Systematic Investigation of the Scope of Transannular C-H Heteroarylation of Cyclic Secondary Amines for Synthetic Application in Medicinal Chemistry

Article abstract of DOI:10.1021/acs.joc.0c00870

Transannular C-H heteroarylation of amines provides rapid access to complex scaffolds that are otherwise difficult to synthesize. Wide adaptation of this emerging reaction for medicinal chemistry requires a broad understanding of substrate scope and more robust experimental conditions. In this article, we report a new ligand to promote the transannular reaction of a range of fused- and bridged-bicyclic secondary amines with a broad set of heteroarenes. The method was also successfully applied to the arylation of one spiro-bicyclic amine, a class of substrates that has not been studied in the context of transannular C-H activation reactions. The broad application of this transannular C-H heteroarylation methodology is currently hampered by the difficulty of removing the directing group. The development of a new directing group that is easier to remove will expand the utility of this reaction.

Full text of DOI:10.1021/acs.joc.0c00870

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Article
A Systematic Investigation of the Scope of Transannular C-H Heteroarylation
of Cyclic Secondary Amines for Synthetic Application in Medicinal Chemistry
Zhe Li, Michael Dechantsreiter, and Sivaraman Dandapani
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00870 • Publication Date (Web): 16 Apr 2020
Downloaded from pubs.acs.org on April 16, 2020
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A Systematic Investigation of the Scope of Transannular C-H
Heteroarylation of Cyclic Secondary Amines for Synthetic
Application in Medicinal Chemistry
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Zhe Li*,†,‡, Michael Dechantsreiter*,†, Sivaraman Dandapani*,†
†Department of Medicinal Chemistry, Biotherapeutic and Medicinal Sciences, Biogen, Cambridge,
MA, USA
‡Biogen Postdoctoral Scientist Program, Biogen, Cambridge, MA, USA
ABSTRACT
Transannular C-H heteroarylation of amines provides rapid access to complex scaffolds that are
otherwise difficult to synthesize. Wide adaptation of this emerging reaction for medicinal chemistry
requires a broad understanding of substrate scope and more robust experimental conditions. In
this article, we report a new ligand to promote the transannular reaction of a range of fused- and
bridged-bicyclic secondary amines with a broad set of heteroarenes. The method was also
successfully applied to the arylation of one spiro-bicyclic amine, a class of substrates that has not
been studied in the context of transannular C-H activation reactions. The broad application of this
transannular C-H heteroarylation methodology is currently hampered by the difficulty of removing
the directing group. The development of a new directing group that is easier to remove will expand
the utility of this reaction.
INTRODUCTION
A very small number of synthetic organic transformations including amide bond formation, cross
coupling, aromatic nucleophilic substitution and reductive amination continues to dominate the
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landscape of chemical reactions used by medicinal chemists to invent small molecule drugs.1
Many modern advances in synthetic organic chemistry can better impact medicinal chemistry if
scopes and limitations of the reactions were better studied.
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Recently, the development of palladium catalyzed sp3 C-H activation of amines to functionalize
inert aliphatic C-H bonds has enabled rapid synthesis of complex scaffolds.2,3,4 In 2018, the Yu
group reported direct site-selective arylation and heteroarylation of aliphatic primary amines using
different transient directing groups (TDGs) and ligands (Scheme 1a).5 Sanford and co-workers
developed the transannular C-H arylation of secondary amines using a pre-installed directing
group (Scheme 1b).6 Presumably, this reaction involves a boat-like palladacycle intermediate for
functionalizing the transannular C-H bond.7,8,9 The arylation of various fused- and bridged-bicyclic
secondary amines were demonstrated successfully under the reaction conditions. However, only
two examples of heteroarylation were presented involving Boc-protected indole and pyridine
substrates.10 In this article, we report a broad investigation into the scope of this relatively new
transannular C-H arylation reaction using a panel of heteroaryl iodides, the identification of an
optimal ligand, as well as the evaluation of diverse fused- / bridged-bicyclic amines and a new
class of spiro-bicyclic amine substrate.
Scheme 1. Development of palladium catalyzed sp3 C-H functionalization of amines
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a) Jin-Quan Yu's work: site selective (hetero)arylation of primary amines
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7
Pd(OAc)2
TDG1
Ligand1
Pd(OAc)2
TDG2
Ligand2
H
R
H
R
Ar
R



NH2 Ar
 R'
NH2
H
NH2
H
(Het)ArI
(Het)ArI
 R'
 R'
8
CF3
NO2
via:
via:
9
O
O
O
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N
N
6
5
Cl
Pd
Pd
O
O
H
H
N
N

MeO
R1
R2
R1
R2

6-Membered Chelate
5-Membered Chelate
b) Melanie S. Sanford's work: transannular arylation of secondary amines
H
Ar
Ar
Pd(OAc)2
Ligand
SmI2
DG
DG
N
N
NH
ArI
C7F7
O
L1
fused and bridged
bicyclic amines
N
DG =
Ligand =
F
F
H Pd
N
F
CF3
F
O
HN
N
OH
via:
3-palladacycle
c) This work: transannular heteroarylation of secondary amines
O
L1
H
HetAr
HetAr
Pd(OAc)2
Ligand
SmI2
DG
DG
N
N
NH
HetArI
fused, bridged and spiro bicyclic amines
RESULTS AND DISCUSSION
Sanford and co-workers have identified 3-azabicyclo[3.1.0]hexane derivative 1 as the preferred
substrate for this transannular C-H activation reaction. Hence, we started our investigation with 1
and five common heteroaryl iodides using the first-generation conditions reported by Sanford
(Table 1). Unfortunately, most reactions failed to afford the desired heteroarylated amines except
the one with 3-iodopyrazole. The pyrazole-coupled amine 4 was detected with 80% uncalibrated
yield in the crude reaction mixture. We postulate that the failure of reactions using the current
conditions results from the large excess amount of heteroaryl iodide (30 equivalent) which may
strongly coordinate to the palladium and hence prohibit the successful completion of the catalytic
cycle. In 2018, the Sanford group reported their second-generation conditions for the transannular
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C-H arylation of amines using picolinic acid (L1) as the ligand to rescue the palladium catalyst
from forming off-cycle inactive species.11 Using this second generation conditions, we also
observed improved yields of products across all cases using only 3 equivalents of the heteroaryl
iodides. For example, quinazoline- and pyrazine-coupled amines (5 & 6) proceeded with more
than 85% uncalibrated yield, although thiazole- and pyridazine-coupled amine (3 & 7) were only
detected with 31% and 3% uncalibrated yields.
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Recently, it was demonstrated that the ligand could play a critical role to promote palladium
catalyzed C-H functionalization reactions by accelerating C-H bond cleavage or stabilizing the
active palladium catalyst.12 Numerous examples have been reported with different types of
ligands. Therefore, we conducted a screen to find a better ligand than picolinic acid (L1) to
improve the yield of heteroarylated amine product. We utilized the on-site automation capabilities
for the development of a rapid medium-throughput ligand screening protocol. A collection of 112
ligands was screened at a 0.01 mmol reaction scale and the high-performance liquid
chromatography (HPLC) yield of product was assessed based on the biphenyl internal standard
(see the Supporting Information for the representative ligands). In general, the employment of a
ligand improved the yields. Compared to other types of mono- and bi-dentate ligands, the
derivatives of pyridine-2-carboxylic acid were found to be superior to promote the reaction (Table
2). Compared to picolinic acid, 6-methylpicolinic acid increased the yield of product 3 from 27%
to 43%. More hindered substituents on the 6-position of the pyridine ligand appeared to be
detrimental. 6-Cl substituent on the ligand did not provide an improved yield of desired product 3.
6-methoxy picolinic acid facilitated the formation of product 3, although still not as effectively as
6-methyl picolinic acid. The bidentate chelation was shown to be necessary and the removal of
either the carboxylic acid or the pyridine functionality resulted in lower yields of 3.
Table 1. Initial investigation of transannular C-H heteroarylation reactionsa,b,c
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F
F
30 mol% Pd(OAc)2
HetAr
DG =
F
CF3
F
H
3.0 eq CsOPiv
t-AmylOH, air
130 oC, 18h
+
HetAr-I
HN
N
N
DG
DG
O
1
7
8
9
N
S
N
N
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N
N
2
3
4
DG
DG
N
DG
HetAr-I
(Sanford's 1st gen conditions)
No ligand,
(30 eq):
94%
94%
0%
80%
77%
L1 HetAr-I
(3.0 eq):
(Sanford's 2nd gen conditions)
5 mol%
,
31%
N
N
N
N
N
N
N
N
5
6
DG
7
DG
N
DG
HetAr-I
No ligand,
(Sanford's 1st gen conditions)
L1 HetAr-I
(30 eq):
0%
18%
86%
0%
3%
5 mol%
,
(3.0 eq):
87%
(Sanford's 2nd gen conditions)
aSanford’s 1st-gen conditions: 1 (0.01 mmol, 1 eq), HetArI (30 eq), Pd(OAc)2 (30 mol%), CsOPiv
(3 eq), t-AmylOH (100 µL), 130 oC, 18h. bSanford’s 2nd-gen conditions: 1 (0.01 mmol, 1 eq), HetArI
(3 eq), L1 (5 mol%), Pd(OAc)2 (30 mol%), CsOPiv (3 eq), t-AmylOH (100 µL), 130 oC, 18h. cHigh
performance liquid chromatography (HPLC) yield was measured without calibration, see the
Supporting Information for details.
Table 2. Ligand evaluationa,b
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N
30 mol% Pd(OAc)2
H
N
10 mol% Ligand
S
+
I
3.0 eq CsOPiv
t-AmylOH, air
130 oC, 18h
N
S
DG
N
N
DG
1
8
3
No Ligand
24%
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CO2H
, 27%
N
CO2H
N
CO2H
N
CO2H
L4
, 19%
L1
L2
, 40%
L3
, 43%
Ph
N
CO2H Cl
N
CO2H MeO
N
CO2H
N
CO2H
L9
, 36%
L5
, 34%
L6
, 29%
L7
L8
, 37%
, 34%
aConditions: 1 (0.01 mmol, 1 eq), 8 (3 eq), ligand (10 mol%), Pd(OAc)2 (30 mol%), CsOPiv (3 eq),
o
b
t-AmylOH (100 µL), 130 C, 18h. Calibrated HPLC yield using internal standard. See the
Supporting Information for the detailed procedure of ligand screening.
Table 3. Conditions optimizationa
N
30 mol% Pd(OAc)2
L3
H
N
10~20 mol%
S
+
I
3.0 eq CsOPiv
t-AmylOH, air
130 oC, 18h
N
S
DG
N
DG
1
8
3
Entry Pd(OAc)2
(mol%)
L3
8
T
HPLC yield Isolated yield
(oC)
(%)b
(%)
(mol%)
(eq)
-
1
2
3
4
5
6
7
8
30
30
30
50
100
50
50
50
10
10
10
10
10
20
10
10
1.3
2.0
3.0
3.0
3.0
3.0
3.0
2.0
130
130
130
130
130
130
150
150
41
48
43
53
20
50
52
38
-
-
40c/ 32d
-
-
-
-
aConditions: 1 (0.01 mmol, 1 eq), 8 (x eq), L3 (y mol%), Pd(OAc)2 (z mol%), CsOPiv (3 eq), t-
AmylOH (100 µL), 130 or 150 oC, 18h. bCalibrated HPLC yield using internal standard. See the
c
Supporting Information for the detailed procedure of conditions optimization. 0.2 mmol scale
reaction. Flash silica gel chromatography purification. d0.2 mmol scale reaction. HPLC purification.
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With the best ligand in hand, we optimized the conditions to improve the HPLC yield of product
up to 53% (Table 3). No attempt was made to decrease the loading of Pd(OAc)2, since this is not
a limiting factor at the discovery stages of a drug development program. Direct preparative HPLC
purification only afforded 18% isolated yield. Following Sanford’s procedure, treating the reaction
mixture with excess amount of aqueous hydrazine could rescue the product 3 from the
coordination to the palladium catalyst and an improved yield (32%) was obtained after preparative
HPLC purification. The yield could be further improved to 40% by switching the preparative HPLC
purification to silica gel chromatography purification.
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With the optimized conditions in hand, we next explored the scope of the heteroaryl iodides using
the 3-azabicyclo[3.1.0]hexane scaffold 1 as the substrate (Table 4). For efficiency of analysis and
separation, the heteroarylated products were isolated using our on-site automatic preparative
HPLC purification service. Heteroarylation with various iodoarenes containing one hetero atom,
such as thiophene, indole and pyridines, proceeded smoothly with around 50% yield of
heteroarylated amines (9-13). A broad collection of heteroarenes with two hetero atoms were all
successfully coupled with the amine substrate 1. The strongly coordinating thiazoles (3 & 14) and
benzothiazole groups (15) were compatible with the reaction conditions, as well as pyrazole (4)
and indazoles (16 & 17). Pyrimidines and pyrazines were also competent coupling partners and
functionalities such as bromo and ester groups were tolerated (5, 6, 18-21), allowing for further
derivatizations. Notably, reactions with protected azaindole (22) proceeded smoothly while those
with unsubstituted azaindole and indazole iodides failed to provide any product, probably due to
poisoned palladium catalyst by these strong coordinating heteroarenes. More importantly, various
heteroarenes containing three heteroatoms, such as aza-indazoles (23-24), imidazopyridine (25)
and imidazopyridazine (26), were also identified with more than 20% yield, which makes this
methodology attractive and synthetically useful for medicinal chemists.
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Table 4. Scope of heteroaryl iodide coupling partnersa,b
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6
7
8
9
30 mol% Pd(OAc)2
H
HetAr
L3
10 mol%
+
HetAr-I
3.0 eq CsOPiv
t-AmylOH, air
130 oC, 8~18h
N
N
DG
DG
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
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50
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52
53
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59
60
H
N
N
N
NC
S
N
N
N
DG
N
DG
DG
DG
b
b
b
9
10
11
12
, 61%
, 36%
, 54%
, 59%
F3C
N
N
N
N
S
S
S
N
N
N
DG
N
DG
DG
DG
b
b
b
13
3
14
15
, 78%
, 60%
, 40%
, 41%
N
N
N
N
N
N
N
N
N
N
N
N
DG
DG
DG
DG
b
16
17
18
, 59%
, 44%
, 31%
4
, 56%
N
N
N
N
CO2Me
Br
N
N
N
N
N
N
N
N
DG
DG
DG
DG
b
b
19
20
, 24%
, 41%
5
6
, 60%
, 56%
X
N
PhO2S
N
N
N
N
N
N
N
N
N
N
N
N
N
DG
DG
DG
X = 2-F-Bn
24
, 29%
DG
21
22
25
23
, 54%
, 45%
, 35%
N
N
N
N
N
N
N
N
DG
DG
26
, 28%
, 18%
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aConditions: 1 (0.2 mmol, 1 eq), HetAr-I (2~3 eq), L3 (10 mol%), Pd(OAc)2 (30 mol%), CsOPiv (3
eq), t-AmylOH (2.0 mL), 130 oC, 8~18h. Unless noted, products were purified by HPLC. bIsolated
yield by flash chromatography purification.
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While our protocol demonstrated extraordinary compatibility of a broad collection of heteroarenes,
numerous unsuccessful examples were also identified (see the supporting information for details).
We propose three possible reasons for the failure of reactions with these heteroaryl iodides. First,
the heteroaryl iodide is unstable under the reaction conditions. For instance, the iodo isoxazole
o
(27) underwent gradual decomposition at 130 C (Scheme 2.1a). Dehalogenation of heteroaryl
iodide in the presence of palladium catalyst, such as 28, was also detected as the major
competing reaction pathway to form the dehalogenated side product (29) dominantly. Second,
the heteroaryl iodide poisons the palladium catalyst. As mentioned above, the unsubstituted iodo
indazole 30 was inactive as a coupling partner in the reaction with 1, probably resulting from the
palladium catalyst poisoning. This postulation was supported by adding the corresponding
indazole (32) into the reaction of amine 1 with iodobenzene (31). The indazole 32 completely
inhibited the formation of arylated product 2 (Scheme 2.2). The third reason was the low reactivity
of heteroaryl iodide towards oxidative addition to palladium catalyst. For example, the success of
5-iodopyrimidine 33 as the coupling partner suggested pyrimidine would not poison the catalyst
under the standard conditions. The decomposition of 2-iodopyrimidine 34 was also excluded
indicated by the LCMS analysis of the reaction mixture and hence the low activity of 34 in the
Pd(II)/Pd(IV) catalytic cycle was likely the reason for the low yield of heteroarylated product 35.
Scheme 2. Rationale for unsuccessful heteroaryl iodides coupling partners
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1). The heteroaryl iodide was unstable under the reaction condition.
O
a)
thermally unstable at 130 oC
gradually decomposed
N
I
27
30 mol% Pd(OAc)2
L3
Bn
Bn
H
10 mol%
H
b)
N
N
N
N
3.0 eq CsOPiv
t-AmylOH, air
130 oC, 18h
+
+
N
N
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DG
DG
I
29
Detected by LCMS
1
28
1
standard condtion
2). Palladium catalyst was poisoned from the strong coordination of heteroarenes.
H
H
Ph
H
N
N
standard condtion
+
I
Ph-
+
N
N
N
N
DG
DG
I
2
30
1
31
32
Condition 1:
Condition 2:
1.0 eq
1.0 eq
3.0 eq
3.0 eq
None
> 90% LC yield
< 5% LC yield
3.0 eq
3). Poor reactivity of heteroaryl iodide towards oxidative addition of palladium catalyst.
N
H
N
standard condition
standard condition
N
+
+
> 80% LC yield
< 10% LC yield
N
N
N
I
DG
DG
N
N
DG
33
18
1
N
H
N
N
N
I
DG
35
1
34
Next, we also examined the scope of amines (Table 5). Transannular C-H bonds of various
bridged- (36-39) and fused-bicyclic amines (40-43) were functionalized smoothly with different
identified heteroarenes in good yields. This appealing reaction provides medicinal chemists a
useful tool for the rapid synthesis of these three-dimensional drug-like scaffolds. More importantly,
an unprecedented transannular arylation of spirocyclic amine was identified (Scheme 3). The
diarylated product 45 could be isolated with moderate yield, although large excess amount of
iodobenzene (31) was required. To our best knowledge, the functionalization of these two
transannular C-H bonds next to the quaternary center were not reported before using other
methods, which indicated the superiority of this transannular C-H activation strategy.
Table 5. Scope of alkyl amines for transannular C-H heteroarylation a
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30 mol% Pd(OAc)2
HetAr
F
F
H
DG =
F
CF3
F
L3
10 mol%
+
HetAr-I
3.0 eq CsOPiv
t-AmylOH, air
130 oC, 8~18h
N
N
HN
DG
DG
O
7
8
9
N
CF3
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
S
N
N
N
DG
DG
N
DG
N
N
N
DG
N
N
O
O
O
36
37
38
39
, 27%
, 33%
, 57%
, 43%
NC
N
N
N
N
S
H
H
H
N
N
N
H
N
N
N
DG
DG
DG
N
DG
EtOOC
Cl
Cl
Cl
Cl
42
Cl
Cl
40
41
43
, 41%
, 32%
, 42%
, 26%
aConditions: Amine (0.2 mmol, 1 eq), HetAr-I (2~3 eq), L3 (10 mol%), Pd(OAc)2 (30 mol%),
CsOPiv (3 eq), t-AmylOH (2.0 mL), 130 oC, 8~18h. Products were purified by HPLC.
Scheme 3. Arylation of spirocyclic amine
Ph
H
30 mol% Pd(OAc)2
L3
10 mol%
+
Ph-I
N
N
3.0 eq CsOPiv
t-AmylOH, air
130 oC, 24h
DG
DG
Ph
45
, 24% yield
H
44
31
With broad scopes of both amines and heteroaryl iodides explored, we investigated the feasibility
to remove the directing group of the heteroarylated amines (Scheme 4). Sanford’s group reported
the directing group (DG) could be successfully cleaved in the transannular arylated 3-
azabicyclo[3.1.0]hexane and piperidine cores using samarium diiodide (SmI2).6,13 However,
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whether SmI2-mediated deprotections are compatible with sensitive heterocycles was not clear.
We chose 4 containing a pyrazole group as the model substrate owing to its relative low
aromaticity and the presence of a reductively sensitive N-N bond. Reaction of 4 with SmI2 and
subsequent trapping of the secondary amines with TsCl only provided trace amount of 46.
However, addition of DMPU significantly improved the yield of 46 to 52% (Scheme 4.1). The major
competing reaction pathways in the reaction were the rapid mono-, di- and tri-defluorinations on
the electron-deficient phenyl ring in the directing group. For those vulnerable heterocycles under
SmI2 condition, such as pyridines, a new method was developed earlier this year by Sanford and
Abbvie to afford acyl amides, although in low yields.14
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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35
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Challenges to remove the directing auxiliary
1) Removal of directing groups in 3-azabicyclo[3.1.0]hexane core:
1) SmI2, additive
MeOH, TEA
N
N
No additive
: trace
N
N
DMPU (11 eq)
: 52% yield
2) TosCl
N
N
Tos
4
46
DG
DG =
F
F
F
CF3
F
2) Removal of directing groups in other bicyclic amine cores:
HN
SmI2
SmI2, HMPA
MeOH, Et3N
O
O
O
N
C7F7
N
C7F7
NH
N
H
N
H
Success:
Failure:
H
NC
S
N
N
H
N
DG
N
DG
N
N
DG
Cl
DG
EtOOC
Cl
N
DG
Cl
EtOOC
Cl
40
41
47
44
50
N
Ph
Ph
DG
N
DG
N
N
DG
DG
N
DG
N
N
O
O
O
Ph
O
51
36
45
48
49
When we attempted to remove the directing group from other bicyclic amine cores, we
encountered significant difficulties (Scheme 4.2). After screening a collection of both amine
substrates and heteroarylated amine products, we found that the reactivity of desired C-N
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cleavage dramatically decreased as the steric hinderance around the amide carbonyl increased,
probably due to the weaker coordination of samarium to the carbonyl. To our surprise, even the
simple arylated bridged-bicyclic amine 51 turned out to be a difficult substrate for directing group
removal.15 These results suggested that the development of a new strategy to remove the DG in
sterically hindered bicyclic amine cores is necessary.
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19
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40
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In consideration of the neutral amine as an inert leaving group, we attempted to convert it to the
labile cationic ammonium. Surprisingly, the amine 51 could not be smoothly methylated probably
due to the steric hinderance from the gem-dimethyl group (Scheme 5a). Next, we examined
different single-electron reduction methods other than SmI2 and the more readily available
compound 54, in which the directing group could be smoothly removed by SmI2, was chosen as
the model substrate. Photoredox catalyzed reduction of -functionalized carbonyl compounds has
been reported involving a single-electron process.16 Unfortunately, no desired free amine 55 was
formed using a variety of photo catalysts, reductants and additives, while the dominant reaction
pathway was still the defluorination reaction of the electron-deficient phenyl ring (Scheme 5b).
Various organic single electron donors (SED) have been developed to reduce the -functionalized
carbonyl compounds.17 One of the most reductive SED (57) was tested and only led to the
decomposition of 54 (Scheme 5c).18 Because of the difficulty to remove the directing group via a
single-electron pathway, we designed a multi-step strategy involving the hydrolysis of amide19
and the subsequent Curtius rearrangement20 to deliver the desired free amine product (Scheme
5d). However, 54 was completely inert under acidic conditions (TFA, HCl, BF3*Et2O) and suffered
from the dominant SNAr side reaction under basic conditions (Scheme 5d). Hydrolysis of the
amide adjacent to a quaternary carbon center remained extremely difficult in compound 62 with
a less electron deficient phenyl ring and only side products from SNAr reaction were detected. In
addition, a two-step procedure, reported by the Jin-Quan Yu group to hydrolyze the same amide
bond next to a tertiary carbon center, was also examined (Scheme 5e).21 The acylation of aniline
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using NaH as the base performed smoothly to afford compound 64. However, NaOMe hydrolyzed
the carbamate in compound 64 to form amide 54 rather than the amide to form ester 65. At last,
an epoxide-mediated deprotection strategy was also investigated.22 Unfortunately, the reaction
still favored SNAr pathway on the electron-deficient phenyl ring over the desired amide hydrolysis
pathway (Scheme 5f). Unfortunately, removal of this directing group remains an open problem.
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51
52
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54
55
56
57
58
59
60
Summary
A novel transannular C-H heteroarylation of fused- and bridged-bicyclic amines was developed.
This methodology allows medicinal chemists to rapidly synthesize transannular heteroarylated 3-
azabicyclo[3.1.0]hexane core. A new ligand was identified to improve the yield of heteroarylation
reactions. The first transannular arylation reaction of spiro-bicyclic amine was also reported for
the rapid functionalization of the spiro-bicyclic scaffold. At the outset, we expected the SmI2-
mediated deprotection may not be compatible to sensitive heterocycles. However, to our surprise,
the SmI2 reaction turned out to be more sensitive to the nature of the amine scaffold. Design of
new directing groups that are easier to remove will advance this transannular C-H activation
reaction.
Scheme 5. Efforts to develop new directing group removal strategy a
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F
F
a.
b.
Ph
Ph
51
H
N
Ph
53
O
Ph
F
MeI (1.2 eq)
rt, overnight
SmI2
DG
DG
N
I
N
N
N
I
F
CF3
O
O
O
O
52
photo catayst
reductant
c.
Ph
Ph
10
NaH
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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30
31
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44
45
46
47
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49
50
51
52
53
54
55
56
57
58
59
60
N
N
additive
NH
NH
DG
DG
hv
54
55
54
55
2I-
catalyst: Ru(bpy)3Cl2, Ir(ppy)3
reductant: Et3N, iPr2NEt, Hantzsch ester
N
N
N
N
NaH
additive: HCO2H, TsOH, BF3•Et2O, Zn(OTf)2, La(OTf)3,
Me2N
NMe2
Me2N
NMe2
Sc(OTf)3, etc.
56
57
d.
Ph
Ph
ArF
O
Ph
hydrolysis
HN
OH
Curtius
rearrangement
N
N
NH
O
54
58
55
F
F
F
HO
HO
HN
CF3
HO
HN
CF3
OH
Ph
CF3
Ph
Ph
N
F
N
F
N
N
O
OH
OH
O
O
59
60
61
F
F
MeO
HN
CF3
F
MeO
HN
CF3
OH
Ph
KOH
low
conversion
OH
Ph
Ph
Ph
+
N
O
N
N
OMe
OMe
O
O
62
58
63
(tace)
e.
O
MeO
N
Ph
ArF
O
Ph
ArF
O
NaOMe
HN
OMe(OH)
O
MeOCOCl
N
N
N
or NaOH
NaH
60% Conv.
54
64
65 (58)
F
f.
O
MeO
HN
CF3
Ph
Ph
ArF
O
HN
OMe
O
OBn
Ph
+
N
N
F
KOAc, MeOH
90 oC, 36h
N
F
O
minor
major
54
65
66
aUnless noted, all reactions were monitored through LC-MS analysis of crude reaction mixture
and the possible products in each reaction were not isolated.
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Experimental Section
8
9
Unless otherwise noted, all reactions were carried out with anhydrous solvents (dichloromethane,
toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile) purchased from Fisher Scientific. All reagents,
including heteroaryl iodides and amines, were purchased from Sigma-Aldrich, Acros, Enamine,
Combi-Blocks, WUXI Tech, Alfa, SpiroChem or TCI and used as received, unless noted otherwise.
Unless indicated, reactions were performed under ambient conditions. Reactions conducted at
elevated temperatures were heated on a hot plate with temperature control (Chemglass) using
an aluminum PIE-Block system (Chemglass). The final compounds were analyzed or purified
according to one of the analytical or purification methods referred to below unless otherwise
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51
52
53
54
55
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1
described and characterized by H, 19F, 13C{1H} NMR, and high-resolution mass spectrometry.
For LC/MS analysis, a sample is dissolved in a suitable solvent such as acetonitrile (MeCN),
dimethyl sulfoxide (DMSO), or methanol (MeOH) and is injected directly into the column using an
automated sample handler. All the compounds in this paper were racemic. The stereocenters
were defined in the structure to indicate the relative configurations and the absolute configuration
was arbitrarily assigned.
The analysis used the following acidic method (3.5 min run): conducted on a Waters Acquity
UPLC BEH. (MS ionization: ESI) instrument equipped with a C18 column (2.1 mm × 50 mm, C18,
1.7 μm), eluting with 0.1% v/v of trifluoroacetic acid (TFA) in water (solvent A) and 0.1% v/v of
TFA in acetonitrile (solvent B). Silica gel column chromatography was performed using 20−40 μm
(particle size) mesh silica gel using a Grace Reveleris X2 with ELSD purification system.
Preparative HPLC purifications were performed on a Waters Acquity UPLC BEH used the
following acidic method (7.0 min run). (MS ionization: ESI) instrument equipped with a SunFire
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Prep C18 OBD column (19 mm × 100 mm, C18, 5 μm), eluting with 0.1% v/v of trifluoroacetic acid
5
6
(TFA) in water (solvent A) and 0.1% v/v of TFA in acetonitrile (solvent B).
7
8
9
The 1H, 19F, 13C{1H} NMR spectra were recorded on a Bruker Ultrashield Plus 500 MHz. Chemical
shifts are expressed in parts per million (ppm) units and referenced to the residual solvent
resonance as noted in the spectra (i.e., CDCl3; 7.27 ppm for 1H & 77.0 ppm for 13C{1H}). Coupling
constants (J) are in units of Hertz (Hz). Splitting patterns describe apparent multiplicities and are
designated as: s (singlet), d (doublet), t (triplet), dd (doubled doublet), dt (doubled triplet), dq
(doubled quartet), m (multiplet), or br (broad). The carbon resonances corresponding to the
perfluoroarene (C7F7), trifluoromethyl (CF3) and fluoro-substituted phenyl ring (F-Ar) in this
compound appear as a complex series of multiplets between 105 ppm to 155 ppm as a result of
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
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60
19
13C/19F coupling. Due to the complexities of the system, the peaks are not listed. F NMR and
HRMS were used to confirm the presence of these ring systems.
High-resolution mass spectrometry data were recorded using Sciex Triple TOF 5600 mass
spectrometer (column: Waters UPLC Acquity HSS T3 C18 1.8 μm, 2.1 mm × 50 mm; mobile
phase: A = 0.1% formic acid in H2O; B = 0.1% formic acid in acetonitrile; method: 7 min, A to B
gradient 5−>65%, positive ionization mode). All masses were reported as the exact masses in
the format of [M + H]+ , unless noted otherwise.
Substrates 1, 44, 47, 48, 49, 50, 54, S-1, S-2 (see the Supporting Information for the structures
of S-1 and S-2) were prepared from the corresponding free amine or amine salts following the
literature procedure.6 Known compounds 1, 47, 48, 54, S-1 were characterized by NMR analysis
and the data matched with the literature. New compounds 44, 49, 50, S-2 were characterized and
the data were shown as follow:
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2-methyl-2-(2-azaspiro[4.5]decan-2-yl)-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propen-
amide (44, 1.84 g, white solid, Yield: 82%). The crude material was purified by silica gel column
chromatography (EtOAc in Heptanes from 0%-15%). 1H NMR (500 MHz, CDCl3) δ ppm 1.34 (s,
6 H), 1.38 - 1.51 (m, 10 H), 1.63 (t, J=6.7 Hz, 2 H), 2.47 (s, 2 H), 2.71 (t, J=7.0 Hz, 2 H). 19F NMR
(471 MHz, CDCl3) δ ppm <-144.04> - <-143.90> (m, 2 F), <-141.35> - <-141.07> (m, 2 F), -55.99
(t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 175.4, 61.8, 46.0, 41.0, 38.2, 26.0,
23.5, 20.6. HRMS (ESI+) m/z: [M + H]+ Calcd for C20H23F7N2O 441.1772; Found 441.1765.
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41
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44
45
46
47
48
49
50
51
52
53
54
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60
2-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-methyl-N-(2,3,5,6-tetrafluoro-4-(trifluorometh-
yl)phenyl)propenamide (49, 1.83 g, white solid, Yield: 74%). The crude material was purified by
silica gel column chromatography (EtOAc in Heptanes from 0%-30%). 1H NMR (500 MHz, CDCl3)
δ ppm 1.32 (s, 6 H), 1.92 - 2.04 (m, 4 H), 2.54 (d, J=11.0 Hz, 2 H), 2.71 (dd, J=11.0, 1.8 Hz, 2 H),
4.39 - 4.43 (m, 2 H), 9.01 (br s, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-143.81> - <-143.62>
(m, 2 F), <-140.97> - <-140.70> (m, 2 F), -56.03 (t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz,
CDCl3) δ ppm 174.9, 74.4, 64.1, 51.9, 28.1, 20.5. HRMS (ESI+) m/z: [M + H]+ Calcd for
C17H17F7N2O2 415.1251; Found 415.1245.
Ethyl (1R,5R)-3-(2-methyl-1-oxo-1-((2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)amino)propan-2
-yl)-3-azabicyclo[3.1.0]hexane-1-carboxylate (50, 354.3 mg, white solid, Yield: 78%). The crude
material was purified by silica gel column chromatography (DCM in Heptanes from 0%-100%). 1H
NMR (500 MHz, CDCl3) δ ppm 1.27 (t, J=7.3 Hz, 3 H), 1.31 (t, J=4.6 Hz, 1 H), 1.34 (s, 3 H), 1.39
(s, 3 H), 1.47 (dd, J=8.6, 4.3 Hz, 1 H), 2.00 - 2.06 (m, 1 H), 2.81 (dd, J=9.2, 3.7 Hz, 1 H), 2.91 (d,
J=9.2 Hz, 1 H), 3.04 (d, J=9.2 Hz, 1 H), 3.10 (d, J=9.2 Hz, 1 H), 4.17 (q, J=7.1 Hz, 2 H), 8.82 (br
s, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-144.25> - <-143.97> (m, 2 F), <-141.05> - <-140.72>
13
(m, 2 F), -56.00 (t, J=21.5 Hz, 3 F). C{1H} NMR (126 MHz, CDCl3) δ ppm 174.5, 172.7, 61.4,
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60.8, 47.3, 47.2, 28.6, 26.3, 21.8, 20.3, 16.0, 14.3. HRMS (ESI+) m/z: [M + H]+ Calcd for
C19H19F7N2O3 457.1357; Found 457.1355.
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8
9
2-((1R,5S)-6-acetyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-methyl-1-(2,3,5,6-tetrafluoro-4-(trifleo-
romethyl)phenyl)propan-1-one (S-2, 386.0 mg, white solid, Yield: 50%). The crude material was
purified by silica gel column chromatography (EtOAc/EtOH=3/1 <v/v> in Heptanes from 0%-30%).
1H NMR (500 MHz, CDCl3) δ ppm 1.38 (s, 3 H), 1.45 (s, 3 H), 1.55 (d, J=8.6 Hz, 1 H), 1.98 (s, 3
H), 2.62 - 2.70 (m, 1 H), 2.79 (d, J=11.0 Hz, 1 H), 2.87 (d, J=11.0 Hz, 1 H), 3.30 (br d, J=9.8 Hz,
1 H), 3.42 (br d, J=9.8 Hz, 1 H), 4.35 (br d, J=3.7 Hz, 2 H), 8.64 (br s, 1 H). 19F NMR (471 MHz,
CDCl3) δ ppm -143.42 (td, J=16.8, 6.4 Hz, 2 F), <-141.26> - <-140.93> (m, 2 F), -56.09 (t, J=21.5
Hz, 3 F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 175.1, 174.7, 63.3, 60.7, 58.2, 47.5, 46.3, 31.3,
24.7, 20.0, 18.2. HRMS (ESI+) m/z: [M + H]+ Calcd for C18H18F7N3O2 442.1360; Found 442.1352.
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47
48
49
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51
52
53
54
55
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58
59
60
Experimental Procedure for Ligand Screening. Each reaction was performed in a 1.0 mL vial
for the 96-well parallel synthesis/optimization plate (see the supporting information). Pd(OAc)2
was prepared as stock solution in DCM (0.05M). Each ligand was prepared as stock solution in
DCM (or MeOH, 0.02M). Amine 1 (1.0 eq) and CsOPiv (3.0 eq) were prepared as stock solution
in t-amylOH (0.1M for 1, volatile ligands were also included in this stock solution if necessary). 4-
CN-4’-Me-biphenyl was employed as internal standard and prepared as stock solution in MeCN
(0.1M). To each vial was added Pd(OAc)2 stock solution (60 uL, 30 mol%) and the corresponding
ligand stock solution (50 uL, 10 mol%). The solution in each vial was stirred and heated to 50~60
oC for 15 min to remove the solvent. After cooling down to room temperature, 2-iodothiazole 8
(3.0 eq) was weighed out and transferred into each vial. Then the stock solution of amine 1 and
CsOPiv (100 uL) was transferred into each vial. The reaction block was sealed, stirred and heated
o
to 130 C for 18h. After cooling down to room temperature, to each vial was added the stock
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solution of internal standard (100 uL) and DMSO (200 uL). Then the mixture in each vial was
transferred into a 2-dr vial and the original reaction vial was rinsed with DMSO (300 uL * 2). The
combined solution of each sample in 2-dr vial was transferred to 96-well plate automatically by
TECAN and subjected to LC/MS analysis. The integrations of UV peaks of each compound and
internal standard were measured at 232 nm and the according calibrated yield was calculated.
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Representative Experimental Procedure for Transannular C-H Heteroarylation of Amines.
A 5 mL microwave vial was charged with amine 1 (0.2 mmol, 1 equiv), Pd(OAc)2 (0.06 mmol, 30
mol %), CsOPiv (0.6 mmol, 3 equiv), L3 (0.02 mmol, 10 mol %), heteroaryl iodide (0.4 mmol, 2
equiv) and t-amylOH (2.0 mL, 0.1 M). The vial was equipped with a magnetic stir bar, sealed and
heated to an external temperature of 130 ºC in an aluminum heating block. After 12 h, the reaction
was cooled to room temperature. Hydrazine hydrate (0.25 mL) was added to the solution and the
mixture was allowed to stir for 30 min at 60 oC to sequester Pd from the product. The mixture was
diluted with EtOAc (3.0 mL), filtered through Celite and rinsed with EtOAc (10 mL). The volatiles
were removed under vacuum, and the residue was purified via reversed-phase preparative HPLC
to afford the desired product. If the compound was very non-polar or inseparable from byproducts
on preparative HPLC, silica gel flash chromatography was employed.
2-((1R,5S,6s)-6-(5-cyanothiophen-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-N-(2,3,5,6-tetra-
fluoro-4-(trifluoromethyl)phenyl)propenamide (9, 35.1 mg, white solid, Yield: 36%). 1H NMR (500
MHz, CDCl3) δ ppm 1.19 (s, 6 H), 2.00 - 2.08 (m, 3 H), 2.90 - 2.98 (m, 2 H), 3.02 (d, J=9.78 Hz,
2 H), 6.74 (s, 1 H), 6.93 (d, J=3.7 Hz, 1 H), 7.31 (d, J=3.7 Hz, 1 H). 19F NMR (471 MHz, CDCl3) δ
ppm -143.00 (td, J=16.5, 5.7 Hz, 2 F), <-140.63> - <-140.33> (m, 2 F), -56.15 (t, J=21.5 Hz, 3 F).
13C{1H} NMR (126 MHz, CDCl3) δ ppm 175.0, 150.0, 137.0, 125.2, 113.6, 107.3, 61.5, 45.3, 22.4,
21.0, 17.8. HRMS (ESI+) m/z: [M + H]+ Calcd for C21H16F7N3OS 492.0975; Found 492.0979.
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2-((1R,5S,6r)-6-(1H-indol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-N-(2,3,5,6-tetrafluoro-4-
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(trifluoromethyl)phenyl)propenamide (10, 54.0 mg, white solid, Yield: 54%). The crude material
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was purified by silica gel column chromatography (EtOAc in Heptanes from 0%-50%). H NMR
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(500 MHz, DMSO-d6) δ ppm 1.02 (s, 6 H), 1.83 - 1.89 (m, 2 H), 2.12 (t, J=7.9 Hz, 1 H), 2.85 (br
d, J=8.6 Hz, 2 H), 2.95 (d, J=8.6 Hz, 2 H), 3.33 (s, 1 H), 5.95 - 6.00 (m, 1 H), 6.13 (s, 1 H), 6.84 -
6.88 (m, 1 H), 7.11 (d, J=7.9 Hz, 1 H), 7.25 (d, J=7.9 Hz, 1 H), 7.36 (s, 1 H), 10.87 (br s, 1 H). 19F
NMR (471 MHz, DMSO-d6) δ ppm <-144.19> - <-143.80> (m, 2 F), <-143.16> - <-142.81> (m, 2
F), -55.39 (t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz, DMSO-d6) δ ppm 175.6 (175.5), 134.1
(134.0), 127.6, 127.3 (127.2), 124.7 (124.5), 121.5, 118.7, 111.2 (111.1), 99.7 (99.6), 60.1, 44.7,
22.4, 20.8, 19.7. HRMS (ESI+) m/z: [M + H]+ Calcd for C24H20F7N3O 500.1568; Found 500.1572.
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2-methyl-2-((1R,5S,6r)-6-(1-methyl-1H-indol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(2,3,5,6-
tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (11, 60.4 mg, white solid, Yield: 59%). The
crude material was purified by silica gel column chromatography (EtOAc in Heptanes from 0%-
50%). 1H NMR (500 MHz, CDCl3) δ ppm 1.04 (s, 6 H), 1.77 - 1.80 (m, 2 H), 2.10 (t, J=7.9 Hz, 1
H), 2.80 - 2.84 (m, 2 H), 2.96 (d, J=9.2 Hz, 2 H), 3.58 (s, 3 H), 5.90 (d, J=3.1 Hz, 1 H), 6.04 (br s,
1 H), 6.54 (d, J=3.1 Hz, 1 H), 7.13 - 7.15 (m, 2 H), 7.36 (s, 1 H). 19F NMR (471 MHz, CDCl3) δ
ppm -144.08 (br s, 2 F), <-143.09> - <-142.79> (m, 2 F), -56.22 (t, J=22.2 Hz, 3 F). 13C{1H} NMR
(126 MHz, CDCl3) δ ppm 176.5, 135.0, 128.6 (two peaks), 128.3, 122.1, 119.8, 109.3, 99.9, 60.8,
45.2, 32.5, 23.0, 20.3. HRMS (ESI+) m/z: [M + H]+ Calcd for C25H22F7N3O 514.1724; Found
514.1719.
2-methyl-2-((1R,5S,6r)-6-(pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(2,3,5,6-tetrafluoro-4-
(trifluoromethyl)phenyl)propenamide (12, 56.2 mg, white solid, Yield: 61%). The crude material
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was purified by silica gel column chromatography (EtOAc in Heptanes from 0%-50%). H NMR
(500 MHz, CDCl3) δ ppm 1.14 (s, 6 H), 1.94 - 2.01 (m, 2 H), 2.05 - 2.12 (m, 1 H), 2.87 - 3.00 (m,
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4 H), 6.37 (br s, 1 H), 7.35 (d, J=4.9 Hz, 2 H), 8.39 (d, J=5.5 Hz, 2 H). 19F NMR (471 MHz, CDCl3)
δ ppm <-143.07> - <-142.81> (m, 2 F), <-140.91> - <-140.58> (m, 2 F), -56.12 (t, J=21.5 Hz, 3
F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 175.4, 149.5, 147.6, 123.8, 61.3, 45.2, 27.3, 22.3, 21.0,
20.1. HRMS (ESI+) m/z: [M + H]+ Calcd for C21H18F7N3O 462.1411; Found 462.1412.
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2-methyl-2-((1R,5S,6r)-6-(pyridin-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(2,3,5,6-tetrafluoro-4-
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(trifluoromethyl)phenyl)propenamide (13, 55.2 mg, white solid, Yield: 60%). H NMR (500 MHz,
MeOD-d4) δ ppm 1.10 (s, 6 H), 1.98 - 2.01 (m, 2 H), 2.07 - 2.13 (m, 1 H), 2.92 - 3.01 (m, 4 H),
4.86 (s, 1 H), 7.32 (dd, J=7.9, 4.9 Hz, 1 H), 7.84 - 7.89 (m, 1 H), 8.21 (d, J=4.9 Hz, 1 H), 8.51 (d,
J=1.2 Hz, 1 H). 19F NMR (471 MHz, MeOD-d4) δ ppm <-145.02> - <-144.83> (m, 2 F), <-143.81>
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- <-143.54> (m, 2 F), -57.67 (t, J=21.5 Hz, 3 F). C{1H} NMR (126 MHz, CDCl3) δ ppm 177.1,
149.9, 147.9, 138.2, 136.2, 125.1, 62.3, 46.1, 21.4, 21.3, 21.0. HRMS (ESI+) m/z: [M + H]+ Calcd
for C21H18F7N3O 462.1411; Found 462.1400.
2-methyl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-2-((1R,5S,6s)-6-(thiazol-2-yl)-3-azabi-
cyclo[3.1.0]hexan-3-yl)propenamide (3, 37.6 mg, light yellow solid, Yield: 40%). The crude
material was purified by silica gel column chromatography (EtOAc in Heptanes from 0%-20%).
1H NMR (500 MHz, CDCl3) δ ppm 1.17 (s, 6 H), 2.03 - 2.09 (m, 2 H), 2.20 (t, J=7.3 Hz, 1 H), 2.86
- 2.95 (m, 2 H), 3.17 (d, J=9.8 Hz, 2 H), 7.17 (d, J=3.1 Hz, 1 H), 7.39 (d, J=3.1 Hz, 1 H), 7.55 (br
s, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-142.36> - <-142.21> (m, 2 F), <-141.36> - <-141.05>
(m, 2 F), -56.08 (t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 175.5, 168.0, 141.7,
119.1, 61.5, 45.4, 22.6, 21.0, 20.7. HRMS (ESI+) m/z: [M + H]+ Calcd for C19H16F7N3OS 468.0975;
Found 468.0969.
2-methyl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-2-((1R,5S,6s)-6-(4-(trifluoromethyl)-
thiazol-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)propenamide (14, 43.7 mg, yellow solid, Yield: 41%).
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The crude material was purified by silica gel column chromatography (EtOAc in Heptanes from
0%-50%). 1H NMR (500 MHz, CDCl3) δ ppm 1.20 (s, 6 H), 2.09 - 2.16 (m, 2 H), 2.22 (t, J=7.9 Hz,
1 H), 2.92 - 2.98 (m, 2 H), 3.19 (d, J=9.2 Hz, 2 H), 7.10 (br s, 1 H), 7.60 (s, 1 H). 19F NMR (471
MHz, CDCl3) δ ppm <-143.34> - <-143.21> (m, 2 F), <-141.58> - <-141.33> (m, 2 F), -64.36 (s, 3
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F), -56.14 (t, J=21.5 Hz, 3 F). C{1H} NMR (126 MHz, CDCl3) δ ppm 174.6, 170.1, 61.6, 45.4,
22.9, 20.9, 20.8. HRMS (ESI+) m/z: [M + H]+ Calcd for C20H15F10N3OS 536.0849; Found 536.0851.
2-methyl-2-((1R,5S,6r)-6-(2-methylbenzo[d]thiazol-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-
(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (15, 82.8 mg, white solid, Yield: 78%).
The crude material was purified by silica gel column chromatography (EtOAc in Heptanes from
0%-20%). 1H NMR (500 MHz, CDCl3) δ ppm 1.12 (s, 6 H), 1.89 - 1.95 (m, 2 H), 2.18 (t, J=7.9 Hz,
1 H), 2.65 (s, 3 H), 2.91 (br d, J=9.2 Hz, 2 H), 3.00 (d, J=9.2 Hz, 2 H), 6.18 (br s, 1 H), 7.43 (d,
J=8.6 Hz, 1 H), 7.71 (s, 1 H), 7.75 (d, J=8.6 Hz, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-143.03>
- <-142.88> (m, 2 F), <-141.65> - <-141.38> (m, 2 F), -55.89 (t, J=21.5 Hz, 3 F). C{1H} NMR
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(126 MHz, CDCl3) δ ppm 175.9, 166.6, 151.8, 135.9, 135.0, 126.5, 122.3, 120.5, 61.0, 45.2, 22.9,
21.1, 20.4, 19.5. HRMS (ESI+) m/z: [M + H]+ Calcd for C24H20F7N3OS 532.1288; Found 532.1284.
2-methyl-2-((1R,5S,6s)-6-(1-methyl-1H-pyrazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(2,3,5,6-
tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (4, 52.0 mg, light yellow solid, Yield: 56%). The
crude material was purified by silica gel column chromatography (EtOAc in Heptanes from 0%-
30%). 1H NMR (500 MHz, CDCl3) δ ppm 1.17 (s, 6 H), 1.82 - 1.89 (m, 3 H), 2.82 - 2.89 (m, 2 H),
3.08 (d, J=8.6 Hz, 2 H), 3.64 (s, 3 H), 6.11 (d, J=1.8 Hz, 1 H), 7.08 (d, J=1.8 Hz, 1 H), 7.59 (br s,
1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-142.88> - <-142.66> (m, 2 F), <-141.35> - <-141.05>
(m, 2 F), -56.07 (t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 176.1, 149.5, 130.1,
105.0, 61.3, 45.6, 38.6, 21.0, 20.4, 16.6. HRMS (ESI+) m/z: [M + H]+ Calcd for C20H19F7N4O
465.1520; Found 465.1524.
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2-methyl-2-((1R,5S,6s)-6-(1-methyl-1H-indazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(2,3,5,6-
tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (16, 45.5 mg, white solid, Yield: 44%). 1H NMR
(500 MHz, CDCl3) δ ppm 1.11 (s, 6 H), 2.06 (s, 3 H), 2.89 (br d, J=9.2 Hz, 2 H), 3.15 (d, J=8.6 Hz,
2 H), 3.97 (s, 3 H), 6.45 (br s, 1 H), 6.82 - 6.89 (m, 2 H), 7.05 (d, J=7.3 Hz, 1 H), 7.70 (d, J=7.3
Hz, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-143.77> - <-143.58> (m, 2 F), <-142.42> - <-142.10>
(m, 2 F), -56.10 (t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 175.7, 141.9, 140.2,
125.6, 123.2, 120.9, 119.9, 108.5, 61.0, 45.7, 35.3, 20.9, 20.0, 15.2. HRMS (ESI+) m/z: [M + H]+
Calcd for C24H21F7N4O 515.1677; Found: 515.1676.
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2-methyl-2-((1R,5S,6r)-6-(1-methyl-1H-indazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(2,3,5,6-
tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (17, 32.1 mg, white solid, Yield: 31%). 1H NMR
(500 MHz, CDCl3) δ ppm 1.10 (s, 6 H), 1.86 - 1.93 (m, 2 H), 2.17 (t, J=7.9 Hz, 1 H), 2.90 (br d,
J=9.2 Hz, 2 H), 2.99 (d, J=9.2 Hz, 2 H), 3.91 (s, 3 H), 6.08 (br s, 1 H), 7.28 (d, J=8.6 Hz, 1 H),
7.40 (d, J=8.6 Hz, 1 H), 7.46 (s, 1 H), 7.54 (s, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-144.63>
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- <-144.29> (m, 2 F), <-142.07> - <-141.78> (m, 2 F), -56.17 (t, J=21.5 Hz, 3 F). C{1H} NMR
(126 MHz, CDCl3) δ ppm 176.0, 138.3, 131.5, 130.1, 127.3, 123.9, 119.3, 109.0, 61.0, 45.2, 35.3,
22.8, 21.1, 20.3. HRMS (ESI+) m/z: [M + H]+ Calcd for C24H21F7N4O 515.1677; Found 515.1676.
2-methyl-2-((1R,5S,6r)-6-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-azabicyclo[3.1.0]h-
exan-3-yl)-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (22, 57.7 mg, white solid,
Yield: 45%). 1H NMR (500 MHz, CDCl3) δ ppm 1.08 (s, 6 H), 1.89 - 1.99 (m, 2 H), 2.05 (t, J=7.3
Hz, 1 H), 2.87 - 3.00 (m, 4 H), 6.25 (br s, 1 H), 6.31 (d, J=3.7 Hz, 1 H), 7.38 - 7.46 (m, 2 H), 7.48
(d, J=3.7 Hz, 1 H), 7.53 (t, J=7.3 Hz, 1 H), 7.77 (s, 1 H), 8.05 - 8.11 (m, 2 H), 8.43 (d, J=1.8 Hz, 1
H). 19F NMR (471 MHz, CDCl3) δ ppm <-143.39> - <-143.18> (m, 2 F), <-141.32> - <-141.00> (m,
2 F), -56.19 (t, J=22.2 Hz, 3 F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 175.4, 145.9, 145.2, 138.3,
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134.2, 129.0, 128.8, 128.6, 127.8, 126.7, 122.4, 104.6, 61.2, 45.3, 21.0, 20.5, 20.2. HRMS (ESI+)
m/z: [M + H]+ Calcd for C29H23F7N4O3S 641.1452; Found 641.1450.
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2-methyl-2-((1R,5S,6r)-6-(pyrimidin-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(2,3,5,6-tetrafluoro-4-
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(trifluoromethyl)phenyl)propenamide (18, 54.4 mg, white solid, Yield: 59%). H NMR (500 MHz,
MeOD-d4) δ ppm 1.09 (s, 6 H), 2.00 - 2.10 (m, 3 H), 2.96 - 3.02 (m, 4 H), 8.79 (s, 2 H), 8.91 (s, 1
H). 19F NMR (471 MHz, MeOD-d4) δ ppm -144.88 (dq, J=16.8, 6.8 Hz, 2 F), <-143.99> - <-143.67>
(m, 2 F), -57.69 (t, J=22.2 Hz, 3 F). 13C{1H} NMR (126 MHz, MeOD-d4) δ ppm 175.9, 157.7, 157.0,
134.1, 62.1, 46.1, 22.1, 20.9, 18.8. HRMS (ESI+) m/z: [M + H]+ Calcd for C20H17F7N4O 463.1364;
Found 463.1363.
2-methyl-2-((1R,5S,6r)-6-(quinazolin-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(2,3,5,6-tetrafluoro-
4-(trifluoromethyl)phenyl)propenamide (5, 56.9 mg, white solid, Yield: 56%). The crude material
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was purified by silica gel column chromatography (EtOAc in Heptanes from 0%-50%). H NMR
(500 MHz, CDCl3) δ ppm 1.09 (s, 6 H), 2.01 (br d, J=7.3 Hz, 2 H), 2.26 (t, J=7.9 Hz, 1 H), 2.90 -
3.04 (m, 4 H), 7.81 (s, 1 H), 7.86 (d, J=8.6 Hz, 1 H), 7.92 (d, J=8.6 Hz, 1 H), 9.09 (s, 1 H), 9.15
(s, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-143.76> - <-143.48> (m, 2 F), <-140.95> - <-140.60>
(m, 2 F), -56.23 (t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 175.3, 159.3, 155.0,
148.5, 138.5, 135.6, 128.4, 125.1, 124.8, 61.2, 45.3, 22.9, 21.0, 20.5. HRMS (ESI+) m/z: [M + H]+
Calcd for C24H19F7N4O 513.1520; Found: 513.1521.
2-methyl-2-((1R,5S,6s)-6-(pyrazin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(2,3,5,6-tetrafluoro-4-
(trifluoromethyl)phenyl)propenamide (6, 55.3 mg, white solid, Yield: 60%). The crude material was
purified by silica gel column chromatography (EtOAc in Heptanes from 0%-50%). 1H NMR (500
MHz, MeOD-d4) δ ppm 1.08 (s, 6 H), 2.05 - 2.10 (m, 2 H), 2.23 (t, J=7.9 Hz, 1 H), 2.95 - 3.00 (m,
2 H), 3.10 (d, J=9.2 Hz, 2 H), 4.88 (s, 1 H), 8.38 (d, J=3.7 Hz, 1 H), 8.46 (dd, J=2.8, 1.5 Hz, 1 H),
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8.67 (s, 1 H). 19F NMR (471 MHz, MeOD-d4) δ ppm -144.89 (dq, J=17.5, 7.0 Hz, 2 F), <-144.02>
- <-143.73> (m, 2 F), -57.65 (t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz, MeOD-d4) δ ppm 175.9,
156.0, 146.5, 144.8, 143.1, 62.1, 46.3, 22.7, 22.3, 21.6. HRMS (ESI+) m/z: [M + H]+ Calcd for
C20H17F7N4O 463.1364; Found 463.1364.
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Methyl 3-((1R,5S,6s)-3-(2-methyl-1-oxo-1-((2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)amino)-
propan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)pyrazine-2-carboxylate (19, 25.0 mg, colorless oil,
Yield: 24%). 1H NMR (500 MHz, CDCl3) δ ppm 1.07 (s, 6 H), 2.06 - 2.12 (m, 2 H), 2.46 (t, J=7.9
Hz, 1 H), 2.75 - 2.82 (m, 2 H), 2.92 (d, J=9.8 Hz, 2 H), 3.91 (s, 3 H), 6.25 (br s, 1 H), 8.45 (d,
J=2.4 Hz, 1 H), 8.63 (d, J=2.4 Hz, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-143.39> - <-143.22>
(m, 2 F), <-141.32> - <-141.03> (m, 2 F), -56.06 (t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz,
CDCl3) δ ppm 174.6, 165.5, 154.6, 145.8, 144.4, 141.5, 61.5, 53.1, 45.5, 23.2, 21.9, 20.7. HRMS
(ESI+) m/z: [M + H]+ Calcd for C22H19F7N4O3 521.1418; Found 521.1423.
2-((1R,5S,6s)-6-(5-bromopyrazin-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-N-(2,3,5,6-
tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (20, 44.8 mg, light yellow solid, Yield: 41%). 1H
NMR (500 MHz, MeOD-d4) δ ppm 1.09 (s, 6 H), 2.02 - 2.06 (m, 2 H), 2.13 (t, J=7.9 Hz, 1 H), 2.93
- 2.98 (m, 2 H), 3.06 (d, J=9.8 Hz, 2 H), 4.86 (br s, 1 H), 8.44 (s, 1 H), 8.58 (d, J=1.2 Hz, 1 H). 19F
NMR (471 MHz, MeOD-d4) δ ppm <-144.72> - <-144.55> (m, 2 F), <-143.73> - <-143.48> (m, 2
F), -57.63 (t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz, MeOD-d4) δ ppm 176.0, 154.5, 147.3,
146.4, 138.8, 62.1, 46.2, 22.4, 22.0, 21.6. HRMS (ESI+) m/z: [M + H]+ Calcd for C20H16BrF7N4O
541.0469; Found: 541.0464.
2-methyl-2-((1R,5S,6r)-6-(quinoxalin-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(2,3,5,6-tetrafluoro-
4-(trifluoromethyl)phenyl)propenamide (21, 55.1 mg, light yellow solid, Yield: 54%). 1H NMR (500
MHz, CDCl3) δ ppm 1.08 (s, 6 H), 1.97 - 2.06 (m, 2 H), 2.27 (t, J=7.9 Hz, 1 H), 2.87 - 2.97 (m, 2
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H), 3.05 (d, J=9.2 Hz, 2 H), 7.77 (dd, J=8.6, 1.8 Hz, 1 H), 7.92 (d, J=8.6 Hz, 1 H), 7.96 (s, 1 H),
8.52 (d, J=1.8 Hz, 1 H), 8.63 (d, J=1.8 Hz, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-143.26> -
<-143.06> (m, 2 F), <-141.41> - <-141.08> (m, 2 F), -56.19 (t, J=22.2 Hz, 3 F). 13C{1H} NMR (126
MHz, CDCl3) δ ppm 175.4, 145.0, 144.5, 142.7, 141.6, 140.9, 131.6, 129.4, 127.4, 61.1, 45.2,
23.1, 21.0, 20.5. HRMS (ESI+) m/z: [M + H]+ Calcd for C24H19F7N4O 513.1520; Found 513.1524.
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2-methyl-2-((1R,5S,6s)-6-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-azabicyclo[3.1.0]hexan-3-
yl)-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (23, 35.9 mg, white solid, Yield:
35%). 1H NMR (500 MHz, CDCl3) δ ppm 1.11 (s, 6 H), 2.05 - 2.11 (m, 3 H), 2.91 (br d, J=9.2 Hz,
2 H), 3.11 (d, J=9.2 Hz, 2 H), 3.98 (s, 3 H), 6.67 (br s, 1 H), 6.88 (dd, J=7.9, 4.3 Hz, 1 H), 8.04
(dd, J=7.9, 1.2 Hz, 1 H), 8.08 (dd, J=4.3, 1.8 Hz, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-143.67>
13
- <-143.43> (m, 2 F), <-141.57> - <-141.27> (m, 2 F), -56.07 (t, J=21.5 Hz, 3 F). C{1H} NMR
(126 MHz, CDCl3) δ ppm 175.6, 150.5, 148.5, 141.3, 129.8, 116.0 ,115.1, 61.1, 45.8, 33.6, 21.0,
20.2, 15.6. HRMS (ESI+) m/z: [M + H]+ Calcd for C23H20F7N5O 516.1629; Found 516.1637.
2-((1R,5S,6s)-6-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-
2-methyl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (24, 35.6 mg, color-less oil,
Yield: 29%). 1H NMR (500 MHz, CDCl3) δ ppm 1.07 (s, 6 H), 2.06 - 2.17 (m, 3 H), 2.90 (br d, J=9.2
Hz, 2 H), 3.10 (d, J=9.2 Hz, 2 H), 5.60 (s, 2 H), 6.90 - 7.02 (m, 4 H), 7.16 - 7.23 (m, 1 H), 7.27 (br
s, 1 H), 8.09 (dd, J=7.9, 1.2 Hz, 1 H), 8.21 (dd, J=4.6, 1.5 Hz, 1 H). 19F NMR (471 MHz, CDCl3) δ
ppm <-143.05> - <-142.73> (m, 2 F), <-141.66> - <-141.22> (m, 2 F), -118.49 (s, 1 F), -56.09 (t,
J=22.2 Hz, 3 F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 175.6, 161.3, 159.4, 150.8, 148.9, 142.3,
129.8, 129.6, 129.5, 129.18, 129.15, 124.29, 124.26, 124.1, 123.9, 116.4, 115.5, 115.4, 61.3,
45.8, 44.1, 44.0, 20.8, 20.7, 16.2. HRMS (ESI+) m/z: [M + H]+ Calcd for C29H23F8N5O 610.1848;
Found 610.1841.
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2-((1R,5S,6r)-6-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-N-
(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (25, 27.7 mg, white solid, Yield: 28%).
1H NMR (500 MHz, CDCl3) δ ppm 1.14 (s, 6 H), 1.98 - 2.03 (m, 2 H), 2.12 (t, J=8.6 Hz, 1 H), 2.93
- 3.04 (m, 4 H), 6.56 (br s, 1 H), 7.56 (dd, J=9.2, 1.2 Hz, 1 H), 7.62 (d, J=9.2 Hz, 1 H), 7.98 (s, 1
H), 8.51 (s, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-143.76> - <-143.54> (m, 2 F), <-140.82> -
<-140.50> (m, 2 F), -56.15 (t, J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 175.0,
153.8, 149.3, 131.6, 126.4, 124.6, 116.3, 61.4, 45.3, 21.1, 20.4, 20.0. HRMS (ESI+) m/z: [M + H]+
Calcd for C22H18F7N5O 502.1473; Found 502.1474.
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2-((1R,5S,6s)-6-(imidazo[1,2-b]pyridazin-6-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-methyl-N-
(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propenamide (26, 18.3 mg, yellow solid, Yield: 18%).
1H NMR (500 MHz, CDCl3) δ ppm 1.16 (s, 6 H), 2.03 - 2.08 (m, 2 H), 2.17 (t, J=7.9 Hz, 1 H), 2.89
- 2.96 (m, 2 H), 3.12 (d, J=9.8 Hz, 2 H), 6.56 (br s, 1 H), 7.10 (d, J=9.2 Hz, 1 H), 7.37 (s, 1 H),
7.67 (s, 1 H), 7.83 (d, J=9.2 Hz, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm <-143.64> - <-143.45>
(m, 2 F), <-141.03> - <-140.74> (m, 2 F), -56.15 (t, J=22.2 Hz, 3 F). 13C{1H} NMR (126 MHz,
CDCl3) δ ppm 174.9, 152.3, 137.7, 133.4, 125.5, 118.8, 116.2, 61.5, 45.5, 22.1, 21.1, 20.5. HRMS
(ESI+) m/z: [M + H]+ Calcd for C22H18F7N5O 502.1473; Found 502.1476.
2-methyl-2-((1R,5S,6S)-6-(pyrazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-(2,3,5,6-tetra-
fluoro-4-(trifluoromethyl)phenyl)propenamide (36, 32.7 mg, white solid, Yield: 33%). 1H NMR (500
MHz, MeOD-d4) δ ppm 0.88 (s, 3 H), 1.11 (s, 3 H), 2.28 (d, J=11.6 Hz, 1 H), 2.36 (td, J=11.9, 7.3
Hz, 1 H), 2.51 - 2.57 (m, 2 H), 2.85 (dd, J=11.3, 2.1 Hz, 1 H), 2.99 (dd, J=12.5, 5.8 Hz, 1 H), 3.93
(dt, J=12.2, 6.1 Hz, 1 H), 4.51 (br d, J=6.7 Hz, 1 H), 4.63 (br d, J=7.3 Hz, 1 H), 8.41 (dd, J=2.4,
1.2 Hz, 1 H), 8.47 (d, J=2.4 Hz, 1 H), 8.69 (d, J=1.2 Hz, 1 H). 19F NMR (471 MHz, MeOD-d4) δ
ppm <-145.16> - <-144.99> (m, 2 F), <-144.07> - <-143.79> (m, 2 F), -57.56 (t, J=21.5 Hz, 3 F).
13C{1H} NMR (126 MHz, MeOD-d4) δ ppm 178.3, 156.1, 148.3, 144.3, 144.1, 79.5, 76.6, 64.9,
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54.2, 48.0, 46.8, 31.0, 25.9 ,14.5. HRMS (ESI+) m/z: [M + H]+ Calcd for C21H19F7N4O2 493.1469;
Found 493.1466.
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2-methyl-N-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-2-((1R,5S,10r)-10-(4-(trifluoromethyl)-
thiazol-2-yl)-1,2,4,5-tetrahydro-3H-1,5-methanobenzo[d]azepin-3-yl)propenamide (37, 69.7 mg,
white solid, Yield: 57%). 1H NMR (500 MHz, CDCl3) δ ppm 1.17 (s, 6 H), 2.68 (dd, J=11.6, 3.7 Hz,
2 H), 3.30 (d, J=11.6 Hz, 2 H), 3.68 (t, J=3.7 Hz, 2 H), 3.84 (t, J=4.3 Hz, 1 H), 7.17 (dd, J=5.5, 3.1
Hz, 2 H), 7.27 - 7.30 (m, 2 H), 7.49 (br s, 1 H), 7.79 (s, 1 H). 19F NMR (471 MHz, CDCl3) δ ppm
<-143.17> - <-142.94> (m, 2 F), <-141.56> - <-141.29> (m, 2 F), -63.96 (s, 3 F), -56.06 (t, J=21.5
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Hz, 3 F). C{1H} NMR (126 MHz, CDCl3) δ ppm 175.9, 171.9, 144.8, 127.4, 122.0, 63.9, 51.2,
44.6, 44.5, 21.6. HRMS (ESI+) m/z: [M + H]+ Calcd for C26H19F10N3OS 612.1162; Found 612.1152.
2-((1R,5S,7s)-6-acetyl-7-(pyrimidin-5-yl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-methyl-1-(2,3,5,6-
tetrafluoro-4-(trifluoromethyl)phenyl)propan-1-one (38, 44.9 mg, white solid, Yield: 43%). 1H NMR
(500 MHz, CDCl3) δ ppm 1.15 (s, 3 H), 1.19 (s, 3 H), 2.02 (s, 3 H), 3.00 (dd, J=11.6, 2.4 Hz, 1 H),
3.09 (dd, J=11.6, 2.4 Hz, 1 H), 3.20 (dd, J=11.6, 1.2 Hz, 1 H), 3.44 (dd, J=11.6, 1.2 Hz, 1 H), 4.06
(t, J=5.8 Hz, 1 H), 4.80 - 4.93 (m, 2 H), 6.59 (br s, 1 H), 8.57 (s, 2 H), 9.04 (s, 1 H). 19F NMR (471
MHz, CDCl3) δ ppm <-143.36> - <-143.17> (m, 2 F), <-140.78> - <-140.43> (m, 2 F), -56.12 (t,
J=21.5 Hz, 3 F). 13C{1H} NMR (126 MHz, CDCl3) δ ppm 173.4, 170.6, 157.5, 153.7, 131.1, 63.6,
63.2, 60.4, 44.6, 42.3, 37.4, 22.5, 20.5, 19.0. HRMS (ESI+) m/z: [M + H]+ Calcd for C22H20F7N5O2
520.1578; Found 520.1575.
2-((1R,5S,7s)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-acetyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-
methyl-1-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)propan-1-one (39, 30.6 mg, white solid,
Yield: 27%). 1H NMR (500 MHz, CDCl3) δ ppm 1.17 (s, 3 H), 1.22 (s, 3 H), 2.05 (s, 3 H), 3.09 (dd,
J=11.6, 2.4 Hz, 1 H), 3.15 (dd, J=11.6, 2.4 Hz, 1 H), 3.23 (dd, J=11.6, 1.2 Hz, 1 H), 3.46 (dd,
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