Palladium-catalyzed cross-coupling between vinyl halides and tert-butyl carbazate: First general synthesis of the unusual N-Boc-N-alkenylhydrazines

Article abstract of DOI:10.1021/ol062726r

(Chemical Equation Presented) N-Boc-N-alkenylhydrazines, an almost unknown type of compounds, have been prepared with high to moderate yields via palladium-catalyzed cross-coupling between alkenyl halides and fert-butyl carbazate. The present methodology represents the first general way to access this highly functionalized and unusual type of hydrazines.

Full text of DOI:10.1021/ol062726r

ORGANIC
LETTERS
2007
Vol. 9, No. 2
275-278
Palladium-Catalyzed Cross-Coupling
between Vinyl Halides and tert-Butyl
Carbazate: First General Synthesis of
the Unusual N-Boc-N-alkenylhydrazines
Jose´ Barluenga,* Patricia Moriel, Fernando Aznar, and Carlos Valde´s*
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”,
UniVersidad de OViedo, Julia´n ClaVer´ıa 8, OViedo 33006, Spain
barluenga@unioVi.es; acVg@unioVi.es
Received November 7, 2006
ABSTRACT
N-Boc-N-alkenylhydrazines, an almost unknown type of compounds, have been prepared with high to moderate yields via palladium-catalyzed
cross-coupling between alkenyl halides and tert-butyl carbazate. The present methodology represents the first general way to access this
highly functionalized and unusual type of hydrazines.
Hydrazine derivatives are versatile intermediates in the
preparation of heterocyclic compounds containing N-N
bonds, such as pyrazoles,1 indazoles,2 cinnolines,3 and
1-aminopyrroles.4 Moreover, they are used in the preparation
of a wide variety of biologically and industrially valuable
organic compounds.5 There are many protocols for the
synthesis of aryl- and alkylhydrazines in the literature.5a,6
However, a general method for the synthesis of N-alkenyl-
hydrazines has not been developed. To the best of our
knowledge, only two particular examples of the preparation
of an alkenylhydrazine, based on the reaction of an alkenyl
boronic acid with tert-butyl carbazate7 and azodicarboxylate,8
respectively, have been previously reported in the literature.9
tert-Butyl carbazate 1 is a popular reagent to prepare
substituted hydrazines.6e-g This simple molecule contains two
different nitrogen atoms, a free NH2, and a Boc-protected
NH. When 1 is reacted with a carbonyl, it provides the
corresponding hydrazone: the reaction occurs through the
more nucleophilic NH2.6g Interestingly, palladium- or copper-
catalyzed cross-coupling reactions with aryl halides afford
the product derived from the reaction through the NHBoc.10
(5) For a review, see: (a) Ragnarsson, U. Chem. Soc. ReV. 2001, 30,
205. (b) Zerga, A. Curr. Med. Chem. 2005, 12, 589. (c) Wagaw, D.; Yang,
B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251.
(6) (a) Huddleston, P. R.; Coutts, I. G. C. In ComprehensiVe Organic
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees,
C. W., Eds.; Pergamon: Oxford, 1995; Vol. 2, pp 371-383. (b) Barluenga,
J.; Merino, I.; Vin˜a, S.; Palacios, F. Synthesis 1990, 398. (c) Grehn, L.;
Lo¨nn, H.; Ragnarsson, U. Chem. Commun. 1997, 1381. (d) Loog, O.;
Ma¨eorg, U.; Ragnarsson, U. Synthesis 2000, 1591. (e) Tsubrik, O.; Ma¨eorg,
U. Org. Lett. 2001, 3, 2297. (f) Kabalka, G. W.; Guchhait, S. K. Org. Lett.
2003, 5, 4129. (g) Meyer, K. G. Synlett 2004, 2355.
(7) Kabalka, G. W.; Guchhait, S. K. Org. Lett. 2003, 5, 4129.
(1) (a) Haunert, F.; Bolli, M. H.; Hinzen, B.; Ley, S. V. J. Chem. Soc.,
Perkin Trans. I 1998, 2235. (b) Katritzky, A. R.; Wang, M.; Zhang, S.;
Voronkov, M. V.; Steel, P. J. J. Org. Chem. 2001, 66, 6787. (c) Staufer, S.
R.; Huang, Y. R.; Aron, Z. D.; Coletta, C. J.; Sun, J.; Katzenellenbogen,
B. S.; Katzenellenbogen, J. A. Bioorg. Med. Chem. 2001, 9, 151.
(2) (a) Boudreault, N; Leblanc, Y. Org. Synth. 1996, 74, 241. (b) Pabba,
C.; Wang, H. J.; Mulligan, S. R.; Chen, Z. J.; Stark, T. M.; Gregg, B. T.
Tetrahedron Lett. 2005, 46, 7553.
(3) (a) Barber, H. J.; Washbourne, K.; Wragg, W. R.; Lunt, E. J. Chem.
Soc. 1961, 2828. (b) Wunsch, B.; Nerdinger, S.; Hofner, G. Liebigs Ann.
1995, 1303. (c) Gomaa, M. A. M. Tetrahedron Lett. 2003, 44, 3493.
(4) McLeod, M.; Boudreault, N.; Leblanc, Y. J. Org. Chem. 1996, 61,
1180.
(8) Uemura, T.; Chatani, N. J. Org. Chem. 2005, 70, 8631.
(9) While preparing this manuscript, Buchwald et al. reported the
employment of bis(tert-butyloxycarbonyl)hydrazine in a tandem Cu ami-
dation/hydroamination sequence leading to pyrazoles: Mart´ın, R.; Rodr´ıguez
Rivero, M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079.
(10) Palladium-catalyzed cross-coupling: (a) Wang, Z.; Skerlj, R. T.;
Bridger, G. J. Tetrahedron Lett. 1999, 40, 3543. (b) Arterburn, J. B.; Rao,
K. V.; Ramdas, R.; Dible, B. R. Org. Lett. 2001, 3, 1351. (c) Lim, Y.-K.;
Lee, K-S.; Cho, C.-G. Org. Lett. 2003, 5, 979. (d) Lim, Y.-K.; Jung, J.-W.;
Lee, H.; Cho, C.-G. J. Org. Chem. 2004, 69, 5778. Copper-catalyzed cross-
coupling: (e) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 7727. (f) Wolter, M.; Klapars, A.; Buchwald,
S. L. Org. Lett. 2001, 3, 3803.
10.1021/ol062726r CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/14/2006

We have recently disclosed the palladium-catalyzed ami-
nation of alkenyl bromides and chlorides.11 This methodol-
ogy, which is an extension of the well-developed Buchwald-
Hartwig amination of aryl halides,12 allows for the preparation
of enamines and imines with high regio- and stereoselectivity.
Continuing with our interest in the application of cross-
coupling reactions of alkenyl halides with nitrogen nucleo-
philes,13 we decided to focus on the preparation of N-alke-
nylhydrazines. In this communication, we report our progress
in the development and optimization of a general and
stereoselective method for the synthesis of this almost
unknown class of hydrazines.
Table 1. Reaction of â-Bromostyrene 2a with tert-Butyl
Carbazate 1[a-c]
In a preliminary study we investigated the coupling
between â-bromostyrene 2a and tert-butyl carbazate 1 under
different catalytic combinations using Pd2(dba)3 as a metal
source and different supporting ligands and reaction condi-
tions. The set of ligands included in our study consisted of
PtBu3, chelating diphosphines, Dpephos 5 and DPPF 6,
electron-rich bulky biphenyls, Xphos 714 and Johnphos 8,15
and Verkade’s proazaphosphatrane 9.16
Pd2(dba)3
(mol %
of Pd)
T
t
ligand
base
solvent (°C) (h) 3a/4a[d]
PtBu3
Cs2CO3 toluene[f] 110 17 22:88
[e]
1
2
3
4
5
6
7
2
4
4
4
4
4
4
5
6
7
7
7
7
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 toluene
Cs2CO3 DMF
K3PO4
NaOtBu DMF
110 18 77:23
110 18 79:21
100 22 87:13
110 18 93:7
110 22 89:11
110 17 0:100
(36%)
110 17 0:100
(26%)[g]
110 10 100:0
110 14 100:0
110 21 100:0
(82%)
Most of the catalytic combinations promoted the formation
of the hydrazine 3a to some extent; however, to our surprise,
in some examples, apart from the desired coupling product,
relatively high amounts of the Ullmann-type17 homocoupling
product 4a were also detected (Table 1).
DMF
8
4
7
NaOtBu DMF
It is worth noting that in a way similar to the reactions
with aryl halides the coupling proceeds regioselectively
through the N-Boc nitrogen. Thereby, it seems that the Pd-
catalyzed C-N bond forming reaction occurs upon depro-
tonation of the more acidic NHBoc proton. The requirement
of an initial deprotonation step might account for the strong
dependence of the reaction on the base and the solvent
employed.18
9
10
11
4
2
1
8
8
8
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
12
13
4
4
9
9
Cs2CO3 DMF
110 19 27:63
Cs2CO3 DMF[h,i] 110 19 0:100
(58%)[g]
110 22 0:100
(45%)
14
4
-
Cs2CO3 DMF
As represented in Table 1, the best results were obtained
using Cs2CO3 as base, DMF as solvent, and the Pd(0)/8
catalytic combination (entries 9-11), which provided the
amidation product 3a with high selectivity and yield. A
[a] Selected data from the optimization of the reaction conditions. [b]All
the reactions were conducted until complete conversion of â-bromostyrene
as judged by GC. [c]General reaction conditions: 0.5 mmol of â-bromosty-
rene; 0.6 mmol of tert-butyl carbazate; Pd2(dba)3 as the metal source; 2:1
molar relationship Pd/ligand; 1.4 equiv of base, 1 mL of solvent.
[d]Determined by analysis of the H NMR spectra of the reaction. Isolated
1
yields are shown in brackets. [e]1:1 molar relationship Pd/Ligand was used.
[f] 2 mL of solvent was used. [g]Without tert-butyl carbazate in the reaction
media. [h]0.7 equiv of base was used. [i]0.5 mL of solvent was used.
(11) (a) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valde´s, C. Chem.
Commun. 2002, 2362. (b) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.;
Valde´s, C. Chem. Commun. 2004, 1400. (c) Barluenga, J.; Ferna´ndez, M.
A.; Aznar, F.; Valde´s, C. Chem.-Eur. J. 2004, 10, 494. (d) Barluenga, J.;
Aznar, F.; Moriel, P.; Valde´s, C. AdV. Synth. Catal. 2004, 346, 1697.
(12) For recent revisions of palladium-catalyzed C-N bond forming
reactions, see: (a) de Meijere, A., Diederich, F., Eds. Metal-Catalyzed Cross
Coupling Reactions; VCH: Weinheim, 2004; Vol. 2, pp 699-760. (b) Muci,
A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (c) Hartwig, J.
F. Handbook of Organopalladium Chemistry of Organic Synthesis; Wiley-
Interscience: New York, 2002; Vol. 1, pp 1051-1096. (d) Schlummer,
B.; Scholz, U. AdV. Synth. Catal. 2004, 346, 1599.
(13) (a) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973.
(b) Barluenga, J.; Valde´s, C. Chem. Commun. 2005, 4891.
(14) Huang, X.; Anderson, W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(15) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158.
(16) Reddy, C.; Reddy, V.; Urgaonkar, S.; Verkade, J. G. Org. Lett. 2005,
7, 4427.
(17) For leading reviews, see: (a) Hassan, J.; Se´vignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (b) Nelson, T. D.;
Crouch, R. D. Org. React. 2004, 63, 265.
(18) Pd-catalyzed arylations and vinylations of amides and related
systems are usually best achieved employing inorganic bases such as
Cs2CO3 and K3PO4: (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 6043. (b) Klapars, A.; Campos, K. R.; Chen, C.-y.; Volante, R. P.
Org. Lett. 2005, 7, 1185 and references cited therein.
catalyst loading of 1 mol % of Pd can be used, even though
the reaction rate decreases substantially (entry 11).
With regard to the homocoupling product 4a, the best
conditions were obtained employing Pd(0)/9 as the catalytic
combination (entry 13). Interestingly, 4a was obtained as a
unique coupling product under several different reaction
conditions (entries 7, 8, 13, and 14); however, only under
the conditions of entry 13, the yield was preparatively
acceptable.
The scope of the reaction to synthesize N-alkenylhydra-
zines was studied using different alkenyl bromides and
chlorides. Under the optimized reaction conditions, a wide
variety of N-alkenylhydrazines were synthesized with high
to moderate yields. The results are shown in Table 2.
The coupling reaction provides good results for electron-
rich, electron-neutral, and electron-poor substituted â-bro-
276
Org. Lett., Vol. 9, No. 2, 2007

NMR spectra. Interestingly, when the coupling reactions were
carried out with bromodiene 2g, which consisted of a 2:1
mixture of E/Z bromoalkenes, respectively, we observed
double bond isomerization to obtain the corresponding
(E)-N-alkenylhydrazine as a pure stereoisomer. Clearly, the
less stable (Z)-isomer undergoes isomerization into the more
stable (E)-isomer.
Table 2. N-tert-Butoxycarbonyl-N-alkenylhydrazines
Prepared[a]
Next, we turned our attention to the homocoupling
reaction. The Ullmann coupling is one of the most important
tools to prepare symmetrical biaryls;17 however, its applica-
tion to the preparation of polyenes has been scarce.20
Noteworthy is that although in most Pd-catalyzed Ullmann
couplings a reducing agent is required to facilitate the
regeneration of Pd(0) species, only in some particular
examples the catalytic coupling takes place in the absence
of an external reducing agent.17a,21 It is believed that the
solvent, in most cases DMF, plays that role. Taking into
account these precedents, we decided to investigate this novel
homocoupling reaction.
At this point of development, the process shows limited
scope, probably due to the harsh conditions and long reaction
times required, which provoked the decomposition of the
alkenyl bromides in several cases. Nevertheless, several
dienes could be synthesized with moderate yields (Table 3).
Table 3. Homocoupling Products Prepared through the
Ullman-Type Reaction[a]
[a] General reaction conditions: 0.5 mmol of haloalkene, 0.6 mmol of
tert-butyl carbazate, 2 mol % of Pd2(dba)3; 8 mol % of Johnphos, 1.4 equiv
of cesium carbonate, 1 mL of DMF, 110 °C. [b]Isolated yields, after flash
chromatography. [c]Used 1 mol % of Pd for catalyst loading. [d]Reaction
conducted at 90 °C. [e]Synthesized as a pure stereoisomer E.
mostyrenes (entries 1-6). Moreover, the reaction can be
carried out in the presence of an aryl chloride (entries 5 and
11) and an aryl bromide (entry 6), given the higher reactivity
of vinyl bromides over aryl halides toward oxidative addition
reactions.19 Besides, 1-bromodienes (entry 7), 4-bromoenynes
(entry 8), and bromoolefins with an aliphatic group (entry
9) can be used in the same way, providing a large variety of
N-alkenylhydrazines.
[a] See Supporting Information for reaction conditions. [b]Isolated yields,
after flash chromatography. [c]Reaction conducted at 90 °C. [d]Obtained as
a unique stereoisomer.
We also examined the participation of less-reactive 1-chlo-
rodienes 2j and 2k. As indicated in Table 2 (entries 10 and
11), using the optimized reaction conditions for alkenyl
bromides, the corresponding N-alkenylhydrazines were ob-
tained with good yield. It is worth noting that the coupling
reaction with chloroalkenes did not require harsher conditions
or a longer reaction time.
In all cases, the (E,E)-dienes were obtained as pure isomers
as deduced by the H NMR spectra. It is worth noting that
1
when the homocoupling reaction was carried out with
bromodiene 2g, which is formed by a 2:1 mixture of E/Z
bromoalkenes, we noticed double bond isomerization to
obtain the corresponding (E,E,E,E)-tetraene as a pure ste-
reoisomer.
With regard to the stereoselectivity of the process, the
reactions with pure (E)-haloalkenes afforded the (E)-N-
alkenylhydrazines as pure isomers as deduced by the H
(20) (a) Lee, P. H.; Seomoon, D.; Lee, K. Org. Lett. 2005, 7, 343. (b)
Banwell, M. G.; Kelly, B. D.; Kokas, O. J.; Lupton, D. W. Org. Lett. 2003,
5, 2497. (c) Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes,
M. O. Org. Lett. 2004, 6, 2741.
1
(19) Barluenga, J.; Ferna´ndez, M. A.; Aznar, F.; Valdes, C. Chem.-
Eur. J. 2005, 11, 2276.
(21) Hassan, J.; Penalva, V.; Laverot, L.; Gozzi, C.; Lemaire, M.
Tetrahedron 1998, 54, 13793.
Org. Lett., Vol. 9, No. 2, 2007
277

In conclusion, we have reported a new and simple
methodology for the synthesis of N-alkenylhydrazines from
readily available substrates, alkenyl bromides, and chlorides.
This report establishes the first general route for the synthesis
of this particular class of hydrazines, which were almost
unknown in the literature. Given the usefulness of hydrazines
in heterocyclic synthesis, we believe that the reaction
presented herein may be of great applicability in synthetic
organic chemistry.
Acknowledgment. Financial support of this work by
Fundacio´n Ramo´n Areces and DGI (Grant MCT-04-
CTQ2004-08077-C02-01) is acknowledged. P.M. wishes to
thank MEC of Spain for a predoctoral fellowship.
Supporting Information Available: Full experimental
details and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL062726R
278
Org. Lett., Vol. 9, No. 2, 2007