MOLECULAR SIEVES

1

Molecular Sieves

1

(electrocyclic reaction cocatalyst; mild acid catalyst; desiccant)

Form Supplied in:

the most common forms are bead, pellet, and

powdered solids with cavity sizes of 3, 4, 5 and 10Å. The bead
and pellet forms are adequate for drying solvents, while the
powdered form is preferred for use in most reactions.

Preparative Methods:

sieves are most effective if activated prior

to use by drying under vacuum (<1 mmHg) at 300

◦

C for at

least 15 h.

Handling, Storage, and Precautions:

all forms of sieves readily

absorb water upon exposure to air and are therefore best stored
in a desiccator. Sieves can be recycled by (a) washing well with
an organic solvent, (b) drying at 100

◦

C for several hours, and

(c) reactivation at ≥ 200

◦

C. Skin contact should be avoided as

the desiccant properties of the sieves cause irritation.

General Information.

Molecular sieves are metal aluminosil-

icates of the general formula M

2/n

O·Al

2

O

3

·

x

SiO

2

·

y

H

2

O (where

n

is the valence of the metal, M) characterized by a regular (zeo-

lite) structure and cavity size which is retained even with loss of
hydration.

2,3

Although they occur in Nature, most sieves are man-

ufactured commercially as they can be designed with properties
specific to their application. Many variations have been synthe-
sized and the field of zeolite design is one of intense investigation.

4

The Linde Division of the Union Carbide Corporation is a major
supplier of molecular sieves for synthetic organic applications. Of
their products, the 3, 4, and 5 Å as well as 13X sieves are the most
commonly employed; these differ both in pore size (3, 4, 5, and
10Å, respectively) and cation constitution (K, Na, Ca, and Na,
respectively).

5

Thus a sieve appropriate to a specific application

can be selected.

Diels–Alder Catalysis.

Whether combined with a Lewis

acid or used alone, molecular sieves are powerful accelerators
of this concerted process. In the former case, great progress has
been made toward combining this reagent with a chiral Lewis
acid to induce asymmetry during reaction between two achiral
molecules.

6

–

12

This has been achieved through the use of the

chiral titanate (1) and achiral auxiliary (2) which aids in coordi-
nation of the dienophile (eqs 1 and 2). Not only is this a highly
successful method for the enantioselective generation of the stere-
ocenters, but it is also catalytic. The power of this methodology is
elegantly demonstrated in eq 2, taken from Narasaka’s synthesis of
the hydronaphthalene portions of mevinic acids, where this cata-
lyst system is employed to introduce four contiguous chiral centers
with complete diastereoselectivity and very high enantioselectiv-

O

O

Ph

O

O

Ti

Cl

Cl

Ph

Ph

Ph Ph

N

O

O

(1)

(2)

= X

ity from an achiral precursor. Although a less dramatic example,
eq 3 displays the ability of sieves to function independently as
cycloaddition catalysts,

13

as attested to by the mild temperature

and short reaction time.

MeO

2

C

X

O

+

CO

2

Me

COX

(1)

5% (1), MS 4A

94% ee

0 °C, toluene–PE

94%

S

S

X

O

S

S

H

H

(2)

COX

rt, toluene–PE, 150 h

70%

single diastereoisomer

>95% ee

30% (1), MS 4A

N

Br

Br

COPh

CO

2

Et

EtO

2

C

N

COPh

+

CO

2

Et

CO

2

Et

(3)

NaI, MS 4A

50–55 °C, DME

30 min

63%

racemic

Ene Reactions.

Utilization of the reagent in ene reactions par-

allels its use in Diels–Alder cycloadditions, although the choice
of the Lewis acid cocatalyst is substrate dependent. The three
most effective chiral metal complexes employed to date are either
the tartrate-based titanate (1), titanium-complexed commercially
available 1,1

′

-binaphthol (see (R)-1,1

′

-Bi-2,2

′

-naphthotitanium

Dichloride

), or the more bulky binaphthol-derived system (3) (eqs

4–6).

14

–

16

Performance of these catalytic systems is comparable

to those employed in the Diels–Alder reaction in both enantiose-
lectivity and mildness of reaction conditions.

O

O

Al

TMS

TMS

Me

(3)

(4)

0 °C, CFCl

2

CF

2

Cl, 4 d

63%

X

O

COX

>98% ee

10% (1), MS 4A

Avoid Skin Contact with All Reagents

2

MOLECULAR SIEVES

(5)

SPh

C

6

F

5

SPh

OH

C

6

F

5

CHO

–78 °C, CH

2

CL

2

, 1.5 h

88%

*

88% ee

20% (3), MS 4A

(6)

O

CO

2

Me

(R)-BINOL, MS 4A

rt, CH

2

Cl

2

, 3 h

87%

+

CO

2

Me

OH

94% ee

10% (i-PrO)

2

TiBr

2

Other Electrocyclic Reactions.

Finally, molecular sieves

have been successful in facilitating asymmetric [2 + 2] cycloaddi-
tions when (1) is present, and in promoting [3 + 2] dipolar cycload-
ditions. Again, in the former case, the optical yields are extremely
good as can be seen from eqs 7–9.

17

–

20

In the latter case, the sieves

generate the nitrile oxide in situ and this species then reacts with
the acrylate acceptor to yield the isoxazole (eq 10). Although this
method requires a relatively long reaction time, the mild condi-
tions have the advantage of suppressing side reactions, including
dimerization of the nitrile oxide, resulting in high yields of very
pure material.

21

MeO

2

C

X

O

•

SMe

TMS

MeO

2

C

COX

TMS

SMe

(7)

0 °C, toluene–PE

quant..

+

>98% ee

10% (1), MS 4A

MeO

2

C

X

O

SMe

(8)

MeO

2

C

COX

10% (1), MS 4A

+

>98% ee

SMe

0 °C, toluene–PE

83%

MeO

2

C

X

O

MeO

2

C

COX

(9)

10% (1), MS 4A

>98% ee

SMe

SMe

SMe

SMe

+

0 °C, toluene–PE

96%

N

O

Cl

HO

CO

2

Me

N O

O

CO

2

Me

+

(10)

rt, CH

2

Cl

2

, 10 d

99%

MS 4A

Acid Scavenging.

In addition to their use as cocatalysts,

molecular sieves also function as acid scavengers, making them

especially suited to the suppression of acid-catalyzed side reac-
tions such as polymerization. For example, they are employed
in the preparation of high-purity methacrylic acid esters from
methacryloyl chloride and various alcohols (primary, secondary,
tertiary, and benzylic).

22

This acid-scavenging ability has also

proven useful in the direct acylation of acid-sensitive, unreactive
tertiary hydroxyl groups and of acid- and base-sensitive amides
with acyl chlorides.

23,24

Sorbtion.

The reagent’s sorbtion ability has been exploited

in a wide range of carbonyl and carboxylate transformations.
Key to their utility is the inclusion of molecules such as wa-
ter and small alcohols into the sieve cavities while excluding
the larger compounds, thus allowing greater control of equilib-
ria. By this method, ketimines and enamines derived from steri-
cally encumbered precursors are more accessible.

25,26

Likewise,

triphenylphosphazenes can be obtained by reaction of N-aminotri-
phenylphosphinime with various aldehydes and ketones.

27

Reductive amination of carbonyls proceeds in better yield with
molecular sieves present to absorb water.

28

When coupled with

tertiary amines such as 1,5-Diazabicyclo[4.3.0]non-5-ene or 1,8-
Diazabicyclo[5.4.0]undec-7-ene

, 3 or 4Å sieves can effect the

alkenation of δ-alkoxy-α,β-unsaturated aldehydes efficiently.

29,30

Amide synthesis with molecular sieves provides a general, high
yielding, and chemoselective route to secondary amides free of
byproducts and impurities.

31

Transesterification of methyl esters

with branched primary, secondary, and tertiary alcohols has been
reported with the 5 Å sieve.

3

Zeolites have been utilized in the

preparation of an asymmetric hydrocyanating agent by reaction
with titanate (1) followed by treatment with 2 equiv of Cyan-
otrimethylsilane

at ambient temperature.

32,33

Addition of this

reagent to aldehydes at −78

◦

C in toluene provides the corre-

sponding cyanohydrins in yields of 67–92% and optical purities
ranging from 61% to 93%.

Acid Catalysis.

The Lewis acid reactivity of this reagent can

be applied to Michael-type reactions as shown in eqs 11 and
12.

34,35

The resulting ring systems can be further transformed

into a variety of useful synthetic building blocks. Molecular sieves
can also be coupled with Lewis acids to promote acetal forma-
tion and exchange. When used with p-Toluenesulfonic Acid as
a cocatalyst, sieves provide a facile synthesis of acetals from
carbonyls, not only when primary but also when secondary al-
cohols are involved.

36,37

Employment with Boron Trifluoride

Etherate

catalyzes exchange between (tributylstannyl)methanol

and Dimethoxymethane to produce the useful hydroxymethyl
anion equivalent Tributyl[(methoxymethoxy)methyl]stannane in
high yield.

38,39

(11)

N

+

O

Ph

CO

2

Me

MeO

2

C

O

–

i

-PrNH

2

, MS 4A

rt, 3 h, then

PhCHO

2 equiv O

2

NCH

2

CO

2

Me

MeOH, Et

2

O, reflux, 6 h

76%

O

N

O

–

Ph

O

O

N

N

Ph

O

O

–

O

–

+

(12)

+

rt, 24 h

82%

+

+

MS 4A

A list of General Abbreviations appears on the front Endpapers

MOLECULAR SIEVES

3

Oxidations.

Titanium silicate molecular sieves have served as

catalysts in the selective oxidation of thioethers to sulfoxides.

40

They effect this transformation under mild conditions (1 equiv
of H

2

O

2

in refluxing acetone) with little over-oxidation to the

sulfone. When used as a promoter in Pyridinium Chlorochromate
and Pyridinium Dichromate oxidations of nucleoside derivatives,
sieves work remarkably well, in contrast to other additives such
as Alumina, Celite, or silica gel which fail to accelerate these
reactions.

41

As drying agents, sieves are a crucial component of

the Sharpless catalytic asymmetric epoxidation.

42

Miscellaneous Reactions.

The shape selectivity of zeolites

has been exploited to selectively brominate either a hindered dou-
ble bond in the presence of an unhindered double bond or vice
versa, depending on the reaction conditions.

43

If the hindered

and unhindered alkene mixture is allowed to equilibrate prior to
bromine addition, bromination of the hindered alkene is greatly
favored (up to a 95:5 preference). Conversely, inclusion of the
bromine in the sieves followed by addition of the alkene mixture
shows opposite selectivity.

Molecular sieves have been employed as acid scavengers in the

transition metal-catalyzed synthesis of carboxylic acids and esters
from iodides under base-free conditions, as represented in eq 13.

44

Another transition metal-catalyzed reaction (eq 14) applies sieves
as a cocatalyst with Iron(III) Chloride to form a nonreducing
disaccharide in an alternative to the conventional Koenigs–Knorr
method.

45

In concert with Tin(II) Trifluoromethanesulfonate and

2,4,6-Collidine

, molecular sieves promote the coupling of aceto-

bromoglucose with various protected sugar derivatives to form
exclusively trans-β-

D

-glucosides with glucose as the reducing

unit.

46

Finally, the use of zeolites as cocatalysts in palladium-

catalyzed oxidative cyclizations has led to substantial improve-
ments in the diastereoselectivity of these reactions.

47,48

This is

exemplified in eq 15, which shows only a 17% de in the absence
of molecular sieves.

EtO

I

O

100 °C, EtOH–THF, 48 h

CO (autoclave)

81%

EtO

OEt

O

O

(13)

Cl

2

Pd(PPh

3

)

2

, MS 4A

O

OBz

BzO

BzO OBz

O

O

O

OBz

OBz

OBz

OBz

BzO

OBz

(14)

38% FeCl

3

, MS 3A

rt, CH

2

Cl

2

, 24 h

51%

H

H

Cl

Cl

H

O

CO

2

H

OXc

H

H

(15)

+

Pd(OAc)

2

, p-benzoquinone

MnO

2

, acetone

rt, 13X MS

39%

62% de

1.

(a) Hölderich, W.; Hesse, M.; Näumann, F., Angew. Chem., Int. Ed. Engl.
1988

, 27, 226. (b) Davis, M., Acc. Chem. Res. 1993, 26, 111. (c) Dyer, A.

An Introduction to Zeolite Molecular Sieves

; Wiley: New York, 1988. (d)

Studies in Surface Science and Catalysis

; Bekkum, H. V.; Flanigen, E.

M.; Jansen, J. C., Eds.; Elsevier: New York, 1991; Vol. 58. (e) Molecular
Sieve Catalysts

; Michiels, P.; De Herdt, O. C. E. Eds., Pergamon: Oxford,

1987.

2.

Hersh, C. K. Molecular Sieves; Reinhold: New York, 1961.

3.

Fieser & Fieser 1967

, 1, 703.

4.

Szostak, R. Handbook of Molecular Sieves; Van Nostrand Reinhold:
New York, 1992.

5.

Linde Division Specialty Gasses; Union Carbide, 1985; Section 9.

6.

Narasaka, K.; Inoue, M.; Okada, N., Chem. Lett. 1986, 1109.

7.

Narasaka, K.; Inoue, M.; Yamada, T.; Sugimuri, J.; Iwasawa, N., Chem.
Lett. 1987

, 2409.

8.

Iwasawa, N.; Hayashi, Y.; Sakurai, H.; Narasaka, K., Chem. Lett. 1989,
1581.

9.

Iwasawa, N.; Sugimori, J.; Kawase, Y.; Narasaka, K., Chem. Lett. 1989,
1947.

10.

Narasaka, K.; Tanaka, H.; Kanai, F., Bull. Chem. Soc. Jpn. 1991, 64, 387.

11.

Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima, M.;
Sugimori, J., J. Am. Chem. Soc. 1989, 111, 5340.

12.

Narasaka, K.; Saitou, M.; Iwasawa, N., Tetrahedron: Asymmetry 1991,
2

, 1305.

13.

Pindur, U.; Haber, M., Heterocycles 1991, 32, 1463.

14.

Narasaka, K.; Hayashi, Y.; Shimada, S., Chem. Lett. 1988, 1609.

15.

Maruoka, K.; Hoshino, Y.; Shirasaka, T.; Yamamoto, H., Tetrahedron
Lett. 1988

, 29, 3967.

16.

Mikami, K.; Terada, M.; Nakai, T., J. Am. Chem. Soc. 1990, 112, 3949.

17.

Ichikawa, Y.; Narita, A.; Shiozawa, A.; Hayashi, Y.; Narasaka, K., J.
Chem. Soc., Chem. Commun. 1989

, 1919.

18.

Hayashi, Y.; Narasaka, K., Chem. Lett. 1989, 793.

19.

Hayashi, Y.; Narasaka, K., Chem. Lett. 1990, 1295.

20.

Hayashi, Y.; Niihata, S.; Narasaka, K., Chem. Lett. 1990, 2091.

21.

Kim, J. N.; Ryu, E. K., Heterocycles 1990, 31, 1693.

22.

Banks, A. R.; Fibiger, R. F.; Jones, T., J. Org. Chem. 1977, 42, 3965.

23.

Nakamura, T.; Fukatsu, S.; Seki, S.; Niida, T., Chem. Lett. 1978, 1293.

24.

Weinstock, L. M.; Karady, S.; Roberts, F. E.; Hoinowski, A. M.; Brenner,
G. S.; Lee, T. B. K.; Lumma, W. C.; Sletzinger, M., Tetrahedron Lett.
1975

, 3979.

25.

Taguchi, K.; Westheimer, F. H., J. Org. Chem. 1971, 36, 1570.

26.

Bonnett, R.; Emerson, T. R., J. Chem. Soc. 1965, 4508.

27.

Walker, C. C.; Shechter, H., Tetrahedron Lett. 1965, 1447.

28.

Borch, R. F.; Bernstein, M. D.; Durst, H. D., J. Am. Chem. Soc. 1971,
93

, 2897.

29.

Ishida, A.; Mukaiyama, T., Chem. Lett. 1975, 1167.

30.

Mukaiyama, T.; Ishida, A., Chem. Lett. 1975, 1201.

31.

Cossy, J.; Pale-Grosdemange, C., Tetrahedron Lett. 1989, 30, 2771.

32.

Narasaka, K.; Yamada, T.; Minamikawa, H., Chem. Lett. 1987, 2073.

33.

Minamikawa, H.; Hayakawa, S.; Yamada, T.; Iwasawa, N.; Narasaka,
K., Bull. Chem. Soc. Jpn. 1988, 61, 4379.

34.

Mélot, J. M.; Texier-Boullet, F.; Foucard, A., Synthesis 1988, 558.

35.

Takabatake, T.; Hasegawa, M., J. Heterocycl. Chem. 1987, 24, 529.

36.

Roelofsen, D. P.; Wils, E. R. J.; van Bekkum, H., Recl. Trav. Chim.
Pays-Bas 1971

, 90, 1141.

37.

Roelofsen, D. P.; van Bekkum, H., Synthesis 1972, 419.

38.

Danheiser, R. L.; Gee, S. K.; Perez, J. J., J. Am. Chem. Soc. 1986, 108,
806.

39.

Danheiser, R. L.; Romines, K. R.; Koyama, H.; Gee, S. K.; Johnson, C.
R.; Medich, J. R., Org. Synth. 1993, 71, 133.

40.

Reddy, R. S.; Reddy, J. S.; Kumar, R.; Kumar, P., J. Chem. Soc., Chem.
Commun. 1992

, 84.

Avoid Skin Contact with All Reagents

4

MOLECULAR SIEVES

41.

Herscovici, J.; Antonakis, K., J. Chem. Soc., Chem. Commun. 1980,
561.

42.

Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B., J. Am. Chem. Soc. 1987, 109, 5765.

43.

Smith, K.; Fry, K. B., J. Chem. Soc., Chem. Commun. 1992, 187.

44.

Urata, H.; Hu, N.; Maekawa, H.; Fuchikami, T., Tetrahedron Lett. 1991,
32

, 4733.

45.

Lerner, L. M., Carbohydr. Res. 1990, 207, 138.

46.

Lubineau, A.; Malleron, A., Tetrahedron Lett. 1985, 26, 1713.

47.

Heumann, A.; Tottie, L.; Moberg, C., J. Chem. Soc., Chem. Commun.
1991

, 218.

48.

Tottie, L.; Baeckström, P.; Moberg, C.; Tegenfeldt, J.; Heumann, A., J.
Org. Chem. 1992

, 57, 6579.

James C. Lanter

The Ohio State University, Columbus, OH, USA

A list of General Abbreviations appears on the front Endpapers