RCM-mediated synthesis of fluorinated cyclic hydrazines

Article abstract of DOI:10.1055/s-2008-1032043

A series of fluorinated cyclic hydrazine derivatives has been prepared in a straightforward manner using ring-closing metathesis (RCM) of fluorinated- and trifluoromethylated olefins as the key step. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032043

LETTER
351
RCM-Mediated Synthesis of Fluorinated Cyclic Hydrazines
S
ynthesis of Fluor
a
inate
d
Cycl
l
ic
H
ydr
e
azines ria De Matteis,a Floris L. van Delft,a Jörg Tiebes,b Floris P. J. T. Rutjes*a
a
Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Fax +31(24)3653393; E-mail: F.Rutjes@science.ru.nl
b
Bayer CropScience AG, Industrial Park, 65926 Frankfurt am Main, Germany,
Received 11 October 2007
group with preparing cyclic hydrazines,7 and in conjunc-
tion with recent results from our8 and other groups9 con-
cerning the RCM-mediated synthesis of N-heterocyclic
building blocks, in particular fluorinated10 and trifluoro-
methylated heterocycles,11 we set out to apply RCM as a
potential tool to synthesize the corresponding cyclic hy-
drazines. Although few RCM examples of fluorinated ole-
fins exist,12 it has never been applied for the synthesis of
this particular class of hydrazines that may have potential-
ly unique properties.
Abstract: A series of fluorinated cyclic hydrazine derivatives has
been prepared in a straightforward manner using ring-closing me-
tathesis (RCM) of fluorinated- and trifluoromethylated olefins as
the key step.
Key words: cyclic hydrazines, ring-closing metathesis, fluorinated
heterocycles, trifluoromethylated heterocycles
Cyclic hydrazine moieties occur in a wide variety of bio-
logically active compounds. Some examples are shown in
Figure 1, such as LY186826 (1), which is part of a new
class of antibiotics,1 and piperazic acid (2), which is a key
component of the class of biologically active sangli-
fehrins.2 A recent example comprises hydrazine 3, which
was shown to possess promising activity against type 2 di-
abetes.3
Retrosynthetically, readily available fluorinated or trifluo-
romethylated olefins of type 5 might serve as suitable pre-
cursors for the preparation of the target cyclic hydrazines
4 using RCM (Scheme 1).
R
R
PG1
PG1
PG2
( )0,1
N
N
( )0,1
O
N
N
PG2
F
F
F
Me
X = F, CF3
R = H, Ar
S
N
N
X
O
X
4
5
H2N
N
CO2H
HCl·
NH2
N
Scheme 1 Retrosynthetic approach
H
O
O
N
OMe
N
Ph
O
To initially probe the viability of this strategy, we first
aimed at preparing a simple six-membered cyclic trifluo-
romethylated hydrazine bearing the same protective
group on both nitrogens. The required RCM precursor 9
was synthesized through two alkylation steps, starting
from diethyl azodicarboxylate 6 (Scheme 2).
1: LY186826
HN
N
N
CO2H
H
3: DPP-IV inhibitor
2: piperazic acid
Figure 1 Biologically active cyclic hydrazines
In addition to the existing methods to synthesize cyclic
hydrazine derivatives,4 it was recently demonstrated that
ring-closing metathesis (RCM) can also be applied for this
purpose.5 Although these approaches give rise to a large
choice of hydrazines of different ring sizes and various
substitution patterns, none of them involves the synthesis
of fluoride-containing rings. Considering that the intro-
duction of fluoride or fluoride-containing substituents of-
ten favorably contributes to the pharmacokinetic profile
of bioactive compounds, an awareness that has led to a
tremendous increase of new organofluorine compounds
and their application in pharmaceutical research,6 we be-
came interested in the synthesis of fluorinated cyclic hy-
drazine derivatives. Based on previous experience in our
NaH, r.t.
then
1)
CO2Et
EtO2C
EtO2C
MgCl
N
N
N
F3C
8
THF, –78 °C
NH
OTs
EtO2C
DMF, r.t., 12 h
2) NH4Cl
6
7 (61%)
EtO2C
EtO2C
EtO2C
N
N
N
Grubbs II
(20 mol%)
EtO2C
N
N
N
Me
EtO2C
PhMe
100 °C
1 h
EtO2C
CF3
F3C
F3C
9 (99%)
10 (58%)
11
Scheme 2 Synthesis of the trifluoromethylated cyclic hydrazine 10
The first alkylation of azodicarboxylate 6 with allylmag-
nesium chloride (THF, –78 °C, workup with NH4Cl) pro-
vided the monoalkylated hydrazo ester 7 in 61% yield.7b
SYNLETT 2008, No. 3, pp 0351–0354
Advanced online publication: 16.01.2008
DOI: 10.1055/s-2008-1032043; Art ID: G31107ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

352
V. De Matteis et al.
LETTER
Subsequently, a second alkylation with the allylating re- Functionalization of the second nitrogen proceeded un-
agent 811 provided the RCM precursor 9 in excellent yield. eventfully, starting with deprotonation of 15 in (NaH,
This precursor molecule was then subjected to RCM using THF, 0 °C to r.t.), followed by alkylation with 8 to give
the second-generation Grubbs catalyst (Grubbs II, 20 precursor 19 in 40% yield (entry 1, Table 1). The other
mol%) added in portions over one hour to the reaction alkylations, however, were carried out in DMF, which
mixture in toluene at 100 °C. As anticipated, the cycliza- consistently gave higher yields. For example, deprotona-
tion proceeded smoothly to produce the desired cyclic hy- tion of 15 with NaH in DMF, followed by alkylation with
drazine 10 in 58%, along with a minor amount (<10%) of commercially available 1-chloro-2-fluoroprop-2-ene (18)
the isomerized enamine 11 as the sole byproduct.13 Al- provided compound 20 in 70% yield (entry 2). Similar
though this first example proved the viability of the RCM yields were obtained for precursors 21–23 using identical
strategy, it also made clear that isomerization could be a conditions (entries 3–5). All diolefinic hydrazines 19–23
problem. To avoid the side reaction and to be able to in- were then subjected to the previously used RCM condi-
troduce additional substituents a somewhat different route tions (Grubbs II catalyst, toluene, 100 °C) as shown in
was developed for the synthesis of RCM precursors Table 1. This led to the corresponding trifluoromethyl- or
(Scheme 3).
fluoro-substituted cyclic hydrazine building blocks 24–28
in reasonable to good yields. In almost all cases, 20 mol%
of catalyst had to be added over a period of approximately
60 minutes in order to reach full conversion. Only in case
of entry 2 somewhat less of the catalyst (15 mol%) ap-
peared sufficient. This new synthetic pathway clearly es-
tablishes that RCM represents a viable pathway to obtain
a novel class of cyclic hydrazine derivatives of potential
biological relevance.
O
Ph
Ph
MgBr
Ph
H
NH2
NH
N
HN
NH
NH
PhMe, r.t.
THF, –78 °C
Boc
Boc
Boc
12
13 (93%)
14 (94%)
NaH, THF
–78 °C to r.t.,
then CbzCl
Ph
Ph
Table 1 RCM of N,N¢-Dialkenylhydrazines
AcPh
Boc
GP
K2CO3, THF
0 °C to r.t.
Et3N, THF
0 °C to r.t.
N
N
Entry Precursor
(yield)
Cat.
(mol%) (h)
Time
Product
(yield)
14
NH
NH
Boc
then BnBr
KHMDS
0 °C to r.t.
then PhAcCl
17 (67%)
Ph
15: PG = Cbz (50%)
16: PG = Bn (36%)
Ph
Cbz
Boc
N
N
Cbz
N
Scheme 3 Synthesis of differentially protected hydrazines 15–17
N
Boc
X
The hydrazines 15–17 were prepared starting from tert-
butyl carbazate 12, which was first condensed with
benzaldehyde7c and then alkylated with vinylmagnesium
bromide to give the Boc-protected hydrazine 14. Advan-
tage of this route is that different (aromatic) groups can be
readily introduced, which as a bonus will significantly
slow down the isomerization process. In order to orthogo-
nally protect the hydrazine moiety, at this stage a number
of different protecting groups were introduced on the sec-
ond nitrogen atom which required extensive experimenta-
tion to reach reasonable selectivity and yields. For
example, the Cbz group was introduced in 50% yield via
deprotonation (NaH, –78 °C), followed by treatment with
benzyl chloroformate and slowly warming to room tem-
perature. Applying similar deprotonation conditions to the
reaction with benzyl bromide led to mixtures of regioiso-
mers. In this case, however, use of K2CO3 at 0 °C in com-
bination with benzyl bromide, followed by adding
KHMDS (1 equiv) and slowly warming to room tempera-
ture provided the desired product 16 in 36% yield. Finally,
acylation of 14 with phenylacetyl chloride (PhAcCl) pro-
ceeded in acceptable yield (67%). In this case, PhAcCl
was first reacted with Et3N at 0 °C in THF for 30 minutes
to form the corresponding ketene, which was then further
reacted with 14 and slowly allowed to warm to room tem-
perature overnight.
X
1
2
19 X = CF3 (40%) 20
20 X = F (70%)
1
1
24 X = CF3 (74%)
25 X = F (66%)
20
Ph
Ph
Bn
N
Bn
N
N
Boc
N
Boc
F
F
21 (70%)
15
1
26 (83%)
Ph
Ph
PhAc
N
PhAc
N
N
Boc
N
Boc
X
X
4
5
22 X = CF3 (76%) 20
23 X = F (70%) 20
1
1
27 X = CF3 (52%)
28 X = F (62%)
In order to show that the orthogonal protection can be ex-
ploited for further functionalization, the Boc group was
replaced in a two-step procedure by a benzyl substituent
(Scheme 4). This was realized via standard Boc deprotec-
tion of 28 with TFA, followed by benzylation of the re-
sulting amine 29 (NaH in DMF at 0 °C, followed by
BnBr) to give hydrazine 30 in 76% overall yield.
Synlett 2008, No. 3, 351–354 © Thieme Stuttgart · New York

LETTER
Synthesis of Fluorinated Cyclic Hydrazines
353
Ph
Ph
Ph
NaH
DMF
PhAc
Boc
PhAc
PhAc
TFA
N
N
N
N
0 °C to r.t.
N
CH2Cl2
0 °C to r.t.
HN
F
F
Bn
F
then BnBr
28
29 (99%)
30 (77%)
Scheme 4 Replacement of Boc with a benzyl substituent
Having successfully demonstrated that RCM readily leads
to fluoro- and trifluoromethyl-substituted six-membered
ring hydrazines, we decided to apply the same technique
for the synthesis of a fluoride-containing seven-mem-
bered-ring hydrazine (Scheme 5).
Acknowledgment
Bayer CropScience is kindfully acknowledged for financial sup-
port.
References and Notes
PhAcCl
Et3N
0 °C
(1) Indelicato, J. M.; Pasini, C. E. J. Med. Chem. 1988, 31, 1227.
(2) For an entry into sanglifehrin synthesis, see e.g.: Lindel, T.
Sanglifehrin A: An Immunosuppressant Natural Product, In
Organic Synthesis Highlights V, Vol. 5; Schmalz, H. G.;
Wirth, T., Eds.; Wiley-VCH: Weinheim, 2003, 350.
(3) Ahn, J. H.; Shin, M. S.; Jun, M. A.; Jung, S. H.; Kang, S. K.;
Kim, K. R.; Rhee, S. D.; Kang, N. S.; Kim, S. Y.; Sohn, S.-
K.; Kim, S. G.; Jin, M. S.; Lee, J. O.; Cheon, H. G.; Kim, S.
S.; Soo, S. Bioorg. Med. Chem. Lett. 2007, 17, 2622.
(4) For reviews, see: (a) Ciufolini, M. A.; Xi, N. Chem. Soc.
Rev. 1998, 27, 437. (b) Müller, E. In Houben-Weyl, 4th ed.,
Vol. 10/2; Müller, E., Ed.; Thieme: Stuttgart, 1971, 123.
(c) Jensen-Korte, U.; Müller, N.; Schallner, O. In Houben-
Weyl, 4th ed., Vol. E16a/1; Klamman, D., Ed.; Thieme:
Stuttgart, 1990, 412.
Ph
Ph
PhAc
Boc
MgBr
THF, –78 °C
HN
NH
N
30 min
13
NH
then 31
0 °C to r.t.
THF
Boc
31 (40%)
32 (89%)
F
Ph
Ph
18
Cl
PhAc
Boc
Grubbs II
(20 mol%)
N
N
PhAc
Boc
N
N
NaH, DMF
0 °C to r.t.
PhMe, 100 °C
2 h
F
F
33 (54%)
34 (64%)
(5) (a) Tae, J.; Hahn, D.-W. Tetrahedron Lett. 2004, 45, 3757.
(b) Kim, Y. J.; Lee, D. Org. Lett. 2004, 6, 4351.
Scheme 5 Synthesis of a fluorinated seven-membered-ring hydra-
zine
(6) (a) Fustero, S.; Sanz-Cervera, J. F.; Piera, J.; Sanchez-
Rosello, M.; Chiva, G.; Simon-Fuentes, A. J. Fluorine
Chem. 2004, 125, 621. (b) Chanteau, F.; Didier, B.; Dondy,
B.; Doussot, P.; Plantier-Royon, R.; Portella, C. Eur. J. Org.
Chem. 2004, 1444. (c) Tews, S.; Miethchen, R.; Reinke, H.
Synthesis 2003, 707. (d) Gille, S.; Ferry, A.; Billard, T.;
Langlois, B. R. J. Org. Chem. 2003, 68, 8932.
Thus, hydrazone 13 was reacted with allylmagnesium
bromide to produce the Boc-protected hydrazine 31 in
40% yield.14 The synthesis then proceeded as described
previously, first selective acylation with PhAcCl via the
intermediate ketene in 89% yield, followed by alkylation
of resulting 32 with NaH and 1-chloro-2-fluoroprop-2-
ene (18) to give RCM precursor 33 in 54% yield. The
compound was then subjected to the standard RCM con-
ditions (20 mol% Grubbs II catalyst added over a period
of 2 hours, toluene, 100 °C) to afford the seven-mem-
bered-ring hydrazine 34 in a satisfactory yield of 64%
along with a small amount of an unidentified side product.
After chromatographic separation and subsequent crystal-
lization, the identity of 34, however, could be unambigu-
(e) Kobayashi, Y.; Taguchi, T. J. Fluorine Chem. 2000, 105,
197. For reviews, see, for example: (f) Leroux, F.; Jeschke,
P.; Schlosser, M. Chem. Rev. 2005, 105, 827. (g) Shimizu,
M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44, 214.
(h) Dolbier, W. R. Jr.; Battiste, M. A. Chem. Rev. 2003, 103,
1071.
(7) (a) Rutjes, F. P. J. T.; Paz, H.; Hiemstra, M. M.; Speckamp,
W. N. Tetrahedron Lett. 1991, 32, 6629. (b) Rutjes, F. P. J.
T.; Hiemstra, H.; Mooiweer, H. H.; Speckamp, W. N.
Tetrahedron Lett. 1988, 29, 6975. (c) Rutjes, F. P. J. T.;
Teerhuis, N. M.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron 1993, 49, 8605. (d) Rutjes, F. P. J. T.;
Hiemstra, H.; Pirrung, F. O. H.; Speckamp, W. N.
Tetrahedron 1993, 49, 10027.
ously
established
via
X-ray
crystallographic
determination of the structure.15
In summary, an efficient and straightforward pathway for
the synthesis of orthogonally protected fluorinateed cyclic
hydrazines has been developed. Key step is the RCM-me-
diated ring closure of trifluoromethyl and fluoro-substi-
tuted olefins that lead to the corresponding cyclic products
in reasonable to good yields. Considering the biological
activity of cyclic hydrazines in general and the increasing
role of fluorine in pharmaceutical products, this provides
an entry into a potentially useful class of products.
(8) (a) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett.
1997, 38, 677. (b) Tjen, K. C. M. F.; Kinderman, S. S.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Chem.
Commun. 2000, 699. (c) Kinderman, S. S.; van Maarseveen,
J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T.
Org. Lett. 2001, 3, 2045. (d) Kinderman, S. S.; de Gelder,
R.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra, H.;
Rutjes, F. P. J. T. J. Am. Chem. Soc. 2004, 126, 4100.
(e) Kinderman, S. S.; Wekking, M. M. T.; van Maarseveen,
J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J.
Org. Chem. 2005, 70, 5519. (f) Wijdeven, M. A.; Botman,
P. N. M.; Wijtmans, R.; Schoemaker, H. E.; Rutjes, F. P. J.
T.; Blaauw, R. H. Org. Lett. 2005, 7, 4005.
Synlett 2008, No. 3, 351–354 © Thieme Stuttgart · New York

354
V. De Matteis et al.
LETTER
(9) For an excellent review on RCM-mediated synthesis of aza-
and oxacycles, see e.g.: Deiters, A.; Martin, S. F. Chem. Rev.
2004, 104, 2199.
(10) (a) De Matteis, V.; van Delft, F. L.; Tiebes, J.; Rutjes, F. P.
J. T. Eur. J. Org. Chem. 2006, 1166. (b) De Matteis, V.;
Dufay, O.; Waalboer, D. C. J.; van Delft, F. L.; Tiebes, J.;
Rutjes, F. P. J. T. Eur. J. Org. Chem. 2007, 2667.
(m, 2 H, CHPh, CH2=CH), 5.14–5.85 (m, 2 H, H2C=CH),
3.72–3.63 (m, 2 H, CH2Ph), 2.73–2.50 (m, 2 H, PhCHCH2),
1.50 and 1.30 (s, 9 H, 3 CH3). 13C NMR (75 MHz, CDCl3,
25 °C): d = 165.2, 150.6, 145.2, 134.7, 130.8, 129.3, 129.1,
128.0, 127.8, 127.3, 126.9, 117.4, 81.9, 58.8, 49.2, 40.6,
28.4. HRMS (CI): m/z calcd for C23H29N2O3 [M+ + H]:
381.2178; found: 381.2188.
(11) (a) De Matteis, V.; van Delft, F. L.; De Gelder, R.; Tiebes,
J.; Rutjes, F. P. J. T. Tetrahedron Lett. 2004, 45, 959.
(b) De Matteis, V.; van Delft, F. L.; Jakobi, H.; Lindell, S.;
Tiebes, J.; Rutjes, F. P. J. T. J. Org. Chem. 2006, 71, 7527.
(12) (a) Salim, S. S.; Bellingham, R. K.; Satcharoen, V.; Brown,
R. Org. Lett. 2003, 5, 3403. (b) Marhold, M.; Buer, A.;
Hiemstra, H.; van Maarseveen, J. H.; Haufe, G. Tetrahedron
Lett. 2004, 45, 57.
(13) For other examples of Ru-mediated isomerization, see e.g.:
(a) Kinderman, S. S.; van Maarseveen, J. H.; Schoemaker,
H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Org. Lett. 2001, 3,
2045. (b) Schmidt, B. Eur. J. Org. Chem. 2004, 1865.
(c) Schmidt, B. J. Mol. Catal. A: Chem. 2006, 254, 53.
(d) Alcaide, B.; Almendros, P.; Alonso, J. M. Chem. Eur. J.
2006, 12, 2874; and references cited therein. (e) Hekking,
K. F. W.; Moelands, M. A. H.; van Delft, F. L.; Rutjes, F. P.
J. T. J. Org. Chem. 2006, 71, 6444.
N-(2-Fluoroallyl)-N¢-phenylacetyl-N¢-(1-phenylbut-3-
enyl)hydrazinecarboxylic Acid tert-Butyl Ester (33)
To a suspension of NaH (14 mg, 0.57 mmol) in DMF (5 mL)
was added at 0 °C compound 32 (166 mg, 0.44 mmol). After
stirring for 15 min at r.t., 1-chloro-2-fluoroprop-2-ene (18,
42 mg, 0.44 mmol) was added slowly. The reaction was
stirred for 12 h, quenched with H2O (5 mL) and extracted
with Et2O (3 × 5 mL). The ether layers were dried (MgSO4),
evaporated, and the residue was purified using column
chromatography (heptane–EtOAc, 10:1) to give 33 (104 mg,
54%) as a colorless oil. IR (neat): 3062, 3032, 2976, 2928,
1718, 1679, 1497, 1450, 1364, 1251, 1156, 1031, 914, 854,
763, 698 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C, TMS,
some signals appear as rotamers): d = 7.41–7.25 (m, 10 H,
Ar), 5.65–5.43 (m, 3 H, CH2=CH, CH2=CH), 5.07–4.35 (m,
6 H, CH2=CH, FC=CH2, CHPh, NCH2), 4.00–3.91 (m, 1 H,
NCH2), 3.72–3.54 (m, 2 H, CH2Ph), 2.92 (br s, 2 H,
PhCHCH2), 1.42 and 1.22 (s, 9 H, 3 CH3). 13C NMR (75
MHz, CDCl3, 25 °C, some signals appear as rotamers):
d = 173.8, 160.3 (d, J = 260.1 Hz, CF), 169.0, 134.3, 134.2,
133.8, 129.2, 129.1, 128.2, 127.8, 127.2, 126.3, 122.9, 95.5–
95.2 (m, CH2=CF), 82.2, 62.8, 39.8, 38.5, 37.5 (d, J = 48.8
Hz, CH2CF), 27.8 and 27.3, HRMS (CI): m/z calcd for
C26H32N2O3F [M+ + H]: 439.2397; found: 439.2389.
6-Fluoro-3-phenyl-2-phenylacetyl-2,3,4,7-
(14) Representative Procedures
N¢-(1-Phenylbut-3-enyl)hydrazinecarboxylic Acid tert-
Butyl Ester (31)
Allylmagnesium bromide (4.57 mL of a 1.0 M solution in
Et2O, 4.57 mmol) was added at –78 °C to a well-stirred
solution of 13 (336 mg, 1.53 mmol) in THF (2 mL). The
mixture was stirred at –78 °C for 1 h and allowed over 12 h
to reach r.t. It was poured into aq sat. NH4Cl and the aqueous
layer was extracted with Et2O (3 × 6 mL). The ether layers
were dried (MgSO4), evaporated, and the crude product 31
(135 mg, 40%) was obtained as a colorless oil. IR (neat):
3403, 3283, 3067, 3028, 2980, 2928, 1709, 1455, 1368,
1282, 1243, 1156, 1022, 919, 759, 698 cm–1. 1H NMR (300
MHz, CDCl3, 25 °C, TMS): d = 7.31–7.24 (m, 5 H, Ph),
6.22, (s, 1 H, BocNH), 5.83–5.69 (m, 1 H, CH=CH2), 5.13–
5.03 (m, 2 H, CH=CH2), 4.32 (br s, 1 H, PhCH), 4.11 (br s,
1 H, BocNHNH), 2.42–2.37 (m, 2 H, PhCHCH2), 1.41 (s, 9
H, 3 CH3). 13C NMR (75 MHz, CDCl3, 25 °C): d = 156.6,
141.9, 134.7, 128.4, 127.8, 127.5, 117.9, 80.3, 63.3, 40.3,
28.4. ESI-HRMS: m/z calcd for C15H22N2O2Na [M+ + Na]:
285.1579; found: 285.15766.
tetrahydro[1,2]diazepine-1-carboxylic Acid tert-Butyl
Ester (34)
To a solution of compound 33 (90 mg, 0.2 mmol) in anhyd
toluene (40 mL) Grubbs II catalyst (20 mol%) was added at
100 °C in small portions over 2 h. The mixture was then
evaporated and the product was purified using column
chromatography (heptane–EtOAc, 10:1) to give 34 (52 mg,
64%) as a white solid; mp 110–113 °C. IR (neat): 3058,
3028, 2967, 2898, 2859, 1722, 1689, 1493, 1450, 1368,
1260, 1230, 1161, 1117, 1096, 1027, 858, 806, 698, 659, 517
cm–1. 1H NMR (300 MHz, CDCl3, 25 °C, TMS, some signals
appear as rotamers): d = 7.37–7.08 (m, 10 H, Ar), 5.48 and
5.30 (br s, 1 H, CHPh), 5.30–4.86 (m, 1 H, CF=CH), 4.74
and 4.41 (d, J = 18.3, 1 H, NCH2), 3.74–3.61 (m, 2 H,
CH2Ph), 3.22–3.12 (m, 1 H, NCH2), 2.74–2.65 (m, 1 H,
CH2CHPh), 2.19–2.10 (m, 1 H, CH2CHPh), 1.56 and 1.51 (s,
9 H, 3 CH3). 13C NMR (75 MHz, CDCl3, 25 °C, some signals
appear as rotamers): d = 173.7 and 173.4, 156.3 and 155.9
(d, J = 254.7 Hz, CF), 155.5 and 154.6, 141.5 and 141.3,
134.9 and 134.4, 129.2, 128.8, 128.7, 128.4, 127.3, 127.1,
126.9, 125.7, 101.2 and 100.6 (d, J = 18.9 Hz, C=CF), 83.5,
65.3 and 64.8, 50.2 and 48.6 (d, J = 42.8 Hz, NCH2), 42.2
and 41.9, 28.3. HRMS (CI): m/z calcd for C24H28FN2O3
[M+ + H]: 411.2084; found: 411.2075.
N¢-Phenylacetyl-N¢-(1-phenylbut-3-enyl)hydrazine-
carboxylic Acid tert-Butyl Ester (32)
To a solution of phenylacetylchloride (64.8 mL, 0.5 mmol) in
THF (2 mL), Et3N (69.7 l, 0.5 mmol) was added at 0 °C and
the mixture was stirred at 0 °C for 30 min. At the same
temperature compound 31 (130 mg, 0.51 mmol) was added
and the mixture was allowed to reach r.t. over 12 h. The
solvent was evaporated and the residue was purified using
column chromatography (heptane–EtOAc, 10:1 to 6:1) to
give 32 (166 mg, 89%) as a white solid; mp 107–109 °C. IR
(neat): 3278, 3028, 2980, 2933, 1705, 1658, 1493, 1455,
1394, 1368, 1251, 1156, 707, 607 cm–1. 1H NMR (300 MHz,
CDCl3, 25 °C, TMS, some signals appear as rotamers):
d = 7.40–7.14 (m, 10 H, Ar), 6.10 (br s, 1 H, NH), 5.88–5.52
(15) Crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC 666813.
Synlett 2008, No. 3, 351–354 © Thieme Stuttgart · New York

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