Manganese-Catalyzed Carboacylations of Alkenes with Alkyl Iodides

Article abstract of DOI:10.1021/acs.orglett.6b02154

A manganese-catalyzed carboacylation of alkenes with alkyl iodides and carbon monoxide is described. This carbonylative difunctionalization uses both primary and secondary alkyl iodides in reactions with a diverse array of cyclic and acyclic substrates. Examples of successful applications to the synthesis of five-, six-, and seven-membered rings are provided. The inexpensive, first-row catalytic system and mild reaction conditions are expected to facilitate applications in complex synthesis.

Full text of DOI:10.1021/acs.orglett.6b02154

Letter
pubs.acs.org/OrgLett
Manganese-Catalyzed Carboacylations of Alkenes with Alkyl Iodides
Caitlin M. McMahon, Matthew S. Renn, and Erik J. Alexanian*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
ABSTRACT: A manganese-catalyzed carboacylation of al-
kenes with alkyl iodides and carbon monoxide is described.
This carbonylative difunctionalization uses both primary and
secondary alkyl iodides in reactions with a diverse array of
cyclic and acyclic substrates. Examples of successful
applications to the synthesis of five-, six-, and seven-membered
rings are provided. The inexpensive, first-row catalytic system
and mild reaction conditions are expected to facilitate applications in complex synthesis.
atalytic reactions of unactivated alkyl halides have led to a
catalysts commonly used in carbonylative processes of
organohalides8 would be an attractive feature of the
carboacylation. Herein, we report the successful development
of such a manganese-catalyzed alkene carboacylation widely
applicable to carbocycle and heterocycle synthesis.
We began by studying the catalytic carboacylation of primary
iodide 1 (Table 1). Inexpensive, commercially available
C
diverse set of valuable C−C bond-forming reactions in
chemical synthesis.1 This class of transformations includes
alkyl-Mizoroki-Heck-type reactions, constituting fundamental
cross-couplings of unactivated alkyl halides with alkenes.2 In
prior studies, we developed a carbonylative variant of this
reaction that yields cyclic enones from alkyl iodides and
pendant alkenes (Figure 1).3 We became interested in pursuing
Table 1. Influence of Reaction Conditions on the Mn-
a
Catalyzed Carboacylation
b
entry
variation from standard conditions above
none
yield (%)
1
2
3
4
5
6
7
8
9
84
14
0
5 mol % Mn(CO)5Br instead of Mn2(CO)10
2.5 mol % Co2(CO)8 instead of Mn2(CO)10
5 mol % Pd(PPh3)4 instead of Mn2(CO)10
1 equiv of iPr2EtN instead of 1 equiv of KHCO3
1 atm of CO instead of 10 atm of CO
5 atm of CO instead of 10 atm of CO
no ambient light
0
76
0
76
0
Figure 1. Metal-catalyzed, carbonylative alkene additions of alkyl
iodides.
no Mn2(CO)10
0
a
b
Reactions were performed with [substrate]0 = 0.13 M. Yields
determined by 1H NMR spectroscopy of crude reaction mixture using
an internal standard.
an alternative process involving alkene difunctionalization
(carboacylation).4 Prior to our studies there was limited
precedent for this class of alkene difunctionalization; a
photochemical palladium-catalyzed carboacylation has been
reported, but requires excess alkyl iodide (1.5 equiv) and was
limited to ketone synthesis using alkylboranes.5
We hypothesized that simple manganese catalysts [e.g.,
Mn2(CO)10] could facilitate the desired alkene carboacylation.
These complexes have shown promise in both the activation
and carbonylation of unactivated alkyl halides, particularly using
intense irradiation or electrolysis.6 Previous studies involving
manganese-catalyzed radical cyclizations required activated α-
halocarbonyls as substrates, however.7 The use of an
inexpensive, first-row metal instead of precious palladium
manganese(0) carbonyl successfully catalyzed the carboacyla-
tion of 1, delivering the substituted cyclopentyl ester 2 in good
yield (84%, entry 1) in EtOH as solvent. Bromopentacarbonyl-
manganese(I) and cobalt(0) carbonyl were both ineffective as
catalysts (entries 2−3), as was Pd(PPh3)4, which we have
previously used in a number of catalytic C−C bond-forming
reactions involving alkyl iodides (entry 4).2e,3a,9 Amine bases
Received: July 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02154
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
could be used in the reaction, although yields were slightly
diminished (entry 5). Reactions performed at various levels of
CO pressure indicated that while reactions using a balloon of
CO (1 atm) were unsuccessful, high pressures were not
required (entries 6−7). We chose 10 atm of CO as our
standard condition owing to the convenience of using a
pressurized glass tube. Interestingly, running the reaction in
complete darkness shut down the catalytic process (entry 8),
suggesting that ambient light plays a role in the catalytic
reaction.10 Control experiments in the absence of manganese
provided no product (entry 9).
With a viable catalytic system in hand, we investigated the
scope of the carboacylation across a diverse range of substrates
(Table 2). Reactions involving both primary and secondary
iodides were successful (entries 1−2). Notably, the carboacy-
lation is not limited to alcohol nucleophiles; diethylamine and
N-methylaniline both afforded amide products in good yields
(entries 3−4). Reactions using a variety of alkenes demon-
strated the notable scope of the carboacylation (entries 5−8).
Reactions involving 1,1-disubstituted and 1,1,2-trisubstituted
alkenes formed tetrahydrofuran and pyrrolidine derivatives
containing quaternary stereocenters in good yield (entries 5−
6). Importantly, the reaction is not limited to five-membered
ring synthesis; acetal substrate 11 undergoes a 6-exo cyclization
to deliver tetrahydropyran 12 (entry 7). Moreover, the
carboacylation of silyloxy iodide 13 proceeded in 7-endo
fashion to produce cyclic silyl ether 14 in good yield (78%,
entry 8). The regioselectivity of this ring closure is consistent
with lower energy endo transition states in radical cyclizations
of halomethylsilyl substrates with terminal alkenes.11 We have
also demonstrated the potential for cascade carboacylation with
triene substrate 15 (entry 9). The reaction of 15 proceeds via
two sequential 5-exo cyclizations to deliver bicyclic product 16
in moderate yield (63%).
Our studies continued with the carboacylations of five- and
six-membered cycloalkenyl substrates (Table 3). These
Table 3. Manganese-Catalyzed Carboacylations of
Cycloalkenyl Substrates
a
Table 2. Manganese-Catalyzed Carboacylations of Acyclic
Alkenes
a
a
b
c
See Table 1 for conditions. Isolated yields. Diastereomeric ratio
based on cyclization (see Supporting Information for more details).
d
10 mol % of Mn2(CO)10 used in MeOH as solvent.
reactions allowed the construction of bicyclic compounds in
efficient fashion, often with good levels of diastereoselectivity.
The carboacylation of carvone-derived substrate 23 proceeded
with lower diastereoselectivity, with a preference for carbon-
ylation on the opposite face from the methyl group.
A plausible catalytic cycle for the carboacylation is depicted
in Scheme 1. Homolysis of the Mn−Mn bond of manganese
carbonyl generates the •Mn(CO)5 radical and initiates the
catalytic pathway.10 Iodine atom abstraction from the substrate
(1) generates a carbon-centered radical (25), which undergoes
an alkene addition to produce radical 26. At this stage, radical
26 can either undergo carbonylation to provide acyl manganese
286 or complete an iodine atom-transfer cyclization to deliver
alkyl iodide 27.7 We have observed iodine atom-transfer
intermediates in a number of our cyclizations; a representative
example is shown in eq 1. Stopping the carboacylation of
a
b
c
See Table 1 for conditions. Isolated yields. 2 equiv amine and
d
e
KHCO3 used. 5 mol % Mn2(CO)10 used. Mixtures of diastereomers
produced (see Supporting Information for more details).
B
DOI: 10.1021/acs.orglett.6b02154
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Plausible Catalytic Cycle
ACKNOWLEDGMENTS
This work was supported by Award No. R01 GM107204 from
the National Institute of General Medical Sciences.
■
REFERENCES
■
(1) (a) Gu, J.; Wang, X.; Xue, W.; Gong, H. Org. Chem. Front. 2015,
2, 1411. (b) Iwasaki, T.; Kambe, N. In Comprehensive Organic Synthesis
II; Knochel, P., Molander, G. A., Eds.; Elsevier: Amsterdam, 2014; Vol.
3, pp 337−391. (c) Hu, X. Chem. Sci. 2011, 2, 1867. (d) Kambe, N.;
Iwasaki, T.; Terao, J. Chem. Soc. Rev. 2011, 40, 4937. (e) Rudolph, A.;
Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656. (f) Frisch, A. C.;
Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674.
(2) (a) Lebedev, S. A.; Lopatina, V. S.; Petrov, E. S.; Beletskaya, I. P.
J. Organomet. Chem. 1988, 344, 253. (b) Terao, J.; Watabe, H.;
Miyamoto, M.; Kambe, N. Bull. Chem. Soc. Jpn. 2003, 76, 2209.
(c) Affo, W.; Ohmiya, H.; Fujioka, T.; Ikeda, Y.; Nakamura, T.;
Yorimitsu, H.; Oshima, K.; Imamura, Y.; Mizuta, T.; Miyoshi, K. J. Am.
Chem. Soc. 2006, 128, 8068. (d) Firmansjah, L.; Fu, G. C. J. Am. Chem.
Soc. 2007, 129, 11340. (e) Bloome, K. S.; McMahen, R. L.; Alexanian,
E. J. J. Am. Chem. Soc. 2011, 133, 20146. (f) Weiss, M. E.; Kreis, L. M.;
Lauber, A.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 11125.
́
́
(g) Millan, A.; Alvarez de Cienfuegos, L.; Miguel, D.; Campana, A. G.;
̃
Cuerva, J. M. Org. Lett. 2012, 14, 5984. (h) McMahon, C. M.;
Alexanian, E. J. Angew. Chem., Int. Ed. 2014, 53, 5974. (i) Zou, Y.;
Zhou, J. Chem. Commun. 2014, 50, 3725. (j) Yang, F.; Fu, S. Y.; Chu,
W.; Li, C.; Tong, D. G. RSC Adv. 2014, 4, 45838. (k) Ilies, L.;
Matsubara, T.; Ichikawa, S.; Asako, S.; Nakamura, E. J. Am. Chem. Soc.
2014, 136, 13126. (l) Parasram, M.; Iaroshenko, V. O.; Gevorgyan, V.
J. Am. Chem. Soc. 2014, 136, 17926. (m) Fu, S. Y.; Li, Y. Z.; Chu, W.;
Li, C.; Tong, D. G. Catal. Sci. Technol. 2015, 5, 1638. (n) Liu, W.; Lu,
L.; Zhengwang, C.; Li, C. Org. Biomol. Chem. 2015, 13, 6170.
(3) (a) Bloome, K. S.; Alexanian, E. J. J. Am. Chem. Soc. 2010, 132,
12823. For a recent intermolecular variant using styrenes, see:
(b) Sumino, S.; Ui, T.; Hamada, Y.; Fukuyama, T.; Ryu, I. Org. Lett.
2015, 17, 4952.
(4) (a) For a photochemical palladium-catalyzed carboacylation
using activated alkyl halides and high CO pressure (45 atm), see:
Fusano, A.; Sumino, S.; Fukuyama, T.; Ryu, I. Org. Lett. 2011, 13,
2114. (b) For aryl carboacylations, see: Seashore-Ludlow, B.;
Danielsson, J.; Somfai, P. Adv. Synth. Catal. 2012, 354, 205. (c) Liu,
C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10250.
(5) Ishiyama, T.; Murata, M.; Suzuki, A.; Miyaura, N. J. Chem. Soc.,
Chem. Commun. 1995, 295.
(6) (a) Fukuyama, T.; Nishitani, S.; Inouye, T.; Morimoto, K.; Ryu, I.
Org. Lett. 2006, 8, 1383. (b) Kondo, T.; Tsuji, Y.; Watanabe, Y.
Tetrahedron Lett. 1988, 29, 3833. (c) Kondo, T.; Sone, Y.; Tsuji, Y.;
Watanabe, Y. J. Organomet. Chem. 1994, 473, 163.
(7) (a) Gilbert, B. C.; Kalz, W.; Lindsay, C. I.; McGrail, P. T.;
Parsons, A. F.; Whittaker, D. T. E. Tetrahedron Lett. 1999, 40, 6095.
(b) Gilbert, B. C.; Kalz, W.; Lindsay, C. I.; McGrail, P. T.; Parsons, A.
F.; Whittaker, D. T. E. J. Chem. Soc., Perkin Trans. 1 2000, 1187.
(8) (a) Wu, L.; Fang, X.; Liu, Q.; Jackstell, R.; Beller, M.; Wu, X.-F.
substrate 1 at partial conversion produces a mixture of both
carboacylation product 2 and iodine atom-transfer cyclization
product 27 in 19% and 18% yields, respectively (1H NMR
analysis). In a separate experiment, iodide 27 underwent
efficient carbonylation under the carboacylation conditions to
deliver ester 2 in 81% yield (eq 2). These experiments are
consistent with iodine atom-transfer cyclization playing a role in
these catalytic transformations, the degree of which is likely
dictated by the particular substrate and the energetics of the
iodine atom transfer step involved. Ultimately, once acylmanga-
nese 28 is formed, nucleophilic substitution delivers the
carboacylation product 2 and regenerates the active catalyst.
In conclusion, we have developed a manganese-catalyzed
carboacylation of alkenes using unactivated alkyl iodides and
moderate pressures of CO. This reaction exhibits broad scope
in carbocycle and heterocycle synthesis, with the potential for
good levels of diastereocontrol in the carboacylation process.
The common molecular functionality and mild reaction
conditions of this alkene difunctionalization are expected to
facilitate future applications in complex molecule synthesis.
ACS Catal. 2014, 4, 2977. (b) Brennfuhrer, A.; Neumann, H.; Beller,
M. Angew. Chem., Int. Ed. 2009, 48, 4114.
̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02154.
■
S
(9) Venning, A. R. O.; Bohan, P. T.; Alexanian, E. J. J. Am. Chem. Soc.
2015, 137, 3731.
(10) (a) Hudson, A.; Lappert, M. F.; Nicholson, B. K. J. Chem. Soc.,
Dalton Trans. 1977, 551. (b) Meyer, T. J.; Caspar, J. V. Chem. Rev.
1985, 85, 187.
(11) (a) Koreeda, M.; Hamann, L. G. J. Am. Chem. Soc. 1990, 112,
8175. (b) Parasram, M.; Iaroshenko, V. O.; Gevorgyan, V. J. Am. Chem.
Soc. 2014, 136, 17926.
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: eja@email.unc.edu.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b02154
Org. Lett. XXXX, XXX, XXX−XXX