Regio- and stereoselective hydrohalogenation of ynamide components in 1,3-butadiynes with in situ generated HX

Article abstract of DOI:10.1016/j.tetlet.2014.02.028

A simple protocol for regio-, and stereoselective hydrohalogenation of ynamide moieties in 1,3-butadiyne structures is described. The facile approach enables exact syn-addition of HX to the diyne components, giving just single isomer of the corresponding dienes and enynes.

Full text of DOI:10.1016/j.tetlet.2014.02.028

Tetrahedron Letters 55 (2014) 2130–2133
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Tetrahedron Letters
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Regio- and stereoselective hydrohalogenation of ynamide compo-
nents in 1,3-butadiynes with in situ generated HX
⇑
Masataka Ide, Kazuhiro Ohashi, Shigenori Mihara, Tetsuo Iwasawa
Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University Otsu, Shiga 520-2194, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple protocol for regio-, and stereoselective hydrohalogenation of ynamide moieties in 1,3-butadiyne
structures is described. The facile approach enables exact syn-addition of HX to the diyne components,
giving just single isomer of the corresponding dienes and enynes.
Received 21 January 2014
Revised 8 February 2014
Accepted 13 February 2014
Available online 20 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Haloenamide
Diene
Hydrohalogenation
Regio- and stereoselective reaction
Enyne
1,3-Dienes are clearly important building blocks in organic syn-
thesis.1 Structural 1,3-diene components are frequently found in
bioactive natural products2 and pharmaceutically interesting mol-
ecules.3–5 They are also capable of participating in a wide range of
complexity-generating transformations1 (e.g., cycloadditions,6
1,2- and 1,4-additions,7 and cycloisomerizations8). From the
synthetic point of view, functionalized 1,3-dienes bearing multi-
heteroatom substituents are versatile variants of 1,3-dienes.9
Among them 1,3-dienes directly-joining to halogen and nitrogen
atoms at their vinyl positions can be especially useful (Scheme 1).
Because halovinyls are readily converted into various functional
groups by halogen-metal exchange and are significant for
carbonAcarbon bond forming reactions by way of transition-metal
catalyzed cross-coupling reactions,10–12 and moreover the enamide
substructures serve as a novel type of nucleophiles in stereoselec-
tive CAC and CAN bond forming reactions.13 Thus, such hybrid but-
adienes combined with halovinyl and enamide are potentially
instructive toward the synthesized nitrogen-containing complex
molecules.14 Despite the utility of such hybrid butadienes, their
synthetic availability still remains a challenge, because of the inher-
ent difficulty in regio- and stereoselective hydrohalogenation of
1,3-diynes.15 As shown in Scheme 1, the stoichiometric addition
of hydrogen halide (HX) to buta-1,3-diyne-1,4-diamine moiety is
one way to prepare the dihalobuta-1,3-diene-1,4-diamine skeleton;
however, the generation and transfer of hygroscopic and gaseous
HX are inconvenient and difficult to perform.16–18 The problem
associated with this type of reactions lies in the difficulty of the for-
mation of a mixture of stereoisomers and side-products caused by
excess of HX,19 and actually Scheme 1 can permit ten products as
1,3-butadienes.
The prototype protocol for efficient hydrohalogenation of
alkynes without using gaseous HX was developed by Ishii and co-
workers in 199020: mixing of chlorotrimethylsilane, sodium iodide,
and water generates in situ HI, and addition of the HI to alkynes
produced
a-vinyl halides. And continuous efforts have aimed to
refine this initial method;21,22 for example, halotrimethylsilane,21
MgX2,14 and HF-SbF5,23 each-mediated in situ generation of HX
converted alkynes into variedly functionalized halovinyls. How-
ever, to the best of our knowledge, any trial for hydrohalogenation
of 1,3-diynes employing in situ generated HX is not performed.
On the other hand, we recently reported simple syntheses of
a
-haloenamides as a single isomer in gram-scale using in situ gen-
erated HX.24 The in situ HX (X = I, Br) was generated from mixing of
1 M halotrimethylsilane (TMSX) in CH2Cl2 and water, and added to
ynamide in nearly quantitative yields with perfect regio- and
stereoselectivity. The method completes the reaction within 1 h
⇑
Corresponding author. Tel.: +81 77 543 7461; fax: +81 77 543 7483.
E-mail address: iwasawa@rins.ryukoku.ac.jp (T. Iwasawa).
Scheme 1. Hydrohalogenation of buta-1,3-diyne-1,4-diamine moiety.
http://dx.doi.org/10.1016/j.tetlet.2014.02.028
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M. Ide et al. / Tetrahedron Letters 55 (2014) 2130–2133
2131
Table 1
Evaluation of the reactivity of 1 conducted via Scheme 2a
Entry
TMSBr (equiv)
Solvent
Temp (°C)
Yield (%)
1
2
1
2
3
1.2
2.4
3.2
4.0
3.2
3.2
3.2
3.2
3.2
3.2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Acetone
Toluene
THF
CH2Cl2
CH2Cl2/H2O (8% v/v)
CH2Cl2
0
0
0
0
rt
rt
rt
ꢀ78
ꢀ78
ꢀ78
28
12
2
2
4
28
72
0
0
0
44
60
68
64
60
52
24
72
69
79
Scheme 2. Synthesis of 2 from 1 (Ts = p-toluenesulfonyl).
4
5b
6b
7b
8
under routine conditions, and showed extensive substrate compat-
ibility, giving novel compounds of not only varied a-haloenamides
but also 1-(1-halovinyl)-1H-indoles and (1-iodovinyl)arenes.
In this Letter, as shown in Scheme 2, we describe a regio- and
stereoselective hydrohalogenation of buta-1,3-diyne-1,4-diamine
moiety (like 1) with in situ generated HX, which yields
N,N0-(1E,3E)-1,4-dihalobuta-1,3-diene-1,4-diyl skeleton (like 2) as
a single isomer. Thus, the protocol provides a simple access to
novel 1,3-butadiene directly-joining to the halogen and nitrogen
atoms at their vinyl positions.
9
10c
a
Reaction conditions: 1 (135 mg, 0.25 mmol), solvent (10 mL), 1 M (CH3)3SiBr in
CH2Cl2, H2O (10 mmol).
The starting 1 did not dissolve at 0 °C; thus the reactions at rt were carried out.
The reaction was performed in eight times scale; 1 (2 mmol), 80 mL of CH2Cl2,
80 mmol of H2O. The product 2 was afforded in 1.1 g.
b
c
At the onset of our study, we focused on the reactivity of 125 for
hydrobromination, based on our previous report.24 The mixture of
1 and 1 M TMSBr was stirred at ꢀ78 °C for 10 min, then water was
added, and the reaction was allowed to warm to ambient temper-
ature. After workup and purification, the product was isolated
through silica gel column chromatography without decomposition,
and both 1H and 13C NMR analyses revealed to be a single isomer.
The molecular structure of 2 was determined by crystallographic
analysis as shown in Figure 1,26 disclosing its stereochemistry as
a N,N0-((1E,3E)-1,4-dibromobuta-1,3-diene-1,4-diyl)bis(4-methyl-
N-phenylbenzenesulfonamide).
As summarized in Table 1, the reactivity of 1 conducted via
Scheme 2 was evaluated. For entries 1–4, the amounts of TMSBr
were surveyed: more than 3.2 equiv were needed for consumption
of the starting 1. The enyne-type product that undergoes one-sided
hydrohalogenation of the triple bonds was not observed through
entries 1–4. For entries 5–7, the yields in acetone, toluene, and
THF resulted in 60%, 52%, and 24%, respectively; they were not
more than 68% in entry 3. For entries 8, the hydrohalogenation in
CH2Cl2 at ꢀ78 °C suitably proceeded in up to 72% yield along with
disappearance of 1. The attempt at ꢀ78 °C was successful presum-
ably due to control over the sharp reactivity of TMSBr. For entry 9,
water was mixed in advance to the solvent of CH2Cl2, and the com-
parable yield of 2 to entry 8 was attained. For entry 10, this proto-
col was amenable to scale up; 1.1 g of 2 was obtained in 79% yield.
Scheme 3 illustrates different halotrimethylsilyl patterns tested.
Like TMSBr, TMSI generated in situ HI, and the HI nicely added to
the triple bonds of 1 to yield iodide 3 in 71%. Unfortunately in
Scheme 3. Hydroiodation and hydrochlorination of 1 to give 3 and 4.
Table 2
Synthesis of 1,3-dienens 5a, 5b, 6a, and 6b
the same condition TMSCl did not activate 1 at all. Then, several
approaches were attempted, and finally the employment of aque-
ous NH4Cl in the mixed solvent of CH2Cl2 and CH3CN achieved
the formation of chloride 4 as a single isomer in acceptable yield
of 65%. It was confirmed that the hydrochlorination never occurred
under only aqueous NH4Cl.27 The increase of ionic chloride in the
system would enhance the addition reaction to produce 4. Dihalide
3 and 4 were stable at ambient temperature under argon atmo-
sphere at least for 1 month with no appreciable decomposition.
With the viable conditions for synthesizing 2 in hand (Table 1,
entries 8 and 10), starting materials of buta-1,3-diyne-1,4-dia-
mines having allyl and p-tolyl groups28 underwent this hydrohalo-
genation, and its resultant products are listed in Table 2 as 5a, 5b,
6a, and 6b. These products are also afforded as single isomers in up
to 79% yield. The type of these halovinyls is an excellent candidate
for use in transition metal-mediated reactions such as an example
(Scheme 4): 5a underwent the cross-coupling with trimethylsilyl
acetylene.29 The starting 5a had two bromines as reaction sites,
and both reacted thoroughly along with forming conjugated bis-
enyne framework of 7 in 69% yield.
Figure 1. ORTEP drawing of 2 with thermal ellipsoids at the 50% probability level.
Hydrogen atoms are omitted for clarity. Selected lengths (Å): C(1)–C(2) = 1.339,
C(1)–Br(1) = 1.919, C(1)–N(1) = 1.394, C(2)–C(2) = 1.454.

2132
M. Ide et al. / Tetrahedron Letters 55 (2014) 2130–2133
Scheme 6. Effect of aqueous NH4Cl and NH4Br on the hydrohalogenations.
molecules from buta-1,3-diyne-1,4-diamine moieties. The in situ
generated HX from halotrimethylsilane and water adds to the al-
kynes in syn-mode, resulting in regio-, and stereoselective installa-
tion of halogen and hydrogen atom. In addition, similar selective
hydrobromination for the unsymmetrical 1,3-diyne was achieved.
This method completes the reactions quickly under the routine
conditions, and was amenable to gram-scale. We hope this proce-
dure finds widespread use in organic synthesis.
Scheme 4. Synthesis of 7 from 5a via Sonogashira reaction.
Acknowledgments
We thank Professor Ken-ichi Yamada at Kyoto University for
useful discussion and gentle assistance with measurement of
X-ray diffraction and scattering. We are very grateful to Professor
Michael P. Schramm at California State University Long Beach for
helpful discussion.
Scheme 5. Effect of the regio-, and stereoselective hydrobromination on 8a, 8b, and
10.
Supplementary data
To amplify this hydrohalogenation method, the unsymmetri-
cally structured 1,3-diynes30 8a and 8b in Scheme 5 were prepared,
because they were tested on the regio-, and stereoselective hydro-
bromination. Actually, the clean conversion of 8a into 9a was
smoothly achieved in 99% yield31: one-sided alkyne of ynamide
8a underwent the hydrobromination, and the other triple bond re-
mained totally unreacted. Similar selective hydrobromination for
the allyl 8b proceeded to afford 9b in 99% yield. On the other hand,
no reaction was observed on the hydrobromination of 10. The elec-
tronic bias in the triple bond of ynamide moiety proved to be
important for straightforward preparation of well-defined enyne
components in 9a and 9b.
The mechanism resulting in high stereochemical control to
derive predominantly syn-adducts is not yet fully known; however,
some points of the reaction process would be estimated. TMSX ini-
tially reacts with water to generate in situ HX. The HX would be
active species because the yields at entries 8 and 9 in Table 1 were
nearly equal regardless of addition of water in advance or not.
Then, the HX regio- and stereoselectively adds to the triple bond
of ynamide structure: according to the nature of the keteniminium
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
028.
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of
N,N0-(1E,3E)-1,4-dihalobuta-1,3-diene-1,4-diyl

M. Ide et al. / Tetrahedron Letters 55 (2014) 2130–2133
2133
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