Trinuclear non-heme iron complexes based on 4-substituted 2,6-diacylpyridine ligands as catalysts in aerobic allylic oxidations

Article abstract of DOI:10.1002/hlca.201100195

Taking the regio- and chemoselectivities of our iron complex precursors with pyridine core in aerobic oxidations into account, we envisioned a more effective influence on catalytic properties by the introduction of different substituents in 4-position of the pyridine moiety. The synthesis of these novel 4-substituted (pyridine-2,6-diyl)dipropanoic acids 4 is described. Analogously to the unsubstituted derivative, ligands 4 reacted with Fe(ClO₄) ₃ to form trinuclear Fe₃(μ₃-O) complexes 3, which were tested in the aerobic Gif-type oxidation of α-pinene to myrtenol, verbenone, myrtenal, and pinene oxide. The electronic nature of the substituents was found to slightly effect the ratio of allylic oxidation/epoxidation, whereas its influence on the oxidation preference of secondary to primary C-H bonds is negligible as compared to the unsubstituted complex. Copyright

Full text of DOI:10.1002/hlca.201100195

Helvetica Chimica Acta – Vol. 95 (2012)
197
Trinuclear Non-Heme Iron Complexes Based on 4-Substituted 2,6-
Diacylpyridine Ligands as Catalysts in Aerobic Allylic Oxidations
by Volker Rabe, Wolfgang Frey, Angelika Baro, and Sabine Laschat*
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart, Pfaffenwaldring 55, DE-70569 Stuttgart
(phone: þ 49-711-685-64565; fax: þ 49-711-685-64285; e-mail: sabine.laschat@oc.uni-stuttgart.de)
Taking the regio- and chemoselectivities of our iron complex precursors with pyridine core in aerobic
oxidations into account, we envisioned a more effective influence on catalytic properties by the
introduction of different substituents in 4-position of the pyridine moiety. The synthesis of these novel 4-
substituted (pyridine-2,6-diyl)dipropanoic acids 4 is described. Analogously to the unsubstituted
derivative, ligands 4 reacted with Fe(ClO4)3 to form trinuclear Fe3(m3-O) complexes 3, which were tested
in the aerobic Gif-type oxidation of a-pinene to myrtenol, verbenone, myrtenal, and pinene oxide. The
electronic nature of the substituents was found to slightly effect the ratio of allylic oxidation/epoxidation,
whereas its influence on the oxidation preference of secondary to primary CꢀH bonds is negligible as
compared to the unsubstituted complex.
Introduction. – Selective catalytic oxidations of hydrocarbons under mild con-
ditions with molecular O2 are an attractive goal in the field of oxidation catalysis, and
many groups have made significant contributions to this research area [1 – 8]. In
particular, non-heme iron complexes have been intensively investigated, stimulated by
the fact that oxidizing enzymes such as methane monooxygenase [9], ribonucleotide
reductase [10][11], stearoyl D9-ACP desaturase, and toluene monooxygenase [12]
possess non-heme iron active sites, and a detailed understanding of the mechanisms
should allow biomimetic oxidations in a preparative scale [13 – 20]. Pioneering work on
aerobic oxidations was done by Barton and co-workers. The so-called Gif-type
oxidations employ a trinuclear m-oxo iron catalyst Fe3(m3-O)(OAc)6L3 (L ¼ py, H2O) in
the presence of a reducing agent under 1 atm of O2 in pyridine/AcOH [21 – 23].
We have recently developed a set of 2,6-diacylpyridine ligands 1 with different
spacer lengths between the carboxylic acid and pyridine moieties, which were
converted to the corresponding trinuclear [Fe3(m3-O)] complexes 2 or 3 depending
on the type of counterion (Scheme 1) [24].
When complexes 2 or 3 were submitted to catalytic aerobic Gif-type oxidations of
cyclohexane, a-pinene, and adamantane, it turned out that the catalytic properties, i.e.,
turnover numbers, and regio- and chemoselectivities were only influenced to a minor
extent by the chain lengths of the tether and by the type of counterion. In particular, the
tether length had no influence on the nuclearity of the Fe complex. Furthermore,
during catalytic aerobic oxidation, freeze-quench Mçssbauer and nuclear inelastic
scattering data revealed that the precursor complexes 2 and 3 undergo cleavage to
mononuclear species [24][25], which is in agreement with Bartonꢂs original proposal of
the catalytic cycle [21b]. We thus anticipated that substituents at C(4) of the pyridine
ꢃ 2012 Verlag Helvetica Chimica Acta AG, Zꢀrich

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 1
ligand 4 should influence the steric, electronic, and catalytic properties of such a
mononuclear species in a more effective way. The results towards this goal are reported
below.
Results and Discussion. – The synthesis of 4-Br-substituted ligand 4a commenced
with the treatment of the known dicarbaldehyde 5 [26 – 28] with trimethyl phospho-
noacetate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and LiCl in
MeCN at 08, which provided a,b-unsaturated methyl ester 6 in 94% and ethyl ester 7 in
89% yield, respectively (Scheme 2). An X-ray crystal-structure analysis of 6 confirmed
the (E)-configuration of the C¼C bond1). Initial attempts to convert the enoates 6 and
7 to the saturated diacylpyridines 8 and 9, respectively, by catalytic hydrogenation,
according to our previously published procedure [24], were of limited success, because
the use of Pd/C, Pd/BaSO4, or PtO2 resulted in reductive debromination prior to C¼C
bond hydrogenation. By using (AcO)2Ni in the presence of 2 equiv. of NaBH4 under 1
atm of H2 in MeOH/AcOEt, the desired hydrogenation to 8 and 9 could be achieved,
albeit with low yields of 32 and 29%, respectively. Even under these conditions, the
1
)
The data for the X-ray analysis are available as supplementary material from the corresponding
author. For compound 6, CCDC-818683 contains the crystallographic data. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 2. Synthesis of Ligands 4a – 4d
199
a) (MeO)2P(O)CH2COOR, DBU, LiCl, MeCN, 08 ! r.t., 19 h. b) 4-ClꢀC6H4ꢀB(OH)2, Pd(PPh3)4,
K2CO3, KF, DME, H2O, 958, 48 h. c) (AcO)2Ni, NaBH4 (2 equiv.), H2 (1 atm), MeOH, AcOEt, r.t.,
15 min. d) Pd/C, H2 (1 atm), MeOH, 608, 15 h. e) POBr3, toluene, 1108, 10 h; 20%. f) Dowex A, H2O,
1008, 72 h. g) HCl, H2O, 1008, 24 h.
reaction progress must be carefully monitored, and the reactions have to be stopped at
incomplete conversion in order to avoid overreduction. As an alternative route, the 4-
OH diester 10 (see below) was treated with POBr3 in toluene at 1108 to yield 9,
however, in only 20% yield. To get access to the free ligand 4a, compound 8 was treated
with Dowex A basic ion-exchange resin in refluxing H2O, followed by washing with
AcOH, and the free acid 4a was isolated in 98% yield.
The corresponding 4-OH-substituted ligand 4b was obtained as the hydrochloride
4b · HCl in 91% yield from 10 by acidic hydrolysis (Scheme 2). Compound 4b · HCl
gave crystals suitable for X-ray crystal-structure analysis2).
4-Methoxypyridine-2,6-dicarbaldehyde (11) [29] was submitted to
a Hor-
nerꢀWadsworthꢀEmmons olefination as described above to yield the a,b-unsaturated
ester 12 in 45%, followed by catalytic hydrogenation with Pd/C to obtain 13 in 91%
2
)
The data for the X-ray analysis are available as supplementary material from the corresponding
author. For compound 4b · HCl, CCDC-818688 contains the crystallographic data. These data can
be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.

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Helvetica Chimica Acta – Vol. 95 (2012)
yield. Final saponification with Dowex A gave the 4-MeO-substituted ligand 4c in 93%
yield (Scheme 2).
The 4-Br substituted bis(enoate) 6 was submitted to a Suzuki cross-coupling with
(4-chlorophenyl)boronic acid, 5 mol-% of Pd(PPh3)4, K2CO3, KF, 1,2-dimethoxy-
ethane (DME), and H2O at 958 to yield the 4-(4-chlorophenyl)pyridine derivative 14 in
86% yield (Scheme 2). X-Ray crystal-structure analysis revealed the (E)-configuration
for both of the C¼C bonds and a dihedral angle of 24.0(3)8 and 15.7(3)8 (1:1 disorder),
respectively, between the two aryl rings3). Subsequent catalytic hydrogenation of 14
provided diester 15 in 89% yield, which was also available via a Suzuki cross coupling of
8 under the above mentioned conditions in 84% yield. Saponification of diester 15 with
Dowex A in MeOH gave the desired dicarboxylic acid 4d in 88%.
The dimethyl ester of chelidamic acid, 16 [30], was treated with 1-bromo-4-
(bromomethyl)benzene and K2CO3 in refluxing MeCN to give 17 in 75% yield
(Scheme 3). Reduction of 17 with NaBH4 gave the diol 18 in 32%. For both diester 17
and the corresponding diol 18, X-ray crystal-structure analyses could be performed4).
Diol 18 was oxidized with SeO2 to the dicarbaldehyde 19 in 84% yield followed by
HornerꢀWadsworthꢀEmmons olefination to the a,b-unsaturated ester 20 in 67% yield,
of which X-ray crystal structure could also be obtained5). However, upon catalytic
hydrogenation, debenzylation was observed, and diethyl 3,3’-(4-hydroxypyridine-2,6-
diyl)dipropanoate (10) was isolated in 93% yield. Therefore, compound 10 was treated
again with 1-bromo-4-(bromomethyl)benzene and K2CO3 to give 21 in 84% yield,
which was saponified with Dowex A to ligand 4e in 94% yield.
Having the ligands 4a – 4e in hand, the corresponding iron complexes 3 were
prepared by deprotonation of 4 with LiOH in MeOH/CHCl3 and subsequent treatment
with Fe(ClO4)3 · 6 H2O in 38 – 69% yield. The 4-OH-substituted ligand 4b could not be
converted to the iron complex 3b (Scheme 4). Presumably, the phenolate moiety
interferes with the complex formation. Unfortunately, X-ray crystal structures of the
complexes 3a and 3c – 3e could not be obtained. However, spectroscopic and analytical
data (ESI-MS, IR, and elemental analysis) were in good agreement with our previously
reported [Fe3(m3-O)] complex 3f (R ¼ H) [24].
The catalytic properties of precursor complexes 3a and 3c – 3e were studied in the
Gif-type oxidation of a-pinene (22). The results are summarized in Scheme 5 and the
Table. For comparison, the known complex 3f (R ¼ H) with an unsubstituted pyridine
moiety was studied as well [24]. The aerobic oxidations yielded the four products
myrtenol (23), verbenone (24), myrtenal (25), and a-pinene oxide (26) albeit with very
3
)
The data for the X-ray analysis are available as supplementary material from the corresponding
author. For compound 14, CCDC-818684 contains the crystallographic data. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.
The data for the X-ray analyses are available as supplementary material from the corresponding
author. For compounds 17 and 18, CCDC-818685 and CCDC-818687, resp. contain the
crystallographic data. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/
data_request/cif.
The data for the X-ray analysis are available as supplementary material from the corresponding
author. For compound 20, CCDC-818686 contains the crystallographic data. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.
4
)
5
)

Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 3. Synthesis of Ligand 4e
201
a) 4-BrꢀC6H4ꢀCH2Br, K2CO3, MeCN, 828, 20 h. b) NaBH4, MeOH, 08 ! 688, 17 h. c) SeO2, dioxane, 958,
20 h. d) (EtO)2P(O)CH2COOEt, DBU, LiCl, MeCN, 08 ! r.t., 20 h. e) Pd/C, 1 atm H2, MeOH, 608, 17 h.
f) Dowex A, H2O, 1008, 72 h.
Scheme 4
poor conversion of the starting material6). Irrespective of the substituent on the
pyridine ligand in iron complexes 3a and 3c – 3f, 24 was the major product, and the
6
)
In contrast to catalytic Gif-type oxidations of adamantane with complex 3f, where formation of
adamantylpyridines via radical reaction was the major pathway (see [24]), the corresponding by-
products could not be observed in the pinene oxidation.

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 5
Table. Product Ratios in Catalytic Oxidations of a-Pinene (22) under Gif-Type Conditionsa)
Entry
Catalyst precursor
Yield [%]
Ox.:Epox.b)
C1:C2
TONc)
23
24
25
26
(23 – 25)/26
(23 þ 25)/24
1
2
3
4
5
3a
3c
3d
0.1
0.1
0.1
0.1
0.1
1.6
3.1
2.0
1.1
2.4
0.1
0.2
0.2
0.1
0.4
0.5
1.4
0.8
0.5
0.7
78 : 22
62 : 38
74 : 26
72 : 28
81 : 19
11 : 89
13 : 87
13 : 87
15 : 85
17: 83
7
13
9
5
10
3e
3fd)
a) Reaction conditions according to Scheme 5. b) Product ratios were determined by capillary GC by
adding a defined amount of 23 as an external standard according to ref. [24]. c) TONs (turnover
numbers) were calculated as follows: total amount of product [mol] per catalyst [mol]. d) Complex 3f
was prepared according to [24].
other allylic oxidation products, 23 and 25, were only obtained as minor products in a
ratio of 1:5 to 1:10 relative to 24.
The ratio of allylic oxidation to epoxidation (i.e., (23 – 25)/26) is only slightly
influenced by the electronic properties of the pyridine moiety in the respective ligands.
Whereas iron complexes 3a and 3f with the 4-Br-substituted pyridine and the
unsubstituted pyridine ligand, respectively, revealed a pronounced preference of 78 :22
and 81:19, towards allylic oxidation, respectively, the ratio decreased with the use of
the iron complexes 3c and 3e with electron-donating substituents at the ligands, and it
was lowest when the 4-MeO-substituted pyridine complex 3c was applied. In contrast,
the preferential oxidation of secondary CꢀH bonds as compared to primary CꢀH bonds
was influenced only to a minor extent by the substituent, and the ratio ranged between
11:89 for 3a and 17:83 for 3f. In addition, the turnover number did not change
significantly, and no clear tendency could be observed with regard to the different
ligands.
Conclusions. – A series of 4-substituted 2,6-diacylpyridine ligands 4a – 4e has been
synthesized and converted to the corresponding trinuclear [Fe3(m3-O)] complexes 3a
and 3c – 3e. The new complexes 3 were compared with complex 3f bearing a 4-
unsubstituted pyridine ligand [24]. Complexes 3 were employed for the catalytic Gif-
type oxidation of a-pinene (22) to the allylic oxidation products myrtenol (23),
verbenone (24), myrtenal (25), and the epoxide a-pinene oxide (26). The type of
substituent at the pyridine moiety in the ligands seemed to have only a slight influence
on the chemoselectivity, and the regioselectivity and activity, i.e., turnover number

Helvetica Chimica Acta – Vol. 95 (2012)
203
(TON), showed no dependency on the substitutents. In general, allylic oxidation
products 23 – 25 were favored over epoxide 26 by a 62 :38 to 81:19 ratio. The strongest
differentiation was found for ligands 4a and 4f, with a 4-Br-substituted and
unsubstituted pyridine moiety, respectively. Allylic oxidation of secondary vs. primary
CꢀH bonds was favored by 85 :15 to 89 :11. The X-ray crystal-structure analysis of
complex 3f with 4-unsubstituted pyridine ligands [24] revealed that the pyridine N-
atom is protonated and thus is not involved in any binding interaction with the iron
center. However, in agreement with Bartonꢂs mechanistic scenario [31][32], we
propose that the trinuclear complex decomposes to a mononuclear species, in which the
external pyridine competes with the 2,6-diacylpyridine as N-donor ligand7). Even if the
4-substituent exerts some influence on the donor properties of the 2,6-diacylpyridine
moiety, these effects are ꢄdilutedꢂ by the large excess of pyridine solvent. Thus, to study
substituent effects more efficiently, the external pyridine must be replaced at least
partially by electronically modified pyridine derivatives. With respect to preparative
applications, our results indicate that trinuclear non-heme iron complexes are less
amenable to optimization of catalytic properties. Therefore, future research on
catalytic aerobic oxidations should be directed to mononuclear iron complexes.
Generous financial support by the Deutsche Forschungsgemeinschaft (SFB 706) and the Ministerium
fꢀr Wissenschaft, Forschung und Kunst des Landes Baden-Wꢀrttemberg is gratefully acknowledged.
Experimental Part
General. Column chromatography (CC): silica gel 60 (SiO2; 40 – 63 mm; Fluka). Melting points
1
(M.p.): Bꢀchi 510; uncorrected. IR Spectra: Bruker Vektor 22 FT-IR spectrophotometer; in cmꢀ1. H-
and 13C-NMR Spectra: Bruker ARX 500 instrument; at 500/125 MHz; d in ppm, J in Hz; signal
assignments are based on DEPT-135 experiments. MS: Finnigan MAT 95, Varian MAT 711, and Bruker
Daltonics micrOTOF_Q spectrometers; in m/z (rel. %).
General Procedure for the HornerꢀWittigꢀEmmons Olefination of Pyridine-2,6-dicarbaldehydes 5,
11, 19 (GP 1). To a soln. of LiCl (4 equiv.) in MeCN (6 ml) were added methyl (dimethoxyphosphor-
yl)acetate, ethyl (dimethoxyphosphoryl)acetate, or ethyl (diethoxyphosphoryl)acetate (4 equiv.) and
DBU (¼1,8-diazabicyclo[5.4.0]undec-7-ene; 3.8 equiv.), and the mixture was stirred at 08 for 20 min.
Then was added dropwise a soln. of the respective pyridine-2,6-dicarbaldehyde (1 equiv.) in MeCN
(7.5 ml), and stirring was continued at 08 for 1.5 h and at r.t. for 18 h. The mixture was filtered through
SiO2, the solvent was evaporated, and the residue was purified by CC (hexanes/AcOEt 1:2).
Dimethyl (2E,2’E)-3,3’-(4-Bromopyridine-2,6-diyl)bisprop-2-enoate (6). According to GP 1, from 5
(263 mg, 1.23 mmol). Yield 376 mg (1.15 mmol, 94%). Colorless solid. M.p. 1468. Rf (hexanes/AcOEt
1:2) 0.67. IR (ATR): 3066, 2948, 2841, 1711, 1643, 1547, 1434, 1395, 1326, 1302, 1222, 1192, 1154, 1119,
1042, 1010, 982, 864, 825. 1H-NMR (500 MHz, CDCl3): 3.84 (s, 2 MeO); 7.04 (d, J ¼ 15.6, 2 HꢀC(2’)); 7.52
(s, HꢀC(3), HꢀC(5)); 7.59 (d, J ¼ 15.6, 2 HꢀC(1’)). 13C-NMR (125 MHz, CDCl3): 52.0 (MeO); 124.2
(C(2’)); 127.5 (C(3), C(5)); 134.0 (C(4)); 141.6 (C(1’)); 154.1 (C(2), C(6)); 166.7 (C¼O). GC/EI-MS: 328
(39, [M þ H]þ), 326 (38, [M þ H]þ), 297 (60, [M þ H ꢀ MeO]þ), 295 (62, [M þ H ꢀ MeO]þ), 269 (64,
[M þ H ꢀ COOMe]þ), 248 (16, [M þ H ꢀ Br]þ), 234 (46), 210 (100, [M þ H ꢀ 2 COOMe]þ), 208 (100,
[M þ H ꢀ 2 COOMe]þ), 162 (16), 103 (40), 75 (36). Anal. calc. for C13H12BrNO4 (326.14): C 47.87, H
3.71, N 4.29; found: C 48.02, H 3.81, N 4.20.
7
)
Due to similar product ratio and low TON for complexes 3a and 3c – 3e, we assume a mechanistic
scenario comparable to the formation of complex 3f with 4-unsubstituted ligand. In this case, the
formation of mononuclear species during catalysis was derived from freeze-quench Mçssbauer and
neutron inelastic scattering (NIS) experiments. For details, see [24][25].

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Helvetica Chimica Acta – Vol. 95 (2012)
Diethyl (2E,2’E)-3,3’-(4-Bromopyridine-2,6-diyl)bisprop-2-enoate (7). According to GP 1, from 5
(561 mg, 2.62 mmol). Yield 826 mg (2.33 mmol, 89%). Colorless solid. M.p. 1028. Rf (hexanes/AcOEt
1:2) 0.68. IR (ATR): 3066, 2979, 2930, 2904, 2870, 1707, 1643, 1553, 1445, 1401, 1366, 1325, 1296, 1222,
1154, 1121, 1038, 986, 971, 864, 832, 811, 758, 694, 626, 615, 541. 1H-NMR (500 MHz, CDCl3): 1.28 (t, J ¼
7.1, 2 MeCH2); 4.22 (q, J ¼ 7.1, 2 MeCH2); 6.97 (d, J ¼ 15.6, 2 HꢀC(2’)); 7.45 (s, HꢀC(3), HꢀC(5)); 7.51
(d, J ¼ 15.6, 2 HꢀC(1’)). 13C-NMR (125 MHz, CDCl3): 14.2 (MeCH2); 60.9 (MeCH2); 124.6 (C(2’));
127.4 (C(3), C(5)); 134.0 (C(4)); 141.3 (C(1’)); 154.2 (C(2), C(6)); 166.3 (C¼O). ESI-MS: 731.0 ([2 M þ
Na]þ), 683.1, 623.1, 554.5, 517.2, 474.0, 396.0/394.0 ([M þ Na þ H2O]þ), 378.0/376.0 ([M þ Na]þ), 356.0/
354.0 ([M þ H]þ), 328.1, 301.1, 288.1, 270.1, 248.1, 216.1, 156.0. HR-ESI-MS: 354.0349 ([M þ H]þ,
C15H1779BrNOþ4 ; calc. 354.0341).
Dimethyl (2E,2’E)-3,3’-(4-Methoxypyridine-2,6-diyl)bisprop-2-enoate (12). According to GP 1, from
11 (978 mg, 5.92 mmol). Yield 741 mg (2.67 mmol, 45%). Colorless solid. M.p. 1618. Rf (hexanes/AcOEt
1:2) 0.63. IR (ATR): 3069, 2953, 2852, 1708, 1644, 1580, 1557, 1459, 1439, 1418, 1358, 1274, 1200, 1165,
1
1153, 1039, 1002, 984, 860. H-NMR (500 MHz, CDCl3): 3.83 (s, 2 MeOOC); 3.90 (s, MeO); 6.88 (s,
HꢀC(3), HꢀC(5)); 7.03 (d, J ¼ 15.7, 2 HꢀC(2’)); 7.62 (d, J ¼ 15.7, 2 HꢀC(1’)). 13C-NMR (125 MHz,
CDCl3): 51.9 (MeOOC); 55.5 (MeO); 110.8 (C(3), C(5)); 122.9 (C(2’)); 143.2 (C(1’)); 154.4 (C(2),
C(6)); 167.0 (C(4)); 167.1 (C¼O). ESI-MS: 318.1 ([M þ Na þ H2O]þ), 300.1 ([M þ Na]þ), 278.1 ([M þ
H]þ), 246.1 ([M ꢀ MeO]þ). HR-ESI-MS: 300.0841 ([M þ Na]þ, C14H15NNaOþ5 ; calc. 300.0848). Anal.
calc. for C14H15NO5 (277.27): C 60.64, H 5.45, N 5.05; found: C 60.42, H 5.48, N 4.97.
Diethyl (2E,2’E)-3,3’-{4-[(4-Bromobenzyl)oxy]pyridine-2,6-diyl}bisprop-2-enoate (20). According
to GP 1, from 19 (494 mg, 1.54 mmol), with ethyl (diethoxyphosphoryl)acetate. Yield 478 mg
(1.04 mmol, 67%). Colorless solid. M.p. 1158. Rf (hexanes/AcOEt 3 :1) 0.40. IR (ATR): 3065, 2987,
2928, 2903, 2866, 1702, 1644, 1582, 1562, 1489, 1476, 1444, 1421, 1354, 1271, 1155, 1116, 1032, 996, 873, 856,
836, 803, 764, 702. 1H-NMR (500 MHz, CDCl3): 1.35 (t, J ¼ 6.9, 2 MeCH2); 4.28 (q, J ¼ 6.9, 2 MeCH2); 5.1
(s, CH2O); 6.9 (s, HꢀC(3), HꢀC(5)); 7.0 (d, J ¼ 15.5, 2 HꢀC(2’’)); 7.29 – 7.30 (m, HꢀC(2’), HꢀC(6’) or
HꢀC(3’), HꢀC(5’)); 7.54 – 7.56 (m, HꢀC(3’), HꢀC(5’) or HꢀC(2’), HꢀC(6’)); 7.6 (d, J ¼ 15.5, 2 HꢀC(1’’)).
13C-NMR (125 MHz, CDCl3): 14.3 (MeCH2); 60.8 (MeCH2); 69.4 (CH2O); 111.3 (C(3), C(5)); 122.6
(C(4’)); 123.6 (C(2’’)); 129.2 (C(2’), C(6’) or C(3’), C(5’)); 132.0 (C(3’), C(5’) or C(2’), C(6’)); 134.2
(C(1’)); 142.8 (C(1’’)); 154.6 (C(2), C(6)); 165.8 (C(4)); 166.6 (C¼O). ESI-MS: 524.1, 502.1, 484.0/482.1
([M þ Na]þ), 462.1/460.0 ([M þ H]þ), 359.2, 328.1, 301.1, 259.0, 247.1, 185.0, 143.0. HR-ESI-MS:
460.0735 ([M þ H]þ, C22H2379BrNOþ5 ; calc. 460.0760).
General Procedure for the Suzuki Coupling of 4-Bromopyridines 6 and 8 (GP 2). To a soln. of 6 or 8
(1 equiv.) in 1,2-dimethoxyethane (DME)/H2O (28 ml, 10 :1) were added sequentially (4-chlorophen-
yl)boronic acid (1.1 equiv.), K2CO3 (5 equiv.), KF (5 equiv.), and Pd(PPh3)4 (0.05 equiv.), and the
mixture was stirred at 958 for 48 h. After cooling to r.t., the solvent was evaporated, the residue was
dissolved in CH2Cl2 (180 ml), washed with H2O (3 ꢁ 80 ml), dried (MgSO4), and evaporated. The crude
product was purified by CC (hexanes/AcOEt).
Dimethyl (2E,2’E)-3,3’-[4-(4-Chlorophenyl)pyridine-2,6-diyl]bisprop-2-enoate (14). According to
GP 2, from 6 (600 mg, 1.84 mmol). Yield 566 mg (1.58 mmol, 86%). Colorless solid. M.p. 1548. Rf
(hexanes/AcOEt 4 :1) 0.34. IR (ATR): 3066, 2949, 2837, 1706, 1640, 1600, 1541, 1495, 1433, 1389, 1260,
1239, 1224, 1187, 1095, 1057, 1032, 1011, 984, 974, 861, 817. 1H-NMR (500 MHz, CDCl3): 3.85 (s, 2 MeO);
7.10 (d, J ¼ 15.6, 2 HꢀC(2’)); 7.48 – 7.50 (m, HꢀC(2’’), HꢀC(6’’) or HꢀC(3’’), HꢀC(5’’)); 7.52 (s, HꢀC(3),
HꢀC(5)); 7.56 – 7.58 (m, HꢀC(3’’), HꢀC(5’’) or HꢀC(2’’), HꢀC(6’’)); 7.73 (d, J ¼ 15.6, 2 HꢀC(1’)).
13C-NMR (125 MHz, CDCl3): 52.0 (MeO); 122.6 (C(3), C(5)); 123.2 (C(2’)); 128.3, 129.6 (C(2’’), C(6’’),
C(3’’), C(5’’)); 135.7, 135.9 (C(1’’), C(4’’)); 142.8 (C(1’)); 149.2 (C(4)); 153.7 (C(2), C(6)); 167.1 (C¼O).
ESI-MS: 398.1 ([M þ Na þ H2O]þ), 380.1 ([M þ Na]þ), 358.1 ([M þ H]þ), 246.1 ([M ꢀ Cl ꢀ C6H4]þ).
HR-ESI-MS: 358.0828 ([M þ H]þ, C19H17ClNO4þ ; calc. 358.0846). Anal. calc. for C19H16ClNO4 (357.79):
C 63.78, H 4.51, N 3.91; found: C 63.69, H 4.58, N 3.63.
Dimethyl 3,3’-[4-(4-Chlorophenyl)pyridine-2,6-diyl]dipropanoate (15). According to GP 2, from 8
(200 mg, 0.61 mmol). Yield 184 mg (0.51 mmol, 84%). Colorless solid. M.p. 328. Following GP 4, from 14
(178 mg, 0.50 mmol) and Pd/C (15 mg). Yield 162 mg (0.45 mmol, 89%). Rf (hexanes/AcOEt 5 :1) 0.23.
IR (ATR): 2950, 1730, 1605, 1577, 1550, 1496, 1435, 1392, 1359, 1267, 1195, 1160, 1093, 1013, 988, 911, 877,
1
824, 730. H-NMR (500 MHz, CDCl3): 2.83 (t, J ¼ 7.4, 2 CH2(2’)); 3.13 (t, J ¼ 7.4, 2 CH2(1’)); 3.68 (s, 2

Helvetica Chimica Acta – Vol. 95 (2012)
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MeO); 7.18 (br. s, HꢀC(3), HꢀC(5)); 7.42 – 7.45 (m, HꢀC(3’’), HꢀC(5’’)); 7.52 – 7.55 (m, HꢀC(2’’),
HꢀC(6’’)). 13C-NMR (125 MHz, CDCl3): 32.8, 32.9 (C(1’), C(2’)); 51.6 (Me); 118.4 (C(3), C(5)); 128.3,
129.2 (C(2’’), C(6’’), C(3’’), C(5’’)); 135.0 (C(4’’)); 137.1 (C(1’’)); 147.9 (C(4)); 160.0 (C(2), C(6)); 173.7
(C¼O). ESI-MS: 384.1 ([M þ Na]þ), 362.1 ([M þ H]þ), 330.1 ([M ꢀ MeO]þ). HR-ESI-MS: 362.1161
([M þ H]þ, C19H21ClNOþ4 ; calc. 362.1159).
General Procedure for the Reduction of 4-Bromopyridines 6 and 7 (GP 3). To a mixture of 6 or 7
(1 equiv.) and NaBH4 (2 equiv.) was added a soln. of (AcO)2Ni (1 equiv.) in MeOH/AcOEt (16 ml, 1:1),
and the mixture was stirred under H2 (1 atm) at r.t. for 15 min. After evaporation of the solvent, the
residue was suspended in H2O/CH2Cl2 (17 ml, 1:1), filtered, and the layers were separated. The aq. layer
was extracted with CH2Cl2 (3 ꢁ 45 ml), the combined org. layers were dried (MgSO4), evaporated, and
the crude product was purified by CC (hexanes/AcOEt 5 :1).
Dimethyl 3,3’-(4-Bromopyridine-2,6-diyl)dipropanoate (8). According to GP 3, from 6 (1.00 g,
3.07 mmol). Yield 330 mg (1.0 mmol, 32%). Colorless solid. M.p. 678. Rf (hexanes/AcOEt 5 :1) 0.32. IR
(ATR): 2951, 2847, 1732, 1647, 1563, 1435, 1365, 1300, 1247, 1195, 1160, 1031, 986, 857, 835, 805. 1H-NMR
(500 MHz, CDCl3): 2.77 (t, J ¼ 7.4, 2 CH2(1’)); 3.04 (t, J ¼ 7.4, 2 CH2(2’)); 3.68 (s, 2 MeO); 7.19 (s, HꢀC(3),
HꢀC(5)). 13C-NMR (125 MHz, CDCl3): 32.4 (C(1’)); 32.5 (C(2’)); 51.6 (MeO); 123.8 (C(3), C(5)); 133.0
(C(4)); 160.7 (C(2), C(6)); 173.4 (C¼O). ESI-MS: 332/330.0 ([M þ H]þ), 300.0/298.0 ([M ꢀ
COOMe]þ), 294.1, 286.1, 280.2, 250.1, 218.1. HR-ESI-MS: 330.0327 ([M þ H]þ, C13H1779BrNOþ4 ; calc.
330.0341).
Diethyl 3,3’-(4-Bromopyridine-2,6-diyl)dipropanoate (9). a) According to GP 3, from 7 (760 mg,
2.15 mmol). Yield 225 mg (0.63 mmol, 29%). Colorless oil. Rf (hexanes/AcOEt 5 :1) 0.38.
b) To a suspension of 10 (443 mg, 1.50 mmol) in toluene (15 ml) was added POBr3 (phosphoryl
bromide; 850 mg, 2.96 mmol), and the mixture was refluxed for 10 h. After cooling to 08, EtOH (15 ml)
was added and the mixture was neutralized with sat. EtONa (in EtOH), filtered through SiO2, and
evaporated. The crude product was purified by CC (hexanes/AcOEt 5 :1) to give 9 (109 mg, 0.30 mmol,
20%). Colorless oil. IR (neat): 2980, 2934, 1728, 1563, 1440, 1372, 1349, 1300, 1245, 1158, 1039, 1020, 945,
858, 789, 600. 1H-NMR (500 MHz, CDCl3): 1.24 (t, J ¼ 7.2, 2 MeCH2); 2.76 (t, J ¼ 7.4, CH2(2’)); 3.04 (t, J ¼
7.4, CH2(1’)); 4.13 (q, J ¼ 7.2, 2 MeCH2); 7.19 (s, HꢀC(3), HꢀC(5)). 13C-NMR (125 MHz, CDCl3): 14.2
(MeCH2); 32.4 (C(2’)); 32.9 (C(1’)); 60.5 (MeCH2); 123.8 (C(3), C(5)); 133.0 (C(4)); 160.8 (C(2), C(6));
173.0 (C¼O). ESI-MS: 360/358.1 ([M þ H]þ), 344.1, 328.0, 312.0, 280.2, 266.1, 234.1. HR-ESI-MS:
358.0659 ([M þ H]þ, C15H2179BrNOþ4 ; calc. 358.0654).
General Procedure for the Catalytic Hydrogenation of Diacrylates 12, 14, and 20 (GP 4). To a
suspension of the respective diacrylate 12, 14, or 20 in MeOH (70 ml) was added Pd/C (10%) and the
mixture was heated under H2 (1 atm) at 608 for 15 h. After filtration through SiO2, the solvent was
removed in vacuo.
Dimethyl 3,3’-(4-Methoxypyridine-2,6-diyl)dipropanoate (13). According to GP 4, from 12 (629 mg,
2.27 mmol) and Pd/C (70 mg). Yield 581 mg (2.07 mmol, 91%). Colorless oil. Rf (hexanes/AcOEt 1:1)
0.19. IR (neat): 2951, 2846, 1732, 1596, 1574, 1463, 1435, 1364, 1259, 1192, 1147, 1065, 1040, 989, 856.
1H-NMR (500 MHz, CDCl3): 2.77 (t, J ¼ 7.5, 2 CH2(2’)); 3.02 (t, J ¼ 7.5, 2 CH2(1’)); 3.68 (s, 2 MeOOC);
3.80 (s, MeO); 6.54 (s, HꢀC(3), HꢀC(5)). 13C-NMR (125 MHz, CDCl3): 32.9 (C(2’)); 33.0 (C(1’)); 51.6
(MeOOC); 55.0 (MeO); 106.5 (C(3), C(5)); 160.9 (C(2), C(6)); 166.3 (C(4)); 173.7 (C¼O). EI-MS:
304.1 ([M þ Na]þ), 282.1 ([M þ H]þ), 250.1 ([M ꢀ MeO]þ). HR-ESI-MS: 304.1159 ([M þ Na]þ,
C14H19NNaOþ5 ; calc. 304.1161). Anal. calc. for C14H19NO5 (281.30): C 59.78, H 6.81, N 4.98; found: C
59.61, H 6.88, N 4.93.
Diethyl 3,3’-(4-Hydroxypyridine-2,6-diyl)dipropanoate (10). According to GP 4, from 20 (1.49 g,
3.25 mmol) was obtained a precipitate, which was recrystallized from CH2Cl2 to give 10 (892 mg,
3.02 mmol, 93%). Colorless solid. M.p. 1068. IR (ATR): 3421, 3257, 3090, 3046, 2911, 2796, 1717, 1626,
1480, 1449, 1417, 1376, 1354, 1297, 1284, 1179, 1161, 1056, 1021, 864, 788, 737. 1H-NMR (500 MHz,
MeOD): 1.23 (t, J ¼ 7.2, 2 MeCH2); 2.73 (t, J ¼ 7.4, 2 CH2(2’)); 2.92 (t, J ¼ 7.4, 2 CH2(1’)); 4.14 (q, J ¼ 7.2,
2 MeCH2); 6.30 (s, HꢀC(3), HꢀC(5)). 13C-NMR (125 MHz, MeOD): 14.5 (MeCH2); 29.1 (C(2’)); 33.6
(C(1’)); 62.0 (MeCH2); 114.3 (C(3), C(5)); 154.1 (C(2), C(6)); 173.4 (C¼O); 180.8 (C(4)). ESI-MS:
332.2 ([M þ H þ 2 H2O]þ), 318.1 ([M þ Na]þ), 296.2 ([M þ H]þ), 250.1 ([M ꢀ EtO]þ). HR-ESI-MS:

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Helvetica Chimica Acta – Vol. 95 (2012)
296.1487 ([M þ H]þ, C15H22NOþ5 ; calc. 296.1498). Anal. calc. for C15H21NO5 · 0.3 CH2Cl2 (323.64): C
56.90, H 6.75, N 4.33; found: C 57.11, H 6.80, N 4.47.
General Procedure for the Saponification of Esters 9, 13, 15, and 21 with Dowex A (GP 5). A
suspension of the respective ester (0.66 – 2.35 mmol) and Dowex Marathon Aꢅ basic ion exchange resin
(2.00 g) in H2O (17 ml) was refluxed for 72 h. Then, the ion exchange resin was isolated by filtration,
washed with MeOH, stirred with AcOH/H2O (1:1, 2 ꢁ 150 ml), removed by filtration and the filtrate was
concentrated. The crude product was dried in a vacuum dessiccator over P4O10 for 7 d.
3,3’-(4-Bromopyridine-2,6-diyl)dipropanoic Acid (4a). According to GP 5, from 9 (366 mg,
1.02 mmol). The crude product was recrystallized from MeOH/H2O 3 :1. Yield 301 mg (1.00 mmol,
98%). Colorless solid. M.p. 1468. IR (ATR): 3066, 2951, 2846, 1731, 1647, 1563, 1435, 1365, 1301, 1247,
1195, 1160, 1031, 986, 883, 857, 835, 805. 1H-NMR (500 MHz, D2O): 2.82 (t, J ¼ 7.2, 2 CH2(2’)); 3.21 (t, J ¼
7.2, 2 CH2(1’)); 7.89 (s, HꢀC(3), HꢀC(5)). 13C-NMR (125 MHz, D2O): 29.3 (C(1’)); 33.7 (C(2’)); 127.2
(C(3), C(5)); 141.7 (C(4)); 157.4 (C(2), C(6)); 177.8 (C¼O). ESI-MS: 304.0/302.0 ([M þ H]þ), 286.0/
284.0 ([M ꢀ OH]þ), 258.2, 238.1, 222.1 ([M ꢀ Br]þ), 206.1. HR-ESI-MS: 302.0012 ([M þ H]þ,
C11H1379BrNOþ4 ; calc. 302.0028).
3,3’-(4-Methoxypyridine-2,6-diyl)dipropanoic Acid (4c). According to GP 5, from 13 (661 mg,
2.35 mmol). Yield 555 mg (2.19 mmol, 93%). Colorless solid. M.p. 1418. IR (ATR): 2929, 2470, 1974,
1702, 1656, 1620, 1540, 1484, 1445, 1405, 1366, 1200, 1160, 939, 855, 822, 804, 708, 647. 1H-NMR
(500 MHz, (D6)DMSO): 2.61 (t, J ¼ 7.5, 2 CH2(2’)); 2.87 (t, J ¼ 7.5, 2 CH2(1’)); 3.78 (s, 2 MeOOC); 3.80 (s,
MeO); 6.69 (s, HꢀC(3), HꢀC(5)). 13C-NMR (125 MHz, (D6)DMSO): 32.4 (C(1’)); 32.8 (C(2’)); 51.6
(MeOOC); 55.1 (MeO); 106.3 (C(3), C(5)); 160.8 (C(2), C(6)); 166.0 (C(4)); 174.0 (C¼O). EI-MS:
253.1 (40, Mþ), 236.1 (10, [M ꢀ OH]þ), 208.1 (100, [M ꢀ COOH]þ), 190.1 (36), 163.1 (24, [M ꢀ 2
COOH]þ), 148.1 (5), 135.1 (5), 119.1 (3), 106.1 (2), 91.1 (2), 77.0 (2), 65.1 (2), 44.0 (2). HR-ESI-MS:
276.0834 ([M þ Na]þ), C12H15NNaOþ5 ; calc. 276.0848).
3,3’-[4-(4-Chlorophenyl)pyridine-2,6-diyl]dipropanoic Acid (4d). According to GP 5, from 15
(240 mg, 0.66 mmol). Yield 194 mg (0.58 mmol, 88%). Colorless solid. M.p. 1578. IR (ATR): 2930,
2470, 1974, 1702, 1656, 1 620, 1541, 1484, 1445, 1405, 1366, 1316, 1200, 1160, 939, 855, 822, 804, 746, 708,
647, 589. 1H-NMR (500 MHz, (D6)DMSO): 2.73 (t, J ¼ 7.4, 2 CH2(2’)); 3.01 (t, J ¼ 7.4, 2 CH2(1’)); 7.32 (br.
s, HꢀC(3), HꢀC(5)); 7.37 – 7.48 (m, HꢀC(3’’), HꢀC(5’’)); 7.58 – 7.65 (m, HꢀC(2’’), HꢀC(6’’)). 13C-NMR
(125 MHz, (D6)DMSO): 33.1, 33.8 (C(1’), C(2’)); 118.9 (C(3), C(5)); 129.3, 129.6 (C(2’’), C(6’’), C(3’’),
C(5’’)); 135.9 (C(4’’)); 137.7 (C(1’’)); 148.2 (C(4)); 160.3 (C(2), C(6)); 175.2 (C¼O). ESI-MS: 334.1
([M þ H]þ), 279.1. HR-ESI-MS: 334.0836 ([M þ H]þ, C17H17ClNOþ4 ; calc. 334.0846).
3,3’-{4-[(4-Bromobenzyl)oxy]pyridine-2,6-diyl}dipropanoic Acid (4e). According to GP 5, from 21
(477 mg, 1.03 mmol). The crude product was recrystallized from MeOH/CHCl3 1:1. Yield 396 mg
(0.97 mmol, 94%). Colorless solid. M.p. 2038. IR (ATR): 2925, 2458, 1974, 1664, 1622, 1540, 1486, 1475,
1
1450, 1415, 1367, 1340, 1320, 1252, 1214, 1170, 1107, 1086, 1052, 1009, 965, 869, 852, 826, 800. H-NMR
(500 MHz, (D6)DMSO): 2.62 (t, J ¼ 7.5, 2 CH2(2’’)); 2.88 (t, J ¼ 7.5, 2 CH2(1’’)); 5.12 (s, CH2O)); 6.77 (s,
HꢀC(3), HꢀC(5)); 7.41 – 7.42 (m, 2 H of HꢀC(2’), HꢀC(6’), HꢀC(3’), HꢀC(5’)); 7.59 – 7.61 (m, 2 H of
HꢀC(2’), HꢀC(6’), HꢀC(3’), HꢀC(5’)). 13C-NMR (125 MHz, (D6)DMSO): 32.3 (C(1’’)); 32.7 (C(2’’));
68.2 (C(7)); 106.9 (C(3), C(5)); 121.2 (C(4’)); 128.5, 129.9 (C(2’), C(6’), C(3’), C(5’)); 135.7 (C(1’));
160.9 (C(2), C(6)); 164.9 (C(4)); 173.9 (C¼O). ESI-MS: 448.0/446.0 ([M þ K]þ), 432.0/430.0 ([M þ
Na]þ), 422.1, 410.0/408.0 ([M þ H]þ). HR-ESI-MS: 430.0252 ([M þ Na]þ, C18H1879BrNNaOþ5 ; calc.
430.0266). Anal. calc. for C18H18BrNO5 · 0.5 H2O (417.25): C 51.81, H 4.59, N 3.36; found: C 51.81, H 4.45,
N 3.34.
3,3’-(4-Hydroxypyridine-2,6-diyl)dipropanoic Acid Hydrochloride (4b · HCl). A soln. of 10 (4.00 g,
13.5 mmol) in conc. HCl/H2O (1.5 :1, 100 ml) was refluxed for 24 h. After evaporation of the solvent, the
crude product was recrystallized from H2O and dried in a vacuum dessiccator over P4O10 for 7 d to give
4b · HCl (3.41 g, 12.4 mmol, 91%). Colorless solid. M.p. 2128. IR (ATR): 3087, 2858, 2460, 1994, 1733,
1708, 1626, 1477, 1419, 1402, 1385, 1324, 1289, 1213, 1181, 1159, 1026, 930, 865, 783, 668, 563, 533.
1H-NMR (500 MHz, D2O): 2.76 (t, J ¼ 7.2, 2 CH2(2’)); 3.04 (t, J ¼ 7.2, 2 CH2(1’)); 6.90 (s, HꢀC(3),
HꢀC(5)). 13C-NMR (125 MHz, D2O): 27.6 (C(1’)); 32.1 (C(2’)); 111.2 (C(3), C(5)); 156.0 (C(2), C(6));
171.3 (C(4)); 175.7 (C¼O). ESI-MS: 262.1 ([M þ Na ꢀ HCl]þ), 240.1 ([M þ H ꢀ HCl]þ), 222.1 ([M ꢀ

Helvetica Chimica Acta – Vol. 95 (2012)
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HCl ꢀ OH]þ). HR-ESI-MS: 240.0857 ([M þ H ꢀ HCl]þ, C11H14NO5þ ; calc. 240.0872). Anal. calc. for
C11H14ClNO5 (275.69): C 47.92, H 5.12, Cl 12.86, N 5.08; found: C 47.74, H 5.08, Cl 12.64, N 4.97.
General Procedure for the Williamson Etherification of 4-Hydroxypyridines 16 and 10 (GP 6). A
suspension of K2CO3 (2 – 2.4 equiv.), the respective ester 16 or 10 (1 equiv.) and 1-bromo-4-
(bromomethyl)benzene (1 equiv.) in MeCN (10 – 25 ml) was heated under reflux for 17 h. After cooling
to r.t., the mixture was filtered and treated with ice water (10 – 25 ml). The resulting precipitate was
isolated by filtration and recrystallized from toluene.
Dimethyl 4-[(4-Bromobenzyl)oxy]pyridine-2,6-dicarboxylate (17). According to GP 6, from 16
(771 mg, 3.65 mmol). Yield 1.04 g (2.74 mmol, 75%). Colorless solid. M.p. 1618. IR (ATR): 3089, 2949,
1739, 1716, 1592, 1493, 1437, 1348, 1250, 1230, 1187, 1161, 1106, 1026, 1002, 891, 880, 801, 795, 786.
1H-NMR (500 MHz, CDCl3): 4.02 (s, 2 MeO); 5.19 (s, CH2O); 7.31 – 7.33 (m, 2 H of HꢀC(2’), HꢀC(6’),
HꢀC(3’), HꢀC(5’)); 7.55 – 7.56 (m, 2 H of HꢀC(2’), HꢀC(6’), HꢀC(3’), HꢀC(5’)); 7.88 (s, HꢀC(3),
HꢀC(5)). 13C-NMR (125 MHz, CDCl3): 53.4 (MeO); 70.0 (CH2O); 114.8 (C(3), C(5)); 122.9 (C(4’));
129.3, 132.1 (C(2’), C(6’), C(3’), C(5’)); 133.7 (C(1’)); 149.9 (C(2), C(6)); 165.1 (C¼O); 166.5 (C(4)).
ESI-MS: 404.0/402.0 ([M þ Na]þ), 382.0/380.0 ([M þ H]þ), 358.1. HR-ESI-MS: 380.0136 ([M þ H]þ,
C16H15BrNOþ5 ; calc. 380.0134). Anal. calc. for C16H14BrNO5 (380.19): C 50.55, H 3.71, N 3.68; found: C
50.34, H 3.82, N 3.63.
Diethyl 3,3’-{4-[(4-Bromobenzyl)oxy]pyridine-2,6-diyl}dipropanoate (21). GP 6 and modified work-
up: reaction of 10 (1.03 g, 3.49 mmol) gave a precipitate, which was isolated by filtration, and the filtrate
was extracted with CHCl3 (3 ꢁ 50 ml), dried (MgSO4), and evaporated. The combined crude products
were purified by CC (hexanes/AcOEt 2 :1, then EtOH/CH2Cl2 1:1). Yield 1.36 g (2.93 mmol, 84%).
Colorless solid. M.p. 308. IR (ATR): 2981, 2939, 2876, 1969, 1722, 1596, 1570, 1489, 1438, 1406, 1373s,
1268s, 1184s, 1144vs, 1009s, 989s, 942m, 862s, 846s, 806s, 718m, 668m, 606m. 1H-NMR (500 MHz, MeOD):
1.23 (t, J ¼ 7.2, 2 MeCH2); 2.73 (t, J ¼ 7.5, 2 CH2(2’’)); 3.01 (t, J ¼ 7.5, 2 CH2(1’’)); 4.11 (q, J ¼ 7.2, 2
MeCH2); 5.14 (s, CH2O); 6.78 (s, HꢀC(3), HꢀC(5)); 7.37 – 7.40 (m, 2 H of HꢀC(2’), HꢀC(6’), HꢀC(3’),
HꢀC(5’)); 7.55 – 7.58 (m, 2 H of HꢀC(2’), HꢀC(6’), HꢀC(3’), HꢀC(5’)). 13C-NMR (125 MHz, MeOD):
14.6 (MeCH2); 33.7 (C(1’’)); 34.6 (C(2’’)); 61.6 (MeCH2); 70.1 (CH2O); 108.7 (C(3), C(5)); 123.0 (C(4));
130.6, 132.8 (C(2’), C(6’), C(3’), C(5’)); 137.0 (C(1’)); 162.7 (C(2), C(6)); 167.5 (C(4)); 174.6 (C¼O). ESI-
MS: 488/486.1 ([M þ Na]þ), 466/464.1 ([M þ H]þ), 418.1, 387/385.2 ([M ꢀ EtOOC(CH2)2]þ), 171/169.0
([Brꢀ C6H4 ꢀ CH2]þ). HR-ESI-MS: 464.1067 ([M þ H]þ, C22H2779BrNO5þ ; calc. 464.1073). Anal. calc.
for C22H26BrNO5 (464.35): C 56.90, H 5.64, N 3.02; found: C 56.63, H 5.57, N 2.96.
{4-[(4-Bromobenzyl)oxy]pyridine-2,6-diyl}dimethanol (18). To an ice-cooled suspension of 17
(3.11 g, 8.18 mmol) in MeOH (60 ml) was added portionwise NaBH4 (1.49 g, 39.23 mmol), and the
mixture was stirred at 08 for 1 h, at r.t. for 2 h, and under reflux for 14 h. After cooling to r.t., the solvent
was evaporated, and the residue was treated with a soln. of K2CO3 (6.00 g) in H2O (25 ml) and refluxed
for 2 h. Then the mixture was continuously extracted with CH2Cl2 for 22 h. After removal of the solvent,
18 was isolated (870 mg, 2.69 mmol, 32%). Colorless solid. M.p. 1528. IR (ATR): 3300, 3093, 2894, 2844,
2716, 1601, 1573, 1489, 1445, 1433, 1353, 1310, 1220, 1150, 1090, 1070, 1032, 1001, 927, 870, 849, 804, 754,
676. 1H-NMR (500 MHz, MeOD): 4.64 (s, 2 CH2OH); 5.24 (s, CH2O); 7.08 (s, HꢀC(3), HꢀC(5)); 7.44 –
7.46 (m, 2 H of HꢀC(2’), HꢀC(6’), HꢀC(3’), HꢀC(5’)); 7.60 – 7.63 (m, 2 H of HꢀC(2’), HꢀC(6’),
HꢀC(3’), HꢀC(5’)). 13C-NMR (125 MHz, MeOD): 65.4 (CH2); 70.2 (CH2O); 106.7 (C(3), C(5)); 123.1
(C(4’)); 130.9, 131.6 (C(2’), C(6’), C(3’), C(5’)); 137.2 (C(1’)); 164.2 (C(2), C(6)); 168.21 (C(4)). ESI-MS:
348.0/346.0 ([M þ Na]þ), 326.0/324.0 ([M þ H]þ), 171.0/169.0 ([Brꢀ C6H4 ꢀ CH2]þ). HR-ESI-MS:
324.0209 ([M þ H]þ, C14H1579BrNOþ3 ; calc. 324.0235).
4-[(4-Bromobenzyl)oxy]pyridine-2,6-dicarbaldehyde (19). To a suspension of 18 (600 mg,
1.88 mmol) in dioxane (10 ml) was added SeO2 (216 mg, 1.95 mmol), and the mixture was heated at
958 for 20 h. After cooling to r.t. and filtration through SiO2, the solvent was evaporated, and the crude
product was purified by CC (CH2Cl2/AcOEt 1:3) to give 19 (507 mg, 1.59 mmol, 84%). Colorless solid.
M.p. 1228. IR (ATR): 3077, 2847, 2856, 1705, 1678, 1593, 1557, 1487, 1459, 1445, 1385, 1367, 1316, 1278,
1210, 1192, 1163, 1071, 1050, 1009, 987, 949, 917, 882, 832, 800, 730, 703. 1H-NMR (500 MHz, CDCl3): 5.20
(s, CH2O); 7.30 – 7.32 (m, 2 H of HꢀC(2’), HꢀC(6’), HꢀC(3’), HꢀC(5’)); 7.54 – 7.56 (m, 2 H of HꢀC(2’),
HꢀC(6’), HꢀC(3’), HꢀC(5’)); 7.69 (m, HꢀC(3), HꢀC(5)); 10.11 (s, 2 CHO). 13C-NMR (125 MHz,
CDCl3): 70.16 (CH2O); 111.7 (C(3), C(5)); 127.8 (C(4’)); 129.5, 132.1 (C(2’), C(6’), C(3’), C(5’)); 133.5

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Helvetica Chimica Acta – Vol. 95 (2012)
(C(1’)); 154.9 (C(2), C(6)); 166.5 (C(4)); 192.2 (CHO). ESI-MS: 408.0/406.0 ([M þ Na þ 2 MeOH]þ),
376.0/374.0 ([M þ Na þ MeOH]þ), 344.0/342.0 ([M þ Na]þ), 301.1, 286.0/284.0 ([M þ Na ꢀ 2 CHO]þ).
HR-ESI-MS: 341.9736 ([M þ Na]þ), C14H1079BrNNaO3þ ; calc. 341.9742).
Iron Complex Fe3(m3-O)(4aH)4(H2O)(ClO4)3 · 5 H2O (3a). A soln. of 4a (140 mg, 463 mmol) and
LiOH (23 mg, 958 mmol) in MeOH (2 ml) was stirred at r.t. for 20 min. Then was added a soln. of
Fe(ClO4)3 · x H2O (164 mg, 463 mmol) in MeOH (0.5 ml) and the mixture was stirred at r.t. for 5 min. The
orange-red precipitate was isolated by filtration, dissolved in MeOH/H2O (2 :1, 5 ml) and heated at
reflux for 1 min. Slow evaporation of the solvent over three weeks gave 3a (140 mg, 80 mmol, 69% based
on 4a). Red solid. M.p. 2388 (dec.). UV/VIS (H2O): 271 (4.50). IR (ATR): 3529, 3293, 3084, 2951, 2768,
2013, 1606, 1560, 1489, 1436, 1401, 1366, 1311, 1200, 1165, 1077, 1004, 980, 949, 875, 851, 741, 678, 652, 620.
ESI-MS: 1385.7 ([C44H42Br4Fe3N4O17]þ), 1362.8, 1316.9, 1100.74 ([C33H32Br3Fe3N3O14]þ), 1082.73,
680.93. HR-ESI-MS: 1381.7351 ([M ꢀ 3 ClO4 ꢀ H2O]þ, C44H44Br4Fe3N4O1þ7 ; 1385.7286).
Attempted Synthesis of Iron Complex Fe3(m3-O)(4bH)4(H2O)(ClO4)3 · 5 H2O (3b). A soln. of 4b
(200 mg, 790 mmol) and LiOH (38 mg, 1.58 mmol) in MeOH (4 ml) was stirred at r.t. for 20 min. Then
was added a soln. of Fe(ClO4)3 · x H2O (280 mg, 791 mmol) in MeOH (1.5 ml) and the mixture was stirred
at r.t. for 5 min. However, no precipitate was obtained.
Iron Complex Fe3(m3-O)(4cH)4(H2O)(ClO4)3 · 5 H2O (3c). A soln. of 4c (200 mg, 790 mmol) and
LiOH (38 mg, 1.58 mmol) in MeOH (4 ml) was stirred at r.t. for 20 min. Then was added a soln. of
Fe(ClO4)3 · x H2O (280 mg, 791 mmol) in MeOH (1.5 ml) and the mixture was stirred at r.t. for 5 min. The
orange-red precipitate was isolated by filtration, dissolved in MeOH/CH2Cl2 (1:3, 4 ml) and refluxed for
1 min. Slow evaporation of the solvent over 3 d gave 3c (118 mg, 75 mmol, 38% based on 4c). Red solid.
M.p. 2478 (dec.). UV/VIS (H2O): 270 (4.78). IR (ATR): 3529, 3293, 3084, 2951, 2768, 2013, 1606, 1560,
1489, 1436, 1401, 1366, 1311, 1200, 1165, 1077, 1004, 980, 949, 875, 851, 741, 678, 652, 620. ESI-MS: 955.0,
937.0, 595.57 ([C48H56Fe3N4O21]2þ), 542.1, 514.5, 460.0, 316.0. HR-ESI-MS: 595.5705 ([M ꢀ 3 ClO4 ꢀ
H2O]2þ), [C48H56Fe3N4O21]2þ; calc. 596.0743).
Iron Complex Fe3(m3-O)(4dH)4(H2O)(ClO4)3 · 3 MeOH (3d). A soln. of 4d (100 mg, 300 mmol) and
LiOH (14.5 mg, 604 mmol) in MeOH (2 ml) and CHCl3 (1 ml) was stirred at r.t. for 20 min. Then was
added a soln. of Fe(ClO4)3 · x H2O (106 mg, 300 mmol) in MeOH (0.5 ml), and the mixture was stirred at
r.t. for 5 min. The yellow precipitate was isolated by filtration, dissolved in MeOH/CHCl3 (1:4, 5 ml),
and refluxed for 1 min. Slow evaporation of the solvent over 2 d gave 3d (62 mg, 34 mmol, 45% based on
4d). Red solid. M.p. 2288 (dec.). UV/VIS (H2O): 271 (4.65). IR (ATR): 3301, 2972, 1716, 1628, 1594,
1544, 1488, 1441, 1402, 1365, 1315, 1229, 1170, 1058, 1011, 978, 882, 830, 809, 733, 669, 619, 556. ESI-MS:
1512.1 ([C68H58Cl4Fe3N4O17]þ), 1480.0, 1197.0 ([C51H44Cl3Fe3N3O14]þ), 1179.0 ([C51H42Cl3Fe3N3O13]þ),
1164.9, 1103.0, 954.0. HR-ESI-MS: 1510.0601 ([M ꢀ 3 ClO4 ꢀ H2O]þ, C68H60Cl4Fe3N4Oþ17 ; calc.
1512.0570).
Iron Complex Fe3(m3-O)(4eH)4(H2O)(ClO4)3 · 3 MeOH (3e). A soln. of 4e (40 mg, 98 mmol) and
LiOH (5 mg, 208 mmol) in MeOH (1 ml) and CHCl3 (2 ml) was stirred at r.t. for 20 min. Then was added
a soln. of Fe(ClO4)3 · x H2O (45 mg, 127 mmol) in MeOH (0.5 ml), and the mixture was stirred at r.t. for
5 min. Slow evaporation of the solvent over 18 h gave 3e (29 mg, 13 mmol, 52% based on 4e). Red solid.
M.p. 2188 (dec.). UV/VIS (H2O): 271 (4.76). IR (ATR): 3291, 2976, 1727, 1626, 1593, 1487, 1441, 1403,
1359, 1315, 1214, 1167, 1092, 1068, 1010, 980, 875, 843, 806, 734, 654, 619, 572. ESI-MS: 1827.9
([C72H68Br4Fe3N4O22]þ), 1809.9 ([C72H66Br4Fe3N4O21]þ), 1420.9 ([C54H50Br3Fe3N3O17]þ), 1402.9
([C54H48Br3Fe3N3O16]þ), 905.05 ([C72H67Br4Fe3N4O21]2þ). HR-ESI-MS: 1805.9035 ([M ꢀ 3 ClO4 ꢀ
H2O]þ, C72H68Br4Fe3N4O2þ1 ; calc. 1809.8960).
Gif-Type Oxidation of a-Pinene (22). a-Pinene (22; 275 mg, 2.02 mmol) and the respective iron
complex 3 (7 mmol) were dissolved in pyridine (27 ml) and AcOH (2.3 ml). Zinc powder (1.31 g,
20.0 mmol) was added, and the mixture was stirred under O2 (1 atm) at r.t. for 18 h. Then, an aliquot
(5 ml) was taken, which was diluted with H2O (5 ml) and extracted with Et2O (3 ꢁ 10 ml). The combined
org. layers were washed sequentially with H2O (30 ml), 1n HCl (30 ml), and brine (30 ml), and then
dried (MgSO4). After filtration, the org. layer was analyzed by capillary GC. The product ratio was
determined by addition of a defined amount of 23. The retention times of a-pinene (22), myrtenol (23),
verbenone (24), myrtenal (25), and a-pinene oxide (26) were compared with authentic reference
samples. The reproducibility was checked by repeating each catalytic experiment three times.

Helvetica Chimica Acta – Vol. 95 (2012)
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Received May 9, 2011