Direct microwave synthesis of N,N′-diacylhydrazines and boc-protected hydrazides by in situ carbonylations under air

Article abstract of DOI:10.1055/s-2004-832837

Palladium-catalyzed hydrazidocarbonylations of aryl iodides and bromides were performed by controlled microwave irradiation, employing Mo(CO)₆ as a convenient CO source. A fluorous phosphine ligand was succesfully used to recycle the catalytic

Full text of DOI:10.1055/s-2004-832837

LETTER
2335
Direct Microwave Synthesis of N,N¢-Diacylhydrazines and Boc-Protected
Hydrazides by in situ Carbonylations under Air
Synthesis of
N,
N
¢
-
Diac
a
ylhydrazine
r
s and Bo
i
c-Prot
a
ected Hydrazide
s
Antonia Herrero,1 Johan Wannberg, Mats Larhed*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box-574, 75123 Uppsala, Sweden
Fax +46(18)4714474; E-mail: mats@orgfarm.uu.se
Received 11 July 2004
aryl iodides 1a–d (0.40 mmol) were allowed to react with
hydrazides 2a–c (3 equiv) in dry THF using palladium
acetate (10 mol%) as the precatalyst, DBU (3 equiv) as the
base and Mo(CO)6 (1 equiv) as the CO-source (Method
Abstract: Palladium-catalyzed hydrazidocarbonylations of aryl io-
dides and bromides were performed by controlled microwave irra-
diation, employing Mo(CO)6 as a convenient CO source. A fluorous
phosphine ligand was succesfully used to recycle the catalytic sys-
tem. Finally, dehydration of a diacylhydrazine to the corresponding A). The reactions were performed in sealed vessels under
1,3,4-oxadiazole was achieved with POCl3 in a one-pot procedure.
air during 15 minutes of high-density microwave irradia-
tion (Scheme 1). Hydrazidocarbonylation were predomi-
nantly achieved at a reaction temperature of 110 °C,
generating N,N¢-diacylhydrazine products 3a–l in moder-
ate to good isolated yields (30–71%, Table 1). The yields
of the protected hydrazides 3c,f,i,l were fairly low (30–
43%). Importantly, full conversions of 1a–c were always
obtained. Analysis of the reaction mixtures by GC- and
LC-MS indicated that benzamide and benzonitrile side
products were formed in most cases, but only traces of
dehalogenated starting material could be detected. We
therefore suspected that the moderate yields obtained
were a consequence of thermal decomposition of products
3 and/or loss of material in the purification step.
Key words: microwave, carbonylation, molybdenum hexacarbon-
yl, hydrazide, fluorous
The demands made on innovative drug discovery are
changing at an unprecedented pace, and the techniques of
organic synthesis and high throughput chemistry must
thus continue to evolve. Today, various strategies have
been developed to rapidly and cleanly deliver novel lead
molecules.2 Although many high throughput chemistry
methods have their roots in efficient separation meth-
ods,3,4 the interest in accelerating organic reactions by
high-density microwave heating (MW) has increased over
the last few years.5 In the field of microwave chemistry,
the use of different solid phase protocols combines short
reaction times with convenient product isolation and puri-
fication.6 The difficulties encountered in performing gas-
eous reactions under microwave irradiation have further
spurred the invention of carbon monoxide releasing solid
phase reagents for high-speed carbonylative applica-
tions.7–10
O
H
R1
R1
Pd(OAc)2
I
H
N
R2
R2
Mo(CO)6, air
N
N
H
+
H2N
O
MW, 110 °C
DBU, THF
(Method A)
O
3a–l
1a–d
2a–c
30–78%
Scheme 1
N,N¢-Diacylhydrazines are well known starting materials
for the preparation of various heterocycles,11 but this func-
tionality can also be found in different types of protease
inhibitors.12,13 Despite their obvious importance, very few
examples of direct carbonylative synthesis of these struc-
tures have been reported in the literature.14,15 By linking
our interest of microwave-promoted metal-catalysis16 and
in situ carbonylation with the quest for an efficient synthe-
sis of diacylhydrazines, we hoped to demonstrate several
preparative advantages. The possibility of converting aryl
halides to protected arylhydrazides by using Boc-hydra-
zine as the nucleophile was also recognized.
Attempts to lower the reaction temperature to minimize
side-product formation resulted in a need for undesirably
long reaction times to reach full conversion.
Decreasing the reaction time, to avoid thermal degrada-
tion,17 led to the observation that most reactions were
completed after only five minutes, with the exception of
the electron rich 1a. The shorter reaction times presented
in Table 1 also generally improved the isolated yields to
36–78%.
We have previously reported that aryl bromides can be
used as substrates in aminocarbonylation reactions with
Herrmann’s palladacycle18 as the precatalyst.8,9 In the
present hydrazidocarbonylation application the catalytic
activity was further improved by addition of Fu’s robust
phosphonium salt, [(t-Bu)3PH]BF4, designed to liberate
free t-Bu3P under basic reaction conditions (Method B).19
Thus, three different reactions starting from aryl bromides
4a,b,d were performed with hydrazide 2a at 130 °C for
five minutes, affording slightly reduced isolated yields
(43–57%) compared to the corresponding aryl iodides
We herein report on a new protocol exploiting easily han-
dled and convenient molybdenum hexacarbonyl as a solid
source of carbon monoxide for performing rapid hydrazi-
docarbonylation reactions with aryl halides. Initially, four
SYNLETT 2004, No. 13, pp 2335–2338
0
3
.1
1
.2
0
0
4
Advanced online publication: 24.09.2004
DOI: 10.1055/s-2004-832837; Art ID: D18604ST
© Georg Thieme Verlag Stuttgart · New York

2336
M. A. Herrero et al.
LETTER
Table 1 Microwave-Heated Hydrazidocarbonylation of Aryl Io-
dides
Unfortunately, aryl chlorides were found to be inert under
the carbonylation conditions of Method B.
Catalyst recycling and reuse can be of crucial importance
in homogeneous reaction protocols employing expensive
metal catalysts. With fluorous biphasic catalysis the abil-
ity of fluorous solvents to form mono- or biphasic systems
with conventional organic solvents, above and below the
consolute temperature is utilized to enable efficient recy-
cling of the fluorous catalyst.20–22 The major advantage
with the fluorous/microwave combination is that the con-
solute temperature can be very rapidly reached by high-
density microwave heating, enabling a catalytic reaction
under truly homogeneous conditions.23 Subsequently, the
biphasic catalyst separation can be accelerated with the
very efficient air-jet cooling system commonly built into
modern microwave synthesizers. Thus, within this hy-
drazidocarbonylation project it was decided to investigate
a commercially available fluorous version of triphenyl
Entry
Aryl iodide
R1
Hydrazide Time
Product
Yield
(%)a
R2
(min)
1
2
4-MeO (1a)
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-Me (1b)
4-Me
Ph (2a)
Ph
15
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
62
65
53
58
43
44
71
78
56
59
39
40
44
53
30
54
30
36
51
57
39
48
40
45
11
3
Bn (2b)
Bn
15
4
11
5
Ot-Bu (2c) 15
6
Ot-Bu
Ph
13
15
5
7
8
Ph
9
4-Me
Bn
15
5
phosphine
{tris[4-(1H,1H,2H,2H-perfluorodecyl)phe-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-Me
Bn
nyl]phosphine} (5) in an organic/fluorous biphasic
system.
4-Me
Ot-Bu
Ot-Bu
Ph
15
7
4-Me
3f
O
2-Me (1c)
2-Me
15
5
3g
3g
3h
3h
3i
2a, P(PhCH2CH2C8F17 3
)
H
N
Ph
I
Pd(OAc)2 , DBU, Mo(CO)6
N
Ph
H
3d
O
MW, air, 110 °C, 5 min
THF, CF-84
+
2-Me
Bn
15
5
1b
Pd[P(PhCH2CH2C8F17)3]n
2-Me
Bn
Recycling of fluorous catalytic phase
2-Me
Ot-Bu
Ot-Bu
Ph
15
5
Scheme 3
2-Me
3i
4-CF3 (1d)
4-CF3
15
5
3j
Ph
3j
4-CF3
Bn
15
5
3k
3k
3l
4-CF3
Bn
4-CF3
Ot-Bu
Ot-Bu
15
5
4-CF3
3l
a Method A, isolated yield after flash chromatography.
(Scheme 2). The somewhat lower yields were probably a
consequence of decomposition of temperature-sensitive
diacylhydrazines 3a,d,j at the elevated reaction tempera-
ture.
Figure 1 Illustration of fluorous biphasic catalysis before, during
and after high-density microwave irradiation.
Fu salt
Palladacycle
Mo(CO)6, air
O
H
The degree to which the catalytic fluorous layer could be
recycled was studied using 4-iodotoluene (1b) and benz-
hydrazide (2a) as reactants, essentially employing iden-
tical microwave conditions as with the organic parent
reaction (Table 1, entry 8) but also including ligand 5 and
the perfluorinated solvent FC-84 (Scheme 3). After each
heating/cooling cycle (Figure 1), the organic layer was
separated and the product isolated. Thereafter charging a
Br
N
Ph
N
2a
+
H
MW, DBU, THF
O
R1
R1
130 °C, 5 min
(Method B)
R1
OMe (3a) 50%
Yield
R1= OMe (4a)
Me (4b)
Me (3d)
CF3 (3j)
57%
43%
CF3 (4d)
Scheme 2
Synlett 2004, No. 13, 2335–2338 © Thieme Stuttgart · New York

LETTER
Synthesis of N,N¢-Diacylhydrazines and Boc-Protected Hydrazides
2337
400 MHz and 100.5 MHz, respectively. GC-MS was used to ana-
lyze the conversion of 1 and 4. Reaction mixtures and pure products
were analyzed using an analytical LC-MS system with a Chro-
molith Performance RP-18e column (100 × 4.6 mm). The mobile
phase was MeCN–H2O with 0.05% HCOOH (4 mL/min, 0–50%
MeCN in H2O, 8 min gradient) employing UV-detection (214 nm
and 254 nm) and a mass selective detector (ESI). Flash column
chromatography was performed on Silica gel 60 or 60 RP-18
(0.040-0.063 mm). THF was freshly distilled over Na/benzophe-
none. All other chemicals were commercially available and used as
received.
reaction vial with the fluorous catalytic media and fresh
1b, 2a, Mo(CO)6, DBU and THF, we were able to achieve
full conversion of 1b and good isolated yields of 3d (64–
79%, Figure 2). This multiple carbonylation protocol may
represent the first example of recycling of a fluorous
metal catalyst in a microwave heated biphasic reaction
system.24 Using the same procedure but omitting the fluo-
rous phosphine ligand 5 yielded only traces of product 3d
after the first recycling (second heating) of the reaction
cocktail.
Finally, we confirmed that the hydrazidocarbonylation
method could be conveniently employed for a one-pot,
two-step generation of an 1,3,4-oxadiazole 6. The cycliza-
tion/dehydration of intermediate 3j was performed with
POCl3 (Scheme 4).14,15 The increased yield of 6 in this
one-pot, two-step procedure, compared to the 43% yield
of pure diacylhydrazine 3j (Scheme 2) indicates the prob-
lems in purifying the free N,N¢-diacylhydrazine products
by flash chromatography.
General Method A. Hydrazidocarbonylation of Aryl Iodides:
A 0.5–2.0 mL process vial was charged with aryl iodide (0.40
mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol), Mo(CO)6 (0.106 g, 0.40
mmol), hydrazide (1.20 mmol), DBU (0.18 mL, 1.20 mmol) and dry
THF (1.00 mL). The vial was immediately capped with a Teflon
septum and irradiated with microwaves to 110 °C for 5–15 min. Af-
ter cooling, the reaction mixture was filtered and the solvent was re-
moved under reduced pressure. The residue was purified by flash
column chromatography using 1:1 hexane–EtOAc as the eluent to
obtain the pure product (>95% purity by 1H NMR).25
General Method B. Hydrazidocarbonylation of Aryl Bromides:
A 0.5–2.0 mL process vial was charged with aryl bromide (0.40
mmol), and Herrman’s palladacycle {Pd2(OAc)2[P(o-tol)3]2, 9.4
mg, 0.01 mmol}, Fu’s salt {[(t-Bu)3PH]BF4), 11.6 mg, 0.04 mmol},
Mo(CO)6 (0.106 g, 0.40 mmol), hydrazide (1.20 mmol), DBU (0.18
mL, 1.20 mmol) and dry THF (1.0 mL). The vial was immediately
capped with a Teflon septum and irradiated with microwaves to
130 °C for 5 min. After cooling, the reaction mixture was filtered
and the solvent was removed under reduced pressure. The residue
was purified by reversed phase flash column chromatography (Sili-
ca gel 60 RP-18) using a 10–60% MeCN in H2O (0.05% HCOOH)
gradient to obtain the pure product (>95% purity by 1H NMR).25
Recycling of the Palladium/Fluorous Liquid Catalyst:
A 2.0–5.0 mL process vial was charged with 4-iodotoluene (0.180
g, 0.40 mmol), Pd(OAc)2 (9.00 mg, 0.04 mmol), Mo(CO)6 (0.106 g,
0.40 mmol), benzhydrazide (0.163 g, 1.20 mmol), DBU (0.18 mL,
1.20 mmol), tris[4-(1H,1H,2H,2H-perfluorodecyl)phenyl]-phos-
phine (0.192 g, 0.12 mmol), dry THF (1.0 mL) and CF-84 (1.5 mL).
The vial was immediately capped with a teflon septum under air and
irradiated with microwaves to 110 °C for 5 min. After cooling, in
order to recycle the fluorous catalytic system, the fluorous phase
was carefully transferred by Pasteur pipette to the second process
vial which was pre-charged with 4-iodotoluene (0.180 g, 0.40
mmol), Mo(CO)6 (0.106 g, 0.40 mmol), benzhydrazide (0.163 g,
1.20 mmol), DBU (0.18 mL, 1.20 mmol) and dry THF (1.00 mL).
The second vial was immediately capped with a teflon septum un-
der air and irradiated with microwaves to 110 °C for 5 min. This
process was repeated until a total of six reactions had been per-
formed. The flourous phase containing the palladium fluorous-
tagged phosphine catalytic system was then left under air for one
week (at r.t.) and then used for one more reaction as described
above, showing no more than 5% consumption of starting material.
In all the cases, the remaining organic parts of the reaction mixtures
Figure 2 Recyclability of the fluorous catalyst phase. Reactions
were performed on 0.40 mmol scale with 5 and THF / FC-84.
Ph
O
Br
N
1) Method B
N
2a
+
2) POCl3, 110 °C, 3 h
(One-pot)
6
50%
F3C
F3C
Scheme 4
By combining the power of high-density microwave heat-
ing with in situ release of carbon monoxide, a novel and
direct method for preparation of aryl substituted diacylhy-
drazines has been demonstrated. The presented hydrazi-
docarbonylation reactions deliver moderate to good yields were filtered and volatile material removed under reduce pressure.
The residues were then purified by silica flash column using 1:1
and were executed under air in 5–15 minutes. By using a
fluorous ligand, the fluorous catalyst was reused five
times.
hexane–EtOAc as the eluent to obtain the six batches of N-benzoyl-
N¢-(4-methyl)benzoylhydrazine (>95% purity by 1H NMR).
One-Pot Dehydration to 1,3,4-Oxadiazole 6:
The carbonylation step was performed according to procedure B al-
though using 2 mL of a mixture of 10% THF in toluene as a solvent.
After cooling, 4 mL of POCl3 was added by syringe through the
septum. The needle was left in the septum to allow formed gases to
The microwave reactions were performed in a SmithSynthesizer
producing controlled irradiation at 2450 MHz with a power of 0–
300 W. The reaction temperature was determined using the built-in
on-line IR-sensor. 1H NMR and 13C NMR spectra were recorded at
Synlett 2004, No. 13, 2335–2338 © Thieme Stuttgart · New York

2338
M. A. Herrero et al.
LETTER
escape. The mixture was stirred in a heating block at 110 °C for 3 h
and then poured onto 100 mL of H2O and extracted with 3 × 100 mL
CH2Cl2. The combined organic layers were dried with MgSO4 and
concentrated under reduced pressure. The residue was purified by
column chromatography (0–2% MeOH in CHCl3) to give 6 in 50%
yield (57.6 mg).26
(25) N-(4-Methoxy)benzoyl-N¢-phenylacetylhydrazine (3b).
Colorless solid; mp 153–154 ºC. LC-MS tR = 4.26 min,
m/z = 285 [M + H+]. 1H NMR (400 MHz, CD3OD): d = 3.58
(s, 2 H), 3.80 (s, 3 H), 6.94 (AA¢XX ¢, 2 H), 7.15–7.34 (m, 5
H), 7.79 (AA¢XX ¢, 2 H) ppm. 13C NMR (100.5 MHz,
CD3OD): d = 43.0, 57.6, 116.5 (2), 127.2, 129.6, 131.2 (2),
131.9 (2), 132.2 (2), 137.9, 166.0, 170.6, 174.9 ppm. Anal.
Calcd for C16H16N2O3 (%): C, 67.59; H, 5.67; N, 9.85.
Found: C, 67.40; H, 5.78; N, 9.70.
Acknowledgment
N-(4-Methoxy)benzoyl-N¢-tert-butoxycarbonylhydrazine
(3c). Colorless solid; mp 148–149 °C. LC-MS tR = 4.58 min,
m/z = 267 [M + H+]. 1H NMR (400 MHz, CD3CN): d = 1.44
(s, 9 H), 3.83 (s, 3 H), 6.95 (AA¢XX ¢, 2 H), 7.76 (AA¢XX ¢,
2 H) ppm. 13C NMR (100.5 MHz, CD3CN): d = 28.3 (3),
56.1, 81.2, 114.7 (2), 125.8, 130.1 (2), 156.5, 163.5, 167.4
ppm. Anal. Calcd for C13H18N2O4 (%): C, 58.64; H, 6.81; N,
10.52. Found: C, 58.54; H, 6.72; N, 10.66.
We acknowledge the financial support from the Swedish Research
Council and from Knut and Alice Wallenberg´s Foundation. We
thank Mr Shane Peterson for linguistic advice and Biotage AB for
providing us with the SmithSynthesizer. M.A.H. acknowledges a
grant from the Junta de Comunidades de Castilla-La Mancha.
References
N-(4-Methyl)benzoyl-N¢-phenylacetylhydrazine (3e).
Colorless solid; mp 175–176 °C. LC-MS tR = 4.71 min,
m/z = 269 [M + H+]. 1H NMR (400 MHz, CD3OD): d = 2.39
(s, 2 H), 3.63 (s, 2 H), 7.20–7.39 (m, 5 H), 7.76 (AA¢XX ¢, 2
H) ppm. 13C NMR (100.5 MHz, CD3OD): d = 21.5, 41.7,
127.9, 128.7 (2), 129.5 (2), 129.8 (2), 130.1, 130.2 (2),
130.6, 136.2, 144.1, 169.2, 173.1 ppm. Anal. Calcd for
C16H16N2O2 + 0.4H2O (%): C, 69.75; H, 6.15; N, 10.17.
Found: C, 69.71; H, 6.04; N, 10.11.
N-(4-Methyl)benzoyl-N¢-tert-butoxycarbonylhydrazine
(3f). Colorless solid; mp 153–154 °C. LC-MS tR = 5.05 min,
m/z = 251 [M + H+]. 1H NMR (400 MHz, CDCl3): d = 1.48
(s, 9 H), 2.38 (s, 3 H), 7.20 (AA¢XX ¢, 2 H), 7.70 AA¢XX ¢,
2 H) ppm. 13C NMR (100.5 MHz, CDCl3): d = 21.7, 28.3 (3),
82.1, 127.4 (2), 129.1, 129.4 (2), 142.9, 155.9, 167.0 ppm.
Anal. Calcd for C13H18N2O3 (%): C, 62.38; H, 7.25; N,
11.19. Found: C, 62.22; H, 7.11; N, 11.06.
N-(2-Methyl)benzoyl-N¢-phenylacetylhydrazine (3h).
Colorless solid; mp 174–175 °C. LC-MS tR = 4.40 min,
m/z = 269 [M + H+]. 1H NMR (400 MHz, CD3OD): d = 2.40
(s, 3 H), 3.60 (s, 2 H), 7.17–7.36 (m, 8 H), 7.43 (dd, J = 7.7,
1.2 Hz, 1 H, ArH) ppm. 13C NMR (100.5 MHz, CD3OD):
d = 18.3, 40.3, 125.4, 126.7, 127.2, 128.2, 128.9, 130.2,
130.5, 134.0, 134.9, 136.4, 165.5, 171.6 ppm. Anal. Calcd
for C16H16N2O2 + 0.5H2O (%): C, 69.30; H, 6.18; N, 10.10.
Found: C, 69.45; H, 6.19; N, 9.96.
N-Phenylacetyl-N¢-(4-trifluoromethyl)benzoylhydrazine
(3k). Colorless solid; mp 195–196 °C. LC-MS tR = 5.92 min,
m/z = 323 [M + H+]. 1H NMR (400 MHz, CD3OD): d = 3.61
(s, 2 H), 7.15–7.35 (m, 5 H), 7.76 (AA¢XX ¢, 2 H), 7.99
(AA¢XX ¢, 2 H) ppm. Anal. Calcd for C16H13F3N2O2 (%): C,
59.63; H, 4.07; N, 8.69. Found: C, 59.41; H, 3.96; N, 8.59.
N-tert-Butoxycarbonyl-N¢-(4-trifluoromethyl)-
(1) New address: Department of Organic Chemistry, C. C.,
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Synlett 2004, 1379.
benzoylhydrazine (3l). Colorless solid; mp 143–144 °C.
LC-MS tR = 6.29 min, m/z = 305 [M + H+]. 1H NMR (400
MHz, CD3OD): d = 1.45 (s, 9 H), 7.80 (AA¢XX ¢, 2 H), 7.94
(AA¢XX ¢, 2 H) ppm. Anal. Calcd for C13H15F3N2O3 (%): C,
51.32; H, 4.97; N, 9.21. Found: C, 51.07; H, 5.06; N, 9.35.
(26) 2-Phenyl-5-(4-trifluoromethyl)phenyl-1,3,4-oxadiazole
(6). Colorless solid; mp 151–152 °C. LC-MS (4 mL/min, 0–
70% MeCN in H2O, 8 min gradient, ESI+) tR = 6.91 min,
m/z = 291 [M + H+]. 1H NMR (400 MHz, CDCl3): d = 7.50–
7.60 (m, 3 H), 7.80 (AA¢XX ¢, 2 H), 8.16 (dd, J = 7.9 and 1.7
Hz, 2 H), 8.27 (AA¢XX ¢, 2 H). Anal. Calcd for C15H9F3N2O
(%): C, 62.07; H, 3.13; N, 9.65. Found: C, 62.08; H, 3.18; N,
9.73.
Synlett 2004, No. 13, 2335–2338 © Thieme Stuttgart · New York