One-pot Synthesis of Protected Alkylhydrazines from Acetals and Ketals. Scope and Limitations

Full text of DOI:10.1080/00304948.2015.1088760

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 Alkylhydrazines
from Acetals and Ketals. Scope and Limitations
Anton Mastitski, Siret Niinepuu, Tõiv Haljasorg & Jaak Järv
To cite this article: Anton Mastitski, Siret Niinepuu, Tõiv Haljasorg & Jaak Järv (2015)
One-pot Synthesis of Protected Alkylhydrazines from Acetals and Ketals. Scope and
Limitations, Organic Preparations and Procedures International, 47:6, 490-498, DOI:
10.1080/00304948.2015.1088760
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Date: 19 November 2015, At: 01:56

Organic Preparations and Procedures International 47:490–498, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1088760
One-pot Synthesis of Protected Alkylhydrazines
from Acetals and Ketals. Scope and Limitations
~
Anton Mastitski, Siret Niinepuu, Toiv Haljasorg,
€
and Jaak Jarv
Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia
Alkylhydrazines are important building blocks in organic synthesis1–6 and their N-pro-
tected derivatives are used for the incorporation of a-aza-amino acids into peptide
sequences to obtain aza-peptides.7 These peptidomimetics, where the a-C atoms of amino
acids are replaced by a nitrogen moiety, retain significant structural compatibility with
common peptides but have much higher resistance to biodegradation. Therefore aza-pep-
tidomimetics have been recognized as promising drug candidates.8–10 and this concept
will certainly be more extensively examined once the difficulties with the efficient syn-
thesis of these aza-peptides are overcome. These problems include also preparation of
aza-amino acid precursors, which are in essence N-protected substituted hydrazines.
Since only a few of these hydrazines can be purchased commercially, two main syn-
thetic routes have been devised for the preparation of substituted hydrazines. The most
frequently used procedure is the reductive alkylation of hydrazine with the appropriate
aldehydes or ketones.7,8,10–15 The second approach involves the direct alkylation of
hydrazine using alkyl halides for example.11,14,16–19 Evidently, the reductive alkylation is
preferred because of its simplicity, availability and relatively low cost of carbonyl com-
pounds; more importantly, it avoids the formation of polyalkylated products. However, if
the aldehyde and/or the ketone contain electronegative groups with hetero-atoms and/or
unsaturated substituents, they are prone to self-condensation and/or to rapid oxidation to
carboxylic acids in the case of aldehydes. This complicates storage and handling of these
aldehydes and ketones which are commonly available as acetals or ketals. Although the
protecting groups may be removed by hydrolysis,11 this additional step could be compli-
cated and indeed, in some cases, has hampered application of the reductive alkylation
method.13 To overcome these difficulties, we devised and reported a one-pot synthesis
method for the preparation of protected alkylhydrazines directly from acetals and ketals,
without prior conversion to aldehydes or ketones, and without the need to isolate the
resulting hydrazones.20 We recently utilized this novel approach for the synthesis of aza-
methionine precursors from the 2-(methylthio)acetaldehyde dimethyl acetal.20 Encour-
aged by these results, we extended this study and explored the limits of this method by
using different acetals and ketals as starting materials as listed in the Scheme and Table.
Received July 6, 2015; in final form July 22, 2015.
€
Address correspondence to Jaak Jarv, Institute of Chemistry, University of Tartu, Ravila 14a,
50411 Tartu, Estonia. E-mail: jaak.jarv@ut.ee
490

Synthesis of Protected Alkylhydrazines
491
It is important to note that this list includes several compounds that correspond to unstable
aldehydes and ketones. Aza-amino acid precursors with Fmoc (9-fluorenylmethyloxycar-
bonyl) and Cbz (benzyloxycarbonyl) protecting groups were prepared.
Acetals or ketals were treated with Fmoc and Cbz carbazates at reflux in ethanol,
containing 10% (vol.) of water in the presence of a catalytic amount of trifluoroacetic
Scheme 1
Table 1
Synthesis of Protected Alkylhydrazines from Acetals and Ketals
RNHNH2
R0
R00
-CH3
-CH3
R D Fmoc
4; Yield: 98%
6; Yield: 62%
R D Cbz
5; Yield: 67%
7; Yield: 76%
a)
2a
2b
2c
2d
2e
2f
-CH2SCH3
-(CH2)2CN
-(CH2)2Cl
-CH2OBn
-CH2CH3 a)
-CH2CH3 8; Yield 67%
9; Yield 65%
(No reaction)
(No reaction)
11; Yield: 63%
13, Yield 66 % in
THF.<20%in EtOH
15; Yield: 80%
b)
-CH2NHCH3 -CH3
-CH2NH2 -CH3
-CH2NHCbz -CH3
-CH3
(Fmoc scission)
(Fmoc scission)
10; Yield 70%
2g
2h
-CH2CH3 12,Yield 74% in
THF.<20%in EtOH
14; Yield: 86%
b)
2i
2j
-CH2NHBz -CH3
-CH2NHBoc -CH3
2k
2l
2m
-CHDCH2
-CH2CH3 c)
-CH3
-CH3
c)
-(CH3)2
-(CH2)5-
16; Yield: 77%
18; Yield: 72%
17; Yield: 64%
19; Yield: 87%
a) Formation of alkylated products and subsequent decomposition of the reaction mixture.
b) Only trace amounts of the hydrazone were detected, as Boc removal by TFA occurred.
c) Only trace amounts of the hydrazone were formed.

492
Ja€rv et al.
acid (TFA, 0.05 equiv. per equiv. of carbazate) according to our published proce-
dure.20 Subsequent reduction of the hydrazone was carried out in the same pot (and
solution) at 45ꢀC, by addition of three (3) equiv. of NaBH3CN in tetrahydrofuran
(THF) and three (3) equiv. of acetic acid. After cooling to room temperature, the reac-
tion was quenched by acidification with 1.5% HCl in the case of acid-stable Fmoc and
Cbz derivatives. The mixture was then stirred until the evolution of hydrogen gas
ceased. Neutralization to pH 8 with saturated aqueous NaHCO3 followed by evapora-
tion to dryness gave a residue that was extracted with ethyl acetate, and the product
was purified by chromatography on silica gel.
It is important to mention that the procedure described here is somewhat differ-
ent from the preparation of aza-methionine precursors reported in our previous
study20 wherein the excess acetic acid was first neutralized in the reaction medium
after the reduction step by addition of saturated aqueous NaHCO3 followed by
reflux of the reaction mixture. The present investigation revealed that this step is
not necessary and moreover, basic conditions led to cleavage of the base-sensitive
Fmoc protecting group thus lowering the yield. Secondly, it was found that decom-
position of the boron adducts with cyanoborohydride anion by simple refluxing of
the reaction mixture was not an efficient method as decomposition of these adducts
occurred very slowly in several cases. To overcome this problem, the reaction mix-
ture was treated with 1.5% hydrochloric acid at room temperature. Although this
method worked perfectly with all hydrazines synthesized in this work, it is also
important to emphasize that it is suitable only in the case of acid-stable compounds
but cannot be used in the case of acid-labile compounds such as tert-butyloxycar-
bonyl (Boc) derivatives. In these latter cases, heating the reaction mixture at reflux
as was recommended in our previous paper20 should be used instead of treatment
with HCl.
The results listed in Table 1 indicate that the procedure reported herein is applicable
in the case of compounds having sulfide, ether, nitrile, carbamate and amide functional
groups or branched and cyclic alkyl groups in substituent R’ (Scheme 1). As mentioned
earlier, the hydrazones should be protected with acid-stable protecting groups such as
Fmoc and Cbz (Table 1, compounds 2a, 2b, 2d, 2g, 2h, 2i, 2l and 2m). In all these cases,
good to excellent yields of the protected monoalkylhydrazines (4–19) were obtained. On
the other hand, there are functional groups in the R’ substituent for which the procedure
is not applicable and these entries are indicated by footnotes marked in Table 1.
First, in the case of halogenated acetals (2c) the mixture of alkylated hydrazines
was formed rapidly and this process was followed by complete decomposition of the
reaction mixture, irrespective of the nature of the carbazate used and/or protected
carbonyl compound. Therefore, it was concluded that halogen-substituted acetals and
ketals cannot be used in this procedure, and the same conclusion is most probably
true for other acetals whose side-chain containing functional groups capable of act-
ing as alkylating agents.
The second limitation of the present method concerns compounds with unprotected
primary and secondary amino groups (2e, 2f). In this case, competition between the car-
bazate and more basic amino group for protons occurred and the reaction did not occur in
the absence of an acid catalyst. Attempts to perform this reaction by using 1.1 equiv. of
TFA to protonate the amino group were also not effective. Therefore the use of Cbz and
Bz (benzoyl) groups to protect the amino groups allowed the synthesis of 10, 11 and 14,
15 (Table 1), while the use of Boc was not efficient, most likely due to instability of this
protecting group in the presence of acid.

Synthesis of Protected Alkylhydrazines
493
Third, experiments with acrolein diethyl acetal (2k) resulted in extensive polymeriza-
tion and only minor amount of the expected hydrazone was obtained. Furthermore, reduc-
tion of this conjugated hydrazone did not occur under these reported conditions.
And finally, it was found that reduction of primary aliphatic hydrazones did not go to
completion in ethanolic medium and reduction in THF was much more efficient for these
compounds. This is illustrated in the case of 1,1-diethoxyethane (2h) for which the yield
in ethanol was less than 20%. At the same time, the reduction of branched or cyclic alkyl-
hydrazones such as the N-protected hydrazones of cyclohexanone and acetone led to
good yields in ethanol.
In summary, the proposed one-pot synthesis of protected alkylhydrazines is efficient
for acetals and ketals bearing different functional groups, and the hydrazines obtained
may be utilized as building blocks for modified aza-peptidomimetics and different other
biologically active substances. The method described also allows the isolation of the
hydrazones (3) by simple removal of volatiles from the reaction mixture after the conden-
sation step.
Experimental Section
All solvents and reagents were purchased from Merck, Sigma-Aldrich or Lach-Ner. NMR
spectra were measured on a 200 and 700 MHz instrument (Bruker, Germany) in DMSO-
d6 or CDCl3 as solvent and using TMS (tetramethylsilane) 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
solvent. IR spectra were determined by using ATR (Attenuated total reflectance) measur-
ing technique on a Perkin-Elmer Spectrum BX spectrometer. Elemental analyses data
were carried out on an Elementar Vario MICRO cube (CHNS or CHN regime). All the
yields are based on the mass of the starting reagents.
Synthesis of Mono-protected Alkylhydrazines (4–11 and 14–19)
One equiv. of carbazate was suspended in EtOH containing 10% (by vol.) of water
(approx. 5 ml per mmol of the carbazate) and 1.05 equiv. of the acetal or ketal was
added, followed by the addition of 0.05 equiv. of TFA. The reaction mixture was heated
to reflux and the progress of the reaction was monitored by TLC (thin layer chromatog-
raphy on silica gel) using ethyl acetate or a mixture of ethyl acetate-light petroleum
mixture (for the correct eluent, see characterization data of the compounds). After the
reaction was complete, the reaction mixture was cooled to about 45ꢀC and three (3)
equiv. of acetic acid was added, followed by the dropwise addition of a THF solution
of three (3) equiv. of NaBH3CN (approx. 1 ml of THF per 1.5 mmol of NaBH3CN).
The reaction mixture was stirred at approx. 45ꢀC for 80 min. Subsequently, the reaction
mixture was cooled to room temperature, acidified using 0.5 M HCl aqueous solution
(6 ml of 0.5 M HCl per 1 mmol of starting carbazate) and stirred until the liberation of
hydrogen ceased. The reaction mixture was neutralized (to pH 8) by the dropwise addi-
tion of a saturated NaHCO3 solution (4 ml per 1 mmol of carbazate). The volatiles
were removed under reduced pressure at approx. 40ꢀC. The residue was dissolved in
ethyl acetate, washed with saturated NaHCO3, twice with water and finally with satu-
rated aqueous sodium chloride. The combined aqueous washes were extracted twice
with ethyl acetate (25 ml per 1 mmol of expected product) and the extracts were
washed with saturated aqueous sodium chloride and combined with the organic phase.

494
Ja€rv et al.
After drying over anhydrous Na2SO4 and evaporation of the solvent under reduced pres-
sure, the residue was purified by column chromatography on silica gel using ethyl ace-
tate-light petroleum (1:1 or 1:2) or ethyl acetate as eluent. For specific information
about the eluent used to monitor the progress of the reaction and for purification, see
the Rf data for each compound.
Synthesis of Mono-protected Alkylhydrazines (12 and 13)
One equiv. of carbazate was suspended in EtOH containing 10% (by vol.) of water
(approx. 5 ml per 1 mmol of the starting carbazate), 1 equiv. of acetal or ketal was added,
followed by the addition of 0.05 equiv. of TFA. The reaction mixture was heated to reflux
and the progress of the reaction was monitored by TLC using ethyl acetate or ethyl ace-
tate-light petroleum mixture (for the correct eluent, see characterization data of the com-
pounds). After the reaction was complete, the volatiles were removed under reduced
pressure and the resulting solid residue was dissolved in THF (approx. 5 ml of THF per
1 mmol of the starting carbazate). Subsequently, three (3) equiv. of acetic acid was added,
followed by the dropwise addition of a THF solution of three (3) equiv. of NaBH3CN
(approx. 1 ml of THF per 1.5 equiv. of NaBH3CN). The reaction mixture was stirred at
approx. 45ꢀC for 80 min. The reaction mixture was then cooled to room temperature,
acidified using 0.5 M HCl solution (6 ml of 0.5 M HCl per 1 mmol of carbazate) and
stirred until the liberation of hydrogen ceased. The reaction mixture was neutralized by
the dropwise addition of a saturated NaHCO3 solution (4 ml per 1 mmol of the carba-
zate). The volatiles were removed under reduced pressure at approx. 40ꢀC. The residue
was dissolved in ethyl acetate, washed with saturated NaHCO3, twice with water and
finally with saturated aqueous sodium chloride. The combined aqueous washes were
extracted twice with ethyl acetate (25 ml per mmol of product) and the combined extracts
were washed with saturated NaCl, dried over anhydrous Na2SO4, and the solvent was
evaporated under reduced pressure. The residue was purified by column chromatography
on silica gel using ethyl acetate-light petroleum (1:1 or 1:2) or ethyl acetate as eluent. For
specific information about the eluent used to monitor the progress of the reaction and for
purification, see the Rf data for each compound.
N-Fluorenylmethyloxycarbonyl-N’-(2-methylthio)ethylhydrazine (4), 98% yield
as a white solid, mp. 131–135ꢀ, lit.20 132–136ꢀ; Rf D 0.12 (1:2 EtOAc-light petroleum).
1H NMR (200 MHz, DMSO-d6): d 2.06 (s, 3H, CH3); 2.53 (t, 2H, J D 6.8 Hz, CH2);
2.92 (t, 2H, J D 7 Hz, CH2); 4.25 (t, 1H, J D 6.2 Hz, CH (Fmoc)); 4.36 (d, 2H, J D
6.2 Hz, CH2 (Fmoc)); 4.70 (br s, 1H, NH); 7.30–7.46 (m, 5H, Ar(H)), 7.71 (d, 2H, J D
7.2 Hz, Ar(H)), 7.88 (q, 2H, J D 6.8 Hz, Ar(H)); 8.77 (br.s, 1H, NH). 13C NMR: d 15.5;
32.5; 47.5; 50.1; 67.2; 120.2; 125.2; 127.3; 128.0; 141.6; 143.9; 157.5.
IR (cm¡1): 3303, 3217, 3099, 2965, 2937,1693,1553, 1261,1147,736.
N-Benzyloxycarbonyl-N’-(2-methylthio)ethylhydrazine (5), 67% yield as a white
solid, mp. 63–65ꢀ; Rf D 0.17 ( 1:2 EtOAc-light petroleum).
1H NMR (200 MHz, CDCl3): d 2.07 (s, 3H, CH3); 2.59 (t, 2H, J D 6.6 Hz, CH2), 3.05
(t, 2H, J D 6.4 Hz, CH2); 4.29 (br s, 1H, NH); 5.15 (s, 2H, CH2 (Cbz)); 6.83 (br s, 1H,
NH), 7.32 (s, 5H, Ar(H)). 13C NMR: d 15.1; 32.2; 49.9; 67.0; 128.1; 128.2; 128.5; 136.1;
157.4. HRMS: m/z for C11H17N2O2S [MCH]C. Calcd: 241.10052. Found: 241.10039.
IR (cm¡1): 3300, 3243, 3087, 2949, 2915, 1694, 1547, 1251, 1148, 1019, 748.
Anal. Calcd for C11H16N2O2S: C, 55.00; H, 6.71; N, 11.66; S, 13.34. Found: C,
55.01; H, 6.65; N, 11.55; S, 13.25.

Synthesis of Protected Alkylhydrazines
495
N-Fluorenylmethyloxycarbonyl-N’-(3-cyano)propylhydrazine (6), 62% yield as a
white solid, mp. 134–137ꢀ; Rf D 0.73 (EtOAc).
1H NMR (200 MHz, DMSO-d6): d 1.66 (quint, 2H, J D 6.4 Hz, CH2); 2.57 (t, 2H,
J D 7.2 Hz); 2.79 (t, 2H; J D 7 Hz; CH2); 4.25 (t, 1H, J D 6.6 Hz, CH (Fmoc)); 4.39
(d, 2H, J D 6.6 Hz, CH2 (Fmoc)); 4.76 (br s, 1H, NH); 7.31–7.46 (m, 4H, Ar(H)
(Fmoc)); 7.72 (d, 2H, J D 7 Hz, Ar(H) (Fmoc)); 7.89 (d, 2H, J D 7 Hz, Ar(H)
(Fmoc)); 8.67 (br s, 1H, NH).
13C NMR: d 13.7; 23.2; 46.8; 48.8; 65.4; 120.0; 120.6; 125.1; 127.0; 127.6; 140.8;
143.8; 156.9. HRMS: m/z for C19H20N3O2 [MCH]C. Calcd: 322.15500. Found:
322.15483.
IR (cm¡1): 3312, 3229, 3010, 2949, 2933, 2247, 1691, 1488, 1268, 1157, 737.
Anal. Calcd for C19H19N3O2 : C, 71.06; H, 5.96; N, 13.08. Found: C, 70.90; H, 5.94;
N, 12.83.
N-Benzyloxycarbonyl-N’-(3-cyano)propylhydrazine (7), 76% yield as a viscous
transparent oil; Rf D 0.73 (EtOAc).
1H NMR (200 MHz, CDCl3): d 1.74 (quint, 2H, J D 6.8 Hz, CH2); 2.38 (t, 2H, J D
7 Hz, CH2); 2.90 (t, 2H, J D 6.4 Hz, CH2); 3.97 ( br s, 1H, NH); 5.01 (s, 2H, CH2 (Cbz));
6.81 (br s, 1H, NH); 7.32 (s, 5H, Ar(H)). 13C NMR: d 14.4; 23.5; 49.7; 67.1; 119.2;
128.1; 128.3; 128.6; 136.1; 157.5. IR (cm¡1): 3309, 3030, 2953, 2924, 2245, 1708, 1518,
1453, 1256, 1151, 738.
HRMS: m/z for C12H16N3O2 [MCH]C. Calcd: 234.12370. Found: 234.12356.
Anal. Calcd for C12H15N3O2: C, 61.82; H, 6.49; N, 18.0. Found: C, 61.83; H, 6.48; N,
17.80.
N-Fluorenylmethyloxycarbonyl-N’-(2-benzyloxy)ethylhydrazine (8), 67% yield
as a white solid, mp. 120–122ꢀ; Rf D 0.42 (1:1 EtOAc-light petorleum).
1H NMR (200 MHz, CDCl3): d 3.01 (t, 2H, J D 6 Hz, CH2); 3.50 (t, 2H, J D 5 Hz;
CH2); 4.17 (t C br s, 2H; J D 6.6 Hz, CH (Fmoc) C NH); 4.42 (d, 2H, J D 6.8 Hz, CH2
(Fmoc)); 4.51 (s, 2H, CH2 (Bn)); 6.64 (br s, 1H, NH); 7.19–7.38 (m, 9H, Ar(H)); 7.54 (d,
2H, J D 7.2 Hz, Ar(H)); 7.70 (d, 2H, J D 7.6 Hz; Ar(H)). 13C NMR: d 47.2; 51.3; 66.9;
68.0; 73.0; 120.0; 125.0; 127.0; 127.6; 127.7; 128.2; 128.4; 138.1; 141.3; 143.8; 157.2.
IR (cm¡1): 3299, 3068, 2949, 1708, 1552, 1449, 1264, 1101, 736.
HRMS: m/z for C24H25N2O3 [MCH]C. Calcd: 389.18597. Found: 389.18589.
Anal. Calcd for C24H24N2O3: C, 74.26; H, 6.33; N, 7.22. Found: C, 74.10; H, 6.16; N,
7.17.
N-Benzyloxycarbonyl-N’-(2-benzyloxy)ethylhydrazine (9), 65% yield as a white
solid, mp. 56-59ꢀ; Rf D 0.42 (1:1 EtOAc-light petroleum).
1H NMR (200 MHz, CDCl3): d 3.01 (t, 2H, J D 5 Hz, CH2); 3.50 (t, 2H, J D 5.6 Hz;
CH2); 4.22 (br s, 1H, NH); 4.44 (s, 2H, CH2-O); 5.08 (s, 2H, CH2 (Cbz)); 6.93 (br s, 1H,
NH); 7.24 (s, 10H; Ar(H)). 13C NMR: d 51.2; 66.9; 68.0; 72.9; 127.5; 127.6; 128.06;
128.1; 128.3; 128.4; 136.2; 138.1; 157.2. IR (cm¡1): 3319, 3030, 2949, 1685, 1545, 1488,
1265, 1102, 731. HRMS: m/z for C17H21N2O3 [MCH]C. Calcd: 301.15467. Found:
301.15454.
Anal. Calcd for C17H20N2O3: C, 68.00; H, 6.77; N, 9.33. Found: C, 67.86; H, 6.63; N,
9.32.
N-Fluorenylmethyloxycarbonyl-N’-(2-N”-benzyloxycarbonyl)ethylhydrazine (10),
70% yield as a white solid, mp. 160–162ꢀ; Rf D 0.61 (EtOAc).
1H NMR (200 MHz, DMSO-d6): d 2.77 (t, 2H, J D 6 Hz, CH2); 3.11 (t, 2H; J D
6.2 Hz, CH2); 4.23 (t, 1H, J D 6 Hz; CH (Fmoc)); 4.34 (d, 2H, J D 6.2 Hz, CH2 (Fmoc));

496
Ja€rv et al.
4.72 ( br s, 1H, NH); 5.03 (s, 2H, CH2 (Cbz)); 7.11 (br s, 1H, NH); 7.29–7.45 (m, 9H, Ar
(H)); 7.70 (d, 2H, J D 7 Hz, Ar(H)); 7.89 (d, 2H, J D 7 Hz, Ar(H)); 8.66 (br s, 1H, NH).
13C NMR: d 38.7; 46.7; 50.4; 65.2; 65.5; 120.0; 125.1; 127.0; 127.4; 127.5; 127.6;
128.2; 137.1; 140.7; 143.7; 156.1; 156.8. IR (cm¡1): 3314, 3042, 2949, 1689, 1531, 1253,
737. HRMS: m/z for C25H26N3O4 [MCH]C. Calcd: 432.19178. Found: 432.19151.
Anal. Calcd for C25H25N3O4 : C, 69.64; H, 5.84; N, 9.75. Found: C, 69.40; H, 5.79;
N, 9.62.
N-Benzyloxycarbonyl-N’-(2-N”-benzyloxycarbonyl)ethylhydrazine (11), 63%
yield as a white solid, mp. 85–88ꢀ; Rf D 0.6 (EtOAc).
1H NMR (200 MHz, CDCl3): d 2.82 ( t, 2H, J D 4 Hz; CH2); 3.19 (t, 2H, J D 4 Hz,
CH2); 4.20 (br s, 1H, NH); 5.05 (s, 4H, 2 x CH2 (Cbz)); 5.86 ( br s, 1H, NH); 7.17 (br s,
1H, NH); 7.26 (s, 10H, Ar(H). 13C NMR: d 38.4; 51.0; 66.6; 67.0; 128.0; 128.02; 128.04;
128.2; 128.4; 128.5; 136.1; 136.6; 156.9; 157.6. IR (cm¡1): 3305, 3032, 2953, 1684,
1539, 1496, 1267, 1133, 737. HRMS: m/z for C18H22N3O4 [MCH]C. Calcd: 344.16048.
Found: 344.16016.
Anal. Calcd for C18H21N3O4 : C, 62.96; H, 6.17; N, 12.24. Found: C, 62.81; H, 6.09;
N, 12.08.
N-Fluorenylmethyloxycarbonyl-N’-ethylhydrazine (12), 74% yield as a white
solid, mp. 152-156ꢀ; Rf D 0.31 (1:1 EtOAc/light petroleum).
1H NMR (200 MHz, CDCl3): d 1.05 (t, 3H, J D 6.5 Hz, CH3); 2.88 (q, 2H, J D
6.2 Hz, CH2); 3.77 (br s, 1H, NH); 4.20 (t, 1H, J D 6.2 Hz, CH (Fmoc)); 4.43 (d,
2H, J D 6.3 Hz, CH2 (Fmoc)); 6.59 (br s, 1H, NH); 7.28–7.39 (m, 4H, Ar(H)); 7.56
(d, 2H, J D 7.4 Hz, Ar(H)); 7.74 (d, 2H, J D 7.5 Hz, Ar(H)). 13C NMR: d 12.7;
46.3; 47.3; 67.0; 120.0; 125.0; 127.1; 127.8; 141.4; 143.8; 157.3. IR (cm¡1): 3290,
3018, 2973, 1699, 1559, 1261, 1146, 734. HRMS: m/z for C17H19N2O2 [MCH]C.
Calcd: 283.14410. Found: 283.14394.
Anal. Calcd for C17H18N2O2 : C, 72.37; H, 6.43; N, 9.93. Found: C, 72.18; H, 6.41;
N, 9.86.
N-Benzyloxycarbonyl-N’-ethylhydrazine (13), 66 % yield as a white solid, mp. 51-
53ꢀ; Rf D 0.31 (1:1 EtOAc-light petroleum).
1H NMR (200 MHz, CDCl3): d 1.04 (t, 3H, J D 7.2 Hz, CH3); 2.88 (q, 2H, J D 7 Hz,
CH2); 3.99 (br s, 1H, NH); 5.12 (s, 2H, CH2 (Cbz)); 6.80 (br s, 1H, NH); 7.34 (s, 5H, Ar
(H)). 13C NMR: d 12.7; 46.2; 67.0; 128.15; 128.23; 128.5; 136.3; 157.4. IR (cm¡1): 3279,
3026, 2969, 1700, 1559, 1258, 1148. HRMS: m/z for C10H15N2O2 [MCH]C. Calcd:
195.11280. Found: 195.11274.
Anal. Calcd for C10H14N2O2 : C, 61.89; H, 7.27; N, 14.43. Found: C, 61.88; H, 7.10;
N, 14.24.
N-Fluorenylmethyloxycarbonyl-N’-(2-N”-benzoyl)ethylhydrazine (14), 86%
yield as a white solid, mp. 133–134ꢀ; Rf D 0.33 (EtOAc).
1H NMR (200 MHz, CDCl3): d 2.92 ( t, 2H, J D 6 Hz, CH2); 3.45 (t, 2H, 5.8 Hz,
CH2); 3.94 (br s, 1H, NH); 4.16 (t, 1H, J D 6.4 Hz, CH (Fmoc)); 4.43 (d, 2H, J D 6.8 Hz,
CH2 (Fmoc)); 6.39 (br s, 1H, NH); 6.98 (br s, 1H, NH); 7.21–7.56 (m, 9H, Ar(H)); 7.74
(t, 4H, J D 7.8 Hz, Ar(H)). 13C NMR: d 37.0; 47.2; 51.0; 67.0; 120.1; 125.0; 127.0;
127.1; 127.8; 128.5; 131.4; 134.4; 141.3; 143.6; 157.9; 167.8. IR (cm¡1): 3310, 3054,
2957, 1689, 1630, 1533, 1270, 736. HRMS: m/z for C24H24N3O3 [MCH]C. Calcd:
402.18122. Found: 402.18101.
Anal. Calcd for C24H23N3O3 : C, 71.80; H, 5.78; N, 10.47. Found: C, 71.77; H, 5.73;
N, 10.22.

Synthesis of Protected Alkylhydrazines
497
N-Benzyloxycarbonyl-N’-(2-N”-benzoyl)ethylhydrazine (15), 80% yield as a
white solid, mp. 103–106ꢀ; Rf D 0.33 (EtOAc).
1H NMR (200 MHz, CDCl3): d 2.91 (t, 2H, J D 5.8 Hz, CH2); 3.46 (t, 2H, J D
5.6 Hz, CH2); 4.00 (br s, 1H, NH); 5.08 (s, 2H, CH2 (Cbz)); 7.29–7.45 (m, 9H, Ar(H));
7.57 (br s, 1H, NH); 7.79 (d, 2H, J D 6.8 Hz, Ar(H) C NH). 13C NMR: d 37.2; 51.0; 67.1;
127.1; 128.0; 128.2; 128.4; 128.5; 131.3; 134.4; 136.1; 157.9; 167.9. IR (cm¡1): 3317,
3026, 2957, 1688, 1630, 1536, 1488, 1269, 694. HRMS: m/z for C17H20N3O3 [MCH]C.
Calcd: 314.14992. Found: 314.14986.
Anal. Calcd for C17H19N3O3 : C, 65.20; H, 6.12; N, 13.42. Found: C, 64.97; H, 6.10;
N, 13.26.
N-Fluorenylmethyloxycarbonyl-N’-isopropylhydrazine (16), 77% yield, mp. 160–
162ꢀC, lit.8 163–164ꢀC; Rf D 0.41 (1:1 EtOAc-light petroleum).
1H NMR (200 MHz, CDCl3): d 1.02 (d, 6H, J D 6 Hz, 2xCH3); 3.16 (sep, 1H, J
D 6.8 Hz, CH(iPr)); 4.21 (t, 1H, J D 6.6 Hz, CH(Fmoc)); 3.85 (br s, 1H, NH); 4.44
(d, 2H, J D 6 Hz, CH2(Fmoc)); 6.05 (br s, 1H, NH); 7.24–7.42 (m, 4H, Ar(H)); 7.57
(d, 2H, J D 7Hz, Ar(H)); 7.75 (d, 2H, J D 6.8 Hz, Ar(H)). 13C NMR: d 20.3; 47.2;
51.2; 67.1; 120.1; 125.0; 127.1; 127.8; 141.4; 143.7; 157.8. LRMS: m/z for
C18H21N2O2 [MCH]C. Calcd: 297.1. Found: 297.0. IR (cm¡1): 3330, 3066, 2972,
1695, 1491, 1268, 1164, 733.
N-Benzyloxycarbonyl-N’-isopropylhydrazine (17), 64% yield as a white solid, mp.
59–61ꢀC, lit.21 59–60ꢀ; Rf D 0.41 ( 1:1 EtOAc-light petroleum).
1H NMR (200 MHz, CDCl3): d 1.01 (d, 6H, J D 6 Hz, 2xCH3); 3.11 (sep, 1H, J D
6.8 Hz, CH (iPr)); 4.28 (br s, 1H, NH); 5.12 (s, 2H, CH2 (Cbz)); 6.79 (br s, 1H, NH); 7.33
(s, 5H, Ar(H)). 13C NMR: d 20.5; 50.8; 52.3; 67.1; 128.1; 128.2; 128.5; 136.2; 157.4.
LRMS: m/z for C11H17N2O2 [MCH]C. Calcd: 209.1. Found: 209.0.
IR (cm¡1): 3325, 3034, 2974, 1688, 1534, 1492, 1273, 1168, 737.
N-Fluorenylmethyloxycarbonyl-N’-cyclohexylhydrazine (18), 72% yield as a
white solid, mp. 153–155ꢀ; Rf D 0.56 (1:1 EtOAc-light petroleum).
1H NMR (700 MHz, CDCl3): d 1.10 (d, 2H, J D 14 Hz); 1.18 (d, 1H, J D 14 Hz);
1.27 (t, 2H; J D 7 Hz); 1.62 (d, 1H, J D 14 Hz); 1.75 (d, 2H, J D 14 Hz); 1.83 (d, 2H, J D
14 Hz); 2.84 (s, 1H, N-CH); 3.96 (br s, 1H, NH); 4.25 (t, 1H; J D 7 Hz; CH (Fmoc));
4.47 (d, 2H, J D 7 Hz, CH2 (Fmoc)); 6.29 (br s, 1H, NH); 7.28–7.43 (m, 4H, Ar(H)); 7.59
(d, 2H, J D 7 Hz, Ar(H)); 7.78 (d, 2H, J D 7 Hz, Ar(H)). 13C NMR: d 24.3; 26.0; 31.1;
47.2; 58.4; 66.9; 120.0; 125.0; 127.1; 127.7; 141.3; 143.7; 157.3. IR (cm¡1): 3290, 3032,
2929, 1700, 1554, 1446, 1266, 1162, 734. HRMS: m/z for C21H25N2O2 [MCH]C. Calcd:
337.19105. Found: 337.19097.
Anal. Calcd for C21H24N2O2: C, 76.86; H, 7.37; N, 8.54. Found: C, 76.65; H, 7.19; N,
8.30.
N-Benzyloxycarbonyl-N’-cyclohexylhydrazine (19), 87% yield as a white solid,
mp. 66-69ꢀ; Rf D 0.55 (1:1 EtOAc-light petroleum).
1H NMR (200 MHz, CDCl3): d 1.17 (m, 5H); 1.72 (m, 5H); 2.82 (s, 1H, N-CH); 4.72
(br s, 1H, NH); 5.10 (s, 2H, CH2 (Cbz)); 7.05 (br s, 1H, NH); 7.32 (s, 5H, Ar(H)).
13C NMR: d 24.4; 26.0; 31.0; 58.5; 67.0; 128.1; 128.2; 128.5; 136.3; 157.6. IR
(cm¡1): 3281, 3034, 2932, 1705, 1542, 1457, 1256, 1140, 696.
HRMS: m/z for C14H21N2O2 [MCH]C. Calcd: 249.15975. Found: 249.15994
Anal. Calcd for C14H20N2O2 : C, 67.76; H, 8.12; N, 11.29. Found: C, 67.73; H, 7.97;
N, 11.25.

498
Ja€rv et al.
Acknowledgements
The authors are grateful to Professor J.-P. Anselme, the Executive Editor of OPPI for his
valuable comments. 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.
References
1. G. Coispeau and J. Elguero, Bull. Soc. Chim. Fr., 2717 (1970).
2. H-J. Liu, S-F. Hung, C-L. Chen and M-H. Lin, Tetrahedron, 69, 3907 (2013).
3. S. Neogi, A. Roy and D. Naskar, J. Comb. Chem., 12, 617 (2010).
4. I. Yavari, M. J. Bayat and S. Skoulika, Synlett, 24, 2591 (2013).
€
€
5. A. Fassler, G. Bold, H.-G. Capraro, R. Cozens, J. Mestan, B. Poncioni, J. Rosel, M. Tintelnot-
Blomley and M. Lang, J. Med. Chem., 39, 3203 (1996).
6. Y. Qian, D. Bolin, K. Conde-Knape, P. Gillespie, S. Hayden, K-S. Huang, A. R. Olivier, T.
Sato, Q. Xiang, W. Yun and X. Zhang, Bioorg. Med. Chem. Lett., 23, 2936 (2013).
7. M. Quibell, W. G. Turnell and T. Johnson, J. Chem. Soc., Perkin Trans. 1, 2843 (1993).
8. D. Boeglin and W. D. Lubell, J. Comb. Chem., 7, 864 (2005).
9. A. Zega, Curr. Med. Chem., 12, 589 (2005).
10. C. Proulx, D. Sabatino, R. Hopewell, J. Spiegel, Y. Garcia Ramos and W. D. Lubell, Future
Med. Chem., 3, 1139 (2011).
11. O. Busnel, L. Bi, H. Dali, A. Cheguillaume, S. Chevance, A. Bondon, S. Muller and M. Baudy-
Floc’h, J. Org. Chem., 70, 10701 (2005).
12. N. S. Freeman, M. Hurevich and C. Gilon, Tetrahedron, 65, 1737 (2009).
13. N. S. Freeman, Y. Tal-Gan, S. Klein, A. Levitzki and C. Gilon, J. Org. Chem., 76, 3078 (2011).
14. O. Busnel and M. Baudy-Floc’h, Tetrahedron Lett., 48, 5767 (2007).
15. R. E. Melendez and W. D. Lubell, J. Am. Chem. Soc., 126, 6759 (2004).
16. J. Lee and M. Bogyo, Chem. Biol., 5, 233 (2010).
€
17. A. Mastitski, K. Kisseljova and J. Jarv, Proc. Estonian Acad. Sci., 63, 438 (2014). doi: 10.3176/
proc.2014.4.09
18. A. Bredihhin and U. Maeeorg, Organic Lett., 9, 4975 (2007).
€
19. A. Mastitski,T. Haljasorg, K. Kipper and J. Jarv, Proc. Estonian Acad. Sci., 64, 168 (2015). doi:
10.3176/proc.2015.2.05
€
20. A. Mastitski and J. Jarv, Org. Prep. Proced. Int., 46, 559 (2014).
21. A. Allais and P. Girault, French Patent 1967, 1468633; Chem. Abstr., 68, 59268a (1967).