Systematic Evaluation of Sulfoxides as Catalysts in Nucleophilic Substitutions of Alcohols

Article abstract of DOI:10.1002/ejoc.201800907

Herein, a method for the nucleophilic substitution (S_N) of benzyl alcohols yielding chloro alkanes is introduced that relies on aromatic sulfoxides as Lewis base catalysts (down to 1.5 mol-%) and benzoyl chloride (BzCl) as reagent. A systematic screening of various sulfoxides and other sulfinyl containing Lewis bases afforded (2-methoxyphenyl)methyl sulfoxide as optimal catalyst. In contrast to reported formamide catalysts, sulfoxides also enable the application of plain acetyl chloride (AcCl) as reagent. In addition, it was demonstrated that weakly electrophilic carboxylic acid chlorides like BzCl promote Pummerer rearrangement of sulfoxides already at room temperature. This side-reaction also provided the explanation, why sulfoxide catalyzed S_N-reactions of alcohols do not allow the effective production of aliphatic and electron deficient chloro alkanes. Comparison experiments provided further insight into the reaction mechanism.

Full text of DOI:10.1002/ejoc.201800907

A Journal of
Accepted Article
Title: Systematic Evaluation of Sulfoxides as Catalysts in Nucleophilic
Substitutions of Alcohols
Authors: Peter Huy, Sebastian Motsch, and Christian Schütz
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800907
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10.1002/ejoc.201800907
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Systematic Evaluation of Sulfoxides as Catalysts in Nucleophilic
Substitutions of Alcohols
Sebastian Motsch,[a] Christian Schütz,[a] and Peter H. Huy*[a]
Abstract: Herein, a method for the nucleophilic substitution (SN) of
benzyl alcohols yielding chloro alkanes is introduced that relies on
aromatic sulfoxides as Lewis base catalysts (down to 1.5 mol%) and
benzoyl chloride (BzCl) as reagent. A systematic screening of various
sulfoxides and other sulfinyl containing Lewis bases afforded
methyl(2-methoxyphenyl)sulfoxide as optimal catalyst. In contrast to
reported formamide catalysts, sulfoxides also enable the application
of plain acetyl chloride (AcCl) as reagent. In addition, it was
demonstrated that weakly electrophilic carboxylic acid chlorides like
BzCl promote Pummerer rearrangement of sulfoxides already at room
temperature. This side-reaction also provided the explanation, why
sulfoxide catalyzed SN-reactions of alcohols do not allow the effective
production of aliphatic and electron deficient chloro alkanes.
Comparison experiments provided further insight into the reaction
mechanism.
DMSO procedures are either limited to primary and tertiary[11b] or
certain benzylic alcohols.[11c] Additionally, in the contribution
utilizing TCT only two examples were performed in the presence
of catalytic amounts of DMSO (20 mol%), whereas the majority of
the products was synthesized under application of DMSO as the
solvent.[11c]
Indeed, the major challenge in Lewis base catalyzed SN-
methods is the minimization of condensation of the nucleophilic
starting material 1 with the electrophilic reagent, which gives rise
of oxalate and benzoate esters of type 4 (see Scheme 1). The
formation of these undesired side-products has been reduced by
(1) comparably high catalyst loadings (typically 10-20 mol%) and
(2) either the slow addition of the reagent to a diluted solution of
the substrate[9] or (3) the utilization of less electrophilic benzoyl
chloride (BzCl) or TCT in substoichiometric amounts instead of
highly reactive oxalyl chloride.[10] The weakly electrophilic nature
of these bulk chemicals enables an improved chemoselectivity in
favor for substitution product 2 (over side-product 4).
Introduction
Sulfoxides account to the most versatile functional groups in
chemistry and have consequently been exploited as directing
groups, metal ligands, chiral auxiliaries and leaving groups in
glycosylations, for instance.[1-3] Moreover, sulfinyl groups (S=O)
can be found as key structural motif in many natural products and
pharmaceuticals and therefore continue to inspire chemists to
develop efficient strategies towards their synthesis.[4] Against this
background, it is surprising that sulfoxides have rarely been
employed as catalyst in nucleophilic substitutions (SN), which
belong to the most fundamental and widely-used chemical
transformations.[5-8] In particular bimolecular nucleophilic
substitutions (SN2) are of paramount importance, as they enable
the stereoselective construction of C-Cl, C-O, C-N and C-C bonds,
for example.
So far, mainly phosphine oxides, cyclopropenone
derivatives, tropone and formamides (by our group) have been
applied as Lewis base catalysts 3 for the SN-type conversion of
[11a]
alcohols 1 to chloro alkanes 2 (Scheme 1).[9,10] Earlier, SeO2
and dimethylsulfoxide (DMSO)[11b,c] have been also engaged as
catalytic species, whereby either trimethylchlorosilane (TMSCl) or
trichlorotriazine (TCT) were used as reagent.[12] In the case of
[a]
S. Motsch[b], C. Schütz, Dr. P. H. Huy,
Saarland University
Institute of Organic Chemistry
P. O. Box 151150, D-66041 Saarbrücken
E-mail: peter.huy@uni-saarland.de
Homepage: peterhuylab.de
present address
Stuttgart University
Institute of Organic Chemistry
Pfaffenwaldring 55, D-70569 Stuttgart
Scheme 1. Catalytic nucleophilic substitutions of alcohols. PMP = para-
methoxyphenyl.
[b]
In light of (1) the strong Lewis basicity of sulfoxides in general and
(2) the manifold opportunities to tune their electron and steric
properties by the adjacent substitutions, we were intrigued to
explore sulfinyl group based catalysts in SN-reactions. From a
systematic and extensive structure activity relationship study,
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800907
European Journal of Organic Chemistry
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sulfoxide 31 arose as optimal catalyst for the transformation of
benzylic alcohols 1 into alkyl chlorides of type 2 (Scheme 1).
As the initial experiments uncovered alkyl aryl substituted
sulfoxides as potent catalyst, subsequently various alkyl phenyl
sulfoxides were probed (Scheme 3 A). While the application of
ethylphenylsulfoxide 39 already resulted in a depleted selectivity,
a vinyl substituted analog and two sulfoxides containing electron-
withdrawing substituents showed basically no catalytic activity.
Exchange of the phenyl group of methylphenylsulfoxide (32)
through a more electron rich indole moiety caused significantly
declined ratios of 21 to 41, which could be rationalized by catalyst
degradation (Scheme 3 B).
Results and Discussion
At the outset, a broad variety of sulfinyl group containing Lewis
bases were tested on their ability to catalyze the reaction of
benzylic alcohol 11 as a simplified model substrate with the
reagent BzCl to chloro alkane 21 (Scheme 2). In the current study,
the catalytic activity is reflected by the ratio of the desired
substitution product 21 in respect to benzoate 41, which is
obtained as major product in the absence of a catalyst (ratio 21/41
19:81). For the purpose of a clearer visualization of the
selectivites, catalyst structures and ratios 21/41 are displayed in
either green, orange or red colour in alignment to a traffic light.
The best chemoselectivity in Scheme 2 was attained with
methylphenylsulfoxide (32). Both, DMSO and diphenylsulfoxide
(33) delivered mixtures of product 21 and 41 in poorer ratios
(Scheme 2 A).
Scheme 2. Screening of various sulfinyl group containing Lewis bases. Yields
and ratios were determined by means of the 1H-NMR of the crude material with
internal standard. [a] Conducted in MeCN.
Scheme 3. Catalyst optimisation. Yields and ratios were determined by means
of the 1H-NMR of the crude material with internal standard. Ar = 4-tBuPh.
Surprisingly, the more polar selenoxide 34 did not show any
catalytic activity at all. Similar results were observed, when the
sulfurous acid derived amide 35 and esters 37 and 38 and sulfinic
acid amide 36, respectively, were utilized as Lewis bases
(Scheme 1 B, for more details see Table S2 in the Supporting
Information = SI). However, in the presence of stoichiometric
amounts of sulfinyl compound 35 benzylic halogenide 35 was
generated in an excellent selectivity (21/41 ≥98:2). This
observation might be explained by decomposition of this Lewis
base. In the following, a solvent screening applying methyl-
phenylsulfoxide as catalyst revealed MeCN as optimal (see Table
S8, SI). Therefore, MeCN was utilized as solvent instead of
CH2Cl2 for the further catalyst refinement.
For the following test reactions, the catalyst loading was
decreased from 10 to 5 mol% in order to more clearly identify the
optimal structure. After having secured that the optimal sulfinyl
based catalyst must contain a methyl and a phenyl group,
substituents were introduced on the phenyl backbone. Although
the mesityl group bearing sulfoxide 314 gave rise of an identical
selectivity compared to methylphenylsulfoxide, the higher steric
demand caused a lower conversion of substrate 11, which is also
reflected by a lower yield (Scheme 3 C). In order not to increase
the steric shielding of the Lewis basic O-atom, we introduced
various substituents in the para-position of the phenyl skeleton
(Scheme 3 D). Neither an electron withdrawing Cl-atom nor
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10.1002/ejoc.201800907
European Journal of Organic Chemistry
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electron donating Me- and MeO-moieties allowed an
improvement of the catalytic activity. This also accounted for
substituents in the ortho-position (see Table S4 to S7, SI) with one
single exception.
Table 1. Method development.
Indeed, the best selectivity in favor of chloride 21 was
achieved utilizing (2-methoxyphenyl)methylsulfoxide (31).
Unexpectedly, sulfoxides carrying two methoxy groups in 2,4-,
2,6- and 3,5-position turned out to be rather poor catalysts
(Scheme 3 E). Apparently, the chemoselectivity 21/41 is especially
influenced by the electron density in the aryl portion. The
deteriorated Lewis basicity of arylmethyl-sulfoxides bearing
electron poor aryl residues should reason the diminished ratios
21/41 in comparison to methylphenyl-sulfoxide (32) as expected
(e.g., 315). Although sulfinyl compounds containing electron-rich
aryl moieties such as 317, 318, 319 and 320 are unquestionable
stronger Lewis bases than 32, they are less feasible as catalysts
for the transformation of alcohol 11 into alkyl chloride 21. Also in
this instances, a low stability of the catalysts under the reaction
conditions could provide a rationalization of the observed
outcome. In the case of optimal sulfoxide 31, however, the steric
repulsion between the ortho-methoxy group and the sulfinyl
moiety should effect a rotation of the S=O bond out of the
orthogonal orientation in respect to the ring plan of the aryl group.
Therefore, the conjugation between this adjacent groups is
diminished in comparison to the para-methoxy substituted
phenylsulfoxide 317, which causes a lower Lewis basicity. As final
conclusion, sulfur catalyst 31 seems to be the best compromise
between Lewis base strength and chemical stability. Indeed,
utilization of sulfoxide catalyst 31 (5 mol%) allowed to isolate
benzylic chloride 21 in 86% yield (Table 1, entry 1).
Pleasingly, a high substrate concentration of 2 M was
identified as optimal, which is a result of the utilization of weakly
electro-philic BzCl (Table S9, SI). In the aforementioned
experiment slightly deteriorated selectivities 21/41 were observed
in comparison to the test reaction on a smaller scale (compare
entries 1+2). Neither, a slow addition of BzCl by means of a
syringe pump nor cooling of the reaction mixture to 0 °C during
the reagent addition could improve the selectivity. A similar impact
of the reaction scale on the ratio 2/4 was also obtained with other
substrates. Nevertheless, an upscaling to gram quantities did not
alter the ratio 21/41 further (see Scheme 4), which verifies a
reasonable scalability of the current method. Moreover, the
catalyst loading could be reduced to 2.5 mol% 31 (entry 3), which
accords to a reasonable turn over number (TON) of 30 under
consideration of 79% isolated yield. Worthy of note, the catalyst
31 could also be prepared in situ from meta-chloroperoxybenzoic
acid (MCPBA) and commercial (2-methoxyphenyl)methylsulfide
(entry 4), whereas N-chloro-succinimide proved to be a less
adequate oxidant. Furthermore, MeCN could not be replaced by
a more environment-friendly solvent (entry 5, see also Table S8
in the SI). The superior catalytic activity of sulfoxide 31 was
highlighted through comparison experiments with 2.5 mol% of N-
formyl pyrrolidine (FPyr)[10a] and DMSO, respectively, which
provided substitution product 21 in moderate yields of 33-66%
(entries 6+7).
entry
changes from standard conditions[a]
ratio
21:41
yield
21 [%]
[b]
1
2
3
4
/
94:6
97:3
86[c]
93[d]
79[c]
82[c]
/
2.5 instead of 5 mol% 31
89:11
91:9
Ar´SMe (7 mol%)
+
MCPBA (5 mol%)
instead of 31
5
6
EtOAc, MTBE or acetone instead of MeCN
≤94:6
≤46[d]
FPyr (2.5 mol%) in dioxane instead of 31 in
MeCN
87:13
66[d]
7
8
DMSO (2.5 mol%) instead of 31
no 31
62:38
15:85
33[d]
4[d]
[a] Standard conditions: BzCl (1.2 equiv), 31 (5 mol%), MeCN (2 M), 13 h rt.
[b] Determined from 1H-NMR of the crude material. [c] Isolated yield. [d] Yield
determined by internal NMR-standard. Ar = 4-tBuPh, Ar´= 2-MeOPh.
After the establishment of the optimized reaction conditions, we
set out to explore the substrate scope of the current protocol
(Scheme 4). While model substrate 11 was produced on a gram
scale with 5 mol% of catalyst 31, the electron rich benzylic
chlorides 22 and 23 were synthesized in good yields employing
just 1.5-2 mol% 31 (TON up to 50). However, in the case of
electron poor benzylic alcohols the sulfoxide quantity had to be
increased (examples 24 to 26). Albeit 4-(methoxycarbonyl)benzyl
chloride (25) was isolated in a reasonable yield of 81%, even in
the presence of 15 mol% 31 no full conversion was achieved
within 24 h of reaction time. 4-Nitrobenzyl chloride (26) on the
other hand could not be accessed in a useful yield anymore.
Example 27 demonstrated that acid sensitive functional
groups such as silylethers are tolerated under the optimized
reaction conditions, which is explained by the formation of weakly
acidic benzoic acid as by-product instead of hydrogenchloride. In
the instance of phenylethyl chloride 29 CH2Cl2 had to be employed
as solvent, because reaction in MeCN afforded significant
amounts of Ritter type acetamide 79 as side product.
Transformation of enantioenriched R-phenyl ethanol 19 (96% ee)
furnished S-phenylethyl chloride 29 under overall inversion in a
diminished ee of 52%, which is a selectivity comparable to
chlorinations with conventional reagents such as SOCl2.[5,10a] In
addition, the allylic chlorides 211 and 212 could be prepared in
moderate yields. In the case of geraniol 112 a 91:9 mixture of
regioisomeric linear and branched allylic chlorides was obtained,
which is a better result than common reagents like SOCl2 allow
for.[10a] Finally we must note that aliphatic alcohols and -
hydroxyesters are non-suitable substrates. Even under variation
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10.1002/ejoc.201800907
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of the reaction temperature, 1-dodecyl chloride 213 was generated
in yields ≤23%, whereas in the case of methyl mandelate 114 no
chlorinated product 214 could be detected. Worthy of note, in the
absence of a feasible catalyst the majority of the alkyl chlorides 2
presented in Scheme 4 were formed in yields ≤25%, which
highlights the crucial role of sulfoxides 31 and 32 (see Scheme S3,
SI).
Scheme 5. A Pummerer rearrangement as side reaction and B chlorination with
acetyl chloride (Ar = 4-tBuPh).
In contrast to FPyr,[10a] sulfoxide catalyst 32 also enabled the
utilization of plain acetyl chloride (AcCl) as reagent (Scheme 5
B).[15] The higher reactivity of AcCl in comparison to BzCl
requested deviations from the optimized reaction conditions such
as a lower substrate 1 concentration (see Table S10 + S11, SI).
Recently we established a cyclopropenone catalyzed
protocol for the dehydroxybromination and -iodination of alcohols
using BzCl and sodium bromide and iodide, respectively, as
halogen source.[14] However, the application of sulfoxides of type
3 instead of cyclopropenone derivatives under elsewise identical
conditions allowed the synthesis of alkyl bromides and iodides
only in moderate yields (see Table S12, SI).). For instance, 4-tert-
butylbenzyl bromide (111) was formed in the presence sulfoxide
31 in a moderate yield of 56% beside benzoate 41 (32%), while in
the absence of a catalytic species 111 was already obtained in
41% yield.
In alignment to the contribution of Li´s[11c] and our work[10]
a
tentative mechanism is proposed in Scheme 6. Initially, the
sulfoxide is anticipated to be acylated by either BzCl or AcCl to
give sulfonium intermediate I, in which the sulfinyl O atom is
activated as a decent leaving group. Nucleophilic substitution of
the carboxy moiety by the alcohol 1 then most probably delivers
intermediate II, in which the hydroxyl group is converted to a good
nucleofuge.[15]
Scheme 4. Substrate scope and limitations. Yields refer to isolated material if
not otherwise mentioned. [a] ee determined by chiral GC. [b] Prepared from the
corresponding R-configured alcohol in 96%ee. [c] Yield determined by internal
NMR-standard.
Indeed, exposure of sulfoxides 31 and 32 towards BzCl delivered
-chlorosulfides of type 6 through a Pummerer rearrangement
(Scheme 5 A).[13] Thus in the case of less reactive alcohols (e.g.,
16, 113 and 114) catalysts of type 3 are consumed by this side-
reaction before the starting material is fully converted. In fact,
chlorosulfides of type 6 were found in all 1H-NMR spectra of crude
chlorides 2. This also explains a similar limitation of the substrate
scope in related chlorinations utilizing DMSO.[11c] Since chloride
products of type 2 were occasionally challenging to separate from
sulfide 61 by means of chromatography, in some examples in
Scheme 4 methylphenylsulfoxide (31) was engaged. Interestingly,
utilization of diphenylsulfoxide (33), which cannot undergo
Pummerer reaction, allowed to increase the yield in the case of
aliphatic chloride 213 and chloroester 214 to 53% and 31%,
respectively (Scheme 4). Other sulfinyl compounds that are
incapable of or less prone to Pummerer rearrangement were ruled
out earlier due to inactivity (Scheme 2 B and Scheme 3 A).
Scheme 6. Proposed mechanism.
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10.1002/ejoc.201800907
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Eventually, the catalyst residue is replaced by the chloride
counterion to deliver alkyl chloride 2. If the plausible intermediate
I is redrawn as illustrated in Scheme 6, the opportunity of an
intermolecular syn-elimination becomes evident. The resulting
sulfenium ion III should undergo an electrophilic addition to the
chloride counterion to furnish -chlorosulfide 6, which
corresponds to a Pummerer reaction. Finally, a couple of
comparison experiments allowed for a further insight into the
reaction mechanism. Brønsted acid cocatalysis can be ruled out,
since the addition of an excess of 2,6-bis-tert-butylpyridine had no
significant influence on our model reaction (Scheme 7 A). A
competition experiment between a primary benzylic and aliphatic
alcohol in the presence of catalyst 31 favored generation of
benzylic chloride 21, albeit the yield of 21 was lower than in the
absence of substrate 113 (Scheme 7 B). Interestingly, the same
experiment with FPyr instead of sulfoxide 31 provided substitution
product 21 in only 10% yield instead of 62% (Scheme 7 C).
gave dodecyl formate 713 after aqueous work up (Scheme 8 C).
Ester 713 is most likely obtained from iminium intermediate IV13a
(see Scheme 8 C) through hydrolysis. Hence, the catalytic cycle
seems to be interrupted at room temperature at the stage of
intermediate IV13b. The comparably high stability of iminium
intermediates of type IV derived from aliphatic alcohols at ambient
temperature was already proven in our previous work (Scheme 8
D).[7a] Sulfonium intermediates of type II could not be identified by
the same approach, which supports the assumption of a
reversible generation of II.
Scheme 8. Comparison experiments II. Ar = 4-tBuPh.
Conclusions
In summary, nucleophilic substitutions of benzylic alcohols to
furnish chloro alkanes with BzCl and AcCl, respectively, that are
catalyzed by aromatic sulfoxides have been developed. The high
Lewis basicity facilitates catalyst loadings below 2 mol% and
consequently TONs of up to 50 in the case of selected examples.
A systematic screening of manifold sulfoxides and sulfinyl group
containing compounds allowed to establish a thorough structure
activity relationship. As conclusions the optimal catalyst contains
(1) a small methyl group and (2) an aromatic substituent, which is
neither electron rich nor electron poor. These criteria were best
met by (2-methoxyphenyl)methyl-sulfoxide (31). Alongside it was
demonstrated that weak acid chlorides such as BzCl also allow
Pummerer rearrangement of sulfoxides. This observation
rationalizes, why less reactive aliphatic and electron poor alcohols
are less feasible for the present protocol.
Scheme 7. Comparison experiments I. Ar = 4-tBuPh.
The difference between the catalysts 31 and FPyr could be
reasoned by a reversible formation of sulfonium intermediate II.
Thus intermediate II13 derived from aliphatic substrate 113 would
redeliver sulfoxide 31 or intermediate I, which could both react with
benzylic starting material 11. In the case of formamide FPyr the
related intermediate IV seems to be generated irreversibly (see
Scheme 8 C + D).
Moreover, reaction of benzylic model substrate 11 and
methylphenylsulfoxide in equimolar amounts with BzCl gave rise
of substitution product 21, while -chlorosulfide 62 was not
obtained (Scheme 8 A).In a similar comparison experiment, in
which dodecanol (113) was utilized instead of benzylic alcohol 11,
mainly chlorosulfide 62 was generated (Scheme 8 B). The latter
test unveils that even an excess of sulfoxide catalyst does not
facilitate the preparation of aliphatic chlorides. Interestingly,
reaction of dodecanol with stoichiometric amounts of FPyr mainly
Experimental Section
Experimental procedures for the synthesis of alkyl chlorides and new
sulfoxides, analytical data, copy of 1H- and 13C-NMR-data and further
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10.1002/ejoc.201800907
European Journal of Organic Chemistry
FULL PAPER
background information can be found in the Supporting Information. The
following procedure may serve as representative example.
Han, V. A. Soloshonok, K. D. Klika, J. Drabowicz, A. Wzorek, Chem. Soc.
Rev. 2018, 47, 1307-1350; see also ref. [3].
[5]
[6]
a) R. C. Larock in Comprehensive Organic Transformations, Wiley-VCH,
New York, 1999, pp. 689-702; b) P. Margaretha in Science of Synthesis,
vol. 35 (Ed. E. Schaumann), Georg Thieme, Stuttgart, 2007, pp. 1-188;
c) M. B. Smith in March’s Advanced Organic Chemistry, 7th ed.; Wiley:
New Jersey, 2013, pp. 500-503; d) J. An; R. M. Denton, T. H. Lambert
and E. D. Nacsa, Org. Biomol. Chem. 2014, 12, 2993–3003; e) P. H. Huy,
T. Hauch, I. Filbrich, Synlett 2016, 27, 2631-2636.
Gram scale synthesis of 4-tert-butylbenzyl chloride (21)
At room temperature a solution of (2-methoxyphenyl)methylsulfoxide (31,
84.1 mg, 0.50 mmol, 5 mol%) and 4-tert-butylbenzyl alcohol (11, 1.66 g,
10.0 mmol, 1.0 equiv) in MeCN (5 mL, 2 M) was treated with BzCl
(1.41 mL, 12.0 mmol, 1.2 equiv) over 15 min by means of a syringe pump.
Afterwards the reaction solution was allowed to stir until TLC control
revealed full conversion of 11 after 12.5 h. In order to quench the remaining
excess of BzCl, 2-ethanolamine (370 L, 6.0 mmol, 0.6 equiv) was added
dropwise under vigorous stirring at ambient temperature and the resulting
suspension was allowed to stir for further 30 min. Then the mixture was
diluted with Et2O (20 mL) and 1 N NaOH solution (aq., 10 mL), the organic
phase was washed with 1 N NaOH solution (aq., 10 mL) and brine (10 mL),
dried over MgSO4 and concentrated under reduced pressure. Finally, the
crude material (1.984 g, 109%) was subjected to column chromatographic
purification on silica gel (17.3 g) with Et2O/nPen 1:99. After drying at
20 mbar at the rotatory evaporator the title compound was obtained as
colourless oil in 86% yield (1.565 g, 8.57 mmol).
For reviews on phosphane promoted nucleophilic substitutions of
alcohols see (Appel and Mitsunobu reaction): a) R. Appel, Angew. Chem.
Int. Ed. 1975, 14, 801-811; Angew. Chem. 1975, 87, 863-874; b) B. R.
Castro in Organic Reactions, vol. 29 (Ed. W. G. Dauben), Wiley, New
York, 1983, pp. 1–162; c) D. L. Hughes in Organic Reactions, vol. 42 (Ed.
L. A. Paquette), Wiley, New York, 1992, pp. 335–656; d) K. C. K. Swamy,
N. N. B. Kumar, E. Balaraman, K. V. P. P. Kumar, Chem. Rev. 2009, 109,
2551–2651; e) T. Y. S. But, P. H. Toy, Chem. Asian J. 2007, 2, 1340-
1355.
[7]
[8]
[9]
For catalytic variants of the Mitsunobu reaction see: a) T. Y. S. B. But, P.
H. Toy, J. Am. Chem. Soc. 2006, 128, 9636-9637; b) C. J. O’Brien, WO
Patent 2010/118042 A2 (2010); c) D. Hirose, T. Taniguchi, H. Ishibashi,
Angew. Chem. Int. Ed. 2013, 52, 4613–4617; Angew. Chem. 2013, 125,
4711-4715; d) J. A. Buonomo, C. C. Aldrich, Angew. Chem. Int. Ed. 2015,
54, 13041–13044; Angew. Chem. 2015, 127, 13233-13236; e) D. Hirose,
M. Gazvoda, J. Kosmrlj, T. Taniguchi, Chem. Sci. 2016, 7, 5148-5159;
f) D. Hirose, M. Gazvoda, J. Kosmrlj, T. Taniguchi, Org. Lett. 2016, 18,
4036−4039.
Acknowledgements
We want to thank the Deutsche Forschungsgemeinschaft and the
Fonds of the Chemical Industry (Liebig fellowship) for generous
support.
For an originally nucleophilic substitution protoctol for alcohols related to
the Appel reaction, which employs 1,2-dihaloethanes instead of CCl4
see: a) J. Chen, J.-H. Lin, J.-C. Xiao, Org. Lett. 2018, 20, 3061−3064; b)
J. Chen, J.-H. Lin, J.-C. Xiao, Chem. Commun. 2018, 54, 7034-7037. In
reference a) P(OEt)3 has been used as substitute for PPh3 to improve
the separation of the oxidized P(V) by-product (OP(OEt)3 instead of
OPPh3). For the same reason P(OEt)3 has been applied earlier as a PPh3
substitute in an Appel type cyclodehydation: c) P. H. Huy, A. M. P.
Koskinen, Org. Lett. 2013, 15, 5178-5181.
Keywords: nucleophilic substitutions • homogenous catalysis •
sulfoxides • organocatalysis • halogenation
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10.1002/ejoc.201800907
European Journal of Organic Chemistry
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suggests the opportunity to develop an asymmetric protocol. However,
attempted kinetic resolution of 1-phenylethanol (19) applying
enantioenriched methylphenylsulfoxide furnished chloride 29 as
racemate. In addition, chiral HPLC uncovered complete racemisation of
the catalyst, which can be explained by the proposed mechanism.
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10.1002/ejoc.201800907
European Journal of Organic Chemistry
FULL PAPER
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Organocatalysis, Sulfoxides*
S. Motsch, C. Schütz, P. H. Huy*[*
Page No. – Page No.
Systematic Evaluation of Sulfoxides
as Catalysts in Nucleophilic
Substitutions of Alcohols
Out of a in-depth study of a range of sulfinyl compounds in the transformation of
alcohols into chloro alkanes emerged (2-methoxyphenyl)methylsulfoxide as optimal
Lewis base catalyst. While this catalyst allowed the synthesis of benzylic chlorides
in turn-over numbers up to 50, aliphatic alcohols are non-suitable substrates due to
competing Pummerer rearrangement .
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