Design of a bisamidinium claisen rearrangement catalyst for monodentate substrates

Article abstract of DOI:10.1021/ol8026945

(Chemical Equation Presented) A bisamidinium catalyst has been designed for the Clalsen rearrangement. The primary design feature is a dual hydrogen bonding array that can coordinate a singular oxygen atom of the substrate. The ability to function as a du

Full text of DOI:10.1021/ol8026945

ORGANIC
LETTERS
2009
Vol. 11, No. 3
621-624
Design of a Bisamidinium Claisen
Rearrangement Catalyst for
Monodentate Substrates
Venkatachalam R. Annamalai, Elizabeth C. Linton, and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104
marisa@sas.upenn.edu
Received November 21, 2008
ABSTRACT
A bisamidinium catalyst has been designed for the Claisen rearrangement. The primary design feature is a dual hydrogen bonding array that
can coordinate a singular oxygen atom of the substrate. The ability to function as a dual hydrogen donor is key as the bisamidinium accelerates
the Claisen rearrangement to a greater extent than Brønsted acids with lower pKa values.
The Claisen rearrangement, discovered in 1912 by Ludwig
von Claisen, is the thermal isomerization of an allyl vinyl
ether or the corresponding nitrogen or sulfur analogues to
afford a bifunctionalized molecule in a [π2s + σ2s + π2s]
process.1 Subsequently, the power of the Claisen rearrange-
ment has been recognized as indicated by its widespread
application.2
with a single Lewis basic moiety in the Claisen rearrange-
ment substrate, enantioselective vaiants of the Claisen
rearrangement require stoichiometric amounts of chiral Lewis
acids.6,7 This requirement prompted us to examine the use
of hydrogen bond (H-bond) donors as catalysts in this
important reaction with the goal of identifying modular
templates that allow turnover for monodentate substrates.
In spite of extensive study of this reaction,2 the lack of
general catalytic, enantioselective variants of the Claisen
rearrangement is striking with only three highly selective
examples presently reported,3-5 all of which require a two-
point interaction with the catalyst. For catalysts which interact
(3) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem.,
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mann, M. Tetrahedron Lett. 2004, 45, 3647–3650. (d) Abraham, L.; Koerner,
M.; Schwab, P.; Hiersemann, M. AdV. Synth. Cat. 2004, 346, 1281–1294,
including references therein. (e) Wang, Q.; Millet, A.; Hiersemann, M.
Synlett 2007, 1683–1686.
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(2) (a) Ziegler, F. E. Acc. Chem. Res. 1977, 10, 227–232. (b) Lutz, R. P.
Chem. ReV. 1984, 84, 205–247. (c) Ziegler, F. E. Chem. ReV. 1988, 88,
1423–1452. (d) Wipf, P. ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: Oxford, England, 1991; Vol. 5, pp 827-873. (e) Enders,
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(f) Ito, H.; Taguchi, T. Chem. Soc. ReV. 1999, 28, 43–50. (g) Chai, Y.;
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Castro, A. M. Chem. ReV. 2004, 104, 2939–3002. (j) Majumdar, K. C.;
Alam, S.; Chattopadhyay, B. Tetrahedron 2008, 64, 597–643. (k) Hierse-
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Weinheim, Germany, 2007.
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(7) For an exception that is proposed to occur via a palldium π-interac-
tion and proceeds with moderate enantioselection, see: Akiyama, K.;
Mikami, K. Tetrahedron Lett. 2004, 45, 7217–7220
.
10.1021/ol8026945 CCC: $40.75
Published on Web 12/31/2008
2009 American Chemical Society

This assertion finds further support in recent work on the
Claisen rearrangement with 2-alkoxycarbonyl-substituted
allyl vinyl ethers. For thioureas, Hiersemann and co-workers
make a compelling argument that the optimal hydrogen
bonding association afforded by a urea favors a two-point
interaction to optimize the desirable angle (see Figure 1c).14
Subsequent studies by Jacobsen and coowokers with the
guanidiniums revealed a similar hydrogen bonding network
that nears the ideal 180° hydrogen bond angles.4
To devise a catalyst capable of undergoing a two-point
interaction with substrates containing a single Lewis basic
atom, we began by identifying the optimal orientation and
distance of an amide N-H bond with an ether. Thus, the
positions for the hydrogen bond donors were obtained by
using Spartan to model the complex between dimethyl ether
and two molecules of acetamide (Figure 2).15
Figure 1. Hydrogen bonding structures in Claisen rearrangements.
Our interest was spurred by an earlier report of the Claisen
rearrangement of allyl vinyl ethers with a C6-methoxy group
being catalyzed by ureas and thioureas, although elevated
temperatures were needed.8 This work was, in turn, inspired
by reports of Claisen rearrangement acceleration by water
which was proposed to arise from hydrogen bonding.9
Subsequent calculations by Jorgensen10 and Hillier11 pro-
vided further support for this hypothesis and identified two
hydrogen bonds with water in the transition state (Figure
1a). For the urea system, it was hypothesized8 that the urea
forms a dual hydrogen bond through the lone pairs on the
oxygen of the allyl vinyl ether (Figure 1b). We found that
MM2* calculations12 of a minimized structure between the
allyl vinyl ether and the urea indicated that the orientation
of the urea hydrogen bond donors were not optimal compared
to the water accelerated system (Figure 1b); rather, an OHN
bond angle of 130° was observed (Figure 1b). We theorized
that the rate of the Claisen rearrangement could be increased
if the hydrogen bond donors were optimized to form an OHN
bond angle of 180°.13
Figure 2. Optimal positions for hydrogen bond donors.
The bond lengths and bond angles of the acetamide
molecules with dimethyl ether correspond to two moderate
hydrogen bonds comparable to those observed in most
catalysis involving hydrogen bonding (Figure 2).13 The bonds
between atoms highlighted in red in Figure 2 were then used
as vectors for the database mining program CAVEAT. Using
the Cambridge Crystal Database, several templating sub-
structures that contain these vectors were found (Figure 3).16
A number of crystal structures were obtained that satisfied
the vectors in Figure 2 to provide both hydrogen bonds in
the optimal positions, but crystal structure 3 was the most
promising candidate (Figure 3). In particular, structure 3
inspired the design of bisamidine 4. Such compounds avoid
self-hydrogen bonding and the rotation about the aryl
substituent bond leads to degenerate conformations. The
modular nature combined with the fact that it could easily
be synthesized made this structural type particularly appeal-
ing. Furthermore, calculations of the bisamidine and bisa-
(8) Curran, D. P.; Kuo, L. H. Tetrahedron Lett. 1995, 36, 6647–6650.
(9) (a) White, W. N.; Wolfarth, E. F. J. Org. Chem. 1970, 35, 2196–
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3585. (c) Ponaras, A. A. J. Org. Chem. 1983, 48, 3866–3868. (d) Coates,
R. M.; Rogers, B. D.; Hobbs, S. J.; Curran, D. P.; Peck, D. R. J. Am. Chem.
Soc. 1987, 109, 1160–1170. (e) Brandes, E.; Grim, P. A.; Gajewski, J. J. J.
Org. Chem. 1989, 54, 515–516. (f) Grieco, P. A.; Brandes, E. B.; McCann,
S.; Clark, J. D. J. Org. Chem. 1989, 54, 5849–5851.
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D. L. J. Chem. Soc., Faraday Trans. 1994, 90, 1727–1732.
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(12) MacroModel V6.5; Still, W. C., Ed.; Columbia University: New
York, 1998. (b) Mohamdi, F.; Richards, N. G.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440–467.
(14) Kirsten, M.; Rehbein, J.; Hiersemann, M.; Strassner, T. J. Org.
Chem. 2007, 72, 4001–4011.
(15) SPARTAN V5.0; Wavefunction, Inc.: Irvine, CA, 2007.
(16) (a) Lauri, G.; Bartlett, P. A. J. Comput.-Aided Mol. Design 1994,
8, 51–66. (b) CAVEAT V2.2; Bartlett, P. A., Ed.; U. C. Berkeley: Berkeley,
CA, 2008. (c) Kozlowski, M. C.; Panda, M. J. Mol. Graphics Modell. 2002,
20, 399–409.
(13) (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006,
45, 1520–1543. (b) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107,
5713–574. (c) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516–532.
622
Org. Lett., Vol. 11, No. 3, 2009

Scheme 1. Synthesis of Bis-amidinium 10
Allylvinyl ether 11 (eq 1) was selected to preclude the
>formation of a [1,3] sigmatropic product.19 The Claisen
rearrangement of 11 occurs via a nonpolarized transition
state19 which should prevent formation of the enolate/allylic
cation pair and favor only the concerted Claisen rearrange-
ment pathway leading to [3,3] sigmatropic product 12.
Figure 3. Substructure obtained from the CAVEAT search (arrows
in structures match the input vectors from Figure 2; rmsd ) root-
mean-square deviation of vectors in crystal structures compared to
input vectors).
With bisamidinium catalyst 10 in hand, the reaction of 11
was screened with various solvents. Very little to no
midinium (Figure 4) with allyl vinyl ether revealed formation
of a dual hydrogen bonding adduct with bond angles (172°)
approaching an ideal linear hydrogen bond.
Figure 4. Hydrogen bonding of the bisamidinium of 4 (R ) H)
with allyl vinyl ether.
To test the applicability of a bisamidine in catalysis of
the Claisen rearrangement, we synthesized 9 in a straight-
forward manner (Scheme 1). Due to the poor solubility of
bisamidine 9, bisamidinium 10 was synthesized by forming
the chloride salt in quantitative yield. Anion exchange with
sodium barfate17 then provided 10 in 90% yield. In addition
to increasing solubility, the doubly cationic nature of 10 also
provides a superior set of hydrogen bond donors.18
Figure 5. Effect of solvent in the bisamidinium catalyzed Claisen
rearrangement (eq 1). Reaction conditions: [11] ) 0.44 M, rt, 25
mol % 10 when employed.
background reaction was observed without catalyst in a range
of solvents. As expected for a catalyst that interacts via
(17) Zuccaccia, C.; Bellachioma, G.; Cardaci, G.; Macchioni, A. J. Am.
Chem. Soc. 2001, 123, 11020–11028.
(19) (a) Gajewski, J. J.; Gee, K. R.; Jurayj, J. J. Org. Chem. 1990, 55,
1813–1822. (b) Aviyente, V.; Houk, K. N. J. Phys. Chem. A 2001, 105,
383–391.
(18) Kraft, A. J. Chem. Soc., Perkin Trans. 1 1999, 705–714.
Org. Lett., Vol. 11, No. 3, 2009
623

(Figure 5). These values approach those estimated between
the reaction of allyl vinyl ether in organic solvents vs water
(∼60-100-fold).10,20
Table 1. Use of Brønsted Acids to Catalyze the Claisen
Rearrangement of 11 (eq 1)a
To illustrate the effectiveness of bisamidinium catalyst 10,
a comparison with other hydrogen bonding catalysts was
undertaken. As such, bisamidinium 10, monoamidinium 13,
ammonium salt 14, trifluoroacetic acid (15), benzoic acid
(16), urea 17, and guanidinium 18 were examined in the
Claisen rearrangement of 11 (Table 1). Interestingly, bisa-
midinium 10 catalyzed the Claisen rearrangement more
rapidly than stronger Brønsted acids 15 and 16. The dual
hydrogen bond donating nature of 10 is crucial for optimal
reactivity as twice the amount of comparable monohydrogen
bond donors (13 and 14) were not as reactive. Bisamidinium
10 is also much more effective than urea 17 which was used
by Curran in his studies of the Claisen rearrangement.8
In conclusion, we have discovered that bisamidinium
10 can catalyze the Claisen rearrangement of allyl vinyl
ether 11. The reactivity of 10 is superior to higher catalyst
loadings of stronger Brønsted acids indicating that hy-
drogen bonding potential is not solely a function of acidity.
Further support for the designed dual hydrogen bonding
motif was found in the lower reactivity of the correspond-
ing monoamidinium. The reaction has been optimized to
take place in a reasonable amount of time, and studies
toward an enantioselective variant are currently under way.
Experiments to expand the use of 10 to other reactions of
interest are being undertaken.
b
a Reaction conditions: 72 h at rt in PhCF3. Smith, M. B.; March, J.
March’s AdVanced Organic Chemistry: Reactions, Mechanisms, and
Structures, 6th ed.; Wiley-Interscience: New Jersey, 2007. Jenks, W. P.;
Regenstein, J. Ionization Constants of Acids and Bases. In Handbook of
Biochemistry and Molecular Biology, 3rd ed.; Fasman, G. D., Ed.; CRC
Press: Ohio, 1975; Vol. 1, pp 305-351. c Determined by 1H NMR
spectroscopy (see Supporting Information). d Obtained 70% isolated yield
of the volatile product.
Acknowledgment. We thank the NIH (GM59945) and the
NSF (CHE-0616885) for financial support.
Supporting Information Available: Experimental details
and characterization of all new compounds is provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
hydrogen-bonding, ethereal solvents strongly inhibited the
catalyst. Among nonpolar solvents, PhCF3 and CH2Cl2 were
optimal; rate accelerations for catalyst 10 with respect to the
uncatalyzed processes were 55- and 95-fold, respectively
OL8026945
(20) Schuler, F. W.; Murphy, G. W. J. Am. Chem. Soc. 1950, 72, 3155–
3159.
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