α-C-H functionalization of π-bonds using iron complexes: Catalytic hydroxyalkylation of Alkynes and Alkenes

Article abstract of DOI:10.1021/jacs.9b11716

The discovery of catalytic systems based on earth-abundant transition metals for the functionalization of C-H bonds enables streamlined and sustainable solutions to problems in synthetic organic chemistry. In this Communication, we disclose an iron-based catalytic system for the functionalization of propargylic and allylic C-H bonds. Inexpensive and readily available cyclopenta-dienyliron(II) dicarbonyl complexes were employed as catalysts for a novel deprotonative activation mode for C-H functionalization, an approach that allows for the direct union of unsaturated building blocks with aryl aldehydes and other carbonyl electrophiles to deliver a range of unsaturated alcohol coupling products under operationally simple and functional group tolerant reaction conditions.

Full text of DOI:10.1021/jacs.9b11716

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Communication
#-C–H Functionalization of #-Bonds Using Iron Complexes:
Catalytic Hydroxyalkylation of Alkynes and Alkenes
Yidong Wang, Jin Zhu, Austin C. Durham, Haley Lindberg, and Yi-Ming Wang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 02 Dec 2019
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α-C–H Functionalization of π-Bonds Using Iron Complexes: Catalytic
Hydroxyalkylation of Alkynes and Alkenes
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Yidong Wang, Jin Zhu, Austin C. Durham, Haley Lindberg, and Yi-Ming Wang*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
Supporting Information Placeholder
Scheme 1. Approaches for Fe-catalyzed C–H functionalization
ABSTRACT: The discovery of catalytic systems based on earth-
abundant transition metals for the functionalization of C–H bonds
enables streamlined and sustainable solutions to problems in synthetic
organic chemistry. In this Communication, we disclose an iron-based
catalytic system for the functionalization of propargylic and allylic C–H
bonds. Inexpensive and readily-available cyclopentadienyliron(II)
dicarbonyl complexes were employed as catalysts for a novel deproto-
native activation mode for C–H functionalization, an approach that
allows for the direct union of unsaturated building blocks with aryl
aldehydes and other carbonyl electrophiles to deliver a range of unsatu-
rated alcohol coupling products under operationally simple and func-
tional group tolerant reaction conditions.
A) C–X formation via high-valent Fe:
B) Directed C–C formation via low-valent Fe:
H2X / [O]
O
O
MR, [O]
LFeR (cat.)
X
H
Fe
X
(cat.)
Ln
Ar
Ar
N
H
N
H
X = O; NR; (CR2 rare)
R = sp3 / sp2
C
R
open-shell ligand-based H atom abstraction
O.A. or s-bond metathesis by chelated Fe
C) Electrophilic a-functionalization via cationic Fe: stabilized propagylic anion (this report)
[Fe]+
E
[Fe]
LnFe+, base
(–)
“
”
H
R2
•
R2
R2
R2
electrophile E+
R1
R1
R1
R1
deprotonation gives Fe-stabilized anion
catalytic intermediate
D) Application to catalytic aldehyde-alkyne coupling
[Fe]+:
pKa ~ 35 – 40
pKa < 10 propargylation ( ) vs. allenylation (
LA
O
)
Fe +
[
]
R1
R3 R4
R2
R2
[Fe]+, LA
–[
Fe +
]
R3N
R1
R1
R3
R4
Fe
OH
+
+
OC
OC
R2
LA
R4
O
R1
O
•
propargylation
R2
[Fe]
R3
R4
unsaturated
Fe+ complex
as catalyst
R3
(SE2') product
The discovery of new strategies and methods for the functionaliza-
tion of readily available hydrocarbon resources using abundant rea-
gents and sustainable catalysts is an important goal in contemporary
synthetic organic chemistry.1 The use of complexes based on iron, the
most earth-abundant transition metal, is a particularly attractive area of
investigation which has seen intensive development in recent years.2 In
one approach, inspired by a variety of enzyme active sites found in
nature, high-valent iron species are used to perform the catalytic O- and
N-functionalization of C–H bonds.3 A wide variety of electron-rich C–
H bonds are susceptible to this oxidative process. However, this ap-
proach is rarely used for the formation of C–C bonds (Scheme 1A). In
a more recently developed catalytic approach, metalation facilitated by
chelating directing groups or by 1,5-hydrogen-atom transfer has ena-
bled the iron-catalyzed oxidative coupling of C-H bonds with main-
group organometallic reagents.4 Although this approach allows for the
installation of more general carbon-based fragments, a directing group
effect appears to be required for good reactivity (Scheme 1B).4c These
complementary strategies have given rise to an impressive array of iron-
catalyzed transformations of C–H bonds. Nevertheless, the formation
of C–C bonds via catalytic C–H functionalization in the absence of a
directing group continues to represent a synthetic challenge, not only
for iron chemistry but for transition-metal catalysis in general.
a. deprotonation facilitated by coordination
b. electrophilic functionalization
E) stoichiometric precedents:
Fp+
ref 11b: general carbon electrophiles
ref 11c: activated carbonyls
R
refs. 11b, 11c
E+
Fp
R
+
E
Considering their wide availability from petrochemical feedstocks,
simple alkenes and alkynes are attractive starting materials for C–H
functionalization processes. Although several well-developed reactions
for the introduction of functional groups at the allylic position are now
available,6 the intermolecular formation of C–C bonds still represents a
challenge. On the other hand, the corresponding functionalization of
alkynes at the propargylic position without concomitant transfor-
mation of the C–C triple bond remains mostly unaddressed, with only
a handful of propargylic C–H functionalization reactions having been
reported.7,8 A few intramolecular amination reactions by nitrenoid
insertion are known.7c,7d Intermolecular processes generally require the
use of directing or activating groups on the alkyne or its partner,8a,8b or
rely on radical chemistry whose regioselectivity would likely suffer in
contexts where comparably weak C–H bonds are present.7b
We hypothesized that a mode of C–H functionalization in which the
hydrogen departs as a proton, rather than hydride or hydrogen atom,
would be particularly suitable for the propargylic functionalization of
internal alkynes, given the higher intrinsic acidity of a propargylic C–H
bond (pKa ~ 35 to 40) compared to an allylic one (pKa ~ 43). 9 As part
of our research group’s interest in developing methods to forge C–C
bonds from readily available building blocks, we targeted the coupling
of internal alkynes and aldehydes to demonstrate the synthetic utility
and prospects of this new approach. Although alkynes and aldehydes
have served as coupling partners in other transition-metal catalyzed
coupling reactions, the proposed coupling at the propargylic position,
without isomerization or reduction of the triple bond, would be a here-
Viewed broadly, strategies for the functionalization of unreactive C–
H bonds typically involve the removal of a hydrogen atom (H•) or
–
hydride anion (H ) equivalent. As an alternative, we considered the
possibility of C–H bond cleavage through the removal of a proton
(H+), facilitated by coordination of an electron-deficient metal frag-
ment to a neighboring π-bond. The resultant organometallic complex
could be conceptualized as a metal-stabilized propargylic anion equiva-
lent, capable of undergoing subsequent reactions with electrophiles to
afford the net α-functionalization product (Scheme 1C). 5
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tofore unreported outcome.10 To implement this strategy, we consid-
intramolecular cyclization of the homopropargylic alcohol product
may present an additional complication,12 as Fp+ is known to activate
triple bonds for nucleophilic attack.11i In this Communication, we re-
port the successful development of the desired catalytic coupling pro-
cess, in spite of these obstacles. A judicious choice of catalyst, reagent,
and reaction conditions eventually led to the development of an opera-
tionally simple catalytic protocol for the coupling of aldehydes and
internal alkynes to deliver a wide range of homopropargylic alcohol
products.13,14
1
2
3
4
5
6
7
8
ered the use of inexpensive and readily-prepared cyclopentadienyl-
iron(II) dicarbonyl complexes and their substituted derivatives
(CpRFe(CO)2 = FpR) as potential catalysts .11 Seminal work by Rosen-
blum and coworkers on Fp(η2-alkene)+ complexes suggests that coor-
dination leads to a dramatic increase in acidity of the allylic position
(from pKa ~43 to <10, Scheme 1D). Moreover, the neutral σ-allyliron
complexes formed upon deprotonation react with a range of carbon
and heteroatom electrophiles to furnish the product of net α-
functionalization of the olefin (Scheme 1E).11b,11c Despite the remarka-
ble reactivity, no catalytic applications of this chemistry have been
reported. On the other hand, aside from a report detailing the depro-
tonation of a Fp(η2-alkyne)+ complex to form an σ-allenyliron com-
plex11f and a report of the reaction of the parent σ-allenyl-Fp with a
cationic troponeiron tricarbonyl complex,11g the chemistry of alkyne-
derived FpR complexes is otherwise underexplored. Nevertheless, we
felt that reported stoichiometric reactivity patterns offered a tantalizing
starting point for the development of catalytic systems for the func-
tionalization of internal alkynes.
We began our initial search for a catalytic coupling procedure by ex-
amining the behavior of 1-phenyl-1-propyne (1a) and 4-
bromobenzaldehyde (2a) as model alkyne and aldehyde coupling
partners, respectively (Table 1). We also selected boron trifluoride
etherate as a convenient and readily available Lewis acid for the activa-
tion of the carbonyl moiety. Bearing in mind the interplay between the
amine base and the Lewis acidic Fe catalyst, we prioritized the exami-
nation of combinations of hindered base and hindered Fe complexes
for desired reactivity. Among an extensive series of combinations ex-
amined, the combination of 2,2,6,6-tetramethylpiperidine (TMPH) as
9
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–
the amine base and [Fp*(thf)]+BF4 (Fp* = (C5Me5)Fe(CO)2+) as the
Table 1. Optimization of reaction conditions
precatalyst for cationic Fe was the most successful combination (Table
1, entry 1). While the use of 2,4,6-collidine in place of TMPH (entry 2)
also delivered a significant amount of product under catalytic condi-
tions, most other bases yielded no desired product (entries 3-6). Ap-
plication of another hindered FpR-based catalyst (FpR
= (1,3-t-
entry
change from standard condition
none
yield (%)a
Bu2C5H3)Fe(CO)2) was partially successful (entry 10), but replace-
ment with the unsubstituted cationic Fp complex (entry 9), another
cationic transition metal catalyst (entry 8), or use of another Lewis acid
activator was ineffective (entry 7). Control experiments showed the
necessity of Fe complex, Lewis acid, and base (entry 15).
1
2
3
4
5
6
7
8c
9
89 (81)b
2,4,6-collidine instead of TMPH
64
0
DBU or Barton’s base instead of TMPH
Proton Sponge, PMP, or iPr2NEt instead of TMPH
iPr2NH instead of TMPH
These conditions were used to examine the generality of the catalyst
system with respect to the two coupling partners (Table 2). A collec-
tion of aryl aldehydes (Table 2, top), ranging from mildly electron-rich
(3af, 3ao) to highly electron-poor (3ad, 3ae) could be used as cou-
pling partners. 2,6-Substitution (3ah, 3ai) was tolerated, as was the
presence of a diaryl ketone (3ap), esters (3ae, 3aj), a difluoroacetal
(3am), a pinacol ester (3ag), and a sulfonamide (3af). Non-enolizable
alkyl aldehydes (3aq, 3ar), an electron-rich heteroaryl aldehyde (3as),
as well as simple (3at) and cyclic (3au-3ax) α,β-unsaturated aldehydes
could also be used as the aldehyde coupling partner. During the course
of examination of the aldehyde scope, it was found that for less reactive
starting materials, the addition of Zn(NTf2)2 (10 mol %) led to im-
proved yields (e.g., 3aq). As a further example of the generality of this
process, we examined N-benzylated isatins as coupling partners. In
these cases, the ketonic carbonyl group of the isatins functioned as the
electrophile to deliver the tertiary homopropargylic alcohol in moder-
ate to good yields (4aa-4ac).
0
0
pyridine instead of TMPH
0
Sc(OTf)3, Al(OTf)3 instead of BF3·Et2O
Fe2+, Zn2+, or Ag+ instead of Fp*(thf)BF4
Fp(thf)BF4 instead of Fp*(thf)BF4
0
0
0
10d FpR(thf)BF4 instead of Fp*(thf)BF4
11 1.5 eq. BF3·Et2O, 2.0 eq. TMPH
24
61
70
74
82
0
12 10 mol % Fp*(thf)BF4 instead of 20 mol %
80 °C instead of 100°C
13
14 PhCF3 instead of PhCH3 as solvent
15 Fp*(thf)BF4, BF3·Et2O or TMPH omitted
aYields were determined by 1H NMR using 1,1,2,2-tetrachloroethane
as the internal standard. bIsolated yield (0.3 mmol scale).
cFe(BF4)2·6H2O, Zn(NTf2)2, or AgBF4 (20 mol %). FpR = (1,3-t-
The scope of the coupling with respect to alkynes was then evaluat-
ed (Table 2, bottom). A range of mildly electron-rich (3ha) to moder-
ately electron-poor (3ga) aryl methyl acetylenes could be coupled
under these conditions, as could higher aryl alkyl acetylenes (3ja-3ma),
albeit with little control over the diastereoselectivity of the coupling
(1.6 to 2.0:1 d.r.). Complex scaffolds derived from cholesterol and
tocopherol could likewise be used (3na, 3oa). With a higher catalyst
loading, certain hindered dialkyl acetylenes (3pa) could also be suc-
cessfully employed.15, 16
d
Bu2C5H3)Fe(CO)2. TMPH = 2,2,6,6-tetramethylpiperidine, PMP =
1,2,2,6,6-pentamethylpiperidine, Barton base
=
2-t-butyl-1,1,3,3-
tetramethylguanidine, Proton Sponge
naphthalene.
= 1,8-bis(dimethylamino)-
At the outset, we were aware that in addition to identification of a
suitable cyclopentadienyl ligand, we also needed to select a compatible
Lewis acid for activation of the aldehyde and base for the deprotona-
tion of the alkyne. In particular, a hindered amine is needed to prevent
irreversible deactivation of both the iron catalyst and Lewis acidic acti-
vator. Simultaneously, it must retain the ability to abstract the α-
proton from the FpR(η2-alkyne)+ complex. Moreover, competitive
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a
Table 2. Reaction scope for homopropargylic alcohol
1
The scope of electrophile
2
3
Ph
OH
Ph
OH
Ph
OH
Ph
OH
Ph
OH
Ph
OH Me
4
5
6
7
8
9
Me
O
Me
Me
Br
R
CO2Me
N
B
Me
Ts
O
3ab, R = F, 72% yield
3aa, 81% yield
Me
3ac, R = OCF3, 69% yield
3ad, R = NO2, 56% yieldc,e
Me
73% yield (5 mmol)g
3ae, 61% yield
3af, 62% yieldb,c
3ag, 60% yield
3ah, R = Me, 64% yield
Br
Ph
OH Cl
Ph
OH
Ph
OH
Ph
OH
Ph
OH
Ph
OH
Me
Me
OMe
CF3
O
O
F
F
O
C
Cl
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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35
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59
60
O
3aj, 61% yieldb,c
3ai, R = Cl, 80% yield
3ak, 70% yield
3al, 62% yield
3am, 76% yield
3an, 76% yield
Me
O
Ph
OH
Ph
OH OBz
Ph
OH
Ph
OH
Ph
OH
Ph
OH
N
Me
Me
Bs
Ph
Me Me
Me
Br
O
3ap, 57% yieldb
3aq, 61% yieldc,d
3ar, 60% yieldc,d
3as, 51% yieldb
3at, 59% yieldc,d,e
3ao, 71% yield
44% yieldd
from Isoxepac
R
Ph
OH
Ph
OH
Ph
OH Br
Ph
OH Cl
Ph
OH Br
Ph
OH Cl
F
O
N
O
N
Bn
O
Bn
4b, R = Me, 61% yieldc,d
4c, R = F, 69% yieldc,d
b,c,d
3ax, 51% yieldc
4a
, 52% yield
3au, 50% yieldb,c
3aw, 56% yieldc
3av
,
55% yieldc
The scope of alkyne
Br
MeO2
C
F
OH
OH
OH
OH
OH
OH
MeO
Br
Cl
3da, 71% yieldc
3fa, 68% yieldc
Br
Br
3ba, 85% yield
3ca, 66% yield
3ea, 69% yield
3ga, 65% yield
Br
Br
Br
Br
OH
Ph
OH
Ph
OH
Ph
OH
OH
OH Cl
Ph
Me
n
Br
Br
Me
Br
Br
Br
Cl
3ja, 84% yield, 1.5:1 d.r.c
3ka, 79% yield, 1.6:1 d.r.c
3la, n = 1, 63% yield, 1.8:1 d.r.c
3pa, 55% yieldc,e
3ha, 61% yield
3ia, 79% yield
c
3ma
, n = 2, 53% yield, 2.0:1 d.r.
Me
Me
Me
HO
HO
OH
Me
3
Me
Me
H
H
H
O
Br
Me O
Br
Me
H
3
3
O
O
O
Me
Me
Me
3na, 65% yieldc,f
from cholesterol
3
Br
Me
Me
3oa
,
59% yieldc,f
from tocopherol
Me
Me
3qa, 43% yieldb,c,d
Me
aCondition: 1a (0.3 mmol), 2 (1.5 eq.), Fp*(thf)BF4 (20 mol %), BF3·Et2O (2.5 eq.), TMPH (3.0 eq.), toluene (0.6 mL), 100 °C. b1a (2.0 eq.), 2
(0.3 mmol), cZn(NTf2)2 (10 mol %) was added. d80 °C, DCE. e30 mol % Fp*(thf)BF4. f0.1 mmol scale. g15 mol % Fp*(thf)BF4, 5 mol% Zn(NTf2)2.
After exploring the scope of the alkyne component, we wondered
whether our optimized conditions would be applicable to olefin sub-
strates. Applying our optimized conditions to terminal olefins, we were
pleased to find that our conditions resulted in allylic functionalization
of these substrates to furnish the homoallylic alcohol products (Table
3). Notably, even unactivated olefins (6aa, 6ba) delivered the cou-
pling product, though substrates with additional electronic activation
(6ca, 6da) provided higher yields of coupling product. These exam-
ples represent rare instances of the catalytic allylic C–H functionaliza-
tion of olefins with carbonyl derivatives reported to date.
To showcase the utility of this transformation, two of the products
(3aa, 3ak) were derivatized using literature methods to produce sever-
al elaborated structures (Scheme 3), including a tetrasubstituted tri-
fluoromethyl alkene (7aa), a tetrahydrofuran (8aa), and two stereode-
fined alkenyl alcohols (9ak, 10ak).
Scheme 3. Divergent transformations of products
a
Table 3. Scope of alkenes for homoallylic alcohol synthesis
OH
[Cp*Fe(CO)2(thf)]+[BF4]–
O
R
+
Ar
H
Ar
BF3•Et2O, TMPH, toluene, 100 °C
R
5
6
2a
, Ar = 4-BrC6H4
OH
OH
OH
OH
Ar
Ar
Ar
Ar
Me
Ph
, 66% yield
C6H4(4-OMe)
6da
, 71% yield
Ph
, 43% yield
1.5:1 d.r.
6aab
6ba
6ca
1.6:1 d.r.
, 40% yield
2.0:1 d.r.
At present, Scheme 4 represents a working model of the catalytic cy-
cle of our coupling reaction. The cycle begins with a cationic alkyne-
iron π-complex of type I (CpR = substituted cyclopentadienyl). The
amine base would then abstract the propargylic proton to give a neutral
allenyliron σ-complex of type II. Subsequently, the electrophilic func-
1.7:1 d.r.
aCondition: 5 (2.0 eq.), 2a (0.3 mmol), Fp*(thf)BF4 (20 mol %),
BF3·Et2O (2.0 eq.), TMPH (3.0 eq.), toluene (0.6 mL), 100 °C.
bZn(NTf2)2 (10 mol %) was added.
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tionalization of II would give a cationic alkyne-iron complex of type III,
Notes
1
2
3
which would then undergo ligand exchange with the starting alkyne to
liberate the coupling product and close the catalytic cycle.
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
Scheme 4. Proposed catalytic cycle
4
5
6
7
8
9
We gratefully acknowledge the funding support from the University of
Pittsburgh. We thank Professor Scott Nelson for the sharing of labora-
tory resources with the Wang group. We would like to acknowledge
Professors Jeffrey Bandar (Colorado State), Mark Levin (Chicago),
Dean Toste (UC Berkeley), and Paul Floreancig (Pittburgh) for help-
ful discussions on this manuscript. We thank Devin A. Dikec for the
synthesis of starting materials for 4b-4c.
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To provide some evidence of this hypothesized catalytic cycle, we
investigated each of the elementary steps therein (Scheme 5). We
began our investigation by exploring the stoichiometric reactivity of the
–
Fp*-alkyne complex 1k-I ([Cp*Fe(CO)2(alkyne)]+[BF4] ), which was
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Rev. 2011, 111, 1293. (b) Cera, G.; Ackermann, L. Iron-catalyzed C-H
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prepared in high yield by heating
a toluene suspension of
Cp*Fe(CO)2I and AgBF4 with 1-phenyl-1-butyne (3.0 equiv) at 50 °C.
Next, Fp*-alkyne complex 1k-I was treated with Et3N to give the σ-
allenyliron complex 1k-II in >80% yield. Finally, 1k-II was reacted
with aldehyde 2a in the presence of BF3·Et2O to deliver the organic
product 3ka with an overall NMR yield of 36%. Notably, each of the
proposed catalytic intermediates could be identified spectroscopically
(Scheme 5 and SI).
(3) (a) Breslow, R.; Gellman, S. H. Tosylamidation of Cyclohexane
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Scheme 5. Stoichiometric mechanistic experiments.
In summary, we have developed an iron-catalyzed functionalization
of propargylic and allylic C–H bonds to deliver a range of unsaturated
alcohol coupling products. These transformations represent initial
explorations of a novel strategy for propargylic and allylic C–H func-
tionalization. Investigations into new synthetic applications and efforts
to improve the robustness, rate, and stereoselectivity of the catalyst
system are ongoing in our laboratories.
ASSOCIATED CONTENT
Supporting Information
(5) For a similar strategy applied to alkenyl C–H functionalization,
see: (a) Schomaker, J. M.; Boyd, W. C.; Stewart, I. C.; Toste, F. D.;
Bergman, R. G. Cobalt Dinitrosoalkane Complexes in the C–H Func-
tionalization of Olefins. J. Am. Chem. Soc. 2008, 130, 3777. (b) Boyd,
W. C.; Crimmin, M. R.; Rosebrugh, L. E.; Schomaker, J. M.; Bergman,
R. G.; Toste, F. D. Cobalt-Mediated, Enantioselective Synthesis of C2
and C1 Dienes. J. Am. Chem. Soc. 2010, 132, 16365. (c) Zhao, C.; Toste,
F. D.; Bergman, R. G. Direct Michael Addition of Alkenes via a Cobalt-
Dinitrosyl Mediated Vinylic C–H Functionalization. J. Am. Chem. Soc.
2011, 133, 10787. (d) Zhao, C.; Crimmin, M. R.; Toste, F. D.; Berg-
man, R. G. Ligand-Based Carbon-Nitrogen Bond Forming Reactions
of Metal Dinitrosyl Complexes with Alkenes and Their Application to
C–H Bond Functionalization. Acc. Chem. Res. 2014, 47, 517. For the
reversed-polarity strategy of stabilizing propargylic cations, see: (e)
Experimental procedures, spectroscopic data for the substrates and
products (PDF), and crystallographic data (CIF) for 3aa (CCDC
1961289), 4b (CCDC 1961290). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* ym.wang@pitt.edu
ORCID
Yidong Wang: 0000-0001-9560-3186
Yi-Ming Wang: 0000-0001-6414-0908
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of Bis(pinacolato)diboron, 1,3-enynes, and aldehydes catalyzed by an
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11(g). Computational studies to elucidate the origins of this selectivity
are currently underway.
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(15) Limitations to the scope: electron-rich aldehydes and alkynes
bearing two primary alkyl substituents are generally unsuitable sub-
strates under the current conditions. For the former (e.g., p-
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quent Friedel-Crafts alkylation to form annulation product, often ac-
companied by unidentified side products. For the latter (e.g., 3-
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materials are not consumed. Simple diaryl and alkyl aryl ketones do
not react under the current conditions.
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