kemp elimination

7242019 Kemp Elimination

httpslidepdfcomreaderfullkemp-elimination 16

Chromatography-Free Entry to Substituted SalicylonitrilesMitsunobu-Triggered Domino Reactions of SalicylaldoximesEllis Whitingdagger ∥ Maryanna E LanningDagger ∥ Jacob A ScheenstraDagger and Steven Fletcher Dagger sect

daggerSchool of Chemistry University of Cardiff Cardiff CF10 3AT UKDaggerDepartment of Pharmaceutical Sciences University of Maryland School of Pharmacy 20 N Pine Street Baltimore Maryland 21201United StatessectUniversity of Maryland Greenebaum Cancer Center 22 S Greene Street Baltimore Maryland 21201 United States

S Supporting Information

ABSTRACT A mild and efficient one-pot procedure is describedto transform salicylaldoximes into salicylonitriles using Mitsunobuchemistry The reactions proceed through the corresponding 12- benzisoxazoles that undergo the Kemp elimination in situ togenerate the target salicylonitriles in excellent yields Thechemistry exhibits a broad scope and the salicylonitriles can bereadily isolated by a simple acidminus base workup In addition tofunctioning as useful synthetic precursors salicylonitriles may serveas more cell penetrable bioisosteres of carboxylic acids

I n connection with our research program on the develop-ment of Mcl-1 inhibitors1 we sought to replace the benzoic

acid moiety of our drug molecules whose interaction with Arg263 is crucial to the activity of the inhibitors withalternative bioisosteres that might exhibit improved cellpermeabilities Toward this goal it was speculated that 2-h y droxybenzonitriles or salicylonitriles bearing p K

arsquos of around

72 might prove remedial In fact Chen and colleagues havedeveloped some Mcl-1 inhibitors that feature a 2-hydroxy-nicotinonitrile moiety wherein the ortho hydroxyl and cyanogroups might together function as a bioisostere of a carboxylicacid3 More generally since the nitrile moiety is a versatilefunctional group salicylonitriles may provide access to morecomplex heterocyclic and pharmaceutically relevant com-pounds such as 3-aminobenzofurans4 benzofuro[32-b]-pyridines4 benzofuro[32-b]q uinolines5 arylbenzofuro-diazepin-6-ones6 and pyrazines7 However there are limitedsynthetic procedures in the literature toward the synthesis of substituted salicylonitriles

One of the more traditional strategies to access salicyloni-triles is the Rosenmundminus von Braun reaction in which a 2-halophenol is treated with CuCN (Scheme 1)8 A caveat of thisapproach is that very high temperatures (up to 200 degC) areoften required for eff ective displacement of the halogen by CN A handful of approaches involve the corresponding salicylalde-hyde For example substituted salicylonitriles can be prepared by treatment of the corresponding salicyaldehyde withhydroxylamine although high temperatures extended reactiontimes and microwave energy may be required to encouragedehydration of the intermediate salicylaldoxime9 The Kempand Woodward method in which the salicylaldehyde is reacted with hydroxylamine O-sulfonic acid has been shown to lead toalmost a 3-fold greater amount of the undesired Beckmann

rearrangement product ortho-hydroxyformanilide over thedesired salicylonitrile10 Recently Anwar and Hansen intro-duced a one-pot procedure for the conversion of substitutedphenols into substituted salicylonitriles although this three-stage reaction requires reaction monitoring before progressionto the next stage11 It should also be noted that in many of theprocedures listed here column chromatography is required inorder to isolate the salicylonitrile Herein we demonstrate thatsubstituted salicylonitriles can be readily and efficiently accessedfrom their corresponding salicylaldoximes by a one-pot two-stage domino reaction initiated by Mitsunobu chemistry thatoccurs quickly at room temperature (RT) and under essentially neutral conditions In contrast to other work columnchromatography is circumvented altogether

In addition to its more contemporary applications in theregioselective alkylation of purines12 benzodiazepin-25-dio-nes13 and 3-hydroxyisoxazoles14 the Mitsunobu reaction15 has been utilized to eff ect c yclodehydrations of salicylaldoximesinto 12-benzisoxazoles10 Since 12-benzisoxazoles are prone toring-opening reactions in the presence of a mild base such assodium acetate to deliver the corresponding salicylonitrile (the

Kemp elimination)16 we hypothesized that an excess of theMitsunobu co-reagents would generate a surplus of the betaineintermediate whose basicity would initiate the Kempelimination Overall this would amount to a cyclodehydra-tionminus β -elimination cascade reaction furnishing the desiredsalicylonitrile from the corresponding salicylaldoxime in onepot

To test our hypothesis we subjected commercially availablesalicylaldoxime 1 (( E)-2-hydroxybenzaldehyde oxime) to 125

Received October 19 2014

Note

pubsacsorgjoc

copy XXXX American Chemical Society A DOI 101021jo502396u

J Org Chem XXXX XXX XXXminusXXX



equiv of diisopropylazodicarboxylate (DIAD) and triphenyl-phosphine (PPh3) in THF (Table 1) A concentration of 007

M was selected as we found this to be optimal in our earlier work on Mitsunobu chemistry12minus14 TLC analysis of thereaction after 15 min revealed considerable starting material

remaining along with a new less polar product that weconsidered might be the 12-benzisoxazole 2 Extending thereaction time to 1 h and then 16 h aff orded no discerniblefurther consumption of remaining starting material Silica gelcolumn chromatography of the reaction mixture followed by 1H NMR revealed that the solitary product generated wasindeed 2 We next repeated the reactions in CH2Cl2 andCH3CN and observed that they were complete within 15 minaff ording excellent yields of 2 in each case Interestingly 1HNMR analysis of the crude mixtures of similar reactions thathad been allowed to stand overnight demonstrated theemergence of salicylonitrile 3 (entries 5 and 6 (δ H C3-H (2)890 ppm δ H OH (3) 111 ppm (d 6-DMSO))) Additional

experiments revealed that 25 equiv of DIAD and PPh 3 weresufficient to convert all of salicylaldoxime 1 into salicylonitrile 3

in CH2Cl2 and CH3CN within 1 h To further investigate if thetransformation of 1 into 3 occurred through 2 underMitsunobu conditions we again treated 1 with 125 equiv of DIAD and PPh3 in CH2Cl2 (entry 11) which after 1 h showedcomplete conversion to 2 and no evidence of 3 Then weintroduced another 125 equiv of DIAD and PPh3 and a TLCcheck of the reaction after an additional 1 h revealed 2 had beencompletely transformed into 3 Taken together our 1047297ndingssuggest that as hypothesized treatment of salicylaldoxime 1 with an excess of the Mitsunobu reagents DIAD and PPh3

triggers a domino reaction of a cyclodehydration to 12- benzisoxazole 2 followed by a ring-opening Kemp eliminationto furnish salicylonitrile 3 We note that ( E)-benzaldehydeoxime underwent dehydration under these conditions to aff ord

benzonitrile in an E2 elimination reaction and so the phenolichydroxyl of salicylaldoxime is sufficiently reactive and correctly positioned to intercept the activated oxime to deliver theobserved 12-benzisoxazole intermediate A plausible mecha-nism for this cascade reaction is proposed in Scheme 2

We next turned our attention to assessing the scope of thismethodology and our results are presented in Table 2 Allsalicylaldoxime substrates therein were prepared by treatmentof the corresponding salicylaldehydes 1 with hydroxylamineaccording to a standard procedure described in theExperimental Section Solitary products were detected in eachcase which were presumed to be the desired ( E)-isomers owingto similar oxime CH chemical shifts to that for unsubstitutedsalicylaldoxime (δ H 817minus854 versus 833) and that the

corresponding oxime proton in (Z)-isomers is often around 1ppm up1047297eld (eg (Z )- para-methoxybenzaldehyde o xime δ H725 vs ( E)- para-methoxybenzaldehyde δ H = 80617) Fur-thermore the ( E) geometry of salicylaldoximes is thermody-namically favored through the formation of intramolecularhydrogen-bonded six-mem bered rings between the phenol OHand the oxime N lone pair18

Mitsunobu reactions were performed using optimizedconditions of 25 equiv of each of PPh3 and DIAD inCH2Cl2 (007 M) at RT Although CH3CN provided a slightly higher yield of 3 (Table 1 entry 10) we elected to use CH2Cl2as the reaction solvent since this would facilitate the workupprocedure Some salicylaldoximes were not completely soluble

Scheme 1 Existing Methods to Prepare Salicylonitriles

Table 1 Screening of Reaction Conditionsa

entry equivalents solvent time ratiob 23 yield (3 )c

1 125 THF 15 min 10 0

2 125 CH2Cl2 15 min gt991 trace

3 125 CH3CN 15 min gt991 trace

4 125 THF 16 h 91 5

5 125 CH2Cl2 16 h 51 14

6 125 CH3CN 16 h 51 16

7 2 CH2Cl2 16 h 25 63

8 25 THF 1 h 551 20

9 25 CH2Cl2 1 h 01 93

10 25 CH3CN 1 h 01 97

11 125 125 CH2Cl2 1 h 1 h 01 93aThe salicylonitrile 1 (05 mmol 1 equiv) and PPh3 were dissolved inthe appropriate solvent (007 M) at RT under an inert (N2)atmosphere After 5 min DIAD was added dropwise then the reaction

was allowed to stir at RT for the time stated bDetermined by 1HNMR analysis of crude material c Isolated yield

The Journal of Organic Chemistry Note

DOI 101021jo502396u J Org Chem XXXX XXX XXXminusXXX

B



in CH2Cl2 (although all were in CH3CN) but upon addingDIAD the reactions became homogeneous In order to purify salicylonitriles 3 we exploited their acidities (p K a le 7) Uponcompletion (TLC in all but one case reactions were complete within 1 h at RT) each reaction mixture was subjected to a basic workup (01 M NaOH) then the basic aqueous layercontaining only the salicylonitrile was acidi1047297ed with 1 M HCland re-extracted into CH2Cl2 avoiding the often-laboriouscolumn chromatography that is associated with Mitsunobureactions Electron-poor electron-rich and electron-neutralsalicylaldoximes were compatible with the reaction conditionsand a range of functional groups was tolerated to aff ord

excellent yields of the target salicylonitriles 3 It should benoted that for entry 5 the workup protocol was modi1047297edslightly to avoid saponi1047297cation of the methyl ester extractioninto the aqueous layer was accomplished with 1 M K 2CO3 inlieu of 01 M NaOH

In the event that a basic workup of the target salicylonitrile isprecluded due to sensitive functionality elsewhere in themolecule silica gel 1047298ash column chromatography may beconducted Conveniently water-soluble azodicarbonyl species(ADDM = azodicarbonyl dimorpholide (both o xidized andreduced forms may be extracted readily into water19 DMEAD= dimethoxyethylazodicarboxylate (the reduced form DMEAD-H2 is removed readily into water20)) may be employed along with PPh3 on resin (PS-PPh3) with no detriment to the yield

(Table 3)In conclusion we have introduced a mild swift and efficienttechnique to generate salicylonitriles from salicylaldoximesusing Mitsunobu chemistry The transformation proceedsthrough the corresponding 12-benzisoxazole intermediates which undergo the Kemp elimination in situ The chemistry isgeneral proving eff ective with electron-neutral electron-richand electron-poor salicylonitriles and is compatible with a rangeof functional groups Owing to their acidities (p K arsquos around 7and below) the salicylonitriles may be isolated by simple acidminus base workups circumventing the need for column chromatog-raphy that often plagues Mitsunobu reactions It is anticipatedthat the chemistry described herein will be readily adopted as

the preferable means by which to synthesize salicylonitrilesgiven that DIAD and PPh3 are cheap chemicals and thepuri1047297cation protocol is fast cost-eff ective and simple Inaddition to their roles in the construction of more complex chemical species salicylonitriles may function as bioisosteres of carboxylic acids and this is an active area of research within ourlaboratory

EXPERIMENTAL SECTION

General Anhydrous solvents were purchased and used as supplied All reactions were conducted using oven-dried glassware and under aninert (N2) atmosphere Reactions were monitored by thin-layerchromatography (TLC) visualizing with a UV lamp (254 nm) andKMnO4 stain Reactions puri1047297ed by 1047298ash column chromatography

were carried out with Merck 60 Aring silica gel (230minus400 mesh) NMR spectra were performed on a 400 MHz NMR spectrometer Spectra

were calibrated to residual solvent peaks CDCl3 (δ H 726 δ C 7721)and d 6-DMSO (δ H 250 δ C 3951) Coupling constants are expressedin Hz and splitting patterns are denoted as follows s singlet ddoublet dd doublet of doublets m multiplet Melting points areuncorrected

Salicylaldoxime Synthesis To a solution of the aldehyde (5mmol) in EtOH (35 mL) was added NH2OHmiddotHCl (25 mmol) andpyridine (10 mmol) The reaction mixture was heated at 60 degC for 3 hTLC con1047297rmed that the reaction was complete The reaction mixture

was concentrated to ca 10 mL and then partitioned between EtOAc(150 mL) and 1 M HCl (50 mL) The EtOAc layer was washed again

with 1 M HCl (50 mL) water (2 times 50 mL) and brine (50 mL) dried(Na

2SO

4) 1047297ltered and concentrated to provide the oxime which

required no further puri1047297cation NOTE Basic oxime 1h waspartitioned between EtOAc and water with the EtOAc layerrepeatedly (times5) washed with water to extract all of the pyridine

(E)-5-Chloro-2-hydroxybenzaldehyde Oxime ( 1a )21 Yield = 832mg 97 white solid Spectral data consistent with pu blished data

(E)-5-Nitro-2-hydroxybenzaldehyde Oxime ( 1b )22 Yield = 892mg 98 yellow solid Spectral data consistent with published data

(E)-5-Methoxy-2-hydroxybenzaldehyde Oxime ( 1c )23 Yield = 828mg 99 white solid Spectral data consistent with published data

(E)-Methyl 4-Hydroxy-3-((hydroxyimino)methyl)benzoate ( 1d )General procedure was modi1047297ed methyl 3-formyl-4-hydroxybenzoate(15 mmol) NH2OHHCl (12 equiv) and pyridine (15 equiv) werestirred in MeOH (15 mL) overnight at room temperature Thereaction mixture was concentrated to ca 5 mL and then worked-up as

Scheme 2 Proposed Mechanism for the Two-Step One-Pot Conversion of Salicylaldoximes to Their Corresponding Salicylonitriles



C



per the general procedure Yield = 278 mg 95 off -white solid mp =160minus163 degC IR (neat cmminus1) 3337 1H NMR (400 MHz d 6-DMSO)

δ 1146 (s 1H) 1092 (s 1H) 836 (s 1H) 817 (d J = 16 Hz 1H)782 (dd J 1 = 76 Hz J 2 = 16 Hz 1H) 698 (d J = 84 Hz 1H) 381(s 1H) 13C NMR (100 MHz d 6-DMSO) δ 1661 1603 1463 13201294 1212 1191 1167 523 MS (ESI) m z Calcd for C9H9NO4

(M+) 1951 Found 1962 (M + H+) Anal Calcd for C9H9NO4 C5539 H 465 N 718 Found C 5561 H 457 N 693

(E)-5-Methyl-2-hydroxybenzaldehyde Oxime ( 1e )23 Yield = 726mg 95 white solid Spectral data consistent with pu blished data

(E)-2-Hydroxy-4-methoxybenzaldehyde Oxime ( 1f )24 Yield = 819mg 98 white solid Spectral data consistent with published data

(E)-4-(Dimethylamino)-2-hydroxybenzaldehyde Oxime ( 1g )

Yield = 828 mg 92 light brown solid mp = 150minus154 degC IR (neat cmminus1) 3410 1H NMR (400 MHz d 6-DMSO) δ 1083 (s 1H)1005 (s 1H) 817 (s 1H) 718 (d J = 88 Hz 1H) 626 (dd J 1 = 88

Hz J 2 = 16 Hz 1H) 614 (d J = 16 Hz 1H) 290 (s 3H) 13C NMR (100 MHz d 6-DMSO) δ 1577 1521 1494 1298 1064 1042 984

397 (obsc) MS (ESI) m z Calcd for C9H12N2O2 (M+

) 1801Found 1812 (M + H+) Anal Calcd for C9H12N2O2 C 5999 H671 N 1555 Found C 6021 H 676 N 1528

(E)-2-Chloro-6-hydroxybenzaldehyde Oxime ( 1h ) Yield = 838mg 98 white solid mp = 154minus158 degC IR (neat cmminus1) 3347 1HNMR (400 MHz d 6-DMSO) δ 1198 (s 1H) 1089 (s 1H) 854 (s1H) 723 (t J = 82 Hz 1H) 697 (d J = 76 Hz 1H) 689 (d J = 88Hz 1H) 13C NMR (100 MHz d 6-DMSO) δ 1582 1473 13271312 1205 1155 1147 MS (ESI) m z Calcd for C7H6ClNO2

(M+) 1710 Found 1721 (M + H+) Anal Calcd for C7H6ClNO2 C4900 H 352 N 816 Found C 4926 H 350 N 791

(E)-3-Bromo-2-hydroxybenzaldehyde Oxime ( 1i )25 Yield = 106 g99 white solid mp = 170minus174 degC IR (neat cmminus1) 3407 1H NMR (400 MHz d 6-DMSO) δ 1179 (s 1H) 1093 (s 1H) 841 (s 1H)

Table 2 Salicylaldoxime Substrate Scopeab

aThe salicylonitrile (05 mmol 1 equiv) and PPh3 (125 mmol 25 equiv) were dissolvedsuspended in CH2Cl2 (007 M) at RT under an inert (N2)atmosphere After 5 min DIAD (125 mmol 25 equiv) was added dropwise If not already so the reaction became homogeneous within 30 s Thereaction was stirred until complete (30minus90 min (TLC)) bIsolated yield



D



755 (d J = 72 Hz 1H) 743 (d J = 76 Hz 1H) 686 (t J = 78 Hz1H) 13C NMR (100 MHz d 6-DMSO) δ 1530 1499 1336 12931209 1191 1098 MS (ESI) m z Calcd for C7H6BrNO2 (M+)2150 Found 2161 (M + H+)

(E)-35-Dibromo-2-hydroxybenzaldehyde Oxime ( 1j ) Yield = 139g 95 pinkish-gray solid mp gt 200 degC IR (neat cmminus1) 3397 1HNMR (400 MHz d 6-DMSO) δ 1195 (s 1H) 1101 (s 1H) 838 (s1H) 774 (d J = 24 Hz 1H) 765 (d J = 24 Hz 1H) 13C NMR (100 MHz d 6-DMSO) δ 1524 1485 1349 1311 1208 11111108 MS (ESI) m z Calcd for C7H5Br2NO2 (M+) 2929 Found2939 (M + H+) Anal Calcd for C7H5Br2NO2 C 2851 H 171 N475 Found C 2853 H 149 N 465

(E)-2-Hydroxy-1-naphthaldehyde Oxime ( 1k )26 Yield = 916 mg98 peach solid mp = 160minus164 degC IR (neat cmminus1) 3311 1H NMR (400 MHz d 6-DMSO) δ 1157 (s 1H) 1118 (s 1H) 909 (s 1H)847 (d J = 88 Hz 1H) 785minus782 (m 2H) 750 (t J = 76 Hz 1H)735 (t J = 74 Hz) 721 (d J = 96 Hz) 13C NMR (100 MHz d 6-DMSO) δ 1561 1476 1316 1314 1286 1274 1233 1226 11831086 MS (ESI) m z Calcd for C11H9NO2 (M+) 1871 Found 1882(M + H+)

Salicylonitrile Synthesis To a solution of the appropriatesalicylaldoxime (05 mmol 1 equiv) and PPh3 (125 mmol 25equiv) in anhydrous CH2Cl2 (7 mL) was added DIAD (125 mmol25 equiv) dropwise at rt (if the salicylaldoxime was not already dissolved the reaction became homogeneous upon addition of DIAD)The reaction was stirred at rt under an inert atmosphere untilcompletion (TLC) The reaction mixture was partitioned betweenfurther CH2Cl2 (100 mL) and 01 N NaOH (50 mL) The aqueouslayer was washed with CH2Cl2 (3 times 50 mL) and then acidi1047297ed with 1N HCl (10 mL) The acidic aqueous was then extracted into CH

2Cl

2(2 times 50 mL) These organic extractions were combined dried(Na2SO4) 1047297ltered and concentrated to provide the salicylonitrile

which needed no further puri1047297cationSalicylonitrile ( 3 ) Yield = 55 mg 93 white solid mp = 96minus99

degC IR (neat cmminus1) 3268 2228 1H NMR (400 MHz d 6-DMSO) δ 1105 (s 1H) 757 (d J = 64 Hz 1H) 748 (t J = 74 Hz 1H) 701(d J = 76 Hz 1H) 692 (t J = 74 Hz 1H) 13C NMR (100 MHz d 6-DMSO) δ 1602 1348 1333 1196 1171 1162 989 MS (ESI) m

z Calcd for C7H5NO (M+) 1190 Found 1420 (M + Na+)5-Chloro-2-hydroxybenzonitrile ( 3a )21 Yield = 73 mg 95 white

solid mp = 167minus170 degC IR (neat cmminus1) 3230 2239 1H NMR (400MHz d 6-DMSO) d 1138 (s 1H) 773 (d J = 24 Hz 1H) 752 (dd

J 1 = 88 Hz J 2 = 24 Hz 1H) 701 (d J = 88 Hz 1H) 13C NMR (100MHz d 6-DMSO) δ 1593 1346 1322 1227 1179 1157 1003 MS

(ESI) m z Calcd for C7H4ClNO (M+) 1530 Found 1540 (M +H+)

5-Nitro-2-hydroxybenzonitrile ( 3b )27 Yield = 75 mg 92 pale yellow solid mp gt 200 degC IR (neat cmminus1) 3144 2254 1H NMR (400 MHz d 6-DMSO) δ 1272 (bs 1H) 859 (d J = 28 Hz 1H) 835(dd J 1 = 94 Hz J 2 = 26 Hz 1H) 716 (d J = 88 Hz 1H) 13C NMR (100 MHz d 6-DMSO) δ 1656 1393 1303 1301 1168 1151 997MS (ESI) m z Calcd for C7H4N2O3 (M+) 1640 Found 1631 (M minus

H+

)2-Hydroxy-5-methoxybenzonitrile ( 3c )28 Yield = 67 mg 90 white solid mp = 133minus136 degC IR (neat cmminus1) 3283 2230 1H NMR (400 MHz d 6-DMSO) δ 1053 (s 1H) 715 (d J = 24 Hz) 710 (dd

J 1 = 96 Hz J 2 = 32 Hz 1H) 693 (d J = 92 Hz 1H) 370 (s 1H)13C NMR (100 MHz d 6-DMSO) δ 1548 1522 1226 1178 11741163 989 562 MS (ESI) m z Calcd for C8H7NO2 (M+) 1491Found 1722 (M + Na+)

Methyl 3-Cyano-4-hydroxybenzoate ( 3d )29 Extraction of theproduct into the aqueous layer was accomplished using 1 M K 2CO3 inplace of 01 M NaOH NOTE Care should be taken when theaqueous layer is acidi1047297ed due to substantial eff ervescence Yield = 77mg 87 white solid mp = 198minus202 degC IR (neat cmminus1) 3154 22491H NMR (400 MHz d 6-DMSO) δ 1208 (s 1H) 812 (d J = 16 Hz1H) 803 (dd J 1 = 96 Hz J 2 = 24 Hz 1H) 710 (d J = 88 Hz 1H)381 (s 1H) 13C NMR (100 MHz d 6-DMSO) δ 1651 1644 13601354 1214 1169 1164 998 526 MS (ESI) m z Calcd forC9H7NO3 (M+) 1770 Found 1781 (M + H+)

2-Hydroxy-5-methylbenzonitrile ( 3e )30 Yield = 63 mg 94 whitesolid mp = 100minus103 degC IR (neat cmminus1) 3241 2233 1H NMR (400MHz d 6-DMSO) δ 1076 (s 1H) 737 (s 1H) 728 (d J = 88 Hz1H) 690 (d J = 84 Hz 1H) 220 (s 1H) 13C NMR (100 MHz d 6-DMSO) δ 1580 1354 1327 1285 1171 1160 984 195 MS(ESI) m z Calcd for C8H7NO (M+) 1331 Found 1561 (M + Na+)

2-Hydroxy-4-methoxybenzonitrile ( 3f )31 Yield = 69 mg 93 white solid mp = 176minus179 degC IR (neat cmminus1) 3217 2226 1H NMR (400 MHz d 6-DMSO) δ 1104 (s 1H) 750 (d J = 88 Hz 1H)653minus650 (m 2H) 376 (s 1H) 13C NMR (100 MHz d 6-DMSO) δ 1640 1618 1344 1174 1067 1010 912 555 MS (ESI) m zCalcd for C8H7NO2 (M+) 1491 Found 1501 (M + H+)

4-(Dimethylamino)-2-hydroxybenzonitrile ( 3g ) Extraction of the

product from the basic aqueous was accomplished through carefulneutralization of the aqueous layer with 1 M HCl then mildacidi1047297cation with saturated NH4Cl Yield = 71 mg 87 gray-brownsolid mp = 157minus162 degC IR (neat cmminus1) 3217 2207 1H NMR (400MHz d 6-DMSO) δ 1049 (s 1H) 728 (d J = 88 Hz 1H) 625 (dd

J 1 = 92 Hz J 2 = 24 Hz 1H) 614 (d J = 16 Hz) 293 (s 6H) 13CNMR (100 MHz d 6-DMSO) δ 1615 1545 1339 1191 1047 978854 399 (obsc) MS (ESI) m z Calcd for C9H10N2O (M+) 1621Found 1632 (M + H+) Anal Calcd for C9H10N2O C 6665 H621 N 1727 Found C 6617 H 627 N 1688

6-Chloro-2-hydroxybenzonitrile ( 3h )32 Yield = 65 mg 85 whitesolid mp = 163minus165 degC IR (neat cmminus1) 3247 2242 1H NMR (400MHz d 6-DMSO) δ 1165 (s 1H) 749 (t J = 82 Hz 1H) 709 (d J = 8 Hz 1H) 698 (d J = 84 Hz 1H) 13C NMR (100 MHz d 6-DMSO) δ 1620 1356 1353 1200 1149 1142 1000 MS (ESI)m z Calcd for C7H4ClNO (M+) 1530 Found 1761 (M + Na+)

3-Bromo-2-hydroxybenzonitrile ( 3i )11 Yield = 88 mg 89 paleorange solid mp = 119minus123 degC IR (neat cmminus1) 3271 2234 1HNMR (400 MHz d 6-DMSO) δ 1105 (bs 1H) 784 (dd J 1 = 96 Hz

J 2 = 16 Hz 1H) 766 (dd J 1 = 8 Hz J 2 = 16 Hz 1H) 693 (t J = 78Hz 1H) 13C NMR (100 MHz d 6-DMSO) δ 1562 1381 13291218 1162 1120 1023 MS (ESI) m z Calcd for C7H4BrNO (M+)1970 Found 2201 (M + Na+)

35-Dibromo-2-hydroxybenzonitrile ( 3j ) Yield = 126 mg 92 white solid mp = 172minus176 degC IR (neat cmminus1) 3281 2239 1H NMR (400 MHz d 6-DMSO) δ 1144 (bs 1H) 807 (s 1H) 794 (s 1H)13C NMR (100 MHz d 6-DMSO) δ 1561 1399 1349 1151 11351112 1039 MS (ESI) m z Calcd for C7H3Br2NO (M+) 2749Found 2760 (M + H+) Anal Calcd for C7H3Br2NO C 3036 H109 N 506 Found C 3042 H 091 N 497

Table 3 Alternative Azodicarbonyl and Phosphine Speciesa

entry azodicarbonyl phosphine yieldb ()

1 DIAD PPh3

95

2 ADDM PPh3 95

3 DMEAD PS-PPh3 94

4 ADDM PS-PPh3 97aThe salicylonitrile (05 mmol 1 equiv) and phosphine (125 mmol25 equiv) were gently stirred in CH2Cl2 (007 M) at RT under aninert (N2) atmosphere After 5 min the azodicarbonyl agent (125mmol 25 equiv) was added at once Entry 1 the reaction mixture wasdry-loaded onto silica gel then puri1047297ed by 1047298ash column chromatog-raphy eluting with a gradient of EtOAc in hexanes Entry 2 as forentry 1 but ADDM and its hydrazine by-product ADDM-H 2 wereremoved by partitioning between ether and water Entries 3 and 4 thePS-PPh3 was removed by 1047297ltration The organic solvent was removedin vacuo and then the residue was partitioned between ether and

water No column chromatography required bIsolated yield



E



2-Hydroxy-1-naphthonitrile ( 3k )33 Yield = 82 mg 97 whitesolid mp = 156minus159 degC IR (neat cmminus1) 3408 2223 1H NMR (400MHz d 6-DMSO) δ 1165 (s 1H) 807 (d J = 96 Hz 1H) 792 (d J = 8 Hz 1H) 786 (d J = 84 Hz 1H) 765 (t J = 76 Hz 1H) 744 (t

J = 74 Hz 1H) 728 (d J = 96 Hz 1H) 13C NMR (100 MHz d 6-DMSO) δ 1613 1351 1330 1291 1288 1270 1244 1227 11771160 912 MS (ESI) m z Calcd for C11H7NO (M+) 1691 Found1922 (M + Na+)

ASSOCIATED CONTENT

S Supporting InformationCopies of 1H and 13C NMR spectra of 1aminus1k and 3minus3k Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATION

Corresponding AuthorE-mail s1047298etcherrxumarylandedu (SF)

Author Contributions∥EW and MEL contributed equally

NotesThe authors declare no competing 1047297nancial interest

ACKNOWLEDGMENTS

We thank the University of Maryland School of Pharmacy for1047297nancial support of this research

REFERENCES

(1) (a) Yap J L Cao X Vanommeslaeghe K Jung K-Y WilderP Nan A MacKerell A D Jr Smythe W R Fletcher S Org

Biomol Chem 2012 10 2928minus2933 (b) Cao X Yap J L Newell-Rogers M K Peddaboina C Hua J Papaconstantinou H T

Jupitor D Rai A Jung K- Y Tub in R P Yu W Vanommeslaeghe K Wilder P T MacKerell A D Jr FletcherS Smythe W R Mol Cancer 2013 12 42 (c) Chen L Lanning ME Fletcher S Austin J Anal Pharm Chem 2014 1 (3) 6

(2) Haynes W M Ed CRC Handbook of Chemistry and Physics 95thed CRC Press Boca Raton FL 2014minus2015

(3) Zhang Z Liu C Li X Song T Wu Z Liang X Zhao YShen X Chen H Eur J Med Chem 2013 60 410minus420

(4) Mederski W K R Wilm C Schmitges C-J Oswald MDorsch D Christadler M Bioorg Med Chem Lett 1999 9 619minus622

(5) Radl S Konvicka P Vachal P J Heterocycl Chem 2000 37 855minus862

(6) Viti G Giannotti D Nannicini R Ricci R Pestellini V JHeterocycl Chem 1990 27 1369minus1375

(7) Taylor E C Pont J L Warner J C Tetrahedron 1987 43 5159minus5168

(8) von Braun J Manz G Liebigs Ann Chem 1931 488 111minus126(9) (a) Aspinall H C Beckingham O Farrar M D Greeves N

Thomas C D Tetrahedron Lett 2011 52 5120minus5123 (b) Chakra- borti A K Kaur G Tetrahedron 1999 55 13265minus13268(c) Supsana P Liaskopoulos T Tsoungas P G Varvounis GSynlett 2007 17 2671minus2674 (d) Tamilselvan T Basavaraju Y BSampathkumar E Murugesan R Catal Commun 2009 10 716minus719 (e) Ghosh P Subba R Tetrahedron Lett 2013 54 4885minus4887

(10) Poissonnet G Synth Commun 1997 27 3839minus3846(11) Anwar H F Hansen T V Tetrahedron Lett 2008 49 4443minus

4445(12) (a) Fletcher S Tetrahedron Lett 2010 51 2948minus2950

(b) Fletcher S Shahani V M Lough A J Gunning P TTetrahedron 2010 66 4621minus4632 (c) Fletcher S Shahani V MGunning P T Tetrahedron Lett 2009 50 4258minus4261

(13) Jung K-Y Fletcher S Med Chem Commun 2012 3 1160minus1163

(14) Chen L Fletcher S Tetrahedron Lett 2014 55 1693minus1696

(15) Kumara Swamy K C Bhuvan Kumar N N Balaraman EPavan Kumar K V P Chem Rev 2009 109 2551minus2651

(16) (a) Casey M L Kemp D S Paul K G Cox D D J OrgChem 1973 38 2294minus2301 (b) Kemp D S Cox D D Paul K G

J Am Chem Soc 1975 97 7312minus7318(17) Owston N A Parker A J Williams J M J Org Lett 2007 9

73minus75(18) Wood P A Forgan R S Henderson D Parsons S Pidcock

E Tasker P A Warren J E Acta Crystallogr Sect B 2006 62 1099minus1111(19) Lanning M E Fletcher S Tetrahedron Lett 2013 54 4624minus

4628(20) Hagiya K Muramoto N Misaki T Sugimura T Tetrahedron

2009 65 6509minus6514(21) Bonomi P Servant A Resmini M J Mol Recognit 2012 25

352minus360(22) Stokker G J Org Chem 1983 48 2613minus2615(23) Aldred R Johnston R Levin D Neilan J J Chem Soc

Perkin Trans 1 1994 1823minus1831(24) Gigant N Claveau E Bouyssou P Gillaizeau I Org Lett

2012 14 844minus847(25) Forgan R S Roach B D Wood P A White F J Campbell

J Henderson D K Kamenetzky E McAllister F E Parsons SPidcock E Richardson P Swart R M Tasker P A Inorg Chem

2011 50 4515minus4522(26) Guo Z Li L Liu G Dong J Acta Crystallogr Sect E Struct

Rep Online 2008 64 o568(27) Casey M L Kemp D S Paul K G Cox D D J Org Chem

1973 38 2294minus2301(28) Shinoda J J Chem Soc 1927 1983minus1985(29) Madsen P Ling A Plewe M Sams C K Knudsen L B

Sidelmann U G Ynddal L Brand C L Andersen B Murphy DTeng M Truesdale L Kiel D May J Kuki A Shi S JohnsonM D Teston K A Feng J Lakis J Anderes K Gregor V Lau J

J Med Chem 2002 45 5755minus5775(30) Collin M J Hatton P M Sternhell S Aust J Chem 1992 45

1119minus1134(31) Magano J Chen M H Clark J D Nussbaumer T J Org

Chem 2006 71 7103minus7105(32) Minutolo F Bellini R Bertini S Carboni I Lapucci A

Pistolesi L Prota G Rapposelli S Solati F Tuccinardi TMartinelli A Stossi F Carlson K E Katzenellenbogen B SKatzenellenbogen J A Macchia M J Med Chem 2008 51 1344minus1351

(33) Aspinall H C Beckingham O Farrar M D Greeves NThomas C D Tetrahedron Lett 2011 52 5120minus5123



F



equiv of diisopropylazodicarboxylate (DIAD) and triphenyl-phosphine (PPh3) in THF (Table 1) A concentration of 007

M was selected as we found this to be optimal in our earlier work on Mitsunobu chemistry12minus14 TLC analysis of thereaction after 15 min revealed considerable starting material

remaining along with a new less polar product that weconsidered might be the 12-benzisoxazole 2 Extending thereaction time to 1 h and then 16 h aff orded no discerniblefurther consumption of remaining starting material Silica gelcolumn chromatography of the reaction mixture followed by 1H NMR revealed that the solitary product generated wasindeed 2 We next repeated the reactions in CH2Cl2 andCH3CN and observed that they were complete within 15 minaff ording excellent yields of 2 in each case Interestingly 1HNMR analysis of the crude mixtures of similar reactions thathad been allowed to stand overnight demonstrated theemergence of salicylonitrile 3 (entries 5 and 6 (δ H C3-H (2)890 ppm δ H OH (3) 111 ppm (d 6-DMSO))) Additional

experiments revealed that 25 equiv of DIAD and PPh 3 weresufficient to convert all of salicylaldoxime 1 into salicylonitrile 3

in CH2Cl2 and CH3CN within 1 h To further investigate if thetransformation of 1 into 3 occurred through 2 underMitsunobu conditions we again treated 1 with 125 equiv of DIAD and PPh3 in CH2Cl2 (entry 11) which after 1 h showedcomplete conversion to 2 and no evidence of 3 Then weintroduced another 125 equiv of DIAD and PPh3 and a TLCcheck of the reaction after an additional 1 h revealed 2 had beencompletely transformed into 3 Taken together our 1047297ndingssuggest that as hypothesized treatment of salicylaldoxime 1 with an excess of the Mitsunobu reagents DIAD and PPh3

triggers a domino reaction of a cyclodehydration to 12- benzisoxazole 2 followed by a ring-opening Kemp eliminationto furnish salicylonitrile 3 We note that ( E)-benzaldehydeoxime underwent dehydration under these conditions to aff ord

benzonitrile in an E2 elimination reaction and so the phenolichydroxyl of salicylaldoxime is sufficiently reactive and correctly positioned to intercept the activated oxime to deliver theobserved 12-benzisoxazole intermediate A plausible mecha-nism for this cascade reaction is proposed in Scheme 2

We next turned our attention to assessing the scope of thismethodology and our results are presented in Table 2 Allsalicylaldoxime substrates therein were prepared by treatmentof the corresponding salicylaldehydes 1 with hydroxylamineaccording to a standard procedure described in theExperimental Section Solitary products were detected in eachcase which were presumed to be the desired ( E)-isomers owingto similar oxime CH chemical shifts to that for unsubstitutedsalicylaldoxime (δ H 817minus854 versus 833) and that the

corresponding oxime proton in (Z)-isomers is often around 1ppm up1047297eld (eg (Z )- para-methoxybenzaldehyde o xime δ H725 vs ( E)- para-methoxybenzaldehyde δ H = 80617) Fur-thermore the ( E) geometry of salicylaldoximes is thermody-namically favored through the formation of intramolecularhydrogen-bonded six-mem bered rings between the phenol OHand the oxime N lone pair18

Mitsunobu reactions were performed using optimizedconditions of 25 equiv of each of PPh3 and DIAD inCH2Cl2 (007 M) at RT Although CH3CN provided a slightly higher yield of 3 (Table 1 entry 10) we elected to use CH2Cl2as the reaction solvent since this would facilitate the workupprocedure Some salicylaldoximes were not completely soluble

Scheme 1 Existing Methods to Prepare Salicylonitriles

Table 1 Screening of Reaction Conditionsa

entry equivalents solvent time ratiob 23 yield (3 )c

1 125 THF 15 min 10 0

2 125 CH2Cl2 15 min gt991 trace

3 125 CH3CN 15 min gt991 trace

4 125 THF 16 h 91 5

5 125 CH2Cl2 16 h 51 14

6 125 CH3CN 16 h 51 16

7 2 CH2Cl2 16 h 25 63

8 25 THF 1 h 551 20

9 25 CH2Cl2 1 h 01 93

10 25 CH3CN 1 h 01 97

11 125 125 CH2Cl2 1 h 1 h 01 93aThe salicylonitrile 1 (05 mmol 1 equiv) and PPh3 were dissolved inthe appropriate solvent (007 M) at RT under an inert (N2)atmosphere After 5 min DIAD was added dropwise then the reaction

was allowed to stir at RT for the time stated bDetermined by 1HNMR analysis of crude material c Isolated yield



B















2SO










C




















D







2Cl









H+















1 DIAD PPh3

95

2 ADDM PPh3 95

3 DMEAD PS-PPh3 94





E





ASSOCIATED CONTENT


AUTHOR INFORMATION




ACKNOWLEDGMENTS


REFERENCES







































F















2SO










C




















D







2Cl









H+















1 DIAD PPh3

95

2 ADDM PPh3 95

3 DMEAD PS-PPh3 94





E





ASSOCIATED CONTENT


AUTHOR INFORMATION




ACKNOWLEDGMENTS


REFERENCES







































F




















D







2Cl









H+















1 DIAD PPh3

95

2 ADDM PPh3 95

3 DMEAD PS-PPh3 94





E





ASSOCIATED CONTENT


AUTHOR INFORMATION




ACKNOWLEDGMENTS


REFERENCES







































F







2Cl









H+















1 DIAD PPh3

95

2 ADDM PPh3 95

3 DMEAD PS-PPh3 94





E





ASSOCIATED CONTENT


AUTHOR INFORMATION




ACKNOWLEDGMENTS


REFERENCES







































F





ASSOCIATED CONTENT


AUTHOR INFORMATION




ACKNOWLEDGMENTS


REFERENCES







































F

kemp elimination

Documents