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

Key words

guanidines - Chan–Evans–Lam coupling - quinazolines - copper catalysis - formylphenylboronic 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 S_NAr 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 4a–g and N,N-disubstituted guanidines (4h–j) provided the corresponding 2-aminoquinazolines 5a–j 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 6a–f were next explored as substrates for the synthesis of aminoquinazolines 7a–f and 8a–f (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

Scheme 1 Synthesis 2-aminoquinazoline from a boronic acid ester and trifluoroborate

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.

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• 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; R_f = 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, R_f = 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.
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