Flow-mediated synthesis of Boc, Fmoc, and Dd iv monoprotected diamines

Article abstract of DOI:10.1021/ol503343b

A series of monoprotected aliphatic diamines (21 examples) were synthesized via continuous flow methods. The carbamates and enamines were obtained in 45-91% yields using a 0.5 mm diameter PTFE tubular flow reactor. Using readily accessible protecting group precursors, the procedure serves as an attractive alternative to existing batch-mode synthetic routes by providing direct, multigram access to N-Boc-, N-Fmoc-, and N-Ddiv-protected compounds with productivity indexes of 1.2-3.6 g/h.

Full text of DOI:10.1021/ol503343b

Letter
pubs.acs.org/OrgLett
Flow-Mediated Synthesis of Boc, Fmoc, and Ddiv Monoprotected
Diamines
ThingSoon Jong and Mark Bradley*
School of Chemistry, EaStCHEM, University of Edinburgh, Joseph Black Building, King’s Buildings, David Brewster Road, EH9 3FJ
Edinburgh, U.K.
S
* Supporting Information
ABSTRACT: A series of monoprotected aliphatic diamines (21 examples)
were synthesized via continuous flow methods. The carbamates and
enamines were obtained in 45−91% yields using a 0.5 mm diameter PTFE
tubular flow reactor. Using readily accessible protecting group precursors,
the procedure serves as an attractive alternative to existing batch-mode
synthetic routes by providing direct, multigram access to N-Boc-, N-Fmoc-,
and N-Ddiv-protected compounds with productivity indexes of 1.2−3.6 g/h.
he use of protecting groups to facilitate the construction
of structurally complex molecules is an indispensable
and S2) was assembled from commercially available parts as a
robust and scalable synthesizer compared to chip reactors that
are often susceptible to material plugging. The carbamates, tert-
butyloxycarbonyl (Boc) and 9-fluorenylmethyloxycarbonyl
(Fmoc), and the enamine 1-(4,4-dimethyl-2,6-dioxocyclohexyl-
idene)isovaleryl (Ddiv) are popular protecting groups and were
therefore selected to protect a series of diamines. Boc anhydride
(Boc2O), Fmoc-succinimide (Fmoc-OSu), and 2-(1-hydroxy-3-
methylbutylidene)-5,5-dimethylcyclohexane-1,3-dione (Ddi-
vOH) are typically used to generate the N-carbamate and
enamine derivatives, respectively (Scheme 1).
T
strategy in organic synthesis.1 However, the selective
monoprotection of a multifunctional molecule is often difficult
to achieve due to competing reactive sites on the unprotected
substrate and reactivity of the monoprotected product. The
problem is exacerbated in a conventional batch environment as
a result of system inhomogeneity, resulting in a mixture of
protected products.2 Monoprotected aliphatic diamines are
important chemical precursors, widely used as spacers,3
linkers,4 and scaffolds,5 and various strategies have been
introduced to achieve monoprotection,6 including the use of
passivated protecting group precursors,7 chemical auxiliaries to
differentiate the reactivity of amino groups,8 solid-phase
functionalization,9 and stoichiometric control.10 These batch
methods, however, have limited success and are often
inconsistent as well as unpractical. The monoacylation of
diamines in a microreactor under ultrasonic irradiation has been
reported.11 This syringe pump-driven method produced good
results (≥87% yields) with piperazine and homopiperazine
when acid chlorides were used as the acylating agent; however,
isolated yields for a series of aliphatic diamines or protecting
group chemistries were not reported.
Scheme 1. Formation of Boc and Fmoc N-Carbamates and
Ddiv Enamines from Primary Amines
Flow synthesis serves as an attractive alternative to the
aforementioned batch methods by inducing reaction selectivity
through spatial and temporal manipulation under continuous
flow conditions.12 This tight window of reaction control offers
the opportunity to limit the propagation of undesirable side
reactions, and consequently delivery of higher yields compared
to batch reactions. Continuous flow reactors have been used in
a variety of synthetic endeavors to promote reaction selectivity
and particle size control, mainly due to the superior physical
transport properties, thermal control and mixing ability
exhibited by narrow reaction chambers.13
The reaction between 1,6-diaminohexane (1a) and Boc2O
was used to optimize the reaction parameters for mono-Boc
protection. The reaction setup for the continuous flow
mediated monoprotection of diamines consisted of two steps
(Figure 1). During the preconditioning stage, the reactants
Here, the selective and scalable monoprotection of sym-
metrical aliphatic diamines via continuous flow synthesis using
a polytetrafluoroethylene (PTFE) tubular reactor is demon-
strated. The flow reactor (Supporting Information, Figures S1
Received: November 18, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503343b
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The intricate relationship between the internal diameter of
tubular flow reactors and the degree of reaction selectivity was
explored (microreactors ≤1 mm i.d., mesoscale reactors >1 mm
i.d.). Thus, the Boc carbamation of 1,6-diaminohexane (1a),
1,4-diaminobutane (1b), and 1,2-diaminoethane (1c) were
performed in 0.5, 1.0, and 1.6 mm i.d. tubular flow reactors.
The 0.5 mm i.d. flow reactor consistently gave mono-Boc-
products 2a−c in 64−65% yields with good product to side
product ratios (>4:1) (Table 2). Moreover, an excellent
Figure 1. Reaction setup for the flow synthesis of monoprotected
diamines.
Table 2. Effect of the Flow Reactor’s i.d. on the Reaction
Monoselectivity
a
were fed into their respective PTFE channels (0.5 mm internal
diameter (i.d.), 0.18 mL internal volume), immersed in a ice
bath at 0 °C. This step reduces the time required for the
reactants to reach thermal equilibrium within the flow reactor
and promotes reaction reproducibility. The reactants were
mixed in the T-mixer and the reaction proceeded along the
PTFE flow reactor (0.5 mm i.d., 2.0 mL internal volume).
Upon exiting the reactor, the reaction stream was immediately
quenched upon an excess of the silica-based trisamine
scavenger in MeOH at −10 °C.
b
c
entry
diamine
reactor i.d. (mm) yield (%) product ratio (%)
a
b
c
d
e
f
1a, n = 5
1a, n = 5
1b, n = 3
1b, n = 3
1c, n = 1
1c, n = 1
0.5
1.6
0.5
1.6
0.5
1.6
64
51
65
59
64
50
2a 84:3a 16
2a 81:3a 19
2b 83:3b 17
2b 72:3b 28
2c 81:3c 19
2c 74:3c 26
Initially, the effect of reactant stoichiometry on the
monoprotection yield was investigated (Table 1). Concen-
a
b
2 mmol scale, 0.10 M Boc2O (limiting reagent). Average isolated
yield of replicate experiments (n = 5, variation in yields within 3%
c
points). The molar ratio of isolated products.
Table 1. Optimization of the Synthesis of Mono-N-Boc-1,6-
diaminohexane 2a in a 0.5 mm i.d. Tubular Flow Reactor
a
reproducibility (variation in yields within 3%) was demon-
strated across replicate experiments (n = 3−5). In contrast,
lower yields were observed in reactors with larger tubular i.d.’s
(1.0 and 1.6 mm). This may be attributed to the efficiency of
the mixing process in flow, which determines the homogeneity
of the solution and is essential in reducing the occurrence of
side reactions.14 In a batch environment, inefficient mechanical
stirring often leads to poor mixing, which creates localized
concentration hotspots of reactants. With the Boc carbama-
tions, sonication of the flow reactor did not have notable effect
on the conversion.
The continuous flow method was applied to the synthesis of
mono-Fmoc diaminoalkanes. The most commonly used
solution strategy relies on a three-step method involving the
mono-Boc protection of the diamine, followed by Fmoc
protection of the remaining free amino moiety, and finally Boc
deprotection.15 The mono-Fmoc-carbamation of 1a with
Fmoc-OSu followed the optimized conditions for the flow
synthesis of N-Boc-1,6-diaminohexane (2a). For the Fmoc
carbamation, DMF was used as the reaction solvent (good
solubility for both the starting materials and the resulting
Fmoc-protected compounds) and the reaction stream was
quenched with HCl in cold MeOH (−10 °C, pH 2−3). Using
Fmoc-Osu as the limiting reagent (0.05 M) and 2.0 equiv of 1a,
the flow procedure (0.5 min, 0 °C) gave a 45% yield of N-
Fmoc-1,6-diaminohexane (4a), showing that Fmoc-protected
carbamates can be obtained in reasonable yields in a single step
without the need for a sacrificial protecting group.
b
c
equiv of
temp
time
yield of 2a
ratio of
entry
1a
(°C)
(min)
(%)
2a:3a
a
b
c
d
e
f
1.0
1.2
1.4
1.6
1.8
2.0
2.0
2.0
2.0
0
0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
2.0
42
48
54
52
57
64
53
63
53
1:0.56
1:0.40
1:0.36
1:0.34
1:0.26
1:0.19
1:0.22
1:0.12
1:0.35
0
0
0
0
g
h
i
25
0
0
a
b
2 mmol scale, 0.10 M Boc2O (limiting reagent). Average isolated
yield of replicate experiments after column chromatography (n = 3,
variation in yields within 3%). The molar ratio of 2a:3a (isolated
c
products).
trations of 0.10 M in MeOH for both reactants (diamine 1a and
Boc2O) resulted in a 42% yield of N-Boc-1,6-diaminohexane
(2a) along with a significant amount of the diprotected product
3a. When the stoichiometric ratio of the diamine was raised
from 1.0 to 2.0 equiv by adjusting the flow rates, the yield of 2a
increased accordingly (64%) and the occurrence of diprotection
was noticeably suppressed (entries a−f, Table 1). Reducing the
residence time from 1.0 to 0.5 min did not show any
appreciable influence on the reaction selectivity (entries f vs h,
Table 1) but a 2.0 min residence time led to a ∼10% drop in
product yield (entries f vs i, Table 1). Similarly, raising the
reaction temperature to 25 °C had a detrimental effect on the
formation of 2a (entry g, Table 1). To demonstrate the
potential of the flow method, a 20 g scale synthesis of 2a was
successfully completed (2 equiv 1a, 1 min at 0 °C).
Having successfully synthesized the monocarbamated dia-
mines, the flow synthesis of enamine derivatives was
investigated using the Ddiv protecting group, commonly used
in solid-phase synthesis.16 In the reaction between 1a and
DdivOH, temperature was found to play a very significant role
in promoting flow-based enamination (Table 3). No product
was observed below 90 °C with a residence time of 2.0 min.
However, using 2.0 equiv of 1a and a residence time of 1 min at
B
DOI: 10.1021/ol503343b
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
mmol to produce 1−3 g of the monoprotected compounds
using a 4.0 mL internal volume flow reactor (0.5 mm i.d.). For
alkyldiamines, the isolated yields of the mono-Boc- and mono-
Fmoc-protected products 2a−e and 4a−e were 51−77%,
demonstrating good overall selectivity (Table 4). Similar
selectivity was also observed with the ethylene glycol-based
diamines 2f−g and 4f−g. Interestingly, substituting Fmoc-OSu
with Fmoc-Cl as the protecting group precursor led to
significantly lower yields (25−42%) of the mono-Fmoc
carbamates. Meanwhile, excellent yields (80−91%) of monop-
rotected enamines 5c,d were obtained with shorter members of
the compund family. With the shorter diaminoalkanes, this may
be due to steric hindrance provided by the first Ddiv group on a
protected amine, thus decreasing the reactivity of the remaining
free amino functionality. The longer chain monoprotected
enamines 5a,b and 5e−g were obtained in ≥58% yield.
Since amines protected with another dimedone-based
protecting group, 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-
ethylene (Dde) are susceptible to N → N′ migration,17 the
stability of the mono-Ddiv protected compounds were of
interest. The isovaleryl handle of Ddiv was designed to provide
steric hindrance, reducing the likelihood of group migration. In
order to determine the stability of the mono-Ddiv diamines
5a−g, their solution (1.1−2.2 mM) half-lives were established
by HPLC analysis to be 8.4−25.4 h at 80 °C (Supporting
Information, Table S1), confirming the suitability of these N-
Ddiv-protected compounds as synthetic building blocks.
In summary, 21 monoprotected N-Boc, N-Fmoc and N-Ddiv
diamines were synthesized via continuous flow with productiv-
ity indexes of 1.2−3.6 g/h. Under flow conditions, short
residence times and low reaction temperatures (≤1 min, 0 °C)
favored the monocarbamation reaction, whereas monoenami-
nation of the diamines required a high reaction temperature (1
min, 130 °C). The selective incorporation of the Boc, Fmoc,
and Ddiv protecting groups onto a series of diamines
demonstrated the versatility of the method. In generating the
monoprotected compounds, each type of reaction responded to
adjustments in physical conditions (temperature, residence
time and solvent) to provide a good degree of selectivity
without the use of any chemical auxiliaries. This easily scalable
method gives unprecedented one-step, multigram scale access
to valuable monoprotected building blocks, thus improving the
efficiency and atom economy of conventional protecting group
chemistry.
Table 3. Optimization of the Flow Synthesis of Mono-N-
Ddiv-1,6-diaminohexane 5a
i
ii
equiv of
1a
temp
(°C)
time
(min)
conversion to 5a
ratio of
iii
entry
(%)
5a:6a
a
b
c
d
e
f
1.2
1.2
1.2
1.2
1.2
1.5
1.5
1.5
1.5
2.0
2.0
2.0
2.0
90
2.0
1.0
2.0
1.0
2.0
1.0
2.0
1.0
2.0
1.0
2.0
1.0
2.0
0
120
120
130
130
120
120
130
130
120
120
130
130
53
44
57
53
65
66
71
65
75
64
81
29
1:0.30
1:0.39
1:0.29
1:0.43
1:0.30
1:0.50
1:0.40
1:0.53
1:0.28
1:0.30
1:0.24
1:2.48
g
h
i
j
k
l
m
i
ii
200 μmol scale, 0.10 M DdivOH (limiting reagent). Measured by
HPLC with UV detection at 254 nm, methyl benzoate as an internal
iii
standard. Integrated peak ratio of 5a and 6a, respectively.
130 °C, 81% conversion to the monoprotected enamine 5a was
observed (entry l, Table 3). Lowering the reaction temperature
from 130 to 120 °C (entry j, Table 3) or reducing the
concentration of 1a consistently gave lower conversion to the
monoprotected product (entries d and h vs. l, Table 3), while
monoselectivity was adversely affected with only 29%
conversion to 5a when the residence time was increased from
1.0 to 2.0 min (entry m, Table 3).
On the basis of the established optimal reaction parameters
for each protecting group, the scope of continuous flow
carbamation and enamination was examined with a series of
aliphatic diamines of varying alkyl and ethylene glycol chain
lengths (Table 4). The scale of syntheses was increased to 10
Table 4. Continuous Flow Synthesis of Boc, Fmoc, and Ddiv
Monoprotected Diamines
ASSOCIATED CONTENT
* Supporting Information
■
S
Flow instrumentation, experimental procedures, compound
characterization, and the stability study of Ddiv-protected
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mark.bradley@ed.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
i
■
Average isolated yield of replicate experiments (n = 3). General flow
We thank the MTEM School of Chemistry Studentship and
University of Edinburgh’s Innovation Initiative Grant for
conditions: 10 mmol scale, diamine (2.0 equiv), 0.05 M Fmoc-OSu or
0.10 M Boc2O and DdivOH.
C
DOI: 10.1021/ol503343b
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
financial support, Dr. Aurelie Brunet (University of Edinburgh)
for help with the stability study, and Dr. Annamaria Lilienkampf
(University of Edinburgh) for assistance with manuscript
preparation.
REFERENCES
■
(1) (a) Jarowicki, K.; Kocienski, P. J. Chem. Soc., Perkins Trans. 1
2001, 2109−2135. (b) Rautio, J.; Kumpulainen, H.; Heimbach, T.;
Oliyai, R.; Oh, D.; Jarvinen, T.; Savolainen, J. Nat. Rev. Drug Discovery
̈
2008, 7, 255−270.
(2) Jacobson, A. R.; Makris, A. N.; Sayre, L. M. J. Org. Chem. 1987,
52, 2592−2594.
(3) (a) Marschutz, M. K.; Veronese, F. M.; Bernkop-Schnurch, A.
̈
̈
Eur. J. Pharm. BioPharm. 2001, 52, 137−144. (b) Yingyongnarongkul,
B.-E.; Radchatawedchakoon, W.; Krajarng, A.; Watanapokasin, R.;
Suksamrarn, A. Bioorg. Med. Chem. 2009, 17, 176−188.
(4) (a) Ghanem, M. A.; Chretien, J.-M.; Pinczewska, A.; Kilburn, J.
D.; Bartlett, P. N. J. Mater. Chem. 2008, 18, 4917−4927.
(b) Mambanda, A.; Jaganyi, D.; Hochreuther, S.; van Eldik, R. Dalton
Trans. 2010, 39, 3595−3608.
(5) (a) Bycroft, B. W.; Chan, W. C.; Hone, N. D.; Millington, S.;
Nash, I. A. J. Am. Chem. Soc. 1994, 116, 7415−7416. (b) Schroder, T.;
̈
Schmitz, K.; Niemeier, N.; Balaban, T.; Krug, H.; Schepers, U.; Brase,
S. Bioconjugate Chem. 2007, 18, 342−354.
̈
(6) Bender, J. A.; Meanwell, N. A.; Wang, T. Tetrahedron 2002, 58,
3111−3128.
(7) Pittelkow, M.; Lewinsky, R.; Christensen, J. B. Synthesis 2002, 15,
2195−2202.
(8) (a) Ham, J.-Y.; Kang, H.-S. Bull. Korean Chem. Soc. 1994, 15,
1025−1026. (b) Zhang, Z.; Yin, Z.; Meanwell, N. A.; Kadow, J. F.;
Wang, T. Org. Lett. 2003, 5, 3399−3402. (c) Chankeshwara, S. V.;
Chakraborti, A. K. Tetrahedron Lett. 2006, 47, 1087−1091. (d) Lee, D.
W.; Ha, H.-J.; Lee, W. K. Synth. Commun. 2007, 37, 737−742.
(e) Pringle, W. Tetrahedron Lett. 2008, 49, 5047−5049. (f) Verma, S.
K.; Acharya, B. N.; Kaushik, M. P. Org. Lett. 2010, 12, 4232−4235.
(9) Oliver, M.; Jorgensen, M. R.; Miller, A. D. Synlett 2003, 3, 0453−
0456.
(10) Krapcho, A. P.; Kuell, C. S. Synth. Commun. 1990, 20, 2559−
2564.
(11) Maurya, R. A.; Hoang, P. H.; Kim, D.-P. Lab Chip 2012, 12,
65−68.
(12) (a) Jas, G.; Kirschning, A. Chem.Eur. J. 2003, 9, 5708−5723.
(b) McQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78, 6384−
6389. (c) Yoshida, J.-I.; Nagaki, A.; Yamada, D. Drug Discovery Today.
2013, 10, e53−e59.
(13) Kockmann, N.; Gottsponer, M.; Zimmermann, B.; Roberge, D.
M. Chem.Eur. J. 2008, 14, 7470−7477.
(14) (a) Hartman, R. L.; McMullen, J. P.; Jense, K. F. Angew. Chem.,
Int. Ed. 2011, 50, 7502−7519. (b) Su, Y.; Straathof, N. J. W.; Hessel,
V.; Noel, T. Chem.Eur. J. 2014, 20, 10562−10589.
̈
(15) Mandal, P. K.; Ren, Z.; Chen, X.; Xiong, C.; McMurray, J. S. J.
Med. Chem. 2009, 52, 6126−6141.
(16) Chhabra, S. R.; Hothi, B.; Evans, D. J.; White, P. D.; Bycroft, B.
W.; Chan, W. C. Tetrahedron Lett. 1998, 39, 1603−1606.
(17) Augustyns, K.; Kraas, W.; Jung, G. J. Pept. Res. 1998, 51, 127−
133.
D
DOI: 10.1021/ol503343b
Org. Lett. XXXX, XXX, XXX−XXX