Efficient Formation of 2,3-Dihydrofurans via Iron-Catalyzed Cycloisomerization of α-Allenols

Article abstract of DOI:10.1021/acscatal.7b03515

Herein, we report a highly efficient iron-catalyzed intramolecular nucleophilic cyclization of α-allenols to furnish substituted 2,3-dihydrofurans under mild reaction conditions. A highly diastereoselective variant of the reaction was developed as well, g

Full text of DOI:10.1021/acscatal.7b03515

Subscriber access provided by READING UNIV
Letter
Efficient Formation of 2,3-Dihydrofurans via Iron-
Catalyzed Cycloisomerization of #-Allenols
Arnar Guðmundsson, Karl Gustafson, Binh Khanh Mai, Bin Yang, Fahmi Himo, and Jan-E. Bäckvall
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03515 • Publication Date (Web): 20 Nov 2017
Downloaded from http://pubs.acs.org on November 20, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth Street
N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
ACS Catalysis
1
2
3
4
5
6
7
Efficient Formation of 2,3-Dihydrofurans via Iron-Catalyzed
8
Cycloisomerization of α-Allenols
Arnar Guðmundsson, Karl P. J. Gustafson, Binh Khanh Mai, Bin Yang*, Fahmi Himo*, and Jan-E.
Bäckvall*
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Supporting Information
ABSTRACT: Herein, we report a highly efficient iron-catalyzed
An iron-based racemization protocol for secondary alcohols, an
intramolecular nucleophilic cyclization of α-allenols to furnish
important extension of transfer hydrogenation catalysis, was
substituted 2,3-dihydrofurans under mild reaction conditions. A
recently developed in our group using a pincer type iron
highly diastereoselective variant of the reaction was developed as
catalyst.10 Unfortunately, this catalyst was not compatible with the
well, giving diastereomeric ratios of up to 98:2. The combination
reaction conditions required for chemoenzymatic dynamic kinetic
of the iron-catalyzed cycloisomerization with enzymatic resolu-
resolution (DKR). Subsequently, 1 and 2 were employed as
tion afforded the 2,3-dihydrofuran in high ee. A detailed DFT
racemization catalysts in chemoenzymatic DKR of secondary
study provides insight into the reaction mechanism and gives a
rationalization for the high chemo- and diastereoselectivity.
alcohols by Rueping’s and our group.11
KEYWORDS: Iron catalysis, -allenols, diastereoselective,
2,3-dihydrofurans, homogeneous.
Although transition metal-catalyzed cyclizations of allenes
have been studied extensively,12 the development of novel
cyclization methods for substituted allenes through iron catalysis
is still lacking. We recently reported13 a one-pot lipase/Ru-cata-
lyzed kinetic resolution of -allenols followed by cycloisomeriza-
tion using catalyst 3, via intermediate B (Scheme 2a). This reac-
tion furnished enantiomerically pure 2,3-dihydrofurans, the for-
mation of which was postulated to proceed via a Ru-carbene
intermediate.13 From that work (Scheme 2a) and our experience
with iron catalyst 111b we envisioned that species A, generated
from 1, might catalyze a similar cyclization of -allenols to
furnish substituted 2,3-dihydrofurans (Scheme 2b). In contrast to
catalyst 3, which requires thermal activation to give B, generation
of the 16-electron complex A from 1 occurs at room temperature,
which could facilitate diastereoselective cyclization of 1,2-sub-
situted -allenols 5.
As the most abundant transition metal, iron, with its low price
and toxicity, has been studied intensively for catalytic reactions.1
The role of iron in catalysis is multifaceted. It can catalyze
cross-couplings2 and redox reactions such as transfer
hydrogenation,3 as well as reactions via carbene or nitrene
intermediates.4 Recently, there has been great interest in the
development of iron-based transfer hydrogenation catalysts.3,5
Catalyst 2 (Scheme 1) was originally isolated by the group of
Knölker in 1999,6,7 although, its first catalytic application was not
demonstrated until 2007 when Casey and Guan reported its use in
the hydrogenation of ketones and aldehydes to alcohols.5 Iron
complexes 2 and A are isoelectronic analogues to ruthenium
complexes 4 and B, respectively, obtained from Shvo’s catalyst
3.8 Complexes A and 2 can be generated in situ from air- and
moisture stable precursor 1. This has allowed for numerous
applications in various transfer hydrogenation reactions including
the alkylation of amines or carbonyls using alcohols.9
Scheme 2. Previous Work and Proposal for This Work
Scheme 1. Iron- and Ruthenium-Based Transfer
Hydrogenation Catalysts
Initial attempts began by using anisole as solvent with 10 mol%
of complex 1 as the catalyst and trimethylamine N-oxide
(TMANO) as activator under Ar atmosphere at room temperature.
This was the solvent of choice in our earlier related DKR study.11
Gratifyingly, the anticipated product 6a was obtained in 70%
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 6
yield as the sole product (Table 1, entry 1). The iron-catalyzed
α-allenols, we next turned our attention to the possible
1
2
3
4
5
6
7
8
protocol proceeded with exclusive chemoselectivity and the
isomeric byproduct 2,5-dihydrofuran was not observed. Following
these results, we turned to screening the reaction conditions with
respect to catalyst loading and solvent. The reaction still
proceeded well with a catalyst loading as low as 5 mol% (Table 1,
entries 2 and 3). Solvent screening showed that non-polar solvents
such as dichloromethane (DCM), ether and toluene (Table 1,
entries 4-7) were superior to polar ones. Acetonitrile and water
failed to give product 6a after 2 h, most likely due to the strong
coordination by these solvents to iron and subsequent poisoning
of the catalyst (Table 1, entries 8-12). DCM, owing to its low
boiling point, was selected as the solvent of choice because of the
relatively high volatility of 6a. Attempts to use a simple iron salt,
Fe(OAc)2, were unsuccessful and did not yield any 6a.
diastereoselectivity of the reaction. If a 1,2-disubstituted α-allenol
is used, two diastereomeric forms of the 2,3-dihydrofuran are
possible. The inherent mild reaction conditions of the
iron-catalyzed cycloisomerization would increase the chances of
obtaining high diastereoselectivity. We were pleased to find that
these substituted α-allenols could be converted into the
corresponding 2,3-dihydrofurans 6k-n in excellent yield and with
a diastereomeric ratio (d.r.) of up to 98:2. It is worth noting that
the d.r. of the previous Ru-protocol for the cyclization of the
1,2-disubstituted allenol to give product 6k is only 4:1, which
further highlights the advantage of the iron-catalyzed
cycloisomerization of -allenols. It is interesting to note that
α-allenols, with an aryl substitution in the 2-position (5o), failed
to yield any product (6o) under the standard reaction conditions,
which most likely can be attributed to the increased stability of the
allene.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of the Reaction Conditions
Scheme 3. Substrate Scope for the Iron-catalyzed
Cycloisomerization of -Allenols 5 to form 2,3-Dihydrofuran 6
Entry Solvent
Catalyst loading
(mol%)
Yield after
2 hb (%)
1
Anisole
Anisole
Anisole
DCM
10
70 %
50 %
14 %
90 %
82 %
95 %
24 %
18 %
11 %
0 %
2
5
3
2.5
5
4
5
Diethyl Ether
Toluene
CPMEc
EtOAc
5
6
5
7
5
8
5
9
THF
5
10
11
12
Acetonitrile
DMF
5
5
3 %
Water
5
0 %
We next investigated the effect of substitution at the terminal
allenic position. Subjecting 5p to the standard reaction conditions
afforded only 26% of product. However, when the reaction was
conducted in toluene at 70 °C, the 2,5-disubstituted
2,3-dihydrofuran 6p was obtained in 96% yield (eq. 1). While
monitoring the reaction, it was observed that at 65% conversion
the remaining starting material had a diastereomeric ratio of
approximately 8:1, showing that the diastereoisomers of 5p react
with substantially different rates.
a General reaction conditions: The reaction was conducted under
Ar atmosphere at r.t. with 0.5 mmol of 5a, 0.05 mmol of 1, 0.1
mmol of TMANO, 0.5 mmol of K2CO3 and 0.5 mL of solvent.
1
bYield determined by H NMR analysis. c Cyclopentyl methyl
ether.
With the optimal conditions in hand (5 mol% of 1 in DCM), we
next studied the reactivity of various functionalized allenols
(Scheme 3). Derivatives bearing electron-donating (5b, 5c),
electron-neutral (5a and 5d), or electron-withdrawing substituents
(5e, 5f) on the aryl group all gave good to excellent yields.
Substituents on the aryl ring in the meta or ortho position had
little effect on the reaction and furnished the 2,3-dihydrofurans 6g
and 6h in good yields. When an aliphatic substituent was present
instead of the aryl group, the reaction proceeded equally well,
giving 92% isolated yield of 6i. Dihydrofuran 6j with a
heterocyclic group in the 2-position could be obtained as well, in
94% yield. After exploring the reactivity of 1-substituted
We also investigated the cycloisomerization in combination
with enzymatic resolution (eq. 2). Kinetic resolution of 5a with
Candida antarctica lipase B (CalB) afforded (S)-5a (97% ee),
which was used for cycloisomerization. In view of the fact that
2
ACS Paragon Plus Environment

Page 3 of 6
ACS Catalysis
iron complex 1 works as racemization catalyst in DKR of
protodemetalation already at Int-2 leading to 2,5-dihydrofuran.
sec-alcohols,11b complex 1 may cause racemization of starting
material (S)-5a. To our delight, the reaction proceeded without
any loss of chirality, yielding (S)-6a in 80% yield and 97% ee.
This is in accordance with the results from the corresponding
Ru-catalyzed reaction.13
The TS for this step, called TS-PD in Figure 1, is calculated to be
5.7 kcal/mol higher in energy than TS-2 that gives the correct
product. This result is consistent with the experimental
observations that 2,3-dihydrofurans 6 are exclusively formed and
that 2,5-dihydrofurans are not intermediates (eq. 3). TS-2 has a
more relaxed 6-membered TS structure, compared to the more
strained 5-membered TS of TS-PD, which in addition lacks the
stabilizing CH-O interaction present in TS-2 (see SI).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Reaction Mechanism for the Iron-Catalyzed
Cycloisomerization Proposed on the Basis of Current DFT
Calculations
Control experiments using 2,5-dihydrofuran as the starting
material were performed (eq. 3). When 7 was exposed to the
standard reaction conditions, no reaction occurred, suggesting that
7 is not an intermediate species in the reaction.
To gain a deeper insight into the mechanism of this novel
cycloisomerization by iron, we performed density functional
theory (DFT) calculations using the formation of 6k as a model
(see SI for computational details). On the basis of these
calculations we propose the reaction mechanism shown in
Scheme 4. The catalytic cycle starts with coordination of the
substrate to A, which is obtained from activation of iron complex
1. Interestingly, the lowest-energy binding mode was found to be
coordination by the hydroxyl group to give Int-0, which is similar
in structure to what Casey and Guan observed.5b The productive
coordination by the terminal C=C bond of the allene moiety
giving Int-1 is calculated to be 8.1 kcal/mol higher in energy.
From Int-1, cyclization via TS-1 can then take place to produce
vinyl iron intermediate Int-2 (see Figure 1). The calculations
show that the lowest-energy TS for this step involves another
allenol molecule that assists in shuttling the proton (see Figure 1).
The barrier for this step is calculated to be 19.2 kcal/mol relative
to Int-0. Next, isomerization of Int-2 to Int-4 is shown to proceed
via the key iron carbene intermediate Int-3. This isomerization
consists of two proton transfer steps in which the non-innocent
cyclopentadienone ligand plays an important role. Subsequent
protodemetalation of Int-4 gives Int-5, which on release of
product 6 regenerates A, thereby closing the catalytic cycle.
According to the calculations, TS-2 is the rate determining step
(RDS) of the reaction, with an overall barrier of 20.9 kcal/mol
(see Figure 1). However, the other steps are quite close in energy
(19.2, 20.0, and 18.8 kcal/mol, for TS-1, TS-3, and TS-4,
respectively), and it is therefore not possible to confidently assign
the RDS on the basis of the calculations alone.
Finally, it was found that the proposed mechanism is consistent
with deuterium-labeling experiments (see Supporting Information
S1 and S2). In all of the labeling experiments there was no loss of
deuterium in the 5-position of the 2,3-dihydrofuran when
4,4-dideuterated α-allenol was used. This observation suggests
that the step from Int-3 to Int-4 is irreversible. We also observed
a small kinetic isotope effect (KIE) of kH/kD = 1.3 in the
cyclization using 5a-d0 and 5a-d1 (deuterated on the hydroxyl
group) in separate experiments (see S1), which suggests that the
cyclization (Int-1 to Int-2) is not the RDS. The small isotope
effect observed may be ascribed to an equilibrium isotope effect.
Negligible deuterium incorporation was observed in position 4,
which is in contrast to the corresponding reaction with
ruthenium.15
In the reaction of 5k, only 6k was observed as product. We
have also considered the formation of the cis isomer of 6k, which
requires the protonation at TS-2 to take place from the other face
of the double bond. For this to happen, a rotation around the Fe-C
bond has first to occur to give Int-2’ (Figure 1). The barrier for
the subsequent transition state, TS-2’, is calculated to be 1.8
kcal/mol higher than TS-2 , which corresponds to a d.r. of about
95:5, in good agreement with the experimental findings (Scheme
3).14
In summary, we have developed a diastereoselective synthesis
of oxygen-containing heterocycles from readily available
α-allenols via iron-carbene intermediates at ambient temperature.
A number of substituted 2,3-dihydrofurans were obtained by this
protocol. A computational study provides a deeper insight into the
mechanism of the reaction. Further studies on the synthetic
applications of the proposed carbene intermediate Int-3 are
currently underway in our laboratory.
Importantly, we have also investigated the possibility that
2,5-dihydrofuran could be generated from
a
direct
3
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
the Berzelii Center EXSELENT, and the Knut and Alice
Wallenberg Foundation is gratefully acknowledged.
After completion of this work, Rueping and coworkers reported
a related study on cycloisomerization of allenols based on our
original work (ref 13).16 Their protocol gave 3,6-di-
REFERENCES
o
hydro-2H-pyrane as the product with an iron complex at 70 C.
(1) (a) Bauer, E. B. Topics in Organometallic Chemistry: Iron
Catalysis II, Bauer, E. B. Eds.; Springer International: Cham
Switzerland, 2015; p 1-18 (b) Bauer, I.; Knölker, H.-J. Chem.
Rev. 2015, 115, 3170. (c) Bolm, C.; Legros, J.; Le Paih, J.; Zani,
L. Chem. Rev. 2004, 104, 6217. (d) Iron Catalysis in Organic
Chemistry, Plietker, B. Ed.; Wiley-VCH Verlag GmbH & Co.
KGaA, Weinheim, Germany, 2008
(2) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 3686. (b) Cahiez, G.; Moyeux, A.; Buendia,
J.; Duplais, C. J. Am. Chem. Soc. 2007, 129, 13788-13789. (c)
Fürstner, A.; De Souza, D.; Parra-Rapado, L.; Jensen, J. T. Angew.
Chem., Int. Ed. 2003, 42, 5358-5360. For recent example within
our research group, see: (d) Kessler, S. N.; Bäckvall, J. -E. Angew.
Chem. Int. Ed. 2016, 55, 3734–3738. (e) Kessler, S. N.;
Hundemer, F.; Bäckvall, J.-E. ACS Catal., 2016, 6, 7448-7451.
(3) (a) Nishiyama, H.; Furuta, A. Chem. Commun. 2007,
760-762. (b) Shaikh, N. S.; Enthaler, S.; Junge, K.; Beller, M.
Angew. Chem. Int. Ed. 2008, 47, 2497-2501. (c) Langlotz, B. K.;
Wadepohl, H.; Gade, L. H. Angew. Chem. Int. Ed. 2008, 47,
4670-4674. (d) Sui-Seng, C.; Freutel, F.; Lough, A. J.; Morris, R.
H. Angew. Chem. Int. Ed. 2008, 47, 940-943.
(4) For recent reviews see: (a) Riener, K; Haslinger, S.; Raba,
A.; Högerl, M. P.; Cokoja, M.; Herrmann, W. A.; Kühn, F. E.
Chem. Rev. 2014, 114, 5215-5272. For selected examples see: (b)
Jolly, P. W.; Petti, R. J. J. Am. Chem. Soc. 1966, 88, 5044-5045.
(c) Brookhart, M.; Humphrey, M. B.; Kratzer, H. J.; Nelson, G. O.
J. Am. Chem. Soc. 1980,102, 7802-7803. (d) Brookhart, M.;
Tucker, J. R.; Husk, G. R. J. Am. Chem. Soc. 1981, 103, 979-981.
(e) Kremer, K. A. M.; Kuo, G. H.; O’Connor, E. J.; Helquist, P;
Kerber, R. C. J. Am. Chem. Soc. 1982, 104, 6119-6121.
We have achieved cycloisomerization at ambient temperature
with the air- and moisture-stable iron complex 1. In addition, the
diastereoselective version of this type of cyclization was also
explored in the present study.
Figure 1. Calculated Free Energy Profile (energies are given
in kcal/mol)
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*binyang@organ.su.se
*fahmi.himo@su.se
*jeb@organ.su.se
Notes
The authors declare no competing financial interest.
Supporting Information
Experimental procedures and compound characterization data,
1
including the H/13C NMR spectra, computational details, figures
of intermediates and transition states, absolute energies and
energy corrections, and Cartesian coordinates of optimized
structures. This material is available free of charge via the Internet
at http://pubs.acs.org.
(5) (a) Casey, C. P.; Guan, H. J. Am. Chem. Soc. 2007, 129,
5816-5817 (b) Casey, C. P.; Guan, H. J. Am. Chem. Soc. 2009,
131, 2499-2507 (c) for related oxidations, see: Coleman, M. G.;
ACKNOWLEDGMENT
Financial support from the European Research Council (ERC
AdG 247014), The Swedish Research Council (621-2013-4653),
4
ACS Paragon Plus Environment

Page 5 of 6
ACS Catalysis
Brown, A. N.; Bolton, B. A.; Guan, H. Adv. Synth. Catal. 2010,
352, 967-970.
Guðmundsson, A.; Lewis, K.; Bäckvall, J. -E. Chem. Eur. J. 2017,
1
2
3
4
5
6
7
8
23, 1048-1051. (c) El-Sepelgy, O.; Brzozowska, A.; Rueping, M.
ChemSusChem, 2017, 10, 1664-1668. (d) Subsequently, Zhou and
coworkers reported a chemoenzymatic DKR using a catalyst
related to 1: Yang, Q.; Zhang, N.; Liu, M.; Zhou, S. Tetrahedron
Lett. 2017, 58, 2487-2489.
(6) For recent reviews on the Knölker-type iron catalyst and
non-innocent ligands, see: (a) Quintard, A.; Rodriguez, J.; Angew.
Chem. Int. Ed. 2014, 53, 4044-4055; Angew. Chem. 2014, 126,
4124-4136. (b) Khusnutdinova, R.; Milstein, D.; Angew. Chem.
Int. Ed. 2015, 54, 12236-12273; Angew. Chem. 2015, 127,
12406-12445. Selected examples of iron-catalyzed asymmetric
hydrogenation (c) Zuo, W.; Lough, A. J.; Li, Y. F.; Morris, R. H.
Science 2013, 342, 1080-1083; (d) Li, Y.; Yu, S.; Wu, X.; Xiao, J.;
Shen, W.; Dong, Z.; Gao, J.; J. Am. Chem. Soc. 2014, 136,
4031-4039.
(12) (a) For a review see: Zhang, D: Liu, J.; Córdova, A.; Liao,
W.-W. ACS Catal. 2017, 7, 7051-7063. (b) Piera, J.; Närhi, K.;
Bäckvall, J.-E. Angew. Chem. Int. Ed. 2006, 45, 6914-6917. (c)
Zhu, C.; Yang, B.; Jiang, T.; Bäckvall, J.-E. Angew. Chem. Int. Ed.
2015, 54, 9066-9069. e) Zhu, C.; Zhang, X.; Lian, X.; Ma, S.
Angew. Chem. Int. Ed. 2012, 51, 7817-7820. (d) Zhu, C.; Ma, S.
Org. Lett. 2013, 15, 2782-2785. (e) Zhu, C.; Ma, S. Adv. Synth.
Catal. 2014, 356, 3897-3911. (f) Zhu, C.; Yang, B.; Bäckvall. J.-E.
J. Am. Chem. Soc., 2015, 137 11868-11871. (g) Zhu, C.; Yang, B.;
Qiu, Y.; Bäckvall, J.-E. Chem. Eur. J. 2016, 22, 2939-2943. (h)
Qiu, Y.; Yang, B.; Zhu, C.; Bäckvall. J.-E. Angew. Chem. Int. Ed.
2016, 55, 6520-6524. (i) Qiu, Y.; Yang, B.; Zhu, C.; Bäckvall.
J.-E. Chem. Sci. 2017, 8, 616-620. (j) Zhu, C.; Yang, B.; Qiu, Y.;
Bäckvall, J.-E. Angew. Chem. Int. Ed. 2016, 55, 14405-14408. (k)
Yang, B.; Qiu, Y.; Jiang, T.; Wulff, W. D.; Yin, X.; Zhu, C.;
Bäckvall. J.-E. Angew. Chem. Int. Ed. 2017, 56, 4535-4539. (l)
Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395-403. (m) Qiu, Y.;
Zhou, J.; Li, J.; Fu, C.; Guo, Y.; Wang, H.; Ma, S. Chem. Eur. J.
2015, 21, 15939-15943. (n) Qiu, Y.; Yang, B.; Jiang, T.; Zhu, C.;
Bäckvall. J.-E. Angew. Chem. Int. Ed. 2017, 56, 3221-3225.
(13) Yang, B.; Zhu, C.; Qiu, Y.; Bäckvall, J.-E. Angew. Chem.
Int. Ed. 2016, 55, 5568-5572.
(14) For an explanation for the difference between TS-2 and
TS-2’ see the Supporting Information.
(15) For the previous ruthenium-catalyzed reaction (ref. 13) the
deuterium incorporation into position 4 of the 2,3-dihydrofuran
varied between 0.18 and 0.52. The corresponding incorporation
for iron varied between 0.03 and 0.09.
(16) El-Sepelgy, O.; Brzozowska, A.; Azofra, L. M.; Jang, Y.
K.; Cavallo, L.; Rueping, M. Angew. Chem. Int. Ed. 2017, 56,
14863-14867.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) Knölker, H. J.; Goesmann, H.; Klauss, R. Angew. Chem. Int.
Ed. 1999, 38, 2064-2066.
(8) (a) Blum, Y.; Shvo, Y.; Isr. J. Chem. 1984, 24, 144-148.
(b) Shvo, Y.; Cezarkie, D.; Rahamim, Y.; Chodosh, D. F. J. Am.
Chem. Soc. 1986, 108, 7400-7402. (c) Larsson, A. L. E.; Persson,
B. A.; Bäckvall, J. -E. Angew. Chem. Int. Ed. 1997, 36,
1211-1212.
(9) (a) Fleischer, S.; Zhou, S. S.; Junge, K. Beller, M. Angew.
Chem. Int. Ed. 2013, 52, 5120-5124; Angew. Chem. 2013, 125,
5224-5228. (b) Moyer, S. A.; Funk, T.; Tetrahederon Lett. 2010,
51, 5430-5433. For selected examples on reductive amination, see:
(c) Pagnoux-Ozherelyeva, A.; Pannetier, N.; Mbaye, M. D.;
Gaillard, S.; Renaud, J.-L. Angew. Chem. Int. Ed. 2012, 51,
4976-4980; Angew. Chem. 2012, 124, 5060-5064. (d) Moulin, S.;
Dentel, H.; Pagnoux-Ozherelyeva, A.; Gaillard, S.; Poater, A.;
Cavallo, L.; Lohier, J. -F.; Renaud, J.-L. Chem. Eur. J. 2013, 19,
17881-17890. (e) Thai, T.-T.; Mrel, D.S.; Poater, A.; Gaillard, S.;
Renaud, J.-L. Chem. Eur. J. 2015, 21, 7066-7070. For selected
examples on direct alkylation of amines with alcohols see: (f) Yan,
T.; Feringa, B. L.; Barta, K.; Nat. Commun. 2014, 5, 5602-5609.
(g) Rawlings, A. J.; Diorazio, L. J.; Wills, M. Org. Lett. 2015, 17,
1086-1089. (h) Yan, T.; Feringa, B. L.; Barta, K. ACS. Catal.
2016, 6, 381-388. For selected examples of Knölker complexes in
dual catalysis, see: (i) Zhou, S.; Fleischer, S.; Junge, K.; Beller, M.
Angew. Chem. Int. Ed. 2011, 50, 5120-5124; Angew. Chem. 2011,
123, 5226-5230;
(10) Bornschein, C.; Gustafson, K. P. J.; Verho, O.; Beller, M.;
Bäckvall, J. -E.; Chem. Eur. J. 2016, 22, 11583-11586.
(11) (a) El-Sepelgy, O.; Alandini, N.; Rueping, M. Angew.
Chem. Int. Ed. 2016, 55, 13602-13605. (b) Gustafson, K.;
5
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 6
1
2
3
Graphical Abstract
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
ACS Paragon Plus Environment