Multicomponent synthesis of substituted and fused-ring imidazoles via phospha-münchnone cycloaddition

Article abstract of DOI:10.1021/jo5028936

A new, one-pot synthesis of imidazoles from imines, acid chlorides, and N-nosyl imines or tethered nitriles is reported. The reaction is mediated by the phosphonite PPh(catechyl) and proceeds via regioselective cycloaddition with an in situ-generated phos

Full text of DOI:10.1021/jo5028936

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Article
Multicomponent Synthesis of Substituted and Fused-
Ring Imidazoles via Phospha-Münchnone Cycloaddition
Sara Aly, Mikhail Romashko, and Bruce Alan Arndtsen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5028936 • Publication Date (Web): 17 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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The Journal of Organic Chemistry
Multicomponent Synthesis of Substituted and Fused-Ring Imidazoles via Phospha-Münchnone
Cycloaddition
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Sara Aly, Mikhail Romashko and Bruce A. Arndtsen*
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Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec, H3A 0B8,
Canada
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bruce.arndtsen@mcgill.ca
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
A new, one pot synthesis of imidazoles from imines, acid chlorides and N-nosyl imines or tethered
nitriles is reported. The reaction is mediated by the phosphonite PPh(catechyl), and proceeds via
regioselective cycloaddition with an in situ generated phospha-Münchnone 1,3-dipole. This provides an
efficient route to construct both highly substituted and polycyclic imidazoles directly from available
substrates, without metal catalysts, and with access to product diversity.
Introduction
Imidazoles are among the most common heterocyclic motifs found in biologically relevant
compounds, with examples including natural products,1 commercial drugs,2 and other pharmaceutically
relevant compounds.3 These heterocycles are also the core of ionic liquids,4 metal-coordinating
ligands,5 N-heterocyclic carbene precursors,6 and various advanced materials.7 In light of this utility,
there have been a broad range of methods developed to construct imidazoles. However, the assembly of
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highly substituted variants remains a challenge. Strategies towards these products often involve
cyclocondensation reactions, TOSMIC cyclization, or substitution reactions on preformed imidazoles,
such as via cross coupling, electrophilic substitution or even C-H activation reactions.8,9 While
effective, these can require the multistep synthesis of the starting materials for cyclization, or iterative
substitution chemistry.
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One of the more convergent approaches to imidazole synthesis is via 1,3-dipolar cycloaddition
reactions. For example, the dipolar cycloaddition of 1,3-oxazolium-5-oxides (Münchnones) developed
by Huisgen10 with N-tosyl substituted imines can provide a useful approach to tetrasubstituted
imidazoles. This transformation was first reported by Ferraccioli and co-workers,11 and has since been
employed in the assembly of a number of substituted derivatives.12 Nevertheless, Münchnones are
typically prepared via the dehydration of pre-synthesized α-amido acid derivatives,10 which can
themselves require a multistep synthesis. N-tosyl substituted imines are also sensitive substrates, and
their cycloaddition leads to the formation of stoichiometric sulfinic acid waste. Some solutions to these
issues have been described. Münchnones can be more easily prepared via the palladium catalyzed
coupling of imines, acid chlorides and CO, and employed in cycloaddition reactions.13 This includes
our report of coupling the catalytic formation with N-tosyl imine cycloaddition to assemble
imidazoles.14 With regard to the dipolarophile, early studies with Münchnones demonstrated that the
more atom economical cycloaddition of nitriles to Münchnones can be performed.15 Unfortunately,
most nitriles are not sufficiently electron deficient to participate in Münchnone cycloaddition, with only
the very electron poor ethyl cyanoformate (EtO2CCN) reacting in good yield.
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Figure 1. Münchnones and Phospha-Münchnones in Imidazole Synthesis.
In considering alternative approach to imidazole synthesis, we have recently reported a new variant
of Münchnones, phospha-Munchnones 1 (Figure 1).16 These dipoles are easily generated from imines,
acid chlorides and PhP(catechyl), and participate in cycloaddition reactions with alkynes in a fashion
analogous to Münchnones. In addition to its one pot synthesis, an important feature of 1 is its high
cycloaddition reactivity towards electron poor dipolarophiles.17 In light of these features, we became
interested in whether these dipoles could provide a more effective platform for cycloaddition with
electron deficient nitrogen-containing dipolarophiles to generate imidazoles. We describe herein that
the in situ formation and cycloaddition of phospha-Münchnones can allow the modular assembly of
imidazoles from simple imines and acid chlorides without the need for metal catalysis. This reaction
can also be extended to tethered-nitrile dipolarophiles, providing a novel route to polycyclic imidazole
products.
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Results and Discussion
Cycloaddition with Imines Our initial work probed the reaction of phospha-Münchnone 1a with
electron deficient imines (Table 1). The in situ formation of 1a followed by the addition of N-tosyl
imine leads to the complete consumption of the dipole over the course of 2 h, but forms imidazole 2a in
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only low yield (20%, entry 1). H and P NMR analysis of the reaction mixture shows that the dipole
has decomposed to a number of unidentifiable side products, together with the near quantitative
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formation of phosphine oxide.18 In order to improve the efficiency of this reaction, both the imine
dipolarophile and phosphine were modified. Firstly, as phospha-Münchnones react most rapidly with
electron poor dipolarophiles, we probed the potential of other N-substituted imines to increase the
reaction yield. The use of an N-p-chloroarylsulfonyl imine leads to similar results to that observed with
N-tosyl imines (entry 2), while the more electron rich N-Boc substituted imine does not react with 1a
(entry 3). However, the use of the highly electron deficient N-nosyl imine leads to the formation of 2a
in useful overall yield (65%, entry 4).
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Table 1. Cycloaddition of Phospha-Münchnones with Electron Deficient Iminesa
Entry
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PR3
EWG
Base
DBU
Time % 2a
PPh(catechyl)
2h
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PPh(catechyl)
PPh(catechyl)
PPh(catechyl)
DBU
DBU
DBU
2hb
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2h
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PPh(catechyl)
P(Cy)3
DBU
2h
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LiHMDSc 18h
DBU 3h
LiHMDSc 18h
LiHMDSc
4h
LiHMDSc 18h
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P(OCH2CF3)3
P(OPh)3
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8d
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(catechyl)POTMS
P(OEt)3
aImine (42 mg, 0.2 mmol), acid chloride (38mg, 0.22 mmol),0.5 mL CDCl3,
30 min. rt; then PhP(catechyl) (48 mg, 0.22 mmol) 30 min. rt; DBU (91 mg,
c
0.6 mmol); imine (87 mg, 0.3 mmol), rt.b 50°C. Added at -78°C. dPR3 added
with 0.2 mmol TMSOTf. e 0.2 mmol TMSCl.
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Previous studies have demonstrated that the structure adopted by 1, and its cycloaddition reactivity
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with alkynes, are strongly influenced by the phosphorus reagent employed (Figure 2).16 We see similar
influences on the reaction with N-nosyl imines (entries 6-10). More electron rich trialkylphosphines,
which adopt an acyclic Wittig-type structure 1’, do not allow cycloaddition (entry 6). However, several
phosphites can mediate imidazole formation in moderate yields, including simple triphenylphosphite
(entry 8) and in situ generated Horner-Wadsworth-Emmons reagents (entries 9-10). Nevertheless,
cycloaddition is most rapid and efficient with PhP(catechyl) (entry 4). The latter presumably reflects
the favored generation of the dipole brought about by the strained catechyl unit in the 5-coordinate
phosphorus of 1a.
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Figure 2. Phosphine Dependent Isomers of phospha-Münchnone 1.
With the optimized conditions, we explored the generality of the reaction. A useful feature of the
phosphorus-based 1,3-dipole 1 is its modular formation from PhP(catechyl), imines, and acid chlorides.
Thus, it is straightforward to tune any of the three dipole substituents. As shown in Table 2, the reaction
proceeds with various C-aryl and C-heteroaryl substituted imines (2c), as well as those with N-alkyl, N-
benzyl or N-aryl substituents (2i). Similarly, a variety of acid chlorides can be employed. These include
not only substituted aroyl chloride, but also heteroaryl (2d, 2g) and alkyl acid chlorides (2h). The N-
nosyl substituted imine can also be modulated with a range of aryl and heteroaryl substituents.
However, aliphatic N-nosyl imines do not undergo cycloaddition, but instead lead to decomposition of
the dipole. Overall, this provides straightforward access to polysubstituted imidazoles where any of the
four substituents can be systematically modified in a one pot reaction.
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Table 2. Synthesis of Diversely Substituted Imidazoles.a
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Chloride
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aConditions of Table 1, entry 4.
Cycloaddition with Nitriles An atom economical alternative to the use of N-nosyl imines in
cycloaddition would be the reaction of nitriles with phospha-Münchnones 1. Nitriles are readily
available, would obviate the need to synthesize N-tosyl imines, and their cycloaddition leads to no waste
from the C=N fragment. Unfortunately, nitriles are also poor cycloaddition substrates. For example,
the formation of phospha-Münchnone 1a in acetonitrile solvent leads to no detectable formation of
imidazole even upon prolonged reaction.
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However, since the phospha-Münchnone is generated from imines and acid chlorides, we postulated
that it should be straightforward to incorporate simple, unactivated nitriles into 1 from nitrile-tethered
imines for a more entropically favorable intramolecular cycloaddition. The nitrile-tethered imine 3a can
be generated from salicylaldehyde and bromoacetonitrile, followed by condensation with ethylamine.19
As was hoped, the formation of phospha-Münchnone from 3a leads to a spontaneous cycloaddition to
generate polycyclic imidazole 4a in 76% yield.
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Similar to the results in Table 2, the generation of polycyclic imidazoles via nitrile cycloaddition is
easily generalized. A number of imines can be used in this imidazole synthesis (Table 3), including
those with electron rich or electron poor aryl- (entries 5 and 6), napthyl- (entry 7) and pyrrole (entries 8
and 9) units. The nitrile tether can be also varied, with oxygen- or nitrogen-tethered nitriles generating
imidazole in good yields (entries 1, 8). Similarly, modulating the tether length can afford 6,6-, 6,5- and
even 5,5-fused ring imidazole products (entries 7-9). Various aryl-, heteroaryl- (entries 2, 5), and even
alkyl- (entry 6) substituted acid chlorides lead to imidazoles in high yields.
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This cycloaddition chemistry can be expanded beyond acid chlorides. Chloroformates and
chlorothioformates are established to react with imines to form iminium salts. The use of the latter in
this reaction provides efficient access to 2-thioalkyl (entry 4) and 2-phenoxy- (entry 3) substituted
products in moderate to good yield. It is notable that each of these cycloadditions involves unactivated,
alkyl-substituted nitriles in cycloaddition. This contrasts with the previous use of electron poor nitriles
in reaction with Münchnones,15,20 and presumably reflects the favored intramolecular cycloaddition as
well as the high reactivity of the phospha-Münchnone.
Table 3. Scope of Polycyclic Imidazole Synthesis via Phospha-Münchnones
Acid
Chloride
Entry
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Substrate
Product (% yield)
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imine (0.2 mmol), acid chloride (0.22 mmol), 0.5 mL CDCl3, 30 min. rt;
then PhP(catechyl) (0.22 mmol) 30 min. rt; DBU (0.4 mmol) b CD3CN
Conclusions
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In conclusion, phospha-Münchnones have been found to participate in 1,3-dipolar cycloaddition
reaction electron deficient imines and tethered-nitriles to generate imidazoles. The latter represents what
is to our knowledge the first general use of nitriles in cycloadditions with Münchnone derivatives, and
forms polycyclic imidazoles in good yield. These reactions are modular, easily generalized, and allow
access to highly substituted or polycyclic imidazoles in one pot from available substrates where all the
substituents can be independently varied with high regiocontrol. Experiments directed towards
exploiting this transformation in directed imidazole synthesis are in progress.
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Experimental Section
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General Procedures All reactions were performed under nitrogen. All reagents were purchased from
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commercial sources and used as received. PCy3 was dried by heating at 120°C under high vacuum.
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Liquid P(OCH2CF3)3 and P(OPh)3 were dried over 4Å molecular sieves.
PhP(catechyl),16a
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(catechyl)POTMS,16b aldehyde precursors to imines,19 and imines21 were prepared as described in the
literature. The nitrile-tethered imines 3 were prepared and characterized as described in the supporting
information. Deuterated CDCl3 was distilled from CaH2 under nitrogen. 1H and 13C NMR spectra were
recorded on 300 and 400 MHz instruments. HRMS were obtained with electron impact (EI) ionization
(TOF mass analyzer).
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Typical Synthesis of Tetra-Substituted Imidazoles 2 In a glovebox, imine p-tolyl(H)C=NBn (41.9
mg, 0.20 mmol) and p-MeOC6H4COCl (37.5 mg, 0.22 mmol) were mixed in CDCl3 (0.5 mL) and
allowed to stand at room temperature for 30 min. PhP(catechyl) (47.5 mg, 0.22 mmol) was added, and
after 30 min DBU (91.0 mg, 0.60 mmol) was added as a solution in CDCl3, followed by the addition of
N-nosyl substituted imine Ph(H)C=NNs (87.1 mg, 0.30 mmol). The reaction was complete within 3 h.
The crude solution was concentrated in vacuo and purified by column chromatography on a 4 g column
of Silica Gel 60 using a ethyl acetate:hexanes gradient (0-40%) on an automated chromatography
system, giving pure 2a as an off-white solid (56.0 mg, 65%).
1-benzyl-2-(4-methoxyphenyl)-4-phenyl-5-(p-tolyl)-1H-imidazole (2a) Isolated yield: 65% (56 mg).
o
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Off white solid. mp 127-129 C. H NMR (400 MHz, CDCl3) δ 7.58 (t, J = 9.3 Hz, 4H), 7.26 – 7.23
(m, 5H), 7.17 – 7.04 (m, 5H), 6.90 (d, J = 6.6 Hz, 2H), 6.83 (d, J = 6.3 Hz, 2H), 5.07 (s, 2H), 3.81 (s,
3H), 2.36 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 160.1, 147.7, 138.5, 137.7, 130.9, 130.4, 129.8, 129.5,
128.6, 128.0, 127.8, 127.3, 126.7, 126.3, 125.9, 114.0, 55.3, 48.1, 21.4. HRMS (ESI+) for C30H27N2O+;
calculated: 431.2118,found: 431.2117.
1-benzyl-4-(4-fluorophenyl)-5-(4-(methylthio)phenyl)-2-(p-tolyl)-1H-imidazole (2b) Isolated yield:
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63% (59 mg). Yellow solid. mp 102-104 oC. H NMR (400 MHz, CDCl3 7.61 – 7.47 (m, 4H), 7.29 –
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7.12 (m, 7H), 7.08 (d, J = 8.3 Hz, 2H), 6.90 (t, J = 8.8 Hz, 2H), 6.85 – 6.78 (m, 2H), 5.08 (s, 2H), 2.48
(s, 3H), 2.36 (s, 3H). HRMS (ESI+) for C30H26N2FS+; calculated: 465.1795, found: 465.1780.
1-ethyl-2,4-diphenyl-5-(thiophen-2-yl)-1H-imidazole (2c) Isolated yield: 77% (51 mg). Yellow solid
mp 102-104 oC. 1H NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 7.9, 1.5 Hz, 2H), 7.65 – 7.57 (m, 2H), 7.54
(dd, J = 4.8, 1.5 Hz, 1H), 7.53 – 7.42 (m, 3H), 7.26 – 7.22 (m, 2H), 7.19 – 7.14 (m, 3H), 3.99 (q, J = 7.2
Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 148.1, 131.4, 130.4, 129.1, 129.1, 128.6,
128.5, 128.1, 127.7, 126.8, 126.6, 126.3, 124.4, 121.1, 39.8, 16.6. HRMS (ESI+) for C21H19N2S+;
calculated: 331.1264, found: 331.1255.
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1-benzyl-5-phenyl-2-(thiophen-2-yl)-4-(p-tolyl)-1H-imidazole (2d) Isolated yield: 62% (50 mg). Light
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yellow oil. H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.2 Hz, 2H), 7.39 – 7.15 (m, 10H), 7.12 (d, J =
2.8 Hz, 1H), 7.07 – 6.89 (m, 4H), 5.19 (s, 2H), 2.29 (s, 3H).13C NMR (75 MHz, CDCl3) δ 141.9, 138.3,
137.3, 136.1, 131.3, 131.0, 130.7, 130.1, 128.81, 128.79, 128.69, 127.4, 127.4, 126.8, 126.8, 126.3,
126.1, 125.8, 124.4, 48.2, 21.2. HRMS (ESI+) for C27H23N2S+; calculated: 407.1576, found: 407.1587.
5-(3-bromophenyl)-1-methyl-4-phenyl-2-(p-tolyl)-1H-imidazole (2e) Isolated yield: 50% (40 mg).
White solid. mp 181-183 oC. 1H NMR (300 MHz, CDCl3) δ 7.68 – 7.50 (m, 6H), 7.36 – 7.27 (m, 4H),
7.27 – 7.13 (m, 3H), 3.50 (s, 3H), 2.42 (s, 3H).13C NMR (75 MHz, CDCl3) δ 148.4, 138.9, 138.2,
134.3, 133.5, 131.6, 130.5, 129.7, 129.3, 128.9, 128.6, 128.2, 127.8, 127.0, 126.5, 124.4, 122.9, 33.2,
21.4. HRMS (ESI+) for C23H20N2Br +; calculated: 403.0804, found: 403.0801.
1-benzyl-2-(4-fluorophenyl)-4-phenyl-5-(p-tolyl)-1H-imidazole (2f) Isolated yield: 41% (34 mg).
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Yellow oil. H NMR (400 MHz, CDCl3) δ 7.62 – 7.57 (m, 4H), 7.23 – 7.20 (m, 5H), 7.14 – 7.04 (m,
7H), 6.82 (d, J = 6.9 Hz, 2H), 5.06 (s, 2H), 2.37 (s, 3H).13C NMR (75 MHz, CDCl3) δ 131.1, 131.0,
130.8, 130.2, 129.6, 128.7, 128.1, 127.5, 126.8, 126.5, 125.8, 115.8, 115.5, 48.1, 21.4. HRMS (ESI+)
for C29H24N2F+; calculated: 419.1918, found: 419.1910.
1-benzyl-2-(furan-2-yl)-4-phenyl-5-(p-tolyl)-1H-imidazole (2g) Isolated yield: 36% (28 mg). Orange
1
oil. H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.3 Hz, 2H), 7.46 (d, J = 1.0 Hz, 1H), 7.28 – 7.18 (m,
6H), 7.15 (dd, J = 7.4, 4.8 Hz, 3H), 7.09 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 6.8 Hz, 2H), 6.72 (s, 1H), 6.43
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(dd, J = 3.4, 1.8 Hz, 1H), 5.25 (s, 2H), 2.38 (s, 3H).13C NMR (75 MHz, CDCl3) δ 142.8, 138.83 137.3,
130.9, 130.4, 129.6, 128.6, 128.0, 127.3, 126.9, 126.5, 125.9, 111.5, 48.3, 21.4. HRMS (ESI+) for
C27H23ON2+; calculated: 391.1805, found: 391.1796.
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1-benzyl-5-(4-chlorophenyl)-4-(furan-2-yl)-2-isopropyl-1H-imidazole (2h) Isolated yield: 45% (34 mg)
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o
1
Yellow-orange solid. mp 129-131 C. H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 2.7 Hz, 2H), 7.30 –
7.24 (m, 5H), 7.17 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 7.0 Hz, 2H), 6.28 (s, 1H), 6.06 (d, J = 3.0 Hz, 1H),
4.97 (s, 2H), 1.34 (d, J = 6.7 Hz, 6H).13C NMR (75 MHz, CDCl3) δ 154.1, 149.5, 141.1, 136.9, 134.7,
132.2, 130.2, 128.9, 128.9, 128.7, 127.6, 126.8, 125.5, 110.7, 105.1, 46.7, 26.6, 21.8. HRMS (ESI+) for
C23H22ON2Cl+; calculated: 377.1415, found: 377.1411.
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4-(furan-2-yl)-1-(4-methoxyphenyl)-5-phenyl-2-(p-tolyl)-1H-imidazole (2i) Isolated yield: 68% (55
mg). White solid. mp 177-179 oC. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 0.9 Hz, 1H), 7.33 (d, J =
8.2 Hz, 2H), 7.29 – 7.24 (m, 3H), 7.20 (dt, J = 7.5, 3.7 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.96 – 6.91
(m, 2H), 6.78 – 6.72 (m, 2H), 6.33 (dd, J = 3.3, 1.8 Hz, 1H), 6.27 (s, 1H), 3.76 (s, 3H), 2.30 (s, 3H).13C
NMR (75 MHz, CDCl3) δ 159.1, 149.4, 147.5, 141.3, 138.2, 131.0, 130.6, 129.9, 129.7, 129.3, 128.8,
128.7, 128.0, 128.0, 127.4, 114.2, 110.8, 105.7, 55.3, 21.3. HRMS (ESI+) for C27H23O2N2+; calculated:
407.1754, found: 407.1743.
5-(benzo[d][1,3]dioxol-5-yl)-1-benzyl-2-phenyl-4-(p-tolyl)-1H-imidazole (2j) Isolated yield: 35% (31
mg). Yellow solid. mp 172-174 oC. 1H NMR (400 MHz, CDCl3) δ 7.64 - 7.63 (m, 2H), 7.51 (d, J = 8.1
Hz, 2H), 7.41 – 7.36 (m, 3H), 7.28 – 7.15 (m, 3H), 7.05 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 7.7 Hz, 2H),
6.75 (d, J = 7.9 Hz, 1H), 6.72 – 6.67 (m, 1H), 6.64 (d, J = 1.4 Hz, 1H), 5.97 (s, 2H), 5.10 (s, 2H), 2.30
13
(s, 3H). C NMR (75 MHz, CDCl3) δ 147.9, 147.8, 147.7, 138.1, 137.6, 135.9, 131.5, 131.0, 129.07,
129.02, 128.8, 128.59, 128.56, 127.3, 126.6, 126.0, 125.1, 124.4, 111.3, 108.7, 101.2, 48.2, 21.2. HRMS
(ESI+) for C30H25N2O2 ; calculated: 445.1911, found: 445.1897.
+
Synthesis of Nitrile-Tethered Imines
3
In analogy to
a
previous report,19 2-(2-
formylphenoxy)acetonitrile was prepared from salicylaldehyde (500 mg, 4.09 mmol) in DMF (15 mL).
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To this solution was added K2CO3 (848 mg, 6.15 mmol) and the solution stirred at rt for 15 min.
Bromoacetonitrile (589 mg, 4.92 mmol) was added and stirred at rt for 18 h. Reaction mixture was
filtered, diluted with EtOAc (100 mL), washed with water (3x100 mL), brine (2x10 mL) and dried over
Na2SO4. The solvent was evaporated and the crude residue was purified by column chromatography
with a solvent gradient of EtOAc/hexanes 0-40% to give the final product, 2-(2-
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formylphenoxy)acetonitrile, as pale yellow solid (84%). To
a
solution of 2-(2-
formylphenoxy)acetonitrile (500 mg, 3.1 mmol) in dichloromethane (15 mL) was added MgSO4 and
ethyl amine (2.0 M in THF, 1.7 mL, 3.41 mmol). The heterogeneous mixture was stirred at room
temperature for 18 h. The reaction mixture was filtered, and the solvent and excess amine was
evaporated in vacuo to provide imine 3a as a dark orange oil in 95% yield (556 mg). All other imines
3b-3f were formed in near quantitative yield (at 1-3 mmol scale) and used in cyclization without any
further purification.
1
(E)-2-(2-((ethylimino)methyl)phenoxy)acetonitrile (3a) Isolated yield 95% (556 mg). Orange oil. H
NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 6.9 Hz, 1H), 7.12 (t, J =
7.5 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 4.84 (s, 2H), 3.66 (q, J = 6.2 Hz, 2H), 1.30 (t, J = 7.3 Hz, 4H).
13C NMR (75 MHz, CDCl3) δ 155.2, 131.7, 128.1, 125.9, 123.4, 114.9, 112.4, 56.2, 54.0, 16.3. HRMS
(ESI+) for C11H13N2O +; calculated: 189.1022, found: 189.1023.
1
(E)-2-(4-bromo-2-((ethylimino)methyl)phenoxy)acetonitrile (3b) Yellow oil. H NMR (300 MHz,
CDCl3) δ 8.57 (s, 1H), 8.13 (d, J = 2.5 Hz, 1H), 7.52 (dd, J = 8.8, 2.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H),
13
4.82 (s, 2H), 3.66 (q, J = 7.3 Hz, 2H), 1.30 (t, J = 7.3 Hz, 3H). C NMR (75 MHz, CDCl3) δ 154.4,
153.8, 134.2, 130.9, 127.7, 116.5, 114.2, 56.2, 54.2, 16.2. HRMS (ESI+) for C11H12N2OBr +; calculated:
267.0128, found: 267.0116.
(E)-2-((1-((ethylimino)methyl)naphthalen-2-yl)oxy)acetonitrile (3c) Yellow oil 1H NMR (400 MHz,
CDCl3) δ 9.09 – 8.81 (m, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.57 (ddd, J = 8.5, 6.8,
1.4 Hz, 1H), 7.45 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.35 – 7.20 (m, 1H), 4.92 (s, 1H), 3.81 (qd, J = 7.3, 1.4
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13
Hz, 1H), 1.43 (t, J = 7.3 Hz, 2H). C NMR (75 MHz, CDCl3) δ 156.7, 154.2, 132.3, 132.0, 130.6,
128.22, 128.19, 125.7, 125.3, 120.8, 114.3, 77.4, 77.0, 76.6, 57.4, 55.7, 16.6. HRMS (ESI+) for
C15H15N2O +; calculated: 239.1179, found: 239.1175.
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8
1
(E)-2-(2-((ethylimino)methyl)-6-methoxyphenoxy)acetonitrile (3d) Yellow oil. H NMR (400 MHz,
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CDCl3) δ 8.68 (s, 1H), 7.57 (dd, J = 7.9, 1.4 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.99 (dd, J = 8.2, 1.4 Hz,
1H), 4.87 (s, 2H), 3.90 (s, 3H), 3.69 (qd, J = 7.3, 1.3 Hz, 2H), 1.31 (t, J = 7.3 Hz, 3H).13C NMR (75
MHz, CDCl3) δ 155.5, 151.8, 130.5, 125.7, 119.2, 115.5, 114.0, 57.7, 56.2, 55.9, 16.2. HRMS (ESI+) for
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+
C12H15N2O2 ; calculated: 219.1128, found: 219.1122.
1
(E)-2-(2-((ethylimino)methyl)-1H-pyrrol-1-yl)acetonitrile (3e) Red oil. H NMR (400 MHz, CDCl3) δ
8.13 (s, 1H), 6.82 (s, 1H), 6.45 (dd, J = 3.8, 1.6 Hz, 1H), 6.23 (dd, J = 3.7, 2.9 Hz, 1H), 5.57 (s, 2H),
13
3.53 (q, J = 7.3 Hz, 2H), 1.26 (t, J = 7.3 Hz, 3H). C NMR (75 MHz, CD3CN) δ 151.6, 127.2, 125.0,
+
117.3, 109.6, 55.5, 36.7, 16.0. HRMS (ESI+) for C9H12N3 ; calculated: 162.1031, found: 162.1026
1
(E)-3-(2-((ethylimino)methyl)-1H-pyrrol-1-yl)propanenitrile (3f) Red oil. H NMR (400 MHz, CDCl3)
δ 8.10 (s, 1H), 6.87 – 6.72 (m, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.17 (dd, J = 3.7, 2.8 Hz, 1H), 4.59 (t, J =
13
6.6 Hz, 2H), 3.51 (q, J = 7.3 Hz, 2H), 2.88 (t, J = 6.6 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H). C NMR (75
+
MHz, CDCl3) δ 151.4, 128.9, 127.4, 117.9, 108.7, 56.1, 44.8, 19.8, 16.7 HRMS (ESI+) for C10H14N3 ;
calculated: 176.1182, found: 176.1187.
Synthesis of Polycyclic Imidazoles 4 In a glovebox, imine 3a (37.8 mg, 0.20 mmol) and p-toluoyl
chloride (33.9 mg, 0.22 mmol) were mixed in CDCl3 (0.5 mL) and allowed to stand at room temperature
for 30 min. PhP(catechyl) (47.5 mg, 0.22 mmol) was added, and after 30 min DBU (91 mg, 0.6 mmol)
was added as a solution in CDCl3. The reaction was complete within 5 min. The crude solution was
concentrated in vacuo and purified by column chromatography on a 4g column of Silica Gel 60 using a
ethyl acetate:hexanes gradient (0-40%) on an automated chromatography system giving pure 4a as a
pale yellow powder (44.3 mg, 76%).
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1-ethyl-2-(p-tolyl)-1,4-dihydrochromeno[3,4-d]imidazole (4a) Isolated yield: 76% (44 mg). Yellow
solid. mp 147-149 oC. 1H NMR (400 MHz, CDCl3) δ 6.42 (d, J = 8.0 Hz, 2H), 6.30 (d, J = 7.9 Hz, 1H),
6.22 (d, J = 7.9 Hz, 2H), 6.12 – 6.00 (m, 1H), 5.94 - 5.90 (m, 2H), 4.30 (s, 2H), 3.22 (q, J = 7.2 Hz, 2H),
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1.36 (s, 3H), 0.39 (t, J = 7.2 Hz, 3H). C NMR (75 MHz, CDCl3) δ 152.9, 149.5, 139.1, 134.2, 129.4,
9
129.0, 127.5, 127.4, 122.2, 121.7, 119.7, 117.9, 117.4, 66.4, 40.7, 21.4, 16.4. HRMS (ESI+) for
C19H19ON2+; calculated: 291.1492, found: 291.1490.
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1-ethyl-2-(4-fluorophenyl)-1,4-dihydrochromeno[3,4-d]imidazole (4b) Isolated yield: 68% (40 mg).
1
white solid. H NMR (400 MHz, CDCl3) δ 7.62 – 7.52 (m, 2H), 7.46 – 7.32 (m, 1H), 7.26 – 7.13 (m,
3H), 7.05 – 6.95 (m, 2H), 6.80 – 6.65 (m, 3H), 5.33 (s, 2H), 4.28 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 164.9, 161.6, 153.0, 148.2, 144.7, 134.1, 131.1, 131.0, 127.8, 126.4,
122.5, 121.8, 120.1, 119.8, 117.7, 117.5, 116.0, 115.7, 115.0, 66.1, 40.8, 16.3. HRMS (ESI+) for
C18H16ON2F+; calculated: 295.1241, found: 295.1232.
1-ethyl-2-(furan-2-yl)-1,4-dihydrochromeno[3,4-d]imidazole (4c) Isolated yield: 74% (40 mg). orange
solid. 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 1.8, 0.8 Hz, 1H), 7.41 – 7.33 (m, 1H), 7.19 – 7.08 (m,
1H), 7.03 - 6.94 (m, 2H), 6.89 (dd, J = 3.5, 0.8 Hz, 1H), 6.54 (dd, J = 3.5, 1.8 Hz, 1H), 5.31 (s, 2H),
13
4.49 (q, J = 7.2 Hz, 2H), 1.59 (t, J = 7.2 Hz, 3H). C NMR (75 MHz, CDCl3) δ 153.1, 145.3, 142.9,
140.0, 134.4, 127.8, 122.6, 121.9, 119.8, 117.6, 115.0, 111.7, 110.2, 66.1, 41.2, 16.2. HRMS (ESI+) for
C16H15O2N2+; calculated: 267.1133, found: 267.1120.
1-ethyl-2-(ethylthio)-1,4-dihydrochromeno[3,4-d]imidazole (4d) Isolated yield: 47% (25 mg). Orange
oil. 1H NMR (300 MHz, CDCl3) δ 7.40 – 7.19 (m, 1H), 7.17 – 7.04 (m, 1H), 6.99 – 6.92 (m, 2H), 5.29
13
(s, 2H), 4.30 (q, J = 7.2 Hz, 2H), 3.11 (q, J = 7.4 Hz, 2H), 1.47 – 1.32 (m, 6H). C NMR (75 MHz,
CDCl3) δ 152.7, 143.2, 134.7, 127.5, 122.8, 121.8, 119.4, 117.6, 117.4, 66.3, 40.7, 29.0, 15.8, 15.1.
HRMS (ESI+) for C14H17ON2S+; calculated: 261.1056, found: 261.1048.
1-ethyl-2-phenoxy-1,4-dihydrochromeno[3,4-d]imidazole (4e) Isolated yield: 51% (30 mg). Orange
oil. 1H NMR (300 MHz, CDCl3) δ 7.42 - 7.36 (m, 2H), 7.29 – 7.14 (m, 4H), 7.14 – 7.04 (m, 1H), 6.99 -
13
6.93 (m, 2H), 5.24 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H). C NMR (75 MHz,
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CDCl3) δ 154.9, 152.5, 151.2, 129.8, 128.8, 127.0, 124.7, 121.7, 118.7, 118.7, 118.0, 117.7, 117.2, 66.1,
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3
+
38.9, 15.7. HRMS (ESI+) for C18H17N2O2 ; calculated: 293.1285, found: 293.1283.
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8-bromo-1-ethyl-2-(thiophen-2-yl)-1,4-dihydrochromeno[3,4-d]imidazole (4f) Isolated yield: 79% (57
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8
9
o
1
mg). Orange solid. mp 95-98 C H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 5.4 Hz, 1H), 7.44 (d, J =
2.2 Hz, 1H), 7.42 – 7.38 (m, 1H), 7.22 (dd, J = 8.6, 2.2 Hz, 1H), 7.19 – 7.13 (m, 1H), 6.87 (d, J = 8.6
Hz, 1H), 5.35 (s, 2H), 4.42 (q, J = 7.3 Hz, 2H), 1.61 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
152.0, 143.7, 135.2, 132.0, 130.2, 127.7, 127.4, 126.3, 122.1, 121.9, 119.4, 119.1, 114.1, 66.3, 40.9,
16.1. HRMS (ESI+) for C16H14ON2BrS+; calculated: 361.0004, found: 361.0002.
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1-ethyl-2-isopropyl-6-methoxy-1,4-dihydrochromeno[3,4-d]imidazole (4g) Isolated yield: 77% (42
mg). Orange oil. 1H NMR (300 MHz, CDCl3) δ 6.96 – 6.89 (m, 2H), 6.82 – 6.66 (m, 1H), 5.35 (s, 2H),
4.16 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.01 (dq, J = 13.6, 6.8 Hz, 1H), 1.42 (t, J = 7.2 Hz, 3H), 1.34 (d, J
13
= 6.8 Hz, 3H). C NMR (75 MHz, CDCl3) δ 154.4, 149.0, 141.3, 132.9, 121.5, 120.6, 118.9, 111.9,
110.3, 66.9, 56.0, 39.2, 25.9, 22.1, 16.4. HRMS (ESI+) for C16H21O2N2+; calculated: 273.1598, found:
273.1589.
1-ethyl-2-(4-methoxyphenyl)-1,4-dihydrobenzo[5,6]chromeno[3,4-d]imidazole (4h) Isolated yield:
o
1
82% (59 mg). Orange solid. mp 213-215 C. H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 1H),
7.82 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 8.1 Hz, 3H), 7.53 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.30
(d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 5.24 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 0.66 (t,
J = 7.1 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 160.2, 152.6, 152.2, 135.7, 130.1, 130.1, 128.6, 128.3,
127.7, 126.1, 125.1, 124.7, 124.0, 123.6, 118.7, 114.2, 112.7, 66.6, 55.4, 43.5, 15.2. HRMS (ESI+) for
C23H21O2N2+; calculated: 357.1597, found: 357.1589.
1-ethyl-2-(p-tolyl)-1,4-dihydroimidazo[4,5-a]pyrrolizine (4i) Isolate yield 63% (33 mg). Yellow oil. 1H
NMR (300 MHz, CDCl3) δ 7.50 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 2.0 Hz, 1H),
6.30 – 6.21 (m, 1H), 6.01 (d, J = 3.1 Hz, 1H), 4.74 (s, 2H), 4.19 (q, J = 7.3 Hz, 2H), 2.41 (s, 3H), 1.54
(t, J = 7.3 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 149.1, 144.8, 138.5, 130.3, 129.3, 129.2, 128.4, 127.9,
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117.9, 110.4, 95.6, 47.0, 41.6, 21.3, 15.8. HRMS (ESI+) for C17H18N3 ; calculated: 264.1495, found:
264.1495.
+
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1-ethyl-2-(p-tolyl)-4,5-dihydro-1H-imidazo[4,5-g]indolizine (4j) Isolated yield: 59% (33 mg). Dark
orange solid. mp 87-88 oC. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.0 Hz,
2H), 6.86 – 6.64 (m, 1H), 6.29 – 6.16 (m, 2H), 4.29 – 4.11 (m, 4H), 3.15 (t, J = 7.0 Hz, 2H), 2.42 (s,
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3H), 1.48 (t, J = 7.2 Hz, 3H). C NMR (126 MHz, CDCl3) δ 146.4, 145.0, 138.7, 129.3, 128.9, 123.3,
121.1, 119.9, 115.0, 108.1, 101.3, 45.7, 40.4, 24.2, 21.3, 15.9. HRMS (ESI+) for C18H20N3+; calculated:
278.1657, found: 278.1641.
ACKNOWLEDGMENT We thank NSERC, CFI, and the FQRNT supported Centre for Green
Chemistry and Catalysis for their financial support of this research.
1 13
Supporting Information Available: H and C NMR spectra for compounds 2-4. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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(18) Control experiments suggest this may be due, at least in part, to the sulfinate byproduct of this
cycloaddition reaction. The addition of sodium p-toluene sulfinate to phospha-Münchnone 1a results in
the rapid decomposition of the 1,3-dipole within 1 h at ambient temperature, generating a complex
mixture of products.
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