Stereomutation of axially chiral aryl coumarins

Article abstract of DOI:10.1021/jo101261k

Coumarins substituted by an aryl group in position 4 display restricted rotation about the Ar-C4 bond, giving rise to conformational or configurational enantiomers (atropisomers) when such a restricted motion leads to a C ₁ symmetry. The dynamics of the stereomutation processes of these axial enantiomers was monitored by dynamic NMR, dynamic enantioselective HPLC, or racemization kinetics, depending on the activation energies involved. These results were further supported by DFT computations. In the two cases where the enantiomers were sufficiently long living as to be physically separated at ambient temperature, the absolute configuration was determined by means of a theoretical simulation of their electronic circular dicroism spectra (ECD).

Full text of DOI:10.1021/jo101261k

pubs.acs.org/joc
Stereomutation of Axially Chiral Aryl Coumarins
Lodovico Lunazzi,† Michele Mancinelli,† Andrea Mazzanti,*,† and Marco Pierini‡
†Department of Organic Chemistry “A. Mangini”, University of Bologna, Viale Risorgimento 4, Bologna
40136, Italy, and ‡Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive,
ꢀ
Universita “La Sapienza”, Piazzale A. Moro, 5, Roma, Italy
mazzand@ms.fci.unibo.it
Received June 28, 2010
Coumarins substituted by an aryl group in position 4 display restricted rotation about the Ar-C4
bond, giving rise to conformational or configurational enantiomers (atropisomers) when such a
restricted motion leads to a C1 symmetry. The dynamics of the stereomutation processes of these axial
enantiomers was monitored by dynamic NMR, dynamic enantioselective HPLC, or racemization
kinetics, depending on the activation energies involved. These results were further supported by DFT
computations. In the two cases where the enantiomers were sufficiently long living as to be physically
separated at ambient temperature, the absolute configuration was determined by means of a
theoretical simulation of their electronic circular dicroism spectra (ECD).
SCHEME 1. Structure of Compounds 1-7a
Introduction
Coumarin derivatives are present in a variety of naturally
occurring substances:1 they display interesting and useful
biological properties in that they can behave as cytotoxic,2
antibacterial,3 and antimalarial4 agents. Coumarin is also
used in the pharmaceutical industry as a precursor for the
synthesis of a number of synthetic anticoagulants.5 For these
reasons a number of syntheses for these types of derivatives
were obtained and, in particular, the preparation of aryl
coumarins has received considerable attention in the past few
aAr=3-methylphenyl (1), 2-methylphenyl (2), 2-ethylphenyl (3), 2,3-
dimethylphenyl (4), 1-naphthyl (5), 2-isopropylphenyl (6), 2-methyl-1-
naphthyl (7).
years.6 A quite useful approach for the synthesis of this class
of molecules has been recently reported.7
ꢁ
(1) Murray, R. D. H. Nat. Prod. Rep. 1995, 12, 477–505. Estevez-Braun,
ꢁ
A. S.; Gonzalez, A. G. Nat. Prod. Rep. 1997, 13, 465–475.
ꢁ
Bruneton, J. J. Nat. Prod. 2001, 64, 563–568.
We considered that 4-aryl coumarins might, in principle,
exhibit restricted rotation about the bond joining the carbon
in position 4 with a conveniently substituted aryl group.
Depending on the size of the aryl substituent, such a chirality
axis might generate either conformationally mobile or con-
figurationally stable enantiomers (atropisomers). The latter,
possibly, could be useful compounds for applications in
asymmetric synthesis, or as precursors for the preparation
ꢁ
ꢁ
(2) Guilet, D.; Helesbeux, J.-J.; Seraphin, D.; Sevenet, T.; Richomme, P.;
(3) Verotta, L.; Lovaglio, E.; Vidari, G.; Vita-Finzi, P.; Neri, M. G.;
Raimondi, S.; Parapini, S.; Taramelli, D.; Riva, A.; Bombardelli, E. Phy-
tochemistry 2004, 65, 2867–2879.
ꢁ
guez-Gutierrez,
guez, M. H.;
(4) Argotte-Ramos, R.; Ramı
~
´
rez-Avila, G.; Rodrı
´
M. d. C.; Ovilla-Munoz, M.; Lanz-Mendoza, H.; Rodrı
´
ꢁ
Gonzalez-Cortazar, M.; Alvarez, L. J. Nat. Prod. 2006, 69, 1442–1444.
(5) Coumarins: Biology, Applications, and Mode of Action; O’Kennedy,
R., Thornes, R. D., Eds.; Wiley: Weinheim, Germany, 1997.
(6) Jia, P.; Piao, D.; Oymada, J.; Lu, W.; Kitamura, T.; Fujivara, Y.
Science 2000, 287, 1992–1995. Shi, Z.; He, C. J. Org. Chem. 2004, 69, 3669–
3671. Li, K.; Zeng, Y.; Neuenswander, B.; Tunge J. Org. Chem. 2005, 70,
6515–6518. Oyamada, J. A.; Kitamura, T. Tetrahedron 2006, 62, 6916–6925.
(7) (a) Yamamoto, Y.; Kirai, N. Org. Lett. 2008, 10, 5513–5516. (b) Rao,
M. L. N.; Venkatesh, V.; Jadhav, D. N. Eur. J. Org. Chem. 2010, 3945–3955.
DOI: 10.1021/jo101261k
r
Published on Web 08/10/2010
J. Org. Chem. 2010, 75, 5927–5933 5927
2010 American Chemical Society

Lunazzi et al.
JOCArticle
TABLE 1. Experimental and DFT Computed Barriers (kcal mol-1) for
the Rotation Process Leading to the Enantiomer Interconversion
compd
method
exptla
computedb
1
2
3
4
5
6
DNMR
DNMR
DNMR
DHPLC
DHPLC
racemization (þ24 °C)
(enantiomerization)
racemization (þ120 °C)
(enantiomerization)
10.0
20.1
21.8
21.5
21.7
23.4 (23.8)
11.0
18.9
20.1
20.4
20.6
22.0
7
>35
35.7
aWithin the errors the experimental ΔGq values are temperature
independent, so the ΔSq is negligible, see the Experimental Section.
bThe reported values refer to the enantiomerization process.
of biologically active atropisomers.8 Accordingly we synthe-
sized compounds 1-7 (Scheme 1) in which an isopropyl
group was inserted in the coumarin moiety to act as a probe
for the NMR detection of the molecular asymmetry.9
Results and Discussion
FIGURE 1. Left: Temperature dependence of the 1H signals of the
methyl isopropyl group of 2 (600 MHz in C2D2Cl4). Right: Com-
puter simulation obtained with the rate constants reported.
In compound 1, which bears a m-tolyl substituent in posi-
tion 4, the 13C single line of the isopropyl methyl groups
broadensoncoolingandeventuallysplitsintoa pairof equally
intense lines, separated by 0.05 ppm, below -80 °C. The line
shape simulation yields the rate constants reported in Figure
S-1 of the Supporting Information: from these values a free
energy of activation (ΔGq) of 10.0 kcal mol-1 was derived
(Table 1). The fact that the isopropyl methyls appear diaster-
eotopic at low temperature indicates that the molecule adopts
an asymmetric (thus chiral) conformation, implying the ex-
istence of two conformational enantiomers that interconvert
with the above-mentioned barrier.
the methyl syn to the CdO moiety. With respect to the
ground state their computed relative energies are essentially
equal (11.2 and 11.1 kcal mol-1, respectively). These values
match satisfactorily the experiment, the difference being only
1 kcal mol-1 (Table 1). In Figure S-2 of the Supporting
Information are displayed the ground and transition states
of these conformational enantiomers, as obtained by DFT
calculations.
In compound 2, where there is an o-tolyl group bonded to
position 4 of coumarin, the isopropyl methyls display aniso-
chronous signals even at ambient temperature. As shown in
Figure 1 the 1H spectrum displays two doublets that coalesce
into a single doublet at high temperature. This implies that
the two enantiomers of 2 can be detected at ambient tem-
perature and this is confirmed by the spectrum obtained in a
chiral environment, where it is shown (Figure S-3 of the
Supporting Information) that the single line of the o-methyl
group splits into two on addition of an enantiopure Pirkle’s
alcohol.12 Line shape simulation of the temperature-depen-
dent isopropyl methyl signals (Figure 1) affords a barrier of
20.1 kcal mol-1 (Table 1).
DFT computations predict that in the ground state of 2
the o-tolyl ring is essentially orthogonal to the plane of
coumarin (the corresponding dihedral angle is 77°). Due to
the steric hindrance exerted by the hydrogen in position 5
of the coumarin ring, the transition state where the tolyl
o-methyl is anti to CdO has a relative computed energy much
higher than when it is syn, the two values being 26.8 and
18.9 kcal mol-1, respectively. The latter thus corresponds to
the pathway followed by the interconversion process because
this barrier not only is lower than the other but it is also much
closer to the experimental value.
DFT calculations10(at the B3LYP/6-31G(d) level) actu-
ally show that compound 1 adopts a twisted conformation.11
Such a situation gives rise to two enantiomeric forms that
exchange via transition states where the coumarin and the
m-tolyl rings are essentially coplanar. There are two such
transition states: one has the tolyl methyl anti, the other has
(8) Cano, C.; Golding, B. T.; Haggerty, K.; Hardcastle, I. R.; Peacock,
M.; Griffin, R. J. Org. Biomol. Chem. 2010, 8, 1922–1928.
(9) (a) Mislow, K.; Raban, M. Top. Stereochem. 1967, 1, 1. (b) Jennings,
W. B. Chem. Rev. 1975, 75, 307. (c) Eliel, E. L. J. Chem. Educ. 1980, 57, 52. (d)
Casarini, D.; Lunazzi, L.; Macciantelli, D. J. Chem. Soc., Perkin Trans. 2
1992, 1363–1370.
(10) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian,
H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski,
J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg,
J. J.;Zakrzewski, V. G.;Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.;
Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, Revision E.01; Gaussian, Inc., Wallingford, CT, 2004.
(11) Actually there are two such twisted conformations (see Figure S-2 of
the Supporting Information), with essentially the same energy: one has the
tolyl methyl syn to CdO (dihedral angle = 53°), the other anti to CdO
(dihedral angle=127°). They exchange through a transition state where the
coumarin and the m-tolyl planes are essentially orthogonal: the correspond-
ing barrier (sometimes referred to as π-barrier) is very low (about 2 kcal
mol-1). This exchange process is therefore extremely fast and does not affect
the variable-temperature NMR spectrum.
An analogous result was obtained in the case of 3, where
the presence of an o-ethyl, rather than an o-methyl substituent
(12) Use was made of the enantiopure R-(-)-2,2,2-trifluoro-1-(9-anthryl)-
ethanol (see: Pirkle, W. H.; Sikkenga, D. L.; Pavlin, M. S. J. Org. Chem. 1977,
42, 384–387.) in a 10:1 molar excess with respect to compound 2.
5928 J. Org. Chem. Vol. 75, No. 17, 2010

Lunazzi et al.
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in the phenyl ring increases the interconversion barrier
(ΔGq=21.8 kcal mol-1, as in Table 1).
Introduction of a second methyl group in the meta posi-
tion of compound 2 yields derivative 4, which shows a quite
noticeable buttressing effect.13 In fact the rotation barrier
interconverting the enantiomers has become much higher
than in the case of 2, so that the effects of the exchange
process were not NMR visible, even at the highest attainable
temperature (þ120 °C).14 According to DFT calculations
this barrier is expected to be 20.4 kcal mol-1, a value that is
1.5 kcal mol-1 higher than that computed for 2 (see Table 1):
this difference thus represents the theoretical evaluation of
the buttressing effect. Taking into account the experimental
values observed for 2 (20.1 kcal/mol), the additional con-
tribution of the buttressing effect should raise the barrier to a
value of about 21.6 kcal mol-1. Such a relatively high barrier
might suggest that a physical separation of the two enantio-
meric forms of 4 might be achieved.
An enantioselective HPLC experiment, however, showed
that the rate interconverting the two enantiomers is such as to
give the typical traces of an “in column” exchange process (i.e.,
dynamic HPLC effect).15 As displayed in Figure 2 simulations
of these traces (see the Experimental Section) at different
temperatures yield the rate constants for the enantiomeriza-
tion, from which the corresponding barrier (that could not be
determined by DNMR) was obtained (ΔGq=21.5 kcal mol-1
,
as in Table 1). The difference between this experimental barrier
and that of 2 is 1.4 kcal mol-1, in good agreement with the
DFT estimation of the buttressing effect (1.5 kcal mol-1).
The naphthalene derivative 5 displays similar behavior to
that of 4 in that the interconversion barrier could not be
determined by dynamic NMR14 and the variable-tempera-
ture enantioselective HPLC experiment showed again the
traces typical for an “in column” interconversion in the
ambient temperature range. The corresponding simulation
of the dynamic HPLC traces (Figure S-4 of the Supporting
FIGURE 2. Temperature-dependent chromatograms of 4 on an
enantioselective HPLC column. Experimental profiles (left, with
the time scale in minutes) vs profiles (right) calculated on the basis of
the best fit rate constants (k, in s-1) for enantiomerization.
traces: that of the first eluted enantiomer is displayed at
the bottom of Figure 3. Two conformations (a and b), differ-
ing by the orientation of the isopropyl group bonded to
coumarin,16 were optimized at the B3LYP/6-31G(d) level,10
and the harmonic vibrational frequencies of each conforma-
tion were calculated at the same level to confirm their
stability (no imaginary frequencies observed), and to evalu-
ate the corresponding free energies. After DFT minimiza-
tion, the free energies of the two conformations were found
essentially equal, as shown in Figure S-5 of the Supporting
Information (top).
Calculations of the ECD spectrum of both conformers
were then carried out using the TD-DFT method17 at the
B3LYP/6-311þþG(2d,p)//B3LYP/6-31G(d) level, and assu-
ming the absolute configuration M (Figure S-5 of the Sup-
porting Information, bottom). The final simulated spectrum
Information) afforded a barrier of 21.7 kcal mol-1
.
In the case of compound 6 the bulkiness of the isopropyl
group in the ortho position of the phenyl ring makes the
enantiomers sufficiently long living as to allow their physical
separation by means of an enantioselective semipreparative
HPLC column (Figure 3, top).
The Electronic Circular Dichroism (ECD) spectra of the
two enantiomers showed the expected opposite phased
(13) (a) Westheimer, F. H. In Steric Effects in Organic Chemistry;
Newman, M. S., Ed.; John Wiley and Sons, Inc.: New York, 1956; Chapter
12. (b) Karnes, H. A.; Rose, M. L.; Collat, J. W.; Newman, M. S. J. Am.
Chem. Soc. 1968, 90, 458–461. (c) Decouzon, M.; Ertl, P.; Exner, O.; Gal,
J.-F.; Maria, P.-C. J. Am. Chem. Soc. 1993, 115, 12071–12078. (d) Heiss, F.;
Marzi, E.; Schlosser, M. Eur. J. Org. Chem. 2003, 4625–4629. (e) Gorecka, J.;
Heiss, C.; Scopelliti, R.; Schlosser, M. Org. Lett. 2004, 6, 4591–4593.
(f) Heiss, C.; Leroux, F.; Schlosser, M. Eur. J. Org. Chem. 2005, 5242–
5247. (g) Schlosser, M.; Cottet, F.; Heiss, C.; Lefebvre, O.; Marull, M.;
Masson, E.; Scopelliti, R. Eur. J. Org. Chem. 2006, 729–734. (h) Lunazzi, L.;
Mancinelli, M.; Mazzanti, A. J. Org. Chem. 2008, 73, 2198–2205.
(14) This was due to the fact that the chemical shift separation of the
isopropyl methyl signals was exceedingly small in the solvents required to
reach the high temperatures. For the same reason, even a high-temperature
EXSY NMR experiment (see: Sanders, J. K. M.; Hunter, B. H. Modern
NMR Spectroscopy, 2nd ed.; Oxford University Press: Oxford, UK, 1993;
p 226.) did not allow us to observe the effects of this exchange process.
(15) (a) Gasparrini, F.; Grilli, S.; Leardini, R.; Lunazzi, L.; Mazzanti, A.;
Nanni, D.; Pierini, M.; Pinamonti, M. J. Org. Chem. 2002, 67, 3089–3095.
(b) Ciogli, A.; Dalla Cort, A.; Gasparrini, F.; Lunazzi, L.; Mandolini, L.;
Mazzanti, A.; Pasquini, C.; Pierini, M.; Schiaffino, L.; Mihan, F. Y. J. Org.
Chem. 2008, 73, 6108–6118. (c) Wolf, C. Dynamic Stereochemistry of Chiral
Compounds; RCS Publishing: Cambridge, UK, 2008; Chapter 4, pp 136-179.
(16) Other possible conformers were found to have energies too high to be
significantly populated and were therefore neglected.
(17) Mazzeo, G.; Giorgio, E.; Zanasi, R.; Berova, N.; Rosini, C. J. Org.
Chem. 2010, 75, 4600–4603. Pescitelli, G.; Di Pietro, S.; Cardellicchio, C.;
Annunziata, M.; Capozzi, M.; Di Bari, L. J. Org. Chem. 2010, 75, 1143–1154.
ꢀ
Jacquemin, D.; Perpete, E. A.; Ciofini, I.; Adamo, C.; Valero, R.; Zhao, Y.;
Truhlar, D. G. J. Chem. Theory Comput. 2010, 6, 2071–2085. Gioia, C.; Fini,
F.; Mazzanti, A.; Bernardi, L.; Ricci, A. J. Am. Chem. Soc. 2009, 131, 9614–
9615. Stephens, P. J.; Pan, J. J.; Devlin, F. J.; Cheeseman, J. R. J. Nat. Prod.
2008, 71, 285–288. For reviews see: Bringmann, G.; Bruhn, T.; Maksimenka,
K.; Hemberger, Y. Eur. J. Org. Chem. 2009, 2717–2727. Bringmann, G.;
Gulder, T. A. M.; Reichert, M.; Gulder, T. Chirality 2008, 20, 628–642.
Berova, N.; Di Bari, L.; Pescitelli, G. Chem. Soc. Rev. 2007, 36, 914.
J. Org. Chem. Vol. 75, No. 17, 2010 5929

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FIGURE 3. Top: Chromatogram of compound 6 on an enantiose-
lective HPLC column. Bottom: Calculated (red) and experimental
(black) ECD spectrum of the first eluted enantiomer in the same
solvent mixture used for the separation.
FIGURE 4. Top: Chromatogram of compound 7 on an enantiose-
lective HPLC column. Bottom: Calculated (red) and experimental
(black) ECD spectrum of the first eluted atropisomer in acetonitrile.
(Figure 3, bottom) was obtained taking into account the
52:48 population ratio determined from the calculated free
energies at the B3LYP/6-31G(d) level, and assuming
Boltzmann statistics. The satisfactory agreement between
the calculated and the experimental ECD spectrum allowed
us to confidently assign the absolute configuration M to the
first eluted enantiomer.
Theoretical simulation of these traces, performed in the
same way as described for compound 6,16 allowed us to
assign the absolute M configuration to the first eluted atropi-
somer (Figure 4, bottom).
The first eluted enantiomer of 6 was then left to racemize
inside the ECD spectrometer at þ24 °C, and the evolution of
this kinetic process was followed by the decay of the ECD
signal at 216 nm. A rate constant of 3.7 ꢀ 10-5 s-1 was
measured (Figure S-6 of the Supporting Information), from
which a barrier (ΔGq) of 23.4 kcal mol-1 (Table 1) was
derived for the racemization process. According to the
well-known relationship existing between enantiomerization
(ke) and racemization (kr) rate constants (i.e., kr=2ke), the
related enantiomerization process is therefore characterized
The second eluted atropisomer P was kept at þ120 °C in a
tetrachloroethane solution for 24 h, but the subsequent
enantioselective HPLC analysis did not display the appear-
ance of the signal due to the M enantiomeric partner, thus
implying18 a barrier higher than 35 kcal mol-1. This result
agrees with the theoretical barrier (35.7 kcal mol-1, as in
Table 1) predicted for their interconversion: it can be thus
concluded that the enantiomers of 7 can be considered config-
urationally stable atropisomers.
by a barrier of 23.8 kcal mol-1
.
Experimental Section
On the basis of the results for the 1-naphthyl derivative 5
and for compound 6, we anticipated that compound 7,
having an even more hindered group as a substituent (i.e.,
2-methyl-1-naphthyl), was likely to give rise to a pair of
atropisomers configurationally stable at ambient tempera-
ture. A computed structure of 7 is reported in Figure S-7 of
the Supporting Information, together with the computed
transition states: the lower energy of the latter is as high as
35.7 kcal mol-1 (Table 1), thus supporting the prediction
that these atropisomers should not be able to interconvert at
ambient temperature, contrary to the cases of 5 and 6. Both
Materials. 2-Methylphenylboronic acid, 2-ethylphenylboronic
acid, 2-isopropylphenylboronic acid, 2,3-dimethylphenylboronic
acid, and 1-naphthylboronic acid were commercially available.
Dimethyl (2-methylnaphthalen-1-yl)boronate was prepared fol-
lowing known procedures.19 4-Arylcoumarins 1-7 were prepared
according to the general procedure7a displayed in Scheme 2.
Compounds 8,20 9,21 10, and 11 were prepared following a
procedure described in ref 7a.
(18) After 24h atþ120 °C, the enantioselectiveHPLCanalysisshowedthat
the amount of the first eluted enantiomer, if present, was certainly much lower
than 1%. If a 1% population is assumed, the corresponding rate constant is
about 10-7 s-1, which corresponds toa barrier of 35.5kcalmol-1. Accordingly
1
the H and 13C spectra show that the methyl groups of the
the barrier for the racemization of 7 must be higher than 35 kcal mol-1
.
isopropyl moiety of 7 remain diastereotopic at any attainable
temperature. The two atropisomers (M and P enantiomers)
were separated by means of an enantioselective HPLC
column (Figure 4, top) and the corresponding ECD spectra
displayed the expected opposite phased traces.
(19) Thompson, W. J.; Gaudino, J. J. Org. Chem. 1984, 49, 5237. Andersen,
N. G.; Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1996, 61, 9556–9559.
(20) Shukla, R.; Lindeman, S. V.; Rathore, R. J. Am. Chem. Soc. 2006,
128, 5328–5329.
(21) Yu, X.; Scheller, D.; Rademacher, O.; Wolff, T. J. Org. Chem. 2003,
68, 7386–7399.
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Hz), 2.46 (s, 3 H), 2.90 (sept, 1 H, J=7.0 Hz), 6.35 (s, 1 H),
SCHEME 2. Synthesis of Coumarins 1-7a
7.25-7.27 (m, 1 H), 7.31-7.36 (m, 3 H), 7.41-7.44 (m, 2 H); 13
C
NMR (150.8 MHz, CDCl3, 25 °C, TMS) δ 21.6 (CH3), 24.2 (2
CH3), 33.8 (CH), 115.1 (CH), 117.3 (CH), 118.9 (Cq), 124.6
(CH), 125.7 (CH), 128.8 (CH), 129.3 (CH), 130.4 (CH), 130.5
(CH), 135.5 (Cq), 138.9 (Cq), 145.0 (Cq), 152.7 (Cq), 156.1 (Cq),
161.3 (COO); HRMS (ESI-FT-ICR) calcd for C19H19O2 [M þ
H]þ 279.1380, found 279.1375.
6-Isopropyl-4-(o-tolyl)-2H-cromen-2-one (2): tR = 7.77 min;
1H NMR (600 MHz, CDCl3, 25 °C TMS) δ 1.16 (d, 3 H, J=7.0
Hz), 1.15 (d, 3 H J=7.0 Hz), 2.16 (s, 3 H), 2.84 (sept, 1 H, J=7.0
Hz), 6.30 (s, 1 H), 6.87 (d, 1 H, J=2.1 Hz), 7.20 (dd, 1 H, J=1.1,
7.6 Hz), 7.34 (m, 3 H), 7.40-7.43 (m, 2 H), 7.41-7.44 (m, 2 H);
13C NMR (150.8 MHz, CDCl3, 25 °C, TMS) δ 20.0 (CH3), 24.0
(CH3), 24.2 (CH3), 33.7 (CH), 115.8 (CH), 117.2 (CH), 119.3
(Cq), 124.5 (CH), 126.3 (CH), 128.7 (CH), 129.4 (CH), 130.4
(CH), 130.7 (CH), 135.1 (Cq), 135.5 (Cq), 145.3 (Cq), 152.3 (Cq),
156.4 (Cq), 161.3 (COO); HRMS (ESI-FT-ICR) calcd for
C19H19O2 [M þ H]þ 279.1380, found 279.1382.
aReagents and conditions: (a), t-BuOK, MOM-Cl, THF, 25 °C;
(b) CBr4, PPh3, NEt3, CH2Cl2, 0 °C; (c) n-BuLi, MeOCOCl, THF,
-78 °C;(d) HBr, Et2O, 0 °C;(e) Ar-B(OH)2, Pd(PPh3)4, K2CO3, benzene/
H2O/EtOH, reflux.
6-Isopropyl-4-(2-ethylphenyl)-2H-cromen-2-one (3): tR=9.24
min; 1H NMR (600 MHz, CDCl3, 25 °C, TMS) δ 1.10 (t, 3 H, J=
7.6 Hz), 1.14 (d, 3 H, J=7.0 Hz), 1.15 (d, 3H, J=7.0 Hz), 2.45 (m,
1 H), 2.49 (m 1 H), 2.83 (sept, 1 H, J=7.0 Hz), 6.32 (s, 1H), 6.86
(d, 1 H, J=2.35 Hz), 7.16 (dd, 1 H, J=1.2, 7.6 Hz), 7.30-7.36
(m, 2 H), 7.39-7.43 (m, 2 H), 7.46-7.49 (m, 1 H); 13C NMR
(150.8 MHz, CDCl3, 25 °C, TMS) δ 15.8 (CH3), 24.0 (CH3), 24.3
(CH3), 26.4 (CH2), 33.8 (CH), 116.0 (CH), 117.2 (CH), 119.8
(Cq), 124.6 (CH), 126.3 (CH), 128.8 (CH), 129.0 (CH), 129.6
(CH), 130.4 (CH), 134.4 (Cq), 141.8 (Cq), 145.3 (Cq), 152.3 (Cq),
156.4 (Cq), 161.3 (COO); HRMS (ESI-Exactive-Orbitrap) calcd
for C20H21O2 [M þ H]þ 293.1536, found 293.1532.
2-(2,2-Dibromovinyl)-4-isopropyl-1-(methoxymethoxy)benzal-
dehyde (10): 1H NMR (400 MHz, CD3CN, 25 °C, TMS) δ 1.20
(d, 6 H, J=6.9 Hz), 2.84 (sept, 1 H, J=6.9 Hz), 3.42 (s, 3 H), 5.16
(s, 2 H), 7.03 (d, 1 H, J=8.4 Hz), 7.20 (dd, 1 H, J=2.4, 8.4 Hz),
7.50 (d, 1 H, J = 2.4), 7.63 (s, 1H); 13C NMR (100.6 MHz,
CD3CN, 25 °C, TMS) δ 24.1 (CH3), 33.9 (CH), 56.4 (CH3), 90.2
(CH2), 95.6 (CH), 115.5 (Cq), 127.9 (CH), 128.8 (CH), 134.7
(CH), 142.8 (Cq), 148.9 (q), 153.1 (Cq).
6-Isopropyl-4-(2,3-dimethlphenyl)-2H-cromen-2-one (4): tR =
9.22 min; 1H NMR (600 MHz, CDCl3, 25 °C, TMS) δ 1.16 (d, 3
H, J=7.0 Hz), 1.15 (d, 3 H, J=7.0 Hz), 2.05 (s, 3 H), 2.38 (s, 3 H),
2.84 (sept, 1 H, J=7.0 Hz), 6.29 (s, 1 H), 6.86 (d, 1 H, J=2.1 Hz),
7.03 (d, 1 H, J=7.6 Hz), 7.23 (t, 1 H, J=7.6 Hz), 7.29 (d, 1 H, J=
7.6 Hz), 7.33 (d, 1 H, J=8.5 Hz), 7.41 (dd, 1 H, J=2.1, 8.5 Hz);
13C NMR (150.8 MHz, CDCl3, 25 °C, TMS) δ 17.2 (CH3), 20.6
(CH3), 24.0 (CH3), 24.3 (CH3), 33.7 (CH), 115.8 (CH), 117.2
(CH), 119.6 (Cq), 124.7 (CH), 126.0 (CH), 126.5 (CH), 130.2
(CH), 130.8 (CH), 134.0 (Cq), 135.2 (Cq), 137.8 (Cq), 145.2 (Cq),
152.2 (Cq), 157.1 (Cq), 161.4 (COO); HRMS (ESI-FT-ICR)
calcd for C20H21O2 [M þ H]þ 293.1536, found 293.1528.
6-Isopropyl-4-(naphthalene-1-yl)-2H-cromen-2-one (5): tR =
8.75 min; 1H NMR (600 MHz, CDCl3, 25 °C, TMS) δ 1.03 (d,
3 H, J=7.0 Hz), 1.04 (d, 3 H, J=7.0 Hz), 2.70 (sept, 1 H, J=7.04
Hz), 6.48 (s, 1 H), 6.82 (d, 1 H, J=1.76 Hz), 7.36-7.62 (m, 7 H),
7.95 (d, 1 H, J=8.2 Hz), 8.01 (d, 1 H, J=8.2 Hz); 13C NMR
(150.8 MHz, CDCl3, 25 °C, TMS) δ 24.0 (CH3), 24.2 (CH3), 33.8
(CH), 117.1 (CH), 117.4 (CH), 120.0 (Cq), 125.2 (CH), 125.6
(CH), 125.8 (CH), 126.8 (2 CH), 127.1 (CH), 128.8 (CH), 130.1
(CH), 130.6 (CH), 131.2 (Cq), 133.2 (Cq), 133.8 (Cq), 145.3 (Cq),
152.4 (Cq), 155.6 (Cq), 161.3 (COO); HRMS (ESI-Exactive-
Orbitrap) calcd for C22H19O2 [M þ H]þ 315.1380, found
315.1373.
Methyl 3-(5-isopropyl-2-(methoxymethoxy)phenyl)propiolate
1
(11): H NMR (400 MHz, CD3CN, 25 °C, TMS) δ 1.18 (d, 6
H, J=7.0 Hz), 2.85 (sept, 1 H, J=7.0 Hz), 3.44 (s, 3 H), 3.78 (s, 3
H), 5.23 (s, 2 H), 7.10 (d, 1 H, J=8.8 Hz), 7.33 (dd, 1 H, J=2.3,
8.8 Hz), 7.41 (d, 1 H, J = 2.3 Hz); 13C NMR (150.8 MHz,
CD3CN, 25 °C, TMS) δ 23.9 (CH3), 33.7 (CH), 53.3 (CH3), 56.5
(CH2), 84.0 (CH), 84.4 (CH), 95.8 (CH3), 110.0 (Cq), 116.0 (C),
131.7 (CH), 133.1 (CH), 143.5 (Cq), 158.2 (COO); HRMS (EI)
calcd for C15H18O4 262.1205, found 262.1208
4-Bromo-6-isopropyl-2H-cromen-2-one (12). Compound 12
was prepared following a procedure described in ref 22: 1H
NMR (600 MHz, CDCl3, 25 °C TMS) δ 1.27 (d, 6 H, J=7.0 Hz),
2.99 (sept, 1 H, J=7.0 Hz), 6.79 (s, 1 H), 7.22 (d, 1 H, J=8.5 Hz),
7.43 (dd, 1 H, J=8.5, 1.8 Hz), 7.61 (d, 2 H, J=1.8 Hz); 13C NMR
(150.8 MHz, CDCl3, 25 °C TMS) δ 24.2 (2 CH3), 33.9 (CH),
117.1 (CH), 118.78 (Cq), 119.5 (CH), 125.5 (CH), 131.9 (CH),
141.9 (Cq), 146.1 (Cq), 151.0 (Cq), 159.1 (COO); HRMS (EI)
calcd for C12H11O2Br 265.9942, found 265.9947.
General Procedure for Compounds 1-6. To a solution of
4-bromo-6-isopropyl-2H-cromen-2-one (12) (0.053 g, 0.2 mmol,
in 2 mL of benzene) were added K2CO3 (2 M solution, 1.0 mL),
the appropriate boronic acid (0.5 mmol, suspension in 2 mL of
THF), and Pd(PPh3)4 (0.046 g, 0.04 mmol) at room tempera-
ture. The stirred solution was refluxed for 2-3 h, the reaction
being monitored by GC-MS. After cooling to room tempera-
ture, Et2O and H2O were added and the extracted organic layer
was dried (Na2SO4) and evaporated. The crude products were
purified by chromatography on silica gel (petroleum ether/Et2O
10:1). Analytically pure samples of 1-6 were obtained by semi-
preparative HPLC on a C18 column (Luna C18(2) 5 μm, 250 ꢀ
10 mm, 5 mL/min, ACN/H2O 90/10 v/v). All the compounds are
colorless oils.
6-Isopropyl-4-(2-isopropylphenyl)-2H-cromen-2-one (6): tR =
10.93 min; 1H NMR (600 MHz, CD3CN, 25 °C, TMS) δ 1.107
(d, 3 H, J=6.9 Hz), 1.123 (d, 3H, J=6.9 Hz), 1.125 (d, 3 H, J=
6.9 Hz), 1.144 (d, 3H, J=6.9 Hz), 2.74 (sept, 1 H, J=6.9 Hz),
2.85 (sept, 1 H, J=6.9 Hz), 6.29 (s, 1 H), 6.84 (d, 1 H, J=2.3 Hz),
7.18-7.19 (m, 1 H), 7.33-7.36 (m, 2 H), 7.50-7.56 (m, 3 H); 13
C
NMR (150.8 MHz, CD3CN, 25 °C, TMS) δ 22.6 (CH3), 23.2
(CH3), 23.5 (CH3), 24.5 (CH3), 30.6 (CH), 33.5(CH), 116.1
(CH), 116.9 (CH), 120.1 (Cq), 124.4 (CH), 126.1 (CH), 126.3
(CH), 128.6 (CH), 129.8 (CH), 130.7 (CH), 133.9 (Cq), 145.2
(Cq), 146.7 (Cq), 152.2 (Cq), 156.2 (Cq), 160.6 (COO); HRMS
(ESI-Exactive-Orbitrap) calcd for C21H23O2 [M þ H]þ
307.1693, found 307.1684.
6-Isopropyl-4-(m-tolyl)-2H-cromen-2-one (1): tR =8.76 min;
1H NMR (600 MHz, CDCl3, 25 °C, TMS) δ 1.21 (d, 6 H, J=7.0
(22) Munt, S. P.; Thomas, E. J. Chem. Commun. 1989, 480–482.
J. Org. Chem. Vol. 75, No. 17, 2010 5931

Lunazzi et al.
JOCArticle
6-Isopropyl-4-(2-methylnaphthalene-1-yl)-2H-cromen-2-one (7).
To a solution of 2-methylnaphthyllithium, obtained at -78 °C by
the dropwise addition of butyllithium (10 mL of a 1.6 M solution
in hexanes) to 1-bromo-2-methylnaphthalene (15 mmol in 40 mL
of dry THF), was added B(OMe)3 (15 mmol) dropwise.19 A1.0mL
sample of the resulting 0.5 M solution of dimethyl (2-methyl-
naphthalen-1-yl)boronate was then used in the coupling reaction
with 4-bromo-6-isopropyl-2H-cromen-2-one (12) (0.2 mmol) and
Pd(PPh3)4 (0.046 g, 0.04 mmol), following the same procedure
as above. An analytically pure sample of 7 as a colorless oil was
obtained by semipreparative HPLC on a C18 column (Luna
C18(2) 5 μm, 250 ꢀ 10 mm, 5 mL/min, ACN/H2O 90/10 v/v): tR=
9.36 min; 1H NMR (600 MHz, CD3CN, 25 °C, TMS) δ 0.99 (d, 3
H, J=7.0 Hz), 1.01 (d, 3 H, J=7.0 Hz), 2.28 (s, 3 H), 2.70 (sept, 1 H,
J=7.0 Hz), 6.36 (s, 1 H), 6.62-6.63 (m, 1 H), 7.38-7.43 (m, 2 H),
7.48-7.57 (m, 4 H), 7.94-7.99 (m, 2 H); 13C NMR (150.8 MHz,
CD3CN, 25 °C, TMS) δ 19.6 (CH3), 23.2 (CH3), 23.3 (CH3), 33.3
(CH), 117.1 (CH), 117.6 (CH), 119.6 (Cq), 124.1 (CH), 125.1 (CH),
125.7 (CH), 126.9 (CH), 128.3 (CH), 128.8 (CH), 129.1 (CH),
130.6 (CH), 130.7 (Cq), 131.6 (Cq), 132.1 (Cq), 133.8 (Cq), 145.5
(Cq), 152.7 (Cq), 154.6 (Cq), 160.7 (COO); HRMS (ESI-FT-ICR)
calcd for C23H21O2 [M þ H]þ 329.1536, found 329.1528.
(rmsd <0.001). Errors associated to the evaluated rate constants
were estimated at less than 2%.
NMR Spectroscopy. The ambient-temperature NMR spectra
were obtained at 600 or 400 MHz for 1H and at 150.8 or 100.6
MHz for 13C. The assignments of the 1H and 13C signals were
obtained by bidimensional experiments (edited-gHSQC25 and
gHMBC26 sequences). The variable-temperature spectra27 were
recorded at 600 MHz for 1H and 150.8 MHz for 13C. Tempera-
ture calibrations were performed before the experiments, using a
Cu/Ni thermocouple immersed in a dummy sample tube filled
with 1,1,2,2-tetrachloroethane, and under conditions as nearly
identical as possible. The uncertainty in the temperatures was
estimated from the calibration curve to be (1 °C. The line shape
simulations were performed by means of a PC version of the
QCPE program DNMR 6 no. 633, Indiana University, Bloo-
mington, IN.
Calculations. Geometry optimizations were carried out at the
B3LYP/6-31G(d)28 level by means of the Gaussian 03 series of
programs:10 the standard Berny algorithm in redundant internal
coordinates and default criteria of convergence were employed.
The computed energies reported in Table 1 represent total
electronic energies. In general, these give the best fit with experi-
mental DNMR data.29 Therefore, the computed numbers have
not been corrected for zero-point energy contributions or other
thermodynamic parameters. This avoids artifacts that might
result from the inevitably ambiguous choice of an adequate
reference temperature, from empirical scaling factors tuned for a
better matching of experimental and theoretical numbers30 and
from the treatment of low-frequency vibration as harmonic
oscillators. This is particularly important in the present case,
where many calculated frequencies fall below the 500-600 cm-1
range.31 Full thermochemistry-corrected data are reported in
the Supporting Information. Harmonic vibrational frequencies
were calculated for all the stationary points. For each opti-
mized ground state the frequency analysis showed the absence of
imaginary frequencies, whereas each transition state showed a
single imaginary frequency. Visual inspection of the correspond-
ing normal mode32 was used to confirm that the correct transition
state had been found. TD-DFT calculations were performed at
the B3LYP/6-311þþG(2d,p)//B3LYP/6-31G(d) level.33 Rota-
tional strength were calculated in both length and velocity
representation. The resulting values are very similar, therefore
the errors due to basis set incompleteness are very small.34 The
ECD spectra were obtained by applying a 0.5 eV Gaussian
shaped line width.32 To cover the 170-400 nm range, 70 transi-
tions were calculated for each conformation.
HPLC and CD Spectra. Dynamic HPLC chromatograms were
obtained with use of a temperature-controlled system. DHPLC
chromatograms of 4 and 5 were obtained with a Daicel Chiralcel
AD-H (98:2 hexane/iPr-OH) and a Phenomenex LUX amilose-2
(65:35 hexane/iPr-OH), respectively. Separation of the two atro-
pisomers of 6 was achieved at þ25 °C on a Phenomenex LUX
amilose-2 250 ꢀ 4.6 mm column, at a flow rate of 1.0 mL/min,
using hexane/iPr-OH 95:5 as eluent. Separation of the two atrop-
isomers of 7 was achieved at þ25 °C on a Daicel Chiralcel OD-H
250 ꢀ 4.6 mm column, at a flow rate of 1.0 mL/min, using hexane/
iPr-OH 70:30 as eluent. To have a sufficient amount to record the
CD spectra, 10 injections (50 μg each) were collected. UV detec-
tion was fixed at 254 nm. UV absorption spectra were recorded at
þ25 °C in hexane on the racemic mixtures, in the 200-400 nm
spectral region. Maximum molar absorption coefficients were
recorded at 209 nm for 6 (ε = 12 150) and 226 nm for 7 (ε =
54 550). ECD spectra were recorded at þ24 °C using the collected
HPLC fractions (hexane/iPr-OH 95:5) in the case of 6, whereas the
spectra of 7 were recorded in acetonitrile at þ24 °C. The same path
length of 0.2 cm was used in both cases, and spectra were recorded
in the range 200-400 nm for 6 and 185-400 for 7, respectively;
reported Δε values are expressed as L mol-1 cm-1
.
Simulation of Dynamic Chromatograms. Simulations of vari-
able-temperature experimental chromatograms of 4-5 were
performed by using the homemade computer program Auto-
DHPLCy2k,23 which implements both stochastic and theoretical
plate models according to mathematical equations and proce-
dures described within.24 The involved algorithms may take into
account all types of first-order interconversions, including there-
fore the case of enantiomerizations, as well as the chance to
reproduce tailing effects. Dynamic chromatograms relevant to
the enantiomerization process of compound 3 were simulated by
the stochastic model, while those relevant to compound 6 were
simulated by the theoretical plate model. In both cases tailing
effects were taken into account. All line shape analyses were
carried out by performing simplex optimization of both chro-
matographic and kinetic parameters, until obtaining the best
agreement between experimental and simulated dynamic profiles
(minimization of the root-mean-square differences, rmsd, be-
tween the compared chromatograms). Simulations were auto-
matically stopped upon achievement of rmsd convergence
Acknowledgment. L.L. and A.M. received financial sup-
port from the University of Bologna (RFO) and from
MIUR, Rome (PRIN national project “Stereoselection in
Organic Synthesis, Methodologies and Applications”).
(25) Bradley, S. A.; Krishnamurthy, K. Magn. Reson. Chem. 2005, 43,
117–123. Willker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W. Magn.
Reson. Chem. 1993, 31, 287–292.
(26) Hurd, R. E.; John, B. K. J. Magn. Reson. 1991, 91, 648–653.
(27) For a recent review see: Casarini, D.; Lunazzi, L.; Mazzanti, A.
Eur. J. Org. Chem. 2010, 2035–2056.
(28) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. Lee, C.; Yang, W.;
Parr, R. G. Phys. Rev. B 1988, 37, 785–789. Stephens, P. J.; Devlin, F. J.;
Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623–11627.
(29) Ayala, P. Y.; Schlegel, H. B. J. Chem. Phys. 1998, 108, 2314–2325.
(30) Tormena, C. F.; Rittner, R.; Abraham, R. J.; Basso, E. A.; Fiorin,
B. C. J. Phys. Org. Chem. 2004, 17, 42–48.
(31) Wong, M. W. Chem. Phys. Lett. 1996, 256, 391–399.
(32) Gaussview 4.1.2, Semichem Inc., 2006.
(33) The use of a moderate basis set is dictated by the molecular size and
by the need of limiting the computational time (about 20-24 h on a 8-core
server).
(23) Cirilli, R.; Costi, R.; Di Santo, R.; La Torre, F.; Pierini, M.; Siani, G.
Anal. Chem. 2009, 81, 3560–3570.
(24) (a) Jung, M. QCPE Bull. 1992, 12, 52. (b) Trapp, O.; Schurig, V.
Comput. Chem. 2001, 25, 187–195.
(34) Stephens, P. J.; McCann, D. M.; Devlin, F. J.; Cheeseman, J. R.;
Frisch, M. J. J. Am. Chem. Soc. 2004, 126, 7514–7521.
5932 J. Org. Chem. Vol. 75, No. 17, 2010

Lunazzi et al.
JOCArticle
Dr. G. Bianco, University of Basilicata, Potenza is gratefully
acknowledged for the acquisition of some HRMS mass
spectra.
ment, computed components of the ECD spectrum of 6, DFT
computed structures of 1 and 7, variable-temperature HPLC
traces of 5, kinetics of the enantiomerization of 6, 1H and 13
C
NMR spectra and computational data of 1-7. This material
is available free of charge via the Internet at http://pubs.acs.
org.
Supporting Information Available: Variable-temperature
NMR spectra of 1, NMR spectrum of 2 in a chiral environ-
J. Org. Chem. Vol. 75, No. 17, 2010 5933