α-Hydroxyacids accelerate the Diels-Alder reaction of dibutyl vinylboronate with cyclopentadiene: Experimental results and mechanistic insights

Article abstract of DOI:10.1039/c5nj03015c

We have found that α-hydroxyacids accelerate the Diels-Alder reaction of dibutyl vinylboronate with cyclopentadiene. When stoichiometric quantities are used, excellent yields are obtained, while catalytic activities are moderate. DFT calculations suggested that the activation of the dienophile occurs by ligand exchange with both functionalities of the α-hydroxyacid.

Full text of DOI:10.1039/c5nj03015c

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DOI: 10.1039/C5NJ03015C
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α-Hydroxyacids accelerate the Diels-Alder reaction of dibutyl
vinylboronate with cyclopentadiene: experimental results and
mechanistic insights
Received 00th January 20xx,
Accepted 00th January 20xx
N. Grimblat, A. M. Sarotti, P. L. Pisano and S. C. Pellegrinet*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We have found that α-hydroxyacids accelerate the Diels-Alder
reaction of dibutyl vinylboronate with cyclopentadiene. When
stoichiometric quantities are used excellent yields are obtained,
while catalytic activities are moderate. DFT calculations suggested
that activation of the dienophile occurs by ligand exchange with
both functionalities of the α-hydroxyacid.
hydroxyacid
48 h
1)
OBu
B
rt,
DCM,
H2O2
+
+
OH
NaOH 3N
0 °C to rt
,
Et
OBu
aq.
2)
THF, 3N,
16 h
OH
8N
2
1
8X
OH
(5 equiv.)
O
OH
OAc
OH OH
HO
HO
OH
OH
OMe
OH
OH
O
O
O
O
Recent years have witnessed a growing interest in the Diels-
Alder (DA) reaction of boron-activated dienophiles.1-11 We
have been devoted to the development of an organocatalytic
version of the DA reactions of alkenylboronates. Initial
attempts using chiral biphenols were unsuccessful. In 2010,
Sugiura and coworkers reported the first example of the use of
chiral α-hydroxyacids as enantioselective organocatalysts in
boronic acids reactions.12 Since then, an increasing amount of
publications that extended this approach have appeared in the
literature.13-19 We figured that α-hydroxyacids could accelerate
the DA reactions of unsaturated boronates.
O
4
5
6
7
3
(2 equiv.)
N.R.
(1 equiv.)
36%
exo
(1 equiv.)
<10%
exo
(1 equiv.)
<10%
exo
48:52
(2 equiv.)
<10%
exo
endo/
66:34 endo/
50:50 endo/
endo/
61:39
Scheme 1. Initial screening of hydroxyacids
We next optimized the reactions conditions using (S)-mandelic
acid (5). Based on previous results from our group, we first
investigated the use of microwave heating.6 A slightly higher
yield (47%) was obtained in 1 h at 70 °C with 2 equivalents of
We evaluated this strategy for the DA reaction of dibutyl
vinylboronate (1) with cyclopentadiene (2) (Scheme 1). The
5
. We then screened the solvent, the temperature, the
addition of an alcohol,20 and the number of equivalents of
5
diastereomeric cycloadducts were oxidized to the alcohols
under standard conditions due to the lability of the dibutyl
(Scheme 2). Best yields were obtained adding 1.7 equivalents
of t-BuOH at 70 °C in DCM under microwave irradiation.21
Protic solvents generated traces of the product, which may be
due to competitive intermolecular interactions or ligand
exchange reactions.
Next, we decided to analyze the effect of the substituent at
the α carbon atom of the α-hydroxyacid. A variety of
structurally related α-hydroxyacids was evaluated in both
catalytic and stoichiometric conditions (Table 1). All α-
hydroxyacids generated greater yields than the background
reaction under all conditions. The increase in the reaction time
from 1 to 2 hours, considerably improved the yields in all
cases. Overall, best yields were obtained using 1 equivalent of
boronate moiety.7 (S,S)-Tartaric acid (
3
) gave the same yield as
the background reaction (<10%, endo/exo 47:53). We then
tested salicylic acid ( ) as a β-hydroxyacid without detecting
the formation of the desired product. Fortunately, (S)-
mandelic acid ( ) afforded a 36% yield. Next, we evaluated the
use of (S)-O-acetylmandelic acid ( ) and (S)-methyl mandelate
). Since both compounds gave much lower yields than
4
5
6
(7
5
(<10%), we demonstrated that both functional groups of the α-
hydroxyacid are necessary.
Instituto de Química Rosario (CONICET), Facultad de Ciencias Bioquímicas y
Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, Rosario (2000),
Argentina. .
α-hydroxyacid (up to 93% with (S)-
5). When 30 mol% was used
yields up to 64% were obtained, which proved that the
reaction can be catalyzed with this type of compounds. We
evaluated the increase of the reaction time to 3 h with 30
Electronic Supplementary Information (ESI) available: Experimental section, 11B
NMR spectra; computational methods; shapes and energies of the FMOs of the
reactants; optimized geometries of transition structures not included in the paper;
cartesian coordinates, absolute energies including zero-point energy corrections,
free energies and number of imaginary frequencies of all the stationary points
reported in the paper and values of imaginary frequencies of all transition
structures.. See DOI: 10.1039/x0xx00000x
mol% of (S)-
enantiomeric excesses were below 20%.22 It is worth noting
that to obtain comparable yields of alcohols in the absence
5 but the yield only raised to 72%. Unfortunately,
8
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of α-hydroxyacids the studied DA reaction has to be performed
at 150 °C with MW irradiation for 1 h (91%, endo/exo
41:59).7,23
View Article Online
O
O
DOI: 10.1039/C5NJ03015C
O
*
O
*
*
O
O
HO
HO
H
*
H
Ph
Ph
Ph
OH
OH
OBu
B
O
O
B
5
5
B
*
OBu
OBu
O
H
O
-
-
BuOH
BuOH
O
1
12
14
π π
-
ꢀinteractions?
-
BuOH
Ph
*
O
O
B
O
13
Scheme 3. Formation of possible dienophiles.
With the aim to identify the key intermediate species of the
reaction, we performed a theoretical study at the B3LYP/6-
311++G** level of theory using methyls instead of the butyl
groups in the starting boronate to reduce the number of
atoms.
Frontier Molecular Orbital (FMO) calculations of the optimized
dienophiles showed that all reactions are normal electron-
demand DA reactions (Table 2). Dioxaborolane 13 is the only
thermodynamically favored structure and also has the lowest
energy LUMO, which would indicate that this is the most
activated dienophile. An analysis of the LUMO coefficients
suggested that the carbonyl group might be responsible for
the activation of this dienophile. Global properties are also
gathered in Table 2.24 Electrophilicity indices are in line with
FMO results and reveal that 13 is the only dienophile that can
be considered a strong electrophile.
Scheme 2. Reaction conditions: a solvent (1 mL), 70 °C, (S)-5 (2 equiv.), MW; b DCM (1
d
mL), (S)-5 (2 equiv.), MW; c DCM (1 mL), 70 °C, alcohol (1 equiv.), (S)-5 (2 equiv.), MW;
DCM (1 mL), 70 °C, (S)-5 (2 equiv.), MW; e DCM (1 mL), 70 °C, t-BuOH (1.70 equiv.), MW.
Table 1. Evaluation of α-hydroxyacids
α
-hydroxyacid
1)
t-BuOH
(1.7 equiv)
°C,
OBu
B
70
1-2 MW
h,
DCM,
H O
+
+
OH
NaOH 3N
,
2
aq.
2)
2
OBu
Et N
THF,
0 °C to3rt
16 h
OH
1
8N
8X
2
(5 equiv.)
Table 2. Free energies from reactants, HOMOdiene
-
LUMOdienophile gaps and global properties
:
=
H
9 R
O
=
10:R
Me
d
η a µb ω c ΔNmáx
R
ΔG
(Kcal/mol)
FMO gap
(eV)
HO
:
5
=
Ph
R
:
Compound
=
11
R
CH2CO2H
OH
-hydroxyacid
(au) (au) (eV) (e)
α
: =
3 R
CH(OH)CO2
H
1
-
-5.16
-5.06
-4.36
-4.91
-
0.24 -0.15 1.37 0.65
0.22 -0.15 1.38 0.69
0.20 -0.16 1.87 0.83
0.21 -0.15 1.47 0.72
0.20 -0.13 1.12 0.65
Yield (%) (endo/exo)a
30 mol% 1 equiv.
1 h 2 h 1 h 2 h
12
13
14
3.92
-0.40
9.15
-
Entry α-hydroxyacid
1
2
3
4
5
6
-
9
10 (43:57) 13 (42:58) 10 (43:57) 13 (42:58)
27 (60:40) 31 (61:39) 41 (56:44) 55 (62:38)
44 (60:40) 61 (59:41) 10 (43:57) 82 (60:40)
29 (60:40)b 64 (60:40) 69 (60:40) 93 (60:40)
41 (51:49) 60 (53:47) 75 (61:39) 79 (54:46)
2
a
b
c
η: chemical hardness. μ: electronic chemical potential. ω:
(S)-10
d
global electrophilicity.
electronic charge that the system might accept
ΔNmax: the maximum amount of
(S)-
(S)-11
(S,S)-
5
3
22 (56:44) 51 (58:42) 21 (56:44) 50 (56:44)
All transition structures (TS) exhibit classical [4 + 2] geometries
and are asynchronous (Figure 1). The non-classical [4+3]
carbon-boron interactions are weak (C-B distances: 2.95-3.12
Å, Wiberg Bond Indices (WBI): 0.05-0.03) and very similar for
the endo and exo approaches.25,26 Also, 14 does not present π-
π stacking interactions as expected.
Table 3 gathers the activation free energies for the most stable
conformers corresponding to the endo and exo approaches of
each possible dienophile and the corresponding calculated
endo/exo and Re/Si selectivities.27
a
1
b
Determined by H NMR integration. i-BuOH (1 equiv.) was
used instead of t-BuOH (1.7 equiv.)
To get a better understanding of the reaction mechanism, we
proposed all the plausible species that could be generated by
the combination of dibutyl vinylboronate (
acid (
) (Scheme 3). The 11B NMR spectrum of a mixture of
and showed a new signal after 2 h under MW irradiation at
70 °C in DCM, which may be an indication of ligand exchange
and formation of a new boron-activated dienophile (see the
Supporting Information).
1) and (S)-mandelic
5
1
5
2 | J. Name., 2012, 00, 1-3
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Figure 1. Most stable TSs for each approach of all possible dienophiles. Energy in Kcal/mol. Distances in Å and WBI between parentheses.
OBu
OR
O
Table 3. Calculated activation free energies and selectivities
B
*
*
B
OBu
*
OR
ΔG≠
*
HO
Entry Dienophile
TS
endo
endo/exo Re/Si
OH
(Kcal/mol)
2 BuOH
ROH
37.06
36.62
36.67
36.42
35.76
35.57
33.95
34.09
33.81
34.11
35.80
36.71
35.14
35.23
1
1
34:66
-
exo
*
Re_endo
Si_endo
Re_exo
Si_exo
O
*
43:57
45:55
54:46
58:42
74:26
53:47
B
*
*
O
O
2
12
21:79
O
B
*
O
O
Re_endo
Si_endo
Re_exo
Si_exo
3
4
13
14
47:53
19:81
Scheme 4. Proposed catalytic cycle.
Re_endo
Si_endo
Re_exo
Si_exo
It should be noted that the computed energy barrier for 13 is
less than 3 Kcal/mol lower than that of the background
reaction with
catalytic activity of (S)-mandelic acid (
1
, which might be an indication of the low
) and also explain the
unsuccessful results obtained in preliminary experiments with
other dienes and/or alkenylboronates. Also, calculations
correctly predicted the poor enantioselecticities observed
experimentally in the reactions of (S)-5. Nevertheless, we
believe that the experimental and theoretical results
presented herein provide essential information to further
5
Once more, based on free energy barriers 13 was computed to
be the most reactive dienophile. Therefore, we propose the
catalytic cycle depicted in Scheme 4. This concurs with
previous studies of this kind of organocatalysts.28
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develop an improved methodology both in terms of yields and 7. A. M. Sarotti, P. L. Pisano and S. C. Pellegrinet,VOiewrgA.rtBiclieoOmnloinle.
DOI: 10.1039/C5NJ03015C
enantioselectivities and are now working towards such goal.
Chem., 2010, 8, 5069-5073.
In conclusion, we have found that α-hydroxyacids accelerate 8. N. Grimblat and S. C. Pellegrinet, Org. Biomol. Chem., 2013,
the DA reaction of dibutyl vinylboronate with cyclopentadiene. 11, 3733-3741.
Under stoichiometric conditions (1 equivalent), (S)-mandelic 9. M. M. Vallejos, N. M. Peruchena and S. C. Pellegrinet, Org.
acid ( ) gives 93% yield of the oxidized cycloadducts, though Biomol. Chem., 2013, 11, 7953-7965.
lower yields are observed with catalytic quantities (30 mol%). 10. M. M. Vallejos, N. Grimblat and S. C. Pellegrinet, J. Phys.
The computational study of the reaction suggested that the Chem. A, 2014, 118, 5559-5570.
mechanism proceeds through a dioxaborolane intermediate 11. M. M. Vallejos, N. Grimblat and S. C. Pellegrinet, RSC
which is activated by the presence of the carbonyl group. Advances, 2014, , 36385-36400.
Further studies on the use of α-hydroxyacids in the DA 12. M. Sugiura, M. Tokudomi and M. Nakajima, Chem.
5
4
reactions of alkenylboronates are currently underway and will
be reported in due course.
Commun., 2010, 46, 7799-7800.
13. P. N. Moquist, T. Kodama and S. E. Schaus, Angew. Chem.
Int. Ed., 2010, 49, 7096-7100.
14. T. Kodama, P. N. Moquist and S. E. Schaus, Org. Lett., 2011,
13, 6316-6319.
Experimental
15. M. Sugiura, R. Kinoshita and M. Nakajima, Org. Lett., 2014,
16, 5172-5175.
Typical procedure for the tandem Diels–Alder reaction of dibutyl
vinylboronate - oxidation (Table 1)
16. Y. Luan, K. S. Barbato, P. N. Moquist, T. Kodama and S. E.
Schaus, J. Am. Chem. Soc., 2015, 137, 3233-3236.
17. S. Roscales and A. G. Csákÿ, Org. Lett., 2015, 17, 1605-
1608.
18. X. Liu, S. Sun, Z. Meng, H. Lou and L. Liu, Org. Lett., 2015,
17, 2396-2399.
19. X. Liu, Z. Meng, C. Li, H. Lou and L. Liu, Angew. Chem. Int.
Ed., 2015, 54, 6012-6015.
20. t-BuOH is believed to accelerate the catalyzed reaction by
facilitating ligand exchange. D. S. Barnett, P. N. Moquist
and S. E. Schaus, Angew. Chem. Int. Ed., 2009, 48, 8679-
8682.
21. It is worth noting that all reactions with mandelic acid
generate a 60:40 endo/exo ratio, while in the absence of α-
hydroxyacid this ratio is 42:58.
22. For the reaction that generates 93% yield, the Re/Si
selectivity obtained was 43:57 for the endo adduct and
49:51 for the exo adduct. Similar yields were obtained
when racemic acid was used.
To an oven-dried 10 mL reaction vial equipped with a stirring bar
were added α-hydroxyacid (0.3 – 2 equivalents), dry DCM (1 mL),
tert-butanol (81 μL, 1.7 equivalents), dibutyl vinylboronate (1) (113
μL, 0.5 mmol) and cyclopentadiene (206 μL, 2.5 mmol) under argon
atmosphere. The resulting reaction mixture was stirred at 70 °C
under microwave irradiation for 1, 2 or 3 h. The reaction mixture
was diluted with THF (3 mL), and transferred to a 25 mL round-
bottom flask. After the addition of Et3N (1 mL), the solution was
cooled to 0 °C and treated alternately with aq. NaOH 3 N (3 mL) and
30% H2O2 (3 mL) under argon atmosphere, and then allowed to
warm to room temperature and stirred overnight (16 h). The
reaction mixture was diluted with water (10 mL) and extracted with
Et2O (3 x 15 mL). The combined organic layers were washed with
saturated NH4Cl (15 mL) and brine (15 mL) and dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure at 0 °C, and the crude was purified by column
chromatography (pentane-Et2O) to afford 5-norbornen-2-ol (8) with
NMR spectra identical to the commercial material.
23. The yield of the boronate cycloadducts when performing
the DA reaction at 100 °C for 4 h was reported to be 83%
with an endo/exo ratio of 39:61. D. S. Matteson and J. O.
Waldbillig, J. Org. Chem. 1963, 28, 366-369.
24. L. R. Domingo, M. J. Aurell, P. Pérez and R. Contreras,
Tetrahedron, 2002, 58, 4417-4423.
Acknowledgements
We thank CONICET, Universidad Nacional de Rosario, ANPCyT
and Fundación Josefina Prats for financial support.
25. D. A. Singleton, J. Am. Chem. Soc., 1992, 114, 6563-6564.
26. S. C. Pellegrinet, M. A. Silva and J. M. Goodman, J. Am.
Chem. Soc., 2001, 123, 8832-8837.
27. If solvent effects are considered, energy barriers decrease
considerably (ca. 17 Kcal/mol).
Notes and references
1. D. G. Hall, Boronic acids: preparation and applications in
organic synthesis and medicine, Wiley-VCH, Weinheim,
2005.
2. G. Hilt and P. Bolze, Synthesis, 2005, 2091-2115.
3. P. M. Delaney, J. E. Moore and J. P. A. Harrity, Chem.
Commun., 2006, 3323-3325.
28. N. Grimblat, M. Sugiura and S. C. Pellegrinet, J. Org. Chem.,
2014, 79, 6754-6758.
4. E. Gomez-Bengoa, M. D. Helm, A. Plant and J. P. A. Harrity,
J. Am. Chem. Soc., 2007, 129, 2691-2699.
5. D. L. Browne, M. D. Helm, A. Plant and J. P. A. Harrity,
Angew. Chem. Int. Ed., 2007, 46, 8656-8658.
6. P. M. Delaney, J. Huang, S. J. F. Macdonald and J. P. A.
Harrity, Org. Lett., 2008, 10, 781-783.
4 | J. Name., 2012, 00, 1-3
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Dibutyl vinylboronate reacts with cyclopentadiene under mild conditions in the presence of (S)-
mandelic acid probably via an actived dioxaborolane intermediate.