Sulfonamide-promoted palladium(II)-catalyzed alkylation of unactivated methylene C(sp3)-H bonds with alkyl iodides

Article abstract of DOI:10.1002/anie.201407848

The alkylation of unactivated b-methylene C(sp³)-H bonds of a-amino acid substrates with a broad range of alkyl iodides using Pd(OAc)₂ as the catalyst is described. The addition of NaOCN and 4-Cl-C₆H₄SO₂

Full text of DOI:10.1002/anie.201407848

Angewandte
Chemie
DOI: 10.1002/anie.201407848
Amino Acids
Sulfonamide-Promoted Palladium(II)-Catalyzed Alkylation of
3
À
Unactivated Methylene C(sp ) H Bonds with Alkyl Iodides**
Kai Chen and Bing-Feng Shi*
3
À
Abstract: The alkylation of unactivated b-methylene C(sp ) H
bonds of a-amino acid substrates with a broad range of alkyl
iodides using Pd(OAc)2 as the catalyst is described. The
addition of NaOCN and 4-Cl-C6H4SO2NH2 was found to be
crucial for the success of this transformation. The reaction is
compatible with a diverse array of functional groups and
proceeds with high diastereoselectivity. Furthermore, various
the reaction to proceed efficiently [Eq. (1); Phth = phthaloyl,
b,b-hetero-dialkyl- and b-alkyl-b-aryl-a-amino acids were
Q = 8-quinolinyl].
3
À
prepared by sequential C(sp ) H functionalization of an
Nonproteinogenic b-alkyl-a-amino acids are considered
to be conformationally constrained analogues of a-amino
acids. Their incorporation into peptides restrict conforma-
tional mobility and increase rigidity, thus leading to enhanced
receptor selectivity and metabolic stability.[13] Consequently,
there is tremendous interest in the synthesis of nonproteino-
alanine-derived substrate, thus providing a versatile strategy
for the stereoselective synthesis of unnatural b-disubstituted a-
amino acids.
O
ver the past several decades, transition-metal-catalyzed
C H alkylation with alkyl halides has emerged as a versatile
genic a-amino acids.[14] As part of our efforts to synthesize
À
[1,2]
3
À
À
and highly efficient tool for the synthesis of C C bonds.
biologically important organic molecules by direct C(sp ) H
2
Compared to the achievements in the area of C(sp ) H
functionalization,[15] we envisioned that b-alkyl-a-amino acids
À
alkylation,[3,4] catalytic alkylation of unactivated C(sp ) H
could be accessed by the alkylation of the b-methylene C H
3
À
À
3
bonds, especially methylene C(sp ) H bonds, remains largely
bonds of simple a-amino acid derivatives.[16] However, this
À
undeveloped.[5–10] In 2013, the group of Chen and our group
independently reported the only two examples of
reaction was rather challenging because of the low reactivity
of methylene C(sp ) H bonds and the tendency of metal alkyl
3
À
(BnO)2PO2H-promoted,
8-aminoquinoline-directed[11,12]
intermediates to undergo side reactions. Recently, several
elegant works have shown that external ligands, such as
3
À
alkylation of b-methylene C(sp ) H bonds with a-haloace-
tates and methyl iodide.[9] However, the scope with respect to
the coupling partners was limited to these two classes of
specific reagents, both of which do not contain b-hydrogen
atoms. Direct alkylation proved to be more challenging if the
alkyl groups containined b-hydrogen atoms.[2] These limita-
simple carboxylic acids,[7a,17] amino acids,[18] pyridines, and
quinolines,[16a,19] could enhance the reactivity of C(sp ) H
3
À
functionalization reactions. Based on these precedents, we
hypothesized that the judicious choice of a ligand or additive
might play an important role in tuning the reactivity.
tions encouraged us to develop a protocol for efficient
To test this hypothesis, we initiated our investigation with
the alkylation of the l-norvaline (Nva) derivative 1a with n-
butyliodide (3a) as the model system. After extensive
optimization, we found that the use of Pd(OAc)2, NaOCN,
and Ag2CO3 as the halide scavenger in 1,4-dioxane afforded
the desired product 4a in a reasonable yield.[20] As expected,
several carboxylic acids, such as PivOH (L1), AdCO2H (L2),
and Boc-Gly-OH (L3) did lead to higher yields, however, the
overall efficiency of the reaction remained unsatisfactory
(Table 1, entries 1–3). To improve the yield further, we sought
3
À
alkylation of unactivated methylene C(sp ) H bonds, a pro-
tocol which would tolerate a broad range of simple alkyl
iodides. In particular, we were drawn to the idea of using this
reaction for the stereoselective synthesis of various b-
alkylated a-amino acids. The results of this investigation are
described herein, and preliminary investigations reveal that
the presence of 4-Cl-C6H4SO2NH2 and NaOCN are crucial for
À
to identify a new class of ligands to facilitate this C H
[*] K. Chen, Prof. Dr. B.-F. Shi
Department of Chemistry, Zhejiang University
Hangzhou 310027 (China)
alkylation reaction. Sulfonamides are recognized as versatile
ligands in various metal-catalyzed reactions. It has been
reported that neutral sulfonamides could serve as labile
ligands because of the electron-withdrawing character of the
sulfonyl group.[21] Therefore, we reasoned that sulfonamides
could reversibly coordinate with palladium to tune reactivity.
Consistent with this hypothesis, we found that the addition of
0.3 equivalents of the commercially available sulfonamides
L4 and L5 to the reaction mixture increased the yield of 4a to
65 and 72%, respectively (entries 4 and 5). Further examina-
tion of different sulfonamides revealed that 4-Cl-
E-mail: bfshi@zju.edu.cn
[**] Financial support from the National Basic Research Program of
China (2015CB856600), the NSFC (21422206, 21272206), the
Fundamental Research Funds for the Central Universities
(2014QNA3008), and the Qianjiang Project (2013R10033) is
gratefully acknowledged. We thank Dr. Keary M. Engle (California
Institute of Technology (USA)) for helpful suggestions and com-
ments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407848.
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Table 1: Optimization of reaction conditions.[a]
Entry
Ligand
Yield [%][b]
d.r.[c]
1a
Recovered [%][b]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
–
59
63
61
65
72
61
71
72
12:1
13:1
8:1
25
18
24
22
15
22
13
12
8
9:1
10:1
10:1
10:1
10:1
10:1
9:1
9
76 (75)[d]
13
10[e]
64
[a] Reaction conditions: 1a (0.15 mmol), 3a (2.0 equiv), Pd(OAc)2
(0.1 equiv), Ag2CO3 (1.5 equiv), NaOCN (2.0 equiv), L (0.3 equiv) in 1,4-
dioxane (1.5 mL), 808C, 20 h. [b] Yield determined by 1H NMR spec-
troscopy using 1,3,5-trimethoxybenzene as the internal standard. [c] The
diastereomeric ratio (d.r.) was determined by 1H NMR spectroscopy.
[d] Yield of isolated product given within parentheses. [e] Conditions
reported in Ref. [9b] were used. Boc=tert-butoxycarbonyl.
Scheme 1. Alkyl iodide scope. [a] Yield of the isolated product. [b] The
diastereomeric ratio was estimated by 1H NMR spectroscopy.
TBDPS=tert-butyldiphenylsilyl.
C6H4SO2NH2 (L9) was the most effective, thus affording 4a in
75% yield upon isolation (entry 9, d.r. ꢀ 10:1). Furthermore,
we compared our optimized reaction with the (BnO)2PO2H-
promoted alkylation process,[9b] and this protocol showed
superior reactivity (entry 10).
Having optimized the reaction conditions, we next sought
to establish the scope of alkyl iodides which were compatible
in the reaction. Coupling partners bearing b-hydrogen atoms
proceeded smoothly under the optimized reaction conditions
(Scheme 1). Generally, linear and branched primary alkyl
iodides afforded the desired alkylated products in good yields
(5a–i). As previously reported, MeI was a superior alkylating
reagent, thus giving the b-methylated product 5a in 72%
yield along with b,g-dimethylated product 5b in 24% yield.
Furthermore, a wide range of functional groups, including
chloro (5j), iodo (5k), trifuoromethyl (5l), methoxycarbonyl
(5m), 1,3-dioxolan-2-yl (5n), cyano (5o), silyl (5p), Cbz-
protected amino (5q), alkynyl (5r), and alkenyl (5s) groups
were compatible with this protocol. The reduced yields in the
cases of 5n, 5o, and 5s may be due to competitive
coordination of the palladium catalyst to the Lewis basic
functional groups. Notably, a TIPS-protected terminal alkyne
remained intact during the reaction (5r). Importantly, the
alkylated products were consistently obtained with good
diastereoselectivity (> 8:1).
Scheme 2. a-Amino acid substrate scope. [a] Yield of the isolated
product. [b] The diastereomeric ratio was estimated by 1H NMR
spectroscopy. [c] 1108C. [d] R-I (3.0 equiv) and Ag2CO3 (2.0 equiv) were
used.
With the alkyl iodide coupling partner scope established,
we then probed the substrate scope of a-amino acid
derivatives (Scheme 2A). Gratifyingly, 2-amino-butyric acid
(Abu; 1b), norvaline (Nva; 1a), lysine (Lys; 1c), ornithine
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(Orn; 1d), and phenylalanine (Phe; 1e) derivatives were all
compatible with the alkylation protocol, thus generating the
alkylated products 6a–f in moderate to good yields. Attempts
to alkylate a substrate derived from leucine (Leu; 1 f) were
lower-yielding (6g and 6h) because of the steric hindrance of
the amino acid side chain.
an arylation step. Gratifyingly, both alkylation/arylation and
arylation/alkylation sequences could be achieved, thus pro-
viding a variety of b-alkyl-b-aryl a-amino acids in good yields
(8g–8l). By simply varying the order in which the two
different coupling partners were introduced, both diastereo-
mers of the b,b-disubstituted a-amino acid products could be
obtained (8a and 8b, 8c and 8d, 8e and 8 f, 8g and 8h, 8i and
8j, 8k and 8l). These sequential functionalization reactions all
proceeded with high diastereoselectivity and in good to
excellent yields, thus providing a versatile tool for the
stereoselective synthesis of b,b-disubstituted a-amino acids
from Ala.
To gain further insight into the reaction mechanism and
the origin of the enhanced reactivity under the optimized
alkylation conditions, we attempted to isolate and character-
ize possible palladium-containing intermediates (see Fig-
ure S1 in the Supporting Information).[20] The phenylalanine
derivative 1e reacted with 1 equivalent Pd(OAc)2 in MeCN at
358C, thus affording the palladium complex 9 in 98% yield.
The structure of 9 was confirmed by NMR analysis. The
compound 9 was subsequently converted into the correspond-
ing palladacycle 10 by heating the complex in a mixture of
DCE/MeCN at 508C for 4 hours. The structure of 10 was
confirmed by single-crystal X-ray diffraction.[22] Attempts to
isolate and characterize a palladium species contianing 4-Cl-
C6H4SO2NH2 were unsuccessful. Indeed, Liu and co-workers
has previously reported that when a different palladacycle
dimer containing two bridging trifluoroacetate anions was
reacted with 4-Cl-C6H4SO2NH2, the putative sulfonamide-
coordinated palladacycle could not be isolated, likely because
of the weak coordination of neutral sulfonamide to palla-
dium.[23]
As shown in Scheme 2B, alkylation of the g-methyl
3
À
C(sp ) H bond of isoleucine (Ile; 1g) also took place in
approximately 30% yield (6i and 6j). When an alanine
derivative (Ala; 1h) was employed as a substrate, homo-
dialkylated products were obtained in good yields ( 6k and 6l;
Scheme 2C). It is worth noting that the alkylation of 1h with
[D5]EtI gave the deuterated ethylation products in 90% total
yield (di/mono = 2:1), thus providing efficient access to
isotope-labeled amino acids.
The synthetic utility of this alkylation protocol was further
demonstrated in the coupling of 1b with the sugar-containing
alkyl iodide 3t [Eq. (2)]. The corresponding product 5t was
obtained in 76% yield (d.r. ꢀ 10:1). This example showcases
the potential of this reaction for applications in the late-stage
modification of complex molecules.
Recently, our group developed palladium-catalyzed
monoalkylation and monoarylation reactions for the selective
3
[9b]
À
functionalization of methyl C(sp ) H bonds.
It was thus
envisioned that these transformations[7a,16c] could be used in
concert with the current protocol to synthesize various b-
3
À
branched a-amino acids by sequential C(sp ) H functional-
To elucidate the importance of NaOCN and 4-Cl-
C6H4SO2NH2 and probe the catalytic competence of 10, we
conducted a series of stoichiometric and catalytic experiments
(see Figure S2 in the Supporting Information).[20] Reaction of
ization of 1h (Scheme 3). In this way, a number of b,b-hetero-
dialkylated a-amino acids could be prepared (8a–f). Addi-
tionally, one of the two alkylation steps could be replaced with
3
3
À
À
Scheme 3. Synthesis of unnatural a-amino acids by palladium-catalyzed sequential C(sp ) H functionalization. Protocol A: Methyl C(sp ) H
3
3
3
À
À
À
alkylation. Protocol B: Methyl C(sp ) H arylation. Protocol C: Methylene C(sp ) H alkylation. Protocol D: Methylene C(sp ) H arylation. See the
Supporting Information for detailed reaction conditions.
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Angew. Chem. 2009, 121, 6213; d) Y. Zhao, G. Chen, Org. Lett.
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10 with n-hexyl iodide in the absence of NaOCN or 4-Cl-
C6H4SO2NH2 was sluggish and gave the desired product 6 f in
diminished yield. In contrast, alkylation of 10 with n-hexyl
iodide in the presence of 4-Cl-C6H4SO2NH2 and NaOCN gave
6 f in 40% yield (see Figure S2A), thus indicating that both 4-
Cl-C6H4SO2NH2 and NaOCN are crucial for the alkylation
step. We also found that 10 was catalytically competent for the
alkylation reaction in the presence of 4-Cl-C6H4SO2NH2 and
NaOCN (see Figure S2B). The moderate yields in both the
stoichiometric and catalytic experiments is likely due to the
fact that the acetonitrile-coordinated palladacycle is less
reactive than the intermediate generated in situ under the
optimized reaction conditions.
Considering that the cyclopalladation can occur at mild
conditions in the absence of 4-Cl-C6H4SO2NH2, we hypothe-
size that the lability of sulfonamide as a ligand may contribute
to the enhanced reactivity in two other ways: 1) dissociation
to provide a vacant coordination site for oxidative addition of
the alkyl halide to the PdII center to generate a new PdIV
species[10a] and 2) subsequent coordination with the PdIV
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À
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À
[6] For selected examples of palladium-catalyzed C(sp ) H alkyla-
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À
center to facilitate C(alkyl) C(alkyl) reductive elimina-
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In summary, we have developed a palladium(II)-catalyzed
3
À
alkylation of unactivated b-methylene C(sp ) H bonds of a-
amino acid substrates using the 8-aminoquinoline (Q) auxil-
iary. The reaction tolerates a broad range of alkyl iodides and
proceeds with high diastereoselectivity. The synthetic utility
of this alkylation reaction was demonstrated in the stereose-
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lective synthesis of various b,b-disubstituted a-amino acids
3
À
through a sequential C(sp ) H functionalization approach. A
135, 2124.
new palladacycle intermediate has been isolated and charac-
terized by single-crystal X-ray diffraction. A series of
stoichiometric and catalytic experiments demonstrated that
the presence of 4-Cl-C6H4SO2NH2 and NaOCN are crucial for
the reaction to proceed efficiently.
3
À
[8] For nickel-catalyzed methyl C(sp ) H alkylation with alkyl
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3
Received: August 1, 2014
Published online: && &&, &&&&
À
H alkylation, see: Y. Feng, Y. Wang, B. Landgraf, S. Liu, G. Chen,
Org. Lett. 2010, 12, 3414; b) One instance of methylene C(sp )
H alkylation of cyclic 8-aminoquinoline amide in low yield, see
Ref. [7b].
3
À
À
Keywords: alkylation · C H activation · palladium ·
.
amino acids · synthetic methods
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J. Am. Chem. Soc. 2012, 134, 18570.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Amino Acids
K. Chen, B.-F. Shi*
&&&& — &&&&
Sulfonamide-Promoted Palladium(II)-
Catalyzed Alkylation of Unactivated
Branching off: The title reaction of un-
(alkyl) bond-forming reaction proceeds in
good yields, and by using sequential
reactions b-branched amino acids can be
obtained.
3
3
À
À
Methylene C(sp ) H Bonds with Alkyl
activated b-methylene C(sp ) H bonds of
Iodides
a-amino acid substrates with alkyl
iodides is described. The C(alkyl)–C-
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!