem. 1981, 46, 3175–3178.
† Deceased November 12, 2008.
(1) (a) Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano, C.; Das,
B. C. J. Am. Chem. Soc. 1998, 120, 8026–8034. (b) Jakubowicz, K.; Ben
Abdeljelil, K.; Herdemann, M.; Martin, M.-T.; Gateau-Olesker, A.;
Al Mourabit, A.; Marazano, C.; Das, B. C. J. Org. Chem. 1999, 64, 7381–
ꢀ ꢀ
7387. (c) Wypych, J.-C.; Nguyen, T. M.; Nuhant, P.; Benechie, M.;
Marazano, C. Angew. Chem., Int. Ed. 2008, 47, 5418–5421.
(2) (a) For reviews on the synthesis of these compounds, see: Feldman,
K. S.; Fodor, M. D.; Skoumbourdis, A. P. Synthesis 2009, 3162–3173.
Weinreb, S. M. Nat. Prod. Rep. 2007, 24, 931–948. Hoffmann, H.; Lindel,
T. Synthesis 2003, 1753–1783. (b) For biosynthetic proposals, see: Al
Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237–243.
(7) Ohno, K.; Machida, M. Tetrahedron Lett. 1981, 22, 4487–4488.
DOI: 10.1021/jo100634z
r
Published on Web 05/25/2010
J. Org. Chem. 2010, 75, 4311–4314 4311
2010 American Chemical Society

Ouairy et al.
JOCNote
TABLE 1. Yields of N-Acylaminopentadienals 6 from Ring Opening of Furans 5
entry
furan
R1
R2
R3
R4
T (°C)a
product
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
5a
5b
5c
5d
5e
CH3
C(CH3)3
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
0
-50
-55
0
6ab
6b
6c
b
b
6f
6g (4)
b
b
6
47
66
4-CH3OC6H4
4-O2NC6H4
pyrrole-2-yl
N-methylpyrrole-2-yl
N-benzylpyrrole-2-yl
CF3
OC(CH3)3
N(CH3)2
Ph
0
5f
-45
-45
0
0
0
-45
0
-55
43
74
5g (3)
5h
5i
5j
5k
5l
6j
44
75
6kc
b
Ph
Ph
4-ClC6H4
H
5m
6m
69
aSee Scheme 2. bStarting material recovered. cMixture of isomers E/Z = 2/1.
SCHEME 3. Possible Mechanism for the Formation ofN-Acylmino-
pentadienals
substituted furans were examined (Scheme 2). The N-acyla-
mines 5 were generally prepared by acylation of the corre-
sponding furfurylamines (see the Supporting Information).
Compounds 5 were treated in the presence of 2.9 equiv of
LDA in THF at -78 °C, and the reaction mixture was
allowed to warm until disappearance of the starting material
(when the ring-opening was effective), as estimated by TLC.
This reaction was accompanied by a color change,6,7 whose
nature depends on the type of compound. Quenching was
carried out either with 1 N HCl or saturated NH4Cl, and the
results are reported in Table 1. Except for entry 1, the
behavior of the furfuryl compounds was clear-cut since
either a ring-opening was observed or the starting furan
was recovered. The aminopentadienals 6 were obtained as
clean (E,E) isomers, except in the case of compound 6k
whose trisubstituted double bond was obtained as a 2/1
mixture of geometric isomers.
From Table 1, it appears that the ring opening generally
affords the desired N-acylaminopentadienals when R1 is a
phenyl ring7 or an electron-donating group. However, it
seems that with an electron-withdrawing substituent on the
carbonyl group capable of stabilizing a negative charge
(entries 4 and 8), the opening of the heterocycle is prevented.
The same observation was also made for the imine 7 and for
the sulfonamide 8, which were recovered after treatment with
(compare entry 5 with entries 6 and 7). The case of the Boc
derivative 5i (entry 9) is particular since the tert-butoxy
group is an electron-donating one; failure is probably due
to difficulties in deprotonating R to nitrogen.9
For the benzamides substituted on the heterocycle moiety
(entries 11-13), the base-induced ring-opening was effective
with the compounds possessing a methyl group at C-3 and
C-5 (furan numbering, entries 11 and 13, respectively) but
not with the C-4-substituted derivatives (entry 12). In the
case of the formation of the N-benzoylaminopentadienal 6k
(entry 11), the product was isolated as a 2/1 mixture of E and
Z isomers for the trisubstituted double bond. It is empha-
sized that the procedure is also useful for the preparation of
N-acylaminopentadienones, as exemplified by the formation
of 6m (entry 13).
Concerning the mechanism of the reaction (Scheme 3),
deprotonation of 1 at nitrogen followed by lateral lithiation
of intermediate 10 should lead to the dilithiated species 11,
which we hypothesize then undergoes opening of the furan
ring into an N-substituted lithium penta-1,3,4-trien-1-olate
12. The thermodynamic balance of this step is expected to be
favorable (lithium carbanion for 11 vs conjugated lithium
enolate for 12), even though the resonance energy of furan is
lost. However, it could be a reversible process (5-exo-dig
cyclization).10 This mechanism is analogous to that pro-
posed for the ring-opening of furfuryl carbanions stabilized
by a dithiane,11 a phenyl, or a trimethylsilyl group12 and
from which allenyl derivatives have been isolated after
€
LDA. This behavior recalls the observation of Schollkopf
whereby the potassium derivative 9, obtained by deprotonation
of the corresponding isocyanide with t-BuOK, was stable in
THF up to -10 °C.8
For the acetamide 5a (entry 1), the yield was very low
probably due to competitive deprotonation of the methyl
group and to the aqueous solubility of the aminopentadienal
(compare with the pivalamide 5b of entry 2). The pyrrole-2-
carboxamide must be N-protected for efficient ring-opening
(10) (a) Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1993, 58, 3435–3443.
(b) Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am. Chem. Soc.
2006, 128, 8132–8133. (c) For the formation of a furan by intramolecular
cyclization of an enol onto an allene, see: Mageswaran, S.; Ollis, W. D.;
Southam, D. A.; Sutherland, I. O.; Thebtaranonth, Y. J. Chem. Soc, Perkin
Trans. 1 1981, 1969–1980. (d) For cyclization reactions of allenes, see: Ma, S.
Acc. Chem. Res. 2009, 42, 1679–1688. and references therein.
(11) Taschner, M. J.; Kraus, G. A. J. Org. Chem. 1978, 43, 4235–4236.
(12) (a) Atsumi, K.; Kuwajima, I. Chem. Lett. 1978, 387–390. (b) Atsumi,
K.; Kuwajima, I. J. Am. Chem. Soc. 1979, 101, 2208–2210.
€
(8) Schollkopf, U.; Frieben, W. Liebigs Ann. Chem. 1980, 1722–1727.
(9) Treatment of 5i with 2.2 equiv of BuLi in THF from -78 to -10 °C led
to recovery of the starting material. This base has been used for N-silylation of
5i and for C-lithiation of the resulting product to achieve a reverse aza-Brook
rearrangement: Liu, G.; Sieburth, S. McN. Org. Lett. 2005, 7, 665–668. How-
ever, double deprotonation of tert-butyl benzylcarbamate required 3 equiv of
s-BuLi in the presence of 2.1 equiv of TMEDA: Kanazawa, A. M.; Correa, A.;
Denis, J.-N.; Luche, M.-J.; Greene, A. E. J. Org. Chem. 1993, 58, 255–257.
4312 J. Org. Chem. Vol. 75, No. 12, 2010

Ouairy et al.
JOCNote
quenching with trimethylsilyl chloride. After the hydrolytic
treatment, a sequence of prototropy-isomerization should
lead, via intermediate 13, to the most stable form (N-acylamino-
pentadienal) and isomer (E,E) of the product 2.13
the mixture was allowed to stir while slowly warming until
disappearance of the starting material (up to the temperature
indicated in Table 1). A color change, depending on the type of
compound, was also observed during this period. Diethyl ether
and 1 N HCl (A), or CH2Cl2 and saturated NH4Cl (B), were then
added. The organic layer was separated, dried (MgSO4), con-
centrated in vacuo, and purified by silica gel column chroma-
tography to afford the N-acylated aminopentadienal 7.
The fact that ring-opening was not observed with an
electron-withdrawing group R (4-O2NC6H4 and CF3, re-
spectively, for 5d and 5h) could be imputed to the increased
stability of the dilithiated species 11, which likely renders the
passage from 11 to 12 thermodynamically unfavorable. A
similar argument can also be used to explain the lack of
reactivity of compounds 7 and 8. In the case of the Boc
derivative 5i, the failure of the reaction might be attributed to
the ineffectiveness of the C-lithiation (slowed formation of
11 with R = t-BuO).9 For the urea 5j, the formation of the
corresponding aminopentadienal 6j needs a higher tempera-
ture (0 °C, entry 10 of Table 1), perhaps owing to a more
difficult lateral lithiation with a more electron-rich species 10
with R = NMe2.
For the heterocycle-substituted compounds 5k-m, the ring-
opening presumably proceeds with an increase in strain in
the transition state (C-C/C-H 1,2-interactions), due to the
increase of internal bond angles of the opening heterocycle as the
C-O bond breaks. This strain is expected to be more important
for 5l (two interactions) than for 5k or 5m (one interaction) and
might hinder the opening step in the former cases.
In conclusion, the ring-opening of N-acylfurfurylamines
with LDA provides a convenient entry into the N-acyl-5-
aminopenta-2,4-dienals when there is a phenyl or an electron-
donating substituent on the carbonyl group. The fine-tuning
observed between the nature of the substituents and the facility
of the isomerization depends on a combination of electronic
and steric effects. This procedure allows the preparation of
compounds not easily available by other methods, and can
be extended to the formation of N-acylaminopentadienones.
These products might be useful to achieve Diels-Alder
reactions,14 and reduction to the corresponding alcohols
with a dienamide moiety,15 followed by linking to a dienophile,
could allow intramolecular cycloadditions.16,17
N-((1E,3E)-5-Oxopenta-1,3-dienyl)pivalamide (6b). The general
procedure was followed with diisopropylamine (540 μL, 3.85
mmol, 2.80 equiv), BuLi (1.6 M/hexanes) (2.50 mL, 4.00 mmol,
2.90 equiv), and 250 mg (1.38 mmol) of N-(furan-2-ylmethyl)-
pivalamide 5b. The reaction mixture was allowed to warm from
-78 to -50 °C and turned from yellow to red. After treatment B
andchromatographyonsilica gel (CH2Cl2/acetone 90/10), 6b (118
mg, 47%) was obtained as a yellow powder: mp 138.9-140.2 °C;
1H NMR (CDCl3, 300 MHz) δ 9.51 (d, J = 8.2 Hz, 1 H), 7.61 (br
s, 1 H), 7.48 (t, J = 12.5 Hz, 1 H), 7.14 (dd, J = 12.5, 15.0 Hz 1 H),
6.07 (m, 2 H), 1.27 (s, 9 H); 13C NMR (CDCl3, 75 MHz) δ 193.4
(C), 176.1 (C), 151.7 (CH), 134.9 (CH), 129.2 (CH), 110.5 (CH),
39.3 (C), 27.4 (3 CH3); FTIR 3275, 1695, 1667, 1596, 983 cm-1
;
MS (ESIþ) m/z182.1 (M þ H)þ,204.1(Mþ Na)þ,220.1(Mþ K)þ,
236.1 (M þ Na þ MeOH)þ; HRMS (ESIþ) calcd for C10H15-
NNaO2 (M þ Na)þ 204.1000, found 204.0994.
4-Methoxy-N-((1E,3E)-5-oxopenta-1,3-dienyl)benzamide (6c).
The general procedure was followed with diisopropylamine
(425 μL, 3.03 mmol, 2.78 equiv), BuLi (1.6 M/hexanes) (2.00 mL,
3.20 mmol, 2.94 equiv), and 252 mg (1.09 mmol) of N-(furan-2-
ylmethyl)-4-methoxybenzamide 5c. The reaction mixture was
allowed to warm from -78 to -55 °C and turned from blue to
green. After treatment B and chromatography on silica gel
(CH2Cl2/acetone 90/10), 6c (167 mg, 66%) was obtained as a
1
beige powder: mp 170.0-171.7 °C; H NMR (DMSO-d6, 300
MHz) δ 10.92 (d, J = 10.2 Hz, 1 H), 9.45 (d, J = 8.2 Hz, 1 H), 7.97
(d, J = 8.9 Hz, 2 H), 7.71 (dd, J = 13.6, 10.2 Hz, 1 H), 7.51 (dd,
J = 14.6, 11.4 Hz, 1 H), 7.08 (d, J = 8.9 Hz, 2 H), 6.38 (dd, J =
13.6, 11.4 Hz, 1 H), 6.09 (dd, J = 14.6, 8.2 Hz, 1 H), 3.85 (s, 3 H);
13C NMR (DMSO-d6, 75 MHz) δ 193.2 (C), 174.5 (C), 163.8 (C),
154.0 (CH), 137.3 (CH), 130.0 (2 CH), 127.6 (CH), 124.6 (C), 113.9
(2 CH), 110.7 (CH), 55.5 (CH3); FTIR: 3306, 1678, 1633, 1604,
1530, 1494, 1254, 1024, 972 cm-1; MS (ESIþ) m/z 232.1 (M þ H)þ,
254.1 (M þ Na)þ, 270.1 (M þ K)þ, 286.1 (M þ Na þ MeOH)þ;
HRMS (ESIþ) calcd for C13H13NNaO3 (M þ Na)þ 254.0793,
found 254.0793.
Experimental Section
1-Benzyl-N-((1E,3E)-5-oxopenta-1,3-dienyl)-1H-pyrrole-2-car-
boxamide (6g) (4). The general procedure was followed with
diisopropylamine (420 μL, 3.00 mmol, 2.80 equiv), BuLi (2.5
M/hexanes) (1.25 mL, 3.12 mmol, 2.92 equiv), and 302 mg (1.07
mmol) of N-(furan-2-ylmethyl)-1-benzyl-1H-pyrrole-2-carboxamide
5g (3). The reaction mixture was allowed to warm from -78 to
-45 °C and turned from red to orange. After treatment A and
chromatography on silica gel (AcOEt/pentane 30/70 to AcOEt),
6g (222 mg, 74%) was obtained as a red powder: mp 164.2-
165.2 °C; 1H NMR (DMSO-d6, 300 MHz) δ 10.61 (d, J = 10.5
Hz, 1 H), 9.41 (d, J = 8.2 Hz 1 H), 7.61 (dd, J = 13.4, 10.5 Hz,
1 H), 7.45 (t, J = 11.3 Hz, 1 H), 7.29 (m, 3 H), 7.23 (m, 1 H), 7.17
(dd, J = 4.1, 1.7 Hz, 1 H), 7.09 (d, J = 8.3 Hz, 2 H), 6.29 (dd, J =
13.4 Hz, 11.3 Hz, 1 H), 6.22 (m, 1 H), 6.04 (dd, J = 14.9, 8.2 Hz,
1H), 5.60 (s, 2 H); 13C NMR (DMSO-d6, 75 MHz) δ 193.0 (C),
158.1 (C), 154.2 (CH), 139.1 (C), 137.1 (CH), 130.3 (C), 128.4 (2
CH), 127.1 (CH), 127.0 (CH), 126.6 (2 CH), 123.2 (CH), 116.0
(CH), 109.6 (CH), 108.2 (CH), 51.1 (CH2); FTIR 3310, 1668,
1652, 1592, 1530, 1493, 1159, 1073, 995, 742 cm-1; MS (ESIþ) m/z
303.1 [M þ Na]þ; HRMS (ESIþ) calcd for C17H16N2NaO2
(M þ Na)þ 303.1109, found 303.1105.
General Procedure for the Base-Induced Ring-Opening of
N-Acylated Furfurylamines. To a stirred solution of diisopropy-
lamine (2.80 equiv) in THF (ca. 0.3 M), under an argon atmo-
sphere between -10 and -20 °C, was added BuLi (2.95 equiv).
The resulting reaction mixture was stirred for 20 min between
-10 and -20 °C and then cooled to -78 °C. A ca. 0.3 M solu-
tion of the N-acylated furfurylamine 5 (see the Supporting
Information for its preparation) in THF was then added, and
(13) A sigmatropic [1,5] hydrogen shift from the enol corresponding to 12,
followed by Z-E isomerization, could also account for the formation of 2.
See, for example: Maynard, D. F.; Okamura, W. H. J. Org. Chem. 1995, 60,
1763–1771.
(14) Gauvry, N.; Huet, F. J. Org. Chem. 2001, 66, 583–588. (b) Aıt
Youcef, R.; Boucheron, C.; Guillarme, S.; Legoupy, S.; Dubreuil, D.; Huet,
F. Synthesis 2006, 633–636.
(15) Aıt Youcef, R.; Boucheron, C.; Guillarme, S.; Legoupy, S.; Dubreuil, D.;
Huet, F. Synthesis 2006, 633–636.
(16) For reviews, see: (a) Petrzilka, M.; Grayson, J. I. Synthesis 1981,
753–786. (b) Campbell, A. L.; Lenz, G. R. Synthesis 1987, 421–452.
(17) This type of approach has been reported with O-acyl glutaconalde-
hydes, principally by Becher’s group: (a) Ingedoh, A.; Becher, J.; Clausen,
H.; Nielsen, H. C. Tetrahedron Lett. 1985, 26, 1249–1252. (b) Becher, J.;
Nielsen, H. C.; Jacobsen, J. P.; Simonsen, O.; Clausen, H. J. Org. Chem.
1998, 53, 1862–1871. (c) Jørgensen, T.; Nielsen, H. C.; Malhotra, N.; Becher,
J.; Begtrup, M. J. Heterocycl. Chem. 1992, 29, 1841–1845. (d) Berthon, L.;
Tahri, A.; Ugen, D. Tetrahedron Lett. 1994, 35, 3937–3940.
1,1-Dimethyl-3-(1E,3E)-5-oxopenta-1,3-dienyl)urea (6j). The
general procedure was followed with diisopropylamine (585 μL,
4.17 mmol, 2.80 equiv), BuLi (2.5 M/hexanes) (1.75 mL,
J. Org. Chem. Vol. 75, No. 12, 2010 4313

Ouairy et al.
JOCNote
4.38 mmol, 2.94 equiv), and 250 mg (1.49 mmol) of N-(furan-2-
ylmethyl)-1,1-dimethylurea (5j). The reaction mixture was
allowed to warm from -78 to 0 °C and turned from pale pink
to yellow. After treatment A and chromatography on silica gel
(CH2Cl2/MeOH 95/5), 6j18 (109 mg, 44%) was obtained as a
yellow powder: mp 113.0-113.7 °C; 1H NMR (CDCl3, 300
MHz) δ 9.39 (d, J = 8.2 Hz, 1 H), 8.23 (d, J = 10.9 Hz, 1 H), 7.52
(dd, J = 13.5, 10.9 Hz, 1 H), 7.15 (dd, J = 14.5, 11.4 Hz 1 H),
5.94 (m, 2 H,), 2.99 (s, 6 H); 13C NMR (CDCl3, 75 MHz) δ 193.8
(C), 154.8 (C), 154.1 (CH), 139.9 (CH), 126.2 (CH), 107.2 (CH),
36.5 (2 CH3); FTIR 3277, 1657, 1599, 1244, 861 cm-1; MS
(ESIþ) m/z 191.1 (M þ Na)þ, 223.1 [M þ Na þ MeOH]þ;
HRMS (ESIþ) calcd for C8H12N2NaO2 (M þ Na)þ 191.0796,
found 191.0788.
N-((1E,3E/Z)-3-Methyl-5-oxopenta-1,3-dienyl)benzamide (2/1)
(6k). The general procedure was followed with diisopropylamine
(355 μL, 2.55 mmol, 2.80 equiv), BuLi (2.5 M/hexanes) (1.25 mL,
3.12 mmol, 2.92 equiv), and 195 mg (0.906 mmol) of N-((3-
methylfuran-2-yl)methyl)benzamide 5k. The reaction mixture
was allowed to warm from -78 to -45 °C and turned from blue
to orange. After treatment B with CHCl3, instead of CH2Cl2, and
chromatography on silica gel (pentane/AcOEt 80/20), 6k (146 mg,
75%) was obtained as a yellow oil and as a 2/1 (E/Z) mixture: 1H
NMR (CDCl3, 300 MHz) δ for the major isomer 10.06 (d, J = 8.4
Hz, 1 H), 8.46 (d, J = 11.3 Hz, 1 H), 7.90 (m, 2 H), 7.80 (dd, J =
14.4, 11.3 Hz, 1 H), 7.50 (m, 3 H), 6.11 (d, J = 14.4 Hz, 1 H), 5.89
(d, J= 8.4 Hz, 1 H), 2.33 (s, 3 H); for the minor isomer 9.98 (d, J =
6.8 Hz, 1 H), 8.63 (d, J = 11.3 Hz, 1 H), 8.09 (dd, J = 8.1, 1.6 Hz,
2 H), 7.74 (dd, J = 14.4, 11.3 Hz, 1 H), 7.60 (m, 3 H), 7.18 (d, J =
14.4 Hz, 1 H), 5.83 (d, J = 6.8 Hz, 1 H), 2.15 (s, 3 H); 13C NMR
(DMSO-d6, 75 MHz) δ for the major isomer 191.0 (C), 164.5
(C), 141.3 (C), 132.7 (C), 131.1 (CH), 128.6 (2 CH), 128.4 (CH),
127.8 (2 CH), 126.7 (CH), 115.7 (CH), 20.4 (CH3); for the
minor isomer 189.1 (C), 155.4 (C), 140.6 (C), 132.4 (C), 129.2
(CH), 128.6 (2 CH), 128.3 (CH), 127.8 (2 CH), 125.2 (CH),
108.5 (CH), 12.6 (CH3); FTIR 3311, 1679,1593, 1514, 1485,
1139, 1175, 689 cm-1; MS (ESIþ) m/z 238.1 (M þ Na)þ; HRMS
(ESIþ) calcd for C13H13NNaO2 (M þ Na)þ 238.0844, found
238.0833.
N-((1E,3E)-5-Oxohexa-1,3-dienyl)benzamide (6m). The gen-
eral procedure was followed with diisopropylamine (455 μL,
3.25 mmol, 2.80 equiv), BuLi (1.6 M/hexanes) (2.70 mL, 4.32
mmol, 3.70 equiv), and 250 mg (1.16 mmol) of N-((5-methylfur-
an-2-yl)methyl)benzamide (5m). The reaction mixture was al-
lowed to warm from -78 to -55 °C and turned from blue to
orange. After treatment B and chromatography on silica gel
(CH2Cl2/acetone 95/5), 6m (174 mg, 69%) was obtained as a
yellow powder: mp 172.4-173.0 °C; 1H NMR (DMSO-d6, 300
MHz) δ 10.92 (d, J = 10.4 Hz, 1 H), 7.96 (dd, J = 7.2, 1.7 Hz,
2 H), 7.67 (dd, J = 13.5, 10.4 Hz, 1 H), 7.57 (m, 3 H), 7.44 (dd,
J = 11.4, 15.1 Hz, 1 H), 6.29 (dd, J = 11.4, 13.5 Hz, 1 H), 6.04 (d,
J = 15.1 Hz, 1 H), 2.20 (s, 3 H); 13C NMR (DMSO-d6, 75 MHz)
δ 197.4 (C), 164.3 (C), 144.3 (CH), 135.5 (CH), 132.7 (C), 132.3
(CH), 128.6 (2 CH), 127.8 (2 CH), 127.1 (CH), 111.6 (CH), 26.6
(CH3); FTIR 3297, 1680, 1595, 1506, 1484, 1248, 1001, 699
cm-1; MS (ESIþ) m/z 238.1 (M þ Na)þ, 270.1 (M þ Na þ
MeOH)þ; HRMS (ESIþ) calcd for C13H13NNaO2 (M þ Na)þ
238.0844, found 238.0835.
Supporting Information Available: Experimental details for
the preparation of 3, 5a-m, 6a,f, 7, and 8 and copies of 1H and
13C NMR spectra for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) Compound 6j has been obtained in D2O solution, as a mixture with
the enolic tautomer, and the 1H NMR spectra and chemical shifts of these
compounds in this solvent are reported in ref 5c.
4314 J. Org. Chem. Vol. 75, No. 12, 2010