Hydrazides as tunable reagents for alkene hydroamination and aminocarbonylation

Article abstract of DOI:10.1021/ja902558j

(Chemical Equation Presented) Benzoic hydrazides (R = Ph), which are remarkably bench and thermally stable reagents (often up to 230°C), afford intramolecular hydroamination products upon heating at high temperatures (120-235°C). A concerted Cope-type hydroamination event, followed by a hydrazide-mediated proton transfer step of the hydrazinium ylide intermediate, is proposed and supported by DFT calculations. In contrast, a simple modification of the reagent structure (R = Ot-Bu or NH₂) favors the formation of aminocarbonylation products at 200°C, and the latter reaction is shown to be stereospecific. Copyright

Full text of DOI:10.1021/ja902558j

Published on Web 06/08/2009
Hydrazides as Tunable Reagents for Alkene Hydroamination and
Aminocarbonylation
Jean-Gre´goire Roveda, Christian Clavette, Ashley D. Hunt, Serge I. Gorelsky, Christopher J. Whipp,
and Andre´ M. Beauchemin*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada, K1N 6N5
Received March 31, 2009; E-mail: andre.beauchemin@uottawa.ca
Table 1. Optimization of Hydroamination/Aminocarbonylation
Since over 90% of pharmaceuticals have at least one nitrogen
atom in their structure and as approximately one reaction out of
six performed in the pharmaceutical industry involves the formation
of a carbon-nitrogen bond, the development of efficient routes to
nitrogen-containing molecules is of paramount importance.1 Ami-
nation reactions involving electron-rich alkenes offer excellent
potential for broad applicability, which continues to attract intense
research interest. Various methodologies have been developed, and
transition metal catalysts are typically used to enable amination
reactivity. In efforts directed toward metal-free hydroamination,2,3
we recently extended the scope of Cope-type hydroaminations of
hydroxylamines to intermolecular reactions of alkenes, alkynes, and
allenes.4,5 Given that hydroxylamines can be sensitive and prone
to decomposition, more practical reagents were sought to extend
the reaction scope. Herein we report that benzoic hydrazides (R )
Ph), which are remarkably bench and thermally stable (often up to
230 °C), offer a practical alternative to perform Cope-type
hydroaminations.6,7 In addition, a simple modification of the reagent
structure (R ) Ot-Bu, NH2) leads to alkene aminocarbonylation
products under metal-free conditions.8
Reactivitya
entry
conditionsa
R
product(s) and yield(s)b
1
2
3
4
5
6
7
8
120 °C, 18 h
Ph
t-Bu
2-pyridyl
OEt
OEt
Ot-Bu
NH2
NH2
2a (93%)
2b (66%)
2c (64%)
150 °C, 16 h
170 °C, 42 h
140 °C, 16 h
200 °C (µw), 5 h
200 °C (µw), 5 h
150 °C (µw), 5 h
200 °C (µw), 15 min
2d (25%)c + 3 (6%)
2d (13%) + 3 (46%)
2e (0%) + 3 (71%)
2f (50%) + 3 (20%)d
2f (10%) + 3 (85%)d
a Heating performed in PhCF3 (0.05 M, sealed tube) unless indicated
otherwise. b Isolated yield. c Other hydroamination byproducts are
formed [ΣHA products ) 76% (1H NMR)]. d NMR yield using an
internal standard.
Table 2. Scope of Intramolecular Hydrohydrazidation Reactivitya
A simple system yielding a pyrrolidine ring upon cyclization
was first investigated to validate the hydroamination (HA) reactivity.
Gratifyingly, the desired product 2a was formed upon heating
phenyl hydrazide 1a at 120 °C (Table 1, entry 1). The parent pyridyl
and tert-butyl hydrazides also formed the HA product, albeit at
higher temperatures (entries 2-3). Fortuitously, oxygen-substituted
reagents yielded a mixture of HA and aminocarbonylation products
under similar conditions (entries 4-5). Further studies showed that
aminocarbonylation is favored at higher temperatures (entry 6) and
that nitrogen analogues also display similar reactivity (entries 7-8).
A preliminary substrate scope for intramolecular hydroamination
and aminocarbonylation reactivity of hydrazides is presented in
Tables 2 and 3, respectively.
As shown in Table 2, various benzoic hydrazides cyclize
efficiently to form intramolecular hydroamination products. Five-
and six-membered azacycles are formed reliably (entries 1-11).
Both primary and secondary hydrazides react under similar reaction
conditions (entries 1 and 2), and heteroatoms can be present in the
substrate as illustrated by the formation of a morpholine (entry 7)
a Heating performed in PhCF3 (0.05 M), in sealed tubes (1-5) or µw
(6-12). b Isolated yield. c 2.4:1 dr. d NMR yield using an internal
standard.
and two piperazines (entries 8 and 9). Several alkene substitution
patterns are also tolerated, although higher reaction temperatures
are required (entries 2, 3, 10, and 11). The reactivity shown in
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8740 J. AM. CHEM. SOC. 2009, 131, 8740–8741
10.1021/ja902558j CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
entries 10 and 11 is noteworthy since most reported examples of
piperidine ring formation via hydroamination have been reported
for terminal alkenes. Overall, this hydroamination procedure is
experimentally simple and compatible with various solvents,9 the
cyclization precursors are typically bench-stable crystalline solids,
and the products can be purified by chromatography.
Both primary and secondary semicarbazides react under similar
reaction conditions (entries 1-4). Alkene substitution at the distal
position is also tolerated, and the reaction is a stereospecific11 syn
addition process (entries 5 and 6 vs 7). This reactivity appears
consistent with in situ formation of an aminoisocyanate intermediate
upon thermolysis above 150 °C,12 followed by cycloaddition.13
In summary, we have shown that efficient intramolecular
hydroamination and aminocarbonylation can be performed simply
upon heating the appropriate hydrazine derivatives. Several exten-
sions of this work are currently under investigation and will be
reported in due course.
DFT studies were performed to gain more insight into this
hydroamination (HA) reactivity and support the pathway shown in
eq 1. Calculated activation energies for a concerted, planar, five-
membered Cope-type HA transition state (∆GHA‡) were determined
to be 28.7 and 34.2 kcal/mol for substrates 4a and 4f, respectively.
For comparison, calculated values for the parent hydroxylamines
are 22.9 and 27.2 kcal/mol. Our calculations also support the
involvement of the carbonyl group of the hydrazide in the proton
transfer step of the dipole intermediate formed by hydroamination
(∆GPT‡ ) 5.2 kcal/mol),9,10 which is consistent with the reaction’s
compatibility with various solvents. The transition state structures
for the hydroamination (A) and proton transfer (B) processes of
substrate 4a are shown in Figure 1. Overall, these results are in
agreement with the higher temperatures required for the cyclization
of hydrazides, which are typically 80-100 °C above that of the
parent hydroxylamines.
Acknowledgment. We thank the University of Ottawa, CFI,
MRI (Ontario), NSERC, the Enantioselective Synthesis Grant
(sponsored by the Canadian Society for Chemistry, AstraZeneca
Canada, Boehringer Ingelheim (Canada) Ltd. and Merck Frosst
Canada) for partial support of this work. We also thank Prof. Louis
Barriault for an insightful discussion.
Supporting Information Available: Experimental procedures,
solvent scan, computational details and spectroscopic characterization
for all new products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Table 3. Scope of Intramolecular Aminocarbonylation Reactivitya
References
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b
entry
alkenyl hydrazide
X
product
yield
%
1
2
3
4
5
6
R1)R2)R3)R4)H
Ot-Bu
NH2
Ot-Bu
NH2
Ot-Bu
NH2
7a
7a
7c
7c
7e
7e
70
(3) For examples of metal-catalyzed hydrohydrazidations, see: (a) Waser, J.;
Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 5676. (b) Waser, J.; Carreira,
E. M. Angew. Chem., Int. Ed. 2004, 43, 4099. (c) Waser, J.; Gaspar, B.;
Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693. (d) Alex,
K.; Tillack, A.; Schwarz, N.; Beller, M. Angew. Chem., Int. Ed. 2008, 47,
2304, and references cited therein. (e) Li, Y.; Shi, Y.; Odom, A. L. J. Am.
Chem. Soc. 2004, 126, 1794. (f) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett.
2002, 4, 2853.
(4) (a) Beauchemin, A. M.; Moran, J.; Lebrun, M.-E.; Se´guin, C.; Dimitrijevic,
E.; Zhang, L.; Gorelsky, S. I. Angew. Chem., Int. Ed. 2008, 47, 1410. (b)
Moran, J.; Gorelsky, S. I.; Dimitrijevic, E.; Lebrun, M.-E.; Be´dard, A.-C.;
Se´guin, C.; Beauchemin, A. M. J. Am. Chem. Soc. 2008, 130, 17893. (c)
Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Be´dard, A.-C.;
Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 874. (d) Moran, J.;
Pfeiffer, J. Y.; Gorelsky, S. I.; Beauchemin, A. M. Org. Lett. 2009, 11,
1895.
”
86
R1)Me, R2)R3)R4)H
74c
84c
66
”
R1)R2)H, R3)Me, R4)H
”
52d
(+13% 7g)
7
R1)R2)R3)H, R4)Me
Ot-Bu
7g
71
a Heating performed in MeCN (200 °C, 30 min, 0.05 M, microwave
reactor). b Isolated yield. c 2:1 dr. d NMR yield using an internal
standard.
(5) Such reactions are also called reverse Cope cyclizations/eliminations. For
a review, see: Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243.
(6) For analogous intermolecular reactivity of hydrazines with alkynes, see:
Cebrowski, P. H.; Roveda, J.-G.; Moran, J.; Gorelsky, S. I.; Beauchemin,
A. M. Chem. Commun. 2008, 492.
(7) For a recent review on methods to access di- and trisubstituted hydrazides,
see: Licandro, E.; Perdicchia, D. Eur. J. Org. Chem. 2004, 665.
(8) For metal-catalyzed variants, see: (a) Hegedus, L. S.; Allen, G. F.; Olsen,
D. J. J. Am. Chem. Soc. 1980, 102, 3583. (b) Hegedus, L. S.; McKearin,
J. M. J. Am. Chem. Soc. 1982, 104, 2444. (c) Beccalli, E. D.; Broggini,
G.; Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107, 5318. (d) Cernak,
T. A.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 3124.
(9) The reaction can also be performed in PhMe, dioxane, MeCN, i-PrOH,
DMF, and H2O. See Supporting Information for details.
(10) For hydroxylamines, the proton transfer step of the N-oxide intermediate
is kinetically relevant, and the increased reactivity observed in protic
solvents (e.g., n-PrOH) is consistent with a bimolecular proton transfer
process (e.g., n-PrOH-mediated). See refs 4a,b.
Figure 1. Transition state structures for the intramolecular hydro-
hydrazidation (A) and subsequent proton transfer of the dipolar intermediate
(B) for substrate 4a. The internuclear distances (Å) are shown only for
relevant chemical bonds.
(11) Formation of product 7g in entry 6 is consistent with epimerization of
product 7e. See Supporting Information for details.
(12) For precedence on aminoisocyanates formation from similar precursors,
see: Wadsworth, W. S.; Emmons, W. D. J. Org. Chem. 1967, 32, 1279.
(13) Reports on the reactivity of aminoisocyanates are scarce, and such species
are known to dimerize and trimerize. For other reactivity, see: (a) Lockley,
W. J. S.; Lwowski, W. Tetrahedron Lett. 1974, 4263. (b) Kurz, M.; Reichen,
W. Tetrahedron Lett. 1978, 1433. (c) Reference 12 (and references cited
therein).
In contrast to benzoic hydrazides, carbazates (X ) Ot-Bu) and
semicarbazides (X ) NH2) form aminocarbonylation products at
elevated temperatures (Table 3). A preliminary substrate scope
suggests that semicarbazides are superior precursors (entries 1-6).
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