The Use of Ureates as Activators for Samarium Diiodide

Article abstract of DOI:10.1021/acs.joc.6b00733

A novel mode of SmI₂ activation has been developed using ureates as reaction promoters. Several ureates formed by treatment of the corresponding ureas with n-BuLi have been shown to activate SmI₂ to a substantial extent toward the reduction of 1-chlorodecane. Complexes formed from SmI₂ and various ureates have been shown to be useful for the reduction of a variety of organohalides, including substrates of low reactivity such as aryl fluorides. Because of ease of synthesis and low molecular weight, the conjugate base of triethylurea (TEU^-) was of primary focus. Visible spectroscopy and reactivity data are consistent with the hypothesis that the same complex is being formed when SmI₂ is combined with either 2 or 4 equiv of TEU^-, in spite of the greater reactivity of SmI₂/4 TEU^- with some alkyl halides. We propose that the active reductant is an N,O chelate formed between SmI₂ and 2 equiv of TEU^-.

Full text of DOI:10.1021/acs.joc.6b00733

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Article
The Use of Ureates as Activators for Samarium Diiodide
Chriss E. McDonald, Jeremy D. Ramsey, Christopher C. McAtee,
Joseph Randall Mauck, Erin M Hale, and Justin A Cumens
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00733 • Publication Date (Web): 20 Jun 2016
Downloaded from http://pubs.acs.org on June 20, 2016
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The Use of Ureates as Activators for Samarium Diiodide
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Chriss E. McDonald*, Jeremy D. Ramsey, Christopher C. McAtee†, Joseph R. Mauck††, Erin M.
Hale, and Justin A. Cumens
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Department of Chemistry, Lycoming College, 700 College Place, Williamsport, PA 17701,
United States
Email address for Chriss E. McDonald: mcdonald@lycoming.edu
ABSTRACT: A novel mode of SmI2 activation has been developed using ureates as reaction
promoters. Several ureates formed by treatment of the corresponding ureas with nꢀBuLi have
been shown to activate SmI2 to a substantial extent towards the reduction of 1ꢀchlorodecane.
Complexes formed from SmI2 and various ureates have been shown to be useful for the
reduction of a variety of organohalides, including substrates of low reactivity such as aryl
fluorides. Due to its ease of synthesis and low molecular weight, the conjugate base of
triethylurea (TEUꢀ) was of primary focus. Visible spectroscopy and reactivity data are consistent
with the hypothesis that the same complex is being formed when SmI2 is combined with either
two or four equivalents of TEUꢀ, in spite of the greater reactivity of SmI2/4 TEUꢀ with some alkyl
halides. We propose that the active reductant is an N,O chelate formed between SmI2 and two
equivalents of TEUꢀ.
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INTRODUCTION
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Samarium diiodide (SmI2) continues to be one of the most important reagents for radical
reduction in organic chemistry. A variety of organic functionalities are amenable to SmI2ꢀ
mediated reduction through complementary one and twoꢀelectron processes.1 However, for
substrates which are reluctant toward radical reduction with SmI2, additives can be employed to
facilitate the reaction. The most common and historically important additive is
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hexamethylphosphoramide (HMPA, 1, Figure 1), which was originally reported by Inanaga to
decrease overall reaction times while substantially increasing the yields for the reduction of alkyl
halides.2 It has been established that HMPA primarily exerts its effect by coordinating to SmI2 to
form the THFꢀsoluble complex [SmI2(HMPA)4(THF)2]2+2Iꢀ.3,4 This complex has proven so
useful that the majority of samarium diiodide chemistry has been performed with HMPA as a
cosolvent.5 The primary drawback of this reduction system is the deleterious health effects
associated with HMPA. HMPA has been shown to be mutagenic,6 carcinogenic,7,8 and
antispermatogenic. 9 The polyhydroxylation of HMPA by cytochrome P450 oxidases is thought
to be responsible for these undesirable health effects.10 Furthermore, the use of HMPA has been
banned in many laboratories.11,12
Chemists have expended a great deal of effort to develop alternative activators for SmI2ꢀ
mediated reactions. Transition metal salts, most importantly NiI2, have proven useful for the
facilitation of several reductive transformations involving alkyl halides,13 imines,14 anomeric
pyridylsulfones,15 acid chlorides,16 and iminium triflates.17,18 Recent mechanistic investigations
by Flowers indicate that transmetallation of alkylsamarium to alkylnickel species is primarily
responsible for the enhancement of reduction in the case of alkyl halide precursors.19
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Curran first reported the ability of water to enhance the reactivity of SmI2 in THF.20 The
reduction of alkyl iodides, ketones, and sulfoxides proceeded more rapidly and in higher yield in
the presence of H2O. Subsequent work has explored the scope of substrates susceptible to
reduction by SmI2/H2O.21 Aromatic carboxylic acid derivatives22 and Nꢀacyl oxazolidines23 can
be reduced with SmI2 in the presence of H2O. These functionalities are resistant to reduction by
SmI2 in the absence of H2O. Furthermore, Procter has employed SmI2/H2O for the
chemoselective reduction of δꢀlactones,24 cyclic 1,3ꢀdiesters,25 and barbituric acids.26 High
concentrations of H2O is thought to lead to a dimeric Sm(II) aquo complex which functions as
the initial electron donor in these reactions.27,28
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Addition of triethylamine or pyrrolidine to the SmI2/H2O reduction system results in a
further enhancement of reactivity. Synthetically useful reductions of alkyl halides,29 conjugated
alkenes and alkynes,30 α,βꢀunsaturated esters,31 unactivated esters,32 carboxylic acids,33 and
amides34 are known. The inclusion of the amine to the SmI2/H2O reaction mixture is thought to
further enhance the reactivity of the reductant by removing a proton from a water molecule
complexed to the Sm(III) species formed after the initial electron transfer to substrate.35
Electron rich compounds such as 1,1,3,3ꢀtetramethylguanidine (TMG),361,8ꢀ
diazabicyclo[5.4.0]undecꢀ7ꢀene (DBU),36 and 1,3ꢀdimethylꢀ2ꢀimidazolidinone (DMI)37 have also
been examined as possible SmI2 activators and have some limited applications. The conjugate
base of hexamethyldisilazine has proven to be extraordinarily effective for the activation of SmI2
towards the reduction of alkyl and aryl fluorides.38 The cosolvent N,N’ꢀdimethylpropyleneurea
(DMPU) has been successfully used in several instances as a surrogate for HMPA.39 Although
less effective than HMPA, DMPU is thought to activate SmI2 in a similar manner, by
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coordination of its oxygen to Sm(II) resulting in an increase of electron density at the metal
center.40
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Over the past several years, we have been engaged in a program to develop
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phosphoramideꢀbased alternative activators for SmI2 (Figure 1A). The dimer of HMPA,
diHMPA (2), has proven to be approximately 1/3 as reactive as HMPA in most applications.41
Tripyrrolidine phosphoric acid triamide (TPPA, 3) was shown to be a substantially better
activator of SmI2 than HMPA in the reduction of alkyl halides and ketones.42` The enhanced
reactivity of this reducing system is attributed to both the increased basicity and the steric
compactness of the pyrrolidino moiety in TPPA relative to the dimethylamino moiety in
HMPA.43,44 Reissig and coworkers have shown that SmI2/TPPA is often superior to SmI2/HMPA
for the reductive dearomatization of γꢀaryl ketones.12 Recently, we have shown that the
conjugate base of the phosphoramide, dipyrrolidinomethylaminophosphoric acid triamide
(DPMPA, 4), is an extremely efficient activator of SmI2 (Figure 1B).45 Complexes formed from
four equivalents of the anion derived from the deprotonation of DPMPA (5) and SmI2 proved to
be at least 100 times more reactive than the analogous SmI2/HMPA complex as determined by
the reduction of 1ꢀchlorodecane. It is presumed that DPMPAꢀ can deliver even greater electron
density to the metal center of SmI2 thus enhancing the reductive ability of the resultant species.
Herein we report the extension of these efforts to the design of a series of ureates for the
activation of SmI2 as shown in Figure 1C. We envision the synthesis of compounds where the
urea functionality is either acyclic/exocyclic (6) or endocyclic (7). A variety of advantages that
ureates might exhibit relative to phosphoramides and phosphoramidates can be enumerated.
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Figure 1. Activators of SmI2.
Because of the lower valency of the functional group’s central atom, ureates will have a lower
molecular weight relative to DPMPAꢀ. It is also reasonable to assume that upon ureate ligation
to Sm(II) the resultant complex would be less sterically encumbered, which might facilitate both
innerꢀ and outerꢀsphere reductive processes. Furthermore, unlike HMPA and DPMPA, the urea
proligands will not possess Nꢀmethylphosphoramide moieties, which are known to produce
mutagenic metabolites upon hydroxylation by cytochrome P450 oxidases.10
Although ureate complexes of Sm(II) have not been reported, several transition metal and
lanthanide metal cations do complex with ureates to form unique organometallic species.
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Ureates have been shown to coordinate with Ti(IV),46 Fe(III),47 Zr(IV),48 Pd(II),49 Hf(IV),50
W(VI),51 and U(IV).52 The Zr(IV) ureates are known to catalyze hydroamination reactions,53
while the Pd(II) ureates are efficient catalysts for the Heck reaction of aryl bromides.49
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RESULTS AND DISCUSSION
We began our investigation with the development of a general strategy towards the
synthesis of the urea proligands which utilized inexpensive starting material, afforded a single
product, and was amenable to scaleꢀup. Our approach to the synthesis of a group of
deprotonatable acyclic/exocyclic ureas is shown in Table 1. The appropriate N,Nꢀ
dialkylcarbamoyl chloride was treated with an excess of primary amine salt and triethylamine in
CH2Cl2 at room temperature.54 After filtration, an extractive workup was performed. Bulb to
bulb distillation afforded the typically crystalline products in good to excellent yield (entries 1ꢀ
6).
Table 1. Synthesis of Acyclic/Exocyclic Ureas.
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A single step synthesis of endocyclic deprotonatable ureas was also developed (Table 2).
In each case an unsymmetrical diamine in CH2Cl2 was treated with 1,1’ꢀcarbonyldiimidazole
(CDI).55 After an aqueous workup with an acidic wash to remove the imidazole byproduct, good
yields of the resultant ureas were obtained. It was determined that this approach was not
practicable for the synthesis of ureas of less than six carbons due to the inability to efficiently
separate the target compound from imidazole.
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Table 2. Synthesis of Endocyclic Ureas.
Deprotonatable ureas of lesser substitution which were used in this study and are
commercially available (Figure 2) include acyclic ethylurea (6g), endocyclic 2ꢀimidazolidinone
(7d), and endocyclic propyleneurea (7e).
Figure 2. Commercially available deprotonatable ureas.
The reduction of 1ꢀchlorodecane was chosen as a screening reaction to provide an initial
assessment of the ability of each ureate to activate SmI2. Ureates were formed in situ following
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nꢀBuLi addition to a solution of urea in THF (Table 3). In many cases (entries 1, 2, 7, 14, and
15) the formation of the ureate was evidenced by the development of a gelꢀlike precipitate. The
other ureates were THFꢀsoluble. It was considered prudent to exclude a proton source from the
reaction mixture because of the likely partial reprotonation of the ureates to the neutral urea. This
would make assessment of the extent of activation difficult. Addition of the deep blue solution
of SmI2 in THF to the ureate resulted in the formation of a brown soluble complex in each case.
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Table 3. Relative Reactivity of SmI2 and Additive with 1ꢀChlorodecane
SmI2 (3.0 eq), (0.05 M in THF)
H3C
H
9
H3C
Cl
9
additive (12.0 eq), n-BuLi (12.0 eq)
time, 0oC
yield (%)
yield (%)
at 1 hb
entrya
additive
6a
at 1 minb
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0
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0
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66
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<1
<1
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<1
<1
0
6bc
6bd
6be
7a
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1
<1
11
43
26
10
5
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77
43
13
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<1
<1
7b
7c
7d
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15
7e
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1c
<1
<1
90
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11
3c
99
22
31
4
H2O/ pyrrolidinec
H2O/ pyrrolidinec,f
b
a1-Chlorodecane added last over 2 s. Yield determined by
GC with tetradecane as internal standard. cn-Bu-Li not used.
dSmI2 not used.eDeprotonation with NaH/DMF. fH2O added
last
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This color change is consistent with the complex formed between SmI2 and DPMPAꢀ.45 In
screening studies of this sort, SmI2 has typically been quenched with 0.1 M I2 in hexane.42,45,56,57
Because of the absence of a proton source in these reaction mixtures, a mixture of decane and 1ꢀ
iododecane is formed upon quenching with I2 in hexane as determined by GCꢀMS. Therefore we
used an openꢀair 0.1 M solution of tꢀBuOH in hexanes as the quench method in order to avoid
the 1ꢀiododecane side product. Thus, one minute after the sequential addition of tetradecane
(internal standard) and 1ꢀchlorodecane were added to the SmI2/ureate mixture, an aliquot was
removed and quenched with tꢀBuOH in hexanes. A second aliquot was removed at 1 hour. This
order of addition, with 1ꢀchlorodecane being added to a mixture of SmI2 and ureate, is one of
several possible orders of addition. A second order of addition will also be explored (vide infra).
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Most of the ureates exhibited an ability to activate SmI2 for the reduction of 1ꢀ
chlorodecane. Acyclic ureas 6aꢀ6c which possess an increasing degree of substitution on the
deprotonatable nitrogen, activate SmI2 to a similar extent (entries 1ꢀ3). Like 6aꢀ6c, the tꢀbutyl
congener 6d forms a brown complex with SmI2, but no reduction of 1ꢀchlorodecane was
observed (entry 4). Diisopropylethylurea (6e) proved to be somewhat more efficient at the
activation of SmI2 relative to 6a-c (entry 5). Pyrrolidinoꢀsubstituted urea 6f was similar to 6aꢀc
in its ability to activate SmI2 (entry 6). Ethylurea (6f) was not an effective activator of SmI2
(entry 7). Entry 8 demonstrates that urea deprotonation is critical to reaction success. The
neutral version of 6b, triethylurea (TEU), forms a violet complex with SmI2, but only traces of
decane was observed under these mild reaction conditions. The necessity of SmI2 in the reaction
mixture is illustrated in entry 9. In the absence of SmI2 no decane is produced. As has been
shown previously, the presence of 12 equivalents of LiBr in the reaction mixture does not
sufficiently activate SmI2 to allow for the reduction of 1ꢀchlorodecane under these mild reaction
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conditions.45 To further examine the potential role of Li+ in this reduction system, the anion of 7b
was produced with NaH. This reaction was surprisingly sluggish. Success was achieved by
heating TEU and NaH with DMF at 100 oC, cooling to rt, then removal of the DMF in vacuo.
Addition of THF and SmI2 afforded a dark brown suspension. This mixture afforded only small
amounts of decane (entry 10).
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The ureates derived from endocyclic ureas 7a-c proved to be excellent activators of SmI2.
The ureate of Nꢀpropyl propyleneurea (7b, PPUꢀ , entry 12) was shown to be an especially good
activator, the best of the ureates, although DPMPAꢀ (entry 18) is substantially better. The anions
derived from the two endocyclic commercially available ureas (7d and 7e) were shown to be
modest activators of SmI2 (entries 14 and 15).
As expected the neutral phosphoramides HMPA (entry 16) and TPPA (entry 17) afforded
only trace amounts of decane under these conditions. On the other hand, the
SmI2/H2O/pyrrolidine reagent system is capable of reducing 1ꢀchlorodecane under these
conditions (0.05 M SmI2 at 0 oC). Using a protocol that most closely matches those described
for the ureates in Table 3 with 1ꢀchlorodecane being added last, yields of 10 and 22% were
afforded at the one minute and one hour mark respectively (entry 19). When the order of
addition was modified to match those typically used for this reagent system (H2O added last) the
yields increased (entry 20).58
Based on this initial screening three ureas were selected for further study. Triethylurea,
TEU (6b), was selected for its ease of synthesis in multiꢀgram quantities, relatively low
molecular weight, and its extended shelf life without discoloration. Its lack of Nꢀmethyl groups
is also a desirable structural feature.10,12 The endocyclic ureas Nꢀbutylimidazolidinone (BI, 7a)
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and Nꢀpropyl propyleneurea (PPU, 7b) were selected for their low molecular weight and greater
degree of SmI2 activation. It should be noted that PPU, the best urea activator found in this
study, has a pair of undesirable properties. It is a low melting solid, which makes it difficult to
manipulate. Furthermore it is not bench stable which is evident by its discoloration after a few
days storage at room temperature.
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Because of the centrality of triethylurea to our program, the next task was to further
explore the reduction of 1ꢀchlorodecane with SmI2/TEUꢀ. Previous work has shown that the
order of addition can be a significant factor in the success of SmI2ꢀmediated reactions.45,59 The
results in Table 3 were generated by the addition of 1ꢀchlorodecane to a mixture of SmI2 and
TEUꢀ. This order of addition corresponds to method A in Table 4. The addition of SmI2 to a
mixture of TEUꢀ and 1ꢀchlorodecane corresponds to method B. It is readily apparent that the
order of addition is a significant factor in this reduction as well. Adding SmI2 last (entry 2,
method B) leads to a substantial increase in yield of the product decane relative to the addition of
1
ꢀchlorodecane last (entry 1, method A). It is unclear why the order of addition has such a
dramatic effect on the efficiency of the reduction. The effect of changing the ratio of TEUꢀ to
SmI2 using method B was also explored. Interestingly, even when a single equivalent of TEUꢀ is
present relative to SmI2, the resultant blueꢀblack solution is capable of reduction and a 21% yield
of decane was obtained at the 1 hour mark (entry 3). As expected the yield of decane increased
as the proportion of TEUꢀ ligand was increased relative to SmI2 (entries 2ꢀ5). Inclusion of a
proton source and its effect on reaction efficacy was examined in entries 6ꢀ8. With the addition
of tertꢀamyl alcohol (tꢀAmOH) there was an observed overall increase in the yield of decane
(entry 6). tꢀAmOH was chosen as the proton source rather than the more typical tꢀBuOH
because it is a liquid at rt, which simplifies the procedure. In the presence of this proton source
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even the 1:2 complex afforded a near quantitative yield of decane at the one hour mark with
5
6
method B (entry 7). The addition of tꢀAmOH facilitated method A as well (entry 8).
7
8
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Table 4. Optimization of the Reduction of 1ꢀChlorodecane with SmI2/TEUꢀ.
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28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SmI2 (3.0 eq), (0.05 M in THF)
H3C
H
9
H3C
Cl
9
TEU, n-BuLi
time, 0oC
t-AmOH
(2.0 eq)
yield (%)
at 1 hb
32
methoda
TEU (eq)
entry
n-BuLi (eq)
1
2
3
4
5
6
7
8
12
12
3
12
12
3
no
A
B
B
B
B
B
B
A
no
85
no
21
6
6
no
66
9
9
no
76
12
6
12
6
yes
yes
yes
99
92
6
6
60
aMethod A:1-chlorodecane added last over 2 s. Method B:SmI2 added last over 30 s.
bYield determined by GC with tetradecane as internal standard.
The first synthetic application of SmI2/ureate complexes to be explored is the reduction
of alkyl and aryl halides. We began by focusing our efforts on the “low ratio” SmI2/ 2 TEUꢀ/2 tꢀ
AmOH combination that was shown to be so effective in the optimization study described in
Table 4 as well as the “high ratio” 1:4 complexes formed with the ureates TEUꢀ, BIꢀ and PPUꢀ.
Results for reductions of various alkyl halides with SmI2/ 2 TEUꢀ/2 tꢀAmOH are shown in Table
5. Typically these reactions are started at 0 oC and allowed to warm to room temperature
overnight. Bromides are smoothly reduced as shown in entries 1 and 2. Because of the presence
of the amide functional group in substrate 8b, this reaction was started at ꢀ84 oC, and allowed to
warm slowly to room temperature (entry 2). The survival of the amide functionality is
noteworthy given that Procter has shown that the highly reactive reducing system
SmI2/H2O/Et3N converts amides to the corresponding reduced alcohols.34 Reduction of alkyl
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chlorides proceeded smoothly and afforded a single product in good to excellent yield (entries 3ꢀ
5). These reaction conditions are substantially milder than what is required for the reduction of
primary alkyl chlorides by SmI2/4 HMPA (8 h at 60 oC).2 Aryl chloride 8f was cleanly reduced
as well, once again with survival of the amide functional group (entry 6). Electron rich aryl
chlorides 8g and 8h proved more difficult to reduce. These reactions did not proceed to
completion with the SmI2/ 2 TEUꢀ/2 tꢀAmOH combination, even when additional reductant was
provided (entries 7ꢀ10). The reduction of pyridyl fluoride 8i proceeded to completion and was
isolated in good yield (entry 11). Aryl fluoride 8j was not reduced under these conditions (entry
12).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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33
34
35
36
37
38
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52
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60
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Table 5. The Reduction of RꢀX with SmI2/2 TEUꢀ.a
3
4
5
6
7
8
SmI2 (3.3 eq), (0.07 M in THF)
R X
R H
TEU (6.6 eq), n-BuLi (6.6 eq)
t-AmOH (2.0 eq)
8
9
9
%
%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entrya
1
8
conversionb
yield (9)
R-X ( )
O
CH3
6
8a
8b
100
91
94
Br
Br
O
2c
100
Ph
3
N
H
H
3
4
8c
8d
100
100
80
87
H
O
H
Cl
O
OEt
Cl
4
O
O
O
O
O
O
5
8e
100
100
74
74
O
O
Cl
4
Cl
O
6c
8f
N
Ph
H
H3C
Cl
O
5
7
8g
71
79
45
57
8d
Cl
9
8h
24
44
11
27
n-Bu
N
10d
Ph n-Bu
N
11
12
8i
8j
100
0
73
0
F
F
O
3
O
n-Bu
aSmI2 added last over 30 s at 0oC. Conversions were measured by 1H NMR integra-
tion calculated as a ratio of product to starting material. cPerformed at -84oC to rt. d5.0 eq
SmI2, 10.0 eq TEU, and 10.0 eq n-BuLi.
b
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As was illustrated in Table 4, it is known that increasing the proportion of ureate in the
reaction vessel enhances the reductive power of the mixture. We therefore performed a series of
reductions with SmI2/4 TEUꢀ as well as the more reactive SmI2/4 BIꢀ, and SmI2/4 PPUꢀ. As
expected reduction of alkyl chlorides worked well with SmI2/4 TEUꢀ (Table 6, entries 1, 3, and
4). The importance of using the correct order of addition can once again be seen in entry 2.
When cholesteryl chloride (8c) is added to SmI2/4 TEUꢀ, large amounts of starting material
remain in the decolorized reaction mixture upon workup. Chloroaryl ether 8g was incompletely
reduced by SmI2/4 TEUꢀ , but could be completely reduced with the more reactive SmI2/4 BIꢀ,
and SmI2/4 PPUꢀ (entries 5ꢀ7). Chloroaniline 8h could be fully reduced only by the most
reductive complex under study, SmI2/4 PPUꢀ (entries 8ꢀ10). Aryl fluoride 8j was amenable to
complete reduction by SmI2/4 PPUꢀ but not other SmI2/ureate complexes (entries 11 and 12).
Fluoroaryl ether 8k can also be efficiently reduced by SmI2/4 PPUꢀ (entry 13). Cholesteryl
fluoride was fully resistant to reduction by SmI2/4 PPUꢀ with or without the addition of two
equivalents of tꢀAmOH (entries 14 and 15).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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59
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Table 6. The Reduction of RꢀX with SmI2/4 Ureateꢀ complexes.a
3
4
5
6
7
8
SmI2 (3.3 eq), (0.07 M in THF)
R X
R H
urea (13.2 eq), n-BuLi (13.2 eq)
8
9
9
%
%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entrya
8
urea conversionb yield (9)
R-X ( )
1
8c
8d
TEU
TEU
100
52
84
44
H
2c
H
H
Cl
O
OEt
O
Cl
O
4
3
4
TEU
TEU
100
100
83
79
O
O
O
O
O
8e
8g
O
O
Cl
4
5d
6d
7d
TEU
BI
75
100
100
55
77
87
H3C
O
5
Cl
PPU
8d
9d
10d
8h
TEU
BI
25
86
15
75
83
Cl
n-Bu
N
PPU
100
n-Bu
F
11d
12d
8j
BI
0
0
O
O
n-Bu
PPU
100
85
3
H3C
O
9
13d
8k
PPU
100
74
F
14
8l
PPU
PPU
0
0
0
0
H
15e
H
H
F
aSmI2 added last over 30 s at 0oC. Conversions were measured by H NMR integra-
tion calculated as a ratio of product to starting material. c8c added last over 2 s. d4.0 eq
SmI2, 16.0 eq urea, and 16.0 eq n-BuLi. e2.0 eq t-AmOH.
b
1
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Dichloride 10 was used to evaluate the ability of various SmI2ꢀbased reagents systems to
effect selective monodechlorination (Table 7). From previous work it was expected that the aryl
chloride bond would be more susceptible to reduction. Reduction of 10 with three equivalents of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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31
32
33
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Table 7. Comparison of Additives in the Reduction of Dichloride 10.a
SmI2/4 HMPA in the presence of 2 equivalents of tꢀAmOH provided a 76% yield of alkyl
chloride 11, a trace of the alternative product, aryl chloride 12, and a 12% yield of the
overreduction product 13 (entry 1). A modest improvement in selectivity was noted with
SmI2/TPPA (entry 2). Reduction with three equivalents of SmI2/ 2 TEUꢀ in the presence of 2
equivalents of tꢀAmOH was more successful, providing almost exclusively the desired 11 (entry
3). When SmI2/4 TEUꢀ was employed the reaction went to completion but a substantial amount
of 13 was observed. The highly reactive phosphoramidateꢀbased reagent SmI2/4 DPMPAꢀ
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proved to be the least selective (entry 5). Thus the SmI2/2 TEUꢀ reagent system has thus been
shown to be the most selective of those evaluated for the monoreduction of dichloride 10.
To gain insight into the nature of the species formed during the addition of SmI2 to TEUꢀ,
a series of alkyl halides and unsaturated hydrocarbons were subjected to reduction. This method
of estimating chemical reduction potential was employed because SmI2/TEUꢀ complexes are not
amenable to the determination of their thermodynamic reduction potential by cyclic voltammetry
due to irreversible oxidation of the species in the electrochemical cell. The inability to obtain
useful information about the reduction potential of very reactive SmI2 complexes by cyclic
voltammetry has been noted previously.29,45 As pointed out by Procter, using the reduction of
hydrocarbons to estimate redox potentials often provides results that are substantially different
than those obtained by cyclic voltammetry. For example SmI2 in THF has a thermodynamic
redox potential of ꢀ0.89 V (vs. SCE) as determined by cyclic voltammetry but can reduce the
aromatic hydrocarbons acenaphthylene (E1/2 = ꢀ1.65 V) and cyclooctatetraene (E1/2 = ꢀ1.83 V).60
In spite of the disparity in values obtained for thermodynamic redox potential by cyclic
voltammetry and effective redox potential by determination of which substrates are susceptible
to reduction, both methodologies have proven useful in the characterization of lanthanide
complexes. It is also worthy of note that the unsaturated hydrocarbons are reduced by an outerꢀ
sphere mechanism,58 while the outerꢀsphere character of the reduction of alkyl halides decreases
from RBr to RCl, and presumably further still with RꢀF.4
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Results for the determination of effective redox potential of both SmI2/2 TEUꢀ and
SmI2/4 TEUꢀ are presented in Table 8. Interestingly, combinations of SmI2 and TEUꢀ in both
ratios behaved identically. Based on the ability of both complexes to rapidly reduce transꢀ
stilbene, 1ꢀbromodecane, naphthalene, styrene, and 1ꢀchlorodecane, but not 1ꢀfluorodecane or
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benzene, an estimate of ca. ꢀ2.8 (vs. SCE) for the effective reducing power of both SmI2/2 TEUꢀ
and SmI2/4 TEUꢀ can be obtained. This represents an estimated increase in effective reducing
power of approximately 1.0 V relative to SmI2 in THF. For comparison, the estimates of
effective reducing power of SmI2/H2O and SmI2/H2O/amine are ꢀ2.2 V60 and ꢀ2.7 V58 vs. SCE
respectively by this methodology.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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37
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39
40
41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 8. Reduction of Hydrocarbons and 1ꢀHalodecanes with SmI2/TEUꢀ Complexes.
Visible spectroscopy was also employed to characterize SmI2/TEUꢀ complexes. The
visible spectrum of SmI2 in THF is typified by a set of three absorbance maxima around 422,
557, and 626 nm.4,45 The solution is deep blue in color. Upon addition of a THF solution of SmI2
to a single equivalent of TEUꢀ the latter two absorption maxima broaden and shift to slightly
lower maxima at 551 and 620 nm (Figure 3). This solution appears blueꢀblack in color. The
visible spectra of the 1:2, 1:3, and 1:4 complexes of SmI2 and TEUꢀ, although not identical, are
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strikingly similar in appearance, with a deep brown color, and very broad absorption maxima at
5
6
407 and 614 nm.
7
8
9
10
11
12
13
14
15
16
17
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20
21
22
23
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Normalized (at 500 nm) visible spectra recorded at 10 mM SmI2 in THF.
This is congruent with our experience examining SmI2/DPMPAꢀ mixtures. The 1:1 mixture of
SmI2 and DPMPAꢀ is blueꢀblack in color, with a broad peak at 546 nm, while the 1:2, 1:3, and
1:4 mixtures of SmI2/DPMPAꢀ are deep brown in color with a single broad absorbance bands
centered at 405 nm.
The available evidence strongly suggest that the same complex is present whether SmI2/2
TEUꢀ, SmI2/3 TEUꢀ, or SmI2/4 TEUꢀ is employed. As shown in Table 4, the dramatic increase in
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the yield of decane at one hour in the reduction of 1ꢀchlorodecane occurs when the ratio changes
from 1:1 SmI2/TEUꢀ (entry 3, 21%) to 1:2 SmI2/TEUꢀ (entry 4, 66%). The smaller additional
gains in reactivity of SmI2/TEUꢀ with alkyl halides when greater than two equivalents of TEUꢀ
are employed in the reaction mixture can be explained by the role very polar species play in the
activation of carbonꢀhalogen bonds.61 As detailed by Flowers, polar species such as HMPA
coordinate to the carbonꢀhalogen bond and activate the bond toward the initial reduction by
Sm(HMPA)4(THF)22+2Iꢀ.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We believe that the presence of TEUꢀ beyond the two equivalents required to saturate the
metal center with ureate ligand in the reaction mixture would similarly activate carbonꢀhalogen
bonds toward electron transfer from SmI2/2 TEUꢀ. The visible spectra shown in Figure 3 are
consistent with the presence of identical complexes at ratios of 1:2, 1:3, and 1:4 of SmI2 and
TEUꢀ. Dramatic changes occur in the visible spectra as the proportion of TEUꢀ increases in
mixtures of SmI2/TEUꢀ until a 1:2 ratio is achieved. Changes in the visible spectra essentially
cease as the proportion of TEUꢀ is changed from 1:2 to 1:4. The results for the reduction of
hydrocarbons and alkyl halides by the two different reagent mixtures (Table 8) also suggests that
there are two equivalents of TEUꢀ coordinated to SmI2 in each case.
The evidence that the active reductant is a 1:2 complex of SmI2 and TEUꢀ implies that the
ligand is coordinating to the Sm(II) center as an N,O chelate. The coordination of two such
ligands around the metal may preclude the incorporation of additional ureates. Indeed
structurally defined bisꢀN,O chelates of monoureates to Ti(IV) and Zr(IV) are known.62
CONCLUSION
In our preceding work we have developed a series of phosphoramideꢀbased HMPA
surrogates (DiHMPA, TPPA, DPMPAꢀ) for the activation of the important reducing agent SmI2.
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This work focused on the synthesis, evaluation, use, and characterization of ureates for the
activation of SmI2. A series of deprotonatable ureas were screened for the ability to activate
SmI2 for the reduction of 1ꢀchlorodecane. One acyclic urea, TEU, and two endocyclic ones, BI
and PPU, were selected for further study. The SmI2/TEUꢀ reducing system has been found to
effectively reduce alkyl and aryl halides. The “low ratio” reagent system SmI2/2 TEUꢀ/2 tꢀ
AmOH is a substantially more powerful reducing agent than SmI2/4 HMPA and is capable of
reducing a range of alkyl chlorides. Selective reductions are also possible. Haloamides can be
selectively dehalogenated by this reagent. The alkyl halide component of an alkylaryl dichloride
can be selectively reduced more efficiently by SmI2/2 TEUꢀ/2 tꢀAmOH than by the four other
SmI2ꢀbased reagent systems that were evaluated. The “high ratio” complexes of SmI2 with TEUꢀ,
BIꢀ, and PPUꢀ are even more reactive and capable of the reduction of even more reluctant radical
precursors such as electron rich aryl chlorides and fluorides. The reduction of 1ꢀchlorodecane
with various SmI2/ureate combinations, which was used as a screening reaction, accurately
predicted the relative degree of activation of SmI2 by TEUꢀ, BIꢀ, and PPUꢀ in subsequent
synthetically relevant reductions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
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57
58
59
60
Determination of which hydrocarbon and alkyl halide substrates are susceptible to
reduction by SmI2/2 TEUꢀ/2 tꢀAmOH and SmI2/4 TEUꢀ/2 tꢀAmOH suggest that the same
reductant may be present in both cases. Estimates of ꢀ2.8 (vs. SCE) V for both SmI2/2 TEUꢀ/tꢀ
AmOH and SmI2/4 TEUꢀ/tꢀAmOH for thermodynamic redox potentials were obtained, which
indicates they are more powerful reductants than the very useful SmI2/H2O and SmI2/H2O/amine
reagent systems. Comparison of visible spectra of various ratios of SmI2 and TEUꢀ suggest that
two TEUꢀ ligands are sufficient to saturate the metal center.
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EXPERIMENTAL SECTION
5
6
7
8
9
General. Dichloromethane, toluene, DMF, 1ꢀchlorodecane, iꢀPr2NH, benzyl bromide, Et3N,
pyridine, pyrrolidine, and HMPA were distilled from CaH2 prior to use. Tetrahydrofuran was
distilled from Na/benzophenone and sparged with argon for 15 min prior to use. Water and
pyrrolidine were also sparged with argon for 15 min prior to use. All ureas, TPPA, and DPMPA
were azeotropically dried with toluene in Schlenkware prior to use in SmI2 reactions. nꢀ
Butyllithium was purchased as a 2.5 M solution and used as received. The concentration of SmI2
in THF was confirmed by titration with I2.63 Glassꢀcoated stir bars were used for all SmI2
reactions. All reactions were performed under nitrogen or argon atmosphere in ovenꢀdried
glassware. Reagent transfer was accomplished using gasꢀtight syringes. NMR spectra were
recorded at room temperature (300 MHz for 1H and 75 MHz for 13C) in CDCl3. Chemical shifts
are reported in δ parts per million referenced to residual solvent proton resonance of CDCl3 (7.28
ppm) or the solvent carbon resonance of CDCl3 (77.0 ppm). Column chromatography was
accomplished using silica gel (70ꢀ230 mesh) as the stationary phase and mixtures of hexanes and
ethyl acetate as the mobile phase. Thinꢀlayer chromatography was performed using silica gel
plates with fluorescent indicator. Visualization was accomplished by UV light (254 nm) or
iodine.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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36
37
38
39
40
41
42
43
44
45
46
47
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51
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58
59
60
GCꢀMS analyses were performed using a GC system equipped with a column of fused silica
(length 30 m, internal diameter 0.25 mm, film 0.25 ꢀm of diphenyl dimethyl polysiloxane) and a
EI/CI ion trap detector. He was used as the carrier gas. The injector temperature was 250 oC.
The initial oven temperature was 40 oC with an initial hold time of 2 min, with a 20 oC/min ramp
to a final temperature of 300 oC and then held at that temperature for 6 min. A split ratio of 10
was employed.
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GC analyses were performed using a GC system equipped with a column of fused silica (length
30 m, internal diameter 0.25 mm, film 0.25 ꢀm of diphenyl dimethyl polysiloxane) and a FID
detector. He was used as the carrier gas. The injector temperature was 250 oC. The initial oven
temperature was 50 oC with an initial hold time of 2 min, with a 10 oC/min ramp to a final
temperature of 250 oC and then held at that temperature for 10 min. A split ratio of 10 was
employed.
10
11
12
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50
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58
59
60
Highꢀresolution mass spectrometry was performed by direct insertion into the EI source. Ions
were separated by a double focusing sector (magnetic and electric sectors) mass analyzer and
then detected. Positive ion mode was employed.
Visible spectra were recorded at room temperature using a spectrometer coupled to an UVꢀvisꢀ
NIR source and a 300 ꢀm transmission dip probe, capable of a transmission path length of 2 mm.
General Procedure for the Synthesis of 1,1-Diethyl-3-alkyl Ureas
Dichloromethane (11 mL) was added to diethylcarbamoyl chloride (2.80 mL, 0.0221 mol). The
appropriate alkylamine hydrochloride (0.0663 mol) was added to the mixture. Triethylamine
(9.3 mL, 0.066 mol) was added and the heterogenous mixture was allowed to stir at rt for 48 h.
Water (15 mL) was added and the mixture was extracted with CHCl3 (5 X 20 mL). The resultant
extract was washed with 10% NaOH (10 mL) and water (10 mL), dried over Na2SO4, and
concentrated under reduced pressure. Distallation afforded the purified product.
1,1-Diethyl-3-methylurea (6a). Distillation (2 mm Hg, 128ꢀ130 oC) yielded 2.18 g (76 %) of the
title compound 6a as a white solid, mp 34ꢀ35 oC (lit.64 34ꢀ35 oC). IR (ATR) cmꢀ1 3227, 2970,
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2931, 1622, 1526, 1490, 1375. H NMR (300 MHz; CDCl3 δ, ppm) 4.85ꢀ4.63 (b, 1H), 3.18 (q, J
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= 7.1 Hz, 4H), 2.70 (d, J = 4.6 Hz, 3H), 1.03 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz; CDCl3 δ,
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1,1-Diethyl-3-ethylurea (6b). Distillation (0.4 mm Hg, 140ꢀ145 oC) yielded 2.67 g (84 %) of the
title compound 6b as a white solid, mp 60ꢀ62 oC (lit.65 62 oC). IR (ATR) cmꢀ1 3443, 2972, 2931,
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2871, 1614, 1529, 1491, 1272. H NMR (300 MHz; CDCl3 δ, ppm) 4.50ꢀ4.39 (b, 1H), 3.22ꢀ3.15
(m, 6H), 1.08ꢀ1.03 (m, 9H). 13C NMR (75 MHz; CDCl3 δ, ppm) 157.1, 40.8, 35.3, 15.5, 13.6.
1,1-Diethyl-3-isopropylurea (6c). Distillation (2 mm Hg, 175ꢀ178 oC) yielded 2.38 g (68 %) of
the title compound 6c as a white solid, mp 68ꢀ69 oC. IR (ATR) cmꢀ1 3359, 3332, 2972, 2929,
1611, 1530, 1491, 1224. 1H NMR (300 MHz; CDCl3 δ, ppm) 4.11ꢀ3.96 (b, 1H), 4.00, (hept, J =
6.3 Hz, 1H), 3.24 (q, J = 7.1 Hz, 4H), 1.16ꢀ1.11 (m, 12H). 13C NMR (75 MHz; CDCl3 δ, ppm)
156.6, 42.3, 41.0, 23.6, 13.8.66
1,1-Diethyl-3-tert-butylurea (6d). Distillation (0.4 mm Hg, 110ꢀ115 oC) yielded 3.49 g (91 %)
of the title compound 6d as a white solid, mp 75ꢀ76 oC. IR (ATR) cmꢀ1 3333, 2967, 2929, 1621,
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1528, 1489, 1357. H NMR (300 MHz; CDCl3 δ, ppm) 4.23ꢀ4.11 (b, 1H), 3.22 (q, J = 7.1 Hz,
4H), 1.35 (s, 9H), 1.12 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz; CDCl3 δ, ppm) 156.5, 50.5, 40.9,
29.6, 13.8.66
1,1-Diisopropyl-3-ethylurea (6e). Dichloromethane (11 mL) was added to
diisopropylcarbamoyl chloride (3.61 g, 0.0221 mol). Ethylamine hydrochloride (5.40 g, 0.0663
mol) was added to the mixture. Triethylamine (9.3 mL, 0.066 mol) was added and the mixture
was allowed to stir at rt for 48 h. Water (15 mL) was added and the mixture was extracted with
CHCl3 (5 X 20 mL). The resultant extract was washed with 10% NaOH (10 mL) and water (10
mL), dried over Na2SO4, and concentrated under reduced pressure. Distillation (0.9 mm Hg,
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145ꢀ152 oC) yielded 3.74 g (98 %) of the title compound 6e as a white solid, mp 75ꢀ77 oC. IR
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(ATR) cmꢀ1 3318, 2968, 2929, 1609, 1525, 1452, 1314, 1301. H NMR (300 MHz; CDCl3 δ,
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ppm) 4.21ꢀ4.09 (b, 1H), 3.89ꢀ3.80 (m, 2H), 3.30ꢀ3.21 (m, 2H), 1.22 (d, J = 6.9 Hz, 12H), 1.12 (t,
J = 7.2 Hz, 3H). 13C NMR (75 MHz; CDCl3 δ, ppm) 157.3, 44.9, 35.3, 21.3, 15.5.67
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3’-Ethyl pyrrolidinecarboxamide (6f). Dichloromethane (5.9 mL) was added to 1ꢀ
pyrrolidinecarbonyl chloride (1.30 mL, 0.0118 mol). Ethylamine hydrochloride (2.89 g, 0.0354
mol) was added to the mixture. Triethylamine (4.9 mL, 0.035 mol) was added and the mixture
was allowed to stir at rt for 48 h. Water (10 mL) was added and the mixture was extracted with
CHCl3 (5 X 15 mL). The resultant extract was washed with 10% NaOH (10 mL) and water (10
mL), dried over Na2SO4, and concentrated under reduced pressure. Distillation (1.3 mm Hg,
175ꢀ180 oC) yielded 1.24 g (74 %) of the title compound 6f as a white solid, mp 83ꢀ84 oC.
HRMS (EI) m/z: [M+] calcd for C7H14N2O 142.1101; found 142.1101. IR (ATR) cmꢀ1 3295,
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2962, 2926, 2865, 1618, 1537, 1435, 1337. H NMR (300 MHz; CDCl3 δ, ppm) 4.99ꢀ4.79 (b,
1H), 3.00ꢀ2.96 (m, 4H), 2.89ꢀ2.85 (m, 2H), 1.54ꢀ1.49 (m, 4H), 0.76 (t, J = 7.1 Hz, 3H). 13C
NMR (75 MHz; CDCl3 δ, ppm) 156.4, 44.6, 34.4, 24.7, 15.0.
General Procedure for the Synthesis of Endocyclic Ureas.
Dichloromethane (65 mL) was added to the appropriate diamine (0.0259 mol). After cooling the
stirred mixture in an iceꢀwater bath, 1,1’ꢀcarbonyldiimidazole (4.20 g, 0.0259 mol) was added in
four portions over 1 h to the mixture. The mixture was allowed to warm to rt and stir for 24 h.
Water (10 mL) was added and the mixture was extracted with CHCl3 (5 X 25 mL). The resultant
extract was stirred with 10% HCl (20 mL) for 30 min, then partitioned. The organic layer was
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washed with 10% NaOH (10 mL) and water (10 mL), dried over Na2SO4, and concentrated
under reduced pressure.
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N-Butylethylene urea (7a). Distillation (0.5 mm Hg, 186ꢀ190 oC) yielded 2.54 g (69 %) of the
title compound 7a as a white solid, mp 39ꢀ40 oC (lit.68 36ꢀ39 oC). IR (ATR) cmꢀ1 3209, 3090,
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2952, 2930, 2867, 1684, 1495, 1457, 1439. H NMR (300 MHz; CDCl3 δ, ppm) 5.36 (b, 1H),
3.41 (b, 4H), 3.16 (t, J = 7.2 Hz, 2H), 1.51ꢀ1.43 (m, 2H), 1.36ꢀ1.29 (m, 2H), 0.92 (t, J = 7.2 Hz,
3H). 13C NMR (75 MHz; CDCl3 δ, ppm) 163.4, 44.9, 43.2, 38.3, 29.6, 19.9, 13.7.
N-Propylpropylene urea (7b). Distillation (1.7 mm Hg, 200ꢀ208 oC) yielded 2.61 g (71 %) of
the title compound 7b as a white solid, mp 39ꢀ40 oC. HRMS (EI) m/z: [M+] calcd for C7H14N2O
142.1101; found 142.1102. IR (ATR) cmꢀ1 3232, 2960, 2933, 2872, 1637, 1516, 1454, 1305. H
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NMR (300 MHz; CDCl3 δ, ppm) 6.96ꢀ5.98 (b, 1H), 3.34ꢀ3.23 (b, 6H), 1.97ꢀ1.89 (m, 2H), 1.61ꢀ
1.48 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz; CDCl3 δ, ppm) 156.6, 49.4, 45.2,
39.9, 21.4, 20.6, 11.0.
N-isoPropylpropylene urea (7c). Distillation (0.9 mm Hg, 199ꢀ202 oC) yielded 2.46 g (67 %) of
the title compound 7c as a white solid, mp 151ꢀ152 oC (lit.69 151ꢀ155 oC). IR (ATR) cmꢀ1 3284,
3197, 3053, 2960, 2969, 2929, 2852, 1644, 1499, 1446, 1309. 1H NMR (300 MHz; CDCl3 δ,
ppm) 5.06ꢀ4.88 (b, 1H), 4.72 (hept, J = 6.7 Hz, 1H), 3.30 (t, J = 5.6 Hz, 2H), 3.19 (t, J = 5.6 Hz,
2H), 1.97ꢀ1.89 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H). 13C NMR (75 MHz; CDCl3 δ, ppm) 156.0,
43.9, 39.7, 37.7, 21.8, 19.2.
General Procedure for the reduction of 1-chlorodecane with SmI2/ 4 ureate (Method A).
To an iceꢀcold mixture of the appropriate urea (2.28 mmol), THF (4.5 mL), and tetradecane (10.0
ꢀL, 0.0384 mmol), was added 0.92 mL of a 2.5 M solution of nꢀBuLi in hexanes (2.3 mmol).
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This mixture was stirred for 5 min, and 6.2 mL of a 0.092 M solution of SmI2 in THF (0.57
mmol) were added, and allowed to stir for 5 min. 1ꢀChlorodecane (38 ꢀL, 0.19 mmol) was
added and the mixture was allowed to stir. Aliquots were removed at 1 min and 1 h and
immediately quenched with a 0.1 M tertꢀbutanol in hexanes solution. The aliquot was mixed
with 0.1 mL of 0.1 M HCl and 1 mL of Et2O. The Et2O extract from this mixture was analyzed
by GC and GCꢀMS to obtain the yield of decane (identity of the product confirmed by
comparison with authentic material).
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1-Bromo-2-O-heptylbenzene (8a). DMF (2.9 mL) was added to 2ꢀbromophenol (500 mg, 2.9
mmol). DBU (0.65 mL, 4.3 mmol) and 1ꢀbromoheptane (0.65 mL, 4.3 mmol) were added. The
mixture was stirred and heated to 60 oC in a pressure tube for 24 h. After cooling for 5 min
water (10 mL) was added and the mixture was extracted with a 2:1 mixture of hexanes and Et2O.
(3 X 15 mL). The combined organic layers were washed with 10% NaOH (10 mL), water (10
mL), dried over Na2SO4, and concentrated under reduced pressure. Distillation (1.0 mm Hg,
175ꢀ180 oC) afforded 0.665 g (82%) of the title compound 8a as a colorless oil. HRMS (EI) m/z:
[M+] calcd for C13H19OBr 270.0625; found 270.0622. IR (ATR) cmꢀ1 2926, 2856, 1587, 1482,
1291, 1276. 1H NMR (300 MHz; CDCl3 δ, ppm) 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.29ꢀ7.24 (m,
1H), 6.92ꢀ6.81 (m, 2H), 4.04 (t, J = 6.5 Hz, 2H), 1.91ꢀ1.84 (m, 2H), 1.55ꢀ1.50 (m, 2H), 1.42ꢀ1.31
(m, 6H), 0.92 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz; CDCl3 δ, ppm) 155.5, 133.3, 128.4, 121.6,
113.2, 112.3, 69.1, 31.8, 29.1, 29.1, 26.0, 22.6, 14.1.
N-(4-Bromophenyl)-4-phenylbutanamide (8b). Benzene (6.1 mL) was added to 4ꢀ
phenylbutanoic acid (1.00 g, 0.00609 mol) and cooled in an iceꢀwater bath. (COCl)2 (0.94 mL,
0.011 mol) was added and the mixture was stirred for 3 h, then concentrated under reduced
pressure. CH2Cl2 (2.1 mL) was added to the crude mixture which was stirred and cooled in an
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iceꢀwater bath. A solution of pyridine (3.0 mL), CH2Cl2 (1.0 mL) and 4ꢀbromoaniline (1.25 g,
0.00731 mol) was slowly added. The mixture was warmed to room temperature and stirred
overnight. Water (10 mL) and saturated NaHCO3 (10 mL) was added and stirred for 30 min.
The mixture was extracted with Et2O (3 X 15 mL). The combined organic layers were washed
with 10% NaOH (10 mL), water (10 mL), 10% HCl (10 mL), water (10 mL), then concentrated
under reduced pressure. The residue was purified by column chromatography (SiO2, gradient
ranging from 2ꢀ10% EtOAc in hexanes) to provide 1.86 g of the title compound 8b (95%) as a
white powder, mp 119ꢀ120 oC. HRMS (EI) m/z: [M+] calcd for C16H16NOBr 317.0421; found
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317.0412. IR (ATR) cmꢀ1 3289, 3065, 3023, 2943, 2867, 1657, 1590, 1520, 1489 cmꢀ1. H
NMR (300 MHz; CDCl3 δ, ppm) 7.44ꢀ7.41 (m, 4H), 7.34ꢀ7.19 (m, 6H), 2.73 (t, J = 7.4 Hz, 2H),
2.36 (t, J = 7.2 Hz, 2H), 2.12ꢀ2.05 (m, 2H). 13C NMR (75 MHz; CDCl3 δ, ppm) 171.1, 141.2,
136.9, 132.0, 128.5, 128.5, 126.1, 121.4, 116.8, 36.7, 35.0, 26.7.
1-O-Ethyl-5-O-(4-chlorobutyl)-2,3-O-isopropylidene-β-D-ribofuranose (8d). Prepared in
accordance with a previously reported procedure as a colorless oil.45 1H NMR (300 MHz;
CDCl3 δ, ppm) 5.08 (s, 1H), 4.68 (d, J = 6.0 Hz, 1H), 4.60 (d, J = 6.0 Hz, 1H), 4.31 (t, J = 7.6
Hz, 1H), 3.75ꢀ3.69 (m, 1H), 3.58 (t, J = 3.4 Hz, 2H), 3.52ꢀ3.40 (m, 5H), 1.95ꢀ1.84 (m, 2H), 1.76ꢀ
1.71 (m, 2H), 1.50 (s, 3H), 1.34 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz; CDCl3 δ,
ppm) 112.3, 107.8, 85.3, 85.0, 82.2, 71.8, 70.4, 62.9, 45.0, 29.4, 27.0, 26.5, 25.0, 14.9.
3-O-(4-Chlorobutyl)-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (8e). Prepared in
accordance with a previously reported procedure as a colorless oil.70 1H NMR (300 MHz; CDCl3
δ, ppm) 5.88 (d, J = 3.6 Hz, 1H), 4.54 (d, J = 3.7 Hz, 1H), 4.30ꢀ4.26 (m, 1H), 4.12ꢀ4.07 (m, 2H),
4.01ꢀ3.96 (m, 1H), 3.87 (d, J = 3.0 Hz, 1H), 3.69ꢀ3.64 (m, 1H), 3.59ꢀ3.54 (m, 3H), 1.91ꢀ1.84 (m,
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