One-Pot Synthesis of Protected Benzylhydrazines from Acetals

Full text of DOI:10.1080/00304948.2018.1468983

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
One-Pot Synthesis of Protected Benzylhydrazines
from Acetals
Anton Mastitski, Siret Niinepuu, Tõiv Haljasorg & Jaak Järv
To cite this article: Anton Mastitski, Siret Niinepuu, Tõiv Haljasorg & Jaak Järv (2018) One-Pot
Synthesis of Protected Benzylhydrazines from Acetals, Organic Preparations and Procedures
International, 50:4, 416-423, DOI: 10.1080/00304948.2018.1468983
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Organic Preparations and Procedures International, 50:416–423, 2018
# 2018 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2018.1468983
One-Pot Synthesis of Protected Benzylhydrazines
from Acetals
~
€
Anton Mastitski, Siret Niinepuu, Toiv Haljasorg, and Jaak Jarv
Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia
Organic derivatives of hydrazine are used for synthesis of various heterocyclic com-
pounds,1–4 pharmaceutical substances,5,6 agricultural chemicals7,8 and modified pepti-
des.9 In the structure of aza-peptides at least one amino acid residue is substituted by a
hydrazino acid and this modification greatly improves the proteolytic stability of a pep-
tide, which, in turn, makes aza-peptides promising drug candidates.10–12
Due to the instability of aza-amino acids (carbazic acids), incorporation of hydrazino
acids into the peptide sequences requires protected alkylhydrazines corresponding to the
natural amino acids. Major approaches to protected alkylhydrazines include direct alkylation
of protected hydrazines,13–19 reductive alkylation of hydrazines by aldehydes or
ketones,9,10,12–14,20–22 and incorporation of protective groups into commercially available
alkylhydrazines.13,14 To overcome the drawbacks of each of these methods, improvements
have been made. For example, efficient alkylation of hydrazine anions was reported.23,24 In
further studies, anions generated from conjugated hydrazones were alkylated by various hal-
ogenides and applied to the synthesis of aza-peptides.25–27 Thereafter the potassium iodide
catalyzed direct alkylation of protected hydrazines was studied and reported by our group.28
Recently, we developed a convenient one-pot synthesis of protected alkylhydrazines
from acetals and ketals that allowed us to avoid deprotection steps and separation of
29,30
intermediates.
Encouraged by these results we extended this method to the synthesis
of protected benzylic hydrazines, which were previously obtained from protected hydra-
zines by direct17 or KI catalyzed alkylation,28 as well as by reductive alkylation of pro-
tected hydrazines with benzaldehyde or substituted benzaldehydes.10,12,20,22 However, the
formed hydrazones are conjugated and their reduction requires Pd(OH)2,10 or Pd/C cata-
lyzed hydrogenation.22 In the case of 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl
(Ddz) protected hydrazones, NaBH3CN was successfully applied for reduction of the
conjugated -CH ¼ N- bond.20 Moreover, aromatic aldehydes, such as benzaldehyde, oxi-
dize to carboxylic acids very easily and should be purified prior to use. Storage of these
compounds in protected form (usually as the acetal) is thus much more favorable. This,
in turn, requires an additional deprotection step.
In the present study a set of five protected hydrazines carrying 9-fluorenylmethylox-
ycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), benzoyl (Bz), 3-nitrobenzoyl (3-NO2Bz) and
3,4-dimethoxybenzoyl (3,4-(OCH3)2Bz) groups was studied. Benzaldehyde dimethyl
Received September 18, 2017; in final form February 3, 2018.
€
Address correspondence to Jaak Jarv, Institute of Chemistry, University of Tartu, Ravila 14a,
50411 Tartu, Estonia. E-mail: jaak.jarv@ut.ee
416

Benzylhydrazines
417
Scheme 1
Table 1
One-Pot Synthesis of Protected Benzylhydrazines from Acetals
RNHNH2
R 5
Fmoc
R 5 3-
3,4-
R0
Ph
R00
-CH3
R 5 Cbz R 5 Bz NO2Bz (OCH3)2Bz
2a
2b
2c
4; 92 % 5; 65 % 6; 93 % 7; 61 % 8; 92 %
2-BrPh -CH2CH3 9; 78 % 10; 71 % 11; 79 % 12; 79 % 13; 73 %
3-BrPh -CH2CH3 14; 56 % 15; 51 % 16; 74 % 17; 91 % 18; 90 %
acetal, 2-bromo- and 3-bromobenzaldehyde diethyl acetals were used as protected car-
bonyl compounds. All the studied compounds are listed in Scheme 1 and Table 1.
The acetals were reacted with Fmoc, Cbz, Bz, 3-NO2Bz and 3,4-(OCH3)2Bz pro-
tected hydrazines in refluxing ethanol containing 10% of water (by volume) in the pres-
ence of a catalytic amount of para-toluenesulfonic acid (TsOH) (0.05 equiv per 1 equiv
of protected hydrazine). For the reduction step, the solvent was exchanged to tetra-
hydrofuran (THF) and the obtained conjugated hydrazone was reduced in the same pot
by BH3-THF complex (3 equiv).
After stirring for three hours the reaction mixture was quenched by the addition of
ethanol and refluxed to completely decompose the boron adducts. After evaporation of
solvents, the residue was extracted with ethyl acetate and purified by column chroma-
tography on silica gel.
It is important to mention that the described procedure is different from the previ-
ously reported methods.29,30 Firstly, in this method we replaced initially used trifluoro-
acetic acid (TFA) by TsOH due to the difficult dosing of small amounts of very volatile
TFA. Application of solid TsOH conveniently afforded effective acidic catalysis for the
condensation of benzaldehyde acetals with protected hydrazines.
Secondly, due to the conjugated nature of the formed hydrazones a 3-fold excess of
BH3-THF complex was applied as a reductant. Although BH3 complexes with amines
and THF were successfully applied for reduction of hydrazones,31–33 there is no prior
information about application of BH3 for synthesis of protected alkylhydrazines.

418
Mastitski et al.
Thirdly, application of BH3 instead of NaBH3CN avoids the possibility of generating
HCN or NaCN. NaBH3CN reduces iminium salts and imines much faster than carbonyl
34
compounds, which makes it very selective reagent for reductive alkylation.
Also,
NaBH3CN tolerates acidic conditions, protic solvents,34 and allows selective reduction in
the presence of amide, ether, nitrile and nitro groups.35 At the same time, BH3 complexes
are powerful, mild and selective electrophilic reductive agents suitable for reduction of
carboxylic acids, aldehydes, ketones, amides, imines and nitriles in the presence of nitro,
ester, lactone, carbamate groups and halogen substituents.36 Aqueous ethanol was unsuit-
able for the reduction step and this required a solvent exchange, as addition of BH3-THF
into the reaction mixture in ethanol results in rapid decomposition of the reductant. In the
new procedure we used azeotropic drying of the crude hydrazone with toluene, followed
by vacuum drying. We also noticed that the reduction step proceeded better in commer-
cially available stabilized THF and complete reduction was achieved after 3 hours at
room temperature. In experiments where dry and distilled THF was used as solvent a sig-
nificant amount of hydrazone remained unreacted after 3 hours of reduction.
As it can be seen from the results in Table 1, the proposed method works well with
protective and functional groups such as Fmoc-, Cbz-, ether-, nitro-, amide as well as
aryl bromides. The condensation and reduction steps proceeded without complication
and gave products with moderate to excellent yields (51-93%).
In conclusion, we developed a general and convenient one-pot synthesis of pro-
tected benzylhydrazines from protected benzaldehydes. The described method allowed
efficient condensation of protected hydrazines with protected carbonyl compounds and
reduction of the formed conjugated hydrazones in the same pot, without the need for
expensive precious metal catalysts and special equipment for hydrogenation.
Experimental Section
All solvents and reagents were purchased from Merck, Sigma-Aldrich or Lach-Ner.
NMR spectra were measured on a 700 MHz instrument (Bruker, Germany) in CDCl3 as
solvent with tetramethylsilane (TMS) as the internal reference. HR (High resolution)
ESI-ICR mass spectra were obtained on a hybrid Varian 910-FT-ICR-MS spectrometer
coupled with Varian J-320 3Q mass-spectrometer using acetonitrile as a solvent. IR spec-
tra were determined by using ATR (attenuated total reflectance) measuring technique on
a Perkin-Elmer Spectrum BX spectrometer. All the yields are based on the mass of the
starting reagents. Safety Note: Since hydrogen is liberated, the procedure should be per-
formed in an efficient hood, and workers should wear appropriate protective equipment.
General Procedure for One-Pot Synthesis of Protected Benzylhydrazines (4-18)
One equiv. of protected hydrazine was dissolved/suspended in EtOH containing 10%
water (approx. 5 ml per 1 mmol of protected hydrazine), 1.05 eq of benzaldehyde acetal
was added, followed by the addition of 0.05 equiv. of TsOH in an ethanolic solution
(10 mg of TsOH per 0.5 ml of EtOH). The obtained reaction mixture was refluxed and
monitored by TLC (silica gel) until full conversion of the starting material was
observed. Ethyl acetate/light petroleum mixtures or pure ethyl acetate were used as
TLC eluents. After completion of the reaction the solvent was removed under reduced
pressure, approx. 15 ml of toluene was added to the residue and the solvent was again
removed under reduced pressure. The obtained crude hydrazone was dissolved in commer-
cial stabilized THF (approx. 4 ml per 1 mmol of hydrazone), the flask was flushed with

Benzylhydrazines
419
argon and 3 equiv. of 1M BH3-THF complex was added at room temperature, followed by
3 hours of stirring. The progress of the reaction was checked by TLC and if some
unreacted hydrazone was left, stirring was continued for an additional 45 min. After the
full conversion of hydrazone EtOH (10 ml) was added to the reaction mixture (Caution:
Liberation of hydrogen!) and the obtained mixture was refluxed for 1 hour. After cooling
to room temperature the solvent was removed under reduced pressure and the residue was
dissolved in ethyl acetate, washed with saturated NaHCO3 solution, water and saturated
NaCl solution. The aqueous phase was extracted twice with ethyl acetate, the extracts were
washed with saturated NaCl solution, combined with the organic phase, dried over anhyd-
rous Na2SO4 and evaporated to dryness. The residue was purified by column chromatog-
raphy on silica gel by using ethyl acetate/light petroleum 1:1 or 1:2 mixtures or pure ethyl
acetate as eluent. For the exact information about the eluent used for monitoring reaction
progress and chromatographic purifications, see the Rf value for each compound.
N-Fluorenylmethyloxycarbonyl-N0-benzylhydrazine (4), 92% yield as a white solid, mp.
140-141 ꢀC, lit.10 143-145 ꢀC; Rf ¼0.53 (1:1 EtOAc - light petroleum). 1H NMR (700MHz,
CDCl3): d 4.00 (s, 2H, CH2), 4.22 (s, 2H, NH þ CH (Fmoc)), 4.45 (d, 2H, J¼ 6.8 Hz,
CH2(Fmoc)), 6.26 (s, 1H, NH), 7.29-7.33 (m, 7H, Ar(H)), 7.40 (t, 2H, J¼ 7 Hz, Ar(H)),
7.55 (d, 2H, J¼ 4.9 Hz, Ar(H)), 7.76 (d, 2H, J¼ 7.7 Hz, Ar(H)). 13C NMR: d 47.18, 55.60,
66.91, 120.02, 124.98, 127.07, 127.60, 127.76, 128.50, 129.02, 137.34, 141.33, 143.66,
157.13. IR (cmꢁ1): 3317.9, 3225.7, 3062.9, 1685.7, 1501.0, 1271.5, 1163.2, 1153.0, 735.6,
698.7. HRMS: m/z for C22H21O2N2þ1 [M þ H]þ: Calcd 345.1598. Found 345.1597.
N-Benzyloxycarbonyl-N0-benzylhydrazine (5), 65% yield as a white solid, mp. 82-
84 ꢀC, lit.37 50 ꢀC; Rf ¼0.58 (1:1 EtOAc - light petroleum). 1H NMR (700 MHz,
CDCl3): d 3.93 (s, 2H, CH2), 4.17 (br s, 1H, NH), 5.08 (s, 2H, CH2(Cbz)), 6.75 (s, 1H,
NH), 7.21-7.30 (m, 10H, Ar(H)). 13C NMR: d 55.48, 66.95, 127.48, 128.10, 128.19,
128.40, 128.48, 128.94, 136.08, 137.35, 157.20. IR (cmꢁ1): 3255.5, 3033.2, 1720.7,
þ1
1514.0, 1453.9, 1280.0, 1229.1, 1145.1, 1023.7, 744.7. HRMS: m/z for C15H17O2N2
[M þ H]þ: Calcd 257.1285. Found 257.1285.
N-Benzoyl-N0-benzylhydrazine (6), 93% yield as a white solid, mp. 114-116 ꢀC, lit.38
1
115 ꢀC; Rf ¼0.49 (1:1 EtOAc - light petroleum). H NMR (700 MHz, CDCl3): d 4.09
(s, 2H, CH2), 5.01 (br s, 1H, NH), 7.31 (t, 1H, J¼ 7.7 Hz, Ar(H)), 7.36 (t, 2H,
J¼ 7.7 Hz, Ar(H)), 7.40-7.43 (m, 4H, Ar(H)), 7.51 (t, 1H, J¼ 7.7 Hz, Ar(H)), 7.64 (br s,
1H, NH), 7.69 (dd, 2H, J1¼ 8.4 Hz, J2¼ 1.4 Hz, Ar(H)). 13C NMR: d 55.98, 126.81,
127.64, 128.55, 128.67, 129.06, 131.85, 132.79, 137.48, 167.37. IR (cmꢁ1): 3237.3,
þ1
3058.8, 1633.0, 1532.4, 1461.8, 1324.3, 729.8, 693.2. HRMS: m/z for C14H15ON2
[M þ H]þ: Calcd 227.1179. Found 227.1178.
Anal. Calcd for C14H14ON2: C, 74.31; H, 6.24; N, 12.38. Found: C, 74.34; H, 6.15;
N, 12.40.
N-(3-Nitro)benzoyl-N0-benzylhydrazine (7), 61% yield as a white solid, mp. 79-84 ꢀC;
Rf ¼0.45 (1:1 EtOAc - light petroleum). 1H NMR (700 MHz, CDCl3): d 4.04
(s, 2H, CH2), 5.20 (br s, 1H, NH), 7.22-7.24 (m, 1H, Ar(H)), 7.27 (td, 2H, J1¼ 7 Hz,
J2¼ 2.1 Hz, Ar(H)), 7.31-7.32 (m, 2H, Ar(H)), 7.57 (t, 1H, J¼ 7.7 Hz, Ar(H)), 8.09 (dt,
1H, J1¼ 7.7 Hz, J2¼ 1.4 Hz, Ar(H)), 8.29 (ddd, 1H, J1¼ 8.4 Hz, J2¼ 2.1 Hz, J3¼ 0.7 Hz,
Ar(H)), 8.58 (s, 1H, Ar(H)), 8.93 (br s, 1H, NH). 13C NMR: d 55.85, 122.06, 126.36,
127.83, 128.61, 129.06, 129.92, 133.22, 134.31, 137.09, 148.13, 165.09. IR (cmꢁ1):
3223.0, 3070.0, 1632.9, 1528.8, 1350.0, 1051.0, 1025.3, 1005.9, 817.9, 756.3, 717.3,
696.5. HRMS: m/z for C14H14O3N3 [M þ H]þ: Calcd 272.1030. Found 272.1029.
þ1

420
Mastitski et al.
Anal. Calcd for C14H13O3N3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.68; H,
5.06; N, 15.30.
N-(3,4-Dimethoxy)benzoyl-N0-benzylhydrazine (8), 92% yield as a white solid, mp.
1
117-120 ꢀC; Rf ¼0.5 (EtOAc). H NMR (700 MHz, CDCl3): d 3.80 (s, 3H, OCH3),
3.84 (s, 3H, OCH3), 4.01 (s, 2H, CH2), 5.20 (br s, 1H, NH), 6.74 (d, 1H, J¼ 8.4 Hz,
Ar(H)), 7.23-7.33 (m, 6H, Ar(H)), 7.39 (d, 1H, J¼ 2.1 Hz, Ar(H)), 8.80 (s, 1H, NH).
13C NMR: d 55.83, 55.88, 55.99, 110.34, 110.37, 119.85, 125.26, 127.56, 128.46,
129.08, 137.43, 148.87, 151.89, 167.09. IR (cmꢁ1): 3250.0, 3002.0, 1616.2, 1513.9,
1312.2, 1261.9, þ11232.4, 1137.9, 1022.1, 811.6, 772.5, 741.9, 698.3, 666.0. HRMS: m/z
for C16H19O3N2 [M þ H]þ: Calcd 287.1390. Found 287.1388.
Anal. Calcd for C16H18O3N2: C, 67.12; H, 6.34; N, 9.78. Found: C, 66.95; H, 6.19;
N, 9.81.
N-Fluorenylmethyloxycarbonyl-N0-(2-bromo)benzylhydrazine (9), 78% yield as a
white solid, mp. 100-103 ꢀC; Rf ¼0.56 (1:2 EtOAc - light petroleum). 1H NMR
(700 MHz, CDCl3): d 4.07 (s þ br s, 3H, CH2 þ NH), 4.18 (s, 1H, CH(Fmoc)); 4.43 (s,
2H, CH2(Fmoc)), 6.41 (s, 1H, NH), 7.10 (td, 1H, J1¼ 7.7 Hz, J2¼ 1.4 Hz, Ar(H)), 7.21-
7-23 (m, 1H, Ar(H)), 7.28 (t, 3H, J¼ 7 Hz, Ar(H)), 7.37 (t, 2H, J¼ 7 Hz, Ar(H)), 7.52
(m, 3H, Ar(H)), 7.73 (d, 2H, J¼ 7 Hz, Ar(H)). 13C NMR: d 47.15, 55.51, 66.92,
119.98, 124.61, 124.97, 127.05, 127.42, 127.73, 129.18, 131.06, 132.91, 136.64,
141.30, 143.65, 157.10.
IR (cmꢁ1): 3316.0, 3014.2, 1689.9, 1502.6, 1447.5, 1272.1, 1157.2, 1029.2,
755.2, 737.6.
HRMS: m/z for C22H20O2N2Brþ1 [M þ H]þ: Calcd 423.0703. Found 423.0702.
Anal. Calcd for C22H19O2N2Br: C, 62.42; H, 4.52; N, 6.62. Found: C, 62.14; H,
4.22; N, 6.42.
N-Benzyloxycarbonyl-N0-(2-bromo)benzylhydrazine (10), 71% yield as a white solid,
1
mp. 73-75 ꢀC; Rf ¼0.53 (1:2 EtOAc - light petroleum). H NMR (700 MHz, CDCl3): d
4.09 (s, 2H, CH2), 4.36 (br s, 1H, NH), 5.11 (s, 2H, CH2(Cbz)), 6.49 (s, 1H, NH), 7.10 (td,
1H, J1¼ 7.7 Hz, J2¼ 1.4 Hz, Ar(H)), 7.22 (t, 1H, J¼ 7.7 Hz, Ar(H)), 7.30-7.33 (m, 6H,
Ar(H)), 7.52 (d, 1H, J¼ 7.7 Hz, Ar(H)). 13C NMR: d 55.49, 67.10, 124.58, 127.42, 128.20,
128.26, 128.52, 129.14, 131.00, 132.88, 136.02, 136.71, 157.15. IR (cmꢁ1): 3324.0,
3034.9, 2924.3, 1690.5, 1515.3, 1470.6, 1273.9, 1149.8, 1049.5, 1027.4, 749.9, 736.2,
694.9. HRMS: m/z for C15H16O2N2Brþ1 [M þ H]þ: Calcd 335.0390. Found 335.0392.
Anal. Calcd for C15H15O2N2Br: C, 53.75; H, 4.51; N, 8.36. Found: C, 53.57; H,
4.60; N, 8.25.
N-Benzoyl-N0-(2-bromo)benzylhydrazine (11), 79% yield as a white solid, mp. 117-
1
121 ꢀC; Rf ¼0.57 (1:1 EtOAc - light petroleum). H NMR (700 MHz, CDCl3): d 4.16
(s, 2H, CH2), 5.25 (br s, 1H, NH), 7.10 (td, 1H, J1¼ 7.7 Hz, J2¼ 1.4 Hz, Ar(H)), 7.22
(td, 1H, J1¼ 7.7 Hz, J2¼ 0.7 Hz, Ar(H)), 7.34 (t, 2H, J¼ 7 Hz, Ar(H)), 7.39 (dd, 1H,
J1¼ 7Hz, J2¼ 1.4 Hz, Ar(H)), 7.45 (t, 1H, J¼ 7.7 Hz, Ar(H)), 7.52 (d, 1H, J¼ 7 Hz,
Ar(H)), 7.70 (d, 2H, J¼ 7 Hz, Ar(H)), 8.45 (s, 1H, NH). 13C NMR: d 55.63, 124.72,
126.99, 127.47, 128.54, 129.21, 131.03, 131.77, 132.63, 132.89, 136.84, 167.46.
IR (cmꢁ1):3236.1, 3054.8, 1625.8, 1538.4, 1456.7, 1354.7, 1313.5, 747.7, 694.4.
HRMS: m/z for C14H14ON2Brþ1 [M þ H]þ: Calcd 305.0284. Found 305.0286.
Anal. Calcd for C14H13ON2Br: C, 55.10; H, 4.29; N, 9.18. Found: C, 54.80; H,
4.27; N, 9.06.

Benzylhydrazines
421
N-(3-Nitro)benzoyl-N0-(2-bromo)benzylhydrazine (12), 79% yield as a white solid, mp.
1
138-141 ꢀC; Rf ¼0.47 (1:1 EtOAc - light petroleum). H NMR (700MHz, CDCl3): d 4.27
(s, 2H, CH2), 4.46 (br s, 1H, NH), 7.20 (td, 1H, J1¼ 7.7 Hz, J2¼ 1.4 Hz, Ar(H)), 7.33 (t,
1H, J¼ 7.7 Hz, Ar(H)), 7.48 (d, 1H, J¼ 7 Hz, Ar(H)), 7.60 (d, 1H, J¼ 7.7 Hz, Ar(H)), 7.66
(t, 1H, J¼ 7.7 Hz, Ar(H)), 7.90 (br s, 1H, NH), 8.10 (d, 1H, J¼ 7.7 Hz, Ar(H)), 8.39 (dd,
1H, J1¼ 7.7 Hz, J2¼ 1.4 Hz, Ar(H)), 8.57 (t, 1H, J¼ 1.4 Hz, Ar(H)). 13C NMR: d 55.69,
121.95, 124.86, 126.48, 127.68, 129.58, 130.03, 131.18, 133.01, 133.13, 134.32, 136.38,
148.28, 165.10. IR (cmꢁ1):3245.8, 3042.6, 1667.0, 1520.9, 1471.6, 1349.5, 1310.2, 758.3,
712.9. HRMS: m/z for C14H13O3N3Brþ1 [M þ H]þ: Calcd 350.0135. Found 350.0135.
Anal. Calcd for C14H12O3N3Br: C, 48.02; H, 3.45; N, 12.00. Found: C, 47.87; H,
3.48; N, 11.89.
N-(3,4-Dimethoxy)benzoyl-N0-(2-bromo)benzylhydrazine (13), 73% yield as a white
1
solid, mp. 120-123 ꢀC; Rf ¼0.62 (EtOAc). H NMR (700 MHz, CDCl3):d 3.83 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 4.16 (s, 2H, CH2), 5.28 (br s, 1H, NH), 6.76 (d, 1H, J¼
8.4 Hz, Ar(H)), 7.10 (td, 1H, J1¼ 7.7 Hz, J2¼ 1.4 Hz, Ar(H)), 7.22 (td, 1H, J1¼ 7 Hz,
J2¼ 0.7 Hz, Ar(H)), 7.27 (dd, 1H, J1¼ 8.4 Hz, J2¼ 2.1 Hz, Ar(H)), 7.37-7.40 (m, 2H,
Ar(H)), 7.52 (dd, 1H, J1¼ 8.4 Hz, J2¼ 1.4 Hz, Ar(H)), 8.50 (s, 1H, NH). 13C NMR: d
55.71, 55.91, 55.93, 110.35, 110.43, 119.79, 124.71, 125.19, 127.45, 129.17, 131.07,
132.86, 136.92, 148.92, 151.95, 167.13. IR (cmꢁ1): 3290.6, 3067.0, 1635.6, 1492.4,
1312.2, 1275.8, 1236.0, 1139.4, 1024.2, 747.3. HRMS: m/z for C16H18O3N2Brþ1
[M þ H]þ: Calcd 365.0495. Found 365.0494.
Anal. Calcd for C16H17O3N2Br: C, 52.62; H, 4.69; N, 7.67. Found: C, 52.51; H,
4.68; N, 7.62.
N-Fluorenylmethyloxycarbonyl-N0-(3-bromo)benzylhydrazine (14), 56% yield as a
white solid, mp. 117-121 ꢀC; Rf ¼0.38 (1:2 EtOAc - light petroleum). 1H NMR
(700MHz, CDCl3): d 3.92 (s, 2H, CH2), 4.18 (s, 2H, CH(Fmoc) þ NH), 4.43 (s, 2H,
CH2(Fmoc)), 6.40 (s, 1H, NH), 7.15 (s, 1H, Ar(H)), 7.19 (s, 1H, Ar(H)), 7.27-7.29 (m,
2H, Ar(H)), 7.38 (t, 3H, J¼ 7.7 Hz, Ar(H)), 7.48 (s, 1H, Ar(H)), 7.52 (d, 2H, J¼ 5.6 Hz,
Ar(H)), 7.73 (d, 2H, J¼ 7.7 Hz, Ar(H)). 13C NMR: d 47.23, 54.95, 67.02, 120.10, 122.61,
125.00, 127.15, 127.57, 127.85, 130.06, 130.69, 131.91, 139.98, 141.39, 143.67, 157.23.
IR (cmꢁ1):3312.2, 1684.4, 1446.2, 1266.4, 1154.2, 756.0, 738.0. HRMS: m/z for
C22H20O2N2Brþ1 [M þ H]þ: Calcd 423.0703. Found 423.0700.
Anal. Calcd for C22H19O2N2Br: C, 62.42; H, 4.52; N, 6.62. Found: C, 62.81; H,
4.70; N, 6.52.
N-Benzyloxycarbonyl-N0-(3-bromo)benzylhydrazine (15), 51% yield as a white solid,
1
mp. 87-90 ꢀC; Rf ¼0.38 (1:2 EtOAc - light petroleum). H NMR (700 MHz, CDCl3): d
3.99 (s, 2H, CH2), 4.24 (br s, 1H, NH), 5.15 (s, 2H, CH2(Cbz)), 6.54 (br s, 1H, NH),
7.19 (t, 1H, J¼ 7.7 Hz, Ar(H)), 7.25 (s, 1H, Ar(H)), 7.36-7.38 (m, 5H, Ar(H)), 7.42 (d,
1H, J¼ 7.7 Hz, Ar(H)), 7.52 (s, 1H, Ar(H)). 13C NMR: d 54.86, 67.17, 122.53, 127.46,
128.14, 128.32, 128.57, 130.00, 130.61, 131.84, 135.95, 139.87, 157.21. IR (cmꢁ1):
3313.5, 1682.4, 1487.0, 1268.4, 1147.1, 1075.6, 1040.6, 876.2, 780.0, 735.5, 696.7.
HRMS: m/z for C15H16O2N2Brþ1 [M þ H]þ: Calcd 335.0390. Found 335.0389.
Anal. Calcd for C15H15O2N2Br: C, 53.75; H, 4.51; N, 8.36. Found: C, 53.52; H,
4.48; N, 8.15.
N-Benzoyl-N0-(3-bromo)benzylhydrazine (16), 74% yield as a white solid, mp. 110-
1
113 ꢀC; Rf ¼0.25 (1:2 EtOAc - light petroleum). H NMR (700 MHz, CDCl3): d 4.02

422
Mastitski et al.
(s, 2H, CH2), 5.02 (br s, 1H, NH), 7.18 (t, 1H, J¼ 7.7 Hz, Ar(H)), 7.28 (d, 1H, J¼
7.7 Hz, Ar(H)), 7.40 (t, 3H, J¼ 7.7 Hz, Ar(H)), 7.50 (t, 1H, J¼ 7 Hz, Ar(H)), 7.55 (s,
1H, Ar(H)), 7.70 (d, 2H, J¼ 7.7 Hz, Ar(H)), 8.05 (br s, 1H, NH). 13C NMR: d 55.26,
122.61, 126.93, 127.60, 128.68, 130.09, 130.72, 131.97, 131.98, 132.60, 139.96,
167.63. IR (cmꢁ1): 3273.6, 3062.2, 1662.6, 1531.8, 1464.8, 1311.1, 880.5, 782.1,
691.8. HRMS: m/z for C14H14ON2Brþ1 [M þ H]þ: Calcd 305.0284. Found 305.0284.
Anal. Calcd for C14H13ON2Br: C, 55.10; H, 4.29; N, 9.18. Found: C, 55.05; H,
4.30; N, 9.16.
N-(3-Nitro)benzoyl-N0-(3-bromo)benzylhydrazine (17), 91% yield as a white solid,
1
mp. 116-119 ꢀC; Rf ¼0.43 (1:1 EtOAc - light petroleum). H NMR (700 MHz, CDCl3):
d 4.10 (s, 2H, CH2), 4.63 (br s, 1H, NH), 7.23 (t, 1H, J¼ 7.7 Hz, Ar(H)), 7.32 (d, 1H,
J¼ 7 Hz, Ar(H)), 7.44 (d, 1H, J¼ 8.4 Hz, Ar(H)), 7.58 (s, 1H, Ar(H)), 7.65 (t, 1H, J¼
7.7 Hz, Ar(H)), 7.90 (br s, 1H, NH), 8.07 (d, 1H, J¼ 7.7 Hz, Ar(H)), 8.37 (dd, 1H, J1¼
7.7 Hz, J2¼ 1.4 Hz, Ar(H)), 8.55 (s, 1H, Ar(H)). 13C NMR: d 55.23, 121.95, 122.75,
126.56, 127.57, 130.06, 130.22, 130.99, 131.97, 132.95, 134.22, 139.50, 148.3, 165.27.
IR (cmꢁ1): 3301.7, 1640.8, 1523.2, 1350.6, 1316.1, 877.6, 785.9, 723.8. HRMS:
m/z for C14H13O3N3Brþ1 [M þ H]þ: Calcd 350.0135. Found 350.0135.
Anal. Calcd for C14H12O3N3Br: C, 48.02; H, 3.45; N, 12.00. Found: C, 47.93; H,
3.44; N, 11.87.
N-(3,4-Dimethoxy)benzoyl-N0-(3-bromo)benzylhydrazine (18), 90% yield as a white
1
solid, mp. 115-119 ꢀC; Rf ¼0.58 (EtOAc). H NMR (700 MHz, CDCl3): d 3.82 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 3.99 (s, 2H, CH2), 5.11 (br s, 1H, NH), 6.77 (d, 1H, J¼
8.4 Hz, Ar(H)), 7.13 (t, 1H, J¼ 7.7 Hz, Ar(H)), 7.24 (d, 1H, J¼ 7.7 Hz, Ar(H)), 7.28
(dd, 1H, J1¼ 8.4 Hz, J2¼ 2.1 Hz, Ar(H)), 7.34-7.37 (m, 2H, Ar(H)), 7.51 (s, 1H,
Ar(H)), 8.64 (s, 1H, NH). 13C NMR: d 55.26, 55.90, 55.93, 110.39, 110.40, 119.89,
122.48, 125.09, 127.60, 130.02, 130.58, 131.94, 140.05, 148.91, 152.03, 167.30.
IR (cmꢁ1): 3272.1, 3058.8, 1625.6, 1516.3, 1485.1, 1313.0, 1275.9, 1234.0,
1135.7, 1024.2, 874.5, 775.0, 683.4. HRMS: m/z for C16H18O3N2Brþ1 [M þ H]þ:
Calcd 365.0495. Found 365.0495.
Anal. Calcd for C16H17O3N2Br: C, 52.62; H, 4.69; N, 7.67. Found: C, 52.34; H,
4.66; N, 7.48.
Acknowledgments
The authors wish to acknowledge the late Professor J.-P. Anselme for his valuable
comments on this project. This work was supported by the Estonian Ministry of
Education and Research Institutional Research (Funding Grant IUT20-15) and by the
Estonian National R & D infrastructure development program of Measure 2.3
“Promotion of development activities and innovation” (Regulation No. 34) funded by
the Enterprise Estonia Foundation.
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