Redox-neutral α-C-H bond functionalization of secondary amines with concurrent C-P bond formation/N-alkylation

Article abstract of DOI:10.1021/ol401858k

Redox-neutral formation of C-P bonds in the α-position of amines was achieved via a process that features a combination of an oxidative α-C-H bond functionalization and a reductive N-alkylation. Benzoic acid functions as an efficient catalyst in this three-component reaction of cyclic secondary amines, aldehydes and phosphine oxides to provide rapid access to α-amino phosphine oxides not easily accessible by classic Kabachnik-Fields reactions.

Full text of DOI:10.1021/ol401858k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Redox-Neutral r‑CꢀH Bond
Functionalization of Secondary
Amines with Concurrent CꢀP Bond
Formation/N‑Alkylation
Deepankar Das and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State University
of New Jersey, Piscataway, New Jersey 08854, United States
seidel@rutchem.rutgers.edu
Received July 3, 2013
ABSTRACT
Redox-neutral formation of CꢀP bonds in the r-position of amines was achieved via a process that features a combination of an oxidative r-CꢀH
bond functionalization and a reductive N-alkylation. Benzoic acid functions as an efficient catalyst in this three-component reaction of cyclic
secondary amines, aldehydes and phosphine oxides to provide rapid access to r-amino phosphine oxides not easily accessible by classic
KabachnikꢀFields reactions.
R-Aminophosphonic acids and their phosphonate
derivatives have received considerable attention as surro-
gates of both natural and unnatural R-amino acids.1 These
compounds are known to exhibit antitumor, antibiotic,
pharmacogenetic, and pharmacological properties and are
widely applied in agrochemistry.2 Not surprisingly, much
effort has been devoted to the efficient synthesis of
R-aminophosphonates and their related R-amino phos-
phine oxides.3 The three-component reaction between
amines, carbonyl compounds and phosphonates, widely
known as the KabachnikꢀFields reaction,4 is one of the
most useful methods for the synthesis of such com-
pounds (eq 1).5 An alternate strategy, namely the direct
R-phosphonation of tertiary amines, has been realized by
oxidative CꢀH functionalization,6,7 including photoredox
catalysis (eq 2).8 Apart from the requirement for an oxidant,
such processes are often limited to N-aryl tetrahydro-
isoquinolines and N,N-dialkylanilines. A copper-catalyzed
(5) Selected reviews: (a) Zefirov, N. S.; Matveeva, E. D. ARKIVOC
2008, 1. (b) Keglevich, G.; Balint, E. Molecules 2012, 17, 12821.
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Ofial, A. R. Chem. Commun. 2009, 6023. (c) Han, W.; Mayer, P.; Ofial,
A. R. Adv. Synth. Catal. 2010, 352, 1667. (d) Xie, J.; Li, H.; Xue, Q.;
Cheng, Y.; Zhu, C. Adv. Synth. Catal. 2012, 354, 1646. (e) Wang, H.; Li,
X.; Wu, F.; Wan, B. Tetrahedron Lett. 2012, 53, 681. (f) Alagiri, K.;
Devadig, P.; Prabhu, K. R. Tetrahedron Lett. 2012, 53, 1456. (g)
Dhineshkumar, J.; Lamani, M.; Alagiri, K.; Prabhu, K. R. Org. Lett.
2013, 15, 1092.
(7) Selected reviews on amine R-functionalization: (a) Murahashi,
S.-I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443. (b) Campos, K. R.
Chem. Soc. Rev. 2007, 36, 1069. (c) Murahashi, S. I.; Zhang, D. Chem.
Soc. Rev. 2008, 37, 1490. (d) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(e) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O.
Chem.;Eur. J. 2010, 16, 2654. (f) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215. (g) Jones, K. M.; Klussmann, M. Synlett 2012, 23, 159.
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(i) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes,
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(1) Kukhar, V. P., Hudson, H. R., Eds. Aminophosphonic and
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& Sons: Chichester, 2000.
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r
10.1021/ol401858k
XXXX American Chemical Society

decarboxylative three-component coupling approach to
ring-substituted R-aminophosphonates was reported by
Wang and co-workers (eq 3).9ꢀ11 We envisioned an alter-
nate three-component reaction in which the amino acid
would be replaced with a simple amine, removing the
requirement for a prefunctionalized substrate (eq 4). This
would result in a method for CꢀP bond formation via
functionalization of relatively unreactive CꢀH bonds. Here,
we report the first examples of such a process.
Figure 1. Competing reaction pathways in the R-CꢀH bond
functionalization of amines.
regioisomers 7.12m In the R-alkynylation, only minimal
isomerization was observed between the propargylic
amines corresponding to 7 and 8.12n Here, good to ex-
cellent ratiosof 7/8 were obtainedby using relatively bulky
and/or electron-deficient aromatic aldehydes (e.g., 2,6-
dichlorobenzaldehyde, mesitaldehyde). The use of these
aldehydes in combination with an appropriate catalyst
(e.g., a carboxylic acid) apparently accelerates the imi-
nium isomerization pathway and/or decreases the rate of
the classic three-component coupling reaction.
With the above considerations in mind, we chose 2,6-
dichlorobenzaldehyde as the reaction partner to evaluate
the proposed reaction of pyrrolidine and different
phosphites/phosphine oxides (Table 1). Based on previous
success, benzoicacidwas selected asthecatalyst. Reactions
proceeded smoothly under microwave irradiation at
200 °C and the desired regioisomer 9 was consistently
isolated as the major product. When diethyl phosphite
(1.5 equiv) was allowed toreact with pyrrolidine (1.2 equiv)
and 2,6-dichlorobenzaldehyde in toluene for 15 min, the
desired product 9a was formed in 54% yield (entry 1).
In addition, compound 11, the apparent product of a
As part of our efforts to develop new amine R-CꢀH
bond functionalization reactions,12,13 we recently reported
amine R-cyanations12m and R-alkynylations.12n These
redox-neutral14 transformations combine a reductive
N-alkylation with an oxidative R-functionalization and fea-
ture azomethine ylides as reactive intermediates (Figure 1).
Water is produced as the only byproduct. The obvious
challenge in the development of such reactions is that they
compete with classic organic reactions (e.g., Strecker reaction),
namely the addition of the nucleophile to the initially
formed iminium ion. An indirect solution to this pro-
blem was developed in the case of the R-cyanation; we
have shown that R-aminonitriles corresponding to 8
can equilibrate to the thermodynamically more stable
(13) Selected recent examples of redox-neutral amine R-functionali-
zations: (a) Matyus, P.; Elias, O.; Tapolcsanyi, P.; Polonka-Balint, A.;
Halasz- Dajka, B. Synthesis 2006, 2625. (b) Ryabukhin, S. V.; Plaskon,
A. S.; Volochnyuk, D. M.; Shivanyuk, A. N.; Tolmachev, A. A. J. Org.
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C. Angew. Chem., Int. Ed. 2008, 47, 6594. (f) Mori, K.; Ohshima, Y.;
Ehara, K.; Akiyama, T. Chem. Lett. 2009, 38, 524. (g) Ruble, J. C.; Hurd,
A. R.; Johnson, T. A.; Sherry, D. A.; Barbachyn, M. R.; Toogood, P. L.;
Bundy, G. L.; Graber, D. R.; Kamilar, G. M. J. Am. Chem. Soc. 2009,
131, 3991. (h) Cui, L.; Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131,
8394. (i) Cui, L.; Ye, L.; Zhang, L. Chem. Commun. 2010, 46, 3351. (j)
Kang, Y. K.; Kim, S. M.; Kim, D. Y. J. Am. Chem. Soc. 2010, 132,
11847. (k) Zhou, G.; Zhang, J. Chem. Commun. 2010, 46, 6593. (l) Cao,
W. D.; Liu, X. H.; Wang, W. T.; Lin, L. L.; Feng, X. M. Org. Lett. 2011,
13, 600. (m) Zhou, G. H.; Liu, F.; Zhang, J. L. Chem.;Eur. J. 2011, 17,
3101. (n) Mori, K.; Ehara, K.; Kurihara, K.; Akiyama, T. J. Am. Chem.
Soc. 2011, 133, 6166. (o) He, Y. P.; Du, Y. L.; Luo, S. W.; Gong, L. Z.
Tetrahedron Lett. 2011, 52, 7064. (p) Mahoney, S. J.; Fillion, E. Chem.;
Eur. J. 2012, 18, 68. (q) Jurberg, I. D.; Peng, B.; Woestefeld, E.;
Wasserloos, M.; Maulide, N. Angew. Chem., Int. Ed. 2012, 51, 1950.
(r) Han, Y. Y.; Han, W. Y.; Hou, X.; Zhang, X. M.; Yuan, W. C. Org.
Lett. 2012, 14, 4054. (s) Chen, L. J.; Zhang, L.; Lv, J.; Cheng, J. P.; Luo,
S. Z. Chem.;Eur. J. 2012, 18, 8891. (t) Noey, E. L.; Luo, Y. D.; Zhang,
L. M.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 1078. (u) Sugiishi, T.;
Nakamura, H. J. Am. Chem. Soc. 2012, 134, 2504. (v) He, Y. P.; Wu, H.;
Chen, D. F.; Yu, J.; Gong, L. Z. Chem.;Eur. J. 2013, 19, 5232.
(14) (a) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem.,
Int. Ed. 2009, 48, 2854. (b) Newhouse, T.; Baran, P. S.; Hoffmann, R. W.
Chem. Soc. Rev. 2009, 38, 3010.
(8) (a) Rueping, M.; Zhu, S.; Koenigs, R. M. Chem. Commun. 2011,
8679. (b) Hari, D. P.; Konig, B. Org. Lett. 2011, 13, 3852. (c) Xue, Q. C.;
Xie, J.; Jin, H. M.; Cheng, Y. X.; Zhu, C. J. Org. Biomol. Chem. 2013, 11,
1606.
(9) Yang, D.; Zhao, D.; Mao, L.; Wang, L.; Wang, R. J. Org. Chem.
2011, 76, 6426.
(10) See also: Firouzabadi, H.; Iranpoor, N.; Ghaderi, A.; Ghavami,
€
M. Tetrahedron Lett. 2012, 53, 5515.
(11) A related oxidative/decarboxylative approach: Hu, J.; Zhao, N.;
Yang, B.; Wang, G.; Guo, L. N.; Liang, Y. M.; Yang, S. D. Chem.;Eur.
J. 2011, 5516.
(12) (a) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc.
2008, 130, 416. (b) Murarka, S.; Zhang, C.; Konieczynska, M. D.; Seidel,
D. Org. Lett. 2009, 11, 129. (c) Zhang, C.; Murarka, S.; Seidel, D. J. Org.
Chem. 2009, 74, 419. (d) Murarka, S.; Deb, I.; Zhang, C.; Seidel, D.
J. Am. Chem. Soc. 2009, 131, 13226. (e) Zhang, C.; Seidel, D. J. Am.
Chem. Soc. 2010, 132, 1798. (f) Deb, I.; Seidel, D. Tetrahedron Lett. 2010,
51, 2945. (g) Zhang, C.; Das, D.; Seidel, D. Chem. Sci. 2011, 2, 233. (h)
Deb, I.; Das, D.; Seidel, D. Org. Lett. 2011, 13, 812. (i) Haibach, M. C.;
Deb, I.; De, C. K.; Seidel, D. J. Am. Chem. Soc. 2011, 133, 2100. (j) Deb,
I.; Coiro, D. J.; Seidel, D. Chem. Commun. 2011, 47, 6473. (k) Vecchione,
M. K.; Sun, A. X.; Seidel, D. Chem. Sci. 2011, 2, 2178. (l) Das, D.;
Richers, M. T.; Ma, L.; Seidel, D. Org. Lett. 2011, 13, 6584. (m) Ma, L.;
Chen, W.; Seidel, D. J. Am. Chem. Soc. 2012, 134, 15305. (n) Das, D.;
Sun, A.; Seidel, D. Angew. Chem., Int. Ed. 2013, 52, 3765. (o) Dieckmann,
A.; Richers, M. T.; Platonova, A. Y.; Zhang, C.; Seidel, D.; Houk, K. N.
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A. Y.; Zhang, C.; Seidel, D. Synthesis 2013, 45, 1730.
B
Org. Lett., Vol. XX, No. XX, XXXX

reductive amination, was also isolated in 13% yield.15,16
The corresponding reaction with dibenzyl phosphite led to
the formation of 9b in 44% yield, accompanied by simul-
taneous formation of 11 in 30% yield (entry 2). Gratify-
ingly, with diphenylphosphine oxide (1.5 equiv) as the
reaction partner, product 9c was obtained exclusively in
86% yield (entry 3). Lowering the amount of diphenylpho-
sphine oxide to 1.2 equiv did have no adverse effect on
the outcome of the reaction (entry 4). A reduction in
catalyst loading to 10 mol % led to a slight decrease in
yield (entry 5). The use of 2-ethylhexanoic acid in place
of benzoic acid resulted in the exclusive formation of
9c in 84% yield (entry 6). Interestingly, the reaction of
2,6-dichlorobenzaldehyde, pyrrolidine and diphenylpho-
sphine oxide also proceeded without the addition of
any catalyst to furnish the desired product 9c in good yield
(entry 7). No product formation was observed with
copper(II) 2-ethylhexanoate, the catalyst that had proved
optimal in the amine R-alkynylation (entry 8).12n
yielded predominantly the undesired regioisomer 10d
(entries 4ꢀ6), showing that the good product ratio in the
uncatalyzed reaction of 2,6-dichlorobenzaldehyde is spe-
cific to that particular aldehyde (see Table 1, entry 7). No
further improvement could be achieved with 2-ethylhex-
anoic acid as the catalyst (entries 7, 8). Trifluoroacetic acid
proved tobe an inferior catalyst (entry 9). This observation
is consistent with the previously established requirement
for a weakly acidic carboxylic acid catalyst.12m
Table 2. Dependence of Product Ratios on Catalyst and
Reaction Timea
time
ratio
entry
catalyst
PhCOOH
(min) 9d/10d yield 9dþ10d (%)
1
2
3
4
5
6
7
8
9
5
15
30
5
4.4:1
10:1
21:1
1:6
86
87
87
83
86
81
92
83
66
Table 1. Evaluation of Reaction Parametersa
PhCOOH
PhCOOH
ꢀ
ꢀ
30
60
5
1:3
ꢀ
1:1
2-ethylhexanoic acid
2-ethylhexanoic acid
TFA
1.2:1
13:1
1:1
30
30
a Reactions were performed on a 0.5 mmol scale.
catalyst
(mol %)
ratio
yield
yield
entry HPOR2 (equiv)
9/10 9 þ 10 (%) 11 (%)
The results shown in Table 2 suggest that the equilibra-
tion of regioisomeric products is an important factor that
affects the observed product ratios. To unambiguously
establish that product isomerization does indeed occur,
compound 10c was exposed to the previously established
reaction conditions (eq 7). In the event, 9c was obtained
in 86% yield as the only detectable regioisomer. In the
otherwise identical experiment with 10d, products 9d/10d
were obtained as an 11:1 regioisomeric mixture in 84%
yield (eq 8). While this result nicely matches the second
entry in Table 2, the product ratio suggests that the
thermodynamic equilibrium ratio is not reached after
15 min. Importantly, no isomerization was observed upon
exposing 9c or 9d to the reaction conditions.
1
2
3
4
5
6
7
8
HPO(OEt)2 (1.5) PhCOOH (20) >25:1
HPO(OBn)2 (1.5) PhCOOH (20) >25:1
54
44
86
86
80
84
86
N/A
13
30
HPOPh2 (1.5)
HPOPh2 (1.2)
HPOPh2 (1.2)
HPOPh2 (1.2)
HPOPh2 (1.2)
HPOPh2 (1.2)
PhCOOH (20) >25:1
PhCOOH (20) >25:1
PhCOOH (10) >25:1
N/A
N/A
N/A
N/A
N/A
N/A
2-EHA (20)
>25:1
>25:1
ꢀ
Cu(2-EH)2 (20) N/A
a Reactions were performed on a 0.5 mmol scale.
To establish the influence that the nature of the aldehyde
exertson productratios, the three-componentreactionwas
performed with unsubstituted benzaldehyde (Table 2). A
favorable product ratio for 9d/10d of 4.4:1 was observed
after a short reaction time of just 5 min (Table 2, entry 1).
An increase in reaction time favorably affected product
ratios (entries 1ꢀ3) and at a reaction time of 30 min,
products 9d/10d were obtained in a 21:1 ratio and 87%
combined yield. In the absence of any catalyst, the reaction
(15) Dialkyl phosphites are known to act as reducing agents: (a)
Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. J. Org. Chem. 1981, 46,
3745. (b) Hirao, T.; Masunaga, T.; Hayashi, K.; Ohshiro, Y.; Agawa, T.
Tetrahedron Lett. 1983, 24, 399.
(16) The competing reduction process in the reaction with diethyl
phosphite was also observed with other aldehydes. For instance, mesi-
taldehyde provided the desired R-functionalized product in a > 25:1
ratio and 36% yield, accompanied by 18% of the product resulting from
reductive amination. With benzaldehyde, R-functionalized product was
obtained in a > 25:1 ratio and 47% yield, accompanied by 25% of
N-benzylpyrrolidine.
The scope of the three-component reaction was explored
under the optimized conditions (Figure 2). Reactions of
pyrrolidine and diphenylphosphine oxide with various
Org. Lett., Vol. XX, No. XX, XXXX
C

tolerated. Heterocyclic aldehydes were also viable sub-
strates. Benzophenone led to the exclusive formation
of ring-substituted product. It was further shown that
dibenzylphosphine oxide gives favorable results which are
comparable to those of diphenylphosphine oxide. The
use of hydrocinnamaldehyde as the substrate gave only
the undesired regioisomer. This outcome is similar to what
was observed in the corresponding cyanation reaction.12m
Upon exposure of piperidine to the reaction conditions
with diphenylphosphine oxide and 2,6-dichlorobenzalde-
hyde, the corresponding product was obtained in a 1:1
regioisomeric ratio, albeit in low yield. Azepane provided
an even less favorable product ratio and morpholine gave
only the regular KabachnikꢀFields reaction product.
In summary, we have developed a convenient approach
for CꢀP bond formation in the R-position of amines by
replacing existing CꢀH bonds. The oxidative R-functio-
nalization is coupled toa reductive N-alkylation, rendering
the overall process redox-neutral. Further applications of
this general concept are currently being developed in our
laboratory.
Acknowledgment. Financial support from the NIHꢀ
NIGMS (Grant No. R01GM101389-01) is gratefully
acknowledged. D.S. is a fellow of the Alfred P. Sloan
Foundation and the recipient of an Amgen Young Inves-
tigator Award.
Figure 2. Scope of the three-component reaction.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
aromatic aldehydes consistently led to the formation of
the desired R-amino phosphine oxides 9 as the major or
nearly exclusive products. Electron-donating and electron-
withdrawing groups at different ring positions were well
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX