Simple resolution of racemic salicylic aldehydes having an isobornyl substituent

Article abstract of DOI:10.1080/00397910902792648

The resolution of the racemic salicylic aldehydes with isobornyl fragment 2 via diastereomer formation with (R)-1-phenylethylamine has been carried out.

Full text of DOI:10.1080/00397910902792648

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Simple Resolution of Racemic
Salicylic Aldehydes Having an
Isobornyl Substituent
a
a
Evgeny V. Buravlev , Irina Y. Chukicheva
&
a
Aleksandr V. Kutchin
a
Institute of Chemistry, Komi Scientific Center,
Ural Branch of the Russian Academy of Sciences ,
Syktyvkar, Republic of Komi, Russia
Published online: 08 Sep 2009.
To cite this article: Evgeny V. Buravlev , Irina Y. Chukicheva & Aleksandr V.
Kutchin (2009) Simple Resolution of Racemic Salicylic Aldehydes Having an
Isobornyl Substituent, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:20, 3639-3646, DOI:
10.1080/00397910902792648
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1
Synthetic Communications , 39: 3639–3646, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902792648
Simple Resolution of Racemic Salicylic
Aldehydes Having an Isobornyl Substituent
Evgeny V. Buravlev, Irina Y. Chukicheva, and Aleksandr V. Kutchin
Institute of Chemistry, Komi Scientific Center, Ural Branch of the Russian
Academy of Sciences, Syktyvkar, Republic of Komi, Russia
Abstract: The resolution of the racemic salicylic aldehydes with isobornyl
fragment 2 via diastereomer formation with (R)-1-phenylethylamine has been
carried out.
Keywords: Enantiomeric resolution, salicylic aldehydes, Schiff bases, terpenoids,
terpenylphenols
INTRODUCTION
Terpenylphenolic compounds are physiologically active substances with
a wide range of activity and low toxicity. In particular, isobornylphenols
are used for the local treatment of infection and inflammation of
[
1]
the throat. Also, recently the isobornylphenol derivative was to
[
2]
have found antiplatetel and antithrombogenic activity. Physiological
activity and the possibility of using these derivatives for further
synthesis requires development of methods for obtaining their optically
active forms.
Alkylation of phenol or p-cresol with optically active camphene leads
to racemic isobornylphenols 1a,b (Fig. 1), which were formed as a result
of Wagner–Meerwein cascade rearrangements. The racemic (ꢀ)-1 have
Received December 22, 2008.
Address correspondence to Evgeny V. Buravlev, Institute of Chemistry, Komi
Scientific Center, Ural Branch of the Russian Academy of Sciences, 48,
Pervomayskaya St., 167982 Syktyvkar, Republic of Komi, Russia. E-mail:
eugeneburavlev@gmail.com
3
639

3640
E. V. Buravlev, I. Y. Chukicheva, and A. V. Kutchin
Figure 1. Racemic o-isobornylphenols 1 and their formylated derivatives 2.
been previously prepared by alkylation of phenol or p-cresol by
[
3]
camphene with (PhO) Al and (4-Me-PhO) Al as a catalysts.
3
3
As far as we know, only a high-performance liquid chromatographic
HPLC) method has been used for the resolution of chiral alkylphenols.
In all cases, the key stage is use of high-priced preparative columns. For
(
example, Saito et al. reported the separation of p-nonylphenols isomers
[4]
by chiral HPLC. Berkessel et al. showed the resolution of (ꢀ)-1b using
[5]
a Chiralcel OJ column. In the same work, enantiomers of aldehyde 2b
were obtained by conversation into imines with (R)-phenylglycinol and
HPLC resolution of diastereomeric imines following hydrolysis. Also,
Schiff bases obtained from enantiomers 2b were successfully applied as
tridentate ligands with two elements of chitality in V-catalyzed asym-
[6]
metric sulfoxidation.
RESULTS AND DISCUSSION
We used a modified combination of the described method to separate
[
5]
(
þ)-2 and (ꢁ)-2. First, racemic aldehydes (ꢀ)-2 were obtained by the
formylation of racemic terpenylphenols (ꢀ)-1 with formaldehyde in the
[
7]
presence of montmorillonite KSF clay with Et N. Synthesis of (ꢀ)-2
3
was achieved by refluxing at atmospheric pressure without using of an
autoclave as described in the original method. This formylation leads
to the salicylaldehyde (ꢀ)-2 with good selectivity and moderate yields
(
Scheme 1).
The resolution of racemic aldehydes (ꢀ)-2 were realized through
Schiff base formation of (ꢀ)-2 by reaction with commercially available
R)-1-phenylethylamine. Diastereomers 3 and 4 were obtained with
8–76% yield and 74–98% de by fractional crystallization from pentane.
(
6
Finally, the enantiomeric enriched aldehydes (þ)-2 and (ꢁ)-2 were liber-
ated via acid hydrolysis of the 3 and 4 with good yields and moderate to
good ee values (see Table 1).

Resolution of Racemic Salicylic Aldehydes
3641
Scheme 1. Reagents and conditions: (i) (a) HCHO, montmorillonite KSF, Et N,
3
toluene, reflux at Ar atmosphere, 15 h, then chromatography on silica gel; (ii) (a)
˚
R)-1-phenylethylamine, 4 A MS, toluene, reflux at Ar atmosphere, 3.5 h; (b)
(
Crystallization from pentane; (iii) aq. HCl (37%), EtOH, rt, 6 h, then chromato-
graphy on silica gel.
In summary, we report a simple procedure for preparation of
enaniomers of salicylaldehydes having an isoborhyl fragment.
EXPERIMENTAL
General
The infrared (IR) spectra were recorded on a Shimadzu IR Prestige 21
1
13
Fourier-transform spectrometer in KBr pellets. The H and C NMR
spectra were measured on Bruker Avance II 300 (300 MHz and
1
3
7
5 MHz) in CDCl . The assignment of the signals was made using
3
C
APT experiments. The melting points were measured on a Kofler
hot-stage apparatus. Specific rotations were measured on a Kruss Optro-
nic P3002RS polarimeter. The course of the reactions was monitored by
thin-layer chromatography (TLC) on Sorbfil plates using hexane–Et O
2
Table 1. Resolution of racemic aldehydes 2 via diastereomeric imines 3 and 4
a
b
Entry
R
Imine Yield (%) De (%)
Aldehyde Yield (%) Ee (%)
1
2
3
4
H
H
4-Me
4-Me
3a
4a
3b
4b
58
60
76
68
98
74
91
98
(ꢁ)-2a
(þ)-2a
(ꢁ)-2b
(þ)-2b
97
96
98
97
98
72
92
96
a
Determined by GC.
b
Determined by HPLC.

3642
E. V. Buravlev, I. Y. Chukicheva, and A. V. Kutchin
solvent systems. To detect the compounds, the plates were treated with a
KMnO solution (15 g of KMnO , 300 mL of H O, and 0.5 mL of concen-
trated H SO ). Toluene was dried over CaCl and distilled over sodium
4
4
2
2
4
2
metal. Pentane and hexane were freshly distilled. Paraformaldehyde was
of reagent-grade quality. Column chromatography used silica gel
(
(
70=230 m, wet packed). Commercially available R-(þ)-1-phenylethylamine
1
Alfa Aesar, ChiPros 99þ %, 99 þ % ee) were employed without
˚
purification. Molecular sieves (4A) and montmorillonite KSF (Acros)
ꢂ
ꢂ
were used after heating for 6 h at 130 C and 3 h at 140 C, respectively.
Racemic Salicylic Aldehydes (ꢀ)-2
A solution of the phenol (ꢀ)-1 (20 mmol), paraformaldehyde (80 mmol),
triethylamine (20 mmol), and montmorillonite KSF (3 g) in toluene
ꢂ
(30 mL) was heated at 100 C under efficient stirring and Ar atmosphere.
After 15 h, the reaction mixture was cooled to room temperature, and the
catalyst was filtered and washed with Et O. The excess of solvent was
2
removed at reduced pressure. The reaction mixture was separated over
a column (silica gel, 70=230m, hexane=Et O, 75:1 ! 20:1) to afford corre-
2
sponding aldehyde (ꢀ)-2.
Data
Rac-2-Hydroxy-3-(1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl)
benzaldehyde (ꢀ)-2a
Yield 60%. Yellowish solid; mp 67–68. Anal. calcd. for C H O : C,
1
7
22
2
7
9.03; H, 8.58. Found: C, 79.07; H, 8.52.
Rac-2-Hydroxy-5-methyl-3-(1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl)
benzaldehyde (ꢀ)-2b
Yield 71%. Yellow solid; mp 100–101. Anal. calcd. for C H O : C,
1
8
24
2
7
9.37; H, 8.88. Found: C, 79.33; H, 8.84.
Spectral characteristics of the compounds (ꢀ)-2a and (ꢀ)-2b are
[
5,8]
consistent with those described previously.
Synthesis of Schiff Bases as Diastereomeric Mixtures 3 and 4
The solution of aldehyde (ꢀ)-2 (7.7 mmol) and R-(þ)-1-phenylethylamine
(7.7 mmol) in 30 mL of anhydrous toluene was stirred at reflux under an

Resolution of Racemic Salicylic Aldehydes
3643
Ar atmosphere for 3.5 h. After filtration from molecular sieves, the
solvent was removed under reduced pressure to yield a mixture of diaster-
eomeric Schiff bases 3 and 4 (100% yield), which were separated by frac-
tional crystallization from pentane.
Diastereomeric excess (de) of 3 and 4 were determined by gas chro-
TM
matography [GC; Supelco SPB -35 column, 30m ꢃ 0.32 mm ꢃ 0.25 mm,
ꢂ
2
55 C (isothermic): t(3a) ¼ 21.6 min, t(4a) ¼ 20.7 min; t(3b) ¼ 22.1 min,
and t(4b) ¼ 23.1 min].
Data
2-(((R)-1-Phenylethylimino)methyl)-6-((1R,2S,4S)-1,7,7-trimethyl-
bicyclo[2.2.1]hept-exo-2-yl)phenol 3a
ꢂ
1
Yield 58%. Yellow solid; mp 118–119 C (from pentane). H NMR
300 MHz, CDCl ): d ¼ 0.79 (s, 3H), 0.85 (s, 3H), 0.92 (s, 3H),
(
1
3
.33–1.43 (m, 1H), 1.56–1.68 (m, 6H), 1.81–1.93 (m, 2H), 2.10–2.19
(
m, 1H), 3.40 (t, 1H, J ¼ 9.0 Hz), 4.56 (q, 1H, J ¼ 6.6 Hz), 6.84 (m,
1
1
1
6
2
H), 7.08 (d, 1H, J ¼ 7.2 Hz), 7.25–7.42 (m, 6H), 8.42 (br.s, 1H),
1
3
3.90 (br.s, 1H). C NMR (75 MHz, CDCl ): d ¼ 163.86, 160.48,
3
44.02, 132.00, 130.78, 128.87, 128.64, 127.17, 126.43, 117.55, 117.98,
8.43, 49.85, 47.94, 45.74, 44.63, 39.83, 34.25, 27.53, 25.03, 21.41,
0.49, 12.39. IR (KBr, cm ): 3439 (OH); 1626 (C¼N). Found (%):
ꢁ
1
C, 83.03; H, 8.66; N, 3.90; calc. for C H NO (%): C, 83.06; H,
2
5
31
8
.64; N, 3.87.
2-(((R)-1-Phenylethylimino)methyl)-6-((1S,2R,4R)-1,7,7-trimethyl-
bicyclo[2.2.1]hept-exo-2-yl)phenol 4a
ꢂ
1
Yield 60%. Yellow solid; mp 92–93 C (from pentane). H NMR
300 MHz, CDCl ): d ¼ 0.84 (s, 3H), 0.87 (s, 3H), 0.93 (s, 3H),
(
1
3
.34–1.43 (m, 1H), 1.56–1.68 (m, 6H), 1.79–1.92 (m, 2H), 2.11–2.18
(
m, 1H), 3.41 (t, 1H, J ¼ 9.0 Hz), 4.56 (q, 1H, J ¼ 6.6 Hz), 6.84 (m,
1
1
1
6
2
H), 7.08 (d, 1H, J ¼ 7.2 Hz), 7.25–7.40 (m, 6H), 8.41 (br.s, 1H),
1
3
3.87 (br.s, 1H). C NMR (75 MHz, CDCl ): d ¼ 163.93, 160.49,
3
43.96, 131.93, 130.78, 128.87, 128.61, 127.16, 126.44, 117.53, 118.05,
8.48, 49.86, 47.96, 45.74, 44.54, 39.77, 34.18, 27.52, 24.90, 21.44,
0.45, 12.34. IR (KBr, cm ): 3437 (OH); 1628 (C¼N). Found (%):
ꢁ
1
C, 83.02; H, 8.71; N, 3.88; calc. for C H NO (%): C, 83.06; H,
2
5
31
8
.69; N, 3.87.

3644
E. V. Buravlev, I. Y. Chukicheva, and A. V. Kutchin
4-Methyl-2-(((R)-1-phenylethylimino)methyl)-6-((1R,2S,4S)-1,7,7-
trimethylbicyclo[2.2.1]hept-exo-2-yl)phenol 3b
ꢂ
1
Yield 76%. Yellow solid; mp 110–112 C (from pentane). H NMR
(
1
1
300 MHz, CDCl ): d ¼ 0.79 (s, 3H), 0.86 (s, 3H), 0.92 (s, 3H),
3
.27–1.42 (m, 1H), 1.55–1.66 (m, 6H), 1.81–1.93 (m, 2H), 2.11–2.20 (m,
H), 2.29 (s, 3H), 3.38 (t, 1H, J ¼ 9.0 Hz), 4.55 (q, 1H, J ¼ 6.6 Hz), 6.88
and 7.19 (both d, each 1H, J ¼ 0.9 Hz, J ¼ 1.2 Hz), 7.27–7.41 (m, 5H),
1
3
8
.37 (br.s, 1H), 13.65 (br.s, 1H).
C NMR (75 MHz, CDCl ):
3
d ¼ 163.86, 158.20, 144.12, 131.84, 131.66, 128.83, 128.62, 126.28,
1
2
1
27.13, 126.46, 117.63, 68.45, 49.84, 47.96, 45.74, 44.59, 39.78, 34.15,
ꢁ1
7.52, 25.07, 21.43, 20.79, 20.48, 12.35; IR (KBr, cm ): 3420 (OH);
632 (C¼N). Found (%): C, 83.16; H, 8.88; N, 3,.70; calc. for
C H NO (%): C, 83.15; H, 8.86; N, 3.73.
2
6
33
4
1
-Methyl-2-(((R)-1-phenylethylimino)methyl)-6-((1S,2R,4R)-
,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl)phenol 4b
ꢂ
1
Yield 68%. Yellow solid; mp 111–113 C (from pentane). H NMR
(
1
1
300 MHz, CDCl ): d ¼ 0.83 (s, 3H), 0.87 (s, 3H), 0.93 (s, 3H),
3
.33–1.42 (m, 1H), 1.56–1.66 (m, 6H), 1.81–1.93 (m, 2H), 2.07–2.19 (m,
H), 2.29 (s, 3H), 3.38 (t, 1H, J ¼ 9.2 Hz), 4.55 (q, 1H, J ¼ 6.6 Hz), 6.87
and 7.19 (both d, each 1H, J ¼ 1.8 Hz, J ¼ 1.8 Hz), 7.22–7.39 (m, 5H),
1
3
8
.36 (br.s, 1H), 13.61 (br.s, 1H).
C NMR (75 MHz, CDCl ):
3
d ¼ 163.93, 158.22, 144.05, 131.82, 131.59, 128.84, 128.58, 126.27,
1
2
1
27.11, 126.45, 117.62, 68.48, 49.85, 47.98, 45.73, 44.50, 39.73, 34.10,
ꢁ1
7.51, 24.91, 21.46, 20.78, 20.45, 12.34; IR (KBr, cm ): 3422 (OH);
632 (C¼N). Found (%): C, 83.11; H, 8.90; N, 3.69; calc. for
C H NO (%): C, 83.15; H, 8.86; N, 3.73.
2
6
33
Absolute configurations of the imines were assigned by comparison
of their optical rotation with literature data of aldehydes (þ)-2b and
(
ꢁ)-2b obtained after hydrolysis reaction (see Ref. 5). The (R=S) config-
uration of 3a and 4a was given by analogy with the (R=S) configuration
of diastereomers of compounds 3b and 4b.
Enantiomeric Enriched Salicylic Aldehydes (þ)-2 and (ꢁ)-2
HCl (37%, 7 mL) was added to solution of diastereomeric enriched imine
3
or 4 (0.5 g) in ethanol (EtOH; 5 mL). The mixture was stirred at room
temperature for 6 h. The excess solvent was removed at reduced pressure,
and the residue was diluted with CH Cl (75 mL). The organic layer was
2
2

Resolution of Racemic Salicylic Aldehydes
3645
washed with water (3 ꢃ 30 mL), dried over anhydrous Na SO , and
2
4
concentrated under reduced pressure and the residue was purified by
chromatography (silica gel, 70=230 m, hexane=Et O, 75:1) to afford cor-
2
responding enantiomer of aldehyde (þ)-2 and (ꢁ)-2.
Enantiomeric excesses of (ꢁ)-2a and (þ)-2a were determined by
HPLC with a Chiralcel OJ-H column (hexane=i-PrOH 200=1, 1.0 mL=min,
2
24 nm; t(ꢁ)-2a¼ 4.54min, t(þ)-2a¼ 6.08min). Enantiomeric excesses of
(
ꢁ)-2b and (þ)-2b were determined by HPLC with a Chiralpak AD
column (hexane=i-PrOH 200=1, 0.5 mL=min, 224 nm; t(ꢁ)-2b¼ 8.22min,
t(þ)-2b¼ 9.02min).
Data
2
-Hydroxy-3-((1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl)
benzaldehyde (ꢁ)-2a
2
D
2
ꢂ
Yield 97%. Yellowish solid, ½aꢄ ¼ ꢁ87.6 (c ¼ 0.6, CHCl ); mp 86–88 C
3
(
from pentane).
2
-Hydroxy-3-((1S,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl)
benzaldehyde (þ)-2a
2
D
2
ꢂ
Yield 98%. Yellowish solid, ½aꢄ ¼ þ55.1 (c ¼ 0.5, CHCl ); mp 88–90 C
3
(
from pentane).
2
2
-Hydroxy-5-Methyl-3-((1R,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-exo-
-yl)benzaldehyde (ꢁ)-2b
2
D
2
Yield 98%. Yellowish solid, ½aꢄ ¼ ꢁ40.9 (c ¼ 0.6, CHCl ); mp 108–
3
ꢂ
10 C (from pentane).
1
2
-Hydroxy-5-Methyl-3-((1S,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-
exo-2-yl)benzaldehyde (þ)-2b
2
D
2
ꢂ
Yield 97%. Yellowish solid, ½aꢄ ¼ þ 41.0 (c ¼ 0.6, CHCl ); mp 109–110 C
3
(
from pentane).
Absolute configurations of 2b were assigned by comparison of their
optical rotation with literature data. The (R=S) configuration of (þ)-2a
and (ꢁ)-2a was given by analogy with the (R=S) configuration of
enantiomers of compound 2b.
[5]

3646
E. V. Buravlev, I. Y. Chukicheva, and A. V. Kutchin
ACKNOWLEDGMENTS
This work was performed with financial support from the Russian
Foundation for Basic Research (Project No. 07-03-01 132) and the
president of the Russian Federation (Program for Support of Leading
Scientific Schools, Project No. NSh4028.2008.3).
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