Recent Reviews:

Matt Mitcheltree

Chiral-pool starting materials have been much used as substrates for the Favorskii reaction, affording functionalized, optically active cyclopentanes.

Chem 115Methods for Ring ContractionMyers

Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556.Silva, Jr. L. F. Tetrahedron 2002, 58, 9137–9161.

•

OCl

O OCH3NaOCH3

Et2O, 35 °C, 2 h

56–61%

O

CH3CH3

O

CH3

(+)-Pulegone

Br2

Et2O

CH3

O

Br CH3CH3

BrCH3 CH3

CO2CH3

CH3

O

CH3 H

H OO CH3

CH3CH3

CH3H

H

CH3CH3

CH3CH3

H

60–67% (2 steps)

(+)-Epoxydictymene (–)-Iridomyrmecin

CH3

(+)-Acoradiene

Common intermediate: Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel's Textbook of Practical Organic Chemistry. 5th ed. Longman: London, 1989.(+)-Epoxydictymene: Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353–4363.(–)-Iridomyrmecin: Wolinsky, J.; Gibson, T.; Chan, D.; Wolf, H. Tetrahedron 1965, 21, 1247–1261.(+)-Acoradiene: Kurosawa, S.; Bando, M.; Mori, K. Eur. J. Org. Chem. 2001, 4395–4399.

CH3

O

(–)-Carvone

OCH3

Cl

THPO

THPO

CH3 CO3CH3

CH3 CH3

80%

Lee, E.; Yoon, C. H. J. Chem. Soc., Chem. Commun. 1994, 479–481.

Anionic Ring ContractionsFavorskii Rearrangement

X

O

O O Nu

O Nu

OM ROR

Anionic

Carbenoid

CationicFor example, the ring contraction of a (+)-pulegone derivative has been used in the synthesis of several terpenoid natural products.

•

Ring contraction reactions can be grouped into three general categories based on mechanism:•

The Favorskii reaction leads to the rearrangement of an !-halo cycloalkanone upon treatment with base. This reaction proceeds through a cyclopropanone intermediate that is opened by nucleophilic attack.

•

NaOCH3

CH3OH

1. TMSCl

Nu:

Nu:

H2O2

NaOH

CH3

O

CH3

O2. DHP, p-TsOH

NaOCH3CH3OH

90% 81% (2 steps)

Cope, A. C.; Graham, E. S. J. Am. Chem. Soc. 1951, 73, 4702–4706.Loftfield, R. B. J. Am. Chem. Soc. 1951, 73, 4707–4714.

OCH3

Organic syntheses; Wiley & Sons: New York, 1963; Coll. Vol. No. 4, pp. 594.

In some cases, enolization is not possible, precluding cyclopropanone formation. An alternate mechanism involves formation of a tetrahedral intermediate that promotes alkyl migration.

•

O

H

Br

H

BrOHOH

Ag+CO2H

H71%

H2O, t-BuOH

AgNO3

O

HCH3

THPOCH3CH3

1

Quasi-Favorskii Rearrangement

Matt Mitcheltree

Chem 115Methods for Ring ContractionMyers

Also referred to as the negative-ion pinacol rearrangement, the quasi-Favorskii rearrangement involves an alkyl shift with concomitant nucleophilic displacement of an aligned leaving group.

•

CH3HOOTs KOt-Bu

THF

CH3O OCH3

90%, 89 : 11

+

Hamon, D. P. G.; Tuck, K. L. Chem. Commun. 1997, 941–942.

Br

OH

Br

OH H

CHO

H

OH

LAH

98%

Harmata, M.; Bohnert, G.; Kürti, L.; Barnes, C. L. Tetrahedron Lett. 2002, 43, 2347–2349.

HO OH

CH3

OMsO

CH3CH3

O

Marshall, J. A.; Brady, S. F. J. Org. Chem. 1970, 35, 4068–4077.

These fragmentations are generally accelerated by oxyanion formation.•

60% (2 steps)

2. KOt-Bu H

CH3

CH3

H

HO

CH3

CH3

(±)-Hinesol

A quasi-Favorskii ring contraction was employed by Harding in the synthesis of (±)-sirenin. The stereochemical outcome of this rearrangement suggests formation of a tetrahedral intermediate that undergoes alkyl shift with halide displacement, rather than cyclopropanone formation as in the classic Favorskii rearrangement.

•

OBn

O

CH3Cl

H

HAgNO3

CH3OH

CH3O

ClCH3H

OH

OBn

CH3

CH3O2C

OBnH

H

Ag+

OH

CH3

CH3HO H

H

(±)-Sirenin

53%

Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org. Chem. 1988, 53, 4877–4883.

CH3 HOBn

O

A common application of the quasi-Favorskii rearrangement is in the rearrangement of fused polycycles.

•

OTsHO

O

O

OHCH3

OO

H

CH3

OO

OTs

OHCH3

HO

O

O

OCH3

HCH3

O

O

87%

(±)-Confertin

LiOH

t-BuOH, 65 °C

Heathcock, C. H.; DelMar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907–1917.

OTs

O

CH3

1. MsCl (1 equiv), pyr

2

Quasi-Favorskii Rearrangement

Matt Mitcheltree

Chem 115Methods for Ring ContractionMyers

Harmata has showcased the power of the quasi-Favorskii rearrangement in the synthesis of several terpenoid natural products.

•

Cl ClO O

HCHO

CH3

H CH3

H H

OH

CH3 CH3

O O

1. LAH2. KH

76% (2 steps)

Harmata, M.; Rashatasakhon, P. Org. Lett. 2001, 3, 2533–2535.

O

Br

HCH3CH3

1. LAH2. KH

91% (3 steps)

CH3CH3

OH

HCH3CH3

CH3

CH3

(±)-Sterpurene

Harmata, M.; Bohnert, G. J. Org. Lett. 2003, 5, 59–61.

Carbenoid Ring ContractionsWolff RearrangementReviews:

Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256.Meier, H.; Zeller, K.-P. Angew. Chem. Int. Ed. 1975, 14, 32–43.

The Wolff rearrangement involves the transformation of an !-diazo ketone via carbene or carbenoid to a ketene, which undergoes further transformation to form a stable adduct.

•

The Wolff rearrangement may be induced by heat, Ag(I) salts, or light.•

R1 R2O

N2R1 R2

O

R1 R2

Oh", #, or AgI Nu-H

R1 R2

O Nu

Nu = -OCH3, -OBn, -OH, -NR2, SR, etc.

ON2

O OCH3h", CH3OH

In the prototypical case depicted below, the Wolff rearrangement proceeds in higher yield relative to the analogous Favorskii system.

•

Tomioka, H.; Okuno, H.; Izawa, Y. J. Org. Chem. 1980, 45, 5278–5283.

> 99%

N2

O

CO2CH3

H

H

CO2CH3

h", CH3OH

92%, 88 : 12

+

Kirmse, W.; Wroblowsky, H.-J. Chem. Ber. 1983, 116, 1118–1131.

OCH3

OH

H+

The stereochemistry of the ! position can be kinetically controlled, determined by the relative rates of protonation of the enol or enolate intermediate.

•

(±)-Spatol

3. LAH

Stereochemistryestablished by X-ray

H+

3

Matt Mitcheltree

Chem 115Methods for Ring ContractionMyers

Ketene intermediates produced in the Wolff rearrangement can also be trapped in [2+2] cycloaddition reactions.

•

O O

O ON2

CH3 CH3

O O

CH3 CH3

OO

h!, THF R' R'

R

R' R'

ROO

O

CH3 CH3

O[2+2]

R R' Yield

H H 84%CH3 CH3 64%

CH3 H 76%

H 54%Ph

Stevens, R. V.; Bisacchi, G. S.; Goldsmith, L.; Strouse, C. E. J. Org. Chem. 1980, 45, 2708–2709.

Livinghouse, T.; Stevens, R. V. J. Am. Chem. Soc. 1978, 100, 6479–6482.

Danheiser and Helgason used such a strategy in the synthesis of salvilenone. The [2+2] cycloadduct in this case underwent retro-[2+2] ring opening followed by electrocyclization.

•

BrN2 O

CH3

h!, DCE

Br

HO OTIPSi-Pr

OTIPS

i-Pr+

O

i-Pr

OTIPS

CH3

Br

CH3

OTIPSi-Pr

OBr

Oi-Pr

O

CH3

CH3

CH3CH3

retro[2+2]

Danheiser, R. L.; Helgason, A. L. J. Am. Chem. Soc. 1994, 116, 9471–9479.

Salvilenone 61–71%

80 °C

Wolff Rearrangement Synthesis of diazo ketones

Compounds such as 1,3-dicarbonyls can be diazotized directly using arenesulfonyl azide reagents.•

In the absence of a " activating group, #-diazo ketones can be formed by formylation-diazotization-deformylation, in a procedure known as Regitz diazo transfer.

•

Similarly, in the Danheiser procedure, reversible #$trifluoroacetylation activates the substrate toward diazotization.

•

O

R

O

R H

OH

NaH

O

ORH N3SO2Ar

R3N

O

RN2

O

R

O

R CF3

OH

LiHMDS

N3SO2Ar

R3N

O

RN2

CF3

O

O

CF3

Danheiser, R. L.; Miller, R. F.; Brisbois, R. B.; Org. Synth. 1996, 73, 134–143.Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959–1964.

ReviewDoyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds. Wiley-Interscience, New York, 1998, pp. 1–60.

See course handout "C–O Bond-Forming Reactions" for further discussion of the synthesis of diazo compounds.

Regitz, M.; Maas, G. Diazo Compounds, Academic Press, New York, 1986, pp. 199–543.Regitz, M. in: The Chemistry of Diazonium and Diazo Groups, Part 2 (Ed.: Patai, S.), Wiley-Interscience, Chichester, 1978, pp. 751–820.

Direct Diazotization

R R'

O O N3SO2ArR R'

O O

N2Et3N

4

Matt Mitcheltree

Chem 115Methods for Ring ContractionMyersSynthesis of diazo ketones

NaHHCO2Et

O HOH

N3TfEt2NH

h!CH3OH

85% 95% 60%

t-BuOOH160 °C

45%Eaton, P. E.; Nyi, K. J. Am. Chem. Soc. 1971, 93, 2786–2788.

Sequential Regitz diazotization–Wolff rearrangement was applied by Eaton and Nyi in their synthesis of [3.2.2]propellane. Thermolytic decarboxylation of a tert-butyl perester provides the final product after ring contraction.

•

O O N2 CO2CH3

OO O

N2

CO2HO

H(CH2)7CO2CH3

+h!

1. NaHMDS, HCO2Et2. N3Ts, Et3N

1. h!, CH3OH2. LiOH

78% 62% (2 steps)

HCHO

1. Regitz2. h!, CH3OH

3. DIBAL-H4. Swern

43% (4 steps) 86% (2 steps)

Pentacycloannamoxic acid methyl ester

Mascitti, V.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 3118–3119.

Similarly, Corey and Mascitti use two Regitz diazotization–Wolff rearrangement reactions in sequence in their enantioselective synthesis of pentacycloannamoxic acid methyl ester.

•

In the Mandler procedure, enolized ketones are diazotized without the assistance of an activating group. These reactions are generally run under phase-transfer conditions, and are therefore not ideal for substrates sensitive to aqueous base (e.g., esters).

•

Lombardo, L.; Mandler, L. N. Synthesis 1980, 368–369.

R

O

R

ON2

1:1 H2O–C6H6

N3SO2Mes(n-Bu)4NBr, KOH, 18-cr-6

N

NN

N

NH2

OTBSO

O

BOTBSO

O

BOTBSO

ON2(CH3)2N

N(CH3)2

HCH3OCH3O

80%

N3Tf

72%

ON

OH

HO

N

N N

NH2

OxetanocinNorbeck, D. W.; Kramer, J. B. J. Am. Chem. Soc. 1988, 110, 7217–7218.

Mild conditions to activate cyclic ketones using dimethylformamide dimethyl acetal have been developed. The resulting enamine intermediates undergo diazotization with electron-poor diazo transfer reagents such as triflyl azide (N3SO2CF3). This approach was used in the synthesis of oxetanocin, a bacterial isolate with anti-HIV activity.

•

Wolff Rearrangement – Applications in target-oriented synthesis

5

Matt Mitcheltree

Chem 115Methods for Ring ContractionMyersWolff Rearrangement – Applications in target-oriented synthesis

O

HOCH3

H

H

CH3 CH3 CO2CH3H

HHOCH3

CH3 CH3H

HHOCH3

CH3 CH3

!9(12)-Capnellene

CH3CH3

CH3OCH3

CH3CH3H H

CH3

CH3CH3

H

CH3

48%

83% Pentalenene

CH3O2C

Ihara, M.; Katogi, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 1988, 2963–2970.

Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 1992, 865–873.

The Wolff rearrangement has been employed in the construction of the fused 5,5,5-tricyclic cores of sesquiterpenes.

•

N

O OBn

H

BocHN

N

CO2CH3

BocHN

HOBn

N

HNO

(±)-Meloscine

Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598–2610.Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Org. Chem. 1989, 54, 1236–1238.

Where other methods failed, the Mandler procedure enabled Overman and co-workers to diazotize a ketone en route to (±)-meloscine.

•

Cation-type rearrangementsPinacol Rearrangement

ReviewsSong, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556.Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143–7157.Overman, L. E. Acc. Chem. Res. 1992, 25, 352–359.

Vicinal diols, when treated with acid, generate a transient cation that may undergo alkyl shift coupled with carbonyl formation.

•

OHOH

OHCH3

CH3

CH3CH3

CH3OCH3H+

Pavlik, C.; Morton, M. D.; Smith, M. B. Synlett 2011, 2191–2194.68–72%

H

CH3OHO

CH3

CH3

BF3•OEt2

C6H6, refluxH

HOCH3

CH3 CH3CH3

O HCH3O

HF3B

Cationic rearrangements can proceed through concerted mechanisms as well, particularly when the migrating bond is aligned with the leaving group.

•

Hariprakasha, H. K.; SubbaRao, G. S. R. Tetradron Lett. 1997, 38, 5343–5346.

90%

–H2O –H+

HO OTs

CH3H

H

CH3 CH3

CH3

HO

CH3 CH3

HH

Al2O3

100%

CH3

H

CH3 CH3

HH

53%(–)-Aromadendrene

Ph3P CH2

Büchi, G.; Hofheinz, W.; Paukstelis, J. V. J. Am. Chem. Soc. 1969, 91, 6473–6478.

Halogens and sulfonate esters can also be used, as demonstrated below.•

H2O

3. h", CH3OH

1. NaH, HCO2Et2. N3Ts, Et3N

3. h", CH3OH

1. NaH, HCO2Et2. N3Ts, Et3N

1:1 C6H6–H2O35 °C, 1h

98%

N

O OBn

H

BocHN

N2

h", CH3OH

95%

N3SO2Ar(n-Bu)4NBr, 18-cr-6, KOH

Ar = 2,4,6-triisopropylphenyl

6

LA

Matt Mitcheltree

Chem 115Methods for Ring ContractionMyersPInacol Rearrangement

Schreiber's synthesis of the bicyclic core of calicheamicin relied on a pinacol rearrangement. Tautomerization of the resulting !-hydroxy ketone gave the enone product shown.

•

MsO

OHOH

H

TBSO

O

OH

HH

TBSO

H

TBSO

OHO

H

Et2AlCl

65%

CH2Cl2

H

O

OHO

H

HN OCH3

O

SSCH3S

O

OHO

HNCH3

O

CH3OEtHN

O

OH

CH3S

OCH3I

OCH3OCH3

O

O

OHCH3OHOCH3

Calicheamicin "1

HO

CH3CH3

OCH3

OOMs O

CH3

CH3

OCH3

OH

(+)-Taxusin

Et2AlCl

CH2Cl2–Hexane–78 # –15 °C

96%

Similarly, Paquette employed a pinacol rearrangement to produce the (+)-taxusin skeleton.•

Paquette, L. A.; Zhao, M. J. Am. Chem. Soc. 1998, 120, 5203–5212.

The reaction of epoxides with Lewis acids can provide ring-contracted products by a pinacol-type mechanism.

•

OLiBr, Al2O3

PhCH3

CHO

Suga, H.; Miyake, H. Synthesis 1988, 394–395.

n

n

1

2

3

Yield

77%

42%

30%

O

OCH3

CH3CH3

BF3•OEt2O

CH3CH3

CHOCH3

93%

Kunisch, F.; Hobert, K.; Weizel, P. Tetrahedron Lett. 1985, 26, 6039–6042.

i-PrOTBS

OCH3

i-Pr

OTBSCHOCH3

82%

Yamamoto and co-workers have described an epoxide-opening ring contraction utilizing a methylaluminum diphenoxide Lewis acid that outperforms boron trifluoride in difficult ring contractions.

•

MABR

t-Bu

t-Bu

BrAr =

Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 6431–6432.

i-PrOTBS

OCH3

i-Pr

OTBSOHC CH3

88%

CH2Cl2, –78 °C

CH2Cl2, –78 °C

MABR = CH3Al(OAr)2

MABR

Schoenen, F. J.; Porco, J. A.; Schreiber, S. L. Tetrahedron Lett. 1989, 30, 3765–3768.

O

CH3

CH3

CH3

HAcO

CH3

OAcAcO

n

7

Matt Mitcheltree

Chem 115Methods for Ring ContractionMyersPinacol Rearrangement

CH3CH3CH3

O

OTIPSOCH3

OHO

OTIPSCH3O

HOCH3

CH3CH3

O

HO

CH3

CH3CH3

CH3

HOHO OH

Ingenol

Kuwajima and Baran both used pinacol-type rearrangements in their syntheses of ingenol.•

Al(CH3)3

CH2Cl2

76%

Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498–1500.Jørgensen, L.; McKerall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. Science 2013, 341, 878–882.A tandem pinacol–Schmidt rearrangement was used to synthesize the core of (±)-stemonamine.•

TMSOCH3

N3O

O O

Cl2Ti

CH3

N3

N

CH3

OH

ON

(±)-Stemonamine

Zhao, Y. M.; Gu, P. M.; Tu, Y. Q.; Fan, C. A.; Zhang, Q. W. Org. Lett. 2008, 10, 1763–1766.

68%

TiCl4

CH2Cl2–78 ! 0 °C

After cationic rearrangement, the resulting cation may be intercepted by elimination of an adjacent proton:

•

TsO CH3

CH3 CH3HH

AcOH, AcOK

Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746–1757.76%

CH3

CH3

CH3H CH3

CH3

CH3H

80 °C, 8 h

"-bulneseneOHO

CH3

CH3

CH3H

OCH3

HOTIPS

Al(CH3)3

NN2

CH3

OO

Cl2Ti

CH3

OH O N3

By elimination of a #-silyl group:•

Hwu, J. R.; Wetzel, J. M. J. Org. Chem. 1992, 57, 922–928.

TMS

CH3OH

CH3

CH3H

O

TMSCH3 CH3

CH3

TMSCH3

HCH3

CH3

FeBr3

–60 °C

CH3

HCH3

CH3

54%

CH3

HCH3

CH3

71%

O

(–)-Solavetivone

t-BuOH

CrO2Cl2

LA

Or by attack with an endogenous nucleophile.•

CH3OMs

CH3CH3HTMSO

CH3CH3

H

CH3

TMSO

H

MgI2HN(TMS)2

CH3

CH3

CH3

O

82%

CH3

CH3

CH3

OHCH

H

H

HOHC

(+)-Isovelleral

Bell, R. P. L.; Wjnberg, J. B. P. A.; de Groot, A. J. Org. Chem. 2001, 66, 2350–2357.

CH3

HOO

OO

CH3

O TMS

CH3

CH3

CH3

OTBS

O

CH3

CH3

CH3CH3

CH3

OTBSOOO

BF3•OEt2

80%

Kuwajima

Baran

CH2Cl2

O

OCH3

CH3

OCH3

8

Matt Mitcheltree

Chem 115Methods for Ring ContractionMyersLead-promoted ring contractions

Lead(IV) salts have been shown to promote ring contractions of ketones and enol ethers. However, these reactions sometimes provide significant amounts of !-acetoxy ketone side-products.

•

OCH3 O

O

CH3

HCH3

HO

CH3 OO

CH3

HCH3

HAcO

OO

CH3

HCH3

H

CH3

CH3O

O+

67% 30%

Pb(OAc)4BF3•OEt2

Miura, H.; Fujimoto, Y.; Tatsuno, T. Synthesis 1979, 898–899.

!-Santonin

HC(OEt)3NH4ClEtOH

EtOCH3 O

O

CH3

HCH3

H

Pb(OAc)4BF3•OEt2, EtOH

C6H6O

O

CH3

HCH3

H

CH3

EtO

O

80%

This reaction is believed to involve Pb–C bond formation followed by pinacol-type rearrangement.•

O O OAc

Pb(OAc)3

O H

OAc

OOAc

OAc

Pb(OAc)4

–Pb(OAc)3–

Norman, R. O. C.; Thomas, T. B. J. Chem. Soc. B. 1967, 604–611.

Lead(IV)-promoted ring contractions have been employed to modify !-santonin. Improved yields were achieved by first converting the substrate to the corresponding ethyl-enol ether.

•

100%

CH3OHCH2Cl2CH3 CH3

CH3

H

CH3

O CH3

OROCH3 CH3

CH3

H

CH3

CHOCH3

ORO

CH3 CH3

CH3

H

CH3

CHOCH3

HO

C6H6

96%

(–)-Hyrtiosal

R = (S)-mandeloyl

The Imamura synthesis of (–)-hyrtiosal employed an epoxide-opening rearrangement that is proposed to mimic the biosynthetic route to the natural product.

•

Lunardi, I.; Santiago, G. M. P.; Imamura, P. M. Tetrahedron Lett. 2002, 43, 3609–3611.

O

BF3•OEt2

An example of a pinacol rearrangement initiated by an endogenous electrophile was demonstrated by Oltra:

•

CH3HO

CH3O

O

OCH3

O

H

OO

HO CH3CH3

TMSO

O

CH3O

O

CH3H

OOHCH3

CH3

O

> 72%

TMSCl,NaI

Rosales, A.; Estévez, R. E.; Cuerva, J. M.; Oltra, J. E. Angew. Chem., Int. Ed. 2005, 44, 319–322.

9

Matt Mitcheltree

Chem 115Methods for Ring ContractionMyersRing contractions of silyl-enol ethers

Cyclic silyl-enol ethers undergo ring contraction upon treatment with electron-deficient sulfonyl azides to give trialkylsilyl imidates, which are readily hydrolyzed to N-acyl sulfonamides.

•

While both triflyl azide (N3Tf) and nonaflyl azide (N3Nf; N3SO2n-C4F9) may be used in the ring contraction of silyl-enol ethers, the latter has the advantage of being a bench-stable, non-volatile liquid that does not detonate spontaneously upon concentration.

•

OSiR3

R

R3SiO

R

NNf R3SiO

NNf

R

O HN

NfR

H HN3SO2C4F9 H2O

Alkyl, vinyl, and aryl migrations are all possible. While 6!5 and 7!6 ring contractions are possible, this method does not permit cyclobutane synthesis.

•

OTMS

OTMS

NHNf

O

OTMS

OTMS

ONHNf

ONHNf

ONHNf

Substrate Product Yield

97%

67%

78%

87%

OTIPS

OO

CH3

CH3CH3

O OCH3 CH3

CH3

O NHNf

65%

Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634–5639.

H

Because alkyl migration is stereospecific, the stereochemistry of the product is determined by the facial selectivity of sulfonyl-azide addition. Lesser facial differentiation leads to lower diastereomeric ratios, as the following series demonstrates.

•

OTMS

CH3

OTMS

CH3

OTMS

CH3

N3Nf

N3Nf

N3Nf

NHNfO

CH3

NHNfO

NHNfO

CH3

NNfTMSO

CH3 singlediastereomer

d.r. = 67 : 33

d.r. = 55 : 45

The resulting N-acyl sulfonamide can be converted to alcohol, ester, or carboxamide products.•

ONHSO2C4F9

OH

OCH3

NH2

O

O

LAH

Et2O, 0!23 °C, 20 min

HCl (0.3 M)

20% CH3OH–PhCH3110 °C, 3 h

SmI2

THF, 23 °C, 30 min

85%

75%

96%

Mitcheltree, M. J.; Konst, Z. A.; Herzon, S. B. Tetrahedron 2013, 69, 5634–5639.

–N2

CH3CN–N2

CH3 CH3

10

Matt Mitcheltree

Chem 115Methods for Ring ContractionMyersSynthesis of regiodefined silyl-enol ethers

Silyl-enol ethers are appealing substrates for ring contractions because they can be synthesized regioselectively.

•

OCH3

OTMSCH3CH3

OTMS

Conditions Yield A : B

A B

LDA, TMSCl 74 99 : 1

Et3N, TMSCl, NaI 10 : 9092

Negishi, E.-I.; Chatterjee, S. Tetrahedron Lett. 1983, 24, 1341–1344.House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org. Chem. 1969, 34, 2324–2336.

Conditions+

Silyl-enol ethers can also be formed by 1,4-addition to !,"-unsaturated carbonyls.•

O

OTBSCH3

CH3

CH3MgBr

CuBr•S(CH3)2TMEDA, TMSCl TBSO

CH3

CH3CH3

OTMS

100%

Nozawa, D.; Takikawa, H.; Mori, K. J. Chem. Soc. Perkin Trans. 1, 2000, 2043–2046.

OTES

i-Pr

OTES

i-Pr

90%

Li, NH3

t-BuOH, THF

Macdonald, T. L. J. Org. Chem. 1978, 18, 3621–3624.

TIPSO CH3 CH3

BrO

O

N BO

PhPh

o-Tol

H

TIPSO CH3

H O

OCH3

Br

Birch reduction of substituted silyloxy aryl ethers gives regiodefined substrates for ring contraction.

•

Silyl-enol ethers can be formed by enantioselective, catalytic Diels–Alder reactions.•

HNTf2–78 °C

96%, 97% e.e.

Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800–4802.

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