Dissecting alkynes: Full cleavage of polarized C≡C moiety via sequential bis-michael addition/retro-mannich cascade

Article abstract of DOI:10.1021/jo201259j

The reaction of diaryl ketoalkynes with 1,2-diamino ethane leads to the full scission of the triple bond with the formation of acetophenone and imidazoline fragments. In this transformation, one of the alkyne carbons undergoes formal reduction with the formation of three C-H bonds, whereas the other carbon undergoes formal oxidation via the formation of three C-N bonds (one π and two σ). Computational analysis confirmed that the key fragmentation step proceeds via a six-membered TS in a concerted manner. Both amines are involved in the fragmentation: the N-H moiety of one amine transfers a proton to the developing negative charge at the enolate oxygen, while the other amine provides direct stereoelectronic assistance to the C-C bond cleavage via a hyperconjugative n_N → σ*_C-C interaction.

Full text of DOI:10.1021/jo201259j

ARTICLE
pubs.acs.org/joc
Dissecting Alkynes: Full Cleavage of Polarized C;C Moiety via
Sequential Bis-Michael Addition/Retro-Mannich Cascade
Saumya Roy,§ Maria P. Davydova,† Runa Pal,§ Kerry Gilmore,§ Genrikh A. Tolstikov,‡
Sergei F. Vasilevsky,*,† and Igor V. Alabugin*,§
†Institute of Chemical Kinetics and Combustion and ‡N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation
§Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306, United States
S Supporting Information
b
ABSTRACT: The reaction of diaryl ketoalkynes with 1,2-
diamino ethane leads to the full scission of the triple bond with
the formation of acetophenone and imidazoline fragments. In
this transformation, one of the alkyne carbons undergoes formal
reduction with the formation of three CꢀH bonds, whereas the other carbon undergoes formal oxidation via the formation of three
CꢀN bonds (one π and two σ). Computational analysis confirmed that the key fragmentation step proceeds via a six-membered TS
in a concerted manner. Both amines are involved in the fragmentation: the NꢀH moiety of one amine transfers a proton to the
developing negative charge at the enolate oxygen, while the other amine provides direct stereoelectronic assistance to the CꢀC
bond cleavage via a hyperconjugative nN f σ*CꢀC interaction.
Scheme 1. Alkyne Disassembly with the Formation of CdC,
CdO, and two CꢀN Bonds at the Expense of the Alkyne Moiety
’ INTRODUCTION
The alkyne moiety plays an important role in organic chem-
istry, lending itself to a variety of cascade transformations.1
Expanding earlier studies on the development of new organic
reactions where multiple CꢀH and CꢀC bonds2 are formed at
the expense of the two alkyne π-systems,3,4 we have shown that it
is possible to break all three bonds of the alkyne moiety, thus
accomplishing its full disassembly via the formation of six new
bonds (Scheme 1).5
Since the strategic use of fragmentation steps occupies an
important niche in the arsenal of synthetic transformations6 and
bioanalytical tools,7,8 we would like to disclose another example
of full alkyne disassembly via the formation of six new bonds at
the two alkyne carbons.9 In this process one carbon undergoes
three formal reduction steps with the formation of three CꢀH
bonds, whereas the second alkyne carbon undergoes formal
oxidation via the formation of three carbonꢀnitrogen bonds.
This process can be considered as a cleavage of the alkyne moiety
Scheme 2. Proposed Pathway for the Complete Dispropor-
tionation of Alkyne Moiety
via disproportionation (Scheme 2).
This work is conceptually related to the literature examples of
efficient Grob fragmentations in 1,4-disubstituted pushꢀpull
systems. Communication of suitable donors (anionic centers,
heteroatom lone pairs, radical centers,10e carbonꢀmetal4 σ-
bonds) with a variety of acceptors (cationic,4 radical,10e and
18
12
radical-cationic8,11 centers; π*CdO, π*CdN
,
π*CdC
,
and σ*C-X
orbitals6a) via a bridge σ-bond weakens this bond, enabling a
number of efficient fragmentation patterns (Figure 1). Due to the
high donor ability of nitrogen lone pairs13 and high acceptor
ability of carbonyl π*-orbitals, we envisioned that the through-
bond interactions10 between a nitrogen and a β-carbonyl group
would also render such a fragmentation possible. Because the
reactant for the fragmentation should be readily available from
Received: June 20, 2011
Published: August 01, 2011
r
2011 American Chemical Society
7482
dx.doi.org/10.1021/jo201259j J. Org. Chem. 2011, 76, 7482–7490
|

The Journal of Organic Chemistry
ARTICLE
Scheme 3. Two Approaches to the Preparation of Ketoalk-
ynes: (a) from Aldehydes, (b) from Benzoyl Chlorides
Table 1. Structures and Isolated Yields of Ketoalkynes
Figure 1. Selected examples of fragmentation patterns in pushꢀpull
1,4-donorꢀacceptor systems. Donors are shown in red, and acceptors
are shown in blue.
double Michael addition to acetylenic ketones, we have chosen
these ketones as our model fragmentation substrates.
’ RESULTS AND DISCUSSION
The keto acetylenes have been prepared via two approaches:
(1) addition of Li-acetylides to an aromatic aldehyde followed by
MnO2 oxidation of the intermediate benzylic alcohol (Scheme 3a)
and (2) one-step reaction involving Pd-catalyzed coupling of
benzoyl chlorides and terminal alkynes14 (Scheme 3b).
a Isolated yield.
If the starting benzoyl chloride is readily available, the latter
synthetic strategy is very efficient and convenient, providing
ketoalkynes in 90ꢀ97% yields (Table 1).
The cascade proceeds beyond the first step only when the reaction
temperature was increased to 101 °C(refluxing dioxane). Interestingly,
only the final retro-Mannich fragmentation products B and C were
found. The intermediate cyclic products of the second (intramolecular)
Michael addition were not observed. This observation suggests that the
σCꢀC bond cleavage in the cyclized intermediate is faster than 5-exo-trig
closure at the π-bond, in an apparent contradiction to the conventional
wisdom that σ-bonds are stronger than π-bonds.
In the case of fragmentation products with a relatively low
molecular weight, a more convenient procedure, which facilitated
further analysis and isolation, involves running the reaction in a
pressure tube in THF. In several cases, the cascade proceeded to
full conversion only at 125 °C and longer reaction times (entries
1ꢀ7, Table 2). In the case of reactive substrates, however, increase
Initial experiments found that the first (intermolecular) Michael
addition proceeds smoothly at room temperature in THF as
solvent. Interestingly, the second (intramolecular) Michael addi-
tion proceeds much more slowly despite corresponding to a 5-exo-
trig closure favored according to the Baldwin rules.16 Even after 18
h of reflux in THF (65 °C), the initial Michael adduct remained
unchanged. This lack of reactivity can be attributed to the
deactivating effect of the donor amino moiety on the Michael
acceptor π-system. Since intramolecular addition is slow, an
intermolecular reaction of the NH2 group in the initial adduct
with a secondketoalkyne is observed. The formation of bis-adducts
can be minimized by decreasing concentrations of the reagents.
7483
dx.doi.org/10.1021/jo201259j |J. Org. Chem. 2011, 76, 7482–7490

The Journal of Organic Chemistry
ARTICLE
Table 2. Reactions of Ketoacetylenes with 1,2-Diaminoethane at Elevated Temperaturesa
a Yields were determined by 1H NMR with benzyl phenyl ether as standard.
Table 3. Reaction of Trimethoxy Substituted Substrates with
1,2-Diaminoethane in Refluxing Dioxane
in the conversion at higher temperature does not lead to a
proportional increase in the product yields (entry 7).
The role of π-system polarization is illustrated by the
contrasting effects of p-F substituents at the keto and the
acetylene ends. Whereas fluorine introduction at the alkyne
termini accelerated the overall cascade (∼90% completion at
110 °C after 3 h), the same substitution at the carbonyl end
decreased the reactivity (∼55% of the cyclic product even
after 12 h at the same temperature). We have also investigated
the reactivity of an aliphatic ketoalkyne (Table 2, entry 8).
A lower reaction yield was observed but the fragmentation still
proceeded.
We have further investigated the effect of donor groups and
alkyne polarization on the efficiency of this cascade using
ketoalkynes deactivated by multiple donor substituents at the
keto end. Considerably longer times are needed to reach
comparable conversions when a donor substituent is added at
the alkyne terminus as well (Table 3).
The nature of the intermediates isolated from these reaction
mixtures supports the proposed sequence of reactions in the
fragmentation cascade. Michael addition to the ketoalkyne
quickly provides the vinyl amine A (Scheme 4). The subsequent
intramolecular Michael addition via a 5-exo-trig closure requires
higher temperatures and is likely to be the rate-limiting step in
the overall cascade. The accelerating effect of the p-NO2
substituent agrees with this notion. The final fragmentation step
can be considered as a retro-Mannich reaction which furnishes
the enol of acetophenone and an oxidized form of imine formally
equivalent to a protected benzoic acid.17
reaction
time (h)
yield B
(%)
yield C
(%)
yield A2
(%)
entry
R
1
2
3
4
24, -OCH3
25, -Ph
16
14
9
24b (47)
24b (43)
24b (45)
24b (35)
24c (23)
25c (18)
16c (42)
27c (34)
24a2 (12)
25a2 (6)
26a2 (6)
27a2 (13)
26, -H
27, -NO2
0.5
A similar transformation has been reported recently by
Nenajdenko et al.,18 who found that treatment of styrenes
bearing acceptors with ethylene diamine gave a mixture of
fluorinated imidazolidines 30 and nonfluorinated imidazolines
32 and 33 (Scheme 5). Formation of imidazolidines 30 occurred
via addition of ethylene diamine at the β-styrene carbon, whereas
compound 31 was formed by the double addition of ethylene
diamine to the halostyrene (or acetylene formed in situ from the
styrene) followed by a fragmentation similar to the one reported
in this work. The CF3 group of the reactant was converted
into C2 of the second imidazoline. Again, one of the alkyne
7484
dx.doi.org/10.1021/jo201259j |J. Org. Chem. 2011, 76, 7482–7490

The Journal of Organic Chemistry
ARTICLE
Scheme 4. Reaction at Room Temperature with THF as
Solvent
Scheme 5. Fragmentations of Acceptor Styrenes Reported by
Nenajdenko et al.18 a
Figure 2. Calculated activation energies, enthalphies and free energies,
reaction free energies, and transition state geometries (incipient bond
lengths are given in Å) for intramolecular Michael additions via 5-exo-trig
ring closure.
and single point calculations at the SCRF-B3LYP/6-31+
G(d,p)//B3LYP/6-31+G(d,p) level with THF solvent using
Gaussian 03 programs.21
The calculated barriers for the 5-exo-trig ring closure via
intramolecular Michael addition at the R,β-unsaturated carbonyl
compound were calculated to be substantial (>26ꢀ30 kcal/mol),
with the barrier height correlating with the donor ability of the
vinyl substituent R. An interesting feature of this process is that the
5-exo ring closure is coupled with intramolecular proton transfer
from the nucleophilicnitrogento the incipient enolate oxygen via a
six-membered resonance-assisted hydrogen bond (RAHB). The
cyclizations are endergonic, slightly less so in THF than in the gas
phase. The data are summarized in Figure 2.
The calculated barrier for the σCꢀC bond fragmentation is
predicted to be slightly lower than that for the 5-exo-trig closure.
This final step proceeds through a six-membered TS in a
concerted fashion22 where the CꢀC, NꢀH and CdO bond
cleavage are coupled with the NdC, CdC and OꢀH bond
formation. This process is slightly exergonic for the formation
of conjugated enol (R = Ph) and essentially thermoneutral for
R = Me (Figure 3). Enolꢀketone tautomerization should make
the overall process thermodynamically favorable for both
substituents. Moreover, inclusion of solvation effects (Self-
Consistent Reaction Field calculations in THF) slightly de-
creased the barriers due to the higher polarity of transition
states in comparison to that of starting materials and made both
cyclizations exergonic.23
a Note that CdN moiety serves as the electrophilic component in the
retro-aldol step instead of CdO moiety in our system.
carbons is reduced, and the other is oxidized from the formal
point of view.
Computational Studies. To gain further insight into the
reaction in the previous section, we performed computational
studies of the key intramolecular steps of the reaction cascade. All
the reactant, product, and transition-state geometries involved in
the fragmentation reaction and intramolecular Michael addition
were optimized at the B3LYP/6-31+G(d,p) level of theory18,20
The TS geometries are shown in Figure 4. These geometries
illustrate the contrasting roles of two amino groups for the
7485
dx.doi.org/10.1021/jo201259j |J. Org. Chem. 2011, 76, 7482–7490

The Journal of Organic Chemistry
ARTICLE
Figure 5. Calculated activation barriers and reaction energies for
classical retro-Mannich27 and retro-aldol reaction.
Figure 3. Calculated activation barriers, reaction energies, and transi-
tion state geometries for fragmentation reaction.
The important role of the second nitrogen is not surprising;
the presence of two heteroatoms is known to enable the
fragmentation even when orbitals are misaligned, e.g., in carbe-
nogenic fragmentations.26
To further understand the importance of the above nN
f
σ*CꢀC stereoelectronic assistance, we have also calculated retro-
aldol barriers for the simpler retro-Mannich27 reaction of
β-amino and retro-aldol reaction of β-hydroxy 1-phenylpro-
pan-1-ones (Figure 5). In the absence of other substituents at
the breaking bond, the retro-aldol barriers are very high, espe-
cially for the fragmentations of amines.
The presence of a Ph group at the breaking CꢀC bond
decreased activation barriers for the classic retro-aldol and its
amino version by ∼4ꢀ5 kcal/mol. In our substrates, the effect of
Ph group is much smaller. We attribute this difference to the effect
of the second amino group described above, which provides so
much stabilization to the TS that the additional conjugating
moiety (the Ph group) does not make a big difference.
Figure 4. (a) Two patterns for H-bond assisted retro-aldol fragmenta-
tion: OꢀH N assistance identified by Hansen et al.24 and NꢀH
O
3 3 3
3 3 3
assistance reported in this work. (b) Stereoelectronic alignment of the
second amine lone pair with the breaking CꢀC bond in the transition
state of Ph- and Me-substituted substrates.
fragmentation. Both roles are, however, essential. The first amine
provides an NꢀH moiety for proton transfer to the developing
’ CONCLUSION
negative charge at the enolate oxygen. The effect of NꢀH
is interesting considering that its formal reverse, an OꢀH
O
N
3 3 3
3 3 3
In summary, we have reported an experimental and computa-
tional study describing a cascade transformation that breaks all
three CꢀC bonds in a polarized alkyne moiety. Facile inter-
molecular Michael addition is followed by the relatively slow
intramolecular steps. The slowest step corresponds to the 5-exo-
trig closure at the carbonyl-substituted alkene. This process is
facilitated by the coupling of the intramolecular Michael addition
with a concerted proton transfer along a resonance-assisted
H-bond path, which avoids the formation of an unfavorable
interaction, has been suggested to play an important role in
amine-catalyzed retro-aldol reactions.24 The second amine pro-
vides direct stereoelectronic assistance to the CꢀC bond cleav-
age via a hyperconjugative nN f σ*CꢀC interaction. Hyper-
conjugative donor ability of the second nitrogen lone pair is
enhancing by rehybridization13,25 from sp4.3 (80.9% s-character)
to sp8.9 (89.8%) for Me and from sp4.1 (80.3%) to sp10.5 (91.3%)
for Ph in the reactants and transition states.
7486
dx.doi.org/10.1021/jo201259j |J. Org. Chem. 2011, 76, 7482–7490

The Journal of Organic Chemistry
ARTICLE
zwitterionic intermediate. The final retro-Mannich27 fragmenta-
tion is also fully concerted.
(Z)-3-((2-Aminoethyl)amino)-3-(4-fluorophenyl)-1-phe-
nylprop-2-en-1-one (18a1). 1H NMR (400 MHz, CDCl3) δ 11.45
(s, 1H), 7.89 (d, J = 7.1 Hz, 2H), 7.47ꢀ7.36 (m, 5H), 7.14 (t, J = 8.1 Hz,
2H), 5.76 (s, 1H), 3.27 (dt, J = 5.8, 5.8 Hz, 2H), 2.86 (bs, 2H), 1.41 (bs,
2H); 13C NMR (100 MHz, CDCl3) δ 188.6, 165.9, 163.4 (d, J = 255.7
Hz), 140.1, 130.8, 129.9, 129.8, 128.2, 127.1, 115.6 (d, J = 22.0 Hz), 93.9,
47.8, 42.5; HRMS (CI) calcd for C17H18FN2O [M + H]+ 285.1403,
found 285.1402.
’ EXPERIMENTAL SECTION
General Information. All NMR spectra were collected at 400, 500,
and 600 MHz for 1H NMR and 100, 125, and 150 MHz for 13C NMR
using CDCl3 as solvent.
(2Z,20Z)-3,30-(Ethane-1,2-diylbis(azanediyl))bis(3-(4-fluoro-
phenyl)-1-phenylprop-2-en-1-one) (18a2). 1H NMR (600 MHz,
CDCl3) δ 11.2 (s, 1H), 7.86 (d, J = 7.3 Hz, 2H), 7.48ꢀ7.37 (m, 3H),
7.31ꢀ7.24 (m, 2H), 7.1 (t, J = 7.3 Hz, 2H), 5.73 (s, 1H), 3.33 (d, J = 3.2
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 188.9, 165.6, 163.3 (J = 250
Hz), 139.8, 131.1, 129.8, 129.7, 128.3, 127.1, 115.8, 94.6, 45.1; HRMS
(CI) calcd for C32H27F2N2O2 [M + H]+ 509.2041, found 509.2035.
1-(p-Tolyl)ethanone (19b)28. 1H NMR (400 MHz, CDCl3)
δ 7.85 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 2.58 (s, 3H), 2.41
(s, 3H).
General Procedure for the Synthesis of Ketoalkyne Com-
pounds. A stirred mixture of Pd(PPh3)2Cl2 (19 mg, 0.028 mmol) and
(11 mg, 0.056 mmol) of CuI in THF (5 mL) was purged with nitrogen
for 30 min. Then 0.2 mL (1.42 mmol) of triethylamine, 1.42 mmol of
acid chloride, and acetylene (1.7 mmol) were added successively. The
reaction mixture was then stirred for 3 h at room temperature. Solvents
were evaporated, and the residue was chromatographed on silica gel
(ethyl acetate/hexane) to give the pure product.
General Procedure for the Alkyne Fragmentation. To a
solution of ketoalkyne compound (0.25 mmol) in 2.5 mL of THF in a sealed
tube was added neat ethylenediamine (0.25 mmol) via a syringe. Depending
on the condition the temperature was raised to 110 or 125 °C and stirred for
around 12ꢀ20 h. Solvent was carefully removed under reduced pressure,
and the yield of the product was determined from crude reaction mixture by
using 1H NMR experiment with benzyl phenyl ether as internal standard.
Acetophenone (16b)28. 1H NMR(400 MHz, CDCl3) δ7.98ꢀ7.95
(m, 2H), 7.58ꢀ7.55 (m, 1H), 7.48ꢀ7.44 (m, 2H), 2.61 (s, 3H).
(Z)-3-((2-Aminoethyl)amino)-3-phenyl-1-(p-tolyl)prop-2-
en-1-one (19a1). 1H NMR (400 MHz, CDCl3) δ 11.45 (s, 1H), 7.80
(d, J = 7.9 Hz, 2H), 7.48ꢀ7.38 (m, 5H), 7.19 (d, J = 7.9 Hz, 2H), 5.78 (s,
1H), 3.27 (dt, J = 6.2, 6.0 Hz, 2H), 2.84 (t, J = 6.0 Hz, 2H), 2.37 (s, 3H),
1.45 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 188.5, 166.7, 141.1,
137.6, 135.8, 129.4, 128.9, 128.6, 127.1, 93.6, 47.8, 42.6, 21.4; HRMS
(CI) calcd for C18H21N2O [M + H]+ 281.1654, found 281.1665.
(2Z,20Z)-3,30-(Ethane-1,2-diylbis(azanediyl))bis(3-phenyl-
1-(p-tolyl)prop-2-en-1-one) (19a2). 1H NMR (400 MHz, CDCl3)
δ 11.2 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.49ꢀ7.36 (m, 3H), 7.31ꢀ7.24
(m, 2H), 7.19 (d, J = 7.8 Hz, 2H), 5.73 (s, 1H), 3.34 (t, J = 3.2 Hz, 2H),
2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 188.7, 166.7, 141.3, 137.3,
135.5, 129.5, 128.9, 127.8, 127.7, 127.2, 94.2, 45.1, 21.5; HRMS (CI)
calcd for C34H33N2O2 [M + H]+ 501.2542, found 501.2536.
29
1
2-Phenyl-4,5-dihydro-1H-imidazole (16c) . H NMR (400
MHz, CDCl3) δ 7.82 (d, J = 7.8 Hz, 2H), 7.40ꢀ7.47 (m, 3H), 6.92 (bs,
1H), 3.60 (s, 4H).
(Z)-3-((2-Aminoethyl)amino)-1,3-diphenylprop-2-en-1-one
(16a1). 1H NMR (400 MHz, CDCl3) δ 11.49 (bs, 1H), 7.89 (d, J = 6.6
Hz, 2H), 7.48ꢀ7.36 (m, 8H), 5.79 (s, 1H), 3.28 (dt, J = 6.1, 5.7 Hz, 2H),
2.86 (bs, 2H), 1.48 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 188.1,
166.7, 139.9, 135.3, 130.4, 129.2, 128.3, 127.9, 127.4, 126.7, 93.4, 47.4,
42.2; HRMS (CI) calcd for C17H19N2O [M + H]+ 267.1497, found
267.1493.
3,30-(Ethane-1,2-diylbis(azanediyl))bis(1,3-diphenylprop-
2-en-1-one) (16a2). 1H NMR (600 MHz, CDCl3) δ 11.26 (bs, 1H),
7.87 (d, J = 6.7 Hz, 2H), 7.48ꢀ7.36 (m, 6H), 7.30 (d, J = 6.7 Hz, 2H),
5.75 (s, 1H), 3.35 (t, J = 3.2 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ
188.7, 166.6, 140.0, 135.1, 130.8, 129.5, 128.7, 128.2, 127.6, 127.1, 94.5,
45.1; HRMS (CI) calcd for C32H29N2O2 [M + H]+ 473.2229, found
473.2231.
18
1
1-(4-Fluorophenyl)ethanone (20b) . H NMR (400 MHz,
CDCl3) δ 8.01ꢀ7.97 (m, 2H), 7.16ꢀ7.11 (m, 2H), 2.60 (s, 3H).
(Z)-3-((2-Aminoethyl)amino)-1-(4-fluorophenyl)-3-phenyl-
prop-2-en-1-one (20a1). 1H NMR (600 MHz, CDCl3) δ 11.46
(s, 1H), 7.90 (dd, J = 8.7, 5.6 Hz, 2H), 7.48ꢀ7.39 (m, 5H), 7.06 (dd,
J = 8.6, 8.6 Hz, 2H), 5.73 (s, 1H), 3.28 (dt, J = 6.2, 6.1 Hz, 2H), 2.85 (t, J =
6.2 Hz, 2H), 1.41 (bs, 2H); 13C NMR (150 MHz, CDCl3) δ 187.1, 167.1,
164.5 (d, J = 250.3 Hz), 136.0 (d, J = 124.1Hz), 129.6, 129.3, 128.6, 127.7,
115.0, 115.1, 93.3, 47.8, 42.5; HRMS (CI) calcd for C17H18FN2O
[M + H]+ 285.1403, found 285.1404.
(2Z,20Z)-3,30-(Ethane-1,2-diylbis(azanediyl))bis(1-(4-fluoro-
phenyl)-3-phenylprop-2-en-1-one) (20a2). 1H NMR (400 MHz,
CDCl3) δ 11.21 (s, 1H), 7.87 (dd, J = 8.6, 5.2 Hz, 2H), 7.47ꢀ7.37
(m, 3H), 7.29ꢀ7.23 (m, 2H), 7.06 (t, J = 8.6 Hz, 2H), 5.69 (s, 1H), 3.34
(t, J = 3.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 187.5, 166.7, 164.6
(d, J = 250.2 Hz), 135.6 (d, J = 124.0 Hz), 129.6, 129.4, 129.3, 128.7, 127.6,
115.2, 94.3, 44.9; HRMS (CI) calcd for C32H27F2N2O2 [M + H]+
509.2041, found 509.2028.
2-(p-Tolyl)-4,5-dihydro-1H-imidazole (17c)28. 1H NMR (400
MHz, CDCl3) δ 7.70 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 5.03
(bs, 1H), 3.78 (s, 4H), 2.39 (s, 3H).
(Z)-3-((2-Aminoethyl)amino)-1-phenyl-3-(p-tolyl)prop-2-
en-1-one (17a1). 1H NMR (400 MHz, CDCl3) δ 11.49 (s, 1H), 7.89
(d, J = 7.0 Hz, 2H), 7.46ꢀ7.36 (m, 3H), 7.32 (d, J = 7.1 Hz, 2H),
7.28ꢀ7.21 (m, 2H), 5.78 (s, 1H), 3.29 (dt, J = 5.1, 5.0 Hz, 2H), 2.85 (bs,
2H), 2.41 (s, 3H), 1.45 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 188.4,
167.3, 140.4, 139.7, 132.8, 130.7, 129.3, 128.2, 127.8, 127.1, 93.7, 47.8,
42.6, 21.4; HRMS (CI) calcd for C18H21N2O [M + H]+ 281.1659, found
281.1654.
30
1
1-(4-Chlorophenyl)ethanone (21b) . H NMR (400 MHz,
CDCl3) δ 7.88 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 2.58 (s, 3H).
(Z)-3-((2-Aminoethyl)amino)-1-(4-chlorophenyl)-3-phenyl-
1
prop-2-en-1-one (21a1). H NMR (600 MHz, CDCl3) δ 11.5 (bs,
(2Z,20Z)-3,30-(Ethane-1,2-diylbis(azanediyl))bis(1-phenyl-
3-(p-tolyl)prop-2-en-1-one) (17a2). 1H NMR (400 MHz, CDCl3)
δ 11.24 (s, 1H), 7.85 (d, J = 7.4 Hz, 2H), 7.46ꢀ7.34 (m, 5H), 7.19 (d, J =
9.0 Hz, 2H), 5.74 (s, 1H), 3.36 (d, J = 3.4 Hz, 2H), 2.41 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 188.6, 166.9, 140.2, 135.1, 139.7, 132.3,
130.8, 129.4, 128.2, 127.6, 127.1, 94.3, 45.1, 21.4; HRMS (CI) calcd for
C34H33N2O2 [M + H]+ 501.2542, found 501.2548.
1H), 7.83 (d, J = 8.4 Hz, 2H), 7.47ꢀ7.44 (m, 3H), 7.43ꢀ7.39 (m, 2H),
7.36 (d, J = 8.4 Hz, 2H), 5.73 (s, 1H), 3.28 (dt, J = 6.1, 6.1 Hz, 2H), 2.86
(t, J = 6.1 Hz, 2H), 1.41 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 186.9,
167.3, 138.6, 136.8, 135.5, 129.6, 128.6, 128.5, 128.4, 127.7, 93.3, 47.8, 42.4;
HRMS(CI) calcdfor C17H18N2OCl [M + H]+ 301.1108, found 301.1114.
(2Z,20Z)-3,30-(Ethane-1,2-diylbis(azanediyl))bis(1-(4-chloro-
phenyl)-3-phenylprop-2-en-1-one) (21a2). 1H NMR (600
MHz, CDCl3) δ 11.30 (s, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.45 (d, J =
7.4 Hz, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.25 (d, J =
8.3 Hz, 2H), 5.69 (s, 1H), 3.34 (t, J = 3.0 Hz, 2H); 13C NMR (100 MHz,
2-(4-Fluorophenyl)-4,5-dihydro-1H-imidazole (18c)18. 1H
NMR (400 MHz, CDCl3) δ 7.78ꢀ7.83 (m, 2H), 7.06 (t, J = 8.6 Hz,
2H), 5.59 (bs, 1H), 3.78 (s, 4H).
7487
dx.doi.org/10.1021/jo201259j |J. Org. Chem. 2011, 76, 7482–7490

The Journal of Organic Chemistry
ARTICLE
CDCl3) δ 187.3, 166.9, 138.4, 137.0, 134.9, 129.6, 128.7, 128.5, 128.4,
127.6, 94.1, 45.1; HRMS (EI) calcd for C32H26N2O2Cl2 [M]+ 540.1371,
found 540.1368.
3-([1,10-Biphenyl]-4-yl)-1-(3,4,5-trimethoxyphenyl)prop-
2-yn-1-one (25). Yield 2 g (53%), mp 160ꢀ162 °C; IR (cmꢀ1) ν
1627 (CdO), 2202 (CtC); 1H NMR (400 MHz, CDCl3) δ 7.75ꢀ7.72
(m, 2H), 7.68ꢀ7.60 (m, 4H), 7.53 (s, 2H), 7.50ꢀ7.45 (m, 2H),
7.43ꢀ7.39 (m, 1H), 3.97 (s, 6H), 3.96 (s, 3H); HRMS found m/z
372.1360 [M]+, C24H20O4, calcd M = 372.1356.
28
1
1-(Naphthalen-2-yl)ethanone (22b) . H NMR (400 MHz,
CDCl3) δ 8.47 (s, 1H), 8.05ꢀ8.02 (m, 1H), 7.98ꢀ7.95 (m, 1H),
7.91ꢀ7.87 (m, 2H), 7.63ꢀ7.54 (m, 2H), 2.73 (s, 3H).
2-([1,10-Biphenyl]-4-yl)-4,5-dihydro-1H-imidazole (25c)35.
Mp 200ꢀ201 °C, lit. mp 177ꢀ179 °C;36 IR (cmꢀ1) ν 1618 (CdN),
3423 (NH); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.2 Hz, 2H),
7.63 (t, J = 8 Hz, 4H), 7.45 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H),
3.81 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 164.3, 143.2, 140.1,;
129.2, 128.7, 127.7, 127.3, 127.0, 126.9. Anal. Calcd for C15H14N2: C
81.05; H 6.35; N 12.60. Found: C 81.44; H 6.76; N 12.18.
(Z)-3-((2-Aminoethyl)amino)-1-(naphthalen-2-yl)-3-phe-
nylprop-2-en-1-one (22a1). 1H NMR (600 MHz, CDCl3) δ 11.59
(bs, 1H), 8.41 (s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.9 (d, J = 8.1 Hz, 1H),
7.85 (dd, J = 8.1, 7.5 Hz, 2H), 7.53ꢀ7.45 (m, 6H), 5.95 (s, 1H), 3.32 (dt,
J = 6.0 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H), 1.47 (bs, 2H); 13C NMR (150
MHz, CDCl3) δ 188.3, 167.1, 137.6, 135.8, 134.6, 132.9, 129.5, 129.2,
128.6, 127.8, 127.6, 127.4, 127.1, 94.0, 47.8, 42.5; HRMS (CI) calcd for
C21H21N2O [M + H]+ 317.1654, found 317.1649.
(2Z,20Z)-3,30-(Ethane-1,2-diylbis(azanediyl))bis(3-([1,10-
biphenyl]-4-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one)
(25a2). Mp 253ꢀ255 °C; IR, cmꢀ1, ν 1664 (CdO), 3430 (NH); 1H
NMR (400 MHz, CDCl3) δ 11.29 (s, 1H), 7.58 (t, J = 8.5 Hz, 4H),
7.46ꢀ7.33 (m, 5H), 7.12 (s, 2H), 5.73 (s, 1H), 3.87 (s, 3H), 3.85 (s, 6H),
3.42 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 187.6, 166.2, 152.8, 142.4,
140.6, 140.5, 135.4, 133.7, 128.8, 128.1, 127.8, 127.4, 127.3, 104.2, 93.9,
60.8, 56.1, 45.1.
(2Z,20Z)-3,30-(Ethane-1,2-diylbis(azanediyl))bis(1-(naphtha-
len-1-yl)-3-phenylprop-2-en-1-one) (22a2). 1H NMR (600 MHz,
CDCl3) δ11.35(bs, 1H), 8.37(s,1H), 7.98(d, J=8.3Hz, 1H), 7.89(d, J=
8.0 Hz, 1H), 7.86ꢀ7.82 (m, 2H), 7.54ꢀ7.45 (m, 3H), 7.42 (dt, J = 7.5, 7.1
Hz, 2H), 7.33 (d, J = 7.1 Hz, 2H), 5.9 (s, 1H), 3.40 (t, J = 7.1 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 188.7, 166.8, 137.4, 135.2, 134.7, 132.8, 129.6,
129.3, 128.7, 127.9, 127.7, 127.6, 127.5, 127.2, 126.3, 124.1, 94.7, 45.4;
HRMS (EI) calcd for C40H32N2O2 [M ]+ 572.2464, found 572.2453.
2-Butyl-4,5-dihydro-1H-imidazole (23c). 1H NMR (400 MHz,
CDCl3) δ 3.55 (bs, 4H), 2.22 (t, J = 7.0 Hz, 2H), 1.60ꢀ1.55 (m, 2H),
1.37ꢀ1.32 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H).
3-Phenyl-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-one
(26)37. Yield 1.1 g (47%), mp 87ꢀ89 °C, lit. mp 94ꢀ95 °C. IR (cmꢀ1) ν
1731 (CdO), 2207 (CtC); 1H NMR (400 MHz, CDCl3) δ 7.65ꢀ7.63
(d, J = 7.3 Hz, 2H), 7.47ꢀ7.41 (m, 5H), 3.94 (s, 9H).
(2Z,20Z)-3,30-(Ethane-1,2-diylbis(azanediyl))bis(3-phenyl-
1-(3,4,5-trimethoxyphenyl) prop-2-en-1-one) (26a2). Mp
202ꢀ204 °C; IR (cmꢀ1) ν 3437 (NH); 1H NMR (400 MHz, CDCl3)
δ 11.26 (s, 1H), 7.44 (m, 3H), 7.26 (m, 2H), 7.12 (s, 2H), 5.68 (s, 1H),
3.88 (s, 9H), 3.33 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 187.7,
166.5, 152.8, 140.5, 135.4, 134.9, 129.4, 128.6, 127.5, 104.2, 93.8, 60.8,
56.1, 44.9. Anal. Calcd for C38H40N2O8: C, 69.96; H, 6.18; N, 4.29.
Found: C, 69.94; H, 6.17; N, 4.35.
(Z)-3-((2-Aminoethyl)amino)-1-(4-fluorophenyl)hept-2-
en-1-one (23a1). 1H NMR (400 MHz, CDCl3) δ 11.46 (s, 1H), 7.86
(dd, J = 8.9, 5.6 Hz, 2H), 7.1 (t, J = 8.9 Hz, 2H), 5.63 (s, 1H), 3.28 (dt, J =
6.0, 6.0 Hz, 2H), 2.97 (t, J = 6.2 Hz, 2H), 2.34 (dd, J = 7.7 Hz, 2H),
1.66ꢀ1.37 (m, 7H), 0.96 (t, J = 7.3 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 186.5, 169.3, 164.5 (d, J = 250.3 Hz), 136.8, 128.8, 115.1,
114.9, 90.9, 46.0, 42.0, 32.4, 30.3, 22.8, 13.8; HRMS (EI) calcd for
C15H22FN2O [M + H]+ 265.1716, found 265.1710.
(2Z,20Z)-3,30-(Ethane-1,2-diylbis(azanediyl))bis(1-(4-fluoro-
phenyl)hept-2-en-1-one) (23a2). 1H NMR (400 MHz, CDCl3) δ
11.58 (s, 1H), 7.87 (dd, J = 8.8, 5.5 Hz, 2H), 7.06 (t, J = 8.8 Hz, 2H), 5.65
(s, 1H), 3.58 (d, J = 3.3 Hz, 2H), 2.33 (dd, J = 7.8, 7.8 Hz, 2H),
1.62ꢀ1.52 (m, 2H), 1.47ꢀ1.38 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 187.0, 169.0, 164.7 (d, J = 253.7 Hz), 136.4
129.6, 115.2, 114.9, 91.4, 43.4, 32.0, 30.9, 22.6, 13.8; HRMS (CI) calcd
for C28H35F2N2O2 [M + H]+ 469.2667, found 469.2663.
3-(4-Nitrophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-
1-one (27)38. Mp 206ꢀ207 °C; IR (cmꢀ1) ν 1646 (CdO), 2214
(CtC). 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.7, 2H), 7.8 (d, J =
8.7, 2H), 7.4 (s, 2H), 3.93 (s, 3H), 3.92 (s, 6H). Anal. Calcd for
C18H15NO6: C 63.36; H 4.51; N 4.22. Found: C 63.34; H 4.43; N 4.10.
2-(4-Nitrophenyl)-4,5-dihydro-1H-imidazole (27c)33. Mp
242ꢀ244 °C, lit. mp 242ꢀ243 °C;34 1H NMR (500 MHz, CDCl3) δ
8.30(d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.5Hz, 2H), 3.95ꢀ3.88 (m, 4H); MS
(ESI): m/z 191.9 [M+ H]+.
3-(4-Methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-
yn-1-one (24)31. Yield 2.23 g (68%), mp 154ꢀ156 °C, lit. mp
1
139ꢀ142 °C. IR (cmꢀ1) ν 1664 (CdO), 2194 (CtC); H NMR
’ ASSOCIATED CONTENT
(400 MHz, CDCl3) δ 7.60 (d, J = 8.9 Hz, 2H), 7.49 (s, 2H), 6.93 (d, J =
8.9 Hz, 2H0), 3.94 (d, J = 4.6 Hz, 9H), 3.81 (s, 3H). Anal. Calcd: C 69.93;
H 5.56 C19H18O5. Found: C 70.01; H 5.69.
S
Supporting Information. Detailed experimental proce-
b
dures for synthesis, H and 13C NMR spectroscopic data, MS,
1
1-(3,4,5-tTrimethoxyphenyl)ethanone (24b)32. IR (neat, cmꢀ1
)
total energy and Cartesian coordinates for each optimized
stationary structures. This material is available free of charge
via the Internet at http://pubs.acs.org.
ν 1680; 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 2H), 3.88ꢀ3.87 (m, 9H),
2.54 (s, 3H); 13C NMR(100 MHz, CDCl3): 196.8, 153.0, 142.5, 132.4,
105.7, 60.9, 56.2, 26.4; EI-MS m/z (%) 210 (90) [M]+; HRMS calcd for
C11H14O4 [M] 210.0892, found 210.0889 [M]+.
’ AUTHOR INFORMATION
2-(4-mMethoxyphenyl)-4,5-dihydro-1H-imidazole (24c)33.
Mp 135ꢀ140 °C, lit. mp 138ꢀ139 °C.34 1H NMR (500 MHz, CDCl3) δ
7.84 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 3.87 (s, 3H), 3.85 (bs,
4H). MS (ESI): m/z 177.0 [M + H] +.
Corresponding Author
*E-mail: vasilev@ns.kinetics.nsc.ru; alabugin@chem.fsu.edu.
(2Z,20Z)-3,30-(Ethane-1,2-diylbis(azanediyl))bis(3-(4-methoxy-
phenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one) (24a2).
Mp223ꢀ225 °C; IR(cmꢀ1) ν 1592 (CdO), 3440 (NH); 1H NMR (400
MHz, CDCl3) δ 11.24 (s, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.10 (s, 2H), 6.92
(d, J = 8.5 Hz, 2H), 5.66 (s, 1H), 3.85 (d, J = 8.5 Hz, 12H), 3.36 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 187.4, 166.5, 160.5, 152.8, 140.50, 135.5,
128.2, 127.2, 114.0, 104.2, 93.8, 60.7, 56.1, 55.2, 44.9; HRMS found m/z
712.2979 [M]+, C40H44O10N2, calcd M = 712.2990.
’ ACKNOWLEDGMENT
This work was supported by the Interdisciplinary Grant No. 93
of SB of the Russian Academy of Sciences (2009ꢀ2011), Grant
RFBR No. 10-03-00257-a (2010ꢀ2012), Grant 5.9.3. of the
Russian Academy of Sciences (2009ꢀ2011) and the Chemical
Service Centre of SB RAS. Work at FSU has been supported by
National Science Foundation (CHE-0848686).
7488
dx.doi.org/10.1021/jo201259j |J. Org. Chem. 2011, 76, 7482–7490

The Journal of Organic Chemistry
ARTICLE
’ REFERENCES
Syka, J. E. P.; Dryhurst, D. D.; Ausio, J.; Shabanowitz, J.; Hunt, D. F. Proc.
Natl. Acad. Sci. U.S.A. 2005, 102, 9463–9468. (f) Stenson, A. C.;
Marshall, A. G.; Cooper, W. T. Anal. Chem. 2003, 75, 1275–1284.
(8) (a) Kottani, R.; Valiulin, R. A.; Kutateladze, A. G. Proc. Natl. Acad.
Sci. U.S.A. 2006, 103, 13917–13921. (b) Kottani, R. R.; Majjigapu, J. R. R.;
Kurchan, A. N.; Majjigapu, K.; Gustafson, T. P.; Kutateladze, A. G.
J. Am. Chem. Soc. 2006, 128, 14794–14795. (c) Mitkin, O.; Wan, Y.;
Kurchan, A.; Kutateladze, A. Synthesis 2001, 8, 1133–1142. (d) Gustafson,
T. P.; Metzel, G. A.; Kutateladze, A. G. Org. Biomol. Chem. 2011, 9,
4752–4755.
(1) Acetylene Chemistry: Chemistry, Biology and Material Science;
Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim,
2005.
(2) FourCꢀCbonds: (a)Zeidan, T. A.;Kovalenko, S.V.;Manoharan,
M.; Clark, R. J.; Ghiviriga, I.; Alabugin, I. V. J. Am. Chem. Soc. 2005,
127, 4270–4285. One CdC and two CꢀH bonds: (b) Alabugin, I. V.;
Kovalenko, S. V. J. Am. Chem. Soc. 2002, 124, 9052–9053. (c) Breiner, B.;
Schlatterer, J. C.; Kovalenko, S. V.; Greenbaum, N. L.; Alabugin, I. V.
Angew. Chem., Int. Ed. 2006, 45, 3666–3670. (d) Yang, W.-Y.; Breiner, B.;
Kovalenko, S. V.; Ben, C.; Singh, M.; LeGrand, S. N.; Sang, Q.-X.;
Strouse, G. F.; Copland, J. A.; Alabugin, I. V. J. Am. Chem. Soc. 2009,
131, 11458–11470. Two CdC bonds: (e) Alabugin, I. V.; Gilmore, K.;
Patil, S.; Manoharan, M.; Kovalenko, S. V.; Clark, R. J.; Ghiviriga, I. J. Am.
Chem. Soc. 2008, 130, 11535–11545. One CdC bond, one C-Cbond, and
one C-H bond: (f) Pal, R.; Clark, R. J.; Manoharan, M.; Alabugin, I. V.
J. Org. Chem. 2010, 75, 8689–8692.
(3) For the intricate metal-catalyzed cascade reactions of alkynes,
creating multiple new CꢀC bonds, see also: (a) Jimꢀenez-Nꢀu~nez, E.;
Echavarren, A. M. Chem. Rev. 2008, 108, 3326–3350. (b) Aubert, C.;
Buisine, O.; Malacria, M. Chem. Rev. 2002, 103, 813–834. (c) Moreau, X.;
Goddard, J.-P.; Bernard, M.; Lemire, G.; L€opez-Romero, J. M.; Mainetti,
E.; Marion, N.; Mouris, V.; Thorimbert, S.; Fensterbank, L.; Malacriaa, M.
Adv. Synth. Catal. 2008, 350, 43–48. (d) Soriano, E.; Marco-Contelles, J.
J. Org. Chem. 2007, 72, 2651–2654. (e) Barluenga, J.; Riesgo, L.; Vicente,
R.; Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2007, 129, 7772–7773. (f)
Soriano, E.; Marco-Contelles, J. J. Org. Chem. 2005, 70, 9345–9353. (g)
Blaszykowski, C.; Harrak, Y.; Gonalves, M.-H.; Cloarec, J.-M.; Dhimane,
A.-L.; Fensterbank, L.; Malacria, M. Org. Lett. 2004, 6, 3771–3774. (h)
Harrak, Y.; Blaszykowski, C.; Bernard, M.; Cariou, K.; Mainetti, E.;
Mouris, V.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem.
Soc. 2004, 126, 8656–8657. (i) Mamane, V.; Gress, T.; Krause, H.;
F€orstner, A. J. Am. Chem. Soc. 2004, 126, 8654–8655.
(4) (a) Bluthe, N.; Gor€e, J.; Malacria, M. Tetrahedron 1986,
42, 1333–1344. (b) Fehr, C.; Vuagnoux, M.; Sommer, H. Chem.—Eur.
J. 2011, 17, 3832–3836. (c) Gagosz, F. Org. Lett. 2005, 7, 4129–4132.
(5) Vasilevsky, S. F.; Baranov, D. S.; Mamatyuk, V. I.; Gatilov, Y. V.;
Alabugin, I. V. J. Org. Chem. 2009, 74, 6143–6150.
(9) (a) Preliminary report: Davydova, M. P.; Vasilevskii, S. F.; Tolstikov.,
G. A. Izv. Akad. Nauk. Ser. Khim. 2011, 1, 180–181.
(10) TB interaction: (a) Hoffmann, R. Acc. Chem. Res. 1971, 4, 1–9.
(b) Gleiter, R.; Paddon-Row, M. N. Angew. Chem., Int. Ed. 2003,
13, 696–701. Charged species: (c) Alabugin, I. V.; Manoharan, M.
J. Am. Chem. Soc. 2003, 125, 4495–4509. (d) Alabugin, I. V.; Manoharan,
M. J. Org. Chem. 2004, 69, 9011–9024. Radicals: (e) Schottelius, M. J.;
Chen, P. J. Am. Chem. Soc. 1996, 118, 4896–4903. (f) Pickard, F. C., I. V.;
Shepherd, R. L.; Gillis, A. E.; Dunn, M. E.; Feldgus, S.; Kirschner, K. N.;
Shields, G. C.; Manoharan, M.; Alabugin, I. V. J. Phys. Chem. A. 2006,
110, 2517–2526.
(11) (a) Ci, X.; Lee, L. Y. C.; Whitten, D. G. J. Am. Chem. Soc. 1987,
109, 2536–2538. (b) Ci, X.; Whitten, D. G. J. Am. Chem. Soc. 1987,
109, 7215–7217. (c) Ci, X.; Kellett, M. A.; Whitten, D. G. J. Am. Chem. Soc.
1991, 113, 3893–3904.
(12) Facilitating effect of this bond weakening in anionic oxy-Cope
rearrangements: (a) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975,
97, 4765–4766. (b) Carpenter, B. K. Tetrahedron 1978, 34, 1877–1884.
(c) Evans, D. A.; Ballallargeon, D. J.; Nelson, J. V. J. Am. Chem. Soc. 1978,
100, 2242–2244. (d) Transition to the dissociative mechanism: Black,
K. A.; Wilsey, S.; Houk, K. N. J. Am. Chem. Soc. 1998, 120, 5622–5627. (e)
Hi, Y. Y.; Houk, K. N. J. Am. Chem. Soc. 1998, 120, 205–206. (f) Black,
K. A.; Wilsey, S.; Houk, K. N. J. Am. Chem. Soc. 2003, 125, 6715–6725.
(g) Synergestic effect of two alkoxy groups on the fragmentations: ref 2f
and references therein.
(13) (a) Alabugin, I. V.; Manoharan, M.; Zeidan, T. A. J. Am. Chem.
Soc. 2003, 125, 14014–14031. (b) Alabugin, I. V.; Manoharan, M.; Buck,
M.; Clark, R. J. THEOCHEM 2007, 813, 21–27. (c) Alabugin, I. V.;
Gilmore, K. M.; Peterson, P. W. WIREs Comp. Mol. Sci. 2011, 1,
109–141.
€
€
(6) (a) Seminal work: Eschenmoser, A.; Frey, A. Helv. Chim. Acta
1952, 35, 1660–1666. (b) Grob, C. A.; Schiess, P. W. Angew. Chem., Int.
Ed. Engl. 1967, 6, 1–15. (c) Wharton, P. S.; Hiegel, G. A. J. Org. Chem.
1965, 30, 3254–3257. (d) Tanabe, M.; Crowe, D. F.; Dehn, R. L.
Tetrahedron Lett. 1967, 3943–3946. (e) Recent review: Prantz, K.; Mulzer,
J. Chem. Rev. 2010, 110, 3741–3766. Representative recent examples:
(f) Alkynogenic fragmentations: Kamijo, S.; Dudley, G. B. J. Am. Chem.
Soc. 2005, 127, 5028–5029. Jones, D. M.; Lisboa, M. P.; Kamijo, S.;
Dudley, G. B. J. Org. Chem. 2010, 75, 3260–3267. Tummatorn, J.; Dudley,
G. B. Org. Lett. 2011, 13, 1572–1575. (g) Allenogenic fragmentations:
Kolakowski, R. V.; Manpadi, M.; Zhang, Y.; Emge, T. J.; Williams, L. J.
J. Am. Chem. Soc. 2009, 131, 12910–12911. (h) Saget, T.; Cramer, N.
Angew. Chem., Int. Ed. 2010, 49, 8962–8965. (i) Shifting unfavorable
equilibrium in 1,2-C,O transpositions: Baroudi, A.; Mauldin, J.; Alabugin,
I. V. J. Am. Chem. Soc. 2010, 132, 967–979. (j) Baroudi, A.; Alicea, J.;
Alabugin, I. V. Chem.—Eur. J. 2010, 16, 7683–7687. Baroudi, A.; Flack, P.;
Alabugin, I. V. Chem.—Eur. J. 2010, 16, 12316–12320. (k) Baroudi, A.;
Alicea, J.; Flack, P.; Kirincich, P.; Alabugin, I. V. J. Org. Chem. 2011,
76, 1521–1537. Other interesting examples: (l) Prantz, K.; Mulzer, J.
(14) Karpov, A. S.; Muller, T. J. J. Org. Lett. 2003, 5, 3451–3454.
(15) Spectroscopic data ofthe known products were identical tothose
reported in the literature: (a) Wu, X. F.; Sundararaju, B.; Neumann, H.;
Dixneuf, P. H.; Beller, M. Chem.—Eur. J. 2011, 17, 106–110. (b) Wu,
X.-F.; Neumann, H.; Beller, M. Chem.—Eur. J. 2010, 16, 12104–12107.
(c) Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 2071–2073.
(16) (a) Baldwin, J. E. J. Chem. Soc. Chem. Commun 1976, 734–736.
(b) Alabugin, I.; Gilmore, K.; Manoharan, M. J. Am. Chem. Soc. 2011
Epub ahead of print, DOI: 10.1021/ja203191f. (c) Gilmore, K.;
Alabugin, I. V. Chem. Rev. 2011 In process, DOI:10.1021/cr200164y.
(17) Although we refer to this step as retro-Mannich,27 the formal
oxidation state at the fragmentation site in our starting material is greater
than that in the typical aldol product. Such reactions has been classified
under the general umbrella of Mannich reactions in the literature:
(a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044–1070. (b) Schleimer, R.; W€urthwein, E.-U. Chem. Ber. 1994,
127, 1437–1440.
(18) Nenajdenko, V. G.; Muzalevskiy, V. M.; Shastin, A. V.;Balenkova,
E. S.; Kondrashov, E. V.; Ushakov, I. A.; Rulev, A. Y. J. Org. Chem. 2010,
75, 5679–5688.
(19) (a) Becke, A. D. Phys. Rev. A. 1988, 38, 3098–3100. (b) Lee,
C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789. (c)
Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem.
1994, 98, 11623–11627.
€
Angew. Chem., Int. Ed. 2009, 48, 5030–5033. (m) ElKaim, L.; Grimaud, L.;
Wagschal, S. Chem. Commun. 2011, 47, 1887–1889. (n) Sword, R.;
Baldwin, L. A.; Murphy, J. A. Org. Biomol. Chem. 2011, 9, 3560–3570.
(7) See for example: (a) Hamidane, H. B.; He, H.; Tsybin, O. Y.;
Emmett, M. R.; Hendrickson, C. L.; Marshall, A. G.; Tsybin, Y. O. J. Am.
Soc. Mass Spectrom. 2009, 20, 1182–1192. (b) Zubarev, R. A.; Kelleher,
N. L.; McLafferty, F. W. J. Am. Chem. Soc. 1998, 120, 3265–3266. (c)
Zubarev, R. A. Mass Spectrom. Rev. 2003, 22, 57–77. (d) Syka, J. E. P.;
Coon, J. J.; Schroeder, M. J.; Shabanowitz, J.; Hunt, D. F. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 9528–9533. (e) Coon, J. J.; Ueberheide, B.;
(20) We have used this level of theory earlier for anionic cyclizations
of N-nucleophiles:Vasilevsky, S. F.; Mikhailovskaya, T. F.; Mamatyuk,
V. I.; Bogdanchikov, G. A.; Manoharan, M.; Alabugin, I. V. J. Org. Chem.
2009, 74, 8106–8117.
7489
dx.doi.org/10.1021/jo201259j |J. Org. Chem. 2011, 76, 7482–7490

The Journal of Organic Chemistry
ARTICLE
(21) Frisch, M. J. et al. Gaussian 03, revision C.01; Gaussian, Inc.:
Wallingford, CT, 2004. See Supporting Information for complete
reference.
(22) (a) Pollack, R. M.; Ritterstein, S. J. Am. Chem. Soc. 1972,
94, 5064–5069. (b) Pollack, R. M.; Cooper, J. D. J. Org. Chem. 1973,
38, 2689–2692. (c) Aꢁnez, R.; Izquierdo, R.; Vidal, A.; Cordova, T.;
Sierraalta, A.; Chuchani, G. J. Phys. Org. Chem. 2006, 19, 836–840.
(23) Dipole moments of reactants were 2.5 and 2.7 D and transition
states 5.0 and 5.1 D for the Ph- and Me-substrates, respectively.
(24) Hansen, D. W.; Sinsheimer, J. E.; Burckhalter, J. H. J. Org. Chem.
1976, 41, 3556–3559.
(25) Importance of rehybridization in organic structure and reactiv-
ity: Alabugin, I. V.; Manoharan, M. J. Comput. Chem. 2007, 28, 373–390.
(26) (a) Alder, R. W.; Blake, M. E.; Chaker, L.; Harvey, J. N.; Paolini,
F.; Sch€utz, J. Angew. Chem, Int. Ed. 2004, 43, 5896–5911. (b) Wanzlick,
H. W. Angew. Chem., Int. Ed. Engl. 1962, 1, 75. (c) Lemal, D. M.; Lovald,
R. A.; Kawano, K. I. J. Am. Chem. Soc. 1964, 86, 2518–2519.
(27) For recent examples of retro-Mannich reactions, see: (a) White,
J. D.; Li, Y.; Ihle, D. C. J. Org. Chem. 2010, 75, 3569–3577. (b) Chen, P.;
Carroll, P. J.; Sieburth, S. M. Org. Lett. 2009, 11, 4540–4543. (c) White,
J. D.; Ihle, D. C. Org. Lett. 2006, 8, 1081–1084. (d) Cramer, N.; Juretschke,
J.; Laschat, S.; Baro, A.; Frey, W. Eur. J. Org. Chem. 2004, 7, 1397–1400.
(e) Page, P. C. B.; Heaney, H.; McGrath, M. J.; Sampler, E. P.; Wilkins,
R. F. Tetrahedron Lett. 2003, 44, 2965–2970. (f) Winkler, J. D.; Siegel,
M. G.; Stelmach, J. E. Tetrahedron Lett. 1993, 34, 6509–6512.
(28) Ruan, J.; Iggo, J. A.; Berry, N. G.; Xiao, J. J. Am. Chem. Soc. 2003,
132, 16689–16699.
(29) Nenajdenko, V. G.; Muzalevskiy, V. M.;Shastin, A. V.; Balenkova,
E. S.; Kondrashov, E. V.; Ushakov, I. A.; Rulev, A. Y. J. Org. Chem. 2010,
75, 5679–5688.
(30) Sharghi, H.; Jokar, M.; Doroodmand, M. M.; Khalifeh, R. Adv.
Synth. Catal. 2010, 352, 3031–3044.
(31) Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377–4380.
(32) Liu, M.; Hyder, Z.; Sun, Y.; Tang, W.; Xu, L.; Xiao, J. Org.
Biomol. Chem. 2010, 8, 2012–2015.
(33) Chen, J.; Wang, Z.; Li, C.-M.; Lu, Y.; Vaddady, P. K.; Meibohm,
B.; Dalton, J. T.; Miller, D. D.; Li, W. J. Med. Chem. 2010, 53, 7414–7427.
(34) Piskov, V. B.; Kasperovich, V. P.; Yakovleva, L. M. Chem.
Heterocycl. Compd. 1976, 12, 917–923.
(35) Anastassiadou, M.; Danoun, S.; Crane, L.; Baziard-Mouysset,
G.; Payard, M.; Caignard, D-H; Rettori, M.-C.; Renard, P. Bioorg. Med.
Chem. 2001, 9, 585–592.
(36) Hill, A. J.; Johnston, J. V. J. Am. Chem. Soc. 1954, 76, 922–923.
(37) Edwards, M. L.; Stemerick, D. M.; Sunkara, P. S. J. Med. Chem.
1990, 33, 1948.
(38) Vasilevsky, S. F.; Davydova, M. P.; Tolstikov, G. A. Chem.
Heterocycl. Compd. (N.Y.) 2008, 44, 1257–1261.
7490
dx.doi.org/10.1021/jo201259j |J. Org. Chem. 2011, 76, 7482–7490