A Cascade Reaction of Cinnamyl Azides with Acrylates Directly Generates Tetrahydro-Pyrrolo-Pyrazole Heterocycles

Article abstract of DOI:10.1021/acs.joc.0c00535

Developing reactions to generate complex and modular building blocks in a concise and direct fashion remains a contemporary synthetic challenge. This work describes a stereoselective cascade reaction between allylic azides and acrylates that directly generates tetrahydro-pyrrolo-pyrazole ring systems. These products contain up to four contiguous stereocenters, two of which may be tetrasubstituted carbon atoms attached to a nitrogen atom. Over 30 examples are provided with an average isolated yield of 71% (ranging from 40% to 94%). The reaction was easily scaled to use more than one gram of starting material, and the products can be readily diversified.

Full text of DOI:10.1021/acs.joc.0c00535

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Article
A Cascade Reaction of Cinnamyl Azides with Acrylates
Directly Generates Tetrahydro-Pyrrolo-Pyrazole Heterocycles
Angela S. Carlson, En-Chih Liu, and Joseph J Topczewski
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00535 • Publication Date (Web): 13 Apr 2020
Downloaded from pubs.acs.org on April 14, 2020
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Page 1 of 18
The Journal of Organic Chemistry
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A Cascade Reaction of Cinnamyl Azides with Acrylates Directly
Generates Tetrahydro-Pyrrolo-Pyrazole Heterocycles
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Angela S. Carlson‡, En-Chih Liu‡, and Joseph J. Topczewski*
Department of Chemistry, University of Minnesota Twin Cities, Minneapolis, MN 55455, United States.
jtopczew@umn.edu
Supporting Information Placeholder
H
>30 examples
 up to 94% yield
new stereocenters
2 new rings
stereoselective
modular

E
N
R
N
E
*
Ar
N3

*
Ar
70 o
C



NH
R
R'
R'
Direct Access to Functionally Dense Heterocycles
ABSTRACT: Developing reactions to generate complex and modular building blocks in a concise and direct fashion remains
a contemporary synthetic challenge. This work describes a stereoselective cascade reaction between allylic azides and
acrylates that directly generates tetrahydro-pyrrolo-pyrazole ring systems. These products contain up to four contiguous
stereocenters, two of which may be tetrasubstituted carbon atoms attached to a nitrogen atom. Over 30 examples are
provided with an average isolated yield of 71% (ranging from 40% to 94%). The reaction was easily scaled to use more than
one gram of starting material and the products can be readily diversified.
INTRODUCTION
Recently, our lab has been developing synthetic methods
that leverage the unique properties of allylic azides. We
showed that allylic azides can react selectively at either the
alkene18–20 or azide21 functional group. These results led us
to ask if a reaction could synergistically utilize both
functional groups. We were encouraged to find an example
of such a reaction. Yang reported a cycloaddition cascade
with cinnamyl azide and methyl acrylate to form
tetrahydro-pyrrolo-pyrazole heterocycles (Scheme 1b).22,23
We were excited to build upon these reports. Unfortunately,
neither report provided full experimental details. Our
attempts to replicate the procedure using cinnamyl azide
afforded a low yield (82% reported, less than 15%
obtained). We speculated that this cascade could be a
powerful tool if a more easily reproducible procedure could
be developed and if the scope of this reaction were
expanded.
Nitrogen containing heterocycles are ubiquitous in
pharmaceuticals, agrochemicals, and natural products.1,2
Often, saturated heterocycles provide particularly
advantageous properties.3–7 Specifically, substituted
tetrahydro-pyrrolo-pyrazole heterocycles are known to be
biologically active with a variety of potential applications
(Figure 1).8–12 A direct and efficient synthesis of these
functionally dense heterocycles from simple starting
materials would be empowering.13,14 Classically,
tetrahydro-pyrrolo-pyrazole heterocycles are generated
through cycloaddition of a diazo species with activated
maleimide
derivatives.8,10
More
recently,
Zard
demonstrated that hydrazones with pendant alkenes can be
oxidized to the corresponding diazo species which
subsequently undergoes an intramolecular cycloaddition
(Scheme 1a).15 Jahn demonstrated that a domino aza-
Michael reaction can afford similar heterocycles using n-
Scheme 1. Synthesis of Tetrahydro-Pyrrolo-Pyrazoles
BuLi and NfN3.16,17
Ar
H
Me
N
H
H
H
N
N
N
OH
N
N
R
O
O
O
MeO
HO2C
N
N
N
NH
H
H
H
Me
R'
Bu
N
O
O
HO2C
R' = (CH2)2Ar Ar = 4-F-Ph
angiotensin II
receptor antagonist
glutamate
receptor inhibitor
HIV-1 integrase inhibitor
Figure 1. Biologically Active Fused Heterocycles
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Page 2 of 18
a) Zard and co-workers
Qualitatively, the cascade reaction appeared to proceed
more efficiently with a cinnamyl azide featuring a polarizing
H
2 equiv I2
2 equiv DBU
N
N
1
2
3
4
5
6
7
8
H2N
N
aryl substituent. This was true regardless of if the
substituent is commonly thought of as electron donating
(e.g. OMe) or withdrawing (e.g. NO2) group (vide infra). The
substrate 2-nitrocinnamyl azide (1b) was selected for
optimization along with methyl acrylate due to the
availability of 2-nitrocinnamaldehyde (Table 2). Solvents
with a range of polarities were examined (entries 1-5).
Polar solvents promoted the conjugate addition that formed
product 4b (entries 1-2), while less polar solvents
suppressed the conjugate addition (entries 4-5). The
observation that formation of product 4b could be
suppressed in less polar media is consistent with the need
to form ionic intermediates during conjugate addition.
When hexane was used, a significant amount of the
conjugate addition was observed because the product was
insoluble in hexane, resulting in a reaction that was pseudo-
neat in methyl acrylate (entry 3).
N
N
Ar
Ar
Ts
Ts
b) Yang and co-workers
H
CO2Me
N
MeO2C
THF
N
Ph
N3
+
NH
rt, several days
82% (reported)
Ph
H
c) This Work
R'
H
E
N
N
E
R'"
DIPEA
C6H6, 70 o
9
R
N3
+
*
*
*
R
*
C
NH
R'"
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R'
R"
R"
direct efficient stereoselective modular




This report provides
a
re-optimized and fully
documented procedure that affords tetrahydro-pyrrolo-
pyrazole heterocycles in high yields from simple cinnamyl
azides. The substrate scope of Yang’s reaction is expanded
to include i) secondary and tertiary azides, ii) cinnamyl
azides substituted at the alpha or beta carbon, iii) the use of
an enantioenriched azide, iv) additional Michael acceptors,
and v) derivatization of the products (Scheme 1c).
Table 2. Cascade Optimization with Methyl Acrylate
CO2Me
H
H
CO2Me
N
CO2Me
N
N
N
3 equiv
CO Me
2
N3
+
Ar
Ar
Ar
solvent (0.2 M)
0.5 equiv additive
70 oC, 24 h
1b
N
NH
H
H
(±)-5b
RESULTS AND DISCUSSION
Ar = 2-NO2-C6H4
(±)-4b
entry solvent additive % 2ba % 4ba % 5ba
This study began by examining the thermally promoted
cascade sequence between methyl acrylate and cinnamyl
azide using the conditions originally reported by Yang
(Table 1).22,23 Yang’s experimental procedure states that
cinnamyl azide was mixed with methyl acrylate (1 or 2
equiv) at room temperature for a time ranging between
several hours to a few days.23 In our hands, the room
temperature reaction with 1 equiv of methyl acrylate did
not fully consume the azide after 3 days (Table 1). Several
intermediates and byproducts could be identified and
quantified (2a – 4a). A yield below 25% was observed, even
if both observable tautomers of the desired product (3a and
5a) are combined. The reaction with cinnamyl azide 1a was
extensively screened and in no case did we observe a yield
exceeding 70% (see SI tables S1-S3). These observations
prompted a re-optimization of this cascade reaction.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DMSO
MeOH
Hexane
THF
C6H6
C6H6
C6H6
C6H6
C6H6
C6H6
-
-
-
-
-
n.d.
n.d.
n.d.
34
14
95
54
n.d.
n.d.
67
77
n.d.
35
46
11
n.d.
17
80
41
85
91
83
72
78
37
AcOH
HFIP
DMAP
pyridine
TEA
DIPEA
DIPEA
TEA
DIPEA
n.d.
n.d.
n.d.
5
n.d.
n.d.
n.d.
n.d.
n.d.
55
8
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
C6H6
PhMe
THF
THF
aReactions were conducted with azide 1b (70 µmol), methyl acrylate
(210 µmol), and additive (35 µmol) in solvent (0.2 M) at 70 oC.
Conversion and yield were determined by calibrated GC-FID analysis.
Reactions were run in duplicate and the average value is reported. Not
detected = n.d.
Table 1. Replicating Yang’s Reported Conditions
CO2Me
N
N
CO2Me
N
N
Having identified THF and benzene as the
optimal solvents, several additives were examined. The
addition of acetic acid or HFIP promoted the conjugate
addition (entries 6-7). Prior work from L’abbe indicated
that the triazoline to diazo-ester equilibrium could be
facilitated by the addition of an amine base (vide infra).24,25
Thus, the addition of an amine base proved most effective at
converting triazoline intermediate 2b to the desired
product (entries 8-14). Given the complications associated
with conjugate addition (e.g. polymerization of acrylate and
over addition), it is perhaps unsurprising that DMAP and
pyridine provided poor results and that less nucleophilic
amine bases were preferred. Ultimately, conditions utilizing
DIPEA in benzene (entry 11) were chosen as the optimal
conditions. Toluene and THF were suitable alternative
solvents (entries 12-14). It is worth noting that at the end of
the reaction, the desired product typically existed as a
mixture of the two tautomers 3b and 5b. TFA was added
N
Ph
NH
+
CO2Me
H
1 or 2
equiv
Ph
Ph
(±)-2a
(±)-3a
N3
Ph
THF (5 M)
rt, 3 days
H
N
H
1a
CO2Me
CO2Me
N
N
N
CO2Me
Ph
N
NH
H
H
(±)-4a
(±)-5a
Entr
y
equiv
MA
% 1a % 2a
% 3a
% 4a
% 5a
1
1
31
4
13
24
8
6
9
13
9
2
2
13
aReactions were conducted with azide 1a (90 µmol) and methyl
acrylate (90 or 180 µmol) in THF (5 M) at rt. Conversion and yield were
determined by 1H NMR. Reactions were run in duplicate and the
average value is reported. MA = methyl acrylate
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The Journal of Organic Chemistry
Yields are reported for isolated and purified products. Yield values
reflect the average of duplicate trials.
during the workup to convert the mixture into the more
1
2
3
4
5
6
7
8
stable conjugated tautomer 5b. In some instances, silica gel
and DBU were also able to promote tautomerization (see
Table 7 in experimental section). When compared to Yang’s
original conditions, this re-optimization reflects a change in
the i) solvent, ii) concentration, iii) temperature, iv)
equivalents of acrylate, v) time, and vi) addition of DIPEA.
The optimized reaction conditions work well with a variety
of cinnamyl azides (Table 3). Compound 5b was isolated in
94% yield under the re-optimized conditions. The product
from cinnamyl azide (5a) was crystalline and diffraction
analysis confirmed the structure (see supporting
information). While the 64% yield of product 5a observed
was a significant improvement over the data shown in Table
1, it was still lower than the yield originally reported by
Yang.22,23 Other cinnamyl azides containing electron
donating groups (5c, 5d, and 5h) and electron withdrawing
groups (5f, 5g, and 5i) were tolerated. Substrates with ortho
substitution were tolerated (5b, 5h, and 5i). Lastly,
products with an electron rich heteroarene (5j and 5k) or
an electron deficient heteroarene (5l - 5n) were isolated in
good yield. As previously noted, substrates with polarizing
groups on the arene appeared to be better suited for this
cascade, with some of the highest yields observed for
products 5b and 5h as well as 5k and 5l. Recent attention
has been focused on developing reactions that are effective
with heterocycles26,27 and the ability of this cascade to
generate products 5j – 5n under identical conditions should
be considered an attribute.
The substrate scope was further expanded (Table
4). A methyl or a phenyl group could be incorporated
adjacent to the azide (5o and 5p). For product 5o, a minor
diastereomer was observed that could arise from the Z-
alkene isomer. A E/Z alkene isomerization could be
occurring under the reaction conditions via the Winstein
rearangement.28–30 The relative configuration of product 5p
was assigned based on a crystal structure (see supporting
information) and that of product 5o was assigned by
analogy to product 5p. A minor diastereomer was not
detected for compound 5p. Tertiary azide 1q afforded
product 5q. A methyl group could be incorporated at the α
or β position relative to the arene, affording compounds 5r
and 5s. In both cases, a minor diastereomer was not
detected. The relative configuration of compound 5s was
assigned by 2-D NMR and is consistent with the alkene
geometry of the starting material as would be expected for
a cycloaddition. The trans relationship between the methyl
and hydrogen on starting azide 1s should be maintained in
the product if the reaction proceeds through a concerted
cycloaddition. A branched allylic azide was suitable and
afforded product 5t, which demonstrated that a cinnamyl
azide was not necessary. Product 5t is noteworthy because
significant eclipsing interactions likely exist between the
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bridgehead substituents. Furthermore,
a cyclic azide
afforded tricyclic products (5u-5w). A proximal arene was
not required for the reaction to proceed and product 5w
was derived from unsaturated ester 1w.
Table 3. Scope of Cascade Reaction with Cinnamyl Azides
H
CO2Me
Table 4. Reaction Scope with Substituted Allylic Azides
CO2Me
N
N
3 equiv
H
N3
CO2Me
CO2Me
N
N
NH
(±)-5
CO2Me
0.5 equiv DIPEA
C6H6, 70 oC, 24 h
R
R
3-5 equiv
rt, neat
N
N
H
R5 R4
R5
R1
R3
N3
1
(1 equiv)
R1
R1
NH or
R3
NH
R3
R2
R2
then
H
H
H
R2
R4
(±)-5 R5
if
R4
CO2Me
CO2Me
CO2Me
N
N
N
N
0.5 equiv DIPEA
C6H6, 70 o
N
NO2
N
(±)-5 R5
if
1
(1 equiv)
C
= H
= H
NH
NH
NH
H
H
H
Starting Azide
R
Product
H
N
Starting Azide
Product
H
N
MeO
5a
64%
5b
94%
5c
82%
CO2Me
CO2Me
N
N
Me
Me
H
H
H
CO2Me
CO2Me
CO2Me
N
N
N
N
Ph
N3
Ph
Ph
N3
Ph
N
N
NH
NH
Me
H
H
Me
R
NH
NH
NH
H
H
H
55%a 8.8:1 drb
76%
d
1q
1o
5o
5p
5q
R = Me
Me
NC
Br
CF3
c
c
5f
79%
5d
5e
69%
73%
1p
48%
R = Ph
H
CO2Me
CO2Me
N
N
Me
N
N
H
H
H
CO2Me
CO2Me
CO2Me
N
N
N
N
Me
Ar
N
OMe N
CF3
Ph
N3
Ar
N3
Ph
NH
NH
Me
H
Me
1r
NH
NH
NH
e
e
H
H
H
1s
Ar = 3,5-bis-CF3-C6H3
5r
5s
64%
55%
5i
63%
H
N
5g
5h
84%
77%
CO2Me
N
CO2Me
H
H
H
N
CO2Me
CO2Me
CO2Me
N
N
N
N
N
N
NH
N
NH
N3
Ph
N3
N
H
H
Ph
1t
Ph
NH
NH
NH
H
H
H
S
S
e
e
5t
N
1u
E
5u
N
64%
68%
5j
N
5k
80%
74%
5l
89%
CO2Me
CO2Me
H
H
N
CO2Me
CO2Me
N
N
N
N
NH
H
N
NH
Ar
N3
N3
H
E
Ar
H
NH
68%
NH
H
H
H
N
e
c
1v
Ar = 4-Me-C6H4
5v
1w
5w
55%
E = CO2Et
42%
5n
60%
5m
Yields are reported for isolated and purified products. Yield values
reflect the average of duplicate trials. aInitial 72 h incubation at rt with
an additional 24 h at 70 °C. bDiastereomeric ratio determined by crude
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1H NMR spectroscopy. cReaction for 48 h at 70 °C. dReaction for 72 h at
X
H
70 °C. eInitial 48 h incubation at rt with an additional 24 h at 70 °C.
N
X
1
N
3 equiv
R
2
3
4
5
6
7
8
9
N3
Ar
Ar
0.5 equiv DIPEA
C6H6, 70 oC, 24 h
NH
(±)-5
A single enantiomer of azide 1v (>99:1 er) was
utilized (Scheme 2).30 Product 5v could be isolated as a
single diastereomer with no loss in enantiomeric purity
(>99:1 er). A crystal structure of (±)-5v·HCl was obtained
to confirm its identity and relative stereochemistry (see
supporting information). This represents a tremendous
amplification of stereochemical complexity. Azide 1v
contains only a single stereocenter. Product 5v contains
four contiguous stereocenters, three of which are generated
from this cascade reaction. Two stereocenters are formed at
H
1b
(1 equiv)
Ar = 2-NO2-C6H4
O
H
O
H
O
H
OEt
N
OtBu
N
OBn
N
N
N
N
N
Ar
Ar
Ar
NH
H
Ar
NH
NH
94%
H
H
5x
5y
5z
94%
87%
O
O
O
H
10
11
12
13
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60
H
H
O
OR
Me
N
N
N
N
Me
N
tetrasubstituted carbon atoms that bear
a nitrogen
Ar
Ar
Ar
NH
78%
NH
NTs
H
H
H
Ph
substituent, which are known to be particularly challenging
5aa
5bb
5cc
R = Me
R = Bn
87%a 3.2:1 drb
80%a 3.8:1 drb
stereocenters to establish.13,31
5dd
58%
O
P
O
N
H
H
H
Scheme 2. Stereospecific Cascade Reaction
NH2
OEt
N
N
N
N
N
N
OEt
NH
d
CO2Me
N3
5 equiv
neat, rt, 48 h
CO2Me
Ar
Ar
N
*
Ar
NH
72%
NH
*
*
H
H
H
H
N
NH
then 0.5 equiv DIPEA
70 oC, 24 h
Ar = 4-CH3-C6H4
c
5ee
Ar
5v
H
5ff
5gg
40%
70%
H
1v >99:1 er
>99:1 er
54%
Yields are reported for isolated and purified products. Yield values
new stereocenter nitrogen bearing tetrasubstituted carbon

*
a
reflect the average of duplicate trials. Reaction for 5 days at 70 °C.
bDiastereomeric ratio determined by crude 1H NMR spectroscopy.
cInitial 24 h incubation neat at 40 oC. Then C6H6 and DIPEA were added
for an additional 24h at 40 °C. dReaction was heated to 90 oC.
The reaction was investigated with other Michael
acceptors (Table 5). Simple acrylates provided high yields
and ethyl (5x), tert-butyl (5y), and benzyl (5z) esters were
isolated. The selective formation of cinnamate 5aa is
interesting because the putative α-diazoester intermediate
selectively engaged one of the two pendant alkenes. The use
of methyl or benzyl crotonate afforded products 5bb and
5cc in high yield and modest dr. The relative configuration
of compound 5bb was determined by X-ray diffraction
analysis and the relative configuration of product 5cc was
assigned by analogy to product 5bb. The use of methyl vinyl
ketone afforded exclusively the product of conjugate
addition (4dd, see experimental section). To prevent this,
TsCl and DMAP were added to trap the initial adduct prior
to conjugate addition, which allowed the isolation of
product 5dd. Other Michael acceptors including acrylamide
(5ee), acrylonitrile (5ff), and diethyl vinyl phosphonate
(5gg) were also effective as partners in this cascade
reaction. This provides access to a diverse array of
functional groups via this cascade.
A plausible mechanism for this cascade reaction
and side product formation are shown in Scheme 3. This
proposal is based on the work of L’abbe24,25 and Yang.22,23
The cascade is thought to proceed via an initial Huisgen
cycloaddition to afford triazoline 2.24,25,32–36 This
cycloaddition generally proceeds with good selectivity, but
the regioisomeric triazoline 2’ was frequently observed
(~5%).24 When diethyl vinyl phosphonate was used as the
Michael acceptor, triazoline 2gg’ was
a significant
byproduct (ca. 1:1). In some cases, the triazoline was stable
to isomerization with base and could be isolated. A crystal
structure of one triazoline, derived from N-
phenylmaleimide, was obtained to verify the structure (see
supporting information).
Triazoline 2 can equilibrate to achiral diazo
species 6.24,37 Amine bases facilitate this equilibrium.24,25
The role of the amine is most likely to deprotonate at the
alpha position of the ester. The resulting ammonium salt then
can facilitate proton transfer to the distal nitrogen, leading to
fragmentation and forming diazo compound 6. Intermediate 6
can undergo an intramolecular cycloaddition between the
diazo and alkene to afford compound 3.22,23 Alternatively, in
the presence of excess acrylate, diazo 6 can intercept a
second equivalent of acrylate to form product 7.22,23,38,39 To
Table 5. Reaction Scope with Different Michael Acceptors
mitigate this side product,
a second procedure was
developed for products where the intramolecular
cyclization was slow (Table 4). The triazoline was pre-
formed by mixing the azide and acrylate neat at room
temperature. Excess acrylate was removed in vacuo. Then
the triazoline was heated in the presence of DIPEA in C6H6,
which triggered the remainder of the cascade.
Scheme 3. Mechanism of Cascade Reaction
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The Journal of Organic Chemistry
E
CO2Me
H
N
X
N
CO2Me
N
N
R
E
1
N
N
5 equiv
2 equiv
E
N
N
+
N3
Ar
1b
Ar
2
3
N3
Ar
3 equiv DIPEA
MTBE, 70 oC, 24 h
N
R
Ar
H
Ar
(1 equiv)
1
(±)-2'
(±)-2
DIPEA
(±)-9
Ar = 2-NO2-C6H4
4
H
H
H
H
5
6
7
CO2Me
CO2Me
CO2Me
N
N
N
N
CO2Me
N
H
N
N2
E
N
N
N
E
E
N
N
N
Ar
Ar
Ar
HN
Ar
N
N
N
N
Ar
Ar
H
H
H
NH
NH
H
Boc
Ts
Tr
H
H
Bn
9c 88%a
= TrCl
9d 81%
R-X
= CBzCl
Ar
9a 80%
R-X
9b 72%
R-X
8
(±)-5
(±)-3
6
R-X
= Boc2O
= TsCl
9
a
E
E
Yields are reported for isolated and purified products. Yield reflects
the sum of both tautomers.
N
-
2
10
11
12
13
14
15
16
17
E
N
Scheme 4. Gram Scale Reaction and Product Derivatization
H
HN
E
E
N
Ar
N
E
E
OH
H
H
H
Ar
N
H
Ar
carbonyl
N
NH
H
CO2H
NH
CO2Me
N
N
N
N
H
NH2
N
N
NO2
NO2
(±)-4
(±)-8
(±)-7
NH
NH
H
H
H
(±)-10
(±)-11
(±)-12
5y
TFA
quant.
from
When compound 3 contains a hydrogen atom at
arene
NaBH4
79%
H2, Pd/C, quant.
CO2Me
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
the benzylic position, it can tautomerize to generate
conjugated product 5.22,23 This tautomerization was readily
accomplished with TFA or DBU during workup (see
experimental section for details). When the benzylic
position was tetra-substituted, product 3 was isolated.
Cyclopropane 8 was observed as a side product in low yield
for substrate 1j. This product likely arises from
intermediate 3 via the loss of nitrogen.22,40 Lastly, products
3 and 5 are sufficiently nucleophilic to engage excess
acrylate in a conjugate addition, affording compound 4.22,23
As shown in the optimization above (Table 2), less polar
solvents generally minimized the conjugate addition by
destabilizing anionic intermediates.
Conducting the cascade reaction in the presence of
various electrophiles was a productive means to extend the
cascade process (Table 6). The addition of Boc2O (9a), TsCl
(9b), TrCl (9c), and CbzCl (9d) all afforded derivatized
products directly in good yield. When TrCl was used, the
product was initially isolated as a mixture of tautomers.
Tautomerization of this mixture was slower than for other
substrates and it was promoted by exposure to 0.5 equiv
DBU, after which only the conjugated isomer was observed
by 1H NMR.
The cascade cyclization could be conducted on a gram
scale without any decrease in efficiency (Scheme 4). Each of
the functional groups present in product 5b could be
selectively derivatized. The nitro group could be selectively
reduced to afford aniline 10. The ester present in product 5
could be reduced to afford alcohol 11 or hydrolyzed to acid
12. The pyrrolidine nitrogen could be alkylated, arylated, or
acylated to afford products 9d, 13, and 14, respectively.
Lastly, the hydrazine motif could be acylated, yielding
compound 15. These results clearly highlight how the dense
functionality present on the tetrahydro-pyrrolo-pyrazole
core can be selectively elaborated and diversified.
H
H
N
CO2Me
CO2Me
N
N
N
NO2
NO2
NO2
BnBr
N3
NH
N
DIPEA
K2CO3
72%
H
(±)-5b
H
Bn
95%
1b
(±)-9d
(1.02 g)
(1.41 g)
gram scale
2-chloro-4-fluoropyridine
DIPEA, 78%
PivCl, DIPEA
88%
amine
CO2allyl
H
H
CO2Me
CO2Me
CO2Me
N
N
N
N
N
N
NO2
NO2
NO2
Br
K2CO3
75%
N
N
Cl
NPiv
H
(±)-15
H
(±)-14
H
Piv
(±)-13
N
hydrazone
CONCLUSION
In conclusion, cinnamyl azides and Michael accepters
can engage in a modular cascade cyclization to directly
generate fused tetrahydro-pyrrolo-pyrazole heterocycles.
The reaction proceeds on an array of coupling partners.
Furthermore, the products can be derivatized in situ. This
reaction rapidly amplifies the complexity of two trivial
starting materials and directly affords functionally dense
bicyclic amine building blocks. This cascade is modular and
amenable to diversification.
EXPERIMENTAL SECTION
Azide Safety: Azides are known to be high energy materials
and explosions have been reported when working with
azides. In the course of this work, no issues were
encountered. All of the azides synthesized in this report
have C/N ratios equal to or above the recommended
guideline of 3. Precautionary safety shields were used for all
reactions using or producing more than 1 mmol of azide.
Safety shields were used both in the fume hood and during
rotary evaporation. All waste and aqueous solution which
could be contaminated with azide were kept in individually
labeled containers and were kept STRICTLY free of acid to
avoid the accidental production on HN3 – DO NOT use
aqueous HCl during work up of any of the reactions
reported herein. Further reading on azide safety is
available.41–43
Table 6. Product Functionalization in Situ to Expand
Cascade
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Methods and Reagents: All reactions conducted at diluted with water and extracted with EtOAc (3 x 100 mL).
1
2
3
4
5
6
7
8
elevated temperature used aluminum heating blocks with
magnetic stirrings (200 rpm). Reported temperatures were
based on an external thermal couple. All commercially
available chemicals were used without further purification.
Dry tetrahydrofuran (THF), toluene, and methylene
chloride were obtained from a commercial solvent system
utilizing activated alumina columns under a positive
pressure of argon. Thin-layer chromatography (TLC) was
used for monitoring reaction progress. Visualization was
conducted by using UV light, KMnO4, or PMA stains. Organic
solutions were concentrated using rotary evaporator under
reduced pressure at or below 40 ˚C. Flash chromatography
was performed on a Teledyne Isco CombiFlash Rf system
utilizing normal phase pre-column load cartridges and gold
high performance columns. Structural assignments were
made with additional information from COSY, HSQC, and
HMBC experiments. All proton (1H) nuclear magnetic
resonance spectra were recorded at 400 MHz or 500 MHz.
All carbon (13C) nuclear magnetic resonance spectra were
recorded at 101 MHz or 126 MHz. The fluorine (19F) nuclear
magnetic resonance spectra was recorded at 376 MHz with
proton decoupling. Chemical shifts are expressed in parts
per million and are referenced to residual solvent (CDCl3:
7.26 ppm), to the central carbon in the NMR solvent (CDCl3:
77.2 ppm). Data is presented as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
sept = septet, and m = multiplet), integration, and coupling
constant in Hertz (Hz). Infrared (IR) spectra were taken in
a Nicolet Nexus 670 FT-IR with salt plates. IR spectra were
reported in cm-1. Enantiomeric excesses were determined
using a Shimadzu HPLC with a PDA detector and RegisPack
5 Micron column or Regis Reflect column (C-Amylose A; 3µ,
250 mm x 4.6 mm).
The combined organic phases were washed with brine,
dried (Na2SO4), filtered, and concentrated under reduced
pressure. Final purification by column chromatography
(EtOAc in hexanes, gradient elution 0 – 5%) afforded
compound 1b (962 mg, 82% over three steps) as a yellow
oil. H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.4 Hz, 1H),
7.68 – 7.57 (m, 2H), 7.51 – 7.41 (m, 1H), 7.18 (d, J = 15.6 Hz,
1
1H), 6.22 (dt, J = 15.6, 6.4 Hz, 1H), 4.04 (d, J = 6.3 Hz, 2H). 13
C
{1H} NMR (101 MHz, CDCl3): δ 147.8, 133.3, 132.0, 129.9,
129.0, 128.7, 127.9, 124.7, 52.6. IR (NaCl, thin film, cm-1):
3072, 2927, 2850, 2094, 1524, 1344, 964. HRMS (CI-TOF)
9
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
+
m/z [M + NH4]+ Calcd for C9H12N5O2 222.0986; Found
222.0978.
CF3
N3
1i
2-trifluoromethylcinnamyl azide (1i). The preparation of
compound 1i was adapted from a known procedure.44
Purification by column chromatography (gradient
EtOAc/hexane from 0% - 40%) afforded compound 1i in
1
53% yield (603 mg) as a colorless oil. H NMR (400 MHz,
CDCl3): δ 7.68 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.54
(t, J = 7.8 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.08 (d, J = 15.6 Hz,
1H), 6.24 (dt, J = 15.6, 6.5 Hz, 1H), 4.00 (d, J = 6.5 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3): δ 135.2 (q, JC-F = 1.8 Hz),
132.0, 130.4 (q, JC-F = 2.1 Hz), 127.8, 127.64, 127.63 (q, JC-F
=
30.1 Hz), 126.9, 125.8 (q, JC-F = 5.7 Hz), 124.2 (q, JC-F = 274.9
Hz), 52.7. 19F{1H} NMR (376 MHz, CDCl3): δ -59.4. IR (NaCl,
thin film, cm-1): 3063, 2198, 2104, 1314, 1160, 1125, 765.
+
HRMS (CI-TOF) m/z [M + NH4]+ Calcd for C10H12F3N4
245.1009; Found 245.1000.
N
N3
1l
(E)-2-(3-azidoprop-1-en-1-yl)pyridine (1l). The preparation
of compound 1l was adapted from a known procedure.44
Purification by column chromatography (gradient
EtOAc/hexane from 0% - 50%) afforded compound 1l in
46% yield (369 mg) as a yellow oil. Note: cinnamyl azide 1l
is not stable to storage at ambient temperature and should
Azide Synthesis
The following cinnamyl azides were prepared through
known procedures and have been previously characterized:
1a,44,45 1c-1d,44,45 1e-1f,44,46 1g,44,47 1h,18,44 1j-1k,44,47 1o,44,45
1p-1q,44 1t,46,48,49 1u-1v,30 1w,49–51 and 1hh.18,44
1
NO2
NO2
be used immediately or stored in a freezer. H NMR (400
1) NaBH4
2) MsCl, TEA
CHO
MHz, CDCl3): δ 8.59 (d, J = 4.8 Hz, 1H), 7.67 (td, J = 7.7, 1.8
Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.19 (dd, J = 7.4, 4.9 Hz, 1H),
6.84 – 6.70 (m, 2H), 4.03 (d, J = 5.0 Hz, 1H). 13C{1H} NMR
(101 MHz, CDCl3): δ 154.4, 149.7, 136.6, 133.4, 127.1,
122.7, 122.0, 52.5. IR (NaCl, thin film, cm-1): 3000, 2918,
2209, 1585, 1470, 1431, 975. HRMS (CI-TOF) m/z [M + H]+
Calcd for C8H9N4+ 161.0822; Found 161.0821.
N3
3) NaN3
1b
2-nitrocinnamylazide (1b). To
a
solution of 2-
nitrocinnamaldehyde (1.02 g, 5.77 mmol) in MeOH (13 mL)
in an ice bath, NaBH4 (257 mg, 6.80 mmol) was added
slowly. After 45 min, the reaction was quenched by the
addition of H2O (25 mL) and the mixture was extracted with
EtOAc (3 x 100 mL). The combined organic phases were
washed with brine, dried (Na2SO4), and concentrated under
reduced pressure. The crude material (1.20 g) was used
without further purification. Characterization data for 2-
nitrocinnamyl alcohol has been reported.52 The crude oil
was reconstituted in DCM (20 mL), cooled in an ice bath, and
TEA (1.6 mL, 12 mmol) was added followed by dropwise
addition of MsCl (0.67 mL, 8.7 mmol). After 1.5 h, the
reaction was quenched by the addition of water and
extracted with DCM (3 x 100 mL). The combined organic
phases were dried (Na2SO4), filtered, and concentrated
under reduced pressure. The crude oil was dissolved in
acetone (5 mL) at rt and an aqueous solution of NaN3 (5 mL,
1.9 M, 9.4 mmol) was added. After 18 h, the reaction was
N
N3
1m
(E)-3-(3-azidoprop-1-en-1-yl)pyridine
(1m).
The
preparation of compound 1m was adapted from a known
procedure.44 Purification by column chromatography
(gradient EtOAc/hexane from 0%
- 70%) afforded
compound 1m in 34% yield (272 mg) as a yellow oil. Note:
cinnamyl azide 1m is not stable to storage at ambient
temperature and should be used immediately or stored in a
1
freezer. H NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 8.56 –
8.50 (m, 1H), 7.77 – 7.71 (m, 1H), 7.32 – 7.25 (m, 1H), 6.67
(d, J = 15.8 Hz, 1H), 6.33 (dtd J = 15.4, 6.3 Hz, 1H), 4.01 (d, J
= 6.5 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 149.2,
148.5, 133.1, 131.7, 130.7, 125.0, 123.5, 52.8. IR (NaCl, thin
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The Journal of Organic Chemistry
compound 1s’’ was adapted from a known method with
film, cm-1): 3031, 2102, 1416, 1243, 971. HRMS (CI-TOF)
m/z [M + H]+ Calcd for C8H9N4+ 161.0822; Found 161.0821.
slight modification.53 An oven dried flask was equipped with
a stir bar, fitted with a septum, sealed under argon, charged
with compound 1s’ (281 mg, 1.00 mmol) and DCM (5 mL).
The solution was cooled in an ice bath. Dropwise addition of
thionyl chloride (0.29 mL, 4.0 mmol) to the flask was
conducted over 5 min. The reaction was gradually warmed
to ambient temperature. After 16 h, the reaction was
quenched by addition of water (5 mL). The resulting
solution was diluted with water (10 mL) and extracted with
DCM (3 x 15 mL). The combined organic solution was
washed with brine, dried (MgSO4), filtered, and
concentrated under reduced pressure. Purification by
column chromatography (hexanes as eluant) afforded
1
2
3
N3
N
1n
(E)-4-(3-azidoprop-1-en-1-yl)pyridine (1n). The preparation
of compound 1n was adapted from a known procedure.44
Purification by column chromatography (DCM in hexanes,
gradient elution 0 - 70 %) afforded compound 1n in 62%
yield (498 mg) as a yellow oil. Note: cinnamyl azide 1n is
not stable to storage at ambient temperature and should be
used immediately or stored in a freezer. 1H NMR (400 MHz,
CDCl3): δ 8.59 (d, J = 6.2 Hz, 2H), 7.28 (d, J = 6.2 Hz, 2H), 6.63
(d, J = 15.9 Hz, 1H), 6.46 (dt, J = 15.9, 6.1 Hz, 1H), 4.03 (d, J =
6.1, 1.5 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 150.3,
143.3, 131.5, 127.6, 121.0, 52.5. IR (NaCl, thin film, cm-1):
3029, 2106, 1596, 1415, 974. HRMS (CI-TOF) m/z [M + H]+
Calcd for C8H9N4+ 161.0822; Found 161.0821.
4
5
6
7
8
9
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
1
target compound 1s’’ as a colorless oil (107 mg, 37%). H
NMR (400 MHz, CDCl3): δ 7.84 (s, 2H), 7.82 (s, 1H), 6.12 (tq,
J = 7.9, 1.4 Hz, 1H), 4.30 (d, J = 7.9 Hz, 2H), 2.21 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 144.3, 138.2, 131.8 (q,
JC-F = 33.3 Hz), 126.2, 126.0 (m), 123.3 (q, JC-F = 273.7 Hz),
121.3 (sept, JC-F = 3.8 Hz), 40.1, 15.8. 19F{1H} NMR (376
MHz, CDCl3): -62.9. IR (NaCl, thin film, cm-1): 2950, 1380,
1280, 1182, 1132, 898. HRMS (EI-TOF) m/z [M – Cl]+ Calcd
for C12H9F6+ 267.0603; Found 267.0598.
Me
O
MgBr
N3
H
Me
DPPA
1r
(3-azido-2-methylprop-1-en-1-yl)benzene
(1r).
The
preparation of compound 1r was adapted from a known
procedure.44 Purification by column chromatography
Me
Me
CF3
CF3
(gradient EtOAc/hexane from 0%
- 20%) afforded
NaN3
Cl
N3
compound 1r in 60% yield (519 mg) as a colorless oil with
a E/Z ratio of 85:15. The major product of the obtained
material provided an identical 1H NMR spectrum.
acetone/H2O
1s''
1s
60 o
C
CF3
CF3
(E)-1-(4-azidobut-2-en-2-yl)-3,5-
O
HO Me
bis(trifluoromethyl)benzene (1s). A flask was charged with
compound 1s’’ (171 mg, 0.592 mmol) and acetone (1 mL),
and equipped with a stir bar. An aqueous solution of sodium
azide (1.0 mL, 0.96 M, 0.96 mmol) was added to the reaction
at ambient temperature. The flask was equipped with a
condenser and the reaction was heated to 60 ˚C. After 3 h,
the reaction was cooled and diluted with water (5 mL). The
resulting solution was extracted with EtOAc (3 x 15 mL).
The combined organic solution was washed with brine,
dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification by column chromatography (EtOAc in
CF3
CF3
MgCl
THF, -78 o
Me
C
1s'
then NH4Cl
CF3
CF3
2-(3,5-bis(trifluoromethyl)phenyl)but-3-en-2-ol (1s’). An
oven dried flask was equipped with a stir bar, fitted with a
septum, sealed under argon, charged with THF (20 mL), and
vinyl magnesium chloride (3.80 mL, 1.6 M in THF, 6.1
mmol). The solution was cooled in an acetone/dry ice bath.
Dropwise
addition
of
3’,5’-
bis(trifluoromethyl)acetophenone (0.90 mL, 5.0 mmol) to
the flask was conducted over 5 min. The reaction was
gradually warmed to ambient temperature. After 16 h, the
reaction was quenched by the addition of water (20 mL).
The resulting solution was diluted with water (20 mL) and
extracted with EtOAc (3 x 30 mL). The combined organic
solution was washed with brine, dried (MgSO4), filtered, and
concentrated under reduced pressure. Purification by
column chromatography (EtOAc in hexanes, gradient
elution 0 - 40%) afforded target compound 1s’ as a colorless
hexanes, gradient elution
0 - 40%) afforded target
compound 1s as a colorless oil (148 mg, 85%). 1H NMR
(400 MHz, CDCl3): δ 7.84 (s, 2H), 7.83 (s, 1H), 6.01 (tq, J =
7.2, 1.4 Hz, 1H), 4.01 (d, J = 7.1 Hz, 2H), 2.19 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 144.4, 138.5, 131.8 (q, JC-F = 33.4
Hz), 126.0, 124.0, 123.3 (q, JC-F = 273.8 Hz), 121.3 (sept, JC-F
= 3.8 Hz), 48.5, 16.3. 19F{1H} NMR (376 MHz, CDCl3): -62.9.
IR (NaCl, thin film, cm-1): 2292, 2103, 1380, 1280, 1179,
1132. HRMS (CI-TOF) m/z [M – N2 + H]+ Calcd for
C12H10F6N+ 282.0712; Found 282.0705.
1
oil (360 mg, 25%). H NMR (400 MHz, CDCl3): δ 7.96 (s,
2H), 7.80 (s, 1H), 6.17 (dd, J = 17.3, 10.6 Hz, 1H), 5.79 (d, J =
17.3 Hz, 1H), 5.28 (d, J = 10.6 Hz, 1H), 2.15 (br, 1H), 1.72 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 149.1, 143.3, 131.5
(q, JC-F = 33.4 Hz), 125.6 (m), 123.4 (q, JC-F = 273.9 Hz), 121.0
(sept, JC-F = 4.0 Hz), 114.3, 74.4, 29.5. 19F{1H} NMR (376
MHz, CDCl3): -62.8. IR (NaCl, thin film, cm-1): 3406, 2917,
1374, 1278, 1174, 1134. HRMS (ESI-TOF) m/z [M]+ Calcd
for C12H10F6O+ 284.0630; Found 284.0629.
Formation of triazoline 2b
O
N
Ph
N
N3
N
N
H
O
H
MeO
MeO
C6H6, 85 o
C
O
1hh
2hh
N
O
Ph
(3aS,6aR)-1-((E)-3-(6-methoxynaphthalen-2-yl)allyl)-5-
phenyl-3a,6a-dihydropyrrolo[3,4-d][1,2,3]triazole-
4,6(1H,5H)-dione (2hh). A 4 mL vial was charged with azide
1hh (119.4 mg, 0.500 mmol), N-phenylmaleimide (86.6 mg,
0.500 mmol), and benzene (0.5 mL). The vial was sealed and
heated to 85˚C. After 24 h, the reaction was cooled. The
crude solid was collected using a Hirsch funnel and washed
Me
HO Me
CF3
CF3
SOCl2
Cl
DCM, 0 o
C
1s'
1s''
CF3
CF3
(E)-1-(4-chlorobut-2-en-2-yl)-3,5-
bis(trifluoromethyl)benzene (1s’’). The synthesis of
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with hexanes (3 x 2 mL). This afforded compound 2hh as a heated to 70 ˚C. After 24 h, the reaction was cooled to
white solid (179.5 mg, 81%). 1H NMR (400 MHz, CDCl3): δ
7.78 – 7.67 (m, 3H), 7.59 (dd, J = 8.6, 1.8 Hz, 1H), 7.53 – 7.41
(m, 3H), 7.32 – 7.26 (m, 2H), 7.21 – 7.12 (m, 2H), 6.91 (d, J =
15.8 Hz, 1H), 6.31 (ddd, J = 15.7, 8.6, 5.4 Hz, 1H), 5.69 (d, J =
10.9 Hz, 1H), 5.02 (dd, J = 15.1, 5.4 Hz, 1H), 4.56 (d, J = 11.0
Hz, 1H), 4.52 (dd, J = 15.2, 8.6 Hz, 1H), 3.95 (s, 3H). 13C{1H}
NMR (126 MHz, CD3CN): δ 171.9, 170.7, 158.0, 134.5,
134.3, 131.82, 131.79, 129.5, 129.2, 129.0, 128.9, 127.2,
126.9, 126.4, 124.1, 122.7, 119.0, 106.0, 82.4, 58.2, 55.0,
51.2. IR (NaCl, thin film, cm-1): 2935, 1723, 1600, 1477,
1378, 1178. HRMS (ESI-TOF) m/z [M – N2 + H]+ Calcd for
C24H20N4NaO3+ 435.1428; Found 435.1433.
ambient temperature, and the solvent was removed under
reduced pressure. The reaction was reconstituted in DCM (2
mL) and TFA (0.15 mL, 2.0 mmol, 5 equiv) was added.
(Note: The treatment with TFA helped promote the
tautomerization to the hydrazone. This step was not
necessary; however, skipping it resulted in a mixture of
tautomers.) After 5 min, the solvent was removed under
reduced pressure. Final purification by column
chromatography (IPA in DCM with 1% TEA, gradient elution
0 - 10%) afforded compound 5b (109 mg, 93%) as an
1
2
3
4
5
6
7
8
9
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
orange oil.
H
R5
CO2Me
R4
1)
3-5 equiv
R3
N
CO2Me
NH
N
CO2Me
N
N
R5
R1
rt, 24-96 h
R1
N3
R2
(1 equiv)
R1
or
NH
R2
R2
Reaction Optimization
2) DIPEA (0.5 equiv)
C6H6, 70 oC, 24-72 h
R4
R4
R3
1
R3
Procedure for Table 1 - A stock solution of azide 1a (87.8
mg, 0.552 mmol) and naphthalene (18.8 mg, 0.147 mmol,
internal standard) was prepared in THF (0.10 mL).
Individual 4 mL vials were charged with 30 μL portions of
this solution and methyl acrylate (10 or 20 μL). The vials
were sealed under air at rt. After 72 h, the reactions were
if R5 = H
if R5 ≠ H
(±)-5
(±)-5
General Procedure II: Two operation synthesis of
tetrahydro-pyrrolo-pyrazoles. Example given for R1 = Ph, R2
= Me, R3 = R4 = R5 = H. A 4 mL vial was charged with azide
1r (86.8 mg, 0.501 mmol, 1 equiv) and methyl acrylate (0.23
mL, 2.5 mmol, 5 equiv). The vial was sealed with a Teflon
lined cap and the reaction was stirred at ambient
temperature. After 48 h, the reaction was transferred to a
20 mL vial and the concentrated under reduced pressure at
ambient temperature. The residual methyl acrylate was
removed under high vacuum for 15 min. The crude
triazoline was reconstituted in benzene (2.0 mL) and DIPEA
(44 µL, 0.25 mmol, 0.5 equiv) was added. The vial was
sealed with a Teflon lined cap and heated to 70 ˚C. After 24
h, the reaction was cooled, and the solvent was removed
under reduced pressure. Final purification by column
chromatography (IPA in DCM with 1% TEA, gradient elution
0 - 10%) afforded compound 5r (91.0 mg, 70%) as a
1
concentrated under reduced pressure and analyzed by H
NMR. All of the reactions were run in duplicate and the
average values are reported.
Procedure for Table 2 (Solvent screening procedure) -
A stock solution of azide 1b (197 mg, 0.964 mmol) and
naphthalene (54.9 mg, 0.429 mmol, internal standard) was
prepared in DCM (455 µL). Individual 4 mL vials were
charged with 50 μL portions of this solution and the DCM
was evaporated. The respective solvent (370 μL) was added
to each vial followed by methyl acrylate (20 μL, 0.22 mmol).
The vials were sealed under air and heated to 70 ˚C. After 24
h, the reactions were cooled to ambient temperature and
TFA (28 µL) was added. After 10 min, each reaction was
diluted with K2CO3 (sat. aq., 1 mL) and EtOAc (1 mL). The
phases were separated and the organic layer was analyzed
by GC-FID to determine the yield. All of the reactions were
run in duplicate and the average values are reported.
Procedure for Table 2 (Additive screening procedure) -
A stock solution of azide 1b (263 mg, 1.29 mmol), methyl
acrylate (0.35 mL, 3.9 mmol), and naphthalene (166 mg,
1.30 mmol, internal standard) was prepared in benzene (6.5
mL). Individual 4 mL vials were charged with 380 μL
portions of this solution. One additive (0.5 equiv) was added
individually to each vial. The vials were sealed under air and
heated to 70 ˚C. After 24 h, the reactions were cooled to
ambient temperature and TFA (28 µL) was added. After 10
min, each reaction was diluted with saturated K2CO3
aqueous solution (1 mL) and EtOAc (1 mL). The phases
were separated and the organic layer was analyzed by GC-
FID to determine percent yields. All of the reactions were
run in duplicate and the average values are reported.
colorless oil.
CO2Me
NH
NO2
N
CO2Me
NO2
R
X
5 equiv 2 equiv
N3
N
R
H
DIPEA (3 equiv)
MTBE, 70 oC, 24 h
1b
(±)-9
(1 equiv)
General Procedure III: Single step synthesis of the N-
protected tetrahydro-pyrrolo-pyrazoles. Example given for
R-X = Boc2O and R = Boc. A 20 mL via was charged with azide
1b (61.0 mg, 0.30 mmol, 1 equiv) and MTBE (1.5 mL). Di-
tert-butyl dicarbonate (0.14 mL, 0.61 mmol, 2 equiv) was
added to the reaction followed by methyl acrylate (0.14 mL,
1.5 mmol, 5 equiv) and DIPEA (0.16 mL, 0.92 mmol, 3
equiv). The vial was sealed with a Teflon lined cap and the
reaction was heated to 70 ˚C. After 24 h, the reaction was
cooled to ambient temperature and the mixture was diluted
with water (5 mL). The resulting solution was extracted
with DCM (3 x 20 mL). The combined organic phase was
washed with brine, dried (MgSO4), filtered, and
concentrated under reduced pressure. Purification by
column chromatography (EtOAc in hexanes, gradient
elution 0 - 100%) afforded target compound 9a as a yellow
CO2Me
H
N
CO2Me
N
N3
3 equiv
R
NH
DIPEA (0.5 equiv)
C6H6, 70 oC, 24 h
H
(±)-5
solid (92.9 mg, 80%).
R
1
(1 equiv)
H
N
CO2Me
NH
N
General Procedure I: Single step synthesis of tetrahydro-
pyrrolo-pyrazoles. Example given for R = 2-NO2. A 20 mL
vial was sequentially charged with azide 1b (81.7 mg, 0.400
mmol, 1 equiv), benzene (2.0 mL), methyl acrylate (0.11 mL,
1.2 mmol, 3 equiv), and DIPEA (35 µL, 0.20 mmol, 0.5
equiv). The vial was sealed with a Teflon lined cap and
H
5a
Methyl (3aS,6aS)-3-phenyl-3a,4,5,6-tetrahydropyrrolo[3,4-
c]pyrazole-6a(1H)-carboxylate (5a).
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The Journal of Organic Chemistry
H
General procedure I was used and the product was
N
CO2Me
NH
N
1
2
3
4
5
6
7
8
isolated in 66% (83.3 mg) and 61% (77.9 mg) yield in
duplicate trials. The average of 64% is reported. The
material provided similar 1H NMR as previously reported.23
1H NMR (400 MHz, CDCl3): δ 7.63 – 7.58 (m, 2H), 7.40 –
7.30 (m, 3H), 6.57 (br, 1H), 4.20 (dd, J = 7.0, 3.6 Hz, 1H), 3.80
(s, 3H), 3.34 – 3.26 (m, 3H), 3.17 (d, J = 12.1 Hz, 1H), 2.50
(br, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 174.2, 153.5,
131.5, 129.2, 128.9, 126.3, 81.5, 61.6, 58.6, 54.8, 53.1. IR
(NaCl, thin film, cm-1): 3317, 2951, 1732, 1679, 1446,
1272, 1219. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for
H
Me
5d
Methyl (3aS,6aS)-3-(p-tolyl)-3a,4,5,6-tetrahydropyrrolo[3,4-
c]pyrazole-6a(1H)-carboxylate (5d).
General procedure I was used and the product was
isolated in 72% (103 mg) and 74% (116 mg) yield in
1
duplicate trials. The average of 73% is reported. H NMR
(500 MHz, C6D6): δ 7.57 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 7.9
Hz, 2H), 6.59 (br, 1H), 3.98 (apparent t, J = 5.3 Hz, 1H), 3.18
(s, 3H), 3.05 (br, 2H), 3.00 (d, J = 5.3 Hz, 2H), 2.07 (s, 3H),
1.67 (br, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 174.1,
153.6, 139.2, 129.4, 128.6, 126.2, 81.2, 61.4, 58.5, 54.6, 53.0,
21.4. IR (NaCl, thin film, cm-1): 3324, 2952, 2873, 1731,
1436, 1272, 1220, 1039. HRMS (ESI-TOF) m/z [M + H]+
9
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
C13H15N3NaO2+ 268.1056, found 268.1059.
H
N
CO2Me
NH
NO2
N
H
5b
Methyl (3aS,6aS)-3-(2-nitrophenyl)-3a,4,5,6-
Calcd for C14H18N3O2+ 260.1394; Found 260.1397.
H
N
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5b).
General procedure I was used and the product was
isolated in 93% (109 mg) and 94% (108 mg) yield in
CO2Me
NH
N
H
1
Br
5e
duplicate trials. The average of 94% is reported. H NMR
(400 MHz, CD2Cl2): δ 7.81 – 7.72 (m, 1H), 7.69 – 7.60 (m,
1H), 7.57 – 7.47 (m, 2H), 6.78 (br, 1H), 4.21 (dd, J = 7.9, 2.1
Hz, 1H), 3.85 (s, 3H), 3.29 (d, J = 12.1 Hz, 1H), 3.24 (dt, J =
12.5, 1.9 Hz, 1H), 3.18 – 3.10 (m, 2H), 2.25 (br, 1H). 13C{1H}
NMR (101 MHz, CD2Cl2): δ 173.5, 149.1, 149.0, 132.2,
129.7, 129.4, 126.2, 124.1, 81.2, 61.4, 60.0, 53.9, 52.9. IR
(NaCl, thin film, cm-1): 3338, 2950, 1736, 1729, 1528,
Methyl (3aS,6aS)-3-(4-bromophenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5e).
General procedure I was used and the product was
isolated in 67% (86.9 mg) and 71% (90.4 mg) yield in
1
duplicate trials. The average of 69% is reported. H NMR
(500 MHz, C6D6): δ 7.25 – 7.19 (m, 4H), 6.58 (br, 1H), 3.79
(dd, J = 8.1, 2.4 Hz, 1H), 3.19 (s, 3H), 3.02 (br, 2H), 2.90 (dd,
J = 12.3, 8.0 Hz, 1H), 2.82 (dd, J = 12.4, 2.5 Hz, 1H), 2.09 (br,
1H). 13C{1H} NMR (126 MHz, C6D6): δ 173.4, 151.0, 131.6
(tentatively assigned as 2C), 131.0, 122.5, 81.6, 61.3, 57.9,
54.3, 51.8. IR (NaCl, thin film, cm-1): 3324, 2951, 1730,
1491, 1399, 1271, 1220, 1070. HRMS (ESI-TOF) [M + H]+
+
1273. HRMS (ESI-TOF) [M + H]+ Calcd for C13H15N4O4 :
291.1088; Found: 291.1089.
Gram scale synthesis of 5b: A 100 mL round-bottom flask
was equipped with a stir bar and charged with azide 1b
(1.02 g, 5.00 mmol), methyl acrylate (1.36 mL, 15.0 mmol, 3
equiv), and benzene (25 mL). DIPEA (0.44 mL, 2.5 mmol, 0.5
equiv) was added to the flask and the flask was sealed with
a glass stopper. The reaction was heated to 70 ˚C. After 24
h, the reaction was cooled and TFA (1.9 mL, 25 mmol) was
added to the flask. After 5 min, the solvent was removed
under reduced pressure. Final purification by column
chromatography (IPA in DCM with 1% TEA, gradient elution
0 - 10%) afforded compound 5b (1.41 g, 97%) as an orange
oil. A duplicate trial afforded compound 5b (1.06 g, 92%).
+
Calcd for C13H15BrN3O2 : 324.0342; Found: 324.0342.
H
N
CO2Me
NH
N
H
CF3
5f
Methyl (3aS,6aS)-3-(4-(trifluoromethyl)phenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5f).
General procedure I was used and the product was
isolated in 78% (103 mg) and 80% (98.6 mg) yield in
1
The average of 95% is reported.
duplicate trials. The average of 79% is reported. H NMR
H
N
(400 MHz, C6D6): δ 7.39 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.6
Hz, 2H), 6.63 (br, 1H), 3.81 (dd, J = 8.0, 2.4 Hz, 1H), 3.21 (s,
3H), 3.01 (br, 2H), 2.92 (dd, J = 12.3, 8.0 Hz, 1H), 2.81 (dd, J
= 12.3, 2.5 Hz, 1H), 170 (br, 1H). 13C{1H} NMR (101 MHz,
C6D6): δ 173.3, 150.4, 135.5, 131.2 (q, JC-F = 271.8 Hz), 129.7
(q, JC-F = 32.5 Hz), 126.0, 125.3 (q, JC-F = 3.8 Hz), 81.9, 61.4,
57.8, 54.3, 51.9. 19F{1H} NMR (471 MHz, CDCl3): δ -62.72.
IR (NaCl, thin film, cm-1): 3305, 2955, 1732, 1327, 1274,
1220, 1165, 1120, 1068. HRMS (ESI-TOF) m/z [M + Na]+
CO2Me
NH
N
H
MeO
5c
Methyl (3aS,6aS)-3-(4-methoxyphenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5c).
General procedure I was used and the product was
isolated in 79% (112 mg) and 84% (118 mg) yield in
1
duplicate trials. The average of 82% is reported. H NMR
Calcd for C14H14F3N3NaO2+ 336.0930; Found 336.0927.
(500 MHz, C6D6): δ 7.58 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.7
Hz, 2H), 6.55 (br, 1H), 3.97 (apparent t, J = 5.3 Hz, 1H), 3.26
(s, 3H), 3.18 (s, 3H), 3.07 (br, 2H), 3.04 – 3.00 (m, 2H), 1.74
(br, 1H). 13C{1H} NMR (126 MHz, C6D6): δ 173.8, 160.2,
152.2, 128.0, 125.0, 114.0, 81.5, 61.5, 58.7, 54.6, 54.5, 51.8.
IR (NaCl, thin film, cm-1): 3323, 2953, 2840, 1731, 1672,
1608, 1516, 1253, 1220, 1176, 1037. HRMS (ESI-TOF) [M +
Na]+ Calcd for C14H17N3NaO3+ 298.1162; Found 298.1161.
H
N
CO2Me
NH
N
H
NC
5g
Methyl (3aS,6aS)-3-(4-cyanophenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5g).
General procedure I was used and the product was
isolated in 76% (104 mg) and 77% (103 mg) yield in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 18
1
duplicate trials. The average of 77% is reported. H NMR
thin film, cm-1): 3277, 2952, 1731, 1659, 1433, 1413, 1271,
1220. HRMS (ESI-TOF) m/z [M + H]+ Calcd for C11H14N3O2S+
1
2
3
4
5
6
7
8
(400 MHz, CD2Cl2): δ 7.75 – 7.69 (m, 2H), 7.69 – 7.65 (m,
2H), 6.82 (br, 1H), 4.20 (dd, J = 8.0, 2.5 Hz, 1H), 3.82 (s, 3H),
3.38 – 3.22 (m, 3H), 3.20 (d, J = 12.1 Hz, 1H), 2.19 (br, 1H).
13C{1H} NMR (101 MHz, CD2Cl2): δ 173.6, 150.8, 136.1,
132.4, 126.2, 118.7, 111.6, 82.0, 61.3, 57.8 54.4, 52.8. IR
(NaCl, thin film, cm-1): 3331, 3050, 2954, 2226, 1728,
1606, 1579, 1435, 1274, 1220. HRMS (ESI-TOF) [M + Na]+
252.0801; Found 252.0805.
H
N
CO2Me
NH
N
S
H
5k
Methyl (3aS,6aS)-3-(benzo[b]thiophen-2-yl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5k).
General procedure I was used and the product was
isolated in 74% (89.4 mg) and 85% (103 mg) yield in
+
Calcd for C14H14N4NaO2 : 293.1009; Found: 293.1010.
H
N
CO2Me
NH
OMe N
9
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
1
duplicate trials. The average of 80% is reported. H NMR
H
5h
(500 MHz, CD2Cl2): δ 7.86 – 7.72 (m, 2H), 7.44 – 7.32 (m,
2H), 7.28 (s, 1H), 6.67 (br, 1H), 4.26 (dd, J = 8.0, 2.2 Hz, 1H),
3.84 (s, 3H), 3.46 (d, J = 12.2 Hz, 1H), 3.41 – 3.28 (m, 2H),
3.21 (d, J = 12.1 Hz, 1H), 2.28 (br, 1H). 13C{1H} NMR (126
MHz, CD2Cl2): δ 173.6, 149.2, 139.8, 139.7, 136.0, 125.3,
124.6, 123.8, 122.8, 122.2, 82.0, 61.4, 59.0, 54.6, 52.8. IR
(NaCl, thin film, cm-1): 3304, 2936, 1725, 1414, 1266,
Methyl (3aS,6aS)-3-(2-methoxyphenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5h).
General procedure I was used and the product was
isolated in 88% (121 mg) and 79% (109 mg) yield in
1
duplicate trials. The average of 84% is reported. H NMR
(500 MHz, C6D6): δ 8.26 (dd, J = 7.9, 1.7 Hz, 1H), 7.02 (td, J
= 7.8, 1.7 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 6.44 (d, J = 8.3 Hz,
1H), 4.50 (dd, J = 8.5, 2.6 Hz, 1H), 3.93 (br, 1H), 3.30 – 3.19
(m, 3H), 3.23 (s, 3H), 3.18 – 3.09 (m, 1H), 3.14 (s, 3H).
13C{1H} NMR (126 MHz, C6D6): δ 173.7, 156.6, 151.1, 129.9,
129.3, 121.0, 120.9, 111.4, 80.3, 60.5, 60.0, 54.5, 54.4, 51.9.
IR (NaCl, thin film, cm-1): 3318, 2950, 1737, 1688, 1680,
1599, 1245, 1200, 1130. HRMS (ESI-TOF) [M + H]+ Calcd
1210, 836. HRMS (ESI-TOF) [M
+
H]+ Calcd for
C15H16N3O2S+: 302.0958; Found: 302;0956.
H
N
CO2Me
NH
N
N
H
5l
Methyl (3aS,6aS)-3-(pyridin-2-yl)-3a,4,5,6-
+
for C14H18N3O3 : 276.1343; Found: 276.1340.
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5l).
General procedure I was used and the product was
isolated in 93% (115 mg) and 84% (104 mg) yield in
H
N
CO2Me
NH
CF3
N
1
duplicate trials. The average of 89% is reported. H NMR
H
5i
(500 MHz, C6D6): δ 8.34 (d, J = 4.8 Hz, 1H), 8.07 (d, J = 8.0
Hz, 1H), 7.02 (td, J = 7.8, 1.7 Hz, 1H), 6.77 (br, 1H), 6.60 –
6.52 (m, 1H), 4.52 (dd, J = 7.9, 2.6 Hz, 1H), 3.44 – 3.31 (m,
2H), 3.14 (s, 3H), 3.09 (d, J = 12.0 Hz, 1H), 3.05 (d, J = 12.0
Hz, 1H), 1.98 (br, 1H). 13C{1H} NMR (126 MHz, C6D6): δ
173.7, 153.6, 151.9, 148.8, 135.4, 122.3, 120.6, 81.0, 61.3,
58.8, 552, 51.7. IR (NaCl, thin film, cm-1): 3272, 2950, 1743,
1680, 1437, 1284, 1202, 1133. HRMS (ESI-TOF) [M + H]+
Methyl (3aS,6aS)-3-(2-(trifluoromethyl)phenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5i).
General procedure I was used and the product was
isolated in 76% (95 mg), 56% (70 mg) and 56% (74 mg)
yield in triplicate trials. The average of 63% is reported. 1H
NMR (400 MHz, CD2Cl2): δ 7.77 (d, J = 7.2 Hz, 1H), 7.63 (t, J
= 7.1 Hz, 1H), 7.57 – 7.50 (m, 2H), 6.74 (br, 1H), 4.25 (dd, J =
7.6, 2.6 Hz, 1H), 3.86 (s, 3H), 3.29 (d, J = 12.0 Hz, 1H), 3.20 –
3.05 (m, 3H), 2.21 (br, 1H). 13C{1H} NMR (101 MHz,
CD2Cl2): δ 173.8, 151.4, 131.9, 131.6 (q, JC-F = 2.1 Hz), 130.5,
128.8, 128.1 (q, JC-F = 30.8 Hz), 126.8 (q, JC-F = 5.6 Hz), 124.1
(q, JC-F = 274.4 Hz), 81.0, 62.0, 61.4, 53.6, 52.8. 19F{1H} NMR
(376 MHz, CD2Cl2): δ -58.7. IR (NaCl, thin film, cm-1):
3329, 2956, 2877, 1729, 1601, 1436, 1312, 1274, 1217,
1170, 1127, 1035, 766. HRMS (ESI-TOF) [M + H]+ Calcd for
+
Calcd for C12H15N4O2 : 247.1190; Found: 247.1197.
H
N
CO2Me
NH
N
N
H
5m
Methyl (3aS,6aS)-3-(pyridin-3-yl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5m).
General procedure I was used and the product was
isolated in 72% (88.0 mg) and 63% (76.4 mg) yield in
+
C14H15F3N3O2 : 314.1111; Found: 314.1112.
H
N
1
duplicate trials. The average of 68% is reported. H NMR
CO2Me
NH
N
(400 MHz, CD2Cl2): δ 8.80 (dd, J = 2.3, 0.9 Hz, 1H), 8.54 (dd,
J = 4.8, 1.7 Hz, 1H), 7.96 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 7.31
(ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 6.78 (br, 1H), 4.22 (dd, J = 7.9,
2.6 Hz, 1H), 3.81 (s, 3H), 3.38 – 3.23 (m, 3H), 3.19 (d, J = 12.2
Hz, 1H), 2.42 (br, 1H). 13C{1H} NMR (101 MHz, CD2Cl2): δ
173.8, 150.1, 149.5, 147.3, 132.9, 127.7, 123.4, 81.5, 61.2,
58.0, 54.3, 52.8. IR (NaCl, thin film, cm-1): 3308, 2953,
1730, 1591, 1434, 1274, 1221. HRMS (ESI-TOF) [M + H]+
S
H
5j
Methyl (3aS,6aS)-3-(thiophen-2-yl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5j).
General procedure I was used and the product was
isolated in 70% (88.7 mg) and 77% (95.8 mg) yield in
1
duplicate trials. The average of 74% is reported. H NMR
+
(400 MHz, CD3CN): δ 7.38 (d, J = 5.1 Hz, 1H), 7.14 (d, J = 3.5
Hz, 1H), 7.04 (dd, J = 4.9, 3.8 Hz, 1H), 6.61 (br, 1H), 4.17 (dd,
J = 7.5, 3.0 Hz, 1H), 3.76 (s, 3H), 3.30 – 3.20 (m, 2H), 3.18 (d,
J = 11.9 Hz, 1H), 3.13 (d, J = 12.1 Hz, 1H).1.30 (br, 1H).
13C{1H} NMR (101 MHz, CD3CN): δ 173.4, 148.3, 136.0,
127.6, 126.6, 126.5, 80.9, 60.3, 58.9, 53.6, 52.4. IR (NaCl,
Calcd for C12H15N4O2 : 247.1190; Found: 247.1189.
H
N
CO2Me
NH
N
H
N
5n
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Methyl (3aS,4R,6aS)-3,4-diphenyl-5-trityl-3a,4,5,6-
Methyl (3aS,6aS)-3-(pyridin-4-yl)-3a,4,5,6-
1
2
3
4
5
6
7
8
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5n).
General procedure I was used and the product was
isolated in 70% (86.7 mg), 49% (61.1 mg) and 61% (74.7
mg) yield in triplicate trials. The average of 60% is reported.
1H NMR (400 MHz, CD2Cl2): δ 8.59 (d, J = 6.2 Hz, 2H), 7.46
(d, J = 6.2 Hz, 2H), 6.88 (br, 1H), 4.19 (dd, J = 7.9, 2.6 Hz, 1H),
3.82 (s, 3H), 3.37 – 3.23 (m, 3H), 3.20 (d, J = 12.1 Hz, 1H),
2.52 (br, 1H). 13C{1H} NMR (101 MHz, CD2Cl2): δ 173.5,
150.2, 150.1, 138.9, 119.9, 81.9, 61.3, 57.6, 54.3, 52.8. IR
(NaCl, thin film, cm-1): 3295, 2954, 2923, 1732, 1599,
1434, 1415, 1275, 1219. HRMS (ESI-TOF) [M + H]+ Calcd
tetrahydro-pyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate
(S1).
To a solution of compound 5p (160 mg, 0.498 mmol) in DCM
(3 mL) was added TEA (0.14 mL, 1.0 mmol) and TrCl (168
mg, 0.602 mmol) at rt. After 6 h, the reaction was quenched
by addition of H2O and extracted with DCM. The combined
organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure. Final purification by
recrystallization in EtOAc/hexanes (ca. 1:5) afforded
compound S1 (194 mg, 69%) as a white solid. 1H NMR (500
MHz, C6D6) δ 7.71 (d, J = 7.5 Hz, 2H), 7.39 (d, J = 7.8 Hz, 6H),
7.04 – 6.98 (m, 4H), 6.98 – 6.94 (m, 3H), 6.94 – 6.90 (m, 7H),
6.88 – 6.83 (m, 3H), 5.31 (s, 1H), 4.46 (s, 1H), 3.62 (d, J = 10.5
Hz, 1H), 3.46 (d, J = 10.6 Hz, 1H), 3.07 (s, 3H). 13C{1H} NMR
(126 MHz, C6D6) δ 172.7, 151.9, 144.0, 143.6, 132.3, 129.8,
129.2, 128.5, 128.4, 128.3, 127.3, 127.1, 126.5, 125.8, 77.1,
73.9, 67.3, 64.1, 58.4, 51.9. IR (NaCl, thin film, cm-1): 3058,
3031, 2952, 1727, 1690, 1597, 1491, 1448, 1265, 1221.
9
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
+
for C12H15N4O2 : 247.1190; Found: 247.1189.
H
N
CO2Me
NH
N
H
Me
5o
Methyl (3aS,4S,6aS)-4-methyl-3-phenyl-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5o).
General procedure II was used and the product was
isolated in 63% and 46% yield. The average of 55% is
+
HRMS (ESI-TOF) m/z [M – CH3]+ Calcd for C37H30N3O2
548.2333; Found 548.2297.
1
reported. The dr was determined by crude H NMR to be
H
N
CO2Me
N
8.81:1 and 8.71:1 in duplicate trials. The average dr of 8.8:1
was reported. Final purification by column chromatography
(gradient IPA/acetone from 0-40%) afforded the major
diastereomer. 1H NMR (400 MHz, CDCl3): δ 7.66 – 7.60 (m,
2H), 7.43 – 7.33 (m, 3H), 6.58 (br, 1H), 3.86 (d, J = 2.6 Hz,
1H), 3.84 (s, 3H), 3.57 (qd, J = 6.9, 2.6 Hz, 1H), 3.46 (d, J =
12.3 Hz, 1H), 3.26 (d, J = 12.3 Hz, 1H), 2.45 (br, 1H), 1.42 (d,
J = 6.9 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 174.1,
153.1, 131.6, 129.1, 128.7, 126.1, 82.3, 65.0, 61.7, 58.6, 53.1,
21.1. IR (NaCl, thin film, cm-1): 3319, 2961, 1731, 1445,
1271, 1227. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for
NH
H
Me
Me
5q
Methyl (3aS,6aS)-4,4-dimethyl-3-phenyl-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5q).
General procedure I was used and the reaction time was
72 h. The product was isolated in 82% (113 mg) and 70%
(95.4 mg) yield in duplicate trials. The average of 76% is
reported. 1H NMR (400 MHz, CD3CN): δ 7.69 – 7.61 (m, 2H),
7.44 – 7.32 (m, 3H), 6.79 (br, 1H), 3.91 (s, 1H), 3.76 (s, 3H),
3.37 (d, J = 12.5 Hz, 1H), 3.12 (d, J = 12.5 Hz, 1H), 2.33 (br,
1H), 1.35 (s, 3H), 0.94 (s, 3H). 13C{1H} NMR (101 MHz,
CD3CN): δ 174.2, 151.9, 133.4, 128.5, 128.4, 126.1, 84.9,
66.1, 66.0, 56.0, 52.4, 28.3, 25.2. IR (NaCl, thin film, cm-1):
3331, 2962, 1730, 1446, 1270, 1241. HRMS (ESI-TOF) m/z
C14H17N3NaO2+ 282.1213; Found 282.1202.
H
N
CO2Me
NH
N
H
5p
[M + Na]+ Calcd for C15H19N3NaO2 296.1369; Found
+
296.1366.
Methyl (3aS,4R,6aS)-3,4-diphenyl-3a,4,5,6-
H
N
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5p).
General procedure I was used and the reaction time was
48 h Final purification by column chromatography (IPA in
hexanes with 1% TEA, gradient elution 10 - 40%) afforded
product 5p in 48% (59.2 mg) and 48% (58.5 mg) yield in
CO2Me
NH
N
Me
5r
Methyl (3aS,6aS)-3a-methyl-3-phenyl-3a,4,5,6-
1
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5r).
General procedure II was used and the product was
isolated in 70% (91.0 mg) and 57% (73.1 mg) yield in
duplicate trials. The average of 48% is reported. H NMR
(500 MHz, CDCl3): δ 7.54 – 7.49 (m, 4H), 7.42 (apparent t, J
= 7.5 Hz, 2H), 7.39 – 7.34 (m, 1H), 7.33 – 7.26 (m, 3H), 6.66
(br, 1H), 4.52 (d, J = 4.0 Hz, 1H), 4.40 (d, J = 4.0 Hz, 1H), 3.87
(s, 3H), 3.59 (d, J = 12.1 Hz, 1H), 3.31 (d, J = 12.1 Hz, 1H) 2.77
(br, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 174.0, 153.0,
142.2, 131.4, 129.1, 128.9, 128.6, 127.7, 127.3, 126.5, 82.5,
69.7, 64.2, 59.5, 53.1. IR (NaCl, thin film, cm-1): 3333, 3031,
2953, 1732, 1446, 1274, 1225. HRMS (ESI-TOF) m/z [M +
Na]+ Calcd for C19H19N3NaO2+ 344.1369; Found 344.1364.
1
duplicate trials. The average of 64% is reported. H NMR
(400 MHz, CD2Cl2): δ 7.75 – 7.61 (m, 2H), 7.49 – 7.29 (m,
3H), 6.35 (br, 1H), 3.81 (s, 3H), 3.74 (d, J = 12.3 Hz, 1H), 3.50
(d, J = 12.3 Hz, 1H), 3.15 (d, J = 12.3 Hz, 1H), 2.98 (d, J = 12.3
Hz, 1H), 2.50 (br, 1H), 1.41 (s, 3H). 13C{1H} NMR (101 MHz,
CD2Cl2): δ 172.7, 154.5, 131.5, 128.5, 128.4, 126.6, 84.7,
66.8, 61.5, 60.0, 52.5, 19.6. IR (NaCl, thin film, cm-1): 3322,
2951, 1727, 1444, 1263. HRMS (ESI-TOF) m/z [M + H]+
Calcd for C14H18N3O2+ 260.1394; Found 260.1399.
N
CO2Me
N
Me
CF3
NH
H
5s
CF3
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Methyl (3S,3aR,6aS)-3-(3,5-bis(trifluoromethyl)phenyl)-3- Methyl (2aS,2a1R,5aR,7aS)-2a-(p-tolyl)-2a,2a1,3,4,5,5a,6,7-
1
2
methyl-3a,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-6a(3H)-
carboxylate (5s).
octahydro-7aH-pyrrolo[4,3,2-cd]indazole-7a-carboxylate
(5v).
General procedure II was used and the product was
isolated in 64% (72.3 mg) and 45% (51.0 mg) yield in
duplicate trials. The average of 55% is reported. H NMR
General procedure II was used and the product was
isolated in 62% (74.3 mg) and 47% (58.1 mg) yield in
duplicate trials. The average of 55% is reported. H NMR
3
4
5
1
1
(400 MHz, CDCl3): δ 7.81 (s, 1H), 7.66 (s, 2H), 3.83 (d, J =
12.1 Hz, 1H), 3.67 (s, 3H), 3.41 (d, J = 12.1 Hz, 1H), 3.28 (d, J
= 12.0 Hz, 1H), 2.99 (dd, J = 12.0, 7.1 Hz, 1H), 2.64 (d, J = 7.0
Hz, 1H), 1.88 (s, 3H), 1.58 (br, 1H). 13C{1H} NMR (101 MHz,
CDCl3): δ 169.2, 147.0, 131.9 (q, JC-F = 33.5 Hz), 125.5 (m),
123.1 (q, JC-F = 273.9 Hz), 121.4 (sept, JC-F = 3.9 Hz), 109.3,
97.1, 55.1, 52.9, 51.2, 50.2, 22.2. 19F{1H} NMR (376 MHz,
CDCl3): -62.9. IR (NaCl, thin film, cm-1): 3323, 2957, 2848,
1739, 1375, 1279, 1182, 1135. HRMS (ESI-TOF) m/z [M +
(400 MHz, CD3CN): δ 7.13 (br, 4H), 3.90 (d, J = 11.4 Hz, 1H),
3.44 (s, 3H), 3.44 – 3.36 (m, 1H), 3.21 (d, J = 11.5 Hz, 1H),
3.05 – 2.96 (m, 1H), 2.85 (d, J = 8.2 Hz, 1H), 2.30 (s, 3H), 2.17
(br, 1H), 2.01 – 1.89 (m, 1H), 1.81 – 1.70 (m, 1H), 1.63 (tt, J
= 14.0, 4.0 Hz, 1H), 1.58 – 1.47 (m, 1H), 1.38 – 1.25 (m, 1H).
13C{1H} NMR (101 MHz, CD3CN): δ 169.1, 142.5, 136.5,
128.8, 125.0, 108.4, 95.9, 56.8, 53.3, 51.8, 46.4, 36.5, 25.9,
20.0, 15.9. IR (NaCl, thin film, cm-1): 2931, 2861, 1736,
1433, 1287, 1212. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for
C17H21N3NaO2+ 322.1526; Found 322.1528.
6
7
8
9
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
Na]+ Calcd for C16H15F6N3NaO2+ 418.0961; Found 418.0949.
H
N
CO2Me
N
CO2Me
N
NH
N
NH
H
H
E
5t
E = CO2Et
5w
Methyl (3aS,6aS)-3a-phenyl-3a,4,5,6-tetrahydropyrrolo[3,4-
c]pyrazole-6a(1H)-carboxylate (5t).
2a1-Ethyl 7a-methyl (2aS,2a1S,5aR,7aS)-3,4,5,5a,6,7-
hexahydro-2a1H-pyrrolo[4,3,2-cd]indazole-2a1,7a(2aH)-
dicarboxylate (5w).
General procedure II was used and the product was
isolated in 67% (80.6 mg) and 60% (79.7 mg) yield in
1
duplicate trials. The average of 64% is reported. H NMR
General procedure I was used with minor modifications.
The reaction time was 48 h and column chromatography
was performed with IPA in hexanes with 1% TEA, gradient
elution 10 - 60%. The product was isolated in 45% (60.2
mg) and 39% (51.9 mg) yield in duplicate trials. The average
of 42% is reported. 1H NMR (500 MHz, CDCl3): δ 4.91 (dd,
J = 6.2, 2.1 Hz, 1H), 4.15 – 4.08 (m, 2H), 3.90 (d, J = 12.7 Hz,
1H), 3.69 (s, 3H), 3.52 (d, J = 12.7 Hz, 1H), 3.46 (d, J = 4.1 Hz,
1H), 3.00 (d, J = 14.5 Hz, 1H), 1.93 (tdd, J = 14.3, 6.2, 3.7 Hz,
1H), 1.86 (d, J = 14.1 Hz, 1H), 1.61 – 1.49 (m, 2H), 1.22 (t, J =
7.2 Hz, 3H), 1.19 – 1.07 (m, 1H). 13C{1H} NMR (126 MHz,
CDCl3): δ 171.6, 166.4, 111.7, 89.5, 62.3, 61.9, 57.7, 52.8,
52.4, 25.4, 25.1, 14.8, 14.1. IR (NaCl, thin film, cm-1): 2939,
2854, 1733, 1446, 1269, 1245, 1106, 1050. HRMS (ESI-
(500 MHz, CD2Cl2): δ 7.37 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.3
Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 6.57 (s, 1H), 6.35 (br, 1H),
3.70 (d, J = 12.6 Hz, 1H), 3.55 (d, J = 12.2 Hz, 1H), 3.45 (d, J =
12.6 Hz, 1H), 3.25 (d, J = 12.2 Hz, 1H), 3.17 (s, 3H), 2.32 (br,
1H). 13C{1H} NMR (126 MHz, CD2Cl2): δ 171.8, 147.2, 137.2,
128.3, 127.6, 127.3, 83.9, 75.8, 61.5, 57.3, 51.9. IR (NaCl,
thin film, cm-1): 3315, 2948, 1728, 1446, 1434, 1259, 1069.
+
HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C13H15N3NaO2
268.1056; Found 268.1063.
CO2Me
N
NH
N
H
H
5u
+
TOF) m/z [M + Na]+ Calcd for C13H19N3NaO4 304.1268,
Methyl (2aS,2a1R,5aR,7aS)-2a-phenyl-2a,2a1,3,4,5,5a,6,7-
octahydro-7aH-pyrrolo[4,3,2-cd]indazole-7a-carboxylate
(5u).
found 304.1273.
H
N
CO2Et
NO2
N
General procedure II was used and the product was
isolated in 67% (76.2 mg) and 69% (78.3 mg) yield in
NH
H
5x
1
duplicate trials. The average of 68% is reported. H NMR
Ethyl (3aS,6aS)-3-(2-nitrophenyl)-3a,4,5,6-
(400 MHz, CD2Cl2): δ 7.36 – 7.28 (m, 2H), 7.28 – 7.19 (m,
3H), 4.00 (d, J = 11.8 Hz, 1H), 3.49 – 3.41 (m, 1H), 3.44 (s,
3H), 3.29 (d, J = 11.8 Hz, 1H), 3.18 – 3.09 (m, 1H), 2.86 (d, J
= 8.2 Hz, 1H), 1.97 (ddd, J = 14.6, 13.6, 3.6 Hz, 1H), 1.91 –
1.83 (m, 1H), 1.71 – 1.56 (m, 2H), 1.49 – 1.40 (m, 1H), 1.35
– 1.21 (m, 1H). 13C{1H} NMR (101 MHz, CD2Cl2): δ 169.0,
145.3, 128.2, 126.8, 125.0, 108.8, 96.2, 57.1, 53.6, 52.1, 47.1,
36.8, 26.1, 16.0. IR (NaCl, thin film, cm-1): 3336, 2934,
2861, 1735, 1445, 1433, 1286, 1212. HRMS (ESI-TOF) m/z
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5x).
General procedure I was used with minor modifications.
The reaction was concentrated and purified directly (no
TFA equilibration was necessary). The product was isolated
in 93% (98.0 mg) and 95% (109 mg) yield in duplicate
trials. The average of 94% is reported. 1H NMR (500 MHz,
CDCl3): δ 7.80 (d, J = 8.1 Hz, 1H), 7.60 (apparent t, J = 7.6 Hz,
1H), 7.53 – 7.45 (m, 2H), 6.72 (br, 1H), 4.31 (q, J = 7.1 Hz,
2H), 4.16 (dd, J = 8.1, 2.2 Hz, 1H), 3.31 (d, J = 12.1 Hz, 1H),
3.23 (d, J = 12.5 Hz, 1H), 3.16 – 3.08 (m, 2H), 2.21 (br, 1H),
1.34 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ
173.1, 149.8, 149.0, 132.5, 130.0, 129.6, 126.8, 124.4, 81.6,
62.3, 61.5, 60.1, 54.1, 14.3. IR (NaCl, thin film, cm-1): 3329,
2982, 2873, 1726, 1529, 1349, 1267, 1214. HRMS (ESI-
+
[M + Na]+ Calcd for C16H19N3NaO2 308.1369; Found
308.1370.
CO2Me
N
NH
N
H
H
Me
5v
+
TOF) m/z [M + Na]+ Calcd for C14H16N4NaO4 327.1064;
Found 327.1071.
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H
N
132.4, 129.9, 129.5, 128.7, 128.4, 126.8, 126.7, 124.4, 122.1,
CO2tBu
NH
NO2
N
81.5, 66.8, 61.5, 60.1, 54.0. IR (NaCl, thin film, cm-1): 3339,
3027, 2937, 2874, 1728, 1529, 1346, 1264, 1209. HRMS
(ESI-TOF) m/z [M + Na]+ Calcd for C21H20N4NaO4+ 415.1377;
1
2
3
4
5
6
7
8
H
5y
Found 415.1380.
tert-Butyl (3aS,6aS)-3-(2-nitrophenyl)-3a,4,5,6-
H
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5y).
General procedure I was used with minor modifications.
The reaction was concentrated and purified directly (no
TFA equilibration was necessary). The product was isolated
in 85% (90.6 mg) and 89% (95.2 mg) yield in duplicate
trials. The average of 87% is reported. 1H NMR (500 MHz,
CDCl3): δ 7.82 (d, J = 8.0 Hz, 1H), 7.59 (apparent t, J = 7.6 Hz,
1H), 7.51 – 7.45 (m, 2H), 6.66 (br, 1H), 4.08 (dd, J = 8.1, 2.2
Hz, 1H), 3.27 (d, J = 12.0 Hz, 1H), 3.18 (d, J = 12.4 Hz, 1H),
3.12 – 3.05 (m, 2H), 2.16 (br, 1H), 1.52 (s, 9H). 13C{1H} NMR
(126 MHz, CDCl3): δ 172.2, 150.1, 148.9, 132.6, 130.2,
129.6, 127.1, 124.5, 83.3, 82.2, 61.4, 60.1, 54.1, 28.1. IR
(NaCl, thin film, cm-1): 3329, 2979, 2934, 2873, 1722,
1530, 1369, 1347, 1284, 1259, 1159. HRMS (ESI-TOF) m/z
CO2Me
N
NO2
N
Me
NH
H
5bb
Methyl (3aS,6S,6aS)-6-methyl-3-(2-nitrophenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate
(5bb).
9
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
General procedure I was used with minor modifications.
The reaction time was 5 days and the reaction was
concentrated and purified directly (no TFA equilibration
was necessary). The product was isolated in 83% (53.1 mg)
and 90% (79.9 mg) yield in duplicate trials with a 3.2:1 dr.
The average of 87% is reported. 1H NMR (500 MHz, CDCl3):
δ 7.82 (d, J = 8.3 Hz, 1H), 7.61 (apparent t, J = 7.6 Hz, 1H),
7.54 – 7.48 (m, 2H), 6.47 (br, 1H), 4.21 (t, J = 5.1 Hz, 1H),
3.87 (s, 3H), 3.40 (q, J = 6.5 Hz, 1H), 3.18 (d, J = 5.1 Hz, 2H),
+
[M + Na]+ Calcd for C16H20N4NaO4 355.1377; Found
355.1372.
1
H
N
2.02 (br, 1H), 1.23 (d, J = 6.4 Hz, 3H). H NMR (500 MHz,
CO2Bn
NH
NO2
N
CDCl3) Minor diastereomer: δ 7.80 (d, J = 8.0 Hz, 1H), 7.61
(apparent t, J = 7.6 Hz, 1H), 7.55 – 7.48 (m, 2H), 6.67 (br, 1H),
4.32 (dd, J = 8.5, 4.1 Hz, 1H), 3.86 (s, 3H), 3.47 – 3.38 (m, 2H),
3.05 (dd, J = 12.5, 4.2 Hz, 1H), 1.16 (d, J = 6.9 Hz, 3H). 13C{1H}
NMR (126 MHz, CDCl3): δ 173.7, 150.3, 148.8, 132.3, 129.9,
129.5, 126.5, 124.3, 83.4, 65.8, 60.4, 53.1, 52.7, 13.3. IR
(NaCl, thin film, cm-1): 3348, 2955, 2882, 1731, 1531,
1435, 1378, 1355, 1274, 1208. HRMS (ESI-TOF) m/z [M +
H
5z
Benzyl (3aS,6aS)-3-(2-nitrophenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5z).
General procedure I was used with minor modifications.
The reaction was concentrated and purified directly (no
TFA equilibration was necessary). The product was isolated
in 91% (123 mg) and 96% (124 mg) yield in duplicate trials.
The average of 94% is reported. 1H NMR (500 MHz, CDCl3):
δ 7.80 (d, J = 8.0 Hz, 1H), 7.60 (apparent t, J = 7.6 Hz, 1H),
7.49 (apparent t, J = 8.7 Hz, 2H), 7.43 – 7.34 (m, 5H), 6.75
(br, 1H), 5.28 (s, 2H), 4.20 (dd, J = 8.1, 2.1 Hz, 1H), 3.32 (d, J
= 12.1 Hz, 1H), 3.23 (d, J = 12.5 Hz, 1H), 3.17 (d, J = 12.1 Hz,
1H), 3.12 (dd, J = 12.5, 8.0 Hz, 1H), 2.24 (br, 1H). 13C{1H}
NMR (126 MHz, CDCl3): δ 173.0, 149.6, 149.0, 135.1, 132.4,
130.0, 129.6, 128.84, 128.75, 128.4, 126.7, 124.4, 81.5, 67.9,
61.5, 60.2, 54.1. IR (NaCl, thin film, cm-1): 3329, 2936,
2874, 1729, 1530, 1347, 1267, 1213. HRMS (ESI-TOF) m/z
Na]+ Calcd for C14H16N4NaO4+ 327.1064; Found 327.1068.
H
N
CO2Bn
Me
NO2
N
NH
H
5cc
Benzyl (3aS,6S,6aS)-6-methyl-3-(2-nitrophenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (5cc).
General procedure I was used with minor modifications.
The reaction time was 5 days and the reaction was
concentrated and purified directly (no TFA equilibration
was necessary). The product was isolated in 83% (70.6 mg)
and 76% (66.6 mg) yield in duplicate trials with a 3.8:1 dr.
The average of 80% is reported. 1H NMR (500 MHz, CDCl3):
δ 7.82 (d, J = 8.0 Hz, 1H), 7.61 (apparent t, J = 7.6 Hz, 1H),
7.53 – 7.47 (m, 2H), 7.45 – 7.35 (m, 5H), 6.49 (br, 1H), 5.29
(s, 2H), 4.23 (t, J = 5.1 Hz, 1H), 3.41 (q, J = 6.4 Hz, 1H), 3.17
(d, J = 5.1 Hz, 2H), 2.06 (br, 1H), 1.20 (d, J = 6.8 Hz, 3H).
1H{1H} NMR (400 MHz, CDCl3) minor diastereomer: δ
7.79 (d, J = 7.9 Hz, 1H), 7.64 – 7.56 (m, 1H), 7.54 – 7.48 (m,
2H), 7.43 – 7.36 (m, 5H), 6.69 (br, 1H), 5.27 (d, J = 12.0 Hz,
1H), 5.26 (d, J = 12.0 Hz, 1H), 4.33 (dd, J = 8.4, 4.1 Hz, 1H),
3.47 – 3.35 (m, 2H), 3.03 (dd, J = 12.5, 4.1 Hz, 1H), 1.08 (d, J
= 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 173.1, 150.3,
148.8, 135.1, 132.4, 129.9, 129.5, 128.8, 128.7, 128.3, 126.5,
124.4, 83.4, 67.8, 65.8, 60.4, 52.6, 13.3. IR (NaCl, thin film,
cm-1): 3342, 2970, 2878, 1727, 1533, 1377, 1353, 1266,
[M + Na]+ Calcd for C19H18N4NaO4 389.1220; Found
+
389.1228.
O
Ph
H
N
N
NO2
O
NH
H
5aa
Cinnamyl (3aS,6aS)-3-(2-nitrophenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate
(5aa).
General procedure I was used with minor modifications.
The reaction was concentrated and purified directly (no
TFA equilibration was necessary). The product was isolated
in 83% (75.3 mg) and 72% (59.6 mg) yield in duplicate
trials. The average of 78% is reported. 1H NMR (500 MHz,
CDCl3): δ 7.82 (d, J = 8.0 Hz, 1H), 7.61 (apparent t, J = 7.6 Hz,
1H), 7.54 – 7.48 (m, 2H), 7.44 (d, J = 7.7 Hz, 2H), 7.36
(apparent t, J = 7.5 Hz, 2H), 7.32 – 7.27 (m, 1H), 6.76 – 6.70
(m, 2H), 6.34 (dt, J = 15.9, 6.6 Hz, 1H), 4.92 (d, J = 6.6 Hz, 2H),
4.22 (d, J = 7.6 Hz, 1H), 3.36 (d, J = 12.1 Hz, 1H), 3.26 (d, J =
12.5 Hz, 1H), 3.23 – 3.12 (m, 2H), 2.23 (br, 1H). 13C{1H} NMR
(101 MHz, CDCl3): δ 172.9, 149.7, 148.9, 135.9, 135.5,
1203. HRMS (ESI-TOF) m/z [M
+
Na]+ Calcd for
C20H20N4NaO4+ 403.1377; Found 403.1375.
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The Journal of Organic Chemistry
Page 14 of 18
COMe
H
148.4, 147.8, 144.5, 133.7, 131.8, 131.5, 130.3, 130.0, 128.0,
NO2
N
N
COMe
N
COMe
N
NO2
N
NO2
N
DMAP
(0.5 equiv)
1
2
5 equiv
rt, 24 h
126.7, 124.8, 81.7, 57.3, 56.7, 51.3, 25.5, 21.6. IR (NaCl, thin
N3
H
H
film, cm-1): 3334, 2292, 2868, 1712, 1529, 1345, 1163.
HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C20H20N4NaO5S+
O
O
1b
(1 equiv)
4dd
4dd'
3
4
5
6
7
8
9
Me
Me
451.1047; Found 451.1036.
4-((3aS,6aS)-6a-acetyl-3-(2-nitrophenyl)-3a,4,6,6a-
tetrahydropyrrolo[3,4-c]pyrazol-5(1H)-yl)butan-2-one
(4dd).
H
CONH2
N
NO2
N
NH
H
A 4 mL vial was charged with azide 1b (61.3 mg, 0.300
mmol) and methyl vinyl ketone (0.13 mL, 1.6 mmol). The
vial was sealed with a Teflon lined cap and the reaction was
stirred at ambient temperature. After 24 h, excess methyl
vinyl ketone was removed under reduced pressure (<15
torr). The resulting oil was directly purified by column
chromatography (EtOAc in hexanes, gradient elution 0 -
80%), which afforded compound 4dd’ as a yellow oil.
Compound 4dd’ was isolated in 95% (98.4 mg) and 79%
(81.7 mg) in duplicate trials. The average of 87% is
reported. Compound 4dd’ tends to gradually tautomerize to
compound 4dd at ambient temperature. Pure 4dd can be
synthesized using the procedure above with minor
modifications. The crude 4dd’ was reconstituted in a 20 mL
vial with DCM (2 mL), and DMAP (18 mg, 0.15 mmol) was
added. The vial was sealed with a Teflon lined cap and the
reaction was stirred at ambient temperature. After 16 h, the
solvent was removed under reduced pressure. Purification
by column chromatography (IPA in DCM with 1% TEA,
gradient elution 0 - 10%) afforded 4dd as a yellow oil (37.7
5ee
(3aS,6aS)-3-(2-Nitrophenyl)-3a,4,5,6-tetrahydropyrrolo[3,4-
c]pyrazole-6a(1H)-carboxamide (5ee).
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
General procedure I was used with minor modifications.
During the reaction, the product precipitated as a yellow
solid. The solid was purified by recrystallization in
MeOH:DCM:hexanes (1:2:10) and the product was isolated
in 75% (82.5 mg) and 68% (69.6 mg) in duplicate trials. The
average of 72% is reported. 1H NMR (500 MHz, DMSO): δ
7.77 (d, J = 8.0 Hz, 1H), 7.68 – 7.65 (m, 2H), 7.62 (br, 1H),
7.57 – 7.51 (m, 1H), 7.41 (br, 2H), 4.03 (d, J = 7.4 Hz, 1H),
3.12 (d, J = 11.9 Hz, 1H), 3.07 – 2.98 (m, 2H), 2.88 (d, J = 11.9
Hz, 1H), 2.28 (br, 1H). 13C{1H} NMR (126 MHz, DMSO): δ
175.4, 149.1, 145.8, 132.4, 129.9, 129.4, 125.5, 124.1, 79.9,
61.2, 59.8, 54.2. IR (NaCl, thin film, cm-1): 3289, 3189,
1630, 1526, 1420, 1356. HRMS (ESI-TOF) m/z [M + Na]+
Calcd for C12H13N5NaO3+ 298.0911; Found 298.0921.
H
N
CN
NO2
N
NH
H
mg, 38%), along with recovered unreacted 4dd’.
5ff
H
N
COMe
NO2
N
(3aS,6aS)-3-(2-Nitrophenyl)-3a,4,5,6-tetrahydropyrrolo[3,4-
c]pyrazole-6a(1H)-carbonitrile (5ff).
N
H
General procedure II was used with minor modifications.
Both parts of the reaction were heated at 40 oC for 24 h. The
product was purified by recrystallization (EtOAc/hexanes).
The product was isolated in 68% (66.3 mg) and 72% (64.4
mg) yield in duplicate trials. The average of 70% is reported.
1H NMR (500 MHz, DMSO-d6): δ 8.36 (br, 1H), 7.85 (d, J =
8.0 Hz, 1H), 7.75 – 7.66 (m, 2H), 7.62 – 7.56 (m, 1H), 4.48
(dd, J = 7.9, 2.5 Hz, 1H), 3.30 (d, J = 12.2 Hz, 1H), 3.18 – 3.07
(m, 2H), 2.96 (d, J = 12.1 Hz, 1H), 2.68 (br, 1H). 13C{1H} NMR
(126 MHz, DMSO-d6): δ 148.9, 146.5, 132.7, 130.3, 130.1,
124.7, 124.3, 120.8, 67.7, 61.7, 61.4, 53.5. IR (NaCl, thin
film, cm-1): 3320, 2926, 2237, 1529, 1345. HRMS (ESI-
O
4dd
Me
1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.2 Hz, 1H), 7.65
(t, J = 7.6 Hz, 1H), 7.58 – 7.50 (m, 2H), 6.50 (br, 1H), 4.02 (dd,
J = 7.5, 3.7 Hz, 1H), 3.02 (d, J = 10.0 Hz, 1H), 2.91 (d, J = 10.0
Hz, 1H), 2.86 – 2.70 (m, 3H), 2.70 – 2.64 (m, 1H), 2.60 (t, J =
7.1 Hz, 2H), 2.37 (s, 3H), 2.16 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 207.3, 206.2, 149.6, 148.1, 133.0, 131.2,
129.7, 127.2, 124.5, 82.2, 64.3, 57.6, 56.3, 49.0, 42.7, 29.9,
25.3. IR (NaCl, thin film, cm-1): 3328, 2913, 2807, 1710,
1529, 1354. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for
C17H20N4NaO4+ 367.1377; Found 367.1374.
TOF) m/z [M + Na]+ Calcd for C12H11N5NaO2 280.0805;
+
H
N
COMe
NO2
N
Found 280.0816.
O
H
OEt
OEt
N
P
O
N
O
NO2
N
H
S
5dd
NH
H
5gg
Me
Diethyl ((3aR,6aR)-3-(2-nitrophenyl)-3a,4,5,6-tetrahydro-
pyrrolo[3,4-c]pyrazol-6a(1H)-yl)phosphonate (5gg).
General procedure I was used and the product was
isolated in 38% (56.4 mg) and 42% (62.0 mg) yield in
1-((3aS,6aS)-3-(2-Nitrophenyl)-5-tosyl-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazol-6a(1H)-yl)ethan-1-one
(5dd).
General procedure III was used with minor modification.
DMAP was used to replace DIPEA. The product was isolated
in 49% (62.0 mg) and 66% (90.4 mg) in duplicate trials. The
1
duplicate trials. The average of 40% is reported. H NMR
(500 MHz, CDCl3): δ 7.78 (d, J = 8.1 Hz, 1H), 7.61 (apparent
t, J = 7.6 Hz, 1H), 7.53 – 7.48 (m, 2H), 6.18 (d, J = 7.3 Hz, 1H),
4.34 – 4.17 (m, 5H), 3.31 (dd, J = 12.7, 6.0 Hz, 1H), 3.24 (dd,
J = 12.6, 3.4 Hz, 1H), 3.16 (d, J = 12.4 Hz, 1H), 3.03 (dd, J =
12.5, 7.6 Hz, 1H), 2.09 (br, 1H), 1.36 (t, J = 7.1 Hz, 6H).
13C{1H} NMR (126 MHz, CDCl3): δ 149.1, 148.2 (d, JC-P = 7.3
Hz), 132.2, 129.8, 129.4, 126.3, 124.3, 74.6 (d, JC-P = 159.7
Hz), 63.4 (d, JC-P = 7.0 Hz), 62.9 (d, JC-P = 7.3 Hz), 59.4 (d, JC-P
1
average of 58% is reported. H NMR (400 MHz, CDCl3): δ
8.04 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 8.2
Hz, 2H), 7.63 – 7.55 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.41 (br,
1H), 4.06 (dd, J = 7.8, 3.3 Hz, 1H), 3.62 (d, J = 10.6 Hz, 1H),
3.62 (d, J = 10.6 Hz, 1H), 3.50 (d, J = 10.7 Hz, 1H), 3.32 (dd, J
= 10.1, 3,4 Hz, 1H), 3.10 (dd, J = 10.1, 7.7 Hz, 1H), 2.46 (s,
3H), 2.40 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 205.0,
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The Journal of Organic Chemistry
= 13.8 Hz), 58.2, 53.7 (d, JC-P = 13.6 Hz), 16.6 (d, JC-P = 5.5 Hz),
129.1, 127.9, 127.6, 126.8, 126.3, 124.3, 75.9, 73.4, 58.4,
16.5 (d, JC-P = 5.6 Hz). 31P{1H} NMR (162 MHz, CDCl3): δ
23.3. IR (NaCl, thin film, cm-1): 3245, 2979, 2928, 2873,
1532, 1236, 1048. HRMS (ESI-TOF) m/z [M + Na]+ Calcd
54.2, 53.0, 50.4. IR (NaCl, thin film, cm-1): 3349, 2057,
1
2
3
4
5
6
7
8
2952, 2831, 1736, 1595, 1530, 1448, 1264, 1071, 738.
+
HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C32H28N4NaO4
for C15H21N4NaO5P+ 391.1142; Found 391.1141.
555.2003; Found 555.2018.
H
N
H
N
N
CO2Me
N
CO2Me
CO2Me
NO2
N
NO2
N
NO2
N
N
N
H
H
H
OtBu
Ph
Ph
Ph
Ph
9a
9c'
9c
O
Ph
Ph
Note:
5-(tert-Butyl) 6a-methyl (3aS,6aS)-3-(2-nitrophenyl)-3a,4-
dihydropyrrolo[3,4-c]pyrazole-5,6a(1H,6H)-dicarboxylate
(9a).
The trityl protected product was isolated as a mixture of the
unconjugated (9c’) and conjugated (9c) isomers. To
determine how to convert the mixture into a single isomer,
a stock solution of the 9c’/9c mixture (45.2 mg, 84.6 µmol)
and 1,3,5-trimethoxybenzene (6.4 mg, 38 µmol) in CDCl3
(2.1 mL) was divided into three portions. TFA (6.5 µL, 38
µmol) was added to one portion, DBU (2.1 µL, 6.4 µmol) was
added to the second portion, and the third was left with no
additive. The three samples were analyzed by 1H NMR after
0.5 and 18 h. After 18 h, the samples containing TFA or DBU
had fully converted to the conjugated tautomer (6d).
Table 7. Tautomerization with TFA and DBU
9
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
General procedure III was used and the product was
isolated in 80% (92.9 mg) as a single tautomer. 1H NMR
(400 MHz, CD3CN): 7.80 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.6
Hz, 1H), 7.62 – 7.54 (m, 2H), 7.05 (br, 1H), 4.28 (dd, J = 8.9,
4.4 Hz, 1H), 3.88 – 3.78 (m, 2H), 3.80 (s, 3H), 3.72 – 3.65 (m,
1H), 3.60 – 3.52 (m, 1H), 1.43 (s, 9H). 13C{1H} NMR (101
MHz, CD3CN): 171.8, 153.6, 148.8, 147.9, 132.4, 130.0,
129.7, 125.2, 124.0, 79.5, 55.9 (br, tentatively assigned as
2C), 52.7, 51.4, 49.3, 27.5. IR (NaCl, thin film, cm-1): 3345,
2979, 2870, 1737, 1693, 1530, 1400, 1367. HRMS (ESI-
Additive (equiv) Time (h) 9c’:9c
+
TOF) m/z [M + Na]+ Calcd for C18H22N4NaO6 413.1432;
None
None
TFA (3)
TFA (3)
DBU (0.5)
DBU (0.5)
0.5
18
0.5
18
0.5
18
55:45
55:45
43:57
0:100
22:78
0:100
Found 413.1424.
H
N
CO2Me
NO2
N
O
N
H
S
9b
O
H
N
CO2Me
NO2
N
Me
Methyl (3aS,6aS)-3-(2-nitrophenyl)-5-tosyl-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (9b).
N
H
Ph
9d
General procedure III was used with R-X
= 4-
Methyl (3aS,6aS)-5-benzyl-3-(2-nitrophenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (9d).
General procedure III was used with R-X = benzyl
chloroformate (CbzCl). Product 9d was isolated in 81%
(93.4 mg) as a single tautomer. 1H NMR (400 MHz, CDCl3):
δ 7.86 (d, J = 8.1 Hz, 1H), 7.62 – 7.54 (m, 1H), 7.53 – 7.45 (m,
2H), 7.40 – 7.31 (m, 3H), 7.29 (d, J = 6.8 Hz, 1H), 7.27 – 7.21
(m, 1H), 6.61 (br, 1H), 4.22 (dd, J = 7.6, 2.5 Hz, 1H), 3.85 (s,
3H), 3.77 (d, J = 13.2 Hz, 1H), 3.59 (d, J = 13.2 Hz, 1H), 3.21
(d, J = 9.5 Hz, 1H), 2.91 – 2.81 (m, 2H), 2.62 (d, J = 9.5, 7.7 Hz,
1H). 13C{1H} NMR (101 MHz, CDCl3): δ 172.9, 150.0, 148.2,
138.2, 132.6, 130.9, 129.5, 128.5, 128.3, 127.2, 127.0, 124.3,
77.1, 65.9, 58.6, 57.0, 56.6, 53.1. IR (NaCl, thin film, cm-1):
3345, 2956, 2804, 1734, 1532, 1347, 1275, 1227. HRMS
(ESI-TOF) m/z [M + Na]+ Calcd for C20H20N4NaO4+ 403.1377;
Found 403.1373.
toluenesulfonyl chloride (TsCl). Product 9b was isolated in
74% (126.7 mg) and 69% (91.6 mg) yield in duplicate trials.
The average of 72% is reported. 1H NMR (400 MHz, CDCl3):
δ 7.93 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.65 (t, J =
7.6 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H),
7.34 (d, J = 8.0 Hz, 2H), 6.64 (br, 1H), 4.21 (dd, J = 8.3, 3.9 Hz,
1H), 3.82 (s, 3H), 3.74 (d, J = 10.2 Hz, 1H), 3.46 (d, J = 10.3
Hz, 1H), 3.37 (dd, J = 10.0, 3.9 Hz, 1H), 3.29 (dd, J = 10.1, 8.3
Hz, 1H), 2.45 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
171.2, 148.8, 147.9, 144.3, 133.2, 132.2, 131.2, 130.1, 129.9,
127.9, 126.3, 124.6, 77.8, 58.7, 56.0, 53.6, 51.3, 21.6. IR
(NaCl, thin film, cm-1): 3332, 2956, 2857, 1738, 1530,
1346, 1164. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for
C20H20N4NaO6S+ 467.0996; Found 467.1000.
H
N
CO2Me
NO2
N
H
N
H
N
CO2Me
CO2Me
NO2
N
NH2
N
N
H
Ph
Ph
H2, Pd/C
MeOH
9c
Ph
NH
NH
H
H
Methyl (3aS,6aS)-3-(2-nitrophenyl)-5-trityl-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (9c).
General procedure III was used and with R-X
5b
10
Methyl (3aS,6aS)-3-(2-aminophenyl)-3a,4,5,6-
=
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (10).
A vial was sequentially charged with compound 5b (61 mg,
0.21 mmol), MeOH (1 mL), and Pd/C (6 mg, 10 wt. % Pd).
The vial was sealed with a septum and purged with
hydrogen gas using a hydrogen balloon without stirring.
After 10 min, the vial was equipped with 2 hydrogen
balloons under ambient pressure. After 4 h, the reaction
was filtered through a short plug of silica gel and rinsed
with MeOH (5 mL). The solvent was removed under
triphenylmethyl chloride (TrCl). Product 9c was isolated in
88% (140.7 mg) as a tautomeric mixture 9c’:9c = 1.5:1. 1H
NMR (500 MHz, CDCl3): δ 7.84 (d, J = 8.1 Hz, 1H), 7.76 (d, J
= 7.7 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.55 – 7.46 (m, 7H),
7.28 – 7.21 (m, 6H), 7.19 – 7.14 (m, 3H), 6.76 (br, 1H), 4.02
(d, J = 7.2 Hz, 1H), 3.75 (s, 3H), 3.44 (d, J = 9.4 Hz, 1H), 3.05
(d, J = 9.6 Hz, 1H), 2.09 – 2.00 (m, 2H). 13C{1H} NMR (126
MHz, CDCl3): δ 172.6, 149.3, 148.5, 132.3, 130.6, 129.3,
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reduced pressure. This procedure afforded the product 10 (160 mg, 1.16 mmol) and benzyl bromide (55 µL, 0.46
in 100% (54 mg) as a yellow oil. 1H NMR (500 MHz,
CD2Cl2): δ 7.17 – 7.06 (m, 2H), 6.76 – 6.66 (m, 2H), 5.89 (br,
1H), 4.29 (d, J = 8.3 Hz, 1H), 3.81 (s, 3H), 3.43 – 3.30 (m, 2H),
3.29 (d, J = 12.0 Hz, 1H), 3.22 (d, J = 12.0 Hz, 1H). 13C{1H}
NMR (126 MHz, CD2Cl2): δ 174.2, 155.8, 147.3, 129.4,
128.8, 116.1, 115.6, 113.2, 79.6, 61.0, 59.8, 55.0, 52.8. IR
(NaCl, thin film, cm-1): 3449, 3314, 2948, 1730, 1613,
1495, 1453, 1267, 1124. HRMS (ESI-TOF) m/z [M + Na]+
Calcd for C13H16N4NaO2+ 283.1165; Found 283.1149.
mmol) were added consecutively. The vial was sealed with
a Teflon lined cap and the reaction was heated to 55˚C. After
16 h, the reaction was diluted with water (5 mL). The
resulting solution was extracted with EtOAc (3 x 20 mL).
The combined organic phases were dried (Na2SO4) and
concentrated under reduced pressure. Purification by
column chromatography (EtOAc in hexanes, gradient
elution 0 - 70%) afforded compound 9d as a yellow oil (104
1
2
3
4
5
6
7
8
1
mg, 72%). The material obtained provided an identical H
9
H
N
H
N
NMR spectra above.
CO2Me
NO2
N
NO2
N
OH
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
H
N
H
N
F
Cl
CO2Me
NH
CO2Me
N
NaBH4
MeOH
NO2
N
NO2
N
NH
NH
N
H
H
5b
11
H
H
DIPEA
Cl
5b
13
((3aS,6aS)-3-(2-Nitrophenyl)-3a,4,5,6-
N
tetrahydropyrrolo[3,4-c]pyrazol-6a(1H)-yl)methanol (11)
To a solution of compound 5b (48.6 mg, 0.168 mmol) in
MeOH (2 mL), NaBH4 (28.4 mg, 0.751 mmol) was added. The
reaction was sealed under air and heated to 60 ˚C. After 1 h,
additional NaBH4 (20.6 mg, 0.545 mmol) was added. After 1
h, the reaction was quenched by the addition of H2O and
brine. The reaction mixture was extracted with EtOAc (6 x
20 mL). The combined organic phases were dried (Na2SO4)
and concentrated under reduced pressure to afford
compound 11 (34.5 mg, 79%). 1H NMR (500 MHz, CDCl3):
δ 7.80 (d, J = 8.1 Hz, 1H), 7.61 (apparent t, J = 7.6 Hz, 1H),
7.54 – 7.47 (m, 2H), 5.99 (br, 1H), 3.80 (s, 2H), 3.74 (d, J =
7.7 Hz, 1H), 3.19 (d, J = 12.3 Hz, 1H), 3.13 (d, J = 12.2 Hz, 1H),
3.04 (dd, J = 12.4, 7.7 Hz, 1H), 2.89 (d, J = 12.3 Hz, 1H), 2.57
(br, 1H). 13C{1H} NMR (126 MHz, MeOD): δ 149.0, 148.8,
132.1, 129.8, 129.1, 126.8, 123.9, 79.4, 63.5, 57.0, 55.6, 51.6.
IR (NaCl, thin film, cm-1): 3290, 2921, 2868, 1528, 1347.
Methyl (3aS,6aS)-5-(2-chloropyridin-4-yl)-3-(2-
nitrophenyl)-3a,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-
6a(1H)-carboxylate (13).
To a solution of compound 5b (61.0 mg, 0.210 mmol) in
DMF (0.5 mL), was added DIPEA (75 µL, 0.42 mmol) and 2-
chloro-4-fluoropyridine (76.8 mg, 0.586 mmol). The
reaction was sealed under air and heated to 80 ˚C. After 16
h, the reaction was cooled to rt and diluted with H2O. The
reaction mixture was extracted with Et2O. The combined
organic phases were washed with H2O, brine, dried
(Na2SO4), and concentrated under reduced pressure. Final
purification by column chromatography (EtOAc in hexanes
with 1% TEA, gradient elution 10 - 65%) afforded
compound 13 (65.9 mg, 78%). 1H NMR (500 MHz, CDCl3):
δ 7.99 (d, J = 5.9 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.68
(apparent t, J = 7.5 Hz, 1H), 7.61 – 7.55 (m, 2H), 6.94 (s, 1H),
6.38 (s, 1H), 6.30 (d, J = 5.9 Hz, 1H), 4.39 (dd, J = 9.5, 5.7 Hz,
1H), 3.92 (s, 3H), 3.86 (s, 2H), 3.71 (t, J = 9.7 Hz, 1H), 3.47
(dd, J = 10.1, 5.7 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ
171.8, 152.9, 152.2, 149.9, 149.3, 148.2, 133.2, 130.7, 130.3,
126.3, 124.7, 107.2, 106.9, 78.8, 57.4, 54.7, 53.7, 51.2. IR
(NaCl, thin film, cm-1): 3337, 2954, 2868, 1736, 1594,
1529, 1498. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for
C18H16ClN5NaO4+ 424.0783; Found 424.0796.
+
HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C12H14N4NaO3
285.0958; Found 285.0956.
H
N
H
N
CO2tBu
CO2H
NH
NO2
N
NO2
N
TFA
NH
H
H
DCM, rt
5y
12
(3aS,6aS)-3-(2-Nitrophenyl)-3a,4,5,6-tetrahydropyrrolo[3,4-
c]pyrazole-6a(1H)-carboxylic acid (12).
To a solution of bicyclic amine 5y (38.7 mg, 0.117 mmol) in
DCM (0.5 mL), TFA (0.5 mL) was added at ambient
H
N
H
N
CO2Me
CO2Me
NO2
N
NO2
N
PivCl
NH
N
H
H
tBu
DIPEA
temperature. After
4 h, the reaction mixture was
5b
14
O
concentrated under reduced pressure to afford the bis-TFA
salt (59.7 mg) in quantitative yield. 1H NMR (500 MHz,
MeOD:TFA 50:1): δ 7.96 (d, J = 8.0 Hz, 1H), 7.75 (apparent
t, J = 7.6 Hz, 1H), 7.70 – 7.63 (m, 2H), 4.51 (dd, J = 9.8, 3.4 Hz,
1H), 3.88 (d, J = 12.0 Hz, 1H), 3.76 (d, J = 12.0 Hz, 1H), 3.71
(dd, J = 12.5, 9.6 Hz, 1H), 3.52 (dd, J = 12.4, 3.6 Hz, 1H).
13C{1H} NMR (126 MHz, MeOD:TFA 50:1): δ 170.9, 148.5,
147.4, 132.7, 130.4, 130.0, 125.2, 124.2, 77.9, 54.8, 54.6,
49.4. IR (NaCl, thin film, cm-1): 3323, 2917, 1779, 1721,
1659, 1519, 1344, 1204, 1160. HRMS (ESI-TOF) m/z [M +
H]+ Calcd for C12H13N4O4+ 277.0931; Found 277.0922.
Methyl (3aS,6aS)-3-(2-nitrophenyl)-5-pivaloyl-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (14).
A 20 mL vial was charged with compound 5b (67.1 mg,
0.231 mmol) and DCM (1 mL). Pivaloyl chloride (57 µL, 0.46
mmol) was added followed by DIPEA (76 µL, 0.46 mmol).
The vial was sealed with a Teflon lined cap and the reaction
was stirred at ambient temperature. After 16 h, the reaction
was quenched by the addition of water (5 mL). The resulting
solution was extracted with DCM (3 x 10 mL). The combined
organic solution was washed with brine, dried (MgSO4),
filtered, and concentrated under reduced pressure.
Purification by column chromatography (EtOAc in hexanes,
gradient elution 0 - 100%) afforded compound 14 as a
yellow solid (75.7 mg, 88%). 1H NMR (400 MHz, CDCl3): δ
7.94 (d, J = 8.2 Hz, 1H), 7.63 (apparent t, J = 7.6 Hz, 1H), 7.59
– 7.50 (m, 2H), 6.75 (br, 1H), 4.21 – 4.15 (m, 1H), 4.19 (d, J =
11.7 Hz, 1H), 3.97 (d, J = 11.8 Hz, 1H), 3.89 (s, 3H), 3.88 –
3.74 (m, 2H), 1.23 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3):
δ 176.4, 171.9, 150.0 (br), 148.1, 133.1, 130.9, 130.0, 126.5,
H
N
H
N
CO2Me
CO2Me
NO2
N
NO2
N
Ph
Br
NH
N
H
H
K2CO3
Ph
5b
9d
Methyl (3aS,6aS)-5-benzyl-3-(2-nitrophenyl)-3a,4,5,6-
tetrahydropyrrolo[3,4-c]pyrazole-6a(1H)-carboxylate (9d).
A 20 mL vial was charged with compound 5b (112 mg,
0.384 mmol) and acetonitrile (9 mL). Potassium carbonate
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The Journal of Organic Chemistry
Award Number R35GM124718. We also acknowledge NIH
124.6, 78.5 (br), 57.2, 54.6, 53.5, 50.6, 38.8, 27.5. IR (NaCl,
thin film, cm-1): 3331, 2529, 2959, 2868, 1738, 1624, 1533,
1141, 1365, 1348, 1276, 1233. HRMS (ESI-TOF) m/z [M +
Na]+ Calcd for C18H22N4NaO5+ 397.1482; Found 397.1464.
O
1
2
3
4
5
6
7
8
Shared Instrumentation Grant #S10OD011952. Both A.S.C. and
E.C.L gratefully acknowledge support from the Wayland E.
Noland Fellowship.
O
H
N
N
CO2Me
N
CO2Me
NO2
N
NO2
N
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To a solution of compound 14 (52.1 mg, 0.139 mmol) in
DMF (0.5 mL), was added K2CO3 (83.2 mg, 0.602 mmol) and
allyl bromide (0.10 mL, 1.6 mmol). The reaction was sealed
under air and heated to 60 ˚C. After 13 h, the reaction was
cooled to rt and diluted with water. The reaction mixture
was extracted with Et2O. The combined organic phases
were washed with water, brine, dried (Na2SO4), and
concentrated under reduced pressure. Final purification by
column chromatography (IPA in hexanes, gradient elution 0
- 15%) afforded compound 15 (44.5 mg, 70%). 1H NMR
(500 MHz, CDCl3): δ 8.18 (d, J = 8.2 Hz, 1H), 7.75 (apparent
t, J = 7.5 Hz, 1H), 7.66 (apparent t, J = 7.9 Hz, 1H), 7.60 (d, J =
7.7 Hz, 1H), 6.01 – 5.91 (m, 1H), 5.38 (d, J = 17.2 Hz, 1H),
5.27 (d, J = 10.5 Hz, 1H), 4.81 (dd, J = 13.3, 5.8 Hz, 1H), 4.77
– 4.67 (m, 2H), 4.37 (d, J = 12.7 Hz, 1H), 4.20 (d, J = 12.2 Hz,
1H), 4.13 (d, J = 8.5 Hz, 1H), 3.91 (s, 3H), 3.52 – 3.40 (m, 1H),
1.26 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3): δ 177.0, 168.8,
153.3, 152.2, 147.6, 134.2, 132.6, 131.8, 131.1, 125.9, 125.2,
119.1, 67.5, 57.2, 55.1, 54.2, 53.6, 49.4, 38.9, 27.6. IR (NaCl,
thin film, cm-1): 2974, 1747, 1704, 1633, 1531, 1435, 1415,
1346, 1277. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for
C22H26N4NaO7+ 481.1694; Found 481.1710.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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Optimization procedures and tables; NMR spectra of all new
compounds; HPLC traces; X-ray data (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
*jtopczew@umn.edu
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Deaton, D. N.; Haffner, C. D.; Henke, B. R.; Jeune, M. R.; Shearer,
B. G.; Stewart, E. L.; Stuart, J. D.; Ulrich, J. C. 2,4-Diamino-8-
Quinazoline Carboxamides as Novel, Potent Inhibitors of the
NAD Hydrolyzing Enzyme CD38: Exploration of the 2-
Position Structure-Activity Relationships. Bioorganic Med.
Chem. 2018, 26, 2107–2150.
Author Contributions
‡These authors contributed equally. All authors have given
approval to the final version of the manuscript.
Notes
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Campos, K. R.; Coleman, P. J.; Alvarez, J. C.; Dreher, S. D.;
Garbaccio, R. M.; Terrett, N. K.; Tillyer, R. D.; Truppo, M. D.;
Parmee, E. R. The Importance of Synthetic Chemistry in the
Pharmaceutical Industry. Science 2019, 363, 244–252.
Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas,
A. W.; Wilson, D. M.; Wood, A. Organic Synthesis Provides
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The authors declare no competing financial interests.
ACKNOWLEDGMENT
Dr. Victor Young Jr. and Ryan Daley are thanked for their
assistance with X-ray crystallography. Duke Ho is thanked for
assistance preparing several known cinnamyl azides. This
research was supported by the National Institute of General
Medical Sciences of the National Institutes of Health under
Quiclet-Sire, B.; Zard, S. Z. Observations on the Reaction of
Hydrazones with Iodine: Interception of the Diazo
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