Improved Cope-type hydroamination reactivity of hydrazine derivatives

Article abstract of DOI:10.1039/c0cc02403a

A systematic investigation on the metal-free, Cope-type hydroamination reactivity of hydrazides and analogues is reported. Optimization of the hydrazide structure resulted in more facile intramolecular reactivity and enabled intermolecular reactions of al

Full text of DOI:10.1039/c0cc02403a

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Improved Cope-type hydroamination reactivity of hydrazine derivativeswz
¨
Francis Loiseau, Christian Clavette, Michael Raymond, Jean-Gregoire Roveda,
Alishya Burrell and Andre M. Beauchemin*
´
´
Received 6th July 2010, Accepted 6th September 2010
DOI: 10.1039/c0cc02403a
A systematic investigation on the metal-free, Cope-type hydro-
amination reactivity of hydrazides and analogues is reported.
Optimization of the hydrazide structure resulted in more facile
intramolecular reactivity and enabled intermolecular reactions
of alkenes, thus providing a direct approach to polysubstituted
hydrazides.
Efficient C–N bond-forming reactions continue to emerge
from efforts to synthesize diverse nitrogen-containing func-
tional groups from simple building blocks. Hydroamination,
the formal addition of N–H bonds across an unsaturated
carbon–carbon p bond, represents a highly desirable and
versatile strategy to form C–N bonds. To overcome the high
activation energy associated with such reactivity, hydroamination
efforts have mostly focused on transition metal catalysis,1
including some recent developments in hydrohydrazination.2
The availability of monosubstituted hydrazine derivatives
has stimulated intense research and led to applications in
agriculture (pesticides), polymer chemistry, photographic
products and pharmaceuticals (both as synthetic intermediates
and end products).3 Specifically, hydrazides (N-acylhydrazines)
have been used in the synthesis of heterocycles, dyestuffs,
polymers, and in peptidomimetics (azapeptides),4 agriculture
(e.g. daminozide, a plant growth regulator) and pharmaceuticals
[e.g. isoniacid (tuberculosis), isocarboxazid (antidepressant),
atazanavir (antiretroviral)].3c With most applications featuring
monosubstituted hydrazines and hydrazides, broadly applicable
methods to access di- and tri-substituted hydrazines are in
particular need. In this context, uses of hydrazines in the
hydroamination of alkenes and alkynes (hydrohydrazination)
are only emerging.2
Scheme 1 Cope-type hydroamination of alkenes.
In contrast to hydroxylamines, hydrazine derivatives are
remarkably thermally stable. Hydrazides are also typically
crystalline and bench stable, and the electron-withdrawing
group can facilitate the proton transfer step from the ammonium
ylide intermediate.6a,b,7 Speculating that optimizing the structure
of the hydrazide group would result in a more facile hydro-
amination event (through stabilization of the developing
charges present in the transition state) and stabilize the dipole
intermediate, we embarked on a systematic investigation of
related hydrazine derivatives (Table 1).
The data shown in Table 1 show the generality of the
approach and allow a comparison of the relative reactivity of
semicarbazides, thiosemicarbazides, phosphohydrazides and
hydrazides in the formation of the pyrrolidine ring system
(Table 1, entries 1–7). Due to side reactions observed with
semicarbazides8 and phosphohydrazides9 at higher tempera-
tures, benzoic hydrazides were selected for further optimization.
Gratifyingly, increased reactivity was observed for substrates
possessing hydrogen-bonding and electron-withdrawing substi-
tuents (entries 9–12). While both hydrazides 1j and 1l resulted in
encouraging reactivity at 70 1C,10 the increased solubility of
hydrazide 1l in organic solvents led us to explore the reactivity of
3,5-bis(trifluoromethyl)benzoic hydrazides in more challenging
intra- and intermolecular reactions.
As part of our interest in metal-free amination methods, we
recently extended the scope of the thermal, concerted, Cope-type
hydroamination5 reactivity of hydroxylamines to intermolecular
reactions of alkenes, alkynes and allenes (Scheme 1).6 We also
recently reported our preliminary results on related reactivity of
hydrazines and hydrazides.7 Herein, we disclose a systematic
evaluation of the reactivity of hydrazine derivatives, leading to
increased reactivity and applicability in intramolecular systems,
and enabling intermolecular alkene hydrohydrazidation.
Thus, we next sought to investigate the cyclization of several
substrates to access pyrrolidine and piperidine ring systems
(Table 2). The reactivity of the simpler benzoic hydrazides7a
(4a–e) is also presented to allow comparison.
As shown in Table 2, the efficiency of the cyclizations to simple
5- and 6-membered rings (5a–e) was comparable to that of the
simple benzhydrazide derivatives (6a–e), with the hydroamination
proceeding at lower temperatures. While only a modest increase
in reactivity was observed, the effect of the improvement was
most noticeable with substrates with distal alkene substituents
(entries 5–6 and 9–10). Such disubstituted alkenes typically afford
lower yields of the cyclised products due to a more challenging
hydroamination event and competing side reactions.11 In such
systems, modified hydrazides resulted in a marked improvement
over reactions obtained using benzoic hydrazides.
Centre for Catalysis Research and Innovation,
Department of Chemistry, University of Ottawa,
10 Marie-Curie, Ottawa, ON K1N 6N5, Canada.
E-mail: andre.beauchemin@uottawa.ca; Fax: +1 613-562-5170;
Tel: +1 613-562-5800, ext. 2245
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Experimental
procedures, optimization data for Table 3 and spectroscopic charac-
terization for all new products. See DOI: 10.1039/c0cc02403a
While intramolecular hydroamination reactivity is possible
through various catalyzed and metal-free approaches,
c
562 Chem. Commun., 2011, 47, 562–564
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Table 1 Scope of intramolecular hydroamination using hydrazine
derivatives
Table 2 Scope of 3,5-bis(trifluoromethyl)benzhydrazides cyclizations
Entry EWG
R1 Temp/1C Product Yieldb (%)
Yieldb
Temp/1C Product (%)
Entry
Substrate
1
2
3
4
5
6
7
8
3a R1 = R2 = R3 = H n = 1
4a
95
120
5a
6a
5b
6b
5c
6c
5d
6d
5e
6e
81
1
2
X = O (1a)
X = S (1b)
H
H
150
100
2a
2b
50
86
93
3b R1 = Me, R2 = R3 = H n = 1 95
85c
98c
91
4b
120
3c R1 = R2 = H, R3 = Me n = 1 150
4c
3d R1 = R2 = R3 = H n = 2
4d
175
175
200
75
82
3
4
R = Et (1c)
R = Ph (1d)
H
H
120
110
2c
2d
>98c
>98c
90
53
9
10
3e R1 = R3 = H, R2 = Et n = 2 195
4e
220
51d
a
Conditions: heated in PhCF3 (0.05 M), in a microwave reactor
b
(10–24 h). Isolated yield. NMR yield using an internal standard.
d
c
Obtained as a mixture of diastereoisomers (see ESIz).
5
6
7
8
R = t-Bu (1e)
R = 2-pyridyl (1f)
R = Ph (1g)
H
H
H
150
170
120
2e
2f
2g
2h
66
64
93
98d
Encouragingly, a mixture of mono- (8) and bis-hydroamina-
tion (9) products was formed upon heating 3,5-bis(trifluoro-
methyl)benzhydrazide 7 with excess norbornene. Reasoning
that this lack of control would be avoided with a substituted
derivative, benzylic substrate 10a was selected for further
development. After optimization of solvent, concentration
and equivalents of alkene (see ESIz), hydroamination products
11a and 12a were obtained in 81% yield and 3.1 : 1 ratio. The
two products are likely formed from a common ammonium
ylide intermediate (A, see Scheme 2),13 with the expected major
product 11a arising from a proton transfer and the minor
product 12a forming through a competing [1,2]-shift of
the norbornyl group.14 Such [1,2]-shifts are related to the
Stevens’ rearrangement and usually occur through a diradical
mechanism.15 The scope of this intermolecular reactivity was
explored with several hydrazides, as shown in Table 3.
R = Ph (1h)
Me 120
9
10
R = H (1i)
R = NO2 (1j)
Me 90
Me 70
2i
2j
90d
88d
11
12
Me 90
2k
2l
91d
H
95
81
Encouragingly, the hydroamination of norbornene proved
efficient with several alkylhydrazides, providing the hydro-
amination products in combined yields ranging from 74–87%
(Table 3, entries 1–7). The presence of alkene and benzyl ether
functionalities on the hydrazide was also well tolerated (entries
6 and 7). In all cases the expected hydroamination product 11
was favored over rearrangement product 12, with the ratio of
products showing little dependence on the size of the
a Conditions: heated in PhCF3 (0.05 M), in sealed tubes (18–40 h) or in
b
a microwave reactor (10–16 h). Isolated yield. NMR yield using
c
d
an internal standard. Obtained as a mixture of diastereoisomers
(see ESIz).
intermolecular processes are more challenging (especially for
alkenes).12 With optimized reagents, we revisited previously
unsuccessful attempts to achieve a metal-free intermolecular
alkene hydrohydrazidation simply upon heating. The lead
result obtained is shown in eqn (1).
Scheme 2 Intermolecular hydrohydrazidation: divergent reactivity
ð1Þ
from the ammonium ylide intermediate.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 562–564 563

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Table 3 Intermolecular hydrohydrazidation scope
126, 5676; (b) J. Waser and E. M. Carreira, Angew. Chem., Int. Ed.,
2004, 43, 4099; (c) J. Waser, B. Gaspar, H. Nambu and
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Y. Shi and A. L. Odom, J. Am. Chem. Soc., 2004, 126, 1794;
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2008, 27, 1005; (k) K. Alex, A. Tillack, N. Schwarz and M. Beller,
Org. Lett., 2008, 10, 2377.
Reaction
time/h
Yieldb (%)/
ratio (11 : 2)
Entry Hydrazide (R)
Products
1
2
Bn
40
11a +
12a
81 (3.1 : 1)
85 (4.3 : 1)
Me
17
11b +
12b
11c + 12c 74 (1.7 : 1)
3 For reviews on the uses of hydrazines and hydrazides:
(a) E. F. Rothgery, Kirk-Othmer Encyclopedia Chemical Technology,
John Wiley & Sons, New York, 5th edn, 2004, vol. 13, pp. 562–607;
(b) U. Ragnarsson, Chem. Soc. Rev., 2001, 30, 205; (c) E. Licandro
and D. Perdicchia, Eur. J. Org. Chem., 2004, 665.
3
4
i-Pr
i-Bu
17
17
11d +
12d
73 (2.7 : 1)
5
6
7
c-C6H11
40
11e + 12e 87 (3.2 : 1)
11f + 12f 87 (3.7 : 1)
4 For a review, see: J. Gante, Synthesis, 1989, 405.
(CH2)2CHQCH2 17
(CH2)3OBn 17
5 For an excellent review of the hydroamination reactivity of
hydroxylamines, see: N. J. Cooper and D. W. Knight, Tetrahedron,
2004, 60, 243.
11g +
12g
86 (3.3 : 1)
a
b
6 (a) A. M. Beauchemin, J. Moran, M.-E. Lebrun, C. Seguin,
´
E. Dimitrijevic, L. Zhang and S. I. Gorelsky, Angew. Chem., Int.
Ed., 2008, 47, 1410; (b) J. Moran, S. I. Gorelsky, E. Dimitrijevic,
Conditions: heated in PhCF3 (2 M), 160 1C, sealed tube, 17–40 h.
Isolated yields.
M.-E. Lebrun, A.-C. Be
J. Am. Chem. Soc., 2008, 130, 17893; (c) J. Bourgeois, I. Dion,
P. H. Cebrowski, F. Loiseau, A.-C. Bedard and A. M. Beauchemin,
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S. I. Gorelsky and A. M. Beauchemin, Org. Lett., 2009, 11,
1895.
7 (a) J.-G. Roveda, C. Clavette, A. D. Hunt, S. I. Gorelsky,
C. J. Whipp and A. M. Beauchemin, J. Am. Chem. Soc., 2009,
131, 8740; (b) P. H. Cebrowski, J.-G. Roveda, J. Moran,
S. I. Gorelsky and A. M. Beauchemin, Chem. Commun., 2008,
492.
8 Heating semicarbazides at higher temperatures (200 1C) results in
the formation of aminoisocyanate intermediates, which can lead to
alkene cycloadducts: see ref. 7a.
dard, C. Seguin and A. M. Beauchemin,
´ ´
hydrazide substituent (R). This observation indicates that
proton transfer of the ammonium ylide intermediate is more
facile than migration of the alkyl substituents. Importantly,
no rearrangement product derived from [1,2]-shift of the R
substituent was detected, highlighting the preference for the
norbornyl substituent to migrate over several alkyl groups.
In summary, we have performed a systematic investigation
of the hydroamination reactivity of hydrazides and related
compounds, showing its generality in simple intramolecular
systems. More reactive benzoic hydrazides were identified, and
3,5-bis(trifluoromethyl)benzhydrazides proved more efficient
in several cyclizations and enabled intermolecular hydro-
hydrazidations. Extensions of this work to access more sub-
stituted ammonium ylides and to enable alkyne hydroamination
are in progress and will be reported in due course.
´
9 An aza-Cope elimination process of an ammonium ylide formed
via proton transfer is suspected at higher temperatures. For related
reactivity, see: D. G. Morris, B. W. Smith and R. J. Wood,
J. Chem. Soc., Chem. Commun., 1968, 1134.
10 See the ESIz for details.
11 Two (slow) competing side reactions have been observed
with hydrazides at high temperatures: aza-Cope elimination
(see ref. 9) and formation of the parent imine through elimination
of 3,5-bis(trifluoromethyl)benzamide.
We thank the University of Ottawa, the Canadian Foundation
for Innovation, the Ontario Ministry of Research and Innova-
tion (Early Researcher Award to A.M.B.), and NSERC for
their support. Scholarships to F.L. (FQRNT), C.C. (NSERC
CREATE) and M.R. (NSERC USRA) are also acknow-
12 For general reviews on alkene hydroamination, see ref. 1a and e.
Even in intramolecular cases, reactivity is usually only general for
5-membered cyclizations, and is diminished by alkene substitution.
The near thermoneutral nature of alkene hydroamination provides
an additional challenge for intermolecular hydroaminations:
A. M. Johns, N. Sakai, A. Ridder and J. F. Hartwig, J. Am. Chem.
Soc., 2006, 128, 9306.
ledged. We also thank Ms Roxanne Clement (CCRI) for
´
assistance in preliminary high throughput screening experi-
ments directed at intermolecular reactivity.
13 Such dipoles are also called aminimides. For a seminal review, see:
W. J. McKillip, E. A. Sedor, B. M. Culbertson and S. Wawzonek,
Chem. Rev., 1973, 73, 255.
Notes and references
1 For selected reviews, see: (a) T. E. Muller, K. C. Hultzsch, M. Yus,
¨
14 The structure of 12 was confirmed through analysis of the
products resulting from the cleavage (SmI2) of the N–N bond.
See ESIz.
F. Foubelo and M. Tada, Chem. Rev., 2008, 108, 3795 and reviews
cited therein; (b) I. Aillaud, J. Collin, J. Hannedouche and E. Schulz,
Dalton Trans., 2007, 5105; (c) K. C. Hultzsch, Adv. Synth. Catal.,
15 For a tutorial review, see: (a) J. B. Sweeney, Chem. Soc. Rev., 2009,
38, 1027. For the rearrangement of hydrazinium ylides see:
(b) S. Wawzonek and E. Yeakey, J. Am. Chem. Soc., 1960, 82,
5718; (c) H. P. Benecke and J. H. Wikel, Tetrahedron Lett., 1971,
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J. Chem. Soc., Perkin Trans. 1, 1983, 1029.
2005, 347, 367; (d) M. Nobis and B. Drieben-Holscher, Angew.
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¨
Chem. Rev., 1998, 98, 675.
2 For selected examples of metal-catalyzed hydrohydrazidations,
see: (a) J. Waser and E. M. Carreira, J. Am. Chem. Soc., 2004,
c
564 Chem. Commun., 2011, 47, 562–564
This journal is The Royal Society of Chemistry 2011