Ring-chain tautomerism of the novel 2-ferrocenyl-2,4-dihydro-1H-3,1- benzoxazine

Article abstract of DOI:10.1021/jo050437v

The synthesis and the study of the spectroscopic and electrochemical properties as well as the solution behavior of the novel 2-ferrocenyl-2,4- dihydro-1H-3,1-benzoxazine (1a) are described. NMR studies reveal the existence of a tautomeric equilibria between the cyclic (1a) and the open-chain form (2a). Electrochemical studies based on cyclic voltametry and ⁵⁷Fe Moessbauer spectroscopy as well as a comparative study of the ring-chain tautomerism of 1a and that of 2-phenyl-2,4-dihydro-1H-3,1-benzoxazine (3a) are also reported.

Full text of DOI:10.1021/jo050437v

SCHEME 1. Six-Endo and Five-Endo-Trig
Processes
Ring-Chain Tautomerism of the Novel
2-Ferrocenyl-2,4-dihydro-1H-3,1-benzoxazine
Sonia Pe´rez,† Concepcio´n Lo´pez,*,† Amparo Caubet,†
Anna Roig,‡ and Elies Molins‡
Departament de Quı´mica Inorga`nica, Facultat de Quı´mica,
Universitat de Barcelona, Martı´ i Franque`s 1-11,
08028-Barcelona, Spain, and Institut de Cie`ncia de
Materials de Barcelona (ICMAB-CSIC),
heterocycle.1 For these systems, Baldwin3 has established
that the formation of 1,3-oxazines (via a 6-endo-trig
process) is more favored than the 5-endo-trig reaction
(Scheme 1), which would lead to oxazolidines. Besides
that, it has been proven that this sort of tautomerism
affects the reactivity of the two species involved in the
process.1,2 This property appears to be specially important
from the point of view of their potential utility in organic
synthesis as well as in medical or physical chemistry.1,2
On the other hand and despite (a) the wide variety of
examples of ring-chain tautomerism of 1,3-oxazines
reported so far,1-2,4 (b) the increasing effort devoted to
the study of the effects induced by the substituents upon
this equilibria,2 and (c) the potential utility of the
incorporation of a ferrocenyl group in the backbone of the
oxazines, as far as we know, oxazines holding ferrocenyl
units have not been reported so far. In the view of this,
and as a part of a project directed toward the synthesis
of ferrocene derivatives containing two different hetero-
atoms with good donor abilities (i.e., N and S, O, or N′),5
in this work we present the first example of a 3,1-
benzoxazine holding a ferrocenyl group at position-2, as
well as the study of the tautomeric equilibrium between
the cyclic and the open-chain (Schiff base) forms.
The reaction between equimolar amounts of ferro-
cenecarboxaldehyde (hereinafter referred to as FcCHO)
and aminobenzyl alcohol in refluxing benzene produced
2-ferrocenyl-2,4-dihydro-1H-3,1-benzoxazine (1a) (Scheme
2). These results are in sharp contrast with those
obtained when FcCHO was treated with H2NCH(R1)CH2-
OH (R1 ) H, Me, or CHMe), which gave [(η5-C5H5)Fe-
{(η5-C5H4)CHdN{CH(R1)CH2OH}],5b-e in agreement with
Baldwin’s rules.3
Campus de la Universitat Auto`noma de Barcelona,
08193-Bellaterra, Spain
conchi.lopez@qi.ub.es
Received March 8, 2005
The synthesis and the study of the spectroscopic and
electrochemical properties as well as the solution behavior
of the novel 2-ferrocenyl-2,4-dihydro-1H-3,1-benzoxazine (1a)
are described. NMR studies reveal the existence of a tau-
tomeric equilibria between the cyclic (1a) and the open-chain
form (2a). Electrochemical studies based on cyclic voltametry
and 57Fe Mo¨ssbauer spectroscopy as well as a comparative
study of the ring-chain tautomerism of 1a and that of
2-phenyl-2,4-dihydro-1H-3,1-benzoxazine (3a) are also re-
ported.
The study of the ring-chain tautomerism1 involving
1,3-O,N-heterocycles has attracted great interest in the
past decade.2 In this sort of process, an imino alcohol
undergoes a reversible intramolecular C-H addition of
the -OH group to the >CdN- moiety giving a 1,3-O,N-
Compound 1a was characterized in the solid state by
elemental analyses, FAB+ mass spectra, infrared, vis-
ible-ultraviolet, 13C{1H} NMR, and Mo¨ssbauer spectros-
copy. The elemental analyses of 1a were consistent with
the proposed formula, and its infrared spectrum showed
* To whom correspondence should be addressed. Tel: (34)-93-403-
91-34. Fax: (34)-93-490-77-25.
† Universitat de Barcelona.
‡ Institut de Cie`ncia de Materials.
(1) Valters, R.; Flitsch, W. Ring-Chain Tautomerism; Plenum: New
York, 1985; and references therein.
(2) (a) La´za´r, L.; Fu¨lo¨p, F. Eur. J. Org. Chem. 2003, 3025-3042 and
references therein. (b) Fu¨lo¨p, F.; Berna´th, G.; Pihlaja, K. Adv. Hetero-
cycl. Chem. 1998, 69, 348 and references therein. (c) Valters, R. E.;
Fu¨lo¨p, F.; Korbonits, D. Adv. Heterocycl. Chem. 1996, 66, 1. (d) Valters,
R. E.; Fu¨lo¨p, F.; Korbonits, D. Adv. Heterocycl. Chem. 1995, 64, 251.
(e) Szatma´ri, I.; Martinek, T. A.; La´za´r, L.; Koch, A.; Kleinpeter, E.;
Neuvonen, K.; Fu¨lo¨p, F. J. Org. Chem. 2004, 69, 3645. (f) Hete´nyi, A.;
Szakonyi, Z.; Klika, K. D.; Pihlaja, K.; Fu¨lo¨p, F. J. Org. Chem. 2003,
68, 2175. (g) Szatma´ri, I.; Martinek, T. A.; La´za´r, L.; Fu¨lo¨p, F.
Tetrahedron 2003, 59, 2877. (h) Alloway, C. L.; Daly, M.; Nieuwen-
huyzen, M.; Saunders: G. C. J. Fluorine Chem. 2002, 115, 91. (i)
Szakonyi, Z.; Fu¨lo¨p, F.; Berna´th, G.; Evanics, F.; Riddell, F. G.
Tetrahedron 1998, 54, 1013. (j) Star, A.; Fuchs, B. J. Org. Chem. 1999,
64, 1166. (k) Riddell, F. G.; Rogerson, M.; Fu¨lo¨p, F.; Berna´th, G. Magn.
Reson. Chem.1995, 33, 600. (l) La´za´r, L.; Lakatos, A. G.; Fu¨lo¨p, F.;
Berna´th, G.; Riddell, F. Tetrahedron 1997, 53, 1081. (m) Riddell, F.
G.; Arumugan, S.; Fu¨lo¨p, F.; Berna´th, G. Tetrahedron 1992, 48, 4979.
(n) Fu¨lo¨p, F.; Pihlaja, K.; Neuvonen, K.; Be´rnath, G.; Argay, G.;
Ka´lma´n, A. J. Org. Chem. 1993, 58, 1967. (o) Neuvonen, K.; Fu¨lo¨p, F.;
Neuvonen, H.; Koch, A.; Kleinpeter, E.; Pihlaya, K. J. Org. Chem. 2001,
66, 4132.
(3) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(4) (a) Saeed, A. H. J. Heterocycl. Chem. 1992, 19, 113. (b) Fu¨lo¨p,
F.; Pihlaja, K.; Mattinen, J.; Berna´th, G. J. Org. Chem. 1987, 52, 3821.
(c) Vainiotalo, P.; Ronkanen, S.; Fu¨lo¨p, F.; Pihlaja, K. Tetrahedron
1990, 46, 3683. (d) Astudillo, M. E. A.; Chokotko, N. C. J.; Jarvis, T.
C.; Johnson, C. D.; Lewis, C. C.; McDonnell, P. D. Tetrahedron 1985,
41, 5919. (e) McDonagh, A. F.; Smith, H. E. J. Chem. Soc., Chem.
Commun. 1966, 374. (f) McDonagh, A. F.; Smith, H. E. J. Org. Chem.
1968, 33, 1 and 8.
(5) (a) Lo´pez, C.; Bosque, R.; Arias, J.; Evangelio, E.; Solans, X.;
Font-Bard´ıa, M. J. Organomet. Chem. 2003, 672, 34. (b) Caubet, A.;
Lo´pez, C.; Bosque, R.; Solans, X.; Font-Bard´ıa, M. J. Organomet. Chem.
1999, 577, 292. (c) Lo´pez, C.; Caubet, A.; Pe´rez, S.; Solans, X.; Font-
Bard´ıa, M. J. Organomet. Chem. 2002, 651, 105. (d) Lo´pez, C.; Caubet,
A.; Solans, X.; Font-Bard´ıa, M. J. Organomet. Chem. 2000, 598, 87.
(e) Lo´pez, C.; Caubet, A.; Pe´rez, S.; Solans, X.; Font-Bard´ıa, M. Chem.
Commun. 2004, 540. (f) Pe´rez, S.; Lo´pez, C.; Caubet, A.; Bosque, R.;
Solans, X.; Font-Bard´ıa, M.; Roig, A.; Molins, E., Organometallics 2004,
24, 224. (g) Lo´pez, C.; Caubet, A.; Bosque, R.; Solans, X.; Font-Bardia,
M. J. Organomet. Chem. 2002, 645, 146.
10.1021/jo050437v CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/12/2005
J. Org. Chem. 2005, 70, 4857-4860
4857

SCHEME 2. Ring-Chain Tautomeric Processes for Compounds under Study
TABLE 1. 57Fe Mo1ssbauer Hyperfine Parameters (at 80
K)a
a sharp and intense band at 3348 cm-1 due to the
stretching of the >N-H functional group of the oxazine.
The solid state 13C{1H} NMR spectrum of 1a showed five
signals in the range 60-95 ppm, of which the most
intense was assigned to the carbon nuclei of the C5H5
ring. The resonances at δ ) 88.4 and 82.7 ppm were due
to the ipso-carbon of the C5H4 ring and that of the
-CHN< fragment of the oxazine ring, respectively, while
the remaining two signals were assigned to the C3 and
C4 nuclei of the C5H4 moiety. In the lower field regions
the signals due to the aromatic carbon nuclei were also
observed.
1a
2b
2c
i.s.
∆Eq
Γ
Epa
Epc
E1/2
∆E
0.489(2)
2.408(2)
0.254(4)
0.525(2)
2.255(4)
0.237(4)
0.502(2)
2.251(4)
0.361(6)
102
232
250
23
62
79
157
194
75
191
184
132
a Isomer shift (i.s.); quadrupole splitting (∆Eq); full-width at
half-heigth (Γ) (in mm/s) and electrochemical data (in mV) [anodic
(Epa), cathodic (Epc), and half-wave potentials (E1/2) (referred to
the ferrocene/ferricinium couple)]; and separation of the peaks (∆E)
for 1a and [(η5-C5H5)Fe{(η5-C5H4)-CHdN-(C6H4-2R2)}] [R2 ) Me
(2b) or SMe (2c)]
It is well-known that the 57Fe Mo¨ssbauer spectroscopic
study of ferrocene derivatives is a very useful tool to
elucidate the effects induced by the substituents upon
the electronic environment of the iron(II) nuclei.6 In
general, it is widely accepted that electron-donating
substituents cause an increase in the quadrupole split-
tings (∆Eq) relative to ferrocene, whereas electron-
withdrawing groups produce a decrease in the ∆Eq
parameter.6c Since as far as we know, 1a is the first
example of a 2-substituted [3,1]-benzoxazine bearing a
ferrocenyl group, it seemed interesting to characterize it
by Mo¨ssbauer spectroscopy. The 57Fe Mo¨ssbauer spec-
trum of 1a (Figure 1) consists of a single quadrupole
moiety has a weaker electron-withdrawing ability than
the >CdN- group but it is greater than that of hydrogen
in ferrocene itself (∆Eq ) 2.41 mm/s at 80 K). These
findings suggest that the electron-withdrawing ability of
the substituents in the three cases increases according
to the sequence H e 3,1-benzoxazine < CHdN(C6H4-2-
R2).
Proton and 13C{1H} NMR spectra of 1a in acetone-d6
at 300 K showed two sets of superimposed signals. One
of them agreed with those expected for the 2-substituted
[3,1]-benzoxazine, while the remaining group of reso-
nances was consistent, according to the literature,5 with
the presence of the Schiff base: [(η5-C5H5)Fe{(η5-C5H4)-
CHdN(C6H4-2-CH2OH)}] (2a), thus suggesting the co-
existence of the ring (1a) and open-chain (2a) tautomers
in solution. The relative proportions 1a/2a were deter-
mined by integration of the well-separated signals due
to the protons of the “N-CH(ring)-O” (for 1a) and that
of the imine group (in 2a). In all cases, the samples were
dissolved in the appropiate deuterated solvent and the
solutions were allowed to stand for some time to be sure
that the equilibria were reached. To elucidate whether
the extent of the tautomeric equilibria would be tuned
by the solvent, the 1H NMR spectra were also registered
at 300 K in methanol-d4 and benzene-d6. The results
obtained7 revealed that the equilibrium is solvent de-
pendent and the percentage of the open-chain form (2a)
increased according to the sequence benzene-d6 < acetone-
d6 < methanol-d4, thus suggesting that the ring form is
less favored in solvents with greater dielectric constants.8
This finding is consistent with the results obtained for
related organic oxazines. The spectrum of a freshly
FIGURE 1. 57Fe Mossbauer spectrum of 1a at 80 K.
doublet indicating a unique iron site. For 1a, the ∆Eq
parameter is greater than those of the Schiff bases: [(η5-
C5H5)Fe{(η5-C5H4)CHdN(C6H4-2-R2)}] [R2 ) Me (2b) or
SMe (2c)5f] (Table 1), thus indicating that the oxazine
(6) (a) Houlton, A.; Miller, J. R.; Silver, J.; Jasim, N.; Ahmet, M. T.;
Axon, T. L.; Bloor, D.; Cross, G. H. Inorg. Chim. Acta,1993, 205, 65.
(b) Houlton, A.; Miller, J. R.; Roberts, R. G. M.; Silver, J. J. Chem.
Soc., Dalton Trans. 1991, 467. (c) Houlton, A.; Bishop, P. T.; Roberts,
R. G. M.; Silver, J.; Herberhold, H. J. Organomet. Chem. 1989, 364,
381.
(7) Molar ratios 1a/2a in benzene-d6 ) 13.7, acetone-d6 ) 2.50,
methanol-d4 ) 0.5, and DMSO-d6 ) 1.1 at 300 K.
(8) Handbook of Chemistry and Physics, 84th ed.; Lide, D. R., Ed.;
CRC Press: Boca Raton, 2004.
(9) Molar ratios 3a/4a ) 14.1 (benzene-d6), 7.4 (acetone-d6), and 2.2
(methanol-d4).
4858 J. Org. Chem., Vol. 70, No. 12, 2005

All these findings are consistent with those expected
for a simple reversible one-electron-transfer process. For
1a, the ∆E value departs from the constant value of 59
mV (theoretically expected for an electrochemically re-
versible one-electron step oxidation-reduction process11),
suggesting that a structural reorganization takes place
on oxidation and the half-wave potential E1/2 is smaller
than the values reported for [(η5-C5H5)Fe{(η5-C5H4)CHd
N(C6H4-2-R2)}] [R2 ) Me (2b) or SMe (2c)5f] (Table 1).
1
Since the H NMR spectrum of 1a in acetonitrile-d3
revealed that in this solvent the tautomeric equilibria is
strongly displaced toward the cyclic form, the results
obtained from the electrochemical studies are consistent
with the better donor ability of the oxazine ring, when
compared with that of the imine moiety in good agree-
ment with the results obtained from the Mo¨ssbauer
studies.
FIGURE 2. Cyclic voltammograms of 10-3 M solutions of 1a
In summary, the studies presented have allowed (a)
the preparation and characterization of the first example
of a new type of 3,1-benzoxazines holding a ferrocenyl
group and (b) the elucidation of the effect induced by the
binding of the oxazine moiety upon the environment of
the iron(II) as well as the relative importance of the
presence of a ferrocenyl (in 1a) or a phenyl (in 3a)
substituent in position 2 on the extent of the tautomeric
equilibria. In particular, for a given solvent, the higher
electron-donor ability of the ferrocenyl moiety produces
a greater displacement of the tautomeric equilibria to the
Schiff base form (2a) than its analogue holding a phenyl
group. Besides that, 1H NMR studies of 1a in CDCl3
revealed that the imine form (2a) degraded slowly, thus
suggesting that 2a is more prone to hydrolyze and
consequently less stable than 4a (which arises from 2a
by replacement of the “(η5-C5H4)Fe(η5-C5H4)” moiety by
a phenyl ring) in CDCl3.
(top)
and
[(η5-C5H5)Fe{(η5-C5H4)-CHdN-(C6H4-2SMe)}]
(bottom) in CH3CN at 20 °C and a scan speed ) 100 mV/s.
prepared solution of 1a in CDCl3 showed a 1a/2a molar
ratio ) 3.0, but after 5 h of storage at 300 K the 1H NMR
spectrum revealed the presence of 1a, 2a, and FcCHO
in a 27.7:10.2:1.0 ratio, thus indicating that partial
hydrolysis of the imine form occurred in solution.
Previous studies on ring-chain tautomeric equilibria
of 2-aryl-substituted benzoxazines have shown that the
ratio between the ring and open-chain forms are strongly
dependent on the electronic character of the substitu-
ents.2,4 To compare the effects induced by the substitu-
ents on position-2 of the oxazine ring on the tautomeric
equilibria we performed a parallel study with 2-phenyl-
2,4-dihydro-1H-3,1-benzoxazine (3a). The results ob-
tained showed that the proportion 3a/4a decreased
according to the sequence benzene-d6 > acetone-d6
>
methanol-d4.9 This trend is similar to that found for the
system 1a T 2a, but the comparison of the ratios [ring
form/open-chain form] obtained in the polar solvents
revealed that the replacement of the phenyl group by a
ferrocenyl moiety produces a significant displacement of
the equilibria to the Schiff base form. Some authors have
reported that for 2-phenyloxazolidines and -perhydro-1,3-
oxazines the influence of the substituents on the aryl ring
upon the relative stability of the tautomers is controlled
by several electronic effects, among which the intra-
molecular hydrogen bonding between the OH group and
the imine nitrogen together with the polarization of the
>CdN- link appear to be particularly important.2e,f The
replacement of the phenyl group in 3a and 4a by the
ferrocenyl unit, which has a stronger electron-donor
ability,10 introduces significant variations on the elec-
tronic density on the imine nitrogen, which would affect
the strength of the intramolecular N‚‚‚OH bond. The
variations observed in the chemical shifts of the 13C nuclei
of the -CH2- moiety for the two imine forms (2a and
4a) also support this hypothesis.
Experimental Section
2-Ferrocenyl-2,4-dihydro-1H-3,1-benzoxazine (1a). A sus-
pension formed by FcCHO (2.70 g, 12.6 × 10-3 mol) and 50 mL
of benzene was stirred at 20 °C for 20 min and filtered out. Then
aminobenzyl alcohol (1.55 g, 12.6 × 10-3 mol) was added to the
filtrate. The reaction flask was connected to a condenser
equipped with a Dean-Stark apparatus, and the mixture was
refluxed until ca. 15 mL of the benzene-water azeotrope had
condensed on the Dean-Stark apparatus. The hot solution was
then filtered out and concentrated to dryness on a rotary
evaporator. The gummy residue was treated with diethyl ether
and stirred at 20 °C for ca. 30 min. The yellow solid formed was
collected by filtration, air-dried, and then dried in a vacuum for
2 days (yield: 3.62 g, 85%). Anal. Calcd for C18H17NOFe: C,
67.73; H, 5.37; N, 4.39. Found: C, 67.7; H, 5.6; N, 4.4. MS (FAB+)
m/z ) 319 [M]+. IR: 3348 cm-1, ν (>NH). Solid-state 13C{1H}
NMR data: δ ) 66.2 (C4), 67.8 (C3), 70.3 (C5H5), 82.8 (>CHN-
), 88.1 (C1), 119.4 (C4′and C6′), 122.8 (C2′), 124.3 (C3′), 127.1 (C5′),
141.5 (C1′), in this case the signals due to the carbon-13 nuclei
of the -CH2- moiety and of the pair (C2 and C5) were masked
by the signal due to the C5H5 fragment. UV-vis data of a solid
sample: λmax (in nm) ) 455 and 277 and of a 1 × 10-4 M solution
of 1a in CH3OH: λmax (in nm) ) 462 (log ꢀ ) 2.8), 334 (sh, log ꢀ
∼ 3.4), and 290 (log ꢀ ) 3.9).
Electrochemical data for 1a were obtained from cyclic
voltammetric studies of freshly prepared solutions (10-3
M) in CH3CN using (Bu4N)[PF6] at different scan rates,
ν {from 0.05 to 1.0 V s-1}. The cyclic voltammogram of
1a (Figure 2) exhibited an anodic peak with a directly
associated reduction in the reverse scan and the Ipa/Ipc
molar ratios were close to 1.
(10) Hansch, C.; Leo, A.; Koekman, D. Exploring QSAR: Hydro-
phobic, Electronic and Steric Constants; American Chemical Society:
Washington, DC, 1995.
(11) Brown, E. R.; Sandifer, J. R. In Physical Methods in Chemistry.
Electrochemical Methods; Rossiter, B. W, Hamilton, J. H., Eds.;
Wiley: New York, 1986; Vol. 4, Chapter 4.
J. Org. Chem, Vol. 70, No. 12, 2005 4859

benzene-d6) (Figure S2) and 3a (in CDCl3) (Figure S3); tables
Acknowledgment. We thank the Ministerio de
Ciencia y Tecnolog´ıa of Spain and the Generalitat de
Catalunya for financial support (Project Nos. BQU2003-
00906 and 2001-SGR-00045, 2001-SGR-00335, respec-
tively).
1
containing H and 13C{1H} NMR spectroscopic data for 1a-
4a, (at 300 K) in several deuterated solvents (Tables S1-S4);
characterization data for 2b and 2c (Table S5), and a detailed
description of the materials and methods used. This material
is available free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: 13C{1H} NMR spec-
trum of a solid sample of 1a (Figure S1), {1H-1H} NOESY
spectra of the solutions obtained after disssolution of 1a (in
JO050437V
4860 J. Org. Chem., Vol. 70, No. 12, 2005