Iron(II) catalyzed reductive radical cyclization reactions of bromoacetals in the presence of NaBH4: optimization studies and mechanistic insights

Article abstract of DOI:10.1016/j.tet.2016.08.039

5-Exo-trig radical reductive cyclization reactions of bromoacetals are catalyzed by iron in the presence of the reducing agent NaBH₄. Both iron(II) and iron(III) were found to effectively mediate these reactions. As shown by cyclic voltammetry, iron(III) can be reduced to an iron(II) precatalyst before passing through an identical reaction mechanism in which monoelectronic activation of the substrate would occur by an anionic hydridoiron(I) complex. Further studies have established that both the substrate (iodo- vs bromo-derivative) and the precatalytic mixture are decisive in determining the reaction outcome.

Full text of DOI:10.1016/j.tet.2016.08.039

Tetrahedron xxx (2016) 1e11
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iron(II) catalyzed reductive radical cyclization reactions of
bromoacetals in the presence of NaBH4: optimization studies and
mechanistic insights
a
,
a
a
a,
*
ꢀ ^
Sara H. Kyne y, Christophe Leveque , Shiwen Zheng , Louis Fensterbank
,
,
a,
Anny Jutand b , Cyril Ollivier
*
*
a
ꢀ
ꢀ
Institut Parisien de Chimie Moleculaire, UMR CNRS 8232, Sorbonne Universites, UPMC Univ Paris 06, 4 Place Jussieu, CC 229, F-75005 Paris, France
Ecole Normale Superieure e PSL Research University, Departement de Chimie, Sorbonne Universites, UPMC Univ Paris 06, CNRS UMR 8640 PASTEUR,
b
ꢀ
ꢀ
ꢀ
24 Rue Lhomond, F-75231 Paris, Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
5-Exo-trig radical reductive cyclization reactions of bromoacetals are catalyzed by iron in the presence of
the reducing agent NaBH4. Both iron(II) and iron(III) were found to effectively mediate these reactions. As
shown by cyclic voltammetry, iron(III) can be reduced to an iron(II) precatalyst before passing through an
identical reaction mechanism in which monoelectronic activation of the substrate would occur by an
anionic hydridoiron(I) complex. Further studies have established that both the substrate (iodo- vs
bromo-derivative) and the precatalytic mixture are decisive in determining the reaction outcome.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 14 April 2016
Received in revised form 4 August 2016
Accepted 12 August 2016
Available online xxx
Keywords:
Iron
Radical cyclization
Homogenous catalysis
Reduction
Electrochemistry
NMR spectroscopy
1. Introduction
A solution to this problem was the design of new metal/hydride
systems that used a catalytic amount of metal complex. The story
Free radical processes are established as powerful and versatile
tools for organic synthesis.1 The notoriety of tin hydrides as reliable
radical chain carriers and good hydrogen donors is well docu-
mented.2 However, providing efficient alternatives that are less
toxic and easier to remove at the end of the reaction is highly de-
sirable for modern synthetic chemistry.3
In this context, intensive research has been conducted on the
development of tin-free mediators, mainly focused on hydrides of
main-group elements including silicon,4 germanium,5 boron6 and
phosphorus7 derivatives. Besides these examples, interesting al-
ternatives have been discovered with hydrides of gallium,8 indium8
and transition metal complexes including titanium,9 zirconium10
and chromium.11 However most of these reactions require stoi-
chiometric or substoichiometric amount of reagents, and chal-
lenges remain to develop catalytic alternatives.
began with the work of Kuivila,12 Corey13 and Stork14 who used
catalytic amounts of tinhydridewith a stoichiometric hydride source
(LiAlH4, NaBH4, NaBH3CN) for the simple reduction of halides. But to
avoid the use of tin, other metal complexes based on gallium,8 in-
dium,15 titanium,9c,16 zirconium,10 chromium,17 cobalt18 and nickel19
associated with a reducing agent such as Red-Al or sodium borohy-
dride have proven to be effective for such reductive transformations.
Frequently, it has been proposed that under reducing conditions
transition metal hydride species are formed, acting as the mediator
for reductive radical reactions. However, the in situ formation of the
hydrido transition metal species, and the subsequent reaction
mechanism have both remained largely unexplored.
Of particular interest was the reactivity of iron for mediating
reductive radical reactions since iron is abundant, cheap and has
a low toxicity. Intermolecular radical reactions mediated by iron
have been established.20 However interestingly, there are consid-
erably fewer examples of related iron-mediated reductive intra-
molecular radical reactions. The first example by Meunier reported
the radical cyclization of 5-hexenyl bromide involving a single
electron transfer process with a stoichiometric amount of an iron
* Corresponding authors. E-mail addresses: louis.fensterbank@upmc.fr
(L. Fensterbank), anny.jutand@ens.fr (A. Jutand), cyril.ollivier@upmc.fr (C. Ollivier).
y
Current address: School of Chemistry, University of Lincoln, Joseph Banks
Laboratories, Lincoln, LN6 7DL, UK.
http://dx.doi.org/10.1016/j.tet.2016.08.039
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039

2
S.H. Kyne et al. / Tetrahedron xxx (2016) 1e11
(II)dGrignard species, Cp(DIPHOS)FeMgBr.21 Later, Oshima pro-
posed catalytic conditions with the use of 5 mol % ferrous chloride
and a Grignard reagent for the radical cyclization of iodo- and
bromoalkenes to unsaturated or partially reduced tetrahydrofurans
depending on the nature of the Grignard compound.22
FeIICl2(dppe)2
NaBH4
+ 1e-
3
NaBH4
HFeICl(dppe)2
-
HFeIICl(dppe)2
To achieve a more effective system for catalytic reduction and
thus avoid the formation of unsaturated products, a preliminary
communication reported the reductive radical reactions of alkyl-
halides catalyzed by iron(II) dichloride (10 mol %) in the presence of
sodium borohydride in acetonitrile (Scheme 1).23 Direct reduction
occurred in good yields, and unsaturated primary and secondary
systems bearing either iodide or bromide radical precursors effi-
ciently provided the corresponding products of tandem cyclization/
reduction reactions.
5
4
I
I
O
O
O
O
1a
NaBH4
FeCl2 (10 mol %)
NaBH4 (1.5 equiv)
H
X
Pathway A
H
H
H
H
MeCN (0.5 M)
50 °C, 16 h
O
O
O
O
H
2a, 73%, dr 87:13
2a, 70%, dr 85:15
1a, X = I
1b, X = Br
O
O
O
O
H
2a
I
H
FeCl2 (10 mol %)
NaBH4 (1.5 equiv)
Br
O
O
Pathway B
NaBH4
H
MeCN (0.5 M)
50 °C, 16 h
2b
Ph Ph
Ph Ph
Scheme 2. Generation and reactivity of the anionic hydridoiron(I) active species
([HFeICl(dppe)2]ꢀ) (5) for the reductive cyclization of 1a via Pathway A (major) and
Pathway B (iodine atom transfer. Note: Initiation by NaBH4 alone is also possible).
B, 78%
A
Scheme 1. Iron(II)-mediated tandem cyclization/reduction reactions in the presence of
NaBH4 (previous work).23
Iron source (X mol%)
H
To gain more insight into the mechanism of these reactions, the
Br
O
Hydride source (X mol%)
iron(II)
precatalyst
[FeCl2(dppe)2]
(3)
(dppe¼1,2-
bisdiphenylphosphinoethane) was selected as a probe due to the
stabilizing effect imparted by the bis-phosphine ligands. Electro-
chemical studies on 3 in the presence of sodium borohydride
clearly identified the formation of an iron monohydride
[HFeIICl(dppe)2] (4) that upon reduction generated the anionic
hydridoiron(I) [HFeICl(dppe)2]ꢀ (5). The catalytic activity of this
species has been demonstrated by an increase of the observed re-
duction current of [HFeIICl(dppe)2] (4) with the number of iodoa-
cetal 1a equivalents (Scheme 2).
MeCN (0.5 M)
50 °C, 16 h
O
O
O
H
1b
2a
Scheme 3. Iron(II)-mediated 5-exo-trig radical cyclization of unsaturated b-bromoa-
cetal 1b in the presence of NaBH4.
2.1.1. Influence of the iron source. A variety of iron salts and iron
complexes were screened under the general reaction conditions
shown in Scheme 3 and a selection of the results are shown in
Table 1 (see the Supplementary data for the complete table of
results for bromoacetal 1b, and results for iodoacetal 1a). The
bromoacetal 1b was found to be more sensitive to the iron source
than the corresponding iodoacetal 1a: for example, while iodoa-
cetal 1a reacted well (62e65% yield) in the presence of iron(II)
dichloride (98%), no reaction was observed with bromoacetal 1b
(Entry 1) or iron(III) trichloride (98%, Entry 4). In contrast, reaction
with high purity iron(II) and (III) chlorides proceeded in similar,
good yields (Entries 2 and 5), interestingly the results with high
purity iron(II) dichlorides were dependent on the commercial
However during the preparative electrolysis of iodide 1a (in the
absence of NaBH4), the formation of the bicyclic byproduct 2b
resulting from iodine atom transfer (ca. 10% yield) was observed.
This could suggest, as also recently proposed by Curran and
Studer,24 that under the standard conditions given in Scheme 1, the
cyclization process could involve iodine atom transfer, followed by
nucleophilic substitution of the resulting primary iodide with the
borohydride to give 2a (Scheme 2, pathway B). In sharp contrast,
the corresponding bromide (1b) is presumably not sufficiently re-
active to undergo the equivalent bromine atom transfer, yet the
reductive cyclization reaction takes place in similar yields from this
substrate.25 It is even more difficult to conceive a bromine atom
transfer taking place in the cyclization of the primary bromide A to
give B as shown in Scheme 1. To follow up on the mechanistic in-
vestigations carried out on 1a, analysis was extended to the bro-
moacetal derivative 1b. These studies have provided new insights
into this interesting transformation.
Table 1
Reactivity of 1b in the presence of [Fe] or [Cu] (10 mol %) and sodium borohydride
(150 mol %)a
Entry
[M], M¼Fe, Cu
Purity%
Yield% (2a)
1
2
3
4
5
6
7
FeCl2
FeCl2
FeCl2
FeCl3
98
0
b
99.99
99.99
98
78
39
0
80
78
14
c
2. Results
FeCl3
99.99
N.D.
99.995
[FeCl2(dppe)2] (3)
CuCl2
2.1. Influence of reaction parameters
a
Reaction conditions: 1b (1.0 mmol, 0.5 M CH3CN), [M] M¼Fe, Cu (10 mol %),
To complement the previous study, the influence of the iron and
hydride sources and their respective loadings on the cyclization of
bromoacetal 1b was investigated as described in Scheme 3.
NaBH4 (150 mol %), 50 ꢁC, 16 h.
b
Commercial supplier: SigmaeAldrich.
Commercial supplier: Alfa Aesar.
c
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039

S.H. Kyne et al. / Tetrahedron xxx (2016) 1e11
3
supplier as shown in Entries 2 and 3 (see Supplementary data). A
78% yield was obtained from the phosphine dichloro complex
[FeIICl2(dppe)2] (3), confirming that the ligand could be employed
without any adverse effect on the reaction outcome (Entry 6).
Copper(II) dichloride also mediated the reaction with bromoacetal
1b however the yield was very low (Entry 7). In this case, a new
side product (14% yield) was also observed arising from the direct
reduction of the substrate.
from the reaction may assist to drive the reaction to completion. In
the case of sodium and lithium borohydride, the co-product of the
reaction (sodium or lithium bromide) is insoluble in acetonitrile.
2.1.3. Iron(II) dichloride loading. It is desirable to decrease the
iron(II) and (III) chloride (99.99%) loading for the reaction of bro-
moacetal 1b (Table 3). The loading of both iron salts could be de-
creased to 5 mol % and a comparable product yield was obtained
(Entries 1 and 3). Any further decreases in iron loading rapidly
resulted in incomplete conversion and subsequent loss in yield
(Entry 2 and 4).
Following these results, the differences in reactivity of the
iron(II) dichloride sources were investigated in more detail. Sam-
ples of FeCl2 (99.99%) and FeCl2 (98%) purity were studied first by
high resolution ESI mass spectrometry. Spectra were collected in
positive-ion mode at þ50 V and þ120 V cone voltage, and negative-
ion mode at ꢀ50 V and ꢀ80 V cone voltage. No significant differ-
ences in the two samples were observed in either mode (see
Supplementary data). These samples were analyzed by ICP mass
spectroscopy and full details of the results are reported in the
Supplementary data. The samples were found to be almost iden-
tical and no large impurities were found in either. The FeCl2
(99.99%) sample contained an iron purity measured at 99.98%,
while the FeCl2 (98%) was found to contain a slightly higher purity,
at 99.99%. The next most significant results were that of manganese
and nickel which were detected at 0.0079% and 0.0038% for FeCl2
(99.99%), and 0.0061% and 0.0070% for FeCl2 (98%), respectively,
most elements were below detection levels. Therefore, there is not
a major elemental impurity in the iron source hindering reaction.
However, these results do not preclude the possibility that an anion
present in one of the samples has a significant impact on the out-
come of the reaction.
Table 3
Reactivity of 1b in the presence of [Fe] (X mol %) and sodium borohydride (150 mol
%)a
Entry
[Fe]
mol %
Yield% (2a)
1
2
3
4
FeCl2
FeCl2
FeCl3
FeCl3
5
2
5
2
67
17
74
13
a
Reaction conditions: 1b (1.0 mmol, 0.5 M CH3CN), [Fe] (X mol %), NaBH4
(150 mol %), 50 ꢁC, 16 h.
2.1.4. Sodium borohydride loading. It is desirable to decrease the
sodium borohydride loading for the reaction of bromoacetal 1b to
improve the potential substrate scope (Table 4). Employing iron(II)
dichloride (99.99%) revealed that decreasing the sodium borohy-
dride loading resulted in a drop in product yields. The yield was
respectable in the presence of 100 mol % and 75 mol % sodium
borohydride (Entries 2 and 3), however attempts to decrease the
loading further resulted in incomplete reaction and low isolated
yield (Entry 4). Similar conditions were tested for reactions with
iron(III) trichloride (99.99%). A comparable yield was obtained from
100 mol % sodium borohydride (Entry 6) as under our standard
reaction conditions. However, decreasing the loading any further
once again resulted in incomplete reactions and low isolated yield
(Entries 7 and 8).
2.1.2. Reducing agent. The suitability of different reducing agents
for the reaction of bromoacetal 1b in the presence of iron(II)
dichloride (99.99%) was investigated (Table 2). Alternative coun-
terions to sodium were first tested. While reduction with lithium
borohydride (Entry 2) gave a 70% yield of bicyclic product 2a, the
corresponding potassium reagent (Entry 3) did not. Milder sodium
based borohydrides were tested without success (Entries 4e6). The
reaction proceeded with tetrabutylammonium borohydride, in
a 59% yield (Entry 7). In the presence of iron(III) trichloride (99.99%)
similar yields were obtained with NaBH4 and nBu4NBH4 (Entries 9
and 11) however in the presence of LiBH4 (Entry 10) the yield de-
creased to 31% without any obvious explanation.
These results show that reducing agents of lower reactivity, for
example, cyanoborohydride, are not effective reagents for the re-
action. Mayr and co-workers have established a hydride donor
scale, which reveals that amine-boranes have comparable re-
activity to cyanoborohydrides, while silanes are significantly less
active.26 Therefore neither of these reagents was tested in our
study. Our results suggest that formation of an insoluble co-product
Table 4
Reactivity of 1b in the presence of [Fe] (X mol %) and sodium borohydride (X mol %)a
Entry
[Fe]
mol %
NaBH4 mol %
Yield% (2a)
1
2
3
4
5
6
7
8
FeCl2
FeCl2
FeCl2
FeCl2
FeCl3
FeCl3
FeCl3
FeCl3
10
10
10
10
5
5
5
5
150
100
75
78
65
65
42
80
78
55
43
50
150
100
75
50
a
Reaction conditions: 1b (1.0 mmol, 0.5 M CH3CN), [Fe] (X mol %), NaBH4 (X mol
%), 50 ꢁC, 16 h.
In conclusion the optimization studies have revealed the best
experimental conditions to be: iron(II) dichloride (99.99%,10 mol %)
in the presence of sodium borohydride (150 mol %) or iron(III) tri-
chloride (99.99%, 5 mol %) in the presence of sodium borohydride
(100 mol %). Reactivity of the substrate was observed in the pres-
ence of both iron(II) and iron(III) chlorides and therefore the initial
oxidation state of the iron source is not critical to the reaction
outcome. Indeed it appears that the oxidation state of the catalyt-
ically active species is available from both sources, as explored in
detail in Section 2.3 (vide infra).
Table 2
Reactivity of 1b in the presence of [Fe] (10 mol %) and reducing agent (X mol %)a
Entry
[Fe]
Reducing agent
mol %
Yield% (2a)
1
2
3
4
5
6
7
8
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl3
FeCl3
FeCl3
NaBH4
LiBH4
KBH4
NaBH3CN
NaBH3CN
NaBH(OAc)3
nBu4NBH4
nBu4NBH3CN
NaBH4
150
150
150
150
600
150
150
150
150
150
150
78
70
0
0
0
0
59
0
80
31
59
9
10
11
2.2. Reaction scope
LiBH4
nBu4NBH4
a
To explore the potential of these catalytic systems, additional
unsaturated halides and phenylseleno derivatives were tested.
Reaction conditions: 1b (1.0 mmol, 0.5 M CH3CN), [Fe] (10 mol %), reducing
agent (X mol %), 50 ꢁC, 16 h.
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039

4
S.H. Kyne et al. / Tetrahedron xxx (2016) 1e11
2.2.1. Unsaturated
riety of unsaturated
b
-haloacetals and primary alkyl bromides. A va-
-haloacetals (1cee) and unsaturated primary
alkyl bromides (1feh) substrates were reacted under the standard
reactions conditions shown in Scheme 4. The unsaturated -hal-
give the cyclic product. Three different substrates 1f, 1g, and 1h
were tested and furnished the respective five-membered rings in
39%, 53% and 60% yields (Scheme 4).
b
b
oacetals were reacted with iron(II) and iron(III) chloride to verify
whether the oxidation state impacted the reaction. Results are
given in Table 5.
2.2.2. Vinyl halides. The reaction system was efficient at generating
alkyl radicals from reactive halides (iodide and bromide). Next, the
generation of vinyl radicals29 starting from the corresponding io-
dide or bromide was investigated to effect 5-exo-trig cyclization
reactions. The high reactivity of vinyl radicals has been exploited in
cascade radical reactions to build multiple new bonds in a single
step, giving rise to polycyclic natural product scaffolds.30 It has also
been used to achieve high degrees of stereocontrol in radical
reactions.31
Diethyldiallyl malonates 6a and 6b were screened under the
standard reaction conditions with both iron(II) and iron(III) chlo-
ride and further experiments were conducted based on these re-
sults. Two products could be identified from these reactions: the
cyclized product (7) and the product (8) arising from direct re-
duction of the substrate (Scheme 5).
R
[Fe] (5-10 mol%)
NaBH4 (100-150 mol%)
R'
R
H
X
R'
MeCN (0.5 M)
50 °C, 16 h
O
O
O
O
H
1c, X = Br, R, R' = Me
1d, X = Cl, R, R' = H
1e, X = SePh, R, R' = H
2a, R, R' = H
2c, R, R = Me
Br
[Fe] (X mol%)
Reducing agent (X mol%)
EtO2C CO2Et
EtO2C CO2Et
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
1f
2f, 39%
X
+
R
FeCl2 (10 mol%)
NaBH4 (150 mol%)
R
MeCN (0.5 M)
50 ºC, 16 h
Br
6a, X = I
6b, X = Br
7a, R = H
7b, R = D
8a, R = H
8b, R = D
N
Ts
N
MeCN (0.5 M)
50 °C, 16 h
Ts
Scheme 5. Iron mediated cyclization and reduction of diethyldiallyl malonates.
1g
2g, 53%
Br
The reactivity of 2-iodo-4,4-(dicarbethoxy)-1,6-heptadiene (6a)
was screened first and the results are given in Table 6. In the
presence of iron(II) dichloride and sodium borohydride conversion
was complete (Entry 1). A 50% yield of products was obtained as an
inseparable mixture of cyclized 7a and directly reduced product 8a.
The reduced product was favored, with a 12:88 ratio of products
(7a:8a) estimated by 1H NMR. In an attempt to favor cyclization,
sodium borodeuteride was employed which is supposed to have
a slower rate of deuterium delivery than the corresponding hy-
dride.32 Indeed, selectivity for the cyclized product 7b increased,
albeit not significantly with a 28:72 ratio of 7b:8b obtained (Entry
2). Also to favor cyclization, the reaction was tested in the presence
of sodium cyanoborohydride, however once again this reagent was
not an effective reducing agent for this reaction (Entry 3).
Ph
Ph
Ph
1h
O
O
Ph
2h, 60%
Scheme 4. Iron(II)-mediated 5-exo-trig radical cyclization of unsaturated b-hal-
oacetals and unsaturated primary alkyl bromides in the presence of NaBH4.
Table 5
Reactivity of haloacetal 1 in the presence of [Fe] (X mol %) and sodium borohydride
(X mol %)a
Entry
Acetal
[Fe]
mol %
NaBH4 mol %
Yield% (2) (1 recovered%)
1
2
3
5
6
7
8
1c
1c
1c
1d
1d
1e
1e
FeCl2
FeCl3
(3)
FeCl2
FeCl3
FeCl2
FeCl3
10
5
10
10
5
150
100
150
150
100
150
100
55
23 (25)
60
0 (59)
0 (>95)
0
Table 6
10
5
Reactivity of iodoacetal 6a in the presence of [Fe] (X mol %) and reducing agent (X
0 (>95)
mol %)a
a
Reaction conditions: 1 (1.0 mmol, 0.5 M CH3CN), [Fe] (X mol %), NaBH4 (X mol %),
50 ꢁC, 16 h.
Entry
[Fe]
mol %
Reducing agent
mol %
Yield% (ratio 7:8)
1
2
3
FeCl2
FeCl2
FeCl2
FeCl3
FeCl3
FeCl3
(3)
10
10
10
5
5
10
10
NaBH4
NaBD4
NaBH3CN
NaBH4
NaBD4
150
150
150
100
100
100
150
50 (12:88)b
42 (28:72)b
0
Previously 3-methyl-2-(2-propenoxy)-3-iodotetrahydropyran
was shown to undergo cyclization (51% yield).23 Similarly, 3-
methyl-2-(2-propenoxy)-3-bromo-tetrahydropyran (1c)7 was
converted cleanly to the corresponding bicyclic product (2c)7 by
iron(II) dichloride and [FeCl2(dppe)2] (3) (Entries 1 and 3). In con-
trast only a 23% yield was observed for the reaction with iron(III)
trichloride (Entry 2).
In contrast to iodide and bromide substrates, less activated
haloacetal radical substrates were not reactive using either iron(II)
or iron(III) chloride. Only substrate was recovered from the reaction
with 2-allyloxy-3-chlorotetrahydropyran (1d)27 (Entries 5 and 6).
Reaction with 2-allyloxy-3-(phenylseleno)tetrahydropyran (1e)28
resulted in significant substrate degradation, however no conver-
sion to the product was observed in these reactions either (Entries 7
and 8).
4b
5c
6
38 (30:70)b
60(19:81)c
0
NaBH3CN
NaBH4
7
40 (0:100)
a
Reaction conditions: 6a (1.0 mmol, 0.5 M in CH3CN), [Fe] (X mol %), reducing
agent (X mol %), 50 ꢁC, 16 h.
b
Products not separable by column chromatography.
Substrate and product not separable by column chromatography; Yields are
c
estimated based on the isolated yield and integration of the 1H NMR.
Iron(III) trichloride mediated the reaction in the presence of
sodium borohydride. As shown in Entry 4, a mixture of products
was again obtained favoring the uncyclized product 8a, with
a 30:70 ratio of 7a:8a. Conversion was incomplete in the presence
of sodium deuteride (Entry 5). Interestingly in the presence of
iron(III) trichloride and sodium cyanoborohydride, the reaction
failed completely (Entry 6). Finally, the phosphine dichloroiron
Primary alkyl radicals were generated from the corresponding
bromides under the optimized conditions, subsequently the pri-
mary radical underwent 5-exo-trig cyclization and reduction to
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039

S.H. Kyne et al. / Tetrahedron xxx (2016) 1e11
5
complex (3) mediated the reaction, with complete selectivity for
the directly reduced product 8a (Entry 7).
The mixture of products arising from the reaction of 2-iodo-4,4-
(dicarboethoxy)-1,6-heptadiene (6a) contrasts with the selectivity
for cyclization observed in the reaction of 6-bromo-4,4,diphe-
nylhex-1-ene (A). These contrasting results may originate from
organometallic mediated heterolytic pathways.
The
corresponding
2-bromo-4,4-(dicarboethoxy)-1,6-
heptadiene (6b)33 was screened under similar conditions to the
iodide 6a, and the results are given in Table 7. Unlike the iodide,
only the directly reduced product 8 was observed in any of these
reactions, never the cyclized product 7.
Table 7
Reactivity of bromoacetal 6b in the presence of [Fe] (X mol %) and reducing agent (X
mol %)a
Entry
[Fe]
mol %
Reducing agent
mol %
Yield% (8)
Fig. 1. Cyclic voltammetry performed at a gold disk electrode (d¼1 mm) at 22 ꢁC in
acetonitrile containing nBu4NBF4 (0.3 M) as the supporting electrolyte at a scan rate of
5 V sꢀ1: (a) Reduction of FeIIICl3 (4 mM); (b) Reduction of FeIIICl3 (4 mM) in the
presence of dppe (2 equiv); (c) Reduction of FeIIICl3 (4 mM) and dppe (2 equiv) in the
presence of NaBH4 (1 equiv); (d) Reduction of FeIIICl3 (4 mM) and dppe (2 equiv) in the
presence of NaBH3CN (8 equiv).
1
2
3
4
5
6
7
FeCl2
FeCl2
FeCl2
FeCl3
FeCl3
FeCl3
(3)
10
10
10
5
5
10
10
NaBH4
NaBD4
NaBH3CN
NaBH4
NaBD4
150
150
150
100
100
100
150
58
65b
0
65b
68b
0
NaBH3CN
NaBH4
49
When 1 equiv of NaBH4 was added to a mixture of [FeIIICl3]
(4 mM) and dppe (2 equiv) in acetonitrile, the reduction peak of
[FeIIICl3] (R1) partly decreased (Fig. 1c). The reduction peak at R2
corresponding to [FeIICl2(dppe)2] (3) was once again observed
(compare Fig. 1b and c). A new reduction peak was observed at
a
Reaction conditions: 6b (1.0 mmol, 0.5 M in CH3CN), [Fe] (X mol %), reducing
agent (X mol %), 50 ꢁC, 16 h.
b
Substrate and product not separable by column chromatography; yield not
determined, approximate yield given based on crude 1H NMR.
EP ¼ꢀ2.05 V (Fig. 1c). The peak at R3 was assigned to the hydri-
Iron(II) dichloride and the phosphine dichloroiron complex (3)
mediated the reaction giving the directly reduced product 8b in
58% and 49% yields, respectively (Entries 1 and 7). Conversion
was incomplete when sodium borohydride was employed with
iron(III) chloride (Entry 4) and sodium borodeuteride with either
iron(II) or iron(III) chloride (Entries 2 and 5). No reactivity was
observed in the presence of sodium cyanoborohydride (Entries 3
and 6). Only substrate was recovered from these reactions in 69%
and 49% yields, respectively, indicating that some degradation
had occurred.
R3
doiron(II) complex [HFeIICl(dppe)2] (4) by comparison with an
authentic sample of the known complex (EP¼ꢀ2.08 V).34 One
equivalent aliquots of NaBH4 were successively added to the mix-
ture to determine the stoichiometry required to completely reduce
iron(III). The reduction peak at EP ¼þ0.04 V completely dis-
R1
appeared upon addition of 4 equiv of NaBH4. At the same time, the
reduction peak at EP ¼ꢀ1.42 V was observed to decrease while the
R2
reduction peak at EP ¼ꢀ2.03 V increased. This confirms that the
R3
chemical reduction of [FeIIICl3] by NaBH4 generates an iron(II)
species which leads to formation of [HFeIICl(dppe)2] (4) after re-
action with NaBH4.
2.3. Mechanistic studies: formation of the hydridoiron
precatalyst
For interest, the ability of sodium cyanoborohydride to reduce
iron(III) trichloride to the hydridoiron(II) complex 4 was tested. One
equivalent aliquots of NaBH3CN were added to a mixture of
[FeIIICl3] (4 mM) and dppe (2 equiv) in acetonitrile. The reduction
peak of [FeIIICl3] at R1 completely disappeared after the addition of
8 equiv of NaBH3CN (Fig. 1d). The reduction peak corresponding to
R2 was hardly observed, whereas the reduction peak at
In the preliminary report, electrochemical studies formed the
basis of the proposed reaction mechanism. This technique, along
with additional information obtained from multi-nuclear NMR
experiments has provided us with a more complete understanding
of the reaction system presented herein and the subsequent
mechanistic implications. These results are discussed below.
EP ¼ꢀ2.07 V was, confirming the formation of [HFeIICl(dppe)2] (4).
R3
These results suggest that iron(III) trichloride in the presence of
1,2-bis(diphenylphosphino)ethane (dppe) is able to undergo re-
duction by a strong reducing agent to form the hydridoiron(II)
complex [HFeIICl(dppe)2] (4). Our previous studies revealed that
[FeIICl2] in the presence of dppe reacts with NaBH4 to form the
same complex. In conclusion, the cyclization reaction mediated by
either iron(II) or iron(III) chloride occurs via an identical
mechanism.
These studies successfully characterized the formation of the
hydridoiron complex (4) by CV in the reaction of either iron(II) or
iron(III) chloride with sodium borohydride in the presence of the
dppe ligand. The next goal was to observe the formation of this
species in situ by spectroscopic techniques, then to study its
reactivity.
2.3.1. Cyclic voltammetry. First, it was necessary to establish
whether iron(II) and iron(III) chloride were acting via the same
mechanism. To achieve this, the reaction with [FeIIICl3] was studied
via cyclic voltammetry (CV) to compare with previous results for
the reaction mediated by [FeIICl2].23
The CV of [FeIIICl3] in acetonitrile (4 mM) exhibited a reversible
reduction peak at EP ¼þ0.04 V versus the standard calomel elec-
R1
trode (SCE; Fig. 1a). An oxidation peak characteristic of an elec-
trogenerated iron(II) species was observed on the reverse scan (O1,
Fig. 1a). Two equivalents of 1,2-bis(diphenylphosphino)ethane
(dppe) ligand were added to [FeIIICl3] in acetonitrile (4 mM) and
a new reduction peak was observed at EP ¼ꢀ1.45 V (Fig. 1b). This
R2
peak was assigned to [FeIICl2(dppe)2] (3) by comparison with an
authentic sample (EP¼ꢀ1.47 V). [FeIIICl3] was still present in the CV
(R1, Fig. 1b) which indicates that [FeIIICl3] does not react directly
with dppe, but a reaction takes place with the electrogenerated
iron(II) species to generate [FeIICl2(dppe)2] (3).
2.3.2. Synthesis and characterization of trans-[HFeCl(dppe)2]
(4). The hydridoiron complex (4) was synthesized following the
procedure reported by Sacco and co-workers, except that
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039

6
S.H. Kyne et al. / Tetrahedron xxx (2016) 1e11
anhydrous iron(II) dichloride was employed, giving a pink-red solid
in 49% yield (Scheme 6).34
2.3.3.2. From
trans-dichlorodi{1,2-bis(diphenylphosphino)eth-
ane}iron (3) (0.005 M). The stability of the phosphine dichloroiron
complex (3) to the reaction conditions was next investigated by
NMR. Interestingly, in the absence of sodium borohydride the
complex was no longer observed after 4 h at room temperature or
2 h at 50 ꢁC (Conditions A and B, respectively). The mechanistic
implications of this finding are discussed in detail, vide infra. A 31
P
{1H} signal at
d
CD3CN¼51.0 ppm corresponds to trans-
Scheme 6. Synthesis of [HFeCl(dppe)2] (4).
[FeCl2(dppe)2] (3). The 31P{1H} signal at
d
CD3CN¼74.9 ppm ob-
served in both cases was tentatively assigned to
a [Fe(NCCH3)2(dppe)2]Cl2 complex, by analogy with a report from
DuBois and Miedaner.38 In their synthesis of trans-
[Fe(NCCH3)2(dppe)2](BF4)2 they reported that the crude reaction
mixture consisted of two products, with 31P{1H} signals observed at
NMR spectra recorded in chloroform-d matched literature re-
ports of the complex and confirmed the trans geometry.34,35 In
acetonitrile-d3, the 1H NMR signal for the H ligand on iron was
shifted slightly upfield compared to the spectrum in chloroform-
CD3CN¼ꢀ29.0 ppm, quintet, 2JP-H¼49.1 Hz vs
d
CD3CN¼74.2 ppm (minor) and
d
CD3CN¼50.6 ppm (major) in
d
d
(d
2
acetonitrile-d3. The later corresponded to the trans product which
they were able to characterize, the minor complex was not isolated.
Two related compounds, trans-[Fe(NCCH3)2(dppe)2](ClO4)2 and
trans-[Fe(NCCH3)2(depe)2]BPh4, have been reported in the litera-
ture but neither were characterized by NMR spectroscopy.39
To verify that [HFeCl(dppe)2] (4) was formed from
[FeCl2(dppe)2] (3) in the presence of reducing agent, the same se-
ries of NMR reactions as described above was repeated starting
from [FeCl2(dppe)2] (3). After 1 h the phosphine dichloro complex
(3) was completely consumed in the presence of sodium borohy-
dride and 1,2-bis(diphenylphosphino)ethane bisborane (10,
CDCl3¼ꢀ26.8 ppm, quintet, JP-H¼49.1 Hz) while no such effect
was observed in the 31P{1H} NMR, with the signal observed at
2
d¼81.5 ppm (doublet, JP-H¼49.1 Hz) for both solvents.
2.3.3. Formation of [HFeCl(dppe)2] (4) by 1H and 31P{1H} NMR. The
formation and subsequent fate of [HFeCl(dppe)2] (4) in situ was
followed by 1H and 31P{1H} NMR spectroscopy under a variety of
conditions (Scheme 7). Reactions were set up as follows: a mixture
of the appropriate iron complex (0.005 mmol) and sodium boro-
hydride (0.0 mmol, 0.015 mmol or 0.17 mmol) were prepared in
a screw cap NMR tube before acetonitrile-d3 (1.0 mL) was added
under argon. The progress of the reaction was monitored via al-
ternating 1H and 31P{1H} NMR spectra (vide infra and Supple-
d
CD3CN¼18.3 ppm) was formed in each case as observed in the 31
P
{1H}
NMR
spectra.
The
hydridoiron
complex
(4,
mentary data for full details). The following results refer to the 31
{1H} NMR spectra observed.
P
d
CD3CN¼84.0 ppm) was formed after 1 h in the presence of
1500 mol % sodium borohydride (Conditions C and D). The complex
was still present in the reaction after 17 h (Conditions C, D and F).
1,2-bis(diphenylphosphinyl)ethane (10,
once again observed (Conditions C and F) and was the major
product at 50 ꢁC. Free dppe (
d
CD3CN¼32.9 ppm) was
d
CD3CN¼ꢀ12.6 ppm) was observed at
50 ꢁC under conditions F, indicating that elevated temperature also
causes the iron complexes to degrade to some extent. Fig. 2 illus-
trates the 31P{1H} NMR spectra for: (a) the reaction mixture from
conditions C, after 1 h; (b) the reaction mixture from conditions C,
after 17 h; (c) an authentic sample of the hydridoiron complex (4);
(d) an authentic sample of dppe; (e) an authentic sample of 1,2-
bis(diphenylphosphine oxide)ethane (10); (f) an authentic sample
of 1,2-bis(diphenylphosphino)ethane bisborane (11); (g) an au-
thentic sample of 1,2-bis(diphenylphosphino)ethane bisborane (11)
after heating to 50 ꢁC for 17 h.
Scheme 7. Formation of [HFeCl(dppe)2] (4) under various conditions.
2.3.3.1. From iron(II) dichloride (0.005 M) and dppe ligand
(2.0 equiv). The formation of [HFeCl(dppe)2] (4) in the presence of
excess sodium borohydride directly from FeCl2 and 2 equiv of dppe
was first investigated. After 1 h [HFeCl(dppe)2] (4) was observed in
2.3.3.3. Trans-hydridochlorodi{1,2-bis(diphenylphosphino)eth-
ane} iron (4) (0.005 M). The stability of the hydridoiron complex (4)
to the reaction conditions was explored employing the series of
NMR reactions detailed in Scheme 7. In the absence of sodium
borohydride the complex was stable even for 18 h at 50 ꢁC (Con-
ditions B). In the presence of sodium borohydride, the hydridoiron
the 31P{1H} NMR spectrum at
dppe ligand (
Scheme 7 (Conditions AeF). [FeCl2(dppe)2] (3,
d
CD3CN¼84.0 ppm, along with free
CD3CN¼ꢀ13.7 ppm) under all the conditions tested in
CD3CN¼51.0 ppm)
d
d
was never detected in this series of reactions. Reactions at room
temperature were fairly clean (Conditions C and D). Additional sig-
nals were detected when the reaction was heated to 50 ꢁC (Condi-
tions E and F). Each of these species was positively identified by first
synthesizing authentic samples of postulated products, and taking
the NMR spectra in acetonitrile-d3. The signals observed upon
heating (Scheme 7) were compared to the spectra of authentic
complex (4,
with free dppe (
CeF) as observed in the 31P{1H} NMR spectra. At room temperature
the hydridoiron complex (4,
d
CD3CN¼84.0 ppm) was still present after 1 h, along
d
CD3CN¼ꢀ13.7 ppm) in each case (Conditions
d
CD3CN¼84.0 ppm) was observed
after 17 h (Conditions C and D), however at elevated temperature
this species disappears after 9e12 h (Conditions E and F, re-
spectively). Therefore, the hydridoiron complex (4) is sufficiently
stable to act as the precatalyst for the length of the reaction, but not
for longer periods. 1,2-Bis(diphenylphosphino)ethane bisborane
samples to confirm their identity. 31P{1H} signals at
and 90.7 ppm observed in Conditions E correspond to the cis-dihy-
dridoiron complex [H2Fe(dppe)2] (9).35 31P{1H} NMR signal at
CD3CN¼31.8 ppm was identified as 1,2-bis(diphenylphosphine
oxide)ethane (10)36 presumably formed by traces of oxygen present
in the reaction (Conditions and F) and signal at
CD3CN¼18.3 ppm corresponded to 1,2-bis(diphenylphosphino)
ethane bisborane (11)37 (Conditions D, E and F).
d
CD3CN¼101.7
A
(11,
d
CD3CN¼18.7 ppm) was detected in most cases, however 1,2-
d
bis(diphenylphosphinyl)ethane (10,
detected only at elevated temperature (Conditions E and F), in none
of these reactions were these observed as the major products. The
d
CD3CN¼32.9 ppm) was
E
a
d
dihydridoiron complex (9,
only at room temperature (Conditions C and D).
d
CD3CN¼101.3, 90.4 ppm) was detected
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039

S.H. Kyne et al. / Tetrahedron xxx (2016) 1e11
7
(a)
[FeCl2(dppe)2] (3), NaBH4 (1500 mol%), 50 ºC, t = 1 h.
(b)
[FeCl2(dppe)2] (3), NaBH4 (1500 mol%), 50 ºC, t = 17 h.
(c) [HFeCl(dppe)2] (4).
(d) dppe.
(e) 1,2-bis(diphenylphosphine oxide)ethane (10).
(f)
1,2-bis(diphenylphosphino)ethane bisborane (11).
(g) 1,2-bis(diphenylphosphino)ethane bisborane (11), 50 ºC.
110 105 100
95
90
85
80
75
70
65
60
55
50
45
f1 (ppm)
40
35
30
25
20
15
10
5
0
-5
-10
-15
-20
Fig. 2. Reaction of [FeCl2(dppe)2] (3) in the presence of NaBH4 (1500 mol %) at 50 ꢁC. 31P{1H} NMR spectra of: (a) reaction mixture (1 h, conditions E); (b) reaction mixture (17 h,
conditions E); (c) [HFeCl(dppe)2] (4); (d) dppe; (e) dppe oxide (10); (f) dppe boron trihydride (11); and (g) dppe boron trihydride (11, 50 ꢁC, 17 h).
Table 8
In conclusion, this series of experiments has shown that
Reactivity of 1a in the presence of [HFeCl(dppe)2] (4) (10 mol %) and reducing agent
[HFeCl(dppe)2] (4) is formed in situ starting from either
[FeCl2(dppe)2] (3) or from free FeCl2 and dppe. In reactions at room
(X mol %)a
Entry
Reducing agent
mol %
Yield% (2a)
temperature and 1500 mol % reducing agent, [H2Fe(dppe)2] (9)
could also be observed as a minor product. [HFeCl(dppe)2] (4) was
found to be stable under the standard reaction conditions for more
than 9 h at 50 ꢁC and can therefore by used as a precatalyst with the
appropriate substrate.
1
2
3
4
5
6
NaBH4
NaBH4
NaBH4
NaBH4
NaBH3CN
NaBH3CN
150
100
20
10
600
10
6323
70
45
55
0
0
a
2.4. Reactivity of trans-hydridochlorodi{1,2-
bis(diphenylphosphino)ethane} iron precatalyst (4)
Reaction conditions: 1a (1.0 mmol, 0.5 M CH3CN), [HFeCl(dppe)2] (4) (10 mol %),
reducing agent (X mol %), 50 ꢁC, 16 h.
The reactivity of the [HFeCl(dppe)2] (4) was explored with
iodoacetal 1a as shown in Scheme 8.
incomplete. A milder reducing agent was once again tested for
reactivity, as it was possible that formation of [HFeCl(dppe)2] (4)
required a strong reducing agent with the subsequent hydrogen
atom transfer reaction proceeding in the presence of a weaker
agent. However, even in the presence of a large excess of sodium
cyanoborohydride, no reactivity was observed (Entries 5 and 6).
Next the reactivity of bromoacetal 1b with [HFeCl(dppe)2] (4)
was explored. In contrast to iodoacetal 1a, bromoacetal 1b was
completely unreactive and [HFeCl(dppe)2] (4) was unable to pro-
mote reaction irrespective of the catalyst loading (10e50 mol %),
the nature of the reducing agent (NaBH4 or NaBH3CN) or the
amount of reducing agent employed (10e150 mol %).
R
R
[HFeCl(dppe)2] (10 mol%)
Reducing agent (X mol%)
R'
X
H
R'
CH3CN (0.5 M)
50 ºC, Ar, 16 h
O
O
O
O
H
1a, X = I, R, R' = H
1b, X = Br, R, R' = H
1c, X = Br, R, R' = Me
2a, R, R' = H
2c, R, R' = Me
Scheme 8. Reaction of iodoacetal 1a in the presence of [HFeCl(dppe)2] (4) under
various conditions.
3-Methyl-2-(2-propenoxy)-3-bromotetrahydropyran (1c) was
reacted with [HFeCl(dppe)2] (4) in the presence of stoichiometric
NaBH4, however once again no reaction was observed.
The ability of [HFeCl(dppe)2] (4) to promote reduction of the
chloroacetal 1d, phenylselenoacetal 1e and the vinyl halides (6a
and 6b) used early in this study was tested. These reactions were
unsuccessful, and [HFeCl(dppe)2] (4) was not sufficiently active to
promote reaction with any of these substrates.
Table 8, Entries 1 and 2 show that 10 mol % 4 promotes the
complete reaction with iodoacetal 1a in the presence of stoichio-
metric loadings of NaBH4. One equivalent of NaBH4 furnished the
bicyclic product in comparable yield to the standard conditions
given in Scheme 2 (i.e., FeCl2/NaBH4 compared to Entry 2). The
amount of reducing agent employed in the reaction was decreased
further, as shown in Entries 3 and 4, substoichiometric loadings
were able to promote reaction, however conversions were
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039

8
S.H. Kyne et al. / Tetrahedron xxx (2016) 1e11
2.5. Mechanistic studies: role of substrate
reaction ceased. Therefore, there has only been sufficient current
passed to reduce the precatalyst and a small amount of substrate
prior to deactivation of the precatalyst 4. Bromoacetal 1b is less
reactive than the corresponding iodoacetal 1a, and thus the cata-
lytic cycle breaks down. The active catalyst (5) is likely to be un-
stable in solution and this result provides evidence to support
a competing degradation pathway for the active catalyst.
The difference in the observed reactivity between the iodo- and
bromacetal substrates raised an important question over the nature
of the precatalyst, the hydridoiron(II) complex (4), and the cata-
lytically active species that warranted detailed exploration.
2.5.1. Cyclic voltammetry. CV had been used effectively in the ear-
lier studies of [HFeIICl(dppe)2] (4) to prove the catalytic activity of
anionic hydridoiron(I) catalyst [HFeICl(dppe)2]ꢀ (5) in the presence
of iodoacetal 1a.23 Therefore electrochemistry was employed to
explore the reactivity of 2-allyloxy-3-bromotetrahydropyran (1b).
The reduction potential of bromoacetal 1b, analyzed as a solution in
acetonitrile, could not be measured as the substrate was not re-
duced before the solvent at ꢀ2.7 V at a scan rate of 5 V sꢀ1. As
shown in Fig. 3a, the reduction of [HFeIICl(dppe)2] (4) in the pres-
ence of iodoacetal 1a results in a lack of reversibility at a scan rate of
5 V sꢀ1. The reduction peak (R3) of [HFeIICl(dppe)2] (4) increases
noticeably with increasing aliquots of iodoacetal 1a (1e4 equiv,
Fig. 3a) confirming that [HFeICl(dppe)2]ꢀ (5) reacts with 1a to
2.6. Role of the substrate on anionic [HFeICl(dppe)2]L (5)
catalytic activity
The following reactions were carried out to help explain the
observed reactivity difference between bromoacetal 1b and
iodoacetal 1a in the presence of the precatalyst [HFeIICl(dppe)2] (4).
2.6.1. Competition reactions. Competition reactions were devised
to verify that the same catalytically active species was formed from
the reaction when the substrate was either iodoacetal 1a or bro-
moacetal 1b. In these reactions, 0.5 equiv of each substrate were
reacted with the different iron complexes used throughout this
study. As shown in Table 9, Entries 1 and 2, in the presence of FeCl2
or FeCl3 both substrates underwent 100% conversion and good
yields of the bicyclic product (2a) were obtained. However, in the
presence of [HFeCl(dppe)2] (4) bromoacetal 1b did not react (Entry
5). In this case bicyclic product 2a and bromoacetal 1b (72% re-
covery from 1b) were isolated from the reaction, while no iodoa-
cetal 1a could be detected. This provides further evidence that the
same catalytically active species is formed in the presence of either
substrate, however anionic [HFeICl(dppe)2]ꢀ (5) would not be suf-
ficiently active to promote reaction with bromoacetal 1b.
ꢀ
generate [1a]ꢂ and regenerate [HFeIICl(dppe)2] (4). Interestingly,
when the experiment was conducted with bromoacetal 1b, the
current peak (R3) was observed to only slightly increase (1e6 equiv,
Fig. 3b). However, this effect was considerably attenuated in the
presence of bromoacetal 1b, in comparison with iodoacetal 1a even
if the timescale of the CV was longer (0.5 V sꢀ1 vs 5 V sꢀ1). Based on
these results, the rate of reduction of 1b by the anionic
[HFeICl(dppe)2]ꢀ (5) is insufficient to maintain the catalytic cycle.
Table 9
Reactivity of haloacetal mixtures (1a and 1b) in the presence of [Fe] (X mol %) and
sodium borohydride (X mol %)a
Entry
Haloacetal
[Fe]
mol %
NaBH4 mol %
Yield% (1b recovered)
1
2
3
4
5
1a/1b
1a/1b
1a/1b
1a/1b
1a/1b
FeCl2
FeCl3
(3)
(3)
(4)
10
5
10
5
150
100
150
150
150
51
68
59
43
5
30 (36)
a
Reaction conditions: 1a (0.5 mmol, 0.5 M in CH3CN), 1b (0.5 mmol, 0.5 M in
CH3CN), [Fe] (X mol %), NaBH4 (X mol %), 50 ꢁC, 16 h.
Fig. 3. Cyclic voltammetry performed at a gold disk electrode (d¼1 mm) at 22 ꢁC in
acetonitrile containing nBu4NBF4 (0.3 M) as the supporting electrolyte: (a) Reduction
of [HFeIICl(dppe)2] (4 mM) at a scan rate of 5 V sꢀ1 in the presence of increasing
amounts of 1a (1 equiv, solid line; 2, 3, and 4 equiv, dashed lines); (b) Reduction of
[HFeIICl(dppe)2] (4 mM) at a scan rate of 0.5 V sꢀ1 in the presence of increasing
amounts of 1b (1 equiv, solid line; 2, 3, 4, 5 and 6 equiv, dashed lines).
2.6.2. Order of reagent addition. CV studies revealed that anionic
[HFeICl(dppe)2]ꢀ (5) exhibited quite poor reactivity with bromoa-
cetal 1b (Fig. 3b). If the active catalyst did not react rapidly with
substrate, then alternative reaction pathways might dominate the
reaction outcome. Indeed if the active species rapidly degraded or
underwent alternative side reactions, this would hinder reaction
with less activated substrates and result in poor product yield. To
explore this possibility further, the order of addition of each reagent
was studied sequentially on the reaction to observe if this had any
impact. Unfortunately, no dramatic differences were observed in
the reaction outcome (Table 10).
2.5.2. Preparative electrolysis. A preparative-scale electrolysis of
a solution of bromoacetal 1b (0.4 mmol) in the presence of
[HFeCl(dppe)2] (4) in acetonitrile was performed at the controlled
reduction potential of [HFeCl(dppe)2] (ꢀ2 V, Scheme 9). After the
passage of 23 Cb (0.27 F) the electrolysis gave the bicyclic product
2a in <10% yield.
2.6.3. Reactivity of [HFeCl(dppe)2] synthesized in acetonitrile
(4*). One hypothesis was that the synthetic procedure employed to
give the authentic [HFeCl(dppe)2] (4) (as compared with the in situ
generated species) effected the reactivity. This could be caused by
the presence and/or use of ethanol in the synthesis of the complex,
the solvent, or the stabilizer present in the solvent. To verify if this
was the case, isolation of the hydridoiron species under conditions
closely replicating the standard reaction conditions was carried out.
Iron(II) dichloride and dppe (2 equiv) were heated to 50 ꢁC in
Scheme 9. Electrolysis of 1b in the presence of [HFeICl(dppe)2]ꢀ (5).
For the reaction to proceed to completion, 85 Cb (2.2 F) would be
required to reduce the precatalyst 4 to active catalyst 5 and reduce
the substrate. However, only 23 Cb (0.27 F) were passed before the
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039

S.H. Kyne et al. / Tetrahedron xxx (2016) 1e11
9
[HFeIICl(dppe)2] (4)) but another species which is more reactive
with 1b than the anionic complex 5.
Table 10
Order of reagent introduction: reactivity of bromoacetal 1b in the presence of
[HFeCl(dppe)2] (4) (10 mol %) and sodium borohydride (150 mol %)a
Entry
1
2
3
4
Observation (NMR)
3. Discussion
1a
2a
3a
4a
5b
6b
(4)
(4)
NaBH4
NaBH4
(4)
1b
1b
1b
1b
NaBH4
NaBH4
NaBH4
NaBH4
(4)
(4)
1b
50 ꢁC
rt
50 ꢁC
rt
rt
50 ꢁC
1b
1b
From these experiments one concludes that [FeIICl2(dppe)2] (3)
is a more efficient precatalyst than [HFeIICl(dppe)2] (4), as clearly
demonstrated by the reactions involving bromoacetal 1b.
1b þ 2ac
1b
1b
1b
As shown in Fig. 4, when [FeIICl2(dppe)2] (3) is used as the
precatalyst it reacts with NaBH4 to form [HFeIICl(dppe)2] (4), and
borane is formed as the by-product of the reaction. Borane is
known to react rapidly with free phosphine to form a very stable
phosphaneeborane complex in an irreversible reaction.40 Under
standard reaction conditions, any dppe that is liberated will react
rapidly with borane to form 1,2-bis(diphenylphosphino)ethane
bisborane (11) (as observed by 31P{1H} NMR, vide supra). Moreover
specific 31P{1H} NMR experiments conducted on [HFeIICl(dppe)2]
with of BH3.THF (1 and 4 equiv) showed the rapid formation 1,2-
bis(diphenylphosphino)ethane bisborane (11) after 30 min (see
Supplementary data) and the amount did not change over 16 h.
Borane may participate in the dissociation of dppe from the iron
centre and subsequent complexation of the free ligand leading to
formation of compound (11) (see 31P{1H} NMR spectra in
Supplementary data). As a consequence of borane complexing with
dppe, a new phosphine-free complex, [HFeIICl(NCCH3)2] (12), may
be formed. This complex could undergo reduction with NaBH4 to
generate the phosphine-free anionic [HFeICl(NCCH3)2]ꢀ (13) spe-
cies which will be able to activate bromoacetal (1b). In competition,
the precatalyst [HFeIICl(dppe)2] (4) may also react with NaBH4 to
form the anionic [HFeICl(dppe)2]ꢀ (5) species and BH4ꢂ radical.41
(4)
1b
a
Reaction conditions: 1þ2 neat, þ3 in CH3CN, 16 h.
b
c
Reaction conditions: 1þ2 in CH3CN, after 15 min þ3 in CH3CN, 16 h.
Traces of bicyclic product 2a observed.
acetonitrile and sodium borohydride (0.6 equiv) added, after 2 h an
orange powder was isolated in 24% yield. This species (4*) exhibited
identical characteristic 1H and 31P{1H} NMR signals to the authentic
complex (4).
Under standard reaction conditions, this species (4*) gave an
88% of bicyclic product 2a starting from iodoacetal 1a (Scheme 10).
Once again the bromoacetal 1b was unreactive, and no conversion
was observed. Therefore, the authentic and in situ generated spe-
cies exhibit the same reactivity. This validates the synthetic pro-
cedure to give [HFeCl(dppe)2] (4).
[HFeCl(dppe)2] (10 mol%)
H
X
NaBH4 (100 mol%)
MeCN (0.5 M)
50 °C, 16 h
O
O
O
O
H
1a, X = I
1b, X = Br
2a
From 1a, 88%
From 1b, 0%
–
•
–
BH4
BH3
BH4
Precatalyst 3 BH4
Scheme 10. Reaction of haloacetals 1 in the presence of [HFeCl(dppe)2] (4*).
[FeIICl2(dppe)2]
[HFeIICl(dppe)2]
–
[HFeICl(dppe)2]
5
– Cl–
3
4
R–I•–
R–I
BH3
2.6.4. Additives to promote reaction. A number of other reactions
were tested to promote reactivity. Potentially, bromoacetal 1b re-
quires a large excess of reducing agent to favor reaction and sustain
the catalytic cycle. In the presence of 10 equivalents of NaBH4 and
iron(II) dichloride (10 mol %), bromoacetal 1b was once again found
to be unreactive and no cyclized product 2a was observed. There
was also the possibility that the substrate and hydridoiron pre-
catalyst may undergo halogen exchange. In this case, the catalyti-
cally active species would be [HFeIX(dppe)]ꢀ. In the presence of
iodoacetal 1a, the hydridoiron iodide [HFeII(dppe)]ꢀ could be
formed, which would be more reactive that the equivalent bro-
mide. Potentially, bromoacetal 1b in the presence of an iodide
source could form the postulated iodide active species to promote
the catalytic cycle. Two crystals of iodine were added to the stan-
dard reaction conditions however no conversion was observed af-
ter the reaction. The electrochemistry studies had revealed that
bromoacetal 1b promoted limited catalytic activity of
[HFeCl(dppe)2] (4), and it was therefore possible that the sup-
porting electrolyte benefited the reaction. nBu4NBF4 (0.3 M) was
added to the standard reaction conditions but once again no con-
version was observed.
dppe(BH3)2
–
•
BH4
BH4
11
–
[HFeICl(NCCH3)2]
13
[HFeIICl(NCCH3)2]
12
R–X•–
R–X
R–Br•–
No reaction
•
–
BH4
R–Br
–
Precatalyst 4 BH4
[HFeIICl(dppe)2]
[HFeICl(dppe)2]
X
4
5
R–I•–
R–I
Fig. 4. Reactions leading to the generation of active catalysts in the presence of
borohydride.
In the same manner, when starting from [HFeIICl(dppe)2] (4) as
the precatalyst, the anionic [HFeICl(dppe)2]ꢀ (5) species and the
BH4 radical are formed (Fig. 4). However, as the hydride transfer
step is not required, no borane is formed in this reaction. Thus any
dppe liberated in this reaction will remain in solution, unable to
form bis(diphenylphosphino)ethane bisborane (11).
These details suggest that formation of borane is critical to
success: the reaction between borane and free dppe is rapid and
irreversible which acts as a driving force for the reaction. Dissoci-
ation of dppe ligand is favored, leaving the iron centre with vacant
coordination sites that may be readily filled by solvent molecules,
further dissociation would give [HFeIICl(NCCH3)2] (12). Studies on
the formation and reactivity of this species are ongoing and will be
reported in due course.
ꢂ
2.6.5. Phosphine iron complex mixtures. The reaction was carried
out in the presence of both [FeIICl2(dppe)2] (3) and [HFeIICl(dppe)2]
(4). In this case, bromoacetal 1b was reacted with 5 mol % of each 3
and 4 under otherwise standard reaction conditions. 100% con-
version of the substrate was observed, and the bicyclic product 2a
isolated in 76% yield. This suggests that the reactive species which
can activate bromoacetal 1b is not the anionic [HFeICl(dppe)2]ꢀ (5)
(which is generated from both [FeIICl2(dppe)2] (3) and
In contrast, the precatalyst [HFeCl(dppe)2] (4) is in equilibrium
with the 19 electron anionic [HFeICl(dppe)2]ꢀ (5) species. Without
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039

10
S.H. Kyne et al. / Tetrahedron xxx (2016) 1e11
borane formation in this reaction, there is also no driving force for
dppe dissociation from the iron species and thus [HFeICl(dppe)2]ꢀ
(5) is an active catalyst for the reaction with iodooacetal 1a but not
sufficiently reactive with bromoacetal 1b.
briefly and the CV performed immediately at a scan rate of 5 V sꢀ1
(towards the reduction potential).
5.5. NMR set up
4. Conclusions
NMR spectra were acquired on a Bruker AV400 instrument fitted
with a QNP probe and the temperature was set to 300 K or 323 K for
all experiments described herein. Spectra acquisition settings were
as follows for 1H NMR; NS¼64 scans; D1¼1.0 s; SW¼150 ppm;
TD¼32,768, AQ¼0.27 s and O1P¼25 ppm; for 31P{1H} NMR:
NS¼1024; TD0¼8; D1¼2.0 s; SW¼400 ppm; O1P¼ꢀ50 ppm. The
sample remained in the instrument for the duration of the exper-
iment (to maintain temperature). The samples were analyzed at
fixed intervals using the Bruker Topspin spooler.
Work is underway to further explain these results with theory
and to explore effective methods to stabilize the anionic hydrio-
do(I) species. This will facilitate the design of potentially more ef-
ficient precatalysts to be used in a wider range of radical reactions
starting from different radical precursors.
5. Experimental section
5.1. General procedure for the preparation of haloacetal
substrates
5.6. General procedure for NMR reactions
The iron complex (0.005 mmol) and sodium borohydride (if
required) were added to a screw cap NMR tube in the glovebox.
Acetonitrile-d3 (1.0 mL) was added under argon, the NMR tube
inserted immediately into the magnet and the time noted. The
reaction was allowed to equilibrate for ca. 15 min then the first
proton-decoupled 31P NMR spectrum taken. Alternate 1H and 31P
{1H} NMR spectra were recorded each 30 min for 18 h.
Full experimental details, procedures, analytical data including
NMR (1H, 13C spectra), ESI-MS, ICP-MS and additional Tables are
given in the Supplementary data.
A
mixture of N-halosuccinimide (76 mmol) and alcohol
(74 mmol) in dichloromethane (40 mL) was cooled to ꢀ10 ꢁC, then
3,4-dihydro-2H-pyran (6.8 mL, 75 mmol) added dropwise under
argon. The reaction mixture was allowed to warm to room tem-
perature over 3 h and stirred at this temperature overnight. The
reaction was diluted with dichloromethane (40 mL) and washed
with saturated sodium thiosulfate (3ꢃ20 mL). The combined
aqueous phase was extracted with dichloromethane (3ꢃ20 mL)
and the combined organic phase washed with brine (20 mL), dried
(phase separation paper) and the solvent removed in vacuo. The
residue was purified by column chromatography (20% diethyl
ether/pentane) to afford the title compound. The product was fil-
tered through neutral alumina prior to use.
Acknowledgements
The research leading to these results received funding from the
European Union Seventh Framework Programme ([FP7/2007-
2013]) under grant agreement nꢁ [2988969] (S.K). This work was
also supported by the UPMC, ENS, CNRS, IUF (L.F.), ANR (ANR-12-
BS07-0031) and COST Action CM1201. Technical assistance was
5.2. General procedure for the cyclization of haloacetal
substrates
The iron complex (0.1 mmol) and reducing agent were added to
a screw cap tube in the glovebox (the tube was capped with a suba
seal). Acetonitrile (1.5 mL) was added under argon, and the mixture
stirred for 15 min at room temperature. A solution of haloacetal
(1.0 mmol) in acetonitrile (0.5 mL) was added under argon, the suba
seal replaced by a screw cap and the reaction heated to 50 ꢁC
overnight. The reaction was cooled to room temperature, quenched
with water (20 mL) and the aqueous phase extracted with
dichloromethane (3ꢃ20 mL). The combined organic phase was
washed with brine (30 mL), dried (phase separation paper) and the
solvent removed in vacuo. The residue was purified by flash chro-
matography (5e20% diethyl ether/pentane).
ꢀ
generously offered by FR 2769. Drs Sebastien Blanchard, Elsa Caytan
and Denis Lesage are acknowledged for providing technical assis-
tance and useful discussions. Professor Henrik Zipse is thanked for
his valuable discussions and suggestions.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.08.039.
References and notes
5.3. Cyclic voltammetry set up
1. (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, Germany, 2001; Vols. 1 and 2; (b) Radicals in Synthesis I and II In
€
Topics in Current Chemistry; Gansauer, A., Ed.; Springer Berlin Heidelberg: 2006;
Cyclic voltammetry (CV) was performed in a three-electrode cell
connected to a Schlenk line (under argon) at room temperature.
The working electrode was a steady gold disk (d¼1 mm), the
counter electrode a platinum wire (ca. 0.2 cm2 apparent area). The
reference was a saturated calomel electrode (SCE) separated from
the solution by a bridge filled with tetrabutylammonium tetra-
fluoroborate in acetonitrile solution (0.3 M, 2 mL). The same solu-
tion (0.3 M, 12 mL) was used as the solvent in the electrochemical
cell for all CV experiments reported herein.
(c) Encyclopedia of Radicals in Chemistry, Biology and Materials; Chatgilialoglu, C.,
Studer, A., Eds.; Wiley: Chichester, 2012.
2. (a) Tin in Organic Synthesis; Pereyre, M., Quintard, J.-P., Rahm, A., Eds.; London:
Butterworth, 1987; (b) Chatgilialoglu, C. In Radicals in Organic Synthesis; Re-
naud, P., Sibi, M., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 28e49.
3. (a) Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072e3082; (b)
Studer, A.; Amrein, S. Synthesis 2002, 835e849.
4. Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188e194.
5. Pike, P.; Hershberger, S.; Hershberger, J. Tetrahedron 1988, 44, 6295e6304.
6. (a) Ryu, I.; Uehara, S.; Hirao, H.; Fukuyama, T. Org. Lett. 2008, 10, 1005e1008; (b)
^
Ueng, S. H.; Fensterbank, L.; Lacote, E.; Malacria, M.; Curran, D. P. Org. Lett. 2010,
^
ꢀ
12, 3002e3005; (c) Pan, X.; Lacote, E.; Lalevee, J.; Curran, D. P. J. Am. Chem. Soc.
2012, 134, 5669e5674.
5.4. General procedure for cyclic voltammetry to measure
reduction potentials
7. (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. Tetrahedron Lett. 1992, 33,
2311e2314; (b) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. J. Org. Chem. 1993,
58, 6838e6842; (c) Graham, S. R.; Murphy, J. A.; Kennedy, A. R. J. Chem. Soc.,
Perkin Trans. 1 1999, 3071e3073; (d) Khan, T. A.; Tripoli, R.; Crawford, J. J.;
Martin, C. G.; Murphy, J. A. Org. Lett. 2003, 5, 2971e2974.
Substrate (0.048 mmol, 4 mM) was added to the electrochemical
cell containing
a
solution of tetrabutylammonium tetra-
8. Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. Tetrahedron
2003, 59, 6627e6635.
fluoroborate in acetonitrile (0.3 M, 12 mL), the mixture was stirred
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039

S.H. Kyne et al. / Tetrahedron xxx (2016) 1e11
11
9. (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110, 8561e8562; (b)
Barden, M. C.; Schwartz, J. J. Am. Chem. Soc. 1996, 118, 5484e5485; (c) Gansauer,
A.; Bluhm, H. Chem. Rev. 2000, 100, 2771e2788 and references cited therein.
10. Fujita, K.; Nakamura, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2001, 123,
3137e3138.
conversion was observed for 1b. An incomplete reaction (t ¼ 6 h) with 1a was
run under standard conditions with 10 mol% FeCl2 and showed the following
distribution: (1a:2a:2b¼1/0.5/1.9) which suggests that the presence of FeCl2
accelerates the formation of 2a at the expense of 2b.
€
26. Horn, M.; Schappele, L. H.; Lang-Wittkowski, G.; Mayr, H.; Ofial, A. R. Chem.
11. Kochi, J. K.; Singleton, D. M.; Andrews, L. J. Tetrahedron 1968, 24, 3503e3515.
12. Kuivila, H. G.; Menapace, L. W. J. Org. Chem. 1963, 28, 2165e2167.
13. Corey, E. J.; Suggs, J. W. J. Org. Chem. 1975, 40, 2554e2555.
14. Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303e304.
15. (a) Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. J. Am. Chem. Soc. 2002, 124,
906e907; (b) Hayashi, N.; Shibata, I.; Baba, A. Org. Lett. 2004, 6, 4981e4983; (c)
Baba, A.; Shibata, I. Chem. Rec. 2005, 5, 323e335.
dEur. J. 2013, 19, 249e263.
27. MacLeod, K. C.; Patrick, B. O.; Smith, K. M. Organometallics 2010, 29, 6639e6641.
28. Engman, L.; Gupta, V. J. Org. Chem. 1997, 62, 157e173.
29. (a) Stork, G.; Baine, N. H. J. Am. Chem. Soc. 1982, 104, 2321e2323; (b) Curran, D.
P.; Shen, W. J. Am. Chem. Soc. 1993, 104, 2321e2323; (c) Curran, D. P.; Sun, S. N.
Aust. J. Chem. 1995, 48, 261e267.
30. (a) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237e1286; (b)
^
16. Liu, Y.; Schwartz, J. Tetrahedron 1995, 51, 4471e4482.
Fensterbank, L.; Dhimane, A.-L.; Wu, S.; Lacote, E.; Bogen, S.; Malacria, M.
17. (a) Smith, D. M.; Pulling, M. E.; Norton, J. R. J. Am. Chem. Soc. 2007, 129,
770e771; (b) Hartung, J.; Pulling, M. E.; Smith, D. M.; Yang, D. X.; Norton, J. R.
Tetrahedron 2008, 64, 11822e11830.
18. Gaspar, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 5758e5760.
19. Kim, H.; Lee, C. Org. Lett. 2011, 13, 2050e2053.
Tetrahedron 1996, 52, 11405e11420; (c) Nishida, M.; Hayashi, H.; Nishida, A.;
Kawara, N. Chem. Commun. 1996, 579e580; (d) Bogen, S.; Gulea, M.; Fen-
sterbank, L.; Malacria, M. J. Org. Chem. 1999, 64, 4920e4925; (e) Fensterbank,
L.; Mainetti, E.; Devin, P.; Malacria, M. Synlett 2000, 1342e1344; (f) Lenoir, I.;
Smith, M. L. J. Chem. Soc., Perkin Trans. 1 2000, 641e643; (g) Maiti, S.; Takasu, K.;
Katsumata, A.; Kuroyanagi, J.; Ihara, M. ARKIVOC 2002, 7, 197e211; (h) Takasu,
K.; Ohsato, H.; Kuroyanagi, J.; Ihara, M. J. Org. Chem. 2002, 67, 6001e6007; (i)
Ueda, M.; Miyabe, H.; Nishimura, A.; Miata, O.; Takemoto, Y.; Naito, T. Org. Lett.
2003, 5, 3835e3838; (j) Jiang, H.; Cheng, Y.; Wang, R.; Zhang, Y.; Yu, S. Angew.
Chem., Int. Ed. 2013, 52, 13289e13292.
20. (a) Freidlina, R. K.; Velichko, F. K. Synthesis 1977, 3, 145e154; (b) Hilt, G.; Bolze,
P.; Harms, K. Chem.dEur. J. 2007, 13, 4312e4325; (c) Zhang, S.-Y.; Tu, Y.-Q.; Fan,
C.-A.; Zhang, F.-M.; Shi, L. Angew. Chem., Int. Ed. 2009, 48, 8761e8765; (d)
ꢀ
Vallee, F.; Mousseau, J.; Charette, A. B. J. Am. Chem. Soc. 2010, 132, 1514e1516;
(e) Shirakawa, E.; Masui, S.; Narui, R.; Watabe, R.; Ikeda, D.; Hayashi, T. Chem.
Commun. 2011, 9714e9716; (f) Pratsch, G.; Anger, C. A.; Ritter, K.; Heinrich, M.
Chem.dEur. J. 2011, 17, 4104e4108; (g) Ito, S.; Itoh, T.; Nakamura, M. Angew.
Chem., Int. Ed. 2011, 50, 454e457 For iron(II) or iron(III)/hydride systems see;
(h) Taniguchi, T.; Goto, N.; Nishibata, A.; Ishibashi, H. Org. Lett. 2010, 12,
112e115; (i) Leggans, E. K.; Barker, T. J.; Duncan, K. K.; Boger, D. L. Org. Lett.
2012, 14, 1428e1431; (j) Barker, T. J.; Boger, D. L. J. Am. Chem. Soc. 2012, 134,
13588e13591; (k) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136,
1304e1307; (l) Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C.-M.; Baran, P. S. Nature 2014, 516,
31. Stereochemistry of Radical Reactions; Curran, D. P., Porter, N. A., Giese, B., Eds.;
VCH: Weinheim, 1995.
32. For reduction of radicals with NaBD3CN, see Ref 6(a); With NaBD4, see: Kropp,
M.; Schuster, G. Tetrahedron Lett. 1987, 28, 5295e5298.
33. (a) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310e7318; (b) Grigg, R.;
Stevenson, P.; Worakun, T. Tetrahedron 1988, 44, 2033e2048.
34. Aresta, M.; Giannoccaro, P.; Rossi, M.; Sacco, A. Inorg. Chim. Acta 1971, 5,
115e118.
€
343e348; (m) For a review on iron catalysis, see: Bauer, I.; Knolker, H.-J. Chem.
35. Bautista, M. T.; Bynum, L. D.; Schauer, C. K. J. Chem. Educ. 1996, 73, 988e991.
36. Petersson, M. J.; Loughlin, W. A.; Jenkins, I. D. Chem. Commun. 2008,
4493e4494.
Rev. 2015, 115, 3170e3387.
21. Felkin, H.; Meunier, B. Nouv. J. Chim. 1977, 1, 281e282.
22. (a) Hayashi, Y.; Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1998, 39, 63e66; (b)
For a review on iron catalyzed hydrofunctionalization, see: Greenhalgh, M. D.;
Jones, A. S.; Thomas, S. P. Chem. Cat. Chem. 2015, 7, 190e222.
37. Busacca, C. A.; Raju, R.; Grinberg, N.; Haddad, N.; James-Jones, P.; Lee, H.; Lor-
enz, J. C.; Saha, A.; Senanayake, C. H. J. Org. Chem. 2008, 73, 1524e1531.
38. DuBois, D. L.; Miedaner, A. Inorg. Chem. 1986, 25, 4642e4650.
39. (a) Bellerby, J. M.; Mays, M. J. J. Chem. Soc., Dalton Trans. 1975, 13, 1281e1283; (b)
Zotti, G.; Zecchin, S.; Pilloni, G. J. Organomet. Chem. 1979, 181, 375e386.
40. Burg, A. B.; Wagner, R. I. J. Am. Chem. Soc. 1953, 75, 3872e3877.
41. (a) Saveant, J. M. Acc. Chem. Res. 1980, 13, 323e329; (b) Amatore, C.; Pinson, J.;
Saveant, J. M.; Thiebault, A. J. Am. Chem. Soc. 1982, 104, 817e826; (c) Amatore,
C.; Combellas, C.; Robveille, S.; Saveant, J. M.; Thiebault, A. J. Am. Chem. Soc.
1986, 108, 4754e4760; (d) See Ref. 31(c).
ꢀ
ꢁ
^
23. Ekomie, A.; Lefevre, G.; Fensterbank, L.; Lacote, E.; Malacria, M.; Ollivier, C.;
Jutand, A. Angew. Chem., Int. Ed. 2012, 51, 6942e6946.
24. (a) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58e102 See also; (b)
Newcomb, M.; Curran, D. P. Acc. Chem. Res. 1988, 21, 206e214.
25. The following control experiments were run: substrates 1a and 1b were treated
separately with 1.5 equivalents NaBH4 in acetonitrile (0.5 M) at 50 ꢁC for 16 h
(no FeCl2 added). The reaction of 1a gave as major product, the iodine atom
transfer reaction accompanied by 1a and 2a (1a:2a:2b ¼1/0.4/3.7). No
Please cite this article in press as: Kyne, S. H.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.08.039