IBX-mediated conversion of primary alcohols and aldehydes to N-hydroxysuccinimide esters

Article abstract of DOI:10.1002/adsc.200303195

Recently, the use of the hypervalent iodine reagent 1-hydroxy-1,2- benziodoxol-3(1H)-one 1-oxide (IBX) for the oxidation of primary alcohols and aldehydes to carboxylic acids was described. During the synthesis of these carboxylic acids the corresponding N-hydroxysuccinimide esters were formed as intermediate products, but their isolation as main reaction products was not successful. We report herein a simple and very efficient method to prepare these synthetically valuable active esters.

Full text of DOI:10.1002/adsc.200303195

FULL PAPERS
IBX-Mediated Conversion of Primary Alcohols and Aldehydes
to N-Hydroxysuccinimide Esters
Agnes Schulze, Athanassios Giannis*
Institut f¸r Organische Chemie, Universit‰t Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax: ( ‡ 49)-341-9736-599, e-mail: giannis@chemie.uni-leipzig.de
Received: October 30, 2003; Accepted: February 3, 2004
Abstract: Recently, the use of the hypervalent iodine reaction products was not successful. We report
reagent 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-ox- herein a simple and very efficient method to prepare
ide (IBX) for the oxidation of primary alcohols and these synthetically valuable active esters.
aldehydes to carboxylic acids was described. During
the synthesis of these carboxylic acids the corre-
sponding N-hydroxysuccinimide esters were formed Keywords: alcohols; aldehydes; hypervalent iodine
as intermediate products, but their isolation as main reagent; oxidation
Introduction
These active esters are valuable intermediates, for
example, in peptide synthesis since their reaction with
The use of hypervalent iodine reagents in organic various amines could lead to the corresponding amides.
synthesis has enjoyed an increasing popularity in the However, although their intermediacy in the above-
last 20 years.[1 7] They can be employed for a wide range mentioned oxidations has been proven, they could only
of chemical transformations, especially as reagents be isolated in low yields and as a mixture with the
for oxidations.[8 23] For these purposes, iodinanes like corresponding carboxylic acids.
(diacetoxyiodo)benzene, [bis(trifluoroacetoxy)iodo]
Herein, we present a simple and efficient method for
benzene, hydroxy(tosyloxy)(iodo)benzene (Koser×s re- the preparation of various active esters (N-hydroxysuc-
agent), the Dess Martin periodinane (DMP) and 1- cinimide esters). Furthermore, we describe reaction
hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX; 1) conditions which allow the chemoselective oxidation of
(Figure 1) are particularly suitable. The advantages of aldehydes in the presence of alcohols.
these reagents are their easy availability, mild reaction
conditions and (with the exception of DMP) stability
against moisture and oxygen. Moreover they can be Results and Discussion
regenerated.
Recently, the IBX-mediated oxidation of primary Under standard reaction conditions [1 equivalent of
alcohols and aldehydes to carboxylic acids was de- IBX and 1 equivalent of N-hydroxysuccinimide (NHS)
scribed.[24] A plausible reaction mechanism is that in DMSO] octanal is oxidized to yield octanoic acid as
aldehyde II, which was generated from a primary the main product (yield 90%) accompanied by a small
alcohol I and an excess of IBX, reacts with suitable amount of the corresponding active ester (9%). Chang-
O-nucleophiles (YO-H) to form intermediate III (not
isolable). This intermediate is further oxidized to the
corresponding active ester IV, which is subsequently
hydrolysed to give the desired carboxylic acid V
(Scheme 1).
Scheme 1. Mechanism of the IBX-mediated oxidation of
primary alcohols to carboxylic acids.
Figure 1. IBX.
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¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/adsc.200303195
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Conversion of Primary Alcohols and Aldehydes to N-Hydroxysuccinimide Esters
FULL PAPERS
Table 1. IBX-mediated oxidation of primary alcohols and
aldehydes to N-hydroxysuccinimide esters.
ing the solvent from DMSO to acetone improved
considerably the profile of the reaction yielding after
4 h the active ester as the main product (yield 87%).
Further improvement was achieved by carrying out the
reaction in ethyl acetate with addition of 2equivalents
of NHS, whereby the active ester was formed in 92%
yield within 1 h (Table 1, entry 1). Alcohols can be
directly oxidized to the corresponding active esters by
employing the above reaction conditions and using
2equivalents of IBX. Thus, octanol was rapidly (3 h)
oxidized in excellent yield (90%; Table 1, entry 2).
Employing the above simple experimental conditions,
a series of aliphatic and aromatic aldehydes and primary
alcohols was efficiently oxidized to the corresponding
active esters (Table 1).
Other functional groups, such as isolated and con-
jugated double bonds, alkyl halides, electron-rich and
-poor aromatic compounds were tolerated. However, it
should be noted that this protocol was not successful in
the case of amino-substituted aldehydes (Table 1, en-
tries 19 and 20).
The observation that the successful oxidation of
aldehydes benefits from the presence of 2equivalents
of NHS led us to speculate that an IBX-NHS adduct VI
is the actual oxidizing agent (Scheme 2). Similar adducts
have been proposed recently by Nicolaou.[21] Reaction
of this putative intermediate with an aldehyde adduct of
type III would finally afford the corresponding N-
hydroxysuccinimide esters IV.
To test our hypothesis we suspended 1 equivalent of
IBX and 1 equivalent of NHS in EtOAc. After refluxing
for 2h a clear yellow solution resulted. Upon removal of
the solvent, a yellow solid was obtained, whose NMR
spectra (600 MHz, CDBr3) are in agreement with the
structure of the proposed adduct VI (Figure 2).
1
Inspection of the H NMR spectra obtained at am-
bient temperature revealed additional signals in the
range of 2.6 3.2 ppm that were initially attributed to
impurities. However, these signals disappeared when
the spectrum was recorded at 858C. This is a strong
Scheme 2. Proposed mechanism of the IBX-mediated oxida-
tion of aldehydes to N-hydroxysuccinimide esters.
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Figure 2. 1H NMR (a) (600 MHz, CDBr3) and 13C NMR (b) spectra of VI.
indication that intermediate VI exists as a mixture of
By comparison, the method presented herein allows
rotamers (Figure 3). To this end we were not able to us to convert primary alcohols and aldehydes into active
further characterize the putative adduct VI. Currently esters. It is mild, easy to accomplish, efficient and fast.
we are trying to obtain crystals for an X-ray investiga- Aromatic and aliphatic aldehydes or primary alcohols
tion.
containing functional groups such as isolated and
Surprisingly enough, octanal is oxidized quantitative- conjugated double bonds, alkyl halides, electron-rich
ly within 1 h when treated with the solution obtained by or -poor aromatic rings can be oxidized within 1 2h
reacting of IBX and NHS in EtOAc (see Experimental (alcohols in 2.5 3 h) in good to excellent yields. Finally,
Section). In a separate experiment under the same use of the above-mentioned putative IBX-NHS-inter-
reaction conditions, however, 1-octanol remained un- mediate seems to allow the chemoselective oxidation of
affected (Scheme 3). We attribute this result to the aldehydes in the presence of alcohols and we are
lower reactivity of the alcohol compared to the hydroxy currently investigating this in more depth.
group of VII (Scheme 3).
Experimental Section
Conclusion
General Remarks
In the past, active esters, such as N-hydroxysuccinimide
Reagents (except for IBX[10]) and solvents were commercially
available and were used without further purification. H and
esters, were usually generated starting from the corre-
sponding carboxylic acid or the acid chloride.
1
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Conversion of Primary Alcohols and Aldehydes to N-Hydroxysuccinimide Esters
FULL PAPERS
(for ESI) or a VG ZAB-HSQ (for EI). The reaction progress
was monitored with a Varian SATURN 2200 GC/MS. Flash
column chromatography was performed on Merck silica gel 60
(0.040 0.063 mm).
Preparation of Active Esters
A solution of the alcohol (1 equivalent, 2mmol) in EtOAc
(7 mL) was treated with IBX (2.2 equivalents, 4.4 mmol)
(when starting from the aldehyde: 1.2equivalent or 2.4 mmol
IBX) and NHS (2.5 equivalents, 5 mmol). The reaction mix-
ture was heated to reflux for 2 3 h depending on the alcohol
(aldehydes: 1 2h) until a yellow solution was formed. After
cooling to ambient temperature, the solution was washed with
saturated aqueous NaHCO3 solution and dried over Na2SO4.
The solvent was removed under reduced pressure and analyti-
cally pure product was obtained by flash column chromatog-
raphy.
Preparation of the Putative IBX-NHS Adduct
A suspension of IBX (1 mmol) and NHS (1 mmol) in EtOAc
(5 mL) was refluxed for 2h until a clear yellow solution was
formed. The solvent was removed under reduced pressure and
a pale yellow solid was obtained. This solid was used without
further purification for the oxidations described in the text. For
NMR spectroscopic investigations this solid was solved in
CDCl3 or CDBr3.
2,5-Dioxopyrrolidin-1-yl octanoate (3): colourless crystals;
mp 568C; Rf ˆ 0.13 (hexane/EtOAc, 10:3); 1H NMR (CDCl3):
d ˆ 0.86 (t, 3H, J ˆ 6.6 Hz), 1.27 1.76 (m, 12H), 2.82 (s, 4H);
13C NMR (CDCl3): d ˆ 14.0, 22.5, 24.5, 25.5, 28.7, 30.9, 31.5,
‡
Figure 3. 1H NMR spectra (600 MHz, CDBr3) measured at
258C (a) and at 858C (b).
33.9, 169.2, 179.4; HRESIMS: calcd. for (2M ‡ Na) : 505.2520;
found: 505.2531.
2,5-Dioxopyrrolidin-1-yl decanoate (4): colourless crystals;
mp 678C; Rf ˆ 0.10 (hexane/EtOAc, 10:3); 1H NMR (CDCl3):
d ˆ 0.87 (t, 3H, J ˆ 6.6 Hz), 1.26 1.76 (m, 16H), 2.83 (s, 4H);
13C NMR (CDCl3): d ˆ 14.0, 22.5, 24.5, 24.6, 25.5, 28.7, 29.2,
13C NMR spectra were recorded on a Varian VXR-Unity (200
and 300 MHz) in CDCl3 with TMS as internal standard. The
spectra at elevated temperature were recorded on a Bruker
DRX-600 in CDBr3. HRMS was obtained on a 7 T APEX II
‡
30.9, 31.5, 33.9, 169.2, 175.2; HRESIMS: calcd. for (2M ‡ Na) :
561.3146; found: 561.3157.
Scheme 3. Reaction of 1-octanol and octanal with VI.
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2,5-Dioxopyrrolidin-1-yl 2-methylpentanoate (5): colour-
less oil; Rf ˆ 0.12(hexane/EtOAc, 10:3); 1H NMR (CDCl3):
d ˆ 0.94 (t, 3H, J ˆ 7.1 Hz), 1.30 (d, 3H, J ˆ 7.1 Hz), 1.34 1.60
(m, 4H), 1.74 1.84 (m, 1H), 2.83 (s, 4H); 13C NMR (CDCl3):
d ˆ 13.8, 16.8, 20.0, 25.6, 35.6, 36.8, 169.2, 171.8; HREIMS:
References and Notes
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‡
calcd. for (M) : 213.1001; found: 213.0997.
2,5-Dioxopyrrolidin-1-yl 2-hexenoate (6): colourless oil;
1
Rf ˆ 0.11 (hexane/EtOAc, 10:3); H NMR (CDCl3): d ˆ 0.95
(t, 3H, J ˆ 7.7 Hz), 1.52(q, 2H, J ˆ 7.7 Hz), 2.27 (dq, 2H, J ˆ
7.7 Hz, 2.0 Hz), 2.85 (s, 4H), 5.90 (dt, 1H, J ˆ 15.9 Hz, 2.0 Hz),
7.25 (dt, 1H, J ˆ 15.9 Hz, 7.1 Hz); 13C NMR (CDCl3): d ˆ 13.6,
20.8, 25.6, 34.8, 115.4, 156.0, 161.3, 169.3; HREIMS: calcd. for
‡
(M) : 211.0844; found: 211.0836.
2,5-Dioxopyrrolidin-1-yl 6-chlorohexanoate (7): colourless
solid; mp 1478C; Rf ˆ 0.2(CHCl 3/MeOH, 30:1); 1H NMR
(CDCl3): d ˆ 1.52 1.58 (m, 2H), 1.70 1.83 (m, 4H), 2.60 (t,
2H, J ˆ 7.1 Hz), 2.80 (s, 4H), 3.52 (t, 2H, J ˆ 6.6 Hz); 13C NMR
(CDCl3): d ˆ 21.7, 23.7, 25.5, 25.9, 30.0, 30.6, 31.9, 44.5, 168.3,
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#36#35, 8019 8022.
‡
169.1; HREIMS: calcd. for (M) : 247.0611; found: 247.0619.
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7948.
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2,5-Dioxopyrrolidin-1-yl 4-methoxybenzoate (8): yellow
1
solid; mp 1428C; Rf ˆ 0.41 (CHCl3/MeOH, 30:1); H NMR
(CDCl3): d ˆ 2.89 (s, 4H), 3.89 (s, 3H), 6.97 (d, 2H, J ˆ 6.6 Hz),
8.09 (d, 2H, J ˆ 6.9 Hz); 13C NMR (CDCl3): d ˆ 25.7, 55.6,
114.2, 119.8, 131.5, 132.8, 164.9, 169.3; HRESIMS: calcd. for
‡
(2M ‡ Na) : 521.1167; found: 521.1171.
2,5-Dioxopyrrolidin-1-yl 4-nitrobenzoate (9): yellow solid;
mp 2148C; Rf ˆ 0.29 (CHCl3/MeOH, 30:1); 1H NMR (CDCl3):
d ˆ 2.94 (s, 4H), 8.32 (d, 2H, J ˆ 9.3 Hz), 8.37 (d, 2H, J ˆ
9.3 Hz); 13C NMR (CDCl3): d ˆ 25.8, 124.1, 130.7, 131.9,
‡
151.7, 160.5, 168.9; HRESIMS: calcd. for (M ‡ Na) :
287.0275; found: 287.0274.
2,5-Dioxopyrrolidin-1-yl 4-cyanobenzoate (10): yellow sol-
id; mp 2308C; Rf ˆ 0.37 (CHCl3/MeOH, 30:1); 1H NMR
(CDCl3): d ˆ 2.93 (s, 4H), 7.82 (d, 2H, J ˆ 8.8 Hz), 8.24 (d,
2H, J ˆ 8.8 Hz); 13C NMR (CDCl3): d ˆ 25.6, 105.4, 117.3,
118.2, 126.9, 129.0, 130.9, 132.5, 160.5, 168.7; HRESIMS: calcd.
‡
for (M ‡ Na) : 267.0382; found: 267.0382.
2,5-Dioxopyrrolidin-1-yl 2-bromobenzoate (11): yellow sol-
id; mp 1888C; Rf ˆ 0.6 (CHCl3/MeOH, 30:1); 1H NMR
(CDCl3): d ˆ 2.90 (s, 4H), 7.26 7.45 (m, 2H), 7.73 7.75 (m,
1H), 8.07 8.09 (m, 1H); 13C NMR (CDCl3): d ˆ 25.7, 123.5,
126.5, 127.4, 132.5, 134.6, 135.0, 160.7, 169.0; HREIMS: calcd.
‡
for (M) : 296.964; found: 296.965.
2,5-Dioxopyrrolidin-1-yl 2-bromo-5-fluorobenzoate (12):
yellow solid; mp 1578C; Rf ˆ 0.49 (CHCl3/MeOH, 30:1);
1H NMR (CDCl3): d ˆ 2.89 (s, 4H), 7.11 (d, 1H, J ˆ 8.6 Hz),
7.74 (dd, 1H, J ˆ 2.6 Hz, 8.6 Hz), 8.17 (d, 1H, J ˆ 2.6 Hz);
13C NMR (CDCl3): d ˆ 25.6, 116.9, 119.0, 119.5, 135.0, 139.4,
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‡
139.6, 164.1, 168.7; HRESIMS: calcd. for (2M ‡ Na) :
654.8962; found: 654.8956.
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Acknowledgements
A. Schulze is grateful for grants from the Graduiertenkolleg
™Mechanistische und Anwendungsaspekte nichtkonventionel-
ler Oxidationsreaktionen∫ Leipzig. Furthermore we thank Dr.
Lothar Hennig for recording and interpreting the NMR spectra.
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