Synthesis of Weinreb amides via Pd-catalyzed aminocarbonylation of heterocyclic-derived triflates

Article abstract of DOI:10.1021/jo7024898

(Chemical Equation Presented) The direct transformation of lactam-, lactone-, and thiolactone-derived triflates into N-methoxy-N-methyl or morpholine Weinreb amides has been realized using Pd-catalyzed aminocarbonylation under CO atmospheric pressure and

Full text of DOI:10.1021/jo7024898

Synthesis of Weinreb Amides via Pd-Catalyzed Aminocarbonylation
of Heterocyclic-Derived Triflates
A. Deagostino,† Paolo Larini,† Ernesto G. Occhiato,‡ Lorena Pizzuto,†
Cristina Prandi,*,† and Paolo Venturello†
Dipartimento di Chimica Generale ed Organica Applicata, UniVersita` di Torino, Corso Massimo
D’Azeglio, 48, I-10125 Torino, Italy, and Dipartimento di Chimica Organica “U. Schiff”, and
HeteroBioLab, UniVersita` di Firenze, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy
cristina.prandi@unito.it
ReceiVed NoVember 20, 2007
The direct transformation of lactam-, lactone-, and thiolactone-derived triflates into N-methoxy-N-methyl
or morpholine Weinreb amides has been realized using Pd-catalyzed aminocarbonylation under CO
atmospheric pressure and at room temperature. The carbonylative coupling can be efficiently carried out
with 2% of catalyst in the presence of Xantphos as a ligand. The amides smoothly react with nucleophiles
to afford acylated aza-, oxa-, and thio-heterocycles. The proposed methodology could be advantageously
exploited for the synthesis of dienones in which one of the double bonds is embedded in a heterocyclic
moiety, as useful substrates for Nazarov cyclization.
Introduction
hydroxylamine hydrochloride in the presence of peptide coupling
reagents.6 Taddei e al.7 reported the synthesis of Weinreb amides
in the presence of 2-chloro-4,6-dimethoxy[1.3.5]triazine (CDMT).
The activation of the carboxylic acid has also been accomplished
with Deoxo-Fluor fluorinating reagent.8 Although these methods
have been widely used, especially in the preparation of
N-methoxy-N-methyl amides of N-protected R-amino acids,
most of them require the use of an excess of expensive coupling
reagent. Interestingly, sterically hindered carboxylic acids can
be converted into Weinreb amides via acyl mesylates with good
yields, even if the purification may be complicated by the
formation of N-methoxy-N-methylmethanesulfonamides as
byproduct.9 A one-pot synthesis of R-siloxy-Weinreb amides
from aldehydes has been very recently published.10 N-Methoxy-
N-methyl amides have in addition been prepared using 4,6-
The N-methoxy-N-methyl amides, otherwise known as Wein-
reb amides, are well-established pivotal acylating agents in
organic chemistry, due to their feature of reacting with orga-
nometallic reagents through stable metal-chelated intermediates,
thus providing ketones without side products.1 Since the first
report in 1981,2 the frequency with which they appear in the
literature as key intermediates in advanced syntheses has rapidly
grown. Weinreb amides are readily prepared starting from acyl
chlorides,3 esters,4 oxazolidinones/thiazolidinones,5 or carboxylic
acids by means of one-pot condensation with N,O-dimethyl-
† Universita` di Torino.
‡ Universita` di Firenze.
(1) For reviews on the applications of N-methoxy-N-methyl amides,
see: (a) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15. (b) Sibi, M. P.;
Marvin, M.; Sharma, R. J. Org. Chem. 1995, 60, 5016. (c) Singh, J.;
Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000, 342, 340. (d) Jackson,
M.; Leverett, C.; Toczko, J. F.; Roberts, J. C. J. Org. Chem. 2002, 67,
5032. (e) Khlestkin, V. K.; Mazhukin, D. G. Curr. Org. Chem. 2003, 7,
967.
(2) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(3) Aidhen, I. S.; Ahuja, J. R. Tetrahedron Lett. 1992, 33, 5431.
(4) (a) Iseki, K.; Asada, D.; Kuroki, Y. J. Fluorine Chem. 1999, 97, 85.
(b) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461. (c) Colobert,
F. C.; Des Mazery, R.; Solladie´, G.; Carren˜o, M. C. Org. Lett. 2002, 4,
1723.
(6) (a) Oppolzer, W.; Cunningham, A. F. Tetrahedron Lett. 1986, 27,
5467. (b) Braun, M.; Waldmu¨ller, D. Synthesis 1989, 856. (c) Maugras, I.;
Poncet, J.; Jouin, P. Tetrahedron 1990, 46, 2807. (d) Einhorn, J.; Einhorn,
C.; Luche, J. L. Synth. Commun. 1990, 20, 1105. (e) Sibi, M. P.; Stessman,
C. C.; Schulz, J. A.; Christensen, J. W.; Lu, J.; Marvin, M. Synth. Commun.
1995, 25, 1255. (f) Tunoori, A. R.; White, J. M.; Georg, G. I. Org. Lett.
2000, 2, 4091. (g) Banwell, M.; Smith, J. Synth. Commun. 2001, 31, 2011.
(7) De Luca, L.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001, 66,
2534.
(8) White, J. M.; Tunoori, A. R.; Turunen, B. J.; Georg, G. I. J. Org.
Chem. 2004, 69, 2573.
(5) (a) Paquette, L. A.; Zuev, D. Tetrahedron Lett. 1997, 38, 5115. (b)
Davis, F. A.; Kasu, P. V. N. Tetrahedron Lett. 1998, 39, 6135.
(9) Woo, J. C. S.; Fenster, E.; Dake, G. R. J. Org. Chem. 2004, 69,
8984.
10.1021/jo7024898 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/26/2008
J. Org. Chem. 2008, 73, 1941-1945
1941

Deagostino et al.
SCHEME 1. Aminocarbonylative Coupling on
Lactam-Derived Triflate 1a
FIGURE 1. Heterocyclic Weinreb amides.
perform the reaction at room temperature, and after 3 h, a TLC
and a GC control showed the complete disappearance of the
starting triflate and a 100% conversion. The amide was
recovered with a 55% yield after workup and flash chromatog-
raphy purification. With THF as a solvent, the yield of the amide
2a after flash chromatography purification rose to 78%. The
use of Xantphos proved to be mandatory as experiments
conducted with dppp or dppf in the role of ligands gave only a
12% conversion (determined by GC as an average of two runs)
after 48 h at room temperature with dppp (5%). Longer reaction
times, various catalyst loadings, or different Pd(OAc)2/Xantphos
ratios did not improve the yield. The optimized experimental
conditions were thus applied to the synthesis of a series of
heterocyclic Weinreb amides as reported in Table 1.
Bearing in mind the importance of N-protecting groups in
determining the reactivity of these intermediates in multistep
synthetic sequences, we investigated the feasibility of the
aforementioned experimental conditions to the synthesis of a
series of lactam-derived N-methyl-N-methoxy amides. N-
COOMe and N-tosyl amides 2d and 2e were recovered in good
yields, and in these cases, the crude reaction mixtures could be
filtered through a short pad of Celite and directly used for
subsequent reactions. Different ring sizes are well-tolerated, so
that the pyrrolidinone-derived amide 2b and the caprolactam-
derived amide 2f were isolated in good yields.19 The same
experimental conditions were applied to the synthesis of lactone-
derived amides 2g-i and thiolactone-derived amides 2j-l.
Morpholino enamides are reported to successfully replace
classical Weinreb amides,20 as their use is often preferable due
to, besides their high reactivity, the low cost of morpholine with
respect to N-methoxy-N-methyl amine hydrochloride. To this
end, we envisioned the possibility of using morpholine as an
amine in the aminocarbonylative process: under the experi-
mental conditions set up for N-methoxy-N-methyl amides,
pyrimidyl urethane and Grignard reagents.11 Among palladium
catalysis based strategies, Stille cross-coupling between N-
methoxy-N-methylcarbamoyl chloride with vinyl or aryl stan-
nanes turned out to be an alternative to other synthetic
methods.12 An aminocarbonylative coupling of a dioxinone
moiety in the presence of dppp has been proposed.13 Further-
more, Buchwald proposed a new approach based on the
aminocarbonylation of aryl bromides, in which the efficiency
of the bidentate phosphine Xantphos, known to possess a large
bite angle, has been exploited. The scope of the reaction has
been extended to electron-deficient, -neutral, and -rich aryl
bromides.14 In the context of an ongoing total synthesis project,
we were interested in generating the Weinreb amides, whose
general structure is represented in Figure 1, from the corre-
sponding triflates. This was due to our recent interest in the
Nazarov reaction,15 which prompted us to investigate new and
convenient synthetic sequences leading to conjugated dienones.
To our knowledge, to date, there is only one reference which
concerns the synthesis of substituted N-methoxy-N-methyl-3,4-
dihydro-2H-pyran-6-carboxyamide (X ) O) using a hetero-
Diels-Alder cycloaddition catalyzed by bis(oxazoline) copper-
(II) complexes.16 We therefore decided to undertake an
investigation aimed at evaluating the feasibility of an aminocar-
bonylative coupling for the syntheses of heterocyclic Weinreb
amides and to identify the optimized reaction conditions in order
to establish this as a general method for the synthesis of
heterocyclic acylated derivatives.
Results and Discussion
Preliminary studies were conducted on the triflate prepared
from tert-butyl-2-oxopiperidine-1-carboxylate, according to the
literature procedure.17 The initially chosen conditions were those
proposed by Buchwald in his aminocarbonylative coupling of
aryl bromides;14 hence triflate 1a (Scheme 1) was treated with
2% of Pd(OAc)2, Na2CO3 (3 equiv), and Xantphos as the sup-
porting ligand in toluene as a solvent under 1 atm pressure of
CO.
(17) (a) Prandi, C.; Ferrali, A.; Guarna, A.; Venturello, P.; Occhiato, E.
G. J. Org. Chem. 2004, 69, 7705. (b) Occhiato, E. G.; Prandi, C.; Ferrali,
A.; Guarna, A.; Venturello, P. J. Org. Chem. 2003, 68, 9728. (c) Occhiato,
E. G.; Prandi, C.; Ferrali, A.; Guarna, A.; Deagostino, A.; Venturello P. J.
Org. Chem. 2002, 67, 7144 and references therein.
On the basis of the remarkable reactivity of heterocyclic-
(18) Occhiato, E. G. Mini-ReV. Org. Chem. 2004, 1, 149.
derived triflates in cross-coupling reactions,18 we decided to
(19) In the case of caprolactam N-Cbz-protected triflate 1f (entry 6),
besides the foreseen amide, we came across an unexpected rearranged
product, isolated with 21% yield, whose structure has tentatively been
assigned and is represented in the figure. See Experimental Section. A
similar rearrangement in the presence of Cbz as protecting group leading
to an oxazolidinone framework has already been observed. For more details,
see ref 17c.
(10) Nemoto, H.; Ma, R.; Moriguchi, H.; Kawamura, T.; Kamiya, M.;
Shibuya, M. J. Org. Chem. 2007, 72, 9850.
(11) Lee, J. I. Bull. Korean Chem. Soc. 2007, 28, 695.
(12) Murakami, M.; Hoshino, Y.; Ito, H.; Ito, Y. Chem. Lett. 1998, 163.
(13) (a) Aungst, R. A.; Funk, R. L. J. Am. Chem. Soc. 2001, 123, 9455.
For the carbonylative synthesis of amides, see also: (b) Morera, E.; Ortar,
G. Tetrahedron Lett. 1998, 39, 2835. (c) Haffner, C. Tetrahedron Lett. 1994,
35, 6117. (d) Lan-Hargest, H. Y.; Elliott, J. D.; Egglestone, D. S.; Holt, D.
A.; Levy, M. A.; Metcalf, B. W. Tetrahedron Lett. 1987, 49, 6117.
(14) Martinelli, J. R.; Freckmann, D. M. M.; Buchwald, S. L. Org. Lett.
2006, 8, 4843.
(15) (a) Bartali, L.; Larini, P.; Guarna, A.; Occhiato, E. G. Synthesis
2007, 1733. (b) Bartali, L.; Larini, P.; Guarna, A.; Occhiato, E. G. Eur. J.
Org. Chem. 2007, 2152. (c) Cavalli, A.; Masetti, M.; Recanatini, M.; Prandi,
C.; Guarna, A.; Occhiato, E. G. Chem.sEur. J. 2006, 12, 2836. (d) Prandi,
C.; Deagostino, A.; Venturello, P:, Occhiato, E. G. Org. Lett. 2005, 7, 4345.
(16) Evans, D. A.; Johnson, J. S.; Edward, J. O. J. Am. Chem. Soc. 2000,
122, 1635.
(20) (a) Martin, R.; Romea, P.; Tey, C.; Urp`ı, F.; Vilarrasa, J. Synlett
1997, 1414. (b) Dhoro, F.; Kristensen, T. E.; Stockmann, V.; Yap, G. P.
A.; Tius, M. A. J. Am. Chem. Soc. 2007, 129, 7256. (c) delos Santos, D.
B.; Banaag, A. R.; Tius, M. A. Org. Lett. 2006, 8, 2579. (d) Banaag, A. R.;
Berger, G. O.; Dhoro, F.; delos Santos, D. B.; Dixon, D. D.; Mitchell, J.
P.; Tokeshi, B. K.; Tius, M. A. Tetrahedron 2005, 61, 3419. (e) Bee, C.,
Tius, M. A. Org. Lett. 2003, 5, 1681 and references therein.
1942 J. Org. Chem., Vol. 73, No. 5, 2008

Synthesis of Weinreb Amides
TABLE 1. Synthesis of Heterocyclic Weinreb Amidesa
a Reactions conditions: triflate 1 (1 equiv), Pd(OAc)2 (2%), Xantphos (2%), N-methoxy-N-methyl amine or morpholine (1 equiv), Na2CO3 (3 equiv),
room temperature overnight under a static atmosphere of CO. b Yields refer to flash chromatography purified products. c Experiments were conducted with
anhydrous DCM and Et3N as a base without substantial variations in yield.
morpholino amides 2c, 2i, and 2l were obtained in 57, 90, and
66% yields, respectively. Moreover, the procedure could be
rewardingly applied to the carbocyclic system as well; a 58%
yield of the cyclohexanone-derived amide 2m was obtained,
though in this case a slight amount of carbonylated homocou-
pling product was detected.
of tosyl as a protecting group determined an enhancement in
the reactivity, so that ketone 4e could be obtained although in
low yield. Satisfactory results were at last obtained with allyl
magnesium bromide, as ketones 4b and 4f were isolated in
excellent yields (91 and 90%, respectively), although in the
course of column chromatography purification, a partial isomer-
ization of the terminal double bond occurred. Concerning the
unexpected low reactivity of N-carbamate-protected Weinreb
amides, it is noteworthy to underline that the saturated analogue
Cbz-protected proline-derived Weinreb amide is reported to react
with organomagnesium reagents under mild conditions.7 On the
basis of our experimental data, we could only presume that both
conformational aspects and metal chelation phenomena due to
the carbamate N-protecting group are accountable to explain
the observed reactivity.21
In order to explore the feasibility of the synthesized hetero-
cyclic amides as useful intermediates in multistep syntheses
involving acylated synthones, we decided to inspect the reactiv-
ity of the amides reported in Table 1 with organometallic
reagents, namely, Grignard and organolithium reagents. In recent
years, we have been largely concerned with the study of the
Nazarov reaction, so that we were particularly interested in new
and efficient synthetic routes leading to functionalized divinyl
ketones. These arguments strongly influenced the choice of the
nucleophiles used to investigate the heterocyclic Weinreb
amides’ potential. First, experiments were conducted on nitrogen
amides 2a and 2d (Table 2) with discouraging results: with
carbamates as protecting groups (Boc, COOMe), the amides
showed an inadequate reactivity and were recovered unchanged
(apart from methyl 6-acryloyl-3,4-dihydropyridine-1(2H)-car-
boxylate 4d obtained in low yield from amide 2d) even under
drastic reaction conditions such as the use of an excess of a
strong organometallic reagent (up to 5 equiv of BuLi, vinyl, or
ethylmagnesium bromide) or high temperatures. The presence
Satisfactory results have been obtained with oxygen, thio-,
or carbocycle amides 2g-m. The reactions with ethyl, allyl, or
vinyl magnesium bromide all proceeded smoothly at -78 °C
and afforded quite pure ketones in less than 1 h. Provided that
the sequence is feasible, the vinylation reaction using the
commercially available and cheap vinyl magnesium bromide
(21) Coupling of indazolyl N-Boc-protected Weinreb amides with
organometallic nucleophiles has recently been reported. See: Crestey, F.;
Stiebing, S.; Legay, R.; Collot, V.; Rault, S. Tetrahedron 2007, 63, 419.
J. Org. Chem, Vol. 73, No. 5, 2008 1943

Deagostino et al.
TABLE 2. Conversion of Heterocyclic Amides into Functionalized
Ketonesa
into N-methoxy-N-methyl or morpholine Weinreb amides by
Pd-catalyzed aminocarbonylation in the presence of Xantphos
as a ligand. The amides smoothly reacted with nucleophiles to
afford acylated aza-, oxa-, and thio-heterocycles. This methodol-
ogy opens the access to interesting functionalized heterocyclic
frameworks that are useful as building blocks in total syntheses.
Experimental Section
General Procedure for the Synthesis of N-Methoxy-N-methyl
amides 2a, 2b, 2d, 2e, 2f, 2g, 2h, 2j, 2k, and 2m. An oven-dried
three-necked round-bottom flask with one tap was equipped with
a magnetic stir bar and was filled with argon. All solid reagents
were added by briefly removing the rubber septum under a flow
of argon: Pd(OAc)2 (0.02 equiv, 0.02 mmol, 4.50 mg), Xantphos
(0.02 equiv, 0.02 mmol, 5.8 mg), N-methoxy-N-methyl amine
hydrochloride (1 equiv, 1 mmol, 97 mg), Na2CO3 (3 equiv, 3 mmol,
318 mg), and THF (10 mL). Then, the reaction was purged for ca.
10 min with CO(g). A solution of triflate (1 equiv, 1 mmol) in 3
mL of THF was then added. A balloon filled with CO(g) was
connected to the reaction vessel, and the reaction mixture was stirred
at room temperature until complete consumption of the triflate as
judged by TLC analysis. The reaction mixture was then diluted
with ethyl acetate (ca. 10 mL), filtered through a plug of Celite
(eluting with ethyl acetate), and concentrated under reduced
pressure. The crude material obtained was purified by flash
chromatography on silica gel.
General Procedure for the Synthesis of Morpholino Amides
2c, 2i, and 2l. The procedure is the same as that applied to the
synthesis of N-methoxy-N-methyl amides, apart from the use of
morpholine (1 equiv, 1 mmol, 87 mg) as an amine.
N-Methoxy-N-methyl-1-tosyl-4,5-dihydro-1H-pyrrole-2-car-
boxamide (2b). After purification by flash chromatography with
petroleum ether/ethyl acetate 1:1 (Rf ) 0.22), 232 mg (75%) of a
yellow oil was recovered: 1H NMR (200 MHz, CDCl3) δ 7.78 (d,
J ) 8.2 Hz, 2H), 7.28 (d, J ) 8.2 Hz, 2H), 5.60 (t, J ) 1.8 Hz,
1H), 3.75 (s, 3H), 3.68 (t, J ) 8.7 Hz, 2H), 3.25 (s, 3H), 2.35 (s,
3H), 2.15 (t, J ) 8.8 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ 173.2,
143.9, 138.3, 132.5, 129.4, 128.1, 119.1, 65.5, 49.2, 47.1, 28.3,
21.4; IR (neat) 3624, 3090, 2937, 1740, 1658, 1387, 1207, 1089,
1029 cm-1; MS (m/z) 310 (M+, 16), 225 (40), 250 (72), 183 (61),
123 (98), 91 (100). Anal. Calcd for C14H18N2O4S: C, 54.18; H,
5.85; N, 9.03. Found: C, 54.36; H, 5.65; N, 9.16.
Benzyl 7-(methoxy(methyl)carbamoyl)-2,3,4,5-tetrahydro-1H-
azepine-1-carboxylate (2f). After purification by flash chroma-
tography with petroleum ether/ethyl acetate 2:1 (Rf ) 0.25), 229
mg (72%) of a yellow oil was recovered: 1H NMR (200 MHz,
CDCl3) δ 7.23 (s, 5H), 6.07 (t, J ) 6.4 Hz, 1H), 5.02 (s, 2H),
3.60-3.51 (m, 2H), 3.22 (s, 3H), 2.85 (s, 3H), 2.22-2.17 (m, 2H),
1.75-1.69 (m, 2H), 1.51-1.48 (m, 2H); 13C NMR (50 MHz,
CDCl3) δ 167.7, 153.8, 137.5, 135.8, 130.6, 128.5, 128.18, 127.9,
67.5, 60.1, 48.1, 33.3, 28.8, 27.0, 23.2; MS (m/z) 318 (M+, 2), 287
(5), 258 (25), 107 (60), 91 (100). Anal. Calcd for C17H22N2O4: C,
64.13; H, 6.97; N, 8.80. Found: C, 64.38; H, 6.85; N, 8.76.
N-Methoxy-N-methyl-3,4-dihydro-2H-pyran-6-carboxam-
ide (2g). After purification by flash chromatography with petroleum
ether/ethyl acetate 3:1 (Rf ) 0.3), 130 mg (76%) of a yellow oil
was recovered: 1H NMR (200 MHz, CDCl3) δ 5.53 (t, J ) 4.0
Hz, 1H), 4.07 (t, J ) 5.1 Hz, 2H), 3.77 (s, 3H), 3.23 (s, 3H), 2.15
(t, J ) 3.4 Hz, 2H), 1.86 (t, J ) 3.45 Hz, 2H); 13C NMR (50 MHz,
CDCl3) δ 165.6, 147.7, 106.4, 66.1, 61.1, 34.3, 21.6, 20.2; MS
(m/z) 171 (M+, 15), 111 (75), 83 (10), 55 (100). Anal. Calcd for
C8H13NO3: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.36; H, 7.55;
N, 8.16.
a The reactions were conducted under an argon atmosphere at -78 °C;
upon the addition of the amide, the temperature was progressively raised
on the basis of the TLC control of the reaction progress. b Yields refer to
flash chromatography column purification.
could be considered of remarkable synthetic worth. In the case
of amide 2i, the reaction with THP-protected lithium but-3-yn-
1-ol efficiently proceeded at -78 °C and was complete within
30 min, affording the corresponding conjugated enynone 4i in
an 87% yield after flash chromatography purification.
In conclusion, we have reported the synthesis of a new class
of heterocyclic Weinreb amides, under extremely mild and
convenient reaction conditions and inexpensive reagents. Lac-
tam-, lactone-, and thiolactone-derived triflates were converted
N-Methoxy-N-methyl-3,4-dihydro-2H-thiopyran-6-carboxa-
mide (2j). After purification by flash chromatography with
petroleum ether/ethyl acetate 3:1 (Rf ) 0.3), 131 mg (70%) of a
yellow oil was recovered: 1H NMR (200 MHz, CDCl3) δ 6.33 (t,
1944 J. Org. Chem., Vol. 73, No. 5, 2008

Synthesis of Weinreb Amides
J ) 4.3 Hz, 1H), 3.71 (s, 3H), 3.26 (s, 3H), 3.00-2.73 (m, 2H),
2.30 (dd, J ) 10.6, 6.3 Hz, 2H), 2.01 (m, 2H); 13C NMR (50 MHz,
CDCl3) δ 167.4, 127.8, 126.3, 61.2, 33.9, 26.8, 24.0, 21.7; MS
(m/z) 187 (M+, 39), 127 (100), 99 (88), 71 (65). Anal. Calcd for
C8H13NO2S: C, 51.31; H, 7.00; N, 7.48; S, 17.12. Found: C, 51.46;
H, 7.05; N, 7.24; S, 17.24.
(3,4-Dihydro-2H-thiopyran-6-yl)(morpholino)methanone (2l).
After purification by flash chromatography with petroleum ether/
ethyl acetate 3:1 (Rf ) 0.3), 140 mg (66%) of a yellow oil was
recovered: 1H NMR (200 MHz, CDCl3) δ 5.92 (t, J ) 4.3 Hz,
1H), 3.73-3.51 (m, 8H), 2.98-2.87 (m, 2H), 2.25 (t, J ) 5.4 Hz,
2H), 2.01 (t, J ) 5.4 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ 167.6,
128.4, 122.0, 66.8 (2C), 30.0 (2C), 26.6, 23.4, 21.3; MS (m/z) 213
(M+, 100), 180 (18), 128 (60), 99 (86). Anal. Calcd for C10H15-
NO2S: C, 56.31; H, 7.09; N, 6.57; S, 15.03. Found: C, 56.31; H,
7.05; N, 6.55; S, 15.45.
(∼10 mL), washed twice with brine, the organic layers were then
dried over sodium sulfate and concentrated under reduced pressure.
The crude material obtained was purified by flash chromatography
on silica gel.
1-(3,4-Dihydro-2H-thiopyran-6-yl)prop-2-en-1-one (4j). After
purification by flash chromatography with petroleum ether/ethyl
acetate 5:1 (Rf ) 0.45), 129 mg (78%) of a white oil was
recovered: 1H NMR (200 MHz, CDCl3) δ 6.98 (t, J ) 4.8 Hz,
1H), superimposed to 6.88 (dd, J ) 17.0, 10.5 Hz, 1H), 6.32 (dd,
J ) 17.0, 1.2 Hz, 1H), 5.74 (d, J ) 10.5 Hz, 1H), 2.95-2.85 (m,
2H), 2.43 (dd, J ) 11.2, 5.8 Hz, 2H), 2.08-1.95 (m, 2H); 13C NMR
(50 MHz, CDCl3) δ 187.6, 136.8, 133.9, 129.9, 128.9, 26.0, 25.00,
21.2; MS (m/z) 154 (M+, 82), 126 (48), 99 (62), 71 (81), 55(100).
Anal. Calcd for C18H24O3S: C, 67.47; H, 7.55; O, 14.98; S, 10.01.
Found: C, 67.12; H, 7.38; S, 9.98.
General Procedure for the Synthesis of Heterocyclic Acyl
Derivatives 4b, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, and 4m. An oven-
dried Schlenk flask equipped with a magnetic stir bar was flame-
dried and kept under an argon atmosphere. A solution of the
appropriate Grignard reagent (2 mmol) in anhydrous THF (5 mL)
was introduced and refrigerated at -78 °C with an acetone/liquid
nitrogen bath. A solution of the appropriate Weinreb amide was
then slowly added. The reaction mixture was stirred and, if
necessary, the temperature was progressively raised at room
temperature until complete consumption of amide as judged by TLC
analysis. The reaction mixture was then diluted with ethyl acetate
Acknowledgment. We thank MIUR and University of Turin
for financial support. Dr. Roberto Buscaino is acknowledged
for his technical support in MS spectra.
Supporting Information Available: Characterization data for
compounds 2a, 2c, 2d, 2e, 2h, 2i, 2k, 2m, 3, 4b, 4d, 4e, 4f, 4g,
1
4h, 4i, 4k, and 4m and copies of the H NMR and 13C spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO7024898
J. Org. Chem, Vol. 73, No. 5, 2008 1945