Badwin rules lecture

D. A. Evans

Rules for Ring Closure: Introduction

Chem 206

The Primary Literature

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Baldwin, J. Chem. Soc., Chem. Comm. 1976, 734, 736.
Baldwin, J. Chem. Soc., Chem. Comm. 1977 233.
Baldwin, J. Org. Chem. 1977, 42, 3846.
Baldwin, Tetrahedron 1982, 38, 2939.

Chemistry 206
Advanced Organic Chemistry

Lecture Number 3

Stereoelectronic Effects-3
"Rules for Ring Closure: Baldwin's Rules"
Kirby, "Stereoelectronic Effects" Chapters 4, 5

Useful LIterature Reviews
Johnson, C. D. (1993). “Stereoelectronic effects in the formation of 5and 6-membered rings: the role of Baldwin's rules.”
Acc. Chem. Res. 26: 476-82. (Handout)
Beak, P. (1992). “Determinations of transition-state geometries by the
endocyclic restriction test: mechanisms of substitution at
nonstereogenic atoms.” Acc. Chem. Res. 25: 215. (Handout)

■ Problems of the Day

Propose mechanisms for the following reactions
HO

R
O

+
HO

R

D. A. Evans

Friday,
September 19, 2003

O
OMe

R

O

R

O

HN NH

NH2–NH2

Me

3-00-Cover Page 9/19/03 8:36 AM

H+

Me

O


D. A. Evans, J. Johnson

Chem 206

Rules for Ring Closure: Introduction

Ring Closure and Stereoelectronic Connsiderations
An Examination of Baldwin's Rules
"Baldwin's Rules" provides a qualitative set of generalizations on the
probability of a given ring closure.

C. Nucleophilic ring closures sub-classified according to hybridization
state of electrophilic component:
(tetrahedral = tet; trigonal = trig; digonal = dig)
D. Nucleophilic ring closures further subclassified according to size of
the fomed ring. For example:

There are circumstances where the "rules" don't apply.
■ They do not apply to non-first-row elements participating in the

cyclization event. The longer bond lengths and larger atomic radii of
2nd row elements result in relaxed geometrical constraints.

5-exo-tet

X
Y

X

Y–

5-exo-trig

For example, a change in a heteroatom from O to S could result in
relaxation of a given geometric constraint.

X

X

Y

Y–

endo

X = O vs S
••

X

Y

X

5-exo-dig

Y

X

X

Y–

Y
■ The "rules" do not apply to electrocyclic processes.

Required trajectories (Baldwin):

Nomenclature
Classes of Ring Closing Processes
A. Exo-cyclization modes identified by the breaking bond
being positioned exocyclic to the forming cycle.
exo

X

X

X

••

••

3-01-Baldwin Rules-1 9/18/03 3:38 PM

= 109

Y

X

*

endo

Y

X

Y

X = first-row element
N, O

Y

X

X

X

Y
Y
B. Endo-cyclization modes identified by the breaking bond
being positioned endocyclic to the forming cycle.

X

= 180

Y

Y

120 *

Y
Will come
back to this
case later

X
Y

Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734.

Rules for Ring Closure: SP3 Carbon & Related Systems

D. A. Evans, J. Johnson

FÜRST-PLATTNER RULE

Tetrahedral Carbon
All exo cyclization modes are allowed: (n-exo-tet, n = 3 )

••

exo

X

C

C

X
Y

Chem 206

Y–

There are stereoelectronic issues to consider for n-exo-tet cyclizations

In this simple model, the transition-state leading to 1 involves the
diaxial orientation of nucleophile and leaving group. This orientation
affords the best overlap of the anti-bonding C–Y orbital and the
nonbonding electron pairs on the nucleophile O–.
In the formation of the diastereomeric epoxide 2, the proper alignment
of orbitals may only be achieved by cyclization through the
less-favored boat conformer. Accordingly, while both cyclizations are
"allowed", there are large rate differences the the rates of ring closure.

Formation of 3-Membered Rings (3-exo-tet)
H H

••

C

X

‡

H

Y

C
H2

C

X

X

Y

H

C
H2

CH2

+ Y–

C
H2

While the FÜRST-PLATTNER RULE deals wilth the microscopic
reverse, in the opening of epoxides by nucleophiles, the
stereoelectronic arguments are the same.

Stereoelectronic Effects in Epoxide Ring Cleavage
Nu

Conformational Effects in Epoxide Ring Formation/cleavage

-

Nu

Me3C

Those stereoelectronic effects that operate in ring cleavage also
influence ring formation. Consider a rigid cyclohexene oxide system:
Y

Y

δ–

H

H

H

chair

boat

3-02-Baldwin Rules-2 9/18/03 3:39 PM

O δ–

Nu-

Nu

H

Nu
Me

O

Y
H

H
H

Me

slower

Me3C

H

O

Y δ– ‡

O–

HO
HO

Nu

Me3C

H

1

δ O

H

H

H

-

–

O–

H

O

H

H

Me3C

H

‡
faster

H

O

O

2

H

HO

H

"The diaxial nucleophilic ring cleavage of epoxides"
For more information on epoxide cleavage see Handout 03A.


D. A. Evans, J. Johnson

Rules for Ring Closure: SP3 Carbon & Related Systems

Tetrahedral Carbon

Case 2: King, J.C.S. Chem. Comm., 1979, 1140.

O

Endo cyclization modes that are disallowed
(n-endo-tet, n = 3
9)

O

O

8-endo-tet
disfavored

S
O
Me
NMe2

Y
C(SP3)

C

••

••

X

Y

SO2OMe
NMe2

The stereoelectronic requirement for a 180° X–C–Y bond angle is only
met when the endo cyclization ring size reaches 9 or 10 members.
SO2OMe

Case 1: Eschenmoser, Helvetica Chim. Acta 1970, 53, 2059.
O

O

O
S

S

O
CX3

O

S

O

NaH
6-endo-tet
disfavored

NMe2

O

Rxn exclusively
intermolecular
(lecture 2)

S

O

O

O

O

S

O

NaH
6-exo-tet
favored

3-03-Baldwin Rules-3 9/18/03 4:07 PM

NMe3+

Rxn exclusively
intermolecular

SO3–

9-endo-tet
borderline

NMe3+

O

CX2
O

S

CY3

Beak, JACS 1991, 113, 6281.

Cl

O–OH

8-endo-tet
disfavored

Cl

n
-

Rxn exclusively
intramolecular
CY3

SO3–

O

O
S

O
CX2I

8-endo-tet
disfavored

Allowed endo cyclization modes will require transition state ring sizes
of at least nine members.

CY3

Cyclization exclusively intermolecular. However the exocyclic analog
is exclusively intramolecular
S

NMe3+

Intramolecular epoxidation has also been evaluated

CY3

O

_

Conclusions

CX3
O

O

84% intermolecular,
16% intramolecular

O-

O

S

Rxn exclusively
intermolecular

endo

X

Chem 206

O

CO2H

n

O

n = 1: rxn exclusively intermolecular
n = 9: rxn is intramolecular

Beak states that the conclusions made with carbon
substitution also hold for oxygen atom transfer.
Beak, P. (1992). “Determinations of transition-state geometries by the
endocyclic restriction test: mechanisms of substitution at nonstereogenic
atoms.” Acc. Chem. Res. 25: 215.


Rules for Ring Closure: SP2 Carbon & Related Systems

D. A. Evans, J. Johnson

Trigonal Carbon
Endo cyclization modes that are disallowed
(3 to 5-endo-trig)

MeO2C

CO2Me
NH2

n-endo-trig
X

••

Y

X
C

C

Y–

X = first-row element
The 5-endo-trig cyclization is a watershed case
distance from reacting centers: 2.77 Å
Case 1: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734.
CO2Me

base

CO2Me

It is possible that a "nonvertical"
trajectory is operational like that
suspected in C=O addition

X

OH

5-endo-trig
Disfavored

however
CO2Me

O

CO2Me

base
S

SH

Second row atom relaxes the cyclization geometrical requirement
Case 2: Baldwin, J. Chem. Soc., Chem. Commun., 1976, 736.
MeO2C

MeO2C

CO2Me

X

NH2

CO2Me
HN

5-endo-trig
0%
MeO2C
HN
O

3-04-Baldwin Rules-4 9/18/03 4:07 PM

5-exo-trig
100%

Chem 206


D. A. Evans, J. Johnson

Rules for Ring Closure: SP2 Carbon & Related Systems

Case 2: continued...
MeO2C

Apparent exceptions to disallowed 5-endo-trig cyclization process
MeO2C

CO2Me

CO2Me

X

NH2

O

HN
N

5-endo-trig
0%

+
N

CH3CO2H

5-exo-trig
100%

HN
O

CO2Me
R HC

N

CO2Me
KOtBu

1

Control experiment: Intermolecular reaction favors conjugate addtion.

CO2Me

Me

Me

H
N

Ph

CO2Me

H
N
O

100%

Ph

R2

R1
HN

Ph

O
Ph

OK

NH2NH2
OMe

65 oC

1) EtO2CCl, pyridine
2) NH2NH2

Ph
HN

NH

Ph

H2N
X

R

R

R

NH

5-endo-trig

CO2Me
R2

HO

(CH2OH)2
O

R

R

O

MeI
200 oC

(CH2OH)2

R

O

HN
3:1

Grigg, J. Chem. Soc., Chem. Commun. 1980, 648.

Does the illustrated
ketalization process
necessarily violate "the
rules"?

O

R2
CO2Me

R1 = aryl, R2 = aryl, alkyl

0%

Case 3:
O

O

CO2Me

R1

CO2Me
PhCH2NH2

N

OH

Filer, J. Am. Chem. Soc. 1979, 44, 285.

MeO2C

Me

Chem 206

O

OH

( )2

H+

H+

R

H+

O

R

O

OH

R

–H2O

R

O

+

( )2
5-endo-trig

disfavored ?

O
Ph

OMe

R
Ph

CO2Me

NH2NH2
65 oC

HN

NH2

3-05-Baldwin Rules-5 9/18/03 4:08 PM

Ph

5-exo-trig

O
HN

+

HO

R
O

OH 5-exo-tet

( )2

favored ?

R

O

R

O

NH

Johnson, C. D. (1993). “Stereoelectronic effects in the formation of 5- and
6-membered rings: the role of Baldwin's rules.”
Acc. Chem. Res. 26: 476-82.


D. A. Evans, J. Johnson

Rules for Ring Closure: SP2 Carbon & Related Systems

More Exceptions

Chem 206

Bu

Zard, Org. Lett. 2002, 4, 1135
O
MeO

S

N

OEt

NaH
Y

O

DMF, 60 °C

HO

Y
O

N
S

ROOR
heat

O

80% O

O

MeO

O

MeO

O
MeO

Bu

X

MeO

X

Y

Cond

Yield

F

F

DMF, 60 °C, 2 h

80

F

H

DMF, 80 °C, 43 h

17

Cl

Cl

DMF, 60 °C, 8 h

––

Br

Br

DMF, 60 °C, 5 h

15

O

N

MeO

N

5-endo-trig

Ichikawa, et al Synthesis 2002, 1917-1936, PDF on Course Website
Numerous other cases are provided in this review.

O

Br

O

O

O

H
O

O

Revisiting Case 2 with Fluorines
O

Bu3SnH

O

AIBN

O

MeO2C

MeO2C

H

N

82%
Ts

O

5-exo-trig

OMe

TsHN

MeO2C

5-endo-trig

Favored

CO2Me
N

Ts

Not Observed

H
O

O

5-endo-trig
O

O

O
CF2

MeO2C

MeO2C

N
Ts

Chem. Comm 2088, 28
Review: "5-Endo-Trig Radical Cyclizatons" Ishibashi, et al Synthesis 2002,
695-713, PDF on Course Website

3-06-Baldwin Rules-6 9/18/03 5:10 PM

O

Not Observed

5-exo-trig

TsHN

OMe
CF2

MeO2C

5-endo-trig

CO2Me
N

Ts

F

Favored


Rules for Ring Closure: SP2 Carbon & Related Systems

D. A. Evans, J. Johnson

Chem 206

Trigonal Carbon: Exocyclic Enolate Alkylation
distance between reacting
centers: 3.37Å

exo
–

C

O

C

C
C

C

O

Y

Y-

C

Br
X

■ By definition, an exo-tet cyclization, but stereoelectronically
behaves as an endo trig.
Me

Me
O

(1)

Me

X

MO

O

only observed
product

distance between reacting
centers: 3.04Å

However:
Me

The relaxed geometrical constraint

provided by the added CH2 group
now renders the 6-membered
cyclization possible

Me
KOt-Bu or LDA

Me
O

Me

O

The overlap for C-alkylation is poor due to
geometrical constraints of 5-membered ring

Me

Br

Me

Me

MO

Br

Me

> 95% by NMR

O

Baldwin, J. Chem. Soc., Chem. Commun. 1977, 233.

■ Given the failure of the enolate alkylation shown above (eq 1),
explain why these two cyclizations are successful.

MO

Br

O

Br
base

NHAr

N

O

O
R

O
Ar

R
NH

Ar

R

Favorskii Rearrangement (Carey, Pt B, pp 609-610)
Your thoughts on the mechanism

R

base

OMs

3-07-Baldwin Rules-7 9/18/03 4:09 PM

O

O

O
Cl MeO–

N
Ar

–HCl

CO2Me
MeO–


D. A. Evans, J. Johnson

Rules for Ring Closure: SP2 & SP Carbon & Related Systems

Trigonal Carbon: Intramolecular Aldol Condensations

Chem 206

Digonal Carbon: Cyclizations on to Acetylenes

Baldwin, Tetrahedron 1982, 38, 2939

DIGONAL: Angle of approach for attack on triple bonds
(Enolendo)-Exo-trig

X

MO
R

Y

R

Baldwin:

Nu-

X

O

YM

120°

Favored: 6-7-(enolendo)-exo-trig
Disfavored: 3-5-(enolendo)-exo-trig

- 3 and 4-Exo-dig are disfavored
- 5 to 7-Exo-dig are favored
- 3 to 7-Endo-dig are favored

120°
E+

(Enolexo)-exo-trig

X

X
O

MO
R

Y

Ab initio SCF 4-31G calculations for the interaction of
hydride with acetylene:

YM
R
H

Favored: 3-7-(enolexo)-exo-trig

_

H

127 o

2.13

H
O

5-(Enolendo)-Exo-trig

Me

Me

H

C

H 156o 1.22

6-(Enolendo)-Exo-trig
Me

O

H
Me
Me

Me

O
Me

O

Houk, J.ACS.1979, 101, 1340.

H
Me

STO-3G minimal basis set

110o -120o

1.5-2.0

favored

Me

4-31G basis set

C

O

O
I

148o H

C

C

Dunitz, Helv Chim. Acta
1978, 61, 2538.

H

O
III

Crystal Structures do not support Baldwin

O
II

O

Statistical Distribution, (I + II)/III = 2:1
Experimental Distribution,
= 0:100

N

N

(KOH, MeOH, r.t., 5 min, 77% y.)

O-

N

2.92

+

O

+

Caution: Baldwin's conclusions assume that the RDS is ring closure;
however, it is well known (by some!) that the rate determining step is

dehydration in a base-catalyzed aldol condensation.

N

104o

2.44
93o

N

86o

N

J. Dunitz and J. Wallis J. C. S. Chem. Comm. 1984, 671.

3-08-Baldwin Rules-8 9/18/03 5:49 PM


Rules for Ring Closure: SP Carbon & Related Systems

D. A. Evans, J. Johnson

Endo Digonal versus Endo Trigonal Cyclizations

Chem 206

■ Indole synthesis:
CH3

5-endo-trig

+

N

C-

CH2R

2 equiv. LDA
2 equiv. RX
-78 oC

+

N

C-

R = Me, Bu, CO2Me

Y

LiTMP

X:

In-plane approach;

nucleophile lone pair is
orthogonal to π*

R

Out-of-plane approach;
nucleophile lone pair can't
achieve Bürgi-Dunitz angle

Saegusa, J. Am. Chem. Soc. 1977, 99, 3532.

N

Li

O

HO

n

X

Me

NaOMe
MeOH
Ph

Magnus, J. Am. Chem. Soc. 1978, 100, 7746.

Me
Me

O

5-endo-dig

Ph

5-exo-dig
O
R
OH

O

NaOMe
X

Li

R

5-endo-trig

O

Ph

Ph

however, the acid catalyzed version does cyclize

4-endo-dig

Baldwin, J. Chem. Soc., Chem. Commun., 1976, 736.
Johnson, Can. J. Chem. 1990, 68, 1780
J. Am. Chem. Soc. 1983, 105, 5090
J. Chem. Soc., Chem. Commun. 1982, 36.

3-09-Baldwin Rules-9 9/19/03 8:38 AM

Li

Ph

R = H, OMe

Li

X

Li

OMe

n

Developing negative charge on the central allenic carbon is

in the same plane as the OMe group

O

O

O

KOtBu

n

n = 1,2

For an opposing viewpoint to Baldwin's view of nucleophile trajectories, see
Menger's article on directionality in solution organic chemistry:
Tetrahedron 1983, 39, 1013.

Me

OMe

MeO

Allowed due to in-plane pi orbitals

Y

HO

Li+

■ Spiro dihydrofuranones:

5-endo-dig
:X

_

Ph


Rules for Ring Closure: SP Carbon & Related Systems

D. A. Evans, J. Johnson

Chem 206

Digonal Cyclizations: Interesting Examples
Et3N, Toluene, reflux
12 h, 65-70% y.

MeO2C

■ Trost, J. Am. Chem. Soc., 1979, 101, 1284.

CN

Proposes E-olefin geometry, E/Z > 95:5

CN
O

O

R

CO2Me

R'

:

5-exo-dig
30-40 kcal/mol

O

HO2C
H

Conclusions and Caveats

Hirsutic Acid C

OTBS

LiCH2NC;
TBS-Cl

OTBS 1) RCOCl
2) AgBF4

71%

Me

Me

+

N

:

R'

?

OH

H

O

R

Me

N+

86%

C

R

CO

Works for varying ring sizes and R groups; acylnitrilium
ion can also work as an electophile in a Friedel-Crafts
type of reaction
5-endo-dig

■ Baldwin's Rules are an effective first line of analysis in
evaluating the stereoelectronics of a given ring closure
■ Baldwin's Rules have provided an important foundation for the
study of reaction mechanism
■ Competition studies between different modes of cyclization only
give information about relative rates, and are
not an absolute indicator of whether a process is "favored" or
"disfavored"
■ Structural modifications can dramatically affect the cyclization
mode; beware of imines and epoxides
EXO

■ Livinghouse, Tetrahedron 1992, 48, 2209.
Tet

O

H

Me
R
N
O

3-10-Baldwin Rules-10 9/18/03 5:21 PM

Trig

ENDO
Dig

3

X

4

X

Tet

Trig
X
X

5

X

6

X

7

X

X

Dig