Download PDF
Synthesis 2010(19): 3295-3300  
DOI: 10.1055/s-0030-1258202
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A New Method for the Synthesis of Iminoquinones via DMP-Mediated Oxidative Reaction

Hengchang Ma*a, Shang Wua, Qiangsheng Suna, Hongyan Lia, Yannan Chena, Wenqing Zhaoa, Bihui Maa, Qing Guoa, Ziqiang Lei*a, Jun Yanb
a Key Laboratory of Polymer Materials of Gansu Province, Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. of China
b Zhejiang HISUN Pharmaceut Co. Ltd, Taizhou, Zhejiang 318000, P. R. of China
Fax: +86(931)7970359; e-Mail: mahc@nwnu.edu.cn;

Further Information

Publication History

Received 20 May 2010
Publication Date:
13 August 2010 (online)

 PDF Download Permissions and Reprints All articles of this category

Abstract

Iminoquinones were synthesized by oxidation of primary and secondary amines with hypervalent iodine reagent Dess-Martin periodinane in average to good yields, and possible mechanisms were postulated. This methodology is convenient to establish a library of diversified iminoquinone compounds and has great significance for their potential application in the field of pharmaceuticals.

Key words

iodine - amines - oxidation - electron transfer - quinones - quinone monoimines

Hypervalent iodine compounds have proved to be mild and selective oxidizing agents in an impressive array of synthetic methodologies and have received much attention in recent years. 2-Iodoxybenzoic acid [IBX, 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide] was first synthesized in 1893; [¹] however, it was rarely used in organic synthesis until 1983 when Dess and Martin transformed IBX into the highly soluble Dess-Martin periodinane. [²]

Dess-Martin periodinane [DMP, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one] has emerged as the reagent of choice for the oxidation of primary and secondary alcohols to aldehydes and ketones. The synthetic applications of DMP have been highlighted in a number of reviews. [³] Its unique oxidizing properties and convenience of use have ensured the advance DMP to a widely employed reagent in the synthesis of biologically important natural products. Recently DMP was used in the key oxidation steps in the total syntheses of cyclo­theonamide B, [4] (±)-deoxypreussomerin A, [5] racemic brevioxime, [6] erythromycin B, [7] (+)-discodermolide, [8] (+)-cephalostatin 7, [9] (+)-cephalostatin 12, [9] (+)-ritterazine K, [9] 3-O-galloyl-(2R,3R)-epicatechin-4β,8-[3-O-galloyl-(2R,3R)-epicatechin], [¹0] fredericamycin A, [¹¹] indolizidine alkaloids (-)-205A, (-)-207A, and (-)-235B, [¹²] 1,19-aza-1,19-desoxy-avermectin B1a, [¹³] angucytcline antibiotics, [¹4] tricyclic β-lactam antibiotics, [¹5] and the platelet aggregation-inhibiting γ-lactam PI-091. [¹6]

The iminoquinone moiety is important in a large number of antineoplastic drugs and plays a significant role in the nucleus of actinomycins, which are powerful, highly toxic, natural antibiotics that target DNA as intercalating agents. [¹7] Recently, we reported an efficient synthetic approach to iminoquinone compounds via hypervalent iodine oxidation of primary amines. A variety of substituted primary amines were tested, and series of 2-amino-1,4-benzoquinone 4-phenylimines were obtained in excellent yields under mild conditions. [¹8] [¹9] In particular cases, two useful compounds 4,4′-diazenediyldianiline and 1-amino-5-aza-10,11-dithiadibenza[a,d]cyclohepten-2-one were obtained, which are of great potential application in the fields of chemosensors and photochemical switches as well as pharmaceuticals.

Our first attempts to establish the generality of DMP oxidized primary amine systems were inspiring. In ongoing research programs, we discerned that tetrabutylammonium bromide (TBAB) is useful in some cases of IBX- or DMP-involved oxidation transformations; it can be used as an activator for hypervalent iodine reagents. Initially, we applied tetrabutylammonium bromide as an additive in the 4-chloroaniline (1a)/DMP reaction system; thin-layer chromatography (TLC) indicated that the starting material had been consumed within two hours. Much to our interest, a different transformation had occurred. After isolation and characterization, the new compound was identified as brominated benzoquinone 2a (Scheme  [¹] ). Encouraged by this result, we next explored the scope of our newly developed process using various primary amines 1; the results are summarized in Figure  [¹] . It was demonstrated that several p-substituted anilines 1a-f were smoothly converted into the corresponding brominated benzoquinones 2a-f in average to good yields. In particular, in the case of p-halo-substituted anilines 1a,d-f, the one-step of oxidation and bromination was of excellent chemoselectivity. However, the limitation of our methodology was obvious. The position of substitution has a decisive impact on the transformation. With the exception of p-substituted anilines, other substituted anilines gave exclusively nonbrominated benzoquinone products or a mixture of both products.

Scheme 1 Synthesis and X-ray crystal structure of 2a [²0]

Figure 1

Akamanchi and co-workers reported a one-step procedure for preparation of brominated unsaturated carbonyl compounds. [²¹] In this case, the acetate ligand of DMP is probably transferred to tetrabutylammonium bromide forming an orange-yellow solution, which may be attributed to the formation of tetrabutylammonium diacetoxybromate I. Similarly, in our reaction system, it is envisaged that the bromate I [²²] is formed in the first instance and it undergoes addition to the double bond in II to form bromoacetoxylated intermediate III. The acetate ion formed in the reaction acts as a base to abstract hydrogen, which is acidic due as a result of C=N conjugation and the electronegativity of bromine atom, to furnish the final product brominated benzoquinone IV (Scheme  [²] ).

Scheme 2 The postulated mechanism

Recognizing that the scope and versatility of the reaction could be enhanced if the library of starting materials was expanded to other available compounds, our further explorations focused on the reaction of diphenylamines in the presence of DMP. Despite great efforts, the most highly substituted diphenylamine gave very complicated results under a variety of reaction conditions. Attempts to further improve the yield of the major products were thwarted by the increased production of side products. Conversely, in special cases, iminoquinones could be formed predominately by correct choice of the designated position and the nature of the specific functional group. When the diphenylamine contains a p-methoxy group, the reaction could be carried out successfully. Apart from this particular case, other alkoxy-substituted diphenylamines gave poor results, for instance, ethoxy, phenoxy, and vinyloxy. As a result, the remarkable collaboration of both NH and OMe groups renders this methodology to be one with unique chemoselectivity.

Our initial screening experiments chose 4-methoxy-2-methyl­-N-(2-tolyl)aniline (3a) as a model substrate (Table  [¹] ). Investigations on a variety of reaction conditions established that in the presence of a small amount of water (20% mol), 3a (1 mmol) and DMP (1.8 mmol) dissolved in dichloromethane (2 mL) and stirred at room temperature for five hours gave the desired product 4a in 87% yield (entry 10). We reasoned that the DMP partially hydrolyzed by small amount water is of stronger nucleophilicity. However, in aqueous media formation of compound 4a was suppressed, resulting in a more complicated product mixture. It also should be noted that when tetrabutylammonium bromide was applied as an additive, no brominated compound was observed, and also no apparent promotion effect was detected.

Table 1 Optimization of the Reaction Conditionsa

Entry DMP (mmol) Solvent Additive (mmol) Yield (%)
 1 1.0 CH2Cl2 - 27
 2 1.0 CHCl3 - 15
 3 1.0 acetone - 20
 4 1.0 CH2Cl2 H2O (0.2) 35
 5 1.0 H2O - -b
 6 1.0 CH2Cl2 TBAB (1.0) 26
 7 1.2 CH2Cl2 H2O (0.2) 64
 8 1.4 CH2Cl2 H2O (0.2) 74
 9 1.6 CH2Cl2 H2O (0.2) 70
10 1.8 CH2Cl2 H2O (0.2) 87
a 3a (1.0 mmol), solvent (2 mL), air atmosphere, r.t., 5 h.
b No reaction.

Having established suitable reaction conditions for the oxidation of diphenylamines with DMP, we proceeded to investigate the scope and limitation of this new methodology. A variety of p-methoxy-substituted diphenylamines 3 were employed, a selection of pertinent examples is displayed in Table  [²] . All diphenylamines 3a-i employed were converted into the corresponding iminoquinones 4a-i in good yields. In general, yields were higher for the multiply substituted diphenylamines than those for less-substituted diphenylamines. For instance, 4-methoxy-N-phenylaniline (3a), 4-methoxy-2-methyl-N-phenylaniline (3d), and N-(2-chlorophenyl)-4-methoxy­aniline (3h) as well as 4-methoxy-N-(biphenyl-4-yl)aniline (3i) gave the corresponding products 4 with average yields. Notably, the reactions were also significantly affected by the electronic properties of the substituents on the benzene ring. Electron-donating groups have evident positive effects. Methyl-substituted substrate 3c was converted into iminoquinone 4c in 65% yield (entry 3); however, for the chlorinated substrate 3h, the reaction was not only relatively sluggish (12 h), but also the isolated yield of 4h was less than 50% (entry 8). For the multiply substituted p-methoxy-substituted diphenylamines, high steric hindrance around the NH group demonstrated no negative effect and compounds 3a,e-g reacted to give the corresponding products 4a,e-g in high isolated yields in less than five hours.

Table 2 Scope of the Substrates 3 for the Formation of Iminoquinones 4 a
Entry Substrateb Time (h) Product Yieldc (%)
1

3a 		 5

4a 		87
2

3b 		 8

4b 		56
3

3c 		 5

4c 		65
4

3d 		 4

4d 		54
5

3e 		 3

4e 		78
6

3f 		 3

4f 		80
7

3g 		 3

4g 		84
8

3h 		12

4h 		47
9

3i 		12

4i 		54
a Substrates are commercially available and used without further purification.
b Conditions: substrate 3 (1.0 mmol), DMP (1.8 mmol), CH2Cl2 (2 mL), H2O (0.2 mmol), r.t.
c Yields indicate product obtained after column chromatography.

Based on a previous report, [²³] we proposed a pathway based on single electron transfer (SET) mechanism (Scheme  [³] ). The hydrolyzed DMP reagent Ac-IBX acts as an extraordinary oxidant which then initiates the single electron transfer from substrate 3b to give intermediate V. After releasing the hydrogen proton, V should rapidly lead to species VI, the resultant free radical VI was probably less stable than its resonance form VII, with the single electron located at the methoxy-attached carbon. Consequently, because of the potential urgency to form a larger conjugative effect, the methyl radical was freed from intermediate VII, and the final product 4b was achieved.

Scheme 3 The postulated mechanism

In conclusion, from the transformation of two classes of amines, iminoquinones were obtained; in particular the brominated products lend themselves to establish easily a library of diversified iminoquinones. The significance of this reaction gives iminoquinones a more important place in the field of potential pharmaceuticals applications. Meanwhile, the apparent collaboration of the specific structure and designated position of functional groups in the aromatic rings gives this methodology unique chemoselectivity.

All NMR spectra were recorded on a Brüker Avance Digital spectrometer [400 MHz (¹H), 100 MHz (¹³C)]; TMS as the internal reference in CDCl3. IR spectra were recorded on a Shimadzu IR-408 spectrometer. Mass spectra were recorded on a HP5989B mass spectrometer. Melting points were uncorrected. Room temperature = 15-25˚C.

Brominated Benzoquinones 2; General Procedure

To a soln of DMP (1.3 g, 2.64 mmol) in CH2Cl2 (5 mL) was added TBAB (0.64 g, 2.0 mmol) and aniline 1 (1.5 mmol). The mixture was stirred at r.t. until complete consumption of the aniline (TLC). The soln was washed with H2O (3 × 5 mL) and the organic phase was dried (anhyd Na2SO4). After filtration, the solvent was removed and the residue was purified by column chromatography (silica gel) to afford a soln 2, which was volatilized at r.t. for period during which time crystallized compounds were formed.

Benzoquinones 4; General Procedure

To a soln of DMP (0.89 g, 1.8 mmol) in CH2Cl2 (5 mL) was added aniline 3 (1.0 mmol) and H2O (0.2 mmol) was added dropwise. The mixture was stirred at r.t. until complete consumption of the aniline (TLC), and purified by column chromatography (silica gel) to afford 4.

2-Amino-3-bromo-5-chloro-4-(4-chlorophenylimino)cyclohexa-2,5-dienone (2a)

Red solid; mp 150-152 ˚C.

IR (KBr): 3477, 3385, 1650, 1618, 1575, 1460, 1200, 1055, 1021, 975, 868 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.32-7.27 (m, 2 H), 6.89 (s, 1 H), 6.76-6.72 (m, 2 H), 5.21 (s, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 181.2, 157.3, 150.8, 147.2, 132.8, 130.2, 123.7, 119.6, 117.6, 110.5.

MS (FAB): m/z = 345.9 [M + H]+.

Anal. Calcd for C12H7BrCl2N2O: C, 41.65; H, 2.04; N, 8.10. Found: C, 41.68; H, 2.08; N, 7.93.

2-Amino-3-bromo-5-methyl-4-(4-tolylimino)cyclohexa-2,5-dienone (2b)

Red solid; mp 138-140 ˚C.

IR (KBr): 3485, 3364, 1650, 1612, 1545, 1460, 1210, 1165, 1080, 865, 838 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.14-7.12 (d, J = 8.0 Hz, 2 H), 6.68-6.66 (d, J = 8.0 Hz, 2 H), 6.48 (s, 1 H), 5.10 (s, 2 H), 2.34 (s, 6 H).

¹³C NMR (100 MHz, CDCl3): δ = 179.8, 150.8, 143.9, 133.4, 129.1, 126.2, 118.8, 118.6, 117.7, 117.6, 29.6, 20.9.

MS (FAB): m/z = 304.0 [M + H]+.

2-Amino-3,5-dibromo-4-(4-bromophenylimino)cyclohexa-2,5-dienone (2d)

Red solid; mp 147-149 ˚C.

IR (KBr): 3476, 3380, 1662, 1620, 1580, 1460, 1210, 1010, 1000, 985, 856 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.35-7.29 (m, 2 H), 6.87 (s, 1 H), 6.74-6.70 (m, 2 H), 5.24 (s, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 182.2, 156.4, 155.8, 143.2, 130.8, 130.2, 124.8, 119.2, 116.6, 110.4.

MS (FAB): m/z = 433.8 [M + H]+.

2-Amino-3-bromo-5-iodo-4-(4-iodophenylimino)cyclohexa-2,5-dienone (2e)

Red solid; mp 155-157 ˚C.

IR (KBr): 3480, 3370, 1650, 1600, 1575, 1458, 1232, 1000, 975, 862 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.42-7.32 (m, 2 H), 6.77 (s, 1 H), 6.75-6.72 (m, 2 H), 5.35 (s, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 182.2, 156.4, 155.8, 143.2, 130.8, 130.2, 124.8, 119.2, 116.6, 110.4.

MS (FAB): m/z = 527.8 [M + H]+.

3-Methyl-4-(2-tolylimino)cyclohexa-2,5-dienone (4a)

Red oil.

IR (KBr): 3356, 1650, 1612, 1570, 1480, 1356, 1034, 766, 654 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.11 (s, 1 H), 7.01-6.98 (d, J = 9.6 Hz, 2 H), 6.57 (s, 1 H), 6.49-6.42 (m, 3 H), 2.33 (s, 3 H), 2.16 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 178.0, 156.1, 148.6, 145.5, 135.3, 133.3, 131.4, 130.4, 129.4, 128.7, 123.6, 118.8, 20.9, 17.9.

MS (FAB): m/z = 211.1 [M + H]+.

4-(Phenylimino)cyclohexa-2,5-dienone (4b)

Red oil.

IR (KBr): 3358, 1650, 1600, 1580, 1453, 1432, 875, 863 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.40-7.39 (t, J = 8.0, 7.6 Hz, 2 H), 7.32-7.22 (m, 2 H), 7.10-7.07 (dd, J = 2.4 Hz 1 H), 6.89-6.87 (d, J = 8.0 Hz, 2 H), 6.71-6.68 (dd, J = 2.0 Hz 1 H), 6.55-6.52 (m, 1 H).

¹³C NMR (100 MHz, CDCl3): δ = 187.5, 157.3, 149.3, 141.8, 133.4, 128.9, 126.1, 120.6.

MS (FAB): m/z = 183.1 [M + H]+.

4-(4-Tolylimino)cyclohexa-2,5-dienone (4c)

Red oil.

IR (KBr): 3346, 1648, 1612, 1580, 1467, 1438, 981, 865, 821 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.50 (s, 1 H), 7.39-7.37 (m, 1 H), 7.24-7.22 (d, J = 8.0 Hz, 1 H), 7.16-7.13 (m, 1 H), 6.96-6.93 (dd, J = 2.4 Hz, 1 H), 6.83-6.81 (d, J = 8.0 Hz, 1 H), 6.73-6.67 (m, 1 H), 6.55-6.52 (m, 1 H), 2.37 (S, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 187.7, 158.4, 145.3, 133.4, 129.6, 128.2, 121.0, 120.5, 20.5.

MS (FAB): m/z = 197.1 [M + H]+.

3-Methyl-4-(phenylimino)cyclohexa-2,5-dienone (4d)

Red oil.

IR (KBr): 3346, 1648, 1612, 1580, 1467, 1438, 981, 865, 821 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.40-7.36 (t, J = 7.6 Hz, 2 H), 7.22-7.18 (t, J = 8.0 Hz, 1 H), 7.08-6.94 (m, 1 H), 6.84-6.82 (d, J = 7.6 Hz, 2 H), 6.55 (s, 1 H), 6.44-6.41 (m, 1 H), 2.27 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 187.7, 157.7, 149.5, 149.4, 132.6, 130.8, 128.8, 128.5, 125.6, 119.9, 18.0.

MS (FAB): m/z = 197.1 [M + H]+.

4-(2,4-Dimethylphenylimino)-3-methylcyclohexa-2,5-dienone (4e)

Red oil.

IR (KBr): 3348, 1658, 1600, 1580, 1478, 1369, 1002, 756, 654 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.09 (s, 1 H), 7.02-6.99 (d, J = 9.6 Hz, 2 H), 6.57 (s, 1 H), 6.49-6.42 (m, 2 H), 2.35 (s, 3 H), 2.33 (s, 3 H), 2.15 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 188.0, 157.1, 149.6, 145.9, 135.8, 132.3, 131.4, 130.6, 129.6, 128.7, 126.6, 118.8, 20.9, 18.1, 17.9.

MS (FAB): m/z = 225.1 [M + H]+.

4-(4-Methoxy-2-methylphenylimino)-3-methylcyclohexa-2,5-dienone (4f)

Red oil.

IR (KBr): 3356, 1660, 1612, 1585, 1450, 1365, 1012, 778, 754 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.07 (s, 1 H), 7.02-6.99 (d, J = 9.6 Hz, 2 H), 6.57 (s, 1 H), 6.48-6.42 (m, 2 H), 3.73 (s, 3 H), 2.36 (s, 3 H), 2.13 (s, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 187.0, 156.1, 148.6, 145.5, 136.8, 134.3, 131.4, 130.4, 129.2, 128.4, 126.6, 116.8, 54.9, 18.1, 17.9.

MS (FAB): m/z = 241.1 [M + H]+.

4-(2,6-Dimethylphenylimino)-3-methylcyclohexa-2,5-dienone (4g)

Red oil.

IR (KBr): 3350, 1648, 1600, 1570, 1488, 1374, 1012, 764, 664 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.07-7.05 (d, J = 8.0 Hz, 2 H), 6.99-6.97 (m, 1 H), 6.63-6.60 (d, J = 10.0 Hz, 1 H), 6.56 (s, 1 H), 6.37-6.34 (m, 1 H), 2.36 (s, 3 H), 1.96 (s, 6 H).

¹³C NMR (100 MHz, CDCl3): δ = 187.6, 158.8, 149.0, 147.8, 132.6, 130.9, 128.3, 127.8, 124.8, 124.3, 18.1, 17.9.

MS (FAB): m/z = 225.1 [M + H]+.

4-(2-Chlorophenylimino)cyclohexa-2,5-dienone (4h)

Red oil.

IR (KBr): 3358, 1652, 1600, 1589, 1478, 1465, 1121, 876, 769, 664 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.49-7.47 (m, 1 H), 7.39-7.36 (m, 1 H), 7.32-7.28 (m, 1 H), 7.20-7.15 (m, 1 H), 6.91-6.88 (m, 1 H), 6.79-6.77 (m, 1 H), 6.74-6.71 (m, 1 H), 6.55-6.52 (m, 1 H).

¹³C NMR (100 MHz, CDCl3): δ = 187.2, 158.8, 146.5, 141.2, 133.6, 133.2, 130.1, 128.3, 127.1, 126.6, 124.6, 120.7.

MS (FAB): m/z = 217.0 [M + H]+.

4-(Biphenyl-4-ylimino)cyclohexa-2,5-dienone (4i)

Red oil.

IR (KBr): 3358, 1650, 1610, 1586, 1478, 1454, 1006, 965, 875 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.67-7.62 (m, 4 H), 7.49-7.45 (t, J = 7.6 Hz, 2 H), 7.40-7.32 (m, 2 H), 7.21-7.18 (m, 1 H), 7.01-6.99 (d, J = 8.4 Hz, 2 H), 6.74-6.71 (dd, J = 2.0 Hz, 1 H), 6.59-6.56 (dd, J = 2.4 Hz, 1 H).

¹³C NMR (100 MHz, CDCl3): δ = 187.6, 157.4, 148.5, 141.8, 140.0, 139.3, 133.4, 132.8, 128.9, 127.7, 126.9, 121.5.

MS (FAB): m/z = 259.1 [M + H]+.

Acknowledgment

We are grateful for the financial support of the National Natural Science­ Foundation of China (No.20376071, No. 20674063 and 20774074) and Young Teacher Research Foundation of Northwest Normal University (NWNU-LKQN-08-8, NWNU-kjcxgc-03-73). We also thank Key Laboratory of Eco-Environment-Related Polymer Materials (Northwest Normal University), Ministry of Education, for financial support.

20

CCDC 643540 contains supplementary crystallographic data for compound 2a; data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

20

CCDC 643540 contains supplementary crystallographic data for compound 2a; data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

   Permissions and Reprints All articles of this category

Scheme 1 Synthesis and X-ray crystal structure of 2a [²0]

Figure 1

Scheme 2 The postulated mechanism

Scheme 3 The postulated mechanism