Computational study-led organocatalyst design: A novel, highly active urea-based catalyst for addition reactions to epoxides

Article abstract of DOI:10.1021/jo702154m

(Chemical Equation Presented) An in silico study examined the stabilities of hydrogen-bonded complexes between simple thiourea catalysts and three different electrophiles and identified a novel, highly active N-tosyl urea catalyst for the promotion of add

Full text of DOI:10.1021/jo702154m

Computational Study-Led Organocatalyst Design: A Novel, Highly
Active Urea-Based Catalyst for Addition Reactions to Epoxides
Eimear M. Fleming, Cormac Quigley, Isabel Rozas,* and Stephen J. Connon*
Centre for Synthesis and Chemical Biology, School of Chemistry, UniVersity of Dublin, Trinity College,
Dublin 2, Ireland
rozasi@tcd.ie; connons@tcd.ie
ReceiVed October 3, 2007
An in silico study examined the stabilities of hydrogen-bonded complexes between simple thiourea catalysts
and three different electrophiles and identified a novel, highly active N-tosyl urea catalyst for the promotion
of addition reactions to epoxide electrophiles. Synthesis and evaluation of 6 revealed it to be a powerful
catalyst for the addition of 1,2-dimethylindole to styrene oxide under conditions in which simple N,N-
bis-aryl ureas and thioureas (including 1) are inactive. Subsequent studies determined 6 to be compatible
with a range of indole and epoxide substrates (including (E)-stilbene oxide) and found that relatively
poor nucleophiles such as sterically and electronically deactivated anilines, thiophenol, and benzyl alcohol
could be efficiently and regioselectively added to oxiranes under mild conditions.
Introduction
Sigman,7 and Schreiner and Wittkopp8,9 later pioneered the
exploitation of this binding mode in catalysis as a method for
the activation of electrophiles incorporating hydrogen-bond
accepting functionality.10,11
Schreiner and Wittkopp first introduced 3,3′,5,5′-tetratrifluo-
romethyl thiocarbanilide (1) as an active catalyst for the
It has been known for almost a century that small, metal-
free organic molecules can act as effective catalysts in a variety
of synthetically useful transformations;1 however, it is only in
the past decade that this field of endeavor has caught the interest
of a significant proportion of the research community. This
renaissance has resulted in spectacular progress in a relatively
short period of time and has propelled organocatalysis from
obscurity to prominence as a complementary technology to
transition metal(ion)-based catalysis in a number of synthetically
useful transformations.2 In the 1980s, Etter and co-workers
observed that N,N-diaryl ureas cocrystallized via the formation
of two hydrogen bonds with a variety of guests incorporating
Lewis basic functional groups such as -nitroaromatics, ethers,
ketones, and sulfoxides.3,4 Curran and Kuo,5,6 Jacobsen and
(2) Recent reviews: (a) Lelais G.; MacMillan D. W. C. In Frontiers in
Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.; Wiley: New York,
2007. (b) Connon, S. J. Org. Biomol. Chem. 2007, 5, 3407. (c) Almas¸i, D.;
Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18, 299. (d) de
Figueiredo, R. M.; Christmann, M. Eur. J. Org. Chem. 2007, 2575. (e)
Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (f) Gaunt, M. J.; Johansson,
C. C. C.; McNally, A.; Vo, N. T. Drug. DiscoVery Today 2006, 12, 8. (g)
List, B. Chem. Commun. 2006, 819. (h) Taylor, M. S.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2006, 45, 1520. (i) Akiyama, T.; Itoh, J.; Fuchibe,
K. AdV. Synth. Catal. 2006, 348, 999. (j) Connon, S. J. Lett. Org. Chem.
2006, 3, 333. (k) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909. (l)
Jayasree, S.; List, B. Org. Biomol. Chem. 2005, 3, 719. (m) Pihko, P. M.
Angew. Chem., Int. Ed. 2004, 43, 2062. (n) Berkessel, A.; Gro¨ger, H.
Asymmetric Organocatalysis; Wiley: New York, 2005. (o) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (p) Houk, K. N.; List,
B. Acc. Chem. Res. 2004, 37, 8.
* Corresponding authors. Fax: 0035316712826.
(1) For selected early examples of organocatalysis, see: (a) Bredig, G.;
Fajans, K. Ber. Dtsch. Chem. Ges. 1908, 41, 752. (b) Bredig, G.; Fiske, P.
S. Biochem. Z. 1912, 46, 7. (c) Wegler, R. Ann. 1932, 498, 62. (d) Prelog,
V.; Wilhelm, H. HelV. Chim. Acta 1954, 37, 1634. (e) Pracejus, H. Justus
Liebigs Ann. Chem. 1960, 634, 9. (f) Borrmann, D.; Wegler, R. Chem. Ber.
1967, 100, 1575. (g) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 16,
4057.
(3) (a) Etter, M. C.; Panunto, T. W. J. Am. Chem. Soc. 1988, 110, 5896.
(b) Etter, M. C.; Urban˜czyk-Lipkowska, Z.; Zia-Ebrahimi, M.; Panunto, T.
W. J. Am. Chem. Soc. 1990, 112, 8415. (c) Etter, M. C. Acc. Chem. Res.
1990, 23, 120. (d) Etter, M. C. J. Phys. Chem. 1991, 95, 4601.
10.1021/jo702154m CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/04/2008
948
J. Org. Chem. 2008, 73, 948-956

A Highly ActiVe Urea-Based Organocatalyst
promotion of Diels-Alder reactions between cyclopentadiene
and R,â-unsaturated dienophiles.8,9 Catalyst 1 possesses a flat,
rotationally restricted structure with two syn-periplanar N-H
bonds available for hydrogen-bond (HB) donation.8,9 The
trifluoromethyl groups augment the HB donating ability of the
catalyst without being either Lewis basic enough to lead to
appreciable catalyst self-association or close enough to the
thiourea moiety to hinder substrate binding.12 This catalyst has
proven to be remarkably versatile; subsequently, it has been
shown to act as an efficient promoter of a number of reactions13
including the addition of cyanide and silyl ketene acetals to
nitrones,14 the Baylis-Hillman reaction,15 Friedel-Crafts-type
reactions,16 acetalizations,17 Claisen rearrangements,6,18 ring-
opening reactions of oxiranes,19 acyl Strecker reactions,20 imine
reductions,21,22 and tetrahydropyranylations.23
of the considerable manifest interest in this field and the recent
advent of highly active Brønsted acidic24 phosphoric acid
organocatalysts,25,2b,i,k it is somewhat surprising that the evalu-
ation of more acidic (thio)urea analogues of 1 as catalysts has
not been reported. As part of an ongoing program aimed at both
the expansion of the scope of (thio)urea derivative-mediated
catalysis and the development of new catalyst systems, we
undertook an unusual yet potentially rapid and convenient in
silico approach to catalyst design in which the relative compat-
ibility of a given catalyst-substrate pair is determined based
on the stability of the catalyst-substrate complex (via DFT
methods), the results of which guide the course of subsequent
experimental studies. A key feature of this strategy is the
concentration on the interaction between the catalyst and the
electrophilic reaction component. We reasoned that while such
an approach ignores the reaction transition state (the stabilization
of which is key in the design of any catalyst system), this is
less of a disadvantage in an exergonic process in which one
aspires toward the development of catalysts in which proton
transfer occurs as early as possible on the reaction coordinate
and is compensated for by the general applicability of the data
(i.e., a transition state calculation is specific for one reaction,
while the current approach could provide useful indicators of
compatibility over a range of reactions in which the nucleophilic
component is varied) and the relative speed and simplicity of
the calculations involved.
While 1 has proven to be highly active in certain transforma-
tions (particularly those involving condensation17,23), in view
(4) See also: Tel, R. M.; Engberts, J. B. F. N. J. Chem. Soc., Perkin
Trans. 2 1976, 483. (b) Kelly, T. R.; Kim, M. H. J. Am. Chem. Soc. 1994,
116, 7072.
(5) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259.
(6) Curran, D. P.; Kuo, L. H. Tetrahedron Lett. 1995, 36, 6647.
(7) For the first chiral (thio)urea catalysts, see: Sigman, M. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 1998, 120, 4901.
(8) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
(9) Schreiner, P. R.; Wittkopp, A. Chem.sEur. J. 2003, 9, 407.
(10) For reviews focused on this topic, see: (a) Schreiner, P. R. Chem.
Soc. ReV. 2003, 32, 289. (b) Takemoto, Y. Org. Biomol. Chem. 2005, 3,
4299. (c) Connon, S. J. Chem.sEur. J. 2006, 12, 5418.
(11) For representative examples of the use of (thio)ureas in host-guest
chemistry, see: (a) Hamann, B. C.; Branda, N. R.; Rebek, J. R., Jr.
Tetrahedron Lett. 1993, 34, 6837. (b) Smith, P. J.; Reddington, M. V.;
Wilcox, C. S. Tetrahedron Lett. 1992, 33, 6085. (c) Wilcox, C. S.; Kim,
E.-I.; Romano, D.; Kuo, L. H.; Burt, A. L.; Curran, D. P. Tetrahedron 1995,
51, 621. (d) Scheerder, J.; Engbersen, J. F. J.; Casnati, A.; Ungaro, R.;
Reinhoudt, D. N. J. Org. Chem. 1995, 60, 6448. (e) Nam, K. C.; Kang, S.
O.; Ko, S. W. Bull. Kor. Chem. Soc. 1999, 20, 953.
Results and Discussion
The geometries and HB patterns exhibited by a series of
(thio)urea-based organic catalysts and their complexes with a
number of substrates were theoretically studied using DFT. This
study allows the prediction of catalyst reactivity and substrate
recognition/interaction and, additionally, tests the predictability
of the model with subsequent experimental studies.
To determine the existence of HBs and their characteristics,
the computed electron charge density for each complex was
analyzed using the atoms in molecules (AIM)26 methodology.
According to this formalism, a necessary condition for the
establishment of an interaction between two atoms is the
formation of a bond critical point (bcp), which corresponds to
a point where the electron density function is a minimum along
the bond path and maximum in the other directions. Hence, an
interaction can be characterized by the properties of the electron
density in that point, and thus, an electron density [F(bcp)] of
approximately 10-2 au and a positive Laplacian of the charge
density [32F(bcp)] at the bcp correspond to what is defined as
closed-shell interaction of the HB type.
(12) It has also been proposed that the trifluoromethyl substituents play
a role in catalyst rigidification: see ref 9.
(13) For selected examples of chiral (thio)ureas in catalysis, see ref 7
and: (a) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
(b) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
(c) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672. (d) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett.
2004, 6, 625. (e) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
4102. (f) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558. (g) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y.
Synlett 2005, 603. (h) Vakulya, B.; Varga, S.; Csa´mpai, A.; Soo´s, T. Org.
Lett. 2005, 7, 1967. (i) McCooey, S. H.; Connon, S. J. Angew. Chem., Int.
Ed. 2005, 44, 6367. (j) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun.
2005, 4481. (k) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119. (l) Berkessel, A.; Cleemann, F.;
Mukherjee, S.; Mu¨ller, T. N.; Lex, J. Chem. Commun. 2005, 1898. (m)
Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int.
Ed. 2005, 44, 6576. (n) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen,
J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929. (o) Liu, T.-Y.;
Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org.
Biomol. Chem. 2006, 4, 2097. (p) Inkouma, T.; Hoashi, Y.; Takemoto, Y.
J. Am. Chem. Soc. 2006, 128, 9413. (q) Fleming, E. M.; McCabe, T.;
Connon, S. J. Tetrahedron Lett. 2006, 47, 7037. (r) Xu, X.; Yabuta, T.;
Yuan, P.; Takemoto, Y. Synlett 2006, 137. (s) Tsogoeva, S. B.; Wei, S.
Chem. Commun. 2006, 1451. (t) Huang, H.; Jacobsen, E. N. J. Am. Chem.
Soc. 2006, 128, 7170. (u) McCooey, S. H.; McCabe, T.; Connon, S. J. J.
Org. Chem. 2006, 71, 7494. (v) Yamaoka, Y.; Miyabe, H.; Takemoto, Y.
J. Am. Chem. Soc. 2007, 129, 6686. (w) Amere, M.; Lasne, M.-C.; Rouden,
J. Org. Lett. 2007, 9, 2621. (x) Procuranti, B.; Connon, S. J. Chem. Commun.
2007, 1421. (y) Song, J.; Shih, H.-W.; Deng, L. Org. Lett. 2007, 9, 603.
(z) Lubkoll, J.; Wennemers, H. Angew. Chem., Int. Ed. 2007, 46, 6841.
(14) Okino, T.; Hoashi, Y.; Takemoto, Y. Tetrahedron Lett. 2003, 44,
2817.
(19) Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315.
(20) Pan, S. C.; Zhou, J.; List, B. Synlett 2006, 3275.
(21) Zhang Z.; Schreiner, P. R. Synlett 2007, 1455.
(22) For reports concerning the reduction of imines/reductive amination
of aldehydes/ketones using thiourea as a catalyst, see: (a) Menche, D.;
Hassfeld, J.; Menche, G.; Ritter A.; Rudolph, S. Org. Lett. 2006, 8, 741.
(b) Menche, D.; Arikan, F. Synlett 2006, 841. (c) Menche, D.; Bo¨hm, S.;
Li, J.; Rudolph, S.; Zander, W. Tetrahedron Lett. 2007, 48, 365. However,
it should be noted that the role of thiourea in these reactions has been
recently brought into question, see ref 21.
(23) Kotke, M.; Schreiner, P. R. Synthesis 2007, 62, 779.
(24) For short review concerning both metal-free and -assisted Brønsted
acid catalysts, see: Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed.
2005, 44, 1924.
(15) Maher, D. J.; Connon, S. J. Tetrahedron Lett. 2004, 45, 1301.
(16) Dessole, G.; Herrera, R. P.; Ricci, A. Synlett 2004, 2374.
(17) Kotke, M.; Schreiner, P. R. Tetrahedron 2006, 62, 434.
(18) Kirsten, M.; Rehbein, J.; Hiersemann, M.; Strassner, T. J. Org.
Chem. 2007, 72, 4001.
(25) For pioneering examples, see: (a) Akiyama, T.; Itoh, J.; Yokota,
K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.;
Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
(26) Bader, R. F. W. Atoms in Molecules. A Quantum Theory; Oxford
University: New York, 1990.
J. Org. Chem, Vol. 73, No. 3, 2008 949

Fleming et al.
FIGURE 1. Minimum energy structure of the complexes found between 1 and 2-4 optimized at the B3LYP/6-31+G* level.
TABLE 1. Interaction Energies, HB Distances, G(bcp), and
32G(bcp) Found for Complexes 2‚1, 3‚1, and 4‚1 Computed at the
B3LYP/6-31+G* Level of Theory
substrate containing a single O atom. We next proceeded to
analyze the nature and pattern of the interactions in each
complex.
complex
EI (kcal mol-1)
HB distance (Å)
F(bcp)
32F(bcp)
In the case of complex 2‚1, we began from a configuration
where the anhydride group established bifurcated HBs between
the central O atom and the two NH atoms and two secondary
bifurcated interactions between the CdO groups and the NH
of the urea and a CH from each phenyl ring. After optimization,
the system evolved to that shown in Figure 1, where parallel
multiple HBs were found between one of the CdO moieties
and one NH, the central O atom and the other NH, and finally
the second CdO bond and one CH from a phenyl ring. In all
cases, a bcp was found between the interacting atoms, and the
characteristics of the electron density at those bcps correspond
to HB interactions (Table 1). In the case of 3‚1, the final
optimized complex shows two bifurcated interactions between
each of the CdO groups and one NH of the thiourea and a CH
from the proximal phenyl ring. All the aforementioned interac-
tions were characterized as HBs according to the electron density
properties found in the corresponding four bcp values (Table
1). Finally, in complex 4‚1, a bifurcated HB is detected between
the oxirane heteroatom and both thiourea NH protons as seen
both from the localization of two bcps and the electronic
characteristics indicated by those points (Table 1).
It has been demonstrated that there is a clear correlation
between the HB distance and the electron density at the bcp
[F(bcp)].27 Thus, the shorter the HB distance, the larger the
electron density and, therefore, the stronger the interaction.
Accordingly, it seems clear that the interaction between the
catalyst and the substrate will be favored not by the number
(complexes 2‚1 and 3‚1 incorporate three and four HBs,
respectively, whereas 3‚1 is characterized by only two strong
HBs) but by the strength of the HBs in the complex (Table 1).
We next explored the interaction of a more acidic catalyst
(5: an N-tosyl analogue of 1) with 4. Initially, the conforma-
tional space of this new28 catalyst was explored at molecular
2‚1
-10.0
NH‚‚‚O 2.07
NH‚‚‚O 2.23
CH‚‚‚O 2.91
NH‚‚‚O 2.05
NH‚‚‚O 2.11
CH‚‚‚O 2.66
CH‚‚‚O 2.81
NH‚‚‚O 2.02
NH‚‚‚O 2.08
0.0201
0.0135
0.0035
0.0198
0.0166
0.0056
0.0046
0.0219
0.0187
0.0640
0.0468
0.0140
0.0667
0.0595
0.0224
0.0181
0.0723
0.0640
3‚1
4‚1
-10.7
-12.8
Initially, we explored the amenability of different substrates
containing anhydride (2), aldehyde (3), or oxirane (4) function-
alities to interaction with 1. These particular substrates were
chosen based on their inherent (yet discrete) reactivity and
synthetic utility, the fact that they have been little studied (in
the context of (thio)urea-mediated catalysis), and the presence
of one, two, or three O atoms (i.e., HB acceptors) in both sp2
and sp3 hybridization modes. Considering the rigidity of the
symmetrical catalyst 1 and the previous computational studies
on this material carried out by Schreiner et al.,8-10,19,23 and
Strassner et al.,18 only that conformer of minimum energy that
orients both thiourea NH protons toward the substrate was
considered. Regarding the substrates, different approaches for
the interaction were taken to cover all conformational possibili-
ties, and the global minimum energy complexes shown in Figure
1 were obtained after optimization at the B3LYP/6-31+G* level.
In terms of interaction energy (calculated as the difference
between the total energy of the complex minus the sum of the
total energy of the host and guest (Table 1)), the most stable
complex was that formed between the thiourea 1 and the oxirane
derivative (4‚1, Figure 1). Considering that it has been postulated
that the activity of this type of organocatalyst is driven by the
formation of an intramolecular net of HB interactions, this is
an extremely interesting outcome. The catalyst model used has
two HB donors in the thiourea moiety; therefore, it could be
expected (a priori) that the larger the number of HB acceptors
(O atoms) in the substrate, the stronger the interaction. However,
the most stable complex was that formed with the oxirane-type
(27) Some theoretical and experimental examples: (a) Alkorta, I.; Rozas,
I.; Elguero, J. J. Struct. Chem. 1998, 9, 243. (b) Alkorta, I.; Barrios, L.;
Rozas, I.; Elguero, J. J. Mol. Struct. 2000, 496, 131. (c) Espinosa, E.;
Alkorta, I.; Elguero, J.; Molins, E. J. Chem. Phys. 2002, 117, 5529.
(28) To the best of our knowledge, no tosyl-substituted (thio)urea catalysts
have been reported to date. For a very recent report concerning the design
of a chiral sulfinamide-substituted urea catalyst, see: Tan, K. L; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2007, 46, 1315.
950 J. Org. Chem., Vol. 73, No. 3, 2008

A Highly ActiVe Urea-Based Organocatalyst
FIGURE 2. Minimum energy structure of the complexes found
between 5 and 4 optimized at the B3LYP/6-31+G* level.
FIGURE 3. Minimum energy structure of the complexes found
between 6 and 4 optimized at the B3LYP/6-31+G* level.
2
TABLE 2. Interaction Energy, HB Distance, G(bcp), and ∇ G(bcp)
Found for Complex 4‚5, Computed at the B3LYP/6-31+G* Level of
2
TABLE 3. Interaction Energy, HB Distance, G(bcp), and ∇ G(bcp)
Theory
Found for Complex 4‚6, Computed at the B3LYP/6-31+G* Level of
2
EI (kcalmol-1)
-14.0
HB distance (Å)
F(bcp)
∇ F(bcp)
Theory
complex
2
complex
EI (kcal mol-1)
-14.1
HB distance (Å)
F(bcp)
∇ F(bcp)
4‚5
NH‚‚‚O 1.90
NH‚‚‚O 2.18
CH‚‚‚O(S) 2.81
CH‚‚‚O(S) 3.05
0.0303
0.0145
0.0050
0.0030
0.0933
0.0529
0.0195
0.0133
4‚6
NH‚‚‚O 1.97
NH‚‚‚O 2.09
CH‚‚‚O(S) 2.48
0.0240
0.0181
0.0086
0.0795
0.0627
0.0307
purpose organocatalyst and often decomposed before complete
conversion of the starting materials in a number of test reactions.
We were therefore encouraged to evaluate (in silico) the
corresponding N-tosyl urea 6 in the expectation that this material
would offer a greater catalyst stability without requiring a
significant compromise on activity. To our delight, treatment
of the interaction between 6 and 4 in the same fashion as used
previously yielded analogous interaction energies to the corre-
sponding thiourea complexes, and the absolute minimum,
complex 4‚6 (Figure 3), was calculated to be actually 0.06 kcal
mol-1 more stable than 4‚5 (Table 3). As in the case of 4‚5,
the complexes formed with urea 6 show not only HBs with the
urea NH protons but also secondary interactions between one
of the sulfonamide O atoms and CH groups of the oxirane or
phenyl rings of the substrate. In particular, the most stable
complex 4‚6 possesses two very strong NH‚‚‚O HBs and a
secondary weak HB formed between one of the O atoms of the
sulfonamide and an ortho-hydrogen atom of the substrate
benzene ring (Figure 3 and Table 3).29
With a potential novel catalyst and substrate identified,
attention now was turned toward the nucleophilic reaction
component and experimental studies. While this work was in
progress, Schreiner and Kleiner reported the first (thio)urea
catalyzed addition of aliphatic amines, thiophenol, and alcohols
to epoxides.19 Yields were low to moderate in dichloromethane
solvent; however, the same reactions (which require ultrasoni-
cation before the addition of the nucleophile) under the influence
of hydrophobic amplification in water were highly efficient. As
a starting point, we selected indole derivatives as the nucleo-
philic reaction partner as (a) they do not incorporate a basic
mechanics level. Three discrete minima were found with the
appropriate orientation of the NH thiourea groups (vide supra).
Considering that both the catalyst and the substrate are not
symmetrically substituted, four different approaches for the
interaction were possible, all of which were explored. Twelve
complexes were found at the B3LYP/6-31G* level, which were
minima on the potential energy surface exhibiting, in 75% of
the cases, interaction energies were stronger than those associ-
ated with complex 4‚1. This is a strong indication that the
oxirane better interacts with nonsymmetrically substituted 5 than
with the symmetrical thiourea 1. The most stable complexes
(within a range of 2 kcal mol-1 over the minima) were optimized
with the 6-31+G* basis setsconverging to four complexes. The
most stable complex 4‚5 is shown in Figure 2, and the
corresponding interaction energy and analysis of the HB
intramolecular interactions found are presented in Table 2. In
complex 4‚5 (and in all of the optimized complexes investi-
gated), not only is the expected bifurcated interaction between
the O atom (from the oxirane) and the two thiourea NH
hydrogen atoms formed, but also secondary interactions are
observed between one of the sulfonamide O atoms and either
the methylene hydrogen atoms of the oxirane ring (as is the
case with complex 4‚5) or a CH of the substrate phenyl moiety
(Figure 2).
In each of the complexes between 4 and 5 examined, all
interactions established between the host and the guest were
identified as HBs according to both AIM theory and analysis
of the electron density. The data obtained for the most stable
complex 4‚5 are shown in Table 2.
An examination of this data reveals that the HBs established
between the NH of the thiourea and the oxirane O atom are
even stronger (i.e., shorter bond length distances and larger
values of F(bcp)) than the corresponding interactions in complex
4‚1. In addition, even though the secondary interactions with
the sulfonamide O atoms are weak, they seem to contribute to
the total stability of the complex. At this juncture, we were
confident that we had computationally identified a promising
novel catalyst-substrate interaction and proceeded to commence
experimentation to validate the in silico findings. Unfortunately,
while catalyst 5 was readily prepared from the corresponding
N-tosyl aniline/thiophosgene and exhibited high activity, it was
not sufficiently hydrolytically stable to be of use as a general-
(29) All interactions established between both components in each of
the complexes studied were identified as HBs according to AIM theory
and analysis of the electron density. Only results obtained for the most
stable complex 4‚6 are shown in Table 3 for the sake of simplicity.
(30) For examples of metal(ion)-based catalysis of this reaction, see: (a)
Kantam, M. L.; Laha, S.; Yadav, J.; Sreedhar, B. Tetrahedron Lett. 2006,
47, 6213. (b) Azizi, M.; Mehrazama, S.; Saidi, M. R. Can. J. Chem. 2006,
84, 800. (c) Bandini, M.; Fagioli, M.; Melloni, A.; Umani-Ronchi, A. AdV.
Synth. Catal. 2004, 346, 573. (d) Bandini, M.; Cozzi, P. G.; Melchiorre,
P.; Umani-Ronchi, A. J. Org. Chem. 2002, 67, 5386.
(31) Kotsuki, H.; Hayashida, K.; Shimanouchi, T.; Nishizawa, H. J. Org.
Chem. 1996, 61, 984.
(32) Subsequently, an interesting report involving the efficient catalysis
of this reaction using HBF4-SiO2 has appeared: Bandgar, B. P.; Patil, A.
V. Tetrahedron Lett. 2007, 48, 173.
J. Org. Chem, Vol. 73, No. 3, 2008 951

Fleming et al.
TABLE 4. Organocatalyzed Addition of 7 to 4
TABLE 5. Addition of 7 to Styrene Oxides 18-24 Catalyzed by 6
entry
substrate
product
time (h)
yield (%)a
1
2
3
4
5
6
7
18 R ) 2-OCH3
19 R ) 4-OCH3
20 R ) 2-CH3
21 R ) 4-CH3
22 R ) 2-Cl
25 R ) 2-OCH3
26 R ) 4-OCH3
27 R ) 2-CH3
28 R ) 4-CH3
29 R ) 2-Cl
26
26
48
90b
90
98
94
80
93
92
48
621
163
77
23 R ) 4-Cl
30 R ) 4-Cl
24 R ) 4-Br
31 R ) 4-Br
a Refers to isolated yield after chromatography. b Same reaction without
molecular sieves gave 75% isolated yield.
SCHEME 1. Addition of 1- and 2-Methylindoles to 24
Catalyzed by 6
entry
catalyst
time (h)
yield (%)a
1
2
3
4
5
6
7
8
9
None
1
9
72
72
72
72
72
72
72
72
72
72
72
245
0
<2
0
0
0
10
11
12
6
13
14
15
16
17
0
71
56
0
10
11
12
39b
0
Next, the compatibility of 6 with styrene oxides of variable
steric and electronic characteristics was investigated (Table 5).
A range of styrene oxides 18-24 could be converted to indole
derivatives 25-31 in good to excellent yields. Both ortho- and
para-substitution is well-tolerated by the catalyst, and styrene
oxides with electron-rich aromatic rings (entries 1-4 in Table
5) react at considerably faster rates than their more electron
deficient counterparts (entries 5-7 in Table 5). Indoles other
than 7 can also be employed as the nucleophile: both 1- and
2-methylindole derivatives could be reacted with 24 to give 34
and 35 in good yields (Scheme 1).
The success of these Friedel-Crafts-type reactions prompted
us to investigate the compatibility of 6 with other nucleophiles.
Preliminary experiments focused on the use of aliphatic
amines;33 however, these were found to be sufficiently reactive
under our reaction conditions to give considerable levels of
amino alcohol products in the absence of catalyst; furthermore,
Schreiner and Kleiner19 had recently developed efficient catalytic
methodologies for their use in aqueous solvent; therefore, we
decided that the addition of less reactive aniline nucleophiles
to 4 would provide a more instructive test of the catalyst’s
activity and utility (Table 6).
21b,c
a Refers to isolated yield after chromatography. b Conversion, determined
by 1H NMR spectroscopy. c (R)-BINOL afforded 8 as a racemate: no kinetic
resolution was observed.
functionality that could possibly deprotonate the acidic urea 6,
(b) the 3-alkyl indole addition products from such reactions are
useful synthetic building blocks for the construction of molecules
of biological interest,30 and (c) at the outset of this study, the
previous benchmark for organocatalysis of this reaction involved
the use of a silica gel catalyst and elevated temperatures and
pressures (10 kbar) to afford moderate to good adduct yields.31,32
The results of initial catalyst screening studies are presented
in Table 4. The addition of 1,2-dimethylindole (7) to 4 in
dichloromethane does not proceed at room temperature (entry
1 in Table 4). The same reaction catalyzed by 1 (10 mol %)
afforded only traces of adduct 8 (entry 2 in Table 4), and N,N-
diaryl (thio)ureas 9-12 were inactive (entries 3-6 in Table 4).
Gratifyingly, N-tosyl urea 6 identified in the in silico study as
potentially suitable for use in conjunction with 4 proved to be
an effective catalyst capable of furnishing 8 in good isolated
yield after 72 h (entry 7 in Table 4). We did not observe
significant decomposition of 6 in this reaction. The contribution
of the urea moiety to the activity of 6 is underlined by the
catalytic inferiority of acyl sulfonamide 13 (entry 8 in Table
4): although it is noteworthy that this material is superior to 1
and 9-12 under these conditions. Thiourea 14, which possesses
an additional HB donating functionality, did not catalyze the
reaction, while of the diols 15-17, only catechol 15 exhibited
an appreciable catalytic activity.
Catalyst 6 could promote the efficient and highly regiose-
lective formation of â-amino alcohol products derived from
aniline (entry 1 in Table 6), N-methyl aniline, and (remarkably)
either sterically or electronically deactivated derivatives thereof
(33) For the first examples of catalysis of this reaction (using a
biphenylenediol catalyst), see: (a) Hine, J.; Linden, S.-M.; Kanagasabapathy,
V. M. J. Am. Chem. Soc. 1985, 107, 1082. (b) Hine, J.; Linden, S.-M.;
Kanagasabapathy, V. M. J. Org. Chem. 1985, 50, 5096.
952 J. Org. Chem., Vol. 73, No. 3, 2008

A Highly ActiVe Urea-Based Organocatalyst
TABLE 6. Organocatalyzed Addition of Anilines to Styrene Oxide
SCHEME 2. Addition of Aniline to (E)-Stilbene Oxide
Catalyzed by 6
SCHEME 3. Addition of Thiophenol and Benzyl Alcohol to
18- and 19 Catalyzed by 6
TABLE 7. Interaction Energies (kcal/mol), HB Distances (Å),
2
G(bcp), and ∇ G(bcp) Found for Complexes 41a‚6 and 41b‚6
Computed at the B3LYP/6-31+G* Level of Theory
2
complex EI (kcal mol-1)
HB distance (Å)
F(bcp) ∇ F(bcp)
41a‚6
41b‚6
-11.5
-13.0
NH‚‚‚N 2.26
NH‚‚‚O 1.94
OH‚‚‚O(S) 1.95
0.0176
0.0288
0.0253
0.0466
0.0852
0.0855
0.0774
0.0524
0.0990
0.0476
0.0269
NH‚‚‚O 2.23 (intra) 0.0168
NH‚‚‚O 2.20
NH‚‚‚O 1.88
NH‚‚‚O(S) 2.23
CH‚‚‚O(S) 2.55
0.0158
0.0310
0.0133
0.0069
to methoxy substituted styrene oxides 18- and 19 in good yield
at room temperature with the assistance of 6 (Scheme 3). In
the absence of the catalyst, no conversion of 18- and 19 was
observed after the same reaction time in either process.
a Refers to isolated yield after chromatography. b 2.0 M concentration.
The crude reaction mixture was determined to be a 94:6 ratio of regioisomers
using 1H NMR spectroscopy. The yield cited corresponds to that of the
isomer shown. c 1.5 M concentration. d Using 20 mol % 6. e Crude reaction
mixture was determined to be a 92:8 ratio of regioisomers using 1H NMR
spectroscopy.
Finally, we studied, from a theoretical point of view, the
relative affinities of the catalyst for the substrate and the product
obtained after the addition of aniline to styrene oxide. The
possible complexes formed between urea catalyst 6 and 41 were
analyzed. Initially, the conformational space of the product was
explored, and the conformer of minimum energy was identified
and then used for the rest of the calculations. The catalyst
conformer utilized was that previously determined (vide supra).
Considering the structure of both molecules, all possible
approximations were taken into account at the B3LYP/6-31G*
level, and 12 complexes of minimum energy were identified.
Eight of these involved interactions between the catalyst urea
moiety and the O atom of the hydroxyl group of the product.
The other four approximations involved dual interactions
between the urea and both the O(H) and the N(H) groups of
the product. Those conformers of minimum energy for each
approximation were further optimized at the 6-31+G* level,
resulting in two different complexes of minimum energy (41a‚
6 and 41b‚6 (Table 7 and Figure 4)).
(entries 3-5 in Table 6) at 10 mol % levels. Only the
considerably hindered amine 39 required an augmented catalyst
loading of 20 mol %. While Schreiner and Kleiner’s study19
did not utilize aniline substrates, Saidi and Azizi34 recently
reported (in a study concerned with the addition of amines to
epoxides in water) that aromatic amines gave poor adduct yields
with all oxirane electrophiles except terminal epoxide 435 under
conditions that resulted in smooth reactions using aliphatic
amines. Accordingly, we were pleased to find that 6 could
catalyze the addition of aniline to the more hindered (E)-stilbene
oxide (46) in high yield at 30 °C (Scheme 2)
The scope of these catalyzed processes was not restricted to
carbon- and nitrogen-based nucleophiles. Thiophenol (48) and
the weakly nucleophilic benzyl alcohol (50) could also be added
Complex 41a‚6 is formed between the catalyst (acting as a
HB donor) and 41 with both the product amino and the hydroxyl
groups acting as HB acceptors (Figure 4), and an additional
(34) Azizi, N.; Saidi, M. R. Org. Lett. 2005, 7, 3649.
(35) Only one example (using aniline itself) as the nucleophile was given.
J. Org. Chem, Vol. 73, No. 3, 2008 953

Fleming et al.
6 possessed unprecedented activity for a (thio)urea catalyst and
promoted the addition of indole 7 to styrene oxide at room
temperature under conditions that other (thio)urea derivatives
(including 1) did not. The catalyst was robust and of high
synthetic utility: various styrene oxides (including a nonterminal
analogue) and indoles were tolerated, and (demonstrating the
general applicability of the methodology) it was found that the
catalyst was equally proficient in the promotion of C-N, C-S,
and C-O bond formation via the addition of weak nucleophiles
to epoxides under conditions that do not give reactions in the
absence of 6. We are currently investigating the use of this
strategy in the design of more complex bifunctional catalyst
systems.
FIGURE 4. Structure of minimum energy found for the complexes
formed between 41 and 6: complexes 41a‚6 (left) and 41b‚6 (right).
The ring of cooperative HBs in complex 41a‚6 is framed.
HB is formed between the hydroxylic proton and one of the O
atoms of the SO2 moiety. Complex 41b‚6 is characterized by
bifurcated HBs between the O atom of the product and the urea
protons and two secondary interactions between the product
amino and the methine protons as HB donors with one of the
catalyst’s sulfonamide O atoms.
Analyzing the electron density surface, it was possible to
identify four HBs in each complex. In the case of the 41a‚6
complex, parallel HBs are formed between the urea NH groups
and the N (medium HB) and O (very strong HB) atoms of the
product, and a very strong HB is established between the
hydroxyl group of the product (which acts now as a HB donor)
and one of the sulfonamide O atoms. Additionally, an intramo-
lecular NH‚‚‚O(H) HB is found in the product molecule (Table
7). The reason behind the strength of the NH‚‚‚O and OH‚‚‚
O(S) bonds lies in the cooperative effect established between
these two HBs formed through the O-H group.36 Thus, it is
possible to identify a ring of HBs connected in a cooperative
fashion: (Ss)NsH‚‚‚OsH‚‚‚OsS(tN).
In complex 41b‚6, bifurcated HBs are formed between both
urea NH protons and hydroxyl O atom. Additionally, two weak
HBs are established between the NH and one CH group of the
product and one of the sulfonamide O atoms. These two
complexes, which are the most stable of all the possible
complexes found at lower levels of computation, are less stable
than complex 4‚6 found between the catalyst and the oxirane
derivative (Table 7).
Experimental Section
Synthesis of Catalyst 6. A 10 mL round-bottomed flask charged
with 3,5-trifluoromethylaniline (600 µL, 3.84 mmol) and dichlo-
romethane (5.0 mL) was fitted with a septum and placed under an
atmosphere of Ar. Subsequently, p-toluenesulfonyl isocyanate (643
µL, 4.22 mmol) was added via a syringe. A white precipitate was
observed after 10 min. The solution was left to stir overnight. The
reaction was filtered, and the product was purified by recrystalli-
zation (CH2Cl2-hexane) to give 6 (1.52 g, 93%) as a white solid,
mp 185-187 °C. 1H NMR (CDCl3) δ 8.94 (br s, 1H, NH), 7.95 (s,
2H), 7.83-7.86 (d, 2H, J ) 5.4 Hz), 7.66 (s, 1H), 7.48 (br s, 1H),
7.39-7.41 (d, 2H, J ) 5.4 Hz), 2.48 (s, 3H). 13C NMR (CDCl3) δ
148.4, 145.9, 138.2, 136.0, 132.6 (q, J ) 33.9 Hz), 130.4, 126.9,
122.9 (q, J ) 273.0 Hz) 119.8, 118.1, 21.6. IR (Nujol) 3157, 1693,
1276, 1162, 1147, 680 cm-1. HRMS (ESI, m/z) calcd for C16H12N2O3-
SF6Na (M + Na)+ 449.0371, found 449.0389
Procedure A: Synthesis of 8 Catalyzed by 6. A 1 mL reaction
vessel equipped with a stir bar and charged with 6 (29.3 mg, 0.069
mmol) and 5 Å molecular sieves (40 mg) was fitted with a septum
and placed under an atmosphere of Ar (balloon). Compound 7 (200
mg, 1.37 mmol), CH2Cl2 (40.4 µL), and 4 (78.5 µL, 0.688 mmol)
were then added, the septum was replaced with a cap, and the
resulting solution was stirred at ambient temperature for 72 h.
Column chromatography of the reaction mixture (4:1 hexane/ethyl
1
acetate, Rf 0.3) yielded 8 (129 mg, 71%) as a pale yellow oil. H
NMR (CDCl3) δ 7.49-7.51 (d, 1H, J ) 8.0 Hz), 7.27-7.36 (m,
5H), 7.16-7.22 (m, 2H), 7.02-7.06 (app. t, 1H, J ) 7.5 Hz), 4.52-
4.56 (app. t, 1H, J ) 7.8 Hz), 4.36-4.38 (m, 2H), 3.71 (s, 3H),
2.41 (s, 3H). 13C NMR (CDCl3) δ: 141.9, 137.0, 135.3, 128.4,
127.9, 126.7, 126.3, 120.7, 119.3, 119.2, 109.2, 108.9, 65.2, 45.4,
29.7, 10.7. NMR spectral data are consistent with that in the
Conclusion
literature.30c IR (neat): 3399, 2936, 1600, 1177, 1031, 739 cm-1
.
To summarize, we utilized computational DFT methods to
evaluate the stabilities of hydrogen-bonded complexes between
thio(urea) catalysts and three different electrophiles that incor-
porate Lewis-basic oxygen-based functionality. These data were
then used to select a (thio)urea-electrophile pair predicted to
be best suited for use in catalytic reactions in conjunction with
a generic nucleophile. While this approach ignores the reaction
transition state, it is rapidly executed, and the results can
potentially be applied to a range of reactions involving a given
electrophile and a number of various nucleophiles if discretion
is exercised regarding nucleophile compatibility with the
catalyst’s acidity. The results of these investigations strongly
indicated that the previously unknown acidic urea-based catalyst
6 would potentially be able to serve as a more active promoter
of addition reactions to epoxide derivatives than benchmark
literature catalyst 1. Synthesis and evaluation of 6 led to the
validation of this computational study-guided design strategy:
HRMS (ESI, m/z) calcd for C18H19NONa (M + Na)+ 288.1364,
found 288.1358.
Synthesis of 25. A 1 mL reaction vessel equipped with a stir
bar charged with 6 (29.3 mg, 0.0688 mmol) and 5 Å molecular
sieves (40 mg) was fitted with a septum and placed under an
atmosphere of Ar (balloon). Compound 7 (200 mg, 1.37 mmol),
CH2Cl2 (40 µL), and 18 (103.3 mg, 0.688 mmol) were then added,
the septum was replaced with a cap, and the resulting solution was
stirred at ambient temperature for 26 h. Column chromatography
of the reaction mixture (CH2Cl2, Rf 0.5) yielded 25 (183 mg, 90%)
1
as a pale yellow solid, mp 124-126 °C. H NMR (DMSO-d6) δ
7.48-7.50 (m, 2H), 7.28-7.30 (d, 1H, J ) 7.8 Hz), 7.10-7.14
(app. t, 1H, J ) 7.8 Hz), 6.95-6.99 (app. t, 1H, J ) 7.5 Hz), 6.83-
6.90 (m, 3H), 4.58-4.62 (m, 2H), 4.16-4.20 (app. t, 1H, J ) 9.5
Hz), 3.94-3.99 (app. t, 1H, J ) 8.8 Hz), 3.72 (s, 3H), 3.62 (s,
3H), 2.40 (s, 3H).13C NMR (DMSO-d6) δ: 157.0, 136.2, 133.9,
130.8, 127.9, 126.7, 126.6, 119.8, 119.5, 118.9, 118.0, 110.6, 110.4,
108.9, 62.7, 55.3, 38.6, 29.3, 10.3. IR (Nujol): 3327, 2917, 1596,
1462, 1117, 1027, 732 cm-1. HRMS (ESI, m/z) calcd for C19H21-
NO2Na (M + Na)+ 318.1470, found 318.1464.
(36) Rozas, I. Phys. Chem. Chem. Phys. 2007, 9, 2782.
954 J. Org. Chem., Vol. 73, No. 3, 2008

A Highly ActiVe Urea-Based Organocatalyst
Synthesis of 26. A 1 mL reaction vessel equipped with a stir
bar charged with 6 (29.3 mg, 0.0688 mmol) and 5 Å molecular
sieves (40 mg) was fitted with a septum and placed under an
atmosphere of Ar (balloon). Compound 7 (200 mg, 1.37 mmol),
CH2Cl2 (40.4 µL), and 19 (78.5 µL, 0.688 mmol) were then added,
the septum was replaced with a cap, and the resulting solution was
stirred at ambient temperature for 26 h. Column chromatography
of the reaction mixture (CH2Cl2, Rf 0.5) yielded 26 (183 mg, 90%)
as a pale yellow oil. 1H NMR (DMSO-d6) δ 7.32-7.34 (dd, 2H, J
) 8.0 Hz), 7.23-7.26 (d, 2H, J ) 8.0 Hz), 6.98-7.02 (app. t, 1H,
J ) 7.5 Hz), 6.84-6.88 (app t, 1H, J ) 7.5 Hz), 6.79-6.81 (d,
2H, J ) 8.0 Hz), 4.68-4.70 (app t, 1H, J ) 5.5 Hz), 4.26-4.30
(app t, 1H, J ) 7.3 Hz), 4.17-4.23 (m, 1H), 3.93-3.98 (m, 1H),
3.69 (s, 3H), 3.63 (s, 3H), 2.36 (s, 3H) 13C NMR (DMSO-d6) δ:
157.1, 136.3, 135.4, 133.6, 128.9, 126.5, 119.7, 118.8, 118.2, 113.3,
111.6, 109.0, 64.0, 55.0, 44.1, 29.3, 10.4. IR (neat): 3399, 3048,
2933, 1610, 1511, 1034 cm-1. HRMS (ESI, m/z) calcd for C19H21-
NO2Na (M + Na)+ 318.1470, found 318.1461.
107.8, 64.2, 43.0, 29.5, 10.6. IR (neat): 3400, 2935, 1611, 1468,
1040, 741 cm-1. HRMS (ESI, m/z) calcd for C18H18NONaCl (M
+ Na)+ 322.0975, found 322.0984.
Synthesis of 30. A 1 mL reaction vessel equipped with a stir
bar charged with 6 (29.3 mg, 0.0688 mmol) and 5 Å molecular
sieves (40 mg) was fitted with a septum and placed under an
atmosphere of Ar (balloon). Compound 7 (200 mg, 1.37 mmol),
CH2Cl2 (66 µL), and 23 (137 mg, 0.688 mmol) were then added,
the septum was replaced with a cap, and the resulting solution was
stirred at ambient temperature for 163 h. Column chromatography
of the reaction mixture (CH2Cl2, Rf 0.3) yielded 30 (191 mg, 93%)
1
as a clear oil. H NMR (DMSO-d6) δ 7.28-7.37 (m, 6H), 6.99-
7.03 (app t, 1H, J ) 7.8 Hz), 6.85-6.89 (app t, 1H, J ) 7.5 Hz),
4.80-4.83 (app t, 1H, J ) 5.0 Hz), 4.32-4.35 (app t, 1H, J ) 7.0
Hz), 4.21-4.27 (m, 1H), 3.92-3.97 (m, 1H), 3.64 (s, 3H), 2.37 (s,
3H). 13C NMR (DMSO-d6) δ: 142.6, 136.3, 133.8, 130.0, 129.9,
127.8, 126.3, 119.9, 118.6, 118.4, 110.9, 109.1, 63.6, 44.3, 29.4,
10.4. IR (neat): 3434, 2250, 1661, 1056, 822, 759, cm-1. HRMS
(ESI, m/z) calcd for C18H19NOCl (M + H)+ 300.1155, found
300.1147.
Synthesis of 27. A 1 mL reaction vessel equipped with a stir
bar charged with 6 (29.3 mg, 0.0688 mmol) and 5 Å molecular
sieves (40 mg) was fitted with a septum and placed under an
atmosphere of Ar (balloon). Compound 7 (200 mg, 1.37 mmol),
CH2Cl2 (78 µL), and 20 (92.3 mg, 0.688 mmol) were then added,
the septum was replaced with a cap, and the resulting solution was
stirred at ambient temperature for 48 h. Column chromatography
of the reaction mixture (CH2Cl2, Rf 0.45) yielded 27 (188 mg, 98%)
Synthesis of 31. A 1 mL reaction vessel equipped with a stir
bar charged with 6 (29.3 mg, 0.0688 mmol) and 5 Å molecular
sieves (40 mg) was fitted with a septum and placed under an
atmosphere of Ar (balloon). Compound 7 (200 mg, 1.37 mmol),
CH2Cl2 (66 µL), and 24 (137 mgs, 0.688 mmol) were then added,
the septum was replaced with a cap, and the resulting solution was
stirred at ambient temperature for 77 h. Column chromatography
of the reaction mixture (CH2Cl2, Rf 0.3) yielded 31 (218 mg, 92%)
1
as a pale yellow oil. H NMR (DMSO-d6) δ 7.57-7.59 (d, 1H, J
) 7.8 Hz), 7.28-7.32 (app t, 2H, J ) 7.8 Hz), 7.18-7.21 (m,
1H), 7.06 (m, 2H), 6.96-7.00 (app t, 1H, J ) 7.8 Hz), 6.80-6.83
(app t, 1H, J ) 7.3 Hz), 4.68-4.70 (app t, 1H, J ) 5.4 Hz), 4.37-
4.40 (app t, 1H, J ) 7.3 Hz), 4.12-4.18 (m, 1H), 3.91-3.97 (m,
1H), 3.62 (s, 3H), 2.33 (s, 3H), 2.13 (s, 3H). 13C NMR (DMSO-
d6) δ: 140.8, 136.6, 136.3, 134.0, 130.1, 127.3, 126.7, 125.6, 125.3,
119.6, 118.4, 118.1, 109.6, 108.9, 63.5, 41.7, 29.3, 19.3, 10.4. IR
(neat): 3410, 3049, 2251, 1657, 1470, 1008 cm-1. HRMS (ESI,
m/z) calcd for C19H21NONa (M + Na)+ 302.1521, found 302.1511.
Synthesis of 28. A 1 mL reaction vessel equipped with a stir
bar charged with 6 (29.3 mg, 0.0688 mmol) and 5 Å molecular
sieves (40 mg) was fitted with a septum and placed under an
atmosphere of Ar (balloon). Compound 7 (200 mg, 1.37 mmol),
CH2Cl2 (78 µL), and 21 (92.3 mg, 0.688 mmol) were then added,
the septum was replaced with a cap, and the resulting solution was
stirred at ambient temperature for 48 h. Column chromatography
of the reaction mixture (4:1 hexane/ethyl acetate, Rf 0.3) yielded
1
as a pale yellow oil. H NMR (DMSO-d6) δ 7.42-7.44 (d, 2H, J
) 8.0 Hz), 7.30-7.35 (m, 4H), 6.99-7.03 (app t, 1H, J ) 7.5
Hz), 6.86-6.89 (app t, 1H, J ) 7.5 Hz), 4.80-4.83 (m, 1H), 4.30-
4.34 (m, 1H), 4.21-4.27 (m, 1H), 3.92-3.97 (m, 1H), 3.64 (s,
3H), 2.37 (s, 3H). 13C NMR (DMSO-d6) δ: 143.0, 136.3, 133.9,
130.7, 130.4, 126.3, 119.9, 118.6, 118.5, 118.4, 110.8, 109.1, 63.6,
44.3, 29.4, 10.4. IR (neat): 3435, 2251, 2125, 1661, 1055, 822,
760 cm-1. HRMS (ESI, m/z) calcd for C18H18NONaBr (M + Na)+
366.0469, found 366.0461.
Synthesis of 34. A 1 mL reaction vessel equipped with a stir
bar charged with 6 (33.3 mg, 0.0782 mmol) and 5 Å molecular
sieves (40 mg) was fitted with a septum and placed under an
atmosphere of Ar (balloon). Compound 32 (200 µL, 1.56 mmol),
CH2Cl2 (424 µL), and 24 (155.7 mg, 0.782 mmol) were then added,
the septum was replaced with a cap, and the resulting solution was
stirred at ambient temperature for 7.8 days. Column chromatography
of the reaction mixture (3:1 hexane/ethyl acetate, Rf 0.5) yielded
1
28 (181 mg, 94%) as a pale yellow oil. H NMR (DMSO-d6) δ
1
7.31-7.35 (app t, 2H, J ) 6.8 Hz), 7.20-7.22 (d, 2H, J ) 8.0
Hz), 6.98-7.04 (m, 3H), 6.84-6.87 (app t, 1H, J ) 7.3 Hz), 4.67-
4.69 (app t, 1H, J ) 5.0 Hz), 4.26-4.30 (app t, 1H, J ) 7.3 Hz),
4.18-4.24 (m, 1H), 3.93-3.98 (m, 1H), 3.63 (s, 3H), 2.36 (s, 3H),
2.22 (s, 3H). 13C NMR (DMSO-d6) δ: 140.5, 136.3, 134.3, 133.6,
128.5, 127.9, 126.5, 119.7, 118.8, 118.2, 111.5, 108.9, 63.8, 44.6,
29.3, 20.6, 10.4. IR (neat): 3392, 3047, 2923, 1470, 1036, 739
cm-1. HRMS (ESI, m/z) calcd for C19H21NONa (M + Na)+
302.1521, found 302.1516.
34 (235 mg, 91%) as a white solid, mp 141-143 °C. H NMR
(CDCl3) δ 7.43-7.45 (m, 3H), 7.32-7.34 (d, 1H, J ) 8.3 Hz),
7.23-7.26 (m, 3H), 7.06-7.09 (app. t, 1H, J ) 6.8 Hz), 6.97 (s,
1H), 4.45-4.47 (app. t, 1H, J ) 6.8 Hz), 4.23-4.26 (dd, 1H, J )
6.7, 10.9 Hz), 4.15-4.18 (dd, 1H, J ) 6.8, 10.9 Hz), 3.80 (s, 3H).
13C NMR (CDCl3) δ: 141.0, 137.3, 131.6, 130.0, 127.2, 126.7,
122.0, 120.5, 119.3, 119.2, 113.9, 109.4, 66.2, 45.0, 32.8. IR
(Nujol): 3302, 2923, 1377, 1053, 1007, 731 cm-1. HRMS (ESI,
m/z) calcd for C17H17NOBr (M + H)+ 330.0494, found 330.0495.
Synthesis of 35. A 1 mL reaction vessel equipped with a stir
bar charged with 6 (32.5 mg, 0.0762 mmol) and 5 Å molecular
sieves (40 mg) was fitted with a septum and placed under an
atmosphere of Ar (balloon). Compound 33 (200 mg, 1.52 mmol),
CH2Cl2 (261 µL), and 24 (151.7 mg, 0.762 mmol) were then added,
the septum was replaced with a cap, and the resulting solution was
stirred at ambient temperature for 7.2 days. Column chromatography
of the reaction mixture (CH2Cl2, Rf 0.5) yielded 35 (221 mg, 89%)
Synthesis of 29. A 1 mL reaction vessel equipped with a stir
bar charged with 6 (29.3 mg, 0.0688 mmol) and 5 Å molecular
sieves (40 mg) was fitted with a septum and placed under an
atmosphere of Ar (balloon). Compound 7 (200 mg, 1.37 mmol),
CH2Cl2 (64 µL), and 22 (106.4 mg, 0.688 mmol) were then added,
the septum was replaced with a cap, and the resulting solution was
stirred at ambient temperature for 621 h. Column chromatography
of the reaction mixture (4:1 hexane/ethyl acetate, Rf 0.3) yielded
29 (165 mg, 80%) as a pale yellow oil. 1H NMR (CDCl3) δ 7.62-
7.65 (d, 1H, J ) 8.0 Hz), 7.57-7.59 (d, 1H, J ) 7.5 Hz), 7.35-
7.37 (d, 1H, J ) 8.0 Hz), 7.29-7.32 (d, 1H, J ) 8.5 Hz), 7.14-
7.24 (m, 3H), 7.04-7.08 (app t, 1H, J ) 7.5 Hz), 4.86-4.89 (dd,
1H, J ) 6.5, 9.0 Hz), 4.37-4.42 (m, 1H), 4.27-4.31 (m, 1H), 3.70
(s, 3H), 2.44 (s, 3H). 13C NMR (CDCl3) δ: 139.3, 136.8, 135.5,
134.1, 129.7, 129.1, 127.5, 126.7, 126.6, 120.5, 119.2, 118.8, 108.9,
1
as a yellow wax. H NMR (DMSO-d6) δ 10.80 (br s, 1H), 7.42-
7.44 (d, 2H, J ) 8.5 Hz), 7.28-7.31 (m, 3H), 7.20-7.22 (d, 1H,
J ) 8.0 Hz), 6.91-6.95 (app t, 1H, J ) 7.5 Hz), 6.80-6.84 (app
t, 1H, J ) 7.5 Hz), 4.78-4.81 (app t, 1H, J ) 5.0 Hz), 4.17-4.28
(m, 2H), 3.91-3.96 (m, 1H), 2.34 (s, 3H). 13C NMR (DMSO-d6)
δ: 143.2, 135.2, 132.2, 130.7, 130.4, 127.3, 119.8, 118.5, 118.4,
118.2, 110.7, 110.5, 63.6, 44.2, 12.0. IR (neat): 3399, 3325, 2926,
J. Org. Chem, Vol. 73, No. 3, 2008 955

Fleming et al.
1618, 1487, 1010, 740 cm-1. HRMS (ESI, m/z) calcd for C17H17-
NOBr (M + H)+ 330.0494, found 330.0498.
1026, 854, 700 cm-1. HRMS (ESI, m/z) calcd for C17H22NO (M +
H)+ 256.1701, found 256.1691.
Synthesis of 45. Prepared as per procedure A using 6 (37.4 mg,
0.0877 mmol), 40 (283 µL, 1.75 mmol), CH2Cl2 (340 µL), and 4
(100 µL, 0.877 mmol). The reaction was stirred for 71 h. Column
chromatography of the reaction mixture (CH2Cl2, Rf 0.7) yielded
Synthesis of 41. Prepared as per procedure A using 6 (37.4 mg,
0.087 mmol), 36 (80 µL, 0.877 mmol), CH2Cl2 (240 µL), and 4
(100 µL, 0.877 mmol). The reaction was stirred for 91 h. Column
chromatography of the reaction mixture (1:1 CH2Cl2/hexane, Rf 0.5)
yielded 41 (161 mg, 86%) as a pale brown wax. 1H NMR (CDCl3)
δ 7.35-7.41 (m, 4H), 7.29-7.31 (m, 1H), 7.11-7.15 (app t, 2H,
J ) 7.8 Hz), 6.70-6.73 (app t, 1H, J ) 7.5 Hz), 6.60-6.61 (d,
2H, J ) 9.0 Hz), 4.53-4.56 (dd, 1H, J ) 4.5, 7.0 Hz), 3.97-4.00
(dd, 1H, J ) 4.0, 11.0 Hz), 3.78-3.82 (dd, 1H, J ) 7.0, 11.0 Hz),
3.52 (s, 1H), 1.55 (br s, 1H). 13C NMR (CDCl3) δ: 146.7, 139.6,
128.7, 128.4, 127.2, 126.3, 117.5, 113.4, 67.0, 59.4. NMR spectral
data are consistent with that in the literature.37 IR (neat): 3399,
3025, 2874, 1599, 1501, 1316, 1066, 697 cm-1. HRMS (ESI, m/z)
calcd for C14H16NO (M + H)+ 214.1232, found 214.1227.
Synthesis of 42: Major Isomer (Table 6). Prepared as per
procedure A using 6 (37.4 mg, 0.087 mmol), 37 (95 µL, 0.877
mmol), CH2Cl2 (225 µL), and 4 (100 µL, 0.877 mmol). The reaction
was stirred for 91 h. Column chromatography of the reaction
mixture (1:1 CH2Cl2/hexane, Rf 0.4) yielded 42 (177 mg, 78%) as
a pale yellow viscous oil. 1H NMR (CDCl3) δ 7.28-7.31 (m, 5H),
7.15-7.17 (d, 2H, J ) 8.8 Hz), 6.96-6.98 (d, 2H, J ) 8.0 Hz),
6.83-6.87 (app t, 1H, J ) 7.3 Hz), 5.10-5.14 (dd, 1H, J ) 6.0,
9.0 Hz), 4.12-4.20 (m, 2H), 2.73 (s, 3H), 2.13 (br s, 1H). NMR
spectral data are consistent with that in the literature.38 13C NMR
(CDCl3) δ: 151.0, 137.3, 129.1, 128.4, 127.5, 127.0, 118.3, 114.7,
64.5, 61.5, 31.9. IR (neat): 3383, 2884, 1597, 1503, 1030, 746,
695 cm-1. HRMS (ESI, m/z) calcd for C15H18NO (M + H)+
228.1388, found 228.1387.
Synthesis of 42: Minor Isomer. Prepared as per procedure A
using 6 (37.4 mg, 0.087 mmol), 37 (95 µL, 0.877 mmol), CH2Cl2
(225 µL), and 4 (100 µL, 0.877 mmol). The reaction was stirred
for 91 h. Column chromatography of the reaction mixture (1:1 CH2-
Cl2/hexane, Rf 0.3) yielded 42 (8 mg, 3%) as a pale yellow oil. 1H
NMR (CDCl3) δ 7.39-7.47 (m, 4H), 7.28-7.36 (m, 3H), 6.87-
6.90 (d, 2H, J ) 8.5 Hz), 6.79-6.83 (app t, 1H, J ) 7.3 Hz), 5.02-
5.05 (dd, 1H, J ) 4.5, 9.0 Hz), 3.44-3.57 (m, 2H), 2.97 (s, 3H),
2.55 (br s, 1H). NMR spectral data are consistent with that in the
literature.42 13C NMR (CDCl3) δ: 149.5, 141.5, 128.8, 128.1, 127.4,
125.5, 117.1, 112.8, 71.3, 61.6, 38.9. HRMS (ESI, m/z) calcd for
C15H18NO (M + H)+ 228.1388, found 228.1379.
1
45 (207 mg, 84%) as a yellow solid, mp 79-81 °C. H NMR
(CDCl3) δ 7.31-7.42 (m, 5H), 6.66 (s, 1H), 6.44 (s, 2H), 4.46-
4.49 (app t, 1H, J ) 5.0 Hz), 3.98-4.01 (dd, 1H, J ) 4.0, 11.0
Hz), 3.79-3.83 (dd, 1H, J ) 6.0, 11.0 Hz). 13C NMR (CDCl3) δ:
148.7, 138.7, 135.2, 128.9, 127.9, 126.4, 117.4, 111.8, 67.0, 59.3.
IR (neat): 3431, 2930, 1593, 1451, 1316, 1069, 703 cm-1. HRMS
(ESI, m/z) calcd for C14H14NOCl2 (M + H)+ 282.0452, found
282.0461.
Synthesis of 47. Prepared as per procedure A using 6 (86.9 mg,
0.20 mmol), 36 (186 µL, 2.04 mmol), CH2Cl2 (324 µL), and 46
(200 mg, 1.02 mmol). The reaction was stirred for 142 h at 30 °C.
Column chromatography of the reaction mixture (1:1 CH2Cl2/
hexane, Rf 0.1) yielded 47 (270 mg, 92%) as a pale pink solid, mp
1
126-127 °C (lit.39 122-124 °C). H NMR (CDCl3) δ 7.26-7.31
(m, 6H), 7.07-7.18 (m, 6H), 6.67-6.70 (app t, 1H, J ) 7.3 Hz),
6.54-6.56 (d, 2H, J ) 7.5 Hz), 5.09-5.10 (d, 1H, J ) 6.8 Hz),
4.69-4.70 (d, 1H, J ) 5.0 Hz), 4.49 (br s, 1H), 2.33 (br s, 1H).
13C NMR (CDCl3) δ: 146.3, 139.5, 138.0, 128.7, 127.9, 127.8,
127.6, 127.5, 127.2, 126.1, 117.5, 113.5, 76.7, 63.2. NMR spectral
data are consistent with that in the literature.39 IR (Nujol): 3345,
3255, 1601, 1057, 752, 690, 624 cm-1. HRMS (ESI, m/z) calcd
for C20H20NO (M + H)+ 290.1545, found 290.1552.
Synthesis of 49. Prepared as per procedure A using 6 (58.7 mg,
0.138 mmol), 48 (141 µL, 1.38 mmol), and 18 (103.3 mg, 0.69
mmol). The reaction was stirred for 20 h. Column chromatography
of the reaction mixture (CH2Cl2, Rf 0.6) yielded 49 (153 mg, 85%)
as a pale yellow oil. 1H NMR (CDCl3) δ 7.37-7.40 (m, 2H), 7.24-
7.30 (m, 5H), 6.91-6.96 (m, 2H), 4.85-4.88 (app t, 1H, J ) 6.5
Hz), 3.89-3.98 (m, 2H), 3.87 (s, 3H), 2.12 (br s, 1H). 13C NMR
(CDCl3) δ: 156.4, 134.2, 131.6, 128.4, 128.3, 127.9, 126.7, 126.6,
120.3, 110.4, 64.1, 55.2, 48.8. IR (neat): 3429, 2937, 1584, 1491,
1246, 1026, 739 cm-1. HRMS (ESI, m/z) calcd for C15H16O2NaS
(M + Na)+ 283.0769, found 283.0769.
Synthesis of 51. Prepared as per procedure A using 6 (58.7 mg,
0.138 mmol), 50 (143 µL, 1.38 mmol), and 19 (103.3 mg, 0.69
mmol). The reaction was stirred for 20 h. Column chromatography
of the reaction mixture (CH2Cl2, Rf 0.2) yielded 51 (146 mg, 82%)
as a pale yellow oil. 1H NMR (CDCl3) δ 7.31-7.40 (m, 7H), 6.95-
6.97 (d, 2H, J ) 6.0 Hz), 4.55-4.57 (d, 1H, J ) 11.5 Hz), 4.51-
4.53 (dd, 1H, J ) 4.0, 9.0 Hz), 4.34-4.36 (d, 1H, J ) 11.5 Hz),
3.85 (s, 3H), 3.75-3.79 (dd, 1H, J ) 9.0, 11.5 Hz), 3.62-3.65
(m, 1H), 2.31 (br s, 1H). 13C NMR (CDCl3) δ: 159.6, 138.0, 130.4,
128.4, 128.3, 127.9, 127.8, 114.1, 81.7, 70.5, 67.4, 56.3. IR (neat):
3435, 2932, 1610, 1512, 1247, 1099, 1034, 832, 698 cm-1. HRMS
(ESI, m/z) calcd for C16H18O3Na (M + Na)+ 281.1154, found
281.1160.
Synthesis of 43. Prepared as per procedure A using 6 (37.4 mg,
0.0877 mmol), 38 (93 µL, 0.877 mmol), CH2Cl2 (386 µL), and 4
(100 µL, 0.877 mmol). The reaction was stirred for 90 h. Column
chromatography of the reaction mixture (CH2Cl2, Rf 0.5) yielded
1
43 (183 mg, 99%) as a pale gray-green solid, mp 81-83 °C. H
NMR (CDCl3) δ 7.35-7.7.42 (m, 4H), 7.28-7.32 (m, 1H), 7.10-
7.12 (d, 1H, J ) 7.0 Hz), 6.97-7.01 (app t, 1H, J ) 8.7 Hz), 6.66-
6.70 (app t, 1H, J ) 7.6 Hz), 6.41-6.42 (d, 1H, J ) 7.6 Hz), 4.57-
4.59 (dd, 1H, J ) 4.0, 7.0 Hz), 4.4 (br s, 1H), 3.99-4.03 (dd, 1H,
J ) 4.0, 11.0 Hz), 3.81-3.85 (dd, 1H, J ) 7.0, 11.0 Hz), 2.31 (s,
3H), 1.81 (br s, 1H). 13C NMR (CDCl3) δ: 144.7, 139.7, 129.7,
128.4, 127.2, 126.5, 126.2, 122.1, 117.0, 111.0, 67.1, 59.3, 17.2.
IR (Nujol): 3302, 2922, 1605, 1376, 1048, 747, 699 cm-1. HRMS
(ESI, m/z) calcd for C15H18NO (M + H)+ 228.1388, found
228.1384.
Acknowledgment. Generous financial assistance from the
Irish Research Council for Science Engineering and Technology
is gratefully acknowledged. The authors thank the IITAC (TCD,
Ireland) for the allocation of computer time.
Note Added after ASAP Publication. There were errors in
ref 3g,o in the version published ASAP January 4, 2008; the
revised version was published ASAP January 9, 2008.
Synthesis of 44. Prepared as per procedure A using 6 (74.8 mg,
1.75 mmol), 39 (246 µL, 1.75 mmol), CH2Cl2 (93 µL), and 4 (100
µL, 0.877 mmol). The reaction was stirred for 147 h. Column
chromatography of the reaction mixture (CH2Cl2, Rf 0.5) yielded
Supporting Information Available: Complete reference for
1
Gaussian 03, details of computational results (PDB files of final
44 (206 mg, 92%) as a pale yellow oil. H NMR (DMSO-d6) δ
1
optimized complexes), general experimental details, and H and
7.32-7.34 (d, 2H, J ) 7.0 Hz), 7.24-7.28 (app t, 2H, J ) 7.5
Hz), 7.17-7.21 (app t, 1H, J ) 7.0 Hz), 6.67 (s, 2H), 4.81-4.84
(app t, 1H, J ) 5.0 Hz), 4.08 (s, 2H), 3.69 (m, 2H), 2.08 (m, 9H).
13C NMR (DMSO-d6) δ: 143.2, 142.9, 129.1, 128.9, 128.5, 127.8,
127.3, 126.5, 65.0, 63.0, 20.1, 18.7. IR (neat): 3368, 2920, 1484,
13C NMR spectra of catalyst 6 and all adducts prepared in this study.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702154M
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