Condition-directable reaction: Regio- and stereoselective elimination of 2,3-dibromo-2-methylpropyl phenyl sulfone via base-solvent selection

Article abstract of DOI:10.1080/00397910500377552

Diversity-oriented organic synthesis is an important approach for combinatorial chemistry and drug discovery. An example of this approach is selective elimination of 2,3-dibromo-2-methylpropyl phenyl sulfone 5 to potentially useful vinyl sulfones 6E/Z and

Full text of DOI:10.1080/00397910500377552

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Condition‐Directable Reaction: Regio‐
and Stereoselective Elimination of
2,3‐Dibromo‐2‐methylpropyl Phenyl Sulfone
via Base‐solvent Selection
Xiaojin Li a
a Laboratory of Immunogenetics, National Institute of Allergy and Infectious
Diseases , National Institutes of Health , Rockville, Maryland, USA
Published online: 19 Aug 2006.
To cite this article: Xiaojin Li (2006) Condition‐Directable Reaction: Regio‐ and Stereoselective Elimination
of 2,3‐Dibromo‐2‐methylpropyl Phenyl Sulfone via Base‐solvent Selection, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:3, 393-399, DOI:
10.1080/00397910500377552
To link to this article: http://dx.doi.org/10.1080/00397910500377552
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Synthetic Communicationsw, 36: 393–399, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500377552
Condition-Directable Reaction: Regio- and
Stereoselective Elimination of 2,3-Dibromo-
2-methylpropyl Phenyl Sulfone via
Base-solvent Selection
Xiaojin Li
Laboratory of Immunogenetics, National Institute of Allergy
and Infectious Diseases, National Institutes of Health,
Rockville, Maryland, USA
Abstract: Diversity-oriented organic synthesis is an important approach for combina-
torial chemistry and drug discovery. An example of this approach is selective elimi-
nation of 2,3-dibromo-2-methylpropyl phenyl sulfone 5 to potentially useful vinyl
sulfones 6E/Z and vinyl bromides 7E/Z, which is achieved by choosing reaction
conditions.
Keywords: Diversity-oriented, reaction condition-directable, regio- and stereo-
selective, elimination, vinyl sulfones, vinyl bromides, dibromo, phenyl sulfone
INTRODUCTION
Regio- and stereoselective synthesis has been a main area of interest in organic
synthesis, and many efforts have focused on asymmetric catalyses[1] and chiral
auxiliaries.[2] However, substrate- and condition-directable reactions have
received far less attention.[3] Herein is reported an example of regio- and
Received in the USA July 12, 2005
This work was done during my graduate research under the guidance of Philip L.
Fuchs in the Department of Chemistry at Purdue University, West Lafayette,
Indiana, USA.
Address correspondence to Xiaojin Li, LIG, NIAID, National Institutes of Health,
12441 Parklawn Dr., Twinbrook II, Rockville, MD 20852, USA. E-mail: lixi@niaid.
nih.gov
393

394
X. Li
Scheme 1.
stereoselective synthesis of vinyl sulfones 6E/Z and vinyl bromides 7E/Z
(Table 1) by appropriate selection of bases and solvents.
Vinyl sulfones,[4] allylic sulfones,[5] and vinyl bromides[6] have been
found to be useful intermediates in organic synthesis. However, their regio-
and stereoselective synthesis has not been well documented.[5a,7] In conjunc-
tion with development of target-oriented conjunctive reagents, we recently
reported phosphonate sulfone 2E as a conjunctive reagent for synthesis of
1,3-dienes 4EE/EZ/ET via a common intermediate 3ET in three operations
(Scheme 1).[5c] (Note: The notion of T in ET or elsewhere in the article stands
for a terminal carbon–carbon double bond in a compound to distinguish it
from the nonterminal double bonds E and Z. The notion was first used in
Ref. 5c.) Reagent 2E was synthesized by a bromination–elimination of
methallyl phenyl sulfone 1[8] via the corresponding dibromo phenyl sufone
5 (Table 1), followed by the Arbuzov reaction of the resulting bromo
vinyl sulfone 6E (Table 1, Scheme 1). Initial synthesis of 6E suffered from
selectivity problems, and the factors involved in chemoselectivity and
stereospecificity in the elimination step were not straightforward. More
extensive studies were carried out to fully explore and better understand
the formation of vinyl sulfones 6E/Z and vinyl bromides 7E/Z in the
dehydrobromination of 5.
RESULTS AND DISCUSSIONS
Initially, dehydrobromination was carried out using triethylamine (TEA) in
CCl4, and the elimination gave vinyl sulfones 6E/Z in 84% yield with an
unexpected 6E/Z ratio of 1.0/1.7 (Table 1, entry 1). With a solvent change
from CCl4 to CHCl3, the reaction even more strongly favored formation of
vinyl sulfone 6Z (6E/Z: 1/3.7) (Table 1, entries 1, 2). With DABCO in
CCl4, the elimination gave Z-dominated vinyl sulfones 6E/Z with a ratio of
1/10.5, and in chloroform, an even higher selectivity for 6Z (6E/Z: 1/14.1)
was observed (Table 1, entries 3, 4). It should be noted that when more
than 0.5 equivalent of DABCO was used, the reaction produced a significant
1
amount of amine–vinyl sulfone adduct salts (detected by H NMR), most
likely from nucleophilic attack of DABCO’s N-atom on the allylic bromide
moiety of vinyl sulfones 6E/Z. When one or more equivalents of DABCO
were used, no bromo vinyl sulfones 6 survived. The same phenomenon was

Condition-Directable Reaction
395
observed, but to a different extent, in cases where DBU or pyridine was used
as the base (Table 1, entries 5, 6).
Interestingly, when weaker amine bases were used, the reaction selecti-
vity for 6E/Z was reversed (Table 1, entries 6–14). With 2,6-lutidine in
CHCl3, vinyl sulfones 6E/Z were afforded in 55% yield in a ratio of 11.1/1
(Table 1, entry 7). With 2,4,6-collidine, an even higher E-selectivity and
high yield of vinyl sulfones 6E/Z resulted (Table 1, entries 8–14). The stereo-
selectivity was solvent dependent: the less polar the solvent, the better the
selectivity observed for vinyl sulfone 6E. The best selectivity (E/Z: 21.0/1)
and nearly quantitative yield of the desired 6E were achieved when
non polar carbon tetrachloride was used as the solvent (Table 1, entry 8).
Table 1. Selective elimination of dibromo phenyl sulfone 5
Product ratiob
(6E/6Z/6T/7E/7Z)
Yield
(%)c
Entry
Conditionsa
1
2
TEA (1.5 eq), CCl4, rt, 2 h
TEA (1.5 eq), CHCl3, rt, 4 h
1/1.7/—/—/—
1/3.7/—/—/—
1/10.5/—/—/—
1/14.1/—/—/—
1.2/1/—/—/—
1.3/1/—/—/—
11.1/1/—/—/—
21.0/1/—/—/—
11.4/1/—/—/—
11.8/1/—/—/—
13.5/1/—/—/—
18.7/1/—/—/—
16.5/1/—/—/—
14.0/1/—/—/—
2.1/1/—/—/—
0.1/—/—/1/3.1
84
71
68
70
91
34
55
99
99
82
98
74
80
89
65
83
3
DABCO (0.5 eq), CCl4, rt, 13 h
DABCO (0.5 eq), CHCl3, rt, 1 d
DBU (0.7 eq), CHCl3, rt, 12 h
Pyridine (1.0 eq), CHCl3, rt, 2 d
2,6-Lutidine (2.0 eq), CHCl3, rt, 2 d
2,4,6-Collidine (2.0 eq), CCl4, rt, 2 d
2,4,6-Collidine (2.0 eq), CHCl3, rt, 2 d
2,4,6-Collidine, CHCl3 (1.5 eq), rt, 2 d
2,4,6-Collidine (2.0 eq), CH2Cl2, rt, 2 d
2,4,6-Collidine (2.0 eq), toluene, rt, 2 d
2,4,6-Collidine (2.0 eq), ether, rt, 2 d
2,4,6-Collidine (2.0 eq), THF, rt, 2 d
K2CO3 (2.0 eq), CH2Cl2, reflux, 1 d
LiOH (2.0 eq), H2O/t-BuOH (10/1),
rt, 20 h,
4
5
6
7
8
9
10
11
12
13
14
15
16
17
KOH (1.0 eq), EtOH, 10 h, rt; KOH
(0.5 eq) more, rt, 2 h
—/—/1/13.2/—
80
aThe reaction was stopped when no further progress was observed over 2 h
1
(monitored by TLC or H NMR) or after two days.
1
bThe ratios were determined by HPLC, except in the case of entry 16, where H
NMR was used. The stereochemistry was determined from “g-gauche effect,” and
the configuration of 7E was confirmed by NOE.[5c]
cThe yields were combined yields and calculated based on limiting reagents used.

396
X. Li
With weak inorganic base K2CO3 in methylene chloride under reflux, the
elimination gave 6E/Z in 65% yield with ratio of 2.1/1 (Table 1, entry 15). Inter-
estingly, with LiOH in water, 6E was observed as a minor product and the vinyl
bromides 7E/Z predominated (6E/7E/7Z: 0.1/1/3.1). The yield in this case
was 83% favoring the 7Z stereoisomer (Table 1, entry 16). With stronger
inorganic base KOH in ethanol, the elimination gave bromo phenyl sulfones
7E/6T in 80% yield with high 7E selectivity (13.2/1) (Table 1, entry 17).
The study demonstrated that the selective elimination of dibromo phenyl
sulfone 5 depends on the nature of bases and the characteristics of solvents
used in the reaction. For the region- and stereoselective formation of vinyl
sulfones 6E/Z (using amine bases), the 3-bromo and phenyl sulfone groups
of 5 might be involved by neighboring group participation. For the
formation of vinyl bromides 7E/Z (using inorganic bases in a protic
solvent), it is likely that the vinyl bromides (or 6T) would arise from elimin-
ation of dibromide 5 followed by base-catalyzed isomerization of 6E/Z, and
the stereoselectivity would be stereoelectronically and sterically governed by
its reaction transition state. However, detailed mechanistic aspects and the
scope of this selective elimination must be examined in the future.
In summary, the potentially useful vinyl sulfones and vinyl bromides
were selectively prepared from a common precursor by appropriate
selection of reaction conditions without requiring the use of a catalyst or
mediator (Scheme 2). The report provides an example of diversity-oriented
organic synthesis.
TYPICAL EXPERIMENTAL PROCEDURES
2,3-Dibromo-2-methylpropyl Phenyl Sulfone (5)[5c]
A solution of bromine (2.6 ml, 51.52 mmoL) in carbon tetrachloride (25.5 mL)
was added to a solution of sulfone 1[8] (10.00 g, 50.95 mmol) in carbon tetra-
chloride (51.0 mL) via a dropping funnel at 08C. The mixture was stirred at
this temperature for 30 min and then stirred at room temperature overnight
Scheme 2.

Condition-Directable Reaction
397
(the reaction was actually completed in 4 h). Removal of the solvent afforded
dibromo phenyl sufone 5 (18.14 g, colorless oil) in quantitative yield (chloro-
form and ether are also suitable solvents for the reaction). 1H NMR (300 MHz,
CDCl3) d 7.94 (d, J ¼ 7.5 Hz, 2 H), 7.62 (m, 3 H), 4.12 (s, 2 H), 3.94
(d, J ¼ 14.4 Hz, 1 H), 3.78 (d, J ¼ 14.7 Hz, 1 H), 2.15 (s, 3 H); 13C NMR
(75 MHz, CDCl3) d 140.4, 134.1, 129.4, 127.9, 65.1, 58.2, 43.1, 30.1.
General Procedure for Elimination of 2,3-Dibromo-2-methylpropyl
Phenyl Sulfone (5)
The elimination of 5 was performed on 0.15-mmol scale, and a representative
procedure (Table 1) is described. 2,4,6-Collidine (39 mL, 0.30 mmol) was
added to a solution of dibromide 5 (53.4 mg, 0.15 mmol) in CCl4 (0.3 mL)
at 08C. After stirring at room temperature for 2 days, the mixture was
acidified with 5% HCl, and the organic layer was separated. The aqueous
layer was extracted with methylene chloride (3 ꢀ 0.3 mL). The combined
organic layers were washed with water and brine and dried over Na2SO4.
After the solvents were removed, the residue was purified by silica-gel
column chromatography (25% ethyl acetate in hexanes) to give 6E/Z
(40.8 mg, 99% with ratio 21/1) as a colorless oil.
2-(Bromomethyl)-2-propenyl Phenyl Sulfone (6T )[5c]
6T was separated by preparative TLC (25% ethyl acetate in hexanes) (Table 1,
entry 17). 1H NMR (300 MHz, CDCl3) d 7.82 (d, J ¼ 7.5 Hz, 2 H), 7.56 (m, 3
H), 5.42 (s, 1 H), 4.94 (s, 1 H), 4.08 (s, 2 H), 3.92 (s, 2 H); 13C NMR (75 MHz,
CDCl3) d 137.9, 133.9, 133.7, 129.1, 128.2, 124.5, 59.6, 35.1.
(1E)-3-Bromo-2-methyl-1-propenyl Phenyl Sulfone (6E)[5c]
6E was separated by preparative LC (5% ethyl acetate in hexane at rate of
20 mL/min) (Table 1, entry 1). 1H NMR (300 MHz, CDCl3) d 7.88
(d, J ¼ 7.2 Hz, 2 H), 7.56 (m, 3 H), 6.45 (s, 1 H), 3.85 (s, 2 H), 2.26 (s,
3 H); 13C NMR (75 MHz, CDCl3) d 150.0, 141.2, 133.5, 129.5, 129.3,
127.3, 36.4, 16.4.
(1Z)-3-Bromo-2-methyl-1-propenyl Phenyl Sulfone (6Z)[5c]
6Z was separated by preparative LC (5% ethyl acetate in hexane at 20 mL/
1
min) (Table 1, entry 1). H NMR (300 MHz, CDCl3) d 7.94 (d, J ¼ 7.2 Hz,
2 H), 7.57 (m, 3 H), 6.17 (s, 1 H), 4.55 (s, 2 H), 2.02 (s, 3 H); 13C NMR
(75 MHz, CDCl3) d 149.5, 140.8, 133.6, 129.3, 128.5, 127.5, 27.1, 23.5.

398
X. Li
(2E)-3-Bromo-2-methyl-2-propenyl Phenyl Sulfone (7E)[5c]
KOH (8.4 mg, 0.15 mmol) was added to a solution of dibromo phenyl sulfone
5 (53.4 mg, 0.15 mmol) in EtOH (0.6 mL) at room temperature. After stirring
at this temperature for 10 h, KOH (4.2 mg, 0.075 mmol) was added to the
mixture. After stirring for 2 h more at room temperature, water (0.6 mL)
was added. The aqueous layer was extracted with methylene chloride
(3 ꢀ 0.6 mL). The combined organic layers were washed with brine and
dried over Na2SO4. After the solvents were removed, the crude light yellow
solid was recrystallized from chloroform in hexanes to afford a mixture of
7E/6T (33.0 mg, 80%) with ratio of 13.2/1 (Table 1, entry 17). 7E was
obtained by further recrystallization, and the stereochemistry was confirmed
by NOE. White solid mp: 116–1178; NMR (300 MHz, CDCl3) d 7.80,
J ¼ 7.5 Hz, 2 H), 7.57 (m, 3 H), 5.90 (s, 1 H), 3.78 (s, 2 H), 1.85 (s, 3 H);
13C NMR (75 MHz, CDCl3) d 137.7, 133.9, 129.8, 129.1, 128.3, 111.6,
63.9, 19.8; IR (neat) cm21 sp2 C–H (3080, 3060, 3045), sp3 C–H (2994,
2944), CH2 (1450), CH3 (1380.), C55C (1621), arom. (1575–1440, 737,
693), SO2 (1302, 1295, 1155), C–Br (535). NOE: between 1-Hs and 3-H
(1.5%), between 1-Hs and 2-Me (1.1%); HRMS (CI, NH3) calcd. for
C13H28O3Si [M þ H]þ: 274.9741; found 274.9745.
(2Z)-3-Bromo-2-methyl-2-propenyl Phenyl Sulfone (7Z).
The procedure for 7E was followed, and 7Z was isolated by preparative TLC
(25% ethyl acetate in hexanes) (Table 1, entry 16). White solids mp: 80–818;
1H NMR (300 MHz, CDCl3) d 7.89 (d, J ¼ 7.2 Hz, 2 H), 7.45 (m, 3 H), 6.15
(s, 1 H), 4.04 (s, 2 H), 2.04 (s, 3 H); 13C NMR (75 MHz, CDCl3) d 138.4,
133.9, 130.3, 129.1, 128.6, 109.7, 61.1, 22.5; IR (KBr) cm21 sp2 C–H
(3080), sp3 C–H (2967, 2913, 2854), CH2 (1445), CH3 (1379), C55C
(1623), arom. (1581–1443, 730, 711), SO2 (1309, 1297, 1142), C–Br (528);
HRMS (CI, NH3) calcd. for C13H28O3Si [M þ H]þ: 274.9743; found 274.9746.
ACKNOWLEDGMENT
I am grateful to Philip L. Fuchs for his guidance during this research and
encouraging me to write this manuscript, John F. Hansen for his valuable
suggestions for the preparation of this manuscript, and Douglas Lantrip for
his support, especially his analytical support.
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