CC BY 4.0 · Synlett 2020; 31(15): 1507-1510
DOI: 10.1055/s-0040-1707080
letter
(2020) The Author(s)

2-Aminoquinazolines by Chan–Evans–Lam Coupling of Guanidines with (2-Formylphenyl)boronic Acids

Vitalii V. Solomin
a  Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia   Email: aigars@osi.lv
b  Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, Riga LV-1048, Latvia
,
Alberts Seins
a  Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia   Email: aigars@osi.lv
b  Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, Riga LV-1048, Latvia
,
a  Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV-1006, Latvia   Email: aigars@osi.lv
b  Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena Str. 3, Riga LV-1048, Latvia
› Author Affiliations
H2020 MSC-ITN project CARTNET “Combating Antimicrobial Resistance Training Network”, Grant agreement ID: 765147
Further Information

Publication History

Received: 30 April 2020

Accepted after revision: 10 June 2020

Publication Date:
08 July 2020 (online)

 


Abstract

A new method is presented for the synthesis of 2-aminoquinazolines, which is based on a Chan–Evans–Lam coupling of (2-formylphenyl)boronic acids with guanidines. Relatively mild conditions involving the use of inexpensive CuI as a catalyst and methanol as a solvent permit the application of the method to a wide range of substrates. Nonsubstituted, N-monosubstituted, and N,N-disubstituted guanidines can be used as reactants to give the corresponding 2-aminoquinazolines in moderate yields from readily available (2-formylphenyl)boronic acids.


#

2-Aminoquinazoline is an important substructure for the development of pharmaceutically relevant compounds, especially for the discovery of kinase inhibitors.[1] [2] [3] [4] [5] [6] A number of methods for the construction of 2-aminoquinazolines are know;[7–16] However, there are only a few approaches that exploit guanidines as reaction components. ortho-Halobenzaldehydes and aryl ketones can be condensed with guanidines in most cases if they contain an additional electron-withdrawing group that facilitates an SNAr reaction.[3] [6] [13] [14] [17] [18] For nonactivated substrates, a copper-catalyzed arylation of guanidines with aryl bromides has been described as a useful method for accessing 2-aminoquinazolines.[19] However, the reaction conditions are very harsh (DMF, 120 °C), which limits the scope of this approach.

The Chan–Evans–Lam coupling[20] [21] [22] [23] [24] is an attractive C–N bond-forming reaction that proceeds under relatively mild copper-catalyzed conditions and tolerates alcoholic solvents. To our knowledge, the only precedent for accessing quinazoline derivatives by using Chan–Evans–Lam coupling is a synthesis of quinazolonimines by arylation of N,N-disubstituted guanidines, formed in situ, with (2-cyanophenyl)boronic acids.[25] To facilitate our kinase-inhibitor-development program, we examined whether the Chan–Evans–Lam coupling might also be applicable to the synthesis of aminoquinazolines under mild conditions by using readily available reagents.

A screening of the reaction conditions was performed for the synthesis of unsubstituted quinazoline-2-amine (3). Representative results are reported in Table [1] [see Supporting Information (SI) for the full set of experiments]. Due to the polarity of the product 3, its purification by chromatography was difficult, and it was therefore purified by trituration from ethyl acetate. An identical scale and workup were applied in all experiments to permit comparison of the effects of other reaction parameters. Methanol as a reaction solvent, CuI as a catalyst, and K2CO3 as a base were found to be productive conditions for the formation of quinazoline-2-amine (3) from (2-formylphenyl)boronic acid (1) and guanidine hydrochloride (2a) (Table [1], entries 1 and 2).

Table 1 Chan–Evans–Lam Conditions for the Synthesis of 2-Aminoquinazoline (3)a

Entry

Solvent

Temp (°C)

Reactant (equiv)

Catalyst

Base (equiv)

Yieldb (%)

1

MeOH

70

2a (1.5)

CuI

K2CO3 (2.5)

31

2

MeOH

70

2a (2.5)

CuI

K2CO3 (3)

44

3

MeOH

70

2a (2.5)

Cu(OAc)2

K2CO3 (3)

35

4

MeOH

70

2a (2.5)

CuCl

K2CO3 (3)

23

5

MeOH

70

2a (1.5)

CuI

KOH (1.5)

34

6

MeOH

70

2a (3)

CuI

K2CO3 (3)

51 (65)c

7

EtOH

90

2a (3)

CuI

K2CO3 (3)

52

8

MeOH

70

2b (3)

CuI

13

9

MeOH

70

2b (1.5)

CuI

KOH (3)

17

a Reactions were performed open to the air, reaction time: 12–17 h.

b Purified by trituration with EtOAc to a purity of >98%.

c NMR yield with 1,3,5-trimethoxybenzene as an internal standard.

Excess amounts of the base and guanidine were beneficial in improving the yield of product 3 (Table [1], entry 2). Other copper catalysts [CuCl and Cu(OAc)2] were found to be less efficient than CuI (entries 3 and 4). The use of KOH as base improved the yield of product 3 when an excess of guanidine was used (entries 5 and 6). EtOH could also be successfully used as the reaction solvent (entry 7). Guanidine carbonate (2b) as a reactant gave a reduced yield of quinazoline 3 (entries 8 and 9). All the experiments listed in Table [1] were performed open to air to ensure reoxidation of the copper catalyst. Performing the reaction under an oxygen atmosphere or adding hydrogen peroxide did not substantially improve the yield of product 3 (see SI).

Next, (2-formylphenyl)boronic acid (1) was treated with a range of guanidines under the most productive reaction conditions (Table [1], entry 6).[26] Both N-monosubstituted guanidines 4ag and N,N-disubstituted guanidines (4hj) provided the corresponding 2-aminoquinazolines 5aj in fairly good yields (Table [2]).

Table 2 Guanidine Scope for the Synthesis of Aminoquinazolines

Entry

Guanidine

R1

R2

Product

Yielda (%)

 1

4a b

H

Me

5a

63

 2

4b c

H

Ph

5b

56

 3

4c b

H

Bn

5c

66d

 4

4d b

H

Ph(CH2)2

5d

52

 5

4e b

H

Me(CH2)4

5e

54

 6

4f b

H

cyclopentyl

5f

55

 7

4g b

H

Cy

5g

37

 8

4h e

Me

Me

5h

43

 9

4i b

(CH2)4

5i

47

10

4j b

(CH2)2O(CH2)2

5j

39

a Purified by column chromatography unless stated otherwise.

b Hydrochloride salt.

c Carbonate salt.

d Purified by trituration with EtOAc.

e Sulfate salt.

Several (2-formylphenyl)boronic acids 6af were next explored as substrates for the synthesis of aminoquinazolines 7af and 8af (Table [3]). Both guanidines 2a and 4a gave the expected products but the isolated yields were generally somewhat higher in the case of the N-methyl-substituted guanidine 4a (Table [3]; entries 3 and 4, 5 and 6, 7 and 8).

Table 3 Boronic Acid Scope for the Synthesis of Aminoquinazolines

Entry

Boronic acid

Guanidine

Product

Yielda (%)

 1

6a, R1 = 4-MeO

2a (R2 = H)

7a

55

 2

4a (R2 = Me)

8a

59b

 3

6b, R = 4-BnO

2a (R2 = H)

7b

32 (53)c

 4

4a (R2 = Me)

8b

57b

 5

6c, R = 5-MeO

2a (R2 = H)

7c

17 (53)c

 6

4a (R2 = Me)

8c

48b

 7

6d, R = 5-F

2a (R2 = H)

7d

36 (45)c

 8

4a (R2 = Me)

8d

52b

 9

6e, R = 3-F

2a (R2 = H)

7e

52

10

4a (R2 = Me)

8e

46b

11

6f, R = 5-Cl

2a (R2 = H)

7f

35

12

4a (R2 = Me)

8f

55b

a Purified by trituration with EtOAc unless stated otherwise.

b Purified by column chromatography.

c NMR yield with 1,3,5-trimethoxybenzene as an internal standard.

Boronic acid derivatives such as the pinacolate ester 9a and the trifluoroborate 9b were also competent substrates, providing aminoquinazoline derivative 5a in yields comparable to those from boronic acid 1 (Scheme [1]). These results complement the relatively few reported cases of the use of boronic acid derivatives as partners for Chan–Evans–Lam coupling.[27] [28]

In contrast, the boronic acids 10a and 10b bearing a keto group were found to be unsuitable reaction partners for the synthesis of the corresponding quinazolines 11a and 11b (Scheme [2]). In the case of these substrates, complex mixtures were obtained containing the O-arylation products 12a and 12b as the only identifiable byproducts. The failure of (2-acylphenyl)boronic acids 10a and 10b to give the expected products implies that the formation of an arylidene guanidine is the first step in the synthesis of aminoquinazolines 3, 5, 7, and 8, followed by intramolecular arylation

Zoom Image
Scheme 1 Synthesis 2-aminoquinazoline from a boronic acid ester and trifluoroborate
Zoom Image
Scheme 2 Attempt to condense keto-group-containing boronic acids with guanidine

In summary, 2-aminoquinazolines can be obtained by Chan–Evans–Lam coupling of (2-formylphenyl)boronic acids with guanidines. The relatively mild reaction conditions permit the use of this method for the synthesis of pharmacologically relevant compounds bearing a 2-aminoquinazoline scaffold.


#

Acknowledgment

We thank Dr. Janis Veliks for his advice and revision of the data.

Supporting Information

  • References and Notes

  • 1 Bathini Y, Singh I, Harvey PJ, Keller PR, Singh R, Micetich RG, Fry DW, Dobrusin EM, Toogood PL. Bioorg. Med. Chem. Lett. 2005; 15: 3881
  • 2 Esvan YJ, Zeinyeh W, Boibessot T, Nauton L, Théry V, Knapp S, Chaikuad A, Loaëc N, Meijer L, Anizon F, Giraud F, Moreau P. Eur. J. Med. Chem. 2016; 118: 170
  • 3 Zeinyeh W, Esvan YJ, Josselin B, Baratte B, Bach S, Nauton L, Théry V, Ruchaud S, Anizon F, Giraud F, Moreau P. Bioorg. Med. Chem. 2019; 27: 2083
  • 4 DiMauro EF, Newcomb J, Nunes JJ, Bemis JE, Boucher C, Buchanan JL, Buckner WH, Cee VJ, Chai L, Deak HL, Epstein LF, Faust T, Gallant P, Geuns-Meyer SD, Gore A, Gu Y, Henkle B, Hodous BL, Hsieh F, Huang X, Kim JL, Lee JH, Martin MW, Masse CE, McGowan DC, Metz D, Mohn D, Morgenstern KA, Oliveira-dos-Santos A, Patel VF, Powers D, Rose PE, Schneider S, Tomlinson SA, Tudor Y.-Y, Turci SM, Welcher AA, White RD, Zhao H, Zhu L, Zhu X. J. Med. Chem. 2006; 49: 5671
  • 5 Vasbinder MM, Aquila B, Augustin M, Chen H, Cheung T, Cook D, Drew L, Fauber BP, Glossop S, Grondine M, Hennessy E, Johannes J, Lee S, Lyne P, Mörtl M, Omer C, Palakurthi S, Pontz T, Read J, Sha L, Shen M, Steinbacher S, Wang H, Wu A, Ye M. J. Med. Chem. 2013; 56: 1996
  • 6 Li C, Shan Y, Sun Y, Si R, Liang L, Pan X, Wang B, Zhang J. Eur. J. Med. Chem. 2017; 141: 506
  • 7 Li J.-S, Fan Y.-H, Zhang Y, Marky LA, Gold B. J. Am. Chem. Soc. 2003; 125: 2084
  • 8 Bathini Y, Sidhu I, Singh R, Micetich RG, Toogood PL. Tetrahedron Lett. 2002; 43: 3295
  • 9 Chen X, Han J, Zhu Y, Yuan C, Zhang J, Zhao Y. Chem. Commun. 2016; 52: 10241
  • 10 Liu Q, Zhao Y, Fu H, Cheng C. Synlett 2013; 24: 2089
  • 11 Sasse K. Synthesis 1978; 379
  • 12 Kikelj D. In Science of Synthesis, Vol. 16. Yamamoto Y, Shinkai I. Thieme; Stuttgart: 2004. Chap. 16.3 573
  • 13 Babu DS, Srinivasulu D, Kotakadi VS. Chem. Heterocycl. Compd. 2015; 51: 60
  • 14 Smith AL, Andrews KL, Beckmann H, Bellon SF, Beltran PJ, Booker S, Chen H, Chung Y.-A, D’Angelo ND, Dao J, Dellamaggiore KR, Jaeckel P, Kendall R, Labitzke K, Long AM, Materna-Reichelt S, Mitchell P, Norman MH, Powers D, Rose M, Shaffer PL, Wu MM, Lipford JR. J. Med. Chem. 2015; 58: 1426
  • 15 Pandya AN, Villa EM, North EJ. Tetrahedron Lett. 2017; 58: 1276
  • 16 Zhou G, Aslanian R, Gallo G, Khan T, Kuang R, Purakkattle B, Ruiz MD, Stamford A, Ting P, Wu H, Wang H, Xiao D, Yu T, Zhang Y, Mullins D, Hodgson R. Bioorg. Med. Chem. Lett. 2016; 26: 1348
  • 17 Bollenbach M, Salvat E, Daubeuf F, Wagner P, Yalcin I, Humo M, Letellier B, Becker LJ, Bihel F, Bourguignon J.-J, Villa P, Obrecht A, Frossard N, Barrot M, Schmitt M. Eur. J. Med. Chem. 2018; 147: 163
  • 18 Huang KH, Barta TE, Rice JW, Smith ED, Ommen AJ, Ma W, Veal JM, Fadden RP, Barabasz AF, Foley BE, Hughes PF, Hanson GJ, Markworth CJ, Silinski M, Partridge JM, Steed PM, Hall SE. Bioorg. Med. Chem. Lett. 2012; 22: 2550
  • 19 Huang X, Yang H, Fu H, Qiao R, Zhao Y. Synthesis 2009; 2679
  • 20 Chan DM. T, Monaco KL, Wang R.-P, Winters MP. Tetrahedron Lett. 1998; 39: 2933
  • 21 Evans DA, Katz JL, West TR. Tetrahedron Lett. 1998; 39: 2937
  • 22 Lam PY. S, Clark CG, Saubern S, Adams J, Winters MP, Chan DM. T, Combs A. Tetrahedron Lett. 1998; 39: 2941
  • 23 Chen J.-Q, Liu X, Guo J, Dong Z.-B. Eur. J. Org. Chem. 2020; 2414
  • 24 Liu X, Dong Z.-B. J. Org. Chem. 2019; 84: 11524
  • 25 Rodrigues R, Tran LQ, Darses B, Dauban P, Neuville L. Adv. Synth. Catal. 2019; 361: 4454
  • 26 Quinazolin-2-amine (3); Typical Procedure A mixture of guanidine hydrochloride (2a; 765 mg, 8 mmol) and KOH (441 mg, 8 mmol) was dissolved in MeOH (30 mL) and the mixture was stirred for 10 min at r.t. (2-Formylphenyl)boronic acid (1; 400 mg, 2.67 mmol) was added in one portion followed by CuI (76 mg, 0.4 mmol), and the resulting mixture was heated at 70 °C overnight. The mixture was then concentrated under reduced pressure and partitioned between aq NH3 (30 mL) and EtOAc (120 mL). The organic layer washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by trituration with EtOAc (3 mL) to give a slightly beige solid; yield: 198 mg (51%); mp 194–196 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 9.10 (s, 1 H), 7.78 (d, J = 8.9 Hz, 1 H), 7.67 (t, J = 8.5 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.21 (t, J = 7.9 Hz, 1 H), 6.82 (s, 2 H). 13C NMR (101 MHz, DMSO-d 6): δ = 162.4, 160.9, 151.2, 134.1, 127.9, 124.5, 122.0, 119.5. LC/MS: m/z [M + H]+ calcd for C8H8N3: 146.17; found: 146.16. The spectral data correspond to the reported values (see Ref. 10). N-Methylquinazolin-2-amine (5a) Prepared from (2-Formylphenyl)boronic acid (1) and N-methylguanidine hydrochloride (4a), and purified by column chromatography [silica gel, EtOAc–PE (20 to 50% gradient)] as a yellowish solid: yield: 134 mg (63%); mp 81–83 °C; Rf = 0.63 (EtOAc). 1H NMR (400 MHz, CDCl3): δ = 9.03 (s, 1 H), 7.72–7.56 (m, 3 H), 7.22 (t, J = 7.9 Hz, 1 H), 5.43 (br s, 1 H), 3.12 (d, J = 4.0 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 162.01, 160.50, 152.44, 134.37, 127.79, 125.83, 122.72, 120.75, 28.77. HRMS: m/z [M + H]+ calcd for C9H10N3: 160.0875; found: 160.0881. 6-(Benzyloxy)-N-methylquinazolin-2-amine (8b) Prepared from boronic acid 6b and N-methylguanidine hydrochloride (4a), and purified by column chromatography [silica gel, EtOAc–PE (20 to 60% gradient)] as a yellowish solid; yield: 150 mg (57%); mp 130–132 °C, Rf = 0.38 (50% EtOAc–PE). 1H NMR (400 MHz, CDCl3): δ = 8.88 (s, 1 H), 7.58 (d, J = 9.2 Hz, 1 H), 7.51–7.32 (m, 6 H), 7.05 (d, J = 2.8 Hz, 1 H), 5.23 (s, 1 H), 5.12 (s, 2 H), 3.10 (d, J = 5.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 160.67, 159.78, 154.12, 148.30, 136.70, 128.80, 128.28, 127.67, 127.23, 127.13, 120.32, 106.82, 70.55, 28.76. HRMS: m/z [M + H]+ calcd for C16H16N3O: 266.1293; found: 266.1292.
  • 27 Marcum JS, McGarry KA, Ferber CJ, Clark TB. J. Org. Chem. 2016; 81: 7963
  • 28 Vantourout JC, Law RP, Isidro-Llobet A, Atkinson SJ, Watson AJ. B. J. Org. Chem. 2016; 81: 3942

  • References and Notes

  • 1 Bathini Y, Singh I, Harvey PJ, Keller PR, Singh R, Micetich RG, Fry DW, Dobrusin EM, Toogood PL. Bioorg. Med. Chem. Lett. 2005; 15: 3881
  • 2 Esvan YJ, Zeinyeh W, Boibessot T, Nauton L, Théry V, Knapp S, Chaikuad A, Loaëc N, Meijer L, Anizon F, Giraud F, Moreau P. Eur. J. Med. Chem. 2016; 118: 170
  • 3 Zeinyeh W, Esvan YJ, Josselin B, Baratte B, Bach S, Nauton L, Théry V, Ruchaud S, Anizon F, Giraud F, Moreau P. Bioorg. Med. Chem. 2019; 27: 2083
  • 4 DiMauro EF, Newcomb J, Nunes JJ, Bemis JE, Boucher C, Buchanan JL, Buckner WH, Cee VJ, Chai L, Deak HL, Epstein LF, Faust T, Gallant P, Geuns-Meyer SD, Gore A, Gu Y, Henkle B, Hodous BL, Hsieh F, Huang X, Kim JL, Lee JH, Martin MW, Masse CE, McGowan DC, Metz D, Mohn D, Morgenstern KA, Oliveira-dos-Santos A, Patel VF, Powers D, Rose PE, Schneider S, Tomlinson SA, Tudor Y.-Y, Turci SM, Welcher AA, White RD, Zhao H, Zhu L, Zhu X. J. Med. Chem. 2006; 49: 5671
  • 5 Vasbinder MM, Aquila B, Augustin M, Chen H, Cheung T, Cook D, Drew L, Fauber BP, Glossop S, Grondine M, Hennessy E, Johannes J, Lee S, Lyne P, Mörtl M, Omer C, Palakurthi S, Pontz T, Read J, Sha L, Shen M, Steinbacher S, Wang H, Wu A, Ye M. J. Med. Chem. 2013; 56: 1996
  • 6 Li C, Shan Y, Sun Y, Si R, Liang L, Pan X, Wang B, Zhang J. Eur. J. Med. Chem. 2017; 141: 506
  • 7 Li J.-S, Fan Y.-H, Zhang Y, Marky LA, Gold B. J. Am. Chem. Soc. 2003; 125: 2084
  • 8 Bathini Y, Sidhu I, Singh R, Micetich RG, Toogood PL. Tetrahedron Lett. 2002; 43: 3295
  • 9 Chen X, Han J, Zhu Y, Yuan C, Zhang J, Zhao Y. Chem. Commun. 2016; 52: 10241
  • 10 Liu Q, Zhao Y, Fu H, Cheng C. Synlett 2013; 24: 2089
  • 11 Sasse K. Synthesis 1978; 379
  • 12 Kikelj D. In Science of Synthesis, Vol. 16. Yamamoto Y, Shinkai I. Thieme; Stuttgart: 2004. Chap. 16.3 573
  • 13 Babu DS, Srinivasulu D, Kotakadi VS. Chem. Heterocycl. Compd. 2015; 51: 60
  • 14 Smith AL, Andrews KL, Beckmann H, Bellon SF, Beltran PJ, Booker S, Chen H, Chung Y.-A, D’Angelo ND, Dao J, Dellamaggiore KR, Jaeckel P, Kendall R, Labitzke K, Long AM, Materna-Reichelt S, Mitchell P, Norman MH, Powers D, Rose M, Shaffer PL, Wu MM, Lipford JR. J. Med. Chem. 2015; 58: 1426
  • 15 Pandya AN, Villa EM, North EJ. Tetrahedron Lett. 2017; 58: 1276
  • 16 Zhou G, Aslanian R, Gallo G, Khan T, Kuang R, Purakkattle B, Ruiz MD, Stamford A, Ting P, Wu H, Wang H, Xiao D, Yu T, Zhang Y, Mullins D, Hodgson R. Bioorg. Med. Chem. Lett. 2016; 26: 1348
  • 17 Bollenbach M, Salvat E, Daubeuf F, Wagner P, Yalcin I, Humo M, Letellier B, Becker LJ, Bihel F, Bourguignon J.-J, Villa P, Obrecht A, Frossard N, Barrot M, Schmitt M. Eur. J. Med. Chem. 2018; 147: 163
  • 18 Huang KH, Barta TE, Rice JW, Smith ED, Ommen AJ, Ma W, Veal JM, Fadden RP, Barabasz AF, Foley BE, Hughes PF, Hanson GJ, Markworth CJ, Silinski M, Partridge JM, Steed PM, Hall SE. Bioorg. Med. Chem. Lett. 2012; 22: 2550
  • 19 Huang X, Yang H, Fu H, Qiao R, Zhao Y. Synthesis 2009; 2679
  • 20 Chan DM. T, Monaco KL, Wang R.-P, Winters MP. Tetrahedron Lett. 1998; 39: 2933
  • 21 Evans DA, Katz JL, West TR. Tetrahedron Lett. 1998; 39: 2937
  • 22 Lam PY. S, Clark CG, Saubern S, Adams J, Winters MP, Chan DM. T, Combs A. Tetrahedron Lett. 1998; 39: 2941
  • 23 Chen J.-Q, Liu X, Guo J, Dong Z.-B. Eur. J. Org. Chem. 2020; 2414
  • 24 Liu X, Dong Z.-B. J. Org. Chem. 2019; 84: 11524
  • 25 Rodrigues R, Tran LQ, Darses B, Dauban P, Neuville L. Adv. Synth. Catal. 2019; 361: 4454
  • 26 Quinazolin-2-amine (3); Typical Procedure A mixture of guanidine hydrochloride (2a; 765 mg, 8 mmol) and KOH (441 mg, 8 mmol) was dissolved in MeOH (30 mL) and the mixture was stirred for 10 min at r.t. (2-Formylphenyl)boronic acid (1; 400 mg, 2.67 mmol) was added in one portion followed by CuI (76 mg, 0.4 mmol), and the resulting mixture was heated at 70 °C overnight. The mixture was then concentrated under reduced pressure and partitioned between aq NH3 (30 mL) and EtOAc (120 mL). The organic layer washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by trituration with EtOAc (3 mL) to give a slightly beige solid; yield: 198 mg (51%); mp 194–196 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 9.10 (s, 1 H), 7.78 (d, J = 8.9 Hz, 1 H), 7.67 (t, J = 8.5 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.21 (t, J = 7.9 Hz, 1 H), 6.82 (s, 2 H). 13C NMR (101 MHz, DMSO-d 6): δ = 162.4, 160.9, 151.2, 134.1, 127.9, 124.5, 122.0, 119.5. LC/MS: m/z [M + H]+ calcd for C8H8N3: 146.17; found: 146.16. The spectral data correspond to the reported values (see Ref. 10). N-Methylquinazolin-2-amine (5a) Prepared from (2-Formylphenyl)boronic acid (1) and N-methylguanidine hydrochloride (4a), and purified by column chromatography [silica gel, EtOAc–PE (20 to 50% gradient)] as a yellowish solid: yield: 134 mg (63%); mp 81–83 °C; Rf = 0.63 (EtOAc). 1H NMR (400 MHz, CDCl3): δ = 9.03 (s, 1 H), 7.72–7.56 (m, 3 H), 7.22 (t, J = 7.9 Hz, 1 H), 5.43 (br s, 1 H), 3.12 (d, J = 4.0 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 162.01, 160.50, 152.44, 134.37, 127.79, 125.83, 122.72, 120.75, 28.77. HRMS: m/z [M + H]+ calcd for C9H10N3: 160.0875; found: 160.0881. 6-(Benzyloxy)-N-methylquinazolin-2-amine (8b) Prepared from boronic acid 6b and N-methylguanidine hydrochloride (4a), and purified by column chromatography [silica gel, EtOAc–PE (20 to 60% gradient)] as a yellowish solid; yield: 150 mg (57%); mp 130–132 °C, Rf = 0.38 (50% EtOAc–PE). 1H NMR (400 MHz, CDCl3): δ = 8.88 (s, 1 H), 7.58 (d, J = 9.2 Hz, 1 H), 7.51–7.32 (m, 6 H), 7.05 (d, J = 2.8 Hz, 1 H), 5.23 (s, 1 H), 5.12 (s, 2 H), 3.10 (d, J = 5.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 160.67, 159.78, 154.12, 148.30, 136.70, 128.80, 128.28, 127.67, 127.23, 127.13, 120.32, 106.82, 70.55, 28.76. HRMS: m/z [M + H]+ calcd for C16H16N3O: 266.1293; found: 266.1292.
  • 27 Marcum JS, McGarry KA, Ferber CJ, Clark TB. J. Org. Chem. 2016; 81: 7963
  • 28 Vantourout JC, Law RP, Isidro-Llobet A, Atkinson SJ, Watson AJ. B. J. Org. Chem. 2016; 81: 3942

Zoom Image
Scheme 1 Synthesis 2-aminoquinazoline from a boronic acid ester and trifluoroborate
Zoom Image
Scheme 2 Attempt to condense keto-group-containing boronic acids with guanidine