Reactivity of cyclic sulfamidates towards lithium acetylides: Synthesis of alkynylated amines

Article abstract of DOI:10.1016/j.tetlet.2011.08.171

A synthetically useful level of reactivity of cyclic sulfamidates toward acetylides is described. Ring-opening reactions of a structurally diverse set of 1,2-and 1,3-cyclic sulfamidates with a range of lithium acetylides from aliphatic, cyclic, aromatic, heteroaromatic, and functionalized alkynes proceed smoothly in a regioselective manner to give the corresponding N-sulfate intermediates. Hydrolysis of these intermediates under acidic conditions furnishes the alkynylated amines in yields ranging from 29% to 98%. The scope of the acetylenic substitution reaction with the structural variations in both the cyclic sulfamidates and alkynes is briefly examined.

Full text of DOI:10.1016/j.tetlet.2011.08.171

Tetrahedron Letters 52 (2011) 6336–6341
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactivity of cyclic sulfamidates towards lithium acetylides: synthesis
of alkynylated amines
⇑
Mustafa Eskici , Abdullah Karanfil, M. Sabih Özer, Cengiz Sarıkürkcü
Department of Chemistry, Faculty of Arts and Science, Celal Bayar University, 45016 Manisa, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetically useful level of reactivity of cyclic sulfamidates toward acetylides is described. Ring-open-
ing reactions of a structurally diverse set of 1,2- and 1,3-cyclic sulfamidates with a range of lithium acet-
ylides from aliphatic, cyclic, aromatic, heteroaromatic, and functionalized alkynes proceed smoothly in a
regioselective manner to give the corresponding N-sulfate intermediates. Hydrolysis of these intermedi-
ates under acidic conditions furnishes the alkynylated amines in yields ranging from 29% to 98%. The
scope of the acetylenic substitution reaction with the structural variations in both the cyclic sulfamidates
and alkynes is briefly examined.
Received 28 June 2011
Revised 12 August 2011
Accepted 30 August 2011
Available online 5 September 2011
Keywords:
Cyclic sulfamidates
Nucleophilic substitution
Lithium acetylides
Alkynylated amines
Ó 2011 Elsevier Ltd. All rights reserved.
Cyclic sulfamidates 1 represent a versatile class of readily
accessible, often enantiomerically pure, aminoalcohol-derived
electrophiles.1 Increasing synthetic use of these heterocyclic
compounds across a wide range of areas of synthesis over the last
decade is based upon the fact that the formation of sulfamidates
activates simultaneously the hydroxy group toward nucleophilic
displacement while providing partially concurrent protection to
the amino group. Nucleophilic attack occurs regioselectively at
the oxygen-bearing carbon center in a stereospecific fashion
(SN2) to form N-sulfate intermediate 2 which can be hydrolyzed
under mild acidic conditions to give the substitution product 3
(Scheme 1).
The reactivity profile of 1,2- and 1,3-cyclic sulfamidates toward
nucleophilic cleavage corresponds to that associated with acti-
vated aziridines and azetidines, respectively, but sulfamidate
chemistry offers several additional advantages.2 The regioselectiv-
ity of nucleophilic attack on the activated aziridines and azetidines
is not a straightforward issue, particularly in the absence of any
steric and/or electronic directing effect. However, with the use of
cyclic sulfamidates, the regioselectivity is largely defined by the
higher reactivity exhibited by the C–O bond which enables a nucle-
ophilic attack to take place in a regioselective manner, and the at-
tack at the C–N bond is not generally observed. In contrast to their
azacycle counterparts that strictly require a highly activating
protecting group such as N-tosyl for efficient displacement, cyclic
sulfamidates allow flexibility with respect to the protecting group
on the nitrogen. A range of protecting groups including Ts, Bn, Cbz,
and Boc can be used with very little effect on the ability of the sul-
famidates to undergo nucleophilic cleavage.3,4 Moving from three-
to four-membered ring systems, azetidines may lack the required
reactivity to be used as electrophiles.5 In the case of cyclic sulfam-
idates, on going from five- to six-membered ring systems, an
acceptable level of activation is achievable as the reactivity of
1,2-cyclic sulfamidates is not largely derived from the ring strain.
Recent studies describing successful fluoro6 and stereoselective3
alkylations with cyclic sulfamidates, otherwise not possible with
azacycles, clearly emphasise the usefulness of sulfamidates.
There are many reports on the ring-opening of cyclic sulfami-
dates with nitrogen,7 oxygen,8 sulfur,9 phosphorus,10 and halogen11
nucleophiles in the literature.12 Of particular value is cleavage with
carbon-based nucleophiles generating a new carbon–carbon bond
that could enable the synthesis of functionalized amines. In this re-
spect, the reactivity of cyclic sulfamidates toward synthetically
more versatile carbon-based nucleophiles has been less widely
exploited. Leading studies, especially by Gallagher and co-workers13
O
O
SO3
Nu
PG
R1
PG
R1
PG
R1
S
NH
Nu
H
Nu
N
N
O
SN2
R2
R2
R2
n
n
n
1
3
2
1,2-cyclic sulfamidate (n=0)
N-sulfate
1,3-cyclic sulfamidate (n=1)
PG: Bn, Ts, Cbz, Boc, etc.
⇑
Corresponding author. Tel.: +90 236 2412151; fax: +90 236 2412158.
E-mail address: mustafa.eskici@bayar.edu.tr (M. Eskici).
Scheme 1. Nucleophilic substitution of cyclic sulfamidates.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.171

M. Eskici et al. / Tetrahedron Letters 52 (2011) 6336–6341
6337
and others14 have demonstrated that cyclic sulfamidates possess a
high level of reactivity toward stabilized-carbon nucleophiles. The
reactivity of 1,2- and 1,3-cyclic sulfamidates toward, for example,
stabilized-enolates could be readily manipulated in a number of
ways for asymmetric syntheses of substitutedpyrrolidineand piper-
idine ring systems, respectively.13 To the best of our knowledge,
there has been no report concerning the reactivity of the sulfami-
dates with acetylides.15 As a closely related class of electrophiles,
cyclic sulfates are known to undergo efficient nucleophilic cleavage
with acetylides to afford alkynylated alcohols.16 Thus a similar
reactivity profile is anticipated with cyclic sulfamidates, and it is
the purpose of this communication to report the reactivity of cyclic
sulfamidates toward acetylides. The acetylenic displacement of cyc-
lic sulfamidates is envisagedto serve as aneffectivealternative route
for the synthesis of alkynylated amines.17
Initially, in trial experiments, enantiomerically pure phenyla-
laninol 1,2-cyclic sulfamidate 6 was prepared using the literature
protocol.12c Phenylacetylene (4a) was lithiated with n-butyllithium
in THF at ꢀ10 °C for 1 h.18 The resulting solution of phenylacetylide
5 then reacted with 6 for 24 h to form N-sulfate intermediate 7.
Acidic hydrolysis of this intermediate was performed with 5 M
HCl solution for 2 h.12c Neutralization of the reaction mixture with
aqueous saturated NaHCO3 solution followed by chromatographic
purification afforded (S)-N-benzyl-1,5-diphenyl-pent-4-yn-2-
amine (8a) in essentially quantitative yield (Scheme 2). A slight
excess (1.5 equiv) of the nucleophilic component 5 was required
for the complete consumption of 6.
Gratified by this result, we decided to perform investigations on
two separate sets in order to define briefly the scope of the acety-
lenic substitution reaction of 1,2-sulfamidates. For the first set, 6
was chosen as the model 1,2-cyclic sulfamidate and the structure
of the alkyne component was varied. In the second set, phenylacet-
ylene (4a) was the model terminal alkyne, and the 1,2-cyclic sul-
famidate structure was altered. Besides, we encountered
aggregation problems with some acetylide species, which was
overcome by the addition of HMPA as a polar solvent.6 Inclusion
of 10% HMPA by volume in the reaction mixtures was found to en-
hance significantly both the reaction rates and yields. For example,
the ring-opening reaction of 6 with 5 was complete in less than 1 h.
Therefore, the substitution reactions were investigated without
(Procedure A) and with HMPA (Procedure B). As 1.5 equiv of nucle-
ophilic component was not sufficient to achieve complete con-
sumption of the sulfamidate, in particular for some of those
reactions studied without HMPA, 2 equiv of the acetylides was
generally used.
4a, conjugated 4b, aliphatic 4c–d, and cyclic 4e alkynes all reacted
efficiently with 6 to deliver the corresponding b-alkynylated
amines 8a–e in excellent yields after the standard acidic-basic
work-up. Reactions of acetylides with acetal 4f and orthoester 4g
functionalities also took place smoothly to form the intermediate
N-sulfates. During the standard acidic hydrolysis of these interme-
diates the orthoester group was hydrolyzed concurrently to an
ethyl ester while the acetal group was sufficiently stable to obtain
the b-alkynylated chiral amine 8f in 85% yield. A similar ring-open-
ing reaction with phenylpropargyl ether 4j, which is prone to rear-
rangments,20 gave a complex mixture rendering the corresponding
alkynylated amine inaccessible. Following procedure A, benzyl
ether-containing alkyne 4i gave alkynylated amine 8i in a modest
yield (remaining mass balance was unreacted 6). Changing the
reaction conditions to procedure B increased drastically the reac-
tion yield to 96%. Without HMPA acetylides from 4h, 4k, and 4l
showed sluggish reactivity in the alkylation reactions. On success-
ful alkylation of the hydrocarbon-based alkynes, the reaction
mixtures were clear pale yellow solutions. On the contrary, the
acetylide solutions of 4h,k,l appeared rather cloudy which could
be caused by aggregation problems. Thus, the addition of HMPA
was necessary to effect the successful alkynylation in these cases.
In this way, b-alkynylated amines 8h and k were obtained in high
yields. Alkylation of the acetylene 4l containing a pyridine moiety
proved to be more problematic. Reaction of 4l with 6 using HMPA
produced an intractable mixture. The reaction temperature had to
be lowered to ꢀ78 °C to achieve a reasonable yield of product 8l
(entry 12).
A representative set of 1,2-cyclic sulfamidates was synthesized
for examination of the structural effect of the sulfamidate on the
alkylation.21 We preferred to use the benzyl group for N-protection
considering the ease of its installation and subsequent removal by
hydrogenation as well as its stability under the basic conditions
employed. Enantiomerically pure primary carbon-centered sul-
famidates 9a–d were prepared from L-alanine, valine, norvaline,
and proline using literature protocols.9a,12c,12g Among secondary
carbon-centered 1,2-cyclic sulfamidates, ephedrine-derived 9e
and lactate-derived 9f were optically pure, 9g was prepared in a
racemic form for convenience.12c The synthesis of 9f from (S)-ethyl
lactate was achieved via amidation with benzylamine,22 reduction
with LAH,23 and
sequence.
a two-step sulfamidate formation reaction
With the exception of proline-derived 9d, primary carbon-cen-
tered 1,2-cyclic sulfamidates 9a–c were found to be particularly
effective in the alkylation reaction with phenylacetylide 5 deliver-
ing the expected b-alkynylated amines 10a–c in excellent yields
(Table 2). The reactivity difference between 9b and 9c can be
attributed to the steric effect of the isopropyl group as the reaction
of 9b proceeded relatively slowly without HMPA. Reaction of bicy-
clic 9d, according to procedure A or B, occured readily to form an
intermediate (all of 9d was consumed in both cases by TLC), but
we were unable to hydrolyze this intermediate using the standard
Nucleophilic cleavages of phenylalaninol 1,2-cyclic sulfamidate
6 with a diverse set of lithium acetylides are shown in Table 1. The
acetylenic substitution appears to be a general reaction with
regard to the structural effect of the nucleophilic component. A
range of functionalities including ether, acetal, orthoester, tertiary
amine, heteroaromatic on the acetylide were tolerated.19 Using
procedure A, hydrocarbon-based lithium acetylides from aromatic
O
O
O
S
n-BuLi
THF, - 10 °C
BnN
Ph
H
Ph
Li
5
4a
Ph
N
6
Bn
SO3Li
NHBn
Ph
5 M HCl
then sat. NaHCO3
98%
Ph
Ph
Ph
8a
7
Scheme 2. Reaction of phenylalaninol 1,2-cyclic sulfamidate 6 with phenylacetylide 5.

6338
M. Eskici et al. / Tetrahedron Letters 52 (2011) 6336–6341
Table 1
Reactions of phenylalaninol sulfamidate 6 with various terminal alkynes at ꢀ10 °C
Entry
Terminal alkyne
4
Product 8
Yield (%)a
98
Procedure
NHBn
Ph
Ph
H
A
1
8a
Ph
4a
4b
NHBn
NHBn
A
H
95
2
3
4
Ph
Ph
8b
8c
A
A
H
H
91
90
4c
NHBn
NHBn
8d
Ph
4d
A
A
95
85
H
H
5
6
8e
OC2H5
Ph
4e
C2H5O
NHBn
OC2H5
8f
4f
Ph
C2H5O
C2H5O
O
NHBn
NHBn
OC2H5
N
7
8
C2H5O
C2H5O
H
A
89
95
Ph
Ph
8g
4g
A
B
N
8h
H
4h
NHBn
A
B
Bn
Ph
O
O
60
96
9
Ph
8i
H
Bn
4i
4j
O
A
B
complex mixture
10
H
S
A
B
19
92
S
NHBn
11
12
H
H
Ph
Ph
8k
4k
4l
N
N
A
B
NHBn
71b
8l
Procedure A: reactions run in THF without the addition of HMPA.
Procedure B: reactions run in THF with the addition of 10% HMPA by volume.
a
Yield of isolated product after chromatographic purification.
Reaction run at ꢀ78 °C.
b
conditions. Attempted hydrolysis of the intermediate under
various acidic conditions (concd. HCl, 20% and 50% H2SO4) failed
to produce any success; heating usually resulted in degradation
of the intermediate.14e Sterically demanding ephedrine-derived
considered to be a test of the given nucleophilic component for
the elimination pathway. Using procedure A, the alkylation
reaction of 9g with
5 led to the formation of the desired
substitution product 10g along with N-benzyl cinnamylamine 11
in 29% and 67% yields, respectively. Performing the reaction in a
more polar solvent system afforded 11 as the sole reaction product
in 85% yield. Increasing the polarity of the solvent system seemed
to favor the elimination pathway. Lowering the reaction tempera-
ture was not effective in altering at the substitution–elimination
product distribution in favor of 10g. This attempt only slowed
the reaction rate without any desirable effect on the formation of
10g.
sulfamidate 9e was completely unreactive with acetylide
5
without HMPA. When HMPA was present, the same reaction run
at either ꢀ10 °C or ꢀ78 °C gave a complex mixture. Secondary
carbon-centered lactic acid derived 9f, of sterically less demanding
nature, underwent uneventful alkylation with 5 in a stereospecific
manner to furnish the amine 10f in 85% yield with an inversion of
stereochemistry. The lability of the sulfamidate 9g toward
elimination has been already reported.12c Thus, the use of 9g is

M. Eskici et al. / Tetrahedron Letters 52 (2011) 6336–6341
6339
Table 2
Reactions of 5 with various 1,2-cyclic sulfamidates 9a–g at ꢀ10 °C
O
O
S
NHBn
Ph
10a-g
A
B
1. Procedure or
2. 5 M HCl, 2 h, then
9a-g sat. NaHCO3
BnN
O
Ph
Li
R
5
R
Yield (%)a
Entry
1,2-Cyclic sulfamidate
10
Product
Procedure
O
O
O
S
NHBn
Ph
A
95
BnN
1
2
10a
9a
O
O
O
NHBn
NHBn
Ph
A
B
60
88
S
BnN
10b
9b
O
O
Ph
S
A
BnN
O
95
3
4
10c
9c
A
B
see text
N
S
9d
O
O
O
O
A
B
S
5
MeN
O
complex mixture
9eb Ph
Ph
A
B
63
85
O
O
S
O
NBn
NHBn
Ph
6
7
10f
9f
Ph
BnHN
A
B
29
O
O
O
10g
S
NBn
Ph
A
B
67
85
9gb
Ph
NHBn
11
Procedure A: reactions run in THF without the addition of HMPA.
Procedure B: reactions run in THF with the addition of 10% HMPA by volume.
a
Yield of isolated product after chromatographic purification.
Reaction performed at ꢀ78 °C (see text).
b
The critical issues of the alkylation reactions described in this
study that require clarification are the stereochemical integrity of
the stereogenic centers of the sulfamidates and the SN2 nature of
the displacement with 9f. For this purpose, amine 10a was
converted into (S)-5-phenyl-2-pentylamine hydrochloride (12)
1. H2, Pd, THF
2. HCl
NHBn
Ph
NH2HCl
Ph
90%
10a
12
(½a 3D0
ꢁ
ꢀ5.5 (c 1, EtOH), for R 12, ½a D20
ꢁ
+3.0 (c 0.63, EtOH), 92%
Ph
e.e.24) by atmospheric hydrogenation over palladium25 (Pd/C and
Pd(OH)2/C) to effect both saturation and debenzylation (Scheme 3).
Similarly, lactate derived-amine 10f was also converted into
known (S)-2-methyl-4-phenylbutylamine (13). The specific rota-
H2, Pd, THF
81%
Ph
NHBn
NH2
13
10f
tion (½a 3D0
ꢀ16.2 (c 1, CHCl3)) of 13 was in close agreement with
ꢁ
Scheme 3. Conversion of alkynylated amines into saturated amine derivatives.

6340
M. Eskici et al. / Tetrahedron Letters 52 (2011) 6336–6341
Procedure B
NHBn
-10 °C
77%
NHBn
Ph
O
O
Bn
S
N
O
15
16
5:1
Ph
Li
5
Procedure B
14
-78 °C
15
75%
Scheme 4. Reaction of 1,3-cyclic sulfamidate 14 with phenylacetylide 5.
the literature value (½a D20
ꢁ
ꢀ15.9 (c 1.11, CHCl3)).26 Derivatization of
2. Hu, X. E. Tetrahedron 2004, 60, 2701.
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corresponding Mosher amides showed that there was a single dia-
stereoisomer present in each case by analysis of 1H NMR spectra.
This result rules out any racemization of the stereogenic centers
occurring during the alkylation reactions. Observation of the
diastereomerically pure Mosher amide derivative of 13 indicates
clean inversion of the stereochemistry during the alkylation of 9f
with 5, which is frequently observed in the literature.13
We were also interested in the reactivity of 1,3-cyclic sulfami-
dates in the alkylation reaction. Methyl substituted 14 as the only
studied 1,3-cyclic sulfamidate exhibited considerably lower reac-
tivity toward 5 compared with alanine-derived 9a (Scheme 4).
Using procedure A, sulfamidate 14 failed to react with 5 even over
a longer reaction time (48 h). The use of HMPA nevertheless
brought about an acceptable degree of reactivity, and the corre-
8. (a) Jiménez-Osés, G.; Avenoza, A.; Busto, J. H.; Rodriguez, F.; Peregrina, J. M.
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S.; Kilbourn, M. R.; Weiland, D. M. J. Med. Chem. 1995, 38, 810.
12. For selected examples of more general ring-opening reactions of cyclic
sulfamidates, see: (a) Rujirawanich, J.; Gallagher, T. Org. Lett. 2009, 11, 5494;
(b) Bower, J. F.; Szeto, P.; Gallagher, T. Org. Lett. 2007, 9, 3283; (c) Williams, A.
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W. D. Can. J. Chem. 2001, 79, 94; (f) Boulton, L. T.; Stock, H. T.; Raphy, J.;
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E. J. Org. Chem. 1991, 56, 3177; (h) Alker, D.; Doyle, K. J.; Harwood, L. M.;
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C.; Schofield, C. Tedrahedron: Asymmetry 1990, 1, 881.
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Szeto, P.; Lawrence, R. M.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 2636; (c)
Bower, J. F.; Szeto, P.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 143; (d) Bower, J.
F.; Szeto, P.; Gallagher, T. Org. Lett. 2007, 9, 4909; (e) Bower, J. F.; Chakthong
Švenda, J.; Williams, A. J.; Lawrence, R. M.; Szeto, P.; Gallagher, T. Org. Biomol.
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sponding reaction of 14 with 5 afforded the desired c-alkynylated
amine 15 along with a by-product. Separation of 15 from the by-
product was not possible by column chromatography. Conversion
of these compounds into the amide or carbamate derivatives did
not facilitate chromatographic separation. The structure of the
by-product was tentatively proposed to be N-benzyl-3-buten-2-
amine (16)28 by analysis of the 1H NMR spectrum of the purified
mixture that could result from the competing elimination path-
way. The ratio of 15/16 was estimated as 5:1 by 1H NMR spectros-
copy and the products were obtained in 77% overall yield.
Fortunately, lowering the reaction temperature to ꢀ78 °C reduced
the amount of 15 to 2–3%.29
In summary, a useful level of reactivity of the cyclic sulfami-
dates toward a range of acetylides has been reported. The ready
availability of cyclic sulfamidates and alkynes coupled with the
reactivity profile provides a practical and efficient entry for the
syntheses of
c- and b- alkynylated amines. Given the array of
versatile functionalities present and the widespread use of amines
in diverse areas of organic synthesis, the alkynylated amines are
valuable compounds for downstream manipulations. Further
exploitation of functionalized alkynylated amines is currently
underway and will be reported elsewhere.
14. (a) Lorion, M.; Agouridas, V.; Couture, A.; Deniau, E.; Grandclaudon, P. Org. Lett.
2010, 12, 1356; (b) Pound, M. K.; Davies, D. L.; Pilkington, M.; de Pina Vaz
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Org. Lett. 2000, 2, 2595; (d) Stiasny, H. C. Synthesis 1996, 259; (e) Cooper, G. F.;
McCarthy, K. E.; Martin, M. G. Tetrahedron Lett. 1992, 33, 5895. See also
citations in Ref. 12.
Acknowledgments
15. For an unsuccessful attempt concerning the nucleophilic displacement of
carbohydrate-based cyclic sulfamidates with lithium trimethylsilyl acetylide,
see: Aguilera, B.; Fernández-Mayoralas, A.; Jaramillo, C. Tetrahedron 1997, 53,
5893.
16. For a review on the reactivity of cyclic sulfates, see: (a) Lohray, B. B. Synthesis
1992, 1035; (b) Bittman, R.; Byun, H.-S.; He, L. Tetrahedron 2000, 56, 7051.
17. Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Tetrahedron 2005, 61, 9586.
18. Ducracy, P.; Lamotte, H.; Rossue, B. Synthesis 1997, 404.
The authors gratefully acknowledge Celal Bayar University for
financial support through a project (FEF-2009-101) and Pelin
SÖZEN AKTASß for obtaining HRMS.
Supplementary data
19. The terminal alkynes used are commercially available except benzylpropargyl
ether 4i and the orthoester-containing variant 4g. Benzylpropargyl ether 4i
was easily prepared via benzylation of propargylic alcohol. Ethyl
orthopropiolate 4g was synthesized from triethylorthopropionate using
bromination and elimination reactions, see: (a) Stetter, H.; Uerdingen, W.
Synthesis 1973, 207; (b) Bates, R. W.; Maiti, T. B. Synth. Commun. 2003, 33, 633;
(c) Gassman, P. G.; Chavan, S. P. Tetrahedron Lett. 1988, 29, 3407; For an
alternative synthesis of triethylorthopropiolate, see: (d) Boche, G.; Bigalke, J.
Tetrahedron Lett. 1984, 25, 955.
Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.171.
References and notes
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