Synthesis of substituted chromenes through the DABCO-catalyzed reaction of but-3-yn-2-one and methyl propiolate with salicyl N-tosylimines (DABCO = 1,4-diazabicyclo[2.2.2]octane)

Article abstract of DOI:10.1002/chem.200501291

The DABCO-catalyzed (DABCO= 1,4-diazabicyclo[2.2.2]octane) reaction of but-3-yn-2-one and methyl propiolate with salicyl N-tosylimines yields highly functionalized chromenes and has been thoroughly investigated; the rational mechanism for the reaction has

Full text of DOI:10.1002/chem.200501291

DOI: 10.1002/chem.200501291
Synthesis of Substituted Chromenes through the DABCO-Catalyzed
Reaction of But-3-yn-2-one and Methyl Propiolate with Salicyl N-Tosylimines
(DABCO=1,4-diazabicyclo[2.2.2]octane)
Yong-Ling Shi and Min Shi*[a]
Abstract: The DABCO-catalyzed (DABCO=1,4-diazabicyclo[2.2.2]octane) reac-
tion of but-3-yn-2-one and methyl propiolate with salicyl N-tosylimines yields
Keywords: Baylis–Hillman
tion chromenes
addition
salicyl n-tosylimines
reac-
Michael
NMR spectroscopy ·
·
·
highly functionalized chromenes and has been thoroughly investigated; the ratio-
·
1
nal mechanism for the reaction has been demonstrated on the basis of H NMR
spectroscopic investigation.
Introduction
Due to their important biological activity and great utility,
chromene derivatives have attracted considerable attention
from a variety of scientific areas.[1] Different processes for
the synthesis of chromenes have been reported during the
past few years.[2] More recently, we have communicated an
efficient approach to substituted chromenes by amine-cata-
lyzed reaction of allenic esters and ketones with salicyl N-
tosylimines in 54–99% yields in dichloromethane
(Scheme 1).[3] Phosphorus-based catalysts such as PPh2Me
could induce the reaction to give the [3+2] cycloadduct in
82% yield in tetrahydrofuran (THF) (Scheme 1, additional
results can be found in Tables S1 and S2 in the Supporting
Information).[3]
Scheme 1. Reaction of allenic esters and ketones with salicyl N-tosyl-
imines.
As an extension of this methodology, we herein report the
reaction of but-3-yn-2-one and methyl propiolate with salicyl
N-tosylimines affording substituted chromenes in the pres-
ence of DABCO. In addition, a detailed reaction mechanism
is proposed on the basis of an H NMR spectroscopic trace
of the reaction solution.
Results and Discussion
Different catalysts were first examined by using the reaction
of salicyl N-tosylimine (1a) with but-3-yn-2-one (2a;
1.2 equiv) as a model. The results are summarized in
Table 1. Dichloromethane was chosen as the solvent and
molecular sieves 4 Š (100 mg for 0.50 mmol of 1a) was
added as a desiccant to prevent the decomposition of imine
1
by
ambient
moisture.
1,4-Diazabicyclo[2.2.2]octane
(DABCO; 10 mol%) was found to be an effective catalyst
in this reaction (Table 1, entries 1–5). In the reaction cata-
lyzed by DABCO, imine 1a was consumed within 1 h, while
the yield of 3a was only 32%. If the reaction time was ex-
tended to 10 h, the yield of 3a could reach 69%. Performing
the reaction at lower temperature did not give 3a in higher
yield. The yield of 3a could be further increased to 71% by
extending the reaction time to 24 h. Other nitrogen- and
[a] Y.-L. Shi, Prof. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 354 Fenglin Lu
Shanghai 200032 (China)
Fax : (+86)21-6416-6128
E-mail: mshi@pub.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
3374
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Chem. Eur. J. 2006, 12, 3374 – 3378

FULL PAPER
Table 1. Reaction of salicyl N-tosylimine 1a (1.0 equiv) with but-3-yn-2-
one 2a (1.2 equiv) in the presence of 10 mol% of catalyst.
Table 2. Reaction of other salicyl N-tosylimines 1 (1.0 equiv) with but-3-
yn-2-one 2a (1.2 equiv) in the presence of 10 mol% of DABCO.
Catalyst
T [8C]
t [h]
Yield of 3a [%][a]
R1
R2
R3
R4
t [h]
Yield of 3 [%][a]
1
2
3
4
5
6
7
8
DABCO
DABCO
DABCO
DABCO
DABCO
Et3N
DMAP
DBU
PPh3
PPh2OMe
PPh2Me
PPhMe2
PMe3
20
20
1
10
10
24
1
32
69
53
71
14
23
66
21
1
2
3
4
5
6
7
8
OMe
H
H
H
H
Cl
H
H
H
OMe
H
H
H
H
H
H
H
H
OMe
Me
Br
H
H
H
H
H
H
H
24
24
24
24
24
24
24
48
3b: 84
3c: 52
3d: 84
3e: 83
3 f: 81
3g: 78
3h: 57
3i: 74
À20
20
À20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
24
29
13
24
24
24
24
24
24
24
24
24
24
24
Cl
NO2
À
À
À
9
20
trace
11
17
trace
trace
no reaction
no reaction
no reaction
63
CH=CH CH=CH
10
11
12
13
14
15
16
17
18[b]
19[c]
[a] Isolated yields.
Table 3. Reaction of salicyl N-tosylimine 1a (1.0 equiv) with methyl pro-
piolate 2b (1.2 equiv) in the presence of DABCO.
PBu3
iPr2NEt
Na2CO3
NaHCO3
DABCO
DABCO
trace
[a] Isolated yields. [b] 1.0 equiv of 2a. [c] 2.0 equiv of 2a.
DABCO
[mol%]
Solvent
T [8C]
t [h]
Yield of
4a [%][a]
1
2
3
4
5
6
7
8
10
30
30
30
30
25
25
25
25
25
25
25
25
25
25
CH2Cl2
CH2Cl2
20
20
20
20
20
80
80
80
80
80
80
80
80
80
80
24
48
48
48
48
24
27
8
34
12
12
8
11
31
13
38
45
67
27
14
32
49
69
30
40
70
79
phosphorus-based catalysts were less effective in this reac-
tion (Table 1, entries 6–14). The weaknucleophile ethyldi-
isopropylamine (iPr2NEt) and inorganic catalysts, such as
Na2CO3 or NaHCO3, showed no catalytic abilities for this
reaction (Table 1, entries 15–17). Reducing the amount of
but-3-yn-2-one 2a to one equivalent and increasing it to two
equivalents both afforded 3a in lower yields under identical
conditions (Table 1, entries 18–19). Thus, we established the
optimal reaction conditions for this reaction: 1.2 equivalents
of 2a, 10 mol% of DABCO, and performing the reaction at
room temperature (208C) for 24 h.
Under these optimized reaction conditions, the reaction
of several other salicyl N-tosylimines 1 with 2a was also ex-
amined. Both electron-withdrawing and electron-donating
substituents were tolerated at various positions on the ben-
zene rings in the imines. The corresponding chromenes 3
were obtained in good yields (Table 2, entries 1–7). Even for
the sterically hindered substrate N-(2-hydroxynaphthalen-1-
yl)-methylene-4-methylbenzenesulfonamide, this reaction
proceeded smoothly to give the corresponding adduct 3i in
tert-amyl-OH
DMSO
CH3CN
CH3CN
toluene
tert-amyl-OH
CH2ClCH2Cl
DMSO
DMF
CH3CN
DMF
CH3CN
DMF
9
10
11
12[b]
13[b]
14[c]
15[c]
12
8
12
[a] Isolated yields. [b] 2.0 equiv of 2b. [c] 1.0 equiv of 2b.
could give a somewhat higher yield (Table 3, entries 3–5).
Then the reaction temperature was raised to 808C and 4a
was obtained in 67% yield (Table 3, entry 6). The corre-
sponding reaction conditions were further optimized by
varying different solvents in this reaction at 808C (Table 3,
entries 7–11). Acetonitrile and N,N-dimethylformamide
(DMF) were found to be the solvents of choice. Then the
amount of 2b was also examined in acetonitrile and DMF,
respectively at 808C (Table 3, entries 12–15). By using one
equivalent of 2b and performing the reaction in DMF, the
highest yield of 4a (Table 3, entry 15) was observed.
Under these optimized reaction conditions, several other
salicyl N-tosylimines were also examined in the reaction
with 2b. Imines with either electron-withdrawing or elec-
tron-donating substituents at various positions on the ben-
zene rings could give the corresponding chromenes 4 in
good yield after
entry 8).
a prolonged reaction time (Table 2,
To test the generality of this methodology, we further sub-
jected methyl propiolate 2b to the reaction. The results are
summarized in Table 3. To our disappointment, the yield of
the corresponding chromene 4a was rather low under these
above optimum reaction conditions (Table 3, entry 1). In-
creasing the amount of the catalyst and extending the reac-
tion time did not give 4a in satisfactory yield either
(Table 3, entry 2). Several other solvents were examined and
it was found that performing the reaction in acetonitrile
Chem. Eur. J. 2006, 12, 3374 – 3378
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www.chemeurj.org
3375

M. Shi and Y.-L. Shi
good yields (Table 4, entries 1–6). For the sterically hindered
imine N-(2-hydroxynaphthalen-1-yl)-methylene-4-methyl-
benzenesulfonamide, a prolonged reaction time was also re-
quired (Table 4, entry 7).
prevent the decomposition of 1a during the spectroscopic
trace process. Some selected spectra are shown below in
Figure 1.
As shown in Figure 1b, when DABCO was added to the
solution of 1a and 2a, imine 1a was consumed in five min-
utes and intermediate 5 was formed (Figure 1b and c). The
specific iminium proton and olefinic protons were assigned
(see partial enlargement in Figure 1c). Then the correspond-
ing intermediate 5 was gradually converted to the final
product 3a after 24 h (Figure 1d). After 83 h, intermediate 5
completely disappeared and the corresponding product 3a
was obtained (Figure 1e). To clarify that product 3a was
really obtained as shown in Figure 1e, the solution was dilut-
ed and some pure compound 3a was added. As can be seen
from Figure 1f, no new peaks occur and only the peaks re-
lated to 3a are enlarged. It should be noted that intermedi-
ate 5 was not stable enough for isolation. The attempt to
isolate intermediate 5 has not yet proved successful, despite
our active endeavors. For the reaction of 1a and 2b, a simi-
lar intermediate was also observed (Figures S1–S8 in the
Supporting Information). The major isomer of intermediate
Table 4. Reaction of other salicyl N-tosylimines 1 (1.0 equiv) with methyl
propiolate 2b (1.0 equiv) in the presence of 25 mol% of DABCO.
R1
R3
R4
t [h]
Yield of 4 [%][a]
1
2
3
4
5
6
7
OMe
H
H
H
Cl
H
H
H
H
H
H
H
H
12
12
12
12
12
12
21
4b: 79
4c: 86
4d: 85
4e: 83
4 f: 74
4g: 51
4h: 29
OMe
Me
Br
Cl
NO2
À
À
À
H
CH=CH CH=CH
[a] Isolated yields.
3
5 was assigned to be Z configuration by comparison the J
value (12.3 Hz) of the olefinic protons with that of the inter-
mediate derived from 1a and 2b (Figures S1–S8 in the Sup-
porting Information).
Concerning the mechanism for the reaction, there may be
three different pathways (Scheme 2).[4–7] The first pathway
starts with a Michael addition to form intermediate 5 fol-
lowed by intramolecular Baylis–Hillman reaction. The
second pathway proceeds through tandem Michael addition/
Mannich reaction. The third pathway is initiated by Baylis–
Hillman reaction and subsequent substitution provides the
final product 3a. Therefore, it is necessary to determine the
reaction pathway in the above interesting reaction.
Based on these observations, we believe that the reaction
was most likely to proceed through the first pathway as
shown in Scheme 2. The fact that no reaction occurred when
weaknucleophiles served as the catalysts (Table 1, en-
tries 15–17) revealed that DABCO functioned not merely as
a base but also as a nucleophile in the Michael addition
step. The detailed mechanistic explanation is shown in
Scheme 3.
DABCO first reacts with 2a to generate a zwitterionic in-
termediate 8,[7] which abstracts a proton from imine 1a to
release anion 11 and form intermediate 9,[6a] which might be
tautomerized with intermediate 10. Then Michael addition
occurs between the intermediate 11 and 2a to give inter-
mediate 6, which subsequently abstracts a proton from 9
yielding intermediate 12. Consequently, intermediate 12
isomerizes to intermediate 5, followed by intramolecular
Baylis–Hillman reaction catalyzed by DABCO affording
product 3a. The intramolecular Baylis–Hillman reaction is
the rate-determining step as indicated by observations of
1H NMR spectra.
Substituents at the terminal alkyne were not tolerated,
presumably due to the steric hindrance. The reaction be-
tween ethyl 2-butynoate 2c and imine 1a did not give the
corresponding chromene derivative in satisfactory yield
under various reaction conditions (Scheme 4).[3]
Scheme 2. Possible pathways for the formation of 3a.
In conclusion, we have developed an efficient process for
the synthesis of highly functionalized chromenes by reaction
of but-3-yn-2-one and methyl propiolate with salicyl N-tos-
ylimines. The reaction mechanism has been demonstrated
based on the observations of H NMR spectra. Efforts are
in progress to develop the asymmetric version of this reac-
tion.
1
To gain further understanding of the mechanism, we
monitored the reaction process of 1a and 2a in CDCl3 by
1H NMR spectra. Molecular sieves 4 A was added as well to
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Chem. Eur. J. 2006, 12, 3374 – 3378

Synthesis of Chromenes
FULL PAPER
Figure 1. a) 1H NMR spectrum of a mixture of 1a and 2a in CDCl3.
b) 1H NMR spectrum taken five minutes after DABCO was added to the
solution of 1a and 2a in CDCl3. c) Partial enlargement of the spectrum
shown in b). d) 1H NMR spectrum taken 12 h after DABCO was added
to the solution of 1a and 2a in CDCl3. e) 1H NMR spectrum taken 83 h
after DABCO was added to the solution of 1a and 2a in CDCl3. f) The
1
solution used for the H NMR spectrum in e) was diluted and some pure
compound 3a was added. g) 1H NMR spectrum of compound 3a in
CDCl3.
Experimental Section
mercially available reagents were used without further purification. Sali-
cyl N-tosylimines[8] and but-3-yn-2-one[9] were prepared according to the
literature. All reactions were monitored by TLC. Flash column chroma-
tography was carried out at increased pressure. Infrared spectra were
General: Unless otherwise stated, all reactions were carried out under
argon atmosphere. All solvents were purified by distillation. Other com-
Chem. Eur. J. 2006, 12, 3374 – 3378
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3377

M. Shi and Y.-L. Shi
Acknowledgements
We thankthe State Key Project of
Basic Research (Project 973) (No.
G2000048007), Shanghai Municipal
Committee of Science and Technology
(04 JC14083), and the National Natural
Science Foundation of China for finan-
cial support (20472096, 203900502, and
20272069).
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Scheme 4. Reaction of 1a with ethyl 2-butynoate 2c.
1
measured on a Perkin–Elmer 983 spectrometer. H and 13C NMR spectra
were recorded on a Varian Mercury vx 300 NMR spectrometer in CDCl3
or CD3SOCD3 with tetramethylsilane as the internal standard. Mass spec-
tra were recorded with an HP-5989 instrument and HRMS was measured
by an Ion Spec 4.7 Tesla FTMS mass spectrometer. Satisfactory CHN mi-
croanalyses were obtained with a Carlo–Erba 1106 analyzer. Melting
points were obtained by means of a micro melting point apparatus and
are uncorrected.
Typical reaction procedure for DABCO-catalyzed reaction of but-3-yn-2-
one with salicyl N-tosylimine (1a): Molecular sieves 4 Š (100 mg),
DABCO (5.6 mg, 0.05 mmol), salicyl N-tosylimine 1a (138 mg,
0.50 mmol), CH2Cl2 (2.0 mL), and but-3-yn-2-one 2a (47 mL, 0.60 mmol)
were added in turn to a flame-dried Schlenktube at room temperature.
The reaction mixture was stirred at room temperature for 24 h. Then the
solvent was removed under reduced pressure and the residue was puri-
fied by flash chromatography (eluent: EtOAc/Petroleum ether 1:4–2:1)
1
to yield 3a (122 mg, 71%) as a colorless solid. M.p. 184–1868C; H NMR
(CDCl3, TMS, 300 MHz): d=2.12 (s, 3H; Me), 2.39 (s, 3H; Me), 5.38 (d,
3J(H,H)=5.4 Hz, 1H; NH), 5.51 (d, 3J(H,H)=5.4 Hz, 1H; CH), 6.98–
7.03 (m, 1H; Ar), 7.08–7.11 (m, 1H; Ar), 7.16 (d, 3J(H,H)=8.4 Hz, 2H;
3
Ar), 7.24–7.34 (m, 2H; Ar), 7.45 (d, J(H,H)=8.4 Hz, 2H; Ar), 7.68 ppm
(s, 1H; CH); 13C NMR (CDCl3, TMS, 75.44 MHz) d=21.5, 24.8, 45.1,
[8] J. H. Wynne, S. E. Price, J. R. Rorer, W. M. Stalick, Synth. Commun.
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116.1, 116.5, 119.3, 125.1, 127.0, 129.0, 129.2, 130.6, 138.9, 142.7, 150.4,
153.8, 195.5 ppm; IR (KBr): n=3339, 1659, 1641, 1331, 1233, 1149 cmÀ1
;
MS (70 eV): m/z (%): 188 (62.7) [M+À155], 173 (100) [M+À170]; ele-
mental analysis calcd (%) for C18H17NO4S: C 62.96, H 4.99, N 4.08;
found: C 62.94, H 4.86, N 3.98.
Received: October 19, 2005
Published online: February 9, 2006
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Chem. Eur. J. 2006, 12, 3374 – 3378