Expedient synthesis of homochiral 1-aryl-substituted 4,5-dihydro-1H-imidazoles and their modification to N-heterocyclic carbene precursors

Article abstract of DOI:10.1002/ejoc.201403560

The amidoamines (S)-Ar¹CONHCHRCH₂NHAr² [Ar¹ = o-C₆H₄SO₃H, R = Bn, iBu, iPr; Ar² = 2,6-iPr₂C₆H₄, 2,6-Et₂C₆H₄

Full text of DOI:10.1002/ejoc.201403560

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FULL PAPER
DOI: 10.1002/ejoc.201403560
Expedient Synthesis of Homochiral 1-Aryl-Substituted 4,5-Dihydro-1H-
imidazoles and Their Modification to N-Heterocyclic Carbene Precursors
Christopher M. Latham,[a] William Lewis,[a] Alexander J. Blake,[a] and Simon Woodward*[a]
Keywords: Synthetic methods / Asymmetric synthesis / Nitrogen heterocycles / Amino alcohols / NHC ligand precursors
The amidoamines (S)-Ar1CONHCHRCH2NHAr2 [Ar1 = o-
C6H4SO3H, R = Bn, iBu, iPr; Ar2 = 2,6-iPr2C6H4, 2,6-Et2C6H4,
2,4,6-Me3C6H2] cyclise to (S) 1-aryl-substituted 4,5-dihydro-
1H-imidazolinium species with HC(OEt)3 in moderate-to-ex-
cellent yields on heating to 150–175 °C (nine examples, four
isolated yields of 48 to Ͼ97%). They are attained as their o-
C6H4(SO3–)(CO2Et) salts. The latter are readily deprotonated
to afford analytically pure (S) 1-aryl-substituted 4,5-dihydro-
1H-imidazoles (imidazolines). The purification of the inter-
mediate sulfonate salts is not always necessary, and analyti-
cally pure imidazolines are isolated by simple kugelrohr dis-
tillation (nine examples, 45–95%) after basification. Imid-
azoline alkylation provides a library of (S)-N-alkylimid-
azolinium salts (23 examples, 74–97%). As the initially re-
quired amidoamines are available in simple one-pot reac-
tions, the overall approach constitutes a rather efficient ap-
proach to this useful family of chiral N-heterocyclic carbene
(NHC) ligand precursors (effectively three steps from com-
mercial N-Boc-α-amino alcohols; BOC
= tert-butyloxy-
carbonyl).
imidazolines and their alkylation products, although some
of the required processes might require forcing conditions
(compare ref.[1] vs. ref.[2]).
Introduction
In 2012, we introduced a cascade method for the efficient
conversion of tert-butyloxycarbonyl-protected (Boc-pro-
tected) α-amino alcohols to the chiral amidoamines 1 using
2-sulfobenzoic anhydride.[1] As these intermediates were
very easy to prepare, we wondered if they could be used to
attain imidazolinium salt libraries either directly or by
the initial formation of the 4,5-dihydro-1H-imidazoles
(imidazolines) followed by their subsequent alkylation
(Scheme 1). Such an approach is desirable owing to its rela-
tive step efficiency. Literature procedures to such N-hetero-
cyclic carbene (NHC) ligand precursors[2] are characterised
by: (1) the closure of natural-pool α-amido alcohols by con-
version of the OH group to a suitable leaving group;[3] (2)
the reduction of amides, derived from protected α-amino
acids, and subsequent closure of the resultant diamine;[4] (3)
the derivatisation of chiral aziridines;[5] or (4) alternative
routes to suitable diamine cyclisation precursors, typically
Buchwald–Hartwig-type couplings.[6] Approaches (1)–(4)
are all rather step intensive, and the attainment of a library
of imidazolines and then their NHC precursors through N-
alkylation can become a rather drawn out process, which
limits the range of chiral ligands that can be prepared in a
timely manner. Although alternative concise approaches to
chiral imidazolinium salts have been reported,[7] the use of
1 offers a potential alternative general route to chiral-pool
Scheme 1. Consideration of 1 as a potential imidazoline and NHC
salt precursor. Compounds 1aa, 1ca and 1cc are known; the others
were prepared in a similar manner (ref.[1] and Supporting Infor-
mation).
[a] School of Chemistry, The University of Nottingham,
University Park, Nottingham NG7 2RD, UK
Results and Discussion
E-mail: simon.woodward@nottingham.ac.uk
http://www.nottingham.ac.uk/~pczsw/SWGroup/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403560.
The amidoamine 1aa, prepared by our previously re-
ported one-pot method,[1] was used as a test bed for the
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C. M. Latham, W. Lewis, A. J. Blake, S. Woodward
FULL PAPER
proposed new chemistry. The condensation of the amine Table 1. Preparation of imidazolinium sulfates (2) by microwave or
autoclave heating.[a]
with triethyl orthoformate is expected to lead to the imin-
R1
Ar
Method
Yield [%]
ium intermediate (Int1), which, if it cyclises and eliminates
ethanol, would provide the NHC precursor salt (Int2) di-
rectly and efficiently (Scheme 2). In practice, the conversion
2aa
2aa
Bn
Bn
Bn
Bn
iBu
iPr
2,6-iPr2C6H3
2,6-iPr2C6H3
2,6-Et2C6H3
2,6-Et2C6H3
2,4,6-Me3C6H2
2,6-iPr2C6H3
A
B
A
B
B
A
Ͼ80[b]
48
67
82
92
of 1aa was very sluggish under simple reflux in ethanol and 2ab
2ab
did not reach completion. However, the heating of the reac-
tion mixture in a commercial microwave reactor at 150 °C
(250 psi) caused the high consumption of 1aa within 1 h.
2bc
2ca
60
[a] Conditions for cyclisation: method A: microwave heating,
150 °C (250 psi), 1 h; method B: heating in autoclave at 175 °C
(300 psi), 5–16 h; isolated yields after chromatography unless other-
wise indicated. [b] Conversion determined by NMR spectroscopy
after 1 h.
Similar reactivity could be attained in an autoclave, but
longer reaction times (up to 16 h) and higher external tem-
peratures (175 °C) were needed to secure complete conver-
sion. The significant darkening of the reaction mixture that
occasionally occurred under these conditions could be
somewhat avoided by the use of HCO2H as a coadditive.
The coelution of 1aa and the new product formed in these
reactions necessitates the completion of the transformation.
In general, the use of the autoclave procedure was preferred
as this allowed significant quantities of 1aa to be used (2 to
Ͼ10 g per run).
Figure 1. X-ray crystal structure of imidazolinium sulfate 2ca. Se-
lected angles [°] and nonbonding distances [Å]: N(1)–C(2)–N(2)
113.1, C(2)–N(1)–C(5)–C(6) 97.0, N(2)···O(4) 3.22.
Selected results from runs that led to isolable crystalline
or tractable samples of 2 are shown in Table 1. The only
common pattern in the reactivity is that the most-hindered
systems, that is, those containing the 2,6-iPr2C6H3 unit, are
Scheme 2. Proposed mechanism of the cyclisation of amidoamine
1aa under treatment with HC(OEt)3 in ethanol.
Initially, it seemed that Int2 could be isolated from a dis- the slowest to react (requiring 16 h in the autoclave but sig-
coloured band under polar chromatography conditions nificantly less under microwave heating). Provided tempera-
(dichloromethane/MeOH 5% v/v). The spectroscopic data tures in the region 150–175 °C are used, high conversions
(1H and 13C NMR) and elemental analysis data were in (often quantitative) are finally attained. Small amounts of
good accord with the presence of an (Int2)·EtOH adduct. dark polar residues are always formed even when 1 is com-
However, attempts to remove the “EtOH” from the sample pletely converted; this is especially the case in reactions with
were unsuccessful, and a molecular ion for Int2 could not initial concentrations of more than 1 m or those that have
be detected in its nominal mass spectra (regardless of the been heated for a long period (Ͼ12 h). The yields shown in
ionisation mode). To shed light on this conundrum, a range Table 1 more accurately reflect the difficulties in the isola-
of additional derivatives was prepared by both microwave tion of 2 rather than the reaction efficiency. These highly
and autoclave heating methods (Table 1). Fortunately, one polar species commonly occlude solvent; must be chro-
of these derivatives (2ca) was crystalline and allowed us to matographed in polar solvent mixtures that commonly lead
identify that the in situ ethanolysis of Int2 leads to the for- to coelution of the starting material, product and byprod-
mation of the imidazolinium sulfonates 2. The molecular ucts; and provide samples that are attained as intractable
connectivity of 2ca is shown in Figure 1. We could not find dark oils.
an exact precedent for the transformation of 1 to 2, but
Because of the issues above, we experimented with basic
some related conversions are known. For example, workups of such oils to isolate the (S)-1-aryl-substituted
ArNH(CH2)2NHCHO units cyclise in the presence of 4,5-dihydro-1H-imidazoles 3 directly from the mixtures.
strong acids.[8]
Compounds 2aa and 2ca were selected for the optimisation,
2
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Homochiral 1-Aryl-Substituted 4,5-Dihydro-1H-imidazoles
Figure 2. (a) Imidazoline 3ca; selected angles [°]: N(1)–C(2)–N(2) 117.8, C(2)–N(1)–C(5)–C(6) 111.5. (b) Imidazoline hydrochloride salt
3ca·HCl (dichloromethane solvate); selected angles [°] and nonbonding distances [Å]: N(1)–C(2)–N(2) 112.9, C(2)–N(1)–C(5)–C(6) 88.7,
N(2)···Cl(1) 3.14.
as they were the product obtained in the lowest yield (48%, conditions were 1% w/w Na2CO3 in SiO2 and CH2Cl2/
Table 1) and the most crystalline example, respectively. MeOH 19:1, which had been filtered through solid
When these samples of 2 were partitioned with dichloro- Na2CO3. Alternatively, crude 3 could be purified to colour-
methane and aqueous sodium hydroxide (2 m), we isolated less oils through kugelrohr distillation (Table 2). This pro-
brown oils, which later solidified. Analysis of these crude vides analytically pure colourless oils that often solidify on
1
materials by H NMR spectroscopy confirmed that depro- cooling. The overall synthesis of 3 from N-Boc-α-amino
tonation had taken place and that the conversion to 3 was alcohols by such “telescoped” procedures (direct use of 2)
essentially complete in both cases with only traces of impu-
1
rities present. The H NMR chemical shift of the NCHN
Table 2. Direct preparation of imidazolines 3 by combined cycli-
imidazoline proton is diagnostic of imidazolinium salts 2 (δ
≈ 8 ppm), and the equivalent chemical shifts of imidazolines
3 (δ ≈ 7 ppm) are in line with the sharp drop in the electron-
withdrawing ability of the nitrogen atom on removal of the
positive charge. The crystallisation of 3ca from pentane
confirmed the success of the deprotonation strategy (Fig-
ure 2, a), whereas an attempted slow recrystallisation from
CH2Cl2/pentane led only to HCl abstraction from the sol-
vent and the formation of 3ca·HCl (Figure 2, b).
sation and deprotonation followed by distillation.[a]
Considerable experimentation revealed four critical is-
sues for the efficient isolation of free imidazolines 3: (1)
They are rather susceptible to protonation; Et2O and anhy-
drous Na2CO3 should be used as the extraction solvent and
drying agent, respectively, rather than CH2Cl2 and Na2SO4.
(2) They have a degree of solubility in 2 m NaOH unless
this is “salted out” with saturated NaCl (brine); if more
concentrated NaOH solutions are used, some degradation
of 3 occurs. (3) The direct isolation of 3 from crude 2 is
possible, but this is facilitated by prior filtration chromatog-
raphy of 2 (if it is not the major component of the crude
material). (4) Owing to their propensity to protonation, the
chromatographic purification of 3 in CH2Cl2/MeOH can be
compromised (trace uncharacterised yellow impurities with
R1 Ar
B.p. [°C]/P [Torr] Yield [%] Ref. (steps)[b]
[9]
3aa Bn 2,6-iPr2C6H3
3ab Bn 2,6-Et2C6H3
3ac Bn 2,4,6-Me3C6H2
3ba iBu 2,6-iPr2C6H3
3bb iBu 2,6-Et2C6H3
3bc iBu 2,4,6-Me3C6H2
3ca iPr 2,6-iPr2C6H3
3cb iPr 2,6-Et2C6H3
3cc iPr 2,4,6-Me3C6H2
213/0.18
210/0.17
143/0.11
164/0.23
161/0.18
117/0.09
143/0.11
163/0.07
163/0.42
95
71
49
94
80
65
83
89
90
(5)
this paper (3)
this paper (3)
this paper (3)
this paper (3)
this paper (3)
this paper (3)
this paper (3)
[4a]
(4)
[a] Conditions: cyclisation: autoclave, 175 °C (300 psi), ca. 5 h; de-
protonation: 2 m NaOH saturated with NaCl; drying: anhydrous
Na2CO3 followed by distillation under the conditions given. The
isolated yields of 3 relative to 1 are given. [b] The number of steps
that require the isolation of an intermediate, as presented in the
Rf = 0.4–0.5 are formed). The optimal chromatographic cited reference.
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C. M. Latham, W. Lewis, A. J. Blake, S. Woodward
FULL PAPER
compares well with existing literature routes to these com- achieve the separation of 4 from any unreacted starting ma-
pounds. Although it is necessary to start from the amino terials before recrystallisation. To confirm the validity of
alcohols, these are commercially available, and this route our approaches, we conducted a representative crystallo-
avoids the problematic reductions of α-amino acid derived graphic study of 4caa (Figure 3). The application of meth-
amide intermediates, which are common to some of the ods C–E allowed the rapid preparation of a wide range of
other routes to 3. Regardless of the comparisons made, the salts 4 in good-to-excellent yields, and the results are sum-
distillation approach via crude 2 that is outlined here is con- marised in Table 3.
venient and suitable for use on larger scales without the
need for chromatography.
To demonstrate the utility of this route to provide ready
access to a range of 3, the imidazolines of Table 2 were al-
kylated with a range of electrophiles (Scheme 3). Acetone is
recognised as the most general solvent for the alkylation
of imidazole-based heterocycles, but such reactions can be
sluggish and often require overnight reflux. The heating of
such reaction mixtures in commercial microwave reactors
typically results in complete conversion in under an hour.
Such conditions are particularly useful for alkylations with
propanesultone [which lead to imidazolinium compounds
–
with pendant (CH2)3SO3 groups; Method D]. For reactive
benzylic halides, rapid conversions could also be attained
under simple heating in toluene (100 °C). Such reactions
gave complete conversions and good-to-excellent yields in
all primary cases tried; secondary Ph2CHBr did not react.
The most problematic electrophiles were simple nBuBr and
the closely related HO(CH2)nBr (n = 2, 3). In these cases,
only sealed-tube reactions in MeCN led to high yields after
extended reaction times (16–22 h). For reasons that are un-
clear, the use of pressurised systems is mandatory; reflux in
MeCN alone at atmospheric pressure gave inferior yields.
The improvements offered to challenging alkylations under
these conditions can be seen in the yield of 4aag versus that
of 4aah (Table 2). The purification of these imidazolinium
salts 4 was normally achieved by simple recrystallisation
from CH2Cl2/pentane. When this approach failed, column
chromatography (CH2Cl2/methanol 5%) was used to
Figure 3. X-ray crystal structure of imidazolinium salt 4caa. Se-
lected angles [°] and nonbonded distances [Å]: N (1)–C(2)–N(2)
113.2, C(2)–N(2)–C(3)–C(4) 89.6; C(2)···Br(1) 3.45.
Table 3. Preparation of imidazolinium salts 4.[a]
R1 Ar
R2
X
Method Yield [%]
4aaa Bn 2,6-iPr2C6H3
4aab Bn 2,6-iPr2C6H3
4aac Bn 2,6-iPr2C6H3
4aae Bn 2,6-iPr2C6H3
4aag Bn 2,6-iPr2C6H3
4aah Bn 2,6-iPr2C6H3
4aba Bn 2,6-Et2C6H3
4abe Bn 2,6-Et2C6H3
Bn
Br
Br
C
C
C
D
C
E
C
D
C
C
D
C
D
C
D
C
C
C
C
E
83
84
98
83
50
83
74
77
85
79
85
78
81
94
85
99
76
92
92
91
41
82
99
2-CF3C6H4CH2
2,4,6-Me3C6H2CH2 Cl
–O3S(CH2)3
HO(CH2)2
HO(CH2)3
Bn
–
Br
Br
Br
–
Br
Br
–
Br
–
Br
–
Br
Cl
Br
Br
Br
Br
Br
Br
–O3S(CH2)3
4aca Bn 2,4,6-Me3C6H2 Bn
4baa iBu 2,6-iPr2C6H3
4bae iBu 2,6-iPr2C6H3
4bba iBu 2,6-Et2C6H3
4bbe iBu 2,6-Et2C6H3
Bn
–O3S(CH2)3
Bn
–O3S(CH2)3
4bca iBu 2,4,6-Me3C6H2 Bn
4bce iBu 2,4,6-Me3C6H2 –O3S(CH2)3
4caa iPr 2,6-iPr2C6H3
4caa iPr 2,6-iPr2C6H3
4cab iPr 2,6-iPr2C6H3
4cad iPr 2,6-iPr2C6H3
4caf iPr 2,6-iPr2C6H3
4cag iPr 2,6-iPr2C6H3
4cba iPr 2,6-Et2C6H3
Bn
Bn
2-CF3C6H4CH2
2-C10H7CH2
nBu
HO(CH2)2
Bn
C
C
C
4cca iPr 2,4,6-Me3C6H2 Bn
[a] Reaction conditions: 1.2 equiv. of alkylating agent, method C–
E. Method C: ArCH2X (1.2 equiv.), toluene, 100 °C, 60 min;
method D: sultone e (1.2 equiv.), acetone, microwave heating,
150 °C (250 psi), 40 min; method E: nBuBr or HO(CH2)nBr (n = 2
or 3; 1.2 equiv.), MeCN, sealed tube, 120 °C, 22 h.
Scheme 3. Alkylation of imidazolines 3 to provide imidazolinium
salts 4. Method C: R2X (1.2 equiv.), toluene, 100 °C, 60 min;
method D: R2X (1.2 equiv.), acetone, microwave heating, 150 °C
(250 psi), 40 min; method E: R2X (1.2 equiv.), MeCN, sealed tube,
120 °C, 22 h. Not all potential combinations of substituents have
been prepared.
Conclusions
Overall, the synthetic sequence Boc-α-amino alcohol to
1 and then 2–4 offers some attractive features. The amido-
4
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Homochiral 1-Aryl-Substituted 4,5-Dihydro-1H-imidazoles
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
amines 1 can be prepared on large scales in one-pot reac-
tions that require no transition metal catalysis to form the
C–NHAr bonds. Similarly, as the present route starts at the
correct (alcohol) oxidation level, no hydride reducing agents
are required (although high temperatures are needed). This
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental data for the preparation of all compounds
is important as alternative routes that require the reduction and their spectra.
of CONHAr units can become capricious as the steric de-
mand of the Ar group becomes larger. In the approach de-
Acknowledgments
scribed here, the ability to prepare and use 2 directly with-
out purification on larger scales allows rapid access to a
range of imidazolines 3, especially if distillative approaches
are used (Table 2). Finally, the conditions for handling and
alkylating 3 have been optimised. The applications of 3 and
4 in asymmetric catalysis are under investigation and will
be reported in due course.
S. W. and C. M. L. thank the University of Nottingham for support
through studentships.
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Experimental Section
General: The general experimental equipment has been described
previously.[10] The preparations of 3 and 4 are representative, and
full experimental details and data are given in the Supporting In-
formation.
(S)-4-Benzyl-1-(2,6-diisopropylphenyl)-4,5-dihydro-1H-imidazole
(3aa):[4a] General method B (see Supporting Information) with
amidoaminesulfonic acid 1a (4.34 g, 8.78 mmol), ethanol (47 mL),
triethyl orthoformate (10 mL) and formic acid (1 mL) for 4 h at
175 °C gave crude 2aa as a green solid (4.68 g) after evaporation
of the solvents. The crude solid was dissolved in dichloromethane
(45 mL), followed by diethyl ether (45 mL), and the mixture was
stirred. Once the solution became homogeneous, sodium hydroxide
solution (25 mL) was added cautiously (exothermic). Once the mix-
ture had cooled (ca. 10 min), solid sodium chloride (5 g) was added.
The reaction mixture was then transferred to a separating funnel,
and the aqueous layer was extracted with dichloromethane (2ϫ
100 mL) and diethyl ether (2ϫ 100 mL). The organic layers were
combined, dried with anhydrous sodium carbonate and filtered,
and the solvents were evaporated. Purification by chromatography
(2–5% methanol in dichloromethane as the eluent, silica) gave 3aa
as a crystalline solid (2.67 g, 95%). The compound could also be
purified by kugelrohr distillation (213 °C at 0.18 Torr) to give a
highly crystalline colourless solid, which could also be recrystallised
from pentane by evaporation to afford small cuboid crystals. The
data in the Supporting Information are consistent with those re-
ported previously.[4a]
[6] For an example, see: Y. Matsumoto, K. Yamada, K. Tomioka,
J. Org. Chem. 2008, 73, 4578–4581.
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12541–12543.
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[9] L. Yang, P. Guan, P. He, Q. Chen, C. Cao, Y. Peng, Z. Shi, G.
Pang, Y. Shi, Dalton Trans. 2012, 41, 5020–5025.
(S)-3,4-Dibenzyl-1-(2,6-diisopropylphenyl)-4,5-dihydro-1H-imidazol-
3-ium Bromide (4aaa):[4a] General method C (see Supporting Infor-
mation) with imidazoline 3aa (0.24 g, 0.75 mmol), benzyl bromide
(100 μL) and toluene (2.0 mL) for 60 min (100 °C) gave a white
crystalline solid (0.29 g, 83%). The data in the Supporting Infor-
mation are consistent with those in the literature.[4a]
[10] V. E. Albrow, A. J. Blake, R. Fryatt, C. Wilson, S. Woodward,
Eur. J. Org. Chem. 2006, 2549–2557.
CCDC-1037080 (for 2ca), -1037081 (for 3ca), -1037082 (for
3ca·HCl) and -1037083 (for 4caa) contain the supplementary crys-
Received: December 2, 2014
Published Online: ᭿
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5

Job/Unit: O43560
/KAP1
Date: 02-02-15 14:24:32
Pages: 6
C. M. Latham, W. Lewis, A. J. Blake, S. Woodward
FULL PAPER
Nitrogen Heterocycles
C. M. Latham, W. Lewis, A. J. Blake,
S. Woodward* ................................... 1–6
Expedient Synthesis of Homochiral 1-Aryl-
Substituted
4,5-Dihydro-1H-imidazoles
and Their Modification to N-Heterocyclic
Carbene Precursors
2-Sulfobenzoic anhydride acts as a tempor-
ary protecting group and allows the
prompt synthesis of chiral imidazolines on
multigram scale without the need for Buch-
wald–Hartwig couplings or reducing ag-
ents.
Keywords: Synthetic methods / Asymmetric
synthesis / Nitrogen heterocycles / Amino
alcohols / NHC ligand precursors
6
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Eur. J. Org. Chem. 0000, 0–0