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Hydrolysis of Acetals and KetalsUsing LiBF4Bruce H. Lipshutz a & Daniel F. Harvey aa Department of Chemistry, University of California,Santa Barbara, California, 93106Version of record first published: 01 Apr 2009.

To cite this article: Bruce H. Lipshutz & Daniel F. Harvey (1982): Hydrolysis of Acetalsand Ketals Using LiBF4 , Synthetic Communications: An International Journal for RapidCommunication of Synthetic Organic Chemistry, 12:4, 267-277

To link to this article: http://dx.doi.org/10.1080/00397918209409233

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SYNTHETIC COMMUNICATIONS, 12(4) , 267-277 (1982)

* HYDROL'ISIS OF ACETALS AND KETALS USING LiBF4

Bruce H. Lipshutz*' and Daniel F. Harvey 2

Department of Chemistry, Universi ty o f C a l i f o r n i a Santa Barbara, Ca l i fo rn ia 93106

P ro tec t ion o f the carbonyl group as its a c e t a l / k e t a l - r e m a i n s

an important s t e p i n designing s y n t h e t i c rou te s toward n a t u r a l

products.

- v i a aqueous a c i d hydrolysis o r a n exchange process employing

f a i r l y s t rong a c i d s and, i n some cases , e levated temperatures

(e.g., 2N H2S04/MeOH-H20, re flu^;^ 3N HCl/THF, rt;' 50% TFA/CHC13-

H20, O o ; 6 TsOH/acetone ). I n t h i s r e p o r t we desc r ibe an

a l t e r n a t i v e procedure using t h e r e a d i l y ava i l ab le , e a s i l y handled

sal t , LiBF4, i n w e t CH CN.

Urnasking t h i s moiety has t r a d i t i o n a l l y been achieved

3

7

3 I n previous work, dry LiBF4 i n warm CH CN w a s shown t o be a n 3

e f f e c t i v e source of f l u o r i d e i o n f o r c leaving an anomeric c e n t e r

i n Lhr ime thy l s i ly l e thano l -p ro tec t ed carbohydrates. a In one case

Dedicated t o Professor Harry H. Wassernan on the occasion of h i s s i x t i e t h birthday. To whom correspondence should be addressed.

9

* 267

Copyright 0 1982 by hlarcel Dckker. Inc.

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268 LIPSHUTZ AND HARVEY

dry Lief,

CH3CN OH

of a pyranose containing a 4,6-benzylidene Sroiij, r*'e observed

concomitant unraveling at both acetal centers.

of a 4,6-diol was attributed to LiBF

trace amounts of water.

bility that LiBF4 might be an effective reagent for cleavage

of the acetallketal function.

The formation

catalyzed hydrolysis with 4

This led us to investigate the possi-

Hence, a variety of aldehydes and ketones were converted

to their respective acetals and ketals under standard conditions

(e.g., ROHIOH, TsOH, reflux, -H20 or ROH/TsOH, orthoformate).

Each was subsequently treated with 1 equiv LiBF4 in 2:;

3

R = H, alkyl R' = alkyl , aryl

aqueous acetonitrile (substrate concentration 0 . 5 9).

reactions were readily monitored by TLC and upon completion,

the aldehydes or ketones xere isolated following an extractive

workup and rapid filtration through silica gel.

the concentrated reaction mixture could be applied directly to

a silica gel column thus avoiding exposure to aqueous media.

Results are summarized in Table I.

The

Alternatively,

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HYDROLYSIS OF ACETALS AND KETALS 269

In general, good yields of free carbonyl compounds have

been realized using this methodology.

(entries 1,2) hydrolyzed at a slower rate than did activated

systems (entries 4,5). In these cases, additional water andfor

LiBF4 were needed (see Table I) for >90% conversion. Aliphatic

aldehydes protected as their enthylene glycol acetals (e.g.,

Aliphatic acyclic acetals

entry 9) reacted more slowly than did similar substrates

masked as their methyl acetals (compare entries 2 and 9).

Methyl substitution on the ethylene glycol framework slowed

the process to an even greater extent (entries 10,ll).g Aliphatic

aldehydes protected with 1,3-propanedial appear to be inert to

these conditions as no reaction was detected (tlc, rmr) after

5h. lo Ketals underwent relatively rapid conversion to ketones

(entries 6,7,8).

The effect of solvent was briefly investigated as this was

Reactions

were carried 4'

3 2

a c-ritical parameter in earlier studies with LiBF

in 2% aqueous solutions of Et20, THF, DHF, and CH NO

out on 2-phenylpropanal dimethyl acetal at room temperature.

No significant aldehyde formation occurred in any of these

solvents with the exception of nitromethane, where a rate compara-

ble t.o that observed in CH3CN was seen. It is worthy of note that

the same substrate, upon treatment with 3 : l : l HOAc:THF:H20 (0.1M)

at room temperature (pH -2.5)

after 5h and s. 50% hydrolysis in 24h. With regard to the mechanism of the reaction, it is tempting

12 showed only E. 15% cleavage 13

+ to simply attribute the hydrolysis to the generation of H30 .

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T,A

6LE

I.

Cle

avag

e of

Ace

tols

/Ket

ols

wit

h Li

BF4

-

Ent

ry

Sub

stra

te

Dep

rote

ctio

na,

Yiel

d (Yo)

Tirn

e(h)

i 3 4

Ph

6 O

Et

84

95

96

96

93

0.75

O.5

Oc

4.25

13

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7 8 9

10

ii

12

Ph

Me0

O

Me

, I

xh

/os

i+

I Ph

96

80

40

c5

'

<5

' O

i

0.73'

5 5

E? 2 et

56 0

m

l-4 m 0

"Th

e p

rodu

ct,

in o

ll d

epra

tdct

ions

, w

as t

he c

orre

spon

ding

fr

ee c

orbo

nyl

com

poun

d.

All

yie

lds

refe

r to

iso

late

d pr

oduc

ts c

ompa

red

(tlc

, ir

, on

d/or

n

mr)

dir

ectly

wit

h au

then

tic

mat

eria

ls.

Add

iiion

ol w

ater

{I - 3

dro

9)

and

LiBF

4 1.

5 10

i.5

equ

iv)

adde

d du

ring

the

cour

se o

f re

octio

n.

Aque

ous

wor

kup

empl

oyed

. 'R

eact

ion

wen

t to

92

% c

ompl

etio

n;

yiel

d ba

sed

on 8

% r

ecov

ered

st

ortin

g m

ater

ial.

@'The co

ncen

trat

ed r

eact

ion

mix

ture

wos

opp

lied

dire

ctly

to

a si

lica

gel

colu

mn.

f

2% s

tort

ing

mot

eria

l re

cove

red;

?Reo

ctio

n w

as

80%

com

plet

e in

3h.

hM

eOH

add

ed

drop

- w

ise

to f

ully

so

lubi

lire

subs

trat

e. 'C

orre

spon

ds t

o

conv

ersi

on

3s

jud

qed

by T

LC.

IN0

prod

uct

wos

det

ecte

d by

TLC

ana

lysi

s.

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27 2 LIPSHUTZ AND HARVEY

However, i t should be noted t h a t t h e amount of w a t e r a v a i l a b l e

i s minimal. A 0.5M so lu t ion of s u b s t r a t e i n 2X aqueous CH CN,

( i n t h e presence of 21 equiv LiBF4) con ta ins ,on ly 2.2 equ iva len t s

of H 0 r e l a t i v e t o a c e t a l / k e t a l , a q u a n t i t y s u f f i c i e n t t o generate

only t h e carbonyl group and 1 .2 equiv of HF.

p o t e n t i a l f o r ar.y boron-containing spec ie s t o f a c i l i t a t e cleavage

must also be considered.

3

2

However, t h e

W e have suggested t h a t dry LiBF4 may

LiBF, Li + BF,-

F- + BF,

*2O " 2 0 BF, - HF + B(OH)F, - etc.

act both as a source o f f l u o r i d e i o n

8 through the e q u i l i b r i a shown above.

however, BF3 would f u r t h e r decompose

HF and b o r i c a c i d ( s ) , depending upon

Hence, i t w a s no t s u r p r i s i n g t o f i n d

and Lewis a c i d (i.e., BF3)

I n t h e presence of H 0,

t o varying percentages of

the amount of H 0 present .

t h a t treatment of 2-phenyl-

2

2

propanal d ine thy l k e t a l w i th BF3*Et20 (2 equiv) i n 5% aqueous

CH CN a t room temperature r e a d i l y gave rise t o t h e corresponding

deprotected aldehyde."

LiBF4 i n 100% H 0 a t room temperature gradual ly decreases i n pH

from a n i n i t i a l value of 5.0 t o G. 2.5 over 12h,

gradual release of HF.I4

would a l s o a i d i n carbonyl formation.

3

We have observed t h a t a 0.5H s o l u t i o n of

2 12 suggest ing a

Residual boron-containing L e w i s a c i d (s)

The r o l e o f t h e c a t i o n w a s a l s o examined. Treatment of

3-phenylpropanal dimethyl acetal wi th a s o l u t i o n containing excess

L i C l O i n 2% aqueous CH CN a t room temperature gave no i n d i c a t i o n 4 3

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HYDROLYSIS OF ACETALS AND KETALS 27 3

of reaction. This suggests that lithium ion alone is not the

reactive species.15 Both NaBF4 and KBF4 were also ineffective

at ambient temperature.

mixtures, however, led to slow hydrolysis with NaBF4, while

KBFq remained inert. The differences in reactivity in going from

the tetrafluoroborate salts of Li to Na to K may be due t o a

Refluxing these two heterogeneous

+ + +

combination of factors including Lewis acidity of the counterion

as well as solubility properties of the salts in the reaction

nedium That is, while at room temperature LiBF4 is completely

in solution in wet CH3CN, NaBF4 appears to be only slightly

soluble, and KBF4 practically insoluble.

In order to rule out the possibility of nucleophilic

fluoride ion-mediated dealkylative cleavage of acetalslketals,

5-chloropentanal ethylene glycol acetal was subjected t o excess

(5 equiv) LiBF in moist CH CN.

reaction misture (at 60% completion) indicated that no

2-fluoroethanol had been forned.17

carboxaldehyde, protected as its dineopentyl acetal likewise

underwent hydrcdysis to the aldehyde at the normal rate.

Direct VPC analysis16 of the 4 3

In addition, cyclohexane-

The unfavorability of fluoride ion attack at the neopentyl center

further argues against an sN2 mode of cleavage.

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274 LIPSHUTZ AND HARVEY

The utility of this reagent for carbonyl regeneration is

apparent in the case of ketal & shown below.

LiBF4 in moist CH3CN at rt overnight gave $,y-unsaturated enone

2 contaminated with (2% of the conjugated enone.

coupares favorably with those obtained using oxalic acid dihydrate

or 80% acetic acid for this type of transformation.

Treatment of with

This result

18

LiBF,

rt 0 w 2% H20 /CH$N 0

2 N

I L o

N

In conclusion, use of LiBF in wet CH CN represents an 4 3

operationally simple procedure for effecting hydrolysis of

acetals/ketals. The reaction conditions are mild, the reagent

commercially available’’ and yields of deprotected material are

consistently high.

to those obtained under conditions usually involving stronger acids

and/or higher temperatures. The cleavage may involve partici-

pation of both HF and boron-containing Lewis acids, although a

complete mechanistic understanding remains to be realized.

In many cases rates of cleavage are comparable

Experimental Section

4-Phenvlcyclohexanone. The hydrolysis of 4-phenylcyclohexanone

diethyl ketal to the title compound can be used to illustrate

the general procedure applied to the substrates listed in

Table I. LiBF (35.8 mg, 0.38 mol) was placed in a pear-shaped

flask, diluted with 0.38 mL of 2% aqueous CH3CN, and added 4

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OF ACETALS AND KETALS 27 5 HYDROLYSIS

cannula to

Additional

4-phenylcyclohexanone diethyl ketal (94.3 mg, 0.38 mol).

solvent (0.38 mL) was used to rinse the LiBF4 solutir-

into the reaction flask bringing the substrate concentration

to 0.5 M.

of starting naterial.

with ether from aqueous NaHC03 solution.

were dried, filtered, and concentrated in vacuo. Filtration

through a silica gel plug (10% Et20/pentane) afforded 61.2 mg

(92%) of the parent ketone, identical with an authentic sample.

After 30 min, TLC indicated the complete disappearance

The mixture was worked up by extraction

The combined extracts

20

Acknowledgment.

Research, UCSB, the Cancer Research Coordinating Committee of

the University of California, the NSF Undergraduate Research

Program, and the UCSB President's Fellowship Committee is

gratefully acknowledged. We also thank Xr. William Elias for

technical assistance, the American Cancer Society for a Junior

Faculty Research Award (JFRA 837 to B.H.L.), and Professors

Don Aue and Clifford Bunton for helpful discussions.

Financial support from the Committee on

References and Notes

1.

2.

3.

4.

Recipient of an American Cancer Society 3unior Faculty Research Award, 1981-1983.

NSF Undergraduate Research Participant, 1980; UCSB President's Undergraduate Fellow, 1980-81.

Green, T . W . , "Protective Groups in Organic Synthesis ," Wiley, New York, 1981.

Cameron, A.F.B., Hunt, J . S . , Oughton, J.F., Wilkinson, P.?., Wilson, B.M., J. Chem. SOC., 1953, 3864.

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27 6 LIPSHUTZ AND HARVEY

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

Wenkert, E., Goodwin, T.E., Syn. Comn., 1977, L, 409. Ellison,R.A., Lukenbach, E . R . , Chiu, C.-W., Tetrahedron Lett., 1975, 499.

Colvin, E.W., Raphael, R.A., Roberts, J .S . , Chen. Corn., 1971, 858.

Lipshutz, B.H., Pegram, J . J . , Florey, M.C.; Tetrahedron Letters, submitted for publication.

This was expected on the basis of literature reports: see Newman, M.S., Harper, R.J., J. AG. Chem. SOC., 1058, so, 6350, and references therein.

Similarly, 2-phenylpropanal 1,3-propanediol acetal showed no hydrolysis even after one week at room temperature. the reaction was performed in the presence of either 2-phenylpropanal dimethyl acetal or 6-bromohexanal dinethyl acetal (Table I, entry 2 ) , only the acyclic acetal was removed. In general, ethylene glycol acetals hydrolyze in acid at a greater rate than do 1,3-dioxanes of aldehydes, which in turn, hydrolyze more slowly than do acyclic systems. For leading references, see (a) reference 3; (b) Dolson, M.G., Swenton, J .S . , J. Org. Chem., 1981, 46, 177; (c) Fife, T.H., Bord, L.H., w., 1968, 33, 4136; (d) Fife, T.H., Hogopian. L., E., 1966, 2, 1772; (e) Fife, T.H., Acct. Chem. Res., 1972, 2, 264 (f) Slavin. M.N., Levi, I.S., Matveeva, A . A . , Kilcot, P . S . , Berlin, X.Y. J. Org. Chem. USSR (Engl. Transl.), 1969, 2, 448; (g) Cordes, E.H., Bull, H.G. , Chem. Rev. , 1974, 76, 581.

This was not, however, a clean reaction as judged by TLC. .

When

Pleasured with pH paper.

These are typical conditions for hydrolysis of THP ethers, usually carried out at 455.3 ethers cleaved only to the extent of -50%, even after cays at room temperature with added LiaFr, andlor H?O. result is in line with the general observation that, in- sofar as the use of LiBF4 is concerned, acyclic acetals hydrolyze at a far greater rate than do cyclic cases.

"The Merck Index", Stecher, P.G. , Ed. , Herck and Co., Inc., Rahway, N.J., 1968, Eighth Edition, pp. 161-162.

At higher temperatures, however, hydrolysis may take place. See, for example, Danishefsky, S., Vaughan, K., Gadwood, R. , Tsuzuki, K. J . Am. Chen. SOC., 1981, 103, 4136.

In the present study, TI'S

This

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HYDROLYCIS OF ACETALS AND KETALS 277

16. VPC analysis was performed on a 12 foot x .125 inch column of 9% DEGS on Chromosorb G .

17. Determined by co-injection with authentic material (Sigma).

18. Babler,J.H., Malek, N.C., Coghlan, M.J., J. Org. Chem., 1978, 43, 1821. hydrolysis of ,1 using 80% HOAc at either room temperature or at 65Q consistently have led to 5-15% of conjugated enone: Aue, D.H., Perdomo, G.R., unpublished results.

Comparative studies conducted on the

19. Available from Alfa Products, Danvers, MA. 01923.

20. Purchased from the Aldrich Chemical Company, Nilwaukee, Wisconsin.

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