Intermolecular Aminoallylation of Alkenes Using Allyl-Oxyphthalimide Derivatives: A Case Study in Radical Polarity Effects

Article abstract of DOI:10.1002/ejoc.201901071

A case study on the polarity effects of radical mediated intermolecular alkene aminoallylation is presented herein. This radical group transfer method pairs vinyl ethers with electronically deficient allyl-oxyphthalimide derivatives to give difunctionalized products while illustrating the guiding effects of polarity on this radical reactivity.

Full text of DOI:10.1002/ejoc.201901071

DOI: 10.1002/ejoc.201901071
Communication
Radicals Reactions
Intermolecular Aminoallylation of Alkenes Using Allyl-
Oxyphthalimide Derivatives: A Case Study in Radical Polarity
Effects**
Samuel W. Lardy[a] and Valerie A. Schmidt*[a]
Abstract: A case study on the polarity effects of radical medi- tronically deficient allyl-oxyphthalimide derivatives to give di-
ated intermolecular alkene aminoallylation is presented herein. functionalized products while illustrating the guiding effects of
This radical group transfer method pairs vinyl ethers with elec- polarity on this radical reactivity.
Introduction
Methods that achieve the difunctionalization of alkenes are par-
ticularly powerful as they rapidly introduce molecular complex-
ity from abundant olefin starting materials in a single synthetic
step.[1–13] Seminal work by Kharasch and co-workers demon-
strated the difunctionalization of unactivated alkenes via atom
transfer radical addition (ATRA) using simple halogenated rea-
gents (Scheme 1A).[14] This work paved the way for the subse-
quent development of a sophisticated class of radical-mediated
alkene difunctionalization methodologies invoking ATRA.[15–18]
Group transfer radical additions (GTRA) allow the transfer of
more complex functionalities to alkenes, with particularly useful
applications in polymer synthesis.[19–25] Despite these advances,
the majority of ATRA and GTRA systems require transition metal
Scheme 1. Prior radical atom/group transfer processes to incorporate N-atom
functionality.
catalysts and are limited by the redox potential of the reagents
used which corresponds to the atoms/groups that are transfera-
ble.
alkene, generating a nucleophilic carbon-centered radical inter-
mediate that is then trapped by an electron-poor heterocycle
(Scheme 1B).[34]
Understanding the effects of radical polarity is an important
design consideration in radical-mediated transformations.[26–28]
Polarity effects of radicals that facilitate hydrogen-atom transfer
processes[29–31] or undergo addition to π-systems[32,33] play a
crucial role in determining the expected reactivities. While
these effects are typically manifested in relative rates – where
proper electronic matching of reactants results in more efficient
processes as compared to electronically mismatched pairs –
they can also exhibit a pronounced impact on chemoselectivity.
A prime example of this is the polarity controlled, three compo-
nent Minisci-type reaction reported by Liu and co-workers
wherein an electrophilic azidyl radical adds to an electron-rich
We recently reported an ATRA O-atom transfer strategy that
achieved intermolecular alkene hydroamination using N-
hydroxyphthalimide (NHPI) as a PhthN· and H-atom source, with
triethyl phosphite as an O-atom acceptor (Scheme 1C).[35] The
electrophilic character of the imidyl radical generated in this
process led us to believe that we could trap the nucleophilic
carbon centered radical formed following PhthN· addition with
a second, electron-deficient alkene. Allyl-oxyphthalimide deriv-
atives have been used as allyl traps of C-radicals while generat-
ing phthalimide N-oxyl radical which serves as the H-atom ab-
stractor.[36] We hypothesized that an allyl-oxyphthalimide deriv-
ative could achieve an intermolecular alkene aminoallylation by
supplying the second, electron-deficient alkene (Scheme 1D).
[a] Department of Chemistry and Biochemistry,
University of California San Diego
9500 Gilman Dr, La Jolla, CA 92093, USA
E-mail: vschmidt@ucsd.edu
http://schmidtgroup.ucsd.edu
Results and Discussion
[**] A previous version of this manuscript has been deposited on a preprint
server (https://doi.org/10.26434/chemrxiv.8479250.v1)
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901071.
We began by subjecting allyl-oxyphthalimide derivative 1, bear-
ing a vinyl cyano-group, to a small excess of triethyl phosphite
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(1.5 equiv.), dilauroyl peroxide [(undecylCO2)2, 0.1 equiv.], and O-atom transfer occurs with trimethyl phosphite while the polar
10 equiv. of n-butyl vinyl ether (NBVE) in 1,2-dichloroethane Arbuzov-type pathway does not.[38] Other thermal radical initia-
(DCE) at 90 °C (Table 1, entry 1).
tors such as 2,2′-azobis(2-methylpropionitrile) (AIBN) or benzoyl
peroxide [(BzO)2] in place of dilauroyl peroxide uniformly re-
sulted in decreased reaction efficiency (Table 1, entries 5 and
6), as did changing solvent from DCE to acetonitrile (MeCN) or
benzene (entries 7 and 8). The necessity of phosphite and initia-
tor was confirmed, as experiments that excluded either did not
result in the formation of 1a (entries 9 and 10).
Table 1. Reaction optimization.[a]
We found that allyl-oxyphthalimide derivatives bearing elec-
tron withdrawing substituents such as esters, nitriles, or elec-
tron deficient arenes were the most successful at undergoing
this aminoallylation process (compounds 1a, 2a, 3a, and 4a,
Scheme 2a). Less electronically deficient substrates bearing sulf-
oxides or amides lead only to decomposition (Scheme 2b),[39]
while precursors containing a sulfide or phenyl substituent, as
well as the parent, unsubstituted allyl group resulted only in
the recovery of starting material. These results highlight the
importance of the allyl-oxyphthalimide olefin polarity.
Entry
PR3
Initiator
Solvent
Yield of 1a[b]
1
2
3
4
5
6
7
8
9
P(OEt)3
(undecylCO2)2
(undecylCO2)2
(undecylCO2)2
(undecylCO2)2
AIBN
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
PhH
DCE
DCE
34 %
P(OtBu)3
P(OiPr)3
P(OMe)3
P(OMe)3
P(OMe)3
P(OMe)3
P(OMe)3
None
< 5 %
20 %
45 %[c]
21 %
(BzO)2
< 5 %
36 %
< 5 %
< 5 %
< 5 %
(undecylCO2)2
(undecylCO2)2
(undecylCO2)2
None
10
P(OMe)3
[a] All reactions carried out with 1 (1 equiv.) and n-butyl vinyl ether (10 equiv.)
in the specified solvent (0.04 ) unless otherwise noted. [b] Determined by
M
gas chromatography using mesitylene as an internal standard. [c] Isolated
yield of 26 % following purification on silica gel.
While aminoallylation product 1a was detected in 34 % yield
as determined by gas chromatography, the major product, iso-
lated in 42 % yield, was N-(O-ethyl) hydroxyphthalimide. We
attribute the formation of this by-product to a polar, SN2′ Arbu-
zov-type pathway producing diethyl (2-cyanoallyl)phosphonate
and N-(O-ethyl) hydroxyphthalimide (Equation 1).
Scheme 2. Electronic requirements of the transferring allyl group.
Noting the importance of the electronic properties of the
In order to prevent this unwanted reactivity, we investigated allyl-oxyphthalimide reagents, we became interested in the ex-
other alkyl phosphites as O-atom acceptors. Using tri-tert-butyl ternal alkenes that would participate in this transformation.
phosphite, which should be less prone to nucleophilic attack at While an array of electron rich vinyl ethers were successfully
the tertiary center, we no longer observed the corresponding functionalized (compounds 3a–3f, Scheme 3), vinyl sulfides and
O-alkylated oxyphthalimide, however the aminoallylation reac- vinylsilanes resulted in only trace amounts of desired products.
tion efficiency fell to only trace formation of 1a (< 5 % yield, Internal vinyl ethers were similarly unsuccessful, which we at-
entry 2). We ascribe this observation to a decreased rate of O- tribute to decreased rates of radical addition. Less electronically
atom transfer to the more sterically encumbered phosphorus unbiased alkenes such as 1-hexene and styrene did not partici-
center. The more accessible triisopropyl phosphite again proved pate, further emphasizing the importance of polarity effects for
successful in minimizing the formation of the O-alkylated oxy- this transformation. It′s relevant to note that alkene hydroamin-
phthalimide by-product, but only improved aminoallylation re- ation was not observed in this study irrespective of the external
action efficiency to 20 % yield (entry 3).
alkene or allyl-oxyphthalimide reagent used.
Contrary to our initial hypothesis, the use of the smallest,
As was the case for both the allyl-oxyphthalimide derivatives
primary alkyl phosphite, trimethyl phosphite, was found to be and the external alkenes amenable to this reaction, substrate
the most successful at promoting aminoallylation, improving electronics played a major role in reaction efficiency, and only
the yield of 1a to 45 %, while minimizing the amount of when electronically deficient allyl-oxyphthalimides were paired
O-alkylation (entry 4). The mass balance is attributed to non- with electron rich alkenes was productive reactivity observed.
selective decomposition of 1a as unreacted starting material We propose that these electronic effects are a result of the need
was not recovered after 12 h. While it has been demonstrated for proper polarity matching of each radical formed. It is well
that the rate of O-atom transfer from peroxyl radicals to tri- known that polarity has a strong influence on the rates of radi-
methyl phosphite is slower than to triethyl or triisopropyl phos- cal-mediated processes, and that the rate of addition of electro-
phite,[37] our data suggests that in the present aminoallylation, philic radicals to electron-rich alkenes is more rapid than to
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Communication
N-centered radical is now poised to selectively add to the elec-
tron-rich alkene substrate in preference to the allyl-oxyphthal-
imide reagent bearing an electron-deficient alkene. The result
is a nucleophilic C-centered radical intermediate that is now
electronically matched to add to the allyl-oxyphthalimide sub-
strate to form the aminoallylated product and regenerate
PhthNO·. This mechanism is consistent with the pronounced
electronic effects observed in our study.
Conclusions
In summary, we report a radical-mediated aminoallylation of
alkenes using allyl-oxyphthalimides that further cements our
mechanistic proposal that both groups connected to the central
O-atom of NHPI or allyl-oxyphthalimides transfer with predicta-
ble regioselectivity to alkenes. The pairing of an electron defi-
cient allyl-oxyphthalimide substrate with an external electron-
rich alkene was found to be essential for productive reactivity,
emphasizing the importance of polarity matching. While some-
what limited in scope, this serves as an excellent example of
radical polarity effects, specifically with respect to how this
dictates reactivity.
Scheme 3. Alkene scope. Yields given of purified material following silica gel
chromatography.
electron deficient alkenes, whereas electron-rich, nucleophilic
radicals are biased to add to electronically deficient alkenes
(Scheme 4A). For the radical mediated aminoallylation reaction
presented herein, proper polarity matching was indeed essen-
tial for product formation.
Experimental Section
General Aminoallylation Procedure: To a 1-dram vial charged
with a magnetic stir bar was added the respective allyl-PINO deriva-
tive (20 mg), dilauroyl peroxide (0.10 equiv.), triethyl phosphite
(1.5 equiv.), olefin (10 equiv.), and 1,2-dichloroethane (3 mL). The
vial was capped and heated to 90 °C. Upon consumption of the
N-(O-allyl)hydroxyphthalimide derivative as judged by TLC (25 %
EtOAc in hexanes), the reaction mixture was concentrated under
reduced pressure and purified by flash column chromatography
(10 % EtOAc in hexanes).
Acknowledgments
Financial support was provided by start-up funds from the Uni-
versity of California San Diego. We would also like to thank
Angel Mendoza and Kathleen Gundran for assistance in sub-
strate preparation during our preliminary studies.
Keywords: Radical chemistry · Polarity effects ·
Aminoallylation · O-atom transfer · Phosphite
[1] S. Patai, in The Chemistry of Alkenes, Wiley Interscience 1964, vol 1.
[2] X. Lan, N. Wang, Y. Xing, Eur. J. Org. Chem. 2017, 5821.
[3] H. Jiang, A. Studer, Chem. Eur. J. 2019, 25, 516.
[4] L. Fu, S. Zhou, X. Wan, P. Chen, G. Liu, J. Am. Chem. Soc. 2018, 140, 10965.
[5] J. Huo, A. Ee, H. Cao, H. Ong, J. Xu, J. Wu, Angew. Chem. Int. Ed. 2018,
57, 17220; Angew. Chem. 2018, 130, 17466.
Scheme 4. Mechanistic proposal.
[6] W. Kong, C. Yu, H. An, Q. Song, Org. Lett. 2018, 20, 4975.
[7] Z. Xiao, Y. Lie, L. Zheng, X. Zhou, Y. Xie, C. Liu, Y. Guo, Q. Chen, Tetrahe-
dron 2018, 74, 6213.
[8] G. Li, T. Chang, B. K. Sharpless, Angew. Chem. Int. Ed. Engl. 1996, 35, 451;
Angew. Chem. 1996, 108, 449.
[9] J. P. Wolfe, Synlett 2008, 2913.
[10] B. A. Hopkins, J. P. Wolfe, Angew. Chem. Int. Ed. 2012, 51, 9886; Angew.
Chem. 2012, 124, 10024.
We propose that aminoallylation initiates by addition of the
primary alkyl radical generated from dilauroyl peroxide ther-
molysis to the allyl-oxyphthalimide (Scheme 4B). This generates
PhthNO· which adds to trimethyl phosphite generating an inter-
mediate now setup to cleave the weak N-O bond via ꢀ-scission.
This step is driven by the formation of the strong phosphoranyl
unit while simultaneously producing PhthN·. This electrophilic
[11] R. M. Romero, T. H. Woste, K. Muniz, Chem. Asian J. 2014, 9, 972.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[12] C. Francesca, A. Goti, Nat. Chem. 2009, 1, 269.
[13] L. V. Desai, M. S. Sanford, Angew. Chem. Int. Ed. 2007, 46, 5737; Angew.
Chem. 2007, 119, 5839.
[14] M. S. Kharasch, E. V. Jensen, W. H. Urry, Science 1945, 102, 128.
[15] P. Renaud, M. P. Sibi, in Radicals in Organic Synthesis Volume 1: Basic
Principles; Wiley-VCH, 2001; pp. 72.
[28]
[29]
[30]
I. Fleming, in Frontier Orbitals and Organic Chemical Reactions, Wiley, New
York, 1976, Chapter 5, pp. 182–186.
F. Minisci, E. Vismara, F. Fontana, G. Morini, M. Serravalle, J. Org. Chem.
1987, 52, 730.
X. Pan, E. Lacote, J. Lalevee, D. P. Curran, J. Am. Chem. Soc. 2012, 134,
5669.
[16] A. Clark, J. Chem. Soc., Rev. 2002, 31, 1.
[31]
[32]
[33]
B. P. Roberts, Chem. Soc. Rev. 1999, 28, 25.
[17] L. Quebatte, K. Thommes, K. Severin, J. Am. Chem. Soc. 2006, 128, 7440.
[18] K. Proinsias, A. Jackowska, K. Radzewicz, M. Gledyk, D. Gryko, Org. Lett.
2018, 20, 296.
[19] R. A. Gossage, L. A. van de Kuil, G. van Koten, Acc. Chem. Res. 1998, 31,
423.
[20] M. Kato, M. Kamigaito, M. Sawamoto, T. Higashimura, Macromolecules
1995, 28, 1721.
[21] F. Minisci, Acc. Chem. Res. 1975, 8, 165.
[22] J. Wang, K. Matyjaszewski, J. Am. Chem. Soc. 1995, 117, 5614.
[23] J. Iqbal, B. Bhatia, N. K. Nayyar, Chem. Rev. 1994, 94, 519.
[24] S. Z. Zard, Angew. Chem. Int. Ed. Engl. 1997, 36, 672; Angew. Chem. 1997,
109, 724.
B. Giese, J. He, W. Mehl, Chem. Ber. 1988, 121, 2063.
F. Minisci, E. Vismara, G. Morini, F. Fontana, S. Levi, M. Serravalle, J. Org.
Chem. 1986, 51, 476.
[34]
[35]
[36]
[37]
[38]
Z. Liu, Z.-Q. Liu, Org. Lett. 2017, 19, 5649.
S. W. Lardy, V. A. Schmidt, J. Am. Chem. Soc. 2018, 140, 12318.
S. Patil, L. Chen, J. M. Tanko, Eur. J. Org. Chem. 2014, 502.
E. Furimsky, J. A. Howard, J. Am. Chem. Soc. 1973, 95, 369.
H. Mayr, M. Patz, Angew. Chem. Int. Ed. Engl. 1994, 33, 938; Angew. Chem.
1994, 106, 990.
[39]
C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165.
[25] S. Z. Zard, Aust. J. Chem. 2006, 59, 663.
[26] E. Godineau, Y. Landais, Chem. Eur. J. 2009, 15, 3044.
[27] F. DeVleeschouwer, V. VanSpeybroeck, M. Waroquier, P. Geerlings, F. De-
Profit, Org. Lett. 2007, 9, 2721.
Received: July 22, 2019
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Communication
Radicals Reactions
S. W. Lardy, V. A. Schmidt* .............. 1–5
Intermolecular Aminoallylation of
Alkenes Using Allyl-Oxyphthalimide
Derivatives: A Case Study in Radical
Polarity Effects**
This work describes the essential radi- Each open shell intermediate along
cal polarity effects manifested in pur- the proposed mechanistic pathway is
suit of a group transfer radical addition steered to preferentially react with
to achieve alkene aminoallylation. only one reagent.
DOI: 10.1002/ejoc.201901071
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