Highly regioselective control of 1,2-addition of organolithiums to α,β-unsaturated compounds promoted by lithium bromide in 2-methyltetrahydrofuran: A facile and eco-friendly access to allylic alcohols and amines

Article abstract of DOI:10.1016/j.tet.2011.01.067

Very high regioselective 1,2-addition of organolithiums to α,α-unsaturated carbonyl-like compounds (ketones, aldehydes, and imines) in the presence of LiBr was achieved by carrying out reactions in the sustainable solvent 2-methyltetrahydrofuran. Excellent yields (in isolated product) of allylic alcohols and allylic amines were recovered under a simple experimental procedure at 0 °C.

Full text of DOI:10.1016/j.tet.2011.01.067

Tetrahedron 67 (2011) 2670e2675
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Tetrahedron
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Highly regioselective control of 1,2-addition of organolithiums to a,b-unsaturated
compounds promoted by lithium bromide in 2-methyltetrahydrofuran: a facile
and eco-friendly access to allylic alcohols and amines
,
,
c
a
a,
Vittorio Pace a b, Laura Castoldi a , Pilar Hoyos , Jose Vicente Sinisterra d, Massimo Pregnolato c,
ꢀ
a
a,
*
ꢀ
ꢀ
Jose M Sanchez-Montero
a
ꢀ
Biotransformations group, Organic and Pharmaceutical Chemistry Department, Pharmacy Faculty, Complutense University, Pza. Ramon y Cajal s/n, 28040 Madrid, Spain
b Department of Drug and Natural Products Synthesis, University of Wien, Althanstrasse 14, 1090 Wien, Austria
c Department of Pharmaceutical Chemistry, Pharmaceutical Biocatalysis Laboratories, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy
d Industrial Biotransformations Service, Scientific Park of Madrid, C/Santiago Grisolia 2, Tres Cantos, 28760 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Very high regioselective 1,2-addition of organolithiums to
a,b-unsaturated carbonyl-like compounds
Received 2 December 2010
Received in revised form 14 January 2011
Accepted 24 January 2011
Available online 28 January 2011
(ketones, aldehydes, and imines) in the presence of LiBr was achieved by carrying out reactions in the
sustainable solvent 2-methyltetrahydrofuran. Excellent yields (in isolated product) of allylic alcohols and
allylic amines were recovered under a simple experimental procedure at 0 ꢀC.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Regioselectivity
Green chemistry
Organometallic reagents
Addition
Enones
1. Introduction
the carbonyl reverse prenylation from the alcohol or aldehyde
oxidation level employing allenes,15 or the Ti-catalyzed addition of
Allylic alcohols and allylic amines represent useful building
blocks in organic synthesis because of their high versatility in
a wide range of organic transformations including asymmetric total
syntheses (e.g., cannabinoid-like compounds).1e4 Furthermore, the
importance of the hydroxyl motifs is well demonstrated by their
inclusion in a plethora of biologically active structures such as the
vinylaluminum to carbonyls;16 alternatively a distinct approach to
allylic alcohols is based on the use of the BayliseHillman re-
action.17,18 Analogously, in the synthesis of allylic amines the use of
transition metal (Pt,19 Fe,20 Pd,21 Ru22) catalyzed amination of allylic
compounds plays a central role.1
By far, the most simple approach to these structures is repre-
sented by the addition of organometallic species to opportune
sesquiterpenes (Z)-
a and (Z)-b santalol, recently isolated from
Santalum album, active against Helicobacter pylori chlaritromicin
resistant.5 Analogously, the allylic aminic functionality is frequently
found in a series of drugs, such as the antimicotic naftifine6 or the
calcium channel blocker flunarizine, active against peripheral vas-
cular diseases.7
a
,
b
-unsaturated carbonyl moieties, which formally is an operation
of CeC bond formation. Since -unsaturated carbonyl compounds
a,b
may be viewed as ambient electrophiles, the reaction with an or-
ganometallic can provide two different products proceeding by the
attack on the carbonyl carbon (1,2-addition) or, alternatively by
Considering the extreme importance of allylic alcohols, their
preparation has been object of intense studies. Indeed, organic
chemists have a series of protocols, among them the hydroboration
of alkynes (i.e., the addition of alkenylzinc to aldehydes),8e12 the Ni-
catalyzed alkylative coupling between aldehydes and alkynes,13,14
the attack on the b carbon, that is, the so-called conjugate 1,4-
addition.23 (Scheme 1) For this reason, it is clear that the regiose-
lective control that would allow the selective preparation of one of
the two possible regioisomers, is the key step to achieve an effective
synthetic strategy. Effectively, this control is the complex result of
different kinetic and thermodynamic parameters, as well as it is
strongly influenced by several factors, such as the nature of both
organometallic species and substrate.24 As a general rule, it was
* Corresponding author. Tel.: þ34 91 3941820; fax: þ34 91 3941822; e-mail ad-
dress: jsanchez@farm.ucm.es (J.Ma Sanchez-Montero).
ꢀ
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.067

V. Pace et al. / Tetrahedron 67 (2011) 2670e2675
2671
Scheme 2. Addition of MeLi to cyclohexenone 1.
Scheme 1. Addition of organometallic species to an
system.
a
,b-unsaturated carbonylic
higher than the stoichiometric, thus excluding the possibility of
a catalytic pathway (Table 1, entries 1e4).
At first glance, the presence of LiBr seems to give an opposite
result to the 1,4-fashion observed by Bertz and Dabbagh41 that
described an organocuprates protocol for the 1,4-addition. How-
ever, this apparent ambiguity can be explained by the different
nature of organometallic species (organocuprates versus organo-
lithiums), which can actually change the regioselectivity.
demonstrated that organolithiums are by far the most popular re-
agents to promote 1,2-addition,24 whereas organocuprates pre-
dominantly promotes conjugate addition.25,26 In fact, according to
Holm kinetic studies27 on the addition of Grignard reagents to
a,b-unsaturated compounds, the 1,2/1,4 ratio depends on both
substrate and reagent: in particular, if the substrate assumes a cisoid
conformation, only the 1,4-addition is observed. However, this same
author notes that such theory does not explain the observed 1,4
reactivity for substrates that only adopt a transoid conformation
(i.e., 2-cyclohexenone): thus, he rationalizes this behavior by in-
voking the concept of homolytic reaction mechanism, which is
probably not generalizable. A different mechanistic approach pro-
posed by Bryson28 and Cohen29 assumes that the regioselectivity of
addition is function of the ion pair structure of the lithium reagent:
thus, according to this model, contact ion pairs (CIP) with an intact
CeLi association give 1,2-addition, while solvent-separated ion pairs
(SIP) afford mainly the 1,4-addition products. Furthermore, an ad-
ditional intriguing factor to be evaluated is the nature of the solvent
and/or the presence of some additive. Hexamethylphosphoramide
(HMPA) is frequently employed to accelerate organolithium re-
actions because its capability to coordinate the lithium cations is
approximately 300 times more strongly than THF,30 the presence
(2 equiv) of such polar aprotic solvent maximizes the 1,4/1,2 ratio
respect to the same reaction carried out in diethyl ether or
THF.31,32 Finally, the temperature plays a crucial role in that, cold
providing mainly 1,4-additions29 (conditions, which favors SIP
formation33).
As a consequence of this high complexity of the regioselective
control, carrying out reactions in the presence of Lewis acids seems
to be a valuable strategy to maximize 1,2-adducts. In fact, the ad-
dition of Grignard reagents in the presence of catalytic amounts of
InCl3 affords predominantly 1,2-products.34 However, as can be
deduced by the opposite effect that the indium salt plays on dif-
ferent Grignard reagents, its applicability is not general. Some im-
provement has been detected by employing organocerium(III)
reagents:35 however, the use of this expensive lanthanide requires
very low temperatures (ꢁ78 ꢀC), thus complicating the possible
scale-up process. For these reasons, it is necessary to develop
synthetic procedures, with the goal of expanding the applicability
on different substrates and to improve feasibility.
It is interesting to underline the better results obtained with
LiBr compared to previously employed CeCl3, which gave a 78%
yield upon addition of MeLi at ꢁ78 ꢀC.42 Analogously, other Lewis
acids afforded poor results with respect to LiBr (Table 1, entries
10e13). The solvent effect seems to be critical to the efficiency of
the process, in fact, switching from normally used THF to its eco-
friendly substitute 2-methyltetrahydrofuran43,44 (MeTHF) en-
hances the reaction giving better results in shortest reaction time
(entry 7). Diethyl ether (Table 1, entry 8) and THF (entry 9) gave
lower yields respect to MeTHF (Table 1, entry 7). This effect is quite
general and is also found at low temperatures (Table 1, entries
5e6). Schmalz noticed the same beneficial effect of MeTHF in
promoting 1,4-addition with Grignard reagents.45 Under opti-
mized conditions [RLi (1.5 equiv), enone (1.0 equiv), LiBr
(1.5 equiv), MeTHF, 0 ꢀC], reactions proceeded cleanly without any
side processes, such as 1,4-addition, enolization or reduction
normally associated to organometallic reactions. The discovery of
reactions in which the best results were obtained with the eco-
friendly solvent MeTHF, it opens the interesting possibility of
combining a high regioselective process with a sustainable organic
synthesis. MeTHF, in fact, is a good substitute of THF for several
reasons: (1) its precursor (furfural) is derived from renewable
sources (corncobs or bagasse), in accordance with the seventh
principle of Green Chemistry, the so-called 3R considerations
(reduce, recycle, reuse). (2) Although this solvent does not show
advantages on THF in terms of peroxides formation in the absence
of stabilizers, it provides very clean organic-water phase separa-
tions with little tendency to form emulsions. Since THF is com-
pletely miscible with water, its substitution with MeTHF allows to
avoid the use of other organic solvents (mainly diethyl ether) prior
to quenching with water. (3) In general, organometallic reagents
show improved solubility/stability profile in MeTHF compared to
Table 1
As a part of the development of synthetic methodologies with
low ambient impact currently undergoing in our laboratory,36e40
herein we show a simple and efficient protocol to allow an abso-
lute1,2-regioselectivity in the addition of organolithiums to
Reaction conditions screening
Entry
Additive
Solvent
Additive
amount
(equiv)
T (ꢀC)
Reaction
time (h)
Isolated
yield
of 2 (%)
a,b-unsaturated carbonyl compounds based on the use of an
1
2
3
4
5
6
7
8
e
THF
THF
THF
THF
e
ꢁ78
ꢁ78
ꢁ78
ꢁ78
ꢁ20
ꢁ20
0
0
0
0
0
12
12
9
7
6
4
2
5
8
70
71
73
77
79
93
Quant.
78
83
additive (LiBr) in a green solvent, that is, 2-methyltetrahydrofuran
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiClO4
LiCl
0.15
0.50
1.00
1.50
1.50
1.50
1.50
1.50
1.50
1.50
1.50
at 0 ꢀC.
THF
MeTHF
MeTHF
Et2O
2. Results and discussion
As a control reaction, we selected the addition of MeLi to
2-cyclohexenone 1. Scheme 2 shows that the addition of LiBr is
beneficial in terms of both regioselectivity and recovered yield. It
must be stressed that the best results are observed when the ratio is
9
THF
10
11
12
MeTHF
MeTHF
MeTHF
4
3.5
6
85
89
67
ZnBr2
0

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V. Pace et al. / Tetrahedron 67 (2011) 2670e2675
THF, increasing interest for the use of this solvent in organome-
tallic reactions. (4) Although a comprehensive toxicological study
is pendingdand thus, MeTHF should not (yet) be regarded as
‘green’ solventdit can be derived as mentioned above from bio-
masses and it is abiotically degraded in air.
interesting to note that the highly basic t-BuLi requires low tem-
perature (ꢁ20 ꢀC) in order to add efficiently to cyclohexenone
(Table 2, entries 3e4). On the contrary, less nucleophilic PhLi re-
quires longer reaction time (Table 2, entry 5). Once again, our
protocol proved to be superior to methodologies based on the use
of Grignard reagents: the use of the aforementioned InCl3,34 gave
a 1:1 mixture of alcohol 7 and its regioisomer derived by 1,4-ad-
dition, as well as it strikingly improve the amount of 1,4-addition
products when PhMgBr or t-BuMgBr was used. Higher 1,2-addition
selectivity was also observed with respect to previously reported n-
BuLi addition in diethyl ether at ꢁ78 ꢀC, which gave a poor 74%
yield.47
On the basis of the shown data, it should be stressed that the
best results in terms of selectivity and yields are obtained in the
presence of the combined system LiBreMeTHF. To the best of our
knowledge, our protocol substantially improves previously de-
scribed procedures. In fact, the addition of Grignard reagents to
cyclohexenone seems to afford different results by using similar
reaction conditions: Baba and co-workers reported only a modest
yield (18%)46 of 2, while Whitwood obtained a 69% yield.47
Subsequently, the protocol was tested with different organo-
lithiums in order to expand its general applicability. As shown in
Table 2, our protocol allowed to obtain excellent yields of the de-
sired allylic alcohols 3e9 in short reaction times, without signifi-
cant differences in the hybridization state of the carbanion, as well
as the eventual presence of substituents (Table 2, entries 2e4). It is
By varying the nature of the
a,b-unsaturated carbonyl com-
pounds is possible to extend the applicability of the methodology to
the regioselective synthesis of widely functionalized tertiary allylic
alcohols. Acyclic ketone (entries 1e2) reacted efficiently without
formation of byproducts as shown in Table 3. High regioselectivity
(with an overall yield of 77%) has previously been achieved by
employing a complex strategy based on the addition of Grignard
reagents to expensive and not readily synthesized N-enoylsultams
(Oppolzer sultams) at ꢁ78 ꢀC48
Analogously, aldehydes reacted smoothly regardless of their
aromatic (Table 3, entries 3e4) or aliphatic nature (Table 3, entries
5e6): we observed better results by employing our combined
LiBreMeTHF strategy instead of simple organomagnesium re-
agents49 or organolithiums added in the absence of LiBr.50,51
From a mechanistic point of view, the presence of LiBr favors
the complexation between the Li cation and the carbonyl group of
Table 2
LiBr mediated 1,2-regioselective addition of different organolithiums in MeTHF to
cyclohexenonea
the
a,b-unsaturated system. This proposed coordination would
increase the positive charge in the carbon of C]O, reducing the
positive charge of C-3. Even more, the R group would be very close
the carbon of C]O. These effects would increase the reaction rate
and the regioselectivity of the subsequent attack of the
Entry RLi
Reaction time (h)
/temperature (ꢀC)
Product
Isolated Yield (%)
Quant.
1
n-Bu
2/0
Table 3
LiBr promoted addition of organolithiums in 2-MeTHF to different
a
,b
-unsaturated
ketones and aldehydesa
Entry
1
Substrate
RLi
Me
Product
Isolated
yield (%)
2
3
s-Bu
t-Bu
4/0
4/0
91
95
91
Complex mixture
e
4
t-Bu
5/ꢁ20
86
2
3
n-Bu
Me
97
92
5
6
7
Ph
7/0
2/0
2/0
93
98
Et
4
5
n-Bu
n-Pr
95
91
n-Bu
n-Bu
88
94
8
n-Pentyl 2/0
6
a
a
Reaction conditions: substrate: RLieLiBr (1:1.5:1.5), 2-MeTHF.
Reaction conditions: substrate: RLieLiBr (1:1.5:1.5), 2-MeTHF, 0 ꢀC, 2 h.

V. Pace et al. / Tetrahedron 67 (2011) 2670e2675
2673
Table 4
allows a simple and high-yielding method for the preparation of
allylic alcohols and allylic amines. This protocol allows to obtain
very high 1,2-regioselectivity with no detection (1H NMR) of un-
desired 1,4-adducts, as well contaminant products that normally
affect organometallic mediated reactions. Notably, the use of the
eco-friendly solvent 2-MeTHF allows to develop a green protocol, in
which the addition of the organometallics takes place at not pro-
hibitive low temperature (only 0 ꢀC), thus constituting the bases for
scale-up processes that are currently undergoing in our laboratory.
LiBr promoted 1,2-regioselective addition of organolithiums in 2-MeTHF to different
aryl and alkyl a,b
-unsaturated iminesa
Entry
1
Substrate
RLi
Me
Product
Isolated
yield (%)
4. Experimental section
4.1. General method
98
All 1H NMR, 13C NMR, were recorded on a Bruker AC-250
spectrometer at 250 MHz and at 62.5 MHz, respectively, using
a convenient deuterated solvent (reported in the characterization
charts) and the residual peak as internal standard TMS in the case of
2
3
4
n-Bu
Me
Quant.
95
CDCl3. Chemical shifts are reported in
d (ppm) referred to 1H (of
residual protons) 13C of the deuterated solvents. IR absorption
spectra were recorded on a PerkineElmer System 2000 FT-IR
spectrophotometer. Compounds 1, 10a, 11a, 11b, 11c as well all
chemicals, solvents, and reagents were purchased from Sigma and
were used without further purification. 2-Methyltetrahydrofuran
was distilled under Na/benzophenone before use. LiBr was dried
over P2O5. Imines 14, 15, and 16 were prepared according to the
established procedures specified in the corresponding paragraphs.
n-Bu
97
5
n-Bu
98
4.2. Synthesis of imines 14, 15, and 16
4.2.1. N-(3-Phenylallylidene)aniline (14). A mixture of cinna-
maldehyde (5.00 mmol, 660 mg), aniline (6.00 mmol, 559 mg), and
MgSO4 (5.00 mmol, 602 mg) was stirred in dried benzene (15 mL)
for 1 h at room temperature. After filtration and removal of the
solvent under reduced pressure, a yellow solid was obtained, which
was recrystallized from methanol (767 mg, 74% yield). Mp: 107 ꢀC
a
Reaction conditions: substrate: RLieLiBr (1:1.5:1.5), 2-MeTHF, 0 ꢀC, 2 h.
organolithium. Effectively, this complexation enhances the rate of
reaction with RLi since the complexed carbonyl group should be
highly polarized as in other cases of acid catalysis of carbonyl
compounds.
Encouraged by these results, we decided to probe the scope of
our methodology for the preparation of allylic amines: in this
regard, due to the poor electrophilicity of the azomethine carbon,
addition of organometallics is often plagued by competitive enoli-
zation, reduction, or coupling reactions.52 Furthermore, in the case
(lit.57 106e108 ꢀC). 1H NMR (250 MHz, CDCl3)
d (ppm): 7.21 (m, 5H),
7.42 (m, 5H), 7.56 (m, 2H), 8.28 (dd, J¼2.1, 6.5 Hz, 1H). 13C NMR
(62.5 MHz, CDCl3)
d (ppm): 120.8, 126.3, 127.9, 129.0, 129.3, 129.4,
129.8, 134.9, 144.1, 152.0, 162.1. IR (NaCl) cmꢁ1 1630, 1598, 1572,
1486, 1445, 753, 689. Anal. Calcd for C15H13 N: C, 86.92; H, 6.32; N,
6.76. Found: C, 86.74; H, 6.14; N, 6.44.
of addition of organometallics to
a,b-unsaturated imine com-
4.2.2. N-(4-Phenylbut-3-en-2-ylidene)aniline (15). A solution of
4-phenylbut-3-en-2-one (4.00 mmol, 584 mg), aniline (4.00 mmol,
372 mg), and anhydrous zinc(II) chloride (5 mol %, 27 mg) in ben-
zene (10 mL) was refluxed for 6 h with azeotropic removal of water
(DeaneStark apparatus). Then, the catalyst was removed by filtra-
tion, the benzene was removed under reduced pressure, giving
a yellow solid, which was purified by recrystallization from ethanol
(65% yield, 575 mg). Mp: 107 ꢀC (lit.58 106e108 ꢀC). 1H NMR
pounds, the 1,2- and 1,4-selectivity has been shown to be de-
pendent not only on the type of the organometallic,53 but also on
the nature of the imine.54 Thus with such reagents, aromatic imines
give predominantly 1,4-addition, while aliphatic ones give the
1,2-addition product.55 By using our protocol (Table 4), we were able
to add organolithiums in a 1,2-fashion regardless the electronic
nature of the imine (aromatic or aliphatic), as well the fact that
the imine is derived from a ketone or an aldehyde. Remarkably, the
addition of highly basic and nucleophilic n-butyl lithium to
N-cyclohexil imine (Table 4, entry 5) occurs with 1,2-regioselectivity,
thus constituting a complementary technique to the use of the
organolithiums in absence of LiBr that add in 1,4-fashion.55 Fur-
thermore, this methodology simplifies the previously LaCl3-medi-
ated 1,2-addition that requires the use of this expensive salt at low
temperature,56 thus representing a versatile procedure for the
preparation of allylic amines.
(250 MHz, CDCl3)
d
(ppm): 1.84 (s, 3H), 7.16e7.23 (m, 5H), 7.32e7.37
(ppm):
(m, 5H), 7.46e7.56 (m, 2H). 13C NMR (62.5 MHz, CDCl3)
d
23.3, 120.6, 125.1, 126.6, 129.3, 129.7, 131.2, 132.0, 136.4, 143.6, 152.9,
165.0. IR (NaCl) cmꢁ1 1656, 1600, 1542, 739. Anal. Calcd for C16H15
N: C, 86.84; H, 6.83; N, 6.33. Found: C, 86.49; H, 6.99; N, 6.18.
4.2.3. N-(3-Phenylallylidene)cyclohexanamine (16). A mixture of
cinnamaldehyde (5.00 mmol, 660 mg), cyclohexylamine
(6.00 mmol, 595 mg), and MgSO4 (5.00 mmol, 602 mg) was stirred
in dried benzene (15 mL) for 2 h at room temperature. After
filtration and removal of the solvent under reduced pressure
a colorless oil was obtained (906 mg, 85% yield). 1H NMR (250 MHz,
3. Conclusions
In this work we show the efficiency of the binary system
(LiBre2-methyltetrahydrofuran) in promoting the additions of
CDCl3)
2H), 7.25e7.45 (m, 5H), 8.04 (m, 2H). 13C NMR (62.5 MHz, CDCl3)
(ppm): 21.7, 24.2, 31.6, 65.2, 120.6, 128.1, 128.5, 130.3, 134.2,
d (ppm): 1.42e1.84 (m, 9H), 4.51e4.60 (m, 1H), 6.91 (m,
organolithiums to different
a
,b
-unsaturated compounds, that
d

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V. Pace et al. / Tetrahedron 67 (2011) 2670e2675
137.8, 160.4. IR (NaCl) cmꢁ1 1622, 3081, 1598, 1562, 919. Anal. Calcd
for C15H19 N: C, 84.86; H, 8.98; N, 6.57. Found: C, 84.71; H, 8.69; N,
6.69.
d (ppm): 13.7, 15.8, 18.1, 32.1, 34.4, 43.8, 74.2, 128.3, 132.1. IR (NaCl)
cmꢁ1: 3444, 2957, 2357, 2339, 2247, 1694, 1682, 1652, 1557, 1454,
912, 731. Anal. Calcd for C9H16O: C, 77.09; H, 11.50. Found: C, 77.24;
H, 11.35.
4.3. General procedure for LiBr mediated 1,2-addition of
different organolithiums in 2-MeTHF to
compounds
a
,
b-unsaturated
4.3.8. 1-n-Pentylcyclohex-2-enol (9). 1H NMR (250 MHz, CDCl3)
d
(ppm): 0.88 (t, J¼7.0 Hz, 3H), 1.18e1.39 (m, 6H), 1.48e1.68 (m,
6H), 1.88e2.06 (m, 2H), 5.56 (d, J¼9.8 Hz, 1H), 5.75 (m, 1H). 13C
In a typical experiment a mixture of
a,
b-unsaturated compound
NMR (62.5 MHz, CDCl3) d (ppm): 14.5, 19.5, 23.6, 25.6, 30.5, 32.8,
(2.00 mmol, 1.0 equiv) and LiBr (3.00 mmol, 1.5 equiv) in freshly
distilled 2-MeTHF (5 mL) was cooled at 0 ꢀC. Organolithium re-
agents (3.00 mmol,1.5 equiv) were then added drop-wise. After 2 h,
reactions were quenched with saturated ammonium chloride
aqueous solution (5 mL). After extraction with ethyl acetate
(2ꢂ10 mL), desiccation over sodium sulfate, filtration, and solvent
removal under reduced pressure, whenever necessary, the crude
products were purified by liquid chromatography.
35.8, 42.7, 70.1, 130.1, 133.3. IR (NaCl) cmꢁ1: 3443, 3018, 2957,
1454. Anal. Calcd for C11H20O: C, 78.51; H, 11.98. Found: C, 78.70;
H, 12.17.
4.3.9. 2-Methyl-4-phenylbut-3-en-2-ol (12a). 1H NMR (250 MHz,
CDCl3)
d
(ppm): 1.47 (s, 6H), 2.02 (br s, 1H), 6.39 (d, J¼16.1 Hz, 1H),
6.64 (d, J¼16.1 Hz, 1H), 7.22e7.26 (m, 1H), 7.31e7.37 (m, 2H), 7.39
(m, 2H). 13C NMR (62.5 MHz, CDCl3)
d
(ppm): 28.8 (ꢂ2), 70.0, 125.9,
127.4, 128.6, 128.9, 131.0, 135.8, 136.5. IR (NaCl) cmꢁ1: 3390, 3082,
1636. Anal. Calcd for C11H14O: C, 81.44; H, 8.70. Found: C, 81.20H,
8.99.
4.3.1. 1-Methylcyclohex-2-enol (2). 1H NMR (250 MHz, CDCl3)
d
(ppm): 1.29 (s, 3H), 1.59e1.91 (m, 7H), 5.63 (d, J¼3.7, 4.1, 10.2 Hz,
1H), 5.70e5.74 (m, 1H, ]CH). 13C NMR (62.5 MHz, CDCl3)
d (ppm):
19.7, 25.2, 29.4, 37.6, 67.7, 129.3, 133.9. IR (NaCl) cmꢁ1 3370, 1655.
Anal. Calcd for C7H12O: C, 74.95; H, 10.78. Found: C, 74.76; H, 10.99.
4.3.10. 3-Methyl-1-phenylhept-1-en-3-ol (12b). 1H NMR (250 MHz,
CDCl3)
d
(ppm): 0.95 (t, J¼7.2 Hz, 3H), 1.36e1.40 (m, 4H), 1.43 (s,
3H), 1.64 (m, 2H), 1.96 (br s, 1H), 6.33 (d, J¼16.1 Hz, 1H), 6.63 (d,
4.3.2. 1-n-Butylcyclohex-2-en-1-ol (3). 1H NMR (250 MHz, CDCl3)
J¼16.1 Hz, 1H), 7.24e7.46 (m, 5H). 13C NMR (62.5 MHz, CDCl3)
d
(ppm): 0.88 (t, J¼7.2 Hz, 3H),1.26e1.38 (m, 4H),1.44e1.55 (m, 3H),
d (ppm): 13.1, 22.1, 25.2, 27.1, 41.6, 72.2, 125.3, 125.4, 125.8, 126.3,
1.60e1.70 (m, 4H), 1.90e2.01 (m, 1H), 2.01e2.10 (m, 1H), 5.59e5.65
(m, 1H), 5.88 (ddd, J¼3.1, 4.1, 10.2 Hz, 1H). 13C NMR (62.5 MHz,
126.4, 127.4, 135.8, 136.0. IR (NaCl) cmꢁ1: 3399, 3078, 1666, 1491,
1456, 936. Anal. Calcd for C14H20O: C, 82.30; H, 9.87. Found: C,
82.56; H, 10.05.
CDCl3)
d (ppm): 13.7, 23.7, 24.8, 35.1, 42.1, 70.4, 130.2, 132.5. IR
(NaCl) cmꢁ1: 3365, 1660. Anal. Calcd for C10H18O: C, 78.87; H, 11.76.
Found: C, 79.05; H, 11.93.
4.3.11. 4-Phenylbut-3-en-2-ol (13a). 1H NMR (250 MHz, CDCl3)
d
(ppm): 1.39 (d, J¼6.5 Hz, 3H), 1.65 (s, 1H), 3.78 (s, 3H), 4.32 (br s,
4.3.3. 1-sec-Butylcyclohex-2-enol (4). 1H NMR (250 MHz, CDCl3)
1H), 6.11 (dd, J¼6.5, 16.3 Hz, 1H), 6.54 (d, J¼16.3 Hz, 1H), 6.86e7.36
d
(ppm): 0.89 (t, J¼7.0 Hz, 3H), 0.95 (d, J¼6.8 Hz, 3H), 1.49 (m, 2H),
(m, 4H). 13C NMR (62.5 MHz, CDCl3)
d (ppm): 23.9, 55.7, 69.5, 114.3,
1.56e1.68 (m, 4H), 1.70 (m, 1H), 1.89e1.95 (m, 1H), 2.03e2.12 (m,
1H), 3.05 (br s,1H), 5.56 (ddt, J¼1.5, 2.6, 8.9 Hz,1H), 5.81 (ddt, J¼2.2,
127.9, 129.1, 129.6, 132.0, 159.5. IR (NaCl) cmꢁ1: 3389, 3074, 1660,
1484, 1442, 921. Anal. Calcd for C14H14O2: C, 74.13; H, 7.92. Found: C,
73.90; H, 8.11.
4.6, 9.1 Hz, 1H). 13C NMR (62.5 MHz, CDCl3)
d (ppm): 16.2, 17.9, 18.4,
25.1, 25.6, 30.3, 36.8, 70.6, 131.0, 133.1. IR (NaCl) cmꢁ1: 3451, 1466,
1435. Anal. Calcd for C10H18O: C, 78.87; H, 11.76. Found: C, 79.58; H,
11.51.
4.3.12. 1-Phenylhept-1-en-3-ol (13b). 1H NMR (250 MHz, CDCl3)
d
(ppm): 0.81 (t, J¼7.5 Hz, 3H), 1.26e1.38 (m, 4H),1.46e1.53 (m, 1H),
2.07 (br s, 1H), 3.73 (s, 3H), 4.21e4.26 (m, 1H), 6.21 (dd, J¼6.5,
4.3.4. 1-tert-Butylcyclohexen-2-enol (5). 1H NMR (250 MHz, CDCl3)
16.2 Hz, 1H), 6.55 (d, J¼16.2 Hz, 1H), 6.73e7.18 (m, 4H). 13C NMR
d
(ppm): 0.82 (s, 9H),1.33e2.41 (m, 7H), 5.78 (d, J¼10.3 Hz,1H), 5.86
(62.5 MHz, CDCl3) d (ppm): 13.0, 21.6, 26.6, 36.1, 54.2, 72.2, 112.9
(ddd, J¼1.9, J¼10.3, 1H). 13C NMR (62.5 MHz, CDCl3)
d
(ppm): 18.9,
(ꢂ2), 126.6 (ꢂ2), 128.0, 130.1, 131.0, 153.3. IR (NaCl) cmꢁ1: 3391,
3062, 1612, 1434, 1422, 1324, 931, 716. Anal. Calcd for C14H20O2: C,
76.33; H, 9.15. Found: C, 76.12; H, 9.36.
25.1, 30.9, 36.8, 72.8, 129.5, 130.9. IR (NaCl) cmꢁ1: 3459, 2962. Anal.
Calcd for C10H18O: C, 77.88; H, 11.74. Found: C, 77.56; H, 11.50.
4.3.5. 1-Phenylcyclohex-2-enol (6). 1H NMR (250 MHz, CDCl3)
4.3.13. Hept-1-en-3-ol (13c). 1H NMR (250 MHz, CDCl3)
d (ppm):
d
(ppm): 1.59 (m, 1H), 1.75 (m, 1H), 1.83 (dd, J¼12.6, 3.0 Hz, 1H),
0.82 (t, J¼6.9 Hz, 3H,), 1.11e1.32 (m, 6H), 1.91 (br s, 1H), 3.97 (dd,
J¼5.1, 7.2 Hz, 1H), 5.06 (dd, J¼10.1, 17.2 Hz, 1H), 5.12 (dd, J¼10.3,
17.2 Hz, 1H), 5.85 (ddd, J¼6.5, 10.3, 17.0 Hz). 13C NMR (62.5 MHz,
1.98e2.20 (m, 4H), 5.72 (d, J¼10.0 Hz, 1H), 6.02 (ddd, J¼3.8, 4.0,
10.0 Hz, 1H), 7.18 (t, J¼1.1, 7.2 Hz, 1H), 7.35 (t, J¼7.9 Hz, 2H), 7.44 (d,
J¼7.9 Hz, 2H). 13C NMR (62.5 MHz, CDCl3)
d
(ppm): 71.9, 124.9,
CDCl3) d (ppm): 14.4, 23.0, 27.9, 37.1, 73.6, 114.9, 141.7. IR (NaCl)
126.6, 128.2, 130.0, 131.8, 147.5. IR (NaCl) cmꢁ1: 3449, 2968, 1462.
Anal. Calcd for C12H14O: C, 82.72; H, 8.10. Found: C, 82.49; H, 8.31.
cmꢁ1: 3378, 3085, 1645. Anal. Calcd for C7H14O: C, 73.63; H, 12.36.
Found: C, 73.89; H, 12.03.
4.3.6. 1-Ethylcyclohex-2-enol (7). 1H NMR (250 MHz, CDCl3)
4.3.14. 2-Methylhept-1-en-3-ol (13d). 1H NMR (250 MHz, CDCl3)
d
(ppm): 0.85 (t, J¼7.5 Hz, 3H), 1.48 (d, J¼7.5 Hz, 2H), 1.61e2.23 (m,
d
(ppm): 0.86 (t, J¼7.0 Hz, 3H,),1.13e1.31 (m, 4H),1.46e1.52 (m, 2H),
7H), 5.59 (d, J¼10.0 Hz, 1H), 5.66 (ddd, J¼2.5, 4.1, 10.0 Hz, 1H). 13C
1.74 (s, 3H), 3.99 (dd, J¼5.0, 7.5 Hz, 1H), 4.75 (d, J¼2.5 Hz), 4.86 (d,
NMR (62.5 MHz, CDCl3)
d
(ppm): 18.1, 19.9, 24.6, 32.1, 33.8, 74.2,
J¼2.6 Hz). 13C NMR (62.5 MHz, CDCl3)
d (ppm): 13.0, 16.4, 21.6, 26.7,
128.4, 131.9. IR (NaCl) cmꢁ1: 3443, 3019, 2959, 2359, 2339, 2249,
1694, 1682, 1652, 1455, 1258, 1177, 1113. Anal. Calcd for C8H14O: C,
76.14; H, 11.18. Found: C, 76.36; H, 10.99.
33.6, 75.0, 109.9, 146.6. IR (NaCl) cmꢁ1: 3386, 3081, 1641, 899. Anal.
Calcd for C8H16O: C, 74.94; H, 12.58. Found: C, 74.70; H, 12.42.
4.3.15. N-(4-Phenylbut-3-en-2-yl)aniline (17a). 1H NMR (250 MHz,
CDCl3)
J¼5.4, 16.0 Hz, 1H), 6.61 (d, J¼16.0 Hz, 1H), 6.66e6.70 (m, 2H),
6.70e6.75 (m, 1H), 7.17e7.22 (m, 2H), 7.22e7.28 (m, 1H), 7.32 (dd,
4.3.7. 1-n-Propylcyclohex-2-enol (8). 1H NMR (250 MHz, CDCl3)
d
(ppm): 1.41 (t, J¼7.1 Hz, 3H), 4.12e4.22 (m, 1H), 6.21 (dd,
d
(ppm): 0.86 (d, J¼7.5 Hz, 3H), 1.20e2.11 (m, 10H), 3.15 (br s, 1H),
5.56 (d, J¼10.0 Hz, 1H), 5.73 (m, 1H). 13C NMR (62.5 MHz, CDCl3)

V. Pace et al. / Tetrahedron 67 (2011) 2670e2675
2675
J¼7.0 Hz, 1H), 7.39 (m, 2H). 13C NMR (62.5 MHz, CDCl3)
d
(ppm):
References and notes
51.3, 114.0, 117.6, 125.9, 127.3, 129.0, 129.4, 129.5, 133.6, 137.8, 147.9.
IR (NaCl) cmꢁ1: 3410, 2970, 1749, 1619, 1514, 1256, 975, 749, 698.
Anal. Calcd for C16H17 N: C, 86.05; H, 7.67; N, 6.27. Found: C, 86.26;
H, 7.48; N, 6.41.
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4.3.16. N-(1-Phenylhept-1-en-3-yl)aniline (17b). 1H NMR (250 MHz,
CDCl3)
d
(ppm): 0.84 (t, J¼7.0 Hz, 3H), 1.25e1.38 (m, 4H),
1.56e1.63 (m, 2H), 3.78 (br s, 1H), 3.86e3.89 (m, 1H), 6.05 (dd,
J¼7.5, 17.5 Hz, 1H), 6.45e6.63 (m, 4H), 7.04e7.30 (m, 7H). 13C NMR
(62.5 MHz, CDCl3)
d (ppm): 14.5, 23.1, 28.6, 36.5, 56.2, 113.8, 117.6,
126.8, 127.3, 128.9, 129.6, 130.5, 132.7, 137.5, 148.1. IR (NaCl) cmꢁ1
:
3402, 3080, 2981, 1741, 1612, 1521, 1276, 981. Anal. Calcd for
C19H23 N: C, 85.99; H, 8.74; N, 5.28. Found: C, 86.18; H, 8.48;
N, 5.11.
4.3.17. N-(2-Methyl-4-phenylbut-3-en-2-yl)aniline (18a). 1H NMR
(250 MHz, CDCl3)
d (ppm): 1.36 (s, 6H), 3.51 (br s), 6.15 (d,
J¼16.8 Hz, 1H), 6.55 (d, J¼16.9 Hz, 1H), 6.97e7.46 (m, 10H). 13C NMR
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18. Wei, H.-X.; Jasoni, R. L.; Hu, J.; Li, G.; Pare, P. W. Tetrahedron 2004, 60, 10233.
(62.5 MHz, CDCl3)
d
(ppm): 27.1 (ꢂ2), 59.9, 111.5, 118.0, 127.0, 128.1,
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129.2, 129.4, 131.0, 133.5, 138.6, 147.9. IR (NaCl) cmꢁ1: 3409, 3086,
2990, 1731, 1616, 1534, 701. Anal. Calcd for C17H19 N: C, 86.03; H,
8.07; N, 5.90. Found: C, 86.30; H, 7.84; N, 5.66.
23. Pelmutter, P. Tetrahedron Organic Chemistry Series; Pergamon: Oxford, 1992;
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4.3.18. N-(3-Methyl-1-phenylhept-1-en-3-yl)aniline (18b). 1H NMR
24. Sikorski, W. H.; Reich, H. J. J. Am. Chem. Soc. 2001, 123, 6527.
(250 MHz, CDCl3)
d
(ppm): 0.94 (t, J¼7.1 Hz, 3H), 1.27e1.40 (m,
~
25. Feringa, B. L.; Badorrey, R.; Pena, D.; Harutyunyan, S. R.; Minnaard, A. J. Proc.
4H), 1.48e1.52 (m, 2H), 1.66 (s, 3H), 3.69 (br s, 1H), 6.11 (dd, J¼6.4,
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17.0 Hz, 1H), 6.57 (d, J¼16.8 Hz, 1H), 6.62e7.36 (m, 10H). 13C NMR
ꢀ
26. Lopez, F.; Minnaard, A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179.
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(62.5 MHz, CDCl3)
d (ppm): 14.9, 23.6, 29.4, 37.2, 63.2, 115.1, 119.0,
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127.5, 127.9, 129.2, 130.9, 131.2, 131.8, 136.9, 146.8. IR (NaCl) cmꢁ1
:
3414, 3079, 2984, 1736, 1623, 1542, 984, 712. Anal. Calcd for
C20H25 N: C, 85.97; H, 9.02; N, 5.01. Found: C, 86.18; H, 8.84;
N, 9.15.
4.3.19. N-(1-Phenylhept-1-en-3-yl)cyclohexanamine (19). 1H NMR
(250 MHz, CDCl3)
d
(ppm): 0.86 (t, J¼7.1 Hz, 3H),1.26e1.65 (m,16H),
ꢀ
ꢀ
36. Pace, V.; Martínez, F.; Fernandez, M.; Sinisterra, J. V.; Alcantara, A. R. Adv. Synth.
2.20 (m, 1H), 3.68 (br s, 1H), 3.81e3.88 (m, 1H), 5.65 (dd, J¼8.5,
Catal. 2009, 351, 3199.
37. Pace, V.; Verniest, G.; Sinisterra, J.-V.; Alcantara, A. R.; De Kimpe, N. J. Org. Chem.
15.7 Hz, 1H), 6.42 (d, J¼15.7 Hz, 1H), 7.14e7.30 (m, 5H). 13C NMR
ꢀ
2010, 75, 5760.
(62.5 MHz, CDCl3)
d
(ppm): 13.8, 21.4, 21.9 (ꢂ2), 25.2, 25.7, 28.0,
38. Pace, V.; Martinez, F.; Fernandez, M.; Sinisterra, J. V.; Alcantara, A. R. Org. Lett.
35.1, 36.6, 58.4, 63.2, 121.6, 129.1, 129.4, 131.7, 135.5, 138.9. IR (NaCl)
cmꢁ1 3021, 2930, 2632, 1601, 1495, 1460, 1375, 1252, 1139, 1044,
975, 895, 760, 695. Anal. Calcd for C19H29 N: C, 84.07; H, 10.77; N,
5.16. Found: C, 84.41; H, 10.99; N, 5.59.
2007, 9, 2661.
ꢀ
ꢀ
ꢀ
ꢀ
39. Pace, V.; Cortes-Cabrera, A; Fernandez, M.; Sinisterra, J. V.; Alcantara, A. R.
Synthesis 2010, 3545.
40. Pace, V.; Martínez, F.; Fernandez, M.; Nova, C. I.; Sinisterra, J. V.; Alcantara, A. R.
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ꢀ
ꢀ
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One of the authors (V.P.) thanks the Austrian Ministry of Edu-
cation for an E. Mach postdoctoral grant. The present work was
supported by a research Project CTQ2009-11801 of Spanish Minis-
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Supplementary data
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Full experimental details for all compounds, as well spectral
data can be founded in the Supplementary data. Supplementary
data associated with this article can be found in online version at
doi:10.1016/j.tet.2011.01.067.