Atom-transfer cyclization with CuSO4/KBH4: A formal "activators generated by electron transfer" process also applicable to atom-transfer polymerization

Article abstract of DOI:10.1021/jo301429a

The 4-exo and 5-exo-trig atom-transfer cyclizations of 1, 8a-e, 9, 12, and 13 can be mediated with as little as 0.05 mol % of Cu(TPMA)SO ₄?5H₂O in the presence of 2.5 mol % of borohydride salts in 10 min at room temperature in air. This formal "activators generated by electron transfer" (AGET) procedure utilizes a cheap and oxidatively stable copper source (CuSO₄?5H₂O) and can be carried out in environmentally benign solvents (EtOH). It is possible to alter the product distribution in the 5-endo radical-polar crossover reactions of 10a,b and 11 by tailoring the amount of borohydride. Cyclization onto alkynes 14 and 15 is also possible in only 20 min. Controlled radical polymerization of styrene, with increased rates over conventional atom-transfer radical polymerization (ATRP), can be carried out in a controlled fashion (Mn, PDI) using either CuBr or CuSO₄?5H₂O and Bu ₄NBH₄.

Full text of DOI:10.1021/jo301429a

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pubs.acs.org/joc
Atom-Transfer Cyclization with CuSO4/KBH4: A Formal “Activators
Generated by Electron Transfer” Process Also Applicable to Atom-
Transfer Polymerization
Andrew J. Clark,* Alana E. C. Collis, David J. Fox, Lauren L. Halliwell, Natalie James, Rachel K. O’Reilly,
Hemal Parekh, Andrew Ross, Andrew B. Sellars, Helen Willcock, and Paul Wilson
Department of Chemistry, University of Warwick, Coventry, West Midlands CV4 7AL, U.K.
S
* Supporting Information
ABSTRACT: The 4-exo and 5-exo-trig atom-transfer cycliza-
tions of 1, 8a−e, 9, 12, and 13 can be mediated with as little as
0.05 mol % of Cu(TPMA)SO4·5H2O in the presence of 2.5
mol % of borohydride salts in 10 min at room temperature in
air. This formal “activators generated by electron transfer”
(AGET) procedure utilizes a cheap and oxidatively stable
copper source (CuSO4·5H2O) and can be carried out in environmentally benign solvents (EtOH). It is possible to alter the
product distribution in the 5-endo radical−polar crossover reactions of 10a,b and 11 by tailoring the amount of borohydride.
Cyclization onto alkynes 14 and 15 is also possible in only 20 min. Controlled radical polymerization of styrene, with increased
rates over conventional atom-transfer radical polymerization (ATRP), can be carried out in a controlled fashion (Mn, PDI) using
either CuBr or CuSO4·5H2O and Bu4NBH4.
Scheme 1. ATRC of 1 and Postulated Mechanism of
CuI(L)X-Mediated ATRC
INTRODUCTION
■
Copper(I) halide catalyzed atom-transfer radical addition
(ATRA),1 polymerization (ATRP),2 and cyclization (ATRC)3
reactions have been extensively studied. The majority of ATRC
reactions utilize CuCl (5−30 mol %) in combination with
bipyridine4 or TMEDA5 to generate radicals from reactive
trichloro- or dichloroacetamide derivatives. Recently, a “ligand
free” process was reported for the 5-exo-trig cyclization of
dichloroacetamides using CuCl (5−20 mol %) in DMF as
solvent,5b but in general, nitrogen-based ligands are preferred
because they are cheap and they provide the scope to fine-tune
catalyst reactivity.6 Polydentate ligands, such as tris(2-
pyridylmethyl)amine7 (TPMA), mediate the cyclization of
less reactive monohalides (e.g., 1 → 2). However, one
disadvantage is that elevated temperatures (50−110 °C) and
high catalyst loadings (∼30 mol %) are still required. Some
“difficult” cyclizations (e.g., onto alkynes)7b often require
stoichiometric amounts of copper mediators. The mechanism
of ATRC has been postulated to be similar to ATRA and ATRP
in that the CuI(L)X complex (the “activator”) reversibly
abstracts a halogen atom from 3 to give radical 4 which then
undergoes cyclization 4 → 5. The oxidized form of the catalyst
([CuII(L)X][X]) then transfers a halogen to the more reactive
cyclized radical 5 regenerating the activator.8 In related ATRA
and ATRP it has been shown that the halide atom transfers
occur through a concerted mechanism via an inner-sphere
electron transfer.1a,9
Some of these, such as the use of biphasic fluorous
solvents10b,11 or solid supported reagents10b,12 have also been
employed in ATRC.13 It has been suggested that relatively high
catalyst loadings are required in ATRC because of a buildup of
the deactivator species ([CuII(L)X][X]) during the course of
the reaction. This may be due to “parasitic” radical−radical
coupling, disproportionation, or reductive side reactions.10
In the related areas of ATRA and ATRP a number of
strategies have been employed to lower catalyst loadings and/
or facilitate purification and recycling of copper catalysts in
order to make the reactions more industrially attractive.1,2,10
Received: July 9, 2012
© XXXX American Chemical Society
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Alternatively, product 6 can be produced by a competitive
nonmetal-mediated atom-transfer reaction by direct abstraction
of a C−X bond in 3 by the reactive radical 5 or electron
transfer; this also leads to accumulation of the deactivator.14
Useful procedures to lower catalyst loadings in ATRP−ATRA
include the addition of reducing agents to the catalytic cycle to
regenerate the activator from the deactivator, Scheme 1. The
two most common techniques are the “activators regenerated
by electron transfer” process (ARGET)15 and the “initiators for
continuous activator regeneration” protocol (ICAR).16 Both
have been extended to cyclization reactions. ARGET−ATRC
has been used to reduce copper catalyst loadings to 2 mol % in
the cyclization of 3 (X = Cl, Cl, Me, R = Bn) with
Cu(PMDETA)Cl and 2.5 mol % of ascorbic acid/Na2CO3 as
reductant.5a Monobromoacetamide 1 can be cyclized using the
ICAR−ATRC protocol with as little as 1 mol % of Cu(TPMA)
Br if 10 mol % AIBN is used as an additive.17 A closely related
approach to mediate atom-transfer reactions, the “activators
generated by electron transfer” protocol (AGET), has been
little applied to ATRC reactions.17 This approach utilizes
[CuII(L)X][X] and a reductant at the start of the reaction
rather than the oxidatively less stable CuI(L)X species.18 We
report a new class of AGET system based upon CuSO4·5H2O
reduction with borohydrides in alcohol solvents. This allows
highly efficient atom-transfer cyclization of the monobromoa-
cetamide 1 → 2 with as little as 0.05 mol % of CuSO4.·5H2O/
2.5 mol % of KBH4 in air. This challenges the current wisdom
that copper halides are required for efficient copper-mediated
atom-transfer cyclization and that these should be carried out
under an inert atmopshere. We also extend the Cu(L)-
SO4·5H2O/borohydride concept to the controlled radical
polymerization of styrene. Polymerization proceeds at increased
rates when borohydride reagents are added but with maintained
control of polymerization. It is expected that this new reagent
combination will also show utility in ATRA reactions.
Table 1. Screening of Additives in the Reaction of 1 → 2
a
run
additive
solvent
conv (%)
yield (%)
1
2
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
MeOH
MeOH
14
5
13
b
3
C6H5OH
10
91
5
b
4
C6H5OH
83
b
5
4-MeOC6H4OH
4-MeOC6H4OH
4-CF3C6H4OH
4-CF3C6H4OH
AIBN
6
18
19
100
50
100
55
19
14
23
100
15
19
51
43
84
9
7
8
9
10
11
12
13
14
15
AIBN
L-ascorbic acid
L-ascorbic acid
NH2NH2
18
11
17
D-glucose
c
NaBH4
82
a
A 0.01 M stock solution of Cu(TPMA)Br in MeOH or CH2Cl2 was
b
used as the copper source. Not measured due to low conversion.
c
Reaction time 10 min at room temperature.
a consequence, we briefly screened a range of different
borohydride reducing agents at room temperature. The most
reactive are shown in Table 2.
Table 2. Screening of Borohydrides as Additives in the
Reaction of 1 → 2
time
(min)
temp
(°C)
conv
(%)
yield
(%)
a
run
additive (mol %)
1
2
3
4
5
6
7
60
10
10
10
10
10
60
LiBH4 (10)
rt
rt
rt
rt
rt
rt
rt
24
67
18
52
74
72
73
31
0
NaBH4 (5)
RESULTS AND DISCUSSION
■
KBH4 (5)
100
100
88
We screened the ATRC reaction 1 → 2 using typical ARGET
reagents previously reported in ATRP namely, phenols,19 D-
glucose,20 L-ascorbic acid,21,5a and hydrazine (Table 1).22 This
allowed us to compare their efficiency as additives to AIBN
(ICAR−ATRC)17 and conventional ATRC. We investigated
the reaction in two solvents, CH2Cl2 and MeOH. Although
ascorbic acid has been reported to mediate the cyclization of
dichloroacetamides,5a it has not been applied to the cyclization
of monosubstituted halides.
NaB(OAc)3H (5)
Ca(BH4)2·2THF (5)
[Bu4N][BH4] (5)
36
b
KBH4 (10)
0
a
A 0.01 M stock solution of Cu(TPMA)Br in MeOH was used as the
b
copper source. No Cu(TPMA)Br was added.
Both the counterion of the borohydride and the solvent
proved to be critical for conversion with KBH4 > NaB(OAc)3H
> CaBH4 > NaBH4 > [Bu4N][BH4] > LiBH4 in MeOH. No
reactions were observed in dry THF. A range of other
conventional ‘hydride’ reducing agents did not mediate the
formation of 2 in either MeOH or dry THF (NaAlH4,
Na(OMe)2AlH2, DIBAL, Li(tBuO)3BH, Li(NMe2)BH3, 9-
BBN, BH3.THF, Et3SiH, or [Me4N][BH4]). Traditionally
borohydride reagents are normally used in ‘hydride’ delivery
processes25 but less common is their participation in radical
chain mechanisms leading to dehalogenation, radical cyclization
or addition. Beckwith and others26 have studied the 5-exo trig
radical cyclization of aryl halides with both LiAlH4 and NaBH4
and a range of initiators (light, peroxides), while NaCNBH3 has
been used to mediate hydroxymethylation of alkyl iodides via
Reaction of CuBr with TPMA in MeOH (run 1) produced a
faint blue solution indicative of [CuII(TPMA)Br][Br]. It is
known that Cu(TPMA)Br disproportionates to give Cu0 metal
and [CuII(TPMA)Br][Br] in polar solvents such as methanol
or DMSO.23 In ATRP, this dissociation mechanism leads to
reaction via a single-electron radical polymerization (SET-LRP)
where the actual catalytic species is Cu0.24 Reaction of substrate
1 led to 14% conversion over 5 h at 50 °C, indicating that the
corresponding single-electron-transfer cyclization process is
relatively inefficient but superior to the normal ATRC process
(run 2). At 50 °C in MeOH only L-ascorbic acid (run 11) was
found to be more reactive than the previously published ICAR
reagent AIBN in MeOH. In the phenol series, the order of
reactivity paralleled their acidity (4-CF3C6H4OH > C6H5OH >
4-MeOC6H4OH) with better conversions in CH2Cl2. On the
other hand, sodium borohydride showed remarkable reactivity
with 100% conversion in only 10 min at room temperature. As
alkyl radical addition to CO.27 It should be highlighted that
these reactions were terminated by a reduction (R• + BH4
→
−
RH + BH3•−) not by atom transfer. In light of this we carried
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out a control reaction (run 7) in which we left out the
Cu(TPMA)Br complex. After 1 h there was no conversion and
only starting material was recovered, indicating that both
Cu(TPMA)Br and KBH4 were necessary to mediate the
cyclization. We also determined that TPMA was a superior
ligand to others used in ATRC namely bipy, PMDETA, or
Me6-tren. Results with 1 mol % of Cu(ligand)Br and 10 mol %
of KBH4 indicated the trend in conversion TPMA (100%) >
Me6-tren (77%) > PMDETA (0%) > bipy (0%).
Upon addition of the borohydride reagent, the solution
immediately turned from faint blue to brown, then over 4−6
min changed again to a faint green color. This occurred both in
the presence and absence of the substrate 1. As the reactions
were carried out in MeOH as solvent, and the initial
Cu(TPMA)Br would have disproportionated to [CuII(TPMA)-
Br][Br] and Cu0, we decided to investigate whether other CuII
salts could be used as precatalysts in an AGET−ATRC
protocol, Table 3.
The nature of the active catalyst is uncertain, but reaction
between Cu(TPMA)SO4 and KBH4 is likely to lead initially to
a Cu(TPMA)BH4 complex, eq 1, where some or all of the
active hydrogens may be displaced by the solvent (e.g.,
Cu(TPMA)B(OMe)nH4−n). The facts that the cyclization
reactions are severely retarded or do not take place in
CH2Cl2 or dry THF suggest that this exchange reaction is
likely to be important. CuBH4 was first reported in 1952 from
the reaction of LiBH4 and CuCl at −20 °C in ether, and on
warming to 0 °C it decomposed to copper hydride and
diborane.28 The stoichiometries of the reactions between
LiBH4 and CuCl2 at room temperature and at −45 °C were
determined by Klingen (eqs 2 and 3).29 They also discovered
that pure CuBH4 decomposed at −12 °C to give Cu0, diborane,
and hydrogen, eq 4.
CuSO + 2KBH4 → CuBH4 + K2SO + 0.5B2H6
4
4
rt
+ 0.5H2
(1)
(2)
Table 3. Screening of Metal Salts in the Reaction of 1 → 2
CuCl2 + 2LiBH4 → Cu + 2LiCl + B2H6 + H2
rt
KBH4
conv
(%)
a
run
MX (mol %)
FeBr2 (1)
(mol %)
yield of B (%)
CuCl2 + 2LiBH4 ⎯⎯⎯⎯⎯⎯→ CuBH4 + 2LiCl + 0.5B2H6
1
2
10
10
10
10
10
10
10
5
0
5
b
−45°C
NiBr·H2O (1)
CrBr3·6H2O (1)
AgBr (1)
b
+ 0.5H6
(3)
(4)
3
0
b
4
7
b
CuBH4 ⎯⎯⎯⎯⎯⎯→ Cu + B2H6 + H2
5
CoBr·H2O (1)
CuBr (1)
7
b
−12°C
6
100
100
23
0
68
84
18
b
If Cu(TMPA)BH4 is formed upon reaction of Cu(TPMA)-
SO4 and KBH4 (eq 1), then this too could decompose to
liberate Cu0 (eq 4). The difference between this and the SET−
ATRC process (Table 1, run 1) is that it is not a
disproportionation (CuI → CuII + Cu0) but ultimately leads
to complete production of Cu0 and gaseous products (CuII →
CuI → Cu0). If this occurs, then a buildup of Cu0 may be
responsible for the enhanced catalysis. Two factors mitigated
against this. First, we did not observe the formation of copper
metal during the reaction, although this is hardly conclusive.
More convincing however, was that no reaction took place
when 1 was exposed to a previously prepared and aged solution
of Cu(TPMA)SO4 and KBH4 (45 min). In order to probe this
further, we followed the formation and decomposition of the
“catalyst” via UV/vis spectrometry in both the presence and
absence of substrate 1. The main area of interest was in the
visible region 400−1100 nm. Addition of KBH4 to the reaction
mixture had a profound effect on the absorption profile. The
characteristic CuII(TPMA)SO4 absorbance between 900 and
950 nm was replaced by an absorbance around 400−500 nm.
After 30 min, the characteristic CuII absorptions were found to
begin to return and for the next 90 min there was little change.
Recently, more thermally stable complexes containing
phenanthroline 7 and phosphine ligands have been developed,
with CuBH4(Ph3P)2 being commercially available.30 Typically,
phosphine complexes, such as CuBH4(Ph3P)2, are much more
stable than their phenanthroline counterparts 7 with the former
able to undergo outersphere charge transfer to phenanthroqui-
none.31 Interestingly, it was possible to mediate the reaction 1
→ 2 (50% conversion, 84% mass balance) with 1.0 mol % of
(Ph3P)2CuBH4 and 20 mol % of KBH4.
7
CuBr2 (1)
8
CuBr (0.1)
9
CuBr2 (0.1)
5
10
11
12
13
14
15
16
17
18
19
20
21
CuOAc (0.1)
5
16
16
43
92
100
100
100
100
32
49
47
40
54
12
14
33
82
85
97
83
85
27
42
40
35
50
Cu(OAc)2·H2O (0.1)
Cu(CF3acac)2 (0.1)
Cu(OTf) (0.1)
Cu(OTf)2 (0.1)
CuSO4·5H2O (0.1)
Cu(acac)2 (0.1)
Cu(ClO4)2·6H2O (0.1)
Cu(NO3)2·H2O (0.1)
Cu(acac)2 (0.05)
Cu(OTf)2 (0.05)
CuSO4·5H2O (0.05)
5
5
5
5
5
5
5
2.5
2.5
2.5
2.5
2.5
22 Cu(ClO4)2·6H2O (0.05)
a
Reactions carried out in MeOH at rt for 10 min at 0.12 M
b
concentration. Not measured due to low conversion.
We also briefly investigated the effect of other metals (Ni, Cr,
Co, and Ag) and a range of other CuI salts, Table 3. The results
indicate that the CuII salts Cu(acac)2, Cu(OTf)2, CuSO4·5H2O,
and Cu(ClO4)2·6H2O (runs 14−17) are superior to either
CuBr or CuBr2 (runs 8 and 9). In all four cases, atom transfer
occurred with 100% conversion with 0.1 mol % of CuII salt/
TPMA and 5 mol % of KBH4 in 10 min. It was possible to drop
the metal loading even further to 0.05 mol % of CuII salt and
2.5 mol % of KBH4 (a 600-fold improvement on conventional
procedures) (runs 19−22) and still obtain reasonable activities
(40−54% conversion). Crucially, it was not necessary to use
anhydrous salts or exclude moisture from the reactions. Out of
these four salts, CuSO4·5H2O was chosen for further study
because of its low cost (∼$0.16 per kilo).
The 2,9-dimethyl-1,10-phenanthroline 7 complex of CuBH4
has been reported to exhibit BH4¯ to phenanthroline ligand-to-
ligand charge transfer at 465 nm.30a This observation, together
with the fact that the transformation 1 → 2 did not occur if
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Figure 1. Phenanthroline CuBH4 complex 7 and cyclization substrates 8−15.
aged catalyst was used, indicates that the “active” catalyst is the
species responsible for the visible spectrum (400−500 nm) and
is similar in structure to 3 (but with TPMA as ligand).
19 (74%, 2.0:1.0 mixture of diastereomers, major isomer
shown) was obtained by reacting 9 under identical conditions.
This compares to a ratio of 5.3:1.0 with 30 mol % Cu(Me6-
tren)Cl at rt for 30 min and 2.7:1.0 for RuCl2(PPh3)3 in
benzene at reflux.32 The differing ratios are a consequence of
the equilibration of both diastereomers of 19 via reversible
removal/attachment of the α-chloro substituent under the
different reaction conditions with different efficiencies. Reaction
of both 8d,e furnished 20 (diastereomer ratio, 3.8:1.0) and 21
(diastereomer ratio, 5.0:1.0) in 91% and 80% yields,
respectively. In these cases the diastereoselectivities (major
isomer shown) are similar to those previously reported using
the ICAR procedure (20, 3.5:1.0 and 21, 6.0:1.0).17 Here the
different ratios are likely due to the difference in temperature
between the two procedures (AGET = rt, ICAR = 50 °C.)17 It
was possible to crystallize the major isomer of 21 and show
from X-ray crystallography that it exhibited the stereochemistry
shown in Figure 2.
We next investigated the scope and limitation of this new
process in a range of 5-exo-trig 8−9, 4-exo-trig 12−13, 5-endo-
trig 10−11, and 5-exo-dig 14−15 cyclizations (Figure 1) as well
as in the controlled radical polymerization of styrene. Electron-
withdrawing N-protecting groups are known to increase the
efficiency and yields of 5-exo cyclizations of acetamides.4f,5a We
therefore investigated the cyclization of the N-tosyl derivatives
8 and 9. Interestingly, reaction of 8a under the standard
conditions (0.1 mol % of Cu(TPMA)SO4 and 10 mol % of
KBH4) led to only 33% conversion to 16. Increasing the time of
the reaction to 1 h made no difference to the conversion or
yield of the isolated product, presumably because the active
complex has fully decomposed after 15−30 min. Increasing the
amount of KBH4 to 50 mol % led to 94% conversion; however,
the concentration of the reaction proved to be the key to
lowering the amounts of metals required, Table 4. Increasing
Table 4. Screening of Reaction of 8a → 16
CuSO4
(mol %)
conc of 8a
(M)
KBH4
(mol %)
conv
(%)
yield
(%)
run
1
2
3
4
5
6
7
8
0.1
0.1
2.5
2.5
1.0
1.0
1.0
0.5
0.12
0.12
0.16
10
50
5
33
94
27
74
60
85
49
43
90
69
69
Figure 2. Products from the cyclization of substrates 8b−e and 9.
a
0.30
5
100
58
a
0.30
5
b
0.30
5
46
The ability to sequence a radical transformation followed by
a separate reaction mediated by a polar (anionic or cationic)
intermediate is known as a radical−polar crossover reac-
tion.33,34 There are two classes of radical−polar crossover
reaction; an oxidative radical−polar crossover reaction, where
the intermediate radical is oxidized to a cation, and a reductive
reaction where the intermediate radical is reduced to an anion.
These transformations can be mediated by metals35 or by
electron transfer from organic systems.34 In particular, 5-endo
oxidative transformations have been mediated mainly by metal
complexes (e.g., manganese,36 copper,37,13a and nickel38).
Hence, reaction of 10a with 30 mol % of Cu(Me6-Tren)Br in
CH2Cl2 furnishes a 1:1 ratio of 27a and 28a in 82% yield.37b
These reactions are generally thought to follow the mechanism
outlined in Scheme 2. Initiation by Cu(L)Br furnishes radical
22 which is predisposed to cyclize in a 5-endo fashion to give
initially 23 but after oxidation to the acyl iminium ion 24, (by
rapid electron transfer from the Cu(L)Br[Br] formed in the
a
0.51
5
100
76
a
0.82
5
a
Reactions carried out in MeOH over 10 min with one drop of
CH2Cl2 to help solubilize substrate 8a. Reaction carried in ethanol.
b
the concentration to 0.51 M allowed the transformation to
occur with just 1 mol % of Cu(TPMA)SO4 and 5 mol % of
KBH4 (run 7). The substrate 8a was not completely soluble in
MeOH at concentrations higher than 0.12 M, and as a
consequence, it was necessary to use either EtOH (a renewable
solvent) or a mixed solvent of MeOH and CH2Cl2 (1−2
drops).
Reaction of a (0.30 M) solution of 8b,c with 2.5 mol % of
Cu(TPMA)SO4 and 5 mol % of KBH4 for 10 min occurred as
expected and gave 17 and 18 in 40% and 70%, respectively. The
relatively slower cyclization of 8b required 10 mol % of KBH4
to obtain a reasonable yield in 10 min (72%). A similar yield of
D
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Scheme 2. Radical−polar Crossover Reaction of 10a and Possible Mechanism in the Presence of KBH4
first step), is terminated by elimination to give 27a and 28a.
Large amounts of copper salts (30−100 mol %) are normally
required to mediate these 5-endo cyclizations, and this has been
postulated to be necessary due to the release of HBr during the
detected in the crude 1H NMR spectrum. It was not possible to
find reaction conditions that led to high yields of 26b but by
changing the solvent to EtOH it was possible to suppress both
reductive cyclization 26b and precyclization 25b to less than
5%. No trapping of the intermediate acyl iminium ion by
MeOH or EtOH was detected. Reaction of tetralone derivative
11 with 2.5 mol % of Cu(TPMA)SO4 and 20 mol % of KBH4
occurred with a 25% conversion only (1:2.9 ratio of 29:30). It
seems that 1 equiv of KBH4 is required for 100% conversions of
the substrates 10a,b and 11. The fact that significant reductive
termination is not observed could suggest that KBH4 is acting
in a dual role as a Cu(II) reductant and as a scavenger of the
HBr liberated in the radical−polar crossover reaction (Figure
3).
reaction;5 in fact, stoichiometric amounts of K2CO3 or
I
Na2CO3 are sometimes added to the reactions to increase
efficiency.5a We were intrigued to determine if it would be
possible to mediate these transformations reductively after
oxidation by in situ trapping of the acyl iminium ion with the
borohydride reagent (KBH4 or Cu(TPMA)BH4). Of course,
the excess borohydride might suppress oxidation of 23 → 24,
but this would not be problematic for the overall process
because (i) intermediate radical 23 may be reduced directly by
BH4 in a process similar to that described by Beckwith26 and
(ii) the activator will be regenerated by borohydride reduction
not oxidation. Another complication is that the acyl iminium
ion intermediate 24 may be trapped by the nucleophilic solvent
required (ROH).
Initial reactions focused on reacting a 0.12 M solution of
10a,b and 11 in MeOH with 1 mol % of Cu(TPMA)SO4 and 1
equiv of KBH4 in MeOH at room temperature for 30 min. For
10b, minor amounts of the reduced compound 26b (as a 1:1
mixture of diastereomers in 11% yield) and oxidatively
terminated enamide 27b (6%) were isolated with the major
product being 28b (69%). Similar results were found for 10a
and 11 under the same reaction conditions (Table 5).
Table 5. Reactions of 10a,b
a
conc
(M)
KBH4
(equiv)
yield (%) of
25:26:27:28
ratio of 27 +
b
compd
28:26
10a
10b
11
0.12
0.12
0.12
0.12
0.02
1
1
0:12:24:47
0:11:6:69
6.0:1.0
6.5:1.0
Figure 3. Products from the cyclizations of substrates 11−13.
c
d
1
18:52
2.9:1.0
e
The 4-exo substrates 12 and 13 were next examined to apply
the chemistry to β-lactam synthesis. Examination of the crude
NMR spectra obtained during the cyclization of 12 indicated
that the atom-transfer product 31 was the major product;
however, during chromatography elimination of HBr from the
tertiary bromide partially occurred, which also led to the
isolation of the alkene 32. This was also observed in the
reaction of 13. If 1 equivalent of KBH4 was used in the reaction
of 12 a minor amount of the reduced precyclized compound 35
(12%) was also produced (31 40%, 32 40%, 35 12%).
We next turned our attention to the previously reported 5-
exo-dig cyclizations of the substrates 14 and 15 (Figure 4).
They have been reported to be approximately 100 times slower
than the corresponding 5-exo cyclization of 8a.7b Using
standard conditions (30 mol % of Cu(TPMA)Br), it was
necessary to reflux 14 at 50 °C for 24 h for 100% conversion.
10b
10b
10
1
30:32:16
2.0:1.0
1.5:1.0
e
82:10:3:5
a
b
MeOH as solvent, 1.0 mol % of Cu(TPMA)SO4. Ratio determined
c
d
from 400 MHz 1H NMR of crude mixture. Yields of 29:30. Ratio of
e
1
30:29 determined from 400 MHz H NMR of crude mixture. Ratio
determined from 400 MHz H NMR spectroscopy.
1
Increasing the amount of KBH4 to 10 equiv in the reaction
of 10b, in the hope of competitively trapping out acyl iminium
ion 24b reductively to give 26b, was partially successful (26b,
32%), but a significant amount of the precyclized reduced
product 25b was now also isolated (30%). Decreasing the
concentration of the reaction (0.12 M → 0.02 M) now led to
25b as the major product (83%), although minor amounts of
26b (10%) and 27b−28b (8%, 1.7:1 = 27b:28b) were also
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Figure 4. Products from the cyclizations of substrates 14 and 15.
With the published ICAR−ATRC protocol,17 it was possible to
lower the loading to 1 mol % of Cu(TPMA)Br with 10 mol %
of AIBN, but it was necessary to heat for 24 h in toluene at
reflux (110 °C) to obtain 52% yield of 36:37 as a 1:1 mixture.
Using the new protocol, 2.5 mol % of Cu(TPMA)SO4 and 20
mol % of KBH4 were required to give a 90% conversion (ratio
of 36:37 = 1:1) in only 20 min at rt. Decreasing the amount of
CuSO4 to 1.0 mol % but increasing the amount of KBH4 to 100
mol % doubled the relative amount of reduction product (67%,
36:37 = 1:2). Cyclization of the less reactive secondary
bromide 15 under the same reaction conditions furnished
sulphonamide 38 in 45% yield after 10 min at rt.
Figure 6. Plot of Mn versus percent conversion for polymerization of
styrene with 0.1 equiv of Bu4NBH4 additive.
was the Mn (Bu4NBH4 = 16.8 KDa, no Bu4NBH4 = 11.3 KDa).
The increase in PDI may be due to the increase in observed
rate compared to the standard system which leads to a loss of
control in the polymerization.
We next investigated the polymerization (ATRP)2 of styrene
with either Cu(NBipy)Br or Cu(NBipy)SO4·5H2O with
Bu4NBH4 (0.1 equiv with respect to Cu salt) as the
borohydride reagent and compared the results to that obtained
without added Bu4NBH4.39 Even though Bu4NBH4 proved to
be one of the least efficient borohydride salts screened in the
reaction of 1 (Table, 2), it was necessary to use a reagent that
dissolved in the bulk monomer. Initial studies focused on the
reaction of Cu(NBipy)Br, with styrene in bulk at 110 °C with
ethyl(bromoisobutyrate) as initiator (180.0 equiv of styrene,
1.00 equiv of initiator, 1.02 equiv of CuBr, 2.56 equiv of
NBipy), with or without added Bu4NBH4 (0.10 equiv). The
rate of polymerization was followed by removal of aliquots for
Changing the copper source to Cu(NBipy)SO4·5H2O for the
bulk styrene reaction (100.0 equiv of styrene, 1.00 equiv of
initiator, 1.02 equiv of CuSO4·5H2O, 2.56 equiv of NBipy, 0.4
equiv of Bu4NBH4) again resulted in an increased rate of
polymerization compared to the standard system (Cu(NBipy)
Br without Bu4NBH4)39 and yielded a relatively well-defined
polymer with good correlation between theoretical and
measured molecular weight. After 5 h, the PDI of the resultant
polymer was slightly increased compared to the standard
system (1.19). End group analysis by 1H NMR (64% end group
fidelity) and elemental analysis (53% end group fidelity)
indicated the expected termination by a bromine atom for the
CuSO4·5H2O-mediated polymerization, and no sulfur was
detected by elemental analysis. The relatively low end group
fidelity may indicate that reduction of the end group is
occurring; this would also explain the slight rise in PDI
compared to the standard system of polymerization. No
polymerization was observed with Cu(NBipy)SO4·5H2O in the
absence of Bu4NBH4 or with Bu4NBH4 in the absence of
Cu(NBipy)SO4·5H2O.
1
analysis by H NMR to calculate conversion of monomer.
These aliquots were then passed through a plug of silica gel to
remove the Cu(NBipy)Br complex and were subsequently
analyzed by GPC analysis. The kinetic plot (Figure 5) and
CONCLUSIONS
■
In conclusion, we have shown that KBH4 is an efficient AGET
reagent for ATRC when used in conjunction with Cu(TPMA)-
SO4·5H2O. While conventional ATRC of 1 requires long
reaction times (24 h) and high copper loadings (30 mol % of
Cu(TPMA)Br), the same reaction can be mediated with 0.1
mol % of Cu(TPMA)SO4·5H2O in the presence of 5 mol % of
KBH4 in only 10 min (a 300 decrease of copper catalyst and a
144 decrease in reaction time). It is applicable to a range of 5-
exo and 4-exo cyclizations as well as 5-endo cyclizations. While
the “reductive” conditions can be used to mediate oxidative
radical-polar crossover reactions, it was not possible to alter the
reaction manifold to terminate the cyclizations reductively by
increasing the amount of borohydride added without significant
side reactions. Cyclization onto alkynes (traditionally difficult
to achieve with copper catalysis 24 h, 110 °C)7b is possible in
only 20 min at room temperature, although higher amounts of
metal species are required to facilitate acceptable yields.
Eglinton or Hay41 type copper mediated sp/sp coupling
reaction of terminal alkynes (typically observed in some ATRC
procedures) were not observed. For 4-exo and 5-exo
Figure 5. Linear first-order kinetic plots of monomer consumption for
the polymerization of styrene with and without Bu4NBH4 (0.1 equiv
with respect to Cu(NBipy)Br).
molecular weight plot (Figure 6) prove that the polymerization
is well-controlled, the linear first-order kinetic plot of monomer
consumption indicates a constant number of active species, and
the linear increase of molecular weight with conversion is
characteristic of a controlled polymerization process. The
addition of Bu4NBH4 increased the rate of polymerization,
which is consistent with other reported reactions where
reducing agents have been added.40 After 5 h the PDI of the
polymer obtained with added Bu4NBH4 was slightly increased
compared to the standard system (1.20 compared to 1.12) as
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bromide (to give 8d), or cinnamyl bromide (to give 8e) (16.1 mmol)
was added. The reaction was stirred overnight and the acetone
removed in vacuo. The resulting residue was dissolved in a 1:1 v/v
ether/water mixture (100 mL) and extracted with ether (2 × 50 mL).
The combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo to yield the crude sulfonamides. n-BuLi (1.6 M
in hexanes, 3.75 mL, 6.0 mmol) was added dropwise to the crude
sulfonamide (5.3 mmol) in dry THF at −78 °C. After 30 min, 2-
bromoisobutyryl bromide (0.87 mL, 7.0 mmol) was added. The
reaction was allowed to warm room temperature overnight. The
reaction was quenched with saturated NH4Cl (10 mL) and partitioned
between saturated NaHCO3 (100 mL) and DCM (100 mL). The
residue was extracted using DCM (2 × 100 mL), and the combined
organic extracts were washed with brine (100 mL), dried (MgSO4),
filtered, and concentrated in vacuo to yield a crude product which was
purified by flash chromatography.
cyclizations high loadings of KBH4 (1 equivalent) led to
reduced starting amides as byproduct (e.g., 12 → 35); however,
no reduced products were observed when low loadings of
KBH4 were used (<5 mol %). We have extended the concept to
ATRP, and have shown that styrene can be polymerized in a
controlled fashion with good control over Mn and PDI. The
addition of Bu4NBH4 as reducing agent causes an increase in
the rate of polymerization, although the PDI in the reaction of
styrene with Cu(TPMA)SO4·5H2O or Cu(Nbipy)Br is slightly
higher than conventional reactions without borohydride
additives. This new class of AGET reagent system may also
have application in ATRA and it is more efficient in ATRC than
conventional ARGET and AGET additives routinely employed
in these areas.5a,17
2-Bromo-2-methyl-N-[(4-methylphenyl)sulfonyl]-N-2-prenylpro-
panamide (8c): yield 1.07 g (53%); white solid; mp 86−88 °C; Rf (3:1
petroleum ether/EtOAc) 0.64; νmax (film)/cm−1 2969, 2934, 1676; δH
(CDCl3, 300 MHz) 7.85 (2H, d, J 8.3 Hz), 7.28 (2H, d, J 8.3 Hz),
5.24−5.22 (1H, m), 4.90 (2H, d, J 6.0 Hz), 2.42 (3H, s), 1.90 (6H, s),
1.76 (6H, d, J 4.8 Hz); δC (CDCl3, 75.5 MHz) 170.2, 143.9, 135.9,
135.6, 128.5, 128.3, 119.9, 56.2, 46.8, 31.2, 31.1, 25.0, 21.1, 17.8; m/z
(ESI) 410 ([M]+Na), found ([M]+Na) 410.0396, C16H22BrNO3S
requires ([M]+Na) 410.0401.
EXPERIMENTAL SECTION
■
1
General Methods. H NMR were recorded at 300, 400, or 500
MHz and 13C NMR recorded at 75.5, 100, or 125 MHz with residual
solvent as internal standard; infrared spectra (IR) were recorded as
neat solutions or solids; and mass spectra were recorded using electron
impact or electrospray ionization techniques. Gel permeation
chromatography (GPC) was carried out using 2X mixed D columns
and a 5 μm guard column.
2-Bromo-2-methyl-N-[(4-methylphenyl)sulfonyl]-N-2-crotylpro-
panamide (8d): yield 1.14 g (56%), 6:1 E:Z isomers; white solid; mp
80−81 °C; Rf (3:1 petroleum ether/EtOAc) 0.64; νmax (film)/cm−1
2938, 1677; δH (CDCl3, 300 MHz) 7.85 (2H, d, J 8.3 Hz), 7.28 (2H,
d, J 8.3 Hz), 5.86−5.78 (1H, m), 5.61−5.53 (1H, m), 4.85 (2H, d, J
5.4 Hz), 2.41 (3H, s). 1.88 (6H, s), 1.73 (3H, dd, J 6.3, 1.2 Hz); δC
(CDCl3, 75.5 MHz) 170.7, 144.6, 136.5, 130.3, 129.2, 129.1, 126.2,
57.1, 50.3, 32.1, 21.8, 17.9; m/z (ESI) 396 ([M]+Na), found
([M]+Na) 396.0239, C15H20BrNO3S requires ([M]+Na) 396.0245.
2-Bromo-2-methyl-N-[(4-methylphenyl)sulfonyl]-N-2-cinnamyl-
propanamide (8e): yield 1.32 g (56%); yellow solid; mp 101−102 °C;
Rf (3:1 petroleum ether/EtOAc) 0.62; νmax (film)/cm−1 2968, 2923,
1676; δH (CDCl3, 300 MHz) 7.88 (2H, d, J 8.4 Hz), 7.32−7.25 (7H,
m), 6.69 (1H, dt, J 16.1, 1.2 Hz), 6.25 (1H, dt, J 16.1, 5.7 Hz), 5.11
(2H, dd, J 5.7, 1.5 Hz), 2.41 (3H, s), 1.94 (6H, s); δC (CDCl3, 75.5
MHz) 170.6, 144.7, 136.2, 136.0, 133.7, 129.2, 129.1, 128.7, 128.1,
126.6, 124.4, 56.9, 50.5, 32.0, 21.7; m/z (ESI) 458 ([M]+Na), found
([M]+Na) 458.0396, C20H22BrNO3S requires ([M]+Na) 458.0401.
N-Benzyl-2-bromo-N-isobutenyl-2-methylpropionamide
(13).7c Benzylamine (2.94 g, 27.5 mmol) and isobutyraldehyde (1.98
g, 27.5 mmol) in dry toluene were heated using a Dean−Stark
apparatus overnight. The crude mixture was cooled to 0 °C, and 2-
bromoisobutyryl bromide (6.33 g, 27.5 mmol) was added followed by
diethylaniline (4.10 g, 27.5 mmol). After 4 h, the reaction was
quenched with 2 M HCl (50 mL), extracted with Et2O (3 × 100 mL),
dried (MgSO4), filtered, and evaporated to dryness. The crude product
was purified by flash chromatography, 9:1 petroleum ether/EtOAc to
afford 13: yield 4.84 g, 57%), clear oil; Rf (3:1 petroleum ether/
EtOAc) 0.74; νmax (film)/cm−1 2975, 2933, 1637; δH (CDCl3, 400
MHz) 7.38−7.27 (5H, m), 6.36 (1H, s), 4.72 (2H, s), 1.99 (6H, s),
1.75 (3H, s), 1.63 (3H, s); δC (CDCl3, 100 MHz) 170.6, 137.3, 134.9,
128.4, 127.9, 127.2, 125.8, 58.3, 54.4, 32.1, 21.8, 18.2; m/z (ESI) 334
([M]+Na), 310 [M]+, found ([M]+Na) 332.0620, C15H20BrNO
requires ([M]+Na) 332.0626.
Synthesis of Known Compounds by Literature Procedures.
N-Allyl-N-(2-bromo-2-methylpropionyl)-4-methylbenzenesulfonamide
8a,7e 2-bromo-2-methyl-N-[(4-methylphenyl)sulfonyl]-N-(2-methyl-2-
propenyl)propanamide 8b,7e N-allyl-N-(2,2-dichloro-2-methylpro-
pionyl)-4-methylbenzenesulfonamide 9,7e N-benzyl-2-bromo-N-(cy-
clohex-1-enyl)-2-methylpropionamide 10a,42 N-benzyl-2-bromo-N-
(cyclooct-1-enyl)-2-methylpropionamide 10b,43 N-benzyl-2-bromo-
N-(3,4-dihydronaphthalen-1-yl)-2-methylpropionamide 11,43 and N-
benzyl-2-bromo-N-(methylenecyclohexane)-2-methylpropionamide
1213a were prepared by literature procedures and exhibited 1H and 13
C
1
NMR spectroscopic details identical to those previously reported. H
NMR was used to check the purity of all the compounds.
General Procedure for the Formation of N-Benzylpropana-
mides 1 and 14. Et3N (0.7 mL, 5.0 mmol) was added to a solution of
N-allyl-N-benzylamine (0.43 g, 2.92 mmol) or N-2-propyny-N-
benzylamine (0.42 g, 2.92 mmol) in Et2O (25 mL) at 0 °C. After
20 min, 2-bromoisobutyryl bromide (0.36 mL, 2.92 mmol) was added,
and the reaction mixture was allowed to warm to room temperature.
After 4 h, the reaction was quenched with satd NH4Cl (10 mL) and
partitioned between satd NaHCO3 (50 mL) and Et2O (50 mL). The
organic layer was collected, and the aqueous layer was extracted using
Et2O (2 × 50 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo to yield 1 and 14 as a
mixture of rotamers.
N-Allyl-N-benzyl-2-bromo-2-methylpropanamide (1): yield 0.72 g
(84%), colorless oil; mixture of rotamers; Rf (1:1 petroleum ether/
EtOAc) 0.84; νmax (film)/cm−1 2980, 2932, 1633; δH (toluene-d8, 400
MHz, 363 K) 7.16−7.06 (5H, m), 5.69−5.61 (1H, m) 5.01 (1H, dd, J
10.3, 1.4 Hz), 4.98 (1H, dd, J 17.2, 1.4 Hz), 4.67 (2H, s), 4.02 (2H, d,
J 5.5 Hz), 1.86 (6H, s); δC (toluene-d8, 125 MHz, 363 K) 170.3, 137.6,
133.5, 128.7, 127.8, 127.4, 117.4, 57.7, 50.6, 50.3, 33.1; m/z (ESI) 318
([M]+Na), found [M]+Na 318.0465 C14H18BrNONa requires
318.0469.
2-Bromo-2-methyl-N-(phenylmethyl)-N-2-propynylpropanamide
(14): yield 0.86 g (99%), pale yellow oil; mixture of rotamers; Rf (1:1
petroleum ether/EtOAc) 0.91; νmax (film)/cm−1 2980, 2932, 1636; δH
(CDCl3, 300 MHz) 7.35−7.22 (5H, m), 4.87 (2H, br s), 4.27 (2H, br
s), 2.24 (1H, s), 2.00 (6H, s); δC (toluene-d8, 125 MHz, 363K) 169.4,
137.0, 128.2, 127.6, 127.2, 72.0, 56.8, 50.3, 37.1, 32.4, 31.8; m/z (CI)
293 [M]+, found [M]+ 293.0420 C14H16BrNO requires 293.0415.
General Procedure for the Formation of 2-Bromo-2-methyl-
N-[(4-methylphenyl)sulfonyl]propanamides 8c−e. To a suspen-
sion of K2CO3 (2.80 g, 20.0 mmol) in acetone (100 mL) at room
temperature was added p-toluenesulfonamide (3.40 g, 20.0 mmol).
After 15 min, either 3,3-dimethylallyl bromide (to give 8c), crotyl
2-Bromo-N-[(4-methylphenyl)sulfonyl]-N-2-propynylpropa-
namide (15). 4-Methyl-N-prop-2-ynylpropanamide (1.02 g, 4.9
mmol) was dissolved in dry THF (50 mL) and cooled to −78 °C.
n-BuLi (1.6 M in hexanes, 4.70 mL, 7.5 mmol) was added dropwise.
After 30 min, 2-bromoisbutyryl bromide (0.79 mL, 7.5 mmol) was
added. The reaction was allowed to warm room temperature
overnight. The reaction was quenched with saturated NH4Cl (10
mL) and partitioned between saturated NaHCO3 (100 mL) and DCM
(100 mL). The residue was extracted using DCM (2 × 100 mL), and
the combined organic extracts were washed with brine (100 mL),
dried (MgSO4), filtered, and concentrated in vacuo to yield a crude
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product which was purified by flash chromatography (5:1 petroleum
ether/EtOAc): yield 0.89 g, (53%), pale yellow oil; Rf (3:1 petroleum
ether/EtOAc) 0.50; νmax (film)/cm−1 2972, 2937, 1698, 1599; δH
(CDCl3, 300 MHz) 7.91 (2H, d, J 8.4 Hz,) 7.34 (2H, d, J 8.4 Hz), 4.97
(1H, q, J 6.6 Hz), 4.84 (1H, dd, J 18.6, 2.5 Hz), 4.60 (1H, dd, J 18.6,
2.5 Hz), 2.44 (3H, s), 2.34 (1H, t, J 2.5 Hz), 1.74 (3H, d, J 6.6 Hz); δC
(CDCl3, 75.5 MHz) 168.9, 145.5, 135.3, 129.8, 128.4, 77.7, 73.5, 39.3,
35.7, 21.1, 20.2; m/z (ESI) 365 ([M]+Na), found ([M]+Na) 365.9770,
C13H14BrNO3S requires ([M]+Na) 365.9775.
νmax (film)/cm−1 2970, 1720, 1595; δH (CDCl3, 300 MHz) 7.92 (2H,
d, J 8.3 Hz), 7.34 (2H, d, J 8.3 Hz), 4,15 (1H, dd, J 10.0, 7.6 Hz), 3.80
(1H, t, J 10.2 Hz), 2.43 (3H, s), 2.27 (1H, dd, J 10.3, 7.6 Hz), 1.86
(6H, d, J 5.5 Hz), 1.28 (3H, s), 1.05 (3H, s); δC (CDCl3, 75.5 MHz)
177.1, 145.3, 134.6, 129.8, 128.0, 65.2, 54.9, 47.7, 46.7, 35.9, 32.9, 26.1,
21.8, 18.9; m/z (ESI) 410 ([M]+Na), found ([M]+Na) 410.0396,
C16H22BrNO3S requires ([M]+Na) 410.0401.
3-Chloro-4-(chloromethyl)-3-methyl-1-(p-toluenesulfonyl)-
pyrrolidin-2-one (19). Cu(TPMA)SO4 2.5 mol %, KBH4 10 mol %
(6:1 MeOH/DCM, 0.30 M); yield 65 mg (66%); white solid; mp
161−162 °C; spectroscopic data matched that previously reported.7e
Mixture of diastereoisomers (ratio 1.96:1.00 cis:trans): νmax (film)/
cm−1 2924, 1735; δH (CDCl3, 400 MHz) cis 7.92 (2H, d, J 8.4 Hz),
7.35 (2H, d, J 8.4 Hz), 4.21 (1H, dd, J 10.0, 7.0 Hz), 3.77 (1H, dd, J
11.5, 5.5 Hz), 3.63 (1H, dd, J 11.5, 9.0 Hz), 3.44 (1H, t, J 10.0 Hz),
2.60−2.50 (1H, m), 2.45 (3H, s), 1.72 (3H, s); trans 7.91 (2H, d, J 8.4
Hz), 7.35 (2H, d, J 8.4 Hz), 4.14 (1H, dd, J 10.6, 6.6 Hz), 3.87 (1H,
dd, J 10.6, 3.6 Hz), 3.65 (1H, dd, J 11.5, 4.3 Hz), 3.37 (1H, dd, J 11.5,
8.5 Hz), 2.89−2.80 (1H, m), 2.45 (3H, s), 1.60 (3H, s); δC (CDCl3,
75.5 MHz) mixture 169.3, 169.1, 146.3 (× 2), 134.4, 134.1, 130.3 (×
2), 130.2 (× 2), 128.6 (2C × 2), 128.5 (× 2), 71.4, 69.4, 47.7, 47.6,
47.4, 47.2, 42.3, 41.4, 24.2 (× 2), 22.2 (× 2). Anal. Calcd for
C13H15Cl2NO3S: C, 46.4; H, 4.5; N, 4.2. Found: C, 46.5; H, 4.5; N,
3.9.
3,3-Dimethyl-4-( )-(1-bromoethyl)-1-(p-toluenesulfonyl)-
pyrrolidin-2-one (20).17 Conditions: Cu(TPMA)SO4 2.5 mol %,
KBH4 10 mol % (6:1 MeOH/DCM, 0.30 M); yield 122 mg (91%,
3.8:1 mixture of diastereomers); white solid; mp 128−130 °C. Data
for major isomer (( ) S,S): Rf (3:1 petroleum ether/EtOAc) 0.59;
νmax (film)/cm−1 2969, 1723, 1597; δH (CDCl3, 300 MHz) 7.86 (2H,
d, J 8.4 Hz), 7.26 (2H, d, J 8.4 Hz), 4.10 (1H, dd, J 10.5, 7.7 Hz), 4.01
(1H, ddd, J 8.6 Hz) 3.40 (1H, dd, J 10.5, 8.6 Hz), 2.37 (3H, s), 2.20
(1H, q, J 8.5 Hz), 1.71 (3H, d, J 6.7 Hz), 1.17 (3H, s,), 0.87 (3H, s);
δC (CDCl3, 100 MHz) 177.1, 145.3, 134.9, 129.7, 128.1, 50.5, 48.9,
48.8, 45.4, 25.7, 25.1, 21.7, 17.5; m/z (ESI) 396 ([M]+Na); found
([M]+Na) 396.0239, C20H22BrNO3S requires ([M]+Na) 396.0245.
3,3-Dimethyl-4-( )-(1-bromophenyl)methyl-1-(p-
toluenesulfonyl)pyrrolidin-2-one (21).17 Conditions: Cu-
(TPMA)SO4 2.5 mol %, KBH4 50 mol % (6:1 MeOH/DCM, 0.30
M); yield 125 mg (80%, 5.0:1 unseparable mixture of diastereomers);
white solid; mp 182−183 °C. Data for major isomer (( ) S,S): Rf (3:1
petroleum ether/EtOAc) 0.57; νmax (film)/cm−1 2961, 1728, 1597; δH
(CDCl3, 400 MHz) 7.88 (2H, d, J 8.3 Hz), 7.30−7.26 (7H, m), 4.84
(1H, d, J 11.3 Hz), 4.32 (1H, dd, J 10.4, 2.9 Hz), 3.45 (1H, t, J 10.5
Hz), 2.93−2.85 (1H, m), 2.38 (3H, s), 0.76 (3H, s), 0.45 (3H, s); δC
(CDCl3, 100 MHz) 177.2, 145.3, 139.7, 134.9, 129.8, 129.4, 129.0,
128.1, 127.8, 53.6, 49.9, 49.6, 45.8, 23.4, 21.7, 17.8; m/z (ESI) 458
([M]+Na); found ([M]+Na) 458.0396, C20H22BrNO3S requires
([M]+Na) 458.0401.
Cyclization of N-Benzyl-2-bromo-N-(cyclohex-1-enyl)-2-
methylpropionamide 10a. Conditions: Cu(TPMA)SO4 1.0 mol
%, KBH4 100 mol % (MeOH, 0.12 M). Purified by silica gel
chromatography 9:1 petroleum ether/EtOAc. 1-Benzyl-3,3-dimethyl-
1,3,3a,4,5,6,7,7a-octahydroindol-2-one (26a): yield 11 mg (12%, as a
1:1 mixture of diastereomers); clear oil; Rf (3:1 petroleum ether/
EtOAc) 0.56; νmax (film)/cm−1 2924, 2855, 1680; δH (CDCl3, 400
MHz) 7.31−7.20 (5H, m, both diastereomers), 5.00 (1H, d, J 12.5 Hz,
one diastereomer), 4.82 (1H, d, J 12.5 Hz, one diastereomer), 4.05
(1H, d, J 12.5 Hz, one diastereomer), 3.91 (1H, d, J 12.5 Hz, one
diastereomer), 3.50 (1H, app q, 3.5 Hz, one diastereomer), 2.81 (1H,
ddd, J 10.5, 6.5, 3.0 Hz, one diastereomer), 2.01−1.99 (1H, m, one
diastereomer), 1.89 (1H, m, one diastereomer), 1.81−1.77 (3H, m,
both diastereomers), 1.58−1.13 (5H, m, both diastereomers), 1.17,
(3H s, one diastereomer), 1.13 (3H, s, one diastereomer), 1.10 (3H, s,
one diastereomer) 0.90 (3H, s, one diastereomer); δC (CDCl3, 125
MHz) 181.1, 180.7, 137.5, 137.2, 128.6, 128.5, 127.9, 127.8, 127.3,
127.2, 58.7, 53.1, 52.5, 44.6, 43.9, 43.7, 42.9, 42.5, 29.8, 29.7, 26.1,
26.0, 24.5, 23.9, 23.6, 23.3, 23.2, 20.7, 19.4, 17.0; m/z (ESI) 280
([M]+Na), 258 ([M]+H), found ([M]+Na) 280.1672, C17H23NO
requires ([M]+Na) 280.1677. 1-Benzyl-3,3-dimethyl-1,3,4,5,6,7-hex-
General Procedure for CuSO4·5H2O/KBH4-Mediated Cycliza-
tion. A 0.01 M stock solution of CuSO4·5H2O and TPA in MeOH
was prepared, and the appropriate amount was added to the substrate
(typically 0.5−2.0 mmol) dissolved in the preferred amount of MeOH
to make up the desired concentration (typically 0.12−0.30 M). If
necessary, 1−2 drops of DCM were added to solubilize the substrate
(up to a 6:1 ratio of MeOH/DCM). To this solution was added KBH4
(typically 2.5−100 mol %). An immediate color change was observed.
The mixture was allowed to stir at room temperature for 10−30 min.
The mixture was filtered through a silica plug using DCM (50 mL) as
eluent, and the resulting filtrate was washed with water (30 mL). The
organic layer was dried (MgSO4) and concentrated in vacuo to give
the crude product, which was further purified by chromatography. A
typical example is given below for the synthesis of compound 2.
3,3-Dimethyl-4-bromomethyl-1-(phenylmethyl)pyrrolidin-2-one
(2). A stock solution of 0.01 M Cu(TPMA)SO4 was prepared (249 mg
of CuSO4·5H2O and 276 mg of TPMA were dissolved in 100 mL of
MeOH in a volumetric flask). To substrate 1 (106 mg, 0.36 mmol) in
MeOH (2.6 mL) was added Cu(TPMA)SO4 (1 mol %, 3.6 × 10−3
mmol, 0.36 mL of 0.01 M stock solution) followed by KBH4 (∼10 mol
%, 2 mg). After 15 min the crude solution was filtered through a silica
plug (50 mL DCM) and washed with water (30 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo to give the crude
product which was further purified by chromatography on silica (3:1
petroleum ether/EtOAc): yield 76 mg, (72%), colorless oil; Rf (3:1
petroleum ether/EtOAc) 0.30; νmax (film)/cm−1 2964, 1684; δH
(CDCl3, 300 MHz) 7.32−7.15 (5H, m, Ar), 4.52 (1H, d, J 14.4
Hz), 4.35 (1H, d, J 14.4 Hz), 3.46 (1H, dd, J 10.0, 4.8 Hz), 3.35 (1H,
dd, J 10.0, 7.5 Hz), 3.22 (1H, t, J 10.5 Hz), 2.88 (1H, t, J 10.2 Hz),
2.40 (1H, m), 1.24 (3H, s), 0.99 (3H, s); δC (CDCl3, 75.5 MHz)
178.5, 136.3, 128.8, 128.1, 127.7, 48.9, 46.7, 46.1, 44.0, 31.5, 24.3, 19.6,
found ([M]+Na) 318.0464, C14H18BrNO requires ([M]+Na)
318.0469.
3,3-Dimethyl-4-bromomethyl-1-(p-toluenesulfonyl)-
pyrrolidin-2-one (16). Conditions: Cu(TPMA)SO4 1.0 mol %,
KBH4 5 mol % (3:1 MeOH/DCM, 0.50M); yield 109 mg (90%);
white solid; mp 131−132 °C; spectroscopic data matched that
previously reported;7e Rf (3:1 petroleum ether/EtOAc) 0.21; νmax
(film)/cm−1 2960, 1757, 1595; δH (CDCl3, 400 MHz) 7.92 (2H, d, J
8.3 Hz), 7.34 (2H, d, J 8.3 Hz), 4.15 (1H, dd, J 10.3, 7.4 Hz), 3.47
(1H, dd, J 10.2, 8.7 Hz), 3.44 (1H, dd, J 10.2, 4.8 Hz), 3.21 (1H, t, J
10.3 Hz), 2.46 (1H, m), 2.44 (3H, s), 1.17 (3H, s), 0.90 (3H, s); δC
(CDCl3, 100 MHz) 177.1, 145.5, 135.0, 129.9, 128.1, 48.9, 45.6, 45.2,
30.1, 23.5, 21.8, 18.0; m/z (ESI) (360 [M]+Na). Anal. Calcd for
C14H18BrNO3S: C, 46.7; H, 5.0; N, 3.9. Found: C, 47.1; H, 5.0; N, 3.8.
3 , 3 - D i m e t h y l - 4 - m e t h y l - 4 - b r o m o m e t h y l - 1 - ( p -
toluenesulfonyl)pyrrolidin-2-one (17). Conditions: Cu(TPMA)-
SO4 2.5 mol %, KBH4 10 mol % (6:1 MeOH/DCM, 0.30 M); yield 88
mg (66%); white solid; mp 174−176 °C; spectroscopic data matched
that previously reported;7e Rf (3:1 petroleum ether/EtOAc) 0.48; νmax
(film)/cm−1 2982, 2937, 1722, 1596; δH (CDCl3, 400 MHz) 7.91 (2H,
d, J 8.3 Hz), 7.34 (2H, d, J 8.3 Hz), 3.85 (1H, d, J 10.8 Hz), 3.57 (1H,
d, J 10.8 Hz), 3.27 (1H, d, J 10.5 Hz), 3.22 (1H, d, J 10.5 Hz), 2.44
(3H, s), 1.09 (3H, s), 1.07 (3H, s), 0.97 (3H, s); δC (CDCl3, 100
MHz) 177.0, 145.3, 135.0, 129.7, 128.0, 54.1, 48.5, 48.2, 38.5, 21.7,
20.0, 19.1, 18.5; m/z (ESI) (396 [M]+Na), 374 ([M]+H), found
([M]+Na) 396.0244, C15H20BrNO3S requires ([M]+Na) 396.0245.
3,3-Dimethyl-4-(2-bromoisopropyl)-1-(p-toluenesulfonyl)-
pyrrolidin-2-one (18). Conditions: Cu(TPMA)SO4 2.5 mol %,
KBH4 5 mol % (6:1 MeOH/DCM, 0.30 M); yield 107 mg, (77%);
white solid; mp 118−119 °C; Rf (3:1 petroleum ether/EtOAc) 0.60;
H
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ahydroindol-2-one (27a): yield 22 mg (24%), clear oil; spectroscopic
data matched that previously reported;13a Rf (3:1 petroleum ether/
EtOAc) 0.48; νmax (film)/cm−1 2924, 2855, 1680; δH (CDCl3, 400
MHz) 7.31−7.16 (5H, m), 4.63 (2H, s), 1.97 (2H, m), 1.64−1.47
(6H, m), 1.26 (6H, s); δC (CDCl3, 100 MHz) 181.1, 138.7, 133.6,
128.5, 17.9, 127.3, 121.4, 42.7, 28.5, 24.8, 22.6, 22.5, 21.9, 22.2; m/z
(ESI) 278 ([M]+Na), 256 ([M]+H), found ([M]+Na) 278.1515,
C17H21NO requires ([M]+Na) 278.1521. 1-Benzyl-3,3-dimethyl-
1,3,3a,4,5,6-hexahydroindol-2-one (28a): yield 43 mg (47%); clear
oil; spectroscopic data matched that previously reported;13a Rf (3:1
petroleum ether/EtOAc) 0.67; νmax (film)/cm−1 2962, 1669; δH
(CDCl3, 400 MHz) 7.35−7.22 (5H, m), 4.81 (1H, dd, J 6.8, 3.0
Hz), 4.66 (1H, d, J 15.6 Hz), 4.56 (1H, d, J 15.6 Hz), 2.48−2.39 (1H,
m), 2.10−1.95 (2H, m), 1.95−1.85 (1H, m), 1.82−1.71 (1H, m),
1.58−1.30 (2H, m), 1.26 (3H, s), 0.99 (3H, s); δC (CDCl3, 100 MHz)
180.6, 139.7, 137.0, 128.7, 128.5, 127.2, 98.5, 45.8, 43.6, 43.0, 23.5,
23.1, 22.2, 21.9, 20.8; m/z (ESI) 278 ([M]+Na), 256 ([M]+H), found
([M]+Na) 278.1515, C17H21NO requires ([M]+Na) 278.1521. N-
cyclohex-1-enyl-N-benzyl-2-methylpropionamide (25a). Condi-
tions: Cu(TPMA)SO4 1.0 mol %, KBH4 1000 mol % (MeOH,
0.12M); crude 2.1:1.0: mixture of 25a:26a; spectroscopic data
matched that previously reported;42 yield 39 mg (42%); pale yellow
solid; mp 78−80 °C; Rf (3:1 petroleum ether/EtOAc) 0.8; νmax (film)/
cm-1 2929, 1634; δH (CDCl3, 400 MHz) 7.32−7.21 (5H, m), 5.40
(1H, s), 4.59 (2H, s), 2.81 (1H, quin, J 6.7 Hz), 2.04−1.90 (4H, m),
1.70−1.59 (2H, m), 1.57−1.45 (2H, m), 1.12 (6H, d, J 6.5 Hz); δC
(CDCl3, 75.5 MHz) 177.0, 138.6, 138.5, 128.7, 128.2, 127.5, 127.0,
49.7, 31.4, 28.8, 24.7, 22.9, 21.5, 20.2; m/z (ESI) 280.2 ([M]+Na)
258.1 [M]+, found ([M]+Na) 280.1672, C17H23NO requires ([M] +
Na) 280.1677.
Cyclization of N-Benzyl-2-bromo-N-(cyclooct-1-enyl)-2-
methylpropionamide (10b). Conditions: Cu(TPMA)SO4 1.0 mol
%, KBH4 100 mol %, (MeOH, 0.12M); purified by silica gel
chromatography 9:1 petroleum ether/EtOAc. 1-Benzyl-3,3-dimethyl-
(1-cyclooctyl)pyrrolidin-2-one (26b): yield 11 mg, (11%), clear oil.
Crude NMR shows a 1:1 mixture of diastereomers. It was possible to
partially remove one of the isomers by chromatography a second time
to give a 2:1 mixture of isomers. Data for mixture: Rf (3:1 petroleum
ether/EtOAc) 0.30; νmax (film)/cm−1 2924, 2854, 1755, 1596; δH
(CDCl3, 400 MHz) 7.35−7.17 (5H, m), 5.04 (1H major, d, J 16.0
Hz), 5.02 (1H minor, d, J 16.0 Hz), 3.97 (1H major, d, J 16.0 Hz),
3.90 (1H minor, d, J 16.0 Hz), 3.38 (1H minor, app t, J = 8.0 Hz), 3.12
(1H, major app dt, J 9.5, 5.0 Hz), 2.12−2.02 (1H, m), 1.89−1.26
(11H, m), 1.17 (3H major, s), 1.15 (3H minor, s), 1.07 (3H minor, s),
0.95 (3H major, s), 0.81 (1H, m); δC (CDCl3, 100 MHz) 179.9, 179.0,
137.0, 137.0, 128.7, 128.6, 128.1, 127.9, 127.4, 127.3, 603, 59.4, 48.9,
46.9, 44.2, 44.0, 43.7, 43.6, 32.1, 29.7, 28.6, 27.5, 27.4, 27.0, 26.7, 25.5
(× 2), 25.4, 25.2, 24.06, 22.74, 21.9, 20.9, 19.6 ; m/z (ESI) 308
([M]+Na), 286 ([M]+H), found:([M]+Na) 308.1985, C19H27NO
requires ([M]+Na) 308.1990. 1-Benzyl-3,3-dimethyl(1-cyclooct-1-
enyl)pyrrolidin-2-one (27b):37b yield 6 mg (6%); clear oil; Rf (3:1
petroleum ether/EtOAc) 0.63; νmax (film)/cm−1 2925, 2855, 1755,
1596; δH (CDCl3, 400 MHz) 7.35−7.12 (5H, m), 4.68 (2H, s), 2.40−
2.15 (4H, m), 1.70−1.35 (8H, m), 1.20 (3H, s); δC (C6D6, 100 MHz)
184.3, 139.6, 135.6, 129.2, 127.7, 127.4, 121.7, 47.7, 43.5, 30.7, 27.6,
26.4, 26.3, 23.4, 23.1; m/z (ESI) 306 ([M]+Na), 284 ([M]+H); found
([M]+Na) 306.1828, C19H25NO requires ([M]+Na) 306.1834. 1-
Benzyl-3,3-dimethyl(1-cyclooct-2-enyl)pyrrolidin-2-one (28b):37b
yield 70 mg (69%); clear oil; Rf (3:1 petroleum ether/EtOAc) 0.74;
νmax (film)/cm−1 2926, 2854, 1702; δH (C6D6, 400 MHz) 7.33−7.10
(5H, m, Ar), 4.78−4.70 (2H, m), 4.59 (1H, d, J 15.1 Hz), 2.45 (1H,
dd, J 12.5, 3.0 Hz), 2.21−1.90 (2H, m), 1.70−0.90 (8H, m) 1.25 (3H,
s), 1.18 (3H, s); δC (C6D6, 100 MHz) 179.8, 143.2, 138.0, 129.6,
128.0, 127.7, 101.2, 47.7, 44.0, 43.9, 32.6, 30.2, 28.0, 26.1, 25.7, 24.4,
19.1; m/z (ESI) 306 ([M]+Na), 284 ([M]+H), found ([M]+Na)
306.1829, C19H25NO requires ([M]+Na) 306.1834.
mg, (20%); white crystalline solid; mp 64−65 °C; Rf (9:1 petroleum
ether/EtOAc) 0.28; νmax (film)/cm−1 2929, 2847, 1639; δH (CDCl3,
400 MHz) 7.33−7.20 (5H, m, Ar), 5.30 (1H, t, J 8.0 Hz), 4.69 (1H, br
s), 2.91 (1H, sept J 6.0 Hz), 2.31 (2H, br s), 2.05 (2H, br s) 1.63−1.40
(8H, m), 1.13 (6H, d, J 6.0 Hz); δC (CDCl3, 100 MHz) 177.4, 140.8,
138.8, 129.5, 128.3, 127.0, 50.6, 31.7, 31.5, 29.1, 28.9, 26.4, 26.0 (x2),
20.1; m/z (ESI) 308 ([M]+Na), 286 ([M]+H), found ([M]+Na)
308.1990, C19H27NO requires ([M]+Na) 308.1990.
Cyclization of N-Benzyl-2-bromo-N-(3,4-dihydronaphtha-
len-1-yl)-2-methylpropionamide (11). Conditions: Cu(TPMA)-
SO4 1.0 mol %, KBH4 100 mol %, (MeOH, 0.12M). Purified by silica
gel chromatography gradient 9:1 petroleum ether: EtOAc → EtOAc.
1-Benzyl-3,3-dimethyl-4-(2,4,5,6-tetrahydronaphthalen)-2-one
(29): yield 20 mg (18%); colorless oil; Rf (3/1 petroleum ether/
EtOAc) 0.48; νmax (film)/cm−1 2927, 1679; δH (CDCl3, 400 MHz)
7.33−6.98 (9H, m), 4.99 (1H, d, J 15.5 Hz), 4.63 (1H, d, J 6.0 Hz),
3.63 (1H, d, J 15.5 Hz), 2.70 (1H, dt, J 16.1, 5.5 Hz), 2.68 (1H, dt, J
16.1, 5.5 Hz), 2.26 (1H, dd, J 13.0, 6.5 Hz), 1.72 (2H, dd, J 13.1, 6.5
Hz), 1.34 (3H, s), 1.24 (3H, s); δC (CDCl3, 100 MHz) 179.8 139.7,
137.3, 131.8, 131.1, 128.7, 128.6, 128.2, 127.5, 127.1, 125.7, 61.8, 55.8,
43.5, 43.4, 28.1, 22.9, 25.1, 20.1; m/z (ESI) 328 ([M]+Na), found
([M]+Na) 328.1672, C21H23NO requires ([M]+Na) 328.1677. 1-
Benzyl-3,3-dimethyl-1,3,4,5-tetrahydrobenzo[g]indol-2-one (30): yield
57 mg (52%); white crystalline solid; mp 94−96 °C; Rf (9/1
petroleum ether/EtOAc) 0.23; νmax (film)/cm−1 2929, 1697; δH
(CDCl3, 400 MHz) 7.31 (2H, t, J 8.2 Hz), 7.26−7.14 (5H, m), 7.10
(1H, t, J 7.3 Hz), 7.03 (1H, t, J 7.6 Hz), 5.06 (2H, s), 2.84, (2H, t J 7.9
Hz), 2.31 (2H, t, J 7.9 Hz), 1.31 (6H, s); δC (CDCl3, 100 MHz) 185.0,
138.0, 136.7, 134.5, 128.8, 128.4, 127.5, 127.2, 127.1, 126.8, 126.6,
126.3, 121.6, 46.1, 45.5, 29.4, 22.5, 19.2; m/z (ESI) 326, ([M]+Na);
found ([M]+Na) 326.1515, C21H21NO requires ([M]+Na) 326.1521].
Anal. Calcd for C21H21NO: C, 83.2; H, 7.0; N, 4.6. Found: C, 82.9; H,
6.9; N, 4.5.
Cyclization of N-Benzyl-2-bromo-N-(methylenecyclohex-
ane)-2-methylpropionamide (12). Conditions: Cu(TPMA)SO4
1.0 mol %, KBH4 100 mol % (MeOH, 0.12 M). Purified by silica
gel chromatography 9:1 petroleum ether/EtOAc. N-Benzyl-4-bromo-
4-cyclohexyl-3.3-dimethylazetidin-2-one (31): yield 50 mg (40%);
clear oil; spectroscopic data matched that previously reported;13a Rf
(3:1 petroleum ether/EtOAc) 0.33; νmax (film)/cm−1 2929, 1736; δH
(CDCl3, 300 MHz) 7.40−7.15 (5H, m), 4.92 (1H, d, J 15.6 Hz), 4.15
(1H, d, J 15.6 Hz), 3.50 (1H, s), 2.15−1.41 (10H, m) 1.50 (3H, s),
1.29 (3H, s); δC (CDCl3, 100 MHz) 175.0, 136.2, 127.8, 128.4, 127.7,
74.4, 72.7, 55.5, 45.5, 37.6, 25.0, 22.6, 22.4, 21.9, 24.5, 18.4; m/z (ESI)
372 ([M]+Na); found ([M]+Na) 372.0933, C18H24BrNO requires
([M]+Na) 372.0939. N-Benzyl-4-cyclohex-1-enyl-3.3-dimethylazeti-
din-2-one (32): yield 39 mg, (40%); clear oil; spectroscopic data
matched that previously reported;13a Rf (3:1 petroleum ether/EtOAc)
0.41; νmax (film)/cm−1 2929, 1736; δH (CDCl3, 300 MHz) 7.40−7.15
(5H, m), 5.56 (1H, br s), 4.80 (1H, d, J 14.8 Hz), 3.85 (1H, d, J 14.8
Hz), 3.37 (1H, s), 2.15−1.48 (8H, m) 1.24 (3H, s), 1.07 (3H, s); δC
(CDCl3, 100 MHz) 174.4, 136.2, 132.8, 128.7, 128.4. 127.6, 123.4,
66.4, 54.9, 44.4, 27.3, 24.8, 22.4, 22.3, 22.5, 16.8; m/z (ESI) 292
([M]+Na), 270 ([M]+H); found ([M]+H) 270.1852, C18H22NO
requires ([M]+H) 270.1858. N-Benzyl-N-(methylenecyclohexane)-2-
methylpropionamide (35): yield 12 mg (12%); clear oil; Rf (3:1
petroleum ether/EtOAc) 0.57; νmax (film)/cm−1 2931, 2855, 1639; δH
(CDCl3, 400 MHz) 7.30−7.21 (5H, m), 5.74 (1H, br s), 4.59 (2H, s),
2.83 (1H, sept, J 6.8 Hz), 2.06 (2H, br t, J 5.8 Hz), 1.90 (2H, t, J 5.8
Hz), 1.50 (4H, tt, J 5.8, 2.7 Hz), 1.29−1.23 (2H, m), 1.06 (6H, d, J 6.8
Hz); δC (CDCl3, 100 MHz) 177.6, 143.2, 137.7, 128.9, 128.3, 127.1,
120.1, 51.0, 33.0, 30.9, 27.9, 26.4, 26.3, 20.7; m/z (ESI) 294
([M]+Na), 272 ([M]+H); found ([M]+H) 272.2009, C18H26NO
requires ([M]+H) 272.2014.
Cyclization of N-Benzyl-2-bromo-N-(methylenecyclohex-
ane)-2-methylpropionamide (13). Conditions: Cu(TPMA)SO4
1.0 mol %, KBH4 100 mol %, (MeOH, 0.12 M); purified by silica
gel chromatography 9:1 petroleum ether/EtOAc. N-Benzyl-4-(2-
methyl-2-bromoethyl)-3,3-dimethylazetidine-2-one (33): yield 68
mg, (61%); clear oil; Rf (3:1 petroleum ether/EtOAc) 0.46; νmax
Conditions: Cu(TPMA)SO4 1.0 mol %, KBH4 1000 mol %,
(MeOH, 0.12 M);1.0:1.0:0.5 mixture of 25b:26b:27b+28b. Purified
by silica gel chromatography 9:1 petroleum ether/EtOAc. N-
Cyclooct-1-enyl-N-benzyl-2-methylpropionamide (25b): yield 21
I
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(film)/cm−1 2962, 2925, 1751; δH (CDCl3, 400 MHz) 7.30−7.15 (5H,
m), 4.86 (1H, d, J 15.1 Hz), 4.16 (1H, d, J 15.1 Hz), 3.54 (1H, s), 1.74
(6H, d, J 4.7 Hz), 1.32 (3H, s), 1.21 (3H, s); δC (CDCl3, 100 MHz)
174.1, 135.9, 128.1, 127.9, 127.0, 72.2, 64.6, 54.7, 44.4, 30.7, 23.4, 17.2;
m/z (ESI) 332 ([M]+Na); found ([M]+Na) 332.0628, C15H20BrNO
requires ([M]+Na) 332.0626]. N-Benzyl-4-(isoprop-1-enyl)-3,3-
dimethylazetidine-2-one (34): yield 18 mg (20%); colorless oil; Rf
(3:1 petroleum ether/EtOAc) 0.23; νmax (film)/cm−1 2962, 2925,
1751; δH (CDCl3, 400 MHz) 7.30−7.15 (5H, m), 4.99 (1H, br s), 4.81
(1H, br s), 4.79 (1H, d, J 14.6 Hz), 3.81 (1H, d, J 14.6 Hz), 3.34 (1H,
s), 1.55 (3H, s), 1.20 (3H, s), 1.04 (3H, s); δC (CDCl3, 100 MHz)
168.4, 136.2, 135.9, 128.8, 128.4, 127.7, 111.9, 66.2, 44.4, 31.2, 29.7,
21.0, 16.6; m/z (ESI) 252 ([M]+Na), 230 ([M]+H); found ([M]+Na)
252.1361, C15H19NO requires ([M]+Na) 252.1364].
Cyclization of 2-Bromo-2-methyl-N-(phenylmethyl)-N-2-
propynylpropanamide (14). Conditions: Cu(TPMA)SO4 1.0 mol
%, KBH4 100 mol % (MeOH, 0.12 M); purified by silica gel
chromatography 9:1 petroleum ether/EtOAc. 3,3-Dimethyl-4-bromo-
methylene-1-(phenylmethyl)-2-pyrrolidinone (36) and 3,3-dimethyl-
4-methylene-1-(phenylmethyl)-2-pyrrolidinone (37):17 yield 86 mg
(82%) as an inseparable mixture (36:37 = 1:2); colorless oil; Rf (3:1
petroleum ether/EtOAc) 0.57; νmax (film)/cm−1 2966, 2926, 1693; δH
(CDCl3, 300 MHz) 7.39−7.20 (10H, m, 36 and 37), 6.11 (1H, t, J 2.7
Hz, 36), 5.03 (1H, t, J 2.4 Hz, 37), 4.96 (1H, t, J 2.0 Hz, 37), 4.53 (2H,
s, 36), 4.51 (2H, s, 37), 3.84−3.80 (4H, m, 36 and 37), 1.31 (6H, s, 36
and 37), 1.27 (6H, s, 36 and 37); δC (CDCl3, 75.5 MHz) 177.5, 148.8,
146.1, 136.3, 135.9, 128.9, 128.8, 128.1, 127.8, 127.6, 106.7, 100.9,
50.1, 49.6, 46.3, 46.2, 44.4, 44.0, 25.6, 25.2; m/z (ESI) 316 ([M]+Na)
294 ([M]+H) (36); found ([M]+Na) 316.0307, C20H22BrNO3S (36)
requires ([M]+Na) 316.0313.
Bu4NBH4 (0.4 equiv) under nitrogen was added degassed styrene
monomer (100 equiv). Heating at 110 °C caused a vigorous reaction
resulting in a brown solution. Ethyl α-bromoisobutyrate (1.00 equiv)
was added to initiate the polymerization. The mixture was stirred at
110 °C, and aliquots were taken at regular intervals to assess the extent
of polymerization. Aliquots were passed through a plug of silica to
remove the Cu/Nbipy complex and precipitated into cold methanol to
remove residual monomer, yielding polystyrene as a white solid.
Conditions with CuSO4·5H2O: 100 equiv of styrene, GPC (THF +
2% TEA) Mn = 7.3 KDa, PDI = 1.19; δH (CDCl3, 400 MHz), 7.30−
6.20 (5H, br m, backbone). 4.60−4.00 (1H, br m, end group) 3.70−
3.30 (2H, br m, CH2 end group), 2.60−0.80 (3H, br m, backbone and
end group). Anal. Calcd for C550H555BrO2: C, 90.78; H, 7.69; Br, 1.10;
S, 0.00 (Br content indicates 64% and 1H NMR analysis indicates 53%
end group fidelity). Found C, 91.38; H, 7.73; Br, 0.70; S, <0.1.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H NMR spectra for 1 (at 298 and 363 K), 2, 8c−e, 13−21,
25−38, and polystyrene prepared by ATRP using CuBr or
CuSO4·5H2O and Bu4NBH4. 13C NMR spectra for 1 (at 298
and 363 K), 2, 8c−e, 13−15, 17−18, 20−21, 25−26, 27b, 28b,
29−30, 33, and 35−38, and X-ray data for 21 (CIF). Visible
spectra of Cu(TPMA)SO4/1 in MeOH with/without KBH4
and the decomposition of the “active catalyst”. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: a.j.clark@warwick.ac.uk.
■
3-Methyl-4-methyl-1-(p-toluenesulfonyl)pyrrolidin-3-en-2-
one (38). Conditions: Cu(TPMA)SO4 1.0 mol %, KBH4 100 mol %
(MeOH, 0.12 M); purified by silica gel chromatography 5:1 petroleum
ether/EtOAc; yield 76 mg (80%); pale yellow oil; Rf (3:1 petroleum
ether/EtOAc) 0.23; νmax (film)/cm−1 2923, 2858, 1709; δH (CDCl3,
400 MHz) 7.94 (2H, d, J 8.5 Hz), 7.32 (2H, d, J 8.5 Hz), 4.23 (2H, s),
2.41 (3H, s), 1.98, (3H, s) 1.70 (3H, s); δC (CDCl3, 100 MHz) 169.8,
150.8, 144.9, 135.6, 128.5, 129.7, 128.0, 53.4, 21.7, 13.5, 8.3; m/z
(ESI) 288 ([M]+Na); found ([M]+Na) 288.0665, C13H15NO3S
requires ([M]+Na) 288.0670.
ACKNOWLEDGMENTS
■
We thank the University of Warwick and the Engineering and
Physical Science Research Council for funding this work. The
Oxford Diffraction Gemini XRD system was obtained through
the Science City Advanced Materials project: Creating and
Characterizing Advanced Materials, with support from
Advantage West Midlands (AWM) and in part funded by the
European Regional Development Fund (EDRF).
General Procedure for the Polymerization of Styrene with
CuBr. To a mixture of 2,2′-nonylbipyridyl (Nbipy, 2.56 equiv), CuBr
(1.02 equiv), and Bu4NBH4 (0.1 equiv) under nitrogen was added
degassed styrene monomer (n equiv). To the solution at 110 °C was
added ethyl α-bromoisobutyrate (1.00 equiv) to initiate polymer-
ization. The mixture was stirred at 110 °C and aliquots were taken at
regular intervals to assess the extent of polymerization. Aliquots were
passed through a plug of silica to remove the Cu/Nbipy complex and
precipitated into cold methanol to remove residual monomer.
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