2-(1,3-Dioxan-2-yl)ethylsulfonyl group: A new versatile protecting and activating group for amine synthesis

Article abstract of DOI:10.1021/ol052545+

(Chemical Equation Presented) 2-(1,3-Dioxan-2-yl)ethylsulfonyl (Dios) chloride was synthesized and used as a new versatile sulfonating agent for amines. Primary and secondary amines were sulfonated very easily in excellent yields with Dios chloride. N-Nonsubstituted and N-monosubstituted Dios-amides, activated amines, were alkylated satisfactorily under new Mitsunobu conditions utilizing (cyanomethylene)tributylphosphorane (CMBP). The Dios group is very stable under basic and reductive conditions and is removed by heating in a hot aqueous solution of trifluoroacetic acid.

Full text of DOI:10.1021/ol052545+

ORGANIC
LETTERS
2006
Vol. 8, No. 1
71-74
2-(1,3-Dioxan-2-yl)ethylsulfonyl Group:
A New Versatile Protecting and
Activating Group for Amine Synthesis
Izumi Sakamoto, Norimasa Izumi, Taeko Yamada, and Tetsuto Tsunoda*
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity,
Tokushima 770-8514, Japan
tsunoda@ph.bunri-u.ac.jp
Received October 20, 2005
ABSTRACT
2-(1,3-Dioxan-2-yl)ethylsulfonyl (Dios) chloride was synthesized and used as a new versatile sulfonating agent for amines. Primary and secondary
amines were sulfonated very easily in excellent yields with Dios chloride. N-Nonsubstituted and N-monosubstituted Dios-amides, activated
amines, were alkylated satisfactorily under new Mitsunobu conditions utilizing (cyanomethylene)tributylphosphorane (CMBP). The Dios group
is very stable under basic and reductive conditions and is removed by heating in a hot aqueous solution of trifluoroacetic acid.
Because many nitrogen-containing molecules possess a wide
variety of interesting biological activities, the synthesis of
such compounds has attracted much attention and has been
accomplished with the development of efficient synthetic
methods.1 In synthesis, protection and/or activation of the
nitrogen atom followed by deprotection procedures are often
required to construct not only nitrogen functional groups but
also other functional groups and carbon frameworks. Thus,
many excellent protecting and/or activating groups have been
developed and applied to various stages of organic synthe-
ses.2 Among them, sulfonamides such as tosylamide (Ts-
amide) and â-trimethylsilylethylsulfonamide (SES-amide)3
occupy an attractive position because of their sufficient
stability toward various reagents under harsh conditions and
their ease of handling. However, because of harsh cleavage
conditions,4 the traditional sulfonyl groups are often unable
to satisfy the requirements for the synthesis of multifunctional
(2) For selected references, see: (a) Greene, T. W.; Wuts, P. G. ProtectiVe
Group in Organic Synthesis, 3rd ed.; John Wiley and Sons: New York,
1998; pp 494-653. (b) Qian, L.; Sun, Z.; Mertes, M. P.; Mertes, K. B. J.
Org. Chem. 1991, 56, 4904. (c) Vedejs, E.; Lin, S.; Klapars, A.; Wang, J.
J. Am. Chem. Soc. 1996, 118, 9796. (d) Sun, P.; Weinreb, S. M. J. Org.
Chem. 1997, 62, 8604.
(3) Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron Lett. 1986,
27, 2099.
(4) For selected references about the Ts group, see: (a) Kovacs, J.;
Ghatak, U. R. J. Org. Chem. 1966, 31, 119. (b) Paul, B. J.; Hobbs, E.;
Buccino, P.; Hudlicky, T. Tetrahedron Lett. 2001, 42, 6433. (c) Ji, S.;
Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson, W. D.; Wriede,
P. J. Am. Chem. Soc. 1967, 89, 5311. (d) Opalka, C. J.; D’Ambra, T. E.;
Faccone, J. J.; Bodson, G.; Cossement, E. Synthesis 1995, 766. (e) Gold,
E. H.; Babad, E. J. Org. Chem. 1972, 37, 2208. (f) Vedejs, E.; Lin, S. J.
Org. Chem. 1994, 59, 1602. (g) Hill, D. C.; Flugge, L. A.; Petillo, P. A. J.
Org. Chem. 1997, 62, 4864. (h) Nayak, S. K. Synthesis 2000, 1575.
(1) (a) Sandler, R.; Karo, W. Organic Functional Group Preparations,
2nd ed.; Academic: New York, 1983; Chapter 13, pp 323-352. (b) Marson,
C. M.; Hobson, A. D. ComprehensiVe Organic Functional Group Trans-
formations; Katritzky, A., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon:
Oxford, 1995; Vol. 2, pp 297-332.
10.1021/ol052545+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/09/2005

molecules. Thus, the Fukuyama method utilizing the o-
nitrobenzenesulfonyl (Ns) group has been widely accepted
and applied to amine synthesis.5 Further, the o-anisylsulfonyl
(Ans) group was recently developed as an alternative
activating/protecting group of nitrogen function.6
Primary and secondary sulfonamides may be subjected to
the Mitsunobu alkylation to synthesize pure primary and
secondary amines, respectively.7 However, the original
Mitsunobu reagent (DEAD-PPh3) mediates the alkylation
with low to moderate yields, except the reaction of Ns-amide,
because of the so-called “pKa restriction” of nucleophiles.8
Furthermore, the use of DEAD-PPh3 fails in the alkylation
of primary sulfonamides such as Ts-amide (1, pKa ) 10.2),
which reacts with PPh3 to form triphenylphosphine tosyl-
imide 2 under the reaction conditions (Scheme 1).9 These
5, an aliphatic sulfonamide, can be estimated to be the same
as that of methanesulfonamides (e.g., MsNHMe: pKa )
11.8).12 This suggested that the Mitsunobu alkylation of Dios-
amides could not be expected to proceed in high yield when
using the original reagent as mentioned above. However, we
can anticipate that the use of new reagents promotes the
desired Mitsunobu alkylation significantly. In this paper, we
would like to describe the results of the newly developed
Dios chemistry.
Dios chloride (Dios Cl) 7, a sulfonyl agent, was prepared
by the following reaction sequence: (1) Easily prepared 2-(2-
chloroethyl)-1,3-dioxane (6)13 was converted to the corre-
sponding sodium 2-(1,3-dioxan-2-yl)ethylsulfonate (Na2SO3,
DME-H2O, reflux, 72 h), and then (2) the sulfonate was
treated with 2.0 equiv of PPh3 and 2.2 equiv of sulfuryl
chloride (CH2Cl2, 0 °C, 2 h). The agent could be purified
by rapid chromatography on silica gel and stored at -15 °C
for long periods of time (Scheme 2).
Scheme 1. Reaction of TsNH2 (1)
Scheme 2. Dios Group and Its Preparation
problems were overcome by using new Mitsunobu reagents
developed by our group.10 The reagents satisfactorily medi-
ated the alkylation reaction of various nucleophiles with a
pKa of 11-23, such as N-methyltosylamide (pKa ) 11.7),10a
geranyl phenyl sulfone (pKa ) 22.5 in DMSO),10b and
others.10c-e In addition, the alkylation of tosylamide 1 was
found to proceed smoothly with the use of only (cyano-
methylene)tributylphosphorane (CMBP),10a,11 one of the
phosphorane types of new Mitsunobu reagents, to give the
desired N-monosubstituted sulfonamides 3 in excellent yields
(Scheme 1), establishing a new facile synthetic method to
primary amines.10f
The reaction of 7 with ammonia afforded water-soluble
N-nonsubstituted Dios-amide 8 in 90% yield (NH3 aqueous,
CH3CN, 0 °C ∼ room temperature, 10 min). Primary and
secondary amines were also sulfonated in excellent yields
(1.1 equiv of 7, 1.5 equiv of NEt3, CH2Cl2, 0 °C, 10 min),
as listed in Table 1.
With this background, we decided to develop a new
versatile sulfonyl group, which can be deprotected easily
under acidic conditions. Thus, 2-(1,3-dioxan-2-yl)ethylsul-
fonyl (Dios) group 4 was proposed. The pKa of Dios-amide
Table 1. List of Amines and % Yield in the Sulfonylation
(5) For a review of Ns chemistry, see: (a) Kan, T.; Fukuyama, T. J.
Synth. Org. Chem. Jpn. 2001, 59, 779. (b) Kan, T.; Fukuyama, T. Chem.
Commun. 2004, 353, and references therein.
(6) Milburn, R. R.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 2004, 43,
892.
(7) For example, see: (a) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.;
Scola, P. M.; Harris, G. D., Jr.; Weinreb, S. M. Tetrahedron Lett. 1989,
30, 5709. (b) Edwards, M. L.; Stemerick, D. M.; McCarthy, J. R.
Tetrahedron Lett. 1990, 31, 3417.
(8) The acidic hydrogen in nucleophiles has to have a pKa less than 11
for the reaction to proceed satisfactorily. See: (a) Mitsunobu, O. Synthesis
1981, 1. (b) Hughes, D. L. Org. React. 1992, 42, 335.
(9) Bittner, S.; Assaf, Y.; Krief, P.; Pomerantz, M.; Ziemnicka, B. T.;
Smith, C. G. J. Org. Chem. 1985, 50, 1712. Also see ref 10f and 11.
(10) (a) Tsunoda, T.; Ozaki, F.; Itoˆ, S. Tetrahedron Lett. 1994, 35, 5081.
(b) Uemoto, K.; Kawahito, A.; Matsushita, N.; Sakamoto, I.; Kaku, H.;
Tsunoda, T. Tetrahedron Lett. 2001, 42, 905. (c) Itoˆ, S.; Tsunoda, T. Pure
Appl. Chem. 1999, 71, 1053. (d) Tsunoda, T.; Itoˆ, S. J. Synth. Org. Chem.
Jpn. 1997, 55, 631. (e) Tsunoda, T.; Kaku, H.; Itoˆ, S. TCIMail 2004, 123,
2. (f) Tsunoda, T.; Yamamoto, H.; Goda, K.; Itoˆ, S. Tetrahedron Lett. 1996,
37, 2457.
a The reaction was carried out for 50 min.
The feature of the reaction of the Dios-amide 8 in the
presence of CMBP was quite similar to that of Ts-amide 1
(11) Sakamoto, I.; Nishii, T.; Ozaki, F.; Kaku, H.; Tanaka, M.; Tsunoda,
T. Chem. Pharm. Bull. 2005, 53, 1508.
72
Org. Lett., Vol. 8, No. 1, 2006

reported previously.10a,14 Thus, the Mitsunobu alkylation of
8 proceeded in satisfactory yields to give 9 even with
secondary alcohol (Table 2), although benzylic and allylic
CMBP. Although the reaction could be expected to be
promoted with satisfactory results by (cyanomethylene)-
trimethylphosphorane (CMMP),10e,15 which is a more highly
reactive Mitsunobu reagent than CMBP, the commercially
available CMBP possessed sufficient reactivity to afford N,N-
disubstituted Dios-amide 10 in excellent yields. The alkyl-
ation of 9 was also accomplished using alkyl halides under
basic conditions. For example, benzyl bromide reacted with
9a (R ) Bn) (K2CO3, DMF, room temperature, 15 h), giving
quantitative yield. However, the reaction of 2-bromooctane,
a secondary alkyl halide, gave poor results owing to
competitive elimination (NaH, DMF or THF, 0 °C ∼ room
temperature).16 On the contrary, a potential advantage of the
Mitsunobu alkylation was that a secondary alkyl group could
be introduced with complete Walden inversion on nitrogen
effectively, as shown in Table 3.17
Table 2. List of Alcohols, Reaction Temperature, and % Yield
of the Product in the Mitsunobu Alkylation of 8
As expected, deprotection of N-monosubstituted and N,N-
disubstituted Dios-amides 9 and 10 was achieved by acid-
catalyzed hydrolysis of the acetal moiety to aldehyde in a
hot aqueous solution of trifluoroacetic acid (TFA) followed
by spontaneous retro-Michael reaction, giving the corre-
sponding primary and secondary amines in high yields (Table
4).18 N-Monosubstituted Dios-amides 9 could be cleaved
a The yield of double alkylation product 10 was shown in parentheses.
Table 4. List of Produced Amines, Reaction Period, and %
Yield in the Desulfurization of 9 and 10
alcohols gave overreacted products 10a and 10b (double
alkylation products) to some extent because of their high
reactivity.
As shown in Table 3, N-monosubstituted Dios-amide 9
could also be subjected to the Mitsunobu alkylation utilizing
Table 3. List of Alcohols, Reaction Temperature, and % Yield
of the Product in the Mitsunobu Alkylation of 9
more easily than N,N-disubstituted Dios-amides 10. A
plausible reaction pathway is shown in Scheme 3. Acrolein
generated as a coproduct did not react with amines produced
under these aqueous conditions.
(12) King, J. F.; Rathore, R.; Lam, J. Y. L.; Guo, Z. R.; Klassen, D. F.
J. Am. Chem. Soc. 1992, 114, 3028.
(13) Gil, G. Tetrahedron Lett. 1984, 25, 3805.
(14) The results of the reaction of 8 using other Mitsunobu reagents are
shown in the Supporting Information as a Table.
(15) Sakamoto, I.; Kaku, H.; Tsunoda, T. Chem. Pharm. Bull. 2003, 51,
474.
(16) The results of the reaction of 9 with primary and secondary alkyl
halides under basic conditions are described in the Supporting Information.
(17) The reaction of (2S)-2-octanol with 9 and a route for preparation of
an authentic sample are shown in the Supporting Information as a Scheme.
LC analysis of the product and the authentic sample shown in the Supporting
Information reveal that the reaction of 9 proceeded with the complete
configurational inversion of (2S)-2-octanol.
(18) Deprotection of the Dios group could also be achieved under other
acidic conditions, which were often employed for the hydrolysis of 1,3-
dioxanes.
a Yield using CMMP was shown in parentheses.
Org. Lett., Vol. 8, No. 1, 2006
73

Scheme 3. Reaction Pathway of Desulfurization
Scheme 5. Conclusion of Dios Methodology
This newly developed Dios group was highly stable unless
the cyclic acetal was hydrolyzed (e.g., 6 N HCl aqueous/
THF ) 2:1, room temperature, 47 h, very slow reaction).
Additionally, the chemistry and the stability of 1,3-dioxanes
are well-known and well-established.19 For example, N,N-
disubstituted Dios-amide was inert under several conditions,
such as: (1) LAH, room temperature, 12 h; (2) 2 N KOH,
95 °C in a sealed tube, 12 h; (3) n-BuLi, -78 °C ∼ room
temperature, 12 h; (4) EtMgBr, -78 °C ∼ room temperature,
12 h.20 Because the Dios group was more stable than a Boc
group in acidic conditions, the treatment (TFA/H2O ) 4:1)
of 10g at 0 °C achieved selective deprotection of the Boc
group to give 11 in 90% yield (Scheme 4). Thus, the Dios
group, and the resulting Dios-amide was alkylated under the
new Mitsunobu conditions. Finally, the Dios group was
cleaved/deprotected under acidic conditions. Thus, because
the Dios group can be used as a versatile activating/protecting
group of amines, the reactions presented herein would be
widely employed as useful methodologies in the synthesis
of nitrogen-containing molecules.
Scheme 4. Selective Deprotection of the Boc Group
Acknowledgment. This work was supported partially by
a Grant-in-Aid for Scientific Research (C) from MEXT (the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan). We are also thankful to MEXT.HAITEKU,
2003-2007.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, LC analysis, and
1H spectra of all the products. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL052545+
group can be utilized not only as an activating group but
also as a new amine-protecting group.
To conclude, the complete reaction sequence is illustrated
in Scheme 5. The Dios group was introduced onto an amino
(19) Greene, T. W.; Wuts, P. G. ProtectiVe Group in Organic Synthesis,
3rd ed.; John Wiley and Sons: New York, 1998; pp 307-326.
(20) The results of the reaction of Dios-amide under these conditions
are shown in the Supporting Information.
74
Org. Lett., Vol. 8, No. 1, 2006