A rationally designed cocatalyst for the Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1016/j.tetlet.2008.05.037

The application of electronic structure calculations to a key transition state in the reaction manifold of the Morita-Baylis-Hillman reaction allows the design of two bis(thiourea) cocatalysts capable of accelerating this reaction through the hydrogen bon

Full text of DOI:10.1016/j.tetlet.2008.05.037

Tetrahedron Letters 49 (2008) 4666–4669
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A rationally designed cocatalyst for the Morita–Baylis–Hillman reaction
*
*
Charlotte E. S. Jones, Simon M. Turega, Matthew L. Clarke , Douglas Philp
EaStCHEM and School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The application of electronic structure calculations to a key transition state in the reaction manifold of the
Morita–Baylis–Hillman reaction allows the design of two bis(thiourea) cocatalysts capable of accelerating
this reaction through the hydrogen bond mediated recognition of both the nucleophile and the
electrophile.
Received 8 April 2008
Revised 1 May 2008
Accepted 7 May 2008
Available online 11 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The rational design of organic catalysts based on hydrogen
bonding1 is an important objective for the burgeoning field of
organocatalysis. We wished to demonstrate that, through the
application of electronic structure calculations, it is possible to de-
sign a catalyst that is capable of recognising and stabilising a tran-
sition state that is assembled from two different reaction partners.
In the past, we have shown2 that the reactivity of organic mole-
cules can be influenced directly by means of appropriately located
recognition elements in the reagents. Further, we3 and others4
have shown that both Michael addition reactions and dipolar
cycloadditions are amenable to acceleration by exploiting hydro-
gen bonds formed between a receptor and one of the reagents. Car-
bon–carbon bond forming reactions mediated by organic catalysts
are currently the focus5 of many research programmes. Several of
these catalysts function by exploiting the fact that hydrogen bond
donors can promote reactions in a similar way to Lewis acid cata-
lysts, and there are many excellent examples6 of effective catalysts
which have been reported to date. Our interest was drawn to the
Morita–Baylis–Hillman (MBH) reaction (Scheme 1), since it is one
of the more sluggish C–C bond forming reactions that requires
more active catalysts in order to realise7 its full potential.
aldehyde, and, hence, design a bis(thiourea) cocatalyst which was
capable of binding 3à tightly, thus accelerating the reaction
between 1 and 2. Consideration of the structure of 3à suggests that
any cocatalyst must be capable of simultaneously associating with,
and, hence, stabilising both the enolate oxygen arising from the
adduct formed between 1 and DMAP and the partial dÀ charge
located on the aldehyde carbonyl oxygen atom. As we proceed
towards the transition state 3à, the relative orientations and the
charges on these two species will change. Therefore, any cocatalyst
design must start from a sound knowledge of the structure and
charge distribution present in 3à.
F
N
O
DMAP
O
N
O
H
N
O
1
2
We chose to focus on the reaction between cyclohexenone 1
and 4-fluorobenzaldehyde 2 (Scheme 1). The formation of the
product 3 can be assayed readily by 19F NMR spectroscopy, and
we were intrigued by the high activity for the elegant bis(thiourea)
cocatalyst 4 reported8 by Nagasawa and co-workers. These work-
ers propose that in the key step of the MBH reaction, the addition
of the DMAP-activated enone to the aldehyde forming the C–C
bond, both the aldehyde and enolate are bound and activated by
this cocatalyst. We believed that we could increase the activity of
this cocatalyst significantly by rational application of computa-
tional methods. Through the application of electronic structure
methods, we could compute the structure and properties of the
transition state 3à, for the addition of the activated enone to the
N
3‡
F
OH
O
Steps
3
F
F3C
S
N
S
N
CF3
CF3
N
N
H
4
H
H
H
F3C
* Corresponding authors. Tel.: +44 1334467264; fax: +44 1334463808 (D.P.).
E-mail address: dp12@st-andrews.ac.uk (D. Philp).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.037

C. E. S. Jones et al. / Tetrahedron Letters 49 (2008) 4666–4669
4667
Figure 1. (a) Schematic view of the transition state of the reaction between 1,
activated by DMAP, and 2. The target oxygen atoms are highlighted. (b) Stick
representation of the calculated (B3LYP/6-31G(d,p)) structure of 3à. Carbon atoms
are green, nitrogen atoms are blue, oxygen atoms are red, hydrogen atoms are white
and fluorine atoms are cyan. The forming C–C bond is the dashed red line and the
location of the anion binding sites are highlighted in blue. Most hydrogen atoms
have been omitted for clarity. (c) Electrostatic potential surface of 3à. Charge is
encoded as a spectrum of red (negative) to blue (positive).
We therefore located and refined the transition state structure
of 3à using9 electronic structure methods. The transition state
was initially located (Fig. 1) using a coordinate scan method using
the semi-empirical AM1 method as implemented by AMSOL 7.1. This
transition state structure was then further refined at the B3LYP/6-
31G(d,p) level of theory providing us with an accurate model of 3à
with which to proceed.
The calculated structure of 3à reveals (Fig. 1) that, as expected,
the regions of highest negative charge are located on the oxygen
atoms of 1 and 2. Interestingly, calculation of the electrostatic
potential surface of 3à (Fig. 1c) reveals that these two sites carry
almost equal negative charge at the transition state, reinforcing
the need for both of these sites to be bound and stabilised by
any cocatalyst. The two oxygen atoms are placed 4.39 Å apart in
the transition state. Interestingly, there is also a C–HÁ Á ÁO hydrogen
bond (C–HÁ Á ÁO distance = 2.39 Å) between the aldehyde carbonyl
oxygen and one of the a protons on the pyridine ring of the DMAP
cocatalyst. As expected, all attempts to dock this transition state
structure with the bis(thiourea) cocatalyst 4 such that both of
the target oxygen atoms in 3à were complexed simultaneously
without significant distortion of the calculated transition state
structure were unsuccessful.
New cocatalyst designs were generated by placing two thiourea
groups at the locations required to recognise the two target oxygen
atoms in 3à and then connecting them by appropriately sized
spacer groups in order to generate approximations to ideal cocata-
lyst structures. These structures were then refined using molecular
mechanics calculations, fixing the atomic positions in 3à, but
allowing all other atoms to relax. These proposed structures for
the transition state bound to the cocatalyst were then optimised
using the semi-empirical AM1 method and the SM5.4A8 solvation
model as before. The results of these calculations (Fig. 2) demon-
strated that the transition state structure 3à was supported equally
well on a cocatalyst that consisted of two thioureas separated by
either an m-xylyl 5 or an o-xylyl 6 bridge.
Figure 2. (a) Stick representation of the calculated (AM1/SM5.4a) structure of 3à
docked to cocatalyst 5. (b) Stick representation of the calculated (AM1/SM5.4a)
structure of 3à docked to cocatalyst 6. In both cases, carbon atoms are green, nitro-
gen atoms are blue, oxygen atoms are red, sulfur atoms are yellow, hydrogen atoms
are white and fluorine atoms are cyan. The forming C–C bond is the dashed red line,
and dashed black lines show hydrogen bonds.
Cocatalysts 5 and 6 were then synthesised in 50% and 72%
yields, respectively, by reaction of 3,5-bis(trifluoromethyl)phenyl-
isothiocyanate and the appropriate diamine in THF at room
temperature.
The ability of the three cocatalysts, 4, 5 and 6, to accelerate the
reaction between 1 and 2 in the presence10 of DMAP was assessed
using a standard set of reaction conditions. In all cases, 1 and 2
were reacted in the absence of solvent. The reaction mixture

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C. E. S. Jones et al. / Tetrahedron Letters 49 (2008) 4666–4669
Figure 4. Key angles in the transition states for C–C bond formation in the presence
of no cocatalyst and in the presence of cocatalysts 5 and 6.
4, the conversion ranges from 26% at 5 mol % loading to 82% at
20 mol % loading. In the presence of cocatalysts 5 and 6, the con-
versions are uniformly higher—>60% for both cocatalysts at
5 mol % loading and >90% at 20 mol % loading. It is therefore clear
that, in agreement with our design, cocatalysts 5 and 6 are both
significantly more active than cocatalyst 4. At a cocatalyst loading
of 1 mol %, no product is formed after 6.5 hours in any of the reac-
tions. However, if the reaction mixtures are left at room tempera-
ture for 32 h, product is detectable in the reactions containing both
cocatalyst 5 (4% conversion) and cocatalyst 6 (2% conversion) indi-
cating that both of these bis(thiourea) cocatalysts retain some
activity at low loadings. Screening of other aldehydes as the elec-
trophile in the MBH reaction (see Supporting Information) reveals
that the pattern of activity observed with 4-fluorobenzaldehyde is
repeated—cocatalyst 6 is between two and three times as active as
cocatalyst 4 under the same conditions.
The difference in activity between 5 and 6 is intriguing. Despite
their structural similarities, in all experiments, cocatalyst 6 outper-
forms cocatalyst 5 significantly. A likely explanation for this differ-
ence in activity can be found by careful examination of the
geometry of the transition state 3à bound (Fig. 4) to each cocata-
lyst. The cyclohexenone ring adopts a twist boat conformation in
the transition state. The geometry of 3à bound to cocatalyst 6 is
much closer to that calculated for 3à in the absence of cocatalyst.
When 3à is bound to cocatalyst 5, however, there is a marked
departure of the conformation of the cyclohexenone ring towards
a true boat geometry. This change in conformation, imposed by
the cocatalyst in order to satisfy the steric and electronic require-
ments of binding, results in an increase in strain within 3à resulting
in lower activity.
Figure 3. Conversion of ketone 1 and aldehyde 2 to product 3 after 6.5 hours at
room temperature in the presence of no cocatalyst (pink) or in the presence of
cocatalyst 4 (green), 5 (yellow) or 6 (blue).
contained 1.0 equiv of cyclohexenone 1 and 0.8 equiv of aldehyde
2. For each of the three cocatalysts, 4, 5 and 6, four different cocat-
alyst loadings were investigated—1 mol %, 5 mol %, 10 mol % or
20 mol %. The ratio of cocatalyst to DMAP was held constant and
was always 1:1.5. The reaction mixtures were sampled at four time
points—after 1.5, 6.5, 32 and 105 h. These samples were diluted
with CDCl3 and the extent of reaction was assessed by
282.3 MHz 19F NMR spectroscopy—deconvolution of the relative
areas of the 19F resonance arising from 2 at d À102.3 and the fluo-
rine resonance arising from the product at d À115.7 allowed the
conversion to be calculated readily. At each cocatalyst loading an
additional control experiment was performed where the appropri-
ate amount of DMAP was added but no cocatalyst was added. For
example, for the 20 mol % cocatalyst loading, the control reaction
was performed with no cocatalyst, but with 30 mol % of added
DMAP.
The results of these screening experiments are summarised in
Figure 3. It is clear that after 6.5 h, at all DMAP concentrations,
the reaction between 1 and 2 does not proceed to any measurable
extent in the absence of a cocatalyst. The benchmark for the accel-
eration of the reaction between 1 and 2 is the performance of
cocatalyst 4. After 6.5 h, the reaction requires at least 5 mol % of
4 to be present for any conversion of 1 and 2 to the product 3 to
be evident. Increasing the loading of 4 from 5 mol % to 20 mol %
increases the conversion from 12% to 31%.
Although cocatalysts 5 and 6 must also be present in at least
5 mol % for any conversion of 1 and 2 to 3 to be evident, their abil-
ity to accelerate the reaction is much better than 4. Whilst a load-
ing of 5 mol % of 5 affords a similar conversion (14%) to that
observed for 4, this cocatalyst performs better at higher loadings.
The conversion at a loading of 10 mol % is 54% and the conversion
rises further to 65% in the presence of 20 mol % of cocatalyst 5. The
best cocatalyst is, however, 6—increasing the loading of 6 from
5 mol % to 20 mol % increases the conversion from 23% to 84%—
almost three times that observed when the reaction is performed
under the same conditions in the presence of 4. After 32 h, there
is still no measurable reaction between 1 and 2 in the presence
of DMAP only. After the same time, in the presence of cocatalyst
In this Letter, we have demonstrated that it is possible to use
electronic structure calculations to design two cocatalysts that
are capable of recognising a key transition state within the reaction
manifold of the Morita–Baylis–Hillman reaction. These cocatalysts
are capable of increasing the rate of the target reaction by a factor
of three and retain some activity even at very low (1 mol %) load-
ings. We believe that the design strategy presented here may be
of significant utility in the design and optimisation of new organic
cocatalysts that utilise hydrogen bonding.
Acknowledgements
We thank the Engineering and Physical Sciences Research
Council and the University of St Andrews for financial support.
Supplementary data
Supplementary data contain synthetic procedures and charac-
terisation data for compounds 3, 5 and 6. Details of the reactions
of other aldehydes using cocatalysts 4 and 6. Coordinates for the
calculated transition states shown in Figures 1 and 2. Supplemen-
tary data associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2008.05.037.

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Lett. 2005, 7, 4293; (d) Maher, D. J.; Connon, S. J. Tetrahedron Lett. 2004, 45,
1301.
References and notes
7. (a) Aggarwal, V. K.; Mereu, D. K.; Williams, R. J. Org. Chem. 2002, 67, 510; (b)
Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68, 692; (c) Santos, L.
S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.; Eberlin, M. N. Angew. Chem., Int. Ed.
2004, 43, 4330; (d) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew.
Chem., Int. Ed. 2005, 44, 26; (e) Price, K. E.; Broadwater, S. J.; Jung, H. M.;
McQuade, D. T. Org. Lett. 2005, 7, 147; (f) Price, K. E.; Broadwater, S. J.; Walker,
B. J.; McQuade, D. T. J. Org. Chem. 2005, 70, 3980; (g) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811.
1. (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558; (b) Dove, A.
P.; Pratt, R. C.; Lohmeijer, B. G. G.; Waymouth, R. M.; Hedrick, J. L. J. Am. Chem.
Soc. 2005, 127, 13798; (c) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005,
127, 8964; (d) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672.
2. (a) Kassianidis, E.; Pearson, R. J.; Philp, D. Chem. Eur. J. 2006, 12, 6829; (b)
Pearson, R. J.; Kassianidis, E.; Slawin, A. M. Z.; Philp, D. Chem. Eur. J. 2006, 12,
8788; (c) Pearson, R. J.; Kassianidis, E.; Philp, D. Org. Lett. 2005, 7, 3833; (d)
Pearson, R. J.; Kassianidis, E.; Slawin, A. M. Z.; Philp, D. Org. Biomol. Chem. 2004,
2, 3434.
8. Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2004,
45, 5589.
9. All SM5.4A/AM1 calculations were performed using AMSOL 7.1 running on a
Linux cluster. (AMSOL Ver. 7.1 by G. D. Hawkins, D. J. Giesen, G. C. Lynch, C. C.
Chambers, I. Rossi, J. W. Storer, J. Li, J. D. Thompson, P. Winget, B. J. Lynch, D.
Rinaldi, D. A. Liotard, C. J. Cramer, D. G. Truhlar; EF routines by F. Jensen). All
3. (a) Ashton, P. R.; Calcagno, P.; Spencer, N.; Harris, K. D. M.; Philp, D. Org. Lett.
2000, 2, 1365; (b) Rowe, H. L.; Spencer, N.; Philp, D. Tetrahedron Lett. 2000, 41,
4475.
4. (a) Kelly, T. R.; Meghani, P.; Ekkundi, V. S. Tetrahedron Lett. 1990, 31, 3381; (b)
Curran, D. P.; Kao, L. H. J. Org. Chem. 1994, 59, 3259; (c) Curran, D. P.;
Kao, L. H. Tetrahedron Lett. 1995, 36, 6647; (d) Schreiner, P. R.; Wittkopp, A. Org.
Lett. 2002, 4, 217; (e) Wittkop, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407.
5. For recent reviews see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001,
40, 3726; (b) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289; (c) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (d) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719; (e) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299;
(f) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 55, 1520.
6. For reviews, see: (a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289; (b) Pihko, P.
M. Angew. Chem., Int. Ed. 2004, 43, 2062; For hydrogen bond promoted Morita-
Baylis–Hillman reactions, see: (c) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org.
*
molecular mechanics calculations were carried out using the AMBER or MMFFs
force field as implemented in MACROMODEL (Ver. 9.5; Schrödinger, Inc.: Portland,
OR, 2007) running on a Linux workstation. DFT calculations were performed
using GAMESS (Ver. dated 24 March 2007, Rev 3). Schmidt, M. W.; Baldridge, K.
K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga,
N.; Nguyen, K. A.; Su, S. J.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J.
Comput. Chem. 1993, 14, 1347.
10. There is no measurable reaction between
1 and 2 under the conditions
employed in this work in the absence of DMAP or in the presence of
30 mol % DMAP and 20 mol % of a mono(thiourea), 3,5-bis(trifluoromethyl)-
phenylbenzylthiourea.