Multisubstituted urea derivatives of hydrazines by a flexible approach with potential application in combinatorial chemistry

Article abstract of DOI:10.1055/s-1998-2217

Using inexpensive, readily available starting materials, a trisubstituted hydrazine was synthesized by our recently developed techniques and converted to the corresponding tosylcarbamoyl derivative (N- tosylsemicarbazide) which can be further alkylated on its carbamoyl nitrogen under Mitsunobu conditions to give compounds of type 6. The yields in all steps are high. Similarly, selectively protected, N,N'-substituted hydrazines can be tosylcarbamoylated twice with intermediary alkylation to give dimeric ureas 11 with four different substituents in addition to the tosyl groups. The latter can in principle be replaced by other sulfonyl groups of higher pharmaceutical interest, thus allowing simultaneous variation of 5 sites in 6 or 6 such in 11. Due to the importance of ureas and sulfonylureas as pharmaceuticals, these new flexible synthetic schemes might therefore be applicable in the search for new lead substances by combinatorial chemistry. In connection with this work an unprecedented N-benzyl cleavage by trifluoroacetic acid of potential practical interest was discovered.

Full text of DOI:10.1055/s-1998-2217

SYNTHESIS
December 1998
1817
Multisubstituted Urea Derivatives of Hydrazines by a Flexible Approach with Potential
Application in Combinatorial Chemistry
Leif Grehn, Ulf Ragnarsson*
Department of Biochemistry, University of Uppsala, Biomedical Center, PO Box 576, S-751 23 Uppsala, Sweden
Fax +46(18)552139; E-mail: urbki@bmc.uu.se
Received 27 April 1998
Abstract: Using inexpensive, readily available starting materials,
a trisubstituted hydrazine was synthesized by our recently devel-
oped techniques and converted to the corresponding tosylcarbam-
ic hydrogenolysis gave 4 as an oil. This was reacted with
oyl derivative (N-tosylsemicarbazide) which can be further
protected intermediate furnished 2 as an oil which was
acylated to afford again a crystalline substance 3. Catalyt-
tosyl isocyanate and the product 5 isolated by crystalliza-
tion. Since this intermediate contains an acidic sulfonyl-
urea proton, we made an attempt to alkylate it with an al-
cohol under Mitsunobu conditions5 and, indeed, succeed-
ed in isolating 6 as an oil in fair yield. At this stage
chromatographic workup was required. Weinreb et al.6
first reported the alkylation of sulfonamides under these
conditions, but obviously N-tosylureas also undergo this
reaction. To the best of our knowledge compound 6 is the
first pentasubstituted semicarbazide prepared so far.
alkylated on its carbamoyl nitrogen under Mitsunobu conditions
to give compounds of type 6. The yields in all steps are high. Sim-
ilarly, selectively protected, N,N'-substituted hydrazines can be
tosylcarbamoylated twice with intermediary alkylation to give
dimeric ureas 11 with four different substituents in addition to the
tosyl groups. The latter can in principle be replaced by other sul-
fonyl groups of higher pharmaceutical interest, thus allowing
simultaneous variation of 5 sites in 6 or 6 such in 11. Due to the
importance of ureas and sulfonylureas as pharmaceuticals, these
new flexible synthetic schemes might therefore be applicable in
the search for new lead substances by combinatorial chemistry. In
connection with this work an unprecedented N-benzyl cleavage by
trifluoroacetic acid of potential practical interest was discovered.
Key words: combinatorial chemistry, multisubstituted hydra-
zines, 1,2-bis(tosylcarbamoyl)hydrazines, Mitsunobu substrate,
ureas
Combinatorial chemistry, which attempts to synthesize
large numbers of new compounds by condensing a small
number of reagents together in many, if not all possible
combinations, is nowadays in high demand for the gener-
ation and optimization of lead compounds for new drugs.1
It can be achieved in many different ways, such as in mix-
tures to produce libraries or in large numbers of parallel
vessels either on a solid support2a,b or in solution.2c Clean
basic chemistry is as usual a prerequisite for success in
work involving multistep schemes. The earliest work in
the combinatorial chemistry field dealt with peptides.
Z = C(O)OBn, 3–6: R3 = 4-FC6H4CO, 6: R4 = Ph(CH2)4. (a) EtI, PTC
conditions (98%); (b) TFA (99%); (c) R3Cl (93%); (d) H2/Pd; (e)
TsNCO (97% from 3); (f) R4OH (Mitsunobu conditions) (61%).
Scheme 1
Having accomplished the synthesis of 6, we reacted com-
pound 2 with tosyl isocyanate and obtained 7 (Scheme 2)
by analogy with 5 as a crystalline solid. This intermediate
was alkylated with two different alcohols under Mitsuno-
bu conditions to give 8a and 8b as oils in 79 and 59%
yield after purification by chromatography. The former
intermediate was hydrogenolyzed catalytically and the
oily 9 reacted a second time with tosyl isocyanate produc-
ing, again, a crystalline solid product 10 in nearly quanti-
tative yield. From this compound we could obtain the de-
sired final product 11 by a Mitsunobu alkylation under the
conditions used for 6 and 8 above. The product 11 is be-
Until recently relatively little work was reported on selec-
tive substitution of hydrazine and preparation of unsym-
metrical hydrazine derivatives.3 Using modern protective
groups we made a couple of triprotected hydrazine re-
agents which allowed rational stepwise alkylation and
acylation to be performed.4 In this paper we describe fur-
ther work with di- and trisubstituted hydrazine derivatives
as starting materials for the preparation of multisubstitut-
ed ureas. Two flexible schemes are presented, both allow-
ing preparation of such compounds under experimentally
simple, carefully controlled conditions in high yield and
purity on a laboratory scale.
For the synthesis of the maximally substituted semicarba-
zide model compound 6 (Scheme 1) we chose the readily
available 2-Boc-1-methyl-1-Z-hydrazine4c as the starting
material, which could be alkylated under the previously
described phase-transfer catalysis (PTC) conditions, and
isolated 1 as a crystalline material in nearly quantitative
yield. Removal of the Boc group from this orthogonally
8a–11: R3 = CD3, 8b: R3 = Me2CHCH2, 11: R4 = Bn. (a) TsNCO (7:
99%; 10: 95% from 8a); (b) R3OH/R4OH (Mitsunobu conditions)
(8a,b 59–79%; 11: 79%); (c) H2/Pd (97%).
Scheme 2

SYNTHESIS
Papers
1818
1-(Benzyloxycarbonyl)-2-(tert-butoxycarbonyl)-2-ethyl-1-methyl-
hydrazine (1):
lieved to be the first hexasubstituted dimeric urea (carba-
zide) of its kind, carrying the maximally conceivable
number of non-hydrogen substituents on its nitrogens and
exploiting the hydrazine moiety as a scaffold exhaustive-
ly. Together with 6 it attests to the usefulness of the selec-
tively protected difunctional reagent used as starting ma-
terial.4c The latter features dual protection of one of the
hydrazine nitrogen atoms,7 as a result of which side reac-
tions are efficiently minimized at this site.
To a solution of 2-Boc-1-Me-1-Z-hydrazine4c (2.80 g, 10.0 mmol) in
anhyd benzene (40 mL) was added Bu4NHSO4 (0.68 g, 2.0 mmol),
finely ground, dried K2CO3 (4.14 g, 30 mmol) and freshly ground
NaOH (1.20 g, 30 mmol) under argon at r.t. The resulting slurry was
vigorously stirred for a few minutes, whereafter neat EtI (4.78 g, 30
mmol) was introduced dropwise with rapid stirring over a period of
30 min. The reaction was then allowed to further proceed under the
above conditions with monitoring by TLC (B). After 30 h, no remain-
ing starting material could be detected and most of the solvent was
removed at reduced pressure. The semisolid residue was partitioned
between Et2O (300 mL) and aq 1 M KHSO4 (150 mL) and the organic
extract was washed in turn with 1 M KHSO4, 1 M NaHCO3 and brine
(3 × 75 mL each) and dried (MgSO4) in the presence of decolorizing
carbon. Removal of the solvent left a colorless viscous oil which soon
solidified. The yield of crude, chromatographically pure (A, B) 1 was
3.02 g (98%) after thorough drying under high vacuum. Recrystalli-
zation from light petroleum (15 mL/g, decolorizing carbon) provided
white, soft needles after 24 h at –20°C; mp 55.5–56°C.
In addition to previously available procedures for the
preparation of unsymmetrical ureas,8a several new, flexi-
ble ones have recently been developed.8b–f Although sev-
eral sulfonylureas are commercially important as antidia-
betic agents and can be prepared from sulfonamides and
isocyanates,9 few alkylated sulfonylureas have been de-
scribed in the literature. The present procedure, involving
alkylation under Mitsunobu conditions, might occasional-
ly be an attractive alternative, when the alcohol is avail-
able, although the yields seem to be significantly lower for
tosylureas than for tosylcarbamates.10 In all other individ-
ual steps involved in the synthesis of our model com-
pounds yields were generally nearly quantitative and
Schemes like 1 and 2 might therefore be applicable in
combinatorial chemistry for the synthesis of small fo-
cused urea and/or sulfonylurea libraries.11 Furthermore,
since many compounds containing such groups are highly
crystalline and easy to purify, individual components of
high purity should result from parallel synthesis.
1H NMR (CDCl3): δ = 1.13/1.16 (2t, J = 7.2 Hz, 3H, CH2CH3), 1.34/
1.37/1.43/1.50 (4s, 9H, Boc-Me), 3.10/3.11/3.15/3.17 (4s, 3H, N-
Me), 3.36–3.66 (complex, 2H, N-CH2), 5.18, 5.10/5.26, 5.08 (2ABq,
J = 12.4 Hz, 2H, Z-CH2), 7.31-7.37 (complex, 5H, Ph-H).
13C NMR (CDCl3): δ = 12.76/12.84/13.32/13.47 (CH2CH3), 28.13/
28.31 (Boc-Me), 37.38/38.34/37.12/38.03 (N-Me), 42.88/42.81/
44.69/44.59 (N-CH2), 67.68/67.79/67.43 (Z-CH2), 80.88/80.73/
81.17/81.26 (Boc-Cq), 127.66, 127.89, 128.02, 128.06, 128.11,
128.29, 128.46, 136.02, 136.19, 136.26, 136.33 (Ar), 154.24/154.81/
154.01/154.40 (Boc-CO), 156.57/156.11/156.83/156.27 (Z-CO).
Anal. Calcd for C16H24N2O4 (308.4): C, 62.32; H, 7.84; N, 9.08.
Found: C, 62.4; H, 7.9; N, 9.2.
Finally, we should like to briefly mention an unexpected
side reaction encountered in connection with Scheme 2. In
an attempt to prepare another derivative of 11, starting
from 1 (Scheme 3), we first performed a hydrogenolysis
and then reacted the intermediate 12 with tosyl isocyanate
and obtained 13. Mitsunobu alkylation with benzyl alco-
hol also provided the expected product 14, but this turned
out to be labile to the trifluoroacetic acid used to cleave
off the Boc group and therefore compound 15 without the
N-benzyl group was formed in the subsequent reaction
with tosyl isocyanate. We interpret this cleavage to be a
consequence of an exceptionally low electron density on
the benzyl nitrogen which favored the release of a benzyl
carbenium ion from the protonated species.
1-(Benzyloxycarbonyl)-2-ethyl-1-methylhydrazine (2):
Recrystallized 1 (2.10 g, 6.81 mmol) was dissolved in CH2Cl2/TFA
(2:1, 35 mL) and left to react for 2 h while protected from atmospheric
moisture. After evaporation to complete dryness the oily residue was
partitioned between CH2Cl2 (60 mL) and 30% aq K2CO3 (30 mL) and
the aqueous layer further extracted with CH2Cl2 (10 mL), whereupon
the combined extracts were washed with brine (30 mL) and dried
(Na2SO4). Removal of the solvent left a colorless liquid (1.41 g, 99%,
after drying under high vacuum). This crude product was essentially
pure by TLC (A, B) and suitable for further work.
1H NMR (CDCl3): δ = 1.07 (t, J = 7.2 Hz, 3H, CH2CH3), 2.89 (q, J =
7.2 Hz, 2H, N-CH2), 3.10 (s, 3H, N-Me), 4.42 (br s, 1H, NH), 5.15 (s,
2H, Z-CH2), 7.30–7.39 (complex, 5H, Ph-H).
13C NMR (CDCl3): δ = 12.84 (CH2CH3), 37.04 (N-Me), 44.15 (N-
CH2), 67.43 (Z-CH2), 127.91, 128.08, 128.50, 136.50 (Ar), 156.76
(CO).
1-(Benzyloxycarbonyl)-2-ethyl-2-(4-fluorobenzoyl)-1-methyl-
hydrazine (3):
Crude 2 (1.39 g, 6.68 mmol) was dissolved in anhyd pyridine (20
mL), and the clear solution cooled in ice under argon. 4-Fluoroben-
zoyl chloride (1.32 g, 8.32 mmol) was then introduced dropwise with
rapid stirring over 15 min, whereafter stirring was continued over-
night at r.t. Most of the pyridine was then stripped off at reduced pres-
sure and the semisolid residue was partitioned between Et2O (150
mL) and 0.2 M citric acid (75 mL), the colorless Et2O extract was
washed in turn with 0.2 M citric acid, 1 M NaHCO3 and brine (3 × 40
mL each) and dried (MgSO4). Removal of the solvent left a pale yel-
low oil weighing 2.22 g (100%) after thorough drying. TLC (A, B)
gave essentially one spot. It could be purified by column chromatog-
raphy (B; recovery 93%) and subsequently obtained as white crystals
from light petroleum (100 mL/g) after several days at –20°C; mp 40–
40.5°C.
(a) H2/Pd (89%); (b) TsNCO (13 97%); (c) BnOH (Mitsunobu con-
ditions (79%); (d) TFA (15 80%).
Scheme 3
The general experimental conditions agreed with those earlier report-
ed.4c TLC systems were: (A) toluene/MeCN 2:1; (B) light petroleum
(bp 40–65 °C)/Et2O 2:1; and (C) CH2Cl2/acetone/HOAc 40:10:1.

SYNTHESIS
December 1998
1819
1H NMR (CDCl3): δ = 1.22/1.27 (2t, J = 7.1 Hz, together 3H,
CH2CH3), 3.07 (perturbed br signal, 3H, N-Me), 3.71 (unresolved br
signal, 2H, N-CH2), 4.97–5.10 and 5.16–5.23 (complex, 2H, Z-CH2),
6.93 (br signal) and 7.20–7.43 (complex, 9H, Ar-H).
13C NMR (CDCl3): δ = 12.95/13.41 (CH2CH3), 21.38 (Ts-Me), 27.34
(PhCH2CH2), 28.21 (Ph(CH2)2CH2), 35.17 (PhCH2), 39.63/41.69 (N-
Me), 47.57/43.67 (CH3CH2), 71.37/70.89 [Ph(CH2)3CH2], 115.42 (d,
2JC,F~17 Hz, C3,5), 125.80, 125.90, 128.28, 128.35, 129.07, 130.27
13C NMR (CDCl3): δ = 12.67/13.25 (CH2CH3), 37.60/38.38/38.07
(N-Me), 42.50/42.86/45.99 (N-CH2), 68.28/67.98 (Z-CH2), 115.28
(Ar), 141.55/142.01 (Ts-C1), 155.49 (br urea-CO), 163.86 (d, 1JC,F
=
250.9 Hz, C4),170.52 (br, 4-FC6H4CO).
2
(d, J C,F = 20.8 Hz, C3,5), 127.87, 128.28, 128.51, 128.59, 131.25,
131.54, 135.42, 135.84 (Ar), 155.47 (Z-CO), 163.50 (d, 1JC,F = 250.3
Hz, C4), 171.32/171.82 (4-FC6H4CO).
1-(Benzyloxycarbonyl)-2-ethyl-1-methyl-2-(tosylcarbamoyl)hy-
drazine (7):
Synthesized from 2 and tosyl isocyanate essentially as described for
5. The yield of crude pure (C) product was 99% in a 5 mmol run;
white, lustrous crystals with mp 117–119°C (CH2Cl2/Et2O 1:20;
–20°C; 60 mL/g).
Anal. Calcd for C18H19FN2O3 (330.4): C, 65.44; H, 5.80; N, 8.48.
Found: C, 65.4; H, 5.8; N, 8.6.
1-Ethyl-1-(4-fluorobenzoyl)-2-methyl-2-(tosylcarbamoyl)hydra-
zine (5):
1H NMR (CDCl3): δ = 1.06 (perturbed t, J = 7.3 Hz, 3H, CH2CH3),
2.40 (s, 3H, Ts-Me), 3.12 (s, 3H, N-Me), 3.39 and 3.52 (ABq, further
split by coupling to Me, J1 = 14.4 and J2 = 7.2 Hz, 2H, CH2CH3), 5.04
and 5.09 (ABq, J = 11.9 Hz, 2H, Z-CH2), 7.23–7.32 (complex, 7H,
Ph-H + Ts-H3,5), 7.86 (d, J = 8.2 Hz, 2H, Ts-H2,6), 8.68 (br s, 1H,
NH).
Recrystallized 3 (330 mg, 1.00 mmol) was dissolved in MeOH (6 mL)
and hydrogenolyzed for 2 h at atmospheric pressure over 5% Pd/C (60
mg). The catalyst was filtered off and the product was worked up es-
sentially as described for 2. The crude, chromatographically pure 1-
ethyl-1-(4-fluorobenzoyl)-2-methylhydrazine (4) was obtained as a
colorless liquid (191 mg, 97%). This product was dissolved in anhyd
CH2Cl2 (1 mL) and cooled in ice under argon, whereupon a solution
of tosyl isocyanate (193 mg, 0.98 mmol) in anhyd CH2Cl2 (1 mL) was
introduced dropwise with rapid stirring over 10 min and left for a few
hours under stirring in ice. A white precipitate was formed, from
which the solvent was stripped off. The solid residue was triturated
with cold Et2O and chilled overnight, the insoluble product was col-
lected by filtration, repeatedly rinsed with cold Et2O and dried in vac-
uo to give crude, chromatographically pure 5 (C; 382 mg, 97% from
3); microcrystalline solid; mp 217–219°C (dec) (CHCl3; –20°C; 20
mL/g).
13C NMR (CDCl3): δ = 12.77 (CH2CH3), 21.62 (Ts-Me), 37.09 (N-
Me), 42.07 (CH2CH3), 68.63 (Z-CH2), 127.99, 128.18, 128.35,
128.55, 129.46, 135.10, 135.89 (Ar), 144.49 (Ts-C1), 151.12 (urea
CO), 155.67 (Z-CO).
Anal. Calcd for C19H23N3O5S (405.48): C, 56.28; H, 5.72; N, 10.36.
Found: C, 56.2; H, 5.8; N, 10.4.
1-(Benzyloxycarbonyl)-2-ethyl-1-methyl-2-
[(trideuteromethyl)tosylcarbamoyl]hydrazine (8a):
Obtained by Mitsunobu alkylation of 7 with [2H3]MeOH as alkylating
agent. Essentially by analogy with 6, a 5 mmol run gave pure (A, B)
8a as a colorless viscous oil in 79% yield which failed to crystallize
even after prolonged storage at –20°C.
1H NMR (DMSO-d6): δ = 1.14 (perturbed t, J = 7.1 Hz, 3H, CH2CH3),
2.42/2.37 (2s, 3H, Ts-Me), 2.72, 3.10 and 3.60 (br signal, together 5H,
N-Me + N-CH2), 6.96–7.69 (br signal) and 7.43/7.36 (2d, J = 7.7/8.3
Hz) and 7.78/7.71 (2d, J = 8.2/8.3 Hz, together ~8H, Ar-H), 11.82/
11.42 (br signal, 1H, NH).
1H NMR (CDCl3): δ = 1.23/1.27 (2t, J = 7.2 Hz, 3H, CH2CH3), 2.42
(s, 3H, Ts-Me), 3.25/3.31 (2s, 3H, N-Me), 3.64–3.81 (2 perturbed m,
2H, CH2CH3), 5.16 and 5.11/5.18 (ABq/s, J = 11.9 Hz, 2H, Z-CH2),
7.29–7.36 (complex, 7H, Ph-H + Ts-H3,5), 7.75/7.81 (2d, J = 8.3 Hz,
2H, Ts-H2,6).
13C NMR (DMSO-d6): δ = 11.61/12.30 (CH2CH3), 21.03/20.87 (Ts-
Me), 36.1, 41.6, 42.2, 45.4 (br signal, partly obscured by solvent, N-
2
Me + N-CH2), 114.90 (d, JC,F = 21.2 Hz, C3,5), 125.59, 127.52,
13C NMR (CDCl3): δ = 12.45 (CH2CH3), 21.57 (Ts-Me), 33.7–34.6
(2 overlapping m, JC,D≈11 Ηz, CD3), 36.48/37.61 (N-Me), 45.73/
45.10 (CH2CH3), 68.27/68.17 (Z-CH2), 127.84, 128.24, 128.29,
128.31, 128.46, 128.56, 128.72, 128.75, 129.45, 133.44, 133.62,
135.52, 135.76 (Ar), 144.49/144.39 (Ts-C1), 155.66, 155.75, 155.79,
156.31 (CO).
128.20, 128.83, 129.32, 130.0, 131.79, 136.98, 141.42, 141.81,
1
143.74 (Ar), 151.82 (br urea-CO), 162.62 (d, JC,F = 246.3 Hz, C4),
170.73 (br, 4-FC6H4CO).
Anal. Calcd for C18H20FN3O4S (393.44): C, 54.95; H, 5.12; N, 10.68.
Found: C, 54.6; H, 5.2; N, 10.6.
1-(Benzyloxycarbonyl)-2-ethyl-2-[(isobutyl)tosylcarbamoyl]-1-
methylhydrazine (8b):
1-Ethyl-1-(4-fluorobenzoyl)-2-methyl-2-[(4-phenylbutyl)tosyl-
carbamoyl]hydrazine (6):
Synthesized from 7 and i-BuOH according to Mitsunobu. A 2.5 mmol
run afforded pure (A, B) 8b in 59% yield as a pale yellow oil.
1H NMR (CDCl3): δ = 0.84/0.91 [t/d, J = ~6/6.7 Hz, 6H, CH(CH3)2],
1.18/1.26 (2t, J = 7.2 Hz, 3H, CH2CH3), 1.83 and 1.94 (2 perturbed
m, 1H, CH), 2.40/2.38 (2s, 3H, Ts-Me), 3.20/3.29 (2s, 3H, N-Me),
3.52–3.60 and 3.68–3.82 (complex, 2H, CH2CH3), 4.04/3.96/4.07/
3.94/3.98 (5d, partly obscured, J = 6.3 Hz, 2H, i-Bu-CH2), 5.15 and
Recrystallized 5 (492 mg, 1.25 mmol) was suspended in anhyd THF
(5 mL; freshly distilled from Na/Ph2CO) and 4-phenylbutanol (235
mg, 1.56 mmol) added with gentle mixing under argon. Anhyd Ph3P
(492 mg, 1.56 mmol) was introduced in one portion and after a few
minutes the resulting turbid mixture was treated with diethyl azodi-
carboxylate (340 µL, 2.19 mmol) dropwise with rapid stirring over 15
min until a pale yellow color prevailed. The now clear mixture was
then stirred for 15 h with exclusion of moisture. The solvent was
stripped off at reduced pressure and the yellow oily residue was dis-
solved in CH2Cl2 and again taken to complete dryness. The residual
semisolid material was dissolved in CH2Cl2 and applied to a silica gel
column packed in CH2Cl2/Et2O 20:1. Slow elution gave first a yel-
lowish forerun (discarded) and then the desired compound as a pure
(C) colorless glassy oil (403 mg, 61%), which failed to crystallize
after prolonged standing at –20°C.
5.12/5.22 and 5.12 (2ABq, J = 12.1 Hz, 2H, Z-CH2), 7.21–7.40 (com-
.
plex, 7H, Ph-H + Ts-H3,5), 7.79/7.83 (2d, J = 8.2 Hz, 2H, Ts-H2,6
)
13C NMR (CDCl3): δ = 13.02/12.66 (CH2CH3), 18.84/18.97/18.82
[CH(CH3)2], 21.41/21.38 (Ts-Me), 27.92/27.85 (CHMe2), 37.89/
36.90 (N-Me), 46.17 and 46.37 (2N-CH2), 68.31/68.45 (Z-CH2),
125.76, 125.84, 128.17, 128.23, 128.43, 128.46, 128.91, 129.02,
135.74, 135.87 (Ar), 141.75/141.89/141.55/142.08 (Ts-C1), 155.30,
155.51, 155.64, 155.83 (CO).
1H NMR (CDCl3): δ = 1.22 (br signal, 3H, CH2CH3), 1.63 [br signal,
4H, PhCH2(CH2)2], 2.38 (s, 3H, Ts-Me), 2.57 (br signal, 2H, PhCH2),
3.36, 3.49 and 3.78 (br signal, together 5H, N-Me + N-CH2CH3), 4.22
[br signal, 2H, Ph(CH2)3CH2], 7.04–7.29 (complex), 7.44 and 7.80
(br signal, together 13H, Ar).
1-Ethyl-2-methyl-2-(tosylcarbamoyl)-1-[(trideuteromethyl)tosyl-
carbamoyl]hydrazine (10):
Chromatographed 8a (380 mg, 0.90 mmol) was dissolved in MeOH
(15 mL) and hydrogenolyzed for 2 h over 5% Pd/C. After filtration
and evaporation, the residual colorless oil was dissolved in CH2Cl2

SYNTHESIS
Papers
1820
and again taken to dryness. This was repeated twice, whereafter the
product was dried in high vacuo to give pure (A) 9 (251 mg, 97%). It
was dissolved in CH2Cl2 (3 mL) and cooled in ice under argon. Tosyl
isocyanate (172 mg, 0.87 mmol) in CH2Cl2 (1 mL) was introduced
dropwise with rapid stirring over a few minutes, whereupon the reac-
tion was allowed to proceed for 2 h at r.t. Traces of turbidity were
filtered off and the filtrate taken to dryness, leaving a white crispy
foam, which was triturated with cold light petroleum and left for 20 h
at –20°C. Filtration, rinsing with cold light petroleum and drying fur-
nished chromatographically pure 10 (416 mg, 95% from 8a); micro-
crystalline solid; mp 94–95°C (softens from ~90°C; EtOAc/light pe-
troleum 1:3, 100 mL/g).
1H NMR (CDCl3): δ = 1.16 (t, J = 7.2 Hz, 3H, CH2CH3), 1.38 (s, 9H,
Boc-Me), 2.43 (s, 3H, Ts-Me), 2.92 (s, 3H, N-Me), 3.24 and 3.67
(2dq, J1 ≈ 7 Hz, J2 ≈ 14 Hz, 1H + 1H, N-CH2), 7.33 (d, J = 8.1 Hz, 2H,
Ts-H3,5), 7.94 (d, J = 8.4 Hz, 2H, Ts-H2,6), 8.27 (br s, 1H, NH).
13C NMR (CDCl3): δ = 12.39 (CH2CH3), 21.58 (Ts-Me), 27.93 (Boc-
Me), 32.62 (N-Me), 42.41 (N-CH2), 82.96 (Boc-Cq), 128.28 (Ts-
C3,5), 129.42 (Ts-C2,6), 136.00 (Ts-C4), 144.59 (Ts-C1), 152.36 (urea
CO), 154.09 (Boc-CO).
Anal. Calcd for C16H25N3O5S (371.44): C, 51.74; H, 6.78; N, 11.31.
Found: C, 51.7; H, 6.8; N, 11.3.
1H NMR (CDCl3): δ = 1.27 (t, J = 7.2 Hz, 3H, CH2CH3), 2.44 and
2.47 (2s, 3H each, Ts-Me), 3.12 (s, 3H, N-Me), 3.82, 3.90 (ABq, fur-
ther split by coupling to Me, J1 = 14.2 Hz, J2 = 7.1 Hz, 2H, CH2CH3),
7.33 and 7.38 (2d, J = 8.1 Hz, 2H + 2H, Ts-H3,5), 7.72 and 7.96 (2d,
J = 8.3 Hz, 2H + 2H, Ts-H2,6), 9.23 (br s, 1H, NH).
1-[(Benzyl)tosylcarbamoyl]-2-(tert-butoxycarbonyl)-2-ethyl-1-
methylhydrazine (14):
Crude 13 (1.86 g, 5.00 mmol) was alkylated with benzyl alcohol by
the Mitsunobu method outlined previously (see compound 11). A
similar chromatographic workup afforded the desired compound as a
colorless viscous oil. The yield of crude, chromatographically pure 14
was 1.82 g (79%). Crystallization from light petroleum (25 mL/g)
gave the analytical specimen as a white microcrystalline solid; mp
79.5–80 °C.
13C NMR (CDCl3): δ = 12.51 (CH2CH3), 21.63 and 21.66 (Ts-Me),
33.64 (m, JC,D = 22.4 Hz, CD3), 33.68 (N-Me), 47.42 (CH2CH3),
128.32, 128.52, 129.42, 130.08, 131.67, 136.22 (Ar), 144.54 and
145.64 (Ts-C1), 151.57 (Ts-NHCO), 156.48 [Ts-N(CD3)CO].
Anal. Calcd for C20D3H23N4O6S2 (485.60): C, 49.47; H, 5.40; N,
11.54. Found: C, 50.0; H, 5.5; N, 11.0.
1H NMR (CDCl3): δ = 1.15 (br. signal, 3H, CH2CH3), 1.40/1.46 (2 br.
signal, 9H, Boc-Me), 2.40 (s, 3H, Ts-Me), 3.37, 3.48 and 3.61 (3 br.
signal, 5H, N-Me and CH2CH3), 5.15 (br. signal, 2H, Bn-CH2), 7.24–
7.31 (complex, 7H, Ph-H + Ts-H3,5), 7.82 (d, J = 8.2 Hz, 2H, Ts-H2,6).
13C NMR (CDCl3): δ = 12.68/13.38 (CH2CH3), 21.40 (Ts-Me), 28.13
(Boc-Me), 42.07/39.39 (N-Me), 43.05/46.21 (CH2CH3), 72.21/72.60
(Ph-CH2), 81.74/82.01 (Boc-Cq), 125.92, 128.17, 128.34, 128.53,
129.07, 134.68, 134.74 (Ar), 141.75/141.94 (Ts-C1), 153.48 (Boc-
CO), 156.31 (urea-CO).
1-[(Benzyl)tosylcarbamoyl]-2-ethyl-1-methyl-2-[(trideuterome-
thyl)tosylcarbamoyl]hydrazine (11):
Recrystallized 10 (195 mg, 0.40 mmol) was suspended in THF (4 mL,
freshly distilled from Na/Ph2CO), benzyl alcohol (48 mg, 0.44 mmol)
added and the mixture cooled in ice under argon. This was treated
with Ph3P (126 mg, 0.48 mmol) and after a few minutes dropwise
over 15 min with diethyl azodicarboxylate (81 µL, 0.52 mmol), dur-
ing which period the turbid mixture became clear, and then it was
allowed gradually to reach r.t. The solvent was stripped off at reduced
pressure and the remaining semisolid material chromatographed (sil-
ica gel, Et2O/CH2Cl2 1:20). Slow elution afforded a pure (A, C) frac-
tion which furnished a waxy solid (181 mg, 79%); white, microcrys-
talline solid; mp 115–116°C (Et2O/light petroleum 1:10, 20 mL).
1H NMR (CDCl3): δ = 1.29 (perturbed signal, 3H, CH2CH3), 2.39 and
2.43 (2s, 3H + 3H, Ts-Me), 3.37/3.49 (2 br s, 3H, N-Me), 3.84/3.72
(2 br signals, 2H, CH2CH3), 5.22 (s, 2H, Bn-CH2), 7.24–7.36 (com-
plex, 9H, Ph-H + 2 × Ts-H3,5), 7.78 (perturbed signal, 4H, 2 × Ts-
H2,6).
Anal. Calcd for C23H31N3O5S (461.58): C, 59.85; H, 6.77; N, 9.10.
Found: C, 59.8; H, 6.9; N, 9.1.
Attempted Preparation of 1-[(Benzyl)tosylcarbamoyl]-2-ethyl-1-
methyl-2-(tosylcarbamoyl)hydrazine. Isolation of Debenzylated
Analog 15:
Chromatographed 14 (1.028 g, 2.23 mmol) was dissolved in CH2Cl2
(15 mL), whereafter TFA (7.5 mL) was added dropwise under argon
at r.t. The resulting clear solution was left for 2 h, whereupon the sol-
vent was stripped off at reduced pressure. After thorough drying in
high vacuo, the residue was dissolved in CH2Cl2 and again taken to
dryness and subsequently dried in high vacuo. This procedure was
repeated twice until the odor of TFA had almost disappeared. The
remaining semisolid material was dissolved in CH2Cl2 (20 mL) and
cooled in ice under argon. Et3N (341 µL, 2.45 mmol) was cautiously
added and after a few min tosyl isocyanate (483 mg, 2.45 mmol), dis-
solved in CH2Cl2 (3 mL), was introduced dropwise over 10 min. The
reaction was allowed to proceed for 14 h at r.t., when evaporation left
a white semisolid residue which was taken up in CH2Cl2 (100 mL).
Extractive workup followed by removal of the solvent left a white
solid residue which was thoroughly triturated with cold Et2O and after
brief cooling the fine-grained insoluble powder was collected by fil-
tration, rinsed with cold Et2O and dried in high vacuo. This gave
831 mg (80%) of pure 15; microcrystalline white solid; mp 207–
208°C (dec.; CHCl3; –20°C; 10 mL/g).
13C NMR (CDCl3): δ = 12.53 (CH2CH3), 21.41 and 21.58 (Ts-Me),
34.21 (m, JC,D = 21.1 Hz, CD3), 39.18/40.51 (N-Me), 46.40
(CH2CH3), 73.34 Bn-CH2), 125.95, 128.60, 128.79, 129.10, 129.48,
133.69, 134.36, 141.38, 142.14, 144.51 (Ar), 155.40, 156.49 (CO).
Anal. Calcd for C27D3H29N4O6S2 (575.73): C, 56.33; H, 5.60; N,
9.73. Found: C, 56.3; H, 5.6; N, 9.5.
1-(tert-Butoxycarbonyl)-1-ethyl-2-methylhydrazine (12):
Recrystallized 1 (3.08 g, 10.0 mmol) was hydrogenolyzed in MeOH
according to the procedure for 4. A similar workup afforded a volatile
colorless liquid with a sweetish aromatic odor. The yield of pure (A,
B) 12, suitable for further work, was 1.54 g (89%).
1H NMR (CDCl3): δ = 1.13 (t, 3H, CH2CH3), 1.48 (s, 9H, Boc-Me),
2.58 (s, 3H, N-Me), 3.36 (q, 2H, N-CH2), 4.20 (br s, 1H, NH).
13C NMR (CDCl3): δ = 13.28 (CH2CH3), 28.40 (Boc-Me), 37.64 (N-
Me), 43.60 (N-CH2), 80.15 (Boc-Cq), 155.66 (CO).
1H NMR (CDCl3): δ = 1.01 (t, 3H, CH2CH3), 2.40 and 2.41 (2s, 3H
each, Ts-Me), 2.98 (s, 3H, N-Me), 3.23 and 3.70 (2dq, J1 = 14.2 Hz,
J2 = 7.1 Hz, 1H + 1H, CH2CH3), 7.29 and 7.30 (2d, J = 8.1 Hz, 2H +
2H, Ts-H3,5), 7.89 and 7.91 (2d, J = 8.2 Hz, 2H + 2H, Ts-H2,6), 8.62
and 8.86 (2 br s, 1H + 1H, NH).
1-(tert-Butoxycarbonyl)-1-ethyl-2-methyl-2-(tosylcarbamoyl)hy-
drazine (13):
Crude 12 (1.54 g, 8.86 mmol) was allowed to react with tosyl isocy-
anate (1.74 g, 8.83 mmol) according to the preparation of 5. An anal-
ogous workup provided crude 13 as a white pure (C) solid (3.18 g,
97%). An analytical specimen was obtained by recrystallization from
CH2Cl2/Et2O ≈1:8 (≈90 mL/g) as white glittering crystals; mp 148–
149°C (dec).
13C NMR (CDCl3): δ = 11.75 (CH2CH3), 21.67 and 21.69 (Ts-Me),
33.77 (N-Me), 41.87 (CH2CH3), 128.32 and 128.42 (2 × Ts-C3,5),
129.59 and 129.63 (2 × Ts-C2,6), 135.54 and 135.57 (2 × Ts-C4),
144.95 (2 × Ts-C1), 152.16, 152.37 (2 × CO).
Anal. Calcd for C19H24N4O6S2 (468.66): C, 48.69; H, 5.16; N, 11.95.
Found: C, 48.6; H, 5.3; N, 12.0.

SYNTHESIS
December 1998
1821
This work was supported by funds from the Swedish Research Coun-
cil for Engineering Sciences and the Swedish Natural Science
Research Council which are gratefully acknowledged.
(4) (a) Mäeorg, U.; Grehn, L.; Ragnarsson, U. Angew. Chem. 1996,
108, 2802; Angew. Chem., Int. Ed. Engl. 1996, 35, 2626.
(b) Grehn, L.; Lönn, H.; Ragnarsson, U. J. Chem. Soc., Chem.
Commun. 1997, 1381.
(c) Grehn, L.; Nyasse, B.; Ragnarsson, U. Synthesis 1997, 1429.
(d) Mäeorg, U.; Ragnarsson, U. Tetrahedron Lett. 1998, 39,
681.
(1) Lowe, G. Chem. Soc. Rev. 1995, 24, 309.
Balkenhohl, F.; von dem Bussche-Hünnefeld, C.; Lansky, A.;
Zechel, C. Angew. Chem. 1996, 108, 2436; Angew. Chem., Int.
Ed. Engl. 1996, 35, 2289.
(5) Mitsunobu, O. Synthesis 1981, 1.
Hughes, D. L. Org. React. 1992, 42, 335.
(6) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Har-
ris, G. D. Jr.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(7) Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1998, 31, 494.
(8) (a) ref 3b, p 406.
See also the following journal issues containing various articles
of interest:
Chemtracts, Organic Chemistry 1995, 8 (1st issue).
Acc. Chem. Res. 1996, 29 (3rd issue).
(b) Freer, R.; McKillop, A. Synth. Commun. 1996, 26, 331.
(c) Leung, M.; Lai, J.-L.; Lau, K.-H.; Yu, H.; Hsiao, H.-J. J.
Org. Chem. 1996, 61, 4175.
Chem. Rev. 1997, 97 (2nd issue).
(2) (a) Früchtel, J. S.; Jung, G. Angew. Chem. 1996, 108, 19; An-
gew. Chem., Int. Ed. Engl. 1996, 35, 17.
(d) Thavonekham, B. Synthesis 1997, 1189.
(b) Multiauthor issues: Applications of Solid-Supported Orga-
nic Synthesis in Combinatorial Chemistry; Tetrahedron Sympo-
sia-in-Print number 63; Bristol, J. A. Ed.; Tetrahedron 1997, 53,
6573–6705.
(e) Katritzky, A. R.; Pleynet, D. P. M.; Yang, B. J. Org. Chem.
1997, 62, 4155.
(f) Xiao, X.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997,
62, 6968.
(c) Multiauthor issues: Solution Phase Combinatorial Chemi-
stry; Tetrahedron Symposia-in-Print number 70; Coffen, D. L.
Ed.; Tetrahedron 1998, 54, 3955–4150.
(9) Cervello, J.; Sastre, T. Synthesis 1990, 221.
(10) Koppel, I.; Koppel, J.; Degerbeck, F.; Grehn, L.; Ragnarsson,
U. J. Org. Chem. 1991, 56, 7172.
(3) (a) Jensen-Korte, U. In Houben-Weyl, 4th ed., Vol. 16a; Kla-
mann, D., Ed.; Thieme: Stuttgart, 1990; p 421.
(b) Brown, B. R. The Organic Chemistry of Aliphatic Nitrogen
Compounds; Clarendon: Oxford, 1994; p 588.
Grehn, L.; Ragnarsson, U. Acta Chem. Scand. 1998, 52, 627.
(11) Scialdone, M. A. Tetrahedron Lett. 1996, 37, 8141.