Synthesis and characterization of chiral guanidines und guanidinium salts derived from 1-phenylethylamine

Article abstract of DOI:10.1515/znb-2012-0407

The synthesis of two new chiral guanidines 5 and 12 and derived guanidinium salts 6, 11, 13 -15 with one and three N-(1-phenylethyl) substituents is described. In both cases, the well-precedented, reliable route via chloro-formamidines was taken. Since di

Full text of DOI:10.1515/znb-2012-0407

Synthesis and Characterization of Chiral Guanidines und Guanidinium
Salts Derived from 1-Phenylethylamine
Ame´lie Castigliaa, Hend M. El Sehrawia, Thomas Orbegozoa, Dietrich Spitznera,
Birgit Claasena, Wolfgang Freya, Willi Kantlehnera,b, and Volker Ja¨gera
a Institut fu¨r Organische Chemie, Universita¨t Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
b Fakulta¨t Chemie/Organische Chemie, HTW Aalen, Beethovenstraße 1, 73430 Aalen, Germany
Reprint requests to Prof. Dr. Volker Ja¨ger. E-mail: jager.ioc@oc.uni-stuttgart.de
Z. Naturforsch. 2012, 67b, 337 – 346; received March 12, 2012
The synthesis of two new chiral guanidines 5 and 12 and derived guanidinium salts 6, 11, 13 – 15
with one and three N-(1-phenylethyl) substituents is described. In both cases, the well-precedented,
reliable route via chloro-formamidines was taken. Since direct attachment of the N-methyl-N-(1-
phenethyl)-amino group failed, the two-step protocol – introduction of the primary 1-phenethylamino
group first followed by N-methylation – was employed. Crystal structures and NMR data reveal, that
the sterically highly congested “tris” salt – with formal C3 symmetry, albeit unsymmetrical in the
crystal – constitutes an intriguing structure with two rotamers present in solution.
Key words: Chiral Guanidine, Chiral Guanidinium Salts, (R)- and (S)-1-Phenylethylamine,
Quaternization, Crystal Structures
Introduction
vanced by Kantlehner et al. [16, 24– 26] seemed most
appropriate. The starting material, or intermediate, is
the respective tetraalkylurea, which is transformed into
to the corresponding chloroamidinium salt. On treat-
ment with an amine, the latter is converted to the pen-
taalkylguanidinium salt, which by deprotonation leads
to the guanidine. The final alkylation would afford
the hexaalkylguanidinium salt. Alternatively, the latter
might be obtained directly from the chloroamidinium
salt upon action of a secondary amine [cf. 10a]. Deriva-
tives with low melting points or liquid at r. t. may result
therefrom, or otherwise may become available by an-
ion metathesis [27, 28, cf. 16 – 18].
Guanidines and their derivatives have found many
applications in Organic Synthesis, notably because
they constitute strong neutral bases [1, 2]. Guanidines
and guanidinium salts are also present in many natu-
ral products [3], for example in the essential amino
acid L-arginine [4] or polycyclic marine alkaloids
such as the crambescidins or ptilomycalin A [3 – 5].
Some guanidino-acetic acids have also been found to
be highly potent sweeteners [6]. Apart from uses as
neutral, non-nucleophilic bases (“superbases”) [7, 8],
guanidines show some potential as catalysts, in partic-
ular when chiral derivatives are at stake. Thus, addi-
tions, cycloadditions, and rearrangements with mostly
useful enantioselectivities induced by chiral guanidine
catalysts have been reported [9 – 15].
Results and Discussion
Synthesis of guanidines and guanidinium salts
As for guanidinium salts, there has been modest, but
recently increasing interest in uses both as r. t. ionic
The synthesis of the mono-N-phenethyl-guanid-
liquids [16 – 18] and further, with chiral derivatives, ine 4 and the guanidinium iodide 6 started with tetra-
as catalysts for asymmetric transformations [19, 20]. methylurea (1) (Scheme 1). The action of phosgene
In view of the few examples known of simple, chiral as described [24] gave the tetramethyl-chloroform-
guanidines and guanidinium salts, we have embarked amidinium chloride (2) which on addition of (R)-1-
on syntheses of fully alkylated derivatives, where one phenylethylamine (3) and triethylamine in acetoni-
or three N-substituents are derived from amply avail- trile reacted exothermally to produce a mixture of the
able (R)-or (S)-1-phenylethylamine [21 – 23]. For the guanidinium chloride 4 and triethylammonium chlo-
synthesis of such penta-substituted guanidines and ride. The guanidinium salt 4 was obtained by treat-
hexa-substituted guanidinium salts the protocol ad- ment with exactly one equivalent of sodium hydrox-
c
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A. Castiglia et al. · Chiral Guanidines und Guanidinium Salts
Scheme 1. Synthesis of the
(R)-guanidine 5 and the (R)-
pentamethyl-(1-phenylethyl)-gu-
anidinium salt 6. Reagents and
conditions: (i) COCl2, ref. [24];
(ii) 1) (R)-H2NCH(CH3)Ph 3,
Et3N, H3CCN, 1 h, r. t.; 2) 1.0
◦
◦
NaOH·aq., 0 C; 30 C, 2 mbar
(yield 81 %); (iii) 3.0 NaOH·aq.,
◦
Et2O, 0 C, 20 min (yield 80 %);
(iv) H3C-I, H3CCN, 82 ◦C, 2 h
(yield 67 %).
Table 1. Crystal structure data and numbers pertinent to data
ide. With an excess of base the guanidine 5 was liber-
ated in 65 % overall yield. Since the ensuing N-methyl-
ation with trimethyloxonium tetrafluoroborate only led
to impure material, this was carried out with methyl
iodide and proceeded satisfactorily (Scheme 1). The
pentamethyl-phenethylguanidiniumiodide (6) was iso-
lated in 67 % yield in the form of colorless crystals,
suitable for crystal structure analysis [29]. It should be
noted that the conversion of 2 to 6 by directly introduc-
ing the N-methyl-N-phenethylamino group had failed.
The synthesis of the tris-phenethyl compounds 11 –
14 was carried out similarly (Scheme 2). First, (S)-
collection and structure refinement of 11 · EtOH and 14.
11 · EtOH
C29H40ClN3O
482.09
0.6×0.6×0.5
orthorhombic
P212121
9.6977(14)
16.493(3)
17.866(2)
90
2857.6(8)
4
14
Formula
Mr
C28H36F6N3P
559.57
Crystal size, mm3
Crystal system
Space group
0.4×0.3×0.3
monoclinic
P21
9.1245(14)
14.596(3)
11.0278(15)
102.355(11)
1434.7(4)
2
˚
a, A
˚
b, A
˚
c, A
β, deg
3
˚
V, A
Z
phenethylamine (10) by formylation [28] and re- Dcalcd, g cm−3
1.12
0.1 (CuKα )
1040
1.30
0.0 (MoKα )
588
µ, cm−1
duction with lithium aluminium hydride was con-
verted to (S)-N-methyl-N-(1-phenylethyl)-amine (7),
F(000), e
Radiation; λ, A
hkl range
˚
CuKα ; 1.54178
MoKα ; 0.71073
a known compound [30, 31]. The (S,S)-bis-(methyl-
phenethyl)-urea (8), a low melting solid, was formed
with phosgene in toluene. Further treatment with
excess phosgene in acetonitrile, according to the
well-established, reliable procedure [24], afforded the
chloro-formamidinium chloride 9 which was kept in
solution for the next step. The third (S)-phenylethyl-
amino substitutent was attached as above, by means
of (S)-1-phenylethylamine (10) and triethylamine at
r. t. (again, direct introduction of the secondary amino
group with 7 had failed). The latter was removed on
base treatment, and the remaining guanidinium salt 11
was finally purified by recrystallization from aceto-
nitrile/diethyl ether/ethanol. Unexpectedly, this salt 11
crystallized with one equivalent of ethanol (!), as
first suspected from the seemingly deviating elemen-
tal analysis and then unambiguously established by a
crystal structure determination (Fig. 1, Table 1).
10, −17 → +19, +12, 19, 14
−18 → +21
θ range, deg
Refl. measured / unique
Rint
5.19 – 66.00
4544 / 4023
0.0559
1.89 – 28.00
7328 / 6916
0.0430
Data / restraints / ref. param. 4023 / 0 / 319
6916 / 91 / 377
0.0783 / 0.1362
0.1561, 0.1597
1.036
R(F) / wR(F2)a,b (I ≥ 2σ(I)) 0.0637 / 0.1356
R(F) / wR(F2)a,b (all data)
GoF (F2)c
0.01028, 0.1640
−0.01(3)
x (Flack)
∆ρfin (max / min), e A
−0.01(3)
−0.17(19)
−3
˚
0.166 / −0.273
0.222 / −0.214
a
b
2
2
R(F) = ΣꢀFo| − |Fcꢀ/Σ|Fo|;
wR(F2) = [Σw(Fo − Fc2
)
/
Σw(Fo2)2]1/2
,
w
=
[σ2(Fo2) + (AP)2 + BP]−1
,
where
P = (Max(Fo2,0) + 2Fc2)/3; GoF = [Σw(Fo − Fc2)2/(nobs
−
c
2
n
param)]1/2
.
Although a solid consisting mostly of the expected
guanidinium salt according to NMR and HRMS data,
purification could not be achieved [32]. On the other
hand, with methyl iodide clean N-methylation of the
guanidine 12 was registered, and the resulting “tris”
salt 13 was isolated in pure form and◦good yield. This
iodide 13 had a m. p. of 105– 107 C, therefore sil-
ver salt metathesis [16 – 18, 27, 28] was called upon
to eventually get access to lower-melting derivatives
The solid pentaalkyl-guanidinium salt 11·EtOH was
deprotonated as above to yield the oily guanidine 12,
ready for the concluding N-methylation. This was
first attempted with trimethyloxonium tetrafluorobo-
rate, however, only an impure product was obtained:
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A. Castiglia et al. · Chiral Guanidines und Guanidinium Salts
339
Fig. 1. Molecular structure of (S,S,S)-N,Nꢁ-dimethyl-N,Nꢁ,Nꢁꢁ-tris-(1-phenethyl)-guanidinium chloride 11·EtOH in the crys-
tal and view of the unit cell along the crystallographic a axis (stereo view).
in view of obtaining new chiral ionic liquids. Thus, a symmetry element in any of the presumed rotamers
the iodide 13 was treated with silver hexafluorophos- and to the presence of ethanol. On the other hand, the
phate and methylsulfonate, respectively, in an acetoni- “tris” salts 13 – 15 provide an intriguing case with the
trile/water mixture. However, the new hexafluorophos- same kind and configuration of substituents at the three
phate 14, a pure solid (97 % yield), showed an even nitrogen atoms which – due to steric interactions – may
higher melting point of 175– 177 ◦C, and the methyl- have planar (sp2) or pyramidal (sp3) properties. With
sulfonate, a viscous liquid, could not be secured in an- regard to the orientation of the phenyl groups, the sim-
alytically pure form (Scheme 2). Crystals of the “tris” plest case would be presented with all three of them
iodide 13 became amorphous after a short period of aligned in the same face of the plane defined by the
time, thus precluding crystal structure determination. CN3 moiety, possessing a C3 axis of symmetry. This
This, however, was feasible with the hexafluorophos- would constitute a three-dimensional equivalent of a
phate 14 as depicted below (Fig. 2, Table 1).
planar “triskele” as known, f. e., from the flag of Sicily
(Fig. 3).
The crystal structure of the “tris” hexafluorophos-
phate 14 clearly shows that one of the three phenyl
groups is situated below the CN3 plane. Further, the
Spectroscopic properties of the “tris” guanidinium
hexafluorophosphate 14
The NMR spectra of the pentaalkyl-substituted dialkylamino groups are twisted out-of-plane, and full
guanidinium salt 11 show more signals than expected resonance stabilization of the CN3 part is not op-
from a single species and could not be analyzed satis- erative. While the crystal structure exhibits a sin-
factorily, due to the complex situation with the lack of gle conformation, the NMR spectra reveal a more
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A. Castiglia et al. · Chiral Guanidines und Guanidinium Salts
Scheme 2. Synthesis of (S,S,S)-tris-(1-phenylethyl)-guanidine◦(12) and guanidinium salts 11, 13 – 15. Reagents and condi-
tions: (i) COCl2 (20 % solution in toluene), CH2Cl2, Et3N, 0 C for 3 h, then r. t. over night (yield 60 – 94 %); (ii) COCl2,
H3CCN, (crude product); (iii) 1) (S)-PhCH(NH2)CH3 10, H3CCN, Et3N, r. t., 2 h; 2) 1.0 NaOH·aq., 0 ◦C (81 % of 11·EtOH);
◦
◦
(iv) Et2O, NaOH·aq. (6 M), 0 C, 1 h, (yield 78 %); (v) H3C-I, H3CCN, 50 C, 12 h (yield of 13 75 %); (vi) AgPF6,
H2O/H3CCN (1 : 1), r. t., 2 h (yield of 14 97 %); (vii) MeSO3Ag, H2O/H3CCN (1 : 1), r. t., 2 h (impure product 15, 100 %).
Fig. 2. Molecular structure of (S,S,S)-N,Nꢁ,Nꢁꢁ-trimethyl-N,Nꢁ,Nꢁꢁ-tris(1-phenethyl)-guanidinium hexafluorophosphate (14)
in the crystal and view of the unit cell along the a axis (stereo view).
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A. Castiglia et al. · Chiral Guanidines und Guanidinium Salts
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Fig. 3. a) “Triskele”, Flag of Sicily (http://de.wikipedia.org/wiki/Sizilien); b) “syn” arrangement of the three N-(1-phenethyl-
amino) substituents in respective guanidinium salts 13 – 15; c) “anti” arrangement.
Fig. 4. 13C NMR spectrum of the guanidinium iodide 13 in CD2Cl2 at 300 K; S and U for the “symmetric”, respectively
“unsymmetric” rotamer of 13.
complex, “dynamic” picture (Fig. 4). In fact, three
In the 1H NMR spectrum four sets of signals are rec-
temperature-dependantprocesses leading to conforma- ognized for C-CH3, N-CH and N-CH3, in an approxi-
tional changes may be operative: (i) rotation around mate ratio of 1 : 1 : 1 : 1, with large shift differences of
the C1–N bonds regardless of the spatial arrangement > 1 ppm for the two pairs each of the N-CH and N-
around the nitrogen atom; (ii) inversion at the nitrogen CH3. A like set of pairs is seen for the C-CH3 absorp-
atoms, since the crystal structure shows considerable tions, with ∆δ of ca. 0.3 ppm. The 13C NMR spec-
pyramidalization for one of them; (iii) rotation around trum more clearly shows sets of four signals from the
the N–CPh bonds which seems to be hindered due to C-methyl and N-methyl carbon absorptions, the same
heavy steric congestion as seen in the crystal structure. for the tertiary carbon atom of CHNMe and for the
The NMR spectra of the three “tris” salts 13 – 15 were ipso-carbon atoms of the phenyl rings, with somewhat
practically identical; the 13C NMR spectrum of the io- different ratios. After peak assignments from HMBC
dide 13 is depicted in Fig. 4.
measurements and C,H COSY, a preliminary conclu-
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A. Castiglia et al. · Chiral Guanidines und Guanidinium Salts
sion is that there are two species, i. e. two rotamers, were calculated from NaD absorption. Elemental analyses
were obtained in the laboratories at the Institut fu¨r Organ-
ische Chemie, Universita¨t Stuttgart.
present in CD2Cl2 solution, in a ratio of ca. 55 : 45.
According to this, the 13C NMR data point to the pres-
ence of a species in which all three substituted amino
groups have identical environments on the 13C NMR
time scale at r. t. This would explain why all alkyl
substitutents give rise to a single peak for the respec-
tive carbon atom absorptions, and this rotamer would
represent the “symmetric one”, S, with C3 symmetry.
The second species for each of the presumably equiv-
alent groups gives rise to three signals of equal in-
tensity and indicates that here no symmetry element
is present, according to an “unsymmetric” species U.
In order to fully rationalize this situation and the pro-
cesses involved, however, more detailed NMR studies
and the temperature-dependentbehavior of absorptions
are needed and, hopefully, will provide coalescence
temperature(s) and heights of rotational barriers [33].
(S)-N-Methyl-N-(1-phenylethyl)-amine (7) was obtained
from (S)-1-phenylethylamine (10) via its N-formyl deriva-
tive [30c] by LiAlH4 reduction; colorless liquid, yield 54 –
81 %, [α]2D0 = −76 (c = 1.00, EtOH), enantiomer [α]2D0 = 74.3
(c = 1.02, CHCl3); ref. [30b]: [α]2D0 = 74.9 (c = 1.02, CHCl3).
(R)-N,N,Nꢁ,Nꢁ-Tetramethyl-Nꢁꢁ-(1-phenylethyl)-guanidinium
chloride (4)
In analogy to the literature procedure given in [24] an
equimolar mixture of (R)-phenylethylamine 3 (1.05 mL,
1.00 g, 8.25 mmol) and triethylamine (1.15 mL, 0.83 g,
8.25 mmol) at r. t. was added to a solution of (R)-N,N,Nꢁ,Nꢁ-
tetramethyl-chloroformamidinium chloride
2
[24d, e]
(1.41 g, 8.25 mmol) in acetonitrile (8.80 mL; 0.94 mol/L)
with vigorous stirring. The mixture warmed up almost to
boiling; it was then stirred for 1◦ h at r. t. and concentrated to
dryness in vacuo (2 mbar, 30 C). The resulting mixture of
salts at 0 ◦C was treated with aq. NaOH (0.33 g, 8.25 mmol
in 1 mL of water), then triethylamine and water were
distilled off (2 mbar, 30 ◦C). The residue, a yellow solid, was
taken up with acetonitrile (1.65 mL) and heated to reflux
for 15 min. The suspension was filtered,◦and the filtrate
was concentrated to dryness (2 mbar, 25 C), leaving the
Conclusion
The known preparation of guanidines and guani-
dinium salts was applied to obtain new chiral deriva-
tives based on optically active 1-phenylethylamines, of
interest with regard to potential uses as chiral bases
and catalysts or ionic liquids. Thus, the “mono” and
the “tris” compounds (referring to the number of N-
1-phenylethyl groups incorporated) were obtained, all
of them being crystalline at r. t. The “tris” salts 13 –
15, for the guanidinium part, show the presence of two
rotamers in solution, a symmetric and an unsymmet-
ric one, as deduced from NMR data. An unsymmet-
ric rotamer of the “tris” hexafluorophosphate 14 is the
species seen is the crystal structure [34]. So far, efforts
to use the “tris” guanidine 12 and the “tris” iodide 13
as catalysts for asymmetric transformations (Morita-
Baylis-Hillman reaction [35], Michael addition [36],
epoxidation [37]) have not led to noteworthy stereose-
lectivities, requiring broader studies.
◦
salt 4 as a pale-yellow solid (1.72 g, 81 %). M. p. 249 C. –
[α]2D0 = −10.5 (c = 1.00, CH3CN). The salt was used for
the next step without further purification. – IR (film): ν =
3414 (NH), 3130, 2973, 1608 (C-NH), 1584, 1397, 706, 534
(CN3+) cm−1. – 1H NMR (250.1 MHz, CDCl3): δ = 1.80
(d, 3 H, CH3CH, 3J = 6.6 Hz), 2.68 (s, 3 H, CH3N), 2.80
(s, 1 H, NH), 2.88 (s, 3 H, CH3N), 3.03 (1 s, 6 H, CH3N),
4.47 (q, 1 H, CH3CH, 3J = 6.6 Hz), 7.27 – 7.44 (m, 5 H,
C6H5). – 13C NMR (62.9 MHz, CDCl3): δ = 24.2 (CH3CH),
39.8 – 40.7 (4 CH3N), 56.5 (CHCH3), 125.7 (pC of C6H5),
127.9 and 129.1 (o, mC of C6H5), 143.1 (iC of C6H5), 161.2
(CN+3 ).
(R)-N,N,Nꢁ,Nꢁ-Tetramethyl-Nꢁꢁ-(1-phenylethyl)-guanidine (5)
According to reference [24] the guanidinium salt 4
(1.25 g, 4.89 mmol) was covered with diethyl ether (7 mL),
and aq. NaOH (0.75 g, 18.72 mmol in 3 mL of water) was
Experimental Section
1H NMR spectra were recorded with Bruker ARX 300 added with vigorous stirring. After 20 min the ethereal phase
and 500 (300.1 and 500.1 MHz) instruments, 13C NMR was separated, and the residue was stirred with another por-
spectra were recorded with the same instruments (75.5 and tion of ether (3 mL). The combined ether phases were dried
125.8 MHz). NMR shifts δ (in ppm) are reported relative (K2CO3), and the filtrate was rota-evaporated (2 mbar) leav-
to tetramethylsilane as internal standard. FT-IR spectra were ing 5 as a yellow liquid (0.855 g, 80 %). – [α]2D0 = 31.4
obtained on a Bruker (IFS 28) spectrometer. Melting points (c = 1.00, CH3CN). – IR (film): ν = 3080, 1610 (C=N),
were measured with a Fischer-Johns heating apparatus and 1581, 1236 (C-N), 1133, 699 cm−1. – 1H NMR (250.1 MHz,
are uncorrected. Angles of rotation were measured with a CDCl3): δ = 1.39 (d, 3 H, CH3CH, 3J = 6.5 Hz); 2.61, 2.71
polarimeter 241 MC of Perkin Elmer. The optical rotations (2 s, 12 H, CH3N); 4.51 (q, 1 H, CH3CH, 3J = 6.5 Hz), 7.09 –
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A. Castiglia et al. · Chiral Guanidines und Guanidinium Salts
343
7.38 (m, 5 H, C6H5). – 13C NMR (62.9 MHz, CDCl3): δ = and 128.3 (o-,m-C of C6H5), 141.5 (iC of C6H5), 165.4
27.2 (CH3CH), 38.7 – 39.8 (4 CH3N), 56.7 (CHCH3), 125.7 (C=O). – Anal. for C19H24N2O (296.2): calcd. C 76.99,
(pC of C6H5), 126.2 and 128.0 (o-,m-C of C6H5), 149.7 (i- H 8.16, N 9.45; found C 77.05, H 8.08, N 9.50.
C of C6H5), 159.4 (CN+). – Anal. for C13H21N3 (219.3):
calcd. C 71.19, H 9.65,3N 19.16; found C 70.57, H 9.59,
N 18.75.
(S,S)-N,Nꢁ-Dimethyl-N,Nꢁ-bis-(1-phenylethyl)-chloroform-
amidinium chloride (9)
(R)-N,N,Nꢁ,Nꢁ,Nꢁꢁ-Pentamethyl-Nꢁꢁ-(1-phenylethyl)-guanid-
inium iodide (6)
To an ice-cooled solution of the urea derivative 8 (11 g,
39 mmol) in acetonitrile a solution of phosgene (40 g,
0.4 mol, 198 g or 211 mL of 20 % in toluene) was slowly
introduced over a period of 25 min. The mixture was stirred
at r. t. over night, and the excess of phosgene was removed
in vacuo (20 ◦C, 200 mbar) together with 30 mL of acetoni-
trile. The colorless solution of 9 was stored at 5 ◦C and used
directly for the next step.
In analogy to a procedure given in ref. [24] the guani-
dine 5 (693 mg, 3.16 mmol) was dissolved in acetonitrile
(10 mL). Methyl iodide (448 mg, 3.16 mmol) in acetonitrile
(0.5 mL) was added. The mixture became warm and then
was heated to reflux for 2 h under exclusion of moisture.
Acetonitrile was distilled off (2 mbar), and the residue was
treated with diethyl ether (abs., 4 mL) causing precipitation
of a solid. The product was several times extracted with boil-
ing ether (2 mL each) to leave colorless crystals suitable for
crystal structure analysis [29] (766 mg, 67 %). M. p. 145 –
(S,S,S)-N-Nꢁ-Dimethyl-N,Nꢁ,Nꢁꢁ-tris-(1-phenylethyl)-guanid-
inium chloride·ethanol (11·EtOH)
In analogy to the procedure given in ref. [24] to a mix-
ture of the chloroformamidinium chloride 9 (18.18 g, c =
0.55 mol kg−1, 10 mmol) and (S)-phenylethylamine (10)
(1.3 mL, 10 mmol) in acetonitrile was added dropwise
1.4 mL of triethylamine (10 mmol) at r. t. After 2 h reaction
◦
146 C. – [α]2D0 = 14.3 (c = 1.00, CH3CN). – IR (film): ν =
3425, 2982, 1604 (C-NH), 1558 (C=N), 1491, 1470, 1450,
1402, 1363, 1299, 1192, 1065, 1053, 980, 772, 707 cm−1. –
1H NMR (250.1 MHz, CDCl3): δ = 1.73 (d, 3 H, CH3CH,
3J = 6.9 Hz), 2.63 (s, 3 H, CH3N), 2.87 (s, 3 H, CH3N), 3.06
(s, 3 H, CH3N), 3.13 (s, 3 H, CH3N), 3.25 (s, 3 H, CH3N),
4.77 (q, 1 H, CH3CH, 3J = 6.9 Hz), 7.24 – 7.44 (m, 5 H,
C6H5). – 13C NMR (62.9 MHz, CDCl3): δ = 16.5 (CH3CH),
34.0 (CH3N); 41.2, 42.0 (CH3N); 60.0 (CHCH3), 126.7 (pC
of C6H5), 128.9 and 129.3 (o, mC of C6H5), 138.5 (iC of
C6H5), 163.6 (CN+3 ).
◦
time, the solvent was removed in vacuo (40 C, 20 mbar),
and the residue was cooled to 0 ◦C. Under vigorous stirring,
1 mL of a 10 M solution of NaOH (10 mmol) was added.
The mixture was evaporated in vacuo (40 ◦C, 20 mbar), and
the residue was dissolved in hot acetronitrile. The resulting
solution was filtered throug◦h a paper filter, and the solvent
was removed in vacuo (40 C, 20 mbar). The yellowish oil
obtained was triturated with diethyl ether, and the resulting
powder was recrystallized from a mixture of acetonitrile/di-
ethyl ether/ethanol affording colorless crystals of the title
compound 11·EtOH (3.88 g, 8.05 mmol, 81 %), suitable for
X-ray analysis. M. p. 171 – 172 ◦C. – [α]D20 = −43 (c = 0.50,
(S,S)-N,Nꢁ-Dimethyl-N,Nꢁ-bis-(1-phenylethyl)-urea (8)
Caution! Phosgene is highly toxic. Exposure to vapors or
solutions containing phosgene must strictly be avoided. All
operations should be conducted in a well-ventilated hood.
To an ice-cooled mixture of (S)-methyl-1-phenylethyl- CH3CN). – IR (film): ν = 3340 (O-H), 3318, 2979, 2868
amine 7 (13.0 mL, 12.1 g, 0.1 mol) and triethylamine (N-H), 1573, 1529 (C=N), 1454, 1400, 1205, 1087, 1058,
(14.0 mL, 10.1 g, 0.1 mol) in methylene chloride (250 mL) 705 cm−1. – Anal. for C27H34N3Cl·(C2H6O) (482.1): calcd.
a solution of phosgene in toluene (20 %, 26 mL, 0.05 mol) C 72.25, H 8.36, N 8.72, Cl 7.35; found C 71.42, H 8.20,
was slowly introduced. The mixture was stirred in an ice N 8.85, Cl 7.57. – 1H NMR (500.1 MHz, CD3CN, at 300 K,
bath for 3 h, then left at r. t. over night. The◦mixture was two rotamers, ratio ca. 56:44): major rotamer: δ = 1.66, 1.72,
concentrated to dryness in vacuo (2 mbar, 60 C) leaving a 1.81 (3 d, 3 H each, CH3CH, 3J = 7.5 Hz); 2.91, 2.95 (2 s, 3 H
solid residue. The residue was dissolved in methylene chlo- each, CH3N), 3.95, 4.92, 5.01 (3 q, 1 H each, CH3CH, 3J =
ride (150 mL), and the resulting solution was washed with 7.5 Hz), 6.57 – 7.59 (m, 15 H, 3 C6H5), 9.71 (s, 1 H, NH+);
aq. HCl (100 mL), then with water (3 × 100 mL). The or- minor rotamer: δ = 1.57, 1.72, 1.78 (3 d, 3 H each, CH3CH,
gan◦ic layer was separated and concentrated in vacuo (2 mbar, 3J = 7.5 Hz); 2.22, 2.46 (2 s, 3 H each, CH3N); 4.07, 4.56,
3
65 C) to give a thick oil that solidifi◦ed to yield a color- 4.96 (3 “t”, 1 H each, CH3CH, J = 7.5, J = 9.0 Hz), 9.41
less product (12.7 g, 86 %). M. p. 32 C. – [α]D20 = −136 (d, 1 H, J = 9.0, NH+); other H signals of C6H5 overlapping
(c = 1.00, EtOH). – 1H NMR (250.1 MHz, CDCl3): δ = with those of the major rotamer. – 13C NMR (125.8 MHz,
1.57 (d, 6 H, CH3CH, 3J = 7.0 Hz), 2.55 (s, 6 H, CH3N), CD3CN, at 300 K, two rotamers, ratio ca. 60 : 40): major ro-
5.20 (q, 2 H, CH3CH, 3J = 7.0 Hz), 7.32 – 7.34 (m, 10 H, 2 tamer: δ = 17.8, 22.3, 22.4 (3 CH3CH), 33.6 (2 CH3N), 57.4,
C6H5). – 13C NMR (62.9 MHz, CDCl3): δ = 16.2 (CH3CH), 59.9, 61.3 (3CHCH3), 127.9 – 130.0 (9 d of o-, m-, p−CH of
31.2 (CH3N), 54.8 (CH-CH3), 126.9 (pC of C6H5), 127.2 3 C6H5), 144.5 (i-C of C6H5), 162.6 (CN+3 ); minor rotamer:
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344
A. Castiglia et al. · Chiral Guanidines und Guanidinium Salts
δ = 16.5, 16.5, 16.8 (3 CH3CH); 33.5. 57.8 (2 CH3N); 57.4, jor rotamer U: δ = 1.55, 1.85, 1.87 (3 d, 3 H each, CH3CH,
57.8, 60.1 (3 CHCH3), 140.2 (i-C of C6H5), 162.6 (CN+3 ); 3J = 7.1 Hz); 2.04, 2.30, 3.20 (3 s, 3 H each, CH3N); 3.98,
other C signals of C6H5 overlapping with those of the major 5.00, 5.05 (3 q, 1 H each, CH3CH, 3J = 7.1 Hz), 6.64, 7.36,
rotamer.
7.58 (3 m, 2 H each, 3 o-C6H5); 7.25, 7.36, 7.52 (3 m, p-
H of 3 C6H5); 7.25, 7.52, 7.58 (3 m, m-H of C6H5); mi-
nor rotamer S: δ = 1.58 (d, 9 H, CH3CH, 3J = 7.1 Hz);
(S,S,S)-N,Nꢁ-Dimethyl-N,Nꢁ,Nꢁꢁ-tris-(1-phenylethyl)-guanid-
ine (12)
3
3.09 (s, 9 H, CH3N); 3.90 (q, 3 H, CH3CH, J = 7.1 Hz);
absorptions of C6H5 overlapped by those of the major ro-
tamer. – 13C NMR (125.8 MHz, CD2Cl2, at 300 K): major
rotamer U: δ = 15.4, 16.0, 17.9 (3 CH3CH), 31.5, 32.1, 35.6
(3 CH3N), 59.8, 62.0, 62.5 (3 CHCH3); 127.6, 127.5, 127.9
(i-C of 3 C6H5), 129.4, 129.8, 130.1, 129.3, 129.9, 130.2 (o-
, m-, p-C of 3 C6H5); 137.0, 137.7, 139.1 (i-C of 3 C6H5),
165.0 (CN+); minor rotamer S: δ = 17.5 (3 CH3CH), 35.4
(3 CH3N),360.9 (CHCH3), 128.0, 129.53, 129.56 (o-, m-, p-
C of 3 C6H5, in part overlapping with signals of U), 138.87
(i-C of C6H5), 164.2 (CN+3 ).
In analogy to the literature procedure [24], to an ice-
cooled solution of the guanidinium chloride 11 (1.5 g,
3.44 mmol) in diethyl ether (9 mL) 3.6 mL (0.02 mol) of
a 6 M solution of NaOH was added dropwise. After 1 h of re-
action at 0 ◦C, the organic phase was separated, and the aque-
ous phase was extracted with diethyl ether (2 × 5 mL). The
combined organic phases were dried over NaS◦O4 over night,
and the solvent was removed in vac◦uo (30 C, 15 mbar).
High vacuum distillation (180 – 190 C at ca. 10−6 mbar)
of the crude product afforded 1.07 g (2.68 mmol, 78 %) of
an analytically pure, viscous yellowish oil. – [α]2D0 = −32
(c = 1.3, CH3CN). – IR (film): ν = 3060, 2922, 1597 (C=N),
1580, 1490, 1294 (C-N), 1077, 1025, 759, 696, 542 cm−1. –
Anal. for C27H33N3 (399.6): calcd. C 81.16, H 8.32, N 10.52;
(S,S,S)-N,Nꢁ,Nꢁꢁ-Trimethyl-N,Nꢁ,Nꢁꢁ-tris-(1-phenylethyl)-
guanidinium hexafluorophosphate (14)
Under exclusion of light, 233 mg (0.92 mmol) of AgPF6
found C 81.06, H 8.40, N 10.61. – 1H NMR (500.1 MHz, was added to a solution of the guanidinium iodide 13
CD3CN): δ = 1.32 (d, CH3CH, 3J = 6.4 Hz); 1.43, 1.54 (500 mg, 0.92 mmol) in 1.6 mL of a H2O-CH3CN (1 : 1) mix-
(2 d, 3 H each, 2 CH3CH, 3J = 6.9 Hz); 2.42, 2.59 (2 s, 3 H ture. The suspension was allowed to react at r. t. for 2 h, then
3
each, 2 CH3N); 4.47, 4.58 (2 q, 1 H each, 2 CH3CH, J = the golden-yellow precipitate of AgI was filtered off through
6.9 Hz), 5.31 (q, 1 H, CH3CH, 3J = 6.4 Hz), 7.20 – 7.50 (m, a small cotton pad. The filtrate was concentrated in vacuo
◦
15 H, 3 C6H5). – 13C NMR (125.8 MHz, CD3CN): δ = 16.1, (40 C, 200 mbar), and the residue was recrystallized from
19.8, 27.3 (3 CH3CH), 30.9, 35.4 (2 CH3N), 55.6, 57.4, 59.8 acetone-CH3CN-Et2O affording 500 mg (0.89 mmol, 97 %)
(3 CHCH3), 126.6 – 129.3 (15 d of CH of 3 C6H5); 143.7, of the guanidinium salt 14 as analytically pure, colorless
◦
144.4, 150.2 (3 i-C of 3 C6H5), 158.1 (CN3).
crystals, suitable for X-ray analysis. M. p. 175 – 177 C. –
[α]2D0 = −36.2 (c = 1.02, (CH3)2CO). – IR (film): ν = 2992,
1524 (C=N), 1454, 1403, 1088, 1058, 702 cm−1. – Anal.
for C28H36N3PF6 (559.6): calcd. C 60.10, H 6.48, N 7.51,
P 5.54; found C 60.18, H 6.49, N 7.49, P 5.56. – NMR data
identical to those given for 13.
(S,S,S)-N,Nꢁ,Nꢁꢁ-Trimethyl-N,Nꢁ,Nꢁꢁ-tris(1-phenylethyl)-
guanidinium iodide (13)
In analogy to the literature procedure [24], into a two-
necked round-bottomed flask equipped with a condenser and
a CaCl2 drying tower the guanidine 12 (360 mg, 0.90 mmol)
and 5 mL of dried acetonitrile were introduced. A solution of
methyl iodide (0.08 ml, 1.35 mmol) in 2.5 mL abs. CH3CN
was added dropwise, and the reaction mixture was heated
(S,S,S)-N,Nꢁ,Nꢁꢁ-Trimethyl-N,Nꢁ,Nꢁꢁ-tris(1-phenyl-ethyl)-
guanidinium methylsulfonate (15)
Under exclusion of light 112 mg (0.54 mmol) of
to 50 ◦C for 12 h. The solvent was removed in vacuo (40 ◦C, AgMeSO3 was added to a solution of the guanidinium io-
200 mbar), and the brownish crude oil was triturated in hex- dide 13 (300 mg, 0.54 mmol) in 1 mL of a H2O/CH3CN
ane until the precipitation of a fine colorless powder. The (1 : 1) mixture. The suspension was allowed to warm to r. t.
solid residue was filtered off and was taken up in 1 mL of for 2 h, and the golden-yellow precipitate of AgI was fil-
MeOH. Addition of 60 mL of hexane and a few drops of tered off through a small cotton pad. The filtrate was con-
◦
diethyl ether initiated a slow crystallization that furnished centrated in vacuo (20 C, 200 mbar), and the residue was
238 mg (0.40 mmol, 75 %) of 13 as a colorless solid. M. p. taken up in ethanol. The solution was filtered again, and the
◦
105 – 107 ◦C. – [α]D20 = −36.4 (c = 1.04, CH3CN). – IR filtrate was concentrated in vacuo (20 C, 200 mbar) to fur-
(film): ν = 3325, 2965, 1572, 1530 (C=N), 1454, 1399, 1086, nish 284 g (0.55 mmol, ‘100 %’) of the guanidinium salt 15
1053, 705 cm−1. – Anal. for C28H36N3I (541.2): calcd. as a colorless, viscous oil with deviating values of elemental
C 62.10, H 6.65, N 7.76, I 23.47; found C 61.86, H 6.74, analysis. – Anal. for C28H39N3SO3 (509.7): calcd. C 68.34,
N 7.67, I 23.27. – Two rotamers of 13 in CD2Cl2 (ratio H 7.71, N 8.24, S 6.29; found C 65.60, H 7.85, N 7.68,
ca. 55 : 45) at 300 K. – 1H NMR (500.1 MHz, CD2Cl2): ma- S 10.12. – NMR data identical to those given for 13.
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A. Castiglia et al. · Chiral Guanidines und Guanidinium Salts
345
Crystal structure determinations
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data request/cif.
For the X-ray crystal structure analyses a Nicolet P3
diffractometer equipped with a graphite monochromator was
used. The measurements were done with CuKα (compound
11·EtOH) or MoKα radiation (compound 14). Crystal data
and numbers pertinent to data collection and structure re-
finement of 11·EtOH and 14 are given in Table 1. Programs
used: SHELXS-97 [38], SHELXL-97 [39], and SHELXTL-
PLUS [40].
Acknowledgements
We are grateful to the Bundesministerium fu¨r Bildung und
Forschung der Bundesrepublik Deutschland (BMBF-Ver-
bundprojekt “Neuartige ionische Flu¨ssigkeiten als innovative
Reaktionsmedien fu¨r die Technische Organische Chemie”,
FKZ 01 RI 05175) for financial support, to BASF SE, Lud-
wigshafen, for gifts of chemicals, and to Al-Azhar Univer-
sity, Cairo, and the government of Egypt for fellowships to
H. M. E. S.
CCDC 870852 (11·EtOH) and CCDC 870853 (14)
contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge
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