Asymmetric crystallization of bisguanidinobenzene derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.09.144

We show that the mono-N-methylated and -ethylated derivatives of the achiral compound bisguanidinobenzene undergo spontaneous asymmetric crystallization into a chiral form with chiral space group P2₁2₁2₁. The absolute conf

Full text of DOI:10.1016/j.tetlet.2007.09.144

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Tetrahedron Letters 48 (2007) 8526–8530
Asymmetric crystallization of bisguanidinobenzene derivatives
Waka Nakanishi,a Akiko Ogino,a Masatoshi Kawahata,b Kentaro Yamaguchib
and Tsutomu Ishikawaa,*
aGraduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
bFaculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
Received 15 August 2007; revised 19 September 2007; accepted 25 September 2007
Available online 22 October 2007
Abstract—We show that the mono-N-methylated and -ethylated derivatives of the achiral compound bisguanidinobenzene undergo
spontaneous asymmetric crystallization into a chiral form with chiral space group P212121. The absolute configurations of the chiral
crystals were determined by X-ray crystallography and correlated with circular dichroism (CD) spectra recorded in the solid state.
The corresponding protonated and isopropylated derivatives, by contrast, afforded achiral crystals.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
units in the formation of supramolecules.6 Recently we
have developed guanidine chemistry focusing on uncov-
ering potential abilities of guanidinyl functions as
chiral auxiliaries.7 In the course of these studies, a new
bisguanidinobenzene derivative, o-phenylenebis(N,N0-
dimethyl-N,N0-ethylene)guanidine (1, Scheme 1) was
designed as a potential hydrogen acceptor8 and was found
to form an isolable crystalline complex with a hydrogen
donor, even a weak hydrogen donor such as benzyl
alcohol. It is notable that the bisguanidinobenzene 1
Optical resolution is one of the most important methods
for obtaining desired chiral materials. In this method,
however, chiral materials can be separated only by the
use of chiral sources. On the other hand, some of the
compounds, such as amide A,1 sulfonamide B,2 and gua-
nidine C3 (Fig. 1) spontaneously crystallize into chiral
forms, and application of spontaneous crystallization
to absolute asymmetric synthesis has been reported.4
Guanidines act not only as superbases5 but also as key
Figure 1. Structures of chiral-crystal-forming compounds.
Keywords: Asymmetric crystallization; Guanidine; CD; X-ray
diffraction.
*
Corresponding author. Tel./fax: +81 43 290 2910; e-mail: benti@
p.chiba-u.ac.jp
Scheme 1. Synthesis of 2.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.144

W. Nakanishi et al. / Tetrahedron Letters 48 (2007) 8526–8530
8527
Figure 2. Asymmetric crystallization of bisguanidinobenzene
derivatives.
Figure 3. Ortep drawings of (a) P-2b, (b) P-2c, and (c) 2d (two
molecules).
co-crystallized in chiral form with benzoic acid in the
absence of a chiral source when water was incorporated.9
In this communication, we report on the ability of
mono-N-methylated (or -ethylated) bisguanidinoben-
zene to asymmetrically crystallize to give enantiomeric
crystals (Fig. 2).
Table 1. Structural and crystal properties of 1 and 2
Bisguanidinobenzene 1 was prepared from o-diamino-
benzene (3) by treatment with 2-chloro-1,3-dimethylim-
idazolium chloride10 (=DMC, 4) (Scheme 1). Mono-N-
methylated and -ethylated compounds (2b and 2c,
respectively) were obtained by reaction of 1 with the al-
kyl iodide, followed by salt formation using NH4PF6.
Note that only mono-alkylation proceeded even in the
presence of excess alkyl halide, and isopropylation did
not occur. The mono-N-isopropylated bisguanidino-
benzene 2d was obtained by treatment of N-isopropyl-
diaminobenzene (5)11 with DMC and then NH4PF6.
Recrystallization of 2b, 2c, and 2d from acetone/ethyl
acetate (ca. 1:1–2:1) afforded colorless prisms analyzable
by X-ray crystallography. Ortep drawings of each
(Fig. 3) show that the compounds have a trans configu-
ration; the structural and crystal features of each
compound are listed in Table 1.12 The N-methyl and
N-ethyl compounds (2b and 2c, respectively) were found
to crystallize in chiral space group P212121, in which
each crystal consists of a single P (right-handed helicity)
or M (left-handed helicity) enantiomer, and the absolute
configurations were determined by the Flack para-
meter.13 Identical crystals of 2c were also obtained when
the compound was recrystallized from methanol rather
than acetone/ethyl acetate. On the other hand, the N-
isopropyl compound 2d crystallized in achiral space
group P21/c, in which each crystal consists of a racemic
mixture.
R
Configuration Crystal system Space group Chirality
1
2a
—
—
trans
cis
Monoclinic
Monoclinic
Orthorhombic P212121
Orthorhombic P212121
P21/c
P21/n
Achiral
Achiral
Chiral
2b Me trans
2c Et trans
2d i-Pr trans
Chiral
Monoclinic
P21/c
Achiral
the P and M enantiomers correspond to (ꢀ) and (+)
signs in the CD spectra. The chirality of the crystal
could be controlled using a seed with the desired chiral-
ity: P-2b and M-2b crystals were obtained from P-2b
and M-2b seeds, respectively. The Cotton effect observed
in the solid-state spectra of 2b and 2c was not observed
in the solution spectra. As expected, 2d was CD-inactive.
Solid-state circular dichroism (CD) spectra of N-methyl
(2b) and N-ethyl (2c) compounds (Fig. 4), measured in
KBr tablets, were very similar, with characteristic peaks
at 235 and 267 nm for 2b and 227 and 269 nm for 2c.
The absolute structure determined by X-ray crystallo-
graphy was associated with the form of the CD spectra:
To investigate the structural features required for asym-
metric crystallization, crystals of the diprotonated

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W. Nakanishi et al. / Tetrahedron Letters 48 (2007) 8526–8530
B2: amide A and sulfonamide B have C2 symmetry,
and 2b and 2c have pseudo-C2 symmetry. In these four
crystals, the chirality originates from the restriction of
two Ar–N bonds in the solid phase. Unlike the struc-
tures of 2b, 2c, A, and B, the previously reported chiral
guanidine C3 has a propeller-like structure in which the
chirality arises from steric repulsions of the substituent
on the acyclic guanidine nitrogen. In contrast, our cyclic
bisguanidinobenzenes 2b and 2c are rather planar, and
not propeller-like. Thus, the bisguanidinobenzenes 2b
and 2c represent a new class of chiral-crystal-forming
compounds.
As mentioned above, the Cotton effect observed in the
CD spectra of 2b and 2c in the solid state disappeared
when the compounds were dissolved in a solvent,
suggested rapid racemization in the solution phase. We
1
therefore performed dynamic H NMR analysis on the
N-ethyl and N-isopropyl derivatives (2c and 2d, respec-
tively), and considered the results along with those we
obtained previously15 for the N-protonated and
N-methyl derivatives (2a and 2b, respectively). Similar
to our previous results for 2a and 2b, which showed no
separation or significant broadening of N-methyl peaks
due to the restriction of Ar–N and/or C@N bond rotation
(even at 179 K),16 we observed only two N-methyl peaks
1
in the H NMR spectra of the N-ethyl derivative 2c (d
2.84 and 2.91) and N-isopropyl derivative 2d (d 2.93
and 3.08) at rt. In contrast to the spectra of 2a and 2b,
however, peak broadening of the N-methyl peaks was
observed in the spectra of both 2c and 2d at 179 K, indi-
cating that the presence of a bulky substituent on the
guanidine nitrogen atom partially restricted bond rota-
tion; however, this effect was not sufficient to completely
restrict Ar–N and/or C@N bond rotations. Thus, race-
mization in N-methyl (2b) and N-ethyl (2c) bisguanidi-
nobenzenes may be caused by cis-trans isomerization
through rotation of the Ar–N bond.
Figure 4. Solid-state CD spectra of (a) 2b, (b) 2c and (c) 2d (100 lg of
each sample/100 mg of KBr).
compound 2a were prepared by recrystallization from
acetone/ethyl acetate. X-ray diffraction analysis showed
that 2a has a cis structure with achiral space group P21/n
(Table 1). The crystal of 2a was CD-inactive, as
expected. We also attempted to crystallize bisguanidino-
benzene 1, which is obtained as a viscous oil, from
acetone/ethyl acetate, methanol, or other solvents at
room temperature (rt), but the compound remained in
oil form. Single crystals of 1 were obtained, however,
by freezing the oil at ꢀ18 °C. From X-ray crystallo-
graphic data, 1 was found to crystallize in achiral space
group P21/c with a trans configuration (Table 1).
In conclusion, we found that mono-N-methylated and -
ethylated bisguanidinobenzenes undergo spontaneous
chiral crystallization, and that the crystallization of
these compounds could be rigidly controlled by use of
a seed crystal with the desired chirality. We are currently
investigating ways to retain the chirality of these crystals
on dissolution in a solvent, as this is important in mole-
cular recognition and asymmetric synthesis applications.
2. Experimentals
Bisguanidinobenzenes 1, 2a, and 2b were synthesized by
Thus, bisguanidinobenzene itself and the protonated salt
do not crystallize asymmetrically, whereas mono-N-
methylated and -N-ethylated bisguanidinobenzenes do
undergo asymmetric crystallization.14 Interestingly, the
ability to asymmetrically crystallize was again lost on
going to mono-N-isopropylated bisguanidinobenzene,
which contains the bulkier isopropyl moiety.
the method previously described by us.8,15
2.1. N,N0-Bis(1,3-dimethyl-2-imidazolidinylidene)-N-
ethyl-o-benzenediammonium bis(hexafluorophosphate)
(2c)
To a solution of 1 (1.00 g, 3.34 mmol) in acetonitrile
(5.0 mL) was added ethyl iodide (0.26 mL, 3.2 mmol)
and the reaction mixture was stirred at 70 °C for 3.5 h,
and evaporated. To complete the reaction, after further
addition of ethyl iodide (0.13 mL, 1.6 mmol) and aceto-
The structural features of our N-methyl (2b) and N-ethyl
(2c) bisguanidinobenzenes show some similarities with
those of the reported chiral amide A1 and sulfonamide

W. Nakanishi et al. / Tetrahedron Letters 48 (2007) 8526–8530
8529
nitrile (1.5 mL) the reaction mixture was stirred at 70 °C
Acknowledgments
for 5 h and evaporated to give slightly yellowish crystals
(1.45 g). To a part of the crystals (1.26 g) were added
H2O (2.2 mL) and NH4PF6 (1.26 g, 7.73 mmol) and
the whole was stirred for 2 min. Filtration of the precip-
itates formed afforded colorless solids (2.02 g), which
were recrystallized from acetone/ethyl acetate to give
2c as colorless prisms (695 mg, 39% from 1): Mp 231–
237 °C; IR (ATR) 3357, 1595; 1H NMR (400 MHz,
acetone-d6): d 1.34 (t, J = 7.2 Hz, 3H), 2.84 (s, 6H),
2.91 (s, 6H), 3.84 (d, J = 0.9 Hz, 4H), 3.98 (s, 4H),
4.03 (q, J = 7.2 Hz, 2H), 7.43 (ddd, J = 8.1, 7.3,
1.4 Hz, 1H), 7.54 (dd, J = 8.2, 1.4 Hz, 1H), 7.60 (ddd,
J = 8.2, 7.3, 1.3 Hz, 1H), 7.75 (dd, J = 8.1, 1.3 Hz,
1H); 13C NMR (100 MHz, acetone-d6):d 13.7, 34.3,
35.2, 47.2, 49.7, 49.8, 125.4, 128.5, 130.5, 130.8, 131.1,
138.1, 156.6, 161.6; MS (FAB) m/z: 329 [MꢀHꢀ2PF6]+,
475 [MꢀPF6]+. Anal. Calcd for C18H30N6F12P2: C,
34.85; H, 4.87; N, 13.55. Found: C, 34.86; H, 4.89; N,
13.61.
We would like to thank Professor Isao Azumaya of
Tokushima Bunri University and Associate Professor
Aya Tanatani of Ochianomizu University for their
helpful discussions. This work was supported by a
Grant-in-Aid for Young Scientists (B) (19790006).
Supplementary data
1H NMR and 13C NMR copies and the crystal data of 1,
2a, 2b, 2c, and 2d. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.09.144.
References and notes
1. Azumaya, I.; Yamaguchi, K.; Okamoto, I.; Kagechika,
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2.2. N,N0-Bis(1,3-dimethyl-2-imidazolidinylidene)-N-iso-
propyl-o-benzenediammonium bis(hexafluorophosphate)
(2d)
To a solution of N-isopropyl-1,2-diaminobenzene (5)
4. Sakamoto, M.; Unosawa, A.; Kobaru, S.; Saito, A.; Mino,
T.; Fujita, T. Angew. Chem., Int. Ed. 2005, 44, 5523; For
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(100 mg, 0.666 mmol) in CH3CN (2.0 mL) was added
triethylamine (0.40 mL, 2.8 mmol).
A solution of
DMC (4), (277 mg, 1.44 mmol) in CH3CN (0.5 mL)
was added to the above solution under ice cooling,
and the mixture was stirred at rt for 3 h and at 70 °C
for 13 h. After further addition of triethylamine
(0.45 mL, 3.2 mmol) and a solution of 4 (315 mg,
1.64 mmol) in CH3CN (0.5 mL), the whole was stirred
at rt for 2 h and at 70 °C for 6 h, and evaporated. The
resulting brown solids (1.32 g) were purified by column
chromatography (NH-coated SiO2 with hexane/ethyl
acetate to ethyl acetate/ethanol) to afford an orange
oil (169 mg, 67%) [IR (ATR) 1594; 1H NMR
(400 MHz, CDCl3): d 1.37 (d, J = 6.7 Hz, 6H), 2.65 (s,
6H), 2.93 (s, 6H), 3.40 (s, 4H), 3.99 (s, 4H), 4.12 (sep,
J = 6.7 Hz, 1H), 6.81–6.84 (m, 2H), 7.11 (ddd, J = 8.1,
7.3, 1.2 Hz, 1H), 7.28 (m, 1H); 13C NMR (100 MHz,
CDCl3): d 22.3, 34.8, 36.5, 48.1, 49.6, 53.9, 77.2, 119.3,
122.8, 127.4, 128.7, 146.5, 157.0, 163.2; HRMS (FAB)
m/z: 343.2578 (calcd for C19H31N6 [MꢀI]+: 343.2610)].
To a solution of the oil (169 mg, 0.405 mmol) in H2O
(0.2 mL), was added NH4PF6 (148 mg, 0.909 mmol)
and stirred at rt for 2 min. The supernatant was
removed and the residue was dried in vacuo to afford
slightly brown solids (162 mg), which were recrystallized
from acetone/ethyl acetate to give 2d as colorless prisms
(76.8 mg, 30%). Mp 234–239 °C; IR (ATR) 3338, 1612;
´
´
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1H NMR (400 MHz, acetone-d6):
d
1.55 (d,
9. The chiral crystals were obtained by complexation of
bisguanidinobenzene 1 and (2S,3S)-(+)-O,O0-dibenzoyl-
tartaric acid. In these crystals, only one enantiomer of the
trans form of 1 exists. Surprisingly, the chiral crystal was
also obtained from the complex of 1 and achiral benzoic
acid and water. In these crystals, the complex formed a
helical supermolecule carrying only the trans enantiomer
of 1. The chirality disappeared when the crystal was
dissolved in a solvent. These results will be reported
elsewhere in the near future.
J = 6.8 Hz, 6H), 2.93 (s, 6H), 3.08 (s, 6H), 3.91 (s,
4H), 4.10 (s, 4H), 4.49 (sep, J = 6.8 Hz, 1H), 7.50 (dd,
J = 7.5, 7.5 Hz, 1H), 7.67 (m, 2H), 7.96 (d, J = 8.2 Hz,
1H), 8.81 (s, 1H); 13C NMR (100 MHz, acetone-d6): d
21.9, 34.4, 35.6, 49.6, 50.0, 56.0, 128.0, 128.6, 131.1,
131.2, 131.9, 137.6, 156.9, 162.4; MS (FAB) m/z: 343
[MꢀHꢀ2PF6]+, 489 [MꢀPF6]+. Anal. Calcd for
C19H32N6F12P2: C, 35.97; H, 5.08; N, 13.25. Found:
C, 35.63; H, 4.82; N, 13.29.

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W. Nakanishi et al. / Tetrahedron Letters 48 (2007) 8526–8530
10. (a) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 5832;
(b) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984;
(c) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6989.
11. Figee, A.; Altenbach, H. J.; Brauer, D. J.; Tielmann, P.
Tetrahedron: Asymmetry 2002, 13, 137–144.
13. Flack, H. D. Acta Crystallogr. Sect. A 1983, 39, 876.
14. Attempts to synthesize dialkylated bisguanidinobenzene
were not successful. Treatment of N,N0-dimethyl-o-di-
aminobenzene with 4 afforded an undesired product
through intermolecular reactions.
´
12. Details of the crystal structure analyses are provided as
Supplementary data. CCDC 654529 (1), CCDC 654532
(2a), CCDC 654536 (P-2b), CCDC 654531 (M-2b), CCDC
654530 (M-2c recrystallized from MeOH), CCDC 654535
(P-2c), CCDC 654534, (M-2c), and CCDC 654533 (2d)
contain the supplementary crystallographic data for this
Letter. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
15. Nakanishi, W.; Ishikawa, T.; Margetic, D. Bull. Chem.
Soc. Jpn. 2007, 80, 1187.
16. From dynamic studies on guanidines, it is known that
both the C@N and Ar–N bonds rapidly rotate at rt. See:
(a) Kessler, H.; Leibfritz, D. Tetrahedron Lett. 1969, 6,
427; (b) Kessler, H.; Leibfritz, D. Tetrahedron 1969, 25,
5127; (c) Kessler, H.; Leibfritz, D. Tetrahedron 1970, 26,
1805.