Ferric Chloride Hexahydrate: A mild hydrolytic agent for the deprotection of acetals

Full text of DOI:10.1021/jo970509l

6
684
J . Org. Chem. 1997, 62, 6684-6686
F er r ic Ch lor id e Hexa h yd r a te: A Mild
Hyd r olytic Agen t for th e Dep r otection of
Aceta ls
reaction with FeCl
ing MOM ether was significantly less reactive. Depro-
tection of this latter material at rt or in refluxing CH Cl
provided a variable mixture of octanol and formaldehyde
dioctyl acetal which could be eliminated by the addition
of acetone.
3
‚6H
2
O at rt; however, the correspond-
2
2
Stephanie E. Sen,* Steven L. Roach, J anet K. Boggs,
Gregory J . Ewing, and J oe Magrath
To better understand the role and nature of the iron
species in solution, the effect of several factors, including
Lewis acid equivalents, reaction time, water content, and
reaction reversibility, was investigated. Removal of the
Department of Chemistry, Indiana University-Purdue
University at Indianapolis, 402 North Blackford Street,
Indianapolis, Indiana 46202
1
,3-dioxolane moiety of octanal using 1-6 equiv of
FeCl ‚6H O showed hyperbolic behavior, with deacetal-
ization reaching nearly maximal yield within 20 min
Figure 1). The addition of increasing equivalents of
Received March 19, 1997
3
2
In tr od u ction
(
Acetals are widely used as protecting groups in organic
Lewis acid resulted in a proportionate increase in octanal
formation up to a maximum of 3.5 equiv; thereafter, the
synthesis and, as a consequence, many methods have
1
been examined for both their formation and removal.
presence of more FeCl
For the more reactive 1,3-dioxolane of benzophenone, the
use of less than 1 equiv of FeCl ‚6H O resulted in efficient
deprotection; reaction yields using fewer equivalents
(0.15, 0.3, and 0.5 equiv of FeCl ‚6H O, entry 5, Table 1)
3
‚6H
2
O had an inhibitory effect.
Typically, deprotection of acetals requires the use of
1
,2
protic or Lewis acids, although more recently alterna-
tive methods that use DDQ, aqueous DMSO, lithium
halides, silanes, or insoluble acidic matrices have been
developed.3 Previously, we reported the utility of ferric
3
2
3
2
suggest that deprotection involves stoichiometric dis-
placement of each of the chloride ligands from the metal
chloride hexahydrate (FeCl
3
2
‚6H O) as a promoter in the
cyclization of an N-acyl enamide polyene having a diox-
olane initiator, where this less commonly used Lewis acid
served as both a deprotecting and cyclization agent.4
Because of the reaction’s mild conditions and apparent
compatibility with acid sensitive functionalities, a more
center. The reversibility of the FeCl
3
2
‚6H O-mediated
deacetalization was demonstrated by the formation of the
1,3-dioxolane of dihydrocinnamaldehyde, by the reaction
of aldehyde with 10 equiv of ethylene glycol in the
presence of 3.5 equiv of FeCl
not shown).
3
2 2 2
‚6H O in CH Cl at rt (data
thorough examination of FeCl
agent was undertaken.
3
2
‚6H O as a deacetalization
Although ferric chloride has been previously demon-
The known acetals (entries 1-12, Table 1) were
prepared and reacted with 3.5 equiv FeCl ‚6H O in
CH Cl . In most cases, the reaction was complete within
5 min at rt and provided aldehyde or ketone in excellent
6
strated by others to promote deprotection chemistry, we
3
2
found that treatment of several acetals with either
2
2
anhydrous FeCl
provided varied results. For the 1,3-dioxolanes of tert-
or FeCl
2
‚6H O absorbed onto silica gel
3
3
1
yield. For materials less susceptible to acetal deprotec-
tion (e.g., entries 6 and 7), using reflux temperature or
adding acetone (to better dissolve the Lewis acid and to
participate in transacetalization) resulted in both in-
creased yields and deacetalization rates. The dioxane
butylcyclohexanone and dihydrocinnamaldehyde, anhy-
drous FeCl
sponding FeCl
, Table 1), while treatment of the dimethyl acetal of
phenylacetaldehyde (entry 9) with anhydrous FeCl
3
deprotection was as efficient as the corre-
3
‚6H O-mediated reactions (entries 2 and
2
6
3
functionality, which is typically difficult to remove under
caused complete decomposition to several unidentified
materials. In our hands, we found that the absorption
5
mild conditions, was effectively hydrolyzed with FeCl
3
‚
6
H
2
O as demonstrated by the near quantitative depro-
tection of the 1,3-dioxane of cinnamaldehyde (entry 8).
The ability of FeCl ‚6H O to cleave related alcohol
of FeCl
3
2
‚6H O onto silica gel provided a generally weaker
deprotecting agent, having similar reaction selectivity to
the corresponding nonabsorbed material. Thus, deac-
etalization of the 1,3-dioxolane of dihydrocinnamaldehyde
and of 3-O-(tert-butyldimethylsilyl)-1,2:5,6-di-O-isopro-
pylidene-R-D-glucofuranose (entry 12) was considerably
3
2
protecting groups such as THP and MOM ethers was also
investigated (entries 10 and 11, respectively, Table 1).
The THP ether of octanol was efficiently removed by
faster when FeCl
3
‚6H
2
O was used.7 For the latter
(
1) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; J ohn Wiley and Sons, Inc.: New York, 1991.
2) (a) Barbot, F.; Miginiac, P. Synthesis 1983, 651-654. (b) Sterzy-
compound, neither hydrated iron reagent caused loss of
the TBDMS group; however, the increased reactivity of
(
cki, R. Synthesis 1979, 724-725. (c) Kantam, M. L.; Swapna, V.;
Santhi, P. L. Synth. Commun. 1995, 25, 2529-2532. (d) Ma, S.;
Venanzi, L. M. Tetrahedron Lett. 1993, 34, 8071-8074. (e) Ford, K.
L.; Roskamp, E. J . J . Org. Chem. 1993, 58, 4142-4143. (f) Chang, C.;
Chu, K. C.; Yue, S. Synth. Commun. 1992, 22, 1217-1220. (g) Sarmah,
P.; Barua, N. C. Tetrahedron Lett. 1989, 30, 4703-4704. (h) Lipshutz,
B. H.; Pollart, D.; Monforte, J .; Kotsuki, H. Tetrahedron Lett. 1985,
FeCl
3
2
‚6H O allowed for selective deprotection of either
one or both acetals by varying the reaction time and the
number of equivalents used.
All of these results are difficult to explain in terms of
a traditional Lewis acid-promoted hydrolysis mechanism
2
1
6, 705-708. (i) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982,
since the solubility of FeCl
3
2 2 2
‚6H O in CH Cl is low,
2, 267-277.
(3) (a) Tanemura, K.; Suzuki, T.; Horaguchi, T. Bull. Chem. Soc.
J pn. 1994, 67, 290-292. (b) Kametani, T.; Kondoh, H.; Honda, T.;
Ishizone, H.; Suzuki, Y.; Mori, W. Chem. Lett. 1989, 901-904. (c) Maiti,
G.; Roy, S. C. J . Org. Chem. 1996, 61, 6038-6039. (d) Chen Y.-H.;
Tseng, Y.-T.; Luh, T.-Y. J . Chem. Soc., Chem. Commun. 1996, 327-
(6) (a) Ikemoto, N.; Kim, O. K.; Lo, L.-C.; Satyanarayana, V.; Chang,
M.; Nakanishi, K. Tetrahedron Lett. 1992, 33, 4295-4298. (b) Park,
M. H.; Takeda, R.; Nakanishi, K. Tetrahedron Lett. 1987, 28, 3823-
3824. (c) Fadel, A.; Yefsah, R.; Sala u¨ n, J . Synthesis, 1987, 37-40. (d)
Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J . Org. Chem. 1986,
51, 404-407. (e) Singh, P. P.; Gharia, M. M.; Dasgupta, F.; Srivastava,
H. C. Tetrahedron Lett. 1977, 439-440.
3
28. (e) Elmorsy, S. S.; Bhatt, M. V.; Pelter, A. Tetrahedron Lett. 1992,
3, 1657-1660. (f) Rao, M. N.; Kumar, P.; Singh, A. P.; Reddy, R. S.
3
Synth. Commun. 1992, 22, 1299-1305. (g) Hoyer, S.; Laszlo, P.
Synthesis 1986, 655-657. (h) Otera, J .; Nozaki, H. Tetrahedron Lett.
(7) It should be noted that increased reaction rate is, in part, a
1
986, 27, 5743-5746. (i) Coppola, G. M. Synthesis 1984, 1021-1023.
function of the amount of FeCl
involving FeCl ‚6H O absorbed onto silica gel, only 1 mol% metal
promoter is used.
3 2
‚6H O present. For deprotections
(
4) Sen, S. E.; Roach, S. J . Org. Chem. 1996, 61, 6646-6650.
5) Stowell, J . C.; Keith, D. R. Synthesis 1979, 132-133.
3
2
(
S0022-3263(97)00509-4 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 19, 1997 6685
Ta ble 1
a
Reaction conditions: FeCl3‚6H2O added to 0.06 M solution of protected compound in CH2Cl2. Using anhydrous FeCl3. c GLC yield
b
d
e
f
after 16 h: 80%. 4:1 CH2Cl2:acetone (v/v). Using FeCl3‚6H2O absorbed onto silica gel. No starting material remaining; decomposition.
Percent octanol formed. Percent formaldehyde dioctyl acetal formed. GLC yield after 16 h: 72%. Removal of both isopropylidene
groups occurred. Monodeprotection to the corresponding 5,6-diol. GLC yield after 24 h: 40%.
g
h
i
j
k
l
making the amount of metal in solution nearly catalytic.
Therefore, it seems likely that deprotection is mediated
by protonation in addition to metal complexation, through
the intermediacy of an as yet uncharacterized hydrated
iron species (eqs 1 and 2, respectively, Scheme 1). The
The above deprotection methodology was successfully
incorporated into a short synthesis of the unnatural
juvenile hormone precursor 5 (Scheme 2). Conjugate
addition of the alkyl cuprate11 of 1 to ethyl 2-pentynoate
gave dioxolane 2, which was subsequently treated with
1
0
fact that the crystal structure of FeCl
3
‚6H
2
2
O is best
and that
2.8 equiv of FeCl
to give isomerically pure aldehyde 3 in an 87% isolated
yield. Deprotection of dioxolane 3, which bears an acid-
3
2 2 2
‚6H O in refluxing CH Cl for 20 min
8
represented as trans-[FeCl (H O) ]Cl‚2H
2
2
4
O
aqueous solutions of FeCl
weakly acidic hydrates [Fe(H
3
contain a mixture of the
3
+
2+ 9
2
O)
6
]
2 5
and [Fe(H O) (OH)]
(9) Nicholls, D. In Comprehensive Inorganic Chemistry; Bailar, J .
supports this premise; whether these or other related
acidic species are reactive forms in FeCl ‚6H O-mediated
C., J r. Emel e´ us, H. J ., Nyholm, R., Trotman-Dickenson, A. F., Eds.;
Pergamon Press: Oxford, 1973, Vol. 3, pp 1038-1049.
3
2
deprotection chemistry has yet to be determined and
awaits further study.
(10) Sen, S. E.; Ewing, G. J . J . Org. Chem. 1997, 62, 3529-3536.
(11) (a) Lipshutz, B. H.; Parker, D. A.; Nguyen, S. L.; McCarthy, K.
E.; Barton, J . C.; Whitney, S. E.; Kotsuki, H. Tetrahedron 1986, 42,
873-2879. (b) Stowell, J . C. Chem. Rev. 1984, 84, 409-435. (c) Bal,
S. A.; Marfat, A.; Helquist, P. J . Org. Chem. 1982, 47, 5045-5050.
2
(8) Lind, M. D. J . Chem. Phys. 1967, 47, 990-993.

6
686 J . Org. Chem., Vol. 62, No. 19, 1997
Notes
Sch em e 2. Syn th esis of
(
2E)-3-Eth yl-7-m eth yl-2,6-octa d ien -1-ola
a
(
a) (1) Mg, THF; (2) 2-ThCu(CN)Li, -78 °C; (3) ethyl 2-pen-
tynoate, THF, -78 °C; (b) 2.8 equiv FeCl3‚6H2O, CH2Cl2, reflux,
0 min; (c) isopropyltriphenylphosphorane, THF, 0 °C; (d) DIBALH,
THF, -40 to 0 °C.
2
F igu r e 1. Deprotection study using increasing equivalents
of FeCl ‚6H O. Reaction conditions: 0.5 M solution of octanal
,3-dioxolane in CH Cl at rt using (9) 1 equiv, (b) 2 equiv,
2) 3.5 equiv, or (+) 6 equiv of FeCl ‚6H O.
FeCl
colored suspension was stirred for 15 min and quenched by the
addition of saturated aqueous NaHCO . The aqueous layer was
extracted three times with CH Cl , and the combined organics
were washed with brine, dried over MgSO , and concentrated
under reduced pressure. The resulting oil was redissolved in a
minimum amount of CH Cl and passed through a short silica
3
2
‚6H O (322 mg, 3.5 equiv). The resulting yellow to amber
3
2
1
(
2
2
3
3
2
2
2
Sch em e 1. P r op osed Mech a n ism for
F eCl ‚6H O-P r om oted Dea ceta liza tion
4
3
2
2
2
gel plug to remove any remaining iron species. Concentration
of the resulting eluent under reduced pressure provided cinna-
maldehyde (42 mg, 94%).
B. F eCl
CH Cl . To a solution of ethyl (E)-3-ethyl-6,6-(ethylenedioxy)-
-hexen-1-oate (2, 1.9 g, 8.3 mmol) in 400 mL of CH Cl at reflux
was added FeCl ‚6H O (6.3 g, 2.8 equiv). After refluxing for 20
min (reaction times greater than 30 min cause decomposition
of FeCl ‚6H O), the reaction was poured into 100 mL of
saturated aqueous NaHCO . The mixture was extracted three
times with CH Cl , washed with brine, dried over MgSO , and
3
‚6H
2
O Dep r ot ect ion of Acet a ls in R eflu xin g
2
2
2
2
2
3
2
3
2
3
2
2
4
concentrated under reduced pressure. Chromatography of the
resulting oil using 7% EtOAc/hexane yielded ethyl (E)-3-ethyl-
sensitive R,â-unsaturated system, was inert to olefin
isomerization when treated with FeCl O, even after
long (>4 h at rt) reaction times. Subsequent Wittig
homologation and DIBALH reduction gave allylic alcohol
3
‚6H
2
6
-oxo-2-hexen-1-oate (3, 1.34 g, 87%).
C. F eCl ‚6H O Dep r otection of Aceta ls Usin g Aceton e
a s Cosolven t. To a solution of dihydrocinnamaldehyde 1,3-
dioxolane (18 mg, 0.1 mmol) in a 4:1 mixture of CH Cl :acetone
1.5 mL) at rt was added FeCl ‚6H O (95 mg, 3.5 equiv). The
resulting yellow solution was stirred for 1 h and quenched by
the addition of saturated aq NaHCO . The aqueous layer was
extracted three times with CH Cl , and the combined organics
were washed with brine, dried over MgSO , and concentrated
under reduced pressure. The resulting oil was redissolved in a
minimum amount of CH Cl and passed through a short silica
3
2
5
in a 36% overall yield.
2
2
(
3
2
Exp er im en ta l Section
3
Anhydrous FeCl
3
and FeCl
3
‚6H
2
O were obtained from Aldrich
2
2
Chemical Co. Acetals were prepared using previously described
4
1
2
methods.
CH
2
Cl
2
was distilled from CaH
and FeCl ‚6H O reactions.
2
prior to use in
1
3
anhydrous FeCl
3
3
2
FeCl
3
‚6H
2
O
2
2
absorbed onto silica gel was prepared by the method of Kim and
gel plug to remove any remaining iron impurities. Concentra-
tion of the resulting eluent under reduced pressure provided
dihydrocinnamaldehyde (13 mg, 98%).
6
d
co-workers. Gas-liquid chromatography was performed using
a DB5-HT 30 m capillary column (J & W Scientific).
Gen er al Depr otection Meth ods. A. Stan dar d FeCl
Dep r otection of Aceta ls. To a solution of cinnamaldehyde 1,4-
dioxane (65 mg, 0.34 mmol) in CH Cl (5 mL) at rt was added
3
‚6H
2
O
Ack n ow led gm en t. This work was partially sup-
ported by the American Heart Association, Indiana
Affiliate. S.L.R. is the recipient of an American Heart
Association predoctoral fellowship. G.J .E. is the recipi-
ent of a Purdue Research Foundation Graduate
Fellowship.
2
2
(12) (a) Daignault, R. A.; Eliel, E. L. Organic Synthesis; Wiley: New
York, 1973; Collect. Vol. V, pp 303-306. (b) Miyashita, N.; Yoshikoshi,
A.; Grieco, P. A. J . Org. Chem. 1977, 42, 3772-3774. (c) Stork, G.;
Takahashi, T. J . Am. Chem. Soc. 1977, 99, 1275-1276.
(
13) Anhydrous FeCl
3
reactions were performed according to the
procedure described in ref 6b.
J O970509L