Stereospecific Synthesis of cis-2,5-Disubstituted Pyrrolidines via N, O-Acetals Formed by Hydroamination Cyclization-Hydroalkoxylation of Homopropargylic Sulfonamides in HFIP

Article abstract of DOI:10.1021/acs.joc.0c00403

We reported a novel two-step stereoselective synthesis of functionalized pyrrolidines from homopropargylic sulfonamides and nucleophiles via an isolable N,O-acetal intermediates. This reaction features mild conditions and good scope of substrates. In addition, the use of hexafluoroisopropanol, acting as a solvent, an additive, a weak nucleophile, and a good leaving group, is pivotal to the success of the method. Moreover, reactions of chiral homopropargylic sulfonamides afford only 2,5-cis-disubstituted pyrrolidines with high diastereoselectivity (up to >99:1 dr) and enantioselectivity (up to >99% ee). The overall reaction constitutes a formal 1,1-bifunctionalization of terminal alkynes, which has hitherto been reported only rarely. Additionally, this method provides efficient access to pharmaceutical intermediate and to carry out postmodification of natural products.

Full text of DOI:10.1021/acs.joc.0c00403

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Article
Stereospecific Synthesis of cis-2,5-disubstituted pyrrolidines
via N,O-acetals Formed by Hydroamination Cyclization-
Hydroalkoxylation of Homopropargylic Sulfonamides in HFIP
Weilin Wang, Xiaohui Cao, Weiguo Xiao, Xiaoyu Shi, Xiaodan Zuo, Lingyan Liu, Weixing Chang, and Jing Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00403 • Publication Date (Web): 12 May 2020
Downloaded from pubs.acs.org on May 12, 2020
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Stereospecific Synthesis of cis-2,5-disubstituted pyrrolidines
via N,O-acetals Formed by Hydroamination Cyclization-
Hydroalkoxylation of Homopropargylic Sulfonamides in
HFIP
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Weilin Wang,1 Xiaohui Cao,3,4 Weiguo Xiao,1 Xiaoyu Shi,1 Xiaodan Zuo,1 Lingyan Liu,*1 Weixing
Chang,1 Jing Li,*1,2
1 the State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, P. R. China
Email: liulingyan@nankai.edu.cn, lijing@nankai.edu.cn
2 Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Weijin Road 94#,
Nankai District, Tianjin 300071, P. R. China
3 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, P. R. China
4 Institute of Organic Chemistry and MOE Key Laboratory of Bioinorganic and Synthetic Chemistry,
School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P. R. China
Application
CF3
NHR3
O
R3
Nu
20 mol% AgOAc
R3
CF3
H
Nu
N
N
R1
HFIP, 50 o
C
76%
NHTs
H
R2
R1
R1
R2
R2
Magic HFIP:
Cyclic N,O-acetals
cis-2,5-disubstituted pyrrolidines
H
O
F3C
CF3
O
Up to 97% yield
50%
N
Nu: C, N, O, S, SCF3 et. al
Up to 99% yield
Up to 99% ee
Up to 99/1 dr
H
F3C
CF3
Mild reaction conditions
Broad substrates scope
Easy to transformation
n
CN
dr > 99:1
a) as a solvent
Ts
b) as an additive
c) as a reactant
d) as a traceless tethered group
trandolapril
KEYWORDS: HFIP, Hydroamination cyclization-hydroalkoxylation, 2,5-cis-Disubstituted pyrrolidine,
Formal nucleophilic substitution
ABSTRACT
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We reported a novel two-step stereoselective synthesis of functionalized pyrrolidines
from homopropargylic sulfonamides and nucleophiles via an isolable N,O-acetals
intermediates. This reaction features mild conditions and good scope of substrates. And the
use of hexafluoroisopropanol, acting as a solvent, an additive, a weak nucleophile and a
good leaving group, is pivotal to the success of the method. Moreover, reactions of chiral
homopropargylic sulfonamides afford only 2,5-cis-disubstituted pyrrolidines with high
diastereoselectivity (up to >99:1 dr) and enantioselectivity (up to >99% ee). The overall
reaction constitutes a formal 1,1-bifunctionalization of terminal alkynes, which has hitherto
been reported only rarely. Additionally, this method provides an efficient access to
pharmaceutical intermediate and to carry out post-modification of natural products.
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INTRODUCTION
The pyrrolidines are ubiquitous building blocks in natural products, pharmaceuticals and
materials.1 Thus the development of effective methods for accessing pyrrolidines has been
a focus of research by synthetic chemists. And many successful synthetic methods have
been reported up to date.2 Among them, the intramolecular hydroamination cyclization
reaction of homoallylic amines is the most significant.3 In contrast, there have been few
reports about the synthesis of pyrrolidines by means of intramolecular hydroamination
cyclization reactions of homopropargylic amines, a strategy that is commonly used to
generate dihydropyrroles and pyrrolidinone derivatives.4 Recently, Zhu and his coworkers
described a three-component cyclizative 1,1-aminoacylation of terminal alkynes. In their
report, a part of multiple substituted pyrrolidine products were obtained in relatively low
diastereoselectivities (Scheme 1a).5 Ye’s research group developed a method to prepare
various enantioenriched 2,5-disubstituted pyrrolidines from chiral homopropargylic
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sulfonamides (Scheme 1b).6 They used the structurally elaborate Au complexes and Et3N
for the intramolecular hydroamination cyclization cascade reaction. And the low
diastereoselectivities were generated in the cases of allylsilane as a strong carbon
nucleophile in this cascade cyclization. Therefore, developing high efficient methodology
for the synthesis of 2, 5-disubstituted pyrrolidines with high diastereoselectivity is
desirable and more challenging.
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OH
HN
HN
O
CO2Et
F
O
H
Ts
N
N
O
N
CN
CO2H
N
N
Et
nBu
Monomorine
H
H
1-Sulfonyl pyrrolidine derivatives
Vildagliptin
Trandolapril
Figure 1. Drugs and natural products containing unsymmetrical 2, 5-disubstituted
pyrrolidines moieties.
On the other hand, the 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) displays unique
properties (weak acidity (pKa 9.3) and nucleophilicity (N -4.23), strong polarity (ENT
1.068) and ionizing power (Y 3.82), etc.) because of its strong electron-withdrawing nature
in many organic reactions.7 Moreover, there have been an increasing reports on the ability
of HFIP to promote organic reactions as an acid component or interaction with reactants
by hydrogen-bonded cluster.8
In light of the existing work on the synthesis of pyrrolidines and as part of ongoing work
in our research group,9 we herein explored the use of HFIP as a solvent for the construction
of 2,5-bifunctionalized pyrrolidines and developed a simple two-step method. This method
involves an intramolecular hydroamination cyclization-hydroalkoxylation reaction of
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homopropargylic sulfonamides to give N,O-acetals 2, which were followed by a formal
intermolecular nucleophilic substitution. The whole reaction constitutes a 1,1-
bifunctionalization of terminal alkynes.10 Moreover, we found that the HFIP played
multiple roles in this process: it acted as not only a solvent, but also an additive, a reactant
and a good leaving group (Scheme 1c). More importantly, the obtained N,O-acetals 2 could
be facilely transformed to other diverse stereodefined cis-2,5-disubstituted pyrrolidines
derivatives 5, especially for the formation of C-X bonds (X = O, S, N etc.), whereas
previous studies pay more attention to the linear N,O-acetals and their application for the
construction of C-C bond.11 Therefore, these results are significant and this method
provides an efficient synthetic strategy for the access to stereospecific 2,5-disubstituted
pyrrolidines.12
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Zhu's work
R3
O
R2 NH2
O
a)
0.1 equiv. AgOAc
toluene, 40 oC
R2
N
R3COOH
+
RNC
+
NHR
R1
R1
yield: 86-99%
dr: 1:1-10:1
Ye's work
PG
b)
PG
PG
Nu:
N3, ally,
TMSNu or HNu
H
Ph3PAuNTf
HN
N
R
N
N
R
Nu
R
chiral homopropargylic amines
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Ts
Ts
N
H
Ts
NHTs
c)
Ag+
N
HFIP
HFIP
N
R
R
R
R
as proton source
HFIP
solvent
as a proton
1
H
Ag trapping reagent
Ag
8
H
O
9
F3C
F3C
CF
O
3
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H
CF3
a good leaving group
n
acid additive
CH3
Ts
N
CF3
F3C
O
Ts
HFIP
Nu
Ag
O
CF3
CF3
O
R
Ts
N
O
N
Nu
H
R
H
H
O
R
H
H
as a reactant
H
CF3
5
F3C
2
H
H
Nu = ally, CN, N3, RO, SCF3
cis-2,5-disubstituted pyrrolidines
cyclic N,O-acetals
the key intermediate
Scheme 1. The synthesis of multisubstituted pyrrolidines
RESULTS AND DISCUSSION
In our initial study, the elegant Ph3PAuCl (5 mol%) was chose to catalyze the possible
intramolecular hydroamination cyclization reaction of the homopropargylic sulfonamide
with HFIP (20 equiv.) as an additive at 50 oC in 1,2-dichloroethane (DCE) for 48 h. To our
delight, a new N,O-acetal 2a was unexpectedly obtained as a minor product, along with N-
Ts dihydropyrrolidine 3a as the major product (entry 1, Table 1). When DCE was replaced
with DMF, no reaction occurred with the great amount of starting material recovered (entry
2). And the similar results were obtained when trifluoroethanol (TFE) or MeOH was used
as an additive (entries 3 and 4). These results demonstrated that HFIP and the solvent had
significant effects on the reaction. Therefore, we carried out the reaction of
homopropargylic sulfonamide in HFIP slovent in the absence of any additives and found
that under these conditions, the reaction smoothly delivered desired product 2a in 80%
yield after 48 h (entry 5). The addition of KF to the reaction mixture did not improve the
results (entry 6). However, attempting to use a combination of Ph3PAuCl and AgNTf2
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catalysts, dimer 4a was obtained in 75% yield (entry 7). Other metal salts, AgOAc,
Cu(OAc)2 and FeCl3 were also examined as catalysts, and AgOAc showed a slight
advantage over the Cu and Fe salts at a loading of 5 mol% (entries 8-10). Surprisingly,
increasing the amount of AgOAc to 10 mol% resulted in a 75% yield of 2a after only 18 h
(entry 11). Intrigued by this result, we increased the amount of AgOAc even further and
found that 20 mol% was optimal, giving 2a in 93% yield (entries 12 and 13). Furthermore,
the reaction time could be reduced to 8 h with 95% yield of desired product generated
(entry 14). Nevertheless, only a trace amount of desired product 2a was detected when the
reaction was carried out at room temperature (entry 15). And in isopropanol solvent, the
homopropargylic sulfonamide 1a delievered the dihydropyrrole 3a in 80% yield (Table 1,
entry 16). Based on the above all results, the optimal reaction conditions were determined
as follows: homopropargylic sulfonamide 1 (0.2 mmol), AgOAc (20 mol%) or Ph3PAuCl
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o
(5 mol%) at 50 C in HFIP (1 mL) for 8 h or 48 h. It should be noted that all the 2-
hexafluoroisopropxy pyrrolidines products were in a cis configuration.
Table 1. Optimization of reaction conditions a
Ts
Ts
N
NHTs
Ts
N
Ts
N
Cat.
N
O
CF3 +
+
Solv, 50 oC
F3C
2a
3a
4a
1a
Entry Cat. (mol%)
Add. (mol%)
HFIP (20)
HFIP (20)
TFE (20)
MeOH (20)
-
Solv.
DCE
DMF
DCE
DCE
HFIP
Time (h)
Yield (%)b
2a+3a/95c
2a/0
1
2
3
4
5
Ph3PAuCl (5)
Ph3PAuCl (5)
Ph3PAuCl (5)
Ph3PAuCl (5)
Ph3PAuCl (5)
48
48
24
24
48
2a/0
2a/0
2a/80
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Ph3PAuCl (5)
Ph3PAuCl/
AgNTf2 (5)
AgOAc (5)
Cu(OAc)2 (5)
FeCl (5)
KF (5)
-
HFIP
HFIP
48
2a/79
10 mins
4a/75d
8
-
-
-
-
-
-
-
-
-
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
iPrOH
48
48
48
18
12
13
8
2a/32
2a/19
2a/0
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AgOAc (10)
AgOAc (20)
AgOAc (50)
AgOAc (20)
AgOAc (20)
AgOAc (20)
2a/75
2a/93
2a/76
2a/95
Tracee
3a/80f
24
18
a Standard procedure: The reaction was carried out with 1a (0.2 mmol) and catalyst at 50 °C. b Isolated yield
of 2a. c The total yield of the mixture 2a and 3a (1:5.5). d The yield of 4a (cis : trans = 1:1). e room temperature.
f The isolated yield of 3a.
With the optimized reaction conditions in hand, the scope of the reaction was then
investigated with either 20 mol% AgOAc (condition A) or 5 mol% Ph3PAuCl (condition
B) as catalyst (Table 2). Remarkably, most of homopropargylic sulfonamides we tested
were competent, affording the corresponding 2-hexafluoroisopropoxy pyrrolidines
derivatives in good to excellent yields with excellent diastereoselectivities. For example,
homopropargylic sulfonamides in which R1 was a phenyl group with one or two electron-
withdrawing or electron-donating substituents rendered the corresponding 1,2,5-
trisubstituted pyrrolidines (2b-2j) in good to excellent yields under the reaction condition
A. When R1 was a naphthyl group or a thiophenyl group, the reaction also proceeded
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smoothly to generate 2k and 2l in 91% and 75% yields, respectively, under the reaction
condition B. Howerver, 3-pyridinyl homopropargylic sulfonamide (1m) failed to produce
2m, for reasons that remain unclear. To our delight, when R1 was H, a benzyl (Bn) or
cyclohexyl group (R2 = H), the corresponding products (2n-2p) were obtained in moderate
to high yields, as was also the case for a fused cyclohexyl substrate (R1, R2 = cyclohexyl,
2q). In addition, when R3 was changed from tosyl to methanesulfonyl, benzenesulfonyl, p-
nitrophenylsulfonyl, or p-methoxylphenylsulfonyl, good yields of the desired products (2r-
2u) were all obtained. However, the diastereoselectivity for 2-hexafluoroisopropoxy
pyrrolidines 2t was unsatisfactory with trans-configuration as a major (cis/trans = 1:6.6).
It was speculated that electron effect on the sulfonyl aromatic ring affected the
diastereoselectivity of this reaction. Reaction of a phenyl substituted internal
homopropargylic sulfonamide only gave the 2,3-dihydropyrrole 3v in 89% yield without
further HFIP adduct. We surmised that the steric hindrance of 5-phenyl of 3v inhibited the
addition of hexafluoroisopropoxy group. Interestingly, the γ-sulfonaminoalkyne gave
dimer 4w in 95% yield. Changing the N-tosyl group to a t-butylsulfinamide group (1x), a
benzoylamine (1y) or an n-butylamine group (1z), no desired product was generated
whether under reaction condition A or B. Benzoylamine 1y afforded compound 5y, which
was generated by reaction of the benzoyl group attacking the alkynyl group. The 1z with
n-butyl substituted homopropargylic amine decomposed. These results indicated the
sulfonyl group played a crucial role in this reaction. In other words, this reaction occurrence
depends on the acidity of NH on the substrates. The absolute structure of 2e was
unambiguously determined by single crystal X-ray diffraction analysis (Figure S1).13
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Table 2. Substrate scope of the intramolecular hydroamination cyclization-hydroalkoxylation
reactiona,b,c
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CF3
CF3
O
R3
Condition A: 20 mol% AgOAc
Condition B: 5 mol% Ph3PAuCl
NHR3
N
R1
R1
R2
HFIP, 50 oC
R2
9
2
1
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Ts
Ts
Ts
MeO
Me
N
N
N
O
O
O
CF3
CF3
CF3
F3C
F3C
F3C
[a]
[a]
[a]
2a
2b
2c
, Yield 95%
, Yield 93%
, Yield 94%
Ts
N
Ts
N
Ts
N
F3C
Cl
F
O
O
O
CF3
CF3
CF3
F3C
F3C
F3C
[a]
[a,c]
[a]
2e
2d
, Yield 97%
, Yield 81%
2f
, Yield 90%
Ts
F
Ts
N
Ts
N
Br
O
O
F3C
N
O
CF3
CF3
CF3
F3C
F
F3C
[b]
[b]
[a]
2h
2i
, Yield 81%
, Yield 85%
2g
, Yield 85%
Br
Ts
N
Ts
N
Ts
F
N
O
O
O
CF3
CF3
CF3
S
F3C
F3C
F3C
[b]
[a,d]
[b]
2k
, Yield 91%
2j
2l
, Yield 75%
, Yield 79%
Ts
N
Ts
Ts
N
N
O
O
CF3
O
CF3
N
CF3
F3C
F3C
, Yield 97%
F3C
[a]
[a,b,e]
[b]
2n
2m
2o
, N.R.
, Yield 83%
Me
Ts
O
O
S
N
Ts
N
N
O
CF3
O
O
CF3
CF3
F3C
F3C
F3C
[b]
[b]
[a]
2p
2q
2r
, Yield 90%
, Yield 57%
, Yield 51%
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NO2
OMe
4
5
6
7
8
O
O
O
O
O
S
O
S
N
S
N
N
O
O
O
CF3
CF3
CF3
9
F3C
F3C
F3C
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[a]
[a,f]
[a]
2u
, Yield 95%
2t
, Yield 75%
2s
, Yield 88%
cis:trans = 1:6.6
O
S
Ts
Ts
N
Ts
N
MeO
N
O
N
CF3
F3C
[a,g]
[a,h]
[b,g]
3v
, Yield 89%
2x
, Yield 0%, N.R.
4w
, Yield 95%
nBu
N
O
N
O
CF3
F3C
[a,i]
[a]
2z
5y
, Yield 0%, N.D.
, Yield 80%
a Method A: The reaction was carried out with 1a (0.2 mmol) and AgOAc (0.04 mmol, 20 mol%) in HFIP (1
b
mL) at 50 °C for 8 h. Method B: The reaction was carried out with 1a (0.2 mmol) and Ph3PAuCl (0.01
mmol, 5 mol%) in HFIP (1 mL) at 50 °C for 48 h. c Isolated yield. d Reaction time, 12 h. e No reaction. f The
g
h
i
mixture of cis/trans = 1/6.6, reaction time, 36 h. Reaction time, 3 h. N.R. = no reaction. N. D. = Not
determined.
The N,O-acetals can be readily transformed to a variety of useful compounds. Therefore,
further reactions of the five-membered cyclic N,O-acetals obtained by means of
hydroamination cyclization-hydroalkoxylation were investigated with the goal of
constructing new C−C or C−X bonds (X = N, O, S) (Table 3). It should be noted that
previous reports pay more attention to the formation of C-C bond from N,O-acetals. In
comparison, there are few researches on the construction of C-X bonds from N,O-acetals.
Herein, we chose compound 2a as a model substrate for reactions with several
representative nucleophiles. As shown in Table 3, carbon nucleophiles (allyltrimethylsilane,
trimethylsilyl cyanide and acetylene), oxygen nucleophiles (3-butyn-1-ol, water, MeOH,
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i
EtOH, PrOH, CF3CH2OH), sulfur nucleophiles (2-Mercaptothiazole, benzyl mercaptan
and AgSCF3) and a nitrogen nucleophile (TMSN3), all smoothly and stereospecifically
produced the corresponding cis-2, 5-disubstituted pyrrolidines (6a-6c, 6e-6g, 6i-6n, 6o) in
good to high yields. Among them, the reaction of 2a with CF3CH2OH produced an
inseparable mixture of trifluoroethoxy pyrrolidine 6i and hexafluoroisopropoxy pyrrolidine
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i
2a (6i : 2a = 25 : 4). And we obtained no target compound 6h when using PrOH as an
oxygen nucleophile. In spite of this, the direct nucleophilic substitution of the
hexafluoroisopropoxy with other different alkoxy groups is very important and will have
potential application in the aspect of carbohydrate chemistry. The ketone 6d was obtained
as a side product of the reaction between 2a and acetylene. Additionally, the
hexafluoroisopropoxy-pyrrolidine could be reduced to 2-substituted pyrrolidine 6q in the
presence of NaBH4. The products 6l and 6m were unstable and readily decomposed at room
temperature. Unfortunately, other amines (aniline or benzylamine or N-methlybenzylamine)
were not applicable in this formal nucleophilic substitution reaction at present.
Table 3. Reactions of hexafluoroisopropoxyl pyrrolidine 2a with nucleophilesa
1 equiv BF3 Et2O
2.0 equiv Nu-
Ts
Ts
N
Ts
N
Ts
N
N
O
Nu
+
CF3
DCM, rt
F3C
2a
6
4
Ts
N
Ts
Ts
N
N
CN
[b]
[c]
[b]
6b
6c
, Yield 60%
, Yield 98%, dr = 1.2/1
6a
, Yield 90%
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6
Ts
N
Ts
N
Ts
N
O
O
O
7
8
[e]
[c,h]
[d]
6f
, Yield 91%
6d
6e
, Yield 81%
, Yield <10%
9
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Ts
Ts
Ts
N
O
N
O
N
O
CF3
[e]
[e]
6g
6h ND [e]
, Yield 90%
,
6i
, Yield 85%
Ts
Ts
Ts
N
N
S
N
S
OH
S
N
6j, Yield 40%[f], dr = 6/1
6k, Yield 95%[d]
6l, Yield 51%[d]
unstable
Ts
N
Ts
N
Ts
N
Ts
CN
N
SCF3
N3
[g]
[b]
[i]
6m
6n
, Yield 99%
, Yield 57%
6o, Yield 98%
6q
, Yield 66%
unstable
a
b
c
Isolated yields. Reaction with 2.0 equiv allyltrimethylsilane or TMSCN or TMSN3 and 2.0 equiv KF.
Reaction with 2.0 equiv acetylene, 2.0 equiv KF, 2.0 equiv CuI. d Reaction with 2.0 equiv 3-butyn-1-ol or 2-
mercaptothiazole or benzyl mercaptan. e Reaction with 4.0 equiv MeOH or EtOH or iPrOH or CF3CH2OH. f
Reaction with 2.0 equiv H2O in 2:1 DCM/CH3CN. g Reaction with 4.0 equiv AgSCF3 in 1:1 DCM/CH3CN.
h This compound was a byproduct of the reaction between 2a and acetylene. i Reaction with 8.0 equiv NaBH4
in HFIP solvent.
Encouraged by the high diastereoselectivity of this hydroamination cyclization-
hydroalkoxylation reaction, we were interested in exploiting chirality transfer from a pre-
existing stereogenic center, such as that in an enantiopure homopropargylic sulfonamide
1a' (Scheme 2). As expected, the reaction of enantiopure 1a' afforded enantiopure N, O-
acetal 2a' with almost complete retention of chirality under the above standard conditions.
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Next, we carried out reactions of 2a' with several typical nucleophiles. Specifically,
enantiopure 2,5-disubstituted pyrrolidines 6a', 6c', 6e' and 6n' were obtained with
excellent enantioselectivities, as shown in Scheme 2.
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Ts
NHTs
Ts
N
20 mol% AgOAc
N
O
Ph
CF3
Nu
Ph
o
HFIP
, 50 C
F3C
1a'
2a'
Yield 95%, ee 97%
6'
Ts
Ts
Ts
N
Ts
N
N
N
N3
O
6a'
Yield 90%, ee 98%
6c'
6e'
6n'
Yield 60%, ee 98%
Yield 81%, ee 99%
Yield 99%, ee >99%
Scheme 2. The enantioselective transformation
To shed light on this reaction mechanism, we carried out some controll experiments
(Scheme 3) and monitoring reaction by 1H NMR spectroscopy. Treatment of N-tosyl-2, 3-
dihydropyrrole 3a with HFIP at 50 oC afforded 2a in 91% or 95% yield in the absence or
presence of AgOAc for 48 h or 3.5 h (Scheme 3, eq.1a and 1b). From these two results we
could conclude that: 1) the reaction of the homopropargylic sulfonamide in HFIP might
proceed via dihydropyrrole intermediate 3a, 2) HFIP served as a hydroalkoxylative reagent
in the addition reaction with no requisition of AgOAc catalyst. To further ascertain the
nucleophilicity of HFIP, the emulative strong nucleophilicity indole was added into the
reaction of dihydropyrrole 3b in HFIP solvent. Consequently, the 2b and 6r were both
1
obtained in 2.6:1 ratio (determined by H NMR spectroscopy of crude product) (Scheme
3, eq.2). This result indicated that the HFIP may attack the dihydropyrrole 3b in a cluster
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mode, which was superior to the nucleophilic addition of indole. And a slight chemical
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1
shift change of protons a, b and c in 3a was observed with HFIP by H NMR spectrum
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8
9
(Figure S2). Monitoring the interaction between HFIP and 2a by 1H NMR also displayed
a little chemical shift change of protons a and b on HFIP (Figure S3). Additionally, we
found that cis-2a decomposed slowly upon storage at room temperature for 3 months (eq.3),
as demonstrated that the N,O-acetals have relative stability. The 1t was subjected to the
optimized conditions for the hydroamination-hydroalkoxylation reaction, the cis/trans ratio
of the corresponding product (2t) decreased continuously with prolonging reaction time
(Scheme 3, eq.4), as was determined by 1H NMR spectrum of protons b and c in 2t (Figure
S4). This phenomenon demonstrated that the hexafluoroisopropoxy moiety was a good
leaving group and that the trans-product was more stable than the cis-product. Besides, the
deuterated HFIP-d2 was used to ascertain the proton source. As a result, nearly all hydrogen
atoms on the 2-site and 3-site of pyrrolidine 2b come from the HFIP (eq.5).
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Ts
N
Ts
N
1)
HFIP, 50 oC
O
CF3
F3C
2a
3a
a) Without AgOAc, 48 h, yield 91%;
b) With 20 mol% AgOAc, 3.5 h, yield 95%.
Ts
N
Ts
Ts
N
O
O
20 mol% AgOAc
HFIP, 50 oC, 3.5 h
2)
3)
O
N
+
O
NH
CF3
+
N
H
F3C
3b
2b
6r
1
2.6
Ts
N
store at rt for 3 months
O
CF3
Complicated
F3C
2a
cis-
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NO2
O2N
5
6
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8
4)
O
S
O
O
20 mol% AgOAc
S
O
12 h, cis:trans = 1:1
CF3 36 h, cis:trans = 1:6.6
48 h, cis:trans = 1:9
NH
N
HFIP, 50 oC
O
9
F3C
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2t
1t
, Yield 75%
59%
D
F3C
Ts
N
CF3
Ts
NHTs
MeO
5)
MeO
75%
NHTs
20 mol% AgOAc
HFIP (d2), 55-60 oC
D
N
D
O
+
+
D
74%
MeO
D
D
D
MeO
74%
3b
Yield 12%
2b
Yield 21%
Yield 59%
1b
Scheme 3. Mechanistic controll experiments.
To provide further understanding of the mechanism for the reaction catalyzed by
AgOAc, quantum chemical investigations based on density functional theory (DFT)
were performed. And a possible reaction pathway was proposed (Figure 2). The whole
catalytic cycle involves two steps: the Intramolecular cycloaddition of sulfonamide to
alkyne group and the stereoselective addition of HFIP to dihydropyrrolidine. In the first
reaction step, the AgOAc actives the alkynyl group by forming the π complex Int-1s
with the substrate 1s solvated by HFIP. Then, the nitrogen atom attacks the activated
alkynyl group to form the Int-2s through transition state TS-1s. The Gibbs free energy
barrier for the whole cyclization process is 25.8 kcal/mol, which is the rate-determing
step and is also in accordance with our experimental results, namely, no significant
accumulation of 3s was observed during the reaction process. Subsequently, the proton
on the nitrogen is trapped by the assitance of two molecular HFIP as a hydrogen-bond
bridge through the TS-2s to afford the Int-3s and concomitant with delivering the proton
of HFIP to the alkenyl carbon to give the stable Int-4s (the compund 3s) through TS-3s.
After the Int-4s is formed, AgOAc will further catalyze the addtion of HFIP to the
carbon-carbon double bond. The oxygen atom on HFIP is coordinated to Ag, the acidity
of molecule is greatly increased and the energy barrier is decreased to 21.9 kcal/mol (TS-
4s-cis). This is consistent with our experimental result that 3a in HFIP solvent to form
2a is rather slow without the participation of AgOAc (Scheme 3, eq.1). In addition, we
also studied the addition process of 3s by isopropanol and found that it required a quite
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high activation energy (32.9 kcal/mol, see supporting information for details). This result
rationalizes why the reaction stays in the process of forming 3s in isopropanol (Table 1,
entry 16). Finally, we search for the key transition states that produce cis and trans
products (Scheme S1). TS-4s-cis is more stable than other transition states to afford the
major product with cis configuration. A relative ∆∆G (1.6 kcal/mol) for TS-4s-trans was
obtained to predict the stereoselectivity of product. The predicted value is 95:5 (cis:trans),
which is close to the experimental results. It should be noted that the proton transfer
bridge composed with one HFIP or two HFIPs and the corresponding transition states
involving one HFIP or two HFIPS in stereoselectivity were also calculated (Figures S5-
S6). Moreover, the addition process of HFIP to the dihydropyrrole was nonsynergistic
(Figure S7). The Figure S8 described the causes of stereoselectivity with more
conformations of the transition states in rate-determining step.
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M062x-D3-SMD(HFIP) /6-311+G(d,p)/SDD// B3LYP-D3-SMD(HFIP)/6-31G(d)/Lanl2dz
ΔG
F3
CF3
C
CF3
O
H
F3
C
H
O
F3
CF3
C
O
CF3
H
O
H
PhO2
S
F3C
H
O
CH3
N
O
O
Ag
H
N
PhO2S
CH3
O
Ag
TS-1s
23.9
TS-2s
18.9
18.5
F3C
F3
C
CF3
F3
C
O
H
O
Int-2s
H
O
PhO2
S
N
F3
CF3
C
CF3
O
O
CH3
H
F3C
H
O
H
O
TS-3s
8.5
CH3
PhO2S
CH3
N
CH
3 O
Ag
O
H3
S
C
Ag
O
H
O
CF3
H
O
F3
C
PhO2
CF3
CF3
N
H
O
CH3
H3C
O
H
CF3
PhO2S
N
H
N
O
H
CF3
O
S
Int-3s
7.5
Ph
SO2Ph
TS-4s-Cis-iPrOH
5.7
O
N
CH3
O
F3C
TS-4s-without Ag
5.2
CF3
O
O
CF3
Ag
O
H
H
F3
C
S
H
O
H
1s
CH3
O
H
O
CH3
CF3
F3
C
CF3
O
Ag
-1.9
F3
C
CF3
O
O
Ag
O
H
0.0
CF3
F3
PhO2
CH3
C
N
O
H
O
O
F3
C
Ag
TS-4s-Trans
-3.7
Int-1s
O
C
F3
C
O
O
C
PhO2S
H
N
PhO2
S
H
H
Ag
CF3
N
CF3
H3
C
O
O
H
CF3
CF3
H
F3
CF3
F3
H3
C
O
H
N
O
H
CF3
AcOAg-HFIP
O
H
Ag
CF3
TS-4s-Cis
-5.3
O
S
CH3
H3
C
O
O
H
Ph
TS-5s-Cis
-6.7
O
O
2HFIP
Int-5s-Cis
-6.9
OH
CH3
CH3
+
Ag
O
CH3
H3
C
CF3
O
-7.7
TS-5s-Trans
F3
C
-7.4
O
Ag
O
H
H
Int-5s-Trans
O
PhO2
S
N
CF3
C
F3
S
O
O
F3
C
O
S
O
O
H
N
CH3
O
CH3
O
O
Ag
CF3
N
H3
C
O
O
H
H
O
Ag
Ag
H
+
H
O
H
O
H
O
O
OH
CF3
CF3
F3
C
F3
C
CF3
CF3
F3
C
CF3
F3
F3
C
C
-27.2
Int-4s
SO2Ph
N
-29.5
CF3
SO2Ph
-30.6
SO2Ph
N
O
H
3s
F3
C
N
O
trans-2s
CF3
F3
C
cis-2s
Figure 2. The DFT calculations of the reaction pathways
A one pot reaction was also carried out (Scheme 4). The details were as follows: 1a (0.2
mmol) and AgOAc (0.04 mmol, 20 mol%) were stirred at 55 °C for 8 h in HFIP (1 mL),
then removing the solvent under vacuo, subsequently adding KF (0.4 mmol, 23.2 mg, 2.0
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equiv.), TMS-allyl (0.4 mmol, 45.6 mg, 2 equiv.) and BF3·Et2O (0.2 mmol, 28.4 mg, 1
equiv.) as well as 1 mL DCM, the mixture was stirred for another 12 h. Consequently, the
reaction afforded the corresponding N-Ts-2-allyl-5-phenyl-pyrrolidine in 62% yield.
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2 equiv. KF
2 equiv. TMS-allyl
1 equiv. BF3 Et2O
Ts
N
NHTs
20 mol% AgOAc
HFIP, 55 oC, 8 h
DCM, rt, 12 h
Remove the solvent
1a
6a
Yield 62%
Scheme 4. A one pot reaction
The practical application of our method was finally test (Scheme 5). When the
intramolecular hydroamination cyclization-hydroalkoxylation reaction of 1a was carried
out on a 2 mmol scale in the presence of 10 mol% AgOAc, desired product 2a was
generated in 86 % yield (Scheme 5, eq. 1). And the pharmaceutical intermediate of
trandolapril could be readily synthesized in good yield from 2q (eq.2). This synthesis
method of trandolapril intermediate 6p was simpler and more efficient than that of
previously reported.14 Besides, we could also successfully achieved the late
functionalization of β-Estradiol (Scheme 5, eq.3).
1) the scale-up experiment
Ts
NHTs
10 mol% AgOAc
N
O
CF3
HFIP, 50 oC
F3C
1a
2a
2 mmol, 0.6 g
0.81 g, Yield 86%
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2) the synthesis of Trandolapril pharmaceutical mediate 6p
4
5
6
7
Ts
N
F3C
O
Ts
N
1.0 equiv BF3 Et2O
2.0 equiv KF
NHTs
CF3
5 mol% Ph3PAuCl
HFIP, 50 o
CN
C
2.0 equiv TMSCN
DCM, rt
8
2q, Yield 51 %
6p, Yield 99%
9
76 %
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HN
O
CO2Et
H
N
CO2H
H
Trandolapril
3) Late modification of -estradiol
β
OH
H3C
H3C
OH
Ts
N
Ts
H
H
1 equiv BF3 Et2O
HFIP, rt
H
H
N
O
+
CF3
H
H
F3C
HO
HO
yield: 85%
dr: cis/trans = 5/4
Scheme 5. The application of this methodology
CONCLUSION
In conclusion, we have developed a simple and highly efficient method for
stereoselective synthesis of 1, 2, 5-trisubstituted pyrrolidines via cyclic N,O-acetals, which
were obtained by means of intramolecular hydroamination cyclization- hydroalkoxylation
in HFIP. Notably, the cyclic N,O-acetals could be further facilely used for the formation of
various C-C and C-S, C-N and other C-O bonds, thus constructing diverse functionalized
multiple substituted pyrrolidines in excellent diastereoselectivity. And we observed that
the HFIP played multiple roles, a solvent, an acidic proton source and a nucleophile as well
as a good leaving group in this method. The weak nucleophilicity of HFIP is amplified as
an advantageous nucleophile by hydrogen-bond cluster and coordination with AgOAc
modes, and the hexafluoroisopropoxy group on the resulting N,O-acetals facilitates late
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modification at the 2-site of pyrrolidine due to its good leaving ability. Additionally,
enantioenriched products could be obtained from simple chiral starting materials. A
possible reaction mechanism was also proposed and DFT study discovered HFIP acting as
a proton-bridge deliever and a cocatalyst with AgOAc. Besides, we demonstrated the utility
of the method by using it to synthesize pharmaceutical intermediate from simple substrate.
From a synthetic viewpoint, the stereospecific cyclic N,O-acetals would endow themselves
diverse reactivity for preparing functionalized stereoselective cyclic amines, as will
provide a highly efficient and highly stereoselective protocol for the synthesis of mulitiple
substituted pyrrolidines.
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EXPERIMENTAL SECTION
1. General Information
The data for NMR spectra (1H NMR, 13C NMR and 19F NMR) were recorded at 293 K
1
13
on a Bruker AVANCE AV 400 (400 MHz, 101 MHz and 376 MHz). H and C NMR
Chemical shifts were calibrated to tetramethylsilane as an internal reference. Chemical
shifts (δ) were reported with respect to the corresponding solvent residual peak at 7.26 ppm
for CDCl3 for 1H NMR. 13C NMR spectra (1H-broadband decoupled) were reported in ppm
using the central peak of CDCl3 (77.16 ppm). Chemical shifts are given in (ppm) and
coupling constants (J) in Hz. The following abbreviations are used to indicate the
multiplicity: s, singlet; d, doublet: t, triplet; q, quartet; m, multiplet; High resolution mass
spectrometric (HRMS) analyses spectrum was determined on the Varian 7.0T FTMS
instrument. Chiral high performance liquid chromatography (HPLC) analysis was
performed using an Agilent 1260II with commercial ChiralCel 4.6 × 250 mm (OD - H)
column and Chiralpak IC column.
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1) Synthesis and characterization of the homopropargylic sulfonamides 1a-1q, 1r-1s,
1v and 4-methyl-N-(pent-4-yn-1-yl) benzenesulfonamide 1w
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Compounds 1a-1g, 1n, 1q, 1r, 1s, 1v and 1w were prepared according to the known
procedures.15
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To a solution of aldehyde (20 mmol) in dry DCM (50 mL) was added sulfonamide
derivatives (1.0 equiv.) and 4Å molecular sieves (1 g/mmol). The resulting reaction
mixture was stirred at 60 oC on a heating block until the reaction was completed (by TLC).
Filtration by flash silical gel chromatography with DCM as eluent and then removal of the
solvent under reduced pressure afforded the desired sulfimides S1 as a white solid, which
was used without further purification.16
To a solution of imide S1 (10.0 mmol, 1.0 equiv.) in THF (30 mL) was added the
activated zinc (975 mg, 15 mmol, 1.5 equiv.) at 0 °C. Then propargylic bromide (1.7 mL,
15 mmol, 1.5 equiv.) was added at 0 °C and the mixture stirred at room temperature for
overnight. Aqueous sat. NH4Cl (10 mL) was added and the aqueous phase extracted with
Et2O (3 x 30 mL). After the organic layers were dried over anhydrous MgSO4 and
concentrated under reduced pressure, the desired compound S2 was isolated. The spectral
data are in good agreement with previous reports.17
N-(1-(2-fluorophenyl) but-3-yn-1-yl)-4-methylbenzenesulfonamide (1h). White solid, mp 117.1-
118.2 °C, 2.4 g, yield 75 %, 1H NMR (400 MHz, Chloroform-d) δ 7.64 – 7.62 (d, J = 8.0
H z, 2H), 7.22 – 7.14 (m, 4H), 7.00 – 6.96 (t, J = 7.6 Hz, 1 H), 6.91 – 6.86 (dd, J = 8.4 Hz,
1H), 5.49 – 5.47 (d, J = 8.0 Hz, 1H), 4.80 – 4.75 (q, J = 6.4 Hz, 1H), 2.66 – 2.64 (q, J =
6.0, 2.0 Hz, 2H), 2.35 (s, 3H), 1.95 – 1.94 (t, J = 2.0 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 161.1 (d, J = 244.4 Hz), 143.5, 137.1, 129.5 (d, J = 8.3 Hz), 129.5, 128.8 (d, J =
4.0 Hz), 127.2, 126.5 (d, J = 12.8 Hz), 124.1 (d, J = 3.2 Hz), 115.5 (d, J = 21.4 Hz), 78.9,
72.2, 51.2, 26.6, 21.6. HRMS (ESI+) calculated for C17H17FNO2S(M+H+) 318.0959; found
318.0950.
N-(1-(3-fluorophenyl) but-3-yn-1-yl)-4-methylbenzenesulfonamide (1i). White solid, mp 115.1-
116.9 °C, 2.27 g, yield 71 %, 1H NMR (400 MHz, Chloroform-d) δ 7.63 – 7.61 (d, J = 8.0
Hz, 2H), 7.20 – 7.16 (t, J = 8.0 Hz, 3H), 6.97 – 6.83 (m, 3H), 5.34 – 5.33 (d, J = 7.2 Hz,
1H), 4.53 – 4.48 (q, J = 6.4 Hz, 1H), 2.66 – 2.55 (m, 2H), 2.39 (s, 3H), 2.00 (s, 1H). 13C{1H}
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NMR (101 MHz, CDCl3) δ 162.8 (d, J = 245.1 Hz), 143.7, 141.9 (d, J = 6.9 Hz), 137.2,
130.1 (d, J = 8.1 Hz), 129.6, 127.3, 122.4 (d, J = 2.8 Hz), 114.9 (d, J = 20.9 Hz), 113.9 (d,
J = 22.3 Hz), 78.7, 72.7, 55.3, 27.3, 21.6. HRMS (ESI+) calculated for C17H17FNO2S
(M+H+) 318.0959; found 318.0963.
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N-(1-(2-bromo-4-fluorophenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide (1j). White solid,
mp 175.9-177.0 °C, 2.17 g, yield 55 %, 1H NMR (400 MHz, Chloroform-d) δ 7.65 – 7.63
(d, J = 8.0 Hz, 2H), 7.29 – 7.27 (t, 1H), 7.20 – 7.18 (d, J = 8.0 Hz, 3H), 6.90 – 6.86 (m,
1H), 5.38 – 5.37 (d, J = 7.2 Hz, 1H), 4.92 – 4.87 (q, J = 6.0 Hz, 1H), 2.69 – 2.50 (m, 2H),
2.38 (s, 3H), 2.00 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.7 (d, J = 249.7 Hz),
143.8, 136.7, 134.4, 129.8 (d, J = 8.5 Hz), 129.6, 127.3, 122.3 (d, J = 9.2 Hz), 119.9 (d, J
= 24.4 Hz), 114.7 (d, J = 20.9 Hz), 78.2, 72.9, 54.1, 26.2, 21.6. HRMS (ESI+) calculated
for C17H16FBrNO2S (M+H+) 396.0064; found 396.0074.
4-methyl-N-(1-(pyridin-3-yl)but-3-yn-1-yl)benzenesulfonamide (1m). Earth yellow solid, 1.11 g,
yield 37 %, 1H NMR (400 MHz, Chloroform-d) δ 8.48 – 8.43 (t, J = 4.8 Hz, 2H), 7.64 –
7.58 (m, 3H), 7.22 – 7.17 (m, 3H), 5.47 – 5.45 (d, J = 7.2 Hz, 1H), 4.58 – 4.53 (q, J = 6.4
Hz, 1H), 2.71 – 2.58 (m, 2H), 2.39 (s, 3H), 2.04 – 2.03 (t, J = 2.4 Hz, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 149.1, 148.3, 143.9, 137.1, 135.1, 134.6, 129.8, 127.3, 123.5, 78.3,
73.2, 53.6, 27.2, 21.7. HRMS (ESI+) calculated for C16H17N2O2S (M+H+) 301.1005; found
301.1013
2) Synthesis and characterization of the homopropargylic sulfonamide 1o
To the solution of phenylacetaldehyde S3 (1.20 g, 10 mmol) and Zn powder (0.98 g, 15
mmol) was added propargylic bromide (1.77 g, 1.2 mL, 15 mmol) at 0 °C and warm up to
room temperature. After the reaction mixture was stirred overnight, it was quenched with
saturated aq NH4Cl (20 mL) and extracted with AcOEt (3 x 30 mL). The organic layer was
dried over with anhydrous MgSO4 and filtrated. The filtrate was concentrated under
reduced pressure. The residue S4 was used without extra purification.
To the solution of PPh3 (1.89 g, 7.2 mmol), N-Boc-4-methylbenzene- sulfonamide (1.63
g, 6.0 mmol) and S4 (754 mg, 6.0 mmol) in THF (43mL) was added DIAD (1.55 mL, 7.2
mmol) at room temperature. After the reaction mixture was stirred for 36 h, it was quenched
with saturated NaHCO3 aqueous (10 mL) and extracted with AcOEt (3 x 15 mL). The
organic layer was washed with brine, dried over with MgSO4 and filtrated. The filtrate was
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concentrated under reduced pressure. The residue was purified by silica gel column
chromatography with AcOEt and Petroleum (1/5) to give S5 (1.98 g, 4.8 mmol, 80%).
To the solution of S5 (1.98 g, 4.8 mmol) in CH2Cl2 (10.0 mL) was added TFA (18.0 mL,
24 mmol) at 0 °C and warm up to room temperature. After the reaction mixture was stirred
for 24 h, it was quenched with saturated aq. NaHCO3 (5 mL) and extracted with AcOEt (3
x 10 mL). The organic layer was washed with brine, dried over with MgSO4 and filtrated.
The filtrate was concentrated under reduced pressure. The residue was purified by silica
gel column chromatography with AcOEt and Petroleum (1/5) to give 1o (689 mg, 2.2 mmol,
45%).
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4-methyl-N-(1-phenylpent-4-yn-2-yl)benzenesulfonamide(1o). White solid, mp 111.7-113.2 °C,
689 mg, yield 45 %, 1H NMR (400 MHz, Chloroform-d) δ 7.64 – 7.62 (d, J = 8.0 Hz, 2H),
7.25 – 7.19 (m, 5H), 7.06 – 4.04 (d, J = 6.0 Hz, 2H), 5.00 – 4.99 (d, J = 8.4 Hz, 1H), 3.55
– 3.54 (d, J = 6.0 Hz, 1H), 2.90 – 2.76 (m, 2H), 2.40 (s, 3H), 2.29 (s, 2H), 2.06 (s, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 143.4, 137.4, 136.8, 129.7, 129.3, 128.6, 127.0, 126.8,
79.6, 72.1, 53.3, 39.9, 24.2, 21.6. HRMS (ESI+) calculated for C18H20NO2S (M+H+)
314.1209; found 314.1201.
3) Synthesis and characterization of the homopropargylic sulfonamides 1t and 1u
4-Nitrobenzenesulfonyl chloride or 4-Methoxybenzenesulfonyl chloride (1.2 mmol) was
added to a mixture of 1-phenylbut-3-yn-1-amine S618 (1 mmol), and Et3N (2 mmol) in
CH2Cl2 (5 mL). The reaction was stirred at room temperature for overnight. The reaction
mixture was diluted with CH2Cl2 (10 mL), washed with 5 % of aqueous NaOH, brine, dried
with anhydrous MgSO4, and concentrated under vacuum. The residue was purified through
silica gel flash chromatography to give desired homopropargyl amine.
4-nitro-N-(1-phenylbut-3-yn-1-yl)benzenesulfonamide (1t). White solid, mp 155.8-157.0 °C,
248 mg, yield 75 %, 1H NMR (400 MHz, Chloroform-d) δ 8.15 – 8.13 (d, J = 8.0 Hz, 2H),
7.81 – 7.79 (d, J = 8.0 Hz, 2H), 7.22 – 7.09 (m, 5H), 5.49 – 5.47 (d, J = 7.2 Hz, 1H), 4.67
– 4.62 (q, J = 6.4 Hz, 1H), 2.77 – 2.61 (m, 2H), 2.06 (s, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 149.9, 146.3, 138.4, 128.7, 128.5, 126.7, 124.0, 78.7, 72.9, 56.3, 27.6. HRMS
+
(ESI+) calculated for C16H18N3O4S (M+NH4 ) 348.1013; found 348.1012.
4-methoxy-N-(1-phenylbut-3-yn-1-yl)benzenesulfonamide (1u). White solid, mp 121.1-
122.2 °C, 72 mg, yield 23 %, 1H NMR (400 MHz, Chloroform-d) δ 7.67 – 7.65 (d, J = 9.2
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Hz, 2H), 7.21 – 7.13 (m, 5H), 6.84 – 6.82 (d, J = 9.2 Hz, 2H), 5.38 – 5.35 (t, J = 7.2 Hz,
1H), 4.51 – 4.46 (q, J = 6.4 Hz, 1H), 3.82 (s, 3H), 2.65 – 2.62 (q, J = 2.4 Hz, 2H), 1.99 –
1.97 (t, J = 2.4 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.9, 139.3, 131.9, 129.4,
128.6, 128.0, 126.7, 114.1, 79.3, 72.2, 55.9, 55.7, 27.4. HRMS (ESI+) calculated for
C17H18NO3S (M+H+) 316.1002; found 316.1004.
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N-(1-phenylpent-4-yn-2-yl)benzamide (1y). Compound 1y was synthesized from the known
literature19. White solid, mp 112.0-113.0 °C, 144 mg, yield = 87.4 %, 1H NMR (400 MHz,
Chloroform-d) δ 7.73 – 7.72 (d, J = 7.2 Hz, 2H), 7.50 – 7.39 (m, 3H), 7.33 – 7.22 (m, 5H),
6.43 – 6.41 (d, J = 8 Hz, 1H), 4.55 – 4.47 (m, 1H), 3.10 – 2.96 (m, 2H), 2.56 – 2.37 (m,
13
2H), 2.14 – 2.13 (t, J = 2.4 Hz, 1H). C{1H} NMR (101 MHz, CDCl3) δ 167.0, 137.5,
134.6, 131.6, 129.4, 128.7, 128.7, 127.0, 126.9, 80.3, 71.7, 48.9, 39.1, 22.8. HRMS (ESI+)
calculated for C18H18NO (M+H+) 264.1383; found 264.1386.
4) The synthesis of the chiral homopropargylic sulfonamine 1a'
To a solution of (R)-tert-butanesulfinamide (2.42 g, 20 mmol) in DCM (24 mL) was
added Ti(OEt)4 (9.12 g, 4.2 mL, 40 mmol) followed by benzaldehyde (2.12 g, 20 mmol).
The mixture was stirred at 60 oC on a heating block overnight. The reaction mixture was
washed by a lot of saturated NaCl solution. The aqueous layer was extracted with AcOEt.
The combined organic layers were dried over MgSO4 and concentrated give sulfinimine
S7 (4.0 g, 88%, colorless liquid).20
To a solution of the sulfinimine S7 (1.33 g, 5 mmol) in DCM (50 mL) was added
propargylmagnesium bromide ether solution (50 mL, 10 mmol) slowly at -48 ºC. The
mixture was stirred at -48 ºC for 2 h and then was allowed to warm to room temperature
and stirred overnight. The reaction mixture was quenched with 15 mL of saturated
ammonium chloride aqueous solution and the aqueous layer was extracted with DCM.
The combined organic layers were dried over MgSO4 and removed the solvent . The
residue was purified through silica gel flash chromatography (eluents: Hexanes: ethyl
acetate = 5 : 1) to give desired product S8 (1.12 g, colorless liquid) in 90% yield.
The above sulfinamide S8 (249 mg, 1.0 mmol) was dissolved in MeOH (12 mL) and the
solution was cooled to 0 ºC. Concentrated hydrochloric acid (2.2 equiv.) was added, and
the reaction mixture was stirred at 0 ºC for 30 minutes. The solvent was evaporated, water
was added and acid base work up to give pure amine S6' (0.142 g, yellow liquid) in 98%
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p-toluenesulfonyl chloride (1.2 mmol) was added to a mixture of S6' (1 mmol), and Et3N
(2 mmol) in CH2Cl2 (5 mL). The reaction was stirred at room temperature for overnight.
The reaction mixture was diluted with CH2Cl2 (10 mL), washed with 5 % of aqueous NaOH,
brine, dried with anhydrous MgSO4, and concentrated under vacuum. The residue was
purified through silica gel flash chromatography to give desired pure homopropargyl amine
1a'.19
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5) Synthesis and characterization of 2
Condition A:
To a solution of the compound 1 (0.2 mmol) in HFIP (1 mL) was added AgOAc (6.6
mg, 0.04 mmol). The reaction was heated to 50 oC on a heating block and stired until the
homopropargylic sulfonamides disappeared. The reaction mixture was purified through
silica gel flash chromatography to give desired compound 2.
Condition B:
To a solution of the homopropargylic sulfonamides (0.2 mmol) in HFIP (1 mL) was
added Ph3PAuCl (5.0 mg, 0.01 mmol). The reaction was heated to 50 oC on a heating block
and stired until the homopropargylic sulfonamides disappeared. The reaction mixture was
purified through silica gel flash chromatography to give desired compound 2.
cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-5-phenyl-1-tosylpyrrolidine (2a/2a'). Condition A:
Colorless solid, mp 57.0 - 58.3 °C, 89 mg, yield 95 %, [α]D20 = −109.0° (c = 0.50, CHCl3),
97.3% ee,1H NMR (400 MHz, Chloroform-d) δ 7.58 – 7.56 (d, J = 8.0 Hz, 2H), 7.30 – 7.21
(m, 7H), 5.67 – 5.66 (d, J = 4.2 Hz, 1H), 5.23 – 5.15 (m, 1H), 4.43 – 4.39 (dd, J = 2.8, 9.6
Hz, 1H), 2.41 (s, 3H), 2.26 – 2.08 (m, 3H), 1.60 – 1.51 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 144.5, 140.6, 134.4, 130.0, 128.4, 127.8, 127.7, 127.0, 93.2, 72.1 (m), 66.7, 34.5,
19
32.7, 21.7. F{1H} NMR (376 MHz, CDCl3): δ - 69.0 to - 69.2 (m, 6F). HRMS (ESI+)
calculated for C20H19F6NNaO3S (M+Na+) 490.0882; found 490.0874. HPLC analysis
(Chiralpak IC column, hexane/2-propanol = 95:5, flow rate = 1.0 mL/min, wavelength =
254 nm): tR = 5.99 min (major) and 7.21 min (minor).
cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-5-(4-methoxyphenyl)-1-tosyl pyrrolidine (2b).
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Condition A: Colorless viscous liquid, 92 mg, yield 93 %, H NMR (400 MHz,
Chloroform-d) δ 7.57 – 7.55 (d, J = 8.4 Hz, 2H), 7.26 – 7.19 (dd, J = 8.4, 8.8 Hz, 4H), 6.81
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– 6.78 (d, J = 6.8 Hz, 2H), 5.66 – 5.65 (d, J = 4.2 Hz, 1H), 5.20 – 5.12 (m, 1H), 4.40 – 4.36
(q, J = 6.8 Hz, 1H), 3.78 (s, 3H), 2.41 (s, 3H), 2.23 – 2.07 (m, 3H), 1.60 – 1.50 (m, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 159.3, 144.4, 134.6, 132.5, 129.9, 128.3, 127.8, 113.9,
93.2, 72.1 (m), 66.2, 55.4, 34.4, 32.6, 21.6. 19F{1H} NMR (376 MHz, CDCl3): δ - 68.7 to
- 69.1 (m, 6F). HRMS (ESI+) calculated for C21H21F6NNaO4S (M+Na+) 520.0988; found
520.0983.
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cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-5-(p-tolyl)-1-tosylpyrrolidine (2c). Condition A:
Colorless viscous liquid, 90 mg, yield 94 %, 1H NMR (400 MHz, Chloroform-d) δ 7.58 –
7.56 (d, J = 8.4 Hz, 2H), 7.26 – 7.24 (d, J = 8.4 Hz, 2H), 7.19 – 7.17 (d, J = 8.0 Hz, 2H),
7.09 – 7.07 (d, J = 8.0 Hz, 2H), 5.65 – 5.64 (d, J = 4.2 Hz, 1H), 5.24 – 5.15 (m, 1H), 4.39
– 4.34 (q, J = 7.2 Hz, 1H), 2.41 (s, 3H), 2.31 (s, 3H), 2.21 – 2.07 (m, 3H), 1.58 – 1.48 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.5, 137.6, 137.5, 134.5, 129.9, 129.2, 127.8,
127.0, 93.2, 72.0 (m), 66.5, 34.4, 32.7, 21.6, 21.2. 19F{1H} NMR (376 MHz, CDCl3): δ -
68.6 to – 68.9 (m, 6F). HRMS (ESI+) calculated forC21H21F6NNaO3S (M+Na+) 504.1039;
found 504.1042.
cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosyl-5-(4-(trifluoromethyl)phenyl) pyrrolidine
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(2d). Condition A: Colorless viscous liquid, 87 mg, yield 81 %, H NMR (400 MHz,
Chloroform-d) δ 7.55 – 7.53 (d, J = 8.4 Hz, 2H), 7.51 – 7.49 (d, J = 8.0 Hz, 2H), 7.39 –
7.37 (d, J = 8.0 Hz, 2H), 7.24 – 7.22 (d, J = 8.0 Hz, 2H), 5.72 – 5.71 (d, J = 4.2 Hz, 1H),
5.21 – 5.12 (m, 1H), 4.51 – 4.47 (q, J = 7.2 Hz, 1H), 2.40 (s, 3H), 2.33 – 2.27 (m, 1H), 2.18
– 2.08 (m, 2H), 1.68 – 1.57 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.9, 144.8 (d,
J = 1.2 Hz), 134.1, 130.0, 127.8, 127.3, 125.4 (q, J = 3.7 Hz), 93.2, 72.2 (m), 65.9, 34.5,
32.8, 21.6. 19F{1H} NMR (376 MHz, CDCl3): δ - 58.2 (s, 3F), - 68.6 to - 69.0 (m, 6F).
HRMS (ESI+) calculated for C21H18F9NNaO3S (M+Na+) 558.0756; found 558.0748.
cis-2-(4-fluorophenyl)-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosyl
pyrrolidine
(2e).
Condition A: Colorless solid, mp 106.7-108.5 °C, 94 mg, yield 97 %, 1H NMR (400 MHz,
Chloroform-d) δ 7.58 – 7.55 (d, J = 8.4 Hz, 2H), 7.28 – 7.24 (m, 4H), 6.98 – 6.93 (m, 2H),
5.66 – 5.65 (d, J = 5.6 Hz, 1H), 5.21 – 5.12 (m, 1H), 4.42 – 4.38 (q, J = 6.8 Hz, 1H), 2.42
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(s, 3H), 2.26 – 2.07 (m, 3H), 1.61 – 1.50 (m, 1H). C{1H} NMR (101 MHz, CDCl3) δ
162.3 (d, J = 245 Hz), 144.8, 136.5 (d, J = 2.9 Hz), 134.2, 130.0, 128.7 (d, J = 8.2 Hz),
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127.7, 115.3 (d, J = 21.5 Hz), 93.2, 72.0 (m), 65.9, 34.4, 32.6, 21.6. F{1H} NMR (376
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MHz, CDCl3): δ - 110.69 to -110.74 (m, 1F), - 68.6 to - 69.0 (m, 6F). HRMS (ESI+)
calculated for C20H18F7NNaO3S (M+Na+) 508.0788; found 508.0793
cis-2-(4-chlorophenyl)-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosyl
pyrrolidine
(2f).
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Condition A: white solid, mp 100.0-102.3 °C, 90 mg, yield 90 %, H NMR (400 MHz,
Chloroform-d) δ 7.57 – 7.55 (d, J = 8.4 Hz, 2H), 7.28 – 7.22 (t, J = 8.0 Hz, 6H), 5.66 –
5.64 (d, J = 5.2 Hz, 1H), 5.22 – 5.13 (m, 1H), 4.40 – 4.36 (q, J = 7.2 Hz, 1H), 2.42 (s, 3H),
2.26 – 2.04 (m, 3H), 1.60 – 1.49 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.8, 139.3,
134.2, 133.5, 130.0, 128.6, 128.4, 127.8, 93.2, 72.1 (m), 65.9, 34.4, 32.7, 21.6. 19F{1H}
NMR (376 MHz, CDCl3): δ - 68.6 to - 68.9 (m, 6F). HRMS (ESI+) calculated for
C20H18ClF6NNaO3S (M+Na+) 524.0492; found 524.0480
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cis-2-(4-bromophenyl)-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosyl
pyrrolidine
(2g).
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Condition A: white solid, mp 98.7-100.3 °C, 92 mg, yield 85 %, H NMR (400 MHz,
Chloroform-d) δ 7.56 – 7.54 (d, J = 8.4 Hz, 2H), 7.39 – 7.37 (d, J = 8.4 Hz, 2H), 7.27 –
7.25 (d, J = 8.0 Hz, 2H),7.16 – 7.14 (d, J = 8.4 Hz, 2H), 5.66 – 5.65 (d, J = 4.2 Hz, 1H),
5.20 – 5.12 (m, 1H), 4.39 – 4.35 (q, J = 7.2 Hz, 1H), 2.43 (s, 3H), 2.27 – 2.04 (m, 3H), 1.62
– 1.51 (m, 1H). C{1H} NMR (101 MHz, CDCl3) δ 144.8, 139.8, 134.2, 131.6, 130.0,
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128.7, 127.8, 121.7, 93.2, 72.1 (m), 65.9, 34.4, 32.7, 21.7. F{1H} NMR (376 MHz,
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CDCl3): δ - 68.8 to - 69.2 (m, 6F). HRMS (ESI+) calculated for C20H18BrF6NNaO3S
(M+Na+) 567.9987; found 567.9980.
cis-2-(2-fluorophenyl)-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosyl
pyrrolidine
(2h).
Condition B: Colorless solid, mp 110.3-111.1 °C, 82 mg, yield 85 %, 1H NMR (400 MHz,
Chloroform-d) δ 7.68 – 7.66 (d, J = 7.6 Hz, 2H), 7.56 – 7.53 (t, J = 6.8 Hz, 1H), 7.33 –
7.31 (d, J = 7.6 Hz, 2H), 7.24 – 7.21 (t, J = 7.6 Hz, 1H), 7.14 – 7.11 (t, J = 6.8 Hz, 1H),
7.00 – 6.95 (t, J = 9.2 Hz, 1H), 5.59 – 5.58 (d, J = 4.4 Hz, 1H), 5.32 – 5.29 (t, 1H), 4.81 –
4.77 (t, J = 6.8 Hz, 1H), 2.42 (s, 3H), 2.28 – 2.26 (d, J = 6.0 Hz, 1H), 2.10 – 2.07 (d, J =
9.2 Hz, 2H), 1.50 – 1.45 (q, J = 7.2 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.1 (d,
J = 243.6 Hz), 144.9, 133.7, 130.2, 129.1 (d, J = 8.3 Hz), 128.5 (d, J = 2.5 Hz), 128.0 (d, J
= 12.3 Hz), 127.9, 124.5 (d, J = 3.4 Hz), 115.0 (d, J = 21.8 Hz), 93.1, 71.9 (m), 59.0, 33.0,
32.7, 21.7. 19F{1H} NMR (376 MHz, CDCl3): δ - 116.7 to -116.8 (m, 1F), - 68.6 to - 68.9
(m, 6F). HRMS (ESI+) calculated for C20H18F7NNaO3S (M+Na+) 508.0788; found
508.0778.
cis-2-(3-fluorophenyl)-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosyl
pyrrolidine
(2i).
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Condition B: Colorless solid, mp 97.0-98.1 °C, 78 mg, yield 81 %, H NMR (400 MHz,
Chloroform-d) δ 7.59 – 7.57 (d, J = 7.6 Hz, 2H), 7.28 – 7.20 (m, 3H), 7.08 – 7.06 (d, J =
7.6 Hz, 1H), 7.00 – 6.97 (d, J = 10.0 Hz, 1H), 6.94 – 6.90 (t, J = 8.4 Hz, 1H), 5.67 – 5.66
(d, J = 5.2 Hz, 1H), 5.22 – 5.15 (m, 1H), 4.42 – 4.39 (t, J = 8.4 Hz, 1H), 2.42 (s, 3H), 2.28
– 2.22 (m, 1H), 2.17 – 2.06 (m, 2H), 1.61 – 1.53 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3)
δ 162.9 (d, J = 244.6 Hz), 144.8, 143.5, 134.2, 130.0, 130.0 (d, J = 8.8 Hz), 127.8, 122.6,
114.6 (d, J = 21.0 Hz), 113.9 (d, J = 22.2 Hz), 93.2, 72.2 (m), 66.0, 34.4, 32.7, 21.7. 19F{1H}
NMR (376 MHz, CDCl3): δ - 108.98 to -109.04 (m, 1F), - 68.8 to - 69.1 (m, 6F). HRMS
(ESI+) calculated for C20H18F7NNaO3S (M+Na+) 508.0788; found 508.0787.
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cis-2-(2-bromo-4-fluorophenyl)-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosyl
pyrrolidine
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(2j). Condition A: Colourless viscous liquid, 89 mg, yield 79 %, H NMR (400 MHz,
Chloroform-d) δ 7.69 – 7.67 (d, J = 8.0 Hz, 2H), 7.61 – 7.57 (dd, J = 6.4 Hz, 1H), 7.34 –
7.32 (d, J = 8.0 Hz, 2H), 7.23 – 7.21 (dd, J = 2.8 Hz, 1H), 7.04 – 7.00 (m, 1H), 5.62 – 5.61
(d, J = 5.6 Hz, 1H), 5.34 – 5.25 (m, 1H), 4.85 – 4.80 (dd, J = 6.8 Hz, 1H), 2.44 (s, 3H),
2.41 – 2.35 (m, 1H), 2.12 – 2.07 (dd, J = 6.0 Hz, 1H), 1.94 – 1.84 (m, 1H), 1.56 – 1.46 (m,
1H). C{1H} NMR (101 MHz, CDCl3) δ 161.6 (d, J = 250.1 Hz), 145.0, 136.2, 133.4,
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130.2, 129.6 (d, J = 8.7 Hz), 128.0, 121.9 (d, J = 9.6 Hz), 119.5 (d, J = 24.3 Hz), 115.5 (d,
J = 21.0 Hz), 93.4, 72.2 (m), 65.1, 33.0, 32.7, 21.8. 19F{1H} NMR (376 MHz, CDCl3): δ -
108.8 (s, 1F), - 68.7 to - 69.0 (d, 6F). HRMS (ESI+) calculated for C20H17BrF7NNaO3S
(M+Na+) 585.9893; found 585.9885.
cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-5-(naphthalen-2-yl)-1-tosylpyrrolidine
(2k). Condition B: White solid, mp 132.1-133.4 °C, 94 mg, yield 91 %, 1H NMR (400 MHz,
Chloroform-d) δ 7.93 – 7.91 (t, J = 2.0, 6.8 Hz, 1H), 7.84 – 7.81 (t, J = 2.8, 6.8 Hz, 1H),
7.72 – 7.70 (t, J = 6.0, 2.8 Hz, 2H), 7.51 – 7.37 (m, 5H), 7.11 – 7.09 (d, J = 8.0 Hz, 2H),
5.83 – 5.82 (d, J = 5.2 Hz, 1H), 5.36 – 5.26 (m, 2H), 2.47 – 2.40 (m, 1H), 2.33 (s, 3H), 2.20
– 2.11 (m, 2H), 1.83 – 1.74 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.5, 135.9,
134.0, 133.7, 130.4, 129.7, 129.2, 128.0, 127.9, 126.2, 125.7, 125.5, 124.8, 122.2, 93.4,
72.7 (m), 63.3, 33.8, 32.8, 21.6. 19F{1H} NMR (376 MHz, CDCl3): - 68.7 to - 69.1 (m, 6F).
HRMS (ESI+) calculated for C24H21F6NNaO3S (M+Na+) 540.1039; found 540.1037.
cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-5-(thiophen-2-yl)-1-tosylpyrrolidine
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(2l). Condition A: Colourless viscous liquid, 71 mg, yield 75 %, H NMR (400 MHz,
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Chloroform-d) δ 7.58 – 7.56 (d, J = 8.0 Hz, 2H), 7.30 – 7.21 (m, 5H), 5.67 – 5.66 (d, J =
5.2 Hz, 1H), 5.23 – 5.15 (m, 1H), 4.43 – 4.39 (q, J = 6.8 Hz, 1H ), 2.41 (s, 3H), 2.26 – 2.08
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(m, 3H), 1.58 – 1.51 (m, 1H). C{1H} NMR (101 MHz, CDCl3) δ 144.5, 140.6, 134.4,
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130.0, 128.4, 127.8, 127.7, 127.0, 93.2, 72.1 (m), 66.7, 34.5, 32.7, 21.7. F{1H} NMR
(376 MHz, CDCl3): - 68.9 to - 69.1 (m, 6F). HRMS (ESI+) calculated for C18H17F6NNaO3S2
(M+Na+) 496.0446; found 496.0436.
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2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosylpyrrolidine (2n). Condition A:
Colourless viscous liquid, 76 mg, yield 97 %, 1H NMR (400 MHz, Chloroform-d) δ 7.69
– 7.67 (d, J = 8.0 Hz, 2H), 7.36 – 7.34 (d, J = 8.0 Hz, 2H), 5.42 – 5.41 (d, J = 4.8 Hz, 1H),
5.18 – 5.11 (m, 1H), 3.56 – 3.52 (t, J = 8.8 Hz, 1H ), 3.15 – 3.08 (q, J = 9.6 Hz, 1H), 2.44
(s, 3H), 2.11 – 2.00 (m, 2H), 1.85 – 1.79 (m, 1H), 1.33 – 1.24 (m, 1H). 13C{1H} NMR (101
MHz, CDCl3) δ 144.7, 134.4, 130.2, 127.5, 91.7, 70.6 (m), 69.9, 48.2, 33.1, 22.8, 21.6 .21
cis-2-benzyl-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosylpyrrolidine
(2o).
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Condition B: Colourless viscous liquid, 80 mg, yield 83 %, H NMR (400 MHz,
Chloroform-d) δ 7.73 – 7.71 (d, J = 8.0 Hz, 2H), 7.37 – 7.35 (t, J = 8.0 Hz, 2H), 7.32 –
7.28 (t, J = 7.2 Hz, 2H), 7.24 – 7.20 (t, J = 7.6 Hz, 3H), 5.42 – 5.41 (d, J = 5.2 Hz, 1H),
5.23 – 5.14 (m, 1H), 3.71 – 3.66 (dd, J = 2.4 Hz, 1H), 3.61 – 3.54 (m, 1H), 2.69 – 2.63 (t,
J = 12 Hz, 1H ), 2.44 (s, 3H), 1.95 – 1.83 (m, 2H), 1.74 – 1.67 (m, 1H), 1.12 – 1.02 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ144.8, 138.5, 134.3, 130.3, 129.2, 128.7, 127.5,
126.7, 93.0, 70.6 (m), 64.4, 43.7, 31.9, 29.8, 21.7. 19F{1H} NMR (376 MHz, CDCl3): - 69.0
to - 69.2 (m, 6F). HRMS (ESI+) calculated for C21H21F6NNaO3S (M+Na+) 504.1039; found
504.1037.
cis-2-cyclohexyl-5-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosylpyrrolidine (2p).
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Condition B: Colourless viscous liquid, 54 mg, yield 57 %, H NMR (400 MHz,
Chloroform-d) δ 7.67 – 7.65 (d, J = 6.4 Hz, 2H), 7.35 – 7.33 (d, J = 6.4 Hz, 2H), 5.42 (s,
1H), 5.14 (s, 1H), 3.37 (s, 1H ), 2.44 (s, 3H), 1.89 – 1.67 (m, 8H), 1.53 – 1.38 (m, 2H),
1.25 – 1.11 (m, 3H), 1.00 – 0.90 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.5, 134.9,
130.2, 127.4, 93.5, 71.7 (m), 67.9, 41.3, 31.9, 31.1, 27.5, 26.6, 26.4, 26.1, 25.8, 21.6.19F{1H}
NMR (376 MHz, CDCl3): - 68.6 to - 68.9 (m, 6F). HRMS (ESI+) calculated for
C20H25F6NNaO3S (M+Na+) 496.1352; found 496.1351.
cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-tosyloctahydro-1H-indole (2q).
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Condition B: Colourless solid, mp 109.3-110.1 °C,40 mg, yield 51 %, 1H NMR (400 MHz,
Chloroform-d) δ 7.67 – 7.66 (d, J = 5.2 Hz, 2H), 7.36 – 7.35 (d, J = 5.2 Hz, 2H), 5.30 (s,
2H), 2.46 (s, 4H), 1.94 – 1.69 (m, 5H ), 1.45 – 1.23 (m, 4H), 0.97 – 0.89 (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 144.7, 133.6, 130.1, 127.8, 91.8, 70.3 (m), 68.1, 42.5, 37.5,
32.4, 29.4, 25.3, 25.0, 21.7. 19F{1H} NMR (376 MHz, CDCl3): - 69.2 to - 69.5 (m, 6F).
HRMS (ESI+) calculated for C18H21F6NNaO3S (M+Na+) 468.1039; found 468.1045.
cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-(methylsulfonyl)-5-
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phenylpyrrolidine (2r). Condition A: Colourless solid, mp 103.0-104.1 °C,70 mg, yield
90 %, 1H NMR (400 MHz, Chloroform-d) δ 7.46 – 7.31 (m, 5H), 5.86 – 5.85 (d, J = 5.2
Hz, 1H), 4.80 – 4.69 (m, 1H), 2.52 – 2.46 (m, 1H), 2.41 (s, 3H), 2.39 – 2.31 (m, 2H ), 2.14
– 2.04 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ139.9, 129.1, 128.7, 128.0, 93.4, 73.9
(m), 65.8, 42.2, 34.5, 33.0. 19F{1H} NMR (376 MHz, CDCl3): - 69.2 to - 69.8 (m, 6F).
HRMS (ESI+) calculated for C14H15F6NNaO3S (M+Na+) 414.0569; found 414.0560.
cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-5-phenyl-1-
(phenylsulfonyl)pyrrolidine (2s). Condition A: Colourless viscous liquid, 80 mg, yield
88 %, 1H NMR (400 MHz, Chloroform-d) δ 7.68 – 7.66 (d, J = 7.6 Hz, 2H), 7.57 – 7.54 (t,
J = 7.2 Hz, 1H), 7.46 – 7.42 (t, J = 7.6 Hz, 2H), 7.29 – 7.22 (m, 5H), 5.71 – 5.70 (d, J =
4.8 Hz, 1H), 5.17 – 5.12 (m, 1H), 4.48 – 4.44 (m, 1H), 2.28 – 2.09 (m, 3H), 1.62 – 1.54
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(m, 1H ). C{1H} NMR (101 MHz, CDCl3) δ 140.4, 137.6, 133.5, 129.3, 128.5, 127.8,
127.7, 127.1, 93.3, 72.2 (m), 66.6, 34.5, 32.7. 19F{1H} NMR (376 MHz, CDCl3): - 68.5 to
- 68.9 (m, 6F). HRMS (ESI+) calculated for C19H17F6NNaO3S (M+Na+) 476.0726; found
476.0720.
cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-((4-nitrophenyl)sulfonyl)-5-
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phenylpyrrolidine (2t). Condition A: Colourless viscous liquid, 74 mg, yield 75 %, H
NMR (400 MHz, Chloroform-d) δ 8.09 – 8.07 (d, J = 8.8 Hz, 2H), 7.62 – 7.59 (d, J = 8.8
Hz, 2H), 7.20 – 7.13 (m, 5H), 5.92 – 5.90 (d, J = 4.8 Hz, 1H), 4.76 – 4.68 (m, 2H), 2.47 –
2.40 (m, 1H), 2.29 – 2.18 (m, 2H), 1.97 – 1.88 (m, 1H ). 13C{1H} NMR (101 MHz, CDCl3)
δ 150.0, 144.6, 138.9, 128.9, 128.6, 128.3, 127.8, 123.8, 93.1, 72.7 (m), 66.3, 34.3, 32.2.
19F{1H} NMR (376 MHz, CDCl3): - 68.8 to - 69.4 (m, 6F). HRMS (ESI+) calculated for
C19H16F6N2NaO5S (M+Na+) 521.0576; found 521.0569.
cis-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)-1-((4-methoxyphenyl)sulfonyl)-5-
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