Betti reaction of cyclic imines with naphthols and phenols - Preparation of new derivatives of Betti's bases

Article abstract of DOI:10.1002/ejoc.201001611

A large library of aminocycloalkylphenols and -naphthols is obtained by the Betti reaction between activated phenols and naphthols and five- and six-membered cyclic imines. Due to the formation of an intramolecular hydrogen bond in the transition state, the attack takes place regioselectively at the position adjacent to the hydroxy group of the aromatic compounds. X-ray crystallography and chirooptical methods (electronic circular dichroism) were used to ascertain the absolute configuration of two aminoalkylnaphthols obtained, after resolution of the corresponding racemates with (R,R)-tartaric acid. In addition, some aminoalkylnaphthols and-phenols were alkylated at the nitrogen atom to obtain N-methylated products in good yields. Copyright

Full text of DOI:10.1002/ejoc.201001611

FULL PAPER
DOI: 10.1002/ejoc.201001611
Betti Reaction of Cyclic Imines with Naphthols and Phenols –
Preparation of New Derivatives of Betti’s Bases
Cristina Cimarelli,*[a] Davide Fratoni,[a] Andrea Mazzanti,[b] and Gianni Palmieri[a]
Keywords: Enantioselectivity / Configuration determination / C–C coupling / Betti base derivatives / Betti reaction
A large library of aminocycloalkylphenols and -naphthols is
obtained by the Betti reaction between activated phenols
and naphthols and five- and six-membered cyclic imines.
Due to the formation of an intramolecular hydrogen bond in
the transition state, the attack takes place regioselectively at
the position adjacent to the hydroxy group of the aromatic
compounds. X-ray crystallography and chirooptical methods
(electronic circular dichroism) were used to ascertain the ab-
solute configuration of two aminoalkylnaphthols obtained,
after resolution of the corresponding racemates with (R,R)-
tartaric acid. In addition, some aminoalkylnaphthols and
-phenols were alkylated at the nitrogen atom to obtain N-
methylated products in good yields.
and other derivatives have been objects of patents for this
purpose.[11] Moreover, they can be used as chiral auxiliaries
for the synthesis of α-aminophosphonic acids[12] and as chi-
ral shift reagents for carboxylic acids.[13]
In this paper, the reaction of activated naphthols and
phenols 1 with cyclic imines 2 is explored, and the synthesis
of new aminocycloalkylphenols and -naphthols 3, 4, and
5 and N-methyl derivatives 6 is reported. The reaction is
operationally simple, requests cheap reagents, does not need
any metal or acid catalyst, and is performed under very
mild conditions, providing the products in good yields and
in short reaction times.
Introduction
Carbon–carbon bond forming reactions play an impor-
tant role in organic synthesis. The formation of new C–
C bonds provides new opportunities in total synthesis, in
medicinal chemistry, in chemical biology, and in nanotechn-
ology. In particular, cross-coupling reactions between aro-
matic and aliphatic compounds have been largely studied.
Usually this type of reactions takes place in the presence of
catalysts such as transition metal complexes, for example
palladium,[1,2] nickel,[2] or copper salts,[3] Lewis acids,[4] or
a combination of them.[5]
Among others, the reaction between 2-naphthol and a
N-phenyltetraisoquinoline to form an aminoalkylnaphthol
was studied by Li et al.[6] This approach requires the use of
CuI salts, and the reaction is not selective, affording a rel-
evant amount of BINOL as byproduct too. Subsequent
studies of this group[7] show that analogues of this amino-
alkylnaphthol can be obtained through an aza-Friedel–
Crafts reaction, an approach that allows the preparation of
these Betti base derivatives[8] in good yields, without metal
catalysts and with 100% atom economy. Another group[9]
studied the effect of microwaves on the solventless reaction
of 3,4-dihydroisoquinoline with naphthols.
Results and Discussion
Activated naphthols and phenols 1a–g react with imines
2a–c, affording in 3–7 h products 3a–g, 4a–g, 5a, 5c–e, and
5g with 37–84% yields (Scheme 1). The reaction is conve-
nient, proceeds quickly, is operationally simple and does
not request the use of microwave[9] or expensive starting
materials. The products obtained and the corresponding
yields are collected in Table 1.
Aminoalkylphenols and -naphthols are interesting com-
pounds, useful as chiral ligands in the enantioselective ad-
dition of diethylzinc to aldehydes.[10] Recently THIQNOL®
[a] School of Science and Technology, Chemistry Division,
University of Camerino,
Via S. Agostino 1, 62032 Camerino, Italy
Fax: +39-0737-637345
E-mail: cristina.cimarelli@unicam.it
[b] Department of Organic Chemistry “A. Mangini”,
University of Bologna,
V.le Risorgimento 4, 40125 Bologna, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001611.
Scheme 1. Synthesis of aminocycloalkylnaphthols 3, 4, and 5 by
reaction of activated naphthols and phenols 1 with cyclic imines 2.
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Betti Reaction of Cyclic Imines with Naphthols and Phenols
Table 1. Yields and structures of products 3, 4, and 5.
[a] Yield of the isolated product.
The new carbon–carbon bond is formed ortho to the
Moreover, when the amino and hydroxy functionalities
hydroxy group. Probably regioselectivity is due to hydrogen- are both present in the same molecule, as in 3-amino-
bond formation in the transition state, as depicted in phenol (1g), only one product is recovered, which results
Scheme 2 for the reaction of imine 2a with β-naphthol (1a) from the reaction at position 6, ortho to the hydroxy
to form product 3a. This hypothesis is confirmed by the group.
experimental observation that substitution of the hydroxy
When the starting imine is substituted with a methyl
group by a methoxy group results in no reaction, as in 4- group at position 2, the reaction does not take place: the
methoxyaniline, and that also aniline, indole, and N-meth- reactions of 1a with 5-methyl-3,4-dihydro-2H-pyrrole and
ylindole, which cannot form any hydrogen bond with the 6-methyl-2,3,4,5-tetrahydropyridine resulted in the recovery
imine, do not react under these conditions.
of the unaltered starting materials.
Scheme 2. Hypothesis of hydrogen bond formation in the mechanism for the reaction between imine 2a and β-naphthol (1a).
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The reaction takes place with naphthols, also substituted (R,R)-tartaric acid. The diastereomeric salt, which precipi-
with electron-donating substituents, and with electron-rich tated on standing, was filtered, and the (R,R)-tartaric acid
phenols, while substrates with electron-withdrawing substit- was removed by treatment with a base (see Experimental
1
uents are unreactive under these conditions. This trend can Section). The resulting product was analyzed by H NMR
be tentatively explained by observing that the HOMO or- spectroscopy in the presence of (S)-(+)-O-acetyl mandelic
bital calculated for β-naphthol (1a) and the LUMO orbital acid.
1
for imine 2a (optimized by using DFT at the B3LYP/6-31G
The triplet at δ = 5.03 ppm in the H NMR spectrum of
level) result to be more developed at the site of attack of product (Ϯ)-3a, attributed to the proton at the 2-position
both molecules, as depicted in Figure 1. In the case of 3- of the pyrrolidine ring, splits into two triplets at 5.07 and
aminophenol (1g), this observation is also in accord with 5.00 ppm in the presence of an equimolecular amount of
the calculated local nucleophilicity index reported in the lit- (S)-(+)-O-acetyl mandelic acid. In the resolved enantiomer,
erature.[14]
the 1H NMR spectrum, registered after addition of (S)-(+)-
O-acetyl mandelic acid, shows only one triplet.
In the same way, the signal of the proton at the 2-posi-
tion of the piperidine ring in product (Ϯ)-4a is a double
doublet, which, in the presence of an equimolecular amount
of (S)-(+)-O-acetyl mandelic acid, splits in two partially
overlapping signals at δ = 4.66 and 4.63 ppm. Analogously,
1
the H NMR spectrum of the resolved enantiomer, regis-
Scheme 3. N-Alkylation of products 3d, 4a, and 5c–e.
Table 2. Yields and structures of N-alkylated products 6a–e.
Figure 1. (a) Transparent potential surfaces of β-naphthol (1a) and
imine 2a and the respective HOMO and LUMO surfaces (opti-
mized using DFT at the B3LYP/6-31G level). (b) Optimized struc-
ture for the six-membered transition structure (at the B3LYP/6-
31G(d) level). The single imaginary frequency corresponds to the
transfer of the hydrogen atom from the oxygen to the nitrogen
atom.
The analysis of the reaction path by DFT calculations
shows that the transition state[15] corresponds to the pro-
tonation of the imine by the phenolic hydrogen. IRC calcu-
lation[16] performed starting from this transition state indi-
cated the formation of the sp3 intermediate at the alpha
position of naphthalene without any additional transition
state. From this intermediate, the final product is generated
by re-aromatization.
In order to obtain an enantiopure product, the racemates
of aminoalkylnaphthols 3a and 4a were resolved by using
(R,R)-tartaric acid. The racemate products were dissolved
in acetone and added to an equimolecular amount of [a] Yield of the isolated product.
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Betti Reaction of Cyclic Imines with Naphthols and Phenols
tered after addition of (S)-(+)-O-acetyl mandelic acid in an this technique has become highly reliable and has been suc-
equimolecular amount, indicates the presence of only one cessfully employed several times to assign the absolute con-
signal. In both cases the enantiomer is isolated with ee figuration of complex organic molecules.[19] It has to be
Ͼ96%.
noted that in the present case the unambiguous knowledge
Several examples[17] reported in the literature show that of the AC of compound 3a can be used as a reference to
N-methylated aminoalkylnaphthols and -phenols perform test the reliability of the ECD-based method. The X-ray
better as catalysts with respect to the corresponding second- structure of 3a-(R,R)-tartrate shows the presence of an in-
ary amines.
tramolecular hydrogen bond that links the amine hydrogen
Betti base derivatives 3d, 4a, 5c, 5d, and 5e were methyl- with the phenolic oxygen of the naphthalene ring. This
ated[10d] at the nitrogen atom by cyclization with formalde- hydrogen bond could be present also in compound 4a, and
hyde to the corresponding oxazolidine, followed by re- it could greatly stabilize the ground state conformation.
duction with sodium triacetoxyborohydride in THF, to
A preliminary conformational search was carried out by
form the corresponding products 6a–e in yields of 49–85% using systematic search together with the MMFF94 molec-
(see Scheme 3 and Table 2). This procedure is a good alter- ular mechanics force field.[20] All the conformations within
native to the one reported in ref.,[7a] which involves the use a 3 kcal/mol window were then optimized by using DFT at
of methyl iodide, because although both methyl iodide and the B3LYP/6-31G(d) level,[21] and the harmonic vibrational
formaldehyde are toxic reagents, the latter is used in aque- frequencies of each conformation were calculated at the
ous solution, differently from the low-boiling methyl iodide, same level to confirm their stability (no imaginary fre-
which is used without dilution. Moreover, the reduction of quencies were observed) and to evaluate the free energy of
the naphthoxazine is performed in one pot, without isolat- each conformation by ZPE correction. After DFT minimi-
ing the intermediate, and thus avoiding any contact with zation, the lowest energy conformation was found to be
formaldehyde.
much more stable with respect to any other (see Figure 3).
This conformation is stabilized by an intramolecular hydro-
gen bond in which the nitrogen acts as the acceptor. This
hydrogen bond, although reversed in polarity, corresponds
to that already observed in the X-ray structure of 3aa-
(R,R)-tartrate. The six-membered ring of 3ab has a chair
conformation, which is further stabilized by the hydrogen
bond, and the naphthalene ring occupies the equatorial po-
sition.
Assignment of Absolute Configurations
The stereochemical assignment of compounds 3a and 4a
has been carried out by means of X-ray crystallography and
chirooptical techniques.
Compound 3a lacks any atom sufficiently heavy to allow
the determination of the absolute configuration (AC) by the
X-ray anomalous dispersion method.[18] For this reason,
crystals were grown as (R,R)-tartrate salts, where the
enantiopure tartrate acts as the chirality reference. Single-
crystal X-ray diffraction analysis showed that the configu-
ration of the asymmetric carbon in compound 3a is the
same as that in the tartrate anion; therefore, the absolute
configuration of 3a is (R) too (see Figure 2).
Figure 2. X-ray structure of the (R,R)-tartrate salt of compound
3a. Dotted lines indicate intra- and intermolecular hydrogen bonds.
In the case of compound 4a, we were unable to grow
good crystals suitable for X-ray analysis. Having in hand
the absolute configuration of compound 3a, we approached
the determination of the absolute configuration of com-
pound 4a by making use of chirooptical techniques. In par-
Figure 3. The lowest energy conformations obtained for 3a and 4a
by molecular mechanics (MM) conformational search followed by
DFT optimization.
As a further indication that the actual theoretical level is
ticular, we made use of the simulation of electronic circular suitable to handle these molecules, the same procedure (i.e.
dichroism (ECD) spectra by TD-DFT calculations, because MM search followed by DFT minimization) has been ap-
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C. Cimarelli, D. Fratoni, A. Mazzanti, G. Palmieri
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plied to compound 3aa as free base, and the best conforma- tion of 4a is (R). This result is also in agreement with the
tion has a structure almost identical to that of the X-ray unambiguously determined (R) configuration of 3a.
structure, the only difference being the disposition of the
phenolic hydrogen. In the free base, this is indeed involved more than one chirooptic method is always desirable. In the
in the hydrogen bond with the nitrogen. present study, both compounds 3a and 4a exhibit large val-
As correctly suggested by some authors,[23] the use of
The results of the calculations indicate that these mole- ues of [α]D (+249 and +135° for 3a and 4a, respectively),
cules are conformationally rigid, and this feature will be which are well outside the “uncertainty zone” suggested by
helpful for the simulation of the ECD spectrum of 4a. The some authors.[24] For this reason, the calculation of the
electronic excitation energies and rotational strengths were [α]D can independently confirm the absolute configuration
calculated with TD-DFT at the B3LYP/6-311++G(2d,p) of 4a. As a benchmark, the [α]D was previously calculated
level by using the optimized geometries and assuming the for compound 3a, yielding a value of +209, in good agree-
(R) absolute configuration for both 3a and 4a; the results ment with the experimental value. The same calculation ob-
are shown in Figure 4a. The calculated curves for (R)-3a tained for (R)-4a provided a value of +173.2, again in agree-
and (R)-4a have a similar pattern: this suggests that the ment with the experimental value.[25]
ECD spectrum is not heavily influenced by the size of the
ring containing the chiral center.
Conclusions
A large number of compounds is obtained by the Betti
reaction of activated phenols and naphthols 1a–g with cy-
clic imines 2a–c. The reaction is operationally simple and is
carried out under mild conditions, affording good yields of
the desired product in short reaction times. Due to the for-
mation of an intramolecular hydrogen bond in the transi-
tion state, the attack takes place regioselectively at the ortho
position of the aromatic compounds. The absolute configu-
ration of products 3a and 4a was ascertained by X-ray
analysis and chirooptical methods (ECD), after resolution
of the corresponding racemates with (R,R)-tartaric acid. In
addition, aminoalkylnaphthols and -phenols 3d, 4a, 5c, 5d,
and 5e were alkylated at the nitrogen atom to obtain N-
methylated products 6a–e in good yields.
Experimental Section
General Remarks: Imines 2a–c were prepared according to litera-
ture[26] methods. Products 5 were prepared according to litera-
ture[7b] methods. 1H and 13C NMR spectra were recorded at 400
and 100 MHz respectively, with CDCl3 as solvent at ambient tem-
perature and were calibrated by using residual undeuteriated sol-
vents as the internal reference. Coupling constants (J) are given in
Hertz. IR spectra were recorded by using FTIR apparatus. Optical
rotations were measured in a 1 dm cell at 20 °C. All reagents are
Figure 4. (a) ECD spectra calculated for (R)-3a and (R)-4a. Calcu-
lations at the TD-DFT B3LYP/6-311++G(2d,p) level. (b) Experi-
mental (solid line) and calculated ECD spectra (dashed line) of
4a. The experimental ECD spectrum was obtained in acetonitrile
solution (1ϫ 10–4 m) with a 0.2 cm cell. Molecular CD (Δε) values
are expressed in Lmol–1 cm–1. The simulated spectrum was scaled
and redshifted by 8 nm for comparison with the experimental trace.
commercially available and of the highest quality; they were puri-
fied by distillation when necessary.
General Procedure for the Synthesis of Aminocycloalkylnaphthols
and -phenols 3, 4, and 5: 3,4-dihydro-2H-pyrrole 2a (2 mmol,
0.138 g) or 2,3,4,5-tetrahydropyridine 2b (2 mmol, 0.166 g) or 3,4-
dihydroisoquinoline 2c (2 mmol, 0.262 g) was dissolved in dichloro-
methane (4 mL) in a round-bottomed flask equipped with magnetic
stirring. Then, naphthols or phenols 1a–g (2 mmol) were added at
room temperature. The reaction was monitored by TLC, with n-
hexane/ethyl acetate (1:1) as eluent, until the starting materials were
consumed. The solvent was evaporated under reduced pressure.
The raw mixture obtained was purified by column chromatography
on silica gel, by using cyclohexane/ethyl acetate (1:1) as the eluent.
Purified aminocycloalkylnaphthols and -phenols 3, 4, and 5 were
crystallized from a cyclohexane/ethyl acetate mixture. Spectral
characterization of products 3a and 4a follow. Spectral characteri-
The rotational strengths were calculated in the length
and velocity representations. The resulting values are very
similar, and errors due to basis set incompleteness are there-
fore very small or negligible.[22] The final simulated ECD
spectrum was obtained by taking into account that only
one conformation was calculated to be populated. The
agreement between the calculated spectrum of 4a and the
experimental spectrum is very good, and the CD simulation
thus supports the conclusion that the absolute configura- zation of compound 5a is in accord with that reported in ref.[9]
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Betti Reaction of Cyclic Imines with Naphthols and Phenols
1-Pyrrolidin-2-yl-naphthalen-2-ol (3a): Yield 78% (0.333 g), white with a Bruker APEX II diffractometer equipped with a CCD area
crystals, m.p. 85–88 °C. ν
(solid) = 3306, 2571, 1620, 1335, 956,
detector using Mo-Kα radiation. Molecular formula: C36H44N2O15,
Mr = 744.73, monoclinic, space group C2 (No. 5), a = 26.963(4) Å,
˜
max
816, 743 cm–1. H NMR (CDCl3): δ = 1.81 (dq, J = 12.5, 8.6 Hz,
1 H, 3Ј-Ha), 1.91–2.05 (m, 2 H, 4Ј-H), 2.42–2.50 (m, 1 H, 3Ј-Hb),
2.56 (br. s, 1 H, NH), 3.11 (q, J = 8.1 Hz, 1 H, 5Ј-Ha), 3.28 (dt, J
1
b
=
7.4562(10) Å,
c = 8.8922(12) Å, β = 93.613(3)°, V =
1784.2(4) Å3, T = 298(2) K, Z = 2, ρc = 1.386 gcm–3, F(000) = 788,
= 10.3, 6.6 Hz, 1 H, 5Ј-Hb), 5.03 (t, J = 8.1 Hz, 1 H, 2Ј-H), 7.07 μ(Mo-Kα) = 0.109 mm–1, 2400 frames, exposure time 10 s, 2.29 Յ
(d, J = 9.0 Hz, 1 H, Ar), 7.28 (t, J = 7.5 Hz, 1 H, Ar), 7.43 (t, J =
7.7 Hz, 1 H, Ar), 7.64 (d, J = 8.5 Hz, 1 H, Ar), 7.74 (t, J = 7.0 Hz,
2 H, Ar), 14.00 (br. s, 1 H, OH) ppm. 13C NMR (CDCl3): δ =
25.5, 33.2, 45.8, 58.9, 115.6, 120.5, 121.3, 122.3, 126.4, 128.4, 128.9,
129.0, 132.4, 156.6 ppm. C14H15NO (213.275): calcd. C 78.84, H
7.09, N 6.57; found C 79.10, H 7.01, N 6.29.
θ Յ 27.50, –34 Յ h Յ 34, –9 Յ k Յ 9, –11 Յ l Յ 11, 10192
reflections collected, 2196 independent (Rint = 0.0237), solution by
direct methods (SHELXS-97)[27] and subsequent Fourier syntheses,
full-matrix least-squares on Fo (SHELXL-97),[27] hydrogen atoms
2
refined with a riding model, data/restraints/parameters = 2196/1/
261, S(F2) = 1.051, R(F) = 0.0320 and wR(F2) = 0.0846 on all
data, R(F) = 0.0315 and wR(F2) = 0.0839 for 2153 reflections with
2-Piperidin-2-yl-naphthalen-2-ol (4a): Yield 81% (0.368 g), white
F0 Ͼ4σ(F0), weighting scheme w = 1/[σ2(Fo2) + (0.0611P)2
+
crystals, m.p. 124–129 °C. ν
(solid) = 3280, 2853, 2536, 1621,
˜
max
0.2845P], where P = (Fo2 + 2Fc )/3, largest difference between peak
and hole was 0.152 and –0.254 eÅ–3. The unit cell contains one
molecule of water. CCDC-798179 contains the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
2
1266, 1099, 820 cm–1. 1H NMR (CDCl3): δ = 1.54 (qt, J = 12.6,
3.7 Hz, 1 H, 3Ј-Ha), 1.65 (qt, J = 12.6, 3.7 Hz, 1 H, 3Ј-Hb), 1.72–
1.94 (m, 4 H, 4Ј-H, 5Ј-H), 2.38 (br. s, 1 H, NH), 2.81 (td, J = 11.6,
2.8 Hz, 1 H, 6Ј-Ha), 3.30 (dq, J = 11.6, 1.9 Hz, 1 H, 6Ј-Hb), 4.62
(dd, J = 11.1, 6.8 Hz, 1 H, 2Ј-H), 7.11 (d, J = 9.1 Hz, 1 H, Ar),
7.27–7.31 (m, 1 H, Ar), 7.42–7.46 (m, 1 H, Ar), 7.67 (d, J = 8.5 Hz,
1 H, Ar), 7.76 (dd, J = 8.1, 1.3 Hz, 1 H, Ar), 7.85 (d, J = 9.0 Hz
1 H, Ar), 12.37 (br. s, 1 H, OH) ppm. 13C NMR (CDCl3): δ = 24.8,
25.3, 30.5, 46.9, 56.3, 118.4, 120.1, 120.9, 122.6, 126.5, 128.6, 129.0,
129.2, 131.6, 155.8 ppm. C15H17NO (227.302): calcd. C 79.26, H
7.54, N 6.16; found C 79.19, H 7.62, N 6.24.
Supporting Information (see footnote on the first page of this arti-
cle): Complete characterization of products 3b–g, 4b–g, 5c–e, 5g
1
and 6a, 6c–e; H and 13C NMR spectra of compounds 3a–d, 4a–
g, 5c–e, 5g and 6a–e. Equilibrium conformers of compounds 3a
and 4a and the number of states calculated for the calculated CD
spectra are also included.
Resolution of (؎)3a and (؎)4a: Product 3a or 4a (3 mmol) was
dissolved in acetone (3 mL) and added to a solution of (R,R)-tar-
taric acid (3 mmol, 0.450 g) in acetone (3 mL). The mixture was
allowed to stand overnight and then filtered. The precipitate ob-
tained was dried under vacuum and then dispersed in dichloro-
methane. After the addition of saturated sodium carbonate solu-
tion until basic pH was reached, the solution was extracted with
CH2Cl2 (2ϫ20 mL) The extract was dried with anhydrous sodium
sulfate, and the solvent was evaporated under vacuum to afford a
white solid in both cases. The optical purity of the isolated enantio-
mers of products 3a and 4a was ascertained by 1H NMR spec-
troscopy in the presence of (S)-(+)-O-acetyl mandelic acid as chiral
solvating agent, yielding a result of 96% ee.
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Synthesis of Products 6a–e: The methylation of products 3d, 4a,
and 5c–e was performed by cyclization to the corresponding oxaz-
ine with formaldehyde and subsequent reductive ring opening with
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1-(1-Methyl-piperidin-2y-l)-naphthalen-2-ol (6b): Yield 85%
(0.410 g), white crystals, m.p. 95–97 °C. ν
(solid) = 2937, 2586,
˜
max
1620, 1471, 1249, 1106, 810, 745 cm–1. 1H NMR (CDCl3): δ = 1.45
(qt, J = 12.0, 4.0 Hz, 1 H, 4Ј-Ha), 1.68–1.96 (m, 5 H, 4Ј-Hb, 3Ј-H,
5Ј-H), 2.24 (td, J = 11.6, 3.6 Hz, 1 H, 6Ј-Ha), 2.25 (s, 3 H, NCH3),
3.19 (d, J = 11.6 Hz, 1 H, 6Ј-Hb), 3.92 (dd, J = 11.3, 3.2 Hz, 1 H,
2Ј-H), 7.10 (d, J = 8.5 Hz, 1 H, Ar), 7.26–7.31 (m, 1 H, Ar), 7.41–
7.46 (m, 1 H, Ar), 7.67 (d, J = 9.0 Hz, 1 H, Ar), 7.77 (d, J = 8.1 Hz,
1 H, Ar), 7.86 (d, J = 9.0 Hz, 1 H, Ar), 12.43 (br. s, 1 H, OH) ppm.
13C NMR (CDCl3): δ = 24.4, 25.9, 31.2, 44.1, 56.5, 64.3, 117.6,
119.5, 120.9, 122.5, 126.4, 128.8, 129.0, 129.1, 132.1, 155.0 ppm.
C16H19NO (241.147): calcd. C 79.63, H 7.94, N 5.80; found C
79.41, H 7.79, N 5.58.
X-ray Crystallography: Crystals of product 3a suitable for X-ray
diffraction were obtained from wet acetone solution and analyzed
Eur. J. Org. Chem. 2011, 2094–2100
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2099

C. Cimarelli, D. Fratoni, A. Mazzanti, G. Palmieri
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2100
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2094–2100