Synthesis of 4-bromocubane-1-carbaldehyde

Article abstract of DOI:10.1007/s11172-006-0416-7

Oxidation of 4-bromo-1-hydroxymethylcubane and 1,4-bis(hydroxymethyl)cubane with the 2,2,6,6-tetramethylpiperidine-N-oxyl-trichloroisocyanuric acid-sodium bicarbonate system afforded the corresponding aldehydes. 4- Bromocubanecarbaldehyde was also obtained in high yield by reduction of 4-bromocubanecarboxylic acid and its methyl ester with bis(N-methylpiperazinyl) aluminum hydride. Springer Science+Business Media, Inc. 2006.

Full text of DOI:10.1007/s11172-006-0416-7

Russian Chemical Bulletin, International Edition, Vol. 55, No. 7, pp. 1304—1306, July, 2006
1304
Synthesis of 4ꢀbromocubaneꢀ1ꢀcarbaldehyde
a
a
a
a
a
A. V. Shastin,a V. V. Zakharov, G. P. Bugaeva, L. T. Eremenko, L. B. Romanova, G. V. Lagodzinskaya,
ꢀ
ꢀ
G. G. Aleksandrov,b and I. L. Eremenkob
aInstitute of Problems of Chemical Physics, Russian Academy of Sciences,
142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 515 5420. Eꢀmail: shastin@icp.ac.ru, vzakh@icp.ac.ru
bN. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
31 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 952 1279. Eꢀmail: ilerem@igic.ras.ru
Oxidation of 4ꢀbromoꢀ1ꢀhydroxymethylcubane and 1,4ꢀbis(hydroxymethyl)cubane with
the 2,2,6,6ꢀtetramethylpiperidineꢀNꢀoxyl—trichloroisocyanuric acid—sodium bicarbonate sysꢀ
tem afforded the corresponding aldehydes. 4ꢀBromocubanecarbaldehyde was also obtained
in high yield by reduction of 4ꢀbromocubanecarboxylic acid and its methyl ester with
bis(Nꢀmethylpiperazinyl)aluminum hydride.
Key words: cubane derivatives, aldehydes, oxidation, reduction, TEMPO, aluminum hyꢀ
drides, Xꢀray diffraction analysis.
Scheme 1
Cubane derivatives find increasingly frequent use as
pharmacologically active compounds.1,2 For this reason,
development of convenient methods for their syntheses
has recently become a topical problem. There is considerꢀ
able interest in cubanecarbaldehydes capable of various
modification at the carbonyl group with the retention of
the cubane framework. Earlier, such aldehydes have been
synthesized by the Swern oxidation of appropriate alcohols
with the DMSO—oxalyl chloride system.3 Substantial
drawbacks to this method include technological and ecoꢀ
logical problems. In recent years, convenient oxidative
systems involving 2,2,6,6ꢀtetramethylpiperidineꢀNꢀoxyl
(TEMPO) as a catalyst in combination with organic or
inorganic oxidants have been widely employed for the
transformation of alcohols into aldehydes.4,5
X = Br (1), CH2OH (3); Y = Br (2), CHO (4)
Here we studied for the first time the oxidation of
4ꢀbromoꢀ1ꢀhydroxymethylcubane (1) into 4ꢀbromoꢀ
cubaneꢀ1ꢀcarbaldehyde (2) and of 1,4ꢀbis(hydroxymeꢀ
thyl)cubane (3) into cubaneꢀ1,4ꢀdicarbaldehyde (4) with
the TEMPO—trichloroisocyanuric acid (TCCA)—sodium
bicarbonate system in CH2Cl2 at room temperature. The
yield of monoaldehyde 2 was 71%. The oxidation of diol 3
gave a complex mixture of products from which dialdeꢀ
hyde 4 was isolated as chloropyridazine bishydrazone 5.
The low yield of dialdehyde 4 (5%) can be due to the poor
solubility of the starting alcohol 3 in CH2Cl2.
Alternatively, aldehyde 2 was obtained by reduction of
acid 6a or its methyl ester 6b with bis(Nꢀmethylpiperꢀ
azinyl)aluminum hydride (7); earlier, this technique has
been proposed for the reduction of carboxylic acids7 or
their esters8 to the corresponding aldehydes (Scheme 2).
Refluxing of acid 6a or its ester 6b with hydride 7 in
THF at 65 °C for 9—12 h gave aldehyde 2 with an impuꢀ
rity of alcohol 1 (5—10%) (see Scheme 2). The yield of
aldehyde 2 after crystallization from hexane was 87—92%.
According to the Xꢀray diffraction data, structure 2
consists of two crystallographically independent molecules
(Fig. 1). One molecule has the symmetry m (see Fig. 1, a),
while the other has the symmetry 2/m (see Fig. 1, b). Both
the molecules are disordered, the aldehyde group and the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1256—1258, July, 2006.
1066ꢀ5285/06/5507ꢀ1304 © 2006 Springer Science+Business Media, Inc.

4ꢀBromocubaneꢀ1ꢀcarbaldehyde
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
1305
Scheme 2
on Silufol UVꢀ254 plates with hexane—acetone (10 : 1) as an
eluent.
Synthesis of 4ꢀbromocubaneꢀ1ꢀcarbaldehyde (2) by the oxiꢀ
dation of alcohol 1. Alcohol 1 was oxidized according to a modiꢀ
fied procedure9 using solid NaHCO3 instead of its aqueous soluꢀ
tion. 4ꢀBromoꢀ1ꢀhydroxymethylcubane (140 mg, 0.62 mmol)
was added at room temperature to a stirred mixture of triꢀ
chloroisocyanuric acid (127 mg, 0.55 mmol), TEMPO (10 mg,
0.064 mmol), and NaHCO3 (100 mg, 1.2 mmol) in CH2Cl2
(7 mL). The reaction was continued until the starting alcohol
disappeared (TLC data). The reaction mixture was filtered and
the residue was washed with CH2Cl2. The combined solution
was washed with water, dried with Na2SO4, passed through a
2 cm column with silica gel, and concentrated. The product
from the residue was extracted with boiling hexane and the
solvent was removed in vacuo. The yield of 4ꢀbromocubaneꢀ1ꢀ
1
carbaldehyde was 100 mg (71%), m.p. 139—140 °C. H NMR
(CDCl3), δ: 4.28—4.47 (m, 6 H, CHcub); 9.77 (s, 1 H, CHO).
13C NMR (CDCl3), δ: 196.8 (CO); 62.3 (C(1)); 53.9 (C(7),
C(5), C(3)); 46.0 (C(2), C(6), C(8)); 45.3 (C(4)). IR (KBr),
ν/cm–1: 2995, 2931, 2809, 2709, 1692, 1380, 1292, 1205, 1035,
930, 837, 806.
R = H (6a), Me (6b)
Conditions: THF, 65 °C, 9—12 h.
Br substituents being interchanged in either (at the C(1),
C(6), and C(7) atoms of cubane).
Synthesis of cubaneꢀ1,4ꢀdicarbaldehyde 4. The reaction mixꢀ
ture obtained in the oxidation of diol 3 (164 mg, 1 mmol) as
described above (with twice as much the amounts of the oxiꢀ
dant, the catalyst, and the base as in the oxidation of monoꢀ
alcohol 1) was passed through a 2ꢀcm column with silica gel and
concentrated. The residue was dissolved in ethanol (10 mL) and
(6ꢀchloropyridazinꢀ3ꢀyl)hydrazine (144 mg, 1 mmol) was added.
The yield of bishydrazone (5) was 21 mg (5% with respect to the
starting diol), decomp. at 260 °C. Found (%): C, 52.3; H, 3.4;
N, 27.0. C18H14Cl2N8. Calculated (%): C, 52.3; H, 3.4; N, 27.1.
1H NMR (DMSOꢀd6), δ: 11.40 (s, 1 H, CH=N); 7.62 (s, 1 H,
NH); 7.56, 7.45 (both d, 1 H each, CH, J = 9.0 Hz); 4.12 (s,
6 H, CHcub). 13C NMR (CDCl3), δ: 158.74 (HC=N—N);
143.56, 129.63, 115.26 (C and CH of pyridazine), 57.44
(Cquat. cub); 45.73 (CHcub). IR (KBr), ν/cm–1: 2990, 2917, 2863,
1603, 1523, 1407, 1382, 1274, 1199, 1130, 1065, 962, 834.
Synthesis of 4ꢀbromocubaneꢀ1ꢀcarbaldehyde (2) by the
reduction of methyl 4ꢀbromocubaneꢀ1ꢀcarboxylate (6b) with
bis(Nꢀmethylpiperazinyl)aluminum hydride (7). A solution of esꢀ
ter 6b (243 mg, 1.01 mmol) in anhydrous THF (15 mL) was
added dropwise for 5 min to a stirred (and cooled on an ice bath)
solution of hydride 7 (664 mg, 2.8 mmol) in THF (10 mL).7 The
reaction mixture was refluxed for 9 h and treated with water
(0.16 mL) at 0—5 °C. Then it was heated to 70 °C for 5 min,
cooled to room temperature, and filtered. The filter cake was
washed with THF (2×5 mL) and ether (10 mL). The filtrate was
concentrated in vacuo. Ether (60 mL) was added and the soluꢀ
tion was successively washed with brine (12 mL), 2 M NaOH
(2×6 mL), 2 M HCl (2×9.5 mL), and a solution of NaCl (6 mL).
The colorless ethereal solution was dried with Na2SO4 and conꢀ
centrated in vacuo to give a product (209 mg) with m.p.
135.5—138.0 °C. Recrystallization from hexane gave aldehyde 2
(196 mg, 92%), m.p. 136.5—140.0 °C. Its spectroscopic characꢀ
teristics were identical with those of the aldehyde obtained by
oxidation.
Thus, our study made 4ꢀbromocubaneꢀ1ꢀcarbaldehyde
synthetically more accessible.
Experimental
The starting 4ꢀbromoꢀ1ꢀhydroxymethylcubane (1),
1,4ꢀbis(hydroxymethyl)cubane (3), 4ꢀbromocubanecarboxylic
acid (6a), and methyl 4ꢀbromocubanecarboxylate (6b) were preꢀ
pared according to known procedures.6,10,11 Hydride 7 was synꢀ
thesized as described earlier.7 Solvents were purified according
to standard procedures. Solutions of hydride 7 were prepared
and used to reduce acid 6a or ester 6b under argon.12
The IR spectra of the compounds obtained were recorded on
1
a Specord Mꢀ82 spectrophotometer. H and 13C NMR spectra
were recorded on Bruker WMꢀ250 and Bruker AMꢀ300 instruꢀ
ments with Me4Si as the internal standard. TLC was carried out
Br(3)
Br(2)
a
b
C(1)
C(7)
C(9)
C(2)
C(4)
C(8A)
C(2A)
C(3A)
C(8)
C(3)
C(8B)
C(9A)
C(8C)
C(5)
C(6)
C(7B)
C(6A)
C(7AA)
O(6)
Reduction of 4ꢀbromocubaneꢀ1ꢀcarboxylic acid (6a) with
bis(Nꢀmethylpiperazinyl)aluminum hydride (7). A solution of
acid 6a (140 mg, 0.617 mmol) in anhydrous THF (10 mL) was
added to a stirred (and cooled on an ice bath) solution of
O(7A)
Fig. 1. Structure of 4ꢀbromocubaneꢀ1ꢀcarbaldehyde (2).

1306
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
Shastin et al.
Table 1. Crystallographic parameters and a summary of data
collection for compound 2
We are grateful to V. P. Lodygina for the analysis of
the IR spectra.
This work was financially supported by the Internaꢀ
tional Scientific and Technical Center (Project No. 1550).
Parameter
Value
Molecular formula
Molecular mass
C9H7BrO
211.06
References
Space group
a/Å
b/Å
C2/m
33.716(7)
6.4550(10)
5.3110(10)
98.08(3)
1144.4(4)
6
1.837
5.317
MoꢀKα
(λ = 0.71073 Å)
1756
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c/Å
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µ/mm–1
Radiation
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Chem. Soc., 1976, 98, 3075.
Number of measured reflections
Number of reflections with I > 2σ
R1
363
0.1077
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hydride 7 (390 mg, 1.73 mmol) in THF (6 mL). The reaction
mixture was refluxed for 12 h and then treated as described
above. The yield of compound 2 was 114 mg (87.5%), m.p.
137.6—140.0 °C.
Xꢀray diffraction experiment was carried out on an Enraf
Nonius CADꢀ4 automatic diffractometer (graphite monochroꢀ
mator, 293 °C, ωꢀscan mode). Crystals for Xꢀray diffraction
analysis were grown from a dilute solution of aldehyde 2 in
hexane. Crystallographic parameters and a summary of strucꢀ
ture refinement for aldehyde 2 are given in Table 1. Structure 2
was solved by the direct methods and refined in the fullꢀmatrix
anisotropic approximation for Br atoms; all the other atoms
were refined isotropically. The calculations were performed with
the SHELX97 program package.13,14 The main geometrical paꢀ
rameters of the compounds studied are close to standard values.
Crystallographic data for compound 2 have been deposited with
the Cambridge Crystallographic Data Center and can be made
available upon request to the authors.
14. G. M. Sheldrick, SHELXL97. Program for the Refinement of
Crystal Structures, University of Göttingen, Göttingen, Gerꢀ
many, 1997.
Received January 25, 2006;
in revised form May 19, 2006