Indian Journal of ChemistryVol. 458, June 2006, pp. 1492-1498

,Microwave assisted fast and clean conversion of mesylate to azide: Synthesis of(lS,2R/IR,2S)-1-azido-2-carbocyclic amines as immediate precursors to versatile

1,2-cis-diamines

T GovindarajuDivision of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411008, India

E-mail: tgraju@dna.ncl.res.in

Received 9 November2004; accepted (revised) 21 June 2005

An efficient and rapid conversion of mesylate to azide under microwave irradiation has been carried out. It proceedsthrough inversion of configuration from chiral mesylates to provide optically pure cis-azides, immediate precursors ofvicinal-cis-I,2-diamines. These diamines can serve as metal ligands in asymmetric catalysis and their derivatives can beemployed as medicinal agents.

IPC: Int.CI.8 C07D

Keywords: Mesylate, azide, microwave irradiation, diamines, asymmetric catalysis, medicinal agent

In synthetic organic chemistry, azido compounds areversatile precursors to access a variety of aminocompounds such as 1,2-aminoalcohols, 1,2-diaminesand j3-aminoacidsl

•2• Efficient methods available for

the reduction of azide to amines has made the azidefunctionality a synthon of choice to access aminocompounds and their -potential derivatives', Routineconversion of alcohol to azide functionality involvesmesylation or tosylation followed by nucleophilicdisplacement by azide anion. A large variety ofmesylates like primary, secondary and stericallyhindered mesylates have been used to access azides.Mesylates react with azide nucleophile often veryslowly, requiring prolonged reaction times and hightemperatures. Under such circumstances, somereactive mesylates undergo decomposition, rearrange-ment, intramolecular cyclizations and prolongedreaction times may cause racemization. In particular,conversion of hindered mesylate to azide requiresvery harsh conditions and even impossible in somecases. Thus, an alternative rapid and efficientmicrowave assisted transformation of mesylate toazides will be of interest to many organic chemistsand in a recent example, microwave irradiation wasemployed for the azidation of tosylate". Themicrowave-enhanced organic reactions are rapidlygaining acceptance and popularity since it provides

opportunity to complete the reactions in minutes andhave manifold application in academia and industry'.

Results and DiscussionDuring the course of our work, we were interested

in making azide from sterically hindered mesylatesubstrates such as 1-9, 11-14 shown in Schemes I andII. The conventional synthetic procedure involvedheating of the mesylate with NaN3 (8.0 eq.) in DMFfor 5-12 hr at 65- 70°C. In microwave method thereaction mixture was treated with microwaveradiation in microwave oven following the microwaveorganic reaction enhancement techniques (MOREtThe reactions were carried out in a conical flaskcovered with a filter funnel to prevent the spillageduring the irradiation. The reaction mixture wasirradiated with microwave in 1-6 cycles of 2 min eachfollowed by 1 min rest until complete conversion ofthe starting material. The domestic microwave ovenof 800 watt at power level of 5 in a scale of 10 raisedthe temperature of the reaction mixture to 90°C in 10min. The temperature was maintained at 90°C bycontrolling the power level depending on conversiontime of substrate and then allowed to cool to roomtemperature. The conversions monitored by TLC werevery clean and no trace of impurities was found. DMFwas a solvent of choice as in conventional method

GOVINDARAJU: MICROWAVE ASSISTED CONVERSION OF MESYLATE TO AZIDE

MsO

"t(yOMe

I 0Boc1

MsO N;; 3"

~ .OMe MW..,"7/n 2min

bbZ 03

1493

MW•.2 min

OMe

o2

OMe

o4

MsO

N3~;,

~OMS MW. N3N 4 min N

~Oc !OC5 6

BOCNH~OMS MW•. BOCNH~N32 min

7 8

BOCNH~OMS MW.., BOCNH~N32 min

9 10Scheme I - Microwave assisted azidation ofmesylates

because of its high boiling point (153°C) and polarityresulting in very good microwave absorption medium.The results are summarized in Tables I and II. Thenucleophile NaN} used was 1.5-2.0 eq. as comparedto 8.0 eq. in conventional method. The products wereeasily purified by just filtration column chromato-graphy to achieve high purity. Almost completeconversion was observed within short periods, leadingto high enantiopurities of azide products and norecemization occurred. The optical rotations and othercharacterization data were in agreement with thereported data'".

The mesylate 7 being unstable, underwent neigh-boring group assisted rearrangement to give slight

amount of cyclic aziridine impurity. Interestingly, theinactive and sterically hindered mesylate 9 gave theazide 10 under microwave irradiation as the exclusiveproduct, which was not possible by conventionalmethod (Scheme I, Table I). Conversion of carbo-cyclic mesylates such as 11-14 into correspondingazides by conventional methods was accompanied byformation of a side product, identified as the cyclicurea (Scheme III, 19) in 7-10% yield, where thestructure was confirmed by NMR and X-raycrystallography (Figure 1). This is probably formedby the thermal decomposition of azide accompaniedby the rearrangement with the adjacent carbamate(Boc) functionality (Scheme III). However, under

,

1494 INDIAN 1. CHEM., SEC B, JUNE 2006

microwave irradiation, no such impurities wereobserved. In general, conversions of trans-cyclohexyl(pentyl) mesylates are very rapid with slightlyimproved optical purities of the products (Scheme II,

aNHBOC

( * DMF.t, MW

1 "'OMS(1R,2R)

n = 1, Cyclopentyl 112, Cyclohexyl 12

2 \\\NHBoc(cr' - DMF.* MW

1 OMS(1S,2S)

n = 1, Cyclopentyl 132, Cyclohexyl 14

ctNHBOC

( **1 N3

(1S,2R)

1516

a~\\\'NHBOC( *

*1""'N

3(1R,2S)

1718

Scheme II - Azidation of carbocyclic mesylates

Table II). Azidation of mesylate accompanied by theinversion of configuration and is clearly seen from thecrystal structures of mesylate 12 and correspondingazide product 16 (Figure 2). The carbocyclic 1,2-diamines were obtained by the reduction of theseamino azides as reported+".

1,2-Diamines are an important class of compounds,with applications as medicinal agents':", chiralauxiliaries' or as metal ligands in catalyticasymmetric synthesis 11.12. They are also present inmany natural products with potential biologicalproperties':':'. Utilizations of the optically pure vicinall-azido-2-carbocyclic amines and their derivativeslead to the development of synthetic methods for thepreparation of 1,2-diamines in their optically pureform. As compared to trans-l ,2-cyclohexyl diamines,cis- I,2-cyclohexyl (pentyl) diamines have not beenexploited to their full potential, in medicinalchemistry" and in catalytic asymmetric synthesis.This is perhaps due to difficulty in obtaining chirallypure cis-l ,2-cycl ic diamines. We recentlydemonstrated the potential of these cis-l,2-diamines(both cyclohexyl and cyclopentyl) in designingconstrained PNA analogues for DNA and RNAdiscrimination't", The microwave procedure discussedhere would be helpful in access a variety of such

Table 1 - Microwave assisted transformations (Scheme I)

Conventional method Microwave irradiationSubstrate Product Time Yield [a]D Time Yield [a]D

(hr) (%) (min) (%)

1 2 9 95 _27° a 2 99 _29° a

3 4 9 96 _240 b 2 99 _240 b

5 6 12 84 _100 c 4 99 -II ° C

7 8 6 75 2 98

9 10 ntd 2 96

a for azides 2 (c 2.28, CHzCI2) at 20°C.b for azides 4 (c 1.37, CHzClz) at 20°CC for azides 6 (c 0.52, CHCI)) at 20°Cd no transformation

Table II - Comparative results on (lS,2R/I R,2S)-azides (Scheme II)

Conventional method Microwave irradiationSubstrate Product Time Yield ·[a]D Time Yield ·[a]D

(hr) (%) (min) (%)

11 15 5 91 +116° 12 97 +117°

12 16 12 87 +102° 8 99 +104°

13 17 5 91 -116° 12 97 _117°

14 18 12 87 -105° 8 99 -105°

a for cyclopentyl azides (c 1.0, CH2CI2) at 20°C.a for cyclohexyl azides (c 1.5, CH2CI2) at 20°C.

------------------ ------~- ----

GOVINDARAJU: MICROWAVE ASSISTED CONVERSION OF MESYLATE TO AZIDE

o

c

oFigure I-Ortepl7 diagram of urea derivative 19

1495

O:::::Nt~--N-":o::::,~>=oo-~~ H17 19

Scheme III -Thermal decomposition of azide 17

L

Figure 2-0rtepl7 diagrams of (a) (IR,2R)-mesylate 12

optically pure azido precursors.In all the microwave irradiation experiments

involving formation of azide products, no incidentshave been observed. The sophisticated single modemicrowave reactors enable the fine control oftemperature and pressure during the microwavereactions, ensuring the safety".

In summary, this report demonstrates the use ofmicrowave-assisted synthesis of substituted azides,which are immediate precursors of aminefunctionality. This procedure is efficient, rapid, cleanand high yielding process, and a better alternative toconventional method. Our synthesis provides an easyaccess to the optically pure enantiomers of cis-l ,2-cyclohexyl and cyclopentyl diamines, which areotherwise difficult to obtain from other methods ascompared to trans-diamines which are commerciallyavailable.

Experimental Section

General. Melting points of samples weredetermined in open capillary tubes on Bruker meltingpoint apparatus B-540 and are uncorrected. IR spectrawere recorded on an infrared Fourier Transformspectrophotometer using KBr pellets or as neat; IHand I3C NMR spectra on Bruker 200 MHz and 500MHz NMR spectrometers (chemical shifts in 0, ppm)and mass spectra were obtained either by FAB or

LCMS techniques. Column chromatographic separa-tions were performed using silica gel 60-120 mesh,solvent systems 10-25% EtOAc-pet. ether and pureDCM to 3% MeOH/DCM.

Conventional method. A stirred mixture of the(1S,2S)-2-(N-t-Boc-amino )cyclopentan-l-methyl sulfo-nate" 13 (700 mg, 2.5 mmoles) and NaN3 (1.3 g, 20.0mmoles) in DMF (5 mL) under nitrogen atmospherewas heated at 68-70°C for 5-6 hr. After cooling thereaction mixture, the solvent was evaporated underreduced pressure. The residue was extracted into ethylacetate (10 mL x 2) and dried over Na2S04. Theorganic layer was removed and the crude product waspurified by column chromatography (EtOAc-pet. ether)to afford white solid of (1R,2S)-2-(-(N-t-Boc-amino)-I-azidocyclopentane 17, yield 91%, [a]~o-116° (c LO,CH2Cb), and the side product 19 (yield 7%).

cis-Cyclopentyl-l,3-urea 19: m.p. 143.0°C; IR(KBr): 3280.69,3016.46,2970.17,1745.46,1409.87,1244.0, 1215.07, 1114.78, 1039.56, 991.34, 946.98,756.04 em"; IH NMR (CDCI3, 200 MHz); 01-1 1.25-1.75 (m, 4H), 1.75-1.9 (s, 2H), 3.9-4.1 (s, IH), 4.75-4.9 (s, IH), 6.5-6.85 (bd, 2H); I3CNMR (CDCI3, 200MHz): Oc 21.5, 33.7, 34.1, 56.5, 81.9, 160.3; Anal.Calcd for C6HION20: C, 57.14; H, 7.93; N, 22.22.Found: C, 56.91; H, 7.97; N, 21.87 (%); MS, LCMS:128.03 [M+2(

•1496 INDIAN 1. CHEM., SEC B, JU E 2006

Crystallographic data for compound 19. Single 3.7 (m, IH), 3.76 (s, 3H, OCH)), 3.8-4.1 (m, IH), 4.2-crystal of cis-cyclopentyl-l,3-urea 19 (colourless 4.5 (bd, IH); I3C NMR (COCl), 300 MHz): Oc 26.4,needles) was obtained from ethyl acetate and 28.1, 33.4, 34.3, 49.1, 52.2, 58.0, 81.0, 118.7, 152.9,petroleum ether. X-ray intensity data was collected on 171.6; Anal. Calcd for C"H,sN404: C, 48.88; H, 6.66;a Bruker SMART APEX CCO diffractometer at room N, 20.74. Found: C, 48.67; H, 6.71; N, 20.57 (%);temperature. - LCMS:271.0[M+l],171.0[M+I-CBoc].

Crystal data of cis-cyclopentyl-l,3-urea 19 (2S,4S)-4-Azido-N-l-benzyloxycarbonyl proline(C6H ION20); M = 126.16; Crystal system: Monoclinic; methyl ester 4: Yield 99%, IR (Neat): 2953, 2106,Crystal dimensions: 0.75 x 0.14 x 0.13 mm, a = 1753,1711,1499,1416 ern"; [0.]~o-24.00 (e 1.37,10.322(3), b = 5.5641(18), e = 11.284(4) A, spacegroup P 2(1),V = 643.5 (4) A3, Z = 4, Dc = 1.302 g CH2CI2); 'H NMR (COCI3, 200 MHz): 0" 2.00-2.15cm", f1 (Mo-Ko.) = 0.091 rnm", T= 293(2) K, F(OOO) (m, IH, C3' H), 2.17-2.33 (m, IH, C)-H), 3.45-3.7 (m,

5H, Cs H, -OCH3), 4.04-4.16 (m, 1H, C4 H), 4.43-4.31= 272, Max. and min. transmission 0.9882 and0.9347,3149 reflections collected, 2090 unique [1> (dd,J=8, 16, IH,C2-H),4.9-5.17(m,2H,-CH2Ph),

7.23-7.27 (m, 5H, C6HS); '3C NMR (COCl3, 30020' (I)], 5= 1.116, R value 0.0595, wR2 = 0.1559 (alldata R = 0.0638, wR2 = 0.1543). CCOC No. 249728 MHz): s, 34.9 (35.9), 51.0 (51.3), 52.2 (52.3), 57.4

hi d fI (57.6),58.1 (59.0),67.1, 125.1, 127.7, 127.9, 128.3,contains the supplementary crystallograp IC ata or 128.8, 136.1, 153.9 (154.3), 171.4 (171.6); Anal.this compound. 8Calcd for CI4H'6N404: C, 55.26; H, 5.26; N, 1(.42.

Microwave irradiation. The mixture of mesylate Found: C, 55.19; H, 5.31; N, 18.19 (%); LCMS: 305.0(15,25)-13 (ref. 16) (700 mg, 2.5 mmoles) and NaN3 [M+l], 205.0 [M+l-t Boc].(0.32 g, 5.0 mmoles) in OMF (5 ml.) was taken in aconical flask covered with filter funnel. The above (2S,4S)-2-Azidomethyl-4-azido-N-1-(tert-butoxy-reaction mixture was irradiated in a microwave oven carbonyl) pyrrolidine 6: Yield 99%, IR (neat):

. Th . . d 3365.5,2977.8,2935.4,2104.19, 1695.31, 1392.51,(BPL-Sanyo) at 90°C for 12 rmn. e reaction peno swere standardized by irradiating the reaction mixtures 1265.2, 1164.9, 1118.6, 773.4 em"; [0.] ~o-11.0 (ein 1-6 cycles, each of 2 min interval and 1 min rest. 0.52, CHCb); 'H NMR (COCl), 200 MHz): OH 4.20-OMF (l00 mL) was placed in another vessel and 4.05 (rn, IH), 4.05-3.90 (m, IH), 3.80-3.65 (m, IH),irradiated simultaneously. The progress of the reaction 3.65-3.55 (m, 2H), 3.40-3.25 (m, 1H), 2.35-2.20 (m,was monitored by TLC (in every 2 min interval). After IH), 2.10-2.00 (m, IH), 1.45 (s, 9H); ,)C MRcooling to room temperature, the solvent evaporated (COCl), 200 MHz): Oc 27.9, 33.5, 51.3, 52.7, 55.5,and the residue was extracted in to EtOAc (10 mL x 2) 58.6, 79.8, 153.4; Anal. Calcd for C'OH'7N702: C,and dried over Na2S04. The organic layer was removed 44.94; H, 6.36; N, 11.98. Found: C, 44.76; H, 6.71; N,and passed through the silica gel column to give the 11.68 (%); MS (FAB+): 268 [M+ 1].azide (lR,25) 17, yield 97%, [0.] ~o-117° (e 1.0, (1S,2R)-2-(N-t-Boc-amino)-I-azidocyclopentaneCH2CI2); m.p. 81.0°C; IR (KBr): 3442.7, 3014.53, 15: Yield 97%; [0.]~0+117° (e 1.0, CH2Ch); m.p.2995.24,2113.84,1706.88 em"; 'H NMR (COCb, 200 81.00C; IR (KBr): 3442.7,3014.53,2995.24,2113.84,MHz): 0" 1.0-1.45(m, IIH, CH2, t-Boc), 1.65-2.0 (m, 1706.88 ern"; 'H NMR (COCl3, 200 MHz): 0" 1.0-4H, C5H2, C3H2), 3.7-4.1 (m, 2H, Cl H. C2H), 4.6-5.0 1.45 (m, 11H, 4-CH

2, t-Boc), 1.65-2.0 (m, 4H, 5-CH2,

(bd, IH,carbamateNH); 13CNMR(COCh,200MHz): 3-CH2),3.7-4.1 (m,2H, I-CH,2-CH),4.6-5.0(bd, IH,Oc 19.8,28.2,28.7,29.0,54.7,64.1, 79.4, 155.3; Anal. carbamate NH); '3C NMR (COCI

3, 200 MHz): Oc

Calcd for C'OH'8N402: C, 53.09; H, 7.96; N, 24.7}. 19.8,28.2,28.7,29.0,54.7,64.1,79.4, 155.3; Anal.Found: C, 52.55; H, 7.98; N, 24.71 (%); MS (FAB ): C I d C' C H NO C 5309' H 796' N 2477a c lor '0 '8 4 2: , . , , . , , . .227 (35%) [M+l], 171 (100%) [M+l- N3], 127 (15%) Found: C, 52.55; H, 7.98; N, 24.71 (%); MS (FAB+):[M+I- t Boc]. 227 (35%) [M+I], 171 (100%) [M+l- N3], 127 (15%)

(2S,4S)-4-Azido-Nl-butyloxycarbonyl proline [M+ 1- t Boc].methyl ester 2: Yield 99%, IR (Neat): 3357, 2979, (JR, 2R)-2-(N-t-Butyloxycarbonylamino)-cyclo-2935,2105,1751,1704,1400,1261,1193,1161 em"; hexan-l-methyl sulfonate 12: Crystal data:[0.] 1°'...£29:0°(e2.28, CH2Ch); 'H NMR (COCl), 200 C'2HnNOsS, M = 293.37; Crystal system: Orthorhorn-MHz): 0" 1.2-1.6 (d, 9H, Boc), 2.2-2.4 (m, IH), 3.5- bic; Crystal dimensions: 0.67 x 0.08 xO.04 mm, a =

••••••••••............. --------------------GOVINDARA.lU: MICROWAVE ASSISTED CONVERSION OF MESYLATE TO AZIDE

5.232(3), b = 9.090(4), c = 32.408(16) A, space groupP2(1)2(1)2(1), V = 1541.4(13) A3, Z = 4, Dc =

1.264 g cm ", J.1 (Mo-Ko.) = 0.225 mm', T = 293(2)K, F(OOO) = 632; Max. and min. transmission 0.9911and 0.8649, 7601 reflections collected, 2709 unique[/>20 (I)], S = 1.191, R value 0.0543, wR2 = 0.1224(all data R = 0.0644, wR2 = 0.1370).

(IS,2R)-2-(N-t- Butyloxycarbonyla mino )-l-azido-cyclohexane 16: Yield 99%, m.p. 69-70°C; IR (KGr):3359,2954,2104,1720,1681,1367,1319 and 1166ern"; [a]~)o+ 104° (c 1.5, CH2C!2); IH NMR (CDCll,500 MHz): 0" 1.21-1.35 (Ill, IH), 1.35-1.51 (12H),1.52-1.64 (rn, 2H), 1.65-1.77 (m, I H), 1.89-2.0 I (m,11-1),3.5-3.65 (bd, IH), 3.8-4.0 (bd, I H), 4.56-4.8 (bd,I H); "c NMR (CDCh, 500 MHz): Oc 19.6, 24.2,27.5, 28.2, 28.6, 51.0, 61.5, 79.4, 154.9; Anal. Calcdfor CIIH20N402: C, 55.00; H, 8.33; N, 23.33. Found:C, 55.18; 1-1,8.00; N, 23.14 (%); MS (FAS+): 241(35%), [M+I], 141 (15%) [M+l- t Bee].

Crystallographic data for compound 16: Singlecrystal of azide 16 (colourIcss needles) was obtainedfrom ethyl acetate and petroleum ether. X-rayintensity data was collected on a Brukcr SMARTAPEX CCD diffractometer at room temperature.

Crystal data of (1S,2R)-2-(N-t-butyloxycarbonyl-aminoj-l-azidocyclohexane 16: CIIH20N402; M =

240.31; Crystal system: Tetragonal; Crystal dimen-sions: 0.66 x 0.36 x 0.18 111m, a = 12.159(6), b =

12.159(6), c= 19.086(13) A, space group P4(3) 2(1) 2,V = 2821 (3) .A.3,Z = 8, Dc = 1.3 I g em-J, J.1 (Mo-Ko.) =

0.080 mm', T = 293(2) K, F(OOO) = 1040; Max. andmin. transmission 0.9860 and 0.9491, 14080 reflectionscollected, 2493 unique [/ >20 (I)], S = 1.143, R value0.0846, lvR2 = 0.2069 (all data R = 0.1 179, wR2 =

0.2283). CCDC No. 249729 contains the supple-mentary crystallographic data for this compound.

(I R,2S)-2-(N-t-Butyloxycarbonylamino )-l-azido-cyclohexane 18: Yield 99%, m.p, 69-70°C; IR(KBr): 3359,2954,2104,1720,1681,1367,1319

-I "0 Iand 1166 em ; [ali) -105.:n° (c 1.5, CH2C!2); I-INMR (CDCI], 500 MHz): 0" 1.21-1.35 (m,IH),I. 35- I. 5 I (I 2 H), 1.52- 1.64 (m, 2 H), 1.65- 1.77 (m,I H), 1.89-2.01 (m, I H), 3.5-3.65 (bd, I H), 3.8-4.0(bd, 1H), 4.56-4.8 (bd, I H); IJC NMR (CDCI3, 500MHz): Oc 19.6,24.2,27.5, 28.2, 28.6, 51.0, 61.5,79.4, 154.9; Anal. Calcd for CII H20N402: C, 55.00;1-1, 8.33; N, 23.33. Found: C, 55. 11; 1-1, 8.07; N,23.21(%); MS (FAS+): 241 (35%) [M+I], 141(15%) [M+ I-t Boc].

rlir

1497

AcknowledgementAuthor thanks the CSIR, New Delhi for Research

fellowship, to Dr K N Ganesh and Dr V A Kumar forvaluable guidance and encouragement.

References and Notes

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1498 I DIAN J. CHEM., SEC B, JU IE 2006

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15 www. Cem.com16 Cyclopcntyl mcsylates are unstable to acidic conditions as the

compounds were decomposed on silica gel colu nn whenattempted to purify, where as cyclohexyl mesylates are verystable.

17 Johnson C K, ORTEP II, report ORNL-5138, Oak RidgeNational Laboratory, Tcnnesse, USA (1976). (Incorporated inSIIELX TL package from Brukcr-axs).