33 methods for ring contraction

Myers

Chem 115

Methods for Ring Contraction

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

Recent Reviews:
Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523–7556.

O

Silva, Jr. L. F. Tetrahedron 2002, 58, 9137–9161.

O
H2O2

CH3

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

O

O

X

NaOH

Nu:

O

O

Nu

CO3CH3

CH3

Carbenoid

O

R

CH3

THPO

Lee, E.; Yoon, C. H. J. Chem. Soc., Chem. Commun. 1994, 479–481.
• For example, the ring contraction of a (+)-pulegone derivative has been used in the synthesis of
several terpenoid natural products.

CH3

CH3

CH3

Br2

Anionic Ring Contractions
Favorskii Rearrangement

O

• 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.

O

O
Cl

80%

R

Cationic

O

H

CH3

CH3

THPO

O

CH3
NaOCH3
CH3OH

Nu:

M

THPO

81% (2 steps)

CH3

(–)-Carvone

Anionic

O

2. DHP, p-TsOH

90%

CH3

Nu

O

Cl
CH3

1. TMSCl

CH3
O

CH3

Br
Br

O

CO2CH3

CH3OH
CH3

CH3
CH3

CH3

60–67% (2 steps)

(+)-Pulegone

OCH3

OCH3

NaOCH3

CH3

Et2O

NaOCH3

Et2O, 35 °C, 2 h
56–61%
Organic syntheses; Wiley & Sons: New York, 1963; Coll. Vol. No. 4, pp. 594.

AgNO3

Br

H2O, t-BuOH

OH
H

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.

H

O

H
71%

CH3

CH3 H

H
CH3
CH3

(+)-Epoxydictymene
CO2H

OH

O
H

Ag+

CH3
CH3

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

Br

CH3

O
H

H
O

CH3

CH3

CH3

(–)-Iridomyrmecin

(+)-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.

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Chem 115

Methods for Ring Contraction

Quasi-Favorskii Rearrangement
• 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.

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

OH

HO

• These fragmentations are generally accelerated by oxyanion formation.

OMs

1. MsCl (1 equiv), pyr
CH3

2. KOt-Bu

HO CH3
OTs

KOt-Bu

CH3

THF

O

CH3

H

CH3

CH3

O

60% (2 steps)

CH3

+

OTs

O

O

O
90%, 89 : 11

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

LAH

O

H

CH3
CH3 H

CHO

Br
O

H

CH3

HO

H

(±)-Hinesol

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

H

CH3

98%
Harmata, M.; Bohnert, G.; Kürti, L.; Barnes, C. L. Tetrahedron Lett. 2002, 43, 2347–2349.
CH3

OH
LiOH

• 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.

O

H
AgNO3

Cl
CH3 H

CH3OH
OBn

CH3O
Cl
Ag+

OH

O
O

HO

t-BuOH, 65 °C
OTs

CH3 OH

CH3

O

O
O H

O

O

O

O

OTs

H

87%

H
CH3

CH3 H

CH3O2C

OBn

H

OBn
53%

CH3 O

O
O

H

CH3

O

(±)-Confertin

H
CH3
CH3

H

OBn

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

CH3
HO

H

OH

(±)-Sirenin
Harding, K. E.; Strickland, J. B.; Pommerville, J. J. Org. Chem. 1988, 53, 4877–4883.

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Chem 115

Methods for Ring Contraction

Quasi-Favorskii Rearrangement

Carbenoid Ring Contractions

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

Wolff Rearrangement
Reviews:
Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256.

1. LAH
2. KH

Meier, H.; Zeller, K.-P. Angew. Chem. Int. Ed. 1975, 14, 32–43.
H

Cl O

CHO

Cl O

• 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.

76% (2 steps)

Stereochemistry
established by X-ray

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

O
R2

R1

h", #,
or AgI

H
H

R1

H
CH3

CH3

O

Nu

R2

R1

R2

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

OH
O

Nu-H

R2

R1

N2

CH3

O

O

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

O
CH3

O

O
N2

(±)-Spatol

h", CH3OH

OCH3

> 99%
Harmata, M.; Rashatasakhon, P. Org. Lett. 2001, 3, 2533–2535.

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

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

H
CH3
CH3

1. LAH
2. KH

O

3. LAH

CH3

H
CH3
CH3

H+

CH3
CH3

Br

OH
91% (3 steps)

CH3
(±)-Sterpurene

O

h", CH3OH

OH
OCH3

N2
H+

H

+

CO2CH3

CO2CH3
H

92%, 88 : 12
Harmata, M.; Bohnert, G. J. Org. Lett. 2003, 5, 59–61.

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

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Chem 115

Methods for Ring Contraction

Wolff Rearrangement

Synthesis of diazo ketones

• Ketene intermediates produced in the Wolff rearrangement can also be trapped in [2+2]
cycloaddition reactions.
R
CH3 CH3
O
N2
O R
O
O
O
O h!, THF
R' R'

Review

O

O

O

O

O

[2+2]

CH3 CH3

CH3 CH3

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.

O

Doyle, 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.
Direct Diazotization

R' R'

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

R

R'

Yield

H

H

84%

CH3

CH3

64%

CH3

H

76%

Ph

H

54%

O

R'

R

O

N3SO2Ar

O

O

R

Et3N

R'
N2

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

• 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.

N2
Br

i-Pr
O

i-Pr

h!, DCE

O

+
CH3

H

OTIPS

80 °C

CH3
CH3

O

HO

CH3
Salvilenone

N2
R

R3N

NaH

OTIPS

OTIPS
Br

Br

O

N3SO2Ar

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.), WileyInterscience, Chichester, 1978, pp. 751–820.

i-Pr

i-Pr
O

OH
H

R

retro
[2+2]
CH3

i-Pr

O
OR

R

Br
OTIPS

O

O

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

O

CH3

CH3

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

CF3

O
O

61–71%

CF3

O

OH

O

R

R
LiHMDS

CF3

O
N3SO2Ar

N2
R

R3N

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.
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Chem 115

Methods for Ring Contraction

Synthesis of diazo ketones

Wolff Rearrangement – Applications in target-oriented synthesis

• 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).

• 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

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

R

N3Tf
Et2NH

NaH
HCO2Et

O
N2
R

1:1 H2O–C6H6

O

O

H

O

HO

85%

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

h!
CH3OH
N2

95%

NH2
TBSO
O

N

N
N

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

N(CH3)2

CH3O
CH3O

H

TBSO
O
(CH3)2N

B

N3Tf

TBSO
O

O

O

O

72%

80%

h!

O

+

1. NaHMDS, HCO2Et
2. N3Ts, Et3N

1. h!, CH3OH
2. LiOH

N
N

NH2

HO
OH

N

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

O
N2
62% (2 steps)

78%

O

45%

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

B

N2

O

60%
t-BuOOH
160 °C

• 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.

N

CO2CH3

1. Regitz
2. h!, CH3OH

N
CHO
H
43% (4 steps)

O

3. DIBAL-H
4. Swern

(CH2)7CO2CH3

CO2H
86% (2 steps)

Pentacycloannamoxic acid methyl ester

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

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Chem 115

Methods for Ring Contraction

Wolff Rearrangement – Applications in target-oriented synthesis

Cation-type rearrangements

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

Pinacol Rearrangement

CH3 CH

3

H
CH3

O

CH3 CH

3
H CO2CH3

CH3

3. h", CH3OH

H

HO

CH3 CH

1. NaH, HCO2Et
2. N3Ts, Et3N

HO

Reviews
Song, 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.

3

H
CH3

H

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

H

HO

!9(12)-Capnellene

48%

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

CH3
CH3
CH3

O

H

1. NaH, HCO2Et
2. N3Ts, Et3N

CH3O2C

OH
OH
CH3

H+

CH3

OH

O

H

CH3
CH3

CH3
–H+

–H2O

CH3

68–72%

CH3

3. h", CH3OH

CH3

CH3

CH3
CH3

Pentalenene

83%

Pavlik, C.; Morton, M. D.; Smith, M. B. Synlett 2011, 2191–2194.

CH3
CH3

H

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

Ihara, M.; Katogi, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. 1 1988, 2963–2970.
• Where other methods failed, the Mandler procedure enabled Overman and co-workers to
diazotize a ketone en route to (±)-meloscine.

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

N

BocHN

BocHN

1:1 C6H6–H2O
35 °C, 1h

OBn

N2
98%

N

H

CH3 CH3

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

OBn
H

HO

CO2CH3

CH3

O

OTs

Ph3P CH2
H

CH3

H

H

H

Al2O3

H

N

BocHN

(±)-Meloscine

H

O

OBn

h", CH3OH

O

H2O

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

O

Ar = 2,4,6-triisopropylphenyl

HN

C6H6, reflux

CH3O CH3
HO
CH3
H
F3B

90%
H

H
O

N

BF3•OEt2

CH3O CH3
HO
CH3
H

CH3

H

CH3 CH

3

100%

CH3

H
CH3 CH

H

CH3

3

53%
(–)-Aromadendrene

95%
Büchi, G.; Hofheinz, W.; Paukstelis, J. V. J. Am. Chem. Soc. 1969, 91, 6473–6478.

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.

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Chem 115

Methods for Ring Contraction

PInacol 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
TBSO

LA

H

H
OH
OH

H

H

O

OH
O

H

Et2AlCl
TBSO

• The reaction of epoxides with Lewis acids can provide ring-contracted products by a pinacol-type
mechanism.
n
Yield
CHO
LiBr, Al2O3
1
77%
O
2
42%
PhCH3
n
n
3
30%

TBSO

OH

CH2Cl2

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

O

O

65%

BF3•OEt2

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

CH3
CH3

CHO

O
CH3

CH3

CH3
CH3
93%

CH3S
CH3 O
I
O
CH3
O
HO
CH3O
OH

CH3
S

OCH3 OH
OCH3

HN
O HO

O

CH3

S
S
O

H

O

H

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

OH
O
HN

O

OCH3

• 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.

O

EtHN
CH3O

CH3

Calicheamicin "1

CH3 CHO

O

MABR
OTBS

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

O
CH3

CH3
CH3

HO

OMs O

Et2AlCl
CH2Cl2–Hexane
–78 # –15 °C

AcO

CH3
CH3
CH3

CH3
H

O

O

96%

AcO

CH3

OAc
CH3
CH3

i-Pr

MABR = CH3Al(OAr)2

82%
OHC

O

CH2Cl2, –78 °C

t-Bu

CH3

MABR
OTBS

i-Pr
H

CH2Cl2, –78 °C

i-Pr

CH3
O

OTBS

Ar =

OTBS

Br
t-Bu

i-Pr
88%

O
(+)-Taxusin
Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 6431–6432.

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

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Myers

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

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

TsO

Kuwajima
CH3
CH3

CH3
O

CH3
CH3

H
Al(CH3)3

OH

CH2Cl2

CH3 H

OTIPS

OCH3

OCH3
OTIPS

O OH

HO

CH3

CH3
CH3

O

CH3O

Baran
CH3

CH3

CH3

CH3

TMS
OTBS

O
O

O

O

CH3

BF3•OEt2 CH3

CH3
CH3

O

CH3

CH3

O
80%

CH3

FeBr3
H

LA

CH3

CH3

O
CH3

CH3

CH3

OH

Ingenol

CH3

O

CH3
CrO2Cl2

CH3

• A tandem pinacol–Schmidt rearrangement was used to synthesize the core of (±)-stemonamine.

(–)-Solavetivone 71%

TiCl4

TMSO
N3

O

OH

O

O

N3

N3

CH2Cl2
–78 ! 0 °C

CH3

CH3

CH3

O

N

O

Cl2
Ti O

N2
N

CH3
O

OH

CH3
CH3

(±)-Stemonamine

MgI2
HN(TMS)2

OMs

CH3

O
OCH3

CH3

H

CH3
54%

• Or by attack with an endogenous nucleophile.

TMSO

N

t-BuOH

H

CH3

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

Cl2
Ti
O

H

CH3

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.

CH3

CH3

TMS

OH
CH3

HO HO
HO

CH3

H

76%
"-bulnesene

OTBS

O
O

H

CH
TMS 3

–60 °C

CH3

CH2Cl2

CH3

CH3

Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746–1757.

TMS

CH3

H

• By elimination of a #-silyl group:

CH3
CH3

O

CH3

CH3

AcOH, AcOK
80 °C, 8 h

OTIPS

Al(CH3)3

CH3

CH3

H
CH3

76%

HO

Chem 115

Methods for Ring Contraction

H

CH3
CH3
CH3

H

CH3
CH3

TMSO

H

CH3
OHC

CH3

CH3

H
OHC

CH3

H
(+)-Isovelleral

CH3
CH3

H
O

H
82%

68%

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

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

Matt Mitcheltree

8

Myers

Chem 115

Methods for Ring Contraction
Lead-promoted ring contractions

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

O
HO

CH3

O
CH3 O

TMSCl,
NaI

H

HO CH3

O

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

CH3

CH3
O

CH3

• 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 sideproducts.

O
O
TMS

O

H CH
3

O

CH3
CH3

O

OH

O
O

O

Pb(OAc)4

OAc

OAc
O

O

OAc
O

H

–
Pb(OAc)3 –Pb(OAc)3

OAc

> 72%
Rosales, A.; Estévez, R. E.; Cuerva, J. M.; Oltra, J. E. Angew. Chem., Int. Ed. 2005, 44, 319–322.

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

O
CH3 CH3
RO

CH3 CH3

R = (S)-mandeloyl

• 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.

CHO
CH3

CH3

H

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

BF3•OEt2
O

C6H6

H
RO

Pb(OAc)4
BF3•OEt2

CH3

CH3 CH3

H
O

O
CH3

CH3 CH3

O
O

CH3OH
CH2Cl2

CH3O

CH3 H O

CH3

H

CH3
O

O

Pb(OAc)4
BF3•OEt2, EtOH

CH3

CH3 CH3

O
30%

CH3

O

H

H
HO

H
O

HC(OEt)3
NH4Cl
EtOH

CHO
CH3

H

CH3

+
CH3

67%

!-Santonin

96%

AcO
H

CH3

H

CH3

O

O

CH3 CH3
(–)-Hyrtiosal
Lunardi, I.; Santiago, G. M. P.; Imamura, P. M. Tetrahedron Lett. 2002, 43, 3609–3611.

EtO
CH3

H

CH3
O

C6H6

EtO

O

O
100%

CH3

CH3 H O
80%

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

Matt Mitcheltree

9


Myers

Chem 115

Methods for Ring Contraction

Ring 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.

• 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.

• 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.

N3Nf

CH3

OSiR3

R3SiO

N3SO2C4F9
R

R3SiO

Nf
N

H

R

CH3CN
–N2

O

N
Nf

H2O

H
N
H

• 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.

Product

OTMS

CH3
CH3
O

N3Nf

single
diastereomer

NHNf
d.r. = 67 : 33

Yield
OTMS

O
N3Nf

O

NHNf

CH3

CH3
OTMS

Substrate

CH3

O
NNf

–N2

Nf

R

R

TMSO

OTMS

NHNf
d.r. = 55 : 45

NHNf
97%

CH3

CH3

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

OTMS

O
NHNf

67%

OH
LAH
85%

O

OTMS

NHNf

O
78%

SO2C4F9
NH

Et2O, 0!23 °C, 20 min
O

OCH3

HCl (0.3 M)
75%
O

OTMS

20% CH3OH–PhCH3
110 °C, 3 h

NHNf
87%

O

NH2

SmI2
OTIPS

96%

THF, 23 °C, 30 min

O

NHNf

H
CH3
CH3

CH3

O
O
CH3

65%
O

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

O

CH3 CH
3

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

Matt Mitcheltree

10


Myers

Chem 115

Methods for Ring Contraction

Synthesis of regiodefined silyl-enol ethers
• Silyl-enol ethers are appealing substrates for ring contractions because they can be synthesized
regioselectively.

O

OTMS
CH3

Conditions

CH3

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

H Ph
O

OTMS
CH3

Br

+
TIPSO
A
Conditions

Yield

A:B

LDA, TMSCl

74

99 : 1

Et3N, TMSCl, NaI

92

10 : 90

CH3

H

N B
o-Tol

CH3
O

B

Ph

O

TIPSO
HNTf2
–78 °C

CH3

O
Br
CH3

O

96%, 97% e.e.
Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 4800–4802.

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

CH3

O
CH3
CH3
OTBS

OTMS

MgBr

CH3

CuBr•S(CH3)2
TMEDA, TMSCl

TBSO

CH3

CH3

100%

Nozawa, D.; Takikawa, H.; Mori, K. J. Chem. Soc. Perkin Trans. 1, 2000, 2043–2046.
• Birch reduction of substituted silyloxy aryl ethers gives regiodefined substrates for ring
contraction.

OTES

OTES
Li, NH3
i-Pr

t-BuOH, THF

i-Pr
90%

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

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