Re2O7-catalyzed three-component synthesis of protected secondary and tertiary homoallylic amines

Article abstract of DOI:10.1039/c2cc15472b

Three-component synthesis of protected secondary and "for the first time" tertiary homoallylic amines is achieved from carbonyl, carbamate, and allyltrimethylsilanes using a Re₂O₇-catalyst under mild and open flask conditions. Excellent chemoselectivities and diastereoselectivities were observed.

Full text of DOI:10.1039/c2cc15472b

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 1820–1822
www.rsc.org/chemcomm
COMMUNICATION
Re2O7-catalyzed three-component synthesis of protected secondary and
tertiary homoallylic aminesw
Suman Pramanik and Prasanta Ghorai*
Received 2nd September 2011, Accepted 7th December 2011
DOI: 10.1039/c2cc15472b
Three-component synthesis of protected secondary and ‘‘for the
first time’’ tertiary homoallylic amines is achieved from carbonyl,
carbamate, and allyltrimethylsilanes using a Re2O7-catalyst under
mild and open flask conditions. Excellent chemoselectivities and
diastereoselectivities were observed.
In recent years, the synthesis of protected homoallylic amines1
via a direct three-component reaction of carbonyl, carbamate,
and semi-metallic allyl-reagents of silicon2,3 or tin4 has become
an attractive strategy, because this eliminated the prior isolation
of sensitive imines.5–7 Unfortunately, these attempts are limited
to the synthesis of secondary homoallylic amines starting from
aldehydes; synthesis of the corresponding tertiary homoallylic
amines from ketones using this strategy still remains elusive.8–11
However, allylsilanes are more desirable as they are less toxic
and more stable than allyltin. But, the low reactivity of
allylsilanes limits their broader synthetic utility and this also
Fig. 1 Strategic representations: (a) a one-pot homoallylic amination
of aldehydes, (b) a one-pot homoallylic amination of aldehydes and
ketones using oxo-rhenium(VII) complexes.
The efficiencies of various oxo-rhenium catalysts were screened
by treatment of benzaldehyde (1a) and allyltrimethylsilane with
benzyl carbamate (2a) in the presence of 3 mol% of the catalyst in
acetonitrile at room temperature (summarized in Table 1). Amongst
the various oxo-rhenium(V)- and oxo-rhenium(VII)-catalysts, Re2O7
(1.5 mol%) was identified as the most efficient catalyst, with which
the reaction proceeded to completion within 1 h to chemoselectively
provide the desired homoallylic amine 3a (Table 1). A further
survey of the reaction conditions revealed that acetonitrile was
the solvent of choice with respect to the rate as well as the
chemoselective homoallylic amine formation.
involves the use of stronger Bronsted or Lewis acid-catalysts,
¨
such as BF3ÁOEt2,2a,c triphenyl methyl perchlorate,2b
Bi(OTf)3,2d I2,2e or phosphomolybdic acid.2f The strongly
acidic conditions for these methods are incompatible with many
functional groups. Also, they suffer from other limitations like,
requirement of stoichiometric Lewis acid,2a,c prior silylation of
the carbamate,2b and long reaction times.2d Therefore, a milder
catalyst aimed towards allylsilane activation to in situ formed
aldimines as well as ketimines is needed. Moreover, achieving the
chemoselectivity of homoallylamine over allyl-alcohol formation
should be an important factor, as imines are relatively less
reactive than carbonyls.7,12
Table 1 Optimization of the reaction conditions
Recently, oxo-rhenium complexes in higher oxidation states
have attracted considerable attention as catalysts for numerous
organic reactions due to their mild reactivity, low toxicity, and air/
moisture-tolerant nature.13 We became interested to utilize those
oxo-rhenium complexes as catalysts for this one-pot reaction
constituted of the carbonyl, carbamate, and allyltrimethylsilane
for the synthesis of the above said amines (Fig. 1).
Entry
Catalyst
t/h
3aa [%]
3a/4b
1
2
3
4
5
6
None
3
3
3
1
1
1
0
—
—
—
ReCl3O(PPh3)2
ReIO2(PPh3)2
ReCl3O(SMe2)PPh3
MeReO3 (MTO)
Re2O7 (1.5 mol%)
Trace
Trace
75
40
90
Trace
60/40
499/o1
Department of Chemistry, Indian Institute of Science Education and
Research Bhopal, Bhopal-462023, India.
E-mail: pghorai@iiserbhopal.ac.in; Fax: +91 7554092329;
Tel: +91 7554092325
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc15472b
a
b
Yield of the isolated product after column chromatography. Ratio
1
was determined by H NMR spectroscopy of the reaction mixture.
c
1820 Chem. Commun., 2012, 48, 1820–1822
This journal is The Royal Society of Chemistry 2012

View Article Online
Table 2 Synthesis of secondary N-protected homoallylic amines
Table 3 Synthesis of tertiary N-protected homoallylic amines
No.
R/Ar (1)
PG
t/h
3, [%]a,b
No. Ketone, 5
t/h 6, PG
[%]a,b (drc)
1
2
3
4
5
6
7
8
p-MeC6H5-(1b)
p-MeO–C6H5-(1c)
p-Cl–C6H5-(1d)
p-NO2–C6H5-(1e)
p-CN–C6H5-(1f)
p-CF3–C6H5-(1g)
3-Thiophenyl-(1h)
a-Naphthyl-(1i)
Cinnamyl-(1j)
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
EtOCO
Cbz
0.5
0.75
1
3
3
0.3
0.25
1
0.25
0.25
0.3
0.3
0.25
0.5
0.75
0.50
3b, 90
3c, 84
3d, 82
3e, 63
3f, 64
3g, 87
3h, 92
3i, 93
3j, 85
3k, 98
3l, 96
3m, 90
3n, 76
3o, 88
3p, 95
3a, 96
1
2
3
4
5
6
7
8
10 6a, Cbz 70
14 6b, CO2Et 75
—
—
5a (X = H)
5b (X = 2-Me)
5c (X = 4-Me)
5d (X = 4-OH)
5e (X = 4-tBu)
16 6c, Cbz
10 6d, Cbz
61
82
76
90
(20 : 80)
(10 : 90)
(23 : 77)
(6 : 94)
(6 : 94)
—
—
—
—
6
8
6
6e, Cbz
6f, Cbz
6g, CO2Et 86
5f (Cycloheptanone)
5g (2-Adamantanone)
5h (R = Me)
10 6h, Cbz
12 6i, Cbz
10 6j, Cbz
12 6k, Cbz
77
68
62
40
9
9
10
11
10
11
12
13
14
15
16
Ph-CRC-(1k)
Cyclohexyl-(1l)
Isobutyl-(1m)
5i (R = Et)
PhCH2-(1n)
i
5j (R = Pr)
PhCH2CH2-(1o)
PhCHO (1a)
PhCH(OMe)2 (1p)
12
12 Cbz
—
—
13
14
5k (n = 4, R = Me)
5l (n = 10, R = Me)
10 6l, Cbz
12 6m, Cbz
54
49
—
—
a
Reaction conditions: 1 (1.0 mmol), 2a or 2b (1.2 mmol, 1.2 equiv.), Re2O7
(0.015 mmol, 1.5 mol%), allyltrimethylsilane (1.5 mmol, 1.5 equiv.),
acetonitrile (4 mL), room temperature. b Yield of the isolated products
after column chromatography; Cbz = carbobenzyloxy.
15
5m (n = 2, R = Et)
18 6n, Cbz
78
76
—
—
Encouraged by the efficiency of the Re2O7-catalyst for the above
reaction, the scope of this methodology was examined with a
variety of aldehydes (see Table 2). Various aromatic aldehydes
having –Me, –OMe, –Cl, –NO2, –CN, and –CF3 substitution at the
para-position provided the corresponding secondary homoallylic
amines in high yields (entries 1–6). Different aromatic aldehydes,
like 3-thiophenyl and a-naphthyl aldehydes, were also successfully
examined (entries 7 and 8 respectively).
16
8
6a, Cbz
a
Reaction conditions: 5 (1.0 mmol), 2a or 2b (1.5 mmol, 1.5 equiv.),
Re2O7 (0.025 mmol, 2.5 mol%), allyltrimethylsilane (2.0 mmol,
b
2.0 equiv.), acetonitrile (4 mL), room temperature. Isolated yield after
c
column chromatography. Diastereoselectivity (dr) was determined by
1H NMR spectroscopy of the product mixture.
Even unsaturated aldehydes (cinnamaldehyde 1j and acetylen-
aldehyde 1k) and aliphatic aldehydes (1l–o) provided the corres-
ponding homoallylamine (entries 9–14) without any complication.
Similar reactivity was observed on replacing Cbz– with EtOCO–
(entry 15). Interestingly, benzaldehyde dimethylacetal also
provided the corresponding homoallylic amine (3a) in excellent
yield, as shown in entry 16.
Interestingly, the reactivity also largely depends on the steric
nature of the ketones. For example, upon changing the sub-
i
stitution from Me- to Et- to Pr-, the observed reactivity
decreased significantly (entries 10 - 11 - 12). Furthermore,
the corresponding dimethylketals of cyclohexanone also equally
worked under the above optimized conditions (entry 16, Table 3).
Finally, we became interested to see the diastereoselectivity
of the present methodology using carbonyls having a pre-existing
stereocenter. This was demonstrated for the tertiary homoallylic
amines obtained from 2-Me, 4-Me, 4-HO, and 4-tert-butyl
cyclohexanones. Encouragingly, the ratio was observed up to
94 : 6 for homoallylic amines from 4-tert-butyl cyclohexanones.
Finally, a series of competitive experiments were performed
to study the chemoselectivity of the present protocol for the
synthesis of secondary vs. tertiary and also between various
tertiary homoallylic amines only (summarized in Table 4).
When an equimolar mixture of aldehyde (1o) and corresponding
methyl ketone 5h was treated with amine 2a and allyl-silane under
the standard reaction conditions, a highly selective secondary
homoallylic amine (3o) was obtained (entry 1) accompanied with
unreactive ketone 5h. The selectivity for the formation of secondary
homoallylic amine (3o) increased on increasing the steric demand
of ketones (e.g., Et- and iPr-) (entries 1 - 2 - 3). Even excellent
selectivity was observed between the formations of tertiary
homoallylic amines. For example, between Me- vs. Et- or
Once the present protocol was well established for various
aldehydes, we were interested to extend it towards ketones,
which have been nearly unachievable so far using these
reagents. Amazingly, the reaction worked smoothly even at
room temperature using 2.5 mol% Re2O7 for cyclohexanone
with Cbz–NH2 (2a) and allyltrimethylsilane to provide the
corresponding tertiary homoallylic amine (entry 1, Table 3).
Eventually, we explored various cyclic and acyclic ketones
(summarized in Table 3). Substituted cyclohexanones, like
2-Me, 4-Me, 4-HO, and 4-tert-butyl cyclohexanones, also were
successful and the obtained yield varied from moderate to high
(entries 3–7). The course of the reaction remained unaltered on
replacement of Cbz–NH2 (2a) by EtOCO–NH2 (2b) (entries 2
and 7). Other cyclic ketones, cycloheptanone (5f) and ada-
mantanone (5g) led to the desired products in good yield.
Furthermore, we also extended the present methodology to
acyclic ketones, which successfully proceeded to provide the
corresponding tertiary homoallylic amines (entries 10–15).
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1820–1822 1821

View Article Online
Table 4 Chemoselective one-pot homoallylic amine synthesis
(d) T. Ollevier and T. Ba, Tetrahedron Lett., 2003, 44, 9003;
(e) P. Phukan, J. Org. Chem., 2004, 69, 4005; (f) G. Smitha,
B. Miriyala and J. S. Williamson, Synlett, 2005, 0839;
(g) K. K. Pasunooti, M. L. Leow, S. Vedachalam, B. K.
Gorityala and X.-W. Liu, Tetrahedron Lett., 2009, 50, 2979.
3 Secondary N-protected homoallylic amines from N-alkoxy-
carbonylamino sulfone: (a) B. Das, K. Damodar, D. Saritha,
N. Chowdhury and M. Krishnaiah, Tetrahedron Lett., 2007,
48, 7930; (b) T. Ollevier and Z. Li, Adv. Synth. Catal., 2009,
351, 3251.
4 Using allyltin: secondary N-protected homoallylic amines are available
only: (a) T. Akiyama, J. Iwai, Y. Onuma and H. Kagoshima, Chem.
Commun., 1999, 2191; (b) B. Das, K. Laxminarayana, B. Ravikanth
and B. Ramarao, Tetrahedron Lett., 2006, 47, 9103; (c) P. Thirupathi
and S. S. Kim, Tetrahedron, 2009, 65, 5168; (d) A. V. Narsaiah,
J. K. Kumar and P. Narsimha, Synthesis, 2010, 1609.
S1 (1 eq.) S2 (1 eq.)
t/h
P1c [%] P1/P2d
1
2
3
4
5
6
1o
1o
1o
5h
5h
5h
5h
5i
5j
5i
5j
2a
2a
2a
3o, 66
3o, 87
3o, 84
97 : 3
499 : 1
499 : 1
499 : 1
499 : 1
499 : 1
15b 6j, 25
15b 6j, 43
PhCHQCHCOMe (5o) 15b 6j, 60
a
S1 and S2 (1 mmol each), 2a (1 mmol), Re2O7 (1.5 mol%), allyl-TMS
b
(1.1 mmol); S1 and S2 (1 mmol each); 2a (1.5 mmol), Re2O7 (6 mol%),
5 Using allylborane: N-unprotected homoallylic amines are available
only: (a) M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem.
Soc., 2004, 126, 7182; (b) S. Kobayashi, K. Hirano and
M. Sugiura, Chem. Commun., 2005, 104.
c
d
allyl-TMS (2 mmol); Isolated yield; Determined by 1H NMR spectro-
scopy of the product mixture.
6 Using allyl halide: secondary N-protected homoallylic amines:
(a) B. Sain, D. Prajapati and J. S. Sandhu, Tetrahedron Lett.,
1992, 33, 4795; (b) P. Merino, T. Tejero, J. I. Delso and
V. Mannucci, Curr. Org. Synth., 2005, 2, 479.
7 For reviews: (a) H. Hiemstra and W. N. Speckamp, in Comprehensive
Organic Synthesis, ed. I. Fleming, Pergamon Press, Oxford, 1991,
vol. 2, p. 1047; (b) Y. Yamamoto and N. Asao, Chem. Rev., 1993,
93, 2207; (c) T. Vilaivan, W. Bhanthumnavin and Y. Sritana-Anant,
Curr. Org. Chem., 2005, 9, 1315; (d) H. Ren and W. D. Wulff, J. Am.
Chem. Soc., 2011, 133, 5656; (e) S. Kobayashi, Y. Mori, J. S. Fossey
and M. M. Salter, Chem. Rev., 2011, 111, 2626.
8 Only examples: (a) Using triphenyl methyl perchlorate provided
nearly 20% yield of corresponding tertiary homoallylic amine (see
ref. 2b) and using stoichiometric BF3ÁOEt2; (b) E. Prusov and
M. E. Maier, Tetrahedron, 2007, 63, 10486.
9 Using FeSO4Á7H2O, a four component reaction of cyclohexanone,
CbzCl, HMDS, and allyltrimethylsilane has been reported to
provide the tertiary homoallylic amine, unfortunately, it was ineffective
in catalyzing the corresponding three-component reaction of
cyclohexanone, Cbz–NH2, and allyltrimethylsilane. See: Q.-Y. Song,
B.-L. Yang and S.-K. Tian, J. Org. Chem., 2007, 72, 5407.
10 One-pot synthesis of tertiary homoallylic amine (using allylborane
to N-unsubstituted amine): B. Dhudshia, J. Tiburcio and
A. N. Thadani, Chem. Commun., 2005, 5551.
Me- vs. iPr-ketones, under similar conditions, selective formation
of Me-substituted homoallylic amine was observed (entries 4
and 5). Finally, the selectivity between ketone (5h) and corres-
ponding a,b-unsaturated ketone (5o) was compared; interestingly,
the only obtained product (6j) was from ketone (5h) (entry 6).
In conclusion, we have developed a mild, one-pot, chemo-
selective, open-flask protocol using the Re2O7 catalyst for the
synthesis of protected secondary and ‘‘for the first time’’
tertiary homoallylic amines from carbonyl, carbamate, and
allyltrimethylsilane. This not only has offered a significant
advantage over the previous reports for the synthesis of secondary
homoallylic amines, but has also provided the unachievable
synthetic protocol for tertiary homoallylic amines with high
diastereoselectivity. The chemoselective formation of secondary
as well as tertiary homoallylic amines has also been demonstrated.
Further utilization of such oxo-rhenium complexes for catalytic
reactions and developing their enantioselective variants are our
current focus.
P.G. thanks the DST, India, for a research grant and
Dr. Deepak Chopra for useful discussions. S.P. thanks the
CSIR, New Delhi, for a fellowship.
11 Tertiary homoallylic amines from preformed imines or hydrazones:
(a) S. Hanessian and R.-Y. Yang, Tetrahedron Lett., 1996,
37, 8997; (b) R. Berger, K. Duff and J. L. Leighton, J. Am. Chem.
Soc., 2004, 126, 5686.
12 (a) S. Kobayashi and S. Nagayama, J. Am. Chem. Soc., 1997,
119, 10049; (b) S. Yamasaki, K. Fujii, R. Wada, M. Kanai and
M. Shibasaki, J. Am. Chem. Soc., 2002, 124, 6536.
Notes and references
1 For recent applications of homoallylic amines: (a) J. C. A. Hunt,
P. Laurent and C. J. Moody, Chem. Commun., 2000, 1771;
(b) M. K. Pandey, A. Bisai, A. Pandey and V. K. Singh, Tetrahedron
Lett., 2005, 46, 5039; (c) J. E. Kropf, I. C. Meigh, M. W. P.
Bebbington and S. M. Weinreb, J. Org. Chem., 2006, 71, 2046;
(d) C. Denhez, J.-L. Vasse, D. Harakat and J. Szymoniak,
Tetrahedron: Asymmetry, 2007, 18, 424; (e) E. Airiau, N. Girard,
M. Pizzeti, J. Salvadori, M. Taddei and A. Mann, J. Org. Chem.,
2010, 75, 8670; (f) M. Morgen, S. Bretzke, P. Li and D. Menche,
Org. Lett., 2010, 12, 4494.
2 Using allylsilane: secondary N-protected homoallylic amines are
available only: (a) S. J. Veenstra and P. Schmid, Tetrahedron Lett.,
1997, 38, 997; (b) L. Niimi, K. Serita, S. Hiraoka and
T. Yokozawa, Tetrahedron Lett., 2000, 41, 7075; (c) M. Billet,
P. Klotz and A. Mann, Tetrahedron Lett., 2001, 42, 631;
13 For selected recent applications: (a) C. C. Romao, F. E. Kuhn and
¨
W. A. Herrmann, Chem. Rev., 1997, 97, 3197; (b) M. R. Luzung
and F. D. Toste, J. Am. Chem. Soc., 2003, 125, 15760; (c) C. Morrill
and R. H. Grubbs, J. Am. Chem. Soc., 2005, 127, 2842; (d) K. A. Nolin,
J. R. Krumper, M. D. Pluth, R. G. Bergman and F. D. Toste, J. Am.
Chem. Soc., 2007, 129, 14684; (e) R. Hua and J.-L. Jiang, Curr. Org.
Synth., 2007, 4, 151; (f) K. Tadpetch and S. D. Rychnovsky, Org. Lett.,
2008, 10, 4839; (g) P. Ghorai and P. H. Dussault, Org. Lett., 2008,
10, 4577; (h) P. Ghorai and P. H. Dussault, Org. Lett., 2009, 11, 213;
(i) S. Bellemin-Laponnaz, ChemCatChem, 2009, 1, 357; (j) A. T.
Herrmann, T. Saito, C. E. Stivala, J. Tom and A. Zakarian, J. Am.
Chem. Soc., 2010, 132, 5962; (k) S. Y. Yun, E. C. Hansen, I. Volchkov,
E. J. Cho, W. Y. Lo and D. Lee, Angew. Chem., Int. Ed., 2010, 49, 4261;
(l) I. Volchkov, S. Park and D. Lee, Org. Lett., 2011, 13, 3530.
c
1822 Chem. Commun., 2012, 48, 1820–1822
This journal is The Royal Society of Chemistry 2012