Intermolecular Cope-type hydroamination of alkenes and alkynes using hydroxylamines

Article abstract of DOI:10.1021/ja806300r

The development of the Cope-type hydroamination as a method for the metal- and acid-free intermolecular hydroamination of hydroxylamines with alkenes and alkynes is described. Aqueous hydroxylamine reacts efficiently with alkynes in a Markovnikov fashion to give oximes and with strained alkenes to give N-alkylhydroxylamines, while unstrained alkenes are more challenging. N-Alkylhydroxy-lamines also display similar reactivity with strained alkenes and give modest to good yields with vinylarenes. Electron-rich vinylarenes lead to branched products while electron-deficient vinylarenes give linear products. A beneficial additive effect is observed with sodium cyanoborohydride, the extent of which is dependent on the structure of the hydroxylamine. The reaction conditions are found to be compatible with common protecting groups, free OH and NH bonds, as well as bromoarenes. Both experimental and theoretical results suggest the proton transfer step of the N-oxide intermediate is of vital importance in the intermolecular reactions of alkenes. Details are disclosed concerning optimization, reaction scope, limitations, and theoretical analysis by DFT, which includes a detailed molecular orbital description for the concerted hydroamination process and an exhaustive set of calculated potential energy surfaces for the reactions of various alkenes, alkynes, and hydroxylamines.

Full text of DOI:10.1021/ja806300r

Published on Web 11/24/2008
Intermolecular Cope-Type Hydroamination of Alkenes and
Alkynes using Hydroxylamines
Joseph Moran, Serge I. Gorelsky, Elena Dimitrijevic, Marie-Eve Lebrun,
Anne-Catherine Be´dard, Catherine Se´guin, and Andre´ M. Beauchemin*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa,
10 Marie-Curie, Ottawa, ON, Canada K1N 6N5
Received August 8, 2008; E-mail: andre.beauchemin@uottawa.ca
Abstract: The development of the Cope-type hydroamination as a method for the metal- and acid-free
intermolecular hydroamination of hydroxylamines with alkenes and alkynes is described. Aqueous
hydroxylamine reacts efficiently with alkynes in a Markovnikov fashion to give oximes and with strained
alkenes to give N-alkylhydroxylamines, while unstrained alkenes are more challenging. N-Alkylhydroxy-
lamines also display similar reactivity with strained alkenes and give modest to good yields with vinylarenes.
Electron-rich vinylarenes lead to branched products while electron-deficient vinylarenes give linear products.
A beneficial additive effect is observed with sodium cyanoborohydride, the extent of which is dependent
on the structure of the hydroxylamine. The reaction conditions are found to be compatible with common
protecting groups, free OH and NH bonds, as well as bromoarenes. Both experimental and theoretical
results suggest the proton transfer step of the N-oxide intermediate is of vital importance in the intermolecular
reactions of alkenes. Details are disclosed concerning optimization, reaction scope, limitations, and
theoretical analysis by DFT, which includes a detailed molecular orbital description for the concerted
hydroamination process and an exhaustive set of calculated potential energy surfaces for the reactions of
various alkenes, alkynes, and hydroxylamines.
1. Introduction
decreased basicity allows for alkene protonation. Strong base
catalysis is also possible but does not allow for any functional
groups more acidic than an amine and requires electronically
biased alkenes.10 As a result of these limitations, significant
Given the ubiquitous nature of nitrogen-containing molecules
and the ready availability of inexpensive olefins, it is not
surprising that the hydroamination of alkenes and alkynes has
become the subject of intense research. Although in recent years
the hydroamination of alkynes has been achieved with fairly
(2) For reviews on the catalytic hydroamination of alkynes, see: (a) Mu¨ller,
T. E.; Hultzsch, K.; Yus, M.; Foubelo, F.; Tada, M. Chem. ReV. 2008,
108, 3795. (b) Severin, R.; Doye, S. Chem. Soc. ReV. 2007, 36, 1407.
(c) Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2006, 45,
2176. (d) Odom, A. L. Dalton Trans. 2005, 225. (e) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079. (f) Beller,
M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43,
3368. (g) Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104. (h)
Molander, G. A.; Romero, J. A. C. Chem. ReV. 2002, 102, 2161. (i)
Beller, M.; Breindl, C.; Eichberger, M.; Hartung, C. G.; Seayad, J.;
Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett 2002, 1579. (j) Brunet,
J.-J.; Neibecker, D. In Catalytic Heterofunctionalization; Togni, A.;
Gru¨tzmacher, H., Eds.; Wiley-VCH: Weinheim, 2001; pp 91-141.
(k) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675.
general scope via several different catalytic approaches,1,2
a
correspondingly general intermolecular reactivity of alkenes has
been much more elusive.3
Intermolecular acid-catalyzed additions of arylamines to
alkenes were first reported by Hickinbottom in 1932, requiring
high temperatures (250-300 °C) and giving very low yields.4
Other strong Brønsted acids have since been found to catalyze
the transformation, though the required harsh conditions inher-
ently preclude broad functional group tolerance and require
electronically deactivated amines (e.g., nitriles,5 anilines,6
azoles,7 hydrazines,8 sulfonamides,9 and amides9c) whose
(3) For general reviews on alkene hydroamination, see refs 2a and 2j.
Even in intramolecular cases, reactivity is only general for 5-membered
cyclizations, and is diminished by alkene substitution. For selected
recent examples of intramolecular catalytic hydroamination of alkenes,
see: (a) Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570.
(b) Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2008, 2741.
(c) Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Chem. Commun.
2008, 1422. (d) Zhang, W.; Werness, J. B.; Tang, W. Org. Lett. 2008,
10, 2023. (e) Bauer, E. B.; Andavan, G. T. S.; Hollis, T. K.; Rubio,
R. J.; Cho, J.; Kuchenbeiser, G. R.; Helgert, T. R.; Letko, C. S.; Tham,
F. S. Org. Lett. 2008, 10, 1175. (f) Dochnahl, M.; Lo¨hnwitz, K.;
Pissarek, J.-W.; Roesky, P. W.; Blechert, S. Dalton Trans. 2008, 2844.
(g) Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc.
2007, 129, 14148. (h) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc.
2007, 129, 4253. (i) LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste,
F. D. J. Am. Chem. Soc. 2007, 129, 2452. (j) Wood, M. C.; Leitch,
D. C.; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem., Int.
Ed. 2007, 46, 354.
(1) For recent examples of catalytic hydroamination of alkynes, see: (a)
Lavallo, V.; Frey, G. D.; Donnadieu, B.; Soleilhavoup, M.; Bertrand,
G. Angew. Chem., Int. Ed. 2008, 47, 5224. (b) Liu, X.-Y.; Ding, P.;
Huang, J.-S.; Che, C.-M. Org. Lett. 2007, 9, 2645. (c) Zhang, Y.;
Donahue, J. P.; Li, C.-J. Org. Lett. 2007, 9, 627. (d) Lingaiah, N.;
Babu, N. S.; Reddy, K. M.; Prasad, P. S. S.; Suryanarayana, I. Chem.
Commun. 2007, 278. (e) Lai, R.-Y.; Surekha, K.; Hayashi, A.; Ozawa,
F.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Organometallics 2007, 26, 1062.
(f) Buil, M. L.; Esteruelas, M. A.; Lo´pez, A. M.; Mateo, A. C.; On˜ate,
E. Organometallics 2007, 26, 554. (g) Kang, J.-E.; Kim, H.-B.; Lee,
J.-W.; Shin, S. Org. Lett. 2006, 8, 3537. (h) Sun, J.; Kozmin, S. A.
Angew. Chem., Int. Ed. 2006, 45, 4991. (i) Kadzimirsz, D.; Hilde-
brandt, D.; Merz, K.; Dyker, G. Chem. Commun. 2006, 661. (j) Zulys,
A.; Dochnahl, M.; Hollmann, D.; Lo¨hnwitz, K.; Herrmann, J.-S.;
Roesky, P. W.; Blechert, S. Angew. Chem., Int. Ed. 2005, 44, 7794.
9
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2008 American Chemical Society
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A R T I C L E S
Moran et al.
effort has been invested into the development of organometallic
hydroamination catalysts. Lanthanide and early metal-based
catalysts have been successful particularly in intramolecular
cases, but suffer from high sensitivity to air or moisture, as well
as low functional group compatibility.11 Recently, superb work
featuring the use of late transition metals has in some cases
exhibited higher tolerance of polar functional groups,12 and
highlighted the thermodynamic limitations of intermolecular
hydroaminations.13 Alternatively, methods based on electrophilic
nitrogen sources14 or free radicals15 offer complementary
reactivity. Asymmetric approaches stemming from several of
these activation modes have been developed, but intermolecular
examples are rare.3i,j,16 Despite this encouraging progress,
hydroamination of alkenes stands out as one of the simplest
and most desirable synthetic transformations for which no
general solution exists and remains a largely unused tool in the
synthesis of complex organic molecules.17
alkenylhydroxylamines simply upon standing at room temper-
ature via a proposed free radical mechanism (eq 1).
18
Seminal studies by Ciganek revealed the scope and limitations
of this hydroamination reaction, however several observations,
as well as those of Black and Doyle, seemed to be more
consistent with a concerted mechanism.19 Finally in 1994,
Oppolzer and co-workers provided compelling stereochemical
evidence for such a mechanism, which proceeds through a
suprafacial five-membered transition state (eqs 1 and 3).20 These
reports revived interest in this reactivity and subsequent
contributions from Holmes, Knight, Ja¨ger and others expanded
the scope to include alkynes,21 investigated its use in saturated
heterocycle synthesis22 and introduced creative ways to access
the cyclization precursors from nitrones.23
A conceptually different approach to hydroamination presents
itself in the form of the microscopic reverse of the Cope
elimination. The reverse Cope cyclization was first reported by
House and co-workers in 1976 to form pyrrolidines from
(4) (a) Hickinbottom, W. J. J. Chem. Soc. 1932, 2646. (b) Hickinbottom,
W. J. J. Chem. Soc. 1934, 319. (c) Hickinbottom, W. J. J. Chem. Soc.
1934, 1981.
(5) (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045. For
a review of the Ritter reaction, see: (b) Krimen, L. I.; Cota, D. J. Org.
React. 1969, 17, 213.
(6) (a) Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc.
2005, 127, 14542. (b) Lapis, A. A. M.; DaSilveira Neto, B. A.;
Scholten, J. D.; Nachtigall, F. M.; Eberlin, M. N.; Dupont, J.
Tetrahedron Lett. 2006, 47, 6775.
(7) (a) Katritzky, A. R.; Puschmann, I. B.; Stevens, C. V.; Wells, A. P.
J. Chem. Soc., Perkin Trans. 2 1995, 1645. (b) Katritzky, A. R.; Qi,
M.; Wells, A. P. Geterotsikl. Soedin. 1996, 1520. (c) Ostrovskii, V. A.;
Koren, A. O. Heterocycles 2000, 53, 1421, and references cited
therein. (d) Gaponik, P. N.; Voitekhovich, S. V.; Klyaus, B. G. Zh.
Org. Khim. 2004, 40, 624. (e) Moran, J.; Cebrowski, P.; Beauchemin,
A. M. J. Org. Chem. 2008, 73, 1004.
(8) (a) Kelly, M. J. Preparation of alkylhydrazines. U.S. Patent 4,954,655,
September 4, 1990. (b) Eichinger, W.; Fiege, H. Process for the
preparation of alkylhydrazine salts. U.S. Patent 5,585,521, December
17, 1996.
(9) (a) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C.
Org. Lett. 2006, 8, 4175. (b) Rosenfeld, D. C.; Shekhar, S.; Takemiya,
A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179. (c)
Motokura, K.; Nakagiri, N.; Mori, K.; Mizugaki, T.; Ebitani, K.;
Jitsukawa, K.; Kaneda, K. Org. Lett. 2006, 8, 4617.
(10) For selected examples of intermolecular strong base-catalyzed hy-
droamination, see: (a) Horrillo-Martinez, P.; Hultsch, K. C.; Gil, A.;
Branchadell, V. Eur. J. Org. Chem. 2007, 3311. (b) Pez, G. P.; Galle,
J. E. Pure Appl. Chem. 1985, 57, 1917. (c) Lehmkuhl, H.; Reinehr,
D. J. Organomet. Chem. 1973, 55, 215. (d) Takabe, K.; Katagiri, T.;
Tanaka, J. Bull. Chem. Soc. Jpn. 1973, 46, 222.
In stark contrast, although Niu and Zhao reported that
N-methylhydroxylamine undergoes a stereospecific 1,4-addition
to R,ꢀ-unsaturated esters via a concerted mechanism (eq 4),
synthetically useful intermolecular variants that do not involve
a biased electrophilic olefin have yet to appear in the literature.24
A report by Laughlin in 1973 hinted that intermolecular Cope-
type hydroamination might have occurred, although the reaction
pathway was obscured by subsequent complex side reactions
(Scheme 1).25 The formation of amines may be rationalized by
an intermolecular Cope-type hydroamination reaction to give
(16) For selected reviews on intramolecular asymmetric hydroamination,
see: (a) Aillaud, I.; Collin, J.; Hannedouche, J.; Schulz, E. Dalton
Trans. 2007, 5105. (b) Hultzsch, K. C. AdV. Synth. Catal. 2005, 347,
367. (c) Hultzsch, K. C.; Gribkov, D. V.; Hampel, F. J. Organomet.
Chem. 2005, 690, 4441. (d) Hultzsch, K. C. Org. Biomol. Chem. 2005,
3, 1819. For a review of intermolecular asymmetric hydroamination,
see: (e) Roesky, P. W.; Mu¨ller, T. E. Angew. Chem., Int. Ed. 2003,
42, 2708.
(11) For selected examples of intermolecular lanthanide-catalyzed hy-
droamination, see: (a) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004,
37, 673. (b) Rastatter, M.; Zulys, A.; Roesky, P. W. Chem.-Eur. J.
2007, 13, 3606. (c) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem.
Soc. 2003, 125, 12584. (d) Li, Y.; Marks, T. J. Organometallics 1996,
15, 3770.
(17) For selected examples of alkene hydroamination in total synthesis,
see: (a) Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2003, 125, 8744.
(b) Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc. 2003,
125, 15878. (c) Molander, G. A.; Dowdy, E. D.; Pack, S. K. J. Org.
Chem. 2001, 66, 4344.
(12) For selected examples of intermolecular late transition metal-catalyzed
hydroamination, see: (a) Johns, A. M.; Utsunomiya, M.; Incarrito,
C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 1828. (b) Zhang,
J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798. (c)
Brouwer, C.; He, C. Angew. Chem., Int. Ed. 2006, 45, 1744. (d)
Nishina, N.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3314.
(13) Johns, A. M.; Sakai, N.; Ridder, A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 9306.
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O. R.; Wilkes, B. E. J. Org. Chem. 1976, 41, 855. (b) House, H. O.;
Lee, L. F. J. Org. Chem. 1976, 41, 863.
(19) (a) Black, D.; St, C.; Doyle, J. E. Aust. J. Chem. 1978, 31, 2317. (b)
Ciganek, E. J. Org. Chem. 1990, 55, 3007. (c) Ciganek, E., Jr.;
Calabrese, J. C. J. Org. Chem. 1995, 60, 5795. (d) Ciganek, E. J.
Org. Chem. 1995, 60, 5803.
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Waser, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 4099.
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47, 779. (b) Guin, J.; Mu¨ck-Lichtenfeld, C.; Grimme, S.; Studer, A.
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1994, 116, 3139. See also: (b) Oppolzer, W. Gazz. Chim. Ital. 1995,
125, 207.
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Intermolecular Cope-Type Hydroamination of Alkenes and Alkynes
A R T I C L E S
Scheme 1. Laughlin’s Report of Amination Reactivity between Alkenes and N,N-Dimethylhydroxylamine
regioisomeric amine N-oxides, followed by reduction with
another molecule of N,N-dimethylhydroxylamine to give a
nitrone and amines 2a-c. The resulting nitrone could then
undergo subsequent [3 + 2] cycloaddition reactions to give the
observed isoxazolidines 3a and 3b.
1), giving near quantitative conversion to the desired oxime (see
Table A of Supporting Information for more details).
Padwa and Wong reported three examples in which an aryl
acetylene (e.g., 4) reacts with an N-alkylhydroxylamine to form
a nitrone intermediate which is then efficiently trapped by a [3
+ 2] cycloaddition (eq 2).26 However, the reaction could not
be extended to simpler substrates lacking a pendant dipolarophile
such as phenyl acetylene, for example.
The scope of alkyne substrates is shown in Table 1. In
general, terminal aryl alkynes react well under these reaction
conditions, with both steric and electronic variations on the arene
ring being well tolerated (entries 1-7). Enynes and alkylacety-
lenes are also reactive, requiring higher temperatures to achieve
good yields (entries 8-10). Notably, the reaction is compatible
with alkynes bearing a basic pyridine group, free hydroxyl
groups,29 and common protecting groups (entries 7, 11-15,
17-19). However, a tetrahydropyran-protected substrate led to
In light of the excellent progress in intramolecular systems
over the past three decades,27 we set out to develop efficient
intermolecular Cope-type hydroaminations where the reactivity
of the products is controlled. Indeed, we recently reported the
successful addition of aqueous hydroxylamine and N-cyclo-
hexylhydroxylamine to both alkynes and strained alkenes.28
Herein, we provide a full account of our work, including reaction
optimization, improved conditions, functional group compat-
ibility studies and expanded scope with respect to both the
hydroxylamine and unsaturated reaction partners. In addition,
experimental and theoretical (DFT) insights into the reaction
mechanism are described.
(21) (a) Pradhan, S. K.; Akamanchi, K. G.; Divakaran, P. P.; Pradhan, P. M.
Heterocycles 1989, 28, 813. (b) Holmes, A. B.; Smith, A. L.; Williams,
S. F.; Hughes, L. R.; Lidert, Z.; Swithenbank, C. J. Org. Chem. 1991,
56, 1393. (c) Fox, M. E.; Holmes, A. B.; Forbes, I. T.; Thompson, M.
Tetrahedron Lett. 1992, 33, 7421. (d) Fox, M. E.; Holmes, A. B.;
Forbes, I. T.; Thompson, M.; Ziller, J. W. Tetrahedron Lett. 1992,
33, 7425. (e) Fox, M. E.; Holmes, A. B.; Forbes, I. T.; Thompson, M.
J. Chem. Soc., Perkin Trans. 1 1994, 3379. (f) Davison, E. C.; Holmes,
A. B.; Forbes, I. T. Tetrahedron Lett. 1995, 36, 9047. (g) Williams,
G. M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B.; Adams, J. P.
J. Am. Chem. Soc. 1999, 121, 4900. (h) Smith, C. J.; Holmes, A. B.;
Press, N. J. Chem. Commun. 2002, 1214.
(22) (a) Bagley, M. C.; Tovey, J. Tetrahedron Lett. 2001, 42, 351. (b)
Knight, D. W.; Leese, M. P.; De Kimpe, N. Tetrahedron Lett. 2001,
42, 2597. (c) Knight, D. W.; Leese, M. P. Tetrahedron Lett. 2001,
42, 2593. (d) Yamada, F.; Hasewaga, T.; Wakita, M.; Sugiyama, M.;
Somei, M. Heterocycles 1986, 24, 1223. (e) Takano, I.; Yasuda, I.;
Nishijima, M.; Hitotsuyanagi, Y.; Takeya, K.; Itokawa, H. J. Org.
Chem. 1997, 62, 8251. (f) Coogan, M. P.; Knight, D. W. Tetrahedron
Lett. 1996, 37, 6417.
2. Results and Discussion
2.1. Intermolecular Cope-Type Hydroamination of Alkynes
with Aqueous Hydroxylamine. In an attempt to avoid the side
products associated with oxidation of N,N-dialkylhydroxy-
lamines observed by Laughlin, we began our investigation with
the reaction of phenylacetylene with hydroxylamine itself, as a
cheap commercially available 50 wt% aqueous solution. We
reasoned that the weaker π bond of an alkyne, combined with
the stability of the oxime products would allow for the greatest
chance of achieving the desired reactivity. Gratifyingly, en-
couraging conversions to acetophenone oxime were observed
upon heating phenylacetylene and hydroxylamine in a sealed
tube in a variety of organic solvents (dioxane, i-PrOH, DMSO,
etc.). Further optimization using dioxane as solvent revealed
that the reaction is most efficient at higher concentrations (eq
(23) For access to reverse Cope cyclization precursors via nucleophilic
additions to nitrones, see: (a) Takahashi, S.; Kusumi, T.; Sato, Y.;
Inouye, Y.; Kakisawa, H. Bull. Chem. Soc. Jpn. 1981, 54, 1777. (b)
Gravestock, M. B.; Knight, D. W.; Malik, K. M. A.; Thornton, S. R.
J. Chem. Soc., Perkin Trans. 1 2000, 3292. (c) Gravestock, M. B.;
Knight, D. W.; Thornton, S. R. J. Chem. Soc., Chem. Commun. 1993,
169. (d) Bell, K. E.; Coogan, M. P.; Gravestock, M. B.; Knight, D. W.;
Thornton, S. R. Tetrahedron Lett. 1997, 38, 8545. (e) Coogan, M. P.;
Gravestock, M. B.; Knight, D. W.; Thornton, S. R. Tetrahedron Lett.
1997, 38, 8549. (f) Wheildon, A. R.; Knight, D. W.; Leese, M. P.
Tetrahedron Lett. 1997, 38, 8553. (g) Hanrahan, J. R.; Knight, D. W.;
Salter, R. Synlett 2001, 1587. (h) Palmer, A. M.; Ja¨ger, V. Eur. J.
Org. Chem. 2001, 1293, 2547. (i) Ja¨ger, V.; Bierer, L.; Dong, H.-R.;
Palmer, A. M.; Shaw, D.; Frey, W. J. Heterocycl. Chem. 2000, 37,
455. (j) Hanrahan, J. R.; Knight, D. W. Chem. Commun. 1998, 2231.
9
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A R T I C L E S
Moran et al.
Table 1. Reaction of Alkynes with Aqueous NH2OH
a Reaction conditions: A: alkyne (1 equiv), aq. NH2OH (2.5 equiv), dioxane (1 M), sealed tube (behind a blast shield), 113 °C, 16-18 h; B: reflux
condenser, 1-butanol (1 M), 16 h; C: 140 °C, dioxane (2 M), 38-40 h; D: i-PrOH (1 M), 140 °C (microwave), 5-10 h; E: 110 °C, i-PrOH (2 M), 70 h,
sealed tube. b Yield of isolated products. Yield of minor regioisomer shown in parentheses. c 2 M in dioxane. d Led to isolation of unprotected oxime in
65% yield.
the isolation of the deprotected product in 65% yield (entry 16).
In general, heating to 140 °C in i-PrOH under microwave
irradiation was found to give improved yields for less reactive
terminal (entries 8-19) and internal alkynes (entries 20-22).
In most cases, the unreacted starting material could be recovered
and the products were conveniently isolated by chromatography
or recrystallization. The transformation has been carried out
easily on scales of over 4 g, and can also be performed without
the use of a sealed tube under typical reflux conditions by
employing a higher boiling solvent such as 1-butanol (entry 1,
condition B).
(24) (a) Niu, D.; Zhao, K. J. Am. Chem. Soc. 1999, 121, 2456. See also: (b)
All control experiments performed appear consistent with a
Cope-type hydroamination pathway. For example, to address
the possibility of hydration of the alkyne to the ketone and
subsequent oxime formation as a mechanistic pathway, pheny-
lacetylene, 1-octyne and 1,1-diphenylpropargyl alcohol were
heated to 140 °C in aqueous i-PrOH under microwave irradiation
and no ketone products were detected in all cases.2b,30 Control
´
´
Moglioni, A. G.; Muray, E.; Castillo, J. A.; Alvarez-Larena, A.;
Moltrasio, G. Y.; Branchadell, V.; Ortun˜o, R. M. J. Org. Chem. 2002,
67, 2402.
(25) Laughlin, R. G. J. Am. Chem. Soc. 1973, 95, 3295.
(26) Padwa, A.; Wong, G. S. K. J. Org. Chem. 1986, 51, 3125.
(27) For an excellent review, see: Cooper, N. J.; Knight, D. W. Tetrahedron
2004, 60, 243.
(28) (a) Beauchemin, A.; Moran, J.; Lebrun, M.; Se´guin, C.; Dimitrijevic,
E.; Zhang, L.; Gorelsky, S. I. Angew. Chem., Int. Ed. 2008, 47, 1410.
For analogous reactivity of hydrazines, see: (b) Cebrowski, P. H.;
Roveda, J.-G.; Moran, J.; Gorelsky, S. I.; Beauchemin, A. M. Chem.
Commun. 2008, 492–493.
(29) For applications of R-hydroxy oximes as ligands in ferromagnetically
coupled complexes see: (a) Pathmalingam, T.; Gorelsky, S. I.; Burchell,
T. J.; Be´dard, A.-C.; Beauchemin, A. M.; Cle´rac, R.; Murugesu, M.
Chem. Commun. 2008, 2782.
(30) For selected reviews on the hydration of alkynes, see: (a) Hintermann,
L.; Labonne, A. Synthesis 2007, 1121. (b) Oestrich, M. In Science of
Synthesis, Vol. 25; Bru¨chner, R., Ed.; Thieme: Stuttgart, 2006; p 199.
(c) Figadie`re, B.; Franck, X. In Science of Synthesis, Vol. 26; Cossy,
J., Ed.; Thieme: Stuttgart, 2004; p 401. (d) Beller, M.; Seayad, J.;
Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368.
9
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Intermolecular Cope-Type Hydroamination of Alkenes and Alkynes
A R T I C L E S
Table 2. Reaction of Aqueous NH2OH with Alkenesa
a Conditions: alkene (1 equiv), aq. NH2OH (x equiv, 5 M in i-PrOH), sealed tube (+ blast shield), 24-48 h. b 12:1 mixture of regioisomers
(branched:linear).
experiments involving heating phenylacetylene in the presence
of either NH2OMe or Me2NOH (in i-PrOH) showed little or no
reactivity (see Supporting Information).
for aromatic alkynes showed almost no reaction. Starting
materials were consumed when DMSO-d6 was employed as
solvent, but despite considerable effort, a complex reaction
mixture containing little desired product was produced. For
alkenes, unlike alkynes, alcoholic solvents proved uniquely
effective to obtain hydroamination products and minimize side
reactions (Table B of the Supporting Information). i-PrOH was
found to be the most effective alcohol for this reaction, most
likely due to its ability to solubilize both aqueous hydroxylamine
and norbornene. Compounds 8a and 9a were formed in 53%
combined conversion (8a:9a ) 9.6:1) simply upon heating to
95 °C in i-PrOH for 14 h. As the reaction appeared to be very
sensitive to changes in the water to i-PrOH ratio, both
concentration and equivalents of aqueous hydroxylamine had
to be studied independently in order to maximize conversion.
At the optimum concentration (5.0 M in i-PrOH), selectivity
for either the mono- or bis-hydroamination product can be
achieved by varying the equivalents of NH2OH. A 10-fold
excess of hydroxylamine gave monohydroamination product 8a
with good selectivity, while a 2-fold excess resulted in a slight
preference for bishydroamination product 9a in 99% combined
yield (eq 2).
2.2. Intermolecular Cope-Type Hydroamination of Alk-
enes with Aqueous Hydroxylamine. Stimulated by the success
with alkynes, investigations were initiated toward the intermo-
lecular Cope-type hydroamination of alkenes. Success in this
venture would allow for the rapid synthesis of N-alkyl- and N,N-
dialkylhydroxylamines, which can be easily reduced to the
parent amines, but also have applications as monoamine oxidase
inhibitors,31 lipid antioxidants,32 and as photographic develop-
ers.33 Initial reactions were performed with norbornene, whose
strain energy renders it significantly more reactive and provides
a thermodynamic driving force, although it was not known if
the produced N-alkylhydroxylamines would survive the reaction
conditions.34,35 After extensive experimentation, the reaction was
found to be very sensitive to solvent and concentration effects.
Surprisingly, initial trials in dioxane under the conditions used
(31) Benington, F.; Morin, R. D.; Clark, L. C., Jr. J. Med. Chem. 1965, 8,
100.
(32) Van Der Veen, J.; Weil, J. T.; Kennedy, T. E.; Olscott, H. S. Lipids
1970, 5, 509.
(33) Green, M.; Adnan, S. A.; Ulrich, H. Aminoalkyl hydroxylamines as
photographic developers. U.S. Patent 3,287,125, November 22, 1966.
(34) For selected examples of norbornene in catalytic hydroamination
reactions, see: refs 6a,9b,12b,15b,c. See also: (a) Taylor, J. G.; Whittall,
N.; Hii, K. K. Org. Lett. 2006, 8, 3561. (b) Karshtedt, D.; Bell, A. T.;
Tilley, T. D. J. Am. Chem. Soc. 2005, 127, 12640. (c) Ackermann,
L.; Kaspar, L. T.; Gschrei, C. J. Org. Lett. 2004, 6, 2515. (d) Anderson,
L. L.; Arnold, J.; Bergman, R. G. Org. Lett. 2004, 6, 2519. (e) Dorta,
R.; Egli, P.; Zurcher, F.; Togni, A. J. Am. Chem. Soc. 1997, 119,
10857.
A variety of strained alkenes displayed excellent reactivity
under these optimized reaction conditions (Table 2). Predictably,
mixtures of mono- and bis-hydroamination products were
observed. While the bis-hydroamination product 9 is typically
favored in the presence of 2 equivalents of NH2OH (entries 1
and 3), the monohydroamination product 8 is favored in the
(35) For an example of an alternate route to exo-norbornylamines, see:
Huang, J.; Bunel, E.; Allgeier, A.; Tedrow, J.; Storz, T.; Preston, J.;
Correll, T.; Manley, D.; Soukup, T.; Jensen, R.; Syed, R.; Moniz, G.;
Larsen, R.; Martinelli, M.; Reider, P. J. Tetrahedron Lett. 2005, 46,
7831.
9
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A R T I C L E S
Moran et al.
Table 3. Reaction of N-Alkylhydroxylamines with Norbornenea
a Conditions: alkene (2 equiv), hydroxylamine (1 equiv), additive: NaCNBH3 (1 equiv), n-PrOH (0.6 M), sealed tube, 110 °C, 18 h. b Conversion
determined by H NMR using 1,4-dimethoxybenzene as an internal standard. c Isolated yield after column chromatography. d No NaCNBH3. e dr ) 1:1.
1
presence of excess NH2OH (entries 2 and 4). More hindered
strained alkenes also led to selective formation of the mono-
hydroamination product 8 (entries 6-7). Given their lack of
strain release energy and a report by Hartwig that hydroami-
nation of vinylarenes are approximately thermoneutral,13 such
substrates were expected to be more challenging. Gratifyingly,
simply heating styrene and other vinylarenes under similar
conditions gave hydroamination products (entries 8-9). Even
the unconjugated 2-allylphenol was found to be reactive, albeit
in very low yield (entry 10). Both the regioselectivity and
preference for forming either the mono- or bis-hydroamination
product were found to be substrate specific, as was the yield.
Nonetheless, these results offered promise that greater alkene
generality was possible.
to 110 °C and employing a 2-fold excess of alkene allowed for
a more efficient reaction even without additive. Finally, com-
bining these improved conditions with the beneficial effects of
NaCNBH3 led to a 91% conversion (83% isolated yield) with
no observable oxime byproduct (eq 3). Expectedly, control
experiments confirmed that the sodium cyanoborohydride was
not simply reducing the oxime back to the hydroxylamine under
the reaction conditions, as acid is typically required to activate
the oxime for such a transformation.37 The additive instead
appears to inhibit the decomposition of both the hydroxylamine
starting materials and the products at the required reaction
temperatures.38
2.3. Cope-Type Hydroamination of Alkenes with N-Alkyl-
hydroxylamines. Besides greatly expanding the synthetic scope
of the reaction, the use of N-alkylhydroxylamines as starting
materials also promises to simplify its outcome by eliminating
the possibility of bis-hydroamination. However, initial attempts
to effect the addition of N-cyclohexylhydroxylamine to nor-
bornene using our previously developed conditions did not prove
fruitful as the major product was found to be the oxidation
byproduct cyclohexanone oxime 12. N-Alkylhydroxylamines are
known to undergo such oxidation chemistry simply upon
dissolution in degassed polar solvents.36 Investigation of other
alcohols revealed n-PrOH as a superior solvent, and the
screening of a large number of additives revealed that sodium
cyanoborohydride partially inhibited this oxidative pathway
(Table C of Supporting Information). Increasing the temperature
With new conditions compatible with N-alkylhydroxylamines
in hand, we investigated the scope of the reaction with respect
to the alkyl substituent on the hydroxylamine. A variety of
N-alkylhydroxylamines successfully perform Cope-type hy-
droamination in good yields when heated to 110 °C with
norbornene in the presence of sodium cyanoborohydride in
n-PrOH (Table 3). Products possessing accessible ꢀ-hydrogens
did not appear to undergo degradation via Cope elimination
(entries 1 and 3-4). Unfortunately, sec-butylhydroxylamine did
not provide any diastereoselectivity in our hands (entry 4).
Hydroxylamines possessing bulky alkyl substituents such as
neopentyl and norbornyl groups performed well under these
conditions (entries 5-6). N-Phenylhydroxylamine underwent
(36) (a) Horiyama, S.; Suwa, K.; Yamaki, M.; Kataoka, H.; Katagi, T.;
Takayama, M.; Takeuchi, T. Chem. Pharm. Bull. 2002, 50, 996. (b)
Beckett, A. H.; Rashid Purkaystha, A.; Morgan, P. H. J. Pharm.
Pharmacol. 1977, 29, 15. (c) Lindeke, B.; Anderson, E. Acta Pharm.
Sueu. 1975, 12, 183. (d) Posner, T. Ann. Chim. 1912, 389, 1. (e)
Fischer, E.; Scheibler, H.; Groh, R. Ber. Dtsch. Chem. Ges. 1910, 43,
2020. (f) Posner, T. Ber. Dtsch. Chem. Ges. 1905, 38, 2316.
(37) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971,
93, 2897.
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Intermolecular Cope-Type Hydroamination of Alkenes and Alkynes
A R T I C L E S
Table 4. Reaction of N-Benzylhydroxylamine with Vinylarenes and Triphenylvinylsilanea
a Conditions: alkene (2 equiv), N-alkylhydroxylamine (1 equiv), n-PrOH (0.6 M), sealed tube, 140 °C, 14-18 h. b Isolated yield after column
chromatography.
hydroamination albeit in low conversions, despite its propensity
to oxidize39 and its predicted nucleophilic deactivation due to
the adjacent phenyl ring (entry 7).40 The extent of the beneficial
effect of sodium cyanoborohydride varies drastically with the
alkyl substitution of the hydroxylamine. For example, the
conversion drops from 91 to 67% if sodium cyanoborohydride
is not employed with N-cyclohexylhydroxylamine (entry 1), but
drops from 99 to 18% if it is not present when N-isopropylhy-
droxylamine undergoes addition (entry 3).
Reinvestigation of alkene scope with N-alkylhydroxylamines
revealed more efficient reactivity with vinylarenes than was
previously observed with aqueous hydroxylamine. A variety of
vinylarenes reacted with N-benzylhydroxylamine in modest to
good yields, consistent with precedent that hydroamination with
such alkenes displays near thermoneutral reaction thermody-
namics (Table 4).13 In most cases, the mass balance was
unreacted starting material and the products could be conve-
niently isolated by column chromatography. Steric variations
near the alkene are well tolerated (entries 6-11), while
electronic variations on the arene ring give slightly better yields
while influencing regioselectivity. The more electron poor arenes
favored the anti-Markovnikov (15) products, offering a simple
route to bioactive phenethylamines.41 Styrene itself and other
relatively less electron poor arenes favored the formation of the
Markovnikov (14) adducts. The complementary nature of this
procedure versus metal-catalyzed methodologies is perhaps best
illustrated by the successful reaction of alkenes possessing an
aniline (entry 8) or aryl bromide moiety (entry 11). Triphenylvi-
nylsilane was also reactive under these conditions, giving
exclusively 15m in 71% yield.
Crossover experiments were designed to test the assertion
that the addition to vinylarenes is indeed under thermodynamic
control. Hydroamination product 14g was heated to 140 °C in
a sealed tube in the presence of one equivalent of N-cyclohexy-
lhydroxylamine (10a) and NaCNBH3. After 16 h, 37% of
crossover product 16 was detected in the unpurified reaction
mixture by 1H NMR spectroscopy (eq 2).42,43 To ensure a direct
comparison, hydroxylamine 16 was synthesized independently
using 4-methoxystyrene and N-cyclohexylhydroxylamine (10a)
under the conditions described in Table 4.42
(38) N-Cyclohexyl-N-hydroxy-exo-bicyclo[2.2.1]heptan-2-amine (11a, 0.10 g,
0.48 mmol) in n-propanol (0.8 mL) was stirred in a sealed tube under
an argon atmosphere while heating to 140 °C in an oil bath for 21
hrs. The tube was cooled to ambient temperature, concentrated under
reduced pressure and taken up in CDCl3. TLC analysis (5% MeOH/
CH2Cl2) and 1H NMR spectra of this solution showed significant
decomposition to compounds believed to be nitrones 11ai and 11aii
(isolated as an inseparable mixture by column chromatography; 5%
MeOH/CH2Cl2). The same experiment, but with the addition of sodium
cyanoborohydride (0.030 g, 0.48 mmol), resulted in nearly quantitative
recovery of starting materials. Only traces of the 1H NMR resonances
thought to correspond to nitrones 11ai and 11aii could be observed
under these conditions.
(39) Becker, A. R.; Sternson, L. A. Proc. Natl. Acad. Sci. U.S.A. 1981,
78, 2003.
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A R T I C L E S
Moran et al.
Scheme 2. Access to Reduced Derivatives of
N-Norbornyl-N-benzylhydroxylamine (11b)
It should be noted that N-benzylhydroxylamine might be
viewed as either an ammonia or a benzylamine equivalent in
the context of the Cope-type hydroamination, as products can
be selectively and efficiently deprotected to give either the
N-alkylamine44 or the N-alkyl-N-benzylamine45 in one step
(Scheme 2).46
3. DFT Calculations and Discussion
Density functional theory (DFT) calculations were performed
to obtain insight on various aspects of this intermolecular
reactivity of alkenes and alkynes. Related calculations on the
Cope elimination have been reported by Komaromi and
Tronchet,47 and Acevedo and Jorgensen,48 but these only
provide information regarding the microscopic reverse of the
intermolecular hydroamination reactivity of alkenes reported
herein (i.e., the Cope elimination). Thus, DFT calculations were
performed in parallel to the experiments detailed previously and
were primarily directed at: (1) mapping the potential energy
surface (PES) of the reactions of alkenes and alkynes, including
activation energies and the evaluation of the thermodynamic
driving force for the reactions (∆Gr), as a specific issue is the
near-thermoneutral nature of some reactions of alkenes; (2) study
the nature of the hydroamination and proton transfer transition
state structures; (3) determination of the impact of alkene and
nitrogen substitution on the reaction rate and product distribu-
tion, which includes the issue of Markovnikov vs anti-
Markovnikov selectivity with specific substrates.
Figure 1. Free energies of reaction species and transition states for
hydroamination of acetylene, C2H2 (black lines) and phenylacetylene, C8H6
(red lines) at the B3LYP/TZVP level of theory.
3.1. Mapping the Potential Energy Surface of the Reactions.
Initial calculations were directed at determining the thermody-
namic profiles for the reactions of alkenes and alkynes with
NH2OH (monohydroamination). The relative energies of reac-
tants, intermediates and products, as well as the energies of the
transition states (TSs) for both the hydroamination and proton
transfer steps (see eqs 10 and 11) were thus first calculated in
the gas phase at the B3LYP/TZVP level of theory (298 K and
1 atm). The potential energy surfaces for reactions of alkynes
(acetylene, C2H2, and phenylacetylene, C8H6) and alkenes
(ethylene, C2H4, and norbornene, C7H10) are shown in Figures
1 and 2, respectively, and calculated free energies are included
in Table 5.
Figure 2. Free energies of reaction species and transition states for
hydroamination of ethylene, C2H4 (black lines) and norbornene, C7H10 (red
lines) at the B3LYP/TZVP level of theory.
30.1 vs 32.0 kcal/mol for PhCCH(M) and C7H10, respectively)
correlate well with the ability of these substrates to undergo
hydroamination at similar temperatures (ca. 100 °C). However,
the calculated energies of: i) the N-oxide intermediates; ii) the
TSs of the proton transfer step; and iii) reaction products are
very different for the reactions of alkynes and alkenes. These
differences likely result from the weaker π bond of alkynes
relative to alkenes (ca. 15 kcal/mol difference), which translates
into increased stability of alkenyl N-oxide intermediates relative
to the alkyl N-oxide intermediates (∆GNO, 2.9 vs 13.9 kcal/mol
for the C2H2 and C2H4 adducts, respectively; 8.7, 13.1 and 18.7
kcal/mol for the PhCCH(M), C7H10 and PhCHCH2 adducts,
respectively). The relative stability of these N-oxide intermedi-
ates is important as it determines the likelihood of the reverse
reaction (the Cope elimination) relative to the subsequent proton
transfer step, which leads to the hydroamination products. This
is important since in the absence of a proton shuttle (Vide infra),
the actiVation energy required to access the TS of the intramo-
lecular proton transfer step (∆GqPT) is high and kinetically
releVant (see section 3.3). While for alkynes the energy barrier
for the proton transfer is close in magnitude to the barrier for
These results reveal both similarities and differences between
the reactivity of alkynes and alkenes. For example, the similar
activation energies calculated for the Cope-type hydroamination
transition states (see Section 3.2) of alkynes and alkenes (∆Gq
,
HA
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Intermolecular Cope-Type Hydroamination of Alkenes and Alkynes
A R T I C L E S
Table 5. Free Energies (kcal/mol) of the Reaction Species for Hydroamination Reactions (NH2OH) with Alkenes and Alkynes (Evaluated at
298 K and 1 atm)a
alkenes
alkynes
Species
CH2CH2
PhCHCH2 AM
PhCHCH2 M
HCCH
PhCCHAM
PhCCHM
RCb
5.1
33.2
13.9
38.3
20.9
-6.4
5.9
38.4
19.5
44.0
26.5d
0.3
5.9
33.4
18.7
44.2
25.7d
-0.5
4.5
28.5
2.9
23.6
7.9
-24.2
-39.2
5.6
33.2
6.9
5.6
30.1
8.7
Hydroamination TS
R-NH2+O-
Intramolecular H+ transfer TS
bimolecular H+ transfer TSc
R-NHOH
28.9
30.1
11.9d
-18.5
-28.2
13.7d
-17.2
-33.4
CdN-OH
c
a Energies are relative to the free reactants. b Reactants complex. Transition state for proton transfer between R-NH2+O- and i-PrOH. d Energy of
the transition state was evaluated using the calculated activation free energy for the proton transfer for the C2H5-NH2O· · ·i-PrOH complex (to form
C2H5-NHOH· · ·i-PrOH) for alkenes and the C2H3-NH2O· · ·i-PrOH complex (to form C2H3-NHOH· · ·i-PrOH) for alkynes (7.0 and 5.0 kcal/mol in
vacuum, respectively and 9.7 and 7.5 kcal/mol in methanol). See ref 49.
the hydroamination step (∆GqHA ) 28.5 vs ∆GqPT ) 23.6 kcal/
mol for C2H2, and ∆Gq ) 30.1 vs ∆Gq ) 30.1 kcal/mol
formation of the hydroamination products is very favorable due
to the relative weakness of the alkyne π bond and due to the
ability of the resulting N-hydroxyenamine intermediates to form
more stable oxime products. For example, formation of the
N-hydroxyenamines is favorable for both C2H2 (-24.2 kcal/
mol) and PhCCH(M) (-17.2 kcal/mol) and the formation of the
related oximes is more favorable (∆Gr ) -39.2 and -33.4 kcal/
mol, respectively). In contrast, the formation of the alkene
hydroamination products is very dependent on the nature of the
alkene. For example, formation of the products is moderately
favored for C2H4 (∆Gr ) -6.6 kcal/mol) and C7H10 (∆Gr )
-7.0 kcal/mol). However, both substrates are biased: ethylene
is less stable than most alkenes since it is unsubstituted and the
reaction of norbornene benefits from partial release of strain
energy. For the more stable vinylarenes, our calculations suggest
that the reaction is thermoneutral (∆Gr ) -0.5 and 0.3 kcal/
mol, respectively, for the Markovnikov and anti-Markovnikov
styrene adducts), in agreement with the moderate yields reported
in Table 4. Furthermore, these results are in agreement with
Hartwig’s observation that the reaction of vinylarenes and
anilines is thermoneutral.13
3.2. Nature of the Cope-Type Hydroamination TS. Pioneer-
ing work by Ciganek19b,c and Oppolzer20a on intramolecular
Cope-type hydroaminations provides strong evidence for a
concerted process, rather than the radical-based mechanism
postulated by House in 1976.18 Notably, the cyclizations
presented in eqs 1 and 3 highlight that at 80 °C alkene ste-
reochemical information is transferred to the products. Based
on this experimental evidence, it appears very likely the
intermolecular reactions documented herein, which are per-
formed at 90-140 °C, are also concerted. Seeking to obtain
more information about the nature of the Cope-type hydroami-
nation, transition state structures were determined for the
hydroamination of several alkenes and alkynes (Figures 3 and
4). In all cases the 5-membered, coplanar transition states
involve a concerted hydroamination process. For the hydroami-
nation of norbornene (C7H10, Figure 3), the high exo selectivity
observed experimentally (Tables 24) was also found to be
consistent with the calculated activation energies for the
hydroamination step (39.1 vs 32.0 kcal/mol for endo and exo
additions, respectively.
HA
PT
for PhCCH (M)), the intramolecular proton transfer step is rate
limiting for reactions of alkenes (∆Gq ) 33.2 vs ∆Gq
)
HA
PT
38.3 kcal/mol for C2H4, and ∆Gq ) 32.0 vs ∆Gq ) 37.7
HA
PT
kcal/mol for C7H10). These results are consistent with the
observed reactivity difference in aprotic solvents: while the
hydroamination of phenylacetylene can be performed in various
solvents (eq 1 and Table A, Supporting Information), the
hydroamination of norbornene could not be performed satisfy-
ingly in aprotic solvents (eq 2 and Table B, Supporting
Information).50 Fortunately, alcoholic solvents appeared uniquely
effective to enable Cope-type hydroamination of alkenes (vide
infra), and also provided improved reactivity with challenging
alkyne substrates (see Table 1, entries 8-22). Finally, the
thermodynamic driving force (∆Gr) for the reactions of alkynes
and alkenes are also markedly different. For alkynes, the
(40) The difficult product isolation in this case was likely due to the
propensity of N-phenyl, N-alkylhydroxylamines to form stable nitroxyl
radicals.
(41) Parker, E. M.; Cubeddon, L. X. J. Pharmacol. Exper. Ther. 1988,
245, 199.
(42) See Supporting Information for details.
(43) For reversibility experiments using a N,N-dialkylhydroxylamine and
NH2OH, see Supporting Information of ref 28a.
(44) ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means, G. E. J.
Org. Chem. 1979, 44, 3442.
(45) Cicchi, S.; Bonanni, M.; Cardona, F.; Revuelta, J.; Goti, A. Org. Lett.
2003, 5, 1773.
(46) For other representative methods for the reduction of N,N-disubstituted
hydroxylamines, see: (a) Murahashi, S.-I.; Imada, Y.; Taniguchi, Y.;
Kodera, Y. Tetrahedron Lett. 1988, 29, 2973. (b) Murahashi, S.-I.;
Shiota, T. Tetrahedron Lett. 1987, 28, 6469. (c) Murahashi, S.-I.; Sun,
J.; Tsuda, T. Tetrahedron Lett. 1993, 34, 2645. (d) Murahashi, S.-I.;
Kodera, Y. Tetrahedron Lett. 1985, 26, 4633. (e) Kodera, Y.;
Watanabe, S.; Imada, Y.; Murahashi, S.-I. Bull. Chem. Soc. Jpn. 1994,
67, 2542. (f) Merino, P.; Anoro, S.; Franco, S.; Gascon, J. M.; Martin,
V.; Merchan, F. L.; Revuelta, J.; Tejero, T.; Tunon, V. Synth. Commun.
2000, 30, 2989. (g) Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29,
1159.
(47) Komaromi, I.; Tronchet, J. M. J. J. Phys. Chem. A 1997, 101, 3554–
3560.
(48) Acevedo, O.; Jorgensen, W. L. J. Am. Chem. Soc. 2006, 128, 6141–
6146.
(49) These activation energies show little variability to the nature of the
proton shuttle. For example, the activation free energy for the proton
transfer for the C2H5-NH2O· · ·HOH and C2H3-NH2O· · ·HOH com-
plexes in vacuum are 7.3 and 5.3 kcal/mol, respectively. The energies
of the other hydroamination reaction species (minima and TSs) were
also evaluated in the presence of H-bound i-PrOH. However, this
produced only a minor energy change for the hydroamination reaction
steps in Figure 1 (except in the proton transfer step).
(50) For example, only low conversions were observed in dioxane and
DMSO-d6 at 95 °C and attempts at higher temperatures were not
successful due to side reactions.
To analyze how the electronic structure of alkenes and alkynes
influence hydroamination, an activation-strain analysis was
performed (eq 12). The energetic cost (distortion energy, Edist
)
associated with distortion of NH2OH and alkenes/alkynes (CC)
from ground state to TS geometries, as well as the energetic
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A R T I C L E S
Moran et al.
Figure 3. Transition state structures for hydroamination of alkenes and alkynes at the B3LYP/TZVP level of theory; M ) Markovnikov product, AM )
anti-Markovnikov product. The internuclear distances (Å) are shown only for relevant chemical bonds.
Figure 4. (Top) The transition states for hydroamination of C2H4 (left) and C2H2 (right) showing the internuclear distances and bond orders (italics) and
NPA charges (blue). (Bottom) Two most important donor-acceptor interactions that contribute to bond formation between NH2OH and C2H4 (left) and C2H2
(right).
gain arising from bringing the fragments together to form the
TS (electronic interaction energy, Eint) were determined (Table
6):
tion between alkenes/alkynes and NH2OH involves only two
donor-acceptor FO interactions: HOMONH2OHfLUMOCC and
HOMOCCfLUMONH2OH (Figure 4). The reactions of pheny-
lacetylene and styrene with NH2OH involves other occupied
and unoccupied FOs of alkenes/alkynes, due to conjugation of
the π and π* orbitals of the double and triple C-C bonds with
the π and π* orbitals of the phenyl ring. The charge transfer Q
from NH2OH to alkenes/alkynes via the HOMONH2OHf
LUMOCC interaction is somewhat greater for alkenes (0.43-0.50
e-) than for alkynes (0.38-0.43 e-, Table 6).
∆E‡)Edist(CC) + Edist(NH2OH) + Eint
(12)
The Eint reflects the strength of electronic interactions between
alkenes/alkynes and NH2OH in the transition state structure. In
order to identify the most important donor-acceptor interac-
tions that contribute toward Eint, the fragment orbital (FO)
analysis has been performed and the charge transfer between
alkenes/alkynes and NH2OH was evaluated from the charge
in fragment orbital populations (Table 6). In all cases except
reactions with phenylacetylene and styrene, the bond forma-
Due to the higher energies of the HOMOs of alkenes relative
to alkynes, the charge transfer from alkenes/alkynes to NH2OH
via the HOMOCC-LUMONH2OH interaction is greater for alkene
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Intermolecular Cope-Type Hydroamination of Alkenes and Alkynes
A R T I C L E S
Table 6. Electronic Energies (kcal/mol), Charge Decomposition Analysis, and Mayer Bond Orders for C-H and C-N Bonds Being Formed
in Hydroamination Transition States
∆Eq
Edist(CC)
Edist(NH2OH)
Eint
QCCfHA
QHAfCC
BC-H
BN-C
Alkynes
C2H2
CH3CCH
18.7
23.6
20.7
12.5
12.7
22.1
20.1
21.5
21.3
21.7
18.8
21.8
22.4
18.7
12.7
18.7
18.6
5.3
8.7
13.6
23.8
-15.5
-16.3
-19.7
-11.7
-17.7
-13.9
-22.4
0.17
0.20
0.21
0.11
0.14
0.16
0.23
0.40
0.39
0.38
0.37
0.43
0.38
0.38
0.30
0.34
0.32
0.17
0.19
0.30
0.35
0.36
0.33
0.31
0.32
0.34
0.36
0.26
AM
M
AM
M
AM
M
CF3CCH
PhCCH
Alkenes
CH2CH2
CH3CHCH2
22.6
26.9
23.1
19.3
22.5
26.4
21.8
13.5
14.8
14.8
18.5
15.5
15.9
12.7
36.3
39.4
36.7
24.8
36.7
34.6
40.9
-27.2
-27.3
-28.4
-24.0
-29.7
-24.0
-31.7
0.30
0.30
0.30
0.24
0.28
0.28
0.30
0.45
0.45
0.43
0.50
0.49
0.44
0.45
0.57
0.61
0.55
0.50
0.55
0.63
0.53
0.38
0.37
0.36
0.46
0.37
0.42
0.36
AM
M
AM
M
AM
M
CF3CHCH2
PhCHCH2
hydroamination TSs (0.24-0.30 e-) than for alkyne hydroami-
nation TSs (0.11-0.23 e-). Since the LUMO of the NH2OH
fragment is the antibonding O-H orbital, σ*OH, the charge
transfer from alkenes/alkynes to NH2OH determines how
concerted the process of the C-H bond formation and the O-H
bond cleavage is. For hydroamination of alkenes, strong charge
transfer from the HOMO (π) of alkenes to the σ*O-H orbital of
NH2OH ensures that the cleavage of the O-H bond and the
formation of the C-H bond are synchronous and the Eint values
are sufficiently negative to compensate for the cost of the O-H
bond elongation (Edist(NH2OH)). For hydroamination of alkynes,
charge transfer from the HOMO (π) of alkynes to σ*O-H is not
strong enough to produce a symmetric TS structure and the Eint
values are less negative than those for the corresponding alkenes.
3.3. Importance of the Proton Transfer Step: the Beneficial
Effects of Protic Solvents. The formation of the Cope-type
hydroamination products must involve proton transfer from the
N-oxide to the hydroxylamine products, and the experimental
results highlight that this step is kinetically relevant. The
calculated transition state energies of the intramolecular proton
transfer process are high, due to its three-membered nature
(Figure 5, A). In accord with the experimental data, the lowest
energy transition state (Figure 5, B) was found for a bimolecular
proton transfer step involving the amine oxide intermediate and
a protic species such as i-PrOH and H2O. Activation free
energies for this proton transfer (∆GqBPT - ∆GNO) for alkynes
(C2H2) and alkenes (C2H4) are ca. 5 and 7 kcal/mol, respectively,
in the gas phase and ca. 8 and 10 kcal/mol, respectively, in
methanol and are relatively independent of the nature of the
proton shuttle (ROH). This pathway involving a bimolecular
proton transfer is favored over an intramolecular alternative by
ca. 15 kcal/mol. Alternatively, an N-oxide dimer such as C
(Figure 5) would collapse to the reaction products.51 However,
the formation of such a dimer is kinetically unlikely and does
not account for the beneficial solvent effect observed with
alcohols (conditions D, Table 2). Optimized transitions state
structures are shown in Figure 6.
Alcoholic solvents are likely also beneficial through increased
stabilization of the N-oxide intermediate in polar solvents. To
evaluate the effect of various solvents on the potential energy
surface of the reaction, DFT calculations were performed for
the hydroamination of C7H10 in C6H6, CHCl3, DMSO and
MeOH (Table 7). Two important trends are observed: (A) The
N-oxide intermediate is best stabilized in polar solvents due to
its polar nature (Table 7), for example the calculated free
energies for the C7H10-derived N-oxide intermediate is 13.1 kcal/
mol in the gas phase and 8.3 kcal/mol in methanol (for C2H4:
13.9 and 4.9 kcal/mol in gas phase and methanol, respectively).
Ciganek has also observed experimentally the increased stabi-
lization of N-oxides in polar (CHCl3) and protic (MeOH)
solvents.19b,c (B) Polar solvents also appear to reduce the
calculated thermodynamic driving force (∆Gr). For the reactions
for C7H10 and NH2OH, ∆Gr is -7.0 and -3.1 kcal/mol in the
Figure 6. Transition state structures for intramolecular and bimolecular
proton transfer in the hydroamination reactions of ethylene and acetylene
at the B3LYP/TZVP level of theory. The internuclear distances (Å) are
shown only for relevant chemical bonds. The TS structures for bimolecular
proton transfer are shown for reactions R-NH2+O- with i-PrOH.
Figure 5. N-Oxide proton transfer pathways investigated computation-
ally.
9
J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008 17903

A R T I C L E S
Moran et al.
Table 7. Gas-Phase Dipole Moments (Debye) and Free Energies (kcal/mol) of the Reaction Species for Hydroamination Reactions (NH2OH)
with C7H10 in C6H6, CHCl3, DMSO, and MeOH (Evaluated at 298 K)a
∆G298K (kcal/mol) in
species
D (Debye)
vacuum
C6H6
CHCl3
DMSO
MeOH
Reactant Complex
Hydroamination TS
R-NH2+O-
0.84
3.03
5.44
4.02
-
5.8
32.0
13.1
38.3
-
8.0
31.9
11.0
37.4
-
8.6
32.4
10.5
38.0
-
9.4
32.4
9.2
37.8
-
-4.6
11.0
34.3
8.3
38.8
18.1
-3.1
Intramolecular H+ transfer TS
bimolecular H+ transfer TS
R-NHOH
0.88
-7.0
-6.1
-5.1
a Energies are relative to the free reactants in solvent.
Table 8. Nitrogen Substitution: Free Energies (kcal/mol) of the
near thermoneutral nature of the reaction (i.e., similar stabilities
of the styrene HA regioisomers) are consistent with this
variability.
Reactions and Activation Free Energies for Hydroamination
Reactions of Various Hydroxylamines with C7H10 and C8H6 in the
Gas Phase (Evaluated at 298 K and 1 atm)a
3.5. Impact of Substitution. The impact of nitrogen and
alkene or alkyne substitution in intramolecular Cope-type
hydroaminations has been delineated experimentally and dis-
cussed in a recent review by Cooper and Knight.27 In general,
π bond substitution translates into a more difficult hydroami-
nation step, with substitution at the distal position of the
unsaturation having a significant impact on rates of cyclization
(up to ∼25 times slower). In contrast, nitrogen substitution is
found to be beneficial in intramolecular systems: N-methyl-N-
alkenylhydroxylamine substrates cyclize significantly faster than
the parent (N-H) N-alkenylhydroxylamines. The latter trend
is in contrast with our experimental results presented in Tables
2 and 3, as hydroaminations with NH2OH and N-alkylhydroxy-
lamines proceed under similar reaction conditions. Therefore,
a comprehensive set of calculations was performed to provide
insight into the substitution effects with respect to both reacting
partners.
Several trends emerge from the data presented in Tables 8
and 9. First, the activation energy for the hydroamination step
does not vary significantly with increased substitution on the
hydroxylamine used (NH2OH vs MeNHOH vs Me2NOH). This
theoretical data also suggests that the increased reactivity of
N-methyl-N-alkenylhydroxylamine with respect to the parent
(N-H) N-alkenylhydroxylamines substrates in intramolecular
systems cannot be attributed to a more facile Cope-type
cyclization step. A possible rationale for this trend could be, in
analogy to the findings documented herein, that the proton
transfer step from the N-oxide intermediate to the hydroxylamine
product is kinetically releVant for Cope-type cyclizations of
(N-H) N-alkenylhydroxylamines, and that such cyclizations
would also benefit from the presence of a proton shuttle.
DFT studies on π bond substitution (Table 9) correlate well
with the experimental data with respect to the reaction temper-
atures required with the various substrates presented in Tables
alkene/alkyne
hydroxylamine
regioselectivity
∆Gq kcal/mol
∆Gr kcal/mol
HA
C7H10
C7H10
C7H10
PhCCH
NH2OH
-
32.0
30.7
32.5
33.2
30.1
32.1
29.7
31.3
30.3
-7.0
-3.7
NH(Me)OH
N(Me)2OH
NH2OH
-
-
+14.9
-28.2
-33.4
-18.3
-14.8
+5.4
AM
M
PhCCH
PhCCH
NH(Me)OH
N(Me)2OH
AM
M
AM
M
+12.0
a Energies are relative to the free reactants.
gas phase and in MeOH, respectively, due to increased stabiliza-
tion of NH2OH relative to the hydroamination product in polar
solvents.
3.4. Reactions under Kinetic Vs Thermodynamic Control.
The calculations and experimental results presented above
suggest that the product distribution observed with alkynes and
norbornene is consistent with kinetic control as the reactions
are thermodynamically favorable. For terminal alkynes, the
observed product distribution favors nitrogen incorporation on
the internal carbon and for methylphenylacetylene, substitution
occurs on the carbon atom proximal to the methyl group (Table
1). Typically, C-N bond formation will occur on the carbon
atom that is best able to stabilize a developing positive charge
in the alkyne hydroamination TS. Overall, the calculated
differences in activation energies leading to both hydroamination
regioisomers are in good agreement with the observed Mark-
ovnikov selectivity (vide infra). In contrast, product distribution
with alkenes (except norbornene) appears consistent with
thermodynamic control.13 The observed preference for the
Markovnikov or anti-Markovnikov adducts and yields (33-79%)
vary significantly depending on the substitution present on the
vinyl arene (Table 4). The experimental observation of revers-
ibility with stryrene (eq 2) and DFT calculations showing the
Table 9. Free Energies (kcal/mol) of the Reaction Species for Hydroamination Reactions (NH2OH) with CH3- and CF3-Substituted Ethylene
and Acetylenes (Evaluated at 298 K and 1 atm)a
alkenes
alkynes
CH3CHCH2
CF3CHCH2
CH3CCH
CF3CCH
species
AM
M
AM
M
AM
M
AM
M
RCb
5.3
38.3c
18.9
43.2
-1.6
-
5.3
34.5c
15.8
40.8
-3.9
-
6.5
6.5
33.1
17.8
42.1
-3.7
-
5.7
5.7
31.2d
6.9
28.5
-19.0
-35.0
7.7
24.9
0.7
20.4
-30.2
-41.3
7.7
25.0
2.1
23.2
-25.1
-39.8
Hydroamination TS
31.2
15.3
40.5
-4.8
-
34.4d
8.1
R-NH2+O-
Intramolecular H+ transfer TS
R-NHOH
29.5
-16.9
-29.7
CdN-OH
a Energies are relative to the free reactants. b Reactants complex. c 38.2 kcal/mol for the hydroamination of cis-CH3-CHdCH-CH3. d 35.5 kcal/mol
for the hydroamination of CH3-CC-CH3.
9
17904 J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008

Intermolecular Cope-Type Hydroamination of Alkenes and Alkynes
A R T I C L E S
(especially iron) and metal ion impurities, oxidizing and reducing
agents, bases, high temperatures above 75 °C, or high concentrations
of hydroxylamine, for example due to evaporation. The use of more
dilute solutions is inherently safer.52 Therefore, under standard
reaction conditions, the hydroxylamine (HAFB) content of the
solution being heated is in the 5-10 wt % range. Hydroxylamine
concentration should not be increased. The use of a blast shield to
perform the experiments in sealed tubes or in flask equipped with
a reflux condensor should be a standard operating procedure.
Alternatively, commercially available microwave synthesizers are
designed for safe operation at elevated temperatures and pressure,
and were used regularly for reactions with aqueous NH2OH. During
the course of our studies (>500 experiments using NH2OH, using
the experimental setups described above), we have performed
reactions up to a 5-g scale and have observed only minimal gas
evolution (ie. a bit of pressure was released upon opening the sealed
tubes to air, at room temperature, at the end of the reaction). No
incidents occurred.
1, 2, and 4, and with the trends documented for intramolecular
Cope-type hydroaminations.27 Importantly and likely due to the
increased stability inherently linked to π bond substitution,
activation free energies for the hydroamination step increase
with π bond substitution. Increased stability of the alkene or
alkyne starting material thus translates into reduced relative
stability of the N-oxide intermediates and hydroamination
products. Conversely, electron-withdrawing substituents reduce
the activation energy required for anti-Markovnikov Cope-type
hydroaminations of alkenes and alkynes, in accord with a more
important HOMONH2OHfLUMOCC interaction. Finally, for
intermolecular reactions of alkenes, substitution can have a direct
impact on reaction efficiency since for styrene the reaction is
nearly thermoneutral.13 Therefore, at 298 K, hydroaminations
of ethylene, strained and terminal alkenes are slightly more
favorable (thermodynamically) than reactions of vinylarenes.
Disubstituted alkenes are also predicted to be more challenging
substrates, both kinetically and thermodynamically. Due to the
negative entropy of intermolecular reactions, the position of the
equilibrium depends on the reaction temperature and the
formation of hydroamination products is obviously more favor-
able at lower temperatures. The data regarding the thermody-
namic driving force of the reactions (∆Gr) should be used from
this perspective, keeping in mind that more challenging hy-
droamination substrates often require higher reaction temper-
atures,whichtranslateintolessfavorablereactionthermodynamics.
Computational Details. Density functional theory (DFT) cal-
culations have been performed using the Gaussian 03 program.53
Optimized molecular geometries were calculated using the B3LYP54
exchange-correlation functional.
The triple-ꢁ TZVP55 basis set and tight SCF convergence criteria
were used for calculations. Wave function stability calculations were
performed to confirm that the calculated wave functions cor-
responded to the ground state. Harmonic frequency calculations
were performed to ensure that the stationary points were true energy
minima or transition states (TSs) and to calculate vibrational zero
point energy and thermal corrections. The unscaled frequencies were
used for calculating Gibbs free energies of the species (at 298 K
and 1 atm). Intrinsic reaction coordinate (IRC)56 calculations were
used to confirm the reaction pathways through the transition states
(TSs) for all reactions.
4. Conclusion
In summary, an intermolecular Cope-type hydroamination has
been developed for unsaturated substrates including terminal
and internal alkynes, strained alkenes and terminal vinylarenes.
The use of alcoholic solvents is beneficial for reactions of
alkynes and is generally necessary for reactions of alkenes to
proceed: it is proposed that the solvent participates in a facile
bimolecular proton transfer of the N-oxide intermediate, thus
facilitating product formation. In addition, a beneficial additive
effect observed with sodium cyanoborohydride has allowed for
the extension of this reactivity from aqueous hydroxylamine to
N-alkylhydroxylamines. All reactions can be carried out in
concentrated alcoholic solvents, do not require rigorous exclu-
sion of water and are easily scalable. The practicality and
functional group tolerance (toward common protecting groups,
free OH and NH bonds, aryl bromides, etc.) of this procedure
highlight its complimentary role among existing intermolecular
hydroamination methods. DFT calculations were also performed
to provide insight into this reactivity, including information on
the potential energy surface of the reactions and on the nature
of the hydroamination and proton transfer transition states. A
detailed molecular orbital description for the concerted hy-
droamination transition states is provided, and highlights the
high electronic tunability of this process with respect to the
alkene, alkyne and hydroxylamine reaction partners. Extensions
and applications of this reactivity, including intramolecular
variants, are underway and will be reported in due course.
The calculation of solvation energies of the species in solvents
(benzene, CHCl3, DMSO, and methanol) were performed by using
the polarizable continuum model (PCM) with the united atom
topological (UAHF) atomic radii. Solvation energies were then used
to evaluate the free energies of species in solvents.
Orbital compositions were calculated using Mulliken population
analysis (MPA)57 using the AOMix program.58 The analysis of the
orbital compositions of the hydroamination transition states in terms
of molecular orbitals of the fragment molecules was performed
using the AOMix-CDA program.59,60 Mayer bond orders61 were
calculated using the AOMix-L program.60 Atomic charges were
evaluated by using the natural population analysis (NPA).62
Acknowledgment. We thank the University of Ottawa (start-
up & CCRI), the Canadian Foundation for Innovation, the Ontario
Ministry of Research and Innovation and NSERC (discovery &
(51) Due to the remarkable efficiency of the bimolecular proton transfer
pathway B (Figure 5), investigations into alternative bimolecular
pathways were not pursued using DFT calculations. Experimentally,
various attempts using either mildly basic (Et3N) or acidic (AcOH)
additives did not result in significant rate accelerations.
(52) For an evaluation of the safety profile of 20 to 85 wt % NH2OH
aqueous solutions, see: (a) Iwata, Y.; Koseki, H. Process Safety
Progress 2002, 21, 136.
(53) Frisch, M. J.; et al. Gaussian 03; Gaussian, Inc.: Pittsburgh, PA, 2003.
(54) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(55) Schafer, A.; Huber, C.; Ahlrichs, R. J. Chem. Phys. 1994, 100, 5829.
(56) (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154. (b)
Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523.
(57) Mulliken, R. S. J. Chem. Phys. 1955, 23, 1833.
(58) Gorelsky, S. I. AOMix, version 6.36 ed.; University of Ottawa: Ottawa,
Canada, 2007.
5. Experimental Section
CAUTION: Hydroxylamine Free Base (HAFB) - 50 wt %
Aqueous Solution. Hydroxylamine free base does not cause any
problems if handled with care. For example, it is currently produced
by BASF (>7000 ton/year) and used for a variety of industrial
applications. However, HAFB can decompose spontaneously with
the liberation of large volumes of gas if not handled properly.
Violent decomposition of hydroxylamine can be caused by metal
(59) Gorelsky, S. I.; Ghosh, S.; Solomon, E. I. J. Am. Chem. Soc. 2006,
128, 278.
(60) Gorelsky, S. I.; Basumallick, L.; Vura-Weis, J.; Sarangi, R.; Hedman,
B.; Hodgson, K. O.; Fujisawa, K.; Solomon, E. I. Inorg. Chem. 2005,
44, 4947.
(61) Mayer, I. Chem. Phys. Lett. 1983, 97, 270.
9
J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008 17905

A R T I C L E S
Moran et al.
CRD grants) for their support. We are also grateful to OGS
(M.-E. L.) and NSERC for postgraduate (J. M. and M.-E. L.) and
undergraduate (E. D. and C. S.) research scholarships. We
acknowledge the Canadian Society for Chemistry, AstraZeneca
Canada, Boehringer Ingelheim (Canada) Ltd. and Merck Frosst
Canada for an Enantioselective Synthesis Grant. Mr. Francis
Loiseau is thanked for repeating results. We also thank Professor
Tom K. Woo for access to the computing facilities funded by the
CFI and ORF.
Supporting Information Available: Typical experimental
procedures, experimental details, optimization tables, charac-
terization for all new compounds and complete ref 53. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(62) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985,
83, 735.
JA806300R
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17906 J. AM. CHEM. SOC. VOL. 130, NO. 52, 2008