The Formation of Seven-Membered Heterocycles under Mild Pictet-Spengler Conditions: A Route to Pyrazolo[3,4]benzodiazepines

Article abstract of DOI:10.1021/acs.joc.6b00710

Reported is a method for the synthesis of seven-membered heterocycles via a Pictet-Spengler condensation reaction under very mild conditions. High substrate scope allows for use of aldehydes using catalytic amounts of acetic acid yielding 39-90% and keton

Full text of DOI:10.1021/acs.joc.6b00710

Note
pubs.acs.org/joc
The Formation of Seven-Membered Heterocycles under Mild Pictet−
Spengler Conditions: A Route to Pyrazolo[3,4]benzodiazepines
Timothy A. Katte, Tristan A. Reekie, William T. Jorgensen, and Michael Kassiou*
School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia
*
S Supporting Information
ABSTRACT: Reported is a method for the synthesis of
seven-membered heterocycles via a Pictet−Spengler con-
densation reaction under very mild conditions. High substrate
scope allows for use of aldehydes using catalytic amounts of
acetic acid yielding 39−90% and ketones using catalytic
amounts of trifluoroacetic acid yielding 25−83%.
he Pictet−Spengler reaction was originally reported in
The initial approach was to develop conditions that allowed
for the mild cyclization of compound 2 using the Pictet−
Spengler reaction. The motivation for using compound 2 as the
test substrate was 3-fold: (1) it afforded useful compounds for
1
T
1911 and has found prominence for the synthesis of
many functional molecules. Some important examples include
tetrahydroisoquinolines (THIQs) and tetrahydro-β-carbolines
(
THBCs) comprising the backbones of important pharmaceut-
12
our research into oxytocin and vasopressin antagonism; (2)
icals such as nomifensine and potential anti-alzheimer’s
2
the aniline aromaticity aids the formation of the more
medication. Recent developments have allowed the Pictet−
7
electrophilic iminium ion; and (3) the electron-rich pyrazole
Spengler cyclization to be applied to the synthesis of anticancer
3
4
should favor cyclization, with a related moiety already
molecules and antitubecular-type compounds.
9e
Pictet−Spengler reactions are often utilized in the synthesis
of six-membered rings, and the conditions for the carbon−
carbon bond formation can vary from quite mild to much more
employed in a Pictet−Spengler reaction, making it the ideal
substrate.
The synthetic pathway to obtain compound 2 is shown in
5
trying conditions. Some report the use of acetic acid (AcOH)
Scheme 1. Cyclocondensation of methyl hydrazine with
6
or trifluoroacetic acid (TFA) as the acid catalyst and typically
in a solvent brought to reflux. There are also examples of more
13
substituted acrylate 3 afforded the amino-ester pyrazole 4,
7
which, following saponification and heat promoted decarbox-
unfavorable reactions, such as using superacids to promote the
14
8
ylation, affords aminopyrazole 5. Electrophilic aromatic
reaction. In contrast, there have only been a few reports on the
synthesis of seven-membered rings via a Pictet−Spengler
reaction pathway, and these have required a combination of
strong acids and/or high temperatures to promote the
a
Scheme 1. Synthesis of Pictet−Spengler Starting Material 2
8
b,9b−e
reaction.
Reported within is a synthetic strategy for the
synthesis of seven-membered heterocycles in moderate to high
yields using very mild conditions in comparison to previously
reported methods
Seven-membered heterocycles are an important class of
10
molecules because of their biological utility and have been an
11
area of focus for our group. Our current research is to develop
syntheses of biologically important heterocycles, and as such,
we were interested in developing a simple procedure for the
synthesis of benzodiazepines with substitution at the 8-position
(Figure 1).
a
Reagents and conditions: (i) MeNHNH , EtOH, reflux, 2 h, 85%; (ii)
2
(
(
a) NaOH (3 M), MeOH, reflux, 3 h; (b) 185 °C; 87% over 2 steps;
iii) KO Bu, o-fluoronitrobenzene, THF, 0 °C−RT, 1 h, 75%; (iv) Pd/
t
C, H , EtOAc, RT, 36 h, 99%.
2
Figure 1. Targeted class of benzodiazepine 1 and targeted test
substrate 2.
Received: April 2, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00710
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
substitution with o-fluoronitrobenzene leads to compound 6,
which is then reduced to form the requisite aniline 2.
tested the necessity of the acid for this reaction (entry 2), which
resulted in no reaction. Using TFA in dichloromethane the
reaction proceeded rapidly (under 10 min), so in order to
better understand the influence of the acid, a stronger and
weaker acid were trialed. 50 mol % of hydrochloric acid (3 M in
water) and acetic acid were tested (entries 3 and 4), but little
difference was observed for both yield and reaction rate so we
then explored the catalyst loading as a factor. Using acetic acid
due to its low cost and high availability, we decreased catalyst
loading (entry 5) and found that only using 20 mol % of acetic
acid allows for slightly better yields but a decrease in the
reaction rate of up to approximately 2 h. With the optimized
catalyst loading established, we then attempted optimization of
the reaction using various solvents. Dichloromethane and
acetonitrile showed the highest yields (entries 5 and 6),
although the reaction was faster in acetonitrile (1 h vs 2 h). The
reaction still progressed with comparable yields using toluene,
tetrahydrofuran, and ethanol (entries 6−9). All solvents were
used as bottle reagents without drying, which suggested trace
amounts of water could be tolerated. Furthermore, entry 3
showed that water in greater than trace amounts was well
tolerated, and hence in order to evaluate the other extreme, we
attempted a reaction using water as the solvent (entry 10). No
obvious dissolution of the aniline was observed, however the
reaction still afforded 7a in 74% yield, suggesting an “on water”
reaction. One would expect water to disfavor the reaction by
shifting the equilibrium in favor of the aldehyde and aniline
rather than the requisite imine. This result suggests that the
reactivity of this system is such that the rate-limiting step is
imine formation and that once formed, cyclization occurs
quickly. With optimized conditions of using 20 mol % of acetic
acid in acetonitrile (entry 6), we could then explore the range
of aldehydes this reaction could accommodate (Table 2).
Initially we tested the simplest aldehyde, formaldehyde,
which afforded unsubstituted benzodiazepine 7b. Knowing that
water could be tolerated in this reaction, we were able to use
formaldehyde as a 37% aqueous solution. The synthesis of 7b
With compound 2 in hand, we could then investigate its
ability to undergo a Pictet−Spengler reaction. Benzaldehyde
was chosen as the aldehyde to optimize reaction conditions,
and we were gratified to see with the addition of TFA the
formation of benzodiazepine 7a (Scheme 2, entry 1).
a
Scheme 2. Pictet−Spengler Cyclization Reaction
a
See Table 1 for conditions.
With the success of the reaction we investigated the influence
of solvent and catalyst for this reaction (Table 1). Initially we
a
Table 1. Acid and Solvent Screen
entry
acid
mol %
solvent
CH Cl
yield (%)
1
2
3
4
5
6
7
8
9
TFA
50
−
70
NR
74
73
75
76
68
65
70
74
2
2
−
HCl
CH Cl
2
2
2
2
2
b
50
50
20
20
20
20
20
20
CH Cl
2
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
CH Cl
2
CH Cl
2
MeCN
PhMe
THF
EtOH
10
H O
2
a
b
All reactions were conducted at room temperature. 3 M HCl in
water.
Table 2. Substrate Scope of Aliphatic and Aromatic Aldehydes
B
DOI: 10.1021/acs.joc.6b00710
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The Journal of Organic Chemistry
Note
Table 3. Scope of Ketones Using TFA in Acetonitrile
has been previously reported via intramolecular lactamization
followed by subsequent reduction or reductive amination.
With the success of the aldehydes, we predicted that equal
success could be achieved when employing ketones in the
Pictet−Spengler reaction (Table 3). A similar approach was
taken when determining the substrate scope, starting with the
simplest ketone, acetone, which afforded compound 8a. Using
acetic acid for this transformation resulted in low yields and
long reaction times (32% after 6 h). It was found that a stronger
acid, in this case TFA, was required to affect the desired
transformation and that the reaction was slightly slower than
with aliphatic aldehydes (2 h vs 1 h). However, the acid was still
only required in catalytic quantities, and the reaction
progressed at room temperature. Reaction with butanone
yielded benzodiazepine 8b in equally good yield. In an attempt
to increase steric bulk, isopropyl methyl ketone was used with
TFA to form 8c. In this instance the reaction did not proceed
when using acetic acid after 24 h at room temperature. This
same reaction mixture was heated, and the desired product was
not formed. From this point on we only used TFA for
investigating the scope of the reaction with ketones.
Attempting to increase the steric bulk further, cyclopentyl
methyl ketone and cyclohexyl methyl ketone yielded
compounds 8d and 8e, respectively. Formation of spirocyclic
benzodiazepines 8f and 8g was achieved using cyclopentanone
and cyclohexanone, respectively, although in slightly lower
yields. It was realized that the steric properties of the substrates
were impacting on the reaction yields, as pinacolone (3,3-
dimethyl-2-butanone) only produced compound 8h in 40%
yield. The steric limitation was found when diisopropyl ketone
was attempted, and after 24 h only starting material was
recovered.
7
15
Previously unreported benzodiazepines 7c and 7d could also be
synthesized and demonstrated that longer aliphatic aldehydes
propanal and hexanal are well tolerated. The effect of steric bulk
of the aldehyde was also investigated using isobutyraldehyde
and pivalaldehyde both of which afforded target compounds 7e
and 7f, respectively, without a significant difference in yield or
reaction time.
We then looked toward substituted benzaldehydes to explore
the electronic limitations that may be present for this
transformation. We have already shown that benzaldehyde
was an acceptable electrophile to afford 7a. The incorporation
of an electron-withdrawing group was anticipated to activate
the aldehyde evidenced by the condensation of p-nitro-
benzaldehyde. The dramatic increase in the rate of formation
of product 7g is suggestive of increased electrophilicity,
however the decreased yield indicates increased reactivity of
this aldehyde has led to unwanted side reactions. When p-
bromobenzaldehyde was employed, then 7h was obtained in an
improved 83% yield, suggesting optimal electronics. Com-
pound 7h has the added benefit of the halogen acting as a
handle for further reactions by cross coupling. To further
investigate the influence of electronics on the reaction, we then
focused on electron-rich aldehydes first using p-methoxyben-
zaldehyde to yield compound 7i. A longer reaction time of 6 h
was required to reach completion, illustrating the reduced
reactivity of the aldehyde due to electronic effects. Surprisingly
though, an increased yield of 90% was obtained. Finally, the use
of p-hydroxybenzaldehyde showed that a free OH combined
with electron donation was tolerated in the reaction to afford
compound 7j.
To test the aromatic ketones, p-nitroacetophenone was
initially used and afforded benzodiazepine 8k in moderate yield.
Acetophenone afforded compound 8j with a reduction in yield,
C
DOI: 10.1021/acs.joc.6b00710
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The Journal of Organic Chemistry
Note
showing that the earlier presence of the electron-withdrawing
effect of the nitro group was significant. Finally, using p-
methoxyacetophenone proved far too electronically unfavorable
for progression, as no reaction was observed after 24 h even
with heating to reflux.
neat): 3297, 3094, 1609, 1572, 1509, 1490, 1340, 1221, 1145, 1075,
−
1 1
1043, 927, 750 cm ; H NMR (300 MHz, chloroform-d) δ 9.11 (s,
1H), 8.25 (d, J = 10.1 Hz, 1H), 7.56 (s, 1H), 7.52−7.38 (m, 1H),
6.96−6.84 (m, 1H), 6.78 (s, 1H), 6.20 (d, J = 2.5 Hz, 1H), 3.76 (s,
3
H); 13C NMR (75 MHz, chloroform-d) δ 142.7 (C), 139.0 (CH),
136.8 (C), 136.3 (C), 133.4 (CH), 126.6 (CH), 118.7 (CH), 115.8
The use of more functionally diverse ketones was illustrated
with the use of 3-oxopentanedioate as a substrate to afford 8m.
Further functionalizing this substrate to establish enhanced
tolerability, we tested the reaction with methyl 3-bromo-2-
oxopropanoate affording the appropriately cyclized product 8n.
This successful result illustrates that even with three electro-
philic sites in the substrate, the carbon bearing the bromine, the
ketone, and the ester, the imine formation and cyclization was
still the most favorable reaction pathway.
In summary, we have described very mild Pictet−Spengler
conditions for the formation of seven-membered heterocycles.
This approach allows for the ease of formation of privileged
scaffolds with extremely mild conditions and a high substrate
scope that is compatible with various solvents and acids. The
benzodiazepines reported herein contain important function-
ality to be included in our research toward compounds active in
the central nervous system.
(
CH), 101.8 (CH), 35.2 (CH ); LRMS (+ESI): m/z 219 (100, [M +
3
+
+
H] ); HRMS (+ESI): [M + Na] calcd for C H NaN O : 241.0696;
found 241.0697
10
10
4
2
1
N -(1-Methyl-1H-pyrazol-5-yl)benzene-1,2-diamine (2).
Compound 6 (16.4 g, 75.1 mmol) and 10% (w/w) palladium on
carbon (800 mg) in ethyl acetate (250 mL) was stirred under a
hydrogen atmosphere for 36 h. The mixture was filtered through basic
alumina and Celite washing with ethyl acetate, and the filtrate
concentrated under reduced pressure to afford compound 2 (14.06 g,
9
9%) as a light pink crystalline solid. MP: 134−135 °C; IR (Diamond
cell, neat): 3326, 3213, 1554, 1498, 1430, 1384, 1281, 993, 927, 733,
6
1
Hz, 1H), 5.81 (d, J = 1.9 Hz, 1H), 5.26 (s, 1H), 3.64 (s, 3H), 3.49 (br.
s, 2H); 13C NMR (75 MHz, chloroform-d) δ 142.1 (C), 138.5 (CH),
136.6 (C), 132.2 (C), 122.9 (CH), 120.3 (CH), 117.9 (CH), 117.3
(CH), 96.7 (CH), 34.9 (CH ); LRMS (+ESI) m/z: 189 (100, [M +
H] ), 211 (80, [M + Na] ); HRMS (+ESI) m/z: [M + Na] calcd for
−1
1
27 cm ; H NMR (300 MHz, chloroform-d) δ 7.40 (d, J = 1.9 Hz,
H), 6.92−6.82 (m, 1H), 6.83−6.70 (m, 2H), 6.63 (dd, J = 7.8, 1.5
3
+
+
+
C H NaN : 211.0954; found 211.0955.
10
12
4
General Procedure A for the Pictet−Spengler Reaction with
EXPERIMENTAL SECTION
■
Aldehydes. Compound 2 (100 mg, 0.56 mmol) and appropriate
aldehyde (0.62 mmol) in acetonitrile (5 mL) was treated with acetic
acid (65 μL, 20 mol %) and allowed to stir at room temperature.
Reaction progress was monitored by TLC and upon completion was
Unless noted otherwise, commercially obtained reagents were used as
purchased without further purification. Solvents for flash chromatog-
raphy were distilled prior to use or used as purchased for HPLC grade,
with the eluent mixture reported as the volume/volume ratio (v/v).
Melting points were measured with a ramp rate of 0.5−2.0 °C/min
and are uncorrected. Infrared absorption spectra were reported as
concentrated under reduced pressure, taken up in NaHCO
extracted with ethyl acetate (3 × 20 mL). The combined organic
phases were dried (MgSO ) and concentrated under reduced pressure.
, and
3
4
−1
vibrational frequency (cm ). Nuclear magnetic resonance spectra
were recorded at 298 K unless stated otherwise, using either a 300 or a
The crude oil was subjected to column chromatography (silica, ethyl
acetate/hexane, 3:2 (v/v)) to afford compounds 7a−i.
5
(
00 MHz spectrometer. The data are reported as the chemical shift
Δ, ppm) relative to the solvent residual peak, relative integral,
1-Methyl-4-phenyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-e]-
[1,4]diazepine (7a). Compound 2 was subjected to General Procedure
A with benzaldehyde (0.063 mL, 0.62 mmoL) and then recrystallized
with dichloromethane/hexane to afford 7a (118 mg, 81%) as a yellow
crystalline solid. MP: 125−126 °C; IR (Diamond cell, neat): 3263,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br. = broad, dd = doublet of doublets, etc.), coupling
constant (J, Hz). Low-resolution mass spectra (LRMS) were recorded
using electrospray ionization (ESI). High-resolution mass spectra were
run recorded using a Fourier transform ion cyclotron resonance mass
spectrometer.
−1 1
2333, 2215, 1649, 1563, 1493, 1432, 1291, 993, 748, 701 cm ; H
NMR (300 MHz, chloroform-d) δ 7.43−7.29 (m, 5H), 6.99−6.78 (m,
3H), 6.77−6.68 (m, 1H), 6.65 (s, 1H), 5.95 (br. s, 1H), 5.18 (s, 1H),
13
13
1
-Methyl-1H-pyrazol-5-amine (5). Compound 4 (20.0 g, 118
3.77 (s, 3H), 1 NH not observed; C NMR (75 MHz, chloroform-d)
mmol) in ethanol (100 mL) was treated with aqueous sodium
hydroxide (50 mL, 3 M). The reaction mixture was heated to reflux
and allowed to stir for 2 h, and the ethanol removed under reduced
pressure. The aqueous solution was cooled to 0 °C and acidified to pH
. The white precipitate was collected by filtration and heated neat to
85 °C, and the sublimed material collected with a coldfinger trap to
δ 142.7 (C), 140.0 (C), 137.4 (C), 137.0 (CH), 133.6 (C), 128.7 (2
CH), 128.1 (CH), 128.0 (2 CH), 123.5 (CH), 123.0 (CH), 122.2
(CH), 119.0 (CH), 105.9 (C), 59.8 (CH), 34.7 (CH ); LRMS (+ESI)
3
+
+
m/z: 277 (100, [M + H] ); HRMS (+ESI) m/z: [M + H] calcd for
5
1
C H N : 277.1448; found 277.1446.
1
7
17
4
1-Methyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-e][1,4]-
afford compound 4 (10.0 g, 87%) as a light brown solid. MP 73−74
diazepine (7b). Compound 2 was subjected to General Procedure A
with formaldehyde (24 μL of a 37% aqueous solution, 0.62 mmoL) to
afford 7b (57 mg, 54%) as an off-white solid. MP: 205−207 °C; IR
(Diamond cell, neat): 3386, 3362, 3251, 3150, 3046, 2788, 1604, 1570,
°
C; IR (Diamond Cell, neat) 3395, 3134, 1643, 1556, 1517, 1431,
−1 1
1
344, 1268, 1207, 999, 928, 758, 632 cm . H NMR (300 MHz,
chloroform-d) δ 7.21 (d, J = 2.0 Hz, 1H), 5.49 (d, J = 2.0 Hz, 1H),
.62 (s, 3H), 3.50 (br. s, 2H); 13C NMR (75 MHz, chloroform-d) δ
−1 1
3
1315, 991, 819, 754, 627 cm ; H NMR (300 MHz, chloroform-d) δ
1
9
44.6 (C), 138.2 (CH), 91.2 (CH), 34.3 (CH ). LRMS (ESI+) m/z:
7.12 (s, 1H), 6.96−6.76 (m, 4H), 5.81 (br. s, 1H), 4.10 (s, 2H), 3.73
3
+
+
13
8 (100, [M + H] ), 120 (50, [M + Na] ). These data matched that
(s, 3H), 1.70 (br. s, 1H); C NMR (75 MHz, chloroform-d) δ 140.4
14
previously reported.
(C), 138.8 (C), 135.9 (CH), 133.4 (C), 123.0 (CH), 122.8 (CH),
1
-Methyl-N-(2-nitrophenyl)-1H-pyrazol-5-amine (6). To a
122.2 (CH), 119.1 (CH), 101.9 (C), 44.7 (CH ), 34.6 (CH ); LRMS
2
3
+
+
magnetically stirred solution of amine 5 (10 g, 103 mmol) in dry
THF (300 mL), potassium tert-butoxide (23 g, 205 mmol) was added
at 0 °C and allowed to stir for 30 min. The resultant suspension was
treated with o-fluoronitrobenzene (12 mL, 113 mmol) at 0 °C.
Reaction was brought to room temperature and allowed to stir for 1 h.
Reaction was quenched with water (300 mL) and extracted with ethyl
(+ESI) m/z: 201 (100, [M + H] ), 223 (40, [M + Na] ); HRMS
+
(+ESI) m/z: [M + Na] calcd for C H NaN : 223.0954; found
11
12
4
223.0958.
4-Ethyl-1-methyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-e]-
[1,4]diazepine (7c). Compound 2 was subjected to General Procedure
A with propanal (45 μL, 0.62 mmoL) to afford 7c (85 mg, 70%) as an
off-white solid. MP: 163−164 °C; IR (Diamond cell, neat): 3369.
3254, 3048, 2965, 2922, 1604, 1572, 1432, 1389, 1313, 1292, 1178,
acetate (3 × 200 mL). Organic extracts were dried (MgSO ), and
4
solvent removed under reduced pressure. The bright yellow residue
was taken up in dichloromethane and purified by flash column
chromatography (silica, 3:5 ethyl acetate/hexane) to afford compound
−
1
1
1160, 1106, 988, 754, 693, 626 cm ; H NMR (300 MHz,
chloroform-d) δ 7.13 (s, 1H), 6.93−6.74 (m, 4H), 6.02 (br. s, 1H),
4.14−3.94 (m, 1H), 3.93 (br. s, 1H), 3.71 (s, 3H), 1.81−1.57 (m, 2H),
6
(16.4 g, 75%) as a yellow solid. MP: 133−135 °C; IR (Diamond cell,
D
DOI: 10.1021/acs.joc.6b00710
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The Journal of Organic Chemistry
Note
1
(
1
.03 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, chloroform-d) δ 139.8
C), 136.4 (C), 135.9 (CH), 133.9 (C), 123.7 (CH), 122.7 (CH),
22.0 (CH), 118.8 (CH), 105.8 (C), 55.9 (C), 34.6 (CH ), 30.7
1H), 3.77 (s, 3H), 1 NH not observed; 13C NMR (75 MHz,
chloroform-d) δ 141.9 (C), 139.9 (C), 137.0 (CH), 133.8 (C), 131.9
(2 CH), 129.7 (2 CH), 123.8 (CH), 123.4 (CH), 122.6 (CH), 122.0
3
+
(
(
2
CH ), 10.6 (CH ); LRMS (+ESI) m/z: 229 (100, [M + H] ); HRMS
+ESI) m/z: [M + Na] calcd for C H NaN : 251.1267; found
51.1271.
-Methyl-4-pentyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-e]-
1,4]diazepine (7d). Compound 2 was subjected to General
(C), 119.1 (CH), 105.2 (C), 59.2 (CH), 34.7 (CH ); LRMS (+ESI)
2
3
3
+
+
+
m/z: 355/357 (100, [M + H] ), 377/379 (20, [M + Na] ); HRMS
(+ESI) m/z: [M + Na] calcd for C H BrNaN : 377.0372/379.0352;
13
16
4
+
17
15
4
1
found 377.0372/379.0351.
[
4-(4-Methoxyphenyl)-1-methyl-1,4,5,10-tetrahydrobenzo[b]-
pyrazolo[3,4-e][1,4]diazepine (7i). Compound 2 was subjected to
General Procedure A with p-methoxybenzaldehyde (75 μL, 0.62
mmoL) to afford 7i (146 mg, 90%) as an off white-solid. MP: 159−
160 °C; IR (Diamond cell, neat): 3267, 3199, 3153, 3050, 2952, 1604,
Procedure A with hexanal (76 μL, 0.62 mmoL) to afford 7d (90
mg, 63%) as a light brown oil. IR (Diamond cell, thin film): 3283,
−1 1
3
101, 2954, 2928, 1571,1501, 1434, 1298, 750 cm ; H NMR (300
MHz, chloroform-d) δ 7.11 (s, 1H), 6.90−6.73 (m, 4H), 6.21 (br. s,
−1 1
1
H), 4.08 (t, J = 6.6 Hz, 1H), 3.68 (s, 3H), 3.51 (br. s, 1H), 1.65 (q, J
1570, 1507, 1437, 1307, 1243, 1171, 1022, 752, 640 cm ; H NMR
(300 MHz, chloroform-d) δ 7.29 (d, J = 8.6 Hz, 2H), 6.96−6.78 (m,
5H), 6.72 (d, J = 7.4 Hz, 1H), 6.65 (s, 1H), 5.91 (br. s, 1H), 5.11 (s,
1H), 3.82 (s, 3H), 3.77 (s, 3H), 1 NH not observed; 13C NMR (75
MHz, chloroform-d) δ 159.5 (C), 139.8 (C), 137.6 (C), 137.2 (CH),
135.2 (C), 133.6 (C), 129.3 (2 CH), 123.6 (CH), 123.1 (CH), 122.4
13
=
7.4, 6.7 Hz, 2H), 1.54−1.19 (m, 6H), 0.96−0.78 (m, 3H); C NMR
(
(
75 MHz, chloroform-d) δ 139.9 (C), 136.4 (C), 135.7 (CH), 133.8
C), 123.6 (CH), 122.6 (CH), 121.9 (CH), 118.8 (CH), 106.0 (C),
5
4.5 (CH), 37.7 (CH ), 34.6 (CH ), 31.7 (CH ), 25.8 (CH ), 22.6
2 3 2 2
+
(
(
2
CH ), 14.1 (CH ); LRMS (+ESI) m/z: 271 (100, [M + H] ); HRMS
+ESI) m/z: [M + Na] calcd for C H NaN : 293.1737; found
93.1737.
-Isopropyl-1-methyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-
2
3
+
(CH), 119.0 (CH), 114.1 (2 CH), 106.3 (C), 59.3 (CH), 55.4 (CH ),
16
22
4
3
+
34.7 (CH ); LRMS (+ESI) m/z: 307 (100, [M + H] ), 329 (40, [M +
Na] ); HRMS (+ESI) m/z: [M + H] calcd for C H N O:
3
+
+
4
18 19 4
e][1,4]diazepine (7e). Compound 2 was subjected to General
Procedure A with isobutyraldehyde (57 μL, 0.62 mmoL) to afford
307.1553; found 307.1552.
4-(1-Methyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-e][1,4]-
diazepin-4-yl)phenol (7j). Compound 2 was subjected to General
Procedure A with p-hydroxybenzaldehyde (76 mg, 0.62 mmol) to
afford 7j as an off white solid that was collected by filtration from the
reaction. MP: 202−203 °C; IR (Diamond Cell, neat): 3608, 3275,
7
e (50 mg, 39%) as a white solid. MP: 156−157 °C; IR (Diamond
cell, neat): 3278, 2955, 1563, 1498, 1432, 1382, 1295, 1261, 993, 926,
1 1
854, 743 cm ; H NMR (300 MHz, chloroform-d) δ 7.09 (s, 1H),
6.89−6.69 (m, 4H), 6.17 (br. s, 1H), 3.74 (d, J = 7.7 Hz, 1H), 3.68 (s,
3H), 1.79 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H),
1
NH not observed; 1 C NMR (75 MHz, chloroform-d) δ 139.9 (C),
136.9 (CH), 136.0 (C), 133.2 (C), 123.4 (CH), 122.2 (CH), 121.6
−1 1
1565, 1495, 1436, 1385, 1291, 1249, 1188, 1001, 816, 744 cm ; H
3
NMR (300 MHz, acetone-d ) δ 8.43 (br s., 1H), 7.50 (s, 1H), 7.16 (d,
6
J = 7.8 Hz, 2H), 7.03 (d, J = 7.5 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H),
(
2
CH), 118.5 (CH), 104.6 (C), 60.7 (CH), 34.6 (CH ), 34.1 (CH),
6.81−6.71 (m, 2H), 6.68 (t, J = 7.5 Hz, 1H), 6.55 (s, 1H), 5.10 (s,
3
+
13
0.4 (CH ), 18.7 (CH ); LRMS (+ESI) m/z: 243 (100, [M + H] );
1H), 4.68 (br. s, 1H), 3.73 (s, 3H); C NMR (75 MHz, acetone-d ) δ
3
3
6
+
HRMS (+ESI) m/z: [M + H] calcd for C H N : 243.1604; found
157.5 (C), 141.1 (C), 138.8 (C), 137.0 (CH), 136.0 (C), 135.0 (C),
14
19
4
2
43.1604.
-(tert-Butyl)-1-methyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-
129.8 (2 CH), 124.0 (CH), 122.5 (CH), 121.8 (CH), 119.6 (CH),
4
115.7 (2 CH), 106.6 (C), 59.4 (CH), 35.1 (CH ); LRMS (+ESI) m/z:
3
+
+
e][1,4]diazepine (7f). Compound 2 was subjected to General
Procedure A with pivalaldehyde (65 μL, 0.62 mmoL) to afford 7f
293 (100, [M + H] ), 315 (40, [M + Na] ); HRMS (+ESI) m/z: [M
+ Na] calcd for C H NaN O: 315.1216; found 315.1220.
+
17
16
4
(
81 mg, 60%) as a light purple solid. MP: 181−182 °C; IR (Diamond
General Procedure B for the Pictet−Spengler Reaction with
Ketones. Compound 2 (100 mg, 0.56 mmol) and appropriate ketone
(0.62 mmol) in acetonitrile (5 mL) was treated with trifluoroacetic
acid (5 μL, 10 mol %) and allowed to stir at room temperature.
Reaction progress was monitored by TLC and upon completion was
cell, neat): 3383, 3288, 2960, 2864, 1571, 1497, 1432, 1386, 1359,
1 1
1
314, 1090, 989, 883, 863, 775, 737, 708 cm ; H NMR (300 MHz,
chloroform-d) δ 7.10 (s, 1H), 6.83−6.64 (m, 4H), 5.98 (br. s, 1H),
.83 (s, 1H), 3.72 (s, 3H), 0.88 (s, 9H), 1NH not observed; 13C NMR
3
(
(
75 MHz, chloroform-d) δ 140.4 (C), 137.9 (CH), 136.3 (C), 131.3
C), 122.1 (CH), 121.4 (CH), 121.1 (CH), 118.1 (CH), 102.4 (C),
concentrated, taken up in NaHCO , and extracted with ethyl acetate
3
(3 × 20 mL). The combined organic phases were dried (MgSO ) and
4
6
2
+
3.3 (CH), 38.8 (C), 34.6 (CH ), 27.2 (3 CH ); LRMS (+ESI) m/z:
concentrated under reduced pressure. The crude oil subjected to
column chromatography (ethyl acetate/hexane, 3:2) to afford
compounds 8a−m.
3
3
+
+
56 (100, [M + H] ), 279 (40, [M + Na] ); HRMS (+ESI) m/z: [M
+
H] calcd for C H N : 257.1761; found 257.1766.
15 21 4
1
-Methyl-4-(4-nitrophenyl)-1,4,5,10-tetrahydrobenzo[b]-
1,4,4-Trimethyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-e][1,4]-
diazepine (8a). Compound 2 was subjected to General Procedure B
with acetone (45 μL, 0.62 mmoL) to afford 8a (100 mg, 83%) as an
off-white crystalline solid. MP: 130−131 °C; IR (Diamond cell, neat):
3279, 2963, 1561, 1494, 1434, 1381, 1309, 1264, 1201, 1165, 991, 90,
pyrazolo[3,4-e][1,4]diazepine (7g). Compound 2 was subjected to
General Procedure A with p-nitrobenzaldehyde (94 mg, 0.62 mmoL)
to afford 7g (82 mg, 48%) as a red solid. MP: 174−175 °C; IR
(
Diamond cell, neat): 3399, 1594, 1558, 1505, 1343, 1321, 1283, 1108,
1
1
−1 1
9
96, 932, 846, 755, 716, 685, 634 cm
;
H NMR (300 MHz,
853, 755, 733, 629 cm ; H NMR (300 MHz, chloroform-d) δ 7.14
(s, 1H), 6.94−6.74 (m, 4H), 5.96 (br. s, 1H), 3.70 (s, 3H), 3.09 (br. s,
1H), 1.47 (s, 6H); 13C NMR (75 MHz, chloroform-d) δ 138.8 (C),
135.9 (C), 135.0 (CH), 134.2 (C), 124.3 (CH), 122.9 (CH), 122.1
(CH), 118.6 (CH), 110.8 (C), 53.8 (C), 34.6 (CH ), 32.3 (2CH );
chloroform-d) δ 8.74 (s, 1H), 8.35 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 8.7
Hz, 2H), 7.51 (s, 1H), 7.27−7.13 (m, 2H), 6.88 (td, J = 7.6, 1.3 Hz,
1
3
1
1
9
2
H), 6.72 (dd, J = 8.2, 1.3 Hz, 1H), 6.67 (s, 1H), 6.13 (s, 1H), 3.78 (s,
H); 13C NMR (75 MHz, chloroform-d) δ 154.8 (CH), 149.4 (C),
41.6 (C), 141.2 (C), 140.0 (C), 138.8, (CH) 135.5 (C), 129.6 (CH),
3
3
+
LRMS (+ESI) m/z: 229 (100, [M + H] ); HRMS (+ESI) m/z: [M +
+
29.4 (2 CH), 124.3 (2 CH), 119.8 (CH), 116.8 (CH), 113.5 (CH),
H] calcd for C H N : 229.1448; found 229.1447.
13
17
4
+
9.7 (CH), 35.2 (CH ); LRMS (+ESI) m/z: 322 (100, [M + H] ),
4-Ethyl-1,4-dimethyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-
e][1,4]diazepine (8b). Compound 2 was subjected to General
Procedure B with butan-2-one (55 μL, 0.62 mmoL) to afford 8b
(103 mg, 80%) as a clear crystalline solid. MP: 155−156 °C; IR
(Diamond cell, neat): 3308, 3255, 2960, 1563, 1495, 1434, 1375, 1201,
3
+
+
79 (30, [M + Na] ); HRMS (+ESI) m/z: [M + H] calcd for
C H N O : 322.1299; found 322.1298.
1
7
16
5
2
4
-(4-Bromophenyl)-1-methyl-1,4,5,10-tetrahydrobenzo[b]-
pyrazolo[3,4-e][1,4]diazepine (7h). Compound 2 was subjected to
General Procedure A with p-bromobenzaldehyde (114 mg, 0.62
mmoL) to afford 7h (188 mg, 83%) as an off white-solid. MP: 165−
1
1
−1 1
996, 762, 669, 469 cm ; H NMR (300 MHz, chloroform-d) δ 7.11
(s, 1H), 6.93−6.73 (m, 4H), 5.86 (br. s, 1H), 3.72 (s, 3H), 3.54 (br. s,
1
3
66 °C; IR (Diamond cell, neat): 3326, 3028, 1571, 1499, 1485, 1437,
1H), 1.82−1.50 (m, 2H), 1.43 (s, 3H), 0.90 (t, J = 7.4 Hz, 3H); C
−1
1
310, 1291, 1069, 1007, 853, 811, 800, 748 cm ; H NMR (300
NMR (75 MHz, chloroform-d) δ 139.0 (C), 135.7 (CH), 135.6 (C),
133.8 (C), 124.2 (CH), 122.6 (CH), 122.0 (CH), 118.4 (CH), 109.5
(C), 56.6 (C), 37.2 (CH ), 34.7 (CH ), 28.8 (CH ), 8.9 (CH );
MHz, chloroform-d) δ 7.47 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz,
H), 6.97−6.77 (m, 3H), 6.73−6.63 (m, 2H), 5.96 (br. s, 1H), 5.15 (s,
2
2
3
3
3
E
DOI: 10.1021/acs.joc.6b00710
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
+
+
LRMS (+ESI) m/z: 243 (100, [M + H] ) 265 (20, [M + Na] );
(C), 41.2 (2 CH ), 34.5 (CH ), 23.3 (2 CH ); LRMS (+ESI) m/z:
255 (100, [M + H] ); HRMS (+ESI) m/z: [M + Na] calcd for
2
3
2
+
+
+
HRMS (+ESI) m/z: [M + H] calcd for C H N : 243.1604; found
1
4
19
4
2
43.1604.
-Isopropyl-1,4-dimethyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo-
3,4-e][1,4]diazepine (8c). Compound 2 was subjected to General
Procedure B with 3-methylbutan-2-one (67 μL, 0.62 mmoL) to afford
C H NaN : 277.1424; found 277.1423.
4-(tert-Butyl)-1,4-dimethyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo-
15
18
4
4
[
[3,4-e][1,4]diazepine (8h). Compound 2 was subjected to General
Procedure B with pinacolone (78 μL, 0.62 mmoL) to afford 8h (57
mg, 40%) as a crystalline solid. MP: 142−143 °C; IR (Diamond cell,
neat): 3298, 2980, 2953, 1570, 1493, 1390, 1315, 1267, 1108, 984,
8
c (101 mg, 75%) as a clear crystalline solid. MP: 91−92 °C; IR
(
Diamond cell, neat): 3263, 3203, 3157, 3055, 2968, 1570, 1507, 1384,
−1
1
−1 1
1
312, 1263, 1107, 992, 831, 732, 538, 491, 463 cm ; H NMR (300
858, 728, 708, 637 cm ; H NMR (300 MHz, chloroform-d) δ 7.15
(s, 1H), 6.85−6.57 (m, 4H), 5.78 (br. s, 1H), 3.79 (br. s, 1H), 3.75 (s,
3H), 1.46 (s, 3H), 0.89 (s, 9H); 13C NMR (75 MHz, chloroform-d) δ
139.5 (C), 137.4 (C), 137.0 (CH), 131.64 (C), 122.06 (CH), 121.71
(CH), 120.96 (CH), 117.82 (CH), 106.8 (C) 62.14 (C), 41.69 (C),
MHz, chloroform-d) δ 7.09 (s, 1H), 6.91−6.72 (m, 4H), 5.86 (br. s,
1
1
H), 3.72 (s, 3H), 1.84 (p, J = 6.8 Hz, 1H), 1.37 (s, 3H), 0.89 (dd, J =
5.1, 6.8 Hz, 6H), 1 NH not observed; 13C NMR (75 MHz,
chloroform-d) δ 138.6 (C), 136.5 (CH), 135.0 (C), 132.8 (C), 123.8
CH), 122.1 (CH), 121.7 (CH), 118.1 (CH), 109.8 (C), 59.2 (C),
7.5 (CH), 34.6 (CH ), 22.8 (CH ), 18.8 (CH ), 16.8 (CH ); LRMS
(
3
34.7 (CH
3
), 26.9 (3 CH
3
), 26.3 (CH
3
); LRMS (+ESI) m/z: 271 (100+,
[M + H] ), 293 (20, [M + Na] ); HRMS (+ESI) m/z: [M + Na]
calcd for C16 : 293.1737 found 293.1736.
+
+
3
3
3
3
+
+
(
+ESI) m/z: 257 (100, [M + H] ) (40, [M + Na] ); HRMS (+ESI)
H22NaN
4
+
m/z: [M + Na] calcd for C H NaN : 279.1580; found 279.1579.
1,4-Dimethyl-4-phenyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-
e][1,4]diazepine (8j). Compound 2 was subjected to General
Procedure B with acetophenone (72 μL, 0.62 mmoL) to afford 8j
(54 mg, 35%) as a crystalline solid. MP: 115−116 °C; IR (Diamond
cell, neat); 3267, 2965, 2155, 1562, 1490, 1432, 1370, 1312, 1263,
15
20
4
4
-Cyclopentyl-1,4-dimethyl-1,4,5,10-tetrahydrobenzo[b]-
pyrazolo[3,4-e][1,4]diazepine (8d). Compound 2 was subjected to
General Procedure B with 1-cyclopentylethan-1-one (65 μL, 0.62
mmoL) to afford 8d (114 mg, 76%) as colorless needles. MP: 155−
−
1 1
1
1
7
3
55 °C; IR (Diamond cell, neat): 2943, 2863, 1565, 1495, 1389, 1319,
1192, 987, 836, 748, 699 cm ; H NMR (300 MHz, chloroform-d) δ
7.32 (dd, J = 8.2, 1.6 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H), 7.22−7.10 (m,
1H), 6.99 (s, 1H), 6.86−6.74 (m, 1H), 6.77−6.65 (m, 2H), 6.65−6.54
(m, 1H), 5.87 (br. s, 1H), 4.00 (br. s, 1H), 3.75 (s, 3H), 1.86 (s, 3H);
−1 1
265, 986, 835, 729, 628 cm ; H NMR (300 MHz, chloroform-d) δ
.07 (s, 1H), 6.87−6.70 (m, 4H), 5.85 (br. s, 1H), 3.80 (br. s, 1H),
.71 (s, 3H), 1.80 (d, J = 12.1 Hz, 1H), 1.69 (d, J = 11.1 Hz, 2H), 1.57
13
13
(
d, J = 10.8 Hz, 2H), 1.37 (s, 4H), 1.12−0.92 (m, 5H); C NMR (75
MHz, chloroform-d) δ 138.7 (C), 136.0 (C), 135.6 (CH), 133.5 (C),
24.0 (CH), 122.3 (CH), 121.9 (CH), 118.1 (CH), 110.0 (C), 58.5
C), 51.5 (CH), 34.7 (CH ), 29.0 (CH ), 26.8 (CH ), 26.2 (CH ),
C NMR (75 MHz, chloroform-d) δ 147.4 (C), 139.3 (C), 136.8
(CH), 135.6 (C), 133.7 (C), 128.2 (2 CH), 127.0 (CH), 126.6 (2
CH), 124.6 (CH), 122.7 (CH), 122.0 (CH), 118.4 (CH), 109.6 (C),
59.9 (C), 34.7 (CH ), 31.6 (CH ); LRMS (+ESI) m/z: 291 (100, [M
1
(
3
2
3
2
3
3
+
+
+
2
3
6.0 (CH ), 25.1 (CH ); LRMS (+ESI) m/z: 283 (100, [M + H] ),
05 (40, [M + Na] ); HRMS (+ESI) m/z: [M + Na] calcd for
+ H] ); HRMS (+ESI) m/z: [M + H] calcd for C H N : 291.1604;
2
2
18 19 4
+
+
found 291.1603.
C H NaN : 305.1737; found 305.1736.
1,4-Dimethyl-4-(4-nitrophenyl)-1,4,5,10-tetrahydrobenzo[b]-
pyrazolo[3,4-e][1,4]diazepine (8k). Compound 2 was subjected to
General Procedure B with p-nitroacetophenone (102 mg, 0.62 mmoL)
to afford 8k (85 mg, 48%) as a crystalline solid. MP: 211−212 °C; IR
(Diamond cell, neat): 3310, 1577, 1511, 1433, 1343, 1323, 1266, 1186,
1
7
22
4
4
-Cyclohexyl-1,4-dimethyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo-
[
3,4-e][1,4]diazepine (8e). Compound 2 was subjected to General
Procedure B with 1-cyclohexylethan-1-one (85 μL, 0.62 mmoL) to
afford 8e (126 mg, 80%) as a light needle-like solid. MP: 178−179 °C;
IR (Diamond cell, neat): 3259, 2921, 1571, 1501, 1437, 1313, 991,
−1
1
1104, 990, 856, 823, 745, 699, 629 cm ; H NMR (300 MHz,
chloroform-d) δ 8.05 (d, J = 8.9 Hz, 2H), 7.43 (d, J = 8.9 Hz, 2H),
7.08 (s, 1H), 6.82 (m, 1H), 6.71 (m, 2H), 6.57 (dd, J = 8.0, 1.5 Hz,
1H), 5.84 (br. s, 1H), 3.80 (s, 3H), 1.92 (s, 3H), 1 NH not observed;
−1 1
8
6
1
08, 750 cm ; H NMR (500 MHz, chloroform-d) δ 7.07 (s, 1H),
.87−6.70 (m, 4H), 5.87 (br. s, 1H), 3.80 (br. s, 1H), 3.71 (s, 3H),
.80 (d, J = 12.1 Hz, 1H), 1.69 (d, J = 11.1 Hz, 2H), 1.57 (d, J = 10.8
1
3
13
Hz, 2H), 1.37 (s, 4H), 1.12−0.92 (m, 5H); C NMR (126 MHz,
chloroform-d) δ 138.6 (C), 136.7 (CH), 134.9 (C), 132.9 (C), 123.8
C NMR (75 MHz, chloroform-d) δ 154.9 (C), 146.8 (C), 139.5 (C),
136.5 (CH), 134.8 (C), 133.7 (C), 127.6 (CH), 124.7 (CH), 123.5
(CH), 123.5 (CH), 122.4 (CH), 118.7 (CH), 108.0 (C), 60.1 (C),
(
4
CH), 122.0 (CH), 121.6 (CH), 118.1 (CH), 109.5 (C), 59.1 (C),
7.8 (CH), 34.6 (CH ), 28.9 (CH ), 27.1 (CH ), 26.9 (CH ), 26.6 (2
+
3
2
3
2
34.8 (CH ), 31.6 (CH ); LRMS (+ESI) m/z: 358 (100, [M + Na] );
3
3
+
+
CH ), 24.2 (CH ); LRMS (+ESI) m/z: 297 (100, [M + H] ); HRMS
HRMS (+ESI) m/z: [M + Na] calcd for C H NaN O : 358.1275;
2
2
18 17 5 2
+
(
+ESI) m/z: [M + Na] calcd for C H N : 297.2074; found
found 358.1274.
18
25
4
2
97.2073.
-Methyl-5,10-dihydro-1H-spiro[benzo[b]pyrazolo[3,4-e][1,4]-
Dimethyl-2,2′-(1-methyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo-
[3,4-e][1,4]diazepine-4,4-diyl)diacetate (8m). Compound 2 was
subjected to General Procedure B with dimethyl 3-oxopentanedioate
(102 mg, 0.62 mmoL) to afford 8m (139 mg, 76%) as a colorless
crystalline solid. MP: 170−171 °C; IR (Diamond cell, neat): 3300,
1
diazepine-4,1′-cyclohexane] (8f). Compound 2 was subjected to
General Procedure B with cyclohexanone (64 μL, 0.62 mmoL) to
afford 8f (85 mg, 60%) as a chalk-like solid. MP: 190−191 °C; IR
−1 1
(
Diamond cell, neat): 3301, 2920, 2849, 1565, 1489, 1431, 1389, 1312,
2951, 1714, 1571, 1499, 1438, 1354, 1320, 1170, 987, 757 cm ; H
NMR (300 MHz, chloroform-d) δ 7.09 (s, 1H), 6.99−6.78 (m, 4H),
5.80 (br. s, 1H), 3.72 (s, 3H), 3.66 (s, 6H), 3.07 (d, J = 15.6 Hz, 2H),
−
1 1
1
267, 983, 901, 857, 751, 728, 713, 628 cm ; H NMR (300 MHz,
chloroform-d) δ 7.19 (s, 1H), 6.90−6.73 (m, 4H), 6.01 (br. s, 1H),
13
13
3
.69 (s, 3H), 1.87−1.41 (m, 10H), 1 NH not observed; C NMR (75
MHz, chloroform-d) δ 139.1 (C), 134.6 (CH), 134.5 (C), 134.1 (C),
24.1 (CH), 122.4 (CH), 121.6 (CH), 118.3 (CH), 112.2 (C), 54.8
C), 38.1 (2 CH ), 34.6 (CH ), 25.1 (CH), 21.8 (2 CH ); LRMS
2.89 (d, J = 15.6 Hz, 2H), 1 NH not observed; C NMR (75 MHz,
chloroform-d) δ 171.9 (2 C), 139.1 (C), 135.4 (C), 134.6 (CH), 134.4
(C), 124.9 (CH), 123.5 (CH), 122.5 (CH), 118.6 (CH), 106.9 (C),
56.2 (C), 51.7 (2 CH ), 43.9 (2 CH ), 34.6 (CH ); LRMS (+ESI) m/
1
(
(
2
3
2
3
2
3
+
+
+
+
+ESI) m/z: 269 (100, [M + H] ); HRMS (+ESI) m/z: [M + Na]
z: 367 (100, [M + Na] ); HRMS (+ESI) m/z: [M + Na] calcd for
calcd for C H NaN : 291.1580; found 291.1580.
C H NaN O : 367.1377; found 367.1376
16
20
4
17 20
4
4
1
-Methyl-5,10-dihydro-1H-spiro[benzo[b]pyrazolo[3,4-e][1,4]-
Methyl-4-(bromomethyl)-1-methyl-1,4,5,10-tetrahydrobenzo[b]-
pyrazolo[3,4-e][1,4]diazepine-4-carboxylate (8n). Compound 2 was
subjected to General Procedure B with methyl 3-bromo-2-
oxopropanoate (66 μL, 0.62 mmoL) to afford 8n (114 mg, 61%) as
an unstable off-white solid. MP: >300 °C; IR (Diamond cell, neat):
3138, 2949, 2850, 1709, 1566, 1494, 1433, 1388, 1293, 1253, 1221,
1175, 1129, 1112, 980, 919, 891, 722 cm ; H NMR (500 MHz,
chloroform-d) δ 7.50 (s, 1H), 7.12−7.07 (m, 2H), 7.01−6.93 (m, 2H),
6.90 (s, 1H), 5.35 (s, 1H), 3.89−3.86 (m, 6H), 3.85 (d, J = 2.4 Hz,
1H), 3.41 (d, J = 10.3 Hz, 1H); 13C NMR (126 MHz, chloroform-d) δ
diazepine-4,1′-cyclopentane] (8g). Compound 2 was subjected to
General Procedure B with cyclopentanone (55 μL, 0.62 mmoL) to
afford 8g (78 mg, 60%) as a crystalline solid. MP: 146−147 °C; IR
(
1
Diamond cell, neat): 3256, 3200, 3156, 3051, 2949, 2870, 1567, 1499,
436, 1311, 1265, 1207, 1002, 944, 730, 475 cm ; H NMR (300
−1 1
−1
1
MHz, chloroform-d) δ 7.15 (s, 1H), 6.97−6.71 (m, 4H), 5.76 (br. s,
13
1
H), 3.73 (s, 3H), 3.58 (br. s, 1H), 1.98−1.75 (m, 8H); C NMR (75
MHz, chloroform-d) δ 139.2 (C), 135.7 (C), 134.6 (CH), 134.4 (C),
24.3 (CH), 122.9 (CH), 121.9 (CH), 118.5 (CH), 109.4 (C), 64.7
1
F
DOI: 10.1021/acs.joc.6b00710
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
1
70.6 (C), 141.9 (C), 135.3 (C), 134.1 (C), 132.8 (CH), 126.0 (CH),
(13) Fandrick, D. R.; Sanyal, S.; Kaloko, J.; Mulder, J. A.; Wang, Y.;
Wu, L.; Lee, H.; Roschangar, F.; Hoffmann, M.; Senanayake, C. H.
Org. Lett. 2015, 17 (12), 2964−2967.
(14) Kojima, N.; Fushimi, T.; Tatsukawa, T.; Yoshimitsu, T.; Tanaka,
T.; Yamori, T.; Dan, S.; Iwasaki, H.; Yamashita, M. Eur. J. Med. Chem.
24.3 (CH), 123.7 (CH), 119.7 (CH), 101.4 (C), 64.5 (CH ), 53.5
3
(
CH ), 52.9 (C), 39.9 (CH ); LRMS (+ESI) m/z: 351/353 (100, [M
2 3
H] ); HRMS (+ESI) m/z: [M + H] calcd for C H BrN O :
+
+
+
3
14
16
4
2
51.0451/353.0431; found 351.0456/353.0436.
2
(
013, 63, 833−839.
15) Frantz, M.-C.; Rodrigo, J.; Boudier, L.; Durroux, T.; Mouillac,
B.; Hibert, M. J. Med. Chem. 2010, 53 (4), 1546−1562.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00710.
1
13
H and C NMR spectra for compounds 2, 7a−j, 8a−h,
8j−k, and 8m−n (PDF)
AUTHOR INFORMATION
■
*
Corresponding Author
E-mail: michael.kassiou@sydney.edu.au.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Australian National Health and
Medical Research Council.
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G
DOI: 10.1021/acs.joc.6b00710
J. Org. Chem. XXXX, XXX, XXX−XXX