Three-component coupling reaction and cyclization of N-tosylimines and TMS-substituted propiolate mediated by DABCO

Article abstract of DOI:10.1021/jo702649q

A new three-component coupling reaction of methyl 3- trimethylsilylpropiolate, N-tosylimine, and tosylamide mediated by DABCO was developed. This reaction was based on the consecutive α- and β-activation method of propiolate involving intramolecular silyl

Full text of DOI:10.1021/jo702649q

to be a good substrate for amine-catalyzed reactions.6 In this
context, we have discovered a new type of reaction between
methyl 3-trimethylsilylpropiolate and N-tosylimines.7 In this
paper, we describe a three-component coupling reaction of
propiolates, N-tosylimines, and sulfonamides mediated by
DABCO8 and the application for chromene-forming reaction.
Three-Component Coupling Reaction and
Cyclization of N-Tosylimines and
TMS-Substituted Propiolate Mediated by
DABCO
Yuji Matsuya,* Kousuke Hayashi, Akiho Wada, and
Hideo Nemoto*
First, we examined the reaction of methyl 3-trimethylsilyl-
propiolate with phenyl N-tosylimine (1) in the presence of
tertiary amine such as DABCO and DBU. These examinations
ended in failure, and considerable amounts of the starting
materials were recovered unchanged, unlike the case using
aldehydes as an electrophile.2 During a search for suitable
reaction conditions, however, we have noticed that a small
amount of new product can be detected by TLC in some cases.
Isolation and structure analysis revealed that the product had a
highly functionalized olefin structure 2 in which new C-C and
C-N bonds were formed at R- and â-positions of the propiolate,
respectively (∼10% yield). The formation of 2 was unexpected
because the latter nitrogen unit was most likely incorporated
by the action of tosylamide, which was accidentally generated
by hydrolytic decomposition of N-tosylimine by ambient
moisture. This finding brought by mere chance led us to
investigate the three-component coupling reaction for practical
use. Thus, phenyl N-tosylimine (1) was allowed to react with
equimolar amounts of methyl 3-trimethylsilylpropiolate and
tosylamide in the presence of tertiary amine as a trigger
nucleophile in refluxing THF for 20 h, and the results are shown
in Scheme 1. As expected, the intended coupling reaction
proceeded to afford the olefin 2 with up to 47% yield when
using DABCO.9
Graduate School of Medicine and Pharmaceutical Sciences,
UniVersity of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
nemotoh@pha.u-toyama.ac.jp
ReceiVed October 1, 2007
A new three-component coupling reaction of methyl 3-tri-
methylsilylpropiolate, N-tosylimine, and tosylamide mediated
by DABCO was developed. This reaction was based on the
consecutive R- and â-activation method of propiolate involv-
ing intramolecular silyl migration previously developed by
our group. On the basis of these results, a new cyclization
reaction was designed to find a chromene-forming reaction
utilizing salicyl N-tosylimine as a bifunctional substrate.
As summarized in Table 1, this coupling reaction was
applicable for variously substituted N-tosylimines. In every case,
the functionalized olefins 2a-j were obtained in moderate
yields.10 These reactions showed exclusive E-selectivity on the
olefin geometry, which was confirmed by NOE observation
between the methine proton on the R-position and the tosylamide
N-H proton on the â-position. Because the reaction of the
isolated 2a with sodium methoxide in refluxing methanol
resulted in no change of the olefin geometry, E-olefin is likely
to be a thermodynamically more stable form.
Development of domino-type reactions has been one of the
most significant research areas of organic chemistry because
of the high efficiency and the applicability for concise syntheses
of complex molecules.1 We have recently explored a new
function of alkynes conjugated with a carbonyl group and
reported that methyl 3-trimethylsilylpropiolate can act as a
versatile synthetic tool which participates in a successive
carbon-carbon bond-forming reaction with aldehydes mediated
by suitable tertiary amines.2 Activation of alkynes and subse-
quent reaction with various reagents have been widely studied
and reported in recent years, including phosphine catalysts,3
metal complex formation,4 and Morita-Baylis-Hillman-type
reactions.5 Acetylene dicarboxylates have also been reported
(5) (a) Kataoka, T.; Kinoshita, H.; Kinoshita, S.; Iwamura, T.; Watanabe,
S. Angew. Chem., Int. Ed. 2000, 39, 2358. (b) Wei, H.-X.; Gao, J. J.; Li,
G. Tetrahedron Lett. 2001, 42, 9119. (c) Wei, H.-X.; Hu, J.; Purkiss, D.
W.; Pare, P. W. Tetrahedron Lett. 2003, 44, 949.
(6) (a) Esmaili, A. A.; Bodaghi, A. Tetrahedron 2003, 59, 1169. (b) Nair,
V.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T.; Devi, B. R.; Menon, R. S.;
Rath, N. P.; Srinivas, R. Synthesis 2003, 1895. (c) Nair, V.; Sreekanth, A.
R.; Vinod, A. U. Org. Lett. 2001, 3, 3495.
(7) For the reaction of N-tosylimines catalyzed by tertiary amines, see:
(a) Li, C.-Q.; Shi, M. Org. Lett. 2003, 5, 4273. (b) Zhao, G.-L.; Huang,
J.-W.; Shi, M. Org. Lett. 2003, 5, 4737.
(8) For three-component coupling reaction based on Morita-Baylis-
Hillman reaction, see: (a) Evans, C. A.; Miller, S. J. J. Am. Chem. Soc.
2003, 125, 12394. For nickel-catalyzed three-component coupling of alkynes
and imines, see: (b) Patel, S.; Jamison, T. F. Angew. Chem., Int. Ed. 2003,
42, 1364.
(9) We have thoroughly explored optimal reaction conditions using
various solvents, tertiary amines, time and temperature, and equivalents of
the reagents. However, an improved result over a 47% yield could not be
obtained. Details of these examinations are described in Supporting
Information.
(10) Besides the desired olefin products 2, unreacted imines were detected
in the reaction mixture, which were hydrolyzed during a workup process.
(1) For recent reviews on this subject, see: (a) Lieby-Muller, F.; Simon,
C.; Constantieux, T.; Rodriguez, J. QSAR Comb. Sci. 2006, 25, 432. (b)
Enders, D.; Grondal, C.; Huettl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570. (c) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76,
1967. (d) Tietze, L. F.; Modi, A. Med. Res. ReV. 2000, 20, 304.
(2) (a) Matsuya, Y.; Hayashi, K.; Nemoto, H. J. Am. Chem. Soc. 2003,
125, 646. (b) Matsuya, Y.; Hayashi, K.; Nemoto, H. Chem.sEur. J. 2005,
5408.
(3) (a) Jung, C.-K.; Wang, J.-C.; Krische, M. J. J. Am. Chem. Soc. 2004,
126, 4118. (b) Wang, J.-C.; Ng, S.-S.; Krische, M. J. J. Am. Chem. Soc.
2003, 125, 3682. (c) Wang, J.-C.; Krische, M. J. Angew. Chem., Int. Ed.
2003, 42, 5855. (d) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997,
119, 7595. (e) Crisp, G. T.; Millan, M. J. Tetrahedron 1998, 54, 637. (f)
Wende, M.; Meier, R.; Gladysz, J. A. J. Am. Chem. Soc. 2001, 123, 11490.
(g) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241.
(4) (a) Trost, B. M.; Oi, S. J. Am. Chem. Soc. 2001, 123, 1230. (b) Suzuki,
D.; Urabe, H.; Sato, F. Angew. Chem., Int. Ed. 2000, 39, 3290.
10.1021/jo702649q CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/12/2008
J. Org. Chem. 2008, 73, 1987-1990
1987

TABLE 2. Reaction of Salicyl N-Tosylimines (5) with Propiolate in
the Presence of DABCO
SCHEME 1
entry
R
solvent
condition
yield (%)
TABLE 1. Reaction of N-Tosylimines with Propiolate and
Tosylamide in the Presence of DABCO
1
2
3
4
5
6
7
a
a
a
a
b
c
H
H
H
H
THF
reflux, 1.5 h
reflux, 1.5 h
rt, 24 h
reflux, 1.5 h
reflux, 4 h
reflux, 4 h
reflux, 2 h
49
40
DCEa
benzene
benzene
benzene
benzene
benzene
trace
81
5,6-benzob
5-Cl
75c
58
d
5-NO2
0d
a 1,2-Dichloroethane. b The numbering on the aromatic ring starts from
the carbon bearing the imine group and proceeds clockwise. c Based on
the recovered imine (37%). d Afforded a complex mixture.
entry
R
yield (%)
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
Ph
47
46
34
39
30
49
42
34
45
34
4-NO2-C6H4
4-Cl-C6H4
bifunctional substrate. The envisaged cyclization occurred when
the compound 5a was reacted with the propiolate, mediated by
DABCO in refluxing THF, to give methyl 2-methoxy-2H-
chromene-3-carboxylate (6a) in 49% yield after acidic MeOH
workup (Table 2, entry 1).11 The reaction yield was finally
improved to 81% when using benzene as a solvent,12 although
heating was required (entries 2-4). Several other substrates
(5b-d) were also examined for the cyclization reaction and
found to afford the corresponding chromene derivatives, except
for the highly electron-deficient substrate 5d (entries 5-7). This
nitro-substituted imine was rather unstable, probably due to
susceptibility to nucleophilic species, to give a complex mixture
under the reaction conditions.
2-Me-C6H4
4-Me-C6H4
2-MeO-C6H4
4-MeO-C6H4
2,6-Me2C6H3
1-naphthyl
tert-Bu
10
j
SCHEME 2
The next experiments (Scheme 3) suggested that the 4H-
chromene derivative 8 possessing a tosylamino group was likely
to be the first cyclized product because the compound 7 could
be trapped by careful workup without acid treatment. This
compound obviously arises from the intermediate 8 via thermal
N-migration. In addition, purely isolated 7 could be easily
transformed into the compound 6a in acidic MeOH solution.13,14
The compound 7 was rather labile under acidic conditions and
probably converted to a benzopyrylium cation, having high
reactivity for various nucleophiles,15 by exclusion of the
(11) For recent examples of organocatalyzed syntheses of the chromene-
type skeleton from salicyl aldehydes, see: (a) Sunden, H.; Ibrahem, I.; Zhao,
G.-L.; Eriksson, L.; Cordova, A. Chem.sEur. J. 2007, 13, 574. (b) Li, H.;
Wang, J.; E-Nunu, T.; Zu, L.; Jiang, W.; Wei, S.; Wang, W. Chem. Commun.
2007, 507. (c) Govender, T.; Hojabri, L.; Moghaddam, F. M.; Arvidsson,
P. I. Tetrahedron: Asymmetry 2006, 17, 1763. (d) Zhao, G.-L.; Shi, Y.-L.;
Shi, M. Org. Lett. 2005, 7, 4527. (e) Lesch, B.; Bra¨se, S. Angew. Chem.,
Int. Ed. 2004, 43, 115. (f) Kaye, P. T.; Musa, M. A.; Nocada, X. W.;
Robinson, R. S. Org. Biomol. Chem. 2003, 1, 1133.
(12) Considering harmfulness of benzene, the reaction of 5a was
investigated using toluene as an alternative solvent, providing a comparable
result (110 °C, 3 h, 72% yield) with the case of benzene.
(13) We suppose that the mechanism of the cyclization reaction (forma-
tion of 8) follows the same pathway as depicted in Scheme 2 in an
intramolecular fashion because the same reaction in the presence of CD3-
OD (this deuterium ought to be exchanged for the phenolic hydrogen of 5)
gave the product 6 in which the deuterium was incorporated at the 2-position
(as well as the methoxy hydrogens).
We suppose the mechanism of the present reaction partially
involves the consecutive activation pathway of the propiolate
including intramolecular TMS migration, as previously described
(Scheme 2).2 Ammonium ylide intermediate 3 may be able to
abstract the acidic proton of tosylamide. Subsequent addition-
elimination process regenerates DABCO and gives the com-
pound 4, which finally affords the observed products 2 by
cleavage of the weak N-Si bond during acid workup. This
reaction mechanism agrees with the facts that (1) when using
deuterated tosylamide (TsND2), the deuterium was incorporated
onto the â-carbon of the acrylate product 2; (2) the trimethylsilyl
group was not retained in the product 2, indicating this group
moved onto the nitrogen atom at least before workup.
(14) For recent reports on chromene-forming reaction of salicyl N-
tosylimine and conjugated alkynes or allenic esters, relating to our reaction
systems but via a different reaction pathway, see: (a) Shi, Y.-L.; Shi, M.
Org. Lett. 2005, 7, 3057. (b) Guo, Y.-W.; Shi, Y.-L.; Li, H.-B.; Shi, M.
Tetrahedron 2006, 62, 5875. (c) Shi, Y.-L.; Shi, M. Chem.sEur. J. 2006,
12, 3374.
The three-component coupling reaction mentioned above
gives a hint that N-tosylimines containing acidic hydrogen
comparable to that of tosylamide can be utilized for a new
cyclization reaction with 3-trimethylsilylpropiolate. With this
purpose in mind, we chose salicyl N-tosylimines (5) as such a
(15) Ohkata, K.; Akiba, K. AdV. Heterocycl. Chem. 1996, 65, 283.
1988 J. Org. Chem., Vol. 73, No. 5, 2008

SCHEME 3
products 2a-j in the yields listed in Table 1. Spectral data for the
compounds 2b-j are provided in Supporting Information.
Methyl (E)-2-[Phenyl-(p-tolylsulfonylamino)methyl]-3-(p-
tolylsulfonylamino)prop-2-enoate (2a): Colorless powder (from
1
hexane); mp 174-176 °C; H NMR (CDCl3) δ ) 2.37 (s, 3H),
2.43 (s, 3H), 3.50 (s, 3H), 5.48 (d, J ) 9.0 Hz, 1H), 6.18 (d, J )
9.0 Hz, 1H), 7.05-7.16 (m, 7H), 7.31 (d, J ) 7.7 Hz, 2H), 7.39
(d, J ) 12 Hz, 1H), 7.46 (d, J ) 8.1 Hz, 2H), 7.80 (d, J ) 8.1 Hz,
2H), 8.72 (d, J ) 12 Hz, 1H); 13C NMR (CDCl3) δ ) 21.8, 21.9,
51.8, 53.5, 109.2, 126.0, 126.9, 127.1, 127.7, 128.6, 129.6, 130.1,
136.4, 136.7, 136.8, 138.1, 143.7, 144.6, 166.5; IR (KBr) 3246,
;
1688, 1599 cm-1 MS m/z 514 (M+). Anal. Calcd for
C25H26N2O6S2: C, 58.35; H, 5.09; N, 5.44. Found: C, 58.39; H,
5.03; N, 5.47.
Reaction of Methyl 3-Trimethylsilylpropiolate with Salicyl
N-Tosylimine (5a): Formation of the Chromene Derivatives 6a
and 7. A solution of methyl 3-trimethylsilylpropiolate (156 mg, 1
mmol), salicyl N-tosylimine (5a, 275 mg, 1 mmol), MS3Å (100
mg), anhydrous methanol (32 mg, 1 mmol), and DABCO (112 mg,
1 mmol) in anhydrous benzene (1.5 mL) was refluxed for 1.5 h.
The mixture was cooled to room temperature and diluted with CH2-
Cl2 (20 mL). This solution was washed with 10% HCl and brine
successively and dried over MgSO4. After evaporation of the
solvent, the residue was subjected to silica gel column chromatog-
raphy to afford 6a (179 mg, 81%) as a pale yellow oil: 1H NMR
(CDCl3) δ ) 3.55 (s, 3H), 3.85 (s, 3H), 5.95 (s, 1H), 7.01-7.09
(m, 2H), 7.29-7.38 (m, 2H), 7.70 (s, 1H); 13C NMR (CDCl3) δ )
51.9, 55.8, 95.2, 116.9, 119.4, 121.2, 121.9, 129.0, 131.9, 134.2,
152.0, 164.8; IR (neat) 2952, 1714 cm-1; MS m/z 220 (M+). Exact
mass calcd for C12H12O4: 220.0736. Found: 220.0736.
The same reaction as above was carried out in the absence of
methanol, and the mixture was concentrated in vacuo and directly
subjected to silica gel column chromatography to afford 7 (270
mg, 75%) as a pale yellow solid: mp 161-163 °C; 1H NMR
(CDCl3) δ ) 2.50 (s, 3H), 3.77 (s, 3H), 5.88 (d, J ) 9.6 Hz, 1H),
6.36 (d, J ) 8.2 Hz, 1H), 6.58 (d, J ) 9.6 Hz, 1H), 6.97-7.02 (m,
1H), 7.18-7.31 (m, 2H), 7.33 (d, J ) 8.0 Hz, 2H), 7.67 (s, 1H),
7.79 (d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3) δ ) 21.7, 52.3, 117.3,
119.2, 120.5, 122.5, 126.3, 127.3, 128.9, 129.1, 129.3, 129.5, 132.2,
134.7, 138.3, 143.4, 150.7, 163.8; IR (KBr) 3285, 2958, 1687, 1433
cm-1; MS m/z 359 (M+). Exact mass calcd for C18H17NO5S:
359.0827. Found: 359.0852.
tosylamino group. Therefore, the compound 7 can be a versatile
intermediate for the syntheses of variously functionalized
chromene derivatives. For example, the reaction of 7 with
allyltrimethylsilane or acetophenone silyl enol ether in the
presence of titanium chloride gave rise to the formation of
2-substituted chromenes 9 and 10 in high yields, respectively
(Scheme 3).16
In summary, we have developed a new three-component
coupling reaction utilizing a consecutive activation protocol of
conjugated alkynes mediated by DABCO, providing unique
nitrogen-containing olefin compounds. This methodology was
successfully applied for a new chromene-forming reaction,
which can be a new efficient access to variously functionalized
chromene derivatives. Efforts to explore further applications are
currently in progress in our laboratory.
The other substituted salicyl N-tosylimines (5b and 5c) were also
reacted with methyl 3-trimethylsilylpropiolate according to the
above procedure (reflux, 4 h) to afford the chromene derivatives
6b and 6c, respectively (yields are indicated in Table 2). Spectral
data for these compounds are provided in Supporting Information.
Reaction of the Chromene Derivative 7 with Silyl Reagents:
Formation of Substituted Chromene Derivatives 9 and 10. To
a stirred solution of the compound 7 (36 mg, 0.1 mmol) and
allyltrimethylsilane (11 mg, 0.1 mmol) in anhydrous THF (1 mL)
was added TiCl4 (1.0 M toluene solution, 0.1 mL, 0.1 mmol), and
the mixture was stirred at room temperature for 3 h. After addition
of saturated NaHCO3 solution, the aqueous mixture was extracted
with Et2O and then dried over MgSO4. Evaporation of the solvent
left a residue, which was chromatographed on silica gel to afford
the allylated product 9 (23 mg, quant.) as a pale yellow oil: 1H
NMR (CDCl3) δ ) 2.29-2.38 (m, 1H), 2.47-2.58 (m, 1H), 3.82
(s, 3H), 5.00-5.09 (m, 2H), 5.26-5.30 (m, 1H), 5.80-5.94 (m,
1H), 6.84-6.95 (m, 2H), 7.15 (dd, J ) 1.7, 7.4 Hz, 1H), 7.23-
7.27 (m, 1H), 7.46 (s, 1H); 13C NMR (CDCl3) δ ) 38.2, 51.9,
73.5, 116.9, 117.8, 120.5, 121.4, 125.3, 128.7, 132.0, 132.9, 133.2,
153.2, 165.1; IR (neat) 2952, 1712 cm-1; MS m/z 230 (M+). Exact
mass calcd for C14H14O3: 230.0943. Found: 230.0921.
Experimental Section
General Remarks. All nonaqueous reactions were carried out
under an Ar atmosphere. Reagents were purchased from commercial
sources and used as received. Anhydrous solvents were prepared
by distillation over CaH2 or purchased from commercial sources.
N-Tosylimines 1a-j and 5a-d were prepared according to the
reported method.17
General Procedure for the Reaction of N-Tosylimines with
Methyl 3-Trimethylsilylpropiolate and Tosylamide in the Pres-
ence of DABCO. A solution of methyl 3-trimethylsilylpropiolate
(156 mg, 1 mmol), N-tosylimine (1a-j, 1 mmol), p-toluenesulfona-
mide (171 mg, 1 mmol), and DABCO (112 mg, 1 mmol) in
anhydrous THF (1 mL) was refluxed for 20 h. The mixture was
cooled to room temperature and diluted with CH2Cl2 (20 mL). This
solution was washed with 10% HCl and brine successively and
dried over MgSO4. After evaporation of the solvent, the residue
was subjected to silica gel column chromatography to afford the
(16) For reports on allylation of benzopyrylium derivatives, see: (a) Lee,
Y. G.; Ishimaru, K.; Iwasaki, H.; Ohkata, K.; Akiba, K. J. Org. Chem.
1991, 56, 2058. (b) Ohkata, K.; Ishimaru, K.; Lee, Y. G.; Akiba, K. Chem.
Lett. 1990, 1725.
(17) McKay, W. R.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1 1981,
2435.
Similarly using acetophenone silyl enol ether instead of allylt-
rimethylsilane as a reagent, the compound 7 afforded the compound
10 (74%) as a pale yellow solid: mp 104-105 °C; 1H NMR
(CDCl3) δ ) 3.34 (dd, J ) 6.9, 14 Hz, 1H), 3.37 (dd, J ) 4.4, 14
J. Org. Chem, Vol. 73, No. 5, 2008 1989

Hz, 1H), 3.75 (s, 3H), 4.53 (dd, J ) 4.4, 6.9 Hz, 1H), 6.98-7.05
(m, 2H), 7.13-7.22 (m, 2H), 7.40-7.45 (m, 2H), 7.50-7.56 (m,
1H), 7.75 (s, 1H), 7.91-7.94 (m, 2H); 13C NMR (CDCl3) δ ) 29.7,
47.3, 51.5, 108.9, 116.3, 123.6, 124.7, 127.7, 127.9, 128.3, 129.0,
132.8, 136.7, 149.8, 151.7, 166.5, 197.5; IR (KBr) 2925, 1709,
1680, 1649 cm-1; MS m/z 308 (M+). Exact mass calcd for
C19H16O4: 308.1049. Found: 308.1046.
Supporting Information Available: Details of investigations
of optimal conditions for the three-component coupling reaction,
characterization data for the compounds 2b-j, 6b, and 6c, and 1H
and 13C NMR spectra of the compounds 2a-j, 6a-c, 7, 9, and 10.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702649Q
1990 J. Org. Chem., Vol. 73, No. 5, 2008