Highly stereoselective double (R)-phenylglycinol-induced cyclocondensation reactions of symmetric aryl bis(oxoacids)

Article abstract of DOI:10.1039/c0ob00970a

The double cyclocondensation of symmetric pyridyl bis(oxoacids) 2b and 3b with (R)-phenylglycinol stereoselectively gave access to bis-phenylglycinol- derived oxazolopyrrolidine 9 and oxazolopiperidone 10, respectively. Application of the stereocontrolled

Full text of DOI:10.1039/c0ob00970a

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PAPER
Highly stereoselective double (R)-phenylglycinol-induced cyclocondensation
reactions of symmetric aryl bis(oxoacids)†‡
Mercedes Amat,*a Carlos Arro´niz,a Elies Molins,b Carmen Escolano*a and Joan Boscha
Received 2nd November 2010, Accepted 22nd December 2010
DOI: 10.1039/c0ob00970a
The double cyclocondensation of symmetric pyridyl bis(oxoacids) 2b and 3b with (R)-phenylglycinol
stereoselectively gave access to bis-phenylglycinol-derived oxazolopyrrolidine 9 and oxazolopiperidone
10, respectively. Application of the stereocontrolled cyclocondensation reaction to phenyl bis-g-oxoacid
4b provided 11, which was converted to the corresponding enantiopure di(pyrrolidinyl)benzene 22. The
absolute configuration of the new stereogenic centers generated in the key cyclocondenstion step was
unambiguously established by X-ray crystallographic analysis.
Introduction
Nitrogen-containing heterocycles, including pyrrolidines and
piperidines, are found in a myriad of natural products and
biologically active compounds. For this reason, synthetic chemists
continue to be interested in the construction and functionalization
of these heterocyclic cores.1
In this context, the synthetic potential of phenylglycinol-derived
oxazolopyrrolidone and oxazolopiperidone lactams as chiral
synthons has been demonstrated.2 They have been used in the
Scheme 1 Synthetic strategy for the enantioselective synthesis of satu-
rated nitrogen heterocycles.
enantioselective synthesis of a great structural variety of complex
alkaloids and bioactive compounds embodying a pyrrolidine or a
piperidine moiety with different substitution patterns.
These lactams are readily available in both enantiomeric series
by a cyclocondensation reaction of the (R)- or (S)-phenylglycinol
with g- or d-oxoacid derivatives (Scheme 1).
Although this key reaction has received considerable attention
over the years from several research groups,3 to the best of our
knowledge there are no references in the literature to double
aminoalcohol-induced cyclocondensation reactions.
In this paper, we report cyclocondensation reactions of aryl
bis(oxoacid) derivatives with (R)-phenylglycinol and the subse-
quent removal of the chiral auxiliary to gain access to enantiopure
aryl bis-substituted nitrogen heterocycles (Scheme 2).
aLaboratory of Organic Chemistry, Faculty of Pharmacy, and Institute
of Biomedicine (IBUB), 08028-Barcelona, Spain. E-mail: amat@ub.edu,
cescolano@ub.edu
Scheme 2 General strategy.
bInstitut de Cie`ncia de Materials de Barcelona (CSIC), Campus UAB,
08193-Cerdanyola, Spain. E-mail: elies@icmab.es
† Dedicated to Professor Pelayo Camps on the occasion of his 65th
Results and discussion
anniversary.
Synthesis of the starting aryl oxoacid and bis(oxoacid) derivatives
1–4
‡ Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra of new products 1–7 and 9–22. Cartesian coordinates
and total energies for compounds 8 and 8-stereoisomer. CCDC reference
numbers 798251–798255. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0ob00970a
Ketoester 1a4 (Scheme 3) was prepared in 50% overall
yield by a Negishi5 coupling of picolinoyl chloride6 and
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Scheme 4 Reagents and conditions: (a) (R)-phenylglycinol, toluene, rfx,
7–24 h, 78%, 7; 95%, 8; 47%, 9; 57%, 10; 61%, 11.
Stereochemical outcome of the cyclocondensation reactions
Scheme
3-ethoxy-3-oxopropylzinc bromide, Pd(PPh3)4, THF,
1a; (iii) NaOH, MeOH, overnight, rt, 86%, 1b; (b) (i)
3-ethoxy-3-oxopropylzinc bromide, [Pd(PPh3)4], THF, 4 h, rt, 60%, 2a;
39%, 4a; 4-ethoxy-4-oxobutylzinc bromide, 68%, 3a; (ii) 4 N NaOH,
MeOH, overnight, rt, 98%, 2b; 98%, 3b; (c) Me2NH·HCl, CH2O, conc
HCl, EtOH, rfx, 15 h, 86%, 5; (d) KCN, H2O–AcOH, 80 ◦C, 5 h, 90%, 6;
(e) conc HCl/AcOH, rfx, 3 h, 69%, 4b.
3
Reagents and conditions: (a) (i) (COCl)2, rt; (ii)
4
h, rt, 50%,
The relationship between the aryl substituent at the angular
position and the C-3 phenyl substituent in the (R)-phenylglycinol
moiety in lactams 7–11 was always cis.
4
N
Notably, the NMR spectra of aryl bis-cyclocondensed products
9 and 11 coincided with those of the mono-cyclocondensed
analogues 7 and 8, thus indicating that the stereochemical outcome
in both groups of compounds was the same. Consequently, 9, 10
and 11 present a C2 symmetry axis. In the 13C NMR spectrum of
oxazolopiperidone 10, the C-2 and the hemiaminal C are shielded
as compared with oxazolopyrrolidones 7, 8, 9 and 11 (3–5 and 6–
7 ppm, respectively; Table 1). Having a pyridyl or a phenyl group as
linker between both oxazolopyrrolidone nuclei does not represent
any significant change in the chemical shift or multiplicity.
Table 1 shows diagnostic signals in the 1H and 13C NMR spectra
of compounds 7–11 (H-2 and C-2, H-3 and C-3, and hemiaminal
quaternary C).
3-ethoxy-3-oxopropylzinc bromide in the presence of [Pd(PPh3)4]
as the catalyst.7 A subsequent saponification led to acid 1b.
The Negishi reaction was also used for the preparation of
symmetric bis(oxoacids) 2b and 3b. Thus, reaction of the commer-
cially available 2,6-pyridinedicarbonyl dichloride with the required
zinc bromide derivative, followed by alkaline hydrolysis of the
intermediate oxoesters 2a and 3a, led to 2b and 3b in 59% and
67% overall yield, respectively.
A
similar reaction from isophthaloyl dichloride gave
The configuration of the stereogenic carbon atoms generated
in the above cyclocondensation reactions was unambigously
established by X-ray crystallographic analysis of bis-lactams 9,
10, and 11 (Fig. 1).
Thestereochemicaloutcome ofthese reactions canbeaccounted
for by considering that the two initially formed oxazolidines A
and B are in equilibrium through the corresponding imine. The
subsequent irreversible lactamization occurs preferentially from
the oxazolidine that allows a less hindered approach of the carboxy
group to the nitrogen atom, that is, anti with respect to both phenyl
groups (Fig. 2).11
bis(oxoester) 4a in low yield, probably as a consequence of the
hygroscopicity of the starting material. However, the correspond-
ing diacid 4b was obtained in 53% overall yield using a three
step procedure: a Mannich reaction between 1,3-diacetylbenzene,
dimethylamine hydrochloride and paraformaldehyde, followed by
treatment of the resulting hydrochloride salt 5 with potassium
cyanide and acid hydrolysis of dinitrile 6.8 This sequence was
successfully applied on a multigram scale.
Cyclocondensation reactions of oxoacids 1b–4b with
(R)-phenylglycinol
Notably, theoretical calculations using ab initio [HF/6-31G(d)]
and DFT [B3LYP/6-31G(d)] methods predicted that 8 is 2.6 and
2.3 kcal mol-1, respectively, more stable than its stereoisomer with
the two phenyl rings in a trans relationship.
Cyclocondensation of 1b with (R)-phenylglycinol took place in
good yield and excellent stereoselectivity to give the bicyclic lactam
7, which bears a 2-pyridyl substituent at the angular position
(Scheme 4).9 Similarly, cyclocondensation of the commercially
available 3-benzoylpropionic acid with (R)-phenylglycinol gave
lactam 8 in 95% yield.10 Gratifyingly, extrapolation of the reaction
conditions to bis-g-oxoacids 2b and 4b, and to bis-d-oxoacid 3b,
led to the corresponding aryl bis-lactams 9, 11 and 10 in acceptable
yields. The reaction was highly stereoselective since only one
diastereoisomer was produced.
Removal of the chiral auxiliary
The removal of the chiral auxiliary from phenylglycinol-derived
oxazolopyrrolidones involves two steps: the reductive cleavage of
the C–O bond of the oxazolidine ring, and the removal of the
2-hydroxy-1-phenylethyl substituent (Scheme 5).
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Table 1 1H and 13C NMR representative signals of lactams 7–11
C-2 (ppm) H-2 (ppm, J Hz)
C-3 (ppm) H-3 (ppm, J Hz)
Hemiaminal C (ppm)
102.4
7
74.7
58.4
5.26 (t, 7.7)
3.99 (dd, 8.8, 7.7)
4.73 (dd, 8.8, 8.0)
75.1
9
57.8
5.26 (t, 7.5)
102.2
95.7
4.03 (dd, 8.8, 7.5)
4.77 (dd, 8.8, 8.0)
69.8
3.84 (dd, 9.1, 8.2)
4.48 (dd, 9.1, 8.2)
73.6
10
8
59.6
5.36 (t, 8.2)
59.1
5.14 (t, 8.0)
102.7
102.6
3.87 (t, 8.8)
4.64 (dd, 8.8, 8.0)
72.6
11
58.7
5.14 (t, 8.0)
3.71 (t, 8.9)
4.56 (dd, 8.9, 8.0)
Fig. 1 ORTEP view of molecular structures of 9, 10 and 11.
Scheme 5 Removal of the chiral auxiliary.
Scheme 6 Reagents and conditions: (a) Et3SiH, TiCl4, CH2Cl2, rfx, 20 h,
71%, 12; (b) SOCl2, THF, 15 min 0 ◦C, rfx, 1.5 h, 93%, 13; (c) DMF, DBU,
85 ◦C, 5 h, 70%, 14; (d) 5 M H2SO4, Et2O, rfx, 20 h, 96%, 15; (e) LiAlH4,
THF, rt, 3 days, 81%, 16.
First of all, model studies were carried out upon the sim-
ple oxazolopyrrolidone derivative 8 (Scheme 6). Titanium(IV)
chloride/triethylsilane12 mediated the ring opening of 8 and the
reduction of the resulting N-acyliminium intermediate, stereose-
lectively providing lactam 12 in 71% yield, with retention of the
configuration at C-5.
Attempts to remove the 2-hydroxy-1-phenylethyl moiety of 12
with sodium in liquid ammonia met with failure; the cleavage
of the endocyclic benzylic bond occurred instead affording the
corresponding linear amide 12a.13 However, the chiral auxiliary
was successfully removed by an alternative procedure. Thus,
conversion of the hydroxyl group of lactam 12 to its corresponding
chloride 13 (93%) and subsequent b-elimination by treatment with
DBU in DMF provided enamide 14 in 70% yield. Hydrolysis of the
enamide was easily accomplished with H2SO4 to afford lactam 15
in nearly quantitative yield.14 Finally, reduction of 15 with LiAlH4
gave (S)-phenylpyrrolidine 16 in 81% yield.
The above procedure was then applied to bislactam 11
(Scheme 7). The chemoselective reductive opening of the oxazoli-
dine rings of 11 by Et3SiH and TiCl4 led to a 2 : 1 mixture of 17 and
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Scheme 7 Reagents and conditions: (a) Et3SiH, TiCl4, CH2Cl2, rfx, 43 h,
60%, 17, 30%, 18; (b) Et3SiH, TiCl4, CH2Cl2, rfx, 24 h, 84%, 17; (c) SOCl2,
THF, 15 min 0 ◦C, rfx, 2 h; (d) DMF, DBU, 85 ◦C, 5 h, 50% (from 17), 20;
(e) 5 M H2SO4, Et2O, rfx, 5 h, 63%, 21; (f) LiAlH4, THF, rfx, 24 h, 74%,
22.
Fig. 2 Proposed mechanism for cyclocondensation reactions.
18 (90%). Attempts to exclusively prepare 17 using more drastic
reaction conditions did not work,15 but a subsequent treatment
of 18 under the same TiCl4/Et3SiH conditions led exclusively to
17. Transformation of the hydroxyl group into a chloride (19),
followed by elimination with DBU as the base led to bis-enamide
20 (50% overall yield). The hydrolysis of 20 was performed in the
best reaction conditions found for the model compound 14 (5 M
H2SO4/Et2O), leading to aryl bis-pyrrolidone 21 (63%). Finally,
the reduction of both amide groups gave the target enantiopure
di(pyrrolidinyl)benzene 22 in good yield (74%).
Fig. 3 ORTEP view of molecular structure of 18.
The stereochemistry of 18 and 21 was unequivocally confirmed
by X-ray crystallographic analysis, which made it evident that
the process occurs with retention of the configuration at the
pyrrolidone 5-position (Fig. 3 and 4).
A comparison of the 1H and 13C NMR spectra of compounds
12–16 and their bis analogues 17 and 19–22 showed basically the
same set of peaks, indicating the presence of a C2 symmetry axis
in the latter.
Fig. 4 ORTEP view of molecular structure of 21.
of the five crystal structures described in this article‡). The two
bicyclic lactams linked to the pyridine ring present opposed
twisting orientations resulting in approximate binary axes for both
independent molecules [t(N1–C2–C21–C22) = 59.2(8), t(N1–C6–
C61–C62 = 65.0(8), t(N1A–C2A–C21A–C22A) = 63.5(8), t(N1A–
C6A–C61A–C62A) = 59.1(8)◦]. Assuming R chiralities for the C26
and C66 (and C26a and C66a) centres, C21 and C61 (and C21a
and C61a) are also R centres.
Structural considerations
The structural attractiveness of aryl bis derivatives 9–11, 18 and
21 deserves a description on their molecular conformations and
crystal packings.
Compound 9 crystallizes as two independent molecules in
the monoclinic P21 space group (see Table 1 in the ESI for a
summary of the crystal data and structure refinement parameters
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Compound 10 also crystallizes as two independent molecules in
the orthorhombic P212121 space group but with a water molecule,
thus constituting a hemihydrate form. The overall conformation
and chiral centres are similar to those of compound 9 (t(N1–
C2–C21–C22) = 73.6(12), t(N1–C6–C61–C62 = 80.7(10), t(N1A–
C2A–C21A–C22A) = 77.2(12), t(N1A–C6A–C61A–C62A) =
80.4(11)◦). The water molecule bridges the two independent
molecules through the hydrogen bonds O1W–H1W ◊ ◊ ◊ O69i (i =
a capillary tube and are uncorrected. Unless otherwise indicated,
NMR spectra were recorded in CDCl3 at 300 or 400 MHz (1H)
and 75.4 or 100.6 MHz (13C), and chemical shifts are reported in
d values downfield from TMS or relative to residual chloroform
(7.26 ppm, 77.0 ppm) as an internal standard. Data are reported
in the following manner: chemical shift, multiplicity, coupling
constant (J) in hertz (Hz), integrated intensity. Multiplicities are
reported using the following abbreviations: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; br s, broad signal.
˚
-x + 1/2, -y + 1, z + 1/2; d(O ◊ ◊ ◊ O) = 2.921(15) A) and O1W–
˚
H2W ◊ ◊ ◊ O25A (d(O ◊ ◊ ◊ O) = 2.849(17) A).
Compound 11 crystallizes in the tetragonal P41212 space group,
the asymmetric unit being a half a molecule, that becomes
complete through a binary axis. The change of pyridine to benzene
as a bridging group increases the twisting of the substituent bicyclic
lactam (t(C2–1–C11–C12) = 99.4(3)◦). Chiral centres are as in 9
and 10.
Compound 18 crystallizes in the orthorhombic P212121 space
group. In this case, the difference in the benzene substituent groups
is also apparent in their different spatial orientation (t(C2–C1–
C11–C12) = 62.8(5), t(C2–C3–C31–C32) = 110.9(5)◦). C16, C31
and C36 are R centres while C11 is an S centre. An intramolecular
hydrogen bond links the ethoxy group with a carbonyl (O18–
Ethyl c-oxo-2-pyridinebutanoate (1a)
Tetrakis(triphenylphosphine)palladium(0) (250 mg, 0.18 mmol)
was added at r.t. to a solution of 3-ethoxy-3-oxopropylzinc
bromide (36 mL of a 0.5 M solution in THF, 18 mmol) in
THF (40 mL). Then, a solution of picolinoyl chloride6 (2.5 g,
18 mmol) in THF (40 mL) was added over a period of 5 min, and
stirring was continued for 4 h at rt. The reaction was quenched
by the addition of saturated aqueous NH4Cl and extracted with
Et2O. The combined organic extracts were dried and concentrated,
and the resulting residue was chromatographed (4 : 1 hexane–
Et2O) to afford 1a (1.8 g, 50%) as a yellowish oil: IR (film) 1700,
1734, 2800–3000 cm-1; 1H NMR (CDCl3, 400 MHz) d 1.26 (t, J =
7.1 Hz, 3H, CH3), 2.76 (t, J = 6.7 Hz, 2H, CH2CO2), 3.56 (t, J =
6.7 Hz, 2H, CH2CO), 4.16 (q, J = 7.1 Hz, 2H, OCH2), 7.48 (ddd,
J = 7.8, 4.7, 1.2 Hz, 1H, H-5), 7.84 (td, J = 7.8, 1.7 Hz, 1H, H-4),
8.05 (dt, J = 7.8, 1.2 Hz, 1H, H-3), 8.70 (dm, J = 4.7 Hz, 1H,
H-6); 13C NMR (CDCl3, 100.6 MHz) d 14.2 (CH3), 28.3 (CH2,
CH2CO2), 32.8 (CH2, CH2CO), 60.5 (CH2, OCH2), 121.7 (CH,
C-3), 127.2 (CH, C-5), 136.8 (CH, C-4), 148.9 (CH, C-6), 153.0
(C, C-2), 172.8 (C, COO), 200.0 (C, CO); HRMS C11H14NO3 (M +
H+), 208.0968; found, 208.0971.
˚
H18 ◊ ◊ ◊ O14, d(O ◊ ◊ ◊ O) = 2.631(6) A).
Compound 21 crystallizes in the monoclinic P21 space group.
Here, the benzene substituent groups are similarly oriented (t(C1–
C6–C61–C65) = -103.1(6), t(C1–C2–C21–C25) = -105.7(7)◦) and
C21 and C61 centres have S chirality. The molecules pack in
infinite one-dimensional chains along [110] and [1–10] directions
through the N22–H22 . . . O63ii (ii = x - 1, y - 1, z; d(O ◊ ◊ ◊ O) =
iii
˚
˚
2.928(6) A) and N62–H62 ◊ ◊ ◊ O23 (iii = x + 1, y + 1, z; d(O ◊ ◊ ◊ O) =
2.952(6) A) hydrogen bonds.
Summary
c-Oxo-2-pyridinebutanoic acid (1b)
The bis-cyclocondensation reaction of (R)-phenylglycinol with
aryl bis(oxoacid) compounds 2b, 3b and 4b stereoselectively led
to aryl bis-bicyclic lactams 9, 10 and 11. The stereochemical
outcome of the cyclocondensation reactions has been rationalised
taking into account that irreversible lactamization occurs from cis-
diphenyl oxazolidine intermediate B. The absolute configuration
of 9, 10 and 11 was confirmed by X-ray crystallographic analysis.
Finally, efficientcleavageofthephenylethanolmoietyderivedfrom
phenylglycinol led to enantiopure di(pyrrolidinyl)benzene 22.
These new bicyclic heterocycles are attractive candidates for
organocatalysts or ligands in metal coordination chemistry.
A solution of oxoester 1a (1.5 g, 7.2 mmol) in MeOH (30 mL)
and 4 N aqueous NaOH (20 mL) was stirred at rt overnight. The
solvent was evaporated, and the resulting residue was dissolved in
H2O. The solution was acidified with 5 N aqueous HCl (pH = 3–4)
and extracted with EtOAc and CH2Cl2. The combined organic
extracts were dried and concentrated to give 1b (1.2 g, 86%) as a
1
white solid: IR (KBr) 1711, 2900–3100 cm-1; H NMR (CDCl3,
300 MHz) d 2.81 (t, J = 6.6 Hz, 2H, CH2CO2), 3.56 (t, J = 6.6 Hz,
2H, CH2CO), 7.49 (ddd, J = 7.7, 4.8, 1.1 Hz, 1H, H-5), 7.84 (td,
J = 7.7, 1.7 Hz, 1H, H-4), 8.05 (dt, J = 7.7, 1.1 Hz, 1H, H-3), 8.70
(ddd, J = 4.8, 1.7, 1.1 Hz, 1H, H-6); 13C NMR (CDCl3, 75.4 MHz)
d 28.0 (CH2, CH2COO), 32.7 (CH2, CH2CO), 121.9 (CH, C-3),
127.3 (CH, C-5), 136.9 (CH, C-4), 148.9 (CH, C-6), 152.8 (C, C-
2), 178.3 (C, CO2), 199.6 (C, CO); HRMS C9H10NO3 (M + H+),
180.0655; found, 180.0656.
Experimental
General
All non-aqueous reactions were performed under inert atmosphere
with dry, freshly distilled solvents using standard procedures.
Drying of organic extracts during the work-up of reactions was
performed over anhydrous Na2SO4 or MgSO4. Evaporation of
solvents was accomplished with a rotatory evaporator. Thin layer
chromatography was done on SiO2 (silica gel 60 F254), and the spots
were located by UV or 1% KMnO4 solution. Chromatography
refers to flash column chromatography and was carried out on SiO2
(silica gel 60, 230–400 mesh). Melting points were determined in
Diethyl c,c¢-dioxo-2,6-pyridinedibutanoate (2a)
Following the procedure described for the preparation of 1a,
tetrakis(triphenylphosphine)palladium(0) (850 mg, 0.74 mmol),
3-ethoxy-3-oxopropylzinc bromide (32 mL of a 0.5 M solution
in THF, 16 mmol), and a solution of 2,6-pyridinedicarbonyl
dichloride (1.5 g, 7.35 mmol) in THF (30 mL) afforded 2a (1.45 g,
60%) as a yellowish solid after column chromatography (9 : 1 to
7 : 3 hexane–EtOAc): IR (film) 1701, 1736 cm-1; 1H NMR (CDCl3,
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◦
300 MHz) d 1.28 (t, J = 7.0 Hz, 6H, CH3), 2.79 (t, J = 7.0 Hz, 4H,
CH2CO2), 3.63 (t, J = 7.0 Hz, 4H, CH2CO), 4.16 (q, J = 7.0 Hz,
4H, OCH2), 8.00 (dd, J = 8.0, 7.0 Hz, 1H, H-4), 8.21 (d, J = 8.0 Hz,
2H, H-3 and H-5); 13C NMR (CDCl3, 75.4 MHz) d 14.2 (2 CH3),
28.1 (2 CH2, 2 CH2CO2), 32.7 (2 CH2, 2 CH2CO), 60.6 (2 CH2, 2
OCH2), 125.0 (2 CH, C-3 and C-5), 138.0 (CH, C-4), 152.1 (2 C,
C-2 and C-6), 172.8 (2 C, 2 CO2), 199.2 (2 C, 2 CO); mp 78-80 ◦C
(EtOAc–hexane); MS-EI m/z 335 (M+, 46), 290 (100), 262 (83),
216 (64), 188 (75), 161 (43), 101 (40); HRMS C17H22NO6 (M +
H+), 336.1441; found, 336.1444. Anal. calcd for C17H21NO6: C,
60.89; H, 6.31; N, 4.18. Found: C, 60.86; H, 6.35; N, 4.11.
177.1 (2 C, 2 CO2), 202.0 (2 C, 2 CO); mp 126-127 C (EtOAc–
Et2O–MeOH); MS-EI m/z 307 (M+, 40), 279 (50), 248 (56), 230
(66), 193 (100), 175 (98), 55 (37); HRMS C15H18NO6 (M + H+),
1
308.1134; found, 308.1125. Anal. calcd for C15H17NO6· /4H2O: C,
57.78; H, 5.66; N, 4.49. Found: C, 57.85; H, 5.51; N, 4.47.
Diethyl d,d’-dioxo-1,3-benzenedibutanoate (4a)
Tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol)
was added to a solution of isophthaloyl dichloride (2.5 g,
12.3 mmol) in THF (60 mL). The mixture was heated at
60 ◦C, stirred over 5 min, and cooled to rt. Then, 3-ethoxy-
3-oxopropylzinc bromide (50 mL of a 0.5 M solution in THF,
25 mmol) was added, and stirring was continued for 5 h at rt.
The reaction was quenched by the addition of saturated aqueous
NH4Cl, and the aqueous solution was extracted with Et2O. The
combined organic extracts were dried and concentrated, and the
resulting residue was chromatographed (9 : 1 to 1 : 1 hexane–Et2O)
to afford 4a (1.6 g, 39%) as a yellowish oil: IR (film) 1687, 1732,
2983 cm-1; 1H NMR (CDCl3, 400 MHz) d 1.27 (t, J = 7.1 Hz, 6H,
CH3), 2.79 (t, J = 6.5 Hz, 4H, CH2CO2), 3.35 (t, J = 6.5 Hz, 4H,
CH2CO), 4.16 (q, J = 7.1 Hz, 4H, OCH2), 7.60 (t, J = 7.8 Hz,
1H, H-5), 8.19 (dd, J = 7.8, 1.7 Hz, 2H, H-4 and H-6), 8.58 (t,
J = 1.7 Hz, 1H, H-2); 13C NMR (CDCl3, 100.6 MHz) d 14.2 (2
CH3), 28.2 (2 CH2, CH2CO2), 33.5 (2 CH2, CH2CO), 60.7 (2 CH2,
OCH2), 127.5 (CH, Ar), 129.1 (CH, Ar), 132.3 (2 CH, Ar), 136.9
(2 C, Ar), 172.7 (2 C, CO2), 197.4 (2 C, CO). Anal. Calcd for
C18H22O6: C, 64.66; H, 6.63. Found: C, 64.36; H, 6.51.
c,c¢-Dioxo-2,6-pyridinedibutanoic acid (2b)
Following the procedure described for the preparation of 1b,
a solution of 2a (1.5 g, 4.48 mmol) in MeOH (20 mL) and
4 N aqueous NaOH (11 mL) afforded 2b (1.1 g, 98%) as
a yellowish solid: IR (film) 1702, 2900–3500 cm-1; 1H NMR
(CD3OD, 300 MHz) d 2.76 (t, J = 6.5 Hz, 4H, CH2CO2), 3.61
(t, J = 6.5 Hz, 4H, CH2CO), 8.11 (dd, J = 8.5, 6.6 Hz, 1H, H-4),
8.21 (dm, J = 8.5 Hz, 2H, H-3 and H-5); 13C NMR (CD3OD,
75.4 MHz) d 28.7 (2 CH2, CH2CO2), 33.7 (2 CH2, CH2CO), 125.8
(2 CH, C-3 and C-5), 139.6 (CH, C-4), 153.4 (2 C, C-2 and C-6),
176.6 (2 C, 2 CO2), 200.7 (2 C, 2 CO); MS-EI m/z 279 (M+, 5),
278 (35), 277 (100), 199 (16), 183 (17), 77 (18). Anal. calcd for
C13H13NO6: C, 55.91; H, 4.69; N, 5.02. Found: C, 56.35; H, 4.82;
N, 4.93.
Diethyl d,d’-dioxo-2,6-pyridinedipentanoate (3a)
1,3-Bis[1-oxo-3-(dimethylamino)propyl]benzene dihydrochloride
(5)
Following the procedure described for the preparation of 1a,
tetrakis(triphenylphosphine)palladium(0) (2 g, 1.7 mmol), 4-
ethoxy-4-oxobutylzinc bromide (100 mL of a 0.5 M solution
in THF, 50 mmol), and a solution of 2,6-pyridinedicarbonyl
dichloride (5 g, 24.5 mmol) in THF (100 mL) afforded 3a (6.1 g,
68%) as a yellowish oil after column chromatography (1 : 1 Et2O–
hexane): IR (film) 1698, 1731 cm-1; 1H NMR (CDCl3, 400 MHz)
d 1.26 (t, J = 7.5 Hz, 6H, CH3), 2.11 (m, 4H, H-3¢), 2.47 (t, J =
7.0 Hz, 4H, H-4¢), 3.34 (t, J = 7.0 Hz, 4H, H-2¢), 4.14 (q, J = 7.5 Hz,
4H, OCH2), 7.99 (tm, J = 7.8 Hz, 1H, H-4), 8.20 (d, J = 7.8 Hz,
2H, H-3 and H-5); 13C NMR (CDCl3, 100.6 MHz) d 14.2 (2 CH3),
19.2 (2 CH2, 2 C-3¢), 33.5 (2 CH2, 2 C-4¢), 36.6 (2 CH2, 2 C-2¢), 60.3
(2 CH2, 2 OCH2), 124.8 (2 CH, C-3 and C-5), 138.0 (CH, C-4),
152.3 (2 C, C-2 and C-6), 173.1 (2 C, 2 CO2), 200.4 (2 C, 2 CO);
MS-EI m/z 363 (M+, 37), 318 (100), 262 (69), 230 (81), 93 (43);
HRMS C19H26NO6 (M + H+), 364.1754; found, 364.1756. Anal.
A mixture of 1,3-diacetylbenzene (20 g, 124 mmol), paraformalde-
hyde (11 g, 370 mmol), dimethylamine hydrochloride (30 g,
370 mmol), and concentrated HCl (0.5 mL, 6 mmol) in absolute
EtOH (125 mL) was refluxed for 15 h. The mixture was poured into
dry acetone (200 mL), and the crude product was filtered affording
5 (37.2 g, 86%) as a white solid: IR (KBr) 1692, 2667 cm-1; H
1
NMR (D2O, 400 MHz) d 3.02 (s, 12H, CH3), 3.66 (t, J = 6.1 Hz,
4H, CH2CO), 3.77 (t, J = 6.1 Hz, 4H, CH2N), 7.78 (t, J = 7.8 Hz,
1H, H-5), 8.33 (dd, J = 7.8, 1.7 Hz, 2H, H-4 and H-6), 8.59 (t,
J = 1.7 Hz, 1H, H-2); 13C NMR (D2O, 100.6 MHz) d 33.2 (2
CH2, CH2CO), 43.0 (4 CH3), 52.7 (2 CH2, CH2N), 127.6 (CH,
Ar), 129.6 (CH, Ar), 133.5 (2 CH, Ar), 135.8 (2 C, Ar), 198.9 (2 C,
CO); HRMS C16H25N2O2 (M + H+), 277.1911; found, 277.1912.
1
calcd for C19H25NO6· /4H2O: C, 62.03; H, 6.99; N, 3.81. Found:
c,c¢-Dioxo-1,3-benzenedibutanenitrile (6)
C, 62.18; H, 7.12; N, 3.88.
A solution of KCN (15 g, 230 mmol) in H2O (50 mL) was added
dropwise to a solution of 5 (20 g, 57 mmol) in H2O (100 mL)
and AcOH (7 mL). The mixture was heated at 80 ◦C for 5 h. The
precipitate was filtered and washed with water to give 6 (12.4 g,
90%) as a dark brown solid: IR (film) 1691, 2250 cm-1; 1H NMR
(CDCl3, 400 MHz) d 2.82 (t, J = 7.1 Hz, 4H, CH2CN), 3.44 (t, J =
7.1 Hz, 4H, CH2CO), 7.67 (t, J = 7.8 Hz, 1H, H-5), 8.2 (dd, J =
d,d’-Dioxo-2,6-pyridinedipentanoic acid (3b)
Following the procedure described for the preparation of 1b, a
solution of 3a (6 g, 16.5 mmol) in MeOH (70 mL) and 4 N aqueous
NaOH (83 mL) afforded 3b (5 g, 98%) as a white solid: IR (film)
1706, 1708, 2500-3200 cm-1; 1H NMR (CD3OD, 400 MHz) d 2.04
(m, J = 7.0 Hz, 4H, H-3¢), 2.44 (t, J = 7.0 Hz, 4H, H-4¢), 3.36 (t, J =
7.0 Hz, 4H, H-2¢), 8.09 (dd, J = 8.0, 6.8 Hz, 1H, H-4), 8.18 (dm, J =
8.0 Hz, 2H, H-3 and H-5); 13C NMR (CD3OD, 100.6 MHz) d 20.5
(2 CH2, 2 C-3¢), 34.2 (2 CH2, 2 C-4¢), 37.7 (2 CH2, 2 C-1¢), 125.8
(2 CH, C-3 and C-5), 139.7 (CH, C-4), 153.8 (2 C, C-2 and C-6),
7.8, 1.7 Hz, 2H, H-4 and H-6), 8.53 (t, J = 1.7 Hz, 1H, H-2); 13
C
NMR (CDCl3, 100.6 MHz) d 11.8 (2 CH2, CH2CN), 34.5 (2 CH2,
CH2CO), 118.9 (2 CN), 127.4 (CH, Ar), 129.7 (CH, Ar), 132.8 (2
CH, Ar), 136.1 (2 C, Ar), 194.5 (2 C, CO); HRMS C14H12N2NaO2
(M + Na+), 263.0791; found, 263.0793.
2180 | Org. Biomol. Chem., 2011, 9, 2175–2184
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c,c¢-Dioxo-1,3-benzenedibutanoic acid (4b)
CH, Ph), 128.3 (4 CH, Ph), 137.8 (CH, C-4¢), 139.1 (2 C, i-Ph),
161.2 (2 C, C-2¢ and C-6¢), 178.6 (2 C, C-5); [a]2D2 -291.5 (c 0.95,
MeOH); mp 178–182 ◦C (EtOAc–hexane); MS-EI m/z 481 (M+,
22), 281 (16), 202 (100), 120 (15); HRMS C29H28N3O4 (M + H+),
482.2074; found, 482.2072. Anal. Calcd for C29H27N3O4 1/3H2O:
C, 71.45; H, 5.72; N, 8.62. Found: C, 71.46; H, 5.72; N, 8.55.
A suspension of 6 (12 g, 50 mmol) in a solution of 1 : 1 conc AcOH–
HCl (125 mL) was refluxed for 3 h. The solution was concentrated
to dryness, and the resulting black solid was taken up with 4 N
aqueous NaOH and extracted with EtOAc. The aqueous solution
was acidified to pH = 1 with 5 N aqueous HCl and extracted
with EtOAc. The organic extracts were dried and concentrated to
afford 4b (9.6 g, 69%) as a brown solid: IR (KBr) 1685, 2800–
3200 cm-1; 1H NMR (DMSO, 400 MHz) d 2.61 (t, J = 7.8 Hz, 4H,
CH2CO2), 3.33 (t, J = 7.8 Hz, 4H, CH2CO), 7.7 (t, J = 7.8 Hz,
1H, H-5), 8.23 (dd, J = 7.8, 1.7 Hz, 2H, H-4 and H-6), 8.48 (t,
J = 1.7 Hz, 1H, H-2), 12.19 (br s, 2H, CO2H); 13C NMR (DMSO,
100.6 MHz) d 27.9 (2 CH2, CH2CO2), 33.3 (2 CH2, CH2CO), 126.9
(CH, Ar), 129.4 (CH, Ar), 132.2 (2 CH, Ar), 136.8 (2 C, Ar), 173.8
(2 C, CO2), 198.2 (2 C, CO); HRMS C14H13O6 (M-H+), 277.0718;
found, 277.0718.
(3R,3¢R,8aR,8a’R)-2,6-Bis(5-oxo-3-phenyl-2,3,6,7,8,8a-
hexahydro-5H-oxazolo[3,2-a]pyrid-8a-yl)pyridine (10)
Following the procedure described for the preparation of 7, from
(R)-phenylglycinol (550 mg, 4 mmol) and 3b (550 mg, 1.79 mmol)
in toluene (25 mL) for 18 h, lactam 10 (520 mg, 57%) was obtained
as a white solid after flash chromatography (SiO2 previously
washed with 8 : 2 Et3N–EtOAc; gradient from 7 : 3 EtOAc–hexane
1
to EtOAc): IR (film) 1651 cm-1; H NMR (CDCl3, 400 MHz,
COSY, HSQC) d 1.39 (m, 2H, H-7), 1.53 (m, 2H, H-7), 1.92 (td,
J = 13.0, 4.3 Hz, 2H, H-8), 2.16 (dt, J = 13.0, 4.3 Hz, 2H, H-8),
2.33 (ddd, J = 18.0, 9.6, 8.0 Hz, 2H, H-6), 2.49 (ddd, J = 18.0, 6.8,
1.5 Hz, 2H, H-6), 3.84 (dd, J = 9.1, 8.2 Hz, 2H, H-2), 4.48 (dd,
J = 9.1, 8.2 Hz, 2H, H-2), 5.36 (t, J = 8.2 Hz, 2H, H-3), 6.81-6.88
(m, 4H, PhH), 7.03-7.12 (m, 6H, PhH), 7.60 (d, J = 8.0 Hz, 2H,
H-3¢ and H-5¢), 7.78 (t, J = 8.0 Hz, 1H, H-4¢); 13C NMR (CDCl3,
100.6 MHz) d 15.3 (2 CH2, C-7), 30.8 (2 CH2, C-6), 35.2 (2 CH2,
C-8), 59.6 (2 CH, C-3), 69.8 (2 CH2, C-2), 95.7 (2 C, C-8a), 119.3
(2 CH, C-3¢ and C-5¢), 127.3 (2 CH, Ph), 127.5 (4 CH, Ph), 128.0 (4
CH, Ph), 138.0 (CH, C-4¢), 138.5 (2 C, i-Ph), 160.4 (2 C, C-2¢ a◦nd
C-6¢), 170.5 (2 C, C-5); [a]D22 -42.1 (c 1.5, MeOH); mp 129–132 C
(EtOAc–hexane); MS-EI m/z 509 (M+, 9), 295 (11), 216 (100), 120
(23); HRMS C31H32N3O4 (M + H+), 510.2387; found, 510.2385.
Anal. Calcd for C31H31N3O4: C, 73.06; H, 6.13; N, 8.25. Found: C,
72.74; H, 6.45; N, 7.89.
(3R,7aR)-3-Phenyl-7a-(2-pyridyl)-2,3,7,7a-tetrahydropyrrolo[2,1-
b]oxazol-5(6H)-one (7)
(R)-Phenylglycinol (410 mg, 3 mmol) was added to a solution of
1b (510 mg, 2.9 mmol) in toluene (25 mL), and the mixture was
heated at reflux temperature for 7 h with azeotropic elimination
of water produced by a Dean–Stark apparatus. Then, the solution
was concentrated under reduced pressure to give a residue, which
was purified by flash chromatography (4 : 1 to 3 : 2 hexane–EtOAc)
to afford 7 (620 mg, 78%) as a yellow solid: IR (film) 1709 cm-1;
1H NMR (CDCl3, 400 MHz, COSY, HSQC) d 2.49–2.56 (m, 2H,
H-7), 2.68 (ddd, J = 16.7, 7.5, 4.8 Hz, 1H, H-6), 3.21 (dt, J = 16.7,
9.9 Hz, 1H, H-6), 3.99 (dd, J = 8.8, 7.7 Hz, 1H, H-2), 4.73 (dd, J =
8.8, 8.0 Hz, 1H, H-2), 5.26 (tap, J = 7.7 Hz, 1H, H-3), 6.96–7.03
(m, 2H, ArH), 7.09–7.22 (m, 4H, ArH), 7.41 (dt, J = 7.8, 1.1 Hz,
1H, PyrH), 7.58 (td, J = 7.8, 1.8 Hz, 1H, PyrH), 8.67 (ddd, J =
4.8, 1.8, 0.9 Hz, 1H, PyrH); 13C NMR (CDCl3, 100.6 MHz) d
33.8 (CH2, C-6), 34.8 (CH2, C-7), 58.4 (CH, C-3), 74.7 (CH2, C-2),
102.4 (C, C-7a), 119.2 (CH, Ar), 123.0 (CH, Ar), 126.0 (2 CH,
Ar), 127.2 (CH, Ar), 128.3 (2 CH, Ar), 136.6 (CH, Ar), 138.9 (C,
i-Ar), 150.0 (CH, Ar), 160.3 (C, i-Ar), 179.6 (C, C-5); [a]2D2 -79.0
(3R,3’R,7aR,7a’R)-1,3-Bis(5-oxo-3-phenyl-2,3,5,6,7,7a-
hexahydropyrrolo[2,1-b]oxazol-7a-yl)benzene (11)
Following the procedure described for the preparation of 7, from
(R)-phenylglycinol (4.9 g, 36 mmol) and 4b (4.5 g, 16 mmol) in
toluene (270 mL) for 24 h, lactam 11 (4.7 g, 61%) was obtained
as a brown solid after flash chromatography (4 : 1 to 1 : 1 hexane–
EtOAc): IR (KBr) 1702 cm-1; 1H NMR (CDCl3, 400 MHz, COSY,
HSQC) d 2.02–2.12 (m, 2H, H-7), 2.47–2.61 (m, 4H, H-7 and H-
6), 2.62–2.75 (m, 2H, H-6), 3.71 (t, J = 8.9 Hz, 2H, H-2), 4.56 (dd,
J = 8.9, 8.0 Hz, 2H, H-2), 5.14 (t, J = 8.0 Hz, 2H, H-3), 7.00–7.06
(m, 4H, PhH), 7.12–7.17 (m, 6H, PhH), 7.31–7.35 (m, 2H, PhH),
7.38–7.43 (m, 2H, PhH); 13C NMR (CDCl3, 100.6 MHz) d 32.6 (2
CH2, C-6), 35.3 (2 CH2, C-7), 58.7 (2 CH, C-3), 72.6 (2 CH2, C-2),
102.6 (2 C, C-7a), 122.5 (CH, Ph), 125.0 (2 CH, Ph), 126.5 (4 CH,
Ph), 127.4 (2 CH, Ph), 128.4 (4 CH, Ph), 129.3 (CH, Ph), 138.7 (2
C, i-Ph), 142.4 (2 C, C-1¢ and C-3¢), 180.3 (2 C, C-5); [a]2D2 -126.9
(c 1.0, CHCl3); mp 198-200 ◦C (EtOAc–hexane); MS-EI m/z 480
(M+, 57), 423 (50), 306 (44), 202 (100), 120 (60), 104 (73), 91 (93),
55 (49); Anal. Calcd for C30H28N2O4: C, 74.98; H, 5.87; N, 5.83.
Found: C, 75.08; H, 5.74; N, 5.62.
◦
(c 1.0, MeOH); mp 81–83 C (EtOAc–hexane); MS-EI m/z 280
(M+, 3), 202 (100), 161 (48), 120 (21); HRMS C17H17N2O2 (M +
H+), 281.1271; found, 281.1277. Anal. Calcd for C17H16N2O2: C,
72.84; H, 5.75; N, 9.99. Found: C, 72.74; H, 5.82; N, 9.90.
(3R,3’R,7aR,7a’R)-2,6-Bis(5-oxo-3-phenyl-2,3,5,6,7,7a-
hexahydropyrrolo[2,1-b]oxazol-7a-yl)pyridine (9)
Following the procedure described for the preparation of 7, from
(R)-phenylglycinol (600 mg, 4.4 mmol) and 2b (600 mg, 2.15 mmol)
in toluene (25 mL) for 18 h, lactam 9 (520 mg, 47%) was obtained
as a white solid after flash chromatography (1 : 1 hexane–EtOAc to
EtOAc): IR (film) 1712 cm-1; 1H NMR (CDCl3, 400 MHz, COSY,
HSQC) d 2.36–2.55 (m, 4H, H-7), 2.68 (ddd, J = 16.6, 10.0, 2.1 Hz,
2H, H-6), 3.24 (dt, J = 16.6, 10.0 Hz, 2H, H-6), 4.03 (dd, J = 8.8,
7.5 Hz, 2H, H-2), 4.77 (dd, J = 8.8, 8.0 Hz, 2H, H-2), 5.26 (tap,
J = 7.5 Hz, 2H, H-3), 6.89–6.95 (m, 4H, PhH), 7.06–7.13 (m, 6H,
PhH), 7.35 (d, J = 8.0 Hz, 2H, H-3¢ and H-5¢), 7.54 (t, J = 8.0 Hz,
1H, H-4¢); 13C NMR (CDCl3, 100.6 MHz) d 34.2 (2 CH2, C-6),
35.4 (2 CH2, C-7), 57.8 (2 CH, C-3), 75.1 (2 CH2, C-2), 102.2 (2
C, C-7a), 118.0 (2 CH, C-3¢ and C-5¢), 125.7 (4 CH, Ph), 127.3 (2
(5S)-1-[(1R)-2-Hydroxy-1-phenylethyl]-5-phenyl-2-pyrrolidone
(12)16
Triethylsilane (1 mL, 6.3 mmol) and TiCl4 (1.1 mL, 10 mmol) were
added to a solution of lactam 8 (700 mg, 2.5 mmol) in CH2Cl2
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(20 mL). The mixture was refluxed for 20 h, quenched by the
cautious addition of saturated aqueous NaHCO3 solution, and
extracted with CH2Cl2. The combined organic extracts were dried
and concentrated, and the resulting residue was chromatographed
(4 : 1 hexane–EtOAc to EtOAc) to afford pyrrolidone 12 (500 mg,
71%) as a white solid: IR (film) 1686, 3200–3500 cm-1; 1H NMR
(CDCl3, 400 MHz, COSY, HSQC) d 1.95 (m, 1H, H-4), 2.44 (m,
1H, H-4), 2.58 (ddd, J = 16.8, 9.5, 6.5 Hz, 1H, H-3), 2.72 (ddd, J =
16.8, 9.5, 6.5 Hz, 1H, H-3), 3.93 (dd, J = 12.3, 3.2 Hz, 1H, H-2¢),
4.06 (dd, J = 7.4, 3.2 Hz, 1H, H-1¢), 4.19 (dd, J = 12.3, 7.4 Hz,
1H, H-2¢), 4.40 (dd, J = 8.2, 5.2 Hz, 1H, H-5), 4.81 (br s, 1H,
OH), 7.05–7.21 (m, 4H, PhH), 7.27–7.41 (m, 6H, PhH); 13C NMR
(CDCl3, 100.6 MHz) d 28.7 (CH2, C-4), 31.3 (CH2, C-3), 63.2
(CH, C-1¢), 64.0 (CH, C-5), 64.4 (CH2, C-2¢), 126.6 (2 CH, Ph),
127.4 (2 CH, Ph), 127.9 (CH, Ph), 128.2 (CH, Ph), 128.7 (2 CH,
Ph), 129.1 (2 CH, Ph), 137.2 (C, Ph), 140.5 (C, Ph), 177.4 (C, C-2);
[a]2D2 +12.3 (c 0.7, CH2Cl2) {lit.16 [a]2D2 +11 (c 0.7, CH2Cl2)}; mp
128.6 (2 CH, Ph), 136.2 (C, C-1¢), 140.9 (C, Ph), 142.0 (C, Ph),
174.9 (C, C-2); [a]2D2 -15.3 (c 0.9, MeOH); MS-EI m/z 263 (M+,
75), 159 (73), 144 (100), 119 (51), 104 (40), 91 (34), 77 (27); HRMS
C18H18NO (M + H+), 264.1382; found, 264.1391.
(S)-5-Phenyl-2-pyrrolidone (15)17
5 M aqueous H2SO4 (15 mL) was added to a solution of 14 (400 mg,
1.5 mmol) in Et2O (60 mL). Then, the resulting mixture was stirred
at reflux temperature until no more starting material was observed
by TLC (20 h). The mixture was washed with a saturated NaHCO3
solution and extracted with EtOAc. The combined organic phases
were dried and evaporated. Flash chromatography (1 : 1 hexane–
EtOAc to EtOAc) provided 15 (234 mg, 96%) as a white solid: IR
(film) 1656, 1693, 3100–3200 cm-1; 1H NMR (CDCl3, 400 MHz)
d 1.98 (m, 1H, H-4), 2.36–2.50 (m, 2H, H-4 and H-3), 2.56 (m,
1H, H-3), 4.75 (t, J = 7.1 Hz, 1H, H-5), 6.23 (br s, 1H, NH), 7.27–
7.33 (m, 3H, ArH), 7.34–7.40 (m, 2H, ArH); 13C NMR (CDCl3,
100.6 MHz) d 30.3 (CH2, C-4), 31.2 (CH2, C-3), 58.1 (CH, C-5),
125.6 (2 CH, Ph), 127.8 (CH, Ph), 128.8 (2 CH, Ph), 128.8 (CH,
Ph), 142.5 (C, Ph), 178.6 (C, CON); [a]2D2 -58.7 (c 1.0, CHCl3)
{lit.17 [a]2D2 -51.0 (c 0.97, CH2Cl2)}.
◦
85–88 C (EtOAc–hexane); MS-EI m/z 281 (M+, 0.2), 250 (57),
162 (29), 117 (53), 106 (100), 91 (63), 77 (32); HRMS C18H20NO2
(M + H+), 282.1489; found, 282.1485.
(5S)-1-[(1R)-2-Chloro-1-phenylethyl]-5-phenyl-2-pyrrolidone (13)
(S)-2-Phenylpyrrolidine (16)10b
SOCl2 (0.5 ml, 7 mmol) was added to a cooled (0 ◦C) solution
of 12 (1 g, 3.55 mmol) in THF (70 mL), and resulting mixture
was stirred for 15 min at 0 C and then refluxed for 1.5 h. After
LiAlH4 (118 mg, 3.1 mmol) was added to a solution of 15 (100 mg,
0.62 mmol) in THF (12 mL), and the mixture was stirred at rt for
3 days. Then, the mixture was carefully poured into 2 N aqueous
NaOH and extracted with EtOAc. The organic phase was washed
with 2 N aqueous HCl, and the aqueous phase was then basified
to pH = 14 with 4 N aqueous NaOH and extracted with EtOAc.
The organic extracts were dried and concentrated to afford 16
◦
evaporation of the solvent, the crude residue was taken up with
EtOAc, washed with a saturated NaHCO3 solution, dried, and
concentrated to yield 13 (930 mg, 93%) as a yellowish solid: IR
1
(film) 1679 cm-1; H NMR (CDCl3, 400 MHz, COSY, HSQC) d
1.95 (m, 1H, H-4), 2.33–2.50 (m, 2H, H-4 and H-3), 2.65 (m, 1H,
H-3), 3.99 (dd, J = 11.1, 6.3 Hz, 1H, H-2¢), 4.38 (dd, J = 9.3,
6.3 Hz, 1H, H-1¢), 4.48 (t, J = 7.0 Hz, 1H, H-5), 4.72 (dd, J =
11.1, 9.3 Hz, 1H, H-2¢), 7.17–7.27 (m, 7H, ArH), 7.28–7.34 (m,
3H, ArH); 13C NMR (CDCl3, 100.6 MHz) d 29.3 (CH2, C-4), 31.1
C-3), 44.1 (C-2¢), 60.3 (C-1¢), 62.9 (C-5), 127.2 (2CHAr), 127.8
(2CHAr), 128.2 (CHAr), 128.2 (CHAr), 128.6 (2CHAr), 128.8
(2CHAr), 137.8 (C-i),◦140.5 (C-i), 176.7 (CON); [a]2D2 - 8.0 (c 1.0,
MeOH); mp 102-105 C (EtOAc–hexane); MS-EI m/z 299 (M+,
1), 263 (100), 250 (80), 106 (55); HRMS C18H19ClNO (M + H+),
300.1149; found, 300.1136. Anal. calcd for C18H18ClNO: C, 72.11;
H, 6.05; Cl, 11.83; N, 4.67. Found: C, 72.09; H, 6.09; N, 4.59.
1
(74 mg, 81%) as a colourless oil. H NMR (CDCl3, 400 MHz,
COSY, HSQC) d 1.67 (m, 1H, H-3), 1.79–1.96 (m, 3H, H-4 and
NH masked), 2.19 (m, 1H, H-3), 3.01 (m, 1H, H-5), 3.21 (ddd,
J = 10.1, 7.7, 5.3 Hz, 1H, H-5), 4.11 (t, J = 7.7 Hz, 1H, H-2),
7.22 (m, 1H, ArH), 7.28–7.38 (m, 4H, ArH); 13C NMR (CDCl3,
100.6 MHz) d 25.6 (CH2, C-4), 34.3 (CH2, C-3), 47.0 (CH2, C-5),
62.6 (CH, C-2), 126.5 (2 CH, Ph), 126.7 (CH, Ph), 128.3 (2 CH,
Ph), 144.8 (C, Ph); [a]D22 -26.8 (c 0.3, MeOH) {lit.10b [a]2D2 -22.0 (c
0.3, MeOH).
(5S,5¢S)-1,3-Bis{1-[(1R)-2-hydroxy-1-phenylethyl]-2-oxo-5-
pyrrolidinyl}benzene (17)
(S)-5-Phenyl-1-(1-phenylvinyl)-2-pyrrolidone (14)
Following the procedure described for the preparation of 12,
lactam 11 (4 g, 8.32 mmol) in CH2Cl2 (80 mL), Et3SiH (6.6 mL,
41.6 mmol) and TiCl4 (7.3 mL, 66.6 mmol) for 43 h afforded 17
(2.4 g, 60%) as a white solid and 18 (1.4 g 30%) as a white solid
after flash chromatography (1 : 1 hexane–EtOAc to 95 : 5 EtOAc–
methanol). 17: IR (film) 1669, 3200–3500 cm-1; 1H NMR (CDCl3,
400 MHz, COSY, HSQC) d 1.84–1.98 (m, 2H, H-4), 2.39–2.51
(m, 2H, H-4), 2.52–2.78 (m, 4H, H-3), 3.87 (ddd, J = 12.3, 6.4,
3.6 Hz, 2H, H-2¢), 4.05 (dd, J = 8.0, 3.6 Hz, 2H, H-1¢), 4.30 (dt,
J = 12.3, 8.0 Hz, 2H, H-2¢), 4.40 (dt, J = 12.3, 6.1 Hz, 2H, H-5),
4.55 (dt, J = 14.4, 7.1 Hz, 2H, OH), 6.91–7.43 (m, 14H, PhH);
13C NMR (CDCl3, 100.6 MHz) d 28.7 (2 CH2, C-4), 31.2 (2 CH2,
C-3), 63.1 (2 CH, C-1¢), 63.6 (2 CH, C-5), 64.1 (2 CH2, C-2¢),
124.8 (CH, Ph), 126.6 (2 CH, Ph), 127.4 (4 CH, Ph), 128.0 (2 CH,
Ph), 128.7 (4 CH, Ph), 129.9 (CH, Ph), 137.1 (2 C, Ph), 141.9
DBU (0.85 mL, 5.6 mmol) was added at rt to a solution of 13
(850 mg, 2.8 mmol) in DMF (9.5 mL), and the mixture was
heated at 85 ◦C for 5 h, cooled, poured into ice and water,
and extracted with Et2O. The combined organic extracts were
washed with saturated NaHCO3 solution, brine, and water, dried
and concentrated. Flash chromatography (1 : 1 hexane–EtOAc)
afforded 14 (530 mg, 70%) as a yellow oil: IR (film) 1693, 2800–
1
3000 cm-1; H NMR (CDCl3, 400 MHz, COSY, HSQC) d 2.02
(m, 1H, H-4), 2.50–2.82 (m, 3H, H-4 and H-3), 4.77 (dd, J = 7.8,
5.8 Hz, 1H, H-5), 5.21 (s, 1H, H-2¢), 5.34 (s, 1H, H-2¢), 7.01–7.10
(m, 2H, ArH), 7.11–7.19 (m, 2H, ArH), 7.20–7.36 (m, 6H, ArH);
13C NMR (CDCl3, 100.6 MHz) d 28.6 (CH2, C-4), 31.1 (CH2,
C-3), 63.4 (CH, C-5), 112.6 (CH2, C-2¢), 126.5 (2 CH, Ph), 126.7
(2 CH, Ph), 127.8 (CH, Ph), 128.2 (2 CH, Ph), 128.4 (CH, Ph),
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(2 C, Ph), 177.3 (2 C, C-2); [a]2D2 -3.0 (c 1.0, CHCl3); MS-EI m/z
484 (M+, 0.03), 454 (100), 436 (35), 347 (99), 106 (87), 91 (36);
HRMS C30H33N2O4 (M + H+), 485.2435; found, 485.2430. 18: IR
(KBr) 1657, 1701, 3200–3300 cm-1; 1H NMR (CDCl3, 400 MHz,
COSY, HSQC) d 1.66–1.78 (m, 1H, H-7), 2.28–2.42 (m, 2H, H-4
and H-7), 2.45–2.75 (m, 4H, H-3, H-4 and H-6), 2.93–3.09 (m,
1H, H-3), 3.78 (ddd, J = 12.2, 6.5, 3.8 Hz, 1H, H-2¢), 3.86 (dd, J =
8.1, 3.8 Hz, 1H, H-1¢), 3.91–4.00 (m, 1H, H-2), 4.23 (dt, J = 12.2,
8.1 Hz, 1H, H-2¢), 4.33 (dd, J = 8.2, 5.5 Hz, 1H, H-5), 4.39 (dd, J =
8.1, 6.5 Hz, 1H, OH), 4.64-4.72 (m, 1H, H-2), 5.22 (t, J = 8.0 Hz,
1H, H-3¢), 6.97–7.09 (m, 5H, PhH), 7.14–7.22 (m, 3H, PhH), 7.23–
7.36 (m, 5H, PhH), 7.43–7.48 (m, 1H, PhH); 13C NMR (CDCl3,
100.6 MHz) d 28.6 (CH2, C-7), 31.3 (CH2, C-6), 32.8 (CH2, C-3),
35.5 (CH2, C-4), 58.7 (CH, C-3¢), 63.0 (CH, C-1¢), 63.6 (CH, C-5),
64.1 (CH2, C-2¢), 73.2 (CH2, C-2), 102.5 (C, C-7a), 123.2 (CH, Ph),
125.3 (CH, Ph), 126.5 (2 CH, Ph), 126.9 (CH, Ph), 127.4 (2 CH,
Ph), 127.4 (CH, Ph), 128.0 (CH, Ph), 128.4 (2 CH, Ph), 128.7 (2
CH, Ph), 129.4 (CH, Ph), 137.1 (C, Ph), 138.8 (C, Ph), 141.2 (C,
Ph), 143.4 (C, Ph), 177.3 (C, C-2), 180.1 (C, C-5); [a]2D2 -62.4 (c
1.0, CHCl3); mp 140–142 ◦C (EtOAc); MS-EI m/z 482 (M+, 0.1),
451 (100), 331 (40), 243 (39), 106 (58); HRMS C30H31N2O4 (M +
H+), 483.2278; found, 483.2282.
C-1¢), 141.3 (2 C, Ph), 141.9 (2 C, Ph), 174.7 (2 C, C-2); [a]2D2 +6.6
(c 1.0, CHCl3); HRMS C30H29N2O2 (M + H+), 449.2223; found,
449.2227.
(5S,5¢S)-1,3-Bis(2-oxo-5-pyrrolidinyl)benzene (21)
5 M aqueous H2SO4 (20 mL) was added to a solution of 20 (500 mg,
1.1 mmol) in Et2O (20 mL). Then, the resulting mixture was stirred
at reflux temperature until no more starting material was observed
by TLC (5 h). The mixture was extracted with EtOAc. The aqueous
layer was basified to pH = 14 with 4 N aqueous NaOH and
extracted with EtOAc. The combined organic phases were dried
and concentrated to afford 21 (170 mg, 63%) as a white solid: IR
(KBr) 1679, 3221 cm-1; 1H NMR (CD3OD, 400 MHz) d 1.85–1.98
(m, 2H, H-4), 2.42 (dd, J = 9.1, 6.7 Hz, 4H, H-3), 2.53–2.65 (m, 2H,
H-4), 4.78–4.83 (m, 2H, H-5), 7.23–7.31 (m, 3H, PhH), 7.34–7.41
(m, 1H, PhH); 13C NMR (CD3OD, 100.6 MHz) d 33.5 (2 CH2,
C-3), 32.2 (2 CH2, C-4), 59.7 (2 CH, C-5), 124.1 (CH, Ph), 126.2
(2 CH, Ph), 130.3 (CH, Ph), 145.0 (2 C, Ph), 181.3 (2 C, C-2); [a]D22
◦
-59.1 (c 0.5, MeOH); mp 260–261 C decomp (MeOH); HRMS
C14H17N2O2 (M + H+), 245.1285; found, 245.1288; Anal. Calcd
for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.61; H,
6.68; N, 11.34.
(5S,5¢S)-1,3-Bis{1-[(1R)-2-chloro-1-phenylethyl]-2-oxo-5-
pyrrolidinyl}benzene (19)
(S)-1,3-Di[2-pyrrolidinyl]benzene (22)
LiAlH4 (93 mg, 2.5 mmol) was added to a solution of 19 (60 mg,
0.25 mmol) in THF (5 mL), and the mixture was stirred at reflux
temperature for 1 day. The mixture was carefully poured into 2
N aqueous NaOH and extracted with EtOAc. The organic phase
was washed with 2 N aqueous HCl, and the aqueous solution was
then basified to pH = 12 with 4 N aqueous NaOH and extracted
with EtOAc. The organic extracts were dried and concentrated to
afford 22 (40 mg, 74%) as a yellow oil: IR (film) 1630, 2961 cm-1;
1H NMR (CDCl3, 400 MHz, COSY, HSQC) d 1.61–1.73 (m, 2H,
H-3), 1.78–1.95 (m, 4H, H-4), 2.11–2.28 (m, 4H, H-3 and NH
masked), 2.95–3.04 (m, 2H, H-5), 3.14–3.25 (m, 2H, H-5), 4.08 (t,
J = 8.2 Hz, 2H, H-2), 7.20–7.25 (m, 3H, ArH), 7.35 (m, 1H, ArH);
13C NMR (CDCl3, 100.6 MHz) d 25.6 (2 CH2, C-4), 34.3 (2 CH2,
C-3), 46.9 (2 CH2, C-5), 62.7 (2 CH, C-2), 124.7 (CH, Ph), 125.0
(2 CH, Ph), 128.3 (CH, Ph), 144.7 (2 C, Ph); [a]2D2 -83.5 (c 1.0,
CHCl3); HRMS C14H21N2 (M + H+), 217.1699; found, 217.1705.
Following the procedure described for the preparation of 13, a
solution of 17 (1.4 g, 2.9 mmol) in THF (55 mL) and SOCl2
(0.9 ml, 11.5 mmol) afforded 19 (1.5 g) as a yellow solid.
Dichlorinated compound 19 was used without further purification
in next reaction. An analytical sample was purified by column
chromatography (4 : 1 hexane–EtOAc) to afford 19 as yellowish
1
solid. H NMR (CDCl3, 400 MHz, COSY, HSQC) d 1.84–1.96
(m, 2H, H-4), 2.35–2.50 (m, 4H, H-3 and H-4), 2.55–2.68 (m, 2H,
H-3), 3.95 (dd, J = 11.2, 6.0 Hz, 2H, H-2¢), 4.34 (dd, J = 10.0,
6.0 Hz, 2H, H¢1¢), 4.47 (t, J = 7.2 Hz, 2H, H-5), 4.82 (dd, J = 11.2,
10.0 Hz, 2H, H-2¢), 7.11 (dd, J = 7.6, 1.6 Hz, 2H, PhH), 7.16–7.28
(m, 2H, PhH); 13C NMR (CDCl3, 100.6 MHz) d 29.1 (2 CH2,
C-4), 31.1 (2 CH2, C-3), 44.2 (2 CH2, C-2¢), 61.0 (2 CH, C-1¢),
62.7 (2 CH, C-5), 125.2 (CH, Ph), 127.5 (2 CH, Ph), 127.8 (4 CH,
Ph), 128.4 (2 CH, Ph), 128.8 (4 CH, Ph), 129.2 (CH, Ph), 137.7 (2
C, Ph), 141.9 (2 C, Ph), 176.8 (2 C, C-5); HRMS C30H31Cl2N2O2
(M + H+), 521.1757; found, 521.1762.
Theoretical calculations
(5S,5¢S)-1,3-Bis[1-(1-phenylvinyl)-2-oxo-5-pyrrolidinyl]benzene
(20)
Initial geometries were obtained using the PCMODEL program.18
Further geometry optimizations were carried out using the Gaus-
sian 03 suite of programs on a Compaq HPC320 computer,19 at the
Hartree–Fock (HF) level,20 and at the Becke’s three-parameter hy-
brid functional with the Lee, Yang and Parr correlation functional
(B3LYP) level,21 using the 6-31G(d) basis set.22 Analytical energy
second derivatives were calculated at all optimized structures to
confirm that these were minima.
Following the procedure described for the preparation of 14, a
solution of 19 (1.5 g, 2.9 mmol) in DMF (12 mL) and DBU
(1.75 mL, 11.5 mmol) afforded 20 (650 mg, 50% from 17) as a
yellowish foam after flash chromatography (1 : 1 hexane–EtOAc
1
to EtOAc): IR (KBr) 1686, 2900–3400 cm-1; H NMR (CDCl3,
400 MHz, COSY, HSQC) d 1.81–1.95 (m, 2H, H-4), 2.43–2.56
(m, 2H, H-4), 2.57–2.76 (m, 4H, H-3), 4.70 (dd, J = 7.6, 6.3 Hz,
2H, H-5), 5.11 (s, 2H, H-2¢), 5.29 (s, 2H, H-2¢), 6.60–6.98 (m, 3H,
PhH), 7.07–7.32 (m, 11H, PhH); 13C NMR (CDCl3, 100.6 MHz)
d 28.6 (2 CH2, C-4), 31.0 (2 CH2, C-3), 63.2 (2 CH, C-5), 112.3 (2
CH2, C-2¢), 124.9 (CH, Ph), 126.1 (2 CH, Ph), 126.4 (4 CH, Ph),
128.2 (4 CH, Ph), 128.4 (2 CH, Ph), 128.9 (CH, Ph), 136.0 (2 C,
Acknowledgements
Financial support from the Ministry of Science and Innova-
tion, Spain (Project CTQ2009-07021/BQU), and the AGAUR,
Generalitat de Catalunya (Grant 2009-SGR-111) is gratefully
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acknowledged. Thanks are also due to the Ministry of Education
and Science for a fellowship for C. A.
12 For a related ring opening in analogues of 8 substituted at the angular
position by an alkyl group, see ref. 10b.
13 Removal of the phenylethanol moiety from 5,6-disubstituted piperi-
dones was successfully accomplished with Na/NH3: M. Amat, C.
Escolano, A. Go´mez-Esque´, O. Lozano, N. Llor, R. Griera, E. Molins
and J. Bosch, Tetrahedron: Asymmetry, 2006, 17, 1581. Spectral data
for a: IR (film) 1646, 3100-3500 cm-1; 1H-NMR (CDCl3, 300 MHz) d
1.90–2.04 (m, 2H, H-3), 2.22 (tap, J = 7.5 Hz, 2H, H-4), 2.52 (br s, 1H,
OH), 2.64 (t, J = 7.5 Hz, 2H, H-2), 3.83 (dap, J = 5.0 Hz, 2H, H-2¢), 5.04
(ddap, J = 12.0, 5.0 Hz, 1H, H-1¢), 6.19 (br s, 1H, NH), 7.11–7.22 (m,
3H, ArH), 7.23–7.41 (m, 7H, ArH); 13 C NMR (CDCl3, 75.4 MHz) d
27.0 (C-3), 35.1 (C-2), 35.7 (C-4), 55.8 (C-1¢), 66.4 (C-2¢), 125.9 (CHAr),
126.6 (2CHAr), 127.8 (CH, Ar), 128.3 (2CHAr), 128.4 (2CHAr), 128.8
(2CHAr), 139.0 (C-i), 141.3 (C-i), 173.3 (C, CON); [a]22D (55.4 (c 1.0,
MeOH); mp 95-97 ◦C (EtOAc–hexane); MS-EI m/z 283 (M +, 3), 252
(31), 179 (36), 148 (45), 106 (100), 91 (45); HRMS C18H22NO2 (M + H
+), 284.1631; found, 284.1636. Anal. calcd for C18H21NO2: C, 76.29;
H, 7.47; N, 4.94. Found: C, 76.56; H, 7.49; N, 4.87.
Notes and references
1 (a) Comprehensive Heterocyclic Chemistry II, A. R. Katritzky,
C. W. Rees and E. F. V. Scriven, ed.; Pergamon: Oxford, 1996, Vol
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Mitchinson and A. Nadin, J. Chem. Soc., Perkin Trans. 1, 2000, 2862
and references therein.
2 Chiral nonracemic amino alcohol-derived bicyclic lactams were initially
studied by Meyers. For reviews, see: (a) D. Romo and A. I. Meyers,
Tetrahedron, 1991, 47, 9503; (b) A. I. Meyers and G. P. Brengel, Chem.
Commun., 1997, 1; (c) M. D. Groaning and A. I. Meyers, Tetrahedron,
2000, 56, 9843; (d) C. Escolano, M. Amat and J. Bosch, Chem.–Eur. J.,
2006, 12, 8198.
3 For some representative examples see the following papers and
references cited therein: (a) J. Jiang, R. J. DeVita, G. A. Doss, M. T.
Goulet and M. J. Wyvratt, J. Am. Chem. Soc., 1999, 121, 593; (b) A. A.
Bahajaj, M. H. Moore and J. M. Vernon, Tetrahedron, 2004, 60, 1235;
(c) M. Penhoat, S. Leleu, G. Dupas, C. Papamicae¨l, F. Marsais and V.
Levacher, Tetrahedron Lett., 2005, 46, 8385; (d) X. Wang, Y. Dong, J.
Sun, X. Xu, R. Li and Y. Hu, J. Org. Chem., 2005, 70, 1897; (e) D. J.
Edwards, D. House, H. M. Sheldrake, S. J. Stone and T. W. Wallace,
Org. Biomol. Chem., 2007, 5, 2658; (f) S. M. Husain, R. Fro¨hlich and B.
Wu¨nsch, Tetrahedron: Asymmetry, 2008, 19, 1613; (g) M. Penhoat,
P. Bohn, G. Dupas, C. Papamicae¨l, F. Marsais and V. Levacher,
Tetrahedron: Asymmetry, 2006, 17, 281; (h) U. Wirt, D. Schepmann
and B. Wu¨nsch, Eur. J. Org. Chem., 2007, 462; (i) A. Bouet, B. Heller,
C. Papamicae¨l, G. Dupas, S. Oudeyer, F. Marsais and V. Levacher, Org.
Biomol. Chem., 2007, 5, 1397; (j) A. Bouet, S. Oudeyer, G. Dupas, F.
Marsais and V. Levacher, Tetrahedron: Asymmetry, 2008, 19, 2396.
4 The synthesis of 1a has previously been described in four steps via the
alkylation of a tert-butyl b-keto ester (a) R. V. Hoffman and H. Kim,
J. Org. Chem., 1995, 60, 5107; (b) H. Imoto, Y. Sugiyama, H. Kimura
and Y. Momose, Chem. Pharm. Bull., 2003, 51, 138.
5 E. Negishi, Q. Hu, Z. Huang, G. Wang and N. Yin, In Chemistry of
Organozinc Compounds, Wiley, 2006; (Pt.1), pp 457.
6 K. I. Na¨ttinen and K. Rissanen, Cryst. Growth Des., 2003, 3, 339.
7 (a) Y. Tamaru, H. Ochiai, T. Nakamura and Z. Yoshida, Org. Synth.,
1993, 8, 274; (b) A similar coupling was described by our group, see:M.
Amat, G. Griera, R. Fabregat, E. Molins and J. Bosch, Angew. Chem.,
Int. Ed., 2008, 47, 3348.
8 W. J. Coates, H. D. Prain, M. L. Reeves and B. H. Warrington, J. Med.
Chem., 1990, 33, 1735.
9 For the only example dealing with the synthesis of a bicyclic lactam
with a 3-pyridyl substituent at the angular position, see (a) M. Amat,
M. Canto´, N. Llor and J. Bosch, Chem. Commun., 2002, 526; (b) M.
Amat, O. Bassas, N. Llor, M. Canto´, M. Pe´rez, E. Molins and J. Bosch,
Chem.–Eur. J., 2006, 12, 7872.
14 (a) C. Agami, F. Couty and G. Evano, Tetrahedron Lett., 1999, 40, 3709;
(b) C. Denhez, J.-L. Vasse, D. Harakat and J. Szymoniak, Tetrahedron:
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15 Increasing either the equivalents of Et3SiH and TiCl4 or the reaction
time did not change the ratio of the monoreduced product 18.
16 I. Baussanne, A. Chiaroni and J. Royer, Tetrahedron: Asymmetry, 2001,
12, 1219.
17 P. Camps, T. Go´mez, D. Mun˜oz-Torrero, J. Rull, L. Sa´nchez, F. Boschi,
M. Comes-Franchini, A. Ricci, T. Calvet, M. Font-Bardia, E. De Clercq
and L. Naesens, J. Org. Chem., 2008, 73, 6657.
18 PCMODEL, Version 8.00.1 for Windows, Serena Software.
19 Theoretical calculations were carried out using Gaussian 03, Revision
B.01. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, Jr., J. A. Montgomery, T. Vreven, K. N.
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C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth,
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Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y.
Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Pittsburgh
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10 (a) A. I. Meyers and L. E. Burgess, J. Org. Chem., 1991, 56, 2294;
(b) L. E. Burgess and A. I. Meyers, J. Org. Chem., 1992, 57, 1656.
11 (a) A. I. Meyers, S. V. Downing and M. J. Weiser, J. Org. Chem., 2001,
66, 1413; (b) L. La´za´r and F. Fu¨lo¨p, Eur. J. Org. Chem., 2003, 3025.
20 P. Echenique and J. L. Alonso, Mol. Phys., 2007, 105, 3057.
21 (a) A. D. Becke, J. Chem. Phys., 1993, 98, 5648; (b) C. Lee, W. Yang
and R. G. Parr, Phys. Rev. B, 1988, 37, 785.
22 P. A. Hariharan and J. A. Pople, Theor. Chim. Acta, 1973, 28, 213.
2184 | Org. Biomol. Chem., 2011, 9, 2175–2184
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