Synthesis of soft alkyl phenolic ether prodrugs using Mitsunobu chemistry

Article abstract of DOI:10.1016/j.tetlet.2006.09.162

The synthesis of soft alkyl phenolic ether prodrugs in excellent yields has been reported by coupling a phenol with a hydroxymethylimide using Mitsunobu chemistry. The imides used in this study include saccharin, phthalimide, succinimide and two other compounds containing acidic imide-like N-H groups, benzotriazole, and imidazole.

Full text of DOI:10.1016/j.tetlet.2006.09.162

Tetrahedron Letters 47 (2006) 8981–8982
Synthesis of soft alkyl phenolic ether prodrugs using
Mitsunobu chemistry
Susruta Majumdar, Juha Juntunen, Sashi Sivendran, Neelam Bharti and K. B. Sloan*
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32608, United States
Received 17 August 2006; revised 28 September 2006; accepted 29 September 2006
Abstract—The synthesis of soft alkyl phenolic ether prodrugs in excellent yields has been reported by coupling a phenol with a
hydroxymethylimide using Mitsunobu chemistry. The imides used in this study include saccharin, phthalimide, succinimide and
two other compounds containing acidic imide-like N–H groups, benzotriazole, and imidazole.
Ó 2006 Elsevier Ltd. All rights reserved.
S
N2 TYPE
The oral bioavailability of phenolic drugs like morphine,
estradiol, and acetaminophen is compromised by pre-
mature metabolism. The medicinal chemistry approach
to transiently mask the phenolic functional group as a pro-
drug so that the degree of first pass metabolism by sulfation
or glucuronidation is reduced has proved useful in numer-
ous cases.1,2 The oral bioavailability of estradiol was
increased 8-fold by using imidomethyl prodrugs where sac-
charin was the imide (compounds containing an acidic NH
functional group).3,4 The hydrolysis of imidomethyl pro-
drugs of phenols has been extensively studied by Sloan
and co-workers.5 These types of prodrugs rely on simple
chemical hydrolysis rather than enzymatic hydrolysis to
revert to the parent drug as shown in Scheme 1.
HYDROLYSIS
O
Imide
-
O
+
ImideCH2OH
X
X
OH
Parent phenolic drug
Imidomethylphenols
Scheme 1.
These prodrugs were synthesized in three steps. The
imide was first reacted with HCHO to give hydroxy-
methylimide which was subsequently converted to chlo-
romethylimides using PCl5/SOCl2. The alkylation of
phenols with chloromethylimides in the presence of
NaI and K2CO3 gave the soft alkyl phenolic ether pro-
drugs (Protocol A).5 The synthesis involved three steps,
harsh reaction conditions, long reaction times and gave
poor yields (Table 1). We therefore decided to investi-
gate the synthesis of these derivatives using an alternate
route (Protocol B).
Structures of imide-like promoieties investigated in this
study.
O
O
O
O
S
NH
NH
NH
Our new protocol relies on converting the imide to its
corresponding hydroxymethylimide by reacting it with
formaldehyde/paraformaldehyde and coupling it di-
rectly to a phenol in the presence of PPh3 and DIAD
using Mitsunobu chemistry.6 Briefly, 1 equiv of phenol
(0.01 mmol) and PPh3 (0.011 mmol) was stirred, while
cooling with an ice bath, in 25 ml dry THF for 5 min.
O
O
O
Succinimide
Pthalimide
Saccharin
N
N
NH
N
N
H
Hydroxymethylimide
(0.011 mmol)
and
DIAD
Imidazole
Benzotriazole
(0.011 mmol) were subsequently added. The reaction
was allowed to equilibrate to room temperature and
the yellow colored solution was stirred overnight. The
desired products were then purified by column chromato-
graphy using ethyl acetate:hexanes as the eluent.7 All
Keywords: Mitsunobu coupling; Imide; Phenolic ethers; Prodrugs.
Corresponding author. Tel.: +1 352 846 1957; fax: +1 352 392
*
9455; e-mail: sloan@cop.ufl.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.162

8982
S. Majumdar et al. / Tetrahedron Letters 47 (2006) 8981–8982
Protocol A
Imide
Phenol
PCl5
HCHO
NaI
ImideCH2OH
ImideCH2OH
ImideCH2Cl
ImideCH2O-phenol
or
or
K2CO3
(CH2O)n
SOCl2
Protocol B
Imide
DIAD
PPh3
HCHO
ImideCH2O-phenol
or
(CH2O)n
THF
Phenol
Table 1. A comparison of yields obtained using protocol A and
protocol B
synthetic protocol is that it does not require the synthe-
sis of chloromethylimide from hydroxymethylimide.
Xa
Imide
Yields (%)
Protocol A Protocol B
References and notes
–NO2
–NHCOCH3
–NO2
–NHCOCH3
–NO2
–NHCOCH3
–NO2
–NHCOCH3
–NO2
–NHCOCH3
Saccharin
Saccharin
26b
11b
13b
12b
11b
14b
63
58
57
25
25
83
58
64
75
56
60
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c
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a white solid. Yield = 80%,
mp = 160–161 °C. 1H NMR (CDCl3): d 8.22 (d, 2H), d
7.95 (q, 2H), d 7.81 (q, 2H), 7.19 (d, 2H), d 7.05 (d, 2H), d
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