Unprecedented synergistic effects between weak Lewis and Bronsted acids in Prins cyclization

Article abstract of DOI:10.1039/c2cc35052a

Novel synergistic effects between Lewis and Bronsted acids in Prins cyclization are reported. Non-reactive Lewis acids and non-reactive Bronsted acids, which failed to perform Prins cyclization when used alone, have shown remarkable synergistic effects wh

Full text of DOI:10.1039/c2cc35052a

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 9316–9318
www.rsc.org/chemcomm
COMMUNICATION
Unprecedented synergistic effects between weak Lewis and Brønsted
acids in Prins cyclizationw
Prashant Borkar,ab Pierre van de Weghe,*a B. V. Subba Reddy,b J. S. Yadavb and
Rene Gree*a
Received 29th June 2012, Accepted 20th July 2012
DOI: 10.1039/c2cc35052a
Novel synergistic effects between Lewis and Brønsted acids in
Prins cyclization are reported. Non-reactive Lewis acids and
non-reactive Brønsted acids, which failed to perform Prins
cyclization when used alone, have shown remarkable synergistic
effects when used in combination to perform the reaction
successfully.
Lewis acids (entries 10–16, Table 1). This order of classifi-
cation was similar to that of Kobayashi et al.,7 based on
reactivity of Lewis acids in other reactions.
Later, we studied the reactivity of Brønsted acids such as
Ts-OH, camphorsulfonic acid and benzoic acid for the same
model reaction, in the presence of an external nucleophile,8 i.e.
Bu4NBr or NaBr in CH2Cl2. In all those cases, no Prins
cyclization product was found and only trace of acetal was
observed in each case. Next, we performed the same reaction
in the presence of a combination of non-reactive Lewis acid,
i.e. MgBr2 (1.1 equiv.), and various non-reactive Brønsted
acids (1 equiv.) in CH2Cl2 and the results are summarized in
Table 2.9 To our surprise, we observed that such a combi-
nation was able to perform the reaction very well. Among the
several Brønsted acids tested for this conversion in combi-
nation with MgBr2, Ts-OH gave the best result in terms
of reaction time (2 h only) and conversion (entry 2, Table 2).
Prins cyclization is a powerful strategy for the stereoselective
construction of functionalized tetrahydropyran rings, the core
structural units in many natural products.1,2 We, and others,
have explored the scope and application of Prins cyclization in
organic synthesis.3,4 It is promoted or catalyzed by various
Lewis, as well as Brønsted, acids with the net addition of
external nucleophiles to the resulting carbenium ion.1–4 The
ability of reagents to perform the reaction when used in
combination with enhanced rates and high conversions as
synergistic effects make them more useful in synthetic organic
chemistry.5 Recently, we have observed cooperative/synergistic
effects between Sc(OTf)3 and Ts-OH in tandem Prins cyclization.6
It encouraged us to explore this effect in more detail in order to
understand mechanistic aspects and to prepare for future
applications in Prins cyclization. During our study, we observed
very intriguing results: weak Lewis acids and weak Brønsted
acids, which are not able to perform this reaction alone, do it
efficiently when used in combination. To the best of our
knowledge, there are no reports on such synergism between
weak Lewis and Brønsted acids in Prins cyclization.
Table 1 Reactivity of various Lewis acids in Prins cyclization of
3-buten-1-ol and 2-methoxybenzaldehyde
Entry Lewis acid Temp./1C Yielda (%) Diastereomeric ratio
1
2
3
4
5
6
ꢀ20
ꢀ40
ꢀ20
ꢀ40
0–rt
0–rt
95
94
90
88
86
75
98 : 2
98 : 2
95 : 5
97 : 3
80 : 20
98 : 2
Initially, we studied the reactivity of various reported,1,2 as
well as unreported, Lewis acids alone in a model reaction
between 3-buten-1-ol and 2-methoxybenzaldehyde in CH2Cl2
(Table 1). We found three different categories of Lewis acids in
this Prins cyclization. The first one is highly reactive Lewis
acids (entries 1–6, Table 1). The second one is moderately
reactive (entries 7–9, Table 1). The third one is non-reactive
7
8
9
0r0t
00
35
28
25
100 : 00
98 : 2
98 : 2
00
00
00
00
00
00
00
10
11
12
13
14
15
16
—
—
Trace
—
—
—
—
—
—
—
—
—
a
´
Universite de Rennes 1, Institut des Sciences Chimiques de Rennes,
CNRS UMR 6226, Avenue du General Leclerc, 35042 Rennes
Cedex, France. E-mail: rene.gree@univ-rennes1.fr;
´
´
Fax: +33 2 23 23 69 78
b Natural Product Chemistry Division, Indian Institute of Chemical
Technology, Uppal Road, Tarnaka, Hyderabad 500607, India
w Electronic supplementary information (ESI) available: Experimental
details, characterization data, copies of 1H and 13C NMR spectrum of
products. See DOI: 10.1039/c2cc35052a
—
—
a
Isolated yield.
c
This journal is The Royal Society of Chemistry 2012
9316 Chem. Commun., 2012, 48, 9316–9318

View Online
Table 2 Synergistic effects between MgBr2 and various Brønsted
acids in Prins cyclization
Table 3 The scope of synergistic effect between MgBr2 and Ts-OH
for the synthesis of 4-bromotetrahydropyran derivatives in Prins
cyclization
Entry Brønsted acid
Conversion (%) Diastereomeric ratio
Diastereo-
meric
Homoallylic Carbonyl
Entry alcohol
compound Producta
Time/
h
1
2
3
4
5
6
7
8
—
p-Toluenesulphonic acid 94
Camphorsulphonic acid 87
4-Nitrobenzoic acid
2-Iodobenzoic acid
Acetic acid
0
—
Yieldb ratio
92 : 8
80 : 20
95 : 5
95 : 5
90 : 10
95 : 5
93 : 7
58
56
55
37
a
b
c
2
3
84
71
92 : 8
Benzoic acid
4-Hydroxybenzoic acid 30
’’
’’
’’
82 : 18
65 : 35
86 : 14
In that case, the corresponding major product 3a was isolated
in 84% yield. From Table 2, it seems that the strength of
synergistic effect is a direct function of the pKa of Brønsted
acid but even weak acids, such as acetic or benzoic acids, show
this synergistic effect.
1.5 60
1.5 76
Inspired by the above results, we compared the reactivity
of various Lewis acids in the absence, or in the presence, of
Ts-OH, in Prins cyclization (Table S1, see ESIw).9,10
d
A similar cooperative effect between several non-reactive
Lewis acids such as NiBr2, LiBr, MgCl2,10 LaCl3, NiCl2, LiCl
with Ts-OH was observed in this reaction (entries 3, 4, 8–11,
Table S1, see ESIw). Further, moderately reactive Lewis acids
i.e. ZnBr2, SnCl2 and ZnCl2 have shown excellent synergistic
effects with Ts-OH, with tremendous enhancement in reaction
rate and conversion (entries 2, 6, 7, Table S1, see ESIw). Even
the active Lewis acids i.e. InBr3 and InCl3 showed enhanced
reaction rate when used in combination with Ts-OH (entries 1
and 5, Table S1, see ESIw). Thus, it clearly demonstrates an
interesting synergism between Lewis and Brønsted acids in
Prins cyclization.
e
f
’’
’’
1
1
83
88 : 12
90 : 10
88c
g
h
i
’’
’’
’’
1.5 56
1.5 58
65 : 35
68 : 32
—
Next, we examined the scope of synergism between MgBr2
and Ts-OH with respect to different carbonyl compounds, as
well as with other homoallylic substrates, in Prins cyclization
and the results are summarized in Table 3.9 It is efficient
with various aromatic aldehydes (entries b–d, f, Table 3).
a,b-Unsaturated aldehydes also participated well with a faster
reaction rate (entry e). Aliphatic aldehydes like pivalaldehyde
and n-hexanal reacted well in this conversion (entries g and h).
Aliphatic ketones like cyclohexanone and 2-pentanone also
underwent smooth cyclization in this protocol (entries i and j).
The other homoallyllic substrates like 1-phenylbut-3-en-1-ol
and non-1-en-4-ol also reacted well with 2-methoxybenzal-
dehyde under the reaction conditions (entries k and l). It
afforded a mixture of two diastereoisomers easily separated
by column chromatography except in entry f. The stereo-
chemistry of all products was established by extensive 1D
and 2D NMR experiments.
4
3
72
80
j
’’
—
k
5
5
75
78
88 : 12
90 : 10
l
a
Products were characterized by 1H and 13C NMR and mass spectro-
b
scopy. Yield refers to a pure single diastereomer after column
c
chromatography. Combined yield of two diastereomers which are
inseparable by column chromatography.
During these studies, in some cases, we could observe and
isolate small amount of acetals which are formed by the
reaction of homoallylic alcohol and aldehydes. This raises
the question of the possible role of such acetals during this
reaction. Therefore, next, we synthesized one model acetal
and studied its reactivity towards Prins cyclization in the
presence of reactive, as well as non-reactive, Lewis acids and
Brønsted acids (Table 4). Apart from reactive Lewis acids such
as InBr3, InCl3, ZnBr2, ZnCl2 which are already working, the
non-reactive Lewis acids such as MgBr2, LiBr, MgCl2, LaCl3
were also able to perform Prins reaction with the acetal alone,
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9316–9318 9317

View Online
Table 4 Reactivity of various Lewis and Brønsted acids in the Prins
cyclization of acetal 6
works efficiently in this reaction. Development of this new
synergistic effect and applications in synthesis are under study
in our groups and will be reported in due course.
This research has been performed as part of the Indo-
French ‘‘Joint Laboratory for Sustainable Chemistry at
Interfaces’’. We thank CNRS, France, and CSIR, India, for
support. P.B. thanks Rennes-Metropole for the award of a
fellowship during internship at the University of Rennes 1.
Entry Acid catalyst
Conversion (%)
Ratio (dr)%
1
2
3
4
5
6
7
8
lnBr3
ZnBr2
MgBr2
LiBr
NiBr2
lnCl3
ZnCl2
MgCl2
96
70
80
35
o2%
88
82
25
20
5
80 : 20
99 : 1
96 : 4
80 : 20
—
97 : 3
98 : 2
99 : 1
98 : 2
—
Notes and references
1 For an excellent recent review on Prins reactions see: (a) C. Olier,
M. Kaafarani, S. S. Gastaldi and M. P. Bertrand, Tetrahedron,
2010, 66, 413; (b) D. R. Adams and S. R. Bhatnagar, Synthesis,
1977, 661; (c) E. Arundale and L. A. Mikeska, Chem. Rev., 1952,
51, 505; (d) I. M. Pastor and M. Yus, Curr. Org. Chem., 2007,
11, 925; (e) E. A. Crane and K. A. Scheidt, Angew. Chem., Int. Ed.,
2010, 49, 8316.
2 (a) B. B. Snider, in The Prins Reaction and Carbonyl Ene
Reactions, ed. B. M. Trost, I. Fleming and C. H. Heathcock,
Pergamon Press, New York, 1991, vol. 2, pp. 527;
(b) L. E. Overman and L. D. Pennington, J. Org. Chem., 2003,
68, 7143; (c) P. A. Clarke and S. Santos, Eur. J. Org. Chem., 2006,
2045.
9
LaCl3
LiCl
NiBr2
10
11
12
13
14
—
32% + 68% hydrolysis 60 : 40
40
—
p-TSA + Bu4NBr
CSA + Bu4NBr
Benzoic acid + Bu4NBr —
65 : 35
—
3 (a) F. Liu and T.-P. Loh, Org. Lett., 2007, 9, 2063; (b) J. Lu,
Z. Song, Y. Zhang, Z. Gan and H. Li, Angew. Chem., Int. Ed.,
2012, 51, 5367; (c) S. Marumoto, J. J. Jaber, J. P. Vitale and
S. D. Rychnovsky, Org. Lett., 2007, 9, 2063; (d) D. Clarisse,
B. Pelotier, O. Piva and F. Fache, Chem. Commun., 2012,
48, 157; (e) B. Yu, T. Jiang, J. Li, Y. Su, X. Pan and X. She,
Org. Lett., 2009, 11, 3442; (f) C. S. Barry, N. Bushby, J. P. H.
Charmant, J. D. Elsworth, J. R. Harding and C. L. Willis, Chem.
Commun., 2005, 5097; (g) L. E. Overman and E. J. Velthuisen,
J. Org. Chem., 2006, 71, 1581; (h) J. D. Elsworth and C. L. Willis,
Chem. Commun., 2008, 1587; (i) O. L. Epstein and T. Rovis, J. Am.
Chem. Soc., 2006, 128, 16480; (j) X.-F. Yang, M. Wang, Y. Zhang
and C.-J. Li, Synlett, 2005, 1912.
Scheme 1 Proposed mechanism of Prins cyclization.
4 (a) J. S. Yadav, P. P. Chakravarthy, P. Borkar, B. V. S. Reddy and
A. V. S. Sarma, Tetrahedron Lett., 2009, 50, 5998; (b) J. S. Yadav,
P. Borkar, P. P. Chakravarthy, B. V. S. Reddy, A. V. S. Sarma,
B. Sridhar and R. Gree, J. Org. Chem., 2010, 75, 2081; (c) B. V. S.
Reddy, S. Jalal, P. Borkar, J. S. Yadav, P. P. Reddy, A. C. Kunwar
and B. Sridhar, Org. Biomol. Chem., 2012, 10, 6562;
(d) J. S. Yadav, B. V. S. Reddy, M. S. Reddy, N. Niranjan and
A. R. Prasad, Eur. J. Org. Chem., 2003, 1779; (e) J. S. Yadav,
M. R. Pattanayak, P. P. Das and D. K. Mohapatra, Org. Lett.,
2011, 13, 1710; (f) J. S. Yadav, B. V. S. Reddy, T. Maity and
G. G. K. S. N. Kumar, Tetrahedron Lett., 2007, 48, 7155;
(g) M. Jacolot, M. Jean, N. Levoin and P. van de Weghe, Org.
Lett., 2012, 14, 58.
5 (a) H. Yamamoto and K. Futatsugi, Angew. Chem., Int. Ed., 2005,
44, 1924; (b) P. Li and H. Yamamoto, Top. Organomet. Chem.,
2011, 37, 161.
6 B. V. S. Reddy, P. Borkar, J. S. Yadav, B. Sridhar and R. Gree,
J. Org. Chem., 2011, 76, 7677.
7 S. Kobayashi, T. Basujima and S. Nagayama, Chem.–Eur. J., 2000,
6, 3491.
8 A. K. Saikia, S. Bondalapati, K. Indukuri and P. Gogoi, Chem.
Lett., 2011, 1176.
without the addition of Brønsted acid (Table 4). Among those
the non-reactive Lewis acid, MgBr2, was found to give the best
results in terms of reactivity (entry 3). The Brønsted acids such
as Ts-OH and camphorsulfonic acid in the presence of an
external nucleophile, such as Bu4NBr, were also able to undergo
this reaction starting from acetal (entries 12 and 13). Among the
various solvents studied for this conversion, CH2Cl2 gave the
best results in terms of conversion.
Based on these observations, we can propose a tentative
mechanism for Prins cyclization.11 Apart from the classical
pathway 1, this reaction may proceed also through the acetal
formation A from homoallyl alcohol and aldehyde and this
reaction could be initiated by a first promoter, such as a
Brønsted acid. Then, the acetal A may undergo rapid formation
of the oxocarbenium ion intermediate B which undergoes
cyclization to give the carbenium ion C. This second step can
be now mediated by a second promoter such as a Lewis acid.12
Then, the formed carbenium ion C may be trapped by bromide
ions to form the corresponding 4-bromotetrahydropyran
derivative (Scheme 1). Therefore, in this second pathway, the
two acid promoters play sequential roles.
9 Reactions were performed on a 1 mmol scale, reaction conversion
and diastereomeric ratio were determined on the basis of 1H NMR
spectra of the crude products.
10 For details on this study, see ESIw.
11 It can also be envisaged that combination of Lewis acids with
Brønsted acids enhances the acidity of latter derivatives and
therefore modifies their reactivity, for instance in Prins
cyclizations.
12 For examples of Prins type cyclizations invoving alkynyl acetals as
intermediates see: (a) P. O. Miranda, D. D. Diaz, J. I. Padron,
J. Bermejo and V. S. Martin, Org. Lett., 2003, 5, 1979; (b) T. Yu,
Z. Yu and L. Wang, Org. Lett., 2009, 10, 2113.
In conclusion, we discovered and studied a new synergistic/
cooperative effect between weak Lewis and Brønsted acids in
Prins cyclization. The combination of a non-reactive Lewis
acid, like MgBr2, and non-reactive Brønsted acid, such as Ts-OH,
c
9318 Chem. Commun., 2012, 48, 9316–9318
This journal is The Royal Society of Chemistry 2012