Letter Cite This: Org. Lett. 2018, 20, 1359−1362
pubs.acs.org/OrgLett
2‑Aminoquinazolin-4(3H)‑one as an Organocatalyst for the Synthesis of Tertiary Amines Maheshwar S. Thakur,†,‡ Onkar S. Nayal,†,‡ Rahul Upadhyay,† Neeraj Kumar,§ and Sushil K. Maurya*,†,‡ †
Natural Product Chemistry and Process Development Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176 061, India ‡ Academy of Scientific and Innovative Research, CSIR-HRDC, Ghaziabad, UP 201 002, India S Supporting Information *
ABSTRACT: The potential of 2-aminoquinazolin-4(3H)-one as an organocatalyst for the activation of aldehydes via noncovalent interaction for the synthesis of tertiary amines using formic acid as a reducing agent is reported for the first time. The developed protocol demonstrated a dilated substrate scope for aromatic and aliphatic amines with aromatic and aliphatic aldehydes. Furthermore, the current method was also fruitful for the derivatization of ciprofloxacin and its derivative in good to excellent yields.
O
density at hypervalent silicon that make the hydride more hydridic and therefore more likely to further coordinate reducible Lewis base functionalities such as carbonyls. Encouraged by this report, we hypothesized that utilizing an organic molecule would catalyze this challenging organic transformation. Previously, we have reported quinazolin-4(3H)-one molecules as H-bonding organocatalysts in transfer hydrogenation reaction for the reduction of nitroarenes,8 where we found that 2-aminoquinazolinone is capable of forming hydrogen bonds with hydrazine hydrate. This interacting behavior of 2-amino4(3H)-quinazolinone realized us that it can also form H-bonds with other hydrogen donating molecules by distorting their geometry. As per the literature, formic acid is a naturally occurring cost-effective, easy to handle, environmentally friendly, and air- and moisture-stable reducing agent which is mostly present in dimer form at high temperature (SI Figure 2).9a Previously, with the combination of formamide or ammonium formate, it has been used in the Leuckart reaction.9b,c Hence, we hypothesized that our catalyst 2amino-4(3H)-quinazolinone can interact with formic acid and distort its geometry. To address this issue, we conducted the infrared spectral analysis of formic acid and found a strong peak at 1726 cm−1 (SI Figure 3A) that corresponds to the CO bond stretch, showing that formic acid is present in dimer form.9 To check our hypothesis further, we carried out the reaction of formic acid with 2-aminoquinazolinone and obtained their infrared spectra during the reaction. As expected, we found a shift in the peak of CO from 1726 to 1732 cm−1 in the IR spectra (SI Figure 3B). The change in peak value confirms our hypotheses that 2-aminoquinazolinone can also interact with formic acid
wing to the immense importance and ubiquity of tertiary amines in numerous biologically active natural products, agro-chemicals, dyes, polymers, and pharmaceuticals, the development and innovation of approaches for their synthesis is of great interest in the modern era.1 Traditionally, direct reductive amination (DRA) approach, Buchwald−Hartwig reaction, borrowing hydrogen methodology (BHM), and nucleophilic addition to imines are the most common approaches for the synthesis of higher amines.2 Perhaps the most straightforward, preferred, and convenient procedure among them is DRA, which has been widely used in the laboratory as well as in industrial production.3 Notably, in the past decade, DRA has been extensively explored for the synthesis of secondary amine using metal and metal-free conditions.4 However, the synthesis of tertiary amines through direct reductive amination of carbonyl compounds with secondary amines is less explored.3,5 This is due to the sterically hindered nature of secondary amines, which disfavors the iminium ion/enamine formation.6 In addition, the in situ transfer hydrogenation of iminium ion is also difficult. Therefore, synthesis of tertiary amines from secondary amines via DRA is always challenging.6 To meet these challenges, some research group have reported metalcatalyzed direct reductive amination approach for the synthesis of tertiary amines using various catalyst such as SnCl2,3 InCl3,7a iridium complex [IrCl(cod)],7b and cyclopentadienyl−iron complex.7c However, these reports are not applicable for late functionalization of biologically active molecules. In this context, the Wang group described a TMEDA-promoted metal-free approach by using trichlorosilane (TMEDA/ HSiCl3 1:2) in a stoichiometric amount for the synthesis of the tertiary amine from secondary amine.5a Moreover, Varjosaari et al. also reported an approach using hydrosilatrane as reductant for the synthesis of tertiary amine.5b In hydrosilatrane, a lone pair of nitrogen increase the electron © 2018 American Chemical Society
Received: January 11, 2018 Published: February 16, 2018 1359
DOI: 10.1021/acs.orglett.8b00127 Org. Lett. 2018, 20, 1359−1362
Letter
Organic Letters and distort its geometry from cyclic dimer to acyclic dimer.9,10 These results encouraged us to utilize the proton of acyclic dimer as a sophisticated hydrogen source in direct reductive amination for the synthesis of the tertiary amine from secondary amines. In this context, the study was initiated by choosing benzaldehyde (1a) and N-methylaniline (2a) as model substrates, formic acid as reducing agent, 2-amino-4(3H)quinazolinone (L2) as catalyst, and acetonitrile as a solvent for the reaction. As reported previously, direct reductive amination reaction in the presence of HCOOH is very challenging, as shown in the Scheme 1. First, the aldehyde (1a) is prone to
The mechanism was also confirmed by isothermal titration calorimetry experiment, which clearly shows the presence of exothermic reaction between L2 and formic acid in acetonitrile, indicating that they are interacting with each other (Figure 1).
Scheme 1. DRA in the Presence of Formic Acid
hydrogenation under these conditions.11 Second, amine substrate undergoes the N-formylation (2a′) reaction dominantly.11 However, the third and important step is the formation of imine (3a′) from aldehydes with amines, which is a reversible reaction and susceptible to water, pH, and temperature.11 Thus, minimal decomposition of imine is a prerequisite for a successful direct reductive amination. Also, to achieve a high selectivity of the desired amine product, the reduction of imine must be significantly faster than the reduction of aldehydes, but under our reaction conditions, the formation of desired product (3a) dominates exclusively, indicating the synergistic role of catalyst with reducing agent. To investigate the mechanism of this transformation further, we carried out some control experiments. First, the model reaction was performed in the presence of L1 catalyst, but surprisingly very low yield (31%) was obtained, indicating less interaction of L1 with formic acid (Scheme 2A). This revealed
Figure 1. Reaction of L2 with formic acid was observed in isothermal titration calorimetry.
Furthermore, the limewater test was carried out to check the formation of CO2 in reaction (Scheme 2D). The cloudy appearance of limewater and the litmus paper test of this solution before and after the reaction confirms the formation of CO2 (SI Figure 3).13 These experiments indicate that hydride ion was evolved from the splitting of formic acid. On the basis of the various control experiments mentioned earlier and our previous study on the H-bond interactions of L2, we proposed a plausible reaction pathway as depicted in Figure 2. First, L2 distorts the
Scheme 2. Control Experiments Performed
Figure 2. Plausible mechanism.
geometry of formic acid (F), and because of that, the acidic proton of formic acid activates the carbonyl group of benzaldehyde (1a) through hydrogen bonding for nucleophilic attack (Figure 2, 1a′).12 Subsequently, N-methylaniline (2a) reacts with benzaldehyde to form iminium ion (3a′). In the meantime, formate ion splits into CO2 and hydride ion, and this hydride ion is trapped by the iminium intermediate to form the desired product (3a). However, this study was initiated from the optimization of organocatalysts, and among various catalysts L1−L5 (Figure 3), L2 afford the maximum yield. Subsequently, other organic reducing agents such as glucose, oxalic acid, and ascorbic acid
the requirement of greater H-bonding sites for interaction with formic acid which are provided by the L2. Next, sodium formate and potassium formate were used as a reducing agents instead of formic acid, but no product formation was observed (Scheme 2B,C). This showed that the reaction was initiated by the proton evolved by the synergistic role of L2 and formic acid.12 1360
DOI: 10.1021/acs.orglett.8b00127 Org. Lett. 2018, 20, 1359−1362
Letter
Organic Letters Scheme 3. Substrate Scope for N-Alkylanilinesa
Figure 3. Quinazolin-4-one catalyst screened for the reaction.
were tested, but no desired product was formed (Table 1).14 Further, salts of formic acid were utilized in this reaction, but Table 1. Optimization of Reaction Conditions
entry
catalyst
reducing agent
solvent
yielda (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
L1 L2 L3 L4 L5 L2 L2 L2 L2 L2 L2 L2 L2 L2 L2 L2 L2 L2 L2 L2
HCOOH HCOOH HCOOH HCOOH HCOOH Ph3SiH oxalic acid glucose ascorbic acid HCOONH4 HCOONa HCOOH HCOOH HCOOH HCOOH HCOOH HCOOH HCOOH HCOOH HCOOH
MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN CH3OH C2H5OH toluene THF 2-propanol DCE n-BuOH H2O MeCN
31 76 55 60 30 5
a Reaction conditions: aldehyde (1, 1.5 mmol), N-alkylaniline (2, 1 mmol), L2 (20 mol %), HCOOH (2 equiv), molecular sieves in MeCN (3 mL) at 100 °C for 5 h. Isolated yield.
One of the important dilemmas associated with reductive amination is intolerance of CC bonds; interestingly, in the current case high chemoselectivity was observed with conjugated CC bonds containing aldehydes (Scheme 3, 3i,j).3 Reductive amination of 3-phenylpropionaldehyde and anthraldehyde proceeded smoothly to give the desired product in moderate yield (Scheme 3, 3k,3l). Moreover, compounds 3m−p showed that reactions of substituted anilines proceeded smoothly with different aldehydes to give good yields. Encouraged by these results, we further extended our study to explore the utility of this method for the functionalization of secondary amine of biologically active ciprofloxacin and their derivative with variety of aldehydes. Previously, Wang et al. reported the three steps protocol to react substituted benzaldehydes with the secondary amine of ciprofloxacin.15 Therefore, here we report a one-step methodology for the N-alkylation of ciprofloxacin with different aldehydes via reductive amination. First, 4 was derivatized with various halobenzaldehydes in good yield (Scheme 4, 5b−e). Then nitro benzaldehyde, anthraldehyde, and p-methoxycinnamaldehyde were reacted with 4, and a good yield of the products was obtained (Scheme 4, 5f−h). After the successful derivatization of 4, we further carried out our study for the functionalization of ciprofloxacin with similar aldehydes, and in these cases, good to excellent yield of the product was also obtained (Scheme 5, 7a−f). In summary, a novel 2-aminoquinazolinone-catalyzed method with a wide substrate scope has been developed for the synthesis of tertiary amines from secondary aliphatic and aromatic amines by using naturally occurring, cost-effective, easy to handle, air- and moisture-stable, and environmentally friendly reducing agent. We report for the first time the potential of 2-aminoquinazolinone as an organocatalyst for the activation of aldehydes via noncovalent interaction using formic acid as a reducing agent. Furthermore, the generality of the current organocatalytic method was demonstrated by the Nalkylation of biologically active ciprofloxacin and its derivative in good to excellent yield.
21 27 5 41 10 54
50b
a
Reaction conditions: benzaldehyde (1a, 1.5 mmol), N-methylaniline (2a, 1 mmol), catalyst (20 mol %), reducing agent (2 equiv), solvent (3 mL), molecular sieves at 100 °C for 5 h; yield was obtained by NMR using tetrachloroethane as internal standard. bReaction carried out at 80 °C.
except HCOOH no other reducing agent showed appreciable yield. After this, optimization of solvent was carried out, and ACN was found to be the best solvent for this transformation. Next, the effect of temperature was studied, and it was found that 100 °C was the optimum temperature. After the optimization of various reaction conditions, the substrate scope was evaluated for a variety of aldehydes with secondary amines with the optimized conditions. First, halogensubstituted benzaldehydes was tested with N-methylaniline. It was perceived that the reaction proceeded smoothly and halogen groups were well tolerated to afford the corresponding anilines in good to excellent yield (Scheme 3, 3b−e,h,m,n). Notably, the reaction of benzaldehydes bearing electrondonating groups with N-methylaniline afforded the desired product in good yield (Scheme 3, 3f−h). Moreover, a less studied challenging substrate combination of polysubstituted aldehydes reacted sleekly with N-methylaniline and gave a moderate to good yield of the desired product (Scheme 3, 3g,h).3 1361
DOI: 10.1021/acs.orglett.8b00127 Org. Lett. 2018, 20, 1359−1362
Organic Letters
■
Scheme 4. Substrate Scope for Ester of Ciprofloxacina
ACKNOWLEDGMENTS We are thankful to the Director, CSIR-IHBT, Palampur (H.P.), for the necessary infrastructure. We are also thankful to Mr. Digvijay Singh Naruka for performing MicroCal Auto-iTC200 at CSIR-IMTECH Chandigarh. M.S.T. is thankful to the University Grants Commission, New Delhi, for a senior research fellowship. S.K.M. is thankful to the SERB, Government of India, for an early career research award (ECR/2016/ 000134). CSIR-IHBT Communication No. 4205.
■
Reaction conditions: aldehyde (1, 1.3 mmol), ciprofloxacin derivative (4, 1 mmol), L2 (20 mol %), HCOOH (2 equiv), MeCN (4 mL), and molecular sieves at 100 °C for 5 h. Isolated yield.
Scheme 5. Substrate Scope for Ciprofloxacina
a Reaction conditions: aldehyde (1, 1.3 mmol), ciprofloxacin (6, 1 mmol), L2 (20 mol %), HCOOH (2 equiv), MeCN (4 mL), and molecular sieves at 100 °C for 5 h. Isolated yield.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00127. Experimental details, data, and spectra (PDF)
■
REFERENCES
(1) (a) Johnson, B. N.; Lennon, C. I.; Moran, H. P.; Ramsden, A. J. Acc. Chem. Res. 2007, 40, 1291. (b) Ruzic, M.; Pecavar, A.; Prudic, D.; Kralj, D.; Scriban, C.; Zanotti-Gerosa, A. Org. Process Res. Dev. 2012, 16, 1293. (c) Wang, C.; Pettman, A.; Basca, J.; Xiao, J. Angew. Chem., Int. Ed. 2010, 49, 7548. (2) (a) Vantourout, J. C.; Law, R. P.; Isidro-Llobet, A.; Atkinson, S. J.; Watson, A. J. B. J. Org. Chem. 2016, 81, 3942. (b) Menche, D.; Arikan, F.; Li, J.; Rudolph, S. Org. Lett. 2007, 9, 267. (c) Lee, O.; Law, K.; Ho, C.; Yang, D. J. Org. Chem. 2008, 73, 8829. (d) Das, B. G.; Ghorai, P. Chem. Commun. 2012, 48, 8276. (e) Pisiewicz, S.; Stemmler, T.; Surkus, A. E.; Junge, K.; Beller, M. ChemCatChem 2015, 7, 62. (f) Nayal, O. S.; Thakur, M. S.; Kumar, M.; Sharma, S.; Kumar, N. Adv. Synth. Catal. 2016, 358, 1103. (g) Shi, S. L.; Buchwald, S. L. Nat. Chem. 2015, 7, 38. (3) Nayal, O. S.; Bhatt, V.; Sharma, S.; Kumar, N. J. Org. Chem. 2015, 80, 5912. (4) (a) Baxter, E. W.; Reitz, A. B. Org. React. 2002, 59, 1. (b) Alinezhad, H.; Yavari, H.; Salehian, F. Curr. Org. Chem. 2015, 19, 1021. (5) (a) Wang, Z.; Pei, D.; Zhang, Y.; Wang, C.; Sun, J. Molecules 2012, 17, 5151. (b) Varjosaari, E.; Skrypai, V.; Suating, P.; Hurley, J. J. M.; Lio, A. M. D.; Gilbert, T. M.; Adler, M. J. Adv. Synth. Catal. 2017, 359, 1872. (6) (a) Borch, R. F.; Bernstein, M. D.; Durst, H. P. J. Am. Chem. Soc. 1971, 93, 2897. (b) Nayal, O. S.; Thakur, M. S.; Bhatt, V.; Kumar, M.; Kumar, N.; Singh, B.; Sharma, U. Chem. Commun. 2016, 52, 9648. (7) (a) Lee, Y. O.; Law, L. K.; Ho, Y. C.; Yang, D. J. Org. Chem. 2008, 73, 8829. (b) Mizuta, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2005, 70, 2195. (c) Moulin, S.; Dentel, H.; Ozherelyeva, A. P.; Gaillard, S.; Poater, A.; Cavallo, L.; Lohier, J. F.; Renaud, J. F. Chem. - Eur. J. 2013, 19, 17881. (8) Thakur, M. S.; Nayal, O. S.; Rana, R.; Kumar, M.; Sharma, S.; Kumar, N.; Maurya, S. K. New J. Chem. 2018, 42, 1373. (9) (a) Gantenberg, M.; Halupka, M.; Sander, W. Chem. - Eur. J. 2000, 6, 1865. (b) Leuckart, R. Ber. Dtsch. Chem. Ges. 1885, 18, 2341. (c) DeBenneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3073. (10) Bartholomew, R. J.; Irish, D. E. J. Raman Spectrosc. 1999, 30, 325. (11) Zhu, M. Catal. Lett. 2014, 144, 1568. (12) Ghafuri, H.; Roshani, M. RSC Adv. 2014, 4, 58280. (13) Bradley, I.; Gale, P.; Winterbottom, M. Heinemann Science Scheme Pupil Book 1; Heinemann Educational Publisher, 2001; p 66. (14) (a) Kumar, M.; Sharma, U.; Sharma, S.; Kumar, V.; Singh, B.; Kumar, N. RSC Adv. 2013, 3, 4894. (b) Song, P.; Zhang, X.; Sun, M.; Cui, X.; Lin, Y. RSC Adv. 2012, 2, 1168. (c) Majhi, B.; Kundu, D.; Ranu, B. C. J. Org. Chem. 2015, 80, 7739. (d) Bu, M. J.; Lu, G. P.; Cai, C. Synlett 2015, 26, 1841. (15) Wang, S.; Jia, X. D.; Liu, M. L.; Lu, Y.; Guo, H. Y. Bioorg. Med. Chem. Lett. 2012, 22, 5971.
a
■
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected],
[email protected]. ORCID
Sushil K. Maurya: 0000-0003-4893-7743 Notes
The authors declare no competing financial interest. § Deceased. 1362
DOI: 10.1021/acs.orglett.8b00127 Org. Lett. 2018, 20, 1359−1362
