CC BY ND NC 4.0 · SynOpen 2018; 02(01): 0050-0057
DOI: 10.1055/s-0036-1591932
paper
Copyright with the author

Synthesis of Sterically Protected Isoindoles from ortho-Phthalaldehyde

Michiyasu Nakao
a  Graduate School of Pharmaceutical Sciences, Tokushima University, Sho-machi, Tokushima 770-8505, Japan   Email: ssano@tokushima-u.ac.jp
,
Nanako Nishikiori
a  Graduate School of Pharmaceutical Sciences, Tokushima University, Sho-machi, Tokushima 770-8505, Japan   Email: ssano@tokushima-u.ac.jp
,
Akihito Nakamura
a  Graduate School of Pharmaceutical Sciences, Tokushima University, Sho-machi, Tokushima 770-8505, Japan   Email: ssano@tokushima-u.ac.jp
,
Murasaki Miyagi
a  Graduate School of Pharmaceutical Sciences, Tokushima University, Sho-machi, Tokushima 770-8505, Japan   Email: ssano@tokushima-u.ac.jp
,
Nao Shibata
a  Graduate School of Pharmaceutical Sciences, Tokushima University, Sho-machi, Tokushima 770-8505, Japan   Email: ssano@tokushima-u.ac.jp
,
Syuji Kitaike
a  Graduate School of Pharmaceutical Sciences, Tokushima University, Sho-machi, Tokushima 770-8505, Japan   Email: ssano@tokushima-u.ac.jp
,
Makoto Fukui
b  Department of Preventive Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8504, Japan
,
Hiro-O Ito
b  Department of Preventive Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8504, Japan
,
Shigeki Sano*
a  Graduate School of Pharmaceutical Sciences, Tokushima University, Sho-machi, Tokushima 770-8505, Japan   Email: ssano@tokushima-u.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 05 December 2017

Accepted after revision: 15 January 2018

Publication Date:
20 February 2018 (online)

 

Abstract

o-Phthalaldehyde (OPA) reacts with O-protected tris(hydroxyalkyl)aminomethanes in the presence of 1-propanethiol to afford a novel class of stable isoindoles. Steric protection provided by the bulkiness of C 3-symmetric primary amines derived from tris(hydroxymethyl)aminomethane could be significant for the stabilization of 1-alkylthio-2-alkyl-substituted isoindoles derived from OPA. A plausible reaction mechanism is proposed to explain the formation of the isoindole and an isoindolin-1-one by-product.


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Benzo[c]pyrrole, also called isoindole,[1] is a regioisomer of benzo[b]pyrrole or, more commonly, indole. In 1971, Roth reported that o-phthalaldehyde (OPA) reacted with amino acids in alkaline medium in the presence of 2-mercaptoethanol to furnish 1-alkylthio-2-alkyl-substituted isoindoles (Scheme [1]).[2] As the resultant isoindole is sensitively detected by its fluorescence (λex = 360 nm, λem = 455 nm), the three-component coupling reaction is generally used as one of the most valuable methods of analyzing primary amines including amino acids.[3] [4] In the OPA method mentioned above, the intrinsically nonfluorescent property of OPA is advantageous to the analysis of primary amines, while a drawback is the instability of the resulting 1-alkylthio-2-alkyl-substituted isoindoles, despite isoindole having a 10π-electron aromatic system. It is said that the steric bulk of the side chains derived from thiols and amines, such as tert-butylamine and tert-butylthiol, increases the stability of the isoindoles.[5] In general, appropriate steric protection of organic molecules is an effective strategy for stabilization.[6] [7] However, from a synthetic point of view, the stabilization effects of these reagents are insufficient to isolate the resulting 1-alkylthio-2-alkyl-substituted isoindoles in pure forms. To the best of our knowledge, few reports are available on the synthesis of stable and isolable 1-alkylthio-2-alkyl-substituted isoindoles based on the OPA method. In 2012, Sipos et al. reported the synthesis and biological activities of isoindole and benzoisoindole derivatives of glycopeptide antibiotics, which have large molecular sizes and function as primary amines in the OPA method.[8] In this paper, we report on the synthesis of sterically protected 1-alkylthio-2-alkyl-substituted isoindoles using C 3-symmetric bulky amines derived from tris(hydroxyalkyl)aminomethane based on the OPA method. HPLC analysis of a mixture of stable isoindoles derived from alkyl thiols, OPA, and O-benzylated tris(hydroxypropyl)aminomethane was also conducted.

Zoom Image
Scheme 1 The reaction of OPA with a primary amine and thiol

A novel series of 1-alkylthio-2-alkyl-substituted isoindoles, which are stable enough to be isolated, has been designed and synthesized, making use of C 3-symmetric primary amines in the OPA method. The C 3-symmetric primary amines employed in this study were chosen to enhance the steric protection effect in isoindole molecules by further increasing the steric bulk of the tert-butylamine. Thus, a series of C 3-symmetric primary amines 5ag was prepared from tris(hydroxymethyl)aminomethane (1) or tris(hydroxypropyl)aminomethane (2), as shown in Scheme [2]. N,N-Dibenzyl tris(hydroxymethyl)aminomethane (3) was synthesized from 1 using benzyl bromide according to a modified procedure.[9] O-Alkylation of 3 with alkyl iodides followed by hydrogenolysis catalyzed by palladium on activated charcoal (Pd-C) gave primary amines 5a and 5b, respectively. N-Boc-tris(hydroxymethyl)aminomethane (6),[10] obtained from 1, was O-alkylated by the corresponding alkyl chlorides to afford N-Boc-protected amines 7ce. Deprotection of 7ce using trifluoroacetic acid (TFA) gave primary amines 5ce. O-Benzylated amine 5f was also synthesized from 2 according to a similar procedure used for the preparation of 5ce. In addition, reaction of 3 with triethyl orthoacetate followed by removal of the benzyl groups by hydrogenolysis furnished 5g,[11] which was regarded as a less bulky primary amine than the other O-protected amines 5af.

Zoom Image
Scheme 2 Synthesis of C 3-symmetric primary amines 5ag starting from tris(hydroxymethyl)aminomethane (1) and tris(hydroxypropyl)amino­methane (2)

Table 1 Synthesis of 1-Alkylthio-2-alkyl-Substituted Isoindoles 11ai by the OPA Methoda

Entry

X

Yield of 11 (%)b

Yield of 12 (%)b

1

OMe (5a)

65 (11a)

18 (12a)

2

OEt (5b)

85 (11b)

12 (12b)

3

OMOM (5c)

57 (11c)

41 (12c)

4

OMEM (5d)

54 (11d)

44 (12d)

5

OBOM (5e)

60 (11e)

39 (12e)

6

(CH2)2OBn (5f)

93 (11f)

ca. 6 (12f)c

7

orthoester (5g)

d (11g)

0 (12g)

8

OH (1)

d (11h)

0 (12h)

9

(CH2)2OH (2)

90 (11i)

0 (12i)

10e

OMOM (5c)

– (11c)

56 (12c)

11e

(CH2)2OH (2)

– (11i)

0 (12i)

a Reaction conditions: OPA (1 equiv), 1-propanethiol (1.1 equiv), amine (1.1 equiv).

b Isolated yield.

c Small amounts of impurities were included.

d Too labile to be isolated.

e Reaction without 1-propanethiol.

In our attempt to synthesize stable and isolable 1-alkylthio-2-alkyl-substituted isoindoles by the OPA method, C 3-symmetric primary amines 1, 2, and 5ae were reacted with OPA and 1-propanethiol in anhydrous MeOH at room temperature in the dark using brown-tinted glassware as shown in Table [1]. O-Protected amines 5a,b afforded isoindoles 11a,b with small amounts of isoindolin-1-ones 12a,b as by-products (entries 1 and 2). As expected, isoindoles 11a,b were stable and isolable by column chromatography on silica gel. When amines 5ce were employed, the isolated yields of isoindoles 11ce (54–60%) were relatively low, and isoindolin-1-ones 12ce were obtained in 39–44% yields (entries 3–5). To examine the influence of the oxygen atom of C 3-symmetric amine 5e originating from 1 on the formation of isoindolin-1-one 12e, O-benzylated tris(hydroxypropyl)aminomethane 5f was reacted with OPA and 1-propanethiol. As a result, 5f afforded isoindole 11f in 93% yield and isoindolin-1-one 12f in ca. 6% yield (entry 6). On the other hand, isoindole 11g, synthesized from less bulky amine 5g, was too labile to be isolated (entry 7). In the reaction of triols 1 and 2, the 1-alkylthio-2-alkyl-substituted isoindoles 11h and 11i were also obtained, but 11h decomposed immediately after isolation by column chromatography on silica gel (entries 8 and 9). In addition, the reaction of OPA with amine 5c in the absence of 1-propanethiol was relatively slow and afforded isoindolin-1-one 12c in 56% yield (entry 10). In the reaction of 2 and OPA without 1-propanethiol, isoindolin-1-one 12i was not obtained at all (entry 11). When isoindole 11c, instead of OPA, was placed under the same reaction conditions as those noted in entry 3, 86% yield of 11c was recovered without production of 12c. Thus, the formation of isoindolin-1-one 12c is presumed not to be attributable to the hydrolysis of 11c under these reaction conditions.

Zoom Image
Scheme 3 Plausible reaction pathways for the formation of 11ae and 12ae
Zoom Image
Figure 1 HPLC analysis for resolution of a mixture of isoindoles 11f, 11j, and 11k formed from 1-propanethiol, 1-octanethiol, and 1-dodecanethiol, respectively

Based on these results, plausible reaction pathways for the formation of isoindoles 11ae (route A) and isoindolin-1-ones 12ae (route B) have been proposed (Scheme [3]). Route A is the standard pathway for the three-component coupling reaction based on the OPA method.[5] On the other hand, neighboring group participation by an oxygen atom of the ether bond of each of amines 5ae is involved in route B. In this case, the formation of the five-membered 1,3-oxazolidin-1-ium intermediate by intramolecular cyclization prevents intermolecular nucleophilic attack of 1-propanethiol. The ratios of the products of 11ae and 12ae seem to depend on the bond angle θ (N-C-C) of the corresponding C 3-symmetric primary amines 5ae. Amines 5ce, which are presumed to have smaller θ values compared with 5a and 5b, are liable to follow pathway B. In the case of amine 5f, in which three oxygen atoms of 5e are replaced by three methylene units, this kind of neighboring group participation of an oxygen atom via a seven-membered 1,3-oxazepan-1-ium intermediate might be difficult to achieve.

Furthermore, 1-octanethiol and 1-dodecanethiol readily reacted with OPA and 5f to afford stable and isolable isoindoles 11j and 11k in 96% and 91% yields, respectively. To provide some preliminary data on the application as a novel method of analyzing thiols, HPLC analysis of an equimolar mixture of isoindoles 11f, 11j, and 11k was investigated with an ODS column. The results showed that isoindoles 11f, 11j, and 11k were easily resolved from one another, as shown in Figure [1]. The area ratio for these three peaks derived from isoindoles 11f, 11j, and 11k (32.35:33.94:33.18) was almost identical to the respective molar ratio (1:1:1).

In summary, we have synthesized a novel series of 1-alkylthio-2-alkyl-substituted isoindoles 11af and 11ik by the three-component coupling reaction of OPA, thiols (1-propanethiol, 1-octanethiol, and 1-dodecanthiol), and C 3-symmetric bulky amines 2 and 5af. These isoindoles were stable enough to be isolated by column chromatography over silica gel. To the best of our knowledge, this is the first report of the synthesis of stable and isolable isoindoles based on the OPA method using modest molecular weight amines. Efforts toward the development of a novel analytical method for thiols by employing the formation of sterically protected isoindoles based on the OPA method are under way.

All melting points were determined with a Yanagimoto micro melting point apparatus and are uncorrected. IR spectra were obtained with a JASCO FT/IR-6200 IR Fourier transform spectrometer. 1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were recorded with a Bruker AV500 spectrometer. Chemical shifts are given in δ values (ppm) using TMS as an internal standard. HRMS (ESI) were recorded with a Waters LCT Premier spectrometer. Elemental combustion analyses were performed with a J-SCIENCE LAB JM10 microcorder. All reactions were monitored by TLC employing 0.25 mm silica gel plates (Merck 5715; 60 F254). Column chromatography was carried out on silica gel [Silica Gel 60N (Kanto Chemical) or Silica Gel PSQ 60B (Fuji Silysia Chemical)]. Anhydrous THF, CH2Cl2, DMF, and toluene were used as purchased from Kanto Chemical. All other reagents were used as purchased.


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N,N-Dibenzyl-1,3-dimethoxy-2-(methoxymethyl)propan-2-amine (4a)

To a suspension of NaH (50–72% in mineral oil, 394 mg, 8.21–11.8 mmol) in anhydrous DMF (5 mL) was added 3 (900 mg, 2.99 mmol) in anhydrous DMF (5 mL) and MeI (614 μL, 9.85 mmol). The reaction mixture was stirred at r.t. for 4 h under argon. H2O (10 mL) was added and the reaction mixture was extracted with EtOAc (50 mL). The organic layer was washed with H2O (3 × 20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The oily residue was purified by column chromatography [silica gel 60N; n-hexane–EtOAc, 9:1] to afford 4a.

Yield: 922 mg (90%); pale-yellow oil.

IR (neat): 3026, 2980, 2889, 2810, 2059, 1946, 1869, 1810, 1603, 1453, 1107 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.27–7.26 (m, 4 H), 7.16–7.13 (m, 4 H), 7.08–7.05 (m, 2 H), 3.98 (s, 4 H), 3.52 (s, 6 H), 3.25 (s, 9 H).

13C NMR (125 MHz, CDCl3): δ = 142.4, 128.4, 127.6, 126.0, 73.6, 64.0, 59.1, 54.8.

HRMS (ESI): m/z [M + Na]+ calcd for C21H29NO3Na: 366.2045; found: 366.2031.

Anal. Calcd for C21H29NO3: C, 73.44; H, 8.51; N, 4.08. Found: C, 73.15; H, 8.65; N, 4.09.


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N,N-Dibenzyl-1,3-diethoxy-2-(ethoxymethyl)propan-2-amine (4b)

Synthesized from 3 and ethyl iodide according to the procedure used to prepare 4a.

Yield: 467 mg (84%); pale-yellow oil.

IR (neat): 2974, 2867, 1494, 1454, 1377, 1113 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.29–7.26 (m, 4 H), 7.15–7.12 (m, 4 H), 7.07–7.04 (m, 2 H), 4.00 (s, 4 H), 3.55 (s, 6 H), 3.38 (q, J = 7.0 Hz, 6 H), 1.16 (t, J = 7.0 Hz, 9 H).

13C NMR (125 MHz, CDCl3): δ = 142.8, 128.4, 127.5, 125.8, 71.3, 66.6, 64.1, 54.8, 15.2.

HRMS (ESI): m/z [M + Na]+ calcd for C24H35NO3Na: 408.2515; found: 408.2504.

Anal. Calcd for C24H35NO3: C, 74.77; H, 9.15; N, 3.63. Found: C, 74.62; H, 9.31; N, 3.58.


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1,3-Dimethoxy-2-(methoxymethyl)propan-2-amine (5a)

A mixture of 4a (270 mg, 0.790 mmol) and 10% Pd/C (84.0 mg, 0.0790 mmol) in MeOH (10 mL) was stirred at r.t. for 1.5 h under H2 atmosphere. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in CHCl3 (30 mL) and washed with sat. aq NaHCO3 (20 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to afford 5a.

Yield: 118 mg (91%); pale-yellow oil.

IR (neat): 3383, 2980, 2892, 2814, 1456, 1109 cm–1.

1H NMR (500 MHz, CDCl3): δ = 3.35 (s, 9 H), 3.29 (s, 6 H), 1.52 (br s, 2 H).

13C NMR (125 MHz, CDCl3): δ = 75.0, 59.4, 55.7.

HRMS (ESI): m/z [M + Na]+ calcd for C7H17NO3Na: 186.1106; found: 186.1091.


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1,3-Diethoxy-2-(ethoxymethyl)propan-2-amine (5b)

Synthesized from 4b according to the procedure used to prepare 5a.

Yield: 170 mg (91%); pale-yellow oil.

IR (neat): 3385, 2976, 2867, 1110, 864 cm–1.

1H NMR (500 MHz, CDCl3): δ = 3.49 (q, J = 7.0 Hz, 6 H), 3.33 (s, 6 H), 1.55 (br s, 2 H), 1.17 (t, J = 7.0 Hz, 9 H).

13C NMR (125 MHz, CDCl3): δ = 72.6, 66.8, 55.7, 15.1.

HRMS (ESI): m/z [M + Na]+ C10H23NO3Na: 228.1576; found: 228.1565.


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tert-Butyl [1,3-Dihydroxy-2-(hydroxymethyl)propan-2-yl]carbamate (6)[10b]

To a solution of 1 (2.00 g, 16.5 mmol) in t-BuOH (27.5 mL)/MeOH (12.5 mL) was added di-tert-butyl dicarbonate (4.70 g, 21.5 mmol). After stirring for 18 h at r.t., the reaction mixture was evaporated in vacuo and the residue was washed with cool EtOAc to afford 6.

Yield: 3.52 g (96%); white solid; mp 142.7–145 °C (colorless needles, EtOAc).

IR (KBr): 3300, 2962, 1680, 1549, 1468, 1369, 1296, 1176 cm–1.

1H NMR (500 MHz, DMSO-d 6): δ = 5.76 (br s, 1 H), 4.50 (t, J = 5.3 Hz, 3 H), 3.51 (d, J = 5.6 Hz, 6 H), 1.37 (s, 9 H).

13C NMR (125 MHz, DMSO-d 6): δ = 154.9, 77.7, 60.3, 60.1, 28.1.

HRMS (ESI): m/z [M + Na]+ calcd for C9H19NO5Na: 244.1161; found: 244.1141.

Anal. Calcd for C9H19NO5: C, 48.86; H, 8.66; N, 6.33. Found: C, 48.73; H, 8.68; N, 6.31.


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tert-Butyl {6-[(Methoxymethoxy)methyl]-2,4,8,10-tetraoxaundecan-6-yl}carbamate (7c)

To a solution of 6 (500 mg, 2.26 mmol) and DIPEA (1.30 mL, 7.46 mmol) in anhydrous THF (6.6 mL) was added MOMCl (0.790 mL, 7.46 mmol). After stirring for 2 h at r.t., DIPEA (1.30 mL, 7.46 mmol) and MOMCl (0.790 mL, 7.46 mmol) were added to the reaction mixture. After stirring for a further 2 h at r.t., DIPEA (1.30 mL, 7.46 mmol) and MOMCl (0.790 mL, 7.46 mmol) were again added to the reaction mixture. After stirring for a final 2 h at r.t., the reaction mixture was evaporated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with brine (2 × 20 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The oily residue was purified by column chromatography [silica gel PSQ 60B; n-hexane–EtOAc, 2:1] to afford 7c.

Yield: 796 mg (100%); pale-yellow oil.

IR (neat): 3450, 3359, 2934, 2889, 2824, 1718, 1502, 1366, 1245, 1150, 1112, 1047 cm–1.

1H NMR (500 MHz, CDCl3): δ = 5.03 (br s, 1 H), 4.63 (s, 6 H), 3.82 (s, 6 H), 3.36 (s, 9 H), 1.42 (s, 9 H).

13C NMR (125 MHz, CDCl3): δ = 154.7, 96.8, 79.1, 67.1, 57.8, 55.3, 28.3.

HRMS (ESI): m/z [M + Na]+ calcd for C15H31NO8Na: 376.1947; found: 376.1922.

Anal. Calcd for C15H31NO8: C, 50.98; H, 8.84; N, 3.96. Found: C, 50.68; H, 8.83; N, 4.02.


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tert-Butyl (9-{[(2-Methoxyethoxy)methoxy]methyl}-2,5,7,11,13,16-hexaoxaheptadecan-9-yl)carbamate (7d)

Synthesized from 6 and MEMCl according to the procedure used to prepare 7c.

Yield: 576 mg (87%); pale-yellow oil.

IR (neat): 3450, 3348, 2931, 2885, 1716, 1500, 1456, 1366, 1246, 1173, 1116, 1045 cm–1.

1H NMR (500 MHz, CDCl3): δ = 5.08 (br s, 1 H), 4.71 (s, 6 H), 3.82 (s, 6 H), 3.69–3.67 (m, 6 H), 3.56–3.54 (m, 6 H), 3.39 (s, 9 H), 1.41 (s, 9 H).

13C NMR (125 MHz, CDCl3): δ = 154.7, 95.9, 79.1, 71.7, 67.3, 66.9, 59.0, 57.9, 28.3.

HRMS (ESI): m/z [M + Na]+ calcd for C21H43NO11Na: 508.2734; found: 508.2727.


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tert-Butyl (6-{[(Benzyloxy)methoxy]methyl}-1,11-diphenyl-2,4,8,10-tetraoxaundecan-6-yl)carbamate (7e)[10b]

Synthesized from 6 and BOMCl according to the procedure used to prepare 7c.

Yield: 481 mg (61%); pale-yellow oil.

IR (neat): 3436, 3063, 3032, 2939, 2885, 1716, 1498, 1366, 1170, 1112, 1046 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.34–7.27 (m, 15 H), 5.01 (br s, 1 H), 4.76 (s, 6 H), 4.59 (s, 6 H), 3.91 (s, 6 H), 1.41 (s, 9 H).

13C NMR (125 MHz, CDCl3): δ = 154.7, 137.7, 128.4, 127.9, 127.7, 95.0, 79.2, 69.4, 67.4, 57.9, 28.4.

HRMS (ESI): m/z [M + Na]+ calcd for C33H43NO8Na: 604.2886; found: 604.2878.


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6-[(Methoxymethoxy)methyl]-2,4,8,10-tetraoxaundecan-6-amine (5c)

To a solution of 7c (400 mg, 1.13 mmol) in anhydrous CH2Cl2 (5.5 mL) was added TFA (2.00 mL, 26.0 mmol) at 0 °C. After stirring for 50 min at 0 °C, 2N Na2CO3 (25 mL) was added and the mixture was extracted with CHCl3 (3 × 30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The oily residue was purified by column chromatography [silica gel PSQ 60B; CHCl3–MeOH, 9:1] to afford 5c.

Yield: 272 mg (95%); pale-yellow oil.

IR (neat): 3378, 2929, 2885, 1587, 1467, 1442, 1403, 1213, 1149, 1110, 1040 cm–1.

1H NMR (500 MHz, CDCl3): δ = 4.64 (s, 6 H), 3.49 (s, 6 H), 3.36 (s, 9 H), 1.56 (br s, 2 H).

13C NMR (125 MHz, CDCl3): δ = 96.8, 69.9, 55.3, 55.2.

HRMS (ESI): m/z [M + Na]+ calcd for C10H23NO6Na: 276.1423; found: 276.1401.


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9-{[(2-Methoxyethoxy)methoxy]methyl}-2,5,7,11,13,16-hexaoxaheptadecan-9-amine (5d)

Synthesized from 7d according to the procedure used to prepare 5c.

Yield: 193 mg (97%); colorless oil.

IR (neat): 2928, 2881, 1457, 1413, 1365, 1244, 1200, 1117, 1043 cm–1.

1H NMR (500 MHz, CDCl3): δ = 4.72 (s, 6 H), 3.69–3.67 (m, 6 H), 3.56–3.55 (m, 6 H), 3.50 (s, 6 H), 3.40 (s, 9 H), 1.66 (br s, 2 H).

13C NMR (125 MHz, CDCl3): δ = 95.9, 71.7, 70.1, 66.8, 59.0, 55.4.

HRMS (ESI): m/z [M + Na]+ calcd for C16H35NO9Na: 408.2210; found: 408.2204.


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6-{[(Benzyloxy)methoxy]methyl}-1,11-diphenyl-2,4,8,10-tetraoxaundecan-6-amine (5e)[10b]

Synthesized from 7e according to the procedure used to prepare 5c.

Yield: 140 mg (84%); pale-yellow oil.

IR (neat): 3379, 3088, 3063, 3031, 2936, 2880, 1586, 1498, 1455, 1381, 1162, 1111, 1041 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.36–7.27 (m, 15 H), 4.77 (s, 6 H), 4.59 (s, 6 H), 3.58 (s, 6 H), 1.62 (br s, 2 H).

13C NMR (125 MHz, CDCl3): δ = 137.7, 128.4, 127.8, 127.7, 95.0, 70.2, 69.4, 55.4.

HRMS (ESI): m/z [M + Na]+ calcd for C28H35NO6Na: 504.2362; found: 504.2313.


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tert-Butyl [1,7-Dihydroxy-4-(3-hydroxypropyl)heptan-4-yl]carbamate (8)

Synthesized from 2 according to the procedure used to prepare 6.

Yield: 1.62 g (99%); mp 103.7–105 °C (colorless needles, CHCl3).

IR (KBr): 3405, 3305, 3262, 2949, 2873, 1691, 1546, 1454, 1366, 1279, 1166 cm–1.

1H NMR (500 MHz, DMSO-d 6): δ = 6.07 (br s, 1 H), 4.36 (t, J = 5.0 Hz, 3 H), 3.34–3.31 (m, 6 H), 1.49–1.47 (m, 6 H), 1.36 (s, 9 H), 1.36–1.27 (m, 6 H).

13C NMR (125 MHz, DMSO-d 6): δ = 153.9, 76.7, 61.3, 56.1, 31.0, 28.2, 26.5.

HRMS (ESI): m/z [M + Na]+ calcd for C15H31NO5Na: 328.2100; found: 328.2104.

Anal. Calcd for C15H31NO5: C, 58.99; H, 10.23; N, 4.59. Found: C, 58.69; H, 10.16; N, 4.53.


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tert-Butyl {1,7-Bis(benzyloxy)-4-[3-(benzyloxy)propyl]heptan-4-yl}carbamate (9)

To a solution of 8 (300 mg, 0.982 mmol) and benzyl bromide (0.760 mL, 6.38 mmol) in anhydrous DMF (1.6 mL) was added KOH (379 mg, 6.75 mmol) at r.t. under argon. The reaction mixture was stirred for 21 h at r.t., for 2 h at 40 °C, and for 2 h at 60 °C. H2O (20 mL) was added and the mixture was extracted with EtOAc (30 mL). The organic layer was washed with H2O (2 × 20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The oily residue was purified by column chromatography [silica gel PSQ 60B; n-hexane–EtOAc, 5:1 to 1:1] to afford 9.

Yield: 211 mg (37%); colorless oil.

IR (neat): 3352, 2945, 2856, 1715, 1497, 1454, 1390, 1364, 1248, 1170, 1100, 736, 698 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.35–7.26 (m, 15 H), 4.48 (s, 6 H), 4.42 (br s, 1 H), 3.45 (t, J = 6.4 Hz, 6 H), 1.67–1.65 (m, 6 H), 1.60–1.53 (m, 6 H), 1.39 (s, 9 H).

13C NMR (125 MHz, CDCl3): δ = 154.1, 138.5, 128.3, 127.6, 127.5, 78.5, 72.9, 70.6, 56.9, 31.9, 28.4, 23.7.

HRMS (ESI): m/z [M + Na]+ calcd for C36H49NO5Na: 598.3508; found: 598.350.

Anal. Calcd for C36H49NO5: C, 75.10; H, 8.58; N, 2.43. Found: C, 74.80; H, 8.54; N, 2.60.


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1,7-Bis(benzyloxy)-4-[3-(benzyloxy)propyl]heptan-4-amine (5f)

Synthesized from 9 according to the procedure used to prepare 5c.

Yield: 266 mg (99%); yellow oil.

IR (neat): 3061, 3031, 2945, 2855, 1719, 1454, 1361, 1276, 1102 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.38–7.26 (m, 15 H), 4.49 (s, 6 H), 3.45 (t, J = 6.6 Hz, 6 H), 1.63–1.57 (m, 8 H), 1.41–1.38 (m, 6 H).

13C NMR (125 MHz, CDCl3): δ = 138.5, 128.3, 127.6, 127.5, 72.9, 70.9, 52.8, 36.4, 24.0.

HRMS (ESI): m/z [M + Na]+ calcd for C31H41NO3Na: 498.2984; found: 498.2968.


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N,N-Dibenzyl-1-methyl-2,6,7-trioxabicyclo[2.2.2]octan-4-amine (10)

To a solution of 3 (1.00 g, 3.32 mmol) in toluene (6 mL) was added triethyl orthoacetate (605 μL, 3.32 mmol) at 0 °C. After stirring for 45 min at 80 °C, for 1.25 h at 100 °C, and for 36 h at 120 °C, the reaction mixture was evaporated in vacuo. The residue was purified by column chromatography [silica gel PSQ 60B; n-hexane–CHCl3, 1:9] to afford 10.

Yield: 536 mg (50%); white solid; mp 122–123 °C.

IR (KBr): 3299, 3063, 2969, 2889, 1952, 1875, 1542, 1255, 1042 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.25–7.19 (m, 10 H), 4.07 (s, 6 H), 3.76 (s, 4 H), 1.42 (s, 3 H).

13C NMR (125 MHz, CDCl3): δ = 139.8, 128.3, 128.1, 127.2, 108.3, 68.6, 53.8, 53.1, 22.9.


#

1-Methyl-2,6,7-trioxabicyclo[2.2.2]octan-4-amine (5g)[11]

Synthesized from 10 according to the procedure used to prepare 5a.

Yield: 16.0 mg (73%); white solid; mp 116–117 °C.

IR (KBr): 3548, 3470, 3414, 3239, 2953, 2893, 2026, 1854, 1734, 1618 cm–1.

1H NMR (500 MHz, CDCl3): δ = 3.90 (s, 6 H), 1.46 (s, 3 H), 1.00 (br s, 2 H).

13C NMR (125 MHz, CDCl3): δ = 108.2, 72.7, 44.9, 22.9.

Anal. Calcd for C6H11NO3: C, 49.65; H, 7.64; N, 9.65. Found: C, 49.35; H, 7.59; N, 9.46.


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Preparation of Isoindoles 11a–f and 11i–k; Typical Procedure

To a solution of OPA (42.0 mg, 0.313 mmol) in anhydrous MeOH (5 mL), 1-propanethiol (31.0 μL, 0.346 mmol) and amine 5a (56.5 mg, 0.346 mmol) were added. After stirring in the dark for 3 h at r.t., the reaction mixture was evaporated in vacuo. The oily residue was purified by column chromatography [silica gel 60N; n-hexane–EtOAc, 9:1 to 3:1] to afford isoindole 11a (69.0 mg, 65%) accompanied by the formation of isoindolin-1-one 12a (16.0 mg, 18%).


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2-[1,3-Dimethoxy-2-(methoxymethyl)propan-2-yl]-1-(propylthio)-2H-isoindole (11a)

Yield: 69.0 mg (65%); pale-blue solid; mp 67–68 °C.

1H NMR (500 MHz, CDCl3): δ = 7.66 (br dq, 1 H), 7.50 (br dt, 1 H), 7.44 (d, J = 0.5 Hz, 1 H), 6.99 (ddd, J = 8.5, 6.5, 0.9 Hz, 1 H), 6.91 (ddd, J = 8.4, 6.4, 0.9 Hz, 1 H), 4.21 (s, 6 H), 3.33 (s, 9 H), 2.66 (t, J = 7.4 Hz, 2 H), 1.66 (sext, J = 7.5 Hz, 2 H), 1.01 (t, J = 7.3 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 131.7, 123.1, 122.2, 120.9, 120.6, 119.1, 115.7, 109.1, 72.6, 67.8, 59.3, 41.4, 23.0, 13.6.

HRMS (ESI): m/z [M + Na]+ calcd for C18H27NO3SNa: 360.1609; found: 360.1608.

Anal. Calcd for C18H27NO3S: C, 64.06; H, 8.06; N, 4.15. Found: C, 63.76; H, 8.09; N, 4.10.


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2-[1,3-Diethoxy-2-(ethoxymethyl)propan-2-yl]-1-(propylthio)-2H-isoindole (11b)

Yield: 122 mg (85%); pale-blue solid; mp 48–49 °C.

1H NMR (500 MHz, CDCl3): δ = 7.67 (br dq, 1 H), 7.53 (d, J = 0.6 Hz, 1 H), 7.51 (br dt, 1 H), 6.99 (ddd, J = 8.5, 6.4, 0.9 Hz, 1 H), 6.91 (ddd, J = 8.4, 6.4, 0.9 Hz, 1 H), 4.25 (s, 6 H), 3.47 (q, J = 7.0 Hz, 6 H), 2.66 (t, J = 7.4 Hz, 2 H), 1.66 (sext, J = 7.5 Hz, 2 H), 1.13 (t, J = 7.0 Hz, 9 H), 1.00 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 131.7, 123.0, 122.0, 120.6, 120.5, 119.2, 116.2, 108.9, 70.5, 68.2, 66.9, 41.4, 23.0, 15.1, 13.6.

HRMS (ESI): m/z [M + Na]+ calcd for C21H33NO3SNa: 402.2079; found: 402.2076.


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2-{6-[(Methoxymethoxy)methyl]-2,4,8,10-tetraoxaundecan-6-yl}-1-(propylthio)-2H-isoindole (11c)

Yield: 91.0 mg (57%); pale-yellow oil.

1H NMR (500 MHz, CDCl3): δ = 7.67 (br dq, 1 H), 7.51–7.50 (br m, 0.5 H), 7.49–7.48 (br m, 1.5 H), 7.00 (ddd, J = 8.5, 6.5, 0.9 Hz, 1 H), 6.92 (ddd, J = 8.4, 6.5, 0.9 Hz, 1 H), 4.59 (s, 6 H), 4.43 (s, 6 H), 3.29 (s, 9 H), 2.71 (t, J = 7.4 Hz, 2 H), 1.67 (sext, J = 7.4 Hz, 2 H), 1.02 (t, J = 7.4 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 131.7, 123.1, 122.2, 121.0, 120.4, 119.2, 115.5, 109.4, 96.8, 67.5, 67.3, 55.5, 41.5, 22.9, 13.6.

HRMS (ESI): m/z [M + Na]+ calcd for C21H33NO6SNa: 450.1926; found: 450.1885.


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2-(9-{[(2-Methoxyethoxy)methoxy]methyl}-2,5,7,11,13,16-hexaoxaheptadecan-9-yl)-1-(propylthio)-2H-isoindole (11d)

Yield: 113 mg (54%); pale-yellow oil.

1H NMR (500 MHz, CDCl3): δ = 7.65 (d, J = 8.6 Hz, 1 H), 7.48 (d, J = 8.3 Hz, 1 H), 7.48 (s, 1 H), 7.01–6.98 (m, 1 H), 6.93–6.90 (m, 1 H), 4.68 (s, 6 H), 4.43 (s, 6 H), 3.56–3.54 (m, 6 H), 3.49–3.47 (m, 6 H), 3.37 (s, 9 H), 2.69 (t, J = 7.4 Hz, 2 H), 1.66 (sext, J = 7.4 Hz, 2 H), 1.01 (t, J = 7.3 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 131.7, 123.0, 122.3, 121.0, 120.4, 119.2, 115.6, 109.4, 95.8, 71.7, 67.7, 67.3, 67.1, 59.0, 41.5, 23.0, 13.6.

HRMS (ESI): m/z [M + Na]+ calcd for C27H45NO9SNa: 582.2713; found: 582.2701.


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2-(6-{[(Benzyloxy)methoxy]methyl}-1,11-diphenyl-2,4,8,10-tetraoxaundecan-6-yl)-1-(propylthio)-2H-isoindole (11e)

Yield: 148 mg (60%); orange oil.

1H NMR (500 MHz, CDCl3): δ = 7.66 (d, J = 8.6 Hz, 1 H), 7.50 (s, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.33–7.27 (m, 15 H), 7.01 (ddd, J = 8.5, 6.5, 0.8 Hz, 1 H), 6.93 (ddd, J = 8.3, 6.5, 0.7 Hz, 1 H), 4.72 (s, 6 H), 4.52 (s, 6 H), 4.48 (s, 6 H), 2.66 (t, J = 7.5 Hz, 2 H), 1.61 (sext, J = 7.4 Hz, 2 H), 0.94 (t, J = 7.4 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 137.6, 131.8, 128.4, 127.8, 127.7, 123.1, 122.3, 121.1, 120.4, 119.3, 115.5, 109.6, 94.9, 69.6, 67.7, 67.4, 41.5, 22.9, 13.5.

HRMS (ESI): m/z [M + Na]+ calcd for C39H45NO6SNa: 678.2865; found: 678.2883.


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2-{1,7-Bis(benzyloxy)-4-[3-(benzyloxy)propyl]heptan-4-yl}-1-(propylthio)-2H-isoindole (11f)

Yield: 224 mg (93%); pale-yellow oil.

1H NMR (500 MHz, CDCl3): δ = 7.68 (d, J = 8.5 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.39 (s, 1 H), 7.33–7.25 (m, 15 H), 7.03–7.00 (m, 1 H), 6.94–6.91 (m, 1 H), 4.44 (s, 6 H), 3.42 (t, J = 6.3 Hz, 6 H), 2.65 (t, J = 7.4 Hz, 2 H), 2.43–2.40 (m, 6 H), 1.60 (sext, J = 7.4 Hz, 2 H), 1.40–1.34 (m, 6 H), 0.94 (t, J = 7.4 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 138.4, 131.9, 128.3, 127.6, 127.5, 122.5, 121.9, 120.8, 120.3, 119.2, 114.3, 109.7, 72.9, 70.2, 66.9, 41.5, 32.9, 23.7, 22.8, 13.6.

HRMS (ESI): m/z [M + Na]+ calcd for C42H51NO3SNa: 672.3487; found: 672.3490.

Anal. Calcd for C42H51NO3S: C, 77.62; H, 7.91; N, 2.16. Found: C, 77.32; H, 7.98; N, 2.13.


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4-(3-Hydroxypropyl)-4-[1-(propylthio)-2H-isoindol-2-yl]heptane-1,7-diol (11i)

Yield: 127 mg (90%); mp 116–118 °C (pale-yellow needles, CHCl3/n-hexane).

1H NMR (500 MHz, CDCl3): δ = 7.69 (dd, J = 8.5, 0.8 Hz, 1 H), 7.50 (dt, J = 8.4, 0.9 Hz, 1 H), 7.43 (s, 1 H), 7.03 (ddd, J = 8.5, 6.5, 0.9 Hz, 1 H), 6.94 (ddd, J = 8.4, 6.5, 0.9 Hz, 1 H), 3.62 (t, J = 6.2 Hz, 6 H), 2.71 (t, J = 7.4 Hz, 2 H), 2.45–2.42 (m, 6 H), 1.69 (sext, J = 7.4 Hz, 2 H), 1.39 (br s, 3 H), 1.36–1.30 (m, 6 H), 1.03 (t, J = 7.4 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 131.9, 122.6, 122.2, 121.0, 120.3, 119.1, 114.3, 109.5, 66.9, 62.5, 41.6, 32.5, 26.4, 22.9, 13.7.

HRMS (ESI): m/z [M + Na]+ calcd for C21H33NO3SNa: 402.2079; found: 402.2067.


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2-{1,7-Bis(benzyloxy)-4-[3-(benzyloxy)propyl]heptan-4-yl}-1-(octylthio)-2H-isoindole (11j)

Yield: 206 mg (96%); pale-yellow oil.

1H NMR (500 MHz, CDCl3): δ = 7.67 (br d, 1 H), 7.48 (br d, 1 H), 7.38 (s, 1 H), 7.33–7.24 (m, 15 H), 7.01 (ddd, J = 8.5, 6.5, 0.9 Hz, 1 H), 6.93 (ddd, J = 8.4, 6.5, 0.8 Hz, 1 H), 4.44 (s, 6 H), 3.42 (t, J = 6.3 Hz, 6 H), 2.67 (t, J = 7.4 Hz, 2 H), 2.43–2.40 (m, 6 H), 1.61–1.54 (m, 2 H), 1.39–1.24 (m, 16 H), 0.88 (t, J = 7.0 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 138.4, 131.8, 128.3, 127.55, 127.48, 122.6, 121.9, 120.8, 120.3, 119.2, 114.2, 109.8, 72.9, 70.2, 66.9, 39.6, 32.9, 31.8, 29.4, 29.3, 29.2, 29.0, 23.7, 22.7, 14.1.

HRMS (ESI): m/z [M + Na]+ calcd for C47H61NO3SNa: 742.4270; found: 742.4276.


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2-{1,7-Bis(benzyloxy)-4-[3-(benzyloxy)propyl]heptan-4-yl}-1-(dodecylthio)-2H-isoindole (11k)

Yield: 210 mg (91%); pale-yellow oil.

1H NMR (500 MHz, CDCl3): δ = 7.67 (d, J = 8.6 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.38 (s, 1 H), 7.33–7.24 (m, 15 H), 7.03–7.00 (m, 1 H), 6.94–6.91 (m, 1 H), 4.44 (s, 6 H), 3.42 (t, J = 6.3 Hz, 6 H), 2.67 (t, J = 7.4 Hz, 2 H), 2.43–2.40 (m, 6 H), 1.60–1.54 (m, 2 H), 1.38–1.25 (m, 24 H), 0.88 (t, J = 6.9 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 138.4, 131.8, 128.3, 127.55, 127.47, 122.6, 121.9, 120.8, 120.3, 119.2, 114.2, 109.8, 72.9, 70.2, 66.9, 39.6, 32.9, 31.9, 29.7, 29.64, 29.56, 29.5, 29.38, 29.36, 29.1, 29.0, 23.7, 22.7, 14.1.

HRMS (ESI): m/z [M + Na]+ calcd for C51H69NO3SNa: 798.4896; found: 798.4892.

Anal. Calcd for C51H69NO3S: C, 78.92; H, 8.96; N, 1.80. Found: C, 78.62; H, 9.01; N, 1.83.


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2-[1,3-Dimethoxy-2-(methoxymethyl)propan-2-yl]isoindolin-1-one (12a)

Yield: 16.0 mg (18%); white solid; mp 63.5–66.0 °C.

IR (KBr): 2976, 2876, 1684, 1471, 1383, 1304, 1103 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.78 (d, J = 7.5 Hz, 1 H), 7.51 (td, J = 7.4, 1.1 Hz, 1 H), 7.44–7.39 (m, 2 H), 4.66 (s, 2 H), 3.97 (s, 6 H), 3.35 (s, 9 H).

13C NMR (125 MHz, CDCl3): δ = 169.6, 142.1, 133.5, 131.1, 127.6, 123.2, 122.3, 71.1, 63.4, 59.3, 50.1.

HRMS (ESI): m/z [M + Na]+ calcd for C15H21NO4Na: 302.1368; found: 302.1342.


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2-[1,3-Diethoxy-2-(ethoxymethyl)propan-2-yl]isoindolin-1-one (12b)

Yield: 14.0 mg (12%); yellow oil.

IR (neat): 2974, 2870, 1684, 1469, 1393, 1301, 1103 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.78 (d, J = 7.5 Hz, 1 H), 7.50 (td, J = 7.4, 1.1 Hz, 1 H), 7.43–7.39 (m, 2 H), 4.71 (s, 2 H), 4.03 (s, 6 H), 3.50 (q, J = 7.0 Hz, 6 H), 1.14 (t, J = 7.0 Hz, 9 H).

13C NMR (125 MHz, CDCl3): δ = 169.6, 142.2, 133.7, 130.9, 127.4, 123.2, 122.2, 68.9, 66.8, 63.6, 50.3, 15.2.

HRMS (ESI): m/z [M + Na]+ calcd for C18H27NO4Na: 344.1838; found: 344.1834.


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2-{6-[(Methoxymethoxy)methyl]-2,4,8,10-tetraoxaundecan-6-yl}isoindolin-1-one (12c)

Yield: 57.2 mg (41%); pale-yellow oil.

IR (neat): 2947, 2890, 2823, 1684, 1470, 1152, 1111, 1041 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.80 (d, J = 7.6 Hz, 1 H), 7.52 (td, J = 7.5, 1.1 Hz, 1 H), 7.45–7.39 (m, 2 H), 4.69 (s, 2 H), 4.64 (s, 6 H), 4.17 (s, 6 H), 3.33 (s, 9 H).

13C NMR (125 MHz, CDCl3): δ = 169.5, 141.9, 133.4, 131.2, 127.7, 123.3, 122.3, 96.9, 66.2, 62.8, 55.4, 50.0.

HRMS (ESI): m/z [M + Na]+ calcd for C18H27NO7Na: 392.1685; found: 392.1664.


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2-(9-{[(2-Methoxyethoxy)methoxy]methyl}-2,5,7,11,13,16-hexaoxaheptadecan-9-yl)isoindolin-1-one (12d)

Yield: 83.2 mg (44%); pale-yellow oil.

IR (neat): 2930, 2886, 2819, 1685, 1470, 1452, 1118, 1046 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.78 (d, J = 7.6 Hz, 1 H), 7.52 (td, J = 7.5, 1.1 Hz, 1 H), 7.45–7.38 (m, 2 H), 4.72 (s, 6 H), 4.66 (s, 2 H), 4.17 (s, 6 H), 3.64–3.62 (m, 6 H), 3.53–3.50 (m, 6 H), 3.37 (s, 9 H).

13C NMR (125 MHz, CDCl3): δ = 169.4, 141.9, 133.3, 131.2, 127.7, 123.2, 122.3, 96.0, 71.7, 67.0, 66.3, 62.8, 59.0, 50.0.

HRMS (ESI): m/z [M + Na]+ calcd for C24H39NO10Na: 524.2472; found: 524.2473.


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2-(6-{[(Benzyloxy)methoxy]methyl}-1,11-diphenyl-2,4,8,10-tetraoxaundecan-6-yl)isoindolin-1-one (12e)

Yield: 87.0 mg (39%); pale-yellow oil.

IR (neat): 2943, 2886, 1684, 1454, 1383, 1169, 1112, 1044 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.79 (d, J = 7.6 Hz, 1 H), 7.51 (td, J = 7.5, 1.1 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.37 (d, J = 7.5 Hz, 1 H), 7.34–7.26 (m, 15 H), 4.76 (s, 6 H), 4.66 (s, 2 H), 4.55 (s, 6 H), 4.26 (s, 6 H).

13C NMR (125 MHz, CDCl3): δ = 169.5, 141.8, 137.7, 133.3, 131.2, 128.4, 127.8, 127.73, 127.67, 123.3, 122.3, 95.1, 69.5, 66.5, 62.9, 50.0.

HRMS (ESI): m/z [M + Na]+ calcd for C36H39NO7Na: 620.2624; found: 620.2635.


#

2-{1,7-Bis(benzyloxy)-4-[3-(benzyloxy)propyl]heptan-4-yl}isoindolin-1-one (12f)

Yield: 13.0 mg (ca. 6%); pale-yellow oil.

1H NMR (500 MHz, CDCl3): δ = 7.77 (d, J = 7.5 Hz, 1 H), 7.49 (td, J = 7.4, 1.2 Hz, 1 H), 7.43 (d, J = 7.4 Hz, 1 H), 7.36–7.22 (m, 16 H), 4.47 (s, 2 H), 4.46 (s, 6 H), 3.46 (t, J = 6.7 Hz, 6 H), 2.13–2.05 (m, 6 H), 1.62–1.52 (m, 6 H).

HRMS (ESI): m/z [M + Na]+ calcd for C39H45NO4Na: 614.3246; found: 614.3204.


#

HPLC Equipment and Conditions

A Gulliver HPLC system (JASCO) equipped with a Rheodyne 7125 injection valve (20 μL loop), UV/Vis detector (UV-970), and HPLC pump (PU-980) was used. HPLC analysis was performed with a TSKgel ODS-80Ts analytical column (250 × 4.6 mm id, 5 μm, Tosoh) by measuring absorbance at 330 nm. The mobile phase was a mixture of MeOH and water (200:1, v/v) at a flow rate of 1.0 mL min–1.


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Supporting Information

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    • 7l Yoshifuji M. Phosphorus, Sulfur, Silicon Relat. Elem. 2016; 191: 1452
    • 8a Sipos A. Török Z. Röth E. Kiss-Szikszai A. Batta G. Bereczki I. Fejes Z. Borbás A. Ostorházi E. Rozgonyi F. Naesens L. Herczegh P. Bioorg. Med. Chem. Lett. 2012; 22: 7092
    • 8b Sipos A. Máté G. Röth E. Borbás A. Batta G. Bereczki I. Kéki S. Jóna I. Ostorházi E. Rozgonyi F. Vanderlinden E. Naesens L. Herczegh P. Eur. J. Med. Chem. 2012; 58: 361
    • 9a Tonhauser C. Schüll C. Dingels C. Frey H. ACS Macro Lett. 2012; 1: 1094
    • 9b Schüll C. Nuhn L. Mangold C. Christ E. Zentel R. Frey H. Macromolecules 2012; 45: 5901
    • 10a Segura M. Sansone F. Casnati A. Ungaro R. Synthesis 2001; 2105
    • 10b Pasha A. Lin M. Tircsó G. Rostollan CL. Woods M. Kiefer GE. Sherry AD. Sun X. J. Biol. Inorg. Chem. 2009; 14: 421
    • 10c Chen Z. Hu W. Wang M. Wang L. Su G. Wang J. Carbohydr. Res. 2016; 429: 81
    • 10d Das R. Mukhopadhyay B. Tetrahedron Lett. 2016; 57: 1775
  • 11 Bundy GL. Pals DT. Lawson JA. Couch SJ. Lipton MF. Mauragis MA. J. Med. Chem. 1990; 33: 2276

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Scheme 1 The reaction of OPA with a primary amine and thiol
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Scheme 2 Synthesis of C 3-symmetric primary amines 5ag starting from tris(hydroxymethyl)aminomethane (1) and tris(hydroxypropyl)amino­methane (2)
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Scheme 3 Plausible reaction pathways for the formation of 11ae and 12ae
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Figure 1 HPLC analysis for resolution of a mixture of isoindoles 11f, 11j, and 11k formed from 1-propanethiol, 1-octanethiol, and 1-dodecanethiol, respectively