Cycloaddition and Cascade Radical Reactions for the Synthesis of Trifluoromethylated Tetrahydrobenzodiazepin-3-ones

Article abstract of DOI:10.1021/acs.joc.9b00448

A reaction sequence involving three-component [3 + 2] cycloaddition of azomethine ylides followed by CuI-catalyzed cascade trifluoromethyl radical addition and cyclization is developed for diastereoselective synthesis of fused-tetrahydrobenzodiazepin-3-ones.

Full text of DOI:10.1021/acs.joc.9b00448

Subscriber access provided by UNIV OF LOUISIANA
Note
[3+2] Cycloaddition and Cascade Radical Reactions for the
Synthesis of Trifluoromethylated Tetrahydrobenzodiazepin-3-ones
Alex Muthengi, Jon Erickson, Rachel E. Muriph, and Wei Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00448 • Publication Date (Web): 01 Apr 2019
Downloaded from http://pubs.acs.org on April 1, 2019
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[
3+2] Cycloaddition and Cascade Radical Reactions for the Synthesis of
Trifluoromethylated Tetrahydrobenzodiazepin-3-ones
Alex Muthengi,Jon Erickson, Rachel E Muriph, Wei Zhang*
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Centre for Green Chemistry and Department of Chemistry, University of Massachusetts Boston,
100 Morrissey Boulevard, Boston, MA 02125, USA
R1
R1
R1
O
N
NH2
N
O
N
O
O
O
O
CO R
2
[3+2]
R2
Togni
CuI
R2
CO R
2
N
+
R2
O
N
CO2R
O
CHO
N3
O
Cl
N
H
N3
1
5 examples
CF3
up to 77 % yield
ABSTRACT: A reaction sequence involving three-component [3+2] cycloaddition of azomethine
ylides followed by CuI-catalyzed cascade trifluoromethyl radical addition and cyclization is developed
for diastereoselective synthesis of fused-tetrahydrobenzodiazepin-3-ones.
Incorporation of CF to small molecules gained increasing popularity in the development of
3
biologically interested compounds to improve their metabolic stability, bioavailability, lipophilicity,
protein binding affinity, and blood–brain barrier penetration capability.1-8 Different from CH group,
3
9
CF has a high electronegativity of 3.2, and a size of 2.2 Å (van der Waals radius) similar to i-Pr. A
3
series of reagents and associated methods for trifluoromethylation have been developed.10,11 Among
them, Togni reagent-based CF radical reactions has been employed for making a series of
3
12
trifluoromethylated ring systems. For example, the Studer group reported the CF radical reaction
3
with aryl isonitriles for phenanthridines (Scheme 1, A).12d The Sodeoka group employed Cu-catalyzed
CF radical for the construction of five- and six-membered rings, but the effort for a seven-membered
3
ring was futile (Scheme 1, B).12e The Shi group reported Cu- or Fe-catalyzed CF radical reactions for
3
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the construction of seven-membered rings (Scheme 1, C).12f Introduced in this paper is our effort on
the development of CF radical reaction of 2-azidobenzyl acrylamides for the synthesis of
3
tetrahydrobenzodiazepin-3-ones (Scheme 1, D).
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Scheme 1. Togni-based CF Radical Reactions
3
Reported examples
F3C
I
O
O
Togni reagent
R2
R2
Togni
t-Bu4NI
R1
R1
(A)
(B)
1
,4-dioxane
N
CF3
NC
R1
R1
Togni, CuI
R3
n
R3
n
R2
1
,4-dioxane
R2
CF3
O
R2
R2
n = 0,1
O
F3C
R4
R2
R4
Togni
[Cu] or [Fe]
R2
N
R1
N
(C)
R1
R3
R3
This work
R1
R1
O
N
N
O
O
O
Togni, CuI
,4-dioxane
R2
R2
CO2Me (D)
N
1
N
CO2Me
O
O
N3
N
H
CF
3
_
_________________________________________________
Di- and tetrahydrobenzodiazepinones are privileged heterocycles which could be found in
numerous biologically active compounds such as diazepam,13a-c falcipain-2-inhibitor,13d halazepam,13e
flurazepam,13f lotrafiban,13g-h and vitamin D receptor (VDR) transcriptional inhibitor13i (Figure 1).
There are many reports on the synthesis of benzodiazepinones, such as CuI-catalyzed Ullmann type
aryl
amination,14a-d
intramolecular
nucleophilic
substitution14e
palladium-catalyzed
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aminocarbonylation,14f 1,3-dipolar cycloaddition and decarboxylative rearrangement,14g and Ugi four-
component reaction.15 Described in this paper is a radical reaction to construct CF -containing
3
benzodiazepinones which have a structure similarity to halazepam shown in Figure 1. Since organic
azides are good radical traps for carbon- and heteroatom-centered radicals,16 2-azidobenzyl
1
1
1
1
1
1
1
1
1
1
2
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2
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acrylamides were employed as substrates for CF radical addition to alkene followed by cyclization to
3
azide for the formation of tetrahydrobenzodiazepinones (Scheme 1, D).
SO R
2
H
N
CF3
O
O
N
O
O
F3C
N
N
H
N
Cl
Cl
N
N
Cl
N
O
O
Diazepam
Falcipain-2 Inhibitor
EtO C
Halazepam or Paxipam
Et
N
N
O
Et
2
O
N
N
O
N
Cl
N
O
N
H2N
N
F
CO H
2
H
H
HN
Vitamin D receptor (VDR)
transcription inhibitor
Flurazepam
Lotrafiban (Antithrombotic agent)
Figure 1. Benzodiazepinone-based Biologically Active Compounds
We have recently reported a series of [3+2] cycloaddition-based synthesis of diverse heterocyclic
structures.17a-d Similarly, other groups have reported the [3+2] cycloaddition of azomethine ylides and
maleimides.17e-h In this work, radical precursors 5 were prepared by one-pot [3+2] cycloaddition of
amino ester 1, maleimides 2, and 2-azidobenzaldehydes 3, followed by N-acylation with acryloyl
chloride (Table 1). After exploring the reaction conditions, the optimized condition for the [3+2]
cycloaddition was to use 1.2:1.1:1 of 1a:2a:3a and 2 equiv. of Et N in MeCN under microwave
3
o
heating at 125 C for 30 min. After precipitating out from the reaction mixture, 4a was obtained in
94% isolated yield with a diastereoselectivity of 39:1. The optimized condition for N-acylation was to
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5
5
6
o
react 1:1.1 of 4a:acryloyl chloride in the presence of Et N at 25 C for 4 h to give 5a in 94% isolated
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yield (Table 1, entry 7). CH Cl was also a good solvent (Table 1, entry 6). But MeCN was chosen
2
2
1
8
since it’s a greener solvent based on the solvent selection guide. Other than Et N, DIPEA and K CO
3
2
3
could also be used as bases for the acylation reaction (Table 1, entries 9 and 10).
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Table 1. Optimization of [3+2] Cycloaddition and N-Acylation Reactionsa
.
NH HCl
Ph
2
O
N
O
CO Me
O
2
CO Me
2
Ph
O
1a
N
Et N
3
Ph
N
NH
CH CN
Cl
3
+
O
CHO
N3
O
CO Me
2

w
N
O
base
N3
o
o
1
25 C
O
25 C, T
N3
5a
30 min
2a
3a
4
a
5a (%)b
entry
solvent
base
(2 equiv)
T (h)
1
2
3
4
5
6
7
8
9
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
Et
Et
Et
Et
Et
Et
3
3
3
3
3
3
N
N
N
N
N
N
2
3
62
81
96
83
95
3.5
3
MeCN
MeCN
3.5
4
CH
2
Cl
2
98
98 (94)c
MeCN
Et
3
N
4
EtOAc
TEA
DIPEA
K CO
4
79
95
96
CH
CH
2
2
Cl
2
2
4
1
0
Cl
4
2
3
a
Reaction conditions: 1.2:1.1:1 of 1a:2a:3a, Et
3
N (2 equiv.) in MeCN,
microwave heating for 30 min for 4a, then 1:1.1 of 4a:acryoyl chloride,
3
N (2 equiv.) at 25 C. Yields based on conversion of 4a. Detected
o
b
Et
c
by LC-MS. Isolated yield in parentheses.
_
____________________________________________________________________________
Radical precursor 5a was used for the development of Togni reagent-based CF radical addition
3
and cyclization for the synthesis of product 6a (Table 2).10,11 The initial reaction using 10 mol% of
CuBr as a catalyst in CH ClCH Cl at 75 °C for 6 h afforded product 6a in 24% LC yield (Table 2,
2
2
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entry 1), and 29% yield by using CuI as a catalyst (Table 2, entry 2). After screening reaction
temperature and solvents including 1,4-dioxane, EtOH, and EtOAc (Table 2, entries 3-11), the best
o
condition was to conduct the reaction using CuI as a catalyst in 1,4-dioxane at 85 C for 24 h which
gave 6a in 60% isolated yield and 5:1 dr (Table 2, entry 8). Reduced CuI loading to
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
a
Table 2. Optimization of CF Radical Reaction
3
Ph
Ph
O
N
N
O
O
O
F3C
I
O
catalyst, T, t
solvent
CO Me
N
2
+
N
CO Me
O
2
O
O
N
H
N3
CF3
5a
6a
entry
cat
mol
solvent
T
( C)
t
6a (%)a,b
o
%
10
10
10
10
10
10
10
10
10
10
10
5
(h)
1
2
3
4
5
6
7
8
9
CuBr
CuI
CuBr
CuBr
CuI
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
-
CH
CH
CH
2
2
2
ClCH
ClCH
ClCH
2
2
2
Cl
Cl
Cl
75
80
80
80
80
80
80
85
85
80
80
85
80
80
6
24
29
6
12
12
12
24
24
24
28
12
12
24
24
24
59
1,4-dioxane
1,4-dioxane
61
64
CH
2
ClCH
2
Cl
69
1,4-dioxane
1,4-dioxane
1,4-dioxane
EtOH
70
73 (60)c
73
1
1
1
0
1
2
15
EtOAc
trace
51
1,4-dioxane
1,4-dioxane
1,4-dioxane
13
-
trace
trace
1
4
Bu
4
NI
-
a
b
Reaction conditions: 1:1.5 of 5a:Togni and 10 mol% of CuI in 1,4-dioxane
Detected by LC-MS. Isolated yield in parentheses.
c
_
____________________________________________________________________
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12d,19
5
mol% lowered the yield to 51% (Table 2, entry 12). Replacement of CuI with Bu NI
or reaction
4
without using a catalyst only resulted in a trace amount of product (Table 2, entries 13 and 14). It is
worth noting that N gas generated during the reaction could help to maintain the inert atmosphere
2
necessary for the reaction process.
0
1
2
3
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9
0
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A number of radical precursors 5 were prepared and used to evaluate the scope of the CF radical
3
reactions for tetrahydrobenzodiazepinone analogs 6 (Table 3). Under the optimized reaction
1
2
conditions using CuI or CuBr as a catalyst, substrates 5a–o with different R and R afforded products
2
6
a–o in 60-77% yields. Among them, unsubstituted arenes (R = H) gave 6a–f in 60-75% yields.
Substrates with electron donating group (MeO) or withdrawing groups (Cl and Br) at different
positions on the aromatic ring did not have significant impact on product yields of 6g–o. Likewise, the
1
substituents on maleimides (R = Me, Et, Pr, t-Bu, Ph, Bn and c-C H ) also had limited impact. The
6
11
results also indicated that the radical trifluoromethylation of 2-azidobenzyl acrylamides are
diastereoselective (dr ≥ 5:1). The stereochemistry of radical precursors 5 generated from the [3+2]
cycloaddition has been well reported.17c-d The new stereogenic center on tetrahydrobenzodiazepinone
ring established during the radical cyclization was determined on the basis of the NOE experiment of
the major diastereomer of 6c (see SupInf).
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Table 3. Synthesis of Tetrahydrobenzodiazepin-3-onesa
R1
N
R1
O
N
O
O
O
F3C
CuI
1,4-dioxane
R2
I
O
R2
CO Me
2
N
N
CO2Me
+
O
85 oC, 24 h
O
O
N3
N
H
CF3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
6
Cy
Ph
Et
N
Pr
N
O
O
O
N
O
N
O
O
O
O
CO Me
CO2Me
O
2
CO Me
CO Me
2
N
2
N
N
N
O
O
O
N
H
N
N
N
CF3
H
CF3
H
CF3
H
CF3
a, 60%b
6b, 75%b
6c, 71%b
6d, 69%b
dr = 5:1
6
dr = 5:1
dr = 8:1
dr >10:1
Bn
Cy
t-Bu
Ph
O
O
O
O
N
N
N
N
O
O
O
O
CO Me
CO Me
CO Me
CO Me
2
2
2
2
N
N
N
N
O
O
O
O
MeO
MeO
N
H
N
N
H
N
H
CF3
H
CF3
O
CF3
CF3
e, 62%b
dr = 6:1
6g, 64%
dr = 7:1
6
6f, 63%
dr = 9:1
6h,
62%
dr = 6.5:1
Pr
N
Bn
O
O
N
O
N
N
O
O
O
O
CO Me Cl
CO2Me
CO Me
2
N
Cl
2
CO Me
N
N
Cl
2
N
O
O
O
O
MeO
N
H
N
H
N
H
N
H
CF3
CF3
CF3
CF3
6i, 66%
6j, 65%
6k, 69%
6l, 63%
dr = 8:1
dr = 7:1
dr = 5.5:1
dr = 6:1
Cy
N
Pr
N
O
O
O
N
O
O
O
CO Me
Cl
CO Me
2
CO Me
2
N
2
N
N
O
O
O
Br
Br
N
H
N
N
H
CF3
H
CF3
CF3
6m, 64%
dr = 5.5:1
6n, 67%
dr = 8:1
6
o, 77 %
dr = 7.5:1
a
o
Reaction conditions: 1:1.5 of 5:Togni reagent and CuI (10 mol %) in degassed 1,4-dioxane at 85 C
1
9
b
under Ar, isolated yield, dr determined by F-NMR of the crude mixture. CuBr (10 mol %) in at
0 °C under N
8
_
2
.
_________________________________________________________________________________________
1
2
On the basis of literature reports, a mechanism for the formation of tetrahydrobenzodiazepinones
is suggested in Scheme 2. The Togni reagent was reduced by Cu(I) to form a CF radical and ortho-
3
−
12d
iodobenzoate (ArylCO ). The CF radical then attacks the terminal alkene of 2-azidobenzyl
2
3
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acrylamide 5 to form acyl group-stabilized radical A. Since the azide group is a good radical
1
6
acceptor, radical A cyclized to the azido group to form radical B. The N -fragmentation of radical B
2
generates a N-centered radical C, which undergoes H-abstraction from the solvent,16 1,4-dioxane,
forming tetrahydrobenzodiazepinone 6, and a dioxanyl radical. The dioxanyl radical is oxidized by the
0
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Cu(II)-species generated in the initial CF -radical formation, hence regenerating the Cu(I)-complex,
3
and an oxy-carbenium ion (3,6-dihydro-2H-1,4-dioxin-4-ium).12g-i The oxy-carbenium ion is likely
−
12b-d
trapped by ortho-iodobenzoate (ArylCO ).
2
Scheme 2. Proposed Mechanism for CF Radical reaction
3
F3C
I
O
O
I
O
R1
R1
O
O
N
O
N
CuI
O
O
ArylCO2
R2
CuII
R2
CO Me
2
N
CO2Me
O
N
O
N3
N
H
CF3
CF3
5
6
O
O
O
O
F3C
I
O
O
O
+
CuII
CuI
H
O
R1
N
I
O
O
R1
N
O
O
O
R1
O
ArylCO2
N
CO2Me
O
R2
CO Me
2
N
N
O
R1
CF3
N
N
O
N
N
A
CF3
C
O
R2
CO Me
2
N
O
N2
N
N
CF3
N
B
In conclusion, we have developed an efficient synthetic approach to trifluoromethylated
I
tetrahydrobenzodiazepinones through Togni reagent and a Cu -catalyzed CF radical reaction of 2-
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azidobenzyl acrylamides to afford diastereoselective products in good yields. The radical precursors
were readily prepared by one-pot and three-component [3+2] cycloaddition followed by N-acylation.
It is a new approach for making biologically interesting tetrahydrobenzodiazepinones bearing CF3
groups.
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EXPERIMENTAL SECTION
General method. Chemicals and solvents were purchased from commercial suppliers and used
as received. H NMR (400 MHz), 13C NMR (101 MHz), and 19F NMR (376 MHz) spectra were
recorded on Agilent NMR spectrometers. The chemical shifts were reported in parts per million (ppm),
and the residual solvent peak was used as an internal reference: proton (chloroform δ 7.26) and carbon
1
(chloroform δ 77.0). Multiplicities were indicated as follows: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), dd (doublet of doublet), br s (broad singlet). Coupling constants were reported
in hertz (Hz).
LC–MS was performed on an Agilent 2100 LC with a 6130 quadrupole MS spectrometer, and a
C18 column (5.0 μm, 6.0 × 50 mm) was used for separation. The mobile phases were MeOH and H O;
2
both containing 0.01% trifluoroacetic acid. A linear gradient of 50:50 (v/v) MeOH/H O to 100%
2
MeOH was used over 7.0 min at a flow rate of 0.7 mL/min. The chromatograms were detected at UV
wavelengths 210, 254, and 365 nm. Low resolution mass spectra were recorded in APCI (atmospheric
pressure chemical ionization). The microwave reactions were performed on a Biotage Initiator 8
system, equipped with an Infrared (IR) sensor (external surface sensor) to monitor the reaction
temperature. The final products were purified on Angela HP-100 pre-LC system with a Venusil PrepG
C18 column (10 μm, 120 Å, 21.2 mm x 250 mm).
HRMS was analyzed by RP-LC-MS: 1 µL of each sample was combined and 500 mL of optima
grade MeCN (0.1 % formic acid) and 500 mL of optima grade H O (0.1 % formic acid) were added
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6
to the mixture. This mixture was then diluted by another factor of 10 with a 75/25 mixture of the
optima grade MeCN and H O. 1 mL of this mixture was analyzed by RP-LC-MS. The mass analyzer
2
was orbitrap.
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Representative procedure for preparation of 2-azidobenzaldehydes 3.
2
0
The 2-azidobenzaldehyde 3 was prepared following the literature procedure. A reaction vessel was
charged with HMPA (7.5 mmol) and 2-nitrobenzaldehyde (5.0 mmol). Once 2-nitrobenzaldehyde was
o
dissolved, NaN (10 mmol) was added dropwise. The reaction mixture was run at 25 C for 24 h. The
3
completion of the reaction was detected using LC-MS. After completion of the reaction, the solvent
was removed under reduced pressure and the residue purified using flash chromatography using 80:20
mixture of hexane/EtOAc as eluent, to provide 2-nitrobenzaldehyde 3.
Representative procedure for [3+2] cycloaddition.
A reaction vial was charged with the corresponding D-alanine methyl ester 1 (1.2 mmol), maleimide
2
(1.1 mmol) and 2-azidobenzaldehyde 3 (1.0 mmol). Then, 2.5 mL of CH CN was added and the
3
o
sealed reaction vial was heated under microwave irradiation at 125 C for 30 min. The reaction mixture
o
was kept at 25 C for 2-3 h and a solid product was formed, washed with 1 mL of water, filtered and
dried to obtain intermediate 4 in >95% purity. The intermediate products 4 were used for the next
reaction without further purification.
Representative procedure for N-acylation.
To a solution of [3+2] cycloaddition adduct 4 (39:1 dr, 1 mmol, 1 equiv.), Acryoyl chloride (1.1 mmol,
1
.1 equiv.) and Et N (2.0 mmol, 2.0 equiv.) in 2.0 mL of CH CN. The reaction mixture in a sealed
3 3
o
reaction vial was run at 25 C for 4 h to obtain intermediate 5. The completion of the reaction was
detected using LC-MS. After completion of the reaction, the solvent was removed under reduced
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pressure and the residue purified using flash chromatography using a 70:30 mixture of hexane/EtOAc
as eluent, to provide the intermediate 5.
General procedure for synthesis of products 6.
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(2-Azidobenzyl)acrylamide 5 (0.1 mmol, 1.0 equiv.), Togni reagent (1.5 mmol, 1.5 equiv.) and
CuI (0.01 mmol, 0.1 equiv.), were added to a dry reaction vial. The reaction vial was evacuated and
backfilled with nitrogen or Argon gas. Then, 1 mL of degassed 1,4-dioxane was added, and the
o
reaction mixture stirred at 85 C for 24 h as monitored by LC-MS. Upon completion of the reaction,
H O was added to the reaction mixture and extracted with EtOAc. The organic layer was then washed
2
with brine and dried over Na SO . After filtration, the filtrate was concentrated under reduced pressure
2
4
and the residue purified by Angela HP-100 pre-LC system on (MeOH/H O = 70:30) to give the
2
trifluoromethylated product 6a–6o as a yellow oil.
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azidophenyl)-1-methyl-4,6-dioxo-5-
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5a): White solid (417.7 mg, 91% yield). MP:
o
1
2
53-255 C. H NMR (400 MHz, CDCl ) δ 8.06 (d, J = 6.5 Hz, 1H), 7.37 (td, J = 7.9, 1.5 Hz, 1H),
3
7.28 (dd, J = 5.4, 3.6 Hz, 2H), 7.26 – 7.24 (m, 1H), 7.21 (dd, J = 8.0, 0.9 Hz, 1H), 7.13 (t, J = 7.6 Hz,
1
1
H), 6.65 – 6.56 (m, 2H), 6.27 (dd, J = 16.5, 1.7 Hz, 1H), 5.97 (d, J = 10.8 Hz, 1H), 5.89 – 5.77 (m,
H), 5.47 (d, J = 10.2 Hz, 1H), 4.23 – 4.15 (m, 1H), 3.89 (s, 3H), 3.54 (d, J = 9.0 Hz, 1H), 1.92 (s,
1
3
1
3H). C{ H} NMR (101 MHz, CDCl ) δ 172.4, 171.8, 170.2, 164.5, 137.8, 130.9, 130.0, 129.9, 129.5,
3
1
29.0, 128.7, 127.8, 125.9, 125.7, 118.4, 69.2, 58.1, 54.7, 53.0, 49.0, 24.2. HRMS (ESI-Orbitrap) m/z:
+
(
M+H) Calcd for C H N O 460.1621, found 460.1607.
2
4
21
5
5
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azidophenyl)-5-ethyl-1-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5b): Yellow solid (369.9 mg, 90% yield). MP:
o
1
2
7
57-260 C. H NMR (400 MHz, CDCl ) δ 7.87 (d, J = 8.2 Hz, 1H), 7.32 (td, J = 7.9, 1.5 Hz, 1H),
3
.18 (dd, J = 8.0, 0.8 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.24 (d, J = 18.3 Hz, 1H), 5.87 (d, J = 10.8 Hz,
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H), 5.78 (dd, J = 16.3, 10.4 Hz, 1H), 5.43 (d, J = 10.3 Hz, 1H), 4.07 – 3.99 (m, 1H), 3.91 (s, 3H),
3
.32 (d, J = 9.1 Hz, 1H), 3.17 (ddd, J = 27.4, 13.4, 6.7 Hz, 2H), 1.87 (s, 3H), 0.74 (t, J = 7.2 Hz, 3H).
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 173.4, 172.6, 170.3, 164.6, 137.7, 129.9, 129.3, 128.4, 127.8,
3
+
1
25.5, 118.1, 69.1, 57.8, 52.9, 48.9, 33.9, 29.7, 24.2, 12.3. HRMS (ESI-Orbitrap) m/z: (M+H) Calcd
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1
2
3
4
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for C H N O 412.1621, found 412.1606.
2
0
21
5
5
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azidophenyl)-1-methyl-4,6-dioxo-5-
propyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5c): Yellow solid (395.3 mg, 93% yield). MP:
o
1
2
28-231 C. H NMR (400 MHz, CDCl ) δ 7.84 (d, J = 7.2 Hz, 1H), 7.35 – 7.30 (m, 1H), 7.18 (dd, J
3
=
8.0, 0.9 Hz, 1H), 7.06 (td, J = 7.6, 0.9 Hz, 1H), 6.23 (d, J = 18.3 Hz, 1H), 5.87 (d, J = 10.9 Hz, 1H),
5.82 – 5.72 (m, 1H), 5.42 (d, J = 10.3 Hz, 1H), 4.08 – 4.01 (m, 1H), 3.90 (s, 3H), 3.34 (d, J = 9.1 Hz,
1
3
1
H), 3.15 – 3.06 (m, 1H), 3.03 – 2.93 (m, 1H), 1.87 (s, 3H), 1.20 – 1.03 (m, 2H), 0.73 (t, J = 7.4 Hz,
1
3
1
H). C{ H} NMR (101 MHz, CDCl ) δ 173.6, 172.9, 170.3, 164.6, 137.7, 129.9, 129.8, 129.2, 128.3,
3
27.9, 125.4, 118.1, 69.2, 57.8, 54.5, 52.9, 48.8, 40.6, 24.1, 20.5, 11.3. HRMS (ESI-Orbitrap) m/z:
+
(M+H) Calcd for C H N O 426.1778, found 426.1762.
2
1
23
5
5
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azidophenyl)-5-cyclohexyl-1-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5d): Light yellow solid (437.1 mg, 94% yield).
o
1
MP: 259-262 C. H NMR (400 MHz, CDCl ) δ 7.91 (d, J = 7.2 Hz, 1H), 7.32 (td, J = 7.9, 1.5 Hz,
3
1
H), 7.17 (dd, J = 8.0, 0.9 Hz, 1H), 7.07 (td, J = 7.6, 0.9 Hz, 1H), 6.23 (dd, J = 16.5, 1.8 Hz, 1H), 5.84
d, J = 10.8 Hz, 1H), 5.81 – 5.71 (m, 1H), 5.42 (d, J = 10.3 Hz, 1H), 4.01 – 3.94 (m, 1H), 3.91 (s, 3H),
3.57 (tt, J = 12.2, 3.8 Hz, 1H), 3.29 (d, J = 9.2 Hz, 1H), 1.86 (s, 3H), 1.65 (dd, J = 18.7, 13.5 Hz, 2H),
(
13
1
1
.56 – 1.48 (m, 2H), 1.26 – 1.00 (m, 6H). C{ H} NMR (101 MHz, CDCl ) δ 173.5, 172.7, 170.3,
3
1
64.5, 137.6, 130.0, 129.8, 129.2, 128.6, 127.9, 125.5, 118.1, 69.1, 57.9, 54.4, 52.9, 52.0, 50.9, 48.6,
+
2
8.4, 27.5, 25.6, 24.8, 24.2. HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for C H N O 466.20907,
24 27
5
5
found 466.2091.
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Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azidophenyl)-5-benzyl-1-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5e): White solid (435.2 mg, 92% yield). MP:
o
1
2
37-240 C. H NMR (400 MHz, CDCl ) δ 7.55 (d, J = 6.8 Hz, 1H), 7.21 (dd, J = 8.1, 4.0 Hz, 4H),
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
7
5
.13 (d, J = 6.6 Hz, 3H), 6.75 – 6.68 (m, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.83 (d, J = 12.5 Hz, 1H),
.78 – 5.68 (m, 1H), 5.38 (d, J = 10.1 Hz, 1H), 4.27 (dd, J = 13.9, 2.5 Hz, 1H), 4.14 (dd, J = 13.9, 2.4
0
1
2
3
4
5
6
7
8
9
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1
Hz, 1H), 4.07 – 3.98 (m, 1H), 3.80 (s, 3H), 3.32 (dd, J = 9.2, 2.5 Hz, 1H), 1.83 (s, 3H). C{ H} NMR
(101 MHz, CDCl ) δ 173.4, 172.5, 170.1, 164.6, 137.3, 134.8, 129.7, 129.6, 129.2, 129.1, 128.5, 128.0,
3
+
1
27.8, 125.4, 117.9, 69.2, 57.5, 54.4, 52.8, 48.8, 42.6, 24.0. HRMS (ESI-Orbitrap) m/z: (M+H) Calcd
for C H N O 474.1778, found 474.1760.
2
5
23
5
5
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azidophenyl)-5-(tert-butyl)-1-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5f): White solid (386.3 mg, 88% yield). MP:
o
1
2
57-260 C. H NMR (400 MHz, CDCl ) δ 7.95 (d, J = 6.8 Hz, 1H), 7.34 (t, J = 8.2 Hz, 1H), 7.18 (d,
3
J = 7.9 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.23 (d, J = 15.2 Hz, 1H), 5.84 (d, J = 10.8 Hz, 1H), 5.74 (d,
J = 16.2 Hz, 1H), 5.42 (d, J = 10.0 Hz, 1H), 3.92 (d, J = 9.6 Hz, 1H), 3.89 (s, 3H), 3.22 (d, J = 9.2 Hz,
1
3
1
1
H), 1.84 (s, 3H), 1.17 (s, 9H). C{ H} NMR (101 MHz, CDCl ) δ 174.2, 173.5, 170.4, 164.5, 137.8,
3
1
30.1, 129.8, 129.2, 128.9, 127.9, 125.4, 118.2, 69.8, 58.6, 54.6, 52.8, 49.0, 27.5, 24.1. HRMS (ESI-
+
Orbitrap) m/z: (M+H) Calcd for C H N O 440.19342, found 440.1934.
2
2
25
5
5
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azido-4-methoxyphenyl)-1-methyl-4,6-dioxo-5-
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5g): Yellow solid (449.9 mg, 92% yield). MP:
o
1
258-261 C. H NMR (400 MHz, CDCl ) δ 7.95 (d, J = 8.2 Hz, 1H), 7.33 – 7.28 (m, 2H), 7.27 (t, J =
3
3
5
1
.2 Hz, 1H), 6.72 – 6.62 (m, 4H), 6.27 (dd, J = 16.6, 1.5 Hz, 1H), 5.87 (dd, J = 18.6, 10.6 Hz, 2H),
.48 (d, J = 10.4 Hz, 1H), 4.14 (d, J = 10.6 Hz, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.52 (d, J = 9.0 Hz,
1
3
1
H), 1.90 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ 172.5, 172.0, 170.2, 164.5, 160.8, 138.8, 131.0,
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29.4, 129.0, 128.7, 127.8, 126.0, 122.2, 111.0, 104.3, 69.1, 60.4, 57.8, 55.5, 53.0, 49.2, 24.1. HRMS
+
(ESI-Orbitrap) m/z: (M+H) Calcd for C H N O 490.17269, found 490.1727.
2
5
23
5
6
Methyl (1R,3S,3aR,6aS)-2-acryloyl-3-(2-azido-4-methoxyphenyl)-5-cyclohexyl-1-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5h): White solid (450.5 mg, 91% yield). MP:
0
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5
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1
2
51-253 C. H NMR (400 MHz, CDCl ) δ 7.81 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 6.60 (d, J = 8.7 Hz,
3
1
H), 6.23 (d, J = 18.0 Hz, 1H), 5.79 (dd, J = 17.5, 10.6 Hz, 2H), 5.43 (d, J = 10.4 Hz, 1H), 3.94 (d, J
= 9.6 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 3.64 – 3.55 (m, 1H), 3.27 (d, J = 9.2 Hz, 1H), 1.84 (s, 3H),
13
1
1
.72 – 1.53 (m, 4H), 1.26 (t, J = 7.1 Hz, 2H), 1.10 (q, J = 18.9, 15.5 Hz, 4H). C{ H} NMR (101
MHz, CDCl ) δ 173.6, 172.9, 170.4, 164.6, 160.7, 138.6, 129.7, 129.1, 127.9, 122.4, 111.0, 104.0,
3
57.6, 55.5, 54.3, 52.8, 52.0, 48.7, 28.4, 27.6, 25.6, 25.6, 24.8. HRMS (ESI-Orbitrap) m/z: (M+H)+
Calcd for C H N O 496.21964, found 496.2196.
2
5
29
5
6
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azido-4-methoxyphenyl)-1,5-dimethyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5i): Light yellow solid (384.3 mg, 90% yield).
o
1
MP: 258-260 C. H NMR (400 MHz, CDCl ) δ 7.71 (d, J = 8.5 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H),
3
6
.61 (dd, J = 8.7, 2.4 Hz, 1H), 6.24 (dd, J = 16.6, 1.3 Hz, 1H), 5.83 (dd, J = 23.8, 10.5 Hz, 2H), 5.45
(d, J = 10.4 Hz, 1H), 4.00 (d, J = 10.6 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 3.32 (d, J = 8.8 Hz, 1H),
1
3
1
2.57 (s, 3H), 1.85 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ 173.6, 173.0, 170.3, 164.5, 160.6,
3
1
38.6, 129.3, 127.8, 122.2, 110.9, 103.8, 68.9, 57.4, 55.4, 54.4, 53.0, 49.2, 24.7, 14.2. HRMS (ESI-
+
Orbitrap) m/z: (M+H) Calcd for C H N O 428.15708, found 428.1570.
2
0
21
5
6
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azido-5-chlorophenyl)-1,5-dimethyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5j): Light yellow solid (379.3 mg, 88% yield).
o
1
MP: 260-262 C. H NMR (400 MHz, CDCl ) δ 7.83 (s, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.13 (dd, J =
3
1
8.5, 8.5 Hz, 1H), 6.28 (d, J = 16.5 Hz, 1H), 5.83 (d, J = 10.5 Hz, 2H), 5.50 (d, J = 9.8 Hz, 1H), 4.04
1
3
1
(d, J = 9.3 Hz, 1H), 3.91 (s, 3H), 3.34 (d, J = 8.7 Hz, 1H), 2.62 (s, 3H), 1.86 (s, 3H). C{ H} NMR
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(
101 MHz, CDCl ) δ 173.2, 172.7, 170.0, 164.4, 136.3, 131.8, 130.0, 129.9, 127.5, 127.5, 119.6, 119.4,
3
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
5
7.5, 54.5, 53.0, 49.0, 46.4, 40.3, 24.7. HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for C H N O Cl
1
9
18
5
5
4
32.1075, found 432.1077.
Methyl (1R,3S,3aR,6aS)-2-acryloyl-3-(2-azido-5-chlorophenyl)-1-methyl-4,6-dioxo-5-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
propyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5k): White solid (408.5 mg, 89% yield). MP:
o
2
69-272 C. 1H NMR (400 MHz, CDCl ) δ 7.84 (s, 1H), 7.28 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (d, J =
3
8.5 Hz, 1H), 6.26 (d, J = 16.5 Hz, 1H), 5.85 – 5.72 (m, 2H), 5.47 (d, J = 10.4 Hz, 1H), 4.01 (t, J = 10.0
Hz, 1H), 3.87 (s, 3H), 3.32 (d, J = 9.2 Hz, 1H), 3.18 – 3.03 (m, 2H), 1.84 (s, 3H), 1.26 – 1.13 (m, 2H),
1
3
1
0
.77 (t, J = 7.4 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 173.4, 172.7, 164.5, 136.4, 131.7, 131.0,
3
129.9, 128.4, 127.6, 119.4, 69.3, 57.6, 54.4, 52.8, 48.7, 40.7, 29.7, 20.8, 11.3. HRMS (ESI-Orbitrap)
+
m/z: (M+H) Calcd for C H N O Cl 460.1388, found 460.1370.
2
1
22
5
5
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azido-5-chlorophenyl)-5-benzyl-1-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5l): White solid (456.3 mg, 90% yield). MP:
o
1
2
50-253 C. H NMR (400 MHz, CDCl ) δ 7.71 (s, 1H), 7.26 – 7.22 (m, 4H), 7.14 (dd, J = 6.8, 2.8
3
Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 6.25 (d, J = 16.5 Hz, 1H), 5.81 (d, J = 10.9 Hz, 1H), 5.71 (d, J = 7.7
Hz, 1H), 5.46 (d, J = 10.1 Hz, 1H), 4.13 (s, 2H), 3.76 (d, J = 4.4 Hz, 1H), 3.72 (s, 3H), 3.34 (d, J = 9.3
1
3
1
Hz, 1H), 1.83 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ 173.2, 172.4, 171.1, 164.5, 136.3, 134.6,
3
1
1
31.4, 130.9, 129.1, 128.9, 128.7, 128.5, 128.1, 128.1, 127.6, 119.3, 60.4, 57.7, 52.7, 48.8, 42.8, 21.1,
+
4.2. HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for C H N O Cl 508.1388, found 508.1374.
2
5
22
5
5
Methyl (1R,3S,3aR,6aS)-2-acryloyl-3-(2-azido-5-chlorophenyl)-5-cyclohexyl-1-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5m): Yellow solid (454.1 mg, 91% yield). MP:
o
1
2
77-280 C. H NMR (400 MHz, CDCl ) δ 7.90 (s, 1H), 7.29 (dd, J = 8.5, 2.3 Hz, 1H), 7.14 (dd, J =
3
1
8.1, 8.5 Hz, 1H), 6.27 (d, J = 17.7 Hz, 1H), 5.81 (d, J = 11.0 Hz, 1H), 5.73 (d, J = 19.6 Hz, 1H), 5.48
(
d, J = 9.7 Hz, 1H), 4.01 – 3.93 (m, 1H), 3.90 (s, 3H), 3.68 – 3.58 (m, 1H), 3.31 (d, J = 9.3 Hz, 1H),
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
1
.84 (s, 3H), 1.71 (t, J = 11.2 Hz, 2H), 1.57 (t, J = 12.2 Hz, 2H), 1.26 – 1.07 (m, 6H). C{ H} NMR
(
101 MHz, CDCl ) δ 173.4, 173.4, 172.8, 164.4, 136.3, 131.9, 129.9, 129.8, 127.6, 127.5, 119.6, 119.4,
3
6
9.4, 57.4, 52.8, 52.1, 52.0, 50.9, 29.7, 28.3, 27.8, 25.6, 25.6, 24.7. HRMS (ESI-Orbitrap) m/z:
+
(M+H) Calcd for C H N O Cl 500.1701, found 500.1703.
2
4
26
5
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azido-4-bromophenyl)-1-methyl-4,6-dioxo-5-
propyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5n): Yellow solid (427.6 mg, 85% yield). MP:
o
1
135-138 C. H NMR (400 MHz, CDCl ) δ 7.54 (d, J = 9.4 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.19 –
3
7
.15 (m, 1H), 6.25 (d, J = 16.5 Hz, 1H), 5.79 (d, J = 10.9 Hz, 1H), 5.72 (d, J = 11.9 Hz, 1H), 5.46 (d,
J = 9.5 Hz, 1H), 4.06 – 3.97 (m, 1H), 3.88 (s, 3H), 3.33 (d, J = 9.4 Hz, 1H), 3.13 (dd, J = 19.3, 8.9 Hz,
1
3
1
2H), 1.85 (s, 3H), 1.14 (dq, J = 16.0, 8.7, 7.7 Hz, 2H), 0.74 (t, J = 7.4 Hz, 3H). C{ H} NMR (101
MHz, CDCl ) δ 173.5, 172.8, 170.1, 164.4, 139.1, 129.8, 127.6, 125.8, 122.7, 121.8, 121.2, 120.0,
3
+
6
1.1, 57.5, 53.1, 53.0, 40.7, 20.6, 17.9, 11.3. HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for
C H N O Br 504.08829, found 504.0887.
21 22
5
5
Methyl
(1R,3S,3aR,6aS)-2-acryloyl-3-(2-azido-4-bromophenyl)-1,5-dimethyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (5o): Light yellow solid (413.3 mg, 87% yield).
o
1
MP: 281-284 C. H NMR (400 MHz, CDCl ) δ 7.73 (s, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.20 (dd, J =
3
8.4, 1.7 Hz, 1H), 6.27 (d, J = 16.5 Hz, 1H), 5.81 (d, J = 10.7 Hz, 1H), 5.75 (d, J = 10.4 Hz, 1H), 5.49
(
d, J = 10.1 Hz, 1H), 4.04 (t, J = 9.8 Hz, 1H), 3.91 (s, 3H), 3.35 (d, J = 8.9 Hz, 1H), 2.59 (s, 3H), 1.86
1
3
1
(
s, 3H). C{ H} NMR (101 MHz, CDCl ) δ 173.4, 172.7, 170.3, 164.3, 139.0, 129.9, 129.1, 128.4,
3
+
127.5, 123.4, 121.2, 69.3, 57.4, 54.5, 53.1, 48.7, 29.7, 24.8. HRMS (ESI-Orbitrap) m/z: (M+H) Calcd
for C H N O Br 476.05699, found 476.0572.
1
9
18
5
5
Methyl
(9R,9aS,12aR)-9-methyl-7,10,12-trioxo-11-phenyl-6-(2,2,2-trifluoroethyl)-
5
,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-d][1,4]diazepine-9-
1
carboxylate (6a): Yellow oil (30 mg, 60% yield). H NMR (400 MHz, CDCl ) δ 7.54 – 7.50 (m, 2H),
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.48 – 7.44 (m, 1H), 7.27 (d, J = 1.5 Hz, 1H), 7.25 – 7.24 (m, 1H), 7.21 – 7.16 (m, 1H), 7.04 (d, J =
.5 Hz, 1H), 6.98 (td, J = 7.5, 1.2 Hz, 1H), 6.82 (dd, J = 7.9, 1.1 Hz, 1H), 5.74 (d, J = 9.5 Hz, 1H),
.22 (s, 1H), 4.23 (t, J = 6.7 Hz, 1H), 3.96 – 3.90 (m, 1H), 3.53 (s, 3H), 3.38 (d, J = 9.3 Hz, 1H), 3.03
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
5
–
1
1
3
1
2.85 (m, 2H), 1.82 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ 173.6, 173.0, 169.0, 143.8, 131.1,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
29.5, 129.3, 129.0, 128.3, 126.4, 125.3, 123.0, 120.8, 71.7, 69.8, 52.8, 52.6, 34.5, 34.2, 23.6. F
+
NMR (376 MHz, CDCl ) δ -64.38 (t, J = 10.6 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for
3
C H N O F 502.1590, found 502.1574.
2
5
22
3
5 3
Methyl
(9R,9aS,12aR)-11-ethyl-9-methyl-7,10,12-trioxo-6-(2,2,2-trifluoroethyl)-
5
,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-d][1,4]diazepine-9-
1
carboxylate (6b): Yellow oil (34 mg, 75% yield). H NMR (400 MHz, CDCl ) δ 7.18 (td, J = 7.6, 1.6
3
Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.96 (td, J = 7.5, 1.2 Hz, 1H), 6.82 (dd, J = 7.9, 1.2 Hz, 1H), 5.61
(dd, J = 8.1, 1.4 Hz, 1H), 5.15 (s, 1H), 4.17 (t, J = 6.7 Hz, 1H), 3.76 – 3.70 (m, 1H), 3.61 (q, J = 7.2
Hz, 2H), 3.52 (s, 3H), 3.18 (d, J = 9.2 Hz, 1H), 2.90 (pd, J = 10.6, 6.6 Hz, 2H), 1.75 (s, 3H), 1.20 (t, J
1
3
1
=
7.2 Hz, 3H). C{ H} NMR (101 MHz, CDCl ) δ 174.3, 173.8, 169.1, 169.0, 144.0, 129.0, 128.5,
3
1
9
1
27.6, 125.3, 122.9, 120.6, 71.5, 69.3, 52.5, 52.4, 47.6, 45.4, 34.5, 34.3, 23.4, 12.9. F NMR (376
+
MHz, CDCl ) δ -64.41 (t, J = 10.6 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for
3
C H N O F 454.1590, found 454.1576.
2
1
22
3
5 3
Methyl
(9R,9aS,12aR)-9-methyl-7,10,12-trioxo-11-propyl-6-(2,2,2-trifluoroethyl)-
5
,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-d][1,4]diazepine-9-
1
carboxylate (6c): Yellow oil (33 mg, 71% yield). H NMR (400 MHz, CDCl ) δ 7.19 (td, J = 7.7, 1.6
3
Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 6.97 (td, J = 7.5, 1.2 Hz, 1H), 6.83 (dd, J = 7.9, 1.2 Hz, 1H), 5.54
(d, J = 8.2 Hz, 1H), 5.15 (s, 1H), 4.14 (t, J = 6.7 Hz, 1H), 3.75 – 3.70 (m, 1H), 3.56 (d, J = 13.0 Hz,
1
1
H), 3.53 (s, 3H), 3.50 (d, J = 10.1 Hz, 1H), 3.17 (d, J = 9.2 Hz, 1H), 2.89 (qd, J = 10.6, 6.8 Hz, 2H),
1
3
1
.74 (s, 3H), 1.64 (dt, J = 14.4, 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). C{ H} NMR (101 MHz, CDCl )
3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
δ 174.6, 174.1, 169.3, 168.9, 144.1, 129.0, 128.9, 125.6, 123.1, 120.7, 71.6, 69.3, 52.5, 52.2, 47.4,
1
9
4
6.0, 41.1, 34.9, 23.2, 20.8, 11.0. F NMR (376 MHz, CDCl ) δ -64.42 (t, J = 10.6 Hz, 3F). HRMS
3
+
(
ESI-Orbitrap) m/z: (M+H) Calcd for C H N O F 468.1747, found 468.1735.
22 24
3
5 3
Methyl
(9R,9aS,12aR)-11-cyclohexyl-9-methyl-7,10,12-trioxo-6-(2,2,2-trifluoroethyl)-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-d][1,4]diazepine-9-
1
carboxylate (6d): Light yellow oil (35 mg, 69% yield). H NMR (400 MHz, CDCl ) δ 7.20 – 7.15 (m,
3
1H), 7.01 (d, J = 7.5 Hz, 1H), 6.95 (td, J = 7.5, 1.2 Hz, 1H), 6.79 (dd, J = 7.9, 1.2 Hz, 1H), 5.64 (d, J
=
8.1 Hz, 1H), 5.14 (s, 1H), 4.18 (t, J = 6.7 Hz, 1H), 3.71 – 3.66 (m, 1H), 3.49 (s, 3H), 3.14 (d, J = 9.3
Hz, 1H), 2.99 – 2.80 (m, 2H), 2.18 – 2.05 (m, 2H), 1.86 (d, J = 13.0 Hz, 2H), 1.74 (s, 3H), 1.70 – 1.56
1
3
1
(m, 4H), 1.38 – 1.19 (m, 3H). C{ H} NMR (101 MHz, CDCl ) δ 174.6, 174.0, 169.0, 144.0, 128.9,
3
1
28.3, 125.0, 122.7, 120.5, 71.5, 69.4, 52.7, 52.4, 52.3, 47.3, 45.1, 34.3, 34.1, 28.7, 28.6, 25.8, 24.9,
1
9
+
2
3.6. F NMR (376 MHz, CDCl ) δ -64.42 (t, J = 10.6 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H)
3
Calcd for C H N O F 508.2060, found 508.2049.
25 28
3
5 3
Methyl
(9R,9aS,12aR)-11-benzyl-9-methyl-7,10,12-trioxo-6-(2,2,2-trifluoroethyl)-
5
,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-d][1,4]diazepine-9-
1
carboxylate (6e): Yellow oil (32 mg, 62% yield). H NMR (400 MHz, CDCl ) δ 7.39 – 7.35 (m, 2H),
3
7.34 – 7.30 (m, 3H), 7.12 (td, J = 7.6, 1.6 Hz, 1H), 7.01 (d, J = 6.4 Hz, 1H), 6.94 (td, J = 7.5, 1.2 Hz,
1
3
H), 6.52 (d, J = 8.9 Hz, 1H), 5.57 (d, J = 9.5 Hz, 1H), 4.93 (s, 1H), 4.11 (t, J = 6.5 Hz, 1H), 3.81 –
.74 (m, 1H), 3.49 (s, 2H), 3.21 (d, J = 9.1 Hz, 1H), 3.17 (s, 3H), 2.89 – 2.77 (m, 2H), 1.72 (s, 3H).
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 174.2, 173.5, 169.0, 168.7, 143.9, 134.9, 128.9, 128.8, 128.6,
3
19
1
28.5, 128.3, 125.1, 123.0, 120.8, 71.5, 69.1, 52.4, 52.1, 47.7, 45.8, 43.0, 34.7, 23.2. F NMR (376
+
MHz, CDCl ) δ -64.37 (t, J = 10.6 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for
3
C H N O F 516.1747, found 516.1738.
26 24
3
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Methyl
(9R,9aS,12aR)-11-(tert-butyl)-9-methyl-7,10,12-trioxo-6-(2,2,2-trifluoroethyl)-
5
,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-d][1,4]diazepine-9-
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
carboxylate (6f): Yellow oil (30 mg, 63% yield). H NMR (400 MHz, CDCl ) δ 7.18 (dd, J = 7.7, 1.6
3
Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.96 (td, J = 7.5, 1.2 Hz, 1H), 6.82 (dd, J = 7.9, 1.1 Hz, 1H), 5.56
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
d, J = 8.0 Hz, 1H), 5.30 (s, 1H), 3.58 – 3.56 (m, 1H), 3.52 (s, 3H), 3.48 (d, J = 6.9 Hz, 1H), 3.06 (d,
1
3
1
J = 9.4 Hz, 1H), 2.96 – 2.84 (m, 2H), 1.72 (s, 3H), 1.59 (s, 9H). C{ H} NMR (101 MHz, CDCl ) δ
3
175.5, 174.9, 169.2, 169.1, 144.1, 128.9, 128.6, 125.3, 122.9, 120.6, 71.9, 69.7, 59.7, 52.5, 52.4, 47.3,
19
4
5.6, 28.1, 23.4. F NMR (376 MHz, CDCl ) δ -64.44 (t, J = 10.6 Hz, 3F). HRMS (ESI-Orbitrap)
3
+
m/z: (M+H) Calcd for C H N O F 482.1903, found 482.1887.
2
3
26
3
5 3
Methyl
(9R,9aS,12aR,12bS)-3-methoxy-9-methyl-7,10,12-trioxo-11-phenyl-6-(2,2,2-
trifluoroethyl)-5,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-
1
d][1,4]diazepine-9-carboxylate (6g): Yellow oil (34 mg, 64% yield). H NMR (400 MHz, CDCl ) δ
3
7
.55 – 7.41 (m, 4H), 7.27 (d, J = 1.5 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 6.36
(
s, 1H), 5.30 (s, 1H), 5.20 (s, 1H), 4.15 (t, J = 6.8 Hz, 1H), 3.90 (d, J = 8.0 Hz, 1H), 3.82 (d, J = 3.7
1
3
1
Hz, 1H), 3.74 (s, 3H), 3.56 (s, 3H), 3.38 (d, J = 9.3 Hz, 1H), 2.95 – 2.83 (m, 2H), 1.81 (s, 3H). C{ H}
NMR (101 MHz, CDCl ) δ 173.7, 173.1, 169.4, 160.2, 144.9, 141.6, 133.1, 131.5, 131.1, 129.5, 129.4,
3
1
9
128.0, 126.4, 117.4, 108.4, 106.4, 90.7, 71.6, 69.8, 66.1, 61.9, 55.3, 52.8, 52.5, 47.6, 23.5. F NMR
+
(
376 MHz, CDCl ) δ -64.27 (t, J = 10.6 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for
3
C H N O F 532.1696, found 532.1681.
2
6
24
3
6 3
Methyl
(9R,9aS,12aR,12bS)-11-cyclohexyl-3-methoxy-9-methyl-7,10,12-trioxo-6-(2,2,2-
trifluoroethyl)-5,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-
1
d][1,4]diazepine-9-carboxylate (6h): Yellow oil (33.3 mg, 62% yield). H NMR (400 MHz, CDCl )
3
δ 6.92 (d, J = 8.5 Hz, 1H), 6.50 (dd, J = 8.5, 2.5 Hz, 1H), 6.36 (s, 1H), 5.59 (dd, J = 8.1, 1.5 Hz, 1H),
5
.30 (d, J = 0.5 Hz, 1H), 4.10 (t, J = 6.7 Hz, 1H), 3.76 (s, 3H), 3.72 – 3.64 (m, 2H), 3.54 (s, 3H), 3.14
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9
1
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1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
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5
5
5
5
5
5
5
5
5
5
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(
d, J = 9.3 Hz, 1H), 2.90 – 2.76 (m, 2H), 2.15 – 2.05 (m, 2H), 1.86 (d, J = 16.2 Hz, 2H), 1.74 (s, 3H),
1
3
1
1
1
.42 – 1.16 (m, 6H). C{ H} NMR (101 MHz, CDCl ) δ 174.6, 174.0, 169.3, 160.1, 145.1, 129.5,
3
1
9
17.3, 108.0, 106.2, 71.4, 69.3, 55.3, 52.6, 52.5, 52.1, 47.1, 31.0, 28.7, 28.6, 25.7, 24.9, 23.5. F NMR
+
(376 MHz, CDCl ) δ -64.31 (t, J = 10.6 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C H N O F 538.2165, found 538.2148.
2
6
30
3
6 3
Methyl
(9R,9aS,12aR,12bS)-3-methoxy-9,11-dimethyl-7,10,12-trioxo-6-(2,2,2-trifluoroethyl)-
5,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-d][1,4]diazepine-9-
1
carboxylate (6i): Light yellow oil (31 mg, 66% yield). H NMR (400 MHz, CDCl ) δ 6.94 (d, J = 8.5
3
Hz, 1H), 6.52 (dd, J = 8.5, 2.6 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 5.53 (dd, J = 8.1, 1.6 Hz, 1H), 5.19
(s, 1H), 4.08 (t, J = 6.8 Hz, 1H), 3.77 (s, 3H), 3.76 – 3.71 (m, 1H), 3.59 (s, 3H), 3.21 (d, J = 9.0 Hz,
13
1
1
1
3
H), 3.06 (s, 3H), 2.92 – 2.79 (m, 2H), 1.75 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ 174.5, 174.1,
3
69.4, 169.3, 160.2, 145.3, 130.0, 117.6, 108.4, 106.4, 71.5, 69.3, 55.4, 52.8, 52.4, 47.2, 45.3, 35.2,
1
9
4.9, 31.0, 25.5, 23.3. F NMR (376 MHz, CDCl ) δ -64.21 (t, J = 10.5 Hz, 3F). HRMS (ESI-Orbitrap)
3
+
m/z: (M+H) Calcd for C H N O F 470.15392, found 470.1529.
2
1
22
3
6 3
Methyl
(9R,9aS,12aR,12bS)-2-chloro-9,11-dimethyl-7,10,12-trioxo-6-(2,2,2-trifluoroethyl)-
5
,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-d][1,4]diazepine-9-
1
carboxylate (6j): Yellow oil (31 mg, 65% yield). H NMR (400 MHz, CDCl ) δ 7.14 (dd, J = 8.4, 2.3
3
Hz, 1H), 6.99 (s, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.67 (d, J = 9.8 Hz, 1H), 5.24 (s, 1H), 3.81 – 3.75 (m,
1
H), 3.56 (s, 3H), 3.50 (d, J = 7.1 Hz, 1H), 3.25 (d, J = 9.2 Hz, 1H), 3.05 (s, 3H), 2.97 – 2.79 (m, 2H),
1
3
1
1.77 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ 174.5, 173.8, 169.2, 168.3, 142.4, 128.9, 128.1,
3
19
1
27.7, 127.4, 126.2, 121.8, 71.1, 69.5, 52.8, 52.7, 47.6, 44.5, 25.5, 23.5, 18.5. F NMR (376 MHz,
+
CDCl ) δ -64.33 (t, J = 10.4 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for C H N O ClF
3
20 19
3
5
3
4
74.10437, found 474.1044.
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Methyl
(9R,9aS,12aR,12bS)-2-chloro-9-methyl-7,10,12-trioxo-11-propyl-6-(2,2,2-
trifluoroethyl)-5,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-
1
d][1,4]diazepine-9-carboxylate (6k): Yellow oil (35 mg, 69% yield). H NMR (400 MHz, CDCl ) δ
3
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
1
9
.14 (dd, J = 8.4, 2.4 Hz, 1H), 7.00 (s, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.64 (d, J = 9.7 Hz, 1H), 5.18 (s,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H), 4.15 (t, J = 6.7 Hz, 1H), 3.79 – 3.73 (m, 1H), 3.54 (s, 3H), 3.51 (d, J = 7.3 Hz, 2H), 3.21 (d, J =
.3 Hz, 1H), 2.98 – 2.79 (m, 2H), 1.76 (s, 3H), 1.61 (d, J = 7.2 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H).
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 174.6, 173.9, 169.0, 168.4, 142.4, 128.9, 128.1, 127.7, 127.4,
3
19
1
26.3, 121.7, 71.2, 69.4, 52.6, 52.5, 47.6, 41.2, 34.2, 33.9, 23.4, 20.8, 11.0. F NMR (376 MHz,
+
CDCl ) δ -64.41 (t, J = 10.4 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for C H N O ClF
3
22 23
3
5
3
502.1357, found 502.1342.
Methyl
(9R,9aS,12aR,12bS)-11-benzyl-2-chloro-9-methyl-7,10,12-trioxo-6-(2,2,2-
trifluoroethyl)-5,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-
1
d][1,4]diazepine-9-carboxylate (6l): Yellow oil (35 mg, 63% yield). H NMR (400 MHz, CDCl ) δ
3
7
.37 (dd, J = 6.8, 3.0 Hz, 2H), 7.35 – 7.31 (m, 3H), 7.03 (dd, J = 8.4, 2.3 Hz, 1H), 6.94 (s, 1H), 6.28
(d, J = 8.5 Hz, 1H), 5.69 (d, J = 9.7 Hz, 1H), 5.30 (s, 1H), 4.70 (s, 2H), 4.13 (t, J = 6.6 Hz, 1H), 3.88
1
3
1
–
3.78 (m, 1H), 3.25 (d, J = 9.3 Hz, 1H), 3.20 (s, 3H), 2.97 – 2.70 (m, 2H), 1.75 (s, 3H). C{ H} NMR
(101 MHz, CDCl ) δ 174.0, 173.4, 168.7, 168.1, 142.0, 134.9, 128.8, 128.7, 128.6, 128.3, 127.7, 127.5,
3
19
1
25.7, 121.8, 71.0, 69.2, 52.7, 52.3, 48.0, 44.2, 43.0, 33.5, 23.5. F NMR (376 MHz, CDCl ) δ -64.41
3
+
(t, J = 10.4 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for C H N O ClF 550.13567, found
2
6
23
3
5
3
550.1352.
Methyl
(9R,9aS,12aR,12bS)-2-chloro-11-cyclohexyl-9-methyl-7,10,12-trioxo-6-(2,2,2-
trifluoroethyl)-5,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-
1
d][1,4]diazepine-9-carboxylate (6m): Yellow oil (35 mg, 64% yield). H NMR (400 MHz, CDCl ) δ
3
7
.13 (d, J = 10.8 Hz, 1H), 6.97 (s, 1H), 6.70 (d, J = 8.5 Hz, 1H), 5.73 (d, J = 8.1 Hz, 1H), 5.18 (s, 1H),
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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5
5
5
5
5
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6
4
1
.19 (t, J = 6.6 Hz, 1H), 3.80 – 3.68 (m, 2H), 3.51 (s, 3H), 3.18 (d, J = 9.4 Hz, 1H), 3.02 – 2.92 (m,
H), 2.79 (ddd, J = 14.7, 10.4, 5.3 Hz, 1H), 2.12 (d, J = 11.0 Hz, 2H), 1.76 (s, 3H), 1.33 (d, J = 16.3
1
3
1
Hz, 2H), 1.30 – 1.21 (m, 6H). C{ H} NMR (101 MHz, CDCl ) δ 174.5, 173.8, 169.1, 168.2, 142.3,
3
1
2
28.8, 127.6, 127.5, 127.3, 125.7, 121.4, 71.1, 69.6, 52.7, 52.6, 52.5, 47.5, 43.9, 33.7, 28.6, 28.6, 25.7,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
4.9, 23.8. F NMR (376 MHz, CDCl ) δ -64.44 (t, J = 10.4 Hz, 3F). HRMS (ESI-Orbitrap) m/z:
3
+
(M+H) Calcd for C H N O ClF 542.16697, found 542.1672.
25 27
3
5
3
Methyl
(9R,9aS,12aR,12bS)-3-bromo-9-methyl-7,10,12-trioxo-11-propyl-6-(2,2,2-
trifluoroethyl)-5,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-
1
d][1,4]diazepine-9-carboxylate (6n): Yellow oil (37 mg, 67% yield) H NMR (400 MHz, CDCl )) δ
3
7.07 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 6.86 (d, J = 8.2 Hz, 1H), 5.67 (d, J = 8.2 Hz, 1H), 5.24 (s, 1H),
4
.14 (t, J = 6.6 Hz, 1H), 3.76 (t, J = 8.8 Hz, 1H), 3.53 (s, 3H), 3.52 – 3.47 (m, 2H), 3.21 (d, J = 9.3
1
3
1
Hz, 1H), 2.99 – 2.73 (m, 2H), 1.76 (s, 3H), 1.64 (d, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). C{ H}
NMR (101 MHz, CDCl ) δ 174.6, 173.9, 168.9, 168.7, 144.9, 129.3, 125.5, 123.8, 123.3, 122.2, 71.0,
3
1
9
6
1
5
9.5, 52.6, 52.4, 47.7, 44.3, 41.2, 34.0, 23.5, 20.8, 11.0. F NMR (376 MHz, CDCl ) δ -64.39 (t, J =
3
+
0.4 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for C H N O BrF 546.08516, found
2
2
23
3
5
3
46.0854.
Methyl
(9R,9aS,12aR,12bS)-3-bromo-9,11-dimethyl-7,10,12-trioxo-6-(2,2,2-trifluoroethyl)-
5
,6,7,9,9a,10,11,12,12a,12b-decahydrobenzo[f]pyrrolo[3',4':3,4]pyrrolo[1,2-d][1,4]diazepine-9-
1
carboxylate (6o): Yellow oil (40 mg, 77% yield). H NMR (400 MHz, CDCl ) δ 7.06 (dd, J = 8.2, 1.9
3
Hz, 1H), 6.98 (d, J = 1.9 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.71 (d, J = 9.7 Hz, 1H), 5.30 (s, 1H), 4.16
(t, J = 6.6 Hz, 1H), 3.78 (t, J = 8.7 Hz, 1H), 3.55 (s, 3H), 3.25 (d, J = 9.3 Hz, 1H), 3.06 (s, 3H), 2.98
1
3
1
–
1
2.77 (m, 2H), 1.78 (s, 3H). C{ H} NMR (101 MHz, CDCl ) δ 174.5, 173.8, 169.2, 168.4, 145.0,
3
1
9
29.4, 125.5, 123.3, 123.2, 122.3, 70.9, 69.5, 52.8, 52.8, 47.6, 34.1, 33.8, 31.0, 25.6, 23.6. F NMR
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(
376 MHz, CDCl ) δ -64.30 (t, J = 10.4 Hz, 3F). HRMS (ESI-Orbitrap) m/z: (M+H) Calcd for
3
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
C H N O BrF 518.05386, found 518.0542.
2
0
19
3
5
3
UNDER ASSOCIATED CONTENT
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Supporting Information
1
13
1
13
The Supporting Information containing copies of H NMR and C NMR of 5a–o, and H NMR, C
1
9
NMR and F NMR spectra of compounds 6a–o is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.joc.
AUTHOR INFORMATION
Corresponding Author
*
E-mail: wei2.zhang@umb.edu.
ORCID
Wei Zhang: 0000-0002-6097-2763
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work was supported by the Centre for Green Chemistry of University of Massachusetts Boston.
REFERENCES
(
1) Jeschke, P. The Unique Role of Fluorine in the Design of Active Ingredients for Modern Crop
Protection. ChemBioChem. 2004, 5, 570.
(
2) Muller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking beyond
Intuition.Science 2007, 317, 1881.
(3) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry.Chem.
Soc. Rev. 2008, 37, 320.
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