Synthesis of hydrazines with aromatic substituents using triarylbismuth reagents

Article abstract of DOI:10.1055/s-2000-7600

Smooth monoarylation of two triprotected hydrazine reagents under mild conditions has been accomplished using triarylbismuthanes in the presence of copper acetate and amine to give products 3 and 6 in excellent yield. Arylation on N² after selective deprotection of derivatives with alkyl or aryl substituents on N¹, resulting in compounds 8 and 9, is also demonstrated. Furthermore, other products derived from these reagents with free N-alkyl and N-aryl functions undergo the same reaction to give substances such as 10 and 11. As a result, the scope of the original hydrazine reagents has been further extended. A few reference compounds have also been prepared directly from phenylhydrazine.

Full text of DOI:10.1055/s-2000-7600

PAPER
1591
Synthesis of Hydrazines with Aromatic Substituents Using Triarylbismuth
Reagents
Olavi Loog,1 Uno Mäeorg,1 Ulf Ragnarsson*
Department of Biochemistry, University of Uppsala, Biomedical Center, PO Box 576, SE-751 23 Uppsala, Sweden
Fax +46(18)552139; E-mail: urbki@bmc.uu.se
Received 15 March 2000; revised 22 May 2000
Dedicated to Professor Ivar Ugi on the occasion of his 70th birthday
ic species are of current interest.5 In order to extend the
scope of A to such compounds we have now explored ar-
omatic substituents and this is the topic of the present
communication.
Abstract: Smooth monoarylation of two triprotected hydrazine re-
agents under mild conditions has been accomplished using triaryl-
bismuthanes in the presence of copper acetate and amine to give
products 3 and 6 in excellent yield. Arylation on N2 after selective
deprotection of derivatives with alkyl or aryl substituents on N1, re-
sulting in compounds 8 and 9, is also demonstrated. Furthermore,
other products derived from these reagents with free N-alkyl and N-
aryl functions undergo the same reaction to give substances such as
10 and 11. As a result, the scope of the original hydrazine reagents
has been further extended. A few reference compounds have also
been prepared directly from phenylhydrazine.
It was shown by Barton et al. that with triphenylbismuth-
ane N-phenylation of a variety of amines takes place un-
der mild conditions in the presence of copper salts.6 More
recently Chan also demonstrated that many derivatives of
amines including amides, sulfonamides and carbamates
with a free NH undergo this reaction, when an additional
tertiary amine is added to the reaction mixture.7 Triphe-
nylbismuthane is now a commercially available reagent
with several additional applications in synthetic chemistry
and many other triarylbismuthanes have been described
and are easy to make.8 Therefore we decided to test this
synthetic methodology9 on reagents of type A for stepwise
introduction of aromatic substituents into hydrazines.
Key words: N-arylations, arylbismuthanes, multisubstituted hydra-
zines, organometallic reagents, stepwise synthesis
For the synthesis of substituted hydrazines2 various tripro-
tected reagents A (Scheme 1) are now available that allow
convenient substitution on nitrogen in high yield.3 The
methodology developed for work with these reagents pro-
ceeds via selective deprotection of intermediates B and is
followed by alternating substitutions and cleavages of
protective groups in a stepwise fashion to furnish ulti-
mately derivatives of type C. Alternatively, after com-
plete deprotection of B, products such as D can also be
obtained.
Our initial experiments on N-arylation were performed
with reagent A4 using commercial triphenylbismuthane.
To provide reference samples for this work, three model
compounds, 2, 3a and 4, were therefore first synthesized
by an independent route from phenylhydrazine (Scheme
2) and carefully characterized. This scheme is based on
synthetic methodology similar to that used for the prepa-
ration of A4.3,10 Compound 1 was first prepared by
Carpino11 and subsequently by Pozdnev12 and others.
Pozdnev also prepared 4.
Among these reagents, A1-A3 allow the full implementa-
tion of the scheme, whereas A4 (all Boc) can only be ap-
plied for targets C with R3 = R4. Initially the scheme
worked well for primary and benzylic R1/R2 and acylic R3/
R4 substituents including a few with additional functional
groups attached. More recently by cleavage of Z from A3
it also became possible to introduce secondary R1 moi-
eties via reduction of ketone hydrazones.4 Among other
types of hydrazines aromatic and mixed aliphatic/aromat-
On reaction of phenylhydrazine with excess Boc2O, as de-
termined by TLC, the starting material quickly disap-
peared. Without isolation of 1, a catalytic amount of
DMAP (4-dimethylaminopyridine) was added, whereup-
on 2 was formed as the major product and characterized in
a separate experiment. After raising the temperature to
Scheme 1
Synthesis 2000, No. 11, 1591–1597 ISSN 0039-7881 © Thieme Stuttgart · New York

1592
O. Loog et al.
PAPER
Scheme 2
Scheme 3
60 ∞C, 3a was obtained as an oil in high yield, from which and requires heating, whereas in the presence of catalyst
it could be obtained as a crystalline pure material, albeit smooth dual protection occurs at the other nitrogen.15
with considerable loss of material. Treatment of 3a in
The first arylation experiments involving triarylbismuth-
MeCN with Mg(ClO4)2 in catalytic amounts13 furnished 4,
anes with addition of anhydrous Cu(OAc)2 and
which is crystalline and more easily isolated and charac-
terized. It is also the compound required to make 8 and
triethylamine7 were carried out using reagent A4 and re-
sulted in monoarylated products 3 (Scheme 4). No side-
similar compounds. This product could also be obtained
product was detectable chromatographically or spectro-
in considerably higher yield directly from phenylhydra-
scopically in this experiment. Compounds 3a-c were ob-
tained as solids, of which 3a was carefully compared with
the reference sample previously prepared from phenylhy-
drazine. The two samples were identical in all respects.
zine by a convenient one-pot reaction. Similarly, starting
from 2-benzyloxycarbonyl-1-phenylhydrazine14 instead
of phenylhydrazine, another set of compounds 5, 6a and 7
was prepared by analogy to 2, 3a and 4 (Scheme 3). Of
them 6a was obtained as an oil, which could be converted
to crystalline 7.
These experiments were followed by similar ones with re-
agent A1 (Scheme 5) to give products 6a-c as oils. The
spectroscopical data for 6a, made in this way, completely
matched those of the sample derived from phenylhydra-
zine. From these results, we conclude that once the re-
quired bismuthane is available it can be used with fair
confidence to effect monoarylation of the two reagents.
It should be noted that Pozdnev prepared 4 directly from
1 with Boc2O in boiling benzene without addition of
DMAP,12 whereas in the presence of this catalyst 2 is
formed prior to 3a and 5 prior to 6a (see experimental
part) as indicated in Schemes 2 and 3. To investigate
After monoarylation of A4 and A1 with triarylbismuth-
whether 2 could also be converted to 3a without addition-
anes had been demonstrated to proceed efficiently, aryla-
al DMAP, a separate, small-scale experiment with 0.2
tion on N2 was examined and from compound 4 we were
able to make 8 with nonidentical aryl moieties on its two
nitrogens (Scheme 4). In the same manner, from two pre-
mmol of 2 and an excess of Boc2O (0.5 mmol) in boiling
benzene was carried out (experiment not described in the
experimental section), which, according to TLC, after 22
viously made monoalkylated derivatives of A1 the corre-
h indicated the complete conversion of 2 to 3a. Obviously
sponding N2-arylated compounds 9 were prepared
(Scheme 6, upper left part). Arylation on N-alkyl nitro-
the reaction with Boc2O at the phenyl-substituted nitrogen
is rather slow both with and without addition of DMAP
Scheme 4
Synthesis 2000, No. 11, 1591–1597 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Hydrazines with Aromatic Substituents Using Triarylbismuth Reagents
1593
gens (compound 10) and in one case also on an N-aryl ni- this procedure. Nevertheless, many new multisubstituted
trogen (compound 11) has also been effected (Scheme 6, hydrazines are now in sight by simple stepwise synthesis
upper right part and lower part, respectively).
and this methodology should also be applicable for other
related reagents.18
Reagents and solvents were used as supplied without prior purifica-
tion. Mps were determined on a Gallenkamp apparatus and are un-
corrected. TLC analyses were performed on 0.25 mm thick
precoated silica plates (Merck Fertigplatten Kieselgel 60F254) with
the mobile phases Et2O/light petroleum, 1:2 (A), EtOAc/light petro-
leum, 1:3 (B) and toluene/Et2O/light petroleum, 1:2:4 (C) and 1:1:2
(D). Spots were visualized by UV, acidic KMnO4 or ethanolic phos-
1
phomolybdenic acid. H and 13C NMR spectra were recorded on a
Scheme 5
JEOL JMN EX 400 spectrometer in ~5% solution at 25 ∞C. Shifts
are given in d (ppm) relative to TMS (dH = 0) and CDCl3
The N-arylation experiments with bismuthanes described (dC = 77.02). IR spectra were recorded on a Mattson Polaris instru-
ment. Solid samples were run as KBr disks and oils as films, applied
above were made on a rather small scale. Nevertheless,
as dilute solution in CDCl3 to KBr disks, after evaporation of the
optimization experiments with respect to the amount of
solvent. Elemental analyses of all novel crystalline compounds
were carried out by Mikro Kemi AB.
bismuthane required have been carried out using A4 and
Ph3Bi in CH2Cl2 (Table 1). The results indicate that the
Triphenylbismuthane was of commercial origin, whereas tris(4-
amount of bismuthane can be reduced in comparison with
methylphenyl)bismuthane was made according to Combes and
that used in the typical experiment. Alternatively, the re-
action can be performed in boiling dichloromethane.
Finet8 in 68% yield, yield could be increased to 90% by chromato-
graphy of the mother liquor in CHCl3/light petroleum (1:10) on a
After this work was completed, a paper appeared16 in
short silica column. Tris(4-methoxyphenyl)bismuthane was also
prepared according to the same authors (mp 197-198 ∞C); in this
which a variety of N-arylaminophthalimides were con-
case the yield could be increased by extraction of the Celite filter
verted to N-phenyl-N-arylaminophthalimides with triphe-
nylbismuthane under conditions similar to those applied
cake in a Soxhlet apparatus with CH2Cl2.
in the experiments referred to in Schemes 4-6. The prod-
ucts, which are reminiscent of 11, were obtained in yields
of 96-99% with one exception.
2,2-Bis(t-butyloxycarbonyl)-1-phenylhydrazine (2)
To phenylhydrazine (0.541 g, 5 mmol) in MeCN (10 mL) was add-
ed Boc2O (3.27 g, 15 mmol) in MeCN (5 mL) under mechanical
stirring. After 30 min, DMAP (15.3 mg, 2.5 mol%) in MeCN (0.3
mL) was added over 3 min, and the solution left to react for 3 h at
r.t. and at 4 ∞C overnight, whereupon TLC indicated formation of 2
and only minor amounts of 3a and remaining 1. (In the presence of
DMAP partial conversion of 2 to 3a was noticed on heating.) Dilu-
In conclusion, several examples have been provided on
the application of triarylbismuthanes for the direct aryla-
tion of triprotected hydrazine reagents and/or subsequent
stepwise introduction of such groups. The reactions take
place under mild conditions and no side-products have tion with Et2O (40 mL), washing with 1 M KHSO4/brine 1:1 (3 ¥ 35
mL), sat. NaHCO3 (5 mL), brine (3 ¥ 5 mL), drying (MgSO4) and
evaporation furnished a golden oil, which after keeping at 4 ∞C un-
der light petroleum afforded 2 (0.86 g, 56%) with mp 84-86 ∞C.
The analytical sample was obtained as colourless crystals from light
petroleum; mp: 88-89.5 ∞C; Rf 0.34 (A), 0.51 (B).
1H NMR (CDCl3): d = 1.46 (s, 18H, Me), 6.06 (br s, 1H, NH), 6.74-
7.25 (3 ¥ m, 2+1+2H, Ar).
been detected so far, as a result of which the yields were
generally essentially quantitative. One drawback of the
procedure is that only one aromatic residue of the bis-
muthane seems to be available for arylation. Furthermore,
as long as the bismuthanes are made via Grignard re-
agents,17 the restrictions with respect to the functional
groups tolerated by the latter, at present, limit the scope of
Scheme 6
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1594
O. Loog et al.
PAPER
Table 1 Optimization of Reaction between Boc3-hydrazine (A4)
and Ph3Bi in the presence of Cu(OAc)2 and Et3N
1,2-Bis(t-butyloxycarbonyl)-1-phenylhydrazine (4) from Phe-
nylhydrazine (One-pot reaction)
This synthesis was initiated as described for 3a above. After com-
pleting the reaction with Boc2O at 60 ∞C, the temperature was low-
ered to 50 ∞C and solid Mg(ClO4)2 (0.2 equiv) was directly added
and allowed to react as in the previous experiment. It was again con-
firmed that the formation of 4 was complete within 10 min. The oil
was crystallized from EtOH (~3 mL) or EtOH/H2O to give needles
(2.40 g, 78% overall yield); mp 109.5-111 ∞C.
Entry
Equiv Ph3Bia Temp (°C)
Time (h)b Yieldc (%)
1
2
3
4
5
1.5/1.5/1.5
1.1/1.5/1.5
1.5/1.5/1.5
1.1/1.5/1.5
1.1/1.1/1.1
r.t.
23
23
6
98
r.t.
97
Reflux, CH2Cl2
Reflux, CH2Cl2
98
7
98
2-Benzyloxycarbonyl-2-(t-butyloxycarbonyl)-1-phenylhydra-
zine (5) and 2-Benzyloxycarbonyl-1,2-bis(t-butyloxycarbonyl)-
1-phenylhydrazine (6a)
DMAP (6 mg, 0.05 mmol) was added to 2-benzyloxycarbonyl-1-
phenylhydrazine14 (0.484 g, 2 mmol) and Boc2O (1.39 g, 6.4 mmol)
in MeCN (3 mL) and allowed to react for 50 min at r.t. The reaction
was monitored by TLC, which indicated that the starting material
disappeared within 30 min with formation of 5 and traces of 6a. The
solution was divided into two parts, which were treated as follows:
Reflux, CH2Cl2 >10
n.d.
a Ph3Bi/Cu(OAc)2/Et3N.
b Reaction monitored by TLC.
c Isolated as an oil as described in the experimental part.
13C NMR (CDCl3): d = 27.9 (Me), 83.6 (Cq), 113.3, 121.2, 129.0,
147.3 (Ar), 152.0 (Boc-CO).
FT-IR (KBr): n = 1713 and 1747 (CO), 3309 and 3377 (NH) cm-1.
A: One half of the solution was worked up directly, essentially as
described for 2 to give a yellow oil, most of which solidified under
light petroleum. This product was crystallized from toluene/light
petroleum (1:2, 3 mL) to give 5 (0.197 g, 58%) as white, fine nee-
dles; mp 73-74.5 ∞C; Rf 0.30 (D).
Anal. Calcd for C16H24N2O4 (308.34): C, 62.32; H, 7.85; N, 9.08.
Found: C, 62.2; H, 8.0; N, 9.1.
1,2,2-Tris(t-butyloxycarbonyl)-1-phenylhydrazine (3a)
1H NMR (CDCl3): d = 1.40 (s, 9H, Me), 5.25 (s, 2H, CH2), 6.12 (br
Another experiment was initiated with phenylhydrazine (1.08 g, 10
mmol) and Boc2O (9.17 g, 42 mmol in MeCN (7 mL) and left to re-
act for 2 h at r.t., whereupon the temperature was increased to 60 ∞C
and the reaction allowed to go to completion with monitoring by
TLC (after 2 h essentially all of 2 was consumed). After a similar
workup, crude 3a was obtained as an oil (104%) contaminated with
Boc2O, which partly crystallized on standing. A solution of the oil
in a small volume of light petroleum after several days deposited
large, slightly yellow prisms (2.80 g, 68%) with mp 64.5-66 ∞C; co-
lourless crystals with mp 65-66 ∞C after two recrystallizations from
light petroleum; Rf 0.52 (A), 0.62 (B).
s, 1H, NH), 6.74-7.31 (compl. sign., 10H, Ar).
13C NMR (CDCl3): d = 27.8 (Me), 68.9 (CH2), 84.2 (Cq), 113.4,
121.5, 128.2, 128.4, 128.5, 129.2, 135.1, 146.9 (Ar), 151.4 and
153.5 (CO).
FT-IR (KBr): n = 1705 and 1778 (CO), 3351 (NH) cm-1.
Anal. Calcd for C19H22N2O4 (342.40): C, 66.65; H, 6.48; N, 8.18.
Found: C, 66.6; H, 6.5; N, 8.2.
B: The second portion of the solution was heated to 50 ∞C for 2 h,
when TLC indicated complete reaction, and then worked up simi-
larly to give a yellow oil. This was dissolved in light petroleum,
from which the product was frozen out in an EtOH/dry ice bath and
the solvent decanted. The procedure was repeated twice, whereupon
the product was finally chromatographed on silica in Et2O/light pe-
troleum (1:3) to afford pure 6a (0.380 g, 86%) as a pale yellow vis-
cous oil; Rf 0.51 (D).
1H NMR (CDCl3): d = 1.50 (s, 27H, Me), 7.15-7.42 (m, 5H, Ar).
13C NMR (CDCl3): d = 27.9 and 28.1 (Me), 82.1 and 83.7 (Cq),
122.9, 125.7, 128.4, 140.8 (Ar), 150.3 and 152.1 (Boc-CO).
FT-IR (KBr): n = 1729 and 1798 (CO) cm-1.
Anal. Calcd for C21H32N2O6 (408.49): C, 61.74; H, 7.90; N, 6.86.
Found: C, 61.7; H, 7.9; N, 6.9.
1H NMR (CDCl3): d = 1.40 (s, 9H, Me), 1.49 (s, 9H, Me), 5.22 and
5.32 (ABq, J = 12.3 Hz, 2H, CH2), 7.15-7.42 (m, 10H, Ar).
13C NMR (CDCl3): d = 27.9 and 28.0 (Me), 69.0 (CH2), 82.5 and
84.3 (Cq), 123.1, 124.9, 126.0, 128.5, 135.0, 140.5 (Ar), 149.9 and
152.0 (CO).
FT-IR (film): n = 1732, 1766 and 1806 (CO), 2979 (CH) cm-1.
1,2-Bis(t-butyloxycarbonyl)-1-phenylhydrazine (4) from 3a
Solid Mg(ClO4)2 (0.76 g, 3.4 mmol) was added under magnetic stir-
ring to a solution of 3a (6.94 g, 17 mmol) in MeCN (40 mL) at 50
∞C under N2,3,13 immediately producing an intensive evolution of
gas. The reaction was monitored by TLC, which indicated that
cleavage of 3a was complete in about 10 min. The reaction mixture
was quenched after 50 min by pouring into 1 M KHSO4/brine (1:1,
300 mL), whereupon the aqueous phase was exhaustively extracted
with Et2O (4 ¥ 50 mL), the combined extracts washed with brine (3
¥ 70 mL) and dried (MgSO4). Evaporation furnished a slightly yel-
low solid which was recrystallized from toluene/light petroleum to
give 4 (4.72 g, 90%); white needles; mp 110-111 ∞C (Lit.12 mp
110-111 ∞C); Rf 0.42 (A), 0.54 (B).
2-Benzyloxycarbonyl-1-(t-butyloxycarbonyl)-1-phenylhydra-
zine (7) from 6a
This small scale experiment was performed with 6a (0.145 g, 0.328
mmol) and Mg(ClO4)2 (15.2 mg, 0.068 mmol) as described for 3a
above in MeCN (4 mL) containing 1% of H2O at 60 ∞C for 3.5 h
with TLC monitoring. H2O slowed the cleavage rate significantly
(in the absence of H2O, a side product was noticed). After a similar
workup, the crude product was obtained as a glass which could be
crystallized from toluene/light petroleum to give 7 (0.103 g, 92%);
white fine crystals; mp 114-115 ∞C; Rf 0.32 (D).
1H NMR (CDCl3): d = 1.49 (s, 18H, Me), 6.79/6.54 (2 ¥ br s, togeth-
er 1H, NH), 7.13-7.43 (compl. sign., 5H, Ar).
13C NMR (CDCl3): d = 28.1 and 28.2 (Me), 81.5/81.8 and 82.2 (Cq),
123.6, 125.5, 128.4, 142.1 (Ar), 153.6 and 155.4 (Boc-CO).
1H NMR (CDCl3): d = 1.43 (s, 9H, Me), 5.20 (s, 2H, CH2), 7.06/
6.87 (2 ¥ br s, together 1H, NH), 7.15-7.42 (compl. sign., 10H, Ar).
13C NMR (CDCl3): d = 28.1 (Me, Boc), 67.8 (CH2Ph), 82.6 (Cq,
Boc), 124.0, 125.9, 128.37, 128.48, 128.53 (Ar), 153.5 (CO, Boc),
156.4 (CO, Z).
FT-IR (KBr): n = 1718 and 1741 (CO), 3286 (NH) cm-1.
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Synthesis of Hydrazines with Aromatic Substituents Using Triarylbismuth Reagents
1595
Table 2 Selected Data for N-Aryl Substituted Hydrazines made with Ar3Bi in the Presence of Cu(OAc)2 and Et3N
Cmpd Structure
Yield
(%); Mp d, J (Hz)
(∞C)
1H NMR (400 MHz, CDCl3/TMS)
13C NMR (100 MHz, CDCl3/TMS)
d, J (Hz)
FT-IR
(cm–1)
3ba
4-Me-C6H4/
Boc/Boc/ Boc 99-100
98;
1.50 and 1.51 (2 ¥ s, 27 H, Me), 2.32 (s, 3 20.9 (MeAr), 27.9 (Me, NBoc2), 28.1 (Me,
H, MeAr), 7.10 and 7.22, and 7.10 and 7.32 NBoc), 81.9 (Cq, NBoc), 83.6 (Cq, NBoc2),
1725, 1746
and 1766
(2 ¥ ABq, J = 8.1, 4 H, Ar)
123.2, 124.7, 129.0, 135.6, 138.2 (Ar), 150.3 (CO), 2935
(CO, NBoc), 152.2 (CO, NBoc2)
and 2977
(CH)
3cb
4-MeO-C6H4/ 97;
Boc/Boc/Boc 69-70
1.52/1.51/1.44 (3 ¥ s, together 27 H, 3 ¥
Boc), 3.79/3.80 (2 ¥ s, 3 H, OMe), 6.85/
28.0 and 28.2 (Boc), 55.4 (OMe), 81.8/82.0 1724, 1741
(Cq, NBoc), 83.6/83.5 (Cq, NBoc2), 113.7/ and 1769
6.83 (2 ¥ d, J = 9.2, together 2 H, Ar-H2,6), 113.4, 125.9/126.9, 133.8/134.4, 157.8/158.0 (CO), 2937
7.38/7.30 (2 ¥ d, J = 9.2, together 2 H,
Ar-H3,5
(Ar), 150.4/150.6 (CO, NBoc), 152.5 (CO,
NBoc2
and 2984
(CH)
)
6a
6b
Ph/Boc/Z/Boc 98; oil
See 6a from 7
See 6a from 7
See 6a from
7
4-Me-C6H4/
Boc/Z/Boc
98; oil
1.38/1.42 (2 ¥ s, together 9 H, BocNAr),
1.49 (s, 9 H, BocNZ), 2.31 (s, 3 H, MeAr), (CH2Ph), 82.2/82.5 (Cq, BocNAr), 84.2 (Cq, and 1805
20.9 (MeAr), 27.9/28.0 (2 ¥ Boc), 68.9
1732, 1766
5.21 and 5.32 (ABq, J = 12.2, together 2 H, BocNZ), 123.5, 125.0, 128.1, 128.5, 129.0, (CO), 2979
CH2Ph), 7.08–7.34 (m, 9 H, Ar)
129.1, 135.1, 135.9, 136.3, 137.9, 138.5 (Ar), (CH)
149.9/150.1 (CO, BocNAr), 152.1/152.2
(2¥CO, BocNZ+Z)
6c
4-MeO-C6H4/ 97; oil
Boc/Z/Boc
1.38/1.41 (2 ¥ s, together 9 H, BocNAr),
27.9/28.0/28.1 (2¥Boc), 55.4 (OMe), 69.0
1732, 1766
1.51/1.50 (2 ¥ s, 9 H, BocNZ), 3.78 (s, 3 H, (CH2Ph), 82.2/82.3 (Cq, BocNAr), 82.4 (Cq, and 1805
OMe), 5.23 and 5.32/5.23 and 5.29 (2 ¥
ABq, J = 12.1, together 2 H, CH2Ph), 6.82/ 128.3, 128.4, 128.5, 133.5, 134.1, 135.0,
6.78 (d, J = 8.8, 2 H, Ar), 7.23-7.37 (compl. 158.0, 158.2 (Ar), 150.0/150.2 (CO, Boc),
BocNZ), 113.5, 113.8, 126.2, 127.2, 128.1, (CO), 2839,
2935 and
2981 (CH)
sign., 7 H, Ar)
152.1/152.3 (CO, Boc), 152.4/152.6 (CO, Z)
8
Ph/4-Me-
C6H4/Boc/Boc
96; oil
96; oil
1.51 (s, 9 H, Boc), 1.52 (s, 9 H, Boc), 2.29 20.9 (MeAr), 28.2 (Me, Boc), 82.1 and 82.2 1727 (CO),
(s, 3 H, Me), 7.08–7.38 (m, 9 H, Ar) (Cq, Boc), 122.7, 125.5, 128.5, 129.1, 135.4, 2932 and
138.6, 141.2 (Ar), 153.1 and 153.3 (CO)
2978 (CH)
9a
C3H5/Ph/Z/
Boc
1.36/1.48 (2 sign, together 9 H, Boc), 4.04 28.1/28.2 (Me, Boc), 51.8/53.8
1644 (allyl),
(compl. m, 1 H) and 4.20 (dd, J1 = 6.4, J2 = (CH2CH=CH2), 68.1 (CH2Ph), 81.7/81.9 (Cq, 1717 and
14.8, 1 H, CH2CH=CH2), 5.03-5.30 (com- Boc), 118.2, 118.8, 123.0, 126.0, 128.0, 1734 (CO),
pl. sign., 4 H, CH2Ph, =CH2), 5.79 (pert. m, 128.3, 128.4, 128.5, 128.59, 128.62, 132.7, 2932, 2978,
1 H, =CH-), 7.17–7.35 (m, 10 H, Ar)
133.1, 135.8, 135.9, 140.8, 141.1
3034 and
(Ar+CH=CH2), 154.3, 154.4 and 154.7 (CO) 3067 (CH)
9b
EtOCOCH2/
Ph/Z/Boc
97; oil
1.10/1.12 (2 ¥ t, J = 7, together 3 H,
CH3CH2), 1.35/1.45 (2 ¥ s, together 9 H,
Boc), 3.95–4.08 (m, 2 H, CH2CO), 3.84
13.9/14.0 (CH3CH2), 28.0/28.1 (Me, Boc), 1732 (CO),
52.6/54.0 (CH2CO), 61.1 (CH2CH3), 68.37/ 2936 and
68.40 (CH2Ph), 82.5/82.7 (Cq, Boc), 115.3, 2980 (CH)
and 4.63/3.86 and 4.51 (2 ¥ ABq, J = 17, 123.6/124.1, 126.2/126.4, 127.9, 128.2,
together 2 H, CH2CH3), 5.14–5.32 (m, 2 H, 128.3, 128.41, 128.45, 128.53, 128.59,
CH2Ph), 7.18–7.53 (m, 10 H, Ar)
135.62/135.71, 140.4/140.5 (Ar), 154.0/154.1
(CO, Boc), 154.7/154.3 (CO, Z), 168.3/168.4
(CO, CO2Et)
10a
Me/Bn/Z/4-
Me-C6H4
98; oil
2.26 (s, 3 H, MeAr ), 2.82 (pert. s, 3 H,
MeN), 4.26 and 4.30 (Abq, J = 14.6, NCH2, (OCH2), 112.0, 127.4, 127.7, 128.2, 128.5,
20.3 (MeAr), 40.1 (MeN), 52.9 (NCH2), 67.5 1706 (CO),
2924 and
1 H) and 5.11 (br sign., 3 H, OCH2 + 2 sign. 129.3, 129.7, 136.2, 137.4, 146.2 (Ar), 157.0 3032 (CH)
from previous ABq), 6.51 and 7.02 (ABq, (CO)
J ª 8, 2+2 H, Me-Ar),-7.0–7.36 (compl.
sign., ~10 H, Ar)
Synthesis 2000, No. 11, 1591–1597 ISSN 0039-7881 © Thieme Stuttgart · New York

1596
O. Loog et al.
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Table 2 (continued)
Cmpd Structure
Yield
(%); Mp d, J (Hz)
(∞C)
1H NMR (400 MHz, CDCl3/TMS)
13C NMR (100 MHz, CDCl3/TMS)
d, J (Hz)
FT-IR
(cm–1)
10b
C3H5/
EtOCOCH2/Z/
4-Me-C6H4
97; oil
1.25/1.19 (2 ¥ t, J = 7, together 3 H,
CH3CH2), 2.27/2.24 (2 ¥ s, together 3 H,
14.1 (CH3CH2), 20.3 (MeAr), 52.5/53.6
(CH2CH=CH2), 57.1/56.7 (CH2CO), 61.3
MeAr), 4.09–4.28 (m, 4 H, CH2CH=CH2 (CH3CH2), 67.9/68.0 (OCH2), 112.6, 112.8, solved CO),
1714-1754
(br, unre-
and CH2Me), 3.93 and 4.61/3.99 and 4.48 116.2, 127.6, 127.9, 128.0, 128.3, 128.5,
(2 ¥ ABq, J = 17.2/18.0, together 2 H, 128.6, 128.9, 129.7, 134.6, 135.1, 136.0,
2938, 2982,
3032 and
NCH2CO), 5.08–5.26 (compl. sign., 4 H, 145.2 (Ar), 156.7/155.0 (CO, Z), 169.0/169.1 3066 (CH)
CH2Ph+=CH2), 5.89/5.97 (2 ¥ m, 1 H,
=CH), 6.63 and 7.02/6.69 and 7.08 (2 ¥
ABq, J = 8.6, 2+2 H, Me-Ar), 7.07–7.34
(compl. sign., ~5 H, Ar)
(CO, CH2CO)
11
Ph/Boc/Z/4-
Me-C6H4
96; oil
1.34 (s, 9 H, Boc), 2.31 (s, 3 H, Me), 5.19 20.8 (MeAr), 28.3 (Me, Boc), 68.8 (CH2Ph), 1760 and
and 5.21 (pert. ABq, J ≈ 12, 2 H, CH2),
6.92–7.24 (m, 14 H, Ar)
84.1 (Cq, Boc), 117.3, 120.0, 121.8, 127.9,
128.1, 128.3, 129.0, 129.6, 132.9, 135.1,
141.6, 144.8 (Ar), 150.9 (CO, Boc), 153.0
(CO, Z)
1797 (CO),
2928, 2980
and 3032
(CH)
a Anal. Calcd for C22H34N2O6 (422.52): C, 62.54; H, 8.11; N, 6.63. Found: C, 62.5; H, 8.1; N, 6.6.
b Anal. Calcd for C22H34N2O7 (438.52): C, 60.26; H, 7.81; N, 6.39. Found: C, 60.5; H, 7.8; N, 6.4.
FT-IR (KBr): n = 1690 and 1743 (CO), 3240 (NH) cm-1.
and 2-Benzyloxycarbonyl-2-(t-butyloxycarbonyl)-1-(4-meth-
ylphenyl)-1-phenylhydrazine (11)
Anal. Calcd for C19H22N2O4 (342.40): C, 66.65; H, 6.48; N, 8.18.
Found: C, 67.2; H, 6.6; N, 8.0.
These compounds were all prepared by analogy with 3a as de-
scribed in the previous paragraph. The starting materials were A4
(for 3b and 3c), A1 (for 6a-c), 4 (for 8 and 12), 1-allyl-2-benzylox-
ycarbonyl-1-(t-butyloxycarbonyl)hydrazine3 (for 9a), 2-benzyloxy-
carbonyl-1-(t-butyloxycarbonyl)-1-(ethoxycarbonylmethyl)hydra-
zine3 (for 9b), 2-benzyl-2-benzyloxycarbonyl-1-methylhydrazine,
made from the corresponding 1-t-butyloxycarbonyl derivative3 by
cleavage with TFA (for 10a), 1-allyl-2-benzyloxycarbonyl-2-
(ethoxycarbonylmethyl)hydrazine, also made from the correspond-
ing 1-t-butyloxycarbonyl derivative3 by cleavage with TFA (for
10b), and 5 (for 11). Selected data for these compounds are listed in
Table 2.
1,2,2-Tris(t-butyloxycarbonyl)-1-phenylhydrazine (3a) from A4
with Triphenylbismuthane; Typical Procedure
To a magnetically stirred mixture of A4 (166 mg, 0.5 mmol), anhyd
Cu(OAc)2 (137 mg, 0.75 mmol) and Et3N (103 mL, 0.75 mmol) in
CH2Cl2 (1.0 mL), under N2, was added triphenylbismuthane (330
mg, 0.75 mmol) in one portion. The mixture was stirred at r.t. until
all A4 had been consumed (TLC), which took about 23 h, whereup-
on the solvent was evaporated and the remainder mixed with of sil-
ica (3-4 mL). This was placed on top of a short silica column,
which was eluted firstly with EtOAc/light petroleum (1:20) to re-
move the excess of bismuthane used. Then the EtOAc/light petro-
leum ratio was changed to 1:5, as a result of which pure 3a could be
eluted from the column to give, after evaporation, a colourless oil
(210 mg, 100%). It could be crystallized, although with massive
loss of material, from light petroleum; mp 64-65 ∞C.
Acknowledgement
This work was supported by the Swedish Natural Science Research
Council (NFR), Carl Tryggers Stiftelse and the Royal Swedish
Academy of Sciences as well as by an ERASMUS scholarship (to
O.L.). The authors thank a referee for bringing ref. 16 to their atten-
tion.
1H NMR (CDCl3), 13C NMR (CDCl3), and FT-IR (KBr) spectra
agreed with those of 3a obtained from phenylhydrazine above.
1,2,2-Tris(t-butyloxycarbonyl)-1-(4-methylphenyl)hydrazine
(3b), 1,2,2-Tris(t-butyloxycarbonyl)-1-(4-methoxyphenyl)hy-
drazine (3c), 2-Benzyloxycarbonyl-1,2-bis(t-butyloxycarbonyl)-
1-phenylhydrazine (6a), 2-Benzyloxycarbonyl-1,2-bis(t-butyl-
oxycarbonyl)-1-(4-methylphenyl)hydrazine (6b), 2-Benzyloxy-
carbonyl-1,2-bis(t-butyloxycarbonyl)-1-(4-methoxyphenyl)hy-
drazine (6c), 1,2-bis(t-butyloxycarbonyl)-2-(4-methylphenyl)-1-
phenylhydrazine (8), 1-Allyl-2-benzyloxycarbonyl-1-(t-butyl-
oxycarbonyl)-2-phenylhydrazine (9a), 2-Benzyloxycarbonyl-1-
(t-butyloxycarbonyl)-1-(ethoxycarbonylmethyl)-2-phenylhy-
drazine (9b), 2-Benzyl-2-benzyloxycarbonyl-1-methyl-1-(4-me-
thylphenyl)hydrazine (10a), 1-Allyl-2-benzyloxycarbonyl-2-
(ethoxycarbonylmethyl)-1-(4-methylphenyl)hydrazine (10b)
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Synthesis 2000, No. 11, 1591–1597 ISSN 0039-7881 © Thieme Stuttgart · New York