One-Pot Substitution of Aliphatic Alcohols Mediated by Sulfuryl Fluoride

Article abstract of DOI:10.1002/chem.202000721

The Mitsunobu reaction is a powerful transformation for the one-pot activation and substitution of aliphatic alcohols. Significant efforts have focused on modifying the classic conditions to overcome problems associated with purification from phosphine-based byproducts. Herein, we report a phosphine free method for alcohol activation and substitution that is mediated by sulfuryl fluoride. This new method is effective for a wide range of primary alcohols using phthalimide, di-tert-butyl-iminodicarboxylate, and aromatic thiol nucleophiles in 74 % average yield. Activated carbon nucleophiles and a deactivated phenol were also effective for this reaction in good yields. Secondary alcohols were also successful substrates using aryl thiols, affording the corresponding sulfides in 56 % average yield with enantiomeric ratios up to 99:1. This new protocol has a distinct synthetic advantage over many existing phosphine-based methods as the byproducts are readily separable. This feature was exploited in several examples that did not require chromatography for purification. Furthermore, the mild reaction conditions enabled further in situ derivatization for the one-pot conversion of alcohols to amines or sulfones. This method also provides a boarder nucleophile scope compared to existing phosphine-free methods.

Full text of DOI:10.1002/chem.202000721

A Journal of
Accepted Article
Title: One-Pot Substitution of Aliphatic Alcohols Mediated by Sulfuryl
Fluoride
Authors: Jia Yi Mo, Maxim Epifanov, Jack Hodgson, Rudy Dubois, and
Glenn Martin Sammis
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To be cited as: Chem. Eur. J. 10.1002/chem.202000721
Link to VoR: http://dx.doi.org/10.1002/chem.202000721
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10.1002/chem.202000721
Chemistry - A European Journal
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One-Pot Substitution of Aliphatic Alcohols Mediated by Sulfuryl
Fluoride
Jia Yi Mo ƚa, Maxim Epifanovƚa, Jack W. Hodgsona, Rudy Duboisa and Glenn M. Sammis *a
Abstract: The Mitsunobu reaction is a powerful transformation for the
one-pot activation and substitution of aliphatic alcohols. Significant
efforts have focused on modifying the classic conditions to overcome
problems associated with purification from phosphine-based by-
products. Herein, we report a phosphine free method for alcohol
activation and substitution that is mediated by sulfuryl fluoride. This
new method is effective for a wide range of primary alcohols using
phthalimide, di-tert-butyl-iminodicarboxylate, and aromatic thiol
nucleophiles in 74% average yield. Activated carbon nucleophiles and
a deactivated phenol were also effective for this reaction in good
yields. Secondary alcohols were also successful substrates using aryl
thiols, affording the corresponding sulfides in 56% average yield with
enantiomeric ratios up to 99:1. This new protocol has a distinct
synthetic advantage over many existing phosphine-based methods as
the by-products are readily separable. This feature was exploited in
several examples that did not require chromatography for purification.
Furthermore, the mild reaction conditions enabled further in situ
derivatization for the one-pot conversion of alcohols to amines or
sulfones. This method also provides a boarder nucleophile scope
compared to existing phosphine-free methods.
Sulfuryl fluoride (SO2F2) has been used as a commodity
chemical for over 50 years, but it has only recently received
significant attention as a reagent for organic synthesis.8 Despite
the recent surge of interest, there are only a few reports on the
use of SO2F2 to activate aliphatic alcohols.9 The most significant
problem with aliphatic alcohol activation is that the corresponding
fluorosulfate intermediate (Scheme 2, 7) is highly reactive and is
prone to undesired side reactions, such as fluoride substitution
(9),10 elimination (10),9a or substitution with solvent (11).9c This
problem is exemplified in a recent study by Ishii and coworkers on
the nucleophilic substitution of alkyl fluorosulfates.9b While Appel-
type reactions were successful, sulfur- and nitrogen-containing
nucleophiles were largely inefficient due to competing fluoride
displacement.
Since the two seminal publications in 1967,1 the Mitsunobu
reaction has become the preferred one-pot method to activate
alcohols for nucleophilic substitution.2 A major limitation of this
classic reaction, however, is the use of stoichiometric
azodicarboxylates and phosphines, both of which often lead to
difficulties in product purification.3 The most common method to
circumvent this issue has been to use modified variants of these
4
reagents,
A complementary, and relatively unexplored,
approach to Mitsunobu reactions is to utilize non-phosphine
activating agents (Scheme 1). Early investigations focused on
using the Vilsmeier reagent (Scheme 1, A).5 Cyclopropenium
ions, derived from the corresponding cyclopropenones (3), have
also been shown to effectively activate alcohols for mesylate
displacements (Scheme 1, B).6 Finally, Lewis and Brønsted acids
can be used to activate alcohols for intramolecular cyclization to
the corresponding oxa-, aza-, and thiacycles (Scheme 1, C).7
Despite these important advances in phosphine-free methods,
they require multiple steps and elevated temperatures (Scheme
1, A), or lack the nucleophile scope of phosphine-based
Mitsunobu protocols (Scheme 1, B, C). Herein, we report a mild
sulfuryl fluoride-mediated, one-pot substitution reaction that is
effective with nitrogen, sulfur, oxygen and carbon nucleophiles
(Scheme 1, D).
Scheme 1. Phosphine-free approaches to one-pot alcohol substitution
reactions.
We previously demonstrated that the high reactivity of
fluorosulfate 7 (Scheme 2) can be attenuated through the use of
1,1-dihydrofluoroalcohols (1, R = perfluoroalkyl, R’ = H) as the
fluorine substituents decrease the rate of undesired product
formation.11,12 A large excess of the 1,1-dihydrofluoroalcohol was
also required for successful amine and thiol 1,1-
dihydrofluoroalkylation. Both of these solutions are too restrictive
[a]
Jia Yi Mo, Maxim Epifanov, Jack W. Hodgson, Rudy Dubois, Glenn M.
Sammis
Department of Chemistry
University of British Columbia
2036 Main Mall
Vancouver, British Columbia V6T 1Z1, Canada
E-mail: gsammis@chem.ubc.ca
Corresponding author
for
a
general substitution method because using 1,1-
dihydrofluoroalcohols narrows the substrate scope, and the
alcohol typically is the limiting reagent. To date, there have been
no high-yielding sulfuryl fluoride-based methods for aliphatic
alcohol activation and substitution using nitrogen or sulfur
nucleophiles.
*
ƚ
These authors contributed equally to this manuscript
Supporting information for this article is given via a link at the end of the
document.
1
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Table 1. Base optimization of the one-pot phthalimide substitution of aliphatic
alcohols mediated by sulfuryl fluoride.
entry
base
none
nucleophile 1a
12a
0
7
22
76
100
92
71
73
9a
0
0
15
0
0
2
0
1
11a
0
21
48
0
0
2
6
21
1
2
3
4
5
6
7
8
9
PhthNH
PhthNH
PhthNH
PhthNH
PhthNH
PhthNH
PhthNH
PhthN-K+
100
Scheme 2. Possible reaction pathways from alkyl fluorosulfate 7.
DIPEA (4 equiv.)
Et3N (4 equiv.)
TMG (4 equiv.)
DBU (4 equiv.)
DBU (1.9 equiv.)
DBU (1.5 equiv.)
Et3N (4 equiv.)
Et3N (3.7 equiv.)
DBU (0.3 equiv.)
72
15
24
0
4
23
5
We began our investigation into sulfuryl fluoride-mediated
aliphatic alcohol activation and substitution by examining the
reaction between a primary alcohol, 3-phenyl-1-propanol (1a),
and phthalimide (PhthNH, Table 1). No reaction was observed
when SO2F2 was bubbled through a solution of 1a and
phthalimide in the absence of base (entry 1). Using DIPEA as a
base13 resulted in a 1:10 ratio of product 12a to starting material
1a, along with a significant amount of formate 11a (entry 2).
Switching to triethylamine, which was utilized by Ishii and
coworkers,9b resulted in higher conversion to product (12a), along
with an increase in the amount of both fluoride product 9a and 11a
PhthN-K+
0
91
0
9
All reactions were carried out on 0.6 mmol scale of 1a. The ratio of products
was determined by 1H NMR analysis of the crude reaction mixture after 20
minutes.
12g-12i were all synthesized in high isolated yields with only
minimal elimination product detected. The reaction was tolerant
of alkyne (12j, 91% yield) and chloride (12k, 89% yield)
substitution, as well as Cbz-protected amines (12l, 67% yield).
Geraniol (1m) was not effective, largely due to competing SN2’
degradation pathways. More complex substrates tropicamide
(1n) and cortexolone (1o) were also effective substrates for the
reaction, affording 12n and 12o in 54% and 82% isolated yields,
respectively. Secondary alcohols were not as effective (<40%
yields) as they were prone to side reactions, such as elimination
or nucleophilic attack by DMF leading to 10 and 11 (Scheme 2).18
(entry 3).
Tetramethylguanidine (TMG)
and
1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU)
both led to clean
formation of the desired amine alkylated product (12a) in only 20
minutes, with the latter having a slight advantage in reaction rate
(entries 4 and 5). Optimization of the solvent found DMF was
optimal, although the reaction was also successful in ethyl acetate,
acetonitrile, THF, and 1,4-dioxane.14 Decreasing the amount of
DBU to 1.9 and 1.5 equivalents led to a slower reaction rate and
a concomitant increase in the amount of formate (entries 6 and
7).15
DBU may be playing two roles in this reaction; it may be
simply serving as a base or it may be also acting as a catalyst.16
To test whether DBU is solely acting as a base to form a high
concentration of the phthalimide salt in situ, we explored the
reaction of a fully deprotonated phthalimide in the presence of a
weaker, less nucleophilic base. Replacing phthalimide with
potassium phthalimide in the presence of triethylamine led to the
formation of 12a in 73% conversion (entry 8). The increase in
conversion relative to triethylamine alone (entry 3) suggests that
the basicity of DBU is a major factor in this reaction. However,
the lower conversion compared to DBU alone (entry 5) implies
that it may also play another role in the reaction. To further test
this, we explored the reaction of potassium phthalimide,
triethylamine, and a catalytic amount of DBU (entry 9) and
observed an increase in the amount of the desired product (12a)
along with a concomitant decrease in the amount of formate (11a).
The increased yield is consistent with DBU having a dual role in
the reaction mechanism, both in deprotonation of the phthalimide
as well as catalytic activation.17
Table 2. Reaction scope for alcohol activation and substitution with phthalimide.
With the optimized conditions in hand, we then explored the
alcohol scope using phthalimide (Table 2). Increasing the sterics
from 3-phenyl-1-propanol to cyclohexyl derivative 1b led to a
slight drop in the isolated yield of desired product 12b. Benzyl
alcohol was an effective substrate, affording 12c in 69% yield.
Electron poor derivatives 12d and 12e were also synthesized in
76% and 85% yield, respectively, but electron rich derivative 12f
was formed in poor yield, presumably due to the high reactivity of
the fluorosulfate intermediate. We next examined phenethyl
derivatives, which are potentially prone to elimination. Gratifyingly,
Reaction conditions: SO2F2 (4.3 equiv.) was bubbled through a solution of
alcohol (1 equiv.), DBU (3.5 equiv.) and nucleophile (2 equiv.) in DMF at room
temperature for 3 minutes, and then the reaction was stirred for an additional 7
min. All reactions were run on 0.6 mmol scale of alcohol unless otherwise
indicated. Isolated yields are reported. aReaction was run in THF instead of DMF.
bThe isolated yield has been corrected for the elimination by-product. See SI for
details.
2
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We next explored the alcohol scope using sulfur
nucleophiles (Table 3). While the reaction between benzothiazole
thiol and primary alcohol 1a provided a slightly lower yield of 13a
compared to the analogous reaction with phthalimide (Table 2),
increasing the sterics had little effect on the reaction yield (13b).
Benzyl alcohol (1c) and electron poor benzyl alcohol derivatives
were also effective, affording 13c-13e in 86-89% isolated yields.
Unlike the reaction with phthalimide, electron rich derivative 1f
was also a viable substrate, affording thiol adduct 13f in 83%
isolated yield. Substrates that are prone to elimination, such as
1g-1i, were successfully converted to the corresponding sulfides
in 75%, 77%, and 80% yield, respectively. Functionalized
substrates 13j-13o were also synthesized in generally high yields.
Benzothiazole was an effective nucleophile for symmetric
secondary alcohol (13p). Enantiopure alcohols 1q-1s could be
cleanly inverted to sulfides 13q-13s, although a slight degradation
in the enantiomeric ratio was observed in the conversion to the
latter product.
electron rich thiophenols, were not effective as they react
competitively with sulfuryl fluoride.
Table 4. Nucleophile scope for alcohol activation and displacement.
Reaction conditions: SO2F2 (4.3 equiv.) was bubbled through a solution of
alcohol (1 equiv.), DBU (3.5 equiv.) and nucleophile (2 equiv.) in DMF, at room
temperature for 3 minutes, and then the reaction was stirred for an additional 7
min. All reactions were run on 0.6 mmol scale of alcohol unless otherwise
indicated. Isolated yields are reported. aHigher amounts of nucleophile and/or
SO2F2 were used. See SI for details. bReaction was run in THF instead of DMF.
Table 3. Substrate scope for alcohol activation and displacement with
benzothiazole thiol.
The SO2F2-mediated reactions were generally clean and the
only major byproducts were sulfate derivatives. This feature may
enable simplified reaction purification or combining several
processes in a single reaction pot. The former was investigated in
the gram-scale synthesis of 12a (Scheme 3). No column
chromatography was required and 12a was isolated in 61%
yield.22 The latter was first explored in the conversion of alcohol
1a to the corresponding amine in a single reaction pot. This could
be accomplished in high yields either by first converting alcohol
1a to the corresponding phthalimide (12a) followed by in situ
hydrazine deprotection (Scheme 3, A), or by displacement of 1a
with di-tert-butyl-iminodicarboxylate, followed by deprotection
with TFA (Scheme 3, B). A one-pot conversion of alcohol 1a to
the corresponding sulfones (24a or 25a) can similarly be achieved
in high yields through SO2F2-mediated sulfide formation followed
by oxidation.23,24
Reaction conditions: SO2F2 (4.3 equiv.) was bubbled through a solution of
alcohol (1 equiv.), DBU (3.5 equiv.) and nucleophile (2 equiv.) in DMF, at room
temperature for 3 minutes, and then the reaction was stirred for an additional 7
min. All reactions were run on 0.6 mmol scale of alcohol unless otherwise
indicated. Isolated yields are reported. aReaction was strirred for 30 minutes in
THF instead of DMF. bThe isolated yield has been corrected for the N-alkylated
by-product. See SI for details.
We then explored the nucleophile scope using 3-phenyl-1-
propanol (1a). More acidic N-methoxybenzenesulfonamide19 and
di-tert-butyl-iminodicarboxylate19 were effective nucleophiles for
the reaction, providing 14a and 15a in 86% and 64% yield,
respectively. An examination of thiol nucleophiles revealed that
1-phenyltetrazole-5-thiol and electron deficient thiols were
effective for this reaction, providing 16a to 18a in good yields.20
Deactivated phenol also afforded the ether product 19a in 75%
isolated yield. Gratifyingly, carbon nucleophiles could also be
successfully employed in this reaction to form 20a, 21a, and 22a
in good yields.21 Less acidic nucleophiles, such as phenols or
Scheme 3 Gram scale substitution and one-pot conversion of 3-phenyl-1-
propanol (1a) to the corresponding amine (23a) and sulfone (24a or 25a).
Overall, we have demonstrated the first example of an
efficient method for SO2F2-mediated activation and substitution of
aliphatic alcohols. This protocol allows the formation of C-N and
C-S bonds starting from a wide range of alcohols, including the
bioactive molecules tropicamide and cortexolone. In addition,
three carbon nucleophiles and a deactivated phenol were also
3
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and K. Ueda, US Pat. 2011/0251403 A1, Central Glass Company, Ltd.,
2011; (c) W.-Y. Fang, G.-F. Zha and H.-L. Qin, Org. Lett., 2019, 21, 8657-
8661.
effective for this reaction. We have also demonstrated that chiral
secondary sulfides can be accessed in high enantiomeric ratios.
The nucleophile scope complements existing phosphine-free
methods. Notably, all of the reactions are complete in less than
30 minutes and can be run at room temperature under ambient
conditions. These mild reaction conditions facilitate reaction
purification and enable telescoping multiple reactions in a single
pot. Efforts to explore this new methodology in the context of
complex pharmaceuticals are currently underway.
[10] A. Ishii, T. Yamazaki and M. Yasumoto, US Pat. 8,426,645B2, Central
Glass Company, Ltd. 2013.
[11] (a) M. Epifanov, P. J. Foth, F. Gu, C. Barrillon, S. S. Kanani, C. S. Higman,
J. E. Hein and G. M. Sammis, J. Am. Chem. Soc., 2018, 140, 16464–
16468; (b) P. J. Foth, F. Gu, T. G. Bolduc, S. S. Kanani and G. M.
Sammis, Chem. Sci., 2019, 10, 10331-10335.
[12] For a study on the effect of halides alpha to the electrophilic center of
SN2 reactions, see: J. Hine and W. H. Brader Jr, J. Am. Chem. Soc., 1953,
75, 3964–3966.
Acknowledgements
[13] The same base that was successfully employed in amine 1,1-
dihydrofluoroalkylation (ref. 11a).
[14] See the SI for further details on solvent optimization.
[15] See the SI for further details on base optimization.
[16] Sharpless and co-workers proposed that catalytic amount of DBU can
facilitate the nucleophilic attack on the S-F bond in Ar-OSO2F through
the fluoride-proton interaction. See: J. Dong, K. B. Sharpless, L. Kwisnek,
J. S. Oakdale and V. V. Fokin, Angew. Chem., Int. Ed., 2014, 53, 9466–
9470.
This work was supported by the University of British Columbia
(UBC), the Natural Sciences and Engineering Research Council
of Canada (NSERC), the NSERC CREATE Sustainable
Synthesis Program for support for JYM and ME.
Keywords: alkyl fluorosulfate • nucleophilic substitution • sulfuryl
[17] For representative examples of nucleophilic catalysis by DBU, see: (a)
W.-C. Shieh, S. Dell and O. Repič, J. Org. Chem., 2002, 67, 2188–2191;
(b) V. Gembus, F. Marsais and V. Levacher, Synlett., 2008, 1463-1466;
(c) J. E. Taylor, S. D. Bull and J. M. J. Williams, Chem. Soc. Rev., 2012,
41, 2109–2121.
fluoride • amines • alkylation
[1]
[2]
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(b) O. Mitsunobu, M. Yamada and T. Mukaiyama, Bull. Chem. Soc. Jpn.,
1967, 40, 935.
[18] For the reaction of phthalimide with a representative secondary alcohol,
see the SI (page S28).
For representative reviews, see: (a) K. C. Kumara Swamy, N. N. Bhuvan
Kumar, E. Balaraman and K. V. P. Pavan Kumar Chem. Rev., 2009, 109,
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10.1002/ejoc.201901495.
[19] Predicted pKa values from SciFinder: HNPhth pKa = 10.39  0.20,
HNBoc2 pKa = 8.25  0.46, and PhSO2NHOMe pKa = 6.24 0.40.
[20] More nucleophilic thiols can competitively react with sulfuryl fluoride, see
ref. 11b for details.
[21] These products can be desulfonylated using numerous literature
methods. For a representative review, see: D. A. Alonso, C. N. Ájera, in
Organic Reactions (Ed.: John Wiley & Sons, Inc.), John Wiley & Sons,
Inc., Hoboken, NJ, USA, 2009, pp. 367–656.
[3]
[4]
See: S. Dandapani and D. P. Curran, Chem. - Eur. J., 2004, 10, 3130–
3138 and references therein.
[22] Purification was achieved using a simple diethyl ether extraction followed
by a hexane wash.
(a) For a representative review, see: R. Dembinski, Eur. J. Org. Chem.,
2004, 2004, 2763–2772; (b) For a recent example of organocatalytic
Mitsunobu using a P(V) reagent, see: R. H. Beddoe, K. G. Andrews, V.
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Shanahan, H. F. Sneddon and R. M. Denton, Science, 2019, 365, 910–
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diphenylphosphoryl azide, see: A. S. Thompson, G. R. Humphrey, A. M.
DeMarco, D. J. Mathre, E. J. J. Grabowski, J. Org. Chem., 1993, 58,
5886–5888.
[23] Both sulfones are commonly used as precursors for Julia olefination: (a)
J. B. Baudin, G. Hareau, S. A. Julia and O. Ruel, Tetrahedron Lett., 1991,
32, 1175–1178; (b) P. R. Blakemore, W. J. Cole, P. J. Kocienski and A.
Morley, Synlett., 1998, 26–28.
[24] 25a can also be efficiently converted to alkyl sulfones and sulfonamides,
see: J. J. Day, D. L. Neill, S. Xu and M. Xian Org. Lett., 2017, 19, 3819–
3822.
[5]
For representative examples, see: (a) A. G. M. Barrett, D. C. Braddock,
R. A. James, N. Koike and P. A. Procopiou, J. Org. Chem., 1998, 63,
6273–6280; (b) Y. Kawano, N. Kaneko and T. Mukaiyama Chem. Lett.,
2005, 34, 1612–1613. For the use of catalytic Vilsmeier reagent, see: (c)
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AbuSalim, M. Pink, M.-H. Baik and S. P. Cook, Angew. Chem., Int. Ed.,
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[6]
[7]
[8]
For representative examples, see: (a) J. Dong, L. Krasnova, M. G. Finn
and K. B. Sharpless, Angew. Chem., Int. Ed., 2014, 53, 9430–9448; (b)
P. S. Hanley, M. S. Ober, A. L. Krasovskiy, G. T. Whiteker and W. J.
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Am. Chem. Soc., 2018, 140, 17666–17673; (b) A. Ishii, M. Yasumoto
4
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Entry for the Table of Contents
A method for alcohol activation and substitution that is mediated by sulfuryl fluoride (SO2F2) is described. This new process
is effective for a wide range of primary alcohols using N, S, O, and C nucleophiles. This new protocol has a distinct
synthetic advantage over many existing phosphine-based methods as the by-products are readily separable, which was
exploited in several examples that did not require chromatography for purification.
5
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