Calcium Dialkylamine Diazeniumdiolates: Synthesis, Stability, and Nitric Oxide Generation

Article abstract of DOI:10.1021/acs.joc.0c00020

The therapeutic application of nitric oxide, an endogenous cellular signaling molecule, has been limited due to the difficulty of developing stable pro-drugs with slow kinetics of NO release. Diazeniumdiolates are valuable NO donors; however, synthetic challenges have hampered their use. O²-alkylation or arylation of diazeniumdiolates form stable pro-drugs which have found application in hypertension, cancer, and as antimicrobial agents. The synthesis of sodium diazeniumdiolates has proven to be challenging due to hazardous reaction conditions (high N₂O concentrations, and flammable solvents), which can lead to detonation and suffered from limited scope. We have previously disclosed that synthesis of calcium diazeniumdiolate salts are a safer and more scalable alternative. Herein, we report the expanded scope of calcium diazeniumdiolates from benzylic amines, amides, and sterically bulky amines hitherto inaccessible and a comparison of their reactivity in comparison to sodium diazeniumdiolate.

Full text of DOI:10.1021/acs.joc.0c00020

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Article
Calcium Dialkylamine Diazeniumdiolates:
Synthesis, Stability, and Nitric Oxide Generation
Nabeelah Kauser, Mark Weisel, Yong-Li Zhong, Michael Man-Chu Lo, and Amjad Ali
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00020 • Publication Date (Web): 13 Mar 2020
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The Journal of Organic Chemistry
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Calcium Dialkylamine Diazeniumdiolates: Synthesis, Stability, and
Nitric Oxide Generation
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Nabeelah I. Kauser, Mark Weisel, Yong-Li Zhong, Michael Man-Chu Lo, and Amjad Ali,*
Departments of † Discovery Chemistry, ‡ Process Research and Development, Merck & Co., Inc, Kenilworth, New Jersey 07033,
United States
KEYWORDS Diazeniumdiolate, nitric oxide, NO donors, calcium diazeniumdiolate
ABSTRACT: The therapeutic application of nitric oxide, an endogenous cellular signaling molecule, has been limited due to the difficulty
of developing stable pro-drugs with slow kinetics of NO release. Diazeniumdiolates are valuable NO donors however synthetic challenges
2
have hampered their use. O -alkylation or –arylation of diazeniumdiolates form stable pro-drugs which have found application in
hypertension, cancer and as anti-microbial agents. The synthesis of sodium diazeniumdiolates proved challenging due to hazardous reaction
conditions, (high N O concentrations, and flammable solvents) which can lead to detonation and suffered from limited scope. We have
2
previously disclosed that synthesis of calcium diazeniumdiolate salts are a safer and more scalable alternative. Herein, we report the expanded
scope of calcium diazeniumdiolates from benzylic amines, amides, and sterically bulky amines hitherto inaccessible, and a comparison of
their reactivity in comparison to sodium diazeniumdiolate.
A)
Introduction
R2
R2
R1 NH
1) NO, Et2O
R1
N
1
Nitric oxide, heralded as molecule of the year in 1992 , acts as a
N+
N
2
2) NaOMe, MeOH
crucial signaling molecule for vasodilation, cellular signaling in
-O
O
Na
3
4
the brain, and defense system against pathogens. First discovered
in 1847, organic nitrates are effective for vasodilation and
treatment of angina but suffer from uncontrollable NO release
profiles, often resulting in unintended side effects such as
2
1
B)
R2
N+
5
6
headaches, and hypotension.
R1
N
NO (250 PSI)
Ca(OH)2 0.6 equiv)
N
R2
R1 NH
-O
O
Ca
Diazeniumdiolates, (DAZD), have shown viability as NO donors
and recently, a representative from this class of NO donors has
advanced into human clinical trials.6,7,8 The sodium
diazeniumdiolate 1 are stable in the solid form but will release 2
moles of NO theoretically and the corresponding amine upon
dissolution in an aqueous solution under physiological conditions.
H2O
R2
R1
O
N
20°C
N+
N
100 h
2
-O
3
Scheme 2. Synthesis of sodium11 and calcium13 diazeniumdiolates.
(
Scheme 1). The rate of NO release is affected by pH. However,
The use of sterically bulky amines was often unsuccessful under
these conditions leading to little or even no product in some cases.
The failures to apply sterically bulky or electronically-varied
amines implied that these diazeniumdiolates were either too
unstable and underwent decomposition too rapid for isolation or
were not applicable to the synthesis of diazeniumdiolates. While
various amines were utilized for the synthesis of diazeniumdiolates,
the challenges of low yields, instability of the product, or a lack of
chemical matter greatly limited the scope of diazeniumdiolates and
their subsequent research into biological or pharmaceutical
applications.
the rate can also be conveniently varied by modifying the R groups.
Numerous diazeniumdiolates, over the past half century, have been
synthesized with half-lives varying from 2 s to 20 h.
7
R2
R1
N
R2
R1 NH
N+
+ 2 NO
N
-O
O Na
1
2
Scheme 1. Decomposition of diazeniumdiolate to amine and NO
The synthesis of the diazeniumdiolate 1 was first reported by
Drago et al, in 1961, through the reaction of nitic oxide with various
Recently studies reported by colleagues in our Process Research
and Development department at Merck & Co., Inc., Kenilworth,
NJ, USA have reported a safer and scalable method for the
synthesis of the calcium diazeniumdiolates 3 on gram- and
1
2
-
amines to form white solids with the structure R R N-N(O)=NO
1
2
+ 9
R R N . (Scheme 2a). These solids were found to be unstable and
1
0
converted to the corresponding nitrosamine overnight. In 2001,
1
3
Keefer et al. reported that converting the unstable solids to the
multikilogram-scale. (Scheme 2b). These reported conditions
enable the reaction to occur at room temperature in the absence of
1
1
sodium diazeniumdiolate salts 1 improved shelf-life. However,
this method of synthesizing the diazeniumdiolate would in our
hands result in the occasional detonation due to the nature of the
flammable solvents used during the synthesis, high nitrous oxide
1
3
a flammable solvent or strong base. Another challenge associated
9
with the sodium diazeniumdiolates, as reported by Drago and
14
Andrei , was that storage of quantities above 250 mg were not
1
2
content and use of a strong alkoxide base.
recommended due to a detonation risk and stability issues.
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O-
Differential scanning calorimetry, DSC analysis showed that the
calcium diazeniumdiolates were more thermally stable compared
to the sodium diazeniumdiolates.
Me
NH
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NO (60 psi)
NaOMe
MeOH, Et2O
Me
N+
O
N
N
Na
1
3,15,16
Results and Discussion
10
5%
6
Herein, we examine the advantages of the calcium
diazeniumdiolate method towards the synthesis of simple
dialkylamines, benzylic amines with various electronic natures and
other various amine functionalities and their physiochemical
properties. We began our investigation by analyzing the synthesis
O-
O-
Me
N+
N+
NH
R
NO (60 PSI)
Ca(OH)2 (0.6 equiv)
H2O
Me
O
O
Me
N
N
Ca
N
N
R
R
1
3
of simple dialkylamines. Some of the sodium dialkylamine salts
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
have been previously synthesized by Drago and others. However,
the yields are generally low and/or the reactions required careful
control of temperature to prevent decomposition.
1
1
12
13
4
5
16
R = H
R = 4-F
R = 4-Me
R = 4-tert-Butyl
R = 4-Br
R = 4-CF3
R = 3-OMe
R = 4-OMe
93%
90%
93%
94%
62%
65%
79%
86%
1
1
Table 1. The synthesis of dialkylamine DAZD calcium salt
1
7
18
A) NO
R1
N
R1
N
R1
N
NaOMe
MeOH
Scheme 3. The synthesis of benzylic amine DAZD calcium salt
R1
N
Na
N
Ca
N
R1
N+
O-
O
R1
N+
O-
O
O
N+
O-
R1
R1 NH
B) NO (250 PSI)
Ca(OH)2 (0.6 equiv)
H2O
The benzyl methyl amine sodium diazeniumdiolate 10 has been
19,20
previously synthesized in 65% yield.
With our improved
a
b
calcium salt method, we were able to synthesize the calcium
diazeniumdiolate 11 in 93%. The more electron rich arenes, such
as 4-tert-butylbenzylamine were also more nucleophilic and
provided the corresponding calcium diazeniumdiolate salts in high
yields. Our method also showed tolerance for aryl halides such as
aryl fluorides or even aryl bromides, while the sodium salts of
these diazeniumdiolates have not been reported.
R1
R2
DAZD
Yield of
Sodium
DAZD Salt
Yield of
Calcium
a
b
DAZD Salt
(
n-Bu)
2
N
(n-Bu)
(i-Bu)
sec-Butyl sec-Butyl
2
N
4
5
6
7
8
9
80%9
98%17
(i-Bu)
2
N
2
N
N. R.
41%
N.R.c
38%d
Table 2. The synthesis of amide and amidine DAZD calcium salt
X
Cy
Cy
N. R.
N. R.
N. R.
28%d
R1
O-
A) NO
NaOMe
MeOH, Et2O
X
HN N+
0%d
R1
O-
HN N+
Cy
tert-Butyl
tert-Butyl
X
N
O
R1
Ca O
O-
N+
HN
Boc
0%d
NH2
B) NO (60 PSI)
Ca(OH)2 (0.6 equiv)
H2O
N
O
N
Na
a
b
a
b
Reported isolated yields of sodium DAZD salt. Procedure b:
All of the reactions were run on a 5.2 mmol scale for 100 h. All
R1
X
DAZD
Yield of
Sodium
DAZD Salt
Yield of
Calcium
DAZD
c
d
yields are isolated yields. Synthesized but no yield reported. 350
psi. N.R. not reported.
a
b
Salt
9
The method developed by Drago or the modification by
1
1
N
N
O
O
N(Me)2
Ph
19
20
21
22
N. R.
92%
83%
32%
70%
Keefer provided little or no yield of the desired diazeniumdiolate
from sterically hindered amines. Drago’s attempt to synthesize the
di-sec-butylamine DAZD 6a resulted only in a low yield of
ammonium nitrate whereas the method provided herein gave the
39%21
Me
10%22
N.R.
9
diazeniumdiolate 6b in 38%. Dicyclohexylamine was able to
2-pyridyl
undergo the reaction in 28% yield. (Table 1) The t-Butyl
cyclohexylamine diazeniumdiolate 8b was not synthesized as the
steric bulk around the nitrogen prevented the reaction from
occurring. Also, the electron-poor amine, N-Boc N-tert-
Butylamine diazeniumdiolate 9b failed to be synthesized as the
nitrogen was most likely not sufficiently electron-rich enough to
a
b
Reported yields of sodium DAZD salt. Procedure b: All of the
reactions were run on a 5.2 mmol scale for 100 h. All yields are
isolated yields. N.R. not reported.
1
8
act as a nucleophile.
Other amine functional groups such as guanidines and amidines
were also found to be viable substrates, forming the DAZD salts 19
and 20 in 92% and 83% yield, respectively. Primary amides,
acetamide and picolinamide formed the DAZD 21 and 22 in 32%
With the success of the dialkylamines, we turned our attention
towards benzylic amines, such that the electronic nature of the
amine could be altered through functionalization of the arene. The
rate-limiting step in the mechanism to synthesize
diazeniumdiolates is reported to be nucleophilic attack of the amine
on the nitric oxide to form the nitrosamine which is then further
and 70%, respectively, compared to the previous reports of 10% for
22,23
acetamide.
(Table 2). The lower yield for the acetamide
diazeniumdiolate is attributed to the difference in nucleophilic
nature between acetamide, a weak nucleophile and picolinamide, a
stronger nucleophile. The nitrogen on the pyridyl ring of the
picolinamide diazeniumdiolate salt may also engage in H-bonding
with the amide moiety to help stabilize the diazeniumdiolate. This
18
reacted to form the diazeniumdiolate. Accordingly, the more
nucleophilic benzylic amines demonstrated that 60 psi of nitric
oxide was sufficient pressure to provide high yields of the
corresponding calcium diazeniumdiolate salt. (Scheme 3).
22
H-bonding event is weaker for the acetamide diazeniumdiolate.
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The Journal of Organic Chemistry
Table 3. NO Release Rates of Calcium Diazeniumdiolates
decreases. Thus, acidic amines undergo the protonation and
1
2
3
4
5
6
7
8
9
subsequent decomposition to the amine and 2 equivalence of NO
much slower than the more basic amines. (Figure 1).
4
26
DAZD Calcium Salt
k X 10
(s )
Half-life
(t1/2)
1
2
-1
a
(
R R N-N(O)=N(O))
2
Ca
The alkylation of the calcium diazeniumdiolates was previously
1
R2
nBu
#
4
R
1
3
reported by Zhong et al. Using previously reported conditions for
the arylation of the sodium diazeniumdiolate 23, the calcium
nBu
iso-butyl
sec-butyl
cyclohexyl
Bn
90
85
77 s
82 s
2
diazeniumdiolate 25 was converted to the O -arylated product in
5
6
7
iso-butyl
sec-butyl
cyclohexyl
Me
1
9
8
1% yield compared to 43% for the sodium diazeniumdiolate 23.
(Scheme 4).
77
90 s
Scheme 4. Application of the sodium and calcium
diazeniumdiolates towards sNAr coupling.
40
2.9 min
56 s24
85 s
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
2
122
85
O-
Et2N N+
NO2
O-
Et2N N+
DMSO
0 °C to 22 °C
N
O
NO2
NO2
1
(p-FC
(p-CH
(p-tert-butyl-C
(p-BrC )CH
(p-F CC )CH
(m-CH OC )CH
OC )CH
NC(N)
6
H
4
)CH
2
Me
F
2
43%
4 h
N
ONa
13
3
C
6
H
4
)CH
2
Me
158
126
84
44 s
NO2
23
24
1
1
1
4
5
6
6
H
4
)CH
2
Me
50 s
O-
6
H
4
2
Me
84 s
O-
Et2N N+
Et2N N+
NO2
DMSO
0 °C to 22 °C
24 h
N
O
NO2
F
3
6
H
4
2
Me
29
4.0 min
81 s
N
O
Ca O
O-
N+
81%
N
NO2
17
3
6
H
4
2
Me
81
NEt2
NO2
25
1
1
8
9
(p-CH
3
6
H
4
2
Me
124
267
56 s
24
We applied the improved calcium diazeniumdiolate salt method
(CH
3
)
2
H
26 s
2
of synthesizing O -arylated DAZD to the synthesis of JS-K, a tool
2
7
molecule described previously for its anti-cancer activity. The
calcium diazeniumdiolate 26 was provided in 96%, compared to
aDecomposition of DAZD calcium salt in 0.1 M pH 7.4
potassium phosphate buffer at 37 °C was measured by UV/Vis
analysis and detected by 250 nm wavelength. Data supported
first-order decomposition.
28
previously reports of 54%. The sodium diazeniumdiolate of 26
can be converted to JS-K in one step through the sNAr reaction or
2
7
2
be converted to the O -(triisopropylsilyloxy) methylated-
diazeniumdiolate which is more stable; this in turn is converted to
JS-K upon addition of TBAF and the aryl fluoride in 70% over two
steps. In comparison, our calcium diazeniumdiolate 26 undergoes
the sNAr in 68% yield for an overall yield of 65% compared to 38%
for the sodium DAZD. (Scheme 5).
The decomposition of the sodium and calcium diazeniumdiolates
is reported to occur at pH 7.4 and 37 °C, which can be monitored
by the decrease in the absorbance at 250 nm wavelength which
represents the diazeniumdiolate chromophore. Decomposition
rates for the sodium and calcium diazeniumdiolates have been
previously reported to be comparable. The half-lives of the
calcium diazeniumdiolate salts were found to be affected by the
(Table 3). The di-n-butylamine
diazeniumdiolate 4b had a half-life of 1.28 min, while branching
the alkyl chain to di-sec-butylamine 6b increased the half-life by
2
7
Scheme 5. Application of the Calcium diazeniumdiolate 26
towards the synthesis of JS-K.
2
6
25
-O
alkyl chain branching.
O
Ca
NO (250 PSI)
Ca(OH)2 (0.6 equiv)
N+
N
NH
N
EtO2CN
2
H O
1
3 s.
100 h
EtO2CN
96%
2
4
-CF
3
2
1
1
35
26
R
pH = 7.4
NO2
N
+N
H
N
+
2 NO
85
35
85
35
O-
R
O2N
N
-O
O-
O
Ca
F
N+
N
-O
NO2
O
NO2
N
N+
N
DMSO
0 °C to 22 °C
24 h
N
4-Br
-OMe
4-F
EtO2CN
3
2
4
-OMe
68%
EtO2CN
H
4-tBu
9.9
4
-Me
26
JS-K
pKa of amine
9.5 9.7
8
.9
9.1
9.3
10.1
In summary, we have expanded the scope and demonstrated the
steric and electronic effects of the amine component on the
synthesis of diazeniumdiolates and the reactivity of calcium
diazeniumdiolate salts. In comparison to the reported method
developed by Drago and Keefer, we have shown that sterically-
hindered amines and electronically diverse amines are well-
Figure 1. Comparison of pKa to half-lives of benzylic amines.
By examining the electronic effects of the aromatic ring on the
half-lives of the diazeniumdiolate, a clear relationship between the
pka and the half-lives was established. As the electron-withdrawing
nature of the substituents on the aromatic ring increases, the pKa
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tolerated by using our reaction conditions. Application of this
method improved the synthesis of JS-K to an overall yield of
8%.
Calcium 1-(di-cyclohexylamino)diazen-1-ium-1,2-diolate
(7). A solution of dicyclohexylamine (943 mg, 5.2 mmol, 1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
2
equiv), Ca(OH) (231 mg, 3.12 mmol, 0.6 equiv) and 3.5 mL
degassed DI H O was charged with 350 psi of nitric oxide and
2
EXPERIMENTAL SECTION
stirred under pressure at room temperature for 100 h to give
380 mg (28%) of the corresponding calcium salt as a white
General. Unless otherwise mentioned, all chemicals were
purchased from commercial sources and used without further
purification. Ultraviolet (UV) spectra were recorded on a
diode array spectrophotometer. Nuclear magnetic resonance
−
1
−1
solid. UV (in 0.01 M NaOH) λmax 250 nm (2.5 mM cm ).
1
H NMR (500 MHz,CD OD): 3.23 (quintet, J = 9.5 Hz, 4H),
3
1.91-1.70 (m, 16H), 1.63 (m, 4H), 1.41-1.12 (m, 20H).
C{1H} NMR (125 MHz,CD OD): 56.9, 29.2, 25.8, 25.1.
3
HRMS (ESI-TOF): [M + OH] calcd for C H CaN O
24 45 6 5
537.3077, found 537.3078.
Calcium 1-(N-methylbenzylamino)diazen-1-ium-1,2-
diolate (11). A solution of N-methyl-1-phenylmethanamine
1
3
(NMR) spectra were collected with a 400 MHz spectrometer
using appropriate deuterated solvents with chemical shifts
reported in parts per million downfield from tetramethylsilane
or 2,2,3,3-tetradeuterotrimethylsilylpropionic acid.
General Procedure for the Synthesis of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Diazeniumdiolate: An 8 mL test-tube was charged with
(0.67 mL, 5.2 mmol, 1 equiv), Ca(OH) (231 mg, 3.12 mmol,
2
dialkylamine (5.2 mmol, 1.0 equiv), Ca(OH)
2
(231 mg, 3.12
0.6 equiv) and 3.5 mL degassed DI H O was charged with 60
2
mmol, 0.6 equiv) and degassed H2O (3.5 mL). (Note: DI
water was degassed by bubbling nitrogen for 2h). The mixture
was then degassed under vacuum and then pressurized by
nitrogen gas. The process of degassing/pressurizing was
repeated 3 times. Then the reaction mixture was pressurized
with NO gas. The reaction mixture was stirred at 800 rpm at
20 ºC.
After the reaction was complete, then the system was
depressurized by releasing the NO gas under nitrogen gas. The
solid was then collected by filtration and washed with 20 mL
psi of nitric oxide and stirred under pressure at room
temperature for 100 h to give 964.7 mg (93%) of the
corresponding calcium salt as a white solid. Spectral data
1
9,20 1
matches with the reported data.
H NMR (500
MHz,CD OD): 7.18-7.42 (m, 10 H), 4.15 (s, 4H), 2.83 (s, 6H).
3
13
C{1H} NMR (125 MHz,CD OD): 129.1, 127.8, 127.3,
3
126.8, 59.1, 41.7. HRMS (ESI-TOF): [M + OH] calcd for
C H CaN O 417.1199, found 417.1219.
1
6
21
6
5
Calcium 1-(-(4-fluorophenyl)-N-
methylmethanamino)diazen-1-ium-1,2-diolate (12). A
solution of 1-(4-fluorophenyl)-N-methylmethanamine (0.69
2
2
Et O. Then, it was dried under vacuum with nitrogen sweep to
give the desired calcium salt.
Calcium 1-(di-n-butylamino)diazen-1-ium-1,2-diolate
mL, 5.2 mmol, 1 equiv), Ca(OH) (231 mg, 3.12 mmol, 0.6
equiv) and 3.5 mL degassed DI H O was charged with 60 psi
2
(
4). A solution of dipropylamine (0.88 mL, 5.2 mmol, 1
equiv), Ca(OH) (231 mg, 3.12 mmol, 0.6 equiv) and 3.5 mL
degassed DI H O was charged with 250 psi of nitric oxide and
of nitric oxide and stirred under pressure at room temperature
for 100 h to give 1.029 g (90%) of the corresponding calcium
2
2
salt as a white solid. UV (in 0.01 M NaOH) λmax 250 nm
−1
−1
1
stirred under pressure at room temperature to give 1.07 (98%)
of the corresponding calcium salt as a white solid. UV (in 0.01
(0.67 mM cm ). H NMR (500 MHz, CD OD): 7.38 (dt, J = 10
3
Hz, 3Hz, 4H), 6.99 (dt, J = 10 Hz, 3Hz, 4H), 4.12 (s, 4H), 2.83 (t,
−
1
−1
1
13
M NaOH) λmax 250 nm (3 mM cm ); H NMR (500
MHz,CD OD): 2.92 (t, J = 8.5 Hz, 8H), 1.38 (m, 16H), 0.90 (t,
J = 8.7 Hz, 12H). C{1H} NMR (CD
J = 2.3Hz, 6H). C{1H} NMR (125 MHz, CD OD): 131.9, 131.1,
3
1
9
129.9, 114.3, 58.2, 41.7. F NMR (470 MHz, CD
3
OD): -117.2.
3
1
3
OD): 54.1, 28.6, 19.7,
2.9. HRMS (ESI-TOF): [M + OH] calcd for C16
33.2451, found 433.2464.
Calcium 1-(di-isobutylamino)diazen-1-ium-1,2-diolate
5). A solution of di-isobutylamine (0.91 mL, 5.2 mmol, 1
equiv), Ca(OH) (231 mg, 3.12 mmol, 0.6 equiv) and 3.5 mL
degassed DI H O was charged with 250 psi of nitric oxide and
stirred under pressure at room temperature for 100 h to give
46 mg (41%) of the corresponding calcium salt as a white
HRMS (ESI-TOF): [M + OH] calcd for C16
453.1011, found 453.1049.
H
2 6 5
19CaF N O
3
1
4
6 5
H37CaN O
Calcium 1-(-(4-methylphenyl)-N-
methylmethanamino)diazen-1-ium-1,2-diolate (13). A
solution of 1-(4-methylphenyl)-N-methylmethanamine (0.77
2
mL, 5.2 mmol, 1 equiv), Ca(OH) (231 mg, 3.12 mmol, 0.6
(
2
equiv) and 3.5 mL degassed DI HvO was charged with 60 psi
of nitric oxide and stirred under pressure at room temperature
for 100 h to give 1.036 g (93%) of the corresponding calcium
salt as a white solid. UV (in 0.01 M NaOH) λmax 250 nm (3.7
2
4
1
solid. H NMR (500 MHz,CD
1.53 (m, J = 10 Hz, 4H), 0.94 (d, J = 10 Hz, 24 H). C{1H}
NMR (125 MHz,CD OD): 62.2, 25.7, 19.5. HRMS (ESI-
TOF): [M + OH] calcd for C16 433.2451, found
33.2475.
Calcium 1-(di-sec-butylamino)diazen-1-ium-1,2-diolate
6). A solution of di-sec-butylamine (0.89 mL, 5.2 mmol, 1
equiv), Ca(OH) (231 mg, 3.12 mmol, 0.6 equiv) and 3.5 mL
degassed DI H O was charged with 350 psi of nitric oxide and
stirred under pressure at room temperature for 100 h to give
11 mg (38%) of the corresponding calcium salt as a white
3
OD): 2.70 (d, J = 10 Hz, 8H),
1
3
−1
−1
1
mM cm ). H NMR (500 MHz,CD
3
OD): 7.25 (d, J = 10 Hz,
4H), 7.08 (d, J =10 Hz, 4H), 4.10 (s, 4H), 2.80 (s, 6H), 2.28 (s,
3
1
3
H
37CaN
6
O
5
6H). C{1H} NMR (125 MHz,CD
128.5, 59.0, 41.5, 19.7. HRMS (ESI-TOF): [M + OH] calcd
445.1512, found 445.1534.
3
OD): 137.0, 132. 7, 129.1,
4
6 5
for C18H25CaN O
(
Calcium 1-(-(4-tert-butylphenyl)-N-
methylmethanamino)diazen-1-ium-1,2-diolate (14). A
solution of 1-(4-(tert-butyl)phenyl)-N-methylmethanamine
2
2
(1.02 mL, 5.2 mmol, 1 equiv), Ca(OH)
2
(231 mg, 3.12 mmol,
4
0.6 equiv) and 3.5 mL degassed DI H O was charged with 60
2
−
1
−1
solid. UV (in 0.01 M NaOH) λmax 250 nm (1.4 mM cm )
psi of nitric oxide and stirred under pressure at room
temperature for 100 h to give 1.243 g (94%) of the
corresponding calcium salt as a white solid. UV (in 0.01 M
1
H NMR (500 MHz,CD
3
OD): 3.32 (sextet, J = 8.5 Hz, 4H),
1
1
.62 (m, 4H), 1.35 (m, 4H), 1.13 (dd, J = 8.5 Hz, 4.8 Hz,
1
3
−1
−1
1
2H), 0.92 (dt, J = 8.5 Hz, 4.8 Hz, 12H). C{1H} NMR (125
OD): 55.3, 25.4, 15.0, 9.5. HRMS (ESI-TOF): [M +
OH] calcd for C16 433.2451, found 433.2467.
NaOH) λmax 250 nm (1.65 mM cm ). H NMR (500
MHz,CD OD): 7.31 (m, 10H), 4.12 (s, 4H), 2.82 (s, 6H), 1.28
MHz,CD
3
3
1
3
H
37CaN
6
O
5
3
(s, 18H). C{1H} NMR (125 MHz,CD OD): 128.8, 127.9,
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The Journal of Organic Chemistry
1
24.9, 124.6, 58.8, 41.7, 30.3. HRMS (ESI-TOF): [M + OH]
NMR (125 MHz,CD OD): 158.0, 36.8. HRMS (ESI-TOF): [M
6 5
+ OH] calcd for C H17CaN10O 349.1009, found 349.1041.
Calcium (benzamidinium)diazen-1-ium-1,2-diolate (20).
3
1
2
3
4
5
6
7
8
9
calcd for C24 529.2451, found 529.2469.
H
37CaN
O
6
5
Calcium 1-(-(4-bromophenyl)-N-
methylmethanamino)diazen-1-ium-1,2-diolate (15). A
solution of 1-(4-bromophenyl)-N-methylmethanamine (1.04
mL, 5.2 mmol, 1 equiv), Ca(OH)
equiv) and 3.5 mL degassed DI H
of nitric oxide and stirred under pressure at room temperature
for 100 h to give 902 mg (62%) of the corresponding calcium
salt as a white solid. UV (in 0.01 M NaOH) λmax 250 nm
A solution of benzamidine (624.8 mg, 5.2 mmol, 1 equiv),
Ca(OH)
degassed DI H
2
(231 mg, 3.12 mmol, 0.6 equiv) and 3.5 mL
O was charged with 60 psi of nitric oxide and
2
(231 mg, 3.12 mmol, 0.6
O was charged with 60 psi
2
2
stirred under pressure at room temperature for 100 h to give
855 mg (83%) of the corresponding calcium salt as a white
solid. Spectral data matches with the reported data.2 H NMR
1 1
(500 MHz,CD
Hz, 2H), 7.46 (t, J = 9.0 Hz, 4H). C{1H} NMR (125
MHz,CD OD): 159.4, 133.4, 130.7, 128.1, 128.1, 126.9.
3
OD): 7.82 (d, J = 9.0 Hz, 4H), 7.53 (t, J = 9.0
−1
−1
1
13
(3.65 mM cm ). H NMR (500 MHz,CD
3
OD): 7.42 (d, J =
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0 Hz, 4H), 7.29 (d, J = 10 Hz, 4H), 4.11 (s, 4H), 2.86 (s, 6H).
3
1
3
C{1H} NMR (125 MHz,CD
130.1, 54.2, 34.0. HRMS (ESI-TOF): [M + OH] calcd for
CaN 572.9410, found 572.9441.
Calcium 1-(-(4-trifluoromethylphenyl)-N-
3
OD): 131.1, 131.0, 130.9,
HRMS (ESI-TOF): [M - H] calcd for C14
found 397.0718.
8 4
H13CaN O 397.0691,
C
16
H
19Br
2
6
O
5
Calcium N-(acetamide)diazen-1-ium-1,2-diolate (21). A
solution of acetamidine (307 mg, 5.2 mmol, 1 equiv), Ca(OH)
2
(231 mg, 3.12 mmol, 0.6 equiv) and 3.5 mL degassed DI
methylmethanamino)diazen-1-ium-1,2-diolate (16). A
solution of 1-(4-trifluoromethylphenyl)-N-methylmethanamine
H O was charged with 60 psi of nitric oxide and stirred under
2
(0.86 mL, 5.2 mmol, 1 equiv), Ca(OH)
2
(231 mg, 3.12 mmol, 0.6
pressure at room temperature for 100 h to give 226.4 mg
equiv) and 3.5 mL degassed DI H O was charged with 60 psi of
2
(
32%) of the corresponding calcium salt as a white solid.
nitric oxide and stirred under pressure at room temperature for
100 h to give 912 mg (65%) of the corresponding calcium salt as
a white solid. UV (in 0.01 M NaOH) λmax 250 nm (1.48
22 1
Spectral data matches with the reported data. H NMR (500
13
MHz,D
77.1, 20.8. HRMS (ESI-TOF): [M + OH] calcd for
CaN 293.0159, found 293.0179.
Calcium N-(picolinamide)diazen-1-ium-1,2-diolate (22).
A solution of picolinamide (635 mg, 5.2 mmol, 1 equiv),
Ca(OH) (231 mg, 3.12 mmol, 0.6 equiv) and 3.5 mL degassed
DI H O was charged with 60 psi of nitric oxide and stirred
under pressure at room temperature for 100 h to give 728.1 mg
2 2
O): 1.68 (s, 6H). C{1H} NMR (125 MHz,D O):
1
C
−
1
−1
1
mM cm ). H NMR (500 MHz,CD
3
OD): 7.56 (m,10H), 4.22
s, 4H), 2.87 (s, 6H). C{1H} NMR (125 MHz,CD OD): 14.0,
5.5, 113.5, 124.6, 129.5, 129.6, 134.9. 19F NMR (470 MHz,
4
H
9
6 7
O
1
3
(
6
3
CD
3
OD): -64.1. HRMS (ESI-TOF): [M + OH] calcd for
553.0947, found 553.0930.
Calcium 1-(-(3-methoxyphenyl)-N-
2
18 6 6 5
C H19CaF N O
2
methylmethanamino)diazen-1-ium-1,2-diolate (17). A
solution of 1-(3-methoxyphenyl)-N-methylmethanamine (0.78
(
(
(
70%) of the corresponding calcium salt as a white solid. UV
−1
−1 1
in 0.01 M NaOH) λmax 250 nm (0.85 mM cm ) H NMR
500 MHz,(CD O): 8.57 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 9.7
mL, 5.2 mmol, 1 equiv), Ca(OH)
equiv) and 3.5 mL degassed DI H
of nitric oxide and stirred under pressure at room temperature
for 100 h to give 953 mg (79%) of the corresponding calcium
salt as a white solid. UV (in 0.01 M NaOH) λmax 250 nm (2.5
2
(231 mg, 3.12 mmol, 0.6
O was charged with 60 psi
3 2
)
2
13
Hz, 2H), 7.52 (t, J = 9.7 Hz, 1H). C{1H} NMR (125
MHz,D O):152.2, 148.3, 138.4, 126.1, 123.9. HRMS (ESI-
2
TOF): [M + OH] calcd for C12
419.0384.
8 7
H11CaN O 419.0377, found
−
1
−1
1
mM cm ). H NMR (500 MHz,CD
Hz, 2H), 6.98 ( t, J = 2.7 Hz, 2H), 6.93 (d, J = 10 Hz, 2H),
3
OD): 7.17 ( t, J = 10
1-(2,4-dinitrophenoxy)-3,3-diethyltriaz-1-ene 2-oxide (24).
In a 24 mL round bottom flask, a solution of Diethyl amino
calcium DAZD 24 (183 mg, 0.6 mmol, 1.25 equiv) in 0.6 mL
DMSO was cooled to 0°C under nitrogen. Then 1-fluoro-2,4-
dinitrobenzotrifluoride (0.127 mL, 1.0 mmol, 1 equiv) in 0.9 mL
DMSO was added dropwise. The mixture was warmed naturally
to room temperature and stirred for 18 hours. The reaction is
6
2
1
.79 (dd, J = 10 Hz, 2.6 Hz, 2H), 4.12 (s, 4H), 3.76 (s, 6H),
1
3
.82 (s, 6H). C{1H} NMR (125 MHz,CD
3
OD): 159.7, 137.4,
28.8, 121.1, 114.3, 112.9, 59.1, 54.2, 41.7. HRMS (ESI-
TOF): [M + OH] calcd for C18
477.1443.
6 7
H25CaN O 477.1411, found
Calcium 1-(-(4-methoxyphenyl)-N-
2 2
quenched with 5 mL H O and extracted with Et O (20 mL x 3).
Then the organic layers were combined and then dried with
sodium sulfate and concentrated under vacuum. The crude oil
product was chromatographed on a 12 g silica gel column and
eluted with a gradient from 100% hexanes to 70:30 hexanes/ethyl
acetate to give 238 mg (80% yield) of 1-(2,4-dinitrophenoxy)-3,3-
diethyltriaz-1-ene 2-oxide as an orange solid. Spectral data
methylmethanamino)diazen-1-ium-1,2-diolate (18). A
solution of 1-(4-methoxyphenyl)-N-methylmethanamine (0.78
mL, 5.2 mmol, 1 equiv), Ca(OH)
equiv) and 3.5 mL degassed DI H
2
(231 mg, 3.12 mmol, 0.6
2
O was charged with 60 psi of
nitric oxide and stirred under pressure at room temperature for
00 h to give 1.028 g (86%) of the corresponding calcium salt as
a white solid. UV (in 0.01 M NaOH) λmax 250 nm (2.65
1
1
9
matches with the reported data.
−1
−1
1
Calcium (Ethyl piperazine-1-carboxylate)diazen-1-ium-
mM cm ). H NMR (500 MHz,CD
2H), 6.81 (d, J = 10 Hz, 2H), 4.07 (s, 4H), 3.74 (s, 6H), 2.79 (s,
3
OD): 7.28 (d, J = 10 Hz,
1
,2-diolate (26). A solution of ethyl piperazine-1-carboxylate
1
3
2
(0.77 mL, 5.2 mmol, 1 equiv), Ca(OH) (231 mg, 3.12 mmol,
6
1
H). C{1H} NMR (125 MHz,CD
13.2, 58.6, 54.2, 41.4. HRMS (ESI-TOF): [M + OH] calcd for
477.1411, found 477.1344.
Calcium (guanidinium)diazen-1-ium-1,2-diolate (19). A
solution of 1,1- dimethylguanidine sulfate (983mg, 5.2 mmol,
equiv), Ca(OH) (616 mg, 8.32 mmol, 1.6 equiv) and 3.5
mL degassed DI H O was charged with 60 psi of nitric oxide
3
OD): 158.3, 130.4, 127.8,
0
2
.6 equiv) and 3.5 mL degassed DI H O was charged with 250
psi of nitric oxide and stirred under pressure at room
temperature for 100 h to give 712 mg (96%) of the
18 6 7
C H25CaN O
1
corresponding calcium salt as a white solid. H NMR (500
MHz,CD
3
OD): 4.13 (t, J = 5 Hz, 4H), 3.65 (m, 4H), 3.42 (m,
1
2
4
H), 3.17 (t, J = 5Hz, 4H), 2.75 (t, J = 5Hz, 4H), 1.26 (q, J =
2
1
3
5Hz, 6H). C{1H} NMR (125 MHz,CD
51.7, 44.8, 13.5. HRMS (ESI-TOF): [M + OH] calcd for
C H CaN O 491.1527, found 491.1541.
3
OD): 155.5, 61.6,
and stirred under pressure at room temperature for 100 h to
give 798 mg (92%) of the corresponding calcium salt as a
white solid. UV (in 0.01 M NaOH) λmax 250 nm (2.1 mM
−
1
14 27
8
9
−
1
1
13
3
cm ). H NMR (500 MHz,CD OD): 3.02 (s, 12 H). C{1H}
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The Journal of Organic Chemistry
Page 6 of 7
JS-K. In a 24 mL round bottom flask, a solution of
ASSOCIATED CONTENT
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
piperidine calcium DAZD 25 (178 mg, 0.375 mmol, 1.25
equiv) in 0.3 mL DMSO was cooled to 0°C under nitrogen.
Then 1-fluoro-2,4-dinitrobenzotrifluoride (0.076 mL, 0.6
mmol, 1 equiv) in 0.5 mL DMSO was added dropwise. The
mixture was warmed naturally to room temperature and stirred
Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1H, 13C, and 19F NMR spectra of new compounds

for 18 hours. The reaction is quenched with 5 mL H
2
O and
AUTHOR INFORMATION
Corresponding Author
extracted with Et O (20 mL x 3). Then the organic layers were
2
combined and then dried with sodium sulfate and concentrated
under vacuum. The crude oil product was chromatographed on
a 12 g silica gel column and eluted with a gradient from 100%
hexanes to 50%:50% hexanes/ethyl acetate to give 157 mg
(68% yield) of 1-(2,4-dinitrophenoxy)-3,3-diethyltriaz-1-ene
2-oxide was isolated as a yellow solid. Spectral data matches
*
Email: amjad_ali@merck.com
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Notes
The authors declare no competing financial interest.
2
7
with the reported data.
ACKNOWLDEGMENT
Kinetic Studies. Kinetic experiments were performed at 37 °C
using a standard UV−visible spectrophotometer. Reactions were
initiated by addition of substrate to a preheated cuvette containing
the buffer. Analyte concentration was measured in 100 μM 0.1M
phosphate buffer, pH 7.4. In each experiment, the data were
analyzed at the λmax and the rate was derived by fitting the data to
an exponential curve typical for first-order processes.
The authors acknowledge support from the MRL Postdoctoral
Research Program.
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Muzzio, D.; Bassan, E.; Dienemann, E.; Weisel, M.; Cowden, C.; Hoerrner, S.; Olsen, W.; Man-Chu Lo, M.; Ali, A. Chemical Safety:
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1
5
See DSC Results: Zhong, Y.-L.; Weisel, M.; Humphrey, G. R.; Muzzio, D. J.; Zhang, L.; Huffman, M. A.; Zhong, W.; Maloney, K. M.;
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At 40 psi, the Calcium 1-(di-n-butylamino)diazen-1-ium-1,2-diolate was isolated in 84% yield.
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2 N
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The acetamide diazeniumdiolate was difficult to separate from the unreacted acetamide.
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Not enough data of decomposition rates of the sodium DAZD salts has been reported to make the comparison for the sodium salts as well.
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NO
(250 PSI)
Ca(OH)2 0.6 equiv)
H2O
20°C
R2
R2
R2
N
N
Ca
N
N
NH
R1
N+
O-
O
O
N+
O-
R1
R1
NO
ToC graphic
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