Oxidation of terminal diols using an oxoammonium salt: A systematic study

Article abstract of DOI:10.1039/c7ob00039a

A systematic study of the oxidation of a range of terminal diols is reported, employing the oxoammonium salt 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (4-NHAc-TEMPO⁺ BF₄^-) as the oxidant. For substrates bearing a hydrocarbon chain of seven carbon atoms or more, the sole product is the dialdehyde. A series of post-oxidation reactions have been performed showing that the product mixture resulting from the oxidation step can be taken on directly to a subsequent transformation. For diols containing four to six carbon atoms, the lactone product is the major product upon oxidation. In the case of 1,2-ethanediol and 1,3-propanediol, when using a 1 : 0.5 stoichiometric ratio of substrate to oxidant, the corresponding monoaldehyde is formed which reacts rapidly with further diol to yield the acetal product. This is of particular synthetic value given both the difficulty of their preparation using other approaches and also their potential application in further reaction chemistry.

Full text of DOI:10.1039/c7ob00039a

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Oxidation of Terminal Diols Using an Oxoammonium Salt: A
Systematic Study
Received 00th January 20xx,
Accepted 00th January 20xx
Shelli A. Miller, James M. Bobbitt* and Nicholas E. Leadbeater*
DOI: 10.1039/x0xx00000x
A systematic study of the oxidation of a range of terminal diols is reported, employing the oxoammonium salt 4-
+
-
4
acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (4-NHAc-TEMPO BF ) as the oxidant. For
www.rsc.org/
substrates bearing a hydrocarbon chain of seven carbon atoms or more, the sole product is the dialdehyde. A series of
post-oxidation reactions have been performed showing that the product mixture resulting from the oxidation step can be
taken on directly to a subsequent transformation. For diols containing four to six carbon atoms, the lactone product is the
major product upon oxidation. In the case of 1,2-ethanediol and 1,3-propanediol, when using a 1:0.5 stoichiometric ratio
of substrate to oxidant, the corresponding monoaldehyde is formed which reacts rapidly with further diol to yield the
acetal product. This is of particular synthetic value given both the difficulty of their preparation using other approaches
and
also
their
potential
application
in
further
reaction
chemistry.
terminal diols using
1. Unlike simple alcohols, in addition to
Introduction
oxidation to the corresponding dialdehyde, there is the
possibility for oxidative lactonization or intermolecular acetal
Oxoammonium salts are environmentally benign, recyclable,
metal-free species that can facilitate oxidation under
1
extremely mild conditions. As such, they have gained
formation. While there is precedent for two of the three
6
stoichiometrically and for
pathways when using analogs of
1
7
lactonization when performing the reaction catalytically,
there has not been a systematic study. We report such a study
here, probing the reaction chemistry of diols of carbon chain
length 2-10. To highlight their synthetic utility, we also
perform a range of transformations on the oxidation products.
popularity as alternatives to more traditional oxidizing
reagents. In our group we have focused particular attention on
+
the use of oxoammonium salt 4-NHAc-TEMPO BF (Bobbitt’s
-
4
salt,
transformations. Using
be oxidized to the corresponding aldehydes and ketones using
slight stoichiometric excess (1.05 equiv.) of the
1), for affecting
a diverse range of oxidative
1, primary and secondary alcohols can
NHAc
NHAc
a
2
OH
R'
O
oxoammonium salt (Figure 1). One disadvantage of this is the
relatively slow reaction rate. Addition of silica gel to the
reaction mixture accelerates the reaction significantly. From a
practical standpoint, the reaction is performed at room
temperature using approximately the same weight of silica gel
as that of the oxidant employed. The exact role of the silica gel
CH
2
Cl
2
+
+
R
N
r.t.
R
R'
N
H
HO
O
BF
4
BF
4
1
2
Scheme 1. Use of oxoammonium salt 1 for the oxidation of alcohols.
1
a
is not fully understood. By using a pyridine base in the place
of silica gel, the substrate scope in the oxidation of alcohols by Results and Discussion
3
can be further augmented. The mechanism of
1
Reaction chemistry of diols with 1
oxoammonium salt oxidations under non-base assisted and
pyridyl-base assisted conditions is thought to involve hydride
We started our study by probing the reaction chemistry of
terminal diols with chain lengths of 7-10 carbon atoms and
using reaction conditions analogous to those employed for the
oxidation of simple primary alcohols. Results are shown in
Table 1. To carry out the oxidation of both alcohol
functionalities, the quantity of oxidant was doubled. The
reactions were performed at room temperature and have the
4
transfer in both cases. This mechanism is also thought to be in
operation in
a
range of oxidative functionalization
5
transformations employing
1.
More recently, our attention has turned to the oxidation of
advantage of being colorimetric since the oxidant
1 is bright
yellow in colour while the spent oxidant 2 is white. Reactions
took 24-72 h to reach completion. In each case the only
oxidized product obtained was the corresponding dialdehyde
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in 64-84% yield (Table 1, entries 1-4). This approach compares
favourably with the relatively few alternatives currently in the
3
4
6
5
-
-
24
36
b
b
3
3
c (84%)
8
literature where oxidants such as Dess-Martin periodinane,
10
9
hexavalent chromium complexes, or Swern conditions are
employed. Even when nitroxides are used catalytically in
d (64%)
1
1
conjunction with metal salts
or hypervalent iodine
1
2
compounds for these reactions, yields do not match those
obtained using our approach and complex product mixtures
are obtained.
5
4
4
7
8
2
d
3
e (26%)
d
4
e (64%)
We moved next to diols containing a hydrocarbon linker of
4-6 carbon atoms. These substrates have received the most
attention previously. In the case of 1,4-butanediol and 1,5-
pentanediol, lactonization is reported to occur when using 4-
6
7
3
2
-
b
4
f (82%)
methoxy-2,2,6,6-tetramethylpiperidine-1-oxoammonium
6
, as a stoichiometric oxidant. The same is true when
chloride,
5
2
,2,6,6-tetramethylpiperidine-based nitroxides are used in
-
48
7
b
b,c
catalytic variants of the reaction. Our results employing
stoichiometric oxidant also bear this out (Table 1, entries 6 and
). When using 1,6-hexanediol we obtain a mixture of lactone
and dialdehyde products (entry 5). This differs in outcome
1
as a
4g (61%) (63%)
a) Reactions were performed on a 10 mmol scale using 1 eq. diol, 2.1 eq. 1, 2
weight eq. silica gel to substrate, and were performed at 0.1 M in CH Cl . b)
7
2
2
Isolated yield. c) Reaction performed under basic conditions (employing 2,6-
6
from both the stoichiometric use of
7
catalyst system (TEMPO = 2,2,6,6-tetramethyl-1-piperidinyl- spectroscopy.
5,
and a Cu/TEMPO
1
dimethylpyridine as base) and run for 2 h. d) Conversion assayed by H-NMR
a
N-oxyl). In the case of the former, lactone product 4e is
The final two diols that formed part of our study were 1,2-
ethanediol and 1,3-propanediol. When using 1:1
stoichiometric ratio of diol to , polymeric products were
obtained. However, when halving the quantity of used,
acetal products and were formed in good yield (Scheme 2).
We postulate that monoaldehyde intermediate is formed
and that this can be readily protonated by the spent oxidant,
. Once protonated, reacts with remaining diol starting
detected only as a trace, and in the latter only a 22% yield of
is obtained, along with 11% of 3e and 25% of the
a
4e
1
monoaldehyde intermediate.
1
Since there are some circumstances where the use of silica
gel is not preferred or when shorter reaction times are sought,
we decided to screen representative diols under base-
mediated conditions. Employing 2,6-dimethylpyridine as the
base of choice, and using reaction conditions optimized
6
7
8
2
8
3
,13
material forming the observed acetal products (Scheme 3).
This method is effectively able to differentiate one alcohol
group from another, leaving the remaining hydroxyl moiety
open for further functionalization. The acetal could then be
cleaved using existing methods, unmasking the alcohol.
previously for monoalcohols, we were able to obtain almost
identical product yields in the cases of 1,4-butanediol and 1,9-
nonanediol; the product being the lactone in the case of the
former and the dialdehyde in the latter (Table 1, entries 2 and
7
). The reactions were complete in two hours.
superstoichiometric quantity of is required in these reactions
because, in the presence of base, the hydroxylamine
byproduct initially formed undergoes a comproportionation
reaction with a further aliquot of to generate two
equivalents of the corresponding nitroxide. Thus a sacrificial
equivalent of is required in order to affect complete
A
1
2
1
1
oxidation of the alcohol substrate.
a
Table 1. Oxidation of diols using 1.
Scheme 2. Oxidation of 1,3-propanediol and 1,2-ethanediol using 1.
Entry
1
n
3
4
Reaction time (h)
48
Scheme 3. Proposed rationale behind the formation of acetal products 6 and 7.
8
-
b
The importance of our route to 6 and 7 comes from the
3
a (76%)
great difficulty preparing these compounds using other
methods reported in the literature. Previous approaches
14
2
7
-
48
b
b,c
involve either multiple steps,
elevated temperatures
3
b (83%) (88%)
1
together with metal catalyst combinations, or yield mixtures
5
2
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1
6
of multiple products. Our methodology allows for the
preparation of these versatile synthetic intermediates in one
step from cheap, readily available starting materials.
O
1
) 1, SiO2, CH2Cl2, filter
HO
HO
HO
OH
OH
OH
6
7
8
2) L-proline, amberlyst-15
9
(52%)
Post-oxidation reactions
1
) 1, SiO2, CH2Cl2, filter
In each case discussed here, isolation of the oxidation product
2) CH3P(Ph)3Br, t-BuOK
Et2O, CH2Cl2
7
is simple. Oxoammonium salt
dichloromethane for the reaction to take place (0.1g / 100 mL).
On the other hand, the reduced oxidant is essentially
1 is soluble enough in
1
0 (86%)
2
OH OH
8
insoluble in dichloromethane (0.01 g / 100 mL). This means
that separation of the desired product from the spent oxidant
and silica gel at the end of the reaction requires a simple
filtration. The filtrate can then be taken on to a subsequent
reaction. To illustrate this point, we performed four
representative post-oxidation reactions (Scheme 5), the first of
which was an intramolecular aldol condensation of the
dialdehyde product 3c derived from 1,8-octanediol. After
1
) 1, SiO2, CH2Cl2, filter
2) CH3MgCl, Et2O
1
1 (89%)
CF3
O
O
CF3
CF3
1
) 1, SiO2, CH2Cl2, filter
HO
OH
2) 1, pyridine, HFIP
F3C
O
O
5
5
1
2 (77%)
oxidation of the alcohol, we filtered the reaction mixture and Scheme 5. Concatenating oxidation and subsequent synthetic transformations.
added L-proline to the filtrate before heating at reflux for 2
days. The desired
isolated in 52% yield over both steps. We next performed a
Wittig reaction on the dialdehyde product 3b derived from 1,9- We have undertaken a systematic study of the oxidation of a
nonanediol by adding the filtrate from the oxidation to a range of terminal diols, employing oxoammonium salt
as the
α,β-unsaturated cyclic product, 9, was
Conclusions
1
diethyl ether solution of methylenetriphenylphosphorane, oxidant. For substrates bearing a hydrocarbon chain of seven
prepared in-situ from methyltriphenylphosphonium bromide carbon atoms or more, the sole product is the dialdehyde and
and sodium t-butoxide. The diene product 10 was obtained in the methodology compares favourably with previous reports
8
6% yield over both steps. In a third example, a Grignard in the literature for this transformation using other oxidants. A
reaction between 3a and methylmagnesium chloride yielded series of post-oxidation reactions have been performed
,11-dodecanediol, 11, in 89% yield.
showing that the product mixture from the oxidation step can
Our final test reaction was an oxidative functionalization to be taken on directly to a subsequent transformation. For diols
generate hexafluoroisopropyl ester using protocol containing four to six carbon atoms, the lactone product is the
developed previously by us and employing as the oxidant. major product upon oxidation with
. In the case of 1,2-
Hexafluoroisopropyl esters are valuable synthetic ethanediol and 1,3-propanediol, when using
1:0.5
intermediates that can be easily converted to other stoichiometric ratio of substrate to oxidant the products are
functionalities, such as amides, under very mild conditions. We acetals
and , respectively. This is of particular synthetic
2
a
a
1
3
1
1
a
6
7
started with 1,7-heptanediol, converting it to 3d, filtering and value given both the difficulty of their preparation using other
then adding pyridine and hexafluoroisopropanol. After stirring approaches and also their potential application in further
for five minutes,
mediated oxidation of alcohols, a superstoichiometric quantity
of is required in this reaction. A 77% yield of the bis-
1 (5 equiv) was added. As with the base- reaction chemistry.
1
hexafluoroisopropyl ester 12 was obtained over the two steps. Experimental Section
The dichloromethane may be removed in vacuo before the
Representative Procedure for Non Base-Mediated Oxidation:
oxidative functionalization, however the reaction is slightly
exothermic.
1
,10-Decanedial (3a)
To a 250-mL round-bottom flask equipped with a stir bar was
added 1,10-decanediol (1.743 g, 10 mmol, 1 equiv) and
dichloromethane (100 mL, 0.1 M in diol). After stirring for 5
min, oxoammonium salt
1 (6.302 g, 21 mmol, 2.1 equiv) was
added, followed by silica gel (2.644 g, 2 mass equiv to
substrate). The flask was sealed with a rubber septum and the
mixture allowed to stir for about 48 h until the slurry became
white. The slurry was filtered through a thin pad of silica gel
and the pad then washed with dichloromethane. The filtrate
was collected and the dichloromethane removed in vacuo by
rotary evaporation to afford the pure dialdehyde product, 3a
17 1
as a pale yellow oil (1.294 g, 76%). H NMR (CDCl
,
3
, 400 MHz)
δ
ppm 1.30 (s, 8 H) 1.56 - 1.65 (m, 4 H) 2.40 (td, J=1.77, 7.30
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1
3
Hz, 4 H) 9.74 (t, J=1.82 Hz, 2 H). C NMR (CDCl
ppm 22.25 (CH ) 29.29 (CH ) 29.36 (CH ) 44.10 (CH
CHO).
3
, 400 MHz)
δ
mmol, 3 equiv to diol) and potassium t-butoxide (1.68 g, 15
2
2
2
2
) 203.04 mmol, 3 equiv to diol) in dry diethyl ether (75 mL, 0.2 M) for 7
hours. The filtered solution of 1,9-nonanedial was added
(
Representative Procedure for Base-Mediated Oxidation: directly to this solution and was stirred overnight. This solution
Butyrolactone, (4g) was filtered and the solvent was removed in vacuo, resulting in
To a 250-mL round-bottom flask equipped with a stir bar was a thick oil. Pentane (50 mL) was added to precipitate excess
added 1,4-butanediol (0.446 g, 5 mmol, 1 equiv.), 2,6-lutidine triphenylphosphine and the oxide byproduct. The resulting
(2.411 g, 22.5 mmol, 4.5 equiv) and dichloromethane (25 mL, slurry was filtered through silica and the solvent was removed
0
.2 M in the diol). The mixture was allowed to stir at room in vacuo to afford the product as a colourless oil (0.655 g,
2
0 1
3
1 (7.503 g, 86%). H NMR (CDCl , 400 MHz) δ ppm 1.34 (m, 10 H). 2.05
temperature for approximately 5 min. At this time,
2
5 mmol, 5 equiv.) was added all at once and the flask was (q, J = 7.1 Hz, 4 H), 4.94 (dd, J=1.4, 8.00 Hz, 2 H) 5.00 (dd, J =
1
3
sealed with a rubber septum. The reaction mixture was stirred 1.9, 17.1 Hz, 2 H) 5.84 (tq, J = 6.8, 14.8 Hz, 2 H). C NMR
at room temperature and gradually turned red. Once the (CDCl , 100 MHz) δ ppm 29.25 (CH ) 29.41 (CH ) 29.66 (CH
reaction was judged complete (≈ 2 h), the the majority of the 34.12 (CH ) 114.41 (CH ) 139.46 (CH).
dichloromethane was removed in vacuo by rotary evaporation 2,11-Dodecanediol (11)
and the product isolated by filtering through a pad of silica The oxidation of 1,10-decanediol (0.870 g, 5 mmol, 1 equiv)
3
2
2
2
)
2
2
using dichloromethane to afford the pure lactone product, 4g
18 1
as a colorless oil (0.540 g, 63%). H NMR (CDCl
,
was performed using the representative procedure, followed
by a subsequent Grignard reaction. A solution of 1,10-
3
, 400 MHz)
δ
ppm 2.24 (quin, J=7.58 Hz, 2 H) 2.47 (t, J=8.26 Hz, 2 H) 4.32 (t, decanedial, filtered off of the silica gel and oxoammonium salt,
1
3
J=7.06 Hz, 2 H). C NMR (CDCl
3
, 100 MHz)
δ
ppm 22.38 (CH
2
)
was added to a solution of commercially available 3 M
methylmagnesium chloride in anhydrous diethyl ether (7 mL,
2
7.98 (CH ) 68.72 (CH ) 177.92 (CO).
2
2
Representative Procedure for Oxidation of 1,2-ethanediol 21 mmol, 4.2 equiv). The solution was stirred overnight, then
and 1,3-propanediol: 2-Hydroxymethyl-1,3-dioxolane (6) aliquots (~25 drops) of aqueous saturated potassium
To a 250-mL round-bottom flask equipped with a stir bar was carbonate were added dropwise about 10 min apart. After 5
added 1,2-ethanediol (2.483 g, 40 mmol, 1 equiv) and aliquots a white precipitate formed. The solution was filtered,
dichloromethane (200 mL, 0.2 M in diol). ). After stirring for 5 and the solvent removed in vacuo to afford the product as
2
1 1
min, oxoammonium salt
3
1 (6.602 g, 22 mmol, 0.55 equiv) was white solid (0.900 g, 89%). H NMR (CDCl , 400 MHz) δ ppm
added, followed by silica gel (1.98 g, 0.8 mass equiv to 1.13 (d, J=8.00 Hz, 6 H) 1.33 (m, 16 H) 1.98 (br. s, 2 H) 3.72 (m,
1
3
substrate). The mixture was refluxed for 20 h, at which point 2 H). C NMR (CDCl
the white slurry was filtered through a pad of silica gel. Due to 29.73 (CH ) 29.83 (CH
volatility, the solvent was removed via evaporation through a Bis(1,1,1,3,3,3-hexafluoropropan-2-yl) heptanedioate (12)
0 cm Vigreux column to afford the product as a pale yellow The oxidation of 1,7-heptanediol (0.676 g, 5 mmol, 1 equiv)
3
, 100 MHz) δ ppm 23.62 (CH
2 2
) 25.95 (CH )
2
2
) 29.53 (CH ) 68.21 (CHOH).
3
3
1
9 1
oil (1.363 g, 65%). H NMR (CDCl3, 400 MHz) δ ppm 3.64 (br. was performed using the representative procedure, followed
d, J=2.40 Hz, 2 H) 3.67 (br. s, 1 H) 3.85 - 4.04 (m, 4 H) 4.96 (t, by subsequent oxidative functionalization using a previously
1
3
13
O) published method. To the solution of 1,7-heptanedialdehyde
J=3.24 Hz, 1 H). C NMR (CDCl
5.09 (CH O) 103.21 (OCHO).
Post Oxidation reactions:
-Cycloheptene-1-carboxaldehyde (9)
3
, 100 MHz) δ ppm 62.68 (CH
2
6
2
(5 mmol), filtered off the silica gel and oxoammonium salt
slurry, was added pyridine (10.085 g, 127.5 mmol, 25.5 equiv)
and hexafluoroisopropanol (5.041 g, 30 mmol, 6 equiv). After
1
The oxidation of 1,8-octanediol (2.5 g, 17.1 mmol, 1 equiv) was stirring for 5 min, the oxoammonium salt (7.502 g, 25 mmol, 5
performed using the representative procedure, followed by a equiv) was added all at once. The flask was sealed with a
subsequent Aldol reaction. The filtrate was transferred to a rubber septum and stirred until the solution turned red. Once
round-bottom flask and L-proline (1.5 g, 13 mmol, 0.76 eq) was the reaction was determined complete by TLC, the
2 2
added, followed by 1.5 g of activated 4Å molecular sieves. The hexafluoroisopropanol and CH Cl was removed in vacuo.
mixture was refluxed for 2 days, then filtered through a pad of Pentane or diethyl ether was added to the resulting slurry to
silica gel. Due to volatility, the solvent was removed via precipitate the nitroxide. After stirring for 5 min, the solution
evaporation through a 30 mm Vigreux column to afford the was filtered through a fritted funnel with medium porosity and
2
0 1
product as an orange oil (1.06 g, 50%). H NMR (CDCl3, 400 transferred to a separatory funnel. The organic layer was
MHz) δ ppm 1.45 (m, 1H) 1.56 (m, 1H) 1.75 (m, 1 H) 2.37 (t, J = washed with 1 M HCl (2×150 mL), deionized water (150 mL),
1
3
5.6 Hz, 1 H) 2.42 (q, J = 5.9 Hz, 1 H) 6.83 (t, J = 6.3 Hz, 1 H).
C
and brine (150 mL). The organic layer was dried over sodium
NMR (CDCl3, 100 MHz) δ ppm 24.01 (CH2) 26.17 (CH2) 26.23 sulfate, and the solvent was removed in vacuo, affording the
1
3,22 1
(
CH2) 30.08 (CH2) 31.89 (CH2) 147.64 (C) 157.22 (CH) 194.54 ester as a pale yellow oil (0.768 g, 77%).
CHO). 400 MHz) δ ppm 1.42 (m, 2 H) 1.74 (m, J = 7.6 Hz, 2 H), 2.53 (t,
,10-Undecadiene (10)
The oxidation of 1,9-nonanediol (0.801 g, 5 mmol, 1 equiv) was MHz) δ ppm 24.29 (CH
performed using the representative procedure, followed by a CH-(CF3)2=34.74 Hz) 120.71 (q, JC-F3)2 = 282.77 Hz) 170.25 (CO).
subsequent Wittig reaction. The Wittig reagent was prepared NMR (CDCl , 377 MHz) δ ppm -76.56 (s, 6 F), -76.57 (s, 6 F).
by stirring methyltriphenylphosphonium bromide (5.355 g, 15 HRMS (ESI+), calcd for C13 [MH]+, calc. 461.0622, obs.
H NMR (CDCl3,
(
1
3
1
J = 7.3 Hz, 4 H), 5.77 (m, J = 6.1 Hz, 2 H). C NMR (CDCl
3
, 100
2
) 28.17 (CH ) 33.23 (CH ) 66.69 (m, JO-
2
2
1
9
F
3
12 12 4
H F O
4
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61.0635; [MNH4]+, calc. 478.0888, obs. 478.0888. FT-IR
ARTICLE
4
-1
(neat, ATR, cm ) 2996-2852 (w, b) 1774 (s) 1381 (m) 1357 (m)
1
287 (s) 1267 (m) 1229 (s) 1193 (vs) 1103 (vs) 901 (s) 730 (w)
89 (s) 529 (w) 488 (w).
6
Acknowledgements
We gratefully acknowledge financial support from the National
Science Foundation Research Experience for Undergraduates
(REU) program (CHE-1359081) and the University of
Connecticut. We thank Miss Alison Army of Mount Holyoke
College for initiating the project, Dr. You-Jun Fu for his
assistance in obtaining HRMS of novel compounds, TCI-
America for a gift of 4-amino-2,2,6,6-tetramethylpiperidine,
7
(a) X. Xie and S. S. Stahl, J. Am. Chem. Soc., 2015, 137, 3767-
3
770. (b) A. Diaz-Rodriguez, L. Martinez-Montero, I.
Lavandera, V. Gotor and V. Gotor-Fernandez, Adv. Synth.
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DOI: 10.1039/C7OB00039A
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The dichloromethane may be removed in vacuo before
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DOI: 10.1039/C7OB00039A
TABLE OF CONTENTS ENTRY
A systematic study of the oxidation of a range of terminal diols is reported, employing the oxoammonium salt 4-
acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (4 NHAc TEMPO+ BF4-) as the oxidant.