Free-radical hydroxymethylation of ketimines generated in situ: A one-pot multicomponent synthesis of β,β-disubstituted-β-aminoalcohols

Article abstract of DOI:10.1016/j.tet.2012.09.107

We report how an acidic TiCl₄-Zn/t-BuOOH system is able to promote the one-pot multicomponent synthesis of β,β-disubstituted- β-aminoalcohols via nucleophilic addition of a hydroxymethyl radical to activated ketimines generated in situ in methanol solvent. While ketimines are generally recognized as less reactive and less stable when compared with aldimines, Ti(IV) plays a key role in facilitating their formation and in enhancing their electrophilic character. As a consequence, the reaction occurs at room temperature and under non-anhydrous conditions in just 1 h, without requiring either the preformation of the ketimine or protection of the amino group. The scope of the reaction is widely explored and a possible mechanism is discussed.

Full text of DOI:10.1016/j.tet.2012.09.107

Tetrahedron 68 (2012) 10151e10156
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Free-radical hydroxymethylation of ketimines generated in situ: a one-pot
multicomponent synthesis of
b
,b-disubstituted-b-aminoalcohols
*
Bianca Rossi, Nadia Pastori, Angelo Clerici, Carlo Punta
Department of Chemistry, Materials, and Chemical Engineering “Giulio Natta”, Politecnico di Milano, P.zza Leonardo da Vinci 32, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2012
Received in revised form 10 September 2012
Accepted 25 September 2012
Available online 29 September 2012
We report how an acidic TiCl4eZn/t-BuOOH system is able to promote the one-pot multicomponent
synthesis of b,b-disubstituted-b-aminoalcohols via nucleophilic addition of a hydroxymethyl radical to
activated ketimines generated in situ in methanol solvent. While ketimines are generally recognized as
less reactive and less stable when compared with aldimines, Ti(IV) plays a key role in facilitating their
formation and in enhancing their electrophilic character. As a consequence, the reaction occurs at room
temperature and under non-anhydrous conditions in just 1 h, without requiring either the preformation
of the ketimine or protection of the amino group. The scope of the reaction is widely explored and
a possible mechanism is discussed.
Keywords:
Aminoalcohols
Ketimine
Multicomponent reaction
Free-radical addition
TiCl4
Ó 2012 Elsevier Ltd. All rights reserved.
Zn
1. Introduction
R
R'
R
H
Ti(III)/t-BuOOH
R'
OH
CH3OH
+
+
N H
H+, H2O
N
R''
The vicinal amino alcohol functionality is present in a wide
range of naturally occurring and synthetic molecules. In particular,
O
R''
b
-aminoalcohols find extensive use as fundamental building blocks
R = Aryl, Alkyl, H
R' = Alkyl, H
R'' = Alkyl, Benzyl, Aryl
for the synthesis of drugs,1 receptor modulators,2 and fungistatic
molecules.3
Among the several methodologies reported for the synthesis of
these compounds, the commonly followed approaches are epoxide
ring opening with amines,3a,4 the aminohydroxylation of terminal
Scheme 1. TiCl3/t-BuOOH mediated hydroxymethylation of imines generated in situ.
C]C bonds5 and the hydrogenation of -amino esters.6
a
Nevertheless, in the last decade the nucleophilic addition of
carbon centered radicals to imine derivatives has been shown to be
a suitable alternative for obtaining substituted amines of chemical
and biological relevance.7,8
In 2008 we reported how the TiCl3/t-BuOOH system was able to
promote the one-pot multicomponent free-radical synthesis of b-
R'
Ar
Ti(III)/t-BuOOH
Ar
OH
N H
+ R'CH2OH
N
R
H+, H2O
R
R'
R = H, Me
R' = H, Me, Et, n-Pr
aminoalcohols by selective hydroxymethylation of aldimines gen-
erated in situ (Scheme 1).9
Scheme 2. Radical domino approach to 1,2-aminoalcohols from aryl amines and al-
cohols triggered by TiCl3/t-BuOOH.
More recently we have also shown that, by operating in the
absence of an aldehyde and in an alcoholic solvent, a similar system
is able to promote a domino reaction, leading to the formation of
Since it is well known that the substitution pattern of the moiety
significantly affects the biological activity of amino alcohols,11 we
wanted to investigate the applicability of our free-radical approach
a,b-disubstituted-b
-aminoalcohols (Scheme 2).10
to the one-pot synthesis of b,b-disubstituted-b-aminoalcohols, by
promoting the direct hydroxymethylation of ketimines generated
in situ.
* Corresponding author. Tel.: þ39 0223993026; fax: þ39 0223993180; e-mail
address: carlo.punta@polimi.it (C. Punta).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.107

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B. Rossi et al. / Tetrahedron 68 (2012) 10151e10156
The extension of the protocol to ketimines is not obvious, as they
complete conversion of the starting aniline, due to the expected
higher stability of the imine, but with very low selectivity for the
desired product (entry 2). This behavior was ascribed to the high
oxidizing power of hydrogen peroxide, which was able to convert
the ketyl radical, generated by hydrogen abstraction from metha-
nol, in to formaldehyde.10 This latter competed with acetone,
leading to the formation of the corresponding aldimine and the
related products of mono- and di-substitution.9
To verify this hypothesis, we wanted to investigate the action of
the milder oxidant tert-butyl hydroperoxide (t-BuOOH) under our
operating conditions. Indeed, the desired product was obtained in
46% yield by simply replacing H2O2 with t-BuOOH (entry 3), while
a further increase of the yield up to 75% was obtained by operating
with double the amount of TiCl4 and Zn with respect to the re-
ported procedure (entry 4).
are generally recognized to be less reactive toward nucleophilic
substitution (poor electrophilicity of the C]N bond) and less stable
in aqueous medium, when compared with aldimines,12 usually
requiring preformation and anhydrous operating conditions during
the reductive addition, in order to inhibit fast hydrolysis.
We recently succeeded in developing the selective carbamoy-
lation of ketimines from formamide, via a previously reported
protocol for the analogous functionalization of aldimines,13 by
replacing the aqueous TiCl3 with stoichiometric amounts of an
anhydrous TiCl4 solution in CH2Cl2 in the presence of Zn powder
and H2O2.14
As a part of our ongoing investigation on the general applica-
bility of the above mentioned protocol in solvents different from
formamide, herein we report the selective synthesis of
b,b-di-
substituted- -aminoalcohols by the one-pot assembly of a primary
aryl amine and a ketone in methanol solvent, promoted by the
TiCl4eZn/t-BuOOH system (Scheme 3).
b
The reaction proceeded with changes of color from orange to
violet, proving the periodic variation of the oxidation state of tita-
nium ion from III (typical violet solution) to IV (typical orange
R'
R''
R'
R''
+
2 H+
TiCl4-Zn
rt
Ar
t-BuOOH
CH OH
2 H O
+ t-BuOH
2
+
+
+
3
Ar NH2 +
N
H
O
OH
3a-r
1a-g
2a-f
Scheme 3. TiCl4eZn/t-BuOOH mediated hydroxymethylation of imines generated in situ.
To the best of our knowledge, this represents the first example of
direct radical hydroxymethylation of ketimines generated in situ
under aqueous conditions.
color), while in the absence of both Zn (entry 5) and TiCl4 (entry 6)
no reaction was observed.
This behavior suggests the possible reaction mechanism re-
ported in Scheme 4. Ti(III) (violet solution) is oxidized to Ti(IV)
(orange solution) by both the hydroperoxide (path ii), leading to the
formation of tert-butoxyl radical, and the aminium radical in-
termediate A (path vii). Ti(IV) is then reduced to Ti(III) by Zn, so
prolonging the redox cycle and justifying the color oscillation. The
tert-butoxyl radical is, in turn, responsible for the formation of the
hydroxymethyl radical by hydrogen abstraction from methanol
(path iv), while Ti(IV) acts as a Lewis acid, promoting the formation
of the ketimine and enhancing its electrophilic character
(path vevi).
2. Results and discussion
The results related to the optimization of the reaction conditions
are reported in Table 1 using p-toluidine 1a and acetone 2a as the
representative aniline and ketone, respectively.
Table 1
Radical addition of methanol to ketimines generated in situ from p-toluidine and
acetonea
OH
H
1/2 Zn2+
1/2 Zn
Peroxide/CH3OH
TiCl3 vs TiCl4/Zn
N
R'
+
NH2
O
R
N
H
Ar
Ar
Ti(IV)
Ti(III)
t-BuOOH
(i)
HO
1a
2a
3a
3a-r
H+
(vii)
(ii)
Entry TiCl3 (mmol) TiCl4 (mmol) Zn (mmol) Hydroperoxide 3a Yieldb (%)
R'
(iii)
1
8
d
d
5
t-BuOOH
H2O2
8
R
N
H
H2O
Ti(III)
Ti(IV)
2c
3
d
d
d
d
d
1
1.7
1.7
3.4
1.7
d
11
46
75
d
d
10
1/2 Zn2+
HO
5
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH
1/2 Zn
A
4
5
10
d
5
(vi)
t-BuO
HO CH3
-Ti(IV)
R
6
7d
3.4
d
a
Compound 1a (2 mmol) was reacted with 5 mmol of 2a in 10 mL of methanol.
(iv)
Yield determined by 1H NMR spectroscopy with acetophenone added as an
b
internal standard to the crude reaction mixture after work up.
O
Ar
N
(v)
HO
t-BuOH
c
CH2
Complete conversion.
Ar NH2
+
d
R
R'
Ti(IV)
t-BuOOH (1 mmol) was added.
R'
Ti(IV)
Scheme 4. Reaction mechanism.
As expected, the use of the aqueous TiCl3/t-BuOOH system was
detrimental for the reaction, affording poor results in terms of
conversion (Table 1, entry 1). This result reflected the low stability
of ketimines under non-anhydrous conditions, as explained before.
A first attempt to apply the TiCl4eZn/H2O2 system, previously
disclosed for the selective carbamoylation of ketimines, led to
Even if aminyl radicals are known to be excellent H-atom ab-
stractors,15 intermediate A seems not to be significantly involved in
hydroxymethyl radical formation, undergoing faster reduction to
the final product by means of Ti(III). In fact, if A would undergo

B. Rossi et al. / Tetrahedron 68 (2012) 10151e10156
10153
Table 2
hydrogen abstraction from methanol, just tiny amounts of hydro-
peroxide would have been sufficient to promote the free-radical
chain. Nevertheless, when the TiCl3/t-BuOOH system was
employed in catalytic amounts, in the presence of an excess of TiCl4
to guarantee the coordination effect of the Lewis acid, poor results
were observed in terms of converted material (Table 1, entry 6).
The intervention of the aminyl radical in the hydrogen ab-
straction step was previously observed by our group in the pres-
ence of secondary N-methyl aniline, when applying the TiCl3/t-
BuOOH system in alcoholic solvent to promote the domino syn-
Radical hydroxymethylation of ketimines generated from aryl amines and acyclic
ketonesa
TiCl4-Zn/t-BuOOH/CH3OH
1a-h + 2a-c
3a-j
rt, N2
Entry
1
2
3 Yieldb, % (yieldc, %)
OH
H
N
1
2
3
4
5
1a
2a
3a: 68 (75)
3b: 52 (58)
3c: 32 (40)
3d: 71 (78)
3e: 59 (65)
thesis of
a,b-disubstituted-b
-aminoalcohols.10a In that case, re-
action stoichiometry required just 1 equiv of hydroperoxide per
mmol of aniline, against the 2 equiv necessary when reacting pri-
mary aryl amines (Scheme 2).
With these results in hand, we wanted to explore the scope of
the reaction by testing a range of aryl amines bearing different
substituents on the aromatic ring (1aeh, Fig. 1) in the presence of
both acyclic (2aec, Fig. 2) and cyclic (2def, Fig. 2) ketones. The
results reported in Tables 2 and 3, respectively, clearly demonstrate
the general efficiency of the protocol.
OH
H
N
1b
1c
1d
1e
2a
2a
2a
2a
OH
H
N
OH
H
N
NH2
NH2
NH2
NH2
NH2
NH2
OH
H
N
H3CO
1d
1b
1c
1a
Cl
OH
H
N
H
N
NH2
6
1f
2a
3f: 64 (70)
Cl
MeO
Cl
1g
1e
1f
1h
Cl
OH
H
N
7
1g
1h
2a
2a
3g: 47 (52)
3h: d (20)
Fig. 1. Representative aryl amines 1aeh.
OH
8d
N
O
O
O
O
O
O
OH
H
N
9
1a
1a
2b
2c
3i: 60 (65)
3j: 17 (22)
2b
2c
2d
2a
2e
2f
OH
H
Fig. 2. Representative ketones 2aef.
N
10
In analogy with what was observed for hydroxymethylation of
aldimines9 and carbamoylation of ketimines,14 steric hindrance
around the C]N bond negatively affected the reaction. Yields
progressively decreased when the position of substituents on the
aromatic ring of aryl amines was changed from para to meta and
ortho (entries 1e3, Tables 2 and 3).
a
The molar ratio of 1/2/TiCl4/Zn was 1:2.5:1.7:5.
Yield of isolated products are based on the starting amine; yields based on
b
converted amines were always ꢀ90%.
c
Yield determined by 1H NMR spectroscopy with acetophenone added as an
internal standard to the crude reaction mixture after work up.
d
Selectivity for the desired product was lower than 30%. See Fig. 3.
For the same reasons, the efficiency of the reaction progressively
decreased by increasing the length of the ketone side-chains (en-
tries 9 and 10, Table 2) or the size of the ring of cyclic ketones, like
for cyclooctanone (entry 10, Table 3).
The reaction is relatively insensitive to the polar nature of the
substituents on the aromatic ring of aniline, indicating that the
polarization of the C]N bond induced by Ti(IV) complexation
overcomes the substituent effect.
besides the desired product 3h, derivatives 3seu were also found in
the final crude mixture (Fig. 3). Furthermore, 1d also reacted with
the excess of acetone leading to the formation of significative
amounts of 3d.
3. Conclusions
Any attempt to extend the protocol to secondary N-methyl an-
iline 1h afforded a mixture of side products (entry 8, Table 2). In-
deed, fast demethylation of 1h occurred, leading to the formation of
aniline 1d and formaldehyde. The latter favored the formation of
aldimines with both 1h and 1d, introducing competitive electron-
poor substrates suitable for nucleophilic radical addition. Thus,
In conclusion, the protocol reported herein represents a novel
synthesis of a new class of
b,b-disubstituted-b-aminoalcohols.
These derivatives, most of which have never been synthesized
before, were prepared in a one-pot manner by simply assembling
a ketone, a primary aryl amine and methanol at room temperature

10154
B. Rossi et al. / Tetrahedron 68 (2012) 10151e10156
Table 3
which tends to occur in the presence of these sources of nucleo-
philic radicals.10
Radical hydroxymethylation of ketimines generated from aryl amines and cyclic
ketonesa
TiCl4-Zn/t-BuOOH/CH3OH
4. Experimental section
1a-f + 2d-f
3k-r
rt, N2
4.1. General experimental methods
Entry
1
2
3 Yieldb, % (yieldc, %)
All materials were purchased from commercial suppliers and
used without further purification. All reactions were performed at
room temperature (20 ꢁC) under atmosphere of nitrogen. The fol-
lowing solutions were used: 1 M solution of TiCl4 in CH2Cl2 and
80 wt % solution of t-BuOOH. NMR spectra were recorded at
400 MHz for 1H and 100 MHz for 13C. ESI-MS were performed with
an Esquire 3000 plus ion-trap mass spectrometer equipped with an
ESI source.
Tandem mass spectra were obtained by CID with helium colli-
sion gas after isolation of the precursor ion. Mass spectra were al-
ternatively performed with a GCeMS instrument, using a gas
chromatograph equipped with an SBP-1 fused silica column
OH
OH
H
N
1
2
3
4
5
1a
2d
3k: 69 (77)
3l: 60 (65)
3m: 53 (59)
3n: 57 (59)
3o: 65 (73)
H
N
1b
1c
1d
1e
2d
2d
2d
2d
OH
H
N
(30 mꢂ0.2 mm i.d., 0.2
mm film thickness) and helium as carrier
gas. IR spectra were obtained by Varian 640 high-performance FTIR
OH
H
N
€
spectrometer. Melting points were measured on Koppfler appara-
tus and are uncorrected.
Flash column chromatography was performed by using
OH
40e63
mm silica gel packing: the eluent was chosen in order to
H
N
move the desired components to Rf¼0.35 on analytical TLC.
H3CO
4.2. General procedure for the synthesis of -disubstituted-
b,b
b-aminoalcohols starting from aryl amines and ketones
OH
H
N
6
9
1f
2d
2e
2f
3p: 88 (96)
3q: 58 (65)
3r: 27 (35)
An aqueous 80 wt % solution of t-BuOOH (10 mmol, ca. 1.24 mL),
Cl
diluted in methanol (9 mL), was added dropwise to a well stirred
homogeneous solution of methanol (10 mL) containing aryl amine
(2 mmol), cyclic or acyclic ketone (5 mmol), TiCl4 (1.7 mmol), with
Zn powder in suspension (300 mg, ca. 5 mmol). The reaction looks
like a titration, which proceeds with periodic changes of color from
orange to violet, t-BuOOH was added until a pale orange was barely
maintained. At this point, a second portion of TiCl4 (1.7 mmol) and
Zn powder in suspension (300 mg, ca. 5 mmol) was added and t-
BuOOH was added again dropwise until the solution reached
a stable orange color. The reaction was then quenched with of H2O
(5 mL) and added with a 30% aqueous NH3 solution until basic pH (a
white precipitate of Ti(IV) hydroxide was observed) and extracted
with EtOAc (3ꢂ50 mL). The combined organic layers were then
dried over Na2SO4 and concentrated in vacuo. Purification by flash
chromatography of the crude residue afforded the hydrox-
ymethylamine 3 as the last eluted products.
OH
H
N
1a
1a
OH
H
N
10
a
The molar ratio of 1/2/TiCl4/Zn was 1:2.5:1.7:5.
Yield of isolated products are based on the starting amine; yields based on
b
converted amines were always ꢀ90%.
c
Yield determined by 1H NMR spectroscopy with acetophenone added as an
internal standard to the crude reaction mixture after work up.
Yields of isolated products are based on the starting amine.
OH
4.2.1. 2-Methyl-2-(p-tolylamino)propan-1-ol (3a). Purification by
FCC (Hex/AcOEt 1:2, Rf¼0.35) afforded a yellow oil (243.6 mg, 68%
isolated yield); FTIR (liquid film) nmax 3390, 2969, 2921, 1616, 1512,
H
N
N
N
OH
OH
OH
1462 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
(ppm): 1.19 (s, 6H, 2ꢂ CH3);
2.26 (s, 3H, CH3); 3.47 (s, 2H, CH2); 3.47 (s, 2H, CH2); 6.71e6.74
(m, 2H, 2CH Ar); 6.98e7.00 (m, 2H, 2CH Ar); 13C NMR (100 MHz,
3t
3s
3u
CDCl3)
d (ppm): 20.1, 25.0, 55.4, 69.4, 120.5, 129.5, 130.2, 143.0;
Fig. 3. Side products 3seu deriving from 1h.
GCeMS (m/z): 148 (100), 179 (5.6), 106 (11.6). HRMS (EI): Mþ, calcd
for C11H17NO: 179.1310; found 179.1315.
under non-anhydrous conditions in just 1 h, without requiring
ether preformation of ketimine or protection of the amino group.
Only a very bulky substituent at the C atom of the intermediate
ketimine or in the ortho position on the aromatic ring of anilines
depresses the yield of 3.
Further investigations will be devoted to the optimization of this
protocol in order to extend the methodology to a wider range of
alcohols and ethers, inhibiting the competitive domino reaction,
4.2.2. 2-Methyl-2-(m-tolylamino)propan-1-ol (3b). Purification by
FCC (CH2Cl2/AcOEt 1:1, Rf¼0.35) afforded an orange oil (207.8 mg,
52% isolated yield); FTIR (liquid film) nmax 3381, 2969, 2926, 1606,
1487 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
(ppm): 1.23 (s, 6H, 2ꢂ CH3),
2.27 (s, 3H, CH3), 2.93 (s br,1H, OH, exchange D2O), 3.51 (s, 2H, CH2),
6.59e6.60 (m, 2H, 2CH Ar), 6.65e6.67 (m, 1H, CH Ar); 7.03e7.08 (m,
1H, CH Ar); 13C NMR (100 MHz, CDCl3)
d (ppm): 21.3, 25.1, 55.0,

B. Rossi et al. / Tetrahedron 68 (2012) 10151e10156
10155
68.9, 116.0, 119.9, 120.9, 129, 138.8, 145.8; GCeMS (m/z): 149 (100),
179 (9.52), 164 (4.76). HRMS (EI): Mþ, calcd for C11H17NO: 179.1310;
found 179.1317.
(8), 134 (6). HRMS (EI): Mþ, calcd for C14H23NO: 221.1780; found
221.1771.
4.2.9. 2-Ethyl-2-(p-tolylamino)butan-1-ol (3j). Purification by FCC
(Hex/AcOEt 4:6, Rf¼0.33) afforded a colorless oil (70.4 mg, 17%
isolated yield); FTIR (liquid film) nmax 3390, 2966, 2936, 2878,
4.2.3. 2-Methyl-2-(o-tolylamino)propan-1-ol (3c). Purification by
FCC (CH2Cl2/AcOEt 1:1, Rf¼0.35) afforded an orange oil (114.6 mg,
32% isolated yield); FTIR (liquid film) nmax 3400, 2969, 2930, 1514,
1616, 1514, 1463 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d (ppm): 0.87 (t,
1482 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
(ppm): 1.31 (s, 6H, 2ꢂ
6H, 2ꢂ CH3, J¼7.5 Hz); 1.51e1.57 (2d, 4H, 2CH2, J1¼J2¼7.5 Hz); 2.27
CH3); 2.20 (s, 3H, CH3); 3.60 (s, 2H, CH2); 6.73e6.77 (m, 1H, CH
(s, 3H, CH3); 3.56 (s, 2H, CH2); 6.71e6.73 (m, 2H, 2CH Ar);
Ar); 6.88e6.90 (m, 1H, CH Ar); 7.07e7.11 (m, 2H, 2CH Ar); 13C NMR
6.99e7.01 (m, 2H, 2CH Ar); 13C NMR (100 MHz, CDCl3)
d (ppm):
(100 MHz, CDCl3)
d
(ppm): 18.0, 18.3, 25.2, 55.2, 69.3, 116.3, 118.7,
7.4, 20.4, 25.7, 60.8, 64.6, 118.9, 129.2, 129.6, 143.2; GCeMS (m/z):
176 (100), 207 (6). HRMS (EI): Mþ, calcd for C13H21NO: 207.1623;
found 207.1629.
125.1, 127.0, 130.2, 141.3; GCeMS (m/z): 148 (100), 179 (5), 164
(0.9); HRMS (EI): Mþ, calcd for C11H17NO: 179.1310; found
179.1308.
4.2.10. (1-(p-Tolylamino)cyclohexyl)methanol (3k). Purification by
FCC (Hex/AcOEt 9:1, Rf¼0.34) afforded a pale orange oil (302.5 mg,
69% isolated yield); FTIR (liquid film) nmax 3390, 2930, 2857, 1615,
4.2.4. 2-Methyl-2-(phenylamino)propan-1-ol (3d). Crude product,
purity ꢀ95%: no purification necessary to afford a yellow oil
(234.4 mg, 71% isolated yield); Rf¼0.40 on analytical TLC with Hex/
AcOEt 1:1 eluent; FTIR (liquid film) nmax 3379, 2970, 2931, 2874,
1513, 1449 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d (ppm): 1.33e1.60 (m,
8H, 8CH Cyc); 1.75e1.79 (m, 2H, 2CH Cyc); 2.28 (s, 3H, CH3); 3.05 (s
1668, 1601, 1497 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
(ppm): 1.27 (s,
br, 1H OH, exchange D2O); 3.57 (s, 2H, CH2); 6.75 (m, 2H, CH Ar);
6H, 2ꢂ CH3); 2.58 (s br, 1H OH, exchange D2O); 3.55 (s, 2H, CH2);
7.01 (m. 2H, CH Ar); 13C NMR (100 MHz, CDCl3)
d (ppm): 20.4, 21.5,
6.80e6.88 (m, 3H, 3CH Ar); 7.18e7.21 (m, 2H, 2CH Ar); 13C NMR
25.8, 33.0, 57.4, 67.4, 119.5, 129.5, 129.5, 142.6; GCeMS (m/z): 188
(100), 219 (6.4), 106 (9). HRMS (EI): Mþ, calcd for C14H21NO:
219.1623; found 219.1615.
(100 MHz, CDCl3) d (ppm): 24.7, 55.2, 69.1, 119.0, 119.8, 128.8, 145.9;
ESI-MS m/z 166 [MþþH], 188 [MþþNa]. HRMS (EI): Mþ, calcd for
C10H15NO: 165.1154; found 165.1144.
4.2.11. (1-(m-Tolylamino)cyclohexyl)methanol (3l). Purification by
FCC (Hex/AcOEt 6:4, Rf¼0.35) afforded an orange oil (263 mg, 60%
isolated yield); FTIR (liquid film) nmax 3398, 2930, 2856, 1604, 1517,
4.2.5. 2-(4-Methoxyphenylamino)-2-methylpropan-1-ol
(3e). Purification by FCC (CH2Cl2/AcOEt/MeOH 2.7:6.4:0.9, Rf¼0.36)
afforded white needles. Mp 59e61 ꢁC (230.2 mg, 59% isolated
yield); FTIR (liquid film) nmax 3424, 2967, 2929, 2888, 1610, 1510,
1486, 1449 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d (ppm): 1.32e1.60 (m,
8H, CH-Cyc); 1.80e1.85 (m, 2H, CH-Cyc), 2.29 (s, 3H, CH3); 2.90 (s br,
1H OH, exchange D2O); 3.60 (s, 2H, CH2); 6.61e6.62 (m, 2H, CH Ar);
6.66e6.68 (m, 1H, CH Ar); 7.05e7.09 (m, 1H, CH Ar); 13C NMR
1472 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
(ppm): 1.05 (s, 6H, 2ꢂ
CH3); 3.33 (s, 2H, CH2); 3.67 (s, 3H, OCH3); 6.67e675 (m, 4H, 4CH
Ar); 13C NMR (100 MHz, CDCl3)
(ppm): 24.8, 55.4, 55.7, 69.0, 114.2,
d
(100 MHz, CDCl3) d (ppm): 21.4, 25.8, 32.9, 57.2, 67.5, 115.4, 119.2,
123.7, 138.4, 155.1; GCeMS (m/z): 164 (100), 180 (0.9), 195 (9.1), 149
(9.1), 108 (14.5). HRMS (EI): Mþ, calcd for C11H17NO2: 195.1259;
found 195.1266.
120.5, 128.8, 168.7, 145.4; ESI-MS m/z 220 [MþþH], 242 [MþþNa];
HMRS HRMS (EI): Mþ, calcd for C14H21NO: 219.1623; found
219.1628.
4.2.6. 2-(4-Chlorophenylamino)-2-methylpropan-1-ol (3f). Purification
by FCC (CH2Cl2/AcOEt 6.5:3.5, Rf¼0.35) afforded a pink oil (254.8 mg,
64% isolated yield); FTIR (liquid film) nmax 3384, 2971, 2932, 1597,1492,
4.2.12. (1-(o-Tolylamino)cyclohexyl)methanol (3m). Purification by
FCC (Hex/AcOEt 8:2, Rf¼0.35) afforded a yellow oil (232.3 mg, 53%
isolated yield); FTIR (liquid film) nmax 3440, 2930, 2856, 1515, 1480,
817 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
(ppm): 1.23 (s, 6H, 2CH3); 3.51
1451 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d (ppm): 1.29e1.58 (m, 8H,
(s, 2H, CH2); 6.70e6.73 (m, 2H, 2CH Ar); 7.11e7.13 (m, 2H, 2CH Ar); 13
C
CH-Cyc); 1.88e1.94 (m, 2H, CH-Cyc), 2.21 (s, 3H, CH3); 3.63 (s, 2H,
CH2); 6.68e6.71 (m, 1H, CH Ar); 6.80e6.82 (m, 1H, CH Ar);
NMR (100 MHz, CDCl3)
d (ppm): 24.9, 55.5, 69.2, 120.1, 124.9, 128.9,
144.6; GCeMS (m/z): 168 (100), 199 (5), 127 (11). HRMS (EI): Mþ, calcd
7.00e7.05 (m, 2H, 2CH Ar); 13C NMR (100 MHz, CDCl3)
d (ppm):
for C10H14ClNO (35Cl): 199.0764; found 199.0758.
18.0, 18.3, 25.2, 55.2, 69.3, 79.7, 116.3, 118.7, 125.1, 127.0, 130.2, 141.3;
GCeMS (m/z): 219 (8), 188 (100), 106 (10). HRMS (EI): Mþ, calcd for
C14H21NO: 219.1623; found 219.1631.
4.2.7. 2-(2-Chlorophenylamino)-2-methylpropan-1-ol (3g). Purification
by FCC (Hex/AcOEt 7.5:3.5, Rf¼0.36) afforded a yellow oil (187.1 mg,
47% isolated yield); FTIR (liquid film) nmax 3391, 2971, 2933, 1596, 1514,
4.2.13. (1-(Phenylamino)cyclohexyl)methanol (3n). Purification by
FCC (Hex/AcOEt 7:3, Rf¼0.35) afforded a pale orange oil (233.9 mg,
57% isolated yield); FTIR (liquid film) nmax 3400, 2931, 2856, 1600,
1468, 742 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
(ppm): 1.32 (s, 6H, 2ꢂ
CH3); 3.60 (s, 2H, CH2); 6.69e6.74 (m, 1H, CH Ar); 6.94e6.97 (m,1H, CH
Ar); 7.08e7.12 (m, 1H, CH Ar); 7.27e7.29 (m, 1H, CH Ar); 13C NMR
1496 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d (ppm): 1.33e1.62 (m, 8H,
(100 MHz, CDCl3)
d
(ppm): 24.9, 55.5, 69.1, 117.0, 122.7, 127.3, 129.5,
CH-Cyc); 1.82e1.86 (m, 2H, CH-Cyc), 2.86 (s br, 1H OH, exchange
D2O); 3.62 (s, 2H, CH2); 6.81e6.87 (m, 3H, CH Ar); 7.18e7.22 (m,
142.4; GCeMS (m/z): 199 (6), 170 (31), 168 (100), 127 (10). HRMS (EI):
Mþ, calcd for C10H14ClNO (35Cl): 199.0764; found 199.0754.
2H, CH Ar); 13C NMR (100 MHz, CDCl3)
d (ppm): 21.5, 25.9, 33.1,
57.4, 67.7, 118.6, 119.8, 129.1, 145.6; GCeMS (m/z): 205 (11), 174
(100), 93 (22). HRMS (EI): Mþ, calcd for C13H19NO: 205.1467; found
205.1475.
4.2.8. 2-Methyl-2-(p-tolylamino)hexan-1-ol (3i). Purification by
FCC (Hex/AcOEt 4:6, Rf¼0.34) afforded white crystal. Mp
44e46 ꢁC (265.4 mg, 60% isolated yield); FTIR (liquid film) nmax
3420, 2952, 2924, 2856, 1615, 1511, 1472 cmꢃ1
;
1H NMR
4.2.14. (1-(4-Methoxyphenylamino)cyclohexyl)methanol
(3o). Purification by FCC (CH2Cl2/AcOEt 6:4, Rf¼0.34) afforded
white crystals. Mp 73e75 ꢁC (305.7 mg, 65% isolated yield); FTIR
(400 MHz, CDCl3)
d (ppm): 0.92 (m, 3H, CH3); 1.27 (s, 3H, CH3);
1.27e1.38 (m, 4H, 2ꢂ CH2); 1.46e1.62 (m, 2H, CH2); 2.29 (s, 3H,
CH3); 3.48 (d, 1H, CH, J¼10.8 Hz); 3.59 (d, 1H, CH, J¼10.8 Hz);
6.72e6.75 (m, 2H, 2CH Ar); 7.00e7.03 (m, 2H, 2CH Ar); 13C NMR
(liquid film) nmax 3287, 2940, 1609, 1509, 1461 cmꢃ1 1H NMR
;
(400 MHz, DMSO)
d (ppm): 1.19e1.29 (m, 1H, CH Cyc); 1.36e1.58
(100 MHz, CDCl3)
d
(ppm): 13.9, 20.4, 22.7, 23.1, 25.6, 36.9, 57.9,
(m, 7H, 7CH Cyc); 1.61e1.67 (m, 2H, 2CH Cyc); 3.30 (s, 2H, 1CH2)
67.4, 119.5, 129.5, 143.1; GCeMS (m/z): 190 (100), 221 (0.5), 164
3.65 (s, 3H, CH3); 4.00 (s br, 1H, NH, exchange with D2O); 4.39 (t,1H,

10156
B. Rossi et al. / Tetrahedron 68 (2012) 10151e10156
OH, exchange with D2O); 6.68e6.60 (m, 2H, CH Ar); 6.68e6.75 (m,
2H, CH Ar); 13C NMR (100 MHz, DMSO)
(ppm): 21.4, 25.9, 32.2,
55.4, 56.8, 66.2, 114.2, 121.2, 140.2, 152.8; GCeMS (m/z): 235 (12.5),
204 (100), 108 (23.1), 122 (11.9), 115 (1.6). HRMS (EI): Mþ, calcd for
C14H21NO2: 235.1572; found 235.1576.
Supplementary data
d
Supplementary data (1H and 13C NMR spectra of compounds
3aer) associated with this article can be found in the online ver-
sion. Supplementary data related to this article can be found online
at http://dx.doi.org/10.1016/j.tet.2012.09.107.
4 . 2 .15 . (1-(4-Chlorophenylamino)cyclohexyl)methanol
(3p). Purification by FCC (Hex/AcOEt 6:4, Rf¼0.35) afforded a pale
yellow oil (420 mg, 88% isolated yield); FTIR (liquid film) nmax
References and notes
3407, 2931, 2856, 1596, 1492, 1462, 816 cmꢃ1 1H NMR (400 MHz,
;
1. (a) Yadav, J. S.; Reddy, A. R.; Narsaiah, A. V.; Reddy, B. V. S. J. Mol. Catal. A 2007,
261, 207e212; (b) Corey, E. J.; Zhang, F. Angew. Chem., Int. Ed. 1999, 38,
1931e1934; (c) Bose, D. S.; Narsaiah, A. V. Bioorg. Med. Chem. 2005, 3, 627e630;
(d) Meinzer, A.; Breckel, A.; Thaher, B. A.; Manicone, N.; Otto, H. H. Helv. Chim.
Acta 2004, 87, 90e105.
CDCl3)
2CH Cyc); 3.50 (s, 2H, CH2); 6.64e6.66 (m, 2H, CH Ar); 7.03e7.06
(m. 2H, CH Ar); 13C NMR (100 MHz, CDCl3)
(ppm): 21.5, 25.8,
d (ppm): 1.32e1.51 (m, 8H, 8CH Cyc); 1.70e1.76 (m, 2H,
d
2. US2010/0093788A1
33.0, 57.6, 67.5, 119.7, 124.7, 129.0, 144.2; GCeMS (m/z): 208 (100),
239 (6.4). HRMS (EI): Mþ, calcd for C13H18ClNO (35Cl): 239.1077;
found 239.1077.
ꢀ
ꢀ
ꢀ
3. (a) Mancilla, G.; Duran-Patron, R. M.; Marcías-Sanchez, A. J.; Collado, I. G.
Bioorg. Med. Chem. Lett. 2010, 20, 6820e6822; (b) Thevissen, K.; Hillaert, U.;
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Alvaro, M.; Garcia, H. Chem.dEur. J. 2010, 16, 8530e8536.
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E. N., Yamamoto, H., Pfaltz, A., Eds.; Springer: Berlin, 1999; vol. II, p 713; (b)
Nilov, D.; Reiser, O. Adv. Synth. Catal. 2002, 344, 1169e1173.
4.2.16. (1-(p-Tolylamino)cyclopentyl)methanol (3q). Purification by
FCC (Hex/AcOEt 75:25, Rf¼0.35) afforded a pale yellow oil
(238.0 mg, 58% isolated yield); FTIR (liquid film) nmax 3391,
ꢁ
2953, 2868, 1616, 1514, 1449 cmꢃ1 1H NMR (400 MHz, CDCl3)
;
6. Studer, M.; Burkhardt, S.; Blaser, H. U. Adv. Synth. Catal. 2001, 343, 802e808.
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3157e3172; (b) Yamada, K.; Tomioka, K. Chem. Rev. 2008, 108, 2874e2886; (c)
Akindele, T.; Yamada, K.; Tomioka, K. Acc. Chem. Res. 2009, 42, 345e355; (d)
Pastori, N.; Gambarotti, C.; Punta, C. Mini-Rev. Org. Chem. 2009, 6, 184e195; (e)
Miyabe, H.; Yoshioka, E.; Kohtani, S. Curr. Org. Chem. 2010, 14, 1254e1264.
8. For some recent examples see: (a) Yamada, K.; Yamamoto, Y.; Maekawa, M.;
Akindele, T.; Umeki, H.; Tomioka, K. Org. Lett. 2006, 8, 87e89; (b) Akindele, T.;
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C. S.; Qin, J. Org. Biomol. Chem. 2011, 9, 4039e4043; (f) Yamada, K.; Konishi, T.;
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d
(ppm): 1.66e1.86 (m, 8H, 8CH Cyc); 2.27 (s, 3H, CH3); 3.64 (s,
2H, CH2); 6.63e6.65 (m, 2H, CH Ar); 6.99e7.01 (m, 2H, CH Ar);
13C NMR (100 MHz, CDCl3)
(ppm): 20.3, 24.4, 36.0, 65.8, 66.5,
d
116.7, 127.9, 129.6, 143.4; GCeMS (m/z): 174 (100), 205 (5), 158
(4). HRMS (EI): Mþ, calcd for C13H19NO: 205.1467; found
205.1468.
4.2.17. (1-(p-Tolylamino)cyclooctyl)methanol (3r). Purification by
FCC (Hex/AcOEt 3:7, Rf¼0.35) afforded white crystal. Mp 93e95 ꢁC
(133.5 mg, 27% isolated yield); FTIR (liquid film) nmax 3419, 2920,
2848, 1616, 1509, 1474 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d (ppm):
9. Clerici, A.; Ghilardi, A.; Pastori, N.; Punta, C.; Porta, O. Org. Lett. 2008, 10,
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1.49e1.70 (m, 14H, 14CH Cyc); 2.28 (s, 3H, CH3); 2.97 (s br, 1H OH,
exchange D2O); 3.50 (s, 2H, CH2); 6.73e6.75 (m, 2H, CH Ar);
7.11e7.02 (m. 2H, CH Ar); 13C NMR (100 MHz, CDCl3)
d (ppm): 20.4,
21.9, 25.3, 28.3, 30.7, 61.4, 65.3, 120.4, 129.5, 130.0, 142.7; GCeMS
(m/z): 216 (100), 247 (2). HRMS (EI): Mþ, calcd for C16H25NO:
247.1936; found 247.1931.
11. Bergmeier, S. C. Tetrahedron 2000, 56, 2561e2576.
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We thank MIUR for continual support of our free-radical (PRIN
2008, project 2008KRBLP5_003) and organic (FIRB-Future in Re-
search 2008, project RBFR08XH0H_001) chemistry.