N,N,N′,N′-Tetramethyl-1,3-propanediamine as the catalyst of choice for the Baylis-Hillman reaction of cycloalkenone: Rate acceleration by stabilizing the zwitterionic intermediate via the ion-dipole interaction

Article abstract of DOI:10.1016/j.tetlet.2004.05.064

N,N,N^′,N^′-Tetramethyl-1,3-propanediamine (TMPDA) can be used as an efficient catalyst for the Baylis-Hillman reaction of cycloalkenones. The increased reaction rate was thought be derived from the stabilizing effect of the zwitterion

Full text of DOI:10.1016/j.tetlet.2004.05.064

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5485–5488
0
0
N,N,N ,N -Tetramethyl-1,3-propanediamine as the catalyst of
choice for the Baylis–Hillman reaction of cycloalkenone: rate
acceleration by stabilizing the zwitterionic intermediate via
the ion–dipole interaction
Ka Young Lee, Saravanan GowriSankar and Jae Nyoung Kim*
Department of Chemistry and Institute of Basic Science, Chonnam National University, Kwangju 500-757, South Korea
Received 18 March 2004; revised 15 April 2004; accepted 7 May 2004
0
0
Abstract—N,N,N ,N -Tetramethyl-1,3-propanediamine (TMPDA) can be used as an efficient catalyst for the Baylis–Hillman
reaction of cycloalkenones. The increased reaction rate was thought be derived from the stabilizing effect of the zwitterionic
intermediate via the ion–dipole interaction.
Ó 2004Elsevier Ltd. All rights reserved.
The Baylis–Hillman reaction provides a simple and
atom economic synthesis of b-hydroxy-a-methylene
various methods for the synthesis of the Baylis–Hillman
adducts of cycloalkenones have been developed with
1;2
4–14
esters, nitriles, ketones, etc.
adducts have many versatile functionality thus make
The Baylis–Hillman
certain limitations.
yl-4H-chalcogenopyran-4-ones (or -4-thiones) and TiCl
The combination of 2,6-diphen-
4
1;2
6a
these adducts as valuable synthetic intermediates. In
these contexts many research groups are studying the
reaction extensively.
in methylene chloride and related methods were
developed for the reactive p-nitrobenzaldehyde and 2-
6
cyclohexen-1-one or 2-cyclopenten-1-one. The combi-
4
nation of LiClO and DABCO in ether could be used for
However, the Baylis–Hillman reaction has some limi-
tations. One of the major drawbacks in the Baylis–
the Baylis–Hillman reaction of benzaldehyde and 2-cy-
7
clohexen-1-one. The use of Et AlI in CH Cl
reaction of enone isolevoglucosenone and C-b-
topyranosylformaldehyde furnished the corresponding
2
2
2
for the
D-galac-
3–5
Hillman reaction is the extremely slow reaction rate.
Thus, the improvement of the reaction rate has been
3–5
8
studied most deeply by many research groups.
Numerous physical and chemical methods have been
Baylis–Hillman adduct. 4-(Dimethylamino)pyridine
(DMAP)-catalyzed hydroxymethylation of 2-cyclohex-
enones with formaldehyde was carried out effectively in
1;3–5
developed to fasten the reaction rate.
Of these
9
methods, the chemical methods have the advantage of
not requiring specialized equipment, and so are more
attractive.
aqueous medium. Tributylphosphine combined with
0
BINOL (1,1 -bi-2-naphthol) was used effectively for
10
cycloalkenone system. Lewis base effects in the Baylis–
Hillman reaction of 2-cyclohexen-1-one and arylalde-
hydes or arylaldehyde N-tosylimines were examined
including DMAP, tributylphosphine and DBU (1,8-
Among the activated alkenes cycloalkenones are famous
4
–14
for their slow reaction rate.
Under the normal reac-
1
1
tion conditions using DABCO (1,4-diazabicy-
clo[2.2.2]octane) no reaction was observed. Recently,
diazabicyclo[5.4.0]undec-7-ene).
Recently, it was
known that TiCl without the use of Lewis base could be
4
12
applied to highly reactive aldehydes. Lithium phenyl-
selenide (PhSeLi) induced Baylis–Hillman reaction was
applied successively to a,b-unsaturated lactone system.
In summary, for the Baylis–Hillman reaction of cyclo-
13
0
0
Keywords: N,N,N ,N -Tetramethyl-1,3-propanediamine; Baylis–Hill-
man reaction; Cycloalkenone; Ion–dipole interaction; Zwitterion.
*
Corresponding author. Tel.: +82-62-530-3381; fax: +82-62-530-3389;
e-mail: kimjn@chonnam.ac.kr
alkenone derivatives, the combination of Lewis acid and
Lewis base system
6;7;10
seemed the only choice except for
0
040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.064

5486
K. Young Lee et al. / Tetrahedron Letters 45 (2004) 5485–5488
9
the reactive formaldehyde. Moreover, most of the re-
ported methods were limited to reactive aldehydes with
low to moderate yields of products.
As a model study, we have chosen the reaction of benz-
aldehyde (1a) and 2-cyclohexen-1-one (2a) with various
commercially available diamines 3a–d (see Table 1). The
reaction showed almost no reaction when we used
DABCO or triphenylphosphine as the catalyst. How-
ever, to our surprise, 87% isolated yield of the desired
adduct 4a was isolated in 72 h at room temperature with
Most recently, Verkade and co-workers have reported a
novel catalyst system for the effective Baylis–Hillman
reaction of cycloalkenones, proazaphosphatrane sulfide
combined with TiCl . But, the method can also be
categorized as the acid–base combination system.
Imidazole-catalyzed Baylis–Hillman reaction, especially
4
0 0
N,N,N ,N -tetramethyl-1,3-propanediamine (TMPDA)
catalyst. As shown in Table 1, N,N,N ,N -tetramethyl-
4
17
0 0
0
0
1,4-butanediamine (3b), N,N,N ,N -tetramethylethyl-
enediamine (3c), 4-[2-(dimethylamino)ethyl]morphorine
(3d), and N,N-dimethylbutylamine (3e) showed lower
yields of product. As generally expected, the diamines 3a
and 3b, which can stabilize the zwitterionic intermediate
via the intramolecular five- and six-membered ring,
showed better results than other amine catalysts.
5b
in basic water solution, was found to be effective for
5
cycloalkenones. We also have reported the DMAP-
catalyzed Baylis–Hillman reaction of cycloalkenones in
14
aqueous THF. Although the yields were moderate (53–
4%), DMAP-catalyzed Baylis–Hillman reaction of cy-
6
clohexenones seemed the most simple and convenient
method until now. However, there is still scope for
further improvements. In order to shed more lights on
our efforts to increase the reaction rate of Baylis–Hill-
man reaction of cycloalkenones, we intended to search
more efficient catalyst. Fortunately, we found a good
catalyst, TMPDA, and wish to report herein the results.
The increased reaction rate when we use TMPDA as the
catalyst might be attributed partly to (1) stabilizing ef-
fect of the zwitterionic intermediates (I and II) by
intramolecular ion–dipole interaction as shown in
Scheme 1, (2) statistically, two equivalents of Lewis
basic site as in DABCO, (3) relatively small steric hin-
drance around the nitrogen atom as in DABCO or
Nonbonding electron pairs on the nitrogen or phos-
phorous atom could stabilize intramolecularly the
neighboring cationic character developed on the N or P
atom. However, such a simple concept has not been
applied much to the Baylis–Hillman reaction.
3h;18
Me
3
N.
Due to the above plausible reasons increased
15
4;6c;11b
In
a
Table 1. Synthesis of 4a from 1a and 2a with amine catalyst 3
the Aggarwal’s paper involving the use of DBU, the
intermediate b-ammonium enolate is stabilized through
conjugation, which increases its equilibrium concentra-
Entry
Amine catalyst
Yield of 4a (%)
N
N
N
N
1
2
3a
3b
87
80
11b
tion, and this results in significantly enhanced rate.
4
6c
Verkade and Kataoka have mentioned about the
stabilization effects of the zwitterionic species by intra-
bridgehead interaction or transannular interaction in
their excellent papers. The use of chiral phosphine, BI-
N
O
3
4
5
N
N
3c
3d
3e
61
46
0
0
NAP (2,2 -bis(diphenylphosphino)-1,1 -binaphthyl), has
been used in order to prepare Baylis–Hillman adducts as
16
enantiomerically enriched form. In these contexts, we
intended to study on the catalytic effects of such tertiary
diamines, which can stabilize the intermediate zwitter-
ionic species during the Baylis–Hillman reaction by
intramolecular ion–dipole interaction as shown in
Scheme 1.
N
N
b
66 (67)
a
Conditions: 1a/2a/3a–e ¼ 1:2:1, aq THF, rt, 72 h.
Conditions: 1a/2a/3e ¼ 1:2:2, aq THF, rt, 72 h.
b
O
N
N
OH O
3a
Ph
PhCHO
+
THF/H2O
1a
2a
4a
3a
- 3a
O
N
O
O
H
Ph
PhCHO
N
N
N
(
I)
(II)
Scheme 1. General reaction pathway.

K. Young Lee et al. / Tetrahedron Letters 45 (2004) 5485–5488
5487
a
Table 2. Synthesis of Baylis–Hillman adducts 4 with TMPDA (3a)
O
N
N
OH
O
3a
R-CHO
+
R
(
CH2)n
THF/H2O
(
CH2)n
1
2 (n = 1 and 2)
4a-j
b
Entry
Aldehyde 1
Cycloalkenone 2
Time (h)
Product 4 (% yield)
4
1
2
3
PhCHO (la)
4-MeOPhCHO (1b)
2-Cyclohexen-1-one (2a)
72
72
72
72
72
72
48
60
72
48
4a (87)
4b (69)
8b
2a
2a
2a
2a
4
2-MeOPhCHO (1c)
c
4c (83)
4d (94)
3i
4
5
6
7
8
9
1
HCHO (
1d)
Hexanal (1e)
14
4e (83)
3i
1a
1b
1c
2-Cyclopenten-1-one (2b)
4f (65)
4g (85)
4h (78)
3
1
e
2b
2b
2b
2b
9
c
5a
1d
1e
4i (56)
4j (74)
14
0
a
b
c
Conditions: 1/2/3a ¼ 1:2:1, aq THF, rt.
Reference.
Excess amount of formaldehyde (ca. 5.0 equiv as aq solution) was used.
amounts of zwitterion could be generated and resulted
in increased reaction rate. Thus, we applied the reaction
conditions toward some aldehydes including the unre-
active ortho- and para-anisaldehydes, and the results are
listed in Table 2. As shown, moderate to good yields of
the Baylis–Hillman adducts 4a–j were obtained even
with p-anisaldehyde and o-anisaldehyde. 2-Cyclopenten-
Acknowledgements
This study was financially supported by special research
fund of Chonnam National University in 2004.
19;20
1
-one showed similar reactivity.
References and notes
However, the application of TMPDA in the reaction of
acyclic alkene such as acrylonitrile (74%) and methyl
vinyl ketone (55%) under the same reaction conditions
did not show good results. Similar to lower yields of
products were obtained as compared with the reported
1. (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
Rev. 2003, 103, 811; (b) Kim, J. N.; Lee, K. Y. Curr. Org.
Chem. 2002, 6, 627; (c) Basavaiah, D.; Rao, P. D.; Hyma,
R. S. Tetrahedron 1996, 52, 8001; (d) Ciganek, E. In
Organic Reactions; John Wiley & Sons: New York, 1997;
Vol. 51, pp 201–350; (e) Drewes, S. E.; Roos, G. H. P.
Tetrahedron 1988, 44, 4653; (f) Langer, P. Angew. Chem.,
Int. Ed. 2000, 39, 3049.
3
methods. Especially, the reaction with methyl acrylate
produced only trace amounts of product, unfortunately.
The reason for the unfavorable results of acyclic alkenes
than the cycloalkenones is hard to explain at this point.
However, we are tentatively supposing the reason might
be arised due to the conformational mobility in the
zwitterions of acyclic alkenes.
2
. (a) Lesch, B.; Brase, S. Angew. Chem., Int. Ed. 2004, 43,
15; (b) Alcaide, B.; Almendrous, P.; Aragoncillo, C.;
1
Rodriguez-Acebes, R. J. Org. Chem. 2004, 69, 826; (c)
Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc.
2003, 125, 13155; (d) Evans, C. A.; Miller, S. J. J. Am.
Chem. Soc. 2003, 125, 12394; (e) McDougal, N. T.;
Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094; (f) Lee,
K. Y.; Kim, J. M.; Kim, J. N. Tetrahedron 2003, 59, 385;
(g) Lee, K. Y.; Kim, J. M.; Kim, J. N. Synlett 2003, 357;
Next we examined the reaction of benzaldehyde and 2-
cyclohexen-1-one with TMPDA in the presence of acid
7
1d
co-catalyst such as LiClO
4
or 1,1,1-trifluoroethanol.
(
h) Im, Y. J.; Lee, C. G.; Kim, H. R.; Kim, J. N.
The acid catalyst did not improve the results significantly
in view of reaction rate or yield of product. We examined
some diphosphine catalysts including 1,3-bis(diph-
Tetrahedron Lett. 2003, 44, 2987; (i) Kim, J. N.; Kim, J.
M.; Lee, K. Y. Synlett 2003, 821; (j) Kim, J. N.; Lee, H. J.;
Lee, K. Y.; Kim, H. S. Tetrahedron Lett. 2001, 42, 3737;
(k) Lee, K. Y.; Kim, J. M.; Kim, J. N. Tetrahedron Lett.
2003, 44, 6737; (l) Kim, J. N.; Lee, K. Y.; Kim, H. S.; Kim,
T. Y. Org. Lett. 2000, 2, 343.
enylphosphino)propane,
1,2-bis(diphenylphosphino)-
ethane, and 1,4-bis(diphenylphosphino)butane, which
did not show significant catalytic activity, unfortunately.
The unfavorable results of diphosphines might be de-
rived from the steric hindrance of phenyl substituents
and the facile air oxidizable nature of phosphine.
3
. (a) Xu, Y.-M.; Shi, M. J. Org. Chem. 2004, 69, 417; (b)
Krishna, P. R.; Manjuvani, A.; Kannan, V.; Sharma, G.
V. M. Tetrahedron Lett. 2004, 45, 1183; (c) Maher, D. J.;
Connon, S. J. Tetrahedron Lett. 2004, 45, 1301; (d) Kim,
E. J.; Ko, S. Y.; Song, C. E. Helv. Chim. Acta 2003, 86,
In summary, we found a useful catalyst, TMPDA, for
8
94; (e) Shi, M.; Xu, Y.-M.; Zhao, G.-L.; Wu, X.-F. Eur.
20
the Baylis–Hillman reaction of cycloalkenones. We are
expecting the simple catalyst system would be used
widely for the preparation of various types Baylis–
Hillman adducts of cycloalkenones.
J. Org. Chem. 2002, 3666; (f) Aggarwal, V. K.; Mereu, A.;
Tarver, G. J.; McCague, R. J. Org. Chem. 1998, 63, 7183;
(g) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413;
(h) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002,

5488
K. Young Lee et al. / Tetrahedron Letters 45 (2004) 5485–5488
4
, 4723; (i) Aggarwal, V. K.; Dean, D. K.; Mereu, A.;
17. (a) Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S.
J. Org. Chem. 2001, 66, 7892; (b) Sundermeier, M.; Zapf,
A.; Mutyala, S.; Baumann, W.; Sans, J.; Weiss, S.; Beller,
M. Chem. Eur. J. 2003, 9, 1828; (c) Rutherford, J. L.;
Hoffmann, D.; Collum, D. B. J. Am. Chem. Soc. 2002,
124, 264; (d) Hoffmann, D.; Collum, D. B. J. Am. Chem.
Soc. 1998, 120, 5810.
Williams, R. J. Org. Chem. 2002, 67, 510; (j) Aggarwal, V.
K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68, 692;
(
k) Kundu, M. K.; Mukherjee, S. B.; Balu, N.; Padma-
kumar, R.; Bhat, S. V. Synlett 1994, 444.
. You, J.; Xu, J.; Verkade, J. G. Angew. Chem., Int. Ed.
003, 42, 5054.
. (a) Gatri, R.; El Gaied, M. M. Tetrahedron Lett. 2002, 43,
4
5
2
18. Basavaiah, D.; Krishnamacharyulu, M.; Jaganmohan
Rao, A. Synth. Commun. 2000, 30, 2061.
7835; (b) Luo, S.; Wang, P. G.; Cheng, J.-P. J. Org. Chem.
2004, 69, 555, and further references on the reaction rate
cited therein.
19. General procedure: A mixture of cycloalkenone (2 mmol),
aldehyde (1 mmol), and TMPDA (1 mmol) in aq THF
(1:1, 0.8 mL) was stirred for 72 h at room temperature.
After appropriate aqueous workup and column chro-
6
. (a) Iwama, T.; Kinoshita, H.; Kataoka, T. Tetrahedron
Lett. 1999, 40, 3741; (b) Kataoka, T.; Iwama, T.;
Tsujiyama, S.-I. Chem. Commun. 1998, 197; (c) Kataoka,
T.; Iwama, T.; Tsujiyama, S.-I.; Iwamura, T.; Watanabe,
S.-I. Tetrahedron 1998, 54, 11813; (d) Bauer, T.; Tarasiuk,
J. Tetrahedron: Asymmetry 2001, 12, 1741.
2 2
matographic purification (hexanes/ether/CH Cl , 4:1:1) we
obtained analytically pure products. All the compounds
except 4h have been reported (Table 2). The spectroscopic
ꢀ
1
data of 4h is as follows. IR (neat) 3433, 1697, 1242 cm
1
;
7
8
9
. Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40,
3
H NMR (CDCl ) d 2.44–2.47 (m, 2H), 2.55–2.61 (m, 2H),
1
539.
3.83 (s, 3H), 3.87 (d, J ¼ 5:4, 1H), 5.84 (d, J ¼ 5:4Hz,
1H), 6.88 (dd, J ¼ 8:1 and 0.9 Hz, 1H), 6.97 (td, J ¼ 7:8
and 0.6 Hz, 1H), 7.23–7.30 (m, 2H), 7.38 (dd, J ¼ 7:8 and
. (a) Zhu, Y.-H.; Vogel, P. Synlett 2001, 79; (b) Pei, W.;
Wei, H.-X.; Li, G. Chem. Commun. 2002, 2412.
. (a) Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39,
1
3
3
1.5 Hz, 1H); C NMR (CDCl ) d 29.97, 49.61, 55.15,
5
965; (b) Sugahara, T.; Ogasawara, K. Synlett 1999, 419.
0. Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000,
1, 2165.
67.19, 109.99, 120.43, 126.24, 128.22, 130.65, 134.16,
1
1
1
155.71, 165.49, 211.18; Anal. Calcd for C13
71.54; H, 6.47. Found: C, 71.48; H, 6.51.
20. For the convenient comparison, we summarized the
14 3
H O : C,
4
1. (a) Shi, M.; Xu, Y.-M. Chem. Commun. 2001, 1876; (b)
Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311.
2. (a) Li, G.; Wei, H.-X.; Gao, J. J.; Caputo, T. D.
Tetrahedron Lett. 2000, 41, 1; (b) Patra, A.; Batra, S.;
Joshi, B. S.; Roy, R.; Kundu, B.; Bhaduri, A. P. J. Org.
Chem. 2002, 67, 5783.
3. Jauch, J. J. Org. Chem. 2001, 66, 609.
4. Lee, K. Y.; Gong, J. H.; Kim, J. N. Bull. Korean Chem.
Soc. 2002, 23, 659.
known methods for the synthesis of 4a: 55% (1a/2a/
1
4
DMAP ¼ 1:1:0.2, aq THF, rt, 72 h), 90% (1a/2a/proaza-
phosphatrane sulfide/TiCl 1:3:0.05:1, CH Cl rt,
10 min), 82% (1a/2a/3-HDQ ¼ 1:2:1, H O, rt, 4h), 60%
69% (1a/2a/imid-
4
,
2
2
,
4
3i
2
1
1b
(1a/2a/DBU ¼ 1:1:1, rt, 0.5 h),
azole ¼ 2:1:0.1, aq THF, rt, 65 days), 61% (1a/2a/imid-
5
a
1
1
5
a
azole ¼ 2:1:0.1, aq THF, 50 °C, 20 days), 45% (1a/2a/
5
b
imidazole ¼ 1:2:1, 1 M NaHCO
2a/Me S/TiCl
BINOL/Bu
LiClO
3
/THF, rt, 90 h), 25% (1a/
6
b
1
1
5. Verkade, J. G. Acc. Chem. Res. 1993, 26, 483.
6. Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki, Y. Chem.
Commun. 1998, 1271.
2
4
¼ 1:3:0.1:1, CH
2 2
Cl , rt, 1 h), 57% (1a/2a/
1
0
3
P ¼ 1:1.5:0.1:0.2, THF, rt, 48 h), 56% (1a/2a/
7
4
/DABCO ¼ 1:1:0.7:0.15, ether, 0 °C, 20 h).