Intermolecular Cope-type hydroamination of alkynes using hydrazines

Article abstract of DOI:10.1039/b715022a

Metal-free, intermolecular hydroaminations are performed upon heating aryl acetylenes and MeNHNH₂ at 140°C, with preferential formation of the linear, "anti-Markovnikov" hydrazones. The Royal Society of Chemistry.

Full text of DOI:10.1039/b715022a

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Intermolecular Cope-type hydroamination of alkynes using hydrazines{
Pamela H. Cebrowski, Jean-Gre´goire Roveda, Joseph Moran, Serge I. Gorelsky{ and Andre´ M. Beauchemin*
Received (in Bloomington, IN, USA) 1st October 2007, Accepted 23rd November 2007
First published as an Advance Article on the web 10th December 2007
DOI: 10.1039/b715022a
phenylacetylene. Encouragingly, 53% conversion to a 2.5 : 1
mixture of regioisomers favouring the ‘‘anti-Markovnikov’’
hydrazone was obtained in i-PrOH at 113 uC. Optimization of
this lead result was performed with MeNHNH2 and led to both
increased conversions and regioselectivities, as shown in Table 1.
Initial screening of reaction conditions using phenylacetylene
(1a) as substrate showed encouraging reactivity in various solvents
(Table 1, entries 1–3), with protic solvents such as i-PrOH
providing optimal conversion and regiocontrol for the formation
of linear hydrazone 3a. In general, the reaction is more efficient at
high concentrations (1 M) and the use of distilled MeNHNH2
under an inert atmosphere is beneficial. Due to its reduced
reactivity compared to 1a, optimization was continued using para-
tolylacetylene (1b, entries 6–10). Gratifyingly, upon heating at
140 uC in i-PrOH for 18 h, good conversion and regioselectivity for
the linear hydrazone 3b was obtained (entry 9). With optimized
conditions in hand, the substrate scope with respect to the alkyne
could be evaluated. The results are presented in Table 2, which also
features the derivatization of the linear hydrazone regioisomer to
allow isolation by column chromatography.
Metal-free, intermolecular hydroaminations are performed
upon heating aryl acetylenes and MeNHNH2 at 140 uC, with
preferential formation of the linear, ‘‘anti-Markovnikov’’
hydrazones.
The addition of N–H bonds across unactivated alkenes and
alkynes represents an efficient access to nitrogen-containing
molecules.1 Intermolecular hydroamination of alkynes provides a
simple approach to imines and analogues, which are useful
building blocks in organic synthesis. Due to the high activation
energy associated with this reaction, most research efforts have
focused on transition metal catalysis.1,2 Notably, regioselective
formation of aldimines or ketimines from terminal alkynes can be
achieved upon selection of a catalyst possessing the appropriate
steric and electronic tuning.3 Despite the significant progress
accomplished, there is still a need to develop methods that have
different substrate scope and functional group compatibility, as
well as alternate strategies to achieve regiocontrol.
Recently, we reported on a simple, metal-free intermolecular
hydroamination procedure that involves heating aqueous hydro-
xylamine and alkynes (or alkenes).4 With aliphatic and aromatic
terminal alkynes, the addition is efficient and favours the
formation of the ketoxime product with good selectivities
(eqn (1)). Reasoning that the reaction occurs through a concerted,
Cope-type, transition state (TS),5 we speculated that the use of
substituted hydroxylamines or hydrazines could destabilize this TS
and lead to a change in regioselectivity. Herein, we report that
hydrazines undergo a similar intermolecular hydroamination
process and that the use of a substituted hydrazine, MeNHNH2,
favours the formation of ‘‘anti-Markovnikov’’ hydrazones
(eqn (2)).6
As shown above, hydroamination of aromatic acetylenes using
MeNHNH2 proceeds in good conversions and good to excellent
regioselectivity for the linear hydrazone products (3a–j).
Substitution on the arene ring is generally well tolerated (entries
2–6 and 8), with the exception of 4-methoxyphenylacetylene which
shows only modest reactivity (entry 7). In addition, heterocyclic
acetylenes also react efficiently under these reaction conditions
(entries 9 and 10).7 In all cases, the semicarbazone derivative of the
Table 1 Optimization of the hydroamination using MeNHNH2
ð1Þ
ð2Þ
Entry
R
Solvent
T/uC
Conversion (%) (3 : 2)a,b
1
2
3
4
5
6
7
8
H
H
H
H
Dioxane
DMSO-d6
i-PrOH
i-PrOH
PhMe
i-PrOH
Dioxane
DMSO-d6
i-PrOH
i-PrOH
113
113
113
140
140
113
140
140
140
140
22 (10 : 1)
41 (5 : 1)
87 (17 : 1)
88 (14 : 1)
26 (9 : 1)
34 (11 : 1)
29 (4 : 1)
53 (6 : 1)
73 (8 : 1)
24 (8 : 1)
Initial trials to extend the reactivity described in eqn (1)
to hydrazines were performed using aqueous hydrazine and
H
Me
Me
Me
Me
Me
Centre for Catalysis Research and Innovation, Department of
Chemistry, University of Ottawa, 10 Marie-Curie, Ottawa, ON, Canada
K1N 6N5. E-mail: andre.beauchemin@uottawa.ca;
Fax: +1 613-562-5170; Tel: +1 613-562-5800, ext. 2245
{ Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic characterization for all new products and
computational details. See DOI: 10.1039/b715022a
9
10c
a
Conversions were determined by 1H NMR of the unpurified
reaction mixture using styrene as an internal standard.
b
c
Regioselectivity was determined by 1H NMR.
MeNHNH2 were used.
2 equiv. of
{ To whom inquiries about DFT calculations should be addressed.
492 | Chem. Commun., 2008, 492–493
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hydrazones in good yields and regioselectivities. Extension of the
reactivity of hydrazines toward alkenes is underway and will be
reported in due course.
Table 2 Determination of substrate scope with different alkynes
We thank the University of Ottawa (start-up & CCRI), the
Canadian Foundation for Innovation, the Ontario Ministry of
Research and Innovation and NSERC (discovery and CRD
grants) for their support. We also acknowledge the Canadian
Society for Chemistry, AstraZeneca Canada, Boehringer
Ingelheim (Canada) Ltd. and Merck Frosst Canada for indirect
support of this work through an Enantioselective Synthesis Grant
directed at analogous alkene reactivity. We thank our colleague
Prof. Tom Woo for providing access to his computer cluster for
DFT calculations.
Conversion Regioselectivity Yield
(%) (2 + 3)a (3 : 2)b
Entry
R
(4)c (%)
1
2
3
4
5
6
7
8
9
C6H5
87
76
77
73
72
66
30
14 : 1
5 : 1
15 : 1
8 : 1
9 : 1
32 : 1
5 : 1
10 : 1
25 : 1
58
50
49
37
44
40
—
31
55
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-FC6H4
2-MeOC6H4
4-MeOC6H4
Notes and references
3,5-(CF3)2C6H3 77
76
1 For selected reviews, see: (a) R. Severin and S. Doye, Chem. Soc. Rev.,
2007, 32, 1407–1420; (b) S. Matsunaga, J. Synth. Org. Chem., Jpn., 2006,
64, 778–779; (c) K. C. Hultzsch, Adv. Synth. Catal., 2005, 347, 367–391;
(d) F. Alonso, I. P. Beletskaya and M. Yus, Chem. Rev., 2004, 104,
3079–3159; (e) P. W. Roesky and T. E. Mu¨ller, Angew. Chem., Int. Ed.,
2003, 42, 2708–2710; (f) F. Pohlki and S. Doye, Chem. Soc. Rev., 2003,
32, 104–114; (g) M. Nobis and B. Drießen-Ho¨lscher, Angew. Chem., Int.
Ed., 2001, 40, 3983–3985; (h) J.-J. Brunet and D. Neibecker, in Catalytic
Heterofunctionalization, ed. A. Togni and H. Gru¨tzmacher, Wiley-VCH,
Weinheim, 2001, pp. 91–141; (i) T. E. Mu¨ller and M. Beller, Chem. Rev.,
1998, 98, 675–703.
2 For selected alternatives, see: (a) Review article on base-catalyzed
hydroaminations: J. Seayad, A. Tillack, C. G. Hartung and M. Beller,
Adv. Synth. Catal., 2002, 344, 795–813; (b) Intramolecular, acid-
catalyzed additions: J. Cossy, D. Belotti, V. Bellosta and C. Boggio,
Tetrahedron Lett., 1997, 38, 2677–2680.
10
81
6 : 1
45
Determined by 1H NMR of the unpurified reaction mixture using
a
b
styrene as an internal standard. Ratio determined by 1H NMR.
Isolated yield after column chromatography.
c
3 For a recent review on the issue of regiocontrol in metal-catalyzed
reactions of alkenes and alkynes, see: M. Beller, J. Seayad, A. Tillack
and H. Jiao, Angew. Chem., Int. Ed., 2004, 43, 3368–3398.
4 A. M. Beauchemin, J. Moran, M.-E. Lebrun, C. Se´guin, E. Dimitrijevic,
L. Zhang and S. I. Gorelsky, Angew. Chem., Int. Ed., 2007, DOI:
10.1002/anie.200703495.
5 (a) For an excellent review on Cope-type hydroaminations, also referred
to as ‘‘reverse Cope cyclisations’’ due to the intramolecular nature of
previous examples, see: N. J. Cooper and D. W. Knight, Tetrahedron,
2004, 60, 243–269; (b) For precedence of intermolecular hydroamina-
tions using MeNHOH, see: A. Padwa and G. S. K. Wong, J. Org.
Chem., 1986, 51, 3125–3133.
6 For metal-catalyzed reactions of alkynes and hydrazines, see: (a)
J. Barluenga, F. Aznar, R. Liz and M. Bayod, J. Chem. Soc., Chem.
Commun., 1988, 121–122; (b) C. Cao, Y. Shi and A. L. Odom, Org.
Lett., 2002, 4, 2853–2856; (c) Y. Li, Y. Shi and A. L. Odom, J. Am.
Chem. Soc., 2004, 126, 1794–1803; For a review article on the reactivity
of hydrazines and alkynes, see: (d) W. Sucrow, Org. Prep. Proced. Int.,
1982, 14, 91–155.
7 To date, trials with aliphatic (1-octyne), vinylic (1-ethynylcyclohexene)
and internal (diphenylacetylene) alkynes have only showed minimal
reactivity under similar reaction conditions.
8 Calculated free energies of TS in gas-phase at 298 K and 1 atm, relative
to the free reactants, B3LYP/TZVP level of theory. See ESI{ for a
discussion regarding solvent effects and computational details.
9 For related examples of aza-Cope eliminations likely occurring through
a similar transition state, see: (a) D. G. Morris, B. W. Smith and
R. J. Wood, Chem. Commun. (London), 1968, 1134–1135; (b) H. Posvic
and D. Rogers, J. Org. Chem., 1974, 39, 1588–1589.
Fig. 1 Calculated activation energies associated with the four possible
hydroamination TS.8
major regioisomer (4a–j) could be isolated after derivatization, in
modest to acceptable yield (over two steps).
DFT calculations8 were also performed to gain insight regarding
a possible concerted mechanism9,10 related to the Cope-type
hydroamination reactivity of hydroxylamines.4,5 In Fig. 1, the
activation free energies (DG{) associated with the four possible
concerted, five-membered, planar transition states (TS) are shown.
As MeNHNH2 is unsymmetrical, both nitrogen atoms can be
involved in the C–N bond-forming event, which can occur also on
both carbons of the alkyne. Using phenylacetylene as substrate,
the TS minimizing steric interactions between the alkyne and
hydrazine substituents, leading to the subsequent formation of the
linear hydrazone 3a, is favored by ca. 1.4 kcal mol21. These
calculations are thus in good agreement with the observed
regioselectivity (14 : 1).
10 Control experiments performed with 1a, MeNHNH2 (5 equiv.) in
i-PrOH (1 M) at 140 uC in the presence of AcOH (1 equiv.) or i-Pr2NEt
led to only slight decreases in total conversions (33 and 35%,
respectively), suggesting alternative acid- or base-catalyzed mechanisms
are not operating under the reaction conditions.
In summary, we have developed a metal-free procedure for the
intermolecular hydroamination of arylacetylenes using methyl
hydrazine, which forms the ‘‘anti-Markovnikov’’, linear
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Chem. Commun., 2008, 492–493 | 493