Tetrahedron Letters 46 (2005) 7193–7196

TetrahedronLetters

A new reaction of diazomethane with norbornyl a-diketones

Faiz Ahmed Khan,* Rashmirekha Satapathy, Ch. Sudheer and Ch. Nageswara Rao

Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India

Received 29 June 2005; revised 8 August 2005; accepted 17 August 2005Available online 6 September 2005

Abstract—A new reaction of diazomethane with norbornyl a-diketones in MeOH as solvent leading regioselectively to ketals isdescribed. The mechanistic details of this intriguing reaction were investigated employing d4-MeOH, EtOH and d6-EtOH. The sur-prising observation of complete deuterium incorporation in the diazomethane-derived methoxy group was accounted for by sequen-tial deuterium exchange between the initially formed hemiketal d4-18 and diazomethane in the presence of d4-MeOH as solvent.� 2005 Published by Elsevier Ltd.

Over the last century, diazomethane has emerged as oneof the most versatile and indispensable one-carbon re-agents in organic synthesis.1 The commercial availabilityof stable solid precursors and apparatus to generate dia-zomethane safely, a yellow gas at room temperature, isperhaps an indicator of its widespread use.2 It is rou-tinely used for methylation and is a convenient reagentfor one-carbon chain elongation/ring expansion.3

Although a large number of examples of diazomethanereactions with ketones are documented in the literature,its reactions with a-diketones are limited. The reactionof camphorquinone is known to give a mixture of b-methoxyketones resulting from ring expansion followedby methylation of the two possible enols.3,4 A literaturesearch revealed that for ketones with electron withdraw-ing substituents, which possess a tendency to form stablehydrates or hemiketals in the presence of moisture oralcohol (e.g., methanol), exclusive formation of epoxideproducts was reported. Eistert�s pioneering work onreactions of diazomethane demonstrated that chloroqui-none gave the corresponding epoxide.5 Lemal et al. havereported an interesting example where treatment of tet-rafluorocyclopentadiene with diazomethane in methanolas solvent gave exclusively a spiro-epoxide.6 The forma-tion of the corresponding dimethyl ketal was clearlyruled out. In a very recent article, Haufe and co-workers

0040-4039/$ - see front matter � 2005 Published by Elsevier Ltd.doi:10.1016/j.tetlet.2005.08.087

Keywords: Diazomethane; a-Diketones; Ketal; Regioselectivity;Oxiranes.* Corresponding author. Tel.: +91 512 2597864; fax: +91 5122597436; e-mail: faiz@iitk.ac.in

reported the formation of spiro-epoxides from polyfluo-rinated cyclohexa-2,5-dienones.7 In a study of solvent ef-fects on the reactivity of 1,10-phenanthroline-5,6-dionetowards diazomethane, Antkowiak and Sobczak re-ported the formation of 5,6-methylenedioxy-1,10-phe-nanthroline as the only product when an aproticmedium such as THF, ether or CH2Cl2 was used whileprotic solvents such as 2-propanol or ethanol resultedin the formation of the corresponding dispiro-epoxideas the main product. Surprisingly, MeOH as solventfurnished dimethyl 2,2 0-bipyridine-3,3 0-dicarboxylateresulting from cleavage of the C5–C6 bond as the onlyproduct, although in a very low (10%) yield.8

We have recently reported, a ruthenium catalyzed noveland efficient conversion of the dihaloalkene moiety intetrahalonorbornyl derivatives to the corresponding a-diketones.9 In connection with our interest to elaboratenorbornyl a-diketones to ring enlarged bicyclic systems,we became interested in studying the reaction of dia-zomethane with these compounds. We herein report,the observation of a new reaction of norbornyl a-dike-tones with diazomethane which furnished, in the major-ity of cases, predominantly ketals when the reaction wascarried out by adding ethereal solution of diazomethaneto the substrate dissolved in methanol. On the otherhand, when ether was used as the solvent, stereo- and re-gio-selective formation of spiro-epoxides was observed(Scheme 1).

Since a small amount of methanol as co-solvent isknown to suppress the formation of spiro-epoxideside-products,1 we initially carried out the reaction by

X

X

OMeMeO

O

O R2a R=Ph, X=Br

X

X

OMeMeO

O

R

MeO

MeO 2b

X

X

OMeMeO

O

RO2c

Solvent

CH2N2 (1) in ether

+

Solvent

MeOH 97 : 3Ether 0 : 100

Ratio (2b : 2c)Isolated Yield

93%90%

(2b+2c)

2-3 h, -10 oC

Ether : MeOH (10 : 1) 26 : 7495%

1

45

Scheme 1. Preferential formation of ketal 2b or epoxide 2c dependingon the solvent used.

7194 F. A. Khan et al. / Tetrahedron Letters 46 (2005) 7193–7196

adding a freshly distilled ethereal solution of diazome-thane 1 to a-diketone 2a in ether–methanol (10:1) at�10 �C. We were astonished to observe the formationof an unexpected product in 21% isolated yield whichwas characterized as ketal 2b. However, the major prod-uct isolated in 74% yield from this reaction turned out tobe the spiro-epoxide 2c. In the subsequent run, when thesolvent for 2a was changed to ether, epoxide 2c wasformed as the sole product. Surprisingly, when methanolwas used as the solvent, ketal 2b was formed as the prin-cipal product with only traces of 2c. This, to our knowl-edge, is the first example where selective ketal formationunder diazomethane reaction conditions has beenobserved.

Intrigued by the observation of the formation of ketals,we extended our study to a variety of monosubstitutednorbornyl a-diketones to probe the mechanistic detailsof this new reaction. Our results are summarized inTable 1. The ketal is the major product in all casesexcept for the bromoethyl and trimethylsilyl substitutedderivatives 9a and 11a (entries 7 and 9) when the reac-tions were carried out by dissolving the substrates inMeOH followed by the addition of an excess of an ethe-real solution of diazomethane at �10 �C. The reactionswere highly regioselective and gave a single regioisomerwith ketalization occurring at the carbonyl carbon diag-onally opposite to the substituent R. This unambiguousstructural assignment is based on a single crystal X-ray

Table 1. Reaction of diazomethane with monosubstituted norbornyla-diketones in MeOH as solvent

Entry Substrate X R Product Yielda

(%)Ratio(b:c)b

1 3a Cl Ph 3b,c 91 67:332 4a Cl OAc 4b,c 89 63:373 5a Cl CO2Me 5b,c 83 68:324 6a Cl OEt 6b,c 94 66:345 7a Cl CH2Cl 7b,c 89 74:266 8a Cl CH2Br 8b,c 88 80:207 9a Cl CH2CH2Br 9b,c 90 45:558 10a Cl CH2OAc 10b,c 82 70:309 11a Cl SiMe3 11b,c 88 23:7710 12a Br OAc 12b,c 90 66:3411 13a Br CO2Me 13b,c 92 74:2612 14a Br OEt 14b,c 90 68:32

a Isolated yield of analytically pure samples.b Determined from 1H NMR integration of reaction mixtures.

analysis of 2b and internal consistency in the 1H as wellas the 13C spectra across the entire series.10 On the otherhand, when ether was used as the solvent in place ofMeOH, spiro-epoxides 3–14c were formed in high yield(86–99%) as the sole products in all cases. Once again, asingle regioisomer resulting from attack of the reagenton the carbonyl carbon diagonally opposite to thesubstituent R was formed. Furthermore, the attack ofdiazomethane took place stereoselectively from theexo-face. The remarkable deshielding effect of theendo-oxygen of the epoxide moiety on the endo-protonof the methylene group (C-5) in the 1H NMR(400 MHz) of 2–14c provided structural proof whichwas further confirmed by NOESY and HMBC experi-ments (500 MHz) on 3c.

2a

Br

Br

OMeMeO

O

Ph

D3CO

D3CO2b (d6), 89%

Br

Br

OMeMeO

O

PhO2c, 4%

MeOH-d4

CH2N2 in ether+

3 h, -10 oC

ð1Þ

In order to gain mechanistic insight, the reaction of 2awas carried out using deuterated methanol as the sol-vent. Surprisingly, both the OMe groups of the newlyformed ketal moiety in 2b were completely deuteratedas evidenced from the complete disappearance of thecorresponding diagnostic singlets from the 1H NMRspectrum (400 MHz). Spiro-epoxide 2c, isolated in 4%yield, showed little incorporation of deuterium as indi-cated by the almost unaltered integral of the oxiranemethylene protons in the 1H NMR spectrum (Eq. 1).It appeared, at this stage, as though both the OCD3

groups of the newly formed ketal were derived fromthe solvent (d4-MeOH) unless there existed an efficientmechanism for deuterium exchange such that the dia-zomethane completely exchanged deuterium beforemethylating the intermediate leading to d6-2b.

To settle the issue, absolute ethanol was used as the sol-vent in place of MeOH and the results obtained with 2aunder these conditions are shown in Scheme 2. Interest-ingly mixed ketals 2b1,b2 were formed but could not beseparated for unambiguous characterization. Therefore12a was used for the same transformation which gavethe mixed ketals 12b1,b2 along with 29% of spiro-epox-ide 12c. Fortunately, the mixed ketals derived from 12awere resolvable on preparative HPLC to afford pure12b1,b2 which were characterized thoroughly. A singlecrystal X-ray analysis of 12b2 established the structureunequivocally.10 This experiment clearly demonstratedthat one of the alkoxy moieties in the newly formed ke-tal was derived from the solvent alcohol while the otheroriginated from diazomethane. Furthermore, unlike d4-MeOH, a varying amount of deuteration of the dia-zomethane-derived OMe group was observed when d6-EtOH was used as the solvent (Scheme 2) clearly indicat-ing that the efficiency of the exchange mechanism wasdifferent in the two cases.

Formation of diastereomer b2 was quite surprising be-cause initial nucleophilic attack of a reagent is preferred

Br

Br

OMeMeO

O

O R

2a R=Ph

Br

Br

OMeMeO

O

RMeO

EtO

2b1

Br

Br

OMeMeO

O

RO

2c, 11%

EtOH

CH2N2 in ether +

6 h, -10 oC

Br

Br

OMeMeO

O

R

MeO

EtO

2b2

+

12a R=OAc 12b1 12b2 12c, 29%

Yield (b1+b2)

57% (ratio=48:52)69% (ratio=22:78)

12a, EtOH-d6CH2N2 in ether

6 h, -10 oC

Br

Br

OMeMeO

O

OAcDnH(3-n)CO

D3CD2CO

Br

Br

OMeMeO

O

OAcO

+

Br

Br

OMeMeO

O

OAc

DnH(3-n)CO

D3CD2CO

+

12b1 (d5+n) 12b2 (d5+n) 12c, 30%Yield (b1+b2)

66% (ratio=34:66)Deuteration at -OCH(3-n)Dn (n=0 to 3): ~37% for 12b1 and ~74% for 12b2

Scheme 2. Reactions of 2a and 12a in EtOH as solvent.

F. A. Khan et al. / Tetrahedron Letters 46 (2005) 7193–7196 7195

from the exo-face, as evident from the exclusive forma-tion of epoxides 2–14c. Our earlier observations on allyl-indium addition to monosubstituted norbornyl a-diketones also substantiated this fact.11 Hence, initial at-tack of EtOH from the endo-face leading eventually tob2 is surely ruled out. A plausible mechanism is depictedin Scheme 3. While both diazomethane 1 and alcoholR1OH compete as nucleophiles for the addition at theelectrophilic carbonyl carbon, the latter predominateswhen pre-dissolved in alcohol R1OH (R1 = Me or Et)leading to the intermediate hemiketal 15. Abstractionof an acidic proton by 1 would lead to the ion pair 16which upon nucleophilic displacement by alkoxide fur-nished the diastereomer b1. On the other hand, the neg-ative charge on the alkoxide oxygen may be delocalized

X

X

OMeMeO

O

O R

X

X

OMeMeO

O

ROH

R1OSolvent: R1-OH

CH2N2 in ether-10 oC

CH2N2 in ether-10 oC

(R1=Me or Et) CH2 N N+

-N

X

OMeO

O

R1O

MeO

Solvent: ether

2-14c

X

X

OMeMeO

O

RO

N2

+

b1 (R1=E

15

1

20

X

Me

O

O

R1O

CH3

Scheme 3. A plausible mechanism for the formation of diastereomeric b1 an

onto the carbonyl oxygen via endo-oxirane intermediate17. The endo-oxirane 17 is capable of reorganizing itselfto the exo-oxirane 18 by an intramolecular nucleophilicattack on the adjacent carbon, thereby inverting theOR1 group to the endo-position leading to ion pair 19and finally to diastereomer b2 (the cationic part forion pairs 17 and 18 is not shown for clarity). The regio-and stereo-selective formation of spiro-epoxides 2–14c,in the absence of the alcohol R1OH, proceeds via the tet-rahedral betaine intermediate 20.

As far as deuteration of the diazomethane-derived OMegroup of the newly formed ketal in 2b and 12b is con-cerned, we believe that sequential deuterium exchangefrom the initially formed d4-15 gives rise to d3-15 and

2

X

Me

R -N2

X

X

OMeMeO

O

RR1O

MeO

t)

6

17 18

19

b2 (R1=Et)

X

X

OMeMeO

O

RR1O

OH

diastereomer of 15

-1

X

OMeO

R

N N+

X

X

OMeMeO

O

R

R1O

O

X

X

OMeMeO

R

O

R1OO

X

X

OMeMeO

O

RR1O

OCH3NN

+

d b2.

X

X

OMeMeO

O

O R

X

X

OMeMeO

O

RDO

D3COCD3ODCH2 N N

+

15 (d4)

16 (d4) (1st cycle)

X

X

OMeMeO

O

ROH

D3CO

15 (d3)

+

CDH N N+

1 (d1) (1st cycle)1

CD3OD (solvent)

i) 1st cycle

ii) 2nd cycle1 (d1)

1 (d2) (2nd cycle)

iii) 3rd cycle1 (d2)

CD2 N N+

+

X

X

OMeMeO

O

RO

D3CO

CDH2 N N

16 (d6)

X

X

OMeMeO

O

RO

D3CO Br

Br

OMeMeO

O

Ph

D3CO

D3CO2b (d6)

16 (d5) (2nd cycle)

12

35

CD3NN+

Scheme 4. A plausible mechanism for the deuterium exchange.

7196 F. A. Khan et al. / Tetrahedron Letters 46 (2005) 7193–7196

d1-1 via d4-16 in the first cycle. Similarly, d3-15 and d2-1are formed from d4-15 and d1-1 via d5-16 in the secondcycle (Scheme 4). Finally, the ion pair d6-16, formed inthe third cycle leads to 2b (or 12b). The unambiguousevidence for the formation of diastereomers of d4-15came from 1H and 13C NMR spectra of diketone 2ain d4-MeOH. A pair of singlets for the OMe groups ofeach diastereomer of d4-15 and a diagnostic influenceof the endo-oxygen substituent on the C-5 methyleneprotons which now appear in the 2.83–2.72 ppmrange,12 closely matching ketal 2b, were observed in1H NMR.13 In 13C NMR, the two carbonyl signalsat 188.3 and 187.1 ppm observed in CDCl3 for thediketone moiety in 2a completely vanished in d4-MeOHto give two close pairs at 198.9, 198.5 and 97.5, 97.1 forthe C-2 carbonyl and C-3 hemiketal carbons for eachdiastereomer of d4-15, respectively.

13

In conclusion, we have observed a novel reaction ofdiazomethane with norbornyl a-diketones which gaveketals regioselectively as the major products whenmethanol was used as the solvent. Changing the solventto ether provided a regio- and stereo-selective entry tospiro-epoxides. A mechanism is proposed to accountfor the formation of the unusual diastereomer as wellas deuterium exchange in the diazomethane-derivedOMe group of the newly formed ketal. The finding thatdiazomethane can be used to prepare ketals under neu-tral conditions adds yet another, hitherto unknown,dimension to the versatility of this century old one-carbon reagent and may be used in sophisticatedapplications.

Acknowledgements

This work was supported by the Department of Scienceand Technology (DST), New Delhi. F.A.K. acknowl-

edges the DST for a Swarnajayanti Fellowship. R.S.,C.S. and C.N.R. thank CSIR/UGC for fellowships.

References and notes

1. Sammakia, T. In Handbook of Reagents for OrganicSynthesis: Reagents, Auxiliaries and Catalysts for C–Cbonds; Coates, R. M., Denmark, S. E., Eds.; John Wileyand Sons Ltd: Chichester, UK, 1999.

2. Black, T. H. Aldrichim. Acta 1983, 16, 3–10.3. Krow, G. R. Tetrahedron 1987, 43, 3–38.4. (a) Favre, P. H.; Marinier, B.; Richer, J.-C. Can. J. Chem.

1956, 34, 1329–1339; (b) Shitole, H. R.; Nayak, U. R.Indian J. Chem. 1984, 23B, 415–417.

5. (a) Eistert, B.; Juraszyk, H. Chem. Ber. 1970, 103, 2707–2708; (b) Eistert, B.; Fink, H.; Muller, A. Chem. Ber. 1962,95, 2403–2415; (c) Eistert, B.; Bock, G. Chem. Ber. 1959,92, 1247–1257.

6. Lemal, D. M.; Klopotek, D. L.; Wilterdink, J. L.;Saunders, W. D. J. Org. Chem. 1991, 56, 157–160.

7. Kovtonyuk, V. N.; Kobrina, L. S.; Kataeva, O. M.;Haufe, G. Eur. J. Org. Chem. 2005, 1178–1183.

8. Antkowiak, W. Z.; Sobczak, A. Tetrahedron 2001, 57,2799–2805.

9. (a) Khan, F. A.; Prabhudas, B.; Dash, J.; Sahu, N. J. Am.Chem. Soc. 2000, 122, 9558–9559; (b) Khan, F. A.; Sahu,N. J. Catal. 2005, 231, 438–442.

10. Details of the X-ray analysis will be published in a fullaccount.

11. Khan, F. A.; Dash, J. Eur. J. Org. Chem. 2004, 2692–2700.12. Khan, F. A.; Dash, J.; Sudheer, Ch. Chem. Eur. J. 2004,

10, 2507–2519.13. To ensure that the chemical shift changes are not just due

to the solvent, d4-MeOH, 1H and 13C NMR spectra ofdiketone 2a in CDCl3 were also recorded with and withoutadded MeOH. When 2 equiv of MeOH were introducedinto a solution of 2a in CDCl3, a �70% diastereomericmixture of 15 (as determined from the 1H NMR integral)showing a similar change in chemical shift values, wasobserved. In d4-MeOH, 2a was completely converted tothe diastereomeric hemiketals 15 (ratio: �57:43).