Nucleophilic substitution of (alkoxymethylene)dimethylammonium chloride with potassium phthalimide; a convenient procedure for the synthesis of imides with inversion of configuration

Article abstract of DOI:10.1039/a607482k

Secondary alcohols are converted into their phthalimido derivatives with inversion of configuration via sequential reaction with (chloromethylene)dimethylammonium chloride and potassium phthalimide.

Full text of DOI:10.1039/a607482k

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Nucleophilic substitution of (alkoxymethylene)dimethylammonium chloride
with potassium phthalimide; a convenient procedure for the synthesis of imides
with inversion of configuration
Anthony G. M. Barrett,*a D. Christopher Braddock,a Rachel A. Jamesa and Panayiotis A. Procopiou*b
a Department of Chemistry, Imperial College of Science, Technology and Medicine, London, UK SW7 2AY
b Department of Medicinal Chemistry, Glaxo Wellcome Research and Development Ltd, Gunnels Wood Road, Stevenage,
Hertfordshire, UK SG1 2NY
Secondary alcohols are converted into their phthalimido
derivatives with inversion of configuration via sequential
reaction with (chloromethylene)dimethylammonium chlor-
ide and potassium phthalimide.
racemisation in the preparation of (S)-N-2-octylphthalamide
(58% ee). It is reasonable to assume that such partial
racemisation was the result of partial substitution via 2-octyl
chloride or via nucleophilic participation of the solvent (DMF)
leading to inverted imidates. The imidate methodology in this
paper should be of use as an alternative to the Mitsunobu
reaction particularly for larger scale applications as the side
products are innocuous (DMF and potassium chloride). The
method is mechanistically similar to the synthesis of glyco-
sides8 and benzyl, allyl and tert-butyl ethers9 via trichloroacet-
imidate activation.
We thank Glaxo Group Research Ltd. for the most generous
endowment (to A. G. M. B.) and for providing a CASE
studentship (to R. A. J.); the Wolfson Foundation for establish-
ing the Wolfson Centre for Organic Chemistry in Medical
Science at Imperial College and the EPSRC for providing a
CASE studentship (to R. A. J.).
The Mitsunobu reaction is the process par excellence for the
conversion of secondary alcohols into esters with inversion of
stereochemistry.1 In this reaction an alcohol is treated with
diethyl azodicarboxylate, triphenylphosphine and a carboxylic
acid to provide the required ester. The reaction can be extended
to a wide range of nucleophiles in addition to carboxylic acids
to provide a variety of SN2 substitution products. The
stereoselective preparation of amines from the corresponding
alcohol can be effected via formation of the phthalimido
derivative.2 There are however disadvantages associated with
the Mitsunobu reaction. Diethyl azodicarboxylate is unstable
and potentially explosive and the by-products, triphenylphos-
phine oxide and diethyl hydrazinedicarboxylate, are of con-
siderable mass making the process non-ideal from the point of
view of atom economy.3 Recently, one of us reported the use of
Vilsmeier chemistry to effect the stereospecific cyclisation of
hydroxyphenols to provide benzodioxans, dihydrobenzopyrans
and dihydrobenzofurans via (alkoxymethylene)dimethyl-
ammonium salts and intramolecular SN2 displacement by
phenoxide.4 This Vilsmeier chemistry has also been extended to
the conversion of alcohols into esters with inversion of
stereochemistry.5,6 Herein we report a further application of this
methodology to form the phthalimide derivatives of secondary
alcohols.
Treatment of a series of secondary alcohols 1 with (chloro-
methylene)dimethylammonium chloride, generated from oxalyl
chloride and dimethylformamide,7 provided the corresponding
imidate salts 2. These were then treated with potassium
phthalimide at 60–70 °C to provide the phthalimide derivative
3 with inversion of stereochemistry (Scheme 1 and Table 1).†
Enantiomeric purities (entries 1, 5, and 6) were established by
HPLC. Clean inversion of stereochemistry was observed for
entries 1 and 5 but substitution of (R)-1-phenylethanol pro-
ceeded with partial racemisation (entry 6, 72% ee). It is
reasonable to speculate that this example either involved a
mixed SN2/SN1 reaction or took place partially via the
corresponding benzylic chloride. Several solvents were exam-
ined in these reactions of which acetonitrile was found to be
superior. No reaction was observed in THF whereas reaction in
DME or DMF gave the desired product in moderate yield.
Furthermore the use of DMF as solvent led to partial
Table 1 Formation of phthalimido derivatives with inversion of ster-
eochemistrya
Yield
(%)
Entry Substrate
OH
Productb
NPhth
eec (%)
Ref.
96
1
95
[α]D +14.0
(c 1.1, CHCl3)
10e
C6H13
C6H13
OH
NPhth
d
‡
2
—
77
C8H17
C8H17
OH
OH
NPhth
NPhth
d
§
—
3
4
90
91
C5H11
C5H11
d
11e
—
92
OH
OH
NPhth
NPhth
12e
12e
[α]D –12.8
(c 1.1, CHCl3)
5
6
92
73
72
[α]D –31.4
Ph
Ph
(c 0.5, CHCl3)
OH
NPhth
d
7
8
98
34
—
13e
14e
OH
NPhth
d
—
R2
R2
H
R2
Cl –
i
ii
R1
OH
R1
O
2
NMe2
+
R1
NPhth
a
All reactions performed with 7 equiv. of potassium phthalimide in
acetonitrile for 1–3 d; b NPhth = phthalimido derivative; c Determined by
1
3
Scheme 1 Reagents and conditions: i, CHClNNMe2+Cl2, MeCN, 0 °C; ii,
KPhth, 60–70 °C, 1–3 d
HPLC on a chiral stationary phase; Racemic substrate employed; The
spectroscopic data were identical to those reported in the literature.
d
e
Chem. Commun., 1997
433

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Footnotes
† In a typical procedure, oxalyl chloride (0.10 cm3, 1.15 mmol) was added
dropwise with stirring to a solution of DMF (0.09 cm3, 1.17 mmol) in dry
dichloromethane (1 cm3) at 0 °C under nitrogen. After 5 min, the white solid
was suspended in dry acetonitrile (30 cm3) and (R)-octan-2-ol (0.16 cm3, 1.0
mmol) and potassium phthalimide (1.3 g, 7 mmol) were added sequentially.
The reaction mixture was heated to 65 °C for 16 h cooled and filtered. The
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‡ Selected data for N-2-decylphthalimide: Rf = 0.40 (light petroleum–
ethylacetate, 10:1); dH (300 MHz; CDCl3) 0.84 (3 H, t, J 6.7 Hz, CH3), 1.24
(12 H, m, 6 3 CH2), 1.47 (3 H, d, J 6.9 Hz, CH3), 1.74 (1 H, m, CH2), 2.05
(1 H, m, CH2), 4.34 (1 H, m, CH), 7.70 (2 H, m, PhH), 7.82 (2 H, m, PhH);
dC (75 MHz; CDCl3) 14.1, 18.7, 22.6, 26.8, 29.2, 29.2, 29.4, 31.8, 33.7,
47.5, 123.0, 132.1, 133.8, 168.6; umax (thin film)/cm21 2927s, 2856m,
1774m, 1710s; m/z (CI+; NH3), 305 (M + NH4+, 100), 288 (M + H+, 45%);
HRMS: C18H25NO2 requires: 287.1885. Found: 287.1873.
§ Selected data for N-3-octylphthalimide: Rf = 0.23 (light petroleum–ethyl
acetate 20:1); dH (300 MHz; CDCl3) 0.86 (6 H, m, 2 3 CH3), 1.26 (6 H,
m, 3 3 CH2), 1.82 (1 H, m, CH2), 2.06 (1 H, m, CH2), 4.12 (1 H, m, CH),
7.72 (2 H, m, PhH), 7.83 (2 H, m, PhH); dC (75 MHz; CDCl3) 11.1, 14.0,
22.5, 25.6, 26.4, 31.5, 32.2, 54.0, 123.1, 131.9, 133.8, 168.9; umax (thin
film)/cm21 2960s, 2931s, 2860m, 1770s, 1711s; m/z (CI+; NH3), 277 (M +
NH4+, 100), 260 (M + H+, 69%); HRMS: C16H21NO2 requires: 259.1572.
Found: 259.1583.
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Received, 4th November 1996; Com. 6/07482K
434
Chem. Commun., 1997