Intermolecular cope-type hydroamination of alkenes and alkynes

Article abstract of DOI:10.1002/anie.200703495

(Chemical Equation Presented) Keep it simple! Intermolecular hydroamination can be achieved simply upon heating alkynes and alkenes with aqueous hydroxylamine. Alkynes react to afford oximes in good to excellent yields, and the formation of Markovnikov products is favored. A mechanism involving Cope-type hydroamination followed by bimolecular proton transfer is suggested and supported by DFT studies.

Full text of DOI:10.1002/anie.200703495

Communications
DOI: 10.1002/anie.200703495
Hydroamination
Intermolecular Cope-Type Hydroamination of Alkenes and Alkynes**
AndrØ M. Beauchemin,* Joseph Moran, Marie-Eve Lebrun, Catherine SØguin,
Elena Dimitrijevic, Lili Zhang, and Serge I. Gorelsky
In memory of Nabi Magomedov
Nitrogen-containing functional groups are ubiquitous in
natural products and pharmaceuticals. The hydroamination
of unactivated alkenes and alkynes is an attractive approach
for the synthesis of such molecules, but it is underdeveloped
and remains challenging, especially for intermolecular reac-
tions. Most recent progress has been accomplished using
Scheme 1. Impact of nitrogen substitution on Cope-type hydroamina-
tion reactivity.
transition-metal catalysis,[1,2] or strong acids with less basic
nitrogen nucleophiles,[3] but often procedures are limited to
specific substrate classes and functional-group compatibility
is either limited or yet undefined.[4] A conceptually different
approach to the functionalization of alkenes and alkynes in
intramolecular reactions is the Cope-type hydroamination
(also referred to as reverse-Cope cyclization).[5,6] While this
strategy has received some attention (particularly in the
formation of five- and six-membered heterocycles), funda-
mental limitations have precluded its application in synthesis
and in more challenging intermolecular reactions. Notably,
the nitrogen atom is usually substituted to increase reactivity,
but this severely limits the reaction scope, leading to the
formation of amine oxides, which are less versatile synthetic
intermediates and less stable products. Consequently, the
intermolecular process is energetically unfavorable
(Scheme 1).
hydroxylamines is associated with a difficult intramolecular
proton-transfer step rather than a difficult hydroamination
step (Scheme 2). Thus, the presence of alcohols or water in
our reaction conditions is crucial to mediate a facile,
bimolecular proton transfer of the amine oxide intermediate.
To expand the use of this concerted hydroamination
strategy, we sought a solution to this requirement for nitrogen
substitution (R’, R’’ = alkyl). Herein, we report that heating
(unsubstituted) aqueous hydroxylamine with alkynes and
alkenes affords the intermolecular hydroamination products
under mild conditions and in the absence of a metal catalyst.
We also present experimental and theoretical evidence which
suggest that the reduced reactivity of less substituted
Scheme 2. For the intermolecular hydroamination the presence of
alcohols or water is crucial to mediate a facile, bimolecular proton
transfer of the amine oxide intermediate.
[*] Prof. Dr. A. M. Beauchemin, J. Moran, M.-E. Lebrun, C. SØguin,
E. Dimitrijevic, L. Zhang, Dr. S. I. Gorelsky[+]
Centre for Catalysis Research and Innovation
Department of Chemistry, University of Ottawa
10 Marie-Curie, Ottawa, ON K1N 6N5 (Canada)
Fax: (+1)613-562-5170
Under such conditions, this reaction is not limited to NH2OH:
hindered c-C6H11NHOH can also be used for intermolecular
hydroamination.
Reasoning that the side reactions described in the rare
examples of intermolecular Cope-type hydroaminations
could be due to hydroxylamine substitution,[7] we focused
our initial studies on commercially available aqueous
NH2OH. In optimizing the reaction conditions, we found
high concentration and solvent dependence. Under optimized
conditions phenylacetylene underwent quantitative conver-
sion upon heating with aqueous NH2OH (2.5 equiv) at 1138C
overnight in concentrated solution in dioxane (1m), leading to
an 87% yield of the Markovnikov product (M) along with 5%
yield of the anti-Markovnikov product (AM). The scope of
alkyne substrates is shown in Table 1. Steric and electronic
E-mail: andre.beauchemin@uottawa.ca
[+] Inquiries about DFT calculations should be addressed to Dr. S. I.
Gorelsky.
[**] We thank the Universityof Ottawa (start-up grant and CCRI), CFI,
MRI (Ontario), NSERC, the Enantioselective Synthesis Grant
(sponsored bythe Canadian Societyfor Chemistry, AstraZeneca
Canada, Boehringer Ingelheim (Canada) Ltd., and Merck Frosst
Canada) for their support. We thank Prof. Tom Woo for providing
access to his computer cluster for DFT calculations.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Reaction of alkynes with aqueous NH2OH.
proved uniquely effective to obtain hydroamination products
and minimize side reactions, which include oxidative hydro-
amination and 1,2-Meisenheimer rearrangement at higher
temperatures. The importance of the solvent is illustrated in
Table 2 (unoptimized conditions).
[a]
EntrySubstrate
Conditions
Major
product
Yield(s) [%][b]
1
2
3
4
R=Ph, R’=H
A
A
87 (5)
83 (3)
71 (8)
45 (11)
Table 2: Solvent effects in the hydroamination of norbornene.[a]
R=4-MeOC6H4,
R’=H
R=4-FC6H4, R’=H A[c]
R=2-MeC6H4,
R’=H
[b]
A
EntrySolvent
Conversion [%]
R=3-MeC6H4,
R’=H
R=4-MeC6H4,
R’=H
1
2
3
4
5
6
7
8
C6D6
dioxane
CDCl3
MeOH
EtOH
iPrOH
[D6]DMSO
none
0
3
5
5
6
A
75 (2)
65 (3)
A
26
14
48
2
7
8
A[c]
73 (15)
0[c]
B
C
62
[a] Reaction conditions: [alkene]=1m, aq. NH2OH (10 equiv), 958C,
14 h. [b] Determined using styrene as an internal standard. [c] Biphasic
mixture.
86 (2)
9
B
C
C
55 (1)
72 (3)
63
Subsequent reaction optimization focused on the encour-
aging lead obtained in iPrOH (Table 2, entry 6). Upon
increasing reaction time and concentration, we observed
quantitative conversion of norbornene (Table 3, entry 1). A
preliminary survey of the reaction scope is presented in
Table 3. A variety of strained alkenes showed excellent
reactivity (Table 3, entries 1–5). Not surprisingly, mixtures
of mono- and bis-hydroamination products formed under the
reaction conditions (Table 3, entries 1–3). While the bis-
hydroamination product 2 is typically favored in the presence
of 2 equivalents of NH2OH (conditions A), the mono-hydro-
10
11
12
R, R’=Ph
B
71
B
C
31 (3)
53 (5)
R=Me, R’=Ph
R, R’=nPr
13
C
12
Table 3: Reaction of aqueous NH2OH with alkenes.[a]
[a] Reaction conditions: A: alkyne (1 equiv), aq. NH2OH (2.5 equiv),
dioxane (1m), sealed tube (behind a blast shield), 1138C, 16–18 h; B:
1408C, dioxane (2m), 38–40 h; C: iPrOH (1m), 1408C (microwave), 5–
10 h. [b] Yield of isolated products. Yield of regioisomer shown in
parentheses. [c] 2m in dioxane.
EntrySubstrate
1
Conditions
Yield
Ratio
1/2
1+2 [%]
A
B
A
B
99
65
98
49
1:2.2
7.1:1
1:1.5
variations on the arene ring are well tolerated (Table 1,
entries 1–7). Less reactive substrates, such as 1-octyne or
disubstituted alkynes, require somewhat more forcing con-
ditions, and the use of iPrOH as solvent is beneficial (Table 1,
entries 8–13). In general, microwave irradiation of iPrOH
solutions proved optimal, leading to higher yields in shorter
reaction times (conditions C). In most cases, the unreacted
starting material could be recovered, and the products were
conveniently isolated by chromatography or recrystallization.
Initial reactions with alkenes were performed with
norbornene, as strain could provide both higher reactivity
and a favorable thermodynamic outcome[8] for the reaction
(DGr). Surprisingly, initial trials under the conditions initially
used for alkynes showed almost no reaction. After consid-
erable optimization, it was found that alcoholic solvents
2
3
4
A
A
95
48
1.9:1
only 1
5
6
A
C
55
39
only 1
1[b]:2.0
[a] Reaction conditions: A: alkene (1 equiv), aq. NH2OH (2.5 equiv),
iPrOH (1m), sealed tube (behind a blast shield), 958C, 24–48 h; B:
Similar to A but with 10 equiv NH2OH; C: Similar to A but at 1408C for
72 h; Boc=butyloxycarbonyl. [b] 12:1 mixture (M/AM).
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Communications
amination product 1 is favored in the presence of excess
bimolecular proton transfer involving the amine oxide
intermediate and a protic species such as H2O and iPrOH.[9]
Activation free energies for this proton transfer (DG°BPT) for
alkynes and alkenes are ca. 5 and 7 kcalmolꢀ1, respectively, in
vacuum and ca. 8 and 10 kcalmolꢀ1, respectively, in methanol
and are relatively independent of the nature of the proton
shuttle (ROH). This pathway is favored over intramolecular
proton transfer by ca. 15 kcalmolꢀ1. Overall, the thermody-
namics of both reactions are favorable, with the formation of
the norbornene adduct (DGr = ꢀ7.0 kcalmolꢀ1) significantly
less favored than that of the phenylacetylene adduct, which is
further stabilized upon formation of the oxime tautomer
(DGr,M = ꢀ33.4 kcalmolꢀ1).[11]
NH2OH (conditions B). In contrast, more hindered alkenes
lead to selective formation of the primary hydroxylamine 1.
An encouraging result was obtained with styrene (Table 3,
entry 6), showing this reactivity is not limited to strained
alkenes. Hartwig et al. had reported that styrene hydroami-
nation is essentially thermoneutral;[8] in line with this,
reversibility experiments suggest this reaction with styrene
has reached equilibrium.[9]
The results presented in Table 3 suggest that this inter-
molecular reaction is not limited to NH2OH, as formation of
bis-hydroamination products 2 must involve the reaction of
mono-hydroamination product 1 and an additional molecule
of alkene. Encouragingly, cyclohexylhydroxylamine also
affords products of intermolecular hydroamination with
both phenylacetylene [Eq. (1)]and norbornene [Eq. (2)].
While the preceding discussion refers to DFT calculations
in the gas phase, solvent effects on optimized structures are
only minimal.[12] Therefore, the trends outlined in Figure 1
suggest that the proton-transfer step is of paramount impor-
tance for intermolecular reactions of alkenes. This picture is
consistent with the beneficial effect of iPrOH in reactions of
alkynes and the spectacular solvent effects shown in Table 2.
In summary, we have reported a unified, metal-free
approach for the intermolecular hydroamination of alkynes
and alkenes. We have shown that alkyl substitution of the
hydroxylamine is not required to achieve high reactivity in
Cope-type hydroaminations, as NH2OH reacts efficiently; we
have also highlighted the importance of the proton-transfer
step on the reaction. These results suggest that the scope of
Cope-type hydroaminations, notably intramolecular variants,
can be significantly expanded. Extensions of this work are in
progress and will be reported in due course.
DFT calculations were undertaken to compare the
reactivity of alkenes and alkynes (Figure 1).[9,10] Activation
free energies for hydroamination (DG°HA) proceeding in a
concerted fashion via a five-membered, planar transition state Experimental Section
(TS) are similar for norbornene (32.0 kcalmolꢀ1) and phenyl-
acetylene (M: 30.1 kcalmolꢀ1, AM: 33.2 kcalmolꢀ1). The
amine oxide intermediate then undergoes proton transfer,
generating the parent alkyl and alkenyl hydroxylamines,
respectively. Two proton-transfer pathways are shown in
Figure 1, and our calculations suggest a remarkably facile
Experimental procedures, spectroscopic characterization of all new
products, and computational details are provided in the Supporting
Information.
CAUTION: Due to the high energy content of NH2OH,
appropriate care should be taken when conducting these experiments.
The use of a blast shield is and should be a standard operating
procedure. The hydroxylamine concentration should not be increased
beyond 5–10 wt% (i.e. the typical reaction conditions). See the
Supporting Information for a discussion.
Received: August 1, 2007
Revised: October 10, 2007
Published online: January 18, 2008
Keywords: alkenes · alkynes · green chemistry · hydroamination ·
.
solvent effects
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Figure 1. DFT calculations on NH2OH-based hydroaminations high-
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[9]See the Supporting Information for details.
[10]For calculations on the Cope elimination, see: a) I. Komaromi,
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[11]Other findings: 1) a similar energy profile for C 2H4 and C2H2,
2) a nearly thermoneutral profile for the reaction of styrene
(DGr = ꢀ0.5 kcalmolꢀ1 for M; DGr = 0.3 kcalmolꢀ1 for AM),
3) similar DG°HA values for the addition of MeNHOH (30.7 kcal
molꢀ1) and Me2NOH (32.5 kcalmolꢀ1) to norbornene. Please see
the Supporting Information for details.
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[12]For example, DGr for the reaction shown in Table 2 varies as
follows: ꢀ7.0 kcalmolꢀ1 (gas phase), ꢀ6.2 kcalmolꢀ1 (C6H6),
ꢀ5.2 kcalmolꢀ1 (CHCl3), ꢀ4.6 kcalmolꢀ1 (DMSO) and
ꢀ3.0 kcalmolꢀ1 (MeOH).
[13]Free energies of reactants, intermediates, and products in the gas
phase at 298 K and 1 atm, B3LYP/TZVP level of theory [RC:
reactant complex (pCC!H-ONH2)]. TS structures are shown for
the reaction with C2H4.
[4]For selected alternatives, see (for radicals): a) J. Guin, C. Mück-
Lichtenfeld, S. Grimme, A. Studer, J. Am. Chem. Soc. 2007, 129,
4498 – 4503. For a review on base-catalyzed hydroaminations,
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