Domino catalysis in the direct conversion of carboxylic acids to esters

Article abstract of DOI:10.1002/adsc.200800268

The combined use of high concentration conditions, auxiliary bases, and new catalysts allows for the rapid synthesis of sterically hindered carboxylic acid esters at room temperature. Mechanistic analysis indicates the intermediate formation of acid anhydrides and subsequent rate-limiting transformation to the ester products.

Full text of DOI:10.1002/adsc.200800268

FULL PAPERS
DOI: 10.1002/adsc.200800268
Domino Catalysis in the Direct Conversion of Carboxylic Acids
to Esters
I. Held,a P. von den Hoff,a D. S. Stephenson,a and H. Zipsea,*
a
Department Chemie und Biochemie, LMU München, Butenandtstr. 5–13, 81377 München, Germany
Fax : (+49)-89-2180-77738; e-mail: zipse@cup.uni-muenchen.de
Received: May 2, 2008; Revised: June 19, 2008; Published online: July 24, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The combined use of high concentration anhydrides and subsequent rate-limiting transforma-
conditions, auxiliary bases, and new catalysts allows tion to the ester products.
for the rapid synthesis of sterically hindered carbox-
ylic acid esters at room temperature. Mechanistic Keywords: ab initio calculations; acylation; esterifi-
analysis indicates the intermediate formation of acid cation; nucleophilic catalysis; sterically hindered car-
boxylates
Introduction
well as by electron-rich pyridines such as N,N-dime-
thylpyridine (DMAP).[2,4] The base-catalyzed ap-
The direct conversion of carboxylic acids to esters proach has also found application in the synthesis of
through in situ activation and subsequent reaction amides and peptides.[5,6] The recent development of
with alcohols represents a well established procedure more potent acylation catalysts based on the DMAP
for the synthesis of esters. Numerous procedures are motif[7–10] now prompts us to reinvestigate the
based on the use of carbodiimides as activating re- Takeda–Gooßen direct esterification procedure, in
agents, which generate urea by-products in the course particular with respect to its utility for the synthesis
of the reaction.[1] Problems with the separation of of sterically highly hindered esters.
these by-products have recently led to attempts to use
dialkyl dicarbonates as activating reagents.[2–4] The by-
products formed in these reactions are CO2 and a Results and Discussion
new alcohol (Scheme 1).
Recent mechanistic studies of the acylation of alco-
hols with anhydrides suggest that the rate of these re-
actions depends linearly on the concentration of all
reactants and on that of the catalyst.[11,12] Given the
experimentally observed intermediacy of mixed anhy-
drides in the synthesis of peptides,[13] one may antici-
pate that the rate of the transformation shown in
Scheme 1 will similarly benefit from high reagent and
catalyst concentrations. To this end initial studies
Scheme 1.
were performed using the reaction of isobutyric acid
(2) with tert-butanol (3) at 238C under high concen-
Earlier work by Takeda et al. and by Gooßen et al. tration conditions[14] to give the corresponding ester 4
has shown that this approach has great general value (Scheme 2). One equivalent of 1,4-dioxane relative to
under the condition that the “substrate” alcohol (here acid 2 was added to the reaction mixture as an inter-
1
R2-OH) is significantly more reactive than the “re- nal standard for H NMR spectroscopy and a small
agent” alcohol (here R3-OH).[2–4] This requirement is excess of 1.3 equiv. of Boc2O was used in order to
easily fulfilled through the use of di-tert-butyl dicar- achieve complete turnover of acid. In the presence of
bonate (Boc2O, 1). It was also found that the reaction 0.05 equiv. of DMAP (8) as the catalyst the following
can be accelerated by a wide range of Lewis acids[3] as observations can be made: acid 2 disappears quantita-
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Scheme 2.
tively within the first 20 min of the reaction (Figure 1)
Whether similar rate enhancements can also be
as indicated by the isopropyl doublet signal at achieved through addition of an auxiliary base was
1
1.14 ppm in the H NMR spectrum. At the same time explored for the DMAP-catalyzed process through
two new, strongly overlapping doublet signals appear addition of 2 equiv. (relative to acid 2) of triethyl-
at 1.190 ppm and 1.195 ppm. The former of these sig-
A
nals is identical to isobutyric anhydride 5, while the auxiliary base depicted in Figure 1 and Figure 2a, the
latter is most likely that of the mixed anhydride 6 reaction now has essentially no lag phase and pro-
(Scheme 2). The intensity of these two anhydride sig- gresses with t1/2 =47 min in the presence of 0.05 equiv.
nals peak at around 20 min reaction time, where both of DMAP as the catalyst. Complete turnover is
anhydrides combined account for 96% of the sub-
A
strate concentration. It is only at this time that forma- vations can be made for the more active catalysts 9,
tion of ester product 4 sets in, detectable through a 11, and 12. Best results are obtained for catalyst 11 in
doublet signal at 1.06 ppm. The reaction is essentially the presence of 2 equiv. of NEt3 with t1/2 =19 min and
complete after 170 min, illustrating the benefit of high complete turnover in less than 60 min. (Table 1). An
concentration reaction conditions.
experiment performed at a slightly larger scale with
Analysis of the time course of the reactant and 0.10 equiv. DMAP as catalyst and 2 equiv. NEt3 turns
product concentrations through monitoring of the iso- over with t1/2 =21 min. The final conversion measured
1
propyl doublet and tert-butyl singlet signals of 1–6 by H NMR spectroscopy is 98% and only one prod-
also shows that formation of the intermediate anhy- uct can be detected at this stage. The final yield of
drides occurs much more rapidly (approximate t1/2
=
product 4 amounts to 75% after isolation and purifi-
3 min) than formation of ester product 4 (approxi- cation by distillation (Table 1).
mate t1/2 =65 min).
All of the results described above can be accounted
Higher absolute rates are observed when using for by assuming the domino catalysis mechanism[15–20]
0.10 equiv. catalyst (Figure 2a). The initial lag phase shown in Scheme 3.
for ester formation is significantly reduced under this
This mechanism involves formation of mixed anhy-
condition and the half-life for the DMAP-catalyzed dride 6 through a first catalytic cycle driven by pyri-
process now amounts to t1/2 =40 min. The rate of re- dine catalysts such as DMAP. The mixed anhydride is
action can be further accelerated by using more elec- subsequently transformed in a second catalytic cycle
tron-rich pyridine derivatives than DMAP such as to an ester product such as 4. In both catalytic cycles
those shown in Scheme 2. While only a small acceler- one equivalent t-BuOH (3) is formed through decar-
ation is observed for the commercially available PPY boxylation of the tert-butylcarbonic ester or its anion.
(9), better results are obtained with the diaminopyri- The evolution of CO2 can be observed right from the
dine compounds 10 and 11. Still, the half-lives ob- beginning of the experiment in form of a steady
served for DMAP (8) and the best catalyst 11 vary by stream of bubbles escaping from the reaction solution
less than a factor of two, a much smaller difference (see Supporting Information). The evolution of CO2
than measured for the reaction of anhydrides with al- to the gas phase makes the reaction practically irre-
cohols under basic reaction conditions.[9]
versible, but does not necessarily deliver the enthalpic
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Domino Catalysis in the Direct Conversion of Carboxylic Acids to Esters
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Figure 1. DMAP-catalyzed reaction of isobutyric
acid (2) with Boc2O (1) and tert-butanol (3)
through intermediate formation of anhydrides 5
and 6.
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I. Held et al.
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nol (3) yield a reaction enthalpy of 15.3 kJmolÀ1 each,
and, if taken together, provide somewhat less than
half of the overall reaction enthalpy. The driving
force of the overall substrate reaction thus stems to
similar parts from the generation of CO2 as a thermo-
chemically stable by-product and from the formation
À
of a thermodynamically stable ester C O bond. Evo-
lution of CO2 from the reaction mixture provides, of
course, an additional entropic driving force.
The initial lag phase observed experimentally at
low catalyst concentrations and in the absence of aux-
iliary base may be caused by inactivation of the cata-
lyst within the first cycle (formation of stable ion
pairs) or outside of the cycle through complexation
with acid substrate (formation of a strong hydrogen
bond or even protonation). Elimination of the lag
phase through addition of 2 equiv. of NEt3 is in sup-
port of this latter option as the 40-fold excess of auxil-
iary base over the catalytic base DMAP will lead to a
largely reduced extent of complexation/protonation of
the latter as described through the competitive com-
plexation equilibria in Scheme 4.
That initial deactivation of the pyridine catalysts
through complexation with substrate acid 2 is at the
heart of the problem is also supported by analysis of
the time-dependence of product development. In the
presence of the best catalysts 11 and NEt3 as the aux-
iliary base, the reaction actually speeds up with in-
creasing turnover (Figure 2b): while the first 50% of
the ester is formed after 22 min, complete conversion
is achieved already after 40 min. This can most simply
be explained by assuming that even with 2 equiv. of
auxiliary base added the catalyst still remains partially
deactivated through complexation with acid 2 at the
beginning of the reaction. With progressive conver-
sion of the substrate acid this deactivation is steadily
reduced, freeing up more catalyst as the reaction pro-
ceeds. That DMAP (8) and PPY (9) have almost the
same catalytic efficiency in these experiments may
also be due to the formation of hydrogen bonded
Figure 2. Reaction of isobutyric acid (2) with tert-butanol (3)
and Boc2O (1) under high-concentration conditions at room
temperature (a) in the presence of 0.1 equiv. catalyst, or (b)
in the presence of 0.05 equiv. catalyst and 2 equiv. NEt3.
driving force of the reaction. This latter point has complexes of acid substrate and the pyridine base.
been addressed through calculation of the reaction Recent determination of nucleophilicity parameters
enthalpies at different stages of the overall substrate for these two pyridines identified a large solvent
reaction at the G3(MP2)B3 level of theory (Table 2). effect, leading to higher nucleophilicities for PPY
A
The accuracy of the G3(MP2)B3 method in predicting than for DMAP in dichloromethane, but to the re-
A
the thermodynamic stability of a variety of small and verse order in protic solvents such as H2O.[23] The
medium sized molecular systems has been estimated combined presence of t-BuOH and acidic substrates
as 5.2 kJmolÀ1.[21,22]
may lead to a similar reduction of the intrinsically
The results in Table 2 show that all steps of the higher nucleophilic activity of PPY in this case. It
overall substrate reaction are exothermic. The most should be added that the reaction proceeds extremely
exothermic step along the reaction pathway involves slowly in the absence of any of the pyridine bases
reaction of tert-butanol (3) with mixed anhydride 6 to (but with 2 equiv. NEt3 present) with a half-life of 5
yield the ester product 4 and carbonic acid tert-butyl days 16 h. When the auxiliary base NEt3 is also miss-
ester. This step is exothermic by 44.2 kJmolÀ1 and ing, no product formation can be detected within 16
thus accounts for slightly more than half of the overall days.
reaction enthalpy. The two decomposition reactions
of carbonic acid tert-butyl ester to CO2 and tert-buta-
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Domino Catalysis in the Direct Conversion of Carboxylic Acids to Esters
Table 1. Direct synthesis of sterically hindered esters through Boc2O-mediated reaction of acids and alcohols at 238C.[a]
FULL PAPERS
Acid
Alcohol
Product
Catalyst (equiv.)[b]
NEt3 [equiv.][b]
t1/2 [min]
Conversion [%][c]
Yield [%][d]
2
3
4
8 (0.1)
8 (0.05)
9 (0.1)
10 (0.1)
11 (0.1)
8 (0.1)
8 (0.05)
8 (0.025)
9 (0.05)
12 (0.05)
11 (0.05)
–
9 (0.05)
9 (0.05)
11 (0.05)
9 (0.05)
11 (0.05)
-
–
–
–
–
40
84
35
30
23
21
47
121
49
99
88
100
98
100
98
99
73
100
93
96
71
–
–
–
–
75%
–
–
–
–
–
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
31
19
8215
–
–
69
[e]
13
15
3
3
14
16
–
93
85
–
89
–
11
100
–
99
96
58
<2.5
164
99
17
3
18
10500
–
[a]
1.3 equiv. of Boc2O have been used.
Equivalents relative to acid.
[b]
[c]
[d]
[e]
1
Final conversion to ester product determined by H NMR measurements.
Isolated yield after product purification.
1
Multiple signal overlaps in the H NMR spectrum.
Scheme 3.
Synthesis of tert-Butyl Esters
The synthesis of ester 14 is complete within 2 h as
determined by TLC and yields 93% product after
The optimized reaction conditions for the conversion column chromatography. The time course of this reac-
of isobutyric acid 2 with t-BuOH (3) offer a very at- tion could, unfortunately, not be monitored by
tractive general protocol for the conversion of steri- 1H NMR spectroscopy due to multiple signal overlaps.
cally hindered substrates, the only limitation being al- The optical rotation measured for 14 shows no loss of
cohols of higher steric hinderance than t-BuOH itself. stereochemical integrity. Why formation of 14 is not
The synthetic value of this protocol was tested for a effective under the original conditions used by
number of sterically hindered substrates as well as Gooßen et al.[4] is not clear at this point. The reaction
other “difficult” systems (Scheme 5).
of Z-protected proline 15 with t-BuOH (3) is similarly
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Table 2. Enthalpy profile at 298 K of the substrate reaction
of Boc2O (1) with isobutyric acid (2) as determined at the
efficient as that of Boc-protected proline 13, leading
to ester 16 as the sole product with a half-life of t1/2
=
G3(MP2)B3 level of theory.
A
11 min using 0.05 equiv. PPY (9) as the catalyst. Com-
plete conversion is achieved after 27 min. Use of the
more active catalyst 11 leads to complete conversion
within 5 min under identical conditions, implying a re-
action half-life of less than 2.5 min. The optical rota-
tion measured for product 16 in ethanol at 238C is
identical to literature values for this compound, indi-
cating no measurable loss of stereochemical informa-
tion under the reaction conditions used here.[2,24,25]
Similar results have been obtained by Takeda et al. in
the presence of 0.3 equiv of DMAP (8) and t-BuOH
(3) as solvent at room temperature.[2] Complete con-
version was achieved under these conditions after
55 min. The newly proposed protocol thus provides a
more than 10-fold speedup over the original proce-
dure while using only 0.05 equiv. instead of 0.3 equiv.
of catalyst. Under the condition that the reaction rate
depends linearly on the catalyst concentration, this
represents a more than 60-fold speedup through the
new catalyst/reagent combination. The esterification
of phenylcyclohexylcarboxylic acid 17 with t-BuOH
(3) was used as a test for the transformation of more
sterically demanding substrates. In the absence of any
catalyst the reaction is very sluggish and reaches 50%
conversion after 10,500 min. In the presence of
0.05 equiv. of PPY (9) and 2 equiv. of NEt3 the reac-
tion is approx. 64 times faster than the background re-
action. Using the more potent catalyst 11 the speedup
over background amounts to a factor of 106. Using
traditional DCC/DMAP conditions in CH2Cl2 the
conversion of acid 17 to tert-butyl ester 18 is not suc-
cessful and the reaction stops at the stage of the anhy-
drides.[26]
Reaction stage
DHrel (kJmolÀ1)
0.0
À3.7
À19.0
À63.2
À78.6
Scheme 4.
Synthesis of Benzyl Esters
The successful application of the optimized protocol
for the synthesis of tert-butyl esters suggests that syn-
thesis of the sterically less hindered benzyl esters
should be straightforward and fast. Based on the mea-
sured reaction rates for the reaction of primary and
tertiary alcohols with acetic anhydride, the reaction
with primary alcohols is expected to be approx. 200
times faster than the reaction of a tertiary alcohol.[12]
It is therefore surprising that the original Gooßen
protocol was reported to fail in coupling benzyl alco-
hol with either 2-fluorobenzoic acid (20) and 3-nitro-
benzoic acid (23) (Scheme 6 and Table 3).[2]
Repeating these reactions using the new protocol
described above with 0.05 equiv. of DMAP (8) as the
catalyst yields the desired benzyl esters 22 and 24 to-
gether with substantial amounts of Boc-protected
benzyl alcohol (25) (Scheme 6). Monitoring substrate
1
Scheme 5.
conversion by H NMR spectroscopy confirms the ex-
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Domino Catalysis in the Direct Conversion of Carboxylic Acids to Esters
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Scheme 6.
Table 3. Direct synthesis of benzyl esters through Boc2O-mediated reaction of acids and benzyl alcohol at 238C.[a]
Acid
Alcohol
Product
Catalyst (equiv.)[b]
NEt3 [equiv.][b]
t1/2 [min]
Conversion [%][c]
Yield [%]d
13
21
19
8 (0.05)
7 (0.05)
8 (0.05)
7 (0.05)
–
8 (0.05)
7 (0.05)
2
2
2
2
2
2
2
–
–
–
–
–
95
–
70
–
–
20
21
22
~2
108
425
~1
–
66
74
66
52
–
23
21
24
84
[a]
1.3 equiv. of Boc2O have been used.
Equivalents relative to acid.
Final yield of ester product determined by H NMR measurement.
Isolated yield after product purification.
[b]
[c]
[d]
1
pected high reactivity of benzyl alcohol, leading to re- tion of the formation of Boc-protected benzyl alcohol
action half-lifes of 2 min or less. The new protocol (25) and the increased yield of the desired benzyl
was also used for the synthesis of proline benzyl ester esters 19, 22, and 24. The optical rotation of ester 19
19, whose formation had previously been completed is in agreement with the literature and implies no loss
with the original Gooßen protocol in 89% yield. of stereochemical information.[28] These results are
None of the ester product 19 was detected with the not easily reconciled with the mechanism shown in
new protocol, which in this case yields Boc-protected Scheme 3. Benzyl ester 25 could potentially form
benzyl alcohol (25) exclusively. Given the extremely through competing reaction of benzyl alcohol with
short reaction times observed with DMAP (8) as the the acylpyridinium cation generated in the first cycle,
catalyst, all three reactions shown in Scheme 6 were implying that this competition is favorable for benzyl
repeated with pyridine (7) as the catalyst. Earlier alcohol in the case of DMAP (8, R1 =NMe2), but not
studies of the catalytic potential of pyridine bases favorable in the case of pyridine (7, R1 =H). Consid-
have shown that the efficiency of 8 is approx. 104 ering the differences in basicity of these catalysts it
higher than that of 7.[27] The efficiency difference be- seems more likely that the direct base-catalyzed reac-
tween these two catalysts found here is somewhat tion of 21 with Boc2O (1) competes with the domino
smaller at approx. 5”102, but a more accurate deter- catalysis mechanism shown in Scheme 3. The first
mination was not possible due to the very short reac- part of this domino mechanism proceeds without par-
tion times for 8. One remarkable consequence of the ticipation of the alcohol, and it should thus be possi-
use of 7 as a much less reactive catalyst is the retarda- ble to modify the reaction conditions such that
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Scheme 7.
enough time is permitted for the initial formation of such as 11 consistently outperform commercially
the mixed anhydride intermediate. This possibility available catalysts such as DMAP (8) and PPY (9).
was explored through reaction of proline derivative Side reactions encountered in coupling reactions of
13 and Boc2O (1) in the presence of 0.05 equiv. of benzyl alcohols can be alleviated through simple
DMAP (8) or PPY (9) and 2 equiv. of NEt3 for modification of the reaction conditions or through the
35 min at 238C, followed by addition of a benzyl alco- use of strongly deactivated catalysts. The direct cou-
hol (21), which yields 75% ester 19 after product iso- pling of adamantanecarboxylic acid with tert-butanol
lation and purification.
is, unfortunately, not successful even under forcing
conditions and thus remains as a challenge for the de-
velopment of new coupling protocols.
Limitations of the Procedure
In order to test the utility of the new protocol for sys- Experimental Section
tems where previous approaches have failed, the
All Schlenk flasks used for the esterification reactions were
direct coupling of adamantanecarboxylic acid (26)
with tert-butanol (3) was studied next (Scheme 7).
Using 0.05 equiv. of DMAP as catalyst yields anhy-
dride 27 in 50% yield and di(tert-butyl) carbonate
(28) in 29% yield, but none of the desired ester 29
after 12 h reaction time at room temperature. Using
more forcing conditions (608C, 24 h reaction time)
did not alter this result, even when combined with
larger concentrations of the most active catalyst 11
(0.20 equiv.).
It thus appears that the acylpyridinium cation gen-
erated from carboxylic acid 26 is so sterically hin-
dered that reaction with a tertiary aliphatic alcohol
does not proceed at an appreciable rate and that the
reaction therefore stops at the stage of the anhydride
27. Once all the acid 26 has been consumed, the re-
maining reagent slowly transforms into the carbonate
28.
kept overnight in a 1258C hot oven and were afterwards
dried again under high vacuum with a hot air blower. The
flask was cooled down under a nitrogen atmosphere. The
ethanol bath for kinetic measurements was tempered at
238C with a JULABO F-25 thermostat. Dichloromethane
was stirred over concentrated H2SO4 for 24 h, then separat-
ed from the inorganic phase, washed twice with saturated
aqueous NaHCO3 solution, and distilled under nitrogen at-
mosphere from CaH2. All deuterated solvents, triethyla-
mine, and pyridine were freshly distilled under a nitrogen
atmosphere from CaH2. Isobutyric acid was distilled from
P2O5 under nitrogen atmosphere and kept in a Schlenk flask
over molecular sieves (4 Š). All other chemicals were pur-
chased from commercial suppliers at the highest available
grade and used as such without any further purification.
General Procedure for Kinetic Measurements (a)
In a 10-mL Schlenk flask was added under a nitrogen at-
mosphere 1 equiv. (5.0 mmol) acid, 1.1 equiv. tert-butanol,
1 equiv. dioxane, and 2 equiv. NEt3. The reaction mixture
was stirred until homogenous, cooled to À208C and com-
bined with 1.3 equiv. of molten Boc2O. The reaction mixture
was stirred for another 2 min at this temperature, the cool-
ing bath was removed, the flask was equipped with a nitro-
gen-filled balloon and then immersed in a temperature-con-
trolled ethanol bath held at 238C. At this point the reaction
visibly starts as indicated through evolution of CO2 and the
reaction mixture turns yellow after some minutes. The
moment when the flask was immersed into the thermostat
held at 238C marks the zero point on the reaction time
Conclusions
A modified version of the Takeda–Gooßen esterifica-
tion reaction has been developed, in which the use of
highly potent catalysts and an auxiliary base has been
combined with high concentration reaction conditions
in order to reduce reaction times from hours or days
to only minutes at room temperature. This facilitates
the synthesis of sterically hindered esters dramatically.
Recently developed 3,4-diaminopyridine catalysts scale. In defined intervals an aliquot of 0.05 mL was taken
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Domino Catalysis in the Direct Conversion of Carboxylic Acids to Esters
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out of the reaction mixture with a syringe and 0.5 mL of dry
deuterated solvent was added. The conversion of the reac-
tion was monitored by H NMR spectroscopy through com-
depending on the substrate for 4 to 24 h and then worked-
up as specified.
1
parison of the signal intensities of the tert-butyl group of
ester product with that of the internal standard dioxane at
3.67 ppm according to Eq. (1). The data points collected in
this way were fitted with either a sigmoidal or monoexpo-
nential function [Eq. (2) an Eq. (3)]. Half-life times are
equal to the time with respect to 50% conversion. For the
fitting of the mixed and symmetrical anhydride data points a
peak function [Eq. (4)] was used. This function describes the
profile of the data points in a reasonable manner.
tert-Butyl Isobutyrate (4)
The reaction was carried out as described in procedure (b)
with 10 mmol of isobutyric acid. After stirring for 6 h the re-
action mixture was diluted with 10 mL of DCM and trans-
ferred to a separatory funnel, then washed with 10 mL of
2N HCl, 10 mL saturated aqueous NaHCO3 and 10 mL
demineralized water. The organic phase was dried over
Na2SO4 and afterwards fractionally distilled (418C,
26 mbar). This furnishes 4 as a colorless liquid; yield: 1.07 g
(7.45 mmol, 75%).
tert-Butyl 1-Phenylcyclohexanecarboxylate (18)
The reaction was carried out as described in general proce-
dure (b) with 5 mmol 1-phenylcyclohexanecarboxylic acid.
The reaction mixture was stirred for 24 h, then diluted with
10 mL DCM and directly purified by flash chromatography
on silica gel (10% EtOAc/isohexane) to afford a white
solid; yield: 1.15 g (4.45 mmol, 89%).
(S)-tert-Butyl Benzyl Pyrrolidine-1,2-dicarboxylate
(16)
The reaction was carried out on a 5-mmol scale of 15 ac-
cording to procedure (b), except for the additional use of
2 mL dry DCM. The reaction mixturewas stirred for 5 h, di-
luted with 10 mL DCM, transferred into a separatory
funnel, washed with 10 mL 2N HCl and 10 mL saturated
aqueous NaHCO3 solution. The organic phase was dried
over MgSO4 and the solvent distilled off via rotary evapora-
tion. The crude product was purified by flash chromatogra-
phy on silica gel (3/10, EtOAc/isohexane) to afford a white
solid; yield: 1.29 g (4.22 mmol, 85%).
All constants in Eqs. (2)–(4) have no physical meaning
and only serve to determine the half-life times as described
before. Relevant signals of reactants and products have
been collected in Table 4.
(S)-Di-tert-butyl Pyrrolidine-1,2-dicarboxylate (14)
General Procedure for the Synthesis of tert-Butyl
Esters (b)
The reaction was carried out as described in general proce-
dure (b) with 5 mmol (S)-1-[(tert-butoxy)carbonyl]pyrroli-
dine-2-carboxylic acid (13). The reaction mixture was stirred
for 2 h, then diluted with 10 mL DCM and transferred into
a separatory funnel. The organic layer was washed with
10 mL 2N HCl and 10 mL aqueous NaHCO3 solution. The
organic phase was dried over MgSO4, filtered and the organ-
ic solvent distilled off. The crude product obtained was puri-
fied on silica gel (10% EtOAc in isohexane) to afford a
clear oil; yield: 1.18 g (93%).
In a 20-mL Schlenk flask was added 1 equiv. (5.0 mmol)
acid, 0.5 mL (5.5 mmol) tert-butanol, 0.427 mL (5 mmol) 1,4-
dioxane, 1.39 mL (10 mmol) NEt3, and 0.05 equiv. PPY. The
reaction mixture was stirred until homogeneous and cooled
to À208C. Afterwards 1.39 mL (6.5 mmol) of molten Boc2O
was added, stirred for 2 min at this temperature and then al-
lowed to warm to room temperature. Stirring was continued
Table 4. 1H NMR signals (in ppm) of reactants and products
for the reaction shown in Scheme 2.
(S)-tert-Butyl Benzyl Pyrrolidine-1,2-dicarboxylate
(19), Procedure A
Compound d t-Bu
d i-Pr
d i-Pr (1H, Other
(9H, s)
(6H, s)
sep)
A 25-mL two-necked flask with stopcock was charged with
1.076 g (5 mmol) (S)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-
carboxylic acid (13), 1.39 mL (10 mmol) NEt3, 0.57 mL
(5.5 mmol) benzyl alcohol (21), and 0.05 equiv. (0.25 mmol,
20 mL) dry pyridine (7). The reaction solution was cooled to
À208C and 1.39 mL (6.5 mmol) molten Boc2O added via sy-
ringe. After stirring for 2 min at this temperature the cooling
bath was removed and the flask was allowed to warm to
room temperature. Stirring was continued for 4 h and the re-
1
2
3
1.49
–
1.22
–
1.14
–
–
2.52
–
–
–
1.88 (1H, s,
OH)
–
–
–
4
5
6
1.39
–
1.48
1.06
1.190
1.195
2.39
2.62
2.59
Adv. Synth. Catal. 2008, 350, 1891 – 1900
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1899

I. Held et al.
FULL PAPERS
action solution then diluted with 10 mL DCM and trans- References
ferred to a separatory funnel. The organic phase was
washed with 10 mL 2N HCl and 10 mL aqueous NaHCO3
solution. The organic phase was dried over MgSO4, filtered
and the organic solvent distilled off. The crude product was
diluted with a small amount of eluent (10% isohexane in
EtOAc) and filtered through a frit charged with silica gel.
Washing was continued with 30 mL of eluent. The collected
eluate was distilled off under reduced pressure to afford of
19 as a clear oil; yield: 1.07 g (4.19 mmol, 84%).
[1] J. Otera, Esterification: Methods, Reactions and Appli-
cations, Wiley-VCH, Weinheim, 2003.
[2] K. Takeda, A. Akiyama, H. Nakamura, S. Takizawa, Y.
Mizuno, H. Takayanagi, Y. Harigaya, Synthesis 1994,
1063.
[3] L. J. Gooßen, A. Dçhring, Adv. Synth. Catal. 2003, 345,
943.
[4] L. J. Gooßen, A. Dçhring, Synlett 2004, 263.
[5] D. K. Mohaptra, A. Datta, J. Org. Chem. 1999, 64,
6879–6880.
[6] a) V. F. Podnez, Tetrahedron Lett. 1995, 36, 7115–7118;
b) V. F. Podnez, Int. J. Pept. Protein Res. 1992, 40, 407–
414; c) V. F. Podnez, Int. J. Pept. Protein Res. 1994, 44,
36–48.
[7] M. R. Heinrich, H. S. Klisa, H. Mayr, W. Steglich, H.
Zipse, Angew. Chem. 2003, 115, 4975; Angew. Chem.
Int. Ed. 2003, 42, 4826.
[8] I. Held, A. Villinger, H. Zipse, Synthesis 2005, 1425.
[9] I. Held, S. Xu, H. Zipse, Synthesis 2007, 1185.
[10] a) S. Singh, G. Das, O. V. Singh, H. Han, Org. Lett.
2007, 9, 401; b) S. Singh, G. Das, O. V. Singh, H. Han,
Tetrahedron Lett. 2007, 48, 1983.
(S)-tert-Butyl Benzyl Pyrrolidine-1,2-dicarboxylate
(19), Procedure B
A 25-mL two necked flask with stop cock was charged with
1.076 g (5 mmol) (S)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-
carboxylic acid (13), 1.39 mL (10 mmol) NEt3, 0.427 mL
(5 mmol) 1,4-dioxane, and 6.10 mg (0.05 equiv.) DMAP. The
reaction solution obtained was cooled to À208C and
1.39 mL (6.5 mmol) molten Boc2O added via syringe. The
flask was allowed to warm to room temperature and then
immersed in an ethanol bath held at 238C. After 35 min stir-
ring at this temperature 0.57 mL (5.5 mmol) benzyl alcohol
(21) was added. Stirring was continued for 40 min and the
reaction then worked up as described in procedure A. After
chromatography on silica gel (20% EtOAc in isohexane) 19
was obtained as a clear oil; yield: 74% 1.13 g (74%).
[11] S. Xu, I. Held, B. Kempf, H. Mayr, W. Steglich, H.
Zipse, Chem. Eur. J. 2005, 11, 4751.
[12] C. B. Fischer, S. Xu, H. Zipse, Chem. Eur. J. 2006, 12,
5779.
[13] F. M. F. Chen, N. L. Benoiton, Can. J. Chem. 1987, 65,
619–625.
Benzyl 2-Fluorobenzoate (22)
[14] a) S. A. Sikchi, P. G. Hultin, J. Org. Chem. 2006, 71,
5888; b) R. Varala, S. Nuvala, S. R. Adapa, J. Org.
Chem. 2006, 71, 8283; c) X. Jia, Q. Huang, J. Li, S. Li,
Q. Yang, Synlett 2007, 806.
[15] L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137;
Angew. Chem. Int. Ed. Engl. 1993, 32, 131; Angew.
Chem. 1993, 105, 137.
[16] L. F. Tietze, Chem. Rev. 1996, 96, 115.
[17] A. Bruggink, R. Schoevaart, T. Kieboom, Org. Process
Res. Dev. 2003, 7, 622.
[18] D. E. Fogg, E. N. dos Santos, Coord. Chem. Rev. 2004,
248, 2365.
A 25-mL two-necked flask with stopcock was charged with
1.076 g (5 mmol) 2-flourobenzoic acid (20), 1.39 mL
(10 mmol) NEt3, 0.57 mL (5.5 mmol) benzyl alcohol (21),
and 0.05 equiv. (0.25 mmol, 20 mL) dry pyridine (7). The re-
action solution obtained was cooled to À208C and 1.39 mL
(6.5 mmol) molten Boc2O added via syringe. After stirring
for 2 min at this temperature the cooling bath was removed
and the flask was allowed to warm to room temperature.
After stirring for 3 h at this temperature the reaction mix-
ture was diluted with 10 mL DCM and worked-up as usual.
Column chromatography on silica gel affords the ester as a
clear oil; yield: 805 mg (70%).
[19] J.-C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan,
Chem. Rev. 2005, 105, 1001.
[20] C. J. Chapman, C. G. Frost, Synthesis 2007, 1.
[21] A. G. Baboul, L. A. Curtiss, P. C. Redfern, K. Raghava-
chari, J. Chem. Phys. 1999, 110, 7650.
As by-products, a 1:2 mixture of the 2-fluorobenzoic acid
tert-butyl ester and tert-butyl benzyl carbonate (25) in a
total amount of 600 mg was isolated, implying an additional
yield of 20% of 2-fluorobenzoic acid tert-butyl ester; Rf =
0.63 (10% EtOAc in isohexane).
[22] Gaussian 03, Revision C.02. Gaussian, Inc. Wallingford
CT, 2004. For full citation see Supporting Information.
[23] F. Brotzel, B. Kempf, T. Singer, H. Zipse, H. Mayr,
Chem. Eur. J. 2007, 13, 336–345.
Benzyl 3-Nitrobenzoate (24)
A 25-mL two-necked flask with stopcock was charged with
1.076 g (5 mmol) 3-nitrobenzoic acid (23), 1.39 mL
(10 mmol) NEt3, 0.57 mL (5.5 mmol) benzyl alcohol (21)
and 0.05 equiv. (0.25 mmol, 20 mL) dry pyridine (7). The re-
action solution obtained was cooled to À208C and 1.39 mL
(6.5 mmol) molten Boc2O added via syringe. After stirring
for 2 min at this temperature the cooling bath was removed
and the flask was allowed to warm to room temperature.
Stirring was continued at this temperature for 4 h and then
10 mL DCM added. After usual work-up the crude material
was purified with chromatography on silica gel (isohexane/
EtOAc, 9/1) to afford a white solid; yield: 1.07 g (84%).
[24] P. Chevallet, P. Garrouste, B. Malawska and J. Marti-
nez, Tetrahedron Lett. 1993, 34, 7409.
[25] G. W. Anderson, F. M. Callahan, J. Am. Chem. Soc.
1960, 82, 3359.
[26] B. Neises, W. Steglich, Angew. Chem. 1978, 90, 556;
Angew. Chem. Int. Ed. Engl. 1978, 17, 522.
[27] G. Hçfle, W. Steglich, H. Vorbrüggen, Angew. Chem.
1978, 90, 602; Angew. Chem. Int. Ed. Engl. 1978, 17,
569.
[28] A. M. M. Marquet, M. A. Gaudry, S. Boru, French
Patent 2585354 A1, 1987.
1900
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1891 – 1900