30 cyclobutane synthesis

O

MV2+ = methyl viologen (N,N'-dimethyl-4,4'-bypyridinium)
H3C N

H3CO

Ph

visible light
MgSO4, MeNO2
88%, dr >10:1

O

5 mol% Ru(bpy)3(PF6)2
15 mol% MV(PF6)2

H

H
O

• Limitation of the method: at least one of the styrenes must bear an electron-donating substituent
at the para or ortho position. Aliphatic olefins are not suitable reaction partners.

N CH3

• Mechanism:

*Ru(bpy)32+
strong
reductant

visible light

• Photoredox catalysis can also be used for [2+2] cycloadditions of enones:

N CH3 (MV2+)

H3C N

Me N

+1 e-

N Me

Ph

(MV-radical)
Ru(bpy)32+
photocatalyst

O

O

Ph

product

Ru(bpy)33+
strong oxidant

visible light
Ru(bpy)3Cl2 (5 mol%)

O

O

H

H

Ph

Ph

LiBF4, i-Pr2NEt
MeCN, 89%, dr >10:1

MV2+
-1 e-

+1 e–

OCH3

p-CH3OC6H4

MV-radical

Ph
OR

p-CH3OC6H4

O

O

Ph
H

H
O

O

Ph

CH3
CH3

visible light
Ru(bpy)3Cl2 (5 mol%)
LiBF4, i-Pr2NEt
MeCN, 84%, dr >10:1

O
Ph

O
CH3

H3C

• Upon photoexcitation, the photocatalyst (Ru(bpy)3(PF6)2) acts as a strong reductant, reducing MV
by a single electron.
• The resulting Ru(III) species acts as a strong oxidant, which oxidizes the electron-rich styrene to
produce a radical cation and regenerates photocatalyst.
• The resulting radical cation undergoes cyclization.

Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572–8574.

Ischay, M. A.; Anzovino, M.E.; Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2008, 130, 12886–12887.
Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2009, 131, 14604–14605.

Danica Rankic

7


Myers

Chem 115

Cyclobutane Synthesis

• Mechanism:

• An intramolecular variant was also developed.
• The product can be converted to acids, esters, thioesters and amides:

visible light
*Ru(bpy)3

2+

i-Pr2NEt

Li

O

LiBF4

Ph

Ru(bpy)32+

O

N

i-Pr2NEt

+1 e–

Ru(bpy)3+

Li

–1 e–

CH3
O

N

O

visible light
Ru(bpy)3Cl2 (2.5 mol%)

OBn

LiBF4, i-Pr2NEt
MeCN, 87%, dr >10:1

O

Ph

Ph
Me

CH3

Me

O

O

O

H

H

BnHN

CH3

O

O

N H

H

H3C
N

OBn

1. MeOTf, CH2Cl2

67%
2. BnNH2, DBU
CH2Cl2, 98%

OBn

98%, dr >10:1
Li

O

O
Ph

–1 e–
CH3

Ph

H3C

Li

O

O

CH3

H3C

Tyson, E. L.; Farney, E. P.; Yoon, T. P. Org. Lett. 2012, 14, 1110–1113.

O

O

Ph

CH3

• Styrenes and alkenes undergo [2+2] cycloaddition in the presence of an Ir catalyst (III) and light.
The catalyst functions as a photosensitizer.

H3C

CF3

F
• Lewis acid coordination decreases the reduction potential of the enone, facilitating single electron
transfer.
• Limitation of the method: one coupling partner must be an aromatic ketone. Aliphatic ketones and
esters do not under go cycloaddition because of their higher reduction potentials.

Ph

CH3

visible light
III (1 mol%)

CH3
CH3
H

Ph

CH3

H
DMSO, 83%

O

N

F

OH
EtO2C
H3C
O

H3C
N
N

visible light
Ru(bpy)3Cl2 (2.5 mol%)

O
CH3
i-Pr

LiBF4, i-Pr2NEt
MeCN, 73%, dr >10:1

H3C
N

O

CH3

F

N
N

O

F

CH3
O

CH3

EtO2C

DMSO, 86%

H3C

t-Bu
CF3

III

H3C CH3
H
H

•
O

CH3

O
CH3

N
i-Pr

HO

visible light
III (1 mol%)

PF6–

IrIII

Ischay, M. A.; Anzovino, M.E.; Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2008, 130, 12886–12887.
Du, J.; Yoon, T.P. J. Am. Chem. Soc. 2009, 131, 14604–14605.

• !,"-Unsaturated 2-imidazolyl ketones also undergo photochemically induced cycloadditions:

t-Bu

N

HO
HO2C
H3C

H3C CH3
H
H

•
O

LiOH
60 ºC
97%

CH3

(±)-cannabiorcicyclolic acid

Lu, Z.; Yoon, T. P. Angew. Chem. Int. Ed. 2012, 51, 10329–10332

Danica Rankic

8


Myers

Chem 115

Cyclobutane Synthesis

• Other Methods for Cyclobutane Synthesis

• Gold(I)-Catalyzed Ring Expansion of Cyclopropanes

• Brook Rearrangement of 1,4-Dicarbonyls

• Alkynyl cyclopropanols can undergo ring expansion upon treatment with catalytic Au(I):

• Treatment of keto acylsilanes with organolithium reagents produces highly functionalized
cyclobutanes favoring cis-stereochemistry between newly formed alcohols

t-Bu
PhLi, THF
i-Pr

TBS
O

O

–80 " –30 ºC

TBSO
Ph

OH
i-Pr

HO
Ph

67%

HO

OTBS

[(p-CF3C6H4)3P]AuCl (0.5 mol%)
AgSbF6 (0.5 mol%)

O

CH2Cl2, 23 ºC, 98%

i-Pr

single isomer

10%

Mechanism:

• The mechanism is proposed to involve a stereospecific 1,2-alkyl shift:

i-Pr

TBS
O

Ph

O

TBSO
Ph

i-Pr
O TBS O

OH
i-Pr

Ph Li

[(p-CF3C6H4)3P]AuCl (1 mol%)
AgSbF6 (1 mol%)

Ph

O

TBSO
CH2Cl2, 23 ºC, 94%

Brook rearrangement

H3C

H3C

CH3

AuL
• Ring Expansion of Cyclopropanes via Pinacol-Type Rearrangements

TBSO

• Hydroxycyclopropyl carbinols can be ring-expanded by treatment with protic or Lewis acids.

H3C

• Either cis- or trans-substituted cyclobutanones could be produced from a single diastereomer of a
an !-hydroxycyclopropyl carbinol:

BF3•Et2O
(20 mol%)

O
n-Bu

80%
17:1 cis:trans

concerted
migration proposed

THF, 23 ºC

HO

Ph
CH3

H+

Takeda, K.; Haraguchi, H.; Okamoto, Y. Org. Lett. 2003, 5, 3705–3707.

Ph

t-Bu

p-TsOH•H2O
(10 mol%)

O

CHCl3, 23 ºC

Ph

Ph

AuL
O

CH3

H3C

Ph

CH3

Markham, J. P.; Staben, S. T.; Toste, D. F. J. Am. Chem. Soc. 2005, 127, 9708–9709.

n-Bu

Ph
OH

single diastereomer

n-Bu

94%
1:17 cis:trans

thermodynamic
product

Hussain, M. M.; Li, H.; Hussain, N.; Urena, M.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc.
2009, 131, 6516–6524.

Danica Rankic

9


Myers

Chem 115

Cyclobutane Synthesis

• Cu-catalyzed 1,4-Ring closure

• The products can be derivatized:

• Homoallylic sulfonates can undergo borylation/cyclization using a CuI catalyst:

Bn(H3C)2Si

OMs
Ph

CuCl (5 mol%)
dppp (5 mol%)

Ph
B2pin2, KOt-Bu
THF, 23 ºC

H3C CH
3
CH3
O
B O CH3

O

CH3
CH3
CH3
CH3

O
B B

O

O

B2pin2

CuCl (5 mol%)
dppp (5 mol%)

(H3C)2PhSi

OMs

(H3C)2PhSi

H3C
H3C
H3C
H3C

H3C CH
3
CH3
O
B O CH3

1. TBAF, THF
23 ºC
2. H2O2, KHCO3
CH3OH, 23 ºC

OBz

49% (2 steps)

(dppp)Cu
(dppp)CuI-Bpin

R2

OBz

Bpin
H

R1
OMs

+KOt-Bu

Bpin

HO

OMs

(dppp)CuIOt-Bu

R1

OBz

R1

pinB Ot-Bu
pinB!Bpin

OBz

HO

1. TBAF, THF
23 ºC
2. H2O2, KHCO3
CH3OH, 23 ºC
57% (2 steps)

R2

R2

Bn(H3C)2Si

2. PhCOCl, C5H5N
CH2Cl2, 0 ºC
61% (2 steps)

1. LiCH2Cl, THF
–78 " 23 ºC
2. H2O2, NaOH
THF, 0 ºC
3. PhCOCl, C5H5N
CH2Cl2, 0 ºC
73% (3 steps)
R3Si

1. H2O2, NaOH
THF, 0 ºC

B2pin2, KOt-Bu

THF, 23 ºC

• Mechanism:

CuCl

BPin

R2
R1

R2 Bpin
H
tBuO CuIII
dppp
R1

t-BuO
K+

CuI
dppp

Bpin

Ph

BPin

1. BCl3, CH2Cl2

23 ºC

Ph

NHBn

2. BnN3, CH2Cl2
0 ºC, 57%

• Note that in each case the stereochemistry of the starting material is preserved in the product.

H
OMs

KOMs

• Limitation of the method: only aryl- or silyl-substituted olefins react; alkyl olefins do not undergo
borocupration.

Ito, H.; Toyoda, T.; Sawamura, M. J. Am. Chem. Soc. 2010, 132, 5990–5992.

Markham, J. P.; Staben, S. T.; Toste, D. F. J. Am. Chem. Soc. 2005, 127, 9708–9709.
Danica Rankic

10