Exploring asymmetric catalytic transformations Guduguntla, Sureshbabu
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187
Efforts
towards
the
development
of
new
asymmetric autocatalytic reactions: H-bond donor
approach
In this chapter, efforts towards the development of new asymmetric autocatalytic reactions based on H-bond donor approach and of an imine based autocatalysis using urea motifs, are discussed.
188
7.1 Introduction
Fundamental features of all living organisms are self-replication and homochirality.1 Dynamic interactions and self-organization of biomolecules through complex molecular networks are involved in replication.2 From a chemical point of view, functions such as autocatalytic, cross catalytic or collective catalytic pathways, with additional information transfer (templating) from product to precursors are key steps in a molecular self-replication process.1,3 Investigations in this area led to the development of synthetic self-replicating systems involving nucleic acids, peptides, mixed protein-nucleic acid systems, as well as purely synthetic organic molecules.1,2 In the self-replicating systems developed so far, homochirality has been predefined with the precursors employed being homochiral.1,2,4 The origin of homochirality of the biologically relevant molecules (D-sugars and L-amino acids) is directly associated with the ‘origin of life’ question.5
In particular chemical systems that show self-replication of chirality in a catalytic manner are especially challenging.1
The main object discussed in this chapter was to develop a new asymmetric autocatalytic reaction based on the H-bond donor concept. We choose two different approaches based on: 1) bifunctional urea or thiourea catalyzed Mannich reactions and 2) bifunctional urea or thiourea catalyzed Kabachnik–Fields (Phospha-Mannich) reactions.
7.1.1 Bifunctional urea or thiourea catalyzed Mannich reaction. The idea of using small organic compounds as catalysts in chemical reactions is known as organocatalysis,6 which has been extensively explored in recent years.7 Organocatalysis has been emerged as efficient methodology for the synthesis of natural products and biologically active compounds.8 Among all the catalysts developed for organocatalysis, thiourea derivatives play a prominent role and have been efficiently used in various synthetic transformations.8,9 The first reports on the application of ureas/thioureas to promote chemical reactions appeared more than fifteen years ago.10 Due to effective molecular recognition via H-bond
189
interactions, ureas/thioureas play an important role in organocatalysis.8,9,10,11 In the transition state, the chiral urea or thiourea moiety contributes a network of H-bonds involving both N–H groups (Scheme 1) and at least one of the reactants.12 In this way, H-bonding secures the chiral environment of the reacting molecules and may also increase the reactivity of the bound components.
Scheme 1: Activation of electrophile in the transition state of urea or thiourea catalyzed
reaction.12
Thioureas are more efficient than urea derivatives due to their higher acidity (pKa: 27 vs 21), showing almost 10-fold increase in complex stability.13 Present strategies for designing novel organocatalysts of this type are generally focused on polyfunctionalised derivatives, which possess additional H-bonding fragments within the proximity of the thiourea moiety.9a,14 Since thioureas acts as H-bond donors; they have been used as catalysts in chemical reactions, one of which is the versatile Mannich reaction.8-10,15
The Mannich reaction, involving the addition of enolate equivalents to imines, represents one of the most powerful methods for accessing chiral β-amino carbonyl compounds.8,9,16
These Mannich adducts are highly significant for the synthesis of β-amino alcohols and β-amino acid derivatives such as β-lactams and β-peptides.8
In 2000, List17 reported for the first time a proline catalyzed asymmetric three-component Mannich reaction. Barbas and co-workers18 showed in 2004, using proline as a catalyst, one of the first cases of the construction of very challenging carbon quaternary stereocenters via an asymmetric Mannich reaction. Furthermore, several other organocatalysts were developed for this transformation, including proline,19 proline derivatives,20 chiral
190
phosphoric acids,21 and cinchonine and cinchonidine,22 etc. (Scheme 2).
8-11,15,23
Scheme 2: Selected organo catalysts for the enantioselective Mannich reaction.
In 2002, Jacobsen and co-workers24 reported the first thiourea catalyzed Mannich reaction (Scheme 3), providing an efficient route to N-Boc protected β-amino acids via the enantioselective addition of silyl ketene acetals to N-Boc aldimines. Later, the same group reported a highly enantioselective thiourea catalyzed nitro-Mannich reaction.25
191
Following these reports several alternative thiourea-based catalysts have been developed for both Mannich and Mannich type of reactions (Scheme 4).8,9,11,15,26,27
Scheme 4: Selected chiral urea and thiourea catalysts for the enantioselective Mannich
reaction.
7.1.2 Bifunctional urea or thiourea catalyzed Kabachnik–Fields (phospha-Mannich) reaction.
The Kabachnik–Fields reaction, which is a three-component reaction involving an aldehyde, an amine and a dialkylphosphite, produces an important class of compounds α-aminophosphonates.28 The derivatives of α-aminophosphonates, α-aminophosphonic acids, are considered as mimics of α-amino acids.29
Incorporation of α-aminophosphonic acids in short peptides leads to an excellent inhibition of a wide range of proteolytic enzymes.30 In addition, they serve as antibacterial31 and anti-HIV32 agents. The biological activity related to α-aminophosphonic acids depends on their absolute configuration. Therefore, it is interesting to develop methodologies which can deliver these precursors in an enantioselective manner. Chiral α-aminophosphonic acids are currently obtained through resolution, using stoichiometric amount of chiral auxiliaries or enantiopure substrates.33 Furthermore considerable efforts have been devoted to the enantioselective synthesis of α-amino phosphonic acids through the asymmetric addition of phosphites to
192
imines.34 Several methods based on metal catalyzed enantioselective addition of phosphites to imines are known.35 Recently organocatalyzed asymmetric methods have been demonstrated for the phospha-Mannich reaction.36 In 2004, Jacobsen and co-workers36a reported the first chiral thiourea catalyzed highly enantioselective hydrophosphonylation reaction between di-(2-nitrobenzyl)phosphite with aliphatic and aromatic N-benzyl imines (Scheme 5).
Scheme 5: Thiourea catalyzed phospha-Mannich reaction.
Following this report,36a several other organocatalysts have been developed for this transformation, including chiral thiourea derivatives,36b,c chiral phosphoric acids,36d,e,f quinine36g,h and quinine derivatives36i (Scheme 6).
193
7.2 Design
Our interest to develop a new asymmetric autocatalytic reaction based on the H-bond donor concept was inspired by work presented in the literature using organocatalysts for the Mannich reaction.8,9 It has been demonstrated that bifunctional urea or thioureas are among the most efficient catalysts for the asymmetric Mannich reaction.8-15,26,27 As such, we aimed to develop an asymmetric autocatalytic reaction of bifunctional ureas (Scheme 7) based on the Mannich reaction.
Scheme 7: Design for an asymmetric autocatalytic reaction based on Mannich reaction
catalyzed by chiral product 2.
We hypothesized that nucleophilic addition to imine 1, which would lead to the chiral product 2. Product 2 may act as a chiral catalyst to activate the imine 1, via H-bond formation during the Mannich reaction through a possible aggregate 3, to facilitate its own production. If this process is shown to accelerate the rate of reaction1e it would have satisfied the requirements of an autocatalytic reaction.
Furthermore, seeding with a catalytic amount of enantioenriched product 2 should form enantioenriched aggregate 3. By the same reasoning, the product 2 could act as an asymmetric catalyst in the Mannich reaction for its own production in an enantioselective manner. If this process would show an enhancement in enantioselectivity with a positive non-linear effect (+NLE),37 this would imply an asymmetric autocatalytic reaction.
In another approach, we were interested to develop an asymmetric autocatalytic synthesis of α-aminophosphonates29-32 due to their
194
invaluable applications. Our approach was based on the Kabachnik– Fields reaction:28,33-36 a three component reaction involving aldehyde 5, amine 4 and dialkylphosphite 6 to yield a chiral α-aminophosphonate 7 (Scheme 8).
Scheme 8: Design for an asymmetric autocatalytic reaction based on Kabachnik–Fields
reaction catalyzed by chiral product 7.
We envisioned that in our design α-aminophosphonate 7 could act as a chiral catalyst to activate both imine 8 (formed in situ) and dialkylphosphite 6 in the nucleophilic addition reaction through a ternary complex A resulting in its own production.
7.3 Results and discussion
7.3.1 Bisurea system: The synthesis of bisurea imine 16 is outlined below.
A mixture of 1,2-ethylene diamine 9 and hexylisocyanate 10 in DCM was stirred at rt for 1 h to give compound 11 bearing both urea and primary amine functional groups in 96% isolated yield (Scheme 9).38
Scheme 9: Synthesis of mono urea 11.
LiAlH4 reduction of 4-carboxyl benzyl amine 12 in dry THF at 80 °C for
18 h led to the corresponding 4-aminomethyl benzyl alcohol 13 in 75% isolated yield.39 A mixture of compound 13 and hexylisocyanate 10 in DCM was stirred at rt for 1 h to afford the alcohol 14 in almost
195
quantitative yield. Benzylic oxidation of alcohol 14 with MnO2 in THF
led to the desired aldehyde 15 in 85% yield (Scheme 10).
Scheme 10: Synthesis of aldehyde 15.
A condensation reaction between the aldehyde 15 and amine 11 in toluene at 50 °C for 21 h led to the desired imine 16 in almost quantitative yield (Scheme 11).
Scheme 11: Synthesis of bisurea imine 16.
With imine 16 in hand, we tested its reactivity in nucleophilic addition reaction. Due to its poor solubility in most organic solvents, the Mannich reaction on imine 16 with acetone was performed in DMF at rt using pyrrolidine (10 mol%) as catalyst. This heterogeneous mixture was stirred at rt for 7 d and no formation of product 17 was observed. Even stirring a mixture of acetone (300 equiv) and imine 16 at rt for 7 d did not provide any traces of product 17 (Scheme 12).This is may be due to the strong urea H-bond interactions present between the imine 16 molecules which may lead to aggregation40 and cause insolubility.
196 7.3.2 Kabachnik–Fields reaction:
In the second approach we performed Kabachnik–Fields reactions (Table 1). After stirring an equimolar mixture of N-phenylurea 18, benzaldehyde 19 and diethyl phosphate 20 in 1,4-dioxane without the presence of any catalyst at rt for 5 d we did not observe any product formation (entry 1).When a catalytic amount of p-toluenesulfonic acid (10 mol%) was used in the reaction ~15% conversion to aminal 23 was observed after 5 d (entry 2). Aminal 23 can be formed by a double condensation reaction of benzaldehyde 19 with N-phenylurea 18 through an intermediate imine 22 (Scheme 13).41 Using a catalytic amount of Et3N (10 mol%) in the reaction led to the formation of compound 24
(~6%) after 5 d (entry 3). This can be formed via nucleophilic addition of diethyl phosphate 20 to benzaldehyde 19 (Pudovik reaction).42 Switching to ethanol as solvent for the three component reaction did not afford any traces of product after 2 d (entry 4).When we employed a catalytic amount of Et3N (10 mol%) as base in the reaction, formation of
compound 24 (~15%) was observed after 2 d (entry 5). Moving to water, a more polar solvent and using Et3N (10 mol%) as base for the reaction,
formation of compound 24 (~50%) and hydrolysis of diethyl phosphate 20 to phosphoric acid was observed after 1 d (entry 6). These results suggest that N-phenyl urea may be acting as a H-bond donor to activate the aldehyde and a base is required for the activation of phosphite in the reaction.
197
Table 1: Three component reaction of N-phenylurea 18, benzaldehyde 19 and diethyl phosphate 20 (Kabachnik–Fields reaction).
S.No.a Solvent Catalyst (10 mol%) Time (d) Product (% conv.)b 1 1,4-Dioxane - 5 - 2 1,4-Dioxane pTsOH 5 23 (~15) 3 1,4-Dioxane Et3N 5 24 (~6) 4 EtOH - 2 - 5 EtOH Et3N 2 24 (~15) 6 H2O Et3N 1 24 (~50)
a) All the reactions were performed on 1.0 mmol of each reagent. b) Reaction progress was monitored by 1H-NMR (n-dodecane as internal standard) and 31P-NMR (31P NMR for 20 δ = 7.3 ppm).
Scheme 13: Formation of aminal 23.
We were also interested to evaluate the effect of aldehydes bearing a base functionality in the three component reaction (Scheme 14).
198
Scheme 14: Selected aldehydes bearing a basic functionality.
Scheme 15: Synthesis of 4-(N,N-dimethylamino)picolinaldehyde 26.
4-(N,N-Dimethylamino)picolinaldehyde 26 was synthesized by following a known literature procedure43 (Scheme 15). Direct lithiation of the commercially available N,N-dimethylaminopyridine 28 using a mixture of n-BuLi and N,N-dimethylaminoethanol (DMAE) in THF followed by quenching with DMF gave the desired product 26 in 30% isolated yield.43
Scheme 16: Synthesis of 2-((N,N-dimethylamino)methyl)benzaldehyde 27.
2-((N,N-Dimethylamino)methyl)benzaldehyde 27 was also synthesized using a known literature44 procedure (Scheme 16). Direct lithiation of commercially available N,N-dimethyl-1-phenylmethanamine 29 with t-BuLi in Et2O and followed by quenching with DMF led to the
corresponding aldehyde 27 in 75% isolated yield.
With aldehydes 25, 26 and 27 in hand we tested their reactivity in the Kabachnik–Fields reaction (Scheme 17). When an equimolar mixture of N-phenylurea 18, diethylphosphite 20 and either aldehyde 25 or 26 in 1,4-dioxane was stirred at rt for 5 d, the desired product formation was not observed. This might be due to the lack of activation of the diethyl phosphate 20 (Scheme 17a, 17b). Interestingly, when an equimolar
199
mixture of N-phenylthiourea 32, diethyl phosphate 20 and aldehyde 27 in 1,4-dioxane was stirred at rt for 5 d, the formation of compound 34 (~66% conversion) was observed instead of product 33. A possible reason for the formation of 34 may be the undesired Pudovik reaction42 in which the thiourea 32 activates the aldehyde functionality in 27, while the tertiary amine moiety in 27 activates the diethyl phosphate 20 and holds it in close proximity for reaction with its aldehyde group (Scheme 17c). These observations suggest the formation of undesired products under basic conditions is dominant, likely because of poor imine formation due to the poor leaving group ability of the hydroxide anion.
Scheme 17: Attempted Kabachnik–Fields reaction using different aldehydes.
7.4 Conclusions
Two approaches were followed to develop a new asymmetric autocatalytic reaction based on H-bond donor concept. We successfully synthesized the imine 16, but due to its poor solubility in most organic solvents it was difficult to perform any Mannich reaction. A possible reason for the low solubility of imine 16 is the strong H-bond interactions between urea motifs present in the molecule. In the Kabachnik–Fields reaction the presence of a catalytic amount of acid leads to the formation of aminal 23. When we employed catalytic amount of base in the reaction
200
formation of side product 24 was observed through a Pudovik reaction. Base was required to activate the phosphite for the reaction and changing to a more polar solvent led to increased formation of side product 24 and the hydrolysis of phosphate 20. By following literature procedures we successfully synthesized the internal base-functionalized aldehydes 26 and 27. Subjecting aldehydes 25 and 26 to the three component reaction, we did not observe any significant reaction to form the desired product. When we used aldehyde 27 in the reaction, formation of side product 34 was observed (vide supra). Formation of undesired products under basic conditions is likely dominant due to the poor imine formation.
Our studies have shown that urea/thiourea type compounds are difficult substrates for autocatalysis following a H-bond approach. This is maybe due to the strong H-bond interactions which lead to poor solubility of the bisurea imine. In addition each component of the reaction requires different conditions for activation. While the urea scaffold is necessary for H-bond donation in order to activate the electrophiles, it is a weaker nucleophile than amine traditionally used in Kabachnik–Fields reaction. Redesigning of the system is required in order to overcome these problems.
7.5 Experimental section
7.5.1 General procedures
Flash column chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by UV, phosphomolybdic acid and potassium permanganate staining. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and
13
C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) or a Varian VXR300 (300 and 75 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the
201
for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Optical rotations were measured on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL). Enantiomeric ratios were determined by HPLC analysis using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP diode array detector.
All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. Dry solvents were used from the solvent purification system (MBRAUN SPS systems, MB-SPS-800).All starting materials were purchased from commercial sources, and used without further purification.
Note: Benzaldehyde was freshly distilled and used. 7.5.2 Synthesis of imine (16)
1-(2-Aminoethyl)-3-hexylurea (11)38
To a stirred solution of ethylenediamine (241 mg, 4.00 mmol, 4 equiv) in dry DCM (10 mL, 0.4 M) at rt was added a solution of hexyl isocyanate (127 mg, 1.00 mmol, 1 equiv) in dry DCM (5 mL, 0.2 M) dropwise over 30 min. After stirring for 3 h at the same temperature the volatiles were evaporated under vacuum. Pentane (10 mL) was added to the crude reaction mixture, it was stirred for 10 min and a white precipitate was observed. Upon filtration a white solid was collected. The solid was washed with pentane (2x10 mL) and dried under vacuum to afford product 11 (170 mg, 91%). This compound was used in the next step without any further purification.
1
H NMR (400 MHz, CD3OD) δ 4.86 (s, 4H), 3.26 (t, J = 6.0 Hz, 2H),
202
6H), 0.90 (t, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CD3OD) δ 160.0,
40.9, 39.8, 39.7, 31.3, 29.9, 26.3, 22.3, 13.0.
(4-(Aminomethyl)phenyl)methanol (13)39
To a stirred suspension of 4-(aminomethyl)benzoic acid (2.00 g, 13.2 mmol, 1 equiv) in dry THF (50 mL, 0.27 M) at 0 °C was added LiAlH4
(2.01 g, 52.9 mmol, 4 equiv) in three portions. After the addition was complete, the mixture was heated to reflux and stirred overnight. It was then cooled to 0 °C and quenched with H2O (2 mL), 15% aq. NaOH (2
mL), H2O (6 mL). After stirring for 10 min at rt the white suspension was
filtered through a pad of celite and washed with EtOAc (20 mL). The collected filtrate was concentrated under vacuum to afford (4-(aminomethyl)phenyl)methanol 13 (1.5 g, 83%) as a white solid which was used in the next step without further purification.
1
H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J = 8.3 Hz, 2H), 7.21 (d, J =
8.3 Hz, 2 H), 4.44 (s, 2 H), 3.66 (s, 2H); 13C NMR (101 MHz, DMSO-d6)
δ 140.8, 127.2, 126.7, 63.2, 45.9.
1-Hexyl-3-(4-(hydroxymethyl)benzyl)urea (14)
To a stirred solution of compound 13 (163 mg, 1.18 mmol, 1 equiv) in dry CHCl3 (10 mL, 0.12 M) at rt was added dropwise over 10 min a
solution of hexyl isocyanate (150 mg, 1.18 mmol, 1 equiv) in dry CHCl3
(5 mL, 0.24 M). The mixture was stirred for another 16 h at the same temperature. The volatiles were removed under vacuum to afford compound 14 (285 mg, 92%) as a yellow solid. The compound was used in the next step without further purification.
1 H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 6.17 (t, J = 6.0 Hz, 1H), 5.83 (t, J = 5.7 Hz, 1H), 5.07 (t, J = 5.6 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 4.12 (d, J = 5.9 Hz, 2H), 2.94 (q, J = 6.5 Hz, 2H), 1.30 (m,2H), 1.21 (m, 6H), 0.82 (t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 158.5, 141.2, 139.7, 127.1, 126.8, 63.1, 43.1, 39.7, 31.5, 30.4, 26.5, 22.5, 14.3.
203 1-(4-Formylbenzyl)-3-hexylurea (15)
To a stirred solution of compound 14 (215 mg, 0.82 mmol, 1 equiv) in dry THF (5 mL, 0.16 M) at rt was added activated MnO2 (~85%, 713 mg,
6.97 mmol, 8.5 equiv). The reaction mixture was stirred for 24 h at rt and filtered through a pad of Celite. The volatiles were evaporated under vacuum to afford the compound 15 (170 mg, 80%) as an off-white solid. This compound was used in the next step without further purification.
1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 7.9 Hz, 2H), 6.39 (t, J = 6.1 Hz, 1H), 5.97 (t, J = 5.6 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 2.98 (q, J = 6.3 Hz, 2H), 1.45 – 1.06 (m, 6H), 0.85 (t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 193.1, 158.5, 149.0, 135.3, 130.0, 127.9, 43.2, 39.8, 31.5, 30.4, 26.5, 22.5, 14.4. Imine (16)
An equimolar mixture of compound 11 (219 mg, 1.17 mmol, 1 equiv) and compound 15 (291 mg, 1.17 mmol, 1 equiv) in dry toluene (6 mL, 0.39 M) at 50 °C was stirred for 18 h. The volatiles were removed under vacuum to afford a suspension. Et2O (10 mL) was added to the
suspension followed by stirring for 10 min after which a white precipitate was observed. The precipitate was collected via filtration and dried under vacuum to afford the desired imine 10 (462 mg, 95%) as a white solid. Due to the poor solubility of the imine its NMR spectra were obtained at 80 °C. 1 H NMR (500 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 6.16 (s, 1H), 5.74 (s, 2H), 5.63 (s, 1H), 4.27 (d, J = 6.1 Hz, 2H), 3.61 (t, J = 5.9 Hz, 2H), 3.31 (q, J= 6.1 Hz, 2H), 3.16 – 2.91 (m, 4H), 1.49 – 1.36 (m, 4H), 1.30 (m, 12H), 0.89 (t, J = 6.8 Hz, 6H); 13C NMR (126 MHz, DMSO-d6) δ 165.2, 164.5, 161.3, 146.9, 138.0, 130.9, 130.3, 63.8, 46.2, 34.1, 33.1, 29.1, 29.1, 25.1, 16.8.
204
7.5.3 Synthesis of 4-(N,N-dimethylamino)picolinaldehyde (26)43
To a solution of N,N-dimethylaminoethanol (6.60 mL, 65.5 mmol, 2 equiv) in dry n-hexane (80 mL, 0.82 M) at –10 °C was added dropwise a solution of n-BuLi (1.7 M in n-hexane, 76.4 mL, 131 mmol, 4 equiv). After stirring for 30 min at the same temperature N,N-dimethylpyridin-4-amine (4.00 g, 32.7 mmol, 1 equiv) was added in two portions. The reaction mixture was allowed to warm to 0 °C and stirred for another 1 h. Subsequently the mixture was cooled to –40 °C and added dropwise a solution of dry DMF (3.80 mL, 49.1 mmol, 1.5 equiv) in dry THF (40 mL, 1.23 M) over 30 min. After stirring for 4 h at the same temperature the reaction mixture was quenched with 1 M aq. HCl (50 mL). The layers were separated and the aqueous layer was extracted with Et2O (3 x 30
mL). The combined organic layers were dried over anhydrous MgSO4,
filtered and the volatiles were evaporated under vacuum. The residue was purified by flash column chromatography on silica using a mixtures of pentane/EtOAc (80:20 to 0:100) to afford the desired aldehyde 26 (1.5 g, 30 %) as a pale yellow oil.
1 H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 8.35 (d, J = 5.9 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 6.63 (dd, J = 5.9, 2.8 Hz, 1H), 3.04 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 194.8, 155.0, 153.3, 150.3, 110.1, 104.6, 39.5. 7.5.4 Synthesis of 2-((N,N-dimethylamino)methyl)benzaldehyde (27)44 To a solution of N,N-dimethylaminomethylbenzene (3.00 mL, 24.6 mmol, 1 equiv) in dry Et2O (60 mL, 0.41 M) at rt was added dropwise a
solution of t-BuLi (1.7 M in pentane, 20 mL, 34 mmol, 1.4 equiv) over 1 h. After stirring for 1 h at rt, DMF (1.6 mL) was added dropwise. The
205
reaction mixture was stirred for 1 h at rt, then cooled to 0 °C. The reaction was quenched with water (30 mL). The layers were separated and the aqueous layer was extracted with Et2O (2 × 30 mL). The
combined organic layers were dried over anhydrous MgSO4, filtered and
the volatiles were removed under vacuum. The residue was purified by flash column chromatography on silica using a mixtures of Et2O/hexane/Et3N (70:20:10) to afford the desired product 27 (2.9 g,
75%) as pale yellow oil.
1
H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H),
7.50 (t, J = 7.4 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.36 (t, J = 6.8 Hz, 1H), 3.72 (s, 2H), 2.22 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 192.1, 141.7,
135.0, 133.2, 130.5, 129.4, 127.7, 60.9, 45.1.
7.5.5 General procedure for the Mannich reaction.
A 4 mL screw capped vial was equipped with a stirring bar and charged with imine 16 (22 mg, 0.05 mmol, 1 equiv), acetone (37 µL, 0.5 mmol, 10 equiv) and pyrrolidine (0.450 µL, 0.005 mmol, 0.1 equiv) in DMF (2 mL) or imine 16 (22 mg, 0.05 mmol, 1 equiv) and acetone (1.1 mL, 15 mmol, 300 equiv). The vial was closed and the reaction mixture was stirred at rt. The progress of the reaction was monitored by 1H-NMR via aliquots (0.1 mL) over the indicated time period. The aliquots were diluted with DMSO-d6 (0.5 mL) and 1H-NMR was acquired at 80 °C.
7.5.6 General procedure for the three component(Kabachnik–Fields) reaction.
A 20 mL screw capped vial was equipped with a stirring bar and charged with aldehyde (1 mmol), urea/thiourea (1 mmol) and diethylphosphite (1 mmol). Solvent (5 mL) was added, the vial was closed and the reaction mixture was stirred at rt. The progress of the reaction was monitored by
1
H-NMR (n-dodecane as internal standard) and 31P-NMR (31P-NMR for 20 δ = 7.3 ppm) via aliquots (0.1 mL) over the indicated time period. The aliquots were diluted with CDCl3 (0.5 mL), passed through a plug of
206
anhydrous MgSO4, 1H-NMR and 31P-NMR was acquired. Due to the
formation of undesired products isolation was not performed.
7.6 References
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2013, 52, 12800.
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