A mild and efficient bisaldolization of ketones and its application towards spirocyclic 1,3-dioxanes and novel 1,3,5-trioxocanes

Article abstract of DOI:10.1055/s-0028-1088130

Bisaldolization of aryl alkyl ketones as well as cyclic ketones with paraformaldehyde in the presence of a catalytic amount of L-proline and low concentration of aqueous sodium hydroxide has been developed in excellent yields. Further, these bisaldols are

Full text of DOI:10.1055/s-0028-1088130

1346
LETTER
A Mild and Efficient Bisaldolization of Ketones and its Application towards
Spirocyclic 1,3-Dioxanes and Novel 1,3,5-Trioxocanes
Bisaldolization of
a
K
etones garapu Srinivas, Vijay K. Marrapu, Kalpana Bhandari*
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
Fax +91(522)2623405; E-mail: bhandarikalpana@rediffmail.com
Received 23 January 2009
with small amount of bisaldol product 2a, but no bis-Man-
Abstract: Bisaldolization of aryl alkyl ketones as well as cyclic
ketones with paraformaldehyde in the presence of a catalytic
amount of L-proline and low concentration of aqueous sodium
hydroxide has been developed in excellent yields. Further, these
nich adduct 3 was observed (Scheme 1). This observation
is consistent with the previous report that the unsubstitut-
ed azoles cannot form iminium ions with aldehydes,10 so
bisaldols are elaborated to the corresponding spirocyclic dioxanes the Mannich adduct of imidazole, such as compound 1
and novel spirocyclic trioxocanes in the presence of p-toluene sul-
fonic acid. The structures and preferred conformations of these
eight-membered spirocyclic 1,3,5-trioxocanes are discussed.
(Scheme 1), is likely to form by a mechanism that pro-
ceeds first through aldol reaction with paraformaldehyde,
then elimination to generate exo-enone and subsequent
conjugate addition of the azole.
Key words: aqueous media, bisaldol, Mannich adduct, Mannich-
aldol, L-proline, spirocylic dioxane, trioxocane
N
N
Bisaldol (1,3-diol) units are frequently found in complex
OH
1
polyol architectures (which are raw material for lubri-
cants, surface coatings, and synthetic resins) of natural
products and have attracted a great deal of attention from
synthetic organic chemists.1 Mostly 1,3-diol units are the
key substrates for the synthesis of dendrimers (drug carri-
ers) and crown-ethers.2 The traditional production meth-
ods of these bisaldols use strong alkali and several anion-
exchange resin catalysts.3 These methods create mixture
of products (aldol, cross-aldol, and acroleins) along with
the required product.4
O
1) imidazole (2 equiv)
2) (HCHO)n (2 equiv)
3) L-proline (0.3 equiv)
>95%
+
OH
H2O, 80 °C
2a
OH
O
O
N
~ 5%
+
N
N
3
O
Cordova and co-workers have demonstrated the L-pro-
line-catalyzed direct stereoselective aldol reaction be-
tween ketone and formaldehyde, which have triggered a
broad interest in organocatalysis.5 However, there is no
report of bisaldolization under similar reaction conditions.
N
0%
Scheme 1 Mannich adducts of azoles with excess of imidazole
Ibrahem et al. have introduced the first enantioselective Herein, we report a very efficient L-proline and aqueous
three-component Mannich reaction of ketone, formalde- NaOH-catalyzed bisaldol reaction of aryl alkyl and cyclic
hyde, and amine using L-proline as catalyst.6 Later, Erk- ketones in water.11 The use of water makes it an easy han-
kila et al. and Wei Wang and co-workers used a similar dling and attractive alternative for large-scale production
type of strategy for synthesis of a,b-unsaturated alde- of bisaldols. We also report the elaboration of these bis-
hydes and ketones, respectively.7 Based on this, we have aldols into corresponding spirocyclic 1,3-dioxanes 9–16a
reported the Mannich adducts and Mannich–aldol prod- and novel spirocyclic 1,3,5-trioxocanes 10b–16b.
ucts of unsubstituted azoles using L-proline as a catalyst
We next performed the above reaction (Scheme 1) using
more than 2.0 equivalents of imidazole and observed that
for the first time.8
In connection with this study and our continued interest the bisaldol product 2a also increased up to certain extent
on azole-based compounds,9 we conducted an initial reac- (5–7%). Hence, we anticipated that bisaldol formation is
tion of ketone (1.0.equiv), paraformaldehyde (2.0 equiv), favored by increasing the basicity of the reaction medium.
and L-proline (0.3 equiv) with excess of imidazole (2.0 This presumption was confirmed by carrying out the reac-
equiv). The reaction proceeded smoothly to furnish the tion of tetralone (1.0 equiv), paraformaldehyde (4.0
Mannich–aldol-type compound 1 (ca. 93–95%) along equiv), and L-proline (40.0 mole%) in aqueous 0.2 M
NaOH (instead of imidazole) at ambient temperature to
furnish exclusively the bisaldol product in excellent yields
SYNLETT 2009, No. x, pp 1346–1350
Advanced online publication: 08.04.2009
DOI: 10.1055/s-0028-1088130; Art ID: G01609ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9
(Table 1, 2a). Consequently, by increasing the molar ratio
of aqueous NaOH (>0.2 M), several products were found
in the reaction mixture (from TLC observation). Howev-

LETTER
Bisaldolization of Ketones
1347
Table 1 L-Proline and Aqueous NaOH-Promoted Bisaldol Reaction of Ketones with Paraformaldehydea
R
R
(HCHO)n (4.0 equiv)
L-proline (40 mol%)
OH
n
n
0.2 M NaOH
OH
O
O
1a–8a
Entry
1
Ketone
Productb
Time (h)
5
Yield (%)c
88
mp (°C)
83
OH
OH
1a
O
O
2
3
4
4
96
95
97
98
OH
2a
OH
O
O
MeO
MeO
4.5
4
106
78
OH
OH
3a
O
O
O
O
O
O
OH
4a
OH
O
O
OH
5
6
4
98
87
84
oil
OH
5a
O
O
6.5
OH
OH
6a
O
O
O
O
Cl
Cl
Cl
Cl
7
8
6
89
89
90
93
OH
OH
7a
O
O
3.5
OH
OH
8a
a For general synthetic procedure see References and Notes section.
b Products identified by 1H NMR and 13C NMR spectroscopy.
c Isolated yields.
er, in the absence of L-proline the ketone was not con- ditions. However, in the presence of secondary amines
sumed, and the formation of bisaldol adduct was not like pyrrolidine or morpholine the Mannich product of
observed.
these amines were obtained in major amount (total amine
involved in the reaction)12 with only traces of the desired
bisaldol product. Thus, the best results for bisaldolization
were obtained with L-proline as catalyst.
Encouraged by the results obtained in the above reaction
and in order to show the generality and scope of this new
protocol, a wide variety of cyclic and aryl alkyl ketones
were evaluated and the results are summarized in Table 1. We speculate that the above reaction proceeds through an
These ketones reacted efficiently with paraformaldehyde L-proline-catalyzed aldol formation13 and subsequent
to afford the desired products in high yields (1a–8a).
generation of enol in the presence of alkali followed by
conjugate addition of formaldehyde to furnish the bis-
aldol. To confirm this, we performed the reaction of a
Further, instead of L-proline different amines were also
examined in bisaldolization using the same reaction con-
Synlett 2009, No. x, 1346–1350 © Thieme Stuttgart · New York

1348
LETTER
Table 2 Transformation of Bisaldols to Corresponding Spirocyclic
ketone with paraformaldehyde and L-proline in the ab-
sence of NaOH. The only product isolated was the mono-
aldol b. On addition of 0.2 M aqueous NaOH, the reaction
proceeded very fast to completion and furnished the de-
sired bisaldol c (Scheme 2).
Compoundsa (continued)
R
n
O
R
(HCHO)n (4.0 equiv)
PTSA (0.05 equiv)
O
O
O
9–16a
O
OH
O
O
n
OH–
L-proline
CH2CI2, r.t.
OH
OH
+
R1
R1
R1
OH
well-recognized
aldol pathway
R
R2
OH
R2
R2
O
1a–8a
n
c
b
O
Scheme 2
O
O
10b–16b
Entry Productb
Time (h) mp (°C) Yield (%)c,d
Table 2 Transformation of Bisaldols to Corresponding Spirocyclic
Compoundsa
O
O
O
R
12a
oil
62
97
(46:51)
O
O
O
n
4
12
O
R
(HCHO)n (4.0 equiv)
PTSA (0.05 equiv)
O
O
O
9–16a
OH
n
O
12b
CH2CI2, r.t.
+
O
O
R
OH
O
1a–8a
O
n
5
9
88
100
98
O
Me
O
O
O
13
O
10b–16b
O
O
O
Entry Productb
Time (h) mp (°C) Yield (%)c,d
6
8
102
128
1
12
82
99
O
14
O
9
O
O
O
Cl
7
8.5
96
O
O
O
10a
47
oil
100
(45:55)
O
O
15
2
11
O
O
O
Cl
O
10b
O
O
O
16a
oil
134
100
(44:56)
MeO
O
O
8
10.5
Cl
O
11a
101
oil
100
(35:65)
O
O
O
3
11.5
MeO
O
16b
O
O
a For general synthetic procedure see References and Notes section.
b Corresponding bisaldols are the starting materials.
c Isolated yields.
O
11b
O
d Both spirocyclic 1,3-dioxane and 1,3,5-trioxocanes mentioned in
specified ratios.
We further elaborated these bisaldols into spirocyclic ring
systems. Thus, a reaction between bisaldol 2a with
paraformaldehyde and catalytic amount of PTSA14 in
CH2Cl2 at room temperature resulted in the expected six-
Synlett 2009, No. x, 1346–1350 © Thieme Stuttgart · New York

LETTER
Bisaldolization of Ketones
1349
membered spirocyclic 1,3-dioxane 10a along with unex- Supporting Information for this article is available online at
pected eight-membered spirocyclic 1,3,5-trioxocane 10b http://www.thieme-connect.com/ejournals/toc/synlett.
in almost equal amounts. Bisaldols 1a–8a15 were used to
furnish the corresponding spirocyclic compounds 9–
Acknowledgment
16b,16 and the results are summarized in Table 2. It can be
The authors are grateful to SAIF for analytical data and Anoop
Srivastava for technical assistance. N.S.V and V.K.M. are thankful
to the UGC and CSIR, New Delhi, India for financial support.
seen from Table 2 that all the bisaldols 1a–8a reacted to
provide corresponding 1,3-dioxanes 9–16a. Interestingly,
it can also be seen that only chromanone and tetralone de-
rived bisaldols 2a, 3a, 4a, and 8a reacted to provide the
corresponding 1,3,5-trioxocanes 10b, 11b, 12b, and 16b,
respectively.
References and Notes
(1) Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021.
(2) (a) Cordova, A.; Janda, K. D. J. Am. Chem. Soc. 2001, 123,
8248. (b) Horva, G.; Huszthy, P.; Szarvas, S.; Szokan, G.;
Redd, J. T.; Bradshaw, J. S.; Izatt, R. M. Ind. Eng. Chem.
Res. 2000, 39, 3576.
(3) (a) Weissermel, K.; Arpe, H. J. Polyhydric Alcohols, In
Industrial Organic Chemistry, 3rd ed.; VCH: New York,
1997, 210. (b) Holm, V. S.; Salmi, T.; Arvela, P. M.;
Paatero, E.; Lindfors, L. P. Org. Process Res. Dev. 2001, 5,
368.
(4) Jan, E. V. Acta. Chem. Scand. Ser. B 1974, 28, 509.
(5) (a) Notz, W.; Tanaka, F.; Barbas III, C. F. Acc. Chem. Res.
2004, 37, 580. (b) Cordova, A.; Barbas III, C. F.
Tetrahedron Lett. 2003, 44, 1923. (c) Casas, J.; Sunden, H.;
Cordova, A. Tetrahedron Lett. 2004, 45, 6117.
(6) Ibrahem, I.; Casas, J.; Cordova, A. Angew. Chem. Int. Ed.
2004, 43, 6528.
(7) (a) Erkkila, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538.
(b) Wang, W.; Mei, Y.; Li, H.; Wang, J. Org. Lett. 2005, 7,
601.
To the best of our knowledge no report concerning spiro-
cyclic 1,3,5-trioxocanes exist. However, limited number
of literature is available regarding 1,2,4-, 1,3,5-, and
1,3,6-trioxocanes.17 Based on earlier reports we hypothe-
sized that the large molecules like the spirotrioxocanes are
unstable under extreme (high temperature, pressure, and
microwave-assisted) conditions.18 However, the reactions
performed at ambient temperature and mild conditions
have permitted us to the isolate and characterize these
novel compounds.19
The structure and conformation of spirocyclic trioxocanes
was deduced from the 1H NMR, 13C NMR, and 2D NMR
data. The conformational flexibility could lead to two
conformers I and II in which the eight-membered trioxo-
cane ring is stable in crown shape (Figure 1). This was
confirmed by the 2D NOESY cross peaks between H-2/H-
8 and H-2/H-4 of all the same pole protons (like H-2, the
H-4, H-6, and H-8 are also correlating). The energy-
minimized structure III also supported the same fact.
(8) Srinivas, N.; Bhandari, K. Tetrahedron Lett. 2008, 49, 7070.
(9) (a) Srinivas, N.; Palne, S.; Nishi Gupta, S.; Bhandari, K.
Bioorg. Med. Chem. Lett. 2009, 19, 324. (b) Bhandari, K.;
Srinivas, N.; Shiva Keshava, G. B.; Shukla, P. K. Eur. J.
Med. Chem. 2009, 437.
(10) Bachman, G. B.; Heisey, L. V. J. Am. Chem. Soc. 1946, 68,
2496.
(11) (a) Li, C. J.; Chan, T. H. Organic Reactions in Aqueous
Media; John Wiley and Sons: New York, 1997. (b)Organic
Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic
and Professional: London, 1998. (c) Blackmond, D. G.;
Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem. Int.
Ed. 2007, 46, 3798.
(12) Kagan, E. S.; Ardashev, B. I. Chem. Heterocycl. Compd.
1967, 3, 701.
(13) (a) Emer, E.; Galletti, P.; Giacomini, D. Tetrahedron 2008,
64, 11205. (b) Zhao, J. F.; He, L.; Jiang, J.; Tang, Z.; Cun,
L. F.; Gong, L. Z. Tetrahedron Lett. 2008, 49, 3372.
(14) Kim, K. S.; Ahn, Y. H. Tetrahedron: Asymmetry 1998, 9,
3601.
(15) General Procedure for the Preparation of Bisaldols 1a–
8a (e.g., 2a)
A solution of a-tetralone (1.0 mmol), paraformaldehyde (4.0
mmol), and L-proline (40 mol%) in H2O (0.5 mL) was stirred
at r.t. for 34 h. To this added 0.53 M NaOH (0.3 mL) solution
slowly. After completion of the reaction (monitored by TLC)
the reaction mixture was extracted with EtOAc (3 × 4 mL).
The combined organic extracts were washed with distilled
H2O (5 × 3 mL), dried over Na2SO4, and removal of the
solvent under reduced pressure furnished the crude product,
which was filtered through SiO2 column (EtOAc–hexane =
1:2, v/v) to give 2a (96%) as a white solid; mp 98–99 °C. 1H
NMR (300 MHz, CDCl3): d = 1.98 (t, J = 6.4 Hz, 2 H), 3.01
(t, J = 6.4 Hz, 2 H), 3.62 (br s, 2 H), 3.71–3.95 (dd, J = 11.3
Hz, 4 H), 6.69 (m, 2 H), 6.84 (d, J = 8.8 Hz, 1 H), 7.97 (d,
Figure 1 Characteristic NOE and energy-minimized structure of 12b
was optimized from MM and MD simulations
In summary, we have developed a very efficient and mild
reaction for synthesizing bisaldols from cyclic and aryl
alkyl ketones and converted them into spirocyclic 1,3-di-
oxanes and novel spirocyclic 1,3,5-trioxocanes. Further
elaboration of this transformation and its synthetic appli-
cations are ongoing in our laboratory.
Synlett 2009, No. x, 1346–1350 © Thieme Stuttgart · New York

1350
LETTER
J = 8.8 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 24.9, 26.4,
51.2, 64 (2 C), 126.8, 127.6, 128.9, 131.6, 134.1, 143.8,
203.1. ESI-MS: m/z (%) = 207 (100) [M + 1]+.
143.2, 198.1. IR (KBr): 3222, 2361, 1708, 1221, 1165, 762,
667 cm–1. ESI-MS: m/z (%) = 219 (77) [M + 1]+.
Compound 10b: oil. 1H NMR (300 MHz, CDCl3): d = 2.26
(t, J = 6.4 Hz, 2 H), 3.04 (t, J = 6.4 Hz, 2 H), 3.82–4.21 (dd,
J = 12.0 Hz, 4 H), 4.8 (d, J = 6.7 Hz, 2 H), 4.96 (d, J = 6.4
Hz, 2 H), 7.34 (m, 2 H), 7.52 (m, 1 H), 8.03 (d, J = 7.8 Hz, 1
H). 13C NMR (75 MHz, CDCl3): d = 24.8 (2 C), 28.7, 29.6,
49.6, 69.9, 95.9, 126.7, 127.8, 128.7, 131.4, 133.5, 143.2,
199.4. IR (neat): 3027, 2367, 1709, 1217, 1161, 767 cm–1.
ESI-MS: m/z (%) = 249 (100) [M + 1]+.
(16) General Procedure for the Preparation of 9–16b (e.g.,
10a,b)
A mixture of 2,2-bishydroxymethyl-3,4-dihydro-2H-
naphthalen-1-one (2a, 1.0 mmol), paraformaldehyde (4.0
mmol), and catalytic amount of PTSA (0.05 equiv) in
CH2Cl2 (6 mL) was stirred at ambient temperature for 11 h.
After completion of reaction (monitored by TLC), the
reaction mixture was filtered through sintered funnel. The
filtrate was washed with 1% aq NaHCO3 solution (2 × 2
mL), followed by H2O (3 × 2 mL), and dried over anhyd
Na2SO4. Removal of the solvent under vacuum afforded the
crude mixture of corresponding spirocyclic 1,3-dioxane 10a
and 1,3,5-trioxocane 10b in quantitative amount. The above
mixture was subjected to Florisil column (EtOAc–hexane =
1:20, v/v) to give pure products (10a and 10b in a 1:1.2 ratio).
Compound 10a: mp 46–47 °C. 1H NMR (300 MHz, CDCl3):
d= 2.92 (t, J = 6.9 Hz, 2 H), 3.66 (d, J = 11.6 Hz, 2 H), 3.98–
4.07 (dd, J = 11.6 Hz, 2 H), 4.69 (d, J = 5.8 Hz, 2 H), 5.24
(d, J = 5.8 Hz, 2 H), 7.18 (m, 1 H), 7.31 (m, 2 H), 7.63 (d,
J = 6.4 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 24.8, 27.5,
45.9, 70.6 (2 C), 94.3, 126.8, 127.7, 128.9, 131.7, 133.9,
(17) (a) Singh, C.; Pandey, S.; Saxena, G.; Srivastava, N.;
Sharma, M. J. Org. Chem. 2006, 71, 9057. (b) Ushigoe, Y.;
Torao, Y.; Masuyama, A.; Nojima, M. J. Org. Chem. 1997,
62, 4949. (c) McCullough, K. J.; Masuyama, A.; Morgan,
K. M.; Nojima, M.; Okada, Y.; Satake, S.; Takeda, S.
J. Chem. Soc., Perkin Trans. 1 1998, 2353. (d) Martin, A.;
Martin, I. P.; Quintanal, L. M.; Suarez, E. Org. Lett. 2007, 9,
1785.
(18) (a) Polshettiwar, V.; Varma, R. S. J. Org. Chem. 2007, 72,
7420. (b) Hiraguri, Y.; Tokiwa, Y. Macromolecules 1997,
30, 3691.
(19) Experimental procedures, characterization and 1D, 2D NMR
spectra are available as supplementary data.
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