Regio-selective synthesis of 1,2-aminoalcohols from epoxides and chlorohydrins

Article abstract of DOI:10.1016/j.tetlet.2012.08.013

A simple and efficient procedure for the regio-selective synthesis of 1,2-aminoalcohols from terminal epoxides and chlorohydrins by using NaHMDS as the source of amine is reported. The wider scope and utility of this method is demonstrated.

Full text of DOI:10.1016/j.tetlet.2012.08.013

Tetrahedron Letters 53 (2012) 5739–5741
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regio-selective synthesis of 1,2-aminoalcohols from epoxides and chlorohydrins
Andiappan Murugan a, , Vasantha Krishna Kadambar , Sreekanth Bachu , M. Rajashekher Reddy ,
⇑
a
a
a
a
a
a
a
Venkatarao Torlikonda , Sulur G. Manjunatha , Sridharan Ramasubramanian , Sudhir Nambiar ,
b
b
Gareth P. Howell , Jane Withnall
a
AstraZeneca India Pvt. Ltd, Off Bellary Road, Bangalore 560024, India
AstraZeneca, Charter way, Silk Road Business Park, Macclesfield, Cheshire SK10 2NX, UK
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient procedure for the regio-selective synthesis of 1,2-aminoalcohols from terminal
epoxides and chlorohydrins by using NaHMDS as the source of amine is reported. The wider scope and
utility of this method is demonstrated.
Received 26 June 2012
Revised 30 July 2012
Accepted 2 August 2012
Available online 13 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
1
,2-Aminoalcohol
Epoxide
Chlorohydrin
NaHMDS
Epoxide opening
Regio-selective
1
,2-Aminoalcohols are important building blocks in the synthe-
O
1
sis of natural products, pharmaceuticals, and other materials.
Generally, these 1,2-aminoalcohols are prepared by nucleophilic
ring opening of epoxides with nitrogen based nucleophiles.
R
1
2
–5
NH
3
Simple ammonolysis of epoxides 1 (Scheme 1) is one of the most
commonly used methods but frequently suffers from poor regio-
6
selectivity (2 vs 3) and over alkylation (4).
HO
R
H
2
N
OH
OH
OH
H
N
N
To circumvent these challenges, alternative methods to synthe-
size this important functional group have received an immense
amount of attention over the years. Widely used methods include
+
+
R
R
R
4
2
3
2
epoxide opening with (i) azides followed by reduction, (ii) phthal-
3
Scheme 1.
imides followed by deprotection (iii) N,N-dibenzylamine followed
4
by debenzylation , (iv) benzhydrilamine followed by deprotec-
5
tion. Despite these advancements, there are still some drawbacks
using NaHMDS as the source of amine for the epoxide ring opening.
When we looked into the literature, we came across a couple of re-
ports indicating the possibility of epoxide ring opening with NaH-
associated with these previously reported methods, such as
involvement of energetic intermediates (azides), toxic reagents
7
(
hydrazine for phthalimide deprotection in [ii]), requirement of
MDS. To our surprise, this methodology has not been explored by
additional steps for deprotection, and in some cases unsatisfactory
selectivity. Therefore, the development of an efficient alternative
method is highly desirable.
In one of our developmental projects, during an effort to ring
open epoxide with a secondary amine using NaHMDS as base, we
observed traces of 1,2-aminoalcohol having primary amine func-
tion. This observation prompted us to explore the possibility of
the synthetic community. We anticipated that the sterically-large
HMDS group might give better regio-control. Herein we report
our results on a highly efficient method for the preparation of
1,2-aminoalcohols from epoxides and chlorohydrins.
We began by probing the ability of NaHMDS to open the epox-
ides. Accordingly, the treatment of styrene oxide (5) with NaHMDS
in THF at 0 °C overnight gave 15% conversion to intermediate 6.
The rate of the reaction increased considerably when the temper-
ature was raised to 20–25 °C and the reaction was complete in
14–15 h. Aqueous work-up gave 1,2-aminoalcohol 7 in excellent
⇑
Corresponding author. Tel.: +91 9986063134; fax: +91 80 23622011.
E-mail address: Andiappan.Murugan@astrazeneca.com (A. Murugan).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.013

5
740
A. Murugan et al. / Tetrahedron Letters 53 (2012) 5739–5741
O
Na+
O–
OH
NaHMDSa, b, THF, 20 h
5 °C
water, 5 h
5 °C
NH2
N(TMS)2
2
2
5
7
6
Scheme 2. (a) 3 Equivalents of 1 M NaHMDS solution in THF was used. (b) NaHMDS was added at 0–5 °C.
Table 1
Table 2
Substrate scope of nucleophilic ring opening of epoxide with NaHMDS
Examples for the synthesis of amino alcohol from chlorohydrin
Yielda (%) Time (h)
(
i) NaHMDSa, b, THF, 25 °C
HO
S. No. Substrate
Product
O
NH2
R
R
(ii) water, 25 °C
OH
OH
2
a -2e
8
-12
Cl
NH
2
1
85
15
Entry
Substrate
R
Product
2a
2b
2c
2d
2e
Time (h)
Yieldc (%)
MeO
MeO
Me
1
2
3
4
5
8
9
10
11
12
4-ClC
4-BrC
4-FC
6
H
4
17
14
17
5
81
87
80
83
70
OH
OH
6
H
4
Cl
NH
2
2
82
83
16
15
6
H
4
C
C
6
H
H
5
OCH
2
Me
4
9
6
OH
OH
a
b
c
Cl
NH2
3
Equivalents of 1 M NaHMDS solution in THF was used.
3
NaHMDS was added at 0–5 °C.
Isolated yields.
a
Isolated yields.
i) NaHMDSa, b, THF
5 °C
OH
(
O
2
NH2
Encouraged by the above results, we extended this methodol-
(
ii) water, 25 °C
F
F
ogy to chlorohydrins, one of the general precursors for epoxides.
Moreover epoxides with electron-releasing substituents in the aryl
ring are generally unstable and are difficult to handle. A method to
convert 1,2-chlorohydrins directly to 1,2-aminoalcohols would be
advantageous. To test this idea, we attempted the reaction with
chlorohydrin 15 (Scheme 4) and demonstrated that upon treat-
ment with NaHMDS, both epoxidation and ring-opening were
achieved to afford the desired product in excellent yield.
To assess the scope of this reaction, we carried out further
experiments with substituted aryl-halohydrins as shown in
Table 2.
(
R)-2c
(
R)-10
c
c
>99.5% ee
>
99.5% ee
Scheme 3. (a) 3 Equivalents of 1 M NaHMDS solution in THF was used. (b) NaHMDS
was added at 0–5 °C. (c) Enantiomeric excess was determined by chiral HPLC; see
Supplementary data for details.
(
i) NaHMDSa, b, THF,
5 °C
OH
OH
2
Cl
NH2
From the results shown in Table 2, it is proved that this meth-
odology allows direct access to the desired 1,2-aminoalcohols from
(ii) water, 25 °C
1
3
7
1
,2-chlorohydrins without the requirement to handle unstable
epoxide intermediates.
Scheme 4. (a) 3 Equivalents of 1 M NaHMDS solution in THF was used. (b) NaHMDS
was added at 0–5 °C.
In summary, a simple, high-yielding, and regio-selective meth-
od for the preparation of 1,2-aminoalcohols from terminal epox-
ides and 1,2-chlorohydrins has been demonstrated. The method
appears to be of general value and works well with both aryl and
alkyl substituted epoxides.
yield (81%) as a single regio-isomer. HPLC analysis of the reaction
mixture did not show any traces of regio-isomer. All our efforts
to characterize the N,N-diTMS intermediate 6 proved to be unsuc-
cessful owing to its instability. It was found that 2.5–3 mole equiv-
alents of NaHMDS was necessary to get a complete reaction.
Increasing the temperature to 50 °C resulted in complex reaction
mixtures. Use of LiHMDS and KHMDS resulted in lower yields. As
anticipated, the sterically demanding HMDS moiety provided a sin-
gle regio-isomer as shown in Scheme 2.
Acknowledgements
The authors are thankful to Dr. John Singleton and Dr. Philip
Cornwall for their helpful discussions.
On the basis of the optimized conditions used, a variety of other
epoxides were examined the results are collected in Table 1.
As shown in Table 1, under these conditions , a wide range of
epoxides, both aromatic as well as aliphatic, underwent nucleo-
philic ring opening with NaHMDS in high yields.
Supplementary data
8
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
08.013.
Mechanistically we do not anticipate any possibility of racemi-
zation at C2 position of the epoxide, but to confirm the stereo-
chemical integrity of the reaction, we employed enantiopure
References and notes
1
.
.
Möller, F., 4th ed. In Methoden der Organischen Chemie (Houben-Weyl); Müller, E.,
Ed.; Thieme-Verlag: Stuttgart, 1957; Vol. 11/1, pp 311–326.
(R)-4-fluorostyrene oxide (10) as starting material (Scheme 3).
The product (R)-2c, as anticipated, did not suffer any loss of chiral-
ity during the course of reaction.
2
(a) Guy, A.; Doussot, J.; Ferroud, C.; Garreau, R.; Godefroy-Falguieres, A. Synthesis
1992, 821; (b) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 298; (c) Chini,

A. Murugan et al. / Tetrahedron Letters 53 (2012) 5739–5741
5741
M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990, 31, 5641; Saito, S.; Yamashita,
S.; Nishikawa, T.; Yokoyama, Y.; Inaba, M.; Moriwake, T. Tetrahedron Lett. 1989,
A. J.; Kuo, L.; Vacca, J. P. J. Med. Chem. 2004, 47, 6447; (e) Shimogawa, H.; Kwon,
Y.; Mao, Q.; Kawazoe, Y.; Choi, Y.; Asada, S.; Kigoshi, H.; Uesugi, M. J. Am. Chem.
Soc. 2004, 126, 3461; (f) Gautier, A.; Mulatier, J.-C.; Crassous, J.; Dutasta, J.-P. Org.
Lett. 2005, 7, 1207; (g) Kaburagi, Y.; Kishi, Y. Tetrahedron Lett. 2007, 48, 8967–
8971.
30, 4153.
3
.
(a) Williams, T. M.; Crumbie, R.; Mosher, H. S. J. Org. Chem. 1985, 50, 91; (b)
Mesropyan, E. G.; Hambardzumyan, G. B.; Avetisyan, A. A.; Galstyan, A. S.;
Khachatryan, A. G. Chem. Hetero. Comp. 2005, 41, 962; (c) Gupta, P.; Taneja, S. C.;
Shah, B. A.; Mukherjee, D.; Parshad, R.; Chimni, S. S.; Qazi, G. N. Tetrahedron:
Asymmetry 1898, 2008, 19.
7. (a) Yanagisawa, A.; Yasue, K.; Yamamoto, H. JCS Chem. Commun. 1994, 2103–
2104; (b) Ramachandran, P. V.; Gong, B.; Brown, H. C. J. Org. Chem. 1995, 60, 41–
46.
4.
5.
6.
(a) Meguro, M.; Asao, N.; Yamamoto, Y. J. Chem. Soc. 1994, 2597; (b) Cepane c´ , I.;
Litvic, M.; Mikulda sꢀ , H.; Bartolin cꢀ i c´ , A.; Vinkovi c´ , V. Tetrahedron, 2003, 59, 2435.
Medina, E.; VidaI-Ferran, A.; Moyano, A.; Perichs, M. A.; Riera, A. Tetrahedron:
Asymmetry 1997, 8, 1581.
For selected examples since 2001, see (a) Hu, B.; Ellingboe, J.; Gunawan, I.; Han,
S.; Largis, E.; Li, Z.; Malamas, M.; Mulvey, R.; Oliphant, A.; Sum, F.-W.; Tillett, J.;
Wong, V. Bioorg. Med. Chem. Lett. 2001, 11, 757; (b) Guangyou, Z.; Yuquing, L.;
Zhaohui, W.; Nohira, H.; Hirose, T. Tetrahedron: Asymmetry 2003, 14, 3297; (c)
Liu, C.-H.; Wang, B.; Li, W.-Z.; Yun, L.-H.; Liu, Y.; Su, R.-B.; Li, J.; Liu, H. Bioorg.
Med. Chem. Lett. 2004, 12, 4701; (d) Stachel, S. J.; Coburn, C. A.; Steele, T. G.;
Jones, K. G.; Loutzenhiser, E. F.; Gregro, A. R.; Rajapakse, H. A.; Lai, M.-T.;
Crouthamel, M.-C.; Xu, M.; Tugusheva, K.; Lineberger, J. E.; Pietrak, B. L.;
Espeseth, A. S.; Shi, X.-P.; Chen-Dodson, E.; Holloway, M. K.; Munshi, S.; Simon,
8. Representative procedure: To a stirred solution of 2-phenyloxirane 5 (1 g,
8.31 mmol) in anhydrous tetrahydrofuran was added sodium bis(trimethylsilyl)
amide (1 M solution in THF, 29.08 mL, 29.08 mmol, 3.0 equiv) at 0–5 °C. The
resultant mixture was allowed to warm to 25 °C and stirred for 20 h, by which
time the reaction was completed as indicated by TLC. The reaction mixture was
then quenched with water (2.5 mL) and stirred for 5 h. The solvent was removed
by distillation under reduced pressure bringing the total volume to one-fourth.
The content of the reaction mixture was extracted with dichloromethane
(2 Â 10 mL). The organic layer was dried over anhydrous Na
2 4
SO and
concentrated under reduced pressure to give the crude product. The crude
product was purified by column chromatography on silica gel to obtain the pure
product as pale yellow solid.