Synthesis of C2-symmetric bisamidines: A new type of chiral metal-free lewis acid analogue interacting with carbonyl groups

Article abstract of DOI:10.1021/jo070534j

(Chemical Equation Presented) The chiral bisamidine 5 has been prepared in just two steps from malonodinitrile. In the monocationic form this compound adopts a planar conformation with an almost convergent orientation of two N-H groups. Ketones, aldehydes

Full text of DOI:10.1021/jo070534j

Synthesis of C -Symmetric Bisamidines: A New Type of Chiral
2
Metal-Free Lewis Acid Analogue Interacting with Carbonyl Groups
Deniz Akalay, Gerd D u¨ rner, Jan W. Bats, Michael Bolte, and Michael W. G o¨ bel*
Johann Wolfgang Goethe UniVersity Frankfurt, Institute of Organic Chemistry and Chemical Biology,
Max-Von-Laue-Str. 7, D-60438 Frankfurt am Main, Germany
M.Goebel@chemie.uni-frankfurt.de
ReceiVed March 15, 2007
The chiral bisamidine 5 has been prepared in just two steps from malonodinitrile. In the monocationic
form this compound adopts a planar conformation with an almost convergent orientation of two N-H
groups. Ketones, aldehydes, and nitro compounds are assumed to bind to this strongly polar cleft via
hydrogen bonds, resulting in a Lewis-acid-like activation of the carbonyl groups. A broad scope of reactions
(
Diels-Alder, hetero-Diels-Alder, Friedel-Crafts) can be catalyzed. The observed accelerations surpass
the rate effects of neutral hydrogen-bond donors such as thioureas or TADDOLs.
Introduction
SCHEME 1. Ionic Hydrogen-Bond Donors in Catalysis:
Axially Chiral Amidine 1 and C -Symmetric Bisamidine 2
2
Lewis-acid catalysis is an important principle in organic
chemistry, applicable to many types of reactions. In particular,
chiral Lewis acids have had a tremendous impact on the
(TFPB: tetrakis[3,5-bis(trifluoromethyl)phenyl]borate)
1
development of enantioselective transformations. A completely
different approach to achieve electrophilic activation of sub-
strates is hydrogen-bond formation with dipolar functional
groups. While individual interactions are weak, a convergent
array of hydrogen-bond donors assembled on a chiral scaffold
may lead to powerful catalysts, in terms of both rates and
2
selectivities. This strategy is typically used by enzymes. The
oxoanion binding site of serine proteases is a well-known
3
example. However, even simple molecules such as water are
capable of inducing important rate effects via hydrogen bonds,
e.g., in water-catalyzed cycloadditions. In the past, we inves-
tigated the catalytic effects of cationic hydrogen-bond donors
synthesis. Significant enantioselectivities have been observed
4
using the axially chiral amidinium ion 1 as catalyst, Scheme
6
1.
on a Diels-Alder reaction of 3-alkyl-cyclopent-3-ene-1,2-
diones. This process constitutes the key step of a steroid total
A drawback of this compound is the limited preparative
accessibility. In contrast to 1, a convenient synthesis exists for
bisamidine 2. Comparable enantioselectivities and even im-
proved reaction rates in the steroid forming cycloaddition are
5
(
1) Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924-
942 (review).
2) (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
7
1
induced by this catalyst. However, bisamidine 2 was designed
(
1
520-1543 (review). (b) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43,
2
062-2064.
(5) Schuster, T.; Kurz, M.; G o¨ bel, M. W. J. Org. Chem. 2000, 65, 1697-
(3) Wharton, C. W. In ComprehensiVe Biological Catalysis I; Academic
1701.
press: London, 1998; pp 345-379.
(6) Schuster, T.; Bauch, M.; D u¨ rner, G.; G o¨ bel, M. W. Org. Lett. 2000,
2, 179-181.
(7) Tsogoeva, S. B.; D u¨ rner, G.; Bolte, M.; G o¨ bel, M. W. Eur. J. Org.
Chem. 2003, 1661-1664.
(4) (a) Blake, J. F.; Jorgensen, W. L. J. Am. Chem. Soc. 1991, 113, 7430-
7
8
432. (b) Blake, J. F.; Lim, D.; Jorgensen, W. L. J. Org. Chem. 1994, 59,
03-805. (c) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289-296.
10.1021/jo070534j CCC: $37.00 © 2007 American Chemical Society
5
618
J. Org. Chem. 2007, 72, 5618-5624
Published on Web 06/22/2007

2
Synthesis of C -Symmetric Bisamidines
SCHEME 2. Synthesis of Bisamidines 5 and 6a
a
(a) HCl(g), EtOH, dioxane, room temperature, 91%. (b) (1R,2R)-Diphenylethylenediamine, EtOH, 75 °C, 16 h, 92%. (c) (1R,2R)-Cyclohexyldiamine,
EtOH, 75 °C, 16 h, 62%. (d) 5b (X ) OTf) AgX, EtOH, 94%; 5c (X ) tetrakis(4-chlorophenyl)borate), KX, CH2Cl2, 82%; 5d (X ) TFPB) NaX, CH2Cl2,
8
9
5%; 5e (X ) TPPB) KX, CH2Cl2, 96%. (e) Picric acid, MeOH, 91%. (f) 1,2-Ethylenediamine, EtOH, ∆, 65%. (g) NaOEt, EtOH, 78%. (h) 6b (X ) OTf)
AgX, EtOH, quant.; 6c (X ) PF6) AgX, EtOH, 93%; 6d (X ) BF4) AgX, EtOH; 6e (X ) SbF6) AgX, EtOH, 92%. (i) 6f (X ) Cl) 1 N HCl, 97%; 6g (X
picrate) picric acid, MeOH, 89%.
)
to be structurally complementary to cyclic 1,2-diketones. Due
to the distance between the amidinium groups, bisamidine 2
cannot bind single carbonyl groups by two hydrogen bonds
simultaneously. To expand the scope of amidinium-catalyzed
reactions, we now focused on bisamidines derived from mal-
onodinitrile, Scheme 2.
The resulting compounds 5 and 6 may coordinate carbonyl
and nitro functions by a pair of properly oriented N-H groups.
They can be compared with the well-known structures of
9
10
11
12
thioureas, BINOLs, BIMBOLs, BAMOLs, and TAD-
FIGURE 1. Crystal structure of the hydrochloride 4a.
DOLs.13
Results and Discussion
1
. Synthesis and Structure. Bisamidines 5 and 6 are
accessible as hydrochlorides in excellent yield by heating of
imidate 3a with appropriate 1,2-diamines in ethanol. The latter
1
4
compound is prepared in a classical Pinner reaction from
(
(
(
8) Meyer, H.; Kurz, J. Liebigs Ann. Chem. 1978, 1491-1504.
9) Connon, S. J. Chem. Eur. J. 2006, 12, 5418-5427 (review).
10) (a) McDougal, N. T.; Trevellini, W. L.; Rodgen, S. A.; Kliman, L.
FIGURE 2. Crystal structure of the bisamidinium hydrochloride 6a.
malonodinitrile. However, (1R, 2R)-cyclohexanediamine does
not form the analogous bisamidine. We could isolate the chiral
amidine 4 instead, characterized by a 7-membered annulated
ring system, Figure 1.
T.; Schaus, S. E. AdV. Synth. Catal. 2004, 346, 1231-1240. (b) McDougal,
N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094-12095.
(
11) Dixon, D. J.; Tillman, A. L. Synlett 2005, 2635-2638.
(12) Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am.
Chem. Soc. 2005, 127, 1336-1337.
Bisamidine 6 is very soluble in water as chloride salt 6a.
This monocation tautomerizes into the enamine-imine form
and, due to conjugation, prefers an almost planar structure with
an C-C-C bond angle of 124.8° at the central methine carbon
(13) (a) McGilvra, J. D.; Unni, A. K.; Modi, K.; Rawal, V. H. Angew.
Chem., Int. Ed. 2006, 45, 6130-6133. (b) Gondi, V. B.; Gravel, M.; Rawal,
V. H. Org. Lett. 2005, 7, 5657-5660. (c) Tanaka, K.; Fujiwara, T. Org.
Lett. 2005, 7, 1501-1503. (d) Momiyama, N.; Yamamoto, H. J. Am. Chem.
Soc. 2005, 127, 1080-1081. (e) Du, H.; Zhao, D.; Ding, K. Chem. Eur. J.
(see Figure 2). The pH-dependent UV spectra in aqueous
2
004, 10, 5964-5970.
14) McElvain, S. E.; Schroeder, J. P. J. Am. Chem. Soc. 1949, 71, 40-
phosphate buffer show major changes around pH 8 and 11.
Above and below this pH range compound 6 (5 is insoluble in
(
6.
4
J. Org. Chem, Vol. 72, No. 15, 2007 5619

Akalay et al.
SCHEME 3. Preferred Tautomers of Bisamidine 6
Depending on the Protonation State
TABLE 1. Chemical Shifts and UV Absorption Maxima for the
a
Neutral, Mono-, and Dicationic Bisamidines 6, 6a, and 6f
6
6a
6f
δNH [ppm]
δC(1)-H [ppm]
δC(1) [ppm]
λmax [nm]
6.25
3.03
29.3
<220
7.80
4.08
56.5
284
10.75
4.10
24.0
224
FIGURE 3. Crystal structure of ent-5f.
SCHEME 4. Diels-Alder Reaction of Cyclopentadiene and
Methyl Vinyl Ketone
a
All NMR spectra were recorded in d6-DMSO; the UV spectra were
recorded in water.
water) absorbs at very low wavelengths only, indicating loss
of conjugation. Between pH 8 and 11, however, a strong
absorption at 284 nm demonstrates the presence of the en-
amine-imine tautomer, Scheme 3 and Table 1.
Thus, the pKa of the mono- and dicationic form in water must
1
13
be close to 11 and 8. H and C NMR spectra confirm that
only the monocation has a clear preference for enamine-imine
conjugation, Table 1. In this tautomer the almost convergent
orientation of two hydrogen-bond donors is adopted voluntarily,
rendering the monocation of 5 a promising electrophile to
catalyze reactions of ketones and aldehydes.
The bisamidinium salt ent-5d led to a 23-fold rate increase
In contrast, the dication does not show conjugation between
the two heterocycles and is free to rotate. The crystal structure
of ent-5f shows the presence of bifurcated hydrogen bonds
between the amidinium nitrogens and the picrate oxygens with
bond lengths ranging from 2.75 to 2.85 Å. The tetrahedral
configuration of the central methylene group can be deduced
from the change of the C-C-C bond angle to 109.2°, Figure
in CDCl3 (1 mol %; corresponding to a more than 2000-fold
-1
acceleration) with a turnover frequency of over 1000 h , Figure
. Enantioselectivities, however, remained constantly low
∼12% ee) between room temperature and -70 °C.
. Catalysis of a Friedel-Crafts Reaction. Appropriate salts
of bisamidine 5 also promote the Friedel-Crafts-type addition
4
(
3
1
6
of indole 8 to nitrostyrene 9. We have taken this reaction as
a reference to compare the influence of different weakly
coordinating counterions, Scheme 5.
3
.
Replacement of chloride in compounds 5a and 6a by weakly
coordinating counterions, e.g., tetrakis[3,5-bis(trifluoromethyl)-
phenyl]borate (TFPB) and tetrakis(pentafluorophenyl)borate
Without catalyst no product could be observed after 4 days.
In contrast, the TFPB salt 5d and the TPPB salt 5e both
transformed more than 90% of nitrostyrene 8 into products (55
h at room temperature, CDCl3); 86% of 10 and ent-10 could be
isolated. Much less product was formed in the presence of the
triflate salt 5b. Notably, the bispicrate 5f turned out to be an
even weaker catalyst in spite of its dicationic nature. Thus,
picrate and even triflate ions can efficiently compete for
substrate binding, Figure 5.
(TPPB), is achieved easily using the corresponding silver,
sodium, or potassium salts (Scheme 2).
2
. Catalysis of a Diels-Alder Reaction. As a first estimate
of the catalytic potential of compound 5d (monocation, coun-
terion TFPB ) we determined the cycloaddition kinetics of
-
1
cyclopentadiene and methyl vinyl ketone by H NMR in CDCl3
as described by Schreiner.15 This reaction is known to be
susceptible to hydrogen-bond catalysis. In the presence of 1 mol
%
of bis-(3,5-trifluoromethylphenyl)thiourea 7, a rate increase
15
(16) (a) Dessolea, G.; Herrera, R. P.; Ricci, A. Synlett 2004, 2374-
378. (b) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem.,
around 5-fold was reported. Scheme 4.
2
Int. Ed. 2005, 44, 6576-6579. (c) Fleming, E. M.; McCabe, T.; Connon,
S. J. Tetrahedron Lett. 2006, 47, 7037-7042.
(15) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407-414.
5620 J. Org. Chem., Vol. 72, No. 15, 2007

2
Synthesis of C -Symmetric Bisamidines
SCHEME 6. Cycloaddition of Diene 11 and Aromatic
Aldehydes
TABLE 2. Cycloaddition of Diene 11 and 3-Chlorobenzaldehyde
12: Comparison of Different Catalysts (toluene, 3 days, room
temperature, 25 mol % catalyst; then treatment with acetyl chloride
at -78 °C)
entry
catalyst
no catalyst
3,3-diphenyl-(R)-BINOL
3,3-di-1-naphtyl-(R)-BINOL
phenyl TADDOL
yield [%]a
ee [%]b
1
2
3
4
5
6
7
8
9
0
0
0
5
5
35
9
1-naphtyl TADDOL
2-naphtyl TADDOL
bisamidinium salt 5b
bisamidinium salt 5f
5d or 5e
7
4
FIGURE 4. Diels-Alder reaction of cyclopentadiene (0.7 M) and
methyl vinyl ketone (0.07 M) in CDCl . Kinetics in the presence of 1
0
3
0
mol % of ent-5d (9) and without catalyst (2) at 27 °C. Solid lines
show the optimal data fit to a pseudo-first-order rate equation.
14
0
15
1
0
bisamidinium salt 2
a
Isolated yield after column chromatography. b The enantiomeric excess
SCHEME 5. Friedel-Crafts Addition of N-Methylindole 8
to â-Nitrostyrene 9
was determined by HPLC on a chiral column.
1
2 when catalysts were absent (Table 2, entry 1). Phenyl-,
1
-naphtyl-, and 2-naphtyl-TADDOLs, well-known catalysts of
1
7
closely related cycloadditions, yielded about 5% of the
pyranone (entries 4-6). Low enantioselectivities were obtained
with the phenyl- and 2-naphtyl-TADDOL (entry 4 and 6). Just
the 1-naphtyl derivative induced moderate ee’s (entry 5).
Bisamidinium salts 5b or 5e yielded 14% of the pyranone 13
with 15% ee (entry 9). In contrast, the corresponding triflate
(5b) and picrate salts (5f) were unable to catalyze the reaction.
No product was formed using BINOLs or the bisamidinium salt
2. The latter finding is remarkable because 2 represents a
dicationic amidinium catalyst with the weakly coordinating
TFPB counterion. The compound, highly potent with regard to
4
. Catalysis of Hetero-Diels-Alder Reactions. Hetero-
Diels-Alder reactions of aldehydes and electron-rich dienes can
be catalyzed by compound 5d and 5e as well. To get a crude
estimate of reaction rates, different aromatic aldehydes were
mixed with the TBS analogue of Danishefsky’s diene 11 in
toluene, Scheme 6.
After 1-3 days at room temperature the primary cycloadducts
were transformed into 2-aryl-2,3-dihydropyran-4-ones. No
conversion at all was found in the case of 3-chlorobenzaldehyde
7
1,2-diketones, completely fails to activate simple aldehydes.
For less reactive systems such as the cycloaddition of 11 and
1
2 an electrophile stronger than compound 5d is clearly
desirable. However, when the dication of 5 is considered as
catalyst, the increased conformational freedom (loss of conjuga-
tion) may counterbalance the intrinsically tighter substrate
binding of the diprotonated form. Conformational restraints can
be introduced most easily by rings.
In the deprotonated form bisamidine 5 reacts with 3-oxo-
pentanedioic acid ester in a Knoevenagel condensation followed
by a 2-fold ring closure. The rigid chiral bislactam 14 is formed
in excellent yield, Scheme 7. This compound is unable to
promote the Friedel-Crafts addition of N-methylindole 8 and
â-nitrostyrene 9 as long as it stays unprotonated (Table 3, entry
2
). However, bislactam 14 can be converted most easily into
the mono-TPPB salt 14a by titration with a solution of
+
-
[
H(OEt2)2] [B(C6F5)4] (15) in CDCl3. Compound 14a acceler-
ates the Friedel-Crafts addition quite efficiently. Just 5 mol %
of 14a produces a roughly 5-fold faster rate than 10 mol % of
the TPPB salt ent-5e (Figure 6, Table 3). The stereoselectivity
of 14a, albeit weak, allows concluding that catalysis is mediated
by the chiral salt and not by freely diffusible protons. In contrast,
FIGURE 5. Counterion largely modulates the catalytic power of
bisamidinium salts: reaction kinetics of N-methylindole 8 (0.72 M)
and â-nitrostyrene 9 (0.36 M) in CDCl
of catalyst at room temperature: (9) TPPB salt 5e, (b) TFPB salt 5d,
1) triflate salt 5b, and (2) picrate salt 5f. Solid lines show the optimal
data fit to a second-order rate equation.
3
in the presence of 10 mol %
(
17) (a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature
(
2003, 424, 146-146 (b) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5846-5850.
J. Org. Chem, Vol. 72, No. 15, 2007 5621

Akalay et al.
SCHEME 7. Synthesis of the Rigid Tetracyclic Bisamidine
have a beneficial effect on stereoselectivities. Monocationic salts
of 5 and weakly coordinating counterions accelerate different
reactions of simple ketones, nitroalkenes, and aldehydes,
presumably by electrophilic activation in hydrogen-bond-
mediated host-guest complexes. Doubly protonated salts of the
bisamidine should exhibit much larger rate effects. On the other
hand, they are less preorganized to bind carbonyl groups.
Conformationally restricted and highly preorganized analogues
of bisamidine 5 can be obtained by ring closure as in the case
of compound 14. The monoprotonated TPPB salt 14a already
shows significantly better results in the Friedel-Crafts reaction
than catalyst 5e. Starting from the bisamidines 5 and 14
presented here, current work tries to develop practically useful
transformations applying the neutral base or the mono- or
diprotonated form of the chiral hydrogen-bond donors.
a
1
4
Experimental Section
a
(
a) satd Na2CO3(aq), CH2Cl2, 100%. (b) Acetonedicarboxylic acid
Malonodiimidic Acid Diethyl Ester Dihydrochloride (3a). A
solution of malonodinitrile (9.9 g, 0.15 mol) in 400 mL of 1,4-
dioxane was added over a period of 12 h to a mixture of 400 mL
of dioxane and 19.2 mL of anhydrous ethanol (0.33 mol, 2.2 equiv)
at 0 °C while HCl gas was continuously passed through the reaction
vessel. The HCl stream was continued for 1 h after addition was
completed. The resulting precipitate was filtered off, washed with
+
-
dimethyl ester, toluene, reflux, 14 h, 90%. (c) [H(OEt2)2] [B(C6F5)4] (15),
CDCl3, -30 °C f room temperature, 100%.
TABLE 3. Friedel-Crafts Addition of N-Methylindole 8 to
â-Nitrostyrene 9: Comparison of Different Catalysts (deuterated
chloroform, room temperature)
entry
catalyst
reaction time [h]
yield [%]a
ee [%]b
dioxane and diethyl ether, and dried in vacuo to give 3a as colorless
1
2
3
4
ent-5e (10 mol %)
14 (5 mol %)
55
96
1
86
0
95
98
-2c
14 1
crystals (31.38 g, 91%); mp 128-129 °C (lit. 119-120 °C).
H
NMR (250 MHz, DMSO) δ 1.32 (t, J ) 7.0 Hz, 6H), 4.23 (q, J )
15 (5 mol %)
0
12
6.8 Hz, 4H), 4.43 (s, 2H), 8.40 (br s, 4H). IR (KBr) 2910(s), 2757-
14a (5 mol %)
12
(s), 2657(s), 1735(w), 1668(s), 1579(s), 1465(m), 1442(m), 1390-
a
Isolated yield after column chromatography. b The enantiomeric excess
(s), 1357(s), 1299(w), 1207(w), 1138(m), 1097(m), 1006(m),
c
was determined by HPLC on a chiral column. A negative ee stands for
an excess of the opposite enantiomer.
-
1
9
51(m), 906(m), 850(w), 825(m), 810(m), 727(w), 637(m) cm
: C, 36.38; H, 6.98; N, 12.12.
Found: C, 36.27; H, 7.15; N, 11.87.
R,R)-4-Imino-4,5,5a,6,7,8,9,9a-octahydro-1H-benzo[b][1,4]-
.
7 2 2 2
Anal. Calcd for C H16Cl N O
(
diazepin-2-ylamine Hydrochloride (4a). (1R,2R)-Cyclohexyl-
diamine (1.0 g, 8.8 mmol) was dissolved in 15 mL of anhydrous
ethanol. After addition of 0.55 equiv of 3a (1.1 g, 4.8 mmol) the
solution was heated to reflux for 16 h. The crude reaction mixture
was concentrated in vacuo, adsorbed on silica gel, and purified
through column chromatography (ethyl acetate/methanol 3:1), which
afforded 4a as a colorless crystalline solid (647 mg, 62%); mp 298-
1
2
1
4
5
99 °C (decomp). H NMR (400 MHz, DMSO) δ 1.22 (m, 4H),
.65 (m, 2H), 2.00 (m, 2H), 2.97 (m, 2H), 3.93 (s, 1H), 6.44 (s,
H), 7.42 (s, 2H). 13C NMR (63 MHz, DMSO) δ 22.89, 30.94,
6.48, 64.60, 159.58. IR (KBr) 3306(s), 3186(s), 2939(m), 2862-
(w), 1636(s), 1618(s), 1593(s), 1524(s), 1448(m), 1386(m), 1364-
(
9
w), 1352(w), 1298(m), 1264(m), 1220(w), 1155(m), 1032(w),
-
1
69(w), 938(w), 897(w), 875(w), 853(w), 756(m), 670(m) cm .
D
Optical rotation: [R] 20 ) +240.0 ° (c ) 1.0 methanol). Anal.
Calcd for C : C, 49.88; H, 7.91; N, 25.85. Found: C, 49.61;
9 4
H17ClN
H, 7.67; N, 25.93. For X-ray-analysis 4a was recrystallized from
ethanol/ethyl acetate.
FIGURE 6. Reaction kinetics of N-methylindole 8 (0.72 M) and
(1R,2R)- and (1S,2S)-1,2-Diphenyl-1,2-ethylenediamine. The
â-nitrostyrene 9 (0.36 M) in CDCl
3
in the presence of (9) 10 mol %
TPPB salt 5e, (b) 5 mol % TPPB salt of tetracyclic bisamidine 14a at
synthesis was carried out according to the reported procedure using
18
L- and D-tartaric acid. The enantiomeric excesses were determined
+ -
2 2 6 5 4
room temperature, and (2) 5 mol % [H(OEt ) ] [B(C F ) ] (15). Solid
using chiral HPLC. For this determination a small amount of
diamine (53 mg, 0.25 mmol) was dissolved in a mixture of 2 mL
of dioxane/water (1:1). After addition of 2.0 equiv of acetic
anhydride (47 µL, 0.5 mmol) the reaction mixture was stirred for
lines show the optimal data fit to a second-order rate equation at room
temperature.
the strong Brønsted acid 15, the most efficient catalyst in terms
of rates, yields an entirely racemic product.
9
0 min at RT. The resulting colorless solid was filtered off, washed
with water, and dried in vacuo to give (1R,2R)- or (1S,2S)-N,N′-
1,2-diphenylethane-1,2-diyl)diacetamide as a colorless solid (54
(
1
Conclsion
mg, 73%). H NMR (250 MHz, DMSO) δ 1.81 (s, 6H), 5.16 (d, J
)
3.8 Hz, 2H), 7.13-7.26 (m, 10H), 8.29 (d, J ) 3.0 Hz, 2H).
The chiral bisamidine 5 can be prepared in ample quantities.
Using other chiral 1,2-diamines, analogous compounds should
be accessible as well. As in the case of TADDOL’s, replacement
of phenyl by sterically more demanding groups is expected to
HPLC: CHIRALCEL OJ, 250 × 4.6 mm (l i.d.), flow rate 0.7
mL/min, n-hexane/isopropyl alcohol 10 + 1. R enantiomer: t
major
) 8.7 min; t
minor
) 6.9 min (>98% ee). S enantiomer: t
major
) 6.8
min; tminor ) 9.5 min (>99% ee).
5622 J. Org. Chem., Vol. 72, No. 15, 2007

2
Synthesis of C -Symmetric Bisamidines
(
R,R,R,R)- and (S,S,S,S)-2,2′-Methylenedi-(4,5-diphenyl-4,5-
dihydro-1H-imidazole) Monohydrochloride (5a and ent-5a).
1R,2R)- or (1S,2S)-1,2-Diphenyl-1,2-ethylenediamine (1.0 g, 4.7
4
BF20N : C, 58.12; H, 2.57; N, 4.93. Found (5e): C, 57.96; H, 2.77;
1
N, 4.82. Found (ent-5e): C, 57.97; H, 2.83; N, 4.77. H NMR
spectra, 19F NMR spectra, IR spectra, and melting point of 5e are
identical to ent-5e.
(
mmol) was dissolved in 10 mL of anhydrous ethanol. After addition
of 0.55 equiv of 3a (600 mg, 2.6 mmol) the solution was heated at
(S,S,S,S)- 2,2′-Methylenedi-(4,5-diphenyl-4,5-dihydro-1H-imi-
dazole) Bispicrate (ent-5f). To a solution of 10 equiv of picric
acid (1.48 g, 3.9 mmol, 60% in water) in 10 mL of refluxing
methanol a warm methanolic solution of ent-5a (191 mg, 0.39
mmol) was added. The reaction mixture was stored overnight at 4
°C. The resulting yellow crystals were collected, recrystallized from
methanol, and dried in vacuo to give ent-5f as yellow crystals (322
mg, 91%). The synthesis of 5f could be reproduced with the same
75 °C for 16 h. The crude reaction mixture was concentrated in
vacuo, adsorbed on silica gel, and purified by column chromatog-
raphy (ethyl acetate/methanol 9:1), which afforded 5a or ent-5a as
a colorless crystalline solid (1.06 g, 92%); mp 173-175 °C
1
(
4
decomp). H NMR (250 MHz, DMSO) δ 4.47 (s, 1H), 4.81 (s,
13
H), 7.32-7.45 (m, 20H), 8.50 (br s, 4H); C NMR (101 MHz,
DMSO) δ 56.79, 68.04 (br), 127.51, 128.82, 129.26, 140.36, 161.72.
1
IR (KBr) 3163(s), 3030(m), 1594(s), 1578(s), 1492(m), 1453(m),
yield; mp 230-232 °C (decomp), H NMR (250 MHz, CDCl ) δ
3
1
8
5
5
358(w), 1279(m), 1194(m), 1101(m), 1075(w), 1028(w), 914(w),
4.81 (s, 2H), 5.39 (s, 4H), 7.26-7.45 (m, 20H), 8.80 (s, 4H), 11.29
-1
13
59(w), 803(w), 753(m), 697(s), 640(w) cm . Optical rotation for
(s, 4H). C NMR (63 MHz, CDCl ) δ 24.58, 70.42, 125.87, 127.00,
3
D
a: [R] 20 ) -74.8° (c ) 1.0 methanol). Optical rotation for ent-
129.45, 129.74, 137.61, 140.98, 161.73, 161.89. IR (KBr) 3082-
(m), 2951(m), 1605(s), 1568(s), 1537(s), 1495(s), 1455(w), 1426-
(m), 1362(s), 1335(s), 1318(s), 1275(s), 1162(m), 1082(m), 1053-
D
a: [R] 20 ) +73.8° (c ) 1.0 methanol). Anal. Calcd for C31
29
H -
4
ClN : C, 75.52; H, 5.93; N, 11.36. Found (5a): C, 75.50; H, 5.91;
1
-1
N, 11.43; Found (ent-5a): C, 75.28; H, 5.89; N, 11.56. H NMR
spectra, 13C NMR spectra, IR spectra, and the melting point of 5a
are identical to ent-5a. For compounds 5b and 5c see Supporting
Information.
(w), 1022(w), 926(w), 911(m), 841(w), 800(w) cm . Optical
D
rotation for 5f: [R] ) +389.8 ° (c ) 1.0 CHCl ). Optical rotation
2
0
3
for ent-5f: [R]D ) -403.2 ° (c ) 1.0 CHCl ) Anal. Calcd for
C H N O : C, 56.46; H, 3.75; N, 15.31. Found (5f): C, 56.69;
H, 3.77; N, 15.10. Found (ent-5f): C, 56.44; H, 3.56; N, 15.17. H
NMR spectra, 13C NMR spectra, IR spectra, and melting point of
5f are identical to ent-5f.
20
3
43
34 10 14
1
(S,S,S,S)- 2,2′-Methylenedi-(4,5-diphenyl-4,5-dihydro-1H-imi-
dazole) Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (ent-5d).
One equivalent of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]-
borate19 (1.80 g, 2.0 mmol) was added to a solution of ent-5a (1.0
g, 2.0 mmol) in 100 mL of methanol. The solvent was completely
removed, and the residue was redissolved in 150 mL of dichlo-
romethane. The solution was washed with water three times, dried
(R,R,R,R)-2,2′-Methylenedi-(4,5-diphenyl-4,5-dihydro-1H-imi-
dazole) (5). A 1.0 g amount of 5a (2.0 mmol) was suspended in
100 mL of dichloromethane. After addition of 100 mL of saturated
Na CO solution the mixture was transferred in a separating funnel
2
3
4
over MgSO , and concentrated in vacuo to give ent-5d as a slightly
and mixed as long as the solid dissolved. The separated aqueous
phase was extracted with 50 mL of dichloromethane. The combined
yellowish solid (2.56 g, 95%). The synthesis of 5d could be
1
reproduced with the same yield; mp 76-77 °C. H NMR (250 MHz,
organic phase was dried over MgSO and concentrated in vacuo to
4
DMSO) δ 4.45 (s, 1H), 4.83 (s, 4H), 7.33-7.44 (m, 20H), 7.62
give 5 as a colorless crystalline product (930 mg, quant.); mp 179-
1
(br s, 8H), 7.70 (br s, 4H), 8.39 (br s, 4H). IR (KBr) 3459(m),
180 °C (decomp). H NMR (300 MHz, CDCl ) δ 3.71 (s, 2H),
3
3
1
411(m), 3038(w), 1597(s), 1583(s), 1498(m), 1458(m), 1356(s),
278(s), 1125(s), 887(m), 839(m), 788(w), 745(m), 713(m), 699-
4.74 (s, 4H), 6.02 (br s, 2H), 7.24-7.39 (m, 20H). IR (KBr) 3060-
(s), 3027(s), 2922(s), 1603(s), 1493(s), 1452(s), 1351(m), 1301-
(w), 1277(m), 1194(m), 1078(w), 1053(w), 1027(m), 940(w),
908(w), 841(w), 756(s), 697(s), 623(w) cm . [R]D ) +172.5°
-
1
(m), 682(m), 668(m), 638(w), 597(w) cm . Optical rotation for
D
-1
5
5
BF24
d: [R] 20 ) -28.3° (c ) 1.0 methanol). Optical rotation for ent-
20
D
d: [R] 20 ) +27.4 ° (c ) 1.0 methanol). Anal. Calcd for C63
H
41
-
(c ) 1.0 CHCl ). Anal. Calcd for C H N : C, 81.55; H, 6.18; N,
3
31 28
4
N
4
: C, 57.29; H, 3.13; N, 4.24. Found (5d): C, 57.31; H,
12.27. Found: C, 81.29; H, 6.24; N, 12.49.
1
3.32; N, 4.30. Found (ent-5d): C, 57.41; H, 3.36; N, 4.27. H NMR
General Procedure for 2,2′-Methylendiimidazolinium Salts.
To a solution of hydrochloride 6a (Supporting Information) in
anhydrous ethanol was added 1.0 equiv of the corresponding silver
salt. The white precipitate was separated through centrifugation.
The clear solution was concentrated and dried in vacuo to give
6b-e as colorless crystals.
13
spectra, C NMR spectra, IR spectra, and melting point of 5d are
identical to ent-5d.
(S,S,S,S)- 2,2′-Methylenedi-(4,5-diphenyl-4,5-dihydro-1H-imi-
dazole) Tetrakis(pentafluorophenyl)borate (ent-5e). One equiva-
lent of potassium tetrakis(pentafluorophenyl)borate20 (189 mg, 0.26
mmol) was added to a solution of ent-5a (130 mg, 0.26 mmol) in
-
1
6
b (anion, OTf): yield 100%; mp 103-105 °C. H NMR (250
2
0 mL of methanol. The solvent was completely removed, and the
residue was redissolved in 30 mL of dichloromethane. The solution
was washed with water four times, dried over MgSO , and
concentrated in vacuo to give ent-5e as a slightly yellowish solid
287 mg, 96%). The synthesis of 5e could be reproduced with the
13
MHz, DMSO) δ 3.53 (s, 8H), 4.08 (s, 1H), 7.54 (br s, 4H,).
C
1
NMR (63 MHz, DMSO) δ 42.91, 56.41, 120.64 (q, JC,F ) 322.1
4
Hz), 162.07. IR (KBr) 3319(s), 2995(w), 2898(w), 1625(s), 1584-
(s), 1529(m), 1474(w), 1449(w), 1420(w), 1365(m), 1262(s), 1229-
(
(
s), 1162(s), 1108(w), 1096(m), 1072(w), 1036(s), 1029(s), 938(m),
1
same yield: mp 114-116 °C. H NMR (400 MHz, DMSO) δ 4.44
s, 1H), 4.82 (s, 4H), 7.32-7.46 (m, 20H), 8.39 (br s, 4H). 19
NMR (282 MHz, DMSO) δ -132.44 (d, J ) 10.7 Hz), -161.28
t, J ) 21.6 Hz), -165.90 (ψt, J ) 18.9 Hz). IR (KBr) 3448(m),
-1
7
61(m), 737(m), 688(m), 646(m), 573(m) cm . Anal. Calcd for
S: C, 31.79; H, 4.33; N, 18.54. Found: C, 31.52; H,
.34; N, 18.26. For compounds 6a, 6c, 6d, and 6e see Supporting
Information.
(
F
8 13 3 4 3
C H F N O
4
(
3
1
9
6
067(w), 3035(w), 1644(m), 1596(s), 1582(s), 1514(s), 1463(s),
364(w), 1330(w), 1300(w), 1278(m), 1198(w), 1089(s), 1029(w),
79(s), 917(w), 859(w), 774(w), 759(m), 699(m), 683(w), 661(m),
2,2′-Methylenedi-(4,5-dihydro-1H-imidazole) Dihydrochloride
(6f). Monohydrochloride 6a (185 mg, 0.98 mmol) was dissolved
in 15 mL of 1 N aqueous HCl. After a short mixing period the
solution was concentrated in vacuo to afford the bishydrochloride
-
1
39(w), 610(w), 599(w), 574(w) cm . Optical rotation for 5e:
D
[R] 20 ) -32.3 ° (c ) 1.0 methanol). Optical rotation for ent-5e:
6
f as colorless solid (214 mg, 97%); mp 277-279 °C (decomp).
H NMR (250 MHz, DMSO) δ 3.86 (s, 8H), 4.10 (s, 2H), 10.75
s, 4H). 13C NMR (63 MHz, DMSO) δ 24.03, 44.54, 162.61; IR
D
[R] 20 ) +34.1 ° (c ) 1.0 methanol). Anal. Calcd for C55
H
29
-
1
(
(
18) Pikul, S.; Corey, E. J. Organic Syntheses; Wiley & Sons: New York,
998; Collect. Vol. 9, p 387. Ann. Vol. 71, p 22.
19) NaTFPB was synthesized according to the reported procedure:
(KBr) 3053(s), 2942(s), 2753(w), 1607(s), 1390(w), 1295(m), 1206-
1
(
(
(
w), 1055(w), 1036(w), 1002(w), 926(w), 746(w), 705(w), 671-
(
-1
w), 562(w) cm . UV (aqueous phosphate buffer) λmax ) 224 nm
Zuccaccia, C.; Bellachioma, G.; Cardaci, G.; Macchioni, A. J. Am. Chem.
Soc. 2001, 123, 11020-11028.
7 14
dominating protonation state at pH < 8). Anal. Calcd for C H -
Cl
2 4
N : C, 37.25; H, 6.27; N, 24.89. Found: C, 37.09; H, 6.39; N,
(20) Potassium tetrakis(pentafluorophenyl)borate was purchased and used
without further purification.
24.85.
J. Org. Chem, Vol. 72, No. 15, 2007 5623

Akalay et al.
2
,2′-Methylenedi-(4,5-dihydro-1H-imidazole) Dipicrate (6g).
ketone, δ
H
(COCH
3
) ) 2.29 ppm. All reactions were repeated four
To a solution of picric acid (3.82 g, 10 mmol, 60% in water) in 10
mL of refluxing methanol was added a warm methanolic solution
of monohydrochloride 6a (755 mg, 4.00 mmol). The reaction
mixture was cooled to room temperature. The resulting yellow
precipitate was collected and dried in vacuo to give bispicrate 6g
times, and the results were averaged.
Kinetics of the Friedel-Crafts Addition between 1-Meth-
ylindole and â-Nitrostyrene: General Procedure. All H NMR
spectra were recorded at 250 MHz. The reactions were carried out
in a 5 mm standard NMR tube containing 0.5 mmol of 1-meth-
ylindole (2.0 equiv, 64.3 µL), 0.25 mmol of â-nitrostyrene (1.0
equiv, 37.3 mg), and 5 or 10 mol % of catalyst in 0.7 mL of CDCl
3
at room temperature. The percentage of conversion was determined
by integrating selected resonances for the product and unreacted
â-nitrostyrene: product, δ
â-nitrostyrene, δ (d, 1H, Ph-CHdCHNO
1
1
as yellow crystals (2.16 g, 89%); mp 272-273 °C (decomp). H
NMR (DMSO) δ 3.87 (s, 8H), 3.96 (s, 2H), 8.59 (s, 2H), 10.21(s,
4
1
1
1
9
H). 13C NMR (63 MHz, DMSO) δ 24.48, 44.59, 124.30, 125.17,
41.72, 160.75, 162.71. IR (KBr) 3315(m), 3083(m), 2950(m),
607(s), 1569(s), 1543(s), 1508(m), 1431(m), 1364(s), 1336(s),
314(s), 1276(s), 1162(m), 1078(m), 1052(w), 1034(w), 1015(w),
42(w), 934(w), 911(m), 819(w), 790(m), 745(m), 705(m), 584-
H
(s, 1H, -NCH
3
-CH-) ) 6.79 ppm;
2
H
) ) 7.75-7.85 ppm.
All reactions were repeated twice, and the results were averaged.
The crude reaction mixture was purified by flash column chroma-
tography (n-hexane/ethyl acetate 19:1) to afford 10 and ent-10 as
a colorless oil. HPLC: CHIRALPAK IA, 250 × 4.6 mm (l × i.d.),
-
1
(
2
w) cm . Anal. Calcd for C19
H
18
N
10
O
14: C, 37.39; H, 2.97; N,
2.95. Found: C, 37.42; H, 3.17; N, 22.91.
R,R,R,R)-Tetracyclic Bisamidine (14). A 406 mg amount of
(0.89 mmol) was suspended in 75 mL of toluene. After addition
(
5
flow rate 0.7 mL/min, n-hexane/isopropyl alcohol 10 + 1, t
1
: 12.1
) δ 3.76 (s, 3H),
) 12.5 Hz, 1H), 5.08 (dd, J )7.5 Hz, J
) 12.6 Hz, 1H), 5.22 (t, J ) 8.1 Hz, 1H), 6.89 (s, 1H), 7.08-7.14
1
of 1.1 equiv of acetonedicarboxylic acid dimethyl ester (144 µL,
.98 mmol) the reaction mixture was refluxed for 14 h under
azeotropic removal of water. The dark brown solution was
concentrated in vacuo, and the residue was purified by column
chromatography (n-hexane/ethyl acetate 1:1) to give 14 as slightly
min, t
4.96 (dd, J
2
: 13.1 min. H NMR (300 MHz, CDCl
) 8.6 Hz, J
3
0
1
2
1
2
13
(m, 1H), 7.24-7.40 (m, 7H), 7.48-7.51 (m, 1H). C NMR (63
MHz, CDCl ) δ 32.75, 47.48, 79.50, 109.46, 112.75, 118.92,
3
yellow crystals (434 mg, 90%). For a correct elemental analysis,
119.40, 122.16, 126.31, 126.49, 127.44, 127.68, 128.84, 137.24,
139.34. IR (film) 3059 (m), 3029 (m), 2915 (m), 1732 (m), 1615
(m), 1552 (s), 1475 (m), 1454 (m), 11428 (m), 1377 (s), 1333 (m),
1248 (m), 1199 (w), 1157 (m), 1133 (m), 1085 (m), 1045 (w), 1014
1
1
4 had to be recrystallized from methanol; mp 171-172 °C. H
NMR (250 MHz, CDCl
3
) δ 3.76 (s, 2H), 5.04 (d, J ) 4.5 Hz, 1H),
.12 (d, J ) 5.5 Hz, 1H), 5.15 (d, J ) 5.8 Hz, 1H), 5.53 (d, J )
.3 Hz, 1H), 5.71 (t, J ) 1.3 Hz, 1H), 7.23-7.47 (m, 20H), 8.43
) δ 36.42, 67.58, 68.36, 68.97,
5
4
(
-
1
(m), 972 (w), 911 (w), 844 (w), 811 (w), 742 (s), 700 (s) cm
Anal. Calcd for C17 : C, 72.84; H, 5.75; N, 9.99. Found:
C, 72.67; H, 5.98; N, 9.87.
.
br s, 1H). 13C NMR (75 MHz, CDCl
16 2 2
H N O
3
7
1
1
8.74, 81.16, 104.38, 125.72, 125.87, 126.03, 126.39, 127.88,
27.99, 128.64, 128.84, 129.01, 129.05, 129.19, 129.38, 138.71,
39.92, 140.53, 142.41, 147.61, 153.24, 153.72, 159.70, 164.20.
General Procedure for the Hetero-Diels-Alder Reaction of
11 with 3-Chlorobenzaldehyde 12. Catalyst (25 mol %) and 2
equiv of 3-chlorobenzaldehyde 12 (2.0 mmol, 228 µL) were
dissolved in 10 mL of abs. toluene. After addition of 1 equiv of 11
(1.0 mmol, 214 mg) the reaction mixture was stirred for 3 d at
room temperature. The reaction was then cooled to -78 °C prior
to dilution with 10 mL abs. dichloromethane and subsequent
addition of 2 equiv of acetyl chloride (20 mmol, 142 µL). This
was allowed to stir for 30 min at -78 °C and 30 min at room
temperature. The crude reaction mixture was purified by flash
chromatography (ethyl acetate/n-hexane 1:3) to afford 2,3-dihydro-
2-(3-chlorophenyl)-4H-pyran-4-one 13 + ent-13. HPLC: CHIRAL-
CEL OD-H, 250 × 4.6 mm (l × i.d.), flow rate 0.6 mL/min,
IR (KBr) 3327(m), 3056(m), 3028(m), 1698(s), 1673(s), 1617(s),
1
1
9
°
556(s), 1493(m), 1455(m), 1423(m), 1356(s), 1324(m), 1284(w),
261(w), 1216(w), 1170(m), 1120(w), 1082(w), 1028(m), 1002 (w),
27 (w), 888 (w), 826 (w), 757 (s), 696 (s) cm-1. [R] 20 ) +51.8
D
3 28 4 2
(c ) 1.0 CHCl ). Anal. Calcd for C36H N O : C, 78.81; H, 5.14;
N, 10.21. Found: C, 78.56; H, 5.19; N, 10.33.
+
]- (15). Under a nitrogen atmosphere using
[H(OEt )
2 2
] [B(C
F )
6 5 4
standard Schlenk techniques a solution of potassium tetrakis-
pentafluorophenyl)borate (359 mg, 0.5 mmol) in diethyl ether (3
(
mL) was cooled to 0 °C. A 6.0 equiv amount of HCl (2 N in diethyl
ether, 3.0 mmol, 1.5 mL) was transferred via syringe. After 1 h
the white precipitate was filtered off and washed with diethyl ether.
n-hexane/isopropyl alcohol 10 + 3, tmajor: 16.0 min, tminor: 20.4
1
The clear solution was concentrated and dried in vacuo to give 15
min. H NMR (250 MHz, CDCl
3
) δ 2.66 (ddd, J
) 14.0 Hz, J
) 14.0 Hz, 1H), 5.54 (dd, J
) 6.3 Hz, 1H), 7.22-7.30 (m, 1H), 7.31-7.40 (m, 2H),
7.42 (æt, J ) 0.8 Hz, 1H), 7.48 (dd, J ) 0.6 Hz, J ) 6.1 Hz,
1H). 13C NMR (63 MHz, CDCl
) δ 43.30, 80.13, 107.54, 124.05,
1
) 1.1 Hz, J
) 16.8 Hz,
) 1.3
2
)
1
as colorless crystals (403 mg, 97%). H NMR (300 MHz, CD
2
Cl
2
)
3.7 Hz, J
1H), 5.40 (dd, J
Hz, J
3
) 16.9 Hz, 1H), 2.86 (dd, J
1
2
δ 1.33 (t, J ) 7.1 Hz, 12H), 3.87 (q, J ) 7.1 Hz, 8H), 13.53 (br s,
1
) 3.8 Hz, J
2
1
19
1
H). 11B NMR (96 MHz, CD
CD Cl ) -131.17 (t, J ) 5.1 Hz), -163.76 (t, J ) 20.3 Hz),
167.67 ppm (t, J ) 10.3 Hz). Anal. Calcd for C32 : C,
6.40; H, 2.56. Found: C, 46.28; H, 2.75.
R,R,R,R)-Tetracyclic Bisamidine Tetrakis(pentafluorophen-
2
Cl
2
) δ -16.69. F NMR (282 MHz,
2
2
2
1
2
-
4
H F
21 20
O
2
3
126.22, 128.97, 130.12, 134.77, 139.83, 162.80, 191.41. IR (film)
3336(w), 3068(m), 2969(w), 2901(m), 2628(w), 1676(s), 1593(s),
1575(s), 1480(m), 1433(m), 1403(s), 1359(m), 1269(s), 1227(s),
1210(s), 1172(m), 1099(w), 1081(m), 1058(w), 1039(s), 993(m),
(
yl)borate (14a). Under a nitrogen atmosphere using standard
Schlenk techniques a solution of 14 (95.5 mg, 0.174 mmol) in
deuterated chloroforme (2 mL) was cooled to - 30 °C. A 0.95
equiv amount of 15 (136.9 mg, 0.165 mmol) in deuterated
chloroform (2.87 mL) was transferred via syringe. The resulting
yellow solution was warmed to room temperature and used as a
-1
953(w), 938(m), 883(s), 837(m), 786(s), 752(w), 695(s) cm . Anal.
Calcd for C11 ClO : C, 63.32; H, 4.35. Found: C, 63.08; H, 4.48.
H
9
2
Acknowledgment. Financial support by the DFG (SPP 1579
Organocatalysis”) and Fazit-Stiftung is gratefully acknowl-
“
3
0.0357 N solution in CDCl to determine the reaction kinetics
edged. We thank Prof. Magnus Rueping and his group for
providing various TADDOLs and BINOLs. We also thank Mr.
Mike Kotke (Prof. Peter Schreiner) for ee determinations by
chiral gas chromatography and Mr. Hannes Vitze (Prof. Matthias
Wagner) for gifts of potassium tetrakis(pentafluorophenyl)-
borate.
between 8 and 9.
Kinetics of the Diels-Alder Reaction between Methylvinyl
1
Ketone and Cyclopentadiene. All H NMR spectra were recorded
at 250 MHz. The reactions were carried out in a 5 mm standard
NMR tube containing 0.05 mmol of methylvinyl ketone (1.0 equiv,
4.1 µL), a 10-fold excess of cyclopentadiene (0.5 mmol, 41.1 µL),
Supporting Information Available: Preparation of compounds
and 1 mol % ent-5d (0.67 mg, 0.5 µmol) in 0.7 mL of deuterated
chloroform at 27 °C. The percentage of conversion was determined
by integrating selected resonances for the Diels-Alder products
13
5
b, 5c, 6a, 6c, 6d, 6e, 6, and 11; 1H NMR, C NMR, and
crystallographic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
and unreacted methylvinyl ketone: endo adduct, δ
H
(COCH
) ) 2.22 ppm; methylvinyl
3
) )
2
.13 ppm; exo adduct, δ
H
(COCH
3
JO070534J
5624 J. Org. Chem., Vol. 72, No. 15, 2007