One-Pot 1,1-Dihydrofluoroalkylation of Amines Using Sulfuryl Fluoride

Article abstract of DOI:10.1021/jacs.8b11309

Sulfuryl fluoride, SO₂F₂, has been known and used as a fumigant for over 50 years but it has only recently gained widespread interest as a reagent for organic synthesis. Herein we report a novel application of sulfuryl fluoride gas in a new 1,1-dihydrofluoroalkylation reaction, which simply involves bubbling SO₂F₂ through a solution of amine, 1,1-dihydrofluoroalcohol, and diisopropylethylamine. The reaction is successful for a wide range of primary and secondary amines, as well as several 1,1-dihydrofluoroalcohols, to afford the 1,1-dihydrofluoroalkylated amines in 42% to 80% isolated yields. The reaction also displays excellent functional group tolerance. The ease of the one-pot activation and alkylation, combined with the wide substrate scope make this new procedure an attractive alternative to existing 1,1-dihydrofluoroalkylation methodologies.

Full text of DOI:10.1021/jacs.8b11309

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Communication
One-Pot 1,1-Dihydrofluoroalkylation of Amines using Sulfuryl Fluoride
Maxim Epifanov, Paul J. Foth, Frances Gu, Charlotte Barrillon, Sahil
S. Kanani, Carolyn S. Higman, Jason E Hein, and Glenn M. Sammis
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 15 Nov 2018
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One-Pot 1,1-Dihydrofluoroalkylation of Amines using
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Maxim Epifanov, Paul J. Foth, Frances Gu, Charlotte Barrillon, Sahil S. Kanani, Carolyn S. Higman,
Jason E. Hein, and Glenn M. Sammis*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
Supporting Information Placeholder
one pot trifluoroethylation methodology that uses trifluoroa-
cetic acid under reducing conditions.9 We envisioned that we
may be able to achieve a one-pot 1,1-dihydrofluoroalkylation
by using SO2F2 and the appropriate alcohol. Procedurally, this
new approach would be more convenient than existing meth-
ods as the alkylations could be performed simply by bubbling
sulfuryl fluoride through a mixture of an alcohol and a nucle-
ophile in a one-pot process.
ABSTRACT: Sulfuryl fluoride, SO2F2, has been known and
used as a fumigant for over 50 years but it has only recently
gained widespread interest as a reagent for organic synthesis.
Herein we report a novel application of sulfuryl fluoride gas in
a new 1,1-dihydrofluoroalkylation reaction, which simply
involves bubbling SO2F2 through a solution of amine, 1,1-
dihydrofluoroalcohol, and diisopropylethylamine. The reac-
tion is successful for a wide range of primary and secondary
amines, as well as several 1,1-dihydrofluoroalcohols, to afford
the 1,1-dihydrofluoroalkylated amines in 42% to 80% isolated
yields. The reaction also displays excellent functional group
tolerance. The ease of the one-pot activation and alkylation,
combined with the wide substrate scope make this new pro-
cedure an attractive alternative to existing 1,1-
dihydrofluoroalkylation methodologies.
Scheme 1. Proposed one-pot alkylation strategy using
SO2F2.
A one-pot activation and substitution presents many interest-
ing selectivity and reactivity challenges (Figure 1). For the
first step, there will be a competition between the reaction of
SO2F2 and 1,1-dihydrofluoroalcohol 1 and the undesired cap-
ture of SO2F2 by the amine (2). Even if 3 could preferentially
be formed, the displacement with amine 2 to afford 4 has no
direct literature precedence.10 All previous reports involving
treatment of alcohol with SO2F2 indicate the formation of alkyl
fluoride 56 or 611 as the major products. Further complicating
matters, treatment of amines with trifluoroethyl fluorosulfate
(3a, R = F), generated through a different method, exclusively
form trifluoroethyl sulfamate (7, R = F),11 To tackle these for-
midable selectivity challenges, we opted to investigate this
reaction using a combination of standard synthetic optimiza-
tion coupled with process analytical technology (PAT),12 to
provide real-time in-situ kinetic data.
Sulfuryl fluoride (SO2F2) is a commodity chemical manufac-
tured by Dow, and has been widely used as a fumigant for
over 50 years.1 Sharpless and coworkers have recently
sparked interest in this reagent in the context of organic
chemistry with the development of Sulfur-Fluoride Exchange
(SuFEx) chemistry,2 in which sulfuryl fluoride rapidly reacts
with an aryl alcohol to form the corresponding aryl fluorosul-
fate. These fluorosulfates are relatively stable and can be used
as intermediates in click reactions with O-silylated phenols,3
as triflate surrogates for transition metal-catalyzed cou-
plings,2,4 or as activating agents in nucleophilic deoxyfluorina-
tions of phenols.5 In contrast, there are significantly fewer
methods that utilize SO2F2 to activate aliphatic alcohols.6 The
rapid reaction of alcohols with SO2F2, coupled with the tri-
flate-like behavior of the resulting alkyl fluorosulfates, pre-
sents the intriguing possibility of using SO2F2 to effect a sub-
stitution reaction where the alcohol activation step and the
substitution step occur in a single reaction pot (Scheme 1).
The success of this strategy hinges upon a thorough under-
standing of both the kinetics of the desired reaction, as well as
the relative rates of all the undesired reaction pathways.
This new strategy using SO2F2 was investigated in the context
of the 1,1-dihydrofluoroalkylation of amines (Scheme 1, R =
fluoroalkyl, Nu = R’R”NH). The products from this reaction are
valuable motifs present in many biologically-active molecules7
and have traditionally been made from the corresponding
iodide or sulfonates, such as tosylates or triflates.8 These pro-
cesses involve two synthetic steps from the corresponding
1,1-dihydrofluoroalcohol and often require forcing reaction
conditions. Recently, Denton and coworkers developed a new,
Figure 1. One-pot 1,1-dihydrofluoroalkylation mediated
by SO2F2 (blue), and associated undesired reaction path-
ways (red)
1,1-Dihydrofluoroalkyl fluorosulfates have been investigated,
but there have been no reports of their direct formation and
13
isolation from SO2F2.11, We anticipated that trifluoroethyl
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fluorosulfate (3a) would be more stable than non-fluorinated
thus far provided information about the formation of trifluo-
roethyl fluorosulfate (3a), and its subsequent reactivity to
form the fluoroethylated amine product (4a) and possible
side products (5, 6, and 7).
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3
4
5
6
7
8
analogs as fluorine alpha to the electrophilic center has been
shown to decrease the rate of substitution reactions.14 Initial
experiments revealed that trifluoroethyl fluorosulfate (3a)
15
was facile to prepare by bubbling SO2F2 through a solution
of trifluoroethanol (TFE, 1a) and DIPEA in a variety of polar
aprotic solvents (Scheme 2).16, 17 After an aqueous work-up, it
is stable for up to a week as a solution in CH2Cl2. A factor that
significantly influenced the reaction was the choice of base;
DIPEA was found to afford 3a in higher purity than triethyla-
mine, but bases such as potassium carbonate and DBU led to
the formation of 43% and 100% of bis(trifluoroethyl)sulfate
(6a) respectively. No trifluoroethyl fluorosulfate (3a) was
formed in the absence of base. These conditions represent the
first time 3a has been synthesized from SO2F2.
Scheme 3. Reactivity of trifluoroethyl fluorosulfate (3a)
with morpholine (2a).
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The last piece of information required for this one-pot process
is the rate of the reaction between SO2F2 and an amine, such
as morpholine (2a), to form fluorosulfamide 8. In-situ React-
IR studies revealed that the reaction between alcohol (1a) or
amine (2a) and SO2F2 have similar rate constants. This was
encouraging as selective formation of 3a in the presence of
morpholine (2a) can be achieved by simply leveraging a con-
centration difference between the two. Gratifyingly, this con-
centration strategy allowed for a viable one-pot procedure;
optimization of the amount of TFE relative to morpholine
revealed that a 10:1 mixture resulted in the optimal yield of
4a while minimizing the total volume of TFE.17 Monitoring the
one-pot process via ReactIR confirmed that capture of SO2F2
by 1a is more rapid than fluoroalkylation of 2a to give 4a,
allowing trifluoroethyl fluorosulfate (3a) to accumulate in-
situ (Figure 3).
Scheme 2. Synthesis of trifluoroethyl fluorosulfate (3a).
We were encouraged by the remarkable stability of fluorosul-
fate 3a. Once synthesized in DMF, 3a is stable in the reaction
environment, displaying a linear decomposition profile with
an approximate observed rate constant of 1.88x10-4 min-1
(Figure 2). This observed decomposition is an aggregate of
both fluoride and TFE (1a) reacting with 3a, giving alkyl fluo-
ride 5a and sulfate 6a respectively. This small rate constant
was exceptionally promising, as it demonstrated that unwant-
ed nucleophilic capture should not be competitive with alkyla-
tion between trifluoroethyl fluorosulfate (3a) and the amine
(2).
Figure 3. Reaction progress curve for the one-pot 1,1-
dihydrofluoroalkylation of morpholine (2a) using SO2F2,
DIPEA, TFE (1a) in DMF. Concentration profile generated
by React-IR; O = 949 cm-1,O = 1241 cm-1,O = 1273 cm-1.
Figure 2. Reaction progress curve showing the formation
and stability of trifluoroethyl fluorosulfate (3a) using
SO2F2, DIPEA, TFE (1a) in DMF. Concentration profile gen-
erated by React-IR, monitoring absorbance at 1241 cm-1.
The scope of this new reaction was then explored with both
primary and secondary amines (Scheme 4). Consistent with
what we observed during optimization, 2a was effectively
trifluoroethylated to afford 4a, although the equivalents of
sulfuryl fluoride had to be increased on larger scale.19 Second-
ary amines, such as piperidine, N-methylpiperazine,20 and
benzylic secondary amines, were trifluoroethylated in high
yields to the corresponding fluoroalkylated products 4b-4e,
respectively. Primary amines, such as benzylamine, n-
hexylamine and propargylamine, were also viable substrates,
affording 4f, 4g and 4h respectively, although the reaction
rates were slightly slower. The reaction was also compatible
with a pendant furan, affording 4i. Phenylalanine methyl ester
Facile generation of trifluoroethyl fluorosulfate (3a) allowed
us to evaluate the subsequent substitution reaction with a
representative amine, morpholine (Scheme 3, 2a).17 Analysis
of this reaction revealed two important features. First, reac-
tion between morpholine (2a) and 3a proceeded exclusively
via displacement of fluorosulfate affording trifluoroethylmor-
pholine (4a) and not sulfamate 7a. This represents the first
example of 3a acting as an amine alkylating agent.18 Second,
the relative rate of formation of trifluoroethyl fluorosulfate 3a
is ~4x the rate of its consumption through reaction with mor-
pholine (2a). This suggests that we expect 3a to accumulate in
the course of the one-pot process. The kinetic experiments
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required a second addition of SO2F2 and DIPEA to achieve
py. We next explored the reaction with (1S,2R)-(+)-
norephedrine (2o), which contains both an unprotected
amine and an unprotected alcohol. Despite the possible side
reactions, trifluoroethylation of 2o under the standard one-
pot reaction conditions afforded trifluoroethyl product 4o in
72% yield.22
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2
3
4
5
6
7
8
good isolated yields of 4j. Other substrates with steric bulk
alpha to the amine, such as cyclohexylamine (2l), also needed
the second addition due to slow reaction rates. Further in-
creasing the steric bulk of the amine, such as with diisoprop-
ylamine, led to no conversion. Aniline derivatives were also
poor substrates for this reaction. Overall, this reaction scope is
comparable with current state-of-the-art methodologies.7, 8
Scheme 4. Trifluoroethylation of amines
9
Scheme 5. 1,1-Dihydrofluoroalkylation of amines
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All reactions were run on 0.6 mmol scale. Unless otherwise
indicated, 2M HCl in ether was added after purification, and
the products were isolated as the HCl salt. Isolated yields are
All reactions were run on 0.6 mmol scale. Unless otherwise
indicated, 2M HCl in ether was added after purification, and
the products were isolated as the HCl salt. Isolated yields are
a
reported with NMR yields in parentheses. The product was
b
isolated as the neutral amine. A second addition of SO2F2 was
a
reported with NMR yields in parentheses. The product was
used.
b
isolated as the neutral amine. A second addition of SO2F2 was
used.
Scheme 6. Functional group compatibility studies.
Studies then focused on whether this new methodology could
be applied to the activation of other 1,1-dihydrofluoroalcohols
(Scheme 5). We initially focused on synthesizing N-
difluoroethyl morpholine (9a) using difluoroethanol (1b).
Initial optimization experiments identified that the in situ-
generated difluoroethyl fluorosulfate was less stable than the
analogous 3a. To maximize the yield of the desired difluoro-
ethylation, the temperature was decreased to ambient tem-
perature and silica gel was added to the reaction mixture.
Using these new conditions, 9a was successfully formed in
70% NMR yield in only 20 minutes.21 Overall, the scope was
comparable to that of trifluoroethylation, although select sub-
strates needed a second addition of SO2F2 and DIPEA. Pen-
tafluoropropanol and heptafluorobutanol were also viable
alcohols when the reaction was run at 40 °C, although longer
reaction times were required to achieve comparable yields of
the 1,1-dihydrofluoroalkylated products 10 and 11.
To further examine the functional group compatibility of this
new method, substrates with pendant nucleophiles were ex-
plored (Scheme 6). The reaction was tolerant of amines, such
as indole (2m) and pyridine (2n), and no trifluoroethylation
of the pendant groups was observed by 19F NMR spectrosco-
As this is the first example of the 1,1-dihydrofluorination of
amines with fluorosulfate derivatives, we next explored the
relative reactivity of trifluoroethyl fluorosulfate (3a) com-
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Reaction for Click Chemistry. Angew. Chem. Int. Ed. 2014, 53, 9430–
9448.
(3) For representative examples, see: (a) Dong, J.; Sharpless, K. B.;
Kwisnek, L.; Oakdale, J. S.; Fokin, V. V. SuFEx-Based Synthesis of Poly-
sulfates. Angew. Chem. Int. Ed. 2014, 53, 9466–9470. (b) Gao, B.;
Zhang, L.; Zheng, Q.; Zhou, F.; Klivansky, L. M.; Lu, J.; Liu, Y.; Dong, J.;
Wu, P.; Sharpless, K. B. Bifluoride-catalysed sulfur(VI) fluoride ex-
change reaction for the synthesis of polysulfates and polysulfonates.
Nat. Chem. 2017, 1083–1088.
(4) For a recent review, see: Revathi, L.; Ravindar, L.; Leng, J.;
Rakesh, K. P.; Qin, H. –L. Synthesis and Chemical Transformations of
Fluorosulfates. Asian J. Org. Chem. 2018, 7, 662–682.
(5) Schimler, S. D.; Cismesia, M. A.; Hanley, P. S.; Froese, R. D. J.;
Jansma, M. J.; Bland, D. C.; Sanford, M. S. Nucleophilic Deoxyfluorina-
tion of Phenols via Aryl Fluorosulfonate Intermediates. J. Am. Chem.
Soc. 2017, 139, 1452–1455.
pared to existing activating groups, such as iodides, tosylates,
1
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3
4
5
6
7
8
mesylates, or triflates. Under our standard reaction condi-
tions with morpholine, trifluoroethyl iodide, trifluoroethyl
tosylate, and trifluoroethyl mesylate were completely unreac-
tive.23 While trifluoroethyl triflate is more reactive, it is signif-
icantly more unstable, particularly under aqueous basic condi-
tions. Furthermore, replacement of sulfuryl fluoride with tri-
flic anhydride in our one-pot process did not afford the de-
sired product.23
Overall,
we
have
developed
a
novel
1,1-
9
dihydrofluoroalkylation method which simply involves bub-
bling SO2F2 through a solution of the starting amine with
DIPEA and the requisite 1,1-dihydrofluoroalcohol. This pro-
cess is effective for both primary and secondary amines using
either trifluoroethanol or difluoroethanol as the fluoroalkyl
precursors. Longer linear 1,1-dihydroperfluoroalkyl alcohols,
such as pentafluoropropanol and heptafluorobutanol, were
also viable, although longer reaction times were required. The
reaction also displays good functional group tolerance. Com-
pared to other fluoroalkylation methods that start from 1,1-
dihydrofluoroalcohols, this is the only method that can be
performed in a single synthetic step. Furthermore, the 1,1-
dihydrofluoroalkyl fluorosulfate intermediate has a useful
balance between reactivity and stability. Our methodology
also compares favorably to the Denton strategy as we can
achieve comparable results under non-reductive conditions.
Additional applications in late-stage pharmaceutical derivati-
zation and materials chemistry are currently underway.
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(6) For a representative example, see: Ishii, A.; Yamazaki, T.; Ya-
sumoto, M. (Central Glass Company, Ltd.) Process for production of
optically active fluoroamine. US 8,426,645 B2, 2013.
(7) For representative pharmaceutical applications of 1,1-
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inal chemistry. Prog. Med. Chem. 2015, 54, 65–133. (b) Morgenthaler,
M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R.; Jaeschke,
G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.;
Diederich, F.; Kansy, M.; Müller, K. Predicting and Tuning Physico-
chemical Properties in Lead Optimization: Amine Basicities.
ChemMedChem. 2007, 2, 1100–1115.
(8) For representative synthetic methods for the preparation of tri-
fluoroethylamines, see: (a) Umemoto, T.; Gotoh, Y. 1,1-
dihydroperfluoroalkylations
of
nucleophiles
with
(1,1-
dihydroperfluoroalkyl)phenyliodonium triflates. J. Fluor. Chem. 1986,
31, 231–236. (b) Wong, J. C.; Tang, G.; Wu, X.; Liang, C.; Zhang, Z.; Guo,
L.; Peng, Z.; Zhang, W.; Lin, X.; Wang, Z.; Mei, J.; Chen, J.; Pan, S.; Zhang,
N.; Liu, Y.; Zhou, M.; Feng, L.; Zhao, W.; Li, S.; Zhang, C.; Zhang, M.;
Rong, Y.; Jin, T.-G.; Zhang, X.; Ren, S.; Ji, Y.; Zhao, R.; She, J.; Ren, Y.; Xu,
C.; Chen, D.; Cai, J.; Shan, S.; Pan, D.; Ning, Z.; Lu, X.; Chen, T.; He, Y.;
Chen, L. Pharmacokinetic Optimization of Class-Selective Histone
Deacetylase Inhibitors and Identification of Associated Candidate
Predictive Biomarkers of Hepatocellular Carcinoma Tumor Response.
J. Med. Chem. 2012, 55, 8903−8925. (c) Luo, H.; Wu, G.; Zhang, Y.;
Wang, J. Silver(I)-Catalyzed N-Trifluoroethylation of Anilines and O-
Trifluoroethylation of Amides with 2,2,2-Trifluorodiazoethane. An-
gew. Chem. Int. Ed. 2015, 54, 14503–14507. (d) Lu, H.; Yang, T.; Xu, Z.;
Lin, X.; Ding, Q.; Zhang, Y.; Cai, X.; Dong, K.; Gong, S.; Zhang, W.; Patel,
M.; Copley, R. C. B.; Xiang, J.; Guan, X.; Wren, P.; Ren, F. Discovery of
Novel 1-Cyclopentenyl-3-phenylureas as Selective, Brain Penetrant,
and Orally Bioavailable CXCR2 Antagonists. J. Med. Chem. 2018,
61, 2518–2532.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures and
methods; kinetic studies and optimization data; MS, IR, and
NMR data including 1H, 13C, and 19F NMR spectra.
AUTHOR INFORMATION
Corresponding Author
*gsammis@chem.ubc.ca
Notes
(9) Andrews, K. G.; Faizova, R.; Denton, R. M. A practical and cata-
lyst-free trifluoroethylation reaction of amines using trifluoroacetic
acid. Nat. Commun. 2017, 8, 15913.
(10) While there are no examples of nitrogen reactivity at the car-
bon of trifluoroethyl fluorosulfate, reactivity at the carbon has been
demonstrated for soft nucleophiles, such as sulfur and bromide. See
reference 11a.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the University of British Colum-
bia (UBC), the Natural Sciences and Engineering Research
Council of Canada (NSERC), the Canadian Foundation for In-
novation (CFI-35883), the NSERC CREATE Sustainable Syn-
thesis Program, and a UBC Work Learn International Under-
graduate Research Award to SSK. We acknowledge Mettler-
Toledo Autochem for the generous donation of process analyt-
ical equipment (React-IR) and MilliporeSigma/Sigma-Aldrich
(USA) for the generous donation of sulfuryl fluoride.
(11) (a) Kinkead, S. A.; Kumar, R. C.; Shreeve, J. M. Reactions of
polyfluoroalkyl fluorosulfates with nucleophiles: an unusual substitu-
tion at the sulfur-fluorine bond. J. Am. Chem. Soc. 1984, 106, 7496-
7500. (b). Huang, T.; Shreeve, J. M. Syntheses and reactions of
polyfluoroalkyl fluorosulfates. Inorg. Chem. 1986, 25, 496-498.
(12) For representative reviews, see: (a) Chung, R.; Hein, J. E. The
More, The Better: Simultaneous In Situ Reaction Monitoring Provides
Rapid Mechanistic and Kinetic Insight. Top. Catal. 2017, 60, 594–608.
(b) Chanda, A.; Daly, A. M.; Foley, D. A.; LaPack, M. A.; Mukherjee, S.;
Orr, J. D.; Reid, G. L., III; Thompson, D. R.; Ward, H. W., II. Industry
Perspectives on Process Analytical Technology: Tools and Applica-
tions in API Development. Org. Process. Res. Dev. 2015, 19, 63–83.
(13) For representative examples of the formation of 1,1-
dihydrofluoroalkyl fluorosulfates, see: (a) Shack, C. J.; Christe, K. Halo-
gen fluorosulfate reactions with fluorocarbons. J. Fluor. Chem. 1980,
16, 63–73. (b) Harmon, L. A.; Lagow, R. J. The synthesis of
bis(trifluoromethyl) sulphone and bis(trifluoromethyl) sulphonate by
direct fluorination. J. Chem. Soc., Perk. Trans. 1, 1979, 2675. (c) Delfi-
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(16) The reaction was successfully completed both using a tank of
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(17) For optimization details, see the SI.
(18) Methyl fluorosulfates are known to react with nitrogen nucle-
ophiles. For representative examples, see: (a) Ahmed, M. G.; Alder, R.
W. Methyl basicity and nucleophilicity: the N- and O-alkylation of
carbamates. Chem. Commun. 1969, 1389–1390. (b) Grigg, R.; Sweeney,
A.; Dearden, G. R.; Jacksen, A. H.; Johnson, A. W. N-methylation of oc-
taethylporphyrin and octaethylchlorin. Chem. Commun. 1970, 1273–
1274.
(19) When the reaction was scaled from 0.28 mmol to 0.6 mmol,
the amount of SDI had to be increased to 2.9 equivalents to maintain
the pressure of SO2F2 in the larger reaction vessels.
(20) Substrate 9c was challenging to separate from DIPEA due to
similar physical properties.
(21) Difluoroethylmorpholine was difficult to separate from DIPEA
due to similar physical properties.
(22) Another ~2.9 equiv. of SO2F2 was bubbled through the solu-
tion after 20 minutes.
(23) For details see the Supporting Information.
Graphical Abstract
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