An unexpected role of a trace amount of water in catalyzing proton transfer in phosphine-catalyzed (3 + 2) cycloaddition of allenoates and alkenes

Article abstract of DOI:10.1021/ja068215h

Through the joint forces of computation and experiment, the detailed mechanism of the Lu phosphine catalyzed (3 + 2) cycloaddition of allenoates and alkenes has been elucidated. The overall potential energy surface of the Lu (3 + 2) reaction has been computed. More importantly, theory and experiment have confirmed that a trace amount of water plays a critical role in assisting the process of [1,2] proton shift in the Lu reaction. Copyright

Full text of DOI:10.1021/ja068215h

Published on Web 02/24/2007
An Unexpected Role of a Trace Amount of Water in Catalyzing Proton
Transfer in Phosphine-Catalyzed (3 + 2) Cycloaddition of Allenoates and
Alkenes
Yuanzhi Xia,†,‡ Yong Liang,† Yuanyuan Chen,† Ming Wang,† Lei Jiao,† Feng Huang,† Song Liu,†
Yahong Li,‡,§ and Zhi-Xiang Yu*,†
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education, College of Chemistry, Peking UniVersity, Beijing 100871, China,
Qinghai Institute of Salt Lakes, Chinese Academy of Sciences, Xining 810008, China, and Key Laboratory of
Organic Synthesis of Jiangsu ProVince, Department of Chemistry and Chemical Engineering, Suzhou UniVersity,
Suzhou 215006, China
Received November 16, 2006; E-mail: yuzx@pku.edu.cn
Scheme 1. The Lu (3 + 2) Reaction and Its Proposed Mechanism
The Lu phosphine catalyzed (3 + 2) cycloaddition between
allenoates and activated alkenes,1,2 as exemplified by the reaction
shown in Scheme 1, provides an efficient approach for the synthesis
of five-membered carbocycles, which are prevalent in many natural
products and compounds of pharmaceutical significance. The
proposed mechanism for the Lu reaction (shown in Scheme 1) starts
from the formation of a zwitterionic intermediate A between
allenoate and phosphine.1,2a Intermediate A acts as a 1,3-dipole and
undergoes a (3 + 2) cycloaddition with an electron-deficient olefin
to give a phosphrous ylide B. Then an intramolecular [1,2] proton
transfer is speculated to convert the phosphorus ylide B to another
zwitterionic intermediate C, which, upon loss of the phosphine
catalyst, gives rise to the final cycloadduct D. The Lu (3 + 2)
cycloaddition is also efficient for the synthesis of five-membered
heterocycles if imines are used as dipolarophiles.3 Through elegant
work in the groups of Zhang and Fu,4 asymmetric versions of the
Lu (3 + 2) cycloaddition have been developed. Applications of
the Lu (3 + 2) cycloaddition to the total synthesis of natural
products have also been documented by Lu, Krische, and Pyne,
respectively.5 Further elegant developments and extensions of the
chemistry of allene-PR3 have been widely pursued by many other
groups as well.6
However, to date, the detailed mechanism of the Lu reaction
has not been investigated either experimentally or theoretically.7
In-depth understanding of the potential energy surface, structures
of the intermediates and transition states, and regio- and stereo-
chemistry in the Lu reaction would be useful. Mechanistic informa-
tion concerning the Lu reaction may help to guide future design of
new organocatalytic reactions.8
Here we wish to communicate our theoretical and experimental
study of the Lu (3 + 2) reaction, with emphasis on the details of
the [1,2] proton-transfer step. Although the typical Lu reaction
condition is supposed to be anhydrous, our study shows that a trace
amount of water existing in the reaction system plays a critical
role in assisting the process of [1,2] proton shift.
(Only the Major Product Is Given).
compared to reactants in the gas phase and benzene solution,
respectively. Calculations indicated that the subsequent (3 + 2)
cycloaddition process between 3 and 2 is stepwise, starting from a
Michael addition to generate a zwitterionic intermediate IN1, which
then converts to IN2 via a ring-closure reaction. These two transition
structures in the stepwise (3 + 2) cycloaddition process are very
close in energy in both the gas phase and solution. The overall
process transforming the reactants and the catalyst to IN2 requires
activation free energies of 31.3 and 28.3 kcal/mol in the gas phase
and benzene solution, respectively. The formation of IN2 is
exothermic by 13.9 kcal/mol; however, this (3 + 2) process is
endergonic by 12.2 and 11.0 kcal/mol in the gas phase and benzene
solution, respectively, suggesting that the formation of IN2 is not
favorable thermodynamically. Therefore, the stepwise (3 + 2) steps
must be followed by some exergonic reactions to drive the reaction
to completion.
The originally proposed [1,2] proton transfer converting IN2 to
IN3 is exergonic by about 8.0 kcal/mol, implying that formation
of IN3 can drive the above stepwise (3 + 2) cycloaddition to occur.
However, the computed activation free energy of the [1,2] proton
transfer from IN2 to IN3 is 39.3 and 39.6 kcal/mol in the gas phase
and in benzene solution,10 indicating that this step is not possible
kinetically, considering the fact that the Lu (3 + 2) cycloadditions
are usually conducted at room temperature.
DFT calculations9 using the B3LYP/6-31+G(d) method have
been applied to understand the Lu reaction, and the computed
potential-energy surfaces for the model reaction of 2,3-butadienoate
1, acrylate 2, and PMe3 are given in Figure 1. Calculations show
that the formation of 1,3-dipole 3 from 1 and PMe3 is slightly
exothermic by 1.0 kcal/mol in terms of ∆E0 in the gas phase. The
free energies of this complex are +11.5 and +9.7 kcal/mol
To obtain more information about the Lu reaction, we conducted
a PPh3 catalyzed (3 + 2) cycloaddition of deuterium labeled 2,3-
butadienoate 8 (2-D incorporation level is about 95%) and fumarate
9 (I, Scheme 2) in anhydrous benzene (refluxed with Na and freshly
distilled prior to use) according to Lu’s procedure.1 It was found
that 4-D and 4-H substituted products 10 and 11 were both obtained
† Peking University.
‡ Qinghai Institute of Salt Lakes.
§ Suzhou University.
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C O M M U N I C A T I O N S
of 28.3 kcal/mol. The generally accepted intramolecular [1,2] proton
shift in the Lu reaction is not possible owing to the very high
activation barrier of 39.6 kcal/mol required for this process.10
Calculations and experiments revealed that water assists this process
with an activation free energy of 7.7 kcal/mol. The discovery of
the catalytic role of a trace amount of water in the Lu reaction
suggests that a trace amount of water could also act as a catalyst
in some other “anhydrous” reactions involving [1,2] or [1,n] proton
shifts.12 The present study could have implications for other
organocatalytic reactions.8,13,14 Further mechanistic investigations
on allene chemistry and other organocatalytic reactions are in
progress.
Figure 1. The DFT computed energy surfaces of the Lu (3 + 2) reaction
(E1 ) E2 ) CO2Me, R ) CH3).9
Acknowledgment. We are indebted to generous financial
support from Peking University and the Natural Science Foundation
of China (Grants 9800445, 0240203, and 20672005).
Scheme 2. Isotopic Labeling Experiments (E ) CO2Me).11
Supporting Information Available: Computational and experi-
mental details. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906.
(2) For reviews on phosphine catalyzed reactions, see: (a) Lu, X.; Zhang,
C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot, J. L.; Roush, W.
R. AdV. Synth. Catal. 2004, 346, 1035.
(3) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu, Z.; Lu, X.
J. Org. Chem. 1998, 63, 5031. (c) Xu, Z.; Lu, X. Tetrahedron Lett. 1999,
40, 549. (d) Zhu, X.-F.; Henry, C. E.; Kwon, O. Tetrahedron 2005, 61,
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(4) (a) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am.
Chem. Soc. 1997, 119, 3836. (b) Wilson, J. E.; Fu, G. C. Angew. Chem.,
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with a ratio of 75:25. This indicates that the [1,2] proton transfer
from IN2 to IN3 is not a simple intramolecular process. We
speculated that the formation of 11 was due to the presence of a
trace amount of water in the reaction system. Therefore, we
computed a possible H2O assisted [1,2] proton shift process, which
is also given in Figure 1. Calculations showed that IN2 can form
a complex with water, and this complexation step is exothermic
by 7.6 kcal/mol and endergonic by 3.9 kcal/mol in benzene. Then
a proton transfer from water to the carbon atom connected with
the phosphorus atom requires only 0.4 kcal/mol activation free
energy in benzene. This step leads to the formation of another
complex 5, in which there is a strong attraction between the
hydroxyl anion and the PMe3 moiety. The subsequent step is the
abstraction of proton by hydroxyl anion with an activation free
energy of 7.7 kcal/mol in benzene, giving rise to another complex
6. Loss of water from complex 6 gives IN3, which can then easily
furnish final (3 + 2) cycloadduct 7 and PMe3 with an activation
free energy of 0.9 kcal/mol in benzene. The water assisted H-shift
process converting IN2 to the final product and PR3 requires only
7.7 kcal/mol activation free energy and is exergonic by 40.9 kcal/
mol.
We also ran the reaction between 8 and 9 in the presence of 1
equiv of H2O (II, Scheme 2). It was found that the ratio of 4-H
substituted product 11 was remarkably increased (from 25% to
88%). To rule out the possibility that the introduction of hydrogen
takes place between 1,3-dipole 3 and H2O, we conducted a control
experiment (Scheme 2). 1H NMR indicated that no deuterium and
hydrogen exchange between allenoate and water occurred, proving
that the hydrogen exchange happens after the formation of IN2
(Figure 1).11 These results further confirm that the intramolecular
[1,2] H-shift is impossible and a trace amount of water does play
a catalytic role in assisting the [1,2] proton transfer.
(5) (a) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6463. (b) Wang, J.-C.; Krische,
M. J. Angew. Chem., Int. Ed. 2003, 42, 5855. (c) Pham, T. Q.; Pyne, S.
G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2005, 70, 6369.
(6) (a) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716. (b)
Tran, Y. S.; Kwon, O. Org. Lett. 2005, 7, 4289. (c) Wurz, R. P.; Fu, G.
C. J. Am. Chem. Soc. 2005, 127, 12234. (d) Evans, C. A.; Miller, S. J. J.
Am. Chem. Soc. 2003, 125, 12394. (e) Wang, L.-C.; Luis, A. L.; Agapiou,
K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402. (f)
Frank, S. A.; Mergott, A. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124,
2404.
(7) Only a few computational studies have been done to rationalize the
regiochemistry in the (3 + 2) cycloaddition step shown in Scheme 1,
see: (a) Pham, T. Q.; Pyne, S. G.; Skelton, B. W.; White, A. H.
Tetrahedron Lett. 2002, 43, 5953. (b) Ung, A. T.; Schafer, K.; Lindsay,
K. B.; Pyne, S. G.; Amornraksa, K.; Wouters, R.; Linden, I. V.; Biesmans,
I.; Lesage, J. A. S.; Skelton, B. W.; White, A. H. J. Org. Chem. 2002,
67, 227. (c) Dudding, T.; Kwon, O.; Mercier, E. Org. Lett. 2006, 8, 3643.
(8) For a recent thematic issue on organocatalysis, see: Houk, K. N.; List,
B. Acc. Chem. ReV. 2004, 137, 487 and references therein.
(9) Computational details and references are given in the Supporting Informa-
tion. The reported relative energies are free energies in benzene (∆Gsol),
and free energies (∆G298) and the zero-point energies corrected electronic
energies (∆E0), both in the gas phase, respectively. Even though for a bi-
or trimolecular process, the computed ∆Gsol values are somehow
overestimated (owing to the overestimation of the entropy contributions
in solution), the main purpose of such calculations is to appreciate how
solvent influences a reaction (such as on its reaction rate, regio- and
stereochemistry). A discussion of regiochemistry is given in the Supporting
Information.
(10) Calculations showed that tunneling effect for this step is negligible.9
(11) There is no deuterium and hydrogen exchange between the deuterated (3
+ 2) cycloadduct 10 and H2O in the presence of PPh3. For details of
these and other experiments, see the Supporting Information.
(12) [1,2] or [1,3] proton shift is proposed in many phosphine catalyzed
reactions: (a) Jung, C.-K.; Wang, J.-C.; Krische, M. J. J. Am. Chem. Soc.
2004, 126, 4118. (b) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am.
Chem. Soc. 2005, 127, 9260. (c) Kuroda, H.; Tomita, I.; Endo, T. Org.
Lett. 2003, 5, 129. (d) Zhu, X.-F.; Schaffner, A.-P.; Li, R. C.; Kwon, O.
Org. Lett. 2005, 7, 2977. (e) Virieux, D.; Guillouzic, A.-F.; Cristau, H.-J.
Tetrahedron 2006, 62, 3710. (f) Fan, R.-H.; Hou, X.-L.; Dai, L.-X. J.
Org. Chem. 2004, 69, 689.
(13) Such water-assisted proton shifts have been found in many enzymatic
reactions, for a recent review, see: Blomberg, M. R. A.; Siegbahn, P. E.
M. Biochim. Biophys. Acta 2006, 1757, 969 and references therein.
(14) (a) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed.
2006, 45, 8100. (b) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103
and references therein.
In conclusion, the Lu (3 + 2) cycloaddition has been investigated
with joint forces of computation and experiment. The formation of
a 1,3-dipole is slightly exothermic, and the subsequent (3 + 2)
cycloaddition is a stepwise process with an activation free energy
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