Chemoselectivity in Esterification Reactions - Size Matters after All

Article abstract of DOI:10.1055/s-0036-1588854

The reaction of carboxylic acid chlorides with secondary alcohols carrying either flexible alkyl or rigid aryl substituents was studied through a series of competition experiments. Aliphatic acid chlorides react preferentially with the aryl-substituted alcohols, while acid chlorides derived from aromatic carboxylic acids react with very low selectivity. Catalysis by 9-azajulolidine (TCAP) increases the selectivity strongly, while solvent and temperature effects are only moderate. The size of the alcohol substituents seems to impact selectivities only for rigid aryl substituents, and highest selectivities have been found for 1-(1-pyrenyl)ethanol.

Full text of DOI:10.1055/s-0036-1588854

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–K
paper
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en
J. Helberg et al.
Paper
Synthesis
Chemoselectivity in Esterification Reactions – Size Matters after
All
Julian Helberg
π–π-stacking
Marta Marin-Luna
H
O
H
O
Hendrik Zipse*
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0
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0
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0
2
0-
5
3
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3-
5
8
5
H
H
Department of Chemistry, LMU München, Butenandtstrasse 5–13,
81377 München, Germany
zipse@cup.uni-muenchen.de
N
N
N
N
O
O
Dedicated to Herbert Mayr on the occasion of his 70th birthday
H
H
Cl
Cl
Chemoselectivity
Received: 05.05.2017
Accepted: 08.05.2017
Published online: 13.06.2017
DOI: 10.1055/s-0036-1588854; Art ID: ss-2017-z0305-op
ceed in a catalyzed as well as uncatalyzed fashion. The chal-
lenge of chemoselectivity arises when molecules contain
two sterically and electronically similar alcohol functions.
Therefore, we have designed intermolecular competition
experiments between two secondary alcohol substrates
containing different structural organization levels each,
that is, a flexible alcohol 1a (smaller effective surface R1)
and a pre-organized (larger effective surface R2) alcohol 1b
(Scheme 1). This was also applied to differently sized preor-
ganized secondary alcohols. As indicated in Scheme 1, dif-
ferentiation between these alcohols is facilitated by (acti-
vated) carboxylic chloride reagents, for which the effect of
the size of the substituent (R3) was investigated. For activa-
tion, we decided to employ 9-azajulodine (TCAP) due to its
well-documented high reactivity in acylation reactions.5
Abstract The reaction of carboxylic acid chlorides with secondary al-
cohols carrying either flexible alkyl or rigid aryl substituents was stud-
ied through a series of competition experiments. Aliphatic acid chlo-
rides react preferentially with the aryl-substituted alcohols, while acid
chlorides derived from aromatic carboxylic acids react with very low se-
lectivity. Catalysis by 9-azajulolidine (TCAP) increases the selectivity
strongly, while solvent and temperature effects are only moderate. The
size of the alcohol substituents seems to impact selectivities only for
rigid aryl substituents, and highest selectivities have been found for 1-
(1-pyrenyl)ethanol.
Key words chemoselective esterification, acyl chlorides, organocatal-
ysis, competition experiments, dispersion energy donor
[cat]
The concept of dispersion energy donor (DED)-guided
chemistry has recently emerged as a new paradigm in
fields as diverse as stereoselective catalysis and main group
organic chemistry.1 The basic tenet of this concept is that
attractive London forces between properly placed large mo-
lecular structures can guide reactions to be more reactive,
more selective, or provide larger driving force as compared
to the same reactions involving smaller substituents. In ad-
dition, notable effects can only be expected when using
fairly rigid DED groups, as otherwise the entropic price for
‘properly placing’ becomes prohibitive. Since experimental
validation of this concept has been sparse so far, we ex-
plored here its applicability in the context of acylation reac-
tions of alcohols, a reaction of fundamental importance in
the synthesis of complex molecular targets.2 Depending on
the reaction conditions and the mode of catalysis these re-
actions involve either carboxylic acids or their activated de-
rivatives such as acid anhydrides or halides.3,4 Due to their
superior intrinsic reactivity we selected here carboxylic
acid chlorides as reagents, as these allow reactions to pro-
R1
R1
R3
O
k1
HO
O
O
1a
3aa
, NEt3
R3
Cl
2a
R2
R2
R3
O
HO
k2
[cat]
O
1b
3ba
Scheme 1 Competition experiment between secondary alcohols car-
rying alkyl and aryl substituents R1 and R2 of different effective surface
Carboxylic acid derivatives carrying large aromatic or
aliphatic substituents such as 1-adamantyl carboxylic acid6
or the substituted benzoic anhydrides in the Yamaguchi7
and Shiina8 esterification reactions, respectively, are known
to be capable of selective transformations. We therefore ini-
tiated our studies with reagents from this latter class and
used acetyl chloride as the smallest possible reference.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

B
J. Helberg et al.
Paper
Synthesis
Kinetic data from these types of 1:1 competition experi-
ments can be extracted following an approach developed
for kinetic resolution experiments.9 While the intrinsic se-
lectivity of this process S is reflected in the ratio of the two
effective rate constants S = k2/k1 (Figure 1, eq. 1), the experi-
mentally determined chemoselectivity C is apparent from
the product distribution (Figure 1, eq. 2) and depends on
the actual conversion of the reaction, which is defined in
Figure 1, eq. 3. Selectivity factors S were therefore derived
from a series of experiments involving the determination of
chemoselectivity C at different conversions.
k2
k1
Selectivity (S) =
(1)
(2)
(3)
[3ba] – [3aa]
[3ba] + [3aa]
Chemoselectivity (C) =
[3ba] + [3aa]
[3aa] + [3ba] + [1a] + [1b]
Conversion [%] =
× 100
Figure 1 Selectivity (eq. 1), chemoselectivity (eq. 2), and conversion
(eq. 3) of benchmark alcohols 1a and 1b with varying carbonyl chlorides
2a
Figure 2 Example of 1H NMR signals used for in situ determination of conversion and chemoselectivity (top) and corresponding chemoselectivity vs
conversion plot underlain by simulated selectivity curves (bottom)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

C
J. Helberg et al.
Paper
Synthesis
How this procedure is put into practice is shown in
Scheme 2 for the competition between dodecan-2-ol (1a)
and 1-(1-naphthyl)ethanol (1b). These two alcohols contain
substituents of identical carbon count, but different de-
grees of preorganization: while the n-decyl side chain in 1a
enjoys a large degree of conformational freedom, all side
chain carbon atoms are confined to the plane of the naph-
thyl ring system in 1b. Equal amounts of these two alcohols
1 (0.1 mol/L each) were reacted with different concentra-
tions of benzoyl chloride (2a; 20, 35, 50, 65, and 80% with
respect to the total amount of both alcohols 1) in CDCl3 in
the presence of NEt3 (1.16 equiv relative to 2a) and TCAP (4;
0%, 2.5%, 5%, or 7.5% with respect to the total amount of
both alcohols 1).
In a first set of experiments, the selectivity between al-
cohols 1a and 1b was tested with a variety of aliphatic chlo-
rides without addition of catalyst 4 (Table 1, entries 1–4).
For the smallest reagent acetyl chloride (2b) used here, re-
action of naphthyl-substituted alcohol 1b is preferred with
S = 7. A slightly lower selectivity is determined for the
much larger diphenylacetyl chloride (2e) (S = 6), while even
lower values are found for the acid chlorides 2c and 2d
(both, S = 3–4). However, in all of these experiments, traces
of secondary products such as β-keto ester 7 are formed,
which might cause the low selectivities observed in these
cases. These β-keto esters are most likely formed via dike-
tene intermediates 6 or from enol ester tautomers 3taut as
shown in Scheme 3 for acetyl chloride (2b).10 The formation
of these secondary products can be reduced to some extent
through slow addition of the acid chlorides, but only
through the use of aromatic carbonyl chlorides lacking a
deprotonable α-position can the formation of these side re-
actions be avoided completely (entries 5–18).
The selectivities determined for uncatalyzed esterifica-
tions of alcohols 1b/1a with aromatic carboxylic acid chlo-
rides show larger variations and range from S = 0.7 in the
case of 1-naphthoyl chloride (2f) to S = 6 when anthrace-
nylcarboxylic acid chloride (2h) is employed (Table 1, en-
tries 5, 9, 13, 17). In fact, the reaction with 1-naphthoyl
chloride (2f) is the only one found to prefer dodecan-2-ol
(1a) over any other alcohol in the 1:1 competition experi-
ments. The broad range of selectivities found for aromatic
carboxylic acid chlorides may, in part, be due to changes in
the substitution mechanism. Scheme 4 summarizes three
of the more likely mechanisms for the reaction of acid chlo-
rides with alcohols. For sterically demanding acid chlorides
such as 9-anthracenylcarboxylic acid chloride (2h) earlier
studies11 have established that the reaction proceeds
through an SN1-type mechanism with rate-limiting forma-
tion of the respective acylium ion S1 and subsequent reac-
tion with the alcohol substrates. This mechanism also ap-
pears to persist in the presence of Lewis base catalysts as
the observed selectivity factor of S = 6 remains unchanged
upon addition of 5% of TCAP (entries 17 and 18).
O
Ph
O
Ph
O
HO
HO
Ph
Cl
O
O
2a
+
+
NEt3
CDCl3
N
1a
1b
3aa
3ba
4
N
Scheme 2 Representative competition experiment between alcohols
1a and 1b with benzoyl chloride 2a
The reactions were stirred under nitrogen at constant
temperature of +23 °C until full turnover of acid chloride
1
was observed by H NMR measurements. The chemoselec-
tivity C was then determined through integration of the re-
actant and product signals (Figure 2, top) and plotted vs.
the actual conversion (Figure 2, bottom) as detailed in the
Supporting Information (SI). Turnover curves correspond-
ing to constant selectivity factors S were then fitted to the
data points such that deviations were minimized. For the
example shown in Scheme 2 the resulting chemoselectivity
versus conversion plot fits best to the selectivity curve with
S = 9.5.
Uncatalyzed reactions of all other (sterically less biased)
acyl chlorides appear to follow an SN2-type pathway involv-
ing direct encounter of acid chlorides and alcohols in the
rate-limiting steps. The selectivity factors observed for
these reactions are quite low and range between 0.7 (for 2f)
to 2.0 (2a and 2g). In these cases, addition of pyridine cata-
lyst 4 leads to a change in selectivity factor S and therefore
to a change in the ratio of the effective rate constants
(k2/k1). The selectivity in this third pathway is thus due to
the interaction of substrate alcohols with acylpyridinium
ions S3 (Scheme 4), whose formation through direct reac-
tion of acid chlorides with the structurally related 4-dime-
thylaminopyridine (DMAP) have been described before.12
+ NEt3
O
2x
Cl
C
OH
O
O
O
1
– HNEt3Cl
R
2b
5b
6b
O
O
O
7b
R
Cl
O
R
OH
R
+ NEt3
Cl
OH
2b
O
O
+
O
O
R
+ NEt3
– HNEt3Cl
– HNEt3Cl
2b
1
3
3taut
Scheme 3 Proposed pathways for formation of β-keto ester 7b
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

D
J. Helberg et al.
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Synthesis
Table 1 Competition Experiments for Alcohols 1a and 1b with Varia-
tions in Acyl Chlorides 2x and Amounts of Catalyst 4
Cl
O
O
4
Cl
N
N
Ar
Cl
Ar
O
Ar
O
R
O
R
O
S3
S1
S2
HO
HO
R
Cl
O
O
OH
OH
OH
R
R
R
(a)
(b)
(c)
2x
+
+
NEt3
O
O
CDCl3
N
O
Cl
H
Cl
H
N
N
Ar
R
Ar
1a
1b
3ax
3bx
O
Ar
O
O
H
R
R
H
Cl
4
N
O
Entry
Chloride 2x
4 (%)
S
R
+ HCl
Ar
O
O
Scheme 4 Limiting mechanisms for reaction of alcohols with acyl chlo-
rides: (a) SN1 pathway with acylium ion S1, (b) SN2 pathway, and (c)
TCAP-catalyzed pathway involving acylpyridinium ion S3.
1
2
0
0
7a
Cl
2b
O
3–4a
Cl
O
The large, planar structure of acylpridinium ion S3 may, in
part, be responsible for the preferred reaction of alcohol 1b
over 1a under these conditions. The selectivity factors S
show no simple dependence on the catalyst concentration,
but a saturation effect between 5% and 7.5% in the case of
2a and 2g. This is presumably caused by the conversion be-
ing dominated by the catalyzed reaction pathway. In the
case of acyl chloride 2f, product transesterification process-
es appear to be involved, which become more notable at
higher (absolute) reagent concentrations and longer reac-
tion times are causing atypical chemoselectivites (see SI).
Therefore, selectivity factors could only be determined with
some confidence at conversion levels below 20% (Table 1,
entries 10–12). Despite these complications, all selectivity
data collected in Table 1 clearly document that acylpyridin-
ium S3 appears to be the most competent ‘selector’ in dif-
ferentiating the two alcohols 1a and 1b.
2c
3
4
0
3–4a
Cl
2d
O
Ph
0
0
6a
Cl
Ph
2e
5
6
2a
O
2.5
5
7a
Cl
7
9.5a
9.5a
0.7a
2a
8
7.5
0
9
O
10
11
12
13
14
2.5
5
3–4b
4–5b
10b
2a
Cl
2f
O
In order to gain insight into the TCAP-catalyzed esterifi-
7.5
0
1
cation of aromatic chlorides, a series of in situ H NMR ex-
periments in CDCl3 were conducted. TCAP (4) was mixed
with equimolar amounts of the aromatic acyl chlorides 2a,
2f, and 2g. Figure 3 shows the spectra obtained with benzo-
yl chloride (2a) (spectrum IV) in comparison to those for
pure TCAP (4) (spectrum III), TCAP·HCl (spectrum II), and
the corresponding pyridinium carboxylate (spectrum I).
Analysis of these spectra allows for the following conclu-
sions: 1) TCAP and benzoyl chloride react quantitatively un-
der formation of two adducts in a ratio of 70:30 (spectrum
IV); 2) The signals for the major component correspond to
acylpyridinium ion S3 due to the large shifts downfield
compared to pure TCAP (spectra III, IV);13 3) These large
shifts of the aromatic proton peak (7.8 → 8.1 ppm) and the
aliphatic ones (especially the one from 3.2 to 3.8 ppm) are
presumably caused by the rehybridization of the nitrogen
atoms in the TCAP/acid chloride adduct (spectra III, IV); 4)
2.5
6a
Cl
15
5
8.5a
2g
16
17
7.5
0
8.5a
6a
O
Cl
18
5
5–6a
2h
a Selectivity values S derived from chemoselectivities at five different turn-
over values (see SI for details).
b Selectivity values S derived from chemoselecivity C at 20% turnover.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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Synthesis
Figure 3 1H NMR investigation of TCAP-activation of benzoyl chloride (2a)
The minor component in spectrum IV most likely corre-
sponds to a rapidly interchanging mixture of TCAP·HCl
(spectrum II) and the pyridinium carboxylate product
(spectrum I) (see SI for further details). The assignments for
TCAP·HCl are further supported through an X-ray crystal
structure obtained after recrystallization from hexane
(Figure 4). The chloride anion is coordinated to the C2–H
bond of the pyridine ring with a Cl–H distance of 263.1 pm.
A similar arrangement may also be envisioned for the aro-
matic chloride adducts S3 shown in Scheme 4.
Table 2 Competition Experiments for Alcohols 1a and 1b with Varia-
tions in the Reaction Conditions
O
O
O
O
O
HO
HO
Cl
2g
+
+
NEt3
CDCl3
1a
1b
3ag
3bg
N
N
4 (5%)
Method
NEt3 (mol/L)
Solvent
Temp (°C) S
Benchmark
0.05, 0.08, 0.12, 0.15, 0.19 CDCl3
0.19 for all experiments CDCl3
0.05, 0.08, 0.12, 0.15, 0.19 CDCl3
23
23
10
8.5a
9.5a
A
B
C
10a
Figure 4 X-ray crystal structure of the TCAP·HCl adduct; the com-
pound crystallizes with one molecule of H2O (removed for clarity)
0.05 for all
PhCF3
CDCl3
MeCN
toluene
benzene
THF
23 for all 11b
9.5b
Having obtained satisfactory selectivities, we turned to-
wards the influence of the reaction conditions on the che-
moselectivity (Table 2). Since the total amount of NEt3
changes with the amount of chloride in all experiments de-
scribed in Table 1, we performed the standard experiment
while keeping the concentration of NEt3 constant at the
highest level used previously for all concentrations of 2g
(Table 2, A). Only a small change in selectivity is observed at
7.5b
6b
5.5b
2–3b
a Selectivity values S derived from chemoselectivities at five different turn-
over values (see SI for details).
b Selectivity values S derived from chemoselecivity C at 10% turnover.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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J. Helberg et al.
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Synthesis
these (on average) higher base concentrations, in line with
the effects of auxiliary bases in other acylation reactions.14
Since a decrease in temperature is commonly expected to
increase selectivity,15 the standard experiment with acyl
chloride 2g was conducted at +10 °C instead of +23 °C (Ta-
ble 2, B). Again, only a moderate increase in selectivity
(S = 8.5 → 10) is observed which translates into a difference
in activation enthalpies of 8.7 kJmol–1 and of activation en-
tropies of 11.6 JK–1mol–1 by use of the Eyring Equation (see
SI).15 In contrast, much larger variations can be observed on
rerunning the 1:1 competition experiment between alco-
hols 1a and 1b in different solvents in the presence of 5%
catalyst 4 (Table 2, C). Selectivity is highest with S = 11 in
trifluoromethylbenzene, closely followed by CDCl3 with
S = 9.5. Still lower values are found for the polar solvent ace-
tonitrile and aromatic solvents such as toluene or benzene.
The reaction is least selective in THF with S = 2–3, and it is
not immediately obvious from this series what solvent
property governs the S-value variations.
Since the results described so far gave little indication to
change the experimental setup, an investigation into the
role of the size and shape of the competing alcohols was
launched. Therefore, we used standard conditions with 2.5%
and 7.5% of catalyst 4 and 2-naphthoyl chloride (2g) while
changing the pair of alcohols (Table 3). In order to study
whether steric hindrance imposed through the aliphatic
chain in dodecan-2-ol (1a) causes the preference for the
pre-organized 1-(1-naphthyl)ethanol (1b) in reactions of all
examined activated aromatic chlorides, a number of experi-
ments with the smaller pentan-2-ol (1c) were conducted.
The comparison of entry 1 with 3 and 2 with 4, respectively,
clearly shows that steric hindrance by the chain of 1a plays
no substantial role in determining the selectivity for the re-
actions of interest in this study.16
Due to these results, we focused on competition experi-
ments comparing differently sized aromatic alcohols. Be-
ginning with the pair of 1-(1-naphthyl)ethanol (1b) and 1-
phenylethanol (1d) we found a small preference (S = 1.5)
towards the larger aromatic system (Table 3, entries 5, 6).
Selectivity is inverted for the pair of 1b and the larger 1-(1-
pyrenyl)ethanol (1e; S = 0.4–0.5), again clearly favoring the
larger aromatic system (entries 7, 8). Since the competition
between aromatic and aliphatic alcohols always showed
the best selectivity, three differently sized aromatic alco-
hols 1b, 1d, and 1e were tested against dodecan-2-ol (1a)
(Figure 5).
Screening catalyst concentrations of 2.5% and 7.5%, ex-
cellent selectivities (S = 25) are obtained for reactions of 1-
(1-pyrenyl)ethanol (1e) as compared to alcohol 1a (Table 3,
entries 11, 12). All of the measurements with a catalyst
concentration of 7.5% clearly show an increase in selectivity
if the size of the aromatic competitor is increased: S = 5 for
1d to S = 8.5 for 1b up to S = 25 for 1e (Figure 5, Table 3, en-
tries 4, 10, 12). Similar, but less distinct, observations can
be made for a concentration of 2.5% of TCAP (4). The overall
Figure 5 Visualization of the competition experiment of different aromatic alcohols with 1a catalyzed by 7.5% of TCAP (Table 3, entries 4, 10, 12)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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J. Helberg et al.
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Table 3 Competitive Acylations of Selected Secondary Alcohol Pairs
with 2-Naphthoyl Chloride (2g)
acylpyridinium ion and the aromatic moiety of the attack-
ing alcohol interact favorably through electrostatic as well
as dispersion forces. This type of orientation may also pro-
vide an argument for the comparatively small dependence
of selectivity factors S on the size of the acyl chloride re-
agent documented in Table 1.17
O
Cl
HO
HO
2g
+
+
R1
1x
R2
1y
O
O
NEt3
CDCl3
1e
H
O
O
O
H
N
N
R1
R2
3xg
3yg
N
N
4
O
S3
H
Cl
Entry Alcohols 1
4 (%)
Sa
Figure 6 Proposed transition state structure causing high selectivity
for alcohols carrying extended aromatic side chains
HO
1
2.5
7.5
2.5
8
1c
2
10
6
HO
In conclusion, we have devised a system of aromatic
carbonyl chlorides and TCAP (4), which react with high se-
lectivity with an equimolar solution of two secondary alco-
hols favoring the one that contains the larger effective sur-
face. For that purpose, we designed intermolecular compe-
tition experiments between pre-organized (aromatic) and
unorganized (aliphatic) secondary alcohols with different
acid chlorides. Catalytic amounts of TCAP (4) have a consid-
erable impact on selectivity. The reaction conditions were
examined, leading us to believe that temperature, concen-
tration of auxiliary base NEt3, and selection of solvent influ-
ence the selectivity to a minor degree. While the influence
of the chain length of the aliphatic alcohol is negligible, the
size of the pre-organized alcohol towards the selectivity of
the esterification reaction is significant. In situ 1H NMR ex-
periments of TCAP-activated acid chlorides in combination
with X-ray structure analysis of TCAP·HCl are used to pro-
pose both a pyridinium acid chloride as selectivity selector
and specific transition state interactions to explain the ob-
served preferences. A combination of electronic effects on
the aromatic alcohols with π–π stacking and dispersive in-
teractions between the aromatic surface of the alcohols and
the pyridinium moiety of the TCAP-acid chloride adducts
are proposed to explain the different selectivities achieved
in favor of the more sizable (pre-organized) alcohols. Ac-
cording to this, a combination of new, larger pyridine-de-
rived catalysts and more sizable alcohols is expected to react
with even higher selectivity. Further investigations, both ex-
perimental and theoretical aiming at full elucidation of the
results described here are currently ongoing.
1b
3b
HO
1a
4b
5
7.5
2.5
7.5
2.5
8.5
1.5
HO
1d
6
1.5
HO
1b
7
0.4–0.5
HO
1e
8
9
7.5
0.4–0.5
2.5
7.5
2.5
4–5
5
HO
1d
10
HO
1a
11
12
25
HO
1e
7.5
25
a Selectivity values S derived from chemoselectivities at five different turn-
over values (see SI for details).
b These results are also included in Table 1.
trend observed for competition experiments between dif-
ferently sized aromatic alcohols as well as one aliphatic al-
cohol with several differently sized aromatic alcohols
shows a correlation between the size of the aromatic sys-
tem and the selectivity: Increase of the aromatic system in-
creases selectivity towards that aromatic system.
These experimental observations may be rationalized
with the transition state cartoon shown in Figure 6, where
π–π stacking interactions between the TCAP-derived
1H NMR spectra were recorded in CDCl3 400 MHz or 600 MHz. 13C
NMR spectra were recorded in CDCl3 at 101 MHz or 151 MHz. The
chemical shifts are expressed in ppm, relative to CHCl3 at δ = 7.26 for
1H, while the chemical shifts for 13C are reported relative to the reso-
nance of CDCl3 at δ = 77.1. Spectra were imported and processed in
the MestreNova 10.0.2 program. Melting points are uncorrected.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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J. Helberg et al.
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Synthesis
Dodecan-2-ol (1a), 1-(1-napthyl)ethanol (1b), pentan-2-ol (1c), 1-
phenylethanol (1d), acetyl chloride (2b), phenylacetyl chloride (2c),
diphenylacetyl chloride (2e), benzoyl chloride (2a), 1-naphthoyl chlo-
ride (2f), 2-naphthoyl chloride (2g), and 9-azajulolidine (4) were pur-
chased from Sigma Aldrich or TCI and used without further purifica-
tion.
isohexane to give the chloride 2h in 66% yield (2.86 g, 11.9 mmol) in
the form of yellow needles; mp 98–101 °C. For X-ray crystal structure,
see SI.
1H NMR (CDCl3, 400 MHz): δ = 8.51 (s, 1 H), 8.13 (dd, J = 8.8, 0.8 Hz, 2
H), 7.99 (d, J = 8.5 Hz, 2 H), 7.65–7.57 (m, 2 H), 7.51 (ddd, J = 7.7, 6.6,
0.9 Hz, 2 H).
The ester compounds 1-(naphthalen-1-yl)ethyl acetate (3bb),18 1-
(naphthalen-1-yl)ethyl 2-phenylacetate (3bc),19 1-(naphthalen-1-
yl)ethyl 2,2-diphenylacetate (3be),20 1-(naphthalen-1-yl)ethyl benzo-
ate (3ba),21 1-(naphthalen-1-yl)ethyl 2-naphthoate (3bg),22 and 1-
(phenalen-1-yl)ethyl 2-napthoate (3dg)23 are already known. Pub-
lished analytical data match with the compounds observed by us.
13C NMR (CDCl3, 101 MHz): δ = 170.66 (s, C=O), 131.70 (s), 130.78 (s),
130.73 (s), 128.86 (CH), 128.04 (CH), 126.25 (s), 125.96 (CH), 123.99
(CH).
HRMS (EI): m/z calcd for C15H9ClO: 240.0342; found: 240.0336.
Anal. Calcd for C15H9ClO (240.69): C, 74.85; H, 3.77. Found: C, 75.09;
H, 3.90.
1-(1-Pyrenyl)ethanol (1e)
Dodecan-2-yl Acetate (3ab) and Dodecan-2-yl 3-Oxobutanoate
(7b)
To a solution of 1-pyrenaldehyde (2.46 g, 10.7 mmol) in anhyd THF
(30 mL) was added a 3 M solution of MeMgBr in THF (8 mL, 14 mmol)
under N2. The reaction mixture was stirred at r.t. for 2 h. Then sat. aq
NH4Cl (10 mL) was added and the resulting mixture was extracted
with CH2Cl2 (2 × 30 mL). The combined organic layers were washed
with brine (2 × 20 mL) and dried (anhyd MgSO4). After removal of the
solvents at reduced pressure, the resulting solid was recrystallized
from n-hexane to give 1e as white prisms in 85% yield (2.27 g, 9.15
mmol).
Dodecan-2-ol (1a; 0.70 g 3.76 mmol) and Et3N (0.61 mL, 4.37 mmol)
were dissolved in CHCl3 (10 mL) under N2. Then, AcCl (0.295 mL, 3.76
mmol) was added and the mixture was stirred at r.t. for 3 d. Salts
were precipitated by addition of THF (50 mL) and filtered off. The
crude product mixture was purified by repeated column chromatog-
raphy on silica gel by using a mixture of CH2Cl2/isohexane (0:1 → 2:1
v/v) as eluent.
1H NMR (CDCl3, 400 MHz): δ = 8.32 (d, J = 9.3 Hz, 1 H, ArH), 8.22 (d, J =
8.0 Hz, 1 H, ArH), 8.18 (d, J = 7.2 Hz, 3 H, ArH), 8.09 (d, J = 9.3 Hz, 1 H,
ArH), 8.04 (s, 2 H, ArH), 8.0 (t, J = 7.6 Hz, 3 H, ArH), 5.96 (q, J = 6.4 Hz,
1 H, OCHCH3), 2.15 (s, 1 H, OH), 1.77 (d, J = 6.4 Hz, 1 H, CH3).
13C NMR (CDCl3, 101 MHz): δ = 139.07 (s), 131.37 (s), 130.64 (s),
130.62 (s) , 127.62 (CH), 127.48 (CH), 127.23 (s), 127.19 (CH), 125.94
(CH), 125.24 (CH), 125.12 (CH),125.03 (CH), 124.91 (s), 124.83 (s),
122.547 (CH), 122.40 (CH), 67.34 (CH), 25.08 (CH3).
3ab
Yield: 0.182 g (0.80 mmol, 21%); colorless oil.
1H NMR (CDCl3, 400 MHz): δ = 4.84–4.78 (m, 1 H, OCHCH3), 1.96 (s, 3
H, COCH3), 1.53–1.46 (m, 1 H, CHCHHCH2), 1.42–1.36 (m, 1 H, CHCH-
HCH2), 1.23–1.19 (m, 16 H, 8 × CH2), 1.13 (d, J = 8.4 Hz, 3 H, OCHCH3),
0.81 (t, J = 8.4 Hz, 3 H, CH2CH3).
13C NMR (CDCl3, 101 MHz): δ = 170.83 (s, C=O), 71.10 (CH), 35.93
(CH2), 31.92 (CH2), 29.62 (CH2), 29.59 (CH2), 29.55 (CH2), 29.47 (CH2),
29.35 (CH2), 29.34 (CH2), 25.43 (CH2), 22.70 (CH2), 21.43 (CH3), 19.98
(CH3), 14.14 (CH3).
HRMS (EI): m/z calcd for C18H14O: 246.1045; found: 246.1040.
2-(Naphthalen-1-yl)acetyl Chloride (2d)
HRMS (EI): m/z calcd for C14H27O (M – OH): 211.2062; found:
211.2054; m/z calcd for C12H25O (M – COCH3): 185.1905; found:
185.1899.
2-(Naphthalen-1-yl)acetic acid (5 g, 26.8 mmol) was suspended in
methyl tert-butyl ether (10 mL) under N2 atmosphere. To this suspen-
sion was added SOCl2 (5.9 mL, 80.6 mmol) and the resulting clear
solution was stirred at r.t. for 3 h. The excess of SOCl2 was removed in
vacuo and the crude product was purified by bulb-to-bulb distillation
(160 °C, 3.8 × 10–1 mbar) to afford the acid chloride 2d in 60% yield
(3.674 g, 19.3 mmol) as a yellow oil.
1H NMR (CDCl3, 400 MHz): δ = 7.96–7.85 (m, 3 H, ArH), 7.58 (m, 2 H,
ArH), 7.52–7.41 (m, 2 H, ArH), 4.59 (s, 2 H, CH2).
13C NMR (CDCl3, 101 MHz): δ = 172.00 (s, C=O), 133.96 (s), 131.77 (s),
129.41 (CH), 129.12 (CH), 128.97 (CH), 128.01 (s), 127.11 (CH), 126.30
(CH), 125.58 (CH), 123.29 (CH), 50.98 (CH2).
Anal. Calcd for C14H28O2 (228): C, 73.63; H, 12.36. Found: C, 73.49; H,
12.24.
7b
Yield: 0.235 g (0.87 mmol, 23%); colorless oil.
1H NMR (CDCl3, 400 MHz): δ = 2.19 [s, 1 H, OH (t)], 4.99–4.94 (m, 1 H,
OCHCH3), 3.42 (s, 2 H, COCH2CO), 2.26 (s, 3 H, COCH3), 1.94 [s, 1 H, CH3
(t)] 1.62–1.56 (m, 1 H, CHCHHCH2), 1.51–1.44 (m, 1 H, CHCHHCH2),
1.25–1.22 (m, 19 H, 8 × CH2 and OCHCH3), 0.88 (t, J = 8.4 Hz, 3 H,
CH2CH3).
HRMS (EI): m/z calcd for C12H9ClO 204.0342; found: 204.0331.
Anal. Calcd for C12H9ClO (204.65): C, 70.43; H, 4.43; Cl, 17.32. Found:
C, 70.20; H, 4.41; Cl, 17.34.
This compound presents keto-enol tautomerism and ‘t’ means: sig-
nals associated to the enol tautomer of 7b.
13C NMR (CDCl3, 101 MHz): δ = 200.75 (s, C=O), 166.79 (s, C=O), 72.50
(CH), 50.54 (CH2), 35.79 (CH2), 31.91 (CH2), 30.12 (CH2), 29.60 (CH2),
29.58 (CH2), 29.53 (CH2), 29.42 (CH2), 29.34 (CH2), 25.35 (CH2), 22.70
(CH3), 19.86 (CH3), 14.14 (CH3).
MS (EI): m/z calcd for C16H30O3: 270.22; found: 270.30 (M+), 185.22
(M – COCH2COCH3).
9-Anthracenoyl Chloride (2h)
Anthracene-9-carboxylic acid (4 g, 18 mmol) was suspended in SOCl2
(12 mL, 165 mmol) and DMF (0.5 mL) under N2. The reaction mixture
turned into a clear solution after stirring for 5 min at r.t., which was
continued for a total of 20 min followed by removal of all liquids in
vacuo. The resulting crude product was recrystallized from boiling
Anal. Calcd for C16H30O3 (270): C, 71.07; H, 11.18. Found: C, 71.17; H,
11.57.
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J. Helberg et al.
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Synthesis
1-(Naphthalen-1-yl)ethyl Anthracene-9-carboxylate (3bh)
13C NMR (CDCl3, 101 MHz): δ = 171.29 (s, C=O), 134.39 (s), 129.20
(CH), 128.49 (CH), 126.95 (CH), 71.57 (CH), 41.83 (CH2), 35.89 (CH2),
31.93 (CH2), 29.63 (CH2), 29.57 (CH2), 29.54 (CH2), 29.41 (CH2), 29.35
(CH2), 25.31 (CH2), 22.72 (CH2), 19.95 (CH3), 14.16 (CH3).
1-(1-Naphthyl)ethanol (1b; 0.3 g 1.74 mmol) and 9-anthracenoyl
chloride (2h; 0.419 g 1.74 mmol) were suspended in Et3N (0.36 mL,
2.6 mmol) and toluene (1 mL) under N2 and stirred at r.t. for 22 h. Af-
ter the addition of acetone (4 mL), the resulting yellow suspension
was filtered and the residue was washed with an additional amount
of acetone (6 mL). All solvents contained in the filtrate were evaporat-
ed and the crude product was recrystallized from acetone/CHCl3 (3
mL, 2:1, v/v) to provide the ester 3bh in 39% yield (0.253 g, 0.67
mmol) in the form of pale yellow crystals; mp 104–106 °C.
1H NMR (CDCl3, 400 MHz): δ = 8.53 (s, 1 H, ArH), 8.33 (d, J = 8.4 Hz, 1
H, ArH), 8.03–8.00 (m, 4 H, ArH), 7.94 (d, J = 8 Hz, 1 H, ArH), 7.86 (d, J
= 8.4 Hz, 1 H, ArH), 7.71 (d, J = 7.2 Hz, 1 H, ArH), 7.63 (t, J = 7.2 Hz, 1 H,
ArH), 7.56 (t, J = 7.6 Hz, 1 H, ArH), 7.49–7.44 (m, 5 H), 7.32 (q, J = 6.8
Hz, 1 H, OCHCH3), 2.01 (d, J = 6.4 Hz, 1 H, CH3).
HRMS (EI): m/z calcd for C20H32O2: 304.2402; found: 304.2399
Anal. Calcd for C20H32O2 (304.48): C, 78.9; H, 10.6. Found: C, 78.65; H,
10.57.
Ester 3bd
Prepared following GP B; yield: 0.470 g (1.3 mmol, 86%); yellow oil.
1H NMR (CDCl3, 400 MHz): δ = 7.97 (m, 2 H, ArH), 7.88–7.75 (m, 4 H,
ArH), 7.50–7.33 (m, 8 H, ArH), 6.66 (q, J = 6.8 Hz, 1 H, OCHCH3), 4.15
(s, 2 H, CH2), 1.65 (d, J = 6.8 Hz, 1 H, CH3).
13C NMR (CDCl3, 151 MHz): δ = 170.87 (s, C=O), 137.10 (s), 133.76 (s),
133.75 (s), 132.12 (s), 130.58 (s), 130.17 (s), 128.83 (CH), 128.68 (CH),
128.42 (CH), 128.06 (CH), 128.04 (CH), 126.297 (CH), 126.21 (CH),
125.77 (CH), 125.61 (CH), 125.48 (CH), 125.25 (CH), 123.88 (CH),
123.28 (CH), 123.19 (CH), 70.28 (CH), 39.58 (CH2), 21.59 (CH3).
13C NMR (CDCl3, 101 MHz): δ = 169.17 (s, C=O), 137.16 (s, CH), 134.00
(s, CH), 131.10 (s, CH), 130.35 (s, CH), 129.37 (s, CH), 129.14 (s, CH),
128.81 (s, CH), 128.71 (s, CH), 128.48 (s, CH), 128.10 (s, CH), 127.00 (s,
CH), 126.61 (s, CH), 125.95 (s, CH), 125.57 (s, CH), 125.13 (s, CH),
123.83 (s, CH), 123.34 (s, CH), 71.05 (OCHCH3), 22.37 (CH3).
HRMS (EI): m/z calcd for C24H20O2: 340.1463; found: 340.1457.
HRMS (EI): m/z calcd for C27H20O2: 376.1463; found: 376.1456.
Anal. Calcd for C24H20O2 (340.42): C, 84.7; H, 5.92. Found: C, 83.96; H,
6.01.
Esters 3; General Procedures
Ester 3ad
General Procedure A
Prepared following GP B; yield: 0.540 g (1.54 mmol, 95%); colorless
oil.
To a solution of selected alcohol 1 (1.6 mmol) in anhyd toluene (5 mL)
was added Et3N (0.3 mL, 2 mmol) under N2. The corresponding acid
chloride 2 (1.7 mmol) was added to the reaction mixture and stirred
at 60 °C for 24–30 h. Then, the crude reaction mixture was filtered
through a thin pad of silica gel (1 cm3) and washed with acetone (6
mL). All solvents were removed under reduced pressure and the
crude product was purified by column chromatography on silica gel
with a mixture of isohexane/EtOAc (9:1 v/v) as eluent.
1H NMR (CDCl3, 600 MHz): δ = 8.04 (d, J = 9.6 Hz, 1 H, ArH), 7.87 (d, J =
8.4 Hz, 1 H, ArH), 7.80 (dd, J = 7.0, 2.5 Hz, 1 H, ArH), 7.54 (t, J = 8.4 Hz,
1 H, ArH), 7.50 (t, J = 8.1 Hz, 1 H, ArH), 7.46–7.42 (m, 2 H, ArH), 4.96–
4.89 (m, 1 H, OCHCH3), 4.05 (s, 2 H, CH2Ar), 1.57–1.49 (m, 1 H, CHCH-
HCH2), 1.46–1.40 (m, 1 H, CHCHHCH2), 1.36–1.12 (m, 19 H, 8 × CH2
and OCHCH3), 0.92 (t, J = 6.6 Hz, 3 H, CH2CH3).
13C NMR (CDCl3, 151 MHz): δ = 171.26 (s, C=O), 133.83 (s), 133.82 (s),
132.14 (s), 132.14 (s), 130.96 (s), 128.67 (s), 127.91 (CH), 127.90 (CH),
126.17 (CH), 125.69 (CH), 125.44 (CH), 123.90 (CH), 71.68 (CH), 39.67
(CH2), 35.85 (CH2), 31.95 (CH2), 29.63 (CH2), 29.55 (CH2), 29.50 (CH2),
29.37 (CH2), 29.37 (CH2), 29.35 (CH2), 25.23 (CH2), 22.72 (CH2), 19.93
(CH3), 14.15 (CH3).
General Procedure B
To a solution of selected alcohol 1 (1.6 mmol) in anhyd toluene (5 mL)
was added Et3N (0.3 mL, 2 mmol) under N2. The corresponding acid
chloride 2 (1.7 mmol) was added to the reaction mixture and stirred
at r.t. overnight. Then, the crude reaction mixture was filtered
through a thin pad of silica gel (1 cm3) washing with acetone (6 mL).
All solvents were removed under reduced pressure and the crude
product was purified by column chromatography on silica gel with a
mixture of isohexane/EtOAc (9.5:0.5 v/v) as eluent.
HRMS (EI): m/z calcd for C24H34O2: 354.2559; found: 354.2553.
Anal. Calcd for C24H34O2 (354.54): C, 81.3; H, 9.67. Found: C, 81.80; H,
9.74.
Ester 3ae
Prepared following GP B; yield: 0.550 g (1.45 mmol, 91%); colorless
oil.
1H NMR (CDCl3, 400 MHz): δ = 7.24–7.15 (m, 10 H, ArH), 4.92–4.87
(m, 1 H, OCHCH3), 4.90 (s, 1 H, CHAr), 1.51–1.45 (m, 1 H, CHCHHCH2),
1.41–1.33 (m, 1 H, CHCHHCH2), 1.25–1.05 (m, 19 H, 8 × CH2 and
OCHCH3), 0.81 (t, J = 6.0 Hz, 3 H, CH2CH3).
13C NMR (CDCl3, 101 MHz): δ = 172.12 (s, C=O), 138.90 (s), 138.88 (s),
128.64 (CH), 128.62 (CH), 128.52 (CH), 128.49 (CH), 127.14 (CH),
127.12 (CH), 71.97 (CH), 57.43 (CH), 35.83 (CH2), 31.94 (CH2), 29.64
(CH2), 29.55 (CH2), 29.52 (CH2), 29.37 (CH2), 29.36 (CH2), 25.26 (CH2),
22.73 (CH2), 19.90 (CH3), 14.16 (CH3).
General Procedure C
Selected alcohol 1 (2 mmol) and 1-naphthoyl chloride (2f) or 2-naph-
thoyl chloride (2g) (0.381 g, 2 mmol) were dissolved in a mixture of
Et3N (0.42 mL, 3 mmol) and anhyd toluene (1 mL) under N2, and
stirred at r.t. for 43 h. The solution was passed through a 1 cm plug of
silica gel and washed with acetone (4 mL). The resulting crude prod-
uct was purified by column chromatography on silica gel by using a
mixture of CH2Cl2/isohexane (1:2 → 2:1 v/v) as eluent.
Ester 3ac
Prepared following GP B; yield: 0.365 g (1.2 mmol, 75%); colorless oil.
1H NMR (CDCl3, 400 MHz): δ = 7.27–7.18 (m, 5 H, ArH), 4.87–4.79 (m,
1 H, OCHCH3), 3.52 (s, 2 H, CH2Ar), 1.51–1.46 (m, 1 H, CHCHHCH2),
1.40–1.35 (m, 1 H, CHCHHCH2), 1.25–1.06 (m, 19 H, 8 × CH2 and
OCHCH3), 0.81 (t, J = 8.0 Hz, 3 H, CH2CH3).
HRMS (EI): m/z calcd for C26H36O2: 380.2715; found: 380.2704.
Anal. Calcd for C26H36O2 (380.55): C, 82.06; H, 9.54. Found: C, 81.52;
H, 9.54.
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J. Helberg et al.
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Synthesis
Ester 3aa
H, ArH), 5.24–5.19 (m, 1 H, OCHCH3), 1.85–1.75 (m, 1 H, CHCHHCH2),
1.70–1.64 (m, 1 H, CHCHHCH2), 1.47–1.24 (m, 19 H, 8 × CH2 and
OCHCH3), 0.87 (t, J = 6.4 Hz, 3 H, CH2CH3).
Prepared following GP A; yield: 0.319 g (1.10 mmol, 69%); colorless
oil.
1H NMR (CDCl3, 600 MHz): δ = 8.05 (d, J = 6.4 Hz, 2 H, ArH), 7.54 (t, J =
6.4 Hz, 1 H, ArH), 7.43 (d, J = 6.4 Hz, 2 H, ArH), 5.18–5.13 (m, 1 H,
OCHCH3), 1.77–1.71 (m, 1 H, CHCHHCH2), 1.64–1.58 (m, 1 H, CHCH-
HCH2), 1.41–1.23 (m, 19 H, 8 × CH2 and OCHCH3), 0.88 (t, J = 6.0 Hz, 3
H, CH2CH3).
13C NMR (CDCl3, 151 MHz): δ = 166.47 (s), 135.50 (s), 132.57 (s),
130.91 (CH), 129.40 (CH), 128.24 (s), 128.16 (CH), 128.10 (CH), 127.82
(CH), 126.62 (CH), 125.39 (CH), 72.01 (CH), 36.19 (CH2), 31.99 (CH2),
29.69 (CH2), 29.67 (CH2), 29.63 (CH2), 29.60 (CH2), 29.42 (CH2), 25.58
(CH2), 22.77 (CH2), 20.25 (CH3), 14.22 (CH3).
13C NMR (CDCl3, 151 MHz): δ = 166.19 (s, C=O), 132.63 (CH), 130.93
(s) , 129.48 (CH), 128.23 (CH), 71.73 (CH), 36.05 (CH2), 31.88 (CH2),
29.58 (CH2), 29.56 (CH2), 29.52 (CH2), 29.48 (CH2), 29.31 (CH2), 25.42
(CH2), 22.66 (CH2), 20.07 (CH3), 14.10 (CH3).
HRMS (EI): m/z calcd for C23H32O2: 340.2402; found: 340.2390.
Ester 3ah
Prepared following GP B; yield: 0.330 g (0.84 mmol, 53%); colorless
prisms; mp 75–77 °C.
HRMS (EI): m/z calcd for C19H30O2: 290.2246; found: 290.2234.
1H NMR (CDCl3, 400 MHz): δ = 8.51 (s, 1 H, ArH), 8.03 (t, J = 8.8 Hz, 1
H, ArH), 7.56–7.47 (m, 4 H, ArH), 5.57–5.49 (m, 1 H, OCHCH3), 1.88–
1.80 (m, 1 H, CHCHHCH2), 1.74–1.65 (m, 1 H, CHCHHCH2), 1.56 (d, J =
6 Hz, 1 H, ArH), 1.53–1.23 (m, 16 H, 8 × CH2), 0.89 (t, J = 6.4 Hz, 3 H,
CH2CH3).
13C NMR (CDCl3, 101 MHz): δ = 169.48 (s, C=O), 131.03 (s), 128.91 (s),
128.68 (s), 128.62 (CH), 128.14 (s), 126.82 (CH), 125.44 (CH), 124.91
(CH), 73.08 (CH), 36.09 (CH2), 31.94 (CH2), 29.66 (CH2), 29.64 (CH2),
29.62 (CH2), 29.48 (CH2), 29.48 (CH2), 29.38 (CH2), 25.68 (CH2), 22.73
(CH2), 20.37 (CH3), 14.17 (CH3).
Anal. Calcd for C19H30O2 (290.45): C, 78.6; H, 10.41. Found: C, 77.51;
H, 10.41.
Ester 3bf
Prepared following GP C; yield: 0.256 g (0.78 mmol, 45%); colorless
oil.
1H NMR (CDCl3, 600 MHz): δ = 8.94 (d, J = 8.4 Hz, 1 H, ArH), 8.26 (t, J =
6.8 Hz, 1 H, ArH), 8.03 (d, J = 8.0 Hz, 1 H, ArH), 7.90 (t, J = 8.0 Hz, 1 H,
ArH), 7.84 (t, J = 8.0 Hz, 1 H, ArH), 7.76 (d, J = 7.2 Hz, 1 H, ArH), 7.61–
7.48 (m, 6 H, ArH), 7.02 (q, J = 6.4 Hz, 1 H, OCHCH3), 1.92 (d, J = 6.4 Hz,
1 H, CH3).
HRMS (EI): m/z calcd for C27H34O2: 390.2559; found: 390.2556.
13C NMR (CDCl3, 151 MHz): δ = 166.87 (s, C=O), 137.66 (s), 133.97 (s),
133.48 (CH), 131.52 (s), 130.41 (s), 130.31 (s), 129.06 (CH), 128.62
(CH), 128.60 (CH), 127.85 (CH), 127.42 (s), 126.52, 126.32 (CH),
125.92 (CH), 125.83 (CH), 125.55 (CH), 124.62 (CH), 123.39 (CH),
123.32 (CH), 70.31 (CH), 22.07 (CH3).
Anal. Calcd for C27H34O2 (390.57): C, 83.03; H, 8.77. Found: C, 82.66;
H, 8.84.
Ester 3cf
Prepared following GP C; yield: 0.358 g (1.4 mmol, 70%); colorless oil.
1H NMR (CDCl3, 600 MHz): δ = 8.92 (d, J = 8.6 Hz, 1 H, ArH), 8.17 (d, J =
7.2 Hz, 1 H, ArH), 8.01 (d, J = 8.2 Hz, 1 H, ArH), 7.89 (d, J = 8.2 Hz, 2 H,
ArH), 7.62 (t, J = 8.5 Hz, 1 H, ArH), 7.54 (t, J = 8.1 Hz, 1 H, ArH), 7.50 (t,
J = 8.2 Hz, 1 H, ArH), 5.34–5.29 (m, 1 H, OCHCH3), 1.83–1.79 (m, 1 H,
CHCHHCH2), 1.69–1.63 (m, 1 H, CHCHHCH2), 1.55–1.45 (m, 4 H, 2 ×
CH2), 1.40 (d, J = 6.4 Hz, 3 H, OCHCH3), 0.98 (t, J = 7.4 Hz, 3 H, CH2CH3).
13C NMR (CDCl3, 151 MHz): δ = 167.28 (s, C=O), 133.84 (s), 132.99
(CH), 131.34 (s), 129.77 (CH), 128.49 (CH), 128.03 (s), 127.59 (CH),
126.12 (CH), 125.83 (CH), 124.49 (CH), 71.58 (CH), 38.29 (CH2), 20.16
(CH2), 18.83 (CH3), 14.01 (CH3).
HRMS (EI): m/z calcd for C23H18O2: 326.1307; found: 326.1300.
Anal. Calcd for C23H18O2 (326.40): C, 84.64; H, 5.56. Found: C, 84.54;
H, 5.75.
Ester 3af
Prepared following GP A; yield: 0.424 g (1.24 mmol, 78%); colorless
oil.
1H NMR (CDCl3, 600 MHz): δ = 8.92 (d, J = 6.4 Hz, 1 H, ArH), 8.17 (d, J
= 6.4 Hz, 1 H, ArH), 8.01 (d, J = 6.4 Hz, 1 H, ArH), 7.88 (d, J = 6.4 Hz, 1 H,
ArH), 7.62 (t, J = 6.4 Hz, 1 H, ArH), 7.54 (t, J = 6.4 Hz, 1 H, ArH), 7.50 (t,
J = 12.0 Hz, 1 H, ArH), 5.34–5.27 (m, 1 H, OCHCH3), 1.86–1.80 (m, 1 H,
CHCHHCH2), 1.70–1.64 (m, 1 H, CHCHHCH2), 1.53–1.23 (m, 19 H, 8 ×
CH2 and OCHCH3), 0.89 (t, J = 6.0 Hz, 3 H, CH2CH3).
HRMS (EI): m/z calcd for C16H18O2: 242.1307; found: 242.1300.
Anal. Calcd for C16H18O2 (242.32): C, 79.31; H, 7.49. Found: C, 79.18;
H, 7.38.
13C NMR (CDCl3, 151 MHz): δ = 167.28 (s, C=O), 133.84 (s), 132.96 (s),
131.33 (s), 129.76 (CH), 128.48 (CH), 128.06 (CH), 127.57 (CH), 126.11
(CH), 125.84 (CH), 124.48 (CH), 71.85 (CH), 36.14 (CH2), 31.90 (CH2),
29.61 (CH2), 29.59 (CH2), 29.56 (CH2), 29.52 (CH2), 29.34 (CH2), 29.33
(CH2), 25.56 (CH2), 22.69 (CH2), 20.15 (CH3), 14.12 (CH3).
Ester 3cg
Prepared following GP C; yield: 0.349 g (1.36 mmol, 68%); colorless
oil.
1H NMR (CDCl3, 600 MHz): δ = 8.61 (s, 1 H, ArH), 8.09 (dd, J = 8.6, 1.7
Hz, 1 H, ArH), 7.96 (d, J = 8.06, 1.7 Hz, 1 H, ArH), 7.88 (d, J = 8.06, 1.7
Hz, 2 H, ArH), 7.58 (td, J = 8.2, 6.8 Hz, 1 H, ArH), 7.54 (td, J = 8.2, 6.8 Hz,
1 H, ArH), 5.28–5.24 (m, 1 H, OCHCH3), 1.84–1.77 (m, 1 H, CHCH-
HCH2), 1.67–1.62 (m, 1 H, CHCHHCH2), 1.47–1.24 (m, 4 H, 2 × CH2),
1.40 (d, J = 6.3 Hz, 3 H, OCHCH3), 0.98 (t, J = 7.4 Hz, 3 H, CH2CH3).
HRMS (EI): m/z calcd for C23H32O2: 340.2402; found: 340.2396.
Anal. Calcd for C23H32O2 (340.51): C, 81.1; H, 9.47. Found: C, 80.53; H,
9.42.
Ester 3ag
13C NMR (CDCl3, 151 MHz): δ = 166.37 (s, C=O), 135.44 (s), 132.51 (s),
130.81 (CH), 129.31 (CH), 128.17 (s), 128.06 (CH), 128.02 (CH), 127.73
(CH), 126.53 (CH), 125.30 (CH), 71.63 (CH), 38.28 (CH2), 20.16 (CH2),
18.76 (CH3), 14.00 (CH3).
Prepared following GP A; yield: 0.380 g (1.12 mmol, 70%); colorless
oil.
1H NMR (CDCl3, 600 MHz): δ = 8.60 (s, 1 H, ArH), 8.17 (d, J = 6 Hz, 1 H,
ArH), 8.06 (d, J = 7.2 Hz, 1 H, ArH), 7.96 (d, J = 8.0 Hz, 1 H, ArH), 7.88
(d, J = 8 Hz, 2 H, ArH), 7.58 (t, J = 7.2 Hz, 1 H, ArH), 7.54 (t, J = 5.6 Hz, 1
HRMS (EI): m/z calcd for C16H18O2: 242.1307; found: 242.1300
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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Synthesis
Anal. Calcd for C16H18O2 (242.32): C, 79.31; H, 7.49. Found: C, 79.07;
H, 7.46.
(2) (a) Zong, G.; Barber, E.; Aljewari, H.; Zhou, J.; Hu, Z.; Du, Y.; Shi,
W. Q. J. Org. Chem. 2015, 80, 9279. (b) Baran, P. S.; Maimone, T.
J.; Richter, J. M. Nature 2007, 446, 404. (c) Koshimizu, M.;
Nagatomo, M.; Inoue, M. Angew. Chem. Int. Ed. 2016, 55, 2493.
(3) (a) Haines, A. H. Adv. Carbohydr. Chem. Biochem. 1976, 33, 11.
(b) Nahmany, M.; Melman, A. Org. Biomol. Chem. 2004, 2, 1563.
(c) Afagh, N. A.; Yudin, A. K. Angew. Chem. Int. Ed. 2010, 49, 262.
(4) (a) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Syn-
thesis; Wiley: New York, 1999. (b) Araki, S.; Kambe, S.; Kameda,
K.; Hirashita, T. Synthesis 2003, 5, 751.
(5) Tandon, R.; Unzner, T.; Nigst, T. A.; de Rycke, N.; Mayer, P.;
Wendt, B.; David, O. R. P.; Zipse, H. Chem. Eur. J. 2013, 19, 6435.
(6) Ishishara, K.; Nakayama, M.; Ohara, S.; Yamamoto, H. Tetrahe-
dron 2002, 58, 8179.
(7) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989. (b) Kawanami, Y.; Dainobu,
Y.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1981, 54, 943.
Ester 3eg
Prepared following GP B; yield: 0.353 g (0.88 mmol, 55%); colorless
prisms; mp 154–156 °C.
1H NMR (CDCl3, 400 MHz): δ = 8.72 (s, 1 H, ArH), 8.52 (d, J = 9.2 Hz, 1
H, ArH), 8.31 (d, J = 7.6 Hz, 1 H, ArH), 8.25–8.16 (m, 5 H, ArH), 8.01–
7.90 (m, 4 H, ArH), 7.89 (t, J = 6 Hz, 1 H, ArH), 7.61–7.53 (m, 2 H, ArH),
7.27 (d, J = 6.4 Hz, 1 H, OCHCH3), 2.02 (td J = 6.4 Hz, 3 H, CH3).
13C NMR (CDCl3, 101 MHz): δ = 166.25 (s, C=O), 135.67 (s), 135.28 (s),
132.59 (s), 131.42 (s), 131.31 (CH), 131.14 (s), 130.76 (s), 129.49 (CH),
128.37 (CH), 128.30 (CH), 128.17 (CH), 127.87 (CH), 127.79 (s), 127.78
(s) 127.63 (CH), 127.49 (CH), 126.75 (CH), 126.13(CH), 125.51 (CH),
125.45 (CH), 125.34 (CH), 125.19 (CH), 125.04 (s), 124.97 (s), 123.55
(CH), 122.64 (CH), 70.75 (CH), 22.73 (CH3).
HRMS (EI): m/z calcd for C29H22O2: 402.1620; found: [M – C11H7O2]
229.18; [M + H – C18H13] 172.10
(8) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org. Chem.
2004, 69, 1822.
(9) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(10) (a) Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.; Grabowski,
E. J. J. J. Am. Chem. Soc. 1989, 111, 7650. (b) Calter, M. A.; Orr, R.
K.; Song, W. Org. Lett. 2003, 5, 4745.
(11) (a) Bayliss, M. A.; Homer, R. B.; Shepherd, M. J. J. Chem. Soc.,
Chem. Commun. 1990, 305. (b) Ruff, F.; Farkas, Ö. J. Phys. Org.
Chem. 2011, 24, 480.
(12) Lutz, V.; Glatthaar, J.; Würtele, C.; Serafin, M.; Hausmann, H.;
Schreiner, P. R. Chem. Eur. J. 2009, 15, 8548.
(13) Vellalath, S.; Van, K. N.; Romo, D. Tetrahedron Lett. 2015, 56,
3647.
9-Azajulolidine Hydrochloride (TCAP·HCl)
9-Azajulolidine (4; 0.130 g 0.74 mmol) was dissolved in aq 2 M HCl (3
mL). The reaction mixture was stirred for 20 min and then, the sol-
vent was removed under vacuum. The crude product was recrystal-
lized from hexane to give 9-azajulolidine hydrochloride in 96% yield
(0.15 g, 0.71 mmol) as colorless prisms; mp >230 °C.
1H NMR (CDCl3, 400 MHz): δ = 14.74 (br s, 1 H, NH), 7.68 (d, J = 5.2 Hz,
2 H, ArH), 3.43 (t, J = 6.4 Hz, 4 H, NCH2), 2.72 (t, J = 6.4 Hz, 4 H, 2 ×
CH2Ar), 2.00 (q, J = 6.4 Hz, 4 H, NCH2CH).
13C NMR (CDCl3, 101 MHz): δ = 152.21 (s), 135.08 (s), 115.99 (CH),
49.92 (CH2), 24.06 (CH2), 19.56 (CH2).
(14) (a) Patschinski, P.; Zhang, C.; Zipse, H. J. Org. Chem. 2014, 79,
8348. (b) Patschinski, P.; Zipse, H. Org. Lett. 2015, 17, 1010.
(15) (a) Giese, B. Angew. Chem., Int. Ed. Engl. 1977, 16, 125. (b) Eyring,
H. J. Chem. Phys. 1935, 3, 107.
Anal. Calcd for C11H15ClN2 (210.69): C, 62.70; H, 7.18; N, 13.3. Found:
C, 60.68; H, 7.31; N, 12.88.
(16) These results are further confirmed by competition esterifica-
tions of 1b, 1c, and 2f, which gave values identical to those of
1a, 1b, and 2f (see SI).
Funding Information
(17) A complementary explanation is brought up by the 1H NMR
shifts of the methine proton OCHCH3 of the aromatic ethanols
1g, 1h, and 1k. These shift more downfield the larger the aro-
matic system becomes (ca. 4.85 ppm, 5.65 ppm, and 5.9 ppm
under reaction conditions). Since the adjacent molecular envi-
ronment is identical, this might hint at different electronic envi-
ronments that could be caused by deshielding from magnetic
anisotropy effects or inductive effects. This would imply selec-
tivity driven by the reactivity difference in the employed alco-
hols.
(18) Savile, C. K.; Kazlauskas, R. J. J. Am. Chem. Soc. 2005, 127, 12228.
(19) Kim, J. M.; Pincock, J. A. Can. J. Chem. 1995, 73, 885.
(20) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347.
(21) Iwata, T.; Miyake, Y.; Nishibayashi, Y.; Uemura, S. J. Chem. Soc.,
Perkin Trans. 1 2002, 13, 1548.
This work was financially supported by the Deutsche Forschungs-
gemeinschaft (DFG) through the Priority Program ‘Control of London
Dispersion Interactions in Molecular Chemistry’ (SPP 1087). Marta
Marin-Luna thanks the ‘Xunta de Galicia’ for her contract (ED481B
2016/166-0).
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Supporting Information
Supporting information for this article is available online at
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References
(22) De Sarkar, S.; Biswas, A.; Song, C. H.; Studer, A. Synthesis 2011,
1974.
(23) Simeonov, S. P.; Simeonov, A. P.; Todorov, A. R.; Kurteva, V. B.
Am. J. Analyt. Chem. 2010, 1, 1.
(1) (a) Grimme, S.; Huenerbein, R.; Ehrlich, S. ChemPhysChem 2011,
12, 158. (b) Grimme, S.; Schreiner, P. R. Angew. Chem. Int. Ed.
2011, 50, 12639. (c) Rösel, S.; Balestrieri, C.; Schreiner, P. R.
Chem. Sci. 2017, 8, 405.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K