The decarboxylative strecker reaction

Article abstract of DOI:10.1021/ol202957d

α-Amino acids react with aldehydes in the presence of a cyanide source to form α-amino nitriles in what can be considered a decarboxylative variant of the classical Strecker reaction. This unprecedented transformation does not require the use of a metal catalyst and provides facile access to valuable α-amino nitriles that are inaccessible by traditional Strecker chemistry.

Full text of DOI:10.1021/ol202957d

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6584–6587
The Decarboxylative Strecker Reaction
Deepankar Das, Matthew T. Richers, Longle Ma, 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 November 3, 2011
ABSTRACT
R-Amino acids react with aldehydes in the presence of a cyanide source to form R-amino nitriles in what can be considered a decarboxylative
variant of the classical Strecker reaction. This unprecedented transformation does not require the use of a metal catalyst and provides facile
access to valuable R-amino nitriles that are inaccessible by traditional Strecker chemistry.
First reported in 1850,1 the Strecker reaction remains of
considerable interest as a valuable tool for the construction
of R-amino nitriles, exceptionally versatile precursors to
amino acids and various other building blocks.2,3 While
the original Strecker reaction used ammonia, a variety of
other amines have been employed. In a prototypical
Strecker reaction, an amine 1 is condensed with an alde-
hyde in the presence of a cyanide source to give product 2
(eq 1). Here we report that R-amino acids 3 react with
aldehydes and different sources of cyanide to form R-
amino nitriles 4 in a remarkably facile fashion (eq 2). This
Transition metal catalyzed decarboxylative CꢀC bond
strategy that enables a variety of useful transformations.4
unprecedented decarboxylative variant of the Strecker
reaction provides rapid access to valuable R-amino nitriles
not accessible via traditional Strecker chemistry.
formations have recently emerged as a valuable synthetic
In the context of metal-free decarboxylative CꢀC bond
formation, the condensationofR-amino acids with various
(1) (a) Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27. (b)
(4) For examples of metal catalyzed decarboxylative CꢀC bond
Strecker, A. Justus Liebigs Ann. Chem. 1854, 91, 349.
formations, see: (a) Myers, A. G.; Tanaka, D.; Mannion, M. R.
J. Am. Chem. Soc. 2002, 124, 11250. (b) Tanaka, D.; Romeril, S. P.;
Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323. (c) Rayabarapu,
D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127, 13510. (d) Gooßen,
L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662. (e) Forgione, P.;
Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F.
J. Am. Chem. Soc. 2006, 128, 11350. (f) Baudoin, O. Angew. Chem., Int.
Ed. 2007, 46, 1373. (g) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc.
2007, 129, 4138. (h) Gooßen, L. J.; Rodriguez, N.; Gooßen, K. Angew.
Chem., Int. Ed. 2008, 47, 3100. (i) Bonesi, S. M.; Fagnoni, M.; Albini, A.
Angew. Chem., Int. Ed. 2008, 47, 10022. (j) Wang, C.; Piel, I.; Glorius, F.
J. Am. Chem. Soc. 2009, 131, 4194. (k) Shang, R.; Fu, Y.; Li, J.-B.;
Zhang, S.-L.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2009, 131, 5738. (l)
Lin, L.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9610. (m)
Zhang, F.; Greaney, M. F. Angew. Chem., Int. Ed. 2010, 49, 2768. (n)
Lindh, J.; Sjoeberg, P. J. R.; Larhed, M. Angew. Chem., Int. Ed. 2010, 49,
7733. (o) Fang, P.; Li, M.; Ge, H. J. Am. Chem. Soc. 2010, 132, 11898. (p)
Shang, R.; Ji, D.-S.; Chu, L.; Fu, Y.; Liu, L. Angew. Chem., Int. Ed. 2011,
50, 4470.
(2) For selected reviews on the Strecker reaction, see: (a) Duthaler,
R. O. Tetrahedron 1994, 50, 1539. (b) Yet, L. Angew. Chem., Int. Ed.
2001, 40, 875. (c) Groeger, H. Chem. Rev. 2003, 103, 2795. (d) Friestad,
G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541. (e) Shibasaki, M.;
Kanai, M.; Mita, T. Org. React. 2008, 70, 1. (f) Connon, S. J. Angew.
Chem., Int. Ed. 2008, 47, 1176. (g) Gawronski, J.; Wascinka, N.; Gajewy,
J. Chem. Rev. 2008, 108, 5227. (h) Syamala, M. Org. Prep. Proced. Int.
2009, 41, 1. (i) Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N.
Acc. Chem. Res. 2009, 42, 1117. (j) Merino, P.; Marques-Lopez, E.;
Tejero, T.; Herrera, R. P. Tetrahedron 2009, 65, 1219. (k) Martens, J.
ChemCatChem 2010, 2, 379. (l) Bergin, E. Sci. Synth., Stereosel. Synth.
2011, 2, 531. (m) Wang, J.; Liu, X.; Feng, X. Chem. Rev. 2011, 111, 6947.
(3) For selected reviews on the utility of R-amino nitriles, see: (a)
Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383. (b) Enders, D.;
Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359. (c) Fleming, F. F.; Zhang,
Z. Tetrahedron 2005, 61, 747. (d) Mattalia, J.-M.; Marchi-Delapierre, C.;
Hazimeh, H.; Chanon, M. ARKIVOC 2006, 90. (e) Opatz, T. Synthesis
2009, 1941.
r
10.1021/ol202957d
Published on Web 11/16/2011
2011 American Chemical Society

aldehydes or ketones has long been recognized to lead to
theformation ofazomethine ylides.5 These reactivedipolar
intermediates have seen tremendous use in synthesis.
However, despite their utility, the chemistry of azomethine
ylides has largely been limited to pericyclic reactions such
as inter- and intramolecular [3 þ 2] cycloadditions as well
as 1,5- and 1,7-electrocyclizations.6 An early example of a
nonpericyclic reaction of azomethine ylides was reported
by Cohen et al. in 1979, namely the reaction of proline with
sterically congested 2-hydroxyacetophenones to form N,
O-acetals.7 As part of our efforts to develop redox-neutral8
reaction cascades for the rapid buildup of molecular
complexity,9 we recently reported decarboxylative three-
component coupling reactions of R-amino acids and alde-
hydes with indoles, naphthols, and nitroalkanes.9e,10 In
addition, we9e and the group of Li11 independently re-
ported a copper catalyzed decarboxylative alkynylation of
R-amino acids. In other work, we were able to show that
related intramolecular reactions enable a rich azome-
thine ylide annulation chemistry.9g,12 These reactions are
thought to proceed through protonation of the intermedi-
ate azomethine ylide by a pronucleophile (e.g., indole),
resulting in the formation of iminium ion pairs that
ultimately give rise to the products.
Table 1. Evaluation of Reaction Parametersa
proline
ratio
yield
(%)
entry (equiv)
solvent
XCN (equiv)
4a:2a
1
2.0
1.5
1.5
1.3
1.2
1.5
1.3
1.2
1.5
1.5
1.5
1.5
1.5
PhMe
PhMe
PhMe
PhMe
PhMe
TMSCN (1.2)
TMSCN (1.2)
TMSCN (1.1)
TMSCN (1.2)
TMSCN (1.2)
4a only 81
2
28:1
17:1
5:1
90
89
81
77
3
4
5
4:1
6
n-BuOH TMSCN (1.2)
n-BuOH TMSCN (1.2)
n-BuOH TMSCN (1.2)
4a only >97
4a only >97
7
8
31:1
17:1
N/A
>97
9
xylenes
TMSCN (1.2)
>97
10
11
12
13
n-BuOH CuCN (1.2)
n-BuOH KCN (1.2)
Trace
4a only 53
(5) (a) Rizzi, G. P. J. Org. Chem. 1970, 35, 2069. (b) Grigg, R.;
Thianpatanagul, S. J. Chem. Soc., Chem. Commun. 1984, 180. (c) Grigg,
R.; Aly, M. F.; Sridharan, V.; Thianpatanagul, S. J. Chem. Soc., Chem.
Commun. 1984, 182.
n-BuOH K3[Fe(CN)6] (1.2) 4a only
n-BuOH EtOCOCN (1.2) 5:1
8
55
a Reactions were performed on a 1 mmol scale.
(6) For selected reviews on azomethine ylide chemistry, see: (a)
Padwa, A. 1,3-Dipolar Cycloaddition Chemistry, Vol. 1; Wiley: New York,
1984. (b) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry, Vol. 2;
Wiley; New York, 1984. (c) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev.
1998, 98, 863. (d) Padwa, A.; Pearson, W. H. Synthetic Applications of
1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products, Vol. 59; Wiley: Chichester, U.K., 2002. (e) Najera, C.; Sansano,
J. M. Curr. Org. Chem. 2003, 7, 1105. (f) Coldham, I.; Hufton, R. Chem.
Rev. 2005, 105, 2765. (g) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem.
Rev. 2006, 106, 4484. (h) Bonin, M.; Chauveau, A.; Micouin, L. Synlett
2006, 2349. (i) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247. (j)
Najera, C.; Sansano, J. M. Top. Heterocycl. Chem. 2008, 12, 117. (k)
Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. (l) Nyerges, M.;
Toth, J.; Groundwater, P. W. Synlett 2008, 1269. (m) Pineiro, M.; Pinho
e Melo, T. M. V. D. Eur. J. Org. Chem. 2009, 5287. (n) Burrell, A. J. M.;
Coldham, I. Curr. Org. Synth. 2010, 7, 312. (o) Adrio, J.; Carretero, J. C.
Chem. Commun. 2011, 47, 6784.
(7) Cohen, N.; Blount, J. F.; Lopresti, R. J.; Trullinger, D. P. J. Org.
Chem. 1979, 44, 4005.
(8) For discussions on redox-economy, see: (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.
(9) (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)
Haibach, M. C.; Deb, I.; De, C. K.; Seidel, D. J. Am. Chem. Soc. 2011,
133, 2100. (i) Deb, I.; Das, D.; Seidel, D. Org. Lett. 2011, 13, 812. (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.
We reasoned that azomethine ylides may be converted to
valuable Strecker-type products if they were exposed to an
appropriate source of cyanide. Consequently, we decided to
investigate this possibility by allowing proline and benzal-
dehyde to react in the presence of various cyanide sources.
Conventional thermal reaction conditions were initially
evaluated but quickly abandoned in favor of reactions
performed under microwave irradiation, as the latter led
to vastly accelerated reaction rates. The results of this survey
are summarized in Table 1. Gratifyingly, the reaction
proceeded as anticipated and the desired regioisomer 4a
was consistently formed as the predominant product, with
only small amounts of 2a being obtained.13ꢀ15 In favorable
cases, the formation of 2a could be suppressed completely.
Although various sources of cyanide including simple po-
tassium cyanide enabled product formation, the use of
(13) The undesired regioisomer 2a is available via classic Strecker
chemistry. For instance, see: (a) Trost, B. M.; Spagnol, M. D. J. Chem.
Soc., Perkin Trans. 1 1995, 2083. (b) Ranu, B. C.; Dey, S. S.; Hajra, A.
Tetrahedron 2002, 58, 2529. (c) Saidi, M. R.; Nazari, M. Monatsh. Chem.
2004, 135, 309. (d) Mojtahedi, M. M.; Abaee, M. S.; Abbasi, H. Can.
J. Chem. 2006, 84, 429. (e) Rajabi, F.; Ghiassian, S.; Saidi, M. R. Green
Chem. 2010, 12, 1349.
(10) For oxidative variants of these reactions, see: (a) Bi, H.-P; Zhao,
L.; Liang, Y.-M; Li, C.-J. Angew. Chem., Int. Ed. 2009, 48, 792. (b) Bi,
H.-P; Chen, W.-W; Liang, Y.-M.; Li, C.-J. Org. Lett. 2009, 11, 3246.
(11) Bi, H.-P.; Teng, Q.; Guan, M.; Chen, W.-W.; Liang, Y.-M.; Yao,
X.; Li, C.-J. J. Org. Chem. 2010, 75, 783.
(12) For other nonpericyclic CꢀC and CꢀX bond formations via
decarboxylation of amino acids, see: (a) Zheng, L.; Yang, F.; Dang, Q.;
Bai, X. Org. Lett. 2008, 10, 889. (b) Wang, Q.; Wan, C.; Gu, Y.; Zhang,
J.; Gao, L.; Wang, Z. Green Chem. 2011, 13, 578. (c) Xu, W.; Fu, H.
J. Org. Chem. 2011, 76, 3846. (d) Yang, D.; Zhao, D.; Mao, L.; Wang, L.;
Wang, R. J. Org. Chem. 2011, 76, 6426. (e) Yan, Y.; Wang, Z. Chem.
Commun. 2011, 47, 9513.
(14) Compound 4a has previously been prepared via oxidative
cyanation. For instance, see: (a) Bonnett, R.; Clark, V. M.; Giddey,
A.; Todd, A. J. Chem. Soc. 1959, 2087. (b) Ho, B.; Castagnoli, N., Jr.
J. Med. Chem. 1980, 23, 133. (c) Sungerg, R. J.; Theret, M. H.; Wright, L.
Org. Prep. Proced. Int. 1994, 26, 386. (d) Yang, T. K.; Yeh, S. T.; Lay,
Y. Y. Heterocycles 1994, 38, 1711. (e) Le Gall, E.; Hurvois, J.-P.;
Sinbandhit, S. Eur. J. Org. Chem. 1999, 2645. (f) Petride, H.; Draghici,
C.; Florea, C.; Petride, A. Cent. Eur. J. Chem. 2004, 2, 302.
(15) For alternate preparations of 4a, see: (a) Zhao, S.; Jeon, H.-B.;
Nadkarni, D. V.; Sayre, L. M. Tetrahedron 2006, 62, 6361. (b) Couty, F.;
David, O.; Larmanjat, B.; Marrot, J. J. Org. Chem. 2007, 72, 1058. (c)
Han, J.; Xu, B.; Hammond, G. B. Org. Lett. 2011, 13, 3450.
Org. Lett., Vol. 13, No. 24, 2011
6585

trimethylsilyl cyanide (TMSCN) was found to be most
convenient. Under optimized microwave conditions, the
reaction of benzaldehyde, 1.3 equiv of proline, and 1.2 equiv
of TMSCN in n-butanol as the solvent gave rise to product
4a as the only detectable regioisomer in near-quantitative
yield (>97%, entry 7). A particularly attractive feature of
this reaction is the brief reaction time, requiring only 10 min
for completion. In comparison, an otherwise identical reac-
tion conducted under reflux in n-butanol for 5 h provided 4a
in 64% yield.
in eqs 7 and 8, single regioisomeric products were also
obtained in reactions of N-benzyl glycine and N-methyl
glycine (sarcosine). Interestingly, products 10 and 12
represent the opposite regioisomers to those ob-
tained with cyclic amino acids. This finding most likely
reflects the different reactivity of the corresponding
azomethine ylides and their individually preferred pro-
tonation sites.
Further analysis of the results displayed in Table 1, in
particular a comparison of entries 1, 2, 4, and 5, revealed
the striking observation that the regioisomeric ratios of 4a
and 2a are apparently dependent on the amount of proline
used. An increase of the equivalents of proline resulted in a
gradual increase of the regioisomeric ratio favoring the
desired product 4a, up to the point where 2a could no
longer be detected. An attempt to rationalize this finding is
provided in Figure 2. Under the reaction conditions,
regioisomer 2a may be in equilibrium with small amounts
of the ion pair 2a0. Interception of 2a0 by proline and the
associated formation of pyrrolidine could thus be a path-
way for regioisomeric enrichment. A sufficient amount of
proline could thus lead to complete consumption of un-
desired 2a.
Figure 1. Scope of the decarboxylative Strecker reaction with
proline.
With the optimized reaction conditions in hand, a series
of different aldehydes was evaluated (Figure 1). Only one
regioisomer was detected in all cases in which no regioiso-
meric ratio (rr) is given. Electron-rich and electron-poor
aromatic aldehydes with different substitution patterns
provided products in generally excellent yields. Heteroaro-
matic aldehydes derived from pyridine, furan, thiophene,
and indole were also viable substrates. Ethyl glyoxylate
and enolizable aliphatic aldehydes also engaged in reac-
tions withprolineand TMSCNtogivethedesiredR-amino
nitriles. Benzophenone, although apparently less reactive
under these conditions, provided the corresponding pro-
duct in moderate yield.
Figure 2. Proposed pathway for regioisomeric enrichment.
Next, we sought to expand the substrate scope to R-
amino acids other than proline. Gratifyingly, the analo-
gous reaction with pipecolic acid as outlined in eq 5
provided the desired product 5 as the only detectable
regioisomer in near-quantitative yield. The corresponding
reaction of tetrahydroisoquinoline-3-carboxylic acid pro-
vided the expected product 7 in 91% yield (eq 6). As shown
To establish whether the mechanism depictedin Figure 2
is indeed operative, a number of control experiments were
performed (eqs 9ꢀ13). Compound 2a was exposed to a
slight excess of proline (1.1 equiv) under the previously
established reaction conditions (eq 9). In line with the
6586
Org. Lett., Vol. 13, No. 24, 2011

above considerations, amino nitrile 4a was obtained as the
only product in near-quantitative yield.
process should provide an intriguing avenue for future
inquiry.
As alluded to earlier, R-amino nitriles are extremely
versatile compounds and their use extends beyond the
synthesis of amino acids.3 For instance, compound 4a
was recently used by Rychnovsky et al. as a precursor in
an intriguing reductive lithiation/intramolecular carbo-
lithiation process.16 Another particularly useful transfor-
mation specific to R-amino nitriles is the Bruylants
reaction, which offers the opportunity to replace the cyano
group for aryl or alkyl groups.17,18 Accordingly, R-amino
nitrile 4a, which to our knowledge had not previously
been used in Bruylants reactions, readily engaged in reac-
tions with phenyl magnesium bromide or n-butyl magne-
sium bromide to form products 14 and 15 in good yields
(Figure 3).
Figure 3. Product modification via the Bruylants reaction.
In summary, we have introduced a decarboxylative
variant of the classical Strecker reaction. Due to the
versatility of the resulting R-amino nitriles, compounds
whose accessibility has now been markedly improved, this
new method isexpectedtofindwidespreaduse in synthesis.
Replacement of proline for pipecolic acid in an other-
wise identical experiment led to the exclusive formation of
5 (eq 10), establishing the role of the amino acid in this
process. Likewise, starting from 6 and proline, 4a was
obtained exclusively (eq 11). As implied above, this strat-
egy can be applied to the adjustment of product distribu-
tion in reactions that are intrinsically less regioselective.
For instance, a 2.2:1 mixture of the cyclohexanecarbalde-
hyde derived product 4t and its corresponding regioisomer
provides regioisomerically pure 4t upon treatment with
proline (eq 12). As may have been anticipated, a control
experiment in which 5 was exposed to an excess of proline
led to no reaction (eq 13). As an interesting and related side
note, the reaction of cyanohydrin 13 and proline also
yielded product 4a in 75% yield (eq 14). This unoptimized
Acknowledgment. This work was supported in part by
the National Science Foundation (Grant CHE-0911192).
D.S. is a fellow of the Alfred P. Sloan Foundation and the
recipient of an Amgen Young Investigator Award.
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.
(18) For selected applications of the Bruylants reaction, see: (a)
Enders, D.; Thiebes, C. Synlett 2000, 1745. (b) Amos, D. T.; Renslo,
A. R.; Danheiser, R. L. J. Am. Chem. Soc. 2003, 125, 4970. (c) Agami, C.;
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A. Synlett 2003, 1778. (e) Reimann, E.; Ettmayr, C. Monatsh. Chem.
2004, 135, 1289. (f) Maloney, K. M.; Danheiser, R. L. Org. Lett. 2005, 7,
3115. (g) Beaufort-Droal, V.; Pereira, E.; Thery, V.; Aitken, D. J.
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(16) (a) Wolckenhauer, S. A.; Rychnovsky, S. D. Org. Lett. 2004, 6,
2745. (b) Bahde, R. J.; Rychnovsky, S. D. Org. Lett. 2008, 10, 4017. (c)
Perry, M. A.; Morin, M. D.; Slafer, B. W.; Wolckenhauer, S. A.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2010, 132, 9591.
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